Antonio Omuro, MD

All Publications

• Advances in Primary Central Nervous System Lymphoma. Current neurology and neuroscience reports Therkelsen, K. E., Omuro, A. 2024; 25 (1): 5

  Abstract

  Optimal initial management can have a significant impact in long-term outcome in primary CNS lymphoma. This article reviews recent advances and the state of the field.Genomic analysis of CSF cell-free DNA has emerged as a new diagnostic tool for PCNSL. Treatment options have likewise evolved, with mature data from first-line chemotherapy-based prospective trials disclosing excellent results in younger (< 60-65) patients, with a cure achieved in a majority. However, results in older patients remain dismal, with several new salvage options under investigation including BTK pathway-targeted therapies, and CAR-T cell treatments. Meanwhile, low-dose radiation has emerged as an additional alternative for consolidation therapy. For younger PCNSL patients, the goal of treatment is now a cure, with the next frontier being the development of therapies affording optimized neurocognitive outcome and lower toxicity. Treatment for older patients remains however an unmet need, with several promising clinical trials ongoing.

  View details for DOI 10.1007/s11910-024-01389-0

  View details for PubMedID 39585484

  View details for PubMedCentralID 3241537

• DEUTERIUM METABOLIC IMAGING (DMI) SHOWS A STRONG RELATION BETWEEN TUMOR GRADE AND GLUCOSE METABOLISM IN PRIMARY BRAIN TUMORS Thaw-Poon, S., Blondin, N. A., Liu, Y., Corbin, Z. A., Baehring, J., Omuro, A., Moliterno, J., Omay, S., Fulbright, R. K., de Graaf, R. A., De Feyter, H. M. OXFORD UNIV PRESS INC. 2024

  View details for DOI 10.1093/neuonc/noae165.0795

  View details for Web of Science ID 001362489800028

• Radiotherapy Plan Quality Assurance in NRG Oncology Trials for Brain and Head/Neck Cancers: An AI-Enhanced Knowledge-Based Approach CANCERS Wang, D., Geng, H., Gondi, V., Lee, N. Y., Tsien, C. I., Xia, P., Chenevert, T. L., Michalski, J. M., Gilbert, M. R., Le, Q., Omuro, A. M., Men, K., Aldape, K. D., Cao, Y., Srinivasan, A., Barani, I. J., Sachdev, S., Huang, J., Choi, S., Shi, W., Battiste, J. D., Wardak, Z., Chan, M. D., Mehta, M. P., Xiao, Y. 2024; 16 (11)

  View details for DOI 10.3390/cancers16112007

  View details for Web of Science ID 001245728900001

• Long-term Outcomes in Primary CNS Lymphoma Following R-MVP and High Dose Chemotherapy With Autologous Hematopoietic Stem Cell Transplant. Neurology Therkelsen, K. E., Schaff, L. R., Nandakumar, S., Omuro, A. M., DeAngelis, L. M., Grommes, C. 2023

  Abstract

  BACKGROUND: Primary central nervous system lymphoma (PCNSL), a rare central nervous system malignancy, is usually treated with high-dose methotrexate in the first line setting, typically followed by consolidation therapy. Due to the broad range of currently available treatments for PCNSL, comparability in long-term follow up studies is limited and the data are scattered across small studies.METHODS: Here we report the long-term survival of patients with newly diagnosed, immunocompetent PCNSL, enrolled in a phase II trial from June 2005 to September 2011. Patients were treated using rituximab, methotrexate, vincristine, and procarbazine (R-MVP) chemotherapy followed by high dose chemotherapy (HDC) and autologous stem cell transplant (ASCT) in those with partial or complete response to R-MVP. In a post hoc analysis, clinical and imaging features were evaluated in those still alive.RESULTS: 26 of 32 patients underwent HDC-ACST consolidation. Of these, 3 patients died from treatment related toxicity, and 2 due to disease progression within one year of ASCT. None of the remaining 21 patients had disease progression with a median follow-up of 12.1 years and were included in the analysis. Compared to the post HDC-ASCT assessment, at last follow up there was no significant difference in the median Karnofsky Performance Status (KPS) (80 (range: 60-100) versus 90 (range: 70-100)), the median Neurologic Assessment in Neuro-Oncology (NANO) score (1 (range: 0-4) versus 1 (range 0-5)) and leukoencephalopathy score (1 (range 0-3) versus 1 (range: 1-4)).CONCLUSION: Long-term follow up demonstrated that treatment was well tolerated in most patients enrolled in this study, with stable leukoencephalopathy on imaging and stable clinical performance status. Disease recurrence was not observed beyond 2 years after HDC-ASCT consolidation.

  View details for DOI 10.1212/WNL.0000000000207490

  View details for PubMedID 37344228

• Comparing Detection Schemes for Adversarial Images against Deep Learning Models for Cancer Imaging. Cancers Joel, M. Z., Avesta, A., Yang, D. X., Zhou, J. G., Omuro, A., Herbst, R. S., Krumholz, H. M., Aneja, S. 2023; 15 (5)

  Abstract

  Deep learning (DL) models have demonstrated state-of-the-art performance in the classification of diagnostic imaging in oncology. However, DL models for medical images can be compromised by adversarial images, where pixel values of input images are manipulated to deceive the DL model. To address this limitation, our study investigates the detectability of adversarial images in oncology using multiple detection schemes. Experiments were conducted on thoracic computed tomography (CT) scans, mammography, and brain magnetic resonance imaging (MRI). For each dataset we trained a convolutional neural network to classify the presence or absence of malignancy. We trained five DL and machine learning (ML)-based detection models and tested their performance in detecting adversarial images. Adversarial images generated using projected gradient descent (PGD) with a perturbation size of 0.004 were detected by the ResNet detection model with an accuracy of 100% for CT, 100% for mammogram, and 90.0% for MRI. Overall, adversarial images were detected with high accuracy in settings where adversarial perturbation was above set thresholds. Adversarial detection should be considered alongside adversarial training as a defense technique to protect DL models for cancer imaging classification from the threat of adversarial images.

  View details for DOI 10.3390/cancers15051548

  View details for PubMedID 36900339

  View details for PubMedCentralID PMC10000732

• Multicenter Phase II Trial of the PARP Inhibitor Olaparib in Recurrent IDH1- and IDH2-mutant Glioma. Cancer research communications Fanucci, K., Pilat, M. J., Shyr, D., Shyr, Y., Boerner, S., Li, J., Durecki, D., Drappatz, J., Puduvalli, V., Lieberman, F. S., Gonzalez, J., Giglio, P., Ivy, S. P., Bindra, R. S., Omuro, A., LoRusso, P. 2023; 3 (2): 192-201

  Abstract

  Isocitrate dehydrogenase (IDH) 1 and IDH2 mutations (IDH1/2mt) are frequent in glioma. Preclinical studies suggest IDH1/2mts confer "BRCAness" phenotype, a vulnerability that can be targeted through PARP inhibition. To test this hypothesis, we conducted a multicenter study of olaparib monotherapy in patients with IDH1/2mt gliomas.Patients with recurrent, contrast-enhancing IDH1/2mt gliomas were enrolled in a two-step phase II trial; the primary endpoint was overall response rate per Response Assessment in Neuro-Oncology (RANO) criteria. Olaparib 300 mg orally twice daily was given.A total of 15 evaluable patients were enrolled. Histology was astrocytoma (N = 12) and oligodendroglioma (N = 3). Most toxicities were grade 1 or 2. Best response was stable disease (SD) in 9 (60%) patients. Median progression-free survival (PFS) was 3.63 months and median overall survival was 20.7 months. For patients with SD, median PFS was 5.53 months; 4 patients had SD for >6 months. Among patients with best response progressive disease (N = 6), 5 had grade 4 tumor and 4 had known CDKN2A alteration. PFS was 5.23 months for grades 2 or 3 tumors (N = 10) versus 1.8 months for grade 4 (N = 5; P = 0.0013).The study did not meet the prespecified response-based activity threshold for moving to step 2. However, prolonged SD was observed in patients with grades 2 and 3 histologies, suggesting olaparib monotherapy could be of clinical benefit in select populations. Grade 4 tumors per 2021 World Health Organization classification defined by histology or CDKN2A alteration derived no benefit from this drug, highlighting the usefulness of this classification for future patient stratification and trial design.A single-arm phase II trial of olaparib in IDH-mutant glioma demonstrated clinically significant prolonged SD for select patients with grade 2/3 disease, suggesting potential benefit of olaparib in IDH-mutant gliomas.

  View details for DOI 10.1158/2767-9764.CRC-22-0436

  View details for PubMedID 36968138

  View details for PubMedCentralID PMC10035510

• Top Advances in Neuro-Oncology M, B., A, O. Cancer. 2023
• Real-time PACS-integrated longitudinal brain metastasis tracking tool provides comprehensive assessment of treatment response to radiosurgery. Neuro-oncology advances Cassinelli Petersen, G., Bousabarah, K., Verma, T., von Reppert, M., Jekel, L., Gordem, A., Jang, B., Merkaj, S., Abi Fadel, S., Owens, R., Omuro, A., Chiang, V., Ikuta, I., Lin, M., Aboian, M. S. 2022; 4 (1): vdac116

  Abstract

  Treatment of brain metastases can be tailored to individual lesions with treatments such as stereotactic radiosurgery. Accurate surveillance of lesions is a prerequisite but challenging in patients with multiple lesions and prior imaging studies, in a process that is laborious and time consuming. We aimed to longitudinally track several lesions using a PACS-integrated lesion tracking tool (LTT) to evaluate the efficiency of a PACS-integrated lesion tracking workflow, and characterize the prevalence of heterogenous response (HeR) to treatment after Gamma Knife (GK).We selected a group of brain metastases patients treated with GK at our institution. We used a PACS-integrated LTT to track the treatment response of each lesion after first GK intervention to maximally seven diagnostic follow-up scans. We evaluated the efficiency of this tool by comparing the number of clicks necessary to complete this task with and without the tool and examined the prevalence of HeR in treatment.A cohort of eighty patients was selected and 494 lesions were measured and tracked longitudinally for a mean follow-up time of 374 days after first GK. Use of LTT significantly decreased number of necessary clicks. 81.7% of patients had HeR to treatment at the end of follow-up. The prevalence increased with increasing number of lesions.Lesions in a single patient often differ in their response to treatment, highlighting the importance of individual lesion size assessments for further treatment planning. PACS-integrated lesion tracking enables efficient lesion surveillance workflow and specific and objective result reports to treating clinicians.

  View details for DOI 10.1093/noajnl/vdac116

  View details for PubMedID 36043121

  View details for PubMedCentralID PMC9412827

• Identifying clinically applicable machine learning algorithms for glioma segmentation: recent advances and discoveries. Neuro-oncology advances Tillmanns, N., Lum, A. E., Cassinelli, G., Merkaj, S., Verma, T., Zeevi, T., Staib, L., Subramanian, H., Bahar, R. C., Brim, W., Lost, J., Jekel, L., Brackett, A., Payabvash, S., Ikuta, I., Lin, M., Bousabarah, K., Johnson, M. H., Cui, J., Malhotra, A., Omuro, A., Turowski, B., Aboian, M. S. 2022; 4 (1): vdac093

  Abstract

  While there are innumerable machine learning (ML) research algorithms used for segmentation of gliomas, there is yet to be a US FDA cleared product. The aim of this study is to explore the systemic limitations of research algorithms that have prevented translation from concept to product by a review of the current research literature.We performed a systematic literature review on 4 databases. Of 11 727 articles, 58 articles met the inclusion criteria and were used for data extraction and screening using TRIPOD.We found that while many articles were published on ML-based glioma segmentation and report high accuracy results, there were substantial limitations in the methods and results portions of the papers that result in difficulty reproducing the methods and translation into clinical practice.In addition, we identified that more than a third of the articles used the same publicly available BRaTS and TCIA datasets and are responsible for the majority of patient data on which ML algorithms were trained, which leads to limited generalizability and potential for overfitting and bias.

  View details for DOI 10.1093/noajnl/vdac093

  View details for PubMedID 36071926

  View details for PubMedCentralID PMC9446682

• Phase 3 Trial of Chemoradiotherapy With Temozolomide Plus Nivolumab or Placebo for Newly Diagnosed Glioblastoma With Methylated MGMT Promoter. Neuro-oncology Lim, M., Weller, M., Idbaih, A., Steinbach, J., Finocchiaro, G., Raval, R. R., Ansstas, G., Baehring, J., Taylor, J. W., Honnorat, J., Petrecca, K., De Vos, F., Wick, A., Sumrall, A., Sahebjam, S., Mellinghoff, I. K., Kinoshita, M., Roberts, M., Slepetis, R., Warad, D., Leung, D., Lee, M., Reardon, D. A., Omuro, A. 2022

  Abstract

  BACKGROUND: Nearly all patients with newly diagnosed glioblastoma experience recurrence following standard-of-care radiotherapy (RT) + temozolomide (TMZ). The purpose of the phase 3 randomized CheckMate 548 study was to evaluate RT+TMZ combined with the immune checkpoint inhibitor nivolumab (NIVO) or placebo (PBO) in patients with newly diagnosed glioblastoma with methylated MGMT promoter (NCT02667587).METHODS: Patients (N=716) were randomized 1:1 to NIVO [(240mg every 2 weeks *8, then 480mg every 4 weeks) + RT (60 Gy over 6 weeks) + TMZ (75mg/m 2 once daily during RT, then 150-200mg/m 2 once daily days 1-5 of every 28-day cycle *6)] or PBO+RT+TMZ following the same regimen. The primary endpoints were progression-free survival (PFS) and overall survival (OS) in patients without baseline corticosteroids and in all randomized patients.RESULTS: As of December 22, 2020, median (m)PFS (blinded independent central review) was 10.6 months (95% CI, 8.9-11.8) with NIVO+RT+TMZ vs 10.3 months (95% CI, 9.7-12.5) with PBO+RT+TMZ (HR, 1.1; 95% CI, 0.9-1.3) and mOS was 28.9 months (95% CI, 24.4-31.6) vs 32.1 months (95% CI, 29.4-33.8), respectively (HR, 1.1; 95% CI, 0.9-1.3). In patients without baseline corticosteroids, mOS was 31.3 months (95% CI, 28.6-34.8) with NIVO+RT+TMZ vs 33.0 months (95% CI, 31.0-35.1) with PBO+RT+TMZ (HR, 1.1; 95% CI, 0.9-1.4). Grade 3/4 treatment-related adverse event rates were 52.4% vs 33.6%, respectively.CONCLUSIONS: NIVO added to RT+TMZ did not improve survival in patients with newly diagnosed glioblastoma with methylated or indeterminate MGMT promoter. No new safety signals were observed.

  View details for DOI 10.1093/neuonc/noac116

  View details for PubMedID 35511454

• Immune-checkpoint inhibitors for glioblastoma: what have we learned? Arquivos de neuro-psiquiatria Omuro, A. 2022; 80 (5 Suppl 1): 266-269

  Abstract

  Glioblastoma, the most common malignant primary brain tumor, remains a lethal disease with few therapeutic options. Immunotherapies, particularly immune checkpoint inhibitors (ICPi), have revolutionized cancer treatment, but their role in glioblastoma is uncertain.To review the state of immunotherapies in glioblastoma, with an emphasis on recently published ICPi clinical trials.In this editorial/opinion article, we critically review results of the first generation of trials of ipilimumab, nivolumab and pembrolizumab in glioblastoma, as well as future directions.Expression of PD-L1 is frequent in glioblastoma, ranging from 60-70% of patients. Phase 1 studies of nivolumab with and without ipilimumab, as well as pembrolizumab, showed no new safety concerns in brain tumors, and no neurotoxicity. However, randomized phase 3 trials of nivolumab showed no survival improvements over bevacizumab in recurrent glioblastoma; no role in newly diagnosed disease as a replacement for temozolomide in unmethylated MGMT promoter tumors; and no benefit as an addition to temozolomide in methylated MGMT tumors. However, studies examining post treatment tumor samples have shown signs of increased immunologic response, and occasional long lasting radiographic responses have been seen. A small study of pembrolizumab suggested a potential role as a "neoadjuvant" treatment in resectable recurrent glioblastoma, while other studies are investigating selection of patients with higher mutational burden and novel agents and combinatorial strategies.Despite initial negative trials, immunotherapy remains of high interest in glioblastoma, and many trials are still ongoing. Improving our mechanistic understanding of the immunosuppression and T cell dysfunction induced by both tumor and the CNS microenvironment remains however crucial for the development of successful immunotherapeutic approaches in this disease.

  View details for DOI 10.1590/0004-282X-ANP-2022-S129

  View details for PubMedID 35976319

  View details for PubMedCentralID PMC9491432

• Radiotherapy Combined With Nivolumab or Temozolomide for Newly Diagnosed Glioblastoma With Unmethylated MGMT Promoter: An International Randomized Phase 3 Trial. Neuro-oncology Omuro, A., Brandes, A. A., Carpentier, A. F., Idbaih, A., Reardon, D. A., Cloughesy, T., Sumrall, A., Baehring, J., van den Bent, M., Bahr, O., Lombardi, G., Mulholland, P., Tabatabai, G., Lassen, U., Sepulveda, J. M., Khasraw, M., Vauleon, E., Muragaki, Y., Di Giacomo, A. M., Butowski, N., Roth, P., Qian, X., Fu, A. Z., Liu, Y., Potter, V., Chalamandaris, A., Tatsuoka, K., Lim, M., Weller, M. 2022

  Abstract

  BACKGROUND: Addition of temozolomide (TMZ) to radiotherapy (RT) improves overall survival (OS) in glioblastoma, but previous studies suggest that patients with tumors harboring an unmethylated MGMT promoter derive minimal benefit. The aim of this open-label, phase 3 CheckMate 498 study was to evaluate the efficacy of nivolumab (NIVO)+RT compared with TMZ+RT in newly diagnosed glioblastoma with unmethylated MGMT promoter.METHODS: Patients were randomized 1:1 to standard RT (60 Gy) + NIVO (240mg every 2 weeks for 8 cycles, then 480mg every 4 weeks) or RT+TMZ (75mg/m 2 daily during RT and 150-200mg/m 2/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 was 13.4 months (95% CI, 12.6-14.3) with NIVO+RT and 14.9 months (95% CI, 13.3-16.1) with TMZ+RT (hazard ratio [HR], 1.31; 95% CI, 1.09-1.58; P=0.0037). Median progression-free survival was 6.0 months (95% CI, 5.7-6.2) with NIVO+RT and 6.2 months (95% CI, 5.9-6.7) with TMZ+RT (HR, 1.38; 95% CI, 1.15-1.65). 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 median OS 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 standard of care for glioblastoma.

  View details for DOI 10.1093/neuonc/noac099

  View details for PubMedID 35419607

• Phase I/randomized phase II trial of TRC105 plus bevacizumab versus bevacizumab in recurrent glioblastoma: North Central Cancer Treatment Group N1174 (Alliance). Neuro-oncology advances Galanis, E., Anderson, S. K., Twohy, E., Butowski, N. A., Hormigo, A., Schiff, D., Omuro, A., Jaeckle, K. A., Kumar, S., Kaufmann, T. J., Geyer, S., Kumthekar, P. U., Campian, J., Giannini, C., Buckner, J. C., Wen, P. Y. 2022; 4 (1): vdac041

  Abstract

  Patients with glioblastoma (GBM) have a poor prognosis and limited effective treatment options. Bevacizumab has been approved for treatment of recurrent GBM, but there is questionable survival benefit. Based on preclinical and early clinical data indicating that CD105 upregulation may represent a mechanism of resistance to bevacizumab, we hypothesized that combining bevacizumab with the anti-CD105 antibody TRC105 may improve efficacy in recurrent GBM.Phase I dose-escalation/comparative randomized phase II trial in patients with GBM. During phase I, the maximum tolerated dose (MTD) of TRC105 in combination with bevacizumab was determined. In phase II, patients were randomized 1:1 to TRC105 and bevacizumab or bevacizumab monotherapy. Patients received TRC105 (10 mg/kg) weekly and bevacizumab (10 mg/kg) every 2 weeks. Efficacy, as assessed by progression-free survival (PFS), was the primary endpoint; safety, quality of life, and correlative outcomes were also evaluated.In total, 15 patients were enrolled in phase I and 101 in phase II; 52 patients were randomized to TRC105 with bevacizumab and 49 to bevacizumab monotherapy. The MTD was determined to be 10 mg/kg TRC105 weekly plus bevacizumab 10 mg/kg every 2 weeks. An increased occurrence of grade ≥3 adverse events was seen in the combination arm, including higher incidences of anemia. Median PFS was similar in both treatment arms: 2.9 months for combination versus 3.2 months for bevacizumab monotherapy (HR = 1.16, 95% CI = 0.75-1.78, P = .51). Quality of life scores were similar for both treatment arms.TRC105 in combination with bevacizumab was well tolerated in patients with recurrent GBM, but no difference in efficacy was observed compared to bevacizumab monotherapy.

  View details for DOI 10.1093/noajnl/vdac041

  View details for PubMedID 35664553

  View details for PubMedCentralID PMC9154335

• Machine Learning in Differentiating Gliomas from Primary CNS Lymphomas: A Systematic Review, Reporting Quality, and Risk of Bias Assessment. AJNR. American journal of neuroradiology Cassinelli Petersen, G. I., Shatalov, J., Verma, T., Brim, W. R., Subramanian, H., Brackett, A., Bahar, R. C., Merkaj, S., Zeevi, T., Staib, L. H., Cui, J., Omuro, A., Bronen, R. A., Malhotra, A., Aboian, M. S. 2022; 43 (4): 526-533

  Abstract

  Differentiating gliomas and primary CNS lymphoma represents a diagnostic challenge with important therapeutic ramifications. Biopsy is the preferred method of diagnosis, while MR imaging in conjunction with machine learning has shown promising results in differentiating these tumors.Our aim was to evaluate the quality of reporting and risk of bias, assess data bases with which the machine learning classification algorithms were developed, the algorithms themselves, and their performance.Ovid EMBASE, Ovid MEDLINE, Cochrane Central Register of Controlled Trials, and the Web of Science Core Collection were searched according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.From 11,727 studies, 23 peer-reviewed studies used machine learning to differentiate primary CNS lymphoma from gliomas in 2276 patients.Characteristics of data sets and machine learning algorithms were extracted. A meta-analysis on a subset of studies was performed. Reporting quality and risk of bias were assessed using the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) and Prediction Model Study Risk Of Bias Assessment Tool.The highest area under the receiver operating characteristic curve (0.961) and accuracy (91.2%) in external validation were achieved by logistic regression and support vector machines models using conventional radiomic features. Meta-analysis of machine learning classifiers using these features yielded a mean area under the receiver operating characteristic curve of 0.944 (95% CI, 0.898-0.99). The median TRIPOD score was 51.7%. The risk of bias was high for 16 studies.Exclusion of abstracts decreased the sensitivity in evaluating all published studies. Meta-analysis had high heterogeneity.Machine learning-based methods of differentiating primary CNS lymphoma from gliomas have shown great potential, but most studies lack large, balanced data sets and external validation. Assessment of the studies identified multiple deficiencies in reporting quality and risk of bias. These factors reduce the generalizability and reproducibility of the findings.

  View details for DOI 10.3174/ajnr.A7473

  View details for PubMedID 35361577

  View details for PubMedCentralID PMC8993193

• Machine Learning Applications for Differentiation of Glioma from Brain Metastasis-A Systematic Review. Cancers Jekel, L., Brim, W. R., von Reppert, M., Staib, L., Cassinelli Petersen, G., Merkaj, S., Subramanian, H., Zeevi, T., Payabvash, S., Bousabarah, K., Lin, M., Cui, J., Brackett, A., Mahajan, A., Omuro, A., Johnson, M. H., Chiang, V. L., Malhotra, A., Scheffler, B., Aboian, M. S. 2022; 14 (6)

  Abstract

  Glioma and brain metastasis can be difficult to distinguish on conventional magnetic resonance imaging (MRI) due to the similarity of imaging features in specific clinical circumstances. Multiple studies have investigated the use of machine learning (ML) models for non-invasive differentiation of glioma from brain metastasis. Many of the studies report promising classification results, however, to date, none have been implemented into clinical practice. After a screening of 12,470 studies, we included 29 eligible studies in our systematic review. From each study, we aggregated data on model design, development, and best classifiers, as well as quality of reporting according to the TRIPOD statement. In a subset of eligible studies, we conducted a meta-analysis of the reported AUC. It was found that data predominantly originated from single-center institutions (n = 25/29) and only two studies performed external validation. The median TRIPOD adherence was 0.48, indicating insufficient quality of reporting among surveyed studies. Our findings illustrate that despite promising classification results, reliable model assessment is limited by poor reporting of study design and lack of algorithm validation and generalizability. Therefore, adherence to quality guidelines and validation on outside datasets is critical for the clinical translation of ML for the differentiation of glioma and brain metastasis.

  View details for DOI 10.3390/cancers14061369

  View details for PubMedID 35326526

  View details for PubMedCentralID PMC8946855

• Using Adversarial Images to Assess the Robustness of Deep Learning Models Trained on Diagnostic Images in Oncology. JCO clinical cancer informatics Joel, M. Z., Umrao, S., Chang, E., Choi, R., Yang, D. X., Duncan, J. S., Omuro, A., Herbst, R., Krumholz, H. M., Aneja, S. 2022; 6: e2100170

  Abstract

  Deep learning (DL) models have rapidly become a popular and cost-effective tool for image classification within oncology. A major limitation of DL models is their vulnerability to adversarial images, manipulated input images designed to cause misclassifications by DL models. The purpose of the study is to investigate the robustness of DL models trained on diagnostic images using adversarial images and explore the utility of an iterative adversarial training approach to improve the robustness of DL models against adversarial images.We examined the impact of adversarial images on the classification accuracies of DL models trained to classify cancerous lesions across three common oncologic imaging modalities. The computed tomography (CT) model was trained to classify malignant lung nodules. The mammogram model was trained to classify malignant breast lesions. The magnetic resonance imaging (MRI) model was trained to classify brain metastases.Oncologic images showed instability to small pixel-level changes. A pixel-level perturbation of 0.004 (for pixels normalized to the range between 0 and 1) resulted in most oncologic images to be misclassified (CT 25.6%, mammogram 23.9%, and MRI 6.4% accuracy). Adversarial training improved the stability and robustness of DL models trained on oncologic images compared with naive models ([CT 67.7% v 26.9%], mammogram [63.4% vs 27.7%], and MRI [87.2% vs 24.3%]).DL models naively trained on oncologic images exhibited dramatic instability to small pixel-level changes resulting in substantial decreases in accuracy. Adversarial training techniques improved the stability and robustness of DL models to such pixel-level changes. Before clinical implementation, adversarial training should be considered to proposed DL models to improve overall performance and safety.

  View details for DOI 10.1200/CCI.21.00170

  View details for PubMedID 35271304

  View details for PubMedCentralID PMC8932490

• Nivolumab plus radiotherapy with or without temozolomide in newly diagnosed glioblastoma: Results from exploratory phase I cohorts of CheckMate 143. Neuro-oncology advances Omuro, A., Reardon, D. A., Sampson, J. H., Baehring, J., Sahebjam, S., Cloughesy, T. F., Chalamandaris, A., Potter, V., Butowski, N., Lim, M. 2022; 4 (1): vdac025

  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.

  View details for DOI 10.1093/noajnl/vdac025

  View details for PubMedID 35402913

• T cell dysfunction in glioblastoma: a barrier and an opportunity for the development of successful immunotherapies. Current opinion in neurology Jansen, J. A., Omuro, A., Lucca, L. E. 2021; 34 (6): 827-833

  Abstract

  Immunotherapies such as immune checkpoint blockade have revolutionized cancer treatment, but current approaches have failed to improve outcomes in glioblastoma and other brain tumours. T cell dysfunction has emerged as one of the major barriers for the development of central nervous system (CNS)-directed immunotherapy. Here, we explore the unique requirements that T cells must fulfil to ensure immune surveillance in the CNS, and we analyse T cell dysfunction in glioblastoma (GBM) through the prism of CNS-resident immune responses.Using comprehensive and unbiased techniques such as single-cell RNA sequencing, multiple studies have dissected the transcriptional state of CNS-resident T cells that patrol the homeostatic brain. A similar approach has revealed that in GBM, tumour-infiltrating T cells lack the hallmarks of antigen-driven exhaustion typical of melanoma and other solid tumours, suggesting the need for better presentation of tumour-derived antigens. Consistently, in a mouse model of GBM, increasing lymphatic drainage to the cervical lymph node was sufficient to promote tumour rejection.For the success of future immunotherapy strategies, further work needs to explore the natural history of dysfunction in GBM tumour-infiltrating T cells, establish whether these originate from CNS-resident T cells and how they can be manipulated therapeutically.

  View details for DOI 10.1097/WCO.0000000000000988

  View details for PubMedID 34569985

  View details for PubMedCentralID PMC8595795

• Erdheim-Chester Disease Presenting With Diplopia: A Challenging Diagnosis With Effective Treatment. Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society Tavakoli, M., Roghaee, S., Gunturu, M., Omuro, A. M., Lam, B. L., Mendoza-Santiesteban, C. E. 2021; 41 (3): e324-e325

  View details for DOI 10.1097/WNO.0000000000001076

  View details for PubMedID 32956221

• Sporadic adamantinomatous craniopharyngioma with double-hit somatic APC mutations. Neuro-oncology advances Hong, C. S., Omuro, A., An, Y., Inzucchi, S. E., Kohli, A. A., McGuone, D., Vining, E. M., Omay, S. B., Erson-Omay, E. Z. 2021; 3 (1): vdab124

  View details for DOI 10.1093/noajnl/vdab124

  View details for PubMedID 34549183

  View details for PubMedCentralID PMC8446933

• A Shortage of Neurologists - We Must Act Now: A Report From the AAN 2019 Transforming Leaders Program. Neurology Majersik, J. J., Ahmed, A., Chen, I. A., Shill, H., Hanes, G. P., Pelak, V. S., Hopp, J. L., Omuro, A., Kluger, B., Leslie-Mazwi, T. 2021; 96 (24): 1122-1134

  Abstract

  In nearly every US state, a large mismatch exists between the need for neurologists and neurologic services and the availability of neurologists to provide these services. Patients with neurologic disorders are rising in prevalence and require access to high-level care to reduce disability. The current neurology mismatch reduces access to care, worsens patient outcomes, and erodes career satisfaction and quality of life for neurologists as they face increasingly insurmountable demands. As a community, we must address this mismatch in the demand and supply of neurologic care in an aggressive and sustained manner to ensure the future health of our patients and our specialty. The American Academy of Neurology has multiple ongoing initiatives to help reduce and resolve the existing mismatch. With the intent of raising awareness and widening the debate nationally, we present a strategic plan that the Academy could implement to coordinate and expand existing efforts. We characterize the suggested strategies as shaping the demand, enhancing the workforce, and advocating for neurologist value. The proposed framework is based on available data and expert opinion when data were lacking. Prioritization of strategies will vary by geography, practice setting, and local resources. The time to act is now to allow concerted effort and targeted interventions to avert this looming public health crisis.

