1,466 results on '"Chang, Susan M"'
Search Results
2. “De novo replication repair deficient glioblastoma, IDH-wildtype” is a distinct glioblastoma subtype in adults that may benefit from immune checkpoint blockade
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Hadad, Sara, Gupta, Rohit, Oberheim Bush, Nancy Ann, Taylor, Jennie W, Villanueva-Meyer, Javier E, Young, Jacob S, Wu, Jasper, Ravindranathan, Ajay, Zhang, Yalan, Warrier, Gayathri, McCoy, Lucie, Shai, Anny, Pekmezci, Melike, Perry, Arie, Bollen, Andrew W, Phillips, Joanna J, Braunstein, Steve E, Raleigh, David R, Theodosopoulos, Philip, Aghi, Manish K, Chang, Edward F, Hervey-Jumper, Shawn L, Costello, Joseph F, de Groot, John, Butowski, Nicholas A, Clarke, Jennifer L, Chang, Susan M, Berger, Mitchel S, Molinaro, Annette M, and Solomon, David A
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Brain Cancer ,Cancer ,Precision Medicine ,Brain Disorders ,Genetics ,Human Genome ,Clinical Research ,Cancer Genomics ,Neurosciences ,Immunotherapy ,Orphan Drug ,Rare Diseases ,2.1 Biological and endogenous factors ,Good Health and Well Being ,Adult ,Humans ,Child ,Middle Aged ,Aged ,Glioblastoma ,Immune Checkpoint Inhibitors ,Homozygote ,Prospective Studies ,Brain Neoplasms ,Sequence Deletion ,Mutation ,Isocitrate Dehydrogenase ,Giant cell glioblastoma ,Hypermutation ,Ultrahypermutation ,Mismatch repair deficiency ,POLE ,Lynch syndrome ,Immune checkpoint blockade ,Molecular neuropathology ,Molecular neuro-oncology ,Neurology & Neurosurgery - Abstract
Glioblastoma is a clinically and molecularly heterogeneous disease, and new predictive biomarkers are needed to identify those patients most likely to respond to specific treatments. Through prospective genomic profiling of 459 consecutive primary treatment-naïve IDH-wildtype glioblastomas in adults, we identified a unique subgroup (2%, 9/459) defined by somatic hypermutation and DNA replication repair deficiency due to biallelic inactivation of a canonical mismatch repair gene. The deleterious mutations in mismatch repair genes were often present in the germline in the heterozygous state with somatic inactivation of the remaining allele, consistent with glioblastomas arising due to underlying Lynch syndrome. A subset of tumors had accompanying proofreading domain mutations in the DNA polymerase POLE and resultant "ultrahypermutation". The median age at diagnosis was 50 years (range 27-78), compared with 63 years for the other 450 patients with conventional glioblastoma (p
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- 2024
3. Challenges in the discovery of tumor-specific alternative splicing-derived cell-surface antigens in glioma
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Nejo, Takahide, Wang, Lin, Leung, Kevin K, Wang, Albert, Lakshmanachetty, Senthilnath, Gallus, Marco, Kwok, Darwin W, Hong, Chibo, Chen, Lee H, Carrera, Diego A, Zhang, Michael Y, Stevers, Nicholas O, Maldonado, Gabriella C, Yamamichi, Akane, Watchmaker, Payal B, Naik, Akul, Shai, Anny, Phillips, Joanna J, Chang, Susan M, Wiita, Arun P, Wells, James A, Costello, Joseph F, Diaz, Aaron A, and Okada, Hideho
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Biological Sciences ,Bioinformatics and Computational Biology ,Biomedical and Clinical Sciences ,Immunology ,Oncology and Carcinogenesis ,Brain Disorders ,Cancer ,Neurosciences ,Biotechnology ,Human Genome ,Rare Diseases ,Brain Cancer ,Genetics ,Inflammatory and immune system ,Generic health relevance ,Humans ,Alternative Splicing ,Antigens ,Surface ,Glioma ,Glioblastoma ,Histocompatibility Antigens ,RNA ,Antigens ,Neoplasm ,Receptor-Like Protein Tyrosine Phosphatases ,Class 5 ,Alternative splicing ,Antigen ,Neojunction ,Bulk RNA-sequencing ,Long-read sequencing ,Intratumoral heterogeneity ,Proteomics - Abstract
Despite advancements in cancer immunotherapy, solid tumors remain formidable challenges. In glioma, profound inter- and intra-tumoral heterogeneity of antigen landscape hampers therapeutic development. Therefore, it is critical to consider alternative sources to expand the repertoire of targetable (neo-)antigens and improve therapeutic outcomes. Accumulating evidence suggests that tumor-specific alternative splicing (AS) could be an untapped reservoir of antigens. In this study, we investigated tumor-specific AS events in glioma, focusing on those predicted to generate major histocompatibility complex (MHC)-presentation-independent, cell-surface antigens that could be targeted by antibodies and chimeric antigen receptor-T cells. We systematically analyzed bulk RNA-sequencing datasets comparing 429 tumor samples (from The Cancer Genome Atlas) and 9166 normal tissue samples (from the Genotype-Tissue Expression project), and identified 13 AS events in 7 genes predicted to be expressed in more than 10% of the patients, including PTPRZ1 and BCAN, which were corroborated by an external RNA-sequencing dataset. Subsequently, we validated our predictions and elucidated the complexity of the isoforms using full-length transcript amplicon sequencing on patient-derived glioblastoma cells. However, analyses of the RNA-sequencing datasets of spatially mapped and longitudinally collected clinical tumor samples unveiled remarkable spatiotemporal heterogeneity of the candidate AS events. Furthermore, proteomics analysis did not reveal any peptide spectra matching the putative antigens. Our investigation illustrated the diverse characteristics of the tumor-specific AS events and the challenges of antigen exploration due to their notable spatiotemporal heterogeneity and elusive nature at the protein levels. Redirecting future efforts toward intracellular, MHC-presented antigens could offer a more viable avenue.
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- 2024
4. Advanced Hyperpolarized 13C Metabolic Imaging Protocol for Patients with Gliomas: A Comprehensive Multimodal MRI Approach
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Autry, Adam W, Vaziri, Sana, Gordon, Jeremy W, Chen, Hsin-Yu, Kim, Yaewon, Dang, Duy, LaFontaine, Marisa, Noeske, Ralph, Bok, Robert, Villanueva-Meyer, Javier E, Clarke, Jennifer L, Bush, Nancy Ann Oberheim, Chang, Susan M, Xu, Duan, Lupo, Janine M, Larson, Peder EZ, Vigneron, Daniel B, and Li, Yan
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Biomedical and Clinical Sciences ,Clinical Sciences ,Clinical Research ,Biomedical Imaging ,Bioengineering ,Neurosciences ,Brain Disorders ,Rare Diseases ,Detection ,screening and diagnosis ,4.2 Evaluation of markers and technologies ,hyperpolarized carbon-13 ,atlas-based prescription ,glioma ,serial imaging ,metabolism ,kinetics ,Warburg ,Oncology and Carcinogenesis ,Oncology and carcinogenesis - Abstract
This study aimed to implement a multimodal 1H/HP-13C imaging protocol to augment the serial monitoring of patients with glioma, while simultaneously pursuing methods for improving the robustness of HP-13C metabolic data. A total of 100 1H/HP [1-13C]-pyruvate MR examinations (104 HP-13C datasets) were acquired from 42 patients according to the comprehensive multimodal glioma imaging protocol. Serial data coverage, accuracy of frequency reference, and acquisition delay were evaluated using a mixed-effects model to account for multiple exams per patient. Serial atlas-based HP-13C MRI demonstrated consistency in volumetric coverage measured by inter-exam dice coefficients (0.977 ± 0.008, mean ± SD; four patients/11 exams). The atlas-derived prescription provided significantly improved data quality compared to manually prescribed acquisitions (n = 26/78; p = 0.04). The water-based method for referencing [1-13C]-pyruvate center frequency significantly reduced off-resonance excitation relative to the coil-embedded [13C]-urea phantom (4.1 ± 3.7 Hz vs. 9.9 ± 10.7 Hz; p = 0.0007). Significantly improved capture of tracer inflow was achieved with the 2-s versus 5-s HP-13C MRI acquisition delay (p = 0.007). This study demonstrated the implementation of a comprehensive multimodal 1H/HP-13C MR protocol emphasizing the monitoring of steady-state/dynamic metabolism in patients with glioma.
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- 2024
5. Novel SOX10 indel mutations drive schwannomas through impaired transactivation of myelination gene programs
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Williams, Erik A, Ravindranathan, Ajay, Gupta, Rohit, Stevers, Nicholas O, Suwala, Abigail K, Hong, Chibo, Kim, Somang, Yuan, Jimmy Bo, Wu, Jasper, Barreto, Jairo, Lucas, Calixto-Hope G, Chan, Emily, Pekmezci, Melike, LeBoit, Philip E, Mully, Thaddeus, Perry, Arie, Bollen, Andrew, Van Ziffle, Jessica, Devine, W Patrick, Reddy, Alyssa T, Gupta, Nalin, Basnet, Kristen M, Macaulay, Robert JB, Malafronte, Patrick, Lee, Han, Yong, William H, Williams, Kevin Jon, Juratli, Tareq A, Mata, Douglas A, Huang, Richard SP, Hiemenz, Matthew C, Pavlick, Dean C, Frampton, Garrett M, Janovitz, Tyler, Ross, Jeffrey S, Chang, Susan M, Berger, Mitchel S, Jacques, Line, Song, Jun S, Costello, Joseph F, and Solomon, David A
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Biomedical and Clinical Sciences ,Clinical Sciences ,Pediatric ,Cancer ,Human Genome ,Neurosciences ,Biotechnology ,Genetics ,Rare Diseases ,Aetiology ,2.1 Biological and endogenous factors ,Humans ,INDEL Mutation ,Transcriptional Activation ,Neurilemmoma ,Neuroma ,Acoustic ,Mutation ,Nerve Sheath Neoplasms ,SOXE Transcription Factors ,myelination ,PMP2 ,Schwann cell ,schwannoma ,SOX10 ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
BackgroundSchwannomas are common peripheral nerve sheath tumors that can cause severe morbidity given their stereotypic intracranial and paraspinal locations. Similar to many solid tumors, schwannomas and other nerve sheath tumors are primarily thought to arise due to aberrant hyperactivation of the RAS growth factor signaling pathway. Here, we sought to further define the molecular pathogenesis of schwannomas.MethodsWe performed comprehensive genomic profiling on a cohort of 96 human schwannomas, as well as DNA methylation profiling on a subset. Functional studies including RNA sequencing, chromatin immunoprecipitation-DNA sequencing, electrophoretic mobility shift assay, and luciferase reporter assays were performed in a fetal glial cell model following transduction with wildtype and tumor-derived mutant isoforms of SOX10.ResultsWe identified that nearly one-third of sporadic schwannomas lack alterations in known nerve sheath tumor genes and instead harbor novel recurrent in-frame insertion/deletion mutations in SOX10, which encodes a transcription factor responsible for controlling Schwann cell differentiation and myelination. SOX10 indel mutations were highly enriched in schwannomas arising from nonvestibular cranial nerves (eg facial, trigeminal, vagus) and were absent from vestibular nerve schwannomas driven by NF2 mutation. Functional studies revealed these SOX10 indel mutations have retained DNA binding capacity but impaired transactivation of glial differentiation and myelination gene programs.ConclusionsWe thus speculate that SOX10 indel mutations drive a unique subtype of schwannomas by impeding proper differentiation of immature Schwann cells.
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- 2023
6. Diagnosis and management of complications from the treatment of primary central nervous system tumors in adults.
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Weller, Michael, Le Rhun, Emilie, Van den Bent, Martin, Chang, Susan M, Cloughesy, Timothy F, Goldbrunner, Roland, Hong, Yong-Kil, Jalali, Rakesh, Jenkinson, Michael D, Minniti, Giuseppe, Nagane, Motoo, Razis, Evangelia, Roth, Patrick, Rudà, Roberta, Tabatabai, Ghazaleh, Wen, Patrick Y, Short, Susan C, and Preusser, Matthias
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Humans ,Lymphoma ,Central Nervous System Neoplasms ,Brain Neoplasms ,Combined Modality Therapy ,Quality of Life ,Adult ,adverse affects ,dose ,interruptions ,prevention ,reexposure ,toxicity ,Patient Safety ,Neurosciences ,Brain Disorders ,Rare Diseases ,Clinical Trials and Supportive Activities ,Brain Cancer ,Cancer ,Clinical Research ,7.3 Management and decision making ,Management of diseases and conditions ,7.1 Individual care needs ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
Central nervous system (CNS) tumor patients commonly undergo multimodality treatment in the course of their disease. Adverse effects and complications from these interventions have not been systematically studied, but pose significant challenges in clinical practice and impact function and quality of life, especially in the management of long-term brain tumor survivors. Here, the European Association of Neuro-Oncology (EANO) has developed recommendations to prevent, diagnose, and manage adverse effects and complications in the adult primary brain CNS tumor (except lymphomas) patient population with a specific focus on surgery, radiotherapy, and pharmacotherapy. Specifically, we also provide recommendations for dose adaptations, interruptions, and reexposure for pharmacotherapy that may serve as a reference for the management of standard of care in clinical trials. We also summarize which interventions are unnecessary, inactive or contraindicated. This consensus paper should serve as a reference for the conduct of standard therapy within and outside of clinical trials.
