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Early prediction of therapeutic outcome is important in determining whether the ongoing therapy is beneficial. In addition to anatomical response determined using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, recent studies have indicated that change in tumor glucose use on or after treatment correlates with histopathologic tumor regression and patient outcomes. This Perspective discusses the use of 18 F-fluorodeoxyglucose-positron emission tomography (FDG-PET) for pharmacodynamic evaluation in a very early phase of treatment to predict clinical outcomes in patients with advanced non–small-cell lung cancer. We conducted a study to assess whether early metabolic response determined using FDG-PET correlated with clinical outcomes in patients treated with gefitinib or those treated with carboplatin plus paclitaxel (CP). Early metabolic response to gefitinib, but not CP, correlated with the late metabolic response, anatomical response, progression-free survival, and even overall survival. A rapid effect of molecular targeted agents might not be aptly evaluated using the conventional criteria, eg, RECIST, in a very early phase of treatment before volumetric shrinkage of the tumor. Based on the findings of several studies, and on the findings from our study, use of FDG-PET might enable prediction of clinical outcomes at a very early stage of treatment, especially in patients treated with molecular targeted agents with rapid clinical efficacy.

Small molecule inhibitors targeting epidermal growth factor receptor (EGFR) are known to be active against non-small cell lung cancer (NSCLC) although the pharmacodynamics of these agents on malignant pleural effusion (MPE) remains unclear. Here we describe a case of lung adenocarcinoma with massive MPE treated successfully by gefitinib and chest drainage. Using sequential MPE samples before and during gefitinib therapy, the morphological changes and apoptosis of cancer cells were analyzed. Apoptosis of cancer cells was detected as early as 4 hours on, but not before, gefitinib therapy, suggesting that the pharmacodynamic assessment of such molecular targeting agents might be feasible for MPE.

Introduction The aim of this study was to determine and evaluate the recommended dose of docetaxel in combination with a novel oral 5-fluorouracil analogue S-1 and evaluate the efficacy and safety in patients with previously treated non-small cell lung cancer. Methods In phase I, patients with previously treated non-small cell lung cancer were treated with docetaxel (starting dose 40 mg/m 2 ) intravenously on day 1 and oral administration of S-1 at a fixed dose of 80 mg/m 2 on days 1 to14 every 3 weeks. The recommended dose was the dose level preceding the maximum tolerated dose; once determined, patients were enrolled in phase II. Results The recommended dose of docetaxel was 40 mg/m 2 in combination with S-1 80 mg/m 2 /d. Of 30 patients enrolled in phase II part, 29 patients were eligible and analyzed. No complete response and 7 (24.1%) partial responses were observed, for an overall response rate of 24.1% (95% confidence interval, 10.3-43.5%). Median overall survival was 11.8 months. The 1-year survival rate was 42%. The grade 3 to 4 hematologic toxicities were neutropenia (34.5%), leukopenia (20.6%), and anemia (10.3%). The grade 3 to 4 nonhematological toxicities included fever 2 (6.9%), diarrhea 1 (3.4%), stomatitis 1 (3.4%), cerebral infarction 1 (3.4%), and pneumonitis 1 (3.4%). There was one treatment-related death due to relapse of drug induced pneumonitis. Conclusions This combination chemotherapy is highly active and well tolerated in previously treated patients with non-small cell lung cancer. These results are encouraging and warrant additional investigation.

目的 : 自動血液塗抹装置が喀痰細胞診標本作製に有益かどうかの検討を目的とした.方法 : 喀痰融解法で処理した肺癌症例45例の喀痰を対象とした. 自動血液塗抹装置はGeometric Data社のヘマプレップ (以下HP) を使用した. 液状化した検体を遠心後, 沈渣をHPを使って塗抹した. 塗抹面6cmを癌細胞の集積を知るために2cmごとに区分し, 塗抹開始位置よりA, B, C領域とした. HPの塗抹速度をレベル0.5から0.5間隔で8段階まで上げ, 各塗抹速度における細胞分布と癌細胞のA, B, C領域への出現状況について検討した. またHP法と通常法の癌細胞のA, B, C領域への出現状況について比較検討した.成績 : HPは塗抹速度0.5～2で細胞が均一に分布する標本の作製が可能であり, 塗抹速度1.5でB領域の平均癌細胞数はA, C領域よりも104%高く (p

目的 : Adobe AcrobatをTelecytologyに用いることが有益であるか検討することを目的とし, 転送ファイルを用いたモニター画面による診断 (モニター細胞診断) の成績を通常の顕微鏡診断 (細胞診・生検組織診) と比較した.方法 : 呼吸器検体56例を対象とした. デジタルカメラで撮影した異型細胞画像と報告書, 症例一覧をPDFに変換しコメントを付加後, デジタルIDによるセキュリティを設定し電子メールで送信した. 細胞診専門医はモニター細胞診断を行い結果を電子メールで返信した.成績 : 診療呼吸器検体で顕微鏡細胞診断陽性27/30例をモニター細胞診断でも陽性と診断した. 肺がん検診検体で顕微鏡細胞診断C, D例は全例モニター細胞診断でも一致した. 推定組織型の一致率は腺癌11/12例, 扁平上皮癌6/7例, 小細胞癌3/3例, 大細胞癌1/1例, LCNEC1/1例, 尿路上皮癌の肺転移1/1例と良好であった. 生検組織診との一致率は顕微鏡細胞診断22/25例, モニター細胞診断24/25例で差を認めなかった.結論 : 安価で強力なセキュリティ機能と豊富な注釈機能をもつAdobe AcrobatをTelecytologyに用いることは有用であると考える.

Background: It is important to detect preinvasive bronchial lesions before they become invasive cancer, because detection of early cancer is expected to lead to a cure. Autofluorescence bronchoscopy is a useful device in the detection of preinvasive and cancerous lesions. Recently, a new autofluorescence bronchoscopic system, autofluorescence imaging (AFI) system, has been developed. Objectives: We evaluated the efficacy of AFI in the diagnosis of precancerous and cancerous lesions. Methods: A total of 31 patients underwent both conventional white-light bronchoscopy (WLB) and AFI from January 2002 to September 2004. We evaluated autofluorescence findings using a four-point scale: AFI-I, II, III, and B. The findings in WLB were evaluated on a three-point scale: WLB-I, II, and III. Abnormal areas by WLB and AFI were biopsied for histopathological examinations. Results: A total of 64 lesions were evaluated. When the AFI-III finding was regarded as positive in AFI and WLB-III as positive in WLB, sensitivity for severe dysplasia or worse was 94.7% with AFI and 73.7% with WLB, respectively. Conclusions: AFI is an effective system for the detection of precancerous and cancerous lesions.

