Pan-cancer molecular tumor board experience with biomarker-driven precision immunotherapy.

Despite remarkable responses to immune checkpoint blockade (ICB) in some advanced cancers, most patients do not benefit, perhaps due to the complexity of tumor/immune/genome interactions. We implemented a multidisciplinary Molecular Tumor Board (MTB) that reviewed multi-omic cancer characteristics to develop N-of-One therapies for patients in the pan-cancer, advanced, refractory setting. This study evaluates the experience of 80 patients who were presented to the MTB and received a treatment regimen that included ICB. Overall, 60/80 patients (75%) who received ICB following MTB discussion had a high degree of matching between tumor molecular characteristics, including ICB biomarkers (reflected by a high Matching Score (≥50%)) and therapy administered. Patients with high versus low Matching Score experienced significantly longer median progression-free survival (6.4 vs. 3.0 months; p = 0.011) and median overall survival (15.3 vs. 4.7 months; p = 0.014) and higher clinical benefit rates (stable disease ≥6 months/partial response/complete response) (53% vs. 21%, p = 0.019). Although most patients (52/80 (65%)) received a personalized combination therapy (e.g., targeted, hormonal, chemotherapy, or a second immunotherapy agent), administering >1 drug was not associated with outcome. Only degree of matching and age, but no other variables, including individual biomarkers (e.g., microsatellite status, tumor mutational burden, or PD-L1 status), were independently correlated with outcome. In the pan-cancer setting, the MTB facilitated a precision medicine strategy to match therapeutic regimens that included ICB alone or combined with matched targeted drugs to patients with advanced malignancy, which was associated with improved clinical outcomes.

Precision medicine-based therapies in advanced colorectal cancer: The University of California San Diego Molecular Tumor Board experience.

Treatment for advanced colorectal cancer is often limited by complex molecular profiles, which promote resistance to systemic agents and targeted monotherapies. Recent studies suggest that a personalized, combinatorial approach of matching drugs to tumor alterations may be more effective. We implemented a precision medicine strategy by forming a Molecular Tumor Board (MTB), a multidisciplinary team of clinicians, scientists, bioinformaticians and geneticists. The MTB integrated molecular profiling information and patient characteristics to develop N-of-One treatments for 51 patients with advanced colorectal cancer. All patients had metastatic disease and 63% had received ≥ 3 prior therapy lines. Overall, 34/51 patients (67%) were matched to ≥ 1 drug recommended by the MTB based on individual tumor characteristics, whereas 17/51 (33%) patients received unmatched therapies. Patients who received matched therapy demonstrated significantly longer progression-free survival (hazard ratio [HR], 0.41; 95% confidence interval [CI], 0.21-0.81; P = 0.01) and a trend towards higher clinical benefit rates (41% vs. 18%, P = 0.058) (all multivariate) compared to patients receiving unmatched therapy. The MTB facilitated personalized matching of drugs to tumor characteristics, which was associated with improved progression-free survival in patients with advanced colorectal cancer.

Case series of outcomes in advanced cancer patients with single pathway alterations receiving N-of-One therapies.

Though advanced cancers generally display complex molecular portfolios, there is a subset of patients whose malignancies possess only one genomic alteration or alterations in one oncogenic pathway. We assess how N-of-One therapeutic strategies impact outcomes in these patients. From 12/2012 to 9/2018, 429 therapy-evaluable patients with diverse treatment-refractory cancers were presented at Molecular Tumor Boards at Moores Cancer Center at UC San Diego. The clinical benefit rate, defined by RECIST1.1, was assessed for patients with solid tumors who underwent next-generation sequencing (NGS) profiling revealing one genomic or pathway alteration, subsequently managed with N-of-One therapies. Nine of 429 patients (2.1%) met evaluation criteria. Using matched therapy indicated by NGS, the clinical benefit rate (stable disease ≥ 6 months/partial/complete response) was 66.7%. Median progression-free survival was 11.3 months (95% CI: 3.4-not evaluable). Thus, a small subset of diverse cancers has single pathway alterations on NGS testing. These patients may benefit from customized therapeutic matching.

