Shigeaki Ogura

Annual change in pulmonary function and clinical phenotype in chronic obstructive pulmonary disease.

RATIONALE Although the rate of annual decline in FEV1 is one of the most important outcome measures in chronic obstructive pulmonary disease (COPD), little is known about intersubject variability based on clinical phenotypes. OBJECTIVES To examine the intersubject variability in a 5-year observational cohort study, particularly focusing on emphysema severity. METHODS A total of 279 eligible patients with COPD (stages I-IV: 26, 45, 24, and 5%) participated. We conducted a detailed assessment of pulmonary function and computed tomography (CT) at baseline, and performed spirometry every 6 months before and after inhalation of bronchodilator. Smoking status, exacerbation, and pharmacotherapy were carefully monitored. Emphysema severity was evaluated by CT and annual measurements of carbon monoxide transfer coefficient. MEASUREMENTS AND MAIN RESULTS Using mixed effects model analysis, the annual decline in post-bronchodilator FEV1 was -32±24 (SD) ml/yr (n=261). We classified the subjects of less than the 25th percentile as Rapid decliners, the 25th to 75th percentile as Slow decliners, and greater than the 75th percentile as Sustainers (-63±2, -31±1, and -2±1 [SE] ml/yr). Emphysema severity, but not %FEV1, showed significant differences among the three groups. Multiple logistic regression analysis demonstrated that the Rapid decliners were independently associated with emphysema severity assessed either by CT or carbon monoxide transfer coefficient. The Sustainers displayed less emphysema and higher levels of circulating eosinophils. CONCLUSIONS Emphysema severity is independently associated with a rapid annual decline in FEV1 in COPD. Sustainers and Rapid decliners warrant specific attention in clinical practice.

CD4+ T cells in cancer stroma, not CD8+ T cells in cancer cell nests, are associated with favorable prognosis in human non‐small cell lung cancers

We investigated intratumoral tumor‐infiltrating lymphocytes (TILs), including CD4+ and CD8+ T cells, in non‐small cell lung cancers (NSCLCs) and their relationships with clinicopathological variables and post‐operative survival. Tumor specimens from 178 NSCLCs were consecutively obtained by surgery at the Hokkaido University Medical Hospital between 1976 and 1994. CD8+ T cells, CD4+ T cells and Ki‐67/CD8+ T cells were visualized immunohistochemically, and counted within cancer cell nests and in cancer stroma. CD8+ T cells and CD4+ T cells were observed at higher frequencies within cancer cell nests in moderately and poorly differentiated tumors compared with well differentiated tumors (P<0.01), and in tumors with high Ki‐67 expression compared with low Ki‐67 expression (P<0.01), that showed severe cellular atypia and a higher growth rate. Patients with higher numbers of CD8+ T cells within cancer cell nests showed significantly shorter survival times compared to those with lower numbers of CD8+ T cells within cancer cell nests (5‐year survival rates, 47% and 60%, respectively; P=0.03). Moreover, patients with higher labeling index of Ki‐67/CD8+ T cells showed significantly shorter survival than those with lower labeling index of Ki‐67/CD8+ T cells within cancer cell nests (5‐year survival rates, 41% and 69%, respectively; P=0.02), and the labeling index of Ki‐67/CD8+ T cells within cancer cell nests was found to be a significant and independent unfavorable prognostic factor by multivariate analysis (P=0.01). On the other hand, higher numbers of CD4+ T cells in cancer stroma, but not within cancer cell nests, were correlated with longer survival times in patients with NSCLC (5‐year survival rates, 64% and 43%, respectively; P=0.04). CD4+ T cells in cancer stroma might reflect immune responses against cancer cells, while CD8+ T cells do not appear to work as effectors in tumor tissues of NSCLC. Moreover, the higher labeling index of Ki‐67/CD8+ T cells within cancer cell nests is a strong indicator of unfavorable clinical outcome.

Real-time tumor-tracking radiation therapy for lung carcinoma by the aid of insertion of a gold marker using bronchofiberscopy.

