千代 雅子

Thymic mucoepidermoid carcinoma (MEC) is a rare tumor, and its characteristics remain to be clarified. Here we investigated 20 cases of thymic MEC to systematically characterize its clinical, histopathologic, and molecular features. The median age of the patients was 56 years (range, 19 to 80 y), there was a slight male predilection (3:2), and 44% of the patients were asymptomatic at diagnosis. The median tumor size was 6.8 cm in diameter, 55% were pT1 tumors, and 50% were TNM stage I tumors. When 4 tumor grading systems for salivary MEC (Armed Forces Institutes of Pathology, Brandwein, modified Healey, and the Memorial Sloan-Kettering) were employed, low-grade, intermediate-grade, and high-grade tumors accounted for 35% to 70%, 5% to 25%, and 25% to 50%, respectively. Many histologic variants were noted, and 70% of the cases were classified as nonclassic variants. MAML2 rearrangement was detected in 56% of cases, and the fusion partner was CRTC1 in all cases. CRTC1-MAML2 fusion was associated with lower pT classification and lower TNM stage. The overall survival rate of all patients was 69% and 43% at 5 and 10 years, respectively. Worse overall survival was associated with higher pT stage, higher TNM stage, residual tumors, greater tumor size, high-grade tumor histology (Armed Forces Institutes of Pathology and Memorial Sloan-Kettering, but not the other 2), and with the absence of CRTC1-MAML2 fusion. Of note, none of the patients with CRTC1-MAML2 fusion-positive tumors died during the follow-up. In conclusion, the clinicopathologic and molecular findings of thymic MEC presented here are expected to contribute to the management of this rare tumor.

BACKGROUND: A pulmonary arteriovenous malformation is an abnormal dilated blood vessel that makes direct communication between a pulmonary artery and pulmonary vein and can be associated with hypoxemia or neurological complications, including brain abscess and cerebral infarction. Treatment of pulmonary arteriovenous malformation includes surgical resection and transcatheter embolotherapy, however the adaptation of therapies should be considered when a patient is in bad condition. CASE PRESENTATION: A 51-year-old man was admitted after developing fever, consciousness disorder, and hypoxemia. Magnetic resonance imaging of the brain showed a brain abscess. Bilateral pulmonary arteriovenous malformations were found by contrast computed tomography. Because of a family history of pulmonary arteriovenous malformation, a history of epistaxis, and the existence of oral mucosa telangiectasia, he was diagnosed with hereditary hemorrhagic telangiectasia and brain abscess caused by intrapulmonary right-to-left shunt. The brain abscess improved with antibiotic treatment; however, the administration of oxygen did not ameliorate his hypoxemia. His hypoxemia was exacerbated by positive pressure ventilation. Considering his systemic and respiratory condition, we considered surgery to involve a high degree of risk. After controlling his brain abscess and pneumonia, transcatheter embolotherapy was performed. This improved his systemic condition, enabling surgical treatment. CONCLUSIONS: This middle-aged patient suffering from brain abscess and severe hypoxemia with multiple pulmonary arteriovenous malformations was successfully treated by a combination of transcatheter embolotherapy and surgery. The adaptation and combination of therapies, as well as the sequence of treatments, should be considered depending on the patient status and lesions.

PURPOSE: The sampling and accurate diagnosis of lymph nodes during the clinical history of lung cancer are essential for selecting the appropriate treatment strategies. This study aims to evaluate the feasibility of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in patients with previously treated lung cancer. METHODS: Patients who underwent EBUS-TBNA after treatment for lung cancer were retrospectively reviewed. We classified the patients into two groups; Group 1 (G1): Indicated to have a recurrence of new lesions after radical surgery or chemo/radiotherapy with a curative intent; and Group 2 (G2): Indicated to have residual tumor cells after undergoing primary treatment for chemo/radiotherapy or re-staging after induction therapy prior to surgery. RESULTS: Seventy previously treated lung cancer cases (G1, n = 52; G2, n = 18) were enrolled. Thirty-two cases (61.5%) had recurrent disease in G1, and 9 cases (50.0%) had nodal metastasis in G2. The diagnostic accuracy was 95.2% in G1 and 88.9% in G2. Twenty-four cases were examined for epidermal growth factor receptor (EGFR) mutations, and 9 (37.5%) cases had mutations, including two cases with a T790M mutation. Furthermore, in one case, a re-biopsy revealed that the initial adenocarcinoma had transformed into small cell lung cancer. CONCLUSION: Performing EBUS-TBNA during lung cancer treatment showed a high diagnostic yield. Samples obtained by EBUS-TBNA were helpful in determining when to perform repeat biomarker testing as well as for making pathological re-evaluations.

BACKGROUND: Obliterative bronchiolitis (OB) is a known issue during minor histocompatibility antigen (mHA) disparity during lung transplantation. This study evaluated gene expression in a murine orthotropic lung transplantation model using microarray analysis. METHODS: Left lungs from C57BL/10(H-2b) donor mice were transplanted into mHA-mismatched C57BL/6(H-2b) recipient mice. Three groups (OB, non-OB, and sham controls) were confirmed pathologically and analyzed. Gene expression changes in the lung grafts were determined by microarray and immunohistochemical staining, and genes were verified by quantitative PCR in the lungs and mediastinal lymph nodes (LNs). RESULTS: A total of 1343 genes were upregulated in the OB lungs compared to the sham group. Significant upregulation was observed for genes related to innate, e.g. Tlr2 and CCL3 and adaptive immunity, e.g. H2-ab1 and Il-21. Positive labeling for MHC class II antigen was observed in the bronchial epithelium of OB accompanied with B cells. We found increased Tlr2, Ccl3, H2-ab1, Il-21, Ighg3, Ifng, and Pdcd1 mRNA expression in the OB lung, and increased Il-21, Ighg3, and Pdcd1 expression in the OB LNs. CONCLUSIONS: Adaptive and innate immune reactions were involved in OB after lung transplantation, and genetic examination of related genes could be used for detection of OB.

BACKGROUND: During endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), the sonographic findings of B-mode imaging, as well as endobronchial elastography, can be obtained noninvasively and used for the prediction of nodal metastasis. METHODS: Patients with lung cancer or suspected lung cancer who underwent EBUS-TBNA were recorded prospectively and reviewed retrospectively. Both the B-mode sonographic and elastographic findings were independently evaluated for each lymph node. The sonographic features were classified according to previously published criteria. If oval shape, indistinct margins, homogenous echogenicity, and the absence of coagulation necrosis sign were all observed by B-mode imaging, then the lymph node was judged to be benign by sonographic imaging. In addition, if the stiffer area comprised more than 31% of the entire lymph node area, then the lymph node was judged to be malignant by elastography. We compared the results of these imaging-based predictions with the pathological diagnoses. RESULTS: The prevalence of nodal metastasis was 78/228 (34.2%). B-mode sonography predicted 95.8% of benign lymph nodes, and elastography predicted 72.1% of malignant lymph nodes. By combining the two modalities, 59 of 71 (83.1%) lymph nodes judged as malignant by both analyses were pathologically proven to be malignant, and 101 of 105 (96.2%) lymph nodes judged as benign by both analyses were pathologically proven to be benign. CONCLUSION: The combination of elastography and sonographic findings showed good sensitivity and a high negative predictive value, which may facilitate selecting the most suspicious lymph nodes for biopsy. KEY POINTS: Significant findings of the study. The combination of endobronchial elastography and sonography resulted in a higher diagnostic yield than either modality alone for predicting benign and malignant lymph nodes in patients with lung cancer. WHAT THIS STUDY ADDS: The combination of endobronchial elastography and sonography will help clinicians identify the most suspicious lymph nodes for puncturing during EBUS-TBNA, which may improve the efficiency of EBUS-TBNA.

