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.

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.

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.

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].

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.

Direct drug susceptibility testing of Mycobacterium tuberculosis for rapid detection of multidrug resistance using the Bactec MGIT 960 system: a multicenter study.

Conventional indirect drug susceptibility testing of Mycobacterium tuberculosis with liquid medium is well established and offers time-saving and reliable results. This multicenter study was carried out to evaluate if drug susceptibility testing (DST) can be successfully carried out directly from processed smear-positive specimens (direct DST) and if this approach could offer substantial time savings. Sputum specimens were digested, decontaminated, and concentrated by the laboratory routine procedure and were inoculated in Bactec MGIT 960 as well as Lowenstein-Jensen (LJ) medium for primary isolation. All the processed specimens which were acid-fast bacterium (AFB) smear positive were used for setting up direct DST for isoniazid (INH) and rifampin (RIF). After the antimicrobial mixture of polymyxin B, amphotericin B, nalidixic acid, trimethoprim, and azlocillin (PANTA) was added, the tubes were entered in the MGIT 960 instrument using the 21-day protocol (Bactec 960 pyrazinamide [PZA] protocol). Results obtained by direct DST were compared with those obtained by indirect DST to establish accuracy and time savings by this approach. Of a total of 360 AFB smear-positive sputum specimens set up for direct DST at four sites in three different countries, 307 (85%) specimens yielded reportable results. Average reporting time for direct DST was 11 days (range, 10 to 12 days). The average time savings by direct DST compared to indirect DST, which included time to isolate a culture and perform DST, was 8 days (range, 6 to 9 days). When results of direct DST were compared with those of indirect DST, there was 95.1% concordance with INH and 96.1% with rifampin. These findings indicate that direct DST with the Bactec MGIT 960 system offers further time savings and is a quick method to reliably detect multidrug resistance (MDR) cases.

Tuberculosis associated immune reconstitution inflammatory syndrome in patients infected with HIV: meningitis a potentially life threatening manifestation.

BACKGROUND: Tuberculosis (TB) is the most common co infection in HIV-infected persons in India, requiring concomitant administration of anti TB and antiretroviral therapies. Paradoxical worsening of tuberculosis after anti-retroviral therapy (ART) initiation is frequently seen. OBJECTIVE: To study the frequency, clinical presentation and outcome of paradoxical tuberculosis associated immune reconstitution inflammatory syndrome (TB-IRIS) in HIV infected patients in a TB hospital in North India. DESIGN: A retrospective chart review of HIV-infected TB patients on anti-tubercular treatment (ATT) at time of ART initiation over a 3 year period. Medical records were reviewed for clinical manifestations and outcome in patients who developed TB-IRIS. RESULTS: 514 HIV-infected patients were enrolled between January 2006 and December 2008. Thirteen (12.6%) of 103 patients who had received ART and ATT simultaneously developed paradoxical TB-IRIS. Clinical presentations of paradoxical TB-IRIS included new lymphadenopathy (n = 3), increase in size of existing lymphadenopathy (n = 3), worsening of existing pulmonary lesions (n = 2), appearance of new pleural effusion (n = 1) and prolonged high grade fever (n = 2). Four patients developed new tubercular meningitis as manifestation of TB-IRIS. Our cases developed TB-IRIS a median of 15 days after starting ART (IQR 15-36). TB-IRIS patients were older (> 35 years) than those with no IRIS (P = 0.03), but were not distinguishable by CD4 T-cell count, duration of ATT before ART or the outcome of TB treatment. Eight (62%) patients had a complete recovery while 5 (38%) patients with TB-IRIS died, of which majority (n = 3) had meningitis. CONCLUSIONS: Paradoxical TB-IRIS is a frequent problem during concomitant ATT and ART in HIV-TB co infected patients in north India. Meningitis is a potentially life threatening manifestation of TB-IRIS.

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.

Unilateral and painless development of isoniazid induced gynecomastia during re-treatment of pulmonary tuberculosis.

A case of isoniazid induced gynecomastia is being reported in an 18-year old male, who received a re-treatment regimen for the relapse of pulmonary tuberculosis (TB). At the end of two months of the treatment, the patient developed a painless unilateral gynecomastia, which completely disappeared after a month of the cessation of isoniazid. A review of literature on isoniazid induced gynecomastia is discussed.

Toll-like receptor 2 and DC-SIGNR1 differentially regulate suppressors of cytokine signaling 1 in dendritic cells during Mycobacterium tuberculosis infection.

