ABSTRACT
Histone deacetylases (HDACs) have a wide range of targets and can rewire both the chromatin and lipidome of cancer cells. In this study, we show that valproic acid (VPA), a brain penetrant anti-seizure medication and histone deacetylase inhibitor, inhibits the growth of IDH1 mutant tumors in vivo and in vitro, with at least some selectivity over IDH1 wild-type tumors. Surprisingly, genes upregulated by VPA showed no enhanced chromatin accessibility at the promoter, but there was a correlation between VPA-downregulated genes and diminished promoter chromatin accessibility. VPA inhibited the transcription of lipogenic genes and these lipogenic genes showed significant decreases in promoter chromatin accessibility only in the IDH1 MT glioma cell lines tested. VPA inhibited the mTOR pathway and a key lipogenic gene, fatty acid synthase (FASN). Both VPA and a selective FASN inhibitor TVB-2640 rewired the lipidome and promoted apoptosis in an IDH1 MT but not in an IDH1 WT glioma cell line. We further find that HDACs are involved in the regulation of lipogenic genes and HDAC6 is particularly important for the regulation of FASN in IDH1 MT glioma. Finally, we show that FASN knockdown alone and VPA in combination with FASN knockdown significantly improved the survival of mice in an IDH1 MT primary orthotopic xenograft model in vivo. We conclude that targeting fatty acid metabolism through HDAC inhibition and/or FASN inhibition may be a novel therapeutic opportunity in IDH1 mutant gliomas.
ABSTRACT
Low-grade and secondary high-grade gliomas frequently contain mutations in the IDH1 or IDH2 metabolic enzymes that are hypothesized to drive tumorigenesis by inhibiting many of the chromatin-regulating enzymes that regulate DNA structure. Histone deacetylase inhibitors are promising anti-cancer agents and have already been used in clinical trials. However, a clear understanding of their mechanism or gene targets is lacking. In this study, the authors genetically dissect patient-derived IDH1 mutant cultures to determine which HDAC enzymes drive growth in IDH1 mutant gliomas. A panel of patient-derived gliomasphere cell lines (2 IDH1 mutant lines, 3 IDH1 wildtype lines) were subjected to a drug-screen of epigenetic modifying drugs from different epigenetic classes. The effect of LBH (panobinostat) on gene expression and chromatin structure was tested on patient-derived IDH1 mutant lines. The role of each of the highly expressed HDAC enzymes was molecularly dissected using lentiviral RNA interference knock-down vectors and a patient-derived IDH1 mutant in vitro model of glioblastoma (HK252). These results were then confirmed in an in vivo xenotransplant model (BT-142). The IDH1 mutation leads to gene down-regulation, DNA hypermethylation, increased DNA accessibility and H3K27 hypo-acetylation in two distinct IDH1 mutant over-expression models. The drug screen identified histone deacetylase inhibitors (HDACi) and panobinostat (LBH) more specifically as the most selective compounds to inhibit growth in IDH1 mutant glioma lines. Of the eleven annotated HDAC enzymes (HDAC1-11) only six are expressed in IDH1 mutant glioma tissue samples and patient-derived gliomasphere lines (HDAC1-4, HDAC6, and HDAC9). Lentiviral knock-down experiments revealed that HDAC1 and HDAC6 are the most consistently essential for growth both in vitro and in vivo and target very different gene modules. Knock-down of HDAC1 or HDAC6 in vivo led to a more circumscribed less invasive tumor. The gene dysregulation induced by the IDH1 mutation is wide-spread and only partially reversible by direct IDH1 inhibition. This study identifies HDAC1 and HDAC6 as important and drug-targetable enzymes that are necessary for growth and invasiveness in IDH1 mutant gliomas.
