Publications by authors named "Anurag Mehta"

216 Publications

Physical Activity and Cardiorespiratory Fitness: Vital Signs for Cardiovascular Risk Assessment.

Curr Cardiol Rep 2021 10 13;23(11):172. Epub 2021 Oct 13.

Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390-9047, USA.

Purpose Of Review: Current risk prediction tools do not include physical activity (PA) or cardiorespiratory fitness (CRF), despite their robust association with adverse cardiovascular disease (CVD) events and their potential as targets for preventive interventions.

Recent Findings: PA and CRF are each associated with cardiovascular (CV) morbidity and mortality, independent of traditional risk factors. Improvement in CRF is associated with reduced risk of atherosclerotic cardiovascular disease (ASCVD) and heart failure (HF). Risk prediction tools have been developed for ASCVD, and more recently for HF, to refine CVD risk assessment and inform CVD prevention strategies. Attempts have been made to incorporate PA and CRF into available CVD risk prediction models. Inclusion of PA and CRF into established CVD risk assessment models improves CVD risk prediction incremental to established CVD risk prediction tools, suggesting PA and CRF are markers of CVD risk and targets for CVD prevention.
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http://dx.doi.org/10.1007/s11886-021-01596-yDOI Listing
October 2021

Apolipoproteins in vascular biology and atherosclerotic disease.

Nat Rev Cardiol 2021 Oct 8. Epub 2021 Oct 8.

Center for Prevention of Cardiovascular Disease, Section on Cardiovascular Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA.

Apolipoproteins are important structural components of plasma lipoproteins that influence vascular biology and atherosclerotic disease pathophysiology by regulating lipoprotein metabolism. Clinically important apolipoproteins related to lipid metabolism and atherogenesis include apolipoprotein B-100, apolipoprotein B-48, apolipoprotein A-I, apolipoprotein C-II, apolipoprotein C-III, apolipoprotein E and apolipoprotein(a). Apolipoprotein B-100 is the major structural component of VLDL, IDL, LDL and lipoprotein(a). Apolipoprotein B-48 is a truncated isoform of apolipoprotein B-100 that forms the backbone of chylomicrons. Apolipoprotein A-I provides the scaffolding for lipidation of HDL and has an important role in reverse cholesterol transport. Apolipoproteins C-II, apolipoprotein C-III and apolipoprotein E are involved in triglyceride-rich lipoprotein metabolism. Apolipoprotein(a) covalently binds to apolipoprotein B-100 to form lipoprotein(a). In this Review, we discuss the mechanisms by which these apolipoproteins regulate lipoprotein metabolism and thereby influence vascular biology and atherosclerotic disease. Advances in the understanding of apolipoprotein biology and their translation into therapeutic agents to reduce the risk of cardiovascular disease are also highlighted.
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http://dx.doi.org/10.1038/s41569-021-00613-5DOI Listing
October 2021

Successful Treatment of -Mutant Synchronous SCLC and Lung Adenocarcinoma With Osimertinib.

JTO Clin Res Rep 2021 Jan 12;2(1):100098. Epub 2020 Sep 12.

Department of Radiology, Rajiv Gandhi Cancer Institute and Research Center, New Delhi, India.

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http://dx.doi.org/10.1016/j.jtocrr.2020.100098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474249PMC
January 2021

Associations Between Inflammation, Cardiovascular Regenerative Capacity, and Cardiovascular Events: A Cohort Study.

Arterioscler Thromb Vasc Biol 2021 Sep 23:ATVBAHA121316574. Epub 2021 Sep 23.

Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, GA. (Z.A., J.H.K., M.G., K.M., B.L., A.M., A.J.S., M.S.H., V.V., A.A.Q.).

Objective: Circulating progenitor cells possess immune modulatory properties and might mitigate inflammation that is characteristic of patients with coronary artery disease. We hypothesized that patients with fewer circulating progenitor cells (CPCs) will have higher inflammatory markers and worse outcomes. Approach and Results: Patients with stable coronary artery disease were enrolled in a prospective study enumerating CPCs as CD (cluster of differentiation)-34-expressing mononuclear cells (CD34+) and inflammation as levels of IL (interleukin)-6 and high-sensitivity CRP (C-reactive protein) levels. Patients were followed for 5 years for the end points of death and myocardial infarction with repeat inflammatory biomarkers measured after a median of 2 years. In the entire cohort of 392 patients, IL-6 and high-sensitivity CRP levels remained unchanged (0.3±2.4 pg/mL and 0.1±1.0 mg/L; =0.45) after 2 years. CPC counts (log-transformed) were inversely correlated with the change in IL-6 levels (r, -0.17; <0.001). Using linear regression, IL-6 and high-sensitivity CRP levels declined by -0.59 (95% CI, -0.90 to -0.20) pg/mL and -0.13 (-0.28 to 0.01) mg/L per 1 log higher CPC counts after adjustment for the demographic and clinical variables, as well as medications. Using Cox models adjusted for these risk factors, a rise in 1 pg/mL of IL-6 was associated with a 11% (95% CI, 9-13) greater risk of death/myocardial infarction. We found that the change in IL6 level partly (by 40%) mediated the higher risk of adverse events among those with low CPC counts.

Conclusions: Reduced cardiovascular regenerative capacity is independently associated with progressive inflammation in patients with coronary artery disease that in turn is associated with poor outcomes.
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http://dx.doi.org/10.1161/ATVBAHA.121.316574DOI Listing
September 2021

Association of physical activity with arterial stiffness among Black adults.

Vasc Med 2021 Sep 22:1358863X211032725. Epub 2021 Sep 22.

Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA.

Arterial stiffness is a precursor for the development of hypertension and premature cardiovascular disease (CVD). Physical activity has been associated with lower arterial stiffness among largely White populations, but the types of activity required and whether these findings apply to Black adults remain unknown. We examined whether physical activity levels were associated with arterial stiffness among Black adults in two independent cohorts. In the Morehouse-Emory Cardiovascular (MECA) Center for Health Equity, 378 Black adults (age 52.8 ± 10.3, 39.7% male) without known CVD living in Atlanta, GA were recruited. Arterial stiffness was measured as pulse wave velocity (PWV). Total and domain-specific physical activity were assessed by self-report. Multiple linear regression models were used to investigate differences across physical activity levels after adjusting for age, sex, CVD risk factors, and socioeconomic status. Findings were validated in an independent cohort of Black adults ( = 55, age 50.4 ± 9.2, 23.6% male). After adjustment for covariates, lower arterial stiffness was associated with higher self-reported levels of sport/exercise (6.92 ± 1.13 vs 7.75 ± 1.14, < 0.001, highest vs lowest quartile) and home/life activities (7.34 ± 1.24 vs 7.73 ± 1.07, = 0.04, highest vs lowest quartile), but not work, active living, or the overall physical activity scores. These findings were replicated in the independent cohort where higher levels of sport/exercise remained associated with lower arterial stiffness (6.66 ± 0.57 vs 8.21 ± 0.66, < 0.001, highest vs lowest quartile). Higher levels of sport/exercise and home/life-related physical activities (in comparison to occupational physical activity) are associated with lower arterial stiffness in Black adults.
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http://dx.doi.org/10.1177/1358863X211032725DOI Listing
September 2021

Robust home brew fragment sizing assay for detection of MET exon 14 skipping mutation in non-small cell lung cancer patients in resource constrained community hospitals.

