A comparative analysis of molecular genotypes of Mycobacterium tuberculosis isolates from HIV-positive and HIV-negative patients.

Setting: Tuberculosis Research Laboratory, Division of Clinical Microbiology and Molecular Medicine, Department of Laboratory Medicine, All India Institute of Medical Sciences, and the National Institute of Tuberculosis and Respiratory Diseases (NITRD), both situated in New Delhi. Objectives: We aimed to identify the distribution of various genotypes of M. tuberculosis among HIV-positive and HIV-negative patients suspected of having Tuberculosis, seen at the National Institute of Tuberculosis and Respiratory Diseases, New Delhi, which is a tertiary care dedicated TB hospital. Patients and methods: Genotyping by Spoligotyping and 24 loci MIRU-VNTR was performed and analyzed using SITVITWEB and MIRU-VNTRplus. Drug susceptibility patterns were also analyzed. Results: A total of 503 subjects who were PTB/EPTB suspected were recruited and 287 were culture positive. Among them, 276 had growth of Mycobacterium tuberculosis (MTB) and in 11 patients non-tuberculous mycobacteria (NTM) were grown. The isolation rate of NTM was predominantly from HIV positive [10 of 130 (7.6%)] patients. Of the total isolates of MTB, 156 (56.5%) were from HIV negative patients and 120 (43.5%) were from HIV positive patients. All 276 M. tuberculosis isolates were genotyped and tested for drug susceptibility patterns. The CAS genotype was most predominant [153 (55.4%)], followed by Beijing lineage [44 (15.9%)], East African India [25 (9.1%)] and others [54 (19.6%)]. Beijing genotype was significantly more common in HIV positive patients (22.5%) than in HIV negative patients (10.9%). In MIRU-VNTR analysis, clustering was found to be more frequent in CAS strains irrespective of HIV status. In the HIV positive group, spoligotyping could differentiate various genotypes in 90% of isolates and MIRU-VNTR analysis in 84.2% of isolates. The clustering of various MTB strains was more associated with drug resistance. Conclusion: The Beijing lineage was predominant in HIV-TB coinfected cases, even though the Central Asian Strain (CAS) was overall more predominant in the region.

Single ascending dose safety, tolerability, and pharmacokinetic study of econazole in healthy volunteers.

INTRODUCTION: Econazole has been found efficacious as antitubercular in in vitro and in vivo animal studies. However, limited information is available for its safety and pharmacokinetics in humans. In our present study we have conducted single ascending dose, safety, and pharmacokinetic evaluation in healthy human volunteers with the purpose of enabling translation for tuberculosis. METHODS: This study was conducted as a single-center, ascending-dose, placebo-controlled, double blind design. Three ascending dose were chosen (250 , 500 , and 1000 mg) to be administered as a single oral dose. The volunteers were screened for potential eligibility. Participants were randomized to receive either Econazole or Placebo in a 6:2 design. Safety assessments and pharmacokinetic evaluations were carried out for each cohort. RESULTS: Econazole was found to be safe at all dose levels. No serious or severe adverse events occurred during the study. The AUC (0-∞) showed a response relationship with a value of 49 ± 3.47 h* µg/ml, 17. 86 ± 8.40 hr* µg/ml, 35.54 ± 13.94 hr* µg/ml for 250 mg, 500 mg, and 1000 mg, respectively. CONCLUSION: Based on the findings of our study, a dose of 500 mg Econazole, once a day orally was considered as appropriate for further evaluation.

The Collaborative Ocular Tuberculosis Study (COTS) Consensus (CON) Group Meeting Proceedings.

An international, expert led consensus initiative was set up by the Collaborative Ocular Tuberculosis Study (COTS) group to develop systematic, evidence, and experience-based recommendations for the treatment of ocular TB using a modified Delphi technique process. In the first round of Delphi, the group identified clinical scenarios pertinent to ocular TB based on five clinical phenotypes (anterior uveitis, intermediate uveitis, choroiditis, retinal vasculitis, and panuveitis). Using an interactive online questionnaires, guided by background knowledge from published literature, 486 consensus statements for initiating ATT were generated and deliberated amongst 81 global uveitis experts. The median score of five was considered reaching consensus for initiating ATT. The median score of four was tabled for deliberation through Delphi round 2 in a face-to-face meeting. This report describes the methodology adopted and followed through the consensus process, which help elucidate the guidelines for initiating ATT in patients with choroidal TB.

