Chitra Sarkar

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

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Publications (341)699.92 Total impact

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    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.
    Brain Pathology 07/2015; DOI:10.1111/bpa.12293 · 4.35 Impact Factor
  • A Kakkar · D Jain · S R Mathur · V K Iyer · C Sarkar · N Ranjan Dash
    Cytopathology 06/2015; DOI:10.1111/cyt.12256 · 1.47 Impact Factor
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    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.
    Ultrastructural Pathology 06/2015; DOI:10.3109/01913123.2015.1027435 · 1.13 Impact Factor
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    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.
    Indian journal of medical and paediatric oncology 06/2015; 36(2):99-104. DOI:10.4103/0971-5851.158838
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    ABSTRACT: Enhancer of zeste homolog 2 (EZH2) mediated down-regulation of CDKN2A/p16 has been observed in cell lines as well as in a few carcinomas. However, there is no study correlating EZH2 expression with CDKN2A/p16 status in gliomas. Hence, the present study was conducted to evaluate EZH2 expression in astrocytic and oligodendroglial tumors and correlate with CDKN2A/p16 status as well as MIB-1 labeling index (LI). Gliomas of all grades (n = 118) were studied using immunohistochemistry to assess EZH2, p16 and MIB-1 LI and fluorescence in situ hybrization to evaluate CDKN2A gene status. EZH2 expression and CDKN2A homozygous deletion (HD) were both significantly more frequent in high-grade gliomas (HGG). Further, strong EZH2 expression (LI ≥ 25%) was significantly more common in HGGs without CDKN2A HD (48.7%; 19/39) as compared to cases with deletion (15.8%; 3/19). Loss of p16 expression was noted in 100% and 51.3% of CDKN2A deleted and non-deleted tumors, respectively. Notably, 80% (16/20) of the CDKN2A non-deleted HGGs with p16 loss had strong EZH2 expression, in contrast to only 15.8% (3/19) in the deleted group. Loss of p16 expression significantly correlated with MIB-1 LI, irrespective of EZH2 status. Thus, this study shows that EZH2 expression correlates with tumor grade in both astrocytic and oligodendroglial tumors and hence can be used as a diagnostic marker to differentiate between low and HGGs. Further, this is the first report demonstrating an inverse correlation of strong EZH2 expression with CDKN2A HD in HGGs. Loss of p16 protein expression is mostly attributable to CDKN2A HD and correlates significantly with MIB-1 LI. Notably, our study for the first time suggests a possible epigenetic mechanism of p16 loss in CDKN2A non-deleted HGGs mediated by strong EZH2 expression. A hypothetical model for control of proliferative activity in low versus HGGs is therefore proposed. © 2015 Japanese Society of Neuropathology.
    Neuropathology 06/2015; DOI:10.1111/neup.12201 · 1.80 Impact Factor
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    ABSTRACT: Pinealoblastoma is a highly malignant embryonal tumour of the pineal region affecting children and young adults. We herein intend to report the clinical features and treatment outcome of patients of pinealoblastoma treated at our institute. Clinical data was collected by retrospective chart review from 2003-2012. Histopathology slides were reviewed, and relevant immunohistochemistry stains were done. Overall survival (OS) and recurrence-free survival (RFS) were analysed by Kaplan-Meier product-limit method. Univariate and multivariate analyses of prognostic factors were done by log rank test and Cox proportional hazard regression model, respectively. Seventeen patients met the study criterion (male:female = 11:6). Median age at presentation was 14 years (range 4-47 years). Surgical resection was gross total in 6 (35.29 %), near-total in 2 (11.76 %), sub-total in 2 (11.76 %), and limited to biopsy in 7 (41.18 %) patients. At presentation, 4 patients had leptomeningeal dissemination. Radiation therapy was delivered in all patients-craniospinal irradiation in 15 (88.24 %), whole brain irradiation in 1 (5.88 %), and whole ventricular irradiation followed by boost in 1 (5.88 %) patient. Systemic chemotherapy (median 6 cycles) was given in 14 (82.35 %) patients. The most common regimen was a combination of carboplatin and etoposide, used in 10 (58.82 %) patients. After a median follow-up of 30.3 months (mean 32.01 months), death and disease recurrences were noted in 3 (17.65 %) and 7 (41.18 %) patients. Amongst the patients with recurrent disease, 4 had spinal drop metastases and 3 had local recurrence along with spinal drop metastases. Median OS was not reached, and estimated median RFS was noted to be 5.49 years. The actuarial rates of OS and RFS at 2 years were 85.6 and 73.1 %, respectively. On univariate analysis, age more than 8 years (P = 0.0071) and M0 stage (P = 0.0483) were significant predictors of improved RFS. Age retained significance on multivariate analysis of RFS (P = 0.02932). Maximal safe resection followed by craniospinal irradiation and systemic chemotherapy with 6 cycles of carboplatin-etoposide regimen is a reasonable treatment strategy in patients of pinealoblastoma more than 8 years of age in a developing nation. However, the same strategy is less effective in younger children and innovative study designs of intensification of post-operative treatment must be explored in this age group.