J Pathol Transl Med 2021 Sep 2;55(5):324-329. Epub 2021 Sep 2.

Section of Molecular Diagnostics, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India.

Background: A mutation/deletion involving donor or acceptor sites for exon 14 results in splicing out of exon 14 of the mesenchymal epithelial transition (MET) gene and is known as "MET exon 14 skipping" (ΔMET14). The two recent approvals with substantial objective responses and improved progression-free survival to MET inhibitors namely capmatinib and tepotinib necessitate the identification of this alteration upfront. We herein describe our experience of ΔMET14 detection by an mRNA-based assay using polymerase chain reaction followed by fragment sizing.

Methods: This is a home brew assay which was developed with the concept that the transcripts from true ΔMET14 will be shorter by ~140 bases than their wild type counterparts. The cases which were called MET exon 14 skipping positive on next-generation sequencing (NGS) were subjected to this assay, along with 13 healthy controls in order to establish the validity for true negatives.

Results: Thirteen cases of ΔMET14 mutation were detected on NGS using RNA-based sequencing. Considering NGS as a gold standard, the sizing assay using both gel and capillary electrophoresis that showed 100% specificity for both with concordance rates of 84.6% and 88.2% with NGS, respectively, were obtained.

Conclusions: Owing to the cost-effective nature and easy to use procedures, this assay will prove beneficial for small- and medium-sized laboratories where skilled technical personnel and NGS platforms are unavailable.
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http://dx.doi.org/10.4132/jptm.2021.07.15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8476318PMC
September 2021

Cross-Sectional Study to Establish the Utility of Serum Tumor Markers in the Diagnosis of Lung Cancer.

Asian Pac J Cancer Prev 2021 Aug 1;22(8):2569-2576. Epub 2021 Aug 1.

Rajiv Gandhi Cancer Institute and Research Centre. India.

Background: Reliable blood markers for aiding lung cancer (LC) diagnosis and differentiating LC from tuberculosis are lacking in India.

Methodology: In this single-centre, cross-sectional, real-world study, serum levels of 5 TMs (CEA, CYFRA 21-1, SCC, ProGRP, NSE) were measured from consented patients with suspicious lung nodules who were candidates for biopsy, and also from healthy controls. TM level measurement was done through electrochemiluminescent immunoassay, followed by histological diagnosis on the biopsied specimen. Using package insert cut-offs, sensitivity and specificity of the 5 TMs were evaluated individually and in combination. Using receiver operating characteristic (ROC) curves of individual TMs, the ability of CEA, CYFRA 21-1, and ProGRP taken together was evaluated for its ability to differentiate LC from no-LC.

Results: Out of 178 subjects, 160 had LC (147 NSCLC; 13 SCLC). NSCLC patients had higher median values of CYFRA 21-1 and SCC; SCLC patients had higher median values of CEA, NSE, and ProGRP. Adenocarcinoma-NSCLC patients had higher median values of CEA, CYFRA 21-1, NSE, and ProGRP; squamous-NSCLC patients had higher median value of SCC. For differentiating LC from no-LC, the combination of all 5 TMs (sensitivity:97.5%, specificity:33.3%) and combination of CEA, CYFRA 21-1 and ProGRP (sensitivity:91.3%, specificity:88.9%) were found suitable.

Conclusion: Combination of all 5 TMs, and combination of CEA, CYFRA 21-1, and ProGRP represents an easy and non-invasive method for aid in LC diagnosis that does not require technical expertise. TM evaluation can also supplement histological diagnosis of LC. 
.
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http://dx.doi.org/10.31557/APJCP.2021.22.8.2569DOI Listing
August 2021

Combination of Radiomics and Machine Learning with Diffusion-Weighted MR Imaging for Clinical Outcome Prognostication in Cervical Cancer.

Tomography 2021 08 5;7(3):344-357. Epub 2021 Aug 5.

Department of Radiology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi 110085, India.

Objectives: To explore the potential of Radiomics alone and in combination with a diffusion-weighted derived quantitative parameter, namely the apparent diffusion co-efficient (ADC), using supervised classification algorithms in the prediction of outcomes and prognosis.

Materials And Methods: Retrospective evaluation of the imaging was conducted for a study cohort of uterine cervical cancer, candidates for radical treatment with chemo radiation. ADC values were calculated from the darkest part of the tumor, both before (labeled preADC) and post treatment (labeled postADC) with chemo radiation. Post extraction of 851 Radiomics features and feature selection analysis-by taking the union of the features that had Pearson correlation >0.35 for recurrence, >0.49 for lymph node and >0.40 for metastasis-was performed to predict clinical outcomes.

Results: The study enrolled 52 patients who presented with variable FIGO stages in the age range of 28-79 (Median = 53 years) with a median follow-up of 26.5 months (range: 7-76 months). Disease recurrence occurred in 12 patients (23%). Metastasis occurred in 15 patients (28%). A model generated with 24 radiomics features and preADC using a monotone multi-layer perceptron neural network to predict the recurrence yields an AUC of 0.80 and a Kappa value of 0.55 and shows that the addition of radiomics features to ADC values improves the statistical metrics by approximately 40% for AUC and approximately 223% for Kappa. Similarly, the neural network model for prediction of metastasis returns an AUC value of 0.84 and a Kappa value of 0.65, thus exceeding performance expectations by approximately 25% for AUC and approximately 140% for Kappa. There was a significant input of GLSZM features (SALGLE and LGLZE) and GLDM features (SDLGLE and DE) in correlation with clinical outcomes of recurrence and metastasis.

Conclusions: The study is an effort to bridge the unmet need of translational predictive biomarkers in the stratification of uterine cervical cancer patients based on prognosis.
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http://dx.doi.org/10.3390/tomography7030031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8396356PMC
August 2021

Genetic testing for homologous recombination repair (HRR) in metastatic castration-resistant prostate cancer (mCRPC): challenges and solutions.

Oncotarget 2021 Aug 3;12(16):1600-1614. Epub 2021 Aug 3.

Professor of Molecular Pathology, Oncology Center School of Medicine, Cairo University, Giza, Egypt.