Background Fluoroscopy-guided bronchoscopy is a safe and routine method used to obtain a histologic or cytologic specimen of peripheral lung nodules, but it has low sensitivity in diagnosing malignant tumors. Although feedback from rapid cytology tests are expected to improve diagnostic rates, the value of the routine use of rapid cytology tests has not been established. Materials and Methods We prospectively studied 657 patients with suspected peripheral malignant lung lesions on chest computed tomography who underwent fluoroscopy-guided bronchoscopy between January 2002 and December 2004. Rapid on-site cytopathologic examinations (ROSE) were performed during bronchoscopic examinations. The additional approach to the lesions was performed immediately after conventional bronchoscopic examinations when ROSE was not considered diagnostic. Results There were 528 patients diagnosed as having malignant lesions. In 477 of these patients (90.3%), final malignant diagnosis was established by the initial bronchoscopy. Among these, 84 patients (15.9%) were diagnosed only with the additional feedback from ROSE. Of 240 peripheral lesions ≤2 cm, 174 were found to be malignant. Without ROSE, 110 (63.2%) of peripheral malignant lesions were diagnosed by bronchoscopy. The integration of ROSE enabled us to diagnose an additional 40 patients (23.0%) by bronchoscopy. ROSE improved diagnostic yield independent of the site and histology of the lesions and experience of the operators. Conclusion ROSE increased the diagnostic yield of bronchoscopy from 74.4% to 90.3% and therefore is an effective reinforcement in bronchoscopic diagnosis of peripheral pulmonary malignancies. The use of ROSE in routine bronchoscopy should be encouraged.

我が国の市町村で行われている肺癌検診は, 年間700万人以上が受診しているが, 肺癌発見数は3600人弱 (発見率51/10万人) で, 受診者の増加に伴っていない. 都道府県別にみると発見率は最大111.5, 最小18.5でその差は最大6.2倍とバラツキは大きかった. 市町村別に見ると, 精検受診率や精検完了率が30%を下回る市町村も認められ, 受診者数5000人以上の市町村の6.3%で過去2年間肺癌は1例も発見されていなかった. 肺癌検診は外的精度管理の枠組みがないまま, 急速に普及していった. 市町村事業と位置づけられてからは, 実施数や費用のみが問題とされており, 精度については検討されておらず, 受診者にも精度に関する情報は提供されていない. 今後は対象者や精度管理指標の基準値を盛り込んだ運用指針の見直しと, 第3者機関による検診成績の情報公開が必要である.

目的. 大阪肺癌集検研究班が担当してきた肺癌集検での喀痰細胞診の成績を検討した.対象と方法.大阪府下8市町の一般住民を対象として, 1981年より胸部X線間接撮影と喀痰細胞診による肺癌検診を行ってきた.喀痰細胞診は40歳以上で喫煙指数400以上の者, および血痰の自覚症状を有する者 (高危険群) を対象とした.成績.1981年から2000年の20年間の受診者総数は297,628人で, この中から235人の肺癌を発見した.喀痰細胞診を行った高危険群からは, 130人の肺癌が発見され扁平上皮癌は64人であった.そのうち36人が肺門部扁平上皮癌で喀痰による発見は34人であった.喀痰細胞診で発見された扁平上皮癌は10万対110と20年間で変わらないが, 肺門部扁平上皮癌が1996年以降では約1/2に低下した.結論喀痰細胞診は, 肺門部早期扁平上皮癌の発見に不可欠な検査で, 肺癌発見率を上昇させるためには高危険群特に50歳以上の男性の多い集団を対象とした検診を行うべきである.さらに十分な精度管理のもとに喀痰細胞診の精度を高めることが必要である.

Background . Pure ground-glass opacity (PGGO) is a new entity that has been clearly defined on high-resolution computed tomography (CT) during the last half decade. It is important to investigate the natural history of PGGO through long-term observation for the management of this new entity. Methods . We investigated 19 patients with PGGO(s) defined on high-resolution computed tomography and retained as PGGO for more than 2 years. The PGGOs of 11 patients were detected at annual mass screening by low-radiation–dose CT (low-dose CT), 7 at follow-up CT after cancer resection, and 1 incidentally on CT. After long-term observation, 10 of 19 patients underwent operation and 9 are currently being followed-up with CT. Their growth characteristics and histologic findings are reported. Results . The median follow-up period was 32 months, ranging from 24 to 124 months. The sizes of PGGOs at the time of discovery were 4 to 18 mm in largest diameter (average 8.6 mm). During follow-up, the size of PGGO showed no change in 8 patients, increased slightly (up to 5 mm) in 6 patients, and increased by more than 5 mm in 5 patients. Ten patients had limited resection (segmentectomy or wide wedge resection) with negative surgical margin by intraoperative lavage cytology of the resection margin of the lung. Of them, 5 patients had adenocarcinoma, 3 pulmonary lymphoproliferative disorder, and 1 each atypical adenomatous hyperplasia and focal fibrosis. There was no clear tendency between the degree of size change and histology. In all but 1 of 9 patients with follow-up only, the PGGOs showed either no change or only a slight increase within 5 mm in largest diameter. Conclusions . These data suggest that some PGGOs will never progress to clinical disease and would be included in the category of overdiagnosis bias. However, a prior history of lung cancer should significantly raise the index of suspicion, as 4 of 5 proven cancer cases in this small series fell into that category. Because of the difficulties of preoperative and intraoperative histodiagnosis of PGGO, minimally invasive surgery may be appropriate from the viewpoints of both diagnosis and curability.

