廣島 健三

Pulmonary capillary haemangiomatosis is a rare disorder characterised by multiple angiomatous lesions composed of proliferating capillary vessels in the lung parenchyma that usually progress rapidly to establish fatal pulmonary hypertension. The 29 year old man presented here, however, has been stable for 3.5 years since the diagnosis without symptoms of pulmonary hypertension. High resolution computed tomographic findings of the pulmonary lesions seemed specific to the disease.

BACKGROUND. Mediastinal teratomas are the most frequent mediastinal germ cell tumor. Whereas mature teratomas are benign tumors, immature teratomas are malignant. The purpose of this study was to find characteristics that could be used to distinguish between the growth and prognosis of the two teratoma types. METHODS. Twenty-four mediastinal teratomas (18 mature and 6 immature) were examined for apoptosis by 3 ' -end labeling of DNA and stained immunohistochemically for proliferating cell nuclear antigen, Bcl-2, Bax, p53 protein, and a-fetoprotein (AFP) expression in formalin fixed, paraffin embedded specimens. RESULTS. AFP was expressed in both immature teratomas and mature teratomas. Whereas p53 protein was expressed by most teratomas, p53 gene mutation was observed in only one patient with an immature teratoma in which the same mutation occurred in all tumor tissue components tested. Bax protein expression was relatively diffuse in mature teratomas but was focally expressed in immature teratomas. Bcl-2 protein was expressed focally in both mature and immature teratomas. Although the proliferative index was significantly higher in immature teratomas compared with mature teratomas (P < 0.001), the apoptotic index (AI) was significantly higher in mature teratomas compared with immature teratomas (P < 0.05). All patients except one in this study remain alive and disease free after undergoing tumor resection. CONCLUSIONS. The relatively high Al in mature teratomas may be due to the overexpression of the p53 protein. In contrast, immature teratomas exhibited higher proliferative activity and lower rates of apoptosis, which may explain the more aggressive behavior of these tumors. However, patients with immature mediastinal teratomas have a good prognosis if the tumor is resected completely after chemotherapy. (C) 2001 American Cancer Society.

The cytologic findings of the tumor cells characteristic of the stages of thymomas were investigated to assess the invasiveness of the tumors. Forty-six patients with thymoma who underwent extensive thymectomy without preoperative corticosteroid therapy were included in this study. The histologic subtypes included 18 round/oval, 20 mixed, and 8 spindle type. The stages of thymoma classified according to Masaoka's clinicopathological classification included 16 stage I, 20 stage II, 6 stage III, 2 stage IVa, and 2 stage IVb, and myasthenia gravis was recognized in 5 patients. Cytologic findings were retrospectively analyzed in the Papanicolaou-stained stamp smears obtained from the cut surfaces of thymoma specimens. Morphometry of the epithelial tumor cells using Cosmozone-1A was performed to evaluate the validity of our cytologic categories. Compared with the cytologic findings of stage I or II thymomas, those of epithelial tumor cells in stage III or IV more frequently showed necrotic background (50.0%-stage III or IV vs 11.1%-stage I or II, p=0.006), large clusters of epithelial tumor cells (70.0% vs 36.1%, p=0.055), marked nuclear enlargement (90.0% vs 52.7%, p-0.033), marked anisokaryosis (100% vs 52.7%, p=0.006), marked nuclear polymorphism (40.0% vs 5.5%, p=0.004), hyperchromasia (50.0% vs 11.4%, p=0.007) and prominent nucleoli (50.0% vs 16.6%, p=0.028) whereas no significant correlation was observed between cytologic findings and tumor volume. Morphometric studies of thymoma tumor cells revealed that the nuclear size (mean values, 78.8 mum(3)-stage III or IV vs 58.2 mum(3)-stage I or II), the coefficient of variation of the nuclear size (0.326 vs 0.282), and the nuclear rotundity (0.849 vs 0.858) differed significantly between the two categories (p<0.05). Our findings demonstrated that there were significant differences between the cytologic findings of epithelial tumor cells of stage I or II thymomas and those of stage III or IV thymomas, and that the cytologic findings of thymoma tumor cells appear to be useful for distinguishing between noninvasive and invasive thymomas.

