Effect of a Cyclooxygenase-2 Inhibitor in Combination with (-)-Epigallocatechin Gallate or Polyphenon E on Cisplatin-Induced Lung Tumorigenesis in A/J Mice.

We investigated the effects of celecoxib combined with (-)-epigallocatechin-3-gallate (EGCG) or polyphenon E in a cisplatin-induced lung tumorigenesis model. Four-week-old female A/J mice were divided into seven groups: (i) Control, (ii) 150 mg/kg celecoxib (150Cel), (iii) 1,500 mg/kg celecoxib (1500Cel), (iv) EGCG+150 mg/kg celecoxib (EGCG+150Cel), (v) EGCG+1,500 mg/kg celecoxib (EGCG+1500Cel), (vi) polyphenon E+150 mg/kg celecoxib (PolyE+150Cel), and (vii) polyphenon E+1,500 mg/kg celecoxib (PolyE+1500Cel). All mice were administered cisplatin (1.62 mg/kg of body weight, i.p.) 1×/week for 10 weeks and sacrificed at week 30; the numbers of tumors on the lung surface were then determined. The tumor incidence and multiplicity (no. of tumors/mouse, mean±SD) were respectively 95% and 2.15±1.50 in Control, 95% and 2.10±1.29 in 150Cel, 86% and 1.67±1.20 in 1500Cel, 71% and 1.38±1.24 in EGCG+150Cel, 67% and 1.29±1.38 in EGCG+1500Cel, 80% and 1.95±1.36 in PolyE+150Cel, and 65% and 1.05±0.10 in PolyE+1500Cel. The combination of high-dose celecoxib with EGCG or polyphenon E significantly reduced multiplicity in cisplatin-induced lung tumors.

Japan Society of Clinical Oncology Clinical Practice Guidelines 2017 for fertility preservation in childhood, adolescent, and young adult cancer patients: part 2.

The Japan Society of Clinical Oncology (JSCO) published the "JSCO Clinical Practice Guidelines 2017 for Fertility Preservation in Childhood, Adolescent, and Young Adult Cancer Patients" in 2017. This was the first guideline in cancer reproductive medicine in Japan. In the field of cancer reproductive medicine, close cooperation between an oncologist and a physician for reproductive medicine is important from before treatment initiation until long after treatment. The guideline takes into consideration disease specificity and provides opinions from the perspective of oncologists and specialists in reproductive medicine that are in line with the current state of the Japanese medical system. It is intended to serve as a reference for medical staff in both fields regarding the availability of fertility preservation therapy before the start of cancer treatment. Appropriate use of this guideline makes it easier to determine whether fertility preservation therapy is feasible and, ultimately, to improve survivorship in childhood, adolescent, and young adult cancer patients. In this article (Part 2), we describe details by organ/system and also for pediatric cancer.

Japan Society of Clinical Oncology Clinical Practice Guidelines 2017 for fertility preservation in childhood, adolescent, and young adult cancer patients: part 1.

In 2017, the Japan Society of Clinical Oncology (JSCO) published the JSCO Clinical Practice Guidelines 2017 for Fertility Preservation in Childhood, Adolescent, and Young Adult Cancer Patients. These were the first Japanese guidelines to address issues of oncofertility. In this field of medicine, sustained close cooperation between oncologists and reproductive specialists is essential from the diagnosis of cancer until many years after completion of cancer treatment. These JSCO guidelines were intended to guide multidisciplinary medical staff in considering the availability of fertility preservation options and to help them decide whether to provide fertility preservation to childhood, adolescent, and young adult cancer patients before treatment starts, with the ultimate goal of improving patient survivorship. The guidelines are presented as Parts 1 and 2. This article (Part 1) summarizes the goals of the guidelines and the methods used to develop them and provides an overview of fertility preservation across all oncology areas. It includes general remarks on the basic concepts surrounding fertility preservation and explanations of the impacts of cancer treatment on gonadal function by sex and treatment modality and of the options for protecting/preserving gonadal function and makes recommendations based on 4 clinical questions. Part 2 of these guidelines provides specific recommendations on fertility preservation in 8 types of cancer (gynecologic, breast, urologic, pediatric, hematologic, bone and soft tissue, brain, and digestive).