Patients with metastatic castration-resistant prostate cancer (mCRPC) have an average survival of only 13 months. Identification of novel predictive and actionable biomarkers in the homologous recombination repair (HRR) pathway in up to a quarter of patients with mCRPC has led to the approval of targeted therapies like (PARPi), with the potential to improve survival outcomes. The approval of PARPi has led to guideline bodies such as the National Comprehensive Cancer Network (NCCN) to actively recommend germline and or somatic HRR gene panel testing to identify patients who will benefit from PARPi. However, there are several challenges as genetic testing is still at an early stage especially in low- and middle-income countries, with cost and availability being major impediments. In addition, there are issues such as choice of optimal tissue for genetic testing, archival, storage, retrieval of tissue blocks, interpretation and classification of variants in the HRR pathway, and the need for pretest and pos-test genetic counseling. This review provides insights into the HRR gene mutations prevalent in mCRPC and the challenges for a more widespread gene testing to identify actionable germline pathogenic variants and somatic mutations in the HRR pathway, and proposes a clinical algorithm to enhance the efficiency of the gene testing process.
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http://dx.doi.org/10.18632/oncotarget.28015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8351605PMC
August 2021

Reliability and Role of Mutation-specific H3F3A (Histone 3-3) G34W Immunohistochemistry to Differentiate Giant Cell Tumor of Bone From its Clinicoradiologic and Histologic Mimics: An Institutional Study.

Appl Immunohistochem Mol Morphol 2021 Aug 4. Epub 2021 Aug 4.

Departments of Pathology Orthopaedic Oncology Radiodiagnosis, Rajiv Gandhi Cancer Institute & Research Centre Department of Musculoskeletal Oncology, Max Institute of Cancer Care, Max Superspeciality Hospital, New Delhi, Delhi Department of Medical Oncology, Homi Bhabha Cancer Hospital and Research Centre, Visakhapatnam, Andhra Pradesh, India.

Giant cell tumor of bone (GCTB) is a benign neoplasm, which can sometimes be a diagnostic challenge, especially in small biopsies, due to its histologic benign and malignant mimics. We evaluated the role of H3.3 G34W immunohistochemistry (IHC) antibody in diagnosing GCTB and its role in differentiating it from its close histologic mimics. A total of 120 cases (80 cases of GCTB and 40 cases of histologic mimics) were retrieved and subjected to IHC. Of 80 cases of GCTB, 72 cases showed a positive nuclear immunoexpression, while all 40 cases of histologic mimics of GCTB showed a negative staining for H3.3 G34W IHC. Sensitivity and specificity of this mutation-specific antibody for diagnosis of GCTB was 90% and 100%, respectively, while, the positive predictive value and the negative predictive value were 100% and 83.3%, respectively. A positive expression of H3.3 G34W was seen in all 5 cases of GCTB, postdenosumab therapy, as well as, in all 3 cases of malignant giant cell tumor. The presented study showed that H3.3 G34W mutation-specific IHC is a reliable and specific marker for GCTB and can help distinguish it from the histologic mimics due to distinct therapeutic implications.
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http://dx.doi.org/10.1097/PAI.0000000000000964DOI Listing
August 2021

Hypertension guidelines and coronary artery calcification among South Asians: Results from MASALA and MESA.

Am J Prev Cardiol 2021 Jun 12;6:100158. Epub 2021 Feb 12.

Ciccarone Center for the Prevention of Cardiovascular Disease, Baltimore, United States.

Untreated hypertension may contribute to increased atherosclerotic cardiovascular disease (ASCVD) risk in South Asians (SA). We assessed HTN prevalence among untreated adults free of baseline ASCVD from the MASALA & MESA studies. The proportion of participants who received discordant recommendations regarding antihypertensive pharmacotherapy use by the 2017-ACC/AHA and JNC7 Guidelines across CAC score categories in each race/ethnic group was calculated. Compared with untreated MESA participants ( = 3896), untreated SA ( = 445) were younger (55±8 versus 59±10 years), had higher DBP (73±10 versus 70±10 mmHg), total cholesterol (199±34 versus 196±34 mg/dL), statin use (16% versus 9%) and CAC=0 prevalence (69% versus 58%), with fewer current smokers (3% versus 15%) and lower 10-year-ASCVD-risk (6.4% versus 9.9%) (all <0.001). A higher proportion of untreated MASALA and MESA participants were diagnosed with hypertension and recommended anti-hypertensive pharmacotherapy according to the ACC/AHA guideline compared to JNC7 (all <0.001). Overall, discordant BP treatment recommendations were observed in 9% SA, 11% Whites, 15% Blacks, 10% Hispanics, and 9% Chinese-American. In each race/ethnic group, the proportion of participants receiving discordant recommendation increased across CAC groups (all <0.05), however was highest among SA (40% of participants). Similar to other race/ethnicities, a higher proportion of SA are recommended anti-hypertensive pharmacotherapy by ACC/AHA as compared with JNC7 guidelines. The increase was higher among those with CAC>100 and thus may be better at informing hypertension management in American South Asians.
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http://dx.doi.org/10.1016/j.ajpc.2021.100158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315395PMC
June 2021

Cardiovascular disease prevention career pathways: The status quo and future directions.

Am J Prev Cardiol 2020 Dec 4;4:100134. Epub 2020 Dec 4.

Divison of Cardiology, Maine Medical Center, Portland, ME, USA.

Cardiovascular disease prevention is a complicated field requiring similar resource allocation and training as any other subspecialty in cardiology. To highlight the increasing need for primordial, primary and secondary cardiovascular disease prevention at a population level, it is necessary to have a clear vision for not only adequate training in the field but also sample career trajectories that today's fellows-intraining (FIT) and early career (EC) physicians can use as a reference. However due to less centralized training, reduced exposure to the discipline and no clear institutional champions, direct access to "role model" careers in cardiovascular disease prevention may be lacking for today's generation of trainees. These trends may change with more formalized recognition and more visibility of career trajectories in the field. In the current short report, we propose career pathways in cardiovascular disease prevention that can serve as a board resource roadmap for today's FIT/EC physicians to design their careers in cardiovascular disease prevention. We explore three types of preventive cardiologists prototypes including; "the researcher", "the clinician" and "the academic" preventive cardiologist models. These models are based on experiences gained in separate preventive cardiology training fellowships in addition to general cardiology training. Further, with advances in the scientific technologies, we highlight the future trajectory in the field. Preventive cardiology, although currently not the most desired path for FIT/EC physicians to pursue today, has the potential to be seen as the lucrative and essential training field in the future.
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http://dx.doi.org/10.1016/j.ajpc.2020.100134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315632PMC
December 2020

Temporal trends in the association of social vulnerability and race/ethnicity with county-level COVID-19 incidence and outcomes in the USA: an ecological analysis.

