Background:Patients with pulmonary Mycobacterium avium-intracellulare complex (MAC) disease who cannot receive standard antimicrobial therapy have limited treatment options. Jiinshihoto, a Kampo formula (traditional Japanese herbal medicine) that is effective for chronic cough and depressive symptoms, has not been evaluated in this population. Objective:To evaluate the physical, immunological, and psychiatric effects of Jiinshihoto in patients with pulmonary MAC who were ineligible for standard antimicrobial treatment. Methods:This single-center, open-label, prospective study was conducted from March 2018 to January 2020. Patients who were not eligible for standard treatment for pulmonary MAC disease were enrolled. Jiinshihoto (3.0 g) was administered three times per day for 12 months. The primary endpoints were 3-month changes in chronic obstructive pulmonary disease assessment test (CAT) scores, body weight, and natural killer (NK) cell activity. Secondary endpoints were 3-month changes in self-rating depression scale (SDS) scores. This study was registered in the UMIN-Clinical Trials Registry (UMIN000033590). Results:In total, 24 patients were enrolled. The mean age was 68 years, and 74% were female; the mean body mass index was 19.3 kg/m2. Of these, 23 patients completed the 3-month follow-up. For the primary endpoints at 3 months, no significant changes were observed in CAT scores (from 11.2 to 11.0, P = .87), body weight (from 48.6 to 48.8 kg, P = .32), or NK cell activity (from 42.6% to 43.9%, P = .58). SDS scores showed significant improvement at 3 months (from 42.2 to 38.5, P = .032) and 12 months (from 42.2 to 40.4, P = .034). Conclusion:Jiinshihoto did not improve respiratory symptoms, weight, or NK cell activity in patients with pulmonary MAC ineligible for standard treatment but may be beneficial for depressive symptoms.

INTRODUCTION:Recent studies have suggested enhanced therapeutic effects of subsequent chemotherapy after immune checkpoint inhibitor (ICI) treatment, highlighting the importance of subsequent treatment selection. Nanoparticle albumin-bound paclitaxel (nab-PTX) is commonly used in subsequent chemotherapies; however, its efficacy as a subsequent treatment after ICI treatment has not been reported. METHODS:We retrospectively evaluated the efficacy and safety of nab-PTX using two prospective studies that we previously reported. The first study evaluated the efficacy and safety of nab-PTX as a second-line treatment after the failure of the first-line cytotoxic chemotherapy, excluding ICI (study 1; n = 32), and the other as a subsequent treatment after failure of ICI treatment, regardless of treatment line (study 2; n = 29). RESULTS:The objective response rate was significantly higher in study 2 {55.2% (95% confidence interval [CI]: 28.1-79.6)} than in study 1 (28.1% [95% CI: 13.7-46.7]) (p = 0.04). Although the disease control rate was slightly higher in study 2 (86.2% [95% CI: 65.9-97.0]) than in study 1 (71.9% [95% CI: 53.3-86.3]), there was no significant difference (p = 0.2). The median progression-free survival was significantly longer in study 2 than in study 1 (3.9 months [95% CI: 2.0-5.5] in study 1 vs. 5.6 months [95% CI: 3.0-12.8] in study 2; hazard ratio [HR]: 0.46 [95% CI: 0.27-0.81], p = 0.006). The median overall survival was slightly longer in study 2 despite the greater number of patients who received nab-PTX in late treatment line, but there was no significant difference between study 1 and study 2 (10.9 months [95% CI: 5.1-16.8] in study 1 vs. 11.9 months [95% CI: 7.6-24.8] in study 2; HR: 0.77 [95% CI: 0.46-1.31], p = 0.34). Safety profiles did not differ between the patients in studies 1 and 2. CONCLUSION:Nab-PTX monotherapy may be an effective subsequent treatment option after ICI treatment.

Thymic carcinoma (TC) presenting with cardiac tamponade has a poor prognosis because of the difficulty in controlling malignant pericardial effusion using conventional chemotherapy. Lenvatinib, a multitargeted kinase inhibitor of vascular endothelial growth factor receptor and other kinases, has recently been proven effective against TC. As the inhibition of vascular endothelial growth factor signaling is effective in malignant pericardial effusion, lenvatinib may also be effective in TC presenting with cardiac tamponade. However, no reports have shown that lenvatinib is effective in such cases. Herein, we present a case of successful treatment with lenvatinib in a patient with TC presenting with cardiac tamponade. The present case suggests that lenvatinib should be considered an effective treatment option for such cases.

