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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.

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 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: 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 8(th) 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 8(th) 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.

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.

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.

Extended sleeve lobectomy (ESL), which is defined as the atypical sleeve resection of more than one lobe, has been widely accepted to preserve the pulmonary function (1-3). Double-barrel anastomosis has been reported as a method of bronchial reconstruction after carinal resection; however, it is rarely applied in the reconstruction of segmental bronchi. We herein report a case in which ESL with double-barrel anastomosis of the middle lobar bronchus (MLB) and basilar bronchus (BB) was successfully applied in the treatment of a patient with centrally located lung adenocarcinoma.

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.

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.

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.

Chronic lung allograft dysfunction (CLAD) is a critical impediment to the long-term survival after lung transplantation. A rat orthotopic lung transplantation model was developed in the early 1970s, and using this model, our laboratory has shown that the immunopathogenesis of CLAD involves both allogeneic immunity and autoimmunity. However, further investigation of CLAD is limited by the scarcity of transgenic and knockout strains. The model most widely used to study CLAD, the mouse model of heterotopic tracheal transplantation, has some incomplete pathophysiologic features of CLAD, which limits the utility of this model. Unlike other solid organ transplants, vascularized and aerated murine lung transplantation has only recently been developed. We have also reported that minor, but not major, histocompatibility antigens mismatch induced the development of CLAD in murine orthotopic lung transplants and that CLAD development was interleukin-17-dependent. This mini-review underscores the history and development of rodent models of CLAD after lung transplant, including the findings from our previous studies. In addition, the future direction of rodent models is also discussed.

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 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.

Patients with N2 nonsmall cell lung cancer (N2-NSCLC) represent heterogeneous groups. Survivin is a member of the inhibitor of apoptosis family. If N2-NSCLC patients could be stratified, based on survivin expression and/or its relation to cell cycle proteins, into homogeneous subgroups, certain therapies could be selected for those patients. Survivin expression in 78 surgically resected primary pathological N2-NSCLC tumours was evaluated using immunohistochemistry. Relationships of survivin expression to overall survival, clinical features and expression of six cell cycle-related proteins (pRb, cyclin D1, p16 INK4A , p53, p21 Waf1 and Ki-67) were analysed. Nuclear survivin and the number of mediastinal lymph node (LN) stations were independent prognostic factors. The patient group with combined negative survivin/single mediastinal LN station were the most favourable prognostic group, and was related to the clinical nodal factor. Indeed, patients with negative survivin/low Ki-67 labelling indices had the best survival, especially in nonsquamous histopathology. The current authors conclude that nuclear survivin is strongly related to lymph node metastasis and proliferative potentials in pathological N2 nonsmall cell lung cancer patients. Pre-operative N2 nonsmall cell lung cancer patients with combined negative nuclear survivin and a single mediastinal lymph node station, or low proliferative indices, particularly in clinical N0-1 disease and nonsquamous histopathology, respectively, are expected to have a favourable post-operative prognosis and may be candidates for primary resection.

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 PaO2/FiO2, 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-γ, TNF-α, and IL-1β locally; and induced significant reductions in PaO2/FiO2. 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.

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.

気管支squamous dysplasiaや上皮内癌(CIS)も含む肺門部早期肺癌など微小病変の早期診断や気管支粘膜表面の毛細血管を明瞭に描出する新たな呼吸器内視鏡領域における特殊光観察—蛍光観察AFIと狭帯域観察NBIを行っている。気管支ビデオスコープを使用するAFIでは，高画質，高解像度の鮮明な画像が得られ，肺門部早期肺癌に加えsquamous dysplasiaの早期診断が可能となった。腫瘍の進展範囲の詳細な把握も可能で，光線力学的治療の照射部位や手術症例の正確な切除範囲の決定に有用である。NBIは青色光へのHbの強い吸収特性を利用し，気管支粘膜表面の微細構造，特に毛細血管を明瞭に描出する。dysplasiaにおける血管網の増生，蛇行，錯綜に加え点状血管が確認され，dysplasia, CIS, micro invasive cancer, invasive cancerと進展するにつれて点状血管，ループ状の腫瘍血管増生が明らかになった。これらは癌の進展に比例し増大している。扁平上皮癌の多段階発癌におけるangiogenesisが内視鏡的に捉えられた。

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.

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.

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.

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.

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.

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.

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

原発性肺癌切除例における咽喉頭食道領域の重複癌について臨床的検討を加え，他臓器発生重複癌症例ならびに非重複例との比較した。1985∼1999年に切除した原発性肺癌1,279例のうち他臓器重複癌128例(10.0%)を対象とした。重複臓器は，3重複以上を含め咽喉頭14例，食道12例，胃十二指腸24例，結腸直腸33例，肝胆膵17例，甲状腺3例，子宮卵巣10例，腎尿路12例，乳腺6例，前立腺5例，リンパ節その他3例であった。重複部位別に，咽喉頭食道領域群26例，非咽喉頭食道領域群102例ならびに非重複群1,151例に分類した。各群の平均喫煙指数は，それぞれ1,031, 693, 714で，咽喉頭食道領域群は他の2群に比べ有意に平均喫煙指数が高かった(p=0.0174, p=0.0192)。肺癌の組織型は，咽喉頭食道領域群，非咽喉頭食道領域ならびに非重複群における扁平上皮癌：腺癌はそれぞれ18:5例，32:61例ならびに394:648例と咽喉頭食道領域群は有意に扁平上皮癌が腺癌に比べ多かった（いずれもp

原発腫瘍径, GTでの縦隔リンパ節腫大の有無, 初診時の腫瘍マーカーを参考にして縦隔鏡 (Video-assisted Mediastino-scopy: VAM) の適応基準を作り, これに則ったVAMを施行することにより, 肺癌の治療方針決定に寄与し得るかを検討した. 対象は当科に入院し治療を受けた原発性肺癌217例のうち75歳以下, 病期IIIA期までの総合的治療プログラムに適応した111例である. このうちVAMの適応になった症例が66例, ならなかった症例は45例で, 前者はVAMを行い, 45例が陰性でそのうち43例に手術が行われ, 21例の陽性例は化学療法2クール後, 効果判定により9例が手術, 残り12例には放射線照射を行った. VAM非適応の後者はそのまま手術を行った. VAM陰性の43切除例のうち3例にN2が認められたが, 1例は左肺癌の#5 (ボタローリンパ節) 転移でありその他2例はfalse negativeの誤診例であった. VAM非施行例で切除になった45例のうち2例がN2であったがいずれも右上葉肺癌の# 3リンパ節転移であった. 縦隔鏡の適応基準を設けることで肺癌の治療方針決定に寄与し得ると考える.

We report a surgical case involving localized honeycomb lung with mucus, caused by colonization of a Schizophyllum commune, which displayed a tumorous shadow in the right upper mediastinum. A 74-year-old male with a history of tuberculosis in the 1970s was referred to Chiba University Hospital (Chiba, Japan) with an abnormal shadow evident in the chest roentgenogram. A transbronchial biopsy failed to yield a definite diagnosis. We resected the right upper lobe, which was found to contain a consolidative lesion filled with viscous mucus in the right upper lobe adjacent to the right upper mediastinum. Microscopic examination revealed a honeycomb lung formation with mucus in the destroyed space. Culture of the mucus yielded a whitish filamentous fungus, positively identified as S. commune. This is the first report of S. commune leading to a deposit of mucus and the formation of a consolidative lesion in the destroyed lung.

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.

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.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.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.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.

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.

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 1 s/forced vital capacity (FEV1/FVC)

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.