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Autologous Heat Shock Protein Peptide Vaccination for Newly Diagnosed Glioblastoma: Impact of Peripheral PD-L1 Expression on Response to Therapy

Bloch, Orin; Lim, Michael; Sughrue, Michael E; Komotar, Ricardo J; Abrahams, John M; O'Rourke, Donald M; D'Ambrosio, Anthony; Bruce, Jeffrey N; Parsa, Andrew T
Purpose: Standard therapy for newly diagnosed glioblastoma (GBM) is surgical resection, followed by concurrent radiotherapy and temozolomide chemotherapy. In this phase II clinical trial, the addition of an autologous heat-shock protein vaccine to standard therapy was evaluated. Tumor-induced immunosuppression, mediated by expression of PD-L1 on tumor and circulating immune cells, may impact the efficacy of vaccination. Expression of PD-L1 on peripheral myeloid cells was evaluated for the first time as a predictor of survival.Experimental Design: In this single arm, phase II study, adult patients with GBM underwent surgical resection followed by standard radiation and chemotherapy. Autologous vaccine (Prophage) was generated from resected tumors and delivered in weekly vaccinations after completion of radiotherapy. The primary endpoint was overall survival.Results: Forty-six patients received the vaccine with a median overall survival of 23.8 months [95% confidence interval (CI), 19.8-30.2]. Median overall survival for patients with high PD-L1 expression on myeloid cells was 18.0 months (95% CI, 10.0-23.3) as compared with 44.7 months (95% CI, incalculable) for patients with low PD-L1 expression (hazard ratio 3.3; 95% CI, 1.4-8.6; P = 0.007). A multivariate proportional hazards model revealed MGMT methylation, Karnofsky performance status, and PD-L1 expression as the primary independent predictors of survival.Conclusions: Vaccination with autologous tumor-derived heat shock proteins may improve survival for GBM patients when combined with standard therapy and warrants further study. Systemic immunosuppression mediated by peripheral myeloid expression of PD-L1 is a recently identified factor that may significantly impact vaccine efficacy. Clin Cancer Res; 23(14); 3575-84. ©2017 AACR.
PMCID:5511566
PMID: 28193626
ISSN: 1078-0432
CID: 4621102

AANS/CNS section on tumors: 30th anniversary special issue

D'Ambrosio, Anthony L; Barker, Fred G
PMID: 25182603
ISSN: 1573-7373
CID: 4677182

Beneficial use of a new hand-held CO2 laser fiber in resection of a calcified and vascular intraventricular tumor [Case Report]

Malone, Hani R; Syed, Omar N; D'Ambrosio, Anthony L; McKhann, Guy M
BACKGROUND:The progression of laser technology in neurosurgery has been limited by the poor maneuverability of traditional line-of-sight carbon dioxide (CO2) lasers and the propensity of other laser energies to cause collateral thermal injury to adjacent neural structures. The advent of a dielectric omnidirectional reflector and the subsequent development of phototonic bandgap fibers (PBF) have transformed the CO2 laser into a low-profile instrument with considerable dexterity and many potential new neurosurgical applications. CASE DESCRIPTION/METHODS:A 48-year-old woman presented with a large mass in the left lateral ventricle that was first diagnosed>20 years ago. The patient was asymptomatic until 1 month before presentation, when she began to experience progressive memory loss and neurocognitive decline. RESULTS:The hand-held CO2 laser was used to debulk the tumor. The CO2 laser vaporized neoplastic cellular material and simultaneously cauterized microvascular structures. CONCLUSIONS:The CO2 laser was exceptionally useful in the resection of this long-standing and extremely calcified, yet vascular mass. A review of the evolution of laser technology applications in neurosurgery is presented, with a specific focus on the innovations that led to the development of the new PBF CO2 laser. This new technology may be advantageous in tumor surgery, particularly in the resection of long-standing calcified and vascular tumors that are not amendable to traditional surgical techniques.
PMID: 22120386
ISSN: 1878-8769
CID: 4621072

Traumatic brain injury in pediatric patients: evidence for the effectiveness of decompressive surgery

Appelboom, Geoffrey; Zoller, Stephen D; Piazza, Matthew A; Szpalski, Caroline; Bruce, Samuel S; McDowell, Michael M; Vaughan, Kerry A; Zacharia, Brad E; Hickman, Zachary; D'Ambrosio, Anthony; Feldstein, Neil A; Anderson, Richard C E
Traumatic brain injury (TBI) is the current leading cause of death in children over 1 year of age. Adequate management and care of pediatric patients is critical to ensure the best functional outcome in this population. In their controversial trial, Cooper et al. concluded that decompressive craniectomy following TBI did not improve clinical outcome of the analyzed adult population. While the study did not target pediatric populations, the results do raise important and timely clinical questions regarding the effectiveness of decompressive surgery in pediatric patients. There is still a paucity of evidence regarding the effectiveness of this therapy in a pediatric population, and there is an especially noticeable knowledge gap surrounding age-stratified interventions in pediatric trauma. The purposes of this review are to first explore the anatomical variations between pediatric and adult populations in the setting of TBI. Second, the authors assess how these differences between adult and pediatric populations could translate into differences in the impact of decompressive surgery following TBI.
PMID: 22044104
ISSN: 1092-0684
CID: 4621062

Preclinical evaluation of postischemic dehydroascorbic Acid administration in a large-animal stroke model

