Anant Mohan

Prevalence of viral infection detected by PCR and RT-PCR in patients with acute exacerbation of COPD: a systematic review.

Background and objective:  Viruses are important aetiological agents of acute exacerbation of COPD (AECOPD). Their reported prevalence varies from region to region. This systematic review calculated the prevalence of respiratory viral infections in AECOPD.

Biomarkers in cancer screening, research and detection: present and future: a review

Abstract Biomarkers provide a powerful and dynamic approach to understanding the spectrum of malignancies with applications in observational and analytic epidemiology, randomized clinical trials, screening, diagnosis and prognosis. Defined as alterations in the constituents of tissues or body fluids, these markers offer a means for homogeneous classification of a disease and risk factor, and they can extend ones basic information about the underlying pathogenesis of disease. The goals in cancer research include finding biomarkers that can be used for the early detection of cancers, design individual therapies, and to identify underlying processes involved in the disease. Because so many myriad processes are involved in the diseased states, the goal is similar to ‘finding a needle in a haystack’. However, the development of many -omic technologies, such as genomics and proteomics, has allowed us to monitor a large number of key cellular pathways simultaneously. This has enabled the identification of biomarkers and signalling molecules associated with cell growth, cell death and cellular metabolism. These are also facilitating in monitoring the functional disturbance, molecular and cellular damage, and damage response. This brief review describes the development of biomarkers in cancer research and detection with emphasis on different proteomic tools for the identification and discovery of new biomarkers, different clinical assays to detect various biomarkers in different specimens, role of biomarkers in cancer screening and last but not the least, the challenges in this direction of cancer research.

Inhibiting the Programmed Death 1 Pathway Rescues Mycobacterium tuberculosis–Specific Interferon γ–Producing T Cells From Apoptosis in Patients With Pulmonary Tuberculosis

BACKGROUND Overexpression of programmed death 1 (PD-1) receptor is thought to inhibit the effector T-cell response in human tuberculosis. However, the precise mechanism of such inhibition remains unclear. The present study addresses the role of PD-1 in dampening host T-cell function among patients with pulmonary tuberculosis. METHODS Expression of PD-1 and its ligands (PD-L1/L2) on T cells, B cells, and monocytes was evaluated by flow cytometry (FACS). In vitro stimulation of peripheral blood mononuclear cells in the presence of Mycobacterium tuberculosis antigens was performed with and without blocking PD-1, and intracellular cytokine production was measured by FACS. RESULTS We showed higher frequencies of T cells, monocytes, and B cells expressing PD-1 and its ligand(s) among patients with pulmonary tuberculosis. Infections with live M. tuberculosis upregulated PD-L1 expression on monocytes. In vitro PD-1 blocking rescued M. tuberculosis-specific interferon γ (IFN-γ)-producing T cells from undergoing apoptosis. The number of PD-1-expressing T cells decreased significantly during therapy and inversely correlated with IFN-γ-dominant T-cell response against M. tuberculosis. CONCLUSIONS Manipulation of PD-1 signaling may restore the host T-cell response and thus may have therapeutic potential. PD-1 also may serve as a biomarker to monitor host immunity among patients with tuberculosis during therapy and vaccine studies.

Chemotherapy alone vs. chemotherapy plus high dose multiple antioxidants in patients with advanced non small cell lung cancer.

