Concomitant Use of Multiple Nephrotoxins including Renal Hypoperfusion Medications Causes Vancomycin-Associated Nephrotoxicity: Combined Retrospective Analyses of Two Real-World Databases.

There is a growing concern about the relationship between vancomycin-associated nephrotoxicity (VAN) and concomitant use of nephrotoxins. We examined this relationship by combined retrospective analyses of two real-world databases. Initially, the FDA Adverse Event Reporting System (FAERS) was analyzed for the effects of concomitant use of one or more nephrotoxins on VAN and the types of combinations of nephrotoxins that exacerbate VAN. Next, electronic medical records (EMRs) of patients who received vancomycin (VCM) at Tokushima University Hospital between January 2006 and March 2019 were examined to confirm the FAERS analysis. An elevated reporting odds ratio (ROR) was observed with increases in the number of nephrotoxins administered (VCM + one nephrotoxin, adjusted ROR (95% confidence interval [CI]) 1.67 [1.51-1.85]; VCM + 2 nephrotoxins, adjusted ROR [95% CI] 1.54 [1.37-1.73]) in FAERS. EMRs analysis showed that the number of nephrotoxins was associated with higher incidences of VAN [odds ratio: 1.99; 95% CI: 1.42-2.78]. Overall, concomitant use of nephrotoxins was associated with an increased incidence of VAN, especially when at least one of those nephrotoxins was a renal hypoperfusion medication (furosemide, non-steroidal anti-inflammatory drugs, and vasopressors). The concomitant use of multiple nephrotoxins, especially including renal hypoperfusion medication, should be avoided to prevent VAN.


Molecular species profiles of plasma ceramides in different clinical types of X-linked adrenoleukodystrophy

X-linked adrenoleukodystrophy (X-ALD) is a genetic disorder associated with peroxisomal dysfunction. Patients with this rare disease accumulate very long-chain fatty acids (VLCFAs) in their bodies because of impairment of peroxisomal VLCFA ?-oxidation. Several clinical types of X-ALD, ranging from mild (axonopathy in the spinal cord) to severe (cerebral demyelination), are known. However, the molecular basis for this phenotypic variability remains largely unknown. In this study, we determined plasma ceramide (CER) profile using liquid chromatography-tandem mass spectrometry. We characterized the molecular species profile of CER in the plasma of patients with mild (adrenomyeloneuropathy;AMN) and severe (cerebral) X-ALD. Eleven X-ALD patients (five cerebral, five AMN, and one carrier) and 10 healthy volunteers participated in this study. Elevation of C26:0 CER was found to be a common feature regardless of the clinical types. The level of C26:1 CER was significantly higher in AMN but not in cerebral type, than that in healthy controls. The C26:1 CER level in the cerebral type was significantly lower than that in the AMN type. These results suggest that a high level of C26:0 CER, along with a control level of C26:1 CER, is a characteristic feature of the cerebral type X-ALD. J. Med. Invest. 70 : 403-410, August, 2023.

The Journal of Medical Investigation : JMI


Safety and immunogenicity of sequential administration of PCV13 followed by PPSV23 in pneumococcal vaccine-naïve adults aged ≥ 65 years: Comparison of booster effects based on intervals of 0.5 and 1.0 year.

The 1.0-y interval provided better booster effects induced by PPSV23 than those of the 0.5-y interval in a sequential administration in pneumococcal vaccine-naïve adults aged ≥ 65 years. No difference was found in the safety profile between both intervals.


Non-recovery of vancomycin-associated nephrotoxicity is related to worsening survival outcomes: Combined retrospective analyses of two real-world databases.

There has been growing concern in worsening survival and renal outcomes following vancomycin-associated nephrotoxicity (VAN) onset, but the factors associated with these phenomena remain unclear. To examine these factors, we performed a retrospective study combining the analysis of two real-world databases. Initially, the FDA Adverse Event Reporting System (FAERS) was used to evaluate the relationship between VAN and mortality using odds ratios (ORs) and 95% confidence intervals (CIs). Next, electronic medical records (EMRs) were examined in a more robust cohort for evaluation of the association between renal outcomes and worsening survival using Cox proportional hazards regression models. FAERS analysis revealed a significant correlation between VAN occurrence and increased mortality (OR: 1.30; 95% CI: 1.17-1.46). EMR analysis showed that non-recovery of VAN was associated with increased hospital mortality (hazard ratio [HR]: 4.05; 95% CI: 2.42-6.77) and 1-year mortality (HR: 3.03, 95% CI: 1.98-4.64). The HR for VAN recovery was lower for patients with acute kidney injury (AKI) stage 2 (HR: 0.09; 95% CI: 0.02-0.40). Thus, worsening survival outcomes were associated with non-recovery of VAN, whereby AKI stage 2 was a significant risk factor. Progression to severe VAN should be prevented for better survival outcomes.

