New CETP inhibitor K-312 reduces PCSK9 expression: a potential effect on LDL cholesterol metabolism.

Despite significant reduction of cardiovascular events by statin treatment, substantial residual risk persists, driving emerging needs for the development of new therapies. We identified a novel cholesteryl ester transfer protein (CETP) inhibitor, K-312, that raises HDL and lowers LDL cholesterol levels in animals. K-312 also suppresses hepatocyte expression of proprotein convertase subtilisin/kexin 9 (PCSK9), a molecule that increases LDL cholesterol.

Design and discovery of 2-oxochromene derivatives as liver X receptor β-selective agonists.

In an attempt to molecularly design liver X receptor (LXR) β-selective agonists, we discovered that the combination of the 2-oxochromene moiety (head) and the imidazoline-2,4-dione moiety (tail) plays an important role in the expression potency and selectivity toward LXRβ. We synthesized a series of 2-oxochromene derivatives and identified 43 as a LXRβ-selective agonist that increased the HDL-C level without significantly elevating the TG level and resulted in a decreased lipid-accumulation area in the aortic arch in a high-fat-and-cholesterol-fed Bio F1B hamster. In this manuscript, we report the design, synthesis and pharmacology of these 2-oxochromene derivatives.

Virtual bronchoscopic navigation combined with endobronchial ultrasound to diagnose small peripheral pulmonary lesions: a randomised trial.

Background: Bronchoscopy using endobronchial ultrasound (EBUS) can help to diagnose small peripheral pulmonary lesions. However, although biopsy sites can be confirmed, a bronchoscope cannot be guided in EBUS. Virtual bronchoscopic navigation (VBN) can guide a bronchoscope with virtual images, but its value has not been confirmed.

Clinical investigation of malignant mesothelioma in Japan.

Purpose: The asbestos-related problems caused much social concern; however, no large-scale study was conducted about clinical features of MM in Japan. Patients with MM who have a history of occupational asbestos exposure (AE) are provided worker's compensation in Japan. However, only about 10% of MM cases were actually claimed and compensated.

Combined survival analysis of prospective clinical trials of gefitinib for non-small cell lung cancer with EGFR mutations.

Purpose: Somatic mutations of the epidermal growth factor receptor (EGFR) gene are associated with an increased response to gefitinib in patients with non-small cell lung cancer. We have examined the impact of gefitinib on progression-free survival and overall survival in patients with EGFR mutation-positive non-small cell lung cancer.

Experimental Design: We searched for all clinical trials that prospectively evaluated the efficacy of gefitinib for advanced non-small cell lung cancer with EGFR mutations in Japan.

Phase I study of amrubicin and vinorelbine in non-small cell lung cancer previously treated with platinum-based chemotherapy.

Background: Combination chemotherapy comprising amrubicin and vinorelbine as a second-line therapy for advanced non-small cell lung cancer (NSCLC) has not been fully evaluated. To determine the maximum tolerated dose (MTD) and recommended dose (RD), the present phase I study examined patients with advanced NSCLC.

Methods: The subjects were nine patients with histologically confirmed advanced NSCLC, Eastern Cooperative Oncology Group performance status 0-1, prior platinum-based first-line chemotherapy, and measurable or evaluable lesions.

First-line gefitinib for patients with advanced non-small-cell lung cancer harboring epidermal growth factor receptor mutations without indication for chemotherapy.

Purpose: This multicenter phase II study was undertaken to investigate the efficacy and feasibility of gefitinib for patients with advanced non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations without indication for chemotherapy as a result of poor performance status (PS).

Patients And Methods: Chemotherapy-naïve patients with poor PS (patients 20 to 74 years of age with Eastern Cooperative Oncology Group PS 3 to 4, 75 to 79 years of age with PS 2 to 4, and >or= 80 years of age with PS 1 to 4) who had EGFR mutations examined by the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method were enrolled and received gefitinib (250 mg/d) alone.

Results: Between February 2006 and May 2007, 30 patients with NSCLC and poor PS, including 22 patients with PS 3 to 4, were enrolled.

Concentrations of clarithromycin and active metabolite in the epithelial lining fluid of patients with Mycobacterium avium complex pulmonary disease.

Objectives: Clarithromycin (CAM) is widely accepted for the treatment of Mycobacterium avium complex (MAC) pulmonary diseases. This study measured (a) the concentrations of CAM and its active metabolite (14OH-CAM) in bronchial epithelial lining fluid (ELF) obtained by bronchoscopic microsampling (BMS), and (b) the minimal inhibitory concentrations (MIC) of CAM for each MAC isolate.