Real-World Data From a Molecular Tumor Board: Improved Outcomes in Breast and Gynecologic Cancers Patients With Precision Medicine.

PURPOSE: Next-generation sequencing is increasingly used in gynecologic and breast cancers. Multidisciplinary Molecular Tumor Board (MTB) may guide matched therapy; however, outcome data are limited. We evaluate the effect of the degree of matching of tumors to treatment as well as compliance to MTB recommendations on outcomes. METHODS: Overall, 164 patients with consecutive gynecologic and breast cancers presented at MTB were assessed for clinicopathologic data, next-generation sequencing results, MTB recommendations, therapy received, and outcomes. Matching score (MS), defined as percentage of alterations targeted by treatment over total pathogenic alterations, and compliance to MTB recommendations were analyzed in context of oncologic outcomes. RESULTS: Altogether, 113 women were evaluable for treatment after MTB; 54% received matched therapy. Patients with MS ≥ 40% had higher overall response rate (30.8% v 7.1%; P = .001), progression-free survival (PFS; hazard ratio [HR] 0.51; 95% CI, 0.31 to 0.85; P = .002), and a trend toward improved overall survival (HR 0.64; 95% CI, 0.34 to 1.25; P = .082) in univariate analysis. The PFS advantage remained significant in multivariate analysis (HR 0.5; 95% CI, 0.3 to 0.8; P = .006). Higher MTB recommendation compliance was significantly associated with improved median PFS (9.0 months for complete; 6.0 months for partial; 4.0 months for no compliance; P = .004) and overall survival (17.1 months complete; 17.8 months partial; 10.8 months none; P = .046). Completely MTB-compliant patients had higher MS (P < .001). In multivariate analysis comparing all versus none MTB compliance, overall response (HR 9.5; 95% CI, 2.6 to 35.0; P = .001) and clinical benefit (HR 8.8; 95% CI, 2.4 to 33.2; P = .001) rates were significantly improved with higher compliance. CONCLUSION: Compliance to MTB recommendations resulted in higher degrees of matched therapy and correlates with improved outcomes in patients with gynecologic and breast cancers.

Comparing Inhaler Use Technique Based on Inhaler Type in Elderly Patients with Respiratory Disease.

BACKGROUND: The aim of this study was to investigate inhaler device handling in elderly patients. Inhaler devices with respect to misuse and error correction were also compared. METHODS: Inhaler use technique was assessed using standardized checklists at the first visit and 3-month follow-up visit after retraining. The primary outcome was difference in the acceptable use ratio among inhaler devices. Secondary outcomes included differences in error correction, the most common step of misuse, and factors affecting the accuracy of inhaler use. RESULTS: A total of 251 patients (mean age, 76.4 years) were included. The handling of 320 devices was assessed in the study. All patients had been trained before. However, only 24.7% of them used inhalers correctly. Proportions of acceptable use for Evohaler, Respimat, Turbuhaler, Ellipta, and Breezhaler/Handihaler were 38.7%, 50.0%, 61.4%, 60.8%, and 43.2%, respectively (p=0.026). At the second visit, the acceptable use ratio had increased. There were no significant differences among inhaler types (Evohaler, 63.9%; Respimat, 86.1%; Turbuhaler, 74.3%; Ellipta, 64.6%; and Breezhaler/Handihaler, 65.3% [p=0.129]). In multivariate analysis, body mass index, Turbuhaler, and Ellipta showed positive correlations with acceptable use of inhalers, whereas Chronic Obstructive Pulmonary Disease Assessment Test score showed a negative correlation. CONCLUSION: Although new inhalers have been developed, the accuracy of inhaler use remains low. Elderly patients showed more errors when using pressurized metered-dose inhalers than using dry powder inhalers and soft-mist inhalers. However, there were no significant differences in misuse among inhaler devices after individual training. Results of this study suggests that repeat training is more important than inhaler type.

Real-world data from a molecular tumor board demonstrates improved outcomes with a precision N-of-One strategy.

