Etsuko Hamada

Plasma CCN2 (connective tissue growth factor; CTGF) is a potential biomarker in idiopathic pulmonary fibrosis (IPF)

BACKGROUND Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and fatal pulmonary fibrotic disease and useful biomarkers are required to diagnose and predict disease activity. CCN2 (connective tissue growth factor; CTGF) has been reported as one of the key profibrotic factors associated with transforming growth factor-β (TGF-β), and its assay has potential as a non-invasive measure in various fibrotic diseases. Recently, we developed a new subtraction method for determination of plasma CCN2 levels. We examined the utility of plasma CCN2 levels as a surrogate marker in IPF. METHODS Plasma CCN2 levels were calculated in 33 patients with IPF, 14 patients with non-IPF idiopathic interstitial pneumonias (IIPs) and 101 healthy volunteers by sandwich enzyme-linked immunosorbent assay (ELISA) using specific monoclonal antibodies for two distinct epitopes of human CCN2. We evaluated the utility of plasma CCN2 levels by comparison with clinical parameters. RESULTS Plasma CCN2 levels were significantly higher in patients with IPF than in those with non-IPF IIPs and healthy volunteers. Importantly, plasma CCN2 levels showed significantly negative correlation with 6-month change of forced vital capacity (FVC) in patients with IPF. CONCLUSIONS Plasma CCN2 is a potential biomarker for IPF.

Plasma connective tissue growth factor levels as potential biomarkers of airway obstruction in patients with asthma

BACKGROUND Bronchial asthma is a chronic inflammatory disorder characterized by airway hyperresponsiveness and airflow limitation. Connective tissue growth factor (CTGF), one of the key profibrotic factors associated with transforming growth factor β, may be related to airway remodeling in asthma. However, no data are available on the association between plasma CTGF levels and clinical and physiologic parameters in patients with asthma. Recently, we developed a novel subtraction method for determination of plasma CTGF levels. OBJECTIVE To investigate the utility of plasma CTGF level as a surrogate biomarker in asthma. METHODS Plasma CTGF levels were measured in 67 patients with stable asthma and 81 healthy volunteers, using the subtraction method. We evaluated correlations between plasma CTGF levels and clinical and physiologic parameters in patients with asthma. RESULTS Plasma CTGF levels were higher in patients with asthma than in healthy volunteers. Asthmatic patients with a percentage of predicted forced expiratory volume in 1 second (FEV1) less than 80% had significantly higher levels of plasma CTGF than those with a percentage of predicted FEV1 of 80% or more. In patients with asthma, plasma CTGF levels had significantly negative correlations with forced vital capacity (FVC), FEV1, percentage of predicted FEV1, FEV1/FVC ratio, forced expiratory flow at 50% of the FVC (FEF50%), percentage of predicted FEF50%, forced expiratory flow at 75% of the FVC (FEF75%), and percentage of predicted FEF75%, parameters that reflect the degree of airway obstruction. Plasma CTGF levels were negatively correlated with Asthma Control Test scores, a patient-based index of clinical control of asthma. CONCLUSION Plasma CTGF may be a potential biomarker for stable asthma when evaluating the degree of persistent airway obstruction. TRIAL REGISTRATION umin.ac.jp/ctr Identifier: UMIN000013081.

Hypofibrinogenemia Associated with a Heterozygous C→T Nucleotide Substitution at Position −1138 BP of the 5′‐Flanking Region of the Fibrinogen Aα‐Chain Gene

Abstract: We found a novel genetic abnormality, heterozygous C→T nucleotide substitution at position −1138 bp in the 5′‐flanking region of the fibrinogen Aα gene, in patients with hypofibrinogenemia. Luciferase reporter assay using the pGL3‐basic vector and CHO cells indicates that the transcriptional activity of a vector incorporated with −1138T was reduced to one‐third that of a vector incorporated with −1138C. These results suggest that the region adjacent to the −1138C bp of the 5′‐flanking region of the fibrinogen Aα gene is one of the most crucial sites for the transcription of the fibrinogen Aα gene.

