173 results on '"Dunn GP"'
Search Results
2. Mycotic pseudoaneurysm of the internal maxillary artery: case report and review of the literature.
- Author
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Dunn GP, Uppaluri R, Hessler JL, Layland MK, Derdeyn CP, and Sunwoo JB
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- 2007
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Catalog
3. Palliating patients who have unresectable colorectal cancer: creating the right framework and salient symptom management.
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Dunn GP
- Published
- 2006
4. Special issue on palliative surgery.
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Hinshaw DB and Dunn GP
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- 2009
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5. GSTM1 null genotype underpins recurrence of NF2 meningiomas.
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Johnson AC, Tsitsikov EN, Phan KP, Zuccato JA, Bauer AM, Graffeo CS, Hameed S, Stephens TM, Liu Y, Dunn GP, Tsytsykova AV, Jones PS, and Dunn IF
- Abstract
Introduction: Meningiomas are the most common primary central nervous system (CNS) tumor in adults, comprising one-third of all primary adult CNS tumors. Although several recent publications have identified molecular alterations in meningioma including characteristic mutations, copy number alterations, and gene expression signatures, our understanding of the drivers of meningioma recurrence is limited., Objective: To identify gene expression signatures of 1p
- 22q- NF2- meningioma recurrence, with concurrent biallelic inactivation of NF2 and loss of chr1p that are heterogenous but enriched for recurrent meningiomas., Methods: Transcriptomic alterations present in recurrent versus primary 1p- 22q- NF2- meningiomas were identified using RNA sequencing (RNA-seq) data in a clinically annotated cohort., Results: Recurrent 1p- 22q- NF2- meningiomas were enriched for a newly identified GSTM1 null genotype compared to primary meningiomas that showed variable GSTM1 expression and independent external validation was performed., Conclusions: The GSTM1 null genotype is a novel biomarker of 1p- 22q- NF2- meningioma recurrence that resolves heterogeneity in existing meningioma subtypes and may be used to guide future clinical management decisions on extent of treatment to improve patient outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Johnson, Tsitsikov, Phan, Zuccato, Bauer, Graffeo, Hameed, Stephens, Liu, Dunn, Tsytsykova, Jones and Dunn.) more...- Published
- 2024
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6. A Phase 1/2 Study of Disulfiram and Copper With Concurrent Radiation Therapy and Temozolomide for Patients With Newly Diagnosed Glioblastoma.
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Huang J, Campian JL, DeWees TA, Skrott Z, Mistrik M, Johanns TM, Ansstas G, Butt O, Leuthardt E, Dunn GP, Zipfel GJ, Osbun JW, Abraham C, Badiyan S, Schwetye K, Cairncross JG, Rubin JB, Kim AH, and Chheda MG more...
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- Humans, Middle Aged, Male, Female, Aged, Adult, Isocitrate Dehydrogenase genetics, Progression-Free Survival, Antineoplastic Agents, Alkylating therapeutic use, Antineoplastic Agents, Alkylating pharmacokinetics, Proto-Oncogene Proteins B-raf genetics, Disulfiram therapeutic use, Disulfiram pharmacokinetics, Disulfiram administration & dosage, Glioblastoma radiotherapy, Glioblastoma genetics, Glioblastoma mortality, Glioblastoma therapy, Glioblastoma drug therapy, Temozolomide therapeutic use, Temozolomide pharmacokinetics, Temozolomide administration & dosage, Copper blood, Copper therapeutic use, Brain Neoplasms radiotherapy, Brain Neoplasms mortality, Brain Neoplasms genetics, Brain Neoplasms therapy, Chemoradiotherapy methods
- Abstract
Purpose: This phase 1/2 study aimed to evaluate the safety and preliminary efficacy of combining disulfiram and copper (DSF/Cu) with radiation therapy (RT) and temozolomide (TMZ) in patients with newly diagnosed glioblastoma (GBM)., Methods and Materials: Patients received standard RT and TMZ with DSF (250-375 mg/d) and Cu, followed by adjuvant TMZ plus DSF (500 mg/d) and Cu. Pharmacokinetic analyses determined drug concentrations in plasma and tumors using high-performance liquid chromatography-mass spectrometry., Results: Thirty-three patients, with a median follow-up of 26.0 months, were treated, including 12 IDH-mutant, 9 NF1-mutant, 3 BRAF-mutant, and 9 other IDH-wild-type cases. In the phase 1 arm, 18 patients were treated; dose-limiting toxicity probabilities were 10% (95% CI, 3%-29%) at 250 mg/d and 21% (95% CI, 7%-42%) at 375 mg/d. The phase 2 arm treated 15 additional patients at 250 mg/d. No significant difference in overall survival or progression-free survival was noted between IDH- and NF1-mutant cohorts compared with institutional counterparts treated without DSF/Cu. However, extended remission occurred in 3 BRAF-mutant patients. Diethyl-dithiocarbamate-copper, the proposed active metabolite of DSF/Cu, was detected in plasma but not in tumors., Conclusions: The maximum tolerated dose of DSF with RT and TMZ is 375 mg/d. DSF/Cu showed limited clinical efficacy for most patients. However, promising efficacy was observed in BRAF-mutant GBM, warranting further investigation., (Copyright © 2024 Elsevier Inc. All rights reserved.) more...
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- 2024
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7. Case 33-2024: A 71-Year-Old Woman with Confusion, Aphasia, and a Brain Mass.
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Arrillaga-Romany I, Ford JN, Dunn GP, Kotton CN, Mount CW, and Latham KA
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- 2024
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8. Radical surgical resection with molecular margins is associated with improved survival in IDH wild-type glioblastoma.
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Massaad E, Smith WJ, Bradley J, Esposito E, Gupta M, Burns E, Burns R, Velarde JK, Berglar IK, Gupta R, Martinez-Lage M, Dietrich J, Lennerz JK, Dunn GP, Jones PS, Choi BD, Kim AE, Frosch M, Barker FG, Curry WT, Carter BS, Nahed BV, Cahill DP, and Shankar GM more...
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- Humans, Male, Female, Middle Aged, Telomerase genetics, Retrospective Studies, Aged, Survival Rate, Prospective Studies, Adult, Prognosis, Follow-Up Studies, Neurosurgical Procedures methods, Promoter Regions, Genetic, Glioblastoma surgery, Glioblastoma genetics, Glioblastoma pathology, Glioblastoma mortality, Glioblastoma diagnostic imaging, Isocitrate Dehydrogenase genetics, Brain Neoplasms surgery, Brain Neoplasms genetics, Brain Neoplasms pathology, Brain Neoplasms mortality, Brain Neoplasms diagnostic imaging, Mutation, Margins of Excision
- Abstract
Background: Survival is variable in patients with glioblastoma IDH wild-type (GBM), even after comparable surgical resection of radiographically detectable disease, highlighting the limitations of radiographic assessment of infiltrative tumor anatomy. The majority of postsurgical progressive events are failures within 2 cm of the resection margin, motivating supramaximal resection strategies to improve local control. However, which patients benefit from such radical resections remains unknown., Methods: We developed a predictive model to identify which IDH wild-type GBMs are amenable to radiographic gross-total resection (GTR). We then investigated whether GBM survival heterogeneity following GTR is correlated with microscopic tumor burden by analyzing tumor cell content at the surgical margin with a rapid qPCR-based method for detection of TERT promoter mutation., Results: Our predictive model for achievable GTR, developed on retrospective radiographic and molecular data of GBM patients undergoing resection, had an area under the curve of 0.83, sensitivity of 62%, and specificity of 90%. Prospective analysis of this model in 44 patients found that 89% of patients were correctly predicted to achieve a residual volume (RV) < 4.9cc. Of the 44 prospective patients undergoing rapid qPCR TERT promoter mutation analysis at the surgical margin, 7 had undetectable TERT mutation, of which 5 also had a GTR (RV < 1cc). In these 5 patients at 30 months follow-up, 75% showed no progression, compared to 0% in the group with TERT mutations detected at the surgical margin (P = .02)., Conclusions: These findings identify a subset of patients with GBM that may derive local control benefits from radical resection to undetectable molecular margins., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.) more...
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- 2024
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9. Integrating Multisector Molecular Characterization into Personalized Peptide Vaccine Design for Patients with Newly Diagnosed Glioblastoma.
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Johanns TM, Garfinkle EAR, Miller KE, Livingstone AJ, Roberts KF, Rao Venkata LP, Dowling JL, Chicoine MR, Dacey RG, Zipfel GJ, Kim AH, Mardis ER, and Dunn GP
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- Humans, Female, Male, Middle Aged, Brain Neoplasms immunology, Brain Neoplasms therapy, Brain Neoplasms genetics, Brain Neoplasms pathology, Adult, Aged, Immunotherapy methods, Protein Subunit Vaccines, Glioblastoma immunology, Glioblastoma therapy, Glioblastoma genetics, Glioblastoma pathology, Cancer Vaccines immunology, Cancer Vaccines administration & dosage, Cancer Vaccines therapeutic use, Vaccines, Subunit immunology, Vaccines, Subunit administration & dosage, Vaccines, Subunit therapeutic use, Precision Medicine methods, Antigens, Neoplasm immunology
- Abstract
Purpose: Outcomes for patients with glioblastoma (GBM) remain poor despite multimodality treatment with surgery, radiation, and chemotherapy. There are few immunotherapy options due to the lack of tumor immunogenicity. Several clinical trials have reported promising results with cancer vaccines. To date, studies have used data from a single tumor site to identify targetable antigens, but this approach limits the antigen pool and is antithetical to the heterogeneity of GBM. We have implemented multisector sequencing to increase the pool of neoantigens across the GBM genomic landscape that can be incorporated into personalized peptide vaccines called NeoVax., Patients and Methods: In this study, we report the findings of four patients enrolled onto the NeoVax clinical trial (NCT0342209)., Results: Immune reactivity to NeoVax neoantigens was assessed in peripheral blood mononuclear cells pre- and post-NeoVax for patients 1 to 3 using IFNγ-ELISPOT assay. A statistically significant increase in IFNγ producing T cells at the post-NeoVax time point for several neoantigens was observed. Furthermore, a post-NeoVax tumor biopsy was obtained from patient 3 and, upon evaluation, revealed evidence of infiltrating, clonally expanded T cells., Conclusions: Collectively, our findings suggest that NeoVax stimulated the expansion of neoantigen-specific effector T cells and provide encouraging results to aid in the development of future neoantigen vaccine-based clinical trials in patients with GBM. Herein, we demonstrate the feasibility of incorporating multisector sampling in cancer vaccine design and provide information on the clinical applicability of clonality, distribution, and immunogenicity of the neoantigen landscape in patients with GBM., (©2024 The Authors; Published by the American Association for Cancer Research.) more...
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- 2024
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10. Glioblastoma-Infiltrating CD8+ T Cells Are Predominantly a Clonally Expanded GZMK+ Effector Population.
