廣島 健三

BACKGROUND. Both genetic and epigenetic changes in nonsmall cell lung cancer (NSCLC) are known to be a common event. METHODS. Mutations in the epidermal growth factor receptor gene (EGFR), HER-2, and KRAS and the methylation profile of 9 genes for NSCLC were analyzed and correlated with clinical and histologic data. RESULTS. Thirty-nine EGFR, 4 HER-2, and 6 KRAS mutations were found in 150 NSCLC cases, with the methylation percentages of the genes ranging from 13% to 54%. Most mutations were present in adenocarcinomas, but mutations of the 3 genes were never found to be present in individual tumors. The frequency of methylation for all the genes was correlated with the Methylation Index, a reflection of the overall methylation pattern (all genes, P <=.01), Supporting the presence of the CpG island methylator phenotype (CIMP) in NSCLC. On the basis of the methylation profile, CRBP1 and CDH13 methylation were good indicators of CIMP in NSCLC, and were correlated with a poorer prognosis in adenocarcinomas. Mutations in EGFR, HER-2, and KRAS were found to be present exclusively, whereas methylation tended to be present synchronously. A comparison of mutation and methylation demonstrated that the EGFR mutation had an inverse correlation with methylation of SPARC (secreted protein acidic and rich in cysteine), an extracellular Ca2+-binding matricellular glycoprotein associated with the regulation of cell adhesion and growth, and the p16(INK4A) gene. CONCLUSIONS. The findings of the Current study suggest that adenocarcinoma cases with CIMP have a poorer prognosis than adenocarcinoma cases without CIMP, and the EGFR mutation was shown to have an inverse correlation with methylation of SPARC and the p16(INK4A) gene in NSCLC.

Background: Obtaining a definitive preoperative diagnosis plays a critical role in deciding upon the treatment approach for lung carcinoma. However, success in making definitive diagnoses of small primary lung cancers will require new approaches because these cancers are difficult to detect using standard biopsy procedures. Methods: We evaluated the results of morphologic definitive diagnosis together with various clinical factors in 1003 primary lung cancers resected surgically. Patients underwent transbronchial brushing, fine needle aspiration cytology, forceps biopsy, and/or forceps biopsy-stamp cytology for preoperative diagnoses, in conjunction with the use of Diff-Quik to confirm that hits had been made on the radiographic shadows before terminating the examinations. Results: Sensitivities of the diagnostic procedures for primary lung cancers were as follows: 64.8% for brushing, 56.1% for transbronchial forceps biopsy, 72.0% for transbronchial forceps biopsy-stamp cytology, and 86.4% for transbronchial fine needle aspiration. The four transbronchial biopsy procedures had a combined overall sensitivity of 92.7%. In patients with peripheral lung cancers of 2 cm or less in diameter, transbronchial fine needle aspiration had a sensitivity of 75.9%, which was the highest sensitivity for all transbronchial examinations. In the subset of 296 patients who underwent all four transbronchial biopsy examinations, transbronchial fine needle aspiration had the highest sensitivity of preoperative diagnosis of all the transbronchial examination methods. Conclusions: The sensitivity of preoperative cytological diagnosis for primary lung cancers, especially transbronchial aspiration cytology, is high. Transbronchial fine needle aspiration cytology is useful for the preoperative diagnosis of primary lung cancer.

A 33-year old woman was referred to our hospital with dyspnea on exertion. She had a history of recurrent spontaneous pneumothraxes. A giant bulla and many bullae were observed on chest computed tomography. She underwent a lung biopsy and bullectomy to obtain a definitive diagnosis and to decrease dyspnea. In pathological findings, a hematoxylin-eosin stained section of the lung biopsy showed smooth muscle proliferation at the alveolar wall and bronchiole immunohistochemical staining of HMB45 revealed the proliferation of LAM cells. After the operation, dyspnea and hemoptysis temporarily appeared. The chest X-ray and chest CT revealed ARDS. However, she improved after the administration of steroids. She underwent progesterone therapy, but her pulmonary functions have deteriorated.