Basic & Clinical Pharmacology & Toxicology


First reported case of Lachnoanaerobaculum gingivalis bacteremia in an acute myeloid leukemia patient with oral mucositis during high dose chemotherapy.

During chemotherapy in patients with oral mucositis, we should consider the possibility of L. gingivalis bacteremia.


Hapten-labeled fusion-polymerase chain reaction of multiple marker genes for the application of immunochromatographic test.

A variety of methods have been reported using polymerase chain reaction (PCR)-based nucleic acid testing (NAT) because of its potential to be used in highly sensitive inspection systems. Among these NATs, fusion-PCR (also called as overlap-extension-PCR) has been focused on this study and adopted to generate the fused amplicon composed of plural marker gene fragments for detection. Generally, conventional agarose gel electrophoresis followed by gel staining is employed to check the PCR results. However, these are time-consuming processes that use specific equipment. To overcome these disadvantages, the immunochromatographic test (ICT) for the detection of PCR amplicons with hapten-labels that were generated by PCR using hapten-labeled primers was also adopted in this study. Based on these concepts, we constructed the systems of hapten-labeled fusion-PCR (HL-FuPCR) followed by ICT (HL-FuPCR-ICT) for the two and three marker genes derived from pathogenic microbe. As a result, we successfully developed a two marker genes system for the pathogenic influenza A virus and a three marker genes system for the penicillin-resistant Streptococcus pneumoniae. These detection systems of HL-FuPCR-ICT are characterized by simple handling and rapid detection within few minutes, and also showed the results as clear lines. Thus, the HL-FuPCR-ICT system introduced in this study has potential for use as a user-friendly inspection tool with the advantages especially in the detection of specific strains or groups expressing the characteristic phenotype(s) such as antibiotic resistance and/or high pathogenicity even in the same species.

Journal of Bioscience and Bioengineering


Lysophosphatidic acid, ceramide 1-phosphate and sphingosine 1-phosphate in peripheral blood of patients with idiophathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial pneumonias. Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are signaling lipids that evoke growth factor-like responses to many cells. Recent studies revealed the involvement of LPA and S1P in the pathology of IPF. In this study, we determined LPA, S1P and ceramide 1-phosphate (C1P) in peripheral blood plasma of IPF patients, and examined correlation to the vital capacity of lung (VC), an indicator of development of fibrosis. Blood plasma samples were taken from eleven patients with IPF and seven healthy volunteers. The lipids of the sample were extracted and subjected to liquid chromatography-tandem mass spectrometry for analysis. Results showed that there is a significant negative correlation between VC and plasma LPA levels, indicating that IPF patients with advanced fibrosis had higher concentration of LPA in their plasma. Average of S1P levels were significantly higher in IPF patients than those in healthy subjects. Although it is not statistically significant, a similar correlation trend that observed in LPA levels also found between VC and S1P levels. These results indicated that plasma LPA and S1P may be associated with deterioration of pulmonary function of IPF patients. J. Med. Invest. 69 : 196-203, August, 2022.


Impact of Area Under the Concentration-Time Curve on the Prevalence of Vancomycin-Induced Nephrotoxicity in Combination With Tazobactam/Piperacillin or Cefepime: A Single-Institution Retrospective Study.

VIN risk was higher with VT than with VC, even when the AUC was controlled to the guideline-recommended range. These results strongly suggest that VIN prevention may be difficult with AUC-guided vancomycin dosing in patients receiving VT.