Subject(s)
Antineoplastic Agents , Brain Neoplasms , Glioma , Humans , Panobinostat/pharmacology , Panobinostat/therapeutic use , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylase Inhibitors/therapeutic use , Glioma/metabolism , Antineoplastic Agents/therapeutic use , Chromatin , Isocitrate Dehydrogenase/genetics , Isocitrate Dehydrogenase/metabolism , Mutation , Brain Neoplasms/pathology , Histone Deacetylase 1/genetics , Histone Deacetylase 6/geneticsABSTRACT
The pathological changes in epigenetics and gene regulation that accompany the progression of low-grade to high-grade gliomas are under-studied. The authors use a large set of paired atac-seq and RNA-seq data from surgically resected glioma specimens to infer gene regulatory relationships in glioma. Thirty-eight glioma patient samples underwent atac-seq sequencing and 16 samples underwent additional RNA-seq analysis. Using an atac-seq/RNA-seq correlation matrix, atac-seq peaks were paired with genes based on high correlation values (|r2| > 0.6). Samples clustered by IDH1 status but not by grade. Surprisingly there was a trend for IDH1 mutant samples to have more peaks. The majority of peaks are positively correlated with survival and positively correlated with gene expression. Constructing a model of the top six atac-seq peaks created a highly accurate survival prediction model (r2 = 0.68). Four of these peaks were still significant after controlling for age, grade, pathology, IDH1 status and gender. Grade II, III, and IV (primary) samples have similar transcription factors and gene modules. However, grade IV (recurrent) samples have strikingly few peaks. Patient-derived glioma cultures showed decreased peak counts following radiation indicating that this may be radiation-induced. This study supports the notion that IDH1 mutant and IDH1 wildtype gliomas have different epigenetic landscapes and that accessible chromatin sites mapped by atac-seq peaks tend to be positively correlated with expression. The data in this study leads to a new model of treatment response wherein glioma cells respond to radiation therapy by closing open regions of DNA.
Subject(s)
Glioma , Chromatin/genetics , Chromatin Immunoprecipitation Sequencing , DNA/genetics , Glioma/genetics , Glioma/pathology , Humans , Transcription Factors/geneticsABSTRACT
OBJECTIVE: Elevated troponin levels are a common occurrence after ischemic stroke and subarachnoid hemorrhage (SAH), and have been described as a neurogenic form of myocardial injury. The prognostic significance of this event is controversial with numerous studies citing conflicting results. The importance of cardiac stress is of particular relevance in the operative management of intracerebral hemorrhage (ICH). To this end, we investigated whether troponin levels were an independent predictor of in-hospital mortality from all causes in surgically treated ICH patients. METHODS: We performed a retrospective analysis of 110 patients admitted to Columbia Presbyterian hospital between 1999 and 2007 for ICH and subsequent clot evacuation. Those with angina or recent myocardial infarction were excluded. CT scans were reviewed to determine hematoma size, location, presence of intraventricular hemorrhage (IVH) or SAH, hydrocephalus, and midline shift. Hospital records were examined for known demographic and clinical predictors of mortality. Univariate analysis was used to screen for predictive factors (P Subject(s)
Cerebral Hemorrhage
, Troponin/metabolism
, Cardiovascular Diseases/diagnosis
, Cardiovascular Diseases/metabolism
, Cerebral Hemorrhage/metabolism
, Cerebral Hemorrhage/mortality
, Cerebral Hemorrhage/surgery
, Electrocardiography
, Female
, Humans
, Male
, Middle Aged
, Predictive Value of Tests
, Retrospective Studies
, Survival Rate
ABSTRACT
OBJECTIVE: Sumatriptan, a serotonin receptor agonist, has been used in the management of primary headache disorders and has been shown to affect trigeminal dural afferents. There is limited literature on the safety and efficacy of sumatriptan for postcraniotomy pain management. This study aimed to identify whether subcutaneous sumatriptan is a safe and efficacious pain management strategy after elective craniotomy. METHODS: The authors retrospectively reviewed patients who underwent supratentorial or suboccipital craniotomy between 2016 and 2019 that was performed by a single provider at a single institution to identify patients given subcutaneous sumatriptan in the postoperative period. Pain scores and intravenous and oral opioid use were compared in patients with (n = 15) and without (n = 45) sumatriptan administration. RESULTS: Patients with and without sumatriptan administration had no significant differences in baseline characteristics or surgery type. There were no sumatriptan-related complications. The average pain score decreased from 3.9 to 1.3 within 1 hour after sumatriptan administration (p = 0.014). In both adult and pediatric patients there was decreased postoperative pain (adults: pain score of 1.1 vs 7.1, p < 0.001; pediatric: 1.1 vs 3.9, p = 0.007) within the first 48 hours. There were decreases in intravenous opioid use, length of intravenous opioid use, maximum dose of intravenous opioid used, oral opioid use, length of oral opioid use, and maximum dose of oral opioid used in both adult and pediatric patients. CONCLUSIONS: The authors identified subcutaneous sumatriptan as a safe and efficacious tool for postoperative pain management after craniotomy. Large multicenter randomized controlled studies are needed to further evaluate the specific role of sumatriptan in postoperative pain management after craniotomy.
