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The immunosuppressant azathioprine (AZA) is classified as a hazardous drug. AZA contamination during tablet-splitting increases exposure risk. However, there is no study on contamination and exposure during AZA tablet splitting and dispensing. AZA tablet splitting and dispensing methods were classified based on whether tweezers are used during splitting and packaging. In Dispensing Method (1), no tweezers were used in either step. In Dispensing Method (2), no tweezers were used during tablet splitting, but were used during packaging. In Dispensing Method (3), tweezers were used in both steps. After AZA half-tablet split-dispensing, we quantified the adherent AZA removed from the tools, packaging machines, and dispensing counters by three consecutive wipings with water-dampened polypropylene cloths. A large amount of AZA adhered to the gloves used in Dispensing Methods (1) and (2), wherein tablets were placed with gloved hands, compared with Dispensing Method (3), wherein tablets were held with tweezers. Thus, the gloves must be replaced before touching the packaging paper during the final step. After three consecutive wipings, AZA was not detected at most of the sites in the third round. Thus, we recommend that (1) AZA tablet splitting should be performed while wearing gloves, (2) the gloves should be changed before packaging the half tablets, and (3) the tools, packaging machines, and dispensing counters should be wiped twice or thrice with a water-dampened cloth after dispensing.

Background In clinical practice, a mixed suspension of clopidogrel bisulfate and magnesium oxide (MgO) tablets is administered frequently via a feeding tube. However, there is no report on the changes occurring when suspensions of these two drugs are combined, including the effects or potential decrease in dose following tube administration. Thus, the purpose of our study was to investigate the (i) changes caused by mixing clopidogrel bisulfate (ion form) and MgO tablets and (ii) effects on the administered clopidogrel dose after passing through a feeding tube. Methods The molecular structure of clopidogrel generated in a mixture of clopidogrel bisulfate and a basic compound, such as sodium bicarbonate or MgO tablet, was determined by 1H-NMR after extraction and purification. The suspension of clopidogrel bisulfate tablet alone and the mixed suspension of clopidogrel bisulfate tablet and MgO tablet were passed through a feeding tube. We compared the yield of the molecular form of clopidogrel from each passed fraction. Results The substance obtained from the mixture of clopidogrel bisulfate tablet and sodium bicarbonate or MgO tablet was identified as the molecular form of clopidogrel, and chemical degradation did not occur under these conditions. In the tube passage test, the yield of clopidogrel (molecular form) from the mixture of clopidogrel bisulfate and MgO tablets was lower than that from the suspension of clopidogrel bisulfate tablet alone. Conclusions The mixture of clopidogrel bisulfate and MgO tablets caused a considerable reduction in the administered dose passed through the feeding tube. Therefore, it is recommended to administer the suspensions of clopidogrel bisulfate and MgO tablets separately for safe and effective pharmacotherapy.

We report a 38-year-old woman with a left lung tumor presenting as obstructive pneumonia. Bronchoscopic examination revealed a polypoid tumor filling the left main bronchus. The tumor was partially resected by a snaring procedure for diagnostic purposes. Microscopic examination revealed a submucosal tumor located underneath normal bronchial epithelium. The tumor was composed of sheets of uniform oval to cuboidal cells encompassing numerous blood vessels. Immunohistochemically, the tumor cells exhibited smooth muscle markers, but were negative for neuroendocrine markers. The diagnosis of primary pulmonary glomus tumor was therefore made. Subsequent bronchoscopic intervention allowed us to pin-point the origin of the tumor: superior segmental B6a/b. She underwent a left lower lobe superior segmental resection successfully. Glomus tumors are relatively rare soft tissue tumors, and those of bronchopulmonary origin are exceedingly rare clinical condition. Among primary lung tumors, the carcinoid tumor is a mimic of the glomus tumor, and differentiating these tumors is known to be difficult, especially using small biopsy samples. In the present case, a large tissue sample obtained by bronchoscopic snaring was quite useful for the correct preoperative diagnosis. Because of the disease rarity, malignancy grade estimation of visceral glomus tumors has not been clearly addressed. Recently, the histopathological diagnostic criteria for malignant glomus tumors was defined in the WHO classification of soft tissue and bone tumors 4th edition. Here we also reviewed the literature on primary bronchopulmonary glomus tumors with special attention to the current concept of malignancy grade estimation.

