19 results on '"Frances Chow"'
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2. Abstract 3124: Identification of sub-clonal loss of heterozygosity (LOH) in glioblastomas analyzed with spatial transcriptomics
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Michelle G. Webb, Frances Chow, Carmel McCullough, Bohan Zhang, Kyle Hurth, John Carpten, Gabriel Zada, and David W. Craig
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Cancer Research ,Oncology - Abstract
We propose a method to leverage spatial transcriptomics and bioinformatic analysis to identify sub-clonal loss of heterozygosity that could otherwise be missed by standard bulk sequencing in glioblastoma tumors. Glioblastomas are highly invasive and aggressive brain tumors with a low five-year survival rate of less than 10%. Current treatment strategies are not sufficient for long term disease outcome, and innovative approaches to analyze glioblastoma are imperative for future improved options. Many factors contribute to difficulty of treatment, though one critical consideration is the diffuse nature and known intratumoral heterogeneity of this cancer. It is important to determine LOH heterogeneity, as this genomic alteration is associated with copy number variation and specific classifications of gliomas. Loss of heterozygosity is an irreversible deletion of DNA that is a common alteration in cancer. Application of spatial transcriptomics can increase our understanding of genomic complexity across a tissue, and unsupervised graph clustering can computationally separate spatial regions with similar gene expression patterns. Our method investigates spatial clusters individually at known heterozygous SNP sites to identify evidence for LOH with Bayesian inference and a hidden Markov model. Our analysis centers on the balance of reference (A) and non-reference (B) spatial transcriptomics read counts at SNPs of interest. B allele frequency is the number of reads aligned to the alternative allele divided by the total number of reads counted at the SNP. At a normal two-copy state at a heterozygous site, B allele frequency is ideally 50 percent. LOH can be identified as this value deviates toward 0 or 100, and copy number alterations impact this frequency. Our method utilizes Bayes factor values, or likelihood ratios between two models, using allele counts to provide support for either LOH or a heterozygous event. For our analysis, spatial transcriptomics BAMs are processed with a graph clustering algorithm and split into cluster-specific BAMs. We calculate allele count coverage for each cluster at pre-selected heterozygous SNP positions identified through germline exome sequencing. Bayes factor values are then calculated at each SNP, resulting in evidence for LOH or a heterozygous event. Chromosomal regions are segmented by a hidden Markov approach. Cumulative metrics for each segment are evaluated to determine a “state” label of heterozygous, LOH, or undefined. We tested our method on three WHO grade 4 IDH wild-type EGFRvIII positive fresh frozen glioblastoma tissue samples. Sub-clonal heterogeneity was identified in two samples and confirmed by bulk exome sequencing, bulk RNA sequencing, and analysis of initial clinical reports. Citation Format: Michelle G. Webb, Frances Chow, Carmel McCullough, Bohan Zhang, Kyle Hurth, John Carpten, Gabriel Zada, David W. Craig. Identification of sub-clonal loss of heterozygosity (LOH) in glioblastomas analyzed with spatial transcriptomics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3124.
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- 2023
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3. CNSC-02. BREAST TO BRAIN METASTASIS IS EXACERBATED WITH CHEMOTHERAPY THROUGH BLOOD-CEREBRAL SPINAL FLUID-BARRIER AND INDUCES ALZHEIMER’S-LIKE PATHOLOGY
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Josh Neman, Behnaz Saatian, Krutika Deshpande, Vahan Martisorian, Peter LaViolette, Adrienne Boire, Frances Chow, Kyle Hurth, Peter Fecci, Mark Shiroishi, and Rachel Eisenbarth
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Cancer Research ,Oncology ,Neurology (clinical) - Abstract
Control of breast to brain metastasis remains an urgent unmet clinical need. While chemotherapies are essential in reducing systemic tumor burden, they have also shown to promote non-brain metastatic invasiveness and drug-driven neurocognitive deficits through formation of neurofibrillary tangles (NFT) independently. Now, in this study we investigated the effect of chemotherapy on brain metastatic progression and promoting tumor-mediated NFT. Results show chemotherapies promote increased brain-barrier permeability and facilitate enhanced tumor infiltration, particularly through the blood-cerebrospinal fluid-barrier (BCSFB). This is attributed to increased expression of matrix metalloproteinase 9 (MMP9) which, in turn, mediates loss of Claudin-6 within the choroid plexus cells of the BCSFB. Importantly, increased MMP9 activity in the choroid epithelium following chemotherapy results in cleavage of Tau released from breast cancer cells. This cleaved Tau forms tumor-derived NFT that further destabilize the BCSFB. Our results underline for the first time the importance of the BCSFB as a vulnerable point of entry for brain-seeking tumor cells post-chemotherapy and indicate that tumor cells themselves contribute to Alzheimer’s-like tauopathy.
