Muneharu Hayasaka

Inflammatory cytokines in BAL fluid and pulmonary hemodynamics in high-altitude pulmonary edema.

To evaluate the pathogenesis of high-altitude pulmonary edema (HAPE), we performed bronchoalveolar lavage (BAL) and pulmonary hemodynamic studies in seven patients with HAPE at its early stage. We measured cell counts, biochemical contents, and concentrations of pro-inflammatory cytokines including interleukin (IL)-1, IL-6, IL-8 and tumor necrosis factor (TNF)-alpha and of anti-inflammatory cytokines including IL-1 receptor antagonist (ra) and IL-10 in the BAL fluid (BALF). All patients showed increased counts for total cells, alveolar macrophages, neutrophils and lymphocytes, and markedly elevated concentrations of proteins, lactate dehydrogenase, IL-1beta, IL-6, IL-8, TNF-alpha and IL-1ra. The levels of IL-1alpha and IL-10 were not increased. Patients also showed pulmonary hypertension with normal wedge pressure. Both the driving pressure obtained as pulmonary arterial pressure minus wedge pressure and the PaO2 under room air were significantly correlated with the concentrations of IL-6 and TNF-alpha in the BALF. These findings suggest that the inflammatory cytokines play a role at the early stage of HAPE and might be related to pulmonary hypertension.

Cytokines in bronchoalveolar lavage fluid in patients with high altitude pulmonary oedema at moderate altitude in Japan.

BACKGROUND: The precise mechanism of high altitude pulmonary oedema (HAPE) remains unclear. The purpose of this study was to evaluate the role of cytokines and P-selectin in the development of HAPE which occurred at moderate altitude in Japan. METHODS: The following cellular and biochemical markers and chemotactic cytokines were measured in the bronchoalveolar (BAL) fluid from four patients with HAPE at 2857-3180 m in the Japanese Alps: total proteins, albumin, lactate dehydrogenase (LDH), and interleukin (IL)-1 alpha, IL-1 beta, IL-1 receptor antagonist (ra), IL-6, IL-8, IL-10, tumour necrosis factor (TNF)-alpha, and the soluble form of P-selectin. RESULTS: At admission there were significant increases in the levels of total cells, especially macrophages and neutrophils, total protein, albumin and LDH when compared with 13 healthy individuals. Furthermore, the levels of IL-1 beta, IL-6, IL-8, and TNF-alpha were also considerably increased but returned quickly to the normal ranges or were not detected after recovery. The levels of IL-1 alpha, IL-10, and P-selectin did not change. CONCLUSIONS: These results suggest that an inflammatory process almost identical with acute respiratory distress syndrome (ARDS) may occur in HAPE, but that these changes are transient and are not associated with any increase in P-selectin levels in the BAL fluid.

Mycobacterium avium-intracellulare pulmonary infection in patients without known predisposing lung disease.

Abstract. We tried to characterize the clinical features and findings on chest high resolution computed tomography (HRCT) of patients with Mycobacterium avium-intracellulare (MAI) pulmonary infection without known predisposing lung disease and with no immunodeficiency. We also aimed to clarify the small airway and alveolar inflammation using bronchoalveolar lavage (BAL) from the affected regions. MAI infection was diagnosed in 53 patients from respiratory samples, including sputum and materials obtained using a fiberoptic bronchoscope. None had a predisposing lung disease or immunodeficiency, as assessed by medical history, routine laboratory data, and previously normal chest radiographs and/or CT scans. The mean age of the 53 patients was 60 ± 11 years, and 48 were nonsmoking females. They had few respiratory symptoms, although 42% had chronic paranasal sinusitis. Chest HRCT findings showed centrilobular small nodules and ectasia of small bronchi and/or bronchioles located mainly in segment (S) 2, 3, 4, and 5. S1, which is usually affected by pulmonary tuberculosis, was completely free of these opacities. The BAL study revealed that the predominant cells were activated T lymphocytes and neutrophils. The CD4+/CD8+ ratio increased significantly. Bacteriology was negative for other bacteria and fungi. Although our patients did not present with distinct respiratory symptoms, the regions affected by MAI showed a chronic inflammation of mainly neutrophils and activated T lymphocytes. The presence of chronic sinusitis may be merely coincidental. However, its high prevalence and the finding of bronchiectasis in chest HRCT raise the question of whether silent bronchiectasis may be a predisposition.

Bronchoalveolar lavage fluid findings in patients with chronic hepatitis C virus infection.

BACKGROUND: Hepatitis C virus (HCV) infection has recently been incriminated as an aetiological agent in idiopathic pulmonary fibrosis. This study was performed to determine the cellularity and lymphocyte phenotypes of bronchoalveolar lavage (BAL) fluid in patients with chronic hepatitis C. METHODS: BAL fluid and lavage lymphocyte subsets from 13 patients (10 men) with active chronic hepatitis C, diagnosed by sustained elevated serum glutamic pyruvic transaminase and typical histological findings in the liver, were analysed. Lavage findings in these patients were compared with those from 13 healthy volunteers (eight men) as controls. RESULTS: There was no difference in total cell counts in lavage fluid between the two groups. Lavage lymphocyte and eosinophil numbers were increased in patients with chronic hepatitis C. Surface marker analysis of the lymphocyte populations showed increases in CD2, CD3, CD4, and HLA-DR. CD4/CD8 ratios were not different. CONCLUSIONS: The numbers of lymphocytes and eosinophils in BAL fluid are increased in patients with chronic hepatitis C. These findings suggest that HCV infection may trigger alveolitis.

