Distinctive patterns of pulmonary function change according to baseline lung volume and diffusing capacity.

SETTING: Multicentre retrospective study in South Korea.OBJECTIVE: To longitudinally evaluate changes in lung volume and diffusing capacity for carbon monoxide (DLCO) with forced expiratory volume in 1 sec (FEV1).DESIGN: A total of 155 patients with chronic obstructive pulmonary disease (COPD), whose pulmonary function parameters were measured annually for 5 years, were selected from a prospective cohort in South Korea. A random coefficients model was used to estimate mean annual FEV1, lung volume parameter and DLCO change rates.RESULTS: Patients were classified into four groups based on baseline DLCO and residual volume/total lung capacity (RV/TLC) measurements. The annual FEV1 decline rate was greater in patients with low DLCO than in those with normal DLCO, with the greatest decline occurring in patients with low DLCO and normal RV/TLC. RV and RV/TLC declined in patients with high RV/TLC, whereas these increased in patients with normal RV/TLC. DLCO decreased longitudinally in all four groups, with the greatest decline occurring in patients with normal DLCO and normal RV/TLC.CONCLUSIONS: Different subgroups of patients with COPD exhibited distinctive pulmonary function change patterns. Baseline DLCO and RV/TLC may be used as physiological markers to predict long-term changes in pulmonary function.

Diagnostic value of bronchoalveolar lavage and bronchial washing in sputum-scarce or smear-negative cases with suspected pulmonary tuberculosis: a randomized study.

OBJECTIVES: Bronchoalveolar lavage (BAL) and bronchial washing (BW) are two major methods used to obtain high-quality respiratory specimens from patients with suspected pulmonary tuberculosis (TB) but a sputum-scarce or smear-negative status. We aimed to compare the value of BAL and BW in the diagnosis of TB in such patients. METHODS: We enrolled patients with suspected pulmonary TB but with a sputum-scarce or smear-negative status who were referred for bronchoscopy between October 2013 and January 2016. Participants were randomized into the BAL and BW groups for evaluation. The primary outcome was the diagnostic yield for TB detection. Secondary outcomes included culture positivity, positivity of nucleic acid amplification tests (NAATs) for Mycobacterium tuberculosis and procedure-related complications. RESULTS: A total of 94 patients were assessed and 91 (43 in the BAL group, 48 in the BW group) were analysed. Twenty-one patients (48.8%) in the BAL group and 30 (62.5%) in the BW group had a final diagnosis of pulmonary TB. The detection rate of M. tuberculosis by culture or NAAT was significantly higher in BAL specimens than in BW specimens (85.7% vs 50.0%, p 0.009). The procedure-related complications were hypoxic events, 2/43 (4.7%) in the BAL group and 5/48 (10.4%) in the BW group; and post-bronchoscopic fever, 3/43 (7.0%) in the BAL group and 4/48 (8.3%) in the BW group. DISCUSSION: As long as it is tolerable, BAL rather than BW, should be used to obtain specimens for the diagnosis of pulmonary TB in sputum-scarce or smear-negative cases.

Hyperprogressive disease during PD-1/PD-L1 blockade in patients with non-small-cell lung cancer.