The histologic types of lung cancer cases diagnosed in 1979-1980 (n=799) and 1987 (n=587) were independently reviewed by two pathologists in order to investigate the reproducibility of the diagnosis of the histologic type when the WHO classification (1981) was used. The specimens from 354 surgical cases and biopsy or cytology specimens from 1032 non-surgical cases were reviewed. The inter-observer agreement was 87.9% (kappa=0.79) for surgical cases and 81.4% (kappa=0.72) for non-surgical cases. When compared to the original diagnosis, the agreement was 86.8% (kappa=0.78) for surgical and 86.4% (kappa=0.79) for non-surgical cases in 1979-1980 and the agreement was 92.8% (kappa=0.87) for surgical and 89.1% (kappa=0.83) for non-surgical cases in 1987. By histologic type, no difference in the agreement was observed except for large cell carcinoma. The distribution of histologic types after the review differed only slightly (less than 6%) from the original distribution. This suggests that in Osaka, Japan, the diagnosis based on the WHO classification (1981) had only a limited influence on the distribution of histologic types, and is not a major reason for the changing trends in lung cancer incidence by histologic type.

Purpose: To evaluate the usefulness of transcutaneous needle biopsy (TCNB). Material and Methods: From May 1988 to December 1994, we performed TCNB under fluoroscopic control in 408 patients with mass lesions of the peripheral lung. The Surecut needle (1.5 mm) was selected mainly because of its ability to obtain specimens large enough for histological examination. Of the 408 patients, 286 had had previous bronchofiberscopic examinations but no definite diagnosis had been reached. Results: A definite diagnosis was obtained by TCNB in 305 (74.7%) of 408 cases (251 malignant neoplasms, 54 benign lesions). In malignant neoplasms, the pathological diagnosis based on cytology and histology together was more reliable than that based on cytology alone. Although the complications of this procedure (such as pneumothorax) were within the range of acceptability, care should be taken to avoid air embolism and the seeding of cancer cells along the needle tract. Conclusion: TCNB with the Surecut needle is a useful procedure with relatively low risk.

Sixty-three patients with extensive-stage small-cell lung cancer were randomized to receive either cyclophosphamide, vincristine, doxorubicin and etoposide (CODE) alone or CODE plus recombinant human granulocyte colony-stimulating factor (rhG-CSF). rhG-CSF administration in support of CODE chemotherapy resulted in increased mean total received dose intensity for all drugs (P = 0.03) with a significant improvement in survival (P = 0.004).

肺腺癌の化学療法に対する効果と細胞形態像を検討した.対象とした原発性肺腺癌26例の化学療法2コース終了後の治療効果はPR9例, NC11例, PD6例であった.細胞形態学的検討には, 擦過あるいは穿刺吸引細胞診のパパニコロウ染色標本を用いて, 癌細胞の核の大きさと形態, クロマチンの染色性, 核小体の形状を観察した.PRが得られた症例に多く出現した腺癌細胞は, 細胞や核が大型で, 大小不同が強く, 核は類円形で微細クロマチンが増量していた.NC症例に多く出現した腺癌細胞は, 細胞および核が小型で, 核形は不整形, クロマチンが不均等疎に分布した.PD症例には粗顆粒状クロマチンを有する腺癌細胞の出現率が高かった.肺腺癌では細胞形態学的検討により, 抗癌化学療法の効果がある程度予想され得ると考えられた.

Early prediction of therapeutic outcome is important in determining whether the ongoing therapy is beneficial. In addition to anatomical response determined using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, recent studies have indicated that change in tumor glucose use on or after treatment correlates with histopathologic tumor regression and patient outcomes. This Perspective discusses the use of (18)F-fluorodeoxyglucose-positron emission tomography (FDG-PET) for pharmacodynamic evaluation in a very early phase of treatment to predict clinical outcomes in patients with advanced non-small-cell lung cancer. We conducted a study to assess whether early metabolic response determined using FDG-PET correlated with clinical outcomes in patients treated with gefitinib or those treated with carboplatin plus paclitaxel (CP). Early metabolic response to gefitinib, but not CP, correlated with the late metabolic response, anatomical response, progression-free survival, and even overall survival. A rapid effect of molecular targeted agents might not be aptly evaluated using the conventional criteria, eg, RECIST, in a very early phase of treatment before volumetric shrinkage of the tumor. Based on the findings of several studies, and on the findings from our study, use of FDG-PET might enable prediction of clinical outcomes at a very early stage of treatment, especially in patients treated with molecular targeted agents with rapid clinical efficacy.

Data on 16 potential risk factors for myelosuppression were assessed in 134 patients who received either vindesine and cisplatin (VP) or mitomycin C, vindesine and cisplatin (MVP) for inoperable stage III or IV non-small cell lung cancer in a randomized trial. Determinant factors for myelosuppression were evaluated by using univariate analysis and the logistic regression model. Recursive partitioning and amalgamation (RPA) was also used to define patient subgroups frequently suffering from severe bone marrow toxicity. Overall, 33 (25%) of 134 patients experienced at least one episode of grade 4 leukopenia. In univariate analysis, age, body surface area, serum creatinine, and pretreatment hemoglobin concentration were associated with severe leukopenia. A multivariate analysis using the logistic regression method showed that only raised creatinine level was an independent predictor for grade 4 leukopenia (P = 0.049). The RPA model generated three distinct subgroups based on age, body surface area and regimen. The three subgroups were distinguished by the frequency of severe (grade 4) leukopenia (50%, 25%, and 2.4%, respectively) (P0.001). Grade 4 leukopenia occurred more frequently in patients in class 3 (ageor = 65 years and treatment with MVP). The RPA model was useful in identifying the risk factors for myelosuppression induced by cisplatin-based chemotherapy, and in defining patient subgroups with elevated risk of toxicity.

