Chitra Sarkar

AIIMS Bhopal All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India

Are you Chitra Sarkar?

Claim your profile

Publications (361)752.54 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: This study aims (1) to evaluate ATRX expression in different grades and subtypes of gliomas and correlate with other hallmark genetic alterations, (2) to identify and characterize mosaic/heterogeneous staining in gliomas in terms of mutation status. 176 cases of glioma were assessed for ATRX immunohistochemistry and subdivided into positive, negative and mosaic/heterogeneous staining patterns. Five cases with heterogeneous staining were further subjected to next generation sequencing. Higher frequency of ATRX immune-negativity was detected in grade II/III astrocytic, oligoastrocytic tumors and secondary glioblastomas (GBMs), while infrequent in primary GBMs and rare in oligodendrogliomas. Loss of expression was significantly associated with IDH1 and/or TP53 mutation, while mutually exclusive with 1p/19q co-deletion. Mosaic/heterogeneous staining was detected almost exclusively in GBMs (21.2%). Two different types of mosaic staining were identified (1) Admixture of positive and negative nuclei or intermixed mosaic and (2) Separate fragments with positive and negative/intermixed mosaic staining. ATRX mutation was identified in 2/5 (40%) cases with mosaic staining while one case showed DAXX mutation. All these cases were characterized by distinctly separate immune-negative and positive/intermixed foci. Hence, it is suggested that cases with heterogeneous staining (especially those with distinctly negative fragments) should be subjected to mutation analysis. This article is protected by copyright. All rights reserved.
    No preview · Article · Feb 2016 · Brain Pathology
  • [Show abstract] [Hide abstract]
    ABSTRACT: Enhancer of Zeste homologue2 (EZH2) is an epigenetic regulator that functions as oncogene in astrocytic tumors, however, EZH2 regulation remains little studied. In this study, we measured EZH2 levels in low (Gr-II,DA) and high grade (Gr-IV,GBM) astrocytic tumors and found significant increased EZH2 transcript level with grade(median DA-8.5, GBM-28.9).However, a different trend was reflected in protein levels, with GBMs showing high EZH2 LI(median-26.5) compared to DA (median 0.3). This difference in correlation of EZH2 protein and RNA levels suggested post-transcriptional regulation of EZH2, likely mediated by miRNAs. We selected eleven miRNAs that strongly predicted to target EZH2 and measured their expression. Three miRNAs (miR-26a-5p,miR27a-3p and miR-498) showed significant correlation with EZH2 protein, suggesting them as regulators of EZH2, however miR-26a-5p levels decreased with grade. ChIP analyses revealed H3K27me3 modifications in miR-26a promoter suggesting feedback loop between EZH2 and miR26a. We further measured six downstream miRNA targets of EZH2 and found significant downregulation of four (miR-181a/b and 200b/c) in GBM. Interestingly, EZH2 associated miRNAs were predicted to target 25 genes in glioma-pathway, suggesting their role in tumor formation or progression. Collectively, our work suggests EZH2 and its miRNA interactors may serve as promising biomarkers for progression of astrocytic tumors and may offer novel therapeutic strategies.
    No preview · Article · Jan 2016 · Brain Tumor Pathology
  • [Show abstract] [Hide abstract]
    ABSTRACT: Ependymomas are relatively uncommon gliomas with poor prognosis despite recent advances in neurooncology. Molecular pathogenesis of ependymomas is not extensively studied. Lack of correlation of histological grade with patient outcome has directed attention towards identification of molecular alterations as novel prognostic markers. Recently, 1q gain has emerged as a potential prognostic marker, associated with decreased survival, especially in posterior fossa, high grade tumors. Cases of intracranial ependymomas were retrieved. Tumors were graded using objective criteria to supplement WHO grading. Fluorescence in situ hybridization for 1q gain was performed on formalin-fixed paraffin embedded sections. Eighty-one intracranial ependymomas were analyzed. Pediatric (76 %) and infratentorial (70 %) ependymomas constituted the majority. 1q gain was seen in 27 cases (33 %), was equally frequent in children (34 %) and adults (32 %), supratentorial (37 %) and infratentorial (32 %) location, grade II (33 %) and III (25 %) tumors. Recurrence was noted in 24 cases and death in 7 cases with 5-year progression-free and overall-survival rates of 37 % and 80 %, respectively. Grade II tumors had a better survival than grade III tumors; histopathological grade was the only prognostically significant marker. 1q gain had no prognostic significance. 1q gain is frequent in ependymomas in Indian patients, seen across all ages, sites and grades, and thus is likely an early event in pathogenesis. The prognostic value of 1q gain, remains uncertain, and multicentric pooling of data is required. A histopathological grading system using objective criteria correlates well with patient outcome and can serve as an economical option for prognostication of ependymomas.
    No preview · Article · Jan 2016 · Journal of Neuro-Oncology