Abstract Background: In Japan, pulmonary Mycobacterium avium-intracellulare complex (MAC) disease is highly prevalent. This study aimed to evaluate the efficacy of Jiinshihoto (JST) for treating pulmonary MAC disease. Methods: Twenty-four patients, not receiving standard treatment for pulmonary MAC disease, were enrolled in this study; of these, 21 patients (3 patients dropped out of the study) were eligible and selected to participate. They were administered JST (3.0 g; Tsumura Co., Tokyo, Japan) three times per day for 12 months. Their weight, chronic obstructive pulmonary disease assessment test (CAT) score, NK cell activity, chest computed tomography (CT) results, blood sample results, Self-rating Depression Scale (SDS) scores, and State-Trait Anxiety Inventory (STAI) scores were measured: (i) before JST administration, (ii) after 3 months, and (iii) at the end of the study. Results: Before JST administration, the exacerbation group (n = 10 patients; 6 patients with worsened conditions at the end of the study and 4 patients who were switched to standard treatment during the study because of exacerbation) had a significantly low body mass index (BMI), mild depression, and high anxiety. The overall patient population showed no significant differences in the chronic obstructive pulmonary disease assessment score, body weight, or natural killer cell activity after 3 months of treatment; however, the SDS score improved significantly. At the end of treatment, the nutritional scores had worsened, but the SDS score improved significantly. Specifically, the SDS scores improved significantly only in the non-exacerbation group (n = 11 patients), and natural killer cell activity improved in the non-exacerbation group. Additionally, a comparison of the data of both groups before and after JST administration showed that the exacerbation group had significantly lower BMI and worse CT scores when using a BMI cutoff of 18.4 (sensitivity, 81.8%; specificity, 70%). Conclusion: Patients with a high BMI and low CT score at the time of initial diagnosis may benefit from JST treatment, which may significantly improve depression and immunity and prevent disease progression. Therefore, JST may be an effective treatment in selected pulmonary MAC patients.Trial registration: This study has been registered in the UMIN-Clinical Trials Registry (UMIN000033590, August 1, 2018).

PURPOSE:Human bronchial smooth muscle cells (BSMCs) contribute to airway obstruction and hyperresponsiveness in patients with bronchial asthma. BSMCs also generate cytokines and matricellular proteins in response to extracellular acidification through the ovarian cancer G protein-coupled receptor 1 (OGR1). Cobalt (Co) and nickel (Ni) are occupational agents, which cause occupational asthma. We examined the effects of Co and Ni on interleukin-6 (IL-6) secretion by human BSMCs because these metals may act as ligands of OGR1.METHODS:Human BSMCs were incubated in Dulbecco's Modified Eagle Medium (DMEM) containing 0.1% bovine serum albumin (BSA) (0.1% BSA-DMEM) for 16 hours and stimulated for the indicated time by exchanging the medium with 0.1% BSA-DMEM containing any of the metals or pH-adjusted 0.1% BSA-DMEM. IL-6 mRNA expression was quantified via reverse transcription polymerase chain reaction (RT-PCR) using the real-time TaqMan technology. IL-6 was measured using an enzyme-linked immunosorbent assay. Dexamethasone (DEX) was added 30 minutes before each stimulation. To knock down the expression of OGR1 in BSMCs, small interfering RNA (siRNA) targeting OGR1 (OGR1-siRNA) was transfected to the cells and non-targeting siRNA (NT-siRNA) was used as a control.RESULTS:Co and Ni both significantly increased IL-6 secretion in human BSMCs at 300 μM. This significant increase in IL-6 mRNA expression was observed 5 hours after stimulation. BSMCs transfected with OGR1-siRNA produced less IL-6 than BSMCs transfected with NT-siRNA in response to either Co or Ni stimulation. DEX inhibited Co- and Ni-stimulated IL-6 secretion by human BSMCs as well as pH 6.3-stimulated IL-6 secretion in a dose-dependent manner. DEX did not decrease phosphorylation of ERK1/2, p38 MAP kinase, and NF-κB p65 induced by either Co or Ni stimulation.CONCLUSION:Co and Ni induce secretion of IL-6 in human BSMCs through activation of OGR1. Co- and Ni-stimulated IL-6 secretion is inhibited by DEX.