BMJ Open 2021 07 22;11(7):e048086. Epub 2021 Jul 22.

Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia, USA

Background: The COVID-19 pandemic adversely affected the socially vulnerable and minority communities in the USA initially, but the temporal trends during the year-long pandemic remain unknown.

Objective: We examined the temporal association of county-level Social Vulnerability Index (SVI), a percentile-based measure of social vulnerability to disasters, its subcomponents and race/ethnic composition with COVID-19 incidence and mortality in the USA in the year starting in March 2020.

Methods: Counties (n=3091) with ≥50 COVID-19 cases by 6 March 2021 were included in the study. Associations between SVI (and its subcomponents) and county-level racial composition with incidence and death per capita were assessed by fitting a negative-binomial mixed-effects model. This model was also used to examine potential time-varying associations between weekly number of cases/deaths and SVI or racial composition. Data were adjusted for percentage of population aged ≥65 years, state-level testing rate, comorbidities using the average Hierarchical Condition Category score, and environmental factors including average fine particulate matter of diameter ≥2.5 μm, temperature and precipitation.

Results: Higher SVI, indicative of greater social vulnerability, was independently associated with higher COVID-19 incidence (adjusted incidence rate ratio per 10 percentile increase: 1.02, 95% CI 1.02 to 1.03, p<0.001) and death per capita (1.04, 95% CI 1.04 to 1.05, p<0.001). SVI became an independent predictor of incidence starting from March 2020, but this association became weak or insignificant by the winter, a period that coincided with a sharp increase in infection rates and mortality, and when counties with higher proportion of white residents were disproportionately represented ('third wave'). By spring of 2021, SVI was again a predictor of COVID-19 outcomes. Counties with greater proportion of black residents also observed similar temporal trends in COVID-19-related adverse outcomes. Counties with greater proportion of Hispanic residents had worse outcomes throughout the duration of the analysis.

Conclusion: Except for the winter 'third wave', when majority of the white communities had the highest incidence of cases, counties with greater social vulnerability and proportionately higher minority populations experienced worse COVID-19 outcomes.
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http://dx.doi.org/10.1136/bmjopen-2020-048086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8300549PMC
July 2021

SMARCA4/BRG1 protein-deficient thoracic tumors dictate re-examination of small biopsy reporting in non-small cell lung cancer.

J Pathol Transl Med 2021 Sep 21;55(5):307-316. Epub 2021 Jun 21.

Department of Radiology, Rajiv Gandhi Cancer Institute and Research Centre (RGCIRC), New Delhi, India.

Background: SMARCA4/BRG1 protein-deficient lung adenocarcinomas and thoracic sarcoma are recently described entities that lack distinctive histological features, transcription termination factor 1 (TTF1) reactivity, and actionable driver mutations. The current diagnostic path for small lung biopsies as recommended by the World Health Organization (WHO, 2015) is likely to categorize these as non- small cell carcinoma-not otherwise specified (NSCC-NOS). The present study attempts to define the subtle but distinctive clinicopathologic features of SMARCA4/BRG1 protein-deficient thoracic tumors; highlight their unique biology; and addresses the unmet need to segregate these using a new, tissue-proficient diagnostic pathway.

Methods: All lung biopsies and those from metastatic sites in patients with suspected advanced lung cancer and classified as NSCC-NOS as per WHO (2015) guidelines were subjected to BRG1 testing by immunohistochemistry. SMARCA4/BRG1 protein-deficient thoracic tumors were evaluated by an extended immunohistochemistry panel. Predictive biomarker and programmed death-ligand 1 testing was conducted in all cases.

Results: Of 110 cases, nine were found to be SMARCA4/BRG1 protein-deficient; six were identified as SMARCA4/BRG1 protein-deficient lung adenocarcinomas, and three were SMARCA4/BRG1 protein-deficient thoracic sarcomas. The histology ranged from poorly differentiated to undifferentiated to rhabdoid. None of the cases showed significant expression of TTF1 or p40, and no actionable mutation was identified.

Conclusions: It is difficult to separate BRG1-deficient lung adenocarcinomas and thoracic sarcomas based on morphology alone. We propose a diagnostic pathway for small biopsies of thoracic tumors to segregate these distinct entities so that they can be studied more efficaciously for new biomarkers and therapeutic options.
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http://dx.doi.org/10.4132/jptm.2021.05.11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8476316PMC
September 2021

Aberrant expression of multiple T cell markers on diffuse large B cell lymphoma: a case report.

J Egypt Natl Canc Inst 2021 Jun 15;33(1):14. Epub 2021 Jun 15.

Department of Laboratory and Transfusion Services, Rajiv Gandhi Cancer Institute & Research Centre, Sector 5, Rohini, Delhi, 110085, India.

Background: Aberrant T cell antigen expression has been well documented in diffuse large B cell lymphomas. However, co-expression of multiple T cell antigens including CD3, which has been considered a specific marker for T cells is extremely rare. Awareness about such aberrant expression is important so as not to misdiagnose or wrongly classify a lymphoma. The aim of this article is to report such a case.

Case Presentation: A 68-year-old postmenopausal lady, diabetic and hypertensive, presented with an axillary lump of one week's duration. There was no other relevant medical history. Ultrasonography revealed multiple hypoechoic cystic lesions varying in size from 3.9 to 4.2 cm. Aspiration was suggestive of an infective pathology. Excision biopsy of the mass was diagnosed as diffuse large B cell lymphoma with aberrant T cell antigen expression. She received 4 cycles of chemotherapy after which she was lost to follow-up.

Conclusion: The case presented as a diagnostic dilemma for the pathologist. The predicament lies in classifying it as a B cell lymphoma with an aberrant expression of T cell markers versus a T cell lymphoma with an aberrant B cell marker expression which has a significant implication on the treatment offered. This can be solved by looking at the expression of the B cell specific transcription factors. The key to diagnosis lies in the knowledge of their existence and the application of a panel of markers.
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http://dx.doi.org/10.1186/s43046-021-00071-7DOI Listing
June 2021

Ecological Analysis of the Temporal Trends in the Association of Social Vulnerability and Race/Ethnicity with County-Level COVID-19 Incidence and Outcomes in the United States.

medRxiv 2021 Jun 7. Epub 2021 Jun 7.

Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, GA.

Background: The COVID-19 pandemic adversely affected the socially vulnerable and minority communities in the U.S. initially, but the temporal trends during the year-long pandemic remain unknown.

Objective: We examined the temporal association between the county-level Social Vulnerability Index (SVI), a percentile-based measure of social vulnerability to disasters, its subcomponents and race/ethnic composition with COVID-19 incidence and mortality in the U.S. in the year starting in March 2020.