Nationwide survey of fertility preservation in patients with hematological malignancies in Japan.

BACKGROUND: Worldwide, there has been a growing interest in oncofertility issues. In 2017, the Japanese Society of Clinical Oncology published clinical practice guidelines for fertility preservation (FP) in cancer patients. We conducted a questionnaire survey to explore the FP practices among hematologists before the publication of this guideline. METHODS: We sent 427 designated cancer hospitals in Japan a questionnaire about FP treatment for patients with hematological malignancies between January and December 2014. RESULTS: Of these, 137 institutions responded, and 81 (19.0%) were included in the analysis. A total of 324 female and 441 male patients, aged < 40 years, were treated. The percentage of patients informed about FP was higher in patients treated with hematopoietic cell transplant than those without. Female patients were less likely to be informed about FP than male patients. FP was performed in a total of 27 female patients: 20 oocyte cryopreservation, 2 embryo cryopreservation, 3 ovarian tissue cryopreservation, and 2 ovarian shielding during total body irradiation. Sperm cryopreservation was performed in 115 male patients. CONCLUSIONS: Our findings indicate the reality of fertility preservation in 2014, before the guideline were issued. Further studies are warranted to investigate the improvement in fertility preservation since the guidelines were issued.

PD-1 modulates regulatory T-cell homeostasis during low-dose interleukin-2 therapy.

CD4+Foxp3+ regulatory T cells (Tregs) play a central role in the maintenance of immune tolerance after hematopoietic stem cell transplantation. We previously reported that low-dose interleukin-2 (IL-2) therapy increased circulating Tregs and improved clinical symptoms of chronic graft-versus-host-disease (cGVHD); however, the mechanisms that regulate Treg homeostasis during IL-2 therapy have not been well studied. To elucidate these regulatory mechanisms, we examined the role of inhibitory coreceptors on Tregs during IL-2 therapy in a murine model and in patients with cGVHD. Murine studies demonstrated that low-dose IL-2 selectively increased Tregs and simultaneously enhanced the expression of programmed cell death 1 (PD-1), especially on CD44+CD62L+ central-memory Tregs, whereas expression of other inhibitory molecules, including CTLA-4, LAG-3, and TIM-3 remained stable. PD-1-deficient Tregs showed rapid Stat5 phosphorylation and proliferation soon after IL-2 initiation, but thereafter Tregs became proapoptotic with higher Fas and lower Bcl-2 expression. As a result, the positive impact of IL-2 on Tregs was completely abolished, and Treg levels returned to baseline despite continued IL-2 administration. We also examined circulating Tregs from patients with cGVHD who were receiving low-dose IL-2 and found that IL-2-induced Treg proliferation was promptly followed by increased PD-1 expression on central-memory Tregs. Notably, clinical improvement of GVHD was associated with increased levels of PD-1 on Tregs, suggesting that the PD-1 pathway supports Treg-mediated tolerance. These studies indicate that PD-1 is a critical homeostatic regulator for Tregs by modulating proliferation and apoptosis during IL-2 therapy. Our findings will facilitate the development of therapeutic strategies that modulate Treg homeostasis to promote immune tolerance.

A retinoid X receptor partial agonist attenuates pulmonary emphysema and airway inflammation.

