Immune heterogeneity of glioblastoma subtypes: extrapolation from the cancer genome atlas.

PURPOSE: The molecular heterogeneity of glioblastoma has been well recognized and has resulted in the generation of molecularly defined subtypes. These subtypes (classical, neural, mesenchymal, and proneural) are associated with particular signaling pathways and differential patient survival. Less understood is the correlation between these glioblastoma subtypes with immune system effector responses, immune suppression and tumor-associated and tumor-specific antigens. The role of the immune system is becoming increasingly relevant to treatment as new agents are being developed to target mediators of tumor-induced immune suppression which is well documented in glioblastoma. EXPERIMENTAL DESIGN: To ascertain the association of antigen expression, immune suppression, and effector response genes within glioblastoma subtypes, we analyzed the Cancer Genome Atlas (TCGA) glioblastoma database. RESULTS: We found an enrichment of genes within the mesenchymal subtype that are reflective of anti-tumor proinflammatory responses, including both adaptive and innate immunity and immune suppression. CONCLUSIONS: These results indicate that distinct glioma antigens and immune genes demonstrate differential expression between glioblastoma subtypes and this may influence responses to immune therapeutic strategies in patients depending on the subtype of glioblastoma they harbor.

The temporal association of sphenoid sinus mucosal thickening on MR imaging with pituitary apoplexy.

AIM: Pituitary apoplexy is an infrequent but potentially devastating complication in patients with pituitary adenomas. Previous studies have cited an association between MR visualized sphenoid sinus mucosal thickening and apoplexy. However, uncertainties still remain on the significance and temporal association of this finding with pituitary apoplexy. We provide a clinical study that better delineates this temporal association and also provides histopathologic data for sinus thickening compared to control subjects. MATERIAL AND METHODS: We report on two patients who received serial MR scans leading to the diagnosis of pituitary apoplexy. Patient 1 demonstrated new sphenoid sinus mucosal thickening with the onset of apoplexy. Patient 2 had progressive thickening of sphenoid sinus mucosa from presentation to repeat scanning demonstrating apoplexy. Both patients underwent transsphenoidal resection of their pituitary adenomas with pathology demonstrating inflamed sphenoid sinus mucosa. CONCLUSION: Sphenoid sinus mucosal thickening, as demonstrated on MRI, is temporally associated with pituitary apoplexy, likely as an acute and precedent finding.

Butterfly glioblastomas: a retrospective review and qualitative assessment of outcomes.

To address a paucity of literature and treatment guidelines regarding the management of butterfly glioblastomas, we performed a ten year retrospective analysis of data from twenty-three consecutive patients treated for this disease at a single institution. Clinical characteristics and outcomes were assessed. Median age was 59 years; 52 % were female; median preoperative Karnofsky performance score (KPS) was 80. Twelve patients underwent biopsy and eleven underwent surgical decompression. The median tumor volume for the biopsy group was 60.6 cm(3) and for the surgically decompressed group 40.5 cm(3). In the biopsy group, five patients received adjuvant therapy but one died prior to its completion; two died prior to the initiation of adjuvant therapy and five were lost to follow up. In the surgical decompression group, seven patients received adjuvant therapy, one died prior to the initiation of adjuvant therapy, two were treated with palliative measures only, and one was lost to follow up. Kaplan-Meier estimates of overall median post surgical-survival of the whole group was 180 days, the biopsy group 48 days, and the surgically decompressed group 265 days (p = 0.14). Our results show that there was a higher median survival in the surgically decompressed group; but a direct correlation could not be established, and that the median KPS did not improve in either group after treatment. A larger multicenter review is required to quantitatively assess the factors, including tumor biomarkers that are associated with patient outcome.

Consensus on the role of human cytomegalovirus in glioblastoma.

The human cytomegalovirus (HCMV) and glioma symposium was convened on April 17, 2011 in Washington, DC, and was attended by oncologists and virologists involved in studying the relationship between HCMV and gliomas. The purpose of the meeting was to reach a consensus on the role of HCMV in the pathology of gliomas and to clarify directions for future research. First, the group summarized data that describe how HCMV biology overlaps with the key pathways of cancer. Then, on the basis of published data and ongoing research, a consensus was reached that there is sufficient evidence to conclude that HCMV sequences and viral gene expression exist in most, if not all, malignant gliomas, that HCMV could modulate the malignant phenotype in glioblastomas by interacting with key signaling pathways; and that HCMV could serve as a novel target for a variety of therapeutic strategies. In summary, existing evidence supports an oncomodulatory role for HCMV in malignant gliomas, but future studies need to focus on determining the role of HCMV as a glioma-initiating event.