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- 2023
7. Objective response rate targets for recurrent glioblastoma clinical trials based on the historic association between objective response rate and median overall survival
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Ellingson, Benjamin M, Wen, Patrick Y, Chang, Susan M, van den Bent, Martin, Vogelbaum, Michael A, Li, Gang, Li, Shanpeng, Kim, Jiyoon, Youssef, Gilbert, Wick, Wolfgang, Lassman, Andrew B, Gilbert, Mark R, de Groot, John F, Weller, Michael, Galanis, Evanthia, and Cloughesy, Timothy F
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Clinical Research ,Clinical Trials and Supportive Activities ,Rare Diseases ,Brain Cancer ,Brain Disorders ,Vaccine Related ,Cancer ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Humans ,Glioblastoma ,Temozolomide ,Brain Neoplasms ,Neoplasm Recurrence ,Local ,Antineoplastic Agents ,Lomustine ,Angiogenesis Inhibitors ,glioblastoma ,objective response rate ,overall survival ,recurrent GBM ,Neurosciences ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
Durable objective response rate (ORR) remains a meaningful endpoint in recurrent cancer; however, the target ORR for single-arm recurrent glioblastoma trials has not been based on historic information or tied to patient outcomes. The current study reviewed 68 treatment arms comprising 4793 patients in past trials in recurrent glioblastoma in order to judiciously define target ORRs for use in recurrent glioblastoma trials. ORR was estimated at 6.1% [95% CI 4.23; 8.76%] for cytotoxic chemothera + pies (ORR = 7.59% for lomustine, 7.57% for temozolomide, 0.64% for irinotecan, and 5.32% for other agents), 3.37% for biologic agents, 7.97% for (select) immunotherapies, and 26.8% for anti-angiogenic agents. ORRs were significantly correlated with median overall survival (mOS) across chemotherapy (R2= 0.4078, P < .0001), biologics (R2= 0.4003, P = .0003), and immunotherapy trials (R2= 0.8994, P < .0001), but not anti-angiogenic agents (R2= 0, P = .8937). Pooling data from chemotherapy, biologics, and immunotherapy trials, a meta-analysis indicated a strong correlation between ORR and mOS (R2= 0.3900, P < .0001; mOS [weeks] = 1.4xORR + 24.8). Assuming an ineffective cytotoxic (control) therapy has ORR = 7.6%, the average ORR for lomustine and temozolomide trials, a sample size of ≥40 patients with target ORR>25% is needed to demonstrate statistical significance compared to control with a high level of confidence (P < .01) and adequate power (>80%). Given this historic data and potential biases in patient selection, we recommend that well-controlled, single-arm phase II studies in recurrent glioblastoma should have a target ORR >25% (which translates to a median OS of approximately 15 months) and a sample size of ≥40 patients, in order to convincingly demonstrate antitumor activity. Crucially, this response needs to have sufficient durability, which was not addressed in the current study.
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- 2023
8. Prognostic validation of a new classification system for extent of resection in glioblastoma: A report of the RANO resect group
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Karschnia, Philipp, Young, Jacob S, Dono, Antonio, Häni, Levin, Sciortino, Tommaso, Bruno, Francesco, Juenger, Stephanie T, Teske, Nico, Morshed, Ramin A, Haddad, Alexander F, Zhang, Yalan, Stoecklein, Sophia, Weller, Michael, Vogelbaum, Michael A, Beck, Juergen, Tandon, Nitin, Hervey-Jumper, Shawn, Molinaro, Annette M, Rudà, Roberta, Bello, Lorenzo, Schnell, Oliver, Esquenazi, Yoshua, Ruge, Maximilian I, Grau, Stefan J, Berger, Mitchel S, Chang, Susan M, van den Bent, Martin, and Tonn, Joerg-Christian
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Brain Disorders ,Rare Diseases ,Brain Cancer ,Cancer ,Neurosciences ,Humans ,Prognosis ,Glioblastoma ,Retrospective Studies ,Brain Neoplasms ,Neurosurgical Procedures ,Treatment Outcome ,EOR ,classification ,glioblastoma ,outcome ,surgical resection ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
BackgroundTerminology to describe extent of resection in glioblastoma is inconsistent across clinical trials. A surgical classification system was previously proposed based upon residual contrast-enhancing (CE) tumor. We aimed to (1) explore the prognostic utility of the classification system and (2) define how much removed non-CE tumor translates into a survival benefit.MethodsThe international RANO resect group retrospectively searched previously compiled databases from 7 neuro-oncological centers in the USA and Europe for patients with newly diagnosed glioblastoma per WHO 2021 classification. Clinical and volumetric information from pre- and postoperative MRI were collected.ResultsWe collected 1,008 patients with newly diagnosed IDHwt glioblastoma. 744 IDHwt glioblastomas were treated with radiochemotherapy per EORTC-26981/22981 (TMZ/RT→TMZ) following surgery. Among these homogenously treated patients, lower absolute residual tumor volumes (in cm3) were favorably associated with outcome: patients with "maximal CE resection" (class 2) had superior outcome compared to patients with "submaximal CE resection" (class 3) or "biopsy" (class 4). Extensive resection of non-CE tumor (≤5 cm3 residual non-CE tumor) was associated with better survival among patients with complete CE resection, thus defining class 1 ("supramaximal CE resection"). The prognostic value of the resection classes was retained on multivariate analysis when adjusting for molecular and clinical markers.ConclusionsThe proposed "RANO categories for extent of resection in glioblastoma" are highly prognostic and may serve for stratification within clinical trials. Removal of non-CE tumor beyond the CE tumor borders may translate into additional survival benefit, providing a rationale to explicitly denominate such "supramaximal CE resection."
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- 2023
9. Isocitrate dehydrogenase (IDH) mutant gliomas: A Society for Neuro-Oncology (SNO) consensus review on diagnosis, management, and future directions
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Miller, Julie J, Castro, L Nicolas Gonzalez, McBrayer, Samuel, Weller, Michael, Cloughesy, Timothy, Portnow, Jana, Andronesi, Ovidiu, Barnholtz-Sloan, Jill S, Baumert, Brigitta G, Berger, Mitchell S, Bi, Wenya Linda, Bindra, Ranjit, Cahill, Daniel P, Chang, Susan M, Costello, Joseph F, Horbinski, Craig, Huang, Raymond Y, Jenkins, Robert B, Ligon, Keith L, Mellinghoff, Ingo K, Nabors, L Burt, Platten, Michael, Reardon, David A, Shi, Diana D, Schiff, David, Wick, Wolfgang, Yan, Hai, von Deimling, Andreas, van den Bent, Martin, Kaelin, William G, and Wen, Patrick Y
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Brain Disorders ,Cancer ,Rare Diseases ,Neurosciences ,Brain Cancer ,Good Health and Well Being ,Adult ,Humans ,Isocitrate Dehydrogenase ,Consensus ,Mutation ,Glioma ,Brain Neoplasms ,D-2HG ,glioma ,Isocitrate dehydrogenase ,D-2HG ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
Isocitrate dehydrogenase (IDH) mutant gliomas are the most common adult, malignant primary brain tumors diagnosed in patients younger than 50, constituting an important cause of morbidity and mortality. In recent years, there has been significant progress in understanding the molecular pathogenesis and biology of these tumors, sparking multiple efforts to improve their diagnosis and treatment. In this consensus review from the Society for Neuro-Oncology (SNO), the current diagnosis and management of IDH-mutant gliomas will be discussed. In addition, novel therapies, such as targeted molecular therapies and immunotherapies, will be reviewed. Current challenges and future directions for research will be discussed.
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- 2023
10. Multi-parametric hyperpolarized 13C/1H imaging reveals Warburg-related metabolic dysfunction and associated regional heterogeneity in high-grade human gliomas
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Autry, Adam W, Vaziri, Sana, LaFontaine, Marisa, Gordon, Jeremy W, Chen, Hsin-Yu, Kim, Yaewon, Villanueva-Meyer, Javier E, Molinaro, Annette, Clarke, Jennifer L, Bush, Nancy Ann Oberheim, Xu, Duan, Lupo, Janine M, Larson, Peder EZ, Vigneron, Daniel B, Chang, Susan M, and Li, Yan
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Brain Cancer ,Neurosciences ,Bioengineering ,Cancer ,Biomedical Imaging ,Orphan Drug ,Rare Diseases ,Brain Disorders ,4.4 Population screening ,Humans ,Bicarbonates ,Glioma ,Lactic Acid ,Glioblastoma ,Pyruvic Acid ,GBM ,Hyperpolarized carbon-13 ,Metabolism ,Treatment effects ,IDH ,Biological psychology ,Clinical and health psychology - Abstract
BackgroundDynamic hyperpolarized (HP)-13C MRI has enabled real-time, non-invasive assessment of Warburg-related metabolic dysregulation in glioma using a [1-13C]pyruvate tracer that undergoes conversion to [1-13C]lactate and [13C]bicarbonate. Using a multi-parametric 1H/HP-13C imaging approach, we investigated dynamic and steady-state metabolism, together with physiological parameters, in high-grade gliomas to characterize active tumor.MethodsMulti-parametric 1H/HP-13C MRI data were acquired from fifteen patients with progressive/treatment-naïve glioblastoma [prog/TN GBM, IDH-wildtype (n = 11)], progressive astrocytoma, IDH-mutant, grade 4 (G4AIDH+, n = 2) and GBM manifesting treatment effects (n = 2). Voxel-wise regional analysis of the cohort with prog/TN GBM assessed imaging heterogeneity across contrast-enhancing/non-enhancing lesions (CEL/NEL) and normal-appearing white matter (NAWM) using a mixed effects model. To enable cross-nucleus parameter association, normalized perfusion, diffusion, and dynamic/steady-state (HP-13C/spectroscopic) metabolic data were collectively examined at the 13C resolution. Prog/TN GBM were similarly compared against progressive G4AIDH+ and treatment effects.ResultsRegional analysis of Prog/TN GBM metabolism revealed statistically significant heterogeneity in 1H choline-to-N-acetylaspartate index (CNI)max, [1-13C]lactate, modified [1-13C]lactate-to-[1-13C]pyruvate ratio (CELval > NELval > NAWMval); [1-13C]lactate-to-[13C]bicarbonate ratio (CELval > NELval/NAWMval); and 1H-lactate (CELval/NELval > NAWMundetected). Significant associations were found between normalized perfusion (cerebral blood volume, nCBV; peak height, nPH) and levels of [1-13C]pyruvate and [1-13C]lactate, as well as between CNImax and levels of [1-13C]pyruvate, [1-13C]lactate and modified ratio. GBM, by comparison to G4AIDH+, displayed lower perfusion %-recovery and modeled rate constants for [1-13C]pyruvate-to-[1-13C]lactate conversion (kPL), and higher 1H-lactate and [1-13C]pyruvate levels, while having higher nCBV, %-recovery, kPL, [1-13C]pyruvate-to-[1-13C]lactate and modified ratios relative to treatment effects.ConclusionsGBM consistently displayed aberrant, Warburg-related metabolism and regional heterogeneity detectable by novel HP-13C/1H imaging techniques.
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- 2023
11. Somatic mosaic SOX10 indel mutations underlie a form of segmental schwannomatosis
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Terry, Merryl, Gupta, Rohit, Ravindranathan, Ajay, Wu, Jasper, Chan, Emily, Bollen, Andrew W., Chang, Susan M., Berger, Mitchel S., Jacques, Line, and Solomon, David A.
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- 2023
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12. Prospective genomically guided identification of “early/evolving” and “undersampled” IDH-wildtype glioblastoma leads to improved clinical outcomes
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Zhang, Yalan, Lucas, Calixto-Hope G, Young, Jacob S, Morshed, Ramin A, McCoy, Lucie, Bush, Nancy Ann Oberheim, Taylor, Jennie W, Daras, Mariza, Butowski, Nicholas A, Villanueva-Meyer, Javier E, Cha, Soonmee, Wrensch, Margaret, Wiencke, John K, Lee, Julieann C, Pekmezci, Melike, Phillips, Joanna J, Perry, Arie, Bollen, Andrew W, Aghi, Manish K, Theodosopoulos, Philip, Chang, Edward F, Hervey-Jumper, Shawn L, Berger, Mitchel S, Clarke, Jennifer L, Chang, Susan M, Molinaro, Annette M, and Solomon, David A
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Biomedical and Clinical Sciences ,Clinical Sciences ,Rare Diseases ,Cancer ,Biotechnology ,Brain Disorders ,Neurosciences ,Clinical Research ,Human Genome ,Brain Cancer ,Genetics ,Detection ,screening and diagnosis ,4.2 Evaluation of markers and technologies ,Adult ,Astrocytoma ,Brain Neoplasms ,Glioblastoma ,Glioma ,Humans ,Isocitrate Dehydrogenase ,Mutation ,Prospective Studies ,genomic profiling ,glioblastoma ,molecular diagnostics ,molecular neuro-oncology ,precision medicine ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
BackgroundGenomic profiling studies of diffuse gliomas have led to new improved classification schemes that better predict patient outcomes compared to conventional histomorphology alone. One example is the recognition that patients with IDH-wildtype diffuse astrocytic gliomas demonstrating lower-grade histologic features but genomic and/or epigenomic profile characteristic of glioblastoma typically have poor outcomes similar to patients with histologically diagnosed glioblastoma. Here we sought to determine the clinical impact of prospective genomic profiling for these IDH-wildtype diffuse astrocytic gliomas lacking high-grade histologic features but with molecular profile of glioblastoma.MethodsClinical management and outcomes were analyzed for 38 consecutive adult patients with IDH-wildtype diffuse astrocytic gliomas lacking necrosis or microvascular proliferation on histologic examination that were genomically profiled on a prospective clinical basis revealing criteria for an integrated diagnosis of "diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV" per cIMPACT-NOW criteria.ResultsWe identified that this diagnosis consists of two divergent clinical scenarios based on integration of radiologic, histologic, and genomic features that we term "early/evolving" and "undersampled" glioblastoma, IDH-wildtype. We found that prospective genomically guided identification of early/evolving and undersampled IDH-wildtype glioblastoma resulted in more aggressive patient management and improved clinical outcomes compared to a biologically matched historical control patient cohort receiving standard-of-care therapy based on histomorphologic diagnosis alone.ConclusionsThese results support routine use of genomic and/or epigenomic profiling to accurately classify glial neoplasms, as these assays not only improve diagnostic classification but critically lead to more appropriate patient management that can improve clinical outcomes.