目的:下咽頭癌は早期に特異的な症状が発現しにくいため, 確定診断時に進行癌であることが多く早期発見が望まれている.早期下咽頭扁平上皮癌発見における喀痰細胞診の有用性の評価を目的とし, その細胞像について検討した.<BR>対象と方法:平成5-15年度の喀痰集検受診者11万237人からの発見癌201例のうち, 下咽頭扁平上皮癌が確定診断された8例を対象とした.同症例の蓄痰標本に出現した中等度異型以上の異型扁平上皮細胞, および扁平上皮癌細胞について細胞学的検討を行った.<BR>成績:発見された下咽頭癌の病期は, I期: 3例, III・IV期: 5例であった.喀痰中の異型上皮細胞および癌細胞数は, I期: 50.8個, III期: 333.3個, IV期: 427.4個で, I期癌では進行期癌と比較し有意に少数であった (P<O.05).さらに異型上皮細胞および癌細胞のタイプ別出現比率では, 傍基底型異型細胞の出現が特徴的であり, また病期が進行しても変性萎縮異型細胞の顕著な増加は認められなかった.<BR>結論:細胞量が十分に塗抹された喀痰標本をより詳細にスクリーニングすることで, 下咽頭癌が早期発見される可能性もあり, 喀痰細胞診の有用性が示唆された.

We herein report a resection of a superior sulcus tumor in a patient with idiopathic thrombocytopenic purpura. A resection of the left upper lobe of the lung, left subclavian artery, and left first to third ribs, as well as a reconstruction of the left subclavian artery, were performed. Postoperative hemorrhaging was controlled due to preoperative high-dose intravenous immunoglobulin therapy and a platelet transfusion both during and following surgery. The resected tumor was diagnosed to be a pulmonary pleomorphic carcinoma, which was pathologically determined to be T3N0M0-Stage 2B. The patient remained in good condition for 20 months following the surgery; however, he eventually died due to bone metastases.

The molecular mechanisms for frequent epidermal growth factor receptor (EGFR, a tyrosine kinase [TK]) and HER2 (the preferred coreceptor of EGFR) overexpression in lung cancer are poorly understood. Recent studies have shown the mutations of the TK domain in EGFR and HER2 to be present in lung cancer. The purpose of this study was to investigate the relationship between mutation status and expression of EGFR and HER2 in lung cancer. Immunostaining took place for EGFR and HER2, and mutational analyses for EGFR, HER2, and KRAS (a signaling protein) were conducted using 130 resected lung cancer specimens. Thirty-seven EGFR mutations (28%) and 8 HER2 mutations (6%), both of the TK domains, and 5 KRAS (4%) mutations were found, whereas 73 (56%) EGFR and 47 (36%) HER2 overexpressions were found. EGFR overexpression was seen more frequently in tumors with EGFR mutation (28/37, 76%) than in tumors without EGFR mutations (45/93, 48%; P =.0059). No correlation was found between HER2 mutation and HER2 expression. Multivariate regression revealed that EGFR mutation, adenocarcinoma histology, and HER2 expression were associated with EGFR expression, whereas female sex, EGFR mutation, and EGFR expression were associated with HER2 expression. In conclusion, EGFR and HER2 overexpression is frequent in lung cancer, and EGFR overexpression correlates with the EGFR TK domain mutations. (c) 2005 Elsevier Inc. All rights reserved.

Malignant tumors induce development of their own stromal tissues during the processes of growth, progression and metastasis. Since the vascular architecture among the various stromal elements is well known to facilitate tumor growth and has been a target of therapy, the importance of stromal fibroblasts has recently been established. To elucidate the interaction between the tumor and its stromal fibroblasts, the present study took advantage of a unique experimental model consisting of a human small-cell lung cancer cell line, WA-ht, and its mouse stromal fibroblast cell line, WA-mFib, both originally derived from a xenograft tumor in a mouse subcutis. Co-culture with the WA-mFib cells significantly augmented the plating efficiency of WA-hT cells in vitro, and their co-inoculation in nude mice shortened latency and tumor doubling time. Histochemical detection of B-gal, transfected into WA-mFib cells, demonstrated their contribution to the nude mouse xenograft tumor formation as its tumor stroma. Elevated hepatocyte growth factor (HGF) from fibroblasts followed by elevated production of vascular endothelial growth factor (VEGF) from both tumor cells and fibroblasts were demonstrated by ELISA in supernatants of their co-culture, accompanied by enhanced colonogenicity of the tumor cells; these enhanced features were not observed in their respective monocultures. Antisense oligonucleotides to HGF cancelled these augmentation effects with co-culture. The findings highlight the substantial roles of tumor stromal fibroblasts, interacting with soluble growth factors, in promoting the malignant propensity of the tumor.

