Malignant bihemispheric cerebral edema after cranioplasty - An extension of the Monro-Kellie doctrine and predictive factors.

Background: Several changes in normal pressure dynamics on the brain occur with a decompressive craniectomy and subsequent cranioplasty. Dead space volume is an important factor contributing to intracranial volume postcranioplasty. A decrease in this volume due to negative suction drain along with relative negative pressure on the brain with the loss of external atmospheric pressure may lead to fatal cerebral edema. Case Description: A 52-year-old gentleman with a 210 mL volume and middle cerebral artery territory infarction underwent an emergency craniectomy and 6 months later a titanium mold cranioplasty. Precranioplasty computed tomography (CT) scan evaluation revealed a sunken skin flap with a 9 mm contralateral midline shift. Immediately following an uneventful surgery, the patient had sudden fall in blood pressure to 60/40 mmHg and over a few min had dilated fixed pupils. CT revealed severe diffuse cerebral edema in bilateral hemispheres with microhemorrhages and expansion of the sunken right gliotic brain along with ipsilateral ventricular dilatation. Despite undergoing a contralateral decompressive craniectomy due to the midline shift toward the right, the outcome was fatal. Conclusion: Careful preoperative risk assessment in cranioplasty and close monitoring postprocedure is crucial, especially in malnourished, poststroke cases, with a sinking skin flap syndrome, and a long interval between decompressive craniectomy and cranioplasty. Elective preventive measures and a low threshold for CT scanning and removal of the bone flap or titanium mold are recommended.

Development and Validation of a Multivariable Model to Predict Surgical Outcome in Patients with Chiari malformations.

Background: Surgical outcome predictive models for Chiari malformations (CM) which are applicable to all age groups and simple enough to use on outpatient basis are lacking. Objective: The aim of this study was to develop and validate a preoperative index for predicting long-term outcomes in Chiari 1 (CM1) and Chiari 0 (CM0) malformations. Materials and Methods: It was a single-institution, ambidirectional, cohort study from 2014 to 2019, having patients between 5 to 70 years. Outcome was assessed using Chicago Chiari outcome score (CCOS) over 2 years follow-up. Preoperative clinical and radiological factors were analyzed using Chi-square test and Mann Whitney U test, in relation to CCOS and those attaining P value ≤0.05, were used to develop model - Chiari Outcome Predictive Index (COPI). COPI was internally validated using 10-fold cross-validation and c-statistic for discrimination. Results: A total of 88 patients (66 in development and 22 in validation cohort) were included in the study. Outcome was negatively associated with presence of motor, sensory or cranial nerve symptoms, poor functional status, basilar invagination, and tonsillar descent. It was positively associated with shorter duration of presenting symptom (<9 months) and syrinx diameter <6 mm. COPI predicted CCOS with 91.1% accuracy (10-fold cross-validation). It had excellent discrimination for improved outcome (c = 0.968 in development and 0.976 in validation cohort), at threshold index of -1. Conclusions: COPI is simple tool that can be administered in outpatient setting. It can facilitate evidence-based preoperative counseling of patients, to help them develop reasonable expectations regarding surgical outcomes.

Immuno-phenotyping of IDH-mutant grade 3 astrocytoma and IDH-wildtype glioblastoma reveals specific differences in cells of myeloid origin.

Gliomas are heavily infiltrated with immune cells of myeloid origin. Past studies have shown that high-grade gliomas have a higher proportion of alternatively activated and suppressive myeloid cells when compared to low-grade gliomas, which correlate with poor prognosis. However, the differences in immune cell phenotypes within high-grade gliomas (between grade 3 and grade 4 or GBM) are relatively less explored, and a correlation of phenotypic characteristics between immune cells in the blood and high-grade tumors has not been performed. Additionally, myeloid cells of granulocytic origin present in gliomas remain poorly characterized. Herein, we address these questions through phenotypic characterizations of monocytes and neutrophils present in blood and tumors of individuals with glioblastoma (GBM, IDH-wild type) or grade 3 IDH-mutant gliomas. We observe that neutrophils are highly heterogeneous among individuals with glioma, and are different from healthy controls. We also show that CD163 expressing M2 monocytes are present in greater proportions in GBM tissue when compared to grade 3 IDH-mutant glioma tissue, and a larger proportion of granulocytic myeloid-derived suppressor cells are present in grade 3 IDH-mutant gliomas when compared to GBM. Finally, we demonstrate that the expression levels of CD86 and CD63 showed a high correlation between blood and tumor and suggest that these may be used as possible markers for prognosis.

Altered transcriptional regulatory proteins in glioblastoma and YBX1 as a potential regulator of tumor invasion.