BACKGROUND: Recently sublobar resection is often indicated for small-sized peripheral lung cancer according to size or the consolidation/tumor ratio on CT; however, the T-factor classification drastically changed in the 8th version. We investigated the relationship between a novel clinical T-factor classification, which includes other clinical information and the pathologic N-factor, to evaluate the applicability of the novel T-factor classification to sublobar resection. METHODS: From January 2013 to October 2017, 545 patients with cTis or cT1 lung cancer underwent surgery. Patients with non-peripheral type, induction treatment, cN≥1, cM1, and those without nodal dissection, preoperative evaluation by thin-sliced CT or FDG-PET were excluded. Finally, 325 patients were eligible for inclusion. All clinical parameters were prospectively collected and retrospectively analyzed. The 8th edition of TNM classification was utilized. RESULTS: Nodal metastasis was detected in 38 (11.7%) patients. Among cTis/1mi/1a/1b/1c patients (n=10/11/51/146/107), pN1 and pN2 were observed in 0/0/2/9/10 and 0/0/1/8/8, respectively. cT1b/c patients showed a significantly higher rate of nodal metastasis (P=0.024). Among 253 cT1b/c patients, solid-type tumors (n=177) were more frequently associated with nodal metastasis. A ROC curve analysis revealed that SUVmax 1.9 was the cutoff value (AUC=0.827) for the presence of nodal metastasis. Using the 2 parameters of solid-type or SUVmax ≥1.9, we could successfully exclude patients with nodal metastasis, for whom sublobar resection is not indicated. CONCLUSIONS: In terms of nodal metastasis, sublobar resection can be applicable for all cTis/1mi tumors; patients with cT1a/b/c tumors with mixed GGO and low SUVmax are candidates for sublobar resection.

PURPOSE: 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. METHODS: Clinical records of lung cancer patients who underwent patch plasty were reviewed retrospectively. RESULTS: 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. CONCLUSION: Patch angioplasty using the ePTFE sheet is a reliable procedure in radical surgery for lung cancer.

BACKGROUND: Sclerosing pneumocytoma is a rare lung tumor that is usually recognized as a solitary nodule in the lung. Surgical removal is recommended; however, its clinical diagnosis is still an issue because it is difficult to differentiate from lung adenocarcinomas using a tiny sample obtained from biopsy. CASE PRESENTATION: We report a case of pulmonary sclerosing pneumocytoma located in the upper lobe of the right lung of a 34-year-old woman, which was diagnosed before surgery by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). A 3-cm irregular mass was detected by chest X-ray without any symptoms. She was referred to our hospital after being followed for 10 years in her previous clinic. During this follow-up period, the tumor had grown to 5 cm. We performed the EBUS-TBNA for the diagnosis. The histological findings obtained by EBUS-TBNA consisted of alveolar type 2-like cells that were positive for napsin A and round cells that were positive for vimentin. Based on these immunostaining results, we successfully diagnosed sclerosing pneumocytoma before surgery. Right upper lobectomy was performed, and the pathological diagnosis of the surgical specimen was also confirmed as sclerosing pneumocytoma. CONCLUSIONS: We herein report a case of sclerosing pneumocytoma, which was clinically diagnosed by EBUS-TBNA and resected surgically.

BACKGROUND: Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a relatively rare subtype of lung malignancy. According to revised 2015 World Health Organization (WHO) criteria for the pathological diagnosis of LCNEC, neuroendocrine markers must be examined by immunohistochemistry. In this study, we reevaluated endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) samples of patients previously diagnosed with LCNEC using the revised WHO criteria. METHODS: Clinical tissue samples that had been obtained by EBUS-TBNA between January 2004 and December 2011, and that had been pathologically diagnosed as LCNEC according to the previous criteria, were reevaluated according to the revised WHO criteria. RESULTS: The records of 471 lung cancer patients with mediastinal or hilar lymph node metastasis diagnosed by EBUS-TBNA were analyzed. Thirteen patients were diagnosed with LCNEC; one of which was diagnosed based on cytology alone because the histological material was insufficient for a histological examination. Among the 12 cases in which a histological examination was performed, nine were diagnosed with possible LCNEC based on neuroendocrine marker positivity, while three were diagnosed with suspected LCNEC because they did not meet the immunostaining criteria. The patient who was cytologically diagnosed was found to have non-small cell carcinoma with neuroendocrine morphology. CONCLUSION: LCNEC could be pathologically diagnosed based on 2015 WHO criteria using EBUS-TBNA samples.

BACKGROUND: The limited negative predictive value of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has often been discussed. OBJECTIVE: The aim of this study was to identify a highly sensitive molecular biomarker for lymph node staging by EBUS-TBNA. METHODS: Five microRNAs (miRNAs) (miR-200a, miR-200b, miR-200c, miR-141, and let-7e) were selected as biomarker candidates for the detection of nodal metastasis in a miRNA expression analysis. After having established a cutoff level of expression for each marker to differentiate malignant from benign lymph nodes among surgically dissected lymph nodes, the cutoff level was applied to snap-frozen EBUS-TBNA samples. Archived formalin-fixed paraffin- embedded (FFPE) samples rebiopsied by EBUS-TBNA after induction chemoradiotherapy were also analyzed. RESULTS: The expression of all candidate miRNAs was significantly higher in metastatic lymph nodes than in benign ones (p < 0.05) among the surgical samples. miR-200c showed the highest diagnostic yield, with a sensitivity of 95.4% and a specificity of 100%. When the cutoff value for miR-200c was applied to the snap-frozen EBUS-TBNA samples, the sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy were 97.4, 81.8, 95.0, 90.0, and 94.0%, respectively. For restaging FFPE EBUS- TBNA samples, the sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy were 100, 60.0, 80.0, 100, and 84.6%, respectively. Among the restaged samples, 4 malignant lymph nodes were false negative by EBUS-TBNA, but they were accurately identified by miR-200c. CONCLUSIONS: miR-200c can be used as a highly sensitive molecular staging biomarker that will enhance nodal staging of lung cancer.