Background Anti-programmed death-1 (anti-PD-1) therapy has shown clinical success in patients with advanced non-small cell lung cancer (NSCLC). However, it is difficult to evaluate the early response to anti-PD-1 therapy. We determined whether changes in 3′-deoxy-3′-[18F]-fluorothymidine (18F-FLT) PET parameters before and soon after treatment initiation predicted the therapeutic effect of anti-PD-1 antibody.Methods Twenty-six patients with advanced NSCLC treated with anti-PD-1 antibody were enrolled prospectively and underwent 18F-FLT PET before and at 2 and 6 weeks after treatment initiation. Changes in maximal standardized uptake value (ΔSUVmax), proliferative tumor volume (ΔPTV) and total lesion proliferation (ΔTLP) of the lesions were calculated and evaluated for their associations with the clinical response to therapy.Results The disease control rate was 64%. Patients with non-progressive disease (non-PD) had significantly decreased TLP at 2 weeks, and decreased SUVmax, PTV, and TLP at 6 weeks, compared with those with PD, while three of eight (37.5%) patients who responded had increased TLP from baseline at 2 weeks (ie, pseudoprogression). Among the parameters that changed between baseline and 2 weeks, ΔPTV0-2 and ΔTLP0-2 had the highest accuracy (76.0%) to predict PD. Among the parameters that changed between baseline and 6 weeks, ΔSUVmax0-6, ΔPTV0-6 and ΔTLP0-6 had the highest accuracy (90.9%) to predict PD. ΔTLP0-2 (≥60%, HR 3.41, 95% CI 1.34–8.65, p=0.010) and ΔTLP0-6 (≥50%, HR 31.4, 95% CI 3.55 to 276.7, p=0.0019) were indicators of shorter progression-free survival.Conclusions Changes in 18F-FLT PET parameters may have value as an early predictive biomarker for the response to anti-PD-1 therapy in patients with NSCLC. However, it should be noted that pseudoprogression was observed in 18F-FLT PET imaging at 2 weeks after treatment initiation.Trial registration number jRCTs051180147.

Background: Bronchoalveolar lavage (BAL) is supposed to be useful for the diagnosis of diffuse lung diseases. Many facilities in Japan usually rinse with physiological saline 3 times 50 ml, but the processing methods of samples are various in each facility. The bronchoalveolar lavage fluid (BALF) collected at each time was analyzed separately (Fraction (Fr.)1-3) and then all were mixed and analyzed (Total). Total was calculated by multiplying the number of cells up to Fr.1-3 by the amount recovered, multiplying each fraction, and summing it up and dividing by the total number of cells. We compared the groups of Fr.1-3 and Total, with Lym > 20%, Neu > 10%, and Eo > 25% (3%) as abnormal values and determined that cases where the diagnosis changed between Fr.3 and Total are different evaluation. Results: In the comparison between Fr.3 and Total, 401 / 2774 cases (13%) showed different evaluation. In total, rate of Macrophage and Lymphocyte were significantly lower and those of Neutrophil and Eosinophil were significantly higher than in Fr.3. In total, rate of Neutrophil and Eosinophil were significantly higher in Fr.1, which might be an airway component. Conclusion: When BALF was evaluated using Total, the results might show wrong evaluation of airway disease, such as chronic airway infection and eosinophilic airway disease. BALF with Fr.3 alone was suggested to reveal accurate evaluation.

Background The early response to treatment with immune-checkpoint inhibitors is difficult to evaluate. We determined whether changes in integrated [18F]-fluoro-2-deoxy-D-glucose positron emission tomography/MRI (18F-FDG PET/MRI) parameters after the first 2 weeks of antiprogrammed death-1 antibody nivolumab therapy could predict the response of patients with non-small cell lung cancer (NSCLC).Methods Twenty-five patients with previously treated NSCLC were enrolled prospectively and underwent 18F-FDG PET/MRI before and at 2 weeks after nivolumab therapy. Changes in maximal standardized uptake value, total lesion glycolysis (ΔTLG) and apparent diffusion coefficient (ΔADC) between the two scans were calculated and evaluated for their associations with the clinical response to therapy.Results The disease control rate was 64%. Patients with non-progressive disease (non-PD) had significantly decreased TLG, increased ADCmean (ie, negative ΔADCmean) and lower ΔTLG+ΔADCmean than patients with PD. Among the parameters tested, receiver operating characteristic curve analysis revealed that a cut-off value of 16.5 for ΔTLG+ΔADCmean had the highest accuracy (92%) for distinguishing between patients with non-PD and PD. A ΔTLG+ΔADCmean value <16.5 was significantly associated with longer median progression-free survival (9.0 vs 1.8 months, p<0.00001) and overall survival (23.6 vs 4.7 months, p=0.0001) compared with ΔTLG+ΔADCmean value ≥16.5. A multivariate Cox model revealed that ≥16.5 ΔTLG+ΔADCmean was an independent predictor of shorter progression-free survival (HR 37.7) and overall survival (HR 9.29).Conclusions A combination of ΔTLG and ΔADCmean measured by integrated 18F-FDG PET/MRI may have value as a predictor of the response and survival of patients with NSCLC following nivolumab therapy.Trial registration number UMIN 000020707.

