86 results on '"Elizabeth R Gerstner"'
Search Results
2. Tandem chimeric antigen receptor (CAR) T cells targeting EGFRvIII and IL-13Rα2 are effective against heterogeneous glioblastoma
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Andrea Schmidts, Ambike A Srivastava, Rishab Ramapriyan, Stefanie R Bailey, Amanda A Bouffard, Daniel P Cahill, Bob S Carter, William T Curry, Gavin P Dunn, Matthew J Frigault, Elizabeth R Gerstner, Jack Y Ghannam, Michael C Kann, Rebecca C Larson, Mark B Leick, Brian V Nahed, Leland G Richardson, Irene Scarfò, Jing Sun, Hiroaki Wakimoto, Marcela V Maus, and Bryan D Choi
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Oncology ,Surgery ,Neurology (clinical) - Abstract
Background Chimeric antigen receptor (CAR) T cells have achieved remarkable responses in patients with hematological malignancies; however, the potential of this therapeutic platform for solid tumors like glioblastoma (GBM) has been limited, due in large part to the targeting of single antigens in a heterogeneous disease. Strategies that allow CAR T cells to engage multiple antigens concomitantly may broaden therapeutic responses and mitigate the effects of immune escape. Methods Here we have developed a novel, dual-specific, tandem CAR T (TanCART) cell with the ability to simultaneously target both EGFRvIII and IL-13Rα2, two well-characterized tumor antigens that are frequently found on the surface of GBM cells but completely absent from normal brain tissues. We employed both standard immunological assays and multiple orthotopic preclinical models including patient-derived xenograft to demonstrate efficacy of this approach against heterogeneous tumors. Results Tandem CAR T cells displayed enhanced cytotoxicity in vitro against heterogeneous GBM populations, including patient-derived brain tumor cultures (P < .05). Compared to CAR T cells targeting single antigens, dual antigen engagement through the tandem construct was necessary to achieve long-term, complete, and durable responses in orthotopic murine models of heterogeneous GBM, including patient-derived xenografts (P < .05). Conclusions We demonstrate that TanCART is effective against heterogeneous tumors in the brain. These data lend further credence to the development of multi-specific CAR T cells in the treatment of GBM and other cancers.
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- 2022
3. SNO and EANO practice guideline update: Anticonvulsant prophylaxis in patients with newly diagnosed brain tumors
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Merry Chen, Patrick Y. Wen, David Schiff, Padmaja Kandula, Tobias Walbert, Elizabeth R. Gerstner, Wolfgang Wick, Edward K. Avila, Jong Woo Lee, Emilie Le Rhun, Rebecca Harrison, Michael Weller, Michael A. Vogelbaum, Glen Stevens, University of Zurich, INSERM, Université de Lille, Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM) - U 1192 (PRISM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)
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Cancer Research ,Pediatrics ,medicine.medical_specialty ,Neurology ,seizure ,[SDV]Life Sciences [q-bio] ,medicine.medical_treatment ,Brain tumor ,610 Medicine & health ,Guidelines ,GBM ,10180 Clinic for Neurosurgery ,antiepileptic drug ,glioma ,Glioma ,medicine ,Valproic Acid ,guideline ,business.industry ,Guideline ,medicine.disease ,10040 Clinic for Neurology ,Anticonvulsant ,Systematic review ,Oncology ,Neurology (clinical) ,Levetiracetam ,business ,medicine.drug - Abstract
Objective To update the 2000 American Academy of Neurology (AAN) practice parameter on anticonvulsant prophylaxis in patients with newly diagnosed brain tumors. Methods Following the 2017 AAN methodologies, a systematic literature review utilizing PubMed, EMBASE Library, Cochrane, and Web of Science databases was performed. The studies were rated based on the AAN therapeutic or causation classification of evidence (class I-IV). Results Thirty-seven articles were selected for final analysis. There were limited high-level, class I studies and mostly class II and III studies. The AAN affirmed the value of these guidelines. Recommendations In patients with newly diagnosed brain tumors who have not had a seizure, clinicians should not prescribe antiepileptic drugs (AEDs) to reduce the risk of seizures (level A). In brain tumor patients undergoing surgery, there is insufficient evidence to recommend prescribing AEDs to reduce the risk of seizures in the peri- or postoperative period (level C). There is insufficient evidence to support prescribing valproic acid or levetiracetam with the intent to prolong progression-free or overall survival (level C). Physicians may consider the use of levetiracetam over older AEDs to reduce side effects (level C). There is insufficient evidence to support using tumor location, histology, grade, molecular/imaging features when deciding whether or not to prescribe prophylactic AEDs (level U).
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- 2021
4. Hypothetical generalized framework for a new imaging endpoint of therapeutic activity in early phase clinical trials in brain tumors
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Benjamin M Ellingson, Elizabeth R Gerstner, Andrew B Lassman, Caroline Chung, Howard Colman, Patricia E Cole, David Leung, Joshua E Allen, Manmeet S Ahluwalia, Jerrold Boxerman, Matthew Brown, Jonathan Goldin, Edjah Nduom, Islam Hassan, Mark R Gilbert, Ingo K Mellinghoff, Michael Weller, Susan Chang, David Arons, Clair Meehan, Wendy Selig, Kirk Tanner, W K Alfred Yung, Martin van den Bent, Patrick Y Wen, Timothy F Cloughesy, and Neurology
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Diagnostic Imaging ,Cancer Research ,Clinical Trials and Supportive Activities ,Oncology and Carcinogenesis ,Review ,Rare Diseases ,SDG 3 - Good Health and Well-being ,Clinical Research ,Humans ,Oncology & Carcinogenesis ,Cancer ,response assessment ,clinical trials ,screening and diagnosis ,Clinical Trials as Topic ,Brain Neoplasms ,Neurosciences ,growth rates ,Brain Disorders ,Brain Cancer ,Detection ,Treatment Outcome ,Oncology ,Neurological ,brain tumors ,Biomedical Imaging ,Neurology (clinical) ,4.2 Evaluation of markers and technologies - Abstract
Imaging response assessment is a cornerstone of patient care and drug development in oncology. Clinicians/clinical researchers rely on tumor imaging to estimate the impact of new treatments and guide decision making for patients and candidate therapies. This is important in brain cancer, where associations between tumor size/growth and emerging neurological deficits are strong. Accurately measuring the impact of a new therapy on tumor growth early in clinical development, where patient numbers are small, would be valuable for decision making regarding late-stage development activation. Current attempts to measure the impact of a new therapy have limited influence on clinical development, as determination of progression, stability or response does not currently account for individual tumor growth kinetics prior to the initiation of experimental therapies. Therefore, we posit that imaging-based response assessment, often used as a tool for estimating clinical effect, is incomplete as it does not adequately account for growth trajectories or biological characteristics of tumors prior to the introduction of an investigational agent. Here, we propose modifications to the existing framework for evaluating imaging assessment in primary brain tumors that will provide a more reliable understanding of treatment effects. Measuring tumor growth trajectories prior to a given intervention may allow us to more confidently conclude whether there is an anti-tumor effect. This updated approach to imaging-based tumor response assessment is intended to improve our ability to select candidate therapies for later-stage development, including those that may not meet currently sought thresholds for “response” and ultimately lead to identification of effective treatments.
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- 2022
5. Radiographic read paradigms and the roles of the central imaging laboratory in neuro-oncology clinical trials
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Elizabeth R. Gerstner, Jonathan G. Goldin, Timothy F. Cloughesy, Amy Barone, Jeffrey A. Bacha, W. K. Alfred Yung, David Leung, Patricia E Cole, Matthew S. Brown, Benjamin M. Ellingson, Martin J. van den Bent, Patrick Y. Wen, Howard Colman, Timothy J. Kaufmann, Jerrold L. Boxerman, and Neurology
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Diagnostic Imaging ,Cancer Research ,medicine.medical_specialty ,RANO ,Imaging Charter ,Clinical Trials and Supportive Activities ,Oncology and Carcinogenesis ,MEDLINE ,Image registration ,Reviews ,03 medical and health sciences ,0302 clinical medicine ,SDG 3 - Good Health and Well-being ,Clinical Research ,Medical imaging ,medicine ,Humans ,Medical physics ,Oncology & Carcinogenesis ,Cancer ,clinical trials ,Operationalization ,Surrogate endpoint ,business.industry ,Brain Neoplasms ,Neurosciences ,Charter ,Review article ,Brain Disorders ,Clinical trial ,Oncology ,030220 oncology & carcinogenesis ,Biomedical Imaging ,Neurology (clinical) ,imaging endpoints ,business ,Laboratories ,neuro-oncology ,030217 neurology & neurosurgery - Abstract
Determination of therapeutic benefit in intracranial tumors is intimately dependent on serial assessment of radiographic images. The Response Assessment in Neuro-Oncology (RANO) criteria were established in 2010 to provide an updated framework to better characterize tumor response to contemporary treatments. Since this initial update a number of RANO criteria have provided some basic principles for the interpretation of changes on MR images; however, the details of how to operationalize RANO and other criteria for use in clinical trials are ambiguous and not standardized. In this review article designed for the neuro-oncologist or treating clinician, we outline essential steps for performing radiographic assessments by highlighting primary features of the Imaging Charter (referred to as the Charter for the remainder of this article), a document that describes the clinical trial imaging methodology and methods to ensure operationalization of the Charter into the workings of a clinical trial. Lastly, we provide recommendations for specific changes to optimize this methodology for neuro-oncology, including image registration, requirement of growing tumor for eligibility in trials of recurrent tumor, standardized image acquisition guidelines, and hybrid reader paradigms that allow for both unbiased measurements and more comprehensive interpretation.
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- 2021
6. A phase II study of dose-dense temozolomide and lapatinib for recurrent low-grade and anaplastic supratentorial, infratentorial, and spinal cord ependymoma
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Jimin Wu, Elizabeth Vera, Kenneth Aldape, Elizabeth R. Gerstner, Patrick Y. Wen, Jing Wu, Terri S. Armstrong, Tito R. Mendoza, Tom Mikkelsen, Mark R. Gilbert, Ying Yuan, Antonio Omuro, H. Ian Robins, and Frank S. Lieberman
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Adult ,Ependymoma ,Oncology ,Cancer Research ,medicine.medical_specialty ,Adolescent ,Population ,Clinical Investigations ,Lapatinib ,Disease-Free Survival ,Internal medicine ,Temozolomide ,medicine ,Humans ,Prospective Studies ,Spinal Cord Neoplasms ,Progression-free survival ,education ,MD Anderson Symptom Inventory - Brain Tumor ,education.field_of_study ,Brain Neoplasms ,business.industry ,Spinal Cord Ependymoma ,Combination chemotherapy ,medicine.disease ,Dacarbazine ,Neurology (clinical) ,business ,medicine.drug - Abstract
Background No standard medical treatment exists for adult patients with recurrent ependymoma, and prospective clinical trials in this population have not succeeded because of its rarity and challenges in accruing patients. The Collaborative Ependymoma Research Network conducted a prospective phase II clinical trial of dose-dense temozolomide (TMZ) and lapatinib, targeting the unmethylated O6-methylguanine-DNA methyltransferase (MGMT) promoter status and increased expression of ErbB2 (human epidermal growth factor receptor 2) and ErbB1 (epidermal growth factor receptor) in ependymomas. Methods Patients age 18 or older with histologically proven and progressive ependymoma or anaplastic ependymoma were eligible and received dose-dense TMZ and daily lapatinib. The primary outcome measure was median progression-free survival (PFS). Landmark 6- and 12-month PFS and objective response were measured. Serial assessments of symptom burden using the MD Anderson Symptom Inventory Brain Tumor (MDASI-BT)/MDASI–Spine Tumor modules were collected. Results The 50 patients enrolled had a median age of 43.5 years, median Karnofsky performance status of 90, and a median of 2 prior relapses. Twenty patients had grade III, 16 grade II, and 8 grade I ependymoma. Half had spinal cord tumors; 15 had a supratentorial tumor, 8 infratentorial, and 2 had disseminated disease. Treatment was well tolerated. The median PFS was 7.8 months (95% CI: 5.5,12.2); the 6- and 12-month PFS rates were 55% and 38%, with 2 complete and 6 partial responses. Measures of symptom burden showed reduction in moderate-severe pain and other disease-related symptoms in most patients. Conclusions This treatment, with demonstrated clinical activity with objective responses and prolonged disease control associated with disease-related symptom improvements, is an option as a salvage regimen for adult patients with recurrent ependymoma.
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- 2020
7. Regional healthy brain activity, glioma occurrence and symptomatology
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Tianne Numan, Lucas C Breedt, Bernardo de A P C Maciel, Shanna D Kulik, Jolanda Derks, Menno M Schoonheim, Martin Klein, Philip C de Witt Hamer, Julie J Miller, Elizabeth R Gerstner, Steven M Stufflebeam, Arjan Hillebrand, Cornelis J Stam, Jeroen J G Geurts, Jaap C Reijneveld, Linda Douw, Anatomy and neurosciences, Amsterdam Neuroscience - Brain Imaging, Amsterdam Neuroscience - Neuroinfection & -inflammation, Medical psychology, Neurosurgery, Amsterdam Neuroscience - Systems & Network Neuroscience, CCA - Cancer biology and immunology, CCA - Imaging and biomarkers, Neurology, Amsterdam Neuroscience - Neurodegeneration, and CCA - Cancer Treatment and quality of life
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Cross-Sectional Studies ,Brain Neoplasms ,Mutation ,Humans ,Brain ,Glioma ,Neurology (clinical) ,Isocitrate Dehydrogenase - Abstract
It is unclear why exactly gliomas show preferential occurrence in certain brain areas. Increased spiking activity around gliomas leads to faster tumour growth in animal models, while higher non-invasively measured brain activity is related to shorter survival in patients. However, it is unknown how regional intrinsic brain activity, as measured in healthy controls, relates to glioma occurrence. We first investigated whether gliomas occur more frequently in regions with intrinsically higher brain activity. Second, we explored whether intrinsic cortical activity at individual patients’ tumour locations relates to tumour and patient characteristics. Across three cross-sectional cohorts, 413 patients were included. Individual tumour masks were created. Intrinsic regional brain activity was assessed through resting-state magnetoencephalography acquired in healthy controls and source-localized to 210 cortical brain regions. Brain activity was operationalized as: (i) broadband power; and (ii) offset of the aperiodic component of the power spectrum, which both reflect neuronal spiking of the underlying neuronal population. We additionally assessed (iii) the slope of the aperiodic component of the power spectrum, which is thought to reflect the neuronal excitation/inhibition ratio. First, correlation coefficients were calculated between group-level regional glioma occurrence, as obtained by concatenating tumour masks across patients, and group-averaged regional intrinsic brain activity. Second, intrinsic brain activity at specific tumour locations was calculated by overlaying patients’ individual tumour masks with regional intrinsic brain activity of the controls and was associated with tumour and patient characteristics. As proposed, glioma preferentially occurred in brain regions characterized by higher intrinsic brain activity in controls as reflected by higher offset. Second, intrinsic brain activity at patients’ individual tumour locations differed according to glioma subtype and performance status: the most malignant isocitrate dehydrogenase-wild-type glioblastoma patients had the lowest excitation/inhibition ratio at their individual tumour locations as compared to isocitrate dehydrogenase-mutant, 1p/19q-codeleted glioma patients, while a lower excitation/inhibition ratio related to poorer Karnofsky Performance Status, particularly in codeleted glioma patients. In conclusion, gliomas more frequently occur in cortical brain regions with intrinsically higher activity levels, suggesting that more active regions are more vulnerable to glioma development. Moreover, indices of healthy, intrinsic excitation/inhibition ratio at patients’ individual tumour locations may capture both tumour biology and patients’ performance status. These findings contribute to our understanding of the complex and bidirectional relationship between normal brain functioning and glioma growth, which is at the core of the relatively new field of ‘cancer neuroscience’.
