Attenuating hypoxia driven malignant behavior in glioblastoma with a novel hypoxia-inducible factor 2 alpha inhibitor.

Hypoxia inducible factor (HIFs) signaling contributes to malignant cell behavior in glioblastoma (GBM). We investigated a novel HIF2α inhibitor, PT2385, both in vitro, with low-passage patient-derived cell lines, and in vivo, using orthotopic models of glioblastoma. We focused on analysis of HIF2α expression in situ, cell survival/proliferation, and survival in brain tumor-bearing mice treated with PT2385 alone and in combination with standard of care chemoradiotherapy. HIF2α expression increased with glioma grade, with over half of GBM specimens HIF2α positive. Staining clustered in perivascular and perinecrotic tumor regions. Cellular phenotype including proliferation, viability, migration/invasion, and also gene expression were not altered after PT2385 treatment. In the animal model, PT2385 single-agent treatment did improve median overall survival compared to placebo (p = 0.04, n = 21) without a bioluminescence correlate (t = 0.67, p = 0.52). No difference in animal survival was seen in combination treatment with radiation (RT)/temozolomide (TMZ)/PT2385 (p = 0.44, n = 10) or mean tumor bioluminescence (t 1.13, p = 0.32). We conclude that HIF2α is a reasonable novel therapeutic target as expressed in the majority of glioblastomas in our cohort. PT2385 as a single-agent was efficacious in vivo, however, an increase in animal survival was not seen with PT2385 in combination with RT/TMZ. Further study for targeting HIF2α as a therapeutic approach in GBM is warranted.

Craniocervical Osteoradionecrosis Treated with Neoadjuvant and Adjuvant Hyperbaric Oxygen in Combination with Posterior Spinal Fusion.

BACKGROUND: Radiation therapy for malignant head and neck cancers includes a risk for off-target effects to bony structures, posing a risk for osteoradionecrosis (ORN). Patients in whom ORN develops can also harbor concomitant osteomyelitis and reduced healing capacity, making for a particularly challenging entity to treat. Hyperbaric oxygen therapy (HBO) has been shown to be effective in the treatment of mandibular ORN in the otolaryngology literature; yet, few reports exist detailing its utility when treating ORN of the craniocervical junction. Herein, we report 2 cases of ORN of the craniocervical junction who received both neoadjuvant and adjuvant HBO in combination with posterior spinal fusion. CASE DESCRIPTION: Two patients with craniocervical junction ORN were treated with HBO delivered over 20 sessions before and after surgery in 90-minute treatments to 2.5 atmospheres of pressure. The patients underwent posterior occipital-cervical fusions with an average operative time of 301 (±21.5) minutes with 250 (±150) mL of blood loss. Both patients stayed in the hospital for 5 days, with no periprocedural complications. Outcomes included a 30% improvement of global assessment of function on follow-up EuroQol 5-Dimension Questionnaire. Postoperative imaging demonstrated solid bony fusion, and both patients returned to full work duty. CONCLUSIONS: ORN is a difficult-to-treat radiation complication in head and neck cancers. Few reports exist detailing treatment options for ORN of the craniocervical junction in conjunction with surgical stabilization. We report 2 successful cases of HBO-assisted treatment of ORN and highlight the important role HBO can play in promoting bony fusion in these at-risk patients.

Hypoxia-inducible factor 2α: a novel target in gliomas.

Hypoxia is an important contributor to aggressive behavior and resistance mechanisms in glioblastoma. Upregulation of hypoxia inducible transcription factors (HIFs) is the primary adaptive cellular response to a hypoxic environment. While HIF1α has been widely studied in cancer, HIF2α offers a potentially more specific and appealing target in glioblastoma given expression in glioma stem cells and not normal neural progenitors, activation in states of chronic hypoxia and expression that correlates with glioma patient survival. A first-in-class HIF2α inhibitor, PT2385, is in clinical trials for renal cell carcinoma, and provides the first opportunity to therapeutically target this important pathway in glioma biology.

Combined interventional and surgical treatment of tandem middle cerebral artery embolus and internal carotid artery occlusion: case report.

