Tata Memorial Centre
  • Mumbai, Maharashtra, India
Recent publications
Purpose To identify the current practices and priorities in Wilms’ tumor management for surgeons in low- and middle-income countries (LMICs). Methods One hundred thirty-seven pediatric surgeons from 44 countries completed surveys on Wilms ’ tumor surgical strategy in LMIC . This survey was distributed through the Global Initiative for Children’s Surgery, Pan-African Pediatric Surgical Association, and Latin American Pediatric Surgical Oncology Group. Results Ninety-two respondents (67.2%) participated from 19 lower middle-income countries (43.2%). Twenty-one respondents (15.3%) participated from nine lower income countries (20.5%). Nineteen respondents (13.9%) participated from 13 upper middle-income countries (29.5%). Most providers do not obtain biopsy for suspected Wilms’ tumor (79%). Delayed resection after preoperative chemotherapy is the preferred approach (70%), which providers chose due to protocol (45%), to decrease tumor rupture (22%), and to decrease complications (8%). The providers’ goal was to prevent tumor spillage and upstaging (46%) or to prevent bleeding, complication, or other organ resections (21%). Most surgeons believed that upfront resection increased the risk of tumor spillage (72%). Conclusion Providers in LMICs prefer delayed resection after preoperative chemotherapy to reduce the incidence of tumor spillage and upstaging of Wilms’ tumor. An evidence-based guideline tailored to the LMIC context can be developed from these findings.
A novel HLA‐B*07:461 and an extended HLA‐C*15:193 allele were detected during routine HLA typing process. This article is protected by copyright. All rights reserved.
Red cell distribution width (RDW) has been evaluated as a potential prognostic marker in ovarian cancers, with higher baseline values being associated with poorer outcomes. The aim of this study was to evaluate the prognostic value of RDW in high grade serous cancer (HGSC) of ovary undergoing optimal debulking surgery. Patients undergoing interval debulking surgery with a primary diagnosis of HGSC from October 2012 to September 2013 were retrospectively analysed from a prospectively maintained database. Patients with baseline haemoglobin (Hb) of < 10 g/dL undergoing non-platinum based chemotherapy and those with gross residual disease (R2 resection) at surgery were excluded. RDW values were collected at baseline. Patients were dichotomised into 2 groups based on the median RDW value. Survival outcomes were analysed. Correlation analysis was done using Pearson’s Correlation. One hundred and twenty seven out of 182 patients were included in the final analysis. The median RDW was 14.9 (range 12.7–28). The 5-year overall survival (OS) and disease free survival (DFS) in patients with RDW < the median and > the median value was 60.8 and 63.8% (p = 0.609) and 14.5 and 17.4% (p = 0.457), respectively. RDW had significant negative correlation with neutrophil–lymphocyte ratio, platelet-lymphocyte ratio, Hb and CA 125. In our study, RDW did not prognosticate for both OS and DFS in patients with HGSC of the ovary achieving platinum sensitivity and optimal cytoreduction. The exact contribution of RDW as a prognostic variable in good biology HGSC (based on platinum response and optimal cytoreduction) should be compared with suboptimal responders (to both chemotherapy and surgery) to ascertain prognostic role in a larger, prospective trial.
Background: Transoral robotic surgery (TORS) is an emerging minimally invasive surgical treatment for residual, recurrent, and new primary head and neck cancers in previously irradiated fields, with limited evidence for its oncological effectiveness. Methods: A retrospective observational cohort study of consecutive cases performed in 16 high-volume international centers before August 2018 was conducted (registered at clinicaltrials.gov [NCT04673929] as the RECUT study). Overall survival (OS), disease-free survival, disease-specific survivals (DSS), and local control (LC) were calculated using Kaplan-Meier estimates, with subgroups compared using log-rank tests and Cox proportional hazards modeling for multivariable analysis. Maximally selected rank statistics determined the cut point for closest surgical resection margin based on LC. Results: Data for 278 eligible patients were analyzed, with median follow-up of 38.5 months. Two-year and 5-year outcomes were 69.0% and 62.2% for LC, 71.8% and 49.8% for OS, 47.2% and 35.7% for disease-free survival, and 78.7% and 59.1% for disease-specific survivals. The most discriminating margin cut point was 1.0 mm; the 2-year LC was 80.9% above and 54.2% below or equal to 1.0 mm. Increasing age, current smoking, primary tumor classification, and narrow surgical margins (≤1.0 mm) were statistically significantly associated with lower OS. Hemorrhage with return to theater was seen in 8.1% (n = 22 of 272), and 30-day mortality was 1.8% (n = 5 of 272). At 1 year, 10.8% (n = 21 of 195) used tracheostomies, 33.8% (n = 66 of 195) used gastrostomies, and 66.3% (n = 53 of 80) had maintained or improved normalcy of diet scores. Conclusions: Data from international centers show TORS to treat head and neck cancers in previously irradiated fields yields favorable outcomes for LC and survival. Where feasible, TORS should be considered the preferred surgical treatment in the salvage setting.