Cytochrome P450 2E1 (CYP2E1) catalyzes the metabolic activation of the procarcinogen, N-nitrosodimethylamine, and cytotoxic carbon tetrachloride compounds. A tandem repeat polymorphism in the 5'-flanking region of the CYP2E1] gene was investigated in non-small cell lung carcinoma (NSCLC) patients to clarify the relationship between CYP2E1 gene polymorphism and lung cancer susceptibility. Blood samples were taken from 236 healthy control subjects (192 males and 44 females) and I I I patients (78 males and 33 females) who underwent surgery for NSCLC in Japan. DNA was isolated from these samples and the 5'-flanking region of the CYP2E1 gene was amplified by polymerase chain reaction and examined for tandem repeat polymorphisms using DNA fragment analysis. Sequence analysis confirmed the presence of three alleles, A2, A3, and A4 (361, 367, and 457 bp, respectively), with:four genotypes observed in the lung cancer group and five genotypes in the control group. There was a statistically significant difference in genotype distribution between the lung adenocarcinoma and control group (P=0.0088, A4/A4 vs. non-A4/A4). In the lung adenocarcinoma group, the univariate risk estimates for the A4/A4 subgroup compared to the most common subgroup (A2/A2) was 4.300 (95% confidence interval = 1.358-13.618, P=0.0131). We conclude that the A4/A4 genotype of the 5'-flanking region of CYP2E1 was significantly more frequent in lung adenocarcinoma cases than in healthy controls and, therefore, may be involved in the development of lung adenocarcinoma.

A 69-year-old woman was admitted with dyspnea on effort and left lung atelectasis on chest X-ray. Fiberoptic bronchoscopy revealed a complete obstruction of the left main bronchus due to a polypoid lesion. This lesion was diagnosed to be a schwannoma arising from the left lower bronchus. Bronchoscopic treatments were performed with electrosurgical snaring and the intratumoral injection of 99.5% ethanol. These treatments were performed once per week for 4 weeks, then were followed with a one-time application of semiconductor laser cautery. These treatments opened the airway and restored the left lung expansion. However, a residual tumor remained at the bifurcation of the left basal bronchus and B6. A cautious follow-up was conducted because schwannoma is a potentially benign tumor. A follow-up bronchoscopic examination at 21 months revealed a regrowth of the residual tumor. A complete resection using a left S6 sleeve segmentectomy was thus performed. The pathologic diagnosis of the tumor was benign schwannoma. There were no complications and no evidence of disease recurrence has been observed after the surgery.

目的.XVIII型コラーゲンは, 血管新生抑制因子の一つであるエンドスタチンの前駆物質であり, 血管および上皮基底膜を構成する細胞外マトリックス蛋白の構成成分である.本研究は非小細胞肺癌におけるXVIII型コラーゲン発現の予後因子としての重要性を明らかにすることを目的とした.対象と方法.1994〜2000年に切除された非小細胞肺癌306例を対象とした.男女比は215:91, 年齢は31〜85歳(平均64.8±9.8歳).扁平上皮癌114例, 腺癌179例, 大細胞癌13例.術後病期I期130例, II期47例, III期113例, IV期16例であった.抗XVIII型コラーゲン抗体にて免疫染色を行い, 臨床的因子(年齢, 性別, 組織型, T因子, N因子, 術後病期)との相関ならびに予後を統計学的に解析した.結果.抗XVIII型コラーゲン抗体による切除標本の染色結果は, 陰性92例, 陽性119例ならびに強陽性95例であった.全体の5年生存率は陰性例70.4%, 陽性例56.5%ならびに強陽性例40.3%で, 強陽性群, 陽性群ではいずれも陰性例に比べ有意に予後不良であった(P<0.0001).多変量解析でも, 免疫染色によるXVIII型コラーゲン発現は独立した予後因子として選択された.結論.非小細胞肺癌におけるXVIII型コラーゲンの発現は69.9%の症例に認められ, XVIII型コラーゲンの発現は予後を強く決定づける因子と考えられた.