  • No preview · Chapter · Dec 2015
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Meningiomas are the most common benign central nervous system tumors. However, a sizeable fraction recurs, irrespective of histological grade. No molecular marker is available for prediction of recurrence in these tumors. Materials and Methods: We analyzed recurrent meningiomas with paired parent and recurrent tumors by fluorescence in situ hybridization for 1p36 and 14q32 deletion, AKT and SMO mutations by sequencing, and immunohistochemistry for GAB1, progesterone receptor (PR), p53, and MIB-1. Results: 18 recurrent meningiomas (11 grade I, 3 grade II, 4 grade III) with their parent tumors (14 grade I, 2 grade II and 2 grade III) were identified. Overall, 61% of parent and 78% of recurrent meningiomas showed 1p/14q co-deletion. Notably, grade I parent tumors showed 1p/14q co-deletion in 64% cases while 82% of grade I recurrent tumors were co-deleted. AKT mutation was seen in two cases, in both parent and recurrent tumors. SMO mutations were absent. GAB1 was immunopositive in 80% parent and 56.3% recurrent tumors. MIB-1 labeling index (LI), PR and p53 expression did not appear to have any significant contribution in possible prediction of recurrence. Conclusion: Identification of 1p/14q co-deletion in a significant proportion of histologically benign (grade I) meningiomas that recurred suggests its utility as a marker for prediction of recurrence. It appears to be a better predictive marker than MIB1-LI, PR and p53 expression. Recognition of AKT mutation in a subset of meningiomas may help identify patients that may benefit from PI3K/AKT pathway inhibitors, particularly among those at risk for development of recurrence, as determined by presence of 1p/14q co-deletion.
    No preview · Article · Nov 2015 · Indian Journal of Pathology and Microbiology
  • Source

