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Prothymosin-α (PTMA), a nuclear protein, is strikingly associated with unfavorable clinical outcomes in many cancers. However, no information about its clinical relevance in glioma was available. Therefore in the present study, we evaluated the prognostic utility of this protein in a cohort of 81 glioma patients. The PTMA expression was assessed by immunohistochemical analysis, quantitative PCR, and Western blotting. Furthermore, the association of PTMA with clinicopathological features and molecular alterations were assessed in the patient cohort and validated in multiomics datasets, The Cancer Genome Atlas (TCGA; n=667) and Chinese Glioma Genome Atlas (CGGA; n=1013). We observed an increase in PTMA expression with increasing histological grades of this malignancy. PTMA immunostaining also displayed a strong positive association with the MIB-1 index. Univariate analysis revealed a superior prognostic value of PTMA to predict overall survival (OS) as compared with the routinely used markers (p53, isocitrate dehydrogenase (IDH) 1 (IDH1), α-thalassemia/intellectual disability syndrome X-linked (ATRX), and Ki-67). Interestingly, in Cox regression analysis it emerged as an independent predictor of OS (hazard ratio (HR) = 13.71, 95% CI = 5.96-31.52, P<0.0001). Thus, our results demonstrate the potential prognostic utility of PTMA in glioma which may prove useful in the management of this deadly malignancy. [ABSTRACT FROM AUTHOR]

Aim: Glioblastoma (GBM) is one of the most aggressive neoplasms of the central nervous system with dismal survival. In recent years, different variants of GBM have been described in the literature. GBM with areas of neuroectodermal differentiation (GBM-PNET) is a relatively new entity in GBM. Presence of the neuroectodermal component increases the propensity of systemic dissemination as with other intracranial primitive neuroectodermal tumors (PNET). The optimal treatment for these patients remains a controversy, with authors reporting local radiotherapy to craniospinal irradiation and chemotherapy. We intend to analyze the pattern of care for GBM with neuroectodermal component.Materials and Methods: We retrieved data of four patients with GBM-PNET treated in our institute; data were also retrieved from published series to derive treatment and outcome results.Results: In this series, we report the outcome of a series of four patients of GBM-PNET treated with adjuvant radiotherapy and temozolomide. All but one patient underwent gross total resection of the tumor. Adjuvant hypofractionated radiation with concurrent and adjuvant temozolomide was used in all cases. The median follow-up was 12.9 months in the present series. One patient experienced local recurrence 18 months after the treatment. A review of published literature on GBM-PNET was done; studies with details of patient outcome were used for an independent analysis. Twenty-three patients were identified, and the pooled analysis revealed a median progression free and overall survival of 10 and 25, months respectively. Extent of surgery, local radiation vs. craniospinal irradiation, and age at presentation had no impact on the survival.Conclusion: GBM PNET is a new entity with only few cases reported so far. Clinical behavior and treatment outcome of these tumors are not different from conventional GBM. However, these patients are at higher risk of CSF dissemination. Hence, an individualized treatment approach is best suited. [ABSTRACT FROM AUTHOR]

Purpose: H3K27M mutant diffuse midline gliomas (DMGs) are considered grade IV irrespective of histological features and have dismal prognosis. We evaluated clinico-pathologic, radiological, and molecular characteristics of DMGs across all ages. Methods: One twenty-six DMGs were identified over 10 years. Immunohistochemistry was done for H3K27M, ATRX, IDH1, and p53, and Sanger sequencing performed for IDH1 and H3K27M mutation. Patient demographics and clinico-radiologic characteristics were reviewed and survival analysis performed. Results: DMGs comprised 5.3% of all gliomas with 49.2% H3K27M mutant and 50.8% wild types. Majority (75.68%) of pediatric and 38.20% of adults were H3K27M mutant (p = 0.0001). Amongst H3K27M mutants, brainstem (46.43%) was the commonest location in pediatric and thalamus (61.76%) in adults. H3K27M mutation was mutually exclusive with IDH mutation in 93.55%, while p53, ATRX mutation were seen in 56.4% and 30.6% cases respectively. Software-based immunohistochemistry evaluation (H-scoring) showed 99.2% concordance with sequencing for H3K27M mutation. Radiologically, no significant difference in contrast enhancement was seen between mutant and wild types (p = 0.05). The difference in overall survival (OS) was not significant in mutant versus wild types, with age or location. Tumor resection independently and on correlation with H3K27M did not influence OS (p = 0.51 and p = 0.47). Adjuvant therapy impacted survival significantly in adults (p = 0.0009), however, not in pediatric cases (p = 0.06). Conclusions: The study highlights the differences in frequency and location of pediatric and adult DMGs. IHC (H-scoring) for H3K27M mutation is an excellent surrogate for sequencing. Prognosis remains dismal irrespective of age, location, and H3K27M status. Potential therapeutic targets need to be explored. [ABSTRACT FROM AUTHOR]