The authors developed fluoroscopic real‐time tumor‐tracking radiation therapy (RTRT) by insertion of a gold marker using bronchofiberscopy to reduce uncertainties in organ motion and set‐up error in external radiotherapy for moving tumors. The purpose of the current study was to evaluate RTRTs feasibility in lung carcinoma treatment.

Small-volume image-guided radiotherapy using hypofractionated, coplanar, and noncoplanar multiple fields for patients with inoperable Stage I nonsmall cell lung carcinomas

Occasionally, medically compromised and/or elderly patients with nonsmall cell lung carcinomas (NSCLCs) cannot be treated surgically. We investigated small‐volume hypofractionated image‐guided radiotherapy (IGRT) without the need for breath control in patients with inoperable Stage I NSCLCs.

Clinical benefit of readministration of gefitinib for initial gefitinib-responders with non-small cell lung cancer

BackgroundGefitinib, an oral agent of epidermal growth factor receptor tyrosine kinase inhibitor, has a certain efficacy against non-small cell lung cancer (NSCLC). Several predictive factors of gefitinib sensitivity have been well described. However, few studies have investigated the clinical features of gefitinib-responders. In the present study, we analyzed the response and disease progression of primary and metastatic lesions to gefitinib in responders and the results of gefitinib readministration following temporary cessation of gefitinib upon progression of initial gefitinib treatment and other treatments.MethodWe retrospectively evaluated the clinical courses of 27 NSCLC patients who received gefitinib and achieved either a complete or partial response.ResultsThe best-response rate and disease-control rate against the initial chemotherapy for the gefitinib-responders were 27.3% and 77.3%, respectively. Favorable efficacy was observed in the primary lesion and metastases to the lung, liver and brain, while there was no obvious effect on bone metastasis. The primary lesion and intrapulmonary metastasis were the sites of major recurrence. Median progression-free survival was 13.8 months, median duration of gefitinib treatment was 17.0 months and median overall survival was 29.2 months. Some of the patients who experienced disease progression after responding to gefitinib were again sensitive to readministration of gefitinib following temporary cessation of gefitinib and other treatments.ConclusionPatients may still be expected to have prolonged survival if they once responded to gefitinib and then underwent various subsequent treatments followed by readministration of gefitinib. These findings might provide valuable information for the management of gefitinib-responders.

Predictive value of expression of P53, Bcl‐2 and lung resistance‐related protein for response to chemotherapy in non‐small cell lung cancers

Chemoresistance is a major problem in the chemotherapy of non‐small cell lung cancers (NSCLCs). Several mechanisms are thought to be involved in drug resistance, including those associated with apoptosis, drug transport and detoxification. Here, we investigated the predictive value of P53, Bcl‐2 and lung resistance‐related protein (LRP) expression for response to platinum‐based chemotherapy, using transbronchial biopsy (TBB) specimens from patients with NSCLC. We evaluated TBB specimens from 57 patients with NSCLC who had not previously been treated with either chemotherapy or radiotherapy before TBB, and who were treated with systemic platinum‐based chemotherapy. The specimens included 33 adenocarcinomas, 22 squamous cell carcinomas and two large cell carcinomas. One to 6 courses of chemotherapy were administered. Expression of P53, Bcl‐2 and LRP was analyzed by immunohistochemistry using TBB specimens. Positive expression of P53, Bcl‐2 and LRP was observed in 28 (49%), 41 (71%) and 42 (73%) of the 57 NSCLCs, respectively. P53 expression correlated significantly with response to chemotherapy in nonsquamous cell carcinomas, including adenocarcinomas and large cell carcinomas (response rates, 38% and 6% for patients with P53‐positive and P53‐negative tumors, respectively, P=0.03). LRP expression significantly correlated inversely with response to chemotherapy in squamous cell carcinomas (response rates, 33% and 100% for patients with LRP‐positive and LRP‐negative tumors, respectively, P=0.02). Bcl‐2 expression did not correlate with response to chemotherapy. These findings indicate that im‐munostaining for P53 and LRP using TBB specimens may be useful for dividing patients with NSCLC into chemoresponsive and chemoresistant groups. (Cancer Sci 2003; 94: 394–399)