The PCR panels presented in Figs. 1 and 2 are incorrect. The authors provide the correct figures below. These changes do not affect the interpretation or conclusions of this work. The authors regret this error. [the original article was published in the International Journal of Oncology 33: 113-119, 2008 DOI: 10.3892/ijo.33.1.113]

Background. Large cell carcinoma of the lung typically occurs in the peripheral lungs and rarely causes airway stenosis. Case. A 65-year-old male presented to a nearby hospital with chief complaints of a progressively worsening cough and dyspnea. Chest CT showed a 6.5x5.8-cm mass at the location of the #4R lymph nodes that had directly invaded the trachea, causing marked stenosis immediately above the tracheal bifurcation. The patient suffered asphyxiation on the day of transfer to our hospital. He received endotracheal intubation and mechanical ventilator support. The next day, he was placed under general anesthesia, and the tumor was partially resected using a rigid endoscope with placement of a Y-stent. Subsequently, his respiratory distress markedly improved. The pathological diagnosis was large cell carcinoma with neuroendocrine differentiation. A wholebody examination revealed no metastasis to distant organ sites, and a diagnosis of stage IIIB (cT4N2M0) was made. The patient received radiation therapy with a total dose of 60 Gy and chemotherapy consisting of four courses of cisplatin and etoposide. Subsequently, the tumor size decreased. The Y-stent was removed a year and a half after the completion of treatment. Conclusion. We herein reported a case of large cell carcinoma with neuroendocrine differentiation in a patient who exhibited a clinical response to chemoradiation therapy after Y-stent placement for central airway stenosis. © 2014 The Japan Lung Cancer Society.

Extraskeletal osteosarcoma is a rare malignant tumor occurring very rarely in the pleura. We herein report the case of 67-year-old man with asbestos exposure, who underwent biopsies of the large tumor from the chest wall, and diagnosed as a suspicious of fibrosarcoma. Surgical resection was done, and the pathological diagnosis was extraskeletal osteosarcoma arising from the pleura. The differential diagnosis is malignant pleural mesothelioma with osseous and cartilaginous which is also very rare and one of the histopathological subtypes with heterologous elements. Identification of epithelial components, labeling for cytokeratins in spindle cells and its' anatomical distribution may help to distinguish them. In the neoplasm arising from the parietal pleura, primary extraskeletal osteosarcoma of the pleura is very rare, but should be considered.

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.

BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive procedure with a high yield for lymph node staging of lung cancer. The aim of this study was to assess the utility of sonographic features of lymph nodes during EBUS-TBNA for the prediction of metastasis in patients with lung cancer and to establish a standard endobronchial ultrasound (EBUS) image classification system. METHODS: Digital images of lymph nodes obtained during EBUS-TBNA in patients with lung cancer were categorized according to the following characteristics: (1) size (short axis) less or more than 1 cm, (2) shape (oval or round), (3) margin (indistinct or distinct), (4) echogenicity (homogeneous or heterogeneous), (5) presence or absence of central hilar structure, and (6) presence or absence of coagulation necrosis sign. The sonographic findings were compared with the final pathologic results. RESULTS: A total of 1,061 lymph nodes were retrospectively evaluated in 487 patients. The accuracy of predicting metastatic property for each category was as high as 63.8% to 86.0%. A multivariate analysis revealed that round shape, distinct margin, heterogeneous echogenicity, and presence of coagulation necrosis sign were independent predictive factors for metastasis. Two hundred eighty-five of the 664 lymph nodes (42.9%) having at least one metastatic feature of the four categories were pathologically proven metastatic, and 96.0% of lymph nodes (381/397) were proven not metastatic when all four categories were determined as benign. CONCLUSIONS: Sonographic features of lymph nodes based on the new EBUS imaging classification may be helpful in the prediction of metastatic lymph nodes during EBUS-TBNA.

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.

BACKGROUND: Lung cancer patients with chronic obstructive pulmonary disease (COPD) have a high risk of developing postoperative pneumonia (POP). This study aims to investigate the impact of COPD on POP and the trends for perioperative bronchial colonisation by micro-organisms. METHODS: A retrospective chart review was made for 626 patients who underwent lung cancer surgeries at the Chiba University Hospital between 1996 and 2005. The patients were categorised as non-COPD (n=475) and COPD (forced expiratory volume in 1s/forced vital capacity (FEV1/FVC) <70%; n=151). All the patients had sputum and bronchial bacterial cultures examined for potentially pathogenic micro-organisms (PPMs). Risk factors for POP and mortality were analysed. RESULTS: Patients with COPD had a significantly higher incidence of POP (23/151, 15.2%) than those without COPD (17/475, 3.6%) (p<0.0001). Preoperative bronchial bacterial examinations showed that 50 of 475 patients without COPD (10.5%) had positive cultures, while the results for 30 of 151 patients with COPD (19.9%) were positive (p=0.0111). Only 31 of 548 patients (5.7%) who did not show any preoperative PPMs had POP, while nine of 78 patients (11.5%) who presented preoperative PPMs had POP (p=0.0469). The PPMs that emerged postoperatively were primarily Staphylococcus aureus (and Gram-negative bacilli (94.4% of PPMs), while they were seen less frequently preoperatively (46.5% of PPMs). Multivariate analysis demonstrated that advanced age and FEV1/FVC were independent risk factors for POP. Patients with POP had significantly worse long-term survivals than those without POP (p=0.0004). CONCLUSION: COPD was a risk factor for POP. Staphylococcus aureus and Gram-negative bacilli should be targets for postoperative prophylactic antibiotic selection. Patients with POP had poor long-term survivals.

BACKGROUND: The diagnosis of sarcoidosis requires both compatible clinical features and pathologic findings as a means to exclude other differential diagnoses. The utility of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for diagnosis of sarcoidosis has been reported, although its indication remains unclear for cases of suspicious sarcoidosis. To clarify the role of EBUS-TBNA for the diagnosis of sarcoidosis, we compared three diagnostic modalities: EBUS-TBNA, transbronchial lung biopsy (TBLB) and bronchoalveolar lavage fluid analysis (BAL). METHODS: Thirty-eight patients with suspicious sarcoidosis who had enlarged hilar and/or mediastinal lymph nodes on chest CT were retrospectively reviewed. Patients with malignancies or prior established diagnosis of sarcoidosis were excluded. BAL was initially performed followed by TBLB and finally EBUS-TBNA at the same setting. Microbacterial examinations were also performed from all samples. RESULTS: Pathological findings compatible with sarcoidosis were obtained in 32 patients. The remaining 6 patients were diagnosed as one case each of chronic eosinophilic pneumonia, atypical mycobacterial infection and tuberculosis, and the remaining three were pathologically indefinite cases. Clinically, 35 patients were diagnosed with sarcoidosis. The diagnostic accuracy of sarcoidosis was significantly better by EBUS-TBNA (91.4%, p<0.001) compared to the other two modalities. According to chest roentgenogram classifications, there were 31 stage I patients and 4 stage II patients. For stage I patients, EBUS-TBNA was significantly better (90.3%, p<0.001), but each modality showed 100% accuracy for stage II patients. CONCLUSION: It is recommended that EBUS-TBNA is added to the conventional diagnostic modalities for patients with suspicious stage I sarcoidosis on chest roentgenogram.

