David A Reardon

Brigham and Women's Hospital, Boston, Massachusetts, United States

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Publications (330)

  • [Show abstract] [Hide abstract] ABSTRACT: Background High-grade gliomas with mutations in the isocitrate dehydrogenase (IDH) gene family confer longer overall survival relative to their IDH-wild-type counterparts. Accurate determination of the IDH genotype preoperatively may have both prognostic and diagnostic value. The current study used a machine-learning algorithm to generate a model predictive of IDH genotype in high-grade gliomas based on clinical variables and multimodal features extracted from conventional MRI. Methods Preoperative MRIs were obtained for 120 patients with primary grades III (n = 35) and IV (n = 85) glioma in this retrospective study. IDH genotype was confirmed for grade III (32/35, 91%) and IV (22/85, 26%) tumors by immunohistochemistry, spectrometry-based mutation genotyping (OncoMap), or multiplex exome sequencing (OncoPanel). IDH1 and IDH2 mutations were mutually exclusive, and all mutated tumors were collapsed into one IDH-mutated cohort. Cases were randomly assigned to either the training (n = 90) or validation cohort (n = 30). A total of 2970 imaging features were extracted from pre- and postcontrast T1-weighted, T2-weighted, and apparent diffusion coefficient map. Using a random forest algorithm, nonredundant features were integrated with clinical data to generate a model predictive of IDH genotype. Results Our model achieved accuracies of 86% (area under the curve [AUC] = 0.8830) in the training cohort and 89% (AUC = 0.9231) in the validation cohort. Features with the highest predictive value included patient age as well as parametric intensity, texture, and shape features. Conclusion Using a machine-learning algorithm, we achieved accurate prediction of IDH genotype in high-grade gliomas with preoperative clinical and MRI features.
    Article · Jun 2016 · Neuro-Oncology
  • Sylvia C Eisele · David A Reardon
    [Show abstract] [Hide abstract] ABSTRACT: Brainstem gliomas in adults are a rare and heterogeneous group of brain tumors that vary with regard to underlying pathology, radiographic appearance, clinical course and prognosis. Diffuse intrinsic pontine gliomas represent the most common subtype. Although still considered aggressive and most often lethal, these brain tumors are associated with a more insidious clinical course and more favorable prognosis compared to the highly aggressive form in children. Treatment options for patients with brainstem gliomas still are limited and insufficiently studied. A better understanding of the pathobiology of these tumors will be crucial for the development of more specific and effective therapies. Cancer 2016. © 2016 American Cancer Society.
    Article · Jun 2016 · Cancer
  • Article · Jun 2016 · Journal of Clinical Oncology
  • [Show abstract] [Hide abstract] ABSTRACT: Background. Fatigue is common among glioma patients undergoing radiotherapy (RT) and impacts quality of life (QOL). We evaluated whether armodafinil, a wakefulness-promoting medication, improves fatigue in glioma patients undergoing RT. Methods. Eligibility criteria included age >= 18 years, Karnofsky performance status >= 60, and grade 2-4 glioma undergoing RT to a total dose of 50-60 Gy. Patients were randomized 1:1 to armodafinil or placebo for 8 weeks beginning within 10 days of starting RT. Fatigue and QOL were assessed at baseline, day 22, day 43, and day 56 with the Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F), the Functional Assessment of Cancer Therapy - General (FACT-G), the Brief Fatigue Inventory (BFI), and the Cancer Fatigue Scale (CFS). The primary aim was to detect a difference in the 42-day change in FACIT-F fatigue subscale between the 2 groups using a 2-sample Wilcoxon statistic. Results. We enrolled 81 patients total (42 armodafinil and 39 placebo). Armodafinil did not significantly improve fatigue or QOL based on the 42-day change in FACIT-F fatigue subscale, FACT-G, CFS, or BFI. Further analysis suggests no difference between the arms even after accounting for the potential bias of missing data. Treatment was well tolerated with few grade 3 or 4 toxicities. Conclusions. While treatment was well-tolerated, an 8-week course of armodafinil did not improve fatigue or QOL in glioma patients undergoing RT in this pilot study. Further studies are needed to determine whether pharmacologic treatment improves fatigue in glioma patients undergoing RT.