Objective: In vitro and animal studies suggest that antitumor effect of chemotherapeutic agents may be enhanced by antioxidants. Therefore, we initiated a clinical study to test the efficacy of high-dose multiple antioxidants (vitamins C, E and beta carotene) as an adjunct to chemotherapy (paclitaxel and carboplatin) in non-small-cell lung cancer. Methods: 136 patients of stage IIIb and stage IV NSCLC were randomized to receive chemotherapy (paclitaxel and carboplatin) alone (chemotherapy arm, n = 72) or chemotherapy in combination with ascorbic acid 6100 mg/day, dl-alpha-tocopherol (vitamin E) 1050 mg/day and beta-carotene 60 mg/day (combination arm, n = 64). Survival were calculated by the Kaplan-Meier method and compared using the log-rank test. Results: An overall response rate (RR) of 33% was observed in chemotherapy arm with 24 patients showing a partial response (PR) and none showing a complete response (CR). In combination arm the overall RR was 37% with 24 patients showing PR and two showing CR. The median survival times in chemotherapy arm and combination arm were nine and 11 months respectively. The overall survival (OS) rates in chemotherapy arm and combination arm at one year were 32.9% and 39.1%, and at two years, 11.1% and 15.6% respectively. None of these differences were statistically significant (p = 0.20). Toxicity profiles were similar in both arms. Conclusions: These results do not support the concern that antioxidants might protect cancer cells from the free radical damage induced by chemotherapy. Larger trials are needed to demonstrate whether high-dose multiple antioxidants in conjunction with chemotherapy increase the response rates and/or survival time in advanced lung cancer.

Foxp3+ regulatory T cells among tuberculosis patients: impact on prognosis and restoration of antigen specific IFN-γ producing T cells.

CD4+CD25+Foxp3+ Regulatory T cells (Treg) and programmed death-1 (PD-1) molecules have emerged as pivotal players in immune suppression of chronic diseases. However, their impact on the disease severity, therapeutic response and restoration of immune response in human tuberculosis remains unclear. Here, we describe the possible role of Treg cells, their M. tuberculosis driven expansion and contribution of PD-1 pathway to the suppressive function of Treg cells among pulmonary tuberculosis (PTB) patients. Multicolor flow cytometry, cell culture, cells sorting and ELISA were employed to execute the study. Our results showed significant increase in frequency of antigen-reactive Treg cells, which gradually declined during successful therapy and paralleled with decline of M. tuberculosis–specific IL-10 along with elevation of IFN-γ production, and raising the IFN-γ/IL-4 ratio. Interestingly, persistence of Treg cells tightly correlated with MDR tuberculosis. Also, we show that blocking PD-1/PD-L1 pathway abrogates Treg-mediated suppression, suggesting that the PD-1/PD-L1 pathway is required for Treg-mediated suppression of the antigen-specific T cells. Treg cells possibly play a role in dampening the effector immune response and abrogating PD-1 pathway on Treg cells significantly rescued protective T cell response, suggesting its importance in immune restoration among tuberculosis patients.

Diagnostic Accuracy of Endobronchial Ultrasound-Guided Transbronchial Needle Biopsy in Mediastinal Lymphadenopathy: A Systematic Review and Meta-analysis

OBJECTIVE: To perform a systematic review and meta-analysis of prospectively conducted studies to define diagnostic performance of endobronchial ultrasound-guided transbronchial needle biopsy (EBUS-TBNB) in mediastinal and hilar lymphadenopathy. METHODS: A comprehensive search was performed using the Embase, Ovid Medline, Ovid Medline In-Process and Other Non-Indexed Citations, All Evidence Based Medicine Reviews—Cochrane Database of Systematic Reviews, American College of Physicians Journal Club, Database of Abstracts of Reviews of Effects (DARE), Cochrane Central Register of Controlled Trials (CCTR), Health Technology Assessment (HTA), and SCOPUS databases, in the second week of November 2010. Studies were selected in 2 phases by 2 reviewers, independently. Data extraction from each study was performed using a standardized data extraction form. Quality assessment of study methodology was done using a checklist that was developed based on a Quality Assessment of Diagnostic Accuracy Studies tool and the nature of the test. Using the 2 × 2 tables, we computed the sensitivity, specificity, and likelihood ratios. RESULTS: The 14 studies included for quantitative data synthesis had a pooled cohort of 1,658 patients, from 8 different countries. The EBUS-TBNB had excellent pooled specificity of 100% (95% CI 0.90–1.00) and a positive likelihood ratio of 5.1 (95% CI 2.7–9.7). The pooled sensitivity was 0.92 (95% CI 0.91–0.93), and the pooled negative likelihood ratio was 0.13 (95% CI 0.09–0.19). The sensitivity of this intervention was not dependent on rapid on-site evaluation use or size of needle used. The pooled diagnostic odds ratio was 62.7 (95% CI 25.7–153.0). Only one major complication was reported, which resulted in early termination of the procedure. CONCLUSIONS: Evidence of moderate quality confirms the high diagnostic performance of EBUS-TBNB for mediastinal and hilar lymphadenopathy, both in malignant and non-malignant conditions. Available evidence also demonstrates the safety of this procedure.

