Hidehisa Hoshino

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.

A comparison of video and autofluorescence bronchoscopy in patients at high risk of lung cancer.

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.

Molecular characterization of chronic obstructive pulmonary disease-related non-small cell lung cancer through aberrant methylation and alterations of EGFR signaling.

BackgroundThe aim of this study was to evaluate the molecular influence of chronic obstructive pulmonary diseases (COPD) on the pathogenesis of non-small cell lung cancer (NSCLC).Materials and MethodsThe methylation profiles of 12 genes, and the epidermal growth factor receptor (EGFR) and KRAS mutations were determined for samples from 229 NSCLC patients. In addition, protein expression of EGFR and HER2 in 116 NSCLCs was analyzed based on the presence or absence of COPD.ResultsIL-12Rβ2 and Wif-1 methylation and HER2 overexpression were more frequent events in the COPD group. Eighty nonmalignant lung tissues had no correlation with any molecular changes between the COPD and the non-COPD group. EGFR mutation was significantly higher in the non-COPD group, while EGFR expression was inversely correlated with %FEV1.0. In the COPD group, unmethylated SPARC and sFRP-2 genes or a negative CpG island methylator phenotype (CIMP) was a negative prognostic factor, while methylation of p16INK4A and WNT antagonist genes was a negative prognostic factor in the non-COPD group.ConclusionsNovel characteristics of COPD-related NSCLC were identified by examination of methylation profiles and alterations of EGFR signaling. In consideration of the high sensitivity to smoking in patients with COPD, NSCLC with COPD might be a distinct population of smoke-related NSCLC, the genetic profile of which is quite different from non-COPD NSCLC.

Narrow band imaging with high-resolution bronchovideoscopy: A new approach for visualizing angiogenesis in squamous cell carcinoma of the lung

OBJECTIVES We investigated the ability of a high-resolution bronchovideoscopy system with narrow band imaging (NBI) to detect blood vessel structures in squamous cell carcinoma (SCC) of bronchi, as well as squamous dysplasia. METHODS Seventy-nine patients with either abnormal sputum cytology or lung cancer were entered into the study. First, high-resolution bronchovideoscopy with white light was performed. Observations were repeated using NBI light to examine microvascular structures in the bronchial mucosa. Spectral features of the RGB (red/green/blue) sequential videoscope system were changed from a conventional RGB filter to the new NBI filter. The wavelength ranges of the NBI filter were: 400-430 nm (blue), 400-430 nm (green) and 520-560 nm (red). RESULTS The following were clearly observed with NBI with high-resolution bronchovideoscopy: increased vessel growth and complex networks of tortuous vessels of various sizes, in squamous dysplasia; some dotted vessels, in addition to increased vessel growth and complex networks of tortuous vessels, in ASD; several dotted vessels and spiral or screw type tumor vessels of various sizes and grades, in SCC. Capillary blood vessel and/or tumor vessel mean diameters of ASD, CIS, microinvasive and invasive carcinoma were 41.4+/-9.8 microm, 63.7+/-8.2 microm, 136.5+/-29.9 microm and 259.4+/-29.6 microm, respectively. These results indicated a statistically significant increase of mean vessel diameters in the four groups (P<0.0001). CONCLUSION NBI with high-resolution bronchovideoscopy was useful for detecting the increased vessel growth and complex networks of tortuous vessels, dotted vessels and spiral or screw type tumor vessels of bronchial mucosa. This may enable detecting the onset of angiogenesis during multi-step carcinogenesis of the lung.