Interleukin-27 (IL-27) is a new IL-12-related heterodimeric cytokine comprising a novel p28 molecule and the Epstein-Barr-virus-induced gene 3 (EBI3) molecules. It augments initiation of T helper type 1-mediated immunity by enhancing the proliferation and cytokine production of T cells. In this study, we examined whether a secreted form of IL-27 subunits would inhibit IL-27-mediated immunological responses. COS-7 cells transduced with the mouse (m) p28 gene secreted a monomeric mp28 protein; however, those transduced with the mEBI3 gene did not detect a mEBI3 protein in the culture supernatants. The secreted mp28 prevented the IL-27-mediated signal transduction and activator of transcription 1 phosphorylation and subsequently inhibited the IL-27-mediated intercellular adhesion molecule-1 induction and interferon-gamma production in CD4(+) T cells. We generated mp28-expressing murine carcinoma Colon 26 cells and inoculated a mixture of the mp28- and mIL-27-expressing Colon 26 cells into syngeneic BALB/c mice. Simultaneous production of mp28 and mIL-27 from Colon 26 cells suppressed IL-27-mediated anti-tumour effects in the mice. We examined the p28-mediated immune suppression by inoculating mp28-expressing myoblasts into allogeneic mice. Forced production of mp28 suppressed the allogeneic cytotoxic T-lymphocyte induction and subsequently retarded the graft rejection. Furthermore, production of both mp28 and mp40, which inhibits the functions of IL-12 and IL-23, prolonged the graft survival longer than the grafts expressing either mp28 or mp40. We propose that p28 can be a regulatory subunit for IL-27-mediated cellular immune responses and a possible therapeutic agent to suppress unfavourable immune responses.

Amyloidosis is an uncommon disease caused by the deposition of abnormal proteins within the soft tissues. Mediastinal lymph node involvement of the disease is rare. When mediastinal lymph nodes are affected, tissue sampling is required for obtaining a firm diagnosis. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive method of sampling tissues from mediastinal and hilar lymph nodes. We report a case of primary amyloidosis involving mediastinal lymph nodes successfully diagnosed by EBUS-TBNA. © 2008 Elsevier Ltd. All rights reserved.

Primary graft dysfunction (PGD) is a major complication following lung transplantation. We reported that anti-type V collagen (col(V)) T cell immunity was strongly associated with PGD. However, the role of preformed anti-col(V) Abs and their potential target in PGD are unknown. Col(V) immune serum, purified IgG or B cells from col(V) immune rats were transferred to WKY rat lung isograft recipients followed by assessments of lung pathology, cytokines, and PaO(2)/FiO(2), an index of lung dysfunction in PGD. Immune serum, purified IgG, and B cells all induced pathology consistent with PGD within 4 days posttransfer; up-regulated IFN-gamma, TNF-alpha, and IL-1beta locally; and induced significant reductions in PaO(2)/FiO(2). Depleting anti-col(V) Abs before transfer demonstrated that IgG2c was a major subtype mediating injury. Confocal microscopy revealed strong apical col(V) expression on lung epithelial, but not endothelial cells; which was consistent with the ability of col(V) immune serum to induce complement-dependent cytotoxicity only in the epithelial cells. Examination of plasma from patients with or without PGD revealed that higher levels of preformed anti-col(V) Abs were strongly associated with PGD development. This study demonstrates a major role for anti-col(V) humoral immunity in PGD, and identifies the airway epithelium as a target in PGD.

BACKGROUND: The diagnosis of centrally located intrapulmonary tumors not visible on bronchoscopy may be a challenge. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has been shown to be useful for the evaluation of mediastinal lymph nodes. However, there have been no reports of the utility of EBUS-TBNA for the diagnosis of intrapulmonary tumors. OBJECTIVES: The purpose of this study was to evaluate the usefulness of EBUS-TBNA for the diagnosis of intrapulmonary tumors located adjacent to the central airway. METHODS: From December 2002 to June 2007, 35 patients with pulmonary masses located close to the central airways were accessed by EBUS-TBNA. Conventional bronchoscopic biopsy before EBUS-TBNA was nondiagnostic in 25 of the 35 cases. Patients with endobronchial lesions were excluded from this study. RESULTS: EBUS-TBNA was performed in 19 peritracheal and 16 peribronchial lesions. Cytologic and/or histologic samples were diagnostic in 33 of 35 patients. The final diagnoses of the pulmonary masses were lung cancer in 26 cases (1 small cell lung cancer, 25 non-small cell lung cancer), metastatic lung tumors in 5, and BALT lymphoma in one. The sensitivity and the diagnostic accuracy of EBUS-TBNA for the diagnosis of unknown pulmonary masses was 94.1% and 94.3%, respectively. CONCLUSIONS: Intrapulmonary lesions not assessable by conventional bronchoscopic procedures can easily be assessed and diagnosed by EBUS-TBNA as long as it is within the reach of the EBUS-TBNA scope. EBUS-TBNA is a real-time procedure with a high yield which can be applied for the diagnosis of lung tumors.

Chemokines play an important role in the pathogenesis of non-small cell lung cancer (NSCLC). However, aberrant methylation of CXCL12 has not been examined in NSCLC. CXCL12 mRNA expression and methylation were examined in 17 NSCLC cell lines by RT-PCR and methylation-specific PCR (MSP). MSP was performed on 236 tumor specimens from NSCLC patients who received curative intent surgery. CXCL12 and CXCR4 protein expression was examined in 90 of the 236 NSCLC specimens by immunohistochemistry. Down-regulation of CXCL12 expression was found in 10 of 17 (59%) NSCLC cell lines compared with normal bronchial cells. Treatment of 8 expression-negative cell lines with a demethylating agent restored expression in all cases. Twelve cell lines (71%) showed aberrant methylation, and good concordance between methylation and expression was present. Aberrant methylation occurred in 85 out of 236 (36%) primary NSCLCs in a tumor-specific manner. In multivariate analysis, CXCL12 methylation correlated strongly and independently with prognosis both in all patients with NSCLCs and in those with stage I NSCLCs (hazard ratio=1.68, P=0.015 and hazard ratio=3.58, P=0.017). Secreted protein CXCL12 and its receptor CXCR4 were abundant in NSCLC cells (72 out of 90, 80%; 57 out of 90, 63%) and correlated with the progression of NSCLCs. In conclusion, epigenetic silencing of CXCL12 is a frequent event in NSCLCs, and could be an independent and powerful prognostic marker in patients with NSCLCs and those with stage I disease. Analysis for CXCL12 may provide novel opportunities for prognosis and therapy of resected NSCLCs.