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Wang AZ, Mashimo BL, Schaettler MO, Sherpa ND, Leavitt LA, Livingstone AJ, Khan SM, Li M, Anzaldua-Campos MI, Bradley JD, Leuthardt EC, Kim AH, Dowling JL, Chicoine MR, Jones PS, Choi BD, Cahill DP, Carter BS, Petti AA, Johanns TM, and Dunn GP more...
- Subjects
- Humans, Lymphocytes, Tumor-Infiltrating immunology, Lymphocytes, Tumor-Infiltrating metabolism, Tumor Microenvironment immunology, Brain Neoplasms immunology, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes metabolism, Glioblastoma immunology, Glioblastoma therapy
- Abstract
Recent clinical trials have highlighted the limited efficacy of T cell-based immunotherapy in patients with glioblastoma (GBM). To better understand the characteristics of tumor-infiltrating lymphocytes (TIL) in GBM, we performed cellular indexing of transcriptomes and epitopes by sequencing and single-cell RNA sequencing with paired V(D)J sequencing, respectively, on TILs from two cohorts of patients totaling 15 patients with high-grade glioma, including GBM or astrocytoma, IDH-mutant, grade 4 (G4A). Analysis of the CD8+ TIL landscape reveals an enrichment of clonally expanded GZMK+ effector T cells in the tumor compared with matched blood, which was validated at the protein level. Furthermore, integration with other cancer types highlights the lack of a canonically exhausted CD8+ T-cell population in GBM TIL. These data suggest that GZMK+ effector T cells represent an important T-cell subset within the GBM microenvironment and may harbor potential therapeutic implications., Significance: To understand the limited efficacy of immune-checkpoint blockade in GBM, we applied a multiomics approach to understand the TIL landscape. By highlighting the enrichment of GZMK+ effector T cells and the lack of exhausted T cells, we provide a new potential mechanism of resistance to immunotherapy in GBM. This article is featured in Selected Articles from This Issue, p. 897., (©2024 American Association for Cancer Research.) more...
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- 2024
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11. A dual fluorescent herpes simplex virus type 1 recombinant reveals divergent outcomes of neuronal infection.
- Author
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Domanico LF, Dunn GP, Kobiler O, and Taylor MP
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- Animals, Humans, Chlorocebus aethiops, Cytomegalovirus genetics, Cytomegalovirus physiology, Gene Expression Regulation, Viral, Genes, Reporter, Luminescent Proteins genetics, Luminescent Proteins metabolism, Vero Cells, Virus Latency genetics, Virus Replication, Herpes Simplex virology, Herpesvirus 1, Human genetics, Herpesvirus 1, Human physiology, Neurons virology, Neurons metabolism
- Abstract
Critical stages of lytic herpes simplex virus type 1 (HSV-1) replication are marked by the sequential expression of immediate early (IE) to early (E), then late (L) viral genes. HSV-1 can also persist in neuronal cells via a non-replicative, transcriptionally repressed infection called latency. The regulation of lytic and latent transcriptional profiles is critical to HSV-1 pathogenesis and persistence. We sought a fluorescence-based approach to observe the outcome of neuronal HSV-1 infection at the single-cell level. To achieve this goal, we constructed and characterized a novel HSV-1 recombinant that enables discrimination between lytic and latent infection. The dual reporter HSV-1 encodes a human cytomegalovirus-immediate early (hCMV-IE) promoter-driven enhanced yellow fluorescent protein (eYFP) to visualize the establishment of infection and an endogenous mCherry-VP26 fusion to report lytic replication. We confirmed that viral gene expression, replication, and spread of infection are not altered by the incorporation of the fluorescent reporters, and fluorescent protein (FP) detection virtuously reports the progression of lytic replication. We demonstrate that the outcome of HSV-1 infection of compartmentalized primary neurons is determined by viral inoculating dose: high-dose axonal inoculation proceeds to lytic replication, whereas low-dose axonal inoculation establishes a latent HSV-1 infection. Interfering with low-dose axonal inoculation via small molecule drugs reports divergent phenotypes of eYFP and mCherry reporter detection, correlating with altered states of viral gene expression. We report that the transcriptional state of neuronal HSV-1 infection is variable in response to changes in the intracellular neuronal environment.IMPORTANCEHerpes simplex virus type 1 (HSV-1) is a prevalent human pathogen that infects approximately 67% of the global human population. HSV-1 invades the peripheral nervous system, where latent HSV-1 infection persists within the host for life. Immunological evasion, viral persistence, and herpetic pathologies are determined by the regulation of HSV-1 gene expression. Studying HSV-1 gene expression during neuronal infection is challenging but essential for the development of antiviral therapeutics and interventions. We used a recombinant HSV-1 to evaluate viral gene expression during infection of primary neurons. Manipulation of cell signaling pathways impacts the establishment and transcriptional state of HSV-1 latency in neurons. The work here provides critical insight into the cellular and viral factors contributing to the establishment of latent HSV-1 infection., Competing Interests: The authors declare no conflict of interest. more...
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- 2024
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12. Immunotherapy for Brain Tumors: Where We Have Been, and Where Do We Go From Here?
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Wang AF, Hsueh B, Choi BD, Gerstner ER, and Dunn GP
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- Humans, Glioblastoma therapy, Glioblastoma immunology, Combined Modality Therapy methods, Treatment Outcome, Disease Management, Clinical Trials as Topic, Brain Neoplasms therapy, Brain Neoplasms immunology, Immunotherapy methods, Tumor Microenvironment immunology
- Abstract
Opinion Statement: Immunotherapy for glioblastoma (GBM) remains an intensive area of investigation. Given the seismic impact of cancer immunotherapy across a range of malignancies, there is optimism that harnessing the power of immunity will influence GBM as well. However, despite several phase 3 studies, there are still no FDA-approved immunotherapies for GBM. Importantly, the field has learned a great deal from the randomized studies to date. Today, we are continuing to better understand the disease-specific features of the microenvironment in GBM-as well as the exploitable antigenic characteristic of the tumor cells themselves-that are informing the next generation of immune-based therapeutic strategies. The coming phase of next-generation immunotherapies is thus poised to bring us closer to treatments that will improve the lives of patients with GBM., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.) more...
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- 2024
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13. Burnout and career satisfaction in young neuro-oncology investigators: Results of the Society for Neuro-Oncology Young Investigator Survey.
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Youssef G, Acquaye-Mallory A, Vera E, Chheda MG, Dunn GP, Moliterno J, O'Brien BJ, Venere M, Yust-Katz S, Lee EQ, and Armstrong TS
- Abstract
Background: Burnout is a syndrome characterized by emotional exhaustion, depersonalization, and a reduced sense of accomplishment, which commonly arises from chronic workplace stress in the medical field. Given the higher risk of burnout in younger age groups reported in some studies, the Society for Neuro-Oncology (SNO) Young Investigator (YI) and Wellness Committees combined efforts to examine burnout in the SNO YI membership to better understand and address their needs., Methods: We distributed an anonymous online survey to SNO members in 2019. Only those meeting the definition of a YI were asked to complete the survey. The survey consisted of questions about personal and professional characteristics as well as the validated Maslach Burnout Inventory-Human Services Survey (MBI-HSS) questionnaire. Statistical analyses included descriptive statistics, univariate and multivariate analyses, and incorporation of previously defined burnout profiles., Results: Data were analyzed for 173 participants who self-identified as YI. Measures of burnout showed that YI members scored higher on emotional exhaustion and depersonalization compared to normative population but similar to those in a prior SNO general membership survey. With respect to burnout profiles, 30% of YI respondents classified as overextended and 15% as burnout. Organizational challenges were the most common contributors to stress., Conclusions: Similar to results from a previous survey completed by general SNO membership, the prevalence of burnout among neuro-oncology clinical and research YI is high, and is mainly characterized by overextension, warranting interventions at institutional and organizational levels., Competing Interests: The authors do not have any conflicts of interest to declare., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European Association of Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.) more...
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- 2024
- Full Text
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14. Letter: Answering Our Nation's Call: A Solution for Military Neurosurgery Wartime Readiness Through Civilian Collaboration.
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Menger RP and Dunn GP
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- Humans, Neurosurgical Procedures, Trauma Centers, Neurosurgery, Military Personnel, Military Medicine
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- 2024
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15. Considering the extent of resection in diffuse glioma.
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Cahill DP and Dunn GP
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- Humans, Glioma surgery, Brain Neoplasms surgery
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- 2023
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16. Lessons for the Next Generation of Scientists from the Second Annual Arthur and Sandra Irving Cancer Immunology Symposium.
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Alvarez-Breckenridge C, Anderson KG, Correia AL, Demehri S, Dinh HQ, Dixon KO, Dunn GP, Evgin L, Goc J, Good Z, Hacohen N, Han P, Hanč P, Hickey J, Kersten K, Liu BC, Buque A, Miao Y', Milner JJ, Pritykin Y, Pucci F, Scharping NE, Sudmeier L, Wang Y, Wieland A, and Williams MM more...
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- Humans, Mentors, Research Personnel, Mentoring, Physicians, Neoplasms therapy
- Abstract
The Arthur and Sandra Irving Cancer Immunology Symposium has been created as a platform for established cancer immunologists to mentor trainees and young investigators as they launch their research career in the field. By sharing their different paths to success, the senior faculty mentors provide an invaluable resource to support the development of the next generation of leaders in the cancer immunology community. This Commentary describes some of the key topics that were discussed during the 2022 symposium: scientific and career trajectory, leadership, mentoring, collaborations, and publishing. For each of these topics, established investigators discussed the elements that facilitate success in these areas as well as mistakes that can hinder progress. Herein, we outline the critical points raised in these discussions for establishing a successful independent research career. These points are highly relevant for the broader scientific community., (©2023 The Authors; Published by the American Association for Cancer Research.) more...
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- 2023
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17. Preexisting tumor-resident T cells with cytotoxic potential associate with response to neoadjuvant anti-PD-1 in head and neck cancer.
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Oliveira G, Egloff AM, Afeyan AB, Wolff JO, Zeng Z, Chernock RD, Zhou L, Messier C, Lizotte P, Pfaff KL, Stromhaug K, Penter L, Haddad RI, Hanna GJ, Schoenfeld JD, Goguen LA, Annino DJ, Jo V, Oppelt P, Pipkorn P, Jackson R, Puram SV, Paniello RC, Rich JT, Webb J, Zevallos JP, Mansour M, Fu J, Dunn GP, Rodig SJ, Ley J, Morris LGT, Dunn L, Paweletz CP, Kallogjeri D, Piccirillo JF, Adkins DR, Wu CJ, and Uppaluri R more...
