Bilateral occipital condyle fracture with an avulsion fracture of the foramen magnum: nonoperative care guided by a traction test. Illustrative case.

BACKGROUND: Bilateral occipital condyle fractures (OCFs) with involvement of the inferior clivus, otherwise known as "avulsion of the anterior foramen magnum," are an exceedingly rare injury with only a few published reports. OBSERVATIONS: A 24-year-old male presented with bilateral OCFs with involvement of the clivus after a motor vehicle accident. The patient had no neurological deficits and was successfully managed nonoperatively using a halo vest. The authors used a traction test to guide the duration of nonoperative care. The operative and nonoperative management of this rare injury is discussed with respect to other cases in the literature. LESSONS: External immobilization through a halo vest is an effective treatment option for bilateral OCFs with clivus involvement. The traction test can be used, along with computed tomography, to guide the duration of treatment.

Does a Multidisciplinary Triage Pathway Facilitate Better Outcomes After Spine Surgery?

STUDY DESIGN: Single-center prospective non-randomized matched cohort comparison. OBJECTIVE: To compare elective lumbar spine surgery outcomes for cases triaged through a multidisciplinary spine pathway versus conventional referral processes. SUMMARY OF BACKGROUND DATA: Many health care systems have facilitated low back pain (LBP) guidelines into primary care practice by creating local or regional "pathways" with the goal of enhanced quality of care, improved patient satisfaction and optimal resource utilization, particularly for imaging and surgery. Few comparative outcomes exist for LBP pathways, particularly for surgical outcomes. METHODS: One-hundred-fifty patients (SSP group n = 75; conventional group n = 75) undergoing elective lumbar surgery for degenerative conditions between 2011 and 2016 were analyzed with 1-year follow-up. Patient self-reported outcomes included the Oswestry disability index (ODI), visual analogue pain scores (VAS) for back and leg, and EuroQol Group 5-Dimension self-report (EQ-5D). We also assessed baseline clinical features, indications for surgery, therapies received prior to surgery, type of surgery, wait times, and overall patient satisfaction. RESULTS: The groups had equivalent baseline demographics, body mass index, Saskatchewan Spine Pathway (SSP) classification of pain pattern, pain scores, functional scores, quality of life scores, indication for surgery, and type of surgery (instrumented or non-instrumented). There was no difference with respect to wait times to see the surgeon or for surgery. Wait time for magnetic resonance imaging (MRI) was significantly shorter for the SSP group (16.8 vs. 63.0 days, P < 0.001). Patients triaged through the SSP were significantly more likely to utilize multiple nonoperative treatment strategies prior to seeing the surgeon (P < 0.04). Patient satisfaction was significantly higher for SSP patients prior to surgical assessment (P = 0.03) but did not differ between groups after surgery. CONCLUSION: The SSP facilitates significantly shorter wait times for MRI and promotes nonoperative treatment strategies. Preoperative patient satisfaction is significantly higher among SSP patients, but there were no significant differences in surgical outcomes.Level of Evidence: 3.

The Concept of an Epilepsy Brain Bank.

Epilepsy comprises more than 40 clinical syndromes affecting millions of patients and families worldwide. To decode the molecular and pathological framework of epilepsy researchers, need reliable human epilepsy and control brain samples. Brain bank organizations collecting and supplying well-documented clinically and pathophysiologically tissue specimens are important for high-quality neurophysiology and neuropharmacology studies for epilepsy and other neurological diseases. New development in molecular mechanism and new treatment methods for neurological disorders have evoked increased demands for human brain tissue. An epilepsy brain bank is a storage source for both the frozen samples as well as the formaldehyde fixed paraffin embedded (FFPE) tissue from epilepsy surgery resections. In 2014, the University of Saskatchewan have started collecting human epilepsy brain tissues for the first time in Canada. This review highlights the necessity and importance of Epilepsy Brain bank that provides unique access for research to valuable source of brain tissue and blood samples from epilepsy patients.

Evaluation of wait times for assessment and epilepsy surgery according the geographic area of residence in the province of Saskatchewan, Canada.