Methods: Counties (n=3091) with ≥ 50 COVID-19 cases by March 6 , 2021 were included in the study. Associations between SVI (and its subcomponents) and county level racial composition with the incidence and death per capita were assessed by fitting a negative-binomial mixed-effects model. This model was also used to examine potential time varying associations between weekly number of cases/deaths and SVI or racial composition. Data was adjusted for percentage of population aged ≥65 years, state level testing rate, comorbidities using the average Hierarchical Condition Category (HCC) score, and environmental factors including average fine particulate matter (PM ), temperature and precipitation.

Results: Higher SVI, indicative of greater social vulnerability, was independently associated with higher COVID-19 incidence (adjusted incidence rate ratio [IRR] per-10 percentile increase:1.02, (95% CI 1.02, 1.03, p<0.001), and death per capita (1.04, (95% CI 1.04, 1.05, p<0.001). SVI became an independent predictor of incidence starting from March 2020, but this association became weak or insignificant by the winter, a period that coincided with a sharp increase in infection rates and mortality, and when counties with higher proportion of White residents were disproportionately represented ("third wave"). By Spring of 2021, SVI was again a predictor of COVID-19 outcomes. Counties with greater proportion of Black residents also observed similar temporal trends COVID-19-related adverse outcomes. Counties with greater proportion of Hispanic residents had worse outcomes throughout the duration of the analysis.

Conclusion: Except for the winter "third wave" when majority White communities had the highest incidence of cases, counties with greater social vulnerability and proportionately higher minority populations, experienced worse COVID-19 outcomes.

Article Summary/strengths & Limitations: Examined full 12 months of county-level data in the US delineating the temporal trends in the association between social vulnerability index and COVID-19 outcomesInvestigated COVID-19 outcomes in predominantly Black and Hispanic communities in comparison to White communities in the USAnalysis is ecological, descriptive, and on the county-level rather than on an individual levelAnalysis adjusted for confounders including county level age ≥ 65, comorbidities, and environmental factorsAnalysis limited to the US.
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http://dx.doi.org/10.1101/2021.06.04.21258355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202439PMC
June 2021

The usefulness of CanAssist breast in the assessment of recurrence risk in patients of ethnic Indian origin.

Breast 2021 Oct 28;59:1-7. Epub 2021 May 28.

OncoStem Diagnostics, Bengaluru, Karnataka, India. Electronic address:

Accurate recurrence risk assessment in hormone receptor positive, HER2/neu negative breast cancer is critical to plan precise therapy. CanAssist Breast (CAB) assesses recurrence risk based on tumor biology using artificial intelligence-based approach. We report CAB risk assessment correlating with disease outcomes in multiple clinically high- and low-risk subgroups. In this retrospective cohort of 925 patients [median age-54 (22-86)] CAB had hazard ratio (HR) of 3 (1.83-5.21) and 2.5 (1.45-4.29), P = 0.0009) in univariate and multivariate analysis. CAB's HR in sub-groups with the other determinants of outcome, T2 (HR: 2.79 (1.49-5.25), P = 0.0001); age [< 50 (HR: 3.14 (1.39-7), P = 0.0008)]. Besides application in node-negative patients, CAB's HR was 2.45 (1.34-4.47), P = 0.0023) in node-positive patients. In clinically low-risk patients (N0 tumors up to 5 cms) (HR: 2.48 (0.79-7.8), P = 0.03) and with luminal-A characteristics (HR: 4.54 (1-19.75), P = 0.004), CAB identified >16% as high-risk with recurrence rates of up to 12%. In clinically high-risk patients (T2N1 tumors (HR: 2.65 (1.31-5.36), P = 0.003; low-risk DMFS: 92.66 ± 1.88) and in women with luminal-B characteristics (HR: 3.24; (1.69-6.22), P < 0.0001; low-risk DMFS: 93.34 ± 1.34)), CAB identified >64% as low-risk. Thus, CAB prognostication was significant in women with clinically low- and high-risk disease. The data imply the use of CAB for providing helpful information to stratify tumors based on biology incorporated with clinical features for Indian patients, which can be extrapolated to regions with similarly characterized patients, South-East Asia.
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http://dx.doi.org/10.1016/j.breast.2021.05.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187842PMC
October 2021

Familial hypercholesterolemia related admission for acute coronary syndrome in the United States: Incidence, predictors, and outcomes.

J Clin Lipidol 2021 May-Jun;15(3):460-465. Epub 2021 Apr 29.

Section on Cardiovascular Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA. Electronic address:

Background: Individuals with Familial Hypercholesterolemia (FH) are at high risk for atherosclerotic cardiovascular disease (ASCVD) events.

Objectives: The purpose of this study was to evaluate the incidence, predictors, and outcomes of admissions for acute coronary syndromes (ACS) in this high-risk group.

Methods: Utilizing the National Readmission Databases, we identified individuals with or without FH admitted to participating hospitals for ACS. The primary outcome was admission for recurrent ACS at 11 month follow-up.

Results: There were a total of 1,697,513 ACS admissions from 10/2016 to 12/2017 (non-FH=1,696,979 and FH=534). Individuals with FH admitted for ACS were younger (median age 57 vs 69 y), had fewer comorbidities (hypertension 74.7% vs 79.6%; diabetes mellitus 30.5% vs 39.0%;p<0.01), were more likely to present with ST-elevation-myocardial infarction (32.8% vs 22.6%;p<0.01) and more likely to undergo multivessel percutaneous coronary intervention (11.4% vs 7.6%;p<0.01) than patients without FH. After propensity-score matching, FH patients more commonly experienced in-hospital VT arrest (11.8% vs 8.0%;p<0.01) and required more mechanical circulatory support (8.6% vs 3.3%; p<0.01). The 30-day readmission in those with FH was more frequently for cardiovascular disease (81.5% vs 46.5%; =p<0.01). At 11-month follow-up, FH patients were more likely to be readmitted with recurrent ACS compared to those without FH (hazard ratio=2.34; 95% confidence interval=1.30-4.23; p<0.01).

Conclusions: Individuals with FH admitted for ACS are younger, have fewer comorbidities, and more frequently present with STEMIs compared to those without FH. FH patients were more likely to suffer in-hospital cardiac complications and have a higher incidence of recurrent ACS.
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http://dx.doi.org/10.1016/j.jacl.2021.04.005DOI Listing
April 2021

Rare epidermal growth factor receptor gene alterations in non-small cell lung cancer patients, tyrosine kinase inhibitor response and outcome analysis.

Cancer Treat Res Commun 2021 13;28:100398. Epub 2021 May 13.