The prevalences of VIN were 29.5% (18/61) and 7.1% (3/42) in the VT and VC groups, respectively. Multivariate logistic regression analysis of data from all patients revealed concurrent use of tazobactam/piperacillin (odds ratio [OR] = 4.59; P = 0.039) and AUC increase (OR = 1.01; P < 0.01) as risk factors for VIN, but only concurrent use of tazobactam/piperacillin was identified as a risk factor in patients with an AUC of <600 μg · h/mL, the guideline-recommended value (OR = 9.52; P = 0.041). Moreover, the vancomycin exposure-toxicity curve showed that in the guideline-recommended AUC range, VIN probability was consistently higher and the slope of VIN probability was greater in the VT group than in the VC group.


Clinical Significance of Carbapenem-Tolerant Pseudomonas aeruginosa Isolated in the Respiratory Tract


Functional analysis of human fibrocytes derived from monocytes reveals their profibrotic phenotype through paracrine effects

Fibrocytes, which are bone marrow-derived collagen-producing cells, were reported to play a role in the pathogenesis of pulmonary fibrosis. However, their function in pulmonary fibrosis is unclear. We analyzed their function compared with that of monocytes and localization in fibrotic tissues in patients with idiopathic pulmonary fibrosis (IPF). We compared the gene expression profile of monocyte-derived fibrocytes with that of monocytes by microarray analysis. Proliferation and differentiation into myofibroblasts were examined by 3H-thymidine incorporation assay and Western blotting. We measured the level of growth factors in the culture supernatant of fibrocytes by ELISA. The localization of fibrocytes in lung tissues of patients with IPF was determined by immunofluorescence staining. Compared with monocytes, fibrocytes had higher expression of extracellular matrix- and growth factor-encoding genes, including PDGF-B, FGF-2 and VEGF-B. Although fibrocytes did not proliferate in response to PDGF, co-culture of fibrocytes stimulated the growth of lung fibroblasts through the production of PDGF-BB. In the lung of IPF patients, CD45+Collagen-I+FSP-1+ cells, which have a similar phenotype to fibrocytes, were detected and co-stained with anti-PDGF antibody. This study suggested that fibrocytes function in pulmonary fibrosis partly by producing PDGF in the lungs of IPF patients. J. Med. Invest. 67 : 102-112, February, 2020.

The Journal of Medical Investigation : JMI


Inactivation of Extended-spectrum β-Lactamase (ESBL)-producing Escherichia Coli by UVA-LED Irradiation System.

The prevalence of extended-spectrum β-lactamase (ESBL)-producing Escherichia coli is increasing rapidly and spreading worldwide, particularly in Asia, compared to other regions. In the last ten years, in our hospital, in particular, there has been a < 30% increase. To prevent the spread of ESBL in hospitals and the community, the ultraviolet (UV) A-light-emitting diode (LED) irradiation device was used to inactivate ESBL-E. coli in human livestock and the environment. ESBL-E. coli and E. coli bacterial samples were collected from patients at Tokushima University Hospital (Tokushima City, Japan). The UVA-LED irradiation system had 365 nm single wavelength, and the current of the circuit was set to 0.23 or 0.50 A consistently. Results demonstrated that UVA-LED was useful for the inactivation of ESBL-E. coli and E. coli. The minimum energy dosage required to inactivate ESBL-E. coli and E. coli was 40.76 J/cm2 (45 min) in the first type of UVA-LED and 38.85 J/cm2 (5 min) in the second type. There were no significant differences between ESBL-E. coli and E. coli. The inactivation of ESBL-E. coli was dependent on energy. These findings suggest that UVA-LED with 365 nm single wavelength could be useful for surface decontamination in healthcare facilities. J. Med. Invest. 67 : 163-169, February, 2020.


Effect of serum concentration and concomitant drugs on vancomycin-induced acute kidney injury in haematologic patients: a single-centre retrospective study.

We retrospectively analysed 150 haematologic patients to whom VCM was administered between April 2010 and March 2018 at Tokushima University Hospital. VCM-induced AKI was defined according to Kidney Disease Improving Global Outcomes (KDIGO) criteria. Multivariate logistic regression analyses were performed to identify risk factors for VCM-induced AKI.

The optimal initial VCM trough concentration was 10-15 mg/L in haematologic patients, considering safety and effectiveness. There were differences in the effect of VCM-induced AKI between nephrotoxic drugs.

