Publications by authors named "John F De Groot"

96 Publications

Report of National Brain Tumor Society Roundtable Workshop on Innovating Brain Tumor Clinical Trials: Building on Lessons Learned from COVID-19 Experience.

Neuro Oncol 2021 Apr 2. Epub 2021 Apr 2.

Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

On July 24, 2020, a workshop sponsored by the National Brain Tumor Society was held on innovating brain tumor clinical trials based on lessons learned from the COVID-19 experience. Various stakeholders from the brain tumor community participated including the US Food and Drug Administration (FDA), academic and community clinicians, researchers, industry, clinical research organizations, patients and patient advocates, and representatives from the Society for Neuro-Oncology and the National Cancer Institute. This report summarizes the workshop and proposes ways to incorporate lessons learned from COVID-19 to brain tumor clinical trials including the increased use of telemedicine and decentralized trial models as opportunities for practical innovation with potential long-term impact on clinical trial design and implementation.
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http://dx.doi.org/10.1093/neuonc/noab082DOI Listing
April 2021

The promise of DNA damage response inhibitors for the treatment of glioblastoma.

Neurooncol Adv 2021 Jan-Dec;3(1):vdab015. Epub 2021 Feb 4.

Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Glioblastoma (GBM), the most aggressive primary brain tumor, has a dismal prognosis. Despite our growing knowledge of genomic and epigenomic alterations in GBM, standard therapies and outcomes have not changed significantly in the past two decades. There is therefore an urgent unmet need to develop novel therapies for GBM. The inter- and intratumoral heterogeneity of GBM, inadequate drug concentrations in the tumor owing to the blood-brain barrier, redundant signaling pathways contributing to resistance to conventional therapies, and an immunosuppressive tumor microenvironment, have all hindered the development of novel therapies for GBM. Given the high frequency of DNA damage pathway alterations in GBM, researchers have focused their efforts on pharmacologically targeting key enzymes, including poly(ADP-ribose) polymerase (PARP), DNA-dependent protein kinase, ataxia telangiectasia-mutated, and ataxia telangiectasia and Rad3-related. The mainstays of GBM treatment, ionizing radiation and alkylating chemotherapy, generate DNA damage that is repaired through the upregulation and activation of DNA damage response (DDR) enzymes. Therefore, the use of PARP and other DDR inhibitors to render GBM cells more vulnerable to conventional treatments is an area of intense investigation. In this review, we highlight the growing body of data behind DDR inhibitors in GBM, with a focus on putative predictive biomarkers of response. We also discuss the challenges involved in the successful development of DDR inhibitors for GBM, including the intracranial location and predicted overlapping toxicities of DDR agents with current standards of care, and propose promising strategies to overcome these hurdles.
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http://dx.doi.org/10.1093/noajnl/vdab015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954093PMC
February 2021

A Prospective Phase II Randomized Trial of Proton Radiotherapy vs. Intensity Modulated Radiotherapy for Patients with Newly Diagnosed Glioblastoma.

Neuro Oncol 2021 Feb 27. Epub 2021 Feb 27.

Deptartment of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: To determine if proton radiotherapy (PT), compared to intensity modulated radiotherapy (IMRT), delayed time to cognitive failure in patients with newly diagnosed glioblastoma.

Methods: Eligible patients were randomized unblinded to PT vs. IMRT. The primary endpoint was time to cognitive failure. Secondary endpoints included overall survival (OS), intracranial progression-free survival (PFS), toxicity, and patient-reported outcomes.

Results: A total of 90 patients were enrolled and 67 were evaluable with median follow-up of 48.7 months (range 7.1-66.7). There was no significant difference in time to cognitive failure between treatment arms (HR, 0.88; 95% CI, 0.45 to 1.75; P=0.74). PT was associated with a lower rate of fatigue (24% vs. 58%, P=0.05), but otherwise there were no significant differences in patient-reported outcomes at 6 months. There was no difference in PFS (HR, 0.74; 95% CI, 0.44 to 1.23; P=0.24) or OS (HR, 0.86; 95% CI, 0.49 to 1.50; P=0.60). However, PT significantly reduced the radiation dose for nearly all structures analyzed. The average number of grade 2 or higher toxicities was significantly higher in patients who received IMRT (mean 1.15, range 0-6) compared to PT (mean 0.35, range 0-3; P=0.02).

Conclusions: In this signal seeking phase II trial, PT was not associated with a delay in time to cognitive failure but did reduce toxicity and patient reported fatigue. Larger randomized trials are needed to determine the potential of PT such as dose escalation for glioblastoma and cognitive preservation in patients with lower grade gliomas with a longer survival time.
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http://dx.doi.org/10.1093/neuonc/noab040DOI Listing
February 2021

PARP mediated PARylation of MGMT is critical to promote repair of temozolomide-induced O6-methylguanine DNA damage in glioblastoma.

Neuro Oncol 2021 Jan 12. Epub 2021 Jan 12.

Department of Neuro-Oncology, Brain Tumor Center, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Background: Temozolomide (TMZ) resistance in Glioblastoma (GBM) is mediated by the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). MGMT promoter methylation (occurs in about 40% patients) is associated with loss of MGMT expression (MGMT-) that compromises DNA repair, leading to a favorable response to TMZ therapy. The 60% of patients with unmethylated MGMT (MGMT+) GBM experience resistance to TMZ; in these patients, understanding the mechanism of MGMT mediated repair and modulating MGMT activity may lead to enhanced TMZ activity. Here, we report a novel mode of regulation of MGMT protein activity by poly-ADP-ribose polymerase (PARP).

Methods: MGMT-PARP interaction was detected by co-immunoprecipitation (IP). PARylation of MGMT and PARP was detected by co-immunoprecipitation with anti-PAR antibody. O 6-methylguanine (O 6-MetG) adducts were quantified by immunofluorescence assay. In vivo studies were conducted in mice to determine the effectiveness of PARP inhibition in sensitizing GBM to TMZ.