We attempted to clarify whether serum levels of a carboxy-terminal fragment of ProGRP, ProGRP(31-98), could serve as a more accurate tumour marker in patients with SCLC than neuron-specific enolase (NSE). ProGRP(31-98) and NSE were measured retrospectively in 101 newly diagnosed untreated patients with SCLC, 111 with non-small-cell lung cancer (NSCLC) and 114 patients with non-malignant lung diseases. ProGRP(31-98) and NSE levels were determined using a sandwich enzyme-linked immunosorbent assay. Sensitivity in SCLC patients was 72.3% for ProGRP(31-98) and 62.4% for NSE. Comparing the area under curve (AUC) of 'receiver operator characteristics' of ProGRP(31-98) with that of NSE, ProGRP(31-98) was the more powerful marker in the diagnosis of SCLC (P = 0.0001). Serum levels of ProGRP(31-98) were higher in the 40 patients with extensive disease than in the 61 patients with limited disease (P = 0.0082). ProGRP(31-98) was significantly higher in patients with pure small-cell carcinoma than in patients with mixed small-cell/large-cell carcinoma (P = 0.02). In serial measurement in 16 patients responding to treatment, a high degree of correlation was noted between the decrease in serum ProGRP(31-98) levels and clinical response during the second week after treatment (P = 0.0045). These results indicate that the determination of serum ProGRP(31-98) levels plays an important role in the diagnosis and treatment of SCLC patients.

Despite recent advances in control of acute emesis following cisplatin-based chemotherapy regimens, delayed emesis remains a significant cause of treatment-related morbidity and factors associated with delayed emesis have not yet been evaluated. A prospective randomised trial was conducted to compare the efficacy and toxicity of granisetron, dexamethasone plus prochlorperazine with granisetron alone in controlling cisplatin-induced delayed emesis and to identify the important factors that influence its occurrence and severity. Seventy cisplatin-naive patients with inoperable solid tumors participated in the trial. Patients who received 80 mg m-2 or 100 mg m-2 of cisplatin were randomly assigned to receive either granisetron 40 micrograms kg-1 intravenously (i.v.) on day 1, dexamethasone 20 mg i.v. on days 2 and 3 and prochlorperazine 5 mg orally thrice daily on days 1-5 or granisetron 40 micrograms kg-1 i.v. on day 1 alone. There was no difference in their acute antiemetic efficacy. A combination regimen was more effective than granisetron alone in preventing delayed symptoms, with superior rates of complete plus major responses of 77% vs 51% (P = 0.0460). Treatment arm was the only determinant factor for the occurrence of delayed emesis (P = 0.0101).

Two phase I trials of irinotecan (CPT-11) in combination with cisplatin were conducted. In both cases, the dose-limiting toxicities were leukopenia and/or diarrhea. During these trials the pharmacokinetics of CPT-11 and its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), were investigated to evaluate the relationship between pharmacokinetic parameters and diarrhea, since this is an unpredictable and severe toxicity of combination chemotherapy using CPT-11 and cisplatin. Twenty-three previously untreated patients with advanced lung cancer were evaluated in the pharmacokinetic study. Ten patients received CPT-11 at 80 or 90 mg/m2 plus cisplatin at 60 mg/m2. The other 13 patients received CPT-11 at 80 or 90 mg/m2 plus cisplatin at 80 mg/m2 with the granulocyte colony-stimulating factor support (2 micrograms/kg x 16 days). CPT-11 was given as a 90-min intravenous infusion on days 1, 8, and 15. Cisplatin was given on day 1. The pharmacokinetics of CPT-11 and SN-38 were analyzed on day 8 during the first course of treatment. The maximum tolerated dose of CPT-11 was 90 mg/m2 in both phase I trials. The severity of diarrhea was best correlated with the peak plasma concentration of SN-38 among the pharmacokinetic parameters tested. In addition, patients with a plasma SN-38 level > 12.4 ng/ml at 1.75 h after the start of CPT-11 infusion had a higher incidence of Eastern Cooperative Oncology Group grade 3-4 diarrhea than those with a lower SN-38 level (P = 0.0003). Stepwise logistic regression analysis identified the SN-38 concentration as a significant contributor to the development of diarrhea (P = 0.0021). We conclude that there is a clear relationship between the SN-38 concentration and diarrhea during chemotherapy with CPT-11 plus cisplatin.

大阪肺癌集検研究班では, 1981年より胸部X線撮影と喀痰細胞診による肺癌検診を実施しているが, 1990年までの10年間に, 喀痰細胞診でDあるいはEと判定された症例の, 精検および追跡調査の結果について報告する. 喀痰を提出した高危険群所属者は, 男女合計16,992人で, 有効喀痰は16,795人が提出した. 要精検者は402例, 原発性肺癌患者は28例であり, したがって陽性反応適中率は6.97%となった. 要精検者のうち判定D群は53例で, 発見された肺癌患者は14例, 陽性反応適中率は26.42%であった. 一方, 判定E群は14例で, 発見された肺癌患者は9例, 陽性反応適中率は64.29%であった. 臨床病期1期肺癌の比率は, 判定D群14例中12例85.7%と, 判定E群6例中2例33.3%よりかなり高かった. また, 判定D群14例中10例は喀痰細胞診単独発見例であり, すべて臨床病期1期であった. 肺癌または喉頭癌以外の判定D群37例, 判定E群3例を追跡し, 5年以上追跡しえた判定D群の16例, 判定E群の2例からは肺癌を発見しえず, Eと判定した2例はfalse positiveと考えられた

Soluble cytokeratin fragment 19 levels were measured with an enzyme immunoassay method developed by Boehringer Mannheim (Enzymun-Test CYFRA 21-1) in the serum of 185 patients with lung cancer [149 with non-small-cell lung cancer (NSCLC) and 36 with small-cell lung cancer (SCLC)] and 97 patients with benign lung diseases in order to determine its clinical usefulness in the diagnosis of lung cancer and follow-up of treatment. We used the cut-off value of 3.5 ng ml-1, established by the Japan CYFRA research group. This cut-off value is based on calculations using the receiver operating characteristic approach instead of using the 95% specificity approach recommended by other authors. The resulting sensitivity and specificity for the group of all lung cancer patients were 65.4% and 84.5% respectively. The sensitivity was highest (76.1%) for squamous cell carcinoma and lowest (44.4%) for SCLC. For NSCLC patients, when CYFRA 21-1 levels were analysed by node (N) factor, patients who presented with mediastinal lymph node metastasis (N2 or N3) demonstrated higher serum CYFRA 21-1 levels (5.6; interquartile range 3.2-11.5 ng ml-1) than patients without mediastinal node metastasis (N0 or N1, 3.9; interquartile range 2.2-10.0 ng ml-1; Mann-Whitney U-test, P = 0.0373). We compared the discriminatory power of CYFRA 21-1 with that of other tumour markers including carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC) and neuron-specific enolase (NSE). The area under the curve (AUC) of each ROC curve was calculated using the CLABROC program for statistical analysis. CYFRA 21-1 appeared to have the most discriminatory power of the markers tested in the diagnosis of lung cancer. In serial measurements of 14 patients receiving chemotherapy or radiotherapy, a high degree of correlation was noted between serum levels of CYFRA 21-1 and extent of clinical response (Wilcoxon, P = 0.0093).