Introduction Adolescents with cancer experience several psychosocial concerns. Cancer among adolescents contributes to one-fifth of cancers in India. Most of the published empirical literature on adolescents’ views about their cancer experience is from high-income countries. Objectives The objectives of the study were to explore the experiences of adolescents with cancer in India. Materials and Methods Twenty-eight adolescents were purposively recruited and participated in prospectively conducted qualitative interviews conducted at the Tata Memorial Hospital, Mumbai, between 2013 and 2015. Interview data were transcribed and analysed using Braun and Clarke’s reflexive thematic analysis. Results Two themes and several subthemes were generated during the analysis. The transition to the new reality of illness was traumatic. It embodied fear about the unknown, disease and symptoms. The experience was isolating and disfigurement further led to peer separation. Inadequate information made the adolescents anxious and worried, and children and parents experienced moments of severe distress. The love and support received from parents, siblings and extended family facilitated positive coping. Peer support was reassuring and enabled them to have a normalising experience. Discovering their inner strength, acceptance of the situation and faith in God made them resilient and hopeful. Conclusion Adolescents with cancer experience significant emotional concerns, which are often unexplored and unaddressed. An adolescent-specific communication framework and psychosocial programme contextual to the Indian setting may be developed based on the study findings.
Background No large studies have addressed the role of endoscopic-ultrasound biliary drainage (EUS-BD) as preoperative biliary drainage (PBD) for malignant extrahepatic biliary obstruction (MEBO). We aimed to discuss the outcomes of EUS antegrade stent placement (EUS-AG) in the preoperative and palliative setting. Methods Retrospective review of patients who underwent EUS-AG for MEBO between December 2019 and December 2021 was done. Primary outcome measures were technical success and clinical success. Secondary outcome measures were number of days of hospitalization postprocedure, adverse events related to EUS-AG procedure, morbidity related to surgery, and 3-month mortality after surgery. Results 54 patients underwent attempt for EUS-AG (mean age 54.8 ± 12.1 years; female 44.4%). Most common primary cancer was pancreatic cancer in 42.1% (23/54) patients. Indication was palliative in 34 (62.9%) patients and PBD in 20 (37%) patients. Level of block was distal in 35 (64.8%) and proximal in 19 (35.1%) patients. Technical success of EUS-AG was 88.7% (47/53). Clinical success was seen in 95.7% (45/47) patients. Median number of days of hospitalization postprocedure was 1 day. No procedure-related severe adverse events were seen. Of 20 patients who underwent EUS-AG as PBD, 19 had technical success (95%) with clinical success in 94.5% (18/19). Surgery was performed in 11 patients, of whom 10 patients underwent successful PPPD (one intraoperative liver metastasis). Two patients had Clavein–Dindo III/IV complication post-PPPD, with one mortality within 30 days of surgery. Conclusion EUS-AG is safe and effective after failed ERCP in both preoperative and palliative setting.
