RESUMEN
OBJECTIVE: For patients with surgically accessible solitary metastases or oligometastatic disease, treatment often involves resection followed by postoperative stereotactic radiosurgery (SRS). This strategy has several potential drawbacks, including irregular target delineation for SRS and potential tumor "seeding" away from the resection cavity during surgery. A neoadjuvant (preoperative) approach to radiation therapy avoids these limitations and offers improved patient convenience. This study assessed the efficacy of neoadjuvant SRS as a new treatment paradigm for patients with brain metastases. METHODS: A retrospective review was performed at a single institution to identify patients who had undergone neoadjuvant SRS (specifically, Gamma Knife radiosurgery) followed by resection of a brain metastasis. Kaplan-Meier survival and log-rank analyses were used to evaluate risks of progression and death. Assessments were made of local recurrence and leptomeningeal spread. Additionally, an analysis of the contemporary literature of postoperative and neoadjuvant SRS for metastatic disease was performed. RESULTS: Twenty-four patients who had undergone neoadjuvant SRS followed by resection of a brain metastasis were identified in the single-institution cohort. The median age was 64 years (range 32-84 years), and the median follow-up time was 16.5 months (range 1 month to 5.7 years). The median radiation dose was 17 Gy prescribed to the 50% isodose. Rates of local disease control were 100% at 6 months, 87.6% at 12 months, and 73.5% at 24 months. In 4 patients who had local treatment failure, salvage therapy included repeat resection, laser interstitial thermal therapy, or repeat SRS. One hundred thirty patients (including the current cohort) were identified in the literature who had been treated with neoadjuvant SRS prior to resection. Overall rates of local control at 1 year after neoadjuvant SRS treatment ranged from 49% to 91%, and rates of leptomeningeal dissemination from 0% to 16%. In comparison, rates of local control 1 year after postoperative SRS ranged from 27% to 91%, with 7% to 28% developing leptomeningeal disease. CONCLUSIONS: Neoadjuvant SRS for the treatment of brain metastases is a novel approach that mitigates the shortcomings of postoperative SRS. While additional prospective studies are needed, the current study of 130 patients including the summary of 106 previously published cases supports the safety and potential efficacy of preoperative SRS with potential for improved outcomes compared with postoperative SRS.
Asunto(s)
Neoplasias Encefálicas , Neoplasias Meníngeas , Radiocirugia , Humanos , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Radiocirugia/efectos adversos , Terapia Neoadyuvante/efectos adversos , Neoplasias Encefálicas/cirugía , Neoplasias Meníngeas/cirugía , Terapia Recuperativa , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
PURPOSE: Endoscopic transsphenoidal surgery (ETSS) is a well-established treatment for patients with nonfunctioning pituitary adenomas (NFPAs). Data on the rates of pituitary dysfunction and recovery in a large cohort of NFPA patients undergoing ETSS and the predictors of endocrine function before and after ETSS are scarce. This study is purposed to analyze the comprehensive changes in hormonal function and identify factors that predict recovery or worsening of hormonal axes following ETSS for NFPA. METHODS: A retrospective review of 601 consecutive patients who underwent ETSS between 2010 and 2018 at one institution was performed. Recovery or development of new hypopituitarism was analyzed in 209 NFPA patients who underwent ETSS. RESULTS: Patients with preoperative endocrine deficits (59.8%) in one or more pituitary axes had larger tumor volumes (P = 0.001) than those without preoperative deficits. Recovery of preoperative pituitary deficit occurred in all four axes, with overall mean recovery of 29.7%. The cortisol axis showed the highest recovery whereas the thyroid axis showed the lowest, with 1-year cumulative recovery rates of 44.3% and 6.1%, respectively. Postoperative hypopituitarism occurred overall in 17.2%, most frequently in the thyroid axis (24.3%, 27/111) and least frequently in the cortisol axis (9.7%, 16/165). Axis-specific predictors of post-operative recovery and deficiency were identified. CONCLUSIONS: Dynamic alterations in pituitary hormones were observed in a proportion of patients following ETSS in NFPA patients. Postoperative endocrine vulnerability, recovery, and factors that predicted recovery or loss of endocrine function depended on the hormonal system, necessitating an axis-specific surveillance strategy postoperatively.