PURPOSE: The aim of this study was to determine and compare the waiting times for surgical assessment, neuropsychological testing and epilepsy surgery between people with epilepsy who live in cities with available neurologists vs not. METHODS: We reviewed all cases referred for epilepsy surgery between 2007 and 2017 at the Saskatchewan Epilepsy Program Royal University Hospital (SEP) (n = 98; Saskatchewan, Canada). Mann-Whitney U test was used to compare wait times from first diagnosis of epilepsy to epilepsy surgery between patients who live in cities with neurologists (mainly urban areas) vs cities without neurologists (mainly rural areas). RESULTS: The mean age of patients who enrolled in SEP was 37.8 ± 12.8 years. The median wait time from date of epilepsy diagnosis to referral was 9.5 years in Saskatoon and Regina (cities with available neurologists) and 14 years in other areas of Saskatchewan (small cities and rural areas with no available neurologists) (p = 0.03). The median wait time from date of epilepsy diagnosis to first consult with the epileptologist was 10 years in Saskatoon and Regina and 15.5 years in other areas of Saskatchewan (p = 0.03). The median wait time from date of first diagnosis to epilepsy surgery was 13.2 years in Saskatoon and Regina and 18.2 years in other areas of Saskatchewan (p = 0.05). CONCLUSION: A notable difference was observed in surgical wait times between patients who live in cities with available neurologists compared with people living in rural areas and cities with no neurologists. This suggests that delayed surgical treatment for epilepsy is related with the availability of neurologists.

Atypical language localization in right temporal lobe epilepsy: An fMRI case report.

We report a 41- year-old, left-handed patient with drug-resistant right temporal lobe epilepsy (TLE). Presurgical fMRI was conducted to examine whether the patient had language functioning in the right hemisphere given that left-handedness is associated with a higher prevalence of right hemisphere dominance for language. The fMRI results revealed bilateral activation in Broca's and Wernicke's areas and activation of eloquent cortex near the region of planned resection in the right temporal lobe. Due to right temporal language-related activation, the patient underwent an awake right-sided temporal lobectomy with intraoperative language mapping. Intraoperative direct cortical stimulation (DCS) was conducted in the regions corresponding to the fMRI activation, and the patient showed language abnormalities, such as paraphasic errors, and speech arrest. The decision was made to abort the planned anterior temporal lobe procedure, and the patient instead underwent a selective amygdalohippocampectomy via the Sylvian fissure at a later date. Post-operatively the patient was seizure-free with no neurological deficits. Taken together, the results support previous findings of right hemisphere language activation in left-handed individuals, and should be considered in cases in which presurgical localization is conducted for left-hand dominant patients undergoing neurosurgical procedures.

HERG channel and cancer: A mechanistic review of carcinogenic processes and therapeutic potential.

The human ether-à-go-go related gene (HERG) encodes the alpha subunit of Kv11.1, which is a voltage-gated K+ channel protein mainly expressed in heart and brain tissue. HERG plays critical role in cardiac repolarization, and mutations in HERG can cause long QT syndrome. More recently, evidence has emerged that HERG channels are aberrantly expressed in many kinds of cancer cells and play important roles in cancer progression. HERG could therefore be a potential biomarker for cancer and a possible molecular target for anticancer drug design. HERG affects a number of cellular processes, including cell proliferation, apoptosis, angiogenesis and migration, any of which could be affected by dysregulation of HERG. This review provides an overview of available information on HERG channel as it relates to cancer, with focus on the mechanism by which HERG influences cancer progression. Molecular docking attempts suggest two possible protein-protein interactions of HERG with the ß1-integrin receptor and the transcription factor STAT-1 as novel HERG-directed therapeutic targeting which avoids possible cardiotoxicity. The role of epigenetics in regulating HERG channel expression and activity in cancer will also be discussed. Finally, given its inherent extracellular accessibility as an ion channel, we discuss regulatory roles of this molecule in cancer physiology and therapeutic potential. Future research should be directed to explore the possibilities of therapeutic interventions targeting HERG channels while minding possible complications.

Resolution of ictal bradycardia and asystole following temporal lobectomy: A case report, and review of available cases using pacemakers.