The multi-faceted high order polymorphic synergistic interactions among nucleotide excision repair genes increase the risk of lung cancer in North Indians.

It is evident that gene-gene interactions are pervasive in the determination of the susceptibility of human diseases. Polymorphisms in nucleotide excision repair pathway (NER) genes can cause variations in the repair capacity and therefore, might lead to increase in susceptibility towards lung cancer through complex gene-gene and gene-smoking interactions. Logistic regression analysis, along with high order genetic interaction were analyzed using data mining tools such as multifactor dimensionality reduction (MDR) and classification and regression tree analysis (CART). Overall, a protective effect was reported when a combinatorial effect of SNPs were studied by applying logistic regression analysis. Multifactor dimensionality reduction (MDR) analysis, revealed that the four factor model i.e. XPC K939Q, XPA 5'UTR, XPG F670W and XPG D1104H had the best ability to predict lung cancer risk (CVC = 100, p < 0.0001). While a two factor model, including smoking and XPG F670W suggested smoking was associated with the risk of developing lung cancer (CVC = 100, p < 0.0001). Individually XPG F670W was identified as the primary risk factor. In classification and regression tree analysis (CART), we observed a 6-fold risk for SCLC patients carrying XPA 5'UTR (M), XPD K751Q (W) (OR: 6.20; 95%CI: 2.40-16.01, p = 0.0001).Polymorphic NER genes might jointly modulate lung cancer risk through gene-gene and gene-smoking interaction.

Treatment correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis: an individual patient data meta-analysis.

BACKGROUND: Treatment outcomes for multidrug-resistant tuberculosis remain poor. We aimed to estimate the association of treatment success and death with the use of individual drugs, and the optimal number and duration of treatment with those drugs in patients with multidrug-resistant tuberculosis. METHODS: In this individual patient data meta-analysis, we searched MEDLINE, Embase, and the Cochrane Library to identify potentially eligible observational and experimental studies published between Jan 1, 2009, and April 30, 2016. We also searched reference lists from all systematic reviews of treatment of multidrug-resistant tuberculosis published since 2009. To be eligible, studies had to report original results, with end of treatment outcomes (treatment completion [success], failure, or relapse) in cohorts of at least 25 adults (aged >18 years). We used anonymised individual patient data from eligible studies, provided by study investigators, regarding clinical characteristics, treatment, and outcomes. Using propensity score-matched generalised mixed effects logistic, or linear regression, we calculated adjusted odds ratios and adjusted risk differences for success or death during treatment, for specific drugs currently used to treat multidrug-resistant tuberculosis, as well as the number of drugs used and treatment duration. FINDINGS: Of 12 030 patients from 25 countries in 50 studies, 7346 (61%) had treatment success, 1017 (8%) had failure or relapse, and 1729 (14%) died. Compared with failure or relapse, treatment success was positively associated with the use of linezolid (adjusted risk difference 0·15, 95% CI 0·11 to 0·18), levofloxacin (0·15, 0·13 to 0·18), carbapenems (0·14, 0·06 to 0·21), moxifloxacin (0·11, 0·08 to 0·14), bedaquiline (0·10, 0·05 to 0·14), and clofazimine (0·06, 0·01 to 0·10). There was a significant association between reduced mortality and use of linezolid (-0·20, -0·23 to -0·16), levofloxacin (-0·06, -0·09 to -0·04), moxifloxacin (-0·07, -0·10 to -0·04), or bedaquiline (-0·14, -0·19 to -0·10). Compared with regimens without any injectable drug, amikacin provided modest benefits, but kanamycin and capreomycin were associated with worse outcomes. The remaining drugs were associated with slight or no improvements in outcomes. Treatment outcomes were significantly worse for most drugs if they were used despite in-vitro resistance. The optimal number of effective drugs seemed to be five in the initial phase, and four in the continuation phase. In these adjusted analyses, heterogeneity, based on a simulated I2 method, was high for approximately half the estimates for specific drugs, although relatively low for number of drugs and durations analyses. INTERPRETATION: Although inferences are limited by the observational nature of these data, treatment outcomes were significantly better with use of linezolid, later generation fluoroquinolones, bedaquiline, clofazimine, and carbapenems for treatment of multidrug-resistant tuberculosis. These findings emphasise the need for trials to ascertain the optimal combination and duration of these drugs for treatment of this condition. FUNDING: American Thoracic Society, Canadian Institutes of Health Research, US Centers for Disease Control and Prevention, European Respiratory Society, Infectious Diseases Society of America.

