Association of immunoglobulin G4 and free light chain with idiopathic pleural effusion.

The cause of pleural effusion remains uncertain in approximately 15% of patients despite exhaustive evaluation. As recently described immunoglobulin (Ig)G4-related disease is a fibroinflammatory disorder that can affect various organs, including the lungs, we investigate whether idiopathic pleural effusion includes IgG4-associated etiology. Between 2000 and 2012, we collected 830 pleural fluid samples and reviewed 35 patients with pleural effusions undiagnosed after pleural biopsy at Yamaguchi-Ube Medical Center. Importantly, IgG4 immunostaining revealed infiltration of IgG4-positive plasma cells in the pleura of 12 patients (34%, IgG4+ group). The median effusion IgG4 level was 41 mg/dl in the IgG4+ group and 27 mg/dl in the IgG4- group (P < 0·01). The light and heavy chains of effusion IgG4 antibodies of patients in the IgG4+ group were heterogeneous by two-dimensional electrophoresis, indicating the absence of clonality of the IgG4 antibodies. Interestingly, the κ light chains were more heterogeneous than the λ light chains. The measurement of the κ and λ free light chain (FLC) levels in the pleural fluids showed significantly different κ FLC levels (median: 28·0 versus 9·1 mg/dl, P < 0·01) and κ/λ ratios (median: 2·0 versus 1·2, P < 0·001) between the IgG4+ and IgG4- groups. Furthermore, the κ/λ ratios were correlated with the IgG4+ /IgG+ plasma cell ratios in the pleura of the IgG4+ group. Taken together, these results demonstrate the involvement of IgG4 in certain idiopathic pleural effusions and provide insights into the diagnosis, pathogenesis and therapeutic opportunities of IgG4-associated pleural effusion.

Regulation of somatostatin receptor 4-mediated cytostatic effects by CD26 in malignant pleural mesothelioma.

BACKGROUND: Malignant pleural mesothelioma (MPM) is an aggressive neoplasm arising from mesothelial lining of pleura. CD26 molecules preferentially expressed on epithelioid type of MPM. This study investigates the molecular mechanisms of CD26 regulating MPM cells in vitro and in vivo. METHODS: Biochemical and cell biological approaches were used for identifying a novel molecular target of MPM. Its contribution to tumour expansion has been also assessed using animal models. The clinical samples of MPM were also assessed for its expression. RESULTS: We identify that cytostatic effects in MPM are mediated by somatostatin (SST) receptor 4 (SSTR4), being inhibited by the interaction of CD26 molecules. We also indicates that SSTR4-mediated cytostatic effects are regulated by SHP-2 PTP, and that this inhibitory effect by SST agonist is enhanced via lipid raft clustering of associated molecules following crosslinking of anti-CD26 antibody. Finally, using an in vivo xenograft model, we demonstrate that the anti-tumour effect of anti-CD26 mAb is enhanced when combined with SSTR4 agonist treatment, and that SSTR4 is highly coexpressed with CD26 on epithelioid or biphasic types of MPM tissues obtained from patients' surgical specimens. CONCLUSIONS: Combination therapy with humanised anti-CD26 mAb and SSTR4 agonist may therefore potentiate anti-tumour effect on MPM.

Synthesis of halogen-substituted 1,5-benzothiazepine derivatives and their vasodilating and hypotensive activities.

In an attempt to improve the effectiveness and duration of the action of diltiazem (1), a 1,5-benzothiazepine calcium channel blocker, its derivatives (2) with halogen substituents on the fused benzene ring were synthesized. These compounds were evaluated for their effects on vertebral and coronary blood flows and antihypertensive activity. The structure-activity relationships are discussed. The 8-chloro derivative ((+)-2b), the most potent compound in this series, was selected for clinical evaluation as a cerebral vasodilating and antihypertensive agent.

Simultaneous measurement of T-helper 1 cytokines in tuberculous pleural effusion.

