Author: "N. Butowski" - Searchworks@Jio Institute Digital Library Search Results

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123 results on '"N. Butowski"'

1. Efficacy signals, long-term exposure and safety data from a phase 1–2 study of a cell-penetrating peptide antagonist of CEBPβ, a novel target, in patients (pts) with refractory solid tumors

Author: E. Fontana, A. Williams, G. Falchook, N. Lakhani, T.R.J. Evans, V. Gondi, F. Iwamoto, M. McKean, S. Symeonides, N. Butowski, A. McLaren, J. Henry, R. Buerki, J. Rotolo, G. Capiaux, R. Michel, S. Kaesshaefer, E. Wiegert, and A. Bexon
Subjects: Cancer Research, Oncology
Published: 2022
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2. 466P Efficacy of BRAF inhibitor FORE8394 in BRAF V600+ patients

Author: E.J. Sherman, F. Tsai, F. Janku, C. Allen, R. Yaeger, N. Ammakkanavar, N. Butowski, G. Michelson, M. Paz, A. Tussay-Lindenberg, K. Wang, S. Shepherd, E. Dehan, M. de la Fuente, and J. Rodon
Subjects: Oncology, Hematology
Published: 2022
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3. A Targeted Gene Expression Risk Score Predicts Meningioma Outcomes and Responses to Radiotherapy

Author: D.S. Solomon, Michael McDermott, Patricia Sneed, Jenny Kan-Suen Pu, Gilberto K.K. Leung, William C. Chen, Arie Perry, M.S. Berger, Steve Braunstein, Lai-Fung Li, N.A. Oberheim, Minh P. Nguyen, Abrar Choudhury, Tai-Chung Lam, June M. Chan, N. Butowski, Stephen Magill, Jessica Schulte, Harish N. Vasudevan, C.H. Lucas, David R. Raleigh, and Javier Villanueva-Meyer
Subjects: Oncology, Cancer Research, medicine.medical_specialty, Radiation, Framingham Risk Score, Proportional hazards model, business.industry, medicine.medical_treatment, medicine.disease, Radiation therapy, Meningioma, Gene expression profiling, Quartile, Internal medicine, Cohort, medicine, Biomarker (medicine), Radiology, Nuclear Medicine and imaging, business
Abstract: Purpose/Objective(s) Indications for postoperative radiotherapy after meningioma resection are controversial. DNA methylation profiling identifies meningiomas at risk for recurrence, but logistic and technical barriers have encumbered clinical translation of this approach. The aim of this study was to optimize and validate a clinically-tractable targeted gene expression biomarker to predict meningioma outcomes and responses to postoperative radiotherapy. Materials/Methods Targeted gene expression and Illumina 850k DNA methylation profiling were performed on a discovery cohort of 173 meningiomas (median follow-up 7.8 years) and an external validation cohort of 331 meningiomas (median follow-up 5.8 years) from patients treated with surgery (n = 504) and postoperative radiotherapy (n = 73) at independent, international institutions (70% WHO grade 1, 24% WHO grade 2, 6% WHO grade 3). RNA sequencing was performed on the discovery cohort, and 125 genes were selected for targeted gene expression profiling based on associations with meningioma recurrence. Regularized Cox regression was used to develop continuous gene expression risk score for local freedom from recurrence (LFFR). The model (34 meningioma genes and 7 housekeeping genes) and risk quartiles (low, low-intermediate, high-intermediate, and high) were locked and validated on the external cohort. Multivariate regressions (MVR) incorporating WHO grade, DNA methylation grouping, extent of resection, primary versus recurrent presentation, and postoperative radiotherapy were used to assess the risk score across clinical contexts. Results The gene expression risk score (concordance-index 0.78 ± 0.03) outperformed DNA methylation grouping (0.71 ± 0.03) and WHO grade (0.65 ± 0.03) in stratifying meningioma LFFR in the validation cohort (n = 331). The risk score classified 43% of WHO grade 1 meningiomas as high-intermediate (n = 82) or high risk (n = 34), with 5-year LFFR and overall survival (OS) of 83% and 89% for high-intermediate risk WHO grade 1 meningiomas, and 41% and 73% for high risk WHO grade 1 meningiomas, respectively. Low risk WHO grade 1 meningiomas (n = 50) had 5-year LFFR and OS of 92% and 88%, respectively. High and high-intermediate risk scores were independently prognostic for LFFR (HR 2.9, 95% CI 1.2-4.4) and OS (HR 2.7, 95% CI 1.3-5.6) on MVR. An interaction term between postoperative radiotherapy and risk score was predictive for LFFR (P = 0.046) and OS (P = 0.001) on MVR in the validation cohort, suggesting meningiomas with higher risk scores derived greater benefit from postoperative radiotherapy. Conclusion Here we use targeted gene expression profiling to develop a risk score predicting meningioma outcomes and responses to postoperative radiotherapy. This cost-effective assay outperforms DNA methylation grouping and WHO grade in discriminating meningioma outcomes, and may be useful for guiding clinical trial design.
Published: 2021
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4. Meningioma epigenetic grouping reveals biologic drivers and therapeutic vulnerabilities

Author: Harish N. Vasudevan, Javier Villanueva-Meyer, Kyounghee Seo, Zhixin Qiu, Michael Martin, David A. Solomon, David R. Raleigh, N. Butowski, Tai-Chung Lam, Abrar Choudhury, Michael W. McDermott, Gilberto Kai-Kit Leung, Arie Perry, Penny K. Sneed, Stephen T. Magill, Briana C. Prager, Siyuan Liu, Jessica Schulte, Matthew S. Susko, Calixto-Hope G Lucas, Jeremy N. Rich, Jason Y. Chang, Joseph F. Costello, Charlotte Eaton, Joanna J. Phillips, Steve Braunstein, Michael Zhang, Jenny Kan-Suen Pu, Nancy Ann Oberheim Bush, Lai-Fung Li, Mitchell S. Berger, and William C. Chen
Subjects: business.industry, Central nervous system, Hla expression, Cell cycle, medicine.disease, nervous system diseases, Merlin (protein), Transcriptome, Meningioma, Lymphatic system, medicine.anatomical_structure, otorhinolaryngologic diseases, Cancer research, Medicine, Epigenetics, business, neoplasms
Abstract: Meningiomas arising from the meningothelial central nervous system lining are the most common primary intracranial tumors, and a significant cause of neurologic morbidity and mortality1. There are no effective medical therapies for meningioma patients2,3, and new treatments have been encumbered by limited understanding of meningioma biology. DNA methylation profiling provides robust classification of central nervous system tumors4, and can elucidate targets for molecular therapy5. Here we use DNA methylation profiling on 565 meningiomas integrated with genetic, transcriptomic, biochemical, and single-cell approaches to show meningiomas are comprised of 3 epigenetic groups with distinct clinical outcomes and biological features informing new treatments for meningioma patients. Merlin-intact meningiomas (group A, 34%) have the best outcomes and are distinguished by a novel apoptotic tumor suppressor function of NF2/Merlin. Immune-enriched meningiomas (group B, 38%) have intermediate outcomes and are distinguished by immune cell infiltration, HLA expression, and lymphatic vessels. Hypermitotic meningiomas (group C, 28%) have the worst outcomes and are distinguished by convergent genetic mechanisms misactivating the cell cycle. Consistently, we find cell cycle inhibitors block meningioma growth in cell culture, organoids, xenografts, and patients. Our results establish a framework for understanding meningioma biology, and provide preclinical rationale for new therapies to treat meningioma patients.
Published: 2020
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5. OS10.6 Infigratinib (BGJ398) in patients with recurrent gliomas with fibroblast growth factor receptor (FGFR) alterations: a multicenter phase II study

Author: Morris D. Groves, J. Raizer, F.Y.F.L. De Vos, Patrick Roth, Andrew B. Lassman, K Steward, J M Gil-Gil, Vinay K. Puduvalli, Paul Clement, Juan M. Sepúlveda-Sánchez, T. Cloughesy, N. Butowski, C Belda-Iniesta, Y Ye, Patrick Y. Wen, and S Moran
Subjects: Cancer Research, Mutation, business.industry, Phases of clinical research, Chromosomal translocation, medicine.disease, medicine.disease_cause, Fusion gene, Oncology, Fibroblast growth factor receptor, Glioma, medicine, Cancer research, Oral Presentations, In patient, Neurology (clinical), Progression-free survival, business
Abstract: BACKGROUND FGFR mutations and translocations occur in approximately 10% of glioblastomas (GBMs). FGFR3-TACC3 fusion has been reported as predictive of response to FGFR tyrosine kinase inhibitor therapy both pre-clinically and clinically. Infigratinib (BGJ398) is a selective small-molecule pan-FGFR kinase inhibitor that has demonstrated anti-tumor activity in several solid tumors with FGFR genetic alterations. Therefore, we conducted a phase II trial to test the efficacy of infigratinib in FGFR-altered recurrent GBM (NCT01975701). METHODS This open-label trial accrued adults with recurrent high-grade gliomas following failure of initial therapy that harbored FGFR1-TACC1 or FGFR3-TACC3 fusions; activating mutations in FGFR1, 2 or 3; or FGFR1, 2, 3, or 4 amplification. Oral infigratinib was administered 125 mg on days 1–21 every 28 days. Prophylaxis for hyperphosphatemia, a common toxicity, was recommended. The primary endpoint was the 6-month progression-free survival (6mPFS) rate by RANO (locally assessed, estimated by K-M method), with a goal of >40%. RESULTS As of the Sep 2017 data cut-off, 26 patients (16 men, 10 women; median age 55 years, range 20–76 years; 50% with ≥2 prior regimens) were treated, and 24 (92.3%) discontinued for disease progression (n=21) or other reasons (n=3). All patients had FGFR1 or FGFR3 gene alterations, and 4 had >1 gene alteration. The estimated 6mPFS rate was 16% (95% CI 5.0–32.5%); median PFS was 1.7 months (95% CI 1.1–2.8 months); median OS was 6.7 months (95% CI 4.2–11.7 months); ORR was 7.7% (95% CI 1.0–25.1%). The best overall response was: partial response 7.7% (FGFR1 mutation n=1; FGFR3 amplification n=1); stable disease 26.9%; progressive disease 50.0%; missing/unknown 15.3%. The most common (>15%) all-grade treatment-related adverse events (AEs) were hyperphosphatemia, fatigue, diarrhea, hyperlipasemia, and stomatitis. There were no grade 4 treatment-related AEs. Eleven patients (42.3%) had treatment-related AEs requiring dose interruptions or reductions (most commonly hyperphosphatemia). CONCLUSIONS Infigratinib induced partial response or stable disease in approximately one-third of patients with recurrent GBM and/or other glioma subtypes harboring FGFR alterations. Most AEs were reversible and manageable. Further potential combinations are being explored in patients with proven FGFR-TACC fusion genes and analysis of biomarker data is ongoing.
Published: 2019

6. OS07.4 Efficacy of a novel antibody-drug conjugate (ADC), ABT-414, as monotherapy in epidermal growth factor receptor (EGFR) amplified (EGFRamp), recurrent glioblastoma (rGBM)

Author: M. van den Bent, H. Gan, A. Lassman, P. Kumthekar, N. Butowski, L. Nabors, J. Simes, D. Maag, and D. Reardon
Subjects: Cancer Research, ORAL PRESENTATIONS, Oncology, Neurology (clinical)
Abstract: Background: Patients (pts) with rGBM have a poor prognosis. EGFRamp is present in ~50% of GBMs. ABT-414 is an ADC that releases a potent toxin, monomethyl auristatin F (MMAF), inside cells with EGFRamp. Here we report the safety and efficacy of ABT-414 monotherapy at the recommended phase 2 dose (RPTD) in EGFRamp, rGBM. Methods: M12-356 (NCT01800695) is an open-label, Phase 1 study with three escalation cohorts. Study design and RPTD was reported previously (ASCO Meeting 2015, SNO Meeting 2015). Sixty pts, all with EGFRamp, rGBM, were enrolled as part of the escalation (12 pts) or expansion (48 pts) cohort treated with ABT-414 monotherapy at 1.25 mg/kg. Adults with measurable (RANO), bevacizumab-naïve, rGBMs with EGFRamp confirmed centrally were eligible. Results: As of March 1, 2016, 60 pts with EGFRamp, rGBM underwent treatment. Median age was 58 years (range, 35–80). Pts underwent 1, 2 (43% each) or 3 (13%) prior therapies. The most common treatment emergent adverse events (TEAEs) (≥20% pts) included blurred vision (65%), headache, fatigue (30% each), eye pain and photophobia (28% each). Grade 3/4 TEAEs (>1 pt) were keratitis (13%), corneal epithelial microcysts (8%), blurred vision (5%), dry eye, ulcerative keratitis and reduced visual acuity (3% each). The best RANO responses of 56 pts with complete data were: 3 (5%) partial responses, 24 (43%) stable diseases and 29 (52%) progressive diseases. Median duration of overall response in 3 patients with partial responses was 4.4 months (range, 1.9–5.6). The 6-month progression-free survival (PFS6) estimate was 25.3% [95% CI=14.8, 37.2]. Conclusions: ABT-414 monotherapy displayed frequent but mostly grade 1/2 ocular toxicities. An encouraging PFS6 (25%) was observed in this rGBM population where 56% had ≥2 prior therapies. A global randomized trial of ABT-414, alone or with TMZ, vs. TMZ or lomustine, is underway in EGFRamp, rGBM (NCT02343406).
Published: 2017

7. P08.01 Impact of cannabis use on quality of life in patients with central nervous system tumors

Author: N. Butowski, Susan M. Chang, Robin A. Buerki, M.S. Berger, Jennie Taylor, Nancy Ann Oberheim-Bush, J R Clarke, and J E Rodriguez Almaraz
Subjects: Cancer Research, medicine.medical_specialty, biology, business.industry, media_common.quotation_subject, Central nervous system, Cancer, Cannabis use, medicine.disease, biology.organism_classification, humanities, Poster Presentations, Quality of life (healthcare), medicine.anatomical_structure, Oncology, Informed consent, Perception, medicine, In patient, Neurology (clinical), Cannabis, Psychiatry, business, media_common
Abstract: BACKGROUND Nearly 80,000 new cases of primary brain tumors are expected to be diagnosed this year in the United States: 32% of CNS tumors are malignant. Anecdotally, patients who report use of cannabis, frequently describe higher quality of life scores (QOL) in standardized instruments. However, the lack of available tools that allow systematic documentation of cannabis use results in a barrier to accurately assess efficacy and potential benefits and risks. MATERIAL AND METHODS We conducted a single center, observational study: patients with primary brain tumors answered a previously validated instrument to explore cannabis use. QOL was assessed using the instruments from the European Organisation for Research and Treatment of Cancer(EORTC): QLQ-C30 and its complementary module BN-20 as well as the EuroQol group’s instrument EQ-5D-5L. Eligible participants were identified as cannabis users or non-users, completing the instruments in a self-administered fashion. RESULTS To date, 45 patients who signed informed consent were enrolled and answered the questionnaires, mean age was 51 (SD 13.5) years, 31 were male, 25 were considered active cannabis users (624% males and 36% females). At baseline, the mean Global Health score in the QLQ-C30 instrument was 68.6 (SD: 20.6) among cannabis users and 82 (SD: 18.05) among non-users. The mean difference in Global Health QOL scores between users and non-users was 13.35 (95%CI: 1.34, 25.35; p=0.03). In contrast the difference between cannabis users and non-users in QOL index in the EQ-5D-5L instrument was 0.13 (0.77 vs 0.91; p=0.002). Among cannabis users, patients perceive their symptoms as moderate before using cannabis and mild after using cannabis (p>0.001). CONCLUSION In our analysis, patients who use cannabis have, on average, lower QOL scores signaling that sicker patients resort to cannabis to improve their symptoms and ultimately their quality of life. Patients’ perception is one of improvement in the overall quality of life when using cannabis. Our findings provide background support to perform prospective studies in the impact of cannabis in quality of life of patients with central nervous system tumors.
Published: 2019
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8. TUMOR MODELS (IN VIVO/IN VITRO)

Author: E. Brognaro, S. Chang, J. Cha, K. Choi, C. Choi, J. DePetro, C. Binding, M. Blough, J. Kelly, S. Lawn, J. Chan, S. Weiss, G. Cairncross, A. Eisenbeis, R. Goldbrunner, M. Timmer, K. Gabrusiewicz, N. Cortes-Santiago, X. Fan, M. B. Hossain, B. Kaminska, A. Heimberger, G. Rao, W. K. A. Yung, F. Marini, J. Fueyo, C. Gomez-Manzano, B. Halle, E. Marcusson, C. Aaberg-Jessen, S. S. Jensen, M. Meyer, M. K. Schulz, C. Andersen, null Bjarne, W. Kristensen, R. Hashizume, Y. Ihara, T. Ozawa, A. Parsa, J. Clarke, N. Butowski, M. Prados, A. Perry, M. McDermott, D. James, R. Jensen, D. Gillespie, T. Martens, M. Zamykal, M. Westphal, K. Lamszus, E. Monsalves, S. Jalali, T. Tateno, S. Ezzat, G. Zadeh, M. K. Nedergaard, K. Kristoffersen, H. S. Poulsen, M.-T. Stockhausen, U. Lassen, A. Kjaer, F. Ohka, A. Natsume, H. Zong, C. Liu, A. Hatanaka, K. Katsushima, K. Shinjo, T. Wakabayashi, Y. Kondo, K. Picotte, L. Li, B. Westerhuis, H. Zhao, S. Plotkin, M. James, M. Kalamarides, W.-n. Zhao, J. Kim, A. Stemmer-Rachamimov, S. Haggarty, J. Gusella, V. Ramesh, F. Nunes, T. Doucette, Y. Yang, G. Fuller, A. Rao, N. O. Schmidt, N. Humke, H. Meissner, F.-J. Mueller, O. Schnell, I. Jaehnert, V. Albrecht, P. Fu, J.-C. Tonn, C. Schichor, G. Shackleford, K. Swanson, X.-H. Shi, M. D'Apuzzo, I. Gonzalez-Gomez, R. Sposto, R. Seeger, A. Erdreich-Epstein, R. Moats, R. W. Sirianni, J. M. Heffernan, D. J. Overstreet, L. Sleire, B. S. Skeie, I. A. Netland, J. Heggdal, P.-H. Pedersen, P. O. Enger, C. Stiles, Y. Sun, S. Mehta, C. Taylor, J. Alberta, T. Sundstrom, I. Wendelbo, I. Daphu, E. Hodneland, A. Lundervold, H. Immervoll, K. O. Skaftnesmo, M. Babic, P. Jendelova, E. Sykova, M. Lund-Johansen, R. Bjerkvig, F. Thorsen, M. Synowitz, M.-C. Ku, S. A. Wolf, D. Respondek, V. Matyash, A. Pohlmann, S. Waiczies, H. Waiczies, T. Niendorf, R. Glass, H. Kettenmann, N. Thompson, D. Elder, K. Hopkins, V. Iyer, N. Cohen, J. Tavare, B. Fite, L. M. Mahakian, J. W. Seo, S. Qin, V. Harrison, P. N. Harter, S. Johnson, E. Ingham, C. Caskey, T. Meade, K. W. Ferrara, B. R. Tschida, A. R. Lowy, C. A. Marek, T. Ringstrom, T. J. Beadnell, S. M. Wiesner, D. A. Largaespada, C. Wenger, P. C. Miranda, A. Mekonnen, R. Salvador, P. Basser, J. Yoon, and H. Shin
Subjects: Abstracts, Cancer Research, Oncology, Neurology (clinical)
Published: 2013
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9. MEDICAL RADIATION THERAPIES

