廣島 健三

Severe combined immune deficiency (SCID) mice were more sensitive to systemic delivery of belomycin (BLM) than the wild-type strain, and died from esophagitis. Lung injury in the SCID mice by its intratracheal injection, however, was of comparable degree but with less lymphocyte infiltration than that in the wild-type mice. Macrophages and lymphocytes increased transiently in bronchoalvelolar lavage fluid of SCID mice, whereas their increase in wild-type was continuous. Unsustainable inflammation in the lung might reduce BLM-induced lung injury in BLM-sensitive SCID mice.

Although the histogenesis of sclerosing hemangioma (SH) of the lung is now thought to be respiratory epithelial in origin, the genetic abnormalities that mediate its development are not known. Because pathophysiology of several syndromes associated with benign tumors may converge on the tuberous sclerosis complex (TSC), serine/threonine kinase 11 (STK11), and mammalian target of rapamycin (mTOR) pathways, the purpose of the present paper was to investigate their roles in the development of SH. Semiquantitative immunohistochemical analysis was done to assess the expression of phospho-mTOR, phospho-S6 ribosomal protein, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), phospho-Akt, STK11, tuberin, hamartin, vascular endothelial growth factor (VEGF), and hypoxia-inducible factor-1 alpha (HIF-1 alpha) in 19 cases of typical SH. To determine whether genetic alteration of STK11 is involved in the development of SH, all encoding exons of STK11 were analyzed by polymerase chain reaction (PCR) amplification and direct sequencing of genomic DNA of six specimens. The six specimens were also investigated for whether promoter hypermethylation exists as an alternative inactivating mechanism for STK11. All specimens showed moderate to marked reaction to phospho-S6 ribosomal protein and PTEN; 16 specimens (84%) showed slight to moderate reaction to phospho-mTOR, negative reaction to STK11, and slight to moderate reaction to hamartin; 11 (58%) showed slight to moderate reaction to phospho-Akt; 18 (95%) showed slight to moderate reaction to tuberin and positive reaction for HIF-1 alpha; and 17 (90%) showed moderate reaction to VEGF. No somatic mutation of STK11 was found and the six specimens were unmethylated in the promoter region. These data imply that aberrant mTOR signaling may play a role in the development of SH, and its vascular nature may be due partially to high levels of VEGF caused by dysregulation of mTOR signaling.

A 60-year-old man was admitted to our hospital complaining of back pain and bloody sputum. Chest CT scan showed characteristic multiple small nodules with central dense opacity and surrounding faint opacity, suggesting lesions with hemorrhage. Bone scintigram and MRI revealed multiple osteolytic lesions in pelvis and lumbar spine. Biopsy of the bone lesion established a diagnosis of angiosarcoma. Chemotherapy with paclitaxel and palliative radiotherapy for the bone were initiated. Pulmonary metastases dramatically diminished after 4 courses of paclitaxel treatment. After eight weeks, the tumor recurred. Salvage chemotherapy of weekly administration of docetaxel yielded limited effects. The patient died of cancer one year after treatment initiation.

Purpose: The Wnt and epidermal growth factor receptor (EGFR) signaling pathways play crucial roles in the pathogenesis of a variety of malignant tumors. Although the details of each cascade are understood, very little is known about their collective effects in non-small cell lung cancer (NSCLC). Experimental Design: At otal of 238 NSCLC samples were examined for methylation of Wnt antagonists [secreted frizzled-related protein (sFRP)-1, sFRP-2, sFRP-5, Wnt inhibitory factor-1, and Dickkopf-3] and for EGFR and KRAS mutations. Protein expression levels of β-catenin were assayed in 91 of the 238 NSCLCs. Results: We found that (a) aberrant methylation of Wnt antagonists is common in NSCLCs (b) methylation of sFRP-2 is more prevalent in females, nonsmokers, and adenocarcinoma cases (c) Dickkopf-3 methylation is significantly associated with a poor prognosis in adenocarcinomas (d) there is a positive correlation between activated EGFR mutation and nuclear accumulation of β-catenin (e) KRAS mutation and aberrant methylation of Wnt antagonists are positively correlated and (f) EGFR mutation is significantly associated with a good prognosis in tumors lacking methylated Wnt antagonist genes. Conclusions: These results contribute to a better understanding of the cross-talk between the Wnt and EGFR signaling pathways and help foster development of chemotherapeutic treatments in NSCLCs. ©2007 American Association for Cancer Research.

