[Case of von Recklinghausen disease complicated with a solitary lung lesion located mainly in the upper lung field].

A 72-year-old man presented with grade III dyspnea according to the Hugh-Jones scale in February, 2007, and he was referred to our department. Massive fibrosis of upper lung field dominance and bilateral pleural effusion were observed on chest X-ray films and CT. A respiratory function test revealed mixed ventilatory disturbance. Thereafter, left-sided pneumothorax developed in February 2008, followed by right-sided pneumothorax. He recovered once; however, respiratory failure progressed. He was re-hospitalized due to pneumonia and CO2 narcosis. Respiratory failure could not be prevented, and he died in September 2008. Macroscopic autopsy findings included fibrous adhesion of the pleura and fibrous consolidation of lung parenchyma which was most dominant in the bilateral apices. These were accompanied by bronchiectasis and brochiolectasis. Microscopically, the core pathology was organizing bronchiolitis and organizing pneumonia. Reported cases of diffuse lung lesions complicated with von Recklinghausen disease mostly comprise fibrosis and emphysematous changes. The unique pathological findings in this case seemed unrelated to any known disease entity.

Adherence with long-term asthma management in patients who experienced hospitalized asthma exacerbation.

BACKGROUND: In Japan, the number of asthma deaths has been gradually decreasing. However, in the management of asthma, there are still some problems originating from patient-related factors and iatrogenic factors, both of which should be further analyzed. METHODS: We investigated clinical and background characteristics of 164 patients with asthma who were admitted to our hospital with acute exacerbations, by reviewing their clinical records. RESULTS: Fifty-two patients had received long-term management (LTM) based on the guidelines (the LTM group), while 112 had not (the non-LTM group). In patients whose asthma severity had been intermittent (step 1), the proportion of severe and near fatal exacerbations was significantly higher in the non-LTM group than in the LTM group. However, even in the LTM-group, 23% of mild persistent (step 2) and 38% of moderately and severely persistent (step 3 & 4) patients had severe or near fatal exacerbations. In these patients, the peak expiratory flow rate significantly improved after discharge, and poor adherence was also significantly higher in the non-LTM group than in the LTM group. A multivariate analysis revealed that the factors associated with poor adherence were: 1) no history of previous admission due to asthma exacerbation; 2) the patient was male; and 3) the patient was young (<60 years). CONCLUSIONS: In the LTM group, re-evaluation of the actual severity of asthma and prompt treatment corresponding to the severity of disease should still be encouraged. In the non-LTM group, establishing countermeasures against factors causing poor adherence would be the next step in ensuring strong adherence with LTM.

A combination therapy of whole lung lavage and GM-CSF inhalation in pulmonary alveolar proteinosis.

Systemic and inhalation therapy of granulocyte-macrophage colony-stimulating factor (GM-CSF) is usually effective in controlling autoimmune pulmonary alveolar proteinosis (PAP), but some cases are refractory to GM-CSF therapy and subjected to whole lung lavage (WLL). A 9-year-old girl developed severe respiratory failure due to autoimmune PAP was treated with inhalational 250 microg of GM-CSF daily, however, it was ineffective. Unilateral WLL was performed three times and subsequent GM-CSF inhalation therapy yielded marked physiological and radiological improvement and was continued for 1 year.

The efficacy of montelukast and airway mast cell profiles in patients with cough variant asthma.

BACKGROUND: Cough variant asthma (CVA) is characterized by chronic cough without apparent wheezing; its pathophysiology is considered to be similar to that of classic asthma. OBJECTIVE: The clinical effects of montelukast, a cysteinyl-leukotriene receptor antagonist, on cough variant asthma were assessed, and the activation profile of airway mast cells was examined. METHODS: Montelukast (10 mg/day) was given orally to 36 CVA patients (25 women and 11 men; median age, 37.5 years). Before treatment, the patients' bronchial mucosa underwent a biopsy with a fiberoptic bronchoscope. The biopsy specimens were double stained with anti-CD63 antibody and anti-human tryptase antibody. RESULTS: After 2 weeks of montelukast treatment, cough symptoms improved in 22 patients (the effective group) but did not improve in 14 patients (the ineffective group); in the ineffective group, the symptoms disappeared 2 weeks after they were switched to fluticasone propionate (400 microg/day) inhalation therapy. In the effective group, the time interval from the onset of symptoms to the initiation of treatment was significantly shorter than in the ineffective group. The bronchial mucosa biopsy specimens showed that the proportion of CD63-positive cells in tryptase-positive mast cells was significantly higher in the effective group than in the ineffective group; although the total numbers of mast cells were not different between the two groups. CONCLUSION: There is a subgroup of CVA patients in whom leukotrienes are closely involved in the pathogenesis of their chronic cough; activation of airway mast cells may be an essential feature in these patients.