    Full-text · Article · Nov 2015 · Neuro-Oncology
  • Source

    Full-text · Article · Nov 2015 · Neuro-Oncology

  • No preview · Article · Nov 2015 · Neuro-Oncology

  • No preview · Article · Nov 2015 · Neuro-Oncology
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aims Primary skull bone tumors, benign or malignant, are rare, and include a vast repertoire of lesions. These tumors are not reported systematically in the literature, with most studies being on individual entities or as single case reports. Methods Primary bone tumors diagnosed over a period of 12 years were retrieved, histological diagnoses reviewed, and clinical parameters noted. Results We identified 125 primary skull bone tumors. The mean age at diagnosis was 32 years (range: 2–65 years). Majority of patients were adults (82.4%); male preponderance was noted (72.8%). Malignant tumors were more frequent than benign tumors. Most common malignant tumor was chordoma (n = 37), while most common benign tumor was osteoma (n = 7). Tumors were most frequently located at the skull base, of which clivus was most common location. Chordomas accounted for majority of clival tumors, while chondrosarcoma predominated at other skull base locations. Benign tumors were extremely rare in skull base. Tumors of the vault bones were infrequent; with chondrosarcoma and osteoma being the most common malignant and benign tumors, respectively. Conclusions This is the largest series of primary skull bone tumors from India. Documentation of such a series will aid in approaching differential diagnosis of skull tumors in a systematic manner.
    No preview · Article · Oct 2015 · Journal of Neurological Surgery, Part B: Skull Base
  • [Show abstract] [Hide abstract]
    ABSTRACT: Abstract BACKGROUND: Corpus callosotomy is a palliative procedure especially for Lennox-Gastaut semiology without localization with drop attacks. OBJECTIVE: To describe endoscopic-assisted complete corpus callosotomy combined with anterior, hippocampal, and posterior commissurotomy. METHODS: Patients with drug refractory epilepsy having drop attacks as the predominant seizure type, bilateral abnormalities on imaging, and moderate to severe mental retardation were included. All underwent a complete workup (including magnetic resonance imaging). RESULTS: Patients (n = 16, mean age 11.4 ± 6.4 years, range 6-19 years) had a mean seizure frequency of 24.5 ± 19.8/days (range 1-60) and a mean intelligence quotient of 25.23 ± 10.71. All had syndromic diagnosis of Lennox-Gastaut syndrome, with the following etiologies: hypoxic insult (10), lissencephaly (2), bilateral band heterotropia (2), and microgyria and pachygyria (2). Surgery included complete callosotomy and the section of anterior and posterior commissure by microscopic approach through a mini craniotomy (11) and endoscopic-assisted approach (5). Complications included meningitis (1), hyperammonemic encephalopathy (2), and acute transient disconnection (5). There was no mortality or long-term morbidity. Mean follow-up was 18 ± 4.7 months (range 16-27 months). Drop attacks stopped in all. Seizure frequency/duration decreased >90% in 10 patients and >50% in 5 patients, and increased in 1 patient. All patients attained presurgical functional levels in 3 to 6 months. Child behavior checklist scores showed no deterioration. Parental questionnaires reported 90% satisfaction attributed to the control of drop attacks. The series was compared retrospectively with an age/sex-matched cohort (where a callosotomy only was performed), and showed better outcome for drop attacks (P < .003). CONCLUSION: This preliminary study demonstrated the efficacy and safety of complete callosotomy with anterior, hippocampal, and posterior commissurotomy in Lennox-Gastaut syndrome (drop attacks) with moderate to severe mental retardation. ABBREVIATIONS: AC, anterior commissureACT, anterior commissurotomyCBCL, child behavior check listCC, corpus callosotomyHC, hippocampalHCT, hippocampal commissurotomyIQ, intelligence quotientPC, posterior commissurePCT, posterior commissurotomy.
    No preview · Article · Oct 2015 · Neurosurgery