Asunto(s)
Adenoma/cirugía , Insuficiencia Suprarrenal/metabolismo , Hipogonadismo/metabolismo , Hipopituitarismo/metabolismo , Hipotiroidismo/metabolismo , Neoplasias Hipofisarias/cirugía , Recuperación de la Función , Adenoma/complicaciones , Adenoma/metabolismo , Insuficiencia Suprarrenal/etiología , Hormona Adrenocorticotrópica/metabolismo , Anciano , Estradiol/metabolismo , Femenino , Hormona Folículo Estimulante/metabolismo , Hormona de Crecimiento Humana/deficiencia , Hormona de Crecimiento Humana/metabolismo , Humanos , Hidrocortisona/metabolismo , Hiperprolactinemia/etiología , Hiperprolactinemia/metabolismo , Hipogonadismo/etiología , Hipopituitarismo/etiología , Sistema Hipotálamo-Hipofisario , Hipotiroidismo/etiología , Factor I del Crecimiento Similar a la Insulina/metabolismo , Hormona Luteinizante/metabolismo , Masculino , Persona de Mediana Edad , Neuroendoscopía , Neoplasias Hipofisarias/complicaciones , Neoplasias Hipofisarias/metabolismo , Pruebas de Función Adreno-Hipofisaria , Sistema Hipófiso-Suprarrenal , Prolactina/metabolismo , Hueso Esfenoides , Testosterona/metabolismo , Tirotropina/metabolismo , Tiroxina/metabolismo , Resultado del TratamientoRESUMEN
BACKGROUND: Seizures occur in 10-20% of patients with subarachnoid hemorrhage (SAH), predominantly in the acute phase. However, anticonvulsant prophylaxis remains controversial, with studies suggesting a brief course may be adequate and longer exposure may be associated with worse outcomes. Nonetheless, in the absence of controlled trials to inform practice, patients continue to receive variable chemoprophylaxis. The objective of this study was to compare brief versus extended seizure prophylaxis after aneurysmal SAH. METHODS: We performed a prospective, single-center, randomized, open-label trial of a brief (3-day) course of levetiracetam (LEV) versus extended treatment (until hospital discharge). The primary outcome was in-hospital seizure. Secondary outcomes included drug discontinuation and functional outcome. RESULTS: Eighty-four SAH patients had been randomized when the trial was terminated due to slow enrollment. In-hospital seizures occurred in three (9%) of 35 in the brief LEV group versus one (2%) of 49 in the extended group (p = 0.2). Ten (20%) of the extended group discontinued LEV prematurely, primarily due to sedation. Four of five seizures (including one pre-randomization) occurred in patients with early brain injury (EBI) on computed tomography (CT) scans (adjusted OR 12.5, 95% CI 1.2-122, p = 0.03). Good functional outcome (mRS 0-2) was more likely in the brief LEV group (83 vs. 61%, p = 0.04). CONCLUSIONS: This study was underpowered to demonstrate superiority of extended LEV for seizure prophylaxis, although a trend to benefit was seen. Seizures primarily occurred in those with radiographic EBI, suggesting targeted prophylaxis may be preferable. Larger trials are required to evaluate optimal chemoprophylaxis in SAH, especially in light of worse outcomes in those receiving extended treatment.
Asunto(s)
Anticonvulsivantes/administración & dosificación , Aneurisma Intracraneal/complicaciones , Levetiracetam/administración & dosificación , Evaluación de Resultado en la Atención de Salud , Convulsiones/prevención & control , Hemorragia Subaracnoidea/complicaciones , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Convulsiones/etiología , Hemorragia Subaracnoidea/etiologíaRESUMEN
BACKGROUND AND PURPOSE: The purpose was to test the hypothesis that increased oxygen extraction fraction (OEF), a marker of severe hemodynamic impairment measured by positron emission tomography, is an independent risk factor for subsequent ischemic stroke in this population. METHODS: Adults with idiopathic moyamoya phenomena were recruited between 2005 and 2012 for a prospective, multicenter, blindly adjudicated, longitudinal cohort study. Measurements of OEF were obtained on enrollment. Subjects were followed up for the occurrence of ipsilateral ischemic stroke at 6-month intervals. Patients were censored at the time of surgical revascularization or at last follow-up. The primary analysis was time to ischemic stroke in the territory of the occlusive vasculopathy. RESULTS: Forty-nine subjects were followed up during a median of 3.7 years. One of 16 patients with increased OEF on enrollment had an ischemic stroke and another had an intraparenchymal hemorrhage. Three of 33 patients with normal OEF had an ischemic stroke. On a per-hemisphere basis, 21 of 79 hemispheres with moyamoya vasculopathy had increased OEF at baseline. No ischemic strokes and one hemorrhage occurred in a hemisphere with increased OEF (n=21). Sixteen patients (20 hemispheres), including 5 with increased OEF at enrollment, were censored at a mean of 5.3 months after enrollment for revascularization surgery. CONCLUSIONS: The risk of new or recurrent stroke was lower than expected. The low event rate, low prevalence of increased OEF, and potential selection bias introduced by revascularization surgery limit strong conclusions about the association of increased OEF and future stroke risk. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00629915.