Endobronchial ultrasound (EBUS) is a promising new modality first introduced during the early 1990s. The radial probe EBUS was initially developed seeking for high-resolution imaging of processes in the airway wall and outside the airways. The structure of special importance was lymph nodes, walls of the central airways, and the mediastinum. After the development of miniaturized radial probes with flexible catheters having a balloon at the tip, it has been applied to aid bronchoscopists during biopsy of patients with respiratory diseases. In particular, the role of EBUS in transbronchial needle aspiration (TBNA) has been established. Radial probe EBUS-guided TBNA has increased the yield of TBNA of mediastinal lymph nodes, although it was still not a real-time procedure with target visualization. New convex probe EBUS (CP-EBUS) with the ability to perform real-time EBUS-guided TBNA (EBUS-TBNA) has emerged to overcome these problems. Indications for EBUS-TBNA are (1) lymph node staging in lung cancer patients; (2) diagnosis of intrapulmonary tumors; (3) diagnosis of unknown hilar and/or mediastinal lymphadenopathy; and (4) diagnosis of mediastinal tumors. Case series using EBUS-TBNA for mediastinal lymph node staging in lung cancer have reported a high yield, ranging from 89% to 98% (average 94.5%). To date, there are no reports of major complications related to EBUS-TBNA. EBUS-TBNA is a novel approach with a high diagnostic yield that is safe. The aim of this article was to review the current role of EBUS-TBNA for the management of lung cancer patients.

Type V collagen (col[V])-reactive lymphocytes contribute to lung transplant rejection, but the mechanisms for emigration into the graft are unknown. Sphingosine-1-phosphate-1 receptors (S1P(1R)) are believed to be required for lymphocyte emigration in other studies, but their role in col(V)-reactive lymphocyte rejection responses is not known. Utilizing small interfering RNA (siRNA) to reduce S1P(1R) expression on col(V)-reactive lymphocytes, we examined the role of S1P(1R) in the rejection response. Quantitative polymerase chain reaction (PCR) revealed strong expression of S1P(1R) messenger RNA (mRNA)on col(V)-reactive lymphocytes isolated from immunized rats. S1P(1R)-specific siRNA (S1P(1R) siRNA) reduced expression of S1P(1R) mRNA and protein, whereas scramble siRNA (SC siRNA) had no effect. Adoptive transfer of lymphocytes treated with S1P(1R) siRNA to rat Wistar Kyoto (WKY) lung isograft recipients resulted in retention of cells within the liver with fewer cells in mediastinal lymph nodes when compared to cells exposed to SC siRNA. S1P(1R)-deficient cells proliferated in response to alloantigens, but not in response to col(V), and produced less interferon (IFN)-gamma in response to col(V) compared to controls. Downregulating S1P(1R) did not affect production of interleukin (IL)-10and tumor necrosis factor (TNF)-alpha, or expression of adhesion molecules critical for migration, but prevented rejection pathology and lowered local levels of IFN-gamma post adoptive transfer. These data demonstrate novel roles of S1P(1R,) which include regulating emigration and modulating lymphocyte activation.

BACKGROUND: Immunity to type V collagen [col(V)] contributes to lung transplant rejection. Matrix metalloproteases (MMPs), which are induced by transplant-related ischemia-reperfusion injury (IRI), could expose col(V) and regulate local IRI-induced inflammation. METHODS: To test the hypothesis that MMPs induce col(V) exposure and inflammation, Wistar-Kyoto rats were treated with the MMP inhibitor, COL-3, before inducing lung IRI without transplantation, and in parallel studies, Wistar-Kyoto lung donor and recipients were treated with COL-3 pre- and postisograft lung transplantation. RESULTS: Ischemia-reperfusion injury induced growth-related oncogene/CINC-1-dependent neutrophil influx, and up-regulated tumor necrosis factor-alpha. MMP2 and MMP9, induced at 4 and 24 hr after IRI, respectively, were associated with detection of antigenic col(V) in bronchoalveolar lavage and lung interstitium because of MMP-mediated matrix degradation. MMP-inhibitor treatment significantly reduced polymorphonuclear leukocytes, growth-related oncogene/CINC-1, and tumor necrosis factor-alpha; abrogated MMP-9 expression; and resulted in lower levels of antigenic col(V) in bronchoalveolar lavage. In the lung transplant model, inhibiting MMPs in the donor before lung harvest and in the recipient after lung transplantation resulted in improved oxygenation and diminished polymorphonuclear leukocyte influx into the isograft. CONCLUSION: MMP inhibition may be a potential therapy to prevent release of antigenic col(V) and ameliorate IRI in the transplant recipient.

Endobronchial ultrasonography (EBUS) has emerged as a new diagnostic tool that allows the bronchoscopist to see beyond the airway. The radial probe EBUS was first introduced to evaluate the airway structure, which has been shown to be useful for identifying the extent of tumor invasion in the central airway. With advance in technology, smaller radial probes are now available that are capable of visualizing peripheral lung nodules. EBUS is also used as a tool to assist in a biopsy in respiratory diseases. The radial probe EBUS-guided transbronchial needle aspiration (TBNA) increases the yield of TBNA of mediastinal processes. By the use of the ultra-miniature probe EBUS along with the guide sheath, peripheral lung lesions can be accessed without the exposure to radiation. However, it is still not a real-time procedure with target visualization. The newest development is the convex probe EBUS (CP-EBUS) with a curvilinear electronic transducer on the tip of a flexible bronchovideoscope. CP-EBUS allows real-time EBUS-guided TBNA. Although the main indication for EBUS-TBNA is lymph node staging, it can also be used for diagnosis of intrapulmonary tumors, of unknown hilar and/or mediastinal lymphadenopathy, and of mediastinal tumors. To date, there are no reports of complications related to EBUS-guided TBNA. It is a novel approach that has a good diagnostic yield with excellent potential in assisting safe and accurate diagnostic interventional bronchoscopy. The aim of this review is to highlight the current status of the different EBUS techniques available and to discuss the future direction of EBUS.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) poses a high risk for postoperative pulmonary complications after lung cancer surgery. We sought to determine the impact of this disease on long-term survival after surgical resection and to identify prognostic factors in pathological stage IA lung cancer. METHODS: A retrospective chart review was completed in 442 patients with pathological stage IA lung cancer, who had a lobectomy with systematic lymph node dissection (30.3%), out of 1,461 patients who underwent lung cancer surgery at our hospital from January 1990 to April 2005. The functional definition of COPD, according to the spirometric guidelines of the Global Initiative for Chronic Obstructive Lung Disease, was forced expiratory volume in 1 second to forced vital capacity less than 70% (FEV1/FVC). The postoperative complications were compared between the non-COPD (362 patients) and COPD (80 patients) groups. Overall survival and disease-free survival were analyzed using the Kaplan-Meier method and log-rank test. Prognostic factors were identified by univariate and multivariate analyses. RESULTS: The frequencies of all pulmonary complications except for pneumonia and tracheostomy were similar between the two groups. Overall survival and disease-free survival in the COPD group were significantly worse than those in the non-COPD group (p < 0.0001 and p = 0.037, respectively). Significant prognostic factors were larger tumor size (p = 0.0035) and COPD (p = 0.0147). Significant risk factors for cancer recurrence were larger tumor size (p = 0.001) and COPD (p = 0.0105) by multivariate analyses. CONCLUSIONS: Patients with COPD had poorer long-term survival. This may be due to a higher incidence of tumor recurrence.

