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Shruti Kate,1 Anuradha Chougule,2 Amit Joshi,1 Vanita Noronha,1 Vijay Patil,1 Rohit Dusane,3 Leena Solanki,1 Priyanka Tiwrekar,2 Vaishakhi Trivedi,1 Kumar Prabhash1 1Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India; 2Department of Molecular Pathology, Tata Memorial Hospital, Mumbai, Maharashtra, India; 3Department of Biostatistics, Clinical Research Secretariat, Tata Memorial Hospital, Mumbai, Maharashtra, India Background: The significance of uncommon EGFR mutations in newly diagnosed advanced non-small-cell lung cancer (NSCLC) patients is incompletely known. We aimed to analyze the demographic profile, outcome, and treatment attributes of these patients.Patients and methods: We retrospectively surveyed 5,738 advanced NSCLC patients who underwent EGFR testing in our center from 2013 to 2017 by in-house primer probes on real time PCR platform. Descriptive data were accumulated from electronic medical records. Survival plot was calculated using Kaplan–Meier method and compared between groups using log-rank test.Results: Out of 1,260 EGFR mutation-positive patients, 83 (6.58%) had uncommon mutations in isolation or in various combinations. Uncommon mutations were more frequent in men, never-smokers, and adenocarcinomas. Overall, exon 18 G719X, exon 20 insertion, exon 20 T790M, exon 20 S768I, and exon 21 (L858R/L861Q) were present in 9.6%, 19.3%, 12%, 3.6%, and 3.6% patients, respectively. Dual mutation positivity was found in 50.6% patients. On classifying patients as per tyrosine kinase inhibitor (TKI) sensitivity, it was found that majority of the patients had a combination TKI sensitive and insensitive mutations. The median duration of follow-up was 13 months. Five patients were lost to follow-up. Median progression-free survival on first line therapy was 6.7 months (95% CI: 4.8–8.5). Median overall survival (OS) of patients who received TKI during the course of their disease was 20.2 months (95% CI: 11.4–28.9). Median overall survival (mOS) of the entire cohort was 15.8 months (95% CI: 10.1–21.5). Among all uncommon mutations, patients with dual mutations did better, with an mOS time of 22.6 months (95% CI: 8.2–37.0, P=0.005). It was observed that TKI sensitive/TKI insensitive dual mutations had a superior OS of 28.2 months (95% CI: 15.2–41.2, P=0.039) as compared to TKI sensitive and TKI insensitive EGFR mutations.Conclusion: Uncommon EGFR mutations constitute a heterogeneous group, hence, it is imperative to understand each subgroup more to define optimal treatment. Keywords: uncommon EGFR mutations, advanced NSCLC, tyrosine kinase inhibitors, complex EGFR mutations, dual EGFR mutations

Vidya H Veldore,1,* Anuradha Choughule,2,* Tejaswi Routhu,1 Nitin Mandloi,1 Vanita Noronha,2 Amit Joshi,2 Amit Dutt,3 Ravi Gupta,1 Ramprasad Vedam,1 Kumar Prabhash2 1MedGenome Labs Private Ltd,, Bangalore, India; 2Tata Memorial Centre, Parel, Mumbai, India; 3The Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Center, Kharghar, Navi Mumbai, Maharashtra, India *These authors contributed equally to this work Abstract: Plasma cell-free tumor DNA, or circulating tumor DNA (ctDNA), from liquid biopsy is a potential source of tumor genetic material, in the absence of tissue biopsy, for EGFR testing. Our validation study reiterates the clinical utility of ctDNA next generation sequencing (NGS) for EGFR mutation testing in non-small cell lung cancer (NSCLC). A total of 163 NSCLC cases were included in the validation, of which 132 patients had paired tissue biopsy and ctDNA. We chose to validate ctDNA using deep sequencing with custom designed bioinformatics methods that could detect somatic mutations at allele frequencies as low as 0.01%. Benchmarking allele specific real time PCR as one of the standard methods for tissue-based EGFR mutation testing, the ctDNA NGS test was validated on all the plasma derived cell-free DNA samples. We observed a high concordance (96.96%) between tissue biopsy and ctDNA for oncogenic driver mutations in Exon 19 and Exon 21 of the EGFR gene. The sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of the assay were 91.1%, 100% 100%, 95.6%, and 97%, respectively. A false negative rate of 3% was observed. A subset of mutations was also verified on droplet digital PCR. Sixteen percent EGFR mutation positivity was observed in patients where only liquid biopsy was available, thus creating options for targeted therapy. This is the first and largest study from India, demonstrating successful validation of circulating cell-free DNA as a clinically useful material for molecular testing in NSCLC. Keywords: liquid biopsy, NSCLC, EGFR, ctDNA, NGS

The Narmada river basin is a highly regulated catchment in central India, supporting a population of over 16 million people. In such extensively modified hydrological systems, the influence of anthropogenic alterations is often underrepresented or excluded entirely by large-scale hydrological models. The Global Water Availability Assessment (GWAVA) model is applied to the Upper Narmada, with all major dams, water abstractions and irrigation command areas included, which allows for the development of a holistic methodology for the assessment of water resources in the basin. The model is driven with 17 Global Circulation Models (GCMs) from the Coupled Model Intercomparison Project Phase 5 (CMIP5) ensemble to assess the impact of climate change on water resources in the basin for the period 2031–2060. The study finds that the hydrological regime within the basin is likely to intensify over the next half-century as a result of future climate change, causing long-term increases in monsoon season flow across the Upper Narmada. Climate is expected to have little impact on dry season flows, in comparison to water demand intensification over the same period, which may lead to increased water stress in parts of the basin.

