Hiroshi Mukae

Relationship between UGT1A1*27 and UGT1A1*7 polymorphisms and irinotecan-related toxicities in patients with lung cancer

The objective of this study was to evaluate the effects of gene polymorphisms, including UGT1A1*7, *27, and *29, on the safety of irinotecan therapy.

Poor pharmacological adherence to inhaled medicines compared with oral medicines in Japanese patients with asthma and chronic obstructive pulmonary disease

Poor pharmacological adherence (adherence) is a problem that reduces quality of life in patients with chronic diseases and leads to wastage of health care resources.1,2 Few comparative studies of adherence to inhaled and oral medicines have been performed in Japanese patients with asthma and chronic obstructive pulmonary disease (COPD).3,4 To investigate adherence levels to inhaled medicines, a multicenter, cross-sectional non-interventional trial was conducted in Japanese patients who had regular use of both inhaled and oral medicines for asthma or COPD by the Kyushu Asthma Seminar Investigator Group, which was approved by each local ethics board (UMIN No. R000015329) (Supplementary Material: Table 1). To investigate adherence in consecutive outpatients with asthma (aged 20 and <80 years) and COPD (aged 40 and <80 years) who were taking at least one regular prescribed inhaled and oral medication without changes in regimens for >6 months (Supplementary Material: Table 2), one inhaled and one oral medicine were selected as the most important among all regular prescribed medicines [mean (±standard deviation) was the number of different inhaled devices and oral medicines (range) 1⁄4 1.1 ± 0.4 (1e3) and 4.3 ± 3.0 (1e18) available to patients with asthma; 1.5 ± 0.5 (1e3) and 5.0 ± 4.1 (1e22) in patients with COPD, respectively] by each physician without consultation with the patient (Supplementary Material). Adherence levels were examined by questionnaire and prescription refill method. The characteristics and lung function data within 6 months of patients were obtained after written consent (see Supplementary Material for definition and control levels of asthma and COPD). Poor adherence to medicines was defined on the basis of <80% adherence to selected inhaled or oral medicines by either the questionnaire or prescription refill method.5,6 We statistically compared the populations of patients with poor adherence to selected inhaled and oral medicines, and calculated the odds ratios [95% confidential interval (CI)] of poor adherence to inhaled medicines in total patients (asthma and COPD), patients with asthma, and patients with COPD by using a Fishers exact tests. By univariate and multivariate analyses, we investigated the risk factors as patient-, social-, and treatment-related factors [odds ratios (95% CI)] for poor adherence to inhaled medicines to compare patients with and without poor

Examination of cryptococcal glucuronoxylomannan antigen in bronchoalveolar lavage fluid for diagnosing pulmonary cryptococcosis in HIV-negative patients

We clarified the performance of a cryptococcal glucuronoxylomannan (GXM) antigen test using bronchoalveolar lavage fluid (BALF) samples, in an HIV-negative Japanese population. Between March 2008 and December 2014, we examined cryptococcal GXM antigens in both serum and BALF specimens from 429 cases at Nagasaki University hospital. The diagnoses, underlying diseases, chest computed tomography findings, and cryptococcal GXM antigen test results were retrospectively investigated. Twenty-three patients were confirmed to have pulmonary cryptococcosis, another six were clinically diagnosed with cryptococcosis because they were seropositive for the GXM antigen, and five possible cryptococcosis cases had BALF samples that were positive for the GXM antigen and serum samples that were negative. The tests sensitivities for detecting cryptococcal GXM antigens in serum and BALF samples, for confirmed cases, were 73.9% and 82.6%, respectively, and their respective specificities were 98.5% and 97.8%. Three of the five putative patients with cryptococcosis were treated with antifungal agents; the pulmonary lesions decreased in size in all treated patients. Both the BALF and serum GXM antigen titers showed positive correlations with the lesion sizes; however, the serum antigen titers showed a higher correlation (r = 0.490, P = .0033) than did the BALF titres (r = 0.312, P = .0724). The rate of GXM-positive BALF samples was higher than the rate for serum samples, especially for patients with pulmonary lesion diameters ≤25xa0mm. Testing for the presence of the cryptococcal GXM antigen in BALF specimens might contribute to the early diagnosis of pulmonary cryptococcosis.