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Supratentorial primitive neuro-ectodermal tumours (SPNET) are high grade, embryonal tumours, which account for around 2–3% of paediatric brain tumours. Materials & methods:We assessed the clinical features and treatment outcome in patients of SPNET by retrospective chart review from 2003-12. Overall survival(OS) and recurrence free survival(RFS) were analyzed by Kaplan-Meier method. Results: Thirty two patients met the study criterion (male: female=21:11). Median age at presentation was 12 years (range 3-49 years). Presenting features (median duration-3 months) included headache in 20(62.5%), vomiting in 15(46.88%), visual deterioration in 11(34.38%), seizures in 6(18.75%) and ataxia in 5(15.63%) patients. Contrast enhanced MRI of brain revealed heterogeneous contrast-enhancing solid cystic supratentorial lesion. Tumour location was pineal in 17, frontal in 3, temporal in 2, occipital in 1, multilobed in 5, ventricular in 1, thalamic in 1, midbrain in 1and suprasellar in 1patient. Median KPS was noted to be 80. Surgical resection was gross-total in 12(37.5%), near-total in 2(6.25%), subtotal in 10(31.25%) and limited to biopsy in 7(21.88%) patients. Histopathology showed sheets of small round blue cell tumour immunopositve for synaptophysin, class III ß-tubulin and neuron specific enolase (NSE) suggestive of SPNET. Median MIB-1 labelling index was 35%. At presentation, 6(18.75%) patients had leptomeningeal dissemintation. Radiation therapy was delivered in 29(90.63%) patients- craniospinal irradiation(CSI) in 24 (36Gy/20fractions/4weeks to craniospinal axis followed by local boost of 20Gy/10fractions/2weeks), whole brain RT in 1, whole ventricular RT in 1 and focal RT in 3 patients. Systemic chemotherapy (median 6 cycles), given in 27(84.38%) patients, included VAC(vincristine,adriamycin,cyclophosphamide) alternating with IE (ifosfamide,etoposide) regimen in non-pineal tumours and EP (carboplatin and etoposide) regimen in pineal tumours. After a median follow-up of 29.22 months (mean 30.35 months), complete response, partial response and progressive disease were noted in 17(53.13%), 1(3.13%) and 14(43.75%) patients respectively. Seven (21.88%) patients died-6 due to disease progression and 1 due to neutropenic sepsis. Recurrence was noted in 13(40.63%) patients-local in 3, leptomeningeal in 5 and both in 5 patients. Median OS was not reached (actuarial rate of OS at 2 and 3 years-80.4% and 75.7% respectively) and estimated median RFS was noted to be 5.49 years (actuarial rate of RFS at 2 and 3 years- 71.7% and 59.5% respectively). On univariate analysis, there was a trend towards inferior RFS in patients with M+ disease (median-2.19 years) compared to those with M0 disease (median-6.38 years) (P=0.06). Conclusion: Maximal safe resection followed by CSI and systemic chemotherapy with 6 cycles of alternating regimen of VAC and IE (in non-pineal tumour) or EP (in pineal tumour) is a reasonable treatment strategy in patients of SPNET in a developing nation.
    Full-text · Conference Paper · Oct 2015
  • [Show abstract] [Hide abstract]
    ABSTRACT: Atypical teratoid/rhabdoid tumor (AT/RT) is an uncommon malignancy with a dismal outcome, which responds poorly to multimodality therapies. Animal studies have revealed Cyclin D1 as a possible therapeutic target. The addition of vascular endothelial growth factor (VEGF) inhibitors to chemotherapeutic regimens has shown promising results in pediatric central nervous system tumors. Enhancer of Zeste homolog 2 (EZH2) overexpression has been implicated in various cancers, including medulloblastomas. H3K27me3 is a new marker for pediatric high-grade gliomas. However, their role in AT/RT has not been evaluated sufficiently. We retrieved cases of AT/RT, and reviewed their clinical data and histopathologic features. Immunohistochemistry for Cyclin D1, VEGF, EZH2, and H3K27me3 was performed. Follow-up was noted when available. Fourteen cases of AT/RT were identified (mean age, 3.4 y; range, 10 mo to 8 y). Cyclin D1 immunopositivity was noted in all cases [labeling index (LI): 5% to 98%; mean, 41.3%]. VEGF positivity was seen in 83.3% of the cases. All cases showed EZH2 overexpression (mean LI, 74.3%; range, 32% to 96%). Reduction of H3K27me3 expression was noted in 63% of the cases, with no correlation with EZH2 LI. Two patients died of postoperative complications. Of the rest, follow-up was available for 7 (range, 7 to 120 wk): 1 achieved clinical remission, whereas 6 developed progressive disease, including 3 deaths. Varying degrees of immunoreactivity to Cyclin D1, VEGF, and EZH2 were noted in the majority of the AT/RTs, and detection of these markers may be of value in the development of novel therapeutic agents and in determining which patients can benefit from them. AT/RTs show reduction in H3K27me3 expression, independent of EZH2 expression, indicating that their interaction requires further evaluation.
    No preview · Article · Oct 2015 · Applied immunohistochemistry & molecular morphology: AIMM / official publication of the Society for Applied Immunohistochemistry

