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. We explored the underlying mechanism for the reduction of PCSK9 expression by K-312. K-312 inhibited in vitro human plasma CETP activity (IC50; 0.06 µM). Administration of K-312 to cholesterol-fed New Zealand White rabbits for 18 wk raised HDL cholesterol, decreased LDL cholesterol, and attenuated aortic atherosclerosis. Our search for additional beneficial characteristics of this compound revealed that K-312 decreases PCSK9 expression in human primary hepatocytes and in the human hepatoma cell line HepG2. siRNA silencing of CETP in HepG2 did not compromise the suppression of PCSK9 by K-312, suggesting a mechanism independent of CETP. In HepG2 cells, K-312 treatment decreased the active forms of sterol regulatory element-binding proteins (SREBP-1 and -2) that regulate promoter activity of PCSK9. Chromatin immunoprecipitation assays demonstrated that K-312 decreased the occupancy of SREBP-1 and SREBP-2 on the sterol regulatory element of the PCSK9 promoter. PCSK9 protein levels decreased by K-312 treatment in the circulating blood of cholesterol-fed rabbits, as determined by two independent mass spectrometry approaches, including the recently developed, highly sensitive parallel reaction monitoring method. New CETP inhibitor K-312 decreases LDL cholesterol and PCSK9 levels, serving as a new therapy for dyslipidemia and cardiovascular disease.

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

In an attempt to molecularly design liver X receptor (LXR) ß-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 LXRß. We synthesized a series of 2-oxochromene derivatives and identified 43 as a LXRß-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. METHODS: This prospective multicentre study examines the value of VBN-assisted EBUS for diagnosing small peripheral pulmonary lesions. 199 patients with small peripheral pulmonary lesions (diameter ≤30 mm) were randomly assigned to VBN-assisted (VBNA) or non-VBN-assisted (NVBNA) groups. A bronchoscope was introduced into the target bronchus of the VBNA group using the VBN system. Sites of specimen sampling were verified using EBUS with a guide sheath under fluoroscopy. RESULTS: The diagnostic yield was higher for the VBNA than for the NVBNA group (80.4% vs 67.0%; p = 0.032). The duration of the examination and time elapsed until the start of sample collection were reduced in the VBNA compared with the NVBNA group (median (range), 24.0 (8.7-47.0) vs 26.2 (11.6-58.6) min, p = 0.016) and 8.1 (2.8-39.2) vs 9.8 (2.3-42.3) min, p = 0.045, respectively). The only adverse event was mild pneumothorax in a patient from the NVBNA group. CONCLUSIONS: The diagnostic yield for small peripheral pulmonary lesions is increased when VBN is combined with EBUS. Clinical trial number UMIN000000569.

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. BMS was performed 3h after the last CAM dose, and the concentrations of CAM and 14OH-CAM were measured in ELF collected from the diseased and normal contralateral pulmonary segments, and in serum. RESULTS: The mean+/-SEM ELF concentrations of CAM (23.85+/-7.64 microg/ml) and CAM+14OH-CAM (28.71+/-8.37 microg/ml) in the 800 mg/day treatment group were significantly higher than in the 400mg/day group (7.48+/-2.58 microg/ml and 9.63+/-2.99 microg/ml, respectively; both p<0.05), while the serum concentrations were similar in both groups. In both treatment groups, the mean ELF concentrations sampled from diseased and normal segments were higher than the MIC against MAC isolates. The mean ELF concentration of CAM in the 400mg/day treatment group was <8 mircog/ml (the breakpoint concentration of CAM against M. avium recommended by the Clinical Laboratories Standards Institute), while the mean concentration in the 800 mg/day treatment group was >8 microg/ml. CONCLUSION: These observations suggest that CAM, 800 mg/day, is an appropriate dose to treat MAC pulmonary disease, and prevent its spread from diseased to non-diseased lung segments.

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. Anti-OX40 mAb in combination with radiotherapy prolonged survival and provided greater efficacy than either single treatment against well-established tumors. An in vivo depletion study suggested that therapeutic immunity was mainly CD8(+) T-cell dependent. OX40(+)CD8(+) T cells were augmented in draining lymph nodes obtained from irradiated mice compared with those from non-irradiated mice. OVA-major histocompatibility complex tetramer(+) CD8(+) T cells had been strongly recruited to the draining lymph nodes obtained from mice treated with anti-OX40 mAb in combination with radiotherapy, and strong antigen-specific cytotoxicity was confirmed by a (51)Cr-release assay. Moreover, a tumor-rechallenge model indicated that this combination therapy induced durable tumor immunity. Thus, anti-OX40 mAb in combination with radiotherapy may potentially help the management of patients with lung cancer.