Functional role of CyclinD1 polymorphism (G870A) in modifying susceptibility and overall survival of North Indian lung cancer patients.

PURPOSE: The purpose of this study was to investigate the potential role of the cyclin D1 gene G870A polymorphism in the likelihood of the development of lung cancer and the overall survival of lung cancer patients in the North Indian population. METHODS: The study consisted of 353 lung cancer cases and 351 age- and gender-matched healthy controls. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLPP) was done for the CCND1 gene. The association analysis was done using the multiple linear regression, and the survival analysis was done using the Kaplan-Meier and the Cox regression models. RESULTS: The GA genotype was associated with an increased risk for overall lung cancer (odds ratio [OR] = 1.63; p = 0.01). Combined variant genotype showed a significant association for overall lung cancer (OR 1.50; p = 0.03). In addition, smokers with the carrier genotype of CCND1 were found to have a significantly higher risk for lung cancer (OR 1.57; p = 0.04). No significant correlation was observed between the overall survival of lung cancer patients and CCND1 polymorphism. However, on stratifying the subjects on the basis of histology, it was evident that small-cell lung cancer (SCLC) patients carrying the mutant (AA) genotype showed nearly a fivefold increased mortality rate compared to the wild (GG) genotype (p = 0.03). CONCLUSIONS: Our results suggest that polymorphic CCND1 may increase the risk of lung cancer in smokers from North India, and it may be associated with the overall survival of SCLC patients.

XPF polymorphism toward lung cancer susceptibility and survival in patients treated with platinum-based chemotherapy.

AIM: To evaluate the association of three XPF polymorphic variants (673 C>T, 11985 A>G, G415A) with lung cancer, overall survival and clinical response in North Indians. METHODS: Genotyping was performed using PCR-restriction fragment length polymorphism. RESULTS: A total of 673 C>T polymorphism was associated with 1.5-fold increased lung cancer risk for heterozygous genotype (CT; p = 0.03). Adenocarcinoma patients with 673 C>T polymorphism carrying heterozygous genotype (CT) had a lower hazard ratio (p = 0.01). Classification and regression tree analysis predicted XPF 673 C>T (M) as the strongest risk factor for the lung cancer (p = 0.003). For 11985 A>G polymorphism, lung cancer subjects treated with irinotecan cisplatin/carboplatin regimen having heterozygous genotype (AG) was associated with high mortality risk (p = 0.0001). CONCLUSION: 673 C>T polymorphism was associated with increased lung cancer risk.

Interactive potential of genetic polymorphism in Xenobiotic metabolising and DNA repair genes for predicting lung cancer predisposition and overall survival in North Indians.

INTRODUCTION: Cancer, a multi-step, multifactorial and multi-gene disease, not only damages the genomic integrity of the cell but also hinders the DNA repair mechanisms of the body. Gene-gene and gene environment interactions amongst the genetic polymorphisms together modulate the susceptibility towards a cancer. We have studied the high order gene interactions between the genetic polymorphism of detoxifying genes (CYP1A1, Ahr, XRCC and GST1) that play a key role in the metabolism of the xenobiotics and have been proved to be prognostic markers for lung cancer METHODS: 237 cases and 250 controls have been genotyped using PCR-RFLP technique. In order to find out the association, unconditional logistic regression approach was used and to analyse high order interactions MDR and CART was used. RESULTS: In the MDR analysis, the best model was one factor model which included GSTM1 (CVC 10/10, Prediction error = 0.43, p < .001). The best three factor model comprised of XRCC1 632, XRCC1 206, GSTM1 (CVC 10/10, Prediction error = 0.45, p < .0001). The CART analysis exhibited that Node 1 carrying mutant type of GSTM1 imposed the highest risk towards lung cancer (OR = 11.0, 95%C.I. = 6.05-20.03, p = .000001). Wild type of GSTM1 when combined with mutant type of CYP1A1 M2 and XRCC1 632, an 8 fold risk towards lung cancer was observed (95%C.I. = 4.07-16.29, p = .00001). The high order interactions were used to predict the prognosis of lung cancer patients. Of all the genetic variants, XRCC1 632, GSTM1 and AhR rs2066853 was the most important determinant of overall survival of lung cancer patients CONCLUSION: Through the study we introduced the concept of polygenic approach to get an insight about the various polymorphic variants in determining cancer susceptibility. Lesser number of subjects were found in the high risk subgroups. Further studies with larger sample size are required to warranty the above findings.