Next-generation sequencing (NGS) can identify novel cancer targets. However, interpreting the molecular findings and accessing drugs/clinical trials is challenging. Furthermore, many tumors show resistance to monotherapies. To implement a precision strategy, we initiated a multidisciplinary (basic/translational/clinical investigators, bioinformaticians, geneticists, and physicians from multiple specialties) molecular tumor board (MTB), which included a project manager to facilitate obtaining clinical-grade biomarkers (blood/tissue NGS, specific immunohistochemistry/RNA expression including for immune-biomarkers, per physician discretion) and medication-acquisition specialists/clinical trial coordinators/navigators to assist with medication access. The MTB comprehensively reviewed patient characteristics to develop N-of-One treatments implemented by the treating physician's direction under the auspices of a master protocol. Overall, 265/429 therapy-evaluable patients (62%) were matched to ≥1 recommended drug. Eighty-six patients (20%) matched to all drugs recommended by MTB, including combinatorial approaches, while 38% received physician's choice regimen, generally with unmatched approach/low degree of matching. Our results show that patients who receive MTB-recommended regimens (versus physician choice) have significantly longer progression-free (PFS) and overall survival (OS), and are better matched to therapy. High (≥50%) versus low (<50%) Matching Score therapy (roughly reflecting therapy matched to ≥50% versus <50% of alterations) independently correlates with longer PFS (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.50-0.80; P < 0.001) and OS (HR, 0.67; 95% CI, 0.50-0.90; P = 0.007) and higher stable disease ≥6 months/partial/complete remission rate (52.1% versus 30.4% P < 0.001) (all multivariate). In conclusion, patients who receive MTB-based therapy are better matched to their genomic alterations, and the degree of matching is an independent predictor of improved oncologic outcomes including survival.

Thromboembolism in Mycobacterium tuberculosis Infection: Analysis and Literature Review.

BACKGROUND: Tuberculosis is associated with hypercoagulation; however, there are few reports of cases thromboembolism and tuberculosis at the same time in the real world. The purpose of this study was to report the incidence and clinical course of thromboembolism in patients diagnosed with tuberculosis. MATERIALS AND METHODS: We retrospectively analyzed the data of patients who were diagnosed with both tuberculosis and thromboembolism including pulmonary thromboembolism (PTE) or deep vein thrombosis (DVT) at Seoul National University Boramae Medical Center from January 2000 through March 2015. RESULTS: Among the 7905 tuberculosis patients, 49 (0.6%) exhibited PTE, DVT, or both at or after the time of tuberculosis diagnosis. All patients treated for tuberculosis started with isoniazid, ethambutol, rifampicin, and pyrazinamide. Eight patients were switched to treatment with second-line medication because of resistance or adverse events. About half of the patients (n = 21, 44.7%) had thrombosis at the time of tuberculosis diagnosis. Of 48 patients treated for thromboembolism, 36 received warfarin. A total of 20 patients improved symptom caused by thrombosis, and 10 patients were confirmed cure by image study such as computed tomography or doppler ultrasonography. Eight patients who were treated with warfarin had persistent thrombosis. Five patients (10.2%) experienced major bleeding that required hospitalization. All of these bleeding events were associated with warfarin therapy. CONCLUSIONS: Careful attention to PTE/DVT is needed at the time of diagnosis of tuberculosis and during anti-tuberculosis therapy. Warfarin therapy administered with anti-tuberculosis medication requires frequent monitoring to prevent major bleeding.

Pleural Effusion in Multiple Myeloma: Characteristics and Practice Patterns.

In many Asian countries battling with the double burden of increasing noninfectious diseases on top of infectious diseases, multiple myeloma (MM) patients presenting with pleural effusion (PE) pose a great diagnostic challenge. Thus, we aimed to analyze the clinical features and practice patterns of such patients. This is a multicenter retrospective study of newly diagnosed MM patients between January 2011 and December 2015. Among 575 MM patients diagnosed during the study period, 80 (13.9%) that were associated with PE were identified and analyzed. The most common cause of PE was parapneumonic (25%), followed by reactive (18.8%). Higher CRP levels and leukocytosis were indicators of parapneumonic PE. There were 7 (8.8%) with myelomatous PE and 2 (2.5%) with tuberculosis. Fifty-six patients underwent additional examinations to determine the exact cause of effusion; 28 patients received computed tomography (CT) of the chest, 5 patients underwent thoracentesis/biopsy, and 23 patients underwent both CT and thoracentesis/biopsy. On the other hand, 24 patients did not undergo additional analyses but were treated empirically. Real-world analyses of practice patterns in MM patients with PE showed the suboptimal use of invasive procedures to determine the exact cause of PE. Since reversible causes and tuberculosis pleurisy are not uncommon, invasive procedures should be actively incorporated as needed.