Author: I. Ahmed, A. Biswas, S. Krishnamurthy, P. Julka, G. Rath, M. Back, D. Huang, C. Gzell, J. Chen, M. Kastelan, P. Gaur, H. Wheeler, S. N. Badiyan, C. G. Robinson, J. R. Simpson, D. D. Tran, K. M. Rich, J. L. Dowling, M. R. Chicoine, E. C. Leuthardt, A. H. Kim, J. Huang, S. R. Michaelsen, I. J. Christensen, K. Grunnet, M.-T. Stockhausen, H. Broholm, M. Kosteljanetz, H. S. Poulsen, M. Tieu, E. Lovblom, M. Macnamara, W. Mason, D. Rodin, E. Tai, K. Ubhi, N. Laperriere, B.-A. Millar, C. Menard, B. Perkins, C. Chung, J. Clarke, A. Molinaro, J. Phillips, N. Butowski, S. Chang, A. Perry, J. Costello, A. DeSilva, J. Rabbitt, M. Prados, A. L. Cohen, C. Anker, D. Shrieve, B. Hall, K. Salzman, R. Jensen, H. Colman, O. Farber, U. Weinberg, Y. Palti, B. Fisher, H. Chen, D. Macdonald, G. Lesser, S. Coons, D. Brachman, S. Ryu, M. Werner-Wasik, J.-P. Bahary, A. Chakravarti, M. Mehta, T. Gupta, V. Nair, S. Epari, J. Godasastri, A. Moiyadi, P. Shetty, S. Juvekar, R. Jalali, U. Herrlinger, N. Schafer, J. Steinbach, A. Weyerbrock, P. Hau, R. Goldbrunner, R. Kohnen, H. Urbach, W. Stummer, M. Glas, C. Houillier, H. Ghesquieres, C. Chabrot, C. Soussain, G. Ahle, S. Choquet, P. Faurie, J.-O. Bay, J. Vargaftig, C. Gaultier, E. Nicolas-Virelizier, K. Hoang-Xuan, O. Iskanderani, F. Izar, A. Benouaich-Amiel, T. Filleron, E. Moyal, C. Iweha, S. Jain, E. Melian, A. Sethi, K. Albain, D. Shafer, B. Emami, X.-T. Kong, S. Green, E. Filka, R. Green, W. Yong, P. Nghiemphu, T. Cloughesy, A. Lai, S. Mallick, S. Roy, S. Purkait, S. Gupta, P. K. Julka, G. K. Rath, C. Marosi, J. Thaler, C. Ay, A. Kaider, E.-M. Reitter, J. Haselbock, M. Preusser, B. Flechl, C. Zielinski, I. Pabinger, S.-I. Miyatake, M. Furuse, T. Miyata, E. Yoritsune, S. Kawabata, T. Kuroiwa, Y. Muragaki, T. Maruyama, H. Iseki, J. Akimoto, S. Ikuta, M. Nitta, K. Maebayashi, T. Saito, Y. Okada, S. Kaneko, A. Matsumura, K. Karasawa, Y. Nakazato, T. Kayama, L. B. Nabors, K. L. Fink, T. Mikkelsen, D. Grujicic, R. Tarnawski, D.-H. Nam, M. Mazurkiewicz, M. Salacz, L. Ashby, L. Thurzo, V. Zagonel, R. Depenni, J. R. Perry, J. Henslee-Downey, M. Picard, D. A. Reardon, N. Nambudiri, L. Nayak, D. LaFrankie, P. Wen, D. Ney, J. Carlson, D. Damek, P. Blatchford, L. Gaspar, B. Kavanagh, A. Waziri, K. Lillehei, K. Reddy, C. Chen, I. Rashed, K. Barton, D. Anderson, V. Prabhu, R. Rusch, M. Belongia, M. Maheshwari, S. Firat, D. Schiff, A. Desjardins, M. Glantz, M. Chamberlain, W. Shapiro, S. Gopal, K. Judy, S. Patel, A. Mahapatra, J. Shan, D. Gupta, K. Shih, J. A. Bacha, D. Brown, W. J. Garner, A. Steino, R. Schwart, S. Kanekal, M. Li, L. Lopez, H. A. Burris, C. Soderberg-Naucler, A. Rahbar, G. Stragliotto, A. J. Song, A. M. S. Kumar, E. S. Murphy, T. Tekautz, J. H. Suh, V. Recinos, S. T. Chao, J. Spoor, K. Korami, J. Kloezeman, R. Balvers, C. Dirven, M. Lamfers, S. Leenstra, A. Sumrall, D. Haggstrom, A. Crimaldi, J. Symanowski, P. Giglio, A. Asher, S. Burri, G. Sunkersett, Z. Khatib, C. M. Prajapati, E. E. Magalona, M. Mariano, I. M. Sih, R. Torcuator, W. Taal, H. Oosterkamp, A. Walenkamp, L. Beerenpoot, M. Hanse, J. Buter, A. Honkoop, D. Boerman, F. de Vos, R. Jansen, F. van der Berkmortel, D. Brandsma, R. Enting, J. Kros, J. Bromberg, I. van Heuvel, M. Smits, R. van der Holt, R. Vernhout, M. van den Bent, W. Wick, C. Suarez, J. Rodon, P. Forsyth, I. Gueorguieva, A. Cleverly, T. Burkholder, D. Desaiah, M. Lahn, L. Zach, D. Guez, D. Last, D. Daniels, O. Nissim, Y. Grober, C. Hoffmann, D. Nass, A. Talianski, R. Spiegelmann, Z. Cohen, and Y. Mardor
Subjects: Abstracts, Cancer Research, medicine.medical_specialty, Text mining, Oncology, business.industry, Medicine, Medical physics, Neurology (clinical), business, Medical radiation
Published: 2013
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10. 138O Efficacy of a novel antibody-drug conjugate (ADC), ABT-414, with temozolomide (TMZ) in recurrent glioblastoma (rGBM)

Author: M. van den Bent, A.B. Lassman, H.K. Gan, D.A. Reardon, P. Kumthekar, N. Butowski, Z. Lwin, T. Mikkelsen, L.B. Nabors, K.P. Papadopoulos, M. Penas-Prado, J. Simes, H. Wheeler, E. Gomez, H-J. Lee, L. Roberts-Rapp, H. Xiong, E. Bain, K. Holen, and R. Merrell
Subjects: Oncology, Hematology
Published: 2016
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11. P08.19 Efficacy of a novel antibody-drug conjugate (ADC), ABT-414, as monotherapy in epidermal growth factor receptor (EGFR) amplified, recurrent glioblastoma (GBM)

Author: M. van den Bent, H. K. Gan, A. B. Lassman, P. Kumthekar, N. Butowski, Z. Lwin, L. B. Nabors, J. Simes, K. Holen, and D. A. Reardon
Subjects: 03 medical and health sciences, Cancer Research, 0302 clinical medicine, Oncology, P08 Glioblastom and Anaplastic gliomas, 030220 oncology & carcinogenesis, 030212 general & internal medicine, Neurology (clinical)
Published: 2016

12. CLIN-NEURO-COGNITIVE

Author: J. L. Scotland, I. R. Whittle, I. J. Deary, E. K. De Witte, P. Marien, R. Jalali, V. Kothawade, T. Gupta, S. Goswami, J. Swamidas, C. A. Racine, J. M. Lupo, A. Molinaro, A. Parks, S. M. Chang, M. S. Berger, N. Butowski, C. Linville, R. Hampson, S. Deadwyler, A. Peiffer, K. B. Peters, S. Woodring, J. E. Herndon, F. McSherry, J. J. Vredenburgh, A. Desjardins, H. S. Friedman, J. S. Wefel, S. Shook, P. D. Brown, N. N. Laack, A. Choucair, J. H. Suh, D. Roberge, V. Kavadi, M. P. Mehta, D. Watkins-Bruner, C. Weiss, C. Nettekoven, V. Neuschmelting, A. Eisenbeis, A. Rehme, C. Grefkes, R. Goldbrunner, A. M. Peiffer, D. Case, E. G. Shaw, S. Rapp, S. Ambert-Pompey, N. D. Doolittle, C. Lacy, R. Fu, R. W. Butler, C. Varallyay, E. A. Neuwelt, A. Jakary, and S. J. Nelson
Subjects: Cancer Research, medicine.medical_specialty, business.industry, Trail Making Test, Controlled Oral Word Association Test, Cognition, National Adult Reading Test, Abstracts, Cognitive epidemiology, Oncology, Cohort, Physical therapy, Medicine, Verbal fluency test, Neurology (clinical), business, Neurocognitive
Abstract: CLIN-NEURO-COGNITIVE NC-02. ASSESSING NEURO-COGNITIVE STATUS IN NEWLY PRESENTING PATIENTS WITH SUPRATENTORIAL INTRACRANIAL TUMOURS. Jennifer L. Scotland1, Ian R. Whittle1, and Ian J. Deary2; University of Edinburgh, Edinburgh, United Kingdom; Centre for Cognitive Ageing and Cognitive Epidemiology, Dept. of Psychology, University of Edinburgh, Edinburgh, United Kingdom INTRODUCTION: Neurocognitive endpoints are increasingly included in clinical trials in neuro-oncological settings (Meyers & Brown, 2006). There is a need to identify short, repeatable measures of cognition that are sensitive to impairment in this group. Previous authors have proposed such batteries. METHODS: Newly presenting patients with a radiological diagnosis of any intracranial tumour (n 1⁄4 118) were assessed, prior to any surgical intervention, on a number of standardised cognitive and other measures as part of a larger study (Scotland et al., 2012). Their performance was compared with that of patients admitted for elective spinal surgery (n 1⁄4 85) and a healthy control group (n 1⁄4 80). RESULTS: Analysis of covariance compared the performance of the three groups. Age, sex, and National Adult Reading Test score (used to assess premorbid function) were the covariates. Patients with intracranial tumours performed significantly worse on the majority of the tests. The intracranial tumour cohort had significantly lower scores than did the spinal surgery and healthy control groups on the following measures: immediate and delayed memory (Rey Auditory Verbal Learning Test, RAVLT; p , 0.001); Trail Making Test Part B (p , 0.001); digit-symbol coding (p , 0.001); and verbal fluency (Controlled Oral Word Association Test, COWAT; p 1⁄4 0.002 and p , 0.001, respectively). There was a moderate-to-large effect size in the participant group for all tests. DISCUSSION/CONCLUSIONS: The RAVLT, Trail Making Test Part B, and COWAT are sensitive measures of cognitive impairment in patients with brain tumours and support Meyers & Brown’s (2006) proposal for the inclusion of these tests in clinical trials that have neurocognitive endpoints. The verbal fluency test, in particular, has a number of potential advantages for use in neuro-oncological settings, given that it can be completed by patients with focal motor deficits and is available in alternate forms to reduce practice effects. NC-03. A STANDARD NEUROLINGUISTIC APPROACH TO
Published: 2012
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13. LAB-EXPERIMENTAL (PRE-CLINICAL) THERAPEUTICS AND PHARMACOLOGY

Author: F. H. Yang, B. Zhang, D. J. Zhou, L. Bie, M. W. Tom, D. C. Drummond, T. Nicolaides, S. Mueller, A. Banerjee, J. W. Park, M. D. Prados, D. C. James, N. Gupta, R. Hashizume, G. W. Strohbehn, J. Zhou, M. Fu, T. R. Patel, J. M. Piepmeier, W. M. Saltzman, Q. Xie, J. Johnson, R. Bradley, M. L. Ascierto, L. Kang, J. Koeman, F. M. Marincola, M. Briggs, K. Tanner, G. F. Vande Woude, S. Tanaka, L. K. Klofas, H. Wakimoto, D. R. Borger, A. J. Iafrate, T. T. Batchelor, A. S. Chi, A. B. Madhankumar, B. Slagle-Webb, E. Rizk, K. Harbaugh, J. R. Connor, G. Sarkar, G. L. Curran, R. B. Jenkins, K. Kurozumi, T. Ichikawa, M. Onishi, K. Fujii, J. Ishida, Y. Shimazu, I. Date, K. Ebsworth, M. J. Walters, L. S. Ertl, Y. Wang, R. D. Berahovich, P. Zhang, J. P. Powers, S.-C. Liu, R. Al Omran, T. J. Sullivan, J. C. Jaen, M. Brown, T. J. Schall, N. Yusuke, S. Shimizu, Y. Shishido-Hara, Y. Shiokawa, M. Nagane, J. Wang, K. Sai, F.-R. Chen, Z.-P. Chen, Z. Shi, J. Zhang, K. Zhang, L. Han, L. Chen, X. Qian, A. Zhang, G. Wang, Z. Jia, P. Pu, C. Kang, L.-Y. Kong, T. A. Doucette, S. D. Ferguson, J. Hachem, Y. Yang, J. Wei, W. Priebe, G. N. Fuller, W. Qiao, G. Rao, A. B. Heimberger, P.-Y. Chen, T. Ozawa, D. Drummond, R. Santos, J. D. Torre, C. Ng, E. L. Lepe, N. Butowski, M. Prados, K. Bankiewicz, C. D. James, Z. Cheng, Y. Gong, Y. Ma, S. Muller-Knapp, S. Knapp, E. Antonio Chiocca, B. Kaur, J. S. Yu, V. Judkowski, A. Bunying, J. Ji, Z. Li, J. Bender, C. Pinilla, V. Srinivasan, M. Dombovy-Johnson, E. Carson-Walter, K. Walter, Z. Xu, B. Popp, D. Schlesinger, L. Gray, J. Sheehan, S. T. Keir, H. S. Friedman, D. D. Bigner, C. Kut, B. Tyler, E. McVeigh, X. Li, D. Herzka, S. Grossman, J. L. Lasky, E. Panosyan, W. H. Meisen, J. Hardcastle, J. Wojton, E. Wohleb, C. Alvarez-Breckenridge, M. Nowicki, J. Godbout, S. Y. Lee, J. M. Sheehan, S. Yin, S. Kaluz, S. N. Devi, R. de Noronha, K. C. Nicolaou, E. G. Van Meir, J. E. Lachowicz, M. Demeule, C. Che, S. Tripathy, S. Jarvis, J.-C. Currie, A. Regina, T. Nguyen, J.-P. Castaigne, K. Zielinska-Chomej, C. Mohanty, K. Viktorsson, R. Lewensohn, J. J. Driscoll, S. Alsidawi, R. E. Warnick, O. Rixe, A. C. deCarvalho, S. Irtenkauf, L. Hasselbach, H. Xin, T. Mikkelsen, J. H. Sherman, A. Siu, O. Volotskova, M. Keidar, D. M. Gibo, P. Dickinson, J. Robertson, J. Rossmeisl, W. Debinski, S. Nair, R. Schmittling, D. Boczkowski, G. Archer, J. H. Sampson, D. A. Mitchell, I. S. Miller, S. Didier, D. W. Murray, M. Issaivanan, S. J. Coniglio, J. E. Segall, Y. Al-Abed, M. Symons, A. Fotovati, K. Hu, J. Triscott, J. Bacha, D. M. Brown, S. E. Dunn, D. J. Daniels, T. E. Peterson, A. B. Dietz, G. J. Knutson, I. F. Parney, R. J. Diaz, B. Golbourn, D. Picard, C. Smith, A. Huang, J. Rutka, N. Saito, J. Fu, J. Yao, S. Wang, D. Koul, W. K. A. Yung, Y. Yuan, E. P. Sulman, H. Colman, F. F. Lang, E. A. Slat, E. D. Herzog, J. B. Rubin, A. S. Carminucci, B. Amendolara, R. Leung, L. Lei, P. Canoll, J. N. Bruce, J. A. Wojton, Z. Chu, C.-H. Kwon, L. M. Chow, M. Palascak, R. Franco, T. Bourdeau, S. Thornton, X. Qi, G. J. Kitange, A. C. Mladek, D. Su, B. L. Carlson, M. A. Schroeder, J. L. Pokorny, K. K. Bakken, S. K. Gupta, P. A. Decker, W. Wu, J. N. Sarkaria, M. P. Oddou, A. Mollard, L. T. Call, H. Vakayalapati, S. L. Warner, S. Sharma, D. J. Bearss, T. C. Chen, H. Cho, W. Wang, F. M. Hofman, C. T. Flores, D. Snyder, L. Sanchez-Perez, C. Pham, H. Friedman, E. Woolf, M. G. Abdelwahab, G. Turner, M. C. Preul, A. Lynch, J. M. Rho, A. C. Scheck, L. Salphati, T. P. Heffron, B. Alicke, K. Barck, R. A. Carano, J. Cheong, J. Greve, L. B. Lee, M. Nishimura, J. Pang, E. G. Plise, H. B. Reslan, X. Zhang, S. G. GOuld, A. G. Olivero, H. S. Phillips, G. Zadeh, S. Jalali, D. Voce, Z. Wei, K. Shijun, K. Nikolai, W. Josh, C. Clayton, Y. Bakhtiar, R. Alkins, A. Burgess, M. Ganguly, W. Wels, K. Hynynen, Y. M. Li, H. Jun, V. Daniel, H. A. Walter, H. Nakashima, T. T. Nguyen, I. Shalkh, W. F. Goins, E. A. Chiocca, I. V. Pyko, M. Nakada, N. Furuyama, T. Lei, Y. Hayashi, K. Kawakami, T. Minamoto, A. S. Fedulau, and J.-i. Hamada
Subjects: Cancer Research, Microarray analysis techniques, Cell, technology, industry, and agriculture, Pharmacology, Biology, Molecular biology, Abstracts, medicine.anatomical_structure, Oncology, Targeted drug delivery, Apoptosis, Gene expression, Cancer cell, medicine, Neurology (clinical), KEGG, Regulator gene
Abstract: Ginsenoside Rg3 is a natural active ingredient that is extracted from Korean red ginseng root. It elevates the therapeutic effect of radiotherapy and chemotherapy, but previous studies found that the application of Rg3 is heavily limited by its low bioavailability and poor absorption via oral administration. To overcome these problems, Rg3-loaded PEG-PLGA-NPs (Rg3-NPs) were prepared by the modified spontaneous emulsification solvent diffusion (SESD) method, and the physicochemical characteristics of Rg3-NPs were investigated. We treated primary glioblastoma with 50 mM Rg3-NPs for 48h. We then used gene expression arrays (Illumina) for genome-wide expression analysis and validated the results for genes of interest by means of real-time PCR. Functional annotations were then performed using the DAVID and KEGG online tools. The results showed that the Rg3-NPs are slick and uniform, the average diameter of the nanoparticles is 75-90 nm, and their entrapment efficiency is 89.7+1.7%. MTT showed that the growth of cells can be significantly inhibited by Rg3-NPs in a dose-dependent manner. FCM testing showed Rg3-NPs can be released from the conjugate nanoparticle and react with the genes in the cell nuclei, causing changes in the gene molecules. We also found that cancer cells treated with Rg3-NPs undergo cell-cycle arrest at different checkpoints. This arrest was associated with a decrease in the mRNA levels of core regulatory genes BUB1, CDC20, TTK, and CENPE, as determined by microarray analysis and verified by real-time PCR. Furthermore, Rg3-NPs induced the expression of the apoptotic and antimigratory protein p53 in cell lines. The results of the present study, together with the results of earlier studies, show that Rg3-NPs target genes involved in theprogressionoftheM-phaseofthecellcycle.Itisassociatedwithseveralimportant pathways, which include apoptosis (p53). Rg3-NPs may be a potent cell-cycle regulation drug targeting the M-phase in glioblastoma cell lines.
Published: 2012
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14. Novel therapies for high-grade gliomas: A vision for future

