Tsutomu Hachiya

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.

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.

Predominant implication of IL-5 in acute eosinophilic pneumonia : Comparison with chronic eosinophilic pneumonia

Background: Acute eosinophilic pneumonia (AEP) is a rare disease with unknown etiology. To examine pathophysiology of AEP we measured the cell number of eosinophils and eosinophil active cytokines in the peripheral blood and bronchoalveolar lavage fluid (BALF) of AEP patients and compared the levels with those measured in chronic eosinophilic pneumonia (CEP) patients. Methods: Cell number of eosinophils in peripheral blood and BALF from patients with AEP (n = 3) and CEP (n = 3) were measured. Eosinophil active cytokines in serum and BALF from the patients were measured using ELISA. Results: Eosinophil cell number in peripheral blood was 274–1,377/mm3 in AEP and 526–2,500/mm3 in CEP. The percentages of BALF eosinophils were high in AEP and CEP. Eosinophilia disappeared after methylprednisolone pulse therapy (1 g for 3 days) in AEP, however the cell number of eosinophils gradually increased after methylprednisolone pulse therapy and then spontaneously decreased to within normal range without any further medication. The concentrations of IL-5 in AEP were very high in serum and in BALF, however the concentrations in CEP were low in serum and BALF. Conclusion: AEP is a disease in which eosinophil active cytokine IL-5 is predominantly involved; CEP is not. The factors involving eosinophil infiltration to inflammatory loci differ between AEP and CEP.

Expression patterns of type II pneumocyte apical surface glycoconjugates in lung adenocarcinoma cells.

Abstract Monoclonal antibodies and lectins were used to examine the expression patterns of apical membrane oligosaccharide sequences specific to type II pneumocytes in atypical adenomatous hyperplasia (AAH) and lung cancer. Atypical cells of AAH and papillary adenocarcinoma cells expressed abundant sialyl Thomsen-Friedenreich (TF) antigen: this was not observed in acinar adenocarcinoma, bronchioloalveolar carcinoma with mucin production or squamous cell carcinoma. Sialyl Tn antigens was also detected on a few cells in AAH and papillary adenocarcinomas. Asialo TF and Tn antigen were not observed on the surface of carcinoma cells of any type. Alpha(α)2,3-linked sialic acids predominated in type II pneumocyte, AAH and papillary adenocarcinoma, whereas ciliated columnar cells expressed α2,6-linked sialic acids. Lewisx and sialyl Lewisx antigens capped the TF antigen in both O- and N-linked side chains on the surface of AAH and papillary adenocarcinoma cells, but were not expressed by type II pneumocytes. The findings demonstrate that papillary adenocarcinoma cells resemble type II pneumocytes in that they express abundant sialyl TF surface antigen, but they also express TF-related antigens not found in type II pneumocytes. Apical surface glycoconjugates of AAH have structural characteristics shared by both type II pneumocytes and papillary adenocarcinoma cells.

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.

A Three-dimensional Analysis of Blood Vessels in Bronchioloalveolar Carcinoma

The three-dimensional architecture of blood vessels within lung adenocarcinomas has not been well studied. In 19 cases with bronchioloalveolar carcinoma with central fibrosis, we three-dimensionally examined blood vessel architecture in 150 μm thick sections stained with elastin staining and anti-CD34 antibody. We examined four regions: normal alveoli and three regions within the tumor including an area adjacent to the normal alveoli (external area), an area in which tumor cells were replacing epithelial cells (replacement area), and a central fibrotic area (fibrotic area). Elastin staining showed that elastic fibers formed the framework of the alveoli, and the alveolar structure shrank more strongly to the center of the tumor due to folding of alveolar walls invaded by adenocarcinoma cells. We also measured three vessel parameters in these four regions. The vessel diameters were 4.08 ± 1.10 μm, 3.95 ± 1.02 μm, 5.04 ± 1.56 μm, and 6.11 ± 2.23 μm, the circumferences of those vessels seen as complete circles were 43.11 ± 12.78 μm, 43.71 ± 12.87 μm, 95.21 ± 39.32 μm, and 126.77 ± 54.65 μm; the lengths between vessel bifurcations were 13.28 ± 3.08 μm, 13.47 ± 4.58 μm, 24.91 ± 9.66 μm, and 41.82 ± 28.08 μm in the normal alveoli, and the external, replacement, and fibrotic areas, respectively. Blood vessel architecture changed such that the vessels became larger and coarser towards the center of the tumor. Our three-dimensional analysis suggests continuous remodeling of alveolar capillaries rather than angiogenesis within bronchioloalveolar carcinoma.

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.

Clinical analysis of patients treated with afatinib for advanced non-small cell lung cancer: A Nagano Lung Cancer Research Group observational study

BACKGROUND Afatinib has been available in Japan for the treatment of epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) since May 2014. We conducted an observational study in patients treated with afatinib in Nagano prefecture, focusing on response and associated toxicities. METHODS We analyzed the clinical records of NSCLC patients treated with afatinib between May 2014 and February 2015. RESULTS The records of a total of 73 patients (27 men, 46 women) with a median age of 69 years (range: 42-85 years) were analyzed. Afatinib was administered to 11 patients as a first-line therapy, but it was predominantly administered as a fifth-line or beyond therapy (32 cases, 43.8%). The overall response rates for afatinib as a first-line therapy and beyond second-line therapy were 80% (95% confidence interval [CI]: 55.2-100.0%) and 27.1% (95% CI: 14.5-39.7%), respectively. The main toxicities grade >3 included diarrhea (8.2%), skin rash (6.8%), nausea (6.8%), and appetite loss (6.8%). A low body surface area (BSA) (<1.5m2) was significantly associated with a higher frequency of diarrhea grade >2, compared with a higher BSA (≥ 1.5m2). Forty-eight patients (63.0%) were treated without a dose reduction of afatinib. CONCLUSIONS Although the survival benefit with afatinib remains unclear, our observational analysis demonstrated the feasibility of using afatinib for EGFR-mutated NSCLC in clinical practice. In particular, a relatively high level of drug delivery is possible. In addition, a lower BSA may be a predictor of diarrhea in patients treated with afatinib.

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.

Left Main Bronchial Stenosis due to Schwannoma

A 58-year-old woman was admitted to our hospital due to shortness of breath. An examination showed that no breath sounds from the left lung were audible. Chest computed tomography revealed a 13-mm mass in the left main bronchus (Picture 1). Bronchoscopy showed left bronchial stenosis with extraluminal compression, suggesting that the tumor had originated from the submucosa (Picture 2A). To resect the tumor, surgery was chosen instead of bronchoscopic treatment. The tumor was completely excised using videoassisted thoracic surgery. The tumor was round, white, and