A hallmark of protective immunity during Mycobacterium tuberculosis (M. tb) infection is the regulated secretion of pro-inflammatory and regulatory cytokines. Suppressors of Cytokine Signaling (SOCS) are key regulators of cytokine secretion and function. In this study we investigated regulation of Toll-like receptor 2 (TLR2) and dendritic cell-specific ICAM-3 grabbing non-integrin receptor 1 (DC-SIGNR1)-mediated SOCS1 expression in DCs during M. tb infection. We show that, compared with TLR2, stimulating DC-SIGNR1 on DCs induces higher SOCS1 expression and lower interleukin-12 production. Co-stimulating DC-SIGNR1 and TLR2 differentially regulates SOCS1 expression depending on the relative concentration of their ligands. Stimulating DC-SIGNR1 with M. tb infection increases SOCS1 expression, while stimulating TLR2 with M. tb infection reduces SOCS1 expression. Knockdown of SOCS1 in DCs by siRNA enhances interleukin-12 transcription and protein expression upon DC-SIGNR1 stimulation. Raf-1 and Syk differentially regulate TLR2- and DC-SIGNR1-mediated SOCS1 expression. In addition, DC-SIGNR1 shows greater association with SOCS1 when compared with TLR2. Interestingly, compared with healthy asymptomatic individuals, peripheral blood mononuclear cells of patients with active tuberculosis disease showed higher expression of SOCS1, which was reduced following chemotherapy. Similarly, stimulating DC-SIGNR1 on DCs from M. tb-infected TLR2(-/-) mice enhanced SOCS1 expression that was reduced following chemotherapy. Further, knockdown of SOCS1 in mouse DCs or human peripheral blood mononuclear cells resulted in increased killing of virulent M. tb. These results indicate that TLR2 and DC-SIGNR1 differentially regulate SOCS1 expression during M. tb infection. This in turn regulates M. tb survival by governing key cytokine expression.

A prospective randomized controlled trial on the efficacy of noninvasive ventilation in severe acute asthma.

BACKGROUND: Noninvasive ventilation (NIV) is an emerging modality in the management of patients with acute respiratory failure. However, its role in severe acute asthma is not well defined. OBJECTIVE: Evaluate the efficacy of NIV in severe acute asthma. METHODS: Patients with severe acute asthma were randomized to receive either standard medical therapy or NIV in addition to medical therapy. The primary outcomes were improvement in forced expiratory volume in the first second (FEV1), intensive care unit (ICU) stay, and hospital stay. The secondary outcomes were rate of improvement in respiratory rate, blood pH, ratio of PaO2 to fraction of inspired oxygen (F(I)O2), PaCO2, requirement for inhaled medications, and failure of primary therapy. RESULTS: Fifty-three patients with severe acute asthma (42 females and 11 males, mean +/- SD age 44 +/- 15 y, FEV1 < 30% of predicted) were randomized to NIV (n = 28) or standard medical therapy (n = 25). The baseline variables were similar in the 2 groups except for the mean duration of asthma, which was shorter in the standard-medical-therapy group. The median inspiratory and expiratory airway pressures applied were 12 cm H2O and 5 cm H2O, respectively. There was a significant improvement in respiratory rate, FEV1, and PaO2/F(I)O2 (but not pH or PaCO2) in both the groups, but no significant difference between the 2 groups. The number of patients who had a > or = 50% improvement in FEV1 at 1, 2, and 4 hours was nonsignificantly greater in the NIV arm. ICU and hospital stay was significantly shorter in the NIV group. The mean dose of inhaled bronchodilator was significantly less in the NIV group. There were 4 instances of standard-medical-therapy failure, and all those patients improved with NIV. Two patients in the NIV arm required invasive ventilation. There was no mortality in either of the arms. CONCLUSION: In patients with severe acute asthma, the addition of NIV to standard medical therapy probably accelerates the improvement in lung function, decreases the inhaled bronchodilator requirement, and shortens the ICU and hospital stay, but a larger study is required to settle this issue.

Ocular and systemic morbidity profile in mass formic acid injuries.