Intermediate risk of multidrug-resistant organisms in patients who admitted intensive care unit with healthcare-associated pneumonia.

BACKGROUND/AIMS: Healthcare-associated pneumonia (HCAP) was proposed asa new pneumonia category in 2005, and treatment recommendations includebroad-spectrum antibiotics directed at multidrug-resistant (MDR) pathogens.However, this concept continues to be controversial, and microbiological data arelacking for HCAP patients in the intensive care unit (ICU). This study was conductedto determine the rate and type of antibiotic-resistant organisms and theclinical outcomes in patients with HCAP in the ICU, compared to patients withcommunity-acquired pneumonia (CAP) or hospital-acquired pneumonia (HAP). METHODS: We conducted a retrospective cohort analysis of patients with pneumonia(n = 195) who admitted to medical ICU in tertiary teaching hospital fromMarch 2011 to February 2013. Clinical characteristics, microbiological distributions,treatment outcomes, and prognosis of HCAP (n = 74) were compared tothose of CAP (n = 75) and HAP (n = 46). RESULTS: MDR pathogens were significantly higher in HCAP patients (39.1%) thanin CAP (13.5%) and lower than in HAP (79.3%, p < 0.001). The initial use of inappropriateantibiotic treatment occurred more frequently in the HCAP (32.6%) andHAP (51.7%) groups than in the CAP group (11.8%, p = 0.006). There were no differencesin clinical outcomes. The significant prognostic factors were pneumoniaseverity and treatment response. CONCLUSIONS: MDR pathogens were isolated in HCAP patients requiring ICU admissionat intermediate rates between those of CAP and HAP.

Predictors of prolonged stay in patients with community-acquired pneumonia and complicated parapneumonic effusion.

BACKGROUND AND OBJECTIVE: Development of CPE in CAP is associated with prolonged hospital stay and it may increase the morbidity and mortality. We aimed to identify microbiological and clinical factors that predicate a prolonged hospital admission in patients treated with a tube thoracostomy to control CPE. METHODS: This retrospective cohort included patients with CPE requiring chest tube drainage in a tertiary referral Korean hospital from 1 January 2004 to 30 July 2012. After dichotomous grouping according to the mean duration of hospital stay, clinical, laboratory and microbiological parameters were compared. RESULTS: The final analysis included 158 patients with CPE. The majority were male (130, 85.0%), and the mean age was 62.8 years. The mean duration of hospital stay was 17.7 (±10.2) days. The mean duration of chest tube drainage was 9.6 (±6.7) days. Streptococcus viridans (48.4%) was the most common pathogen. Intrapleural fibrinolysis was performed in 85 (53.8%); additional tube insertion was needed in 40 (25.3%) patients. In the multivariate analysis after adjusting for covariates, a prolonged hospital stay was associated with fever (aOR: 3.42, P = 0.02), lower PaO2 (aOR: 4.89, P = 0.007) and haemoglobin (aOR: 4.90, P = 0.003) levels, and an increased blood neutrophil fraction (aOR: 3.83, P = 0.01) on admission as well as the identification of microbes in CPE (aOR: 4.14, P = 0.03), and ineffective pleural drainage (aOR: 3.28, P = 0.03). CONCLUSIONS: This study suggests that physicians should note the clinical symptoms and laboratory findings of severe infection and effectiveness of pleural drainage to predicate which patients with a CAP needing thoracostomy for CPE will have a prolonged hospital stay.

Overweight in mice and enhanced adipogenesis in vitro are associated with lack of the hedgehog coreceptor boc.