BACKGROUND: Upregulation of matrix metalloproteinases (MMPs) has been associated with chronic lung allograft rejection known as bronchiolitis obliterans syndrome. It has been suggested that MMP inhibition could prevent the rejection response. However, the effect of MMP inhibition on lung allograft rejection has not been reported. METHODS: Utilizing a rat model of lung transplantation, tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) were overexpressed by gene therapy in F344 rat lung allografts prior to transplantation into WKY recipient rats. Separately, WKY rats that received F344 lung allografts were treated systemically with COL-3, a global MMP inhibitor. RESULTS: TIMP-1 and TIMP-2 had differential effects on delayed type hypersensitivity (DTH) responses to donor antigens and type V collagen, an autoantigen involved in the rejection response. Neither TIMP-1 or TIMP-2 affected the onset of rejection pathology. COL-3 suppressed DTH responses to donor antigens and type V collagen, abrogated local production of tumor necrosis factor-alpha, and interleukin-1beta. Although it did not prevent rejection pathology, COL-3 (30 mg/kg) induced intragraft B cell hyperplasia suggestive of posttransplant proliferative disorder (PTLD). CONCLUSIONS: These data identify a complex role for MMPs and TIMPs in the immunopathogenesis of lung allograft rejection, and indicate their effects are not limited to matrix remodeling.

Immunity to collagen V [col(V)] contributes to lung 'rejection.' We hypothesized that ischemia reperfusion injury (IRI) associated with lung transplantation unmasks antigenic col(V) such that fresh and well-healed lung grafts have differential susceptibility to anti-col(V)-mediated injury and expression of the autoimmune cytokines, IL-17 and IL-23, are associated with this process. Adoptive transfer of col(V)-reactive lymphocytes to WKY rats induced grade 2 rejection in fresh isografts, but induced worse pathology (grade 3) when transferred to isograft recipients 30 days post-transplantation. Immunhistochemistry detected col(V) in fresh and well-healed isografts but not native lungs. Hen egg lysozyme-reactive lymphocytes (HEL, control) did not induce lung disease in any group. Col(V), but not HEL, immunization induced transcripts for IL-17 and IL-23 (p19) in the cells utilized for adoptive transfer. Transcripts for IL-17 were upregulated in fresh, but not well-healed isografts after transfer of col(V)-reactive cells. These data show that IRI predisposes to anti-col(V)-mediated pathology col(V)-reactive lymphocytes express IL-17 and IL-23 and anti-col(V)-mediated lung disease is associated with local expression of IL-17. Finally, because of similar histologic patterns, the pathology of clinical rejection may reflect the activity of autoimmunity to col(V) and/or alloimmunity. © 2006 The American Society of Transplantation and the American Society of Transplant Surgeons.

Interleukin (IL)-23 is a heterodimeric cytokine consisting of a novel p19 molecule and the p40 subunit of IL-12. Since secreted p40 can act as an antagonist for IL-12, we investigated whether p40 also inhibited IL-23-mediated immunological functions. p40 did not induce interferon (IFN)-gamma or IL-17 production from splenocytes but impaired IL-23-induced cytokine production by competitive binding to the IL-23 receptors. Furthermore, a mixed population of murine colon carcinoma Colon 26 cells transduced with the p40 gene and those transduced with the IL-23 gene developed tumours in syngenic mice, whereas the IL-23-expressing Colon 26 cells were completely rejected. p40 also suppressed IFN-gamma production of antigen-stimulated splenocytes and IL-23-mediated cytotoxic T-lymphocyte activities in the mice that rejected Colon 26 cells expressing IL-23. p40 can thereby antagonize IL-23 and is a possible therapeutic agent for suppression of IL-23 functions.

PURPOSE: The characteristics of tumor extension determine whether pneumonectomy or lobectomy with bronchoplasty should be performed for central lung cancer. We investigated how the characteristics of tumor extension determined the operative methods and the surgical outcomes. METHODS: We conducted a retrospective chart review of 151 patients with positive bronchoscopic findings who underwent lung cancer operations between January 1995 and March 2002. Twenty-five patients underwent pneumonectomy, 88 underwent lobectomy/segmentectomy (Lob/Seg), and 38 underwent Lob/Seg with bronchoplasty. RESULTS: Pathologic staging was higher in the pneumonectomy group than in the Lob/Seg groups, with or without bronchoplasty (P = 0.002). Interlobar extension and hilar lymph node involvement were more frequent, and mucosal invasion was less frequent, in the pneumonectomy group than in the Lob/Seg with bronchoplasty group. The frequencies of all specific pulmonary complications and 30-day mortality were similar among the three groups. The 5-year overall survival rates were 23.7%, 51.5%, and 72.8% for the pneumonectomy, Lob/Seg, and Lob/Seg with bronchoplasty groups, respectively (P = 0.0004). There was a significant difference in survival between patients with mucosal and those with submucosal types of lung cancer (P = 0.0114). CONCLUSIONS: Lob/Seg with bronchoplasty was feasible without a higher risk of operative complications or poorer long-term survival. The nature of tumor extension was important in the selection of operative methods and in predicting survival.

During the staging process of lung cancer, accurate mediastinal lymph node staging is one of the important factors which affect patient management. The purpose of the current study was to evaluate the usefulness of direct real-time endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) for staging and diagnosis of lung cancer in patients with mediastinal lymph nodes suspected of malignancy and to assess the impact of this method in patient management. One hundred and eight patients with mediastinal lymph nodes with known or suspected lung cancer were included. The convex probe EBUS integrated with a convex scanning probe on its tip was used in all cases. Final diagnosis was based on cytology, surgical results, and/or clinical follow-up. In 105 patients, EBUS-TBNA was successfully performed to obtain samples from 163 lymph nodes. With respect to the correct prediction of lymph node stage, EBUS-TBNA had a sensitivity of 94.6%, specificity of 100%, positive predictive value of 100%, negative predictive value of 89.5%, and diagnostic accuracy rate of 96.3%. In the 20 suspected lung cancer cases, mediastinal lymph node was used for tissue diagnosis of malignancy as well as staging. As a result of EBUS-TBNA, 29 mediastinoscopies, 8 thoracotomies, 4 thoracoscopies, and 9 CT-guided PCNB were avoided. The procedure was uneventful without complications. EBUS-TBNA is a safe and sensitive method for lymph node staging in patients with lung cancer. It spares invasive staging procedures which has a major impact on patient management.