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- 2022
13. GABP couples oncogene signaling to telomere regulation in TERT promoter mutant cancer
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McKinney, Andrew M, Mathur, Radhika, Stevers, Nicholas O, Molinaro, Annette M, Chang, Susan M, Phillips, Joanna J, and Costello, Joseph F
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Biochemistry and Cell Biology ,Biological Sciences ,Brain Cancer ,Brain Disorders ,Genetics ,Rare Diseases ,Aging ,Cancer ,AMP-Activated Protein Kinases ,Adenosine Monophosphate ,ErbB Receptors ,GA-Binding Protein Transcription Factor ,Glioblastoma ,Humans ,Mutation ,Oncogenes ,RNA ,Messenger ,Telomerase ,Telomere ,CNS cancer ,CP: Cancer ,EGFR ,GABP ,TERT promoter mutations ,glioblastoma ,telomere maintenance ,Medical Physiology ,Biological sciences - Abstract
Telomerase activation counteracts senescence and telomere erosion caused by uncontrolled proliferation. Epidermal growth factor receptor (EGFR) amplification drives proliferation while telomerase reverse transcriptase promoter (TERTp) mutations underlie telomerase reactivation through recruitment of GA-binding protein (GABP). EGFR amplification and TERTp mutations typically co-occur in glioblastoma, the most common and aggressive primary brain tumor. To determine if these two frequent alterations driving proliferation and immortality are functionally connected, we combine analyses of copy number, mRNA, and protein data from tumor tissue with pharmacologic and genetic perturbations. We demonstrate that proliferation arrest decreases TERT expression in a GABP-dependent manner and elucidate a critical proliferation-to-immortality pathway from EGFR to TERT expression selectively from the mutant TERTp through activation of AMP-mediated kinase (AMPK) and GABP upregulation. EGFR-AMPK signaling promotes telomerase activity and maintains telomere length. These results define how the tumor cell immortality mechanism keeps pace with persistent oncogene signaling and cell cycling.
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- 2022
14. Spectroscopic imaging of D-2-hydroxyglutarate and other metabolites in pre-surgical patients with IDH-mutant lower-grade gliomas
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Autry, Adam W, Lafontaine, Marisa, Jalbert, Llewellyn, Phillips, Elizabeth, Phillips, Joanna J, Villanueva-Meyer, Javier, Berger, Mitchel S, Chang, Susan M, and Li, Yan
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Medical Biochemistry and Metabolomics ,Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Neurosciences ,Cancer ,Clinical Research ,Brain Disorders ,Brain Cancer ,Biomedical Imaging ,Rare Diseases ,Brain Neoplasms ,Glioma ,Glutarates ,Humans ,Inositol ,Isocitrate Dehydrogenase ,Magnetic Resonance Spectroscopy ,Mutation ,Receptors ,Antigen ,T-Cell ,Tumor Suppressor Protein p53 ,Lower-grade glioma ,D-2-Hydroxyglutarate ,IDH ,MRSI ,Image-guided ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
PurposePrognostically favorable IDH-mutant gliomas are known to produce oncometabolite D-2-hydroxyglutarate (2HG). In this study, we investigated metabolite-based features of patients with grade 2 and 3 glioma using 2HG-specific in vivo MR spectroscopy, to determine their relationship with image-guided tissue pathology and predictive role in progression-free survival (PFS).MethodsForty-five patients received pre-operative MRIs that included 3-D spectroscopy optimized for 2HG detection. Spectral data were reconstructed and quantified to compare metabolite levels according to molecular pathology (IDH1R132H, 1p/19q, and p53); glioma grade; histological subtype; and T2 lesion versus normal-appearing white matter (NAWM) ROIs. Levels of 2HG were correlated with other metabolites and pathological parameters (cellularity, MIB-1) from image-guided tissue samples using Pearson's correlation test. Metabolites predictive of PFS were evaluated with Cox proportional hazards models.ResultsQuantifiable levels of 2HG in 39/42 (93%) IDH+ and 1/3 (33%) IDH- patients indicated a 91.1% apparent detection accuracy. Myo-inositol/total choline (tCho) showed reduced values in astrocytic (1p/19q-wildtype), p53-mutant, and grade 3 (vs. 2) IDH-mutant gliomas (p
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- 2022
15. Intracranial mesenchymal tumors with FET‐CREB fusion are composed of at least two epigenetic subgroups distinct from meningioma and extracranial sarcomas
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Sloan, Emily A, Gupta, Rohit, Koelsche, Christian, Chiang, Jason, Villanueva‐Meyer, Javier E, Alexandrescu, Sanda, Eschbacher, Jennifer M, Wang, Wesley, Mafra, Manuela, Din, Nasir Ud, Carr‐Boyd, Emily, Watson, Michael, Punsoni, Michael, Oviedo, Angelica, Gilani, Ahmed, Kleinschmidt‐DeMasters, Bette K, Coss, Dylan J, Lopes, M Beatriz, Reddy, Alyssa, Mueller, Sabine, Cho, Soo‐Jin, Horvai, Andrew E, Lee, Julieann C, Pekmezci, Melike, Tihan, Tarik, Bollen, Andrew W, Rodriguez, Fausto J, Ellison, David W, Perry, Arie, von Deimling, Andreas, Chang, Susan M, Berger, Mitchel S, and Solomon, David A
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Brain Cancer ,Neurosciences ,Pediatric ,Cancer ,Clinical Research ,Brain Disorders ,Human Genome ,Genetics ,Rare Diseases ,Adolescent ,Adult ,Biomarkers ,Tumor ,Brain Neoplasms ,Child ,Child ,Preschool ,Epigenesis ,Genetic ,Epigenomics ,Hemangioma ,Histiocytoma ,Malignant Fibrous ,Humans ,Meningeal Neoplasms ,Meningioma ,Oncogene Proteins ,Fusion ,RNA-Binding Protein EWS ,Soft Tissue Neoplasms ,Young Adult ,angiomatoid fibrous histiocytoma ,ATF1 ,brain tumor ,clear cell sarcoma ,CREB1 ,CREM ,EWSR1 ,intracranial mesenchymal tumor with FET-CREB fusion ,intracranial myxoid mesenchymal tumor ,molecular neuropathology ,sarcoma ,Clinical Sciences ,Neurology & Neurosurgery ,Clinical sciences - Abstract
'Intracranial mesenchymal tumor, FET-CREB fusion-positive' occurs primarily in children and young adults and has previously been termed intracranial angiomatoid fibrous histiocytoma (AFH) or intracranial myxoid mesenchymal tumor (IMMT). Here we performed genome-wide DNA methylation array profiling of 20 primary intracranial mesenchymal tumors with FET-CREB fusion to further study their ontology. These tumors resolved into two distinct epigenetic subgroups that were both divergent from all other analyzed intracranial neoplasms and soft tissue sarcomas, including meningioma, clear cell sarcoma of soft tissue (CCS), and AFH of extracranial soft tissue. The first subgroup (Group A, 16 tumors) clustered nearest to but independent of solitary fibrous tumor and AFH of extracranial soft tissue, whereas the second epigenetic subgroup (Group B, 4 tumors) clustered nearest to but independent of CCS and also lacked expression of melanocytic markers (HMB45, Melan A, or MITF) characteristic of CCS. Group A tumors most often occurred in adolescence or early adulthood, arose throughout the neuroaxis, and contained mostly EWSR1-ATF1 and EWSR1-CREB1 fusions. Group B tumors arose most often in early childhood, were located along the cerebral convexities or spinal cord, and demonstrated an enrichment for tumors with CREM as the fusion partner (either EWSR1-CREM or FUS-CREM). Group A tumors more often demonstrated stellate/spindle cell morphology and hemangioma-like vasculature, whereas Group B tumors more often demonstrated round cell or epithelioid/rhabdoid morphology without hemangioma-like vasculature, although robust comparison of these clinical and histologic features requires future study. Patients with Group B tumors had inferior progression-free survival relative to Group A tumors (median 4.5 vs. 49 months, p = 0.001). Together, these findings confirm that intracranial AFH-like neoplasms and IMMT represent histologic variants of a single tumor type ('intracranial mesenchymal tumor, FET-CREB fusion-positive') that is distinct from meningioma and extracranial sarcomas. Additionally, epigenomic evaluation may provide important prognostic subtyping for this unique tumor entity.
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- 2022
16. The oncological role of resection in newly diagnosed diffuse adult-type glioma defined by the WHO 2021 classification: a Review by the RANO resect group
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Karschnia, Philipp, Gerritsen, Jasper K W, Teske, Nico, Cahill, Daniel P, Jakola, Asgeir S, van den Bent, Martin, Weller, Michael, Schnell, Oliver, Vik-Mo, Einar O, Thon, Niklas, Vincent, Arnaud J P E, Kim, Michelle M, Reifenberger, Guido, Chang, Susan M, Hervey-Jumper, Shawn L, Berger, Mitchel S, and Tonn, Joerg-Christian
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- 2024
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17. Liquid biopsy in gliomas: A RANO review and proposals for clinical applications.
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Soffietti, Riccardo, Bettegowda, Chetan, Mellinghoff, Ingo K, Warren, Katherine E, Ahluwalia, Manmeet S, De Groot, John F, Galanis, Evanthia, Gilbert, Mark R, Jaeckle, Kurt A, Le Rhun, Emilie, Rudà, Roberta, Seoane, Joan, Thon, Niklas, Umemura, Yoshie, Weller, Michael, van den Bent, Martin J, Vogelbaum, Michael A, Chang, Susan M, and Wen, Patrick Y
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Humans ,Glioma ,DNA ,Neoplasm ,Neoplastic Cells ,Circulating ,Biomarkers ,Tumor ,Liquid Biopsy ,Circulating Tumor DNA ,CSF ,circulating tumor cells ,ctDNA ,extracellular vesicles ,gliomas ,Neurosciences ,Brain Cancer ,Cancer ,Clinical Research ,Rare Diseases ,Brain Disorders ,Detection ,screening and diagnosis ,4.2 Evaluation of markers and technologies ,Good Health and Well Being ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
BackgroundThere is an extensive literature highlighting the utility of blood-based liquid biopsies in several extracranial tumors for diagnosis and monitoring.MethodsThe RANO (Response Assessment in Neuro-Oncology) group developed a multidisciplinary international Task Force to review the English literature on liquid biopsy in gliomas focusing on the most frequently used techniques, that is circulating tumor DNA, circulating tumor cells, and extracellular vesicles in blood and CSF.ResultsctDNA has a higher sensitivity and capacity to represent the spatial and temporal heterogeneity in comparison to circulating tumor cells. Exosomes have the advantages to cross an intact blood-brain barrier and carry also RNA, miRNA, and proteins. Several clinical applications of liquid biopsies are suggested: to establish a diagnosis when tissue is not available, monitor the residual disease after surgery, distinguish progression from pseudoprogression, and predict the outcome.ConclusionsThere is a need for standardization of biofluid collection, choice of an analyte, and detection strategies along with rigorous testing in future clinical trials to validate findings and enable entry into clinical practice.
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- 2022
18. Improving the noninvasive classification of glioma genetic subtype with deep learning and diffusion-weighted imaging
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Cluceru, Julia, Interian, Yannet, Phillips, Joanna J, Molinaro, Annette M, Luks, Tracy L, Alcaide-Leon, Paula, Olson, Marram P, Nair, Devika, LaFontaine, Marisa, Shai, Anny, Chunduru, Pranathi, Pedoia, Valentina, Villanueva-Meyer, Javier E, Chang, Susan M, and Lupo, Janine M
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Clinical Research ,Rare Diseases ,Brain Cancer ,Brain Disorders ,Neurosciences ,Cancer ,Biomedical Imaging ,4.2 Evaluation of markers and technologies ,Detection ,screening and diagnosis ,Brain Neoplasms ,Deep Learning ,Diffusion Magnetic Resonance Imaging ,Glioma ,Humans ,Isocitrate Dehydrogenase ,Magnetic Resonance Imaging ,Mutation ,ADC ,convolutional neural network ,deep learning ,diffusion-weighted imaging ,glioma subtype ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
BackgroundDiagnostic classification of diffuse gliomas now requires an assessment of molecular features, often including IDH-mutation and 1p19q-codeletion status. Because genetic testing requires an invasive process, an alternative noninvasive approach is attractive, particularly if resection is not recommended. The goal of this study was to evaluate the effects of training strategy and incorporation of biologically relevant images on predicting genetic subtypes with deep learning.MethodsOur dataset consisted of 384 patients with newly diagnosed gliomas who underwent preoperative MRI with standard anatomical and diffusion-weighted imaging, and 147 patients from an external cohort with anatomical imaging. Using tissue samples acquired during surgery, each glioma was classified into IDH-wildtype (IDHwt), IDH-mutant/1p19q-noncodeleted (IDHmut-intact), and IDH-mutant/1p19q-codeleted (IDHmut-codel) subgroups. After optimizing training parameters, top performing convolutional neural network (CNN) classifiers were trained, validated, and tested using combinations of anatomical and diffusion MRI with either a 3-class or tiered structure. Generalization to an external cohort was assessed using anatomical imaging models.ResultsThe best model used a 3-class CNN containing diffusion-weighted imaging as an input, achieving 85.7% (95% CI: [77.1, 100]) overall test accuracy and correctly classifying 95.2%, 88.9%, 60.0% of the IDHwt, IDHmut-intact, and IDHmut-codel tumors. In general, 3-class models outperformed tiered approaches by 13.5%-17.5%, and models that included diffusion-weighted imaging were 5%-8.8% more accurate than those that used only anatomical imaging.ConclusionTraining a classifier to predict both IDH-mutation and 1p19q-codeletion status outperformed a tiered structure that first predicted IDH-mutation, then 1p19q-codeletion. Including apparent diffusion coefficient (ADC), a surrogate marker of cellularity, more accurately captured differences between subgroups.
