An inhaled inducible nitric oxide synthase inhibitor reduces damage of Candida-induced acute lung injury.

Excessive nitric oxide (NO) generated by inducible nitric oxide synthase (iNOS) aggravates acute lung injury (ALI) by producing peroxynitrite. We previously showed by immunostaining that the expression of iNOS was suppressed by inhalation of N(G)-nitro-L-arginine methyl ester in mice with Candida-induced ALI. This study tested the hypothesis that a novel iNOS inhibitor suppresses not only iNOS expression, but also iNOS messenger RNA (mRNA) production by interrupting a positive feedback loop at the time of NO production in Candida-induced ALI. Mice were pretreated by inhalation of saline or ONO-1714, a selective iNOS inhibitor, and were given an intravenous injection of Candida albicans to induce ALI. After inhalation of 1 mM aerosolized ONO-1714, the nitrite-nitrate concentration in bronchoalveolar lavage fluid (BALF) at 24 h was significantly lower than that after inhalation of saline. Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) levels and neutrophils in BALF were decreased by inhalation of ONO-1714. Inhalation of ONO-1714 markedly suppressed nitrotyrosine production and inhibited the expression of iNOS mRNA as well as proteins in the lung. Survival was prolonged by inhalation of ONO-1714. We conclude that pretreatment with inhaled ONO-1714 suppresses the production of peroxinitrite and decreases oxidative stress associated with peroxinitrite in Candida-induced ALI.

Phase I/II trial of biweekly docetaxel and cisplatin with concurrent thoracic radiation for stage III non-small-cell lung cancer.

OBJECTIVES: We conducted phase I and II studies of biweekly docetaxel and cisplatin with concurrent radiotherapy, followed by consolidation chemotherapy with the same drugs in patients with locally advanced, unresectable non-small-cell lung cancer (NSCLC). Our objectives were to define the maximum-tolerated dose and dose-limiting toxicity (DLT) in the phase I study, and to determine the response rate, toxicity, and survival rate at the recommended dose (RD) in the phase II study. METHODS: Patients with unresectable stage IIIA and IIIB NSCLC were studied. Six to eight cycles of docetaxel and cisplatin were administered at 2-week intervals. In the phase I study, patients received four dose levels: level 1, docetaxel/cisplatin=30/40 mg/m2; level 2, 35/40; level 3, 40/40; and level 4, 45/40. Radiotherapy was delivered at a rate of 2 Gy per fraction/day up to a total dose of 60 Gy over the course of 6 weeks, during the first three cycles of chemotherapy. RESULTS: DLT comprised neutropenia at level 4 in the phase I study (n=15), and level 3 was considered the RD. In the phase II study (n=46), two patients had a complete response (4.3%) and 34 had a partial response (73.9%), for an overall response rate of 78.2% [95% CI (66.3-90.2%)]. The survival rate was 69.1% at 1 year and 39.6% at 2 years, with a median survival time of 19.1 months. Leukopenia, neutropenia, anemia, and radiation esophagitis were the most common toxic reactions, with Grade > or = 3 reactions occurring at rates of 77, 70, 17, and 8%, respectively. CONCLUSION: Biweekly docetaxel and cisplatin with concurrent RT was active and well tolerated in patients with unresectable stage III NSCLC.

[Six cases of thymic carcinoma: a clinical review].

Thymic carcinoma is rarer than thymoma and carries a very poor prognosis. No standard treatment has yet been established. Chemotherapy and radiation therapy are usually given to patients in whom surgery is not indicated. We clinically review six patients with thymic carcinoma (three men and three women) who were admitted to our hospital from 1992 through 2002. Their ages ranged from 56 to 81 years (median 70.5). Four patients had chest pain, two were unable to swallow, and in one, who was asymptomatic, the tumor was detected by chance. Histologically, five cases were squamous cell carcinomas, and one was a lymphoepithelioma-like carcinoma. Four of the six patients had distant metastasis at diagnosis. Only one patient was able to undergo surgery, two received radiation therapy alone, and three were administered chemoradiation. The response to the chemoradiation was progression of the disease in two patients and no change in one. The response to radiation therapy was partial response in one patient and no change in one. In summary, chest pain is the most common symptom of thymic carcinoma. A symptomatic case suggests a poor prognosis resulting from the clinical behavior of thymic carcinoma, such as early distant metastasis or direct invasion of surrounding organs. Histologically, squamous cell carcinoma is the most common, and thymic carcinoma appears to be generally resistant to chemotherapy and radiotherapy.

Improvement of sleep hypopnea by antiparkinsonian drugs in a patient with Parkinson's disease: a polysomnographic study.

An 80-year-old man was admitted to our hospital because of bradykinesia, muscle rigidity and respiratory dysfunction during sleep. Concerning bradykinesia and muscle rigidity, we diagnosed him as the early/moderate stage of Parkinson's disease without autonomic dysfunction. Polysomnography (PSG) showed a series of obstructive hypopneas and apneas. After administration of antiparkinsonian drugs, rigidity of the neck and trunk was diminished along with a drastic decrease in hypopnea on PSG. We consider that sleep hypopnea in this patient is caused by involvement of the striated musculature surrounding the upper-airway and/or rigidity in the trunk. These conditions are treatable with antiparkinsonian drugs.

Effect of inhaled NG-nitro-L-arginine methyl ester on Candida-induced acute lung injury.