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. The gating window ranged from +/-2 to 3 mm. The dose fractionation schedule was 40 or 48 Gy in four fractions within 1 week. The dose was prescribed at the center of the planning target volume, giving more than an 80% dose at the planning target volume periphery. RESULTS: For 28 patients treated with 48 Gy in four fractions, the overall actuarial survival rate at 3 years was 82% for those with Stage IA and 32% for those with Stage IB. For patients treated with 40 Gy in four fractions within 1 week, the overall actuarial survival rate at 3 years was 50% for those with Stage IA and 0% for those with Stage IB. A significant difference was found in local control between those with Stage IB who received 40 Gy vs. 48 Gy (p = 0.0015) but not in those with Stage IA (p = 0.5811). No serious radiation morbidity was observed with either dose schedule. CONCLUSION: The results of our study have shown that 48 Gy in four fractions within 1 week is a safe and effective treatment for peripherally located, Stage IA non-small-cell lung cancer. A steep dose-response curve between 40 and 48 Gy using a daily dose of 12 Gy delivered within 1 week was identified for Stage IB non-small-cell lung cancer in stereotactic body radiotherapy using real-time tumor tracking radiotherapy.

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. RESULTS: Fibrotic changes and hyperplasia of type 2 pneumocytes around the markers were seen 5 or 7 days after insertion, and fibrin exudation without fibrosis was detected 1 or 2 days after insertion. CONCLUSIONS: Because fibroblastic changes start approximately 5 days after gold marker insertion, real-time tumor-tracking radiotherapy should be started >5 days after gold marker insertion.

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). XAGE-1b expression was observed in 27 (32.5%) adenocarcinoma specimens. In the other histological types, positive staining was observed in only 1 specimen. HLA class I expression in these samples was assessed previously. XAGE-1b expression had no correlation with overall survival. However, both XAGE-1b and HLA class I expression correlated with prolonged survival (P = 0.019). Moreover, expression of XAGE-1b combined with down-regulated HLA class I expression correlated with poor survival (P = 0.01). The density of cancer nest-infiltrating CD8+ T-cells in tumors expressing both XAGE-1b and HLA class I was higher than that in other groups. The findings suggest that XAGE-1b and HLA class I expression elicited a CD8+ T-cell response against minimal residual disease after surgery and resulted in prolonged survival of NSCLC patients.

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. Computed tomography (CT) data were transferred into this system, and virtual bronchial images were automatically produced by setting the lesion as the target. While virtual images with the target were displayed for comparison with real images by the system, a thin bronchoscope was advanced to the target bronchus. Transbronchial biopsy (TBB) was then performed by EBUS-GS. The system automatically produced virtual images to a median of fifth- (third- to seventh-) order bronchi. In all patients, the thin bronchoscope could be guided along the planned route, and observation to a median of fifth- (third- to seventh-) order bronchi was possible. Thirty lesions (93.8%) were successfully visualized by EBUS, and 27 (84.4%) could be pathologically diagnosed. In lesions < or =30mm in size, the EBUS visualization yield was 91.7% (22/24), and the diagnostic yield was 79.2% (19/24). The median total examination time was 22.3 (9.8-41.5) min. In summary, using the bronchoscope insertion guidance system, virtual images can be readily produced, and the bronchoscope can be successfully guided to the target. This method is promising as a routine examination method in the biopsy of peripheral pulmonary lesions.

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. Under full vitamin supplementation, pemetrexed was intravenously administered on Day 1 of a 21-day cycle, followed by cisplatin. A cohort of six patients, starting from pemetrexed 500 mg/m(2) and cisplatin 75 mg/m(2) (Level 1), were studied in the dose-escalation Phase I (Step 1). The RD determined in Step 1 was carried forward into Phase II (Step 2). Planned number of patients treated with Pem/Cis was 18-38. RESULTS: In Step 1, 13 patients were enrolled: seven in Level 1 and six in Level -1 (pemetrexed 500 mg/m(2), cisplatin 60 mg/m(2)). Two of six evaluable patients had dose-limiting toxicities (pneumonitis and neutropenia) in Level 1, establishing Level 1 as the RD. In Step 2, 12 patients were enrolled, for a total of 19 patients treated at the RD. Seven patients achieved a partial response among these patients, for a response rate of 36.8% (95% confidence interval: 16.3-61.6); overall survival was 7.3 months. One drug-related death occurred due to worsening of a pre-existing pneumonia. Common grade 3/4 toxicities were neutropenia and decreased-hemoglobin. CONCLUSION: The Pem/Cis combination provides promising activity and an acceptable safety profile for chemonaive Japanese MPM patients with the same recommend dosage and schedule used in rest of the world.