  • No preview · Article · Sep 2015 · Lung India
  • [Show abstract] [Hide abstract]
    ABSTRACT: •Glutamatergic tone is high in tissues obtained from patients with MTLE. •Current transient measurement revealed increased neuronal firing in MTLE. •Endogenous activity of NMDA receptors contributes to the hyper excitability. Abstract Altered excitatory synaptic transmission is one of the primary causes of seizure generation in patients with mesial temporal lobe epilepsy (MTLE). The present study is designed to delineate the contribution of glutamatergic tone under resting conditions to the hyper excitability in patients with MTLE. Resected hippocampal tissues were obtained from patients with MTLE. In these samples spontaneous excitatory postsynaptic currents (EPSCs), sensitive to NMDA receptor antagonist APV (50 μM) and AMPA receptor antagonist CNQX (10 μM) were recorded from pyramidal neurons at -70 mV. We observed that frequency of EPSCs were 28.2% higher in slices obtained from patients with MTLE compared to that in case of non-epileptic controls. We also examined spontaneous fast current transients (CTs) recorded from these pyramidal neurons under cell-attached configuration. The frequency of CTs increased in the absence of extracellular Mg2+ in brain slice preparations and were completely blocked by APV. We found that the frequency of CTs in pyramidal neurons were higher in case of MTLE samples compared to non-epileptic controls. This study suggests that enhanced endogenous activity of NMDA receptor contributes to excitability in pyramidal neurons of slice preparations obtained from patients with MTLE.
    No preview · Article · Aug 2015 · Epilepsy Research
  • [Show abstract] [Hide abstract]
    ABSTRACT: Highlights •Glutamatergic tone is high in tissues obtained from patients with MTLE. •Current transient measurement revealed increased neuronal firing in MTLE. •Endogenous activity of NMDA receptors contributes to the hyper excitability. Abstract Altered excitatory synaptic transmission is one of the primary causes of seizure generation in patients with mesial temporal lobe epilepsy (MTLE). The present study is designed to delineate the contribution of glutamatergic tone under resting conditions to the hyper excitability in patients with MTLE. Resected hippocampal tissues were obtained from patients with MTLE. In these samples spontaneous excitatory postsynaptic currents (EPSCs), sensitive to NMDA receptor antagonist APV (50 μM) and AMPA receptor antagonist CNQX (10 μM) were recorded from pyramidal neurons at -70 mV. We observed that frequency of EPSCs were 28.2% higher in slices obtained from patients with MTLE compared to that in case of non-epileptic controls. We also examined spontaneous fast current transients (CTs) recorded from these pyramidal neurons under cell-attached configuration. The frequency of CTs increased in the absence of extracellular Mg2+ in brain slice preparations and were completely blocked by APV. We found that the frequency of CTs in pyramidal neurons were higher in case of MTLE samples compared to non-epileptic controls. This study suggests that enhanced endogenous activity of NMDA receptor contributes to excitability in pyramidal neurons of slice preparations obtained from patients with MTLE.
    No preview · Article · Aug 2015 · Epilepsy research
  • [Show abstract] [Hide abstract]
    ABSTRACT: Medulloblastoma (MB) is composed of 4 molecular subgroups viz. WNT, SHH, groups 3 and 4, identified using various high-throughput methods. Translation of this molecular data into pathologist-friendly techniques that would be applicable in laboratories all over the world is a major challenge. Ninety-two MBs were analyzed using a panel of 10 IHC markers, real-time PCR for mRNA and miRNA expression, and FISH for MYC amplification. β-catenin, GAB1 and YAP1 were the only IHC markers of utility in classification of MBs into 3 subgroups viz. WNT (9.8%), SHH (45.6%) and non-WNT/SHH (44.6%). mRNA expression could further classify some non-WNT/SHH tumors into groups 3 and 4. This, however, was dependent on integrity of RNA extracted from FFPE tissue. MYC amplification was seen in 20% of non-WNT/SHH cases and was associated with worst prognosis. For routine diagnostic practice, we recommend classification of MBs into 3subgroups: WNT, SHH and non-WNT/SHH, with supplementation by prognostic markers like MYC for non-WNT/SHH tumors. Using this panel, we propose a new three-tier risk stratification system for MBs. Molecular subgrouping with this limited panel is rapid, economical, works well on FFPE tissue and is reliable as it correlates significantly with clinicopathological parameters and patient survival. This article is protected by copyright. All rights reserved.
    No preview · Article · Jul 2015 · Brain Pathology
  • A Kakkar · D Jain · S R Mathur · V K Iyer · C Sarkar · N Ranjan Dash