European Journal of Clinical Pharmacology


The novel inhibitor PRI-724 for Wnt/β-catenin/CBP signaling ameliorates bleomycin-induced pulmonary fibrosis in mice.

These results suggest that the β-catenin/CBP inhibitor PRI-724 is a potent antifibrotic agent that acts by modulating the activity of macrophages in the lungs.


Blockade of platelet-derived growth factor receptor-β, not receptor-α ameliorates bleomycin-induced pulmonary fibrosis in mice.

Platelet-derived growth factor (PDGF) has been implicated in the pathogenesis of pulmonary fibrosis. Nintedanib, a multi-kinase inhibitor that targets several tyrosine kinases, including PDGF receptor (PDGFR), was recently approved as an anti-fibrotic agent to reduce the deterioration of FVC in patients with idiopathic pulmonary fibrosis (IPF). However, the effects of PDGFR-α or -β on pulmonary fibrosis remain unclear. In an attempt to clarify their effects, we herein used blocking antibodies specific for PDGFR-α (APA5) and -β (APB5) in a bleomycin (BLM)-induced pulmonary fibrosis mouse model. The effects of these treatments on the growth of lung fibroblasts were examined using the 3H-thymidine incorporation assay in vitro. The anti-fibrotic effects of these antibodies were investigated with the Ashcroft score and collagen content of lungs treated with BLM. Their effects on inflammatory cells in the lungs were also analyzed using bronchoalveolar lavage fluid. We investigated damage to epithelial cells and the proliferation of fibroblasts in the lungs. APA5 and APB5 inhibited the phosphorylation of PDGFR-α and -β as well as the proliferation of lung fibroblasts induced by PDGF-AA and BB. The administration of APB5, but not APA5 effectively inhibited BLM-induced pulmonary fibrosis in mice. Apoptosis and the proliferation of epithelial cells and fibroblasts were significantly decreased by the treatment with APB5, but not by APA5. The late treatment with APB5 also ameliorated fibrosis in lungs treated with BLM. These results suggest that PDGFR-α and -β exert different effects on BLM-induced pulmonary fibrosis in mice. A specific approach using the blocking antibody for PDGFR-β may be useful for the treatment of pulmonary fibrosis.


Potential Usefulness of Early Potassium Supplementation for Preventing Severe Hypokalemia Induced by Liposomal Amphotericin B in Hematologic Patients: A Retrospective Study.

This study showed that starting administration of a potassium formulation within 2 days from the start of L-AMB administration was a risk reduction factor for L-AMB-induced hypokalemia. This finding indicates that early potassium supplementation should be incorporated into the regimen of hypokalemia management when L-AMB is used.


Clinical evaluation of pharmacist interventions in patients treated with anti-methicillin-resistant Staphylococcus aureus agents in a hematological ward

The therapeutic effects of anti-methicillin-resistant Staphylococcus aureus (MRSA) agents, vancomycin (VCM), teicoplanin (TEIC), and arbekacin (ABK), depend on their concentrations in blood. Therefore, therapeutic drug monitoring (TDM) is important when these antibiotics are used. In the hematological ward at Tokushima University Hospital, pharmacists have ordered the measurement of blood VCM, TEIC, and ABK concentrations to promote the use of TDM in accordance with an agreed protocol since 2013. Moreover, the infection control team includes several medical disciplines and has advised on the optimal treatment using VCM, TEIC, and ABK since 2013. This study aimed to investigate the clinical effectiveness of these pharmacist interventions. We retrospectively studied 145 cases in which patients were treated with VCM, TEIC, or ABK between January 2012 and December 2013 in the hematological ward at Tokushima University Hospital. The patients were divided into a control group (71 cases) and an intervention group (74 cases), and their clinical outcomes were compared. The rate of achievement of effective drug concentrations significantly increased in the intervention group (74%), compared to the rate in the control group (55%). Moreover, univariate and multivariate Cox proportional hazard regression revealed that pharmacist intervention and appropriate concentrations of anti-MRSA agents were independent factors associated with reduced hospitalization periods in patients with lymphoma. Our study revealed that proactive pharmacist intervention may improve the therapeutic effect of anti-MRSA agents in hematology ward patients.