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. The objective of the present study was to determine the time versus concentration profile of clarithromycin and its active metabolite, 14-hydroxy-clarithromycin, in bronchial ELF, as determined by BMS. METHODS: BMS was performed at 1, 2, 3, 5 and 10 h after a single oral administration of 200 mg clarithromycin in five healthy volunteers. BAL was performed 3 h after administration to determine clarithromycin concentrations in alveolar ELF and alveolar macrophages (AM). RESULTS: The maximum concentration (C(max)) of clarithromycin was 0.36 +/- 0.07 mg/L in serum and 1.44 +/- 0.49 mg/L in bronchial ELF (P < 0.01). C(max) for 14-hydroxy-clarithromycin was 0.34 +/- 0.13 mg/L in serum and 0.68 +/- 0.34 mg/L in bronchial ELF. The area under the concentration-time curve from 0 to 10 h (AUC(0-10)) for clarithromycin was 2.10 +/- 0.49 mg.h/L for serum and 7.37 +/- 2.07 mg.h/L for bronchial ELF (P < 0.01). The concentrations of clarithromycin in alveolar ELF and AM, 3 h after oral administration, were 4.84 +/- 3.39 mg/L and 10.7 +/- 8.7 mg/L, respectively. CONCLUSIONS: A single oral dose of clarithromycin produces a significantly higher C(max) and AUC(0-10) for clarithromycin in bronchial ELF than in serum, and higher concentrations in alveolar ELF and AM than in serum. BMS might be useful for measuring the pharmacokinetic profile of clarithromycin in bronchial ELF.

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. Such a strong therapeutic activity was not induced by intratumoral injection of Th1 cells plus OVA. Compared with other treatment, radiation therapy combined with Th1 cells and OVA was superior to induce the generation of OVA/H-2(b) tetramer(+) tumor-specific cytotoxic T lymphocyte (CTL) with a strong cytotoxicity against LLC-OVA in draining lymph node (DLN). Moreover, the combined therapy is demonstrated to inhibit the growth of tumor mass, which grew at contralateral side. These results indicated that radiotherapy combined with Th1 cell/vaccine therapy induced a systemic antitumor immunity. These findings suggested that combination therapy with radiotherapy and Th1 cell/vaccine therapy may become a practical strategy for cancer treatment.

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) 15 mm and

Factors related to diagnostic sensitivity using an ultrathin bronchoscope under CT guidance.

BACKGROUND: We investigated factors related to the diagnostic sensitivity of CT-guided transbronchial biopsy (TBB) using an ultrathin bronchoscope and virtual bronchoscopy (VB) navigation for small peripheral pulmonary lesions. METHOD: We have performed this procedure on 83 patients with 85 small peripheral pulmonary lesions (< 20 mm in diameter). We analyzed the relationship between the diagnostic sensitivity and the location of the lesions, the bronchial generation to which an ultrathin bronchoscope was inserted, and the lesion-bronchial and lesion-pulmonary arterial relationships on high-resolution CT. RESULTS: Fifty-six of the 85 lesions (66%) were diagnosed following CT-guided TBB using an ultrathin bronchoscope with VB navigation. The lesions located in the left superior segment of the lower lobe (S6) had a significantly low diagnostic sensitivity compared to other locations (p < 0.01). When an ultrathin bronchoscope could be inserted to the fifth or greater bronchial generation, the yield was above the average diagnostic sensitivity of 66%. Moreover, not only the patients with the presence of a bronchus leading directly to a lesion (CT-bronchus sign), but also the patients with the presence of a pulmonary artery leading to a lesion (CT-artery sign), had high diagnostic sensitivity (p < 0.01). Multivariate analysis revealed that the location of lesion was an independent predictor of diagnostic sensitivity (p < 0.05). CONCLUSIONS: The location of the lesion, the bronchial generation to which an ultrathin bronchoscope was inserted, and the presence of a bronchus as well as a pulmonary artery leading to the lesion were valuable for predicting successful CT-guided TBB using an ultrathin bronchoscope with VB navigation.