Author: G Kohanbash, C Belka, RE Coleman, D Barba, JH Kim, H Burris, E Razis, C Sturiale, Lesniak, SA Grossman, B Dhokia, MP Gustafson, ZQ Han, P Traxler, AM Sandmair, LM DeAngelis, G Franceschi, P Msaouel, G Kaur, MJ Zhu, S Taillibert, I Yang, M Brown, AT Bruce, HP Kalofonos, T Todo, TC Liu, HS Hochster, KL Black, C Royce, D Fukumura, NL Spector, P Duic, MP Sayers, M Koslow, C Stanton, KL Fink, L Kim, JM Reid, AK Muhammad, JS Yu, AH Friedman, T Gohongi, KA Kreuzer, R Cozens, GP Dunn, DA Haas-Kogan, KB Hymes, JH Sampson, DD Song, RB Herberman, R Ramina, K Kawakami, GG Gomez, N Jelluma, E Galanis, SC Saris, S Thomas, Sy Lim, FM Iwamoto, AJ Grant, H Bender, W Xia, C Wallace, LH Merchant, S Kunwar, RD Schreiber, RE Merchant, AM Kaplan, Vivek Tandon, JS Hardwick, K Ballman, Berger, I Stroud, D Fabbro, JM Piepmeier, WK Yung, JC Hiserodt, K Moore, YB Wang, L Zhang, R Alemany, N Dmitrieva, HJ Choi, KM Kroeger, CD Stiles, D Schiff, LJ Old, JL Clarke, AL Asher, DV Woo, JL Mahaley, R Brandt, P Clement, JI Kreisberg, M Ehtesham, FK Miura, EM Hiesiger, I Cokgor, PY Wen, IK Na, C Crane, LB Nabors, HI Robins, HT Chung, G Ibrahim, NK Kim, A Arista, K Panageas, S Ahmad, RK Jain, KL Penne, JJ Vredenburgh, GD King, M Weller, CT Kuan, T Tihan, H Wakimoto, R Sakalas, CW Reynolds, JC Buckner, S Lassiter, HF Young, M Kioi, H Fukuhara, J Wykosky, MA Vogelbaum, TN Kreisl, H Okada, RE McLendon, V Jendrossek, CJ Wikstrand, P Puranen, M Puranen, W Xiong, Mahaley, YY Kim, C Sauvageot, JA Quinn, SR Husain, S Labropoulos, IF Pollack, CH Tung, J Laterra, JM Dowell, HS Friedman, A Desjardins, EC Dees, K Shah, BK Cho, C Valiengo Lda, GC Gonzalez, P Forsyth, M Assenberg, W Debinski, P Riva, JC Rodrigues, DA Eberhard, S Xia, SM Chang, Jy Yoo, J Hardcastle, CA Kruse, TJ Liu, R Weissleder, Jr MahaleyMS, D Snook, W Roth, Subhashree Mahapatra, M Frattarelli, KC Wang, FF Lang, KA Jaeckle, EA Chiocca, K Terada, C Gomez-Manzano, PR Lowenstein, JJ Kelly, SA Rosenberg, P Selviaridis, Prados, IV Ulasov, E Tyminski, S Sinha, RL Hayes, J Brueggen, T Kuroda, GJ Baker, J Sul, G Simpson, M Rackover, SK Kim, DD Bigner, S Desideri, K Hopkins, XO Breakefield, JN Rich, H Ikeda, M Kawakami, JM Bruner, M Rosenfeld, ND Arvold, PH Aguiar, LW Brady, D Morris, G Roldan, M Candolfi, S Kesari, B Seed, BH Joshi, M Holdhoff, RL Martuza, YG Kwon, SX Jiang, JT Kemshead, M Campone, NL Vujanovic, Y Chen, DA Reardon, TF Cloughesy, A Dispenzieri, M van den Bent, M Kossila, B Hildebrandt, EH Oldfield, S Puri, T Zhang, K Kurozumi, S Loimas, MK Wibowo, C Holder, EM Rosen, H Hurwitz, G Dresemann, EC Kim, H Assi, BL Liu, N Butowski, C Appelt, Groves, EJ Moore, SJ Han, CA Palmer, N Ramakrishna, J Emrich, MJ Maurer, RK Puri, JL Norris, P Waterman, J Clarke, S Piantadosi, T Peery, JF Curtin, LE Abrey, AS Chi, N Courtenay-Luck, A Hemingway, Y Saeki, AB Lassman, V Papanastassiou, J Boni, ED Day, E Hussain, C Miyamoto, AK Mahapatra, R Scholz, AT Parsa, RB Greeno, KL Low, T Mikkelsen, S Chang, C Sarkar, J Fueyo, DV Cramer, PR Allegrini, A Dowlati, DM Gibo, L Xu, M Dey, MM Ames, M Shaffrey, HA McDonald, SB Omay, TR Pawlikowska, RL Hamilton, D George, N Riva, Ashok Kumar Mahapatra, A Immonen, TA Mattei, M Bamberg, X Ye, and B Woodhall
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, medicine.medical_treatment, Genetic enhancement, lcsh:Surgery, Disease, 030105 genetics & heredity, lcsh:RC346-429, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Glioma, novel therapy, medicine, current studies, lcsh:Neurology. Diseases of the nervous system, Chemotherapy, business.industry, Standard treatment, Immunotherapy, malignant glioma, lcsh:RD1-811, medicine.disease, gene therapy, Oncolytic virus, Radiation therapy, business, 030217 neurology & neurosurgery
Abstract: The treatment for high-grade glioma remains an enigma. The standard treatment using surgery, radiation therapy and chemotherapy for such highly malignant lesions has only yielded modest results, in terms of survival and improving the quality of life of patients. Less than 10% of such patients survive beyond two years. All conventional therapies have failed to increase the survival beyond this extent. There has been a growing interest in the molecular approaches for the treatment of high-grade gliomas which include gene therapy, oncolytic virotherapy, and immunotherapy. These new therapies are in preclinical and investigational stages. They may not substitute the conventional therapies; they may not be the ultimate elixir for this deadly disease. However, in the coming years, they are likely to have synergistic and complimentary roles alongside conventional therapies. Through this paper, we have attempted to highlight the rationale behind gene therapy which can be used for cytotoxic approaches, immunomodulation strategy, and targeted toxin delivery in the tumor cell. We have reviewed current available literature and through this paper focus on reporting such therapeutic options, their potential usage, benefits and limitations.
Published: 2012
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15. Reirradiation of Recurrent High Grade Gliomas: Outcomes and Prognostic Factors

Author: Jared Hara, Patricia Sneed, Susan M. Chang, Jean L. Nakamura, Shannon Fogh, Christopher H. Chapman, N. Butowski, Jennifer Leigh Clarke, David R. Raleigh, and Steve Braunstein
Subjects: Oncology, Cancer Research, medicine.medical_specialty, Radiation, business.industry, Internal medicine, medicine, Radiology, Nuclear Medicine and imaging, business
Published: 2018
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16. Pre-clinical Experimental Therapeutics and Pharmacology

Author: R. L. Jensen, D. Gilliespie, N. Ajewung, R. Faure, D. Kamnasaran, D. Poirier, K. Tamura, H. Wakimoto, S. D. Rabkin, R. L. Martuza, K. Shah, R. Hashizume, Y. Aoki, L. P. Serwer, D. Drummond, C. Noble, J. Park, K. Bankiewicz, D. C. James, N. Gupta, B. Agerholm-Larsen, H. K. Iversen, K. S. Jensen, J. Moller, P. Ibsen, F. Mahmood, J. Gehl, E. Corem, Z. Ram, D. Daniels, D. Last, R. Shneor, S. Salomon, B. Perlstein, S. Margel, Y. Mardor, G. Charest, D. Fortin, D. Mathieu, L. Sanche, B. Paquette, H.-F. Li, S. Hariono, T. Dasgupta, J.-S. Kim, D. Haas-Kogan, W. A. Weiss, C. D. James, T. Waldman, T. Nicolaides, T. Ozawa, S. Rao, H. Sun, C. Ng, J. De La Torre, R. Santos, M. Prados, N. Butowski, K. Michaud, D. A. Solomon, M. D. Prados, H. Pandya, D. Gibo, W. Debinski, S. Vinchon-Petit, D. Jarnet, E. Jadaud, L. Feuvret, E. Garcion, P. Menei, R. Chen, J.-C. Yu, C. Liu, Z. M. Jaffer, J. C. Chabala, N. Winssinger, A. E. Rubenstein, L. Emdad, H. Kothari, Z. Qadeer, E. Binello, I. Germano, H. Hirschberg, S.-K. Baek, Y. J. Kwon, C. H. Sun, S. C. Li, S. Madsen, T. Liu, S.-W. Wang, D. M. Gibo, Q.-W. Fan, C. Cheng, C. Hackett, M. Feldman, B. T. Houseman, S. A. Oakes, J. Debnath, K. M. Shokat, K. Sai, F. Chen, Z. Qiu, Y. Mou, X. Zhang, Q. Yang, Z. Chen, T. R. Patel, J. Zhou, J. M. Piepmeier, W. M. Saltzman, S. Banerjee, A. Kaul, S. M. Gianino, U. Christians, D. H. Gutmann, J. Wu, R. Shen, V. Puduvalli, D. Koul, W. K. Alfred Yung, J. Yun, A. Sonabend, M. Stuart, T. Yanagihara, S. Dashnaw, T. Brown, P. McCormick, A. Romanov, M. Sebastian, P. Canoll, J. N. Bruce, L. Piao, K. Joshi, R. J. Lee, I. Nakano, S. J. Madsen, C. C. Chou, J. W. Blickenstaff, C.-H. Sun, Y.-H. Zhou, C. M. L. Tome, J. Wykosky, E. Palma, E. Nduom, R. Machaidze, M. Kaluzova, Y. Wang, S. Nie, C. Hadjipanayis, R. Saito, T. Nakamura, Y. Sonoda, T. Kumabe, T. Tominaga, X. Lun, F. Zemp, H. Zhou, O. Stechishin, J. J. Kelly, S. Weiss, M. G. Hamilton, G. Cairncross, B. A. Rabinovich, J. Bell, G. McFadden, D. L. Senger, P. A. Forsyth, P. Kang, E. P. Jane, D. R. Premkumar, I. F. Pollack, J. Y. Yoo, A. Haseley, A. Bratasz, K. Powell, E. A. Chiocca, B. Kaur, T. G. Johns, P. Ferruzzi, F. Mennillo, A. De Rosa, M. Rossi, C. Giordano, R. Magrini, G. Benedetti, G. l. Pericot, L. Magnoni, E. Mori, R. Thomas, P. Tunici, A. Bakker, J. Pradarelli, A. Kaka, C. Alvarez-Breckenridge, Q. Pan, T. Teknos, L. Cen, J. L. Ostrem, M. A. Schroeder, A. C. Mladek, S. R. Fink, R. B. Jenkins, J. N. Sarkaria, A. B. Madhankumar, B. Slagle-Webb, A. Park, M. Pang, M. Klinger, K. S. Harbaugh, J. M. Sheehan, J. R. Connor, T. C. Chen, W. Wang, F. M. Hofman, D. C. Drummond, C. O. Noble, J. W. Park, Y. Zhou, J. D. Marks, M. M. Alonso, C. Gomez-Manzano, N. Cortes-Santiago, F. P. Roche, J. Fueyo, T.-C. A. Johannessen, A. Grudic, B. B. Tysnes, J. Nigro, R. Bjerkvig, A. D. Joshi, W. Parsons, V. E. Velculescu, G. J. Riggins, R. S. Bindra, M. Jasin, S. N. Powell, J. Fu, R.-J. Shen, H. Colman, F. F. Lang, M. R. Jensen, G. K. Friedman, M. Haas, K. A. Cassady, G. Y. Gillespie, V. Nguyen, L. T. Murphy, A. S. Beauchamp, C. K. Hollingsworth, A. Mintz, S. Garg, S. Kridel, C. A. Conrad, T. Madden, Y. Ji, W. Priebe, O. Seleverstov, B. W. Purow, G. A. Grant, C. Wilson, M. Campbell, P. Humphries, S. Li, J. Li, A. Johnson, D. Bigner, M. Dewhirst, J. L. Pokorny, G. J. Kitange, B. L. Carlson, M. Suphangul, B. Petro, L. Mukhtar, M. S. Baig, J. Villano, N. Mahmud, S. T. Keir, D. A. Reardon, M. Watson, G. C. Shore, D. D. Bigner, H. S. Friedman, and S. Gururangan
Subjects: Cancer Research, Oncology, Neurology (clinical)
Published: 2010
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17. Quality of Life

Author: M. R. Lucas, T. S. Armstrong, A. Acquaye, D. Balachandran, A. Mahajan, D.-H. Kang, E. Vera-Bolanos, M. R. Gilbert, M. P. Lovely, M. Page, K. Mogensen, J. Arzbaecher, C. Amidei, K. Lupica, M. E. Maher, P. Sherwood, S. Kagan, E. M. Sizoo, H. R. W. Pasman, J. C. Reijneveld, J. J. Heimans, L. Deliens, M. J. Taphoorn, R. Sheth, B. T. Bagan, M. N. Baig, C. Karas, D. I. Jacobs, S. A. Grimm, A. Rademaker, L. Rice, J. P. Chandler, K. Muro, M. Marymount, I. B. Helenowski, L. I. Wagner, C. L. Bennett, J. J. Raizer, A. Evans, G. Dhall, J. Finlay, K. Wong, G. McComb, R. Soffietti, R. P. Mueller, U. Abacioglu, S. Villa, F. Fauchon, B. Baumert, L. Fariselli, G. Tridello, M. Kocher, A. Bottomley, C. Pendleton, H. Adams, G. I. Jallo, B. S. Carson, E. Ahn, A. Quinones-Hinojosa, A. A. Acquaye, B. N. Bekele, J. Chandler, V. Nestor, K. Fink, M. Nashed, M. Linskey, D. A. Bota, W. Hoeben, K. Hilverda, T. J. Postma, J. Buter, J. Lenting, E. H. Collette, M. Klein, D. van Nieuwenhuizen, L. Bosscher, E. Szymanska, S. M. Peerdeman, T. Erdmann, S. N. Lawrence Recht, T. Armstrong, I. Gning, C. Cleeland, T. R. Mendoza, N. Jouniaux-Delbez, J. Y. Delattre, S. T. du Montcel, N. Butowski, R. Parvataneni, A. Nicole, K. Lamborn, M. Polley, J. Clarke, S. Chang, M. Prados, A. Liepa, P. Shi, D. Thornton, C. A. Kahlenberg, C. E. Fadul, R. Scott, D. W. Roberts, V. Thadani, K. Bujarski, E. C. Lallana, B. C. Jobst, J. G. Walker, D. Schultz, K. Grisdale, M. D. Groves, K. B. Peters, D. A. Reardon, J. J. Vredenburgh, A. Desjardins, H. S. Friedman, D. H. Allen, B. Carlson, V. Neelon, K. Giovanello, J. Carlson, R. Raynor, R. Lall, S. Ha, M. Marymont, S. Grimm, J. Raizer, and S. T. Keir
Subjects: Wait and scan, Meningioma, Health related quality of life, Cancer Research, Pediatrics, medicine.medical_specialty, Oncology, business.industry, medicine, Neurology (clinical), business, medicine.disease
Published: 2010
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18. Radiology

