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OBJECTIVES The purpose of this study was to investigate the feasibility of lung wedge resection by combining 3-dimensional (3D) image analysis with transbronchial indocyanine green (ICG) instillation, in order to delineate the intended area for resection. METHODS From December 2017 to July 2020, 28 patients undergoing wedge resection (17 primary lung cancers, 11 metastatic lung tumours) were enrolled, and fluorescence-guided wedge resection was attempted. Virtual sublobar resections were created preoperatively for each patient using a 3D Image Analyzer. Surgical margins were measured in each sublobar resection simulation in order to select the most optimal surgical resection area. After transbronchial instillation of ICG, near-infrared thoracoscopic visualization allowed matching of the intended area for resection to the virtual sublobar resection area. To investigate the effectiveness of ICG instillation, the clarity of the ICG-florescent border was evaluated, and the distance from the true tumour to the surgical margins was compared to that of simulation. RESULTS Mean tumour diameter was 12.4 ± 4.3 mm. The entire targeted tumour was included in resected specimens of all patients (100% success rate). The shortest distances to the surgical margin via 3D simulation and by actual measurement of the specimen were11.4 ± 5.4 and 12.2 ± 4.1 mm, respectively (P = 0.285) and were well correlated (R2 = 0.437). While all specimens had negative malignant cells at the surgical margins, one loco-regional recurrence was observed secondary to the dissemination of neuroendocrine carcinoma. CONCLUSIONS ICG-guided lung wedge resection after transbronchial ICG instillation and preoperative 3D image analysis allow for adequate negative surgical margins, providing decreased risk of local recurrence.

We conducted a phase I study of the trans-bronchial injection of α-galactosylceramide (αGalCer)-pulsed antigen presenting cells (APCs) to evaluate their safety, immune responses, and anti-tumor activities. Patients with advanced or recurrent non-small cell lung cancer (NSCLC) refractory to standard treatments were eligible. αGalCer-pulsed APCs were administered intratumorally or intranodally by bronchoscopy. Twenty-one patients were enrolled in this study. No severe adverse events related to the cell therapy were observed during this study in any patient. After αGalCer-pulsed APCs were administrated, increased iNKT cell numbers were observed in PBMCs from eight cases, and IFN-γ producing cells were increased in the peripheral blood of 10 cases. Regarding clinical responses, one case exhibited a partial response and eight were classified as stable disease. In the tumor microenvironment, IFN-γ expression was upregulated after treatment in partial response or stable disease cases and TGF-β was upregulated in progressive disease cases.

The confirmation of an appropriate resection margin from the tumor is crucial for reducing the risk of local recurrence after sublobar resection for pulmonary malignancies.From October 2014 to April 2018, 66 operative cases in 64 patients( primary lung cancer 42, metastatic lung tumor 21, benign disease 3) were enrolled. In lung cancer, active limited resection was done in 29 and passive limited resection was done in 13. Preoperatively, each patient created several virtual sublobar resections by using 3-dimensional (3D) volume analyzer. We measured the surgical margin in each simulated sublobar resection and selected the most appropriate procedure. Surgical resection matched with virtual sublobar resection was done by using an infrared thoracoscopy with transbronchial indocyanine green (ICG) instillation. In lung cancer, we compared surgical outcomes between ICG cases and 47 historical segmentectomy cases.The types of sublobar resection were subsegmental resection in 5, simple segmentectomy in 15, complex segmentectomy in 16 and extended segmentectomy in 22 and anatomical super deep wedge resection in 8. The shortest distance of surgical margin by simulation and an actual measurement were 20.8±11.1 mm and 22.6±8.3 mm, respectively( p=0.186). Postoperative recurrence was found in 8 cases (distant in 7 and mediastinal lymph node in 1). No locoregional recurrence was found in all cases. Postoperative recurrence was similar between the 2 groups in active and passive limited resection, respectively.ICG-guided sublobar resection by transbronchial ICG instillation is applicable to any type of sublobar resection and can control local recurrence of lung neoplasms.