  View details for DOI 10.1212/WNL.0000000000012111

  View details for PubMedID 33931527

• Comparison of radiomic feature aggregation methods for patients with multiple tumors. Scientific reports Chang, E., Joel, M. Z., Chang, H. Y., Du, J., Khanna, O., Omuro, A., Chiang, V., Aneja, S. 2021; 11 (1): 9758

  Abstract

  Radiomic feature analysis has been shown to be effective at analyzing diagnostic images to model cancer outcomes. It has not yet been established how to best combine radiomic features in cancer patients with multifocal tumors. As the number of patients with multifocal metastatic cancer continues to rise, there is a need for improving personalized patient-level prognosis to better inform treatment. We compared six mathematical methods of combining radiomic features of 3,596 tumors in 831 patients with multiple brain metastases and evaluated the performance of these aggregation methods using three survival models: a standard Cox proportional hazards model, a Cox proportional hazards model with LASSO regression, and a random survival forest. Across all three survival models, the weighted average of the largest three metastases had the highest concordance index (95% confidence interval) of 0.627 (0.595-0.661) for the Cox proportional hazards model, 0.628 (0.591-0.666) for the Cox proportional hazards model with LASSO regression, and 0.652 (0.565-0.727) for the random survival forest model. This finding was consistent when evaluating patients with different numbers of brain metastases and different tumor volumes. Radiomic features can be effectively combined to estimate patient-level outcomes in patients with multifocal brain metastases. Future studies are needed to confirm that the volume-weighted average of the largest three tumors is an effective method for combining radiomic features across other imaging modalities and tumor types.

  View details for DOI 10.1038/s41598-021-89114-6

  View details for PubMedID 33963236

  View details for PubMedCentralID PMC8105371

• A phase II study of dose-dense temozolomide and lapatinib for recurrent low-grade and anaplastic supratentorial, infratentorial, and spinal cord ependymoma. Neuro-oncology Gilbert, M. R., Yuan, Y., Wu, J., Mendoza, T., Vera, E., Omuro, A., Lieberman, F., Robins, H. I., Gerstner, E. R., Wu, J., Wen, P. Y., Mikkelsen, T., Aldape, K., Armstrong, T. S. 2021; 23 (3): 468-477

  Abstract

  No standard medical treatment exists for adult patients with recurrent ependymoma, and prospective clinical trials in this population have not succeeded because of its rarity and challenges in accruing patients. The Collaborative Ependymoma Research Network conducted a prospective phase II clinical trial of dose-dense temozolomide (TMZ) and lapatinib, targeting the unmethylated O6-methylguanine-DNA methyltransferase (MGMT) promoter status and increased expression of ErbB2 (human epidermal growth factor receptor 2) and ErbB1 (epidermal growth factor receptor) in ependymomas.Patients age 18 or older with histologically proven and progressive ependymoma or anaplastic ependymoma were eligible and received dose-dense TMZ and daily lapatinib. The primary outcome measure was median progression-free survival (PFS). Landmark 6- and 12-month PFS and objective response were measured. Serial assessments of symptom burden using the MD Anderson Symptom Inventory Brain Tumor (MDASI-BT)/MDASI-Spine Tumor modules were collected.The 50 patients enrolled had a median age of 43.5 years, median Karnofsky performance status of 90, and a median of 2 prior relapses. Twenty patients had grade III, 16 grade II, and 8 grade I ependymoma. Half had spinal cord tumors; 15 had a supratentorial tumor, 8 infratentorial, and 2 had disseminated disease. Treatment was well tolerated. The median PFS was 7.8 months (95% CI: 5.5,12.2); the 6- and 12-month PFS rates were 55% and 38%, with 2 complete and 6 partial responses. Measures of symptom burden showed reduction in moderate-severe pain and other disease-related symptoms in most patients.This treatment, with demonstrated clinical activity with objective responses and prolonged disease control associated with disease-related symptom improvements, is an option as a salvage regimen for adult patients with recurrent ependymoma.

  View details for DOI 10.1093/neuonc/noaa240

  View details for PubMedID 33085768

  View details for PubMedCentralID PMC7992893

• Genetic characterization of an aggressive optic nerve pilocytic glioma. Brain tumor pathology Hong, C. S., Fliney, G., Fisayo, A., An, Y., Gopal, P. P., Omuro, A., Pointdujour-Lim, R., Erson-Omay, E. Z., Omay, S. B. 2021; 38 (1): 59-63

  Abstract

  Optic nerve glioma (ONG) is a rare, typically slow-growing WHO I grade tumor that affects the visual pathways. ONG is most commonly seen in the pediatric population, in association with neurofibromatosis type 1 syndrome. However, sporadic adult cases may also occur and may clinically behave more aggressively, despite benign histopathology. Genetic characterization of these tumors, particularly in the adult population, is lacking. A 39-year-old female presented with 1 month of progressive left-sided visual loss secondary to a enhancing mass along the left optic nerve sheath. Initial empiric management with focal radiotherapy failed to prevent tumor progression, prompting open biopsy which revealed a WHO I pilocytic astrocytoma of the optic nerve. Whole-exome sequencing of the biopsy specimen revealed somatic mutations in NF1,FGFR1 and PTPN11 that may provide actionable targets for molecularly guided therapies. Genetic characterization of ONG is lacking but is needed to guide the management of these rare but complex tumors. The genomic alterations reported in this case contributes to understanding the pathophysiology of adult sporadic ONG and may help guide future clinical prognostication and development of targeted therapies.

  View details for DOI 10.1007/s10014-020-00383-x

  View details for PubMedID 33098465

  View details for PubMedCentralID PMC7585354

• Editorial: Advances in Neuro-Oncology: stepping in the right direction A, O. Opin Neurol. 2021

  Abstract

  doi: 10.1097/WCO.0000000000001000

• Consolidation Therapy in Primary Central Nervous System Lymphoma. Current treatment options in oncology Kim, P., Omuro, A. 2020; 21 (9): 74

  Abstract

  Primary central nervous system lymphoma is a complex disease with no agreed-upon standard-of-care therapy. Induction therapy involves multiagent chemotherapy based on high-dose methotrexate, with several regimens available. We have a preference for a regimen using rituximab, methotrexate (3.5 g/m2), procarbazine, and vincristine (R-MPV) for initial induction therapy, given the favorable balance between toxicities and very high response rates (80-90%), which allow for decreasing disease burden and increasing the effectiveness of consolidation treatments. However, in the absence of consolidation therapies, R-MPV is not an effective regimen to achieve long-term remission.Based on high rates of long-term remission, our first choice for consolidation therapy is high-dose chemotherapy with autologous stem-cell transplant using thiotepa, busulfan, and cyclophosphamide as a myeloablative regimen, with a curative intent. This typically applies to patients with a favorable performance status at the end of induction, typically with ECOG performance status of 2 or better, adequate organ function, and age younger than 70. Patients with a high transplant-related mortality risk may still be considered for milder myeloablative regimens such as carmustine/thiotepa.For patients who are not transplant candidates, we typically offer consolidation with reduced dose whole-brain radiation therapy (WBRT) (23.4 Gy), which seems to be associated with lower risks of neurotoxicity as compared with higher doses of radiation. For patients who are not transplant candidates and that do not accept the risk of cognitive decline from the radiotherapy, we typically offer consolidation high-dose cytarabine, provided the patient understands the high risk of relapse. For these patients, a clinical trial is strongly recommended.

  View details for DOI 10.1007/s11864-020-00758-4

  View details for PubMedID 32725379

• Effect of Nivolumab vs Bevacizumab in Patients With Recurrent Glioblastoma The CheckMate 143 Phase 3 Randomized Clinical Trial JAMA ONCOLOGY Reardon, D. A., Brandes, A. A., Omuro, A., Mulholland, P., Lim, M., Wick, A., Baehring, J., Ahluwalia, M. S., Roth, P., Baehr, O., Phuphanich, S., Sepulveda, J., De Souza, P., Sahebjam, S., Carleton, M., Tatsuoka, K., Taitt, C., Zwirtes, R., Sampson, J., Weller, M. 2020; 6 (7): 1003–10

  Abstract

  Clinical outcomes for glioblastoma remain poor. Treatment with immune checkpoint blockade has shown benefits in many cancer types. To our knowledge, data from a randomized phase 3 clinical trial evaluating a programmed death-1 (PD-1) inhibitor therapy for glioblastoma have not been reported.To determine whether single-agent PD-1 blockade with nivolumab improves survival in patients with recurrent glioblastoma compared with bevacizumab.In this open-label, randomized, phase 3 clinical trial, 439 patients with glioblastoma at first recurrence following standard radiation and temozolomide therapy were enrolled, and 369 were randomized. Patients were enrolled between September 2014 and May 2015. The median follow-up was 9.5 months at data cutoff of January 20, 2017. The study included 57 multicenter, multinational clinical sites.Patients were randomized 1:1 to nivolumab 3 mg/kg or bevacizumab 10 mg/kg every 2 weeks until confirmed disease progression, unacceptable toxic effects, or death.The primary end point was overall survival (OS).A total of 369 patients were randomized to nivolumab (n = 184) or bevacizumab (n = 185). The MGMT promoter was methylated in 23.4% (43/184; nivolumab) and 22.7% (42/185; bevacizumab), unmethylated in 32.1% (59/184; nivolumab) and 36.2% (67/185; bevacizumab), and not reported in remaining patients. At median follow-up of 9.5 months, median OS (mOS) was comparable between groups: nivolumab, 9.8 months (95% CI, 8.2-11.8); bevacizumab, 10.0 months (95% CI, 9.0-11.8); HR, 1.04 (95% CI, 0.83-1.30); P = .76. The 12-month OS was 42% in both groups. The objective response rate was higher with bevacizumab (23.1%; 95% CI, 16.7%-30.5%) vs nivolumab (7.8%; 95% CI, 4.1%-13.3%). Grade 3/4 treatment-related adverse events (TRAEs) were similar between groups (nivolumab, 33/182 [18.1%]; bevacizumab, 25/165 [15.2%]), with no unexpected neurological TRAEs or deaths due to TRAEs.Although the primary end point was not met in this randomized clinical trial, mOS was comparable between nivolumab and bevacizumab in the overall patient population with recurrent glioblastoma. The safety profile of nivolumab in patients with glioblastoma was consistent with that in other tumor types.ClinicalTrials.gov Identifier: NCT02017717.

  View details for DOI 10.1001/jamaoncol.2020.1024

  View details for Web of Science ID 000552068600008

  View details for PubMedID 32437507

  View details for PubMedCentralID PMC7243167

• Cerebrospinal fluid circulating tumor cells as a quantifiable measurement of leptomeningeal metastases in patients with HER2 positive cancer. Journal of neuro-oncology Malani, R., Fleisher, M., Kumthekar, P., Lin, X., Omuro, A., Groves, M. D., Lin, N. U., Melisko, M., Lassman, A. B., Jeyapalan, S., Seidman, A., Skakodub, A., Boire, A., DeAngelis, L. M., Rosenblum, M., Raizer, J., Pentsova, E. 2020; 148 (3): 599-606

  Abstract

  The CellSearch® system has been used to identify circulating tumor cells (CTCs) in cerebrospinal fluid (CSF) to diagnose leptomeningeal metastasis (LM) in patients with epithelial cancers. Using this system, we prospectively explored sequential CSF CTC enumeration in patients with LM from HER2+ cancers receiving intrathecal (IT) trastuzumab to capture dynamic changes in CSF CTC enumeration.CSF from patients enrolled in an IRB-approved phase I/II dose escalation trial of IT trastuzumab for LM in HER2+ cancer (NCT01325207) was obtained on day 1 of each cycle and was evaluated by the CellSearch® platform for CTC enumeration. The results were correlated with CSF cytology from the same sample, along with clinical and radiographic response.Fifteen out of 34 patients with HER2+ LM were enrolled in CSF CTC analysis; 14 were women. Radiographic LM was documented in 14 (93%) patients; CSF cytology was positive in 6 (40%) and CSF CTCs were identified in 13 (87%). Median CSF CTC was 22 CTCs (range 0-200 +) per 3 ml. HER2/neu expression analysis of CTCs was performed in 8 patients; 75% had confirmed expression of HER2/neu positivity in CSF and HER2/neu expression was absent in 25%. Four of 10 patients received 7 or more cycles of IT trastuzumab; in 3 of these patients, increase in CSF CTCs enumeration from baseline was detected 2-3 months prior to changes seen on MRI, and while CSF cytology remained negative.Our study demonstrates that enumeration of CSF CTCs may provide dynamic, quantitative assessment of tumor burden in the central nervous system compartment during treatment for LM and prior to changes on MRI or CSF cytology.Clinicaltrials.gov: NCT01325207; registered March 29th, 2011.

  View details for DOI 10.1007/s11060-020-03555-z

  View details for PubMedID 32506369

  View details for PubMedCentralID PMC7438284

• Erdheim-Chester disease among neuroinflammatory syndromes: the case for precision medicine. Neurology(R) neuroimmunology & neuroinflammation de la Fuente, M. I., Rosenblum, M. K., Diamond, E. L., Tabar, V. S., Omuro, A. 2020; 7 (3)

  View details for DOI 10.1212/NXI.0000000000000686

  View details for PubMedID 32123043

  View details for PubMedCentralID PMC7136060

• Phase I clinical trial of temsirolimus and perifosine for recurrent glioblastoma. Annals of clinical and translational neurology Kaley, T. J., Panageas, K. S., Pentsova, E. I., Mellinghoff, I. K., Nolan, C., Gavrilovic, I., DeAngelis, L. M., Abrey, L. E., Holland, E. C., Omuro, A., Lacouture, M. E., Ludwig, E., Lassman, A. B. 2020; 7 (4): 429-436

  Abstract

  Malignant glioma (MG) is the most deadly primary brain cancer. Signaling though the PI3K/AKT/mTOR axis is activated in most MGs and therefore a potential therapeutic target. The mTOR inhibitor temsirolimus and the AKT inhibitor perifosine are each well-tolerated as single agents but with limited activity reclinical data demonstrate synergistic anti-tumor effects from combined treatment. Therefore, we initiated a phase I trial of combined therapy in recurrent MGs to determine safety and a recommended phase II dose.Adults with recurrent MG, Karnofsky Performance Status ≥ 60 were enrolled, with no limit on the number of prior therapies. Temsirolimus dose was escalated using standard 3 + 3 design from 15 mg to 170 mg administered once weekly. Perifosine was fixed as a 600 mg load on day 1 followed by 100 mg nightly (single agent MTD) until dose level 7 when the load increased to 900 mg.We treated 35 patients with with glioblastoma (17) or other MGs (18; including nine anaplastic astrocytoma, nine anaplastic oligodendroglioma, one anaplastic oligoastrocytoma, and two low grade astrocytomas with radiographic transformation to MG). We observed five dose-limiting toxicities (DLTs): one at dose level 3 (50mg temsirolimus), then two at dose level 7 expansion (170 mg temsirolimus), and then two more at dose level 6 expansion (170 mg temsirolimus). DLTs included thrombocytopenia (n = 3), intracerebral hemorrhage (n = 1) and lung infection (n = 1).Combining the mTOR inhibitor temsirolimus dosed at 115 mg weekly and the AKT inhibitor perifosine dosed at 100 mg daily (following 600 mg load) is tolerable in heavily pretreated adults with recurrent MGs.

  View details for DOI 10.1002/acn3.51009

  View details for PubMedID 32293798

  View details for PubMedCentralID PMC7187704

• Meningiomas - Comprehensive Strategies for Management J, M., A, O. 2020
• Complications associated with immunotherapy for brain metastases. Current opinion in neurology Tran, T. T., Jilaveanu, L. B., Omuro, A., Chiang, V. L., Huttner, A., Kluger, H. M. 2019; 32 (6): 907-916

  Abstract

  Median survival after the diagnosis of brain metastases has historically been on the order of months. With the recent development of immune checkpoint inhibitors, intracranial activity and durable responses have been observed in brain metastases on multiple phase 2 clinical trials, which have primarily been conducted in patients with melanoma. Immune-related adverse events related to checkpoint inhibitor therapy of brain metastasis can present unique challenges for the clinician and underscore the need for a multidisciplinary team in the care of these patients. The goal of this review is to address the current knowledge, limitations of understanding, and future directions in research regarding immune therapy trials and neurologic toxicities based on retrospective, prospective, and case studies.Immune therapy has the potential to exacerbate symptomatic edema and increase the risk of radiation necrosis in previously irradiated lesions. Neurologic toxicities will likely increase in prevalence as more patients with brain metastatic disease are eligible for immune therapy.An improved understanding and heightened awareness of the unique neurologic toxicities that impact this patient group is vital for mitigating treatment-related morbidity and mortality.

  View details for DOI 10.1097/WCO.0000000000000756

  View details for PubMedID 31577604

  View details for PubMedCentralID PMC7398556

• Applications of artificial intelligence in neuro-oncology. Current opinion in neurology Aneja, S., Chang, E., Omuro, A. 2019; 32 (6): 850-856

  Abstract

  To discuss recent applications of artificial intelligence within the field of neuro-oncology and highlight emerging challenges in integrating artificial intelligence within clinical practice.In the field of image analysis, artificial intelligence has shown promise in aiding clinicians with incorporating an increasing amount of data in genomics, detection, diagnosis, classification, risk stratification, prognosis, and treatment response. Artificial intelligence has also been applied in epigenetics, pathology, and natural language processing.Although nascent, applications of artificial intelligence within neuro-oncology show significant promise. Artificial intelligence algorithms will likely improve our understanding of brain tumors and help drive future innovations in neuro-oncology.

  View details for DOI 10.1097/WCO.0000000000000761

  View details for PubMedID 31609739

• Genomic Correlates of Disease Progression and Treatment Response in Prospectively Characterized Gliomas. Clinical cancer research : an official journal of the American Association for Cancer Research Jonsson, P., Lin, A. L., Young, R. J., DiStefano, N. M., Hyman, D. M., Li, B. T., Berger, M. F., Zehir, A., Ladanyi, M., Solit, D. B., Arnold, A. G., Stadler, Z. K., Mandelker, D., Goldberg, M. E., Chmielecki, J., Pourmaleki, M., Ogilvie, S. Q., Chavan, S. S., McKeown, A. T., Manne, M., Hyde, A., Beal, K., Yang, T. J., Nolan, C. P., Pentsova, E., Omuro, A., Gavrilovic, I. T., Kaley, T. J., Diamond, E. L., Stone, J. B., Grommes, C., Boire, A., Daras, M., Piotrowski, A. F., Miller, A. M., Gutin, P. H., Chan, T. A., Tabar, V. S., Brennan, C. W., Rosenblum, M., DeAngelis, L. M., Mellinghoff, I. K., Taylor, B. S. 2019; 25 (18): 5537-5547

  Abstract

  The genomic landscape of gliomas has been characterized and now contributes to disease classification, yet the relationship between molecular profile and disease progression and treatment response remain poorly understood.Experimental Design: We integrated prospective clinical sequencing of 1,004 primary and recurrent tumors from 923 glioma patients with clinical and treatment phenotypes.Thirteen percent of glioma patients harbored a pathogenic germline variant, including a subset associated with heritable genetic syndromes and variants mediating DNA repair dysfunctions (29% of the total) that were associated with somatic biallelic inactivation and mechanism-specific somatic phenotypes. In astrocytomas, genomic alterations in effectors of cell-cycle progression correlated with aggressive disease independent of IDH mutation status, arose preferentially in enhancing tumors (44% vs. 8%, P < 0.001), were associated with rapid disease progression following tumor recurrence (HR = 2.6, P = 0.02), and likely preceded the acquisition of alkylating therapy-associated somatic hypermutation. Thirty-two percent of patients harbored a potentially therapeutically actionable lesion, of whom 11% received targeted therapies. In BRAF-mutant gliomas, response to agents targeting the RAF/MEK/ERK signaling axis was influenced by the type of mutation, its clonality, and its cellular and genomic context.These data reveal genomic correlates of disease progression and treatment response in diverse types of glioma and highlight the potential utility of incorporating genomic information into the clinical decision-making for patients with glioma.

  View details for DOI 10.1158/1078-0432.CCR-19-0032

  View details for PubMedID 31263031

  View details for PubMedCentralID PMC6753053

• Longitudinal cognitive assessment in patients with primary CNS lymphoma treated with induction chemotherapy followed by reduced-dose whole-brain radiotherapy or autologous stem cell transplantation. Journal of neuro-oncology Correa, D. D., Braun, E., Kryza-Lacombe, M., Ho, K. W., Reiner, A. S., Panageas, K. S., Yahalom, J., Sauter, C. S., Abrey, L. E., DeAngelis, L. M., Omuro, A. 2019; 144 (3): 553-562

  Abstract

  The standard treatment for primary central nervous system lymphoma (PCNSL) involves induction methotrexate-based chemotherapy with or without consolidation whole brain radiotherapy (WBRT). As WBRT carries a substantial risk for cognitive impairment, alternative consolidation treatments have been used to reduce neurotoxicity, including reduced-dose WBRT (rdWBRT) or high-dose chemotherapy with autologous stem cell transplant (HDC-ASCT). In this study, we characterized cognitive functions in PCNSL patients achieving long-term remission following rdWBRT or HDC-ASCT.PCNSL patients completed cognitive evaluations at diagnosis, post-induction chemotherapy, and yearly up to 5 years following rdWBRT or HDC-ASCT. Quality of life (QoL), white matter (WM) disease, and cortical atrophy (CA) on MRI were assessed at similar intervals.Performance was impaired on most cognitive tests at diagnosis. Linear mixed model analyses in each group showed statistically significant improvement from baseline up to year 3 in attention/executive functions, graphomotor speed, and memory; however, there was a decline in attention/executive functions and memory after year 3 in both groups. WM abnormalities increased over time in both groups, but more patients treated with rdWBRT developed CA and WM changes. There were no significant longitudinal group differences in cognitive performance or QoL.Results indicated improvement in cognitive function up to 3 years post-treatment, but a decline at later time points and an increase in brain structure abnormalities in both groups. The findings suggest that rdWBRT and HDC-ASCT may be associated with delayed neurotoxicity in progression-free patients and underscore the need for long-term follow-up to characterize cognitive dysfunction in PCNSL patients.

  View details for DOI 10.1007/s11060-019-03257-1

  View details for PubMedID 31377920

  View details for PubMedCentralID PMC7392129

• INO-5401 and INO-9012 delivered by electroporation (EP) in combination with cemiplimab (REGN2810) in newly-diagnosed glioblastoma (GBM) (NCT03491683) Reardon, D., Nagpal, S., Soltys, S., Brem, S., Omuro, A., De La Fuente, M., Bredlau, A., Lowy, I., Fury, M., Morrow, M., Kraynyak, K., McMullan, T., Santo, A. L., Sacchetta, B., Skolnik, J. AMER ASSOC CANCER RESEARCH. 2019

  View details for DOI 10.1158/1538-7445.AM2019-CT114

  View details for Web of Science ID 000488129900102

• Sequencing and curation strategies for identifying candidate glioblastoma treatments. BMC medical genomics Frank, M. O., Koyama, T., Rhrissorrakrai, K., Robine, N., Utro, F., Emde, A. K., Chen, B. J., Arora, K., Shah, M., Geiger, H., Felice, V., Dikoglu, E., Rahman, S., Fang, A., Vacic, V., Bergmann, E. A., Vogel, J. L., Reeves, C., Khaira, D., Calabro, A., Kim, D., Lamendola-Essel, M. F., Esteves, C., Agius, P., Stolte, C., Boockvar, J., Demopoulos, A., Placantonakis, D. G., Golfinos, J. G., Brennan, C., Bruce, J., Lassman, A. B., Canoll, P., Grommes, C., Daras, M., Diamond, E., Omuro, A., Pentsova, E., Orange, D. E., Harvey, S. J., Posner, J. B., Michelini, V. V., Jobanputra, V., Zody, M. C., Kelly, J., Parida, L., Wrzeszczynski, K. O., Royyuru, A. K., Darnell, R. B. 2019; 12 (1): 56

  Abstract

  Prompted by the revolution in high-throughput sequencing and its potential impact for treating cancer patients, we initiated a clinical research study to compare the ability of different sequencing assays and analysis methods to analyze glioblastoma tumors and generate real-time potential treatment options for physicians.A consortium of seven institutions in New York City enrolled 30 patients with glioblastoma and performed tumor whole genome sequencing (WGS) and RNA sequencing (RNA-seq; collectively WGS/RNA-seq); 20 of these patients were also analyzed with independent targeted panel sequencing. We also compared results of expert manual annotations with those from an automated annotation system, Watson Genomic Analysis (WGA), to assess the reliability and time required to identify potentially relevant pharmacologic interventions.WGS/RNAseq identified more potentially actionable clinical results than targeted panels in 90% of cases, with an average of 16-fold more unique potentially actionable variants identified per individual; 84 clinically actionable calls were made using WGS/RNA-seq that were not identified by panels. Expert annotation and WGA had good agreement on identifying variants [mean sensitivity = 0.71, SD = 0.18 and positive predictive value (PPV) = 0.80, SD = 0.20] and drug targets when the same variants were called (mean sensitivity = 0.74, SD = 0.34 and PPV = 0.79, SD = 0.23) across patients. Clinicians used the information to modify their treatment plan 10% of the time.These results present the first comprehensive comparison of technical and machine augmented analysis of targeted panel and WGS/RNA-seq to identify potential cancer treatments.

  View details for DOI 10.1186/s12920-019-0500-0

  View details for PubMedID 31023376

  View details for PubMedCentralID PMC6485090

• Bilateral radiation therapy followed by methotrexate-based chemotherapy for primary vitreoretinal lymphoma. American journal of hematology de la Fuente, M. I., Alderuccio, J. P., Reis, I. M., Omuro, A., Markoe, A., Echegaray, J. J., Davis, J. L., Harbour, J. W., Lossos, I. S. 2019; 94 (4): 455-460

  Abstract

  Primary vitreoretinal lymphoma (PVRL) is a subset of primary CNS lymphoma that presents as isolated ocular disease without brain involvement. Although ocular radiotherapy (RT) is an effective treatment for PVRL, the optimal treatment is uncertain. PVRL may later involve the brain in 56%-85% of patients. We report on 12 PVRL patients treated with a combination of bilateral RT and a systemic chemotherapy (CT) regimen containing high-dose methotrexate (M). Ten received RT (30-40 Gy) followed by CT, one received RT, and one was treated with intravitreal M; all achieved a complete response (CR). Three patients had tumor recurrence in the brain and received CT and one patient relapsed in the eye with a second recurrence in the brain. Three patients achieved CR-2 remain alive and one died of dementia. One died from recurrent CNS disease. With a median follow of 68 months (range, 17-154 months), median progression-free and overall survival have not been reached. Bilateral RT followed by M-based CT is an effective treatment for reducing CNS progression and prolonging survival.

  View details for DOI 10.1002/ajh.25414

  View details for PubMedID 30663807

• Buparlisib in Patients With Recurrent Glioblastoma Harboring Phosphatidylinositol 3-Kinase Pathway Activation: An Open-Label, Multicenter, Multi-Arm, Phase II Trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Wen, P. Y., Touat, M., Alexander, B. M., Mellinghoff, I. K., Ramkissoon, S., McCluskey, C. S., Pelton, K., Haidar, S., Basu, S. S., Gaffey, S. C., Brown, L. E., Martinez-Ledesma, J. E., Wu, S., Kim, J., Wei, W., Park, M. A., Huse, J. T., Kuhn, J. G., Rinne, M. L., Colman, H., Agar, N. Y., Omuro, A. M., DeAngelis, L. M., Gilbert, M. R., de Groot, J. F., Cloughesy, T. F., Chi, A. S., Roberts, T. M., Zhao, J. J., Lee, E. Q., Nayak, L., Heath, J. R., Horky, L. L., Batchelor, T. T., Beroukhim, R., Chang, S. M., Ligon, A. H., Dunn, I. F., Koul, D., Young, G. S., Prados, M. D., Reardon, D. A., Yung, W. K., Ligon, K. L. 2019; 37 (9): 741-750

  Abstract

  Phosphatidylinositol 3-kinase (PI3K) signaling is highly active in glioblastomas. We assessed pharmacokinetics, pharmacodynamics, and efficacy of the pan-PI3K inhibitor buparlisib in patients with recurrent glioblastoma with PI3K pathway activation.This study was a multicenter, open-label, multi-arm, phase II trial in patients with PI3K pathway-activated glioblastoma at first or second recurrence. In cohort 1, patients scheduled for re-operation after progression received buparlisib for 7 to 13 days before surgery to evaluate brain penetration and modulation of the PI3K pathway in resected tumor tissue. In cohort 2, patients not eligible for re-operation received buparlisib until progression or unacceptable toxicity. Once daily oral buparlisib 100 mg was administered on a continuous 28-day schedule. Primary end points were PI3K pathway inhibition in tumor tissue and buparlisib pharmacokinetics in cohort 1 and 6-month progression-free survival (PFS6) in cohort 2.Sixty-five patients were treated (cohort 1, n = 15; cohort 2, n = 50). In cohort 1, reduction of phosphorylated AKTS473 immunohistochemistry score was achieved in six (42.8%) of 14 patients, but effects on phosphoribosomal protein S6S235/236 and proliferation were not significant. Tumor-to-plasma drug level was 1.0. In cohort 2, four (8%) of 50 patients reached 6-month PFS6, and the median PFS was 1.7 months (95% CI, 1.4 to 1.8 months). The most common grade 3 or greater adverse events related to treatment were lipase elevation (n = 7 [10.8%]), fatigue (n = 4 [6.2%]), hyperglycemia (n = 3 [4.6%]), and elevated ALT (n = 3 [4.6%]).Buparlisib had minimal single-agent efficacy in patients with PI3K-activated recurrent glioblastoma. Although buparlisib achieved significant brain penetration, the lack of clinical efficacy was explained by incomplete blockade of the PI3K pathway in tumor tissue. Integrative results suggest that additional study of PI3K inhibitors that achieve more-complete pathway inhibition may still be warranted.

