Tanaka Y,  Kimula Y
Virchows Arch A Pathol Anat Histol 1976 Oct 7;371(4):351-362
Terminal plate fracture in vertebrae of the aged.
The terminal plate fracture of human vertebrae was studied morphologically on midsagittal specimens from 92 autopsy cases which included 82 patients over 60 years. 1. Histologically, the terminal plate fracture was classified into three types by its representative histology. (a) Fracture with intervertebral disk (ID) prolapse: a healed fracture characterized by the presence of the prolapsed ID at the fractured site. ID prolapse in the marrow cavity may or may not be present. The group includes the typical case of the Schmorl's nodule. (b) Fracture with the granulation tissue: The fracture site was embedded by the granulation tissue. Callus and ID prolapse, if any, were insignificant. (c) Diffuse replacement of the hyaline cartilage layer by osteoid tissue: The alteration is seen often at a concaved surface of the terminal plate of significantly deformed vertebrae. 2. The fracture may be classified by the depth of the ID prolapse. (a) Grade 1: ID prolapse may be seen within the fracture aperture, but, not in the marrow cavity. (b) Grade 2: ID prolapse is confined to a labyrinth of subcortical trabeculae. (c) Grade 3: ID prolapse extends to a deep marrow space. The typical Schmorl's nodule belongs to this group. 3. In the present study, the terminal plate fracture was noted in 78% of the patients over 60 years. The female group was affected more often (68% in male, 86% in female). Grade 2 was more often seen in atrophic vertebrae than Grade 1. However, in Grade 3, the fracture appeared unrelated to the atrophy of the vertebrae. 4. The terminal plate fracture was more often seen in the lower deck than the upper deck at the site of two-thirds dorsal from the ventral edge of the vertebral body. The site corresponds roughly to the nucleus pulposus. 5. Histologic variations of the terminal plate fracture and of ID prolapse may relate to senescence of both vertebrae and ID.

Takabe K,  Tsukada Y, Shimizu T, Takagiwa J, Hirayama M, Nakayama M, Miura H, Akabane H, Takayama S, Aida S, Kimura Y
Malignant lymphoma involving the penis following malignant pleural mesothelioma.
Intern Med 1997 Oct;36(10):712-715
A 74-year-old man who had been diagnosed with malignant mesothelioma developed malignant lymphoma of B-cell origin involving the penis. He had a history of occupational exposure to asbestos as a construction worker. The association of malignant mesothelioma with lymphoma is rare, and the possibility of asbestos exposure as a common etiology is discussed. The intense stimulation of B lymphocytes and decreased T lymphocyte activity in asbestos-exposed populations may result in development of B-cell malignancies. Though the relationship between asbestos exposure and malignant mesothelioma is firmly established, the relationship between asbestos exposure and lymphoma remains to be investigated.

Takabe K，Shimizu T, Takagiwa J，Hirayama M，Nakayama M，Miura H，Akabane H，Takayama S, Aida S, Kimura Y.  Thoracoscopic Appearance and Histological Findings of Nine Cases of Pleural Malignant Mesothelioma in Relation to Clinical Findings.  Lung Cancer 37:335-345, 1997

We examined the thoracoscopic appearance and histological finding of nine cases of malignant pleural mesothelioma and classified them into two types: multiple nodular type (5 cases) and non-specific pleural thickening type (4 cases). We determined the relationship between these types and the clinical findings to evaluate the significance of this classification. The mean age of the patients was 66. Seven cases were epithelial type and the rest were biphasic type. Pleural biopsy under thoracoscopic guidance led to a diagnosis in six of nine cases (67%). Histologically, in multiple nodular type disease, the parietal pleura was covered with multiple small, flat nodules and tumor cells were, spread on the mesothelial surface. In non-specific pleural thickening type cases, the parietal pleura was thickened, and small nodules were rare. Histologically, tumor cells were not detected (2 cases) or were confined to the submesothelial tissue (2 cases). We speculate that this thoracoscopic appearance is caused by the submesothelial spread of tumor cells. In nodular type cases, serum inflammatory reaction was rare, while in the pleural thickening type, it was frequent. Hyaluronic acid in the pleural effusion was significantly elevated in the nodular type (814±259 vs 36±8 μg/ml ｢mean±SEM｣, p=0.01, Mann-Whitney U-test). We conclude that this classification is useful for evaluating clinical findings in cases of pleural malignant mesothelioma.