Pulmonary artery reconstruction is sometimes utilized as an alternative to pneumonectomy in lung cancer surgery. We herein report our experience of pulmonary artery reconstruction using an expanded polytetrafluoroethylene (ePTFE) patch based on the surgical results and long-term outcome. Clinical records of lung cancer patients who underwent patch plasty were reviewed retrospectively. Between 2003 and 2017, pulmonary artery patch plasty were performed in 21 patients [18 males, 3 females; mean age 65 (range 47–79) years]. Induction chemoradiotherapy was performed in three patients. Bronchoplasty was performed in five patients. The pathologic stages were stage I in 3 patients, stage II in 6 and stage III in 12. Pneumonectomy, lobectomy and segmentectomy were performed in 2, 18 and 1 patient, respectively. The left upper lobe was the most frequent origin of lung cancer (15 patients). There was no reconstruction-related morbidity or mortality. The overall survival rate at 5 years was 64.1% with a mean follow-up of 39.5 months, and the survival rates for N0–1 and N2–3 were 80.8% and 28.6%, respectively. Patch angioplasty using the ePTFE sheet is a reliable procedure in radical surgery for lung cancer.

We developed a novel approach combined with 3D image analyzer and infrared thoracoscopy for pulmonary sublobar resection. The purpose of this study was to investigate the feasibility of this procedure. From October 2014 to April 2018, 65 cases were enrolled, and 58 cases were evaluated. For each case, several virtual sublobar resections were created by 3D image analyzer preoperatively. The surgical margin was measured in each simulated sublobar resection and the most appropriate procedure was selected. Surgical resection with matching virtual sublobar resection was performed using infrared thoracoscopy with transbronchial indocyanine green (ICG) instillation. We evaluated the border clarity of ICG fluorescence to investigate success of ICG injection and compared pre- and postoperative CTs to determine whether the correct area could be removed according to the simulation. We also compared short-term surgical outcomes between the ICG cases and historical segmentectomy cases by propensity score matching. The success rate of transbronchial ICG injections was 89.2% (58/65). These 58 patients were eligible for evaluation of our procedure. Sublobar resection included subsegmental resection (5), simple segmentectomy (15), complex segmentectomy (16), and extended segmentectomy (22). The shortest distances to the surgical margin by simulation and by actual measurement were 21.5 ± 11.2 mm and 23.5 ± 8.3, respectively (P = 0.190). Fifty-four of 58 cases underwent sublobar resection matched with the simulation (93.1% concordance rate). Operative results and short-term outcomes were similar between the 2 groups by propensity score matching. ICG-guided sublobar resection by transbronchial ICG instillation is feasible and applicable to any type of sublobar resection.

We retrospectively investigated whether histological cell type could affect patient prognosis for each stage according to the seventh edition of the TNM classification. Clinical records of 1623 consecutive non-small cell lung cancer patients who underwent surgery between 1990 and 2007 were retrospectively reviewed. Over 92% of these patients had either adenocarcinoma (Ad; n = 1043, 64.3%) or squamous cell carcinoma (Sq; n = 452, 27.9%). The overall 5-year survival rates for patients of all stages with Ad, Sq, large cell carcinoma (La), and adenosquamous cell carcinoma (As) were 67%, 56%, 58%, and 41%, respectively. Ad patients experienced better survival than Sq, As, or La patients (HR: 0.66, P0.0001; HR: 0.38, P = 0.011; HR: 0.69, P = 0.057, respectively). Stage IA Ad patients experienced better survival than stage IA Sq patients (5-year survival; Ad/Sq = 91%/78%, log-rank test, P = 0.001). Such a difference was also observed among seventh-edition TNM stage IB patients (5-year survival; Ad/Sq = 78%/64%, log-rank test, P = 0.048), but not for sixth-edition stage IB patients. Multivariate analysis demonstrated that histological cell type is a significant prognostic factor among stage I ≥ T1b Ad and Sq patients. Survival after complete resection of new stage I ≥ T1b Sq patients is significantly worse than that of Ad patients, which could be partially attributed to stage migration effect in stage IB disease between the sixth and seventh editions of the TNM staging system.

