Faculty Bibliography

The authors report on an 81-year-old woman with a pathologic hangman's fracture secondary to a complex arteriovenous fistula (AVF). The patient presented with severe, unremitting neck pain and was found to have fractures bilaterally through the pars interarticularis of C-2 with significant anterior subluxation of C-2 over C-3 along with widening of the left transverse foramen. Due to an abnormally appearing left vertebral artery (VA) on CT angiography, the patient underwent conventional angiography, which revealed a complex AVF stemming from the left VA at the level of C-2 with dilated posterior cervical veins and a large venous varix. Given the radiographic evidence of bone remodeling and the chronicity of the AVF, it is believed that the C-2 vertebra was weakened over time by the pulsatile and compressive force of the vascular malformation eventually leading to fracture with minimal stress. Coil embolization of the AVF was performed followed by surgical fixation of C-1 to C-4. This case highlights the importance of investigating an underlying disease process in patients who present with significant spinal fractures in the absence of trauma.

OBJECTIVE The authors sought to determine the effects of eliminating the use of prolonged prophylactic systemic antibiotics (PPSAs) in patients with subdural and subgaleal drains. METHODS Using a retrospective database, the authors collected data for patients over the age of 17 years who had undergone cranial surgery at their institution between December 2013 and July 2014 (PPSAs period) or between December 2014 and July 2015 (non-PPSAs period) and had subdural or subgaleal drains left in place postoperatively. RESULTS One hundred five patients in the PPSAs period and 80 in the non-PPSAs period were identified. The discontinuation of PPSAs did not result in an increase in the frequency of surgical site infection (SSI). The frequency of Clostridium difficile (CDI) and the growth of resistant bacteria were reduced in the non-PPSAs period in comparison with the PPSAs period. In the 8 months after the drain prophylaxis protocol was changed, $93,194.63 were saved in the costs of antibiotics and complications related to antibiotics. CONCLUSIONS After discontinuing PPSAs for patients with subdural or subgaleal drains at their institution, the authors did not observe an increase in the frequency of SSI. They did, however, note a decrease in the frequency of CDI and the growth of resistant organisms. It appears that not only can patients in this population do without PPSAs, but also that complications are avoided when antibiotic use is limited to 24 hours after surgery.

Palliative cervical cordotomy can be performed via percutaneous radiofrequency ablation of the lateral C1-2 spinothalamic tract. This rare procedure can be safe, effective, and advantageous in mitigating medically intractable unilateral extremity pain for selected patients with end-stage cancer. This report reviews the indications, techniques, risks, and potential benefits of cordotomy. We describe our recent experience treating 3 patients with CT-guided C1-2 cordotomy and provide the first characterization of spinal cord diffusion MR imaging changes associated with successful cordotomy.

Introduction Postoperative antibiotics (PA) are often administered to patients after instrumented spinal surgery until all drains are removed to prevent surgical site infections (SSI). This practice is discouraged by numerous medical society guidelines, so our institutional Neurosurgery Quality Improvement Committee decided to discontinue use of PA for this population. Methods We retrospectively reviewed data for patients who had instrumented spinal surgery at our institution for seven months before and after this policy change and compared the frequency of SSI and development of antibiotic related complications in patients who received PA to those who did not (non- PA). Results We identified 188 PA patients and 158 non-PA patients. Discontinuation of PA did not result in an increase in frequency of SSI (2% of PA patients vs. 0.6% of non-PA patients, p=0.4). Growth of resistant bacteria was not significantly reduced in the non-PA period in comparison to the PA period (2% vs. 1%, p=1). The cost of antibiotics for PA patients was $5,499.62, whereas the cost of antibiotics for the non- PA patients was $0. On a per patient basis, the cost associated with antibiotics and resistant infections was significantly greater for patients who received PA than for those who did not (median of $26.32 with IQR $9.87-$46.06 vs. median of $0 with IQR $0-$0; p<0.0001). Conclusions After discontinuing PA for patients who had instrumented spinal procedures, we did not observe an increase in the frequency of SSI. We did, however, note that there was a non-significant decrease in the frequency of growth of resistant organisms. These findings suggest that patients in this population do not need PA, and complications can be reduced if PA are withheld

