Usefulness of a selective neutrophil elastase inhibitor, sivelestat, in acute lung injury patients with sepsis.

BACKGROUND: Neutrophil elastase plays a crucial role in the development of acute lung injury (ALI) in patients with systemic inflammatory response syndrome (SIRS). The clinical efficacy of the neutrophil elastase inhibitor, sivelestat, for patients with ALI associated with SIRS has not been convincingly demonstrated. The aim of this study was to determine if there are clinical features of patients with this condition that affect the efficacy of sivelestat. METHODS: This was a retrospective study of 110 ALI patients with SIRS. Clinical information, including the etiology of ALI, the number of organs failing, scoring systems for assessing the severity of illness, and laboratory data, was collected at the time of diagnosis. Information on the number of ventilator-free days (VFDs) and changes in PaO(2)/F(I)O(2) (ΔP/F) before and 7 days after the time of ALI diagnosis was also collected. The effect of sivelestat on ALI patients was also examined based on whether they had sepsis and whether their initial serum procalcitonin level was ≥0.5 ng/mL. RESULTS: There were 70 patients who were treated with sivelestat and 40 control patients. VFDs and ΔP/F were significantly higher in the treated patients than in the control patients. However, there was no significant difference in the patient survival rate between the two groups. Sivelestat was more effective in ALI patients with a PaO(2)/F(I)O(2) ratio ≥ 140 mmHg or sepsis. Sivelestat significantly prolonged survival and led to higher VFDs and increased ΔP/F in septic patients and patients with initial serum procalcitonin levels ≥ 0.5 ng/mL. CONCLUSION: The results may facilitate a future randomized controlled trial to determine whether sivelestat is beneficial for ALI patients with sepsis.

Antitumor activity of MEK and PI3K inhibitors against malignant pleural mesothelioma cells in vitro and in vivo.

Malignant pleural mesothelioma (MPM) is an aggressive malignancy for which there is no approved targeted therapy. We examined the therapeutic efficacy of the mitogen-activated protein kinase kinase (MEK) and phosphatidylinositol 3-kinase (PI3K) inhibitors against human MPM cell lines both in vitro and orthotopically inoculated into severe combined immunodeficient (SCID) mice. In addition, the molecular mechanisms of these agents were confirmed in vitro and in vivo. The MEK or the PI3K inhibitor suppressed MPM cell growth in vitro in a dose-dependent manner via induction of G1 cell cycle arrest and apoptosis. In addition, combined use of the MEK and PI3K inhibitors showed an additive or synergistic inhibitory effect on MPM cell growth compared to treatment with either individual drug. Treatment with MEK or PI3K inhibitor suppressed the production of thoracic tumors and pleural effusion and prolonged the survival time of EHMES-10 cell-bearing SCID mice. The combination therapy more effectively prolonged the survival time compared to treatment with either individual drug. Immunohistochemical and western blot analysis of thoracic tumors suggested that these agents induced cell cycle arrest, apoptosis and inhibition of tumor angiogenesis. Our results suggest that a combination of MEK and PI3K inhibitors is a promising therapeutic strategy for MPM.

Antitussive effect of bakumondoto a fixed kampo medicine (six herbal components) for treatment of post-infectious prolonged cough: controlled clinical pilot study with 19 patients.

Bakumondoto (TJ-29) is a traditional herbal medicine that has been used in Japan for the treatment of bronchitis, bronchial asthma, and cough. This study investigated the effect of TJ-29 for the treatment of post-infectious prolonged cough. We performed a multicenter randomized controlled trial treating patients without (group A, n=11) or with TJ-29 (group B, n=8) for a total of 2 weeks using a beta 2 stimulant as the basal agent. Efficacy and safety were compared by a cough diary, VAS and sleeping questionnaire. At 4 and 5 days after treatment, the cough score of group B showed significant improvement compared with group A, demonstrating an early antitussive effect. At the assessment 2 weeks after treatment start, both groups showed similar levels of improvement in the cough score. No significant difference was observed in the VAS and the sleeping questionnaire items. In conclusion, oral TJ-29 administration could be useful and safe for the treatment of post-infectious prolonged cough.

A case of pulmonary nodular lymphoid hyperplasia with a resected cavity, followed by spontaneous regression of the remaining lesions.

A 50-year-old man was admitted to our hospital for examination of an abnormal shadow on chest radiography. Computed tomography revealed multiple small nodular shadows in bilateral lung fields, with cavitation in a right S3 lesion that was resected by video-assisted thoracoscopic surgery. Histopathological examination revealed marked proliferation of lymphoid tissue, including many plasma cells that were polyclonal in nature. This case was considered to be pulmonary nodular lymphoid hyperplasia (PNLH). Several residual nodules spontaneously disappeared during the 6 years of follow-up. This was a rare case of PNLH with a resected cavity, followed by spontaneous regression of the remaining lesions.