Glioma-associated cytomegalovirus mediates subversion of the monocyte lineage to a tumor propagating phenotype.

PURPOSE: Cytomegalovirus (CMV) has been ubiquitously detected within high-grade gliomas, but its role in gliomagenesis has not been fully elicited. EXPERIMENTAL DESIGN: Glioblastoma multiforme (GBM) tumors were analyzed by flow cytometry to determine CMV antigen expression within various glioma-associated immune populations. The glioma cancer stem cell (gCSC) CMV interleukin (IL)-10 production was determined by ELISA. Human monocytes were stimulated with recombinant CMV IL-10 and levels of expression of p-STAT3, VEGF (vascular endothelial growth factor), TGF-ß, viral IE1, and pp65 were determined by flow cytometry. The influence of CMV IL-10-treated monocytes on gCSC biology was ascertained by functional assays. RESULTS: CMV showed a tropism for macrophages (MΦ)/microglia and CD133+ gCSCs within GBMs. The gCSCs produce CMV IL-10, which induces human monocytes (the precursor to the central nervous system MΦs/microglia) to assume an M2 immunosuppressive phenotype (as manifested by downmodulation of the major histocompatibility complex and costimulatory molecules) while upregulating immunoinhibitory B7-H1. CMV IL-10 also induces expression of viral IE1, a modulator of viral replication and transcription in the monocytes. Finally, the CMV IL-10-treated monocytes produced angiogenic VEGF, immunosuppressive TGF-ß, and enhanced migration of gCSCs. CONCLUSIONS: CMV triggers a feedforward mechanism of gliomagenesis by inducing tumor-supportive monocytes.

Olfactory ensheathing cell tumor: case report.

Subfrontal schwannomas, sometimes referred to as olfactory groove schwannomas, are rare tumors (34 cases reported to date). Despite the name and several theories proposed in the literature, there is no officially recognized description of the tumor's cell origin. Yasuda proposed the concept of an olfactory ensheathing cell (OEC) tumor in 2006. Olfactory ensheathing cells are glial cells that ensheath the axons of the first cranial nerve. Microscopically, both olfactory ensheathing cells and Schwann cells have similar morphological and immunohistochemical features. However, immunohistochemically olfactory ensheathing cells are negative for Leu7 and Schwann cells positive. A 30-year-old woman presented with a subfrontal, extraaxial, enhancing tumor, and underwent gross total resection. Immunohistochemical reactivity data suggested a schwannoma (positive for S-100 and negative for epithelial membrane antigen). However, the tumor was negative for Leu7. Accordingly, our final diagnosis was that of an OEC tumor. Subfrontal schwannoma immunohistochemical staining, if negative for Leu7, is indicative of an OEC tumor. It is possible that schwannoma-like extraaxial tumors at the anterior skull base are OEC tumors, which negative Leu7 staining can confirm.

Intraosseous meningioma of the sphenoid bone.

A 50-year-old female presented to the Neurosurgery clinic with dimness of vision and proptosis of her right eye. Maxillofacial CT showed a hyperostotic mass involving the right sphenoid ridge, anterior clinoid process, orbital roof, and lateral wall with mass effect on the intraorbital contents and lateral wall of the sphenoid sinus. MRI of the brain and orbit showed a heterogeneous enhancement of underlying dura and right orbital apex extending into the cavernous sinus. The patient underwent a staged resection in which pathological analysis showed an intraosseous meningioma. When a hyperostotic mass of the skull is encountered, meningioma should be considered in the differential diagnosis. Although primary intraosseous meningiomas are rare benign tumors, they can be associated with morbidity secondary to mass effect.

Diabetes insipidus, panhypopituitarism, and severe mental status deterioration in a patient with chordoid glioma: case report and literature review.