  View details for DOI 10.1200/JCO.18.01207

  View details for PubMedID 30715997

• Residual Tumor Volume, Cell Volume Fraction, and Tumor Cell Kill During Fractionated Chemoradiation Therapy of Human Glioblastoma using Quantitative Sodium MR Imaging. Clinical cancer research : an official journal of the American Association for Cancer Research Thulborn, K. R., Lu, A., Atkinson, I. C., Pauliah, M., Beal, K., Chan, T. A., Omuro, A., Yamada, J., Bradbury, M. S. 2019; 25 (4): 1226-1232

  Abstract

  Spatial and temporal patterns of response of human glioblastoma to fractionated chemoradiation are described by changes in the bioscales of residual tumor volume (RTV), tumor cell volume fraction (CVF), and tumor cell kill (TCK), as derived from tissue sodium concentration (TSC) measured by quantitative sodium MRI at 3 Tesla. These near real-time patterns during treatment are compared with overall survival.Bioscales were mapped during fractionated chemoradiation therapy in patients with glioblastomas (n = 20) using TSC obtained from serial quantitative sodium MRI at 3 Tesla and a two-compartment model of tissue sodium distribution. The responses of these parameters in newly diagnosed human glioblastomas undergoing treatment were compared with time-to-disease progression and survival.RTV following tumor resection showed decreased CVF due to disruption of normal cell packing by edema and infiltrating tumor cells. CVF showed either increases back toward normal as infiltrating tumor cells were killed, or decreases as cancer cells continued to infiltrate and extend tumor margins. These highly variable tumor responses showed no correlation with time-to-progression or overall survival.These bioscales indicate that fractionated chemoradiotherapy of glioblastomas produces variable responses with low cell killing efficiency. These parameters are sensitive to real-time changes within the treatment volume while remaining stable elsewhere, highlighting the potential to individualize therapy earlier in management, should alternative strategies be available.

  View details for DOI 10.1158/1078-0432.CCR-18-2079

  View details for PubMedID 30487127

  View details for PubMedCentralID PMC7462306

• Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nature genetics Samstein, R. M., Lee, C. H., Shoushtari, A. N., Hellmann, M. D., Shen, R., Janjigian, Y. Y., Barron, D. A., Zehir, A., Jordan, E. J., Omuro, A., Kaley, T. J., Kendall, S. M., Motzer, R. J., Hakimi, A. A., Voss, M. H., Russo, P., Rosenberg, J., Iyer, G., Bochner, B. H., Bajorin, D. F., Al-Ahmadie, H. A., Chaft, J. E., Rudin, C. M., Riely, G. J., Baxi, S., Ho, A. L., Wong, R. J., Pfister, D. G., Wolchok, J. D., Barker, C. A., Gutin, P. H., Brennan, C. W., Tabar, V., Mellinghoff, I. K., DeAngelis, L. M., Ariyan, C. E., Lee, N., Tap, W. D., Gounder, M. M., D'Angelo, S. P., Saltz, L., Stadler, Z. K., Scher, H. I., Baselga, J., Razavi, P., Klebanoff, C. A., Yaeger, R., Segal, N. H., Ku, G. Y., DeMatteo, R. P., Ladanyi, M., Rizvi, N. A., Berger, M. F., Riaz, N., Solit, D. B., Chan, T. A., Morris, L. G. 2019; 51 (2): 202-206

  Abstract

  Immune checkpoint inhibitor (ICI) treatments benefit some patients with metastatic cancers, but predictive biomarkers are needed. Findings in selected cancer types suggest that tumor mutational burden (TMB) may predict clinical response to ICI. To examine this association more broadly, we analyzed the clinical and genomic data of 1,662 advanced cancer patients treated with ICI, and 5,371 non-ICI-treated patients, whose tumors underwent targeted next-generation sequencing (MSK-IMPACT). Among all patients, higher somatic TMB (highest 20% in each histology) was associated with better overall survival. For most cancer histologies, an association between higher TMB and improved survival was observed. The TMB cutpoints associated with improved survival varied markedly between cancer types. These data indicate that TMB is associated with improved survival in patients receiving ICI across a wide variety of cancer types, but that there may not be one universal definition of high TMB.

  View details for DOI 10.1038/s41588-018-0312-8

  View details for PubMedID 30643254

  View details for PubMedCentralID PMC6365097

• Imaging biomarkers for brain metastases: more than meets the eye. S, A., A, O. Neuro Oncol. 2019

  Abstract

  doi10.1093/neuonc/noz19

• Phase 1 study of pomalidomide and dexamethasone for relapsed/refractory primary CNS or vitreoretinal lymphoma. Blood Tun, H. W., Johnston, P. B., DeAngelis, L. M., Atherton, P. J., Pederson, L. D., Koenig, P. A., Reeder, C. B., Omuro, A. M., Schiff, D., O'Neill, B., Pulido, J., Jaeckle, K. A., Grommes, C., Witzig, T. E. 2018; 132 (21): 2240-2248

  Abstract

  The combination of pomalidomide (POM) and dexamethasone (DEX) was evaluated for relapsed/refractory primary central nervous system lymphoma (PCNSL) and primary vitreoretinal lymphoma (PVRL) to determine the maximal tolerated dose (MTD) of POM as the primary objective, and overall response rate (ORR), progression-free survival (PFS), and safety profile as secondary objectives. A cohorts-of-3 study design was used with a dose-escalation schedule consisting of POM (3, 5, 7, or 10 mg) orally daily for 21 days every 28 days and DEX 40 mg orally every week. After 2 cycles, POM was continued alone until disease progression, intolerance, or subject withdrawal. Following MTD determination, the MTD cohort was expanded. Twenty-five of 29 patients with the median of 3 prior treatments were eligible for assessment as per international PCNSL collaborative group criteria. The MTD of POM was 5 mg daily for 21 days every 28 days. Whole-study ORR was 48% (12 of 25; 95% confidence interval [CI], 27.8%, 68.7%) with 6 complete response (CR), 2 complete response, unconfirmed (CRu), and 4 partial response (PR). MTD cohort ORR was 50% (8 of 16; 95% CI, 24.7%, 75.4%) with 5 CR, 1 CRu, and 2 PR. Median PFS was 5.3 months (whole study) and 9 months (for responders). One patient had pseudoprogression. Grade 3/4 hematologic toxicities included neutropenia (21%), anemia (8%), and thrombocytopenia (8%). Grade 3/4 nonhematologic toxicities included lung infection (12%), sepsis (4%), fatigue (8%), syncope (4%), dyspnea (4%), hypoxia (4%), respiratory failure (8%), and rash (4%). POM/DEX treatment is feasible with significant therapeutic activity against relapsed/refractory PCNSL and PVRL. This trial was registered at www.clinicaltrials.gov as #NCT01722305.

  View details for DOI 10.1182/blood-2018-02-835496

  View details for PubMedID 30262659

  View details for PubMedCentralID PMC6265643

• Multicenter Phase IB Trial of Carboxyamidotriazole Orotate and Temozolomide for Recurrent and Newly Diagnosed Glioblastoma and Other Anaplastic Gliomas. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Omuro, A., Beal, K., McNeill, K., Young, R. J., Thomas, A., Lin, X., Terziev, R., Kaley, T. J., DeAngelis, L. M., Daras, M., Gavrilovic, I. T., Mellinghoff, I., Diamond, E. L., McKeown, A., Manne, M., Caterfino, A., Patel, K., Bavisotto, L., Gorman, G., Lamson, M., Gutin, P., Tabar, V., Chakravarty, D., Chan, T. A., Brennan, C. W., Garrett-Mayer, E., Karmali, R. A., Pentsova, E. 2018; 36 (17): 1702-1709

  Abstract

  Purpose Carboxyamidotriazole orotate (CTO) is a novel oral inhibitor of non-voltage-dependent calcium channels with modulatory effects in multiple cell-signaling pathways and synergistic effects with temozolomide (TMZ) in glioblastoma (GBM) models. We conducted a phase IB study combining CTO with two standard TMZ schedules in GBM. Methods In cohort 1, patients with recurrent anaplastic gliomas or GBM received escalating doses of CTO (219 to 812.5 mg/m2 once daily or 600 mg fixed once-daily dose) combined with TMZ (150 mg/m2 5 days during each 28-day cycle). In cohort 2, patients with newly diagnosed GBM received escalating doses of CTO (219 to 481 mg/m2/d once daily) with radiotherapy and TMZ 75 mg/m2/d, followed by TMZ 150 mg to 200 mg/m2 5 days during each 28-day cycle. Results Forty-seven patients were enrolled. Treatment was well tolerated; toxicities included fatigue, constipation, nausea, and hypophosphatemia. Pharmacokinetics showed that CTO did not alter TMZ levels; therapeutic concentrations were achieved in tumor and brain. No dose-limiting toxicities were observed; the recommended phase II dose was 600 mg/d flat dose. Signals of activity in cohort 1 (n = 27) included partial (n = 6) and complete (n = 1) response, including in O6-methylguanine-DNA methyltransferase unmethylated and bevacizumab-refractory tumors. In cohort 2 (n = 15), median progression-free survival was 15 months and median overall survival was not reached (median follow-up, 28 months; 2-year overall survival, 62%). Gene sequencing disclosed a high rate of responses among EGFR-amplified tumors ( P = .005), with mechanisms of acquired resistance possibly involving mutations in mismatch-repair genes and/or downstream components TSC2, NF1, NF2, PTEN, and PIK3CA. Conclusion CTO can be combined safely with TMZ or chemoradiation in GBM and anaplastic gliomas, displaying favorable brain penetration and promising signals of activity in this difficult-to-treat population.

  View details for DOI 10.1200/JCO.2017.76.9992

  View details for PubMedID 29683790

  View details for PubMedCentralID PMC5993168

• Nivolumab with or without ipilimumab in patients with recurrent glioblastoma: results from exploratory phase I cohorts of CheckMate 143 NEURO-ONCOLOGY Omuro, A., Vlahovic, G., Lim, M., Sahebjam, S., Baehring, J., Cloughesy, T., Voloschin, A., Ramkissoon, S. H., Ligon, K. L., Latek, R., Zwirtes, R., Strauss, L., Paliwal, P., Harbison, C. T., Reardon, D. A., Sampson, J. H. 2018; 20 (5): 674–86

  Abstract

  Immunotherapies have demonstrated efficacy across a diverse set of tumors supporting further evaluation in glioblastoma. The objective of this study was to evaluate the safety/tolerability and describe immune-mediated effects of nivolumab ± ipilimumab in patients with recurrent glioblastoma. Exploratory efficacy outcomes are also reported.Patients were randomized to receive nivolumab 3 mg/kg every 2 weeks (Q2W; NIVO3) or nivolumab 1 mg/kg + ipilimumab 3 mg/kg every 3 weeks (Q3W) for 4 doses, then nivolumab 3 mg/kg Q2W (NIVO1+IPI3). An alternative regimen of nivolumab 3 mg/kg + ipilimumab 1 mg/kg Q3W for 4 doses, then nivolumab 3 mg/kg Q2W (NIVO3+IPI1) was investigated in a nonrandomized arm.Forty patients were enrolled (NIVO3, n = 10; NIVO1+IPI3, n = 10; NIVO3+IPI1, n = 20). The most common treatment-related adverse events (AEs) were fatigue (NIVO3, 30%; NIVO1+IPI3, 80%; NIVO3+IPI1, 55%) and diarrhea (10%, 70%, 30%, respectively). AEs leading to discontinuation occurred in 10% (NIVO3), 30% (NIVO1+IPI3), and 20% (NIVO3+IPI1) of patients. Three patients achieved a partial response (NIVO3, n = 1; NIVO3+IPI1, n = 2) and 8 had stable disease for ≥12 weeks (NIVO3, n = 2; NIVO1+IPI3, n = 2; NIVO3+IPI1, n = 4 [Response Assessment in Neuro-Oncology criteria]). Most patients (68%) had tumor-cell programmed death ligand-1 expression ≥1%. Immune-mediated effects mimicking radiographic progression occurred in 2 patients.Nivolumab monotherapy was better tolerated than nivolumab + ipilimumab; the tolerability of the combination was influenced by ipilimumab dose. These safety and exploratory findings merit further investigation of immunotherapies in glioblastoma.

  View details for DOI 10.1093/neuonc/nox208

  View details for Web of Science ID 000430161300012

  View details for PubMedID 29106665

  View details for PubMedCentralID PMC5892140

• Overall survival in patients with glioblastoma before and after bevacizumab approval. Current medical research and opinion Johnson, D. R., Omuro, A. M., Ravelo, A., Sommer, N., Guerin, A., Ionescu-Ittu, R., Shi, S., Macalalad, A., Uhm, J. H. 2018; 34 (5): 813-820

  Abstract

  Glioblastoma (GBM) is an aggressive disease with limited therapeutic options. While bevacizumab was approved in 2009 for the treatment of patients with progressive GBM, its impact on overall survival (OS) remains unclear. Using US population-based cancer registry data (SEER), this study compared OS of patients diagnosed with GBM before and after bevacizumab approval.Adult patients from SEER with a GBM diagnosis were divided into two cohorts: patients diagnosed in 2006-2008 (pre-bevacizumab cohort, n = 6,120) and patients diagnosed in 2010-2012 (post-bevacizumab cohort, n = 6,753). Patients were included irrespective of the treatments received. OS post-diagnosis was compared between the study cohorts utilizing Kaplan-Meier analyses and multivariate Cox proportional hazards regression.Among 12,873 patients with GBM, the median age was 62 years, 41% were women, 31% underwent gross total resection, and 75% received radiation therapy. Survival was stable within the 2006-2008 period (median survival = 9 months for each year), but increased after year 2009 (median survival = 10 and 11 months for years 2010/2011 and 2012, respectively). The adjusted hazard of death was significantly lower in the post-bevacizumab approval cohort (hazard ratio = 0.91, p < .01).The results of this large population-based study suggested an improvement in OS among patients with a GBM diagnosis in 2010-2012 compared to 2006-2008. While the cause of this improvement cannot be proven in a retrospective analysis, the timing of the survival increase coincides with the approval of bevacizumab for the treatment of patients with progressive GBM, indicating a possible benefit of bevacizumab in this population.

  View details for DOI 10.1080/03007995.2017.1392294

  View details for PubMedID 29025274

• In Vivo PET Assay of Tumor Glutamine Flux and Metabolism: In-Human Trial of 18F-(2S,4R)-4-Fluoroglutamine. Radiology Dunphy, M. P., Harding, J. J., Venneti, S., Zhang, H., Burnazi, E. M., Bromberg, J., Omuro, A. M., Hsieh, J. J., Mellinghoff, I. K., Staton, K., Pressl, C., Beattie, B. J., Zanzonico, P. B., Gerecitano, J. F., Kelsen, D. P., Weber, W., Lyashchenko, S. K., Kung, H. F., Lewis, J. S. 2018; 287 (2): 667-675

  Abstract

  Purpose To assess the clinical safety, pharmacokinetics, and tumor imaging characteristics of fluorine 18-(2S,4R)-4-fluoroglutamine (FGln), a glutamine analog radiologic imaging agent. Materials and Methods This study was approved by the institutional review board and conducted under a U.S. Food and Drug Administration-approved Investigational New Drug application in accordance with the Helsinki Declaration and the Health Insurance Portability and Accountability Act. All patients provided written informed consent. Between January 2013 and October 2016, 25 adult patients with cancer received an intravenous bolus of FGln tracer (mean, 244 MBq ± 118, <100 μg) followed by positron emission tomography (PET) and blood radioassays. Patient data were summarized with descriptive statistics. FGln biodistribution and plasma amino acid levels in nonfasting patients (n = 13) were compared with those from patients who fasted at least 8 hours before injection (n = 12) by using nonparametric one-way analysis of variance with Bonferroni correction. Tumor FGln avidity versus fluorodeoxyglucose (FDG) avidity in patients with paired PET scans (n = 15) was evaluated with the Fisher exact test. P < .05 was considered indicative of a statistically significant difference. Results FGln PET depicted tumors of different cancer types (breast, pancreas, renal, neuroendocrine, lung, colon, lymphoma, bile duct, or glioma) in 17 of the 25 patients, predominantly clinically aggressive tumors with genetic mutations implicated in abnormal glutamine metabolism. Acute fasting had no significant effect on FGln biodistribution and plasma amino acid levels. FGln-avid tumors were uniformly FDG-avid but not vice versa (P = .07). Patients experienced no adverse effects. Conclusion Preliminary human FGln PET trial results provide clinical validation of abnormal glutamine metabolism as a potential tumor biomarker for targeted radiotracer imaging in several different cancer types. © RSNA, 2018 Online supplemental material is available for this article. Clinical trial registration no. NCT01697930.

  View details for DOI 10.1148/radiol.2017162610

  View details for PubMedID 29388903

  View details for PubMedCentralID PMC5929369

• Radiographic patterns of recurrence and pathologic correlation in malignant gliomas treated with bevacizumab. CNS oncology Thomas, A., Rosenblum, M., Karimi, S., DeAngelis, L. M., Omuro, A., Kaley, T. J. 2018; 7 (1): 7-13

  Abstract

  Interpretation of MRI abnormalities in patients with malignant gliomas (MG) treated with bevacizumab is challenging. Recent reports describe quantitative analyses of diffusion-weighted imaging abnormalities not available in standard clinical settings, to differentiate tumor recurrence from treatment necrosis. We retrospectively reviewed bevacizumab treated MG patients who underwent surgery or autopsy to correlate radiographic recurrence patterns with pathologic findings. 32 patients with MG (26 glioblastoma, three anaplastic astrocytoma and three anaplastic oligodendroglioma) were identified. Recurrence patterns: local enhancing (n = 23), distant enhancing (n = 1), nonenhancing (n = 7) and leptomeningeal (n = 1).tumor (n = 25), mixed tumor/necrosis (n = 5) and all necrosis (n = 2). On diffusion-weighted imaging, 5/32 had restricted diffusion (three mixed and two necrosis). Irrespective of radiographic recurrence pattern, tumor was found in 94% of cases. Restricted diffusion correlated with necrosis.

  View details for DOI 10.2217/cns-2017-0025

  View details for PubMedID 29388793

  View details for PubMedCentralID PMC6001559

• Chemotherapy for Primary CNS Lymphomas Handbook of Brain Tumor Chemotherapy, Molecular Therapeutics, and Immunotherapy, 2nd Edition M, D., A, O. 2018
• Multicenter, Phase 1, Dose Escalation Study of Hypofractionated Stereotactic Radiation Therapy With Bevacizumab for Recurrent Glioblastoma and Anaplastic Astrocytoma. International journal of radiation oncology, biology, physics Clarke, J., Neil, E., Terziev, R., Gutin, P., Barani, I., Kaley, T., Lassman, A. B., Chan, T. A., Yamada, J., DeAngelis, L., Ballangrud, A., Young, R., Panageas, K. S., Beal, K., Omuro, A. 2017; 99 (4): 797-804

  Abstract

  To establish the maximum tolerated dose of a 3-fraction hypofractionated stereotactic reirradiation schedule when delivered with concomitant bevacizumab to treat recurrent high-grade gliomas.Patients with recurrent high-grade glioma with Karnofsky performance status ≥60, history of standard fractionated initial radiation, tumor volume at recurrence ≤40 cm3, and absence of brainstem or corpus callosum involvement were eligible. A standard 3+3 phase 1 dose escalation trial design was utilized, with dose-limiting toxicities defined as any grade 3 to 5 toxicities possibly, probably, or definitely related to radiation. Bevacizumab was given at a dose of 10 mg/kg every 2 weeks. Hypofractionated stereotactic reirradiation was initiated after 2 bevacizumab doses, delivered in 3 fractions every other day, starting at 9 Gy per fraction.A total of 3 patients were enrolled at the 9 Gy × 3 dose level cohort, 5 in the 10 Gy × 3 cohort, and 7 in the 11 Gy × 3 cohort. One dose-limiting toxicity of grade 3 fatigue and cognitive deterioration possibly related to hypofractionated stereotactic reirradiation was observed in the 11 Gy × 3 cohort, and this dose was declared the maximum tolerated dose in combination with bevacizumab. Although no symptomatic radionecrosis was observed, substantial treatment-related effects and necrosis were observed in resected specimens. The intent-to-treat median overall survival was 13 months.Reirradiation using a 3-fraction schedule with bevacizumab support is feasible and reasonably well tolerated. Dose-escalation was possible up to 11 Gy × 3, which achieves a near doubling in the delivered biological equivalent dose to normal brain, in comparison with our previous 6 Gy × 5 schedule. Promising overall survival warrants further investigation.

  View details for DOI 10.1016/j.ijrobp.2017.06.2466

  View details for PubMedID 28870792

  View details for PubMedCentralID PMC5654655

• Multicenter phase II study of temozolomide and myeloablative chemotherapy with autologous stem cell transplant for newly diagnosed anaplastic oligodendroglioma. Neuro-oncology Thomas, A. A., Abrey, L. E., Terziev, R., Raizer, J., Martinez, N. L., Forsyth, P., Paleologos, N., Matasar, M., Sauter, C. S., Moskowitz, C., Nimer, S. D., DeAngelis, L. M., Kaley, T., Grimm, S., Louis, D. N., Cairncross, J. G., Panageas, K. S., Briggs, S., Faivre, G., Mohile, N. A., Mehta, J., Jonsson, P., Chakravarty, D., Gao, J., Schultz, N., Brennan, C. W., Huse, J. T., Omuro, A. 2017; 19 (10): 1380-1390

  Abstract

  Anaplastic oligodendroglioma (AO) and anaplastic oligoastrocytoma (AOA) are chemotherapy-sensitive tumors with prolonged survival after radiochemotherapy. We report a prospective trial using induction temozolomide (TMZ) followed by myeloablative high-dose chemotherapy (HDC) with autologous stem-cell transplant (ASCT) as a potential strategy to defer radiotherapy.Patients with AO/AOA received 6 cycles of TMZ (200 mg/m2 × 5/28 day). Responding patients were eligible for HDC (thiotepa 250 mg/m2/day × 3 days, then busulfan 3.2 mg/kg/day × 3 days), followed by ASCT. Genomic characterization was performed using next-generation sequencing.Forty-one patients were enrolled; 85% had 1p/19q codeleted tumors. After induction, 26 patients were eligible for HDC-ASCT and 21 agreed to proceed. There were no unexpected adverse events or toxic deaths. After median follow-up of 66 months, 2-year progression-free survival (PFS) for transplanted patients was 86%, 5-year PFS 60%, and no patient has died. Among all 1p/19q codeleted patients (N = 33), 5-year PFS was 50% and 5-year overall survival (OS) 93%, with median time to radiotherapy not reached. Next-generation sequencing disclosed typical oligodendroglioma-related mutations, including IDH1, TERT, CIC, and FUBP1 mutations in 1p/19q codeleted patients, and glioblastoma-like signatures in 1p/19q intact patients. Aside from IDH1, potentially oncogenic/actionable mutations were variable, depicting wide molecular heterogeneity within oligodendroglial tumors.TMZ followed by HDC-ASCT can be safely administered to patients with newly diagnosed 1p/19q codeleted AO. This strategy was associated with promising PFS and OS, suggesting that a chemotherapy-based approach may delay the need for radiotherapy and radiation-related toxicities. Raw data for further genomic and meta-analyses are publicly available at http://cbioportal.org/study?id=odg_msk_2017, accessed 6 January 2017.NCT00588523.

  View details for DOI 10.1093/neuonc/nox086

  View details for PubMedID 28472509

  View details for PubMedCentralID PMC5596171

• Cerebrospinal fluid circulating tumor cells: a novel tool to diagnose leptomeningeal metastases from epithelial tumors. Neuro-oncology Lin, X., Fleisher, M., Rosenblum, M., Lin, O., Boire, A., Briggs, S., Bensman, Y., Hurtado, B., Shagabayeva, L., DeAngelis, L. M., Panageas, K. S., Omuro, A., Pentsova, E. I. 2017; 19 (9): 1248-1254

  Abstract

  Diagnosis of leptomeningeal metastasis (LM) remains challenging due to low sensitivity of CSF cytology and infrequent unequivocal MRI findings. In a previous pilot study, we showed that rare cell capture technology (RCCT) could be used to detect circulating tumor cells (CTC) in the CSF of patients with LM from epithelial tumors. To establish the diagnostic accuracy of CSF-CTC in the diagnosis of LM, we applied this technique in a distinct, larger cohort of patients.In this institutional review board-approved prospective study, patients with epithelial tumors and clinical suspicion of LM underwent CSF-CTC evaluation and standard MRI and CSF cytology examination. CSF-CTC enumeration was performed through an FDA-approved epithelial cell adhesion molecule-based RCCT immunomagnetic platform. LM was defined by either positive CSF cytology or imaging positive for LM. ROC analysis was utilized to define an optimal cutoff for CSF-CTC enumeration.Ninety-five patients were enrolled (36 breast, 31 lung, 28 others). LM was diagnosed in 30 patients (32%) based on CSF cytology (n = 12), MRI findings (n = 2), or both (n = 16). CSF-CTC were detected in 43/95 samples (median 19.3 CSF-CTC/mL, range 0.3 to 66.7). Based on ROC analysis, 1 CSF-CTC/mL provided the best threshold to diagnose LM, achieving a sensitivity of 93%, specificity of 95%, positive predictive value 90%, and negative predictive value 97%.We defined ≥1 CSF-CTC/mL as the optimal cutoff for diagnosis of LM. CSF-CTC enumeration through RCCT is a robust tool to diagnose LM and should be considered in the routine LM workup in solid tumor patients.

  View details for DOI 10.1093/neuonc/nox066

  View details for PubMedID 28821205

  View details for PubMedCentralID PMC5570249

• Ibrutinib Unmasks Critical Role of Bruton Tyrosine Kinase in Primary CNS Lymphoma. Cancer discovery Grommes, C., Pastore, A., Palaskas, N., Tang, S. S., Campos, C., Schartz, D., Codega, P., Nichol, D., Clark, O., Hsieh, W. Y., Rohle, D., Rosenblum, M., Viale, A., Tabar, V. S., Brennan, C. W., Gavrilovic, I. T., Kaley, T. J., Nolan, C. P., Omuro, A., Pentsova, E., Thomas, A. A., Tsyvkin, E., Noy, A., Palomba, M. L., Hamlin, P., Sauter, C. S., Moskowitz, C. H., Wolfe, J., Dogan, A., Won, M., Glass, J., Peak, S., Lallana, E. C., Hatzoglou, V., Reiner, A. S., Gutin, P. H., Huse, J. T., Panageas, K. S., Graeber, T. G., Schultz, N., DeAngelis, L. M., Mellinghoff, I. K. 2017; 7 (9): 1018-1029

  Abstract

  Bruton tyrosine kinase (BTK) links the B-cell antigen receptor (BCR) and Toll-like receptors with NF-κB. The role of BTK in primary central nervous system (CNS) lymphoma (PCNSL) is unknown. We performed a phase I clinical trial with ibrutinib, the first-in-class BTK inhibitor, for patients with relapsed or refractory CNS lymphoma. Clinical responses to ibrutinib occurred in 10 of 13 (77%) patients with PCNSL, including five complete responses. The only PCNSL with complete ibrutinib resistance harbored a mutation within the coiled-coil domain of CARD11, a known ibrutinib resistance mechanism. Incomplete tumor responses were associated with mutations in the B-cell antigen receptor-associated protein CD79B. CD79B-mutant PCNSLs showed enrichment of mammalian target of rapamycin (mTOR)-related gene sets and increased staining with PI3K/mTOR activation markers. Inhibition of the PI3K isoforms p110α/p110δ or mTOR synergized with ibrutinib to induce cell death in CD79B-mutant PCNSL cells.Significance: Ibrutinib has substantial activity in patients with relapsed or refractory B-cell lymphoma of the CNS. Response rates in PCNSL were considerably higher than reported for diffuse large B-cell lymphoma outside the CNS, suggesting a divergent molecular pathogenesis. Combined inhibition of BTK and PI3K/mTOR may augment the ibrutinib response in CD79B-mutant human PCNSLs. Cancer Discov; 7(9); 1018-29. ©2017 AACR.See related commentary by Lakshmanan and Byrd, p. 940This article is highlighted in the In This Issue feature, p. 920.

  View details for DOI 10.1158/2159-8290.CD-17-0613

  View details for PubMedID 28619981

  View details for PubMedCentralID PMC5581705

• Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients NATURE MEDICINE Zehir, A., Benayed, R., Shah, R. H., Syed, A., Middha, S., Kim, H. R., Srinivasan, P., Gao, J., Chakravarty, D., Devlin, S. M., Hellmann, M. D., Barron, D. A., Schram, A. M., Hameed, M., Dogan, S., Ross, D. S., Hechtman, J. F., DeLair, D. F., Yao, J., Mandelker, D. L., Cheng, D. T., Chandramohan, R., Mohanty, A. S., Ptashkin, R. N., Jayakumaran, G., Prasad, M., Syed, M. H., Rema, A., Liu, Z. Y., Nafa, K., Borsu, L., Sadowska, J., Casanova, J., Bacares, R., Kiecka, I. J., Razumova, A., Son, J. B., Stewart, L., Baldi, T., Mullaney, K. A., Al-Ahmadie, H., Vakiani, E., Abeshouse, A. A., Penson, A. V., Jonsson, P., Camacho, N., Chang, M. T., Won, H. H., Gross, B. E., Kundra, R., Heins, Z. J., Chen, H., Phillips, S., Zhang, H., Wang, J., Ochoa, A., Wills, J., Eubank, M., Thomas, S. B., Gardos, S. M., Reales, D. N., Galle, J., Durany, R., Cambria, R., Abida, W., Cercek, A., Feldman, D. R., Gounder, M. M., Hakimi, A., Harding, J. J., Iyer, G., Janjigian, Y. Y., Jordan, E. J., Kelly, C. M., Lowery, M. A., Morris, L. T., Omuro, A. M., Raj, N., Razavi, P., Shoushtari, A. N., Shukla, N., Soumerai, T. E., Varghese, A. M., Yaeger, R., Coleman, J., Bochner, B., Riely, G. J., Saltz, L. B., Scher, H. I., Sabbatini, P. J., Robson, M. E., Klimstra, D. S., Taylor, B. S., Baselga, J., Schultz, N., Hyman, D. M., Arcila, M. E., Solit, D. B., Ladanyi, M., Berger, M. F. 2017; 23 (6): 703-+

  Abstract

  Tumor molecular profiling is a fundamental component of precision oncology, enabling the identification of genomic alterations in genes and pathways that can be targeted therapeutically. The existence of recurrent targetable alterations across distinct histologically defined tumor types, coupled with an expanding portfolio of molecularly targeted therapies, demands flexible and comprehensive approaches to profile clinically relevant genes across the full spectrum of cancers. We established a large-scale, prospective clinical sequencing initiative using a comprehensive assay, MSK-IMPACT, through which we have compiled tumor and matched normal sequence data from a unique cohort of more than 10,000 patients with advanced cancer and available pathological and clinical annotations. Using these data, we identified clinically relevant somatic mutations, novel noncoding alterations, and mutational signatures that were shared by common and rare tumor types. Patients were enrolled on genomically matched clinical trials at a rate of 11%. To enable discovery of novel biomarkers and deeper investigation into rare alterations and tumor types, all results are publicly accessible.