Results: We demonstrated that PARP physically binds with MGMT and PARylates MGMT in response to TMZ treatment. In addition, PARylation of MGMT by PARP is required for MGMT binding to chromatin to enhance the removal of O 6-MetG adducts from DNA after TMZ treatment. PARP inhibitors reduced PARP-MGMT binding and MGMT PARylation, silencing MGMT activity to repair O 6-MetG. PARP inhibition restored TMZ sensitivity in vivo in MGMT expressing GBM.

Conclusion: This study demonstrated that PARylation of MGMT by PARP is critical for repairing TMZ-induced O6-MetG, and inhibition of PARylation by PARP inhibitor reduces MGMT function rendering sensitization to TMZ, providing a rationale for combining PARP inhibitors to sensitize TMZ in MGMT unmethylated GBM.
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http://dx.doi.org/10.1093/neuonc/noab003DOI Listing
January 2021

A validated integrated clinical and molecular glioblastoma long-term survival-predictive nomogram.

Neurooncol Adv 2021 Jan-Dec;3(1):vdaa146. Epub 2020 Oct 31.

Departments of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Background: Glioblastoma (GBM) is the most common primary malignant brain tumor in adulthood. Despite multimodality treatments, including maximal safe resection followed by irradiation and chemotherapy, the median overall survival times range from 14 to 16 months. However, a small subset of GBM patients live beyond 5 years and are thus considered long-term survivors.

Methods: A retrospective analysis of the clinical, radiographic, and molecular features of patients with newly diagnosed primary GBM who underwent treatment at The University of Texas MD Anderson Cancer Center was conducted. Eighty patients had sufficient quantity and quality of tissue available for next-generation sequencing and immunohistochemical analysis. Factors associated with survival time were identified using proportional odds ordinal regression. We constructed a survival-predictive nomogram using a forward stepwise model that we subsequently validated using The Cancer Genome Atlas.

Results: Univariate analysis revealed 3 pivotal genetic alterations associated with GBM survival: both high tumor mutational burden ( = .0055) and mutations ( = .0235) negatively impacted survival, whereas mutations positively impacted survival ( < .0001). Clinical factors significantly associated with GBM survival included age ( < .0001), preoperative Karnofsky Performance Scale score ( = .0001), sex ( = .0164), and clinical trial participation ( < .0001). Higher preoperative T1-enhancing volume ( = .0497) was associated with shorter survival. The ratio of TI-enhancing to nonenhancing disease (T1/T2 ratio) also significantly impacted survival ( = .0022).

Conclusions: Our newly devised long-term survivalpredictive nomogram based on clinical and genomic data can be used to advise patients regarding their potential outcomes and account for confounding factors in nonrandomized clinical trials.
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http://dx.doi.org/10.1093/noajnl/vdaa146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780842PMC
October 2020

Depletion of CLK2 sensitizes glioma stem-like cells to PI3K/mTOR and FGFR inhibitors.

Am J Cancer Res 2020 1;10(11):3765-3783. Epub 2020 Nov 1.

Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center Houston, Texas, USA.

The Cdc2-like kinases (CLKs) regulate RNA splicing and have been shown to suppress cell growth. Knockdown of CLK2 was found to block glioma stem-like cell (GSC) growth through the AKT/FOXO3a/p27 pathway without activating mTOR and MAPK signaling, suggesting that these pathways mediate resistance to CLK2 inhibition. We identified CLK2 binding partners using immunoprecipitation assays and confirmed their interactions in GSCs. We then tested the cellular viability of several signaling inhibitors in parental and CLK2 knockdown GSCs. Our results demonstrate that CLK2 binds to 14-3-3τ isoform and prevents its ubiquitination in GSCs. Stable CLK2 knockdown increased PP2A activity and activated PI3K signaling. Treatment with a PI3K/mTOR inhibitor in CLK2 knockdown cells led to a modest reduction in cell viability compared to drug treatment alone at a lower dose. However, FGFR inhibitor in CLK2 knockdown cells led to a decrease in cell viability and increased apoptosis. Reduced expression of CLK2 in glioblastoma, in combination with FGFR inhibitors, led to synergistic apoptosis induction and cell cycle arrest compared to blockade or either kinase alone.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716149PMC
November 2020

Proton therapy reduces the likelihood of high-grade radiation-induced lymphopenia in glioblastoma patients: phase II randomized study of protons vs photons.

Neuro Oncol 2021 02;23(2):284-294

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: We investigated differences in radiation-induced grade 3+ lymphopenia (G3+L), defined as an absolute lymphocyte count (ALC) nadir of <500 cells/µL, after proton therapy (PT) or X-ray (photon) therapy (XRT) for patients with glioblastoma (GBM).

Methods: Patients enrolled in a randomized phase II trial received PT (n = 28) or XRT (n = 56) concomitantly with temozolomide. ALC was measured before, weekly during, and within 1 month after radiotherapy. Whole-brain mean dose (WBMD) and brain dose-volume indices were extracted from planned dose distributions. Univariate and multivariate logistic regression analyses were used to identify independent predictive variables. The resulting model was evaluated using receiver operating characteristic (ROC) curve analysis.

Results: Rates of G3+L were lower in men (7/47 [15%]) versus women (19/37 [51%]) (P < 0.001), and for PT (4/28 [14%]) versus XRT (22/56 [39%]) (P = 0.024). G3+L was significantly associated with baseline ALC, WBMD, and brain volumes receiving 5‒40 Gy(relative biological effectiveness [RBE]) or higher (ie, V5 through V40). Stepwise multivariate logistic regression analysis identified being female (odds ratio [OR] 6.2, 95% confidence interval [CI]: 1.95‒22.4, P = 0.003), baseline ALC (OR 0.18, 95% CI: 0.05‒0.51, P = 0.003), and whole-brain V20 (OR 1.07, 95% CI: 1.03‒1.13, P = 0.002) as the strongest predictors. ROC analysis yielded an area under the curve of 0.86 (95% CI: 0.79-0.94) for the final G3+L prediction model.