Background: Interleukin-12 receptor β2 (IL-12Rβ2) knock-out mice develop lung adenocarcinoma, and epigenetic silencing by CpG methylation leads to loss of this gene in B-cell malignancies. The aim of this study was to determine whether IL-12Rβ2 methylation is a common feature in human lung cancer. Methods: We examined mRNA expression of IL-12Rβ2 in lung cancer cell lines, and normal bronchial, and tracheal epithelial cells using RT-PCR, and we examined the methylation status of IL-12Rβ2 in primary lung cancers. Results: Loss of expression was found in 10 of 13 (77%) NSCLC cell lines, and 2 of 5 (40%) SCLC cell lines compared with normal bronchial or tracheal cells. Treatment of 11 expression-negative cell lines with a demethylating agent restored expression in all cases. Aberrant methylation status of IL-12Rβ2 gene was reversely concordant with its mRNA expression. IL-12Rβ2 methylation was detected in 96 of 230 primary NSCLCs (42%) and 3 of 6 primary SCLCs (50%). IL-12Rβ2 methylation correlated with poorer prognosis in lung adenocarcinomas (hazard ratio = 2.33, P = 0.0059). Conclusions: We conclude that epigenetic silencing of IL-12Rβ2 is a frequent event in lung cancers. Aberrant methylation of this gene seems to be a useful predictor of long-term outcome for adenocarcinoma of the lung. © 2007 Society of Surgical Oncology.

A 72-year-old man with tongue carcinoma complained of dyspnea on exertion 18 days after starting treatment with S-1. Chest radiograph and CT scan suggested diffuse interstitial lesions with ground glass opacity on both lungs. Bronchoalveolar lavage and transbronchial lung biopsy revealed moderate lymphocyte infiltration with granuloma. Drug lymphocyte stimulation test was positive against tegafur, one of the components of S-1. These findings were consistent with S-1-induced lung injury. Both his symptoms and the radiographic findings were resolved dramatically after high-dose corticosteroid therapy. Clinicians should be aware that S-1 has the potential to cause lung injury when it is included in chemotherapy. © 2007 The Japanese Society of Internal Medicine.

Background. TS-1 is effective in the treatment of head and neck, breast, gastric, and non-small cell lung cancer, however its anti-tumor effect on a cancer of unknown primary site has not been established. Case. A 60-year-old woman was admitted to our hospital because of right cervical, left supraclavicular and mediastinal lymphadenopathy. A biopsy specimen from the supraclavicular lymph node demonstrated papillary adenocarcinoma. Because all examination failed to identify the primary site, a diagnosis of a cancer of unknown primary site was established. Although several treatments, including cisplatin plus docetaxel, cisplatin plus irinotecan, cisplatin plus gemcitabine, carboplatin plus paclitaxel, and gefitinib yielded partial response, the tumor relapsed after cessation of the treatment. After TS-1 was initiated, the tumor significantly regressed and no re-growth was observed for 15 months, until relapse. Conclusion. TS-1 may be effective for the cancers of unknown primary site. © 2007 The Japan Lung Cancer Society.

A diagnosis of sarcoidosis should be substantiated by pathological means in order to thoroughly exclude other diseases. The role of real-time endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in the diagnosis of sarcoidosis has not been reported. The purpose of the present study is to evaluate the diagnostic yield of EBUS-TBNA in demonstrating the pathological features of sarcoidosis. In total, 65 patients with suspected sarcoidosis, with enlarged hilar or mediastinal lymph nodes on computed tomography, were included in the study. Patients with a suspected or known malignancy or previously established diagnosis of sarcoidosis were excluded. Convex probe endobronchial ultrasonography integrated with a separate working channel was used for EBUS-TBNA. Surgical methods were performed in those in whom no granulomas were detected by EBUS-TBNA. Patients were followed up clinically. EBUS-TBNA was performed on a total of 77 lymph node stations in 65 patients. A final diagnosis of sarcoidosis was made for 61 (93.8%) of the patients. The remaining four patients were diagnosed as having Wegener's granulomatosis (n=1) or indefinite (n=3). In patients with a final diagnosis of sarcoidosis, EBUS-TBNA demonstrated noncaseating epithelioid cell granulomas in 56 (91.8%) of the patients, No complications were reported. Endobronchial ultrasound-guided transbronchial needle aspiration proved to be a safe procedure with a high yield for the diagnoses of sarcoidosis. Copyright©ERS Journals Ltd 2007.

