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.

Dorsal vertebral body tumor and non-compressive quadriparesis - A rare case report of a phosphaturic mesenchymal tumor.

Background: Phosphaturic mesenchymal tumors cause renal phosphate wasting leading to hypophosphatemia manifesting as bone pain and fractures. About 95% of these tumors involve the extremities and the appendicular skeleton, with spinal tumors being exceedingly rare. We describe a case of non-compressive quadriparesis, caused by a thoracic vertebral body phosphaturic mesenchymal tumor (PMT). Case Description: A 34-year-old gentleman presented with a 3-year history of gradually progressive quadriparesis, predominantly involving proximal muscles. Magnetic resonance imaging neither showed evidence of compressive lesions nor myelopathy. On routine biochemistry, he was found to have hypophosphatemia and phosphaturia, with serum phosphorus levels of 1.84 mg/dl, and fractional excretion of phosphorus >5%. A DOTATOC positron emission tomography scan suggested the possibility of a PMT in the D10 vertebral body with a corresponding hyperdense/sclerotic focus on non-contrast computed tomography. After instituting phosphate replacement therapy and complete surgical excision of the hyperdense focus, he made a full neurological recovery. His phosphate levels normalized without the need for supplements. Histopathological examination showed spindle cells with positive staining for Vimentin, a mesenchymal cell marker. At 5 years of follow-up, the patient continues to be asymptomatic with a full return to normal function and no residual weakness. Conclusion: PMTs involving the spine are a rare reversible cause of non-compressive quadriparesis. Early diagnosis and excision of the lesion correct the hypophosphatemia and result in complete neurological recovery.

Multi-Omics Analysis of Glioblastoma and Glioblastoma Cell Line: Molecular Insights Into the Functional Role of GPR56 and TG2 in Mesenchymal Transition.

G protein-coupled receptor 56 (GPR56/ADGRG1) is an adhesion GPCR with an essential role in brain development and cancer. Elevated expression of GPR56 was observed in the clinical specimens of Glioblastoma (GBM), a highly invasive primary brain tumor. However, we found the expression to be variable across the specimens, presumably due to the intratumor heterogeneity of GBM. Therefore, we re-examined GPR56 expression in public domain spatial gene expression data and single-cell expression data for GBM, which revealed that GPR56 expression was high in cellular tumors, infiltrating tumor cells, and proliferating cells, low in microvascular proliferation and peri-necrotic areas of the tumor, especially in hypoxic mesenchymal-like cells. To gain a better understanding of the consequences of GPR56 downregulation in tumor cells and other molecular changes associated with it, we generated a sh-RNA-mediated GPR56 knockdown in the GBM cell line U373 and performed transcriptomics, proteomics, and phospho-proteomics analysis. Our analysis revealed enrichment of gene signatures, pathways, and phosphorylation of proteins potentially associated with mesenchymal (MES) transition in the tumor and concurrent increase in cell invasion and migration behavior of the GPR56 knockdown GBM cells. Interestingly, our analysis also showed elevated expression of Transglutaminase 2 (TG2) - a known interactor of GPR56, in the knockdown cells. The inverse expression of GPR56 and TG2 was also observed in intratumoral, spatial gene expression data for GBM and in GBM cell lines cultured in vitro under hypoxic conditions. Integrating all these observations, we propose a putative functional link between the inverse expression of the two proteins, the hypoxic niche and the mesenchymal status in the tumor. Hypoxia-induced downregulation of GPR56 and activation of TG2 may result in a network of molecular events that contribute to the mesenchymal transition of GBM cells, and we propose a putative model to explain this functional and regulatory relationship of the two proteins.

Gelatin methacrylate hydrogels culture model for glioblastoma cells enriches for mesenchymal-like state and models interactions with immune cells.

Glioblastoma is the most lethal primary malignant brain tumor in adults. Simplified two-dimensional (2D) cell culture and neurospheres in vitro models fail to recapitulate the complexity of the tumor microenvironment, limiting its ability to predict therapeutic response. Three-dimensional (3D) scaffold-based models have emerged as a promising alternative for addressing these concerns. One such 3D system is gelatin methacrylate (GelMA) hydrogels, and we aimed to understand the suitability of using this system to mimic treatment-resistant glioblastoma cells that reside in specific niches. We characterized the phenotype of patient-derived glioma cells cultured in GelMA hydrogels (3D-GMH) for their tumorigenic properties using invasion and chemoresponse assays. In addition, we used integrated single-cell and spatial transcriptome analysis to compare cells cultured in 3D-GMH to neoplastic cells in vivo. Finally, we assessed tumor-immune cell interactions with a macrophage infiltration assay and a cytokine array. We show that the 3D-GMH system enriches treatment-resistant mesenchymal cells that are not represented in neurosphere cultures. Cells cultured in 3D-GMH resemble a mesenchymal-like cellular phenotype found in perivascular and hypoxic regions and recruit macrophages by secreting cytokines, a hallmark of the mesenchymal phenotype. Our 3D-GMH model effectively mimics the phenotype of glioma cells that are found in the perivascular and hypoxic niches of the glioblastoma core in situ, in contrast to the neurosphere cultures that enrich cells of the infiltrative edge of the tumor. This contrast highlights the need for due diligence in selecting an appropriate model when designing a study's objectives.

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.

Value of Surgery and Nonsurgical Approaches for Cervical Spondylotic Myelopathy: WFNS Spine Committee Recommendations.

Cervical spondylotic myelopathy (CSM) is a common cause of adult spinal cord dysfunction. Although the therapeutic options for moderate to severe CSM patients have been established well, the existing guidelines for therapeutic decisions in mild cases of CSM are unclear. We present a review of literature on conservative treatment and surgery for CSM and suggest general recommendations applicable in various clinical presentations and in different geographic locations across the globe, with due considerations to available resources and locally prevalent practices.