Ictal bradycardia (IB) and ictal asystole (IA) are uncommonly recognized phenomena that increase morbidity in patients with epilepsy by causing syncope and seizure-related falls. These arrhythmias are also suspected to be involved in the pathophysiology of sudden unexpected death in epilepsy (SUDEP). We report a case of a 57-year-old male with left temporal lobe epilepsy who experienced both IB and IA. This patient was initially managed with pacemaker implantation, prior to undergoing left temporal lobectomy. Following surgery, the patient had no ongoing IB or IA on his pacemaker recordings, and his seizure control was greatly improved. His pacemaker was removed approximately one year post-operatively and he continued treatment with anti-seizure drugs (ASDs). A literature review of cases of IB and IA that were managed with pacemakers was performed. Pacemaker implantation appears to be quite effective for reducing seizure-related syncope and falls in the setting of IB/IA. Epilepsy surgery also seems to be an effective treatment option for IB/IA, as many patients are able to have their pacemakers removed post-operatively. Further investigations into the pathophysiology of IB and IA and long-term outcomes using different treatment modalities are clearly needed to help formulate treatment guidelines and, potentially, to reduce the occurrence of SUDEP in these patients.

Intracranial investigation of a patient with nodular heterotopia and hippocampal sclerosis: dealing with a dual pathology.

The pre-operative assessment and surgical management of patients with dual pathology is challenging. We describe a patient with drug-resistant focal epilepsy with hippocampal sclerosis and extensive periventricular nodular heterotopia in the same hemisphere. The semiology, scalp EEG, and imaging were divergent, but the presence of focal interictal and ictal epileptic discharges of the putative ictal onset zone resulted in successful localization of the epileptogenic zone. A less aggressive resection was performed based on intracranial EEG recording. The patient has been seizure-free for three years since resection. Electroclinical hypotheses and challenges in defining the epileptogenic network are discussed.

Presurgical language mapping in epilepsy: Using fMRI of reading to identify functional reorganization in a patient with long-standing temporal lobe epilepsy.

We report a 55-year-old, right-handed patient with intractable left temporal lobe epilepsy, who previously had a partial left temporal lobectomy. The patient could talk during seizures, suggesting that he might have language dominance in the right hemisphere. Presurgical fMRI localization of language processing including reading of exception and regular words, pseudohomophones, and dual meaning words confirmed the clinical hypothesis of right language dominance, with only small amounts of activation near the planned surgical resection and, thus, minimal eloquent cortex to avoid during surgery. Postoperatively, the patient was rendered seizure-free without speech deficits.

How many adults with temporal epilepsy have a mild course and do not require epilepsy surgery?

Temporal lobe epilepsy (TLE) is the most common type of drug-resistant epilepsy in adults and commonly requires surgical treatment. While an overwhelming preponderance of literature supports the notion that a large percentage of patients with TLE benefit from surgery, there is a paucity of outcome data on patients who demonstrate a sustained response to pharmacological treatment. In this study, we present an adult cohort of patients with TLE, with the purpose of identifying the proportion of patients with a mild course of the disease, as well as potential risk factors. A prospective cohort study of all patients with TLE assessed and followed by the Saskatchewan Epilepsy Program, from 1 March 2007 to Jan 29(th) 2014. Patients were dichotomized as having a mild (seizure freedom without surgical intervention) or severe (surgical intervention required and/or failure to achieve seizure remission) course. Descriptive statistics, odds ratios and confidence intervals were calculated to identify predictors of seizure freedom. The cohort consisted of 159 patients. Mean patient age at last follow-up visit was 46±14.4 (range: 19-88) years. Mean follow-up period was 43.4±22.6 (6 to 84) months. Forty-six patients (29%) demonstrated mild-course TLE while 113 (71%) had a severe course of TLE. Patients with a mild course of TLE were more likely to be older (p = 0.002), have late-onset epilepsy (p < 0.001) with shorter evolution (p < 0.001). A good response to the first antiepileptic drug (OR: 6.8; 95% CI: 2.5-19; p < 0.001) was associated with a mild course of TLE. Although a majority of patients with TLE eventually require surgery, operative treatment is not necessary for all patients. This study identifies prognostic factors that may help patients and clinicians characterize long-term outcome.

Triage of spine surgery referrals through a multidisciplinary care pathway: a value-based comparison with conventional referral processes.

