Fabio Iwamoto, MD

All Publications

• Immunodeficiency-associated primary CNS lymphomas: an International Primary CNS Lymphoma Collaborative Group study. Blood Kaulen, L. D., Nayak, L., Karschnia, P., Kraai, I., Galluzzo, D., de Groot, F. A., Witterholt, M., Donovan, L., Bhella, S., Kuschel, L. P., Fox, C. P., Seidel, S., Paterson, J., Richter, B., Dixit, K. S., Zeyen, T., Alderuccio, J. P., Montoto, S., Kuittinen, O., Traub, B. L., Doubrovinskaia, S., Rohdjess, H., Müller, K. J., Enting, R., de Bresser, J., Kuitunen, H., Iwamoto, F. M., Alencar, A., Herrlinger, U., Platten, M., Cwynarski, K., Mendez, J., Roth, P., von Baumgarten, L., Prica, A., Bhagat, G., Lurain, K., Schiff, D., Vermaat, J. S., Baehring, J. M., Nijland, M., Dietrich, J., Batchelor, T. T., Wick, W. 2026; 148 (1): 58-70

  Abstract

  Immunodeficiency-associated primary central nervous system lymphoma (ID-PCNSL) represents a clinicopathologically distinct PCNSL subtype, for which large studies and prognostic models are lacking. To address this gap, the International PCNSL Collaborative Group conducted a retrospective multicenter study, integrating clinical, radiological, and pathological data from 308 ID-PCNSL cases, diagnosed at 23 participating sites in 7 countries. Preexisting immunodeficiency included administration of immunosuppressants for transplantation (41.2%) or autoimmunity (36.7%) and HIV infection (21.7%). All tumors were diffuse large B-cell lymphomas, with Epstein-Barr virus (EBV) detected in 79.2%. Immune reconstitution together with rituximab and methotrexate-based chemotherapy was associated with the highest response rates and prolonged progression-free survival, irrespective of immunodeficiency subtype and EBV status. Survival outcomes were highly variable, with a 54-month median overall survival. Multivariable Cox regression identified age (per year increment; hazard ratio [HR], 1.05 (95% confidence interval [CI], 1.02-1.07); P< .001), Karnofsky performance status (KPS) <70 (HR, 3.10; 95% CI, 1.67-5.87; P< .001), and EBV positivity (HR, 3.26; 95% CI, 1.47-7.33; P = .004) as prognostic factors for overall survival. A prognostic score was developed based on the sum of these adverse variables (age >60 years, KPS <70, EBV positivity). Stratification by this score yielded median survival times of 135, 29, and 3 months in patients with up to 1, 2, and 3 unfavorable markers (P< .0001). It allowed improved prognostic stratification of ID-PCNSL as compared with the Memorial Sloan Kettering Cancer Center and International Extranodal Lymphoma Study Group models developed for immunocompetent PCNSL. Collectively, this large international cohort defines clinicobiological features of ID-PCNSL and introduces a prognostic system with potential to guide future management.

  View details for DOI 10.1182/blood.2025031869

  View details for PubMedID 41843467

• Clinical Utility of [18F]-Fluciclovine PET/MRI for Differentiating True Progression from Treatment-Related Changes in Patients with Glioblastoma. AJNR. American journal of neuroradiology Ivanidze, J., Vu, K. V., Fu, R., Brandmaier, A., Szidonya, L., Choudhary, G., Starkey, J., Wang, T. J., Sisti, M., McKhann, L. G., Puri, S., Konner, M., Roytman, M., Lin, E., Kuhn, A., Osborne, J. R., Stieg, P. E., Beal, K., Ramakrishna, R. R., Singh, G., Lignelli-Dipple, A., Doubrovin, M., Vo, A. H., Welch, M., Iwamoto, F., Haggiagi, A., Donovan, L., Ordonez, M. D., Gill, B., Liechty, B., Pisapia, D. J., Walker, J., Magge, R. S., Wood, M., Corzo, V. M., Sanusi, O. R., Raslan, A., Dogan, A., Bowden, S., Nehmeh, S. A., Nickerson, J., Mallak, N., Ruiz, A., Ambady, P., Nabavizadeh, A., Barajas, R. F. 2026; 47 (6): 1578-1586

  Abstract

  Differentiating true progression from treatment-related changes in patients with glioblastoma (GBM) remains a major diagnostic challenge. Amino acid PET tracers such as [18F]-fluciclovine provide biologically specific information, but clinical real-world validation across institutions is limited. We aimed to evaluate the clinical diagnostic performance of [18F]-fluciclovine PET/MRI for distinguishing true progression from treatment-related change in patients with presumed GBM progression across 2 academic centers.In this retrospective, multi-institutional, institutional review board-approved study, we analyzed [18F]-fluciclovine PET/MRI scans performed in patients with presumed GBM progression. All PET/MRI examinations were clinically indicated and performed as part of routine standard-of-care imaging. Clinical classification was based on histopathology or imaging and clinical follow-up. Maximum standardized uptake value (SUVmax) was measured in enhancing lesions. Group comparisons were assessed with Mann-Whitney U tests. Diagnostic performance was evaluated using receiver operating characteristic (ROC) analysis, including derivation of an optimal cutoff using Youden index and validation of the previously published diagnostic threshold of 4.66. Subgroup analyses compared diagnostic performance across institutions.Thirty-six patients with presumed GBM progression (Institution 1, n=17; Institution 2, n=19) provided 22 examinations classified as true tumor progression and 14 as treatment-related change. There were no significant differences in clinical or demographic study population characteristics between the 2 institutions. SUVmax was significantly higher in true tumor progression than in treatment-related change (median [interquartile range], 8.73 [5.86-10.83] versus 3.71 [1.70-4.67]; P < .01). Combined ROC analysis demonstrated excellent diagnostic performance (area under the curve [AUC] = 0.90; 95% CI, 0.79-0.98). The optimal threshold of 5.7 yielded 86% sensitivity (0.70-0.99) and 86% specificity (0.64-0.99). Applying the published threshold of 4.66 produced similar results (AUC = 0.90), with 91% sensitivity (0.71-0.99) and 71% specificity (0.42-0.92). A stratified analysis demonstrated comparable diagnostic performance across both institutions.[18F]-Fluciclovine PET/MRI demonstrated high diagnostic accuracy for differentiating true GBM progression from treatment-related changes, with consistent SUVmax thresholds across 2 institutions. These findings support the generalizability of [18F]-fluciclovine PET as a biologically specific adjunct to conventional MR imaging for patients with presumed GBM progression.

  View details for DOI 10.3174/ajnr.A9120

  View details for PubMedID 41326230

  View details for PubMedCentralID PMC13020911

• Evaluation of Regorafenib in Newly Diagnosed and Recurrent Glioblastoma: GBM AGILE Phase II/III Bayesian Randomized Platform Trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Wen, P. Y., Berry, D. A., Buxton, M. B., Colman, H., de Groot, J., Lim, M., Mellinghoff, I., Perry, J. R., Weller, M., Blondin, N. A., Butt, O. H., Damek, D. M., de la Fuente, M. I., Drappatz, J., Dunbar, E., Giglio, P., Hyddmark, E. V., Iwamoto, F., Jaeckle, K. A., Kim, L., Kling, H. M., Lee, E. Q., Mantica, M., Mikkelsen, T., Nabors, B., Newton, H. B., Olson, J. J., Schiff, D., Walbert, T., Weathers, S. P., Cloughesy, T., Lassman, A. B. 2026: JCO2501137

  Abstract

  GBM AGILE (ClinicalTrials.gov identifier: NCT03970447) is a phase II/III Bayesian adaptive platform registration trial testing multiple arms against a common control; the primary end point is overall survival (OS). Regorafenib, a multikinase inhibitor, showed OS benefit in recurrent (RD) glioblastoma in the phase II REGOMA trial and entered GBM AGILE as the first investigational arm.Patient subtypes included in the regorafenib arm of GBM AGILE were newly diagnosed unmethylated (NDU) and RD glioblastoma. Prospective defined sets of subtypes, or arm signatures, were NDU, RD, and all (NDU + RD). As the first investigational arm in GBM AGILE, regorafenib was equally randomized to the control arm. Treatment in the control arm is temozolomide + radiotherapy (in newly diagnosed) or lomustine (in RD). Efficacy was assessed by OS hazard ratio (HR), arm/control, and demonstrated when the Bayesian probability of benefit (HR <1.00) was ≥98%. Analysis was performed monthly for limited efficacy, which occurs when the Bayesian predictive power is <25% for all signatures, and determines stopping enrollment. Follow-up continued for 12 months after accrual stopped.When the predictive power was <25% in all predefined signatures for regorafenib, accrual stopped for limited efficacy. The final analysis did not demonstrate OS improvement in the regorafenib arm in RD nor NDU glioblastoma. Median HRs were 1.05 (NDU), 1.07 (RD), and 1.07 (all) with final probabilities of benefit (HR <1.00) of 0.421 (NDU), 0.312 (RD), and 0.296 (all). Regorafenib was associated with increased toxicity relative to control.GBM AGILE did not show superiority of regorafenib over control in RD (lomustine) or NDU (temozolomide + radiotherapy) glioblastoma, yet caused increased toxicities. Regorafenib has been removed from National Comprehensive Cancer Network guidelines as a treatment option for RD.

  View details for DOI 10.1200/JCO-25-01137

  View details for PubMedID 41980234

• [68Ga]-DOTATATE PET SUV Reduction After Bevacizumab in High-Grade Meningioma: A Potential Treatment Response Biomarker. AJNR. American journal of neuroradiology Vu, K. V., Otis, H. G., Brandmaier, A., Osborne, J. R., Stieg, P. E., Ramakrishna, R. R., Haghdel, A., Kim, S. H., Liechty, B., Rosen, K., Beal, K., Pannullo, S. C., Knisely, J. P., Magge, R. S., Welch, M., Iwamoto, F., Pan, P. C., Ivanidze, J. 2026

  Abstract

  Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor A, is emerging as a promising therapy for high-grade meningioma, an aggressive central nervous system tumor with limited systemic treatment options. While clinical stabilization has been observed in prior trials, radiographic response on conventional MRI is often minimal, highlighting the need for alternative imaging biomarkers to monitor treatment effect. [68Ga]-DOTATATE is a somatostatin analog that binds with high affinity to somatostatin receptor 2, which is overexpressed in meningiomas. In this case series, we present three patients with WHO grade 3 meningioma who underwent baseline and follow-up [68Ga]-DOTATATE PET imaging in the setting of bevacizumab therapy. All patients had biopsy-confirmed high-grade disease and demonstrated multifocal [68Ga]-DOTATATE-avid lesions at baseline. Across 12 lesions, 67% showed a reduction in SUVmax following therapy. In contrast, matched control patients who underwent serial [68Ga]-DOTATATE PET imaging without bevacizumab or other systemic therapy demonstrated no significant change in SUVmax Linear mixed-effects modeling confirmed a significant treatment effect, with a 7.2-unit greater reduction in SUVmax in the bevacizumab-treated group than in controls (p = 0.01). Our findings raise the possibility that [68Ga]-DOTATATE PET may capture early biologic responses to antiangiogenic therapy not reflected by anatomic imaging alone, potentially reflecting changes in somatostatin receptor expression, tumor perfusion, or metabolic activity. This series suggests that [68Ga]-DOTATATE PET may serve as a noninvasive, biologically informative adjunct to conventional imaging and supports further investigation of its role as a molecular imaging biomarker of bevacizumab response in high-grade meningioma.

  View details for DOI 10.3174/ajnr.A9260

  View details for PubMedID 41730635

• Phase I study of ABM-1310 as monotherapy and in combination with cobimetinib for BRAF-mutated advanced solid tumors: safety, efficacy, and dose expansion. ESMO open Piha-Paul, S. A., De La Fuente, M., Iwamoto, F., Zhu, J. J., Nagpal, S., Braiteh, F., Chandra, S., Fu, Y., Chen, C., Yang, Z., Tsai, K. K. 2026; 11 (2): 106047

  Abstract

  ABM-1310 is an investigational, orally bioavailable BRAF V600 inhibitor with high blood-brain barrier (BBB) penetration.This first-in-human, phase I trial evaluated patients with BRAF V600-mutated advanced solid tumors, including brain metastases (≤3 cm) and primary central nervous system (CNS) tumors. Patients received ABM-1310 monotherapy [25-250 mg twice a day (b.i.d.); Parts A/C] or in combination (ABM-1310 : 100-200 mg b.i.d.; cobimetinib 60 mg once a day, days 1-21 of each 28-day cycle; Part B). Primary endpoints included safety, tolerability, and maximum tolerated dose (MTD); secondary endpoints included pharmacokinetic (PK) profile and antitumor activity per RECIST v1.1 or Response Assessment in Neuro-Oncology criteria.Fifty-three patients were enrolled (36 monotherapy, 17 combination). Median age was 55 years; 68% were male, 72% had ≥3 prior treatment lines, 92.5% had BRAF V600E mutations, 75% of patients had received prior BRAF plus MEK inhibitor therapy, and 7.5% had BRAF inhibitor monotherapy. Common tumor types included melanoma (47%), glioblastoma (17%) and thyroid cancer (13%). The most frequent treatment-related adverse events were QT prolongation and rash. Dose-limiting toxicities (DLTs) occurred in 6/37 patients (16.2%), all at doses ≥150 mg. All DLTs involved asymptomatic electrocardiogram QT prolonged, with two cases presenting co-occurring toxicities: one with rash and one with renal failure-establishing the MTD at 200 mg b.i.d. Among 50 efficacy-evaluable patients, the objective response rate (ORR) was 12% and disease control rate (DCR) was 64%. Median progression-free survival was 4.96 months (2.07-8.31) and median overall survival was 24.48 months 11.6-not estimable. In patients with primary CNS tumors (n = 13), ORR was 23.1% and DCR 76.9%. PK analyses showed dose-proportional exposure and moderate accumulation.ABM-1310 showed a favorable safety profile and encouraging intracranial activity. These findings support continued evaluation for CNS tumors and in cancer patients with prior BRAF inhibitor exposure.

  View details for DOI 10.1016/j.esmoop.2025.106047

  View details for PubMedID 41604813

  View details for PubMedCentralID PMC12865634

• Multicenter Randomized Phase II Study of R-MPV-A Chemoimmunotherapy With or Without Low-Dose Whole-Brain Radiotherapy for Newly-Diagnosed Primary CNS Lymphoma. Neuro-oncology Omuro, A., DeAngelis, L. M., Polley, M. C., Correa, D., Wefel, J. S., Bovi, J. A., Rosenblum, M., Corn, B. W., Aneja, S., Grommes, C., Peereboom, D. M., Lallana, E. C., Werner-Wasik, M., Rogers, C. L., Iwamoto, F. M., Yu, H. M., Donnelly, E. D., Struve, T. D., Won, M., Mehta, M. P. 2025

  Abstract

  Methotrexate-based chemoradiotherapy is effective in primary central nervous system lymphoma (PCNSL) but carries a risk of severe neurotoxicity. In a single-arm study, a regimen with methotrexate, procarbazine, vincristine and cytarabine was combined with rituximab (R-MPV-A) and substantially reduced doses of whole-brain radiotherapy (LD-WBRT), resulting in excellent progression-free survival (PFS) and overall survival (OS). Because R-MPV-A had never been tested without radiation, we sought to evaluate the efficacy of R-MPV-A with and without LD-WBRT, as well as determining if such low radiotherapy doses influenced disease control and/or neurotoxicity.Patients were randomized to receive R-MPV-A alone (Chemo arm) or combined with LD-WBRT (ChemoRT arm), given at 2,340 cGy (180cGy X13). Primary endpoint was intent-to-treat (ITT) PFS. A sample size of 89 would provide 80% power to detect a hazard ratio (HR) of 0.63 (one-sided alpha = 0.15).Ninety-one patients were randomized, with 44 analyzed in the ChemoRT and 46 in the Chemo arm. Median age was 66 and 59.5, respectively. R-MPV-A was well tolerated, achieving complete response rate of 92.3% (ChemoRT) and 76.3% (Chemo). After median follow-up of 4.6 years, median PFS was not reached (ChemoRT) vs 2.1 years (Chemo), HR = 0.47 (p = 0.007; 95% CI: 0.26 to 0.87). The 2-year PFS was 78.7% vs 54%, respectively. Differences in OS did not reach statistical significance (HR 0.71; p = 0.33). Neuropsychological evaluation showed no differences in cognitive outcomes, with several tests favoring ChemoRT.R-MPV-A is a highly efficacious and safe regimen with or without LD-WBRT. LD-WBRT contributes to disease control and increases PFS in PCNSL.

  View details for DOI 10.1093/neuonc/noaf221

  View details for PubMedID 41189315

• TIRABRUTINIB FOR THE TREATMENT OF RELAPSED OR REFRACTORY PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA: EFFICACY AND SAFETY FROM THE PHASE II PROSPECT STUDY Nayak, L., Grommes, C., Kallam, A., Peereboom, D., Ambady, P., Mendez, J., Aregawi, D., Sumrall, A., Omuro, A., Iwamoto, F., Dietrich, J., Umemura, Y., Munker, R., Chukwueke, U., Schaff, L., Prados, S., Takazawa, A., Aoi, A., Batchelor, T. OXFORD UNIV PRESS INC. 2025: v135

  View details for DOI 10.1093/neuonc/noaf201.0535

  View details for Web of Science ID 001612037600007

• Post-Chemoradiation Lymphopenia and Baseline Eosinophil Counts as Prognostic Markers in Glioblastoma. Research square Giannaris, E., Sedor, G., Spina, C. S., Hsieh, K., Elliston, C., Cheng, S. K., Iwamoto, F. M., McKhann, G. M., Sisti, M. B., Bruce, J. N., Wang, T. J., Gallitto, M. 2025

  Abstract

  To evaluate whether post-treatment lymphopenia and white-cell differentials predict overall survival (OS) in glioblastoma (GBM).We retrospectively analyzed 93 GBM patients treated with standard surgery, radiotherapy (60 Gy in 30 fractions), and temozolomide. Clinical data (age, Karnofsky performance status, extent of resection, MGMT methylation, corticosteroid use, dose metrics) and hematologic indices (absolute lymphocyte count (ALC), neutrophil-to-lymphocyte ratio (NLR), absolute eosinophil (AEC) and basophil counts, etc.) were collected at baseline and up to 3 months post-chemoradiation.Median OS in our cohort was 24.7 months (95% CI, 20.8-35.0). On univariate analysis, ALC < 0.75 ×103/μL at 3 months was associated with shorter OS (HR 1.88; p = 0.042), and higher AEC correlated with improved OS at baseline (HR 0.71; p = 0.022) and at 1-2 months (HR 0.44 and 0.57; p = 0.046 and 0.016). In the combined multivariable model-controlling for age, extent of resection, MGMT status, steroid usage and dose metrics-baseline AEC remained independently prognostic (aHR 0.57; p = 0.016), whereas the association for 3-month ALC < 0.75 ×103/μL attenuated (aHR 1.27; p = 0.49).Baseline eosinophils were independently associated with improved survival, while post-treatment lymphopenia was adverse only on univariate analysis. Such findings highlight the importance of host immunity and baseline eosinophils as a potential prognostic marker of OS in GBM and warrant larger, prospective studies on lymphocyte-sparing treatment strategies and prognostic marker validation.

  View details for DOI 10.21203/rs.3.rs-7715242/v1

  View details for PubMedID 41282244

  View details for PubMedCentralID PMC12632714

• Dual Immune Check Point Blockade in MGMT-Unmethylated Newly Diagnosed Glioblastoma: NRG Oncology BN007, a Randomized Phase II/III Clinical Trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Lassman, A. B., Polley, M. C., Iwamoto, F. M., Sloan, A. E., Wang, T. J., Aldape, K. D., Wefel, J. S., Gondi, V., Gutierrez, A. N., Manasawala, M. H., Gilbert, M. R., Sulman, E. P., Wolchok, J. D., Green, R. M., Neil, E. C., Lukas, R. V., Goldlust, S. A., Snuderl, M., Galbraith, K., Dignam, J. J., Won, M., Mehta, M. P. 2025; 43 (27): 3032-3040

  Abstract

  New therapies for glioblastoma are needed, especially MGMT-unmethylated (uMGMT) disease. NRG Oncology BN002 (phase I) demonstrated safety and suggested efficacy of ipilimumab (ipi) with nivolumab (nivo) in newly diagnosed glioblastoma, leading to this phase II/III trial.Adults with newly diagnosed uMGMT glioblastoma and Karnofsky performance status (KPS) ≥70 were randomly assigned to radiotherapy with either immunotherapy (ipi and nivo) or temozolomide (TMZ), stratified by recursive partitioning analysis (RPA) class and intention to use tumor treating fields. With 95% power to detect a hazard ratio (HR) ≤0.58 for progression-free survival (PFS) at a one-sided significance level (P) of .15, superior PFS with immunotherapy in phase II would lead to phase III overall survival (OS) testing. Corticosteroids were disallowed when starting immunotherapy. Diagnosis, biomarkers, and PFS were centrally assessed.One hundred fifty-nine participants were randomly assigned (79 immunotherapy and 80 TMZ). Arms were well balanced for age (median 60 years, range, 28-79), sex (male n = 105, 66%), KPS (90-100 n = 97, 61%), resection extent (gross total, n = 103, 65%), and RPA class (III, n = 16, 10%; IV, n = 116, 73%; V, n = 27, 17%). A preplanned analysis of phase II data conducted after 100 centrally determined PFS events showed no significant PFS improvement for ipi and nivo versus TMZ (median 7.7 months v 8.5 months, HR, 1.47 [70% CI, 1.19 to 1.83]; one-sided P = .96 [95% CI, 0.98 to 2.2]). OS is immature (>50% alive) but with no observed difference between arms (median approximately 13 months each, HR, 0.95 [95% CI, 0.61 to 1.49]; P = .36).Ipi and nivo did not improve PFS among patients with newly diagnosed uMGMT glioblastoma versus TMZ. Accrual closed permanently; the trial will not proceed to phase III. No new safety signals were identified. Molecular correlative analyses and survival follow-up are ongoing.

  View details for DOI 10.1200/JCO-25-00618

  View details for PubMedID 40779733

  View details for PubMedCentralID PMC12440284

• Tirabrutinib for the treatment of relapsed or refractory primary central nervous system lymphoma: Efficacy and safety from the phase II PROSPECT study. Nayak, L., Grommes, C., Kallam, A., Peereboom, D. M., Ambady, P., Mendez, J. S., Aregawi, D., Sumrall, A., Omuro, A., Iwamoto, F., Dietrich, J., Umemura, Y., Munker, R., Chukwueke, U., Schaff, L., Prados, S., Takazawa, A., Aoi, A., Batchelor, T. LIPPINCOTT WILLIAMS & WILKINS. 2025

  View details for DOI 10.1200/JCO.2025.43.16_suppl.2019

  View details for Web of Science ID 001509527500001

• Re-Irradiation Plus Pembrolizumab: A Phase II Study for Patients with Recurrent Glioblastoma CLINICAL CANCER RESEARCH Iwamoto, F. M., Tanguturi, S. K., Nayak, L., Wang, T. J., Desai, A., Lustig, R. A., Bagley, S., Wong, E. T., Hertan, L. M., Mccluskey, C., Hayden, J., Muzikansky, A., Nakhawa, S., Japo, J., Bossi, C. C., Meylan, M., Tian, Y., Barlow, G. L., Speliakos, P., Ayoub, G., Meredith, D. M., Ligon, K. L., Haas-Kogan, D., Huang, K., Wucherpfennig, K. W., Wen, P. Y., Reardon, D. A. 2025; 31 (2): 316-327

  Abstract

  Radiotherapy may enhance antitumor immune responses by several mechanisms, including induction of immunogenic cell death. We performed a phase 2 study of pembrolizumab with re-irradiation in patients with recurrent glioblastoma.Sixty patients with recurrent glioblastoma received pembrolizumab with re-irradiation alone (cohort A, bevacizumab-naïve; n = 30) or with bevacizumab continuation (cohort B, n = 30). Dual primary endpoints, including the overall response rate and overall survival (OS) at either 12 (OS-12; cohort A) or 6 months (OS-6; cohort B), were assessed per cohort relative to historic benchmarks. Paired paraffin-embedded formalin-fixed tumor samples were assessed for immunologic biomarkers by IHC using digital quantification and co-detection-by-indexing (CODEX).Study therapy was well tolerated, with most toxicities being grade ≤3. For cohort B, the primary endpoint of OS-6 was achieved (57%); however, survival was not improved for cohort A patients. The overall response rate was 3.3% and 6.7% for cohorts A and B, respectively. CODEX analysis of paired tumor samples from five patients revealed an increase of activated T cells in the tumor microenvironment after study therapy.Compared with historic controls, re-irradiation plus pembrolizumab seemed to improve survival among bevacizumab-refractory patients but not among bevacizumab-naïve patients. CODEX revealed evidence of intratumoral infiltration of activated immune effector cells. A randomized, properly controlled trial of PD-1 blockade plus re-irradiation is warranted to further evaluate this regimen for bevacizumab-refractory patients, but alternative approaches are needed for bevacizumab-naïve patients.

  View details for DOI 10.1158/1078-0432.CCR-24-1629

  View details for Web of Science ID 001447076700014

  View details for PubMedID 39513953

• Phase 1b/2 study of orally administered pexidartinib in combination with radiation therapy and temozolomide in patients with newly diagnosed glioblastoma. Neuro-oncology advances Mendez, J. S., Cohen, A. L., Eckenstein, M., Jensen, R. L., Burt, L. M., Salzman, K. L., Chamberlain, M., Hsu, H. H., Hutchinson, M., Iwamoto, F., Ligon, K. L., Mrugala, M. M., Pelayo, M., Plotkin, S. R., Puduvalli, V. K., Raizer, J., Reardon, D. A., Sterba, M., Walbert, T., West, B. L., Wong, E. T., Zhang, C., Colman, H. 2024; 6 (1): vdae202

  Abstract

  Glioblastoma (GBM) has a median survival of <2 years. Pexidartinib (PLX3397) is a small-molecule inhibitor of CSF1R, KIT, and oncogenic FTL3, which are implicated in GBM treatment resistance. Results from glioma models indicate that combining radiation therapy (RT) and pexidartinib reduces radiation resistance. We added pexidartinib to standard-of-care RT/temozolomide (TMZ) in patients with newly diagnosed GBM to assess the therapeutic benefit of altering the tumor microenvironment with pexidartinib.In this open-label, dose-escalation, multicenter, Phase 1b/2 trial, pexidartinib was administered in combination with RT/TMZ followed by adjuvant pexidartinib + TMZ. During Phase 1b, pexidartinib was given 5 or 7 days/week at multiple dosing levels. The primary Phase 1b endpoint was the recommended Phase 2 dose (RP2D). Phase 2 patients received the RP2D with the primary endpoint of median progression-free survival (mPFS). Secondary objectives were median overall survival (mOS), pharmacokinetics, and safety.The RP2D of pexidartinib was 800 mg/day for 5 days/week during RT/TMZ, followed by 800 mg/day for 7 days/week with adjuvant TMZ. mPFS was 6.7 months (90% CI: 4.5, 11.5) for the modified intention-to-treat population. The actual mOS was 13.1 months (90% CI: 11.5, 24.5), and the mOS corrected for comparison with matched historical controls was 18.8 months (95% CI: 12.6, 28.0).This trial established the RP2D of pexidartinib in combination with RT/TMZ and adjuvant TMZ. Pexidartinib was generally safe and well tolerated. Although the study regimen with pexidartinib was not efficacious, pharmacodynamic studies showed modulation of systemic markers that could lead to alteration of the tumor microenvironment.