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. One hundred seventy six 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 codeletion. Mosaic/heterogeneous staining was detected 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Several letters to the editor are presented discussing the progression of Pilocytic astrocytoma and Leptomeningeal disease in children.

Intracranial tuberculoma in infants are a rare occurrence. We report a 7-month-old male infant presenting to our tertiary care referral center with complaints of global developmental delay and right hemiparesis for 3 months. Radiologic imaging was suggestive of large left frontoinsular space–occupying lesion with initial differential of primitive neuroectodermal tumor or desmoplastic infantile ganglioglioma. Considering the clinicoradiologic findings and no history suggestive of immunodeficiency or contact with tuberculosis, surgical decompression was done. Final histopathology revealed multiple epithelioid granulomas suggestive of tubercular etiology or intracranial Langerhans cell histiocytosis. He was started on antitubercular therapy after ruling out Langerhans cell histiocytosis using CD1a and Langerin immunohistochemistry staining. Interpretation of tuberculous etiology in infants can be challenging for clinicians, radiologists, and pathologists. A high index of suspicion is necessary to diagnose such lesions, predominantly in endemic regions. [ABSTRACT FROM AUTHOR]

Assessment of promoter methylation of the O6-methylguanine DNA methyltransferase (MGMT) gene has recently gained importance in molecular profiling of high-grade gliomas. It has emerged not only as an important prognostic marker but also as a predictive marker for response to temozolomide in patients with newly diagnosed glioblastoma. Further, recent studies indicate that MGMT promoter methylation has strong prognostic relevance even in anaplastic (grade III) gliomas, irrespective of therapy (chemotherapy or radiotherapy). This article provides an overview of its use as a predictive and prognostic biomarker, as well as the methods employed for its assessment and use in therapeutic decision making. [ABSTRACT FROM AUTHOR]

Background: Due to overlapping histomorphological features, difference in clinical behavior and treatment response, establishing potential molecular markers to facilitate diagnosis of various genetic subtypes of diffuse gliomas is essential. Aim: To analyze 1p/19q status in diffuse gliomas and correlate it with epidermal growth factor receptor (EGFR) and p53 protein expression. Materials and Methods: 1p/19q status in 43 cases was evaluated by fluorescence in situ hybridization assay. Glial fibrillary acidic protein (GFAP), EGFR and p53 were assessed by immunohistochemistry. Results: Glial fibrillary acidic protein immunopositivity was observed in oligodendrogliomas within minigemistocytes and gliofibrillary oligodendrocytes as perinuclear homogenous blobs. It also highlighted the intermingled reactive astrocytes. Astrocytomas and the astrocytic component of oligoastrocytomas showed a diffuse fibrillary type of staining. 1p and/or 19q loss was seen in 65% (13/20) of oligodendrogliomas and 66.6% (5/9) of mixed oligoastrocytomas. There was one case each of pediatric oligodendroglioma and mixed oligoastrocytoma, none of which showed 1p/19q loss. None of the astrocytomas including two pediatric cases showed this alteration (P < 0.05). p53 was expressed in 57.1% of astrocytomas (8/14), 33% of mixed oligoastrocytomas (3/9) and 10% of oligodendrogliomas (2/20). Majority of oligodendrogliomas (85%; 17/20) and oligodendroglial areas in mixed oligoastrocytomas (77.7%; 7/9) showed a membranous lace-like immunopositivity with EGFR. In contrast, all astrocytomas (Grade II and III) were EGFR negative. Conclusion: Loss of 1p/19q is strongly associated with oligodendroglial phenotype, while astrocytic tumors are more likely to show p53 over-expression. p53 expression and 1p/19q status appear to be mutually exclusive. [ABSTRACT FROM AUTHOR]