Author: B. M. Ellingson, W. B. Pope, A. Lai, P. L. Nghiemphu, T. F. Cloughesy, C. Juhasz, S. Mittal, O. Muzik, D. C. Chugani, P. K. Chakraborty, G. Bahl, G. R. Barger, J. A. Carrillo, P. Nghiemphu, A. Tran, P. Moftakhar, C. Bruggers, K. Moore, S. Khatua, M. K. Gumerlock, E. Stolzenberg, K.-M. Fung, M. L. Smith, K. Kedzierska, G. Chacko, R. B. Epstein, J. Holter, R. Parvataneni, A. Kadambi, I. Park, A. Elkhaled, E. Essock-Burns, I. Khayal, N. Butowski, K. Lamborn, S. Chang, S. Nelson, E. Sanverdi, B. Ozgen, K. K. Oguz, F. Soylemezoglu, M. Mut, J.-J. Zhu, R. Pfannl, D. Do-Dai, K. Yao, J. Mignano, J. K. Wu, N. Linendoll, K. Beal, T. Chan, Y. Yamamda, A. Holodny, P. H. Gutin, Z. Zhang, R. J. Young, J. M. Lupo, S. Cha, S. M. Chang, S. J. Nelson, N. Laperriere, J. Perry, D. Macdonald, W. Mason, J. Easaw, R. Del Maestro, W. Kucharczyk, D. Hussey, K. Greaves, S. Moore, J.-F. Pouliot, P. K. Rauschkolb, S. D. Smith, C. J. Belden, E. C. Lallana, C. E. Fadul, L. Bosscher, M. Slot, E. Sanchez, B. M. Uitdehaag, W. P. Vandertop, S. M. Peerdeman, D. T. Blumenthal, F. Bokstein, M. Artzi, M. Palmon, O. Aizenstein, R. Sitt, K. Gurevich, A. Kanner, Z. Ram, B. Corn, D. Ben Bashat, N. Martinez, R. Gorniak, L. Tartaglino, M. Scanlan, J. Glass, A. Kleijn, J. W. Chen, P. Z. Sun, J. Buhrman, S. D. Rabkin, R. Weissleder, R. L. Martuza, M. L. Lamfers, G. Fulci, K. A. Brong, K. Hekmatyar, N. Jerome, M. Wilson, R. A. Kauppinen, K. Mok, M. M. Valenca, E. Sherafat, A. Olivier, E. Pentsova, M. Rosenblum, L. Palomba, A. Omuro, G. J. Murad, A. T. Yachnis, E. M. Dunbar, Y. Li, J. Lupo, M.-Y. Polley, N. Kohler, R. Quisling, K. R. Swanson, S. Gu, G. Chakraborty, A. Alessio, J. Claridge, R. C. Rockne, M. Muzi, K. A. Krohn, A. M. Spence, E. C. Alvord, A. R. Anderson, P. Kinahan, A. E. Boone, M. M. Mrugala, M. Gutova, V. Khankaldyyan, K. A. Herrmann, I. Harutyunyan, Y. Abramyants, A. J. Annala, J. Najbauer, R. A. Moats, G. M. Shackleford, M. E. Barish, and K. S. Aboody
Subjects: Cancer Research, Oncology, Neurology (clinical)
Published: 2010
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19. Nivolumab (nivo) in combination with radiotherapy (RT) ± temozolomide (TMZ): Updated safety results from CheckMate 143 in pts with methylated or unmethylated newly diagnosed glioblastoma (GBM)

Author: Gordana Vlahovic, N. Butowski, John Sampson, Solmaz Sahebjam, Michael Carleton, Alba A. Brandes, Michael Lim, T. Cloughesy, Prashni Paliwal, David A. Reardon, Antonio Omuro, Joachim M. Baehring, Ricardo Zwirtes, and Von Potter
Subjects: 0301 basic medicine, Brachial Plexus Neuritis, Oncology, medicine.medical_specialty, Temozolomide, business.industry, medicine.medical_treatment, Checkmate, Hematology, Newly diagnosed, medicine.disease, Radiation therapy, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, 030220 oncology & carcinogenesis, Internal medicine, medicine, business, Glioblastoma, medicine.drug
Published: 2017
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20. Abstract 4686: Omx a hypoxia modulator reverses the immunosuppressive glioblastoma microenvironment by stimulating T cell infiltration and activation that results in increased number of long-term survivors

Author: Jonathan W. Winger, Sarah Ng, Natacha Le Moan, Ana Krtolica, N. Butowski, Philberta Y. Leung, Carol Liang, Cary Stephen P L, and Tina Davis
Subjects: Cancer Research, Tumor microenvironment, Tumor hypoxia, business.industry, medicine.medical_treatment, T cell, Immunotherapy, Hypoxia (medical), medicine.anatomical_structure, Oncology, Immunology, Cancer research, medicine, Cytotoxic T cell, Cytokine secretion, medicine.symptom, business, CD8
Abstract: Oxygen is one of the key modulators of tumor microenvironment whereby low oxygen or hypoxia is associated with resistance to chemo- and radio- therapies and poor patient outcomes. Hypoxia favors an immunosuppressive tumor microenvironment by promoting Treg recruitment and activation and suppressing T cell and NK cell proliferation and effector function and pro-inflammatory cytokine secretion. Therefore, reversing tumor hypoxia could create an immunopermissive microenvironment and improve the efficacy of several immunotherapies. Omniox has developed an oxygen carrier OMX that can specifically deliver oxygen to hypoxic tumor regions without affecting oxygenation of tissues within physiologic oxygen levels. Due to its biochemical features, OMX is well tolerated in small (rats and mice) and large (sheep and dogs) animals. Following intravenous administration, OMX extravasates through leaky tumor vasculature and accumulates within immunocompetent rodent orthotopic glioblastoma models as well as spontaneous canine brain tumors. Consequently, OMX decreases hypoxia levels in the tumor tissue measured directly using oxygen sensor probes and indirectly with exogenous hypoxia markers using ELISA, immunohistochemistry and flow cytometry methods. Here we evaluated OMX’ activity in reversing the immunosupressive tumor microenvironment using a combination of immunohistochemistry, flow cytometry and Luminex methods. Moreover, we investigated the efficacy of OMX in improving mouse survival and effectiveness of checkpoint inhibitors (CPI). Similar to previously published findings, we demonstrated that T lymphocytes are mostly excluded from hypoxic tumor areas in the GL261 model. A single OMX treatment in GL261 tumor-bearing mice reduces tumor hypoxia, enhances T cell localization in previously hypoxic tumor areas, and increases CD8 accumulation by ~4-fold. Specifically, OMX treatment increased the activated cytotoxic T lymphocytes (CTLs) fraction by ~2 fold and reduced the immunosuppressive Treg fraction by 2-fold, resulting in a 3-fold increase of Teff/Treg ratio, which indicates a switch from an immunosupressive to an immunopermissive microenvironment. When combined with CPI, OMX reverses the immunosuppressive tumor microenvironment by increasing CD8 T cell infiltration, proliferation and cytotoxic activity, and modulating IFNg and IFNg-inducible cytokines that may polarize T cells towards a Th1 phenotype. Furthermore, treatment of late-stage GL261 tumor-bearing mice with the combination of OMX-CPI increases mouse survival by 80%. By delivering oxygen specifically to the hypoxic tumor microenvironment, OMX may restore anti-cancer immune responses in glioblastoma patients and synergize with radiotherapy and immunotherapy to enhance tumor control and improve patient outcomes. Citation Format: Natacha Le Moan, Philberta Leung, Sarah Ng, Tina Davis, Carol Liang, Jonathan W. Winger, Stephen P. Cary, Nicolas Butowski, Ana Krtolica. Omx a hypoxia modulator reverses the immunosuppressive glioblastoma microenvironment by stimulating T cell infiltration and activation that results in increased number of long-term survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4686. doi:10.1158/1538-7445.AM2017-4686
Published: 2017
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21. P09.59 Phase 2 trial of palbociclib in adult patients with recurrent Rb positive glioblastoma

Author: Joanna J. Phillips, Annette M. Molinaro, Michael D. Prados, Jennifer Leigh Clarke, Jennie Taylor, M.S. Berger, N. Oberheim Bush, C. D. James, Susan M. Chang, and N. Butowski
Subjects: 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Bevacizumab, Population, Palbociclib, 03 medical and health sciences, Internal medicine, Medicine, Progression-free survival, education, POSTER PRESENTATIONS, education.field_of_study, biology, business.industry, Cyclin-dependent kinase 4, Cancer, medicine.disease, 030104 developmental biology, Pharmacodynamics, biology.protein, Biomarker (medicine), Neurology (clinical), business, medicine.drug
Abstract: Alterations in the CDK4/6 – RB signaling pathway are common causes of dysregulation of the cell cycle in many cancers, including glioblastoma. Palbociclib is an oral, highly selective, reversible inhibitor of CDK4/6, which leads to phosphorylation of RB and cell-cycle arrest. In a two-arm study, we evaluated the efficacy and safety of palbociclib in patients with recurrent glioblastoma. Notable eligibility criteria included confirmation of RB proficiency by IHC; ≤ 3 relapses; KPS ≥ 60; secondary glioblastomas were included; there were no limitation on prior treatments including bevacizumab. Patients were administered oral palbociclib 125 mg daily for 21 consecutive days followed by a 7 day break. Arm 1 planned for 15 patients to receive palbociclib for 7 days prior to indicated surgical resection for progression, followed by palbociclib. Arm 2 planned for 15 patients to receive palbociclib without additional resection. The primary objective was PFS-6, which was hypothesized to be 30% in this heavily pretreated population, and null hypothesis of 10%. Secondary objectives of toxicity, OS, and ORR. Exploratory results included biomarker assessment and pharmacodynamic effects for the surgical Arm 1 patients. A total of 22 patients were enrolled; 6 on Arm 1 and 16 on Arm 2. Median age for all arms was 47.5 years old (range 23 – 78 years old); 54% (12 patients) were male; and the median KPS was 90 (range 60 – 100). Palbociclib was started at first recurrence in 50% (11 patients – 3 in Arm 1 and 8 in Arm 2) of patients; at second recurrence in 36% (8 patients – 3 in Arm 1 and 5 in Arm 2); and at third recurrence in 14% (3 patients, all in Arm 2). Bevacizumab had previously been used in 77% (17 patients – 4 in Arm 1 and 13 in Arm 2) of cases. The trial was stopped early secondary to futility, with 95% (18 of 19) evaluable patients progressing within 6 months of intiating treatment. Four samples were available for immunohistochemistry for Rb and Ki67. There were no consistent changes in Rb expression or cell proliferation when compared to samples from diagnosis. Median progression free survival for all patients was 5.14 weeks (range 5 days – 142 weeks) and median overall survival was 15.4 weeks (range 2 – 274 weeks). Two patients (10%) had treatment related AEs that were grade ≥3. In this trial, palbociclib did not appear to have been an effective treatment for recurrent glioblastoma. However, this was a heavily pretreated patient population and targeting the CDK4/6 pathway may deserve further exploration.
Published: 2017
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22. OS07.3 Nivolumab in Combination With Radiotherapy With or Without Temozolomide in Patients With Newly Diagnosed Glioblastoma: Updated Results From CheckMate 143

Author: T. Cloughesy, Gordana Vlahovic, N. Butowski, John Sampson, Joachim M. Baehring, David A. Reardon, Antonio Omuro, Ricardo Zwirtes, Solmaz Sahebjam, and Michael Lim
Subjects: Oncology, Cancer Research, medicine.medical_specialty, medicine.medical_treatment, Checkmate, ORAL PRESENTATIONS, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, 0502 economics and business, medicine, Survival rate, Temozolomide, business.industry, 05 social sciences, O-6-methylguanine-DNA methyltransferase, Cancer, medicine.disease, Radiation therapy, 030220 oncology & carcinogenesis, 050211 marketing, Neurology (clinical), Nivolumab, business, medicine.drug, Glioblastoma
Abstract: Background: Patients with glioblastoma (GBM) have a 5-year survival rate of approximately 5%, indicating that novel therapeutic options are critically needed. Nivolumab, a fully human IgG4 monoclonal antibody inhibitor of the programmed death-1 receptor, has provided durable and clinically significant responses in multiple cancer types. In CheckMate 143 (NCT02017717), exploratory cohorts 1c and 1d evaluated the safety and tolerability of nivolumab in combination with radiotherapy (RT) ± temozolomide (TMZ) in patients with newly diagnosed GBM. Methods: In cohort 1c, patients with methylated, unmethylated, or indeterminate MGMT were treated with nivolumab 3 mg/kg every 2 weeks (Q2W) in combination with standard RT and concurrent TMZ (75 mg/m2 daily), followed by adjuvant TMZ (150–200 mg/m2 for 5 days per 28-day cycle for ≥ 6 cycles). I n cohort 1d, patients with unmethylated MGMT received nivolumab 3 mg/kg Q2W with standard RT without TMZ. Patients in both cohorts continued to receive nivolumab 3 mg/kg Q2W until confirmed disease progression or unacceptable toxicity. Results: Enrollment in the study has been completed (N = 110 patients); 57 patients with methylated (19%), unmethylated (68%), or indeterminate (12%) MGMT were treated in cohort 1c and 53 patients with unmethylated (96%) or indeterminate (4%) MGMT were treated in cohort 1d. Treatment discontinuations in cohorts 1c (39%) and 1d (51%) resulted from suspected radiographic progression (1c, 19%; 1d, 43%), patient decision (1c, 9%), study drug toxicity (1c, 5%; 1d, 4%), death (2% each), adverse event (AE) unrelated to study drug (1c, 2%), or unknown cause (2% each). Treatment-related AEs (TRAEs) occurred in 67% (1c) and 70% (1d) of patients, with the most common (≥ 15% in either cohort [1c, 1d]) being fatigue (28%, 26%), headache (21%, 13%), and increased ALT (16%, 9%). Grade 3–4 TRAEs reported in > 2 patients in either cohort (1c, 1d) included increased ALT (5%; 6%) and lipase (2%; 8%). AEs leading to discontinuation in cohort 1c were increased transaminases (5%) and asthenia, fatigue, and hypotension (2% each); in cohort 1d, AEs leading to discontinuation included increased ALT, increased lipase, herpes simplex virus encephalitis, and acute injury (2% each). No treatment-related deaths were reported. Signals of enhanced immune cell infiltration were observed in some patients who had surgery on study for suspected disease progression. Updated efficacy results will be presented. Conclusions: In this first prospective clinical trial of an immune checkpoint inhibitor in patients with newly diagnosed GBM, data suggest that nivolumab combined with RT ± TMZ was well tolerated, with no new safety signals. Rapid accrual in this study supports the feasibility of conducting a trial in patients with newly diagnosed unmethylated MGMT GBM without TMZ. Encouraging results warrant phase 2/3 studies, which have been initiated.
Published: 2017
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23. P17.38THE EFFECT OF TIMING OF RADIOTHERAPY (RT) IN PATIENTS WITH NEWLY-DIAGNOSED GLIOBLASTOMA MULTIFORME (GBM) RECEIVING TEMOZOLOMIDE (TMZ): AN ANALYSIS BASED ON THE UCSF EXPERIENCE

Author: N. Butowski, William Caleb Rutledge, Jennifer Leigh Clarke, Annette M. Molinaro, M.S. Berger, Susan M. Chang, Michael D. Prados, and Seunggu J. Han
Subjects: Oncology, Cancer Research, Prognostic variable, medicine.medical_specialty, Temozolomide, Intention-to-treat analysis, medicine.diagnostic_test, Proportional hazards model, business.industry, medicine.medical_treatment, Surgery, Clinical trial, Radiation therapy, Poster Presentations, Internal medicine, Biopsy, medicine, Neurology (clinical), Progression-free survival, business, medicine.drug
Abstract: BACKGROUND: The effect of timing of initiation of radiotherapy (RT) after surgery on the outcome of patients with glioblastoma (GBM) remains controversial. Most neurosurgeons and neuro-oncologists believe that early initiation of RT may result in clinical benefits. However, certain reports suggested that delayed RT may be positively associated with survival for GBM patients. To further explore this issue, we analyzed three clinical trials for newly diagnosed GBM patients receiving temozolomide (TMZ) conducted at UCSF. METHODS: From 2004 through 2010, 207 adult patients with supratentorial GBM were enrolled into 3 clinical trials which consisted of RT plus TMZ and an experimental agent. Timing of RT was defined as the time interval between definitive surgery and commencement of RT, which was intended to be within 6 weeks per protocol eligibility. Overall survival (OS) and Progression-free survival (PFS), measured from study registration, were estimated using the Kaplan-Meier method. Analysis by classification and regression trees was used to determine the cut-off values for timing of RT at which there was a significant difference in OS and PFS. Cox proportional hazards model was used to assess the effect of RT timing (in days) on clinical outcomes, adjusting for treatment protocol, age, KPS, and extent of resection. RESULTS: The median wait time between surgery and RT was 29.5 days (range: 7-89 days). There was no significant difference in timing of RT with respect to baseline variables, except for resection extent: patients who were given RT earlier were more likely to have undergone a biopsy than more extensive surgery. Unexpectedly, a short delay in RT administration (at 30-34 days) was predictive of prolonged OS (HR = 0.58, p < 0.02) as well as prolonged PFS (HR = 0.55, p < 0.001), compared to early initiation of RT (
Published: 2014