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- 2022
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4. PATH-22. CLINICAL FEATURES AND MOLECULAR CHARACTERIZATION OF LEPTOMENINGEAL DISEASE IN PATIENTS WITH HIGH GRADE GLIOMA
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Madison Shoaf, Frances Chow, Joanne Xiu, Michael Glantz, Sonikpreet Aulakh, David Ashley, Eric S Lipp, Giselle Lopez, Ashley Sumrall, Phillip Walker, David Spetzler, Theodore Nicolaides, and Katherine B Peters
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Cancer Research ,Oncology ,Neurology (clinical) - Abstract
INTRODUCTION Leptomeningeal disease (LMD) is a challenging complication of high grade glioma (HGG) and critical questions remain unanswered regarding clinicopathologic risk factors, molecular associations, and optimal treatment. METHODS Patients with molecularly-profiled HGG (Caris Life Sciences; Phoenix, AZ) with LMD at two institutions were included. Medical records were reviewed for clinicopathological characteristics, treatment, and outcome. Kaplan-Meier estimates of patient survival were performed on censored data using Cox’s proportional hazard model. RESULTS 43 patients (male: 33, female: 10; median age: 56 years) were identified, comprising 41 grade 4 (glioblastoma: 38; gliosarcoma: 2; H3K27M diffuse midline glioma: 1) and 2 grade 3 tumors (astrocytoma: 1; pleomorphic xanthoastrocytoma: 1). LMD diagnosed at HGG diagnosis (n=18) versus recurrence (n=22) was associated with longer post-LMD survival [pLMD-OS: 15.3m vs. 4.8m, HR: 0.07, 95% CI: 0.02-0.29, p=0.0004] but similar overall survival [mOS: 15.3m vs. 12.3m; HR: 0.82; 95% CI: 0.36-1.85; p=0.63]. Pathology-diagnosed LMD (n=15) versus MRI-diagnosed LMD (n=26) was associated with longer post-LMD survival [pLMD-OS: 15.4m vs. 5.2m, HR: 14.9, 95% CI: 0.01-0.30, p=0.0004] but similar overall survival [mOS: 17.1m vs. 12.3m; HR: 0.66; 95% CI: 0.3-1.58; p=0.38]. Post-LMD survival was significantly prolonged for supratentorial (n=28) versus infratentorial/spinal (n=4) locations regardless of the diagnostic modality [pLMD-OS: 2.6m vs. 11.3m, HR: 14.4, 95% CI: 2.73-75.7, p=0.0017], and did not significantly differ between symptomatic (n=20) and asymptomatic (n=23) patients [pLMD-OS: 4.8m vs. 11.2m, HR: 1.75, 95% CI: 0.82-3.77, p=0.15). pTERT mutation (81%), EGFR amplification (43%), and MGMT methylation (33%) were prevalent but IDH1 mutation was rare (2.8%). Comparison with a separate glioblastoma cohort (n=1400) suggested more frequent amplification of CHIC2, MDM4, and KDR, higher mutation rates of RUNX1, APC, and RAD51C, colder tumor microenvironment (TME), and lower expression of immune checkpoint-related genes. CONCLUSIONS Clinicopathological characteristics affect post-LMD survival, and cohort comparison suggests molecular and TME differences in LMD-HGG tumors.
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- 2022
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5. CTNI-17. A MULTI-INSTITUTIONAL RANDOMIZED CLINICAL TRIAL COMPARING ASSAY - GUIDED CHEMOTHERAPY WITH PHYSICIAN-CHOICE TREATMENT FOR RECURRENT HIGH-GRADE GLIOMA (NCT03632135)
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Tulika Ranjan, Soma Sengupta, Michael Glantz, Richard Green, Alexander Yu, Dawit Aregawi, Rekha Chaudary, Ricky Chen, Mario Zuccarello, Christine Lu-Emerson, Hugh Moulding, Neil Belman, Jon Glass, Aaron Mammoser, Mark Anderson, Nicholas Marko, Jason Schroeder, Steven Jubelirer, Frances Chow, Anthony Alberico, Candace Howard, Seth Lirette, Krista Denning, Jagan Valluri, and Pier Paolo Claudio
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Cancer Research ,Oncology ,Neurology (clinical) - Abstract
The presence of therapy-resistant cancer stem cells (CSCs) in recurrent high-grade glioma (HGG) patients contributes to poor clinical outcomes. The ChemoID functional anti-cancer assay targets cancer stem cells along with the bulk of the tumor cells. This trial aims to determine if ChemoID assay-guided treatment improves survival rates for recurrent HGG patients compared to the empirically physician-selected treatment. Patients with grade-III/IV recurrent glioma who failed standard of care (SOC) therapy were randomized (1:1) between two intervention groups. They received one of fourteen mono or combination chemotherapies based on the ChemoID assay or physician choice. The study met the primary outcome in the first interim analysis of 50 patients as per protocol. The ChemoID group had an improved survival rate (vs physician-choice). Median OS (mOS) was 12.5 months in the ChemoID group (95% CI, 10.2-14.7) vs 9 months in the physician-choice (95% CI, 4.2-13.8; log-rank P = .010). Mortality risk was lower in the ChemoID group (HR = 0.44; 95% CI, 0.24-0.81; P = .008). Median progression-free survival was 10.1 months in the ChemoID group vs 3.5 months in the physician choice (95% CI, 4.8-15.4 vs 1.9-5.1; log-rank < 0.001). Risk of progression was lower in the ChemoID group (HR = 0.25; 95% CI, 0.14-0.44; P < 0.001). The intention to treat (ITT) analysis of 78 patients showed substantially improved OS. The ChemoID group had a statistically significant longer median survival of 4.5 months. mOS was 12.0 months in the ChemoID group (95% CI, 10.8-13.2) vs 7.5 in the physician-choice group (95% CI, 3.5-11.5; log-rank P = .009). The ChemoID group had a decreased mortality risk (HR = 0.52; 95% CI, 0.24-0.81; P = .008). Compared with the physician-choice, the ChemoID group had a significantly longer OS in the ITT population. Our findings support that screening standard cytotoxic chemotherapies with a patient-specific anti-cancer assay improves survival outcomes in recurrent HGG patients.