ABSTRACT
INTRODUCTION: Surgical resection and systemic chemotherapy with temozolomide remain the mainstay for treatment of glioblastoma. However, many patients are not candidates for surgical resection given inaccessible tumor location or poor health status. Furthermore, despite being first line treatment, temozolomide has only limited efficacy. METHODS: The development of injectable hydrogel-based carrier systems allows for the delivery of a wide range of chemotherapeutics that can achieve high local concentrations, thus potentially avoiding systemic side effects and wide-spread neurotoxicity. To test this modality in a realistic environment, we developed a diblock copolypeptide hydrogel (DCH) capable of carrying and releasing paclitaxel, a compound that we found to be highly potent against primary gliomasphere cells. RESULTS: The DCH produced minimal tissue reactivity and was well tolerated in the immune-competent mouse brain. Paclitaxel-loaded hydrogel induced less tissue damage, cellular inflammation and reactive astrocytes than cremaphor-taxol (typical taxol-carrier) or hydrogel alone. In a deep subcortical xenograft model of glioblastoma in immunodeficient mice, injection of paclitaxel-loaded hydrogel led to local tumor control and improved survival. However, the tumor cells were highly migratory and were able to eventually escape the area of treatment. CONCLUSIONS: These findings suggest this technology may be ultimately applicable to patients with deep-seated inoperable tumors, but as currently formulated, complete tumor eradication would be highly unlikely. Future studies should focus on targeting the migratory potential of surviving cells.
Subject(s)
Antineoplastic Agents, Phytogenic/therapeutic use , Glioblastoma/drug therapy , Hydrogels/chemistry , Paclitaxel/therapeutic use , Peptides/chemistry , Animals , Antineoplastic Agents, Phytogenic/chemistry , Cell Line, Tumor , Central Nervous System/pathology , Drug Carriers/chemistry , Glioblastoma/mortality , Glioblastoma/pathology , Humans , Mice , Mice, Inbred NOD , Mice, SCID , Paclitaxel/chemistry , Survival Rate , Temozolomide/chemistry , Temozolomide/therapeutic use , Xenograft Model Antitumor AssaysABSTRACT
BACKGROUND AND PURPOSE: The purpose of this study was to assess the frequency, severity, and predictors of neurological deficits after adjuvant embolization for cerebral arteriovenous malformations. METHODS: From 1997 to 2006, 202 of 275 patients with arteriovenous malformation received embolization before microsurgery (n=176) or radiosurgery (n=26). Patients were examined before and after endovascular embolization and at clinical follow-up (mean, 43.4+/-34.6 months). Outcome was classified according to the modified Rankin Scale. New neurological deficits after embolization were defined as minimal (no change in overall modified Rankin Scale), moderate (modified Rankin Scale < or =2), or significant (modified Rankin Scale >2). RESULTS: Two hundred two patients were treated in 377 embolization procedures. There were a total of 29 new clinical deficits after embolization (8% of procedures; 14% of patients), of which 19 were moderate or significant. Postembolization deficits resolved in a significant number of patients over time (P<0.0001). Five patients had persistent neurological deficits due to embolization (1.3% of procedures; 2.5% of patients). In multivariate analysis, the following variables significantly predicted new neurological deficit after embolization: complex arteriovenous malformation with treatment plan specifying more than one embolization procedure (OR, 2.7; 95% CI, 1.4 to 8.6), diameter <3 cm (OR, 3.2; 95% CI, 1.2 to 9.1), diameter >6 cm (OR, 6.2; 95% CI, 1.0 to 57.0), deep venous drainage (OR, 2.7; 95% CI, 1.1 to 6.9), or eloquent location (OR, 2.4; 95% CI, 1.0 to 5.7). These variables were weighted and used to compute an arteriovenous malformation Embolization Prognostic Risk Score for each patient. A score of 0 predicted no new deficits, a score of 1 predicted a new deficit rate of 6%, a score of 2 predicted a new deficit rate of 15%, a score of 3 predicted a new deficit rate of 21%, and a score of 4 predicted a new deficit rate of 50% (P<0.0001). CONCLUSIONS: Small and large size, eloquent location, deep venous drainage, and complex vascular anatomy requiring multiple embolization procedures are risk factors for the development of immediate postembolization neurological deficits. Nevertheless, a significant number of patients with treatment-related neurological deficits improve over time. The low incidence of permanent neurological deficits underscores the usefulness of this technique in carefully selected patients.