24. RADIATION THERAPY

Author: M. Anwar, J. Lupo, A. Molinaro, J. Clarke, N. Butowski, M. Prados, S. Chang, D. HaasKogan, S. Nelson, J. Ashman, J. Drazkowski, R. Zimmerman, T. Lidner, C. Giannini, A. Porter, N. Patel, I. Atean, N. Shin, A. Toltz, C. Laude, C. Freeman, J. Seuntjens, D. Roberge, M. Back, M. Kastelan, L. Guo, H. Wheeler, P. Beauchesne, G. Faure, G. Noel, T. Schmitt, L. Martin, E. Jadaud, C. Carnin, J. Bowers, N. Bennion, H. Lomas, K. Spencer, M. Richardson, W. McAllister, J. Sheehan, D. Schlesinger, R. Kersh, J. Brower, S. Gans, W. Hartsell, S. Goldman, J. H.-C. Chang, N. Mohammed, M. Siddiqui, V. Gondi, E. Christensen, S. Klawikowski, A. Garg, M. McAleer, L. Rhines, J. Yang, P. Brown, E. Chang, S. Settle, A. Ghia, M. Edson, G. N. Fuller, P. Allen, J. Li, A. Garsa, S. Badiyan, J. Simpson, J. Dowling, K. Rich, M. Chicoine, E. Leuthardt, A. Kim, C. Robinson, B. Gill, D. Peskorski, R. Lalonde, M. S. Huq, J. Flickinger, A. Graff, P. Clerkin, H. Smith, R. Isaak, J. Dinh, D. Grosshans, J. de Groot, S. McGovern, M. Gilbert, A. Mahajan, T. Gupta, S. Mohanty, S. Kannan, R. Jalali, J. Hardie, N. Laack, S. Kizilbash, J. Buckner, J. Uhm, I. Parney, R. Jenkins, P. Decker, J. Voss, R. Hiramatsu, S. Kawabata, M. Furuse, S.-I. Niyatake, T. Kuroiwa, M. Suzuki, K. Ono, C. Hobbs, L. Vallow, J. Peterson, K. Jaeckle, M. Heckman, R. Bhupendra, D. Horowitz, C.-S. Wuu, W. Feng, D. Drassinower, A. Lasala, A. Lassman, T. Wang, D. Indelicato, R. Rotondo, J. Bradley, E. Sandler, P. Aldana, N. Mendenhall, R. Marcus, R. Kabarriti, W. F. Mourad, D. M. Mejia, J. Glanzman, S. Patel, R. Young, M. Bernstein, L. Hong, J. Fox, P. LaSala, S. Kalnicki, M. Garg, S. Khatua, P. Hou, J. Wolff, J. Hamilton, W. Zaky, L. Ketonen, S.-H. Kim, S. R. Lee, null Ji, Y. Oh, U. Krishna, N. Shah, R. Pathak, A. Lila, P. Menon, A. Goel, R. Lall, T. Smith, A. Schumacher, A. McCaslin, J. Kalapurakal, J. Chandler, W. Magnuson, H. I. Robins, P. Mohindra, S. Howard, D. Manfredi, C. L. Rogers, M. Palmer, E. Hillebrandt, S. Bilton, G. Robinson, K. Velasco, M. Mehta, J. McGregor, J. Grecula, M. Ammirati, C. Pelloski, L. Lu, N. Gupta, S. Bell, S. Moller, I. Law, P. M. a. Rosenschold, J. Costa, H. S. Poulsen, S. A. Engelholm, A. Morrison, B. Cuglievan, Z. Khatib, T. Santiago, D. M. Blakaj, M. Welch, J. Graber, L. X. Hong, A. Patel, A. Tandon, M. B. Bernstein, R. A. Shourbaji, M. D. Kinon, J. L. Fox, P. Lasala, M. K. Garg, S. Nicholas, R. Salvatori, M. Lim, K. Redmond, A. Quinones, G. Gallia, D. Rigamonti, L. Kleinberg, W. Mourad, R. Yaparpalvi, O. Mian, M. Degaonkar, H. Sair, S. Terezakis, T. McNutt, M. Wharam, M. Mahone, A. Horska, U. Rezvi, E. Melian, M. Surucu, I. Mescioglu, V. Prabhu, J. Clark, D. Anderson, J. Robbins, R. Yechieli, S. Ryu, M. I. Ruge, B. Suchorska, C. Hamisch, K. Mahnkopf, R. Lehrke, H. Treuer, V. Sturm, J. Voges, A. Sahgal, A. Al-Omair, L. Masucci, L. Masson-Cote, E. Atenafu, D. Letourneau, E. Yu, R. Rampersaud, S. Lewis, A. Yee, I. Thibault, M. Fehlings, W. Shi, J. Palmer, L. Kenyon, J. Glass, L. Kim, M. Werner-wasik, D. Andrews, S. Susheela, S. Revannasiddaiah, S. Muzumder, G. Mallarajapatna, A. Basavalingaiah, M. Gupta, K. Kallur, M. Hassan, R. Bilimagga, K. Tamura, M. Aoyagi, N. Ando, T. Ogishima, M. Yamamoto, K. Ohno, T. Maehara, Z. Xu, M. L. Vance, D. Blakaj, P. A. LaSala, J. J. Graber, A. L. Zimmerman, M. A. Vogelbaum, G. H. Barnett, E. S. Murphy, J. H. Suh, L. Angelov, C. A. Reddy, and S. T. Chao
Subjects: Cancer Research, Abstracts, Oncology, Neurology (clinical)
Published: 2013

25. RADIOBIOLOGY

Author: M. Artesi, J. Kroonen, M. Deprez, M. Bredel, A. Chakravarti, C. Poulet, T. Seute, B. Rogister, V. Bours, P. Robe, S.-C. Liu, S. Chernikova, M. Merchant, T. Jang, S. Zollner, A. Kruschinski, G.-o. Ahn, L. Recht, M. Brown, E. C.-J. Moyal, C. Delmas, M. Taurand, S. Mazoyer, M. Farge, C. Toulas, S. Rao, C. Thompson, J. Cheng, A. Haimovitz-Friedman, Z. Fuks, R. Kolesnick, Q. Wen, L. Jalilian, E. Essock-Burns, Y. Li, S. Cha, S. Chang, M. Prados, N. Butowski, S. Nelson, C. Ke, K. Tran, A. T. Di Donato, N. Ru, M. E. Linskey, C. Limoli, and Y.-H. Zhou
Subjects: Cancer Research, Abstracts, Oncology, Neurology (clinical)
Published: 2013

26. EXPERIMENTAL THERAPEUTICS AND PHARMACOLOGY

Author: C. Aaberg-Jessen, L. Fogh, B. Halle, V. Jensen, N. Brunner, B. W. Kristensen, T. Abe, Y. Momii, J. Watanabe, I. Morisaki, A. Natsume, T. Wakabayashi, M. Fujiki, B. Aldaz, A. W. M. Fabius, J. Silber, G. Harinath, T. A. Chan, J. T. Huse, S. Anai, T. Hide, H. Nakamura, K. Makino, S. Yano, J.-i. Kuratsu, I. V. Balyasnikova, M. S. Prasol, D. K. Kanoija, K. S. Aboody, M. S. Lesniak, T. Barone, C. Burkhart, A. Purmal, A. Gudkov, K. Gurova, R. Plunkett, K. Barton, K. Misuraca, F. Cordero, E. Dobrikova, H. Min, M. Gromeier, D. Kirsch, O. Becher, L. B. Pont, J. Kloezeman, M. van den Bent, R. Kanaar, A. Kremer, S. Swagemakers, P. French, C. Dirven, M. Lamfers, S. Leenstra, R. Balvers, A. Kleijn, S. Lawler, X. Gong, A. Andres, J. Hanson, J. Delashaw, D. Bota, C.-C. Chen, N.-W. Yao, W.-J. Chuang, C. Chang, P.-Y. Chen, C.-Y. Huang, K.-C. Wei, Y. Cheng, Q. Dai, R. Morshed, Y. Han, B. Auffinger, D. Wainwright, L. Zhang, A. Tobias, E. Rincon, B. Thaci, A. Ahmed, C. He, M. Lesniak, Y. A. Choi, H. Pandya, D. M. Gibo, I. Fokt, W. Priebe, W. Debinski, Y. Chornenkyy, S. Agnihotri, P. Buczkowicz, P. Rakopoulos, A. Morrison, M. Barszczyk, C. Hawkins, S. Chung, S. Decollogne, P. Luk, H. Shen, W. Ha, B. Day, B. Stringer, P. Hogg, P. Dilda, K. McDonald, S. Moore, M. Hayden-Gephart, J. Bergen, Y. Su, H. Rayburn, M. Edwards, M. Scott, J. Cochran, A. Das, A. K. Varma, G. C. Wallace, Y. N. Dixon-Mah, W. A. Vandergrift, P. Giglio, S. K. Ray, S. J. Patel, N. L. Banik, T. Dasgupta, A. Olow, X. Yang, S. Mueller, M. Prados, C. D. James, D. Haas-Kogan, N. D. Dave, P. B. Desai, G. A. Gudelsky, L. M. L. Chow, K. LaSance, X. Qi, J. Driscoll, K. Ebsworth, M. J. Walters, L. S. Ertl, Y. Wang, R. D. Berahovic, J. McMahon, J. P. Powers, J. C. Jaen, T. J. Schall, Z. Eroglu, J. Portnow, A. Sacramento, E. Garcia, A. Raubitschek, T. Synold, S. Esaki, S. Rabkin, R. Martuza, H. Wakimoto, S. Ferluga, C. L. Tome, H. E. Forde, I. A. Netland, L. Sleire, B. Skeie, P. O. Enger, D. Goplen, M. Giladi, A. Tichon, R. Schneiderman, Y. Porat, M. Munster, M. Dishon, U. Weinberg, E. Kirson, Y. Wasserman, Y. Palti, D. Gramatzki, M. Staudinger, K. Frei, M. Peipp, M. Weller, C. Grasso, L. Liu, N. Berlow, L. Davis, M. Fouladi, A. Gajjar, E. Huang, E. Hulleman, M. Hutt, C. Keller, X.-N. Li, P. Meltzer, M. Quezado, M. Quist, E. Raabe, P. Spellman, N. Truffaux, D. van Vurden, N. Wang, K. Warren, R. Pal, J. Grill, M. Monje, A. L. Green, S. Ramkissoon, D. McCauley, K. Jones, J. A. Perry, L. Ramkissoon, C. Maire, S. Shacham, K. L. Ligon, A. L. Kung, K. Zielinska-Chomej, V. Grozman, J. Tu, K. Viktorsson, R. Lewensohn, S. Gupta, A. Mladek, K. Bakken, B. Carlson, F. Boakye-Agyeman, S. Kizilbash, M. Schroeder, J. Reid, J. Sarkaria, P. Hadaczek, T. Ozawa, L. Soroceanu, Y. Yoshida, L. Matlaf, E. Singer, E. Fiallos, C. S. Cobbs, R. Hashizume, M. Tom, Y. Ihara, R. Santos, J. D. L. Torre, E. Lepe, T. Waldman, D. James, X. Huang, L. Yu-Jen, N. Gupta, D. Solomon, Z. Zhang, T. Hayashi, K. Adachi, S. Nagahisa, M. Hasegawa, Y. Hirose, M. H. Gephart, Y. S. Su, S. Hingtgen, R. Kasmieh, I. Nesterenko, J.-L. Figueiredo, R. Dash, D. Sarkar, P. Fisher, K. Shah, E. Horne, P. Diaz, N. Stella, C. Huang, H. Yang, K. Wei, T. Huang, J. Hlavaty, D. Ostertag, F. L. Espinoza, B. Martin, H. Petznek, M. Rodriguez-Aguirre, C. Ibanez, N. Kasahara, W. Gunzburg, H. Gruber, D. Pertschuk, D. Jolly, J. Robbins, B. Hurwitz, J. Y. Yoo, C. Bolyard, J.-G. Yu, J. Wojton, J. Zhang, Z. Bailey, D. Eaves, T. Cripe, M. Old, B. Kaur, L. Serwer, N. Le Moan, S. Ng, N. Butowski, A. Krtolica, S. P. L. Cary, T. Johns, S. Greenall, J. Donoghue, T. Adams, G. Karpel-Massler, M.-A. Westhoff, R. E. Kast, A. Dwucet, C. R. Wirtz, K.-M. Debatin, M.-E. Halatsch, N. Merkur, F. Kievit, Z. Stephen, K. Wang, D. Kolstoe, R. Ellenbogen, M. Zhang, G. Kitange, E. Haefner, K. Knubel, B. M. Pernu, A. Sufit, A. M. Pierce, S. K. Nelson, A. K. Keating, S. S. Jensen, J. Lachowicz, M. Demeule, A. Regina, S. Tripathy, J.-C. Curry, T. Nguyen, J.-P. Castaigne, T. Davis, A. Davis, K. Tanaka, T. Keating, J. Getz, G. T. Kapp, J. M. Romero, S. Lee, S. Ramisetti, B. Slagle-Webb, A. Sharma, J. Connor, W.-S. Lee, M. Kluk, J. C. Aster, K. Ligon, S. Sun, D. Lee, A. S. W. Ho, J. K. S. Pu, Z.-q. Zhang, N. P. Lee, P. J. R. Day, G. K. K. Leung, Z. Liu, X. Liu, A. B. Madhankumar, P. Miller, B. Webb, J. R. Connor, Q. X. Yang, M. Lobo, S. Green, M. Schabel, Y. Gillespie, R. Woltjer, M. Pike, Y.-J. Lu, H. A. Luchman, O. Stechishin, S. Nguyen, J. G. Cairncross, S. Weiss, X. Lun, J. C. Wells, X. Hao, N. Grinshtein, D. Kaplan, A. Luchman, D. Senger, S. Robbins, A. Madhankumar, E. Rizk, R. Payne, A. Park, M. Pang, K. Harbaugh, A. Wilisch-Neumann, D. Pachow, E. Kirches, C. Mawrin, S. McDonell, J. Liang, Y. Piao, N. Nguyen, A. Yung, R. Verhaak, E. Sulman, C. Stephan, F. Lang, J. de Groot, Y. Mizobuchi, T. Okazaki, T. Kageji, K. Kuwayama, K. T. Kitazato, H. Mure, K. Hara, R. Morigaki, K. Matsuzaki, K. Nakajima, S. Nagahiro, S. Kumala, M. Heravi, S. Devic, T. Muanza, K. H. Knubel, A. Neuwelt, Y. J. Wu, A. Donson, R. Vibhakar, S. Venkatamaran, V. Amani, E. Neuwelt, L. Rapkin, N. Foreman, F. Ibrahim, P. New, K. Cui, H. Zhao, D. Chow, W. Stephen, K. Nozue-Okada, M. Nagane, K. L. McDonald, D. Ogawa, E. Chiocca, J. Godlewski, A. Patel, N. Pasupuleti, F. Gorin, A. Valenzuela, L. Leon, K. Carraway, C. Ramachandran, S. Nair, K.-W. Quirrin, Z. Khatib, E. Escalon, S. Melnick, A. Phillips, E. Boghaert, K. Vaidya, P. Ansell, D. Shalinsky, Y. Zhang, M. Voorbach, S. Mudd, K. Holen, R. Humerickhouse, E. Reilly, S. Parab, O. Diago, T. Ryken, S. Agarwal, M. Al-Keilani, M. Alqudah, Z. Sibenaller, M. Assemolt, K. Sai, W.-y. Li, W.-p. Li, Z.-p. Chen, R. Saito, Y. Sonoda, M. Kanamori, Y. Yamashita, T. Kumabe, T. Tominaga, G. Sarkar, G. Curran, R. Jenkins, R. Scharnweber, Y. Kato, J. Lin, R. Everson, H. Soto, C. Kruse, L. Liau, R. Prins, S. Semenkow, Q. Chu, C. Eberhart, R. Sengupta, J. Marassa, D. Piwnica-Worms, J. Rubin, R. Shai, T. Pismenyuk, I. Moshe, T. Fisher, S. Freedman, A. Simon, N. Amariglio, G. Rechavi, A. Toren, M. Yalon, Y. Shimazu, K. Kurozumi, T. Ichikawa, K. Fujii, M. Onishi, J. Ishida, T. Oka, M. Watanabe, Y. Nasu, H. Kumon, I. Date, R. W. Sirianni, R. L. McCall, J. Spoor, M. van der Kaaij, M. Geurtjens, O. Veiseh, C. Fang, M. Leung, G. Strohbehn, K.-K. Atsina, T. Patel, J. Piepmeier, J. Zhou, W. M. Saltzman, M. Takahashi, G. Valdes, A. Inagaki, S. Kamijima, K. Hiraoka, E. Micewicz, W. H. McBride, K. S. Iwamoto, H. E. Gruber, J. M. Robbins, D. J. Jolly, C. McCully, J. Bacher, T. Thomas, R. Murphy, E. Steffen-Smith, R. McAllister, D. Pastakia, B. Widemann, P. Chen, M. Hua, H. Liu, E. C. Woolf, M. G. Abdelwahab, K. E. Fenton, Q. Liu, G. Turner, M. C. Preul, A. C. Scheck, W. Shen, D. Brown, H. Pedersen, S. Hariono, T.-W. Yao, A. Sidhu, W. A. Weiss, T. P. Nicolaides, and T. Olusanya
Subjects: Cancer Research, Abstracts, Oncology, business.industry, Medicine, Neurology (clinical), Pharmacology, business
Published: 2013

27. Omission of Radiation Therapy for Low-Grade Gliomas: Molecular and Radiographic Correlates of Treatment Response and Disease Progression on a Phase 2 Clinical Trial of Adjuvant Temozolomide

Author: Michael D. Prados, Manisha R. Dayal, N. Butowski, Susan M. Chang, Sarah J. Nelson, Joanna J. Phillips, M.S. Berger, Jennifer Leigh Clarke, Arie Perry, Annette M. Molinaro, Joseph F. Costello, Michael Wahl, Daphne A. Haas-Kogan, and Yi Lin
Subjects: Oncology, Cancer Research, medicine.medical_specialty, Treatment response, Radiation, Temozolomide, business.industry, Radiography, medicine.medical_treatment, Disease progression, Phases of clinical research, Surgery, Radiation therapy, Internal medicine, Medicine, Radiology, Nuclear Medicine and imaging, business, Adjuvant, medicine.drug
Published: 2016
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28. PC3 - 154 Phase I/II Study of VAL-083 in Patients with Recurrent Glioblastoma