Department of Research, Rajiv Gandhi Cancer Institute & Research Centre, Rohini, Delhi-110085, India. Electronic address:

Background: The predictive value of rare epidermal growth factor receptor gene (EGFR) mutations for non-small cell lung carcinoma (NSCLC) patients remain elusive. We evaluated the distribution, clinicopathological association, tyrosine kinase inhibitor (TKI) response, and outcome of NSCLC patients carrying uncommon EGFR aberrations in comparison to classical EGFR mutations.

Methods: Treatment naïve, advanced NSCLC cases tested by Next-Generation sequencing (NGS) method between 2015 and 2020 were included. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were analyzed.

Results: A total of 237 tumor samples were sequenced. Among the sixty-nine (29%) EGFR mutated cases, 41 (59.4%) harbored classical mutation (37.7% Del19, 21.7% p.L858R). Non-classical aberrations included missense mutations in exon 18/20/21 (15.9%), EGFR amplification (8.7%), exon 20 insertions (7.2%), EGFR Variant III (4.3%), exon 18 indel (2.9%), exon 21 missense (2.9%) and exon 19 missense mutation (1.4%). These occurred as complex mutations in 16% of cases. Oral TKI was administered in 66.7% cases. The patients harboring non-classical variants had a lower ORR and DCR (23.1% and 61.5%) than those carrying a common mutation (57.6% and 84.8%). Collectively, compared to the patients with common EGFR mutations, the uncommon group showed early disease progression and had shorter overall survival.

Conclusion: NGS testing has the capacity to reveal a diverse spectrum of uncommon EGFR variants. Our study can contribute to the database of uncommon EGFR mutations with a positive influence on evidence-based care of advanced lung cancer patients with EGFR mutations.
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http://dx.doi.org/10.1016/j.ctarc.2021.100398DOI Listing
May 2021

Performance of the American Heart Association/American College of Cardiology Pooled Cohort Equations to Estimate Atherosclerotic Cardiovascular Disease Risk by Self-reported Physical Activity Levels.

JAMA Cardiol 2021 Jun;6(6):690-696

Department of Medicine (Cardiology), Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Importance: The American Heart Association/American College of Cardiology pooled cohort equations (PCEs) are used for predicting 10-year atherosclerotic cardiovascular disease (ASCVD) risk. Pooled cohort equation risk prediction capabilities across self-reported leisure-time physical activity (LTPA) levels and the change in model performance with addition of LTPA to the PCE are unclear.

Objective: To evaluate PCE risk prediction performance across self-reported LTPA levels and the change in model performance by adding LTPA to the existing PCE model.

Design, Setting, And Participants: Individual-level pooling of data from 3 longitudinal cohort studies-Atherosclerosis Risk in Communities, Multi-Ethnic Study of Atherosclerosis, and Cardiovascular Health Study-was performed. A total of 18 824 participants were stratified into 4 groups based on self-reported LTPA levels: inactive (0 metabolic equivalent of task [MET]-min/wk), less than guideline-recommended (<500 MET-min/wk), guideline-recommended (500-1000 MET-min/week), and greater than guideline-recommended (>1000 MET-min/wk). Pooled cohort equation risk discrimination was studied using the C statistic and reclassification capabilities were studied using the Greenwood Nam-D'Agostino χ2 goodness-of-fit test. Change in risk discrimination and reclassification on adding LTPA to PCEs was evaluated using change in C statistic, integrated discrimination index, and categorical net reclassification index.

Main Outcomes And Measures: Adjudicated ASCVD events during 10-year follow-up.

Results: Among 18 824 participants studied, 10 302 were women (54.7%); mean (SD) age was 57.6 (8.2) years. A total of 5868 participants (31.2%) were inactive, 3849 (20.4%) had less than guideline-recommended LTPA, 3372 (17.9%) had guideline-recommended LTPA, and 5735 (30.5%) had greater than guideline-recommended LTPA level. Higher LTPA levels were associated with a lower risk of ASCVD after adjustment for risk factors (hazard ratio [HR] per 1-SD higher LTPA, 0.91; 95% CI, 0.86-0.96). Across LTPA groups, PCE risk discrimination (C statistic, 0.76-0.78) and risk calibration (all χ2 P > .10) was similar. Addition of LTPA to the PCE model resulted in no significant change in the C statistic (0.0005; 95% CI, -0.0004 to 0.0015; P = .28) and categorical net reclassification index (-0.003; 95% CI, -0.010 to 0.010; P = .95), but a minimal improvement in the integrated discrimination index (0.0008; 95% CI, 0.0002-0.0013; P = .005) was observed. Similar results were noted when cohort-specific coefficients were used for creating the baseline model.

Conclusions And Relevance: Higher self-reported LTPA levels appear to be associated with lower ASCVD risk and increasing LTPA promotes cardiovascular wellness. These findings suggest the American Heart Association/American College of Cardiology PCEs are accurate at estimating the probability of 10-year ASCVD risk regardless of LTPA level. The addition of self-reported LTPA to PCEs does not appear to be associated with improvement in risk prediction model performance.
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http://dx.doi.org/10.1001/jamacardio.2021.0948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082430PMC
June 2021

COVID-19 and cancer: Sailing through the tides.

Pathol Res Pract 2021 May 26;221:153417. Epub 2021 Mar 26.

Rajiv Gandhi Cancer Institute and Research Centre, Delhi, India.

The COVID-19 (coronavirus disease) pandemic caused by SARS-CoV-2 with its rapid expansion has led to extraordinary implications in our understanding of viral infections and their management globally. In this current scenario of unusual circumstances and public health emergency, the cancer care per se is facing unprecedented challenges. The peculiarity of the SARS-CoV-2 infections is still being uncovered as the pandemic spreads across the populations than showing signs of its curtailment. The review highlights the significance of idiosyncrasy of the SARS-Cov-2 infection especially putting forth the importance of immunosenescence, both in the COVID-19 specific immune response in the infected lungs of the elderly and in the cancer patients infected with SARS-CoV-2.The focus of the article is directed towards demystifying the unparalleled essence of a proprotein convertase, Furin in the biology of the SARS-Cov-2 infection and its role in facilitating viral transmission through expedited cellular entry into alveolar epithelial cells in COVID-19 infected cancer patients. The risk stratification of the cancer treatment and guidelines shaped up by national and international oncology societies in providing uncompromised patient care during the COVID-19 crisis have also been addressed. The global efforts towards vaccination in developing SARS CoV-2 immunity are also discussed in this article.
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http://dx.doi.org/10.1016/j.prp.2021.153417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997300PMC
May 2021

Vascular Regenerative Capacity and the Obesity Paradox in Coronary Artery Disease.

Arterioscler Thromb Vasc Biol 2021 06 15;41(6):2097-2108. Epub 2021 Apr 15.

Division of Cardiology, Department of Medicine, Emory Clinical Cardiovascular Research Institute (A. Mehta, S.J.I., D.S.D., Z.A., A.N., A.A.A., A.H., A.V., S.F.A., A. Mokhtari, I.H., L.S.S., Y.-A.K., A.A.Q.), Emory University School of Medicine, Atlanta, GA.