BACKGROUND: Immune checkpoint blockade with Programmed cell death 1 (PD-1)/PD-L1 inhibitors has been effective in various malignancies and is considered as a standard treatment modality for patients with non-small-cell lung cancer (NSCLC). However, emerging evidence show that PD-1/PD-L1 blockade can lead to hyperprogressive disease (HPD), a flair-up of tumor growth linked to dismal prognosis. This study aimed to evaluate the incidence of HPD and identify the determinants associated with HPD in patients with NSCLC treated with PD-1/PD-L1 blockade. PATIENTS AND METHODS: We enrolled patients with recurrent and/or metastatic NSCLC treated with PD-1/PD-L1 inhibitors between April 2014 and November 2018. Clinicopathologic variables, dynamics of tumor growth, and treatment outcomes were analyzed in patients with NSCLC who received PD-1/PD-L1 blockade. HPD was defined according to tumor growth kinetics (TGK), tumor growth rate (TGR), and time to treatment failure (TTF). Immunophenotyping of peripheral blood CD8+ T lymphocytes was conducted to explore the potential predictive biomarkers of HPD. RESULTS: A total of 263 patients were analyzed. HPD was observed in 55 (20.9%), 54 (20.5%), and 98 (37.3%) patients according to the TGK, TGR, and TTF. HPD meeting both TGK and TGR criteria was associated with worse progression-free survival [hazard ratio (HR) 4.619; 95% confidence interval (CI) 2.868-7.440] and overall survival (HR, 5.079; 95% CI, 3.136-8.226) than progressive disease without HPD. There were no clinicopathologic variables specific for HPD. In the exploratory biomarker analysis with peripheral blood CD8+ T lymphocytes, a lower frequency of effector/memory subsets (CCR7-CD45RA- T cells among the total CD8+ T cells) and a higher frequency of severely exhausted populations (TIGIT+ T cells among PD-1+CD8+ T cells) were associated with HPD and inferior survival rate. CONCLUSION: HPD is common in NSCLC patients treated with PD-1/PD-L1 inhibitors. Biomarkers derived from rationally designed analysis may successfully predict HPD and worse outcomes, meriting further investigation of HPD.

PIN1 is a new therapeutic target of craniosynostosis.

Gain-of-function mutations in fibroblast growth factor receptors (FGFRs) cause congenital skeletal anomalies, including craniosynostosis (CS), which is characterized by the premature closure of craniofacial sutures. Apert syndrome (AS) is one of the severest forms of CS, and the only treatment is surgical expansion of prematurely fused sutures in infants. Previously, we demonstrated that the prolyl isomerase peptidyl-prolyl cis-trans isomerase interacting 1 (PIN1) plays a critical role in mediating FGFR signaling and that Pin1+/- mice exhibit delayed closure of cranial sutures. In this study, using both genetic and pharmacological approaches, we tested whether PIN1 modulation could be used as a therapeutic regimen against AS. In the genetic approach, we crossbred Fgfr2S252W/+, a mouse model of AS, and Pin1+/- mice. Downregulation of Pin1 gene dosage attenuated premature cranial suture closure and other phenotypes of AS in Fgfr2S252W/+ mutant mice. In the pharmacological approach, we intraperitoneally administered juglone, a PIN1 enzyme inhibitor, to pregnant Fgfr2S252W/+ mutant mice and found that this treatment successfully interrupted fetal development of AS phenotypes. Primary cultured osteoblasts from Fgfr2S252W/+ mutant mice expressed high levels of FGFR2 downstream target genes, but this phenotype was attenuated by PIN1 inhibition. Post-translational stabilization and activation of Runt-related transcription factor 2 (RUNX2) in Fgfr2S252W/+ osteoblasts were also attenuated by PIN1 inhibition. Based on these observations, we conclude that PIN1 enzyme activity is important for FGFR2-induced RUNX2 activation and craniofacial suture morphogenesis. Moreover, these findings highlight that juglone or other PIN1 inhibitors represent viable alternatives to surgical intervention for treatment of CS and other hyperostotic diseases.

Bronchial angles are associated with nodular bronchiectatic non-tuberculous mycobacteria lung disease.

BACKGROUND: The nodular bronchiectatic (NB) form of non-tuberculous mycobacteria (NTM) lung disease usually involves the right middle lobe (RML) and the left upper lobe lingular segment. However, the reason underlying this preference is not known. METHODS: Fifty patients with NB NTM lung disease who had both positive NTM culture(s) and NB lesions in the RML or lingular segment on computed tomography (CT) of the chest, and 100 healthy subjects matched for sex, age, height and body weight with normal chest CT, were randomly selected. Using reconstructed curved multiplanar reformation (MPR) images, the lengths, diameters and angles of the RML and lingular bronchi were measured. RESULTS: Of the 150 individuals, 64% were female; the mean age was 55 years. The angles of the bronchi were significantly more acute in patients than in healthy subjects, both in the RML (patients, mean 46.75° ± standard deviation 8.87° vs. healthy subjects, mean 51.73° ± 7.76°; P = 0.001) and in the lingular segments (patients, mean 26.94° ± 8.16° vs. healthy subjects, mean 34.65° ± 9.75°; P < 0.001). In addition, the angles of the bronchi in the involved segments were more acute than those in the non-involved segments, both in the RML and the lingular segments. There were no differences in the lengths and bronchi diameters between groups. CONCLUSIONS: An acute angle (obtuse slope) of RML/lingular bronchi could be an anatomical risk factor for NB NTM lung disease.