OBJECTIVE: Tuberculosis, the leading cause of death among infectious diseases worldwide, is a major cause of lymphocytic exudative pleural effusion. T-helper 1 cytokines, including interferon-gamma (IFN-gamma), interleukin (IL)-12p40 and IL-18 are predominantly associated with cell-mediated immune responses, and play an important role in immunity to Mycobacterium tuberculosis. DESIGN: We studied 55 patients presenting with pleural effusion at the National Sanyo Hospital between April 2000 and September 2001 (42 men and 13 women; mean age 67 years). Twenty patients (36%) had tuberculous pleurisy, while 18 (33%) had malignant effusions and 17 (31%) had an effusion with another aetiology. Pleural fluid concentrations of IL-12p40 and IL-18 as well as IFN-gamma measured by enzyme-immunoassays. RESULTS: Concentrations of all three cytokines were significantly higher in tuberculous than other pleural effusions. Significant correlations were evident between IFN-gamma and IL-12. We found particularly high concentrations of IL-12p40 and IFN-gamma in tuberculous patients with high fever. CONCLUSION: The results indicate that T-helper 1 cytokines are involved in intrapulmonary cellular immune responses to M. tuberculosis, and suggest that the interactions between them may play an important role in the pathogenesis and severity of the pleural effusion. Understanding the development of this response may enhance our understanding of the pathogenesis of tuberculous pleural effusion and suggest new therapies.

Radical cyclization in heterocycle synthesis. 11.(1) A novel synthesis of alpha,beta-disubstituted gamma-lactones via sulfanyl radical addition-cyclization using hydroximates as a tether

A combination of sulfanyl radical addition-cyclization of dienes connected with hydroximates and subsequent conversion of the resulting cyclic hydroximate to the lactones provides a novel method for the construction of alpha,beta-disubstituted gamma-lactones. Upon treatment with thiophenol in the presence of AIBN, dienes connected with hydroximates smoothly underwent sulfanyl radical addition-cyclization to give cyclic cis- and trans-hydroximates. Hydrolysis of cyclic hydroximates gave the desired cis- and trans-lactones in high yield. This method was successfully applied to the practical synthesis of (+/-)-oxo-parabenzlactone.

Effect of docetaxel with cisplatin or vinorelbine on lung cancer cell lines.

Docetaxel shows substantial activity against lung cancer. To find the optimal drug combination for docetaxel, we evaluated the effects of cisplatin, etoposide, mitomycin C, irinotecan, vindesine, and vinorelbine using three human lung cancer cell lines, ABC-1, EBC-1, and SBC-3. Drug cytotoxicity was determined by MTT assay. Tumor cells were incubated for 96 hours in the presence of docetaxel and each of the test drugs stated above. The combined drug interaction was evaluated by median-effect plot analysis and improved IC50-isobologram analysis. Both methods showed strong antagonism (subadditive or protective effect) between docetaxel and etoposide when tested on ABC-1 and EBC-1 cells. Docetaxel and cisplatin displayed additive effects on all cell lines tested, when evaluated by improved IC50-isobologram analysis. The combination of docetaxel and vinorelbine exerted synergistic effect on the growth inhibition of SBC-3 cells, which showed a wide range of fractional cytotoxicity when analyzed by median-effect plot and supraadditive when analyzed by improved IC50-isobologram. These observations suggest a possibility that docetaxel can be used in combination with vinorelbine or cisplatin in the treatment of lung cancer.

An alteration of ganglioside composition in cisplatin-resistant lung cancer cell line.

Previously we established cell lines resistant to Adriamycin and cisplatin to elucidate the mechanisms involved in acquired drug-resistance. In this study, we investigated ganglioside composition in drug-resistant cell lines. The Adriamycin-resistant cell line, SBC-3/ADM100, exhibited a ganglioside composition ratio similar to that of the parent SBC-3 cells. Densitometric analysis by resorcinol showed a 1.61-fold increase of ganglioside GM2 in SBC-3/ADM100 cells, when compared to the parent SBC-3 cells. The cisplatin-resistant cell line, SBC-3/CDDP, showed a simplified ganglioside pattern, expressing only gangliosides GM3 and GM2. SBC-3/CDDP cells showed a marked increase in ganglioside GM3. These findings suggest that the alteration of ganglioside composition may be actively involved in the acquisition of drug-resistance.