Introduction. Adamantinoma is sub-classified into classic/biphasic, osteofibrous dysplasia-like, and de-differentiated type. We present six adamantinomas with a prominent spindle cell component mimicking intraosseous synovial sarcomas. Methods. Six patients were either referred with a diagnosis of intraosseous synovial sarcoma or wherein synovial sarcoma was a differential diagnosis. Three tumors were tested for SS18 gene rearrangement by FISH and two for SS18::SSX fusion by RT-PCR technique. Results. There were three males and three females with an average age of 20.6 years. Radiologically, the lesions were expansile and showed lytic and/or sclerotic components, involving the cortex and/or medulla. Five lesions occurred in the tibia and two in the fibula. Two tumors displayed soft tissue extension and two occurred as multifocal lesions. Two patients were diagnosed with synovial sarcoma and a single patient with sarcomatoid carcinoma, elsewhere. Two “in-house” patients were initially diagnosed with synovial sarcomas. On review, all tumors were cellular comprising monomorphic spindle-shaped cells arranged in sheets and fascicles (n = 6), including a “herringbone-like” pattern (n = 3), focal tubules (n = 1), cohesive nests (n = 5), cords (n = 2), including pseudocystic component (n = 2). Immunohistochemically, tumor cells were positive for p63 (6/6), p40 (4/4), EMA (2/3), AE1/AE3 (5/6), various keratins (2/2), and TLE1 (2/4). Three tumors tested for SS18 rearrangement were negative, while two tumors tested for SS18::SSX fusion were negative. Conclusions. Adamantinomas with spindle cell morphology display overlapping features with synovial sarcoma. A clinico-radiological index of suspicion immunostains (p63 and p40) and molecular test for t(X; 18) translocation are useful in an exact diagnosis, which has treatment-related implications.
Background: Neuroendocrine differentiation in the prostate gland ranges from clinically insignificant neuroendocrine differentiation detected with markers in an otherwise conventional prostatic adenocarcinoma to a lethal high-grade small/large cell neuroendocrine carcinoma. The concept of neuroendocrine differentiation in prostatic adenocarcinoma has gained considerable importance due to its prognostic and therapeutic ramifications and pathologists play a pivotal role in its recognition. However, its awareness, reporting, and resource utilization practice patterns among pathologists are largely unknown. Methods: Representative examples of different spectrums of neuroendocrine differentiation along with a detailed questionnaire were shared among 39 urologic pathologists using the survey monkey software. Participants were specifically questioned about the use and awareness of the 2016 WHO classification of neuroendocrine tumors of the prostate, understanding of the clinical significance of each entity, and use of different immunohistochemical (IHC) markers. De-identified respondent data were analyzed. Results: A vast majority (90%) of the participants utilize IHC markers to confirm the diagnosis of small cell neuroendocrine carcinoma. A majority (87%) of the respondents were in agreement regarding the utilization of type of IHC markers for small cell neuroendocrine carcinoma for which 85% of the pathologists agreed that determination of the site of origin of a high-grade neuroendocrine carcinoma is not critical, as these are treated similarly. In the setting of mixed carcinomas, 62% of respondents indicated that they provide quantification and grading of the acinar component. There were varied responses regarding the prognostic implication of focal neuroendocrine cells in an otherwise conventional acinar adenocarcinoma and for Paneth cell-like differentiation. The classification of large cell neuroendocrine carcinoma was highly varied, with only 38% agreement in the illustrated case. Finally, despite the recommendation not to perform neuroendocrine markers in the absence of morphologic evidence of neuroendocrine differentiation, 62% would routinely utilize IHC in the work-up of a Gleason score 5 + 5 = 10 acinar adenocarcinoma and its differentiation from high-grade neuroendocrine carcinoma. Conclusion: There is a disparity in the practice utilization patterns among the urologic pathologists with regard to diagnosing high-grade neuroendocrine carcinoma and in understanding the clinical significance of focal neuroendocrine cells in an otherwise conventional acinar adenocarcinoma and Paneth cell-like neuroendocrine differentiation. There seems to have a trend towards overutilization of IHC to determine neuroendocrine differentiation in the absence of neuroendocrine features on morphology. The survey results suggest a need for further refinement and development of standardized guidelines for the classification and reporting of neuroendocrine differentiation in the prostate gland.