Author: L.M. Lopez, Jeffrey A. Bacha, M.R. Patel, H.A. Burris, D.M. Brown, Anne Steino, N. Butowski, G.S. Falchook, S. Kanekal, R. Schwartz, S.H. Kizilbash, and K.C. Shih
Subjects: Oncology, medicine.medical_specialty, Temozolomide, Bevacizumab, business.industry, Cmax, General Medicine, Dianhydrogalactitol, Clinical trial, Neurology, Pharmacokinetics, Refractory, Internal medicine, medicine, Neurology (clinical), Adverse effect, business, medicine.drug
Abstract: Glioblastoma (GBM) is the most common brain cancer. Resistance to front-line systemic therapy with temozolomide (TMZ) is correlated with O6-methylguanine-DNA-methyltransferase (MGMT) expression. Second-line treatment with bevacizumab has not improved overall survival. Dianhydrogalactitol (VAL-083) is a bi-functional alkylating agent that has MGMT-independent cell-kill activity against GBM cell-lines and cancer stem cells in vitro. VAL-083 crosses the blood-brain barrier and showed promise against CNS tumors in prior NCI-sponsored clinical trials. The goal of this clinical trial is to determine appropriate VAL-083 dosing for advancement to Phase III trials as a new treatment for recurrent GBM. METHODS: Patients must have recurrent GBM following surgery, radiation, TMZ and bevacizumab. Phase I: Open-label, single-arm, dose-escalation study. Patients received VAL-083 on days 1,2,3 of a 21-day cycle, until reaching MTD. Phase II: Additional patients enrolled at MTD to further assess safety and outcomes. RESULTS: Phase I: 29 patients were enrolled across 9 dose cohorts (1.5-50 mg/m2/d). 40mg/m2/d was confirmed as MTD. Myelosuppression was mild; no drug-related serious adverse events were reported at doses up to 40mg/m2/d. Dose limiting G4 thrombocytopenia was observed at higher doses. Platelet nadir occurred around day 20 and resolved rapidly and spontaneously. A dose-related survival improvement was observed. Pharmacokinetic analyses show 1-2h plasma terminal half-life; average Cmax 781ng/mL at 40mg/m2/d. Phase II: 14 patients were enrolled at 40mg/m2/d. To date, safety observations in Phase II are consistent with Phase I. CONCLUSIONS: VAL-083 at 40mg/m2/d exhibits a favorable safety profile and dose-related trend toward clinically meaningful improved survival in refractory GBM patient
Published: 2016
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29. RADIOLOGY

Author: S. Bluml, A. Panigrahy, M. Laskov, G. Dhall, M. D. Nelson, J. L. Finlay, F. H. Gilles, H. Arita, M. Kinoshita, N. Kagawa, Y. Fujimoto, N. Hashimoto, T. Yoshimine, J. D. Hamilton, J. Wang, V. A. Levin, P. Hou, M. E. Loghin, M. R. Gilbert, N. E. Leeds, J. F. deGroot, V. Puduvalli, E. F. Jackson, W. K. A. Yung, A. J. Kumar, B. M. Ellingson, T. F. Cloughesy, W. B. Pope, T. Zaw, H. Phillips, S. Lalezari, P. L. Nghiemphu, H. Ibrahim, K. Motevalibashinaeini, A. Lai, R. Harris, L. Douw, M. E. Van de Nieuwenhuijzen, J. J. Heimans, J. C. Baayen, C. J. Stam, J. C. Reijneveld, C. Juhasz, S. Mittal, D. Altinok, N. L. Robinette, O. Muzik, P. K. Chakraborty, G. R. Barger, T. M. Zaw, J. Goldin, W. Chen, M. A. Ahlman, P. Giglio, T. J. Kaufmann, S. K. Anderson, K. A. Jaeckle, J. H. Uhm, D. W. Northfelt, P. J. Flynn, J. C. Buckner, E. Galanis, O. Zalatimo, C. Weston, D. Allison, D. Bota, S. Kesari, M. Glantz, J. Sheehan, R. E. Harbaugh, Y. Chiba, A. Tsuboi, J. Hatazawa, H. Sugiyama, T. Nariai, J. Toyohara, Y. Tanaka, M. Inaji, M. Aoyagi, M. Yamamoto, K. Ishiwara, K. Ohno, L. Jalilian, E. Essock-Burns, S. Cha, S. Chang, M. Prados, N. Butowski, S. Nelson, Y. Kawahara, M. Nakada, Y. Hayashi, Y. Kai, N. Uchiyama, J.-i. Kuratsu, J.-i. Hamada, K. Yeom, J. Rosenberg, J. B. Andre, P. G. Fisher, M. S. Edwards, P. D. Barnes, S. Partap, J. M. Lupo, J. C. Crane, S. M. Chang, S. J. Nelson, C. A. Romanowski, N. Hoggard, D. A. Jellinek, S. Clenton, F. McKevitt, S. Wharton, I. Craven, A. Buller, C. Waddle, J. Bigley, I. D. Wilkinson, P. Metherall, L. J. Eckel, G. F. Keating, N. M. Wetjen, C. Giannini, C. Wetmore, R. Jain, J. Narang, A. S. Arbab, L. Schultz, L. Scarpace, T. Mikkelsen, A. Babajni-Feremi, L. Poisson, D. Gutman, C. Jaffe, J. Saltz, A. Flanders, B. Daniel, L. Zach, D. Guez, D. Last, D. Daniels, C. Hoffman, Y. Mardor, N. Guha-Thakurta, J. M. Debnam, C. Kotsarini, D. Jellinek, P. D. Griffiths, N. Khandanpour, P. Bambrough, S. Prabhu, R. L. Bassett, W. A. Yung, C. J. Campen, S. Soman, K. W. Yeom, M. J. Vos, J. Berkhof, T. J. Postma, E. Sanchez, E. M. Sizoo, F. J. Lagerwaard, J. Buter, D. P. Noske, R. R. Colen, B. Mahajan, F. A. Jolesz, P. O. Zinn, A. Molinaro, K. Lawton, D. Alexandru, M. E. Linskey, M. M. Chaumeil, B. Gini, H. Yang, A. Iwanami, S. Subramanian, T. Ozawa, E. J. Read, R. O. Pieper, P. Mischel, C. D. James, S. M. Ronen, P. S. LaViolette, E. Cochran, M. Al-Gizawiy, J. M. Connelly, M. G. Malkin, S. D. Rand, W. M. Mueller, K. M. Schmainda, A. D. Cohen, M. Prah, C. J. Hartman, X. J. Qiao, R. He, M. Brown, and T. Cloughesy
Subjects: Cancer Research, Abstracts, Oncology, Neurology (clinical)
Published: 2011

30. O2.04 * TREATMENT WITH OMX-4.80, A TUMOR-PENETRATING TUNABLE OXYGEN CARRIER, REDUCES TUMOR HYPOXIA AND DRAMATICALLY ENHANCES RADIATION THERAPY IN INTRACRANIAL MODELS OF GLIOBLASTOMA

Author: N. Butowski, Tomoko Ozawa, Ana Krtolica, Cary Stephen P L, Laura Serwer, David James, N. Le Moan, and Yasuyuki Yoshida
Subjects: Cancer Research, Pathology, medicine.medical_specialty, Tumor hypoxia, medicine.medical_treatment, Brain tumor, Hypoxia (medical), Biology, medicine.disease, Radiation therapy, Oncology, Hypoxia-inducible factors, Oral Presentations, medicine, Cancer research, Pimonidazole, Immunohistochemistry, Neurology (clinical), medicine.symptom, Immunostaining
Abstract: We have developed OMX-4.80, a tunable oxygen carrier from the H-NOX protein family, that preferentially accumulates in tumor tissue, reduces hypoxia and enhances radiotherapy (RT). Tumor hypoxia is associated with poor patient outcomes in multiple solid tumors including glioblastoma (GB) and is thought to be a major contributor to poor cancer responses to chemo and radiation therapy. Here, we show that OMX-4.80 administered i.v. into the tail vein of mice bearing orthotopic GB passes the blood-tumor barrier, penetrates deep into intracranial tumors, and significantly reduces tumor hypoxia in a dose-dependent manner. Hypoxia reduction is demonstrated by a significant decrease in levels of hypoxia inducible factor, HIF1α, and the external hypoxia marker pimonidazole as assessed by IHC and image analysis. Furthermore, hypoxia before and after treatment is compared in the individual tumors by concurrent immunostaining of tumors with a long-term hypoxia marker, Glut1, and short-lived HIF-1α. These data reveal >50% reduction in hypoxic tumor area after OMX-4.80 treatment confirming the effectiveness of OMX-4.80 in reducing hypoxia in individual tumors. When OMX-4.80 treatment was coupled with a single high dose of RT, we observed a 2.7-fold increase in tumor growth delay and 2.9-fold longer survival (p < 0.05, by logrank). Toxicology studies in rodents and dogs with single and multiple supratherapeutic doses of OMX-4.80 revealed a good safety profile affirming its suitability for clinical development. In conclusion, our results indicate that OMX-4.80 is an effective and promising RT enhancer that warrants clinical development in GB patients.
Published: 2014
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31. Radiographic and Molecular Correlates of Progression in Patients with Recurrent Low-Grade Gliomas Treated with Everolimus Under a Phase II Clinical Trial

Author: Michael Wahl, Joanna J. Phillips, Janine M. Lupo, Michael D. Prados, Arie Perry, N. Butowski, Jennifer Leigh Clarke, M.S. Berger, Annette M. Molinaro, Susan M. Chang, Daphne A. Haas-Kogan, and Sarah J. Nelson
Subjects: Oncology, Cancer Research, Prognostic variable, medicine.medical_specialty, Radiation, Everolimus, business.industry, Subtotal Resection, Resection, Clinical trial, Internal medicine, Medicine, Radiology, Nuclear Medicine and imaging, In patient, business, Male gender, Treatment Arm, medicine.drug
Abstract: previously reported improvement in PFS (10.4 vs. 4.0 years, p Z 0.002; HR Z 0.50). Treatment arm was identified as a prognostic variable in favor of RT + PCV for both OS (p Z 0.003; HR Z 0.59) and PFS (p < 0.001; HR Z 0.49). Histology was prognostic for OS (p < 0.001; HR Z 2.16) and PFS (p < 0.001; HR Z 1.85) in favor of O compared to A. Male gender was prognostic for inferior OS (p Z 0.02; HR Z 1.51). Molecular markers were not pre-specified; post-hoc analysis of these is ongoing. Conclusions: For “high-risk” LGG, defined as age < 40 years with subtotal resection/biopsy or 40 years with any degree of resection, RT followed by 6 cycles of PCV prolongs both OS and PFS, and RT plus chemotherapy should therefore be considered a new standard of care for such patients. Astrocytic histology and male gender predict for poorer survival. Acknowledgment: This project was supported by RTOG grant U10 CA21661, and CCOP grant U10 CA37422 from the National Cancer Institute (NCI). Author Disclosure: M.P. Mehta: E. Research Grant; Novocure. F. Honoraria; Research to Excellence, Soreno Foundation. G. Consultant; Abbvie, BMS, Elekta, Merck, Novocure, Novelos, Phillips. I. Travel Expenses; Abbvie, Celldex, Elekta, Phillips, Roche. K. Advisory Board; Celldex, Roche. N. Stock Options; Pharmacyclics, Accuray. P. Royalty; Demos. S. Leadership; RTOG. M. Won: None. E.G. Shaw: None. J. Buckner: None. M. Gilbert: E. Research Grant; Merck, Genentech, GSK. F. Honoraria; Genentech, Merck. K. Advisory Board; Merck, Genentech, BMS, Abbvie, EMD Serono. G. Barger: None. S. Coons: None. P. Ricci: None. D. Bullard: None. P.D. Brown: None. K. Stelzer: None. D.G. Brachman: None. J.H. Suh: G. Consultant; Varian. C. Schultz: None. J. Bahary: None. B.J. Fisher: None. H. Kim: None. A.D. Murtha: None. W.J. Curran: S. Leadership; RTOG.
Published: 2014
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32. A phase I study of convection-enhanced delivery (CED) of liposomal-irinotecan using real-time magnetic resonance imaging in patients with recurrent high-grade glioma.

Author: Narsinh KH, Kumar K, Bankiewicz K, Martin AJ, Berger M, Clarke J, Taylor J, Bush NAO, Molinaro AM, Aghi M, and Butowski N
Abstract: Background: Irinotecan demonstrates anti-tumor efficacy in preclinical glioma models but clinical results are modest due to drug delivery limitations. Convection enhanced delivery (CED) improves drug delivery by increasing intratumoral drug concentration. Real-time magnetic resonance imaging of infusate delivery during CED may optimize tumor coverage. This phase 1 trial examines the safety and tolerability of liposomal irinotecan and gadolinium delivered via CED using real-time MRI guidance in recurrent high-grade glioma patients., Methods: Initially, a 3 + 3 dose-escalating, single dose trial was planned with 4 cohorts based on a fixed drug dose and volume. After 9 patients, a protocol amendment allowed for variable volume and dose of the study agent based on tumor size. The amended design specified 'personalized' drug volume but fixed concentration of 20 mg/mL of liposomal irinotecan in the first cohort escalating to 40 mg/mL in the second cohort., Results: Eighteen patients with recurrent WHO grade 3 or 4 gliomas (diameter 1-4 cm) were treated. Based on the tumor volume, the total dose of liposomal irinotecan was 20-680 mg in a total volume of 2-17 ml. Technical challenges were overcome by real-time MRI guidance and protocol amendment. The only dose-limiting toxicity (DLT) was a grade 3 stroke. Safety and survival information is presented., Conclusions: CED of liposomal irinotecan using real-time MRI in patients with recurrent high-grade glioma is feasible. Image-guidance allowed for improved placement of CED cannulas and optimal tumor coverage. Our results warrant further study with repeat CED dosing., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)
Published: 2025
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33. Fc-enhanced anti-CTLA-4, anti-PD-1, doxorubicin, and ultrasound-mediated blood-brain barrier opening: A novel combinatorial immunotherapy regimen for gliomas.

Author: Kim KS, Habashy K, Gould A, Zhao J, Najem H, Amidei C, Saganty R, Arrieta VA, Dmello C, Chen L, Zhang DY, Castro B, Billingham L, Levey D, Huber O, Marques M, Savitsky DA, Morin BM, Muzzio M, Canney M, Horbinski C, Zhang P, Miska J, Padney S, Zhang B, Rabadan R, Phillips JJ, Butowski N, Heimberger AB, Hu J, Stupp R, Chand D, Lee-Chang C, and Sonabend AM
Subjects: Animals, Mice, Humans, Immune Checkpoint Inhibitors pharmacology, Immune Checkpoint Inhibitors therapeutic use, Glioma drug therapy, Glioma immunology, Glioma therapy, Glioma pathology, Immunoglobulin Fc Fragments, Tumor Microenvironment drug effects, Female, Combined Modality Therapy, Mice, Inbred C57BL, Glioblastoma drug therapy, Glioblastoma therapy, Glioblastoma immunology, Glioblastoma pathology, Xenograft Model Antitumor Assays, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Antineoplastic Combined Chemotherapy Protocols pharmacology, Doxorubicin administration & dosage, Doxorubicin pharmacology, Brain Neoplasms drug therapy, Brain Neoplasms immunology, Brain Neoplasms therapy, Brain Neoplasms pathology, Blood-Brain Barrier drug effects, Programmed Cell Death 1 Receptor antagonists & inhibitors, Immunotherapy methods, CTLA-4 Antigen antagonists & inhibitors
Abstract: Background: Glioblastoma is a highly aggressive brain cancer that is resistant to conventional immunotherapy strategies. Botensilimab, an Fc-enhanced anti-CTLA-4 antibody (FcE-aCTLA-4), has shown durable activity in "cold" and immunotherapy-refractory cancers., Methods: We evaluated the efficacy and immune microenvironment phenotype of a mouse analogue of FcE-aCTLA-4 in treatment-refractory preclinical models of glioblastoma, both as a monotherapy and in combination with doxorubicin delivered via low-intensity pulsed ultrasound and microbubbles (LIPU/MB). Additionally, we studied 4 glioblastoma patients treated with doxorubicin, anti-PD-1 with concomitant LIPU/MB to investigate the novel effect of doxorubicin modulating FcγR expressions in tumor-associated macrophages/microglia (TAMs)., Results: FcE-aCTLA-4 demonstrated high-affinity binding to FcγRIV, the mouse ortholog of human FcγRIIIA, which was highly expressed in TAMs in human glioblastoma, most robustly at diagnosis. Notably, FcE-aCTLA-4-mediated selective depletion of intratumoral regulatory T cells (Tregs) via TAM-mediated phagocytosis, while sparing peripheral Tregs. Doxorubicin, a chemotherapeutic drug with immunomodulatory functions, was found to upregulate FcγRIIIA on TAMs in glioblastoma patients who received doxorubicin and anti-PD-1 with concomitant LIPU/MB. In murine models of immunotherapy-resistant gliomas, a combinatorial regimen of FcE-aCTLA-4, anti-PD-1, and doxorubicin with LIPU/MB, achieved a 90% cure rate, that was associated robust infiltration of activated CD8+ T cells and establishment of immunological memory as evidenced by rejection upon tumor rechallenge., Conclusions: Our findings demonstrate that FcE-aCTLA-4 promotes robust immunomodulatory and anti-tumor effects in murine gliomas and is significantly enhanced when combined with anti-PD-1, doxorubicin, and LIPU/MB. We are currently investigating this combinatory strategy in a clinical trial (clinicaltrials.gov NCT05864534)., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
Published: 2024
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34. NRG-BN002: Phase I study of ipilimumab, nivolumab, and the combination in patients with newly diagnosed glioblastoma.