BACKGROUND. In 1999, the World Health Organization categorized large cell neuroendocrine carcinoma, large cell carcinoma with neuroendocrine differentiation, and large cell carcinoma with neuroendocrine morphology as a variant of large cell carcinoma. Patients with large cell carcinoma vith neuroendocrine features have poor prognoses, comparable to those for small cell lung carcinoma. Small cell lung carcinoma is sensitive to chemotherapy; however, it is still unclear whether large cell carcinoma with neuroendocrine features is responsive to adjuvant chemotherapy. METHODS. The authors analyzed 73 patients with large cell carcinoma with neuroendocrine features who underwent resection of the tumor and studied the effect Chiba, Japan. of adjuvant chemotherapy for large cell carcinoma with neuroendocrine features. RESULTS. in patients with Stage I disease, the overall survival for patients with cer Research, Chiba University School of Medicine, adjuvant chemotherapy based on cisplatin, carboplatin, or cyclophosphamide, Chiba, Japan. which were used as standard chemotherapy for small cell lung carcinoma, were significantly higher than the overall survival for patients without adjuvant chemotherapy. In patients with Stage II, III, and IV disease, there was no significant difference between patients with adjuvant chemotherapy and without adjuvant chemotherapy. CONCLUSIONS. Adjuvant chemotherapy based on cisplatin, carboplatin, or cyclophosphamide prolongs survival of patients with large cell carcinoma vith neuroendocrine features in early stage. (C) 2001 American Cancer Society.

BACKGROUND. Telomerase activation is believed to be play a critical role in the immortalization of cells and carcinogenesis. Telomerase activity is undetectable in normal somatic cells (except for those cells undergoing proliferation) but is expressed in the majority of human tumors including lung carcinoma. The expression of hTERT mRNA has been found to be correlated with telomerase activity. In the current study, the authors analyzed telomerase activity and hTERT mRNA expression in preinvasive bronchial lesions using biopsy specimens obtained by fluorescence bronchoscopy. METHODS. The authors studied 150 bronchial biopsy specimens obtained by fluorescence bronchoscopy. The intensity of telomerase activity was determined by the fluorescence-based telomeric repeat amplification protocol method in 74 bronchial biopsy specimens (22 normal bronchial epithelium or bronchitis cases, 15 squamous metaplasia cases, 23 dysplasia cases, and 14 squamous cell carcinoma cases), and the level of hTERT mRNA was analyzed in another 76 specimens (24 normal bronchial epithelium or bronchitis cases, 15 squamous metaplasia cases, 20 dysplasia cases, and 17 squamous cell carcinoma cases) by real-time polymerase chain reaction. RESULTS. The mean values ( the standard deviation [SD]) of telomerase activity in normal bronchial epithelium or bronchitis, squamous metaplasia, dysplasia, and squamous cell carcinoma cases were 6.2 +/- 7.5, 13.9 14.8, 18.5 20.8, and 54.5 22.3 U/mug protein, respectively. The upper limit of telomerase activity in normal bronchial epithelium or bronchitis was 21 U/mug protein (mean + 2SD). It is interesting to note that, 5 of 15 squamous metaplasia biopsies (33%), 8 of 23 dysplasia biopsies (35%), and all squamous cell carcinoma biopsies (100%) exhibited levels of telomerase activity that were > 21 U/mug protein. The mean levels of hTERT mRNA in normal bronchial epithelium or bronchitis, squamous metaplasia, dysplasia, and squamous cell carcinoma cases were 891 +/- 840, 1936 +/- 1704, 3019 +/- 2607, and 12965 +/- 18008 copies/mug total RNA, respectively. Telomerase activity and hTERT mRNA expression were found to increase in proportion to the severity of histologic change from normal bronchial epithelium or bronchitis to squamous cell carcinoma. CONCLUSIONS. These results suggest that an increase in telomerase activity and hTERT mRNA expression are features of the early stages of the development of squamous cell carcinoma of the lung, with strong telomerase activity and hTERT mRNA expression being prominent during the latter stages. (C) 2001 American Cancer Society.