Takayama S,  Kataoka N, Usui Y, Inase N, Natori Y, Nakayama M, Miura H, Kimula Y
Nippon Kyobu Shikkan Gakkai Zasshi 1990 Oct;28(10):1326-1331
[CA 19-9 in patients with benign pulmonary diseases].
Although serum CA 19-9 is considered to be a useful and specific tumor marker for pancreatic cancer, some patients with benign pulmonary diseases show elevated serum CA 19-9 levels. We measured serum CA 19-9 levels of 156 patients with benign pulmonary diseases (55 with asbestosis, 11 with bronchial asthma, 32 with bronchiectasis, 16 with idiopathic pulmonary fibrosis (IPF), 13 with healed pulmonary tuberculosis (HPT) and 29 other benign diseases). The percentage of patients with positive serum CA 19-9 was 42.3% (14.5% in asbestosis, 27.3% in bronchial asthma, 59.4% in bronchiectasis, 81.3% in IPF, 61.5% in HPT and 51.7% in others). In some patients, serum CA 19-9 levels were as high as those found in malignant gastrointestinal diseases. Serum CA 19-9 levels correlated well with disease activity. Immunohistochemically, CA 19-9 was expressed in mucous cells of the bronchial gland and surface of the bronchiolar surface epithelium cells in benign pulmonary disease. Gel filtration study suggested some difference in molecular weight between the serum CA 19-9 antigen of lung cancer and that of benign pulmonary diseases. It is suggested that serum CA 19-9 increases in the case of hyperplasia of the bronchiolar epithelium cells or the mucous cells of the bronchial gland. We conclude that benign pulmonary disease is one of the factors that affect serum CA 19-9 levels.

Takahashi Y,  Aida S, Suzuki E, Ito Y, Miura T, Kimula Y
Toxicol Appl Pharmacol 1994 Oct;128(2):207-215
Cytochrome P450 2B1 immunoreactivity in bronchiolar and alveolar epithelial cells after exposure of rats to ozone.
Pulmonary cytochrome P450 (P450) plays an important role in the metabolism of xenobiotics. We have previously demonstrated that exposure to ozone (O3), a major oxidant of photochemical smog, increases P450 content and xenobiotic metabolizing activities in the rat lung. Therefore, it is conceivable that O3 exposures modify the pattern and potency of xenobiotic metabolism. The aim of this study is to examine the effect of O3 exposure on localization of P450 in the lung. After exposure of rats to 0.4 ppm O3 for 14 days, the consentration of P450 2B1, the main isozyme of P450 in the lung, increased to 214% of the control value. By immunohistochemical analyses, O3 exposure caused hypertrophy and hyperplasia of P450 2B1-positive non-ciliated bronchiolar epithelial (Clara) cells, showing an increase in the cell number to 128% of the control level. At the proximal alveoli, O3 exposure induced hypertrophic epithelial cells that presented immunoreactivity to P450 2B1 and morphological characteristics of both type 1 and type 2 cells. These hypertrophic cells had lamellar inclusion bodies, microvilli, and extended cytoplasm. Typical type 2 cells did not react with anti-P450 2B1 antibody even after O3 exposure. These data suggest that O3 exposure may activate the P450-mediated xenobiotic metabolism in the pulmonary epithelial cells, and that expression of P450 2B1 in the pulmonary epithelial cells might be regulated by the factors involved in the process of the differentiation from type 2 to type 1 cells.

