Early pharmacokinetic evaluation of anti-tubercular treatment as a good indicator of treatment success in pulmonary tuberculosis patients on a retreatment regimen

Mohan Anant,Bhatnagar Anuj,Gupta Tarang,Ujjalkumar Das,Kanswal Sunita,Velpandian Thirumurthy,Guleria Randeep,Singh Urvashi B. 한국약제학회 2022 Journal of Pharmaceutical Investigation Vol.52 No.4

Purpose Patients with pulmonary tuberculosis (PTB) who fail therapy or develop a relapse are initiated on a retreatment regimen. These patients are at high risk for adverse outcomes. This study aimed to assess the relationship between plasma levels of anti-tubercular drugs and therapy outcome in patients on retreatment. Methods Pharmacokinetics of retreatment regimen drugs [isoniazid (INH), rifampicin (RIF), pyrazinamide (PZA), ethambutol (EMB), and streptomycin (STM)] were compared between cured and not-cured patients using liquid chromatographytandem mass spectrometry (LC-MS/MS) in 134 patients with PTB on a retreatment regimen. Results Of 134 patients, 108 were cured, 17 developed multi-drug resistant TB (MDR-TB), and 9 remained smear-positive after completion of the retreatment (8 months). Two-hour plasma levels ( C2hr) at Day 0 were lower in ‘not cured’ subjects than ‘cured’ subjects and reflected the drug levels achieved later in the duration of retreatment. Notably, in the 26 ‘not cured’ subjects, C2hr plasma levels after the first dose at Day 0 were significantly low (INH: 0.86 vs. 2.94 mg/L, p ≤ 0.002, RIF: 0.56 vs. 2.55 mg/L, p ≤ 0.003, PZA: 1.85 vs. 26.58 mg/L, p ≤ 0.001 and EMB: 0.72 vs. 1.53 mg/L, p ≤ 0.010). Conclusion Therapeutic failure in patients with PTB on a retreatment regimen is associated with lower plasma drug levels. Therapeutic drug monitoring would prove useful for obtaining a favorable clinical outcome. C2hr levels on Day 0 reflected drug levels achieved later and could be a good predictor of patient outcome.

Cell Free EGFR mRNA Expression and Implications for Survival and Metastasis in Non-Small Cell Lung Cancer Cases

Masroor, Mirza,Mir, Rashid,Javid, Jamsheed,Prasant, Y,Imtiyaz, A,Mariyam, Z,Mohan, Anant,Ray, PC,Saxena, Alpana Asian Pacific Journal of Cancer Prevention 2015 Asian Pacific journal of cancer prevention Vol.16 No.15

Background: NSCLC is a disease involving uncontrolled cell growth, which could result in metastases into nearby tissues beyond the lungs. Materials and Methods: The aim of the present study was to analyze the influence of epidermal growth factor receptor (EGFR) gene expression on metastasis and survival in NSCLC patients. The present case-control study included 100 cases of NSCLC patients and 100 age and sex matched controls. EGFR gene expression was analyzed by quantitative real time PCR using serum RNA. Association with NSCLC patient survival was analyzed by the Kaplan-Meier method. Results: We analyzed EGFR gene expression and observed mean increased gene expression of 13.5 fold in NSCLC patients. Values reflected overall survival of patients with a median of 15.8 months in the cases of <13 fold increased gene expression vs 6.7 months with >13 fold increased EGFR gene expression (p=0.005). Distant metastatic patients with <13 fold increased EGFR gene expression had 7.9 months of median survival time while>13 fold increased EGFR gene expression had only 5 months of median survival time (p=0.03). Non metastatic patients with <13 fold increased EGFR gene expression had 18 months of median survival time as compared to only 7.1 months with >13 fold increased expression. Conclusions: Higher cell free EGFR mRNA expression may play an important role in causing distant metastases and reducing overall survival of NSCLC patients in the Indian population.