Conclusions: Sex, baseline ALC, and whole-brain V20 were the strongest predictors of G3+L for patients with GBM treated with radiation and temozolomide. PT reduced brain volumes receiving low and intermediate doses and, consequently, reduced G3+L.
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http://dx.doi.org/10.1093/neuonc/noaa182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906048PMC
February 2021

Glioblastoma-mediated Immune Dysfunction Limits CMV-specific T Cells and Therapeutic Responses: Results from a Phase I/II Trial.

Clin Cancer Res 2020 07 16;26(14):3565-3577. Epub 2020 Apr 16.

Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Purpose: Cytomegalovirus (CMV) antigens occur in glioblastoma but not in normal brains, making them desirable immunologic targets.

Patients And Methods: Highly functional autologous polyclonal CMV pp65-specific T cells from patients with glioblastoma were numerically expanded under good manufacturing practice compliant conditions and administered after 3 weeks of lymphodepleting dose-dense temozolomide (100 mg/m) treatment. The phase I component used a 3+3 design, ascending through four dose levels (5 × 10-1 × 10 cells). Treatment occurred every 6 weeks for four cycles. persistence and effector function of CMV-specific T cells was determined by dextramer staining and multiparameter flow cytometry in serially sampled peripheral blood and in the tumor microenvironment.

Results: We screened 65 patients; 41 were seropositive for CMV; 25 underwent leukapheresis; and 20 completed ≥1 cycle. No dose-limiting toxicities were observed. Radiographic response was complete in 1 patient, partial in 2. Median progression-free survival (PFS) time was 1.3 months [95% confidence interval (CI), 0-8.3 months]; 6-month PFS was 19% (95% CI, 7%-52%); and median overall survival time was 12 months (95% CI, 6 months to not reached). Repeated infusions of CMV-T cells paralleled significant increases in circulating CMV CD8 T cells, but cytokine production showing effector activity was suppressed, especially from T cells obtained directly from glioblastomas.

Conclusions: Adoptive infusion of CMV-specific T cells after lymphodepletion with dose-dense temozolomide was well tolerated. But apparently CMV seropositivity does not guarantee tumor susceptibility to CMV-specific T cells, suggesting heterogeneity in CMV antigen expression. Moreover, effector function of these T cells was attenuated, indicating a requirement for further T-cell modulation to prevent their dysfunction before conducting large-scale clinical studies.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0176DOI Listing
July 2020

Role of Neutrophils and Myeloid-Derived Suppressor Cells in Glioma Progression and Treatment Resistance.

Int J Mol Sci 2020 Mar 13;21(6). Epub 2020 Mar 13.

Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.

Recent efforts in brain tumor research have been directed towards the modulation of the immune system for therapeutic interventions. Several human cancers, including gliomas, are infiltrated with immune cell types-including neutrophils and myeloid-derived suppressor cells-that contribute to tumor progression, invasiveness, and treatment resistance. The role of tumor-associated neutrophils and myeloid-derived suppressor cells in cancer biology remains elusive, as these cells can exert a multitude of pro-tumor and antitumor effects. In this review, we provide the current understanding and novel insights on the role of neutrophils and myeloid-derived suppressor cells in glioma progression and treatment resistance, as well as the mechanisms of pleiotropic behaviors in these cells during disease progression, with an emphasis on possible strategies to reprogram these cells towards their antitumor actions.
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http://dx.doi.org/10.3390/ijms21061954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139844PMC
March 2020

Impact of adverse events of bevacizumab on survival outcomes of patients with recurrent glioblastoma.

J Clin Neurosci 2020 Apr 23;74:36-40. Epub 2020 Jan 23.

Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.

Background: Bevacizumab is widely used for treatment of recurrent glioblastoma (rGB). It is well known that adverse events (AEs) due to bevacizumab can cause early discontinuation of treatment. However, the association between AEs and survival outcomes is not well defined.

Methods: We retrospectively identified patients with rGB, who were treated with single-agent bevacizumab or bevacizumab-based combination regimens from 07/2005 through 07/2014, and who discontinued bevacizumab due to either AEs or physician's decision. Those who discontinued bevacizumab because of tumor progression were excluded. Demographic, treatment, and survival data were collected from the database.

Results: Of 298 adults with rGB treated with bevacizumab in our database, 65 patients discontinued bevacizumab due to AEs (n = 39, 60%) or physician's decision (n = 26, 40%). There were no statistically significant differences in regards to age, performance status, extent of resection, number of lesions, the time between diagnosis and first recurrence, time between diagnosis and initiation of bevacizumab, number of recurrences before bevacizumab initiation, and duration of bevacizumab treatment between the two groups. Interestingly, patients who discontinued bevacizumab because of AEs progressed earlier after bevacizumab discontinuation (3.9 months vs 5.7 months; p = 0.02), had significantly shorter progression-free survival (PFS) (10.4 months vs 14.2 months; p = 0.01) and shorter overall survival (OS) from bevacizumab initiation (13.9 months vs 32.5 months; p = 0.01) as well as shorter OS from tumor diagnosis (20 months vs 49.3 months; p = 0.007) when compared to patients who discontinued bevacizumab due to a physician's decision.

Conclusions: Our results indicate that the development of AEs to bevacizumab or bevacizumab-containing regimens is associated with unfavorable glioma-related survival outcomes in patients with rGB.
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http://dx.doi.org/10.1016/j.jocn.2020.01.066DOI Listing
April 2020

Amplification Induces Increased DNA Damage Response and Renders Selective Sensitivity to Talazoparib (PARP Inhibitor) in Glioblastoma.