Role of PDGF/PDGFR axis in the trafficking of circulating fibrocytes in pulmonary fibrosis

Circulating fibrocytes have been reported to migrate into the injured lungs, and contribute to fibrogenesis via CXCL12-CXCR4 axis. In contrast, we report that imatinib mesylate prevented bleomycin (BLM)-induced pulmonary fibrosis in mice by inhibiting platelet-derived growth factor receptor (PDGFR), even when it was administered only in the early phase. The goal of this study was to test the hypothesis that platelet-derived growth factor (PDGF) might directly contribute to the migration of fibrocytes to the injured lungs. PDGFR expression in fibrocytes was examined by flow cytometry and RT-PCR. The migration of fibrocytes was evaluated by using a chemotaxis assay for human fibrocytes isolated from peripheral blood. The numbers of fibrocytes triple-stained for CD45, collagen-1, and CXCR4 were also examined in lung digests of BLM-treated mice. PDGFR mRNA levels in fibrocytes isolated from patients with idiopathic pulmonary fibrosis were investigated by real-time PCR. Fibrocytes expressed both PDGFR-α and -β, and migrated in response to PDGFs. PDGFR inhibitors (imatinib, PDGFR-blocking antibodies) suppressed fibrocyte migration in vitro, and reduced the number of fibrocytes in the lungs of BLM-treated mice. PDGF-BB was a stronger chemoattractant than the other PDGFs in vitro, and anti-PDGFR-β-blocking antibody decreased the numbers of fibrocytes in the lungs compared with anti-PDGFR-α antibody in vivo. Marked expression of PDGFR-β was observed in fibrocytes from patients with idiopathic pulmonary fibrosis compared with healthy subjects. These results suggest that PDGF directly functions as a strong chemoattractant for fibrocytes. In particular, the PDGF-BB-PDGFR-β biological axis might play a critical role in fibrocyte migration into the fibrotic lungs.

American Journal of Respiratory Cell and Molecular Biology


ブレオマイシン肺線維症モデルにおけるFAKシグナル阻害薬の抗線維化効果

ブレオマイシン肺線維症モデルにおけるFAKシグナル阻害薬の抗線維化効果


Use of Ethanol-Based Hand Rub Foams in The Clinical Setting

医療従事者における泡状アルコール性手指消毒剤の殺菌効果，塗布面積及び使用感に関する検討

Alcohol-based hand rubs are recommended for use by healthcare staff worldwide. In addition to gel and liquid rubs, ethanol-based foam is available for hand hygiene. Ethanol-based foam was launched as the first alcohol-based foaming hand rub available in Japan in June 2011. Ethanol-based foam has gained attention among healthcare staff because ethanol-based foam does not drip from the hands, and allows good visual coverage. This study compared the effectiveness of ethanol-based gel and foam for bacterial removal and the percentage of areas covered with gel or foam. The Parm-Stamp Test was used to prove that ethanol-based foam has the same efficacy against bacteria as gel. To examine if the hands were fully covered with gel or foam, we used the Black Lights device and fluorescence powder. The results showed that the ethanol-based foam provided significantly improved coverage compared with the gel. According to the questionnaire results, ethanol-based foam has a lot of unique benefits, such as no dripping, easy spreading, good visual coverage, and no sticky feeling. Due to the effective cleaning with excellent skin feel during and after use, ethanol-based hand rub foam is very useful in the clinical setting for hand hygiene among healthcare workers.

Japanese Journal of Infection Prevention and Control


Antifibrotic effects of focal adhesion kinase inhibitor in bleomycin-induced pulmonary fibrosis in mice.

Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase involved in various biological functions, including cell survival, proliferation, migration, and adhesion. FAK is an essential factor for transforming growth factor to induce myofibroblast differentiation. In the present study, we investigated whether the targeted inhibition of FAK by using a specific inhibitor, TAE226, has the potential to regulate pulmonary fibrosis. TAE226 showed inhibitory activity of autophosphorylation of FAK at tyrosine 397 in lung fibroblasts. The addition of TAE226 inhibited the proliferation of lung fibroblasts in response to various growth factors, including platelet-derived growth factor and insulin-like growth factor I, in vitro. TAE226 strongly suppressed the production of type I collagen by lung fibroblasts. Furthermore, treatment of fibroblasts with TAE226 reduced the expression of -smooth muscle actin induced by transforming growth factor , indicating the inhibition of differentiation of fibroblasts to myofibroblasts. Administration of TAE226 ameliorated the pulmonary fibrosis induced by bleomycin in mice even when used late in the treatment. The number of proliferating mesenchymal cells was reduced in the lungs of TAE226-treated mice. These data suggest that FAK signal plays a significant role in the progression of pulmonary fibrosis and that it can become a promising target for therapeutic approaches to pulmonary fibrosis.