Asunto(s)
Isquemia Encefálica/diagnóstico por imagen , Enfermedad de Moyamoya/diagnóstico por imagen , Acoplamiento Neurovascular , Tomografía de Emisión de Positrones/métodos , Accidente Cerebrovascular/diagnóstico por imagen , Adulto , Anciano , Isquemia Encefálica/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Medio Oeste de Estados Unidos/epidemiología , Enfermedad de Moyamoya/epidemiología , Oxígeno/metabolismo , Recurrencia , Factores de Riesgo , Método Simple Ciego , Accidente Cerebrovascular/epidemiologíaRESUMEN
BACKGROUND AND PURPOSE: Cerebral arterial vasospasm (CVS) is a common complication of aneurysmal subarachnoid hemorrhage strongly associated with neurological deterioration and delayed cerebral ischemia (DCI). The utility of screening for CVS as a surrogate for early detection of DCI, especially in patients without clinical signs of DCI, remains uncertain. METHODS: We performed a retrospective analysis of 116 aneurysmal subarachnoid hemorrhage patients who underwent screening digital subtraction angiography to determine the association of significant CVS and subsequent development of DCI. Patients were stratified into 3 groups: (1) no symptoms of DCI before screening, (2) ≥1 episodes of suspected DCI symptoms before screening, and (3) unable to detect symptoms because of poor examination. RESULTS: Patients asymptomatic before screening had significantly lower rates of CVS (18%) compared with those with transient symptoms of DCI (60%; P<0.0001). None of the 79 asymptomatic patients developed DCI after screening, regardless of digital subtraction angiography findings, compared with 56% of those with symptoms (P<0.0001). Presence of CVS was significantly associated with DCI in those with transient symptoms and in those whose examinations did not permit clear assessment (odds ratio 16.0, 95% confidence interval 2.2-118.3, P=0.003). CONCLUSIONS: Patients asymptomatic before screening have low rates of CVS and seem to be at negligible risk of developing DCI. Routine screening of asymptomatic patients seems to have little utility. Screening may still be considered in patients with possible symptoms of DCI or those with examinations too poor to clinically detect symptoms because finding CVS may be useful for risk stratification and guiding management.
Asunto(s)
Angiografía de Substracción Digital , Tamizaje Masivo , Vasoespasmo Intracraneal/diagnóstico por imagen , Vasoespasmo Intracraneal/epidemiología , Angiografía de Substracción Digital/métodos , Estudios de Cohortes , Bases de Datos Factuales , Femenino , Humanos , Masculino , Tamizaje Masivo/métodos , Persona de Mediana Edad , Estudios Prospectivos , Estudios Retrospectivos , Factores de Riesgo , Hemorragia Subaracnoidea/diagnóstico por imagen , Hemorragia Subaracnoidea/epidemiologíaRESUMEN
PURPOSE: The clinical benefit of combined intraoperative magnetic resonance imaging (iMRI) and endoscopy for transsphenoidal pituitary adenoma resection has not been completely characterized. This study assessed the impact of microscopy, endoscopy, and/or iMRI on progression-free survival, extent of resection status (gross-, near-, and sub-total resection), and operative complications. METHODS: Retrospective analyses were performed on 446 transsphenoidal pituitary adenoma surgeries at a single institution between 1998 and 2012. Multivariate analyses were used to control for baseline characteristics, differences during extent of resection status, and progression-free survival analysis. RESULTS: Additional surgery was performed after iMRI in 56/156 cases (35.9%), which led to increased extent of resection status in 15/156 cases (9.6%). Multivariate ordinal logistic regression revealed no increase in extent of resection status following iMRI or endoscopy alone; however, combining these modalities increased extent of resection status (odds ratio 2.05, 95% CI 1.21-3.46) compared to conventional transsphenoidal microsurgery. Multivariate Cox regression revealed that reduced extent of resection status shortened progression-free survival for near- versus gross-total resection [hazard ratio (HR) 2.87, 95% CI 1.24-6.65] and sub- versus near-total resection (HR 2.10; 95% CI 1.00-4.40). Complication comparisons between microscopy, endoscopy, and iMRI revealed increased perioperative deaths for endoscopy versus microscopy (4/209 and 0/237, respectively), but this difference was non-significant considering multiple post hoc comparisons (Fisher exact, p = 0.24). CONCLUSIONS: Combined use of endoscopy and iMRI increased pituitary adenoma extent of resection status compared to conventional transsphenoidal microsurgery, and increased extent of resection status was associated with longer progression-free survival. Treatment modality combination did not significantly impact complication rate.
