Hidemi Ohwada

High magnification bronchovideoscopy combined with narrow band imaging could detect capillary loops of angiogenic squamous dysplasia in heavy smokers at high risk for lung cancer

Background: We investigated the use of high magnification bronchovideoscopy combined with narrow band imaging (NBI) for the detailed examination of angiogenic squamous dysplasia (ASD). This was carried out in relation to bronchial vascular patterns with abnormal mucosal fluorescence in heavy smokers at high risk for lung cancer. Methods: Forty eight patients with sputum cytology specimens suspicious or positive for malignancy were entered into the study. Conventional white light and fluorescence bronchoscopic examination was first performed. Observations by high magnification bronchovideoscopy with conventional white light were made primarily at sites of abnormal fluorescence, and then repeated with NBI light to examine microvascular networks in the bronchial mucosa. Spectral features on the RGB (Red/Green/Blue) sequential videoscope system were changed from the conventional RGB broadband filter to the new NBI filter. The wavelength ranges of the new NBI filter were B1: 400–430 nm, B2: 420–470 nm, and G: 560–590 nm. ASD tissues were also examined using a confocal laser scanning microscope equipped with argon-krypton (488 nm) and argon (514 nm) laser sources. Results: The microvessels, vascular networks of various grades, and dotted vessels in ASD tissues were clearly observed in NBI-B1 images. Diameters of the dotted vessels visible on NBI-B1 images agreed with the diameters of ASD capillary blood vessels diagnosed by pathological examination. Capillary blood vessels were also clearly visualised by green fluorescence by confocal laser scanning microscopy. There was a significant association between the frequency of dotted vessels by NBI-B1 imaging and tissues confirmed as ASD pathologically (p=0.002). Conclusions: High magnification bronchovideoscopy combined with NBI was useful in the detection of capillary blood vessels in ASD lesions at sites of abnormal fluorescence. This may enable the discrimination between ASD and another pre-invasive bronchial lesion.

Smoking before surgery predicts poor long-term survival in patients with stage I non-small-cell lung carcinomas.

PURPOSE The majority of lung carcinoma patients requiring resection have smoking habits prior to surgical treatment, and the correlation of smoking with postoperative complications is well known. However, few studies have investigated the correlation between long-term survival and cigarette smoking in patients with primary, resected lung carcinoma. We analyzed the relationship between clinical factors, including cigarette smoking before surgery, and 10-year survival in stage I non-small-cell lung carcinoma (NSCLC). PATIENTS AND METHODS Cigarette smoking habit and other factors influencing either the overall survival or the disease-specific survival rates of patients with stage I primary, resected NSCLC were evaluated according to the Cox proportional hazards model using a total of 369 patients with stage I-NSCLC. RESULTS Comparison of the cause of death in patients with 30 or more pack-years and patients with less than 30 pack-years showed significant differences in the prevalence of recurrent disease and onset of nonmalignant disease. Multivariate analysis demonstrated significant correlations between overall survival and age and pack-years. Disease-specific survival showed significant correlations with age, tumor classification, and visceral pleural invasion. CONCLUSION Smoking pack-years is an important clinical prognostic factor in evaluating overall long-term survival in patients with stage I primary, resected NSCLC.

Fluorescence bronchoscopy in the detection of preinvasive bronchial lesions in patients with sputum cytology suspicious or positive for malignancy

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

Subepithelial vascular patterns in bronchial dysplasias using a high magnification bronchovideoscope

Background: We have developed a method of high magnification bronchovideoscopy that enables improved observation of subepithelial vascular patterns of the bronchial mucosa. A study was undertaken to investigate the value of high magnification bronchovideoscopy in the detailed examination of dysplasia in the bronchial mucosa of patients with abnormal mucosal fluorescence. Methods: Thirty one patients with sputum cytology specimens suspicious or positive for malignancy were entered into the study. Conventional white light examination was first performed under local anaesthesia and fluorescence bronchoscopy was also carried out using a light induced fluorescence endoscopy (LIFE) lung system. A high magnification bronchovideoscope (XBF 200HM2) was then used to examine the microvascular network in the bronchial mucosa at sites of normal and abnormal fluorescence and the images obtained were compared with pathological diagnoses from bronchial biopsy specimens. Vascular area ratios were calculated using image analysing apparatus. Results: Vascular networks with regular patterns were observed at 20 of 22 abnormal fluorescence sites in biopsy specimens from patients with bronchitis. However, vascular networks with increased vessel growth and complex networks of tortuous vessels of various sizes were observed in 15 of 21 abnormal fluorescence sites in dysplasia specimens. There was a significant difference between bronchitis and dysplasia specimens (OR=25, 95% CI 5.5 to 113, p<0.0001). Mean vascular area ratios from 16 normal bronchial epithelium specimens with normal fluorescence, and 22 bronchitis and 21 dysplasia specimens with abnormal fluorescence were 0.054 (95% CI 0.039 to 0.07), 0.095 (95% CI 0.072 to 0.118), and 0.173 (95% CI 0.143 to 0.203), respectively. The results indicate a statistically significant increase in vascular area in the three groups (p<0.0001). Conclusion: Areas of increased vessel growth and complex networks of tortuous vessels in the bronchial mucosa detected using a high magnification bronchovideoscope at sites of abnormal fluorescence may enable discrimination between bronchitis and dysplasia.

Levels of soluble Fas ligand in myocarditis

Serum levels of soluble Fas ligand (sFasL) increased with the severity of congestive heart failure (p <0.01), and the percentages of apoptotic myocytes detected by in situ DNA nick-end labeling were significantly higher in the patients with increased levels of sFasL than in those with normal levels of sFasL (p <0.05). These findings indicated that sFasL may play an important role in pathogenesis of myocarditis.