  View details for DOI 10.1093/noajnl/vdae202

  View details for PubMedID 39734810

  View details for PubMedCentralID PMC11672110

• TUMOR RESPONSES IN A RANDOMIZED PHASE IIB TRIAL OF A CMV VACCINE IMMUNOTHERAPEUTIC CANDIDATE (VBI-1901) IN RECURRENT GLIOBLASTOMAS Merrell, R., Wen, P., Forst, D., Schulte, J., Odia, Y., Bota, D., Nagpal, S., Bonm, A., Diaz-Mitoma, F., Anderson, D., Lassman, A., Iwamoto, F. OXFORD UNIV PRESS INC. 2024

  View details for DOI 10.1093/neuonc/noae165.0362

  View details for Web of Science ID 001362488100044

• GBM PATIENTS CONTINUE TO FACE BARRIERS TO PERSONALIZED AND COMPREHENSIVE CARE THAT MAY IMPACT LONGEVITY AND QUALITY-OF-LIFE Ostrum, Q. T., Iwamoto, F. M., Nayak, L., Duprey, K., Pilkington, E., Ellen, J., Robles, D. OXFORD UNIV PRESS INC. 2024

  View details for DOI 10.1093/neuonc/noae165.1046

  View details for Web of Science ID 001362534300014

• EARLY SAFETY DATA FROM A RANDOMIZED, MULTICENTER, DOUBLE-BLIND, PHASE 2B STUDY OF IGV-001, AN AUTOLOGOUS CELL IMMUNOTHERAPY, VERSUS PLACEBO, IN NEWLY DIAGNOSED GLIOBLASTOMA (NDGBM) Elder, J., Hanft, S., Lee, I. Y., Farrell, C., Boockvar, J. A., Zacharia, B. E., Kim, L., Schulder, M., Correia, C., Ramakrishna, R., Wong, E. T., Wu, J., Agarwal, V., Amankulor, N., Bhatia, A., Evans, L. T., Brennan, C., Gill, B. J., Sengupta, S., Quinones-Hinojosa, A., Giglio, P., Wu, K., Wu, S. H., Falo, C., Walbert, T., Robin, A., Alnahhas, I., Vojnic, M., Wernicke, A., Aregawi, D., Maurer, R., Ghatan, S., Singer, S., Jeyapalan, S., Magge, R., Malik, A. N., Patel, N., Chan, A., Iwamoto, F., Hormigo, A., Higgins, D., Dey, M., Moss, N. S., Sherman, W., Neese, L., Pennock, G. K., Scott, C., Perez-Olle, R., Andrews, D. W. OXFORD UNIV PRESS INC. 2024

  View details for DOI 10.1093/neuonc/noae165.0347

  View details for Web of Science ID 001362484900022

• GBM PATIENTS FACE TTF ACCESS AND INFORMATION INEQUITY THAT MAY IMPACT PATIENT OUTCOMES AND QUALITY-OF-LIFE Ostrom, Q. T., Iwamoto, F. M., Nayak, L., Duprey, K., Pilkington, E., Ellen, J., Robles, D. OXFORD UNIV PRESS INC. 2024

  View details for DOI 10.1093/neuonc/noae165.0582

  View details for Web of Science ID 001362467400040

• A PHASE II, OPEN LABEL, SINGLE ARM STUDY OF NIVOLUMAB FOR RECURRENT OR PROGRESSIVE IDH MUTANT GLIOMAS WITH PRIOR EXPOSURE TO ALKYLATING AGENTS Yim, E., Donovan, L., Bargo, A., Nayak, L., Odia, Y., Wong, E., Pring, K., Malig, M., Genfi, Y., Wright, N., Kesari, L., Russ, A., Chang, R., Torres, D., Manjrekar, K., Ana, S., Sender, N., Mistretta, S., Iwamoto, F. OXFORD UNIV PRESS INC. 2024

  View details for DOI 10.1093/neuonc/noae165.0340

  View details for Web of Science ID 001362580000032

• The IDH paradox: Meta-analysis of alkylating chemotherapy in IDH-wild type and -mutant lower grade gliomas. Neuro-oncology Kinslow, C. J., Roy, S., Iwamoto, F. M., Brown, P. D., DeStephano, D. M., Canoll, P. D., Qureshi, S. S., Gallito, M., Sisti, M. B., Bruce, J. N., Horowitz, D. P., Kachnic, L. A., Neugut, A. I., Yu, J. B., Mehta, M. P., Cheng, S. K., Wang, T. J. 2024; 26 (10): 1839-1849

  Abstract

  IDH-wild type (-wt) status is a prerequisite for the diagnosis of glioblastoma (GBM); however, IDH-wt gliomas with low-grade or anaplastic morphology have historically been excluded from GBM trials and may represent a distinct prognostic entity. While alkylating agent chemotherapy improves overall survival (OS) and progression-free survival (PFS) for IDH-wt GBM and also IDH-mutant gliomas, irrespective of grade, the benefit for IDH-wt diffuse histologic lower-grade gliomas is unclear.We performed a meta-analysis of randomized clinical trials for World Health Organization (WHO) grades 2-3 gliomas (2009 to present) to determine the effect of alkylating chemotherapy on IDH-wt and -mutant gliomas using a random-effects model with inverse-variance pooling.We identified 6 trials with 1204 patients (430 IDH-wt, 774 IDH-mutant) that evaluated alkylating chemoradiotherapy versus radiotherapy alone, allowing us to perform an analysis focused on the value of adding alkylating chemotherapy to radiotherapy. For patients with IDH-wt tumors, alkylating chemotherapy added to radiotherapy was associated with improved PFS (HR:0.77 [95% CI: 0.62-0.97], P = .03) but not OS (HR:0.87 [95% CI: 0.64-1.18], P = .17). For patients with IDH-mutant tumors, alkylating chemotherapy added to radiotherapy improved both OS (HR:0.52 [95% CI: 0.42-0.64], P < .001) and PFS (HR = 0.47 [95% CI: 0.39-0.57], P < .001) compared to radiotherapy alone. The magnitude of benefit was similar for IDH-mutant gliomas with or without 1p19q-codeletion.Alkylating chemotherapy reduces mortality by 48% and progression by 53% for patients with IDH-mutant gliomas. Optimal management of IDH-wt diffuse histologic lower-grade gliomas remains to be determined, as there is little evidence supporting an OS benefit from alkylating chemotherapy.

  View details for DOI 10.1093/neuonc/noae102

  View details for PubMedID 38943513

  View details for PubMedCentralID PMC11449043

• NRG-BN002: Phase I study of ipilimumab, nivolumab, and the combination in patients with newly diagnosed glioblastoma. Neuro-oncology Sloan, A. E., Winter, K., Gilbert, M. R., Aldape, K., Choi, S., Wen, P. Y., Butowski, N., Iwamoto, F. M., Raval, R. R., Voloschin, A. D., Kamiya-Matsuoka, C., Won, M., Mehta, M. P. 2024; 26 (9): 1628-1637

  Abstract

  Immune checkpoint inhibitors (ICIs) have efficacy in several solid tumors but limited efficacy in glioblastoma (GBM). This study evaluated the safety of anti-CTLA-4 and anti-PD-1 ICIs alone or in combination in newly diagnosed GBM after completion of standard radiochemotherapy with the subsequent intent to test combinatorial ICIs in this setting.The primary endpoint was dose-limiting toxicity (DLT) for adults with unifocal, supratentorial newly diagnosed GBM after resection and chemoradiation. Ipilimumab and nivolumab were tested separately and in combination with a planned expansion cohort dependent upon DLT results.Thirty-two patients were enrolled at 9 institutions: 6 to each DLT assessment cohort and 14 to the expansion cohort. Median age: 55 years, 67.7% male, 83.9% White. Treatment was well tolerated with 16% Grade 4 events; the combination did not have unexpectedly increased toxicity, with no Grade 5 events. One DLT was seen in each single-agent treatment; none were observed in the combination, leading to expanded accrual of the combined treatment. The median follow-up was 19.6 months. For all patients receiving combination treatment, median overall survival (OS) and progression-free survival (PFS) were 20.7 and 16.1 months, respectively.IPI and NIVO are safe and tolerable with toxicities similar to those noted with other cancers when given in combination with adjuvant temozolomide for newly diagnosed GBM. Combination IPI + NIVO is not substantially more toxic than single agents. These results support a subsequent efficacy trial to test the combination of ICIs in Phase II/III for patients with newly diagnosed GBM.NCT02311920.

  View details for DOI 10.1093/neuonc/noae058

  View details for PubMedID 38874333

  View details for PubMedCentralID PMC11376446

• A real-world observation of patients with glioblastoma treated with a personalized peptide vaccine. Nature communications Latzer, P., Zelba, H., Battke, F., Reinhardt, A., Shao, B., Bartsch, O., Rabsteyn, A., Harter, J., Schulze, M., Okech, T., Golf, A., Kyzirakos-Feger, C., Kayser, S., Pieper, N., Feldhahn, M., Wünsche, J., Seitz, C., Hadaschik, D., Garbe, C., Hauser, T. K., la Fougère, C., Biskup, D., Brooke, D., Parker, D., Martens, U. M., Illerhaus, G., Blumenthal, D. T., Merrell, R., Lorenzo, L. S., Hidvégi, M., de Robles, P., Kebir, S., Li, W. W., Li, V. W., Williams, M., Miller, A. M., Kesari, S., Castro, M., Desjardins, A., Ashley, D. M., Friedman, H. S., Wen, P. Y., Neil, E. C., Iwamoto, F. M., Sipos, B., Geletneky, K., Zender, L., Glas, M., Reardon, D. A., Biskup, S. 2024; 15 (1): 6870

  Abstract

  Current treatment outcome of patients with glioblastoma (GBM) remains poor. Following standard therapy, recurrence is universal with limited survival. Tumors from 173 GBM patients are analysed for somatic mutations to generate a personalized peptide vaccine targeting tumor-specific neoantigens. All patients were treated within the scope of an individual healing attempt. Among all vaccinated patients, including 70 treated prior to progression (primary) and 103 treated after progression (recurrent), the median overall survival from first diagnosis is 31.9 months (95% CI: 25.0-36.5). Adverse events are infrequent and are predominantly grade 1 or 2. A vaccine-induced immune response to at least one of the vaccinated peptides is detected in blood samples of 87 of 97 (90%) monitored patients. Vaccine-specific T-cell responses are durable in most patients. Significantly prolonged survival is observed for patients with multiple vaccine-induced T-cell responses (53 months) compared to those with no/low induced responses (27 months; P = 0.03). Altogether, our results highlight that the application of personalized neoantigen-targeting peptide vaccine is feasible and represents a promising potential treatment option for GBM patients.

  View details for DOI 10.1038/s41467-024-51315-8

  View details for PubMedID 39127809

  View details for PubMedCentralID PMC11316744

• Efficacy and biomarker analysis of phase 2 (P2) and window-of-opportunity (WoO) cohorts of patients with recurrent glioblastoma (rGBM) treated with ST101, an inhibitor of the transcription factor C/EBPβ. Iwamoto, F., Haras, A., Rotolo, J., Levrero, C., Shaich, E., Al Dalahmah, O., Buerki, R. LIPPINCOTT WILLIAMS & WILKINS. 2024

  View details for Web of Science ID 001275557400374

• Interim analysis of ABM-1310, a blood-brain barrier-penetrant BRAF inhibitor, in patients with <i>BRAF V600</i>-mutated solid tumors Piha-Paul, S. A., De La Fuente, M., Iwamoto, F., Nagpal, S., Weise, A. M., Zhu, J., Chandra, S., Chen, C., Fu, Y., Yang, Z., Tsai, K. K. LIPPINCOTT WILLIAMS & WILKINS. 2024

  View details for Web of Science ID 001275557400710

• H3K27M mutation loss in a recurrent diffuse midline glioma Fecher, R., Iwamoto, F., McKhann, G., Goldman, J., Faust, P. OXFORD UNIV PRESS INC. 2024: 440

  View details for Web of Science ID 001443623300030

• Phase 1 study of MDM2 antagonist ASTX295 in patients with solid tumors with wild-type TP53 Dumbrava, E. E., Iwamoto, F. M., Agulnik, M., Milhem, M., Tolcher, A. W., Chugh, R., Demeure, M. J., Mita, A., Demel, K., Diamond, M., Mirakhur, B., Wilson, L., Oganesian, A., Chan, D., Keer, H. N., Taylor, J., Sims, M. J., Biondo, A., Jueliger, S., Spira, A. AMER ASSOC CANCER RESEARCH. 2024

  View details for DOI 10.1158/1538-7445.AM2024-CT066

  View details for Web of Science ID 001203184200046

• Where Do We (INDI)GO From Here? International journal of radiation oncology, biology, physics Kinslow, C. J., Brown, P. D., Iwamoto, F. M., Wu, C. C., Yu, J. B., Cheng, S. K., Wang, T. J. 2024; 118 (2): 330-333

  View details for DOI 10.1016/j.ijrobp.2023.09.008

  View details for PubMedID 38220255

• DYNAMICS OF TUMOR GENOME SHAPING AND CLINICAL RESPONSE IN GLIOBLASTOMAS UNDER IMMUNE CHECKPOINT INHIBITORS Choi, S., Rabadan, R., Iwamoto, F., Pan, P. OXFORD UNIV PRESS INC. 2023

  View details for Web of Science ID 001115245400484

• THE COLUMBIA NEURO-ONCOLOGY RESEARCH DASHBOARD: A WEB-BASED TOOL TO ASSESS CLINICAL TRIAL RECRUITMENT AND ACCRUAL METRICS Welch, M., Pan, P., Haggiagi, A., Donovan, L., Diaz, M., Iwamoto, F., Lassman, A. OXFORD UNIV PRESS INC. 2023

  View details for Web of Science ID 001115245401157

• GBM AGILE PLATFORM TRIAL FOR NEWLY DIAGNOSED AND RECURRENT GBM: RESULTS OF FIRST EXPERIMENTAL ARM, REGORAFENIB Wen, P., Alexander, B., Berry, D., Buxton, M., Cavenee, W., Colman, H., de Groot, J., Ellingson, B., Gordon, G., Hyddmark, E., Khasraw, M., Lim, M., Mellinghoff, I., Mikkelsen, T., Perry, J., Powell, A., Sulman, E., Tanner, K., Weller, M., Yung, W., Blondin, N., Brenner, A., Butt, O., de la Fuente, M., Drappatz, J., Iwamoto, F., Kim, L., Lee, E., Mantica, M., Nabors, B., Newton, H., Schiff, D., Walbert, T., Weathers, S., Cloughesy, T., Lassman, A. OXFORD UNIV PRESS INC. 2023

  View details for Web of Science ID 001115245400367

• A PHASE 2 STUDY OF A NOVEL IMMUNOTHERAPY SL-701 IN ADULTS WITH RECURRENT GLIOBLASTOMA: EXPLORING THE PROGNOSTIC VALUE OF TREATMENT-INDUCED CD8+CD57+T-CELLS AS A MARKER FOR SURVIVAL Peereboom, D., Lindsay, R., Badruddoja, M., Nabors, L., Kumthekar, P., Lieberman, F., Schiff, D., Sherman, J., Butowski, N., Dunbar, E., Fink, K., Iwamoto, F., Moertel, C., Schulder, M., Walbert, T., Chattopadhyay, P., Habboubi, N., Grzegorzewski, K., Brooks, C., Reardon, D. OXFORD UNIV PRESS INC. 2023

  View details for Web of Science ID 001115245400247

• MGMT promoter methylation in 1p19q-intact gliomas. Research square Kinslow, C., Siegelin, M. D., Iwamoto, F. M., Gallitto, M., Neugut, A. I., Yu, J. B., Cheng, S. K., Wang, T. J. 2023

  Abstract

  Standard-of-care for 1p19q-intact anaplastic gliomas is defined by the international randomized phase III CATNON trial, which found an overall survival (OS) benefit for adjuvant temozolomide (TMZ) when added to radiotherapy. Paradoxically, TMZ did not appear to benefit patients with IDH-wildtype gliomas, regardless of MGMT promoter status. The authors concluded that well-powered prospective study on the clinical efficacy of TMZ for patients with IDH-wildtype anaplastic gliomas (meeting criteria for glioblastoma) is warranted. Given that the prognostic and predictive role of MGMT status for grade 2-3 gliomas is unresolved, we determined the effect of MGMT status on OS in patients with 1p19q-intact gliomas in the National Cancer Database (NCDB).We queried the NCDB from 2018-2019 for patients with IDH-wildtype or -mutant astrocytomas who received chemotherapy with follow-up through 2022. The Kaplan-Meier method and Cox proportional hazards regressions models were used to determine the association of MGMT with OS.We identified 1,514 patients who were newly diagnosed with IDH-wildtype (n = 802, 33% methylated) or - mutant astrocytomas (n = 712, 48% methylated) and received chemotherapy during initial management. An unmethylated promoter was associated with poorer survival in patients with IDH-wildtype (3-year OS 34% [95%CI 29-39%] vs. 46% [95%CI 39-54%], p < .001, adjusted HR 1.53 [95%CI 1.24-1.89]) but not IDH-mutant astrocytomas (3-year OS 79% [95%CI 74-84%] vs. 80% [95%CI 75-86%], p = .81, HR 1.04 [95%CI 0.73-1.50]).This ancillary analysis supports adjuvant TMZ as standard-of-care for anaplastic astrocytomas (IDH-mutant and 1p19q-intact), irrespective of MGMT status. Determining the optimal strategy for diffuse gliomas that are IDH-wildtype will be particularly important. MGMT promoter methylation should be considered as a stratification factor in future clinical trials for these patients.

  View details for DOI 10.21203/rs.3.rs-3393238/v1

  View details for PubMedID 37886555

  View details for PubMedCentralID PMC10602117

• NRG ONCOLOGY STUDY BN007: RANDOMIZED PHASE II/III TRIAL OF IPILIMIUMAB (IPI) PLUS NIVOLUMAB (NIVO) VS. TEMOZOLOMIDE (TMZ) IN MGMT-UNMETHYLATED (UMGMT) NEWLY DIAGNOSED GLIOBLASTOMA (NGBM) Lassman, A. B., Polley, M. C., Iwamoto, F. M., Sloan, A. E., Wang, T. C., Aldape, K. D., Wefel, J. S., Gondi, V., Gutierrez, A. N., Manasawala, M., Gilbert, M. R., Sulman, E. P., Wolchok, J. D., Greene, R. M., Neil, E. C., Lukas, R. V., Goldlust, S. A., Snuderl, M., Dignam, J. J., Won, M., Movsas, B., Mehta, M. P. OXFORD UNIV PRESS INC. 2023

  View details for DOI 10.1093/neuonc/noad137.005

  View details for Web of Science ID 001300535600006

• MGMT promoter methylation predicts overall survival after chemotherapy for 1p/19q-codeleted gliomas. Clinical cancer research : an official journal of the American Association for Cancer Research Kinslow, C. J., Rae, A. I., Taparra, K., Kumar, P., Siegelin, M. D., Grinband, J., Gill, B. J., McKhann, G. M., Sisti, M. B., Bruce, J. N., Canoll, P. D., Iwamoto, F. M., Horowitz, D. P., Kachnic, L. A., Neugut, A. I., Yu, J. B., Cheng, S. K., Wang, T. J. 2023

  Abstract

  PURPOSE: While MGMT promoter methylation (mMGMT) is predictive of response to alkylating chemotherapy and guides treatment decisions in glioblastoma, its role in grade 2 and 3 glioma remains unclear. Recent data suggests that mMGMT is prognostic of progression-free survival in 1p/19q-codeleted oligodendrogliomas, but an effect on overall survival (OS) has not been demonstrated.EXPERIMENTAL DESIGN: We identified patients with newly diagnosed 1p/19q-codeleted gliomas and known MGMT promoter status in the National Cancer Database from 2010-2019. Multivariable Cox proportional hazards regression modeling was used to assess the effect of mMGMT on OS after adjusting for age, sex, race, co-morbidity, grade, extent of resection, chemotherapy, and radiotherapy.RESULTS: We identified 1,297 eligible patients, 938 (72.3%) of whom received chemotherapy in their initial course of treatment. The MGMT promoter was methylated in 1,009 (77.8%) patients. Unmethylated MGMT (uMGMT) was associated with worse survival compared to mMGMT (70% [95%CI 64-77%] vs. 81% [95%CI 78-85%], P<.001, adjusted hazard ratio [aHR] 2.35 [95%CI 1.77-3.14]). uMGMT was associated with worse survival in patients who received chemotherapy (63% [95%CI 55-73%] vs. 80% [95%CI 76-84%], P<.001, aHR 2.61 [95%CI 1.89-3.60]) but not in patients who did not receive chemotherapy (P=.38, HR 1.31 [95%CI 0.71- 2.42]). Similar results were observed regardless of WHO grade and after single- or multiagent chemotherapy.CONCLUSIONS: Our study demonstrates an association between mMGMT and OS in 1p/19qcodeleted gliomas. MGMT promoter status should be considered as a stratification factor in future clinical trials of 1p/19q-codeleted gliomas that use OS as an endpoint.

  View details for DOI 10.1158/1078-0432.CCR-23-1295

  View details for PubMedID 37611077

• A Transcriptome-Based Precision Oncology Platform for Patient-Therapy Alignment in a Diverse Set of Treatment-Resistant Malignancies. Cancer discovery Mundi, P. S., Dela Cruz, F. S., Grunn, A., Diolaiti, D., Mauguen, A., Rainey, A. R., Guillan, K., Siddiquee, A., You, D., Realubit, R., Karan, C., Ortiz, M. V., Douglass, E. F., Accordino, M., Mistretta, S., Brogan, F., Bruce, J. N., Caescu, C. I., Carvajal, R. D., Crew, K. D., Decastro, G., Heaney, M., Henick, B. S., Hershman, D. L., Hou, J. Y., Iwamoto, F. M., Jurcic, J. G., Kiran, R. P., Kluger, M. D., Kreisl, T., Lamanna, N., Lassman, A. B., Lim, E. A., Manji, G. A., McKhann, G. M., McKiernan, J. M., Neugut, A. I., Olive, K. P., Rosenblat, T., Schwartz, G. K., Shu, C. A., Sisti, M. B., Tergas, A., Vattakalam, R. M., Welch, M., Wenske, S., Wright, J. D., Canoll, P., Hibshoosh, H., Kalinsky, K., Aburi, M., Sims, P. A., Alvarez, M. J., Kung, A. L., Califano, A. 2023; 13 (6): 1386-1407

  Abstract

  Predicting in vivo response to antineoplastics remains an elusive challenge. We performed a first-of-kind evaluation of two transcriptome-based precision cancer medicine methodologies to predict tumor sensitivity to a comprehensive repertoire of clinically relevant oncology drugs, whose mechanism of action we experimentally assessed in cognate cell lines. We enrolled patients with histologically distinct, poor-prognosis malignancies who had progressed on multiple therapies, and developed low-passage, patient-derived xenograft models that were used to validate 35 patient-specific drug predictions. Both OncoTarget, which identifies high-affinity inhibitors of individual master regulator (MR) proteins, and OncoTreat, which identifies drugs that invert the transcriptional activity of hyperconnected MR modules, produced highly significant 30-day disease control rates (68% and 91%, respectively). Moreover, of 18 OncoTreat-predicted drugs, 15 induced the predicted MR-module activity inversion in vivo. Predicted drugs significantly outperformed antineoplastic drugs selected as unpredicted controls, suggesting these methods may substantively complement existing precision cancer medicine approaches, as also illustrated by a case study.Complementary precision cancer medicine paradigms are needed to broaden the clinical benefit realized through genetic profiling and immunotherapy. In this first-in-class application, we introduce two transcriptome-based tumor-agnostic systems biology tools to predict drug response in vivo. OncoTarget and OncoTreat are scalable for the design of basket and umbrella clinical trials. This article is highlighted in the In This Issue feature, p. 1275.

  View details for DOI 10.1158/2159-8290.CD-22-1020

  View details for PubMedID 37061969

  View details for PubMedCentralID PMC10239356

• Post-marketing surveillance safety analysis of patients with CNS malignancies treated with tumor treating fields (TTFields) therapy between 2011-2022 Mrugala, M. M., Shi, W., Iwamoto, F., Lukas, R., Palmer, J., Suh, J. H., Glas, M. LIPPINCOTT WILLIAMS & WILKINS. 2023

  View details for Web of Science ID 001053772000372

• Association of MGMT Promotor Methylation With Survival in Low-grade and Anaplastic Gliomas After Alkylating Chemotherapy. JAMA oncology Kinslow, C. J., Mercurio, A., Kumar, P., Rae, A. I., Siegelin, M. D., Grinband, J., Taparra, K., Upadhyayula, P. S., McKhann, G. M., Sisti, M. B., Bruce, J. N., Canoll, P. D., Iwamoto, F. M., Kachnic, L. A., Yu, J. B., Cheng, S. K., Wang, T. J. 2023

  Abstract

  O6-methylguanine-DNA methyltransferase (MGMT [OMIM 156569]) promoter methylation (mMGMT) is predictive of response to alkylating chemotherapy for glioblastomas and is routinely used to guide treatment decisions. However, the utility of MGMT promoter status for low-grade and anaplastic gliomas remains unclear due to molecular heterogeneity and the lack of sufficiently large data sets.To evaluate the association of mMGMT for low-grade and anaplastic gliomas with chemotherapy response.This cohort study aggregated grade II and III primary glioma data from 3 prospective cohort studies with patient data collected from August 13, 1995, to August 3, 2022, comprising 411 patients: MSK-IMPACT, EORTC (European Organization of Research and Treatment of Cancer) 26951, and Columbia University. Statistical analysis was performed from April 2022 to January 2023.MGMT promoter methylation status.Multivariable Cox proportional hazards regression modeling was used to assess the association of mMGMT status with progression-free survival (PFS) and overall survival (OS) after adjusting for age, sex, molecular class, grade, chemotherapy, and radiotherapy. Subgroups were stratified by treatment status and World Health Organization 2016 molecular classification.A total of 411 patients (mean [SD] age, 44.1 [14.5] years; 283 men [58%]) met the inclusion criteria, 288 of whom received alkylating chemotherapy. MGMT promoter methylation was observed in 42% of isocitrate dehydrogenase (IDH)-wild-type gliomas (56 of 135), 53% of IDH-mutant and non-codeleted gliomas (79 of 149), and 74% of IDH-mutant and 1p/19q-codeleted gliomas (94 of 127). Among patients who received chemotherapy, mMGMT was associated with improved PFS (median, 68 months [95% CI, 54-132 months] vs 30 months [95% CI, 15-54 months]; log-rank P < .001; adjusted hazard ratio [aHR] for unmethylated MGMT, 1.95 [95% CI, 1.39-2.75]; P < .001) and OS (median, 137 months [95% CI, 104 months to not reached] vs 61 months [95% CI, 47-97 months]; log-rank P < .001; aHR, 1.65 [95% CI, 1.11-2.46]; P = .01). After adjusting for clinical factors, MGMT promoter status was associated with chemotherapy response in IDH-wild-type gliomas (aHR for PFS, 2.15 [95% CI, 1.26-3.66]; P = .005; aHR for OS, 1.69 [95% CI, 0.98-2.91]; P = .06) and IDH-mutant and codeleted gliomas (aHR for PFS, 2.99 [95% CI, 1.44-6.21]; P = .003; aHR for OS, 4.21 [95% CI, 1.25-14.2]; P = .02), but not IDH-mutant and non-codeleted gliomas (aHR for PFS, 1.19 [95% CI, 0.67-2.12]; P = .56; aHR for OS, 1.07 [95% CI, 0.54-2.12]; P = .85). Among patients who did not receive chemotherapy, mMGMT status was not associated with PFS or OS.This study suggests that mMGMT is associated with response to alkylating chemotherapy for low-grade and anaplastic gliomas and may be considered as a stratification factor in future clinical trials of patients with IDH-wild-type and IDH-mutant and codeleted tumors.