大阪肺癌集検研究班が, 1981-1990年の10年間に行った肺癌検診において, 高危険群所属者22,753人 (受診者の24.5%) に喀痰容器が配布されたが, 回収率は87.3%, 有効検体率は98.7%であった. 精検は76人 (0.4%) で, 精検受診率は98.7%, 精検完了率は96.0%であった.高危険群所属者で, 喀痰細胞診により発見された肺癌は29人 (中心型扁平上皮癌は21人) で, このうち喀痰細胞診のみによる発見は15人 (中心型扁平上皮癌は13人) であった. 中心型扁平上皮癌の, 経年受診7人中6人, その他の受診14人中9人が臨床病期1期であった.喀痰細胞診により発見された肺癌の切除率は48.3%, 絶対的治癒切除率は27.6%であった. 1981-1983年, 1984-1986年, 1987-1990年の3時期にわけて男性中心型扁平上皮癌の標準化発見比を算出した結果, それぞれ1.595, 1.189および0.680となった.

OBJECTIVE The purpose of this study was to evaluate the diagnostic accuracy of bronchoscopy with virtual bronchoscopy (VB) navigation. PATIENTS AND METHODS Forty-two consecutive patients with ≤30-mm diameter peripheral pulmonary shadows or lesions that were difficult or impossible to identify on plain x-rays regardless of size were selected. Before bronchoscopy, multidetector computed tomography was performed, and VB images were created. Then, ultrathin bronchoscopy was carried out with VB navigation followed by conventional 4-mm diameter bronchoscopy. RESULTS Thirty-seven patients were finally enrolled. There were 12 re-examination cases in which earlier conventional bronchoscopy was nondiagnostic. Diagnosis was established in 28 patients (25 malignant and 3 benign lesions), with the diagnostic yield of 75.7% (sensitivity 86.2%, specificity 62.5%, positive predictive value 89.3%, negative predictive value 55.6%, and accuracy 81.1%). The diagnostic yield for lesions of diameter ≤20 mm, 21 to 30 mm, and ≥31 mm were 76.9%, 76.5%, and 71.4%, respectively, for all patients, and 90%, 84.6%, and 83.3%, respectively, for malignant cases. The diagnostic yield in patients who underwent re-examinations was 83.3% for all cases and 88.9% for malignant cases. Three patients had completely invisible shadows on x-ray fluoroscopy and all of these cases were diagnosed on bronchoscopy. No statistically significant difference was observed between the diagnostic yield for the different sizes, pathology, and number of bronchoscopies required. CONCLUSIONS Bronchoscopy with VB navigation yielded high accuracy even for small peripheral pulmonary nodules and shadows that were difficult or impossible to identify on plain x-rays, even for patients in whom earlier conventional bronchoscopy was nondiagnostic.

Background and Methods. Thirty-nine roentgenologically occult lung cancers in 29 patients were treated using photodynamic therapy (PDT) and/or thoracic radiotherapy (TRT) from January 1986 to March 1992. With the exception of one mixed-tumor case, all were squamous cell carcinomas. Results. Initial PDT achieved complete responses in 25 of 39 (64%) of the cancers. Of the remaining 14 cancers that showed less than complete response (CR), 10 of the 14 (71.4%) showed a CR when subsequently treated with TRT, yielding an overall CR rate of 89.7% for cancers treated. Although nine patients experienced recurrences, six of these had CR when treated with PDT and/or TRT. To date, 22 patients are alive. Causes of death in the patients enrolled in this study are as follows: pyothorax (2); heart failure due to pulmonary hypertension (1); chronic respiratory insufficiency (1); subsequent primary brain cancer (1); and subsequent primary lung cancer (1). Only one died of primary lung cancer. Conclusions. These findings suggest that PDT and/or TRT may be used as an alternative to surgery in the treatment of selected patients with roentgenologically occult lung cancer.

PURPOSE Since leukopenia was one of the dose-limiting toxicities of the combination of irinotecan (CPT-11) and cisplatin in a previous trial, we conducted a phase I trial to investigate whether support with recombinant human granulocyte colony-stimulating factor (rhG-CSF) would permit further intensification of the CPT-11 dose in combination with a fixed cisplatin dose. PATIENTS AND METHODS Twenty previously untreated patients with stage IIIB or IV non-small-cell lung cancer (NSCLC) were treated with CPT-11 on days 1, 8, and 15 in combination with cisplatin 80 mg/m2 intravenously on day 1. In addition, rhG-CSF (2 micrograms/kg/d) was administered on days 4 to 21, except on the days of CPT-11 treatment. The starting dose of CPT-11 was 70 mg/m2, and the CPT-11 dose was escalated in 10-mg/m2 increments until the maximum-tolerated dose was reached. RESULTS Diarrhea was the dose-limiting toxicity at 90 mg/m2. Two of six patients experienced either grade 3 or 4 diarrhea or grade 3 leukopenia during the first course of therapy at this dose level. Modest escalation of the CPT-11 dose from 80 to 90 mg/m2 resulted in a marked increase in the plasma concentration of 7-ethyl-10-hydroxycamptothecin (SN-38). Occurrence of diarrhea was well correlated with the peak plasma concentration (Cmax) of SN-38 (P = .035). There were 10 partial responses (50%) among 20 patients. CONCLUSION The recommended dose for phase II studies is 80 mg/m2 of CPT-11, and 80 mg/m2 of cisplatin plus rhG-CSF. With the use of rhG-CSF, the CPT-11 dose can be increased 33% above that in the original regimen (60 mg/m2 of CPT-11 and 80 mg/m2 of cisplatin).