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- 2022
19. Designing Clinical Trials for Combination Immunotherapy: A Framework for GlioblastomaCombining Immunotherapy for Glioblastoma
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Singh, Kirit, Batich, Kristen A, Wen, Patrick Y, Tan, Aaron C, Bagley, Stephen J, Lim, Michael, Platten, Michael, Colman, Howard, Ashley, David M, Chang, Susan M, Rahman, Rifaquat, Galanis, Evanthia, Mansouri, Alireza, Puduvalli, Vinay K, Reardon, David A, Sahebjam, Solmaz, Sampson, John H, Simes, John, Berry, Donald A, Zadeh, Gelareh, Cloughesy, Tim F, Mehta, Minesh P, Piantadosi, Steven, Weller, Michael, Heimberger, Amy B, and Khasraw, Mustafa
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Cancer ,Immunization ,Clinical Research ,Rare Diseases ,Brain Disorders ,Vaccine Related ,Clinical Trials and Supportive Activities ,Brain Cancer ,5.1 Pharmaceuticals ,Health and social care services research ,8.4 Research design and methodologies (health services) ,Development of treatments and therapeutic interventions ,Brain Neoplasms ,Glioblastoma ,Humans ,Immune Tolerance ,Immunosuppression Therapy ,Immunotherapy ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
Immunotherapy has revolutionized treatment for many hard-to-treat cancers but has yet to produce significant improvement in outcomes for patients with glioblastoma. This reflects the multiple and unique mechanisms of immune evasion and escape in this highly heterogeneous tumor. Glioblastoma engenders profound local and systemic immunosuppression and is remarkably effective at inducing T-cell dysfunction, posing a challenge to any immunotherapy-based approach. To overcome these mechanisms, multiple disparate modes of immune-oriented therapy will be required. However, designing trials that can evaluate these combinatorial approaches requires careful consideration. In this review, we explore the immunotherapy resistance mechanisms that have been encountered to date and how combinatorial approaches may address these. We also describe the unique aspects of trial design in both preclinical and clinical settings and consider endpoints and markers of response best suited for an intervention involving multiple agents.
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- 2022
20. Glioblastoma Clinical Trials: Current Landscape and Opportunities for ImprovementCurrent Glioblastoma Clinical Trial Landscape
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Bagley, Stephen J, Kothari, Shawn, Rahman, Rifaquat, Lee, Eudocia Q, Dunn, Gavin P, Galanis, Evanthia, Chang, Susan M, Nabors, Louis Burt, Ahluwalia, Manmeet S, Stupp, Roger, Mehta, Minesh P, Reardon, David A, Grossman, Stuart A, Sulman, Erik P, Sampson, John H, Khagi, Simon, Weller, Michael, Cloughesy, Timothy F, Wen, Patrick Y, and Khasraw, Mustafa
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Brain Disorders ,Neurosciences ,Rare Diseases ,Brain Cancer ,Clinical Research ,Clinical Trials and Supportive Activities ,Cancer ,Adult ,Brain Neoplasms ,Glioblastoma ,Humans ,Research Design ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
Therapeutic advances for glioblastoma have been minimal over the past 2 decades. In light of the multitude of recent phase III trials that have failed to meet their primary endpoints following promising preclinical and early-phase programs, a Society for Neuro-Oncology Think Tank was held in November 2020 to prioritize areas for improvement in the conduct of glioblastoma clinical trials. Here, we review the literature, identify challenges related to clinical trial eligibility criteria and trial design in glioblastoma, and provide recommendations from the Think Tank. In addition, we provide a data-driven context with which to frame this discussion by analyzing key study design features of adult glioblastoma clinical trials listed on ClinicalTrials.gov as "recruiting" or "not yet recruiting" as of February 2021.
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- 2022
21. Isocitrate Dehydrogenase Mutant Grade II and III Glial Neoplasms
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Mellinghoff, Ingo K, Chang, Susan M, Jaeckle, Kurt A, and van den Bent, Martin
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Orphan Drug ,Rare Diseases ,Hematology ,Genetics ,Cancer ,Brain Cancer ,Brain Disorders ,Adult ,Brain Neoplasms ,Glioma ,Humans ,Isocitrate Dehydrogenase ,Leukemia ,Myeloid ,Acute ,Mutation ,Isocitrate dehydrogenase ,Low-grade glioma ,Cancer metabolism ,Response assessment in neuro-oncology ,Cardiorespiratory Medicine and Haematology ,Oncology & Carcinogenesis ,Cardiovascular medicine and haematology - Abstract
Mutations in isocitrate dehydrogenase (IDH) 1 or IDH2 occur in most of the adult low-grade gliomas and, less commonly, in cholangiocarcinoma, chondrosarcoma, acute myeloid leukemia, and other human malignancies. Cancer-associated mutations alter the function of the enzyme, resulting in production of R(-)-2-hydroxyglutarate and broad epigenetic dysregulation. Small molecule IDH inhibitors have received regulatory approval for the treatment of IDH mutant (mIDH) leukemia and are under development for the treatment of mIDH solid tumors. This article provides a current view of mIDH adult astrocytic and oligodendroglial tumors, including their clinical presentation and treatment, and discusses novel approaches and challenges toward improving the treatment of these tumors.
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- 2022
22. Randomized trial of neoadjuvant vaccination with tumor-cell lysate induces T-cell response in low-grade gliomas
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Ogino, Hirokazu, Taylor, Jennie W, Nejo, Takahide, Gibson, David, Watchmaker, Payal B, Okada, Kaori, Saijo, Atsuro, Tedesco, Meghan R, Shai, Anny, Wong, Cynthia M, Rabbitt, Jane E, Olin, Michael R, Moertel, Christopher L, Nishioka, Yasuhiko, Salazar, Andres M, Molinaro, Annette M, Phillips, Joanna J, Butowski, Nicholas A, Clarke, Jennifer L, Bush, Nancy Ann Oberheim, Hervey-Jumper, Shawn L, Theodosopoulos, Philip, Chang, Susan M, Berger, Mitchel S, and Okada, Hideho
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Clinical Research ,Prevention ,Vaccine Related ,Cancer ,Clinical Trials and Supportive Activities ,Orphan Drug ,Brain Cancer ,Neurosciences ,Immunization ,Brain Disorders ,Biotechnology ,Rare Diseases ,Evaluation of treatments and therapeutic interventions ,Prevention of disease and conditions ,and promotion of well-being ,3.4 Vaccines ,6.1 Pharmaceuticals ,Infection ,Good Health and Well Being ,Adult ,Aged ,CD8-Positive T-Lymphocytes ,Cancer Vaccines ,Carboxymethylcellulose Sodium ,Female ,Glioma ,Humans ,Male ,Middle Aged ,Neoadjuvant Therapy ,Poly I-C ,Polylysine ,Tumor Microenvironment ,Vaccination ,Brain cancer ,Cancer immunotherapy ,Oncology ,T cells ,Vaccines ,Medical and Health Sciences ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
BACKGROUNDLong-term prognosis of WHO grade II low-grade gliomas (LGGs) is poor, with a high risk of recurrence and malignant transformation into high-grade gliomas. Given the relatively intact immune system of patients with LGGs and the slow tumor growth rate, vaccines are an attractive treatment strategy.METHODSWe conducted a pilot study to evaluate the safety and immunological effects of vaccination with GBM6-AD, lysate of an allogeneic glioblastoma stem cell line, with poly-ICLC in patients with LGGs. Patients were randomized to receive the vaccines before surgery (arm 1) or not (arm 2) and all patients received adjuvant vaccines. Coprimary outcomes were to evaluate safety and immune response in the tumor.RESULTSA total of 17 eligible patients were enrolled - 9 in arm 1 and 8 in arm 2. This regimen was well tolerated with no regimen-limiting toxicity. Neoadjuvant vaccination induced upregulation of type-1 cytokines and chemokines and increased activated CD8+ T cells in peripheral blood. Single-cell RNA/T cell receptor sequencing detected CD8+ T cell clones that expanded with effector phenotype and migrated into the tumor microenvironment (TME) in response to neoadjuvant vaccination. Mass cytometric analyses detected increased tissue resident-like CD8+ T cells with effector memory phenotype in the TME after the neoadjuvant vaccination.CONCLUSIONThe regimen induced effector CD8+ T cell response in peripheral blood and enabled vaccine-reactive CD8+ T cells to migrate into the TME. Further refinements of the regimen may have to be integrated into future strategies.TRIAL REGISTRATIONClinicalTrials.gov NCT02549833.FUNDINGNIH (1R35NS105068, 1R21CA233856), Dabbiere Foundation, Parker Institute for Cancer Immunotherapy, and Daiichi Sankyo Foundation of Life Science.
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- 2022
23. Longitudinal MR spectroscopy to detect progression in patients with lower-grade glioma in the surveillance phase.
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Avalos, Lauro N, Luks, Tracy L, Gleason, Tyler, Damasceno, Pablo, Li, Yan, Lupo, Janine M, Phillips, Joanna, Oberheim Bush, Nancy Ann, Taylor, Jennie W, Chang, Susan M, and Villanueva-Meyer, Javier E
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Brain Cancer ,Clinical Research ,Biomedical Imaging ,Cancer ,Bioengineering ,Neurosciences ,Brain Disorders ,Rare Diseases ,4.1 Discovery and preclinical testing of markers and technologies ,4.2 Evaluation of markers and technologies ,Detection ,screening and diagnosis ,lower-grade glioma ,magnetic resonance spectroscopic imaging ,progression - Abstract
BackgroundMonitoring lower-grade gliomas (LrGGs) for disease progression is made difficult by the limits of anatomical MRI to distinguish treatment related tissue changes from tumor progression. MR spectroscopic imaging (MRSI) offers additional metabolic information that can help address these challenges. The goal of this study was to compare longitudinal changes in multiparametric MRI, including diffusion weighted imaging, perfusion imaging, and 3D MRSI, for LrGG patients who progressed at the final time-point and those who remained clinically stable.MethodsForty-one patients with LrGG who were clinically stable were longitudinally assessed for progression. Changes in anatomical, diffusion, perfusion and MRSI data were acquired and compared between patients who remained clinically stable and those who progressed.ResultsThirty-one patients remained stable, and 10 patients progressed. Over the study period, progressed patients had a significantly greater increase in normalized choline, choline-to-N-acetylaspartic acid index (CNI), normalized creatine, and creatine-to-N-acetylaspartic acid index (CRNI), than stable patients. CRNI was significantly associated with progression status and WHO type. Progressed astrocytoma patients had greater increases in CRNI than stable astrocytoma patients.ConclusionsLrGG patients in surveillance with tumors that progressed had significantly increasing choline and creatine metabolite signals on MRSI, with a trend of increasing T2 FLAIR volumes, compared to LrGG patients who remained stable. These data show that MRSI can be used in conjunction with anatomical imaging studies to gain a clearer picture of LrGG progression, especially in the setting of clinical ambiguity.
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- 2022
24. Association of Neurological Impairment on the Relative Benefit of Maximal Extent of Resection in Chemoradiation-Treated Newly Diagnosed Isocitrate Dehydrogenase Wild-Type Glioblastoma
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Aabedi, Alexander A, Young, Jacob S, Zhang, Yalan, Ammanuel, Simon, Morshed, Ramin A, Ore, Cecilia Dalle, Brown, Desmond, Phillips, Joanna J, Bush, Nancy Ann Oberheim, Taylor, Jennie W, Butowski, Nicholas, Clarke, Jennifer, Chang, Susan M, Aghi, Manish, Molinaro, Annette M, Berger, Mitchel S, and Hervey-Jumper, Shawn L
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Biomedical and Clinical Sciences ,Clinical Sciences ,Clinical Research ,Brain Cancer ,Neurosciences ,Rare Diseases ,Brain Disorders ,Cancer ,Brain Neoplasms ,Chemoradiotherapy ,Glioblastoma ,Humans ,Isocitrate Dehydrogenase ,Prognosis ,Retrospective Studies ,Glioma ,Cognition ,Neurological impairments ,Neurology & Neurosurgery ,Clinical sciences ,Biological psychology - Abstract
BackgroundIncreases in the extent of resection of both contrast-enhanced (CE) and non-contrast-enhanced (NCE) tissue are associated with substantial survival benefits in patients with isocitrate dehydrogenase wild-type glioblastoma. The fact, however, remains that these lesions exist within the framework of complex neural circuitry subserving cognition, movement, and behavior, all of which affect the ultimate survival outcome. The prognostic significance of the interplay between CE and NCE cytoreduction and neurological morbidity is poorly understood.ObjectiveTo identify a clinically homogenous population of 228 patients with newly diagnosed isocitrate dehydrogenase wild-type glioblastoma, all of whom underwent maximal safe resection of CE and NCE tissue and adjuvant chemoradiation. We then set out to delineate the competing interactions between resection of CE and NCE tissue and postoperative neurological impairment with respect to overall survival.MethodsNonparametric multivariate models of survival were generated via recursive partitioning to provide a clinically intuitive framework for the prognostication and surgical management of such patients.ResultsWe demonstrated that the presence of a new postoperative neurological impairment was the key factor in predicting survival outcomes across the entire cohort. Patients older than 60 yr who suffered from at least one new impairment had the worst survival outcome regardless of extent of resection (median of 11.6 mo), whereas those who did not develop a new impairment had the best outcome (median of 28.4 mo) so long as all CE tissue was resected.ConclusionOur data provide novel evidence for management strategies that prioritize safe and complete resection of CE tissue.