XPC Polymorphism and Risk for Lung Cancer in North Indian Patients Treated with Platinum Based Chemotherapy and Its Association with Clinical Outcomes.

Xeroderma pigmentosum complementation group C plays an important role in the human repair system. As reported in previous studies its polymorphism are associated with lung cancer susceptibility. The purpose of this study is to investigate the association of XPC gene with lung cancer susceptibility, overall response and clinical outcomes amongst North Indians. A hospital based study of 370 lung cancer cases and 370 healthy controls was conducted and genotypes were determined using PCR-RFLP assay. Results were assessed using logistic linear regression adjusted for age, sex and smoking status. Survival analysis was conducted using Kaplan-Meier survival analysis and Cox regression analysis. The treatment outcomes of 167 lung cancer patients treated with platinum based chemotherapy were evaluated.The mutant genotypic variant of XPC Lys939Gln has been associated with elevated risk of lung cancer(OR:2.30;95%CI:1.41-3.73;p=0.0007) whereas XPC Ala499Val showed a highly protective effect (OR:0.25;95%CI:0.10-0.63;p=0.003). The mutant genotype of XPC Lys939Gln presented a higher risk of developing lung cancer in heavy smokers (OR: 3.71; 95%CI:1.46-9.45; p=0.005). The survival analysis presented that heterozygous genotype showed least survival in comparison with mutant genotype in XPC Ala499Val genetic variant whereas no significant association was observed in XPC Lys939Gln. In conclusion, XPC Lys939Gln is associated with significant risk towards the lung cancer whereas on contrary XPC Ala499Val shows a protective effect.

Xeroderma pigmentosum complementation group D polymorphism toward lung cancer susceptibility survival and response in patients treated with platinum chemotherapy.

AIM: The study investigated role of xeroderma pigmentosum complementation group D (XPD) single nucleotide polymorphisms in modulating lung cancer risk and its association with overall survival and clinical outcomes. METHODS:  XPD polymorphisms were detected using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). RESULTS:  CC genotype of A751C polymorphism was associated with an increased lung cancer risk (p = 0.01). Classification and Regression Tree (CART) analysis depicted C156A as the major contributing factor. Patients having CC, treated with irinotecan-cisplatin/carboplatin regimen showed a better survival (median survival time = 25.2) whereas a poor survival was for XPD G312A. Similarly, patients treated with pemetrexed and carrying heterozygous genotype of G312A polymorphism had a poor survival (p = 0.01). CONCLUSION:  A751C and G312A act as a predictive marker in lung cancer patients treated with platinum chemotherapy. These findings might facilitate therapeutic decisions for individualized therapy in lung cancer patient. [Formula: see text].

Association study between genetic variations in Axin2 gene and lung cancer risk in North Indian population: A multiple interaction analysis.

Wnt pathway has been implicated in the process of human carcinogenesis. Axis inhibition protein2 ( Axin2), a major scaffold protein is an antagonist of Wnt pathway and is potent to act as a tumor suppressor gene in various human cancers. Therefore, the seven polymorphic sites of Axin2 gene were analyzed, in relation to lung cancer susceptibility in North Indians. A total of 608 subjects were genotyped using PCR-RFLP technique for each polymorphic site including 303 cases and 305 controls. Further association analysis was carried out using logistic regression approach to obtain adjusted odds ratio and statistical significance. MDR and CART analysis were applied to evaluate high order interactions between the SNP's. Three out of seven studied polymorphic sites showed a strong protective effect in subjects having mutant genotype for Axin2 148 C >T and heterozygous genotype for 1365 G > A and 1712 + 19 G > T towards lung cancer risk. The other important finding was the significant association of Axin2 148 C >T in SQCC patients having variant (TT) genotype. Axin2 1712 + 19 G >T showed a decreased risk for all the histological subtypes in patients with heterozygous (GT) genotype. MDR analysis predicted a best interaction model ( Axin2 148, Axin2 2062 and Axin2 1712 +19) with maximum CVC (10/10) and minimum prediction error (0.38) along with significant permutation p-value. CART analysis gave a wide spectrum of interactive combinations which exhibited a major contribution in modulating lung cancer susceptibility. Axin2 148 and Axin2 1712 + 19 were found to play a major role in modulating lung cancer risk.