[Figure: see text].
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http://dx.doi.org/10.1161/ATVBAHA.120.315703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147702PMC
June 2021

Prevention of atherosclerotic cardiovascular disease in South Asians in the US: A clinical perspective from the National Lipid Association.

J Clin Lipidol 2021 May-Jun;15(3):402-422. Epub 2021 Mar 29.

Advocate Lutheran General Hospital, Park Ridge, IL, United States.

It is now well recognized that South Asians living in the US (SAUS) have a higher prevalence of atherosclerotic cardiovascular disease (ASCVD) that begins earlier and is more aggressive than age-matched people of other ethnicities. SA ancestry is now recognized as a risk enhancer in the US cholesterol treatment guidelines. The pathophysiology of this is not fully understood but may relate to insulin resistance, genetic and dietary factors, lack of physical exercise, visceral adiposity and other, yet undiscovered biologic mechanisms. In this expert consensus document, we review the epidemiology of ASCVD in this population, enumerate the challenges faced in tackling this problem, provide strategies for early screening and education of the community and their healthcare providers, and offer practical prevention strategies and culturally-tailored dietary advice to lower the rates of ASCVD in this cohort.
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http://dx.doi.org/10.1016/j.jacl.2021.03.007DOI Listing
March 2021

Are all ALK variants created equal? Clinicopathologic features and outcomes: a propensity-matched study.

Int J Clin Oncol 2021 Jul 12;26(7):1221-1228. Epub 2021 Apr 12.

Department of Laboratory Services, Molecular Diagnostics and Transfusion Medicine, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India.

Anaplastic lymphoma kinase (ALK) rearranged NSCLC comprises a molecularly distinct subgroup occurring in 10% cases. Various EML4-ALK and non EML4 variants are known to occur which can be detected only on NGS and show differential TKI responses. 113 ALK-IHC positive cases were subjected to a custom panel-based NGS for detection of ALK variants. Clinicopathologic features and outcomes were studied and propensity-matched analysis was done. The median age of the overall cohort was 53 years. 91 (80.5%) cases were NGS positive, the most common being EML4-ALK (90, 98.9%) cases. The most common EML4 variant was Variant 1 (40, 35%) cases, Variant 3 (28, 25%) cases, and Variant 2 (17, 15%) cases. One novel EML4-ALK variant was also encountered which was found to be intrinsically resistant to crizotinib. On pre-weight-adjusted comparison, Variant 1 group had a higher occurrence of brain and extrathoracic metastases. The median OS was 44 months for the entire cohort. 49 patients received crizotinib as first-line TKI. Among these, the median OS for Variant 2 was not reached; it was 38 months and 24 months for Variant 1 and Variant 3, respectively. The median PFS for crizotinib treated patients was 8.3 months (Variant 2: 11 months, Variant 1: 8 months, and Variant 3: 9 months). On propensity-matched analyses, there was no difference in OS and PFS between Variant 1 and Variant 3, with higher HR for Variant 3. We present a large data set evaluating clinical and outcome differences between ALK variants. The unique standpoint of this study involves the propensity-weighted model to account for differences among the groups, with no prognostic differences between Variant 1 and Variant 3, which is distinct from literature.
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http://dx.doi.org/10.1007/s10147-021-01916-wDOI Listing
July 2021

Association of Carotid Artery Plaque With Cardiovascular Events and Incident Coronary Artery Calcium in Individuals With Absent Coronary Calcification: The MESA.

Circ Cardiovasc Imaging 2021 04 8;14(4):e011701. Epub 2021 Apr 8.

Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison (M.C.T., J.H.S.).

Background: Absence of coronary artery calcium (CAC) identifies asymptomatic individuals at low cardiovascular disease risk. Carotid artery plaque is a marker of increased risk, but its association with cardiovascular risk and incident CAC in people without CAC is unclear.

Methods: Multi-Ethnic Study of Atherosclerosis participants with CAC score of 0 at enrollment who also underwent carotid plaque measurement using B-mode ultrasonography were prospectively followed for incident coronary heart disease, stroke, and cardiovascular disease events, and CAC (score >0 on up to 3 serial computed tomography scans). The association of carotid plaque presence and plaque score (Ln[score+1]) at baseline with cardiovascular events and incident CAC was evaluated with Cox proportional hazards regression models adjusted for demographics, risk factors, and statin use.

Results: Among these 2673 participants (58 years, 64% women, 34% White, 30% Black, 24% Hispanic, and 12% Chinese), carotid plaque at baseline was observed in 973 (36%) and the median plaque score (range, 1-12) among those with plaque was 1. A total of 79 coronary heart disease, 80 stroke, and 151 cardiovascular disease events were observed during 16.1 years of follow-up. Carotid plaque presence and plaque score were independently associated with coronary heart disease risk (HRs, 1.66 [95% CI, 1.04-2.66]; and 1.48 [95% CI, 1.01-2.17], respectively) but not with stroke and cardiovascular disease risk. A total of 973 (36.4%) participants developed CAC over the evaluation period (median 9.3 years). Carotid plaque presence and plaque score were independently associated with incident CAC (HRs, 1.34 [95% CI, 1.18-1.54]; and 1.37 [95% CI, 1.21-1.54]), respectively.

Conclusions: The presence and extent of carotid plaque are associated with long-term coronary heart disease risk and incident CAC among middle-aged asymptomatic individuals with an initial CAC score of 0.
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http://dx.doi.org/10.1161/CIRCIMAGING.120.011701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058258PMC
April 2021

Creation and Validation of a Novel Sex-Specific Mortality Risk Score in LVAD Recipients.

J Am Heart Assoc 2021 04 25;10(7):e020019. Epub 2021 Mar 25.

Division of Cardiology Department of Medicine Emory Clinical Cardiovascular Research InstituteEmory University School of Medicine Atlanta GA.