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- 2022
25. Conserved features of TERT promoter duplications reveal an activation mechanism that mimics hotspot mutations in cancer
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Barger, Carter J, Suwala, Abigail K, Soczek, Katarzyna M, Wang, Albert S, Kim, Min Y, Hong, Chibo, Doudna, Jennifer A, Chang, Susan M, Phillips, Joanna J, Solomon, David A, and Costello, Joseph F
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Biological Sciences ,Bioinformatics and Computational Biology ,Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Genetics ,Cancer ,Rare Diseases ,Aetiology ,2.1 Biological and endogenous factors ,Glioblastoma ,Humans ,Mutation ,Promoter Regions ,Genetic ,Telomerase - Abstract
Mutations in the TERT promoter represent the genetic underpinnings of tumor cell immortality. Beyond the two most common point mutations, which selectively recruit the ETS factor GABP to activate TERT, the significance of other variants is unknown. In seven cancer types, we identify duplications of wildtype sequence within the core promoter region of TERT that have strikingly similar features including an ETS motif, the duplication length and insertion site. The duplications recruit a GABP tetramer by virtue of the native ETS motif and its precisely spaced duplicated counterpart, activate the promoter and are clonal in a TERT expressing multifocal glioblastoma. We conclude that recurrent TERT promoter duplications are functionally and mechanistically equivalent to the hotspot mutations that confer tumor cell immortality. The shared mechanism of these divergent somatic genetic alterations suggests a strong selective pressure for recruitment of the GABP tetramer to activate TERT.
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- 2022
26. Assessment of higher-order singular value decomposition denoising methods on dynamic hyperpolarized [1-13C]pyruvate MRI data from patients with glioma
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Vaziri, Sana, Autry, Adam W, Lafontaine, Marisa, Kim, Yaewon, Gordon, Jeremy W, Chen, Hsin-Yu, Hu, Jasmine Y, Lupo, Janine M, Chang, Susan M, Clarke, Jennifer L, Villanueva-Meyer, Javier E, Bush, Nancy Ann Oberheim, Xu, Duan, Larson, Peder EZ, Vigneron, Daniel B, and Li, Yan
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Biomedical and Clinical Sciences ,Clinical Sciences ,Biomedical Imaging ,Brain Disorders ,Neurosciences ,Bioengineering ,Cancer ,Rare Diseases ,Brain Cancer ,Humans ,Pyruvic Acid ,Bicarbonates ,Glioma ,Magnetic Resonance Imaging ,Lactic Acid ,Hyperpolarized ,Carbon-13 ,Denoising ,Signal-to-noise ratio ,Higher-order singular value decomposition ,Biological psychology ,Clinical and health psychology - Abstract
BackgroundReal-time metabolic conversion of intravenously-injected hyperpolarized [1-13C]pyruvate to [1-13C]lactate and [13C]bicarbonate in the brain can be measured using dynamic hyperpolarized carbon-13 (HP-13C) MRI. However, voxel-wise evaluation of metabolism in patients with glioma is challenged by the limited signal-to-noise ratio (SNR) of downstream 13C metabolites, especially within lesions. The purpose of this study was to evaluate the ability of higher-order singular value decomposition (HOSVD) denoising methods to enhance dynamic HP [1-13C]pyruvate MRI data acquired from patients with glioma.MethodsDynamic HP-13C MRI were acquired from 14 patients with glioma. The effects of two HOSVD denoising techniques, tensor rank truncation-image enhancement (TRI) and global-local HOSVD (GL-HOSVD), on the SNR and kinetic modeling were analyzed in [1-13C]lactate data with simulated noise that matched the levels of [13C]bicarbonate signals. Both methods were then evaluated in patient data based on their ability to improve [1-13C]pyruvate, [1-13C]lactate and [13C]bicarbonate SNR. The effects of denoising on voxel-wise kinetic modeling of kPL and kPB was also evaluated. The number of voxels with reliable kinetic modeling of pyruvate-to-lactate (kPL) and pyruvate-to-bicarbonate (kPB) conversion rates within regions of interest (ROIs) before and after denoising was then compared.ResultsBoth denoising methods improved metabolite SNR and regional signal coverage. In patient data, the average increase in peak dynamic metabolite SNR was 2-fold using TRI and 4-5 folds using GL-HOSVD denoising compared to acquired data. Denoising reduced kPL modeling errors from a native average of 23% to 16% (TRI) and 15% (GL-HOSVD); and kPB error from 42% to 34% (TRI) and 37% (GL-HOSVD) (values were averaged voxelwise over all datasets). In contrast-enhancing lesions, the average number of voxels demonstrating within-tolerance kPL modeling error relative to the total voxels increased from 48% in the original data to 84% (TRI) and 90% (GL-HOSVD), while the number of voxels showing within-tolerance kPB modeling error increased from 0% to 15% (TRI) and 8% (GL-HOSVD).ConclusionPost-processing denoising methods significantly improved the SNR of dynamic HP-13C imaging data, resulting in a greater number of voxels satisfying minimum SNR criteria and maximum kinetic modeling errors in tumor lesions. This enhancement can aid in the voxel-wise analysis of HP-13C data and thereby improve monitoring of metabolic changes in patients with glioma following treatment.
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- 2022
27. T2 FLAIR Hyperintensity Volume Is Associated With Cognitive Function and Quality of Life in Clinically Stable Patients With Lower Grade Gliomas
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Luks, Tracy L, Villanueva-Meyer, Javier E, Weyer-Jamora, Christina, Gehring, Karin, Jakary, Angela, Hervey-Jumper, Shawn L, Braunstein, Steve E, Bracci, Paige M, Brie, Melissa S, Smith, Ellen M, Chang, Susan M, and Taylor, Jennie W
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Neurosciences ,Brain Disorders ,Cancer ,Rare Diseases ,Clinical Research ,Brain Cancer ,Neurodegenerative ,Biomedical Imaging ,Acquired Cognitive Impairment ,Rehabilitation ,Basic Behavioral and Social Science ,Aging ,Behavioral and Social Science ,glioma ,neuroimaging ,neuro-oncology ,neuropsychology ,cognition ,Clinical Sciences ,Psychology - Abstract
Survival outcomes for patients with lower grade gliomas (LrGG) continue to improve. However, damage caused both by tumor growth and by the consequences of treatment often leads to significantly impaired cognitive function and quality of life (QoL). While neuropsychological testing is not routine, serial clinical MRIs are standard of care for patients with LrGG. Thus, having a greater understanding of MRI indicators of cognitive and QoL impairment risk could be beneficial to patients and clinicians. In this work we sought to test the hypothesis that in clinically stable LrGG patients, T2 FLAIR hyperintensity volumes at the time of cognitive assessment are associated with impairments of cognitive function and QoL and could be used to help identify patients for cognitive and QoL assessments and interventions. We performed anatomical MR imaging, cognitive testing and QoL assessments cross-sectionally in 30 clinically stable grade 2 and 3 glioma patients with subjective cognitive concerns who were 6 or more months post-treatment. Larger post-surgical T2 FLAIR volume at testing was significantly associated with lower cognitive performance, while pre-surgical tumor volume was not. Older patients had lower cognitive performance than younger patients, even after accounting for normal age-related declines in performance. Patients with Astrocytoma, IDH mutant LrGGs were more likely to show lower cognitive performance than patients with Oligodendroglioma, IDH mutant 1p19q co-deleted LrGGs. Previous treatment with combined radiation and chemotherapy was associated with poorer self-reported QoL, including self-reported cognitive function. This study demonstrates the importance of appreciating that LrGG patients may experience impairments in cognitive function and QoL over their disease course, including during periods of otherwise sustained clinical stability. Imaging factors can be helpful in identifying vulnerable patients who would benefit from cognitive assessment and rehabilitation.
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- 2022
28. Glioblastoma evolution and heterogeneity from a 3D whole-tumor perspective
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Mathur, Radhika, Wang, Qixuan, Schupp, Patrick G., Nikolic, Ana, Hilz, Stephanie, Hong, Chibo, Grishanina, Nadia R., Kwok, Darwin, Stevers, Nicholas O., Jin, Qiushi, Youngblood, Mark W., Stasiak, Lena Ann, Hou, Ye, Wang, Juan, Yamaguchi, Takafumi N., Lafontaine, Marisa, Shai, Anny, Smirnov, Ivan V., Solomon, David A., Chang, Susan M., Hervey-Jumper, Shawn L., Berger, Mitchel S., Lupo, Janine M., Okada, Hideho, Phillips, Joanna J., Boutros, Paul C., Gallo, Marco, Oldham, Michael C., Yue, Feng, and Costello, Joseph F.
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- 2024
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29. PET-based response assessment criteria for diffuse gliomas (PET RANO 1.0): a report of the RANO group
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Albert, Nathalie L, Galldiks, Norbert, Ellingson, Benjamin M, van den Bent, Martin J, Chang, Susan M, Cicone, Francesco, de Groot, John, Koh, Eng-Siew, Law, Ian, Le Rhun, Emilie, Mair, Maximilian J, Minniti, Giuseppe, Rudà, Roberta, Scott, Andrew M, Short, Susan C, Smits, Marion, Suchorska, Bogdana, Tolboom, Nelleke, Traub-Weidinger, Tatjana, Tonn, Joerg-Christian, Verger, Antoine, Weller, Michael, Wen, Patrick Y, and Preusser, Matthias
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- 2024
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30. Diffuse hemispheric glioma, H3 G34-mutant: Genomic landscape of a new tumor entity and prospects for targeted therapy
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Lucas, Calixto-Hope G, Mueller, Sabine, Reddy, Alyssa, Taylor, Jennie W, Bush, Nancy Ann Oberheim, Clarke, Jennifer L, Chang, Susan M, Gupta, Nalin, Berger, Mitchel S, Perry, Arie, Phillips, Joanna J, and Solomon, David A
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Brain Neoplasms ,Genomics ,Glioma ,Histones ,Humans ,Mutation ,Neurosciences ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Published
- 2021
31. Temozolomide-induced hypermutation is associated with distant recurrence and reduced survival after high-grade transformation of low-grade IDH-mutant gliomas
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Yu, Yao, Villanueva-Meyer, Javier, Grimmer, Matthew R, Hilz, Stephanie, Solomon, David A, Choi, Serah, Wahl, Michael, Mazor, Tali, Hong, Chibo, Shai, Anny, Phillips, Joanna J, Wainer, Bruce H, McDermott, Michael, Haas-Kogan, Daphne, Taylor, Jennie W, Butowski, Nicholas, Clarke, Jennifer L, Berger, Mitchel S, Molinaro, Annette M, Chang, Susan M, Costello, Joseph F, and Bush, Nancy Ann Oberheim
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Brain Disorders ,Neurosciences ,Brain Cancer ,Cancer ,Rare Diseases ,Orphan Drug ,Clinical Research ,Brain ,Brain Neoplasms ,Glioma ,Humans ,Mutation ,Neoplasm Recurrence ,Local ,Temozolomide ,hypermutation ,IDH-mutant ,low-grade glioma ,temozolomide ,tumor mutational burden ,IDH-mutant ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
BackgroundChemotherapy improves overall survival after surgery and radiotherapy for newly diagnosed high-risk IDH-mutant low-grade gliomas (LGGs), but a proportion of patients treated with temozolomide (TMZ) will develop recurrent tumors with TMZ-induced hypermutation. We aimed to determine the prevalence of TMZ-induced hypermutation at recurrence and prognostic implications.MethodsWe sequenced recurrent tumors from 82 patients with initially low-grade IDH-mutant gliomas who underwent reoperation and correlated hypermutation status with grade at recurrence and subsequent clinical outcomes.ResultsHypermutation was associated with high-grade disease at the time of reoperation (OR 12.0 95% CI 2.5-115.5, P = .002) and was identified at transformation in 57% of recurrent LGGs previously exposed to TMZ. After anaplastic (grade III) transformation, hypermutation was associated with shorter survival on univariate and multivariate analysis (HR 3.4, 95% CI 1.2-9.9, P = .024), controlling for tumor grade, subtype, age, and prior radiotherapy. The effect of hypermutation on survival after transformation was validated in an independent, published dataset. Hypermutated (HM) tumors were more likely to develop discontiguous foci of disease in the brain and spine (P = .003). To estimate the overall incidence of high-grade transformation among low-grade IDH-mutant tumors, data from a phase II trial of TMZ for LGG were analyzed. Eight-year transformation-free survival was 53.8% (95% CI 42.8-69.2), and 61% of analyzed transformed cases were HM.ConclusionsTMZ-induced hypermutation is a common event in transformed LGG previously treated with TMZ and is associated with worse prognosis and development of discontiguous disease after recurrence. These findings impact tumor classification at recurrence, prognostication, and clinical trial design.
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- 2021
32. Denoising of hyperpolarized 13C MR images of the human brain using patch‐based higher‐order singular value decomposition
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Kim, Yaewon, Chen, Hsin‐Yu, Autry, Adam W, Villanueva‐Meyer, Javier, Chang, Susan M, Li, Yan, Larson, Peder EZ, Brender, Jeffrey R, Krishna, Murali C, Xu, Duan, Vigneron, Daniel B, and Gordon, Jeremy W
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Communications Engineering ,Engineering ,Rare Diseases ,Biomedical Imaging ,Bioengineering ,Algorithms ,Brain ,Computer Simulation ,Humans ,Lactic Acid ,Magnetic Resonance Imaging ,Pyruvic Acid ,Signal-To-Noise Ratio ,higher-order singular value decomposition ,hyperpolarized C-13 pyruvate ,image denoising ,Biomedical Engineering ,Nuclear Medicine & Medical Imaging ,Biomedical engineering - Abstract
PurposeTo improve hyperpolarized 13 C (HP-13 C) MRI by image denoising with a new approach, patch-based higher-order singular value decomposition (HOSVD).MethodsThe benefit of using a patch-based HOSVD method to denoise dynamic HP-13 C MR imaging data was investigated. Image quality and the accuracy of quantitative analyses following denoising were evaluated first using simulated data of [1-13 C]pyruvate and its metabolic product, [1-13 C]lactate, and compared the results to a global HOSVD method. The patch-based HOSVD method was then applied to healthy volunteer HP [1-13 C]pyruvate EPI studies. Voxel-wise kinetic modeling was performed on both non-denoised and denoised data to compare the number of voxels quantifiable based on SNR criteria and fitting error.ResultsSimulation results demonstrated an 8-fold increase in the calculated SNR of [1-13 C]pyruvate and [1-13 C]lactate with the patch-based HOSVD denoising. The voxel-wise quantification of kPL (pyruvate-to-lactate conversion rate) showed a 9-fold decrease in standard errors for the fitted kPL after denoising. The patch-based denoising performed superior to the global denoising in recovering kPL information. In volunteer data sets, [1-13 C]lactate and [13 C]bicarbonate signals became distinguishable from noise across captured time points with over a 5-fold apparent SNR gain. This resulted in >3-fold increase in the number of voxels quantifiable for mapping kPB (pyruvate-to-bicarbonate conversion rate) and whole brain coverage for mapping kPL .ConclusionsSensitivity enhancement provided by this denoising significantly improved quantification of metabolite dynamics and could benefit future studies by improving image quality, enabling higher spatial resolution, and facilitating the extraction of metabolic information for clinical research.