Subject(s)
Embolization, Therapeutic/methods , Enbucrilate/administration & dosage , Intracranial Arteriovenous Malformations/drug therapy , Nervous System Diseases/etiology , Postoperative Complications/etiology , Adolescent , Adult , Aged , Chemotherapy, Adjuvant , Child , Child, Preschool , Female , Follow-Up Studies , Humans , Intracranial Arteriovenous Malformations/surgery , Male , Middle Aged , Nervous System Diseases/prevention & control , Postoperative Complications/prevention & control , Predictive Value of Tests , Retrospective Studies , Treatment Outcome , Young AdultABSTRACT
Recent evidence has shown that after the initial occlusion, a large portion of stroke patients achieve some degree of reperfusion either through collateral circulation or clot dissolution. However, it appears that this reperfusion may lead to increased inflammation-induced damage. Even though the exact mechanism of this secondary injury is unclear, several experimental studies have indicated an intimate connection between complement and this secondary form of damage. We review the available literature and attempt to identify promising clinical therapeutic targets.
Subject(s)
Complement Activation/drug effects , Complement Inactivating Agents/therapeutic use , Reperfusion Injury/drug therapy , Stroke/drug therapy , Animals , Brain/physiopathology , Complement Activation/physiology , Disease Models, Animal , Humans , Models, Biological , Neurogenesis/drug effects , Reperfusion Injury/physiopathology , Stroke/complications , Stroke/physiopathologyABSTRACT
OBJECT: The optimal treatment of medically refractory intracranial atheroocclusive disease remains unclear. The EC-IC Bypass Study Investigators found that patients with internal carotid and middle cerebral artery (ICA and MCA) occlusion received no benefit from direct superficial temporal artery to MCA bypass, and that patients with ICA occlusion and MCA stenosis may have actually fared worse after surgery, perhaps in part due to flow reversal in critical perforator-bearing segments. Although the results of recent investigations have suggested that direct bypass may be beneficial in a subgroup of patients with hemodynamic failure secondary to unilateral ICA occlusion, similar data do not exist for patients with hemodynamic failure from other intracranial stenoocclusive diseases. Indirect bypass via encephaloduroarteriosynangiosis offers a surgical alternative that may avoid rapid flow reversal while providing additional flow to at-risk, distal vascular territories. METHODS: Twelve patients with medically resistant hemodynamic failure from intracranial atheroocclusive disease underwent indirect vascular bypass. Eight patients had ICA occlusion and coexistent MCA stenosis, 1 patient had tandem ICA stenoses and MCA stenosis, 1 patient had tandem ICA and MCA occlusion, 1 patient had ICA and posterior cerebral artery occlusion and an ischemic hemisphere supplied via a proximal superficial temporal artery branch, and 1 patient had poor donor arteries and severe medical comorbidities that precluded the use of general anesthesia. Patient evaluation included clinical assessment of neurological status, CT scanning, MR imaging, digital subtraction angiography, and transcranial Doppler ultrasonography with CO(2) reactivity, or SPECT with acetazolamide challenge. Patient records were reviewed and patients were interviewed for outcome assessment, including transient ischemic attack (TIA), cerebral infarction, change in cerebral perfusion, graft patency, and functional level according to the modified Rankin scale. Kaplan-Meier cumulative failure curves for the primary end point of cerebral infarction were used to compare these patients to a control group of 81 patients derived from the literature who received medical management for severe symptomatic hemodynamic failure. RESULTS: Eleven patients underwent encephaloduroarteriosynangiosis and 1 patient received bur holes with dural and arachnoid incisions; the mean length of follow-up was 51.2 +/- 40.1 months. Five patients had decreased perfusion on follow-up despite graft patency, and 10 patients suffered new infarctions or TIAs during the follow-up period. Five patients (42%) suffered infarctions within 1 year of surgery. A meta-analysis of 4 studies of patients with symptomatic ICA occlusion and severe hemodynamic failure who underwent medical treatment revealed a new infarction rate of 30% in the first year after entry into the study. There was no significant difference between patients with severe hemodynamic failure who underwent surgery and those in the medically treated control group (log-rank test, p = 0.179). CONCLUSIONS: The authors found that indirect bypass does not promote adequate pial collateral artery development and appears to be of limited utility in patients with symptomatic ICA or MCA stenoocclusive disease and secondary hemodynamic failure. Rates of postoperative TIAs or cerebral infarctions after indirect bypass in this patient population do not differ from previous reports in patients who received medical management only.