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

A 21-month-old Japanese boy was admitted with cough and hypoxemia. Chest X-ray showed massive right pleural effusion, which consisted of chyle. Computed tomography showed poor contrast area at superior and anterior mediastinum. Magnetic resonance imaging showed granular T2-low area at the same area. Lymphangioscintigraphy revealed a hot spot at superior mediastinum. These findings lead us to diagnose as mediastinal lymphangioma accompanied with chylothorax. Noninvasive treatments including total parenteral nutrition, administration of octreotide and sclerotherapy were tried, but all of them proved to be ineffective. Transfusions of blood products were frequently needed during these therapies. On the 48th hospital day, the mediastinal tumor and the thymus were excised through a median sternotomy. A leakage point of lymph into the intrathoracic space was not found, in spite of preoperative administration of milk with dye. Since the pleural effusion had continued to be drained, pleuroperitoneal shunt was placed on the 90th hospital day. The shunting amount continued to decline soon after the shunting, and had been under 10 ml/day since the 142nd day. The shunt was removed on the 148th day. There has been no reaccumulation of the pleural effusion and no recurrence of the mediastinal tumor for 1 year of observation.

In patients with lung cancer accompanied by idiopathic pulmonary fibrosis (IPF), acute exacerbation of the IPF often occurs after pulmonary resection; however, few studies have been done to identify its preexisting risk factors. We analyzed the high-resolution computed tomography (HRCT) findings of IPF to identify the radiological characteristics of IPF susceptible to acute exacerbation after lung cancer surgery. We reviewed retrospectively 28 lung cancer patients with IPF who underwent pulmonary resection. Clinical data, respiratory function, HRCT findings, and historical features were compared between the acute exacerbation (n = 9) and nonexacerbation (n = 19) groups. The classification of radiological findings of IPF on HRCT was done using a scoring system of seven factors related to the interstitial shadow, including fibrosis, ground-glass opacity, and low-attenuation area. There were no significant differences in clinical background, respiratory function, composite physiologic index, or pathological features between the groups; however, the degree of fibrosis on preoperative HRCT was significantly higher in the exacerbation group (P < 0.003). The fibrosis score was higher on the opposite side to the lung cancer in the exacerbation group (P < 0.05). Although it is difficult to predict postoperative acute IPF exacerbation, the degree and laterality of co-existing fibrosis seem to be predictors.

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

The investigation of many lung diseases currently requires bronchoscopic or surgical histopathological tissue biopsy. This creates risks for patients and entails processing costs and delays in diagnosis. However, several mainly probe-based biophotonic techniques that can image solitary lesions and diffuse lung diseases are fuelling a paradigm shift toward real-time in vivo diagnosis. Optical coherence tomography (OCT) uses near-infrared light in a process analogous to ultrasonography to image the mucosal and submucosal tissue boundaries of the bronchial tree. With 15-μm resolution, early work suggests it can differentiate between neoplasia, carcinoma in situ, dysplasia, and metaplasia based around epithelial thickness and breaches in the basement membrane. Probe-based confocal laser endomicroscopy (pCLE) has superior resolution but less penetration than OCT and employs blue argon laser light to fluoresce the endogenous elastin of (1) the acinar scaffold of the peripheral lung and (2) the basement membrane lying under bronchial mucosa. Initial studies suggest that the regular fibre arrangement of the basement membrane is altered in the presence of overlying malignant epithelium. pCLE produces detailed representations of the alveolar septal walls, microvessels, and some inflammatory cells. A third device, the endocytoscope, is a contact microscope requiring contrast agent to provide subcellular resolution of bronchial mucosa. Further development of these "optical biopsy" techniques and evaluation of diagnostic sensitivity and specificity of the acquired images are needed before they can be considered effective methods for eliminating the need for, and thus risks of, pinch biopsy to enable real-time diagnosis to streamline management.