Obesity arises from a combination of genetic, environmental, and behavioral factors. However, the processes that regulate white adipose tissue (WAT) expansion at the level of the adipocyte are not well understood. The Hedgehog (HH) pathway plays a conserved role in adipogenesis, inhibiting fat formation in vivo and in vitro, but it has not been shown that mice with reduced HH pathway activity have enhanced adiposity. We report that mice lacking the HH coreceptor BOC displayed age-related overweight and excess WAT. They also displayed alterations in some metabolic parameters but normal food intake. Furthermore, they had an exacerbated response to a high-fat diet, including enhanced weight gain and adipocyte hypertrophy, livers with greater fat accumulation, and elevated expression of genes related to adipogenesis, lipid metabolism, and adipokine production. Cultured Boc(-/-) mouse embryo fibroblasts showed enhanced adipogenesis relative to Boc(+/+) cells, and they expressed reduced levels of HH pathway target genes. Therefore, a loss-of-function mutation in an HH pathway component is associated with WAT accumulation and overweight in mice. Variant alleles of such HH regulators may contribute to WAT accumulation in human individuals with additional genetic or lifestyle-based predisposition to obesity.

Inhibitory effects of ginsenoside-rb2 on nicotinic stimulation-evoked catecholamine secretion.

The aim of the present study was to investigate whether ginsenoside-Rb2 (Rb2) can affect the secretion of catecholamines (CA) in the perfused model of the rat adrenal medulla. Rb2 (3~30 µM), perfused into an adrenal vein for 90 min, inhibited ACh (5.32 mM)-evoked CA secretory response in a dose- and time-dependent fashion. Rb2 (10 µM) also time-dependently inhibited the CA secretion evoked by DMPP (100 µM, a selective neuronal nicotinic receptor agonist) and high K(+) (56 mM, a direct membrane depolarizer). Rb2 itself did not affect basal CA secretion (data not shown). Also, in the presence of Rb2 (50 µg/mL), the secretory responses of CA evoked by veratridine (a selective Na(+) channel activator (50 µM), Bay-K-8644 (an L-type dihydropyridine Ca(2+) channel activator, 10 µM), and cyclopiazonic acid (a cytoplasmic Ca(2+)-ATPase inhibitor, 10 µM) were significantly reduced, respectively. Interestingly, in the simultaneous presence of Rb2 (10 µM) and L-NAME (an inhibitor of NO synthase, 30 µM), the inhibitory responses of Rb2 on ACh-evoked CA secretory response was considerably recovered to the extent of the corresponding control secretion compared with the inhibitory effect of Rb2-treatment alone. Practically, the level of NO released from adrenal medulla after the treatment of Rb2 (10 µM) was greatly elevated compared to the corresponding basal released level. Collectively, these results demonstrate that Rb2 inhibits the CA secretory responses evoked by nicotinic stimulation as well as by direct membrane-depolarization from the isolated perfused rat adrenal medulla. It seems that this inhibitory effect of Rb2 is mediated by inhibiting both the influx of Ca(2+) and Na(+) into the adrenomedullary chromaffin cells and also by suppressing the release of Ca(2+) from the cytoplasmic calcium store, at least partly through the increased NO production due to the activation of nitric oxide synthase, which is relevant to neuronal nicotinic receptor blockade.

Diagnostic yield of bronchial washing fluid analysis for hemoptysis in patients with bronchiectasis.

PURPOSE: Bronchiectasis is the main cause of hemoptysis. When patients with bronchiectasis develop hemoptysis, clinicians often perform bronchoscopy and bronchial washing to obtain samples for microbiological and cytological examinations. Bronchial washing fluids were analyzed from patients with bronchiectasis who developed hemoptysis, and the clinical impacts of these analyses were examined. MATERIALS AND METHODS: A retrospective observational study of patients who underwent fiberoptic bronchoscopy for hemoptysis in Seoul National University Bundang Hospital, a university affiliated tertiary referral hospital, between January 2006 and December 2010 were reviewed. Among them, patients who had bronchiectasis confirmed by computed tomography and had no definite cause of hemoptysis other than bronchiectasis were reviewed. The demographic characteristics, bronchoscopy findings, microbiological data, pathology results and clinical courses of these patients were retrospectively reviewed. RESULTS: A total of 130 patients were reviewed. Bacteria, non-tuberculous mycobacteria (NTM), and Mycobacterium tuberculosis were isolated from bronchial washing fluids of 29.5%, 21.3%, and 0.8% patients, respectively. Suspected causal bacteria were isolated only from bronchial washing fluid in 19 patients, but this analysis led to antibiotics change in only one patient. Of the 27 patients in whom NTM were isolated from bronchial washing fluid, none of these patients took anti-NTM medication during the median follow-up period of 505 days. Malignant cells were not identified in none of the patients. CONCLUSION: Bronchial washing is a useful method to identify microorganisms when patients with bronchiectasis develop hemoptysis. However, these results only minimally affect clinical decisions.