Underutilization of Curative Treatment among Patients with Non Small Cell Lung Cancer: Experience from a Tertiary Care Centre in India

Malik, Prabhat Singh,Malik, Anita,Deo, Suryanarayana Venkata,Mohan, Anant,Mohanti, Bidhu Kalyan,Raina, Vinod Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.6

Background: Lung cancer is one of the commonest and most lethal cancers throughout the world. The majority of the patients present at advance stage and are not suitable for curative intent treatment. Even among patients with localized disease, there has been underutilization of curative treatment modalities. The aim of this study was to analyze the radical treatment utilization rates in patients with non small cell lung cancer (NSCLC) treated at our centre. Materials and Methods: We analyzed case records of 104 patients with a pathologically confirmed diagnosis of NSCLC having stage 1-3B disease who were treated at our centre over last 3 years, to assess the utilization of curative treatment modalities i.e. surgery or radical radiotherapy. Results: The median age of this cohort was 58 years. Out of 104 patients only 33 (31.7%) received curative intent treatment, 14 undergoing curative resection and 19 receiving radical doses of radiotherapy. The baseline characteristics of both the groups (with or without radical treatment) were not different. Major factors associated with underutilization with curative treatment were progressive disease or loss of follow up after chemotherapy and inappropriate use of TKI and/or palliative radiotherapy in patients with stage 1-3B disease. Patients who did not receive radical treatment had inferior PFS and OS than those who received radical treatment. Conclusions: In our practice we observed gross underutilization of curative intent treatment modalities in patients with NSCLCs which is associated with inferior survival.

Correlation of TTF-1 immunoexpression and EGFR mutation spectrum in non–small cell lung carcinoma

Tripti Nakra,Varsha Singh,Aruna Nambirajan,Prabhat Singh Malik,Anant Mohan,Deepali Jain 대한병리학회 2021 Journal of Pathology and Translational Medicine Vol.55 No.4

Background: Thyroid transcription factor (TTF-1) is a diagnostic marker expressed in 75%–85% of primary lung adenocarcinomas (ACs). Activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene is the most common targetable driver alteration in lung AC. Previous studies have shown a positive correlation between TTF-1 and EGFR mutation status. We aimed to determine the predictive value of TTF-1 immunoexpression for underlying EGFR mutation status in a large Indian cohort. Methods: This retrospective designed study was conducted with medical record data from 2011 to 2020. All cases of primary lung AC and non–small cell lung carcinoma not otherwise specified (NSCLC, NOS) with known TTF-1 expression diagnosed by immunohistochemistry using 8G7G3/1 antibodies and EGFR mutation status diagnosed by quantitative polymerase chain reaction were retrieved, reviewed, and theresults were analyzed. Results: Among 909 patient samples diagnosed as lung AC and NSCLC, NOS, TTF-1 was positive in 76.8% cases (698/909) and EGFR mutations were detected in 29.6% (269/909). A strong positive correlation was present between TTF-1 positivity and EGFR mutation status (odds ratio, 3.61; p < .001), with TTF-1 positivity showing high sensitivity (90%) and negative predictive value (87%) for EGFR mutation. TTF-1 immunoexpression did not show significant correlation with uncommon/dual EGFR mutations (odds ratio, 1.69; p = .098). EGFR–tyrosine kinase inhibitor therapy was significantly superior to chemotherapy among EGFR mutant cases irrespective of TTF-1 status; however, no significant differences among survival outcomes were observed. Conclusions: Our study confirms a strong positive correlation between TTF-1 expression and common EGFR mutations (exon 19 deletion and exon 21 L858R) in advanced lung AC with significantly high negative predictive value of TTF-1 for EGFR mutations.

Clinical Implication of EGF A61G Polymorphism in the Risk of Non Small Cell Lung Adenocarcinoma Patients: A Case Control Study

Masroor, Mirza,Amit, Jain,Javid, Jamsheed,Mir, Rashid,Prasant, Y,Imtiyaz, A,Mariyam, Z,Mohan, Anant,Ray, PC,Saxena, Alpana Asian Pacific Journal of Cancer Prevention 2015 Asian Pacific journal of cancer prevention Vol.16 No.17

Background: The epidermal growth factor (EGF) plays important roles in non-small cell lung cancer (NSCLC) susceptibility and functional polymorphism in the EGF (+61A/G) gene has been linked to increased risk of NSCLC. This study aimed to evaluate the role of the EGF +61A/G polymorphism in risk of NSCLC adenocarcinoma (ADC) occurrence and survival in an Indian population. Materials and Methods: This casecontrol study included 100 histopathologically confirmed NSCLC (ADC) patients and 100 healthy controls. EGF (A61G) was genotyped by AS-PCR to elucidate putative associations with clinical outcomes. The association of the polymorphism with the survival of NSCLC patients was estimated by Kaplan-Meier curves. Results: It was found that EGF 61AG heterozygous and GG homozygous genotype is significantly associated with increased risk of NSCLC (ADC) occurrence compared to AA genotype, [OR 2.61 (1.31-5.18) and 3.25 (1.31-8.06), RR 1.51(1.15-2.0) and 1.72 (1.08-2.73) and RD 23.2 (6.90-39.5) and 28.53(7.0-50.1) for heterozygous AG (p=0.005) and homozygous GG (p=0.009)]. Patients homozygous for the G allele exhibited a significantly poor overall survival. The median survival time for patients with EGF 61 AA, AG, and GG genotypes was 10.5, 7.4, and 7.1 months (p=0.02), respectively. NSCLC (ADC) patients with GG + AG exhibited 7.3 months median survival compared to the AA genotype (p=0.009). Conclusions: The present study revealed that the EGF A61G genotype may be a novel independent prognostic marker to identify patients at higher risk of occurrence and an unfavourable clinical outcome.