Adverse renal effects of anaplastic lymphoma kinase inhibitors and the response to alectinib of an ALK+ lung cancer patient with renal dysfunction

A 62-year-old female patient with renal dysfunction and pulmonary adenocarcinoma developed postoperative recurrence and received carboplatin/pemetrexed and maintenance pemetrexed. As an anaplastic lymphoma kinase (ALK) gene translocation was identified, the therapy was changed to crizotinib. However, the patient’s blood creatinine level increased, and her physical status worsened. Alectinib also induced exacerbation of renal dysfunction but was controlled by dose reduction of 140 mg twice daily for 2 weeks treatment and 2 weeks break were repeated, and exhibited a partial response for 16 months. Here, we describe the case in which alectinib treatment had beneficial clinical effects on ALK-positive lung adenocarcinoma, which controlled the adverse renal effects by dose reduction and drug breaks.

Performance evaluation of the Verigene®Clostridium difficile nucleic acid test, an automated multiplex molecular testing system for detection of C. difficile toxin

The Verigene®Clostridium difficile nucleic acid test (Verigene® CDF test) is an automatic and rapid detection system for the genes encoding tcdA, tcdB, binary toxin, and the single nucleotide deletion at base pair 117 in the tcdC based on microarray and PCR amplification. We compared the performance of the Verigene® CDF test to that of two enzyme immunoassays, C.xa0DIFF QUIK CHEK COMPLETE and X/Pect Toxin A/B, using 118 specimens. We found overall concordance rates of 81.4% and 78.8% between C.xa0DIFF QUIK CHEK COMPLETE and Verigene® CDF test, and X/Pect Toxin A/B and Verigene® CDF test. The Verigene® CDF test showed the highest sensitivity (93.9%) and had a specificity of 96.5%. The sensitivity and specificity were respectively 45.5 and 94.1% for C.xa0DIFF QUIK CHEK COMPLETE and 27.3 and 100.0% for X/Pect Toxin A/B. These results indicated that the Verigene® CDF test was highly accurate for the detection of C.xa0difficile toxin in fecal specimens and supported its use in daily diagnostic practice.

The impact of MET inhibition on small-cell lung cancer cells exhibiting aberrant activation of the HGF/MET pathway

Small‐cell lung cancer (SCLC) accounts for approximately 15% of all lung cancers, and is characterized as extremely aggressive, often displaying rapid tumor growth and multiple organ metastases. In addition, the clinical outcome of SCLC patients is poor due to early relapse and acquired resistance to standard chemotherapy treatments. Hence, novel therapeutic strategies for the treatment of SCLC are urgently required. Accordingly, several molecular targeted therapies were evaluated in SCLC; however, they failed to improve the clinical outcome. The receptor tyrosine kinase MET is a receptor for hepatocyte growth factor (HGF), and aberrant activation of HGF/MET signaling is known as one of the crucial mechanisms enabling cancer progression and invasion. Here, we found that the HGF/MET signaling was aberrantly activated in chemoresistant or chemorelapsed SCLC cell lines (SBC‐5, DMS273, and DMS273‐G3H) by the secretion of HGF and/or MET copy number gain. A cell‐based in vitro assay revealed that HGF/MET inhibition, induced either by MET inhibitors (crizotinib and golvatinib), or by siRNA‐mediated knockdown of HGF or MET, constrained growth of chemoresistant SCLC cells through the inhibition of ERK and AKT signals. Furthermore, treatment with either crizotinib or golvatinib suppressed the systemic metastasis of SBC‐5 cell tumors in natural killer cell‐depleted SCID mice, predominantly through cell cycle arrest. These findings reveal the therapeutic potential of targeting the HGF/MET pathway for inhibition, to constrain tumor progression of SCLC cells showing aberrant activation of HGF/MET signaling. We suggest that it would be clinically valuable to further investigate HGF/MET‐mediated signaling in SCLC cells.

Efficacy and Pharmacokinetics of the Combination of OP0595 and Cefepime in a Mouse Model of Pneumonia Caused by Extended-Spectrum-Beta-Lactamase-Producing Klebsiella pneumoniae.