Author: Sloan AE, Winter K, Gilbert MR, Aldape K, Choi S, Wen PY, Butowski N, Iwamoto FM, Raval RR, Voloschin AD, Kamiya-Matsuoka C, Won M, and Mehta MP
Subjects: Humans, Male, Female, Middle Aged, Adult, Aged, Follow-Up Studies, Survival Rate, Prognosis, Chemoradiotherapy methods, Glioblastoma drug therapy, Glioblastoma pathology, Ipilimumab administration & dosage, Ipilimumab adverse effects, Nivolumab administration & dosage, Nivolumab adverse effects, Nivolumab therapeutic use, Brain Neoplasms drug therapy, Antineoplastic Combined Chemotherapy Protocols therapeutic use
Abstract: Background: Immune checkpoint inhibitors (ICIs) have efficacy in several solid tumors but limited efficacy in glioblastoma (GBM). This study evaluated the safety of anti-CTLA-4 and anti-PD-1 ICIs alone or in combination in newly diagnosed GBM after completion of standard radiochemotherapy with the subsequent intent to test combinatorial ICIs in this setting., Methods: The primary endpoint was dose-limiting toxicity (DLT) for adults with unifocal, supratentorial newly diagnosed GBM after resection and chemoradiation. Ipilimumab and nivolumab were tested separately and in combination with a planned expansion cohort dependent upon DLT results., Results: Thirty-two patients were enrolled at 9 institutions: 6 to each DLT assessment cohort and 14 to the expansion cohort. Median age: 55 years, 67.7% male, 83.9% White. Treatment was well tolerated with 16% Grade 4 events; the combination did not have unexpectedly increased toxicity, with no Grade 5 events. One DLT was seen in each single-agent treatment; none were observed in the combination, leading to expanded accrual of the combined treatment. The median follow-up was 19.6 months. For all patients receiving combination treatment, median overall survival (OS) and progression-free survival (PFS) were 20.7 and 16.1 months, respectively., Conclusions: IPI and NIVO are safe and tolerable with toxicities similar to those noted with other cancers when given in combination with adjuvant temozolomide for newly diagnosed GBM. Combination IPI + NIVO is not substantially more toxic than single agents. These results support a subsequent efficacy trial to test the combination of ICIs in Phase II/III for patients with newly diagnosed GBM., Clinicaltrials.gov Registration: NCT02311920., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
Published: 2024
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35. Functional prediction of response to therapy prior to therapeutic intervention is associated with improved survival in patients with high-grade glioma.

Author: Ledford A, Rodriguez A, Lipinski L, Abad A, Fenstermaker R, Edenfield J, Kanos C, Redjal N, Mansouri A, Zacharia B, Butowski N, Liu J, Han SJ, Ziu M, Cohen AL, Fabiano AJ, Miles K, Rayner M, Thompson J, Tollison K, Azimzadeh P, Holmes L, Gevaert M, and DesRochers TM
Subjects: Humans, Female, Male, Middle Aged, Adult, Aged, Prognosis, Antineoplastic Agents, Alkylating therapeutic use, Treatment Outcome, Neoplasm Grading, Progression-Free Survival, Temozolomide therapeutic use, Glioma mortality, Glioma therapy, Glioma pathology, Glioma drug therapy, Brain Neoplasms mortality, Brain Neoplasms therapy, Brain Neoplasms pathology, Brain Neoplasms drug therapy
Abstract: Patients with high-grade glioma (HGG) have an extremely poor prognosis compounded by a lack of advancement in clinical care over the past few decades. Regardless of classification, most newly diagnosed patients receive the same treatment, radiation and temozolomide (RT/TMZ). We developed a functional precision oncology test that prospectively identifies individual patient's response to this treatment regimen. Tumor tissues isolated from patients with newly diagnosed HGG enrolled in 3D PREDICT REGISTRY were evaluated for response to chemotherapeutic agents using the 3D Predict™ Glioma test. Patients receiving RT/TMZ were followed for 2 years. Clinical outcomes including imaging, assessments, and biomarker measurements were compared to patient matched test-predicted therapy response. Median survival between test-predicted temozolomide responders and test-predicted temozolomide non-responders revealed a statistically significant increase in progression-free survival when using the test to predict response across multiple subgroups including HGG (5.8 months), glioblastoma (4.7 months), and MGMT unmethylated glioblastoma (4.7 months). Overall survival was also positively separated across the subgroups at 7.6, 5.1, and 6.3 months respectively. The strong correlation of 3D Predict Glioma test results with clinical outcomes demonstrates that this functional test is prognostic in patients treated with RT/TMZ and supports aligning clinical treatment to test-predicted response across varying HGG subgroups., (© 2024. The Author(s).)
Published: 2024
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36. ONC201 (Dordaviprone) in Recurrent H3 K27M-Mutant Diffuse Midline Glioma.

Author: Arrillaga-Romany I, Gardner SL, Odia Y, Aguilera D, Allen JE, Batchelor T, Butowski N, Chen C, Cloughesy T, Cluster A, de Groot J, Dixit KS, Graber JJ, Haggiagi AM, Harrison RA, Kheradpour A, Kilburn LB, Kurz SC, Lu G, MacDonald TJ, Mehta M, Melemed AS, Nghiemphu PL, Ramage SC, Shonka N, Sumrall A, Tarapore RS, Taylor L, Umemura Y, and Wen PY
Subjects: Humans, Adult, Female, Male, Adolescent, Middle Aged, Young Adult, Child, Aged, Neoplasm Recurrence, Local genetics, Neoplasm Recurrence, Local drug therapy, Child, Preschool, Pyrimidines therapeutic use, Pyrimidines adverse effects, Pyridones therapeutic use, Glioma genetics, Glioma drug therapy, Glioma pathology, Brain Neoplasms genetics, Brain Neoplasms drug therapy, Brain Neoplasms pathology, Mutation, Histones genetics
Abstract: Purpose: Histone 3 (H3) K27M-mutant diffuse midline glioma (DMG) has a dismal prognosis with no established effective therapy beyond radiation. This integrated analysis evaluated single-agent ONC201 (dordaviprone), a first-in-class imipridone, in recurrent H3 K27M-mutant DMG., Methods: Fifty patients (pediatric, n = 4; adult, n = 46) with recurrent H3 K27M-mutant DMG who received oral ONC201 monotherapy in four clinical trials or one expanded access protocol were included. Eligible patients had measurable disease by Response Assessment in Neuro-Oncology (RANO) high-grade glioma (HGG) criteria and performance score (PS) ≥60 and were ≥90 days from radiation; pontine and spinal tumors were ineligible. The primary end point was overall response rate (ORR) by RANO-HGG criteria. Secondary end points included duration of response (DOR), time to response (TTR), corticosteroid response, PS response, and ORR by RANO low-grade glioma (LGG) criteria. Radiographic end points were assessed by dual-reader, blinded independent central review., Results: The ORR (RANO-HGG) was 20.0% (95% CI, 10.0 to 33.7). The median TTR was 8.3 months (range, 1.9-15.9); the median DOR was 11.2 months (95% CI, 3.8 to not reached). The ORR by combined RANO-HGG/LGG criteria was 30.0% (95% CI, 17.9 to 44.6). A ≥50% corticosteroid dose reduction occurred in 7 of 15 evaluable patients (46.7% [95% CI, 21.3 to 73.4]); PS improvement occurred in 6 of 34 evaluable patients (20.6% [95% CI, 8.7 to 37.9]). Grade 3 treatment-related treatment-emergent adverse events (TR-TEAEs) occurred in 20.0% of patients; the most common was fatigue (n = 5; 10%); no grade 4 TR-TEAEs, deaths, or discontinuations occurred., Conclusion: ONC201 monotherapy was well tolerated and exhibited durable and clinically meaningful efficacy in recurrent H3 K27M-mutant DMG.
Published: 2024
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37. A systematic review of high impact CpG sites and regions for MGMT methylation in glioblastoma [A systematic review of MGMT methylation in GBM].

Author: Gibson D, Vo AH, Lambing H, Bhattacharya P, Tahir P, Chehab FF, and Butowski N
Subjects: Humans, DNA Methylation genetics, DNA Modification Methylases genetics, DNA Repair Enzymes genetics, Prognosis, Tumor Suppressor Proteins genetics, Brain Neoplasms genetics, Glioblastoma genetics, Glioma genetics
Abstract: Background: MGMT (O 6 -methylguanine-DNA methyltransferase) promoter methylation is a commonly assessed prognostic marker in glioblastoma (GBM). Epigenetic silencing of the MGMT gene by promoter methylation is associated with greater overall and progression free survival with alkylating agent regimens. To date, there is marked heterogeneity in how MGMT promoter methylation is tested and which CpG sites are interrogated., Methods: To further elucidate which MGMT promoter CpG sites are of greatest interest, we performed comprehensive searches in PubMed, Web of Science, and Embase and reviewed 2,925 article abstracts. We followed the GRADE scoring system to assess risk of bias and the quality of the studies we included., Results: We included articles on adult glioblastoma that examined significant sites or regions within MGMT promoter for the outcomes: overall survival, progression free survival, and/or MGMT expression. We excluded systemic reviews and articles on lower grade glioma. fifteen articles met inclusion criteria with variable overlap in laboratory and statistical methods employed, as well as CpG sites interrogated. Pyrosequencing or BeadChip arrays were the most popular methods utilized, and CpG sites between CpG's 70-90 were most frequently investigated. Overall, there was moderate concordance between the CpG sites that the studies reported to be highly predictive of prognosis. Combinations or means of sites between CpG's 73-89 were associated with improved OS and PFS. Six studies identified CpG sites associated with prognosis that were closer to the transcription start site: CpG's 8, 19, 22, 25, 27, 32,38, and CpG sites 21-37, as well as low methylation level of the enhancer regions., Conclusion: The following systematic review details a comprehensive investigation of the current literature and highlights several potential key CpG sites that demonstrate significant association with OS, PFS, and MGMT expression. However, the relationship between extent of MGMT promoter methylation and survival may be non-linear and could be influenced by potential CpG hotspots, the extent of methylation at each CpG site, and MGMT enhancer methylation status. There were several limitations within the studies such as smaller sample sizes, variance between methylation testing methods, and differences in the various statistical methods to test for association to outcome. Further studies of high impact CpG sites in MGMT methylation is warranted., (© 2024. The Author(s).)
Published: 2024
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38. Targeted gene expression profiling predicts meningioma outcomes and radiotherapy responses.

Author: Chen WC, Choudhury A, Youngblood MW, Polley MC, Lucas CG, Mirchia K, Maas SLN, Suwala AK, Won M, Bayley JC, Harmanci AS, Harmanci AO, Klisch TJ, Nguyen MP, Vasudevan HN, McCortney K, Yu TJ, Bhave V, Lam TC, Pu JK, Li LF, Leung GK, Chan JW, Perlow HK, Palmer JD, Haberler C, Berghoff AS, Preusser M, Nicolaides TP, Mawrin C, Agnihotri S, Resnick A, Rood BR, Chew J, Young JS, Boreta L, Braunstein SE, Schulte J, Butowski N, Santagata S, Spetzler D, Bush NAO, Villanueva-Meyer JE, Chandler JP, Solomon DA, Rogers CL, Pugh SL, Mehta MP, Sneed PK, Berger MS, Horbinski CM, McDermott MW, Perry A, Bi WL, Patel AJ, Sahm F, Magill ST, and Raleigh DR
Subjects: Humans, Biomarkers, Gene Expression Profiling, Neoplasm Recurrence, Local pathology, Prospective Studies, Meningeal Neoplasms genetics, Meningeal Neoplasms radiotherapy, Meningeal Neoplasms pathology, Meningioma genetics, Meningioma radiotherapy, Meningioma pathology
Abstract: Surgery is the mainstay of treatment for meningioma, the most common primary intracranial tumor, but improvements in meningioma risk stratification are needed and indications for postoperative radiotherapy are controversial. Here we develop a targeted gene expression biomarker that predicts meningioma outcomes and radiotherapy responses. Using a discovery cohort of 173 meningiomas, we developed a 34-gene expression risk score and performed clinical and analytical validation of this biomarker on independent meningiomas from 12 institutions across 3 continents (N = 1,856), including 103 meningiomas from a prospective clinical trial. The gene expression biomarker improved discrimination of outcomes compared with all other systems tested (N = 9) in the clinical validation cohort for local recurrence (5-year area under the curve (AUC) 0.81) and overall survival (5-year AUC 0.80). The increase in AUC compared with the standard of care, World Health Organization 2021 grade, was 0.11 for local recurrence (95% confidence interval 0.07 to 0.17, P < 0.001). The gene expression biomarker identified meningiomas benefiting from postoperative radiotherapy (hazard ratio 0.54, 95% confidence interval 0.37 to 0.78, P = 0.0001) and suggested postoperative management could be refined for 29.8% of patients. In sum, our results identify a targeted gene expression biomarker that improves discrimination of meningioma outcomes, including prediction of postoperative radiotherapy responses., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Published: 2023
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39. A multicenter, phase 1, dose escalation clinical trial (G-FORCE-1) of XRT, RRx-001 and temozolomide followed by temozolomide +/- RRx-001 in newly diagnosed glioblastoma.

Author: Fine H, Reid T, Caroen S, Oronsky B, Abrouk N, and Butowski N
Abstract: Introduction: The current standard of care for newly diagnosed glioblastoma (GBM) is maximum surgical resection followed by concurrent treatment with temozolomide (TMZ) and radiotherapy (RT) and then six to twelve cycles of maintenance TMZ. RRx-001, an NLRP3 inhibitor and nitric oxide (NO) donor with chemoradiosensitizing, vascular normalizing and macrophage repolarizing properties, is currently in a Phase III trial for small cell lung cancer (SCLC). The purpose of this non-randomized trial was to establish the safety and look for a signal of clinical activity of RRx-001 as an add-on to RT and TMZ in patients with newly diagnosed glioblastoma., Methods: In this non-randomized, open-label, two part trial called G-FORCE-1 (NCT02871843), the first four cohorts of adult patients with histologically confirmed high grade gliomas received fractionated radiotherapy (60 Gy in 30 fractions over 6 weeks), daily 75 mg/m2 temozolomide and escalating doses of once weekly RRx-001 from 0.5 mg to 4 mg according to a 3+3 design followed by a 6 week no treatment interval and then standard maintenance TMZ (150 mg/m2 Cycle 1 and 200 mg/m2 in subsequent cycles) until disease progression. The second two cohorts of patients received fractionated radiotherapy (60 Gy in 30 fractions over 6 weeks), daily 75 mg/m2 temozolomide and once weekly RRx-001 4 mg followed by a 6 week no treatment interval and then two different maintenance schedules until disease progression according to the same 3+ 3 design: 1. 0.5 mg RRx-001 once weekly + 100 mg/m2 TMZ 5 days/week for up to 6 cycles of therapy; 2. 4 mg RRx-001 once weekly + 100 mg/m2 TMZ 5 days/week for up to 6 cycles of therapyThe primary endpoint was the recommended dose/maximally tolerated dose of the combination of RRx-001, TMZ and RT. Secondary endpoints were overall survival, progression free survival, objective response rate, duration of response and clinical benefit response., Results: A total of 16 newly diagnosed glioblastoma patients were enrolled. No dose limiting toxicities were observed and no MTD was reached. The recommended dose is 4 mg. After 24 months of follow up the median OS was 21.9 months (95% CI: 11.7 - NA). PFS median was 8 months (95% CI: 5 - NA). The overall response rate was 18.8% (3 PR out of 16) and the disease control rate was 68.8% (3 PR, 8 SD out of 16)., Conclusions: The addition of RRx-001 to TMZ and RT and to TMZ during maintenance was safe and well-tolerated and deserves further study., Competing Interests: Authors BO, TR, and SC are employed by the company EpicentRx. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Fine, Reid, Caroen, Oronsky, Abrouk and Butowski.)
Published: 2023
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40. Targeting the IL4 receptor with MDNA55 in patients with recurrent glioblastoma: Results of a phase IIb trial.

Author: Sampson JH, Singh Achrol A, Aghi MK, Bankiewicz K, Bexon M, Brem S, Brenner A, Chandhasin C, Chowdhary S, Coello M, Ellingson BM, Floyd JR, Han S, Kesari S, Mardor Y, Merchant F, Merchant N, Randazzo D, Vogelbaum M, Vrionis F, Wembacher-Schroeder E, Zabek M, and Butowski N
Subjects: Humans, Receptors, Interleukin-4 therapeutic use, Neoplasm Recurrence, Local drug therapy, Neoplasm Recurrence, Local pathology, Tumor Microenvironment, Glioblastoma drug therapy, Glioblastoma genetics, Glioblastoma pathology, Brain Neoplasms drug therapy, Brain Neoplasms genetics, Brain Neoplasms pathology
Abstract: Background: MDNA55 is an interleukin 4 receptor (IL4R)-targeting toxin in development for recurrent GBM, a universally fatal disease. IL4R is overexpressed in GBM as well as cells of the tumor microenvironment. High expression of IL4R is associated with poor clinical outcomes., Methods: MDNA55-05 is an open-label, single-arm phase IIb study of MDNA55 in recurrent GBM (rGBM) patients with an aggressive form of GBM (de novo GBM, IDH wild-type, and nonresectable at recurrence) on their 1st or 2nd recurrence. MDNA55 was administered intratumorally as a single dose treatment (dose range of 18 to 240 ug) using convection-enhanced delivery (CED) with up to 4 stereo-tactically placed catheters. It was co-infused with a contrast agent (Gd-DTPA, Magnevist®) to assess distribution in and around the tumor margins. The flow rate of each catheter did not exceed 10μL/min to ensure that the infusion duration did not exceed 48 h. The primary endpoint was mOS, with secondary endpoints determining the effects of IL4R status on mOS and PFS., Results: MDNA55 showed an acceptable safety profile at doses up to 240 μg. In all evaluable patients (n = 44) mOS was 11.64 months (80% one-sided CI 8.62, 15.02) and OS-12 was 46%. A subgroup (n = 32) consisting of IL4R High and IL4R Low patients treated with high-dose MDNA55 (>180 ug) showed the best benefit with mOS of 15 months, OS-12 of 55%. Based on mRANO criteria, tumor control was observed in 81% (26/32), including those patients who exhibited pseudo-progression (15/26)., Conclusions: MDNA55 demonstrated tumor control and promising survival and may benefit rGBM patients when treated at high-dose irrespective of IL4R expression level.Trial Registration: Clinicaltrials.gov NCT02858895., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)
Published: 2023
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41. Interactive Effects of Molecular, Therapeutic, and Patient Factors on Outcome of Diffuse Low-Grade Glioma.