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- 2022
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6. Complementary and Alternative Medicine for the Treatment of Gliomas: Scoping Review of Clinical Studies, Patient Outcomes, and Toxicity Profiles
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Frances Chow, Tyler Cardinal, Eliza M. Kellman, Ben A. Strickland, Gabriel Zada, Martin J. Rutkowski, Frank J. Attenello, Andrew Brunswick, Dhiraj J. Pangal, and Hans Baertsch
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Oncology ,Complementary Therapies ,medicine.medical_specialty ,medicine.medical_treatment ,Recurrent Glioma ,03 medical and health sciences ,0302 clinical medicine ,Mistletoe extract ,Carbogen ,Internal medicine ,Glioma ,medicine ,Humans ,business.industry ,Brain Neoplasms ,Evidence-based medicine ,medicine.disease ,Treatment Outcome ,030220 oncology & carcinogenesis ,Toxicity ,Surgery ,Carbogen Breathing ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,Ketogenic diet - Abstract
Introduction Complementary and alternative medicine (CAM) are highly used among those diagnosed with glioma. Further research is warranted, however, as it remains important to clearly delineate CAM practices that are unproven, disproven, or promising for future research and implementation. Methods A systematic review was conducted to identify all articles that investigated the effect of any CAM therapy on survival of patients with newly diagnosed or recurrent glioma. Results Eighteen papers and 4 abstracts pertaining to the effects of ketogenic diet (4), antioxidants (3), hyperbaric oxygen (4), cannabinoids (2), carbogen and nicotinamide (3), mistletoe extract (2), hypocupremia and penicillamine (1), and overall CAM use (3) on overall and progression-free survival in patients with low- and high-grade glioma were identified (Levels of Evidence I-IV). Ketogenic diets, hyperbaric oxygen therapy, and cannabinoids appear to be safe and well tolerated by patients; preliminary studies demonstrate tumor response and increased progression-free survival and overall survival when combined with standard of care therapies. Antioxidant usage exhibit mixed results perhaps associated with glioma grade with greater effect on low-grade gliomas; vitamin D intake was associated with prolonged survival. Conversely, carbogen breathing and hypocupremia were found to have no effect on the survival of patients with glioma, with associated significant toxicity. Most modalities under the CAM umbrella have not been appropriately studied and require further investigation. Conclusions Despite widespread use, Level I or II evidence for CAM for the treatment of glioma is lacking, representing future research directions to optimally counsel and treat glioma patients.
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- 2021
7. 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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Frances Chow, Michael Platten, Wolfgang Wick, Benjamin M. Ellingson, Pavlina Chuntova, David A. Reardon, Christine E. Brown, Derek A. Wainwright, Timothy F. Cloughesy, Ming Li, Michael Lim, Duane Mitchell, Yvonne Y. Chen, Hideho Okada, Ronald A. DePinho, Jay A. Berzofsky, James R. Heath, Kim Margolin, Payal Watchmaker, Masaki Terabe, Robert M. Prins, Peter E. Fecci, William Timmer, Evan W. Newell, Aaron Diaz, Mildred Galvez, E. Antonio Chiocca, Joseph F. Costello, E. John Wherry, Noriyuki Kasahara, Patrick Y. Wen, Linda M. Liau, Amy B. Heimberger, Christel Herold-Mende, and Gavin P. Dunn
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Oncology ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Neuro oncology ,Oncology and Carcinogenesis ,Meeting Report ,Medical Oncology ,Vaccine Related ,Rare Diseases ,Cancer immunotherapy ,Internal medicine ,Neoplasms ,medicine ,Tumor Microenvironment ,Humans ,Oncology & Carcinogenesis ,Cancer immunology ,Cancer ,Tumor microenvironment ,immunosuppression ,business.industry ,Brain Neoplasms ,glioblastoma ,Neurosciences ,clinical trial ,Immunotherapy ,medicine.disease ,Immune checkpoint ,Brain Disorders ,Clinical trial ,Brain Cancer ,conference report ,Orphan Drug ,Good Health and Well Being ,Immunization ,Neurology (clinical) ,immunotherapy ,business ,Glioblastoma - 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.
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- 2021
8. Abstract CT224: Multi-institutional randomized phase-3 trial comparing cancer stem cell-targeted vs physician-choice treatments in patients with recurrent high-grade gliomas (NCT03632135)
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Tulika Ranjan, Soma Sengupta, Alexander Yu, Candace M. Howard, Ricky Chen, Rekha Chaudhary, Nicholas Marko, Dawit Aregawi, Michael Glantz, Jon Glass, Richard M. Green, Christine Lu-Emerson, Aaron Mammoser, Hugh Moulding, Steven Jubelirer, Jason Schroeder, Mark Anderson, Frances Chow, Seth Lirette, Krista Denning, Anthony Alberico, Jagan Valluri, and Pier Paolo Claudio
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Cancer Research ,Oncology - Abstract
Background: Clinical outcomes in patients with recurrent high-grade glioma (HGG) remain poor. Cancer stem cells (CSCs) have been implicated in metastasis, treatment resistance and recurrence of HHGs. We have shown in several clinical studies that anti-CSC-directed therapy provides benefits in many cancer types; however, this is the first report of a randomized clinical trial evaluating it for recurrent HGGs. Objective: Determine whether CSC-targeted cytotoxic agents selected by ChemoID assay-guided therapy improves survival in patients with recurrent HGG. Design, Settings, and Participants: In this parallel-group, randomized, phase-3 clinical trial, patients at 13 clinical sites in the USA with grade-III/IV recurrent glioma (2016 WHO guidelines) were randomized 1:1 to either ChemoID assay-guided therapy or physician-choice therapy, and then treated and followed until unacceptable toxic effects, hospice, or death. Main Outcomes and Measures: The primary endpoint was overall survival (OS). Results: Combined median follow-up was 9 months. Median OS (mOS) was 12.5 months (95% CI, 10.2-14.7) in the ChemoID assay-guided group vs 9 months (95% CI, 4.2-13.8) in the physician-choice group (log-rank P = .010). Risk of death was significantly lower in the ChemoID assay group (HR = 0.44; 95% CI, 0.24-0.81; P = .008). Median progression free survival (PFS) was 10.1 vs 3.5 months (95% CI, 4.8-15.4 vs 1.9-5.1) (HR, 0.25; 95% CI, 0.14-0.44; P < .001). Conclusions and Relevance: Primary endpoint was met in this randomized clinical trial. The mOS was 3.5 months longer in the ChemoID assay-guided group vs the physician-choice group demonstrating the clinical advantage of treating HGG patients using CSC personalized therapy. Citation Format: Tulika Ranjan, Soma Sengupta, Alexander Yu, Candace M. Howard, Ricky Chen, Rekha Chaudhary, Nicholas Marko, Dawit Aregawi, Michael Glantz, Jon Glass, Richard M. Green, Christine Lu-Emerson, Aaron Mammoser, Hugh Moulding, Steven Jubelirer, Jason Schroeder, Mark Anderson, Frances Chow, Seth Lirette, Krista Denning, Anthony Alberico, Jagan Valluri, Pier Paolo Claudio. Multi-institutional randomized phase-3 trial comparing cancer stem cell-targeted vs physician-choice treatments in patients with recurrent high-grade gliomas (NCT03632135) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT224.