    Child s Nervous System 06/2015; 31(8). DOI:10.1007/s00381-015-2751-1 · 1.16 Impact Factor
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    ABSTRACT: Supra-tentorial primitive neuroectodermal tumors (SPNET) are high-grade, hemispheric tumors, which account for around 2-3 % of pediatric brain tumors. We herein intend to report the clinical features and treatment outcome of patients with nonpineal SPNET treated at our institute. Clinical data were collected by retrospective chart review from 2006 to 2012. Histopathology slides were reviewed, and relevant immunohistochemistry stains were done. Overall survival (OS), recurrence-free survival (RFS) and event-free survival (EFS) were analyzed by the Kaplan-Meier product-limit method. Fifteen patients met the study criterion (male: female = 2:1). Median age at presentation was 11 years (range 3-49 years). Surgical resection was gross total in 6 (40 %) and subtotal in 8 (53.33 %) patients. At presentation, two patients had leptomeningeal dissemination. Radiation therapy was delivered in 11 (73.33 %) patients: craniospinal irradiation in 8 (36 Gy/20 fractions/4 weeks to the craniospinal axis followed by a local boost of 20 Gy/10 fractions/2 weeks) and focal RT in 3 patients. Systemic chemotherapy (median 6 cycles; range 1-16 cycles), given in 13 (86.67 %) patients, included the VAC regimen (vincristine, adriamycin, cyclophosphamide) alternating with IE (ifosfamide,etoposide). After a median follow-up of 22.6 months (mean, 24.47 months), complete response and progressive disease were noted in 8 (53.33 %) and 7 (46.67 %) patients, respectively. Median OS was not reached, and estimated median EFS was noted to be 4.12 years (actuarial rate of EFS at 2 years, 55.2 %). Maximal safe resection followed by craniospinal irradiation and systemic chemotherapy with 6-12 cycles of an alternating regimen of VAC and IE is a reasonable treatment strategy in patients with nonpineal SPNET.
    Acta Neurochirurgica 05/2015; DOI:10.1007/s00701-015-2444-2 · 1.79 Impact Factor
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    ABSTRACT: Pediatric high grade gliomas (HGGs) are highly malignant tumors that remain incurable and relatively understudied. The crucial role of non-coding RNAs (ncRNAs) has been reported in various cancers. However, study on miRNAs in pediatric HGGs is scant and there is no report till date on status of other small ncRNAs. Genome-wide microarray analysis was performed to investigate small ncRNA expression in pediatric HGG (n=14) and compared with adult GBM signature. Validation of miRNAs and snoRNAs was done by real-time PCR. TP53 and H3F3A mutation specific miRNA and snoRNA profiles were generated and analyzed. Pediatric HGGs showed upregulation of miR-17/92 and its paralog clusters (miR106b/25 and miR-106a/363) while majority of downregulated miRNAs belonged to miR379/656 cluster (14q32). Unsupervised hierarchical clustering identified two distinct groups. Interestingly, group-2 with downregulated 14q32 cluster showed better overall survival. The miRNAs unique to pediatric HGG as compared to adult GBM were predicted to affect PDGFR and SMAD2/3 pathways. Similarities were seen between pediatric HGG and TP53 mutant miRNA profiles as compared to wild types. Several of H3F3A mutation regulated genes were found to be the targets of H3F3A mutant specific miRNAs. Remarkably, a significant downregulation of HBII-52 snoRNA cluster was found in pediatric HGGs, and was specific to H3F3A non mutants. This is first genome-wide profiling study on miRNAs and snoRNAs in pediatric HGGs with respect to H3F3A and TP53 mutations. The comparison of miRNA profiles of pediatric HGGs and adult GBM reiterates the overlaps and differences as also seen with their gene expression and methylation-signatures. This article is protected by copyright. All rights reserved. © 2014 Wiley Periodicals, Inc. © 2015 UICC.