Integration of radiotherapy and chemotherapy for abdominal lymph node recurrence in gastric cancer.

PURPOSE: Abdominal lymph node (ALN) recurrence in gastric cancer (GC) is rare and usually unresectable. We investigated the effects of integration of radiotherapy (RT) and chemotherapy against ALN recurrence in GC. METHODS: We retrospectively categorized GC patients with ALN recurrence treated between 2005 and 2013 into two groups: those treated with integration of RT and chemotherapy (RCT) and those who received systemic chemotherapy only (CT). The median follow-up period after ALN recurrence for all patients was 20 months. RESULTS: Of 53 patients, 31 and 22 were in the RCT and CT groups, respectively. Isolated distant failure (DF; 35.5%) without local progression (LP) was the dominant pattern of failure (POF) in the RCT group (median DF-free period, 26 months). LP followed by DF (31.8%) was the dominant POF in the CT group; LP (median LP-free period, 8 months) occurred 10 months earlier than DF (median DF-free period, 18 months). RCT patients had significantly longer median progression-free survival (PFS) compared to CT patients (25 vs. 8 months; P = 0.021). On multivariate analysis, treatment (CT vs. RCT) was an independent prognostic factor for PFS (hazard ratio 2.085; 95% confidence interval 1.073-4.050; P = 0.013). CONCLUSIONS: Integration of RT and chemotherapy achieved long-term local control and prolonged PFS in GC patients with ALN recurrence. Local RT is feasible for treating isolated ALN recurrences.

Locoregional relapse after gastrectomy with D2 lymphadenectomy for gastric cancer.

BACKGROUND: Risk for and site of locoregional relapse have not been well studied in patients undergoing gastrectomy with D2 lymphadenectomy for gastric cancer. METHODS: Patients who had undergone gastrectomy with D2 lymphadenectomy for gastric cancer between 2004 and 2007 were identified from an institutional database. The locoregional relapse rate was estimated by competing risk analysis, and risk groups were derived according to locoregional relapse risk using recursive partitioning analysis (RPA). The locations of nodal relapses were evaluated according to Japanese Classification of Gastric Carcinoma criteria. RESULTS: Some 2618 patients were included. With a median follow-up of 78·0 (range 28·5-122·6) months, relapse was diagnosed in 471 of 2618 patients (18·0 per cent). The cumulative incidence of locoregional relapse at 5 years was 8·5 (95 per cent c.i. 7·4 to 9·6) per cent. The 5-year locoregional recurrence rates for high-risk (N3), intermediate-risk (N1-2) and low-risk (N0) groups were 32·4, 12·3 and 1·7 per cent respectively (P < 0·001). Among patients with regional relapse, 90·4 per cent had involvement outside the D2 dissected area, and the most commonly involved site was station 16b1. This pattern was maintained in the RPA risk groups (P = 0·329). CONCLUSION: Locoregional relapse at 5 years after gastrectomy with D2 lymphadenectomy was 8·5 per cent, and was most often seen outside the D2 dissected area.

Tumor-related leukocytosis is associated with poor radiation response and clinical outcome in uterine cervical cancer patients.