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. METHODS: An EBUS-GS was inserted and advanced to the PPL without fluoroscopy. Once we obtained the EBUS image, the probe was withdrawn and the GS was left in place. TBB and/or bronchial brushing were performed via the GS. When an EBUS image could not be obtained, we changed to the bronchoscopic examination under fluoroscopy. RESULTS: Seventy-six of 123 PPLs (61.8%) were diagnosed by EBUS-GS guidance without fluoroscopy. The diagnostic yield for PPLs > 20 mm in diameter (75.6%) was significantly higher than that for those

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. Sequencing analysis of her tumor tissue revealed deletion of 15 nucleotides in E746-A750 of exon 19. She started daily administration of 250mg gefitinib with hemodialysis three times a week. Her pharmacokinetic pattern after gefitinib administration was similar to those in patients with normal renal function and 88.7% of gefitinib was kept in the plasma through hemodialysis. Her symptoms and signs of meningitis carcinomatosa on brain magnetic resonance images improved. Thirteen months later, the meningitis got worse again and she stopped gefitinib administration. During gefitinib administration, there were no signs of adverse events. In summary, gefitinib is not eliminated by hemodialysis and was safely administered to a patient with non-small cell lung cancer and chronic renal failure who was undergoing hemodialysis.

Virtual bronchoscopic navigation system shortens the examination time--feasibility study of virtual bronchoscopic navigation system.

Computed tomography (CT)-guided transbronchial biopsy (TBB) using an ultrathin bronchoscope with simulation by virtual bronchoscopy (VB) is effective for diagnosing small peripheral pulmonary lesions. However, we occasionally lose the proper bronchi to the lesion when a bronchoscope is inserted into peripheral bronchi with severe rotation. To overcome this problem, the virtual bronchoscopic navigation system that can display real-time VB images during TBB procedures in comparison with actual bronchi has been developed. We evaluated the usefulness of the virtual bronchoscopic navigation system for CT-guided TBB using an ultrathin bronchoscope (navigation method) to diagnose small peripheral pulmonary lesions, and compared the results to those with previous method that uses VB images in a simulation (simulation method). We performed CT-guided TBB using an ultrathin bronchoscope for 69 patients with 71 small peripheral pulmonary lesions (mean diameter, 13.7 mm) between November 2002 and November 2005 with the navigation method. CT-guided TBB with the navigation method was performed safely without any serious complications for all patients. Mean time to the initial scan, time to the first biopsy and total examination time were 5.3, 8.5 and 24.5 min, respectively. Fifty lesions (70%) were diagnosed by this procedure. Compared to simulation method, diagnostic sensitivity was higher in the navigation method, but the difference was not significant. However, the time to the first biopsy and total examination time were significantly shorter in the navigation method than in the simulation method (p<0.05). In summary, the virtual bronchoscopic navigation system was safely used, effective for diagnosing small peripheral pulmonary lesions, and useful for shortening the examination time of CT-guided TBB using an ultrathin bronchoscope.

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, 16.2mm). A standard bronchoscope was used in 38 cases, and an ultrathin bronchoscope in 58 cases. Virtual bronchoscopic images were reconstructed from helical CT data. All the examinations were performed under X-ray fluoroscopy with virtual bronchoscopic navigation system, we referred both virtual bronchoscopic images and actual bronchoscopic images simultaneously to navigate the bronchoscopic pathway to the PPLs. Specimens for pathological examination were collected by transbronchial biopsy (TBB) and/or brushing. Virtual images accorded well with actual bronchoscopic images. The average total examination time was 24.1+/-7.4min (mean+/-S.D.). The overall diagnostic yields were 62.5% (60 of 96 PPLs), 71.1% (27 of 38 PPLs) with the standard bronchoscope, and 56.9% (33 of 58 PPLs) with the ultrathin bronchoscope. Diagnostic rates were 35%, 61.4% and 94.7% for lesions < or =10, 10-20, and >20mm, respectively. There were eight ground glass opacity (GGO) lesions confirmed only on CT scans; seven cases were pathologically diagnosed. All the examinations were performed safely with no complications. Bronchoscopy with virtual bronchoscopic navigation under X-ray fluoroscopy is useful for the diagnosis of small PPLs.