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- 2021
33. Loneliness and symptom burden in oncology patients during the COVID‐19 pandemic
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Miaskowski, Christine, Paul, Steven M, Snowberg, Karin, Abbott, Maura, Borno, Hala T, Chang, Susan M, Chen, Lee May, Cohen, Bevin, Cooper, Bruce A, Hammer, Marilyn J, Kenfield, Stacey A, Kober, Kord M, Laffan, Angela, Levine, Jon D, Pozzar, Rachel, Rhoads, Kim, Tsai, Katy K, Van Blarigan, Erin L, and Van Loon, Katherine
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Behavioral and Social Science ,Cancer ,Depression ,Mental Health ,2.3 Psychological ,social and economic factors ,Aetiology ,Mental health ,Good Health and Well Being ,Anxiety ,COVID-19 ,Humans ,Loneliness ,Neoplasms ,Public Health Surveillance ,Risk Factors ,SARS-CoV-2 ,Social Isolation ,Surveys and Questionnaires ,anxiety ,cancer ,coronavirus disease 2019 ,depression ,loneliness ,sleep disturbance ,social isolation ,Oncology and Carcinogenesis ,Public Health and Health Services ,Oncology & Carcinogenesis - Abstract
BackgroundLoneliness and social isolation are significant public health problems that are being exacerbated during the coronavirus disease 2019 pandemic. Little is known about the associations between loneliness and symptom burden in oncology patients before and during the pandemic. Study purposes include determining the prevalence of loneliness in a sample of oncology patients; evaluating for differences in demographic, clinical, and symptom characteristics between lonely and nonlonely patients; and determining which demographic, clinical, and symptom characteristics were associated with membership in the lonely group.MethodsA convenience sample (n = 606) completed online surveys that evaluated the severity of loneliness, social isolation, and common symptoms (ie, anxiety, depression, fatigue, sleep disturbance, cognitive dysfunction, and pain) in oncology patients. Parametric and nonparametric tests were used to evaluate for differences in scores between the lonely and nonlonely groups. Logistic regression analysis was used to determine risk factors for membership in the loneliness group.ResultsOf the 606 patients, 53.0% were categorized in the lonely group. The lonely group reported higher levels of social isolation, as well as higher symptom severity scores for all of the symptoms evaluated. In the multivariate model, being unmarried, having higher levels of social isolation, as well as higher levels of anxiety and depressive symptoms were associated with membership in the lonely group.ConclusionsStudy findings suggest that a significant number of oncology patients are experiencing loneliness, most likely as a result of mandate social distancing and isolation procedures. The symptom burden of these patients is extremely high and warrants clinical evaluation and interventions.
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- 2021
34. Systematic review on the use of patient-reported outcome measures in brain tumor studies: part of the Response Assessment in Neuro-Oncology Patient-Reported Outcome (RANO-PRO) initiative.
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Dirven, Linda, Vos, Maartje E, Walbert, Tobias, Armstrong, Terri S, Arons, David, van den Bent, Martin J, Blakeley, Jaishri, Brown, Paul D, Bulbeck, Helen, Chang, Susan M, Coens, Corneel, Gilbert, Mark R, Grant, Robin, Jalali, Rakesh, Leach, Danielle, Leeper, Heather, Mendoza, Tito, Nayak, Lakshmi, Oliver, Kathy, Reijneveld, Jaap C, Le Rhun, Emilie, Rubinstein, Larry, Weller, Michael, Wen, Patrick Y, and Taphoorn, Martin JB
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Neurosciences ,Clinical Research ,Brain Cancer ,Cancer ,Rare Diseases ,Brain Disorders ,activities of daily living ,brain tumor ,health-related quality of life ,patient-reported outcome ,symptoms ,Oncology and carcinogenesis - Abstract
BackgroundThe Response Assessment in Neuro-Oncology Patient-Reported Outcome (RANO-PRO) working group aims to provide guidance on the use of PROs in brain tumor patients. PRO measures should be of high quality, both in terms of relevance and other measurement properties. This systematic review aimed to identify PRO measures that have been used in brain tumor studies to date.MethodsA systematic literature search for articles published up to June 25, 2020 was conducted in several electronic databases. Pre-specified inclusion criteria were used to identify studies using PRO measures assessing symptoms, (instrumental) activities of daily living [(I)ADL] or health-related quality of life (HRQoL) in adult patients with glioma, meningioma, primary central nervous system lymphoma, or brain metastasis.ResultsA total of 215 different PRO measures were identified in 571 published and 194 unpublished studies. The identified PRO measures include brain tumor-specific, cancer-specific, and generic instruments, as well as instruments designed for other indications or multi- or single-item study-specific questionnaires. The most frequently used instruments were the EORTC QLQ-C30 and QLQ-BN20 (n = 286 and n = 247), and the FACT-Br (n = 167), however, the majority of the instruments were used only once or twice (150/215).ConclusionMany different PRO measures assessing symptoms, (I)ADL or HRQoL have been used in brain tumor studies to date. Future research should clarify whether these instruments or their scales/items exhibit good content validity and other measurement properties for use in brain tumor patients.
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- 2021
35. A single institution retrospective analysis on survival based on treatment paradigms for patients with anaplastic oligodendroglioma
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Bush, Nancy Ann Oberheim, Young, Jacob S, Zhang, Yalan, Dalle Ore, Cecilia L, Molinaro, Annette M, Taylor, Jennie, Clarke, Jennifer, Prados, Michael, Braunstein, Steve E, Raleigh, David R, Chang, Susan M, Berger, Mitchel S, and Butowski, Nicholas A
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Brain Disorders ,Clinical Research ,Cancer ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,6.4 Surgery ,Astrocytoma ,Brain Neoplasms ,Humans ,Oligodendroglioma ,Retrospective Studies ,Glioma ,Anaplastic Oligodendroglioma ,Chemotherapy ,Radiation ,Neurosciences ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
IntroductionAnaplastic oligodendrogliomas are high-grade gliomas defined molecularly by 1p19q co-deletion. There is no curative therapy, and standard of care includes surgical resection followed by radiation and chemotherapy. However, the benefit of up-front radiation with chemotherapy compared to chemotherapy alone has not been demonstrated in a randomized control trial. Given the potential long-term consequences of radiation therapy, such as cognitive impairment, arteriopathy, endocrinopathy, and hearing/visual impairment, there is an effort to balance longevity with radiation toxicity.MethodsWe performed a retrospective single institution analysis of survival of patients with anaplastic oligodendroglioma over 20 years.Results159 patients were identified as diagnosed with an anaplastic oligodendroglioma between 1996 and 2016. Of those, 40 patients were found to have AO at original diagnosis and had documented 1p19q co-deletion with a median of 7.1 years of follow-up (range: 0.6-16.7 years). After surgery, 45 % of patients were treated with radiation and chemotherapy at diagnosis, and 50 % were treated with adjuvant chemotherapy alone. The group treated with chemotherapy alone had a trend of receiving more cycles of chemotherapy than patients treated with radiation and chemotherapy upfront (p = 0.051). Median overall survival has not yet been reached. The related risk of progression in the upfront, adjuvant chemotherapy only group was almost 5-fold higher than the patients who received radiation and chemotherapy (hazard ratio = 4.85 (1.74-13.49), p = 0.002). However, there was no significant difference in overall survival in patients treated with upfront chemotherapy compared to patients treated upfront with chemotherapy and radiation (p = 0.8). Univariate analysis of age, KPS, extent of resection, or upfront versus delayed radiation was not associated with improved survival.ConclusionsInitial treatment with adjuvant chemotherapy alone, rather than radiation and chemotherapy, may be an option for some patients with anaplastic oligodendroglioma, as it is associated with similar overall survival despite shorter progression free survival.
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- 2021
36. Intracranial mesenchymal tumor with FET-CREB fusion-A unifying diagnosis for the spectrum of intracranial myxoid mesenchymal tumors and angiomatoid fibrous histiocytoma-like neoplasms.
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Sloan, Emily A, Chiang, Jason, Villanueva-Meyer, Javier E, Alexandrescu, Sanda, Eschbacher, Jennifer M, Wang, Wesley, Mafra, Manuela, Ud Din, Nasir, Carr-Boyd, Emily, Watson, Michael, Punsoni, Michael, Oviedo, Angelica, Gilani, Ahmed, Kleinschmidt-DeMasters, Bette K, Coss, Dylan J, Lopes, M Beatriz, Raffel, Corey, Berger, Mitchel S, Chang, Susan M, Reddy, Alyssa, Ramani, Biswarathan, Ferris, Sean P, Lee, Julieann C, Hofmann, Jeffrey W, Cho, Soo-Jin, Horvai, Andrew E, Pekmezci, Melike, Tihan, Tarik, Bollen, Andrew W, Rodriguez, Fausto J, Ellison, David W, Perry, Arie, and Solomon, David A
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CREB ,EWSR1 ,angiomatoid fibrous histiocytoma ,brain tumor ,intracranial myxoid mesenchymal tumor ,molecular neuropathology ,sarcoma ,Neurology & Neurosurgery ,Clinical Sciences ,Neurosciences - Abstract
Intracranial mesenchymal tumors with FET-CREB fusions are a recently described group of neoplasms in children and young adults characterized by fusion of a FET family gene (usually EWSR1, but rarely FUS) to a CREB family transcription factor (ATF1, CREB1, or CREM), and have been variously termed intracranial angiomatoid fibrous histiocytoma or intracranial myxoid mesenchymal tumor. The clinical outcomes, histologic features, and genomic landscape are not well defined. Here, we studied 20 patients with intracranial mesenchymal tumors proven to harbor FET-CREB fusion by next-generation sequencing (NGS). The 16 female and four male patients had a median age of 14 years (range 4-70). Tumors were uniformly extra-axial or intraventricular and located at the cerebral convexities (n = 7), falx (2), lateral ventricles (4), tentorium (2), cerebellopontine angle (4), and spinal cord (1). NGS demonstrated that eight tumors harbored EWSR1-ATF1 fusion, seven had EWSR1-CREB1, four had EWSR1-CREM, and one had FUS-CREM. Tumors were uniformly well circumscribed and typically contrast enhancing with solid and cystic growth. Tumors with EWSR1-CREB1 fusions more often featured stellate/spindle cell morphology, mucin-rich stroma, and hemangioma-like vasculature compared to tumors with EWSR1-ATF1 fusions that most often featured sheets of epithelioid cells with mucin-poor collagenous stroma. These tumors demonstrated polyphenotypic immunoprofiles with frequent positivity for desmin, EMA, CD99, MUC4, and synaptophysin, but absence of SSTR2A, myogenin, and HMB45 expression. There was a propensity for local recurrence with a median progression-free survival of 12 months and a median overall survival of greater than 60 months, with three patients succumbing to disease (all with EWSR1-ATF1 fusions). In combination with prior case series, this study provides further insight into intracranial mesenchymal tumors with FET-CREB fusion, which represent a distinct group of CNS tumors encompassing both intracranial myxoid mesenchymal tumor and angiomatoid fibrous histiocytoma-like neoplasms.
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- 2021
37. Systematic review of combinations of targeted or immunotherapy in advanced solid tumors
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Tan, Aaron C, Bagley, Stephen J, Wen, Patrick Y, Lim, Michael, Platten, Michael, Colman, Howard, Ashley, David M, Wick, Wolfgang, Chang, Susan M, Galanis, Evanthia, Mansouri, Alireza, Khagi, Simon, Mehta, Minesh P, Heimberger, Amy B, Puduvalli, Vinay K, Reardon, David A, Sahebjam, Solmaz, Simes, John, Antonia, Scott J, Berry, Don, and Khasraw, Mustafa
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Clinical Research ,Cancer ,Clinical Trials and Supportive Activities ,Good Health and Well Being ,Combined Modality Therapy ,Humans ,Immunotherapy ,Neoplasms ,immunotherapy ,drug therapy ,combination ,clinical trials as topic ,Oncology and carcinogenesis - Abstract
With rapid advances in our understanding of cancer, there is an expanding number of potential novel combination therapies, including novel-novel combinations. Identifying which combinations are appropriate and in which subpopulations are among the most difficult questions in medical research. We conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-guided systematic review of trials of novel-novel combination therapies involving immunotherapies or molecular targeted therapies in advanced solid tumors. A MEDLINE search was conducted using a modified Cochrane Highly Sensitive Search Strategy for published clinical trials between July 1, 2017, and June 30, 2020, in the top-ranked medical and oncology journals. Trials were evaluated according to a criterion adapted from previously published Food and Drug Administration guidance and other key considerations in designing trials of combinations. This included the presence of a strong biological rationale, the use of a new established or emerging predictive biomarker prospectively incorporated into the clinical trial design, appropriate comparator arms of monotherapy or supportive external data sources and a primary endpoint demonstrating a clinically meaningful benefit. Of 32 identified trials, there were 11 (34%) trials of the novel-novel combination of anti-programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) and anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) therapy, and 10 (31%) trials of anti-PD-1/PD-L1 and anti-vascular endothelial growth factor (VEGF) combination therapy. 20 (62.5%) trials were phase II trials, while 12 (37.5%) were phase III trials. Most (72%) trials lacked significant preclinical evidence supporting the development of the combination in the given indication. A majority of trials (69%) were conducted in biomarker unselected populations or used pre-existing biomarkers within the given indication for patient selection. Most studies (66%) were considered to have appropriate comparator arms or had supportive external data sources such as prior studies of monotherapy. All studies were evaluated as selecting a clinically meaningful primary endpoint. In conclusion, designing trials to evaluate novel-novel combination therapies presents numerous challenges to demonstrate efficacy in a comprehensive manner. A greater understanding of biological rationale for combinations and incorporating predictive biomarkers may improve effective evaluation of combination therapies. Innovative statistical methods and increasing use of external data to support combination approaches are potential strategies that may improve the efficiency of trial design. Designing trials to evaluate novel-novel combination therapies presents numerous challenges to demonstrate efficacy in a comprehensive manner. A greater understanding of biological rationale for combinations and incorporating predictive biomarkers may improve effective evaluation of combination therapies. Innovative statistical methods and increasing use of external data to support combination approaches are potential strategies that may improve the efficiency of trial design.