Asunto(s)
Endoscopía/métodos , Imagen por Resonancia Magnética/métodos , Neoplasias Hipofisarias/mortalidad , Neoplasias Hipofisarias/cirugía , Adulto , Anciano , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estudios Retrospectivos , Adulto JovenRESUMEN
Perforating arteries rarely project from the fundus of an aneurysm. We present the case of a 35-year-old woman who was found to have a right posterior communicating artery (PCOM) aneurysm via catheter angiography. Superselective microcatheter angiography revealed that perforating arteries arose from the aneurysm fundus that supplied the anterolateral thalamus. Microsurgical exploration confirmed several small perforating arteries arising from the aneurysm dome as well as an atretic distal PCOM artery. Given the complex anatomy, the lesion was unsuitable for clipping. We propose that this aneurysm represents a developmental variant whereby the proximal PCOM artery becomes atretic and terminates in PCOM perforators. The video can be found here: http://youtu.be/iDcp9fsDjq4.
Asunto(s)
Arterias/patología , Procedimientos Endovasculares/métodos , Aneurisma Intracraneal/cirugía , Microcirugia/métodos , Adulto , Angiografía Cerebral , Femenino , HumanosRESUMEN
BACKGROUND: North American and Asian forms of moyamoya have distinct clinical characteristics. Asian adults with moyamoya are known to respond better to direct versus indirect revascularization. It is unclear whether North American adults with moyamoya have a similar long-term angiographic response to direct versus indirect bypass. METHODS: A retrospective review of surgical revascularization for adult moyamoya phenomenon was performed. Preoperative and postoperative cerebral angiograms underwent consensus review, with degree of revascularization quantified as extent of new middle cerebral artery (MCA) territory filling. RESULTS: Late angiographic follow-up was available in 15 symptomatic patients who underwent 20 surgical revascularization procedures. In 10 hemispheres treated solely with indirect arterial bypass, 3 had 2/3 revascularization, 4 had 1/3 revascularization, and 3 had no revascularization of the MCA territory. In the 10 hemispheres treated with direct arterial bypass (8 as a stand-alone procedure and 2 in combination with an indirect procedure), 2 had complete revascularization, 7 had 2/3 revascularization, and 1 had 1/3 revascularization. Direct bypass provided a higher rate of "good" angiographic outcome (complete or 2/3 revascularization) when compared with indirect techniques (P = .0198). CONCLUSIONS: Direct bypass provides a statistically significant, more consistent, and complete cerebral revascularization than indirect techniques in this patient population. This is similar to that reported in the Asian literature, which suggests that the manner of presentation (ischemia in North American adults versus hemorrhage in Asian adults) is likely not a contributor to the extent of revascularization achieved after surgical intervention.
Asunto(s)
Angiografía de Substracción Digital , Angiografía Cerebral/métodos , Revascularización Cerebral/métodos , Arteria Cerebral Media/diagnóstico por imagen , Arteria Cerebral Media/cirugía , Enfermedad de Moyamoya/diagnóstico por imagen , Enfermedad de Moyamoya/cirugía , Arterias Temporales/diagnóstico por imagen , Arterias Temporales/cirugía , Adulto , Revascularización Cerebral/efectos adversos , Circulación Cerebrovascular , Femenino , Humanos , Masculino , Persona de Mediana Edad , Arteria Cerebral Media/fisiopatología , Missouri/epidemiología , Enfermedad de Moyamoya/epidemiología , Enfermedad de Moyamoya/fisiopatología , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Arterias Temporales/fisiopatología , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND AND PURPOSE: Spontaneous idiopathic subarachnoid hemorrhage (SAH) with a perimesencephalic bleeding pattern is usually associated with a benign course, whereas a diffuse bleeding pattern has been associated with a higher risk of vasospasm and disability. We evaluated whether volume of bleeding explains this disparity. METHODS: Pattern and amount of bleeding (by Hijdra and intraventricular hemorrhage scores) were assessed in 89 patients with nonaneurysmal SAH. Outcomes included angiographic vasospasm, delayed cerebral ischemia, and functional outcome at 1 year. RESULTS: Diffuse bleeding was associated with significantly higher Hijdra and intraventricular hemorrhage scores than perimesencephalic SAH, P≤0.003. Angiographic vasospasm was more likely in diffuse versus perimesencephalic SAH (45% versus 27%; odds ratio, 2.9; P=0.08), but adjustment for greater blood burden only partially attenuated this trend (adjusted odds ratio, 2.2; 95% confidence interval, 0.69-7.2; P=0.18); delayed cerebral ischemia was only seen in those with diffuse bleeding. Patients with diffuse bleeding were less likely to be discharged home (68% versus 90%; P=0.01) and tended to have more residual disability (modified Rankin scale, 3-6; 20% versus 6%; P=0.18). CONCLUSIONS: Nonaneurysmal SAH can still result in vasospasm and residual disability, especially in those with diffuse bleeding. This disparity is only partially accounted for by greater cisternal or intraventricular blood, suggesting that the mechanism and distribution of bleeding may be as important as the amount of hemorrhage in patients with idiopathic SAH.