  View details for DOI 10.1038/nm.4333

  View details for Web of Science ID 000402768000013

  View details for PubMedID 28481359

  View details for PubMedCentralID PMC5461196

• Dynamic contrast-enhanced MRI perfusion for differentiating between melanoma and lung cancer brain metastases. Cancer medicine Hatzoglou, V., Tisnado, J., Mehta, A., Peck, K. K., Daras, M., Omuro, A. M., Beal, K., Holodny, A. I. 2017; 6 (4): 761-767

  Abstract

  Brain metastases originating from different primary sites overlap in appearance and are difficult to differentiate with conventional MRI. Dynamic contrast-enhanced (DCE)-MRI can assess tumor microvasculature and has demonstrated utility in characterizing primary brain tumors. Our aim was to evaluate the performance of plasma volume (Vp) and volume transfer coefficient (Ktrans ) derived from DCE-MRI in distinguishing between melanoma and nonsmall cell lung cancer (NSCLC) brain metastases. Forty-seven NSCLC and 23 melanoma brain metastases were retrospectively assessed with DCE-MRI. Regions of interest were manually drawn around the metastases to calculate Vpmean and Kmeantrans. The Mann-Whitney U test and receiver operating characteristic analysis (ROC) were performed to compare perfusion parameters between the two groups. The Vpmean of melanoma brain metastases (4.35, standard deviation [SD] = 1.31) was significantly higher (P = 0.03) than Vpmean of NSCLC brain metastases (2.27, SD = 0.96). The Kmeantrans values were higher in melanoma brain metastases, but the difference between the two groups was not significant (P = 0.12). Based on ROC analysis, a cut-off value of 3.02 for Vpmean (area under curve = 0.659 with SD = 0.074) distinguished between melanoma brain metastases and NSCLC brain metastases (P < 0.01) with 72% specificity. Our data show the DCE-MRI parameter Vpmean can differentiate between melanoma and NSCLC brain metastases. The ability to noninvasively predict tumor histology of brain metastases in patients with multiple malignancies can have important clinical implications.

  View details for DOI 10.1002/cam4.1046

  View details for PubMedID 28303695

  View details for PubMedCentralID PMC5387174

• Patterns of response and relapse in primary CNS lymphomas after first-line chemotherapy: imaging analysis of the ANOCEF-GOELAMS prospective randomized trial. Neuro-oncology Tabouret, E., Houillier, C., Martin-Duverneuil, N., Blonski, M., Soussain, C., Ghesquières, H., Houot, R., Larrieu, D., Soubeyran, P., Gressin, R., Gyan, E., Chinot, O., Taillandier, L., Choquet, S., Alentorn, A., Leclercq, D., Omuro, A., Tanguy, M. L., Hoang-Xuan, K. 2017; 19 (3): 422-429

  Abstract

  Our aim was to review MRI characteristics of patients with primary CNS lymphoma (PCNSL) enrolled in a randomized phase II trial and to evaluate their potential prognostic value and patterns of relapse, including T2 fluid attenuated inversion recovery (FLAIR) MRI abnormalities.Neuroimaging findings in 85 patients with PCNSL enrolled in a prospective trial were reviewed blinded to outcomes. MRI characteristics and responses according to International PCNSL Collaborative Group (IPCG) criteria were correlated with progression-free survival (PFS) and overall survival (OS).Multivariate analysis showed that objective response at 2 months (P < .001) and at end of treatment (P = .015) were predictors of prolonged OS. Infratentorial location (P = .008) and large (>11.4 cm3) enhancing tumor volume (P = .006) were associated with poor OS and PFS, respectively. Ratio of change in product of largest diameters at early MRI evaluation but not timing of complete response achievement (early vs delayed) was prognostic for OS. Sixty-nine patients relapsed. Relapse in the brain (n = 52) involved an initial enhancing site, a different site, or both in 46%, 40%, and 14% of patients, respectively. At baseline, non-enhancing T2-FLAIR hypersignal lesions distant from the enhancing tumor site were detected in 18 patients. These lesions markedly decreased (>50%) in 16 patients after chemotherapy, supporting their neoplastic nature. Of these patients, 10/18 relapsed, half (n = 5) in the initially non-enhancing T2-FLAIR lesions.Baseline tumor size and infratentorial localization are of prognostic value in PCNSL. Our findings provide evidence that non-enhancing FLAIR abnormalities may add to overall tumor burden, suggesting that response criteria should be refined to incorporate evaluation of T2-weighted/FLAIR sequences.

  View details for DOI 10.1093/neuonc/now238

  View details for PubMedID 27994065

  View details for PubMedCentralID PMC5464299

• Phase I trial of aflibercept (VEGF trap) with radiation therapy and concomitant and adjuvant temozolomide in patients with high-grade gliomas. Journal of neuro-oncology Nayak, L., de Groot, J., Wefel, J. S., Cloughesy, T. F., Lieberman, F., Chang, S. M., Omuro, A., Drappatz, J., Batchelor, T. T., DeAngelis, L. M., Gilbert, M. R., Aldape, K. D., Yung, A. W., Fisher, J., Ye, X., Chen, A., Grossman, S., Prados, M., Wen, P. Y. 2017; 132 (1): 181-188

  Abstract

  Anti-vascular endothelial growth factor (VEGF) therapy has shown promise in the treatment of high-grade gliomas (HGG). Aflibercept is a recombinant human fusion protein that acts as a soluble decoy receptor for VEGF-A, VEGF-B and placental growth factor, depleting circulating levels of these growth factors. The Adult Brain Tumor Consortium conducted a phase I trial of aflibercept and temozolomide (TMZ) in patients with newly diagnosed HGG with 2 dose levels and a 3+3 design. Three arms using aflibercept were examined; with radiation and concomitant temozolomide; with adjuvant temozolomide using the 5/28 regimen; and with adjuvant temozolomide using the 21/28 day regimen. Fifty-nine patients were enrolled, 21 in arm 1, 20 in arm 2 and 18 in arm 3. Median age was 56 years (24-69); median KPS 90 (60-100). The maximum tolerated dose (MTD) of aflibercept for all 3 arms was 4 mg/kg every 2 weeks. Dose limiting toxicities at the MTD were: Arm 1: 0/21 patients; Arm 2: 2/20 patients (G3 deep vein thrombosis, G4 neutropenia; Arm 3: 3/18 patients) (G4 biopsy-confirmed thrombotic microangiopathy, G3 rash, G4 thrombocytopenia). The median number of cycles of aflibercept was 5 (range, 1-16). All patients stopped treatment; 28 (47%) for disease progression, 21 (36%) for toxicities, 8 (14%) for other reasons, and 2 (3%) patients completed the full treatment course. This study met its primary endpoint and the MTD of aflibercept with radiation and concomitant and adjuvant temozolomide is 4 mg/kg every 2 weeks.

  View details for DOI 10.1007/s11060-016-2357-9

  View details for PubMedID 28116649

  View details for PubMedCentralID PMC5588922

• Diagnostic Accuracy of T1-Weighted Dynamic Contrast-Enhanced-MRI and DWI-ADC for Differentiation of Glioblastoma and Primary CNS Lymphoma. AJNR. American journal of neuroradiology Lin, X., Lee, M., Buck, O., Woo, K. M., Zhang, Z., Hatzoglou, V., Omuro, A., Arevalo-Perez, J., Thomas, A. A., Huse, J., Peck, K., Holodny, A. I., Young, R. J. 2017; 38 (3): 485-491

  Abstract

  Glioblastoma and primary CNS lymphoma dictate different neurosurgical strategies; it is critical to distinguish them preoperatively. However, current imaging modalities do not effectively differentiate them. We aimed to examine the use of DWI and T1-weighted dynamic contrast-enhanced-MR imaging as potential discriminative tools.We retrospectively reviewed 18 patients with primary CNS lymphoma and 36 matched patients with glioblastoma with pretreatment DWI and dynamic contrast-enhanced-MR imaging. VOIs were drawn around the tumor on contrast-enhanced T1WI and FLAIR images; these images were transferred onto coregistered ADC maps to obtain the ADC and onto dynamic contrast-enhanced perfusion maps to obtain the plasma volume and permeability transfer constant. Histogram analysis was performed to determine the mean and relative ADCmean and relative 90th percentile values for plasma volume and the permeability transfer constant. Nonparametric tests were used to assess differences, and receiver operating characteristic analysis was performed for optimal threshold calculations.The enhancing component of primary CNS lymphoma was found to have significantly lower ADCmean (1.1 × 10-3 versus 1.4 × 10-3; P < .001) and relative ADCmean (1.5 versus 1.9; P < .001) and relative 90th percentile values for plasma volume (3.7 versus 5.0; P < .05) than the enhancing component of glioblastoma, but not significantly different relative 90th percentile values for the permeability transfer constant (5.4 versus 4.4; P = .83). The nonenhancing portions of glioblastoma and primary CNS lymphoma did not differ in these parameters. On the basis of receiver operating characteristic analysis, mean ADC provided the best threshold (area under the curve = 0.83) to distinguish primary CNS lymphoma from glioblastoma, which was not improved with normalized ADC or the addition of perfusion parameters.ADC was superior to dynamic contrast-enhanced-MR imaging perfusion, alone or in combination, in differentiating primary CNS lymphoma from glioblastoma.

  View details for DOI 10.3174/ajnr.A5023

  View details for PubMedID 27932505

  View details for PubMedCentralID PMC5352508

• A Comprehensive Assessment of Toxicities in Patients with Central Nervous System Lymphoma Undergoing Autologous Stem Cell Transplantation Using Thiotepa, Busulfan, and Cyclophosphamide Conditioning. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation Scordo, M., Bhatt, V., Hsu, M., Omuro, A. M., Matasar, M. J., DeAngelis, L. M., Dahi, P. B., Moskowitz, C. H., Giralt, S. A., Sauter, C. S. 2017; 23 (1): 38-43

  Abstract

  High-dose therapy and autologous stem cell transplantation (ASCT) with thiotepa, busulfan, and cyclophosphamide (TBC) conditioning has emerged as an effective postinduction treatment strategy for patients with primary central nervous system lymphoma (PCNSL) or secondary central nervous system lymphoma (SCNSL), but it is associated with considerable toxicity and transplantation-related mortality (TRM) in the modern era. Forty-three adult patients with chemosensitive PCNSL or SCNSL underwent TBC-conditioned ASCT between 2006 and 2015. Twenty-eight of these patients received pharmacokinetically (PK)-targeted busulfan dosing. The median number of clinically relevant individual grade ≥3 nonhematologic toxicities per patient was 5. We found no association between pretransplantation patient characteristics and the presence of more than 5 grade ≥3 nonhematologic toxicities. Patients with elevated first-dose busulfan area under the curve values did not experience more toxicity. Paradoxically, patients treated with more than 2 regimens before undergoing ASCT had lower first-dose busulfan AUC values. With a median follow-up among survivors of 20 months, 1-year progression-free survival (PFS) and overall survival (OS) from the time of ASCT were 83% and 87%, respectively. Although this study reaffirms the favorable PFS and OS associated with TBC-conditioned ASCT for PCNSL or SCNSL, this treatment strategy carries a large toxicity burden.

  View details for DOI 10.1016/j.bbmt.2016.09.024

  View details for PubMedID 27713090

  View details for PubMedCentralID PMC5518313

• OncoKB: A Precision Oncology Knowledge Base JCO PRECISION ONCOLOGY Chakravarty, D., Gao, J., Phillips, S., Kundra, R., Zhang, H., Wang, J., Rudolph, J. E., Yaeger, R., Soumerai, T., Nissan, M. H., Chang, M. T., Chandarlapaty, S., Traina, T. A., Paik, P. K., Ho, A. L., Hantash, F. M., Grupe, A., Baxi, S. S., Callahan, M. K., Snyder, A., Chi, P., Danila, D. C., Gounder, M., Harding, J. J., Hellmann, M. D., Iyer, G., Janjigian, Y. Y., Kaley, T., Levine, D. A., Lowery, M., Omuro, A., Postow, M. A., Rathkopf, D., Shoushtari, A. N., Shukla, N., Voss, M. H., Paraiso, E., Zehir, A., Berger, M. F., Taylor, B. S., Saltz, L. B., Riely, G. J., Ladanyi, M., Hyman, D. M., Baselga, J., Sabbatini, P., Solit, D. B., Schultz, N. 2017; 1

  View details for Web of Science ID 000462058200028

• Molecular and Clinical Effects of Notch Inhibition in Glioma Patients: A Phase 0/I Trial. Clinical cancer research : an official journal of the American Association for Cancer Research Xu, R., Shimizu, F., Hovinga, K., Beal, K., Karimi, S., Droms, L., Peck, K. K., Gutin, P., Iorgulescu, J. B., Kaley, T., DeAngelis, L., Pentsova, E., Nolan, C., Grommes, C., Chan, T., Bobrow, D., Hormigo, A., Cross, J. R., Wu, N., Takebe, N., Panageas, K., Ivy, P., Supko, J. G., Tabar, V., Omuro, A. 2016; 22 (19): 4786-4796

  Abstract

  High-grade gliomas are associated with a dismal prognosis. Notch inhibition via the gamma-secretase inhibitor RO4929097 has emerged as a potential therapeutic option based on modulation of the cancer-initiating cell (CIS) population and a presumed antiangiogenic role.In this phase 0/I trial, 21 patients with newly diagnosed glioblastoma or anaplastic astrocytoma received RO4929097 combined with temozolomide and radiotherapy. In addition to establishing the MTD, the study design enabled exploratory studies evaluating tumor and brain drug penetration and neuroimaging parameters. We also determined functional effects on the Notch pathway and targeting of CISs through analysis of tumor tissue sampled from areas with and without blood-brain barrier disruption. Finally, recurrent tumors were also sampled and assessed for Notch pathway responses while on treatment.Treatment was well tolerated and no dose-limiting toxicities were observed. IHC of treated tumors showed a significant decrease in proliferation and in the expression of the Notch intracellular domain (NICD) by tumor cells and blood vessels. Patient-specific organotypic tumor explants cultures revealed a specific decrease in the CD133+ CIS population upon treatment. Perfusion MRI demonstrated a significant decrease in relative plasma volume after drug exposure. Gene expression data in recurrent tumors suggested low Notch signaling activity, the upregulation of key mesenchymal genes, and an increase in VEGF-dependent angiogenic factors.The addition of RO4929097 to temozolomide and radiotherapy was well tolerated; the drug has a variable blood-brain barrier penetration. Evidence of target modulation was observed, but recurrence occurred, associated with alterations in angiogenesis signaling pathways. Clin Cancer Res; 22(19); 4786-96. ©2016 AACR.

  View details for DOI 10.1158/1078-0432.CCR-16-0048

  View details for PubMedID 27154916

  View details for PubMedCentralID PMC5050072

• Second-opinion interpretations of neuroimaging studies by oncologic neuroradiologists can help reduce errors in cancer care. Cancer Hatzoglou, V., Omuro, A. M., Haque, S., Khakoo, Y., Ganly, I., Oh, J. H., Shukla-Dave, A., Fatovic, R., Gaal, J., Holodny, A. I. 2016; 122 (17): 2708-14

  Abstract

  The purpose of this study was to investigate the utility and clinical impact of second-opinion interpretations of outside neuroimaging studies by oncologic neuroradiologists at a National Cancer Institute-designated cancer center.We performed a retrospective analysis of initial outside and second-opinion radiology reports from 300 computed tomography and magnetic resonance imaging studies and identified cases with discrepancies between the two reports. An adult neuro-oncologist, pediatric neuro-oncologist, and head and neck surgeon reviewed each pair of discrepant reports based on their area of expertise, patient age, and the type of study performed. The clinicians were blinded to the origin of each report and recorded whether the differences in the reports would have led to a change in patient management and/or disease staging. Histopathologic analysis, clinical assessment, and/or minimum 3-month imaging follow-up served as the reference standards to establish which of the 2 reports was correct.Among the 283 cases that met our study criteria, there were 55 neuroimaging studies with disagreements (19%) between the initial outside report and second-opinion interpretation. Patient management and/or disease stage would have been altered in 42 of 283 cases (15%) based on report differences as determined by the 2 neuro-oncologists and the surgeon participating in the study. Sufficient follow-up was available in 35 of 42 cases (83%). The second-opinion interpretation was correct 100% of the time (35/35).Second-opinion interpretations of neuroimaging studies by subspecialized oncologic neuroradiologists provide added value by reducing error and optimizing the care of cancer patients. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2708-2714. © 2016 American Cancer Society.

  View details for DOI 10.1002/cncr.30083

  View details for PubMedID 27219108

  View details for PubMedCentralID PMC4992439

• Primary Oculocerebral Lymphoma: MTX Polychemotherapy Alone on Intraocular Disease Control. Ophthalmology Nguyen, D. T., Houillier, C., Choquet, S., Cassoux, N., Soussain, C., Le Cossec, C., Legarf-Tavernier, M., Costopoulos, M., LeHoang, P., Bodaghi, B., Omuro, A., Hoang-Xuan, K., Touitou, V. 2016; 123 (9): 2047-50

  View details for DOI 10.1016/j.ophtha.2016.03.043

  View details for PubMedID 27137876

• High-dose methotrexate-based chemotherapy as treatment for histiocytic sarcoma of the central nervous system. Leukemia & lymphoma Curry, R. C., Faivre, G., Akkari, L., Joyce, J. A., Lin, O., Rosenblum, M., Diamond, E. L., Fisher, R., Omuro, A. 2016; 57 (8): 1961-4

  View details for DOI 10.3109/10428194.2015.1120867

  View details for PubMedID 26727454

• Therapeutic Impact of Cytoreductive Surgery and Irradiation of Posterior Fossa Ependymoma in the Molecular Era: A Retrospective Multicohort Analysis JOURNAL OF CLINICAL ONCOLOGY Ramaswamy, V., Hielscher, T., Mack, S. C., Lassaletta, A., Lin, T., Pajtler, K. W., Jones, D. T., Luu, B., Cavalli, F. M., Aldape, K., Remke, M., Mynarek, M., Rutkowski, S., Gururangan, S., McLendon, R. E., Lipp, E. S., Dunham, C., Hukin, J., Eisenstat, D. D., Fulton, D., van Landeghem, F. K., Santi, M., van Veelen, M. C., Van Meir, E. G., Osuka, S., Fan, X., Muraszko, K. M., Tirapelli, D. P., Oba-Shinjo, S. M., Marie, S. K., Carlotti, C. G., Lee, J. Y., Rao, A. A., Giannini, C., Faria, C. C., Nunes, S., Mora, J., Hamilton, R. L., Hauser, P., Jabado, N., Petrecca, K., Jung, S., Massimi, L., Zollo, M., Cinalli, G., Bognar, L., Klekner, A., Hortobagyi, T., Leary, S., Ermoian, R. P., Olson, J. M., Leonard, J. R., Gardner, C., Grajkowska, W. A., Chambless, L. B., Cain, J., Eberhart, C. G., Ahsan, S., Massimino, M., Giangaspero, F., Buttarelli, F. R., Packer, R. J., Emery, L., Yong, W. H., Soto, H., Liau, L. M., Everson, R., Grossbach, A., Shalaby, T., Grotzer, M., Karajannis, M. A., Zagzag, D., Wheeler, H., von Hoff, K., Alonso, M. M., Tuon, T., Schueller, U., Zitterbart, K., Sterba, J., Chan, J. A., Guzman, M., Elbabaa, S. K., Colman, H., Dhall, G., Fisher, P. G., Fouladi, M., Gajjar, A., Goldman, S., Hwang, E., Kool, M., Ladha, H., Vera-Bolanos, E., Wani, K., Lieberman, F., Mikkelsen, T., Omuro, A. M., Pollack, I. F., Prados, M., Robins, H. I., Soffietti, R., Wu, J., Metellus, P., Tabori, U., Bartels, U., Bouffet, E., Hawkins, C. E., Rutka, J. T., Dirks, P., Pfister, S. M., Merchant, T. E., Gilbert, M. R., Armstrong, T. S., Korshunov, A., Ellison, D. W., Taylor, M. D. 2016; 34 (21): 2468-?

  Abstract

  Posterior fossa ependymoma comprises two distinct molecular variants termed EPN_PFA and EPN_PFB that have a distinct biology and natural history. The therapeutic value of cytoreductive surgery and radiation therapy for posterior fossa ependymoma after accounting for molecular subgroup is not known.Four independent nonoverlapping retrospective cohorts of posterior fossa ependymomas (n = 820) were profiled using genome-wide methylation arrays. Risk stratification models were designed based on known clinical and newly described molecular biomarkers identified by multivariable Cox proportional hazards analyses.Molecular subgroup is a powerful independent predictor of outcome even when accounting for age or treatment regimen. Incompletely resected EPN_PFA ependymomas have a dismal prognosis, with a 5-year progression-free survival ranging from 26.1% to 56.8% across all four cohorts. Although first-line (adjuvant) radiation is clearly beneficial for completely resected EPN_PFA, a substantial proportion of patients with EPN_PFB can be cured with surgery alone, and patients with relapsed EPN_PFB can often be treated successfully with delayed external-beam irradiation.The most impactful biomarker for posterior fossa ependymoma is molecular subgroup affiliation, independent of other demographic or treatment variables. However, both EPN_PFA and EPN_PFB still benefit from increased extent of resection, with the survival rates being particularly poor for subtotally resected EPN_PFA, even with adjuvant radiation therapy. Patients with EPN_PFB who undergo gross total resection are at lower risk for relapse and should be considered for inclusion in a randomized clinical trial of observation alone with radiation reserved for those who experience recurrence.

  View details for DOI 10.1200/JCO.2015.65.7825

  View details for Web of Science ID 000381497000006

  View details for PubMedID 27269943

  View details for PubMedCentralID PMC4962737

• Evaluating Cancer of the Central Nervous System Through Next-Generation Sequencing of Cerebrospinal Fluid. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Pentsova, E. I., Shah, R. H., Tang, J., Boire, A., You, D., Briggs, S., Omuro, A., Lin, X., Fleisher, M., Grommes, C., Panageas, K. S., Meng, F., Selcuklu, S. D., Ogilvie, S., Distefano, N., Shagabayeva, L., Rosenblum, M., DeAngelis, L. M., Viale, A., Mellinghoff, I. K., Berger, M. F. 2016; 34 (20): 2404-15

  Abstract

  Cancer spread to the central nervous system (CNS) often is diagnosed late and is unresponsive to therapy. Mechanisms of tumor dissemination and evolution within the CNS are largely unknown because of limited access to tumor tissue.We sequenced 341 cancer-associated genes in cell-free DNA from cerebrospinal fluid (CSF) obtained through routine lumbar puncture in 53 patients with suspected or known CNS involvement by cancer.We detected high-confidence somatic alterations in 63% (20 of 32) of patients with CNS metastases of solid tumors, 50% (six of 12) of patients with primary brain tumors, and 0% (zero of nine) of patients without CNS involvement by cancer. Several patients with tumor progression in the CNS during therapy with inhibitors of oncogenic kinases harbored mutations in the kinase target or kinase bypass pathways. In patients with glioma, the most common malignant primary brain tumor in adults, examination of cell-free DNA uncovered patterns of tumor evolution, including temozolomide-associated mutations.The study shows that CSF harbors clinically relevant genomic alterations in patients with CNS cancers and should be considered for liquid biopsies to monitor tumor evolution in the CNS.

  View details for DOI 10.1200/JCO.2016.66.6487

  View details for PubMedID 27161972

  View details for PubMedCentralID PMC4981784

• A prospective trial of dynamic contrast-enhanced MRI perfusion and fluorine-18 FDG PET-CT in differentiating brain tumor progression from radiation injury after cranial irradiation. Neuro-oncology Hatzoglou, V., Yang, T. J., Omuro, A., Gavrilovic, I., Ulaner, G., Rubel, J., Schneider, T., Woo, K. M., Zhang, Z., Peck, K. K., Beal, K., Young, R. J. 2016; 18 (6): 873-80

  Abstract

  The aim of this study was to assess the effectiveness of fluorine-18 fluorodeoxyglucose (FDG) PET-CT and dynamic contrast-enhanced (DCE) MRI in differentiating tumor progression and radiation injury in patients with indeterminate enhancing lesions after radiation therapy (RT) for brain malignancies.Patients with indeterminate enhancing brain lesions on conventional MRI after RT underwent brain DCE-MRI and PET-CT in a prospective trial. Informed consent was obtained. Lesion outcomes were determined by histopathology and/or clinical and imaging follow-up. Metrics obtained included plasma volume (Vp) and volume transfer coefficient (K(trans)) from DCE-MRI, and maximum standardized uptake value (SUVmax) from PET-CT; lesion-to-normal brain ratios of all metrics were calculated. The Wilcoxon rank sum test and receiver operating characteristic analysis were performed.The study included 53 patients (29 treated for 29 gliomas and 24 treated for 26 brain metastases). Progression was determined in 38/55 (69%) indeterminate lesions and radiation injury in 17 (31%). Vpratio (VP lesion/VP normal brain, P < .001), K(trans) ratio (P = .002), and SUVratio (P = .002) correlated significantly with diagnosis of progression versus radiation injury. Progressing lesions exhibited higher values of all 3 metrics compared with radiation injury. Vpratio had the highest accuracy in determining progression (area under the curve = 0.87), with 92% sensitivity and 77% specificity using the optimal, retrospectively determined threshold of 2.1. When Vpratio was combined with K(trans) ratio (optimal threshold 3.6), accuracy increased to 94%.Vpratio was the most effective metric for distinguishing progression from radiation injury. Adding K(trans) ratio to Vpratio further improved accuracy. DCE-MRI is an effective imaging technique for evaluating nonspecific enhancing intracranial lesions after RT.

  View details for DOI 10.1093/neuonc/nov301

  View details for PubMedID 26688076

  View details for PubMedCentralID PMC4864262

• Orally administered colony stimulating factor 1 receptor inhibitor PLX3397 in recurrent glioblastoma: an Ivy Foundation Early Phase Clinical Trials Consortium phase II study. Neuro-oncology Butowski, N., Colman, H., De Groot, J. F., Omuro, A. M., Nayak, L., Wen, P. Y., Cloughesy, T. F., Marimuthu, A., Haidar, S., Perry, A., Huse, J., Phillips, J., West, B. L., Nolop, K. B., Hsu, H. H., Ligon, K. L., Molinaro, A. M., Prados, M. 2016; 18 (4): 557-64

  Abstract

  The colony stimulating factor 1 receptor (CSF1R) ligands, CSF1 and interleukin-34, and the KIT ligand, stem cell factor, are expressed in glioblastoma (GB). Microglia, macrophages, blood vessels, and tumor cells also express CSF1R, and depletion of the microglia reduces tumor burden and invasive capacity. PLX3397 is an oral, small molecule that selectively inhibits CSF1R and KIT, penetrates the blood-brain barrier in model systems, and represents a novel approach for clinical development.We conducted a phase II study in patients with recurrent GB. The primary endpoint was 6-month progression-free survival (PFS6). Secondary endpoints included overall survival response rate, safety, and plasma/tumor tissue pharmacokinetics. Exploratory endpoints included pharmacodynamic measures of drug effect in blood and tumor tissue.A total of 37 patients were enrolled, with 13 treated prior to a planned surgical resection (Cohort 1) and 24 treated without surgery (Cohort 2). PLX3397 was given at an oral dose of 1000 mg daily and was well tolerated. The primary efficacy endpoint of PFS6 was only 8.6%, with no objective responses. Pharmacokinetic endpoints revealed a median maximal concentration (Cmax) of 8090 ng/mL, with a time to attain Cmax of 2 hour in plasma. Tumor tissue obtained after 7 days of drug exposure revealed a median drug level of 5500 ng/g. Pharmacodynamic changes included an increase in colony stimulating factor 1 and reduced CD14(dim)/CD16+ monocytes in plasma compared with pretreatment baseline values.PLX3397 was well tolerated and readily crossed the blood-tumor barrier but showed no efficacy. Additional studies are ongoing, testing combination strategies and potential biomarkers to identify patients with greater likelihood of response.

  View details for DOI 10.1093/neuonc/nov245

  View details for PubMedID 26449250

  View details for PubMedCentralID PMC4799682

• Integration of 2-hydroxyglutarate-proton magnetic resonance spectroscopy into clinical practice for disease monitoring in isocitrate dehydrogenase-mutant glioma. Neuro-oncology de la Fuente, M. I., Young, R. J., Rubel, J., Rosenblum, M., Tisnado, J., Briggs, S., Arevalo-Perez, J., Cross, J. R., Campos, C., Straley, K., Zhu, D., Dong, C., Thomas, A., Omuro, A. A., Nolan, C. P., Pentsova, E., Kaley, T. J., Oh, J. H., Noeske, R., Maher, E., Choi, C., Gutin, P. H., Holodny, A. I., Yen, K., DeAngelis, L. M., Mellinghoff, I. K., Thakur, S. B. 2016; 18 (2): 283-90

  Abstract

  The majority of WHO grades II and III gliomas harbor a missense mutation in the metabolic gene isocitrate dehydrogenase (IDH) and accumulate the metabolite R-2-hydroxyglutarate (R-2HG). Prior studies showed that this metabolite can be detected in vivo using proton magnetic-resonance spectroscopy (MRS), but the sensitivity of this methodology and its clinical implications are unknown.We developed an MR imaging protocol to integrate 2HG-MRS into routine clinical glioma imaging and examined its performance in 89 consecutive glioma patients.Detection of 2-hydroxyglutarate (2HG) in IDH-mutant gliomas was closely linked to tumor volume, with sensitivity ranging from 8% for small tumors (<3.4 mL) to 91% for larger tumors (>8 mL). In patients undergoing 2HG-MRS prior to surgery, tumor levels of 2HG corresponded with tumor cellularity but not with tumor grade or mitotic index. Cytoreductive therapy resulted in a gradual decrease in 2HG levels with kinetics that closely mirrored changes in tumor volume.Our study demonstrates that 2HG-MRS can be linked with routine MR imaging to provide quantitative measurements of 2HG in glioma and may be useful as an imaging biomarker to monitor the abundance of IDH-mutant tumor cells noninvasively during glioma therapy and disease monitoring.