In vitro and in vivo therapeutic efficacy of the PPAR-γ agonist troglitazone in combination with cisplatin against malignant pleural mesothelioma cell growth.

Malignant pleural mesothelioma (MPM), an aggressive and refractory tumor type, is increasing in frequency throughout the world. Peroxisome proliferator activated receptor-γ (PPAR-γ) agonists have anticancer activity against several cancer cell lines in vitro and in vivo. However, there have been no reports that PPAR-γ agonists induce growth inhibition of MPM cell lines. In this study, we investigated the inhibitory effect of a PPAR-γ agonist in combination with an anticancer agent on MPM cell growth in vitro and in vivo. We examined the therapeutic efficacy of the PPAR-γ agonist troglitazone (TGZ) in combination with cisplatin against a human MPM cell line, both in vitro and orthotopically inoculated into severe combined immunodeficient (SCID) mice. Troglitazone (TGZ) alone inhibited MPM cell growth in vitro in a dose-dependent manner via induction of G1 cell cycle arrest and apoptosis. The combination of TGZ and cisplatin showed an additive inhibitory effect on MPM cell growth compared to treatment with either individual drug. Treatment with 500 mg/kg or 1000 mg/kg TGZ effectively inhibited the production of thoracic tumors and pleural effusion in EHMES-10 cell-bearing SCID mice. Moreover, treatment with 500 mg/kg TGZ in combination with 3 mg/kg cisplatin more effectively prolonged survival compared to treatment with either individual drug. These results suggest that TGZ in combination with cisplatin may become a novel therapy for MPM.

Comparative evaluation of serum markers in pulmonary sarcoidosis.

BACKGROUND: Although several serum markers have shown their ability to reflect lymphocytic alveolitis and disease progression in pulmonary sarcoidosis, to our knowledge no prior study has made comparative evaluations of these markers. METHODS: Forty-three patients with pulmonary sarcoidosis were enrolled. BAL fluid (BALF) cells were analyzed, and serum levels of serum amyloid A (SAA), soluble interleukin 2 receptor (sIL-2R), lysozyme, angiotensin-converting enzyme (ACE), and the mucin-like, high-molecular-weight glycoprotein KL-6 were measured at disease presentation. Clinical data, including chest radiographs, were collected at presentation and during follow-ups. Univariate and multivariate analyses were used to identify markers best predictive of increased parenchymal infiltration. RESULTS: Significantly higher serum levels of sIL-2R, lysozyme, and KL-6 were found in patients with parenchymal infiltration compared with those without parenchymal infiltration. The numbers of total cells and lymphocytes in BALF were significantly higher in patients with parenchymal infiltration. Serum levels of sIL-2R, lysozyme, and KL-6 were significantly correlated with the numbers of total cells, lymphocytes, and CD4(+) T lymphocytes in BALF. At the cutoff levels determined by receiver operating characteristic curves, sIL-2R, lysozyme, KL-6 serum levels, and the number of BAL lymphocytes showed significant correlations with increased parenchymal infiltrations by univariate analysis. However, multivariate analysis revealed that only KL-6 was a predictor of increased parenchymal infiltration. CONCLUSION: Our results suggest that initial serum sIL-2R, lysozyme, and KL-6 levels may reflect lymphocytic alveolitis in pulmonary sarcoidosis. Furthermore, initial serum KL-6 tends to associate with increased parenchymal infiltration in pulmonary sarcoidosis.

Pulmonary tumor thrombotic microangiopathy associated with lung cancer.

We describe a case of pulmonary tumor thrombotic microangiopathy (PTTM) associated with lung cancer. A 63-year-old woman, who had been treated for lung cancer, was admitted to our hospital because of progressive dyspnea. Chest CT films showed reticular shadows in the middle and left upper lobes, and echocardiography revealed severe pulmonary hypertension. Because drug induced pneumonitis and either pulmonary thromboembolism or pulmonary tumor embolism were suspected, corticosteroid and anti-coagulant therapy were administered. Despite these treatments, she died 50 days after admission. Postmortem examination revealed PTTM associated with lung cancer. PTTM should be considered in cancer patients who show progressive respiratory failure and pulmonary hypertension.

Docetaxel and cisplatin as second-line chemotherapy for advanced non-small cell lung cancer.