Asunto(s)
Hemorragia Subaracnoidea/patología , Vasoespasmo Intracraneal/patología , Adulto , Anciano , Angiografía de Substracción Digital , Volumen Sanguíneo/fisiología , Isquemia Encefálica/etiología , Isquemia Encefálica/patología , Angiografía Cerebral , Estudios de Cohortes , Intervalos de Confianza , Evaluación de la Discapacidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Valor Predictivo de las Pruebas , Estudios Prospectivos , Punción Espinal , Hemorragia Subaracnoidea/complicaciones , Tomografía Computarizada por Rayos X , Vasoespasmo Intracraneal/etiologíaRESUMEN
The human cerebrovascular system is responsible for maintaining neural function through oxygenation, nutrient supply, filtration of toxins, and additional specialized tasks. While the cerebrovascular system has resilience imparted by elaborate redundant collateral circulation from supportive tertiary structures, it is not infallible, and is susceptible to developing structural vascular abnormalities. The causes of this class of structural cerebrovascular diseases can be broadly categorized as 1) intrinsic developmental diseases resulting from genetic or other underlying aberrations (arteriovenous malformations and cavernous malformations) or 2) extrinsic acquired diseases that cause compensatory mechanisms to drive vascular remodeling (aneurysms and arteriovenous fistulae). Cerebrovascular diseases of both types pose significant risks to patients, in some cases leading to death or disability. The drivers of such diseases are extensive, yet inflammation is intimately tied to all of their progressions. Central to this inflammatory hypothesis is the role of peripheral macrophages; targeting this critical cell type may lead to diagnostic and therapeutic advancement in this area. Here, we comprehensively review the role that peripheral macrophages play in cerebrovascular pathogenesis, provide a schema through which macrophage behavior can be understood in cerebrovascular pathologies, and describe emerging diagnostic and therapeutic avenues in this area.
Asunto(s)
Aneurisma Intracraneal , Malformaciones Arteriovenosas Intracraneales , Humanos , Malformaciones Arteriovenosas Intracraneales/diagnóstico , MacrófagosRESUMEN
BACKGROUND: Cervical arterial tortuosity is associated with adverse outcomes in Loeys-Dietz syndrome and other heritable aortopathies. METHODS AND RESULTS: A method to assess tortuosity based on curvature of the vessel centerline in 3-dimensional space was developed. We measured cervical carotid tortuosity in 65 patients with Loeys-Dietz syndrome from baseline computed tomography angiogram/magnetic resonance angiogram and all serial images during follow-up. Relations between baseline carotid tortuosity, age, aortic root diameter, and its change over time were compared. Patients with unoperated aortic roots were assessed for clinical end point (type A aortic dissection or aortic root surgery during 4 years of follow-up). Logistic regression was performed to assess the likelihood of clinical end point according to baseline carotid tortuosity. Total absolute curvature at baseline was 11.13±5.76 and was relatively unchanged at 8 to 10 years (fold change: 0.026±0.298, P=1.00), whereas tortuosity index at baseline was 0.262±0.131, with greater variability at 8 to 10 years (fold change: 0.302±0.656, P=0.818). Baseline total absolute curvature correlated with aortic root diameter (r=0.456, P=0.004) and was independently associated with aortic events during the 4-year follow-up (adjusted odds ratio [OR], 2.64 [95% CI, 1.02-6.85]). Baseline tortuosity index correlated with age (r=0.532, P<0.001) and was not associated with events (adjusted OR, 1.88 [95% CI, 0.79-4.51]). Finally, baseline total absolute curvature had good discrimination of 4-year outcomes (area under the curve=0.724, P=0.014), which may be prognostic or predictive. CONCLUSIONS: Here we introduce cervical carotid tortuosity as a promising quantitative biomarker with validated, standardized characteristics. Specifically, we recommend the adoption of a curvature-based measure, total absolute curvature, for early detection or monitoring of disease progression in Loeys-Dietz syndrome.