RCAS1 expression : a potential prognostic marker for adenocarcinomas of the lung

Objective: RCAS1 (receptor-binding cancer antigen expressed on SiSo cells) is a new tumor-associated antigen recognized by 22-1-1 monoclonal antibody. RCAS1 expressed on human cancer cells acts as a ligand for a putative receptor present on peripheral lymphocytes. RCAS1 has been shown to inhibit the in vitro growth of receptor-expressing cells and to induce apoptosis, which may contribute to the ability of tumor cells to evade host immune surveillance. In this study, we evaluated the prognostic significance of RCAS1 expression in primary lung adenocarcinomas. Methods: Immunohistochemical analysis was performed on tissue specimens surgically obtained from 102 patients with primary lung adenocarcinomas. Then, the association of RCAS1 expression with clinicopathological variables and prognosis of patients were analyzed. Results: Of 102 lung adenocarcinomas, positive RCAS1 expression was observed in 82 cases (80%). There was no correlation between RCAS1 expression and clinicopathological variables. In 70 potentially curatively resected lung adenocarcinomas, patients with RCAS1-positive tumors had a significantly shorter survival than those with RCAS1-negative tumors (p = 0.02), and RCAS1 expression was a significant and independent prognostic factor by multivariate analysis (p = 0.03). Conclusions: These results indicate that RCAS1 expression predicts prognosis in patients with lung adenocarcinomas, and this new antigen could be a novel tumor marker which reflects the clinical outcome of lung cancers.

Nucleolar organizer regions in precancerous and cancerous lesions of the bronchus.

Using a silver staining technique, nucleolar organizer region‐associated proteins (Ag‐NOR) were studied in paraffin sections of five specimens of normal bronchial epithelium, eight of atypical squamous metaplasia, five of carcinoma in situ, and seven of microinvasive squamous cell carcinoma. The mean number of Ag‐NOR in the nucleus were normal epithelium 1.2 ± 0.1 (mean ± SD), atypical squamous metaplasia (borderline lesion) 2.2 ± 0.5, carcinoma in situ 3.8 ± 0.6, and microinvasive squamous cell carcinoma 4.8 ± 1.1. There was a highly significant difference between the Ag‐NOR numbers in the atypical squamous metaplasia and those in the carcinoma in situ (P < 0.01). The Ag‐NOR staining is a useful technique for the differential diagnosis of difficult borderline lesions in the bronchial epithelium.

A rare case of bronchial glomus tumor

A 48-year-old man was admitted because of bloody sputum in whom a chest computed tomography (CT) scan and fiberoptic bronchoscopy demonstrated a polypoid tumor in the left main bronchus. The tumor was surgically resected, and the pathological and immunohistochemical findings led to diagnosis of the tumor as a bronchial glomus tumor.

Atomic force microscopy of living cells

This paper is a review of our results of the application of atomic force microscopy (AFM) to the three-dimensional observation of living cells. First, we showed AFM images of living cultured cells in fluid. Contact mode AFM of living cells provided precise information on the shape of cellular processes (such as spike-like processes or lamellipodia) at the cellular margin. The contour of cytoskeletal elements just beneath the cell membrane was also clearly observable on the upper surface of the cells. Secondly, we showed the data on the discrepancy between the AFM images of living cells and fixed cells. These findings were useful for evaluating AFM images of living cells. Finally, we described the time-lapse AFM of living cells. A fluid chamber system enabled us to obtain AFM images of living cells for over 1 h at time intervals of 2–4 min. A series of these AFM images were useful for examining the movements of cellular processes in relation to subcellular cytoskeletal elements. Time-lapse movies produced by sequential AFM images also gave a realistic view of the cellular dynamics.