Long-acting bronchodilators are recommended as a first-line treatment for chronic obstructive pulmonary disease (COPD), although their effects for postoperative lung cancer patients with COPD are still not well known. A prospective randomized trial was used to examine the efficacy of bronchodilators on postoperative pulmonary function and quality of life (QOL). Twenty lung cancer patients with COPD who had lobectomies were randomized. A control group (n = 10) did not receive bronchodilators. An experimental group (n = 10) received tiotropium and salmeterol. Patients were divided into two COPD grades: stage I COPD and stage II–III COPD. Results for pulmonary function, 6-minute walking test, and the St. George’s Respiratory Questionnaire (SGRQ) were compared. Diaphragmatic motion on dynamic magnetic resonance imaging was also analyzed. The patient demographics were similar in the two groups. Except for pulmonary function results at 2 weeks, no other parameters were significantly different. However, in stage II–III COPD, forced expiratory volume in 1 second, forced vital capacity, inspiratory capacity, the total score of the SGRQ, and diaphragmatic motion in the experimental group (n = 5) were significantly better than those in the control group (n = 4) at various time points (all P < 0.05). The daily inhalation of bronchodilators was effective for maintaining the respiratory function and QOL in lung cancer patients with moderate to severe COPD.

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.

A surgical resection for locally advanced non-small cell lung carcinoma (NSCLC) remains controversial. This study analyzed the clinicopathological profile and surgical outcome of patients with locally advanced NSCLC to identify the predictors of survival.This study retrospectively analyzed clinical data from 86 patients with pathological T3 or T4 primary NSCLC treated at Chiba University Hospital, and evaluated prognostic factors.Sixty-eight of 86 cases were treated with a complete resection, and 18 were evaluated as an incomplete resection. The 5-year overall survival rate of all cases was 45.7%. Univariate analyses of survival were performed to determine the predictors of overall survival in patients with pathological T3 or T4 NSCLC. Age of 70 years or more, tumor length more than 5 cm, lymph node metastases, incomplete resection, and histology of non-adenocarcinoma were significantly associated with an unfavorable prognosis. Multivariate analyses revealed that older age, incomplete resection, and lymph node metastases were independent predictors of shorter survival.A complete resection for selected cases is acceptable in the management of T3 or T4 NSCLC.

BACKGROUND: The functional criteria for curative surgery for patients with non-small cell lung cancer (NSCLC) and coexisting chronic obstructive pulmonary disease (COPD) remain controversial. We aimed to clarify long-term outcomes after resection. METHODS: Between January 1990 and April 2005, 36 consecutive patients with NSCLC and severe COPD underwent pulmonary resection. All had severe (30-50 % pred FEV1) or very severe COPD (30 % > pred FEV1) preoperatively. Survival, short- and long-term complications were analyzed retrospectively. Prognostic factors were also analyzed. RESULTS: The 5-year survival rate of these patients was significantly worse than that of patients with better pulmonary function (50 % < pred FEV1) ( P < 0.0001). Patients with interstitial pneumonia (IP) had a significantly poorer prognosis ( P = 0.0099). With regard to long-term complications three months after surgery, 30 % of patients reported worsening of dyspnea, and 20 % experienced pneumonia recurrence. No deaths were related to COPD progression. CONCLUSION: Patients with stage IA NSCLC and severe COPD may undergo curative surgical resection; however, postoperative complications and long-term survival remain unsolved problems. IP is a contraindication for surgery in patients with severe COPD.

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.

BACKGROUND Multigene aberrant methylation profiling may predict response to chemotherapy in lung cancer. The purpose of this study was to analyze the feasibility of detecting aberrant methylation in biopsy samples obtained by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). METHODS Lymph node samples from 30 patients with nonsmall cell lung cancer diagnosed as metastatic carcinoma by EBUS-TBNA were analyzed. Histologic cores obtained by EBUS-TBNA were separately stored at -80°C. DNA was extracted from EBUS-TBNA samples and bisulfate modification was performed. We evaluated the methylation status of a panel of 6 genes (FANCF, Reprimo, TMS1/ASC, activated protein-2α, CHFR, and ATM) using methylation-specific polymerase chain reaction. Twenty-four patients with adenocarcinoma or squamous cell carcinoma metastasis received platinum-based combination chemotherapy. We reviewed their response to chemotherapy in correlation to the methylation status. RESULTS Bisulfate modification was successfully performed in all samples using DNA obtained from EBUS-TBNA samples by checking p16 unmethylation expression. Aberrant methylation was detected as follows: 9 cases of FANCF (30.0%), 14 cases of Reprimo (46.7%), 10 cases of TMS1/ASC (33.3%), and 19 cases of activated protein-2α (63.3%). In response to chemotherapy, there were 1 complete response, 6 partial response, 12 stable disease, and 5 progressive disease (PD) cases. The number of methylated genes was significantly smaller in the PD group than in the non-PD groups (P=0.0435). CONCLUSIONS Aberrant methylation analysis can be performed in metastatic lymph nodes sampled by EBUS-TBNA. EBUS-TBNA allows for genetic evaluations of tumor cells and may help to guide the most effective treatment strategies in the near future.