Clinico-pathological Profile of Lung Cancer at AIIMS: A Changing Paradigm in India

Malik, Prabhat Singh,Sharma, Mehar Chand,Mohanti, Bidhu Kalyan,Shukla, N.K.,Deo, S.V.S.,Mohan, Anant,Kumar, Guresh,Raina, Vinod Asian Pacific Journal of Cancer Prevention 2013 Asian Pacific journal of cancer prevention Vol.14 No.1

Background: Lung cancer is one of the commonest and most lethal cancers throughout the world. The epidemiological and pathological profile varies among different ethnicities and geographical regions. At present adenocarcinoma is the commonest histological subtype of non-small cell lung cancer (NSCLC) in most of the Western and Asian countries. However, in India squamous cell carcinoma has been reported as the commonest histological type in most of the series. The aim of the study was to analyze the current clinico-pathological profile and survival of lung cancer at our centre. Materials and Methods: We analyzed 434 pathologically confirmed lung cancer cases registered at our centre over a period of three years. They were evaluated for their clinical and pathological profiles, treatment received and outcome. The available histology slides were reviewed by an independent reviewer. Results: Median age was 55 years with a male:female ratio of 4.6:1. Some 68% of patients were smokers. There were 85.3% NSCLC and 14.7% SCLC cases. Among NSCLCs, adenocarcinoma was the commonest histological subtype after the pathology review. Among NSCLC, 56.8% cases were of stage IV while among SCLC 71.8% cases had extensive stage disease. Some 29% of patients did not receive any anticancer treatment. The median overall and progression free survivals of the patients who received treatment were 12.8 and 7.8 months for NSCLC and 9.1 and 6.8 months for SCLC. Conclusions: This analysis suggests that adenocarcinoma may now be the commonest histological subtype also in India, provided a careful pathological review is done. Most of the patients present at advanced stage and outcome remains poor.

Clinical Significance of the NQO1 C609T Polymorphism in Non Small Cell Lung Adenocarcinoma Patients

Masroor, Mirza,Jain, Amit,Javid, Jamsheed,Mir, Rashid,Prashant, Y,Imtiyaz, A,Mariyam, Z,Mohan, Anant,Ray, PC,Saxena, Alpana Asian Pacific Journal of Cancer Prevention 2015 Asian Pacific journal of cancer prevention Vol.16 No.17

Background: NAD(P)H:quinone oxidoreductase 1 (NQO1) is part of the antioxidant defence system involved in detoxification. This study aimed to analyze the influence of NQO1 (C609T) genetic polymorphism in non small cell lung cancer (NSCLC)as a putative risk factor. Materials and Methods: Present study included 100 cases of NSCLC (adenocarcinoma) patients and 100 age and sex matched healthy controls. NQO1 (C609T) genotyping was performed by allele specific PCR for assessment of putative associations with clinical outcome and genotypes of. The association of the polymorphism with the survival of NSCLC patients' was analyzed by Kaplan-Meier method. Results: In Indian NSCLC (adenocarcinoma) patients increased risk of developing NSCLC was found to be associated with NQO1 609TT genotype [OR 3.68(0.90-14.98), RR 2.04(0.78-5.31)] for CT [OR 2.91(1.58-5.34), RR 1.74(1.23-2.44) p=0.0005 for CT], for CT+TT [ OR 3.26(1.82-5.82), RR 1.87(1.34-2.61) p<0.0001 for CT+TT]. A significant difference (p=0.0009) was observed in genotype distribution among cases and healthy controls. Patients with CT+TT genotype exhibited a significant poor overall survival compared with patients displaying homozygous CC genotype (p=0.03) and when survival independently compared with CC, TT and CT genotype was also found to be significantly associated (p=0.02). Overall median survival times were CT 6.0 months, TT 8.2 months, and CT + TT (6.4 months)]. Conclusions: The present study revealed that NQO1 CT, TT and CT+TT genotypes may be associated with clinical outcome and risk of developing NSCLC in the Indian population.