Bio


Dr. Omuro is a neuro-oncologist and chair of the Department of Neurology & Neurological Sciences. Previously, Dr. Omuro held leadership roles including chief of Neuro-Oncology at Yale Cancer Center and chief of the Neuro-Oncology Division at the University of Miami. He received fellowship training in neuro-oncology from Memorial Sloan Kettering Cancer Center in New York.

As a worldwide leader in neuro-oncology, Dr. Omuro is at the forefront of the latest advances in cancer care. He is passionate about developing new therapies to treat glioblastoma and other types of gliomas (tumors of the brain or spine). He specializes in innovative treatments, including targeted medications, immune-checkpoint inhibitors, and other immunotherapies (treatments that activate or suppress the immune system).
Dr. Omuro is a physician-researcher who has been the principal investigator in multiple clinical trials, and he has been awarded dozens of research grants from organizations all over the globe. His research interests include novel treatments for gliomas and primary central nervous system lymphoma. He has also studied the neurological effects of cancer. Dr. Omuro led the largest international clinical trial ever conducted to explore treatments for glioblastoma.

Dr. Omuro has presented and lectured to colleagues across the nation and around the world, including in South Korea, Brazil, France, Japan, and Switzerland. He has published more than 140 articles in dozens of peer-reviewed journals, such as American Journal of Neuroradiology, Cancer, Neuro-Oncology, and Neuro-Oncology Advances. Dr. Omuro completed his residency in Neurology at the University of Sao Paulo School of Medicine in Brazil, his native country, and worked as a clinician and researcher at Pitie-Salpetriere Hospital, Sorbonne Universities in Paris, France.

He has reviewed articles for more than 30 medical journals, including The New England Journal of Medicine and The Lancet. Dr. Omuro has also published several book chapters, and he cowrote a book entitled Meningiomas: Comprehensive Strategies for Management. In addition, Dr. Omuro has served on the editorial board for many academic journals, including the Journal of Neuro-Oncology and Current Opinion in Neurology.

Dr. Omuro is a fellow of the American Academy of Neurology. He is a member of the American Society of Clinical Oncology, Society for Neuro-Oncology, and American Association for Cancer Research. Dr. Omuro is committed to advancing diversity, equity, and inclusion in health care, and he has served as a mentor for many physicians and researchers.

Clinical Focus


  • Neurology

Academic Appointments


  • Professor, Neurology
  • Member, Bio-X

Professional Education


  • Fellowship: Memorial Sloan Kettering Cancer Center (2004) NY
  • Residency: University of Sao Paulo School of Medicine (2000) Brazil
  • Residency: University of Sao Paulo School of Medicine (1997) Brazil
  • Medical Education: University of Sao Paulo School of Medicine (1994) Brazil

All Publications


  • 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
  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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