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- 2022
8. Volumetric analysis of IDH-mutant lower-grade glioma: a natural history study of tumor growth rates before and after treatment
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Elizabeth R. Gerstner, Susan M. Chang, Patrick Y. Wen, Benjamin M. Ellingson, Timothy F. Cloughesy, John Kim, Robert J. Young, Ingo K. Mellinghoff, Katherine B. Peters, Florent Tixier, Raymond Y. Huang, Wei Wang, Rasheed Nawaz, Tracy Luks, David Schiff, Hyemin Um, and Harini Veeraraghavan
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Adult ,Cancer Research ,medicine.medical_specialty ,IDH1 ,medicine.medical_treatment ,Clinical Investigations ,Urology ,Fluid-attenuated inversion recovery ,03 medical and health sciences ,0302 clinical medicine ,Glioma ,medicine ,Humans ,Retrospective Studies ,Chemotherapy ,Brain Neoplasms ,Surrogate endpoint ,business.industry ,medicine.disease ,Magnetic Resonance Imaging ,Chemotherapy regimen ,Isocitrate Dehydrogenase ,Radiation therapy ,Oncology ,030220 oncology & carcinogenesis ,Mutation ,Neurology (clinical) ,Neoplasm Grading ,business ,030217 neurology & neurosurgery ,Chemoradiotherapy - Abstract
Background Lower-grade gliomas (LGGs) with isocitrate dehydrogenase 1 and/or 2 (IDH1/2) mutations have long survival times, making evaluation of treatment efficacy difficult. We investigated the volumetric growth rate of IDH mutant gliomas before and after treatment with established glioma therapies to determine whether a significant change in growth rate could be documented and perhaps be used in the future to evaluate treatment response to investigational agents in LGG trials. Methods In this multicenter retrospective study, 230 adult patients with IDH1/2 mutated LGGs (World Health Organization grade II or III) undergoing surgery, radiation, or chemotherapy for progressive non-enhancing tumor were identified. Subjects were required to have 3 MRI scans containing T2/fluid attenuated inversion recovery imaging spanning a minimum of 6 months prior to treatment. A mixed-effect model was used to estimate tumor growth prior to treatment. A subset of 95 patients who received chemotherapy, radiotherapy, or chemoradiotherapy and had 2 posttreatment imaging time points available were evaluated for change in pre- and posttreatment volumetric growth rates using a piecewise mixed model. Results The pretreatment volumetric growth rate across all 230 patients was 27.37%/180 days (95% CI: [23.36%, 31.51%]). In the 95 patients with both pre- and posttreatment scans available, there was a significant difference in volumetric growth rates before (26.63%/180 days, 95% CI: [19.31%, 34.40%]) and after treatment (−15.24% /180 days, 95% CI: [−21.37%, −8.62%]) (P < 0.0001). The growth rates for patient subgroup with 1p/19q codeletion (N = 118) was significantly slower than the rate of the 1p/19q non-codeleted group (N = 68) (22.84% vs 35.49%, P = 0.0108). Conclusion In this study, we evaluated the growth rates of IDH mutant gliomas before and after standard therapy. Further study is needed to establish whether a change in growth rate is associated with patient survival and its use as a surrogate endpoint in clinical trials for IDH mutant LGGs.
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- 2020
9. Consensus recommendations for a dynamic susceptibility contrast MRI protocol for use in high-grade gliomas
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Martin J. van den Bent, Lalitha K. Shankar, Marion Smits, Wolfgang Wick, Timothy F. Cloughesy, Mark R. Gilbert, W. K. Al Yung, Jayashree Kalpathy-Cramer, Susan M. Chang, Evanthia Galanis, C. Chad Quarles, Patrick Y. Wen, Paula M. Jacobs, Raymond Huang, Elizabeth R. Gerstner, Michael Weller, Benjamin M. Ellingson, Kathleen M. Schmainda, Timothy J. Kaufmann, Jerrold L. Boxerman, Caroline Chung, Daniel P. Barboriak, Bradley J. Erickson, Bruce R. Rosen, Leland S. Hu, Radiology & Nuclear Medicine, Neurology, Department of Arts and Culture Studies, and University of Zurich
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Cancer Research ,Consensus ,Brain tumor ,Reviews ,Contrast Media ,610 Medicine & health ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,0302 clinical medicine ,Flip angle ,Glioma ,medicine ,Humans ,1306 Cancer Research ,Dosing ,medicine.diagnostic_test ,business.industry ,Brain Neoplasms ,Magnetic resonance imaging ,medicine.disease ,Magnetic Resonance Imaging ,10040 Clinic for Neurology ,Clinical trial ,Preload ,2728 Neurology (clinical) ,Oncology ,2730 Oncology ,Neurology (clinical) ,Nuclear medicine ,business ,030217 neurology & neurosurgery ,Algorithms ,Dynamic susceptibility - Abstract
Despite the widespread clinical use of dynamic susceptibility contrast (DSC) MRI, DSC-MRI methodology has not been standardized, hindering its utilization for response assessment in multicenter trials. Recently, the DSC-MRI Standardization Subcommittee of the Jumpstarting Brain Tumor Drug Development Coalition issued an updated consensus DSC-MRI protocol compatible with the standardized brain tumor imaging protocol (BTIP) for high-grade gliomas that is increasingly used in the clinical setting and is the default MRI protocol for the National Clinical Trials Network. After reviewing the basis for controversy over DSC-MRI protocols, this paper provides evidence-based best practices for clinical DSC-MRI as determined by the Committee, including pulse sequence (gradient echo vs spin echo), BTIP-compliant contrast agent dosing (preload and bolus), flip angle (FA), echo time (TE), and post-processing leakage correction. In summary, full-dose preload, full-dose bolus dosing using intermediate (60°) FA and field strength-dependent TE (40–50 ms at 1.5 T, 20–35 ms at 3 T) provides overall best accuracy and precision for cerebral blood volume estimates. When single-dose contrast agent usage is desired, no-preload, full-dose bolus dosing using low FA (30°) and field strength-dependent TE provides excellent performance, with reduced contrast agent usage and elimination of potential systematic errors introduced by variations in preload dose and incubation time.
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- 2020
10. Consensus recommendations for a standardized brain tumor imaging protocol for clinical trials in brain metastases
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Christina Tsien, Jerrold L. Boxerman, Evanthia Galanis, Terry C. Burns, Nan Lin, Caroline Chung, Michael Weller, Patrick Y. Wen, Benjamin M. Ellingson, Daniel P. Barboriak, Paul D. Brown, Ian F. Parney, Elizabeth R. Gerstner, Lalitha K. Shankar, Timothy J. Kaufmann, Raymond Y. Huang, Martin J. van den Bent, Marion Smits, Gavin P. Dunn, Priscilla K. Brastianos, Radiology & Nuclear Medicine, and Neurology
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Cancer Research ,medicine.medical_specialty ,Consensus ,Clinical Trials and Supportive Activities ,Oncology and Carcinogenesis ,Brain tumor ,Reviews ,Contrast Media ,Gadolinium ,Fluid-attenuated inversion recovery ,Tumor response ,03 medical and health sciences ,0302 clinical medicine ,Rare Diseases ,Clinical Research ,brain metastases ,medicine ,Medical imaging ,Image acquisition ,Humans ,protocol ,Oncology & Carcinogenesis ,Cancer ,Protocol (science) ,medicine.diagnostic_test ,business.industry ,Brain Neoplasms ,Neurosciences ,imaging ,Magnetic resonance imaging ,medicine.disease ,Magnetic Resonance Imaging ,Brain Disorders ,Clinical trial ,Brain Cancer ,Oncology ,030220 oncology & carcinogenesis ,Biomedical Imaging ,Neurology (clinical) ,Radiology ,business ,030217 neurology & neurosurgery ,MRI - Abstract
A recent meeting was held on March 22, 2019, among the FDA, clinical scientists, pharmaceutical and biotech companies, clinical trials cooperative groups, and patient advocacy groups to discuss challenges and potential solutions for increasing development of therapeutics for central nervous system metastases. A key issue identified at this meeting was the need for consistent tumor measurement for reliable tumor response assessment, including the first step of standardized image acquisition with an MRI protocol that could be implemented in multicenter studies aimed at testing new therapeutics. This document builds upon previous consensus recommendations for a standardized brain tumor imaging protocol (BTIP) in high-grade gliomas and defines a protocol for brain metastases (BTIP-BM) that addresses unique challenges associated with assessment of CNS metastases. The “minimum standard” recommended pulse sequences include: (i) parameter matched pre- and post-contrast inversion recovery (IR)–prepared, isotropic 3D T1-weighted gradient echo (IR-GRE); (ii) axial 2D T2-weighted turbo spin echo acquired after injection of gadolinium-based contrast agent and before post-contrast 3D T1-weighted images; (iii) axial 2D or 3D T2-weighted fluid attenuated inversion recovery; (iv) axial 2D, 3-directional diffusion-weighted images; and (v) post-contrast 2D T1-weighted spin echo images for increased lesion conspicuity. Recommended sequence parameters are provided for both 1.5T and 3T MR systems. An “ideal” protocol is also provided, which replaces IR-GRE with 3D TSE T1-weighted imaging pre- and post-gadolinium, and is best performed at 3T, for which dynamic susceptibility contrast perfusion is included. Recommended perfusion parameters are given.
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- 2020
11. CTIM-30. PHASE II TRIAL OF PEMBROLIZUMAB IN RECURRENT AND RESIDUAL HIGH-GRADE MENINGIOMAS
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Naema Nayyar, Anita Giobbie-Hurder, Deborah Forst, Daniel P. Cahill, Kevin S. Oh, Sandro Santagata, Priscilla K. Brastianos, Helen A. Shih, William T. Curry, Eudocia Q. Lee, Jay S. Loeffler, Kevin Lou, Elizabeth R. Gerstner, Nancy Wang, Isabel Arrillaga-Romany, Juliana M Larson, Fred G. Barker, Albert H. Kim, Ugonma Chukwueke, April F. Eichler, Joana L. Mora, and Jorg Dietrich
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Cancer Research ,Materials science ,Oncology ,business.industry ,Phase (matter) ,Neurology (clinical) ,Pembrolizumab ,26th Annual Meeting & Education Day of the Society for Neuro-Oncology ,Residual ,Nuclear medicine ,business - Abstract
INTRODUCTION High-grade meningiomas are associated with significant neuro-cognitive morbidity and a poor prognosis. Systemic therapies, to date, have demonstrated minimal efficacy. We recently found that high-grade meningiomas harbor an immunosuppressive tumor microenvironment and that programmed cell death-ligand 1 (PD-L1) expression may contribute to the aggressive phenotype of these tumors. Therefore, we conducted a single-arm, open-label phase II trial evaluating efficacy of pembrolizumab, a PD-1 inhibitor, in a cohort of 24 patients with recurrent and progressive grade II and III meningiomas. METHODS The primary endpoint was the rate of progression-free survival at 6 months. The trial distinguished between 6-month PFS (PFS-6) rates of 26% vs. 52%. If at least 10 patients demonstrated a 6-month PFS, among the 24 patients, the agent would be considered worthy of further study. This design has at least 88% power using an exact binomial test with a one-sided significance level of 0.1. RESULTS Between November 2017 to December 2019, twenty-four patients were enrolled. The majority of the patients in our cohort were heavily pre-treated; prior to enrolling to the study, twenty patients underwent more than one surgical resection and twelve patients had received more than one round of radiotherapy. Our study met its primary endpoint and achieved a 6-month progression-free survival rate of 0.50 (90% exact CI: 0.32-0.68) and a median PFS of 8.3 months (90% CI: 4.1-12.9 months). For the twelve patients who achieved the PFS-6 primary endpoint, median PFS from the start of treatment was 17.3 months (90% CI: 9.7 – 24.3 months). Four patients had grade-3 or higher adverse events that were at least possibly treatment-related, including colitis, skin infection, encephalopathy and transaminitis. CONCLUSION Our study achieved its primary endpoint. These results suggest that pembrolizumab exerts promising activity on these tumors and results in prolonged PFS compared to historical controls.
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- 2021
12. TAMI-29. MR SPECTROSCOPY MEASURES OF LAC/NAA AND NAA/CHO DIFFERENTIATE SURVIVORSHIP IN PATIENTS WITH RECURRENT GLIOBLASTOMA TREATED WITH ANTI-ANGIOGENIC THERAPY
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Elizabeth R. Gerstner, Bruce R. Rosen, Eva-Maria Ratai, Jorg Dietrich, Pratik Talati, Otto Rapalino, Deborah Forst, Ovidiu C. Andronesi, Sharif N Natheir, Jayashree Kalpathy-Cramer, Mark Vangel, Yi-Fen Yen, Daniel Kim, Ramon Gonzalez, Tracy T. Batchelor, Melanie Fu, Michael Wenke, Mohamed El-Abtah, Isabel Arrillaga-Romany, Julian He, and Anna Vaynrub
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In vivo magnetic resonance spectroscopy ,Cancer Research ,business.industry ,Recurrent glioblastoma ,Anti angiogenic ,26th Annual Meeting & Education Day of the Society for Neuro-Oncology ,nervous system diseases ,nervous system ,Oncology ,Survivorship curve ,mental disorders ,Cancer research ,Medicine ,In patient ,Neurology (clinical) ,business - Abstract
Patients with recurrent glioblastoma (rGBM) are often started on anti-angiogenic therapy such as bevacizumab. However, determining treatment failure using conventional MRI methods remains challenging. We prospectively collected longitudinal MR spectroscopy data in 33 patients with rGBM and quantified various metabolites including N-acetylaspartate (NAA), Choline (Cho), and Lactate (Lac). After stratifying patients by 9 month survival, we found that longer-term survivors had decreased Lac/NAA and increased NAA/Cho compared to shorter-term survivors. ROC analyses illustrated that intratumoral changes in NAA/Cho were predictive of survival at 1 day (AUC 0.92), 2 weeks (AUC 0.75), 8 weeks (AUC 0.71) and 16 weeks (AUC 0.85) but not 4 weeks (AUC 0.60). Intratumoral changes in Lac/NAA were predictive of survival at all time points tested (AUCs > 0.76 for all time points). At 8 weeks, 90% of patients with increased Lac/NAA from baseline and 88% of patients with decreased NAA/Cho did not survive 9 months. Changes in NAA/Cho and Lac/NAA may serve as early biomarkers of anti-angiogenic treatment failure.
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- 2021
13. CTIM-02. PHASE II STUDY OF IPILIMUMAB AND NIVOLUMAB IN LEPTOMENINGEAL CARCINOMATOSIS
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April F. Eichler, Daniel P. Cahill, Nancy Wang, Helen A. Shih, Brian V. Nahed, Justine Cohen, Albert H. Kim, Deborah Forst, Christopher Alvarez-Breckenridge, Maura Mahar, Ibiayi Dagogo-Jack, Michael White, Nan Lin, Kevin S. Oh, Wendy Y. Chen, Jorg Dietrich, Ryan J. Sullivan, Beth Overmoyer, Aditya Bardia, Pamela S. Jones, Matthew R. Strickland, Joana L. Mora, Ugonma Chukwueke, Dejan Juric, Naema Nayyar, Anita Giobbie-Hurder, Scott L. Carter, Priscilla K. Brastianos, Elizabeth R. Gerstner, and Eudocia Q. Lee
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Phases of clinical research ,Ipilimumab ,26th Annual Meeting & Education Day of the Society for Neuro-Oncology ,Internal medicine ,Medicine ,Neurology (clinical) ,Nivolumab ,business ,medicine.drug - Abstract
Leptomeningeal disease (LMD) is an increasingly common complication from solid tumor malignancies with a poor prognosis and limited treatment options. We conducted a single arm Phase II study of combined ipilimumab and nivolumab in patients with LMD from solid tumor malignancies (NCT02939300). Patients received manufacturer-specific dosing regimens of combined ipilimumab and nivolumab based on primary-tumor histology until definitive progression or unacceptable toxicity. The primary end point was rate of overall survival at 3 months (OS3). A Simon two-stage design was used to compare a null hypothesis OS3 of 18% against an alternative of 44%. Eighteen patients with diverse primary tumor histologies were enrolled and all received at least one dose of combined ipilimumab and nivolumab. Median follow up based on patients still alive was 8.0 months (range: 0.5 to 15.9 months). The study met its primary endpoint as 8 of 18 (OS3 0.44; 90% CI: 0.24 to 0.66) patients were alive at three months after enrollment. One third of patients experienced one (or more) grade-3 or higher adverse events possibly related to treatment. Two patients discontinued protocol treatment due to unacceptable toxicity (hepatitis and colitis, respectively). The most frequent adverse events overall included fatigue (N=7), nausea (N=6), fever (N=6), anorexia (N=6) and rash (N=6). Combined ipilimumab and nivolumab has an acceptable safety profile and demonstrates promising activity in LMD patients; this therapeutic approach should be studied in larger, multicenter clinical trials to validate these results as well as better identify patients who will benefit.