  View details for DOI 10.1093/neuonc/nov307

  View details for PubMedID 26691210

  View details for PubMedCentralID PMC4724186

• Long-term survival in AIDS-related primary central nervous system lymphoma. Neuro-oncology Gupta, N. K., Nolan, A. n., Omuro, A. n., Reid, E. G., Wang, C. C., Mannis, G. n., Jaglal, M. n., Chavez, J. C., Rubinstein, P. G., Griffin, A. n., Abrams, D. I., Hwang, J. n., Kaplan, L. D., Luce, J. A., Volberding, P. n., Treseler, P. A., Rubenstein, J. L. 2016

  Abstract

  The optimal therapeutic approach for patients with AIDS-related primary central nervous system lymphoma (AR-PCNSL) remains undefined. While its incidence declined substantially with combination antiretroviral therapy (cART), AR-PCNSL remains a highly aggressive neoplasm for which whole brain radiotherapy (WBRT) is considered a standard first-line intervention.To identify therapy-related factors associated with favorable survival, we first retrospectively analyzed outcomes of AR-PCNSL patients treated at San Francisco General Hospital, a public hospital with a long history of dedicated care for patients with HIV and AIDS-related malignancies. Results were validated in a retrospective, multicenter analysis that evaluated all newly diagnosed patients with AR-PCNSL treated with cART plus high-dose methotrexate (HD-MTX).We provide evidence that CD4+ reconstitution with cART administered during HD-MTX correlates with long-term survival among patients with CD4 <100. This was confirmed in a multicenter analysis which demonstrated that integration of cART regimens with HD-MTX was generally well tolerated and resulted in longer progression-free survival than other treatments. No profound differences in immunophenotype were identified in an analysis of AR-PCNSL tumors that arose in the pre- versus post-cART eras. However, we detected evidence for a demographic shift, as the proportion of minority patients with AR-PCNSL increased since advent of cART.Long-term disease-free survival can be achieved in AR-PCNSL, even among those with histories of opportunistic infections, limited access to health care, and medical non-adherence. Given this, as well as the long-term toxicities of WBRT, we recommend that integration of cART plus first-line HD-MTX be considered for all patients with AR-PCNSL.

  View details for DOI 10.1093/neuonc/now155

  View details for PubMedID 27576871

• Multicenter phase 2 study of patupilone for recurrent or progressive brain metastases from non-small cell lung cancer. Cancer Nayak, L., DeAngelis, L. M., Robins, H. I., Govindan, R., Gadgeel, S., Kelly, K., Rigas, J. R., Peereboom, D. M., Rosenfeld, S. S., Muzikansky, A., Zheng, M., Urban, P., Abrey, L. E., Omuro, A., Wen, P. Y. 2015; 121 (23): 4165-72

  Abstract

  Treatment options for patients with non-small cell lung cancer (NSCLC) with brain metastases are limited. Patupilone (EPO906), a blood-brain barrier-penetrating, microtubule-targeting, cytotoxic agent, has shown clinical activity in phase 1/2 studies in patients with NSCLC. This study evaluates the efficacy, pharmacokinetics, and safety of patupilone in NSCLC brain metastases.Adult patients with NSCLC and confirmed progressive brain metastases received patupilone intravenously at 10 mg/m(2) every 3 weeks. The primary endpoint of this multinomial 2-stage study combined early progression (EP; death or progression within 3 weeks) and progression-free survival at 9 weeks (PFS9w) to determine drug activity.Fifty patients with a median age of 60 years (range, 33-74 years) were enrolled; the majority were men (58%), and most had received prior therapy for brain metastases (98%). The PFS9w rate was 36%, and the EP rate was 26%. Patupilone blood pharmacokinetic analyses showed mean areas under the concentration-time curve from time zero to 504 hours for cycles 1 and 3 of 1544 and 1978 ng h/mL, respectively, and a mean steady state distribution volume of 755 L/m(2) . Grade 3/4 adverse events (AEs), regardless of their relation with the study drug, included diarrhea (24%), pulmonary embolisms (8%), convulsions (4%), and peripheral neuropathy (4%). All patients discontinued the study drug: 31 (62%) for disease progression and 13 (26%) for AEs. Twenty-five of 32 deaths were due to brain metastases. The median time to progression and the overall survival were 3.2 and 8.8 months, respectively.This is the first prospective study of chemotherapy for recurrent brain metastases from NSCLC. In this population, patupilone demonstrated activity in heavily treated patients.

  View details for DOI 10.1002/cncr.29636

  View details for PubMedID 26308485

  View details for PubMedCentralID PMC5941922

• Phase I dose-escalation study of the PI3K/mTOR inhibitor voxtalisib (SAR245409, XL765) plus temozolomide with or without radiotherapy in patients with high-grade glioma. Neuro-oncology Wen, P. Y., Omuro, A., Ahluwalia, M. S., Fathallah-Shaykh, H. M., Mohile, N., Lager, J. J., Laird, A. D., Tang, J., Jiang, J., Egile, C., Cloughesy, T. F. 2015; 17 (9): 1275-83

  Abstract

  This phase I study aimed to evaluate safety, maximum tolerated dose, pharmacokinetics, pharmacodynamics, and preliminary efficacy of voxtalisib (SAR245409, XL765), a pan-class I phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor, in combination with temozolomide (TMZ), with or without radiation therapy (RT), in patients with high-grade glioma.Patients received voxtalisib 30-90 mg once daily (q.d.) or 20-50 mg twice daily (b.i.d.), in combination with 200 mg/m(2) TMZ (n = 49), or voxtalisib 20 mg q.d. with 75 mg/m(2) TMZ and RT (n = 5). A standard 3 + 3 dose-escalation design was used to determine the maximum tolerated dose. Patients were evaluated for adverse events (AEs), plasma pharmacokinetics, pharmacodynamic effects in skin biopsies, and tumor response.The maximum tolerated doses were 90 mg q.d. and 40 mg b.i.d. for voxtalisib in combination with TMZ. The most frequently reported treatment-related AEs were nausea (48%), fatigue (43%), thrombocytopenia (26%), and diarrhea (24%). The most frequently reported treatment-related grade ≥3 AEs were lymphopenia (13%), thrombocytopenia, and decreased platelet count (9% each). Pharmacokinetic parameters were similar to previous studies with voxtalisib monotherapy. Moderate inhibition of PI3K signaling was observed in skin biopsies. Best response was partial response in 4% of evaluable patients, with stable disease observed in 68%.Voxtalisib in combination with TMZ with or without RT in patients with high-grade gliomas demonstrated a favorable safety profile and a moderate level of PI3K/mTOR pathway inhibition.

  View details for DOI 10.1093/neuonc/nov083

  View details for PubMedID 26019185

  View details for PubMedCentralID PMC4588757

• Clinical Reasoning: Worsening neurologic symptoms in a brain tumor patient. Neurology Faivre, G., Pentsova, E., Demopoulos, A., Taillibert, S., Rosenblum, M., Omuro, A. 2015; 85 (7): e57-61

  View details for DOI 10.1212/WNL.0000000000001848

  View details for PubMedID 26283762

  View details for PubMedCentralID PMC4548283

• First-line treatment and outcome of elderly patients with primary central nervous system lymphoma (PCNSL)--a systematic review and individual patient data meta-analysis. Annals of oncology : official journal of the European Society for Medical Oncology Kasenda, B., Ferreri, A. J., Marturano, E., Forst, D., Bromberg, J., Ghesquieres, H., Ferlay, C., Blay, J. Y., Hoang-Xuan, K., Pulczynski, E. J., Fosså, A., Okoshi, Y., Chiba, S., Fritsch, K., Omuro, A., O'Neill, B. P., Bairey, O., Schandelmaier, S., Gloy, V., Bhatnagar, N., Haug, S., Rahner, S., Batchelor, T. T., Illerhaus, G., Briel, M. 2015; 26 (7): 1305-13

  Abstract

  To investigate prognosis and effects of first-line therapy in elderly primary central nervous system lymphoma (PCNSL) patients.A systematic review of studies about first-line therapy in immunocompetent patients ≥60 years with PCNSL until 2014 and a meta-analysis of individual patient data from eligible studies and international collaborators were carried out.We identified 20 eligible studies; from 13 studies, we obtained individual data of 405 patients, which were pooled with data of 378 additional patients (N = 783). Median age and Karnofsky Performance Score (KPS) was 68 years (range: 60-90 years) and 60% (range: 10%-100%), respectively. Treatments varied greatly, 573 (73%) patients received high-dose methotrexate (HD-MTX)-based therapy. A total of 276 patients received whole-brain radiotherapy (median 36 Gy, range 28.5-70 Gy). KPS ≥ 70% was the strongest prognostic factor for mortality [hazard ratio (HR) 0.50, 95% confidence interval (CI) 0.41-0.62]. After a median follow-up of 40 months, HD-MTX-based therapy was associated with improved survival (HR 0.70, 95% CI 0.53-0.93). There was no difference between HD-MTX plus oral chemotherapy and more aggressive HD-MTX-based therapies (HR 1.39, 95% CI 0.90-2.15). Radiotherapy was associated with an improved survival, but correlated with an increased risk for neurological side-effects (odds ratio 5.23, 95% CI 2.33-11.74).Elderly PCNSL patients benefit from HD-MTX-based therapy, especially if combined with oral alkylating agents. More aggressive HD-MTX protocols do not seem to improve outcome. WBRT may improve outcome, but is associated with increased risk for neurological side-effects. Prospective trials for elderly PCNSL patients are warranted.

  View details for DOI 10.1093/annonc/mdv076

  View details for PubMedID 25701456

  View details for PubMedCentralID PMC4735103

• Pretreatment Dynamic Susceptibility Contrast MRI Perfusion in Glioblastoma: Prediction of EGFR Gene Amplification. Clinical neuroradiology Gupta, A., Young, R. J., Shah, A. D., Schweitzer, A. D., Graber, J. J., Shi, W., Zhang, Z., Huse, J., Omuro, A. M. 2015; 25 (2): 143-50

  Abstract

  Molecular and genetic testing is becoming increasingly relevant in GBM. We sought to determine whether dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI) perfusion imaging could predict EGFR-defined subtypes of GBM.We retrospectively identified 106 consecutive glioblastoma (GBM) patients with known EGFR gene amplification, and a subset of 65 patients who also had known EGFRvIII gene mutation status. All patients underwent T2* DSC MRI perfusion. DSC perfusion maps and T2* signal intensity time curves were evaluated, and the following measures of tumor perfusion were recorded: (1) maximum relative cerebral blood volume (rCBV), (2) relative peak height (rPH), and (3) percent signal recovery (PSR). The imaging metrics were correlated to EGFR gene amplification and EGFRvIII mutation status using univariate analyses.EGFR amplification was present in 44 (41.5 %) subjects and absent in 62 (58.5 %). Among the 65 subjects who had undergone EGFRvIII mutation transcript analysis, 18 subjects (27.7 %) tested positive for the EGFRvIII mutation, whereas 47 (72.3 %) did not. Higher median rCBV (3.31 versus 2.62, p = 0.01) and lower PSR (0.70 versus 0.78, p = 0.03) were associated with high levels of EGFR amplification. Higher median rPH (3.68 versus 2.76, p = 0.03) was associated with EGFRvIII mutation.DSC MRI perfusion may have a role in identifying patients with EGFR gene amplification and EGFRvIII gene mutation status, potential targets for individualized treatment protocols. Our results raise the need for further investigation for imaging biomarkers of genetically unique GBM subtypes.

  View details for DOI 10.1007/s00062-014-0289-3

  View details for PubMedID 24474262

  View details for PubMedCentralID PMC4712066

• Methotrexate and temozolomide versus methotrexate, procarbazine, vincristine, and cytarabine for primary CNS lymphoma in an elderly population: an intergroup ANOCEF-GOELAMS randomised phase 2 trial. The Lancet. Haematology Omuro, A., Chinot, O., Taillandier, L., Ghesquieres, H., Soussain, C., Delwail, V., Lamy, T., Gressin, R., Choquet, S., Soubeyran, P., Huchet, A., Benouaich-Amiel, A., Lebouvier-Sadot, S., Gyan, E., Touitou, V., Barrié, M., del Rio, M. S., Gonzalez-Aguilar, A., Houillier, C., Delgadillo, D., Lacomblez, L., Tanguy, M. L., Hoang-Xuan, K. 2015; 2 (6): e251-9

  Abstract

  No standard chemotherapy regimen exists for primary CNS lymphoma, reflecting an absence of randomised studies. We prospectively tested two promising methotrexate-based regimens, one more intensive and a milder regimen, for primary CNS lymphoma in the elderly population, who account for most patients.In this open-label, randomised phase 2 trial, done in 13 French institutions, we enrolled immunocompetent patients who had neuroimaging and histologically confirmed newly diagnosed primary CNS lymphoma, were aged 60 years and older, and had a Karnofsky performance scale score of 40 or more. Participants were stratified by Karnofsky performance scale score (<60 vs ≥60) and treating institution and randomly assigned (1:1) to receive methotrexate (3·5 g/m(2)) with temozolomide (150 mg/m(2)) or methotrexate (3·5 g/m(2)), procarbazine (100 mg/m(2)), vincristine (1·4 mg/m(2)), and cytarabine (3 mg/m(2)). Neither regimen included radiotherapy; both included prophylactic G-CSF and corticosteroids. The primary endpoint was 1-year progression-free survival. Analysis was intent to treat, in a non-comparative phase 2 trial design. This study is registered with ClinicalTrials.gov, number NCT00503594.Between July 16, 2007, and March 25, 2010, 98 patients were enrolled, of whom 95 were randomly assigned and analysed; 48 to methotrexate with temozolomide and 47 to methotrexate, procarbazine, vincristine, and cytarabine. 1-year progression-free survival was 36% (95% CI 22-50) in the methotrexate, procarbazine, vincristine, and cytarabine group and 36% (22-50) in the methotrexate with temozolomide group; median progression-free survival was 9·5 months (95% CI 5·3-13·8) versus 6·1 months (3·8-11·9), respectively. Objective responses were noted in 82% (95% CI 68-92) of patients in the methotrexate, procarbazine, vincristine, and cytarabine group versus 71% (55-84) of patients in the methotrexate with temozolomide group. Median overall survival was 31 months (95% CI 12·2-35·8) in the methotrexate, procarbazine, vincristine, and cytarabine group and 14 months (8·1-28·4) in the methotrexate with temozolomide group. No differences were noted in toxic effects between the two groups. The most common grades 3 and 4 toxicities in both groups were liver dysfunction (21 [4%] in the the methotrexate and temozolomide group and 18 [38%] in the methotrexate, procarbazine, vincristine, and cytarabine group), lymphopenia (14 [29%] and 14 [30%]), and infection (six [13%] and seven [15%]). To date, 33 (69%) patients in the methotrexate and temozolomide group have died, versus 31 (55%) in the methotrexate, procarbazine, vincristine and cytarabine group. Quality-of-life evaluation (QLQ-C30 and BN20) showed improvements in most domains (p=0·01-0·0001) compared with baseline in both groups. Prospective neuropsychological testing showed no evidence of late neurotoxicity.In this study of two different methotrexate-based combination regimens in elderly patients, the efficacy endpoints tended to favour the methotrexate, procarbazine, vincristine, and cytarabine group. Both regimens were associated with similar, moderate toxicity, but quality of life improved with time, suggesting pursuing treatment in these poor prognosis patients is worthwhile. New alternatives are needed to improve response duration in this population.Schering-Plough/Merck and French Government.

  View details for DOI 10.1016/S2352-3026(15)00074-5

  View details for PubMedID 26688235

• Diffusion and perfusion MRI to differentiate treatment-related changes including pseudoprogression from recurrent tumors in high-grade gliomas with histopathologic evidence. AJNR. American journal of neuroradiology Prager, A. J., Martinez, N., Beal, K., Omuro, A., Zhang, Z., Young, R. J. 2015; 36 (5): 877-85

  Abstract

  Treatment-related changes and recurrent tumors often have overlapping features on conventional MR imaging. The purpose of this study was to assess the utility of DWI and DSC perfusion imaging alone and in combination to differentiate treatment-related effects and recurrent high-grade gliomas.We retrospectively identified 68 consecutive patients with high-grade gliomas treated by surgical resection followed by radiation therapy and temozolomide, who then developed increasing enhancing mass lesions indeterminate for treatment-related changes versus recurrent tumor. All lesions were diagnosed by histopathology at repeat surgical resection. ROI analysis was performed of the enhancing lesion on the ADC and DSC maps. Measurements made by a 2D ROI of the enhancing lesion on a single slice were recorded as ADCLesion and rCBVLesion, and measurements made by the most abnormal small fixed diameter ROI as ADCROI and rCBVROI. Statistical analysis was performed with Wilcoxon rank sum tests with P = .05.Ten of the 68 patients (14.7%) had treatment-related changes, while 58 patients (85.3%) had recurrent tumor only (n = 19) or recurrent tumor mixed with treatment effect (n = 39). DWI analysis showed higher ADCLesion in treatment-related changes than in recurrent tumor (P = .003). DSC analysis revealed lower relative cerebral blood volume (rCBV)Lesion and rCBVROI in treatment-related changes (P = .003 and P = .011, respectively). Subanalysis of patients with suspected pseudoprogression also revealed higher ADCLesion (P = .001) and lower rCBVLesion (P = .028) and rCBVROI (P = .032) in treatment-related changes. Applying a combined ADCLesion and rCBVLesion model did not outperform either the ADC or rCBV metric alone.Treatment-related changes showed higher diffusion and lower perfusion than recurrent tumor. Similar correlations were found for patients with suspected pseudoprogression.

  View details for DOI 10.3174/ajnr.A4218

  View details for PubMedID 25593202

  View details for PubMedCentralID PMC4731220

• Clinical course and progression-free survival of adult intracranial and spinal ependymoma patients NEURO-ONCOLOGY Vera-Bolanos, E., Aldape, K., Yuan, Y., Wu, J., Wani, K., Necesito-Reyes, M. J., Colman, H., Dhall, G., Lieberman, F. S., Metellus, P., Mikkelsen, T., Omuro, A., Partap, S., Prados, M., Robins, H. I., Soffietti, R., Wu, J., Gilbert, M. R., Armstrong, T. S. 2015; 17 (3): 440-447

  Abstract

  Ependymomas are rare CNS tumors. Previous studies describing the clinical course of ependymoma patients were restricted to small sample sizes, often with patients at a specific institution.Clinically annotated ependymoma tissue samples from 19 institutions were centrally reviewed. Patients were all adults aged 18 years or older at the time of diagnosis. Potential prognostic clinical factors identified on univariate analysis were included in a multivariate Cox proportional hazards model with backwards selection to model progression-free survival.The 282 adult ependymoma patients were equally male and female with a mean age of 43 years (range, 18-80y) at diagnosis. The majority were grade II (78%) with the tumor grade for 20 cases being reclassified on central review (half to higher grade). Tumor locations were spine (46%), infratentorial (35%), and supratentorial (19%). Tumor recurrence occurred in 26% (n = 74) of patients with a median time to progression of 14 years. A multivariate Cox proportional hazards model identified supratentorial location (P < .01), grade III (anaplastic; P < .01), and subtotal resection, followed or not by radiation (P < .01), as significantly increasing risk of early progression.We report findings from an ongoing, multicenter collaboration from a collection of clinically annotated adult ependymoma tumor samples demonstrating distinct predictors of progression-free survival. This unique resource provides the opportunity to better define the clinical course of ependymoma for clinical and translational studies.

  View details for DOI 10.1093/neuonc/nou162

  View details for Web of Science ID 000352479700016

  View details for PubMedID 25121770

• R-MPV followed by high-dose chemotherapy with TBC and autologous stem-cell transplant for newly diagnosed primary CNS lymphoma. Blood Omuro, A., Correa, D. D., DeAngelis, L. M., Moskowitz, C. H., Matasar, M. J., Kaley, T. J., Gavrilovic, I. T., Nolan, C., Pentsova, E., Grommes, C. C., Panageas, K. S., Baser, R. E., Faivre, G., Abrey, L. E., Sauter, C. S. 2015; 125 (9): 1403-10

  Abstract

  High-dose methotrexate-based chemotherapy is the mainstay of treatment of primary central nervous system lymphoma (PCNSL), but relapses remain frequent. High-dose chemotherapy (HDC) with autologous stem-cell transplant (ASCT) may provide an alternative to address chemoresistance and overcome the blood-brain barrier. In this single-center phase-2 study, newly diagnosed PCNSL patients received 5 to 7 cycles of chemotherapy with rituximab, methotrexate (3.5 g/m(2)), procarbazine, and vincristine (R-MPV). Those with a complete or partial response proceeded with consolidation HDC with thiotepa, cyclophosphamide, and busulfan, followed by ASCT and no radiotherapy. Primary end point was 1-year progression-free survival (PFS), N = 32. Median age was 57, and median Karnofsky performance status 80. Following R-MPV, objective response rate was 97%, and 26 (81%) patients proceeded with HDC-ASCT. Among all patients, median PFS and overall survival (OS) were not reached (median follow-up: 45 months). Two-year PFS was 79% (95% confidence interval [CI], 58-90), with no events observed beyond 2 years. Two-year OS was 81% (95% CI, 63-91). In transplanted patients, 2-year PFS and OS were 81%. There were 3 treatment-related deaths. Prospective neuropsychological evaluations suggested relatively stable cognitive functions posttransplant. In conclusion, this treatment was associated with excellent disease control and survival, an acceptable toxicity profile, and no evidence of neurotoxicity thus far. This trial was registered at www.clinicaltrials.gov as NCT00596154.

  View details for DOI 10.1182/blood-2014-10-604561

  View details for PubMedID 25568347

  View details for PubMedCentralID PMC4342354

• Glutamine-based PET imaging facilitates enhanced metabolic evaluation of gliomas in vivo. Science translational medicine Venneti, S., Dunphy, M. P., Zhang, H., Pitter, K. L., Zanzonico, P., Campos, C., Carlin, S. D., La Rocca, G., Lyashchenko, S., Ploessl, K., Rohle, D., Omuro, A. M., Cross, J. R., Brennan, C. W., Weber, W. A., Holland, E. C., Mellinghoff, I. K., Kung, H. F., Lewis, J. S., Thompson, C. B. 2015; 7 (274): 274ra17

  Abstract

  Glucose and glutamine are the two principal nutrients that cancer cells use to proliferate and survive. Many cancers show altered glucose metabolism, which constitutes the basis for in vivo positron emission tomography (PET) imaging with (18)F-fluorodeoxyglucose ((18)F-FDG). However, (18)F-FDG is ineffective in evaluating gliomas because of high background uptake in the brain. Glutamine metabolism is also altered in many cancers, and we demonstrate that PET imaging in vivo with the glutamine analog 4-(18)F-(2S,4R)-fluoroglutamine ((18)F-FGln) shows high uptake in gliomas but low background brain uptake, facilitating clear tumor delineation. Chemo/radiation therapy reduced (18)F-FGln tumor avidity, corresponding with decreased tumor burden. (18)F-FGln uptake was not observed in animals with a permeable blood-brain barrier or neuroinflammation. We translated these findings to human subjects, where (18)F-FGln showed high tumor/background ratios with minimal uptake in the surrounding brain in human glioma patients with progressive disease. These data suggest that (18)F-FGln is avidly taken up by gliomas, can be used to assess metabolic nutrient uptake in gliomas in vivo, and may serve as a valuable tool in the clinical management of gliomas.

  View details for DOI 10.1126/scitranslmed.aaa1009

  View details for PubMedID 25673762

  View details for PubMedCentralID PMC4431550

• Autologous stem cell transplant in recurrent or refractory primary or secondary central nervous system lymphoma using thiotepa, busulfan and cyclophosphamide. Leukemia & lymphoma Welch, M. R., Sauter, C. S., Matasar, M. J., Faivre, G., Weaver, S. A., Moskowitz, C. H., Omuro, A. M. 2015; 56 (2): 361-7

  Abstract

  The prognosis for patients with central nervous system (CNS) involvement by recurrent or refractory diffuse large B-cell lymphoma is poor, with overall survival (OS) of 4-10 months. High-dose chemotherapy (HDC) and autologous stem cell transplant (ASCT) is a potential treatment alternative. We reviewed patients with recurrent primary (PCNSL) or secondary (SCNSL) CNS lymphoma referred for consolidation HDC-ASCT utilizing thiotepa, busulfan and cyclophosphamide (TBC). Among the 17 patients included, all had achieved a complete remission after salvage induction chemotherapy, which incorporated methotrexate in 82% of patients. Two patients failed stem-cell harvesting and 15 (88%) underwent transplant. The estimated 3-year progression-free survival (PFS) and OS were both 93% (95% confidence interval 61-99%). Median PFS and OS were not reached. There was no transplant-related mortality. These results confirm the benefit of TBC followed by ASCT in select patients with recurrent PCNSL and suggest a potential role for the regimen in those with SCNSL. Further investigation is warranted.

  View details for DOI 10.3109/10428194.2014.916800

  View details for PubMedID 24745937

• Phase II trial of sunitinib for recurrent and progressive atypical and anaplastic meningioma. Neuro-oncology Kaley, T. J., Wen, P., Schiff, D., Ligon, K., Haidar, S., Karimi, S., Lassman, A. B., Nolan, C. P., DeAngelis, L. M., Gavrilovic, I., Norden, A., Drappatz, J., Lee, E. Q., Purow, B., Plotkin, S. R., Batchelor, T., Abrey, L. E., Omuro, A. 2015; 17 (1): 116-21

  Abstract

  No proven effective medical therapy for surgery and radiation-refractory meningiomas exists. Sunitinib malate (SU011248) is a small-molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor, abundant in meningiomas.This was a prospective, multicenter, investigator-initiated single-arm phase II trial. The primary cohort enrolled patients with surgery and radiation-refractory recurrent World Health Organization (WHO) grades II-III meningioma. An exploratory cohort enrolled patients with WHO grade I meningioma, hemangiopericytoma, or hemangioblastoma. Sunitinib was administered at 50 mg/d for days 1-28 of every 42-day cycle. The primary endpoint was the rate of 6-month progression-free survival (PFS6), with secondary endpoints of radiographic response rate, safety, PFS, and overall survival. Exploratory objectives include analysis of tumoral molecular markers and MR perfusion imaging.Thirty-six patients with high-grade meningioma (30 atypical and 6 anaplastic) were enrolled. Patients were heavily pretreated (median number of 5 recurrences, range 2-10). PFS6 rate was 42%, meeting the primary endpoint. Median PFS was 5.2 months (95% CI: 2.8-8.3 mo), and median overall survival was 24.6 months (95% CI: 16.5-38.4 mo). Thirteen patients enrolled in the exploratory cohort. Overall toxicity included 1 grade 5 intratumoral hemorrhage, 2 grade 3 and 1 grade 4 CNS/intratumoral hemorrhages, 1 grade 3 and 1 grade 4 thrombotic microangiopathy, and 1 grade 3 gastrointestinal perforation. Expression of VEGFR2 predicted PFS of a median of 1.4 months in VEGFR2-negative patients versus 6.4 months in VEGFR2-positive patients (P = .005).Sunitinib is active in recurrent atypical/malignant meningioma patients. A randomized trial should be performed.

  View details for DOI 10.1093/neuonc/nou148

  View details for PubMedID 25100872

  View details for PubMedCentralID PMC4483051

• Current role of anti-angiogenic strategies for glioblastoma. Current treatment options in oncology Thomas, A. A., Omuro, A. 2014; 15 (4): 551-66

  Abstract

  Glioblastoma, an incurable, malignant, and highly vascular tumor, is a seemingly ideal target for anti-angiogenic therapies such as bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody. Phase II trials in recurrent glioblastoma demonstrated bevacizumab was associated with clinical benefits, including decreases in brain edema and corticosteroids use resulting from reduced vascular permeability, as well as radiographic responses in 25 %-40 % of patients. In newly diagnosed disease, a phase III trial (AVAglio) showed adding bevacizumab to standard chemoradiotherapy improved progression free survival (PFS), with preservation of quality of life, and reduced corticosteroids use, but did not improve overall survival (OS). Another similar phase III trial (RTOG 0825) found similar PFS and OS trends, but suggested that the addition of bevacizumab resulted in more frequent cognitive decline compared with standard chemoradiotherapy. However, interpretation of those findings is limited by the fact that progressing patients were not evaluated, and patients remained longer on study in the bevacizumab arm. It is possible that the observed cognitive decline represented unrecognized tumor progression, rather than deleterious bevacizumab effects. Regardless, even if real, it is difficult to ascertain how improvements in PFS and quality of life compare with the associated economic costs and increased toxicities of bevacizumab, in the setting of no survival benefit. Further studies in recurrent disease are being conducted; preliminary results of a randomized trial showed favorable results with the combination with CCNU, and final results are awaited. Meanwhile, outside the realm of clinical trials, the current trend appears to be to reserve bevacizumab for use in recurrent disease, or for patients with moderate or severe neurologic symptoms, either in the newly diagnosed or recurrent setting. Further research efforts are needed to determine optimal candidates for this treatment from a molecular standpoint, as well as to develop imaging tools capable of accurately identifying response and progression, and to establish new drug combinations that could result in unquestionable clinical benefit and improved survival in these patients.

  View details for DOI 10.1007/s11864-014-0308-2

  View details for PubMedID 25173555

• Emerging therapies for glioblastoma. JAMA neurology Thomas, A. A., Brennan, C. W., DeAngelis, L. M., Omuro, A. M. 2014; 71 (11): 1437-44

  Abstract

  Glioblastoma is the most common primary malignant brain tumor, but despite multimodal treatment with surgery, radiotherapy, and temozolomide chemotherapy, the prognosis is poor, with a median survival of 16 to 19 months and poor quality of life throughout the disease course. New treatments are needed.Articles were identified through a search of PubMed references from March 2005 through January 2014, using the terms glioblastoma, glioma, malignant glioma, and brain neoplasm, as well as by search of the authors' files. Clinical trials were identified in the Clinicaltrials.gov registry.Advances in the understanding of the molecular biology of glioblastoma are being rapidly translated into innovative clinical trials, capitalizing on improved genomic, epigenetic, transcriptional, and proteomic characterization of glioblastomas as well as host factors, including the brain microenvironment and immune system interactions. Therapies targeting tumor growth factor receptors and downstream pathways, angiogenesis, modulation of cancer stemlike cells, cell cycle regulation, oncolytic viruses, new radiotherapy techniques, and immunotherapy, including vaccines and modulation of immune checkpoints (eg, programmed cell death 1 and cytotoxic T-lymphocyte antigen 4), are under investigation. In addition to novel agents, techniques to circumvent the blood-brain barrier to facilitate central nervous system drug exposure are being developed.Glioblastoma is an aggressive tumor with heterogeneous molecular features and complex host interactions, many of which are amenable to therapeutic intervention. Meaningful treatment advances will depend on identifying agents that target mechanistic vulnerabilities that are relevant to specific subgroups of patients; increasing patient enrollment into clinical trials is essential to accelerate the development of patient-tailored treatments.