The impact of lifestyle behaviors on the acquisition of pandemic (H1N1) influenza infection: a case-control study.

PURPOSE: The purpose of this study was to evaluate the effects of lifestyle behaviors and health habits on the risk for acquiring pandemic influenza (H1N1) virus infection. MATERIALS AND METHODS: We conducted a case-control study in a secondary care hospital in South Korea between November 2009 and August 2010. We enrolled patients with H1N1 infection, as confirmed by a positive result of the real-time reverse transcriptase polymerase chain reaction assay; for each patient, we enrolled 4 age- and gender-matched controls with no history of H1N1 infection or severe acute respiratory illness during the H1N1 pandemic in South Korea (1:4 match). RESULTS: During the study period, 33 cases and 132 age- and gender-matched controls were enrolled. The case group had a higher percentage of current smokers (p<0.01), fewer subjects reporting regular physical activity (p=0.03), or regular vitamin supplementation (p<0.01), and more subjects reporting a higher annual incidence of the common cold (p=0.048) as compared to the control group. In the multivariable analysis, 2 factors were independently associated with the acquisition of H1N1 infection: current smoking [adjusted odds ratio (OR)=5.53; 95% confidence interval (CI), 1.60-19.16; p<0.01] and a higher annual incidence of the common cold (adjusted OR=1.24; 95% CI, 1.002-1.53; p=0.048). CONCLUSION: A current smoking status and a history of frequent colds were associated with an increased risk of acquiring H1N1 infection.

Multivariate analysis of prognostic factors in patients with pulmonary actinomycosis.

BACKGROUND: There have been few studies of pulmonary actinomycosis, which is an uncommon anaerobic infection. Consequently, the optimal therapeutic regimen, appropriate duration of treatment, long-term prognosis, and factors predicting prognosis are not well established. METHODS: We retrospectively reviewed the medical records of histopathologically confirmed cases of pulmonary actinomycosis seen between November 2003 and December 2012. RESULTS: The study included 68 patients with a mean age of 58.4 ± 11.6 years. Of the 68, initial surgery was performed in 15 patients (22.1%), while the remaining 53 (77.9%) received antibiotic therapy initially. In the initial antibiotic group, 45/53 (84.9%) were cured without relapse (median antibiotic duration 5.3 months). 5/53 (9.4%) patients were refractory medically (median antibiotic duration 9.7 months), and 3/53 (5.7%) experienced a recurrence (median time to relapse 35.3 months). In the initial surgery group, 14/15 (93.3%) were cured and treatment failure occurred in one (6.7%). In the multivariate analysis, the absence of an antibiotic response at 1 month was the only independent factor associated with a poor treatment outcome, with an adjusted odds ratio of 49.2 (95% CI, 3.34-724.30). There was no significant difference in treatment outcome based on the size of the parenchymal lesion, comorbidities, whether intravenous antibiotics were used, antibiotic therapy duration, or whether the initial treatment was surgical. CONCLUSIONS: Antibiotic treatment with or without surgery was effective for treatment of pulmonary actinomycosis. Nevertheless, treatment failure or recurrence occurred in a considerable proportion of patients, especially those resistant to the initial antibiotic treatment.

Comparison of clinical characteristics between patients with ALK-positive and EGFR-positive lung adenocarcinoma.