Subject(s)
Cerebral Revascularization/methods , Intracranial Arteriosclerosis/surgery , Angiography, Digital Subtraction , Female , Follow-Up Studies , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Postoperative Complications , Tomography, Emission-Computed, Single-Photon , Tomography, X-Ray Computed , Treatment Outcome , Ultrasonography, DopplerABSTRACT
OBJECT: Chronic hydrocephalus requiring shunt placement is a common complication following aneurysmal subarachnoid hemorrhage (SAH). Controversy exists over whether microsurgical fenestration of the lamina terminalis during aneurysm surgery affords a reduction in the development of shunt-dependent hydrocephalus. To resolve this debate, the authors performed a systematic review and quantitative analysis of the literature to determine the efficacy of lamina terminalis fenestration in reducing aneurysmal SAH-associated shunt-dependent hydrocephalus. METHODS: A MEDLINE (1950-2007) database search was performed using the following keywords, singly and in combination: "ventriculoperitoneal shunt," "hydrocephalus," "subarachnoid hemorrhage," "aneurysm," "fenestration," and "lamina terminalis." Additional studies were manually singled out by scrutinizing references from identified manuscripts, major neurosurgical journals and texts, and personal files. A recent study from the authors' institution was also incorporated into the review. Data from included studies were analyzed using the chi-square analysis and Student t-test. The Cochran-Mantel-Haenszel test was used to compare overall incidence of shunt-dependent hydrocephalus. RESULTS: The literature search revealed 19 studies, but only 11 were included in this review, involving 1973 patients. The fenestrated and nonfenestrated cohorts (combined from the various studies) differed significantly with regard to patient sex, age, and clinical grade as well as aneurysm location (p=0.0065, 0.0028, 0.0003, and 0.017, respectively). The overall incidence of shunt-dependent hydrocephalus in the fenestrated cohort was 10%, as compared with 14% in the nonfenestrated cohort (p=0.089). The relative risk of shunt-dependent hydrocephalus in the fenestrated cohort was 0.88 (95% CI 0.62-1.24). CONCLUSIONS: This systematic review revealed no significant association between lamina terminalis fenestration and a reduced incidence of shunt-dependent hydrocephalus. The interpretation of these results, however, is restricted by unmatched cohort differences as well as other inherent study limitations. Although the overall literature supports lamina terminalis fenestration, a number of authors have questioned the technique's benefits, thus rendering its efficacy in reducing shunt-dependent hydrocephalus unclear. A well-designed, multicenter, randomized controlled trial is needed to definitively address the efficacy of this microsurgical technique.
Subject(s)
Hydrocephalus , Subarachnoid Hemorrhage/complications , Subarachnoid Hemorrhage/surgery , Ventriculoperitoneal Shunt , Humans , Hydrocephalus/etiology , Hydrocephalus/prevention & control , Hydrocephalus/surgeryABSTRACT
OBJECT: Heparin-induced thrombocytopenia Type II (HIT II) is a serious complication that occurs in 0.2-3% of patients treated with heparin and is associated with a high risk of thrombotic events. One center recently reported an incidence of HIT II of 15% in a population of patients with aneurysmal subarachnoid hemorrhage (aSAH). Because these patients are typically exposed to heparin during angiography, controversy exists regarding whether prophylaxis with enoxaparin rather than heparin affords any reduction in the risk of developing HIT II. In this study, the authors investigated the effect of heparin compared with enoxaparin on the incidence of HIT II in patients with aSAH. METHODS: The authors reviewed the medical records of 300 patients treated for aSAH who received thromboprophylaxis with either heparin or enoxaparin, and identified patients who developed HIT II. The incidences of HIT II in the 2 treatment groups were then compared. RESULTS: One hundred sixty-six patients with aSAH were treated with heparin, and 134 patients were treated with enoxaparin. Sixteen (5.3%) of 300 patients met the diagnostic criteria for HIT II. Of those treated with heparin, 8 (4.8%) of 166 developed HIT II, compared with 8 (6%) of 134 treated with enoxaparin (difference not significant). CONCLUSIONS: The authors report a lower incidence of HIT II in patients with aSAH than has previously been reported. The data also suggest that patients with aSAH who receive heparin are at no greater risk of developing HIT II than those who receive enoxaparin. This finding challenges the merit of choosing enoxaparin rather than heparin for thromboprophylaxis in patients with a SAH.