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- 2022
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9. CTNI-17. A PHASE 1 WITH DOSE EXPANSION/PHASE 2 STUDY OF SELINEXOR IN COMBINATION WITH STANDARD OF CARE THERAPY FOR NEWLY DIAGNOSED OR RECURRENT GLIOBLASTOMA
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Howard Colman, Frances Chow, Jatin P. Shah, Gregory Mundy, Andrew B. Lassman, Rebecca Harrison, Yasaman Damestani, Yang Liu, Vyshak Venur, Warren P. Mason, Nicholas Butowski, Minesh P. Mehta, Paul Duic, Sharon Tamir, Michael Schulder, John A. Boockvar, Kai Li, Yazmin Odia, Patrick Y. Wen, Erin M. Dunbar, Samuel Goldlust, Sharon Shacham, Scott R. Plotkin, Eric Sbar, and Priya Kumthekar
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Oncology ,Cancer Research ,medicine.medical_specialty ,Standard of care ,Temozolomide ,Bevacizumab ,business.industry ,Recurrent glioblastoma ,O-6-methylguanine-DNA methyltransferase ,Lomustine ,26th Annual Meeting & Education Day of the Society for Neuro-Oncology ,medicine.disease ,Glioma ,Internal medicine ,Troponin I ,medicine ,Neurology (clinical) ,business ,medicine.drug - Abstract
BACKGROUND Glioblastoma (GBM) is the most common and aggressive primary brain tumor with median overall survival of 15 months and 5-7 months for patients with newly diagnosed or recurrent disease (nGBM or rGBM), respectively. Selinexor is a first-in-class, oral, selective inhibitor of nuclear export which blocks exportin 1 (XPO1), forcing the nuclear retention and reactivation of tumor suppressor proteins, ultimately causing cancer cell death. Increased XPO1 expression in gliomas is associated with higher pathological grade and poorer prognosis. Consistent with these data, selinexor inhibited tumor growth and prolonged survival in an animal model of GBM. Importantly, selinexor showed encouraging intra-tumoral penetration and single-agent efficacy in rGBM (KING study). The current trial tests the hypothesis that adding selinexor to standard therapy will improve clinical outcomes for patients with nGBM or rGBM. METHODS To facilitate the successful development of new therapies, consensus recommendations are to use biomarker enrichment and flexible design that allows expansion of promising cohorts. Accordingly, this phase 1a dose finding study is followed by a phase 1b dose expansion (and ultimately by a 1:1 randomized phase 2 efficacy exploration trial) to independently evaluate: radiation + selinexor in nGBM with unmethylated MGMT promoter (Arm A), radiation + temozolomide + selinexor for nGBM with methylated MGMT promoter (Arm B), and lomustine + selinexor in rGBM (Arm C). Bevacizumab or TTField + selinexor in rGBM (Arms D & E, respectively) are being considered. The Phase 1a primary endpoint is maximum tolerated dose/recommended phase 2 dose. The phase 1b primary endpoint is PFS at 3 months against historic controls. The phase 1b dose expansion is included to evaluate preliminary efficacy before launching into a randomized phase 2 trial. Patient quality of life during the trial will be objectively measured using digital devices (e.g. smartwatch/customized smartphone app). We are currently enrolling patients nationwide. Clinical Trial Registration number: NCT04421378.