BACKGROUND: To evaluate response to radiation and clinical outcome of uterine cervical cancer patients with tumor-related leukocytosis (TRL) at initial diagnosis and during definitive radiotherapy. PATIENTS AND METHODS: We retrospectively analyzed 2456 patients with stage IA-IVA uterine cervical cancer who received definitive radiotherapy with (37.4%) or without (62.6%) platinum-based chemotherapy between 1986 and 2012. TRL was defined as two or more occurrences of leukocytosis over 9000/µl at the time of diagnosis and during the course of treatment. Locoregional failure-free survival (LFFS) and overall survival (OS) were compared between patients with or without TRL. RESULTS: The median age of all patients was 55 years, and the median follow-up time was 65.1 months. TRL was observed in 398 patients (16%) at initial diagnosis; TRL (+) patients were younger and had larger tumors, advanced stage, and more frequent lymph node metastases (all P < 0.05). TRL (+) patients showed a significantly lower rate of complete remission than TRL (-) patients (89.9% versus 96.3%, respectively, P = 0.042). Ten-year LFFS and OS for all patients were 84% and 78%, respectively. LFFS and OS were significantly lower in TRL (+) patients than TRL (-) patients (10-year LFFS: 69% versus 87% respectively, P < 0.001; 10-year OS: 63% versus 81% respectively P < 0.001). After propensity score matching, LFFS and OS rates in TRL (+) patients remained significantly lower than for TRL (-) patients; this significant difference was also observed on multivariate analysis. Twenty-six percent of patients with locoregional failure (n = 345) were TRL (+) and had significantly poorer median OS (6 versus 12 months, P = 0.001). CONCLUSION: This study reveals the aggressive nature of cervical cancer with TRL and its poor response to radiation therapy. Given the unfavorable prognosis and higher probability of treatment failure, optimal diagnostic and therapeutic approaches and careful monitoring for early detection of recurrence should be considered for these patients.

Determinants of recurrence after successful treatment of Mycobacterium avium complex lung disease.

BACKGROUND: The long-term treatment outcomes of Mycobacterium avium complex (MAC) lung disease (LD) have not been adequately evaluated. OBJECTIVE: We evaluated the determinants of microbiological recurrence after successful treatment for MAC LD. DESIGN: The medical records of 295 MAC LD patients treated with combination chemotherapy from 2004 to 2013 were reviewed. The clinical data, microbiological study results and chest computerised tomography findings were collected for each patient. RESULTS: Ninety-one patients who maintained negative sputum conversion during treatment and had a minimum 10-month follow-up period after treatment were included. The median duration of follow-up was 25 months. Seventy-one (78.0%) patients remained microbiologically disease-free, while 20 (22.0%) had microbiological recurrence after successful treatment. Age, sex and body mass index were not associated with microbiological recurrence. Longer intervals between initial diagnosis and administration of medication (P = 0.024), increased number of involved lobes (P = 0.033) and failure of sputum conversion within 6 months of initiating treatment (P = 0.017) were significantly associated with microbiological recurrence. CONCLUSION: Microbiological recurrence after successful anti-MAC chemotherapy was associated with the time interval between initial diagnosis and administration of medication, number of lobes involved and time to sputum conversion during treatment.

Emphysematous phenotype is an independent predictor for frequent exacerbation of COPD.

SETTING: Frequent exacerbation is an important phenotype in chronic obstructive pulmonary disease (COPD), while emphysema is associated with many comorbidities and lung function decline. OBJECTIVE: To investigate unique features of frequent exacerbators and test the hypothesis that emphysematous phenotype is associated with frequent exacerbations of COPD. METHODS: A total of 380 COPD patients were recruited from 16 hospitals in Korea from June 2005 to April 2012 for analysis. We searched for independent predictors of frequent exacerbators in comparison with non-exacerbators. RESULTS: As the severity of emphysema increased, forced expiratory volume in 1 s (FEV1), and FEV1/FVC (forced volume capacity) worsened; hyperinflationary features characterised by higher total lung capacity (TLC) were observed (P < 0.05). Frequent exacerbators had lower body mass index (BMI), higher St George's Respiratory Questionnaire (SGRQ) scores, higher residual volume (RV)/TLC, more severe airflow limitation (lower FEV1 and FEV1/FVC), lower carbon monoxide diffusion capacity, lower serum protein levels and a higher emphysema index than non-exacerbators (P < 0.05). In multivariate analysis, frequent exacerbators were independently associated with a higher emphysema index, lower serum protein levels and higher RV/TLC (P < 0.05). CONCLUSION: Our data show that the severity of emphysema, severe static hyperinflation and serum lower protein levels are independent predictors of frequent exacerbations in COPD patients.