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- Humans, Neoadjuvant Therapy, CD8-Positive T-Lymphocytes, Squamous Cell Carcinoma of Head and Neck, Tumor Microenvironment, Head and Neck Neoplasms drug therapy, Antineoplastic Agents
- Abstract
About 50% of patients with locally advanced head and neck squamous cell carcinoma (HNSCC) experience recurrences after definitive therapy. The presurgical administration of anti-programmed cell death protein 1 (PD-1) immunotherapy results in substantial pathologic tumor responses (pTR) within the tumor microenvironment (TME). However, the mechanisms underlying the dynamics of antitumor T cells upon neoadjuvant PD-1 blockade remain unresolved, and approaches to increase pathologic responses are lacking. In a phase 2 trial (NCT02296684), we observed that 45% of patients treated with two doses of neoadjuvant pembrolizumab experienced marked pTRs (≥50%). Single-cell analysis of 17,158 CD8
+ T cells from 14 tumor biopsies, including 6 matched pre-post neoadjuvant treatment, revealed that responding tumors had clonally expanded putative tumor-specific exhausted CD8+ tumor-infiltrating lymphocytes (TILs) with a tissue-resident memory program, characterized by high cytotoxic potential (CTX+ ) and ZNF683 expression, within the baseline TME. Pathologic responses after 5 weeks of PD-1 blockade were consistent with activation of preexisting CTX+ ZNF683+ CD8+ TILs, paralleling loss of viable tumor and associated tumor antigens. Response was associated with high numbers of CD103+ PD-1+ CD8+ T cells infiltrating pretreatment lesions, whereas revival of nonexhausted persisting clones and clonal replacement were modest. By contrast, nonresponder baseline TME exhibited a relative absence of ZNF683+ CTX+ TILs and subsequent accumulation of highly exhausted clones. In HNSCC, revival of preexisting ZNF683+ CTX+ TILs is a major mechanism of response in the immediate postneoadjuvant setting. more...- Published
- 2023
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18. A pilot study of lymphoscintigraphy with tracer injection into the human brain.
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Coxon AT, Desai R, Patel PR, Vellimana AK, Willie JT, Dowling JL, Leuthardt EC, Kim AH, Johanns TM, Siegel BA, and Dunn GP
- Subjects
- Humans, Pilot Projects, Radiopharmaceuticals, Lymphatic Metastasis, Lymphoscintigraphy methods, Sentinel Lymph Node Biopsy methods
- Abstract
Many groups have reported lymphatic and glymphatic structures in animal and human brains, but tracer injection into the human brain to demonstrate real-time lymphatic drainage and mapping has not been described. We enrolled patients undergoing standard-of-care resection or stereotactic biopsy for suspected intracranial tumors. Patients received peritumoral injections of
99m Tc-tilmanocept followed by planar or tomographic imaging. Fourteen patients with suspected brain tumors were enrolled. One was excluded from analysis because of tracer leakage during injection. There was no drainage of99m Tc-tilmanocept to regional lymph nodes in any of the patients. On average, after correcting for radioactive decay, 70.7% (95% CI: 59.9%, 81.6%) of the tracer in the injection site and 78.1% (95% CI: 71.1%, 85.1%) in the whole-head on the day of surgery remained the morning after, with variable radioactivity in the subarachnoid space. The retained fraction was much greater than expected based on the clearance rate from non-brain injection sites. In this pilot study, the lymphatic tracer99m Tc-tilmanocept was injected into the brain parenchyma, and there was no drainage outside the brain to the cervical lymph nodes. Our work demonstrates an inefficiency of drainage from peritumoral brain parenchyma and highlights a therapeutic opportunity to improve immunosurveillance of the brain. more...- Published
- 2023
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19. Computational prediction of MHC anchor locations guides neoantigen identification and prioritization.
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Xia H, McMichael J, Becker-Hapak M, Onyeador OC, Buchli R, McClain E, Pence P, Supabphol S, Richters MM, Basu A, Ramirez CA, Puig-Saus C, Cotto KC, Freshour SL, Hundal J, Kiwala S, Goedegebuure SP, Johanns TM, Dunn GP, Ribas A, Miller CA, Gillanders WE, Fehniger TA, Griffith OL, and Griffith M more...
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- Humans, T-Lymphocytes, Mutation, Peptides genetics, Antigens, Neoplasm genetics, Neoplasms
- Abstract
Neoantigens are tumor-specific peptide sequences resulting from sources such as somatic DNA mutations. Upon loading onto major histocompatibility complex (MHC) molecules, they can trigger recognition by T cells. Accurate neoantigen identification is thus critical for both designing cancer vaccines and predicting response to immunotherapies. Neoantigen identification and prioritization relies on correctly predicting whether the presenting peptide sequence can successfully induce an immune response. Because most somatic mutations are single-nucleotide variants, changes between wild-type and mutated peptides are typically subtle and require cautious interpretation. A potentially underappreciated variable in neoantigen prediction pipelines is the mutation position within the peptide relative to its anchor positions for the patient's specific MHC molecules. Whereas a subset of peptide positions are presented to the T cell receptor for recognition, others are responsible for anchoring to the MHC, making these positional considerations critical for predicting T cell responses. We computationally predicted anchor positions for different peptide lengths for 328 common HLA alleles and identified unique anchoring patterns among them. Analysis of 923 tumor samples shows that 6 to 38% of neoantigen candidates are potentially misclassified and can be rescued using allele-specific knowledge of anchor positions. A subset of anchor results were orthogonally validated using protein crystallography structures. Representative anchor trends were experimentally validated using peptide-MHC stability assays and competition binding assays. By incorporating our anchor prediction results into neoantigen prediction pipelines, we hope to formalize, streamline, and improve the identification process for relevant clinical studies. more...
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- 2023
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20. Integrated analysis of genomic and transcriptomic data for the discovery of splice-associated variants in cancer.
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Cotto KC, Feng YY, Ramu A, Richters M, Freshour SL, Skidmore ZL, Xia H, McMichael JF, Kunisaki J, Campbell KM, Chen TH, Rozycki EB, Adkins D, Devarakonda S, Sankararaman S, Lin Y, Chapman WC, Maher CA, Arora V, Dunn GP, Uppaluri R, Govindan R, Griffith OL, and Griffith M more...
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- Humans, Genomics, RNA Splicing genetics, Genome, Alternative Splicing genetics, Transcriptome genetics, Neoplasms genetics
- Abstract
Somatic mutations within non-coding regions and even exons may have unidentified regulatory consequences that are often overlooked in analysis workflows. Here we present RegTools ( www.regtools.org ), a computationally efficient, free, and open-source software package designed to integrate somatic variants from genomic data with splice junctions from bulk or single cell transcriptomic data to identify variants that may cause aberrant splicing. We apply RegTools to over 9000 tumor samples with both tumor DNA and RNA sequence data. RegTools discovers 235,778 events where a splice-associated variant significantly increases the splicing of a particular junction, across 158,200 unique variants and 131,212 unique junctions. To characterize these somatic variants and their associated splice isoforms, we annotate them with the Variant Effect Predictor, SpliceAI, and Genotype-Tissue Expression junction counts and compare our results to other tools that integrate genomic and transcriptomic data. While many events are corroborated by the aforementioned tools, the flexibility of RegTools also allows us to identify splice-associated variants in known cancer drivers, such as TP53, CDKN2A, and B2M, and other genes., (© 2023. The Author(s).) more...
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- 2023
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21. Spontaneous rupture of an arachnoid cyst in an adult: illustrative case.
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Leavitt LA, Nanda P, Stemmer-Rachamimov A, Dunn GP, and Jones PS
- Abstract
Background: Arachnoid cysts are common intracranial mass lesions frequently discovered as incidental findings on radiographic imaging. It is routine practice to monitor these lesions as a large majority remain stable. Although traumatic cyst rupture is a known risk, it is rare for patients to present with spontaneous rupture., Observations: The authors report the case of a 32-year-old patient who required emergent neurosurgical intervention for spontaneous rupture of a left hemispheric arachnoid cyst., Lessons: Patients with ruptured arachnoid cysts can present with vague, nonspecific symptoms that may delay diagnosis. If not diagnosed and treated promptly, arachnoid cyst rupture can progress to a neurosurgical emergency as the subdural collection may cause extensive mass effect and even cerebral herniation. more...
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- 2023
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22. TCR-engineered adoptive cell therapy effectively treats intracranial murine glioblastoma.
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Schaettler MO, Desai R, Wang AZ, Livingstone AJ, Kobayashi DK, Coxon AT, Bowman-Kirigin JA, Liu CJ, Li M, Bender DE, White MJ, Kranz DM, Johanns TM, and Dunn GP
- Subjects
- Mice, Humans, Animals, Antigens, Neoplasm, CD8-Positive T-Lymphocytes, Receptors, Antigen, T-Cell, Immunotherapy, Adoptive, Glioblastoma
- Abstract
Background: Adoptive cellular therapies with chimeric antigen receptor T cells have revolutionized the treatment of some malignancies but have shown limited efficacy in solid tumors such as glioblastoma and face a scarcity of safe therapeutic targets. As an alternative, T cell receptor (TCR)-engineered cellular therapy against tumor-specific neoantigens has generated significant excitement, but there exist no preclinical systems to rigorously model this approach in glioblastoma., Methods: We employed single-cell PCR to isolate a TCR specific for the Imp3
D81N neoantigen (mImp3) previously identified within the murine glioblastoma model GL261. This TCR was used to generate the Mutant Imp3-Specific TCR TransgenIC (MISTIC) mouse in which all CD8 T cells are specific for mImp3. The therapeutic efficacy of neoantigen-specific T cells was assessed through a model of cellular therapy consisting of the transfer of activated MISTIC T cells and interleukin 2 into lymphodepleted tumor-bearing mice. We employed flow cytometry, single-cell RNA sequencing, and whole-exome and RNA sequencing to examine the factors underlying treatment response., Results: We isolated and characterized the 3×1.1C TCR that displayed a high affinity for mImp3 but no wild-type cross-reactivity. To provide a source of mImp3-specific T cells, we generated the MISTIC mouse. In a model of adoptive cellular therapy, the infusion of activated MISTIC T cells resulted in rapid intratumoral infiltration and profound antitumor effects with long-term cures in a majority of GL261-bearing mice. The subset of mice that did not respond to the adoptive cell therapy showed evidence of retained neoantigen expression but intratumoral MISTIC T cell dysfunction. The efficacy of MISTIC T cell therapy was lost in mice bearing a tumor with heterogeneous mImp3 expression, showcasing the barriers to targeted therapy in polyclonal human tumors., Conclusions: We generated and characterized the first TCR transgenic against an endogenous neoantigen within a preclinical glioma model and demonstrated the therapeutic potential of adoptively transferred neoantigen-specific T cells. The MISTIC mouse provides a powerful novel platform for basic and translational studies of antitumor T-cell responses in glioblastoma., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.) more...- Published
- 2023
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23. The Conventional Dendritic Cell 1 Subset Primes CD8+ T Cells and Traffics Tumor Antigen to Drive Antitumor Immunity in the Brain.