Prospective Study of Gefitinib Readministration After Chemotherapy in Patients With Advanced Non–Small-Cell Lung Cancer Who Previously Responded to Gefitinib

INTRODUCTION Salvage treatment for acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitor in patients with non-small-cell lung cancer is a matter of clinical concern. Several retrospective reports have indicated the usefulness of epidermal growth factor receptor tyrosine kinase inhibitor readministration; however, there have been few prospective studies. MATERIALS AND METHODS This study was designed to prospectively evaluate the clinical efficacy of gefitinib readministration in patients with advanced or metastatic non-small-cell lung cancer who responded well to initial gefitinib treatment. The subjects received at least 1 regimen of cytotoxic chemotherapy after progressive disease with the initial gefitinib therapy. Gefitinib administration (250 mg/d, orally) was started after progressive disease with the previous chemotherapeutic regimen. The primary endpoint in the present study was the response rate. RESULTS Twenty patients were enrolled between April 2007 and May 2011. Three patients achieved partial response, and 6 showed stable disease. Thus, the overall response rate and disease control rate of gefitinib readministration were 15% (95% CI, 3.21-37.9) and 45% (95% CI, 23.1-68.5), respectively. Median progression-free survival and overall survival from the start of gefitinib readministration were 2.0 months (95% CI, 0.9-3.1 months) and 12.0 months (95% CI, 8.0-16.0 months), respectively. CONCLUSION These results suggest that gefitinib readministration may be an option, albeit with a low response rate and short progression-free survival, for patients who responded well to initial gefitinib followed by systemic chemotherapy. These findings provide valuable information for the management of previous gefitinib responders.

Invasive Thymoma with Hypogammaglobulinemia Spreading within the Bronchial Lumen

A case of invasive thymoma with hypogammaglobulinemia showing endobronchial growth is presented. A 63-year-old man was admitted for evaluation of a left hilar mass. A biopsy specimen obtained from the intraluminal mass, which occluded the left upper division bronchus, was highly suggestive of thymoma. The laboratory tests were almost normal except for hypogammaglobulinemia. The tumor was resected with the left upper lobe. Most of the tumor invaded the left upper lobe, and grew into the bronchi. The case was diagnosed histologically as invasive thymoma spreading within the bronchial lumen.

Unilateral Hilar Lymphadenopathy of Sarcoidosis or Sarcoid Reaction Compressing the Trunk of the Right Pulmonary Artery

A case of sarcoidosis or sarcoid reaction with a rare manifestation of unilateral lymphadenopathy compressing the trunk of the right pulmonary artery is presented. A 71-year-old woman was admitted for evaluation of a left hilar mass. Chest CT scans showed a mass invading the right pulmonary artery. A frozen section obtained following open lung biopsy showed lymph node tissue largely replaced by noncaseous granulomas indicating sarcoidosis or sarcoid reaction. Old uveitis was compatible with sarcoidosis, and no malignancy was evident. These findings suggested sarcoidosis, however, other evidence of sarcoidosis was not obtained.

Phase I trial of bi-weekly paclitaxel and gemcitabine as second-line therapy for patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy

A phase I study was conducted to evaluate the maximum tolerated dose, feasibility, and efficacy of biweekly-administered paclitaxel and gemcitabine in patients with non-small-cell lung cancer (NSCLC) who had prevously been treated with platinum-based chemotherapy. In a dose-escalation study, 18 patients, under 75 yr old, with unresectable NSCLC that had relapsed or was resistant after platinum-containing chemotherapy with performance status of 0–2 were enrolled. Patients were treated with paclitaxel and gemcitabine biweekly. The dose escalation levels of paclitaxel (mg/m2) at a fixed dose of gemcitabine 1000 mg/m2 were 110 (level 1), 130 (level 2), 150 (level 3), and 170 (level 4), respectively. All patients were eligible for evaluation of toxicities. At level 4, one patient developed an infection with grade 3 neutropenia and two other patients developed severe neurotoxicity (over grade 3). Thus, the recommended dose for phase II was paclitaxel 150 mg/m2 and gemcitabine 1000 mg/m2 due to dose-limiting toxicities including neutropenia and peripheral neurotoxicity. Partial response was seen in 4 cases of the 18 assessable patients, with an overall response of 22%. Bi-weekly paclitaxel and gemcitabine is feasible and appears to be an efficacious combination chemotherapy as second-line chemotherapy in refractory and recurrent patients with NSCL C who had been previously exposed to platinum-containing chemotherapy.

Basal layer reactivity in hyperplastic and metaplastic lesions of the bronchi as studied by lectin histochemistry.

The relationship between squamous metaplasia and squamous cell carcinoma of the bronchi has been the subject of controversy. We investigated basal cell hyperplasia, stratification, squamous metaplasia, and squamous cell carcinoma by means of lectin histochemistry with peanut agglutinin (PNA), Ulex europeus agglutinin-I, soybean agglutinin, and Dolichos biflorus agglutinin for all normal basal cells that are reactive. A basal layer stained with PNA was observed in basal cell hyperplasia, stratification, and squamous metaplasia, but this layer was not exhibited by squamous cell carcinoma. In hyperplasia and metaplasia, PNA staining was biased toward the lowest (basal) layer, whereas staining for the other lectins was more uniformly distributed across the layers. A PNA-positive basal layer may be important for the morphologic reversibility of the bronchial mucosa in hyperplastic and metaplastic lesions, and destruction of this layer may be associated with a progression from metaplasia to squamous cell carcinoma.