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- 2021
14. BIOM-09. MYO-INOSITOL LEVELS ON MR SPECTROSCOPY CAN PREDICT FAILURE OF ANTI-ANGIOGENIC TREATMENT IN RECURRENT GLIOBLASTOMA
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Elizabeth R. Gerstner, Pratik Talati, Ramon Gonzalez, Otto Rapalino, Ovidiu C. Andronesi, Mark Vangel, Akila Weerasekera, Eva-Maria Ratai, Julian He, Daniel Kim, Yi-Fen Yen, Anna Vaynrub, Tracy T. Batchelor, Michael Wenke, Melanie Fu, Isabel Arrillaga-Romany, Jorg Dietrich, Bruce R. Rosen, Deborah Forst, and Mohamed El-Abtah
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In vivo magnetic resonance spectroscopy ,Cancer Research ,Tumor microenvironment ,Bevacizumab ,business.industry ,Angiogenesis ,Recurrent glioblastoma ,Anti angiogenic ,26th Annual Meeting & Education Day of the Society for Neuro-Oncology ,medicine.disease ,chemistry.chemical_compound ,Oncology ,chemistry ,Cancer research ,Medicine ,Inositol ,Neurology (clinical) ,business ,medicine.drug ,Glioblastoma - Abstract
BACKGROUND Recurrent glioblastoma (rGBM) patients are often treated with anti-angiogenic agents such as bevacizumab (BEV). Despite therapeutic promise, conventional MR methods fail to determine which patients may not benefit. PURPOSE: The purpose of this study was to utilize magnetic resonance spectroscopic imaging (MRSI) with intermediate and short echo time to generate corrected Myo-inositol normalized by contralateral creatine (mI/c-Cr) in patients with rGBM treated with BEV and investigate whether it can predict survivorship prior to BEV initiation (baseline) and at 1-day, 4-weeks, and 8-weeks thereafter. METHODS We conducted a prospective, longitudinal study and evaluated spectroscopic data of myo-inositol (mI), a glial marker and osmoregulator within the brain, normalized to contralateral-creatine (mI/c-Cr) in the intratumoral, contralateral normal appearing white matter, and peritumoral volumes of rGBM patients. Area under the ROC curve (AUC) was calculated for all volumes at baseline, 1-day, 4-weeks, and 8-weeks after treatment to determine mI/c-Cr’s ability to predict survivorship. RESULTS 21 participants (62 ± 12 years, 15 men) were evaluated. Lower mI/c-Cr in the tumor prior to and during BEV treatment predicted poor survivorship, with ROC analyses illustrating an AUC of 0.75 at baseline, 0.87 at 1-day, and 1 at 8 weeks. Lower levels of mI/c-Cr were also observed in the contralateral and the peritumoral volumes for shorter-term survivors. In the contralateral volume, lower mI/Cr was predictive of shorter-term survival at baseline and all other timepoints. Within the peritumoral volume, lower mI/c-Cr was predictive of shorter-term survival at baseline (AUC=0.80), 1-day (AUC=0.93), and 4-weeks (AUC=0.68). CONCLUSIONS Lower levels of mI/c-Cr within intratumoral, contralateral, and peritumoral volumes were predictive of poor survivorship and anti-angiogenic treatment failure as early as one month before BEV treatment. Acquiring MRSI alongside conventional MR imaging modalities can convey critical information regarding tumor microenvironment that informs management of patients with rGBM.
- Published
- 2021
15. CTIM-01. PHASE II TRIAL OF PEMBROLIZUMAB AND LENVATINIB FOR LEPTOMENINGEAL METASTASES
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Daniel P. Cahill, Elizabeth R. Gerstner, Kevin S. Oh, Nancy Wang, Jennifer E Cahill, and Priscilla K. Brastianos
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Pembrolizumab ,26th Annual Meeting & Education Day of the Society for Neuro-Oncology ,chemistry.chemical_compound ,chemistry ,Internal medicine ,Phase (matter) ,medicine ,Neurology (clinical) ,Lenvatinib ,business - Abstract
Leptomeningeal metastasis (LMD) is a late complication of cancer with poor prognosis and median survival of approximately 4-6 weeks without treatment. Whole brain radiation remains the mainstay of treatment, however it can cause significant neurocognitive sequelae and has not been shown to prolong overall survival. Thus, new treatment strategies are urgently needed to improve outcomes in patients with LMD. Results from recent Phase 2 studies of immune checkpoint inhibitors in LMD shows promising improvement in overall survival. Combining anti-VEGF therapy and immunotherapy may control symptoms due to inflammation and tumor-induced irritation, minimize steroid use, and promote improved efficacy of immunotherapy through modulation of the tumor immune microenvironment. We designed a multi-institutional, single-arm Phase 2 study of pembrolizumab in combination with lenvatinib in patients with LMD from any solid tumor. The primary objective is to estimate the overall survival rate at 6 months (OS6). A Simon two-stage design with a total sample size of 19 evaluable patients will be used to compare a null hypothesis of OS6 of 25% against an alternative hypothesis of 55%. Secondary objectives include assessing safety of pembrolizumab and lenvatinib in this patient population, systemic response rate, intracranial/intraspinal response rate, and progression-free survival. We will also explore clinician-reported neurologic outcomes and patient-reported quality of life and symptom burden. Blood, cerebrospinal fluid, and tissue biomarkers will be analyzed to determine predictors of response. Patients must be on minimal doses of steroids prior to study enrollment and cannot have received prior immune checkpoint inhibitor or anti-VEGF therapy. Response to treatment will be determined using RANO-BM for intracranial disease and RECIST 1.1 for systemic disease. Study accrual is anticipated over 12-24 months with anticipated total study duration of 30 months.
- Published
- 2021
16. Volumetric measurements in low-grade glioma: Are we there yet?
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Elizabeth R Gerstner
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Cancer Research ,Oncology ,Neurology (clinical) - Published
- 2022
17. Automatic assessment of glioma burden: a deep learning algorithm for fully automated volumetric and bidimensional measurement
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Otto Rapalino, Andrew Beers, Bruce R. Rosen, Bo Xiao, Marco C. Pinho, Paul J. Zhang, Harrison X. Bai, Jerrold L. Boxerman, Yinyan Wang, Alessandro Boaro, Jayashree Kalpathy-Cramer, Ken Chang, Tracy T. Batchelor, James M. Brown, Patrick Y. Wen, Xuejun Li, Joeky T. Senders, Li Yang, Raymond Y. Huang, Weihua Liao, Hao Zhou, Elizabeth R. Gerstner, Wenya Linda Bi, Vasileios K. Kavouridis, Omar Arnaout, Chang Su, Qin Shen, and K. Ina Ly
- Subjects
G740 Computer Vision ,RANO ,Cancer Research ,Treatment response ,A300 Clinical Medicine ,Intraclass correlation ,Fluid-attenuated inversion recovery ,Preoperative care ,longitudinal response assessment ,Automation ,03 medical and health sciences ,Deep Learning ,0302 clinical medicine ,Artificial Intelligence ,G730 Neural Computing ,Glioma ,Image Processing, Computer-Assisted ,medicine ,Humans ,Longitudinal Studies ,Postoperative Care ,medicine.diagnostic_test ,Brain Neoplasms ,business.industry ,segmentation ,Editorials ,Magnetic resonance imaging ,Prognosis ,medicine.disease ,Magnetic Resonance Imaging ,Hyperintensity ,Tumor Burden ,Oncology ,Fully automated ,030220 oncology & carcinogenesis ,Basic and Translational Investigations ,Neurology (clinical) ,G760 Machine Learning ,B140 Neuroscience ,business ,Algorithm ,Algorithms ,030217 neurology & neurosurgery - Abstract
Background Longitudinal measurement of glioma burden with MRI is the basis for treatment response assessment. In this study, we developed a deep learning algorithm that automatically segments abnormal fluid attenuated inversion recovery (FLAIR) hyperintensity and contrast-enhancing tumor, quantitating tumor volumes as well as the product of maximum bidimensional diameters according to the Response Assessment in Neuro-Oncology (RANO) criteria (AutoRANO). Methods Two cohorts of patients were used for this study. One consisted of 843 preoperative MRIs from 843 patients with low- or high-grade gliomas from 4 institutions and the second consisted of 713 longitudinal postoperative MRI visits from 54 patients with newly diagnosed glioblastomas (each with 2 pretreatment “baseline” MRIs) from 1 institution. Results The automatically generated FLAIR hyperintensity volume, contrast-enhancing tumor volume, and AutoRANO were highly repeatable for the double-baseline visits, with an intraclass correlation coefficient (ICC) of 0.986, 0.991, and 0.977, respectively, on the cohort of postoperative GBM patients. Furthermore, there was high agreement between manually and automatically measured tumor volumes, with ICC values of 0.915, 0.924, and 0.965 for preoperative FLAIR hyperintensity, postoperative FLAIR hyperintensity, and postoperative contrast-enhancing tumor volumes, respectively. Lastly, the ICCs for comparing manually and automatically derived longitudinal changes in tumor burden were 0.917, 0.966, and 0.850 for FLAIR hyperintensity volume, contrast-enhancing tumor volume, and RANO measures, respectively. Conclusions Our automated algorithm demonstrates potential utility for evaluating tumor burden in complex posttreatment settings, although further validation in multicenter clinical trials will be needed prior to widespread implementation.
- Published
- 2019
18. CTIM-18. LUMINOS-101: INITIAL SAFETY AND TOLERABILITY OF PVSRIPO AND PEMBROLIZUMAB COMBINATION THERAPY IN RECURRENT GLIOBLASTOMA
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Mitchel S. Berger, Shirley Ong, Daniel Landi, Andrew E. Sloan, Andrea Kelly, Adam Dickinson, E. Antonio Chiocca, Ketan R. Bulsara, A. Desjardins, J. Bradley Elder, Robin Buerki, Bruno Bockorny, Rafael A. Vega, Prakash Ambady, Allan H. Friedman, Lori Mixson, William T. Curry, Elizabeth R. Gerstner, Kevin Becker, Patrick Y. Wen, Chris A. Learn, LeAnn Jackson, Nicholas Butowski, Eric Sauvageau, W Garrett Nichols, and Robert Cavaliere
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Tolerability ,Combination therapy ,business.industry ,Recurrent glioblastoma ,Internal medicine ,Medicine ,Neurology (clinical) ,Pembrolizumab ,business - Abstract
BACKGROUND Recurrent glioblastoma (rGBM) is rapidly fatal with current therapies. PVSRIPO is an intratumoral immunotherapy targeting CD155 on antigen-presenting and malignant cells of solid tumors. Preclinically, PVSRIPO treatment leads to systemic, tumor antigen-specific, polyfunctional T-cell–mediated anti-tumor response, predominately driven by type I/III interferons. This inflammatory signature generates anti-tumor immunity and upregulates the programmed death (PD)-1 immune checkpoint in the tumor microenvironment. Preclinical models (including GBM) have shown that PVSRIPO+anti-PD-1/L1 therapy was more efficacious than either agent alone, warranting further investigation. METHODS Adults with histologically confirmed rGBM (1-2 prior progressions), Karnofsky performance status (KPS) ≥70, and an active, supratentorial, contrast-enhancing lesion (1-5.5 cm), received PVSRIPO (5x107 TCID50) intratumorally via convection-enhanced delivery (Day 1), followed by 200 mg pembrolizumab IV at week 2, given every 3 weeks for up to 24 months, to evaluate the safety/efficacy of the combination. A safety lead-in period (n=3-6) with a minimum 21–28-day delay before treatment of subsequent patients was planned, with a data safety monitoring board (DSMB) evaluating safety/tolerability prior to expansion (up to N=30). RESULTS The first 3 patients enrolled (ages 55-60, KPS 90-100) all received PVSRIPO followed by pembrolizumab (1-5 cycles), as planned. At cutoff (26-106 days of follow-up), there were no dose-limiting toxicities, treatment-emergent (TE) serious adverse events (SAE), or TEAEs necessitating a delay in initial/subsequent pembrolizumab treatments. All patients experienced a related TEAE, all grade 1 or 2 in severity. One patient experienced an AE of special interest (peritumoral edema, resulting in headache and hemiparesis), successfully managed with low-dose bevacizumab and corticosteroids. The DSMB unanimously recommended the study proceed without modification. CONCLUSIONS Intratumoral PVSRIPO+pembrolizumab was reasonably well tolerated, warranting continued investigation of the safety and efficacy of this combination in patients with rGBM.
- Published
- 2021
19. Clinical, radiological and genomic features and targeted therapy in BRAF V600E mutant adult glioblastoma
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David A. Reardon, Deborah Forst, J. Bryan Iorgulescu, Mary Jane Lim-Fat, Brian M Andersen, Patrick Y. Wen, Kun Wei Song, Isabel Arrillaga-Romany, Elizabeth R. Gerstner, and Justin T. Jordan
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Oncology ,Adult ,Proto-Oncogene Proteins B-raf ,Cancer Research ,medicine.medical_specialty ,Monosomy ,medicine.medical_treatment ,Article ,Targeted therapy ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,CDKN2A ,Internal medicine ,Medicine ,PTEN ,Humans ,neoplasms ,Protein Kinase Inhibitors ,Aged ,Retrospective Studies ,Mitogen-Activated Protein Kinase Kinases ,biology ,business.industry ,MEK inhibitor ,Cancer ,Retrospective cohort study ,Genomics ,Middle Aged ,medicine.disease ,Rash ,Neurology ,030220 oncology & carcinogenesis ,Mutation ,biology.protein ,Female ,Neurology (clinical) ,medicine.symptom ,business ,Glioblastoma ,030217 neurology & neurosurgery - Abstract
PURPOSE: Although uncommon, detection of BRAF V600E mutations in adult patients with glioblastoma has become increasingly relevant given the widespread application of molecular diagnostics and encouraging therapeutic activity of BRAF/MEK inhibitors. METHODS: We performed a retrospective study of adult glioblastoma patients treated at Dana-Farber Cancer Institute/Brigham and Women’s Hospital or Massachusetts General Hospital from January 2011 to July 2019 with an identified BRAF V600E mutation by either immunohistochemistry or molecular testing. Patient characteristics, molecular genomics, and preoperative MRI were analyzed. RESULTS: Nineteen glioblastoma patients were included, with median age at diagnosis of 41-years-old (range 22–69). Only 1/18 was IDH1/2-mutant; 10/17 had MGMT unmethylated tumors. The most common additional molecular alterations were CDKN2A/2B biallelic loss/loss-of-function (10/13, 76.9%), polysomy 7 (8/12, 66.7%), monosomy 10 (5/12, 41.7%), PTEN biallelic loss/loss-of-function (5/13, 38.5%) and TERT promoter mutations (5/15, 33.3%). Most tumors were well-circumscribed (11/14) and all were contrast-enhancing on MRI. Twelve patients eventually developed subependymal or leptomeningeal dissemination. Six patients were treated with BRAF/MEK inhibition following disease progression after standard of care therapy, with 4/6 patients showing partial response or stable disease as best response. Median time to progression after BRAF/MEK inhibition was 6.0 months (95% CI 1.2–11.8). Grade 1 skin rash was present in 2 patients, but no other adverse events were reported. Median OS for the entire cohort was 24.1 months (95% CI 15.7–38.9). CONCLUSION: Understanding the natural history and features of BRAF V600E glioblastoma may help better identify patients for BRAF/MEK inhibition and select therapeutic strategies.