STUDY DESIGN: Retrospective medical record review. OBJECTIVE: To (1) determine if outpatient referrals for low back pain (LBP) and leg pain triaged through a multidisciplinary spine care pathway (group A) were more likely to be candidates for surgery than conventional physician referrals (group B); (2) compare relevant clinical differences in the 2 groups (e.g., diagnosis, pain scores, level of disability); and (3) compare wait times for magnetic resonance imaging and surgical assessment. SUMMARY OF BACKGROUND DATA: The Saskatchewan Spine Pathway was introduced on the basis of evidence that a co-ordinated, multidisciplinary, and stratified approach to the assessment and management of LBP may improve quality. During early implementation, some physicians began to refer patients to Saskatchewan Spine Pathway clinics, whereas others continued to refer patients directly to the surgeon through the conventional process. METHODS: We retrospectively analyzed consecutive new outpatient referrals for LBP and leg pain, June 1, 2011 through May 30, 2012 for 2 surgeons. RESULTS: We identified 215 referrals, including 66 (30.7%) in group A and 149 (69.3%) in group B. There was no difference in overall health (mean EuroQol Group 5-Dimension Self-Report Questionnaire visual analogue scale) or lower back-related disability score (Oswestry Disability Index). Group A patients were significantly more likely to be candidates for surgery (59.1% vs. 37.6% for group B; P = 0.0034, χ test), had significantly poorer scores for EuroQol Group 5-Dimension Self-Report Questionnaire mobility, a higher proportion of leg dominant pain, and a lower proportion of back dominant pain. Group A patients also had significantly shorter wait times for magnetic resonance imaging and surgical assessment. CONCLUSION: A co-ordinated multidisciplinary pathway with a stratified approach to LBP assessment and care provided a greater proportion of surgery candidates than the conventional referral process. The implementation of such processes may allow surgeons to restrict their practices to patients who are more likely to benefit from their services, thereby reducing wait times and potentially reducing costs. LEVEL OF EVIDENCE: 3.

Is rapid withdrawal of anti-epileptic drug therapy during video EEG monitoring safe and efficacious?

PURPOSE: Video electroencephalographic monitoring (VEM) is used to record ictal and interictal epileptiform activity and to ascertain the level of concordance between the two. Often, taper or discontinuation of anti-epileptic (AED) therapy is needed to facilitate seizure occurrence. The safety of this practice is unclear and long-term sequelae have yet to be elucidated. METHODS: This is a prospective study of 158 patients subjected to combined sleep-deprived VEM with rapid AED withdrawal, for evaluation of seizure-like episodes over 24 months under the care of an epileptologist with direct nursing observation and EEG technician support in our telemetry unit. In most cases, AEDs were discontinued within 24h of admission. We assessed the diagnostic yield and safety of VEM as well as epilepsy surgery outcomes. RESULTS: VEM answered the study question in 90.5% of cases but failed to record ictal events in 9.5%. This diagnostic yield was achieved over a mean VEM duration of 4.53±1.44 days, with no benefit of longer monitoring. These findings improved quality of life by optimizing medical and surgical therapeutic planning, leading to improved seizure control. Overall, 32.9% of the cohort received epilepsy surgery. The complication rate was 5.06%, characterized largely by musculoskeletal pain secondary to clinical seizure activity, with no mortality observed. In the first month following VEM 2.5% of patients received emergency-room admission for seizure clustering. CONCLUSIONS: VEM with combined sleep deprivation and protocolized rapid AED withdrawal is a safe and effective investigative technique with no adverse long-term sequelae. It is a reliable strategy for therapeutic planning and can be used to determine candidacy for surgical treatment.

A prospective randomized trial of perioperative seizure prophylaxis in patients with intraparenchymal brain tumors.