Drug resistance detection and mutation patterns of multidrug resistant tuberculosis strains from children in Delhi.

A total of 312 sputum samples from pediatric patients presumptive of multidrug resistant tuberculosis were tested for the detection of drug resistance using the GenoTypeMTBDRplus assay. A total of 193 (61.8%) patients were smear positive and 119 (38.1%) were smear negative by Ziehl-Neelsen staining. Line probe assay (LPA) was performed for 208 samples/cultures (193 smear positive samples and 15 cultures from smear negative samples). Valid results were obtained from 198 tests. Of these, 125/198 (63.1%) were sensitive to both rifampicin (RIF) and isoniazid (INH). 73/198 (36.9%) were resistant to at least INH/RIF, out of which 49 (24.7%) were resistant to both INH and RIF (multidrug resistant). Children with tuberculosis are often infected by someone close to them, so strengthening of contact tracing in the program may help in early diagnosis to identify additional cases within the household. There is a need to evaluate newer diagnostic assays which have a high sensitivity in the case of smear negative samples, additional samples other than sputum among young children not able to expectorate, and also to fill the gap between estimated and reported cases under the program.

Functional Role of CyclinD1 Polymorphism (G870A) in Modifying Susceptibility and Overall Survival of North Indian Lung Cancer Patients.

Purpose The purpose of this study was to investigate the potential role of the cyclin D1 gene G870A polymorphism in the likelihood of the development of lung cancer and the overall survival of lung cancer patients in the North Indian population. Methods The study consisted of 353 lung cancer cases and 351 age- and gender-matched healthy controls. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLPP) was done for the CCND1 gene. The association analysis was done using the multiple linear regression, and the survival analysis was done using the Kaplan-Meier and the Cox regression models. Results The GA genotype was associated with an increased risk for overall lung cancer (odds ratio [OR] = 1.63; p = 0.01). Combined variant genotype showed a significant association for overall lung cancer (OR 1.50; p = 0.03). In addition, smokers with the carrier genotype of CCND1 were found to have a significantly higher risk for lung cancer (OR 1.57; p = 0.04). No significant correlation was observed between the overall survival of lung cancer patients and CCND1 polymorphism. However, on stratifying the subjects on the basis of histology, it was evident that small-cell lung cancer (SCLC) patients carrying the mutant (AA) genotype showed nearly a fivefold increased mortality rate compared to the wild (GG) genotype (p = 0.03). Conclusions Our results suggest that polymorphic CCND1 may increase the risk of lung cancer in smokers from North India, and it may be associated with the overall survival of SCLC patients.

Efficacy of 18F-fluorodeoxyglucose positron emission tomography/computed tomography as a predictor of response in locally advanced non-small-cell carcinoma of the lung.

OBJECTIVE: The study assessed the role of (18)F-fluorodeoxyglucose ((18)F-FDG) Positron emission tomography (PET)/computed tomography (CT) in evaluating the prognostic value of metabolic response for progression-free survival (PFS) and overall survival (OS) in patients with locally advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Thirty patients with locally advanced NSCLC were enrolled in this prospective study and randomly allocated to one of two treatment arms. Arm A (n=15) received two cycles of neoadjuvant chemotherapy [paclitaxel (200 mg/m(2)) and carboplatin (AUC5)] and external beam radiotherapy (60 Gy/30 fractions/6 weeks). Arm B (n=15) received the same neoadjuvant chemotherapy followed by external beam radiotherapy (48 Gy/20 fractions/4 weeks) with concomitant cisplatin 30 mg/m(2) weekly. Patients underwent (18)F-FDG PET/CT at baseline and after 6 weeks of completion of intended treatment. Pretreatment and post-treatment maximum standardized uptake values (SUVmax) were noted. Patients with a reduction of SUVmax more than 50% were considered to be metabolic responders and those with a reduction 50% or less as nonresponders. Median follow-up was 18.98 months. RESULTS: Twenty-one patients completed the intended treatment. The median pretreatment and post-treatment SUVmax values were 14 and 6.4 for arm A and 15.3 and 3.5 for arm B, respectively. Significant decrease in SUVmax was observed in both arms. Metabolic response in arm A and arm B was 50 and 64%, respectively. The median PFS and OS of the responders were 22.31 and 24.73 months and those for nonresponders were 7.83 and 8.26 months, respectively. No significant difference in OS and PFS was observed between responders and nonresponders in the two arms. CONCLUSION: PET/CT distinguishes responders from nonresponders early after completion of chemoradiation in patients with locally advanced NSCLC, but did not provide any prognostic significance.