Takayama S,  Miura H, Kimula Y
Respiration 1991;58(2):115-116
A case of 'bronchial string'--a rare anomaly of the bronchus.
An incidental string-like structure spanning the lumen of the intermediate bronchus was found during bronchoscopy in an 18-year-old woman. We consider that the lesion may be a rare fibrous anomaly of the bronchus and may be closely related to a bronchial web. We have named this unusual structure 'bronchial string'.

Tanoue M,  Yoshizawa Y, Sato T, Yano H, Kimula Y, Miyamoto K
Int Arch Allergy Immunol 1993;101(1):47-51
The role of complement-derived chemotactic factors in lung injury induced by preformed immune complexes. Department of Internal Medicine, Yokohama Red Cross Hospital, Japan. Our previous studies have suggested a role for complement fragments presumably activated by immune complexes in patients with hypersensitivity pneumonitis. The present study has shown that circulating complement depletion by cobra venom factor resulted in the reduction in severity of immune-complex-mediatedpulmonary inflammation. The activity of chemotactic factors for neutrophils generated in bronchoalveolar lavage fluids in complement-depleted animals was significantly diminished to 61.2% compared to the undepleted animals. In addition, reduced activity of chemotactic factors resulted in a marked reduction of accumulation of neutrophils in bronchoalveolar lavage fluids indicating that chemotactic factors play an important role in the sequestration of neutrophils on the alveolar side of the lung. In conclusion, chemotactic factors in bronchoalveolar lavage fluids which preceded the accumulation of polymorphonuclear cells are partially derived from complement.

Tanoue M,  Yoshizawa Y, Kimula Y, Yano H, Hasegawa S, Aoki N
Nippon Kyobu Shikkan Gakkai Zasshi 1989 May;27(5):583-590
[Serial changes in lung injury produced by preformed immune complexes]. [Article in Japanese]
A previous study demonstrated increased levels of C5a des Arg and increased numbers of polymorphonuclear cells (PMNs) in bronchoalveolar lavage (BAL) fluids of acutely ill patients with summer type hypersensitivity pneumonitis (HP), suggesting the role of immune complexes (IC) in the early stage of HP. The present study was undertaken to compare the BAL findings in patients with acute HP and in animals which were injected intratracheally with preformed IC and to determine the correlation between the sequential BAL findings and the serial histology in animals. The results indicated that total cells recovered by BAL increased up to 24 hours. However, the most striking observation was that the increased number and percentage of PMNs in BAL cells shortly after the intratracheal injection, which the number of macrophages in BAL cells tended to be high, the increase was not statistically significant. Histological examinations revealed peribronchial and intraalveolar infiltration with PMNs at the early stage when intraalveolar infiltration were predominant, and the latest lesions consisted of infiltration with mononuclear cells in the alveolar walls. Furthermore, the cellular findings of BAL cells reflected the histological findings in involved lungs. The present study demonstrated that the sequential BAL changes of acutely ill patients with HP were similar to those of IC-injected animals, suggesting the possibility that IC formed in the airways is involved in the early stage of HP.

Tsunoda HS,  Saida Y, Doy M, Kimula Y, Matsueda K, Kurosaki Y, Kuramoto K, Akisada M
Nippon Igaku Hoshasen Gakkai Zasshi 1989 Sep 25;49(9):1112-1121
[Pulmonary infarction associated with bronchogenic carcinoma].
Pulmonary infarction may be associated with bronchogenic carcinoma. Radiopathological correlation was performed in four patients. There were two cases of squamous cell carcinoma, one case of adenocarcinoma and one case of large cell carcinoma. Infarcts in patients with squamous cell carcinoma were obscured on plain radiographs by a large primary tumor or atelectasis of the affected lobe. Infarcts in adenocarcinoma and large cell carcinoma were clearly demonstrated on plain radiographs; 1 to 2 cm in size, round or polygonal in shape, blurred in margin, and located at the periphery of the same lobe as the primary tumor. Rapid appearance of infarcts was helpful in distinguishing from intrapulmonary metastasis. Invasion of the pulmonary artery, pulmonary vein and bronchial wall in hilar region was thought to be responsible for pulmonary infarction. Pulmonary infarct should be considered in patients with centrally invasive bronchogenic carcinoma, when a small ill-defined opacity appears at the periphery of the involved lobe over a short period.