Efficacy of circulating plasma DNA as a diagnostic tool for advanced non-small cell lung cancer and its predictive utility for survival and response to chemotherapy.

BACKGROUND Increased presence of circulating DNA has been reported in lung cancer. However, the utility of circulating DNA as a diagnostic and prognostic marker and in assessing therapeutic efficacy is yet to be realized. METHODS Circulating plasma DNA levels were quantified in 100 patients with non-small cell lung cancer and 100 age-matched controls. Forty-two patients received platinum-based chemotherapy for a minimum of three cycles after which response was assessed by computed tomography. Association of circulating plasma DNA levels with lactate dehydrogenase (LDH) levels, leukocyte counts, response to therapy and survival was determined. RESULTS The mean (±SD) plasma level of circulating DNA in lung cancer patients was 122.7 (±47.4)ng/mL, which was significantly higher than the controls (74.0 (±19.8)ng/mL; p<0.001). At 95% specificity, circulating plasma DNA levels detected lung cancer with a sensitivity of 52% at a cut-off of 104.5 ng/mL. Circulating plasma DNA levels significantly correlated with higher LDH levels, but not with leukocyte counts or any of the prognostic factors. There was no significant difference in pre-treatment circulating plasma DNA levels between responders and non-responders to chemotherapy. However, circulating plasma DNA levels were significantly higher in patients with progressive disease as compared to patients with partial remission or stable disease. CONCLUSIONS In our opinion, circulating DNA can serve as a diagnostic tool, especially if combined with other more sensitive tumor markers or imaging modalities. Further, circulating DNA may predict therapeutic efficacy which may help in better management of cancer patients.

Plasma DNA level in predicting therapeutic efficacy in advanced nonsmall cell lung cancer.

Assessment of total plasma DNA can be a promising noninvasive tool for monitoring the effect of cytotoxic therapies in order to predict therapeutic efficacy at an early stage. Cell-free plasma DNA levels were quantified before the first, second and third cycle of chemotherapy in 42 patients with advanced nonsmall cell lung cancer and correlated with response to therapy, as assessed by computed tomography following the third chemotherapy cycle. A significantly lower plasma DNA level, measured before various treatment cycles, was found in patients with remission or stable disease than in those with progression. Higher levels and insufficient decrease in plasma DNA levels during the course of chemotherapy indicated poor outcome. For predicting insufficient therapy response, a sensitivity of 26.9% was achieved at 100% specificity using plasma DNA levels before the first therapy cycle. Prediction of disease progression was achieved with a sensitivity of 35.7% at 100% specificity using plasma DNA levels before the first therapy cycle. Monitoring of plasma DNA levels during the course of chemotherapy could identify patients who are likely to exhibit an insufficient therapeutic response and disease progression at an early stage. This may help in individualising treatment, and could lead to better management of advanced-stage lung cancer.

Clinico-pathological profile of lung cancer at AIIMS: a changing paradigm in India.

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 could 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.

Invasive tracheobronchial aspergillosis in an immunocompetent person.

Tracheobronchial involvement is an uncommon form of invasive pulmonary aspergillosis and is found mainly in immunocompromised individuals such as patients with leukemia and prolonged granulocytopenia due to cytotoxic therapy, organ transplant recipients receiving high-dose corticosteroids, or patients with chronic granulomatous diseases. Rarely, such a pattern can also be seen in immunocompetent persons or can involve atypical sites such as the paranasal sinuses, skin, and the tracheobronchial tree. Occasionally, these patients require a prolonged course of antifungal agents. We report a case of aspergillosis involving the tracheobronchial tree in an immunocompetent young male that presented a diagnostic dilemma.