Genetic polymorphisms in GSTM1, GSTT1 and GSTP1 genes and risk of lung cancer in a North Indian population.

BACKGROUND: A number of studies done so far in different populations have shown that polymorphisms within the GST genes play an important role in determining individual susceptibility to lung cancer; however, data obtained so far have been contradictory within the same or different populations. Few studies have focused on the combinatorial effect of the GST genes on susceptibility to lung cancer and also for different histological subtypes. Our aim is to investigate the roles of GSTM1, GSTT1, and GSTP1 polymorphisms as genetic modifiers of risk for lung cancer and histological subtypes using a larger sample size in a North Indian population. METHODS: In total 540 subjects (270 lung cancer cases and 270 controls) were evaluated for the GST polymorphism. Genotyping for the GSTM1, GSTT1 and GSTP1 gene was done by using a multiplex PCR and PCR-RFLP method. RESULTS: GSTM1 null genotype was found to be associated with lung cancer (OR=1.65, 95%CI: 116-2.3, P=0.005) and this risk was higher in cases of adenocarcinoma (ADCC). GSTT1 and GSTP1 did not show any significant association with lung cancer; however, when stratified for histological subtypes a significant association was observed for ADCC and small-cell lung cancer (SCLC) for both GSTT1 null and variant GSTP1 genotypes. The combined 'at risk' genotypes of null GSTM1 and GSTT1 genes were found to be associated with lung cancer risk, and this risk was higher in cases of ADCC (OR=4.09, 95%CI: 110-10.2, P=0.002). There is a twofold increased risk for lung cancer with the null GSTM1 and wild-type GSTP1 genotypes (P=0.0004); similarly, a fourfold increased risk was observed with the null GSTT1 and wild-type GSTP1 genotypes (P=0.0001). CONCLUSIONS: The deficient GST genotypes seem thus to be important risk modifiers for lung cancer and related histological subtypes, especially in combination.

Functional genetic variants in pre-miR-146a and 196a2 genes are associated with risk of lung cancer in North Indians.

OBJECTIVE: To find the association of two pre-miRNA polymorphisms with risk of lung cancer in North Indians. MATERIALS & METHODS: Genotyping of 250 cases and 255 controls for miR-146a and miR-196a2 using PCR-RFLP. RESULTS: Heterozygous subjects showed a risk toward lung cancer (LC), especially for adenocarcinoma (OR: 1.82; 95% CI: 1.04-3.20; p = 0.03) in miR-146a gene. TT genotype for miR-196a2 gene also showed 3.2-fold risk toward LC and the risk was fivefold higher for squamous cell carcinoma. Survival rate was significantly lower in subjects with TT genotype as compared with the CC genotype in miR-196a2. CONCLUSION: Both the single nucleotide polymorphism variants showed a positive association toward risk of lung cancer.

Proteomic analysis of HEK293 cells expressing non small cell lung carcinoma associated epidermal growth factor receptor variants reveals induction of heat shock response.

In view of the fact that certain non small cell lung carcinoma associated epidermal growth factor receptor mutations keep the receptor constitutively active, the downstream effectors of altered activity of mutant receptors are largely unknown. By 2D gel electrophoresis and MALDI-TOF/MS analysis, we showed that increased activity of EGFR mutants, L858R, L861Q and A871G induce heat shock proteins such as Hsp70, Hsp60, Hsp90B1, Hsp5a, Hsp71 and few transcriptional factors. Of which, Hsp70 was observed to be regulated more selectively to L861Q mutant. Our results suggest the possible role of heat shock proteins in lung tumor progression considering EGFR mutations.

First and second line drug resistance among treatment naïve pulmonary tuberculosis patients in a district under Revised National Tuberculosis Control Programme (RNTCP) in New Delhi.