    Article · Jun 2016 · Neuro-Oncology
  • [Show abstract] [Hide abstract] ABSTRACT: Meningiomas are increasingly appreciated to share similar features with other intra-axial central nervous system neoplasms as well as systemic cancers. Immune checkpoint inhibition has emerged as a promising therapy in a number of cancers, with durable responses of years in a subset of patients. Several lines of evidence support a role for immune-based therapeutic strategies in the management of meningiomas, especially high-grade subtypes. Meningiomas frequently originate juxtaposed to venous sinuses, where an anatomic conduit for lymphatic drainage resides. Multiple populations of immune cells have been observed in meningiomas. PD-1/PD-L1 mediated immunosuppression has been implicated in high-grade meningiomas, with association between PD-L1 expression with negative prognostic outcome. These data point to the promise of future combinatorial therapeutic strategies in meningioma.
    Article · Jun 2016 · Immunotherapy
  • [Show abstract] [Hide abstract] ABSTRACT: Pituitary spindle cell oncocytoma (SCO) is an uncommon primary pituitary neoplasm that presents with mass effect on adjacent neurovascular structures, similar to non-hormone-producing pituitary adenomas. To determine the molecular etiology of SCO, we performed exome sequencing on four SCO cases, with matched normal controls, to assess somatic mutations and copy number alterations. Our analysis revealed a low mutation rate and a copy-neutral profile, consistent with the low-grade nature of this tumor. However, we identified a co-occurring somatic HRAS (p.Q61R) activating point mutation and MEN1 frameshift mutation (p.L117fs) present in a primary and recurrent tumor from one patient. Other SCOs demonstrated mutations in SND1 and FAT1, which are associated with MAPK pathway activation. Immunohistochemistry across the SCO cohort demonstrated robust MAPK activity in all cases (n=4), as evidenced by strong phospho-ERK staining, while phospho-AKT levels suggested only basal levels of PI3K pathway activation. Taken together, this identifies the MAPK signaling pathway as a novel therapeutic target for spindle cell oncocytoma, which may offer a powerful adjunct for aggressive tumors refractory to surgical resection.
    Article · May 2016 · Oncotarget
  • Ken Chang · Biqi Zhang · Xiaotao Guo · [...] · Raymond Y. Huang
    [Show abstract] [Hide abstract] ABSTRACT: Background Bevacizumab is a humanized antibody against vascular endothelial growth factor approved for treatment of recurrent glioblastoma. There is a need to discover imaging biomarkers that can aid in the selection of patients who will likely derive the most survival benefit from bevacizumab. Methods The aim of the study was to examine if pre- and posttherapy multimodal MRI features could predict progression-free survival and overall survival (OS) for patients with recurrent glioblastoma treated with bevacizumab. The patient population included 84 patients in a training cohort and 42 patients in a testing cohort, separated based on pretherapy imaging date. Tumor volumes of interest were segmented from contrast-enhanced T1-weighted and fluid attenuated inversion recovery images and were used to derive volumetric, shape, texture, parametric, and histogram features. A total of 2293 pretherapy and 9811 posttherapy features were used to generate the model. Results Using standard radiographic assessment criteria, the hazard ratio for predicting OS was 3.38 (P < .001). The hazard ratios for pre- and posttherapy features predicting OS were 5.10 (P < .001) and 3.64 (P < .005) for the training and testing cohorts, respectively. Conclusion With the use of machine learning techniques to analyze imaging features derived from pre- and posttherapy multimodal MRI, we were able to develop a predictive model for patient OS that could potentially assist clinical decision making.
