Supriya Mallick

Integrating Molecular Subclassification of Medulloblastomas into Routine Clinical Practice: A Simplified Approach

Medulloblastoma (MB) is composed of four 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 three 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 the worst prognosis. For routine diagnostic practice, we recommend classification of MBs into three subgroups: 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.

Genome-wide ChIP-seq analysis of EZH2-mediated H3K27me3 target gene profile highlights differences between low- and high-grade astrocytic tumors

Enhancer of zeste homolog-2(EZH2) is a key epigenetic regulator that functions as oncogene and also known for inducing altered trimethylation of histone at lysine-27 (H3K27me3) mark in various tumors. However, H3K27me3 targets and their precise relationship with gene expression are largely unknown in astrocytic tumors. In this study, we checked EZH2 messenger RNA and protein expression in 90 astrocytic tumors of different grades using quantitative PCR and immunohistochemistry, respectively. Further, genome-wide ChIP-seq analysis for H3K27me3 modification was also performed on 11 glioblastomas (GBMs) and 2 diffuse astrocytoma (DA) samples. Our results showed EZH2 to be highly overexpressed in astrocytic tumors with a significant positive correlation with grade. Interestingly, ChIP-seq mapping revealed distinct differences in genes and pathways targeted by these H3K27me3 modifications between GBM versus DA. Neuroactive ligand receptor pathway was found most enriched in GBM (P = 9.4 × 10-25), whereas DA were found to be enriched in metabolic pathways. Also, GBM showed a higher enrichment of H3K27me3 targets reported in embryonic stem cells and glioma stem cells as compared with DAs. Our results show majority of these H3K27me3 target genes were downregulated, not only due to H3K27me3 modification but also due to concomitant DNA methylation. Further, H3K27me3 modification-associated gene silencing was not restricted to promoter but also present in gene body and transcription start site regions. To the best of our knowledge, this is the first high-resolution genome-wide mapping of H3K27me3 modification in adult astrocytic primary tissue samples of human, highlighting the differences between grades. Interestingly, we identified SLC25A23 as important target of H3K27me3 modification, which was downregulated in GBM and its low expression was associated with poor prognosis in GBMs.

Primary pediatric mid-brain lymphoma: Report of a rare pediatric tumor in a rare location

Primary central nervous system lymphoma (PCNSL) is a rare disease in pediatric age group. A thirteen-year-old male child presented with complaints of headache for six months, vomiting and diplopia for three days. Magnetic resonance imaging of the brain showed a single lesion of 1.7 cm × 1.6 cm × 1.6 cm in the mid brain and tectum. He underwent a gross total resection of the tumor. The histopathological evaluation revealed B cell high grade non Hodgkin lymphoma. The patient was treated with High dose methotrexate and cranio spinal radiation. The patient was alive without disease 12 mo after completion of treatment. This case highlights importance of keeping PCNSL as differential in brain stem lesions of pediatric patients also. Radiation and chemotherapy remains the most important treatment for such patients.

Patterns of care and survival outcomes in patients with an extraventricular neurocytoma: An individual patient data analysis of 201 cases

Introduction: Extraventricular neurocytoma is a rare neuronal tumor arising outside the ventricles. However, because of its rarity, its optimum treatment remains undefined. Materials and Methods: We intended to perform an individual patient data analysis to examine the patterns of care and prognostic factors involved in the treatment of extraventricular neurocytomas. PubMed, SCOPUS, and Google Scholar were searched with the following MeSH terms: “Neurocytoma, Extra ventricular neurocytoma, Spinal neurocytoma AND treatment, Survival” to find all possible publications pertaining to EVN. Results: From 108 publications, we retrieved 201 patients of extraventricular neurocytoma. Their median age was 30 years (range: 0.6–78 years). Sixty seven patients were in the pediatric (age ≤20 years) age group. There was a bimodal age distribution. Surgical details were available for 132 cases, and 51.5% underwent a gross total resection whereas 41.7% underwent a subtotal resection. Adjuvant radiation was used in 40% cases. For the entire cohort, the median progression free survival was 77 months (53.3–100.7). However, we could not find an impact of any of the prognostic factors on survival. Conclusion: An extraventricular neurocytoma is a very rare disease with varied presentations and different sites of origin. Gross total resection remains the standard of care. Adjuvant radiation may be used for salvage. However, radiation therapy after subtotal resection of an atypical neurocytoma may be administered.

Neoadjuvant chemotherapy for larynx preservation: Has it lost importance?

Over the time, the aim of treatment for locally advanced laryngeal and hypopharyngeal carcinoma has changed from cure to cure with the functional larynx. Chemoradiation has emerged as the most important therapeutic modality for patients with locally advanced disease. However, systemic failure remains an important area of concern. Induction chemotherapy has emerged as promising organ preservation approach as it gives an window to select responders and continuing treatment with nonsurgical approach as well as reduces systemic recurrence and improve survival with a functional larynx. However, there are questions about the efficacy of this approach. In this context, we aim to evaluate the trials for locally advanced laryngeal and hypopharyngeal cancer attempting to optimize therapeutic outcome with addition of induction chemotherapy. This present review intends to look into the therapeutic ratio of induction chemotherapy for disease control, organ preservation.