  View details for DOI 10.1001/jamaoncol.2023.0990

  View details for PubMedID 37200021

  View details for PubMedCentralID PMC10196932

• Patients with glioblastoma (GBM) treated with tumor treating fields (TTFields) therapy: post-marketing safety data over the last decade Mrugala, M. M., Shi, W., Iwamoto, F., Lukas, R. V., Palmer, J. D., Suh, J. H., Glas, M. AMER ASSOC CANCER RESEARCH. 2023

  View details for DOI 10.1158/1538-7445.AM2023-3221

  View details for Web of Science ID 001008499100191

• Alliance A071401: Phase II Trial of Focal Adhesion Kinase Inhibition in Meningiomas With Somatic NF2 Mutations. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Brastianos, P. K., Twohy, E. L., Gerstner, E. R., Kaufmann, T. J., Iafrate, A. J., Lennerz, J., Jeyapalan, S., Piccioni, D. E., Monga, V., Fadul, C. E., Schiff, D., Taylor, J. W., Chowdhary, S. A., Bettegowda, C., Ansstas, G., De La Fuente, M., Anderson, M. D., Shonka, N., Damek, D., Carrillo, J., Kunschner-Ronan, L. J., Chaudhary, R., Jaeckle, K. A., Senecal, F. M., Kaley, T., Morrison, T., Thomas, A. A., Welch, M. R., Iwamoto, F., Cachia, D., Cohen, A. L., Vora, S., Knopp, M., Dunn, I. F., Kumthekar, P., Sarkaria, J., Geyer, S., Carrero, X. W., Martinez-Lage, M., Cahill, D. P., Brown, P. D., Giannini, C., Santagata, S., Barker, F. G., Galanis, E. 2023; 41 (3): 618-628

  Abstract

  Patients with progressive or recurrent meningiomas have limited systemic therapy options. Focal adhesion kinase (FAK) inhibition has a synthetic lethal relationship with NF2 loss. Given the predominance of NF2 mutations in meningiomas, we evaluated the efficacy of GSK2256098, a FAK inhibitor, as part of the first genomically driven phase II study in recurrent or progressive grade 1-3 meningiomas.Eligible patients whose tumors screened positively for NF2 mutations were treated with GSK2256098, 750 mg orally twice daily, until progressive disease. Efficacy was evaluated using two coprimary end points: progression-free survival at 6 months (PFS6) and response rate by Macdonald criteria, where PFS6 was evaluated separately within grade-based subgroups: grade 1 versus 2/3 meningiomas. Per study design, the FAK inhibitor would be considered promising in this patient population if either end point met the corresponding decision criteria for efficacy.Of 322 patients screened for all mutation cohorts of the study, 36 eligible and evaluable patients with NF2 mutations were enrolled and treated: 12 grade 1 and 24 grade 2/3 patients. Across all grades, one patient had a partial response and 24 had stable disease as their best response to treatment. In grade 1 patients, the observed PFS6 rate was 83% (10/12 patients; 95% CI, 52 to 98). In grade 2/3 patients, the observed PFS6 rate was 33% (8/24 patients; 95% CI, 16 to 55). The study met the PFS6 efficacy end point both for the grade 1 and the grade 2/3 cohorts. Treatment was well tolerated; seven patients had a maximum grade 3 adverse event that was at least possibly related to treatment with no grade 4 or 5 events.GSK2256098 was well tolerated and resulted in an improved PFS6 rate in patients with recurrent or progressive NF2-mutated meningiomas, compared with historical controls. The criteria for promising activity were met, and FAK inhibition warrants further evaluation for this patient population.

  View details for DOI 10.1200/JCO.21.02371

  View details for PubMedID 36288512

  View details for PubMedCentralID PMC9870228

• Primary Vitreo-retinal lymphoma Global Perspectives in Ocular Oncology Yuen, C., Iwamoto, F. M., Nayak, L. 2023
• CONCORDANCE FOR CDKN2A/B LOSS AND TERT MUTATION IN WHO 2021 CLASSIFICATION GRADE 3 MENINGIOMAS: A RETROSPECTIVE STUDY Yuen, C., Pan, P., Teasley, D., Miller, M., Sun, Y., Canoll, P., Joanta-Gomez, A., Bargo, A., Iwamoto, F. OXFORD UNIV PRESS INC. 2022: 157

  View details for Web of Science ID 000888571000609

• COMPREHENSIVE BIOMARKER ANALYSIS OF RESPONDERS AND NON-RESPONDERS IN A PHASE IIA TRIAL OF A CMV VACCINE IMMUNOTHERAPEUTIC CANDIDATE (VBI-1901) Wen, P. Y., Reardon, D. A., Forst, D., Lee, E., Daoud, T., Berthoud, T., Soare, C., Diaz-Mitoma, F., Anderson, D. E., Lassman, A., Iwamoto, F. OXFORD UNIV PRESS INC. 2022: 62

  View details for Web of Science ID 000888571000249

• PHASE 2 STUDY OF A NOVEL IMMUNOTHERAPY SL-701 IN ADULTS WITH RECURRENT GBM: IDENTIFICATION OF TREATMENT-INDUCED CD8+CD107A+CD57+PD-1-MEMORY T-CELLS THAT ARE ASSOCIATED WITH INCREASED SURVIVAL Peereboom, D., Lindsay, R., Badruddoja, M., Nabors, L., Kumthekar, P., Lieberman, F., Tran, D., Phuphanich, S., Schiff, D., Sherman, J., Butowski, N., Dunbar, E., Fink, K., Iwamoto, F., Moertel, C., Schulder, M., Walbert, T., Habboubi, N., Grzegorzewski, K., Brooks, C., Reardon, D. A. OXFORD UNIV PRESS INC. 2022: 67

  View details for Web of Science ID 000888571000264

• TUMOR TREATING FIELDS (TTFIELDS; 200 KHZ) POST-MARKETING SAFETY DATA FROM PATIENTS WITH GLIOBLASTOMA TREATED BETWEEN 2011-2022 Mrugala, M., Shi, W., Iwamoto, F., Lukas, R., Palmer, J., Suh, J., Glas, M. OXFORD UNIV PRESS INC. 2022: 142

  View details for Web of Science ID 000888571000551

• AUTOLOGOUS TUMOR LYSATE-LOADED DENDRITIC CELL VACCINATION IMPROVES SURVIVAL IN PATIENTS WITH NEWLY DIAGNOSED AND RECURRENT GLIOBLASTOMA: SURVIVAL RESULTS FROM A PHASE 3 TRIAL Liau, L. M., Ashkan, K., Brem, S., Campian, J., Trusheim, J., Iwamoto, F., Tran, D., Anstass, G., Cobbs, C., Heth, J., Salacz, M., D'Andre, S., Aiken, R., Moshel, Y., Nam, J., Pillainayagam, C., Wagner, S., Walter, K., Chaudary, R., Goldlust, S., Lee, I., Bota, D., Elinzano, H., Grewal, J., Lillehei, K., Mikkelsen, T., Walbert, T., Abram, S., Brenner, A., Ewend, M., Khagi, S., Lovick, D., Portnow, J., Kim, L., Loudon, W., Martinez, N., Thompson, R., Avigan, D., Fink, K., Geoffroy, F., Giglio, P., Gligich, O., Krex, D., Lindhorst, S. M., Lutzky, J., Meisel, H., Nadji-Ohl, M., Sanchin, L., Sloan, A., Bosch, M. OXFORD UNIV PRESS INC. 2022: 66

  View details for Web of Science ID 000888571000262

• ST101, A PEPTIDE ANTAGONIST OF NOVEL I/O TARGET CEBPβ, REPROGRAMS MDSC POLARIZATION AND DECREASES TUMOR-ASSOCIATED TREGS, SUGGESTING AN IMMUNE COMPONENT TO OBSERVED CLINICAL RESPONSES Scuoppo, C., Falchook, G., Fontana, E., Williams, A., Lakhani, N., Evans, J., Iwamoto, F., McKean, M., Symeonides, S., McLaren, A., Henry, J., Capiaux, G., Michel, R., Kaesshaefer, S., Bexon, A., Rotolo, J. BMJ PUBLISHING GROUP. 2022: A1216

  View details for DOI 10.1136/jitc-2022-SITC2022.1173

  View details for Web of Science ID 000919423401283

• PHASE 2 STUDY OF PD-1 BLOCKADE WITH PEMBROLIZUMAB PLUS RE-IRRADIATION FOR RECURRENT GLIOBLASTOMA (RGBM) (NCT03661723) Iwamoto, F., Tanguturi, S., Desai, A., Nayak, L., Uhlmann, E., Wang, T., Lustig, R., Hertan, L., Bagley, S., Hayden, J., Laforest-Roys, C., Muzikansky, A., McCluskey, C., Chukwueke, U., McFaline-Figueroa, J., Lee, E., Wen, P. Y., Reardon, D. OXFORD UNIV PRESS INC. 2022: 63-64

  View details for Web of Science ID 000888571000253

• THE IMPACT OF MISMATCH REPAIR DEFICIENCY (MMRD) ON SURVIVAL OF TEMOZOLOMIDE (TMZ)-TREATED PATIENTS WITH MGMT METHYLATED (M-MGMT) GLIOBLASTOMA (GBM): A CELLWORKS COMPUTATIONAL BIOSIMULATION PILOT STUDY Castro, M., Iwamoto, F., Ahluwalia, M., Usmani, S., Kumar, A., Kapoor, S., Suseela, R., Kulkarni, S., Mohanty, J., Shyamasundar, V., Ghosh, A., Prasad, N., Patil, M., Choudhury, S., Chauhan, J., Sauban, M., Joseph, V., Kumari, P., Mitra, U., Pampana, A., Azam, H., Poornachandra, G., Prakash, A., Basu, S. OXFORD UNIV PRESS INC. 2022: 116-117

  View details for Web of Science ID 000888571000445

• NRG-BN010: A SAFETY RUN-IN AND PHASE II STUDY EVALUATING THE COMBINATION OF TOCILIZUMAB, ATEZOLIZUMAB, AND FRACTIONATED STEREOTACTIC RADIOTHERAPY IN RECURRENT GLIOBLASTOMA - TRIAL IN PROGRESS Bagley, S., Polley, M., Kotecha, R., Brem, S., Tolakanahalli, R., Iwamoto, F., Gilbert, M., Won, M., Mehta, M. OXFORD UNIV PRESS INC. 2022: 64

  View details for Web of Science ID 000888571000256

• Chronic convection-enhanced delivery of topotecan for patients with recurrent glioblastoma: a first-in-patient, single-centre, single-arm, phase 1b trial LANCET ONCOLOGY Spinazzi, E. F., GArgenziano, M., Upadhyayula, P. S., Banu, M. A., Neira, J. A., Higgins, D. M. O., Wu, P. B., Pereira, B., Mahajan, A., Humala, N., Al-Dalahmah, O., Zhao, W., Save, A., Gill, B. A., Boyett, D. M., Marie, T., Furnari, J. L., Sudhakar, T. D., Stopka, S. A., Regan, M. S., Catania, V., Good, L., Zacharoulis, S., Behl, M., Petridis, P., Jambawalikar, S., Mintz, A., Lignelli, A., Agar, N. Y. R., Sims, P., Welch, M. R., Lassman, A. B., Iwamoto, F. M., D'Amico, R. S., Grinband, J., Canoll, P., Bruce, J. N. 2022; 23 (11): 1409-1418

  Abstract

  Topotecan is cytotoxic to glioma cells but is clinically ineffective because of drug delivery limitations. Systemic delivery is limited by toxicity and insufficient brain penetrance, and, to date, convection-enhanced delivery (CED) has been restricted to a single treatment of restricted duration. To address this problem, we engineered a subcutaneously implanted catheter-pump system capable of repeated, chronic (prolonged, pulsatile) CED of topotecan into the brain and tested its safety and biological effects in patients with recurrent glioblastoma.We did a single-centre, open-label, single-arm, phase 1b clinical trial at Columbia University Irving Medical Center (New York, NY, USA). Eligible patients were at least 18 years of age with solitary, histologically confirmed recurrent glioblastoma showing radiographic progression after surgery, radiotherapy, and chemotherapy, and a Karnofsky Performance Status of at least 70. Five patients had catheters stereotactically implanted into the glioma-infiltrated peritumoural brain and connected to subcutaneously implanted pumps that infused 146 μM topotecan 200 μL/h for 48 h, followed by a 5-7-day washout period before the next infusion, with four total infusions. After the fourth infusion, the pump was removed and the tumour was resected. The primary endpoint of the study was safety of the treatment regimen as defined by presence of serious adverse events. Analyses were done in all treated patients. The trial is closed, and is registered with ClinicalTrials.gov, NCT03154996.Between Jan 22, 2018, and July 8, 2019, chronic CED of topotecan was successfully completed safely in all five patients, and was well tolerated without substantial complications. The only grade 3 adverse event related to treatment was intraoperative supplemental motor area syndrome (one [20%] of five patients in the treatment group), and there were no grade 4 adverse events. Other serious adverse events were related to surgical resection and not the study treatment. Median follow-up was 12 months (IQR 10-17) from pump explant. Post-treatment tissue analysis showed that topotecan significantly reduced proliferating tumour cells in all five patients.In this small patient cohort, we showed that chronic CED of topotecan is a potentially safe and active therapy for recurrent glioblastoma. Our analysis provided a unique tissue-based assessment of treatment response without the need for large patient numbers. This novel delivery of topotecan overcomes limitations in delivery and treatment response assessment for patients with glioblastoma and could be applicable for other anti-glioma drugs or other CNS diseases. Further studies are warranted to determine the effect of this drug delivery approach on clinical outcomes.US National Institutes of Health, The William Rhodes and Louise Tilzer Rhodes Center for Glioblastoma, the Michael Weiner Glioblastoma Research Into Treatment Fund, the Gary and Yael Fegel Foundation, and The Khatib Foundation.

  View details for DOI 10.1016/S1470-2045(22)00599-X

  View details for Web of Science ID 000886922400036

  View details for PubMedID 36243020

  View details for PubMedCentralID PMC9641975

• Efficacy signals, long-term exposure and safety data from a phase 1-2 study of a cell-penetrating peptide antagonist of CEBPβ, a novel target, in patients (pts) with refractory solid tumors Fontana, E., Williams, A., Falchook, G., Lakhani, N., Evans, T. J., Gondi, V., Iwamoto, F., McKean, M., Symeonides, S., Butowski, N., McLaren, A., Henry, J., Buerki, R., Rotolo, J., Capiaux, G., Michel, R., Kaesshaefer, S., Wiegert, E., Bexon, A. ELSEVIER SCI LTD. 2022: S82-S83

  View details for Web of Science ID 000876973400209

• A multi-institutional phase II trial of bevacizumab for recurrent and refractory meningioma. Neuro-oncology advances Kumthekar, P., Grimm, S. A., Aleman, R. T., Chamberlain, M. C., Schiff, D., Wen, P. Y., Iwamoto, F. M., Gursel, D. B., Reardon, D. A., Purow, B., Kocherginski, M., Helenowski, I., Raizer, J. J. 2022; 4 (1): vdac123

  Abstract

  Systemic therapies for refractory meningiomas are limited with no FDA-approved therapeutics. Vascular endothelial growth factor (VEGF) is a signaling protein associated with neovascularization, peritumoral edema, and meningioma tumorigenesis.This phase II study investigates the efficacy of bevacizumab (BEV), a VEGF binding monoclonal antibody, in patients with progressive Grade I (G1M), Grade II (G2M), Grade III (G3M) meningioma, and other non-parenchymal tumors including vestibular schwannoma (n = 4) and hemangiopericytoma (n = 4) with the primary endpoint of progression-free survival rate at 6-months (PFS-6). Non-meningiomas were included with the respective meningioma grade in the analysis. Secondary endpoints include median overall survival (mOS) and response rate.Fifty Patients (26 women; median age 54 years; range 23-81), 42 with progressive meningioma were treated: 10 G1M, 20 G2M, and 12 G3M. Prior treatments include surgical resection (41 patients), radiosurgery (24 patients), external beam radiotherapy (28 patients), and chemotherapy (14 patients). Median infusions administered were 16 (range, 2-68). Response was graded using the Macdonald's criteria. PFS-6, median PFS, and mOS were 87%, 22 months, 35 months for G1M; 77%, 23 months, 41 months for G2M; and 46%, 8 months, 12 months for G3M. Best radiographic responses include stable disease (G1M: 100%; G2M: 85%; G3M: 82%); partial response (G1M: 0%; G2M: 5%; G3M: 0%) and progressive disease (G1M: 0%; G2M: 10%; G3M:18%). The most common toxicities were hypertension (n = 19, 42.2%), proteinuria (n = 16, 35.6%), and fatigue (n = 14, 31.1%).This study showed BEV is well tolerated and appears to be a promising systemic treatment option for patients with recurrent and refractory meningiomas.

  View details for DOI 10.1093/noajnl/vdac123

  View details for PubMedID 36225651

  View details for PubMedCentralID PMC9549880

• Safety, tolerability and efficacy of agonist anti-CD27 antibody (varlilumab) administered in combination with anti-PD-1 (nivolumab) in advanced solid tumors. Journal for immunotherapy of cancer Sanborn, R. E., Pishvaian, M. J., Callahan, M. K., Weise, A., Sikic, B. I., Rahma, O., Cho, D. C., Rizvi, N. A., Sznol, M., Lutzky, J., Bauman, J. E., Bitting, R. L., Starodub, A., Jimeno, A., Reardon, D. A., Kaley, T., Iwamoto, F., Baehring, J. M., Subramaniam, D. S., Aragon-Ching, J. B., Hawthorne, T. R., Rawls, T., Yellin, M., Keler, T. 2022; 10 (8)

  Abstract

  BACKGROUND: Phase 1/2 dose-escalation and expansion study evaluating varlilumab, a fully human agonist anti-CD27 mAb, with nivolumab in anti-PD-1/L1 naive, refractory solid tumors.METHODS: Phase 1 evaluated the safety of varlilumab (0.1-10 mg/kg) with nivolumab (3 mg/kg) administered once every 2 weeks. Phase 2 evaluated varlilumab regimens (3 mg/kg once every 2 weeks, 3 mg/kg once every 12 weeks, and 0.3 mg/kg once every 4 weeks) with nivolumab 240 mg once every 2 weeks in tumor-specific cohorts. Primary objective was safety; key clinical endpoints included objective response rate (ORR) and overall survival rate at 12 months (OS12) (glioblastoma (GBM) only). Exploratory objectives included determination of effects on peripheral blood and intratumoral immune signatures.RESULTS: 175 patients were enrolled (36 in phase 1 and 139 in phase 2). Phase 1 dose-escalation proceeded to the highest varlilumab dose level without determining a maximum tolerated dose. In phase 2, ORR were ovarian 12.5%, squamous cell carcinoma of the head and neck 12.5%, colorectal cancer 5%, and renal cell carcinoma 0%; GBM OS12 was 40.9%. Increased tumor PD-L1 and intratumoral T cell infiltration were observed in ovarian cancer patients, with increases of ≥5% associated with better progression-free survival. The most common treatment related adverse events were fatigue (18%), pruritus (16%), and rash (15%).CONCLUSION: Varlilumab and nivolumab were well tolerated, without significant toxicity beyond that expected for each agent alone. Clinical activity was observed in patients that are typically refractory to anti-PD-1 therapy, however, overall was not greater than expected for nivolumab monotherapy. Treatment was associated with proinflammatory changes in the tumor microenvironment, particularly in ovarian cancer where the changes were associated with better clinical outcomes.TRIAL REGISTRATION NUMBER: NCT02335918.

  View details for DOI 10.1136/jitc-2022-005147

  View details for PubMedID 35940825

• Evaluation of tumor responses and overall survival in patients with recurrent glioblastoma (GBM) from a phase IIa trial of a CMV vaccine immunotherapeutic candidate (VBI-1901). Wen, P. Y., Reardon, D. A., Forst, D., Lee, E., Haas, B., Daoud, T., Berthoud, T., Diaz-Mitoma, F., Anderson, D. E., Lassman, A. B., Iwamoto, F. LIPPINCOTT WILLIAMS & WILKINS. 2022

  View details for Web of Science ID 000863680300665

• Efficacy proof-of-concept from a phase 1 study of a novel therapeutic peptide, ST101, targeting the oncogenic transcription factor C/EBPß in patients with refractory solid tumors Evans, T., Lakhani, N. J., Arkenau, H., McKean, M., Symeonides, S. N., Iwamoto, F., Rotolo, J., Capiaux, G., Michel, R., Kaesshaefer, S., Bexon, A., Falchook, G. LIPPINCOTT WILLIAMS & WILKINS. 2022

  View details for Web of Science ID 000863680300907

• The PROTECT Study: A phase II, open-label trial of prophylactic skin toxicity therapy with clindamycin and triamcinolone in patients with glioblastoma treated with tumor-treating fields Lacouture, M. E., Ketosugbo, K., Dusza, S. W., Goldlust, S. A., Kumthekar, P., Iwamoto, F. LIPPINCOTT WILLIAMS & WILKINS. 2022

  View details for Web of Science ID 000863680304836

• Axicabtagene Ciloleucel in Patients Ineligible for ZUMA-1 Because of CNS Involvement and/or HIV: A Multicenter Experience. Journal of immunotherapy (Hagerstown, Md. : 1997) Yuen, C. A., Hsu, J. M., Van Besien, K., Reshef, R., Iwamoto, F. M., Haggiagi, A., Liechty, B., Zhang, C., Wesley, S. F., Magge, R. 2022; 45 (5): 254-262

  Abstract

  Secondary central nervous system lymphoma (SCNSL) is associated with poor prognosis and new therapeutic approaches are needed. The pivotal trial that led to US Food and Drug Administration (FDA) approval of axicabtagene ciloleucel excluded patients with SCNSL and human immunodeficiency virus. In this multi-institutional retrospective study, 14 SCNSL patients treated with axicabtagene ciloleucel, 3 of whom had human immunodeficiency virus, experienced rates of severe neurotoxicity and complete response of 32% and 58%, respectively. This is similar to rates observed in the pivotal ZUMA-1 trial that led to the approval of axi-cel at median follow-up of 5.9 months. Chimeric antigen receptor T-cell therapy is potentially a life-saving therapy for SCNSL patients and should not be withheld.

  View details for DOI 10.1097/CJI.0000000000000416

  View details for PubMedID 35404315

  View details for PubMedCentralID PMC13215045

• Diagnosis of Leptomeningeal Metastasis in Women With Breast Cancer Through Identification of Tumor Cells in Cerebrospinal Fluid Using the CNSide™ Assay. Clinical breast cancer Wooster, M., McGuinness, J. E., Fenn, K. M., Singh, V. M., Franks, L. E., Lee, S., Cieremans, D., Lassman, A. B., Hershman, D. L., Crew, K. D., Accordino, M. K., Trivedi, M. S., Iwamoto, F., Welch, M. R., Haggiagi, A., Schultz, R. D., Huynh, L., Sales, E., Fisher, D., Mayer, J. A., Kreisl, T., Kalinsky, K. 2022; 22 (4): e457-e462

  Abstract

  Diagnosis of LM is limited by low sensitivity of cerebrospinal fluid (CSF) cytopathology. Detecting tumor cells in CSF (CSF-TCs) might be more sensitive. We evaluated if CNSide (CNSide), a novel assay for tumor cell detection in CSF, can detect CSF-TCs better than conventional CSF cytology.We enrolled adults with metastatic breast cancer and clinical suspicion for LM to undergo lumbar puncture (LP) for CSF cytopathology and CNSide. CNSide captured CSF-TCs using a primary 10-antibody mixture, streptavidin-coated microfluidic channel, and biotinylated secondary antibodies. CSF-TCs were assessed for estrogen receptor (ER) expression by fluorescent antibody and HER2 amplification by fluorescent in situ hybridization (FISH). CSF cell-free DNA (cfDNA) was extracted for next-generation sequencing (NGS). Leptomeningeal disease was defined as positive CSF cytology and/or unequivocal MRI findings. We calculated sensitivity and specificity of CSF cytology and CNSide for the diagnosis of LM.Ten patients, median age 51 years (range, 37-64), underwent diagnostic LP with CSF evaluation by cytology and CNSide. CNSide had sensitivity of 100% (95% Confidence Interval [CI], 40%-100%) and specificity of 83% (95% CI, 36%-100%) for LM. Among these patients, concordance of ER and HER2 status between CSF-TCs and metastatic biopsy were 60% and 75%, respectively. NGS of CSF cfDNA identified somatic mutations in three patients, including one with PIK3CA p.H1047L in blood and CSF.CNSide may be a viable platform to detect CSF-TCs, with potential use as a diagnostic tool for LM in patients with metastatic breast cancer. Additional, larger studies are warranted.

  View details for DOI 10.1016/j.clbc.2021.11.002

  View details for PubMedID 34920954

  View details for PubMedCentralID PMC9106761

• ERK1/2 Phosphorylation Predicts Survival Following anti-pd-1 Immunotherapy in Recurrent Glioblastoma Gonzalez, V., Amidei, C., Basu, U., Brat, D., Bruce, J., Burdett, K., Burks, J., Canoll, P., Chen, A., Chen, L., Cieremans, D., Cloughesy, T., Cooper, L., Dmello, C., Gould, A., Heimberger, A., Horbinski, C., Iwamoto, F., Jaishankar, D., Kane, J., Kang, S., Kassab, C., Laffleur, B., Lee-Chang, C., Ling, X., Lukas, R., McCord, M., Prins, R., Rabadan, R., Rothschild, G., Shilati, J., Sims, P., Sonabend, A., Upadhyayula, P., Yamaguchi, J., Yuan, J., Zhang, B., Zhang, D., Zhang, H., Zhao, J., Zhao, W. AMER ASSOC NEUROLOGICAL SURGEONS. 2022

  View details for Web of Science ID 001132701400131

• Causes of Death and End-of-Life Care in Patients With Intracranial High-Grade Gliomas: A Retrospective Observational Study. Neurology Barbaro, M., Blinderman, C. D., Iwamoto, F. M., Kreisl, T. N., Welch, M. R., Odia, Y., Donovan, L. E., Joanta-Gomez, A. E., Evans, K. A., Lassman, A. B. 2022; 98 (3): e260-e266

  Abstract

  To understand patterns of care and circumstances surrounding end of life in patients with intracranial gliomas.We retrospectively analyzed end-of-life circumstances in patients with intracranial high-grade gliomas at Columbia University Irving Medical Center who died from January 2014 to February 2019, including cause of death, location of death, and implementation of comfort measures and resuscitative efforts.There were 152 patients (95 men, 57 women; median age at death 61.5 years, range 24-87 years) who died from January 2014 to February 2019 with adequate data surrounding end-of-life circumstances. Clinical tumor progression (n = 117, 77.0%) was the most common cause of death, with all patients transitioned to comfort measures. Other causes included, but were not limited to, infection (19, 12.5%); intratumoral hemorrhage (5, 3.3%); seizures (8, 5.3%); cerebral edema (4, 2.6%); pulmonary embolism (4, 2.6%); autonomic failure (2, 1.3%); and hemorrhagic shock (2, 1.3%). Multiple mortal events were identified in 10 (8.5%). Seventy-three patients (48.0%) died at home with hospice. Other locations were inpatient hospice (40, 26.3%); acute care hospital (34, 22.4%), including 27 (17.8%) with and 7 (4.6%) without comfort measures; skilled nursing facility (4, 3.3%), including 3 (2.0%) with and 1 (0.7%) without comfort measures; or religious facility (1, 0.7%) with comfort measures. Acute cardiac or pulmonary resuscitation was performed in 20 patients (13.2%).Clinical tumor progression was the most common (77.0%) cause of death, followed by infection (12.5%). Hospice or comfort measures were ultimately implemented in 94.7% of patients, although resuscitation was performed in 13.2%. Improved understanding of circumstances surrounding death, frequency of use of hospice services, and frequency of resuscitative efforts in patients with gliomas may allow physicians to more accurately discuss end-of-life expectations with patients and caregivers, facilitating informed care planning.