Investigation of unexpected serum CA19-9 elevation in Lewis-negative cancer patients

Background Cancer patients with a Lewis (a−b−) phenotype have no carbohydrate antigen 19-9 (CA19-9) in their serum. However, we found a small but distinct elevation in the serum CA19-9 level in three cancer patients with the Lewis-negative phenotype. Here, we investigated the reason of such phenomena. Methods Six cancer patients with a Lewis-negative phenotype were selected by very low CA19-9 concentrations: three showed a small elevation (Group A) and the other three showed no elevation (Group B) in the serum CA19-9. We investigated the difference by analyzing the Lewis/Secretor genotypes. Results All of the six patients with a Le (a−b−) phenotype were genuine Le-negative genotypes: four individuals were homozygous for le1 (le59,508 ), one patient was compound heterozygous for le1 (le59,508 ) and le2 (le59,1067 ) and one patient was compound heterozygous for le1 and le202,314 . As for the Secretor gene, the three patients in Group B were homozygous for Se2 (one patient) or compound heterozygous for Se2 and sej (two patients), while the patients in Group A were all homozygous for sej genotypes. Conclusions Even genuinely Le-negative patients, who genetically lack the Le enzyme and theoretically never produce CA19-9, occasionally show a slight increase in serum CA19-9 level when they are homozygous for Se-negative genotypes and suffer from advanced cancer with overproduction of glycans as precursors of CA19-9. Although such cases are not frequent, we should be acquainted with the correlation between serum CA19-9 values and genotypes of Lewis and Secretor genes.

Evaluation of serum bone alkaline phosphatase activity in patients with liver disease: Comparison between electrophoresis and chemiluminescent enzyme immunoassay

BACKGROUND Serum bone alkaline phosphatase (ALP) is a marker of bone formation and metabolism. However, existing methods for measuring it have their limitations and their accuracy has not been determined. METHODS We measured serum bone ALP activity in 127 patients with liver disease using 2 methods: electrophoresis and chemiluminescent enzyme immunoassay (CLEIA). The results of these 2 methods were compared and analyzed according to gender, age and several serum biochemical markers. RESULTS When ALP3 (%; bone-type isozyme activity as a percentage of total ALP activity) values were high, the 2 methods showed good correlation. However, with a decrease in ALP3 (%) levels, the correlation coefficient (R) also decreased. Starting with ALP3 (%)<23, R values markedly decreased to <0.50 (p>0.05). Five outliers displayed low ALP3 (%) activity levels. Furthermore, in regard to genders, there were significant differences in total cholesterol (TC), γ-glutamyltransferase (γ-GTP), ALP and ALP3 (%) levels (p<0.05). CONCLUSIONS When serum ALP3 (%) levels were high in patients with liver disease, the accuracy of electrophoresis was comparable to that of CLEIA. However, the accuracy of electrophoresis needs to be evaluated with further when patient samples under certain conditions.

A case of treatment with voriconazole for chronic progressive pulmonary aspergillosis in a patient receiving tacrolimus for dermatomyositis-associated interstitial lung disease

We report a successful treatment with voriconazole (VRCZ) for chronic progressive pulmonary aspergillosis (CPPA) in a patient with dermatomyositis-associated interstitial lung disease (DM-ILD) treated with tacrolimus. A 73-year-old man with DM-ILD, treated with tacrolimus and prednisolone, complained of productive cough and his chest X-ray showed infiltration in the left upper lung field. We diagnosed CPPA and added VRCZ. Although we reduced the dose of tacrolimus for drug interaction, serum VRCZ level increased after the treatment. The patient was found to have cytochrome P450 (CYP) 2C19 *2/*2, a genetic polymorphism in poor metabolizers of VRCZ. We adjusted the doses of both drugs and treated him successfully. We recommend performing individual therapeutic drug monitoring (TDM) in CYP-mediated drug interactions and considering the effect of CYP polymorphisms.