  View details for DOI 10.1001/jamaneurol.2014.1701

  View details for PubMedID 25244650

• Phase II study of bevacizumab, temozolomide, and hypofractionated stereotactic radiotherapy for newly diagnosed glioblastoma. Clinical cancer research : an official journal of the American Association for Cancer Research Omuro, A., Beal, K., Gutin, P., Karimi, S., Correa, D. D., Kaley, T. J., DeAngelis, L. M., Chan, T. A., Gavrilovic, I. T., Nolan, C., Hormigo, A., Lassman, A. B., Mellinghoff, I., Grommes, C., Reiner, A. S., Panageas, K. S., Baser, R. E., Tabar, V., Pentsova, E., Sanchez, J., Barradas-Panchal, R., Zhang, J., Faivre, G., Brennan, C. W., Abrey, L. E., Huse, J. T. 2014; 20 (19): 5023-31

  Abstract

  Bevacizumab is associated with decreased vascular permeability that allows for more aggressive radiotherapy schedules. We conducted a phase II trial in newly diagnosed glioblastoma utilizing a novel hypofractionated stereotactic radiotherapy (HFSRT) schedule combined with temozolomide and bevacizumab.Patients with tumor volume ≤60 cc were treated with HFSRT (6 × 6 Gy to contrast enhancement and 6 × 4 Gy to FLAIR hyperintensity with dose painting) combined with concomitant/adjuvant temozolomide and bevacizumab at standard doses. Primary endpoint was 1-year overall survival (OS): promising = 70%; nonpromising = 50%; α = 0.1; β = 0.1.Forty patients were enrolled (median age: 55 years; methylated MGMT promoter: 23%; unmethylated: 70%). The 1-year OS was 93% [95% confidence interval (CI), 84-100] and median OS was 19 months. The median PFS was 10 months, with no pseudo-progression observed. The objective response rate (ORR) was 57%. Analysis of The Cancer Genome Atlas glioblastoma transcriptional subclasses (Nanostring assay) suggested patients with a proneural phenotype (26%) fared worse (ORR = 14%, vs. 77% for other subclasses; P = 0.009). Dynamic susceptibility-contrast perfusion MRI showed marked decreases in relative cerebral blood volume over time (P < 0.0001) but had no prognostic value, whereas higher baseline apparent diffusion coefficient (ADC) ratios and persistent hypermetabolism at the 6-month FDG-PET predicted poor OS (P = 0.05 and 0.0001, respectively). Quality-of-life (FACT-BR-4) and neuropsychological test scores were stable over time, although some domains displayed transient decreases following HFSRT.This aggressive radiotherapy schedule was safe and more convenient for patients, achieving an OS that is comparable with historical controls. Analysis of advanced neuroimaging parameters suggests ADC and FDG-PET as potentially useful biomarkers, whereas tissue correlatives uncovered the poor prognosis associated with the proneural signature in non-IDH-1-mutated glioblastoma.

  View details for DOI 10.1158/1078-0432.CCR-14-0822

  View details for PubMedID 25107913

  View details for PubMedCentralID PMC4523080

• Transcriptional diversity of long-term glioblastoma survivors. Neuro-oncology Gerber, N. K., Goenka, A., Turcan, S., Reyngold, M., Makarov, V., Kannan, K., Beal, K., Omuro, A., Yamada, Y., Gutin, P., Brennan, C. W., Huse, J. T., Chan, T. A. 2014; 16 (9): 1186-95

  Abstract

  Glioblastoma (GBM) is a highly aggressive type of glioma with poor prognosis. However, a small number of patients live much longer than the median survival. A better understanding of these long-term survivors (LTSs) may provide important insight into the biology of GBM.We identified 7 patients with GBM, treated at Memorial Sloan-Kettering Cancer Center (MSKCC), with survival >48 months. We characterized the transcriptome of each patient and determined rates of MGMT promoter methylation and IDH1 and IDH2 mutational status. We identified LTSs in 2 independent cohorts (The Cancer Genome Atlas [TCGA] and NCI Repository for Molecular Brain Neoplasia Data [REMBRANDT]) and analyzed the transcriptomal characteristics of these LTSs.The median overall survival of our cohort was 62.5 months. LTSs were distributed between the proneural (n = 2), neural (n = 2), classical (n = 2), and mesenchymal (n = 1) subtypes. Similarly, LTS in the TCGA and REMBRANDT cohorts demonstrated diverse transcriptomal subclassification identities. The majority of the MSKCC LTSs (71%) were found to have methylation of the MGMT promoter. None of the patients had an IDH1 or IDH2 mutation, and IDH mutation occurred in a minority of the TCGA LTSs as well. A set of 60 genes was found to be differentially expressed in the MSKCC and TCGA LTSs.While IDH mutant proneural tumors impart a better prognosis in the short-term, survival beyond 4 years does not require IDH mutation and is not dictated by a single transcriptional subclass. In contrast, MGMT methylation continues to have strong prognostic value for survival beyond 4 years. These findings have substantial impact for understanding GBM biology and progression.

  View details for DOI 10.1093/neuonc/nou043

  View details for PubMedID 24662514

  View details for PubMedCentralID PMC4136896

• Methotrexate re-challenge for recurrent primary central nervous system lymphoma. Journal of neuro-oncology Pentsova, E., Deangelis, L. M., Omuro, A. 2014; 117 (1): 161-5

  Abstract

  The prognosis of primary CNS lymphoma (PCNSL) recurring after methotrexate is poor (objective response rates [ORR] = 26-53 %; 1-year overall survival [OS] = 35-57 %). Salvage PCNSL chemotherapies have been based on the use of different agents to avoid cross-resistance; however, methotrexate is the most active agent in PCNSL, and methotrexate re-challenge may be an effective strategy for recurrent disease. We report our experience with methotrexate re-challenge in PCNSL. We reviewed 39 patients with histologically confirmed PCNSL who responded to methotrexate at initial diagnosis, experienced disease relapse and received methotrexate re-challenge. At the time of re-challenge, median age was 66 and median Karnofsky performance score (KPS) was 70. Median time from initial diagnosis was 26 m. Twenty-six patients were at first relapse and 13 at second or later relapse. At re-challenge, methotrexate was given in combination with other agents to 33 patients and as a single agent to six. The objective response rate was 85 %, with a complete response in 29 (75 %) patients, partial response in four (10 %) and disease progression in six (15 %). At median follow-up of 26 m, the median progression-free survival was 16 m; 1-year OS was 79 % (95 % CI 63-89) and median OS was 41 m. KPS was a prognostic factor for progression free survival (p = 0.04). In this population selected by previous methotrexate response, methotrexate re-challenge was a safe and effective strategy, indicating chemosensitivity was retained. Efficacy compared favorably to other salvage treatments suggesting methotrexate re-challenge should be considered in recurrent PCNSL patients who previously responded to methotrexate.

  View details for DOI 10.1007/s11060-014-1370-0

  View details for PubMedID 24481997

  View details for PubMedCentralID PMC5256683

• Potential role of preoperative conventional MRI including diffusion measurements in assessing epidermal growth factor receptor gene amplification status in patients with glioblastoma. AJNR. American journal of neuroradiology Young, R. J., Gupta, A., Shah, A. D., Graber, J. J., Schweitzer, A. D., Prager, A., Shi, W., Zhang, Z., Huse, J., Omuro, A. M. 2013; 34 (12): 2271-7

  Abstract

  Epidermal growth factor receptor amplification is a common molecular event in glioblastomas. The purpose of this study was to examine the potential usefulness of morphologic and diffusion MR imaging signs in the prediction of epidermal growth factor receptor gene amplification status in patients with glioblastoma.We analyzed pretreatment MR imaging scans from 147 consecutive patients with newly diagnosed glioblastoma and correlated MR imaging features with tumor epidermal growth factor receptor amplification status. The following morphologic tumor MR imaging features were qualitatively assessed: 1) border sharpness, 2) cystic/necrotic change, 3) hemorrhage, 4) T2-isointense signal, 5) restricted water diffusion, 6) nodular enhancement, 7) subependymal enhancement, and 8) multifocal discontinuous enhancement. A total of 142 patients had DWI available for quantitative analysis. ADC maps were calculated, and the ADCmean, ADCmin, ADCmax, ADCROI, and ADCratio were measured.Epidermal growth factor receptor amplification was present in 60 patients (40.8%) and absent in 87 patients (59.2%). Restricted water diffusion correlated with epidermal growth factor receptor amplification (P = .04), whereas the other 7 morphologic MR imaging signs did not (P > .12). Quantitative DWI analysis found that all ADC measurements correlated with epidermal growth factor receptor amplification, with the highest correlations found with ADCROI (P = .0003) and ADCmean (P = .0007).Our results suggest a role for diffusion MR imaging in the determination of epidermal growth factor receptor amplification status in glioblastoma. Additional work is necessary to confirm these results and isolate new imaging biomarkers capable of noninvasively characterizing the molecular status of these tumors.

  View details for DOI 10.3174/ajnr.A3604

  View details for PubMedID 23811973

  View details for PubMedCentralID PMC4712068

• Glioblastoma and other malignant gliomas: a clinical review. JAMA Omuro, A., DeAngelis, L. M. 2013; 310 (17): 1842-50

  Abstract

  Glioblastomas and malignant gliomas are the most common primary malignant brain tumors, with an annual incidence of 5.26 per 100,000 population or 17,000 new diagnoses per year. These tumors are typically associated with a dismal prognosis and poor quality of life.To review the clinical management of malignant gliomas, including genetic and environmental risk factors such as cell phones, diagnostic pitfalls, symptom management, specific antitumor therapy, and common complications.Search of PubMed references from January 2000 to May 2013 using the terms glioblastoma, glioma, malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma, and brain neoplasm. Articles were also identified through searches of the authors' own files. Evidence was graded using the American Heart Association classification system.Only radiation exposure and certain genetic syndromes are well-defined risk factors for malignant glioma. The treatment of newly diagnosed glioblastoma is based on radiotherapy combined with temozolomide. This approach doubles the 2-year survival rate to 27%, but overall prognosis remains poor. Bevacizumab is an emerging treatment alternative that deserves further study. Grade III tumors have been less well studied, and clinical trials to establish standards of care are ongoing. Patients with malignant gliomas experience frequent clinical complications, including thromboembolic events, seizures, fluctuations in neurologic symptoms, and adverse effects from corticosteroids and chemotherapies that require proper management and prophylaxis.Glioblastoma remains a difficult cancer to treat, although therapeutic options have been improving. Optimal management requires a multidisciplinary approach and knowledge of potential complications from both the disease and its treatment.

  View details for DOI 10.1001/jama.2013.280319

  View details for PubMedID 24193082

• Primary leptomeningeal lymphoma: International Primary CNS Lymphoma Collaborative Group report. Neurology Taylor, J. W., Flanagan, E. P., O'Neill, B. P., Siegal, T., Omuro, A., Deangelis, L., Baehring, J., Nishikawa, R., Pinto, F., Chamberlain, M., Hoang-Xuan, K., Gonzalez-Aguilar, A., Batchelor, T., Blay, J. Y., Korfel, A., Betensky, R. A., Lopes, M. S., Schiff, D. 2013; 81 (19): 1690-6

  Abstract

  To evaluate clinical presentation, optimal diagnostic evaluation and treatment, and outcome in primary leptomeningeal lymphoma, a rare form of primary CNS lymphoma without parenchymal or systemic involvement.The International Primary CNS Lymphoma Collaborative Group, a multidisciplinary group of physicians with a particular interest in primary CNS lymphoma, retrospectively identified cases of lymphoma isolated to the leptomeninges as diagnosed by CSF cytology, flow cytometry, or biopsy, without systemic or parenchymal brain/spinal cord lymphoma or immunodeficiency.Forty-eight patients were identified, with median age at diagnosis of 51 years and median Eastern Cooperative Oncology Group performance status of 2. Presenting symptoms were multifocal in 68%. Leptomeningeal enhancement was seen in 74% and CSF profile was abnormal in all cases. CSF cytology detected malignant lymphocytes in 67%. Flow cytometry identified monoclonal population in 80%, as did receptor gene rearrangement studies in 71%. Sixty-two percent had B-cell lymphoma, 19% T-cell, and 19% unclassified. Treatment varied and included fractionated radiotherapy (36%), systemic chemotherapy (78%), and intra-CSF chemotherapy (66%), with 66% receiving ≥ 2 modalities. Seventy-one percent had a favorable clinical response; ultimately, 44% received salvage treatment. Median overall survival was 24 months, with 11 patients still alive at 50 months follow-up.Primary leptomeningeal lymphoma is a rare form of primary CNS lymphoma. Patients usually present with multifocal symptoms, with evidence of leptomeningeal enhancement and diagnostic CSF analysis. Although treatment is highly variable, patients have a better prognosis than previously reported and a subset may be cured.

  View details for DOI 10.1212/01.wnl.0000435302.02895.f3

  View details for PubMedID 24107866

  View details for PubMedCentralID PMC3812109

• Rituximab, methotrexate, procarbazine, and vincristine followed by consolidation reduced-dose whole-brain radiotherapy and cytarabine in newly diagnosed primary CNS lymphoma: final results and long-term outcome. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Morris, P. G., Correa, D. D., Yahalom, J., Raizer, J. J., Schiff, D., Grant, B., Grimm, S., Lai, R. K., Reiner, A. S., Panageas, K., Karimi, S., Curry, R., Shah, G., Abrey, L. E., DeAngelis, L. M., Omuro, A. 2013; 31 (31): 3971-9

  Abstract

  A multicenter phase II study was conducted to assess the efficacy of rituximab, methotrexate, procarbazine, and vincristine (R-MPV) followed by consolidation reduced-dose whole-brain radiotherapy (rdWBRT) and cytarabine in primary CNS lymphoma.Patients received induction chemotherapy with R-MPV (five to seven cycles); those achieving a complete response (CR) received rdWBRT (23.4 Gy), and otherwise, standard WBRT was offered (45 Gy). Consolidation cytarabine was given after the radiotherapy. The primary end point was 2-year progression-free survival (PFS) in patients receiving rdWBRT. Exploratory end points included prospective neuropsychological evaluation, analysis of magnetic resonance imaging (MRI) white matter changes using the Fazekas scale, and evaluation of the apparent diffusion coefficient (ADC) as a prognostic factor.Fifty-two patients were enrolled, with median age of 60 years (range, 30 to 79 years) and median Karnofsky performance score of 70 (range, 50 to 100). Thirty-one patients (60%) achieved a CR after R-MPV and received rdWBRT. The 2-year PFS for this group was 77%; median PFS was 7.7 years. Median overall survival (OS) was not reached (median follow-up for survivors, 5.9 years); 3-year OS was 87%. The overall (N = 52) median PFS was 3.3 years, and median OS was 6.6 years. Cognitive assessment showed improvement in executive function (P < .01) and verbal memory (P < .05) after chemotherapy, and follow-up scores remained relatively stable across the various domains (n = 12). All examined MRIs (n = 28) displayed a Fazekas score of ≤ 3, and no patient developed scores of 4 to 5; differences in ADC values did not predict response (P = .15), PFS (P = .27), or OS (P = .33).R-MPV combined with consolidation rdWBRT and cytarabine is associated with high response rates, long-term disease control, and minimal neurotoxicity.

  View details for DOI 10.1200/JCO.2013.50.4910

  View details for PubMedID 24101038

  View details for PubMedCentralID PMC5569679

• Histological Predictors of Outcome in Ependymoma are Dependent on Anatomic Site Within the Central Nervous System BRAIN PATHOLOGY Raghunathan, A., Wani, K., Armstrong, T. S., Vera-Bolanos, E., Fouladi, M., Gilbertson, R., Gajjar, A., Goldman, S., Lehman, N. L., Metellus, P., Mikkelsen, T., Necesito-Reyes, M. J., Omuro, A., Packer, R. J., Partap, S., Pollack, I. F., Prados, M. D., Robins, H. I., Soffietti, R., Wu, J., Miller, C. R., Gilbert, M. R., Aldape, K. D. 2013; 23 (5): 584-594

  Abstract

  Ependymomas originate in posterior fossa (PF), supratentorial (ST) or spinal cord (SC) compartments. At present, grading schemes are applied independent of anatomic site. We performed detailed histological examination on 238 World Health Organization grade II and III ependymomas. Among PF ependymomas, the presence of hypercellular areas, necrosis, microvascular proliferation and elevated mitotic rate (all P < 0.01) were significantly associated with worse progression-free survival (PFS), while extensive ependymal canal formation was not (P = 0.89). Similar to the PF tumors, microvascular proliferation (P = 0.01) and elevated mitotic rate (P = 0.03) were significantly associated with worse PFS in the ST tumors. However, in contrast to PF tumors, extensive ependymal canals (P = 0.03) were associated with worse clinical outcome in ST ependymomas, but hypercellularity (P = 0.57) and necrosis (P = 0.47) were not. On multivariate Cox regression, after adjusting for relevant clinical variables, individual histological factors and a composite histological score remained significant among ST and PF ependymoma. In contrast to both PF and ST ependymoma, histological features were not found to be associated with PFS in SC tumors. Taken together, the clinical relevance of specific histological features in ependymoma appears to be related to the anatomic site of origin and suggests that site-specific grading criteria be considered in future classification systems.

  View details for DOI 10.1111/bpa.12050

  View details for Web of Science ID 000329280700009

  View details for PubMedID 23452038

• Bevacizumab for acute neurologic deterioration in patients with glioblastoma. CNS oncology Kaley, T., Nolan, C., Carver, A., Omuro, A. 2013; 2 (5): 413-8

  Abstract

  Glioblastoma causes neurologic dysfunction owing to the tumor's location and peritumoral edema. Bevacizumab improves symptoms and steroid dependence, and may rescue glioblastoma patients hospitalized for acute neurologic dysfunction, allowing them to return home for outpatient treatment.We carried out a retrospective review of glioblastoma patients with severe neurologic dysfunction who received bevacizumab as inpatients.Nine patients (median age: 51 years; median Karnofsky Performance Status [KPS]: 40%) received one dose of bevacizumab while admitted for neurologic deterioration. Seven patients were treated at recurrence, two at diagnosis. Six patients clinically improved and continued outpatient treatment, while five decreased/discontinued dexamethasone.Single bevacizumab treatment administered to naive hospitalized patients with glioblastoma improves function and quality of life through avoidance of prolonged hospitalization and rehabilitation admissions, and decreased dexamethasone administration.

  View details for DOI 10.2217/cns.13.40

  View details for PubMedID 25054664

  View details for PubMedCentralID PMC6136096

• MRI perfusion in determining pseudoprogression in patients with glioblastoma. Clinical imaging Young, R. J., Gupta, A., Shah, A. D., Graber, J. J., Chan, T. A., Zhang, Z., Shi, W., Beal, K., Omuro, A. M. 2013; 37 (1): 41-9

  Abstract

  We examine the role of dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI) perfusion in differentiating pseudoprogression from progression in 20 consecutive patients with treated glioblastoma. MRI perfusion was performed, and relative cerebral blood volume (rCBV), relative peak height (rPH), and percent signal recovery (PSR) were measured. Pseudoprogression demonstrated lower median rCBV (P=.009) and rPH (P<.001), and higher PSR (P=.039) than progression. DSC MRI perfusion successfully identified pseudoprogression in patients who did not require a change in treatment despite radiographic worsening following chemoradiotherapy.

  View details for DOI 10.1016/j.clinimag.2012.02.016

  View details for PubMedID 23151413

  View details for PubMedCentralID PMC4755513

• Rare cell capture technology for the diagnosis of leptomeningeal metastasis in solid tumors. Neurology Nayak, L., Fleisher, M., Gonzalez-Espinoza, R., Lin, O., Panageas, K., Reiner, A., Liu, C. M., Deangelis, L. M., Omuro, A. 2013; 80 (17): 1598-605; discussion 1603

  Abstract

  To evaluate the utility of rare cell capture technology (RCCT) in the diagnosis of leptomeningeal metastasis (LM) from solid tumors through identification of circulating tumor cells (CTCs) in the CSF.In this pilot study, CSF samples from 60 patients were analyzed. The main patient cohort consisted of 51 patients with solid tumors undergoing lumbar puncture for clinical suspicion of LM. Those patients underwent initial MRI evaluation and had CSF analyzed through conventional cytology and for the presence of CTCs using RCCT, based on immunomagnetic platform enrichment utilizing anti-epithelial cell adhesion molecule antibody-covered magnetic nanoparticles. An additional 9 patients with CSF pleocytosis but without solid tumors were separately analyzed to ensure accurate differentiation between CTCs and leukocytes.Among the 51 patients with solid tumors, 15 patients fulfilled criteria for LM. CSF CTCs were found in 16 patients (median 20.7 CTCs/mL, range 0.13 to >150), achieving a sensitivity of 100% as compared with 66.7% for conventional cytology and 73.3% for MRI. One patient had a false-positive CSF CTC result (specificity = 97.2%); however, that patient eventually met LM criteria 6 months after the tap. CSF CTCs were not found in any of the additional 9 patients with CSF pleocytosis.RCCT is an accurate, novel method for the detection of LM in solid tumors, potentially providing earlier diagnostic confirmation and sparing patients from repeat lumbar punctures.

  View details for DOI 10.1212/WNL.0b013e31828f183f

  View details for PubMedID 23553479

  View details for PubMedCentralID PMC3662321

• Phase II trial of continuous low-dose temozolomide for patients with recurrent malignant glioma. Neuro-oncology Omuro, A., Chan, T. A., Abrey, L. E., Khasraw, M., Reiner, A. S., Kaley, T. J., Deangelis, L. M., Lassman, A. B., Nolan, C. P., Gavrilovic, I. T., Hormigo, A., Salvant, C., Heguy, A., Kaufman, A., Huse, J. T., Panageas, K. S., Hottinger, A. F., Mellinghoff, I. 2013; 15 (2): 242-50

  Abstract

  In this phase II trial, we investigated the efficacy of a metronomic temozolomide schedule in the treatment of recurrent malignant gliomas (MGs).Eligible patients received daily temozolomide (50 mg/m2) continuously until progression. The primary endpoint was progression-free survival rate at 6 months in the glioblastoma cohort (N = 37). In an exploratory analysis, 10 additional recurrent grade III MG patients were enrolled. Correlative studies included evaluation of 76 frequent mutations in glioblastoma (iPLEX assay, Sequenom) aiming at establishing the frequency of potentially "drugable" mutations in patients entering recurrent MG clinical trials.Among glioblastoma patients, median age was 56 y; median Karnofsky performance score (KPS) was 80; 62% of patients had been treated for ≥2 recurrences, including 49% of patients having failed bevacizumab. Treatment was well tolerated; clinical benefit (complete response + partial response + stable disease) was seen in 10 (36%) patients. Progression-free survival rate at 6 months was 19% and median overall survival was 7 months. Patients with previous bevacizumab exposure survived significantly less than bevacizumab-naive patients (median overall survival: 4.3 mo vs 13 mo; hazard ratio = 3.2; P = .001), but those patients had lower KPS (P = .04) and higher number of recurrences (P < .0001). Mutations were found in 13 of the 38 MGs tested, including mutations of EGFR (N = 10), IDH1 (N = 5), and ERBB2 (N = 1).In spite of a heavily pretreated population, including nearly half of patients having failed bevacizumab, the primary endpoint was met, suggesting that this regimen deserves further investigation. Results in bevacizumab-naive patients seemed particularly favorable, while results in bevacizumab-failing patients highlight the need to develop further treatment strategies for advanced MG. Clinical trials.gov identifier NCT00498927 (available at http://clinicaltrials.gov/ct2/show/NCT00498927).

  View details for DOI 10.1093/neuonc/nos295

  View details for PubMedID 23243055

  View details for PubMedCentralID PMC3548585

• Diffusion-weighted MR imaging and MGMT methylation status in glioblastoma: a reappraisal of the role of preoperative quantitative ADC measurements. AJNR. American journal of neuroradiology Gupta, A., Prager, A., Young, R. J., Shi, W., Omuro, A. M., Graber, J. J. 2013; 34 (1): E10-1

  View details for DOI 10.3174/ajnr.A3467

  View details for PubMedID 23275590

  View details for PubMedCentralID PMC4724797

• Multicenter phase II study of rituximab and temozolomide in recurrent primary central nervous system lymphoma. Leukemia & lymphoma Nayak, L., Abrey, L. E., Drappatz, J., Gilbert, M. R., Reardon, D. A., Wen, P. Y., Prados, M., Deangelis, L. M., Omuro, A. 2013; 54 (1): 58-61

  Abstract

  We initiated a prospective multicenter phase II trial using rituximab and temozolomide in immunocompetent patients with progressive or recurrent primary central nervous system lymphoma (PCNSL) based on activity observed in retrospective studies. Treatment consisted of an induction phase with rituximab (750 mg/m(2)) on days 1, 8, 15 and 22 and temozolomide (150 mg/m(2)) days 1-7 and 15-21, followed by six cycles of consolidation temozolomide (150-200 mg/m(2) × 5/28 days), followed by maintenance with methylprednisolone (1 g IV every 28 days) until progression. Sixteen patients were enrolled, and a complete response was seen in 2/14 (14%) evaluable patients. The median progression-free survival was 7 weeks and median overall survival was not reached (median follow-up: 37 months). Treatment was well tolerated, but due to slow accrual and preliminary analysis suggesting futility, the trial was closed early. Given the overall modest activity, this regimen should be reserved for patients who are not candidates for other, more aggressive salvage treatments.

  View details for DOI 10.3109/10428194.2012.698736

  View details for PubMedID 22656234

  View details for PubMedCentralID PMC4802006

• HISTOLOGICAL PREDICTORS OF OUTCOME IN EPENDYMOMA ARE DEPENDENT ON TUMOR LOCATION IN THE CENTRAL NERVOUS SYSTEM 17th Annual Scientific Meeting and Education Day of the Society-for-Neuro-Oncology (SNO) Raghunathan, A., Wani, K., Armstrong, T. S., Vera-Bolanos, E., Fouladi, M., Gajjar, A., Goldman, S., Lehman, N. L., Metellus, P., Mikkelsen, T., Necesito-Reyes, M. J., Omuro, A., Packer, R. J., Partap, S., Pollack, I. F., Prados, M. D., Robbins, H. I., Soffietti, R., Wu, J., Gilbert, M. R., Aldape, K. D. OXFORD UNIV PRESS INC. 2012: 107–108

  View details for Web of Science ID 000310971300427

• Outcomes of the oldest patients with primary CNS lymphoma treated at Memorial Sloan-Kettering Cancer Center. Neuro-oncology Welch, M. R., Omuro, A., Deangelis, L. M. 2012; 14 (10): 1304-11

  Abstract

  Up to 20% of all primary CNS lymphoma (PCNLS) patients are aged 80 years or older, yet data are limited on how best to treat this rapidly growing population. Despite demographic pressures and the proven efficacy of methotrexate (MTX)-based regimens, automatic de-escalation of care based on age is standard practice outside of tertiary care centers. We performed a retrospective review of all PCNSL patients aged 80 years or older treated at Memorial Sloan-Kettering Cancer Center from 1993 to 2011. Demographic and clinical variables were evaluated as predictors of survival by multivariate analysis. Twenty-three of 24 patients were treated with chemotherapy (92% with high-dose MTX, typically in combination with vincristine and procarbazine). One patient received ocular radiation alone for disease limited to the eyes. Response to treatment was noted in 62.5% of patients; 9 (37.5%) had refractory disease. Median overall survival was 7.9 months (95% confidence interval [CI]: 5.8-53), and median progression-free survival was 6.5 months (95% CI: 4.4-29.5). Two-year survival rate was 33%; 3-year survival rate was 17%. Three patients lived more than 4 years postdiagnosis. Most patients tolerated therapy well, and despite low baseline creatinine clearance, no significant renal toxicity was noted. Response status and deep brain involvement were identified as the most important predictors of survival. Multidrug regimens containing high-dose MTX are feasible and efficacious among the oldest patients, particularly those who achieve a complete response by their fifth treatment cycle. Aggressive therapy should be offered to select patients irrespective of advanced age.

  View details for DOI 10.1093/neuonc/nos207

  View details for PubMedID 22952196

  View details for PubMedCentralID PMC3452344

• CLINICAL COURSE AND PROGRESSION-FREE SURVIVAL OF ADULT AND PEDIATRIC EPENDYMOMA: A WORKING MODEL 17th Annual Scientific Meeting and Education Day of the Society-for-Neuro-Oncology (SNO) Vera-Bolanos, E., Gilbert, M. R., Aldape, K., Necesito-Reyes, M. J., Fouladi, M., Gajjar, A., Goldman, S., Metellus, P., Mikkelsen, T., Omuro, A., Packer, R., Partap, S., Pollack, I. F., Prados, M., Robins, H. I., Soffietti, R., Wu, J., Armstrong, T. S. OXFORD UNIV PRESS INC. 2012: 77–77

  View details for Web of Science ID 000310971300311

• Atypical and anaplastic meningiomas treated with bevacizumab. Journal of neuro-oncology Nayak, L., Iwamoto, F. M., Rudnick, J. D., Norden, A. D., Lee, E. Q., Drappatz, J., Omuro, A., Kaley, T. J. 2012; 109 (1): 187-93

  Abstract

  Atypical and anaplastic (WHO Grades II and III) meningiomas are aggressive tumors, and patients often progress despite surgery and radiation. There is no known effective chemotherapeutic option for these patients. Meningiomas have a high expression of vascular endothelial growth factor receptor (VEGFR). We sought to retrospectively study the activity of bevacizumab, which is an anti-angiogenic agent targeting the VEGF pathway in these tumors. This is a retrospective review of WHO Grade II and III meningiomas treated at four institutions, selecting only those patients who received bevacizumab. We analyzed radiographic response according to standard RANO criteria, progression-free survival (PFS) and overall survival from the initiation of bevacizumab therapy using Kaplan-Meier statistics. We identified 15 patients across four institutions who carried a diagnosis of atypical or anaplastic meningioma and were treated with bevacizumab. Best radiographic response was stable disease. MR perfusion studies showed decreased tumor blood volume in one patient. Three patients developed non-fatal intratumoral hemorrhage. Median PFS was 26 weeks (95 % CI, 10-29 weeks). Six month PFS rate was 43.8 % (95 % CI, 15.7-69.1 %). Bevacizumab was well-tolerated in our patients, and may be considered in patients who have exhausted radiation and surgical options. Prospective studies are required to define the safety and efficacy of bevacizumab in atypical and anaplastic meningiomas.