Clin Cancer Res 2020 03 18;26(6):1395-1407. Epub 2019 Dec 18.

Department of Neuro-Oncology, Brain Tumor Center, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Purpose: Exploration of novel strategies to extend the benefit of PARP inhibitors beyond -mutant cancers is of great interest in personalized medicine. Here, we identified amplification as a potential biomarker to predict sensitivity to PARP inhibition, providing selection for the glioblastoma (GBM) patient population who will benefit from PARP inhibition therapy.

Experimental Design: Selective sensitivity to the PARP inhibitor talazoparib was screened and validated in two sets [test set ( = 14) and validation set ( = 13)] of well-characterized patient-derived glioma sphere-forming cells (GSC). FISH was used to detect copy number. DNA damage response following talazoparib treatment was evaluated by γH2AX and 53BP1 staining and neutral comet assay. PARP-DNA trapping was analyzed by subcellular fractionation. The selective monotherapy of talazoparib was confirmed using glioma models.

Results: -amplified GSCs showed remarkable sensitivity to talazoparib treatment. amplification was associated with increased reactive oxygen species (ROS) and subsequent increased basal expression of DNA-repair pathways to counterelevated oxidative stress, and thus rendered vulnerability to PARP inhibition. Following talazoparib treatment, -amplified GSCs showed enhanced DNA damage and increased PARP-DNA trapping, which augmented the cytotoxicity. amplification-associated selective sensitivity was further supported by the experimental results showing that talazoparib significantly suppressed tumor growth in -amplified subcutaneous models but not in nonamplified models.

Conclusions: -amplified cells are highly sensitive to talazoparib. Our data provide insight into the potential of using amplification as a selection biomarker for the development of personalized therapy.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-2549DOI Listing
March 2020

A randomized controlled phase III study of VB-111 combined with bevacizumab vs bevacizumab monotherapy in patients with recurrent glioblastoma (GLOBE).

Neuro Oncol 2020 05;22(5):705-717

Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

Background: Ofranergene obadenovec (VB-111) is an anticancer viral therapy that demonstrated in a phase II study a survival benefit for patients with recurrent glioblastoma (rGBM) who were primed with VB-111 monotherapy that was continued after progression with concomitant bevacizumab.

Methods: This pivotal phase III randomized, controlled trial compared the efficacy and safety of upfront combination of VB-111 and bevacizumab versus bevacizumab monotherapy. Patients were randomized 1:1 to receive VB-111 1013 viral particles every 8 weeks in combination with bevacizumab 10 mg/kg every 2 weeks (combination arm) or bevacizumab monotherapy (control arm). The primary endpoint was overall survival (OS), and secondary endpoints were objective response rate (ORR) by Response Assessment in Neuro-Oncology (RANO) criteria and progression-free survival (PFS).

Results: Enrolled were 256 patients at 57 sites. Median exposure to VB-111 was 4 months. The study did not meet its primary or secondary goals. Median OS was 6.8 versus 7.9 months in the combination versus control arm (hazard ratio, 1.20; 95% CI: 0.91-1.59; P = 0.19) and ORR was 27.3% versus 21.9% (P = 0.26). A higher rate of grades 3-5 adverse events was reported in the combination arm (67% vs 40%), mainly attributed to a higher rate of CNS and flu-like/fever events. Trends for improved survival with combination treatment were seen in the subgroup of patients with smaller tumors and in patients who had a posttreatment febrile reaction.

Conclusions: In this study, upfront concomitant administration of VB-111 and bevacizumab failed to improve outcomes in rGBM. Change of treatment regimen, with the lack of VB-111 monotherapy priming, may explain the differences from the favorable phase II results.

Clinical Trials Registration: NCT02511405.
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http://dx.doi.org/10.1093/neuonc/noz232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229248PMC
May 2020

The association between BMI and BSA-temozolomide-induced myelosuppression toxicities: a correlative analysis of NRG oncology RTOG 0525.

Neurooncol Pract 2019 Dec 6;6(6):473-478. Epub 2019 Apr 6.

Baptist Hospital of Miami, FL.

Background: Fearing increased myelotoxicity, many practitioners adjust the body surface area (BSA)-calculated doses in obese patients. Regarding temozolomide (TMZ), a prior study suggested men with a BSA >2 m may experience increased toxicity; however, surprisingly, the inverse observation was noted in women, ie, BSA <2 m was associated with higher toxicity. To further clarify this issue, data derived from a large clinical trial were analyzed.

Methods: The incidence of grade 3 and 4 myelotoxicity in a newly diagnosed glioblastoma phase 3 trial (RTOG 0525) was statistically correlated with BMI and separately with BSA. All patients received radiation and TMZ followed by adjuvant standard dose TMZ vs dose-dense TMZ; dosing regimen-associated myelotoxicity and BMI/BSA were analyzed separately. was defined as a BMI ≥30.

Results: There was no statistically significant correlation between gender and BSA and the occurrence of myotoxicities. For the standard arm, surprisingly the incidence of grade 3/4 myotoxicities in patients with a BMI <30 was significantly higher than in patients with a BMI ≥30 (12% vs 1%, odds ratio [OR] 12.5, < .001). There was no significant difference between obese and nonobese patients (BMI "cut-point" of 30) in the dose-dense arm (OR = 0.9, 95% confidence interval: 0.4-1.6). The grade hematological 3/4 toxicity rate was significantly higher in women vs men (14% vs 8%) = .009 in spite of the lack of association between gender and BSA or BMI.

Conclusion: TMZ dosing based on actual BSA is recommended with the caveat that woman are likely at higher toxicity risk.
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http://dx.doi.org/10.1093/nop/npz006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899045PMC
December 2019

High-risk Meningioma: Initial Outcomes From NRG Oncology/RTOG 0539.

Int J Radiat Oncol Biol Phys 2020 03 29;106(4):790-799. Epub 2019 Nov 29.