A 66-year-old woman with small-cell lung cancer was administered chemo-radiotherapy consisting of cisplatin (CDDP) and etoposide (ETP). From day 3, she developed vomiting and hyponatremia that persisted despite fluid infusion and cortico-steroid administration. On day 7, the hyponatremia worsened (serum sodium level, 109 mEq/L), leading to disturbed consciousness and convulsions. The serum sodium level gradually increased after intravenous administration of hypertonic saline; on day 22, the serum sodium level was almost normal without any neurological implication. We diagnosed this clinical condition as renal salt-wasting syndrome (RSWS) on the basis of dehydration and high urinary sodium excretion at the onset. In the second course of chemotherapy, CDDP was replaced with carboplatin (CBDCA); consequently, hyponatremia was not observed. Hyponatremia that develops after the administration of CDDP may be due to not only the syndrome of inappropriate secretion of anti diuretic hormone (SIADH) but also RSWS. When RSWS is suspected, hypertonic saline should be administered.

PURPOSE The purpose of this study was to determine the maximum-tolerated dose and the dose-limiting toxicities of CPT-11, a new derivative of camptothecin, in combination with a fixed dose of cisplatin in patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Twenty-seven previously untreated patients with stage IIIB or IV NSCLC were assessable for toxicity, and 26 were assessable for response. The initial dose of CPT-11 was 30 mg/m2 given as a 90-minute intravenous (IV) infusion on days 1, 8, and 15 in combination with cisplatin (80 mg/m2 IV on day 1) given every 4 weeks. The dose of CPT-11 was escalated in increments of 10 mg/m2 until severe or life-threatening toxic effects were observed. RESULTS Significant toxicity was infrequent up to 60 mg/m2 of CPT-11. The maximum-tolerated toxicity was reached at a dose of 70 mg/m2. Three of six patients either had leukocyte count nadirs of less than 2,000/microL or experienced grade 4 diarrhea during the first cycle of therapy at 70 mg/m2. The major toxic effects were leukopenia and diarrhea. There were 14 partial responses (54%) among the 26 patients. CONCLUSIONS A combination of CPT-11 and cisplatin seems to be effective against NSCLC with acceptable toxicities. The recommended dose for phase II studies is 60 mg/m2 of CPT-11 on days 1, 8, and 15, and 80 mg/m2 of cisplatin on day 1 every 4 weeks.

BACKGROUND In the classification recently proposed by the Pathology Committee of International Association for the Study of Lung Cancer, small cell lung carcinoma (SCLC) was divided into three subtypes: pure SCLC, mixed small cell/large cell carcinoma (mixed SC/LC), and combined SCLC. METHODS To examine the clinical utility of this classification, histologic specimens, cytologic specimens obtained by brushing or fine-needle aspiration, and sputum cytologic specimens from 430 patients with SCLC were reviewed. RESULTS When the subtype of SCLC was determined from the biopsy specimen, cytologic specimen obtained by brushing or fine-needle aspiration, and sputum cytologic specimen, the frequency of mixed SC/LC was 25 of 299 (8.4%), 75 of 400 (18.8%), and 8 of 232 (3.4%), respectively. Whatever the diagnostic method, patients with mixed SC/LC showed a poorer response to treatment and worse prognosis than those with pure SCLC: a median survival of 144 days versus 285 days when classified with the use of biopsy specimens; 160 days versus 275 days with cytologic specimens obtained by brushing or fine-needle aspiration; and 47 days versus 259 days with sputum cytologic specimens, respectively. CONCLUSIONS These findings showed that mixed SC/LC should be separated from pure SCLC as a distinctive group and that cytologic studies of specimens obtained by brushing or fine-needle aspiration were sensitive and useful procedures for this purpose.

PURPOSE To evaluate the activity of CPT-11, which is a new derivative of camptothecin, against refractory or relapsed small-cell lung cancer (SCLC). PATIENTS AND METHODS Sixteen patients with refractory or relapsed SCLC were entered onto a prospective, non-randomized, single-institution phase II trial. All 16 patients had been pretreated heavily with some form of cisplatin-based combination chemotherapy. Five patients had received previous chemotherapy with cisplatin, vincristine, doxorubicin, and etoposide (CODE) as an induction therapy. Six patients had been treated with concurrent cisplatin and etoposide plus chest x-ray. The median time off chemotherapy was 7.3 months (range, 1.9 to 15.1 months). Patients were treated with a CPT-11 starting dose of 100 mg/m2 body surface given as a 90-minute intravenous (IV) infusion every week with subsequent doses based on toxicity. Fifteen patients were assessable for toxicity, response, and survival. RESULTS Seven patients (47%; 95% confidence limits for an overall response rate, 21.4% to 71.9%) responded to CPT-11 with a median duration of response of 58 days. The major toxicities were myelosuppression (predominantly leukopenia), diarrhea, and pulmonary toxicity. CONCLUSION CPT-11 is an active agent against refractory or relapsed SCLC and deserves to be studied more closely as both a single agent and in combination with other drugs to treat patients with SCLC.

Objective: To establish cytological features of pulmonary pleomorphic carcinoma (PC) or giant cell carcinoma (GC), we evaluated the cytological characteristics of these tumors using a multidisciplinary approach. Study Design: Samples from 13 surgically resected and histologically confirmed PC or GC patients were collected from our institutes. Eight cases without prior chemotherapy before surgery were selected, and cytological features were analyzed. Results: The background contained numerous lymphocytes and neutrophils. The tumor cells were arranged in flat loose clusters, but some were in fascicles. The shape of the tumor cell was spindle or pleomorphic, and the sizes of the tumor cells varied by more than 5-fold. The tumor cells had an abundant, thick and well-demarcated cytoplasm. The location of the nucleus was centrifugal, and the nucleus was oval or irregularly shaped. Multinucleated giant cells were frequently observed. The size of the nucleus was more than 5 times that of normal lymphocytes, and its size also varied by more than 5-fold. The nuclear membrane was thin, and nuclear chromatin was coarsely granular, while the nucleolus was single and round. Conclusion: PC or GC has characteristic cytological features, however, spindle cells tended to be hardly observed in cytological specimens in some cases.