  View details for DOI 10.1007/s11060-012-0886-4

  View details for PubMedID 22544653

• Chemotherapy-related magnetic resonance imaging abnormalities mimicking disease progression following intraventricular liposomal cytarabine and high dose methotrexate for neurolymphomatosis. Leukemia & lymphoma Pentsova, E., Rosenblum, M., Holodny, A., Palomba, M. L., Omuro, A. 2012; 53 (8): 1620-2

  View details for DOI 10.3109/10428194.2012.656632

  View details for PubMedID 22242822

• New Treatments for Leptomeningeal Metastases Are Urgently Needed <i>Response</i> JOURNAL OF THORACIC ONCOLOGY Morris, P. G., Omuro, A. M. 2012; 7 (7): 1204-1205

  View details for DOI 10.1097/JTO.0b013e3182598d49

  View details for Web of Science ID 000306458700126

• Continuing the search for MR imaging biomarkers for MGMT promoter methylation status: conventional and perfusion MRI revisited. Neuroradiology Gupta, A., Omuro, A. M., Shah, A. D., Graber, J. J., Shi, W., Zhang, Z., Young, R. J. 2012; 54 (6): 641-3

  View details for DOI 10.1007/s00234-011-0970-z

  View details for PubMedID 22006425

  View details for PubMedCentralID PMC4724213

• Limited overall survival in patients with brain metastases from triple negative breast cancer. The breast journal Morris, P. G., Murphy, C. G., Mallam, D., Accordino, M., Patil, S., Howard, J., Omuro, A., Beal, K., Seidman, A. D., Hudis, C. A., Fornier, M. N. 2012; 18 (4): 345-50

  Abstract

  Patients with breast cancer, which lacks ER, PR, and HER2; "triple negative" (TNBC), are at increased risk of brain metastases (BMs). However, the impact of modern therapy on the risk of BMs and outcomes remains largely unknown. In this retrospective, single-institution study we assessed the incidence of BMs, the therapeutic options, and overall survival, in a recent cohort of patients with TNBC. Women diagnosed with early stage TNBC from January 1, 1998 to December 31, 2007 were identified through institutional databases. Electronic medical records were reviewed to assess patterns of recurrence, treatment, and survival. In total, 1,323 patients, median age 53 years (range 20-91), were identified. There were 298 patients (23%) who developed metastatic disease, of whom, 99 (33%) developed BMs, representing 7.5% of the entire cohort. Following BM diagnosis, treatment consisted of: radiotherapy 87 (88%) patients, resection 26 (26%) patients, and systemic chemotherapy 70 (71%) patients, with a median of 1.0 (range 0-8) chemotherapy regimens. The actuarial median survival from diagnosis of BMs is 5 months (95% CI 4-7 months). This single-institution, retrospective study confirms that the prognosis for patients with BMs from TNBC remains poor. This group of patients urgently needs improved therapies.

  View details for DOI 10.1111/j.1524-4741.2012.01246.x

  View details for PubMedID 22607041

• A prognostic gene expression signature in infratentorial ependymoma. Acta neuropathologica Wani, K., Armstrong, T. S., Vera-Bolanos, E., Raghunathan, A., Ellison, D., Gilbertson, R., Vaillant, B., Goldman, S., Packer, R. J., Fouladi, M., Pollack, I., Mikkelsen, T., Prados, M., Omuro, A., Soffietti, R., Ledoux, A., Wilson, C., Long, L., Gilbert, M. R., Aldape, K. 2012; 123 (5): 727-38

  Abstract

  Patients with ependymoma exhibit a wide range of clinical outcomes that are currently unexplained by clinical or histological factors. Little is known regarding molecular biomarkers that could predict clinical behavior. Since recent data suggest that these tumors display biological characteristics according to their location (cerebral vs. infratentorial vs. spinal cord), rather than explore a broad spectrum of ependymoma, we focused on molecular alterations in ependymomas arising in the infratentorial compartment. Unsupervised clustering of available gene expression microarray data revealed two major subgroups of infratentorial ependymoma. Group 1 tumors over expressed genes that were associated with mesenchyme, Group 2 tumors showed no distinct gene ontologies. To assess the prognostic significance of these gene expression subgroups, real-time reverse transcriptase polymerase chain reaction assays were performed on genes defining the subgroups in a training set. This resulted in a 10-gene prognostic signature. Multivariate analysis showed that the 10-gene signature was an independent predictor of recurrence-free survival after adjusting for clinical factors. Evaluation of an external dataset describing subgroups of infratentorial ependymomas showed concordance of subgroup definition, including validation of the mesenchymal subclass. Importantly, the 10-gene signature was validated as a predictor of recurrence-free survival in this dataset. Taken together, the results indicate a link between clinical outcome and biologically identified subsets of infratentorial ependymoma and offer the potential for prognostic testing to estimate clinical aggressiveness in these tumors.

  View details for DOI 10.1007/s00401-012-0941-4

  View details for PubMedID 22322993

  View details for PubMedCentralID PMC4013829

• A phase II study of the Ras-MAPK signaling pathway inhibitor TLN-4601 in patients with glioblastoma at first progression. Journal of neuro-oncology Mason, W. P., Belanger, K., Nicholas, G., Vallières, I., Mathieu, D., Kavan, P., Desjardins, A., Omuro, A., Reymond, D. 2012; 107 (2): 343-9

  Abstract

  This phase II trial was undertaken to evaluate the efficacy of TLN-4601 in patients with glioblastoma (GBM) at first progression. TLN-4601 inhibits the Ras-MAPK signaling pathway, and in animal models crosses the blood-brain barrier and accumulates in implanted gliomas, possibly by binding specifically to the peripheral benzodiazepine receptor. A maximum of 40 patients with recurrent GBM were to be enrolled in this study. TLN-4601 was administered at a dose of 480 mg/m(2)/day by continuous intravenous (CIV) administration. Each 21-day cycle consisted of a 14-day CIV administration and a 7-day recovery period. Samples were obtained from all patients for pharmacokinetic evaluations (PK) and for Raf-1 and pERK biomarker assessment using immunohistochemistry and flow cytometry. Following enrollment of 20 patients, this study was terminated due to a lack of efficacy. Of 17 evaluable patients, 14 had MR scans performed after two cycles of TLN-4601. Of these 14 patients, three had stable disease and 11 had disease progression. Only three patients had MR scans performed after four cycles and all had evidence of radiographic progression. Serum PKs confirmed that patients were exposed to TLN-4601 at targeted drug levels. TLN-4601 was generally well tolerated although two patients discontinued treatment due to adverse events. Biomarker analysis did not show consistent changes. TLN-4601 infused via CIV at 480 mg/m(2)/day for 14 of 21 days is well tolerated by patients with progressive GBM. However, this agent is ineffective in progressive GBM when administered as monotherapy in this schedule.

  View details for DOI 10.1007/s11060-011-0747-6

  View details for PubMedID 22048878

• Leptomeningeal metastasis from non-small cell lung cancer: survival and the impact of whole brain radiotherapy. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer Morris, P. G., Reiner, A. S., Szenberg, O. R., Clarke, J. L., Panageas, K. S., Perez, H. R., Kris, M. G., Chan, T. A., DeAngelis, L. M., Omuro, A. M. 2012; 7 (2): 382-5

  Abstract

  Leptomeningeal metastasis (LM), or leptomeningeal carcinomatosis, is a devastating complication of non-small cell lung cancer (NSCLC), and the optimal therapeutic approach remains challenging. A retrospective review was carried out to assess the impact of whole brain radiotherapy (WBRT), intrathecal therapy (IT), and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) on outcomes.Patients with newly diagnosed LM from NSCLC from January 2002 to December 2009 were identified through institutional databases and medical records reviewed. Survival was assessed by Kaplan-Meier and landmark analyses by administered treatment to minimize selection bias.We identified 125 patients (45 men, 80 women) with LM from NSCLC, median age 59 years (range, 28-87 years). Almost all (123 [98%]) patients have died and median overall survival was 3.0 months (95% confidence interval, 2.0-4.0). No differences in survival were seen between patients who were treated with WBRT (n =46) and those who were not (n =59, p =0.84) in a landmark analysis. In the seven patients selected to receive IT chemotherapy, median survival was 18 months (range, 5-33 months) and appeared superior to those not selected for this treatment (p =0.001) in a landmark analysis. The median survival of the nine patients with known EGFR mutations (all of whom received TKIs at some point) was 14 months (range, 1-28 months).This retrospective study, the largest published series, demonstrates the poor survival of LM from NSCLC. In this study, survival was not improved by WBRT. The survival of patients selected for IT chemotherapy and those with EGFR mutations treated with TKIs highlights the importance of developing novel agents.

  View details for DOI 10.1097/JTO.0b013e3182398e4f

  View details for PubMedID 22089116

• CMV encephalitis in BMT recipients. Bone marrow transplantation Sarva, H., Graber, J., Remanan, R., Rosenblum, M., Omuro, A. 2012; 47 (2): 318-20

  View details for DOI 10.1038/bmt.2011.80

  View details for PubMedID 21460874

• Prophylactic intrathecal chemotherapy in primary CNS lymphoma. Journal of neuro-oncology Sierra Del Rio, M., Ricard, D., Houillier, C., Navarro, S., Gonzalez-Aguilar, A., Idbaih, A., Kaloshi, G., Elhallani, S., Omuro, A., Choquet, S., Soussain, C., Hoang-Xuan, K. 2012; 106 (1): 143-6

  Abstract

  The role of prophylactic intrathecal chemotherapy in the treatment of primary central nervous system lymphoma remains controversial. We report a retrospective single center study of a cohort of 69 patients with primary central nervous system lymphoma who had been treated with a regimen that combined high intravenous doses of Methotrexate, CCNU, procarbazine and methylprednisolone. Before 2000, patients systematically received intrathecal prophylaxis including Methotrexate, cytarabine, and hydrocortisone delivered either by intraventricular or lumbar injection along with the systemic chemotherapy (group A, n = 39). After this date, the procedure was changed and intrathecal chemotherapy was withdrawn from the protocol (group B, n = 30). The median age and Karnofsky index were comparable in both groups. At the time of analysis, we found no significant difference between patients with and without intrathecal prophylaxis in terms of objective response rate, patterns of relapse, progression-free survival or overall survival. In our study, intrathecal prophylaxis withdrawal from a high dose intravenous Methotrexate-based chemotherapy regimen did not influence disease control and outcome of primary central nervous system lymphoma. Further studies prospectively investigating the role of intrathecal chemoprophylaxis are warranted for this disease.

  View details for DOI 10.1007/s11060-011-0649-7

  View details for PubMedID 21739169

• Neurologic Complications of Radiotherapy to the Central Nervous System Handbook of Clinical Neurology (Volume on Neoplasms) A, O., N, M., JY, D. 2012
• Neurologic Complications of Non-Hodgkin Lymphoma Lymphoma and Leukemia of the Nervous System M, K., A, N., M, G., A, O. 2012
• Primary Central Nervous System Lymphomas Neuro-Oncology J, G., A, O. 2012
• Cognitive functions in primary CNS lymphoma after single or combined modality regimens. Neuro-oncology Correa, D. D., Shi, W., Abrey, L. E., Deangelis, L. M., Omuro, A. M., Deutsch, M. B., Thaler, H. T. 2012; 14 (1): 101-8

  Abstract

  The standard treatment for primary CNS lymphoma (PCNSL) involves high-dose methotrexate-based chemotherapy (HD-MTX) alone or in combination with whole brain radiotherapy (WBRT). The combined modality regimen carries a substantial risk for cognitive impairment, and HD-MTX alone has been used more often recently in part to reduce neurotoxicity. In this study, we assessed cognitive functioning and quality of life in PCNSL survivors treated with WBRT + HD-MTX or HD-MTX alone. Fifty PCNSL patients in disease remission underwent a posttreatment baseline neuropsychological evaluation, and a subset of patients completed a follow-up evaluation. Quality of life and extent of white matter disease and atrophy on MRI were assessed. Comparisons according to treatment type after controlling for age and time since treatment completion showed that patients treated with HD-MTX alone had significantly higher scores on tests of selective attention and memory than patients treated with the combined modality regimen. Patients treated with WBRT + HD-MTX had impairments across most cognitive domains, and these were of sufficient severity to interfere with quality of life, as over 50% were not working due to their illness. Patients treated with HD-MTX alone did not meet criteria for cognitive impairment but scored within 1 SD below the normative sample on most tests. Patients with more extensive white matter disease had lower scores on tests of set-shifting and memory. Cognitive dysfunction was more prevalent in PCNSL survivors treated with WBRT + HD-MTX compared with patients treated with HD-MTX alone.

  View details for DOI 10.1093/neuonc/nor186

  View details for PubMedID 22013168

  View details for PubMedCentralID PMC3245999

• Primary central nervous system lymphoma: is there still a role for radiotherapy? Current opinion in neurology Graber, J. J., Omuro, A. 2011; 24 (6): 633-40

  Abstract

  Adding high-dose methotrexate to whole-brain radiotherapy improves survival in primary central nervous system lymphoma. However, the high neurotoxicity rates observed, especially in the elderly, raised interest in exploring other alternatives such as reduced-dose radiotherapy and chemotherapy-only treatments.Phase II studies suggested that omitting radiotherapy decreases progression-free survival (PFS) but not overall survival. A randomized phase III trial testing chemotherapy with/without radiation found similar results. However, interpretation of that trial has been difficult because of the chemotherapy regimen used (methotrexate with/without ifosfamide), intrinsic methodological problems and lack of neuropsychological evaluation. It also remains unclear whether chemotherapy-only treatments could ultimately result in worse cognitive outcomes in comparison with combined chemotherapy and radiotherapy because the higher rates of relapses could result in additional neurotoxicity from salvage treatments and brain damage by relapsing tumor. Given differences in relapses and neurotoxicity rates according to age, it is also unclear how results apply to younger versus older patients.Given the lack of better data, omitting radiotherapy currently seems a justifiable choice in routine practice, particularly in the elderly, but the question remains unsettled. Ongoing studies are investigating other consolidation options, including reduced-dose radiotherapy and high-dose chemotherapy with stem-cell rescue, aiming at improving disease control and decreasing neurotoxicity.

  View details for DOI 10.1097/WCO.0b013e32834cbdef

  View details for PubMedID 21968551

• Methotrexate area under the curve as a prognostic factor in primary central nervous system lymphoma treated with immunochemoradiotherapy. Leukemia & lymphoma Morris, P. G., Abrey, L. E., Reiner, A. S., Wu, N., Panageas, K. S., Seko, B. S., Deangelis, L. M., Omuro, A. 2011; 52 (10): 1891-7

  Abstract

  A higher methotrexate area under the curve (MTX AUC) observed during the first chemotherapy cycle has been associated with improved tumor control in patients with primary central nervous system lymphoma. To confirm these findings, we conducted a post hoc analysis of data from a prospective phase II trial of rituximab, methotrexate, procarbazine, vincristine, cytarabine, and low-dose radiotherapy. Thirty-nine patients were included (24 men; 15 women). The median age was 60 years (range 30-76) and median Karnofsky performance status (KPS) score was 70 (range 50-100). There was substantial inter-individual variability in MTX AUC (median: 795.5 µM*h/L, range 44.8-8326.44). However, there were no differences in progression-free survival (PFS) in patients below and above the median MTX AUC (2-year PFS 78% vs. 85% respectively; p = 0.51). Similarly, there were no differences in response rates or overall survival according to MTX AUC, suggesting that intra-patient dose escalation to increase MTX exposure is unnecessary when our regimen is utilized.

  View details for DOI 10.3109/10428194.2011.585527

  View details for PubMedID 21699456

• Primary CNS lymphoma in patients younger than 60: can whole-brain radiotherapy be deferred? Journal of neuro-oncology Omuro, A., Taillandier, L., Chinot, O., Sierra Del Rio, M., Carnin, C., Barrie, M., Soussain, C., Tanguy, M. L., Choquet, S., Leblond, V., Hoang-Xuan, K. 2011; 104 (1): 323-30

  Abstract

  Whole brain radiotherapy (WBRT) has been increasingly omitted as the first treatment of primary central nervous system lymphoma (PCNSL) because of neurotoxicity risks. However, neurotoxicity risks are lower in young (<60 years) patients; deferring WBRT may not be necessary and may compromise disease control. To investigate this question, we report a consecutive series of young (<60 years) PCNSL patients uniformly treated with a response-adjusted approach, with WBRT omitted in patients with chemosensitive disease. Treatment started with induction chemotherapy consisting of methotrexate (3 g/m(2)), CCNU, procarbazine, methylprednisolone and intrathecal methotrexate, cytarabine, and methylprednisolone. Patients achieving complete response (CR) received five additional chemotherapy cycles and no further treatment. Patients with less than CR were treated on an individual basis, typically with WBRT or high-dose chemotherapy (HDC) with stem cell rescue. Sixty-four patients were included (median age: 47; median KPS: 70). Median progression-free survival (PFS) was 12 months; median overall survival (OS) was 63 months (median follow-up: 108 months). Objective response after induction was 87% (CR: 54%; PR: 33%). To date, salvage WBRT has been given to a total of 27 patients and HDC to 29. Neurotoxicity developed in five patients (none in patients treated with chemotherapy only). Deferring WBRT in chemosensitive patients seems to compromise PFS but not OS. Neurotoxicity was reduced but not eliminated, as salvage WBRT was frequently required. HDC and WBRT were effective salvage treatments. As the objective of treatment in this population is a cure, withholding WBRT may not be the best strategy and deserves further investigation. Ongoing studies are investigating whether upfront treatment with HDC can replace WBRT in this setting.

  View details for DOI 10.1007/s11060-010-0497-x

  View details for PubMedID 21170569

• Pharmacotherapy for primary CNS lymphoma: progress beyond methotrexate? CNS drugs Graber, J. J., Omuro, A. 2011; 25 (6): 447-57

  Abstract

  Studies conducted in the 1990s have established that high-dose methotrexate-based chemotherapy added to whole-brain radiotherapy improves survival in primary CNS lymphoma (PCNSL). However, radiotherapy-related delayed neurotoxicity has emerged as a serious complication of chemo-radiotherapy, particularly in the elderly. Unfortunately, omitting radiotherapy results in decreased progression-free survival, and therefore establishing more effective chemotherapy regimens is necessary in order to improve the number of long-term remissions. Recent studies have suggested that a combination of drugs is superior to single-agent methotrexate, but the optimal chemotherapy combination and the role of alternative consolidation treatments such as reduced-dose radiotherapy and high-dose chemotherapy with stem cell rescue remain to be defined. In this article, we review the multiple chemotherapy options reported in newly diagnosed and in progressive/refractory PCNSL, including recently reported and ongoing clinical trials, as well as future perspectives.

  View details for DOI 10.2165/11589030-000000000-00000

  View details for PubMedID 21649446

• Potential utility of conventional MRI signs in diagnosing pseudoprogression in glioblastoma. Neurology Young, R. J., Gupta, A., Shah, A. D., Graber, J. J., Zhang, Z., Shi, W., Holodny, A. I., Omuro, A. M. 2011; 76 (22): 1918-24

  Abstract

  To examine the potential utility of conventional MRI signs in differentiating pseudoprogression (PsP) from early progression (EP).This retrospective study reviewed initial postradiotherapy MRI scans of 321 patients with glioblastoma undergoing chemotherapy and radiotherapy. A total of 93 patients were found to have new or increased enhancing mass lesions, raising the possibility of PsP. Final diagnosis of PsP or EP was established upon review of surgical specimens from a second resection or by clinical and radiologic follow-up. A total of 11 MRI signs potentially helpful in the differentiation between PsP and EP were examined on the initial post-RT MRI and were correlated with the final diagnosis through χ(2) or Fisher exact test.Sixty-three (67.7%) of the 93 patients had EP, of which 22 (34.9%) were diagnosed by pathology. Thirty patients (32.3%) had PsP; 6 (16.7% of the 30) were diagnosed by pathology. Subependymal enhancement was predictive for EP (p = 0.001) with 38.1% sensitivity, 93.3% specificity, and 41.8% negative predictive value. The other 10 signs had no predictive value (p = 0.06-1.0).Conventional MRI signs have limited utility in diagnosing PsP in patients with recently treated glioblastomas and worsening enhancing lesions. We did not find a sign with a high negative predictive value for PsP that would have been the most useful for the clinical physician. When present, subependymal spread of the enhancing lesion is a useful MRI marker in identifying EP rather than PsP.

  View details for DOI 10.1212/WNL.0b013e31821d74e7

  View details for PubMedID 21624991

  View details for PubMedCentralID PMC3115805

• Up-front temozolomide in elderly patients with anaplastic oligodendroglioma and oligoastrocytoma. Journal of neuro-oncology Ducray, F., del Rio, M. S., Carpentier, C., Psimaras, D., Idbaih, A., Dehais, C., Kaloshi, G., Mokhtari, K., Taillibert, S., Laigle-Donadey, F., Omuro, A., Sanson, M., Delattre, J. Y., Hoang-Xuan, K. 2011; 101 (3): 457-62

  Abstract

  Optimal treatment of anaplastic oligodendroglial tumors (AOT) in elderly patients is debatable. We report a retrospective study of 44 consecutive patients aged 70 years or older [median age: 74 years; median Karnofsky performance status (KPS): 70] treated with up-front chemotherapy using temozolomide (TMZ) at conventional doses until tumor progression. O(6)-methylguanine-DNA methyltransferase promoter (MGMTP) methylation was assessed in 38 patients. Of the 41 evaluable patients, partial response (PR) was seen in 13 (32%) patients, 17 (41%) patients achieved stable disease, while the disease progressed in 11 (27%) patients. Median progression-free survival (PFS) and overall survival (OS) were 6.9 and 12.4 months, respectively. Hematotoxicity grades 3-4 occurred in nine patients (20%). MGMTP was methylated in 50% of patients and was associated with both longer PFS (8.7 versus 5.7 months, P = 0.01) and longer OS (16.1 versus 12.4 months, P = 0.05). The rate of responders to chemotherapy was similar in MGMTP-methylated (38%) and in MGMTP-unmethylated patients (31%), but duration of response was significantly longer in responders with methylated MGMTP than in responders with unmethylated MGMTP (16.1 versus 9.6 months, P = 0.0004). This study demonstrates that a substantial number of elderly patients with AOT can achieve prolonged survival with up-front chemotherapy using TMZ. Further investigation is needed to determine whether this treatment is preferable to initial radiation therapy.

  View details for DOI 10.1007/s11060-010-0264-z

  View details for PubMedID 20556480

• Efficacy and safety of bevacizumab in active brain metastases from non-small cell lung cancer. Journal of neuro-oncology De Braganca, K. C., Janjigian, Y. Y., Azzoli, C. G., Kris, M. G., Pietanza, M. C., Nolan, C. P., Omuro, A. M., Holodny, A. I., Lassman, A. B. 2010; 100 (3): 443-7

  Abstract

  Bevacizumab is effective for the treatment of non-small cell lung cancer (NSCLC). Ongoing trials are exploring the safety of bevacizumab in patients with inactive, previously treated brain metastases. However, bevacizumab safety and efficacy in the treatment of active brain metastases is unknown. Bevacizumab received accelerated FDA approval for progressive glioblastoma, a primary brain tumor, because of high response rates and low incidence of intracranial hemorrhage. We retrospectively identified patients treated with bevacizumab for active (treatment naïve or progressive) central nervous system (CNS) metastases from NSCLC. MRI scans performed at least 6 weeks after initiating bevacizumab were assessed for response. There were six patients, four women and two men with a median age of 60 years (range 59-77) at initiation of bevacizumab. Five patients had progressive CNS metastases despite prior treatment including surgery, radiotherapy, and/or chemotherapy; one patient had treatment-naïve brain metastases. Two patients had leptomeningeal metastases, isolated or coexistent with parenchymal brain metastases in one patient each. Bevacizumab was administered alone to one patient and in combination with various cytotoxic chemotherapies in the others. Toxicity included an asymptomatic (Grade 1) intra-tumoral hemorrhage which occurred in one of three patients receiving concurrent anticoagulation with bevacizumab. There was no recurrent CNS bleeding in two patients with a prior history of such hemorrhage. Best CNS response (RECIST) was partial in two, stable disease in three, and progression in one. Median progression-free survival (PFS) was 7.8 months and median overall survival (OS) was 14.1 months following initiation of bevacizumab. Clinical benefit was also observed in the form of improved symptoms and reduced corticosteroid requirements. Bevacizumab should be used with caution in patients with active CNS metastases pending additional safety data. This series suggests bevacizumab may be safe and effective for progressive brain metastases from NSCLC and deserves further study.

  View details for DOI 10.1007/s11060-010-0200-2

  View details for PubMedID 20440540

  View details for PubMedCentralID PMC3246379

• Nitrosourea-based chemotherapy for low grade gliomas failing initial treatment with temozolomide. Journal of neuro-oncology Kaloshi, G., Sierra del Rio, M., Ducray, F., Psimaras, D., Idbaih, A., Laigle-Donadey, F., Taillibert, S., Houillier, C., Dehais, C., Omuro, A., Sanson, M., Delattre, J. Y., Hoang-Xuan, K. 2010; 100 (3): 439-41

  Abstract

  There is a growing evidence of using Temozolomide as upfront therapy for progressive low grade gliomas. No data exist on the efficacy of nitrosoureas as an alternative to radiotherapy in those patients who progress after Temozolomide. We retrospectively reviewed 30 patients with median age of 46 years. Twenty-one patients had pure oligodendrogliomas. Thirteen patients had a non-enhancing tumor at progression after Temozolomide. The chromosomes 1p/19q were co-deleted in 5 cases and retained in 10 cases. Response rate was 10% (3 minor responses achieved in non-enhancing tumors). Tolerance was acceptable (17% grade III and IV myelosupression). Median PFS was 6.5 months. Median OS from start of salvage treatment was 23.4 months. Tumors without contrast enhancement demonstrated a better prognosis than those with contrast enhancement both in term of PFS (P = 0.0003) and OS (P = 0.0006). Chromosomes 1p/19q codeletion was not predictive for objective response to salvage treatment but correlated with a better PFS (P = 0.02). In conclusion, salvage NU chemotherapy provide disappointing results in TMZ-pretreated low grade gliomas (LGG), which should be treated in priority by conventional radiotherapy especially in LGG that display contrast enhancement at progression.

  View details for DOI 10.1007/s11060-010-0197-6

  View details for PubMedID 20464625

• Antiangiogenic Strategies for the Treatment of Gliomas Glioblastoma: Molecular Mechanisms of Pathogenesis and Current Therapeutic Strategies E, B., A, O. 2009
• Exploring multi-targeting strategies for the treatment of gliomas. Current opinion in investigational drugs (London, England : 2000) Omuro, A. M. 2008; 9 (12): 1287-95

  Abstract

  Molecularly targeted therapies hold the promise of providing new anticancer treatments that are more effective and less toxic than traditional cytotoxic chemotherapy. Unfortunately, results of first generation targeted therapy trials for malignant gliomas (glioblastomas and anaplastic forms of astrocytomas, oligodendrogliomas and oligoastrocytomas) have been disappointing. While combination strategies targeting angiogenesis through inhibition of the VEGFR pathway (eg, bevacizumab combined with irinotecan) have demonstrated promising activity, single-agent drugs have been largely unsuccessful when tested in recurrent disease clinical trials. These single agents include EGF receptor tyrosine kinase inhibitors (gefitinib and erlotinib), PDGF receptor inhibitors (imatinib), mTOR inhibitors (temsirolimus and everolimus), and VEGFR, protein kinase C-beta and other angiogenesis pathway inhibitors (vatalanib and enzastaurin). A new generation of trials is seeking to define whether inhibiting multiple targets simultaneously through utilization of less specific, multi-targeting drugs, or through combination of two or more single-targeted drugs, can overcome tumor resistance. In this review, the rationale and challenges of developing such multi-targeted strategies in gliomas are presented.

  View details for PubMedID 19037835

• Primary CNS lymphoma with intraocular involvement: International PCNSL Collaborative Group Report. Neurology Grimm, S. A., McCannel, C. A., Omuro, A. M., Ferreri, A. J., Blay, J. Y., Neuwelt, E. A., Siegal, T., Batchelor, T., Jahnke, K., Shenkier, T. N., Hall, A. J., Graus, F., Herrlinger, U., Schiff, D., Raizer, J., Rubenstein, J., Laperriere, N., Thiel, E., Doolittle, N., Iwamoto, F. M., Abrey, L. E. 2008; 71 (17): 1355-60

  Abstract

  To describe the demographics, diagnostic details, therapeutic management, and outcome in patients with primary CNS lymphoma (PCNSL) with ocular involvement.A retrospective study of 221 patients was assembled from 16 centers in seven countries. Only HIV-negative, immunocompetent patients with brain and ocular lymphoma were included; none had systemic lymphoma.Median age at diagnosis was 60. Fifty-seven percent were women. Median Eastern Cooperative Oncology Group performance status was 2. Ocular disturbance and behavioral/cognitive changes were the most common presenting symptoms. Diagnosis of lymphoma was made by brain biopsy (147), vitrectomy (65), or CSF cytology (11). Diagnosis of intraocular lymphoma was made by vitrectomy/choroidal/retinal biopsy (90) or clinical ophthalmic examination (141). CSF cytology was positive in 23%. Treatment information was available for 176 patients. A total of 102 received dedicated ocular therapy (ocular radiotherapy 79, intravitreal methotrexate 22, and both 1) in addition to treatment for their brain lymphoma. Sixty-nine percent progressed at a median of 13 months; sites of progression included brain 52%, eyes 19%, brain and eyes 12%, and systemic 2%. Patients treated with local ocular therapy did not have a statistically significant decreased risk of failing in the eyes (p = 0.7). Median progression free survival and overall survival for the entire cohort were 18 and 31 months.This is the largest reported series of primary CNS lymphoma (PCNSL) with intraocular involvement. Progression free and overall survival was similar to that reported with PCNSL. Dedicated ocular therapy improved disease control but did not affect overall survival.

  View details for DOI 10.1212/01.wnl.0000327672.04729.8c

  View details for PubMedID 18936428

  View details for PubMedCentralID PMC4109164

• Adjuvant dibromodulcitol and BCNU chemotherapy in anaplastic astrocytoma: results of a randomised European Organisation for Research and Treatment of Cancer phase III study (EORTC study 26882). European journal of cancer (Oxford, England : 1990) Hildebrand, J., Gorlia, T., Kros, J. M., Afra, D., Frenay, M., Omuro, A., Stupp, R., Lacombe, D., Allgeier, A., van den Bent, M. J. 2008; 44 (9): 1210-6

  Abstract

  In a previous randomised EORTC study on adjuvant dibromodulcitol (DBD) and bichloroethylnitrosourea (BCNU) in adults with glioblastoma multiforme (GBM) and anaplastic astrocytoma (AA), a clinically significant trend towards a longer overall survival (OS) and a progression-free survival (PFS) was observed in the subgroup of AA. The aim of the present study was to test this adjuvant regimen in a larger number of AA patients.Continuation of the previous phase III trial for newly diagnosed AA according to the local pathologist. Patients were randomised to either radiotherapy only or to radiotherapy in combination with BCNU on day 2 and weekly DBD, followed by adjuvant DBD and BCNU in cycles of six weeks for a maximum total treatment duration of one year. OS was the primary end-point.Patients (193 ) with newly diagnosed AA according to local pathological assessment were randomised to radiotherapy (RT) alone (n=99), or to RT plus DBD/BCNU (n=94); 12 patients were considered not eligible. At central pathology review, over half (53%) of the locally diagnosed AA cases could not be confirmed. On intent-to-treat analysis, no statistically significant differences in OS (p=0.111) and PFS (p=0.087) were observed, median OS after RT was only 23.9 months 95% confidence interval (CI), [18.4-34.0] after RT plus DBD/BCNU 27.3 months 95% CI [21.4-46.8].No statistically significant improvement in survival was observed after BCNU/DBD adjuvant chemotherapy in AA patients. The trend towards improved survival is consistent with previous reports. Central pathology review of grade 3 tumours remains crucial.