  View details for DOI 10.1212/WNL.0000000000013057

  View details for PubMedID 34795049

  View details for PubMedCentralID PMC8792811

• COGNITIVE FUNCTION (CF) & QUALITY OF LIFE (QOL) IN PATIENTS TREATED WITH PROCARBAZINE, CCNU, & VINCRISTINE (PCV) plus RADIOTHERAPY (RT) VS. RT FOR ANAPLASTIC OLIGODENDROGLIOMA (AO) ON NRG RTOG TRIAL 9402 Donovan, L., Won, M., Cairncross, J., Iwamoto, F., Buckner, J., Fink, K., Bahary, J., Hartford, A., Souhami, L., Nguyen, T., Cescon, T., Mishra, M., Barani, I., Pu, A., Roa, W., Huang, J., Polley, M., Mehta, M. OXFORD UNIV PRESS INC. 2021: 154

  View details for Web of Science ID 000757356200605

• NEUROTOXICITY RELATED TO CAR T-CELL THERAPY IN PATIENTS WITH SECONDARY CENTRAL NERVOUS SYSTEM LYMPHOMA Yuen, C., Wesley, S., Van Besien, K., Hsu, J., Reshef, R., Iwamoto, F., Haggiagi, A., Magge, R. OXFORD UNIV PRESS INC. 2021: 147

  View details for Web of Science ID 000757356200577

• STATUS AS A CLINICAL TRIAL PARTICIPANT AND OUTCOME IN IDH-WILDTYPE GLIOBLASTOMA Pan, P., Joanta-Gomez, A., Iwamoto, F., Welch, M., Haggiagi, A., Donovan, L., Barbaro, M., Yuen, C., Lassman, A. OXFORD UNIV PRESS INC. 2021: 157-158

  View details for Web of Science ID 000757356200620

• Evaluation of GM-CSF and AS01_B adjuvants in a phase I/IIa trial of a therapeutic CMV vaccine (VBI-1901) against recurrent glioblastoma (GBM). Wen, P. Y., Reardon, D. A., Forst, D., Lee, E., Iwamoto, F., Diaz-Mitoma, F., Anderson, D. E., Lassman, A. B. LIPPINCOTT WILLIAMS & WILKINS. 2021

  View details for DOI 10.1200/JCO.2021.39.15_suppl.2047

  View details for Web of Science ID 000708120601006

• Focal Mass Lesions Merritt’s Neurology Bell, M., Khandji, A., Iwamoto, F. M. 2021; 14
• Surgery plus adjuvant radiotherapy for primary central nervous system lymphoma. British journal of neurosurgery Kinslow, C. J., Rae, A. I., Neugut, A. I., Adams, C. M., Cheng, S. K., Sheth, S. A., McKhann, G. M., Sisti, M. B., Bruce, J. N., Iwamoto, F. M., Sonabend, A. M., Wang, T. J. 2020; 34 (6): 690-696

  Abstract

  Objective: Recent studies of primary central nervous system lymphoma (PCNSL) have found a positive association between cytoreductive surgery and survival, challenging the traditional notion that surgery is not beneficial and potentially harmful. However, no studies have examined the potential added benefits of adjuvant treatment in the post-operative setting. Here, we investigate survival in PCNSL patients treated with surgery plus radiation therapy (RT).Methods: The Surveillance, Epidemiology, and End-Results Program was used to identify patients with PCNSL from 1995-2013. We retrospectively analyzed the relationship between treatment, prognostic factors, and survival using case-control design. Treatment categories were compared to biopsy alone.Results: We identified 5417 cases. Median survival times for biopsy alone (n = 1824, 34%), biopsy + RT (n = 1460, 27%), surgery alone (n = 1222, 27%), and surgery + RT (n = 911, 17%) were 7, 8, 20, and 27 months, respectively. On multivariable analysis, surgery + RT was associated with improved survival over surgery alone (hazard ratio [HR] = 0.58 [95% confidence interval = 0.53-0.64] vs. HR = 0.71 [0.65-0.77]). Adjuvant RT was associated with improved survival, regardless of the extent of resection. HR's for subtotal resection, gross-total resection, subtotal resection + RT, and gross-total resection + RT were 0.77 (0.66-0.89), 0.66 (0.57-0.76), 0.62 (0.52-0.72), and 0.54 (0.46-0.63), respectively. Survival improved after adjuvant RT in patients under and over 60 years old. All findings were confirmed by multivariable analysis of cause-specific survival.Conclusion: Adjuvant RT was associated with improved survival in PCNSL patients who underwent surgery. Although these data are hypothesis-generating, additional information on neurotoxicity, dosing, and concurrent chemotherapy will be necessary to validate these findings. Cytoreductive surgery for PCNSL is common in the general population, and more studies are needed to assess optimal treatment in the post-operative setting.

  View details for DOI 10.1080/02688697.2019.1710820

  View details for PubMedID 31931632

• Successful Clinical Trial of Chronic Convection-Enhanced Drug Delivery Via an Implanted Pump Bruce, J. N., Spinazzi, E. F., Lassman, A., Iwamoto, F., Welch, M., Banu, M. A., Argenziano, M., Upadhyayula, P. S., Lignelli, A., Grinband, J., Sims, P., D'Amico, R., Canoll, P. D. OXFORD UNIV PRESS INC. 2020: 314

  View details for Web of Science ID 000616638600782

• Effect of Vocimagene Amiretrorepvec in Combination With Flucytosine vs Standard of Care on Survival Following Tumor Resection in Patients With Recurrent High-Grade Glioma: A Randomized Clinical Trial. JAMA oncology Cloughesy, T. F., Petrecca, K., Walbert, T., Butowski, N., Salacz, M., Perry, J., Damek, D., Bota, D., Bettegowda, C., Zhu, J. J., Iwamoto, F., Placantonakis, D., Kim, L., Elder, B., Kaptain, G., Cachia, D., Moshel, Y., Brem, S., Piccioni, D., Landolfi, J., Chen, C. C., Gruber, H., Rao, A. R., Hogan, D., Accomando, W., Ostertag, D., Montellano, T. T., Kheoh, T., Kabbinavar, F., Vogelbaum, M. A. 2020; 6 (12): 1939-1946

  Abstract

  New treatments are needed to improve the prognosis of patients with recurrent high-grade glioma.To compare overall survival for patients receiving tumor resection followed by vocimagene amiretrorepvec (Toca 511) with flucytosine (Toca FC) vs standard of care (SOC).A randomized, open-label phase 2/3 trial (TOCA 5) in 58 centers in the US, Canada, Israel, and South Korea, comparing posttumor resection treatment with Toca 511 followed by Toca FC vs a defined single choice of approved (SOC) therapies was conducted from November 30, 2015, to December 20, 2019. Patients received tumor resection for first or second recurrence of glioblastoma or anaplastic astrocytoma.Patients were randomized 1:1 to receive Toca 511/FC (n = 201) or SOC control (n = 202). For the Toca 511/FC group, patients received Toca 511 injected into the resection cavity wall at the time of surgery, followed by cycles of oral Toca FC 6 weeks after surgery. For the SOC control group, patients received investigators' choice of single therapy: lomustine, temozolomide, or bevacizumab.The primary outcome was overall survival (OS) in time from randomization date to death due to any cause. Secondary outcomes reported in this study included safety, durable response rate (DRR), duration of DRR, durable clinical benefit rate, OS and DRR by IDH1 variant status, and 12-month OS.All 403 randomized patients (median [SD] age: 56 [11.46] years; 62.5% [252] men) were included in the efficacy analysis, and 400 patients were included in the safety analysis (3 patients on the SOC group did not receive resection). Final analysis included 271 deaths (141 deaths in the Toca 511/FC group and 130 deaths in the SOC control group). The median follow-up was 22.8 months. The median OS was 11.10 months for the Toca 511/FC group and 12.22 months for the control group (hazard ratio, 1.06; 95% CI 0.83, 1.35; P = .62). The secondary end points did not demonstrate statistically significant differences. The rates of adverse events were similar in the Toca 511/FC group and the SOC control group.Among patients who underwent tumor resection for first or second recurrence of glioblastoma or anaplastic astrocytoma, administration of Toca 511 and Toca FC, compared with SOC, did not improve overall survival or other efficacy end points.ClinicalTrials.gov Identifier: NCT02414165.

  View details for DOI 10.1001/jamaoncol.2020.3161

  View details for PubMedID 33119048

  View details for PubMedCentralID PMC7596685

• COVID-19 INFECTION DURING CHEMOTHERAPY FOR MALIGNANT GLIOMA: OUTCOMES AMONG 3 PATIENTS Kim, E., Koshy, A., Higgins, S., Lassman, A., Iwamoto, F. OXFORD UNIV PRESS INC. 2020: 25

  View details for Web of Science ID 000590061300104

• IDENTIFICATION OF A BASELINE BIOMARKER ASSOCIATED WITH TUMOR RESPONSES IN A PHASE I/IIA TRIAL OF A THERAPEUTIC CMV VACCINE AGAINST RECURRENT GLIOBLASTOMA (GBM) Wen, P., Reardon, D., Forst, D., Lee, E., Iwamoto, F., Diaz-Mitoma, F., Anderson, D., Lassman, A. OXFORD UNIV PRESS INC. 2020: 34

  View details for Web of Science ID 000590061300142

• DISAPPEARING DOTS - TRANSIENT LATE ENHANCING LESIONS YEARS AFTER BRAIN RADIOTHERAPY Pan, P., Padilla, O., Buss, E., Elliston, C., Wang, T., Joanta-Gomez, A., Lignelli-Dipple, A., Iwamoto, F., Kreisl, T., Welch, M., Haggiagi, A., Donovan, L., Barbaro, M., Bruce, J., Canoll, P., Lassman, A. OXFORD UNIV PRESS INC. 2020: 163

  View details for Web of Science ID 000590061300681

• PREDICTIVE EVALUATION OF QUANTITATIVE SPATIAL PROFILING OF THE TUMOR MICROENVIRONMENT BY MULTIPLEX IMMUNOFLUORESCENCE IN RECURRENT GLIOBLASTOMA TREATED WITH PD-1 INHIBITORS Cieremans, D., Kim, J., Valencia, A., Santos, J., Bordeaux, J., Tran, T., Vaupel, C., Dakappagari, N., Tangri, S., Iwamoto, F. OXFORD UNIV PRESS INC. 2020: 7

  View details for Web of Science ID 000590061300028

• PHASE IB CLINICAL TRIAL OF CHRONIC CONVECTIONENHANCED DELIVERY OF TOPOTECAN FOR RECURRENT GLIOBLASTOMA Bruce, J., Spinazzi, E., Lassman, A., Iwamoto, F., Welch, M., Banu, M., Argenziano, M., Upadhyayula, P., Agar, N. Y. R., Humala, N., Marie, T., Pereira, B., Sudhakar, T., Mahajan, A., Neira, J., Lignelli-Dipple, A., Grinband, J., Sims, P., D'Amico, R., Canoll, P. OXFORD UNIV PRESS INC. 2020: 48

  View details for Web of Science ID 000590061300193

• A Bayesian adaptive randomized phase II multicenter trial of bevacizumab with or without vorinostat in adults with recurrent glioblastoma. Neuro-oncology Puduvalli, V. K., Wu, J., Yuan, Y., Armstrong, T. S., Vera, E., Wu, J., Xu, J., Giglio, P., Colman, H., Walbert, T., Raizer, J., Groves, M. D., Tran, D., Iwamoto, F., Avgeropoulos, N., Paleologos, N., Fink, K., Peereboom, D., Chamberlain, M., Merrell, R., Penas Prado, M., Yung, W. K., Gilbert, M. R. 2020; 22 (10): 1505-1515

  Abstract

  Bevacizumab has promising activity against recurrent glioblastoma (GBM). However, acquired resistance to this agent results in tumor recurrence. We hypothesized that vorinostat, a histone deacetylase (HDAC) inhibitor with anti-angiogenic effects, would prevent acquired resistance to bevacizumab.This multicenter phase II trial used a Bayesian adaptive design to randomize patients with recurrent GBM to bevacizumab alone or bevacizumab plus vorinostat with the primary endpoint of progression-free survival (PFS) and secondary endpoints of overall survival (OS) and clinical outcomes assessment (MD Anderson Symptom Inventory Brain Tumor module [MDASI-BT]). Eligible patients were adults (≥18 y) with histologically confirmed GBM recurrent after prior radiation therapy, with adequate organ function, KPS ≥60, and no prior bevacizumab or HDAC inhibitors.Ninety patients (bevacizumab + vorinostat: 49, bevacizumab: 41) were enrolled, of whom 74 were evaluable for PFS (bevacizumab + vorinostat: 44, bevacizumab: 30). Median PFS (3.7 vs 3.9 mo, P = 0.94, hazard ratio [HR] 0.63 [95% CI: 0.38, 1.06, P = 0.08]), median OS (7.8 vs 9.3 mo, P = 0.64, HR 0.93 [95% CI: 0.5, 1.6, P = 0.79]) and clinical benefit were similar between the 2 arms. Toxicity (grade ≥3) in 85 evaluable patients included hypertension (n = 37), neurological changes (n = 2), anorexia (n = 2), infections (n = 9), wound dehiscence (n = 2), deep vein thrombosis/pulmonary embolism (n = 2), and colonic perforation (n = 1).Bevacizumab combined with vorinostat did not yield improvement in PFS or OS or clinical benefit compared with bevacizumab alone or a clinical benefit in adults with recurrent GBM. This trial is the first to test a Bayesian adaptive design with adaptive randomization and Bayesian continuous monitoring in patients with primary brain tumor and demonstrates the feasibility of using complex Bayesian adaptive design in a multicenter setting.

  View details for DOI 10.1093/neuonc/noaa062

  View details for PubMedID 32166308

  View details for PubMedCentralID PMC7686463

• Prevention and Management of Dermatologic Adverse Events Associated With Tumor Treating Fields in Patients With Glioblastoma. Frontiers in oncology Lacouture, M. E., Anadkat, M. J., Ballo, M. T., Iwamoto, F., Jeyapalan, S. A., La Rocca, R. V., Schwartz, M., Serventi, J. N., Glas, M. 2020; 10: 1045

  Abstract

  Importance: Tumor Treating Fields (TTFields) are an anti-mitotic treatment approved for treating newly diagnosed and recurrent glioblastoma, and mesothelioma. TTFields in glioblastoma comprise alternating electric fields (200 kHz) delivered continuously, ideally for ≥18 h/day, to the tumor bed via transducer arrays placed on the shaved scalp. When applied locoregionally to the tumor bed and combined with systemic temozolomide chemotherapy, TTFields improved overall survival vs. temozolomide alone in patients with newly diagnosed glioblastoma. Improved efficacy outcomes with TTFields were demonstrated, while maintaining a well-tolerated and manageable safety profile. The most commonly-reported TTFields-associated adverse events (AEs) are beneath-array dermatologic events. Since survival benefit from TTFields increases with duration-of-use, prevention and management of skin AEs are critical to maximize adherence. This paper describes TTFields-associated dermatological AEs and recommends prevention and management strategies based on clinical trial evidence and real-world clinical experience. Observations: TTFields-associated skin reactions include contact dermatitis (irritant/allergic), hyperhidrosis, xerosis or pruritus, and more rarely, skin erosions/ulcers and infections. Skin AEs may be prevented through skin-care and shifting (~2 cm) of array position during changes. TTFields-related skin AE management should be based on clinical phenotype and severity. Depending on diagnosis, recommended treatments include antibiotics, skin barrier films, moisturizers, topical corticosteroids, and antiperspirants. Water-based lotions, soaps, foams, and solutions with minimal impact on electrical impedance are preferred with TTFields use over petroleum-based ointments, which increase impedance. Conclusions: Early identification, prophylactic measures, and symptomatic skin AE management help patients maximize TTFields usage, while maintaining quality-of-life and optimizing therapeutic benefit. Implications for practice: TTFields confer a survival benefit in patients with glioblastoma that correlates positively with duration of daily use. Skin events (rash) are the primary treatment-related AE that can limit duration of use. The recommendations described here will help healthcare professionals to recognize, prevent, and manage dermatologic AEs associated with TTFields treatment. These recommendations may improve cutaneous health and support adherence to therapy, both of which would maximize treatment outcomes.

  View details for DOI 10.3389/fonc.2020.01045

  View details for PubMedID 32850308

  View details for PubMedCentralID PMC7399624

• Predictive evaluation of quantitative spatial profiling of the tumor microenvironment by multiplex immunofluorescence in recurrent glioblastoma treated with PD-1 inhibitors. Cieremans, D., Kim, J., Valencia, A., Santos, J., Bordeaux, J., Thai Tran, Vaupel, C., Dakappagari, N., Tangri, S., Iwamoto, F. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for Web of Science ID 000560368304583

• Randomized phase II study of rituximab, methotrexate (MTX), procarbazine, vincristine, and cytarabine (RMPV-A) with and without low-dose whole-brain radiotherapy (LD-WBRT) for newly diagnosed primary CNS lymphoma (PCNSL). Omuro, A., DeAngelis, L., Karrison, T., Bovi, J. A., Rosenblum, M., Corn, B. W., Correa, D., Wefel, J., Aneja, S., Grommes, C., Schaff, L., Waggoner, S. E., Lallana, E. C., Werner-Wasik, M., Iwamoto, F., Robinson, T. J., Donnelly, E., Struve, T., Won, M., Mehta, M. P., NRG LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for Web of Science ID 000560368301196

• Phase II trial of bevacizumab and temozolomide for treatment of elderly patients with newly diagnosed glioblastoma. Molaie, D., Lai, A., Ellingson, B. M., Thien Nguyen, Bahng, H., Filka, E., Green, S., Pope, W. B., Leng, M., Yong, W. H., Green, R. M., Polikoff, J., Spier, L., Iwamoto, F., Lassman, A. B., Cloughesy, T., Nghiemphu, P. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for Web of Science ID 000560368301235

• Diagnosis of leptomeningeal metastasis (LM) through identification of circulating tumor cells (CTCs) in cerebrospinal fluid (CSF). Fenn, K., Singh, V. M., Lee, S., Cieremans, D., Lassman, A. B., Hershman, D. L., Crew, K. D., Accordino, M., Trivedi, M. S., Iwamoto, F., Schultz, R., Huynh, L., Sales, E., Fisher, D. M., Mayer, J. A., Kreisl, T., Kalinsky, K. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for Web of Science ID 000560368301458

• Can patient selection and neoadjuvant administration resuscitate PD-1 inhibitors for glioblastoma? Journal of neurosurgery Arrieta, V. A., Iwamoto, F., Lukas, R. V., Sachdev, S., Rabadan, R., Sonabend, A. M. 2020; 132 (5): 1667-1672

  View details for DOI 10.3171/2019.9.JNS192523

  View details for PubMedID 31812138

• Successful Clinical Trial of Chronic Convection-Enhanced Drug Delivery via an Implanted Pump Bruce, J. N., Spinazzi, E., Lassman, A., Iwamoto, F., Welch, M., Banu, M., Lignelli, A., Grinband, J., Sims, P., D'Amico, R., Canoll, P. AMER ASSOC NEUROLOGICAL SURGEONS. 2020: 85

  View details for Web of Science ID 000523185100172

• Neuro-oncological emergencies On-Call Neurology Iwamoto, F. M. 2020
• TOCA 511 & TOCA FC VERSUS STANDARD OF CARE IN PATIENTS WITH RECURRENT HIGH GRADE GLIOMA Cloughesy, T., Petrecca, K., Walbert, T., Butowski, N., Salacz, M., Perry, J., Damek, D., Bota, D., Bettegowda, C., Zhu, J., Iwamoto, F., Placantonakis, D., Martinez, N., Elder, J., Kaptain, G., Cachia, D., Moshel, Y., Brem, S., Picconi, D., Nam Tran, Nam, D., Park, C., Landolfi, J., Tran, D., Ramakrishna, R., Fink, K., Heros, D., Zadeh, G., Nicholas, G., Mehta, V., Robins, H., Chen, C., Pitz, M., Heth, J., Nagpal, S., Pearlman, M., Ahluwalia, M., Mohile, N., Merrell, R., Schiff, D., Thompson, R., Davis, R., Macdonald, D., Kheoh, T., Kabbinavar, F., Lossos, A., Vogelbaum, M. OXFORD UNIV PRESS INC. 2019: 284

  View details for Web of Science ID 000509478706204

• TRIAL IN PROGRESS: CA209-9Y8 PHASE 2 TRIAL OF TUMOR TREATING FIELDS (TTFS), NIVOLUMAB PLUS/MINUS IPILIMUMAB FOR BEVACIZUMAB-NAIVE, RECURRENT GLIOBLASTOMA Odia, Y., Iwamoto, F. OXFORD UNIV PRESS INC. 2019: 3

  View details for Web of Science ID 000509478700009

• INTERIM RESULTS OF THE EXTENSION PHASE OF A PHASE I/IIA TRIAL OF A THERAPEUTIC CMV VACCINE AGAINST RECURRENT GLIOBLASTOMA (GBM) Wen, P., Reardon, D., Lee, E., Iwamoto, F., Anderson, D., Diaz-Mitoma, F., Lassman, A. OXFORD UNIV PRESS INC. 2019: 7

  View details for Web of Science ID 000509478700026

• HYPERPROGRESSIVE DISEASE IN PATIENTS WITH RECURRENT HIGH GRADE GLIOMAS TREATED WITH IMMUNE CHECKPOINT INHIBITORS OR CYTOTOXIC THERAPIES Donovan, L., Gedailovich, S., Joanta-Gomez, A., Lassman, A., Iwamoto, F. OXFORD UNIV PRESS INC. 2019: 146

  View details for Web of Science ID 000509478703085

• PATTERNS OF CARE AT END OF LIFE IN PATIENTS WITH GLIOMA Barbaro, M., Blinderman, C., Iwamoto, F., Kreisl, T., Welch, M., Odia, Y., Donovan, L., Evans, K., Lassman, A. OXFORD UNIV PRESS INC. 2019: 204-205

  View details for Web of Science ID 000509478704157

• SINGLE AGENT ONC201 IN PREVIOUSLY-TREATED, PROGRESSIVE ADULT H3 K27M-MUTANT GLIOMA Arrillaga-Romany, I., Kurz, S., Sumrall, A., Butowski, N., Harrison, R., DeGroot, J., Chi, A., Sulman, E., Shonka, N., Umemura, Y., Odia, Y., Mehta, M., Iwamoto, F., Nghiemphu, P., Cloughesy, T., Tarapore, R., Merdinger, K., Oster, W., Allen, J., Batchelor, T., Lassman, A., Wen, P. OXFORD UNIV PRESS INC. 2019: 20-21

  View details for Web of Science ID 000509478700078

• Immunotherapy Against Gliomas: is the Breakthrough Near? Drugs Lukas, R. V., Wainwright, D. A., Horbinski, C. M., Iwamoto, F. M., Sonabend, A. M. 2019; 79 (17): 1839-1848

  Abstract

  Immunotherapeutic approaches have been, and continue to be, aggressively investigated in the treatment of infiltrating gliomas. While the results of late-phase clinical studies have been disappointing in this disease space thus far, the success of immunotherapies in other malignancies as well as the incremental gains in our understanding of immune-tumour interactions in gliomas has fuelled a strong continued interest of their evaluation in these tumours. We discuss a range of immunotherapeutic approaches including, but not limited to, vaccines, checkpoint inhibitors, oncolytic viruses, and gene therapies. Potential biomarkers under investigation to help elucidate which patients may respond or not respond to immunotherapeutic regimens are reviewed. Directions for future investigations are also noted.

  View details for DOI 10.1007/s40265-019-01203-z

  View details for PubMedID 31598900

  View details for PubMedCentralID PMC6868342

• Hyperprogressive disease in patients with recurrent high grade gliomas treated with immune checkpoint inhibitors or other therapies. Donovan, L., Gedailovich, S., Joanta-Gomez, A., Schulte, J., Teri Nguyen Kreisl, Lassman, A. B., Welch, M., Haggiagi, A., Iwamoto, F. AMER SOC CLINICAL ONCOLOGY. 2019

  View details for DOI 10.1200/JCO.2019.37.15_suppl.e13575

  View details for Web of Science ID 000487345800389

• Study of a smartphone-based symptom assessment (OurBrainBank) for subjects with glioblastomas. Morris, J., Hellman, B., Duprey, K., Ellen, J., Nayak, L., Iwamoto, F. AMER SOC CLINICAL ONCOLOGY. 2019

  View details for DOI 10.1200/JCO.2019.37.15_suppl.e13574

  View details for Web of Science ID 000487345800388

• Interim results of a phase I/IIa trial of a therapeutic CMV vaccine against recurrent glioblastoma (GBM). Lassman, A. B., Reardon, D. A., Lee, E., Iwamoto, F., Diaz-Mitoma, F., Anderson, D. E., Wen, P. Y. AMER SOC CLINICAL ONCOLOGY. 2019

  View details for DOI 10.1200/JCO.2019.37.15_suppl.2048

  View details for Web of Science ID 000487345804430

• Incidence of Distant Recurrence in Adult Gliomas Pan, P., Wang, T., Iwamoto, F., Kreisl, T., Welch, M., Haggiagi, A., Lignelli, A., Lassman, A. LIPPINCOTT WILLIAMS & WILKINS. 2019

  View details for Web of Science ID 000475965900245

• Craniotomy and Survival for Primary Central Nervous System Lymphoma. Neurosurgery Rae, A. I., Mehta, A., Cloney, M., Kinslow, C. J., Wang, T. J., Bhagat, G., Canoll, P. D., Zanazzi, G. J., Sisti, M. B., Sheth, S. A., Connolly, E. S., McKhann, G. M., Bruce, J. N., Iwamoto, F. M., Sonabend, A. M. 2019; 84 (4): 935-944

  Abstract

  Cytoreductive surgery is considered controversial for primary central nervous system lymphoma (PCNSL).To investigate survival following craniotomy or biopsy for PCNSL.The National Cancer Database-Participant User File (NCDB, n = 8936), Surveillance, Epidemiology, and End Results Program (SEER, n = 4636), and an institutional series (IS, n = 132) were used. We retrospectively investigated the relationship between craniotomy, prognostic factors, and survival for PCNSL using case-control design.In NCDB, craniotomy was associated with increased median survival over biopsy (19.5 vs 11.0 mo), independent of subsequent radiation and chemotherapy (hazard ratio [HR] 0.80, P < .001). We found a similar trend with survival for craniotomy vs biopsy in the IS (HR 0.68, P = .15). In SEER, gross total resection was associated with increased median survival over biopsy (29 vs 10 mo, HR 0.68, P < .001). The survival benefit associated with craniotomy was greater within recursive partitioning analysis (RPA) class 1 group in NCDB (95.1 vs 29.1 mo, HR 0.66, P < .001), but was smaller for RPA 2-3 (14.9 vs 10.0 mo, HR 0.86, P < .001). A surgical risk category (RC) considering lesion location and number, age, and frailty was developed. Craniotomy was associated with increased survival vs biopsy for patients with low RC (133.4 vs 41.0 mo, HR 0.33, P = .01), but not high RC in the IS.Craniotomy is associated with increased survival over biopsy for PCNSL in 3 retrospective datasets. Prospective studies are necessary to adequately evaluate this relationship. Such studies should evaluate patients most likely to benefit from cytoreductive surgery, ie, those with favorable RPA and RC.

  View details for DOI 10.1093/neuros/nyy096

  View details for PubMedID 29660011

  View details for PubMedCentralID PMC6500886

• Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma. Nature medicine Zhao, J., Chen, A. X., Gartrell, R. D., Silverman, A. M., Aparicio, L., Chu, T., Bordbar, D., Shan, D., Samanamud, J., Mahajan, A., Filip, I., Orenbuch, R., Goetz, M., Yamaguchi, J. T., Cloney, M., Horbinski, C., Lukas, R. V., Raizer, J., Rae, A. I., Yuan, J., Canoll, P., Bruce, J. N., Saenger, Y. M., Sims, P., Iwamoto, F. M., Sonabend, A. M., Rabadan, R. 2019; 25 (3): 462-469

  Abstract

  Immune checkpoint inhibitors have been successful across several tumor types; however, their efficacy has been uncommon and unpredictable in glioblastomas (GBM), where <10% of patients show long-term responses. To understand the molecular determinants of immunotherapeutic response in GBM, we longitudinally profiled 66 patients, including 17 long-term responders, during standard therapy and after treatment with PD-1 inhibitors (nivolumab or pembrolizumab). Genomic and transcriptomic analysis revealed a significant enrichment of PTEN mutations associated with immunosuppressive expression signatures in non-responders, and an enrichment of MAPK pathway alterations (PTPN11, BRAF) in responders. Responsive tumors were also associated with branched patterns of evolution from the elimination of neoepitopes as well as with differences in T cell clonal diversity and tumor microenvironment profiles. Our study shows that clinical response to anti-PD-1 immunotherapy in GBM is associated with specific molecular alterations, immune expression signatures, and immune infiltration that reflect the tumor's clonal evolution during treatment.