Antifibrotic effects of CXCR4 antagonist in bleomycin-induced pulmonary fibrosis in mice.

Circulating fibrocytes had been reported to migrate into the injured lungs, and contribute to fibrogenesis via chemokine-chemokine receptor systems including CXCL12-CXCR4 axis. Here we hypothesized that blockade of CXCR4 might inhibit the migration of fibrocytes to the injured lungs and the subsequent pulmonary fibrosis. To explore the antifibrotic effects of blockade of CXCR4, we used a specific antagonist for CXCR4, AMD3100, in bleomycin-induced pulmonary fibrosis model in mice. Administration of AMD3100 significantly improved the loss of body weight of mice treated with bleomycin, and inhibited the fibrotic lesion in subpleural areas of the lungs. The quantitative analysis demonstrated that treatment with AMD3100 reduced the collagen content and fibrotic score (Aschcroft score) in the lungs. Although AMD3100 did not affect cell classification in bronchoalveolar lavage fluid on day 7, the percentage of lymphocytes was reduced by AMD3100 on day 14. AMD3100 directly inhibited the migration of human fibrocytes in response to CXCL12 in vitro, and reduced the trafficking of fibrocytes into the lungs treated with bleocmycin in vivo. These results suggest that the blockade of CXCR4 might be useful strategy for therapy of patients with pulmonary fibrosis via inhibiting the migration of circulating fibrocytes.

The Journal of Medical Investigation : JMI


CCN6 as a profibrotic mediator that stimulates the proliferation of lung fibroblasts via the integrin β1/focal adhesion kinase pathway.

Idiopathic pulmonary fibrosis is a progressive and lethal disease of the lung that is characterized by the proliferation of fibroblasts and increased deposition of the extracellular matrix. The CCN6/WISP-3 is a member of the CCN family of matricellular proteins, which consists of six members that are involved in many vital biological functions. However, the regulation of lung fibroblasts mediated by CCN6 protein has not been fully elucidated. Here, we demonstrated that CCN6 induced the proliferation of lung fibroblasts by binding to integrin β1, leading to the phosphorylation of FAK(Y397). Furthermore, CCN6 showed a weak, but significant, ability to stimulate the expression of fibronectin. CCN6 was highly expressed in the lung tissues of mice treated with bleomycin. Our results suggest that CCN6 plays a role in the fibrogenesis of the lungs mainly by stimulating the growth of lung fibroblasts and is a potential target for the treatment of pulmonary fibrosis.


Blockade of Th1 chemokine receptors ameliorates pulmonary granulomatosis in mice.

Sarcoidosis is a granulomatous disease of unknown aetiology. We identified immunological targets for the treatment of pulmonary granulomatosis using a murine model generated with Propionibacterium acnes. Sensitisation and challenge using heat-killed P. acnes and dendritic cells (DCs) were performed to produce pulmonary granulomatosis in C57BL/6 mice. Immunological analyses using ELISA as well as cDNA microarray analysis were used to search for cytokines or chemokines associated with the formation of granulomas in the lungs. Co-administration of P. acnes and DCs reproducibly induced the formation of pulmonary granulomas, which resembled sarcoid granulomas. The cDNA microarray assay demonstrated that the gene expression of CXCL9 and CXCL10, ligands for CXCR3, and of CCL4, a ligand for CCR5, was strongly upregulated during granulomatosis. ELISA confirmed that levels of CXCL9 and CXCL10 as well as T-helper (Th)1 cytokines and chemokines including tumour necrosis factor-α and interferon-γ were elevated in bronchoalveolar lavage fluid (BALF). The blockade of Th1 chemokine receptors using TAK-779, a dual blocker for CXCR3 and CCR5, led to reduced numbers of CXCR3+CD4+ and CCR5+CD4+ T-cells in BALF. Furthermore, administration of TAK-779 ameliorated the granulomatosis. The targeted inhibition of Th1 chemokines might be useful for inhibiting Th1-biased granulomatous diseases, including sarcoidosis.