AIMS AND BACKGROUND: Docetaxel and cisplatin are both active against non-small cell lung cancer (NSCLC). This pilot study evaluated the efficacy and toxicity of docetaxel and cisplatin as second-line chemotherapy for patients with advanced NSCLC. PATIENTS AND METHODS: Eleven patients with advanced NSCLC who had no response to platinum-based treatment or had recurrence after a partial response were enrolled (2 stage III B, 9 stage IV; 8 men, 3 women). Median age was 58 years (range, 40 to 74 years). Seven patients had an Eastern Cooperative Oncology Group performance status of 0, and four had a performance status of 1. Four weeks or more after the end of previous therapy, all 11 patients received docetaxel 60 mg/m2 and cisplatin 80 mg/m2 on day 1 every four weeks. RESULTS: Two patients (18.2%) achieved a partial response,five (45.4%) patients had stable disease, and four (36.4%) patients showed progressive disease after initiation of second-line therapy. Median survival was 277 days. Median time to disease progression was 101 days, and the one-year survival rate was 36.4%. Hematological toxicities were moderate. Grade 3 and 4 leukocytopenia and neutropenia were observed in five (45.4%) patients. Grade 3 anemia occurred in one (9 .1%) patient. No severe non-hematological toxicities were observed except grade 3 nausea in two (18.2%) patients. CONCLUSIONS: The regimen of docetaxel and cisplatin has reasonable efficacy with moderate toxicity as second-line chemotherapy for patients with previously treated, advanced NSCLC.

[A case of small cell lung cancer with intramedullary spinal cord metastasis].

An 83-year-old man was admitted with paraplegia and loss of all sensation below the level of umbilicus, with bowel and bladder dysfunction. Stage IV small cell lung cancer had been diagnosed two years ago and had received several courses of chemotherapies. A magnetic resonance imaging revealed an enhanced mass in the intramedullary spinal cord at the level of Th10-L1. Metastatic spinal tumor was diagnosed by clinical and radiological examinations. This is a rare case of small cell lung cancer with intramedullary spinal cord metastasis which caused various neurological symptoms.

Successful treatment of obstructive sleep apnea syndrome improves autonomic nervous system dysfunction.

Autonomic nervous system (ANS) dysfunction may be implicated in the subsequent development of cardiovascular disease in patients with obstructive sleep apnea syndrome (OSAS). To confirm the relation between OSAS and ANS dysfunction, we prospectively investigated ANS function in 7 patients with moderate or severe OSAS; 7 healthy age-matched volunteers were for control. We also studied ANS function before and after treatment in the patients with OSAS to evaluate the effect of OSAS treatment on ANS dysfunction. The body mass index of patients with OSAS was 32.2 (27.4-45) (median [range]) kg/m2. The patients were treated by nasal continuous positive airway pressure (n = 5) or uvulopalatopharyngoplasty (n = 2). The apnea/hypopnea index decreased markedly from 42.1 (30.6-77.2) events/hr of sleep before treatment to 2.3 (1.4-3.8) after treatment. To evaluate ANS function, the coefficient of variation of the RR interval (CV-RR) and corrected QT (QTc) interval on the electrocardiogram at rest and the heart rate (HR) responses to blood pressure (BP) changes during the Valsalva maneuver were studied. Baseline HR of OSAS patients was significantly higher than that of the control subjects (p < .05). The Valsalva ratio (VR), baroreflex sensitivity (BRS), and CV-RR values in patients with OSAS were significantly lower than those of the control subjects (all, p < .005). However, there were no significant differences in systolic and diastolic BP or QTc intervals. After treatment, VR, BRS, and CV-RR values increased significantly compared with those before treatment in patients with OSAS (all, p < .05). There were no significant differences in systolic and diastolic BP, HR, or QTc intervals measured before and after treatment. These results suggest that impaired ANS function is present in patients with OSAS and can be improved by successful treatment of OSAS.

[A case of central diabetes insipidus caused by metastatic small cell lung cancer].

A 58-year-old man was admitted to our hospital because of cough, polydipsia and polyuria. Chest CT films showed mediastinal lymphadenopathy, nodules in the lung fields, and pleural effusion. Histopathologic examination of transbronchial biopsy specimens showed oat cell carcinoma. MRI films revealed tumorous swelling of the pituitary stalk. Central diabetes insipidus caused by pituitary metastasis of small cell lung cancer was diagnosed. After treatment with whole-brain irradiation and chemotherapy, the size of the swollen pituitary stalk was reduced and his urine volume decreased. He died of respiratory insufficiency 15 months after the initial diagnosis. No recurrence of pituitary metastasis was apparent. This was a rare case of central diabetes insipidus caused by pituitary metastasis of small cell lung cancer successfully treated with radiotherapy and chemotherapy.