ABSTRACT OP0595 (RG6080) is a novel diazabicyclooctane that inhibits class A and C serine beta-lactamases. Although the combination of OP0595 and cefepime (FEP) showed good in vitro activity against extended-spectrum-beta-lactamase (ESBL)-producing pathogens, the effect of the combination therapy against severe infections, such as pneumonia or bacteremia, remains unknown in vivo. In this study, we investigated the efficacy and pharmacokinetics of the combination therapy of OP0595 and FEP in a mouse model of pneumonia caused by Klebsiella pneumoniae harboring SHV- and CTX-M-9-type ESBLs. The infected BALB/c mice were intraperitoneally administered saline (control), 100 mg/kg of body weight of FEP, 20 mg/kg of OP0595, or both FEP and OP0595, twice a day. The MIC of FEP against the bacteria was 8 mg/liter and markedly improved to 0.06 mg/liter with the addition of 0.5 mg/ml of OP0595. In the survival study, the combination of FEP and OP0595 significantly improved the survival rate compared with that reported with either OP0595 or FEP alone (P < 0.001). The number of bacteria in the lungs and blood significantly decreased in the combination therapy group compared to that reported for the monotherapy groups (P < 0.001). In addition, the in vivo effect depended on the dose of FEP. However, pharmacokinetic analysis revealed that the percentage of time above MIC remained constant when increasing the dose of FEP in combination with 20 mg/kg of OP0595. The results of our study demonstrated the in vivo effectiveness of the combination of OP0595 and FEP.

Elevated α-defensin levels in plasma and bronchoalveolar lavage fluid from patients with myositis-associated interstitial lung disease

BackgroundInterstitial lung disease (ILD) is a prognostic indicator of poor outcome in myositis. Although the pathogenesis of myositis-associated ILD is not well understood, neutrophils are thought to play a pivotal role. Neutrophils store azurophil granules that contain defensins, which are antimicrobial peptides that regulate the inflammatory response. Here, we evaluated levels of the human neutrophil peptides (HNPs) α-defensin 1 through 3 in patients with myositis-associated ILD to determine whether HNPs represent disease markers and play a role in the pathogenesis of myositis-associated ILD.MethodsHNP levels were measured in the plasma and bronchoalveolar lavage fluid (BALF) of 56 patients with myositis-associated ILD and 24 healthy controls by enzyme-linked immunosorbent assay.ResultsAnalysis revealed significantly higher HNP levels in plasma and BALF samples from patients with myositis-associated ILD as compared to those of healthy controls; however, plasma HNPs were significantly correlated with total cell counts in BALF. Additionally, BALF HNP levels were positively correlated with serum surfactant protein-A and the percentage of neutrophils in BALF, and BALF HNP levels correlated with the percentage of reticular opacities in high-resolution computed tomography results for patients with anti-aminoacyl-tRNA synthetase (ARS) antibody positive myositis-associated ILD. Survival did not differ between patients with higher and lower levels of plasma and BALF HNPs.ConclusionsPlasma and BALF HNPs might reflect the disease activities of myositis-associated ILD, especially in patients with anti-ARS antibody positive myositis-associated ILD. However further studies are necessary to clarify whether HNPs represent disease markers and play roles in disease pathogenesis.

Clinical and Microbiological Characteristics of Candida guilliermondii and Candida fermentati

ABSTRACT A total of 46 clinical isolates of Candida guilliermondii and Candida famata were reidentified genetically, resulting in 27 C. guilliermondii and 12 Candida fermentati strains. The majority of C. guilliermondii strains, but not C. fermentati strains, were isolated from blood cultures. C. fermentati was more sensitive to antifungals, hydrogen peroxide, and killing by murine macrophages than was C. guilliermondii. The C. guilliermondii isolates were echinocandin susceptible in vitro but resistant to micafungin in a murine model of invasive candidiasis.

Risk factors for acquisition of fluoroquinolone or aminoglycoside resistance in addition to carbapenem resistance in Pseudomonas aeruginosa

Background: Carbapenems, fluoroquinolones (FQs), and aminoglycosides (AGs) are key drugs for treating Pseudomonas aeruginosa infections, and accumulation of drug resistances make antibiotic therapy difficult. Methods: We evaluated 169 patients with imipenem (IPM)-resistant P. aeruginosa and compared patient background and microbiological characteristics between groups with or without FQ resistance. Similar analyses were performed for AG. Results: Of the 169 IPM-resistant strains, 39.1% showed resistance to FQs and 7.1% to AGs. The frequency of exposure to FQs within 90 days previously was higher in the group with FQ resistance (45.5%) than in the group without FQ resistance (13.6%). Similarly, 33.3% of patients in the group with AG resistance had been previously administered AGs, higher than the 7.6% of patients without AG resistance. Frequencies of metallo-β-lactamase (MBL) production were higher in the group with FQ or AG resistance (16.7% or 33.3%) than in the group without FQ or AG resistance (2.9% or 6.4%). Multivariate analyses showed exposures to FQs or AGs were related to the respective resistances. MBL production was a common factor for resistance to FQs or AGs, in addition to IPM-resistant P. aeruginosa. Conclusion: As well as promoting appropriate use of antibiotics, MBL production should be detected as a target of intervention for infection control.