Usui Y,  Aida H, Kimula Y, Miura H, Aoyagi Y, Nakayama M, Takayama S
Respiration 1992;59(2):125-128
A case of cyclophosphamide-induced interstitial pneumonitis diagnosed by bronchoalveolar lavage.
A successfully treated case of cyclophosphamide pneumonitis, which developed during treatment for a leukemic phase of B-cell non-Hodgkin's lymphoma, is documented. Subtyping of lymphocytes in the peripheral blood and the bronchoalveolar lavage fluid easily excluded a possible diagnosis of pulmonary involvement of lymphoma. Bronchoalveolar lavage is a useful approach to determine the correct etiology of pneumonitis.

Usui Y,  Miura H, Kimura Y, Takayama S, Nakayama M
Hepatocellular carcinoma producing carcinoembryonic antigen and carbohydrate antigen 19-9.
Intern Med 1992 Jun;31(6):791-793
A case of hepatocellular carcinoma producing carcinoembryonic antigen and carbohydrate antigen 19-9 is reported. The serum level of carcinoembryonic antigen was 26,800 ng/ml and carbohydrate antigen 19-9, 5,500 U/ml on the final day. Immunohistochemical study revealed positive monoclonal antibodies for these two antigens within the cytoplasm of the hepatocellular carcinoma cells.

Usui Y,  Takayama S, Nakayama M, Miura H, Kimula Y
Respiration 1992;59(2):112-115
Case report of desquamative interstitial pneumonia: documentation of preserved pulmonary function after twelve clinical relapses.
We describe a case of desquamative interstitial pneumonia diagnosed in a 25-year-old woman who relapsed 12 times during a 20-year follow-up period. In each relapse, the involved sites were different and the patient ultimately recovered without resultant pulmonary ventilatory defects. Bronchoalveolar lavage performed during the 12th relapse revealed a remarkable increase in the number of total cells and showed a low CD4+/CD8+ ratio in the lymphocyte subset.

Usui Y,  Aida H, Kimula Y, Miura H, Takayama S, Nakayama M
Intern Med 1992 Jul;31(7):912-916
Hypersensitivity pneumonitis induced by hexamethylene diisocyanate.
A case of hypersensitivity pneumonitis (HP) induced by hexamethylene diisocyanate (HDI) is described. Serial determinations of the lymphocyte surface phenotypes by two-color assay revealed the following: 1) increased activated cytotoxic T lymphocytes in the bronchoalveolar lavage fluid (BALF), and 2) increased percentage and absolute number of non-major histocompatibility complex (MHC)-restricted natural killer (NK) cells in the peripheral blood (PB) during the recovery phase of the disease. These findings were considered to be related to the activity of the disease.

Usui Y,,  Kimula Y
Nippon Kyobu Shikkan Gakkai Zasshi 1992 Dec;30(12):2158-2162
[A case of endobronchial minute leiomyoma and literature review of the 66 cases of endotracheal and endobronchial leiomyoma reported in Japan]. A case of endobronchial minute leiomyoma successfully treated by bronchoscopically directed forceps biopsy is described. A 42-year-old male with a 20 pack-year smoking history was admitted for dry cough occurring at night. Chest X-ray showed no abnormal shadows. The tumor, measuring 2 by 2 mm, was located in the right B7. The clinical characteristics of the 66 cases of endotracheal and endobronchial leiomyoma reported in Japan are also discussed. The male to female ratio of this disease was 2:3. Middle-aged people were most, commonly affected. Usually, obstructive pneumonia or atelectasis, which develops distal to the lesion, causes respiratory symptoms and chest X-ray abnormality. However, 10% of cases were asymptomatic and 30% had a negative chest X-ray. There were 7 cases of endobronchial minute leiomyoma, measuring less than 10 mm in diameter. Of these, three cases had only hemoptysis and had no chest X-ray abnormality. In such cases fiberoptic bronchoscopy is may be the only useful procedure for the diagnosis of this disease.