Although hematological toxicities (HT) are the leading adverse events of systemic chemotherapy, the estimation of severe HT is challenging. Recently, 3′-deoxy-3′-[18F]-fluorothymidine (18F-FLT) accumulation with PET has been considered a biomarker of the cell proliferation. This study aims to elucidate whether the vertebral accumulation of 18F-FLT could estimate severe HT during platinum-doublet chemotherapy.

Human airway smooth muscle cells (ASMCs) contribute to bronchial contraction and airway hyperresponsiveness in patients with bronchial asthma. They also generate cytokines, chemokines, and matricellular proteins. Ovarian cancer G protein-coupled receptor 1 (OGR1) senses extracellular protons and mediates the production of interleukin-6 (IL-6) and connective tissue growth factor (CTGF) in ASMCs.

The association between UGT1A1 polymorphism and etoposide-induced toxicities is still not clear. The aim of this study was to assess the association between uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene polymorphism and severe hematologic toxicities in Japanese patients receiving etoposide plus platinum chemotherapy for small-cell lung cancer.

Purpose: Aspergillus species are omnipresent organisms that can be found in every region. Invasive aspergillosis infections are often found to be associated with hospital construction or renovation, which can increase the amount of airborne aspergillus, causing in high-risk patients. The severity of aspergillosis is determined by various factors. The goal of this study was to (1) examine fungal hospital-acquired infections that were detected in our facility and (2) to evaluate infection prevention and control measures in our hospital based on previous experiences, evidence and guidelines. Methods & Materials: We surveyed aspergillosis for these 10 years in our facility. From January 2008 to December 2017, diagnosis, treatment, clinical courses were surveyed using medical records in our facility. We showed 5 cases with hematological malignancies in clean room. They were treated just empirically without definite diagnosis. Results: Five patients with leukemia were infected with aspergillosis in a clean room at hematology ward. Three cases of them were infected in the same room within 8 months. Invasive aspergillosis was highly suspected. They could not take bronchoscopic examination. Intervention by ICT did not detect definitive findings. Air condition and the facility around the room were not contaminated. That room was closed, however, another patients with AML was diagnosed as aspergillus sinusitis. All the patients were compromised hosts. In hematological ward, once aspergisosis prevails, it is not easy to terminate them because of the limitation to eliminate particles including aspergillus spore completely. In our survey of aspergillosis, 209 aspergillosis including 104 cases with hematological malignancies and 35 other kinds of malignancies, were treated by antifungal drugs. Inspection implementation rates for β-D-glucan and Aspergillus antigen in 30 cases of chronic pulmonary diseases were higher than average of all cases (63.2%, 55.5%), however, those of cases with hematological malignancies were lower. Empirical treatments were common in hematological diseases. As treatment, MCFG iv (54%), CPFG iv (25%) and VRCZ per os (43%), ITCZ per os (43%) were occupied in all patients. Conclusion: Performing infection control risk assessments and implementing the reliable control measures is essential to prevent healthcare-associated fungal outbreaks.

[Background] The purposes of Infectious Control Team (ICT) activity are to decrease hospital associated infection (HAI) and to take emergent measures against HAI. Our slogan is to lower the rate of Methicillin-resistant Staphylococcus aureus (MRSA) (MRSA bacteremia/Staphylococcus aureus bacteremia) detection to less than 30% and listed the concrete goals as follow. 1) Used amount of hand hygiene disinfectant is over 15L/1000 patients/day. 2) Quantity consumption of carbapenems and TAZ/PIPC are less than AUD 20 (DDD/1000 patients /day) and 20% decrease of the 3rd generation cephem antibiotics. 3) Prompt report to ICT office when suspected cases are detected. Our facility has established a network system with more than 20 hospitals in our prefecture taking the cooperation each other and monitoring regularly. [Purposes] The aim is to promote our activity in ICT. Antibiotics surveillance and Hand hygiene surveillance were performed and compared with those of other facilities in our prefecture. [Methods] We analyzed usage amount of antibiotics, detection of positive blood culture, detection of resistant bacteria and quantify consumed of hand hygiene disinfectant, retrospectively, from 2014 through 2016 in our hospital. And then our data were compared with the same surveillances that were performed in 4 other hospitals which obtained additional certificate to control infections from official health institution. [Results] Antibiotics uses were AUD 15～22 in our hospital and 7～20 (Hospital A,B,C), 20～40(Hospital D). Quantify consumed of hand hygiene disinfectant, were 5～6 (ml/patient/day) in our facility. Others were 6～11(Hospital A) and 1～6 (B,C, D). Rates of performing blood culture were 2.3% (in our hospital) vs 0.8% (the average in other 4 hospitals), Rates of MRSA were 27% vs 38% and detection numbers of Clostridium difficile (CD) were 0.25 persons /1000 patients /day vs 0.12. [Conclusion] Due to antibiotics surveillance, rates of MRSA and other resistant bacteria were lower except occurrence number of CD in comaparison between our facility and other 4 hospitals. Quantify consumed of hand hygiene disinfectant is supposed to strongly related with those outcome.