There is limited information of level of drug resistance to first-line and second line anti-tuberculosis agents in treatment naïve pulmonary tuberculosis (PTB) patients from the Indian region. Therefore, the present prospective study was conducted to determine the antimicrobial susceptibility to first-line and second line anti-TB drug resistance in such patients. Sputum samples from consecutive treatment naïve PTB cases registered in Lala Ram Sarup (LRS) district, under RNTCP containing 12 Directly Observed Treatment Centre's (DOTS), were enrolled using cluster sampling technology. A total of 453 samples were received from July 2011 to June 2012. All samples were cultured on solid medium followed by drug susceptibility to first and second line anti-tubercular drugs as per RNTCP guidelines. Primary multi-drug resistance (MDR) was found to be 18/453; (4.0%). Extensively drug resistance (XDR) was found in one strain (0.2%), which was found to be resistant to other antibiotics. Data of drug resistant tuberculosis among treatment naïve TB patients are lacking in India. The presence of XDR-TB and high MDR-TB in small population studied, calls for conducting systematic multi-centric surveillance across the country.

Role of medical thoracoscopy and closed-blind pleural biopsy in undiagnosed exudative pleural effusions: a single-center experience of 348 patients.

BACKGROUND: Medical thoracoscopy (MT) performed either with rigid or the semirigid thoracoscope has been shown to have diagnostic accuracy superior to closed-blind pleural biopsy (CBPB) in exudative pleural effusions (EPE), which remain undiagnosed after thoracentesis. However, in resource-constrained settings, CBPB continues to be performed. In this study, we compare the outcome of thoracoscopy with CBPB. METHODS: This was a retrospective analysis of data collected over a 10-year period (2004 to 2014) of patients who underwent pleural biopsy for the evaluation of undiagnosed EPE. We report the comparative procedural yield and safety of CBPB and MT. RESULTS: During the study period, 84 and 264 patients (mean age, 49.8 y) underwent CBPB and MT, respectively. No clinical or radiologic finding could predict the correct histologic diagnosis with reasonable certainty in patients with undiagnosed EPE. The procedural yield of MT was significantly higher than CBPB (93.2% vs. 84.5%, P=0.02). The yield of MT significantly improved when chest ultrasound was used to guide the choice and point of entry of the thoracoscope (98.7% vs. 90.6%, P=0.04). Thoracoscopy was associated with mortality and complication rates of 0.37% and 5.6%, respectively, whereas the complication rate with CBPB was 8.3% with no mortality. CONCLUSIONS: MT is the procedure of choice in the evaluation of undiagnosed EPE, due to its higher success rate and an acceptable safety profile. However, in centers where thoracoscopy is not feasible, CBPB should be performed in preference to initiating empiric treatment.

Endoscopic ultrasound-guided fine-needle aspiration with an echobronchoscope in undiagnosed mediastinal lymphadenopathy: First experience from India.

BACKGROUND AND AIM: Several studies have reported the performance of combining endoscopic ultrasound fine-needle aspiration with an echobronchoscope (EUS-B-FNA), with endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), for the diagnosis of mediastinal lymphadenopathy. Herein we report our initial experience with this technique. PATIENTS AND METHODS: In this retrospective study, we report the outcome of patients who underwent EUS-B-FNA with or without EBUS-TBNA during the same session. Details of the lymph nodes sampled, number of passes, duration of the procedure, results of the cytological examination, and the final diagnosis of all the patients are presented. RESULTS: Eleven patients underwent EUS-B-FNA during the study period. EUS-B-FNA and EBUS-TBNA together yielded a sensitivity and specificity of 72.7 and 100%, respectively. The number of lymph nodes sampled per patient and the number of passes per lymph node were significantly higher with EBUS-TBNA compared to EUS-B-FNA. The mean duration of procedure was also significantly higher in the EBUS-TBNA group. The most common reason (five patients (45.5%)) for resorting to EUS-B-FNA was the patient being unfit for EBUS-TBNA or the inability of the operator to complete the procedure. Sarcoidosis was the most frequent final diagnosis in the study patients (four cases), followed by bronchogenic carcinoma (three cases). CONCLUSIONS: EUS-B-FNA is a useful additional tool for the diagnosis of mediastinal lymphadenopathy. In combination with EBUS-TBNA, it has a fairly good diagnostic yield and is a good alternative in situations where EBUS-TBNA is not feasible.