BACKGROUND: Retinoid X receptors (RXRs) are members of the nuclear receptor (NR) superfamily that mediate signalling by 9-cis retinoic acid, a vitamin A derivative. RXRs play key roles not only as homodimers but also as heterodimeric partners, e.g., for retinoic acid receptors, vitamin D receptors, and peroxisome proliferator-activated receptors. The NR family may also play important roles in the development of emphysema. However, the role of RXRs in the pathogenesis of emphysema is not well defined. METHODS: We developed a novel RXR partial agonist (NEt-4IB) and investigated its effect and mechanism compared to a full agonist (bexarotene) in a murine model of emphysema. For emphysema induction, BALB/c mice received intraperitoneal cigarette smoke extract (CSE) or intratracheal porcine pancreas elastase (PPE). Treatment with RXR agonists was initiated before or after emphysema induction. RESULTS: Treatment with NEt-4IB significantly suppressed the increase in static lung compliance and emphysematous changes in CSE-induced emphysema and PPE-induced established and progressive emphysema. NEt-4IB significantly suppressed PPE-induced neutrophilic airway inflammation and the levels of keratinocyte chemoattractant (KC), C-X-C motif ligand5 (CXCL5), interferon (IFN)-γ and IL-17. NEt-4IB also improved the matrix metalloproteinase-9 (MMP-9)/tissue inhibitor of metalloproteinase-1 (TIMP-1) imbalance and the reduced anti-oxidant activity in bronchoalveolar lavage (BAL) fluid. NEt-4IB suppressed PPE-induced vascular endothelial growth factor (VEGF) expression in the airway. Treatment with NEt-4IB and bexarotene significantly suppressed the increase in static lung compliance and emphysematous changes. However, adverse effects of RXR agonists, including hypertriglyceridemia and hepatomegaly, were observed in bexarotene-treated mice but not in NEt-4IB-treated mice. CONCLUSION: These data suggest that RXRs play crucial roles in emphysema and airway inflammation, and novel partial RXR agonists could be potential therapeutic strategies for the treatment of PPE- and CSE-induced emphysema.

A Japanese nationwide survey on the cryopreservation of embryos, oocytes and ovarian tissue for cancer patients.

AIM: The survival rates of cancer patients have greatly improved owing to the advances in oncology. The preservation of fertility in cancer patients is an important task. To determine the reality of cryopreservation of embryos, oocytes and ovarian tissue in cancer patients, large-scale survey analysis was performed in Japan. METHODS: We sent 613 Japan Society of Obstetrics and Gynecology-certified assisted reproductive technology institutions a questionnaire about their experience of performing cryopreservation for cancer patients between January 2011 and December 2015. Subsequently, the institutions that conducted cryopreservation for cancer patients were sent a second questionnaire. RESULTS: We received replies from 481 (78.5%) institutions. Among them, 126 (26.2%) conducted cryopreservation for cancer patients. These 126 institutions were sent a second questionnaire. Of these, 108 (85.7%) institutions responded. At the 108 institutions, 1085 embryo or oocyte cryopreservation procedures and 122 ovarian tissue cryopreservation procedures were conducted for cancer patients. Cryopreservation was mainly performed for breast cancer patients (~70%), followed by patients with hematological malignancy. A total of 361 and 19 embryo transfer cycles were performed for patients whose embryos and oocytes were cryopreserved, respectively, and 42 and seven institutions reported pregnancy outcomes after embryo transfer in patients that underwent embryo and oocyte cryopreservation, respectively. However, pregnancy was not observed in the seven cases that underwent ovarian tissue transfer. CONCLUSION: Indications, age limits and ovarian stimulation protocols for cryopreservation widely varied between the institutions. A national registration system for oncofertility must be established to evaluate the safety and efficacy of the current system.

Second primary cancer in survivors of locally advanced non-small cell lung cancer treated with concurrent chemoradiation followed by surgery.

The standard treatment for patients with locally advanced non-small-cell lung cancer (LA-NSCLC) is chemoradiotherapy (CRT), but surgical resection following induction CRT can extend overall survival in a select population. However, patients who survive longer are at risk of developing a second primary cancer (SPC). This is the first report to determine the incidence of SPC in survivors with LA-NSCLC after trimodal therapy. Between October 1997 and October 2013, 112 Stage III NSCLC patients underwent trimodal therapy in our hospital. The 5-year overall survival rate was 71.8%. SPC developed in 10 of the 112 patients 0.60-15.0 (median 5.49) years after initiating CRT. The observed incidence of SPC was 1.8 per 100 patient-years. Although trimodal therapy can prolong patient survival, the estimated incidence of SPC does not increase. A large prospective study with a longer follow-up time is required to determine the effects of trimodal therapy, including the development of SPC.

Persistent detection of alternatively spliced BCR-ABL variant results in a failure to achieve deep molecular response.