In vitro evaluation of antimicrotubule agents in human small-cell lung cancer cell lines.

BACKGROUND: The improvement of treatment outcome of small-cell lung cancer (SCLC), and search for new effective drugs and to overcome drug-resistance are essential. MATERIALS AND METHODS: We evaluated the cytotoxicity of antimicrotubule agents to seven human SCLC cell lines consisting of one cell line (SBC-3) established from a previously untreated patient as a representative of drug-sensitive cell line, three cell lines (SBC-2, SBC-4, and -7) derived from treated patients as representatives of intrinsic drug-resistance cell lines, and three drug-resistant sublines (SBC-3/ADM, SBC-3/ETP, and SBC-3/CDDP) selected by continuous exposure of the SBC-3 cell line to increasing concentrations of doxorubicin, etoposide, or cisplatin as representatives of acquired drug-resistant cell lines. RESULTS: IC50 values for SBC-2, -3, -4, and -7 cells of antimicrotubule agents were markedly lower than those of doxorubicin, etoposide, and cisplatin. Both SBC-3/ADM and SBC-3/ETP subline were highly resistant to paclitaxel, docetaxel, vinorelbine, vincristine, vindesine, and vinblastine. However, an SBC-3/ADM subline was not fully cross-resistant to rhizoxin, and an SBC-3/ETP subline was as sensitive to rhizoxin as an SBC-3 cell line. A cisplatin-resistant subline, SBC-3/CDDP, showed no cross-resistance to the antimicrotubule agents. CONCLUSION: These results suggest that antimicrotubule agents are useful for SCLC, and rhizoxin may be particularly effective in the salvage treatment of refractory or relapsed patients.

Cardiorespiratory responses during cycle ergometer exercise with different ramp slope increments in patients with chronic obstructive pulmonary disease.

OBJECTIVE: The ramp exercise test has been widely used to evaluate cardiopulmonary responses to an incremental exercise load. This study was performed to clarify whether different slopes of the ramp exercise test influence exercise tolerance, exercise limiting factors, and respiratory pattern in patients with chronic obstructive pulmonary disease (COPD). SUBJECTS AND METHODS: We applied three different slopes (5 W/min, 10 W/min and 20 W/min) of the ramp exercise test in 9 patients with COPD and evaluated cardiopulmonary responses. RESULTS: There were no significant differences in peak oxygen uptake, anaerobic threshold (AT), minute ventilation, heart rate, arterial oxygen saturation, expired tidal volume, or respiratory rate at the maximal load among the three different ramp exercises tested. AT could be determined in six of nine patients (67%) at the slope of 5 W/min, in 8/9 (89%) at the slope of 10 W/min, and in 9/9 (100%) at the slope of 20 W/min. CONCLUSION: The findings suggest that the ramp slope does not affect exercise tolerance, exercise limiting factors, or respiratory patterns and each of these ramp slopes is useful for the evaluation of COPD. Ramp slopes of 10 W/ min or 20 W/min should be appropriate for the determination of AT.

Bronchial atresia with transient spontaneous disappearance of a mucocele.

We report the transient spontaneous disappearance of a mucocele due to bronchial atresia. Two years before presentation, a chest radiograph showed a hyperlucent right upper lung and a mucocele near the right hilum. A chest radiograph taken 1 year later showed that the mucocele had disappeared leaving an ovoid outline of a dilated bronchus. A chest radiograph obtained 3 months before presentation showed that the mucocele was present again. Atresia of the B3b bronchus of the right upper lobe was noted on thoracotomy. The "disappearance" of the mucocele probably was due to the clearance of mucoid material through collateral airways.

Pulmonary lymphoma of large B-cell type mimicking Wegener's granulomatosis.