Medulloblastomas (MBs) are the most common malignant brain tumors in children. Current therapeutic approaches combine surgery, radiotherapy, and chemotherapy. Although, there has been significant improvement in long-term survival rates, the tumor remains incurable in about a third of patients while cognitive deficits and other sequelae of therapy are common among long-term survivors. Hence a major challenge remains to differentiate high-from low-risk patients and to tailor therapy based on the degree of biological aggressiveness. A clinical risk-stratification system has been widely used in MBs based on age, extent of resection and the Chang staging system. However, recent reports indicate that these clinical variables are inadequate methods of defining disease risk. This has prompted search for new markers for MB stratification. Recent studies indicate that the classification of MBs according to profiles of histopathology and molecular abnormalities possibly help better risk-stratification of patients, thereby rationalizing approaches to therapy, increasing cure rate, reducing long-term side effects and developing novel therapeutic strategies. The most accurate outcome prediction till date has been obtained through microarray gene expression profiling. In this article, the current histopathological classification and the recent advances in molecular genetics of MBs are reviewed. Global efforts to translate this knowledge of disease biology into clinical practice especially as outcome predictors are highlighted. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme (GBM) Patients generally have a dismal prognosis, with median survival of 10-12 months. GBM with long-term survival (LTS) of ≥ 5 years is rare, and no definite markers indicating better prognosis have been identified till date. The present study was undertaken to evaluate GBMs with LTS in order to identify additional correlates associated with favourable outcome. The cases were evaluated for relevant clinicopathological data, proliferation index and expression of tumortumour suppressor gene (p53), cyclin-dependant kinase-inhibitors (p27 and p16) and epidermal growth factor receptor (EGFR) proteins. Six cases of GBM with LTS with an average survival of 9 years (range 5-15 years) were identified. All were young patients with mean age of 27 years (range 8-45 years). Histology of three cases was consistent with conventional GBM, while two showed prominent oligodendroglial component admixed with GBM areas. One was a giant cell GBM, which progressed to gliosarcoma on recurrence. The mean MIB-1LI was 12% (range 6-20%). p53 was immunopositive in 4 out of 5 cases. EGFR and p27 were immunonegative in all, whereas p16 was immunonegative in 3 out of 5 cases. Currently, in the absence of specific molecular and genetic markers, GBM in young patients should be meticulously evaluated for foci of oligodendroglial component and/or giant cell elements, in addition to proliferative index and p53 expression, since these probably have prognostic connotations, as evident in this study. The role of p16 and p27 however needs better definition with study of more number of cases. [ABSTRACT FROM AUTHOR]

Background: p53 is a tumor suppressor gene implicated in the genesis of a variety of malignancies including brain tumors. Overexpression of the p53 protein is often used as a surrogate indicator of alterations in the p53 gene. Aims: In this study, data is presented on p53 protein expression in adult cases (>15 years of age) of astrocytic (n=152) and oligodendroglial (n=28) tumors of all grades. Of the astrocytic tumors, 86% were supratentorial in location while remaining 14% were located infratentorially - 8 in the the cerebellum and 13 in the brainstem. All the oligodendrogliomas were supratentorial. Materials and Methods: p53 protein expression was evaluated on formalin-fixed paraffin-embedded sections using streptavidin biotin immunoperoxidase technique after high temperature antigen retrieval. Results: Overall 52% of supratentorial astrocytic tumors showed p53 immunopositivity with no correlation to the histological grade. Thus, 58.8% of diffuse astrocytomas (WHO Grade II), 53.8% of anaplastic astrocytomas (WHO Grade III) and 50% of glioblastomas (WHO Grade IV) were p53 protein positive. In contrast, all the infratentorial tumors were p53 negative except for one brainstem gliobiastoma. Similarly, pilocytic astrocytomas were uniformly p53 negative irrespective of the location. Among oligodendroglial tumors, the overall frequency of p53 immunopositivity was lower (only 28%), though a trend of positive correlation with the tumor grade was noted - 25% in Grade II and 31.5% in grade III (anaplastic oligodendroglioma). Interestingly, p53 labeling index (p53 LI) did not correlate with the histopathological grade in both astrocytic and oligodendroglial tumors. Conclusions; Thus, this study gives an insight into the genetic and hence biological heterogeneity of gliomas, not only between astrocytic tumors vs. oligodendrogliomas but also within astrocytic tumors with regard to their grade and location. With p53 gene therapy trials in progress, this will possibly have future therapeutic implications. [ABSTRACT FROM AUTHOR]

The article describes the case of an 18-year-old male who developed angiocentric glioma (AG). The patient presented with complex partial seizures since the age of 4 years. AG refers to a rare tumor of the central nervous system (CNS) in children and young adults, and accounts for 2.3% of tumors associated with chronic pediatric epilepsy.