Treatment with tyrosine kinase inhibitors (TKI) may sequentially induce TKI-resistant BCR-ABL mutants in chronic myeloid leukemia (CML). Conventional PCR monitoring of BCR-ABL is an important indicator to determine therapeutic intervention for preventing disease progression. However, PCR cannot separately quantify amounts of BCR-ABL and its mutants, including alternatively spliced BCR-ABL with an insertion of 35 intronic nucleotides (BCR-ABLIns35bp ) between ABL exons 8 and 9, which introduces the premature termination and loss of kinase activity. To assess the clinical impact of BCR-ABL mutants, we performed deep sequencing analysis of BCR-ABL transcripts of 409 samples from 37 patients with suboptimal response to frontline imatinib who were switched to nilotinib. At baseline, TKI-resistant mutations were documented in 3 patients, whereas BCR-ABLIns35bp was detected in all patients. After switching to nilotinib, both BCR-ABL and BCR-ABLIns35bp became undetectable in 3 patients who attained complete molecular response (CMR), whereas in the remaining all 34 patients, BCR-ABLIns35bp was persistently detected, and minimal residual disease (MRD) fluctuated at low but detectable levels. PCR monitoring underestimated molecular response in 5 patients whose BCR-ABLIns35bp was persisted, although BCR-ABLIns35bp does not definitively mark TKI resistance. Therefore, quantification of BCR-ABLIns35bp is useful for evaluating "functional" MRD and determining the effectiveness of TKI with accuracy.

Phase II study of intrabone single unit cord blood transplantation for hematological malignancies.

The outcomes of cord blood transplantation with non-irradiated reduced-intensity conditioning for hematological malignancies need to be improved because of graft failure and delayed engraftment. Intrabone infusion of cord blood cells has the potential to resolve the problems. In this phase II study, 21 adult patients with hematological malignancy received intrabone transplantation of serological HLA-A, B, and DR ≥4/6 matched single cord blood with a median number of cryopreserved total nucleated cells of 2.7 × 107 /kg (range, 2.0-4.9 × 107 /kg) following non-irradiated fludarabine-based reduced-intensity conditioning. Short-term methotrexate and tacrolimus were given as graft-versus-host disease prophylaxis, and granulocyte colony-stimulating factor was given after transplantation. No severe adverse events related to intrabone injection were observed. The cumulative incidences of neutrophils ≥0.5 × 109 /L, reticulocytes ≥1%, and platelets ≥20 × 109 /L recoveries were 76.2%, 71.4%, and 76.2%, respectively, with median time to recoveries of 17, 28, and 32 days after transplantation, respectively. The probability of survival with neutrophil engraftment on day 60 was 71.4%, and overall survival at 1 year after transplantation was 52.4%. The incidences of grade II-IV and III-IV acute graft-versus-host disease were 44% and 19%, respectively, with no cases of chronic graft-versus-host disease. The present study showed the safety of direct intrabone infusion of cord blood. Further analysis is required to confirm the efficacy of intrabone single cord blood transplantation with non-irradiated reduced-intensity conditioning for adult patients with hematological malignancy. This study was registered with UMIN-CTR, number 000000865.

Acute improvement of endothelial functions after oral ingestion of isohumulones, bitter components of beer.

Isohumulones, principal components of the bitter taste of beers, have antioxidant capacity. We studied i) the effects of oral ingestion of isomerized hop extract (IHE) on the endothelial functions in smokers as well as non-smokers and ii) the effects of IHE on cultured endothelial cells in high oxidative stress state. Twelve cigarette smokers and eleven non-smokers ingested IHE and placebo in a randomized crossover design. Flow-mediated vasodilatation (FMD) was measured using ultrasonography. We also studied the effects of isohumulones on i) the cell viability under hypoxia and ii) the levels of angiotensin II (AT-II)-induced reactive oxygen species (ROS) in the cultured human aortic endothelial cells (HAECs). At baseline, the FMDs of the smokers were significantly lower than those of the non-smokers. The FMDs increased significantly after 30 min and 120 min of IHE ingestion in both the smokers and the non-smokers. IHE protected the HAECs from hypoxia-induced cell death as assessed by cell viability. IHE also reduced the AT-II-induced intracellular ROS level. Oral ingestion of IHE appears to exert acute beneficial effects on the endothelial functions in both the smokers and non-smokers, and the in vitro experiments using HAECs suggested that the effect be through reducing intracellular oxidative stress.