A novel cytokine interleukin-27 (IL-27), composed of p28 and Epstein-Barr virus-induced gene 3 (EBI3), is produced from activated dendritic cells and is involved in an early phase of T-helper type I differentiation. We examined whether Colon 26 murine colon carcinoma cells that were retrovirally transduced with the p28-linked EBI3 gene (Colon 26/IL-27) could produce antitumor effects in inoculated mice. Although proliferation in vitro of Colon 26/IL-27 cells was not different from that of parent cells, syngeneic BALB/c mice rejected Colon 26/IL-27 tumors inoculated and subsequently acquired tumor-specific protective immunity. In contrast, mice inoculated with Colon 26 cells transduced with either the p28 or EBI3 gene developed tumors and survival of the mice remained the same as that of the mice inoculated with parent cells. Syngeneic nude mice developed Colon 26/IL-27 tumors, but the growth was retarded compared to that of parent tumors. Depletion of natural killer cells from nude mice with anti-asialo GM(1) antibody diminished the growth retardation of Colon 26/IL-27 tumors. Survival of severe combined immunodeficient mice that received subcutaneous inoculation of Colon 26/IL-27 cells was not different from that of the immunodeficient mice inoculated with parent cells. Interferon-gamma was produced from CD4(+) and CD8(+) T, and natural killer cells of the mice that rejected Colon 26/IL-27 tumors and cytotoxic activity against Colon 26 cells were also detected from the mice. These data collectively suggest that expressed IL-27 in tumors produces T cell-dependent and-independent antitumor effects and is a possible therapeutic strategy for cancer.

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: The purpose of this study was to investigate the impact of pulmonary rehabilitation on surgical morbidity and lung function in lung cancer patients with chronic obstructive pulmonary disease (COPD). METHODS: Prospectively, 22 lung cancer patients with COPD who underwent lobectomy between 2000 and 2003 were enrolled for this study as a rehabilitation group (Rehab. Group). The criteria of COPD were preoperative forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) < or =70% and more than 50% of low attenuation area in a computed tomography. Preoperatively patients performed aggressive pulmonary exercise for two weeks and received chest physiotherapy postoperatively. As a historical control, 60 patients with lung cancer who fulfilled the same criteria but did not receive rehabilitation between 1995 and 1999 (control group) were entered in this study. RESULTS: Patient backgrounds were all equivalent between the two groups. However, FEV1 and FEV1/FVC were significantly lower in the Rehab. Group (p < 0.05). Prolonged oxygen supplement and tracheostomy tended to be more frequent in the control group. The ratio of actual postoperative to predicted postoperative FEV1 was significantly better in the Rehab. Group (p = 0.047). Furthermore, postoperative hospital stay was significantly longer in the control group (p = 0.0003). CONCLUSION: Despite lower FEV1 and FEV1/FVC in the Rehab. Group, postoperative pulmonary complications and long hospital stay could be effectively prevented and FEV1 was well preserved by rehabilitation and physiotherapy.

Neurogenic benign tumors arising from the trachea and bronchus are relatively rare. We experienced three cases of neurofibroma of the bronchus which were successfully treated by transbronchial electrical snaring and Nd-YAG laser abrasion. The first was a 67-year-old man with right lung cancer, who was pointed out to have a neurofibroma in the left main bronchus. The second was a 34-year-old man with an obstruction in the right main bronchus due to neurofibroma. The third was a 66-year-old woman with a complete obstruction in the left main bronchus due to schwannoma. All patients were successfully treated to remove the tumors and obtain a patency of the bronchus by transbronchial electrical snaring and Nd-YAG laser abrasion. We also review 23 reported cases of endobronchial neurogenic tumors and discuss the efficacy of endoscopic treatments for endobronchial neurogenic tumors.

In following up a patient with non-Hodgkin's lymphoma, we encountered a case of pulmonary pleomorphic carcinoma with mediastinal direct invasion. A 65-year-old man with hemoptysis was found to have an abnormal shadow in the right upper lung field. A 6.4 x 4.8-cm tumor adjacent to the upper mediastinum occupied the right anterior segment of the upper lobe (S3) and invaded the superior vena cava (SVC). The serum level of neuron-specific enolase was elevated to 11.9 ng/ml. A specimen from a transbronchial lung biopsy of the right B3b bronchus revealed giant tumor cells. A right upper lobectomy with SVC reconstruction was performed. The resected tumor was diagnosed as a pulmonary pleomorphic carcinoma with a large component of giant and spindle cells, and it is considered to be a rare histologic type.

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.

PURPOSE: The aim of this study was to determine whether collagen XVIII expression is correlated with circulating serum endostatin and whether this has any prognostic value in patients with non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: Serum endostatin levels were measured quantitatively by a competitive enzyme immunoassay, and collagen XVIII expression in tumor tissue was investigated with an immunohistochemical method in a series of 94 patients who underwent surgery for NSCLC. RESULTS: Sixty cases (63.8%) had positive immunohistochemical staining with anticollagen XVIII polyclonal antibodies, including strongly positive staining in 11 (11.7%) cases. The mean (+/- SD) serum endostatin level was 41.6 +/- 34.4 ng/ml in the patient group and 16.3 +/- 10.3 ng/ml in the control group (P < 0.0001). The 11 cases who were strongly collagen XVIII-positive had significantly higher serum endostatin levels than the cases who were negative or weakly positive (P = 0.0297). The 5-year survival rates of negative, weakly positive, and strongly positive patients were 77.8%, 56.9%, and 43.8%, respectively. The cases with strongly positive collagen XVIII expression had a significantly poorer outcome than cases with negative expression (P = 0.0027). A multivariate analysis with Cox proportional hazards model for disease-specific survival revealed that expression of collagen XVIII (strongly positive versus negative; weakly positive versus negative), tumor classification, and regional lymph node classification were independent prognostic factors. CONCLUSIONS: Our results suggest that expression of collagen XVIII in tumor tissue is strongly associated with a poorer outcome in NSCLC and correlates with elevated levels of circulating serum endostatin.