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- 2021
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10. IMMU-20. SINGLE-CELL RNASEQ OF TUMOR INFILTRATING IMMUNE CELLS FROM NEOADJUVANT ANTI-PD1 TREATED GBM PATIENTS REVEALS GLOBAL TRANSCRIPTIONAL CHANGES AND IMMUNOSUPPRESSIVE ADAPTIVE RESPONSES BY MYELOID CELLS
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Lu Sun, Joey Orpilla, Steven J. Bensinger, Frances Chow, Jeremy Reynoso, Robert M. Prins, David Nathanson, Linda M. Liau, Carolina Chavez, Jenny Kienzler, Timothy F. Cloughesy, Mildred Galvez, Richard Everson, Aaron Mochizuki, Willy Hugo, William H. Yong, and Alexander Lee
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Cancer Research ,medicine.anatomical_structure ,Immune system ,Oncology ,Cell ,Myeloid cells ,Immunology ,Cancer research ,medicine ,Neurology (clinical) ,Biology ,Anti pd1 - Abstract
INTRODUCTION Neoadjuvant anti-PD1 therapy (neo-aPD1) was previously shown to significantly increase the survival of recurrent glioblastoma patients in a small randomized clinical trial. However, neo-aPD1 alone was not curative so defining the limitations of neo-aPD1 and discovering where other immunotherapies can be used alongside neo-aPD1 is needed. METHODS To understand how immune cells in the tumor microenvironment change with neo-aPD1, we used single-cell RNAsequencing to analyze cells from 27 glioma patients (n = 105,143 cells) of which 9 patients had received neo-aPD1 (n = 33,325 cells). Using unsupervised clustering and pseudotime trajectory analysis, we characterized the transcriptional changes within immune cells and how these populations changed with therapy. RESULTS We defined the immune landscape of the glioblastoma tumor microenvironment. Compared to no immunotherapy treatment, neo-aPD1 significantly increased the ratio of T cells to myelo-monocytic cells and led to significant increases in the effector and memory T cell populations but no significant changes in myeloid cell composition. Our differential gene expression analysis of the myeloid compartment showed significant increases in interferon-γ-responsive genes and down-regulation of genes associated with M2 macrophages and MDSCs, suggestive that neo-aPD1 influences the transcriptional profile of myeloid cells in the tumor microenvironment. Interestingly, our psuedotime trajectory analysis showed that neo-aPD1 was associated with cells expressing both lymphoid and myeloid-related genes, which we theorized to actually be lymphoid-myeloid cell doublets caused by increased interactions between myeloid and lymphoid cells. These doublets were highly enriched in MHC I and II, macrophage, T cell, and T cell activation and exhaustion genes indicating that neo-aPD1 may result in some adaptive immunosuppressive mechanism by increasing these interactions. This could explain why neo-aPD1 alone is not curative for glioblastoma patients. CONCLUSIONS In total, neoadjuvant anti-PD1 therapy enhances effector T cell activity, but may concomitantly induce adaptive resistance mediated by myeloid cells in glioblastoma.
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- 2020
11. Comorbid depression in surgical cancer patients associated with non-routine discharge and readmission
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Edith Yuan, Casey A. Jarvis, Phillip A. Bonney, Li Ding, Frank J. Attenello, Frances Chow, William J. Mack, Gabriel Zada, and Anthony W. Kim
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Adult ,Male ,medicine.medical_specialty ,Databases, Factual ,Skilled Nursing ,Intermediate Care Facility ,Patient Readmission ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,Sex Factors ,Risk Factors ,Home health ,Internal medicine ,Neoplasms ,Outcome Assessment, Health Care ,medicine ,Prevalence ,Humans ,030212 general & internal medicine ,Depression (differential diagnoses) ,Aged ,Retrospective Studies ,Depressive Disorder ,business.industry ,Cancer ,Middle Aged ,medicine.disease ,Primary cancer ,Primary tumor ,Patient Discharge ,Oncology ,030220 oncology & carcinogenesis ,Surgery ,Female ,business - Abstract
To characterize the rates of depression across primary cancer sites, and determine the effects of comorbid depression among surgical cancer patients on established quality of care indicators, non-routine discharge and readmission.Patients undergoing surgical resection for cancer were selected from the Nationwide Readmissions Database (2010-2014). Multivariable analysis adjusted for patient and hospital level characteristics to ascertain the effect of depression on post-operative outcomes and 30-day readmission rates. Non-routine discharge encompasses discharge to skilled nursing, inpatient rehabilitation, and intermediate care facilities, as well as discharge home with home health services.Among 851,606 surgically treated cancer patients, 8.1% had a comorbid diagnosis of depression at index admission (n = 69,174). Prevalence of depression was highest among patients with cancer of the brain (10.9%), female genital organs (10.9%), and lung (10.5%), and lowest among those with prostate cancer (4.9%). Depression prevalence among women (10.9%) was almost twice that of men (5.7%). Depression was associated with non-routine discharge after surgery (OR 1.20, CI:1.18-1.23, p 0.0001*) and hospital readmission within 30 days (OR 1.12, CI:1.09-1.15, p 0.001*).Rates of depression vary amongst surgically treated cancer patients by primary tumor site. Comorbid depression in these patients is associated with increased likelihood of non-routine discharge and readmission.
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- 2020
12. TAMI-01. NEOADJUVANT PD-1 ANTIBODY BLOCKADE REMODELS THE IMMUNE MICROENVIRONMENT OF METASTATIC BRAIN TUMORS
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Won Kim, Frances Chow, Richard Everson, William H. Yong, Lu Sun, Alexander Lee, Jenny Kienzler, Willy Hugo, Carolina Chavez, and Robert M. Prins
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Cancer Research ,Oncology ,biology ,business.industry ,Immune microenvironment ,biology.protein ,Cancer research ,Medicine ,Tumor Microenvironment/Angiogenesis/Metabolism/Invasion ,Neurology (clinical) ,Antibody ,business ,Blockade - Abstract
Brain metastases (BM) commonly arise in patients with melanoma, lung, and breast cancer. Currently, there are limited options for GBM and BM patients who have failed the first-line standard treatment, underscoring the importance of developing new therapeutic strategies. Last year, we and other groups evaluated the neoadjuvant timing of anti-PD-1 checkpoint blockade therapy in recurrent GBM (rGBM) patients, which resulted in a modest survival benefit. In light of the known effectiveness of anti-PD-1 as a systemic therapy to control melanoma and non-small cell lung cancer BM, we set out to study the anti-tumor immune response of BM patients to anti-PD-1 in the neoadjuvant setting. We posited that neoadjuvant anti-PD-1 in patients with BM would result in a stronger antitumoral immune response, which could be quantified at the single cell level. To test this, we made use of contemporary single cell techniques, including multiplex immunofluorescence, time-of-flight mass cytometry (CyTOF) and single-cell RNA sequencing (scRNAseq), to characterize the intratumoral immune cell populations and their transcriptomic profiles. We found that neoadjuvant anti-PD-1 significantly increased the number of tumor infiltrating T lymphocytes in BM compared to rGBM (2.5 fold in BM, p= 0.02 vs. 1.4 fold in rGBM, p= 0.19). Multiplex immunofluorescence analysis of T cells in BM samples revealed a change from T cell exclusion to a diffusely infiltrating phenotype after anti-PD-1 treatment. Importantly, BM showed a higher fraction of effector/cytotoxic T cells compared to rGBM (7.3% vs. 0.9% of lymphoid cells, p= 0.005) and anti-PD-1 further enhanced this population. In the myeloid compartment of BM, neoadjuvant anti-PD-1 increased the frequency of HLA-DR+CD206- M1-like macrophages, implicating a pro-inflammatory microenvironment. In summary, our study delineated the immune cell subtypes altered by neoadjuvant anti-PD-1 and offers insights into new combination therapies that can help understand the clinical efficacy of immunotherapy for BM and GBM patients.