Asunto(s)
Arterias Carótidas , Angiografía por Tomografía Computarizada , Síndrome de Loeys-Dietz , Angiografía por Resonancia Magnética , Humanos , Femenino , Masculino , Medición de Riesgo , Adulto , Síndrome de Loeys-Dietz/genética , Síndrome de Loeys-Dietz/complicaciones , Síndrome de Loeys-Dietz/diagnóstico , Síndrome de Loeys-Dietz/diagnóstico por imagen , Persona de Mediana Edad , Arterias Carótidas/diagnóstico por imagen , Arterias Carótidas/patología , Factores de Riesgo , Adulto Joven , Valor Predictivo de las Pruebas , Disección Aórtica/diagnóstico por imagen , Disección Aórtica/diagnóstico , Disección Aórtica/cirugía , Malformaciones Vasculares/diagnóstico por imagen , Malformaciones Vasculares/diagnóstico , Imagenología Tridimensional , Reproducibilidad de los Resultados , Enfermedades Cutáneas Genéticas/genética , Enfermedades Cutáneas Genéticas/diagnóstico por imagen , Enfermedades Cutáneas Genéticas/diagnósticoRESUMEN
PURPOSE: Outcomes for patients with glioblastoma (GBM) remain poor despite multimodality treatment with surgery, radiation, and chemotherapy. There are few immunotherapy options due to the lack of tumor immunogenicity. Several clinical trials have reported promising results with cancer vaccines. To date, studies have used data from a single tumor site to identify targetable antigens, but this approach limits the antigen pool and is antithetical to the heterogeneity of GBM. We have implemented multisector sequencing to increase the pool of neoantigens across the GBM genomic landscape that can be incorporated into personalized peptide vaccines called NeoVax. PATIENTS AND METHODS: In this study, we report the findings of four patients enrolled onto the NeoVax clinical trial (NCT0342209). RESULTS: Immune reactivity to NeoVax neoantigens was assessed in peripheral blood mononuclear cells pre- and post-NeoVax for patients 1 to 3 using IFNγ-ELISPOT assay. A statistically significant increase in IFNγ producing T cells at the post-NeoVax time point for several neoantigens was observed. Furthermore, a post-NeoVax tumor biopsy was obtained from patient 3 and, upon evaluation, revealed evidence of infiltrating, clonally expanded T cells. CONCLUSIONS: Collectively, our findings suggest that NeoVax stimulated the expansion of neoantigen-specific effector T cells and provide encouraging results to aid in the development of future neoantigen vaccine-based clinical trials in patients with GBM. Herein, we demonstrate the feasibility of incorporating multisector sampling in cancer vaccine design and provide information on the clinical applicability of clonality, distribution, and immunogenicity of the neoantigen landscape in patients with GBM.
Asunto(s)
Antígenos de Neoplasias , Vacunas contra el Cáncer , Glioblastoma , Medicina de Precisión , Vacunas de Subunidad , Humanos , Glioblastoma/inmunología , Glioblastoma/terapia , Glioblastoma/genética , Glioblastoma/patología , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/administración & dosificación , Vacunas contra el Cáncer/uso terapéutico , Vacunas de Subunidad/inmunología , Vacunas de Subunidad/administración & dosificación , Vacunas de Subunidad/uso terapéutico , Medicina de Precisión/métodos , Antígenos de Neoplasias/inmunología , Femenino , Masculino , Persona de Mediana Edad , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Adulto , Anciano , Inmunoterapia/métodos , Vacunas de Subunidades ProteicasRESUMEN
BACKGROUND AND PURPOSE: Reduced risk and severity of stroke in adult females are thought to depend on normal levels of endogenous estrogen, which is a known neuro- and vasoprotective agent in experimental cerebral ischemia. Recently, a novel G protein-coupled estrogen receptor (GPER, formerly GPR30) has been identified and may mediate the vasomotor and -protective effects of estrogen. However, the signaling mechanisms associated with GPER in the cerebral microcirculation remain unclear. We investigated the mechanism of GPER-mediated vasoreactivity and also its vasoprotective effect after hypoxia/reoxygenation (H/RO) injury. METHODS: Rat cerebral penetrating arterioles from both sexes were isolated, cannulated, and pressurized. Vessel diameters were recorded by computer-aided videomicroscopy. To investigate vasomotor mechanism of the GPER agonist (G-1), several inhibitors with or without endothelial impairment were tested. Ischemia/reperfusion injury was simulated using H/RO. Vasomotor responses to adenosine triphophate after H/RO were measured with or without G-1 and compared with controls. RESULTS: G-1 produced a vasodilatory response, which was partially dependent on endothelium-derived nitric oxide (NO) but not arachidonic acid cascades and endothelial hyperpolarization factor. Attenuation of G-1-vasodilation by the NO synthase inhibitor and endothelium-impairment were greater in vessels from female than male animals. G-1 treatment after H/RO injury fully restored arteriolar dilation to adenosine triphophate compared with controls. CONCLUSIONS: GPER agonist elicited dilation, which was partially caused by endothelial NO pathway and induced by direct relaxation of smooth muscle cells. Further, GPER agonist restored vessel function of arterioles after H/RO injury and may play an important role in the ability of estrogen to protect the cerebrovasculature against ischemia/reperfusion injury.