We retrospectively reviewed the contribution of widely used devices such as the standard fiberoptic bronchoscope in the diagnosis of peripheral pulmonary lesions (PPLs) in patients who presented with respiratory distress.We performed bronchoscopy for 106 PPLs in January-December 2007, and diagnosed access to the lesions to be difficult.For these lesions, we applied Sasada transbronchial angled forceps (STAF), transbronchial needle aspiration cytology (TBAC), thin bronchoscopy, and ultra-thin bronchoscopy, which are widely used devices, after routinely performing biopsy with standard forceps and saved each specimen separately, and finally compared the pathological diagnosis.The diagnostic yield obtained with specimens using standard forceps was 36.8%; however, the overall diagnosis was improved to 70.8% after we used these other devices and methods. We achieved diagnosis with STAF (10 lesions), followed by thin bronchoscopy (5 lesions), and ultra-thin bronchoscopy (14 lesions). No diagnosis was made by TBAC.We conclude that these widely employed devices can contribute to improvements in the diagnosis of cases of respiratory distress in which arrival to the lesions is difficult.

A 68-year-old man was referred to our hospital due to general fatigue, fever and weight loss. His chest radiograph showed a nodule (2.8 cm) in the right middle lobe. Computed tomography and positron emission tomography showed multiple metastases to the bone, liver and lymph nodes. The lung nodule was not accessible by standard transbronchial forceps. However, biopsy specimens obtained using Sasada Transbronchial Angled Biopsy Forceps (STAF) pathologically confirmed the diagnosis of malignant lymphoma. We report the case, and discuss the utility of STAF for lung lesions that are difficult to access with standard forceps.

7-Ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin (CPT-11) is a novel camptothecin derivative that has been selected for clinical evaluation because of its broad spectrum of antitumor activity in animal models and its unique inhibitory effects on mammalian DNA topoisomerase I. Seventeen patients with advanced non-small-cell lung cancer were treated with CPT-11 at weekly dose levels ranging from 50 to 150 mg/m2. At least three weekly doses were given to all patients except four, and a total of 74 weekly doses were given to the 17 patients. The dose-limiting toxic effects were myelosuppression (predominantly leukopenia) and unpredictable diarrhea. Gastrointestinal toxic effects were severe and not well controlled by standard therapy in some patients. Interpatient variability of toxic effects was substantial (including two deaths) and did not correlate with the pharmacokinetic parameters of CPT-11 and 7-ethyl-10-hydroxycamptothecin, its major metabolite. Two previously untreated patients, who received doses of 100 and 125 mg/m2, had partial responses lasting 3.2 and 4.0 months, respectively. The maximum tolerated dose on this schedule was 100 mg/m2, which we also recommend as a starting dose for phase II studies. This schedule appears to allow a CPT-11 dose intensity which is double the dose intensity possible on a once-a-month schedule. However, careful supervision to assess gastrointestinal toxic effects and myelosuppression is indispensable because of wide individual differences in drug tolerance.

Between August 1983 and March 1985, a randomized study was conducted that compared cisplatin (CDDP) (80 mg/m2 on day 1) alone with CDDP plus vindesine (VDS) (3 mg/m2 on days 1, 8, and 15) in 160 consecutive patients with inoperable non-small cell lung cancer (NSCLC). There were no complete responses. The response rate for CDDP plus VDS (22 of 77 patients, 29%) was significantly higher than that for CDDP alone (9 of 78 patients, 12%) (P less than 0.05). However, no difference existed in the median duration of response (20 weeks for CDDP plus VDS versus 20 weeks for CDDP alone) or the median survival time (45 weeks for CDDP plus VDS versus 39 weeks for CDDP alone). No significant differences in toxicity were detected between the two arms; myelosuppression, alopecia, and peripheral neuropathy occurred more frequently with CDDP plus VDS and there was one lethal episode of hepatorenal syndrome in the CDDP plus VDS arm. Among the variables Eastern Cooperative Oncology Group (ECOG) performance status (PS), age, sex, stage, weight loss, serum lactate dehydrogenase (LDH) level, albumin level, histologic cell type, and chemotherapy arm, only chemotherapy arm was a significant factor leading to a major response (P = 0.019, multiple logistic regression analysis). The significant predictors of survival were PS (P = 0.000), sex (P = 0.000), and stage (P = 0.002) (Cox's proportional hazards model), with a PS of 0 or 1, female sex, and lower stage yielding the best survival. Although a significantly higher response rate was obtained in the combination arm than in the single agent arm, the survival benefit to patients receiving such combination chemotherapy was not determined and more effective chemotherapy regimens are required.

To facilitate the studies in cell biology and drug sensitivity of non-small cell lung cancer, cell samples from 55 patients have been used to establish cell lines in culture using a chemically defined medium (ACL-4). A total of 20 cell lines (36 percent) were directly established and characterized: 14 (44 percent) from pleural effusions, five (29 percent) from resected primary tumors, and one (25 percent) from ascitic fluids. They comprised 16 adenocarcinoma, two large cell carcinoma, one squamous cell carcinoma, and one malignant mesothelioma. Each cell line had distinct gross morphologic features and population doubling times from 21 to 75 h. The plating efficiency was 0.01 to 9.51 percent. The modal chromosome number varied from 45 to 108. Secretion of tumor markers (carcinoembryonic antigen, sialyl Lewis Xi, CA 50, CA 125, and CA 19-9) into the medium was also different in each cell line. Most of the cell lines have been xenografted into nude mice and found to be tumorigenic. Survival of 20 patients whose tumor cell specimens continually grew in culture at any time during their clinical course was significantly shorter than that of 35 patients with no in vitro tumor growth (median survival time of 28 weeks vs 53 weeks, p = 0.0093). Our study indicates that in vitro tumor cell growth appears to be an adverse prognostic factor in patients with non-small cell lung cancer. (Chest 1991; 100:429-38)