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Bowman-Kirigin JA, Desai R, Saunders BT, Wang AZ, Schaettler MO, Liu CJ, Livingstone AJ, Kobayashi DK, Durai V, Kretzer NM, Zipfel GJ, Leuthardt EC, Osbun JW, Chicoine MR, Kim AH, Murphy KM, Johanns TM, Zinselmeyer BH, and Dunn GP more...
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- Animals, Mice, CD8-Positive T-Lymphocytes, Antigens, Neoplasm, Brain, Dendritic Cells, Neoplasms
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The central nervous system (CNS) antigen-presenting cell (APC) that primes antitumor CD8+ T-cell responses remains undefined. Elsewhere in the body, the conventional dendritic cell 1 (cDC1) performs this role. However, steady-state brain parenchyma cDC1 are extremely rare; cDCs localize to the choroid plexus and dura. Thus, whether the cDC1 play a function in presenting antigen derived from parenchymal sources in the tumor setting remains unknown. Using preclinical glioblastoma (GBM) models and cDC1-deficient mice, we explored the presently unknown role of cDC1 in CNS antitumor immunity. We determined that, in addition to infiltrating the brain tumor parenchyma itself, cDC1 prime neoantigen-specific CD8+ T cells against brain tumors and mediate checkpoint blockade-induced survival benefit. We observed that cDC, including cDC1, isolated from the tumor, the dura, and the CNS-draining cervical lymph nodes harbored a traceable fluorescent tumor antigen. In patient samples, we observed several APC subsets (including the CD141+ cDC1 equivalent) infiltrating glioblastomas, meningiomas, and dura. In these same APC subsets, we identified a tumor-specific fluorescent metabolite of 5-aminolevulinic acid, which fluorescently labeled tumor cells during fluorescence-guided GBM resection. Together, these data elucidate the specialized behavior of cDC1 and suggest that cDC1 play a significant role in CNS antitumor immunity., (©2022 American Association for Cancer Research.) more...
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- 2023
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24. Tandem chimeric antigen receptor (CAR) T cells targeting EGFRvIII and IL-13Rα2 are effective against heterogeneous glioblastoma.
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Schmidts A, Srivastava AA, Ramapriyan R, Bailey SR, Bouffard AA, Cahill DP, Carter BS, Curry WT, Dunn GP, Frigault MJ, Gerstner ER, Ghannam JY, Kann MC, Larson RC, Leick MB, Nahed BV, Richardson LG, Scarfò I, Sun J, Wakimoto H, Maus MV, and Choi BD more...
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Background: Chimeric antigen receptor (CAR) T cells have achieved remarkable responses in patients with hematological malignancies; however, the potential of this therapeutic platform for solid tumors like glioblastoma (GBM) has been limited, due in large part to the targeting of single antigens in a heterogeneous disease. Strategies that allow CAR T cells to engage multiple antigens concomitantly may broaden therapeutic responses and mitigate the effects of immune escape., Methods: Here we have developed a novel, dual-specific, tandem CAR T (TanCART) cell with the ability to simultaneously target both EGFRvIII and IL-13Rα2, two well-characterized tumor antigens that are frequently found on the surface of GBM cells but completely absent from normal brain tissues. We employed both standard immunological assays and multiple orthotopic preclinical models including patient-derived xenograft to demonstrate efficacy of this approach against heterogeneous tumors., Results: Tandem CAR T cells displayed enhanced cytotoxicity in vitro against heterogeneous GBM populations, including patient-derived brain tumor cultures ( P < .05). Compared to CAR T cells targeting single antigens, dual antigen engagement through the tandem construct was necessary to achieve long-term, complete, and durable responses in orthotopic murine models of heterogeneous GBM, including patient-derived xenografts ( P < .05)., Conclusions: We demonstrate that TanCART is effective against heterogeneous tumors in the brain. These data lend further credence to the development of multi-specific CAR T cells in the treatment of GBM and other cancers., (© The Author(s) 2022. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.) more...
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- 2022
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25. Impact of CD4 T cells on intratumoral CD8 T-cell exhaustion and responsiveness to PD-1 blockade therapy in mouse brain tumors.
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Khan SM, Desai R, Coxon A, Livingstone A, Dunn GP, Petti A, and Johanns TM
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- Female, Mice, Animals, CD4-Positive T-Lymphocytes, Programmed Cell Death 1 Receptor, T-Cell Exhaustion, CD8-Positive T-Lymphocytes, Tumor Microenvironment, Glioblastoma drug therapy, Brain Neoplasms drug therapy
- Abstract
Background: Glioblastoma is a fatal disease despite aggressive multimodal therapy. PD-1 blockade, a therapy that reinvigorates hypofunctional exhausted CD8 T cells (T
ex ) in many malignancies, has not shown efficacy in glioblastoma. Loss of CD4 T cells can lead to an exhausted CD8 T-cell phenotype, and terminally exhausted CD8 T cells (Tex term ) do not respond to PD-1 blockade. GL261 and CT2A are complementary orthotopic models of glioblastoma. GL261 has a functional CD4 T-cell compartment and is responsive to PD-1 blockade; notably, CD4 depletion abrogates this survival benefit. CT2A is composed of dysfunctional CD4 T cells and is PD-1 blockade unresponsive. We leverage these models to understand the impact of CD4 T cells on CD8 T-cell exhaustion and PD-1 blockade sensitivity in glioblastoma., Methods: Single-cell RNA sequencing was performed on flow sorted tumor-infiltrating lymphocytes from female C57/BL6 mice implanted with each model, with and without PD-1 blockade therapy. CD8+ and CD4+ T cells were identified and separately analyzed. Survival analyses were performed comparing PD-1 blockade therapy, CD40 agonist or combinatorial therapy., Results: The CD8 T-cell compartment of the models is composed of heterogenous CD8 Tex subsets, including progenitor exhausted CD8 T cells (Tex prog ), intermediate Tex , proliferating Tex , and Tex term . GL261 is enriched with the PD-1 responsive Tex prog subset relative to the CT2A and CD4-depleted GL261 models, which are composed predominantly of the PD-1 blockade refractory Tex term subset. Analysis of the CD4 T-cell compartments revealed that the CT2A microenvironment is enriched with a suppressive Treg subset and an effector CD4 T-cell subset that expresses an inhibitory interferon-stimulated ( Isc ) signature. Finally, we demonstrate that addition of CD40 agonist to PD-1 blockade therapy improves survival in CT2A tumor-bearing mice., Conclusions: Here, we describe that dysfunctional CD4 T cells are associated with terminal CD8 T-cell exhaustion, suggesting CD4 T cells impact PD-1 blockade efficacy by controlling the severity of exhaustion. Given that CD4 lymphopenia is frequently observed in patients with glioblastoma, this may represent a basis for resistance to PD-1 blockade. We demonstrate that CD40 agonism may circumvent a dysfunctional CD4 compartment to improve PD-1 blockade responsiveness, supporting a novel synergistic immunotherapeutic approach., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.) more...- Published
- 2022
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26. Survival After Resection of Newly-Diagnosed Intracranial Grade II Ependymomas: An Initial Multicenter Analysis and the Logistics of Intraoperative Magnetic Resonance Imaging.
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Yahanda AT, Rich KM, Dacey RG Jr, Zipfel GJ, Dunn GP, Dowling JL, Smyth MD, Leuthardt EC, Limbrick DD Jr, Honeycutt J, Sutherland GR, Jensen RL, Evans J, and Chicoine MR
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- Humans, Adult, Retrospective Studies, Disease-Free Survival, Magnetic Resonance Imaging methods, Brain Neoplasms diagnostic imaging, Brain Neoplasms surgery, Ependymoma diagnostic imaging, Ependymoma surgery, Supratentorial Neoplasms diagnostic imaging, Supratentorial Neoplasms surgery
- Abstract
Objective: To identify factors, including the use of intraoperative magnetic resonance imaging (iMRI), impacting overall survival (OS) and progression-free survival (PFS) after resections of newly diagnosed intracranial grade II ependymomas performed across 4 different institutions., Methods: Analyses of a multicenter mixed retrospective/prospective database assessed the impact of patient, treatment, and tumor characteristics on OS and PFS. iMRI workflow and logistics were also outlined., Results: Forty-three patients were identified (mean age 25.4 years, mean follow-up 52.8 months). The mean OS was 52.8 ± 44.7 months. Univariate analyses failed to identify prognostic factors associated with OS, likely due to relatively shorter follow-up time for this less aggressive glioma subtype. The mean PFS was 43.7 ± 39.8 months. Multivariate analyses demonstrated that gross-total resection was associated with prolonged PFS compared to both subtotal resection (STR) (P = 0.005) and near-total resection (P = 0.01). Infratentorial location was associated with improved PFS compared to supratentorial location (P = 0.04). Log-rank analyses of Kaplan-Meier survival curves showed that increasing extent of resection (EOR) led to improved OS specifically for supratentorial tumors (P = 0.02) and improved PFS for all tumors (P < 0.001). Thirty cases (69.8%) utilized iMRI, of which 12 (27.9%) involved additional resection after iMRI. Of these, 8/12 (66.7%) resulted in gross-total resection, while 2/12 (16.7%) were near-total resection and 2/12 (16.7%) were subtotal resection. iMRI was not an independent prognosticator of PFS (P = 0.72)., Conclusions: Greater EOR and infratentorial location were associated with increased PFS for grade II ependymomas. Greater EOR was associated with longer OS only for supratentorial tumors. A longer follow-up is needed to establish prognostic factors for this cohort, including use of iMRI., (Copyright © 2022 Elsevier Inc. All rights reserved.) more...
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- 2022
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27. Neoadjuvant stereotactic radiosurgery for brain metastases: a new paradigm.