Objectives: We investigated the capabilities of a pCLE that enables microscopic imaging of the tracheobronchial tree including peripheral lung tumor during bronchoscopy after administration of 10% fluorescein. Methods: thirty-one patients with suspected lung cancer were underwent bronchoscopy with pCLE using fluorescein. Following localization of peripheral lung tumor with endobronchial ultrasonography-guided sheath and of central airways tumor with white light, narrow band imaging (NBI) and autofluorescence imaging (AFI) bronchoscopy, pCLE was performed followed by bronchoscopic tumor biopsy. Histological examinations using haematoxylin and eosin staining were made of biopsied specimens. Analyzed pCLE images were compared with the corresponding histological examinations. Results: Of the 31 patients, 24 lung cancers and 3 inflammatory tumors were identified pathologically. In adenocarcinoma, confocal images demonstrated large, irregular, dark or black tumor cells were visible and some of abnormal structures were also similar to acinar and papillary differentiated types. In squamous cell carcinoma, large, dark or black, polymorphic tumor cells showed increased cellular densities with irregular stratified patterns and capillary blood vessels, tumor vessels with flow of red blood cells also visible. Of 24 pathological diagnosed lung cancers, large, dark or black, tumor cells were visible in 21 lesions. Conclusion: pCLE was useful for the detection malignant tumor cells during bronchoscopy in real time. This novel technology has an excellent potential to provide in vivo diagnosis during bronchoscopic examinations.

Objective Nodal staging of lung cancer is important for selecting surgical candidates. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) was evaluated as a modality for nodal staging of patients with potentially node-positive non-small cell lung cancer (NSCLC). Methods Endobronchial ultrasound-guided transbronchial needle aspiration was used for nodal staging of NSCLC patients with radiological N2/3 disease (short axis >10 mm on computed tomography and/or standardized positron emission uptake value >2.5 on 2-deoxy-2[F-18] fluoro-d-glucose positron emission tomography), T-stage ≥ T2, or positive serum carcinoembryonic antigen. Data on eligible patients were extracted from the database of our institution and analyzed for differences in nodal stages between radiological staging (RS) and EBUS-TBNA-integrated staging (ES), with validation by pathological staging of patients who had undergone surgery. Results Of 480 eligible patients, there were 135 N0/1 and 345 N2/3 patients according to RS. Out of the 345 patients staged as N2/3 by RS, 113 (33 %) were downgraded to N0/1 by ES. Out of the 135 patients staged as N0/1 by RS, 12 (9 %) were upgraded to N2/3 by ES. Patients were restaged as N0/1 in 236 cases and N2/3 in 244 cases by ES, and the distributions of nodal stage between RS and ES were significantly different (p

Objectives: We retrospectively investigated whether histological cell type could affect patient prognosis for each stage according to the seventh edition of the TNM classification. Patients and methods: Clinical records of 1623 consecutive non-small cell lung cancer patients who underwent surgery between 1990 and 2007 were retrospectively reviewed. Over 92% of these patients had either adenocarcinoma (Ad; n = 1043, 64.3%) or squamous cell carcinoma (Sq; n = 452, 27.9%). Results: The overall 5-year survival rates for patients of all stages with Ad, Sq, large cell carcinoma (La), and adenosquamous cell carcinoma (As) were 67%, 56%, 58%, and 41%, respectively. Ad patients experienced better survival than Sq, As, or La patients (HR: 0.66, P < 0.0001; HR: 0.38, P = 0.011; HR: 0.69, P = 0.057, respectively). Stage IA Ad patients experienced better survival than stage IA Sq patients (5-year survival; Ad/Sq = 91%/78%, log-rank test, P = 0.001). Such a difference was also observed among seventh-edition TNM stage IB patients (5-year survival; Ad/Sq = 78%/64%, log-rank test, P = 0.048), but not for sixth-edition stage IB patients. Multivariate analysis demonstrated that histological cell type is a significant prognostic factor among stage I ≥ T1b Ad and Sq patients. Conclusions: Survival after complete resection of new stage I ≥ T1b Sq patients is significantly worse than that of Ad patients, which could be partially attributed to stage migration effect in stage IB disease between the sixth and seventh editions of the TNM staging system.

The 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.Patients 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.Four 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.The administration of α-GalCer-pulsed APCs successfully induced the dramatic infiltration and activation of iNKT cells in the tumor microenvironment.