A dose escalation study of daily oral etoposide and cisplatin was carried out on 22 patients with advanced cancer using starting doses of 20 mg/m2/d of etoposide given orally for 21 days and 80 mg/m2 of cisplatin given intravenously (IV) on day 1. A total of 40 courses were given. Myelosuppression was the major dose-limiting toxicity, with a maximum tolerated dose of 50 mg/m2/d of oral etoposide for 21 days plus 80 mg/m2 of IV cisplatin on day 1. Doses of 40 mg/m2/d of etoposide for 21 days plus 80 mg/m2 of cisplatin for 1 day in four of eight courses (50%) were associated with Grade 3 or worse leukopenia that occurred between days 18 and 26. However, no Grade 3 or worse thrombocytopenia occurred at this dose level. Nausea and vomiting occurred in most patients at each dose level but were mild and could be controlled by antiemetics. Alopecia also occurred frequently. Significant mucositis (Grade 4) occurred in one patient, but no other toxicities were observed. Four partial responses that lasted from 1.3 to 5.8+ months were observed in patients with cervical (one patient), small cell lung (one patient), and squamous cell lung cancer (two patients); one of them had been heavily pretreated with platin analogue-containing regimens. The recommended doses for Phase II studies on this schedule are 40 mg/m2/d of oral etoposide for 21 days plus 80 mg/m2 of IV cisplatin on day 1. A combination regimen on this schedule seems particularly effective in patients with etoposide-sensitive malignancies.

The synergism of combined high-dose etoposide with standard dose cisplatin (HD-EP) was evaluated in 20 patients who had relapsed after treatment of small cell lung cancer. Each patient was given etoposide at 500 mg/m2/day on days 1 to 3 and cisplatin at 80 mg/m2 (two patients given 120 mg/m2) on day 1; autologous bone marrow was not transplanted. Five patients were given recombinant human granulocyte colony-stimulating factor (rhG-CSF, 50 micrograms/m2) in an attempt to reduce HD-EP induced neutropenia. The overall response was 50% (9 of 18); one complete response (6%), eight partial responses (44%), seven no change (39%), and two progressions of disease (11%). Of the 18 evaluable patients, 12 had been treated with regimens of conventional doses of etoposide with conventional doses of cisplatin or carboplatin, and of these, five (42%) achieved a partial response. The median duration of response was 8.4 weeks (range, 5.3 to 17.7) and the median survival time was 20.3 weeks (range, 1.6 to 91). All of the patients developed severe myelosuppression; rhG-CSF did not shorten the period of the leukopenia. Mucositis and liver dysfunction were the major nonhematologic manifestations of toxicity. Two treatment-related deaths resulted from sepsis. These results suggest that the activities of high doses etoposide with standard doses of cisplatin are synergistic against small cell lung cancer.

From January 1978 to March 1984, a series of 159 patients with newly diagnosed small cell lung cancer (SCLC) was treated with combination chemotherapy with or without chest radiation at the Osaka Prefectural Habikino Hospital. By March 31, 1989, ten patients (6.3%) had survived for 5 years or more after the initial chemotherapy, including nine of 95 patients (9.5%) with limited disease and one of 64 patients (1.6%) with extensive disease. All these 5-year disease-free survivors, except for one patient whose response could not be assessed by chest radiograph because of radiation fibrosis, had a complete response. Nine of the 71 patients (12.7%) treated with combination regimens containing doxorubicin survived 5 years or more, and only one of the 88 (1.1%) treated with regimens without doxorubicin had long-term survival (P less than 0.01). The sex, performance status (PS), and chest radiation after systemic chemotherapy did not correlate statistically with long-term survival (P greater than 0.05). Three of the ten patients died free of SCLC. Two of the ten patients (20%) developed second malignancies and died. The remaining patient died of pneumonia. The Cox regression analysis identified the PS and doxorubicin-containing regimens as important factors indicating improved survival. Combination regimens containing doxorubicin have, therefore, been found to be very effective in improving survival and achieving long-term survival.

The mechanism by which soluble proteins, such as carboxypeptidase Y, reach the vacuole inSaccharomyces cerevisiaeis very similar to the mechanism of lysosomal protein sorting in mammalian cells. Vps10p is a receptor for transport of soluble vacuolar proteins inS. cerevisiae.vps10+, a gene encoding a homologue ofS. cerevisiae PEP1/VPS10, has been identified and deleted from the fission yeastSchizosaccharomyces pombe. Deletion of thevps10+gene resulted in missorting and secretion ofSch. pombevacuolar carboxypeptidase Cpy1p, indicating that it is required for targeting Cpy1p to the vacuole.Sch. pombeVps10p (SpVps10p) is a type I transmembrane protein and its C-terminal cytoplasmic tail domain is essential for Cpy1p transport to the vacuole. Cells expressing green fluorescent protein-tagged SpVps10p produced a punctate pattern of fluorescence, indicating that SpVps10p was largely localized in the Golgi compartment. In addition,Sch. pombe vps26+,vps29+andvps35+, encoding homologues of theS. cerevisiaeretromer componentsVPS26,VPS29andVPS35, were identified and deleted. Fluorescence microscopy demonstrated that SpVps10p mislocalized to the vacuolar membrane in these mutants. These results indicate that thevps26+,vps29+andvps35+gene products are required for retrograde transport of SpVps10p from the prevacuolar compartment back to the Golgi inSch. pombecells.

The demand for minimally invasive therapies is increasing in the treatment of small peripheral non-small cell lung cancer (NSCLC).Twelve patients with T1-2 N0 M0 peripheral NSCLC were treated by high-dose-rate brachytherapy with (192)Ir radioactive source.A (192)Ir source was introduced into the tumors percutaneously in five patients (percutaneous brachytherapy) or transbronchially in seven patients (transbronchial brachytherapy). Whereas irradiation was performed with a single fraction of 20 Gy in percutaneous brachytherapy, it was hypofractionated from 5 x 5 Gy to 2 x 12.5 Gy in transbronchial brachytherapy. Complications were generally mild in all patients, although focal radiation pneumonitis was observed in most patients. Primary recurrence occurred in three patients, including one with a T2 tumor and one treated by brachytherapy as a salvage treatment for recurrence after conformal radiotherapy. When brachytherapy is evaluated as a primary treatment for T1 N0 M0 NSCLC, local control rate is 88.9% and estimated 5-year survival rate is between 60% and 70%.Brachytherapy has a potential to be a method to treat peripheral T1 N0 M0 NSCLC.