[A case of radiation pneumonitis with eosinophilia in bronchoalveolar lavage fluid].

A 78-year-old man was admitted to our hospital for irradiation therapy of non-resectable primary lung squamous cell carcinoma of the right middle lobe (T3N2M0). The Linac irradiation through opposing 2 gates (2Gy per day and 60Gy in total) was performed to the affected area including the metastatic right hilar and mediastinal lymphadenopathy. One week after completing the irradiation therapy, fever developed with infiltrates in the area from the right middle lobe to the right lower lobe, which did not necessarily coincide with the irradiated area. Antibiotic therapies were not effective. Both the serum LDH level and eosinophil count in the peripheral blood increased. Bronchoalveolar lavage was performed at the right B8, and differential cell counts of the lavage fluid were: macrophages, 17%; lymphocytes, 60%; neutrophils, 5%; and eosinophils, 18%. No significant organisms were obtained by culture of the lavage fluid. The %VC and DLCO/VA became lower than before the irradiation therapy. Thus, the patient was given a diagnosis of radiation pneumonitis. Treatment with 40mg/day oral prednisolone was commenced with a stepwise dose-reduction (5mg every two weeks) until reaching the maintenance dose of 15mg/day. The serum LDH level and blood eosinophil count recovered promptly to the normal range. The pulmonary infiltrates and the lung functions substantially improved. There have been few reports of radiation pneumonitis in which eosinophil counts increased in peripheral blood and bronchoalveolar lavage fluid after irradiation therapy. In the present case report, the possible mechanisms for the irradiation-induced eosinophilia were also reviewed.

Reliable and fast allele-specific extension of 3'-LNA modified oligonucleotides covalently immobilized on a plastic base, combined with biotin-dUTP mediated optical detection.

In the present work, a convenient microarray SNP typing system has been developed using a plastic base that covalently immobilizes amino-modified oligonucleotides. Reliable SNP allele discrimination was achieved by using allelic specificity-enhanced enzymatic extension of immobilized oligonucleotide primer, with a locked nucleic acid (LNA) modification at the SNP-discriminating 3'-end nucleotide. Incorporation of multiple biotin-dUTP molecules during primer extension, followed by binding of alkaline phosphatase-conjugated streptavidin, allowed optical detection of the genotyping results through precipitation of colored alkaline phosphatase substrates onto the surface of the plastic base. Notably, rapid primer extension was demonstrated without a preliminary annealing step of double-stranded template DNA, allowing overall processes to be performed within a couple of hours. Simultaneous evaluation of three SNPs in the genes TGFB1, SOD2 and APEX1, previously investigated for association with radiation sensitivity, in 25 individuals has shown perfect assignment with data obtained by another established technique (MassARRAY system).

Gene expression profile changes correlating with radioresistance in human cell lines.

PURPOSE: To identify gene expression profiles specific to radioresistance of human cells. METHODS AND MATERIALS: Global gene expression profiles of a total of 15 tumor and normal fibroblast cell lines were analyzed using DNA microarrays and statistical clustering methods. Initially, six of the cell lines were categorized into radioresistant (RG) or nonradioresistant (NRG) groups according to the radiation dose required to reduce their survival to 10% (D10). Genes for which expression was specific to each group at 1 or 3 h after irradiation were identified using statistical procedures including analysis of variance and a two-dimensional hierarchical clustering method. The remaining nine cell lines were subjected to the k-nearest neighbor pattern classification. RESULTS: The nine test cell lines were successfully classified by their D10 value using 46 and 44 genes for which transcription levels had significantly changed at 1 and 3 h after irradiation, respectively. Of these genes, 25 showed altered expression at both time points in the NRG or RG, but independently were unable to classify the test cell lines. CONCLUSIONS: Radioresistant cell lines analyzed in this study showed certain radiation-induced changes in gene expression profiles that are different from the profile changes of the more-sensitive cell lines.

Potential in a single cancer cell to produce heterogeneous morphology, radiosensitivity and gene expression.

Morphologically heterogeneous colonies were formed from a cultured cell line (KYSE70) established from one human esophageal carcinoma tissue. Two subclones were separated from a single clone (clone13) of KYSE70 cells. One subclone (clone13-3G) formed mainly mounding colonies and the other (clone 13-6G) formed flat, diffusive colonies. X-irradiation stimulated the cells to dedifferentiate from the mounding state to the flat, diffusive state. Clone 13-6G cells were more radiosensitive than the other 3 cell lines. Clustering analysis for gene expression level by oligonucleotide microarray demonstrated that in the radiosensitive clone13-6G cells, expression of genes involved in cell adhesion was upregulated, but genes involved in the response to DNA damage stimulus were downregulated. The data demonstrated that a single cancer cell had the potential to produce progeny heterogeneous in terms of morphology, radiation sensitivity and gene expression, and irradiation enhanced the dedifferentiation of cancer cells.