Mutant isocitrate dehydrogenase 1 (IDH1) is common in gliomas, and produces D-2-hydroxyglutarate (D-2-HG). The full effects of IDH1 mutations on glioma biology and tumor microenvironment are unknown. We analyzed a discovery cohort of 169 World Health Organization (WHO) grade II-IV gliomas, followed by a validation cohort of 148 cases, for IDH1 mutations, intratumoral microthrombi, and venous thromboemboli (VTE). 430 gliomas from The Cancer Genome Atlas were analyzed for mRNAs associated with coagulation, and 95 gliomas in a tissue microarray were assessed for tissue factor (TF) protein. In vitro and in vivo assays evaluated platelet aggregation and clotting time in the presence of mutant IDH1 or D-2-HG. VTE occurred in 26-30 % of patients with wild-type IDH1 gliomas, but not in patients with mutant IDH1 gliomas (0 %). IDH1 mutation status was the most powerful predictive marker for VTE, independent of variables such as GBM diagnosis and prolonged hospital stay. Microthrombi were far less common within mutant IDH1 gliomas regardless of WHO grade (85-90 % in wild-type versus 2-6 % in mutant), and were an independent predictor of IDH1 wild-type status. Among all 35 coagulation-associated genes, F3 mRNA, encoding TF, showed the strongest inverse relationship with IDH1 mutations. Mutant IDH1 gliomas had F3 gene promoter hypermethylation, with lower TF protein expression. D-2-HG rapidly inhibited platelet aggregation and blood clotting via a novel calcium-dependent, methylation-independent mechanism. Mutant IDH1 glioma engraftment in mice significantly prolonged bleeding time. Our data suggest that mutant IDH1 has potent antithrombotic activity within gliomas and throughout the peripheral circulation. These findings have implications for the pathologic evaluation of gliomas, the effect of altered isocitrate metabolism on tumor microenvironment, and risk assessment of glioma patients for VTE.

High-grade glioma (HGG), a deadly primary brain malignancy, manifests radioresistance mediated by cell-intrinsic and microenvironmental mechanisms. High levels of the cytokine transforming growth factor-beta (TGF-beta) in HGG promote radioresistance by enforcing an effective DNA damage response and supporting glioma stem cell self-renewal. Our analysis of HGG TCGA data and immunohistochemical staining of phosphorylated Smad2, which is the main transducer of canonical TGF-beta signaling, indicated variable levels of TGF-beta pathway activation across HGG tumors. These data suggest that evaluating the putative benefit of inhibiting TGF-beta during radiotherapy requires personalized screening. Thus, we used explant cultures of seven HGG specimens as a rapid, patient-specific ex vivo platform to test the hypothesis that LY364947, a small molecule inhibitor of the TGF-beta type I receptor, acts as a radiosensitizer in HGG. Immunofluorescence detection and image analysis of gamma-H2AX foci, a marker of cellular recognition of radiation-induced DNA damage, and Sox2, a stem cell marker that increases post-radiation, indicated that LY364947 blocked these radiation responses in five of seven specimens. Collectively, our findings suggest that TGF-beta signaling increases radioresistance in most, but not all, HGGs. We propose that short-term culture of HGG explants provides a flexible and rapid platform for screening context-dependent efficacy of radiosensitizing agents in patient-specific fashion. This time- and cost-effective approach could be used to personalize treatment plans in HGG patients.

Utilizing advanced 3D printing techniques, a multimaterial model was created for the surgical planning of a complex deformity of the skull base and craniovertebral junction. The model contained bone anatomy as well as vasculature and the previously placed occipital cervical instrumentation. Careful evaluation allowed for a unique preoperative perspective of the craniovertebral deformity and instrumentation options. This patient-specific model was invaluable in choosing the most effective approach and correction strategy, which was not readily apparent from standard 2D imaging. Advanced 3D multimaterial printing provides a cost-effective method of presurgical planning, which can also be used for both patient and resident education.

Glioblastoma (GBM) is a deadly primary brain malignancy with extensive intratumoral hypoxia. Hypoxic regions of GBM contain stem-like cells and are associated with tumor growth and angiogenesis. The molecular mechanisms that regulate tumor growth in hypoxic conditions are incompletely understood. Here, we use primary human tumor biospecimens and cultures to identify GPR133 (ADGRD1), an orphan member of the adhesion family of G-protein-coupled receptors, as a critical regulator of the response to hypoxia and tumor growth in GBM. GPR133 is selectively expressed in CD133+ GBM stem cells (GSCs) and within the hypoxic areas of PPN in human biospecimens. GPR133 mRNA is transcriptionally upregulated by hypoxia in hypoxia-inducible factor 1alpha (Hif1alpha)-dependent manner. Genetic inhibition of GPR133 with short hairpin RNA reduces the prevalence of CD133+ GSCs, tumor cell proliferation and tumorsphere formation in vitro. Forskolin rescues the GPR133 knockdown phenotype, suggesting that GPR133 signaling is mediated by cAMP. Implantation of GBM cells with short hairpin RNA-mediated knockdown of GPR133 in the mouse brain markedly reduces tumor xenograft formation and increases host survival. Analysis of the TCGA data shows that GPR133 expression levels are inversely correlated with patient survival. These findings indicate that GPR133 is an important mediator of the hypoxic response in GBM and has significant protumorigenic functions. We propose that GPR133 represents a novel molecular target in GBM and possibly other malignancies where hypoxia is fundamental to pathogenesis.