Objectives To assess risk of lung cancer (LC) in patients with preinvasive bronchial lesions and to identify factors associated with higher risk. Methods 124 patients with one or more preinvasive bronchial lesions and normal chest computed tomography (CT) (mean age 66.7 years, 121 males and 3 females), followed-up by white light and autofluorescence bronchoscopy (AFB) every 4–6 mo and chest CT every 6–12 mo, end points were development of carcinoma in situ (CIS) or LC. Results Among 124 patients with 240 preinvasive bronchial lesions, 20 CIS or LC lesions were detected during follow-up in 20 (16%) patients, 7 were detected as new endobronchial lesions, 10 as new peripheral lesions and 3 as local progression from severe dysplasia to CIS. Median time to progression from the same site or development of CIS/LC elsewhere was 24 months (range: 6–54 mo). The Cumulative risk of development of CIS/LC was 7% at one year, 20% at three years and 44% at 5 years. Among detected lung cancers, 80% were stage 0 or stage I and underwent treatment with curative intent. Diagnosis of new SD during follow-up (p = 0.0001), chronic obstructive pulmonary disease (COPD) (p = 0.001) or smoking index >52 pack-year (p = 0.042) was associated with higher risk. Even after controlling for other risk factors, COPD was associated with risk for lung cancer. Baseline lesion grade was not predictive of patient outcome (p = 0.146). Conclusion Patients with preinvasive bronchial lesions, especially those with new SD during follow-up, COPD or smoking >52 pack-year are at high risk of LC, AFB and CT follow-up facilitated early detection and treatment with curative intent.

Pulmonary sclerosing hemangioma is relatively rare and is usually considered a benign tumor. There have been no reports of pulmonary sclerosing hemangioma with pleural dissemination. This report presents an extremely rare case of pulmonary sclerosing hemangioma with pulmonary dissemination. A 57-year-old woman was found to have an abnormal shadow in the right lower lung field on chest X-ray. Chest computed tomography (CT) indicated a 2.5-cm mass in the right lower lobe. A bronchoscopic biopsy failed to identify malignant cells, which led to the patient undergoing an excisional lung biopsy. Intraoperative findings showed a tumor in the right lower lobe with multiple small nodules in the pleura. The pathological findings revealed that the tumor was sclerosing hemangioma with pleural dissemination. Annual follow-up CT showed irregular pleural thickness, which suggested progressive dissemination 3 years after the operation. Although pulmonary sclerosing hemangioma is regarded as a benign tumor, the potential for malignancy may be a consideration in this setting.

症例は29歳，男性．左主気管支原発の腺様嚢胞癌で病変は下位気管および右主気管支と広範に及んでいた．広範囲気道切除再建に際し，再建時の人工心肺使用，吻合部大網被覆等を考慮し胸骨正中経路にて左Sleeve pneumonectomyを施行した．腫瘍が左主気管支周囲で壁外浸潤（肺動脈分岐部）しており，左肺全摘を先行した後，人工心肺使用下に肺動脈合併切除および気管5リング，気管分岐部，右主気管支2リングの広範囲気道切除再建を円滑に施行し得た．術後人工呼吸管理を要したが良好な経過が得られた．左Sleeve pneumonectomyは頻度も低く，手技が複雑で術後死亡率も高い術式ではあるが，適切な症例選択，手術手技，麻酔管理，術後管理を行うことにより，良好な経過が可能となる．

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 μm, 63.7 ± 8.2 μm, 136.5 ± 29.9 μm and 259.4 ± 29.6 μm, respectively. These results indicated a statistically significant increase of mean vessel diameters in the four groups (P 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.

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

Objective: Failure or prolongation of treatment for refractory thoracic empyema by the current chesttube drainage technique is often due to sterilization difficulties. Insufficient sterilization prolongs hospitalization, and is often associated with life-threatening complications and/or additional invasive surgical procedures. A new chest-tube sterilization technique aimed at making it less invasive and shortening the therapy is proposed.Methods: Following pretreatment for complications including loculation, bronchopleural fistula, or corticated lung, a double-lumen trocar catheter was introduced at the bottom of the empyemic cavity through the lateral chest wall. Then, a Foley balloon urethra-catheter was inserted and attached just inside the anterior chest wall at the top of the cavity for the evacuation of intrathoracic air. After irrigation of the cavity with distilled water once or twice, the cavity was completely filled with a bactericidal solution which was left in place for 30–60 minutes, followed by an antibiotic solution for more than 20 hours.Results: Among the five treated post-lobectomy or pneumonectomy cases, sterilization was obtained after only one treatment in four cases and after two courses in the other. Catheterization duration from the initial treatment was 2–13 days. Neither recurrence nor treatment-related major complications were observed.Conclusions: This balloon-tube thoracostomy technique is simple, minimally invasive and cost-effective, due to shortening of the treatment time with minimal manpower and equipment requirements. It is thus a promising therapeutic approach to thoracic empyema and has the potential for application to other intrathoracic disorders.