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Li YD, Coxon AT, Huang J, Abraham CD, Dowling JL, Leuthardt EC, Dunn GP, Kim AH, Dacey RG, Zipfel GJ, Evans J, Filiput EA, and Chicoine MR
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- Humans, Adult, Middle Aged, Aged, Aged, 80 and over, Neoadjuvant Therapy adverse effects, Salvage Therapy, Retrospective Studies, Treatment Outcome, Radiosurgery adverse effects, Brain Neoplasms surgery, Meningeal Neoplasms surgery
- Abstract
Objective: For patients with surgically accessible solitary metastases or oligometastatic disease, treatment often involves resection followed by postoperative stereotactic radiosurgery (SRS). This strategy has several potential drawbacks, including irregular target delineation for SRS and potential tumor "seeding" away from the resection cavity during surgery. A neoadjuvant (preoperative) approach to radiation therapy avoids these limitations and offers improved patient convenience. This study assessed the efficacy of neoadjuvant SRS as a new treatment paradigm for patients with brain metastases., Methods: A retrospective review was performed at a single institution to identify patients who had undergone neoadjuvant SRS (specifically, Gamma Knife radiosurgery) followed by resection of a brain metastasis. Kaplan-Meier survival and log-rank analyses were used to evaluate risks of progression and death. Assessments were made of local recurrence and leptomeningeal spread. Additionally, an analysis of the contemporary literature of postoperative and neoadjuvant SRS for metastatic disease was performed., Results: Twenty-four patients who had undergone neoadjuvant SRS followed by resection of a brain metastasis were identified in the single-institution cohort. The median age was 64 years (range 32-84 years), and the median follow-up time was 16.5 months (range 1 month to 5.7 years). The median radiation dose was 17 Gy prescribed to the 50% isodose. Rates of local disease control were 100% at 6 months, 87.6% at 12 months, and 73.5% at 24 months. In 4 patients who had local treatment failure, salvage therapy included repeat resection, laser interstitial thermal therapy, or repeat SRS. One hundred thirty patients (including the current cohort) were identified in the literature who had been treated with neoadjuvant SRS prior to resection. Overall rates of local control at 1 year after neoadjuvant SRS treatment ranged from 49% to 91%, and rates of leptomeningeal dissemination from 0% to 16%. In comparison, rates of local control 1 year after postoperative SRS ranged from 27% to 91%, with 7% to 28% developing leptomeningeal disease., Conclusions: Neoadjuvant SRS for the treatment of brain metastases is a novel approach that mitigates the shortcomings of postoperative SRS. While additional prospective studies are needed, the current study of 130 patients including the summary of 106 previously published cases supports the safety and potential efficacy of preoperative SRS with potential for improved outcomes compared with postoperative SRS. more...
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- 2022
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28. Editorial: It takes a village: The expanding multi-disciplinary approach to brain metastasis.
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Fecci PE, Rao G, Brastianos PK, Dunn GP, and Anders CK
- Abstract
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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- 2022
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29. The deep roots of military service in neurological surgery: an academic genealogical analysis of the founding generation.
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Rallo MS and Dunn GP
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- Armed Conflicts, History, 20th Century, Humans, Neurosurgical Procedures methods, United States, Craniocerebral Trauma, Military Medicine, Military Personnel, Neurosurgery history
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Throughout human history, advancements in medicine have evolved out of periods of war. The carnage of battlefield injuries provided wartime surgeons an unprecedented opportunity to study anatomy, develop novel techniques, and improve systems of care. As a specialty that was established and evolved during the first half of the 20th century, neurological surgery was heavily influenced by the experiences of its founders during the World Wars I and II. Utilizing the published Neurosurgery Tree, the authors conducted an academic genealogical analysis to systematically define the influence of wartime service on neurosurgery's earliest generations. Through review of the literature and military records, the authors determined that at least 60% of American neurosurgical founders and early leaders served during World Wars I and/or II. Inspired by the call to serve their nation as forces for good, these individuals were heralded as expert clinicians, innovative systems thinkers, and prolific researchers. Importantly, the service of these early leaders helped highlight the viability of neurosurgery as a distinct specialty and provided a framework for early neurosurgical education and expansion. The equipment, techniques, and guidelines that were developed during these wars, such as management of craniocerebral trauma, peripheral nerve repair, and hemostasis, set the foundation for modern neurosurgical practice. more...
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- 2022
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30. Considerations for personalized neoantigen vaccination in Malignant glioma.
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Dunn GP, Sherpa N, Manyanga J, and Johanns TM
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- Antigens, Neoplasm, Humans, Immunologic Factors, Immunotherapy, Vaccination, Cancer Vaccines therapeutic use, Glioblastoma drug therapy, Glioma drug therapy, Neoplasms drug therapy
- Abstract
Malignant gliomas are the most common primary brain cancer diagnosed and still carry a poor prognosis despite aggressive multimodal management. Despite the continued advances in immunotherapy for other cancer types, however, there remain no FDA approved immunotherapies for cancers such as glioblastoma. OF the many approaches being explored, cancer vaccine programs are undergoing a renaissance due to the technological advances and personalized nature of their contemporary design. Neoantigen vaccines are a form of immunotherapy involving the use of DNA, mRNA, and proteins derived from non-synonymous mutations identified in patient tumor tissue samples to stimulate tumor-specific T-cell reactivity leading to enhance tumor targeting. In the last several years, the study of neoantigens as a therapeutic target has increased, with the routine workflow implementation of comprehensive next generation sequencing and in silico peptide binding prediction algorithms. Several neoantigen vaccine platforms are being evaluated in clinical trials for malignancies including melanoma, pancreatic cancer, breast cancer, lung cancer, and glioblastoma, among others. In this review, we will review the concept of neoantigen discovery using cancer immunogenomics approaches in glioblastoma and explore the disease-specific issues being addressed in the design of effective personalized cancer vaccine strategies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.) more...
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- 2022
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31. Circulating Immune Cell and Outcome Analysis from the Phase II Study of PD-L1 Blockade with Durvalumab for Newly Diagnosed and Recurrent Glioblastoma.
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Nayak L, Standifer N, Dietrich J, Clarke JL, Dunn GP, Lim M, Cloughesy T, Gan HK, Flagg E, George E, Gaffey S, Hayden J, Holcroft C, Wen PY, Macri M, Park AJ, Ricciardi T, Ryan A, Schwarzenberger P, Venhaus R, Reyes ML, Durham NM, Creasy T, Huang RY, Kaley T, and Reardon DA more...
- Subjects
- Antibodies, Monoclonal, B7-H1 Antigen antagonists & inhibitors, Bevacizumab therapeutic use, Biomarkers, Tumor analysis, Humans, Ki-67 Antigen, Dexamethasone therapeutic use, Glioblastoma drug therapy, Glioblastoma genetics, Glioblastoma pathology, Neoplasm Recurrence, Local drug therapy, Neoplasm Recurrence, Local pathology
- Abstract
Purpose: PD-L1 is upregulated in glioblastoma and supports immunosuppression. We evaluated PD-L1 blockade with durvalumab among glioblastoma cohorts and investigated potential biomarkers., Patients and Methods: MGMT unmethylated newly diagnosed patients received radiotherapy plus durvalumab (cohort A; n = 40). Bevacizumab-naïve, recurrent patients received durvalumab alone (cohort B; n = 31) or in combination with standard bevacizumab (cohort B2; n = 33) or low-dose bevacizumab (cohort B3; n = 33). Bevacizumab-refractory patients received durvalumab plus bevacizumab (cohort C; n = 22). Primary endpoints were: OS-12 (A), PFS-6 (B, B2, B3), and OS-6 (C). Exploratory biomarkers included: a systematic, quantitative, and phenotypic evaluation of circulating immune cells; tumor mutational burden (TMB); and tumor immune activation signature (IAS)., Results: No cohort achieved the primary efficacy endpoint. Outcome was comparable among recurrent, bevacizumab-naïve cohorts. No unexpected toxicities were observed. A widespread reduction of effector immune cell subsets was noted among recurrent patients compared with newly diagnosed patients that was partially due to dexamethasone use. A trend of increased CD8+Ki67+ T cells at day 15 was noted among patients who achieved the primary endpoint and were not on dexamethasone. Neither TMB nor IAS predicted outcome., Conclusions: Patients with recurrent glioblastoma have markedly lower baseline levels of multiple circulating immune cell subsets compared with newly diagnosed patients. An early increase in systemic Ki67+CD8+ cells may warrant further evaluation as a potential biomarker of therapeutic benefit among patients with glioblastoma undergoing checkpoint therapy. Dexamethasone decreased immune cell subsets. PD-L1 blockade and combination with standard or reduced dose bevacizumab was ineffective., (©2022 American Association for Cancer Research.) more...
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- 2022
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32. Single-cell profiling of human dura and meningioma reveals cellular meningeal landscape and insights into meningioma immune response.
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Wang AZ, Bowman-Kirigin JA, Desai R, Kang LI, Patel PR, Patel B, Khan SM, Bender D, Marlin MC, Liu J, Osbun JW, Leuthardt EC, Chicoine MR, Dacey RG Jr, Zipfel GJ, Kim AH, DeNardo DG, Petti AA, and Dunn GP more...
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- Animals, Endothelial Cells pathology, Humans, Immunity, Meninges pathology, Mice, Tumor Microenvironment, Meningeal Neoplasms genetics, Meningeal Neoplasms pathology, Meningioma genetics, Meningioma pathology
- Abstract
Background: Recent investigations of the meninges have highlighted the importance of the dura layer in central nervous system immune surveillance beyond a purely structural role. However, our understanding of the meninges largely stems from the use of pre-clinical models rather than human samples., Methods: Single-cell RNA sequencing of seven non-tumor-associated human dura samples and six primary meningioma tumor samples (4 matched and 2 non-matched) was performed. Cell type identities, gene expression profiles, and T cell receptor expression were analyzed. Copy number variant (CNV) analysis was performed to identify putative tumor cells and analyze intratumoral CNV heterogeneity. Immunohistochemistry and imaging mass cytometry was performed on selected samples to validate protein expression and reveal spatial localization of select protein markers., Results: In this study, we use single-cell RNA sequencing to perform the first characterization of both non-tumor-associated human dura and primary meningioma samples. First, we reveal a complex immune microenvironment in human dura that is transcriptionally distinct from that of meningioma. In addition, we characterize a functionally diverse and heterogenous landscape of non-immune cells including endothelial cells and fibroblasts. Through imaging mass cytometry, we highlight the spatial relationship among immune cell types and vasculature in non-tumor-associated dura. Utilizing T cell receptor sequencing, we show significant TCR overlap between matched dura and meningioma samples. Finally, we report copy number variant heterogeneity within our meningioma samples., Conclusions: Our comprehensive investigation of both the immune and non-immune cellular landscapes of human dura and meningioma at single-cell resolution builds upon previously published data in murine models and provides new insight into previously uncharacterized roles of human dura., (© 2022. The Author(s).) more...
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- 2022
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33. A Low Subfrontal Dural Opening for Operative Management of Anterior Skull Base Lesions.