Usui Y,  Takabe K, Takayama S, Miura H, Kimula Y
Chest 1991 Jan;99(1):235-236
Minute squamous cell carcinoma arising in the wall of a congenital lung cyst.
A case of minute squamous cell carcinoma arising in a congenital lung cyst is reported. Two aspects of this case were notable. First, we were able to make the diagnosis of squamous cell carcinoma by bronchial lavage at an early stage. Second, to our knowledge, this is the first case of probable de novo origin of squamous cell carcinoma in a congenital lung cyst.

Usui Y,  Takayama S, Nakayama M, Miura H, Kimula Y
Interstitial lattice shadow and mediastinal lymphadenopathy with an elevation of carcinoembryonic antigen in severe pulmonary alveolar proteinosis.
Intern Med 1992 Mar;31(3):422-425
A case of severe pulmonary alveolar proteinosis (PAP) with interstitial involvement, mediastinal lymphadenopathy and an elevation of carcinoembryonic antigen (CEA) in the bronchoalveolar lavage (BAL) fluid and the serum is presented. Alveolar macrophages may play a major role in these rare and seemingly unrelated findings.

Usui Y,  Kimula Y, Miura H, Kodaira Y, Takayama S, Nakayama M, Kataoka N
Respiration 1992;59(2):122-124
A case of bronchiolitis obliterans organizing pneumonia associated with primary Sjogren's syndrome who died of superimposed diffuse alveolar damage.
Bronchiolitis obliterans organizing pneumonia (BOOP) developed in association with primary Sjogren's syndrome in a 69-year-old female. She died of diffuse alveolar damage superimposed on BOOP in spite of corticosteroid therapy.

Watanabe T,　Tanaka Y, Kimula Y
Virchows Arch B Cell Pathol Incl Mol Pathol 1984;46(3):265-268
A cytophotometrical study on the centenarian hepatocyte.
Size alterations, both of cell and nucleus, of the centenarian hepatocyte followed a pattern proportionate to aging which was observed in the hepatocyte of non-centenarian groups and clearly followed nonagenarian in location on the graph. When size alterations of the hepatocyte were considered as an aging parameter, the present observation suggests that the centenarian could be a group next to the nonagenarian. The results obtained by present cytomorphometrical analysis do not favor a hypothesis that the centenarian is a select population in terms of longevity.

Yoshizawa Y,　Tanoue M, Yano H, Sato T, Ohtsuka M, Hasegawa S, Kimula Y
Clin Immunol Immunopathol 1991 Dec;61(3):376-386
Sequential changes in lung injury induced by preformed immune complexes.
Immune complexes formed in the airside may be involved in the early parenchymal changes in hypersensitivity pneumonitis. The present study was undertaken to compare the responses of animals after an intratracheal injection with preformed immune complexes to those of patients with acute hypersensitivity pneumonitis, with special emphasis on sequential bronchoalveolar lavage findings and the possible role of chemotactic factors in the immune complex-induced lung injury. An increased number and percentage of polymorphonuclear cells could be detected in bronchoalveolar lavage fluids of guinea pigs within 48 hr following an intratracheal injection of preformed immune complexes. Chemotactic factor activity preceded the observed increase of polymorphonuclear cells in bronchoalveolar lavage fluids, suggesting a role for chemotactic factors in the sequestration of these cells in the lung. In addition, this study confirmed the usefulness of bronchoalveolar lavage in evaluating the pulmonary findings because the changes in bronchoalveolar lavage cell populations correlated with sequential histological findings. The sequential characteristics of the involved areas were noted to be of a peribronchial or bronchiolar infiltration with polymorphonuclear cells at early stages, then alveolar sac infiltration, followed by mild infiltration of mononuclear cells into the alveolar walls. The findings suggest a possible role for chemotactic factors in the accumulation of polymorphonuclear cells, and the sequential changes of bronchoalveolar lavage and histological findings in animals are comparable to those in patients with acute hypersensitivity pneumonitis.