Miami Cancer Institute, Baptist Health, Miami, Florida.

Background: Phase 2 cooperative group meningioma trial assessing the safety and efficacy of risk-adaptive management strategies. This is the initial analysis of the high-risk cohort.

Methods And Materials: High-risk patients were those with a new or recurrent World Health Organization (WHO) grade III meningioma of any resection extent, recurrent WHO grade II of any resection extent, or new WHO grade II after subtotal resection. Patients received intensity-modulated radiotherapy (IMRT) using a simultaneous integrated boost technique (60 Gy high dose and 54 Gy low dose in 30 fractions). Three-year progression-free survival (PFS) was the primary endpoint. Adverse events (AEs) were scored per NCI Common Terminology Criteria for Adverse Events version 3.

Results: Of 57 enrolled patients, 53 received protocol treatment. Median follow-up was 4.0 years (4.8 years for living patients). Two patients withdrew without progression before year 3; for the remaining 51 patients, 3-year PFS was 58.8%. Among all 53 protocol-treated patients, 3-year PFS was 59.2%. Three-year local control was 68.9%, and overall survival was 78.6%. Of 51 patients, 1 patient (1.9%) experienced a late grade-5 necrosis-related AE. All other acute (23 of 53 patients) and late (21 of 51 patients) AEs were grades 1 to 3.

Conclusions: Patients with high-risk meningioma treated with IMRT (60 Gy/30) experienced 3-year PFS of 58.8%. Combined acute and late AEs were limited to grades 1 to 3, except for a single necrosis-related grade 5 event. These results support postoperative IMRT for high-risk meningioma and invite ongoing investigations to improve outcomes further.
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http://dx.doi.org/10.1016/j.ijrobp.2019.11.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7117785PMC
March 2020

Longitudinal molecular trajectories of diffuse glioma in adults.

Nature 2019 12 20;576(7785):112-120. Epub 2019 Nov 20.

The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.

The evolutionary processes that drive universal therapeutic resistance in adult patients with diffuse glioma remain unclear. Here we analysed temporally separated DNA-sequencing data and matched clinical annotation from 222 adult patients with glioma. By analysing mutations and copy numbers across the three major subtypes of diffuse glioma, we found that driver genes detected at the initial stage of disease were retained at recurrence, whereas there was little evidence of recurrence-specific gene alterations. Treatment with alkylating agents resulted in a hypermutator phenotype at different rates across the glioma subtypes, and hypermutation was not associated with differences in overall survival. Acquired aneuploidy was frequently detected in recurrent gliomas and was characterized by IDH mutation but without co-deletion of chromosome arms 1p/19q, and further converged with acquired alterations in the cell cycle and poor outcomes. The clonal architecture of each tumour remained similar over time, but the presence of subclonal selection was associated with decreased survival. Finally, there were no differences in the levels of immunoediting between initial and recurrent gliomas. Collectively, our results suggest that the strongest selective pressures occur during early glioma development and that current therapies shape this evolution in a largely stochastic manner.
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http://dx.doi.org/10.1038/s41586-019-1775-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6897368PMC
December 2019

Immune biology of glioma-associated macrophages and microglia: functional and therapeutic implications.

Neuro Oncol 2020 02;22(2):180-194

Departments of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.

CNS immune defenses are marshaled and dominated by brain resident macrophages and microglia, which are the innate immune sentinels and frontline host immune barriers against various pathogenic insults. These myeloid lineage cells are the predominant immune population in gliomas and can constitute up to 30-50% of the total cellular composition. Parenchymal microglial cells and recruited monocyte-derived macrophages from the periphery exhibit disease-specific phenotypic characteristics with spatial and temporal distinctions and are heterogeneous subpopulations based on their molecular signatures. A preponderance of myeloid over lymphoid lineage cells during CNS inflammation, including gliomas, is a contrasting feature of brain immunity relative to peripheral immunity. Herein we discuss glioma-associated macrophage and microglia immune biology in the context of their identity, molecular drivers of recruitment, nomenclature and functional paradoxes, therapeutic reprogramming and polarization strategies, relevant challenges, and our perspectives on therapeutic modulation.
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http://dx.doi.org/10.1093/neuonc/noz212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442334PMC
February 2020

Treatment strategies for glioblastoma in older patients: age is just a number.

J Neurooncol 2019 Nov 23;145(2):357-364. Epub 2019 Oct 23.

Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Unit 431, 1515 Holcombe Blvd, Houston, TX, 77030-4009, USA.

Background/purpose: Optimal care for elderly patients with glioblastoma (GBM) remains in question due to their exclusion from and underrepresentation in many clinical trials (including EORTC 22,981) as well as their historically poor overall survival.

Methods: A retrospective chart review was conducted at a single high-volume cancer center for newly diagnosed elderly (65 years old or older) GBM patients diagnosed from 2011 through 2017.

Results: A total of 158 newly diagnosed GBM patients aged 65 years and older were identified. One hundred forty-four patients (91.1%) received radiotherapy (RT) and 130 patients (90.3%) received concurrent temozolomide with RT. Sixty-one patients (38.6%) completed concurrent chemoradiation and 6 cycles of adjuvant temozolomide. 23% of patients discontinued temozolomide during concurrent or adjuvant treatment due to side effects or complications of chemotherapy. With a median follow-up time of 35.0 months, median overall survival (OS) time for the full cohort was 18.6 months, with estimated OS rates of 74.8%, 35.9%, and 9.5% at 1, 2, and 5 years, respectively. On multivariable analysis, higher KPS (p = 0.002, HR 0.46; 95% CI 0.63-0.82), completing planned RT course (p = 0.01, HR 0.29; 95% CI 0.11-0.75), and completing 6 cycles of adjuvant temozolomide (p = 0.01, HR 2.62; 95% CI 1.67-4.12) were independently associated with improved OS.