The pathogenesis of severe pulmonary hypertension seems to be related to inflammatory response in diseased sites. Monocyte chemoattractant protein-1 (MCP-1) has been reported to play a role in the development of congestive heart failure. In this immunological response, activation and migration of leukocytes including macrophages to the inflammatory region are important factors. We hypothesized that the severity of pulmonary hypertension may be related to MCP-1, which is thought to be upregulated by blood pressure or shear stress in pulmonary vasculature as well as by immunological and inflammatory reactions in chronic thromboembolic pulmonary hypertension (CTEPH). Circulating levels of MCP-1, interleukin-1 beta (IL-1 beta), and tumor necrosis factor-alpha (TNF-alpha) were measured by sandwich ELISA in 14 patients with CTEPH. The plasma level of MCP-1 was significantly correlated with pulmonary vascular resistance. In IL-1 beta and TNF-alpha, on the other hand, there was no correlation between cytokines and pulmonary hemodynamics. Pathological specimens obtained from the patients with CTEPH undergoing thromboendarterectomy demonstrated immunoreactivity of MCP-1 in endothelium, smooth muscle cells, and macrophages within neointima in the hypertensive large elastic pulmonary artery. We conclude that MCP-1 is upregulated in the remodeling of pulmonary arteries in close association with increased pulmonary vascular resistance in CTEPH.

Few studies on sarcomas have examined the relationships between microsatellite alterations in particular loci, tumor prognosis and tumorigenesis, because sarcomas are uncommon and those prognoses can be confounded by coexisting factors, such as tumor site. We studied the relationship between microsatellite alterations and prognosis in 31 patients with thoracic sarcoma. The frequency of loss of heterozygosity (LOH) at 17p13 in stage IV sarcomas was significantly higher than that in stage I and III sarcomas (p <0.05). The 5-year survival for patients with LOH at 17p13 was significantly lower than that for patients without LOH (p <0.05). Six of 31 cases (19.4%) revealed replication error. These results suggest that p53 abnormality occurs during advanced stages of sarcoma and are related to patient prognosis, and it is possible that aberrations in mismatch repair activity are related to sarcoma tumorigenesis.

Background. Therapeutic principles for managing subclinical pleural cancer found unexpectedly during intraoperative examination are unclear. We analyzed prognostic factors including the tumor proliferative marker Ki-67 in these circumstances. Methods. The cases of 65 surgically treated patients with lung cancer and subclinical T4 pleural cancer, microscopic in 25 and macroscopic in 40, were reviewed. Results. The overall 5-year survival rate of patients undergoing lobectomy was 14.3%. For patients with T4 NO disease, the 5-year survival rate was 46.7%. In patients with a low Ki-67 labeling index, the 5-year survival rate was 28.6%. The Ki-67 labeling index was a significant (p < 0.05) indicator of survival. Multivariate analysis demonstrated Ki-67 labeling index, lymph node involvement, and tumor differentiation to be the most influential prognostic factors for postoperative survival (p < 0.01). Conclusions. In the treatment of lung cancer patients with subclinical pleural cancer found at thoracotomy, tumor resection is not necessarily contraindicated. Resection appears to be beneficial in patients with no nodal involvement or a low tumor Ki-67 labeling index. This index is a good therapeutic indicator for lung cancer patients.

BACKGROUND. Large cell carcinoma has been classified as four potential types based on its neuroendocrine morphology and evidence of neuroendocrine differentiation discernible by immunohistochemistry or electron microscopy. However, the clinical relation among these four categories has not been clearly defined. In 1999, the World Health Organization (WHO) categorized large cell neuroendocrine carcinoma as a variant of large cell carcinoma. MATERIAL AND METHODS. The authors analyzed 119 cases of large cell carcinoma from a total of 2070 primary lung carcinoma cases resected surgically between 1969-1999. Using light microscopy, electron microscopy, and immunohistochemical staining, the authors reclassified these cases into large cell neuroendocrine carcinoma (LCNEC), large cell carcinoma with neuroendocrine differentiation (LCCND), large cell carcinoma with neuroendocrine morphology (LCCNM), and classic large cell carcinoma (CLCC). RESULTS. In multivariate analyses, the authors found that large cell carcinoma with neuroendocrine features, which combined LCNEC, LCCND, and LCCNM, impacted both the overall survival and disease-free survival of patients. The clinical behavior of LCCNM was similar to that of LCNEC. CONCLUSIONS. Large cell carcinomas with neuroendocrine features appear to be more clinically aggressive than CLCCs. The authors' findings suggest that the histologic identification of neuroendocrine features in tumor tissue from patients diagnosed with large cell carcinoma of the lung may have clinical relevance. Cancer 2001;91:1992-2000. (C) 2001 American Cancer Society.