A 27-year-old man with a primary pulmonary lymphoma of large B-cell type is described. Symptoms involved both the upper and lower respiratory tract. A chest roentgenogram showed a dense mass with cavitation. Transbronchial biopsy specimens revealed no atypical cells, rather they demonstrated granulomatous infiltration and vasculitis consistent with but not conclusively diagnostic of Wegener's granulomatosis. The pulmonary mass became smaller after sulfamethoxazole-trimethoprim therapy. These features suggested Wegener's granulomatosis. However, an open biopsy specimen was diagnostic for diffuse lymphoma of large B-cell type. High-grade pulmonary lymphoma should be considered in the differential diagnosis of patients with clinical and pathologic features suggesting Wegener's granulomatosis.

Prognostic significance of proliferating cell nuclear antigen (PCNA) expression in non-small cell lung cancer.

Formalin-fixed, paraffin-embedded tissue sections of resected tumors from 90 patients were immunohistochemically studied to assess the prognostic value of proliferating cell nuclear antigen (PCNA) expression in non-small cell lung cancer. The individual tumors were classified into groups of high, moderate or low proliferative grade, and 38 (42.2%) patients had a high grade of proliferation. No statistically significant correlations were observed between PCNA grade and TNM status, pathological stage, resectability, histological type, degree of histological differentiation. Only vascular invasion significantly correlated with proliferative grade (p < 0.05). Survival analysis showed that patients with low proliferative grade tumors survived significantly longer (a 5-year survival rate of 83.3%) than those with high proliferative grade tumors (39.4%, p < 0.005). Cox's multivariate analysis revealed that PCNA grade was a significant prognostic determinant of survival. These results suggest that PCNA expression provides an independent prognostic variable for patients with non-small cell lung cancer and that it may be useful to consider this factor in treatment planning.

Establishment of a drug sensitivity panel using human lung cancer cell lines.

We established a drug sensitivity panel consisting of 24 human lung cancer cell lines. Using this panel, we evaluated 26 anti-cancer agents: three alkylators, three platinum compounds, four antimetabolites, one topoisomerase I inhibitor, five topoisomerase II inhibitors, seven antimitotic agents and three tyrosine kinase inhibitors. This panel showed the following: a) Drug sensitivity patterns reflected their clinically-established patterns of action. For example, doxorubicin and etoposide were shown to be active against small cell lung cancer cell lines and mitomycin-C and 5-fluorouracil were active against non-small cell lung cancer cell lines, in agreement with clinical data. b) Correlation analysis of the mean graphs derived from the logarithm of IC50 values of the drugs gave insight into the mechanism of each drug's action. Thus, two drug combinations with reverse or no correlation, such as the combination of cisplatin and vinorelbine, might be good candidates for the ideal two drug combination in the treatment of lung cancer, as is being confirmed in clinical trials. c) Using cluster analysis of the cell lines in the panel with their drug sensitivity patterns, we could classify the cell lines into four groups depending on the drug sensitivity similarity. This classification will be useful to elucidate the cellular mechanism of action and drug resistance. Thus, our drug sensitivity panel will be helpful to explore new drugs or to develop a new combination of anti-cancer agents for the treatment of lung cancer.

Effects of short-term pulmonary rehabilitation on exercise capacity and quality of life in patients with chronic obstructive pulmonary disease.

Although the rehabilitation of patients with chronic obstructive pulmonary disease (COPD) improves both exercise capacity and quality of life, a standard protocol for COPD patients has not been established. To clarify whether physiologic and quality-of-life improvements can be achieved by an inpatient pulmonary rehabilitation program 5 days per week for 3 weeks, 18 patients with COPD were enrolled in a rehabilitation program. The physical exercise training regimen consisted of respiratory muscle stretch gymnastics and cycle ergometer exercise training. Pulmonary function tests, an incremental ergometer exercise test, a 6-min walking test, and a quality of life assessment by the Chronic Respiratory Questionnaire were administered before and after the program. The peak VO2, an indicator of maximal exercise capacity, did not increase, although the 6-min walking distance, an indicator of functional exercise capacity, increased significantly after rehabilitation. There was a significant improvement in the quality of life in terms of dyspnea, fatigue, and emotional state. These findings suggest that even a 3-week program may be beneficial for COPD patients. Increases in functional exercise capacity, even without an increase in maximal exercise capacity, are helpful for reducing dyspnea and improving quality of life parameters in patients with COPD.