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.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.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; p0.001) 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: p0.001). 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.We established and validated currently useful criteria for VAMs in the management of primary lung cancer.

BACKGROUND Normal bronchial epithelium gradually acquires cellular and genetic changes that result in the formation of invasive tumors. The objective of this study was to evaluate the degree of proliferative change and the amount of neovascularization in both normal and preneoplastic lesions in smokers who were at high risk for developing lung carcinoma. METHODS The authors studied bronchial biopsy specimens from 7 nonsmokers and 52 smokers. Immunohistochemical staining of the specimens with antibodies for the presence of p53 protein, Ki-67 and CD34 antigens, and vascular endothelial growth factor was performed. The proliferation index (PI) was assessed by immunohistochemical staining for Ki-67 antigen. RESULTS Overexpression of p53 protein was observed frequently in regions of squamous dysplasia and in squamous cell carcinoma tissue. The PI of normal epithelium from smokers was increased compared with nonsmokers, and the difference was statistically significant (P < 0.05). The microvessel count (MC) in normal mucosa obtained from smokers was higher compared with the MC in normal mucosa obtained from nonsmokers (P < 0.05). A significant difference in MC also was observed between regions of squamous metaplasia or dysplasia with projections of capillary loops into the bronchial mucosa and similar lesions without capillary loops (P < 0.005); however, there was no difference in either the PI or the incidence of p53 overexpression between these groups. CONCLUSIONS These results show that smoking appears to induce both a proliferative response and neovascularization in bronchial mucosa. The projection of capillary loops into the bronchial mucosa also may be a result of neovascularization occurring within the lamina propria of the bronchial wall. Cancer 2002;95:1539–45. © 2002 American Cancer Society. DOI 10.1002/cncr.10850

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.

BACKGROUND 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. METHODS Cytologic features were analyzed for 15 sclerosing hemangiomas, and cytologic features of sclerosing hemangioma were compared with features of 22 cases of well-differentiated papillary adenocarcinoma classified as pathologic Stage 1A. RESULTS Blood and round cells were observed more frequently in SH than in adenocarcinomas (P < 0.05), whereas necrosis was seen more frequently in adenocarcinomas than in SH (P < 0.05). The presence of nucleoli, nuclear indentations, irregularities of nuclear margins, nuclear polymorphisms, and high nuclear-cytoplasmic (NC) ratios of tumor cells were observed less frequently in SH. Polynuclear (having three or more nuclei) tumor cells were observed only in adenocarcinoma cases. In morphometric studies, the nuclear areas, cytoplasmic areas, NC ratios, long axes of nuclei, short axes of nuclei, and nuclear rotundity ratios were significantly higher in adenocarcinoma cells than in SH cells (P < 0.05). CONCLUSIONS The presence of polymorphous cells and tumor cells with bland nuclei are characteristic cytologic findings associated with sclerosing hemangioma. It is possible to make accurate diagnoses for SH cases preoperatively by careful cytologic characterization. Cancer (Cancer Cytopathol) 2002. © 2002 American Cancer Society.

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.