Risk factors for deterioration of nodular bronchiectatic Mycobacterium avium complex lung disease.

UNLABELLED: SETTING The long-term natural course of Mycobacterium avium complex (MAC) disease with nodular bronchiectasis, the most common pulmonary non-tuberculous mycobacterial disease, is not well described. OBJECTIVE: To identify risk factors for the deterioration of nodular bronchiectatic MAC lung disease over a 5-year follow-up period. DESIGN: Clinical and laboratory data of 67 patients with nodular bronchiectatic MAC lung disease were collected. Chest computerised tomographic images were used to count the number of lung segments involved at diagnosis and measure subcutaneous fat thickness during follow-up. RESULTS: The 34 patients who showed deterioration had significantly lower body mass index (BMI) (P = 0.004) and % predicted forced vital capacity (P = 0.032), higher numbers of lung segments involved (P < 0.001) and MAC-positive sputum cultures (P = 0.028), and thinner chest subcutaneous fat during follow-up (P < 0.001) than patients without deterioration. In particular, patients with both BMI <21.0 kg/m(2) and more than four lung segments involved had a 240-fold increased risk of deterioration (P < 0.001). CONCLUSION: Patients with poor nutritional status and extensive lung involvement tend to experience deterioration of nodular bronchiectatic MAC lung disease.

A Feasibility Study of a Tilted Head Position in Helical Tomotherapy for Fractionated Stereotactic Radiotherapy of Intracranial Malignancies.

Herein, we evaluated the feasibility of placing patients in a tilted head position as part of routine clinical practice for fractionated stereotactic radiotherapy (FSRT) of intracranial tumors using helical tomotherapy (HT), by assessing its dosimetric benefit and setup accuracy. We reviewed treatment plans of four cases that were to receive FSRT for brain lesions in normal and head-tilted positions. These patients underwent two computed tomography (CT) scans: first in the normal supine position and then in the supine position with the head tilted at a 458 angle. Two separate HT plans for each position were generated in these four patients, using the same planning parameters. Plans were compared for target conformity and dose homogeneity. Maximum and average doses to critical organs, including normal brain, brain stem, optic chiasm, optic nerves, and the eyes, were considered. To evaluate setup accuracy, patient movement during treatment was assessed by post-treatment megavoltage CT scans. Both HT plans achieved similar conformal and homogeneous dose coverage to the target. Head-tilted HT delivered lower average and maximum doses to critical organs in the cases where the tumor was located on the same plane with critical organs, particularly when they were not directly attached. Placement in the head-tilted position without a mouthpiece allowed for increased patient movement during treatment, while use of a mouthpiece reduced patient movement to even less than that observed for normal setup in the supine position. This pilot study showed that placement in a tilted head position for FSRT of intracranial tumors using HT may be of clinical use, but depends on the tumor location.

Effect of inhalers on the development of haemoptysis in patients with non-cystic fibrosis bronchiectasis.

BACKGROUND: The association of inhaler use with haemoptysis has rarely been reported in patients with non-cystic fibrosis (CF) bronchiectasis. OBJECTIVE: To elucidate the effect of inhaler use on the development of haemoptysis in patients with non-CF bronchiectasis. METHODS: In a case-crossover study of 192 non-CF bronchiectasis patients with a history of haemoptysis and inhaler use, the risk of haemoptysis associated with the use of inhalers was elucidated. Two inhaled corticosteroids/long-acting ß2-agonists (ICS/LABA), one long-acting muscarinic antagonist and one short-acting ß2-agonist (SABA) were evaluated. The case and control periods were defined respectively as 030 and 180210 days before haemoptysis. RESULTS: The risk of haemoptysis during the case period was 3.51 times higher than during the control period with any use of inhalers (95%CI 1.966.28). The results of clinically significant haemoptysis showed good agreement with those of total events. These associations were consistent with the sensitivity analyses. In the sub-analysis according to inhaler type, ICS/LABA and SABA were significantly associated with an increased risk of haemoptysis (aOR 2.62, 95%CI 1.255.45; aOR 2.51, 95%CI 2.235.15). CONCLUSIONS: In patients with non-CF bronchiectasis, the use of inhalers, especially including 2-agonist, was associated with an increased risk of haemoptysis.