Clinical benefit of readministration of gefitinib for initial gefitinib-responders with non-small cell lung cancer.

BACKGROUND: Gefitinib, an oral agent of epidermal growth factor receptor tyrosine kinase inhibitor, has a certain efficacy against non-small cell lung cancer (NSCLC). Several predictive factors of gefitinib sensitivity have been well described. However, few studies have investigated the clinical features of gefitinib-responders. In the present study, we analyzed the response and disease progression of primary and metastatic lesions to gefitinib in responders and the results of gefitinib readministration following temporary cessation of gefitinib upon progression of initial gefitinib treatment and other treatments. METHOD: We retrospectively evaluated the clinical courses of 27 NSCLC patients who received gefitinib and achieved either a complete or partial response. RESULTS: The best-response rate and disease-control rate against the initial chemotherapy for the gefitinib-responders were 27.3% and 77.3%, respectively. Favorable efficacy was observed in the primary lesion and metastases to the lung, liver and brain, while there was no obvious effect on bone metastasis. The primary lesion and intrapulmonary metastasis were the sites of major recurrence. Median progression-free survival was 13.8 months, median duration of gefitinib treatment was 17.0 months and median overall survival was 29.2 months. Some of the patients who experienced disease progression after responding to gefitinib were again sensitive to readministration of gefitinib following temporary cessation of gefitinib and other treatments. CONCLUSION: Patients may still be expected to have prolonged survival if they once responded to gefitinib and then underwent various subsequent treatments followed by readministration of gefitinib. These findings might provide valuable information for the management of gefitinib-responders.

Pharmacokinetics of gatifloxacin after a single oral dose in healthy young adult subjects and adult patients with chronic bronchitis, with a comparison of drug concentrations obtained by bronchoscopic microsampling and bronchoalveolar lavage.

BACKGROUND: Bronchoalveolar lavage (BAL) is an established technique for measuring antibiotic concentrations in the epithelial lining fluid (ELF) of the bronchiolar and alveolar regions; however, the results may not reflect concentrations in bronchial regions. Bronchoscopic microsampling (BMS) is a technique that makes it possible to obtain multiple samples from bronchial ELF. OBJECTIVE: BMS and BAL were used to analyze the pharmacokinetics of gatifloxacin in bronchial ELF from healthy young adult subjects and adult patients with chronic bronchitis. METHODS: Bronchial ELF samples were obtained by BMS at 1, 2, 3, 4, 6, 10, and 24 hours after administration of a single oral dose of gatifloxacin 200 mg in healthy young adult (aged 20-25 years) subjects, and at 1, 2, 4, and 10 hours after a single dose in patients with chronic bronchitis (aged > or =20 years). At least 1 month after the initial BMS, alveolar (BAL) and bronchial (BMS) ELF samples were obtained from another group of healthy subjects 2 hours after administration of a single oral dose of gatifloxacin 200 mg for comparison of gatifloxacin concentrations in samples obtained by the 2 techniques. RESULTS: Bronchial ELF samples were obtained from 8 healthy subjects and 5 patients with chronic bronchitis; alveolar ELF samples were obtained from a separate group of 5 healthy subjects. For the healthy subjects, the mean (SD) AUC(0-24) in serum and bronchial ELF, corrected for mg/kg doses, was 4.6 (1.1) and 7.6 (3.5) mg x h/L, respectively. In the patients with chronic bronchitis, the AUC(0-10) in serum and bronchial ELF, corrected for mg/kg doses, was 3.9 (0.8) and 4.1 (1.5) mg x h/L. The C(max) in serum and bronchial ELF, corrected for mg/kg doses, was 0.6 (0.2) and 1.4 (0.8) mg/L in healthy subjects and 0.7 (0.2) and 0.7 (0.2) mg/L in patients with chronic bronchitis. In healthy subjects, the C(max) and AUC(0-24) were significantly higher in bronchial ELF than in serum (both, P < 0.05). Gatifloxacin concentrations were significantly lower in bronchial ELF obtained by BMS than in alveolar ELF obtained by BAL (P < 0.05). CONCLUSIONS: Based on the findings of this study in small numbers of healthy young adult volunteers and patients with chronic bronchitis, BMS appears to be a promising method for measuring drug concentrations and determining the pharmacokinetic profile of gatifloxacin in bronchial ELF. Additional studies are needed to correlate measured concentrations obtained by BMS with clinical and/or microbiologic outcomes in larger populations.