Dose-adjusted EPOCH chemotherapy for untreated peripheral T-cell lymphomas: a multicenter phase II trial of West-JHOG PTCL0707.

The standard CHOP therapy for peripheral T-cell lymphoma has resulted in unsatisfactory outcomes and it is still not clear what is the optimal front-line therapy. We conducted a multicenter phase II study of dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine and prednisone (EPOCH) for untreated peripheral T-cell lymphoma patients. In this prospective study, 41 patients were treated with dose-adjusted-EPOCH as initial therapy: peripheral T-cell lymphoma-not otherwise specified, n=21; angioimmunoblastic T-cell lymphoma, n=17; anaplastic lymphoma kinase-positive anaplastic large cell lymphoma, n=2; and anaplastic lymphoma kinase-negative anaplastic large cell lymphoma, n=1. Median patient age was 64 years (range: 32-79 years). According to the International Prognostic Index criteria, 51.2% were at high-intermediate or high risk. The overall response and complete response rates were 78.0% [95% confidence interval (CI): 62.4-89.4%] and 61.0% (95%CI: 44.5-75.8%), respectively. At the median follow up of 24.0 months, the 2-year progression-free survival and overall survival were 53.3% (95%CI: 36.4-67.5%) and 73.2% (95%CI: 56.8-84.1%), respectively. The younger patients (≤ 60 years old) had a high response rate (overall response 94.1% and complete response 70.6%) and survival rate (progression-free survival 62.5% and overall survival 82.4%). The most common grade ≥ 3 adverse events were neutropenia (74.5%), anemia (40.8%), thrombocytopenia (22.0%), and febrile neutropenia (9.0%). Dose-adjusted-EPOCH had a high response rate with a tolerable toxicity profile. Our results indicate that dose-adjusted-EPOCH is a reasonable first-line approach for peripheral T-cell lymphoma patients and may improve outcomes.

Effect of a retinoid X receptor partial agonist on airway inflammation and hyperresponsiveness in a murine model of asthma.

BACKGROUND: Retinoid X receptors (RXRs) are members of the nuclear receptor (NR) superfamily that mediate signaling by 9-cis retinoic acid, a vitamin A (retinol) derivative. RXRs play key roles not only as homodimers but also as heterodimeric partners-e.g., retinoic acid receptors (RARs), vitamin D receptors (VDRs), liver X receptors (LXRs), and peroxisome proliferator-activated receptors (PPARs). The NR family was recently associated with allergic diseases, but the role of RXRs in allergen-induced airway responses is not well defined. The goal of this study is to elucidate the role of RXRs in asthma pathogenesis and the potency of RXR partial agonist in the treatment of allergic airway inflammation and airway hyperresponsiveness using a murine model of asthma. METHODS: We investigated the effect of a novel RXR partial agonist (NEt-4IB) on the development of allergic airway inflammation and airway hyperresponsiveness (AHR) in a murine model of asthma. Balb/c mice were sensitized (days 0 and 14) and challenged (days 28-30) with ovalbumin (OVA), and airway inflammation and airway responses were monitored 48 h after the last OVA challenge. NEt-4IB was administered orally on days 25 to 32. RESULTS: Oral administration of NEt-4IB significantly suppressed AHR and inflammatory cell accumulation in the airways and attenuated the levels of TNF-α in the lung and IL-5, IL-13 and NO levels in bronchoalveolar lavage (BAL) fluid and the number of periodic acid Schiff (PAS)-positive goblet cells in lung tissue. Treatment with NEt-4IB also significantly suppressed NF-κB expression. CONCLUSION: These data suggest that RXRs may be of crucial importance in the mechanism of allergic asthma and that the novel RXR partial agonist NEt-4IB may be a promising candidate for the treatment of allergic airway inflammation and airway hyperresponsiveness in a model of allergic asthma.