BACKGROUND: The discovery of the chromosomal fusion product of anaplastic lymphoma kinase (ALK) with echinoderm microtubule-associated protein-like 4 (EML4) (EML4-ALK) has changed the treatment paradigm of lung cancer. In this study, we analysed the clinical characteristics, including bronchoscopic findings, of patients with EML4-ALK-positive adenocarcinoma and compared them with those of EGFR mutation-positive patients. MATERIALS AND METHODS: In this retrospective cohort study, the clinical characteristics and bronchoscopic findings of patients with ALK fusion-positive lung cancers were compared to patients with EGFR-mutant lung cancers. RESULTS: Among the 440 patients with adenocarcinoma of lung screened for this study, 46 (10.4%) harboured the EML4-ALK fusion, 90 (20.4%) harboured an activating EGFR mutation, and all had adenocarcinoma. In univariate analysis, ALK-positive patients were significantly younger than EGFR-positive patients (p = 0.004) and were more commonly male (p = 0.021). An initial status of stage IV metastatic cancer was more frequently noted in EML4-ALK-positive patients (p = 0.012), with initial brain metastasis frequently observed (p = 0.007). Compared with EGFR-positive patients, EML4-ALK-positive patients were significantly more likely to have positive bronchoscopic findings, which suggested a more centralized origin (p = 0.001). EML4-ALK patients also had significantly more positive bronchoscopic findings and were more commonly male in multivariate analysis. CONCLUSIONS: The EML4-ALK fusion defines a new molecular subset of NSCLC that has distinct clinical and bronchoscopic findings suggesting more proximal origin when compared to tumours harbouring EGFR mutations.

CD4(+)FoxP3(+) T regulatory cells in drug-susceptible and multidrug-resistant tuberculosis.

Regulatory T cells (Treg) increase in active tuberculosis (TB). However, whether Treg-mediated immune suppression affect the susceptibility to active TB or development of multidrug-resistant (MDR) TB is not yet clear. We compared circulatory Treg frequencies in drug susceptible (DS) and MDR TB before and after anti-TB treatment. Circulatory Treg frequencies were measured in blood samples from 33 DS TB, 7 mycobacterial culture-positive active MDR TB, 16 stable MDR TB who had been culture negative for at least 6 months, and 14 healthy controls before and after treatment. Treg frequency was measured by flow cytometry using cell-surface marker CD4 and intracellular marker FoxP3. Treg frequency was higher in DS TB and active MDR TB patients than in healthy controls (p < 0.05), with no significant difference between the former. Treg frequency was higher in patients with sputum acid-fast bacilli smear-positive TB than in patients with smear-negative TB, but the increase did not correlate with the radiologic extent of TB or presence of a cavity. After successful treatment, Treg decreased to control levels in DS TB and MDR TB patents. The pattern of change, in which Treg frequency increased during active infection and normalized to control levels after successful treatment, was similar in DS and MDR TB patients.

Measurement of fractional exhaled nitric oxide in stable bronchiectasis.

BACKGROUND: Fractional exhaled nitric oxide (FeNO) can be measured easily, rapidly, and noninvasively for the assessment of airway inflammation, particularly mediated by eosinophil, such as asthma. In bronchiectasis (BE), the pathogenesis has been known as chronic airway inflammation and infection with abnormal airway dilatation; however, there are little studies to evaluate the role of FeNO in BE. METHODS: From March 2010 to February 2012, 47 patients with BE, diagnosed by high resolution computed tomography (HRCT), performed FeNO, compared with asthma and chronic obstructive pulmonary disease (COPD). All patients carried out a complete blood count including eosinophil count, chemistry, sputum examination, and spirometry, if indicated. A retrospective analysis was performed to elucidate the clinical role of FeNO in BE patients. RESULTS: The mean FeNO levels in patients with BE was 18.8±1.5 part per billion (ppb), compared to 48.0±6.4 and 31.0±4.3 in those with asthma and COPD, respectively (p<0.001). The FeNO levels tended to increase along with the disease severity scores by HRCT; however, it was statistically not significant. FeNO in BE with a co-infection of nontuberculous mycobacteria was the lowest at 17.0±3.5 ppb among the study population. CONCLUSION: FeNO in BE was lower than other chronic inflammatory airway diseases, particularly compared with asthma. For clinical application of FeNO in BE, more large-scaled, prospective studies should be considered.

Influence of Fimasartan (a Novel AT(1) Receptor Blocker) on Catecholamine Release in the Adrenal Medulla of Spontaneously Hypertensive Rats.