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- 2020
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13. Targeted next-generation sequencing of 565 neuro-oncology patients at UCLA: A single-institution experience
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Stephanie Pan, Thomas J Lai, Matthew Ji, Frances Chow, Sean T Pianka, Phioanh L. Nghiemphu, Bryan Kevan, Linda M. Liau, Devin N Reeh, Christopher D Cox, Nhung T Nguyen, Regina Liu, Tie Li, William H. Yong, Timothy F. Cloughesy, Albert Lai, Blaine S C Eldred, Donna Molaie, and Gang Li
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Concordance ,PALB2 ,Clinical Investigations ,DNA sequencing ,03 medical and health sciences ,Rare Diseases ,0302 clinical medicine ,targeted next-generation sequencing ,Clinical Research ,Internal medicine ,Glioma ,glioma ,medicine ,CNS TUMORS ,Medical diagnosis ,Cancer ,screening and diagnosis ,Proportional hazards model ,business.industry ,Neurosciences ,glioblastoma ,CNS tumors ,medicine.disease ,Brain Disorders ,4.1 Discovery and preclinical testing of markers and technologies ,3. Good health ,Brain Cancer ,Detection ,Good Health and Well Being ,030104 developmental biology ,030220 oncology & carcinogenesis ,genomic profiling ,business ,4.2 Evaluation of markers and technologies ,Glioblastoma - Abstract
Background Targeted next-generation sequencing (NGS) is frequently obtained at the University of California, Los Angeles (UCLA) for clinical characterization of CNS tumors. In this study, we describe the diagnostic reliability of the Foundation Medicine (FM) targeted NGS platform and its ability to explore and identify tumor characteristics of prognostic significance in gliomas. Methods Neuro-oncology patients seen at UCLA who have received FM testing between August 2012 and March 2019 were included in this study, and all mutations from FM test reports were recorded. Initial tumor diagnoses and diagnostic markers found via standard clinical methods were obtained from pathology reports. With overall and progression-free survival data, elastic net regularized Cox regression and Cox proportional hazards models were used to determine whether any mutations of unknown significance detected by FM could predict patient outcome in glioblastoma (GBM). Results Six hundred and three samples tested by FM from 565 distinct patients were identified. Concordance of diagnostic markers was high between standard clinical testing methods and FM. Oligodendroglial markers detected via FM were highly correlated with 1p19q codeletion in IDH mutated gliomas. FM testing of multiple tumor samples from the same patient demonstrated temporal and spatial mutational heterogeneity. Mutations in BCORL1, ERBB4, and PALB2, which are mutations of unknown significance in GBM, were shown to be statistically significant in predicting patient outcome. Conclusions In our large cohort, we found that targeted NGS can both reliably and efficiently detect important diagnostic markers in CNS tumors.
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- 2020
14. IMMU-02. NEOANTIGENS ARISING FROM ALTERNATIVE SPLICING EVENTS MAY BE TARGETED BY TUMOR INFILTRATING LYMPHOCYTES IN GLIOBLASTOMAS
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Frances Chow, Robert M. Prins, Anthony C. Wang, Linda M. Liau, Alexander Lee, Aaron Mochizuki, Richard Everson, Yi Xing, Mildred Galvez, David Nathanson, and Yang Pan
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Cancer Research ,integumentary system ,Tumor-infiltrating lymphocytes ,medicine.medical_treatment ,Alternative splicing ,Immunology ,Cancer ,Immunotherapy ,Human leukocyte antigen ,Biology ,medicine.disease ,Immune system ,Oncology ,Antigen ,RNA splicing ,medicine ,Cancer research ,Neurology (clinical) - Abstract
INTRODUCTION Alternative splicing, the cellular process that converts premature mRNA to mature mRNA and allows for single genes to produce multiple protein products, is frequently dysregulated in many cancers, including glioblastoma. However, along with non-synonymous mutations in the DNA, altered splicing mechanisms in cancers may produce novel antigens (so-called neoantigens) that distinguish cancer cells from healthy cells and can thus be targeted by the immune system. METHODS We developed a new computation pipeline (IRIS – Isoform peptides from RNA splicing for Immunotherapy targets Screening) that took bulk RNA-sequencing data from 23 glioblastoma patient tumor samples and predicted neoantigens that may arise from alternative splicing events. We prioritized predicted neoantigens that arose in HLA*A02:01 and HLA*A03:01 patients and selected 8 potential neoantigens to generate peptide:MHC Class 1 dextramers. We tested PBMCs and/or ex vivo expanded tumor infiltrating lymphocytes (TIL) from 6 of our glioblastoma patients against these dextramers, sorted for any neoantigen-reactive T cells, and performed single-cell RNAsequencing on the sorted population to determine the TCR sequence. RESULTS Among the 8 predicted neoantigens tested, 7 of the neoantigens were recognized by at least 1 patient’s T cells. 1 HLA*A03:01 epitope was recognized in 3 of the 4 HLA*A03:01 patients tested and this epitope was highly positive in an expanded TIL population, representing 1.7% of all CD3+ CD8+ cells. When we sorted for those neoantigen reactive T cells from the expanded TIL population and performed single-cell RNAsequencing, we found 325 unique T cell clonotypes, but the top 10 clonotypes represented 83.6% of all TCR clonotypes. The most frequent TCR clonotype represented 39.1% of the repertoire and suggests that clonal expansion of a select few TCR clones occurred within the tumor. CONCLUSIONS In total, our data indicates that neoantigens arising from alternative splicing events may represent a potential target for immunotherapy in glioblastoma.