- Published
- 2021
20. PATH-27. CLINICAL, RADIOLOGIC AND PROGNOSTIC PROFILE OF IDH WILD TYPE DIFFUSE ASTROCYTOMA WITH MOLECULAR FEATURES OF GLIOBLASTOMA
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Maria Martinez-Lage Alvarez, Elizabeth R. Gerstner, Wesley R Samore, and Oluwatosin Akintola
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Cancer Research ,Oncology ,Diffuse Astrocytoma ,Path (graph theory) ,medicine ,Cancer research ,Wild type ,Molecular Pathology & Classification ,Neurology (clinical) ,Biology ,medicine.disease ,Glioblastoma - Abstract
BACKGROUND cIMPACT-NOW-3 recommends that IDH-wildtype diffuse astrocytic glioma Grade II or III with EGFR amplification, or combined whole chromosome 7 gain and whole chromosome 10 loss, or TERT promoter mutation should receive an integrated classification: Diffuse astrocytic glioma, IDH-wildtype with molecular features of glioblastoma, WHO grade IV. The aims of this study were: Outline the features of a cohort of patients with molecular glioblastoma according to the above criteria; Assess clinical and molecular factors that may inform prognosis; Determine if cIMPACT-NOW-3 recommendation changed clinical practice and clinical trial enrolment. METHODS 61 patients diagnosed with IDH-wildtype diffuse astrocytic glioma Grade II or III and EGFR amp or mTERT or chromosome (+7/-10) between 2011 and 2019 at MGH were included in this single center retrospective cohort study. Data collected: sex, age, extent of surgery, functional status, histological grade, molecular diagnostics and treatment. Progression was defined using RANO criteria, progression was quantified in terms of months from the initial surgery. Survival was defined in terms of months from initial surgery to date of death or last known visit. RESULTS mOS was 16 months, mPFS was 9 months. 14 patients (23%) survived > 24 months, 7 ≥ 36 months (mOS 32 months; 9 deceased). The probability of survival in patients with markedly enhancing tumors was 0.5 at 3 months versus 0.5 at 11 months in non-enhancing tumors. The probability of survival in patients who underwent biopsy only was 0.5 at 5 months compared to 0.5 at 12 months in patients with maximally resected tumors. 1 patient was enrolled in a clinical trial at diagnosis. 6 were enrolled at time of recurrence. CONCLUSIONS mOS and pFS in the deceased patients was comparable to historical data on survival in IDH wild-type glioblastomas. Inclusion criteria in clinical trials have not reflected the cIMPACT-NOW-3 recommendation so far.
- Published
- 2020
21. Reply to Koekkoek et al. concerning SNO and EANO practice guideline update
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Tobias Walbert and Elizabeth R Gerstner
- Subjects
Cancer Research ,Oncology ,Neurology (clinical) - Published
- 2022
22. Commentary: Chimeric Antigen Receptor T-Cell Therapy: Updates in Glioblastoma Treatment
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Elizabeth R. Gerstner, Brian V. Nahed, Xiaoling Yu, Daniel P. Cahill, Bryan D. Choi, Marcela V. Maus, Bob S. Carter, and William T. Curry
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Receptors, Chimeric Antigen ,Brain Neoplasms ,business.industry ,Cell- and Tissue-Based Therapy ,Review ,medicine.disease ,Immunotherapy, Adoptive ,Text mining ,Cancer research ,Humans ,Medicine ,Surgery ,Chimeric Antigen Receptor T-Cell Therapy ,Neurology (clinical) ,Glioblastoma ,business - Abstract
Glioblastoma multiforme (GBM) are the most common and among the deadliest brain tumors in adults. Current mainstay treatments are insufficient to treat this tumor, and therefore, more effective therapies are desperately needed. Immunotherapy, which takes advantage of the body's natural defense mechanism, is an exciting emerging field in neuro-oncology. Adoptive cell therapy with chimeric antigen receptor (CAR) T cells provides a treatment strategy based on using patients’ own selected and genetically engineered cells that target tumor-associated antigens. These cells are harvested from patients, modified to target specific proteins expressed by the tumor, and re-introduced into the patient with the goal of destroying tumor cells. Here, we review the history of CAR T-cell therapy, and describe the characteristics of various generations of CAR T therapies, and the challenges inherent to treatment of GBM. Finally, we describe recent and current CAR T clinical trials designed to combat GBM.
- Published
- 2021
23. ACTR-61. A RANDOMIZED PHASE 2 TRIAL OF CEDIRANIB IN COMBINATION WITH OLAPARIB VERSUS BEVACIZUMAB IN PATIENTS WITH RECURRENT GLIOBLASTOMA
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Andrew B. Nixon, Douglas E. Ney, Jan Drappatz, Alona Muzikansky, S. Percy Ivy, Mary Welch, Biswajit Das, Isabel Arrillaga-Romany, P. Mickey Williams, John L. Villano, Eudocia Q. Lee, Elizabeth M. Swisher, Robert Aiken, Pierre Giglio, Chris Karlovich, Elizabeth R. Gerstner, Tracy T. Batchelor, David Picconi, Benjamin M. Ellingson, Jian Campian, Kevin P. Becker, and Solmaz Sahebjam
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Temozolomide ,Bevacizumab ,business.industry ,Surrogate endpoint ,Phases of clinical research ,Olaparib ,Cediranib ,chemistry.chemical_compound ,chemistry ,Internal medicine ,Adult Clinical Trials - Non-Immunologic ,Medicine ,In patient ,Neurology (clinical) ,Progression-free survival ,business ,medicine.drug - Abstract
BACKGROUND Like most proliferating tumors, GBM relies heavily on accurate DNA repair for maintenance of genome stability. Dysfunction in repair of both single and double strand DNA breaks by PARP inhibition and impairment of homologous recombination, respectively, would be synthetically lethal. In this study we combined the PARP inhibitor olaparib with cediranib, a pan VEGF receptor inhibitor. Cediranib may mediate disruption in the homologous recombination pathway through its antiangiogenic properties. METHODS Through the Experimental Therapeutics Clinical Trials Network, we performed an open-label randomized phase II study of bevacizumab (BEV)- naive adult patients with first or second recurrence of glioblastoma after radiation and temozolomide. Patients were randomized 1:1 to receive either olaparib 200 mg by mouth twice daily with cediranib 30 mg by mouth daily or BEV 10 mg/kg IV every 2 weeks. The primary endpoint was progression-free survival at 6 months (PFS6). Secondary endpoints included safety and overall survival. Exploratory objectives included blood, tissue and imaging-based biomarkers of response to treatment. RESULTS Seventy patients were enrolled. Median age was 60.5 years (range: 19–79), 39% females, median KPS was 90 (range: 60–100). Baseline characteristics were well balanced. With a data cut-off of 5/2/2019, PFS6 was 14% [95% CI 4–30%] in the cediranib/olaparib arm vs 30.9% [95% CI 12.7–51.2%] in the BEV arm. Median OS was 247 days in the cediranib/olaparib arm vs 201 days in the BEV arm, HR 0.816, 95% CI (0.431, 1.546). Related grade 3, 4 or 5 toxicity was experienced in 29% vs 12% of patients for the cediranib/olaparib vs BEV arm. CONCLUSION Treatment with cediranib/olaparib failed to increase PFS and OS in patients with recurrent GBM. Blood, tissue and imaging correlates will be presented to help understand why this treatment combination was unsuccessful.
- Published
- 2019
24. GENE-63. GENOMIC CHARACTERIZATION OF HUMAN BRAIN METASTASES IDENTIFIES NOVEL DRIVERS OF LUNG ADENOCARCINOMA PROGRESSION
- Author
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Juan Carlos Martinez-Gutierrez, Michael White, Elizabeth R. Gerstner, Corey M. Gill, Darrell R. Borger, Benjamin Kaufman, Kaitlin Hoang, Scott L. Carter, Ibiayi Dagogo-Jack, Naema Nayyar, Sandro Santagata, Daniel P. Cahill, Tracy T. Batchelor, Matthias Preusser, Megan R. D'Andrea, Ivanna Bihun, Franziska M. Ippen, Priscilla K. Brastianos, A. John Iafrate, Maria Martinez-Lage, Emily Batchelor, Devin McCabe, Ryan P. Frazier, Anna S. Berghoff, Matthew Lastrapes, Parker H. Merrill, Matthew R. Strickland, Christopher Alvarez-Breckenridge, Sung Hye Park, Deepika Nagabhushan, Mia Bertalan, Sun Ha Paek, Nicholas D. Camarda, Elisa Aquilanti, David Shih, Andrew Kaneb, Benjamin M. Kuter, Bruce E. Johnson, Alexander Kaplan, Ugonma Chukwueke, Brandyn A. Castro, Matthew P. Frosch, and Magali De Sauvage
- Subjects
Genetics and Epigenetics ,Cancer Research ,Lung ,Tumor cells ,Human brain ,Biology ,medicine.disease ,Genome ,Intracardiac injection ,medicine.anatomical_structure ,Oncology ,Cancer research ,medicine ,Adenocarcinoma ,Neurology (clinical) ,Gene ,Exome sequencing - Abstract
Although lung adenocarcinomas frequently metastasize to the brain, treatment options for lung adenocarcinoma brain metastases are limited. We discovered novel candidate drivers of progression by using case-control analyses to compare whole-exome sequencing data from a cohort of 73 lung adenocarcinoma brain metastases to a control cohort of 503 primary lung adenocarcinomas. We identified 3 genomic regions with significantly more frequent amplifications in brain metastases compared to the control cohort: MYC (12% vs 6%), YAP1 (7% vs 0.8%) and MMP13 (10% vs 0.6%). We also identified CDKN2A/B as a region deleted at a significantly greater frequency in brain metastases compared to primary lung adenocarcinomas (27% vs 13%, respectively). We confirmed frequent amplifications of MYC and YAP1/MMP13 in an independent validation cohort of 105 lung adenocarcinoma brain metastasis samples using fluorescence in situ hybridization. We further validated that MYC, YAP1 and MMP13 can drive brain metastases in a patient-derived xenograft mouse model. We found a higher incidence of metastases to the brain in mice receiving intracardiac injections of tumor cells expressing the candidate drivers compared to tumor cells expressing LacZ as a control. These results indicate that somatic alterations can drive lung adenocarcinomas to metastasize to the brain. The candidate brain metastasis drivers that we identified may serve as therapeutic targets in patients with lung adenocarcinomas who develop this devastating complication.
- Published
- 2019
25. The impact of surgery on survival after progression of glioblastoma: A retrospective cohort analysis of a contemporary patient population
- Author
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Rahul A. Sastry, Elizabeth R. Gerstner, Ganesh M. Shankar, and William T. Curry
- Subjects
Adult ,Male ,Reoperation ,medicine.medical_specialty ,Bevacizumab ,medicine.medical_treatment ,Context (language use) ,Kaplan-Meier Estimate ,Neurosurgical Procedures ,Cohort Studies ,03 medical and health sciences ,Antineoplastic Agents, Immunological ,0302 clinical medicine ,Physiology (medical) ,Biopsy ,Humans ,Medicine ,Karnofsky Performance Status ,Aged ,Proportional Hazards Models ,Retrospective Studies ,Aged, 80 and over ,Chemotherapy ,medicine.diagnostic_test ,Brain Neoplasms ,business.industry ,Proportional hazards model ,Retrospective cohort study ,General Medicine ,Middle Aged ,medicine.disease ,Combined Modality Therapy ,Surgery ,Neurology ,030220 oncology & carcinogenesis ,Multivariate Analysis ,Disease Progression ,Female ,Neurology (clinical) ,Glioblastoma ,business ,030217 neurology & neurosurgery ,Progressive disease ,Cohort study ,medicine.drug - Abstract
Despite updated management of glioblastoma (GB), progression is virtually inevitable. Previous data suggest a survival benefit from resection at progression; however, relatively few studies have evaluated the role of surgery in the context of contemporary GB treatment and widespread use of bevacizumab and chemotherapy. As such, the purpose of this study is to evaluate outcomes following surgical resection in patients with progressive GB since 2008. The records of all patients who underwent biopsy or resection of GB between January 1, 2008, and December 31, 2015, were retrospectively reviewed to identify 368 patients with progressive GB. Median survival and 95% confidence intervals were generated with the Kaplan-Meier method. Multivariate analysis, which controlled for age, Karnofsky Performance Status (KPS), extent of resection, adjuvant chemotherapy and radiation, tumor location, and tumor multifocality, of post-progression survival was carried out using a Cox proportional hazards model. Of 368 patients with progressive disease, 77 (20.9%) underwent resection at first documented progression. The median post-progression survivals for patients who did and did not undergo resection at this time were 12.8 and 7.0 months, respectively. In multivariate analysis, KPS ≥ 70 at progression (HR 0.438), receipt of bevacizumab at first progression (HR 0.756), and receipt of chemotherapy at first progression (HR 0.644) were associated with increased post-progression survival. Thus, surgery for progressive GB may not improve post-progression survival in the context of contemporary maximal non-surgical therapy. Further investigation is necessary to elucidate what role, if any, bevacizumab has in prolonging post-progression survival in patients with progressive GB.
- Published
- 2018
26. BIOM-04. SENSITIVE DETECTION OF LEPTOMENINGEAL DISEASE USING CELL-FREE DNA FROM CEREBROSPINAL FLUID
- Author
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Daniel P. Cahill, Naema Nayyar, Elizabeth R. Gerstner, Robert H. Klein, Anita Giobbie-Hurder, Jackson Stocking, Matthew Lastrapes, Viktor A. Adalsteinsson, Benjamin M. Kuter, Scott Carter, Denisse Rotam, Maura Mahar, Mohini Singh, Justin Rhoades, Aarushi Jain, Brian Shaw, Megha Subramanian, Greg Gydush, Mia Bertalan, Joana L. Mora, Samuel Markson, Alexander Kaplan, Deepika Nagabhushan, Priscilla K. Brastianos, Ryan J. Sullivan, Albert H. Kim, Kevin S. Oh, Michael White, and Christopher Alvarez-Breckenridge
- Subjects
Cancer Research ,Pathology ,medicine.medical_specialty ,business.industry ,Cancer ,Gold standard (test) ,26th Annual Meeting & Education Day of the Society for Neuro-Oncology ,medicine.disease ,DNA sequencing ,Cerebrospinal fluid ,Oncology ,Cell-free fetal DNA ,Cytology ,medicine ,LEPTOMENINGEAL DISEASE ,Neurology (clinical) ,business - Abstract
Leptomeningeal disease is a devastating complication of cancer that is frequently underdiagnosed due to the low sensitivity of cerebrospinal fluid cytology, the current gold-standard diagnostic method. We performed genomic sequencing on cerebrospinal fluid specimens obtained from patients with suspected or confirmed leptomeningeal disease to identify tumor-derived cell-free DNA. From the same fluid draw, cerebrospinal fluid cytology was assayed for comparison. 30 patients underwent cytology and cell-free DNA analysis. This study consisted of two patient populations: 22 patients with cytology-confirmed leptomeningeal disease without parenchymal tumors abutting their cerebrospinal fluid and 8 patients with parenchymal brain metastases with no evidence of leptomeningeal disease. The primary outcome was the diagnostic accuracy of cell-free DNA, defined as the number of correct diagnoses out of the total number of tests assayed. A total of 30 patients, 23 female and 7 male, with a median age of 51 participated in this study. Participants mostly presented with metastatic solid malignancies. In patients previously diagnosed with leptomeningeal disease via cytology with no parenchymal tumor abutting cerebrospinal fluid, cell-free DNA was accurate in diagnosis of leptomeningeal disease in 45 of 48 follow-up samples (94%; 95% CI, 83%-99%). Cytology was accurate in 36 of 48 follow-up samples (75%; 95% CI, 60%-86%). Cell-free DNA was significantly more accurate (P=.02) and sensitive (P=.02) than cytology in patients without parenchymal tumors abutting the cerebrospinal fluid. In three patients with parenchymal brain metastases abutting the cerebrospinal fluid and no suspicion for leptomeningeal disease, cytology was negative in all three patients; whereas, cell-free DNA was positive in all three. This study demonstrates the improved sensitivity and accuracy of cell-free DNA in diagnosing leptomeningeal disease with the exception of parenchymal tumors abutting cerebrospinal fluid. Overall, these results will lead to improved diagnosis of leptomeningeal disease and potentially earlier intervention and clinical trial enrollment.