    Article · May 2016 · Neuro-Oncology
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    Full-text Article · Mar 2016 · Practical Radiation Oncology
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    [Show abstract] [Hide abstract] ABSTRACT: Purpose: To present evidence-based guidelines for radiation therapy in treating glioblastoma not arising from the brainstem. Methods and materials: The American Society for Radiation Oncology (ASTRO) convened the Glioblastoma Guideline Panel to perform a systematic literature review investigating the following: (1) Is radiation therapy indicated after biopsy/resection of glioblastoma and how does systemic therapy modify its effects? (2) What is the optimal dose-fractionation schedule for external beam radiation therapy after biopsy/resection of glioblastoma and how might treatment vary based on pretreatment characteristics such as age or performance status? (3) What are ideal target volumes for curative-intent external beam radiation therapy of glioblastoma? (4) What is the role of reirradiation among glioblastoma patients whose disease recurs following completion of standard first-line therapy? Guideline recommendations were created using predefined consensus-building methodology supported by ASTRO-approved tools for grading evidence quality and recommendation strength. Results: Following biopsy or resection, glioblastoma patients with reasonable performance status up to 70 years of age should receive conventionally fractionated radiation therapy (eg, 60 Gy in 2-Gy fractions) with concurrent and adjuvant temozolomide. Routine addition of bevacizumab to this regimen is not recommended. Elderly patients (≥70 years of age) with reasonable performance status should receive hypofractionated radiation therapy (eg, 40 Gy in 2.66-Gy fractions); preliminary evidence may support adding concurrent and adjuvant temozolomide to this regimen. Partial brain irradiation is the standard paradigm for radiation delivery. A variety of acceptable strategies exist for target volume definition, generally involving 2 phases (primary and boost volumes) or 1 phase (single volume). For recurrent glioblastoma, focal reirradiation can be considered in younger patients with good performance status. Conclusions: Radiation therapy occupies an integral role in treating glioblastoma. Whether and how radiation therapy should be applied depends on characteristics specific to tumor and patient, including age and performance status.
    Full-text Article · Mar 2016 · Practical Radiation Oncology
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    [Show abstract] [Hide abstract] ABSTRACT: Background: Meningiomas are the most common primary intracranial tumor in adults. Identification of SMO and AKT1 mutations in meningiomas has raised the possibility of targeted therapies for some patients. The frequency of such mutations in clinical cohorts and the presence of other actionable mutations in meningiomas are important to define. Methods: We used high-resolution array-comparative genomic hybridization to prospectively characterize copy-number changes in 150 meningiomas and then characterized these samples for mutations in AKT1, KLF4, NF2, PIK3CA, SMO, and TRAF7. Results: Similar to prior reports, we identified AKT1 and SMO mutations in a subset of non-NF2-mutant meningiomas (ie, ∼9% and ∼6%, respectively). Notably, we detected oncogenic mutations in PIK3CA in ∼7% of non-NF2-mutant meningiomas. AKT1, SMO, and PIK3CA mutations were mutually exclusive. AKT1, KLF4, and PIK3CA mutations often co-occurred with mutations in TRAF7. PIK3CA-mutant meningiomas showed limited chromosomal instability and were enriched in the skull base. Conclusion: This work identifies PI3K signaling as an important target for precision medicine trials in meningioma patients.