Lung cancer is a global epidemic and the number one cause of death among all cancers, with a very high morbidity. A new strategy for the treatment of lung cancer is the detection and eradication of pre-invasive bronchial lesions before they become invasive carcinomas. We conducted a detailed investigation into the use of fluorescence bronchoscopy in the detection of pre-invasive bronchial lesions in patients with sputum cytology suspicious or positive for malignancy. We also studied the distinctive cytological findings in the sputum specimens corresponding to the pre-invasive bronchial lesions. Sputum examinations were performed by mass screening a high-risk group of participants. From 1997 to 1999, 61 participants with sputum cytology suspicious or positive for malignancy were referred to our institute, and were examined with both white-light and fluorescence bronchoscopy. For the cytological findings, the collection of sputum was performed in the early morning. Conventional white-light examinations were first performed, and areas with abnormal findings were recorded for subsequent biopsy. Fluorescence bronchoscopy examinations were then carried out. Biopsy specimens for a pathological examination were taken from all the suspicious or abnormal areas discovered by the white-light bronchoscopy, or fluorescence bronchoscopy examination, or both. The laser-induced fluorescence bronchoscopic examination showed a high sensitivity for invasive carcinoma, carcinoma in situ, as well as severe, moderate, and mild dysplasia. In the sputum cytological findings, a thickened cytoplasm and slight hyperchromasia were frequently observed in the mild dysplasias compared with the squamous cells without atypia. Hyperchromasia and an Orange G (OG)-philic cytoplasm of squamous cells were frequently observed in the moderate compared with the mild dysplasias. A thickened cytoplasm, a nuclear pleomorphism, a thickened nuclear rim, a coarse chromatin, an uneven chromatin distribution, and an OG-philic cytoplasm were frequently observed in the carcinomas in situ and severe dysplasias compared with the moderate dysplasias. We found that the use of fluorescence bronchoscopy in addition to conventional white-light examination can enhance the detection and localization of pre-invasive bronchial lesions in patients with sputum cytology suspicious or positive for malignancy. Sputum cytology is therefore a potential approach to diagnosing pre-invasive bronchial lesions.

A 53-year-old woman was referred to Matsudo City Hospital for palliative care of stage IVb invasive thymoma with multiple pulmonary metastases and dissemination. Moderate doses of corticosteroid were administered for palliative effects during the preterminal stage of the disease for 2 years. The thymoma progressed slowly but continuously. At age 55, she was admitted to our hospital for a whole-body eruption and high body temperature. We could not identify the pathogen or allergen. Based on the results of a skin biopsy, with the exception of corticosteroid we stopped administering all suspicious medications, including folk medicines. After 1 month of antipyretic therapy, whole-body eruption disappeared and we encountered rapid regression of the thymoma. Unfortunately she died of interstitial pneumonitis only 2 months after the regression.

Spontaneous regression of a pulmonary lesion in patients with Wegener's granulomatosis (WG) is rare, and only a few such reports have been published. We describe a rare case of a patient with WG in which the pulmonary lesion regressed spontaneously. The patient was a 76-year-old man presenting with fever, sputum and cough. On serial CTs, he had a solitary nodule in the right lung that regressed spontaneously while new multiple nodules developed during a 1-month interval. Biopsy of the new lesions by video-assisted thoracostomy (VATS) established a diagnosis of WG. Treatment with glucocorticoid and cyclophosphamide significantly ameliorated his condition. Concordant with similar previous reports, the mechanisms behind spontaneous regression of pulmonary lesions in the present case seemed to include spontaneous improvement of infection or infarction caused by vasculitis, in addition to regression of the WG lesion itself. Although it occurs rarely, physicians should be aware of the phenomenon that pulmonary lesions in WG could progress and regress spontaneously.