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.

It was previously reported that magnolol strongly inhibited the mutagenicity induced by the indirect mutagens [benzo(a)pyrene (B(a)P), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-aminodipyrido[1,2-a:3',2'-d]imidazole (Glu-P-2), 2-aminoanthracene (2AA), and 7,12-dimethylbenz[a]anthracene (DMBA)] in Salmonella typhimurium TA98 and TA100 in the Ames test, and that the mechanism of this anti-mutagenic effect may involve the inhibition of the metabolic activation of indirect mutagen enzymes. In this study, the in vivo anti-clastogenic effect of magnolol against clastogenicity induced by B(a)P was evaluated using the micronucleus test in mice. Animals were treated with an oral administration of magnolol (1, 10, and 100 mg/kg) at -24, 0, 24, 48, 72, and 96 h before a single intraperitoneal injection of B(a)P. Peripheral blood specimens were prepared 48 h after administration of B(a)P, and analyzed by the acridine orange (AO) technique. The results indicated that magnolol inhibited clastogenicity induced by B(a)P at various administration times. In order to elucidate the mechanism behind this effect, we measured the activity of the detoxifying enzymes [UDP-glucuronosyltransferase (UGT) and glutathione-S-transferase (GST)] and antioxidative enzymes [superoxide dismutase (SOD) and catalase] in the liver when treated with an oral administration of magnolol at various administration times. Its effect on clastogenicity created by exposure to oxidative DNA damage-inducing X-ray irradiation was also evaluated using the micronucleus test in mice. Results showed that magnolol increased the activity of both UGT and SOD enzymes, and also inhibited the clastogenicity induced by X-ray irradiation. Magnolol had an anti-clastogenic effect on B(a)P in the micronucleus test as well as an anti-mutagenic effect on indirect mutagens in the Ames test. The anti-clastogenic effect of magnolol was also suggested by the increases in UGT and SOD enzyme activity, and by the attenuation of oxidative damage induced by X-ray irradiation.

In order to elucidate the involvement of metallothionein (MT) in radiation carcinogenesis, we examined the susceptibility of MT-I/II null mice to carcinogenesis and oxidative DNA damage resulting from X-irradiation. Eight-week-old female MT-I/II null mice and wild-type mice were exposed to whole-body X-irradiation at doses of 1.0, 1.5 or 2.0 Gy once a week for 6 weeks. Incidence of thymic lymphoma was determined at 24 weeks after the first exposure to X-irradiation. The frequency of thymic lymphomas induced by X-irradiation (at 1.5 and 2.0 Gy) was significantly higher in MT-I/II null mice than in wild-type mice. In addition, although the levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) were increased in the serum and urine of both strains of mice 24 hr after exposure to a single bout of whole body X-irradiation, these increases were significantly greater in the MT-I/II null mice than in the wild-type mice. Thus, the present results suggest that MT plays a protective role against carcinogenesis and oxidative DNA damage caused by X-irradiation.

In order to elucidate the role of metallothionein (MT) in preventing the adverse effects of X-ray irradiation, we examined the susceptibility of MT-I/II null mice to bone marrow injury caused by X-irradiation and effects of pretreatment with MT-inducing metals on X-ray injury. Eight-week-old male mice were exposed to a single bout of whole-body X-irradiation at a dose between 0.1 and 6.0 Gy. The numbers of leukocytes, reticulocytes with micronuclei (MNRET) in the blood, and polychromatic erythrocytes with micronuclei (MNPCE) in the bone marrow were determined 24 hr after X-irradiation. X-irradiation significantly decreased the total number of leukocytes in MT-I/II null mice and wild-type mice in a dose-dependent manner, but the total number of leukocytes was significantly lower in MT-I/II null mice than in wild-type mice at a low dose of irradiation, between 0.1 and 1.0 Gy. X-irradiation (0.1 and 0.5 Gy) significantly increased the appearance of MNRET and MNPCE in both strains, but the increase was greater in the MT-I/II null mice than in the wild-type mice. Additional groups of mice were pre-administered bismuth nitrate or zinc sulfate to induce MT in the bone marrow cells prior to X-irradiation; the X-ray injury was prevented by such treatments in wild-type mice only. Thus, the present results suggest that MT plays a protective role against a low dose of X-ray injury.