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Cler SJ, Dunn GP, Zipfel GJ, Dacey RG, and Chicoine MR
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Introduction A low subfrontal dural opening technique that limits brain manipulation was assessed in patients who underwent frontotemporal approaches for anterior fossa lesions. Methods A retrospective review was performed for cases using a low subfrontal dural opening including characterization of demographics, lesion size and location, neurological and ophthalmological assessments, clinical course, and imaging findings. Results A low subfrontal dural opening was performed in 23 patients (17F, 6M), median age of 53 years (range 23-81) with a median follow-up duration of 21.9 months (range 6.2-67.1). Lesions included 22 meningiomas (nine anterior clinoid, 12 tuberculum sellae, and one sphenoid wing), one unruptured internal carotid artery aneurysm clipped during a meningioma resection, and one optic nerve cavernous malformation. Maximal possible resection was achieved in all cases including gross total resection in 16/22 (72.7%), near total in 1/22 (4.5%), and subtotal in 5/22 (22.7%) in which tumor involvement of critical structures limited complete resection. Eighteen patients presented with vision loss; 11 (61%) improved postoperatively, three (17%) were stable, and four (22%) worsened. The mean ICU stay and time to discharge were 1.3 days (range 0-3) and 3.8 days (range 2-8). Conclusion A low sub-frontal dural opening for approaches to the anterior fossa can be performed with minimal brain exposure, early visualization of the optico-carotid cistern for cerebrospinal fluid release, minimizing need for fixed brain retraction, and Sylvian fissure dissection. This technique can potentially reduce surgical risk and provide excellent exposure for anterior skull base lesions with favorable extent of resection, visual recovery, and complication rates., Competing Interests: Conflict of Interest None declared., (Thieme. All rights reserved.) more...
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- 2022
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34. Glioblastoma Clinical Trials: Current Landscape and Opportunities for Improvement.
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Bagley SJ, Kothari S, Rahman R, Lee EQ, Dunn GP, Galanis E, Chang SM, Nabors LB, Ahluwalia MS, Stupp R, Mehta MP, Reardon DA, Grossman SA, Sulman EP, Sampson JH, Khagi S, Weller M, Cloughesy TF, Wen PY, and Khasraw M more...
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- Adult, Humans, Research Design, Brain Neoplasms diagnosis, Brain Neoplasms therapy, Glioblastoma therapy
- 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., (©2021 American Association for Cancer Research.) more...
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- 2022
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35. Multivariate analysis of associations between clinical sequencing and outcome in glioblastoma.
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Yang PH, Tao Y, Luo J, Paturu M, Lu HC, Ramkissoon S, Heusel JW, Leuthardt EC, Chicoine MR, Dowling JL, Dunn GP, Duncavage E, Dahiya S, Chattherjee AR, and Kim AH
- Abstract
Background: Many factors impact survival in patients with glioblastoma, including age, Karnofsky Performance Status, postoperative chemoradiation, IDH1/2 mutation status, MGMT promoter methylation status, and extent of resection. High-throughput next-generation sequencing is a widely available diagnostic tool, but the independent impact of tumors harboring specific mutant genes on survival and the efficacy of extent of resection are not clear., Methods: We utilized a widely available diagnostic platform (FoundationOne CDx) to perform high-throughput next-generation sequencing on 185 patients with newly diagnosed glioblastoma in our tertiary care center. We performed multivariate analysis to control for clinical parameters with known impact on survival to elucidate the independent prognostic value of prevalent mutant genes and the independent impact of gross total resection., Results: When controlling for factors with known prognostic significance including IDH1/2 mutation and after multiple comparisons analysis, CDKN2B and EGFR mutations were associated with reduced overall survival while PTEN mutation was associated with improved overall survival. Gross total resection, compared to other extent of resection, was associated with improved overall survival in patients with tumors harboring mutations in CDKN2A , CDKN2B , EGFR , PTEN , TERT promoter, and TP53 . All patients possessed at least one of these 6 mutant genes., Conclusions: This study verifies the independent prognostic value of several mutant genes in glioblastoma. Six commonly found mutant genes were associated with improved survival when gross total resection was achieved. Thus, even when accounting for known predictors of survival and multiple mutant gene comparisons, extent of resection continues to be strongly associated with survival., (© The Author(s) 2022. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.) more...
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- 2022
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36. Characterization of the Genomic and Immunologic Diversity of Malignant Brain Tumors through Multisector Analysis.
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Schaettler MO, Richters MM, Wang AZ, Skidmore ZL, Fisk B, Miller KE, Vickery TL, Kim AH, Chicoine MR, Osbun JW, Leuthardt EC, Dowling JL, Zipfel GJ, Dacey RG, Lu HC, Johanns TM, Griffith OL, Mardis ER, Griffith M, and Dunn GP more...
- Subjects
- Brain Neoplasms genetics, Brain Neoplasms immunology, Genomics, Glioblastoma genetics, Glioblastoma immunology, Humans, Immunotherapy, Neoplasm Metastasis, Tumor Microenvironment, Exome Sequencing, Brain Neoplasms pathology, Glioblastoma secondary, Receptors, Antigen, T-Cell genetics
- Abstract
Despite some success in secondary brain metastases, targeted or immune-based therapies have shown limited efficacy against primary brain malignancies such as glioblastoma (GBM). Although the intratumoral heterogeneity of GBM is implicated in treatment resistance, it remains unclear whether this diversity is observed within brain metastases and to what extent cancer cell-intrinsic heterogeneity sculpts the local immune microenvironment. Here, we profiled the immunogenomic state of 93 spatially distinct regions from 30 malignant brain tumors through whole-exome, RNA, and T-cell receptor sequencing. Our analyses identified differences between primary and secondary malignancies, with gliomas displaying more spatial heterogeneity at the genomic and neoantigen levels. In addition, this spatial diversity was recapitulated in the distribution of T-cell clones in which some gliomas harbored highly expanded but spatially restricted clonotypes. This study defines the immunogenomic landscape across a cohort of malignant brain tumors and contains implications for the design of targeted and immune-based therapies against intracranial malignancies. SIGNIFICANCE: This study describes the impact of spatial heterogeneity on genomic and immunologic characteristics of gliomas and brain metastases. The results suggest that gliomas harbor significantly greater intratumoral heterogeneity of genomic alterations, neoantigens, and T-cell clones than brain metastases, indicating the importance of multisector analysis for clinical or translational studies. This article is highlighted in the In This Issue feature, p. 1 ., (©2021 The Authors; Published by the American Association for Cancer Research.) more...
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- 2022
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37. Therapeutic applications of the cancer immunoediting hypothesis.
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Desai R, Coxon AT, and Dunn GP
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- Animals, Humans, Immunologic Surveillance, Immunotherapy, Neoplasms metabolism, Neoplasms pathology, Neoplasms therapy, Tumor Microenvironment, Disease Susceptibility immunology, Immune System, Neoplasms etiology
- Abstract
Since the late 19th century, the immune system has increasingly garnered interest as a novel avenue for cancer therapy, particularly given scientific breakthroughs in recent decades delineating the fundamental role of the immune system in tumorigenesis. The immunoediting hypothesis has articulated this role, describing three phases of the tumor-immune system interaction: Elimination, Equilibrium, and Escape wherein tumors progress from active immunologic surveillance and destruction through dynamic immunologic stasis to unfettered growth. The primary goals of immunotherapy are to restrict and revert progression through these phases, thereby improving the immune system's ability to control tumor growth. In this review, we detail the development and foundation of the cancer immunoediting hypothesis and apply this hypothesis to the dynamic immunotherapy field that includes checkpoint blockade, vaccine therapy, and adoptive cell transfer., (Copyright © 2021. Published by Elsevier Ltd.) more...
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- 2022
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38. Sonobiopsy for minimally invasive, spatiotemporally-controlled, and sensitive detection of glioblastoma-derived circulating tumor DNA.
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Pacia CP, Yuan J, Yue Y, Xu L, Nazeri A, Desai R, Gach HM, Wang X, Talcott MR, Chaudhuri AA, Dunn GP, Leuthardt EC, and Chen H
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- Animals, Blood-Brain Barrier, Cell Line, Tumor, Humans, Mice, Swine, Brain Neoplasms genetics, Brain Neoplasms metabolism, Circulating Tumor DNA metabolism, Glioblastoma genetics, Glioblastoma metabolism, Liquid Biopsy methods, Sonication methods
- Abstract
Though surgical biopsies provide direct access to tissue for genomic characterization of brain cancer, they are invasive and pose significant clinical risks. Brain cancer management via blood-based liquid biopsies is a minimally invasive alternative; however, the blood-brain barrier (BBB) restricts the release of brain tumor-derived molecular biomarkers necessary for sensitive diagnosis. Methods: A mouse glioblastoma multiforme (GBM) model was used to demonstrate the capability of focused ultrasound (FUS)-enabled liquid biopsy (sonobiopsy) to improve the diagnostic sensitivity of brain tumor-specific genetic mutations compared with conventional blood-based liquid biopsy. Furthermore, a pig GBM model was developed to characterize the translational implications of sonobiopsy in humans. Magnetic resonance imaging (MRI)-guided FUS sonication was performed in mice and pigs to locally enhance the BBB permeability of the GBM tumor. Contrast-enhanced T
1 -weighted MR images were acquired to evaluate the BBB permeability change. Blood was collected immediately after FUS sonication. Droplet digital PCR was used to quantify the levels of brain tumor-specific genetic mutations in the circulating tumor DNA (ctDNA). Histological staining was performed to evaluate the potential for off-target tissue damage by sonobiopsy. Results: Sonobiopsy improved the detection sensitivity of EGFRvIII from 7.14% to 64.71% and TERT C228T from 14.29% to 45.83% in the mouse GBM model. It also improved the diagnostic sensitivity of EGFRvIII from 28.57% to 100% and TERT C228T from 42.86% to 71.43% in the porcine GBM model. Conclusion: Sonobiopsy disrupts the BBB at the spatially-targeted brain location, releases tumor-derived DNA into the blood circulation, and enables timely collection of ctDNA. Converging evidence from both mouse and pig GBM models strongly supports the clinical translation of sonobiopsy for the minimally invasive, spatiotemporally-controlled, and sensitive molecular characterization of brain cancer., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).) more...- Published
- 2022
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39. Competitive binding of E3 ligases TRIM26 and WWP2 controls SOX2 in glioblastoma.
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Mahlokozera T, Patel B, Chen H, Desouza P, Qu X, Mao DD, Hafez D, Yang W, Taiwo R, Paturu M, Salehi A, Gujar AD, Dunn GP, Mosammaparast N, Petti AA, Yano H, and Kim AH
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- Animals, B30.2-SPRY Domain, Binding, Competitive genetics, Female, Gene Knockdown Techniques, Glioblastoma metabolism, HEK293 Cells, Humans, Mice, Mice, Inbred NOD, Mice, SCID, Proteomics, SOXB1 Transcription Factors metabolism, Tripartite Motif Proteins metabolism, Ubiquitin-Protein Ligases metabolism, Ubiquitination, Binding, Competitive physiology, Brain Neoplasms genetics, Glioblastoma genetics, SOXB1 Transcription Factors genetics, Tripartite Motif Proteins genetics, Ubiquitin-Protein Ligases genetics
- Abstract
The pluripotency transcription factor SOX2 is essential for the maintenance of glioblastoma stem cells (GSC), which are thought to underlie tumor growth, treatment resistance, and recurrence. To understand how SOX2 is regulated in GSCs, we utilized a proteomic approach and identified the E3 ubiquitin ligase TRIM26 as a direct SOX2-interacting protein. Unexpectedly, we found TRIM26 depletion decreased SOX2 protein levels and increased SOX2 polyubiquitination in patient-derived GSCs, suggesting TRIM26 promotes SOX2 protein stability. Accordingly, TRIM26 knockdown disrupted the SOX2 gene network and inhibited both self-renewal capacity as well as in vivo tumorigenicity in multiple GSC lines. Mechanistically, we found TRIM26, via its C-terminal PRYSPRY domain, but independent of its RING domain, stabilizes SOX2 protein by directly inhibiting the interaction of SOX2 with WWP2, which we identify as a bona fide SOX2 E3 ligase in GSCs. Our work identifies E3 ligase competition as a critical mechanism of SOX2 regulation, with functional consequences for GSC identity and maintenance., (© 2021. The Author(s).) more...