Author: Hervey-Jumper SL, Zhang Y, Phillips JJ, Morshed RA, Young JS, McCoy L, Lafontaine M, Luks T, Ammanuel S, Kakaizada S, Egladyous A, Gogos A, Villanueva-Meyer J, Shai A, Warrier G, Rice T, Crane J, Wrensch M, Wiencke JK, Daras M, Oberheim Bush NA, Taylor JW, Butowski N, Clarke J, Chang S, Chang E, Aghi M, Theodosopoulos P, McDermott M, Jakola AS, Kavouridis VK, Nawabi N, Solheim O, Smith T, Berger MS, and Molinaro AM
Subjects: Humans, Retrospective Studies, Neurosurgical Procedures methods, Treatment Outcome, Oligodendroglioma pathology, Brain Neoplasms, Glioma pathology, Astrocytoma pathology
Abstract: Purpose: In patients with diffuse low-grade glioma (LGG), the extent of surgical tumor resection (EOR) has a controversial role, in part because a randomized clinical trial with different levels of EOR is not feasible., Methods: In a 20-year retrospective cohort of 392 patients with IDH-mutant grade 2 glioma, we analyzed the combined effects of volumetric EOR and molecular and clinical factors on overall survival (OS) and progression-free survival by recursive partitioning analysis. The OS results were validated in two external cohorts (n = 365). Propensity score analysis of the combined cohorts (n = 757) was used to mimic a randomized clinical trial with varying levels of EOR., Results: Recursive partitioning analysis identified three survival risk groups. Median OS was shortest in two subsets of patients with astrocytoma: those with postoperative tumor volume (TV) > 4.6 mL and those with preoperative TV > 43.1 mL and postoperative TV ≤ 4.6 mL. Intermediate OS was seen in patients with astrocytoma who had chemotherapy with preoperative TV ≤ 43.1 mL and postoperative TV ≤ 4.6 mL in addition to oligodendroglioma patients with either preoperative TV > 43.1 mL and residual TV ≤ 4.6 mL or postoperative residual volume > 4.6 mL. Longest OS was seen in astrocytoma patients with preoperative TV ≤ 43.1 mL and postoperative TV ≤ 4.6 mL who received no chemotherapy and oligodendroglioma patients with preoperative TV ≤ 43.1 mL and postoperative TV ≤ 4.6 mL. EOR ≥ 75% improved survival outcomes, as shown by propensity score analysis., Conclusion: Across both subtypes of LGG, EOR beginning at 75% improves OS while beginning at 80% improves progression-free survival. Nonetheless, maximal resection with preservation of neurological function remains the treatment goal. Our findings have implications for surgical strategies for LGGs, particularly oligodendroglioma.
Published: 2023
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42. Targeted gene expression profiling predicts meningioma outcomes and radiotherapy responses.

Author: Raleigh D, Chen W, Choudhury A, Youngblood M, Polley MY, Lucas CH, Mirchia K, Maas S, Suwala A, Won M, Bayley J, Harmanci A, Harmanci A, Klisch T, Nguyen M, Vasudevan H, McCortney K, Yu T, Bhave V, Lam TC, Pu J, Leung G, Chang J, Perlow H, Palmer J, Haberler C, Berghoff A, Preusser M, Nicolaides T, Mawrin C, Agnihotri S, Resnick A, Rood B, Chew J, Young J, Boreta L, Braunstein S, Schulte J, Butowski N, Santagata S, Spetzler D, Bush NAO, Villanueva-Meyer J, Chandler J, Solomon D, Rogers C, Pugh S, Mehta M, Sneed P, Berger M, Horbinski C, McDermott M, Perry A, Bi W, Patel A, Sahm F, and Magill S
Abstract: Background: Surgery is the mainstay of treatment for meningioma, the most common primary intracranial tumor, but improvements in meningioma risk stratification are needed and current indications for postoperative radiotherapy are controversial. Recent studies have proposed prognostic meningioma classification systems using DNA methylation profiling, copy number variants, DNA sequencing, RNA sequencing, histology, or integrated models based on multiple combined features. Targeted gene expression profiling has generated robust biomarkers integrating multiple molecular features for other cancers, but is understudied for meningiomas., Methods: Targeted gene expression profiling was performed on 173 meningiomas and an optimized gene expression biomarker (34 genes) and risk score (0 to 1) was developed to predict clinical outcomes. Clinical and analytical validation was performed on independent meningiomas from 12 institutions across 3 continents (N = 1856), including 103 meningiomas from a prospective clinical trial. Gene expression biomarker performance was compared to 9 other classification systems., Results: The gene expression biomarker improved discrimination of postoperative meningioma outcomes compared to all other classification systems tested in the independent clinical validation cohort for local recurrence (5-year area under the curve [AUC] 0.81) and overall survival (5-year AUC 0.80). The increase in area under the curve compared to the current standard of care, World Health Organization 2021 grade, was 0.11 for local recurrence (95% confidence interval [CI] 0.07-0.17, P < 0.001). The gene expression biomarker identified meningiomas benefiting from postoperative radiotherapy (hazard ratio 0.54, 95% CI 0.37-0.78, P = 0.0001) and re-classified up to 52.0% meningiomas compared to conventional clinical criteria, suggesting postoperative management could be refined for 29.8% of patients., Conclusions: A targeted gene expression biomarker improves discrimination of meningioma outcomes compared to recent classification systems and predicts postoperative radiotherapy responses., Competing Interests: Conflict of Interest Notification: MP has received honoraria for lectures, consultation, or advisory board participation from the following for-profit companies: Bayer, Bristol-Myers Squibb, Novartis, Gerson Lehrman Group (GLG), CMC Contrast, GlaxoSmithKline, Mundipharma, Roche, BMJ Journals, MedMedia, Astra Zeneca, AbbVie, Lilly, Medahead, Daiichi Sankyo, Sanofi, Merck Sharp & Dome, Tocagen, Adastra, Gan & Lee Pharmaceuticals. WCC and DRR are the inventors on patent PCT/US 21/70288 describing the use of targeted gene expression profiling to predict meningioma outcomes and radiotherapy responses.
Published: 2023
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43. Radiotherapy combined with nivolumab or temozolomide for newly diagnosed glioblastoma with unmethylated MGMT promoter: An international randomized phase III trial.

Author: Omuro A, Brandes AA, Carpentier AF, Idbaih A, Reardon DA, Cloughesy T, Sumrall A, Baehring J, van den Bent M, Bähr O, Lombardi G, Mulholland P, Tabatabai G, Lassen U, Sepulveda JM, Khasraw M, Vauleon E, Muragaki Y, Di Giacomo AM, Butowski N, Roth P, Qian X, Fu AZ, Liu Y, Potter V, Chalamandaris AG, Tatsuoka K, Lim M, and Weller M
Subjects: Humans, Temozolomide therapeutic use, Nivolumab therapeutic use, Disease-Free Survival, Progression-Free Survival, Antineoplastic Agents, Alkylating therapeutic use, DNA Modification Methylases genetics, Tumor Suppressor Proteins genetics, DNA Repair Enzymes genetics, Glioblastoma drug therapy, Glioblastoma genetics, Brain Neoplasms drug therapy, Brain Neoplasms genetics
Abstract: Background: Addition of temozolomide (TMZ) to radiotherapy (RT) improves overall survival (OS) in patients with glioblastoma (GBM), but previous studies suggest that patients with tumors harboring an unmethylated MGMT promoter derive minimal benefit. The aim of this open-label, phase III CheckMate 498 study was to evaluate the efficacy of nivolumab (NIVO) + RT compared with TMZ + RT in newly diagnosed GBM with unmethylated MGMT promoter., Methods: Patients were randomized 1:1 to standard RT (60 Gy) + NIVO (240 mg every 2 weeks for eight cycles, then 480 mg every 4 weeks) or RT + TMZ (75 mg/m2 daily during RT and 150-200 mg/m2/day 5/28 days during maintenance). The primary endpoint was OS., Results: A total of 560 patients were randomized, 280 to each arm. Median OS (mOS) was 13.4 months (95% CI, 12.6 to 14.3) with NIVO + RT and 14.9 months (95% CI, 13.3 to 16.1) with TMZ + RT (hazard ratio [HR], 1.31; 95% CI, 1.09 to 1.58; P = .0037). Median progression-free survival was 6.0 months (95% CI, 5.7 to 6.2) with NIVO + RT and 6.2 months (95% CI, 5.9 to 6.7) with TMZ + RT (HR, 1.38; 95% CI, 1.15 to 1.65). Response rates were 7.8% (9/116) with NIVO + RT and 7.2% (8/111) with TMZ + RT; grade 3/4 treatment-related adverse event (TRAE) rates were 21.9% and 25.1%, and any-grade serious TRAE rates were 17.3% and 7.6%, respectively., Conclusions: The study did not meet the primary endpoint of improved OS; TMZ + RT demonstrated a longer mOS than NIVO + RT. No new safety signals were detected with NIVO in this study. The difference between the study treatment arms is consistent with the use of TMZ + RT as the standard of care for GBM.ClinicalTrials.gov NCT02617589., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)
Published: 2023
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44. Recent advances in the molecular prognostication of meningiomas.

Author: Wang EJ, Haddad AF, Young JS, Morshed RA, Wu JPH, Salha DM, Butowski N, and Aghi MK
Abstract: Meningiomas are the most common primary intracranial neoplasm. While traditionally viewed as benign, meningiomas are associated with significant patient morbidity, and certain meningioma subgroups display more aggressive and malignant behavior with higher rates of recurrence. Historically, the risk stratification of meningioma recurrence has been primarily associated with the World Health Organization histopathological grade and surgical extent of resection. However, a growing body of literature has highlighted the value of utilizing molecular characteristics to assess meningioma aggressiveness and recurrence risk. In this review, we discuss preclinical and clinical evidence surrounding the use of molecular classification schemes for meningioma prognostication. We also highlight how molecular data may inform meningioma treatment strategies and future directions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wang, Haddad, Young, Morshed, Wu, Salha, Butowski and Aghi.)
Published: 2023
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45. NCCN Guidelines® Insights: Central Nervous System Cancers, Version 2.2022.

Author: Horbinski C, Nabors LB, Portnow J, Baehring J, Bhatia A, Bloch O, Brem S, Butowski N, Cannon DM, Chao S, Chheda MG, Fabiano AJ, Forsyth P, Gigilio P, Hattangadi-Gluth J, Holdhoff M, Junck L, Kaley T, Merrell R, Mrugala MM, Nagpal S, Nedzi LA, Nevel K, Nghiemphu PL, Parney I, Patel TR, Peters K, Puduvalli VK, Rockhill J, Rusthoven C, Shonka N, Swinnen LJ, Weiss S, Wen PY, Willmarth NE, Bergman MA, and Darlow S
Subjects: Adult, Humans, Central Nervous System, Mutation, Central Nervous System Neoplasms diagnosis, Central Nervous System Neoplasms therapy, Brain Neoplasms diagnosis, Brain Neoplasms genetics, Brain Neoplasms therapy
Abstract: The NCCN Guidelines for Central Nervous System (CNS) Cancers focus on management of the following adult CNS cancers: glioma (WHO grade 1, WHO grade 2-3 oligodendroglioma [1p19q codeleted, IDH-mutant], WHO grade 2-4 IDH-mutant astrocytoma, WHO grade 4 glioblastoma), intracranial and spinal ependymomas, medulloblastoma, limited and extensive brain metastases, leptomeningeal metastases, non-AIDS-related primary CNS lymphomas, metastatic spine tumors, meningiomas, and primary spinal cord tumors. The information contained in the algorithms and principles of management sections in the NCCN Guidelines for CNS Cancers are designed to help clinicians navigate through the complex management of patients with CNS tumors. Several important principles guide surgical management and treatment with radiotherapy and systemic therapy for adults with brain tumors. The NCCN CNS Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel's most recent recommendations regarding molecular profiling of gliomas.
Published: 2023
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46. Therapeutic and Supportive Effects of Cannabinoids in Patients with Brain Tumors (CBD Oil and Cannabis).

Author: Rodriguez-Almaraz JE and Butowski N
Subjects: Humans, Quality of Life, Cannabinoids adverse effects, Cannabis, Cannabidiol therapeutic use, Brain Neoplasms drug therapy
Abstract: Opinion Statement: The potential medicinal properties of Cannabis continue to garner attention, especially in the brain tumor domain. This attention is centered on quality of life and symptom management; however, it is amplified by a significant lack of therapeutic choices for this specific patient population. While the literature on this matter is young, published and anecdotal evidence imply that cannabis could be useful in treating chemotherapy-induced nausea and vomiting, stimulating appetite, reducing pain, and managing seizures. It may also decrease inflammation and cancer cell proliferation and survival, resulting in a benefit in overall patient survival. Current literature poses the challenge that it does not provide standardized guidance on dosing for the above potential indications and cannabis use is dominated by recreational purposes. Furthermore, integrated and longitudinal studies are needed but these are a challenge due to arcane laws surrounding the legality of such substances. The increasing need for evidence-based arguments about potential harms and benefits of cannabis, not only in cancer patients but for other medical use and recreational purposes, is desperately needed., (© 2023. The Author(s).)
Published: 2023
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47. Novel intraoperative strategies for enhancing tumor control: Future directions.

Author: Haddad AF, Aghi MK, and Butowski N
Subjects: Humans, Magnetic Resonance Imaging methods, Neurosurgical Procedures methods, Brain Neoplasms surgery, Glioma surgery
Abstract: Maximal safe surgical resection plays a key role in the care of patients with gliomas. A range of technologies have been developed to aid surgeons in distinguishing tumor from normal tissue, with the goal of increasing tumor resection and limiting postoperative neurological deficits. Technologies that are currently being investigated to aid in improving tumor control include intraoperative imaging modalities, fluorescent tumor makers, intraoperative cell and molecular profiling of tumors, improved microscopic imaging, intraoperative mapping, augmented and virtual reality, intraoperative drug and radiation delivery, and ablative technologies. In this review, we summarize the aforementioned advancements in neurosurgical oncology and implications for improving patient outcomes., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)
Published: 2022
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48. Intratumor and informatic heterogeneity influence meningioma molecular classification.

Author: Vasudevan HN, Choudhury A, Hilz S, Villanueva-Meyer JE, Chen WC, Lucas CG, Braunstein SE, Oberheim Bush NA, Butowski N, Pekmezci M, McDermott MW, Perry A, Solomon DA, Magill ST, and Raleigh DR
Subjects: Biomarkers, Tumor, Genetic Heterogeneity, Humans, Informatics, Mutation, Meningeal Neoplasms genetics, Meningioma genetics
Published: 2022
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49. Meningioma DNA methylation groups identify biological drivers and therapeutic vulnerabilities.

Author: Choudhury A, Magill ST, Eaton CD, Prager BC, Chen WC, Cady MA, Seo K, Lucas CG, Casey-Clyde TJ, Vasudevan HN, Liu SJ, Villanueva-Meyer JE, Lam TC, Pu JK, Li LF, Leung GK, Swaney DL, Zhang MY, Chan JW, Qiu Z, Martin MV, Susko MS, Braunstein SE, Bush NAO, Schulte JD, Butowski N, Sneed PK, Berger MS, Krogan NJ, Perry A, Phillips JJ, Solomon DA, Costello JF, McDermott MW, Rich JN, and Raleigh DR
Subjects: DNA Methylation genetics, Humans, Neurofibromin 2 genetics, Proteomics, Meningeal Neoplasms genetics, Meningioma genetics
Abstract: Meningiomas are the most common primary intracranial tumors. There are no effective medical therapies for meningioma patients, and new treatments have been encumbered by limited understanding of meningioma biology. Here, we use DNA methylation profiling on 565 meningiomas integrated with genetic, transcriptomic, biochemical, proteomic and single-cell approaches to show meningiomas are composed of three DNA methylation groups with distinct clinical outcomes, biological drivers and therapeutic vulnerabilities. Merlin-intact meningiomas (34%) have the best outcomes and are distinguished by NF2/Merlin regulation of susceptibility to cytotoxic therapy. Immune-enriched meningiomas (38%) have intermediate outcomes and are distinguished by immune infiltration, HLA expression and lymphatic vessels. Hypermitotic meningiomas (28%) have the worst outcomes and are distinguished by convergent genetic and epigenetic mechanisms driving the cell cycle and resistance to cytotoxic therapy. To translate these findings into clinical practice, we show cytostatic cell cycle inhibitors attenuate meningioma growth in cell culture, organoids, xenografts and patients., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Published: 2022
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50. Nivolumab plus radiotherapy with or without temozolomide in newly diagnosed glioblastoma: Results from exploratory phase I cohorts of CheckMate 143.

Author: Omuro A, Reardon DA, Sampson JH, Baehring J, Sahebjam S, Cloughesy TF, Chalamandaris AG, Potter V, Butowski N, and Lim M
Abstract: Background: The phase 1 cohorts (1c+1d) of CheckMate 143 (NCT02017717) evaluated the safety/tolerability and efficacy of nivolumab plus radiotherapy (RT) ± temozolomide (TMZ) in newly diagnosed glioblastoma., Methods: In total, 136 patients were enrolled. In part A (safety lead-in), 31 patients ( n = 15, methylated/unknown MGMT promoter; n = 16, unmethylated MGMT promoter) received nivolumab and RT+TMZ (NIVO+RT+TMZ) and 30 patients with unmethylated MGMT promoter received NIVO+RT. In part B (expansion), patients with unmethylated MGMT promoter were randomized to NIVO+RT+TMZ ( n = 29) or NIVO+RT ( n = 30). Primary endpoint was safety/tolerability; secondary endpoint was overall survival (OS)., Results: NIVO+RT±TMZ was tolerable; grade 3/4 treatment-related adverse events occurred in 51.6% (NIVO+RT+TMZ) and 30.0% (NIVO+RT) of patients in part A and 46.4% (NIVO+RT+TMZ) and 28.6% (NIVO+RT) in part B. No new safety signals were detected. In part A, median OS (mOS) with NIVO+RT+TMZ was 33.38 months (95% CI, 16.2 to not estimable) in patients with methylated MGMT promoter. In patients with unmethylated MGMT promoter, mOS was 16.49 months (12.94-22.08) with NIVO+RT+TMZ and 14.41 months (12.55-17.31) with NIVO+RT. In part B, mOS was 14.75 months (10.01-18.6) with NIVO+RT+TMZ and 13.96 months (10.81-18.14) with NIVO+RT in patients with unmethylated MGMT promoter., Conclusions: CheckMate 143 was the first trial evaluating immune checkpoint inhibition with first-line treatment of glioblastoma. Results showed that NIVO can be safely combined with RT±TMZ, with no new safety signals. Toxicities, including lymphopenia, were more frequent with NIVO+RT+TMZ. OS was similar with or without TMZ in patients with unmethylated MGMT promoter, and differences by MGMT methylation status were observed., (© The Author(s) 2022. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)
Published: 2022
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