Background. A body of data indicates that vascular endothelial growth factor (VEGF) expression by carcinomas is closely related to the prognosis of carcinomas. However, the relationship between VEGF expression and the prognosis of sarcomas is contradictory. Methods. Tissue from 27 cases of thoracic sarcoma was analyzed immunohistochemically for VEGF expression while tumor vascularity was quantified using an antibody directed against endothelial CD34. The relationship between VEGF expression and the prognosis of patients with sarcomas was then evaluated semiquantitatively. Results. The microvessel count in sarcomas with strong VEGF expression was significantly higher than that in sarcomas with absent or faint VEGF expression. The disease-free survival rates of sarcomas with strong VEGF expression were significantly lower than those of sarcomas with absent or faint VEGF expression. We found that strong VEGF expression impacted on the disease-free survival in multivariate analyses. Conclusions. VEGF expression of thoracic sarcomas is directly related to angiogenesis and tumor vascularity, and our findings suggest that strong VEGF expression is an independent prognostic factor in patients with thoracic sarcomas. (Ann Thorac Surg 2001;71:1635-9) (C) 2001 by The Society of Thoracic Surgeons.

Background: a new strategy in the treatment of squamous cell carcinoma of the tracheobronchial tree is the detection and eradication of preinvasive bronchial lesions before they become invasive cancers. It is, however, difficult to detect preinvasive lesions by conventional white-light bronchoscopy alone. Purpose: we conducted a detailed investigation on the use of fluorescence bronchoscopy in the detection of preinvasive bronchial lesions in patients with sputum cytology suspicious or positive for malignancy, Methods: 64 participants with sputum cytology suspicious or positive for malignancy were examined with both white light and fluorescence bronchoscopy (LIFE group). Earlier to this study, before fluorescence bronchoscopy became available in our institute, 48 participants having sputum cytology suspicious or positive for malignancy were examined with white light bronchoscopy alone (control group). Biopsy specimens for pathological examinations were taken of all abnormal areas discovered by white light or fluorescence bronchoscopy examination. Results: in sputum cytology suspicious or positive for malignancy, the diagnosis of preinvasive bronchial lesions was greatly enhanced in the LIFE group as compared with the control group (45 vs. 7 lesions). The percentage of participants with preinvasive bronchial lesions was also significantly higher in the LIFE group than in the control group (40.6 vs. 12.5%, P = 0.00087, respectively). Conclusions: our study suggests that the use of fluorescence bronchoscopy in addition to conventional white-light examination could greatly enhance the detection and localization of preinvasive bronchial lesions in patients with sputum cytology suspicious or positive for malignancy. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.

We report a surgical case involving localized honeycomb lung with mucus, caused by colonization of a Schizophyllum commune, which displayed a tumorous shadow in the right upper mediastinum. A 74-year-old male with a history of tuberculosis in the 1970s was referred to Chiba University Hospital (Chiba, Japan) with an abnormal shadow evident in the chest roentgenogram. A transbronchial biopsy failed to yield a definite diagnosis. We resected the right upper lobe, which was found to contain a consolidative lesion filled with viscous mucus in the right upper lobe adjacent to the right upper mediastinum. Microscopic examination revealed a honeycomb lung formation with mucus in the destroyed space. Culture of the mucus yielded a whitish filamentous fungus, positively identified as S. commune. This is the first report of S. commune leading to a deposit of mucus and the formation of a consolidative lesion in the destroyed lung. Copyright (C) 2001 S. Karger AG, Basel.