Purpose The aim of this retrospective study was to evaluate the relevance of surgery in non-small cell lung cancer (NSCLC) patients with ipsilateral pulmonary metastases. Methods The clinical records of 1,623 consecutive NSCLC patients who underwent surgery between 1990 and 2007 were retrospectively reviewed. Overall, 161 (9.9 %) and 21 (1.3 %) patients had additional nodules in the same lobe as the primary lesion (PM1) and additional nodules in the ipsilateral different lobe (PM2), respectively. Results The 5-year survival rate was 54.4 % in the PM1 patients and 19.3 % in the PM2 patients (log-rank test: p = 0.001). Tumor size B3 cm, N0-1 status and surgical procedures less extensive than bilobectomy were identified as favorable prognostic factors in the PM1 patients. The 5-year survival rate in the PM1-N0-1 patients was 68.7 %, while that in the PM1-N2-3 patients was 29.1 % (p \ 0.0001). Compared to the non-PM1 stage IIIA patients, the stage IIIA patients with PM1 disease (PM1-N1) tended to experience longer survival times (p = 0.06). Squamous cell types and bilobectomy or more extensive procedures were found to be unfavorable factors in the PM2 patients. The survival of the PM2 patients was significantly worse than that of the other T4 patients (p = 0.007). Conclusions PM1 patients with N0-1 disease are good candidates for surgery, whereas PM2 patients do not appear to benefit from surgery.

Background N-methyl-D-aspartate receptors (NMDAR) act as tumor suppressors of digestive malignancies. The expression and genetic methylation patterns of NMDAR2B in non-small cell lung cancer (NSCLC) are unknown. Methods The relationship between gene methylation and expression of NMDAR2B was analyzed in NSCLC cell lines (N = 9) and clinical tissues (N = 216). The cell lines were studied using RT-PCR and 5-aza-2'-deoxycytidine treatment, while the clinical tissues were examined by methylation specific real-time quantitative PCR and immunohistochemistry. Retrospective investigation of patient records was used to determine the clinical significance of NMDAR2B methylation. Results NMDAR2B was silenced in five of the nine cell lines; 5-aza-2'-deoxycytidine treatment restored expression, and was inversely correlated with methylation. Aberrant methylation of NMDAR2B, detected in 61% (131/216) of clinical NSCLC tissues, was inversely correlated with the status of protein expression in 20 randomly examined tumors. Aberrant methylation was not associated with clinical factors such as gender, age, histological type, or TNM stage. However, aberrant methylation was an independent prognostic factor in squamous cell carcinoma cases. Conclusions Aberrant methylation of the NMDAR2B gene is a common event in NSCLC. The prognosis was significantly better for cases of squamous cell carcinoma in which NMDAR2B was methylated. It may have different roles in different histological types.

OBJECTIVES: The prognosis of non-small-cell lung cancer (NSCLC) patients with malignant pleural disease (MPD), characterized by malignant pleural effusion and/or malignant pleural nodules, is reported to be poor, and patients with MPD are generally not subjected to surgery. However, whether or not the primary tumor should be resected, when MPD is first detected at thoracotomy, is controversial. METHODS: The clinical records of 1623 consecutive NSCLC patients, who underwent surgery between 1990 and 2007, were retrospectively reviewed. A hundred patients (6.2%) were classified with pathological stage IV disease according to the seventh edition of the Union for International Cancer Control (UICC) staging system. There were 73 patients with MPD, which included 32 with effusion without nodules (MPE) and 41 with nodules with or without effusion (MPN). Intra- or postoperative pleural chemotherapy was administered to 37 MPD patients. RESULTS: The median survival time, the 3-year survival rate and the 5-year survival rate for MPD patients were 25.9 months, 41.4%, and 23.7%, respectively, which are better outcomes than those for M1b patients (8.7 months, 18% and 18%, respectively) (log-lank test: p = 0.014). Among MPD patients, N0–1 disease was determined to be a favorable prognostic factor (p = 0.01). MPD status (MPE or MPN) was not prognostically significant (p = 0.40). MPE patients with N0–1 disease had a significantly better prognosis with a 5-year survival rate of 63.6% compared to MPE patients with N2–3 disease (p = 0.003). Twenty-seven percent of MPN patients with N0–1 disease achieved 5-year survival, whereas none of the MPD patients with N2–3 disease survived longer than 5 years after surgery. CONCLUSIONS: The prognosis of patients with surgically detected MPD, who underwent resection, was better than that of M1b patients. MPE patients with N0–1 disease may be candidates for resection.