OBJECT: Seizures are a potentially devastating complication of resection of brain tumors. Consequently, many neurosurgeons administer prophylactic antiepileptic drugs (AEDs) in the perioperative period. However, it is currently unclear whether perioperative AEDs should be routinely administered to patients with brain tumors who have never had a seizure. Therefore, the authors conducted a prospective, randomized trial examining the use of phenytoin for postoperative seizure prophylaxis in patients undergoing resection for supratentorial brain metastases or gliomas. METHODS: Patients with brain tumors (metastases or gliomas) who did not have seizures and who were undergoing craniotomy for tumor resection were randomized to receive either phenytoin for 7 days after tumor resection (prophylaxis group) or no seizure prophylaxis (observation group). Phenytoin levels were monitored daily. Primary outcomes were seizures and adverse events. Using an estimated seizure incidence of 30% in the observation arm and 10% in the prophylaxis arm, a Type I error of 0.05 and a Type II error of 0.20, a target accrual of 142 patients (71 per arm) was planned. RESULTS: The trial was closed before completion of accrual because Bayesian predictive probability analyses performed by an independent data monitoring committee indicated a probability of 0.003 that at the end of the study prophylaxis would prove superior to observation and a probability of 0.997 that there would be insufficient evidence at the end of the trial to choose either arm as superior. At the time of trial closure, 123 patients (77 metastases and 46 gliomas) were randomized, with 62 receiving 7-day phenytoin (prophylaxis group) and 61 receiving no prophylaxis (observation group). The incidence of all seizures was 18% in the observation group and 24% in the prophylaxis group (p = 0.51). Importantly, the incidence of early seizures (< 30 days after surgery) was 8% in the observation group compared with 10% in the prophylaxis group (p = 1.0). Likewise, the incidence of clinically significant early seizures was 3% in the observation group and 2% in the prophylaxis group (p = 0.62). The prophylaxis group experienced significantly more adverse events (18% vs 0%, p < 0.01). Therapeutic phenytoin levels were maintained in 80% of patients. CONCLUSIONS: The incidence of seizures after surgery for brain tumors is low (8% [95% CI 3%-18%]) even without prophylactic AEDs, and the incidence of clinically significant seizures is even lower (3%). In contrast, routine phenytoin administration is associated with significant drug-related morbidity. Although the lower-than-anticipated incidence of seizures in the control group significantly limited the power of the study, the low baseline rate of perioperative seizures in patients with brain tumors raises concerns about the routine use of prophylactic phenytoin in this patient population.

Outpatient ambulatory EEG as an option for epilepsy surgery evaluation instead of inpatient EEG telemetry.

Outpatient ambulatory EEG is more cost-effective than inpatient EEG telemetry and may provide adequate seizure localization in a presurgical evaluation. A 51-year-old right-handed male had been unable to work or drive since the age of 35 due to intractable partial onset epilepsy. A 72-hour outpatient ambulatory EEG recorded 18 seizures from the right temporal region. No epileptiform activity was seen in the left hemisphere. Magnetic resonance imaging showed right mesial temporal sclerosis as well as an area of encephalomalacia at the medial inferior right temporal lobe. Neuropsychological assessment found that the patient was a good neurosurgery candidate. At this point, the patient was considered to be a candidate for a right temporal lobectomy. A standard right temporal lobectomy was performed. The patient has been seizure-free for 10 months after the surgery. Follow-up EEGs show no epileptiform activity. The patient is preparing to go back to work, and his driver's license was reinstated 9 months postsurgery. Neuropsychological reassessment is pending, but no apparent change in cognition has been noticed by the patient or his family. Cases with a high congruence between diagnostic imaging and the EEG abnormalities identified in the portable EEG may provide enough information regarding seizure frequency and localization to eliminate the need for inpatient EEG telemetry in the evaluation of patients for epilepsy surgery. We believe that the use of aEEG in preoperative planning should be restricted to cases of TLE and to patients with a high frequency of seizures.

Hydrogenolysis of ß-O-4 lignin model dimers by a ruthenium-xantphos catalyst.

Hydrogenolysis reactions of so-called lignin model dimers using a Ru-xantphos catalyst are presented (xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene). For example, of some nine models studied, the alcohol, 2-(2-methoxyphenoxy)-1-phenylethanol (1), with 5 mol% Ru(H)(2)(CO)(PPh(3))(xantphos) (18) in toluene-d(8) at 135 °C for 20 h under N(2), gives in ~95% yield the C-O cleavage hydrogenolysis products, acetophenone (14) and guaiacol (17), and a small amount (<5%) of the ketone, 2-(2-methoxyphenoxy)-1-phenylethanone (4), as observed by (1)H NMR spectroscopy. The in situ Ru(H)(2)(CO)(PPh(3))(3)/xantphos system gives similar findings, confirming a recent report (J. M. Nichols et al., J. Am. Chem. Soc., 2010, 132, 12554). The active catalyst is formulated 'for convenience' as 'Ru(CO)(xantphos)'. The hydrogenolysis mechanism proceeds by initial dehydrogenation to give the ketone 4, which then undergoes hydrogenolysis of the C-O bond to give 14 and 17. Hydrogenolysis of 4 to 14 and 17 also occurs using the Ru catalyst under 1 atm H(2); in contrast, use of 3-hydroxy-2-(2-methoxyphenoxy)-1-phenyl-1-propanone (7), for example, where the CH(2) of 4 has been changed to CHCH(2)OH, gives a low yield (≤15%) of hydrogenolysis products. Similarly, the diol substrate, 2-(2-methoxyphenoxy)-1-phenyl-1,3-propanediol (9), gives low yields of hydrogenolysis products. These low yields are due to formation of the catalytically inactive complexes Ru(CO)(xantphos)[C(O)C(OC(6)H(4)OMe)=C(Ph)O] (20) and/or Ru(CO)(xantphos)[C(O)CH=C(Ph)O] (21), where the organic fragments result from dehydrogenation of CH(2)OH moieties in 7 and 9. Trace amounts of Ru(CO)(xantphos)(OC(6)H(4)O), a catecholate complex, are isolated from the reaction of 18 with 1. Improved syntheses of 18 and lignin models are also presented.