Accumulation of Activated Invariant Natural Killer T Cells in the Tumor Microenvironment after α-Galactosylceramide-Pulsed Antigen Presenting Cells

PurposeThe intravenous administration of α-Galactosylceramide (α-GalCer)-pulsed antigen presenting cells (APCs) is well tolerated and the increased IFN-γ producing cells in the peripheral blood after the treatment appeared to be associated with prolonged survival. An exploratory study protocol was designed with the preoperative administration of α-GalCer-pulsed APCs to clarify the mechanisms of these findings, while especially focusing on the precise tumor site.MethodsPatients with operable advanced lung cancer received an intravenous injection of α-GalCer-pulsed APCs before surgery. The resected lung and tumor infiltrating lymphocytes (TILs) as well as peripheral blood mononuclear cells were collected and the invariant NKT (iNKT) cell-specific immune responses were analyzed.ResultsFour patients completed the study protocol. We observed a significant increase in iNKT cell numbers in the TILs and augmented IFN-γ production by the α-GalCer-stimulated TILs.ConclusionThe administration of α-GalCer-pulsed APCs successfully induced the dramatic infiltration and activation of iNKT cells in the tumor microenvironment.

A prospective study of indications for mediastinoscopy in lung cancer with CT findings, tumor size, and tumor markers

BACKGROUND Biopsies by mediastinoscopy remain the most reliable preoperative staging method for N2 lung cancer. Because it is neither practical nor economical to recommend mediastinoscopy for all candidates for surgery, we developed indicational criteria for video-assisted mediastinoscopy (VAM) and carried out a prospective study to validate its usefulness. METHODS Patients with resectable primary lung cancer were chosen for VAM when at least one of three clinical indicators was present: (1) computed tomographic evidence of mediastinal adenopathy, (2) elevated levels of serologic tumor markers, and (3) diameters of primary cancers (> 2 to 3 cm). Patients without positive nodes (group 2) underwent thoracotomy, and patients with positive nodes (group 3) received induction therapy. When none of these criteria were met (group 1), thoracotomy with R2b lymph node dissection was performed without VAM. RESULTS One hundred twenty-one men and 82 women (total, 203) were eligible for the study. The mean age of the patients was 64.4 years (range, 39 to 75 years) with primary lung cancer. The patients were comprised of 135 adenocarcinomas, 46 squamous cell cancers, and 22 other carcinomas. There were 78 patients in group 1, 87 in group 2, and 38 in group 3. The stages of group 2 patients were more advanced (chi2 = 63.2668; p < 0.001) than those of group 1. As the incidence of positive indicators for VAM increased, the ratios of N2 patients increased from 2.5% (all negative) to 90.4% (triple positive: p < 0.001). The correlation of our criteria with the pathology findings revealed a diagnostic sensitivity of 95.8% and a negative predictive value of 97.4%. Using three indicators for N2 prediction, we selected 96% (46 of 48) pN2, N3 patients and avoided 37% (76 of 203) unnecessary VAMs. CONCLUSIONS We established and validated currently useful criteria for VAMs in the management of primary lung cancer.

Applicability of the revised International Association for the Study of Lung Cancer staging system to operable non-small-cell lung cancers

OBJECTIVE A new staging system for lung cancer has been proposed by The International Association for the Study of Lung Cancer Staging Committee. We assessed the feasibility of this system for surgical patients. METHODS We reviewed the surgical outcome of 1623 consecutive patients with non-small-cell lung cancer (NSCLC), who underwent pulmonary resection in our institution, with regard to the subpopulations categorised in the current and proposed (2009) systems for postoperative pathologic staging. RESULTS The proportion of patients staged as IIA, IIB, IIIA and IV increased, while those staged as IB and IIIB decreased. Diseases staged as IIIA or earlier were significantly increased in the new system (current system: N=1281, 78.9% vs new system: N=1457, 89.8%). The 5-year survival rates of patients with new stages IB and IIA were clearly dissociated with 72.5% and 51.3%, respectively (P<0.0001). The 5-year survival rates of the newly classified T1 patients were 90.3% for T1aN0M0 and 81.5% for T1bN0M0 (P=0.009). Re-classification of T2bN0M0 as stages IIA and T3 (same lobe nodules) N0M0 as stage IIB appropriately emphasised prognostic differences, while T4 (ipsilateral different lobe nodules) N2-3M0 (stage IIIB) and M1a (pleural effusion, stage IV) did not. CONCLUSIONS This study demonstrated that the new system is superior to the current system in terms of the proportion and prognostic prediction of each stage, although it contains minor contradictions. Therefore, revision of the staging system will contribute to the decision for limited operation and adjuvant therapy of resected NSCLC.