  View details for DOI 10.1038/s41591-019-0349-y

  View details for PubMedID 30742119

• PHASE 2 TRIAL OF SL-701+BEVACIZUMAB IN PATIENTS WITH PREVIOUSLY TREATED GLIOBLASTOMA (GBM) MEETS PRIMARY ENDPOINT OF OS-12, WITH PRELIMINARY CORRELATION BETWEEN LONG-TERM SURVIVAL AND TARGET-SPECIFIC CD8+T CELL IMMUNE RESPONSE Peereboom, D., Nabors, L., Kumthekar, P., Badruddoja, M., Fink, K., Lieberman, F., Phuphanich, S., Dunbar, E., Walbert, T., Schiff, D., Tran, D., Ashby, L., Butowski, N., Iwamoto, F., Lindsay, R., Bullington, J., Schulder, M., Sherman, J., Brooks, C., Reardon, D. OXFORD UNIV PRESS INC. 2018: 2

  View details for Web of Science ID 000460646300005

• CMV gB/pp65 eVLPs FORMULATED WITH GM-CSF AS A THERAPEUTIC VACCINE AGAINST RECURRENT GLIOBLASTOMA (GBM) Iwamoto, F., Diaz-Mitoma, F., Anderson, D., Lassman, A. B. OXFORD UNIV PRESS INC. 2018: 3

  View details for Web of Science ID 000460646300011

• PILOT STUDY OF A SMARTPHONE-BASED SYMPTOM ASSESSMENT (OURBRAINBANK) FOR SUBJECTS WITH GLIOBLASTOMAS Morris, J., Duprey, K., Hellman, B., Zak, C., Nayak, L., Iwamoto, F. OXFORD UNIV PRESS INC. 2018: 139-140

  View details for Web of Science ID 000460646300585

• FACTORS INFLUENCING RECEPTIVITY TO CLINICAL RESEARCH IN AN URBAN NEURO-ONCOLOGY PRACTICE Welch, M., Conway, G., Hillyer, G., Segall, L., Otap, D., Donovan, L., Kreisl, T., Iwamoto, F., Lassman, A. B. OXFORD UNIV PRESS INC. 2018: 139

  View details for Web of Science ID 000460646300582

• ANTI-CD27 AGONIST ANTIBODY VARLILUMAB IN COMBINATION WITH NIVOLUMAB FOR RECURRENT GLIOBLASTOMA (rGBM): PHASE 2 CLINICAL TRIAL RESULTS Reardon, D., Kaley, T., Iwamoto, F., Baehring, J., Subramaniam, D., Rawls, T., He, Y., Keler, T., Yellin, M. OXFORD UNIV PRESS INC. 2018: 6

  View details for Web of Science ID 000460646300020

• In Reply: Craniotomy and Survival for Primary Central Nervous System Lymphoma. Neurosurgery Rae, A. I., Iwamoto, F. M., Sonabend, A. M. 2018; 83 (4): E192

  View details for DOI 10.1093/neuros/nyy328

  View details for PubMedID 30085238

• Results of phase II trial of SL-701, a novel immunotherapy targeting IL-13Ra2, EphA2, and survivin, in adults with second-line recurrent glioblastoma (GBM) Peereboom, D., Nabors, L. B., Kumthekar, P., Badruddoja, M., Fink, K., Lieberman, F., Phuphanich, S., Dunbar, E., Walbert, T., Schiff, D., Tran, D. D., Ashby, L. S., Butowski, N., Iwamoto, F., Lindsay, R., Bullington, J., Schulder, M., Sherman, J., Brooks, C., Reardon, D. OXFORD UNIV PRESS. 2018

  View details for Web of Science ID 000459277300364

• First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma. Journal of translational medicine Liau, L. M., Ashkan, K., Tran, D. D., Campian, J. L., Trusheim, J. E., Cobbs, C. S., Heth, J. A., Salacz, M., Taylor, S., D'Andre, S. D., Iwamoto, F. M., Dropcho, E. J., Moshel, Y. A., Walter, K. A., Pillainayagam, C. P., Aiken, R., Chaudhary, R., Goldlust, S. A., Bota, D. A., Duic, P., Grewal, J., Elinzano, H., Toms, S. A., Lillehei, K. O., Mikkelsen, T., Walbert, T., Abram, S. R., Brenner, A. J., Brem, S., Ewend, M. G., Khagi, S., Portnow, J., Kim, L. J., Loudon, W. G., Thompson, R. C., Avigan, D. E., Fink, K. L., Geoffroy, F. J., Lindhorst, S., Lutzky, J., Sloan, A. E., Schackert, G., Krex, D., Meisel, H. J., Wu, J., Davis, R. P., Duma, C., Etame, A. B., Mathieu, D., Kesari, S., Piccioni, D., Westphal, M., Baskin, D. S., New, P. Z., Lacroix, M., May, S. A., Pluard, T. J., Tse, V., Green, R. M., Villano, J. L., Pearlman, M., Petrecca, K., Schulder, M., Taylor, L. P., Maida, A. E., Prins, R. M., Cloughesy, T. F., Mulholland, P., Bosch, M. L. 2018; 16 (1): 142

  Abstract

  Standard therapy for glioblastoma includes surgery, radiotherapy, and temozolomide. This Phase 3 trial evaluates the addition of an autologous tumor lysate-pulsed dendritic cell vaccine (DCVax®-L) to standard therapy for newly diagnosed glioblastoma.After surgery and chemoradiotherapy, patients were randomized (2:1) to receive temozolomide plus DCVax-L (n = 232) or temozolomide and placebo (n = 99). Following recurrence, all patients were allowed to receive DCVax-L, without unblinding. The primary endpoint was progression free survival (PFS); the secondary endpoint was overall survival (OS).For the intent-to-treat (ITT) population (n = 331), median OS (mOS) was 23.1 months from surgery. Because of the cross-over trial design, nearly 90% of the ITT population received DCVax-L. For patients with methylated MGMT (n = 131), mOS was 34.7 months from surgery, with a 3-year survival of 46.4%. As of this analysis, 223 patients are ≥ 30 months past their surgery date; 67 of these (30.0%) have lived ≥ 30 months and have a Kaplan-Meier (KM)-derived mOS of 46.5 months. 182 patients are ≥ 36 months past surgery; 44 of these (24.2%) have lived ≥ 36 months and have a KM-derived mOS of 88.2 months. A population of extended survivors (n = 100) with mOS of 40.5 months, not explained by known prognostic factors, will be analyzed further. Only 2.1% of ITT patients (n = 7) had a grade 3 or 4 adverse event that was deemed at least possibly related to the vaccine. Overall adverse events with DCVax were comparable to standard therapy alone.Addition of DCVax-L to standard therapy is feasible and safe in glioblastoma patients, and may extend survival. Trial registration Funded by Northwest Biotherapeutics; Clinicaltrials.gov number: NCT00045968; https://clinicaltrials.gov/ct2/show/NCT00045968?term=NCT00045968&rank=1 ; initially registered 19 September 2002.

  View details for DOI 10.1186/s12967-018-1507-6

  View details for PubMedID 29843811

  View details for PubMedCentralID PMC5975654

• Correlating Radiographical and Pathological Response to Immunotherapy in Primary Brain Tumors Schulte, J., Canoll, P., Lignelli, A., Iwamoto, F. LIPPINCOTT WILLIAMS & WILKINS. 2018

  View details for Web of Science ID 000453090803074

• Clinical and molecular characteristics of gliosarcoma and modern prognostic significance relative to conventional glioblastoma. Journal of neuro-oncology Smith, D. R., Wu, C. C., Saadatmand, H. J., Isaacson, S. R., Cheng, S. K., Sisti, M. B., Bruce, J. N., Sheth, S. A., Lassman, A. B., Iwamoto, F. M., Wang, S. H., Canoll, P., McKhann, G. M., Wang, T. J. 2018; 137 (2): 303-311

  Abstract

  Gliosarcoma is a rare histopathologic variant of glioblastoma traditionally associated with a poor prognosis. While gliosarcoma may represent a distinct clinical entity given its unique histologic composition and molecular features, its relative prognostic significance remains uncertain. While treatment of gliosarcoma generally encompasses the same standardized approach used in glioblastoma, supporting evidence is limited given its rarity. Here, we characterized 32 cases of gliosarcoma and retrospectively evaluated survival relative to 451 glioblastoma patients diagnosed during the same era within the same institution. Overall, we identified 22 primary gliosarcomas, representing 4.7% of WHO Grade IV primary glioblastomas, and 10 secondary gliosarcomas. With median age of 62, patients were predominately Caucasian (87.5%) and male (65.6%). Tumors with available molecular profiling were primarily MGMT-unmethylated (87.5%), IDH-1-preserved (100%) and EGFR wild-type (100%). Interestingly, while no significant median survival difference between primary gliosarcoma and glioblastoma was observed across the entire cohort (11.0 vs. 14.8 months, p = 0.269), median survival was worse for gliosarcoma specifically among patients who received modern temozolomide-based (TMZ) chemoradiotherapy (11.0 vs. 17.3 months, p = 0.006). Matched-pair analysis also trended toward worse median survival among gliosarcomas (11.0 vs. 19.6 months, log-rank p = 0.177, Breslow p = 0.010). While adjuvant radiotherapy (HR 0.206, p = 0.035) and TMZ-based chemotherapy (HR 0.531, p = 0.000) appeared protective, gliosarcoma emerged as a significantly poor prognostic factor on multivariate analysis (HR 3.27, p = 0.012). Collectively, our results suggest that gliosarcoma may still portend worse prognosis even with modern trimodality therapy.

  View details for DOI 10.1007/s11060-017-2718-z

  View details for PubMedID 29264835

  View details for PubMedCentralID PMC7297205

• MITIGATING SKIN IRRITATIONS WITH TUMOR TREATING FIELDS THERAPY IN GLIOBLASTOMA Lacouture, M., Iwamoto, F., Armentano, F., Kim, E. ONCOLOGY NURSING SOC. 2018

  View details for Web of Science ID 000459359400286

• Go, no-go decision making for phase 3 clinical trials: ACT IV revisited Reply LANCET ONCOLOGY Weller, M., Butowski, N., Tran, D. D., Recht, L. D., Lim, M., Hirte, H., Ashby, L., Mechtler, L., Goldlust, S. A., Iwamoto, F., Drappatz, J., O'Rourke, D. M., Wong, M., Hamilton, M. G., Finocchiaro, G., Perry, J., Wick, W., Green, J., He, Y., Turner, C. D., Yellin, M. J., Keler, T., Davis, T. A., Stupp, R., Sampson, J. H. 2017; 18 (12): E709–E710

  View details for Web of Science ID 000417001900003

• Go, no-go decision making for phase 3 clinical trials: ACT IV revisited - Authors' reply. The Lancet. Oncology Weller, M., Butowski, N., Tran, D. D., Recht, L. D., Lim, M., Hirte, H., Ashby, L., Mechtler, L., Goldlust, S. A., Iwamoto, F., Drappatz, J., O'Rourke, D. M., Wong, M., Hamilton, M. G., Finocchiaro, G., Perry, J., Wick, W., Green, J., He, Y., Turner, C. D., Yellin, M. J., Keler, T., Davis, T. A., Stupp, R., Sampson, J. H. 2017; 18 (12): e709-e710

  View details for DOI 10.1016/S1470-2045(17)30856-2

  View details for PubMedID 29208433

• KARNOFSKY PERFORMANCE STATUS AND STEROID USE IN PHASE II TRIAL OF BEVACIZUMAB AND TEMOZOLOMIDE FOR UPFRONT TREATMENT OF ELDERLY PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA Bahng, H., Green, S., Lai, A., Hu, J., Green, R., Iwamoto, F., Lassman, A. B., Cloughesy, T., Nghiemphu, P. OXFORD UNIV PRESS INC. 2017: 20

  View details for Web of Science ID 000415152500075

• PHASE 2 TRIAL OF SL-701, A NOVEL IMMUNOTHERAPY COMPRISED OF SYNTHETIC SHORT PEPTIDES AGAINST GBM TARGETS IL-13R.2, EphA2, AND SURVIVIN, IN ADULTS WITH SECOND-LINE RECURRENT GBM Reardon, D., Nabors, B., Kumthekar, P., Badruddoja, M., Fink, K., Lieberman, F., Hu, J., Dunbar, E., Walbert, T., Schiff, D., Sherman, J., Tran, D., Ashby, L. S., Butowski, N., Iwamoto, F., Moertel, C., Schulder, M., Chen, J., Bullington, J., Shemesh, S., Brooks, C., Goswami, T., Peereboom, D. M. OXFORD UNIV PRESS INC. 2017: 28

  View details for Web of Science ID 000415152500107

• EFFECTS OF INTEGRATIVE THERAPIES ON DISTRESS, PAIN, AND FATIGUE IN PATIENTS WITH PRIMARY BRAIN TUMORS: PRELIMINARY RESULTS FROM AN INTEGRATIVE MEDICINE REGISTRY Donovan, L., Rusilowski, A., Taromina, K., Kreisl, T., Welch, M., Lassman, A. B., Ladas, E., Iwamoto, F. OXFORD UNIV PRESS INC. 2017: 209

  View details for Web of Science ID 000415152503207

• STUDY OF PEMBROLIZUMAB, TUMOR TREATMENT FIELDS (OPTUNE®) AND TEMOZOLOMIDE FOR OLDER SUBJECTS WITH NEWLY DIAGNOSED GLIOBLASTOMA Donovan, L., Cieremans, D., Kreisl, T., Welch, M., Lassman, A. B., Iwamoto, F. OXFORD UNIV PRESS INC. 2017: 27

  View details for Web of Science ID 000415152500104

• Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial LANCET ONCOLOGY Weller, M., Butowski, N., Tran, D. D., Recht, L. D., Lim, M., Hirte, H., Ashby, L., Mechtler, L., Goldlust, S. A., Iwamoto, F., Drappatz, J., O'Rourke, D. M., Wong, M., Hamilton, M. G., Finocchiaro, G., Perry, J., Wick, W., Green, J., He, Y., Turner, C. D., Yellin, M. J., Keler, T., Davis, T. A., Stupp, R., Sampson, J. H., ACT IV Trial Investigators 2017; 18 (10): 1373–85

  Abstract

  Rindopepimut (also known as CDX-110), a vaccine targeting the EGFR deletion mutation EGFRvIII, consists of an EGFRvIII-specific peptide conjugated to keyhole limpet haemocyanin. In the ACT IV study, we aimed to assess whether or not the addition of rindopepimut to standard chemotherapy is able to improve survival in patients with EGFRvIII-positive glioblastoma.In this randomised, double-blind, phase 3 trial, we recruited patients aged 18 years and older with glioblastoma from 165 hospitals in 22 countries. Eligible patients had newly diagnosed glioblastoma confirmed to express EGFRvIII by central analysis, and had undergone maximal surgical resection and completion of standard chemoradiation without progression. Patients were stratified by European Organisation for Research and Treatment of Cancer recursive partitioning analysis class, MGMT promoter methylation, and geographical region, and randomly assigned (1:1) with a prespecified randomisation sequence (block size of four) to receive rindopepimut (500 μg admixed with 150 μg GM-CSF) or control (100 μg keyhole limpet haemocyanin) via monthly intradermal injection until progression or intolerance, concurrent with standard oral temozolomide (150-200 mg/m2 for 5 of 28 days) for 6-12 cycles or longer. Patients, investigators, and the trial funder were masked to treatment allocation. The primary endpoint was overall survival in patients with minimal residual disease (MRD; enhancing tumour <2 cm2 post-chemoradiation by central review), analysed by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01480479.Between April 12, 2012, and Dec 15, 2014, 745 patients were enrolled (405 with MRD, 338 with significant residual disease [SRD], and two unevaluable) and randomly assigned to rindopepimut and temozolomide (n=371) or control and temozolomide (n=374). The study was terminated for futility after a preplanned interim analysis. At final analysis, there was no significant difference in overall survival for patients with MRD: median overall survival was 20·1 months (95% CI 18·5-22·1) in the rindopepimut group versus 20·0 months (18·1-21·9) in the control group (HR 1·01, 95% CI 0·79-1·30; p=0·93). The most common grade 3-4 adverse events for all 369 treated patients in the rindopepimut group versus 372 treated patients in the control group were: thrombocytopenia (32 [9%] vs 23 [6%]), fatigue (six [2%] vs 19 [5%]), brain oedema (eight [2%] vs 11 [3%]), seizure (nine [2%] vs eight [2%]), and headache (six [2%] vs ten [3%]). Serious adverse events included seizure (18 [5%] vs 22 [6%]) and brain oedema (seven [2%] vs 12 [3%]). 16 deaths in the study were caused by adverse events (nine [4%] in the rindopepimut group and seven [3%] in the control group), of which one-a pulmonary embolism in a 64-year-old male patient after 11 months of treatment-was assessed as potentially related to rindopepimut.Rindopepimut did not increase survival in patients with newly diagnosed glioblastoma. Combination approaches potentially including rindopepimut might be required to show efficacy of immunotherapy in glioblastoma.Celldex Therapeutics, Inc.

  View details for PubMedID 28844499

• Assessing the Safety of Craniotomy for Resection of Primary Central Nervous System Lymphoma: A Nationwide Inpatient Sample Analysis. Frontiers in neurology Yun, J., Yang, J., Cloney, M., Mehta, A., Singh, S., Iwamoto, F. M., Neugut, A. I., Sonabend, A. M. 2017; 8: 478

  Abstract

  Unlike many other central nervous system (CNS) tumors, the surgical management of primary central nervous system lymphomas (PCNSL) is traditionally limited by diagnostic biopsy. Studies that predate the use of modern neurosurgical techniques have reported a prohibitive operative morbidity for this surgery. These early experiences have dictated the non-surgical management of PCNSL, whereas resection for cytoreduction is a mainstay of treatment in other CNS malignancies. Recent studies have suggested that craniotomy with the goal of cytoreduction might be associated with a favorable overall and progression-free survival for some patients with PCNSL. To challenge the traditional non-surgical paradigm, it is essential to first investigate the safety of resection for PCNSL.To determine the operative morbidity of resection for this disease, we performed a population-based assessment of complications using the nationwide inpatient sample database for the years 1998-2013 for biopsies and open craniotomies for PCNSL and other brain tumors.Among 95 patients who underwent biopsy and 34 patients who underwent craniotomy, we found no significant difference in complication rates between craniotomy for resection and biopsy procedures for PCNSL (23.16 versus 20.59%). The types of complications differ between diagnoses, with the PCNSL cohort suffering mainly medical complications and the non-PCNSL cohort suffering mainly from neurological complications.These findings support the safety of craniotomies in PCNSL and help provide a rationale for future prospective studies to evaluate the safety and efficacy of resection for this disease.

  View details for DOI 10.3389/fneur.2017.00478

  View details for PubMedID 28955300

  View details for PubMedCentralID PMC5600910

• Rates and impact of combination immunotherapy with tumor treating fields in a glioma cohort Odia, Y., Schulte, J., Iwamoto, F. AMER ASSOC CANCER RESEARCH. 2017

  View details for DOI 10.1158/1538-7445.AM2017-CT102

  View details for Web of Science ID 000442496700091

• PD-1 blockade with nivolumab in relapsed/refractory primary central nervous system and testicular lymphoma. Blood Nayak, L., Iwamoto, F. M., LaCasce, A., Mukundan, S., Roemer, M. G., Chapuy, B., Armand, P., Rodig, S. J., Shipp, M. A. 2017; 129 (23): 3071-3073

  Abstract

  Primary central nervous system (CNS) lymphoma (PCNSL) and primary testicular lymphoma (PTL) are rare extranodal large B-cell lymphomas with similar genetic signatures. There are no standard-of-care treatment options for patients with relapsed and refractory PCNSL and PTL, and the overall prognosis is poor. PCNSLs and PTLs exhibit frequent 9p24.1 copy-number alterations and infrequent translocations of 9p24.1 and associated increased expression of the programmed cell death protein 1 (PD-1) ligands, PD-L1 and PD-L2. The activity of PD-1 blockade in other lymphomas with 9p24.1 alterations prompted us to test the efficacy of the anti-PD1 antibody, nivolumab, in 4 patients with relapsed/refractory PCNSL and 1 patient with CNS relapse of PTL. All 5 patients had clinical and radiographic responses to PD-1 blockade, and 3 patients remain progression-free at 13+ to 17+ months. Our data suggest that nivolumab is active in relapsed/refractory PCNSL and PTL and support further investigation of PD-1 blockade in these diseases.

  View details for DOI 10.1182/blood-2017-01-764209

  View details for PubMedID 28356247

  View details for PubMedCentralID PMC5766844

• Phase II trial of bevacizumab and temozolomide for upfront treatment of elderly patients with newly diagnosed glioblastoma. Nghiemphu, P., Bahng, H., Lai, A., Faiq, N., Yong, W. H., Green, R. M., Polikoff, J., Spier, C., Iwamoto, F., Lassman, A. B., Cloughesy, T. AMER SOC CLINICAL ONCOLOGY. 2017

  View details for DOI 10.1200/JCO.2017.35.15_suppl.2012

  View details for Web of Science ID 000411895703182

• The Neurologic Assessment in Neuro-Oncology (NANO) scale: a tool to assess neurologic function for integration into the Response Assessment in Neuro-Oncology (RANO) criteria. Neuro-oncology Nayak, L., DeAngelis, L. M., Brandes, A. A., Peereboom, D. M., Galanis, E., Lin, N. U., Soffietti, R., Macdonald, D. R., Chamberlain, M., Perry, J., Jaeckle, K., Mehta, M., Stupp, R., Muzikansky, A., Pentsova, E., Cloughesy, T., Iwamoto, F. M., Tonn, J. C., Vogelbaum, M. A., Wen, P. Y., van den Bent, M. J., Reardon, D. A. 2017; 19 (5): 625-635

  Abstract

  The Macdonald criteria and the Response Assessment in Neuro-Oncology (RANO) criteria define radiologic parameters to classify therapeutic outcome among patients with malignant glioma and specify that clinical status must be incorporated and prioritized for overall assessment. But neither provides specific parameters to do so. We hypothesized that a standardized metric to measure neurologic function will permit more effective overall response assessment in neuro-oncology.An international group of physicians including neurologists, medical oncologists, radiation oncologists, and neurosurgeons with expertise in neuro-oncology drafted the Neurologic Assessment in Neuro-Oncology (NANO) scale as an objective and quantifiable metric of neurologic function evaluable during a routine office examination. The scale was subsequently tested in a multicenter study to determine its overall reliability, inter-observer variability, and feasibility.The NANO scale is a quantifiable evaluation of 9 relevant neurologic domains based on direct observation and testing conducted during routine office visits. The score defines overall response criteria. A prospective, multinational study noted a >90% inter-observer agreement rate with kappa statistic ranging from 0.35 to 0.83 (fair to almost perfect agreement), and a median assessment time of 4 minutes (interquartile range, 3-5).The NANO scale provides an objective clinician-reported outcome of neurologic function with high inter-observer agreement. It is designed to combine with radiographic assessment to provide an overall assessment of outcome for neuro-oncology patients in clinical trials and in daily practice. Furthermore, it complements existing patient-reported outcomes and cognition testing to combine for a global clinical outcome assessment of well-being among brain tumor patients.

  View details for DOI 10.1093/neuonc/nox029

  View details for PubMedID 28453751

  View details for PubMedCentralID PMC5464449

• The safety of resection for primary central nervous system lymphoma: a single institution retrospective analysis. Journal of neuro-oncology Cloney, M. B., Sonabend, A. M., Yun, J., Yang, J., Iwamoto, F., Singh, S., Bhagat, G., Canoll, P., Zanazzi, G., Bruce, J. N., Sisti, M., Sheth, S., Connolly, E. S., McKhann, G. 2017; 132 (1): 189-197

  Abstract

  Surgical resection is not the standard of care for primary central nervous system lymphoma (PCNSL), as historical studies have demonstrated unfavorable complication rates and limited benefits. Some recent studies suggest that resection may provide a therapeutic benefit, yet the safety of these procedures has not been systematically investigated in the setting of modern neurosurgery. We examined the safety of surgical resection for PCNSL. We retrospectively analyzed all patients with PCNSL treated at Columbia University Medical Center between 2000 and 2015 to assess complications rates following biopsy or resection using the Glioma Outcomes Project system. We identified predictors of complications and selection for resection. Well-validated scales were used to quantify patients' baseline clinical characteristics, including functional status, comorbid disease burden, and cardiac risk. The overall complication rate was 17.2% after resection, and 28.2% after biopsy. Cardiac risk (p = 0.047, OR 1.72 [1.01, 2.95]), and comorbid diagnoses (p = 0.004, OR 3.05 [1.42, 6.57]) predicted complications on multivariable regression. Patients who underwent resection had better KPS scores (median 70 v. 80, p = 0.0068, ∆ 10 [0.0, 10.00]), and were less likely to have multiple (46.5% v. 27.6%, p = 0.030, OR 1.42 [1.05, 1.92]) or deep lesions (70.4% v. 39.7%, p = 0.001, OR 1.83 [1.26, 2.65]). Age (p = 0.048, OR 0.75 per 10-year increase [0.56, 1.00]) and deep lesions (p = 0.003, OR 0.29 [0.13, 0.65]) influenced selection for resection on multivariable regression. Surgical resection of PCNSL is safe for select patients, with complication rates comparable to rates for other intracranial neoplasms. Whether there is a clinical benefit to resection cannot be concluded.

  View details for DOI 10.1007/s11060-016-2358-8

  View details for PubMedID 28116650

  View details for PubMedCentralID PMC5367383

• A state-of-the-art review and guidelines for tumor treating fields treatment planning and patient follow-up in glioblastoma. CNS oncology Trusheim, J., Dunbar, E., Battiste, J., Iwamoto, F., Mohile, N., Damek, D., Bota, D. A., Connelly, J. 2017; 6 (1): 29-43

  Abstract

  Tumor treating fields (TTFields) are an integral treatment modality in the management of glioblastoma and extend overall survival when combined with maintenance temozolomide in newly diagnosed patients. Complexities exist regarding correct selection of imaging sequences with which to perform TTFields treatment planning. Guidelines are warranted first, to facilitate treatment planning standardization across medical disciplines and institutions, to ensure optimal TTFields delivery to the tumor and peritumoral brain zone while maximizing patient safety, and also to mitigate the risk of premature cessation of a potentially beneficial treatment. This summary guideline outlines methods for starting patients on TTFields, for monitoring patient response to therapy and provides a framework for evaluating when therapy should be re-planned, based on the extent of sequential imaging changes.

  View details for DOI 10.2217/cns-2016-0032

  View details for PubMedID 27628854

  View details for PubMedCentralID PMC6027938

• Hypofractionated radiation therapy versus standard fractionated radiation therapy with concurrent temozolomide in elderly patients with newly diagnosed glioblastoma. Practical radiation oncology Wang, T. J., Wu, C. C., Jani, A., Estrada, J., Ung, T., Chow, D. S., Soun, J. E., Saad, S., Qureshi, Y. H., Gartrell, R., Saadatmand, H. J., Saraf, A., Garrett, M. D., Grubb, C., Isaacson, S. R., Cheng, S. K., Sisti, M. B., Bruce, J. N., Sheth, S. A., Lassman, A. B., Iwamoto, F. M., McKhann, G. M. 2016; 6 (5): 306-314

  Abstract

  Adjuvant hypofractionated radiation therapy (HRT) for elderly patients with newly diagnosed glioblastoma (GBM) is a reasonable option compared with standard fractionation radiation therapy (SFRT). Outcomes in patients receiving HRT in the presence of temozolomide (TMZ) compared with SFRT with TMZ are unclear. We examined HRT for GBM with TMZ in comparison to SFRT with TMZ.We conducted a retrospective analysis of patients ≥60 years of age with newly diagnosed GBM who received SFRT or HRT from 1994 to 2014 in the postoperative setting. Inclusion criteria included SFRT (60 Gy/30 fractions or 59.4 Gy/33 fractions) versus HRT (40 Gy/15 fractions).In this cohort, 158 patients were treated with SFRT versus 26 with HRT. Median survival in patients receiving SFRT compared with HRT was 430 and 475 days (P = .550), respectively. Ninety-five percent of the SFRT patients received TMZ versus 100% of those treated with HRT. Patients receiving HRT were older (median, 72 vs 66 years). All HRT patients were treated with the intensity modulated radiation therapy (IMRT) technique versus SFRT, in which 57% had IMRT. Multivariate Cox regression showed decreased overall survival (OS) associated with patient age >70 (hazard ratio [HR], 1.84), lower Karnofsky performance status (HR, 5.25), biopsy versus surgical resection (HR, 4.18), radiation therapy planning technique 3- or 2-dimensional planning versus IMRT (HR, 1.91; HR, 3.40, respectively). Analysis restricted to patients receiving IMRT-based planning showed no difference in OS between HRT and SFRT. For patients receiving TMZ, there was no survival difference between those treated with HRT and those treated with SFRT.Elderly GBM patients receiving HRT and those receiving SFRT had similar OS. Subset analysis patients receiving concurrent TMZ showed no difference in OS between the HRT and SFRT groups.