  View details for DOI 10.1016/j.ejca.2007.12.005

  View details for PubMedID 18248979

• Intensive chemotherapy followed by hematopoietic stem-cell rescue for refractory and recurrent primary CNS and intraocular lymphoma: Société Française de Greffe de Moëlle Osseuse-Thérapie Cellulaire. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Soussain, C., Hoang-Xuan, K., Taillandier, L., Fourme, E., Choquet, S., Witz, F., Casasnovas, O., Dupriez, B., Souleau, B., Taksin, A. L., Gisselbrecht, C., Jaccard, A., Omuro, A., Sanson, M., Janvier, M., Kolb, B., Zini, J. M., Leblond, V. 2008; 26 (15): 2512-8

  Abstract

  The prognosis of relapsing primary CNS lymphoma (PCNSL) is poor. We report the results of a prospective multicenter trial of intensive chemotherapy followed by autologous hematopoietic stem-cell rescue (IC + HCR) in immunocompetent adult patients with PCNSL or intraocular lymphoma (IOL) after failure of high-dose methotrexate-based treatment.Salvage treatment consisted of two cycles of high-dose cytarabine and etoposide (CYVE). Intensive chemotherapy combined thiotepa, busulfan, and cyclophosphamide. Forty-three patients (median age, 52 years; range, 23 to 65 years) were included, with relapse (n = 22), refractory disease (n = 17), or a partial response to first-line treatment (n = 4). The response to CYVE was not assessable in three cases because of treatment-related death. Twenty patients (47%) were chemosensitive to CYVE: 15 of them proceeded to IC + HCR. IC + HCR was also administered to 12 patients who did not respond to CYVE. All but one of the 27 patients who underwent IC + HCR entered complete remission.With a median follow-up of 36 months, the median overall survival was 18.3 months in the overall population, and 58.6 months among patients who completed IC + HCR. The respective median progression-free survival (PFS) times after IC + HCR were 11.6 and 41.1 months. The 2-year overall survival probability was 45% in the whole population and 69% among the 27 patients who received IC + HCR. The 2-year PFS probability was 43% among all the patients and 58% in the IC + HCR subpopulation.IC + HCR is an effective treatment for refractory and recurrent PCNSL.

  View details for DOI 10.1200/JCO.2007.13.5533

  View details for PubMedID 18413641

• A phase II trial of vinorelbine and intensive temozolomide for patients with recurrent or progressive brain metastases. Journal of neuro-oncology Iwamoto, F. M., Omuro, A. M., Raizer, J. J., Nolan, C. P., Hormigo, A., Lassman, A. B., Gavrilovic, I. T., Abrey, L. E. 2008; 87 (1): 85-90

  Abstract

  To investigate the efficacy and safety of the combination of vinorelbine and intensive temozolomide for recurrent or progressive brain metastases from solid tumors.Patients > or =18 years of age and with Karnofsky performance scale (KPS) > or = 60, adequate organ function and progressive or recurrent brain metastases were eligible. This was a phase II trial with 28-day cycles using temozolomide (150 mg/m(2), days 1-7 and 15-21) and vinorelbine 25 or 30 mg/m(2 )on days one and eight. The primary endpoint was objective radiographic response.Thirty-eight patients (15 men, 23 women) with a median age of 57 years (range, 39-75) and median KPS of 80 were enrolled. The primary tumor sites were lung (n = 20), breast (n = 11), colorectal (n = 2), kidney (n = 2), bladder (n = 1), endometrium (n = 1), head and neck (n = 1). Prior therapies included chemotherapy (97%), whole-brain radiation therapy (79%), brain metastasis resection (53%) and stereotatic radiosurgery (47%). Objective radiographic response rate was 5% (one complete response and one minor response); five patients had stable disease, 29 progressive disease and two patients were not evaluable. Twenty-nine patients (76%) have died and the median follow-up of survivors was six months. Median progression-free and overall survivals were 1.9 and 5 months, respectively. Grade 3/4 toxicities were mainly hematological and two patients discontinued the study due to myelosuppression.In this heavily pretreated population of patients with brain metastases, adding vinorelbine and increasing the intensity of temozolomide do not improve response rates compared to previous studies with single-agent temozolomide at standard doses.

  View details for DOI 10.1007/s11060-007-9491-3

  View details for PubMedID 17987262

• Chemo radiotherapy for Primary CNS Lymphoma Progress in Neurotherapeutics and Neuropsychopharmacology A, O., J, Y., L, A. 2008
• What is the Relevance of Determining EGFR-Variant-III Status in Glioblastomas? A, O. Nat Clin Pract Oncol. 2008
• What is the place of bevacizumab and irinotecan (CPT11) in the treatment of glioblastoma and other malignant gliomas? A, O., JY, D. Curr Opin Neurol 21(6): 717-9. 2008
• Dementia and Brain Tumors Handbook of Clinical Neurology (Volume on Dementia), 3rd series A, O., JY, D. 2008
• Molecular genetic markers as predictors of response to chemotherapy in gliomas. Current opinion in oncology Idbaih, A., Omuro, A., Ducray, F., Hoang-Xuan, K. 2007; 19 (6): 606-11

  Abstract

  This review summarizes recent studies on applications of molecular markers such as chromosome 1p/19q codeletion and MGMT status in the treatment of glioma.Prospective trials confirmed that 1p/19q codeletion represents a strong and independent favourable prognostic factor in anaplastic oligodendroglial tumours. Other retrospective studies have suggested that 1p/19q loss is also predictive of chemosensitivity to alkylating agents (nitrosoureas and temozolomide) in low-grade gliomas. Recent reports have provided evidence that 1p and 19q deletions are mediated by unbalanced translocation. The targeted genes remain to be identified, however. Promoter methylation of MGMT gene silencing has been shown to predict benefit from chemotherapy in glioblastoma. MGMT promoter methylation and low expression of MGMT-encoded protein are frequently observed in low-grade gliomas and anaplastic oligodendroglial tumours. In such tumours, however, preliminary studies have yielded contradictory results on the predictive value of MGMT status regarding objective response to chemotherapy and correlation with 1p/19q deletion.There is mounting evidence that 1p/19q deletion and MGMT inactivation are relevant prognostic markers and predictors of chemosensitivity in gliomas. Although such markers remain to be formally validated by ongoing and planned prospective trials, it is likely that they will soon become essential for optimizing treatment decisions.

  View details for DOI 10.1097/CCO.0b013e3282f075f3

  View details for PubMedID 17906460

• Temozolomide and methotrexate for primary central nervous system lymphoma in the elderly. Journal of neuro-oncology Omuro, A. M., Taillandier, L., Chinot, O., Carnin, C., Barrie, M., Hoang-Xuan, K. 2007; 85 (2): 207-11

  Abstract

  Treatment for primary CNS lymphoma (PCNSL) in the elderly is associated with lower response rates and higher risks of acute and late delayed toxicity as compared to younger patients. Temozolomide has emerged as a new alternative treatment for PCNSL and constitutes an attractive option for the elderly because of its favorable toxicity profile. In this study we report outcomes of a consecutive series of PCNSL elderly patients initially treated with an innovative regimen combining methotrexate and temozolomide without radiotherapy or intra-thecal chemotherapy.Histologically confirmed newly-diagnosed PCNSL patients older than 60 years were included. An induction chemotherapy was initially given (methotrexate 3 g /m(2) on days 1, 10, and 20, and temozolomide 100 mg/m(2) on days 1-5). Patients achieving a partial or complete response proceeded to a maintenance phase (up to 5 monthly cycles of methotrexate 3 g/m(2) on day 1, and temozolomide 100 mg/m(2 )days 1-5). Non-responders were treated on an individual basis.Among the 23 included patients, a complete response was observed in 55%, and disease progressed in the other 45%. Median event-free survival was 8 months, and median overall survival was 35 months. Grades 3 or 4 toxicities included nephrotoxicity in three patients, and hematotoxicity in five; no neurotoxicity has been observed to date. One patient died while on treatment from complications of intestinal obstruction.Our efficacy results are comparable to other reported regimens, with the advantages of a favorable toxicity profile, and absence of intra-thecal chemotherapy. Prospective, controlled studies are warranted to confirm such results.

  View details for DOI 10.1007/s11060-007-9397-0

  View details for PubMedID 17896079

• Primary intraocular lymphoma: an International Primary Central Nervous System Lymphoma Collaborative Group Report. Annals of oncology : official journal of the European Society for Medical Oncology Grimm, S. A., Pulido, J. S., Jahnke, K., Schiff, D., Hall, A. J., Shenkier, T. N., Siegal, T., Doolittle, N. D., Batchelor, T., Herrlinger, U., Neuwelt, E. A., Laperriere, N., Chamberlain, M. C., Blay, J. Y., Ferreri, A. J., Omuro, A. M., Thiel, E., Abrey, L. E. 2007; 18 (11): 1851-5

  Abstract

  Primary intraocular lymphoma (PIOL) is an uncommon subset of primary central nervous system lymphoma. Because it is rare and difficult to diagnose, the natural history and optimal management are unknown.A retrospective study of 83 HIV negative, immunocompetent PIOL patients was assembled from 16 centers in seven countries.Median age at diagnosis was 65. Median ECOG performance status was 0. Presenting symptoms included blurred vision, decreased visual acuity, and floaters. Median time to diagnosis was 6 months. Diagnosis was made by vitrectomy (74), choroidal/retinal biopsy (6) and ophthalmic exam (3). Eleven percent had positive CSF cytology. Initial treatment was categorized as focal in 23 (intra-ocular methotrexate, ocular radiotherapy) or extensive in 53 (systemic chemotherapy, whole brain radiotherapy). Six received none; details are unknown in one. Forty-seven relapsed: brain 47%, eyes 30%, brain and eyes 15%, and systemic 8%. Median time to relapse was 19 months. Focal therapy alone did not increase risk of brain relapse. Median progression free (PFS) and overall survival (OS) were 29.6 and 58 months, respectively, and unaffected by treatment type.Treatment type did not affect relapse pattern, median PFS or OS. Focal therapy may minimize treatment toxicity without compromising disease control.

  View details for DOI 10.1093/annonc/mdm340

  View details for PubMedID 17804469

• Lessons learned in the development of targeted therapy for malignant gliomas. Molecular cancer therapeutics Omuro, A. M., Faivre, S., Raymond, E. 2007; 6 (7): 1909-19

  Abstract

  The prognosis of patients with glioblastoma, anaplastic astrocytoma, and anaplastic oligodendroglioma remains poor despite standard treatment with radiotherapy and temozolomide. Molecular targeted therapy holds the promise of providing new, more effective treatment options with minimal toxicity. However, the development of targeted therapy for gliomas has been particularly challenging. The oncogenetic process in such tumors is driven by several signaling pathways that are differentially activated or silenced with both parallel and converging complex interactions. Therefore, it has been difficult to identify prevalent targets that act as key promoters of oncogenesis and that can be successfully addressed by novel agents. Several drugs have been tested, including epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (gefitinib and erlotinib), mammalian target of rapamycin (mTOR) inhibitors (temsirolimus and everolimus), and vascular endothelial growth factor receptor (VEGFR), protein kinase C-beta, and other angiogenesis pathways inhibitors (vatalanib, bevacizumab, and enzastaurin). Although preliminary efficacy results of most trials in recurrent disease have fallen short on expectations, substantial advances have been achieved by associated translational research. In this article, we seek to recapitulate the lessons learned in the development of targeted therapy for gliomas, including challenges and pitfalls in the interpretation of preclinical data, specific issues in glioma trial design, insights provided by translational research, changes in paradigms, and future perspectives.

  View details for DOI 10.1158/1535-7163.MCT-07-0047

  View details for PubMedID 17620423

• Temozolomide for low-grade gliomas: predictive impact of 1p/19q loss on response and outcome. Neurology Kaloshi, G., Benouaich-Amiel, A., Diakite, F., Taillibert, S., Lejeune, J., Laigle-Donadey, F., Renard, M. A., Iraqi, W., Idbaih, A., Paris, S., Capelle, L., Duffau, H., Cornu, P., Simon, J. M., Mokhtari, K., Polivka, M., Omuro, A., Carpentier, A., Sanson, M., Delattre, J. Y., Hoang-Xuan, K. 2007; 68 (21): 1831-6

  Abstract

  To evaluate the predictive impact of chromosome 1p/19q deletions on the response and outcome of progressive low-grade gliomas (LGG) treated with up-front temozolomide (TMZ) chemotherapy.Adult patients with measurable, progressive LGG (WHO grade II) treated with TMZ delivered at the conventional schedule (200 mg/m(2)/day for 5 consecutive days, repeated every 28 days) were retrospectively evaluated for response by central review of MRI-s. Chromosome 1p and 19q deletions were detected by the loss of the heterozygosity technique (LOH).A total of 149 consecutive patients were included in this retrospective, single center observational study. The median number of TMZ cycles delivered was 14 (range 2 to 30). Seventy-seven patients (53%) experienced an objective response (including 22 [15%] cases of partial response and 55 [38%] cases of minor response), 55 (37%) patients had stable disease, and 14 (10%) had a progressive disease. The median time to maximum tumor response was 12 months (range 3 to 30 months). The median progression-free survival (PFS) was 28 months (95% CI: 23.4 to 32.6). Material for genotyping was available for 86 patients. Combined 1p/19q LOH was present in 42% of the cases and was significantly associated with a higher rate (p = 0.02) and longer objective response to chemotherapy (p = 0.017), and both longer PFS (p = 4.10(-5)) and overall survival (p = 0.04).Low-grade gliomas respond to temozolomide and loss of chromosome 1p/19q predicts both a durable chemosensitivity and a favorable outcome.

  View details for DOI 10.1212/01.wnl.0000262034.26310.a2

  View details for PubMedID 17515545

• Dynamic history of low-grade gliomas before and after temozolomide treatment. Annals of neurology Ricard, D., Kaloshi, G., Amiel-Benouaich, A., Lejeune, J., Marie, Y., Mandonnet, E., Kujas, M., Mokhtari, K., Taillibert, S., Laigle-Donadey, F., Carpentier, A. F., Omuro, A., Capelle, L., Duffau, H., Cornu, P., Guillevin, R., Sanson, M., Hoang-Xuan, K., Delattre, J. Y. 2007; 61 (5): 484-90

  Abstract

  To evaluate the natural progression and the impact of temozolomide in low-grade gliomas and to correlate these changes with the profile of genetic alterations.The mean tumor diameter (MTD) of low-grade gliomas was evaluated on serial magnetic resonance images before (n = 39), during, and after (n = 107) treatment with neoadjuvant temozolomide. MTD growth curves were correlated with chromosomes 1p-19q loss and p53 overexpression in the tumors.Before temozolomide onset, MTD increased linearly over time, indicating a continuous growth that was significantly slower in 1p-19q deleted tumors (3.4 vs 5.9mm/year; p = 0.0016) and in tumors that did not overexpress p53 (4.2 vs 6.3mm/year; p = 0.05). During temozolomide treatment, almost all patients (92%) experienced initial decrease of MTD. Subsequently, some tumors started to resume growth despite continuous administration of temozolomide, with a lower rate of relapse in 1p-19q deleted tumors (16.6 vs 58%; p = 0.0004) and in tumors that did not overexpress p53 (26 vs 68%; p = 0.003). When temozolomide was discontinued in the absence of tumor progression, a majority of tumors resumed their progressive growth within a year.Untreated low-grade gliomas grow continuously at a rate that is influenced by the genetic alterations of the tumors. Temozolomide reverses this pattern at the onset, but this effect is often brief in patients whose tumors overexpress p53 and do not harbor the 1p-19q codeletion, suggesting acquired chemoresistance. A majority of tumors will resume their growth when treatment is discontinued, raising the issue of the optimal duration of treatment in continuously responding patients.

  View details for DOI 10.1002/ana.21125

  View details for PubMedID 17469128

• What is new in the treatment of gliomas? A, O., JYD, D. Curr Opin Neurol. 2007
• Is there a role for temozolomide in the treatment of primary central nervous system lymphoma? A, O. Nat Clin Prac Oncol. 2007
• Pitfalls in the diagnosis of brain tumours. The Lancet. Neurology Omuro, A. M., Leite, C. C., Mokhtari, K., Delattre, J. Y. 2006; 5 (11): 937-48

  Abstract

  Establishing the diagnosis of a brain tumour is not always a straightforward process. Many non-neoplastic neurological diseases can mimic brain neoplasms on neuroimaging or on histological examination, including multiple sclerosis, stroke, pyogenic abscess, toxoplasmosis, tuberculosis, cysticercosis, fungal infections, syphilis, sarcoidosis, Behçet disease, radiation necrosis, venous thrombosis, and others. Conversely, several types of brain neoplasms, such as glioblastomas, low-grade gliomas, CNS lymphomas, and brain metastases, can present in the absence of typical tumefactive lesions, posing significant diagnostic challenges. In this Review, we discuss the process of accurately establishing the diagnosis of brain tumours, focusing on pitfalls commonly encountered in clinical practice. We also discuss the rational use and limitations of new diagnostic techniques, such as diffusion-weighted MRI, perfusion-weighted MRI, magnetic resonance spectroscopy, single-photon emission tomography, and positron emission tomography, as well as new tools for histological examination, such as immunohistochemistry and molecular genetics analysis.

  View details for DOI 10.1016/S1474-4422(06)70597-X

  View details for PubMedID 17052661

• Vinorelbine combined with a protracted course of temozolomide for recurrent brain metastases: a phase I trial. Journal of neuro-oncology Omuro, A. M., Raizer, J. J., Demopoulos, A., Malkin, M. G., Abrey, L. E. 2006; 78 (3): 277-80

  Abstract

  Temozolomide (TMZ) has shown modest efficacy in the treatment of recurrent brain metastasis (BM). We designed a new regimen utilizing dose-intensified, protracted course of TMZ in combination with vinorelbine, a lipophilic large-spectrum agent, in an attempt to improve the efficacy of TMZ. This phase I study was conducted to establish the maximum tolerated dose (MTD) of vinorelbine for this combination. Patients with recurrent or progressive BM were eligible. Chemotherapy consisted of 28-day cycles with TMZ (150 mg/m2, days 1-7 and 15-21) and vinorelbine (days one and eight at escalating doses). The starting dose was 15 mg/m2, with increments of 5 mg/m2 for each cohort of 3-6 patients, until MTD was reached (30 mg/m2). A total of 21 patients were enrolled; the median age was 59 (41-77). The primary tumor was lung cancer in 13 patients (NSCLC in 10, SCLC in 3), breast in 6, renal in 1 and endometrial in 1. Vinorelbine dose was 15 mg/m2 in seven patients, 20 mg/m2 in five, 25 mg/m2 in four and 30 mg/m2 in six. Grades 3 and 4 neutropenia developed in six patients, lymphopenia in nine, and thrombocytopenia in six; other toxicities were rare. No dose-limiting toxicity was seen. Out of 18 evaluable patients 2 had a radiographic response (one partial and one minor). Disease was stable in 6 of 18 patients and the median survival was 27 weeks. This regimen was well tolerated and a phase II trial using a dose of 30 mg/m2 of vinorelbine is warranted.

  View details for DOI 10.1007/s11060-005-9095-8

  View details for PubMedID 16614943

• Hypersexuality following bilateral thalamic infarction: case report. Arquivos de neuro-psiquiatria Mutarelli, E. G., Omuro, A. M., Adoni, T. 2006; 64 (1): 146-8

  Abstract

  Hypersexuality is a rare but well recognized condition following brain injury. It has been described secondarily to dysfunction in the hypothalamus, the temporal and frontal lobes. We report a 63 year-old man that developed neuropsychological disturbances with hypersexuality as a prominent feature, disinhibition and moderate memory loss, hypersomnia and irritability after a bilateral paramedian thalamic infarction. A SPECT showed frontal hypoperfusion. We believe that these findings are expression of frontal-subcortical circuits dysfunction, particularly the orbitofrontal circuit, secondary to dorso medial thalamic infarction which probably plays a role in the determination of human sexual behavior. This case favors a thalamic modulation of frontal function.

  View details for DOI 10.1590/s0004-282x2006000100032

  View details for PubMedID 16622574

• Current Trends in the Treatment for Brain Metastasis. European Pharmacotherapy. Touch Briefings Series A, O. Touch Briefings . 2006
• Chemotherapy for primary Central Nervous System lymphoma A, O., LE, A. Neurosurg Focus . 2006
• Salvage temozolomide for prior temozolomide responders. Cancer Franceschi, E., Omuro, A. M., Lassman, A. B., Demopoulos, A., Nolan, C., Abrey, L. E. 2005; 104 (11): 2473-6

  Abstract

  Temozolomide (TMZ) often is used as adjuvant or first-line therapy for patients with glioma. Because of potential hematologic complications, it usually is discontinued after 12-18 cycles, even in responders. Subsequent salvage therapies are reported to have limited efficacy at the time of disease recurrence. In the current study, the authors assessed the outcome and complications of reusing TMZ at the time of disease recurrence in patients who previously responded to treatment.A retrospective review of patients with recurrent/progressive glioma who had a history of response to TMZ and were treated with the same agent at the time of disease recurrence was conducted.Fourteen patients were identified (8 men and 6 women). The median age of the patients was 56 years (range, 25-67 yrs) at the time of diagnosis; 9 patients had glioblastoma, 3 had anaplastic astrocytoma, and 2 patients had low-grade oligodendroglioma. No patient developed disease progression while receiving the initial TMZ treatment. At the time of the initial disease recurrence, 13 patients were readministered TMZ. One patient received TMZ at the time of second disease recurrence. All patients were assessed for radiographic response. Objective response or stable disease was achieved in 6 patients (43%; 95% confidence interval [95% CI], 21-67%) and the 6-month progression-free survival was 36% (95% CI, 16-61%).TMZ was found to be well tolerated and effective in this setting, suggesting that repeat use of TMZ in previous responders warrants further investigation.

  View details for DOI 10.1002/cncr.21564

  View details for PubMedID 16270316

• Delayed neurotoxicity in primary central nervous system lymphoma. Archives of neurology Omuro, A. M., Ben-Porat, L. S., Panageas, K. S., Kim, A. K., Correa, D. D., Yahalom, J., Deangelis, L. M., Abrey, L. E. 2005; 62 (10): 1595-600

  Abstract

  Treatment for primary central nervous lymphoma (PCNSL) with chemotherapy and radiotherapy has resulted in improved survival, but some patients develop neurologic deterioration that represents a treatment-related toxic effect. This delayed neurotoxicity has been poorly defined in the literature, and the underlying mechanisms are unknown.To describe the clinical findings, time course, and pathophysiologic mechanisms associated with neurotoxicity in an attempt to generate hypotheses for future studies that address prevention and treatment of this complication of successful PCNSL therapy.Retrospective review.Department of Neurology, Memorial Sloan-Kettering Cancer Center.One hundred eighty-five patients treated for PCNSL, including 43 who developed neurotoxicity.Potential risk factors, clinical course, and neuropsychological, neuroimaging, and histologic findings.The 5-year cumulative incidence of neurotoxicity was 24%; this incidence increases over time. Neurotoxicity presented as a rapidly progressive subcortical dementia characterized by psychomotor slowing, executive and memory dysfunction, behavioral changes, gait ataxia, and incontinence. Imaging findings revealed diffuse white matter disease and cortical-subcortical atrophy. Available autopsy data showed white matter damage with gliosis, thickening of small vessels, and demyelination. Statistical analyses were performed, accounting for death as a competing risk. Older age (P = .01), mental status changes at diagnosis (P = .04), female sex (P = .05), and radiotherapy (P<.001) predicted neurotoxicity on univariate analysis, but only radiotherapy remained significant in the multivariate setting.These findings suggest that the core pathophysiologic mechanism is the interruption of frontal-subcortical circuits mediated by radiation damage, possibly caused by progressive microvascular alterations, loss of oligodendrocyte progenitors, or oxidative stress.

  View details for DOI 10.1001/archneur.62.10.1595

  View details for PubMedID 16216945

• High incidence of disease recurrence in the brain and leptomeninges in patients with nonsmall cell lung carcinoma after response to gefitinib. Cancer Omuro, A. M., Kris, M. G., Miller, V. A., Franceschi, E., Shah, N., Milton, D. T., Abrey, L. E. 2005; 103 (11): 2344-8

  Abstract

  Gefitinib is an epidermal growth factor receptor tyrosine kinase inhibitor that induces an early and dramatic response in 10% of patients with advanced nonsmall cell lung carcinoma (NSCLC). Long- term outcome and patterns of disease recurrence after response have not been described.The authors evaluated 139 patients with NSCLC treated with gefitinib at Memorial Sloan-Kettering Cancer Center (New York, NY) between 1998 and 2002. They focused on patterns of disease recurrence, risk of brain metastases (BM) and leptomeningeal metastasis (LM), and long-term outcome after initial response to gefitinib.Of the 139 patients treated with gefitinib, 21 (15%) achieved a partial response. The median age of the responders was 64 years (range, 38-87 years), the median Karnofsky performance score was 80 (range, 60-90), and 4 of the patients were men. All responders had adenocarcinoma. The central nervous system (CNS) was the initial site of disease recurrence in 7 (33%) patients (BM in 5 and LM in 2). In 9 (43%) patients, the initial site of disease recurrence was the lung and in 1 it was the liver and bone. Four (57%) of the patients with disease recurrence in the CNS had lung disease under control. BM also developed in 2 patients who had initial disease recurrence in the lungs. The actuarial 5-year incidence of CNS metastases was 60%. The median overall survival periods were 15 months and 23 months for patients with and without CNS metastases, respectively (P = 0.24).The CNS was a frequent site of disease recurrence in patients with NSCLC after an initial response to gefitinib, regardless of disease control in the lungs. Patients should be carefully monitored for neurologic symptoms. Intrinsic resistance of metastatic clones, incomplete CNS penetrance of the drug, and longer survival are possible explanations for this high incidence.

  View details for DOI 10.1002/cncr.21033

  View details for PubMedID 15844174

• Ventriculoperitoneal shunt in patients with leptomeningeal metastasis. Neurology Omuro, A. M., Lallana, E. C., Bilsky, M. H., DeAngelis, L. M. 2005; 64 (9): 1625-7

  Abstract

  The authors reviewed 37 patients with leptomeningeal metastasis (LM) who required a ventriculoperitoneal shunt (VP shunt) for management of intracranial hypertension. Improvement was seen in 27 (77%) patients; subdural hematoma developed in one and shunt malfunction in three. Median overall survival was 2 months (range 2 days to 3.6 years) after VP shunt placement, but there was no procedure-related mortality. The prognosis of LM remained poor, but VP shunt can be an effective palliative tool when required.

  View details for DOI 10.1212/01.WNL.0000160396.69050.DC

  View details for PubMedID 15883329

• EGFR tyrosine kinase domain mutations in human gliomas. Neurology Marie, Y., Carpentier, A. F., Omuro, A. M., Sanson, M., Thillet, J., Hoang-Xuan, K., Delattre, J. Y. 2005; 64 (8): 1444-5

  Abstract

  Gefitinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor effective in patients with lung cancer with mutations in exons 19 and 21 of the EGFR tyrosine kinase domain. In this study, the authors tested the presence of such mutations in 95 gliomas including glioblastomas, anaplastic oligodendrogliomas, and low-grade gliomas. No mutation was found, which suggests that the biology of EGFR in gliomas is different from lung cancer and that this may be a factor in the resistance of glioblastomas to gefitinib.

  View details for DOI 10.1212/01.WNL.0000158654.07080.B0

  View details for PubMedID 15851741

• Chemoradiotherapy for primary CNS lymphoma: an intent-to-treat analysis with complete follow-up. Neurology Omuro, A. M., DeAngelis, L. M., Yahalom, J., Abrey, L. E. 2005; 64 (1): 69-74

  Abstract

  To assess the efficacy and safety of a preradiation chemotherapy regimen in patients with primary CNS lymphoma (PCNSL), with emphasis on long-term outcomes.In this prospective phase II trial, patients with a new diagnosis of PCNSL received two cycles of intrathecal (12 mg) and IV (1 g/m2) methotrexate (MTX), thiotepa (30 mg/m2), and procarbazine (75 mg/m2), prior to whole-brain radiotherapy (RT).Seventeen patients were enrolled (ages 26 to 71, median 53). Median Karnofsky performance scale score was 70. After chemotherapy, 7 patients (41%) had a complete response (CR) and 7 (41%) a partial response (PR). After RT, 13 (76%) patients achieved a CR, 2 (12%) a PR, and 2 (12%) had disease progression. Relapse occurred in 7 (41%) patients; median disease-free survival was 18 months. Fifteen (88%) patients have died: 8 (47%) from PCNSL, 5 (29%) from neurotoxicity, and 2 (12%) from unknown causes. Median overall survival was 32 months. Two patients (12%) are alive and disease free at 12 years follow-up. Nephrotoxicity was a minor complication, but grades 3 and 4 myelosuppression were found in 5 (29%) patients.This regimen resulted in an efficacy and toxicity profile comparable to other combined modality treatments, despite the relatively low dose of methotrexate. It may be a useful option in patients unable to tolerate higher doses. Procarbazine and thiotepa are potential candidates for incorporation into chemotherapy regimens aiming to decrease the incidence of neurotoxicity. First relapse and neurotoxicity within 2 years of diagnosis seem to be critical for predicting long-term outcomes.

  View details for DOI 10.1212/01.WNL.0000148641.98241.5E

  View details for PubMedID 15642906

• Glioblastoma. Website based guideline for the American College of Physicians- Physicians Information and Education Resource (PIER) A, O., LE, A. pier.acponline.org. 2005

  Abstract

  htttp://pier.acponline.org/physicians/diseases/d044/d044.html

• Brain Metastases A, O., LE, A. Curr Neurol Neurosis Rep. 2004
• Mental Status Changes in the Elderly Geriatric Emergencies (in Portuguese- Urgencias em Geriatria) EG, M., A, O. 2001