    Full-text Article · Jan 2016 · Neuro-Oncology
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    [Show abstract] [Hide abstract] ABSTRACT: Purpose: Symptomatic epilepsy is a common complication of glioblastoma and requires pharmacotherapy. Several uncontrolled retrospective case series and a post hoc analysis of the registration trial for temozolomide indicated an association between valproic acid (VPA) use and improved survival outcomes in patients with newly diagnosed glioblastoma. Patients and methods: To confirm the hypothesis suggested above, a combined analysis of survival association of antiepileptic drug use at the start of chemoradiotherapy with temozolomide was performed in the pooled patient cohort (n = 1,869) of four contemporary randomized clinical trials in newly diagnosed glioblastoma: AVAGlio (Avastin in Glioblastoma; NCT00943826), CENTRIC (Cilengitide, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma and Methylated Gene Promoter Status; NCT00689221), CORE (Cilengitide, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma and Unmethylated Gene Promoter Status; NCT00813943), and Radiation Therapy Oncology Group 0825 (NCT00884741). Progression-free survival (PFS) and overall survival (OS) were compared between: (1) any VPA use and no VPA use at baseline or (2) VPA use both at start of and still after chemoradiotherapy. Results of Cox regression models stratified by trial and adjusted for baseline prognostic factors were analyzed. The same analyses were performed with levetiracetam (LEV). Results: VPA use at start of chemoradiotherapy was not associated with improved PFS or OS compared with all other patients pooled (PFS: hazard ratio [HR], 0.91; 95% CI, 0.77 to 1.07; P = .241; OS: HR, 0.96; 95% CI, 0.80 to 1.15; P = .633). Furthermore, PFS and OS of patients taking VPA both at start of and still after chemoradiotherapy were not different from those without antiepileptic drug use at both time points (PFS: HR, 0.92; 95% CI, 0.74 to 1.15; P = .467; OS: HR, 1.10; 95% CI, 0.86 to 1.40; P = .440). Similarly, no association with improved outcomes was observed for LEV use. Conclusion: The results of this analysis do not justify the use of VPA or LEV for reasons other than seizure control in patients with newly diagnosed glioblastoma outside clinical trials.
    Full-text Article · Jan 2016 · Journal of Clinical Oncology
  • Patrick Y Wen · David A Reardon
    Article · Jan 2016 · Nature Reviews Neurology
  • Riccardo Soffietti · Roberta Rudà · David Reardon
    [Show abstract] [Hide abstract] ABSTRACT: This chapter describes the epidemiology, pathology, molecular characteristics, clinical and neuroimaging features, treatment, outcome, and prognostic factors of the rare glial tumors. This category includes subependymal giant cell astrocytoma, pleomorphic xanthoastrocytoma, astroblastoma, chordoid glioma of the third ventricle, angiocentric glioma, ganglioglioma, desmoplastic infantile astrocytoma and ganglioma, dysembryoplastic neuroepithelial tumor, papillary glioneuronal tumor, and rosette-forming glioneuronal tumor of the fourth ventricle.Many of these tumors, in particular glioneuronal tumors, prevail in children and young adults, are characterized by pharmacoresistant seizures, and have an indolent course, and long survival following surgical resection. Radiotherapy and chemotherapy are reserved for recurrent and/or aggressive forms. New molecular alterations are increasingly recognized.
    Chapter · Jan 2016
  • David A. Reardon · Jorg Dietrich · Thomas Kaley · [...] · Ralph Venhaus
    Article · Jan 2016 · Cancer Immunology Research
  • Conference Paper · Dec 2015
  • [Show abstract] [Hide abstract] ABSTRACT: Background: Cabozantinib inhibits mesenchymal-epithelial transition factor (MET) and vascular endothelial growth factor receptor 2 (VEGFR2) and has demonstrated activity in patients with recurrent glioblastoma, warranting evaluation of the addition of cabozantinib to radiotherapy (RT) and temozolomide (TMZ) for patients with newly diagnosed high-grade glioma. Methods: Cabozantinib doses of 40 mg and 60 mg were explored. Patients on the concurrent treatment arm received cabozantinib daily with standard TMZ and after RT continued cabozantinib daily with adjuvant TMZ. In the maintenance arm, patients who