Conclusions: Our cohort of elderly GBM patients was predominantly treated with standard of care therapy based on EORTC 22,981. Despite their age, these patients generally tolerated treatment well and had favorable outcomes compared to those reported for patients treated on EORTC 22,981. Based on these findings, using advanced age as the basis for treatment de-escalation or as an exclusionary criterion in clinical trials should be discouraged.
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http://dx.doi.org/10.1007/s11060-019-03304-xDOI Listing
November 2019

Barriers to accrual and enrollment in brain tumor trials.

Neuro Oncol 2019 09;21(9):1100-1117

Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

Many factors contribute to the poor survival of malignant brain tumor patients, some of which are not easily remedied. However, one contributor to the lack of progress that may be modifiable is poor clinical trial accrual. Surveys of brain tumor patients and neuro-oncology providers suggest that clinicians do a poor job of discussing clinical trials with patients and referring patients for clinical trials. Yet, data from the Cancer Action Network of the American Cancer Society suggest that most eligible oncology patients asked to enroll on a clinical trial will agree to do so. To this end, the Society for Neuro-Oncology (SNO) in collaboration with the Response Assessment in Neuro-Oncology (RANO) Working Group, patient advocacy groups, clinical trial cooperative groups, including the Adult Brain Tumor Consortium (ABTC), and other partners are working together with the intent to double clinical trial accrual over the next 5 years. Here we describe the factors contributing to poor clinical trial accrual in neuro-oncology and offer possible solutions.
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http://dx.doi.org/10.1093/neuonc/noz104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594546PMC
September 2019

Clinical trial participation of patients with glioblastoma at The University of Texas MD Anderson Cancer Center.

Eur J Cancer 2019 05 2;112:83-93. Epub 2019 Apr 2.

Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 0431, Houston, TX 77030, USA. Electronic address:

Background: It is estimated only 8-11% of patients with glioblastoma (GBM) enrol in clinical trials, limiting treatment development. We analysed the clinical and demographic features of patients with GBM enroled in clinical trials at the University of Texas MD Anderson Cancer Center (MDACC).

Methods: We reviewed the records of adult patients treated for primary GBM between 2007 and 2012 at the MDACC. A total of 755 patients were identified: 133 were deemed non-eligible, 111 were deemed trial eligible but received standard care and 511 participated in a clinical trial (311 for newly diagnosed glioblastoma [nGBM] and 200 for recurrent glioblastoma [rGBM]). Population characteristics were analysed using descriptive statistics, and survival end-points were evaluated with the Kaplan-Meier method.

Results: The median age of clinical trial participants and trial eligible patients was 53.2 years (standard deviation 12.1). Most patients (49.4%) were enroled in a clinical trial protocol for nGBM. The majority of nGBM trial participants were male patients (65.1%), white (86.3%), married (84.4%) and in state (59.9%). Employment status, education, symptoms, tumour location, performance status, extent of resection and treatment facility differed between nGBM trial participants and non-participants. Patients who were eligible but did not enrol tended to be older, have worse performance status and live farther away from the MDACC.

Conclusion: Numerous disease and demographic barriers exist in trial enrolment in patients with GBM. This study highlights some of these obstacles, which require attention to improve patient enrolment to clinical trials. Patient and physician engagement in novel therapeutic strategies is essential to improving outcomes in this disease.
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http://dx.doi.org/10.1016/j.ejca.2019.02.007DOI Listing
May 2019

Prospective Clinical Sequencing of Adult Glioma.

Mol Cancer Ther 2019 05 29;18(5):991-1000. Epub 2019 Mar 29.

Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Malignant gliomas are a group of intracranial cancers associated with disproportionately high mortality and morbidity. Here, we report ultradeep targeted sequencing of a prospective cohort of 237 tumors from 234 patients consisting of both glioblastoma (GBM) and lower-grade glioma (LGG) using our customized gene panels. We identified 2,485 somatic mutations, including single-nucleotide substitutions and small indels, using a validated in-house protocol. Sixty-one percent of the mutations were contributed by 12 hypermutators. The hypermutators were enriched for recurrent tumors and had comparable outcome, and most were associated with temozolomide exposure. was the most frequently mutated gene in our cohort, followed by and We detected at least one mutation in 23% of LGGs, which was significantly higher than 6% seen in The Cancer Genome Atlas, a pattern that can be partially explained by the different patient composition and sequencing depth. hotspot mutations were found with higher frequencies in LGG (83%) and secondary GBM (77%) than primary GBM (9%). Multivariate analyses controlling for age, histology, and tumor grade confirm the prognostic value of mutation. We predicted 1p/19q status using the panel sequencing data and received only modest performance by benchmarking the prediction to FISH results of 50 tumors. Targeted therapy based on the sequencing data resulted in three responders out of 14 participants. In conclusion, our study suggests ultradeep targeted sequencing can recapitulate previous findings and can be a useful approach in the clinical setting.
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http://dx.doi.org/10.1158/1535-7163.MCT-18-1122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6497568PMC
May 2019

Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma.

Nat Med 2019 03 11;25(3):477-486. Epub 2019 Feb 11.

Department of Medical and Molecular Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.

Glioblastoma is the most common primary malignant brain tumor in adults and is associated with poor survival. The Ivy Foundation Early Phase Clinical Trials Consortium conducted a randomized, multi-institution clinical trial to evaluate immune responses and survival following neoadjuvant and/or adjuvant therapy with pembrolizumab in 35 patients with recurrent, surgically resectable glioblastoma. Patients who were randomized to receive neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that were randomized to receive adjuvant, post-surgical programmed cell death protein 1 (PD-1) blockade alone. Neoadjuvant PD-1 blockade was associated with upregulation of T cell- and interferon-γ-related gene expression, but downregulation of cell-cycle-related gene expression within the tumor, which was not seen in patients that received adjuvant therapy alone. Focal induction of programmed death-ligand 1 in the tumor microenvironment, enhanced clonal expansion of T cells, decreased PD-1 expression on peripheral blood T cells and a decreasing monocytic population was observed more frequently in the neoadjuvant group than in patients treated only in the adjuvant setting. These findings suggest that the neoadjuvant administration of PD-1 blockade enhances both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor.
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http://dx.doi.org/10.1038/s41591-018-0337-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6408961PMC
March 2019

Buparlisib in Patients With Recurrent Glioblastoma Harboring Phosphatidylinositol 3-Kinase Pathway Activation: An Open-Label, Multicenter, Multi-Arm, Phase II Trial.