Influence of previous tuberculosis treatment history on acid-fast bacilli smear and culture conversion.

SETTING: A teaching hospital in the Republic of Korea, 2003-2009. OBJECTIVE: To evaluate the effect of previous tuberculosis (TB) treatment history on sputum smear and culture conversion. DESIGN: Data, including sputum acid-fast bacilli (AFB) results at baseline and at weeks 2, 4, 8, 12, 16, 20 and 24, were collected from patients with AFB sputum smear-positive and culture-confirmed pulmonary TB. Patients with multidrug-resistant TB or those with poor adherence were excluded. AFB conversion was compared between patients with a previous history of anti-tuberculosis treatment and those without. RESULTS: The median age of the 208 patients was 49.0 years; 58.3% were male, while 43 (20.7%) had a history of previous anti-tuberculosis treatment. Patients with a history of previous treatment had significantly lower sputum smear-negative conversion at 2 weeks of treatment compared with patients without (70.0% vs. 44.8%, P = 0.005). However, the two groups did not differ in culture conversion and in smear conversion at 4, 8, 12, 16, 20 and 24 weeks of anti-tuberculosis treatment. CONCLUSION: Patients with a history of previous anti-tuberculosis treatment are more likely to have positive sputum AFB smear at 2 weeks of treatment. However, sputum culture conversion is not affected by previous treatment history.

Different therapeutic responses in chronic obstructive pulmonary disease subgroups.

SETTING: Eleven referring hospitals in South Korea. OBJECTIVE: To compare therapeutic responses in chronic obstructive pulmonary disease (COPD) subgroups, classified by diffusing capacity of the lung for carbon monoxide (DL(CO)) and lung volume. DESIGN: A total of 130 stable male COPD patients were classified into four subgroups according to baseline DL(CO) and residual volume/total lung capacity (RV/TLC) ratio. We compared therapeutic responses to short acting ß(2)-agonist (SABA) and 3-month combined inhalation of long-acting ß(2)-agonist (LABA) and corticosteroid among patients with these subgroups. RESULTS: Among the 130 COPD patients, 41 (31.5%) had normal DL(CO) and RV/TLC, 28 (21.5%) low DL(CO) and normal RV/TLC, 31 (23.8%) normal DL(CO) and high RV/TLC, and 30 (23.1%) low DL(CO) and high RV/TLC. The normal DL(CO)/high RV/TLC subgroup showed a significantly larger flow response (changes in forced expiratory volume in 1 s) to salbutamol than the normal DL(CO)/RV/TLC subgroups, and a larger volume response (changes in forced vital capacity) than the two normal RV/TLC subgroups. The normal DL(CO)/high RV/TLC subgroup also showed significantly larger flow and volume response to 3-month combined inhalation of LABA and corticosteroid than the two normal RV/TLC subgroups. CONCLUSION: COPD subgroups classified by DL(CO) and RV/TLC may have different pulmonary function responses to pharmacological treatment.

Pulmonary artery pressure in chronic obstructive pulmonary disease without resting hypoxaemia.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) can lead to pulmonary hypertension and cor pulmonale, which are predictors of mortality. OBJECTIVE: To identify predictors of increased pulmonary artery pressure (PAP) in COPD patients without resting hypoxaemia, and to characterise COPD patients with increased PAP. DESIGN: A study of 117 COPD patients from the Korean Obstructive Lung Disease (KOLD) cohort who had measurable tricuspid regurgitant flow under transthoracic Doppler echocardiography and no resting hypoxaemia. RESULTS: The mean patient age was 67 years. Mean forced expiratory volume in 1 second (FEV(1)) was 47% predicted, mean haemoglobin (Hb) concentration was 145 g/l and mean systolic PAP (sPAP) was 33 mmHg. Multiple linear regression analysis showed that Hb was the only factor independently associated with sPAP (beta = -1.752, P = 0.005). Cluster analysis using FEV(1)% predicted, sPAP and Hb concentration as variables indicated three patient clusters: Cluster 1 (n = 36; mean FEV(1) 44% predicted, mean sPAP 39 mmHg, mean Hb 132 g/l), Cluster 2 (n = 45; FEV(1) 35% predicted, sPAP 31 mmHg, Hb 154 g/l), and Cluster 3 (n = 36; FEV(1) 65% predicted, sPAP 29 mmHg, Hb 148 g/l). CONCLUSION: Elevated PAP was linked to low haemoglobin levels in COPD without resting hypoxaemia.