    International Journal of Cancer 05/2015; DOI:10.1002/ijc.29610 · 5.01 Impact Factor
  • M. Sharma · K. Kumari · A. Kakkar · C. Sarkar · V. Suri · S. Chandra
    Neuro-Oncology 04/2015; 17(suppl 3):iii35-iii35. DOI:10.1093/neuonc/nov061.140 · 5.29 Impact Factor
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    ABSTRACT: Glycogen branching enzyme deficiency/Andersen disease can manifest with a spectrum of clinical phenotypes, making the diagnosis difficult. An 11-year-old Pakistani boy presented with a history of progressive weakness and delayed milestones. Echocardiography showed features of dilated cardiomyopathy. He was suspected to have congenital myopathy and was evaluated further. Muscle biopsy showed subsarcolemmal accumulation of basophilic material, which stained positively with Periodic acid-Schiff reagent (diastase-resistant). Ultrastructural examination revealed accumulation of structurally abnormal forms of filamentous glycogen, confirming the diagnosis as Andersen disease. As histopathological and immunohistochemical evaluation of muscle biopsies is not always diagnostic, ultrastructural examination may serve as a valuable adjunct in difficult cases.
    Ultrastructural Pathology 04/2015; DOI:10.3109/01913123.2015.1014612 · 1.13 Impact Factor
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    ABSTRACT: To examine Juvenile Angiofibroma (JA) tissue for expression of vascular endothelial growth factor (VEGF), and to explore its relationship with puberty status, stage, recurrence and the intraoperative blood loss. Retrospective cohort study of 36 histologically proven cases of JA. Minimum follow up period was 3 years. VEGF expression on tumor cells assessed by immunohistochemistry and graded on two criteria - percentage of cells expressing positivity and the intensity of positivity. These two parameters assessed for impact on puberty status, stage, recurrence, and blood loss. VEGF expression noted on the tumor endothelial cells in 36/36, and on the tumor stromal cells in 34/36. The percentage of cells expressing VEGF and the intensity of expression were not significantly related to puberty status, tumor stage, recurrence, or intra-operative blood loss (p values 0.3-1.0). VEGF expression is near universal in JA. Such expression is independent of puberty status and stage, and does not impact on intra operative blood loss and recurrence. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    International journal of pediatric otorhinolaryngology 04/2015; 79(6). DOI:10.1016/j.ijporl.2015.03.033 · 1.32 Impact Factor
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    ABSTRACT: Semi-quantitative and quantitative assessment of the effect of bone marrow-derived mononuclear cells (BM-MNC) on early and late phase of nerve regeneration in rat sciatic nerve model. Sciatic nerve transection and repair was performed in 50 inbred female Wistar albino rats divided equally in two groups. In the test group the gap was filled with BM-MNCs obtained from the two male rats and fibrin sealant, while in the control group only fibrin sealant was used. Sciatic nerve was harvested at 15 days and at 60 days interval. Parameters of regeneration were assessed at anastomosis (G), intermediate distal (C), and distal site (A). Semi-quantitative (histopathological) and quantitative (morphometric) parameters were analyzed. At 15 days there was a statistically significant difference found in mean axon diameter, mean nerve thickness and myelin thickness at the repair site (P < 0.05). However, in the distal areas, the axons were sparse and myelin rings were very thin in both the groups. At 60 days, the difference in above-mentioned parameters was statistically significant at the distal most sites. FISH assay confirmed the presence of Y chromosome, confirming the presence of BM-MNCs from the male rats. Transplanting BM-MNCS at the site of peripheral nerve injury leads to significantly better recovery. These differences were evident at the repair site and at the intermediate distal site at 15 days and at the distal most sites at 60 days. With practically no ethical issue regarding their isolation and application, they can be easily used for clinical trials.