J Clin Oncol 2019 03 4;37(9):741-750. Epub 2019 Feb 4.

1 Dana-Farber Cancer Institute, Boston, MA.

Purpose: Phosphatidylinositol 3-kinase (PI3K) signaling is highly active in glioblastomas. We assessed pharmacokinetics, pharmacodynamics, and efficacy of the pan-PI3K inhibitor buparlisib in patients with recurrent glioblastoma with PI3K pathway activation.

Methods: This study was a multicenter, open-label, multi-arm, phase II trial in patients with PI3K pathway-activated glioblastoma at first or second recurrence. In cohort 1, patients scheduled for re-operation after progression received buparlisib for 7 to 13 days before surgery to evaluate brain penetration and modulation of the PI3K pathway in resected tumor tissue. In cohort 2, patients not eligible for re-operation received buparlisib until progression or unacceptable toxicity. Once daily oral buparlisib 100 mg was administered on a continuous 28-day schedule. Primary end points were PI3K pathway inhibition in tumor tissue and buparlisib pharmacokinetics in cohort 1 and 6-month progression-free survival (PFS6) in cohort 2.

Results: Sixty-five patients were treated (cohort 1, n = 15; cohort 2, n = 50). In cohort 1, reduction of phosphorylated AKT immunohistochemistry score was achieved in six (42.8%) of 14 patients, but effects on phosphoribosomal protein S6 and proliferation were not significant. Tumor-to-plasma drug level was 1.0. In cohort 2, four (8%) of 50 patients reached 6-month PFS6, and the median PFS was 1.7 months (95% CI, 1.4 to 1.8 months). The most common grade 3 or greater adverse events related to treatment were lipase elevation (n = 7 [10.8%]), fatigue (n = 4 [6.2%]), hyperglycemia (n = 3 [4.6%]), and elevated ALT (n = 3 [4.6%]).

Conclusion: Buparlisib had minimal single-agent efficacy in patients with PI3K-activated recurrent glioblastoma. Although buparlisib achieved significant brain penetration, the lack of clinical efficacy was explained by incomplete blockade of the PI3K pathway in tumor tissue. Integrative results suggest that additional study of PI3K inhibitors that achieve more-complete pathway inhibition may still be warranted.
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http://dx.doi.org/10.1200/JCO.18.01207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6553812PMC
March 2019

Effect of health disparities on overall survival of patients with glioblastoma.

J Neurooncol 2019 Apr 22;142(2):365-374. Epub 2019 Jan 22.

Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Unit 431, 1515 Holcombe Blvd, Houston, TX, 77030-4009, USA.

Background: Examine the potential effects of health disparities in survival of glioblastoma (GB) patients.

Methods: We conducted a retrospective chart review of newly diagnosed GB patients from 2000 to 2015 at a free standing dedicated cancer center (MD Anderson Cancer Center-MDACC) and a safety net county hospital (Ben Taub General Hospital-BT) located in Houston, Texas. We obtained demographics, insurance status, extent of resection, treatments, and other known prognostic variables (Karnofsky Score-KPS) to evaluate their role on overall GB survival (OS).

Results: We identified 1073 GB patients consisting of 177 from BT and 896 from MDACC. We found significant differences by ethnicity, insurance status, KPS at diagnosis, extent of resection, and percentage of patients receiving standard of care (SOC) between the two centers. OS was 1.64 years for MDACC patients and 1.24 years for BT patients (p < 0.0176). Only 81 (45.8%) BT patients received SOC compared to 577 (64%) of MDACC patients (p < 0.0001). However, there was no significant difference in OS for patients who received SOC, 1.84 years for MDACC patients and 1.99 years for BT patients (p < 0.4787). Of the 96 BT patients who did not receive SOC, 29 (30%) had KPS less than 70 at time of diagnosis and 77 (80%) lacked insurance.

Conclusions: GB patients treated at a safety net county hospital had similar OS compared to a free standing comprehensive cancer center when receiving SOC. County hospital patients had poorer KPS at diagnosis and were often lacking health insurance affecting their ability to receive SOC.
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http://dx.doi.org/10.1007/s11060-019-03108-zDOI Listing
April 2019

Disparities along the glioblastoma clinical trials landscape.

Neuro Oncol 2019 02;21(2):285-286

The University of Texas MD Anderson Cancer Center, Houston, Texas.

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http://dx.doi.org/10.1093/neuonc/noy176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6374758PMC
February 2019

Lower-grade gliomas: the wrong target for bevacizumab.

Neuro Oncol 2018 11;20(12):1559-1560

Neuro-Oncology Department, The MD Anderson Cancer Center, Houston, Texas.

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http://dx.doi.org/10.1093/neuonc/noy165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6231203PMC
November 2018

Phase 1 lead-in to a phase 2 factorial study of temozolomide plus memantine, mefloquine, and metformin as postradiation adjuvant therapy for newly diagnosed glioblastoma.

Cancer 2019 02 25;125(3):424-433. Epub 2018 Oct 25.

Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: Repurposed memantine, mefloquine, and metformin have putative anticancer activity. The objective of this phase 1 study was to determine the maximum tolerated doses (MTDs) of combinations of these agents with temozolomide (TMZ).