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- 2021
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40. Salvage therapies for radiation-relapsed isocitrate dehydrogenase-mutant astrocytoma and 1p/19q codeleted oligodendroglioma.
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Ma S, Rudra S, Campian JL, Chheda MG, Johanns TM, Ansstas G, Abraham CD, Chicoine MR, Leuthardt EC, Dowling JL, Dunn GP, Kim AH, and Huang J
- Abstract
Background: Optimal management for recurrent IDH-mutant glioma after radiation therapy (RT) is not well-defined. This study assesses practice patterns for managing recurrent IDH-mutant astrocytoma (Astro) and 1p/19q codeleted oligodendroglioma (Oligo) after RT and surveys their clinical outcomes after different salvage approaches., Methods: Ninety-four recurrent Astro or Oligo patients after RT who received salvage systemic therapy (SST) between 2001 and 2019 at a tertiary cancer center were retrospectively analyzed. SST was defined as either alkylating chemotherapy (AC) or nonalkylating therapy (non-AC). Overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan-Meier method from the start of SST. Multivariable analysis (MVA) was conducted using Cox regression analysis., Results: Recurrent Oligo (n = 35) had significantly higher PFS (median: 3.1 vs 0.8 years, respectively, P = .002) and OS (median: 6.3 vs 1.5 years, respectively, P < .001) than Astro (n = 59). Overall, 90% of recurrences were local. Eight-three percent received AC as the first-line SST; 50% received salvage surgery before SST; approximately 50% with local failure >2 years after prior RT received reirradiation. On MVA, non-AC was associated with worse OS for both Oligo and Astro; salvage surgery was associated with improved PFS and OS for Astro; early reirradiation was associated with improved PFS for Astro., Conclusions: Recurrent radiation-relapsed IDH-mutant gliomas represent a heterogeneous group with variable treatment approaches. Surgery, AC, and reirradiation remain the mainstay of salvage options for retreatment., (© The Author(s) 2021. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.) more...
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- 2021
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41. Re-evaluating Biopsy for Recurrent Glioblastoma: A Position Statement by the Christopher Davidson Forum Investigators.
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Nduom EK, Gephart MH, Chheda MG, Suva ML, Amankulor N, Battiste JD, Campian JL, Dacey RG, Das S, Fecci PE, Hadjipanayis CG, Hoang KB, Jalali A, Orringer D, Patel AJ, Placantonakis D, Rodriguez A, Yang I, Yu JS, Zipfel GJ, Dunn GP, Leuthardt EC, and Kim AH more...
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- Biopsy, Humans, Mutation, Neoplasm Recurrence, Local diagnosis, Brain Neoplasms diagnosis, Brain Neoplasms genetics, Brain Neoplasms therapy, Glioblastoma diagnosis, Glioblastoma genetics, Glioblastoma therapy
- Abstract
Patients with glioblastoma (GBM) need bold new approaches to their treatment, yet progress has been hindered by a relative inability to dynamically track treatment response, mechanisms of resistance, evolution of targetable mutations, and changes in mutational burden. We are writing on behalf of a multidisciplinary group of academic neuro-oncology professionals who met at the collaborative Christopher Davidson Forum at Washington University in St Louis in the fall of 2019. We propose a dramatic but necessary change to the routine management of patients with GBM to advance the field: to routinely biopsy recurrent GBM at the time of presumed recurrence. Data derived from these samples will identify true recurrence vs treatment effect, avoid treatments with little chance of success, enable clinical trial access, and aid in the scientific advancement of our understanding of GBM., (© Congress of Neurological Surgeons 2021.) more...
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- 2021
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42. Immune profiling of pituitary tumors reveals variations in immune infiltration and checkpoint molecule expression.
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Mei Y, Bi WL, Agolia J, Hu C, Giantini Larsen AM, Meredith DM, Al Abdulmohsen S, Bale T, Dunn GP, Abedalthagafi M, and Dunn IF
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- Humans, Immunohistochemistry, MutS Proteins, Neoplasm Recurrence, Local, Tumor Microenvironment, B7-H1 Antigen, Pituitary Neoplasms genetics
- Abstract
Purpose: Pituitary tumors are the second most common primary brain tumors. Functional tumors demonstrate increased PD-L1 expression, but expression of other checkpoint regulators has not been characterized. We sought to characterize the immune microenvironment of human pituitary tumors to identify new treatment opportunities., Methods: 72 pituitary tumors were evaluated for expression of the immune regulatory markers programmed death ligand 1 (PD-L1), programmed death ligand 2 (PD-L2), V-domain Ig suppressor of T cell activation (VISTA), lymphocyte activation gene 3 (LAG3) and tumor necrosis factor receptor superfamily member 4 (OX40) by immunohistochemistry (IHC). Lymphocyte infiltration, macrophage infiltration, and angiogenesis were analyzed using IHC. Expression of pituitary tumor initiating cell marker CD15 and mismatch repair proteins MutS protein homolog 2 (MSH2) and MutS protein homolog 6 (MSH6) was also assessed., Results: Pituitary tumors were infiltrated by macrophages and T cells, and they expressed varying levels of PD-L1, PD-L2, VISTA, LAG3, and OX40. Functional tumors and tumors with high expression of tumor stem cell markers had higher immune cell infiltration and greater expression of immunosuppressive checkpoint regulators. Increased PD-L1 and LAG3 and reduced VISTA were observed in primary tumors compared to recurrent tumors., Conclusion: Immune cell infiltration and checkpoint regulator expression vary depending on functional status and presence of pituitary tumor initiating cells. Functional tumors may have a particularly immunosuppressive microenvironment. Further studies of immune checkpoint blockade of pituitary tumors, particularly functional tumors, are warranted, though combination therapy may be required. more...
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- 2021
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43. U.S. Neurosurgical Response to COVID-19: Forging a Path Toward Disaster Preparedness.
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Ravindra VM, Dunn GP, Belverud S, Carroll CP, Zuckerman SL, Menger R, Malone D, Cooke J, Porenksy P, Klugh Iii A, Gilhooly J, Tomlin J, Bell R, and Ikeda DS
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- Humans, Neurosurgeons, Pandemics, SARS-CoV-2, COVID-19, Disasters
- Abstract
Introduction: The worldwide COVID-19 pandemic poses challenges to healthcare capacity and infrastructure. The authors discuss the structure and efficacy of the U.S. Navy's response to COVID-19 and evaluate the utility of this endeavor, with the objective of providing future recommendations for managing worldwide healthcare and medical operational demands from the perspective of Navy Neurosurgery., Materials and Methods: The authors present an extensive review of topics and objectively highlight the efforts of U.S. Navy Neurosurgery as it pertains to the humanitarian mission during the COVID-19 pandemic., Results: During the humanitarian mission (March 27, 2020-April 14, 2020), the response of active duty and reserve neurosurgeons in the U.S. Navy was robust. Neurosurgical coverage was present on board the U.S. Navy Ships Mercy and Comfort, with additional neurosurgical deployment to New York City for intensive care unit management and coverage., Conclusions: The U.S. Navy neurosurgical response to the COVID-19 pandemic was swift and altruistic. Although neurosurgical pathologies were limited among the presenting patients, readiness and manpower continue to be strong influences within the Armed Forces. The COVID-19 response demonstrates that neurosurgical assets can be rapidly mobilized and deployed in support of wartime, domestic, and global humanitarian crises to augment both trauma and critical care capabilities., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2021. This work is written by (a) US Government employee(s) and is in the public domain in the US.) more...
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- 2021
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44. Optimized polyepitope neoantigen DNA vaccines elicit neoantigen-specific immune responses in preclinical models and in clinical translation.
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Li L, Zhang X, Wang X, Kim SW, Herndon JM, Becker-Hapak MK, Carreno BM, Myers NB, Sturmoski MA, McLellan MD, Miller CA, Johanns TM, Tan BR, Dunn GP, Fleming TP, Hansen TH, Goedegebuure SP, and Gillanders WE more...
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- Adult, Animals, Antigen Presentation immunology, Cell Proliferation, Disease Models, Animal, Female, HeLa Cells, Humans, Immune Checkpoint Inhibitors, Immunotherapy, Male, Mammary Neoplasms, Animal pathology, Mice, Inbred C57BL, Neoplasm Metastasis, Neuroendocrine Tumors immunology, Neuroendocrine Tumors pathology, Peptides immunology, T-Lymphocytes immunology, Mice, Antigens, Neoplasm immunology, Epitopes immunology, Immunity, Translational Research, Biomedical, Vaccines, DNA immunology
- Abstract
Background: Preclinical studies and early clinical trials have shown that targeting cancer neoantigens is a promising approach towards the development of personalized cancer immunotherapies. DNA vaccines can be rapidly and efficiently manufactured and can integrate multiple neoantigens simultaneously. We therefore sought to optimize the design of polyepitope DNA vaccines and test optimized polyepitope neoantigen DNA vaccines in preclinical models and in clinical translation., Methods: We developed and optimized a DNA vaccine platform to target multiple neoantigens. The polyepitope DNA vaccine platform was first optimized using model antigens in vitro and in vivo. We then identified neoantigens in preclinical breast cancer models through genome sequencing and in silico neoantigen prediction pipelines. Optimized polyepitope neoantigen DNA vaccines specific for the murine breast tumor E0771 and 4T1 were designed and their immunogenicity was tested in vivo. We also tested an optimized polyepitope neoantigen DNA vaccine in a patient with metastatic pancreatic neuroendocrine tumor., Results: Our data support an optimized polyepitope neoantigen DNA vaccine design encoding long (≥20-mer) epitopes with a mutant form of ubiquitin (Ub
mut ) fused to the N-terminus for antigen processing and presentation. Optimized polyepitope neoantigen DNA vaccines were immunogenic and generated robust neoantigen-specific immune responses in mice. The magnitude of immune responses generated by optimized polyepitope neoantigen DNA vaccines was similar to that of synthetic long peptide vaccines specific for the same neoantigens. When combined with immune checkpoint blockade therapy, optimized polyepitope neoantigen DNA vaccines were capable of inducing antitumor immunity in preclinical models. Immune monitoring data suggest that optimized polyepitope neoantigen DNA vaccines are capable of inducing neoantigen-specific T cell responses in a patient with metastatic pancreatic neuroendocrine tumor., Conclusions: We have developed and optimized a novel polyepitope neoantigen DNA vaccine platform that can target multiple neoantigens and induce antitumor immune responses in preclinical models and neoantigen-specific responses in clinical translation. more...- Published
- 2021
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45. Yap1 Mediates Trametinib Resistance in Head and Neck Squamous Cell Carcinomas.