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. Patients who have pathologic N2 (pN2) nonsmall cell lung cancer (pN2 NSCLC) represent a heterogeneous group with regard to prognosis and treatment. Molecular features of NSCLC seem to be of interest. For the current study, to select an appropriate therapeutic strategy for each patient, patients with N2 NSCLC were stratified into homogenous subgroups according to the expression profiles of cell cycle-related markers. METHODS. The expression levels of retinoblastoma protein (pRb), cyclin D1, p16, p53, and p21 proteins and values of the Ki-67 labeling index were evaluated in 61 primary surgically resected tumor specimens from patients with pN2 NSCLC using immunohistochemistry. The prognostic impact of these markers on overall survival was analyzed in both univariate and multivariate analyses. RESULTS. In univariate analysis, p21, p16, and Ki-67 were correlated significantly with survival. In multivariate analysis, only p21 and p16 influenced survival. Indeed, the group of patients with pN2 NSCLC who were positive for p21 and p16 had the most favorable overall survival (P = .001) and were correlated significantly with the clinical lymph node (cN) status (cN2 disease; P = .008). Moreover, no significant difference in survival was observed between patients with cN0/cN1 disease and patients with cN2 disease within the group (P = .4333). CONCLUSIONS. Loss of control of cell-cycle checkpoints is a common occurrence in pN2 NSCLC. Functional cooperation between different cell-cycle regulators constitutes another level of regulation in cell growth control and tumor suppression. Preoperative patients with pN2 NSCLC, even those with cN2 disease, who have positive p21 and p16 protein expression in their primary tumors are expected to have a favorable postoperative prognosis and may be candidates for primary resection. Cancer 2007. © 2007 American Cancer Society.

A 53-year-old woman was referred to Matsudo City Hospital for palliative care of stage IVb invasive thymoma with multiple pulmonary metastases and dissemination. Moderate doses of corticosteroid were administered for palliative effects during the preterminal stage of the disease for 2 years. The thymoma progressed slowly but continuously. At age 55, she was admitted to our hospital for a whole-body eruption and high body temperature. We could not identify the pathogen or allergen. Based on the results of a skin biopsy, with the exception of corticosteroid we stopped administering all suspicious medications, including folk medicines. After 1 month of antipyretic therapy, whole-body eruption disappeared and we encountered rapid regression of the thymoma. Unfortunately she died of interstitial pneumonitis only 2 months after the regression.

A diagnosis of sarcoidosis should be substantiated by pathological means in order to thoroughly exclude other diseases. The role of real-time endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in the diagnosis of sarcoidosis has not been reported. The purpose of the present study is to evaluate the diagnostic yield of EBUS-TBNA in demonstrating the pathological features of sarcoidosis. In total, 65 patients with suspected sarcoidosis, with enlarged hilar or mediastinal lymph nodes on computed tomography, were included in the study. Patients with a suspected or known malignancy or previously established diagnosis of sarcoidosis were excluded. Convex probe endobronchial ultrasonography integrated with a separate working channel was used for EBUS-TBNA. Surgical methods were performed in those in whom no granulomas were detected by EBUS-TBNA. Patients were followed up clinically. EBUS-TBNA was performed on a total of 77 lymph node stations in 65 patients. A final diagnosis of sarcoidosis was made for 61 (93.8%) of the patients. The remaining four patients were diagnosed as having Wegener9s granulomatosis (n = 1) or indefinite (n = 3). In patients with a final diagnosis of sarcoidosis, EBUS-TBNA demonstrated noncaseating epithelioid cell granulomas in 56 (91.8%) of the patients. No complications were reported. Endobronchial ultrasound-guided transbronchial needle aspiration proved to be a safe procedure with a high yield for the diagnoses of sarcoidosis.