Background: The presence of somatic mutations in epidermal growth factor receptor (EGFR) predicts the effectiveness of EGFR tyrosine kinase inhibitors (TKIs). It would be ideal if an EGFR mutation could be detected in biopsy samples, since the majority of non-small cell lung cancer patients are inoperable at the time of presentation. We have reported the usefulness of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for the lymph node staging of lung cancer. EBUS-TBNA enables the sampling of histologic cores, which can be used for genetic analysis. Methods: The purpose of this study was to develop and analyze the feasibility of detecting EGFR mutations in samples obtained by EBUS-TBNA. Forty-six patients with primary lung cancer in whom metastatic adenocarcinoma in the hilar and/or mediastinal lymph node was diagnosed by EBUS-TBNA were enrolled into the study. DNA was extracted from paraffin-embedded samples, and the EGFR mutation was analyzed in exons 19 and 21 using a newly developed loop-hybrid mobility shift assay. The results were confirmed by direct sequencing. Results: Forty-three cases were eligible for analysis and in 11 cases, EGFR mutation (25.6%) was detected one case was an in-frame deletion (E746-A750del) of exon 19, nine cases were point mutations (L858R) of exon 21, and one case was a double point mutation (L858R+L861V). All cases with EGFR mutations were confirmed by direct sequencing. Conclusions: EGFR mutation can easily be detected in metastatic lymph nodes sampled by EBUS-TBNA. EBUS-TBNA allows genetic evaluations of tumor cells within the lymph node and may provide us with indications for EGFR-TKI therapy in the near future.

Pulmonary epithelioid haemangioendothelioma (PEH) is a rare pulmonary neoplasm. A patient with PEH with lymph node and pleural metastases that were discovered incidentally is described. An abnormal left upper lobe shadow was noticed on CXR in a 70-year-old woman during an assessment for the sudden onset of nausea and vomiting. Transbronchial lung biopsy did not provide a diagnosis. Lobectomy and lymph node resection were performed. The histological diagnosis of PEH was confirmed immunohistochemically by positive reactions to factor VIII-related antigen and CD34. Data on 93 patients with PEH including the present case report were analysed by Cox regression analysis using forward stepwise method to identify the risk factors, and the independent predictors of survival in patients with PEH. It revealed that male, symptomatic patients, presence of cough, haemoptysis, chest pain, multiple unilateral nodules, pleural effusion, metastases to more than one site and lymph node metastases were all significant risk factors for PEH (P < 0.05). Symptomatic patients and presence of pleural effusion were the independent predictors of survival in patients with PEH.

Background. Patients with pulmonary large cell neuroendocrine carcinoma ( LCNEC) have a very poor prognosis, but the benefit of adjuvant chemotherapy for these patients has not been established. We performed a prospective analysis of adjuvant chemotherapy for patients with completely resected pulmonary LCNECs to assess the effect of adjuvant chemotherapy. Methods. The adjuvant mixture consisted of cisplatin and VP-16 and was administered after surgery to 15 patients with LCNECs from 2000 to 2005. We compared patient survival with historical data for LCNEC patients treated without platinum-based adjuvant chemotherapy after surgery. Results. There were no differences in age, gender, surgical methods, and staging between the adjuvant chemotherapy group and the control group. Median follow-up was 33 months for the adjuvant group and 42 months for the control group. Of the 15 patients in the adjuvant chemotherapy group, 2 patients had disease recurrence and 1 died of interstitial pneumonia. The overall survival rate at 2 and 5 years of patients with adjuvant chemotherapy was 88.9%. The overall survival rate between patients with adjuvant chemotherapy and the historical control group was significantly different. Conclusions. Adjuvant chemotherapy consisting of cisplatin and VP-16 after surgery appears promising for the improvement of the prognosis for patients with completely resected LCNECs, and it should be evaluated further in larger multi-institutional trials.