Autofluorescence bronchoscopy is an important tool for the early detection of preinvasive bronchial lesions. However, autofluorescence bronchoscopy has difficulty distinguishing between preinvasive lesions and other benign epithelial changes. A new autofluorescence imaging bronchovideoscope system (AFI) comprises three signals, including an autofluorescence (460-690 nm) on excitation blue light (395-445 nm) and two different bands of reflected Light: G' (550 nm) and R (610 nm). We hypothesized that color analyses of these three wave lengths would improve our ability to differentiate between inflammation and preinvasive lesions. In order to prove this hypothesis and to evaluate the efficacy of AFI for detecting preinvasive lesions, we conducted a prospective study. A total of 32 patients with suspected or known lung cancer were entered into this study. Conventional white tight bronchovideoscopy (WLB) and light induced fluorescence endoscopy (LIFE) were performed prior to using AFI. WLB and LIFE detected 62 lesions, including Lung cancers (n = 2), squamous dysplasias (n = 30), and bronchitis (n = 30). By utilizing AFI, 24 dysplasias and 2 cancer lesions were magenta in color, white 25 bronchitis lesions were blue. The sensitivities of detecting dysplasia by LIFE and AFI were 96.7% and 80%, respectively. The specificity of AFI (83.3%) was significantly higher than that of LIFE (36.6%) (p = 0.0005). We conclude that AFI appears to represent a significant advance in distinguishing preinvasive and malignant lesions from bronchitis or hyperplasia under circumstances where LIFE would identify these all as abnormal lesions. (c) 2004 Elsevier Ireland Ltd. All rights reserved.

The aim of this study was to compare the diagnostic yield of flexible video bronchoscopy (FVB) and autofluorescence bronchoscopy (i.e. lung imaging fluorescence endoscopy (LIFE)) in 151 patients at a high risk of lung cancer and with moderate dysplasia or worse on sputum cytology mass screening. Findings from FVB and LIFE were classified as either normal, abnormal or suspicious for cancer. Endobronchial biopsies (EBX) were obtained from abnormal or suspicious areas on FVB and/or LIFE, or randomly when FVB and LIFE were normal. Moderate dysplasia and worse were defined as pathologically positive. Overall, 83 out of 343 (24%) EBX were pathologically positive. The sensitivity of FVB was 72% and LIFE 96%. Relative sensitivity of LIFE over FVB was 1.33. Specificities of FVB and LIFE were 53 and 23%, respectively. The numbers of pathologically positive EBX from sites designated normal, abnormal or suspicious were: from FVB, 23 out of 162 (14%), 37 out of 151 (25%) and 23 out of 30 (77%); from LIFE, three out of 69 (4%), 44 out of 212 (21%) and 36 out of 62 (58%). In normal or abnormal areas at FVB, there was a significant increase in the yield of EBX guided by abnormal and suspicious sites noted at LIFE. In conclusion, endobronchial biopsies of suspicious findings from lung imaging fluorescence endoscopy and flexible video bronchoscopy have a good diagnostic yield. Lung imaging fluorescence endoscopy is more useful when flexible video bronchoscopy is either normal or abnormal.

We report a case of lymphangioleiomyomatosis (LAM) with a giant bulla. A 33-year-old woman was referred to our department for treatment of dyspnea. Chest computed tomography showed a giant bulla with many smaller bullae. To obtain a definitive diagnosis and relieve the dyspnea, we performed a lung biopsy and bullectomy, after which her symptoms and pulmonary function improved remarkably. She was commenced on progesterone, which improved her condition even further. This case report retrospectively follows the progression of her disease from the onset of symptoms 5 years before she was referred to us for treatment.

SPARC (secreted protein acidic and rich in cysteine) is an extracellular Ca2+-binding matricellular glycoprotein associated with the regulation of cell adhesion and growth. We investigated loss of expression of SPARC gene and promoter methylation in lung cancers and correlated the data with clinicopathological features. We observed loss of SPARC expression in 12 of 20 (60%) lung cancer cell lines. Treatment of expression-negative cell lines with a demethylating agent restored expression in all cases. Methylation frequencies of SPARC gene were 55% in 20 lung cancer cell lines. Primary tumours had methylation at a rate of 69% (119 of 173), while nonmalignant lung tissues (n = 60) had very low rates (3%). In lung adenocarcinomas, SPARC methylation correlated with a negative prognosis (P = 0.0021; relative risk 4.65, 95% confidence interval 1.75-12.35, multivariate Cox's proportional-hazard model). Immunostaining revealed protein expression in bronchial epithelium (weak intensity) and in juxtatumoral stromal tissues (strong intensity) accompanied by frequent loss in cancer cells that correlated with the presence of methylation (P&lt;0.001). Our findings are of biological interest and potentially of clinical importance in human lung cancers.