    04/2015; 6(2):152-9. DOI:10.4103/0976-3147.153218
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    ABSTRACT: Hypoxia is a hallmark of solid tumors including glioblastoma (GBM). Its synergism with Notch signaling promotes progression in different cancers. However, Notch signaling exhibits pleiotropic roles and the existing literature lacks a comprehensive understanding of its perturbations under hypoxia in GBM with respect to all components of the pathway. We identified the key molecular cluster(s) characteristic of the Notch pathway response in hypoxic GBM tumors and gliomaspheres. Expression of Notch and hypoxia genes was evaluated in primary human GBM tissues by q-PCR. Clustering and statistical analyses were applied to identify the combination of hypoxia markers correlated with upregulated Notch pathway components. We found well-segregated tumor-clusters representing high and low HIF-1α/PGK1-expressors which accounted for differential expression of Notch signaling genes. In combination, a five-hypoxia marker set (HIF-1α/PGK1/VEGF/CA9/OPN) was determined as the best predictor for induction of Notch1/Dll1/Hes1/Hes6/Hey1/Hey2. Similar Notch-axis genes were activated in gliomaspheres, but not monolayer cultures, under moderate/severe hypoxia (2%/0.2% O2). Preliminary evidence suggested inverse correlation between patient survival and increased expression of constituents of the hypoxia-Notch gene signature. Together, our findings delineated the Notch-axis maximally associated with hypoxia in resected GBM, which might be prognostically relevant. Its upregulation in hypoxia-exposed gliomaspheres signify them as a better in-vitro model for studying hypoxia-Notch interactions than monolayer cultures.
    PLoS ONE 03/2015; 10(3):e0118201. DOI:10.1371/journal.pone.0118201 · 3.23 Impact Factor
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    ABSTRACT: Fungal granulomas of the central nervous system are rare, and have high mortality and morbidity irrespective of treatment. The authors report their experience of managing 66 patients over 15 years and discuss the clinical, radiological, surgical and pathological findings. This is among the largest reported series. A retrospective analysis was performed on patients with intracranial fungal granulomas (ICFGs), treated in our institution, between January 1997 and May 2011. Only mass forming histopathologically proven ICFG were included in this study. The age of the patients ranged from 7 years to 67 years (mean= 32.3 yrs) and most patients were in the third and fourth decades of life. The study population had 47 males and 19 females. The most common symptom was headache (41 patients), followed by vomiting (16 patients) and blurring of vision (16 patients). Only 3 patients had fever as a presenting feature. The duration of symptoms was less than 6 months in all cases and less then 3 months in 39 cases. Anterior cranial fossa and frontal lobe was involved in 35 cases (54.5%), followed by middle cranial fossa in 20 cases (30.3%).Three cases had granulomas in CP angle. Three cases had multi-compartmental involvement and four multi-lobar involvement. Nine patients had predisposing factors for fungal infection Based on clinical and imaging data, preoperative diagnosis of a possible fungal lesion was made in 44 (some had only CT imaging) patients. All the patients were treated surgically, followed by antifungal treatment with amphotericin-B and/ fluconazole/ itraconazole for a period of six weeks. Eight patients had symptomatic recurrence of lesions 3-12 weeks after treatment and were re-operated. Six patients were lost to follow up. Nine patients died in the post-operative period (within 30 days postoperatively). Fifteen patients died during follow up due to recurrent lesions, repeat surgery, renal failure and unrelated causes. Overall mortality was 24 (36.3%). Poor neurological status before surgery, emergency craniotomy, severe brain edema with mass effect and opening of ventricles during surgery was associated with poor outcome. Aspergillus species were the causative organism in an overwhelming majority of patients (n=52) followed by Mucor in 7 cases, Cladiosporium in 3 cases, Eumycetoma in 2 cases, Maduramycosis and Blastomycosis in 1case each. ICFG have high morbidity and mortality rates. Early diagnosis, radical surgery and antifungal treatment for 6 weeks may improve outcome. Poor neurological status of patients at the time of presentation, immunocompromised state, contamination of ventricular CSF during surgery and renal failure (due to amphotericin-B) are associated with poor outcome. Copyright © 2015 Elsevier Inc. All rights reserved.