非小細胞肺癌患者のpatient-reported outcome(PRO)評価法の現状と問題点 ―第III 相臨床試験論文のreview―

Background. Recently, much attention has been paid to patient-reported outcomes (PRO) as self-administered assessment instruments in the quality of life evaluation of cancer patients. Objective and Methods. In the present study, we reviewed a total of 24 published articles (1999 through 2007) which reported phase III clinical trials for non-small-cell lung cancer, all of which set PRO assessment as one of the study endpoints. We evaluated the questionnaires used for PRO assessment, assessment intervals and patient compliance with PRO assessment in each trial. Several kinds of questionnaires were used in most PRO assessment trials. Results. The European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) was used in 17 out of 24 trials. PRO was commonly assessed before each course of chemotherapy, at the end of chemotherapy and 1-3 months after treatment cessation. Patient compliance at the final assessment had significantly deteriorated compared with baseline PRO assessment, presumably due to the increment of missing data. Conclusion. Further studies which evaluate the problems of PRO assessment as a surrogate marker of therapeutic efficacy in lung cancer patients are warranted.

背景．近年，癌患者のquality of life(QOL)評 価は治療法選択に重要な要素として注目されている．欧 米ではQOL を把握する目的からpatient-reported outcome( PRO)が評価項目の1 つとして評価されつつある が，本邦においてはPRO の認知度は低い．目的．非小細 胞肺癌のQOL 評価(PRO)の現状を検討する．対象と方 法．今回，非小細胞肺癌に対する癌薬物療法の有用性を 比較検討した第III 相臨床試験の中から，患者の自己申 告によるQOL 評価であるPRO 評価を評価項目とした 報告(24 試験)を抽出し，PRO の評価方法，評価時期， PRO 評価に対する患者のコンプライアンスなどについ て検討した．結果．対象とした臨床試験の大多数では複 数の評価方法によりPRO 評価が行われており，European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire-Core 30(EORTC QLQ-C30)が最も頻用されていた(17 試験;70.8%)． PRO 評価の多くは治療開始前，各コース開始直前，治療 終了時，その後1∼3 ヶ月ごとに行われていたが，患者の コンプライアンスは治療経過に伴って有意に低下し，全 身状態の悪化などがその要因と考えられた．考察．PRO評価が，臨床試験における癌薬物療法の優劣を評価する方法の1 つとして十分な情報となるよう問題点の検討を さらに進めていく必要があると思われる．


Epidemiological and clinical features of lung cancer patients from 1999 to 2009 in Tokushima Prefecture of Japan

Lung cancer is the leading cause of malignancy-related death worldwide. In the present study, we reviewed the epidemiologic and clinical features of lung cancer in Tokushima Prefecture, Japan. Between January 1999 and December 2009, 2,183 patients with lung cancer were enrolled in this study. One thousand five hundred ninety-one (73%) patients were male and 592 (27%) patients were female. Median age was 70 years, with a range of 15-93 years. Seventy-six percent of patients had smoking history. One thousand nine hundred five (87%) patients were non-small cell lung cancer and the predominant histological type was adenocarcinoma (51%). Among all 2,183 patients, 702 (32%) belonged to elderly population. Four hundred seventy-one (22%), 213 (10%), 24 (1%), 116 (5%), 238 (11%), 370 (17%) and 678 (31%) patients had stage IA, IB, IIA, IIB, IIIA, IIIB and IV lung cancer, respectively. In Tokushima University Hospital, 516 (29%), 191 (11%), 58 (3%), 755 (43%) and 216 (12%) patients were initially treated with chemotherapy, chemo-radiotherapy, thoracic radiotherapy, operation and best supportive care, respectively. The median time to progression (TTP) and the median survival time (MST) of patients treated with chemotherapy and chemo-radiotherapy were 3.5 months, 13.0 months and 7.0 months, 18.0 months, respectively. The median TTP and the MST of 33 elderly patients treated with chemotherapy were 3.3 months and 18.0 months, respectively, which were comparable with those of total population. These results indicated the benefit of chemotherapy in elderly patients with advanced lung cancer by proper selection.