Ducruet, Andrew F; Mack, William J; Mocco, J; Hoh, Daniel J; Coon, Alexander L; D'Ambrosio, Anthony L; Winfree, Christopher J; Pinsky, David J; Connolly, E Sander
Dehydroascorbic acid (DHA), a blood-brain barrier transportable form of ascorbic acid, confers robust neuroprotection following murine stroke. In an effort to translate this promising neuroprotective strategy into human clinical trial, we evaluated postischemic DHA administration in a large-animal stroke model. Thirty-six adult male baboons were initially randomized to undergo transorbital craniectomy to induce transient cerebral artery occlusion and to receive postischemic dosing of either 500 mg/kg of DHA or vehicle. Primary outcomes included infarct volume, determined by magnetic resonance imaging, as well as neurological function evaluated on the day of sacrifice. The midpoint interim analysis (n = 9 per cohort) revealed that DHA administration did not significantly improve either infarct volume or neurological function. The study was terminated after a determination of statistical futility. We were unable to confirm a neuroprotective effect for postischemic DHA administration in our large-animal model using a dosing scheme that was previously successful in rodents. Further analysis of the efficacy of DHA administration must thus be undertaken prior to clinical translation.
PMID: 24323656
ISSN: 1868-4483
CID: 4621082

Management of brain metastases. Preface

D'Ambrosio, Anthony L; Rao, Ganesh
PMID: 21109142
ISSN: 1558-1349
CID: 4621022

Radiosurgical management of brain metastases

D'Ambrosio, Anthony L; DeYoung, Chad; Isaacson, Steven R
Stereotactic radiosurgery (SRS) should be considered in the comprehensive treatment paradigm for all patients with brain metastases. This technique has proven benefits for local tumor control in individuals with as many as 4 lesions, and when combined with structured radiographic follow-up, will likely preserve a better quality of life for appropriately selected patients. Institutions and physicians treating patients with brain metastases should have the capability of safely performing SRS and individual cases should be prospectively reviewed by multidisciplinary teams to provide the best comprehensive care.
PMID: 21109148
ISSN: 1558-1349
CID: 4621032

Surgical management of brain metastases

Kellner, Christopher P; D'Ambrosio, Anthony L
In the past 20 years, surgical resection has found an established role in the management of metastatic brain tumors. Several factors, however, make strong evidence-based medicine impossible to provide for all possible patient presentations. These important factors, such as patient variables (eg, age, medical comorbidities, preoperative performance), tumor variables (eg, number, size, location, histology), and primary disease status must be taken into account on a case-by-case basis to guide patient selection and treatment strategy. Although progress has been made to answer some of the major questions in the management of metastatic brain tumors, several important questions remain. Future studies comparing surgery with stereotactic radiosurgery, for example, are needed to delineate patient selection, complications, and outcome for both of these important modalities.
PMID: 21109149
ISSN: 1558-1349
CID: 4621042

Simulation in neurosurgery: a review of computer-based simulation environments and their surgical applications

Malone, Hani R; Syed, Omar N; Downes, Michael S; D'Ambrosio, Anthony L; Quest, Donald O; Kaiser, Michael G
BACKGROUND:Computer-based surgical simulators create a no-risk virtual environment where surgeons can develop and refine skills through harmless repetition. These applications may be of particular benefit to neurosurgeons, as the vulnerability of nervous tissue limits the margin for error. The rapid progression of computer-processing capabilities in recent years has led to the development of more sophisticated and realistic neurosurgery simulators. OBJECTIVE:To catalogue the most salient of these advances and characterize our current effort to create a spine surgery simulator. METHODS:An extensive search of the databases Ovid-MEDLINE, PubMed, and Google Scholar was conducted. Search terms included, but were not limited to: neurosurgery combined with simulation, virtual reality, haptics, and 3-dimensional imaging. RESULTS:A survey of the literature reveals that surgical simulators are evolving from platforms used for preoperative planning and anatomic education into programs that aim to simulate essential components of key neurosurgical procedures. This evolution is predicated upon the advancement of 3 main components of simulation: graphics/volume rendering, model behavior/tissue deformation, and haptic feedback. CONCLUSION/CONCLUSIONS:The computational burden created by the integration of these complex components often limits the fluidity of real-time interactive simulators. Although haptic interfaces have become increasingly sophisticated, the production of realistic tactile sensory feedback remains a formidable and costly challenge. The rate of future progress may be contingent upon international collaboration between research groups and the establishment of common simulation platforms. Given current limitations, the most potential for growth lies in the innovative design of models that expand the procedural applications of neurosurgery simulation environments.
PMID: 20881575
ISSN: 1524-4040
CID: 4621012

Approaches to anterior and anterolateral foramen magnum lesions: A critical review

Komotar, Ricardo J; Zacharia, Brad E; McGovern, Robert A; Sisti, Michael B; Bruce, Jeffrey N; D'Ambrosio, Anthony L
Foramen magnum (FM) lesions represent some of the most complex cases for the modern neurosurgeon because of their location near vital brainstem structures, the vertebral arteries, and lower cranial nerves. In particular, anterior or anterolaterally located FM tumors have traditionally been most difficult to resect with high morbidity and mortality resulting from approaches through the posterior midline or transorally. For many neurosurgeons, the far lateral, extreme lateral approach, and more recently, endoscopic endonasal approaches have become the preferred modern methods for the resection of anterior or anterolateral FM tumors. In this review, we examine both operative and non-operative approaches to FM tumors, including surgical anatomy, surgical technique, and indications for operative intervention in these complex cases. In addition, we compared outcomes from prior series.
PMCID:3075834
PMID: 21572629
ISSN: 0976-9285
CID: 4621052