The distinction between pulmonary large cell neuroendocrine carcinoma and small cell carcinoma is difficult in some cases. Some propose that these carcinomas should be classified as one high-grade neuroendocrine carcinoma. We examined biological features of small cell carcinoma (n=23), large cell neuroendocrine carcinoma (n=17), and classic large cell carcinoma (n=12). The average ratio of nuclear diameter of the tumor cells to that of lymphocytes for small cell carcinoma was smaller than that for large cell neuroendocrine carcinoma (P < 0.0001). The frequencies of the expressions of CD56, mASH1, TTF-1, and p16 were higher and that of NeuroD was lower in small cell carcinoma than in large cell neuroendocrine carcinoma. The frequency of loss of heterozygosity at 3p was higher in high-grade neuroendocrine carcinomas than in classic large cell carcinoma (P=0.0002). Allelic losses at D5S422 (5q33) were more frequent in small cell carcinoma than in large cell neuroendocrine carcinoma (P=0.0091). Mean fractional regional loss indices of the tumors were 0.38, 0.65, and 0.72 for patients with classic large cell carcinoma, large cell neuroendocrine carcinoma, and small cell carcinoma, respectively (P=0.0003). Five-year overall survivals of patients with classic large cell carcinoma, large cell neuroendocrine carcinoma and small cell carcinoma in stage I were 67, 73, 60%, respectively. Patients with NeuroD expression had better survivals, and those with p63 expression had poorer survivals in large cell neuroendocrine carcinoma. Patients with TTF-1 expression had poorer survivals in small cell carcinoma. Our data suggest that large cell neuroendocrine carcinoma and small cell carcinoma are different morphologically, phenotypically, and genetically, although there are some overlapping features. Although further studies are needed to analyze the biological behavior of high-grade neuroendocrine carcinomas including sensitivity to chemotherapy, the pathological distinction of large cell neuroendocrine carcinoma from small cell carcinoma may be necessary to treat the patients with neuroendocrine tumors.

Benign metastasizing leiomyomaは子宮平滑筋腫の既往のある女性の肺に異型の乏しい平滑筋腫が多発する疾患である.肺への転移例が多く認められるが,深部組織,骨,リンパ節,大網,腸間膜,脊髄,心臓への転移も報告されている.今回我々は子宮筋腫手術12年後に皮下転移,多発肺内転移を呈した症例を経験したので,若干の文献的考察を加え報告する.

Background: Most patients with pathologic stage Ia non - small cell lung carcinoma have a good prognosis, and adjuvant chemotherapy is currently not being used in the management of this stage of the disease. However, if significant negative prognostic factors become evident in patients with pathologic stage Ia non - small cell lung carcinoma, patients with negative prognostic factors should have adjuvant treatment after surgery. Methods: We analyzed 335 cases of pathologic stage Ia non - small cell lung carcinoma treated between 1988 and 2003 by complete resection. The pathologic stage Ia non - small cell lung carcinomas comprised 259 adenocarcinomas, 65 squamous cell carcinomas, and 11 large cell neuroendocrine carcinomas. The prognostic impact of various clinical variables was investigated by the Cox proportional hazards multivariable regression model. Results: Univariate analysis showed that large cell neuroendocrine carcinoma histology, old age, large tumor size, male gender, and smoking predicted poorer overall survival. Large cell neuroendocrine carcinoma had a significantly poorer prognosis than other non - small cell carcinomas. Multivariate analysis revealed that large cell neuroendocrine carcinoma was predictive of poorer overall survival ( P =.0200, hazard ratio 2.787). Conclusions: Large cell neuroendocrine histology has a significant adverse prognostic impact on pathologic stage Ia non - small cell carcinoma. Therefore, surgical resection alone represents insufficient treatment for large cell neuroendocrine carcinoma, even for pathologic stage Ia disease.

Primary leiomyosarcoma of the pulmonary artery is extremely uncommon and its cause remains unclear. We document a case of pulmonary artery leiomyosarcoma expressing Epstein-Barr virus DNA sequences in an immunocompetent patient 4 years after symptomatic Epstein-Barr virus infection.