We have studied differentially regulated nuclear proteome of the clinical tissue specimens of glioblastoma (GBM, WHO Grade IV) and lower grades of gliomas (Grade II and III) using high resolution mass spectrometry- based quantitative proteomics approach. The results showed altered expression of many regulatory proteins from the nucleus such as DNA binding proteins, transcription and post transcriptional processing factors and also included enrichment of nuclear proteins that are targets of granzyme signaling - an immune surveillance pathway. Protein - protein interaction network analysis using integrated proteomics and transcriptomics data of transcription factors and proteins for cell invasion process (drawn from another GBM dataset) revealed YBX1, a ubiquitous RNA and DNA-binding protein and a transcription factor, as a key interactor of major cell invasion-associated proteins from GBM. To verify the regulatory link between them, the co-expression of YBX1 and six of the interacting proteins (EGFR, MAPK1, CD44, SOX2, TNC and MMP13) involved in cell invasion network was examined by immunohistochemistry on tissue micro arrays. Our analysis suggests YBX1 as a potential regulator of these key molecules involved in tumor invasion and thus as a promising target for development of new therapeutic strategies for GBM.

Identification of a Novel Splice Variant of Neural Cell Adhesion Molecule in Glioblastoma Through Proteogenomics Analysis.

Splice variants are known to be important in the pathophysiology of tumors, including the brain cancers. We applied a proteogenomics pipeline to identify splice variants in glioblastoma (GBM, grade IV glioma), a highly malignant brain tumor, using in-house generated mass spectrometric proteomic data and public domain RNASeq dataset. Our analysis led to the identification of a novel exon that maps to the long isoform of Neural cell adhesion molecule 1 (NCAM1), expressed on the surface of glial cells and neurons, important for cell adhesion and cell signaling. The presence of the novel exon is supported with the identification of five peptides spanning it. Additional peptides were also detected in sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) gel separated proteins from GBM patient tissue, underscoring the presence of the novel peptides in the intact brain protein. The novel exon was detected in the RNASeq dataset in 18 of 25 GBM samples and separately validated in additional 10 GBM tumor tissues using quantitative real-time-polymerase chain reaction (qRT-PCR). Both transcriptomic and proteomic data indicate downregulation of NCAM1, including the novel variant, in GBM. Domain analysis of the novel NCAM1 sequence indicates that the insertion of the novel exon contributes extra low-complexity region in the protein that may be important for protein-protein interactions and hence for cell signaling associated with tumor development. Taken together, the novel NCAM1 variant reported in this study exemplifies the importance of future multiomics research and systems biology applications in GBM.

Microsomal membrane proteome of low grade diffuse astrocytomas: Differentially expressed proteins and candidate surveillance biomarkers.

Diffuse astrocytoma (DA; WHO grade II) is a low-grade, primary brain neoplasm with high potential of recurrence as higher grade malignant form. We have analyzed differentially expressed membrane proteins from these tumors, using high-resolution mass spectrometry. A total of 2803 proteins were identified, 340 of them differentially expressed with minimum of 2 fold change and based on ≥2 unique peptides. Bioinformatics analysis of this dataset also revealed important molecular networks and pathways relevant to tumorigenesis, mTOR signaling pathway being a major pathway identified. Comparison of 340 differentially expressed proteins with the transcript data from Grade II diffuse astrocytomas reported earlier, revealed about 190 of the proteins correlate in their trends in expression. Considering progressive and recurrent nature of these tumors, we have mapped the differentially expressed proteins for their secretory potential, integrated the resulting list with similar list of proteins from anaplastic astrocytoma (WHO Grade III) tumors and provide a panel of proteins along with their proteotypic peptides, as a resource that would be useful for investigation as circulatory plasma markers for post-treatment surveillance of DA patients.

Ventriculosubgaleal shunts in the management of infective hydrocephalus.

INTRODUCTION: Temporary diversion of cerebrospinal fluid (CSF) is often required due to patient and CSF related factors, of which infection is a significant one. The various methods available have significant disadvantages. Ventriculosubgaleal shunts (VSG) have been earlier demonstrated to be useful in a variety of circumstances. MATERIALS AND METHODS: Hospital charts of 21 consecutive children during a 4-year period were analyzed retrospectively. Infection was defined based on a positive CSF culture or a history of recently treated meningitis with abnormal CSF findings. The conversion to a permanent shunt was based on normalization of CSF values in a functioning VSG shunt or when the VSG shunt is ineffective. The end point was control of raised intracranial pressure (ICP) features and infection. RESULTS: The ages ranged from 1 month to 7 years with a median age of 2 months. Five (23.8%) were born premature. Twelve children (57.1%) had a previously untreated hydrocephalus, whereas nine (42.8%) had undergone some procedure. A positive CSF culture was obtained in ten (47.6%). Repeat VSG shunts were required in five children (23.8%). Seventeen (80.9%) of these children underwent conversion to a ventriculoperitoneal (VP) shunt. Of the remaining four, one did well without any further procedure, two died due to their primary problems, and one refused any further procedure due to poor neurological status. There were two wound complications-one CSF leak and one shunt migration. CONCLUSION: VSG shunts are a simple and efficient way of managing infective hydrocephalus.