Methods: Adults with newly diagnosed glioblastoma who completed chemoradiation were eligible. The patients were assigned to receive doublet, triplet, or quadruplet therapy with TMZ combined with mefloquine, memantine, and/or metformin. Dose-limiting toxicities (DLTs) were determined, using a 3 + 3 study design.

Results: Of 85 enrolled patients, 4 did not complete cycle 1 (the DLT observation period) for nontoxicity reasons, and 81 were evaluable for DLT. The MTDs for doublet therapy were memantine 20 mg twice daily, mefloquine 250 mg 3 times weekly, and metformin 850 mg twice daily. For triplet therapy, the MTDs were memantine 10 mg twice daily, mefloquine 250 mg 3 times weekly, and metformin 850 mg twice daily. For quadruplet therapy, the MTDs were memantine 10 mg twice daily, mefloquine 250 mg 3 times weekly, and metformin 500 mg twice daily. DLTs included dizziness (memantine) and gastrointestinal effects (metformin). Lymphopenia was the most common adverse event (66%). From study entry, the median survival was 21 months, and the 2-year survival rate was 43%.

Conclusions: Memantine, mefloquine, and metformin can be combined safely with TMZ in patients with newly diagnosed glioblastoma.
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http://dx.doi.org/10.1002/cncr.31811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7180384PMC
February 2019

The prognostic value of maximal surgical resection is attenuated in oligodendroglioma subgroups of adult diffuse glioma: a multicenter retrospective study.

J Neurooncol 2018 Dec 11;140(3):591-603. Epub 2018 Sep 11.

Department of Neurosurgery, Huashan Hospital, Fudan University, 12# Mid Wulumuqi Road, Shanghai, China.

Purpose: Maximal surgical resection is associated with survival benefit in the majority of studies in adult diffuse glioma. This study aims to characterize the prognostic value of surgical resection in molecular subgroups of diffuse glioma.

Methods: 1178 patients with diffuse glioma from our centers and 422 from TCGA dataset were collected. The Kaplan-Meier analysis and multivariable Cox regression models were conducted to identify the prognostic value of surgical resection through different histological and molecular stratifications.

Results: Firstly, we confirmed progression-free survival (PFS) benefit associated with gross total resection (GTR) over sub-total resection (STR) in lower-grade glioma (HR 1.49; 95% CI 1.17-1.90; P = 0.001). Intriguingly however, we were unable to detect a significant PFS or overall survival (OS) benefit in oligodendroglioma (N = 397; HR 1.36; 95% CI 0.86-2.14; P = 0.19 and HR 1.05; 95% CI 0.55-1.99; P = 0.89, respectively). Secondly, when analyzed in molecular subgroups, we were similarly unable to detect a significant PFS or OS benefit in IDH MT/codel subgroup (N = 269; HR 1.47; 95% CI 0.92-2.34; P = 0.11 and HR 1.54; 95% CI 0.78-3.05; P = 0.21, respectively), oligodendroglioma with IDH MT/codel subgroup (N = 233; HR 1.33; 95% CI 0.79-2.21; P = 0.28 and HR 1.16; 95% CI 0.53-2.54; P = 0.70, respectively) or other relevant subgroups. TCGA validation also showed a significant survival benefit in astrocytoma rather than oligodendroglioma. Exploratory RNAseq analysis displayed that fewer cell proliferation-related gene expression features were specific to oligodendroglioma.

Conclusion: These results suggest that the benefit of maximal surgery may be attenuated in patients within oligodendroglioma relevant subgroups because of the chemosensitive and indolent nature. The aggressive surgery accompanying with risk of neurologic morbidity may be unnecessary for these patients given the lack of survival benefit with gross total resection.
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http://dx.doi.org/10.1007/s11060-018-2985-3DOI Listing
December 2018

A Coclinical Radiogenomic Validation Study: Conserved Magnetic Resonance Radiomic Appearance of Periostin-Expressing Glioblastoma in Patients and Xenograft Models.

Clin Cancer Res 2018 12 27;24(24):6288-6299. Epub 2018 Jul 27.

Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Purpose: Radiomics is the extraction of multidimensional imaging features, which when correlated with genomics, is termed radiogenomics. However, radiogenomic biological validation is not sufficiently described in the literature. We seek to establish causality between differential gene expression status and MRI-extracted radiomic-features in glioblastoma.

Experimental Design: Radiogenomic predictions and validation were done using the Cancer Genome Atlas and Repository of Molecular Brain Neoplasia Data glioblastoma patients ( = 93) and orthotopic xenografts (OX; = 40). Tumor phenotypes were segmented, and radiomic-features extracted using the developed radiome-sequencing pipeline. Patients and animals were dichotomized on the basis of Periostin ( expression levels. RNA and protein levels confirmed RNAi-mediated knockdown in OX. Total RNA of tumor cells isolated from mouse brains (knockdown and control) was used for microarray-based expression profiling. Radiomic-features were utilized to predict expression status in patient, mouse, and interspecies.

Results: Our robust pipeline consists of segmentation, radiomic-feature extraction, feature normalization/selection, and predictive modeling. The combination of skull stripping, brain-tissue focused normalization, and patient-specific normalization are unique to this study, providing comparable cross-platform, cross-institution radiomic features. expression status was not associated with qualitative or volumetric MRI parameters. Radiomic features significantly predicted expression status in patients (AUC: 76.56%; sensitivity/specificity: 73.91/78.26%) and OX (AUC: 92.26%; sensitivity/specificity: 92.86%/91.67%). Furthermore, radiomic features in OX were significantly associated with patients with similar expression levels (AUC: 93.36%; sensitivity/specificity: 82.61%/95.74%; = 02.021E-15).

Conclusions: We determined causality between radiomic texture features and expression levels in a preclinical model with clinical validation. Our biologically validated radiomic pipeline also showed the potential application for human-mouse matched coclinical trials.
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http://dx.doi.org/10.1158/1078-0432.CCR-17-3420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538261PMC
December 2018