Bisphenol A is used as a monomer in the production of polycarbonate plastic products. The widespread use of bisphenol A has raised concerns about its effects in humans. Since there is little information on the mutagenic potential of the chemical, the mutagenicity of bisphenol A was tested using human RSa cells, which has been utilized for identification of novel mutagens. In genomic DNA from cells treated with bisphenol A at concentrations ranging from 1 x 10(-7) to 1 x 10(-5) M, base substitution mutations at K-ras codon 12 were detected using PCR and differential dot-blot hybridization with mutant probes. Mutations were also detected using the method of peptide nucleic acid (PNA)-mediated PCR clamping. The latter method enabled us to detect the mutation in bisphenol A-treated cells at a dose (1 x 10(-8) M) equivalent to that typically found in the environment Induction of ouabain-resistant (Oua(R)) phenotypic mutation was also found in cells treated with 1 x 10(-7) and 1 x 10(-5) M of bisphenol A. The induction of K-ms codon 12 mutations and OuaR mutations was suppressed by pretreating RSa cells with human interferon (HuIFN)-alpha prior to bisphenol A treatment. The cells treated with bisphenol A at the concentration of 1 x 10(-6) M elicited unscheduled DNA synthesis (UDS). These findings suggested that bisphenol A has mutagenicity in RSa cells as well as mutagens that have been tested in these cells, and furthermore, that a combination of the PNA-mediated PCR clamping method with the human RSa cell line may be used as an assay system for screening the mutagenic chemicals at very low doses. (C) 2001 Elsevier Science B.V. All rights reserved.

[原著] Kimura H, Okada O, Tanabe N, Tanaka Y, Terai M, Takiguchi Y, Masuda M, Nakajima N, Hiroshima K, Inadera H, Matsushima K, Kuriyama T.: Plasma monocyte chemoattractant protein-1 and pulmonary vascular resistance in chronic thromboembolic pulmonary hypertension

[原著] Shibuya K, Fujisawa T, Hoshino H, Baba M, Saitoh Y, Iizasa T, Suzuki M, Otsuji M, Hiroshima K, Ohwada H.: Fluorescence bronchoscopy in the detection of preinvasive bronchial lesions in patients with sputum cytology suspicious or positive for malignancy

Primary liposarcomas of the mediastinum are very rare. We report on a 13-year-old girl who presented with a huge mediastinal tumor. The tumor was extirpated by a median sternotomy with a right thoracotomy. The tumor included the superior vena cava in the anterior mediastinum. It therefore probably originated from the anterior mediastinal fat tissue, possibly from the thymus. A pathological examination revealed myxoid liposarcoma. At 35 months postoperatively, the patient has not shown any recurrence.

わが国における肺癌による死亡数は, 近年, 急激に増加している。肺癌を発生させる原因は, 喫煙が最も重要であり, 喫煙者が肺癌になるリスクは非喫煙者に対して, 10〜15倍高いといわれている。中枢性肺癌の多くは扁平上皮癌で、これは過形成, 扁平上皮化生, 異形成, 上皮内癌, 進行癌の順に進行すると考えられる。末梢肺に発生する異型腺腫様過形成は肺腺癌の前癌病変と考えられている。肺癌は癌原遺伝子(myc, K-ras等)が活性化したり, 癌抑制遺伝子(p53, RB等)が不活化したりすることにより発生する。マイクロサテライトマーカーを用いたヘテロ接合性の消失の検討により, 肺癌には1p, 1q, 3p, 5q, 8p, 9p, 11p, 13q, 17p, 22q等の欠失の頻度が高いと報告されている。たばこに含まれる多くの発癌物質が気道上皮に遺伝子変異をおこし, この変異が細胞内に順次蓄積して, 肺癌が発生する。肺癌を発症していない喫煙者の気管支の前癌病変にも遺伝子異常が起きている。喫煙者の気道上皮の増殖能は非喫煙者に比して亢進している。喫煙者が禁煙しても, 非喫煙者と同じリスクには戻らない理由は, 喫煙者に見られる気道の前癌病変に, 既に細胞学的変化や遺伝子変異が起きているからであると考えられる。近年, 喀痰や気管支肺胞洗浄液を用いた肺癌の遺伝子診断に関する報告がなされている。肺癌による死亡率を減少させるためには, 厳重な禁煙が重要であるが, 蛍光内視鏡や分子生物学的手法を用いた肺癌の早期発見と治療, 前癌状態の発見および肺癌への進行の予防が重要である。