Vikram Gota,1 Krunal Kavathiya,1 Kartik Doshi,1 Murari Gurjar,1 Solai E Damodaran,1 Vanita Noronha,2 Amit Joshi,2 Kumar Prabhash2 1Department of Clinical Pharmacology, Advanced Centre for Treatment Research and Education in Cancer, 2Department of Medical Oncology, Tata Memorial Hospital, Mumbai, India Background: Pemetrexed-platinum doublet therapy is a standard treatment for stage IIIb/IV nonsquamous non small cell lung cancer (NSCLC). While the regimen is associated with several grade ≥3 toxicities, hyponatremia is not a commonly reported adverse effect. Here we report an unusually high incidence of grade ≥3 hyponatremia in Indian patients receiving pemetrexed-platinum doublet, and the pharmacological basis for this phenomenon. Methods: Forty-six patients with advanced NSCLC were enrolled for a bioequivalence study of two pemetrexed formulations. All patients received the pemetrexed-platinum doublet for six cycles followed by single-agent pemetrexed maintenance until progression. Pharmacokinetic blood samples were collected at predefined time points during the first cycle and the concentration-time profile of pemetrexed was investigated by noncompartmental analysis. Hyponatremic episodes were investigated with serum electrolytes, serum osmolality, urinary sodium, and urine osmolality. Results: Sixteen of 46 patients (35%) had at least one episode of grade ≥3 hyponatremia. Twenty-four episodes of grade ≥3 hyponatremia were observed in 200 cycles of doublet chemotherapy. Plasma exposure to pemetrexed was significantly higher in patients with high-grade hyponatremia than in those with low-grade or no hyponatremia (P=0.063 and P=0.001, respectively). Pemetrexed clearance in high-grade hyponatremia was quite low compared with normal and low-grade hyponatremia (P=0.001 and P=0.055, respectively). Median pemetrexed exposure in this cohort was much higher than that reported in the literature from Western studies. Conclusion: Higher exposure to pemetrexed is associated with grade ≥3 hyponatremia. The pharmacogenetic basis for higher exposure to pemetrexed in Indian patients needs further investigation. Keywords: non small cell lung carcinoma, platinum compounds, pharmacokinetics, pharmacogenetics

Aims Calcific aortic valve disease (CAVD) is the most common valve disease, which consists of a chronic interplay of inflammation, fibrosis, and calcification. In this study, sortilin (SORT1) was identified as a novel key player in the pathophysiology of CAVD, and its role in the transformation of valvular interstitial cells (VICs) into pathological phenotypes is explored. Methods and results An aortic valve (AV) wire injury (AVWI) mouse model with sortilin deficiency was used to determine the effects of sortilin on AV stenosis, fibrosis, and calcification. In vitro experiments employed human primary VICs cultured in osteogenic conditions for 7, 14, and 21 days; and processed for imaging, proteomics, and transcriptomics including single-cell RNA-sequencing (scRNA-seq). The AVWI mouse model showed reduced AV fibrosis, calcification, and stenosis in sortilin-deficient mice vs. littermate controls. Protein studies identified the transition of human VICs into a myofibroblast-like phenotype mediated by sortilin. Sortilin loss-of-function decreased in vitro VIC calcification. ScRNA-seq identified 12 differentially expressed cell clusters in human VIC samples, where a novel combined inflammatory myofibroblastic-osteogenic VIC (IMO-VIC) phenotype was detected with increased expression of SORT1, COL1A1, WNT5A, IL-6, and serum amyloid A1. VICs sequenced with sortilin deficiency showed decreased IMO-VIC phenotype. Conclusion Sortilin promotes CAVD by mediating valvular fibrosis and calcification, and a newly identified phenotype (IMO-VIC). This is the first study to examine the role of sortilin in valvular calcification and it may render it a therapeutic target to inhibit IMO-VIC emergence by simultaneously reducing inflammation, fibrosis, and calcification, the three key pathological processes underlying CAVD. [ABSTRACT FROM AUTHOR]

Byline: D. Doval, R. Deshpande, B. Dhabhar, K. Babu, K. Prabhash, R. Chopra, P. Sripada, C. Deshmukh, M. Suryavanshi More than 50% of non-small cell lung cancer (NSCLC) cases harbor [...]