We report a case of a 67-year-old woman with stage IIIB locally advanced non-small cell lung cancer who had also suffered from hyperthyroidism with persistent atrial fibrillation (AF). Thiamazole provided euthyroid status, but medication failed to resolve AF. A computed tomography (CT)-scan revealed a 5×5-cm mass in the left hilar region that involved the left atrium (LA) and bifurcation of the pulmonary artery. Left pneumonectomy, LA partial resection and reconstruction of the bifurcation of the pulmonary artery were performed. In addition, a maze procedure was performed using cardiopulmonary bypass and cardiac arrest. We present the first case report of advanced lung cancer surgery with a maze procedure. Follow-up by CT-scan 34 months later did not show any recurrence and attacks of AF (no medication after surgery) were completely resolved after the operation.

The prognosis for non-small cell lung cancer (NSCLC) with chest wall invasion can vary due to the heterogeneous nature of the cell population. Because NSCLC with large tumors (>7 cm) have been reclassified as T3, the applicability of the new designation must be evaluated. We reviewed 140 patients with chest wall T3 and 28 patients with T3 NSCLC with large tumors, but no chest wall invasion who underwent resection at our institution. Among chest wall T3 patients, elderly T3 patients (≥80 years old) who died within 42 months, patients with either lymph node or pulmonary metastasis, or patients with a large tumor (>7 cm) had poorer prognoses than those who had not. The survival rates for cases with chest wall T3 and cases with a large tumor without chest wall invasion were not significantly different. NSCLC patients with chest wall T3 with lymph node, or pulmonary metastasis, or with a large tumor should be considered for further multimodal treatment with or without resection to enhance their survival time. Elderly patients with chest wall invasion may not be good candidates for resection. A large tumor is so aggressive that re-classification of large tumor cases as T3 is suitable.

Objectives We investigated the capabilities of an endo-cytoscopy system (ECS) that enables microscopic imaging of the tracheobronchial tree during bronchoscopy, including normal bronchial epithelium, dysplastic mucosa and squamous cell carcinoma. Methods The newly developed ECS has a 3.2 mm diameter that can be passed through the 4.2 mm working channel of a mother endoscope for insertion of the ECS. It has a high magnification of 570× on a 17 in. video monitor. Twenty-two patients (7 squamous cell carcinoma, 11 squamous dysplasia and 4 after PDT therapies) were underwent white light, NBI light and AFI bronchoscopy. Both abnormal areas of interest and normal bronchial mucosa were stained with 0.5% methylene blue and examined with ECS at high magnification (570×). Histological examinations using haematoxylin and eosin staining were made of biopsied specimens. Analyzed ECS images were compared with the corresponding histological examinations. Results In normal bronchial mucosa, ciliated columnar epithelial cells were visible. In bronchial squamous dysplasia, superficial cells with abundant cytoplasm were arranged regularly. In squamous cell carcinoma, large, polymorphic tumor cells showed increased cellular densities with irregular stratified patterns. These ECS images corresponded well with the light-microscopic examination of conventional histology. Conclusion ECS was useful for the discrimination between normal bronchial epithelial cells and dysplastic cells or malignant cells during bronchoscopy in real time. This novel technology has an excellent potential to provide in vivo diagnosis during bronchoscopic examinations.

We herein report a case of acute respiratory distress syndrome (ARDS) that appeared to be related to a granulocyte colony-stimulating factor (G-CSF)-producing lung cancer. A 77-year-old man with arterial sclerotic obstruction (ASO) underwent reconstructive surgery of the left femoral artery. He developed ARDS on the 5th postoperative day, which resolved following mechanical ventilation with steroid pulse treatment. Four months later, he was admitted with a fever and right arm pain. Chest computed tomography showed a malignant lesion in the right apical lung, and percutaneous needle biopsy demonstrated adenocarcinoma. Laboratory data revealed neutrophilia with elevated serum G-CSF levels. He underwent a right upper lobectomy with chest wall resection, and administration of sivelestat sodium to treat his postoperative pre-acute lung injury state. Pathology revealed a G-CSF-producing pleomorphic carcinoma. Retrospectively, a tumor shadow was noted on chest X-ray at the time of ARDS just after ASO surgery. The relationship between an abnormal G-CSF level and ARDS was considered, and the implications are herein discussed.