OBJECTIVE: To describe a rare progressive case of chordoid glioma clinically masquerading as idiopathic diabetes insipidus (DI). METHODS: We describe the clinical, radiographic, and laboratory findings of the study patient and briefly review the relevant literature. RESULTS: A 41-year-old woman was referred to our center for evaluation of worsening mental status changes, a newly diagnosed suprasellar mass, and possible endocrine dysfunction. Three years earlier, a physician at another institution diagnosed idiopathic DI and prescribed desmopressin. At that time, laboratory workup and magnetic resonance imaging (MRI) revealed no brain lesions or other hormonal irregularities. Slow, progressive symptomatology in the following 3 years included mental status changes, nonhealing skin lesions, recurrent infections, temperature dysregulation, and midsection weight gain. She became withdrawn and emotionally labile and developed a flat affect, short-term memory loss, poor concentration, and sleep disturbance. MRI revealed a 2.2 x 2.1 x 1.9-cm suprasellar region lesion. Biopsy samples from the third ventricular lesion revealed a circumscribed glial tumor. Chordoid glioma is a rare tumor, and the 50 previously reported cases have been located in the suprasellar region. This is the third reported case of a chordoid glioma positive for neurofilament protein, which brings into question the hypothesis of a single phenotype for glial tumors. Tumors in this region frequently result in endocrine dysfunction that prompts patients to seek medical attention. CONCLUSIONS: There is no formally recognized treatment protocol for chordoid glioma, and postoperative mortality and morbidity is high. Our report emphasizes the necessity of close follow-up of patients after a diagnosis of idiopathic DI. Early detection of any evolving occult hypothalamic-pituitary stalk lesion may improve outcome.

Placement of baclofen pumps through the foramen magnum and upper cervical spine.

INTRODUCTION: The baclofen pump has been utilized in children with refractory spasticity. However, in children with prior lumbar fusion, the implantation of such a device is difficult and fraught with complications. As an alternative to placing the pump catheter through the lumbar spine, we report our experience with placement of the catheter in the spinal canal via a cervical approach through the foramen magnum. METHODS: We have followed three patients with prior lumbar fusion and refractory spasticity, each of whom has undergone placement of the intrathecal component of a baclofen pump via the foramen magnum. Appropriate positioning of the catheter tip at the T6 spinal level was determined using intraoperative fluoroscopy. The catheter was then tunneled to the pump in the abdominal wall. RESULTS: All patients experienced a significant decrease in the severity of spasticity with pump placement. The pumps continued to function properly over a follow-up period of 24, 24, and 44 months respectively. In one patient, the catheter recoiled into the subcutaneous tissues several months after its placement, thus necessitating repositioning. One of the pumps was removed 2 years later secondary to a VP shunt infection. However, there were no immediate complications related to placement of the spinal catheter. CONCLUSIONS: Placement of the intraspinal component of a baclofen pump via the foramen magnum is a viable alternative for patients with spastic quadriparesis with prior lumbar fusion. The tip of the spinal catheter can be positioned in the thoracic region in a similar manner to the placement traditional lumbar pumps. In our series, there were no adverse sequelae related to the surgery or catheter positioning.

A blinded assessment of radiographic criteria for atlanto-occipital dislocation.

STUDY DESIGN: Blinded comparison of 5 methods to diagnose atlanto-occipital dislocation (AOD) on plain radiographs and computerized tomography (CT) of the cervical spine. OBJECTIVE: To determine the best method to diagnose AOD. SUMMARY OF BACKGROUND DATA: Several methods are proposed for the diagnosis of AOD, including the Power's ratio, X-line method, basion-dens interval, condylar gap, and Harris method. No blinded comparison of the results of these methods has been compared to patient outcome, and there is no information available regarding the accuracy of these methods applied to CT scans. METHODS: Plain lateral radiographs and CTs of the cervical spine were reviewed in 104 patients, including 6 with AOD. Images underwent a blinded review by a board certified neurosurgeon (D.K.R.), orthopedist (P.A.A.), radiologist (J.C.), and emergency physician (D.B.B.). Each diagnostic method for AOD was applied for determination of sensitivity, specificity, and positive and negative predictive values. The ability to identify relevant anatomic landmarks was also tabulated. RESULTS: Average values for sensitivities, specificities, positive and negative predictive values for each method applied to plain radiographs are: 0.4625-1.0, 0.8933-0.9725, 0.2775-0.45, and 0.975-1.0, respectively. These values for each method applied to CT scans are: 0.7075-1.0, 0.8725-0.9775, 0.3175-1, and 0.98-1.0, respectively. Identification of relevant anatomic landmarks occurred 99.75% of the time when these methods were applied to CT scans compared to 39% to 84% of the time on plain radiographs. CONCLUSIONS: Sensitivity, specificity, positive and negative predictive values of these methods improve when applied to CT scans because of better visualization of anatomic landmarks. This result suggests CT scans of the cervical spine may be warranted in all trauma patients suspected of having cervical spine injury.