Methods: We studied eight patients with MAC pulmonary disease treated with oral CAM, 400 (n=4) or 800 (n=4) mg/day.

Randomized phase II trial comparing amrubicin with topotecan in patients with previously treated small-cell lung cancer: North Japan Lung Cancer Study Group Trial 0402.

Purpose: Amrubicin, a new anthracycline agent, and topotecan are both active for previously treated small-cell lung cancer (SCLC). No comparative study of these agents has been reported. This randomized phase II study was conducted to select amrubicin or topotecan for future evaluation.

Prolonged survival of patients with lung adenocarcinoma expressing XAGE-1b and HLA class I antigens.

XAGE-1b is a cancer/testis antigen that has been shown to be expressed at a significant frequency and to be immunogenic in non-small cell lung cancer (NSCLC). In the present study, we investigated correlations between XAGE-1b expression and NSCLC patient survival. XAGE-1b expression was examined immunohistochemically using USO9-13, an anti-XAGE-1b monoclonal antibody, in 121 NSCLCs (83 adenocarcinomas and 38 other histological types).

Efficacy and safety of pemetrexed in combination with cisplatin for malignant pleural mesothelioma: a phase I/II study in Japanese patients.

Background: Pemetrexed in combination with cisplatin (Pem/Cis) is used globally for the treatment of malignant pleural mesothelioma (MPM). This Phase I/II study was conducted to determine the recommended dose (RD) (Phase I) of Pem/Cis, and evaluate the efficacy and safety (Phase II) in Japanese MPM patients.

Methods: Key eligibility criteria were histologic diagnosis of MPM incurable by surgery, no prior chemotherapy, and a performance status 0-1.

Surmounting tumor-induced immune suppression by frequent vaccination or immunization in the absence of B cells.

Tumor-induced immune suppression is one of the most difficult obstacles to the success of tumor immunotherapy. Here, we show that established tumors suppress CD8 T cell clonal expansion in vivo, which is normally observed in tumor-free mice upon antigen-specific glycoprotein (gp) 96-chaperone vaccination. Suppression of CD8 T-cell expansion by established tumors is independent of tumor-associated expression of the antigen that is recognized by the CD8-T-cell receptor.

Recurrent gefitinib-induced interstitial lung disease.

Gefitinib, the epidermal growth factor receptor tyrosine kinase inhibitor, is effective for patients with non-small cell lung cancer. However, a serious adverse effect, interstitial lung disease (ILD), has been reported. The re-administration of gefitinib might be considered when there is no other choice of treatment and a therapeutic effect can be expected; however, there is no published data on the safety of restarting gefitinib after its discontinuation in cases suspected of having gefitinib-induced ILD.

Pharmacokinetics of clarithromycin in bronchial epithelial lining fluid.

Background And Objective: BAL is an established technique for measuring antibiotic concentrations in the epithelial lining fluid (ELF) of the bronchiolar-alveolar regions. However, the results may not reflect concentrations in bronchial regions. Bronchoscopic microsampling (BMS) is a technique for repeated sampling of bronchial ELF.

Anti-OX40 monoclonal antibody therapy in combination with radiotherapy results in therapeutic antitumor immunity to murine lung cancer.

The therapeutic effect of agonistic anti-OX40 (CD134) monoclonal antibody (mAb) in combination with radiotherapy was evaluated in a murine lung cancer model. After intradermal transplantation of ovalbumin (OVA)-transfected Lewis lung carcinoma, C57BL/6 mice were irradiated locally with a single dose of 20 Gy in combination with an intratumoral injection of anti-OX40 mAb at 50 microg on day 4 after transplantation, which is when the major axis of the inoculated tumor reached a diameter of 7-9 mm. On days 8, 11, and 14, the tumor-bearing mice were further treated with the same dose of anti-OX40 mAb.

Diagnosis of peripheral pulmonary lesions using a bronchoscope insertion guidance system combined with endobronchial ultrasonography with a guide sheath.

We developed a bronchoscope insertion guidance system that produces virtual images by extracting the bronchi by automatic threshold adjustment, and searching for the bronchial route to the determined target. We used this system in combination with a thin bronchoscope and endobronchial ultrasonography with a guide sheath (EBUS-GS), and evaluated its practicability, usefulness and safety. The subjects were 31 patients with 32 peripheral pulmonary lesions.