蛍光気管支内視鏡の開発により，白色光観察単独では発見が困難であった，preinvasive bronchial lesionの検出が容易になった．蛍光気管支内視鏡技術はさらなる発展を遂げ，気管支ファイバースコープの観察から気管支ビデオスコープを用いた観察に移行しており，高画質，多機能化が図られただけでなく，操作性も向上している．蛍光気管支内視鏡は，preinvasive bronchial lesionの早期発見のみならず，光線力学的治療や手術を目的とした悪性病変の進展範囲の正確な判定にも使用される．蛍光気管支内視鏡が多くの施設で使用されるようになってきたことから，内視鏡画像所見についての所見分類の必要性が高まっている．本稿では現在市販されている気管支ビデオスコープを使用する2機種について，代表的な画像所見を挙げ解説する．蛍光気管支内視鏡検査の実施にあたっては，使用する機器の特徴を十分にふまえたうえで，施行することが望ましい．本報告をもとに次回の肺癌取扱い規約では，蛍光気管支内視鏡画像所見分類（案）を追加する予定である．

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。

Background Patients with pulmonary large cell neuroendocrine carcinoma (LCNEC) have a very poor prognosis, but the benefit of adjuvant chemotherapy for these patients has not been established. We performed a prospective analysis of adjuvant chemotherapy for patients with completely resected pulmonary LCNECs to assess the effect of adjuvant chemotherapy. Methods The adjuvant mixture consisted of cisplatin and VP-16 and was administered after surgery to 15 patients with LCNECs from 2000 to 2005. We compared patient survival with historical data for LCNEC patients treated without platinum-based adjuvant chemotherapy after surgery. Results There were no differences in age, gender, surgical methods, and staging between the adjuvant chemotherapy group and the control group. Median follow-up was 33 months for the adjuvant group and 42 months for the control group. Of the 15 patients in the adjuvant chemotherapy group, 2 patients had disease recurrence and 1 died of interstitial pneumonia. The overall survival rate at 2 and 5 years of patients with adjuvant chemotherapy was 88.9%. The overall survival rate between patients with adjuvant chemotherapy and the historical control group was significantly different. Conclusions Adjuvant chemotherapy consisting of cisplatin and VP-16 after surgery appears promising for the improvement of the prognosis for patients with completely resected LCNECs, and it should be evaluated further in larger multi-institutional trials.

The purpose of this study was to clarify the clinical benefits of perioperative administration of high-dose prednisolone (PSL) combined with extended thymectomy on the long-term outcomes of 116 consecutive patients with generalized myasthenia gravis (MG).A retrospective review was conducted on 116 patients diagnosed with generalized MG who received alternate-day oral administration of high-dose PSL (100 mg/alternate days) and had undergone transsternal extended thymectomy. Incidences of postoperative myasthenic crisis, adverse effects of steroid, long-term outcomes, such as complete stable remission (CSR), pharmacologic remission (PR) or improvement (Imp), and disease recurrence after CSR were evaluated.Six patients (5.2%) experienced post-thymectomy myasthenic crisis. Crude cumulative CSR and PR + CSR rates were 44.8 and 62.7%, respectively. Life table analysis showed that 41.8, 52.8 and 63.4% of the patients were in CSR at 3, 5 and 10 years, respectively. Multivariate analysis revealed that age and pretreatment classification according to the Myasthenia Gravis Foundation of America (MGFA) criteria tended to be independent predictors of CSR. There were 6.9% with compressive vertebral fracture, 13.8% with cataract, and 5.2% with steroid-induced diabetes. Life table analysis revealed that recurrence rates after CSR were 36.8 and 46.0% at 3 and 5 years, respectively. Patients with thymoma had a significantly higher rate of recurrence than those without thymoma (p = 0.001).Alternate-day administration of high-dose prednisolone reduced the risk of post-thymectomy myasthenic crisis. Presence of thymoma was a risk factor for MG recurrence after CSR.

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.

目的:下咽頭癌は早期に特異的な症状が発現しにくいため, 確定診断時に進行癌であることが多く早期発見が望まれている.早期下咽頭扁平上皮癌発見における喀痰細胞診の有用性の評価を目的とし, その細胞像について検討した.対象と方法:平成5-15年度の喀痰集検受診者11万237人からの発見癌201例のうち, 下咽頭扁平上皮癌が確定診断された8例を対象とした.同症例の蓄痰標本に出現した中等度異型以上の異型扁平上皮細胞, および扁平上皮癌細胞について細胞学的検討を行った.成績:発見された下咽頭癌の病期は, I期: 3例, III・IV期: 5例であった.喀痰中の異型上皮細胞および癌細胞数は, I期: 50.8個, III期: 333.3個, IV期: 427.4個で, I期癌では進行期癌と比較し有意に少数であった (P