STUDY OBJECTIVES: Nitric oxide (NO) and peroxynitrite play a crucial role in acute lung injury (ALI). Whether NO synthase (NOS) inhibition is beneficial in the treatment of lung injury remains controversial. The objective of this study was to test the hypothesis that local inhibition of NOS in the lung reduces lung injury. DESIGN: We developed a model of Candida-induced ALI in the mouse by IV injection of Candida albicans. To evaluate the effect of NOS inhibitor, mice were pretreated by inhalation of saline solution or N(G)-nitro-L-arginine methyl ester (L-NAME) before induction of Candida-induced ALI. MEASUREMENTS AND RESULTS: After inhalation of 1 mM aerosolized L-NAME, nitrite-nitrate concentrations in BAL fluid (BALF) were significantly lower at 24 h and 48 h than those in mice treated with C albicans alone. Tumor necrosis factor-alpha, interleukin-1beta, and macrophage inflammatory protein-2 concentrations in lung homogenates, measured by enzyme-linked immunosorbent assay, and neutrophil counts in BALF were decreased by inhalation of L-NAME (n = 6 per group). Immunohistochemical analysis of inducible NOS (iNOS) and nitrotyrosine, a major product of protein nitration by peroxynitrite, revealed that alveolar macrophages and alveolar epithelial cells were positive for both substances in Candida-induced ALI. Inhalation of L-NAME markedly suppressed iNOS protein expression and nitrotyrosine production. Histologic evidence of lung injury decreased and survival improved after inhalation of L-NAME. CONCLUSIONS: We conclude that NO might play a crucial role in the pathogenesis of Candida-induced ALI, and such injury might be reduced by local inhibition of NOS. Our findings suggest that inhalation of L-NAME is beneficial in the treatment of Candida-induced ALI.

Multidisciplinary therapy including high-dose chemotherapy followed by peripheral blood stem cell transplantation for invasive thymoma.

We describe two patients with invasive thymomas who responded to high-dose chemotherapy followed by peripheral blood stem cell transplantation (PBSCT) combined with surgery and radiotherapy. The first patient was a 42-year-old man admitted to the hospital with chest pain, and the second patient was a 45-year-old man admitted with myasthenia gravis. Both patients had nonresectable thymomas (stage IVa) because of invasion of the aorta, pulmonary artery, or both, and dissemination to the pericardium. They initially received two cycles of chemotherapy consisting of adriamycin (40 mg/m(2), day 1), cisplatin (50 mg/m(2), day 1), vincristine (0.6 mg/m(2), day 3), and cyclophosphamide (700 mg/m(2), day 4) at 3-week intervals. Four weeks later, they were administered high-dose etoposide (300 mg/m(2), days 1 to 5) followed by granulocyte colony-stimulating factor (G-CSF) [50 micro g/m(2)/d] subcutaneously to mobilize stem cells into the blood. After two additional cycles of adriamycin, cisplatin, vincristine, and cyclophosphamide (ADOC), the patients received high-dose ifosfamide (1.5 g/m(2), days 1 to 4), carboplatin (400 mg/m(2), days 3 to 5), and etoposide (200 mg/m(2), days 1 to 5) followed by PBSCT. They were administered G-CSF (50 micro g/m(2)/d) after PBSCT, with subsequent rapid recovery of neutrophil and platelet level. The tumors shrank remarkably, and could be excised completely in both patients. Postoperatively, 50 Gy of irradiation was administered. Disease-free status has been maintained for 5 years in the first patient and 2 years in the second patient. Our findings suggest that high-dose ifosfamide, carboplatin, and etoposide followed by PBSCT in combination with an ADOC regimen, surgery, and radiotherapy is very effective and well tolerated in patients with advanced nonresectable thymoma.

[A case of mediastinal teratoma with elevated serum tumor marker levels].

A 27-year-old man complaining of cough was admitted to our hospital because of a giant mediastinal tumor on the chest radiograph. Chest CT and MRI revealed a giant polycystic mediastinal tumor. Chest radiographs on admission showed left pleural effusion due to perforation of the cyst. Laboratory data showed high serum and pleural fluid concentrations of CA 125, CA 19-9, SLX and others. The mediastinal mass was resected and diagnosed pathologically as a mature teratoma. It is reported that patients with mediastinal teratomas often have pleural fluid as a result of self-digestion by pancreatic enzymes, and some mediastinal teratomas have high serum tumor marker levels. We suspected that the high serum tumor marker levels in our case were caused by the high concentrations of tumor markers in the pleural fluid. We suggest that serum tumor marker levels may be useful in the preoperative differential diagnosis of anterior mediastinal cystic tumors.

[Mycobacterium abscessus infection complicated with diabetes mellitus].

We report a case of Mycobacterium abscessus infection complicated with diabetes mellitus. A 38-year-old man with diabetes mellitus as an underlying disease, was admitted to our hospital because of a productive cough. He had had pulmonary tuberculosis two years before. Chest radiography revealed infiltration in both lung apices and chest CT showed a cavitary lesion in the left upper lobe. Gaffky 2 was found on a sputum smear. However, in the examination of PCR on sputum, not only M. tuberculosis but M. avium complex was negative, and repeated cultures of sputum were positive for M. abscessus. On the basis of the diagnosis of an M. abscessus infection, the patient was initially treated with amikacin, imipenem/cilastatin and levofloxacin during hospitalization while receiving insulin for diabetes mellitus. The smear and culture of sputum became negative for Mycobacterium, and the findings of chest radiography and chest CT improved. After discharge, treatment was continued with clarithromycin and levofloxacin. It is considered that the choice of effective drugs and the additional treatment of an underlying disease are very important for the treatment of a Mycobacterium abscessus infection.