Combination of vorinostat and adenovirus-TRAIL exhibits a synergistic antitumor effect by increasing transduction and transcription of TRAIL in lung cancer cells.

Soluble TRAIL and adenovirus (ad)-TRAIL exhibit a strong antitumor effect by inducing apoptosis. Vorinostat is the histone deacetylase (HDAC) inhibitor that induces cell death in cancer cell lines and regulates the expression of epigenetically silenced genes, such as Coxackie adenoviral receptor (CAR), the receptor for adenoviral entry. We propose a new strategy in which vorinostat will induce high expression of ad-TRAIL and a strong antitumor response, and investigated the mechanism involved. The effect of vorinostat on transcription and expression of TRAIL from ad-TRAIL-transduced lung cancer cells were confirmed by reverse transciption-PCR (RT-PCR), quantitative real time-PCR and western blot assay. Anti-tumor effects were measured after cotreatment of vorinostat and ad-TRAIL, and the drug interactions were analyzed. After combined treatment of vorinostat and ad-TRAIL, apoptosis and western blot assays for Akt, Bcl-2 and caspase were performed. Vorinostat increased the expression of CAR in lung cancer cell lines and increased the expression of luciferase (luc) from ad-luc-transduced cells and TRAIL from ad-TRAIL-transduced cells. RT-PCR and quantitative real time-PCR, after sequential vorinostat treatment, revealed that vorinostat may enhance TRAIL expression from ad-TRAIL by increasing transduction through enhanced CAR expression and increasing adenoviral transgene transcription. Combined vorinostat and ad-TRAIL treatment showed the synergistic anti-tumor effect in lung cancer cell lines. Combined vorinostat and ad-TRAIL induced stronger apoptosis induction, suppression of NF-κB activation and breakdown of the anti-apoptotic molecule Bcl-2. In conclusion, the vorinostat synergistically enhanced the anti-tumor effect of ad-TRAIL by (1) increasing adenoviral transduction through the increased expression of CAR and (2) increasing adenoviral transgene (TRAIL) transcription in lung cancer cell lines.

The impact of previous tuberculosis history on T-SPOT.TB® interferon-gamma release assay results.

SETTING: Seoul National University Bundang Hospital, a tertiary referral hospital in Korea. OBJECTIVE: To evaluate whether previous tuberculosis (TB) history has a long-term effect on T-SPOT.TB® results after anti-tuberculosis treatment. DESIGN: We retrospectively reviewed 489 adults (age ≥18 years) who underwent T-SPOT.TB as part of their evaluation between January 2008 and July 2009. RESULTS: Among 489 subjects analysed, 369 were finally included. Active TB was diagnosed in 121/369 (32.8%). T-SPOT.TB was positive in 110 (90.9%) active TB patients. Of the 248 subjects without active TB, T-SPOT.TB positivity was significantly different between the 51 patients with a previous TB history and the 197 without (84.3% vs. 26.9%, P < 0.001). The difference in T-SPOT.TB positivity between the 51 non-active TB patients with a TB history and the 121 active TB patients was not statistically significant (84.3% vs. 90.9%, P = 0.208). Among the 51 non-active TB individuals with a TB history, the mean time since anti-tuberculosis treatment was 22.7 years (range 1-59); this had no correlation with total region of difference 1 (RD1) spot-forming cells (r = -0.076, P = 0.597). CONCLUSION: T-SPOT.TB has a limited role in the diagnosis of TB infection in individuals with a previous history of TB.