Correlation between endobronchial ultrasonography (EBUS) images and histologic findings in normal and tumor-invaded bronchial wall

The aim of this study was to examine the ability of endobronchial ultrasonography (EBUS) to image the bronchial wall structure in order to assess the depth of bronchial tumor invasion. Sixty-one patients who underwent lobectomy, pneumonectomy or forceps biopsy were included in this study. In 21 patients with bronchoscopically visible bronchial malignant tumors, EBUS was performed during bronchoscopy. In the remaining 40 patients, ultrasonography was performed on the resected specimens. The EBUS findings obtained using thin ultrasonic probes (20 MHz radial scanner) were compared with the macroscopic and histologic findings of the corresponding areas in the resected specimens. When the bronchial walls were imaged while immersed in normal saline, six ultrasonically distinct layers were detected in the cartilaginous and membranous portions. A similar wall structure was imaged when EBUS was performed during bronchoscopy using a latex balloon sheath. The image of the lamina propria and submucosa was occasionally compressed and mixed with a balloon echo due to the latex balloon sheath, whereas the cartilage layer was always distinctly imaged. A good correlation was observed between the EBUS-determined cartilage thickness and the actual histologic measurement, as measured with vernier calipers. Malignant tissues were imaged as hypoechoic areas, and tumor invasion of the cartilage layer was clearly detected. In conclusion, using high-resolution (20 MHz) ultrasonic probes, the bronchial wall structure could be imaged as six distinct layers. The cartilage layer was easily identified and could be used as a reference to evaluate the rest of the bronchial wall structure.

Pulmonary large cell carcinomas with neuroendocrine features are high-grade neuroendocrine tumors

BACKGROUND In 1999, the World Health Organization (WHO) categorized large cell carcinoma with neuroendocrine features as variants of large cell carcinoma and reclassified neuroendocrine lung tumors, especially typical and atypical carcinoid tumors. However, to date, the clinical relationship between these categories of neuroendocrine lung tumors has not been clearly defined. METHODS We analyzed 133 cases of neuroendocrine tumors from primary lung carcinoma cases surgically resected. Using electron microscopy and immunohistochemical staining, we classified these cases as typical carcinoid (TC), atypical carcinoid (AC), large cell carcinoma with neuroendocrine features (LCNF), or small cell lung carcinoma (SCLC) based upon the WHO classification. RESULTS TC and AC tumors were not related to smoking (p < 0.001) and, unlike LCNF, were found in younger patients (p < 0.001) without a male predominance (p < 0.001). Multivariate analysis revealed that LCNF predicted poorer overall and disease-free survivals comparable with SCLC (overall survival, p = 0.019, hazards ratio, 6.34; disease-free survival, p = 0.007, hazards ratio, 8.19). CONCLUSIONS The prognoses of LCNF are comparable with those of SCLC, and LCNF should be classified as high-grade neuroendocrine tumors.

Synchronous and metachronous lung carcinomas: Molecular evidence for multicentricity

The present study Is aimed to evaluate the genetic evidence for multicentricity of synchronous and metachronous multiple lung carcinomas. Nineteen cases of synchronous multlple lung carcinomas and 11 cases of metachronous multiple lung carcinomas were analyzed for p53 protein overexpression by lmmunohistochemlstry (DO‐7) and for genetic abnormality of the p53 gene by loss of heterozygosity (LOH) at chromosome 17p and by poly‐merase chaln reaction (PCR)‐singlestrand conformation polymorphism (SSCP) analysis. They were also analyzed for K‐ras mutation. DNA from three patients was also sequenced by the dideoxy sequencing method to confirm the presence of mutations and determine the base substitutions. Different spectrums of genetic changes, which were evaluated by a combination of p53 mutation, LOH at chromosome 17p and p53 overexpression, were observed in 11 of 19 cases of synchronous multiple lung carcinomas (57.9%) In the present study. Slmllarly, five of 11 cases of metachronous multiple lung carcinomas (45.4%) showed a different pattern of genetic changes. The present data suggest that some of the multiple carcinomas have dlfferent clonal orlgins, although their histological types are identical, and support the use of genetic markers In the differential diagnosis between metastasis and second primary carcinoma of the lung.

Alpha-fetoprotein-producing lung carcinoma: Report of three cases

Three cases of alpha‐fetoprotein (AFP)‐producing lung carcinoma were studied histologically and immunohistochemically. Samples were obtained from two men and one woman who ranged in age from 64 to 71 years. Serum AFP levels for the three samples were 9826, 74.4 and 24.3 ng/mL. One case was classified as stage IIIA and two as stage IIIB. Two cases were diagnosed as large cell neuroendocrine carcinoma, and AFP expression was detected immunohistochemically. One of these samples showed differentiation to a hepatoid carcinoma, while the other was combined with a squamous cell carcinoma. The remaining case was a squamous cell carcinoma, and AFP was detected in only some of the tumor cells. All patients died within 2 years. The Ki‐67 labeling indices of the AFP‐producing pulmonary carcinomas (30.2 ± 4.6%) were significantly higher than those of AFP‐negative pulmonary carcinomas (P < 0.05). The high proliferative activity, advanced stage at presentation, vascular endothelial growth factor expression and vascular invasion observed in these tumors may explain the poor prognosis of AFP‐producing lung carcinomas.

Levels of Soluble Fas in Patients With Myocarditis, Heart Failure of Unknown Origin, and in Healthy Volunteers 1

This study showed that serum levels of sFas were elevated in patients with myocarditis, and that this elevation was correlated with sIL-2R level as a marker of T-cell activation. Therefore, sFas levels may be associated with T-cell activation in patients with myocarditis, and elevation of sFas may inhibit apoptosis in activated T cells, leading to persistent cell-mediated destruction of myocytes in myocarditis.