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- 2021
38. A framework for standardised tissue sampling and processing during resection of diffuse intracranial glioma: joint recommendations from four RANO groups
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Aldape, Kenneth, Baehring, Joachim M., Bello, Lorenzo, Brat, Daniel J., Cahill, Daniel P., Chung, Caroline, Colman, Howard, Dietrich, Jorg, Drummond, Katharine, Esquenazi, Yoshua, Gerstner, Elizabeth R., Furtner, Julia, Garibotto, Valentina, Kaufmann, Timothy J., Komori, Takashi, Kotecha, Rupesh, Liau, Linda M., Lupo, Janine M., Minniti, Giuseppe, Narita, Yoshitaka, Niyazi, Maximilian, Perry, Arie, Preusser, Matthias, Rudà, Roberta, Sanai, Nader, Schmidt, Nils-Ole, Steinbach, Joachim P., Thust, Stefanie C., Tolboom, Nelleke, van der Hoorn, Anouk, van der Vaart, Thijs, Verger, Antoine, Vik-Mo, Einar Osland, Watts, Colin, Westphal, Manfred, Wesseling, Pieter, Young, Jacob S., Karschnia, Philipp, Smits, Marion, Reifenberger, Guido, Le Rhun, Emilie, Ellingson, Benjamin M, Galldiks, Norbert, Kim, Michelle M, Huse, Jason T, Schnell, Oliver, Harter, Patrick N, Mohme, Malte, von Baumgarten, Louisa, Albert, Nathalie L, Huang, Raymond Y, Mehta, Minesh P, van den Bent, Martin, Weller, Michael, Vogelbaum, Michael A, Chang, Susan M, Berger, Mitchel S, and Tonn, Joerg-Christian
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- 2023
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39. Primary brain tumours in adults
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van den Bent, Martin J, Geurts, Marjolein, French, Pim J, Smits, Marion, Capper, David, Bromberg, Jacoline E C, and Chang, Susan M
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- 2023
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40. Academic performance in Jamaican children with sickle cell disease
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King, Lesley G., Ali, Susanna Bortolusso, Chang, Susan M., Reid, Marvin E., and Soares, Deanne P.
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- 2023
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41. Tensor image enhancement and optimal multichannel receiver combination analyses for human hyperpolarized 13C MRSI
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Chen, Hsin‐Yu, Autry, Adam W, Brender, Jeffrey R, Kishimoto, Shun, Krishna, Murali C, Vareth, Maryam, Bok, Robert A, Reed, Galen D, Carvajal, Lucas, Gordon, Jeremy W, van Criekinge, Mark, Korenchan, David E, Chen, Albert P, Xu, Duan, Li, Yan, Chang, Susan M, Kurhanewicz, John, Larson, Peder EZ, and Vigneron, Daniel B
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Engineering ,Biomedical Engineering ,Biomedical Imaging ,Bioengineering ,Clinical Research ,Cancer ,Carbon Isotopes ,Child ,Humans ,Image Enhancement ,Magnetic Resonance Imaging ,Magnetic Resonance Spectroscopy ,Pyruvic Acid ,Signal-To-Noise Ratio ,cancer imaging ,hyperpolarized C-13 pyruvate ,tensor rank truncation image enhancement ,Nuclear Medicine & Medical Imaging ,Biomedical engineering - Abstract
PurposeWith the initiation of human hyperpolarized 13 C (HP-13 C) trials at multiple sites and the development of improved acquisition methods, there is an imminent need to maximally extract diagnostic information to facilitate clinical interpretation. This study aims to improve human HP-13 C MR spectroscopic imaging through means of Tensor Rank truncation-Image enhancement (TRI) and optimal receiver combination (ORC).MethodsA data-driven processing framework for dynamic HP 13 C MR spectroscopic imaging (MRSI) was developed. Using patient data sets acquired with both multichannel arrays and single-element receivers from the brain, abdomen, and pelvis, we examined the theory and application of TRI, as well as 2 ORC techniques: whitened singular value decomposition (WSVD) and first-point phasing. Optimal conditions for TRI were derived based on bias-variance trade-off.ResultsTRI and ORC techniques together provided a 63-fold mean apparent signal-to-noise ratio (aSNR) gain for receiver arrays and a 31-fold gain for single-element configurations, which particularly improved quantification of the lower-SNR-[13 C]bicarbonate and [1-13 C]alanine signals that were otherwise not detectable in many cases. Substantial SNR enhancements were observed for data sets that were acquired even with suboptimal experimental conditions, including delayed (114 s) injection (8× aSNR gain solely by TRI), or from challenging anatomy or geometry, as in the case of a pediatric patient with brainstem tumor (597× using combined TRI and WSVD). Improved correlation between elevated pyruvate-to-lactate conversion, biopsy-confirmed cancer, and mp-MRI lesions demonstrated that TRI recovered quantitative diagnostic information.ConclusionOverall, this combined approach was effective across imaging targets and receiver configurations and could greatly benefit ongoing and future HP 13 C MRI research through major aSNR improvements.
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- 2020
42. MGMT promoter methylation level in newly diagnosed low-grade glioma is a predictor of hypermutation at recurrence
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Mathur, Radhika, Zhang, Yalan, Grimmer, Matthew R, Hong, Chibo, Zhang, Michael, Bollam, Saumya, Petrecca, Kevin, Clarke, Jennifer, Berger, Mitchel S, Phillips, Joanna J, Oberheim-Bush, Nancy Ann, Molinaro, Annette M, Chang, Susan M, and Costello, Joseph F
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Human Genome ,Genetics ,Brain Cancer ,Brain Disorders ,Cancer ,Rare Diseases ,Clinical Research ,Antineoplastic Agents ,Alkylating ,Brain Neoplasms ,DNA Methylation ,DNA Modification Methylases ,DNA Repair Enzymes ,Glioma ,Humans ,Neoplasm Recurrence ,Local ,Temozolomide ,Tumor Suppressor Proteins ,biomarker ,glioma ,hypermutation ,MGMT ,temozolomide ,Neurosciences ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
BackgroundEmerging data suggest that a subset of patients with diffuse isocitrate dehydrogenase (IDH)-mutant low-grade glioma (LGG) who receive adjuvant temozolomide (TMZ) recur with hypermutation in association with malignant progression to higher-grade tumors. It is currently unclear why some TMZ-treated LGG patients recur with hypermutation while others do not. MGMT encodes O6-methylguanine-DNA methyltransferase, a DNA repair protein that removes cytotoxic and potentially mutagenic lesions induced by TMZ. Here, we hypothesize that epigenetic silencing of MGMT by promoter methylation facilitates TMZ-induced mutagenesis in LGG patients and contributes to development of hypermutation at recurrence.MethodsWe utilize a quantitative deep sequencing assay to characterize MGMT promoter methylation in 109 surgical tissue specimens from initial tumors and post-treatment recurrences of 37 TMZ-treated LGG patients. We utilize methylation arrays to validate our sequencing assay, RNA sequencing to assess the relationship between methylation and gene expression, and exome sequencing to determine hypermutation status.ResultsMethylation level at the MGMT promoter is significantly higher in initial tumors of patients that develop hypermutation at recurrence relative to initial tumors of patients that do not (45.7% vs 34.8%, P = 0.027). Methylation level in initial tumors can predict hypermutation at recurrence in univariate models and multivariate models that incorporate patient age and molecular subtype.ConclusionsThese findings reveal a mechanistic basis for observed differences in patient susceptibility to TMZ-driven hypermutation. Furthermore, they establish MGMT promoter methylation level as a potential biomarker to inform clinical management of LGG patients, including monitoring and treatment decisions, by predicting risk of hypermutation at recurrence.
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- 2020
43. Multiplatform molecular analyses refine classification of gliomas arising in patients with neurofibromatosis type 1
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Lucas, Calixto-Hope G., Sloan, Emily A., Gupta, Rohit, Wu, Jasper, Pratt, Drew, Vasudevan, Harish N., Ravindranathan, Ajay, Barreto, Jairo, Williams, Erik A., Shai, Anny, Whipple, Nicholas S., Bruggers, Carol S., Maher, Ossama, Nabors, Burt, Rodriguez, Michael, Samuel, David, Brown, Melandee, Carmichael, Jason, Lu, Rufei, Mirchia, Kanish, Sullivan, Daniel V., Pekmezci, Melike, Tihan, Tarik, Bollen, Andrew W., Perry, Arie, Banerjee, Anuradha, Mueller, Sabine, Gupta, Nalin, Hervey-Jumper, Shawn L., Oberheim Bush, Nancy Ann, Daras, Mariza, Taylor, Jennie W., Butowski, Nicholas A., de Groot, John, Clarke, Jennifer L., Raleigh, David R., Costello, Joseph F., Phillips, Joanna J., Reddy, Alyssa T., Chang, Susan M., Berger, Mitchel S., and Solomon, David A.
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- 2022
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44. Glioblastoma in adults: a Society for Neuro-Oncology (SNO) and European Society of Neuro-Oncology (EANO) consensus review on current management and future directions
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Wen, Patrick Y, Weller, Michael, Lee, Eudocia Quant, Alexander, Brian M, Barnholtz-Sloan, Jill S, Barthel, Floris P, Batchelor, Tracy T, Bindra, Ranjit S, Chang, Susan M, Chiocca, E Antonio, Cloughesy, Timothy F, DeGroot, John F, Galanis, Evanthia, Gilbert, Mark R, Hegi, Monika E, Horbinski, Craig, Huang, Raymond Y, Lassman, Andrew B, Le Rhun, Emilie, Lim, Michael, Mehta, Minesh P, Mellinghoff, Ingo K, Minniti, Giuseppe, Nathanson, David, Platten, Michael, Preusser, Matthias, Roth, Patrick, Sanson, Marc, Schiff, David, Short, Susan C, Taphoorn, Martin JB, Tonn, Joerg-Christian, Tsang, Jonathan, Verhaak, Roel GW, von Deimling, Andreas, Wick, Wolfgang, Zadeh, Gelareh, Reardon, David A, Aldape, Kenneth D, and van den Bent, Martin J
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Neurosciences ,Rare Diseases ,Cancer ,Brain Disorders ,Brain Cancer ,Good Health and Well Being ,Brain Neoplasms ,Chemoradiotherapy ,Clinical Trials ,Phase III as Topic ,Consensus ,Glioblastoma ,Humans ,Isocitrate Dehydrogenase ,Randomized Controlled Trials as Topic ,glioblastoma ,diagnosis ,therapy ,clinical trials ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
Glioblastomas are the most common form of malignant primary brain tumor and an important cause of morbidity and mortality. In recent years there have been important advances in understanding the molecular pathogenesis and biology of these tumors, but this has not translated into significantly improved outcomes for patients. In this consensus review from the Society for Neuro-Oncology (SNO) and the European Association of Neuro-Oncology (EANO), the current management of isocitrate dehydrogenase wildtype (IDHwt) glioblastomas will be discussed. In addition, novel therapies such as targeted molecular therapies, agents targeting DNA damage response and metabolism, immunotherapies, and viral therapies will be reviewed, as well as the current challenges and future directions for research.
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- 2020
45. Optimizing eligibility criteria and clinical trial conduct to enhance clinical trial participation for primary brain tumor patients.
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Lee, Eudocia Q, Weller, Michael, Sul, Joohee, Bagley, Stephen J, Sahebjam, Solmaz, van den Bent, Martin, Ahluwalia, Manmeet, Campian, Jian L, Galanis, Evanthia, Gilbert, Mark R, Holdhoff, Matthias, Lesser, Glenn J, Lieberman, Frank S, Mehta, Minesh P, Penas-Prado, Marta, Schreck, Karisa C, Strowd, Roy E, Vogelbaum, Michael A, Walbert, Tobias, Chang, Susan M, Nabors, L Burt, Grossman, Stuart, Reardon, David A, and Wen, Patrick Y
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Clinical Research ,Rare Diseases ,Brain Disorders ,Brain Cancer ,Clinical Trials and Supportive Activities ,Cancer ,Brain Neoplasms ,Humans ,Patient Selection ,clinical trials ,primary brain tumor ,eligibility ,inclusion criteria ,exclusion criteria ,Neurosciences ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
Building on an initiative to enhance clinical trial participation involving the Society for Neuro-Oncology, the Response Assessment in Neuro-Oncology Working Group, patient advocacy groups, clinical trial cooperative groups, and other partners, we evaluate the impact of eligibility criteria and trial conduct on neuro-oncology clinical trial participation. Clinical trials often carry forward eligibility criteria from prior studies that may be overly restrictive and unnecessary and needlessly limit patient accrual. Inclusion and exclusion criteria should be evaluated based on the goals and design of the study and whether they impact patient safety and/or treatment efficacy. In addition, we evaluate clinical trial conduct as a barrier to accrual and discuss strategies to minimize such barriers for neuro-oncology trials.