Graft-versus-leukemia effect with a WT1-specific T-cell response induced by azacitidine and donor lymphocyte infusions after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Azacitidine (Aza) and donor lymphocyte infusion (DLI) therapy has recently been reported as an effective salvage therapy for relapsed acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Despite the high response rate and relatively long period of remission, most patients relapse again. The immunologic mechanism of the response and limited efficacy remain unknown. CASE REPORT: Aza + DLI therapy was performed for a patient with therapy-related MDS (t-MDS), who had relapsed after allogeneic peripheral blood stem cell transplantation. We observed a powerful graft-versus-leukemia (GVL) effect accompanied by an evident Wilms tumor antigen 1 (WT1)-specific CD8 T-cell response. Remission continued for 15 months, but finally the patient relapsed. The kinetics of the WT1-specific CD8 T cells were inversely associated with WT1 messenger RNA (mRNA), suggesting a WT1-driven GVL effect. DISCUSSION: A difference of T-cell phenotype between the whole T cells and the WT1-specific CD8 T cells was observed. It is of note that the memory phenotype of the WT1-specific T cell was limited and decreased early. The immunoescape mechanism was partly supported by loss of the memory phenotype due to failure of expansion and differentiation. CONCLUSION: Our data suggested that a WT1-specific T-cell response at least partly contributes to the GVL effect induced by Aza + DLI. A strategy for maximizing and maintaining the memory phenotype of the CTL may be required for durable remission.

A nationwide survey of hypoplastic myelodysplastic syndrome (a multicenter retrospective study).

Hypoplastic myelodysplastic syndrome (hMDS) is a distinct entity with bone marrow (BM) hypocellularity and the risk of death from BM failure (BMF). To elucidate the characteristics of hMDS, the data of 129 patients diagnosed between April 2003 and March 2012 were collected from 20 institutions and the central review team of the National Research Group on Idiopathic Bone Marrow Failure Syndromes, and compared with 115 non-hMDS patients. More RA and fewer CMMoL and RAEB-t in French-American-British (FAB) and more RCUD and MDS-U and fewer RCMD in World Health Organization (WHO) classifications were found in hMDS than non-hMDS with significant differences. The overall survival (OS) and AML progression-free survival (AML-PFS) of hMDS were higher than those of non-hMDS, especially in patients at age ≥50 and of lower risk in Revised International Prognostic Scoring System (IPSS-R). In competing risks analysis, hMDS exhibited decreased risk of AML-progression in lower IPSS or IPSS-R risk patients, and higher risk of death from BMF in patients at age ≥50. Poor performance status (PS ≥2) and high karyotype risks in IPSS-R (high and very high) were significant risk factors of death and AML-progression in Cox proportional hazards analysis.

Anti-IL-12/23 p40 antibody attenuates experimental chronic graft-versus-host disease via suppression of IFN-γ/IL-17-producing cells.

Chronic graft-versus-host disease (GVHD) is a major cause of late death and morbidity after allogeneic hematopoietic cell transplantation. Recently, in addition to Th2 cells, Th1 and Th17 cells have been shown to contribute to chronic GVHD progression. IL-12 induces Th1 cells and IL-23 plays a role in stabilizing and/or amplifying Th17 cells, as well as in inducing IFN-γ/IL-17 double-producing cells. Because mAb targeting the p40 subunit common to both IL-12 and IL-23 can inhibit both IL-12R and IL-23R-mediated signaling, we investigated the effects of anti-p40 mAb on a well-defined chronic GVHD mice model. Treatment of anti-p40 mAb in allogeneic recipients significantly reduced the severity of clinical and pathological chronic GVHD. Intracellular staining revealed that IFN-γ single-positive (IL-17(-)) and IFN-γ/IL-17 double-positive cells were suppressed in anti-p40 mAb-treated allogeneic recipients compared with control recipients. The cytokine levels of IFN-γ and IL-17 were also decreased in serum from anti-p40 mAb-treated allogeneic recipients. T-bet expression of donor IL-17(+) CD4(+) T cells was reduced significantly in anti-p40 mAb-treated recipients, and this reduction in T-bet expression was associated with IL-22 production by donor T cells. These results suggested that anti-p40 mAb attenuated chronic GVHD via suppression of IFN-γ/IL-17-producing cells, and that targeting the IL-12/IL-23 pathway may represent a promising therapeutic strategy for preventing and treating chronic GVHD.