Imprint cytologic features of pulmonary sclerosing hemangioma: comparison with well-differentiated papillary adenocarcinoma.

Sclerosing hemangiomas (SH) of the lung are uncommon tumors and are thought to be benign. However, histogenesis of these tumors has not yet been characterized adequately. Moreover, there are few reports dealing with their cytologic features, and it is generally considered difficult to make accurate diagnoses of sclerosing hemangiomas that have a predominantly papillary pattern.

Preoperative cytodiagnosis of very small-sized peripheral-type primary lung cancer

To demonstrate the importance of preoperative diagnosis of pulmonary cancers presenting as peripheral small-sized solitary shadows we evaluated the results of morphologic definitive diagnosis together with various clinical factors in 91 tumors with less than 15-mm diameter resected surgically between 1983 and 1999. Histologically, these tumors consisted of 73 adenocarcinomas, nine squamous cell carcinomas, and nine other types. Regarding the pathologic stage, 57 tumors were classified in stage IA, three in IB, six in IIA, seven in IIIA, 14 in IIIB, and four in IV. Comparing various biopsy techniques, the sensitivity of preoperative cytodiagnosis was 43.7% for transbronchial brushing (n = 48), 52.9% for transbronchial forceps biopsy-stamp cytology (n = 51), 66.6% for transbronchial fine needle aspiration (n = 78), and 85.0% for percutaneous fine needle aspiration (n = 20). The overall sensitivity of preoperative cytodiagnosis was 79.0% for transbronchial biopsy (n = 81), and 87.3% for transbronchial and percutaneous biopsy (n = 87). Of 73 clinical N0 cases in which lobectomy was performed, 10 cases (13.6%) were diagnosed as between pathological degrees N1, N2 and N3. However, lung cancer cases with less than 10-mm diameter did not have lymph node metastasis. Our study of histologic differentiation showed that all cases of well-differentiated adenocarcinomas (n = 20) were pathological degree N0. The overall sensitivity of preoperative diagnosis increased to 89.1% in cases (n = 74) of tumors with 11-15-mm diameter. The sensitivity of cytodiagnosis for peripheral small-sized primary lung cancers is high, and we can estimate histological differentiation based on the cytological findings. Therefore, cytodiagnosis is an effective and indispensable diagnostic method for determination of the optimal treatment approach, including approaches such as intentionally limited resection.

Spectroscopic analysis of the autofluorescence from human bronchus using an ultraviolet laser diode.

A GaN based ultraviolet (UV) laser diode (LD) was used to study the autofluorescence (AF) spectrum of the normal and tumor human bronchial tissues under ex vivo conditions. The UV LD generates a coherent short wavelength (around 400 nm) light beam with an intensity of about a few watts. AF spectrum data can be obtained without interference by excitation light. A clear blue peak located at around 483 nm was observed along with a green peak at around 560 nm in the normal tissue. The peak intensities observed were very weak for the tumor tissues. The AF imaging and spectrum analysis were performed along with a histopathological study. The spatial distribution of the elastin in the bronchial tissue affected the intensity of the AF whereas the spectrum shape was not affected. Strong AF was observed from regions that include a high density of the elastin. Biopsy measurements were performed for ex vivo samples, and depth profiling of the elastin was studied along with variations of the AF spectrum. AF spectra excited by the UV LD for fluorescence materials including FAD, NADH, and elastin were measured. The spectrum shape of the elastin as well as of NADH was similar to that of normal bronchial tissues.