- Published
- 2021
27. IMMU-26. SAFETY AND EFFICACY OF PVSRIPO IN RECURRENT GLIOBLASTOMA: LONG-TERM FOLLOW-UP AND INITIAL MULTICENTER RESULTS
- Author
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Mitchel S. Berger, Patrick Y. Wen, Andrew E. Sloan, William T. Curry, Andrea Kelly, Robert Cavaliere, Allan H. Friedman, Adam Dickinson, E. Antonio Chiocca, Henry S. Friedman, Nicholas Butowski, Matthias Gromeier, Darell D. Bigner, W Garrett Nichols, Lori Mixson, Robin Buerki, A. Desjardins, Eric Sauvageau, David M. Ashley, Elizabeth R. Gerstner, Daniel Landi, Chris A. Learn, and Kristin Orr
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Oncology ,Cancer Research ,medicine.medical_specialty ,Long term follow up ,business.industry ,Recurrent glioblastoma ,Internal medicine ,Medicine ,Neurology (clinical) ,26th Annual Meeting & Education Day of the Society for Neuro-Oncology ,business - Abstract
BACKGROUND Recurrent glioblastoma (rGBM) is rapidly fatal (median overall survival [mOS] of ~9 months; OS at 12 months [OS12] < 35%) with approved therapies (lomustine±bevacizumab). PVSRIPO is an intratumoral immunotherapy targeting CD155 on antigen-presenting and malignant cells of solid tumors. Preclinically, PVSRIPO delivers a systemic, tumor antigen-specific, polyfunctional T-cell mediated anti-tumor response. Interim, single-center, phase (Ph) 1 results showed greater long-term survival with PVSRIPO vs. criteria-matched external control rGBM patients (Desjardins 2018). Updates to Ph1 safety (at the Ph2 dose) and efficacy and interim multicenter (Ph2) results are presented. METHODS Adults with histologically-confirmed rGBM, Karnofsky performance status ≥ 70, and an active, supratentorial, contrast-enhancing lesion (1-5.5cm) received PVSRIPO (5x107 TCID50) intratumorally via convection-enhanced delivery on Day 1, with a planned follow-up of 24 months. Safety (treatment-emergent adverse events [TEAEs]), efficacy (reported as OS12, OS24, mOS), and blood/tissue were assessed. RESULTS 149 patients (>90% with 1-2 prior progressions, including failure of SOC and patients with prior bevacizumab failure) received the Ph2 dose of PVSRIPO (n=30 received other doses in Ph1 with safety summarized previously). Follow-up durations for surviving patients were 51-74 months (Ph1) and 10-44 months (Ph2). No dose-limiting toxicities occurred; up to 97% of patients experienced mostly grade 1-2 related TEAEs; ≤ 23% patients experienced grade ≥ 3 related events. Neurologic symptoms related to peritumoral edema were most common ( > 90% patients) and were effectively managed with low-dose bevacizumab/corticosteroids. Survival estimates were: OS12: 54%, 50%; OS24: 18%, 17%; mOS: 12.3 (95% CI 10,15.3), 12 (10.6,13.7) months, for the Ph1 and Ph2 trials, respectively. Baseline correlates of longer survival included smaller lesions and methylated MGMT-promoter status. CONCLUSIONS The multicenter/Ph2 study replicated the single-center/Ph1 results. Relative to published data with approved therapies, PVSRIPO was associated with greater long-term survival and mOS in patients with rGBM and was generally well-tolerated.
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- 2021
28. CTNI-53. RADIATION TREATMENT VOLUMES BEFORE AND AFTER BRAF/MEK THERAPY IN NEWLY DIAGNOSED PAPILLARY CRANIOPHARYNGIOMAS: A CORRELATIVE ANALYSIS OF THE ALLIANCE A071601 PHASE II TRIAL
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Elizabeth R. Gerstner, Sandro Santagata, Fred G. Barker, Helen A. Shih, Evanthia Galanis, Erin Twohy, Brian Kabat, Michael W. Ruff, Macarena I. de la Fuente, Michael V. Knopp, Priscilla K. Brastianos, Shervin Tabrizi, Daniel P. Cahill, Susan Geyer, David A. Reardon, Adam B. Cohen, Shivangi Vora, Pankaj K Agarwalla, Priya Kumthekar, Timothy J. Kaufmann, Daniela A. Bota, Jian Campian, Paul D. Brown, and Glen Lesser
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Oncology ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Oncology and Carcinogenesis ,Newly diagnosed ,Papillary craniopharyngioma ,chemistry.chemical_compound ,Rare Diseases ,MICROBIOLOGY PROCEDURES ,Clinical Research ,Internal medicine ,Troponin I ,Genetics ,medicine ,Oncology & Carcinogenesis ,Vemurafenib ,Cancer ,Cobimetinib ,business.industry ,Neurosciences ,medicine.disease ,Craniopharyngioma ,Radiation therapy ,chemistry ,Neurology (clinical) ,business ,medicine.drug - Abstract
PURPOSE Standard of care for craniopharyngiomas is surgery with or without radiotherapy (RT). Cohort A of Alliance A071601 evaluated the efficacy of BRAF/MEK inhibition with vemurafenib/cobimetinib in patients with previously untreated papillary craniopharyngiomas (PCP), which carry the BRAF V600E mutation. Cohort B is currently enrolling patients with recurrence after RT. In a correlative analysis, we examined changes in RT volumes after BRAF/MEK therapy in Cohort A. METHODS Previously unirradiated patients with BRAF-mutated PCP were treated with vemurafenib/cobimetinib. Sixteen patients had scans available before starting vemurafenib/cobimetinib (“pre-therapy”) and after completing therapy (“post-therapy”). Two patients went off study treatment after 8 and 9 days due to side-effects and were excluded for this analysis. Gross target volumes (GTV) were contoured on pre-therapy and post-therapy scans. On post-therapy scans, an additional target comprising gross disease and at-risk regions for microscopic residual disease (GTV-micro) was defined and considered the treatment volume. Clinical target volume (CTV) was a 5-mm uniform expansion on pre-therapy GTV and post-therapy GTV-micro. Volumes were independently reviewed by two radiation oncologists. Changes in volumes from pre- versus post-therapy were compared using the Wilcoxon signed rank test. RESULTS In 14 patients evaluated, 57% were female and median age at enrollment was 49.5 years (range 33-83). Median time on treatment was 8.9 months (range 4.0-18.0). Median GTV pre-therapy was 3.8 mL (range 0.2-23.4) versus 0.3 mL (range 0.0-3.2) post-therapy (p=0.0001) and 1.7 mL (range 0.1-8.0) post-therapy GTV-micro (p=0.0001). Median CTV pre-therapy was 13.7 mL (range 2.8-51.8) versus 9.1 mL (range 2.2-27.5) post-therapy (p=0.0001). All tumors abutted the optic chiasm pre-therapy, only 6 did post-therapy. CONCLUSIONS Vemurafenib/cobimetinib resulted in smaller RT volumes. BRAF/MEK inhibitors could reduce RT volumes and spare dose to surrounding normal structures. Enrollment to Cohort B of Alliance A071601 should be considered for patients with recurrent tumors after RT. SUPPORT https://acknowledgments.alliancefound.org
- Published
- 2021
29. CTNI-54. A SINGLE ARM PHASE II STUDY OF THE DUAL MTORC1/MTORC2 INHIBITOR VISTUSERTIB PROVIDED FOR SPORADIC PATIENTS WITH GRADE II-III MENINGIOMAS THAT RECUR OR PROGRESS AFTER SURGERY AND RADIATION
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Patrick Y. Wen, Fred G. Barker, Vijaya Ramesh, Anat Stemmer-Rachamimov, Alona Muzikansky, Miriam J. Smith, Justin T. Jordan, Roberta L. Beauchamp, Priya Kumthekar, Elizabeth R. Gerstner, and Scott R. Plotkin
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Cancer Research ,medicine.medical_specialty ,business.industry ,Surrogate endpoint ,Nausea ,Phases of clinical research ,medicine.disease ,Meningioma ,Oncology ,Troponin I ,Vomiting ,Medicine ,Neurology (clinical) ,Radiology ,Progression-free survival ,medicine.symptom ,business ,Adverse effect - Abstract
Grade II/III meningiomas have increased rates of recurrence with no approved medical therapies. The historical progression-free survival at 6 months (PFS-6) is 25% with rates >35% declared of interest for drug development. NF2 gene inactivation occurs in about half of meningiomas. Based on our studies showing mTORC1 and mTORC2/SGK1 pathway activation in NF2-deficient meningiomas and the paradoxical activation of the mTORC2/AKT pathway, we hypothesized that mTORC1/mTORC2 inhibitors would be active in meningiomas. We studied the effect of vistusertib in patients with progressive/recurrent grade II/III meningiomas (NCT03071874). Vistusertib was administered orally at 125mg twice daily on two consecutive days each week. MRIs were obtained every 56 days. Tumor size was defined as the largest cross-sectional area. Progression was defined as ≥ 25% increase in the sum of products of all measurable lesions over smallest sum observed. The primary endpoint was PFS-6. Secondary endpoints included toxicity, radiographic response, and correlative studies including immunohistochemistry for mTORC1/2 pathway activation and genetic biomarkers. Twenty-eight patients (13 female, median age 58 years, median KPS 80%) were enrolled. Median tumor size was 4.4cm; 71% were grade II and 50% harbored pathogenic NF2 variants. Four patients discontinued treatment voluntarily and 1 each withdrew for intercurrent illness and non-compliance. PFS-6 is 47% (CI, 26%-65%) and OS-12 is 72% (95%CI, 48%-86%). PFS but not OS was shorter for patients with grade 3 meningiomas; there was no difference in PFS/OS between genetic groups. Adverse events at least possibly related to vistusertib with frequency >10% include nausea, fatigue, hypophosphatemia, diarrhea, anorexia, dry mouth, hypertriglyceridemia, hypertension, vomiting, increased ALT, constipation, and weight loss. Vistusertib treatment was associated with a PFS-6 rate exceeding the target of 35% for recurrent high-grade meningioma. Adverse events were tolerable in this patient population. These data support the continued development of mTORC1/2 inhibitors in this setting.
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- 2021
30. Phase I/II trial of vorinostat combined with temozolomide and radiation therapy for newly diagnosed glioblastoma: results of Alliance N0874/ABTC 02
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S. Keith Anderson, Eudocia Q. Lee, Stuart A. Grossman, Patrick Y. Wen, David Schiff, Glenn J. Lesser, Manmeet Ahluwalia, Karla V. Ballman, Jane H. Cerhan, Caterina Giannini, Michael D. Prados, Jan C. Buckner, Kurt A. Jaeckle, Dennis F. Moore, Jann N. Sarkaria, Andrey Loboda, Keith L. Ligon, Evanthia Galanis, C. Ryan Miller, Elizabeth R. Gerstner, Michael Nebozhyn, Galanis E., Keith Anderson S., Miller C.R., Sarkaria J.N., Jaeckle K., Buckner J.C., Ligon K.L., Ballman K.V., Moore D.F., Nebozhyn M., Loboda A., Schiff D., Ahluwalia M.S., Lee E.Q., Gerstner E.R., Lesser G.J., Prados M., Grossman S.A., Cerhan J., Giannini C., and Wen P.Y.
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Male ,0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_treatment ,phase I/II trial ,temozolomide ,Cohort Studies ,0302 clinical medicine ,Antineoplastic Combined Chemotherapy Protocols ,Aged, 80 and over ,Vorinostat ,Brain Neoplasms ,Chemoradiotherapy ,Middle Aged ,Prognosis ,Survival Rate ,Tolerability ,030220 oncology & carcinogenesis ,Female ,Human ,medicine.drug ,Adult ,medicine.medical_specialty ,Maximum Tolerated Dose ,Combination therapy ,Prognosi ,Clinical Investigations ,Neutropenia ,Follow-Up Studie ,Brain Neoplasm ,Young Adult ,03 medical and health sciences ,Internal medicine ,medicine ,Humans ,histone deacetylase inhibitor ,Survival rate ,Aged ,Antineoplastic Combined Chemotherapy Protocol ,Temozolomide ,business.industry ,glioblastoma ,medicine.disease ,Radiation therapy ,030104 developmental biology ,Neurology (clinical) ,Cohort Studie ,business ,Follow-Up Studies - Abstract
BACKGROUND: Vorinostat, a histone deacetylase (HDAC) inhibitor, has shown radiosensitizing properties in preclinical studies. This open-label, single-arm trial evaluated the maximum tolerated dose (MTD; phase I) and efficacy (phase II) of vorinostat combined with standard chemoradiation in newly diagnosed glioblastoma. METHODS: Patients received oral vorinostat (300 or 400 mg/day) on days 1–5 weekly during temozolomide chemoradiation. Following a 4- to 6-week rest, patients received up to 12 cycles of standard adjuvant temozolomide and vorinostat (400 mg/day) on days 1–7 and 15–21 of each 28-day cycle. Association between vorinostat response signatures and progression-free survival (PFS) and overall survival (OS) was assessed based on RNA sequencing of baseline tumor tissue. RESULTS: Phase I and phase II enrolled 15 and 107 patients, respectively. The combination therapy MTD was vorinostat 300 mg/day and temozolomide 75 mg/m(2)/day. Dose-limiting toxicities were grade 4 neutropenia and thrombocytopenia and grade 3 aspartate aminotransferase elevation, hyperglycemia, fatigue, and wound dehiscence. The primary efficacy endpoint in the phase II cohort, OS rate at 15 months, was 55.1% (median OS 16.1 mo), and consequently, the study did not meet its efficacy objective. Most common treatment-related grade 3/4 toxicities in the phase II component were lymphopenia (32.7%), thrombocytopenia (28.0%), and neutropenia (21.5%). RNA expression profiling of baseline tumors (N = 76) demonstrated that vorinostat resistance (sig-79) and sensitivity (sig-139) signatures had a reverse and positive association with OS/PFS, respectively. CONCLUSIONS: Vorinostat combined with standard chemoradiation had acceptable tolerability in newly diagnosed glioblastoma. Although the primary efficacy endpoint was not met, vorinostat sensitivity and resistance signatures could facilitate patient selection in future trials.
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- 2017
31. CMET-33. PHASE II STUDY OF PALBOCICLIB IN BRAIN METASTASES HARBORING CDK PATHWAY ALTERATIONS
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Scott L. Carter, Daniel P. Cahill, Anita Giobbie-Hurder, Priscilla K. Brastianos, Sandro Santagata, Justine V. Cohen, Elizabeth R. Gerstner, A. John Iafrate, Donald P. Lawrence, Eudocia Q. Lee, David P. Ryan, Keith T. Flaherty, Tracy T. Batchelor, Maura Keeley, Kevin S. Oh, Ryan J. Sullivan, Nancy Wang, Jennifer A. Ligibel, Michael White, and Ugonma Chukwueke
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CNS Metastasis ,Cancer Research ,biology ,business.industry ,Melanoma ,Phases of clinical research ,Cancer ,Palbociclib ,medicine.disease ,Breast cancer ,Oncology ,Cyclin-dependent kinase ,medicine ,biology.protein ,Cancer research ,Neurology (clinical) ,Adverse effect ,business ,Gene - Abstract
BACKGROUND Up to 25% of all cancer patients will develop brain metastases and prognosis remains poor. In preclinical work, we discovered that more than 50% brain metastases genomically diverge from primary tumors and harbor alterations in genes involved with cell cycle regulation. We thus initiated a phase II study to evaluate the efficacy and safety of the cyclin dependent kinase (CDK) 4/6 inhibitor, palbociclib, in patients with recurrent brain metastases with alterations in the CDK pathway (NCT02896335). METHODS The primary endpoint of the trial is the rate of intracranial benefit (defined as CR, PR, or SD, per RANO) at 8 weeks after the start of palbociclib. A Simon two-stage design was used to compare the rate of intracranial benefit for a null rate of 10% against an alternative of 30%. Fifteen patients were to be enrolled in the first stage. If fewer than 2 responders were observed, then the study would stop for insufficient evidence of efficacy. If 6 or more responders were observed among the total of 30, this treatment regimen would be considered worthy of further study. CSF, blood samples and tumor samples were collected to elucidate the genomic determinants of response to CDK inhibitors in the brain. RESULTS A total of 14 patients have been accrued (5 with breast cancer, 4 with melanoma, 3 esophageal and 2 with non-small cell lung cancer) thus far. One or more grade-3 or higher adverse events at least possibly related to treatment were seen in six (42%) patients, the majority being hematologic toxicities. At the time of the data analysis, eight (57%) patients had achieved intracranial benefit. Therefore, the study met primary endpoint. CONCLUSIONS In this unique, genomically-guided brain metastasis trial, we demonstrate that the CDK 4/6 inhibitor, palbociclib, is well-tolerated and has activity in patients with brain metastases.