Asunto(s)
Encéfalo/irrigación sanguínea , Circulación Cerebrovascular/efectos de los fármacos , Ciclopentanos/farmacología , Microvasos/efectos de los fármacos , Quinolinas/farmacología , Receptores Acoplados a Proteínas G/agonistas , Daño por Reperfusión/fisiopatología , Animales , Benzodioxoles/farmacología , Encéfalo/efectos de los fármacos , Circulación Cerebrovascular/fisiología , Estrógenos/fisiología , Femenino , Masculino , Microvasos/fisiopatología , Modelos Animales , Ratas , Ratas Endogámicas Lew , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Factores Sexuales , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Vasodilatación/efectos de los fármacos , Vasodilatación/fisiologíaRESUMEN
BACKGROUND: Intracranial fusiform aneurysms are circumferential dilations of cerebral arteries that can lead to complications including ischemic stroke due to vessel occlusion, subarachnoid hemorrhage, or intracerebral hemorrhage. Treatment options for fusiform aneurysms have expanded significantly in recent years. Microsurgical treatment options include proximal and distal surgical occlusion and microsurgical trapping of the aneurysm, usually in association with high-flow bypass procedures. Endovascular treatment options include the placement of coils and/or flow diverters. OBSERVATIONS: Here the authors report a case of aggressive surveillance and treatment of a man with multiple progressive, recurrent, and de novo fusiform aneurysms of the left anterior cerebral circulation over 16 years. Because the long-term course of his treatment coincided with the recent expansion of endovascular treatment options, he underwent every type of treatment listed above. LESSONS: This case demonstrates the wide range of therapeutic options for fusiform aneurysms and how the treatment model for these lesions has evolved.
RESUMEN
Introduction A low subfrontal dural opening technique that limits brain manipulation was assessed in patients who underwent frontotemporal approaches for anterior fossa lesions. Methods A retrospective review was performed for cases using a low subfrontal dural opening including characterization of demographics, lesion size and location, neurological and ophthalmological assessments, clinical course, and imaging findings. Results A low subfrontal dural opening was performed in 23 patients (17F, 6M), median age of 53 years (range 23-81) with a median follow-up duration of 21.9 months (range 6.2-67.1). Lesions included 22 meningiomas (nine anterior clinoid, 12 tuberculum sellae, and one sphenoid wing), one unruptured internal carotid artery aneurysm clipped during a meningioma resection, and one optic nerve cavernous malformation. Maximal possible resection was achieved in all cases including gross total resection in 16/22 (72.7%), near total in 1/22 (4.5%), and subtotal in 5/22 (22.7%) in which tumor involvement of critical structures limited complete resection. Eighteen patients presented with vision loss; 11 (61%) improved postoperatively, three (17%) were stable, and four (22%) worsened. The mean ICU stay and time to discharge were 1.3 days (range 0-3) and 3.8 days (range 2-8). Conclusion A low sub-frontal dural opening for approaches to the anterior fossa can be performed with minimal brain exposure, early visualization of the optico-carotid cistern for cerebrospinal fluid release, minimizing need for fixed brain retraction, and Sylvian fissure dissection. This technique can potentially reduce surgical risk and provide excellent exposure for anterior skull base lesions with favorable extent of resection, visual recovery, and complication rates.
RESUMEN
OBJECTIVE: Loeys-Dietz syndrome (LDS) is a heritable aortopathy associated with craniofacial abnormalities and dilatation and dissection of the aorta and its branches, as well as increased risk for intracranial aneurysms (ICAs). Given the rarity of the disease, the authors aimed to better define the natural history and role for the treatment for ICAs in these patients. METHODS: The medical records of 83 patients with LDS were retrospectively reviewed to obtain clinical and genetic history and vascular imaging of the aorta, aortic branches, and intracranial vessels. Serial radiology reports and cervical and intracranial vascular images were reviewed to determine presence, location, and size of ICAs. RESULTS: In total, 55 patients (66.3%) had at least two screening intracranial vascular examinations, and 19 (22.9%) had at least 1 ICA detected. Aneurysms were typically small (mean ± SD 3.2 ± 1.8 mm). ICAs were most often located in the cavernous carotid, followed by the ophthalmic and anterior cerebral artery vessels. The rate of ICA growth was 0.43 ± 0.53 mm/year, similar to that of the general population. Three patients underwent intervention for an ICA, with 1 procedure complicated by stroke and resulting in transient hemiparesis. Several illustrative cases detail the authors' experience with ICA growth, de novo aneurysm formation, and ICA intervention in this rare patient population. CONCLUSIONS: ICAs in patients with LDS are common, are frequently small, and have a growth rate similar to that of unruptured ICAs in the general population. More aggressive or earlier intervention for asymptomatic ICAs identified in LDS patients compared with the general population is likely unwarranted based on the authors' experience at their institution.