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- 2019
15. TMIC-06. MYELOID POPULATIONS AND THE EFFECT OF NEOADJUVANT PD-1 INHIBITION IN THE GLIOBLASTOMA MICROENVIRONMENT: A SURFACEOMIC AND TRANSCRIPTOMIC DISSECTION AT THE SINGLE-CELL LEVEL
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Robert M. Prins, Joey Orpilla, Mildred Galvez, Tom B. Davidson, Alexander Lee, Jenny Kienzler, Timothy F. Cloughesy, Linda M. Liau, Aaron Mochizuki, Anthony C. Wang, Frances Chow, and Richard Everson
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Cancer Research ,Myeloid ,Cell cycle checkpoint ,medicine.medical_treatment ,Melanoma ,Pembrolizumab ,Immunotherapy ,Biology ,medicine.disease ,Transcriptome ,medicine.anatomical_structure ,Cytokine ,Oncology ,medicine ,Cancer research ,Tumor Microenvironment ,Neurology (clinical) ,Neoadjuvant therapy - Abstract
INTRODUCTION Glioblastoma (GBM) is the most common malignant brain tumor in adults and is associated with a dismal prognosis. Neoadjuvant anti-PD-1 blockade has demonstrated efficacy in melanoma, non-small cell lung cancer and recurrent GBM; however, responses vary. While T cells have garnered considerable attention in the context of immunotherapy, the role of myeloid cells in the GBM microenvironment remains controversial. METHODS We isolated CD45+ immune populations from patients who underwent brain tumor resection at UCLA. We hypothesized that myeloid cells in glioblastoma contribute to T cell dysfunction; however, this immune suppression can be mitigated by neoadjuvant PD-1 inhibition. To test this, we utilized mass cytometry and single-cell RNA sequencing to characterize these immune populations. RESULTS Mass cytometry profiling of tumor infiltrating lymphocytes from patients with GBM demonstrated a preponderance of CD11b+ myeloid populations (75% versus 25% CD3+). At the transcriptomic level, myeloid cells in newly diagnosed GBMs exhibited decreased expression of CCL4 (loge fold change -1.18, Bonferroni-adjusted P = 1.62x10-254) and its ligands compared to anaplastic astrocytoma. In ranked gene set enrichment analysis, patients who received neoadjuvant pembrolizumab demonstrated enrichment in TNFα-, NFκB- and lipid metabolism-related gene sets by bootstrapped Kolmogorov-Smirnov test (Benjamini-Hochberg adjusted P = 4.74x10-3, 1.45x10-2 and 2.48x10-3, respectively) in tumor-associated myeloid populations. Additionally, single-cell trajectory analysis demonstrated increased CCL4 and decreased ISG15 with neoadjuvant checkpoint inhibition. CONCLUSIONS Here, we utilize mass cytometry and single-cell RNA sequencing to demonstrate the predominance and transcriptomic features of myeloid populations in GBM. Myeloid cells in patients who receive neoadjuvant PD-1 blockade re-express increased levels NFκB, TNFα and CCL4, a cytokine crucial for the recruitment of dendritic cells to the tumor for antigen-specific T cell activation. By delving into the GBM microenvironment at the single-cell level, we hope to better delineate the role of myeloid populations in this uniformly fatal tumor.
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- 2019
16. ATIM-16. VALIDATION OF RESPONSE TO NEOADJUVANT ANTI-PD-1 IMMUNOTHERAPY IN RECURRENT GLIOBLASTOMA
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Timothy F. Cloughesy, Mildred Galvez, Robert M. Prins, Richard Everson, Frances Chow, Joey Orpilla, Alexander Lee, Linda M. Liau, and Aaron Mochizuki
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Adult Clinical Trials–Immunologic ,Recurrent glioblastoma ,medicine.medical_treatment ,Anti pd 1 ,Pembrolizumab ,Immunotherapy ,Tumor excision ,Internal medicine ,medicine ,Combined Modality Therapy ,Neurology (clinical) ,Progression-free survival ,business ,Neoadjuvant therapy - Abstract
BACKGROUND Recurrent glioblastoma has a poor median overall survival despite multimodal treatment. The use of pembrolizumab, an anti-PD-1 monoclonal antibody, demonstrates promise, including improved overall survival and increased immune response, when used in the neoadjuvant setting. METHODS We evaluated 13 patients with surgically accessible recurrent glioblastoma who were treated at the University of California, Los Angeles with neoadjuvant checkpoint inhibition prior to tumor resection. Combining data with our previously published multi-center study, we followed this cohort prospectively, performing tumor gene expression to validate the immune response and improved survival following neoadjuvant therapy with pembrolizumab. RESULTS When combined with findings from our prior study, patients in the neoadjuvant group (n = 27) had an overall survival of 400 days, whereas those in the adjuvant-only group (n = 19) had a median overall survival of 228 days by Kaplan-Meier estimator (P = 0.029, log-rank test). Progression-free survival in the neoadjuvant group was 108 days, whereas in the adjuvant-only group it was 72.5 days (P = 0.017, log-rank test). In elastic net penalized Cox proportional hazards regression, neoadjuvant anti-PD-1 blockade continued to be associated with improved overall survival, with a hazard ratio of 0.11 (P=0.003, log-rank test). Bulk tumor gene expression corroborates our previously described pattern of increased T-cell- and IFN-g-related gene expression, decreased cell-cycle-related signatures and their association with clinical response. Additionally, epigenetic regulation inversely correlated with clinical response. CONCLUSIONS Our findings support the neoadjuvant timing of PD-1 blockade in enhancing local immune responses and prolonging overall- and progression-free-survival. Correlative biological studies suggest a potential role for cell-cycle-related gene expression as a biomarker to predict response to therapy. Continued data collection and the addition of patients to the neoadjuvant arm of the trial, will be crucial to determine the potential role of checkpoint inhibition in the treatment of this deadly disease.