Neurocognitive function before and after surgery for insular gliomas.

OBJECT: Insular gliomas can be resected with acceptable rates of neurological morbidity, but little is known with regard to impairment of higher-order neurocognitive functions. The frequency and functional impact of neurocognitive deficits in patients with gliomas has until recently been underappreciated. The authors therefore examined neurocognitive function in patients with insular gliomas and compared the findings in this group to those in a matched control group of patients with gliomas in nearby brain regions. METHODS: Thirty-three patients with WHO Grade II or III insular gliomas participated in neuropsychological evaluations before and after resection. To establish whether the pattern of neurocognitive performance was different from that of other patients with tumors in neighboring areas, patients with insular tumors were matched with control patients for age, educational level, preoperative Karnofsky Performance Scale score, tumor side, grade, and volume. The control group comprised patients in whom gliomas had been resected from frontal, temporal, and parietal areas near the insula. Baseline pre- and postoperative neurocognitive test results were compared between and within groups. RESULTS: Preoperative neurocognitive impairment was common in both insular and control groups. Patients with insular tumors had significantly worse preoperative performance on naming tests. In both groups, postoperative decline occurred in most neurocognitive domains. There were no statistically significant differences between patients in the insular and control groups with regard to rates of postoperative decline on any test. However, there were trends suggesting differential cognitive performance postoperatively, because patients with insular tumors were more likely to experience greater decline in learning and memory. Neurological morbidity was similar to prior rates reported in the literature. CONCLUSIONS: Few statistically significant differences in cognitive function were observed between patients in the insular and control groups at either the pre- or postoperative evaluation, although there was a trend for patients with insular tumors to exhibit greater postoperative decline in learning and memory. Although technically more challenging, surgery for insular region glioma appears feasible without profound neurological or cognitive morbidity for many patients.

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.

Hypoxia potentiates glioma-mediated immunosuppression.

Glioblastoma multiforme (GBM) is a lethal cancer that exerts potent immune suppression. Hypoxia is a predominant feature of GBM, but it is unclear to the degree in which tumor hypoxia contributes to this tumor-mediated immunosuppression. Utilizing GBM associated cancer stem cells (gCSCs) as a treatment resistant population that has been shown to inhibit both innate and adaptive immune responses, we compared immunosuppressive properties under both normoxic and hypoxic conditions. Functional immunosuppression was characterized based on production of immunosuppressive cytokines and chemokines, the inhibition of T cell proliferation and effector responses, induction of FoxP3+ regulatory T cells, effect on macrophage phagocytosis, and skewing to the immunosuppressive M2 phenotype. We found that hypoxia potentiated the gCSC-mediated inhibition of T cell proliferation and activation and especially the induction of FoxP3+T cells, and further inhibited macrophage phagocytosis compared to normoxia condition. These immunosuppressive hypoxic effects were mediated by signal transducer and activator of transcription 3 (STAT3) and its transcriptionally regulated products such as hypoxia inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF). Inhibitors of STAT3 and HIF-1α down modulated the gCSCs' hypoxia-induced immunosuppressive effects. Thus, hypoxia further enhances GBM-mediated immunosuppression, which can be reversed with therapeutic inhibition of STAT3 and HIF-1α and also helps to reconcile the disparate findings that immune therapeutic approaches can be used successfully in model systems but have yet to achieve generalized successful responses in the vast majority of GBM patients by demonstrating the importance of the tumor hypoxic environment.