    World Neurosurgery 02/2015; 83(6). DOI:10.1016/j.wneu.2015.01.053 · 2.42 Impact Factor
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    ABSTRACT: Purpose. To determine the impact of intraoperative magnetic resonance imaging (iMRI) in epilepsy surgeries on the extent of surgical resection and seizure outcome along with its feasibility and limitations. Methods. Patients with pharmacoresistant epilepsy (PRE), who underwent surgeries in operating theater equipped with high-field 1.5-Tesla MRI, were evaluated for extent of resection, operative time, scanning time, pathologies, resultant extra resection, and seizure outcomes. Results. Thirty-nine patients with mean age of 18 (range: 3-65) years with PRE underwent surgical intervention. Mean duration of epilepsy was 10.2 years. Surgical interventions included tumor resection (31%), resection of focal cortical dysplasia (28%), mesial temporal lobe surgeries (18%), and disconnection surgeries (23%). iMRI alone, apart from navigation and electrophysiology, improved resection rates in 13% (5 out of 39) of these patients. In lesional group, iMRI modified operative strategy resulting in increased resections in 21% (5/23) patients. Complete resection was observed in 87% of patients. iMRI scanning time constituted 25% (mean: 72 ± 21 min) of time spent under anesthesia by the patient. Major and minor complications were observed in 2.5% and 7.5% of patients, respectively. The mean follow-up was 14 months. Favorable postoperative seizure control (Engel Classes I and II) was achieved in 85% and complete seizure freedom was achieved in 77% of patients (Engel Class IA) at 1-year follow-up. Conclusions. iMRI increases the extent of resection mainly in lesional epilepsy surgeries translating into good seizure outcomes but not found to be much beneficial in prototype mesial temporal sclerosis surgeries and disconnection surgeries.
    British Journal of Neurosurgery 02/2015; 29(3):1-6. DOI:10.3109/02688697.2014.1003034 · 0.95 Impact Factor
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    ABSTRACT: Pediatric oligodendrogliomas (pODGs) are rare central nervous system tumors, and comparatively little is known about their molecular pathogenesis. Co-deletion of 1p/19q; and IDH1, CIC, and FUBP1 mutations, which are molecular signatures of adult oligodendrogliomas, are extremely rare in pODGs. In this report, two pODGs, one each of grade II and grade III, were evaluated using clinical, radiological, histopathologic, and follow-up methods. IDH1, TP53, CIC, H3F3A, and BRAF-V600 E mutations were analyzed by Sanger sequencing and immunohistochemical methods, and 1p/19q co-deletion was analyzed by fluorescence in situ hybridization. PDGFRA amplification, BRAF gain, intragenic duplication of FGFR-TKD, and KIAA1549-BRAF fusion (validated by Sanger sequencing) were analyzed by real-time reverse transcription PCR. Notably, both cases showed the oncogenic KIAA1549_Ex15-BRAF_Ex9 fusion transcript. Further, immunohistochemical analysis showed activation of the MAPK/ERK pathway in both of these cases. However, neither 1p/19q co-deletion; IDH1, TP53, CIC, H3F3A, nor BRAF-V600 E mutation; PDGFRA amplification; BRAF gain; nor duplication of FGFR-TKD was identified. Overall, this study highlights that pODGs can harbor the KIAA1549-BRAF fusion with aberrant MAPK/ERK signaling, and there exists an option of targeting these pathways in such patients. These results indicate that pODGs with the KIAA1549-BRAF fusion may represent a subset of this rare tumor that shares molecular and genetic features of pilocytic astrocytomas. These findings will increase our understanding of pODGs and may have clinical implications. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cancer Genetics 02/2015; 208(3). DOI:10.1016/j.cancergen.2015.01.009 · 2.42 Impact Factor