  View details for DOI 10.1016/j.prro.2015.12.001

  View details for PubMedID 26952813

• Nivolumab (Anti-PD1) Therapy for Relapsed/Refractory Primary Central Nervous System Lymphoma and Primary Testicular Lymphoma Nayak, L., Iwamoto, F., LaCasce, A. S., Mukundan, S., Roemer, M. G. M., Chapuy, B., Armand, P., Rodig, S. J., Shipp, M. A. AMER SOC HEMATOLOGY. 2016

  View details for DOI 10.1182/blood.V128.22.930.930

  View details for Web of Science ID 000394446804066

• ACT IV: AN INTERNATIONAL, DOUBLE-BLIND, PHASE 3 TRIAL OF RINDOPEPIMUT IN NEWLY DIAGNOSED, EGFRvIII-EXPRESSING GLIOBLASTOMA Weller, M., Butowski, N., Tran, D., Recht, L., Lim, M., Hirte, H., Ashby, L., Mechtler, L., Goldlust, S., Iwamoto, F., Drappatz, J., O'Rourke, D., Wong, M., Finocchiaro, G., Perry, J., Wick, W., He, Y., Davis, T., Stupp, R., Sampson, J. OXFORD UNIV PRESS INC. 2016: 17

  View details for Web of Science ID 000398604100070

• RATES AND OUTCOMES OF COMBINATION TUMOR TREATING FIELDS AND IMMUNOTHERAPY IN A GLIOMA COHORT Odia, Y., Donovan, L., Schulte, J., Iwamoto, F. OXFORD UNIV PRESS INC. 2016: 25

  View details for Web of Science ID 000398604101035

• Multiparametric Subtraction Maps Guide Treatment Decisions in Focally Recurrent High-Grade Glioma Yanagihara, T. K., Grinband, J., Rowley, J., Lee, A. W., Cauley, K., Chu, A., Garrett, M., Saadatmand, H. J., Sheth, S. A., Sisti, M. B., Bruce, J. N., McKhann, G. M., Iwamoto, F. M., Lassman, A. B., Cheng, S. K., Wang, T. C. ELSEVIER SCIENCE INC. 2016: E114

  View details for DOI 10.1016/j.ijrobp.2016.06.878

  View details for Web of Science ID 000387655802279

• The genetic landscape of dural marginal zone lymphomas. Oncotarget Ganapathi, K. A., Jobanputra, V., Iwamoto, F., Jain, P., Chen, J., Cascione, L., Nahum, O., Levy, B., Xie, Y., Khattar, P., Hoehn, D., Bertoni, F., Murty, V. V., Pittaluga, S., Jaffe, E. S., Alobeid, B., Mansukhani, M. M., Bhagat, G. 2016; 7 (28): 43052-43061

  Abstract

  The dura is a rare site of involvement by marginal zone lymphoma (MZL) and the biology of dural MZL is not well understood. We performed genome-wide DNA copy number and targeted mutational analysis of 14 dural MZL to determine the genetic landscape of this entity. Monoallelic and biallelic inactivation of TNFAIP3 by mutation (n=5) or loss (n=1) was observed in 6/9 (67%) dural MZL exhibiting plasmacytic differentiation, including 3 IgG4+ cases. In contrast, activating NOTCH2 mutations were detected in 4/5 (80%) dural MZL displaying variable monocytoid morphology. Inactivating TBL1XR1 mutations were identified in all NOTCH2 mutated cases. Recurrent mutations in KLHL6 (n=2) and MLL2 (n=2) were also detected. Gains at 6p25.3 (n=2) and losses at 1p36.32 (n=3) were common chromosomal imbalances, with loss of heterozygosity (LOH) of these loci observed in a subset of cases. Translocations involving the IGH or MALT1 genes were not identified. Our results indicate genetic similarities between dural MZL and other MZL subtypes. However, recurrent and mutually exclusive genetic alterations of TNFAIP3 and NOTCH2 appear to be associated with distinct disease phenotypes in dural MZL.

  View details for DOI 10.18632/oncotarget.9678

  View details for PubMedID 27248180

  View details for PubMedCentralID PMC5190007

• Development of practice algorithms to guide treatment planning with TTFields for the management of glioblastoma (GB). Dunbar, E. M., Iwamoto, F., Trusheim, J. E., Mohile, N., Battiste, J., Connelly, J., Damek, D., Bota, D. AMER SOC CLINICAL ONCOLOGY. 2016

  View details for DOI 10.1200/JCO.2016.34.15_suppl.e13519

  View details for Web of Science ID 000404665403088

• Frailty in Geriatric Glioblastoma Patients: A Predictor of Operative Morbidity and Outcome. World neurosurgery Cloney, M., D'Amico, R., Lebovic, J., Nazarian, M., Zacharia, B. E., Sisti, M. B., Bruce, J. N., McKhann, G. M., Iwamoto, F. M., Sonabend, A. M. 2016; 89: 362-7

  Abstract

  Frailty is an emerging means of assessing overall health status and guiding management for geriatric patients. Frailty is associated with outcomes for many surgical indications in this age group. While half of all glioblastoma patients are 65 years old or older, frailty has not been examined in relation to surgery for glioblastoma.We performed a retrospective study of patients age 65 years and older with pathologically confirmed glioblastoma at Columbia Presbyterian Hospital from 2000 to 2012; 319 patients were identified, 243 of whom underwent craniotomy for lobar lesions. Frailty was quantified using the Canadian Study of Health and Aging Modified Frailty Index. Postoperative complications were classified according the Glioma Outcomes Project system. Systemic, regional, neurologic, and overall complications were examined in relation to age, Karnofsky performance status, frailty, comorbid disease burden, cardiovascular risk, and tumor sidedness.Frailer patients were less likely to undergo surgical resection (P = 0.0002; odds ratio [OR], 0.15; 95% confidence interval [CI], 0.05-0.40) as opposed to biopsy, had longer hospital stays (log-rank test for trend, P = 0.0061), an increased overall risk of complications (P = 0.0123; OR, 1.40; 95% CI, 1.08-1.83), and decreased overall survival (Log rank test for trend, P = 0.0028).Frailer patients with glioblastoma receive less aggressive intervention, have longer hospital stays, and experience more complications. Frailty may be an underused metric for the preoperative risk assessment of geriatric glioblastoma patients.

  View details for DOI 10.1016/j.wneu.2015.12.096

  View details for PubMedID 26775233

• PD-1 Inhibitors for Recurrent High Grade Glioma (HGG) Donovan, L., Schaff, L., Lassman, A., Wang, T., Carvajal, R., Rizvi, N., Fox, A., Iwamoto, F. LIPPINCOTT WILLIAMS & WILKINS. 2016

  View details for Web of Science ID 000411328607356

• A phase II trial of enzastaurin (LY317615) in combination with bevacizumab in adults with recurrent malignant gliomas. Journal of neuro-oncology Odia, Y., Iwamoto, F. M., Moustakas, A., Fraum, T. J., Salgado, C. A., Li, A., Kreisl, T. N., Sul, J., Butman, J. A., Fine, H. A. 2016; 127 (1): 127-35

  Abstract

  We evaluated the efficacy of combination enzastaurin (LY317615) and bevacizumab for recurrent malignant gliomas and explored serologic correlates. We enrolled 81 patients with glioblastomas (GBM, n = 40) and anaplastic gliomas (AG, n = 41). Patients received enzastaurin as a loading dose of 1125 mg, followed by 500 or 875 mg daily for patients on non-enzyme-inducing or enzyme-inducing antiepileptics, respectively. Patients received bevacizumab 10 mg/kg intravenously biweekly. Clinical evaluations were repeated every 4 weeks. Magnetic resonance imaging was obtained at baseline and every 8 weeks from treatment onset. Phosphorylated glycogen synthase kinase (GSK)-3 levels from peripheral blood mononuclear cells (PBMCs) were checked with each MRI. Median overall survival was 7.5 and 12.4 months for glioblastomas and anaplastic glioma cohorts, with median progression-free survivals of 2.0 and 4.4 months, respectively. Of GBM patients, 3/40 (7.5 %) were not evaluable, while 8/37 (22 %) had partial or complete response and 20/37 (54 %) had stable disease for 2+ months. Of the 39 evaluable AG patients, 18 (46 %) had an objective response, and 16 (41 %) had stable disease for 2+ months. The most common grade 3+ toxicities were lymphopenia (15 %), hypophosphatemia (8.8 %) and thrombotic events (7.5 %). Two (2.5 %) GBM patients died suddenly; another death (1.3 %) occurred from intractable seizures. Phosphorylated GSK-3 levels from PBMCs did not correlate with treatment response. A minimally important improvement in health-related quality of life was self-reported in 7-9/24 (29.2-37.5 %). Early response based on Levin criteria was significantly associated with significantly longer progression free survival for glioblastomas. Enzastaurin (LY317615) in combination with bevacizumab for recurrent malignant gliomas is well-tolerated, with response and progression-free survival similar to bevacizumab monotherapy.

  View details for DOI 10.1007/s11060-015-2020-x

  View details for PubMedID 26643807

• PHASE 2 TRIAL OF SL-701, A NOVEL IMMUNOTHERAPY COMPRISED OF SYNTHETIC SHORT PEPTIDES AGAINST GBM TARGETS IL-13Ra2, EphA2, AND SURVIVIN, IN ADULTS WITH SECOND-LINE RECURRENT GBM: INTERIM RESULTS NEURO-ONCOLOGY Peereboom, D., Reardon, D., Nabors, B., Fink, K., Phuphanich, S., Mikkelsen, T., Dunbar, E., Badruddoja, M., Schiff, D., Lieberman, F., Tran, D., Schulder, M., Butowski, N., Ashby, L., Moertel, C., Iwamoto, F., Sherman, J., Chen, J., McDonald, P., Poradosu, E., Brooks, C., Shemesh, S., Raizer, J. 2016
• Focal Mass Lesions Merritt’s Neurology Bell, M., Khandji, A., Iwamoto, F. M. 2016
• Changes in Diffusion Weighted Imaging Pre and Post Chemoradiation Therapy With Standard and Hypofractionation for Glioblastoma Yanagihara, T., Chu, A., Garrett, M., Salah, K., Grinband, J., Jani, A., Isaacson, S. R., Sisti, M. B., Bruce, J. N., Mckhann, G. M., Iwamoto, F. M., Lassman, A. B., Wang, T. J. ELSEVIER SCIENCE INC. 2015: E56-E57

  View details for DOI 10.1016/j.ijrobp.2015.07.685

  View details for Web of Science ID 000373215300140

• The Safety of Surgery in Elderly Patients with Primary and Recurrent Glioblastoma. World neurosurgery D'Amico, R. S., Cloney, M. B., Sonabend, A. M., Zacharia, B., Nazarian, M. N., Iwamoto, F. M., Sisti, M. B., Bruce, J. N., McKhann, G. M. 2015; 84 (4): 913-9

  Abstract

  Glioblastoma (GBM) occurs more commonly in elderly patients. However, these patients are often excluded from clinical trials. The absence of solid evidence has resulted in a nihilistic view of GBM in the elderly and a traditionally conservative treatment approach. In particular, the safety of surgical resection for both primary and recurrent GBM is poorly understood in elderly patients.In a retrospective cohort of patients aged ≥65 years, we examined selection for biopsy, surgical resection, and reoperation for recurrent disease. We also analyzed complication rates after initial resection and reoperation for recurrent disease. We identified 319 elderly patients with pathologically proven GBM who underwent a total of 274 craniotomies at our institution between 2000 and 2012. Events were reported according to the methods used in the Glioma Outcomes Project.The overall rate of complications after resection was 21.9%, with a rate of neurological complications of 7.7%. The rates of neurological, regional, and systemic complications were not significantly different after initial craniotomy and reoperation for GBM in elderly patients. Reoperations were not associated with an increased risk of complications. Low cardiovascular risk, improved functional status, and hemispheric GBM were associated with selection for more aggressive surgical treatment. Younger age and improved functional status were associated with a reduced likelihood of complications.We conclude that in select patients, age alone should not preclude the decision to pursue aggressive surgical management.

  View details for DOI 10.1016/j.wneu.2015.05.072

  View details for PubMedID 26074434

• Brain Tumor Trials Collaborative Bayesian Adaptive Randomized Phase II trial of bevacizumab plus vorinostat versus bevacizumab alone in adults with recurrent glioblastoma (BTTC-1102) Puduvalli, V. K., Wu, J., Yuan, Y., Armstrong, T. S., Groves, M. D., Raizer, J. J., Giglio, P., Colman, H., Peereboom, D. M., Walbert, T., Avgeropoulos, N., Iwamoto, F., Chamberlain, M. C., Paleologos, N., Fink, K. L., Merrell, R., Yung, W., Gilbert, M. R. AMER SOC CLINICAL ONCOLOGY. 2015

  View details for DOI 10.1200/jco.2015.33.15_suppl.2012

  View details for Web of Science ID 000358036900471

• Factorial clinical trials: a new approach to phase II neuro-oncology studies. Neuro-oncology Iwamoto, F. M., Lassman, A. B. 2015; 17 (2): 174-6

  View details for DOI 10.1093/neuonc/nou314

  View details for PubMedID 25452393

  View details for PubMedCentralID PMC4288526

• Comment: Medical therapy for recurrent or progressive meningiomas remains elusive. Neurology Iwamoto, F. M. 2015; 84 (3): 285

  View details for DOI 10.1212/WNL.0000000000001170

  View details for PubMedID 25527267

• MYC protein expression in primary diffuse large B-cell lymphoma of the central nervous system. PloS one Gill, K. Z., Iwamoto, F., Allen, A., Hoehn, D., Murty, V. V., Alobeid, B., Bhagat, G. 2014; 9 (12): e114398

  Abstract

  Primary diffuse large B-cell lymphoma of the central nervous system (CNS DLBCL) is a rare, aggressive subtype of DLBCL, the biology of which is poorly understood. Recent studies have suggested a prognostic role of MYC protein expression in systemic DLBCL, but little is known about the frequency and significance of MYC protein expression in CNS DLBCL. Hence, we investigated MYC protein expression profiles of CNS DLBCL and assessed the relationship between MYC expression and a variety of histopathologic, immunophenotypic, genetic, and clinical features. Fifty-nine CNS DLBCL diagnosed at our institution over the past 13 years were evaluated. The majority of cases (80%) showed centroblastic morphology, and 12 (20%) displayed a perivascular pattern of infiltration. According to the Hans criteria, 41 (69%) cases had a non-germinal center B-cell and 18 (31%) had a germinal center B-cell cell-of-origin (COO) phenotype. Mean MYC protein expression was 50% (median: 50%, range: 10-80%). Forty-three cases (73%) showed MYC overexpression (≥ 40%), and 35 (60%) showed MYC/BCL2 coexpression. MYC overexpression was seen in the single case harboring MYC translocation and in the cases showing increased copies of MYC (27%); however, no significant difference in mean MYC expression was seen between groups harboring or lacking MYC aberrations. In our series, age was associated with a significantly increased risk of death, and the perivascular pattern of infiltration was associated with a significantly increased risk of disease progression. Neither MYC expression (with or without BCL2 coexpression) nor other variables, including COO subtype were predictive of clinical outcome. Our findings indicate that the proportion of CNS DLBCL overexpressing MYC is higher compared to systemic DLBCL, and MYC overexpression appears to be independent of genetic MYC abnormalities. Thus, MYC expression and other immunophenotypic markers used for prognostication of systemic DLBCL might not apply to CNS DLBCL due to differences in disease biology.

  View details for DOI 10.1371/journal.pone.0114398

  View details for PubMedID 25479599

  View details for PubMedCentralID PMC4257680

• Recursive partitioning analysis of prognostic variables in newly diagnosed anaplastic oligodendroglial tumors. Neuro-oncology Panageas, K. S., Reiner, A. S., Iwamoto, F. M., Cloughesy, T. F., Aldape, K. D., Rivera, A. L., Eichler, A. F., Louis, D. N., Paleologos, N. A., Fisher, B. J., Ashby, L. S., Cairncross, J. G., Urgoiti, G. B., Wen, P. Y., Ligon, K. L., Schiff, D., Robins, H. I., Rocque, B. G., Chamberlain, M. C., Mason, W. P., Weaver, S. A., Green, R. M., Kamar, F. G., Abrey, L. E., DeAngelis, L. M., Jhanwar, S. C., Rosenblum, M. K., Lassman, A. B. 2014; 16 (11): 1541-6

  Abstract

  Anaplastic oligodendroglial tumors are rare, and median survival varies widely. Analysis of 1p19q deletion is performed commonly and is an important prognostic factor. However, age and other clinical variables also carry prognostic value, and it is unclear how to incorporate them into clinical decision making or to combine them for prognostication.We compiled a retrospective database of 1013 patients with newly diagnosed anaplastic oligodendrogliomas or oligoastrocytomas and performed a recursive partitioning analysis to generate independent prognostic classes among 587 patients with informative 1p19q status. Variables included for survival classification were age (continuous), history of prior low-grade glioma, 1p19q deletion status, histology (presence or absence of an astrocytic component), tumor lobe, tumor hemisphere, gender, extent of resection, postresection treatment, and performance status at diagnosis.Recursive partitioning analysis identified 5 prognostic groups based on hazard similarity: class I (age <60 y, 1p19q codeleted), class II (age <43 y, not codeleted), class III (age 43-59 y, not codeleted, frontal lobe tumor or age ≥60 y, codeleted), class IV (age 43-59 y, not codeleted, not frontal lobe tumor or age 60-69 y, not codeleted), and class V (age ≥70 y, not codeleted). Survival differences were highly significant (P < .0001), with medians ranging from 9.3 years (95% CI: 8.4-16.0) for class I to 0.6 years (95% CI: 0.5-0.9) for class V.These 5 distinct classification groups were defined using prognostic factors typically obtained during routine management of patients with anaplastic oligodendroglial tumors. Validation in a prospective clinical trial may better differentiate patients with respect to treatment outcome.

  View details for DOI 10.1093/neuonc/nou083

  View details for PubMedID 24997140

  View details for PubMedCentralID PMC4201067

• A RANDOMIZED PHASE II TRIAL OF VANDETANIB (ZD6474) IN COMBINATION WITH CARBOPLATIN VERSUS CARBOPLATIN ALONE IN ADULTS WITH RECURRENT GLIOBLASTOMA McNeill, K., Iwamoto, F., Kreisl, T., Sul, J., Shih, J., Fine, H. OXFORD UNIV PRESS INC. 2014

  View details for DOI 10.1093/neuonc/nou237.38

  View details for Web of Science ID 000350452200068

• INTERMITTENT HIGH DOSE (PULSATILE) ERLOTINIB FOR EGFRvIII MUTANT RECURRENT MALIGNANT GLIOMAS: A PILOT CLINICAL TRIAL Lassman, A., Grommes, C., Panageas, K., Iwamoto, F., DeAngelis, L., Kaley, T., Gavrilovic, I., Pentsova, E., Omuro, A., Corpuz, C., Briggs, S., Otap, D., Qin, W., Cross, J., Mellinghoff, I. OXFORD UNIV PRESS INC. 2014

  View details for DOI 10.1093/neuonc/nou237.35

  View details for Web of Science ID 000350452200065

• OPTIMIZING RADIATION THERAPY FOR GLIOBLASTOMA PATIENTS: A COMPARATIVE STUDY OF USING DIFFERENT MRI MODALITIES TO MINIMIZE RADIATION INJURY Kim, A., Lee, A., Lee, A., Yanagihara, T., Jani, A., Isaacson, S. R., Cheng, S. K., Bruce, J. N., Sisti, M. B., McKhann, G. M., Iwamoto, F., Lassman, A., Wang, T. J. C. OXFORD UNIV PRESS INC. 2014

  View details for DOI 10.1093/neuonc/nou270.10

  View details for Web of Science ID 000350452200752

• Ipilimumab for recurrent gliobiastoma (GBM). Schaff, L. R., Lassman, A. B., Goldlust, S. A., Cloughesy, T., Singer, S., Schwartz, G. K., Iwamoto, F. LIPPINCOTT WILLIAMS & WILKINS. 2014

  View details for DOI 10.1200/jco.2014.32.15_suppl.e13026

  View details for Web of Science ID 000358613200193

• Unveiling YKL-40, from Serum Marker to Target Therapy in Glioblastoma. Frontiers in oncology Iwamoto, F. M., Hormigo, A. 2014; 4: 90

  Abstract

  Glioblastoma is the most common primary brain tumor in the adult and carries a poor prognosis with a median survival of only 14 months. Patients with glioblastoma are followed with MRI scans, but this technique has several limitations including low specificity to differentiate between tumor and treatment effect. Development of serum markers could significantly improve the care of glioblastoma patients. We review the current concept of developing YKL-40 as one of the most promising serum markers for glioblastoma, the recent advances on understanding the role of YKL-40 in gliomagenesis, and the promising evidence emerging from preclinical models on using this protein as a target for anti-glioma therapy.

  View details for DOI 10.3389/fonc.2014.00090

  View details for PubMedID 24809021

  View details for PubMedCentralID PMC4009441

• Semiautomated volumetric measurement on postcontrast MR imaging for analysis of recurrent and residual disease in glioblastoma multiforme. AJNR. American journal of neuroradiology Chow, D. S., Qi, J., Guo, X., Miloushev, V. Z., Iwamoto, F. M., Bruce, J. N., Lassman, A. B., Schwartz, L. H., Lignelli, A., Zhao, B., Filippi, C. G. 2014; 35 (3): 498-503

  Abstract

  A limitation in postoperative monitoring of patients with glioblastoma is the lack of objective measures to quantify residual and recurrent disease. Automated computer-assisted volumetric analysis of contrast-enhancing tissue represents a potential tool to aid the radiologist in following these patients. In this study, we hypothesize that computer-assisted volumetry will show increased precision and speed over conventional 1D and 2D techniques in assessing residual and/or recurrent tumor.This retrospective study included patients with native glioblastomas with MR imaging performed at 24-48 hours following resection and 2-4 months postoperatively. 1D and 2D measurements were performed by 2 neuroradiologists with Certificates of Added Qualification. Volumetry was performed by using manual segmentation and computer-assisted volumetry, which combines region-based active contours and a level set approach. Tumor response was assessed by using established 1D, 2D, and volumetric standards. Manual and computer-assisted volumetry segmentation times were compared. Interobserver correlation was determined among 1D, 2D, and volumetric techniques.Twenty-nine patients were analyzed. Discrepancy in disease status between 1D and 2D compared with computer-assisted volumetry was 10.3% (3/29) and 17.2% (5/29), respectively. The mean time for segmentation between manual and computer-assisted volumetry techniques was 9.7 minutes and <1 minute, respectively (P < .01). Interobserver correlation was highest for volumetric measurements (0.995; 95% CI, 0.990-0.997) compared with 1D (0.826; 95% CI, 0.695-0.904) and 2D (0.905; 95% CI, 0.828-0.948) measurements.Computer-assisted volumetry provides a reproducible and faster volumetric assessment of enhancing tumor burden, which has implications for monitoring disease progression and quantification of tumor burden in treatment trials.

  View details for DOI 10.3174/ajnr.A3724

  View details for PubMedID 23988756

  View details for PubMedCentralID PMC7964732

• BRAINSTEM VENOUS CONGESTION DUE TO DURAL ARTERIO-VENOUS FISTULA MIMICKING BRAINSTEM TUMORS Bell, M., Harrison, C., Armentano, F., Lassman, A., Connolly, E., Khandji, A., Iwamoto, F. OXFORD UNIV PRESS INC. 2013: 100

  View details for Web of Science ID 000327456200404

• A PHASE I TRIAL OF PEPTIDE-BASED GLIOMA VACCINE IMA950 IN PATIENTS WITH GLIOBLASTOMA: STUDY DESIGN AND PRELIMINARY RESULTS Sul, J., Hilf, N., Kutscher, S., Schoor, O., Lindner, J., Reinhardt, C., Kreisl, T., Iwamoto, F., Fine, H., Singh-Jasuja, H. OXFORD UNIV PRESS INC. 2013: 73

  View details for Web of Science ID 000327456200302

• RADIOGRAPHIC RESPONSE OF AN INCIDENTAL MENINGIOMA IN A PATIENT WITH GLIOBLASTOMA ON NovoTTF THERAPY Schaff, L., Armentano, F., Harrison, C., Lassman, A., McKhann, G., Iwamoto, F. OXFORD UNIV PRESS INC. 2013: 99

  View details for Web of Science ID 000327456200398

• Chemoirradiation for glioblastoma multiforme: the national cancer institute experience. PloS one Ho, J., Ondos, J., Ning, H., Smith, S., Kreisl, T., Iwamoto, F., Sul, J., Kim, L., McNeil, K., Krauze, A., Shankavaram, U., Fine, H. A., Camphausen, K. 2013; 8 (8): e70745

  Abstract

  Standard treatment for glioblastoma (GBM) is surgery followed by radiation (RT) and temozolomide (TMZ). While there is variability in survival based on several established prognostic factors, the prognostic utility of other factors such as tumor size and location are not well established.The charts of ninety two patients with GBM treated with RT at the National Cancer Institute (NCI) between 1998 and 2012 were retrospectively reviewed. Most patients received RT with concurrent and adjuvant TMZ. Topographic locations were classified using preoperative imaging. Gross tumor volumes were contoured using treatment planning systems utilizing both pre-operative and post-operative MR imaging.At a median follow-up of 18.7 months, the median overall survival (OS) and progression-free survival (PFS) for all patients was 17.9 and 7.6 months. Patients with the smallest tumors had a median OS of 52.3 months compared to 16.3 months among patients with the largest tumors, P = 0.006. The patients who received bevacizumab after recurrence had a median OS of 23.3 months, compared to 16.3 months in patients who did not receive it, P = 0.0284. The median PFS and OS in patients with periventricular tumors was 5.7 and 17.5 months, versus 8.9 and 23.3 months in patients with non-periventricular tumors, P = 0.005.Survival in our cohort was comparable to the outcome of the defining EORTC-NCIC trial establishing the use of RT+TMZ. This study also identifies several potential prognostic factors that may be useful in stratifying patients.

  View details for DOI 10.1371/journal.pone.0070745

  View details for PubMedID 23940635

  View details for PubMedCentralID PMC3733728

• Age-specific signatures of glioblastoma at the genomic, genetic, and epigenetic levels. PloS one Bozdag, S., Li, A., Riddick, G., Kotliarov, Y., Baysan, M., Iwamoto, F. M., Cam, M. C., Kotliarova, S., Fine, H. A. 2013; 8 (4): e62982

  Abstract

  Age is a powerful predictor of survival in glioblastoma multiforme (GBM) yet the biological basis for the difference in clinical outcome is mostly unknown. Discovering genes and pathways that would explain age-specific survival difference could generate opportunities for novel therapeutics for GBM. Here we have integrated gene expression, exon expression, microRNA expression, copy number alteration, SNP, whole exome sequence, and DNA methylation data sets of a cohort of GBM patients in The Cancer Genome Atlas (TCGA) project to discover age-specific signatures at the transcriptional, genetic, and epigenetic levels and validated our findings on the REMBRANDT data set. We found major age-specific signatures at all levels including age-specific hypermethylation in polycomb group protein target genes and the upregulation of angiogenesis-related genes in older GBMs. These age-specific differences in GBM, which are independent of molecular subtypes, may in part explain the preferential effects of anti-angiogenic agents in older GBM and pave the way to a better understanding of the unique biology and clinical behavior of older versus younger GBMs.