RESUMEN
OBJECTIVE: Loeys-Dietz syndrome (LDS) is a rare autosomal dominant condition characterized by aneurysms of the aorta, aortic branches, and intracranial arteries; skeletal and cutaneous abnormalities; and craniofacial malformations. Previous authors have reported that higher craniofacial severity index (CFI) scores, which indicate more severe craniofacial abnormalities, correlate with the severity of aortic aneurysm pathology. However, the association between syndromic features and the formation of intracranial aneurysms in LDS patients has yet to be determined. In this study, the authors evaluate the incidence of phenotypic abnormalities, craniofacial features, and Chiari malformation type I (CM-I) in a large LDS cohort and explore possible risk factors for the development of intracranial aneurysms. METHODS: This was a retrospective cohort study of all patients with LDS who had been seen at the Marfan Syndrome and Aortopathy Center at Washington University School of Medicine in St. Louis in 2010-2022. Medical records were reviewed to obtain demographic, clinical, and radiographic data. The prevalence of craniofacial, skeletal, and cutaneous pathologies was determined. Bivariate logistic regression was performed to identify possible risk factors for the formation of an intracranial aneurysm. RESULTS: Eighty-one patients with complete medical records and intracranial vascular imaging were included in the analysis, and 18 patients (22.2%) had at least 1 intracranial aneurysm. Patients frequently demonstrated the thin or translucent skin, doughy skin texture, hypertelorism, uvular abnormalities, and joint hypermobility typical of LDS. CM-I was common, occurring in 7.4% of the patients. Importantly, the patients with intracranial aneurysms were more likely to have CM-I (22.2%) than those without intracranial aneurysms (3.2%). The mean CFI score in the cohort with available data was 1.81, with higher means in the patients with the TGFBR1 or TGFBR2 disease-causing variants (2.05 and 3.30, respectively) and lower in the patients with the SMAD3, TGFB2, or TGFB3 pathogenic variants (CFI < 1). No significant CFI difference was observed in patients with or without intracranial aneurysms (2.06 vs 1.74, p = 0.61). CONCLUSIONS: CM-I, and not the CFI, is significantly associated with the presence of intracranial aneurysms in patients with LDS. Surveillance for intracranial aneurysms is essential in all patients with LDS and should not be limited to those with severe phenotypes. Long-term monitoring studies will be necessary to determine whether a correlation between craniofacial abnormalities and adverse outcomes from intracranial aneurysms (growth, intervention, or rupture) exists.
Asunto(s)
Anomalías Craneofaciales , Aneurisma Intracraneal , Síndrome de Loeys-Dietz , Humanos , Síndrome de Loeys-Dietz/genética , Estudios Retrospectivos , Anomalías Craneofaciales/genética , FenotipoRESUMEN
Oligodendrogliomas are rare central nervous system (CNS) tumors in children. The purpose of this study was to identify prognostic factors for progression free survival (PFS) and overall survival (OS) in pediatric patients with oligodendrogliomas. We retrospectively analyzed clinical data on 37 pediatric patients with oligodendroglial tumors treated at Washington University. Kaplan-Meier method was used to calculate survival rates. Log-rank was used to detect the difference between survival curves. The median age was 11.1 years (range 10 months-18 years), and median follow-up was 4.5 years (range 2 months-30.5 years). The 5-year PFS and OS were 66.4 and 93.4%, respectively. Mixed histology was associated with worse OS compared to patients with pure oligodendroglioma, 5-year OS 77.6 versus 100% (P < 0.01). Patients who underwent gross total resection (GTR) experienced an improved 5-year PFS of 100% compared to 28.8% (P = 0.03) in patients treated with subtotal resection (STR) or biopsy alone. Age >3 years at diagnosis correlated with improved 5-year PFS, 33.3 versus 69.8% (P = 0.01). Neither post-operative chemotherapy nor radiation therapy correlated with improved outcome. GTR and age >3 years at diagnosis remained significant for improved PFS on multivariate analysis. There were no factors correlated with improved overall survival on multivariate analysis. Pediatric oligodendroglial tumors are associated with excellent OS; however, a third of patients developed progressive disease. Our data demonstrate that patients with less than GTR and <3 years at diagnosis are at increased risk for progression and may benefit from more aggressive therapy.