STUDY OBJECTIVES: Although various techniques are available for obtaining pathology specimens from the mediastinal lymph nodes, including conventional bronchoscopic transbronchial needle aspiration (TBNA), transesophageal ultrasonography-guided needle aspiration, and mediastinoscopy, there are limitations to these techniques, which include low yield, poor access, need for general anesthesia, or complications. To overcome these problems, we undertook the current study to evaluate the clinical utility of the newly developed ultrasound puncture bronchoscope to visualize and perform real-time TBNA of the mediastinal and hilar lymph nodes under direct endobronchial ultrasonography (EBUS) guidance. DESIGN: Prospective patient enrollment. SETTING: University teaching hospital. PATIENTS: From March 2002 to September 2003, 70 patients were included in the study. INTERVENTIONS: The new convex probe (CP) EBUS is integrated with a convex scanning probe on its tip with a separate working channel, thus permitting real-time EBUS-guided TBNA. The indications for CP-EBUS were the diagnosis of mediastinal and/or hilar lymphadenopathy for known or suspected malignancy. Lymph nodes and the surrounding vessels were first visualized with CP-EBUS using the Doppler mode. The dimensions of the lymph nodes were recorded, followed by real-time TBNA under direct EBUS guidance. Final diagnosis was based on cytology, surgical results, and/or clinical follow-up. RESULTS: All lymph nodes that were detected on the chest CT scan could be visualized using CP-EBUS. In 70 patients, CP-EBUS-guided TBNA was performed to obtain samples from mediastinal lymph nodes (58 nodes) and hilar lymph nodes (12 nodes). The sensitivity, specificity, and accuracy of CP-EBUS-guided TBNA in distinguishing benign from malignant lymph nodes were 95.7%, 100%, and 97.1%, respectively. The procedure was uneventful, and there were no complications. CONCLUSIONS: Real-time CP-EBUS-guided TBNA of mediastinal and hilar lymph nodes is a novel approach that is safe and has a good diagnostic yield. This new ultrasound puncture bronchoscope has an excellent potential for assisting in safe and accurate diagnostic interventional bronchoscopy.

DNA polymerase theta (Pol theta) is a recently identified family A polymerase that contains an intrinsic helicase domain. Drosophila Pol theta mutants are hypersensitive to bifunctional DNA crosslinking agents and exhibit an elevated frequency of spontaneous chromosomal aberrations, suggesting a role for Pol theta in repair of DNA interstrand crosslinks and in the general maintenance of genome stability. To investigate a possible involvement of Pol theta in tumorigenesis, we have examined its expression in various normal and malignant tissues. Paired tumor and adjacent nontumorous tissues from patients with lung (n = 27), stomach (n = 28) and colon (n = 26) cancer, as well as 26 normal human tissues, were examined for Pol theta expression by RT-PCR, Northern or Western blot analysis. Pol theta was predominantly expressed in primary lymphoid organs including the fetal liver, thymus and bone marrow where lymphocyte progenitors undergo V(D)J rearrangements of their antigen receptor genes. In addition, Pol theta expression was upregulated in germinal center B cells, in which class switch recombination of the immunoglobulin genes occurs. Examination of Pol theta expression in matched cancer specimens revealed that Pol theta was barely detectable in the nontumorous tissues but was upregulated in 17 of 27 (63%) lung, 11 of 28 (39%) stomach and 20 of 26 (77%) colon cancers. Moreover, patients with high levels of Pol theta expression had a significantly poorer clinical outcome compared with those expressing low levels of Pol theta. These results implicate that Pol theta may have a specialized function in lymphocytes and that its overexpression may contribute to tumor progression.

The radial endobronchial ultrasound (EBUS) probe is conventionally inserted through the working channel of the flexible bronchoscope and limits interventional diagnostics and therapeutics under direct ultrasound control. The aim of this study was to assess the new convex probe EBUS (CP-EBUS) in the visualization of the hilar lymph nodes in surgically resected specimens and explore its feasibility to perform transbronchial needle aspiration (TBNA) under direct EBUS guidance prior to its clinical use. Fourteen surgically resected specimens from lung cancer (n=12) and metastatic lung cancer (n=2) patients were included in the study. The resected specimens included eight right upper lobes, one right middle lobe, and five left lower lobes. The EBUS examination was performed with a flexible bronchoscope equipped with a 7.5 MHz convex probe (CP) that scans parallel to the insertion direction of the bronchoscope. The appearance of the hilar lymph nodes using this CP-EBUS was noted. The size of hilar lymph nodes was measured at CP-EBUS and compared with the actual size of the lymph nodes, which was measured with a Vernier's caliper. Hilar lymph nodes could be clearly visualized with CP-EBUS. There was a good correlation between the actual size of the lymph node and that measured using CP-EBUS (R(2)=0.950). A dedicated transbronchial aspiration needle could be inserted into the hilar lymph node under direct ultrasonic control. There is a possibility in the underestimation of the size of large lymph nodes due to the scanning nature of the convex probe. The CP-EBUS was successfully used to visualize the hilar lymph node and perform TBNA in surgical resected lung specimens. This technique has an excellent potential to perform direct ultrasound guided TBNA of mediastinal and hilar lymph nodes.

Interleukin (IL)-23 and IL-27 have been recently identified as members of the IL-12 heterodimeric cytokine family. The cytokines are released from activated dentritic cells and play a crucial role in cell-mediated immunity. Expression profiles of the cytokines' receptors suggest that target cells of the cytokines are distinct depending on T cell maturation and differentiation. We first examined whether murine colon carcinoma cells (Colon 26) expressing IL-27 (Colon 26/IL-27) could produce antitumor effects in syngeneic mice. The mice developed small Colon 26/IL-27 tumors and subsequently rejected them, whereas parent tumors continued to grow. Since Colon 26/IL-12 and Colon 26/IL-23 cells were also rejected in syngeneic mice, we then investigated the combinatory antitumor effects of the cytokines. We inoculated Colon 26/IL-12, Colon 26/IL-23, Colon 26/IL-27 cells or mixed populations of the cytokine producers into one flank of the mice that simultaneously received parent tumors in the other flank. The parent tumor growth influenced by the cytokine producers was similar to each other. Combinatory antitumor effects were not produced by the cytokine producers and application of the cytokines did not show any synergistic effects.

BACKGROUND: This study investigated postoperative morbidity, mortality, and the long-term survival for patients with lung cancer who have interstitial lung diseases. METHODS: A retrospective chart review of 931 patients with lung cancer who underwent pulmonary resection at Chiba University Hospital between 1990 and 2000 was undertaken. Interstitial lung disease was defined by medical history, physical examination, and abnormalities compatible with bilateral lung fibrosis on chest computed tomography or high-resolution computed tomography (36 patients: 3.9%, interstitial lung diseases group). The remaining 895 patients (96.1%) were categorized as non-interstitial lung disease group. RESULTS: The incidence of postoperative pneumonia and acute or exacerbation of interstitial pneumonia was higher in the interstitial lung disease group (all P <.05). Thirty-day mortality was statistically equivalent between the interstitial lung disease and the non-interstitial lung disease groups (P =.30). The 5-year overall survivals were 62.5% (non-interstitial lung disease) and 35.6% (interstitial lung disease). Respiratory failure was the second main cause of death after the recurrence of primary cancer in the interstitial lung disease group. The risk factors for long-term mortality were interstitial lung diseases, advanced pathologic stage, male sex, high age, and positive smoking history (all P <.05). CONCLUSIONS: Interstitial lung disease was a risk factor for developing postoperative morbidity and mortality and poor long-term survival due to the occurrence of respiratory failure.