[Orchiectomy for tuberculous epididymitis: a report of two cases with intractable to antituberculosis treatment].

This paper describes two cases with tuberculous epididymitis. The first case was a 69-year-old man who was admitted to our hospital because of ulceration or right scrotum. Physical examination revealed a hard, rounded, a little bigger than egg-sized mass in the right scrotum. The second case was a 40-year-old man who was admitted to our hospital because of cough, fever and body weight loss. He was treated for pulmonary tuberculosis with isoniazid, rifampicin, streptomycin and pyrazinamide. Six months after admission, he complained of a painless swelling of the right scrotum. Physical examination revealed a hard, rounded, more than egg-sized mass in the right scrotum. Right orchiectomy was performed in these two cases, and they were cured.

[A case report of a mediastinal bronchogenic cyst with back pain].

We performed thoracoscopic surgery for a mediastinal bronchogenic cyst with complaining of back pain. The patient, a 38-year-old male, was admitted with an abnormal shadow on chest X-ray. Chest CT showed a localized tumor on the mediastine. MRI showed a cyst. Under thoracoscopy the tumor was based on parietal pleura and movable in chest cavity. We concluded that back pain was caused by a stimulus of a nerve in parietal pleura. Pathological diagnosis was a bronchogenic cyst.

[A resected case of a bronchiolo-alveolar cell carcinoma of the lung accompanying pneumonia-like shadow on chest roentgenogram].

A 67-year-old female was admitted to our hospital because of pneumonia-like shadow on chest roentgenogram with persistent cough and sputum of 4 months duration. Diagnosis as lung cancer was delayed more than 4 months. She showed fever and inflammatory reactions. Antibiotics were effective to inflammatory reactions, but not effective to pneumonia-like shadow. Transbronchial lung biopsy was useful for the diagnosis. Right lower lobectomy was performed. In this case, tumor extents were limited within one lobe. Tumor cells did not invade blood and lymphatic vessels, and extrathoracic metastases were not detected. The prognosis of bronchiolo-alveolar cell carcinoma was determined by intra-pulmonary tumor extent. Based on a comparison with the outcome of unresected cases, bronchiolo-alveolar cell carcinoma limited within one lobe should be surgically resected.

[A case of lung cancer with pericardial effusion without cardiac tamponade].

Cardiac tamponade as an initial manifestation of primary lung cancer is uncommon. All such cases had shown symptoms of cardiac tamponade at the first visit of the hospital. We report a case of lung cancer with pericardial effusion without cardiac tamponade. Echocardiography, revealed little pericardial effusion and it has not increased for 3 months. Pericardiotomy revealed adenocarcinoma and lung cancer was confirmed by bronchial biopsy. It is necessary to further examine patients with even slight amounts of pericardial effusion.

[Clinical evaluation of benign asbestos pleurisy].

Seventeen cases of benign asbestos pleurisy were evaluated clinically. All cases were male and almost all cases were more than 60 years-old. Most cases presented with chief complaints of chest pain and dyspnea, but 2 cases had no complaints. Pleural effusion appeared predominantly in the right side. Six cases had 2 or 3 episodes of pleural effusion, and 1 case had 5. Ten cases had an occupational history of asbestos exposure in shipyards and 5 other cases had a history in building construction. Almost all cases had more than 30 years of exposure to asbestos and benign asbestos pleurisy appeared after more than 30 years from the first exposure to asbestos. Among the patients, 6 cases had diffuse pleural thickening and 2 cases had malignancies. Pleural fluid was bloody in 14 of 17 cases (82%) and all pleural fluid showed an exudate. Lymphocytes represented 70% and eosinophils 15% of the cellular population of the pleural fluid. Hyaluronic acid in pleural fluid in cases of benign asbestos pleurisy averaged 29.5 micrograms/ml, which was significantly (p < 0.05) lower than in malignant pleural mesothelioma. Leukocytosis in peripheral blood and a high CRP value were uncommon in benign asbestos pleurisy.