  View details for DOI 10.1371/journal.pone.0062982

  View details for PubMedID 23658659

  View details for PubMedCentralID PMC3639162

• Continuous daily sunitinib for recurrent glioblastoma. Journal of neuro-oncology Kreisl, T. N., Smith, P., Sul, J., Salgado, C., Iwamoto, F. M., Shih, J. H., Fine, H. A. 2013; 111 (1): 41-8

  Abstract

  Bevacizumab ((BEV) has become a mainstay of treating recurrent glioblastoma, but eventual tumor resistance is expected. Targeting multiple growth-associated signaling pathways may result in more effective treatment than targeting VEGF alone. Patients with recurrent glioblastoma were stratified by prior BEV exposure and treated with sunitinib 37.5 mg daily in this phase II study. Response evaluations were performed at baseline and at the end of every 4 week cycle. Six-month progression-free survival (PFS6) was the primary endpoint for both arms of the study. Secondary endpoints included health related quality of life measures and FDG-PET correlatives with patient outcomes. Sixty-three patients were accrued to this study; thirty-two were BEV-naïve, 31 were BEV-resistant. PFS6 was 10.4 % [95 % CI 3.2-33.8] in the BEV-naïve cohort and 0 % in the BEV-resistant cohort. Median overall survival was 9.4 months [95 % CI 6.15-21.90] in the BEV-naïve cohort and 4.37 months [95 % CI 3.02-6.21] in the BEV-resistant cohort. 3/29 patients (10 %) of the BEV-naïve, and 0/27 BEV-resistant patients achieved radiographic response. Thrombocytopenia, leukopenia, and neutropenia were the most common drug-associated adverse events and occurred with higher frequency than expected. Sunitinib treatment in BEV-naïve patients did not appear to affect outcomes with subsequent BEV therapy. Continuous daily sunitinib did not prolong progression-free survival in BEV-naïve nor BEV-resistant patients with recurrent glioblastoma.

  View details for DOI 10.1007/s11060-012-0988-z

  View details for PubMedID 23086433

• Immediate titanium mesh cranioplasty for treatment of postcraniotomy infections. World neurosurgery Wind, J. J., Ohaegbulam, C., Iwamoto, F. M., Black, P. M., Park, J. K. 2013; 79 (1): 207.e11-3

  Abstract

  Postcraniotomy infections have generally been treated by debridement of infected tissues, disposal of the bone flap, and delayed cranioplasty several months later to repair the resulting skull defect. Debridement followed by retention of the bone flap has also been advocated. Here we propose an alternative operative strategy for the treatment of postcraniotomy infections.Two patients presenting with clinical and radiographic signs and symptoms of postcraniotomy infections were treated by debridement, bone flap disposal, and immediate titanium mesh cranioplasty. The patients were subsequently administered antibiotics, and their clinical courses were followed.The patients treated in this fashion did not have recurrence of their infections during 3-year follow-up periods.Surgical debridement, bone flap disposal, and immediate titanium mesh cranioplasty may be a suitable option for the treatment of postcraniotomy infections. This treatment strategy facilitates the eradication of infectious sources and obviates the risks and costs associated with a second surgical procedure.

  View details for DOI 10.1016/j.wneu.2011.02.013

  View details for PubMedID 22120410

  View details for PubMedCentralID PMC3290757

• A phase I/II trial of vandetanib for patients with recurrent malignant glioma. Neuro-oncology Kreisl, T. N., McNeill, K. A., Sul, J., Iwamoto, F. M., Shih, J., Fine, H. A. 2012; 14 (12): 1519-26

  Abstract

  Vandetanib is a once-daily multitargeted tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2, epidermal growth factor receptor, and the rearranged-during-transfection oncogene. A phase I trial was conducted to describe the pharmacokinetics of vandetanib in patients with recurrent glioma on enzyme-inducing anti-epileptic drugs (EIAEDs) and to identify the maximum tolerated dose (MTD) in this population. A phase II trial evaluated the efficacy of vandetanib in patients with recurrent malignant glioma not on EIAEDs as measured by 6-month progression-free survival (PFS6). In the phase I trial, 15 patients were treated with vandetanib at doses of 300, 400, and 500 mg/day, in a standard dose-escalation design. The MTD in patients on EIAEDs was 400 mg/day, and steady-state levels were similar to those measured in patients not on EIAEDs. Dose-limiting toxicities were prolonged QTc and thromboembolism. Thirty-two patients with recurrent glioblastoma multiforme (GBM) and 32 patients with recurrent anaplastic gliomas (AGs) were treated in the phase II trial, at a dosage of 300 mg/day on 28-day cycles. Six patients (4 GBM, 2 AG) had radiographic response. PFS6 was 6.5% in the GBM arm and 7.0% in the AG arm. Median overall survival was 6.3 months in the GBM arm and 7.6 months in the AG arm. Seizures were an unexpected toxicity of therapy. Vandetanib did not have significant activity in unselected patients with recurrent malignant glioma.

  View details for DOI 10.1093/neuonc/nos265

  View details for PubMedID 23099652

  View details for PubMedCentralID PMC3499018

• Recursive partitioning analysis of prognostic factors for glioblastoma patients aged 70 years or older. Cancer Scott, J. G., Bauchet, L., Fraum, T. J., Nayak, L., Cooper, A. R., Chao, S. T., Suh, J. H., Vogelbaum, M. A., Peereboom, D. M., Zouaoui, S., Mathieu-Daudé, H., Fabbro-Peray, P., Rigau, V., Taillandier, L., Abrey, L. E., DeAngelis, L. M., Shih, J. H., Iwamoto, F. M. 2012; 118 (22): 5595-600

  Abstract

  The most-used prognostic scheme for malignant gliomas included only patients aged 18 to 70 years. The purpose of this study was to develop a prognostic model for patients ≥70 years of age with newly diagnosed glioblastoma.A total of 437 patients ≥70 years of age with newly diagnosed glioblastoma, pooled from 2 tertiary academic institutions, was identified for recursive partitioning analysis (RPA). The resulting prognostic model, based on the final pruned RPA tree, was validated using 265 glioblastoma patients ≥70 years of age from a data set independently compiled by a French consortium.RPA produced 9 terminal nodes, which were pruned to 4 prognostic subgroups with markedly different median survivals: subgroup I = patients <75.5 years of age who underwent surgical resection (9.3 months); subgroup II = patients ≥75.5 years of age who underwent surgical resection (6.4 months); subgroup III = patients with Karnofsky performance status of 70 to 100 who underwent biopsy only (4.6 months); and subgroup IV = patients with Karnofsky performance status <70 who underwent biopsy only (2.3 months). Application of this prognostic model to the French cohort also resulted in significantly different (P < .0001) median survivals for subgroups I (8.5 months), II (7.7 months), III (4.3 months), and IV (3.1 months).This model divides elderly glioblastoma patients into prognostic subgroups that can be easily implemented in both the patient care and the clinical trial settings. This purely clinical prognostic model serves as a backbone for the future incorporation of the increasing number of potential molecular prognostic markers.

  View details for DOI 10.1002/cncr.27570

  View details for PubMedID 22517216

  View details for PubMedCentralID PMC3402652

• A PHASE II TRIAL OF INVESTIGATIONAL AGENT TANDUTINIB IN COMBINATION WITH BEVACIZUMAB FOR PATIENTS WITH RECURRENT GLIOBLASTOMA Sul, J., Odia, Y., Zhang, W., Shih, J., Butman, J. A., Hammoud, D., Kreisl, T. N., Iwamoto, F., Fine, H. A. OXFORD UNIV PRESS INC. 2012: 73

  View details for Web of Science ID 000310971300292

• PATTERNS OF TREATMENT AND SURVIVAL OF GBM PATIENTS WITH DIABETES MELLITUS Yin, C., Iwamoto, F. M., Fraum, T. J., Nayak, L. OXFORD UNIV PRESS INC. 2012: 77

  View details for Web of Science ID 000310971300309

• Radiotherapy and concomitant temozolomide may improve survival of elderly patients with glioblastoma JOURNAL OF NEURO-ONCOLOGY Barker, C. A., Chang, M., Chou, J. F., Zhang, Z., Beal, K., Gutin, P. H., Iwamoto, F. M. 2012; 109 (2): 391-397

  Abstract

  Survival of elderly patients with glioblastoma (GBM) is poor, but improves with tumor resection and radiotherapy (RT). Concurrent temozolomide (TMZ) chemotherapy during RT improves the survival of younger patients with GBM, but the benefit in elderly patients is unclear. Medical records of patients ≥65 years old with primary GBM, histologically confirmed at Memorial Sloan-Kettering Cancer Center and treated with RT, were reviewed. Survival was associated with patient (age, performance status), tumor (single or multiple), and treatment (extent of surgery, RT field, technique, fractionation and use of concurrent TMZ) characteristics in a multivariable Cox regression model. Grade ≥3 hematologic toxicity rates were compared to reported rates in younger patients. Median age of the 291 patients studied was 71 years. Longer survival was associated with younger age, tumor resection, and concomitant TMZ and RT (p < 0.01). Concurrent TMZ and RT improved median survival of patients with favorable prognostic factors from 12 to 21 months and from 10 to 13 months in patients 65-70 and ≥71 years old, respectively. Concomitant TMZ and RT increased the 2 year OS rate from 14 to 41 % and from 5 to 24 % in patients 65-70 and ≥71 years old, respectively. Grade 3-4 thrombocytopenia was significantly more frequent in the present cohort. Survival of elderly patients with GBM may be prolonged with the use of concomitant TMZ during RT. An ongoing randomized study will determine the benefit of this approach in a prospective fashion.

  View details for DOI 10.1007/s11060-012-0906-4

  View details for Web of Science ID 000308250200021

  View details for PubMedID 22688802

• 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

• Initial treatment patterns over time for anaplastic oligodendroglial tumors. Neuro-oncology Panageas, K. S., Iwamoto, F. M., Cloughesy, T. F., Aldape, K. D., Rivera, A. L., Eichler, A. F., Louis, D. N., Paleologos, N. A., Fisher, B. J., Ashby, L. S., Cairncross, J. G., Roldán Urgoiti, G. B., Wen, P. Y., Ligon, K. L., Schiff, D., Robins, H. I., Rocque, B. G., Chamberlain, M. C., Mason, W. P., Weaver, S. A., Green, R. M., Kamar, F. G., Abrey, L. E., Deangelis, L. M., Jhanwar, S. C., Rosenblum, M. K., Lassman, A. B. 2012; 14 (6): 761-7

  Abstract

  Anaplastic oligodendroglial tumors are rare neoplasms with no standard approach to treatment. We sought to determine patterns of treatment delivered over time and identify clinical correlates of specific strategies using an international retrospective cohort of 1013 patients diagnosed from 1981-2007. Prior to 1990, most patients received radiotherapy (RT) alone as initial postoperative treatment. After 1990, approximately 50% of patients received both RT and chemotherapy (CT) sequentially and/or concurrently. Treatment with RT alone became significantly less common (67% in 1980-1984 vs 5% in 2005-2007, P < .0001). CT alone was more frequently administered in later years (0% in 1980-1984 vs 38% in 2005-2007; P < .0001), especially in patients with 1p19q codeleted tumors (57% of codeleted vs 4% with no deletion in 2005-2007; P < .0001). Temozolomide replaced the combination of procarbazine, lomustine, and vincristine (PCV) among patients who received CT alone or with RT (87% vs 2% in 2005-2007). In the most recent time period, patients with 1p19q codeleted tumors were significantly more likely to receive CT alone (with temozolomide), whereas RT with temozolomide was a significantly more common treatment strategy than either CT or RT alone in cases with no deletion (P < .0001). In a multivariate polytomous logistic regression model, the following were significantly associated with type of treatment delivered: date (5-year interval) of diagnosis (P < .0001), 1p19q codeletion (P < .0001), pure anaplastic oligodendroglioma histology (P < .01), and frontal lobe predominance (P < .05). Limited level 1 evidence is currently available to guide treatment decisions, and ongoing phase III trials will be critical to understanding the optimal therapy.

  View details for DOI 10.1093/neuonc/nos065

  View details for PubMedID 22661585

  View details for PubMedCentralID PMC3367843

• Spinal cord glioneuronal tumor with neuropil-like islands with 1p/19q deletion in an adult with low-grade cerebral oligodendroglioma. Journal of neuro-oncology Fraum, T. J., Barak, S., Pack, S., Lonser, R. R., Fine, H. A., Quezado, M., Iwamoto, F. M. 2012; 107 (2): 421-6

  Abstract

  Glioneuronal tumor with neuropil-like islands (GTNI) is considered a rare variant of astrocytoma, characterized by discrete aggregates of cells expressing neuronal markers that punctuate a GFAP-positive glial background. Of the 24 published GTNI cases, only two occurred in adult spinal cords; none occurred concurrent with another CNS tumor; and none of those tested exhibited the 1p/19q deletion typical of oligodendroglioma. A 48-year-old man without significant past medical history was diagnosed with a WHO grade II oligodendroglioma by stereotactic biopsy of a lesion discovered after the patient suffered a generalized tonic-clonic seizure. By FISH analysis, this tumor exhibited the 1p/19q deletion present in up to 80% of oligodendrogliomas. The patient received 14 monthly cycles of temozolomide, and his cerebral tumor had a minor response. When the patient subsequently reported progressive paresthesias of his lower extremities, an MRI revealed an enhancing, cystic tumor of the thoracic spinal cord that was diagnosed as GTNI by histological analysis. By FISH analysis, this lesion exhibited the same 1p/19q deletion present in the concurrent cerebral oligodendroglioma. This case of a spinal cord GTNI with 1p/19q deletions constitutes the third report of a spinal cord GTNI in an adult patient; the first report of a GTNI in an individual with a separate CNS neoplasm; and the first report of a GTNI with 1p/19q deletions. This case establishes a potential genetic kinship between GTNI and oligodendroglioma that warrants further investigation.

  View details for DOI 10.1007/s11060-011-0760-9

  View details for PubMedID 22083647

  View details for PubMedCentralID PMC7446125

• Recursive Partitioning Analysis Identifies Prognostic Groups for Glioblastoma Patients Aged 70 Years or Older Nayak, L., Scott, J., Bauchet, L., Fraum, T., Cooper, A., Chao, S., Suh, J., Abrey, L., Peereboom, D., Zouaoui, S., Fabbro-Peray, P., Taillandier, L., Rigao, V., Vogelbaum, M., Mathieu-Daude, H., DeAngelis, L., Shih, J., Iwamoto, F. LIPPINCOTT WILLIAMS & WILKINS. 2012

  View details for Web of Science ID 000303204804095

• Longitudinal prospective study of matrix metalloproteinase-9 as a serum marker in gliomas. Journal of neuro-oncology Iwamoto, F. M., Hottinger, A. F., Karimi, S., Riedel, E., Dantis, J., Jahdi, M., Panageas, K. S., Lassman, A. B., Abrey, L. E., Fleisher, M., Deangelis, L. M., Holland, E. C., Hormigo, A. 2011; 105 (3): 607-12

  Abstract

  The objective of this study was to evaluate if longitudinal measurements of serum matrix metalloproteinase-9 (MMP-9) correlated with disease status or survival in adults with gliomas. Serum samples were collected prospectively and concurrently with MRI scans at multiple time points during the course of the disease. MMP-9 levels were determined by ELISA and correlated with radiographic disease status and survival. Forty-one patients with low-grade gliomas, 105 with anaplastic gliomas, and 197 with glioblastoma enrolled in this study from August 2002 to September 2008. A total of 1,684 serum samples (97.1% of all MMP-9 samples) had a matching MRI scan. No statistically significant association was observed between levels of serum MMP-9 and radiographic disease status in low-grade gliomas (P = 0.98), anaplastic gliomas (P = 0.39) or glioblastomas (P = 0.33). Among patients with glioblastoma, longitudinal increases in MMP-9 had a weak association with shorter survival (HR = 1.1 per each doubling in MMP-9 levels, 95% CI, 1.0-1.3, P = 0.04) but they were not independently associated with survival when adjusted for age, extent of resection, and performance status. Changes in serum MMP-9 were not associated with survival in the anaplastic glioma cohort. Serum MMP-9 showed no utility in determining glioma disease status and was not a clinically relevant prognostic marker of survival.

  View details for DOI 10.1007/s11060-011-0628-z

  View details for PubMedID 21710351

  View details for PubMedCentralID PMC7398421

• Ischemic stroke and intracranial hemorrhage in glioma patients on antiangiogenic therapy. Journal of neuro-oncology Fraum, T. J., Kreisl, T. N., Sul, J., Fine, H. A., Iwamoto, F. M. 2011; 105 (2): 281-9

  Abstract

  Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), recently received FDA approval for recurrent glioblastoma. Additionally, several VEGF receptor (VEGFR) tyrosine kinase inhibitors (TKIs) have entered trials for recurrent glioma. Phase II studies of bevacizumab for recurrent GBM have reported incidents of ischemic stroke (IS) and intracranial hemorrhage (ICH); however, their clinical features and outcomes were not described in detail. We conducted a retrospective study of recurrent malignant glioma patients with radiographically-confirmed IS or ICH while on antiangiogenic therapy. The study population included patients treated between 2005 and 2010 at the National Cancer Institute on four different phase I and II trials of antiangiogenic agents for recurrent malignant glioma, as well as patients receiving bevacizumab off clinical trial during this same period. Eight patients developed IS (50% lacunar) and 14 experienced ICH (79% intratumoral) while on antiangiogenic therapy for malignant glioma recurrence. The median age was 53 years, 17 patients (77%) were men, and 59% had glioblastoma. The frequencies of IS and ICH were 1.9% and 1.9% in bevacizumab trials. None of the patients on VEGFR TKI trials developed IS, while 3.8% experienced ICH. Patients with IS were treated with antiangiogenic agents longer than those with ICH (median, 16.2 vs. 2.6 months, P = 0.001). Median survival was 7.8 months after IS and 2.6 months after ICH. The most common IS subtype was lacunar, while most ICHs were asymptomatic and intratumoral. Overall, IS seems to be a complication of prolonged antiangiogenic therapy, while intratumoral bleeds often occur in the setting of tumor progression.

  View details for DOI 10.1007/s11060-011-0579-4

  View details for PubMedID 21603965

  View details for PubMedCentralID PMC3168718

• BEVACIZUMAB IN MULTIPLY RECURRENT AGGRESSIVE MENINGIOMAS Nayak, L., Iwamoto, F. M., Rudnick, J. D., Norden, A. D., Omuro, A., Kaley, T. J. OXFORD UNIV PRESS INC. 2011: 61

  View details for Web of Science ID 000297026600248

• TIME TRENDS IN TREATMENT OF ANAPLASTIC OLIGODENDROGLIAL TUMORS Panageas, K. S., Iwamoto, F. M., Cloughesy, T. F., Aldape, K. D., Rivera, A. L., Eichler, A. F., Louis, D. N., Paleologos, N. A., Fisher, B. J., Ashby, L. S., Cairncross, J. G., Roldan, G. B., Wen, P. Y., Ligon, K. L., Schiff, D., Robins, H. I., Rocque, B. G., Chamberlain, M. C., Mason, W. P., Weaver, S. A., Green, R. M., Kamar, F. G., Abrey, L. E., DeAngelis, L. M., Jhanwar, S. C., Rosenblum, M. K., Lassman, A. B. OXFORD UNIV PRESS INC. 2011: 62-63

  View details for Web of Science ID 000297026600256

• Serum YKL-40 is a marker of prognosis and disease status in high-grade gliomas. Neuro-oncology Iwamoto, F. M., Hottinger, A. F., Karimi, S., Riedel, E., Dantis, J., Jahdi, M., Panageas, K. S., Lassman, A. B., Abrey, L. E., Fleisher, M., DeAngelis, L. M., Holland, E. C., Hormigo, A. 2011; 13 (11): 1244-51

  Abstract

  The objective of this study was to evaluate whether longitudinal levels of serum YKL-40 correlate with disease status or survival in adults with gliomas. Patients with histologically confirmed gliomas were eligible for this longitudinal study. Serum samples were collected prospectively and concurrently with MRI scans at multiple time points during the course of the disease. YKL-40 levels determined by ELISA were correlated with radiographic disease status and survival. We performed a multivariate survival analysis including well-known prognostic factors such as age, performance status, and extent of surgical resection. Three hundred and forty-three patients with gliomas (41 low-grade, 105 anaplastic, and 197 glioblastoma) were accrued. Two-year survival from registration was 29% for glioblastomas, 62% for anaplastic gliomas, and 83% for low-grade gliomas. A total of 1740 serum samples were collected, and 95.6% of samples had matching MRI scans. Serum YKL-40 level was significantly lower in patients with no radiographic disease compared with patients with radiographic disease in both the anaplastic glioma (P= .0008) and the glioblastoma (P= .0006) cohorts. Serum levels of YKL-40 in patients with low-grade gliomas were not associated with radiographic disease status. Increases in YKL-40 were independently associated with worse survival in anaplastic gliomas (hazard ratio [HR] = 1.4, P= .01) and glioblastomas (HR = 1.4, P< .0001). Longitudinal increases in serum YKL-40 are associated with increased risk of death in patients with glioblastomas and anaplastic gliomas. YKL-40 is also a putative indicator of disease status in these patients.

  View details for DOI 10.1093/neuonc/nor117

  View details for PubMedID 21831900

  View details for PubMedCentralID PMC3199155

• A phase II trial of single-agent bevacizumab in patients with recurrent anaplastic glioma. Neuro-oncology Kreisl, T. N., Zhang, W., Odia, Y., Shih, J. H., Butman, J. A., Hammoud, D., Iwamoto, F. M., Sul, J., Fine, H. A. 2011; 13 (10): 1143-50

  Abstract

  The purpose of this study was to evaluate the activity of single-agent bevacizumab in patients with recurrent anaplastic glioma and assess correlative advanced imaging parameters. Patients with recurrent anaplastic glioma were treated with bevacizumab 10 mg/kg every 2 weeks. Complete patient evaluations were repeated every 4 weeks. Correlative dynamic contrast-enhanced MR and (18)fluorodeoxyglucose PET imaging studies were obtained to evaluate physiologic changes in tumor and tumor vasculature at time points including baseline, 96 h after the first dose, and after the first 4 weeks of therapy. Median overall survival was 12 months (95% confidence interval [CI]: 6.08-22.8). Median progression-free survival was 2.93 months (95% CI: 2.01-4.93), and 6-month progression-free survival was 20.9% (95% CI: 10.3%-42.5%). Thirteen (43%) patients achieved a partial response. The most common grade ≥ 3 treatment-related toxicities were hypertension, hypophosphatemia, and thromboembolism. Single-agent bevacizumab produces significant radiographic response in patients with recurrent anaplastic glioma but did not meet the 6-month progression-free survival endpoint. Early change in enhancing tumor volume at 4 days after start of therapy was the most significant prognostic factor for overall and progression-free survival.

  View details for DOI 10.1093/neuonc/nor091

  View details for PubMedID 21865400

  View details for PubMedCentralID PMC3177658

• YKL-40 and MMP-9 as serum markers for patients with primary central nervous system lymphoma. Annals of neurology Hottinger, A. F., Iwamoto, F. M., Karimi, S., Riedel, E., Dantis, J., Park, J., Panageas, K. S., Lassman, A. B., Abrey, L. E., Fleisher, M., Holland, E. C., DeAngelis, L. M., Hormigo, A. 2011; 70 (1): 163-9

  Abstract

  To evaluate YKL-40 and MMP-9 proteins as tumor biomarkers in serum samples from patients with primary central nervous system lymphoma (PCNSL).In this prospective longitudinal study, serum samples from consecutive patients with histologically confirmed PCNSL were collected concurrently with magnetic resonance imaging (MRI) scans at multiple time points and were analyzed for levels of YKL-40 and MMP-9 by enzyme-linked immunosorbent assay. Marker levels were correlated to disease status and survival.Forty-five patients with PCNSL were accrued. Median follow-up for survivors was 25 months, and 21 (47%) died during the study. A total of 230 serum samples were collected, and 93% had corresponding MRI scans. PCNSL patients without evidence of radiographic disease (29 patients, 131 samples) had significantly lower levels of serum YKL-40 and MMP-9 than patients with active tumor (n = 34 patients, 84 samples; p = 0.03 and 0.01, respectively). There was a significant inverse correlation between survival and doubling of the YKL-40 level (hazard ratio, 1.7; p = 0.01).In patients with PCNSL, serum levels of YKL-40 and MMP-9 are associated with radiographic disease status. Longitudinal increase in serum levels of YKL-40, but not MMP-9, predicts survival in patients with PCNSL.

  View details for DOI 10.1002/ana.22360

  View details for PubMedID 21391238

  View details for PubMedCentralID PMC7295085

• International retrospective study of over 1000 adults with anaplastic oligodendroglial tumors. Neuro-oncology Lassman, A. B., Iwamoto, F. M., Cloughesy, T. F., Aldape, K. D., Rivera, A. L., Eichler, A. F., Louis, D. N., Paleologos, N. A., Fisher, B. J., Ashby, L. S., Cairncross, J. G., Roldán, G. B., Wen, P. Y., Ligon, K. L., Schiff, D., Robins, H. I., Rocque, B. G., Chamberlain, M. C., Mason, W. P., Weaver, S. A., Green, R. M., Kamar, F. G., Abrey, L. E., DeAngelis, L. M., Jhanwar, S. C., Rosenblum, M. K., Panageas, K. S. 2011; 13 (6): 649-59

  Abstract

  Treatment for newly diagnosed anaplastic oligodendroglial tumors is controversial. Radiotherapy (RT) alone and in combination with chemotherapy (CT) are the most well studied strategies. However, CT alone is often advocated, especially in cases with 1p19q codeletion. We retrospectively identified 1013 adults diagnosed from 1981-2007 treated initially with RT alone (n = 200), CT + RT (n = 528), CT alone (n = 201), or other strategies (n = 84). Median overall survival (OS) was 6.3 years and time to progression (TTP) was 3.1 years. 1p19q codeletion correlated with longer OS and TTP than no 1p or 19q deletion. In codeleted cases, median TTP was longer following CT + RT (7.2 y) than following CT (3.9 y, P = .003) or RT (2.5 y, P < .001) alone but without improved OS; median TTP was longer following treatment with PCV alone than temozolomide alone (7.6 vs. 3.3 y, P = .019). In cases with no deletion, median TTP was longer following CT + RT (3.1 y) than CT (0.9 y, P = .0124) or RT (1.1 y, P < .0001) alone; OS also favored CT + RT (median 5.0 y) over CT (2.2 y, P = .02) or RT (1.9 y, P < .0001) alone. In codeleted cases, CT alone did not appear to shorten OS in comparison with CT + RT, and PCV appeared to offer longer disease control than temozolomide but without a clear survival advantage. Combined CT + RT led to longer disease control and survival than did CT or RT alone in cases with no 1p19q deletion. Ongoing trials will address these issues prospectively.

  View details for DOI 10.1093/neuonc/nor040

  View details for PubMedID 21636710

  View details for PubMedCentralID PMC3107101

• A phase I/II trial of the histone deacetylase inhibitor romidepsin for adults with recurrent malignant glioma: North American Brain Tumor Consortium Study 03-03 NEURO-ONCOLOGY Iwamoto, F. M., Lamborn, K. R., Kuhn, J. G., Wen, P. Y., Yung, W. K., Gilbert, M. R., Chang, S. M., Lieberman, F. S., Prados, M. D., Fine, H. A. 2011; 13 (5): 509-516

  Abstract

  Romidepsin, a potent histone deacetylase inhibitor, has shown activity in preclinical glioma models. The primary objectives of this trial were to determine the pharmacokinetics of romidepsin in patients with recurrent glioma on enzyme-inducing antiepileptic drugs (EIAEDs) and to evaluate the antitumor efficacy of romidepsin in patients with recurrent glioblastoma who were not receiving EIAEDs. Two dose cohorts were studied in the phase I component of the trial (13.3 and 17.7 mg/m(2)/d). Patients in the phase II component were treated with intravenous romidepsin at a dosage of 13.3 mg/m(2)/day on days 1, 8, and 15 of each 28-day cycle. Eight patients were treated on the phase I component. A similar romidepsin pharmacokinetic profile was demonstrated between patients receiving EIAEDs to those not receving EIAEDs. Thirty-five patients with glioblastoma were accrued to the phase II component. There was no objective radiographic response. The median progression-free survival (PFS) was 8 weeks and only 1 patient had a PFS time ≥6 months (PFS6 = 3%). To date, 34 patients (97%) have died, with a median survival duration of 34 weeks. Despite in vitro studies showing that romidepsin is primarily metabolized by CYP3A4, no decrease in exposure to romidepsin was seen in patients receiving potent CYP3A4 inducers. Romidepsin, at its standard dose and schedule, was ineffective for patients with recurrent glioblastomas. ClinicalTrials.gov identifier: NCT00085540.