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- 2019
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17. Patterns of long-term survivorship following bevacizumab treatment for recurrent glioma: a case series
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Albert Lai, Benjamin M. Ellingson, Frances Chow, Matthew Ji, Richard M. Green, Phioanh L. Nghiemphu, Linda M. Liau, Sean T Pianka, Donna Molaie, Liang Yen Liu, Nhung T Nguyen, and Timothy F. Cloughesy
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Adult ,Male ,Oncology ,medicine.medical_specialty ,Long Term Survivorship ,recurrence ,Bevacizumab ,Angiogenesis Inhibitors ,bevacizumab ,Recurrent Glioma ,California ,Cohort Studies ,Young Adult ,Rare Diseases ,glioma ,Internal medicine ,Glioma ,medicine ,Humans ,Case Series ,Survivors ,Retrospective Studies ,Aged ,Cancer ,relapse ,Series (stratigraphy) ,business.industry ,glioblastoma ,Neurosciences ,General Medicine ,Middle Aged ,medicine.disease ,Brain Disorders ,Large cohort ,Brain Cancer ,Neoplasm Recurrence ,Treatment Outcome ,Local ,survivor ,Female ,long term ,lipids (amino acids, peptides, and proteins) ,progression ,Neoplasm Recurrence, Local ,business ,medicine.drug ,Glioblastoma - Abstract
Aim: Long-term survivors (LTS)after glioma recurrence while on bevacizumab (Bev)therapy are rarely reported in the current literature. The purpose of this case series is to confirm the existence of and describe a large cohort of recurrent glioma LTS treated with Bev (Bev-LTS). Patients & methods: We identified Bev-LTS as patients with post-Bev initiation survival times of ≥3 years among 1397 Bev treated recurrent glioma patients. Results: Among 962 grade-IV,221 grade III, and214 grade II Bev-treated glioma patients, we identified 28 (2.9%),14 (6.3%) and8(3.7%)Bev-LTS patients, respectively. 45Bev-LTS patients recurred on Bev, with 36 of those patients continuing therapy.Conclusion: Our study shows that a small portion of grade-IV, -III,and -II glioma patients can have long-term survival on Bev therapy even after Bev recurrence.
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- 2019
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18. Temozolomide and Other Potential Agents for the Treatment of Glioblastoma Multiforme
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Daniel T. Nagasawa, Frances Chow, Andrew Yew, Isaac Yang, Won Kim, and Nicole Cremer
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Oncology ,medicine.medical_specialty ,Standard of care ,Bevacizumab ,Internal medicine ,Temozolomide ,Humans ,Medicine ,Treatment resistance ,Antineoplastic Agents, Alkylating ,Survival rate ,Brain Neoplasms ,business.industry ,General Medicine ,medicine.disease ,Dacarbazine ,Treatment Outcome ,Surgery ,Neurology (clinical) ,Glioblastoma ,business ,Stage iv ,Median survival ,medicine.drug - Abstract
This article provides historical and recent perspectives related to the use of temozolomide for the treatment of glioblastoma multiforme. Temozolomide has quickly become part of the standard of care for the modern treatment of stage IV glioblastoma multiforme since its approval in 2005. Yet despite its improvements from previous therapies, median survival remains approximately 15 months, with a 2-year survival rate of 8% to 26%. The mechanism of action of this chemotherapeutic agent, conferred advantages and limitations, treatment resistance and rescue, and potential targets of future research are discussed.
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- 2012
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19. Molecular characteristics and pathways of Avastin for the treatment of glioblastoma multiforme
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Marko Spasic, Frances Chow, Isaac Yang, Daniel T. Nagasawa, and Claire Tu
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Oncology ,Vascular Endothelial Growth Factor A ,medicine.medical_specialty ,genetic structures ,Bevacizumab ,medicine.medical_treatment ,Angiogenesis Inhibitors ,Antibodies, Monoclonal, Humanized ,Disease-Free Survival ,Food and drug administration ,Internal medicine ,medicine ,Humans ,Adverse effect ,Chemotherapy ,business.industry ,Brain Neoplasms ,General Medicine ,medicine.disease ,Primary tumor ,Gene Expression Regulation, Neoplastic ,Invasive phenotype ,Monoclonal ,Surgery ,Neurology (clinical) ,Neoplasm Recurrence, Local ,business ,Glioblastoma ,medicine.drug - Abstract
This article provides historical background and current research involving the use of bevacizumab for the treatment of recurrent glioblastoma. Although bevacizumab, approved by the Food and Drug Administration, prolongs glioblastoma progression free survivial, decreases tumor vascularization, and reduces permeability of vessels, it does not seem to prolong overall survival. Despite slowed primary tumor progression, bevacizumab treatment may facilitate transformation to a more invasive phenotype. Adaptive responses, which make glioblastoma particularly resistant to various treatment modalities have been described. Conferred benefits, adverse effects, mechanisms of resistance, and potential areas for future research are discussed.
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- 2012
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