BACKGROUND AND OBJECTIVE: A report on formic acid-induced ocular and systemic injuries. PATIENTS AND METHODS: Forty-two passengers (84 eyes) with formic acid burns following a tanker and bus collision were evaluated and treated. The severity of ocular chemical injury was assessed using the Roper-Hall classification. Standard protocol for management of ocular chemical burns was adopted in all patients. Immediate irrigation of the eyes was done with tap water and all patients received frequent topical steroids, cycloplegics, and lubricating eye drops. Systemic injuries were evaluated and managed collectively by plastic and orthopedic surgeons and internists. RESULTS: On presentation, 48 (57.14%) eyes had grade 0, 13 (15.48%) eyes had grade I, 16 (19.1%) eyes had grade II, 3 (3.57%) eyes had grade III, and 4 (4.76%) eyes had grade IV chemical injuries. Thirty patients (71.43%) had superficial and 12 (28.57%) had deep skin burns. One (2.38%) patient died due to severe pulmonary edema and 6 (14.29%) patients had severe pulmonary complications requiring oxygen treatment. Seventy-two (87.8%) eyes healed without residual sequelae, 10 (12.2%) eyes had nebulo-macular corneal opacities, and 2 (2.44 %) eyes developed secondary glaucoma and dry eye. CONCLUSION: Formic acid injuries can lead to a significant ocular and systemic morbidity. Immediate ocular and systemic management is necessary to reduce morbidity and mortality. Strict regulations are needed for the transportation of dangerous chemicals to prevent accidental chemical injuries.

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.

Outcomes of noninvasive ventilation in acute hypoxemic respiratory failure in a respiratory intensive care unit in north India.

OBJECTIVES: To determine the outcomes of noninvasive ventilation (NIV) and the factors associated with NIV failure in patients with acute hypoxemic respiratory failure (AHRF). METHODS: This was a prospective observational study and all patients with AHRF requiring NIV over a one-and-a-half-year period were enrolled in the study. We recorded the etiology of AHRF and prospectively collected the data for heart rate, respiratory rate, arterial blood gases (pH, P(aO2), P(aCO2)) at baseline, 1 hour, and 4 hours. The patients were further classified into 2 groups, based on the etiology of AHRF: either acute lung injury/acute respiratory distress syndrome [ALI/ARDS], or AHRF due to other causes. The primary outcome was the need for endotracheal intubation during the ICU stay. RESULTS: During the study period, 287 patients were admitted in the ICU, and of these 40 (13.9%) (21 ALI/ARDS, 19 AHRF due to other causes; 16 male, 24 female patients; mean +/- SD age 43.2 +/- 20.6 years) patients with AHRF were initiated on NIV. The baseline characteristics were similar in the 2 groups. After 1 hour there was a significant decrease in respiratory rate and heart rate, with increase in pH and P(aO2); however, there was no difference in improvement of clinical and blood-gas parameters between the 2 groups. The NIV failures, the mean ICU and hospital stay, and the hospital mortality were similar in the 2 groups. In the univariate logistic regression model the only factor associated with NIV failure was the baseline ratio of P(aO2) to fraction of inspired oxygen (P(aO2)/F(IO2)) (odds ratio 0.97, 95% confidence interval 0.95-0.99). CONCLUSIONS: NIV should be judiciously used in patients with AHRF. A low baseline P(aO2)/F(IO2) ratio was associated with NIV failure.

Profile of HIV associated tuberculosis at a tertiary institute in setting of free anti-retroviral therapy.

SETTING: With the rollout of the national program, free of cost antiretroviral therapy is available to the Indian population since 2004, resulting in sea change in outcome of HIV associated tuberculosis. OBJECTIVE: To assess the presentation and outcome in patients being treated for concurrent TB and HIV. DESIGN: Retrospective analysis of data from standardized patient records. RESULTS: Seventy-three (29.1%) of the 251 HIV infected patients, who reported to the ART centre at LRS Institute of TB and Respiratory Diseases, New Delhi, between January 2006 and June 2007, were diagnosed with concurrent active tuberculosis. The mean CD4 count at presentation was 108.2 cells/microl and 87.6% patients had CD4 counts less than 200 cells/microl. 38.4% patients had purely pulmonary tuberculosis, 39.7% had purely extra-pulmonary tuberculosis and 21.9% had both. Sputum positivity in those with pulmonary involvement was 34.1%. Immune reconstitution inflammatory syndrome was seen in 20.5% patients. 67.2% patients had a favorable outcome (cure and treatment completed). 17.8% case fatality was observed in the study period. CONCLUSION: Despite severe immune suppression, treatment with ATT and ART leads to an improved outcome in patients with concurrent HIV and 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.

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.

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.