Helicoverpa armigera is one of the major devastating pests of crop plants. In this context a serine peptidase inhibitor purified from the seeds of Butea monosperma was evaluated for its effect on developmental physiology of H. armigera larvae. B. monosperma peptidase inhibitor on 12% denaturing polyacrylamide gel electrophoresis exhibited a single protein band of ~14 kDa with or without reduction. In vitro studies towards total gut proteolytic enzymes of H. armigera and bovine trypsin indicated measurable inhibitory activity. B. monosperma peptidase inhibitor dose for 50% mortality and weight reduction by 50% were 0.5% w/w and 0.10% w/w, respectively. The IC50 of B. monosperma peptidase inhibitor against total H. armigera gut proteinases activity was 2.0 µg/mL. The larval feeding assays suggested B. monosperma peptidase inhibitor to be toxic as reflected by its retarded growth and development, consequently affecting fertility and fecundity of pest and prolonging the larval-pupal duration of the insect life cycle of H. armigera. Supplementing B. monosperma peptidase inhibitor in artificial diet at 0.1% w/w, both the efficiencies of conversion of ingested as well as digested food were downregulated, whereas approximate digestibility and metabolic cost were enhanced. The efficacy of Butea monosperma peptidase inhibitor against progressive growth and development of H. armigera suggest its usefulness in insect pest management of food crops.

Objective: Surgery is the recommended treatment for resectable T4a laryngeal and hypopharyngeal carcinoma. Non-surgical treatment is an option in a select few patients. Method: This retrospective study was undertaken to assess the treatment outcomes in patients with resectable T4a carcinoma of the larynx and hypopharynx who received either surgical or non-surgical treatment at our institute and to assess factors influencing these outcomes. Results: A total of 120 patients were included in the study. They were divided into groups A, B and C based on the presence of extralaryngeal spread through laryngeal membrane, cartilage or both. The overall survival was better among patients who received surgery than those who received non-surgical treatment in the three groups. The factor influencing overall survival was the treatment given in the form of surgical versus non-surgical treatment. Conclusion: Surgery is the preferred treatment for T4a laryngeal and hypopharyngeal carcinoma, even in patients with extralaryngeal spread without cartilage erosion. [ABSTRACT FROM AUTHOR]

Byline: V. Noronha, V. Sharma, A. Joshi, V. Patil, S. Laskar, K. Prabhash BACKGROUND: Cisplatin-based chemoradiation (CTRT) is the standard of care in locally advanced head and neck cancers. Limited [...]

Byline: V. Noronha, M. Chandrakanth, A. Joshi, V. Patil, A. Chougule, A. Mahajan, A. Janu, R. Chanana, K. Prabhash ROS1 rearrangement acts as a driver mutation in 1-2% of NSCLC. [...]

Byline: D. Pandey, P. Ramanathan, R. Pandey, K. Prabhash Mediastinal staging is a crucial factor in the decision making in patients with non-metastatic non-small cell lung cancer (NSCLC). Mediastinoscopy has [...]

Byline: M. Chandrakanth, V. Noronha, A. Joshi, V. Patil, A. Mahajan, K. Prabhash Sir, There is no evidence to support any cancer-directed therapy in patients with advanced lung cancer with [...]

Byline: V. Noronha, S. Jandyal, A. Joshi, V. Patil, A. Mahajan, K. Prabhash Sir, Expanded panel test beyond epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK)/c-ros oncogene 1 (ROS1) is [...]

Byline: V. Patil, V. Noronha, A. Joshi, L. Nayak, N. Pande, A. Chandrashekharan, S. Dhumal, A. Bhattacharjee, S. Banavali, K. Prabhash BACKGROUND: Metronomic chemotherapy has shown promising results in selected [...]

Byline: S. Zanwar, V. Noronha, A. Joshi, V. Patil, A. Chougule, R. Kumar, S. More, S. Goud, A. Janu, A. Mahajan, K. Prabhash INTRODUCTION: The feasibility and success rate of [...]

Byline: N. Purandare, C. Pramesh, J. Agarwal, A. Agrawal, S. Shah, K. Prabhash, G. Karimundackal, S. Jiwnani, S. Tandon, V. Rangarajan BACKGROUND: Fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) has become [...]

Byline: C. Hotwani, J. Agarwal, K. Prabhash, A. Munshi, A. Joshi, S. Misra, D. Kumar, S. Das, S. Laskar BACKGROUND: Majority of patients of lung cancer present with locally advanced [...]

Byline: A. Mathew, J. Agarwal, A. Munshi, S. Laskar, C. Pramesh, G. Karimundackal, S. Jiwnani, K. Prabhash, V. Noronha, A. Joshi, V. Rangarajan, N. Purandare, N. Jambhekar, S. Tandon, A. [...]

Byline: V. Patil, V. Noronha, A. Joshi, V. Agarwala, V. Muddu, A. Ramaswamy, A. Chandrasekharan, S. Dhumal, S. Juvekar, A. Arya, A. Bhattacharjee, K. Prabhash BACKGROUND: The present match pair [...]