Subject(s)
Anticoagulants/adverse effects , Anticoagulants/therapeutic use , Enoxaparin/therapeutic use , Heparin/adverse effects , Heparin/therapeutic use , Subarachnoid Hemorrhage/drug therapy , Thrombocytopenia/chemically induced , Aged , Cerebral Angiography , Cohort Studies , Female , Humans , Male , Middle Aged , Prospective Studies , Subarachnoid Hemorrhage/complications , Thrombocytopenia/epidemiology , Thromboembolism/prevention & control , Tomography, X-Ray ComputedABSTRACT
Stroke is a leading cause of morbidity and mortality in the US, with secondary damage following the initial insult contributing significantly to overall poor outcome. Prior investigations have shown that the metabolism of certain polyamines such as spermine, spermidine, and putrescine are elevated in ischemic parenchyma, resulting in an increase in their metabolite concentration. Polyamine metabolites tend to be cytotoxic, leading to neuronal injury in the penumbra following stroke and expansion of the area of infarcted tissue. Although the precise mechanism is unclear, the presence of reactive aldehydes produced through polyamine metabolism, such as 3-aminopropanal and acrolein, have been shown to correlate with the incidence of cerebral vasospasm, disruption of oxidative metabolism and mitochondrial functioning, and disturbance of cellular calcium ion channels. Regulation of the polyamine metabolic pathway, therefore, may have the potential to limit injury following cerebral ischemia. To this end, we review this pathway in detail with an emphasis on clinical applicability.
Subject(s)
Brain Injuries/etiology , Brain Injuries/metabolism , Brain Ischemia/complications , Polyamines/metabolism , Animals , Humans , Polyamines/chemistryABSTRACT
The goal of cerebral arteriovenous malformation (AVM) treatment is to eliminate intracerebral hemorrhage risk and to preserve or maximize neurological functions of the patient. Interventional planning must determine the modality or combination of modalities with the greatest success rate according to patient characteristics, AVM architecture, and the capabilities of the treatment option to fulfill the goals of treatment. Although there is a lack of data from randomized trials to guide AVM management, microsurgery is a mainstay of therapy in patients receiving definitive intervention. In this paper, we review current guidelines for surgical planning, risk-benefit analysis, and prediction of outcome in AVM patients.
Subject(s)
Intracranial Arteriovenous Malformations/surgery , Microsurgery/methods , Practice Guidelines as Topic , Age Factors , Algorithms , Cerebral Hemorrhage/epidemiology , Cerebral Hemorrhage/etiology , Cerebral Hemorrhage/surgery , Combined Modality Therapy , Decision Support Techniques , Embolization, Therapeutic , Humans , Intracranial Aneurysm/etiology , Intracranial Aneurysm/surgery , Intracranial Arteriovenous Malformations/complications , Intracranial Arteriovenous Malformations/pathology , Male , Microsurgery/adverse effects , Postoperative Care/methods , Recurrence , Severity of Illness Index , Stereotaxic Techniques , Treatment OutcomeABSTRACT
BACKGROUND: Vertebral artery dissecting aneurysm (VADA) involving the origin of the posterior inferior cerebellar artery (PICA) is a complex disease entity in which the dual goals of preventing future rebleeding and maintaining perfusion of the lateral medulla must be considered. We present an illustrative case and review the literature surrounding treatment strategies. CASE DESCRIPTION: We report a patient presenting with extensive subarachnoid hemorrhage due to rupture of an intracranial VADA involving the PICA origin. After consideration of the patient's cerebral vasculature and robustness of collaterals, a flow-diverting stent was placed with angiographic resolution of the lesion and maintenance of antegrade PICA flow. Ultimately, the patient experienced a contralateral intraparenchymal hemorrhage leading to death. Review of the literature identified 124 cases of VADA involving the PICA origin described over the past decade. The methods of surgical and endovascular treatment of these cases were reviewed, with particular focus on the rationale of treatment, outcomes, and complications. CONCLUSION: Numerous treatment options for VADA involving PICA have been reported with different risk and benefit profiles. Flow-diverting stents appear to offer the most favorable balance of securing the aneurysm and avoiding medullary infarction, but the risks and optimal anti-thrombotic treatment strategy are incompletely understood. In select cases, in which the surgical risk is low or in which the anatomy is favorable (e.g., nondominant parent vessel or robust collateral circulation in the involved territories), parent artery trapping with or without microsurgical revascularization can be considered.
ABSTRACT
The management of cerebral arteriovenous malformations (AVMs) continues to present a challenge to neurosurgeons. The natural history of this condition, as well as the morbidity and mortality of therapeutic interventions, remains incompletely elucidated. Predictive factors and grading scales in AVM management allow risk-benefit analysis of treatment options and comparison of outcomes. Stereotactic radiosurgery is one of the established treatment modalities for AVMs and is generally used to treat lesions that are high risk for surgical resection. Radiosurgery aims to obliterate AVMs and thus prevent hemorrhage or seizure without any new or worsening of existing symptoms. Lesion characteristics and postsurgical complications differ markedly in patientstreated by radiosurgery versus microsurgery. Radiosurgery-based grading systems account for factors that have been associated with various aspects of radiosurgical outcomes including obliteration, hemorrhage, and postoperative complications, particularly those induced by radiation. The purpose of this paper is to describe the most current predictive factors and grading systems for radiosurgical treatment of cerebral AVMs.