Tandem internal carotid artery (ICA) origin occlusion and middle cerebral artery (MCA) thromboembolism is a life-threatening condition with poor neurological outcome. The authors report on a patient presenting with acute ischemic stroke from a tandem ICA and MCA occlusion with penumbra. Emergency MCA mechanical thrombectomy was performed through percutaneous cervical ICA access due to the inability to cross the cervical carotid occlusion. Emergency carotid endarterectomy to reperfuse the poorly collateralized hemisphere and repair the ICA access site was performed 2 hours after completion of tissue plasminogen activator (tPA) infusion. This case illustrates the shortest reported interval between tPA infusion and open surgical intervention for carotid revascularization, as well as the role of direct carotid artery access for mechanical thrombectomy. The authors also describe the use of a temporizing femoral artery-to-ICA shunt to maintain cerebral perfusion in the setting of ICA occlusion.

Subdural Instillation of a Thrombolytic Agent for Treatment of Recurrent Subdural Hematoma.

OBJECTIVE: This study aims to report the case of a patient with recurrent subdural hemorrhage (SDH) who was administered tissue plasminogen activator through a subdural drain to enhance drainage and prevent recurrence. METHODS: An 85-year-old man was treated for subacute over chronic SDH that kept on reaccumulating despite serial twist drill drainage, burr hole drainage, and craniotomy. No coagulopathy was identified with adequate blood pressure control. RESULTS: Treatment with tissue plasminogen activator resulted in successful drainage of the SDH, and the patient had no further recurrence at 9-month follow-up.

Evaluation of a Traumatic Vertebral Artery Occlusion.

BACKGROUND: Penetrating neck injury occurs in 5%-10% of all trauma cases and carries a significant burden of morbidity and mortality (15%). We describe the evaluation and management of a 25-year-old man shot in the neck with occlusion of the left vertebral artery from its origin to C6. This is a case report in which medical data were analyzed retrospectively with institutional review board approval. CASE DESCRIPTION: Neurologic examination revealed paresthesias and dysesthesias in a left C8 dermatomal distribution. Computed tomography angiography of the neck demonstrated no opacification of the left vertebral artery from its origin to C6. Magnetic resonance imaging of the cervical spine revealed an acute infarct in the left cerebellum. A cerebral angiogram highlighted hemodynamic compromise, and the patient was felt to be at significant risk of further cerebral infarction. Augmenting flow to the posterior circulation would mitigate that risk. The patient was taken to the operating room for a transposition of the vertebral artery to the common carotid artery. CONCLUSIONS: The patient presented with silent cerebellar infarction due to a vertebral artery injury and impending vertebrobasilar insufficiency. This case demonstrates clinical evaluation of the posterior circulation and treatment with a bypass technique through mobilization of the vertebral artery from the boney vertebral foramen with anastomosis to the common carotid.

Fungal Contamination of Methylprednisolone Causing Recurrent Lumbosacral Intradural Abscess.

Fungal meningitis transmitted through injections of methylprednisolone contaminated with Exserohilum rostratum affected 753 persons and caused 61 deaths in the United States in 2012. We report a case of infection recurrence after 24-months with the unique manifestation of an intradural fungal abscess. Fungal disease should remain on the differential diagnosis list for previously exposed patients.

Spinal stability after resection of nerve sheath tumors.

BACKGROUND: The aim of this paper was to present a generalizable group of patients who have undergone resection of spinal nerve sheath tumors and attempt to identify factors that may be predictive of the need for intraoperative fusion. METHODS: We conducted a retrospective review of patients who underwent excision of spinal nerve sheath tumors performed by the senior author at the University of Miami/Jackson Memorial Medical Center. RESULTS: Out of the 48 cases reviewed in this study, a total of 7 (14.6%) underwent fusion at the same time as decompression and tumor excision. Fusion was deemed necessary in these cases for a number of different reasons, including preexisting scoliosis, cervical instability, preexisting listhesis, and tumor size and/or aggressiveness warranting more extensive bony exposure. Cervical tumors in patients with NF-1 and total facetectomy being performed were both factors found to be predictive of the decision to perform intraoperative fusion with instrumentation (P values of 0.009 and <0.001, respectively). There were seven cases in which partial facetectomies were performed without fusion, none of which later developed instability. Finally, excision of malignant peripheral nerve sheath tumors was also associated with the decision to perform fusion (P=0.008). The average length of follow­up was 2 years, 11 months (SEM 8 months). CONCLUSIONS: Most patients can undergo resection of spinal nerve sheath tumors without fusion. Patients with pre­existing deformity or instability, a history of NF-1 together with the tumor in the cervical region, malignant nerve sheath tumors, or those who undergo a total facet resection may require instrumented spinal fusion during tumor excision. We also observed that removal of one third or even half of a facet joint complex appears to be well tolerated with no instability seen on follow­up.