拡大気管支ビデオスコープ(HMB)を用いsquamous dysplasia (Dys)を観察, 内視鏡下のangiogenesisを検討した.1. 気管支ビデオスコープ(BF240)とLIFE施行後, HMBにて気管支粘膜の観察を行い, 画像解析装置にて血管面積比を算出した.2. BF240, LIFE, HMB観察後, 光源をNarrow Band Imaging (NBI)に切り換えた.NBIでは, Blue 1 : 400〜430nm, Blue 2 : 420〜470nm, Green : 560〜590nmの狭帯域フィルターに変更, Blue 1は, Hbの吸光度に一致し血管構造が鮮明に描出される.3. 通常倍率と拡大倍率の対物レンズを搭載, 同時2画面による通常観察と拡大観察が可能なDual HMBを用いた.1. Dysでは, 気管支粘膜の微細血管網が増生しており, 15部位(71.4%)で血管網の増生, 蛇行が顕著であった.血管面積比では, 正常気管支上皮, 気管支炎, squamous dysplasiaの順に増加し, 有意差を認めた(p<0.0001). 2. DysのNBI-Blue 1画像では詳細な微細血管, 微細血管網, 点状血管の観察が可能で, 点状血管は, 形態計測の結果angiogenic squamous dysplasia (ASD)のcapillary loopの径と一致した.3. Dual HMBではDys 12部位で明瞭な血管網の増生, 6部位で軽度の血管網を認めた.HMBは, 特にNBIを用いることでDysの血管網増生, ASDのcapillary loopを捉えることが可能で, Dysのangiogenesisを内視鏡的に確認し得る.

Background. The aim of this study was to clarify preoperative lung function as a prognostic factor for the long-term survival of, and to discuss the appropriateness of lobectomy for, patients with stage I non-small cell lung carcinoma who have poor preoperative pulmonary function. Methods. The study group consisted of 402 lobectomized patients with stage I non-small cell lung carcinoma treated by complete resection from 1985 to 1997. Preoperative percent forced vital capacity [(forced vital capacity/predicted forced vital capacity) x 100], FEV1% [(forced expiratory volume in 1 second/forced vital capacity) x 100], arterial carbon dioxide tension, and smoking were statistically analyzed as prognostic factors together with other host and tumor biologic factors. Results. Multivariate analysis demonstrated that tumor size (p &lt; 0.0001) was the most significant prognostic factor for survival from primary lung cancer. Age (p &lt; 0.0001), sex (p = 0.0036), and FEV1% (p = 0.0046) were found to be independent prognostic factors for survival from death by nonprimary lung cancer-related causes. Smoking was highly correlated with FEV1% (correlation coefficient = -0.511; p &lt; 0.0001). The 100 patients with a preoperative FEV1% less than 70% included 34 patients with nonprimary lung cancer-related deaths, whereas the 302 patients with an FEV1% of 70% or greater included only 23 patients (p &lt; 0.0001). Conclusions. Along with tumor size, FEV1% is the most significant prognostic factor for patients with stage I non-small cell lung carcinoma with regard to survival from death by other causes. Lobectomy may not be preferred as an appropriate surgical modality for patients with stage I non-small cell lung carcinoma with small peripheral nodules who exhibit poor pulmonary function, especially lowered FEV1%. (C) 2004 by The Society of Thoracic Surgeons.

自家蛍光に2つの反射光を組み合わせて観察する電子蛍光気管支鏡(AFI)の有用性について報告する. 2003年10月より2004年5月までに75症例に対し検査を行った. 男性73名(喫煙者70名, 平均年齢68.3±8.4歳), 検査理由は喀痰異常症例60例, 胸部異常影9例, その他血痰6例であった. 今回使用した改良型AFIは通常の電子スコープと同様の使用方法にて観察生検が可能である. 光源の切り替えをワンタッチで行い通常の観察から蛍光観察へ, また蛍光から通常観察へ簡便に移行できる. 白色および蛍光で異常所見部位を記録し異常が疑われる部位は生検を行った. 43箇所より生検:し12箇所(11症例)の肺癌と1例の上咽頭癌および11箇所のdysplasiaを検出した. 白色電子スコープによる癌およびdysplasiaの検出の感度は23/25(92%)特異度は7/18(38.8%)で, 蛍光では感度24/25(96%)特異度12/18(66.6%)であった. また, 中枢型肺癌12症例については手術(気管支形成術)6例, 重粒子治療3例, 化学療法3例, LASER治療1例を施行した.