    No preview · Article · Jun 2015 · Cytopathology
  • [Show abstract] [Hide abstract]
    ABSTRACT: Cerebellar liponeurocytoma is a rare tumor of the central nervous system which shows neuronal and variable astrocytic differentiation, along with foci of lipomatous differentiation. It is usually located in the cerebellum, and may be mistaken for medulloblastoma with lipidized cells or lipomatous ependymoma. Histopathological examination, supplemented by immunohistochemistry and electron microscopy, is required to distinguish between these entities. This 35-year-old male presented with vomiting and headache for three months, followed by gait imbalance. Neurological examination showed positive cerebellar signs with ataxic gait. Magnetic resonance imaging showed a lesion measuring 4.4 cm× 4.3 cm× 3.9 cm involving the cerebellum. The patient underwent midline suboccipital craniotomy to excise the tumor. Histopathological examination showed a circumscribed, cellular tumor composed of round to polygonal cells with moderate cytoplasm and minimal pleomorphism. Clear intracytoplasmic vacuoles were seen within the tumor cells. These tumor cells were immunopositive for synaptophysin, NSE, and MAP-2, confirming their neurocytic origin. On ultrastructural examination, lipid vacuoles as well as dense-core neurosecretory granules were identified within these neurocytic cells, confirming the diagnosis of liponeurocytoma. No cilia, microvilli, or gap junctions were identified in the tumor cells, ruling out the possibility of lipomatous ependymoma. The differentiation of liponeurocytoma from its morphological mimics is imperative, as their treatment differs drastically. The role of electron microscopy is extremely important in this differential diagnosis.
    No preview · Article · Jun 2015 · Ultrastructural Pathology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Pediatric glioblastoma (pGBM) patients are underrepresented in major trials for this disease. We aimed to explore the outcome of pGBM patients treated with concurrent and adjuvant temozolomide (TMZ). 23 patients of pGBM treated from 2004 to 2010 were included in this retrospective analysis. Adjuvant therapy included conformal radiation 60 gray at 2 gray/fraction daily over 6 weeks with concurrent TMZ 75 mg/m(2) followed by six cycles of adjuvant TMZ 150-200 mg/m(2) (day 1-5) every 4 weeks. Kaplan-Meier estimates of overall survival (OS) were determined. Univariate analysis with log-rank test was used to determine the impact of prognostic variables on survival. Median age at presentation was 11.5 years (range: 7-19 years) and M:F ratio was 15:8. All patients underwent maximal safe surgical resection; 13 gross total resection and 10 sub-total resection. At a median follow-up of 18 months (range: 2.1-126 months), the estimated median OS was 41.9 months. The estimated median OS for patients receiving only concurrent TMZ was 8 months while that for patients receiving concurrent and adjuvant TMZ was 41.9 months (P = 0.081). Estimated median OS for patients who did not complete six cycles of adjuvant TMZ was 9.5 months versus not reached for those who completed at least six cycles (P = 0.0005). Other prognostic factors did not correlate with survival. Our study shows the benefit of TMZ for pGBM patients. Both concurrent and adjuvant TMZ seem to be important for superior OS in this group of patients.
    Full-text · Article · Jun 2015 · Indian journal of medical and paediatric oncology

Publication Stats

4k Citations
752.54 Total Impact Points

Institutions

  • 2005-2015
    • AIIMS Bhopal All India Institute of Medical Sciences
      Bhopal, Madhya Pradesh, India
  • 1987-2015
    • All India Institute of Medical Sciences
      • • Department of Pathology
      • • Department of Neuropathology
      • • Department of Biochemistry
      • • Department of Neurosurgery
      • • Department of Medical Oncology
      • • Department of Neurology
      New Dilli, NCT, India
  • 2011
    • University Health Network
      Toronto, Ontario, Canada
  • 2009
    • Maulana Azad Medical College
      • Department of Pathology
      New Dilli, NCT, India
  • 2004
    • Hôpital La Pitié Salpêtrière (Groupe Hospitalier "La Pitié Salpêtrière - Charles Foix")
      Lutetia Parisorum, Île-de-France, France