Fusion rates in multilevel, instrumented anterior cervical fusion for degenerative disease with and without the use of bone morphogenetic protein.

OBJECT: The goal of this study was to compare the rates of solid arthrodesis and complications following multilevel, instrumented anterior cervical fusion in patients treated with and without bone morphogenetic protein (BMP). METHODS: The authors conducted a retrospective cohort study of patients who underwent multilevel (2+ level) anterior cervical fusions performed for degenerative disc disease with or without the concurrent use of BMP-2 from 1997 to 2012. The dosage throughout the study ranged from 2.1 to 0.26 mg/level (mean 1.0 mg/level). All patients were evaluated postoperatively by means of radiographs and CT scans to determine fusion status. RESULTS: The overall fusion rate for the patients treated without BMP (n = 23) was 82.6% compared with a 100% fusion rate in the group treated with BMP (n = 22) (p = 0.04). The pseudarthrosis rates increased with number of fusion levels in patients who did not receive BMP, whereas all patients in the group treated with BMP had solid arthrodesis. Furthermore, there were 2 instrumentation failures in the non-BMP group. There was a direct correlation between the incidence of complications and the dosage of BMP used per level, with no complications reported at doses equal to or less than 1.1 mg/level. CONCLUSIONS: The overall rate of bony arthrodesis was increased following the use of BMP in multilevel anterior cervical fusion. Traditional methods without BMP had a high rate of pseudarthrosis. The complications associated with the use of BMP appeared to be dose related and of low incidence when BMP is used in doses equal to or less than 1.1 mg/level.

Asiatic acid, a pentacyclic triterpene from Centella asiatica, is neuroprotective in a mouse model of focal cerebral ischemia.

Asiatic acid, a triterpenoid derivative from Centella asiatica, has shown biological effects such as antioxidant, antiinflammatory, and protection against glutamate- or beta-amyloid-induced neurotoxicity. We investigated the neuroprotective effect of asiatic acid in a mouse model of permanent cerebral ischemia. Various doses of asiatic acid (30, 75, or 165 mg/kg) were administered orally at 1 hr pre- and 3, 10, and 20 hr postischemia, and infarct volume and behavioral deficits were evaluated at day 1 or 7 postischemia. IgG (blood-brain barrier integrity) and cytochrome c (apoptosis) immunostaining was carried out at 24 hr postischemia. The effect of asiatic acid on stress-induced cytochrome c release was examined in isolated mitochondrial fractions. Furthermore, its effects on cell viability and mitochondrial membrane potential were studied in HT-22 cells exposed to oxygen-glucose deprivation. Asiatic acid significantly reduced the infarct volume by 60% at day 1 and by 26% at day 7 postischemia and improved neurological outcome at 24 hr postischemia. Our studies also showed that the neuroprotective properties of asiatic acid might be mediated in part through decreased blood-brain barrier permeability and reduction in mitochondrial injury. The present study suggests that asiatic acid may be useful in the treatment of cerebral ischemia.

Carnosine is neuroprotective against permanent focal cerebral ischemia in mice.

BACKGROUND AND PURPOSE: Carnosine is a naturally occurring dipeptide with multiple neuroprotective properties. In addition, it is well tolerated in high doses with minimal side effects. The purposes of this study were to determine whether carnosine is neuroprotective in permanent focal cerebral ischemia and to determine potential mechanisms of neuroprotection. METHODS: We investigated the efficacy of carnosine in a mouse model of permanent focal cerebral ischemia. The effects of carnosine were investigated with respect to neuronal damage and infarct formation, endogenous antioxidant status, and matrix metalloproteinase activity. RESULTS: Carnosine significantly decreased infarct size and neuronal damage when administered at time points both before and after the induction of ischemia. Carnosine also decreased reactive oxygen species levels in the ischemic brain, preserved normal glutathione levels, and decreased matrix metalloproteinase protein levels and activity. CONCLUSIONS: Carnosine is neuroprotective in focal cerebral ischemia and appears to influence deleterious pathological processes that are activated after the onset of ischemia.