Supratentorial anaplastic ependymoma is an uncommon tumor which can rarely present as a cyst with mural nodule on imaging. Authors present this unusual radiological appearance of supratentorial extraventricular anaplastic ependymoma in a 9-year-old boy. [ABSTRACT FROM AUTHOR]

Abstract: Object: Mutations of the gene encoding isocitrate dehydrogenase (IDH) have been shown in a significant proportion of diffuse gliomas. These mutations are specific to gliomas and their utility for diagnosis and prognostication of these tumors is being proclaimed. The present study was conducted with the aim of assessing frequency of IDH1 mutations in gliomas, their correlation with other molecular alterations along with a comprehensive review of available literature. Methods: A total of 100 gliomas of various grades and subtypes from Indian patients were screened for assessing frequency of IDH1 mutations. The findings were correlated with TP53 mutations, 1p/19q deletion, EGFR amplification and PTEN deletion status. The detailed comprehensive review of literature was performed comparing all studies available till date. Results: IDH1 mutations in codon 132 were observed in 46% cases. The frequency was 68.8% in grade II, 85.7% in grade III and 12.8% in GBMs. R132H mutation was most frequent (84.8%). Overall frequency of these mutations was relatively higher in oligodendroglial tumours as compared to astrocytic phenotype (66.7% versus 38.4%; p=0.06). Primary GBMs showed IDH1 mutation in only 4.4% cases. In contrast, 66.7% of secondary GBMs harboured this alteration. Patients with IDH1 mutations were significantly younger as compared to those without mutation (p=0.001). There was a significant correlation between IDH1 mutation and TP53 mutation (p=0.004). Although IDH1 mutation showed a positive correlation with 1p/19q deletion, the association was not statistically significant (p=0.653). There was no correlation with EGFR amplification or PTEN deletion. Conclusion: IDH1 mutations are present in large proportion of Indian patients with diffuse astrocytic and oligodendroglial neoplasms similar to the reported literature form west. The frequency is lower in primary GBMs and as compared to secondary GBMs. Association with younger age and positive correlation with TP53 mutation and 1p/19q loss is observed. More importantly it is emerging as an independent prognostic marker. Hence the greatest challenge now is establishing a reliable user friendly test for incorporating this novel genetic alteration to routine clinical practice. [Copyright &y& Elsevier]

Abstract: Several single nucleotide polymorphisms of the TP53 gene have been reported, amongst which polymorphism in codon 72 (rs1042522) has received significant attention and shown to be associated with disease susceptibility in different cancer types. However, there are variable reports on this polymorphism in gliomas from worldwide with inconsistent results. In addition, the implications of other polymorphic loci are not much explored in gliomas. Hence, in the present study the TP53 sequence was analyzed for all polymorphism and mutations in a total of 84 gliomas of different types and grades from patients of Indian origin. The complete sequence of all coding exons (2 to 11) and introns 2, 3, 5 and 8 of TP53 gene were studied while for introns 1, 4, 6, 7, 9 and 10, only exon flanking regions could be studied. The polymorphic loci were compared with control population. In addition to the well known codon 72 polymorphism (rs1042522), three other polymorphisms rs1642785, rs1800370 and a 16 base pair insertion in intron-3 were found. At codon 72, our study showed higher Arg/Arg genotype in gliomas compared to normal population (38% versus 13%). The Arg allele frequency in glioma patients was comparatively higher than controls (0.55 versus 0.45; P=0.037). The Arg allele frequency was also high in adult glioblastomas compared to paediatric counterparts (0.55 versus 0.36). However, there was no significant association of TP53 mutations with any genotype of codon 72. At rs1642785, the G allele frequency was significantly higher in gliomas than in control population (0.55 versus 0.36, P=0.005). The genotype at a 16 base pair insertion in intron-3 was almost similar in case and control. However, the polymorphism at rs1800370 was exclusive to gliomas. This is the first report of TP53 gene polymorphism in glioma patients from India. Our study also delineates the frequency of four polymorphisms in gliomas for the first time. The codon 72 variant (rs1042522) and rs1642785 polymorphisms possibly poses risk to glioma development in Indian population. However, the functional significance of these polymorphism needs further elucidation. [Copyright &y& Elsevier]