The aim of this study was to determine whether fimasartan, a newly developed AT(1) receptor blocker, can affect the CA release in the isolated perfused model of the adrenal medulla of spontaneously hypertensive rats (SHRs). Fimasartan (5~50 µM) perfused into an adrenal vein for 90 min produced dose- and time-dependently inhibited the CA secretory responses evoked by ACh (5.32 mM), high K(+) (56 mM, a direct membrane depolarizer), DMPP (100 µM) and McN-A-343 (100 µM). Fimasartan failed to affect basal CA output. Furthermore, in adrenal glands loaded with fimasartan (15 µM), the CA secretory responses evoked by Bay-K-8644 (10 µM, an activator of L-type Ca(2+) channels), cyclopiazonic acid (10 µM, an inhibitor of cytoplasmic Ca(2+)-ATPase), and veratridine (100 µM, an activator of Na(+) channels) as well as by angiotensin II (Ang II, 100 nM), were markedly inhibited. In simultaneous presence of fimasartan (15 µM) and L-NAME (30 µM, an inhibitor of NO synthase), the CA secretory responses evoked by ACh, high K(+), DMPP, Ang II, Bay-K-8644, and veratridine was not affected in comparison of data obtained from treatment with fimasartan (15 µM) alone. Also there was no difference in NO release between before and after treatment with fimasartan (15 µM). Collectively, these experimental results suggest that fimasartan inhibits the CA secretion evoked by Ang II, and cholinergic stimulation (both nicotininc and muscarinic receptors) as well as by membrane depolarization from the rat adrenal medulla. It seems that this inhibitory effect of fimasartan may be mediated by blocking the influx of both Na(+) and Ca(2+) through their ion channels into the rat adrenomedullary chromaffin cells as well as by inhibiting the Ca(2+) release from the cytoplasmic calcium store, which is relevant to AT(1) receptor blockade without NO release.

Genetic blockade of insulin-like growth factor-1 receptor via recombinant adenovirus in lung cancer can be enhanced by the histone deacetylase inhibitor, vorinostat.

BACKGROUND: Many approaches have been suggested as anti-tumor therapy for targeting insulin-like growth factor 1 receptor (IGF-1R), such as monoclonal antibodies and tyrosine kinase inhibitor. We introduced recombinant adenoviruses expressing antisense, dominant negative or short hairpin RNA to IGF-1R. Moreover, we demonstrated that histone deacetylase inhibitor (vorinostat) can increase the transduction efficiency of adenoviruses by increasing CAR-induced transduction and by enhancing the transcription of the adenoviral transgene. In the present study, we showed that the combination of ad-sh (short hairpin) IGF-1R with vorinostat leads to a synergistic enhancement of IGF-1R blockade. METHODS: We measured the change in IGF-1R upon cotreatment with vorinostat and ad-shIGF-1R. Changes in transduction efficiency of ad-shIGF-1R were measured by fluorescent microscopy. Changes in apoptotic proportion and cell survival after the cotreatment were measured by the sub-G1 assay and cell counts. The effect of nuclear factor (NF)-κB activation was also measured by NF-κB p65 activation enzyme-linked immunosorbent assay. Drug interactions were analyzed upon cotreatment with ad-shIGF-1R, vorinostat and cisplatin. RESULTS: Combined treatment of ad-shIGF-1R and vorinostat synergistically suppressed the IGF-1R expression in lung cancer cell lines and also increased the transduction efficiency of ad-shIGF-1R. Ad-shIGF-1R and vorinostat cotreatment increased apoptotic cell death and synergistically suppressed cell growth compared to ad-shIGF-1R or vorinostat treatment alone. Vorinostat suppressed NF-κB activation, which was activated by ad-shIGF-1R. Moreover, triple combination of ad-shIGF-1R, vorinostat and cisplatin demonstrated synergistic cytotoxicity on lung cancer cells. CONCLUSIONS: Vorinostat enhanced the blocking capability of ad-shIGF-1R. The combined treatment of vorinostat and ad-sh-IGF-1R appears to have promising potential as a new therapeutic approach for lung cancer.