The aggressive and recurrent nature of glioblastoma is multifactorial and has been attributed to its biological heterogeneity, dysfunctional metabolic signaling pathways, rigid blood-brain barrier, inherent resistance to standard therapy due to the stemness property of the gliomas cells, immunosuppressive tumor microenvironment, hypoxia and neoangiogenesis which are very well orchestrated and create the tumor's own highly pro-tumorigenic milieu. Once the relay of events starts amongst these components, eventually it becomes difficult to control the cascade using only the balanced contemporary care of treatment consisting of maximal resection, radiotherapy and chemotherapy with temozolamide. Over the past few decades, implementation of contemporary treatment modalities has shown benefit to some extent, but no significant overall survival benefit is achieved. Therefore, there is an unmet need for advanced multifaceted combinatorial strategies. Recent advances in molecular biology, development of innovative therapeutics and novel delivery platforms over the years has resulted in a paradigm shift in gliomas therapeutics. Decades of research has led to emergence of several treatment molecules, including immunotherapies such as immune checkpoint blockade, oncolytic virotherapy, adoptive cell therapy, nanoparticles, CED and BNCT, each with the unique proficiency to overcome the mentioned challenges, present research. Recent years are seeing innovative combinatorial strategies to overcome the multifactorial resistance put forth by the GBM cell and its TME. This review discusses the contemporary and the investigational combinatorial strategies being employed to treat GBM and summarizes the evidence accumulated till date.
The past decade has witnessed a change in landscape of cancer management with the advent of precision oncology. Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment and have played an important role in improving patient survival. While the patients are living longer, treatment with ICIs are sometimes associated with adverse effects, some of which could be fatal. Radiologists can play a crucial role by early identification of some of these adverse effects during restaging scans. Our paper focuses on the imaging features of commonly occurring ICI toxicities based on organ system.
The novel alleles HLA‐A*68:175:02 and ‐A*68:287 each differ from ‐A*68:01:02:02 by a single nucleotide This article is protected by copyright. All rights reserved.
Osimertinib, a third-generation EGFR tyrosine kinase inhibitor, shows significant benefit among patients with EGFR T790M mutation at disease progression. We analyzed the whole exome sequence of 48 samples obtained from 16 lung cancer patients with a longitudinal follow-up: treatment-naïve-baseline primary tumors positive for EGFR activating-mutations, paired re-biopsies upon disease progression but negative for EGFR T790M mutation based on qPCR, and their matched normal blood samples. Our Next generation sequencing (NGS) analysis identified an additional set of 25% re-biopsy samples to harbor EGFR T790M mutation occurring at a low-allele frequency of 5% or less, undetectable by conventional qPCR-based assays. Notably, the clinical utility of osimertinib among patients harboring low-allele frequency of EGFR T790M in tissue biopsy upon disease progression remains less explored. We established erlotinib-resistant PC-9R cells and twenty single-cell sub-clones from erlotinib-sensitive lung cancer PC-9 cells using in vitro drug-escalation protocol. NGS and allele-specific PCR confirmed the low-allele frequency of EGFR T790M present at 5% with a 100-fold higher resistance to erlotinib in the PC-9R cells and its sub-clones. Additionally, luciferase tagged PC-9, and PC-9R cells were orthotopically injected through the intercostal muscle into NOD-SCID mice. The orthotopic lung tumors formed were observed by non-invasive bioluminescence imaging. Consistent with in vitro data, osimertinib, but not erlotinib, caused tumor regression in mice injected with PC-9R cells, while both osimertinib and erlotinib inhibited tumors in mice injected with PC-9 cells. Taken together, our findings could extend the benefit of osimertinib treatment to patients with low EGFR T790M mutation allele frequency on disease progression.