Steep dose-response relationship for stage I non-small-cell lung cancer using hypofractionated high-dose irradiation by real-time tumor-tracking radiotherapy.

Purpose: To investigate the clinical outcomes of patients with pathologically proven, peripherally located, Stage I non-small-cell lung cancer who had undergone stereotactic body radiotherapy using real-time tumor tracking radiotherapy during the developmental period.

Methods And Materials: A total of 41 patients (25 with Stage T1 and 16 with Stage T2) were admitted to the study between February 2000 and June 2005. A 5-mm planning target volume margin was added to the clinical target volume determined with computed tomography at the end of the expiratory phase.

Histopathologic consideration of fiducial gold markers inserted for real-time tumor-tracking radiotherapy against lung cancer.

Purpose: Internal fiducial gold markers, safely inserted with bronchoscopy, have been used in real-time tumor-tracking radiotherapy for lung cancer. We investigated the histopathologic findings at several points after the insertion of the gold markers.

Methods And Materials: Sixteen gold markers were inserted for preoperative marking in 7 patients who subsequently underwent partial resection of tumors by video-assisted thoracoscopic surgery within 7 days.

Combination tumor immunotherapy with radiotherapy and Th1 cell therapy against murine lung carcinoma.

Mice bearing established Lewis lung carcinoma (LLC) expressing model tumor antigen, ovalbumin (OVA) (LLC-OVA) marginally responded to local radiotherapy, but none of the mice was cured. In contrast, treatment of the tumor-bearing mice with intratumoral injection of tumor-specific T helper type 1 (Th1) cells and tumor antigen (OVA) after radiotherapy dramatically prolonged the survival days and induced complete cure of the mice at high frequency (80%). Radiation therapy combined with Th1 cells or OVA alone showed no significant therapeutic activity against LLC-OVA.

HLA class I antigen expression is associated with a favorable prognosis in early stage non-small cell lung cancer.

Human leukocyte antigen (HLA) class I displays a repertoire of endogenously processed peptides to CD8(+) T lymphocytes. The present study assessed correlations between HLA class I expression, clinicopathologic factors, and tumor-infiltrating immune cells in human non-small cell lung cancers (NSCLC). Expression of HLA class I was assessed in 161 resected primary NSCLC by immunohistochemistry using EMR8-5, a novel monoclonal anti-pan HLA class I heavy chain antibody.

Gefitinib administration in a patient with lung cancer undergoing hemodialysis.

Gefitinib is mainly metabolized by the liver and its excretion is mostly in bile excrements. However, the feasibility of gefitinib in patients with chronic renal failure undergoing hemodialysis has not, so far, been reported. A 58-year-old woman with chronic renal failure due to polycystic kidney disease, undergoing hemodialysis, experienced diplopia due to meningitis carcinomatosa by lung adenocarcinoma.

Factors related to diagnostic yield of transbronchial biopsy using endobronchial ultrasonography with a guide sheath in small peripheral pulmonary lesions.

Study Objectives: To evaluate factors predicting the diagnostic yield of transbronchial biopsy (TBB) using endobronchial ultrasonography with a guide sheath (EBUS-GS) in small peripheral pulmonary lesions (PPLs)
Design: Retrospective analysis.

Patients And Methods: One hundred fifty-five consecutive patients with 158 small PPLs underwent TBB using EBUS-GS.

Diagnostic value of endobronchial ultrasonography with a guide sheath for peripheral pulmonary lesions without X-ray fluoroscopy.

Study Objectives: We evaluated the feasibility and efficacy of transbronchial biopsy (TBB) and bronchial brushing by endobronchial ultrasonography (EBUS) with a guide sheath (GS) as a guide for diagnosing peripheral pulmonary lesions (PPLs) without radiographic fluoroscopy.

Patients: One hundred twenty-one patients with 123 PPLs (mean diameter, 31.0 mm) whose bronchoscopic findings were normal.

A virtual bronchoscopic navigation system under X-ray fluoroscopy for transbronchial diagnosis of small peripheral pulmonary lesions.

We had reported the utility of virtual bronchoscopic navigation system under CT-guidance for the diagnosis of small peripheral pulmonary lesions (PPLs). This study investigated the efficacy of virtual bronchoscopic navigation system for the diagnosis of small PPLs under X-ray fluoroscopy. We performed bronchoscopy with this system for 94 consecutive patients with 96 PPLs (< or =30mm in longest diameter; mean longest diameter, 16.