Hypermethylation of promoter CpG islands is a major inactivation mechanism of tumor suppressor genes, some of which are thought to be related to the prognosis of patients with non-small cell lung cancer (NSCLC). Therefore, hypermethylation of the specific genes may be expected to serve as a prognostic biomarker for NSCLC. In this study, the methylation status of 14 genes was analyzed in 44 stage IA NSCLC cases using methylation-specific PCR. Hypermethylation was detected in PTGER2 (70% of cases), DRM/Gremlin (66%), sFRP-2 (57%), IL-12Rbeta2 (48%), Reprimo (41%), APC (39%), CXCL12 (39%), HPP1 (30%), SPARC (30%), sFRP-5 (30%), p16 (25%), RUNX3 (20%), sFRP-1 (20%) and Wif-1 (16%). Patients with p16, sFRP-5, Wif-1 or CXCL12 methylation had a significantly shorter duration of relapse-free survival than their counterparts with an unmethylated gene (p16, P=0.011; sFRP-5, P=0.030, Wif-1, P=0.036; CXCL12, P=0.026). Also, those with methylated HPP1, p16 or Wif-1 had a significantly shorter duration of overall survival (HPP1, P=0.031; p16, P=0.026; Wif-1, P=0.008). Multivariate analysis revealed that p16 methylation in relapse-free survival and Wif-1 methylation in overall survival were the strongest independent prognostic factors (p16, P=0.036; Wif-1, P=0.035). In conclusion, the hypermethylation of the p16 and Wif-1 genes has potential as biomarkers that may be used to predict the prognosis of stage IA NSCLC.

A 32-year-old woman with ocular-typed myasthenia gravis (MG) without thymoma was admitted to the hospital to undergo surgical treatment. Video-assisted thoracoscopic surgery (VATS) extended thymectomy was successfully performed with three small ports using manual manipulators, the Radius Surgical System (RSS). The device may facilitate many degrees of freedom to general thoracic surgery.

Several studies have described p16INK4A and prostaglandin E2 (PGE2) co-alterations in various solid tumors, including non-small cell lung cancer (NSCLC). In this study, we examined the correlation between PGE2 receptor 2 (EP2) expression and p16INK4A methylation in NSCLC, and the association with clinicopathological features and prognostic significance. We retrospectively reviewed 88 NSCLC patients who underwent resection from July 1993 to May 1997. The tumors included 43 adenocarcinomas, 39 squamous cell carcinomas, and 6 large cell carcinomas. EP2 expression was determined by immunostaining, and p16INK4A methylation was analyzed by methylation specific PCR. EP2 was overexpressed in 44% of NSCLC patients, 61% of adenocarcinoma cases, 28% of squamous cell carcinoma cases, and 33% of large cell carcinoma cases. EP2 expression positively correlated with lymph node metastasis (P=0.034), especially in patients with squamous cell carcinoma (P

The 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).The 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.IL-12Rbeta2 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 p16(INK4A) and WNT antagonist genes was a negative prognostic factor in the non-COPD group.Novel 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.

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.

Some dysplasias in the bronchial epithelium are thought to be precancerous lesions that can develop into squamous cell carcinomas. In this investigation, we assessed the biological behavior of bronchial squamous dysplasia in order to define which dysplasias have the potential to progress to squamous cell carcinoma. Using autofluorescence bronchoscopy, we followed up periodically localized dysplasias and examined for correlation between histological outcome and smoking status during the follow-up period, telomerase activity, Ki-67 labeling index, and p53 immunoreactivity of initial biopsy specimens. Ninety-nine dysplasias from 50 participants mainly with sputum cytology suspicious or positive for malignancy were followed up. Of 99 dysplasias, 3 dysplasias progressed to squamous cell carcinoma, 41 dysplasias remained as dysplasia, 6 dysplasias changed to metaplasia, 14 dysplasias changed to hyperplasia, and 35 dysplasias regressed to bronchitis or normal bronchial epithelium. There were no significant associations between histological outcome and smoking status. Mean initial telomerase activity and Ki-67 labeling index values in the dysplasias increased in proportion to the severity of the histological outcome at the second biopsy. There was also a significant difference between p53-positive and p53-negative dysplasia in terms of histological outcome at the second biopsy. Our results suggested that dysplasias with high telomerase activity, increased Ki-67 labeling index, and p53-positivity tended to remain as dysplasia and might have the potential to progress to squamous cell carcinoma. Patients with dysplastic lesions with these characteristics should be carefully followed up.