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Mudianto T, Campbell KM, Webb J, Zolkind P, Skidmore ZL, Riley R, Barnell EK, Ozgenc I, Giri T, Dunn GP, Adkins DR, Griffith M, Egloff AM, Griffith OL, and Uppaluri R
- Subjects
- Animals, Biopsy, Cell Line, Tumor, Female, Gene Expression Regulation, Neoplastic, Gene Knockout Techniques, Head and Neck Neoplasms genetics, Head and Neck Neoplasms pathology, Hippo Signaling Pathway genetics, Humans, MAP Kinase Signaling System genetics, Mice, Pyridones therapeutic use, Pyrimidinones therapeutic use, RNA-Seq, Squamous Cell Carcinoma of Head and Neck genetics, Squamous Cell Carcinoma of Head and Neck pathology, Exome Sequencing, Xenograft Model Antitumor Assays, YAP-Signaling Proteins genetics, Drug Resistance, Neoplasm genetics, Head and Neck Neoplasms drug therapy, Pyridones pharmacology, Pyrimidinones pharmacology, Squamous Cell Carcinoma of Head and Neck drug therapy, YAP-Signaling Proteins metabolism
- Abstract
Purpose: In a head and neck squamous cell carcinoma (HNSCC) "window of opportunity" clinical trial, we reported that trametinib reduced MEK-Erk1/2 activation and resulted in tumor responses in a subset of patients. Here, we investigated resistance to trametinib and molecular correlates in HNSCC cell lines and patient samples., Experimental Design: HNSCC cell lines were treated with trametinib to generate resistant lines. Candidate bypass pathways were assessed using immunoblotting, CRISPR knockout, and survival assays. Effectiveness of combined trametinib and verteporfin targeting was evaluated. Patient-derived xenografts (PDXs) from responder patients were treated with trametinib and resistant tumors were analyzed. Window trial clinical samples were subjected to whole-exome and RNA sequencing., Results: HNSCC cell lines developed resistance (CAL27-TR and HSC3-TR) after prolonged trametinib exposure. Downstream effectors of the Hippo pathway were activated in CAL27-TR and HSC3-TR, and combined trametinib and verteporfin treatment resulted in synergistic treatment response. We defined the Hippo pathway effector Yap1 as an induced survival pathway promoting resistance to trametinib in HSC3-TR. Yap1 was necessary for HSC3-TR trametinib resistance, and constitutively active Yap1 was sufficient to confer resistance in parental HSC3. Analysis of trametinib neoadjuvant trial patient tumors indicated canonical MEK-Erk1/2 pathway activating mutations were infrequent, and Yap1 activity increased following trametinib treatment. Trametinib treatment of a PDX from a responder patient resulted in evolution of resistance with increased Yap1 expression and activity., Conclusions: These studies identify a Yap1-dependent resistance to trametinib therapy in HNSCCs. Combined Yap1 and MEK targeting may represent a strategy to enhance HNSCC response., (©2021 American Association for Cancer Research.) more...
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- 2021
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46. Cytokine Profiling in Plasma from Patients with Brain Tumors Versus Healthy Individuals using 2 Different Multiplex Immunoassay Platforms.
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Bender DE, Schaettler MO, Sheehan KC, Johanns TM, and Dunn GP
- Abstract
We compared the performance of two 96-well multiplex immunoassay platforms in assessing plasma cytokine concentrations in patients with glioblastoma (GBM; n = 27), individuals with melanoma, breast or lung cancer metastases to the brain (n = 17), and healthy volunteers (n = 11). Assays included a bead-based fluorescence MILLIPLEX
® assay/Luminex (LMX) platform and 4 planar electrochemiluminescence kits from Meso Scale Discovery (MSD). The LMX kit evaluated 21 cytokines and the 3 MSD kits evaluated 20 cytokines in total, with 19 overlapping human cytokines between platforms (GM-CSF, IFNγ, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, IL-17A, IL-21, IL-23, MIP-1α, MIP-1β, MIP-3α, TNFα). The MSD platform had lower LLoQs (lower limits of quantification) than LMX for 17/19 cytokines, and higher LLoQs for IFN-γ and IL-21. The ULoQs were higher in LMX versus MSD assays for 17/19 shared analytes, but lower than MSD for IL-17A and IL-21. With LMX, all 19 shared analytes were quantifiable in each of 55 samples. Although MSD recombinant protein standard curves indicated lower LLoQs than LMX for most cytokines, MSD detected 7/19 (37%) native analytes in <75% of samples, including 0% detection for IL-21 and 8% for IL-23. The LMX platform categorized identical samples at greater concentrations than the MSD system for most analytes (MIP-1β the sole exception), sometimes by orders of magnitude. This mismatched quantification paradigm was supported by Bland-Altman analysis. LMX identified significantly elevated levels of 10 of 19 circulating cytokines in GBM: GM-CSF, IFN-γ, IL-1β, IL-5, IL-10, IL-17A, IL-21, IL-23, MIP-1α, and MIP-3α, consistent with prior findings and confirming the utility of applying appropriate multiplex immunoassay technologies toward developing a cytokine signature profile for GBM., Competing Interests: Declaration Of Conflicting Interests:The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: GD reports being cofounder of Immunovalent Therapeutics Incorporated (St. Louis, MO), a company that develops immunologic cancer therapies, and is a member of the Scientific Advisory Board of Ziopharm Oncology (Boston, MA). No other author has any potential conflicts of interest to disclose., (© The Author(s) 2021.) more...- Published
- 2021
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47. Unique challenges for glioblastoma immunotherapy-discussions across neuro-oncology and non-neuro-oncology experts in cancer immunology. Meeting Report from the 2019 SNO Immuno-Oncology Think Tank.
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Chuntova P, Chow F, Watchmaker PB, Galvez M, Heimberger AB, Newell EW, Diaz A, DePinho RA, Li MO, Wherry EJ, Mitchell D, Terabe M, Wainwright DA, Berzofsky JA, Herold-Mende C, Heath JR, Lim M, Margolin KA, Chiocca EA, Kasahara N, Ellingson BM, Brown CE, Chen Y, Fecci PE, Reardon DA, Dunn GP, Liau LM, Costello JF, Wick W, Cloughesy T, Timmer WC, Wen PY, Prins RM, Platten M, and Okada H more...
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- Humans, Immunotherapy, Medical Oncology, Tumor Microenvironment, Brain Neoplasms therapy, Glioblastoma therapy, Neoplasms
- Abstract
Cancer immunotherapy has made remarkable advances with over 50 separate Food and Drug Administration (FDA) approvals as first- or second-line indications since 2015. These include immune checkpoint blocking antibodies, chimeric antigen receptor-transduced T cells, and bispecific T-cell-engaging antibodies. While multiple cancer types now benefit from these immunotherapies, notable exceptions thus far include brain tumors, such as glioblastoma. As such, it seems critical to gain a better understanding of unique mechanistic challenges underlying the resistance of malignant gliomas to immunotherapy, as well as to acquire insights into the development of future strategies. An Immuno-Oncology Think Tank Meeting was held during the 2019 Annual Society for Neuro-Oncology Scientific Conference. Discussants in the fields of neuro-oncology, neurosurgery, neuro-imaging, medical oncology, and cancer immunology participated in the meeting. Sessions focused on topics such as the tumor microenvironment, myeloid cells, T-cell dysfunction, cellular engineering, and translational aspects that are critical and unique challenges inherent with primary brain tumors. In this review, we summarize the discussions and the key messages from the meeting, which may potentially serve as a basis for advancing the field of immune neuro-oncology in a collaborative manner., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.) more...
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- 2021
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48. Serving on the Navy's Hospital Ships During the Response to COVID-19: Perspective from Two Deployed Missouri Physicians.
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Dunn GP and Bernstein B
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- Humans, Missouri, SARS-CoV-2, Ships, COVID-19, Emergency Responders psychology, Military Personnel psychology, Physicians psychology
- Published
- 2021
49. Photosensitivity Reaction From Operating Room Lights After Oral Administration of 5-Aminolevulinic Acid for Fluorescence-Guided Resection of a Malignant Glioma.
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Yahanda AT, Dunn GP, and Chicoine MR
- Abstract
Orally administered 5-aminolevulinic acid (5-ALA), which was approved in the United States in 2017, is preferentially metabolized by malignant glioma cells into protoporphyrin IX and enhances tumor visualization when using a blue light filter on an operating microscope. Photosensitivity after 5-ALA administration is a known side effect, but a photosensitivity reaction from operating room lights has not yet been documented. We report the case of a 56-year-old man with a history of previous resection of a grade II astrocytoma who presented with imaging concerning for tumor recurrence and possible malignant transformation. Repeat surgical resection utilized 5-ALA. Soon after the surgery, he developed reddening of his skin, particularly over the right side of his head and neck, with blistering and peeling in a distribution that was particularly exposed to operating room lights during surgery. No other areas of his skin experienced the same redness, blistering, or peeling. Topical lotions were applied and the skin changes resolved spontaneously over weeks. Significant photosensitivity after administration of oral 5-ALA is a rare complication, but neurosurgeons who perform fluorescence-guided tumor resection should remain cognizant of its potential association with exposure to intense light, including in the operating room. Phototoxicity typically is self-limited, but awareness is important to minimize its occurrence., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Yahanda et al.) more...
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- 2021
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50. Correction: Neoadjuvant and Adjuvant Pembrolizumab in Resectable Locally Advanced, Human Papillomavirus-unrelated Head and Neck Cancer: A Multicenter, Phase II Trial.
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Uppaluri R, Campbell KM, Egloff AM, Zolkind P, Skidmore ZL, Nussenbaum B, Paniello RC, Rich JT, Jackson R, Pipkorn P, Michel LS, Ley J, Oppelt P, Dunn GP, Barnell EK, Spies NC, Lin T, Li T, Mulder DT, Hanna Y, Cirlan I, Pugh TJ, Mudianto T, Riley R, Zhou L, Jo VY, Stachler MD, Hanna GJ, Kass J, Haddad R, Schoenfeld JD, Gjini E, Lako A, Thorstad W, Gay HA, Daly M, Rodig SJ, Hagemann IS, Kallogjeri D, Piccirillo JF, Chernock RD, Griffith M, Griffith OL, and Adkins DR more...
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- 2021
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