completed RT and ≥1 adjuvant cycle of TMZ continued adjuvant TMZ with added cabozantinib (3 schedules: days 1-28, days 1-14, or days 8-21). Results: A total of 26 patients (25 with recurrent glioblastoma and 1 patient with anaplastic astrocytoma) aged 30 to 72 years were enrolled (10 to the concurrent arm and 16 to the maintenance arm). The median number of post-RT TMZ cycles was 4.5 (range, 0-14 cycles) in the concurrent arm and 5.5 (range, 1-12 cycles) in the maintenance arm. Cabozantinib at a dose of 60 mg daily was the maximum administered dose and a dose of 40 mg daily was determined to be the maximum tolerated dose for both treatment arms (schedule of days 1-28). The most frequent grade 3/4 adverse events were thrombocytopenia (31% of patients), leukopenia (27% of patients, including 5 patients with neutropenia), and deep vein thrombosis and/or pulmonary embolism (23% of patients) (adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 3.0]). Conclusions: Cabozantinib at a dose of 40 mg daily with RT plus TMZ and post-RT TMZ for patients with newly diagnosed high-grade glioma was generally well tolerated, and demonstrated no pharmacokinetic interactions with concurrent TMZ. Given the strong theoretical rationale for combining anti-VEGF and anti-MET activity with standard therapy, cabozantinib at a dose of 40 mg daily warrants evaluation in combination with standard therapy for patients with newly diagnosed glioblastoma. Cancer 2015. © 2015 American Cancer Society.
    Article · Nov 2015 · Cancer
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    David A Reardon · Prafulla C Gokhale · Sarah R Klein · [...] · Gordon J Freeman
    [Show abstract] [Hide abstract] ABSTRACT: Inhibition of immune checkpoints including cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1) and its ligand PD-L1 has demonstrated exciting and durable remissions across a spectrum of malignancies. Combinatorial regimens blocking complementary immune checkpoints further enhance the therapeutic benefit. The activity of these agents for patients with glioblastoma, a generally lethal primary brain tumor associated with significant systemic and microenvironmental immunosuppression, is not known. We therefore systematically evaluated the anti-tumor efficacy of murine antibodies targeting a broad panel of immune checkpoint molecules including CTLA-4, PD-1, PD-L1, and PD-L2 when administered as single agent therapy and in combinatorial regimens against an orthotopic, immunocompetent murine glioblastoma model. In these experiments, we observed long-term tumor-free survival following single agent anti-PD-1, anti-PD-L1, or anti-CTLA-4 therapy in 50%, 20%, and 15% of treated animals, respectively. Combination therapy of anti-CTLA-4 plus anti-PD-1 cured 75% of the animals, even against advanced, later stage tumors. In long-term survivors, tumor growth was not seen upon intracranial tumor re-challenge, suggesting that tumor-specific immune memory responses were generated. Inhibitory immune checkpoint blockade quantitatively increased activated CD8+ and NK cells, and decreased suppressive immune cells in the tumor microenvironment and draining cervical lymph nodes. Our results support prioritizing the clinical evaluation of PD-1, PD-L1, and CTLA-4 single agent targeted therapy as well as combination therapy of CTLA-4 plus PD-1 blockade for patients with glioblastoma.
    Full-text Article · Nov 2015 · Cancer Immunology Research
  • A. Omuro · J. Baehring · S. Sahebjam · [...] · D. A. Reardon
    Article · Nov 2015 · Neuro-Oncology
  • S. Sahebjam · A. Omuro · J. Baehring · [...] · D. A. Reardon
    Article · Nov 2015 · Neuro-Oncology
  • L. Nayak · A. Brandes · A. Omuro · [...] · D. Reardon
    Article · Nov 2015 · Neuro-Oncology

Publication Stats

13k Citations

Institutions

  • 2015
    • Brigham and Women's Hospital
      Boston, Massachusetts, United States
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2002-2015
    • Duke University
      Durham, North Carolina, United States
    • Duke University Medical Center
      • Department of Surgery
      Durham, NC, United States
  • 2013
    • University of Alabama at Birmingham
      Birmingham, Alabama, United States
  • 2010
    • University of Texas MD Anderson Cancer Center
      Houston, Texas, United States