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- 2020
46. Phase I/II study of sorafenib in combination with erlotinib for recurrent glioblastoma as part of a 3-arm sequential accrual clinical trial: NABTC 05-02
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Chen, Huanwen, Kuhn, John, Lamborn, Kathleen R, Abrey, Lauren E, DeAngelis, Lisa M, Lieberman, Frank, Robins, H Ian, Chang, Susan M, Yung, WK Alfred, Drappatz, Jan, Mehta, Minesh P, Levin, Victor A, Aldape, Kenneth, Dancey, Janet E, Wright, John J, Prados, Michael D, Cloughesy, Timothy F, Wen, Patrick Y, and Gilbert, Mark R
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Clinical Trials and Supportive Activities ,Brain Disorders ,Rare Diseases ,Clinical Research ,Brain Cancer ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,6.2 Cellular and gene therapies ,erlotinib ,glioblastoma ,molecular therapy ,novel trial design ,sorafenib - Abstract
BackgroundReceptor tyrosine kinases such as epidermal growth factor receptors (EGFRs) and their downstream signaling pathways such as the Ras-Raf-mitogen-activated protein kinase (MAPK) pathway play important roles in glioblastoma (GBM). This study investigated the safety, pharmacokinetics, and efficacy of sorafenib (Ras/Raf/MAPK inhibitor) in combination with erlotinib (EGFR inhibitor) for treatment of recurrent GBMs.MethodsPatients with recurrent GBM were eligible. A novel sequential accrual trial design was used, where patients were sequentially accrued into separate treatment arms in phase I and phase II investigations to optimize recruitment efficiency. In phase I, a standard 3 + 3 format was used to identify dose-limiting toxicities (DLTs), determine maximum tolerated dose (MTD), and investigate pharmacokinetics. Phase II followed a 2-stage design with the primary endpoint being 6-month progression-free survival (PFS6).ResultsSixteen patients were recruited for phase I, and the MTD was determined to be sorafenib 200 mg twice daily and erlotinib 100 mg once daily. DLTs include Grade 3 hypertension, Grade 3 elevated liver transaminases, and Grade 4 elevated lipase. While erlotinib did not affect sorafenib levels, sorafenib reduced erlotinib levels. In phase II, 3 of 19 stage 1 participants were progression free at 6 months. This did not meet the predetermined efficacy endpoint, and the trial was terminated.ConclusionThis study identified the MTD and DLTs for sorafenib and erlotinib combination therapy for recurrent GBMs; however, efficacy data did not meet the primary endpoint. This study also demonstrates the feasibility of a novel sequential accrual clinical trial design that optimizes patient recruitment for multiarm studies, which is particularly effective for multicenter clinical trials.
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- 2020
47. Proceedings of the Comprehensive Oncology Network Evaluating Rare CNS Tumors (NCI-CONNECT) Oligodendroglioma Workshop.
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Penas-Prado, Marta, Wu, Jing, Cahill, Daniel P, Brat, Daniel J, Costello, Joseph F, Kluetz, Paul G, Cairncross, J Gregory, van den Bent, Martin, Verhaak, Roel GW, Aboud, Orwa, Burger, Peter, Chang, Susan M, Cordova, Christine, Huang, Raymond Y, Rowe, Lindsay S, Taphoorn, Martin JB, Gilbert, Mark R, Armstrong, Terri S, and NCI-CONNECT Oligodendroglioma Workshop
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NCI-CONNECT Oligodendroglioma Workshop ,NCI-CONNECT ,oligodendroglioma ,rare CNS tumors ,workshop ,Rare Diseases ,Neurosciences ,Clinical Research ,Cancer ,Good Health and Well Being - Abstract
BackgroundOligodendroglioma is a rare primary central nervous system (CNS) tumor with highly variable outcome and for which therapy is usually not curative. At present, little is known regarding the pathways involved with progression of oligodendrogliomas or optimal biomarkers for stratifying risk. Developing new therapies for this rare cancer is especially challenging. To overcome these challenges, the neuro-oncology community must be particularly innovative, seeking multi-institutional and international collaborations, and establishing partnerships with patients and advocacy groups thereby ensuring that each patient enrolled in a study is as informative as possible.MethodsThe mission of the National Cancer Institute's NCI-CONNECT program is to address the challenges and unmet needs in rare CNS cancer research and treatment by connecting patients, health care providers, researchers, and advocacy organizations to work in partnership. On November 19, 2018, the program convened a workshop on oligodendroglioma, one of the 12 rare CNS cancers included in its initial portfolio. The purpose of this workshop was to discuss scientific progress and regulatory challenges in oligodendroglioma research and develop a call to action to advance research and treatment for this cancer.ResultsThe recommendations of the workshop include a multifaceted and interrelated approach covering: biology and preclinical models, data sharing and advanced molecular diagnosis and imaging; clinical trial design; and patient outreach and engagement.ConclusionsThe NCI-CONNECT program is well positioned to address challenges in oligodendroglioma care and research in collaboration with other stakeholders and is developing a list of action items for future initiatives.
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- 2020
48. Patient-derived cells from recurrent tumors that model the evolution of IDH-mutant glioma.
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Jones, Lindsey E, Hilz, Stephanie, Grimmer, Matthew R, Mazor, Tali, Najac, Chloé, Mukherjee, Joydeep, McKinney, Andrew, Chow, Tracy, Pieper, Russell O, Ronen, Sabrina M, Chang, Susan M, Phillips, Joanna J, and Costello, Joseph F
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IDH1-mutant glioma ,hypermutation ,intracranial xenograft ,intratumoral heterogeneity and evolution ,patient-derived cells ,Neurosciences ,Brain Cancer ,Cancer ,Genetics ,Brain Disorders ,Rare Diseases ,Human Genome - Abstract
BackgroundIDH-mutant lower-grade gliomas (LGGs) evolve under the selective pressure of therapy, but well-characterized patient-derived cells (PDCs) modeling evolutionary stages are lacking. IDH-mutant LGGs may develop therapeutic resistance associated with chemotherapy-driven hypermutation and malignant progression. The aim of this study was to establish and characterize PDCs, single-cell-derived PDCs (scPDCs), and xenografts (PDX) of IDH1-mutant recurrences representing distinct stages of tumor evolution.MethodsWe derived and validated cell cultures from IDH1-mutant recurrences of astrocytoma and oligodendroglioma. We used exome sequencing and phylogenetic reconstruction to examine the evolutionary stage represented by PDCs, scPDCs, and PDX relative to corresponding spatiotemporal tumor tissue and germline DNA. PDCs were also characterized for growth and tumor immortality phenotypes, and PDX were examined histologically.ResultsThe integrated astrocytoma phylogeny revealed 2 independent founder clonal expansions of hypermutated (HM) cells in tumor tissue that are faithfully represented by independent PDCs. The oligodendroglioma phylogeny showed more than 4000 temozolomide-associated mutations shared among tumor samples, PDCs, scPDCs, and PDX, suggesting a shared monoclonal origin. The PDCs from both subtypes exhibited hallmarks of tumorigenesis, retention of subtype-defining genomic features, production of 2-hydroxyglutarate, and subtype-specific telomere maintenance mechanisms that confer tumor cell immortality. The oligodendroglioma PDCs formed infiltrative intracranial tumors with characteristic histology.ConclusionsThese PDCs, scPDCs, and PDX are unique and versatile community resources that model the heterogeneous clonal origins and functions of recurrent IDH1-mutant LGGs. The integrated phylogenies advance our knowledge of the complex evolution and immense mutational load of IDH1-mutant HM glioma.
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- 2020
49. Clinical, radiologic, and genetic characteristics of histone H3 K27M-mutant diffuse midline gliomas in adults
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Schulte, Jessica D, Buerki, Robin A, Lapointe, Sarah, Molinaro, Annette M, Zhang, Yalan, Villanueva-Meyer, Javier E, Perry, Arie, Phillips, Joanna J, Tihan, Tarik, Bollen, Andrew W, Pekmezci, Melike, Butowski, Nicholas, Bush, Nancy Ann Oberheim, Taylor, Jennie W, Chang, Susan M, Theodosopoulos, Philip, Aghi, Manish K, Hervey-Jumper, Shawn L, Berger, Mitchel S, Solomon, David A, and Clarke, Jennifer L
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Brain Cancer ,Brain Disorders ,Pediatric Cancer ,Genetics ,Pediatric ,Pediatric Research Initiative ,Cancer ,Rare Diseases ,Neurosciences ,Aetiology ,2.1 Biological and endogenous factors ,adult ,diffuse midline glioma ,genetics ,H3 K27M ,survival - Abstract
Background"Diffuse midline glioma (DMG), H3 K27M-mutant" is a new tumor entity established in the 2016 WHO classification of Tumors of the Central Nervous System that comprises a set of diffuse gliomas arising in midline structures and is molecularly defined by a K27M mutation in genes encoding the histone 3 variants H3.3 or H3.1. While this tumor entity is associated with poor prognosis in children, clinical experience in adults remains limited.MethodsPatient demographics, radiologic and pathologic characteristics, treatment course, progression, and patient survival were collected for 60 adult patients with DMG, H3 K27M-mutant. A subset of tumors also underwent next-generation sequencing. Analysis of progression-free survival and overall survival was conducted using Kaplan-Meier modeling, and univariate and multivariate analysis.ResultsMedian patient age was 32 years (range 18-71 years). Tumors were centered in the thalamus (n = 34), spinal cord (10), brainstem (5), cerebellum (4), or other midline sites (4), or were multifocal (3). Genomic profiling revealed p.K27M mutations exclusively in the H3F3A gene and an absence of mutations in HIST1H3B or HIST1H3C, which are present in approximately one-third of pediatric DMGs. Accompanying mutations in TP53, PPM1D, FGFR1, NF1, and ATRX were frequently found. The overall survival of this adult cohort was 27.6 months, longer than historical averages for both H3 K27M-mutant DMG in children and IDH-wildtype glioblastoma in adults.ConclusionsTogether, these findings indicate that H3 K27M-mutant DMG represents a heterogeneous disease with regard to outcomes, sites of origin, and molecular pathogenesis in adults versus children.
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- 2020
50. Characterization of serial hyperpolarized 13C metabolic imaging in patients with glioma
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Autry, Adam W, Gordon, Jeremy W, Chen, Hsin-Yu, LaFontaine, Marisa, Bok, Robert, Van Criekinge, Mark, Slater, James B, Carvajal, Lucas, Villanueva-Meyer, Javier E, Chang, Susan M, Clarke, Jennifer L, Lupo, Janine M, Xu, Duan, Larson, Peder EZ, Vigneron, Daniel B, and Li, Yan
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Brain Cancer ,Bioengineering ,Cancer ,Brain Disorders ,Clinical Research ,Biomedical Imaging ,Neurosciences ,Rare Diseases ,Contrast Media ,Gadolinium ,Glioma ,Humans ,Magnetic Resonance Imaging ,Prospective Studies ,Pyruvic Acid ,Hyperpolarized ,Carbon-13 ,Metabolism ,Kinetics ,Bevacizumab ,Biological psychology ,Clinical and health psychology - Abstract
BackgroundHyperpolarized carbon-13 (HP-13C) MRI is a non-invasive imaging technique for probing brain metabolism, which may improve clinical cancer surveillance. This work aimed to characterize the consistency of serial HP-13C imaging in patients undergoing treatment for brain tumors and determine whether there is evidence of aberrant metabolism in the tumor lesion compared to normal-appearing tissue.MethodsSerial dynamic HP [1-13C]pyruvate MRI was performed on 3 healthy volunteers (6 total examinations) and 5 patients (21 total examinations) with diffuse infiltrating glioma during their course of treatment, using a frequency-selective echo-planar imaging (EPI) sequence. HP-13C imaging at routine clinical timepoints overlapped treatment, including radiotherapy (RT), temozolomide (TMZ) chemotherapy, and anti-angiogenic/investigational agents. Apparent rate constants for [1-13C]pyruvate conversion to [1-13C]lactate (kPL) and [13C]bicarbonate (kPB) were simultaneously quantified based on an inputless kinetic model within normal-appearing white matter (NAWM) and anatomic lesions defined from 1H MRI. The inter/intra-subject consistency of kPL-NAWM and kPB-NAWM was measured in terms of the coefficient of variation (CV).ResultsWhen excluding scans following anti-angiogenic therapy, patient values of kPL-NAWM and kPB-NAWM were 0.020 s-1 ± 23.8% and 0.0058 s-1 ± 27.7% (mean ± CV) across 17 HP-13C MRIs, with intra-patient serial kPL-NAWM/kPB-NAWM CVs ranging 6.8-16.6%/10.6-40.7%. In 4/5 patients, these values (0.018 s-1 ± 13.4% and 0.0058 s-1 ± 24.4%; n = 13) were more similar to those from healthy volunteers (0.018 s-1 ± 5.0% and 0.0043 s-1 ± 12.6%; n = 6) (mean ± CV). The anti-angiogenic agent bevacizumab was associated with global elevations in apparent rate constants, with maximum kPL-NAWM in 2 patients reaching 0.047 ± 0.001 and 0.047 ± 0.003 s-1 (±model error). In 3 patients with progressive disease, anatomic lesions showed elevated kPL relative to kPL-NAWM of 0.024 ± 0.001 s-1 (±model error) in the absence of gadolinium enhancement, and 0.032 ± 0.008, 0.040 ± 0.003 and 0.041 ± 0.009 s-1 with gadolinium enhancement. The lesion kPB in patients was reduced to unquantifiable values compared to kPB-NAWM.ConclusionSerial measures of HP [1-13C]pyruvate metabolism displayed consistency in the NAWM of healthy volunteers and patients. Both kPL and kPB were globally elevated following bevacizumab treatment, while progressive disease demonstrated elevated kPL in gadolinium-enhancing and non-enhancing lesions. Larger prospective studies with homogeneous patient populations are planned to evaluate metabolic changes following treatment.
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- 2020
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