BACKGROUND: The p53 signaling pathway may be important for the pathogenesis of emphysematous changes in the lungs of smokers. Polymorphism of p53 at codon 72 is known to affect apoptotic effector proteins, and the polymorphism of mouse double minute 2 homolog (MDM2) single nucleotide polymorphism (SNP) 309 is known to increase MDM2 expression. The aim of this study was to assess polymorphisms of the p53 and MDM2 genes in smokers and confirm the role of SNPs in these genes in the pathogenesis of pulmonary emphysema.METHODS: This study included 365 patients with a smoking history, and the polymorphisms of p53 and MDM2 genes were identified. The degree of pulmonary emphysema was determined by means of CT scanning. SNPs, MDM2 mRNA, and p53 protein levels were assessed in human lung tissues from smokers. Plasmids encoding p53 and MDM2 SNPs were used to transfect human lung fibroblasts (HLFs) with or without cigarette smoke extract (CSE), and the effects on cell proliferation and MDM2 promoter activity were measured.RESULTS: The polymorphisms of the p53 and MDM2 genes were associated with emphysematous changes in the lung and were also associated with p53 protein and MDM2 mRNA expression in the lung tissue samples. Transfection with a p53 gene-coding plasmid regulated HLF proliferation, and the analysis of P2 promoter activity in MDM2 SNP309-coding HLFs showed the promoter activity was altered by CSE.CONCLUSIONS: Our data demonstrated that p53 and MDM2 gene polymorphisms are associated with apoptotic signaling and smoking-related emphysematous changes in lungs from smokers.

A 62-year-old man was admitted to our hospital because of wheezing and dyspnea. Chest computed tomography showed ground-glass opacity and some centrilobular nodules. Chronic eosinophilic pneumonia complicated with Mycoplasma pneumoniae infection was diagnosed on the basis of bronchoalveolar lavage eosinophilia and blood findings. However, based on the clinical course, the patient was suspected to have eosinophilic bronchiolitis. This case suggests the possibility that eosinophilic inflammation can occur concomitantly in the central airway and distal airway.

Background: Cigarette smoke induced oxidative stress has been shown to reduce silent information regulator 1 (Sirt1) levels in lung tissue from smokers and patients with COPD patients. Sirt1 is known to inhibit endothelial senescence and may play a protective role in vascular cells. Endothelial progenitor cells (EPCs) are mobilized into circulation under various pathophysiological conditions, and are thought to play an important role in tissue repair in chronic obstructive lung disease (COPD). Therefore, Sirt1 and EPC-associated mRNAs were measured in blood samples from patients with COPD and from cultured CD34(+) progenitor cells to examine whether these genes are associated with COPD development.Methods: This study included 358 patients with a smoking history of more than 10 pack-years. RNA was extracted from blood samples and from CD34(+) progenitor cells treated with cigarette smoke extract (CSE), followed by assessment of CD31, CD34, Sirt1 mRNA, miR-34a, and miR-126-3p expression by real-time RT-PCR.Results: The expression of CD31, CD34, Sirt1 mRNAs, and miR-126-3p decreased and that of miR-34a increased in moderate COPD compared with that in control smokers. However, no significant differences in these genes were observed in blood cells from patients with severe COPD compared with those in control smokers. CSE significantly decreased Sirt1 and increased miR-34a expression in cultured progenitor cells.Conclusion: Sirt1 expression in blood cells from patients with COPD could be a biomarker for disease stability in patients with moderate COPD. MiR-34a may participate in apoptosis and/or senescence of EPCs in smokers. Decreased expression of CD31, CD34, and miR-126-3p potentially represents decreased numbers of EPCs in blood cell from patients with COPD.