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- 2019
32. NIMG-43. LONGITUDINAL TRACKING AND GROWTH RATE CHARACTERIZATION OF BRAIN METASTASES ON MAGNETIC RESONANCE IMAGING
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Katharina Hoebel, Andrew Beers, Elizabeth R. Gerstner, James M. Brown, Ken Chang, Raymond Y. Huang, Bruce R. Rosen, Jay B. Patel, Jayashree Kalpathy-Cramer, and Priscilla K. Brastianos
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Physics ,Cancer Research ,medicine.diagnostic_test ,Parietal lobe ,Magnetic resonance imaging ,Tracking (particle physics) ,Characterization (materials science) ,Nuclear magnetic resonance ,Oncology ,Frontal lobe ,Neuro-Imaging ,medicine ,Medical imaging ,Neurology (clinical) - Abstract
PURPOSE Measuring treatment response is vital for assessing efficacy of treatment regimen for patients with brain metastases (BM). Unfortunately, manual delineation of all lesions on MRI across time-points is prohibitively time-consuming, making it infeasible to track individual lesion growth/shrinkage rates as part of the clinical workflow. To overcome this challenge, we propose a deep learning approach to segment all BM, and furthermore, show that certain brain regions are more prone to high-growth rate lesions. METHODS 163 longitudinal MRIs from 77 patients with MPRAGE-post contrast imaging protocol were prospectively obtained from Massachusetts General Hospital (MGH). An expert neuro-oncologist provided ground truth segmentations for all patients. A 3D U-Net architecture was trained to automatically segment BM; training was stopped when validation set Dice score plateaued to prevent overfitting. To enable lesion tracking, all time-points per patient were affinely registered to each other. Every lesion was subsequently classified based on its growth rate (responder: overall lesion shrinkage; inconclusive: 0% to 40% lesion growth; non-responder: more than 40% lesion growth). Characterization of global lesion growth rate patterns was accomplished by affinely registering all time-points to the MNI brain atlas. Segmented lesions were projected onto the atlas, which was qualitatively analyzed to identify spatial regions composed primarily of one class of lesion. RESULTS For automatic segmentation, we report a mean dice score of 0.778, 0.737, and 0.704 on training, validation, and testing sets respectively. Furthermore, we find that the largest BM with the highest average growth rate (non-responders) tend to be located in the posterior frontal/parietal lobes, while smaller, lower growth rate lesions (responders) tend to be localized in the frontal lobes. The posterior fossa was found to be heterogeneous in lesion size and growth rate. CONCLUSION We developed automatic metastatic lesion tracking over time-points and identified brain regions associated with differing growth rate lesions.
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- 2019
33. Standard chemoradiation in combination with VEGF targeted therapy for glioblastoma results in progressive gray and white matter volume loss
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Pavlina Polaskova, Morgan L Prust, Tracy T. Batchelor, Elizabeth R. Gerstner, Jayashree Kalpathy-Cramer, Kourosh Jafari-Khouzani, and Jorg Dietrich
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Adult ,Male ,Vascular Endothelial Growth Factor A ,0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,VEGF receptors ,Gray (unit) ,Targeted therapy ,03 medical and health sciences ,0302 clinical medicine ,Neuroimaging ,White matter volume loss ,Internal medicine ,medicine ,Humans ,Gray Matter ,Letter to the Editor ,Aged ,Aged, 80 and over ,biology ,business.industry ,Neurotoxicity ,Chemoradiotherapy ,Middle Aged ,medicine.disease ,Magnetic Resonance Imaging ,White Matter ,030104 developmental biology ,biology.protein ,Female ,Neurology (clinical) ,Glioblastoma ,business ,030217 neurology & neurosurgery - Published
- 2018
34. Dose diversification in newly diagnosed glioblastoma
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Elizabeth R. Gerstner
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,MEDLINE ,Editorials ,Newly diagnosed ,Diversification (marketing strategy) ,medicine.disease ,Text mining ,Internal medicine ,medicine ,Neurology (clinical) ,business ,Glioblastoma - Published
- 2019
35. ACTR-51. PHASE 2 STUDY TO EVALUATE THE SAFETY, PHARMACOKINETICS AND CLINICAL ACTIVITY OF PI3K/MTOR INHIBITOR GDC-0084 GIVEN TO GLIOBLASTOMA (GBM) PATIENTS WITH UNMETHYLATED O(6)-METHYLGUANINE-METHYLTRANSFERASE PROMOTER STATUS
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Jeremy Simpson, Timothy F. Cloughesy, John de Groot, James Garner, Alan G. Olivero, Patrick Y. Wen, James Battiste, and Elizabeth R. Gerstner
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Cancer Research ,Methyltransferase ,Phosphoinositide 3-kinase ,Temozolomide ,biology ,business.industry ,Phases of clinical research ,O-6-methylguanine-DNA methyltransferase ,medicine.disease ,Abstracts ,Oncology ,Pharmacokinetics ,Glioma ,Cancer research ,medicine ,biology.protein ,Neurology (clinical) ,business ,PI3K/AKT/mTOR pathway ,medicine.drug - Abstract
BACKGROUND: GDC-0084 is a potent, oral, selective small molecule inhibitor of class I phosphoinositide 3-kinase and mammalian target of rapamycin (PI3K/mTOR) efficacious in GBM models driven by activation of the PI3K pathway. GDC-0084 crosses the blood-brain barrier (BBB) and achieves a brain / plasma ratio of approximately 1.0 in three animal species. GDC-0084 was given as once daily oral dosing in a phase 1 study (Wen et al, J Clin Oncol 34, 2016(15) suppl.2012; NCT01547546) in 47 patients with recurrent high-grade gliomas. The adverse events were generally consistent with the established Class I PI3K/mTOR inhibitor class-effects. GDC-0084 was rapidly absorbed and demonstrated linear- and dose-proportional increases in exposure. The MTD was determined to be 45 mg once daily, with 7/8 patients receiving this dose having drug exposures consistent with anti-tumor activity in pre-clinical models. Fluorodeoxyglucose-positron emission tomography (FDG-PET) scans suggested that GDC-0084 crossed the BBB, with a uniform distribution throughout the brain. The current phase 2 study will investigate the efficacy and safety of GDC 0084 in patients with newly diagnosed GBM, with unmethylated O6-methylguanine-methyltransferase (MGMT) promoter status. METHODS: This protocol (NCT03522298) has a 2-part design. The phase 1b component consists of an open-label, multicenter dose-escalation study with expansion assess the safety, tolerability, RP2D, PK and clinical activity of GDC 0084 in patients with newly-diagnosed GBM with unmethylated MGMT. The dose-escalation portion of the study will use a standard “3 + 3” design to determine the MTDs for QD, QOD and 3 days on/4 days off schedules. At each of the identified MTDs 10 subjects will be recruited in an expansion cohort. The RP2D will be selected from the three dose schedules being tested. The phase 2 component will evaluate clinical activity of GDC-0084 at the RP2D vs temozolomide as adjuvant therapy following surgical resection and chemoradiation in 224 patients.
- Published
- 2018
36. NIMG-05. ADVANCED IMAGING TO ASSESS LONGITUDINAL VASCULAR CHANGES IN BRAIN METASTASES TREATED WITH CHECKPOINT INHIBITION
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Jonathan Cardona, Ken Chang, James M. Brown, Kyrre E. Emblem, Albert H. Kim, Priscilla K. Brastianos, Beverly Moy, Michael White, Sara M. Tolaney, Eudocia Q. Lee, Justine V. Cohen, Helen A. Shih, Ugonma Chukwueke, Ryan J. Sullivan, Anita Giobbie-Hurder, Jayashree Kalpathy-Cramer, Elizabeth R. Gerstner, Andrew Beers, Kevin S. Oh, Nan Lin, Donald P. Lawrence, Lakshmi Nayak, and Daniel P. Cahill
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Cancer Research ,Oncology ,business.industry ,Immune checkpoint inhibitors ,Cancer research ,Medicine ,Neuroimaging ,Neurology (clinical) ,business - Abstract
Immune checkpoint inhibitors (ICI) have recently been shown to be effective for brain metastases (BM) in melanoma and lung cancer. However, accurately assessing intracranial response in patients undergoing ICI is a challenge, as current measures cannot reliably distinguish pseudoprogression from true tumor progression. To identify potential biomarkers of response, we analyzed standard post-contrast and dynamic susceptibility contrast MRI to identify characteristic vascular signatures as part of an ongoing Phase 2 study of pembrolizumab for patients with untreated or progressive, previously treated BM from any histology. Tumor volume measurements were calculated by summating all enhancing voxels. A volumetric increase of >40% was categorized as progressive disease (PD), a decrease of >60% as partial response (PR), and stable disease (SD) as between -60% and +40%. 78 patients have been enrolled, of whom 44 have received at least baseline advanced MR imaging. Histologies include 21 with breast cancer, 5 with non-small cell lung cancer, 4 with melanoma, and 13 with other cancers. At baseline, the total number of BM was 1-50+ per patient. Based on summing the entire enhancing intracranial disease burden, best volumetric responses for the 33 evaluable patients include 4 PR, 10 SD, and 19 PD. On preliminary analysis, there was a correlation between increased tumor cerebral blood volume/flow with tumor progression. Correlation of additional vascular physiologic parameters (e.g. vessel caliber, tissue oxygenation) to volumetric response, patient outcome, and standardized response criteria (iRANO) are ongoing. Our data provides potential evidence that effective ICI is associated with a decrease in perfusion. Ongoing analyses to uncover additional vascular changes – specifically longitudinal metrics reflecting vascular structure and function - within BM to ICI are pending. These findings have potential to explore mechanisms of ICI response and resistance, as well as biomarkers of response.
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- 2020
37. NIMG-34. MULTI-PARAMETRIC MR-PET IMAGING PREDICTS PHARMACOKINETICS AND CLINICAL RESPONSE TO GDC-0084 IN HUMAN RECURRENT HIGH-GRADE GLIOMA
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Benjamin M. Ellingson, Jingwen Yao, Jordi Rodon, Timothy F. Cloughesy, Alan G. Olivero, Jeremy Simpson, Elizabeth R. Gerstner, David Nathanson, James Garner, Lars Mueller, Catalina Raymond, and Patrick Y. Wen
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Cancer Research ,Multi parametric ,Phosphoinositide 3-kinase ,biology ,business.industry ,Cmax ,Pet imaging ,medicine.disease ,Oncology ,Pharmacokinetics ,Glioma ,Neuro-Imaging ,medicine ,Cancer research ,Medical imaging ,biology.protein ,Neurology (clinical) ,Progression-free survival ,business - Abstract
Alterations in the PI3K pathway are found in the majority of malignant gliomas, but lack of efficacy has caused investigators to question the viability of this target, particularly due to lack of brain penetration. GDC-0084 was specifically optimized to penetrate the brain, targeting both PI3K and mTOR. Since these two targets alter tumor vascularity and metabolism, respectively, we hypothesized that multi-parametric MR-PET could be used to quantify the response, estimate pharmacokinetic (PK) parameters, and predict progression-free survival (PFS) in patients with recurrent malignant gliomas. In this first-in-man, multicenter, phase I, dose-escalation study (NCT01547546), we show in 47 patients that the measured maximum concentration (Cmax) of GDC0084 was associated with a decrease in enhancing tumor volume (P=0.0287) and an increase in fractional anisotropy (FA) (P=0.0418). Post-treatment tumor volume, 18F-FDG uptake, Ktrans, and relative cerebral blood volume (rCBV) were all correlated with Cmax. A linear combination of change in 18F-FDG PET uptake, apparent diffusion coefficient (ADC), FA, Ktrans, vp, and rCBV were able to estimate both Cmax (R2=0.4113, P< 0.0001) and drug exposure (AUC) (R2=0.3481, P< 0.0001). Using this composite multi-parametric MR-PET imaging response biomarker to predict PK, patients with an estimated Cmax >0.1 uM and AUC > 1.25 uM*hr demonstrated significantly longer PFS compared with patients with a lower estimated concentration and exposure (P=0.0039 and P=0.0296, respectively). Results from the current study suggest composite biomarkers created from multi-parametric MR-PET imaging targeting metabolic and/or physiologic processes specific to the drug mechanism of action may be useful for subsequent evaluation of treatment efficacy for larger phase II-III studies.
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- 2019
38. Validation of postoperative residual contrast-enhancing tumor volume as an independent prognostic factor for overall survival in newly diagnosed glioblastoma
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Olivier Chinot, Whitney B. Pope, Tracy T. Batchelor, Roger Henriksson, Sarah J. Nelson, Jennie Taylor, Susan M. Chang, Patrick Y. Wen, Arnav Mehta, Elizabeth R. Gerstner, Ryo Nishikawa, Brian M. Alexander, Timothy J. Kaufmann, Ingo K. Mellinghoff, Benjamin M. Ellingson, Keith L. Ligon, Howard Colman, John de Groot, Josep Garcia, Robert J. Young, Frank Saran, Warren P. Mason, Nicholas Butowski, Raymond Y. Huang, Isabel Arrillaga-Romany, Evanthia Galanis, Timothy F. Cloughesy, Lauren E. Abrey, Michael D. Prados, Wolfgang Wick, David A. Reardon, Rivkah Colen, Département de neurooncologie, Hôpital de la Timone [CHU - APHM] (TIMONE), Department of Radiation Sciences, Oncology, Umeå University, Department of Neurooncology, Heidelberg University Hospital [Heidelberg], Hadassah Hebrew University Medical Center [Jerusalem], Massachusetts General Hospital [Boston], Loughborough University, School of Environment and Technology, University of Sussex, Department of Molecular Medicine, Mayo Clinic, Hôpital de la Timone [CHU - APHM] ( TIMONE ), and Massachusetts General Hospital [Boston] ( MGH )
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Oncology ,Male ,Cancer Research ,contrast-enhancing tumor volume ,[SDV]Life Sciences [q-bio] ,Contrast Media ,0302 clinical medicine ,Antineoplastic Combined Chemotherapy Protocols ,ComputingMilieux_MISCELLANEOUS ,Cancer ,Vorinostat ,Chemoradiotherapy ,Middle Aged ,Prognosis ,Magnetic Resonance Imaging ,3. Good health ,Survival Rate ,030220 oncology & carcinogenesis ,Residual ,6.1 Pharmaceuticals ,Female ,medicine.drug ,medicine.medical_specialty ,Prognostic factor ,Bevacizumab ,Clinical Trials and Supportive Activities ,Oncology and Carcinogenesis ,Newly diagnosed ,bevacizumab ,Imaging data ,GBM ,03 medical and health sciences ,Rare Diseases ,Clinical Research ,Internal medicine ,medicine ,Overall survival ,Temozolomide ,Humans ,Oncology & Carcinogenesis ,Retrospective Studies ,Postoperative Care ,clinical trials ,[ SDV ] Life Sciences [q-bio] ,business.industry ,T1 subtraction ,Neurosciences ,O-6-methylguanine-DNA methyltransferase ,Evaluation of treatments and therapeutic interventions ,medicine.disease ,Image Enhancement ,new glioblastoma ,nervous system diseases ,Brain Disorders ,Clinical trial ,Brain Cancer ,Neoplasm ,Neurology (clinical) ,business ,Glioblastoma ,030217 neurology & neurosurgery ,Follow-Up Studies - Abstract
BackgroundIn the current study, we pooled imaging data in newly diagnosed glioblastoma (GBM) patients from international multicenter clinical trials, single institution databases, and multicenter clinical trial consortiums to identify the relationship between postoperative residual enhancing tumor volume and overall survival (OS).MethodsData from 1511 newly diagnosed GBM patients from 5 data sources were included in the current study: (i) a single institution database from UCLA (N = 398; Discovery); (ii) patients from the Ben and Cathy Ivy Foundation for Early Phase Clinical Trials Network Radiogenomics Database (N = 262 from 8 centers; Confirmation); (iii) the chemoradiation placebo arm from an international phase III trial (AVAglio; N = 394 from 120 locations in 23 countries; Validation); (iv) the experimental arm from AVAglio examining chemoradiation plus bevacizumab (N = 404 from 120 locations in 23 countries; Exploratory Set 1); and (v) an Alliance (N0874) phase I/II trial of vorinostat plus chemoradiation (N = 53; Exploratory Set 2). Postsurgical, residual enhancing disease was quantified using T1 subtraction maps. Multivariate Cox regression models were used to determine influence of clinical variables, O6-methylguanine-DNA methyltransferase (MGMT) status, and residual tumor volume on OS.ResultsA log-linear relationship was observed between postoperative, residual enhancing tumor volume and OS in newly diagnosed GBM treated with standard chemoradiation. Postoperative tumor volume is a prognostic factor for OS (P < 0.01), regardless of therapy, age, and MGMT promoter methylation status.ConclusionPostsurgical, residual contrast-enhancing disease significantly negatively influences survival in patients with newly diagnosed GBM treated with chemoradiation with or without concomitant experimental therapy.