Purpose Imatinib is a substrate of CYP3A4, ABCB1 and ABCG2, and is known to have wide variability in pharmacokinetics (PK). At the same time, a clear relationship between drug levels and response also exists for imatinib in chronic myeloid leukaemia (CML). Therefore, pharmacogenetic-based dosing of imatinib is an attractive proposition. This study aims to characterize the population pharmacokinetics of imatinib in order to identify significant covariates including pharmacogenetic variants. Methods Forty-nine patients with CML were enrolled in the study after being on imatinib for at least 4 consecutive weeks. Steady-state pharmacokinetic sampling was performed either in a sparse (4 samples each, n = 44) or intensive manner (9 samples each, n = 5). An additional pharmacogenetic sample was also collected from all patients. Plasma imatinib levels were estimated using a validated HPLC method. Pharmacogenetic variants were identified using the PharmacoScan array platform. Population pharmacokinetic analysis was carried out using NONMEM v7.2. Seven SNPs within CYP3A4, ABCB1 and ABCG2 genes were evaluated for covariate effect on the clearance of imatinib. Results Imatinib PK was well characterized using a one-compartment model with zero-order absorption. The clearance and volume of distribution were found to be 10.2 L/h and 389 L respectively. Only SNP rs1128503 of the ABCB1 gene had a small but insignificant effect on imatinib clearance, with a 25% reduction in clearance observed in patients carrying the polymorphism. Twenty-three out of forty-nine patients (47%) carried the polymorphic allele, of whom 17 were heterozygous and six were homozygous. Conclusion Our study conclusively proves that genetic polymorphisms in the CYP3A4 and ABC family of transporters do not have any role in the personalized dosing of imatinib in CML.
The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of prostate cancer was published in 2020. It was therefore decided, by both the ESMO and the Singapore Society of Oncology (SSO), to convene a special, virtual guidelines meeting in November 2021 to adapt the ESMO 2020 guidelines to take into account the differences associated with the treatment of prostate cancer in Asia. These guidelines represent the consensus opinions reached by experts in the treatment of patients with prostate cancer representing the oncological societies of China (CSCO), India (ISMPO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence and was independent of the current treatment practices and drug access restrictions in the different Asian countries. The latter were discussed when appropriate. The aim is to provide guidance for the optimisation and harmonisation of the management of patients with prostate cancer across the different regions of Asia.
Spindle cell/sclerosing rhabdomyosarcoma (RMS), characterized by MYOD1 (L122R) mutation in a subset of cases is a newly described subtype of RMS. Presently, there is no documentation of cytomorphological features, especially of sclerosing RMS. Case 1: A 24‐year‐old male presented with pain and swelling in his wrist for a one‐year duration. MRI revealed a well‐defined soft tissue lesion measuring 5.3 cm, encasing the lower end of the ulna. Fine‐needle aspiration cytology (FNAC) smears revealed clusters of tumor cells with round to oval to spindle‐shaped nuclei, scant to moderate amount of cytoplasm with the wisps of the metachromatic stroma. Histopathological examination revealed a malignant tumor comprising cells with polygonal to spindle‐shaped nuclei, arranged in a sclerotic stroma. Immunohistochemically, the tumor cells were positive for desmin, myogenin, and MYOD1. A diagnosis of sclerosing RMS was offered. Furthermore, the tumor revealed MYOD1 (L122R) mutation. Case 2: A 43‐year‐old male presented with a 4‐month history of “nasal stuffiness” and pressure. Imaging revealed a poorly defined infiltrative lesion in his nasal cavity. FNAC smears revealed loose and tightly cohesive clusters of malignant cells with oval to spindle‐shaped nuclei, a moderate amount of ill‐defined bluish to finely vacuolated cytoplasm, and focal streak artifact with interspersed stromal fragments. Histopathological examination revealed a malignant tumor composed of oval to spindle‐shaped nuclei, embedded in a variably hyalinized stroma. Immunohistochemically, the tumor cells were positive for desmin, and myogenin. Diagnosis of spindle cell/sclerosing RMS was offered. The present study constitutes one of the first documentation of cytomorphological features of two rare cases of spindle cell/sclerosing RMS. The differential diagnoses and treatment‐related implications are presented.