Background Prior studies have shown that women have worse 3-month survival after receiving a left ventricular assist device compared with men. Currently used prognostic scores, including the Heartmate II Risk Score, do not account for the increased residual risk in women. We used the IMACS (International Society for Heart and Lung Transplantation Mechanically Assisted Circulatory Support) registry to create and validate a sex-specific risk score for early mortality in left ventricular assist device recipients. Methods and Results Adult patients with a continuous-flow LVAD from the IMACS registry were randomly divided into a derivation cohort (DC; n=9113; 21% female) and a validation cohort (VC; n=6074; 21% female). The IMACS Risk Score was developed in the DC to predict 3-month mortality, from preoperative candidate predictors selected using the Akaike information criterion, or significant sex × variable interaction. In the DC, age, cardiogenic shock at implantation, body mass index, blood urea nitrogen, bilirubin, hemoglobin, albumin, platelet count, left ventricular end-diastolic diameter, tricuspid regurgitation, dialysis, and major infection before implantation were retained as significant predictors of 3-month mortality. There was significant ischemic heart failure × sex and platelet count × sex interaction. For each quartile increase in IMACS risk score, men (odds ratio [OR], 1.86; 95% CI, 1.74-2.00; <0.0001), and women (OR, 1.93; 95% CI, 1.47-2.59; <0.0001) had higher odds of 3-month mortality. The IMACS risk score represented a significant improvement over Heartmate II Risk Score (IMACS risk score area under the receiver operating characteristic curve: men: DC, 0.71; 95% CI, 0.69-0.73; VC, 0.69; 95% CI, 0.66-0.72; women: DC, 0.73; 95% CI, 0.70-0.77; VC, 0.71 [95% CI, 0.66-0.76; <0.01 for improvement in receiver operating characteristic) and provided excellent risk calibration in both sexes. Removal of sex-specific interaction terms resulted in significant loss of model fit. Conclusions A sex-specific risk score provides excellent risk prediction in LVAD recipients.
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http://dx.doi.org/10.1161/JAHA.120.020019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174331PMC
April 2021

IHC versus FISH versus NGS to detect ALK gene rearrangement in NSCLC: all questions answered?

J Clin Pathol 2021 Mar 22. Epub 2021 Mar 22.

Laboratory Services, Transfusion Medicine and Research, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India.

Aims: Anaplastic lymphoma kinase () rearranged non-small cell lung carcinoma (NSCLC) is a distinct molecular subtype and rapid approval of tyrosine kinase inhibitors (TKIs) has necessitated rapid and sensitive diagnostic modalities for the detection of this alteration. Gene rearrangements can be identified using many techniques including fluorescence in situ hybridisation (FISH), reverse transcriptase-PCR, next-generation sequencing (NGS) and immunohistochemistry (IHC) for fusion oncoprotein expression. We aimed to determine the concordance between IHC, FISH and NGS for biomarker detection, and determine differences in sensitivity, and survival outcomes.

Methods: We analysed the concordance between IHC using D5F3 monoclonal antibody, FISH (break-apart) and NGS using a custom panel containing 71 different variants.

Results: Among 71 cases included in this study, FISH was evaluable in 58 cases. The concordance of ALK IHC with FISH was 75.9% and that with NGS was 84.5%. The sensitivities of FISH and NGS were 75.6% and 87.5%, respectively. The median progression-free survival of ALK IHC-positive and FISH-negative group was 5.5 months and that of both positive was 9.97 months.

Conclusion: Although NGS offers a better throughput and visualisation, IHC still remains the quintessential screening tool in upfront diagnosis of ALK rearranged NSCLC.
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http://dx.doi.org/10.1136/jclinpath-2021-207408DOI Listing
March 2021

EGFR mutation testing on plasma and urine samples: A pilot study evaluating the value of liquid biopsy in lung cancer diagnosis and management.

Curr Probl Cancer 2021 Mar 3:100722. Epub 2021 Mar 3.

Department of Pathology, All India Institute of Medical Sciences, New Delhi, India. Electronic address:

Background: Cell free DNA (cfDNA) shed by cancer cells into blood and body fluids is a potential substrate for molecular testing. While plasma is approved for EGFR mutation testing in certain clinical settings, mutation testing on urine is not well explored in lung cancer. In this study, we assess the feasibility and diagnostic accuracy of EGFR mutation analysis on plasma and urine samples.

Methods: Matched plasma and urine were collected prospectively from TKI-naïve lung adenocarcinoma (ADCA) patients (Group A) with available tumor tissue. Only plasma was collected from TKI-treated, known EGFR mutant ADCA patients developing TKI resistance (Group B). qPCR (tumor tissue) or digital droplet-PCR (urine/plasma) was performed for exon 19 deletions, exon 21 L858R and exon 20 T790M.

Results: Eighty-one patients (60 Group A, 21 Group B) were included. In Group A, EGFR mutations were detected in tissue in 34/60 (57%) patients. Mutations were detected in matched plasma in 24 (24/34, 70.5% sensitivity), and in matched urine in 15 (15/25, 60% sensitivity) of the 34 EGFR mutant cases, with no false positives (100% positive predictive value). Plasma and urine mutation results showed moderate agreement (70%) with a combined sensitivity of 88% (22/25). In Group B, new T790M mutations were detected in plasma in 61% (13/21) patients.

Conclusion: Liquid biopsies show moderate sensitivity (plasma > urine) with 100% positive predictive rates for EGFR mutations. Testing of more than one type of liquid biopsy sample increases sensitivity. In TKI-resistant settings, liquid biopsies can obviate need for invasive biopsies in >60% patients.
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http://dx.doi.org/10.1016/j.currproblcancer.2021.100722DOI Listing
March 2021

Malfeasance of KRAS mutations in carcinogenesis.

Clin Exp Med 2021 Aug 12;21(3):439-445. Epub 2021 Mar 12.

Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, Delhi, India.

Activating mutations in the KRAS gene (Kirsten rat sarcoma 2 viral oncogene homolog gene) are commonly seen across the various solid organ and hematolymphoid neoplasms. With the likelihood of the mutation specific KRAS inhibitor entering clinical practice, the present studies profiled the landscape of these mutations in the Indian population to add to databases and posit the clinical utility of its emerging inhibitors. This study included 489 formalin fixed paraffin-embedded (FFPE) tissue samples from consecutive patients during a 5-year period (2015-2019). The clinical records were obtained from the medical record archives of the institution. Library preparation was done using the Oncomine Assay™. Sequencing was performed using the Ion PGM Hi-Q Sequencing Kit on the Ion Torrent Personal Genome Machine (Ion PGM) as well as on Ion Torrent S5 sequencer using the S5 sequencing kit. Ion Torrent Suite™ Browser version 5.10 and Ion Reporter™ version 5.10 were used for data analysis. A total of 50 cases with KRAS mutations were observed occurring most commonly in the codons 12 and 13. The G12D mutation was the most commonly encountered subtype in our cohort (21/50), whereas the G12C mutation was observed in 5 cases, and interestingly, this mutation was only seen in patients with non-small cell lung carcinoma (NSCLC). In the largest cohort from Indian subcontinent reporting spectrum of KRAS mutations in human cancers, an incidence of 11% was observed across all cancer types. Therapies targeting the G12C mutations can benefit up to 20% KRAS-mutated NSCLC. Building databases of spectrum of KRAS mutations in different populations across diverse cancer types is the anticipatory step to this end.
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http://dx.doi.org/10.1007/s10238-021-00694-zDOI Listing
August 2021
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