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- 2018
39. NIMG-09. CHARACTERIZING GLIOMA MICROENVIRONMENT WITH ULTRA-HIGH GRADIENT DIFFUSION MRI
- Author
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Qiuyun Fan, Barbara Wichtmann, Bruce R. Rosen, Daniel P. Cahill, Ina Ly, Aapo Nummenmaa, Tracy T. Batchelor, Susie Y. Huang, William T. Curry, Alexandra J. Golby, Jayashree Kalpathy-Cramer, Ovidiu C. Andronesi, Elizabeth R. Gerstner, and Brian V. Nahed
- Subjects
Cancer Research ,Materials science ,business.industry ,Treatment outcome ,medicine.disease ,White matter ,Abstracts ,Nuclear magnetic resonance ,Text mining ,medicine.anatomical_structure ,Oncology ,Glioma ,medicine ,Medical imaging ,Magnetic resonance imaging unit ,Neurology (clinical) ,business - Published
- 2017
40. CMET-20. EVIDENCE OF CNS RESPONSE OF PEMBROLIZUMAB FOR LEPTOMENINGEAL CARCINOMATOSIS AT A SINGLE CELL RESOLUTION
- Author
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Christopher Alvarez-Breckenridge, Justine V. Cohen, Ryan J. Sullivan, Daniel P. Cahill, Nan Lin, Anita Giobbie-Hurder, Scott L. Carter, Ivanna Bihun, Priscilla K. Brastianos, Kevin S. Oh, Michael White, Sara M. Tolaney, Sanjay Prakadan, Alex K. Shalek, Eudocia Q. Lee, Elizabeth R. Gerstner, Ugonma Chukwueke, Donald P. Lawrence, and Lakshmi Nayak
- Subjects
Cancer Research ,Palliative care ,business.industry ,medicine.medical_treatment ,Cell ,Phases of clinical research ,Cancer ,Pembrolizumab ,Immunotherapy ,medicine.disease ,Abstracts ,medicine.anatomical_structure ,Tissue specimen ,Oncology ,Cancer research ,Medicine ,Neurology (clinical) ,Central nervous system lesion ,business - Abstract
Approximately 8% of patients with cancer develop leptomeningeal carcinomatosis (LMD). LMD is associated with approximately 4 week median survival and a paucity of treatment options beyond palliative shunting. We performed a phase II study of the PD-1 inhibitor pembrolizumab in LMD from any solid tumor malignancy (NCT02886585). The primary endpoint is the rate of overall survival at 3 months (OS3). A Simon two-stage design was used to compare a null hypothesis OS3 of 18% against an alternative of 43%. Serial CSF, blood samples and tumor samples were collected to elucidate the genomic and transcriptional determinants of response to immunotherapy in central nervous system lesions. A total of 18 patients were accrued and the median follow-up of patients still alive was 6.8 months (range: 2.2 to 7.6 months). At the time of data retrieval, 11 patients (61%) were alive at three months after enrollment (OS3). Therefore, the study met its primary endpoint. Whole exome sequencing of tissue samples and cell-free DNA from CSF and blood, as well as single-cell RNA sequencing of CSF, were carried out to decipher tumor evolution, track immune cell recruitment, and identify biomarkers of response. Analysis of 7877 tumor and immune cells across 6 patients demonstrated patient-specific tumor clustering and evidence of T cell and antigen presenting cells recruited to the CSF following pembrolizumab treatment. Longitudinal CSF samples demonstrated genetic and transcriptomic differences in tumor and immune cells suggesting response to treatment in patients that reached OS3 compared with those that did not. These findings suggest that pembrolizumab has activity in LMD and that CSF provides an opportunity to monitor the clonal evolution of the tumor and immune microenvironment in LMD.
- Published
- 2018
41. Phase II study of tivozanib, an oral VEGFR inhibitor, in patients with recurrent glioblastoma
- Author
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Andrew S. Chi, Elizabeth R. Gerstner, Kyrre E. Emblem, Linda Douw, Patrick Y. Wen, Dan G. Duda, Rakesh K. Jain, Tracy T. Batchelor, Bruce R. Rosen, John G Evans, Alona Muzikansky, Jorg Dietrich, Vyshak Chandra, Jayashree Kalpathy-Cramer, Xuezhu Cai, Xiao Da, Stephen Stufflebeam, Yangming Ou, Anatomy and neurosciences, Amsterdam Neuroscience - Brain Imaging, Amsterdam Neuroscience - Neuroinfection & -inflammation, and CCA - Imaging and biomarkers
- Subjects
Male ,0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Pathology ,Tivozanib ,Angiogenesis ,Administration, Oral ,Phases of clinical research ,Antineoplastic Agents ,Vascular permeability ,Article ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Biomarkers, Tumor ,medicine ,Humans ,Progression-free survival ,Survival analysis ,Aged ,Neovascularization, Pathologic ,Brain Neoplasms ,business.industry ,Phenylurea Compounds ,Middle Aged ,medicine.disease ,Survival Analysis ,Receptors, Vascular Endothelial Growth Factor ,Treatment Outcome ,030104 developmental biology ,Neurology ,030220 oncology & carcinogenesis ,Dynamic contrast-enhanced MRI ,Quinolines ,Female ,Neurology (clinical) ,Neoplasm Recurrence, Local ,Glioblastoma ,business ,Progressive disease ,medicine.drug - Abstract
Targeting tumor angiogenesis is a potential therapeutic strategy for glioblastoma because of its high vascularization. Tivozanib is an oral pan-VEGF receptor tyrosine kinase inhibitor that hits a central pathway in glioblastoma angiogenesis. We conducted a phase II study to test the effectiveness of tivozanib in patients with recurrent glioblastoma. Ten adult patients were enrolled and treated with tivozanib 1.5 mg daily, 3 weeks on/1 week off in 28-day cycles. Brain MRI and blood biomarkers of angiogenesis were performed at baseline, within 24-72 h of treatment initiation, and monthly thereafter. Dynamic contrast enhanced MRI, dynamic susceptibility contrast MRI, and vessel architecture imaging were used to assess vascular effects. Resting state MRI was used to assess brain connectivity. Best RANO criteria responses were: 1 complete response, 1 partial response, 4 stable diseases, and 4 progressive disease (PD). Two patients were taken off study for toxicity and 8 patients were taken off study for PD. Median progression-free survival was 2.3 months and median overall survival was 8.1 months. Baseline abnormal tumor vascular permeability, blood flow, tissue oxygenation and plasma sVEGFR2 significantly decreased and plasma PlGF and VEGF increased after treatment, suggesting an anti-angiogenic effect of tivozanib. However, there were no clear structural changes in vasculature as vessel caliber and enhancing tumor volume did not significantly change. Despite functional changes in tumor vasculature, tivozanib had limited anti-tumor activity, highlighting the limitations of anti-VEGF monotherapy. Future studies in glioblastoma should leverage the anti-vascular activity of agents targeting VEGF to enhance the activity of other therapies.
- Published
- 2017
42. NIMG-01. DIFFUSION MRI PHENOTYPES PREDICT OVERALL SURVIVAL BENEFIT FROM ANTI-VEGF MONOTHERAPY IN GLIOBLASTOMA AT FIRST OR SECOND RELAPSE
- Author
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Dana T. Aftab, Elizabeth R. Gerstner, Ray Huang, Rivka R. Colen, Patrick Y. Wen, Benjamin M. Ellingson, Lauren E. Abrey, Gisela Schwab, Tracy T. Batchelor, Whitney B. Pope, Timothy F. Cloughesy, Martin J. van den Bent, Renske Gahrmann, Marion Smits, John de Groot, and Colin Hessel
- Subjects
Oncology ,Anti vegf ,Cancer Research ,medicine.medical_specialty ,business.industry ,medicine.disease ,Phenotype ,Abstracts ,Text mining ,Internal medicine ,Overall survival ,Medicine ,Neurology (clinical) ,business ,Glioblastoma ,Diffusion MRI - Abstract
Anti-VEGF therapies remain controversial in the treatment of recurrent GBM. In the current study we demonstrate that recurrent GBM patients with a specific diffusion MR imaging signature have an OS advantage when treated with anti-VEGF therapy at first or second recurrence. These findings were then validated using data from a separate trial.
- Published
- 2017
43. NIMG-63. ADVANCED IMAGING FOR ASSESSING VOLUMETRIC RESPONSES IN BRAIN METASTASES TREATED WITH CHECKPOINT BLOCKADE
- Author
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James M. Brown, Jonathan Cardona, Donald P. Lawrence, Michael White, Lakshmi Nayak, Sara M. Tolaney, Jayashree Kalpathy-Cramer, Kevin S. Oh, Beverly Moy, Andrew Beers, Nan Lin, Justine V. Cohen, Priscilla K. Brastianos, Eudocia Q. Lee, Anita Giobbie-Hurder, Elizabeth R. Gerstner, Ugonma Chukwueke, Ken Chang, Helen A. Shih, Ryan J. Sullivan, and Daniel P. Cahill
- Subjects
Oncology ,Abstracts ,Cancer Research ,medicine.medical_specialty ,business.industry ,Internal medicine ,Medicine ,Neurology (clinical) ,business ,Blockade - Abstract
BACKGROUND: Immunotherapy has been effective therapy for brain metastases (BM) from melanoma and lung cancer, prompting interest in using PD-1 targeting drugs in more patients with BM. However, accurately assessing response in patients undergoing immunotherapy continues to be a challenge. Thus, we prospectively evaluated radiographic characteristics and changes during immunotherapy. METHODS: As part of an ongoing Phase 2 study of pembrolizumab for patients with untreated or progressive, previously treated BM from any histology, patients underwent advanced MRI that includes tumor volume measurements and perfusion imaging with dynamic susceptibility contrast MRI.. To calculate volumetric radiographic response, all enhancing voxels were summated. A volumetric increase of >40% was categorized as progressive disease (PD), a decrease of >60% as partial response (PR), and stable disease (SD) as between -60% and +40%. RESULTS: Forty-eight patients have been enrolled of whom 38 have undergone at least baseline advanced MR imaging. Histologies include 16 with breast cancer (12 HER2-, 4 HER2+), 5 with non-small cell lung cancer, 4 with melanoma, and 11 with other cancers. At baseline, the total number of BM was 1–50+ per patient. Based on summing the entire enhancing intracranial disease burden, best volumetric responses for the 25 evaluable patients include 2 PR, 9 SD, and 14 PD. Cerebral blood volume tended to increase with increasing tumor size. Correlation of volumetric response to patient outcome and standardized response criteria (iRANO) is ongoing. CONCLUSIONS: Pembrolizumab may have activity in metastatic brain cancer. Ongoing analyses are evaluating if physiological MRI can shed light on the biological impact of pembrolizumab and response mechanisms in this patient population.
- Published
- 2018
44. NIMG-68. MRI CHANGES IN NEWLY DIAGNOSED GLIOBLASTOMA PATIENTS TREATED AS PART OF A PHASE II TRIAL WITH BAVITUXIMAB, RADIATION, AND TEMOZOLOMIDE
- Author
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Jonathan Cardona, Ina Ly, Deborah Forst, Jayashree Kalpathy-Cramer, Eudocia Q. Lee, Andrew Beers, Tracy T. Batchelor, Isabel Arrillaga-Romany, Justin T. Jordan, Lakshmi Nayak, Elizabeth R. Gerstner, David A. Reardon, Ken Chang, Jorg Dietrich, James M. Brown, and Patrick Y. Wen
- Subjects
Cancer Research ,medicine.medical_specialty ,Bavituximab ,Temozolomide ,medicine.diagnostic_test ,business.industry ,Cancer ,Phases of clinical research ,O-6-methylguanine-DNA methyltransferase ,Magnetic resonance imaging ,Newly diagnosed ,medicine.disease ,Abstracts ,Oncology ,medicine ,Neurology (clinical) ,Radiology ,business ,medicine.drug ,Glioblastoma - Abstract
BACKGROUND: Glioblastoma and tumor endothelial cells express phosphatidylserine, a highly immunosuppressive membrane phospholipid. Bavituximab a chimeric monoclonal antibody binds to 2-glycoprotein 1 (2-GP1) to form a complex of 2-GP1 with phosphatidylserine, resulting in immune activation against tumor cells and anti-angiogenic effects. Phase I/II trials in other solid cancers have demonstrated response rates up to 85% when bavituximab was given with cytotoxic chemotherapy. Pre-clinical data in glioblastoma models suggested synergistic effects of phosphatidylserine blockade, radiation, and temozolomide (TMZ). METHODS: In this ongoing phase II trial (NCT03139916), adult patients with IDH-wild-type newly diagnosed glioblastoma receive 6 weeks of chemoradiation, followed by 6 cycles of adjuvant TMZ (C1-C6 aTMZ). Bavituximab (3 mg/kg) is given weekly, starting week 1 of chemoradiation, for 18 weeks with the option to continue if tolerated. Physiologic MRIs are performed pre-treatment, pre-C1, pre-C3, and pre-C5 aTMZ. Within the enhancing tumor region, we measured median tumor Ktrans (reflecting vascular permeability) and relative cerebral blood volume (rCBV). Median percent changes during treatment were compared to pre-treatment values. RESULTS: To date, 25 of 36 anticipated patients have enrolled (10 with MGMT promoter methylation). All patients underwent pre-treatment scans. 13 have evaluable pre-C1 and 8 pre-C3 aTMZ scans. On the pre-C1 MRIs, enhancing volume decreased by 39% and median tumor Ktrans and rCBV did not change significantly. On the pre-C3 MRIs, enhancing volume decreased by 11% and Ktrans and rCBV decreased by 17% and 21%, respectively. Five patients experienced radiographic disease progression after a median of 2.6 months and 1 patient died 76 days after diagnosis due to disease progression. Bavituximab was generally well tolerated. CONCLUSIONS: Combining bavituximab with radiation and temozolomide results in decreased enhancing tumor volume, permeability, and cerebral perfusion. Continued patient accrual and imaging marker evaluation are underway to investigate the correlation between bavituximab, MRI changes, and survival.