Subject(s)
Intracranial Arteriovenous Malformations/classification , Intracranial Arteriovenous Malformations/surgery , Radiosurgery/methods , Weights and Measures , Animals , Humans , Intracranial Arteriovenous Malformations/pathology , Predictive Value of Tests , Prognosis , Treatment Outcome , Weights and Measures/standardsABSTRACT
Cerebral ischemia and reperfusion initiate an inflammatory process which results in secondary neuronal damage. Immunomodulatory agents represent a promising means of salavaging viable tissue following stroke. The complement cascade is a potent mediator of inflammation which is activated following cerebral ischemia. Complement is deposited on apoptotic neurons which likely leads to injury in adjacent viable cells. Studies suggest that blocking the complement cascade during the early phases of infarct evolution may result in decreased penumbral tissue infarction and limit the extent of brain injury. Additionally, other elements of the complement cascade may play a critical role in cell survival. In this paper, we review the role of the complement cascade in neuronal damage following ischemic injury and emphasize possible therapeutic targets.
Subject(s)
Complement System Proteins/therapeutic use , Stroke/drug therapy , Brain Ischemia/physiopathology , Humans , Inflammation/drug therapy , Neurons/pathology , Reperfusion Injury/drug therapy , Reperfusion Injury/physiopathologyABSTRACT
The 1985 International Extracranial-Intracranial (EC-IC) Bypass Trial failed to show a surgical benefit of EC-IC bypass in patients with varying degrees of angiographic stenosis. This study was limited by the technology available at the time it was conducted. In the 20 years since, there has been considerable progress in imaging techniques that now enable the identification of a subset of stroke patients with hemodynamic ischemia. In the present study, the authors review the relevant literature and propose a reevaluation of the benefits of the EC-IC bypass procedure using these new imaging techniques. The authors reviewed the admission criteria for the EC-IC Bypass Trial in the light of more recently discovered neurovascular physiology and showed that the imaging criteria used in that trial are not physiologically adequate. A MED-LINE (1985-2007) database search for EC-IC case studies was conducted, and additional studies were identified manually by scrutinizing references from identified manuscripts, major neurosurgical journals and texts, and personal files.
Subject(s)
Carotid Stenosis/surgery , Cerebral Revascularization , Carotid Stenosis/diagnosis , Carotid Stenosis/physiopathology , Cerebral Angiography , Cerebrovascular Circulation , Clinical Trials as Topic , Humans , Patient Selection , Positron-Emission TomographyABSTRACT
INTRODUCTION: Recent studies have shown that patients with increased oxygen extraction fraction (OEF) as measured by positron emission tomography (PET) have a substantially increased risk of stroke as a result of hemodynamic insufficiency. These patients appear to be ideal candidates for extracranial (EC)-intracranial (IC) bypass. The feasibility of this screening protocol, however, is controversial given PET's limited availability and high expense. A better understanding of the clinical factors that identify patients with potential hemodynamic insufficiency would streamline screening and improve cost-efficiency. METHODS: We performed a MEDLINE (1985-2007) database search for studies identifying clinical and radiographic predictors of hemodynamic failure and increased OEF on PET. We used the following key words, singly and in combination: "EC-IC bypass," "hemodynamic failure," and "misery perfusion." Additional studies were identified manually by scrutinizing references from manuscripts, major neurosurgical journals and texts, and personal files. Each study was reviewed for methodology, clinical criteria, and correlation with subsequent PET findings and stroke rates. A consensus was determined regarding the predictive value of each marker. RESULTS: Our literature search revealed 5 clinical and radiographic markers that have been used to identify patients with hemodynamic failure: orthostatic limb shaking, blurry vision on exposure to heat, leptomeningeal and ophthalmic collateral circulation on angiography, watershed infarction, and impaired vasodilatory response to acetazolamide. Orthostatic limb shaking is a rare finding but is predictive of hemodynamic failure and is associated with increased stroke risk. Blurry vision on exposure to heat is not predictive of increased stroke risk. Leptomeningeal and ophthalmic collateral circulation is a sensitive but not specific marker. Watershed infarction is highly sensitive and impaired vasodilatory response to acetazolamide is associated with increased OEF but may not be interchangeable. CONCLUSIONS: Orthostatic limb shaking, watershed infarction, collateral circulation, and impaired vasoreactivity to acetazolamide in patients with athero-occlusive disease may predict hemodynamic failure, increased OEF on PET, and high stroke rates. Recognition of these predictive markers may improve patient selection for surgical intervention, as such individuals appear to benefit from EC-IC bypass.