Objective Saliva a non-invasive biofluid, offers diagnostic potential due to its vicinity with tumour along with systemic pooling of biomarkers. The present study evaluated the feasibility of Raman spectroscopy to identify biochemical alterations in saliva samples of healthy volunteers, habitués and oral cancer subjects. Methods The saliva samples collected from healthy volunteers (HV, n=27), oral cancer subjects (T, n=59) and tobacco habitués (HC, n=62) were subjected to Raman spectroscopy analysis. Results The 3-model and 2-model Principal Component Linear Discriminant Analysis (PC-LDA) clearly distinguished HV spectra from HC and T spectra while misclassifications were observed among HC and T groups. The sensitivity and misclassifications in 3- and 2-model analysis for HC and T groups was seen to be 55.93% and 65.52% and 35% and 40% respectively. This could be ascribed to similar tobacco habits and prolonged tobacco exposure possibly leading to cancer field effects and the shedding of clinically undetectable micro-tumours in tobacco habitués. The 3-model approach for classification between HC, HV and T groups, yielded distinct stratification of HV (93%), while the 2-model approach using HV and HC and HV and T distinctly classified HV with 93% and 96% efficiency. The higher classification efficiency highlights the utility of Raman spectroscopy in stratifying the healthy volunteers (HV) from tobacco habitués (HC) and tumour (T) groups. Conclusions Despite the low stratification accuracy of HC and T groups, distinct classification of HV demonstrates the utility of Saliva Raman spectroscopy as an early diagnostic screening technique to identify high risk individuals.
Machine learning techniques, popularly used as a tool for dimensionality reduction and pattern recognition of features, have been utilized extensively in data mining. In survival analysis, where the primary outcome is the time until a specific event occurs, identifying relevant features for building an efficient prediction model is essential. This is where machine learning can be a suitable option. However, there is an existing gap in utilizing machine learning techniques in high-dimensional survival data due to the non-availability of convenient programming functions and packages. In this article, we have developed an efficient machine learning procedure for analyzing survival data associated with high-dimensional gene expressions. Though there are several R libraries available for performing machine learning, no package support is available to implement machine learning with classification on high-dimensional survival data. highMLR, our developed R package, is capable of implementing machine learning methods on high dimensional survival data and provides a way of feature selection based on the logarithmic loss function. Several statistical methods for survival analysis have been incorporated into this machine learning algorithm. A high-dimensional gene expression dataset has been analyzed using the proposed R library to show its efficacy in feature selection.
Elevated expression of anti-apoptotic proteins, such as Bcl-2 and Mcl-1 contributes to poor prognosis and resistance to current treatment modalities in multiple cancers. Here, we report the design, synthesis and characterization of benzimidazole chalcone and flavonoid scaffold-derived bicyclic compounds targeting both Bcl-2 and Mcl-1 by optimizing the structural differences in the binding sites of both these proteins. Initial docking screen of Bcl-2 and Mcl-1 with pro-apoptotic protein Bim revealed possible hits with optimal binding energies. All the optimized bicyclic compounds were screened for their in vitro cytotoxic activity against two oral cancer cell lines (AW8507 and AW13516) which express high levels of Bcl-2 and Mcl-1. Compound 4d from the benzimidazole chalcone series and compound 6d from the flavonoid series exhibited significant cytotoxic activity (IC50 7.12 μM and 17.18 μM, respectively) against AW13516 cell line. Time Resolved-Fluorescence Resonance Energy Transfer (TR-FRET) analysis further demonstrated that compound 4d and compound 6d could effectively inhibit the Bcl-2 and Mcl-1 proteins by displacing their BH3 binding partners. Both compounds exhibited potent activation of canonical pathway of apoptosis evident from appearance of cleaved Caspase-3 and PARP. Further, treatment of oral cancer cells with the inhibitors induced dissociation of the BH3 only protein Bim from Mcl-1 and Bak from Bcl-2 but failed to release Bax from Bcl-xL thereby confirming the nature of compounds as BH3-mimetics selectively targeting Bcl-2 and Mcl-1. Our study thus identifies bicyclic compounds as promising candidates for anti-apoptotic Bcl-2/Mcl-1 dual inhibitors with a potential for further development. Graphical abstract
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444 members
Ashish Gulia
  • Orthopedic oncology, Bone and soft tissue services, Dept. of surgical oncology
Omshree Shetty
  • Molecular Pathology
Mythili Kameswaran
  • Nuclear Medicine
Venkata Raghuram
  • Advanced Centre for Treatment, Research and Education in Cancer (ACTREC)
Pratik Chandrani
  • Medical Oncology Molecular Laboratory
Dr. E Borges Road, Parel, 400012, Mumbai, Maharashtra, India