- Published
- 2018
45. RARE-24. OBJECTIVE RESPONSE AND CLINICAL BENEFIT IN RECURRENT EPENDYMOMA IN ADULTS: FINAL REPORT OF CERN 08-02: A PHASE II STUDY OF DOSE-DENSE TEMOZOLOMIDE AND LAPATINIB
- Author
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Tito R. Mendoza, Terri S. Armstrong, Antonio Omuro, Kenneth Aldape, Tom Mikkelsen, Patrick Y. Wen, Mark R. Gilbert, Elizabeth R. Gerstner, Elizabeth Vera, Jing Wu, Jimin Wu, H. I. Robins, Ying Yuan, and Frank S. Lieberman
- Subjects
Ependymoma ,Oncology ,Cancer Research ,medicine.medical_specialty ,Temozolomide ,Surrogate endpoint ,business.industry ,Phases of clinical research ,medicine.disease ,Lapatinib ,Chemotherapy regimen ,Abstracts ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Neurology (clinical) ,Progression-free survival ,business ,Objective response ,030217 neurology & neurosurgery ,medicine.drug - Abstract
BACKGROUND: Ependymoma is a rare tumor for which the role of chemotherapy has not been established either for newly diagnosed or recurrent disease. We report on the first prospective adult clinical trial of chemotherapy for recurrent ependymoma. METHODS: Adult (> 18 years) were treated with dose-dense temozolomide (125–150 mg/m2, 7days on/7days off) and daily lapatinib (1250 mg/day). Efficacy was based on serial imaging of either brain or spine using MRI. Clinical benefit was evaluated using longitudinal assessment of symptom burden (MDASI-BT/MDASI-Spine) and performance status. Primary endpoint was progression free survival. Additional endpoints included 12-month PFS rate, objective response and clinical benefit (KPS and changes in proportion of moderate-severe disease-related symptom burden through cycle 6). RESULTS: 50 patients were treated with this regimen. Median age = 43.5, median KPS = 90, median number of prior relapse = 2. By tumor grade: III n = 19, II n = 16, I n = 8. 25 patients had spinal cord, 15 had supratentorial and 8 had infratentorial tumors. Treatment was well tolerated with a 10% Grade 3–4 myelotoxicity rate. Median PFS = 0.65 years (95%CI 0.46, 1.02). 1-year PFS=38%, with 1 complete and 4 partial responses. KPS improved in all but 1 patient and MDASI measures were completed on 86% of cases with reduction in moderate-severe pain in 53% and 71% of brain and spine patients respectively. Patients with spine tumors reported improvement in numbness (57%), weakness (24%), fatigue (23%)and autonomic dysfunction (bladder control (73%), sexual function (9%), and bowel function (36%)). CONCLUSIONS: These results demonstrate evidence of clinical activity, including objective responses and a nearly 40% stable disease rate at one year, with improvement in disease-related symptoms. This combination regimen was well tolerated and should be considered as a standard salvage regimen for adult patients with recurrent ependymoma.
- Published
- 2018
46. Increase in tumor-associated macrophages after antiangiogenic therapy is associated with poor survival among patients with recurrent glioblastoma
- Author
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Rakesh K. Jain, Jorg Dietrich, Matija Snuderl, Nathaniel D. Kirkpatrick, Tracy T. Batchelor, Jennie Taylor, Andrew S. Chi, Christian Davidson, Lars Riedemann, Yuhui Huang, Scott R. Plotkin, Percy Ivy, Jermaine Goveia, Anat Stemmer-Rachamimov, Dan G. Duda, Christine Lu-Emerson, Marek Ancukiewicz, April F. Eichler, and Elizabeth R. Gerstner
- Subjects
Male ,Cancer Research ,Pathology ,Myeloid ,medicine.medical_treatment ,Angiogenesis Inhibitors ,Immunoenzyme Techniques ,80 and over ,Tumor Microenvironment ,Cancer ,relapse ,Aged, 80 and over ,Tumor ,Brain Neoplasms ,CD68 ,Middle Aged ,Flow Cytometry ,Prognosis ,Chemotherapy regimen ,CD ,Survival Rate ,medicine.anatomical_structure ,Local ,Oncology ,myeloid cells ,Female ,Autopsy ,Adult ,medicine.medical_specialty ,Adolescent ,CD14 ,Oncology and Carcinogenesis ,Clinical Investigations ,Young Adult ,Rare Diseases ,Antigens, CD ,Biomarkers, Tumor ,medicine ,Humans ,Oncology & Carcinogenesis ,Antigens ,Survival rate ,Aged ,Chemotherapy ,Tumor microenvironment ,business.industry ,Macrophages ,glioblastoma ,Neurosciences ,Brain Disorders ,Brain Cancer ,Radiation therapy ,Neoplasm Recurrence ,antiangiogenic therapy ,Cancer research ,Neurology (clinical) ,Neoplasm Grading ,Neoplasm Recurrence, Local ,Glioblastoma ,business ,Biomarkers ,Follow-Up Studies - Abstract
Antiangiogenic therapy is associated with increased radiographic responses in glioblastomas, but tumors invariably recur. Because tumor-associated macrophages have been shown to mediate escape from antiangiogenic therapy in preclinical models, we examined the role of macrophages in patients with recurrent glioblastoma. We compared autopsy brain specimens from 20 patients with recurrent glioblastoma who received antiangiogenic treatment and chemoradiation with 8 patients who received chemotherapy and/or radiotherapy without antiangiogenic therapy or no treatment. Tumor-associated macrophages were morphologically and phenotypically analyzed using flow cytometry and immunohistochemistry for CD68, CD14, CD163, and CD11b expression. Flow cytometry showed an increase in macrophages in the antiangiogenic-treated patients. Immunohistochemical analysis demonstrated an increase in CD68+ macrophages in the tumor bulk (P < .01) and infiltrative areas (P = .02) in antiangiogenic-treated patients. We also observed an increase in CD11b+ cells in the tumor bulk (P < .01) and an increase in CD163+ macrophages in infiltrative tumor (P = .02). Of note, an increased number of CD11b+ cells in bulk and infiltrative tumors (P = .05 and P = .05, respectively) correlated with poor overall survival among patients who first received antiangiogenic therapy at recurrence. In summary, recurrent glioblastomas showed an increased infiltration in myeloid populations in the tumor bulk and in the infiltrative regions after antiangiogenic therapy. Higher numbers of CD11b+ cells correlated with poor survival among these patients. These data suggest that tumor-associated macrophages may participate in escape from antiangiogenic therapy and may represent a potential biomarker of resistance and a potential therapeutic target in recurrent glioblastoma.
- Published
- 2013
47. Volumetric relationship between 2-hydroxyglutarate and FLAIR hyperintensity has potential implications for radiotherapy planning of mutant IDH glioma patients
- Author
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Gilberto Gonzalez, Tracy T. Batchelor, Kourosh Jafari-Khouzani, Daniel P. Cahill, Helen A. Shih, Andrew S. Chi, Otto Rapalino, Ovidiu C. Andronesi, Jan Unkelbach, Bruce R. Rosen, Wolfgang Bogner, Franziska Loebel, and Elizabeth R. Gerstner
- Subjects
Adult ,Male ,Cancer Research ,IDH1 ,Magnetic Resonance Spectroscopy ,Fluid-attenuated inversion recovery ,Glutarates ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Basic and Translational Investigation ,Glioma ,Medical imaging ,medicine ,Humans ,Radiation treatment planning ,Aged, 80 and over ,medicine.diagnostic_test ,business.industry ,Brain Neoplasms ,Radiotherapy Planning, Computer-Assisted ,Magnetic resonance spectroscopic imaging ,Brain ,Magnetic resonance imaging ,Middle Aged ,medicine.disease ,Magnetic Resonance Imaging ,Hyperintensity ,Isocitrate Dehydrogenase ,Oncology ,030220 oncology & carcinogenesis ,Mutation ,Female ,Neurology (clinical) ,Nuclear medicine ,business ,030217 neurology & neurosurgery - Abstract
Background Gliomas with mutant isocitrate dehydrogenase (IDH) produce high levels of 2-hydroxyglutarate (2HG) that can be quantitatively measured by 3D magnetic resonance spectroscopic imaging (MRSI). Current glioma MRI primarily relies upon fluid-attenuated inversion recovery (FLAIR) hyperintensity for treatment planning, although this lacks specificity for tumor cells. Here, we investigated the relationship between 2HG and FLAIR in mutant IDH glioma patients to determine whether 2HG mapping is valuable for radiotherapy planning. Methods Seventeen patients with mutant IDH1 gliomas were imaged by 3 T MRI. A 3D MRSI sequence was employed to specifically image 2HG. FLAIR imaging was performed using standard clinical protocol. Regions of interest (ROIs) were determined for FLAIR and optimally thresholded 2HG hyperintensities. The overlap, displacement, and volumes of 2HG and FLAIR ROIs were calculated. Results In 8 of 17 (47%) patients, the 2HG volume was larger than FLAIR volume. Across the entire cohort, the mean volume of 2HG was 35.3 cc (range, 5.3-92.7 cc), while the mean volume of FLAIR was 35.8 cc (range, 6.3-140.8 cc). FLAIR and 2HG ROIs had mean overlap of 0.28 (Dice coefficients range, 0.03-0.57) and mean displacement of 12.2 mm (range, 3.2-23.5 mm) between their centers of mass. Conclusions Our results indicate that for a substantial number of patients, the 2HG volumetric assessment of tumor burden is more extensive than FLAIR volume. In addition, there is only partial overlap and asymmetric displacement between the centers of FLAIR and 2HG ROIs. These results may have important implications for radiotherapy planning of IDH mutant glioma.
- Published
- 2016
48. NIMG-23A CONNECTOMIC PHENOTYPE OF 1p/19q LOSS OF HETEROZYGOSITY IN LOW-GRADE GLIOMA
- Author
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Elizabeth R. Gerstner, Julie J. Miller, and Linda Douw
- Subjects
Cancer Research ,Pathology ,medicine.medical_specialty ,Performance status ,business.industry ,medicine.disease ,Phenotype ,Loss of heterozygosity ,Text mining ,Oncology ,Glioma ,medicine ,Connectome ,Low-Grade Glioma ,Neurology (clinical) ,business ,Nuclear medicine ,Abstracts from the 20th Annual Scientific Meeting of the Society for Neuro-Oncology ,Diffusion MRI - Abstract
The efficiency of a healthy brain network (the ‘connectome’) is positively related to physical and cognitive function. We sought to determine whether changes in network efficiency were related to loss of heterozygosity (LOH) at 1p/19q, a favorable prognostic marker in low-grade glioma (LGG). The presurgical diffusion tensor imaging (DTI) of LGG patients (WHO grade II) with known 1p/19q status treated at MGH were retrospectively analyzed. Processing included co-registration with anatomical 3D images, probabilistic tractography with FSL, and binary network construction based on the number of streamlines connecting each parcel from the Automated Anatomical Labeling atlas for which a benchmark healthy connectome (HC) is available. Path length (the average shortest number of steps between each network region) of the whole brain and the hemisphere contralateral to the tumor were compared to the HC by one-sample Wilcoxon signed rank tests. Path lengths of patients with and without LOH were compared using Mann-Whitney U tests. Thirteen patients with images acquired between 2008-2014 were included (8 male, mean age 42 ± 14 years, 8 left-sided tumors, median KPS 90). Four patients showed LOH. At the group level, patients had longer whole-brain path length (2.5 ± 0.3 steps, p = 0.023) and contralateral path length (2.0 ± 0.2 steps, p = 0.033) than the HC (2.3 and 1.9 steps, resp.), indicating a less efficient connectome. Patients with LOH had shorter contralateral path length than those without (2.5 ± 0.3 versus 2.3 ± 0.1 steps, p = 0.011). Age, gender, presurgical tumor volume, and performance status did not influence these results significantly. These results indicate that patients with LGG have decreased connectome efficiency even in the contralateral hemisphere, highlighting the global impact of local tumors. 1p/19q LOH is associated with a more efficient connectome, supporting the more favorable performance status and prognosis in these patients. Connectivity is therefore a promising noninvasive biomarker for prognosis and holds potential for treatment monitoring.
- Published
- 2015
49. Phase I trial with biomarker studies of vatalanib (PTK787) in patients with newly diagnosed glioblastoma treated with enzyme inducing anti-epileptic drugs and standard radiation and temozolomide
- Author
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Tracy T. Batchelor, Patrick Y. Wen, Lei Xu, Elizabeth R. Gerstner, Rakesh K. Jain, Scott R. Plotkin, Dan G. Duda, Jan Drappatz, Colin Doyle, and April F. Eichler
- Subjects
Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Vatalanib ,Maximum Tolerated Dose ,Pyridines ,Dacarbazine ,Antineoplastic Agents ,Pharmacology ,Neutropenia ,Polymorphism, Single Nucleotide ,Article ,Pharmacokinetics ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Biomarkers, Tumor ,Temozolomide ,Humans ,Medicine ,Aged ,Vascular Endothelial Growth Factor Receptor-1 ,Leukopenia ,Radiotherapy ,Brain Neoplasms ,business.industry ,Membrane Proteins ,Middle Aged ,medicine.disease ,Combined Modality Therapy ,Receptor, TIE-2 ,Vascular Endothelial Growth Factor Receptor-2 ,Neurology ,Concomitant ,Phthalazines ,Biomarker (medicine) ,Anticonvulsants ,Female ,Neurology (clinical) ,medicine.symptom ,Glioblastoma ,business ,medicine.drug - Abstract
Targeting angiogenesis in glioblastoma (GBM) may improve patient outcome by normalizing tumor vasculature and improving delivery of chemotherapeutics and oxygen. Consequently, concomitant administration of small molecule inhibitors of the VEGF pathway will likely have a positive impact on chemoradiation treatment outcome. We conducted a Phase I study of vatalanib, a small molecule inhibitor of VEGFR, PDGFR, and c-kit in patients with newly diagnosed GBM receiving radiation, temozolomide, and an enzyme-inducing anti-epileptic drug in order to determine the MTD of vatalanib in this patient population. We incorporated circulating biomarker and SNP analyses and pharmacokinetic studies. Nineteen patients were enrolled and the MTD was not reached at the time of study termination. Vatalanib was well tolerated with only 2 DLTs (thrombocytopenia and elevated transaminases). Other grade 3/4 toxicities included leukopenia, lymphopenia, neutropenia, and hand-foot syndrome. There were no wound-healing complications. Of the 13 patients evaluable for a radiographic response, 2 had a partial response and 9 had stable disease. Vatalanib significantly increased PlGF and sVEGFR1 in plasma circulation and decreased sVEGFR2 and sTie2. Plasma collagen IV increased significantly by day 50 of treatment. Vatalanib was well tolerated and this study demonstrates the safety of oral small molecule inhibitors in newly diagnosed GBM patients. Blood biomarkers may be useful as pharmacodynamic markers of response to anti-angiogenic therapies.
- Published
- 2010
50. NIMG-53. POST-SURGICAL, RESIDUAL ENHANCING TUMOR VOLUME IS PROGNOSTIC FOR OVERALL SURVIVAL IN NEWLY DIAGNOSED GLIOBLASTOMA: EVIDENCE FROM 1,458 PATIENTS POOLED FROM INTERNATIONAL TRIALS, SINGLE INSTITUTION DATABASES, AND MULTICENTER CONSORTIUMS
- Author
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Benjamin M. Ellingson, Robert J. Young, Sarah J. Nelson, Timothy F. Cloughesy, Keith L. Ligon, Jennie Taylor, Olivier Chinot, Wolfgang Wick, Patrick Y. Wen, Susan M. Chang, Isabel Arrillaga-Romany, David A. Reardon, Ryo Nishikawa, Rivka R. Colen, Nicholas Butowski, Warren P. Mason, John de Groot, Howard Colman, Whitney B. Pope, Josep Garcia, Lauren E. Abrey, Frank Saran, Roger Henriksson, Michael D. Prados, Ingo K. Mellinghoff, Tracy T. Batchelor, Elizabeth R. Gerstner, and Ray Huang
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Post surgical ,business.industry ,Newly diagnosed ,medicine.disease ,Surgery ,Abstracts ,Internal medicine ,Overall survival ,Medicine ,Neurology (clinical) ,Single institution ,business ,Glioblastoma - Abstract
The prognostic significance of residual contrast enhancing tumor volume after initial surgery to predict OS in newly diagnosed GBM remains poorly understood and not controlled for in prospective clinical trials. In the current study we pooled imaging data in >1,400 newly diagnosed GBM patients from international multicenter clinical trials, single institution databases, and multicenter clinical trial consortiums identify relationships between clinical parameters, MGMT methylation status, treatment, and residual enhancing tumor volume on OS.
- Published
- 2017
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