Subject(s)
Brain Ischemia/diagnostic imaging , Cerebral Arteries/diagnostic imaging , Cerebrovascular Disorders/diagnostic imaging , Intracranial Arteriosclerosis/diagnostic imaging , Positron-Emission Tomography/standards , Brain Ischemia/physiopathology , Cerebral Arteries/physiopathology , Cerebral Revascularization/standards , Cerebrovascular Circulation/physiology , Cerebrovascular Disorders/physiopathology , Humans , Intracranial Arteriosclerosis/physiopathology , Mass Screening , Patient Selection , Positron-Emission Tomography/trends , Predictive Value of TestsABSTRACT
OBJECT While malpractice litigation has had many negative impacts on health care delivery systems, information extracted from lawsuits could potentially guide toward venues to improve care. The authors present a comprehensive review of lawsuits within a tertiary academic neurosurgical department and report institutional and departmental strategies to mitigate liability by integrating risk management data with quality improvement initiatives. METHODS The Comprehensive Risk Intelligence Tool database was interrogated to extract claims/suits abstracts concerning neurosurgical cases that were closed from January 2008 to December 2012. Variables included demographics of the claimant, type of procedure performed (if any), claim description, insured information, case outcome, clinical summary, contributing factors and subfactors, amount incurred for indemnity and expenses, and independent expert opinion in regard to whether the standard of care was met. RESULTS During the study period, the Department of Neurosurgery received the most lawsuits of all surgical specialties (30 of 172), leading to a total incurred payment of $4,949,867. Of these lawsuits, 21 involved spinal pathologies and 9 cranial pathologies. The largest group of suits was from patients with challenging medical conditions who underwent uneventful surgeries and postoperative courses but filed lawsuits when they did not see the benefits for which they were hoping; 85% of these claims were withdrawn by the plaintiffs. The most commonly cited contributing factors included clinical judgment (20 of 30), technical skill (19 of 30), and communication (6 of 30). CONCLUSIONS While all medical and surgical subspecialties must deal with the issue of malpractice and liability, neurosurgery is most affected both in terms of the number of suits filed as well as monetary amounts awarded. To use the suits as learning tools for the faculty and residents and minimize the associated costs, quality initiatives addressing the most frequent contributing factors should be instituted in care redesign strategies, enabling strategic alignment of quality improvement and risk management efforts.
Subject(s)
Malpractice/statistics & numerical data , Neurosurgery/education , Neurosurgery/organization & administration , Quality Improvement/organization & administration , Risk Management/statistics & numerical data , Clinical Competence , Communication , Data Interpretation, Statistical , Databases, Factual , Expert Testimony , Humans , Judgment , Liability, Legal , Malpractice/economics , Neurosurgery/legislation & jurisprudence , Organizational Culture , Retrospective Studies , Treatment OutcomeABSTRACT
BACKGROUND: Immunotherapy is an ideal treatment modality to specifically target the diffusely infiltrative tumor cells of malignant gliomas while sparing the normal brain parenchyma. However, progress in the development of these therapies for glioblastoma has been slow due to the lack of immunogenic antigen targets that are expressed uniformly and selectively by gliomas. METHODS: We utilized human glioblastoma cell cultures to induce expression of New York-esophageal squamous cell carcinoma (NY-ESO-1) following in vitro treatment with the demethylating agent decitabine. We then investigated the phenotype of lymphocytes specific for NY-ESO-1 using flow cytometry analysis and cytotoxicity against cells treated with decitabine using the xCelligence real-time cytotoxicity assay. Finally, we examined the in vivo application of this immune therapy using an intracranially implanted xenograft model for in situ T cell trafficking, survival, and tissue studies. RESULTS: Our studies showed that treatment of intracranial glioma-bearing mice with decitabine reliably and consistently induced the expression of an immunogenic tumor-rejection antigen, NY-ESO-1, specifically in glioma cells and not in normal brain tissue. The upregulation of NY-ESO-1 by intracranial gliomas was associated with the migration of adoptively transferred NY-ESO-1-specific lymphocytes along white matter tracts to these tumors in the brain. Similarly, NY-ESO-1-specific adoptive T cell therapy demonstrated antitumor activity after decitabine treatment and conferred a highly significant survival benefit to mice bearing established intracranial human glioma xenografts. Transfer of NY-ESO-1-specific T cells systemically was superior to intracranial administration and resulted in significantly extended and long-term survival of animals. CONCLUSION: These results reveal an innovative, clinically feasible strategy for the treatment of glioblastoma.