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    ABSTRACT: Background– Post-excision residual disease in Vidian canal is speculated to contribute to recurrence in juvenile angiofibroma (JA).Methods– Prospective cohort of sixteen consecutive JA patients (stage IIA-IIIB). Pre-surgical Vidian canal assessment by CECT (1.2mm collimation). At surgery following complete tumor excision, Vidian canal tissue sampled for histology.Post-excision drilling of Vidian canal in 8/15 to remove microscopic residual disease. 24-48 months follow-up.Results– Pre-surgical radiology indicated ipsilateral Vidian canal enlargement (≥3mm)/destruction in 13/16. Radiologically occult involvement documented only by histology in another 1/16. Post-excision sampling of the Vidian canal noted microscopic residual tumor in 3/15.No recurrences noted in 8 cases (0/8) with post-excision drilling of the Vidian canal and 2 recurrences in 7 cases(2/7) with no drilling; p=0.20.Conclusions– Vidian canal involvement in JA is almost universal (14/16) and may be occult to CT evaluation. The site may harbor microscopic residual tumor after seemingly complete excision. Surgical attention towards it may reduce recurrences. This article is protected by copyright. All rights reserved.
    Head & Neck 01/2015; DOI:10.1002/hed.24012 · 3.01 Impact Factor
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    ABSTRACT: Mutations in H3.3-ATRX-DAXX chromatin remodeling pathway have been reported in pediatric GBMs. H3.3 (H3F3A) mutations may affect transcriptional regulation by altered global histone-methylation. Therefore, we analyzed yet partly understood global histone code (H3K-4/9/27/36) trimethylation pattern in H3F3A-ATRX mutants and wild-type. H3F3A, HIST1H3B, IDH1, ATRX, DAXX and Tp53 mutations were identified by sequencing/immunohistochemistry in 27 pediatric GBMs. Global histone-methylation H3K-4/9/27/36me3 and Polycomb-protein EZH2 expression were evaluated by immunohistochemistry. H3F3A-ATRX mutation was observed in 66.7 % (18/27) of pediatric GBMs. K27M and G34R-H3F3A mutations were found in 37 % (10/27) and 14.8 % (4/27) patients respectively. G34V-H3F3A, HIST1H3B and IDH1 mutations were absent. Notably, commonest global histone-methylation mark lost was H3K27me3 (17/25, 68 %) followed by H3K4me3 (45.5 %, 10/22) and H3K9me3 (18.2 %, 4/22). Global H3K36me3 showed no loss. Most significant observation was loss of one or more histone-trimethylation mark in 80 % (20/25) pediatric GBMs. Notably, simultaneous loss of H3K27me3 and H3K4me3 were present in 7/22 (31.8 %) of pediatric GBMs. Low expression of EZH2 was found in 12/24 (50 %) of cases. However no significant correlation of loss of histone-marks or EZH2 expression with H3F3A-ATRX mutants (loss of at least one histone-marks in 87.5 % (14/16) cases) versus wild-types (loss of at least one histone-marks in 75 % (6/8) cases) was seen. The present study highlights for the first time combinatorial loss of one or more histone-trimethylation marks associated with majority of pediatric GBMs and the finding suggests significant role of histone-code in the molecular biology that underlies pediatric GBMs. Hence therapies for patients with particular combinations of histone modifications present opportunity to design innovative patient-tailored treatment protocols.
    Journal of Neuro-Oncology 12/2014; 121(3). DOI:10.1007/s11060-014-1675-z · 2.79 Impact Factor
  • Neurology India 11/2014; 62(6):677-9. DOI:10.4103/0028-3886.149405 · 1.08 Impact Factor
  • Cancer Research 10/2014; 74(19 Supplement):2077-2077. DOI:10.1158/1538-7445.AM2014-2077 · 9.28 Impact Factor

Publication Stats

3k Citations
699.92 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 Neuropathology
      • • Department of Pathology
      • • Department of Biochemistry
      • • Department of Neurosurgery
      • • 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