Discomfort during bronchoscopy performed after endobronchial intubation with fentanyl and midazolam: a prospective study.

OBJECTIVE: Although endobronchial intubation during a bronchoscopic examination is useful for invasive procedures, it is not routine practice in Japan. The present study evaluated discomfort due to endobronchial intubation using fentanyl and midazolam sedation during bronchoscopy. METHODS: Thirty-nine patients were enrolled prospectively from November 2014 to September 2015 at Okayama University Hospital. Fentanyl (20 µg) was administered to the patients just before endobronchial intubation, and fentanyl (10 µg) and midazolam (1 mg) were added as needed during the procedure. A questionnaire survey was administered 2 h after the examination. In the questionnaire, patient satisfaction was scored using a visual analog scale as follows: excellent (1 point), good (2 points), normal (3 points), uncomfortable (4 points) and very uncomfortable (5 points). An additional question ('Do you remember the bronchoscopic examination?') was also asked. Predefined parameters (blood pressure, heart rate, oxygen saturation and complications) were recorded. RESULTS: The enrolled patients included 22 males and 17 females; their median age was 70 (range: 28-88) years. The patients received a mean dose of 47.9 µg of fentanyl (range: 30-90 µg) and 2.79 mg of midazolam (range: 1-7 mg). In total, 28 patients (71.7%) agreed to undergo a second bronchoscopic examination; the mean levels of discomfort and for the re-examination were 2.07 points each. About 41% of the patients remembered the bronchoscopic examination. No severe complications were reported. CONCLUSION: Endobronchial intubation using fentanyl and midazolam sedation during an invasive bronchoscopic procedure might be recommended. CLINICAL TRIAL REGISTRATION: UMIN000015578 in the UMIN Clinical Trials Registry.

Protective Effects of Bisoprolol against Acute Exacerbation in Moderate-to-Severe Chronic Obstructive Pulmonary Disease.

Although recent retrospective studies suggested that the use of ß-blockers appears to help improve the mortality rate and decrease the rate of exacerbation in chronic obstructive pulmonary disease (COPD) patients with heart failure, the effects of ß-blockers on COPD patients without heart failure have not been established. Based on previous reports, we have launched a multicenter, prospective, single-arm phase II study to evaluate the preventive effect of the cardioselective ß-blocker bisoprolol in COPD exacerbation, in Japanese individuals with moderate-to-severe COPD who do not have heart failure but do have hypertension requiring the use of medication. The primary endpoint is the rate of mild-to-severe COPD exacerbation. The results of this study will clarify whether bisoprolol can prevent exacerbation in COPD patients without heart failure.

Lavender Essential Oil and Its Main Constituents Inhibit the Expression of TNF-α-induced Cell Adhesion Molecules in Endothelial Cells.

Lavender essential oil (Lvn) has anti-inflammatory effects in an ovalbumin-sensitized murine model of asthma, and inhibits inflammatory cell infiltration into the lungs. The anti-inflammatory effects of Lvn on cell adhesion molecules are not clear. Here we evaluated the effects of Lvn and its main constituents, linalyl acetate (LA) and linalool (LO), on the expression of tumor necrosis factor-alpha (TNF-α)-induced cell adhesion molecules in murine brain endothelial bEnd.3 cells and human umbilical vein endothelial cells (HUVECs). The bEnd.3 cells were treated with Lvn, LA, or LO and subsequently stimulated with TNF-α. The mRNA expression levels of cell adhesion molecules were detected using RT-PCR. E-selectin and P-selectin protein and phosphorylated-NF-κB p65 were detected by western blotting. The effects of Lvn on HUVECs were measured by RT-PCR. In bEnd.3 cells, Lvn and LA suppressed TNF-α-induced E-selectin, P-selectin, vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and phosphorylated-NF-κB p65 in the nucleus; LO did not suppress P-selectin or phosphorylated-NF-κB p65. Lvn inhibited TNF-α-induced E-selectin mRNA in HUVECs. These results indicate that Lvn and LA inhibit TNF-α-induced cell adhesion molecules in endothelial cells through the suppression of NF-κB activation. Consequently, Lvn or other essential oils including LA may be useful as alternative anti-inflammatory medicines.