  View details for DOI 10.1093/neuonc/nor017

  View details for Web of Science ID 000291450200005

  View details for PubMedID 21377994

  View details for PubMedCentralID PMC3093337

• Magnetic resonance spectroscopy imaging in radiotherapy planning for recurrent glioma. Medical physics Ballangrud, A. M., Lymberis, S., Thakur, S. B., Karimi, S., Huang, W., Abrey, L. E., Beal, K., Iwamoto, F. M., Brennan, C., Gutin, P. H., Chang, J. 2011; 38 (5): 2724-30

  Abstract

  The purpose of this study was to investigate how incorporation of magnetic resonance spectroscopy imaging (MRSI) into radiotherapy planning would increase the target volume for patients with recurrent glioma.After prior standard radiotherapy, 25 patients with recurrent glioma were treated with bevacizumab and concurrent hypofractionated stereotactic radiotherapy (HFSRT), delivering 30 Gy in five fractions. MRSI were acquired for 12 patients. Areas with markedly higher choline levels relative to the levels of total creatine and N-acetylaspartate were identified and referred to as MRSI voxels with elevated metabolite ratios (EMR). Gross tumor volume (GTV) consisted of contrast-enhancing tumor on T1-weighted magnetic resonance images (MRI) and computed tomography. Clinical target volume (CTV) was GTV + 5 mm margin and MRSI voxels with EMR. Overall survival (OS) and 6-month progression free survival (PFS) for these patients were reported in a prior publication [Gutin et al., Int. J. Radiat. Oncol., Biol., Phys. 75(1), 156-163 (2009)], and the outcome was correlated with the GTV and the volume of MRSI voxels with EMR in this study.Seven of the 12 patients had MRSI voxels with EMR. If none of the MRSI voxels with EMR were included, the CTV would range from 9.2 to 73.0 cm3 with a median of 31.0 cm3, whereas if all voxels were included, the CTV would range from 27.4 to 74.4 cm3 with a median of 35.0 cm3. For three of the seven patients, including the voxels with EMR, would have increased the CTV by 14%-23%. For one patient, where the MRSI voxels with EMR did not overlap the GTV, including these voxels would increase the CTV by 198%. No correlation could be found between the OS and PFS and the GTV or the volume of MRSI voxels with EMR.Seven of 12 patients with recurrent glioma had MRSI voxels with EMR. For four of these seven patients, including the MRSI voxels with EMR, significantly increased the CTV. This study does not have statistical power to conclude on the importance of including areas with MRSI-suspect disease into the radiation target volume.

  View details for DOI 10.1118/1.3574884

  View details for PubMedID 21776809

• Ischemic Stroke and Intracranial Hemorrhage in Recurrent Glioma Patients on Antiangiogenic Therapy Fraum, T. J., Sul, J., Kreisl, T. N., Fine, H. A., Iwamoto, F. M. LIPPINCOTT WILLIAMS & WILKINS. 2011: A167

  View details for Web of Science ID 000288149300677

• Neuromuscular junction toxicity with tandutinib induces a myasthenic-like syndrome. Neurology Lehky, T. J., Iwamoto, F. M., Kreisl, T. N., Floeter, M. K., Fine, H. A. 2011; 76 (3): 236-41

  Abstract

  Tandutinib (MLN 518, Millennium Pharmaceuticals, Cambridge, MA) is an orally active multitargeted tyrosine kinase inhibitor that is currently under evaluation for the treatment of glioblastoma and has been used in the treatment of leukemia. In prior clinical and animal studies, a dose-dependent muscular weakness has been observed with this drug, though the etiology of the weakness has not been defined.Standard neurophysiologic techniques, including repetitive nerve stimulation, needle EMG, and single-fiber EMG, were used to evaluate patients who developed weakness while being treated with tandutinib and bevacizumab (Avastin, Genentech, South San Francisco, CA) for glioblastoma (NCT00667394).Six patients were observed to develop a reversible weakness that correlated with the administration of the tandutinib. The onset of weakness after starting tandutinib occurred within 3 to 112 days and in less than 15 days in 3 patients. Electrophysiologic studies showed that all patients developed abnormal repetitive nerve stimulation studies. Four patients had short duration motor unit potentials. Two of these patients also had abnormal single-fiber EMG, as did a third patient who did not have standard needle EMG. The clinical and electrophysiologic abnormalities improved with the termination or reduction in the dose of tandutinib.These observations suggest that tandutinib is toxic to the neuromuscular junction, possibly by reversibly binding to a molecule on the postsynaptic acetylcholine receptor complex.This study provides Class III evidence that tandutinib 500 mg twice daily induces reversible muscle weakness and electrophysiologic changes consistent with neuromuscular junction dysfunction.

  View details for DOI 10.1212/WNL.0b013e3182074a69

  View details for PubMedID 21242491

  View details for PubMedCentralID PMC3034397

• Bevacizumab with hypofractionated stereotactic irradiation for recurrent malignant gliomas Controversies in Neuro-Oncology – Volume 1: Avastin & Malignant Gliomas Iwamoto, F. M., Gutin, P. H. 2011
• Primary and metastatic central nervous system malignancies ACP Medicine Iwamoto, F. M., Fine, H. A. 2011
• Scale to predict survival after surgery for recurrent glioblastoma multiforme. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Park, J. K., Hodges, T., Arko, L., Shen, M., Dello Iacono, D., McNabb, A., Olsen Bailey, N., Kreisl, T. N., Iwamoto, F. M., Sul, J., Auh, S., Park, G. E., Fine, H. A., Black, P. M. 2010; 28 (24): 3838-43

  Abstract

  Despite initial treatment with surgical resection, radiotherapy, and chemotherapy, glioblastoma multiforme (GBM) virtually always recurs. Surgery is sometimes recommended to treat recurrence. In this study, we sought to devise a preoperative scale that predicts survival after surgery for recurrent glioblastoma multiforme.The preoperative clinical and radiographic data of 34 patients who underwent re-operation of recurrent GBM tumors were analyzed using Kaplan-Meier survival analysis and Cox proportional hazards regression modeling. The factors associated with decreased postoperative survival (P < .05) were used to devise a prognostic scale which was validated with a separate cohort of 109 patients.The factors associated with poor postoperative survival were: tumor involvement of prespecified eloquent/critical brain regions (P = .021), Karnofsky performance status (KPS) < or = 80 (P = .030), and tumor volume > or = 50 cm(3) (P = .048). An additive scale (range, 0 to 3 points) comprised of these three variables distinguishes patients with good (0 points), intermediate (1 to 2 points), and poor (3 points) postoperative survival (median survival, 10.8, 4.5, and 1.0 months, respectively; P < .001). The scale identified three statistically distinct groups within the validation cohort as well (median survival, 9.2, 6.3, and 1.9 months, respectively; P < .001).We devised and validated a preoperative scale that identifies patients likely to have poor, intermediate, and good relative outcomes after surgical resection of a recurrent GBM tumor. Application of this simple scale may be useful in counseling patients regarding their treatment options and in designing clinical trials.

  View details for DOI 10.1200/JCO.2010.30.0582

  View details for PubMedID 20644085

  View details for PubMedCentralID PMC2940401

• Phase II trial of pazopanib (GW786034), an oral multi-targeted angiogenesis inhibitor, for adults with recurrent glioblastoma NEURO-ONCOLOGY Kunwar, S., Chang, S., Westphal, M., Vogelbaum, M., Sampson, J., Barnett, G., Shaffrey, M., Ram, Z., Piepmeier, J., Prados, M., Croteau, D., Pedain, C., Leland, P., Husain, S. R., Joshi, B. H., Puri, R. K. 2010; 12 (8): 871-881

  Abstract

  Convection-enhanced delivery (CED) of cintredekin besudotox (CB) was compared with Gliadel wafers (GW) in adult patients with glioblastoma multiforme (GBM) at first recurrence. Patients were randomized 2:1 to receive CB or GW. CB (0.5 microg/mL; total flow rate 0.75 mL/h) was administered over 96 hours via 2-4 intraparenchymal catheters placed after tumor resection. GW (3.85%/7.7 mg carmustine per wafer; maximum 8 wafers) were placed immediately after tumor resection. The primary endpoint was overall survival from the time of randomization. Prestated interim analyses were built into the study design. Secondary and tertiary endpoints were safety and health-related quality-of-life assessments. From March 2004 to December 2005, 296 patients were enrolled at 52 centers. Demographic and baseline characteristics were balanced between the 2 treatment arms. Median survival was 36.4 weeks (9.1 months) for CB and 35.3 weeks (8.8 months) for GW (P = .476). For the efficacy evaluable population, the median survival was 45.3 weeks (11.3 months) for CB and 39.8 weeks (10 months) for GW (P = .310). The adverse-events profile was similar in both arms, except that pulmonary embolism was higher in the CB arm (8% vs 1%, P = .014). This is the first randomized phase III evaluation of an agent administered via CED and the first with an active comparator in GBM patients. There was no survival difference between CB administered via CED and GW. Drug distribution was not assessed and may be crucial for evaluating future CED-based therapeutics.

  View details for DOI 10.1093/neuonc/noq054

  View details for Web of Science ID 000280705800013

  View details for PubMedID 20511192

  View details for PubMedCentralID PMC2940677

• Primary brain tumors in the elderly. Current neurology and neuroscience reports Nayak, L., Iwamoto, F. M. 2010; 10 (4): 252-8

  Abstract

  The incidence of primary brain tumors is highest in elderly patients, and advanced age often is a negative prognostic factor. Nevertheless, large randomized studies in this population are scarce. Elderly patients with primary brain tumors also present unique challenges, such as the presence of multiple comorbidities and polypharmacy, decreased tolerance to chemotherapy, and an increased risk for radiation-induced neurotoxicity. This review gives an overview of the treatment options for older patients with glioblastoma and other gliomas, primary central nervous system lymphomas (PCNSLs), and meningiomas. Selected elderly glioblastoma patients with good performance status may benefit from aggressive treatment with surgical resection, radiotherapy, and possibly chemotherapy. For older patients with PCNSLs, high-dose methotrexate-based chemotherapy should be the mainstay option; whole-brain radiation therapy should be avoided in chemosensitive tumors because of the high risk of irreversible and progressive neurotoxicity. Meningiomas often may be followed up in elderly patients, as they usually are asymptomatic and have a slow growth rate. Treatment for elderly patients with primary brain tumors should be individualized, and age alone should not preclude the use of more aggressive treatments.

  View details for DOI 10.1007/s11910-010-0110-x

  View details for PubMedID 20461477

  View details for PubMedCentralID PMC7398448

• Prognostic factors for glioblastoma (GBM) in individuals age 70 and older: A study of 446 patients from two tertiary centers. Scott, J. G., Chao, S. T., Suh, J. H., Cooper, A., Reiner, A. S., Nayak, L., Panageas, K., Abrey, L. E., Iwamoto, F. M. AMER SOC CLINICAL ONCOLOGY. 2010

  View details for DOI 10.1200/jco.2010.28.15_suppl.2034

  View details for Web of Science ID 000208852003029

• Bevacizumab for malignant gliomas. Archives of neurology Iwamoto, F. M., Fine, H. A. 2010; 67 (3): 285-8

  Abstract

  Malignant gliomas are the most common and aggressive primary brain tumors in adults. Despite optimal treatment with surgery, radiotherapy, and temozolomide, tumor recurrences are frequent and patients with malignant gliomas continue to have poor prognoses. Malignant gliomas are often highly vascularized, and significant advances have been made in the last few decades in our understanding of the mechanisms of tumor angiogenesis. Recently, bevacizumab, an antibody against vascular endothelial growth factor, has demonstrated significant activity in recurrent glioblastomas, resulting in US Food and Drug Administration approval and raising the prospect for other antiangiogenic drugs now entering clinical trials.

  View details for DOI 10.1001/archneurol.2010.11

  View details for PubMedID 20212225

  View details for PubMedCentralID PMC7243880

• Clinical considerations for older patients with glioblastoma Abrey, L. E., Finnegan, T., Iwamoto, F. M. Clinical Advances in Hematology & Oncology. 2010
• Prognosis and patterns of care in elderly patients with glioma. Cancer Iwamoto, F. M., Reiner, A. S., Nayak, L., Panageas, K. S., Elkin, E. B., Abrey, L. E. 2009; 115 (23): 5534-40

  Abstract

  The current study was conducted to evaluate the patterns of care and survival of older adults with oligodendroglioma (OLI) and astrocytoma (AST) from a large population-based registry.The authors identified a cohort of OLI and AST patients aged >or=65 years from Surveillance, Epidemiology and End Results (SEER) cancer registry data linked with Medicare claims between 1994 and 2002. Patients with a diagnosis of glioblastoma were excluded. The impact of demographic characteristics and comorbidities on the probability of undergoing surgical resection, radiotherapy (RT), and chemotherapy within 6 months of diagnosis was assessed using multivariate logistic regression.A total of 1067 patients (891 with AST and 176 with OLI) were included; the median survival was 9 months for patients with low-grade AST, 4 months for patients with anaplastic AST, 57 months for patients with low-grade OLI, and 9 months for patients with anaplastic OLI. Approximately 54% of patients underwent resection at the time of diagnosis; 66% received RT, and 13% received chemotherapy within 6 months of diagnosis. In a multivariate regression analysis, age and tumor grade were found to be the most significant predictors of resection, RT, or chemotherapy. Patients with anaplastic tumors were treated with resection, RT, and chemotherapy more often than patients with low-grade tumors, and OLI patients received chemotherapy more frequently than AST.Data from the current study suggested that histologic diagnosis and tumor grade retained significant prognostic value in this elderly AST and OLI population. Furthermore, age and tumor grade were found to influence the probability of undergoing surgery, RT, and chemotherapy in this cohort.

  View details for DOI 10.1002/cncr.24612

  View details for PubMedID 19708033

  View details for PubMedCentralID PMC7263427

• Patterns of relapse and prognosis after bevacizumab failure in recurrent glioblastoma. Neurology Iwamoto, F. M., Abrey, L. E., Beal, K., Gutin, P. H., Rosenblum, M. K., Reuter, V. E., DeAngelis, L. M., Lassman, A. B. 2009; 73 (15): 1200-6

  Abstract

  Bevacizumab has recently been approved by the US Food and Drug Administration for recurrent glioblastoma (GBM). However, patterns of relapse, prognosis, and outcome of further therapy after bevacizumab failure have not been studied systematically.We identified patients at Memorial Sloan-Kettering Cancer Center with recurrent GBM who discontinued bevacizumab because of progressive disease.There were 37 patients (26 men with a median age of 54 years). The most common therapies administered concurrently with bevacizumab were irinotecan (43%) and hypofractionated reirradiation (38%). The median overall survival (OS) after progressive disease on bevacizumab was 4.5 months; 34 patients died. At the time bevacizumab was discontinued for tumor progression, 17 patients (46%) had an increase in the size of enhancement at the initial site of disease (local recurrence), 6 (16%) had a new enhancing lesion outside of the initial site of disease (multifocal), and 13 (35%) had progression of predominantly nonenhancing tumor. Factors associated with shorter OS after discontinuing bevacizumab were lower performance status and nonenhancing pattern of recurrence. Additional salvage chemotherapy after bevacizumab failure was given to 19 patients. The median progression-free survival (PFS) among these 19 patients was 2 months, the median OS was 5.2 months, and the 6-month PFS rate was 0%.Contrast enhanced MRI does not adequately assess disease status during bevacizumab therapy for recurrent glioblastoma (GBM). A nonenhancing tumor pattern of progression is common after treatment with bevacizumab for GBM and is correlated with worse survival. Treatments after bevacizumab failure provide only transient tumor control.

  View details for DOI 10.1212/WNL.0b013e3181bc0184

  View details for PubMedID 19822869

  View details for PubMedCentralID PMC2839807

• PHASE II TRIAL OF TALAMPANEL, A GLUTAMATE RECEPTOR INHIBITOR, FOR ADULTS WITH RECURRENT MALIGNANT GLIOMAS Iwamoto, F. M. DUKE UNIV PRESS. 2009: 624

  View details for Web of Science ID 000270494800269

• Safety and efficacy of bevacizumab with hypofractionated stereotactic irradiation for recurrent malignant gliomas. International journal of radiation oncology, biology, physics Gutin, P. H., Iwamoto, F. M., Beal, K., Mohile, N. A., Karimi, S., Hou, B. L., Lymberis, S., Yamada, Y., Chang, J., Abrey, L. E. 2009; 75 (1): 156-63

  Abstract

  Preclinical studies suggest that inhibition of vascular endothelial growth factor (VEGF) improves glioma response to radiotherapy. Bevacizumab, a monoclonal antibody against VEGF, has shown promise in recurrent gliomas, but the safety and efficacy of concurrent bevacizumab with brain irradiation has not been extensively studied. The objectives of this study were to determine the safety and activity of this combination in malignant gliomas.After prior treatment with standard radiation therapy patients with recurrent glioblastoma (GBM) and anaplastic gliomas (AG) received bevacizumab (10 mg/kg intravenous) every 2 weeks of 28-day cycles until tumor progression. Patients also received 30 Gy of hypofractionated stereotactic radiotherapy (HFSRT) in five fractions after the first cycle of bevacizumab.Twenty-five patients (20 GBM, 5 AG; median age 56 years; median Karnofsky Performance Status 90) received a median of seven cycles of bevacizumab. One patient did not undergo HFSRT because overlap with prior radiotherapy would exceed the safe dose allowed to the optic chiasm. Three patients discontinued treatment because of Grade 3 central nervous system intratumoral hemorrhage, wound dehiscence, and bowel perforation. Other nonhematologic and hematologic toxicities were transient. No radiation necrosis was seen in these previously irradiated patients. For the GBM cohort, overall response rate was 50%, 6-month progression-free survival was 65%; median overall survival was 12.5 months, and 1-year survival was 54%.Bevacizumab with HFSRT is safe and well tolerated. Radiographic responses, duration of disease control, and survival suggest that this regimen is active in recurrent malignant glioma.

  View details for DOI 10.1016/j.ijrobp.2008.10.043

  View details for PubMedID 19167838

  View details for PubMedCentralID PMC3659401

• Glioblastoma in the elderly: the Memorial Sloan-Kettering Cancer Center Experience (1997-2007). Cancer Iwamoto, F. M., Cooper, A. R., Reiner, A. S., Nayak, L., Abrey, L. E. 2009; 115 (16): 3758-66

  Abstract

  Glioblastoma (GBM) is the most common malignant primary brain tumor, and approximately 50% of cases occur in patients aged > or =65 years. However, to the authors' knowledge, there is no accepted standard treatment for elderly GBM patients, and specific prognostic factors in the elderly GBM population have not been systematically studied to date.The Memorial Sloan-Kettering Cancer Center institutional database was used to identify patients with histologically confirmed GBM who were aged > or =65 years at the time of diagnosis.Three hundred ninety-four GBM patients with a median age of 71.9 years (59% of whom were men) were included. Approximately 18% of patients underwent biopsy, whereas 82% underwent tumor resection; 81% received radiotherapy (RT), and 43% received adjuvant chemotherapy. The median overall survival was 8.6 months; at the time of last follow-up, 90% of patients had died, and the median follow-up of the 39 surviving patients was 12 months. In a multivariate analysis, younger age, better Karnofsky performance status (KPS), single tumor, and surgical resection were found to be independent predictors of survival. Comparing 103 patients who received adjuvant chemotherapy with 48 who were only followed after RT, there was a 55% decrease in the risk of death (hazards ratio, 0.45; 95% confidence interval, 0.30-0.66 [P < .0001]) after adjusting for age, KPS, extent of surgical resection, and number of lesions.Similar to studies in younger GBM patients, advancing age, KPS, and extent of tumor resection were found to be independent prognostic factors in the current study. Although survival is inferior in older GBM patients, age alone should not disqualify patients from aggressive therapy with surgical resection, RT, and chemotherapy.

  View details for DOI 10.1002/cncr.24413

  View details for PubMedID 19484785

  View details for PubMedCentralID PMC7295086

• Randomized phase II trial of chemoradiotherapy followed by either dose-dense or metronomic temozolomide for newly diagnosed glioblastoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Clarke, J. L., Iwamoto, F. M., Sul, J., Panageas, K., Lassman, A. B., DeAngelis, L. M., Hormigo, A., Nolan, C. P., Gavrilovic, I., Karimi, S., Abrey, L. E. 2009; 27 (23): 3861-7

  Abstract

  Alternative dosing schedules of temozolomide may improve survival in patients with newly diagnosed glioblastoma (GBM) by increasing the therapeutic index, overcoming common mechanisms of temozolomide resistance, or both. The goal of this randomized phase II study was to evaluate two different temozolomide regimens in the adjuvant treatment of newly diagnosed GBM.Adult patients with newly diagnosed GBM were randomly assigned to receive standard radiotherapy with concurrent daily temozolomide followed by six adjuvant cycles of either dose-dense (150 mg/m(2) days 1 to 7 and 15 to 21) or metronomic (50 mg/m(2) continuous daily) temozolomide. Maintenance doses of 13-cis-retinoic acid were then administered until tumor progression. The primary end point was overall survival (OS) at 1 year. Tumor tissue was assayed to determine O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation status.Eighty-five eligible patients were enrolled; 42 were randomly assigned to dose-dense and 43 to metronomic temozolomide. The 1-year survival rate was 80% for the dose-dense arm and 69% for the metronomic arm; median OS was 17.1 months (95% CI, 14.0 to 28.1 months) and 15.1 months (95% CI, 12.3 to 18.9 months), respectively. The most common toxicities were myelosuppression (leukopenia, neutropenia, and thrombocytopenia) and elevated liver enzymes. Pseudoprogression was observed in 37% of assessable patients and may have had an impact on estimates of progression-free survival (6.6 months in the dose-dense arm and 5.0 months in the metronomic arm).Both dose-dense and metronomic temozolomide regimens were well tolerated with modest toxicity. The dose-dense regimen appears promising, with 1-year survival of 80%.

  View details for DOI 10.1200/JCO.2008.20.7944

  View details for PubMedID 19506159

  View details for PubMedCentralID PMC2727290

• Intracranial dural metastases. Cancer Nayak, L., Abrey, L. E., Iwamoto, F. M. 2009; 115 (9): 1947-53

  Abstract

  : Intracranial dural metastases (IDM) are found at autopsy in 9% of patients with advanced systemic cancer. However, to the authors' knowledge, IDM have not been studied systematically in the modern neuroimaging era. The objective of the current study was to evaluate the demographics, clinical presentation, imaging, treatment, and prognosis of patients with IDM.: The current study was a retrospective review of 122 patients with IDM diagnosed at Memorial Sloan-Kettering Cancer Center between 1999 and 2006. Patients with concurrent brain or leptomeningeal metastases were excluded.: Sixty-one percent of the patients were women; the median age at diagnosis was 59 years, the median Karnofsky performance scale (KPS) at diagnosis was 80, and the median time to IDM diagnosis from initial cancer diagnosis was 37 months. Breast (34%) and prostate (17%) cancers were the most frequent primary tumors associated with IDM. Fifty-six percent of patients had a single dural metastasis. On imaging, 70% had metastases of the overlying skull, 44% had dural tail metastases, 53% had vasogenic edema, and 34% had brain invasion. Direct extension from skull metastases was the most common mode of spread. Eighty-three percent of patients had active systemic disease at the time of IDM diagnosis. A lower KPS and lung cancer were associated with worse overall survival. Surgical resection and chemotherapy improved progression-free survival, but only resection was found to be associated with improved overall survival.: IDM affect a significant proportion of cancer patients. KPS and status of systemic cancer should guide treatment decisions. Cancer 2009. (c) 2009 American Cancer Society.

  View details for DOI 10.1002/cncr.24203

  View details for PubMedID 19241421

• Prospective cognitive follow-up in primary CNS lymphoma patients treated with chemotherapy and reduced-dose radiotherapy. Journal of neuro-oncology Correa, D. D., Rocco-Donovan, M., DeAngelis, L. M., Dolgoff-Kaspar, R., Iwamoto, F., Yahalom, J., Abrey, L. E. 2009; 91 (3): 315-21

  Abstract

  High-dose chemotherapy and whole brain radiotherapy (WBRT) can prolong survival in primary CNS lymphoma (PCNSL) patients, but is often associated with clinically significant cognitive decline. In this study we assessed neuropsychological functioning prospectively in newly diagnosed PCNSL patients treated with induction chemotherapy followed by reduced-dose WBRT. Twelve patients underwent neuropsychological evaluations at diagnosis, after induction chemotherapy, and 6 and 12 months after WBRT. Nine patients completed additional cognitive evaluations 18 and 24 months post-treatment. At diagnosis, patients had impairments in Executive Functions, Verbal Memory, and Motor Speed. There was a significant improvement in Executive Functions (P < 0.01) and Verbal Memory (P < 0.05) following induction chemotherapy, and scores remained relatively stable up to 12 months post-treatment. Among the nine patients who completed a 2-year follow-up, there was a significant improvement in the Executive domain (P < 0.05) and a trend toward a decline in the Verbal Memory domain. Executive and Verbal Memory functions improved following induction chemotherapy, likely due to decreased tumor burden and discontinuation of corticosteroid and anticonvulsant medications. There was no significant cognitive decline up to 24 months post-chemotherapy and reduced-dose WBRT in this group of PCNSL patients, however, difficulties in Verbal Memory and Motor speed persisted over the follow-up period.

  View details for DOI 10.1007/s11060-008-9716-0

  View details for PubMedID 18974934

  View details for PubMedCentralID PMC7213759

• Synchronous presentation of systemic and brain non-Hodgkin lymphoma. Leukemia & lymphoma Bazzoli, E., Iwamoto, F. M., Zelenetz, A. D., Deangelis, L. M., Abrey, L. E. 2008; 49 (12): 2370-3

  View details for DOI 10.1080/10428190802404055

  View details for PubMedID 19052988

• Patterns of care in elderly glioblastoma patients. Annals of neurology Iwamoto, F. M., Reiner, A. S., Panageas, K. S., Elkin, E. B., Abrey, L. E. 2008; 64 (6): 628-34

  Abstract

  To evaluate the patterns of care in elderly glioblastoma (GBM) patients from a large population-based registry.We identified a cohort of GBM patients 65 years or older from Surveillance, Epidemiology, and End Results cancer registry data linked with Medicare claims between 1994 and 2002. We assessed the impact of demographic characteristics and comorbidities on the probability of undergoing surgical resection, radiotherapy (RT), and chemotherapy within 3 months of diagnosis using multivariate logistic regression.A total of 4,137 patients with GBM were included, with a median overall survival of 4 months. Sixty-one percent of patients underwent resection at diagnosis; 65% received RT and 10% received chemotherapy within 3 months of diagnosis. In a multivariate regression analysis, age was the most significant predictor of resection, RT, or chemotherapy. Black race (odds ratio [OR], 0.64; p = 0.008) was associated with lower rates of surgical resection. Factors associated with decreased likelihood of receiving RT included unmarried marital status (OR, 0.64; p < 0.0001) and more comorbidities (OR, 0.55; p < 0.0001). Factors associated with decreased likelihood of receiving chemotherapy included unmarried marital status (OR, 0.59; p = 0.0002) and more comorbidities (OR, 0.56; p = 0.02).Survival of elderly GBM patients was poor in this population-based study. Age, marital status, and comorbidities influenced the probability of receiving RT or chemotherapy in this cohort.

  View details for DOI 10.1002/ana.21521

  View details for PubMedID 19107984

• 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

• Primary central nervous system lymphoma: the role of consolidation treatment after a complete response to high-dose methotrexate-based chemotherapy. Cancer Ekenel, M., Iwamoto, F. M., Ben-Porat, L. S., Panageas, K. S., Yahalom, J., DeAngelis, L. M., Abrey, L. E. 2008; 113 (5): 1025-31

  Abstract

  The most effective treatment for a new diagnosis of primary central nervous system lymphoma is high-dose methotrexate (MTX)-based chemotherapy followed by whole-brain radiation therapy (WBRT). However, this combined modality treatment carries an increased risk of delayed neurotoxicity. For patients who achieve a complete response (CR) after induction that uses high-dose MTX-based chemotherapy, it is not clear if consolidation treatment is necessary. Therefore, a retrospective study was conducted to assess the impact of consolidation treatment after a CR to initial induction chemotherapy on disease control and survival.The authors retrospectively analyzed 122 patients who achieved a CR after initial MTX-based chemotherapy. The benefit of consolidation WBRT, high-dose cytarabine (HDAC), or both on failure-free (FFS) and overall survival (OS) was assessed.With a median follow-up of 60 months, FFS was longer in patients who received WBRT plus HDAC as consolidation treatment (P = .03 by univariate analysis); there was no difference in OS observed among patients who received no consolidation treatment, HDAC alone, WBRT plus HDAC, or WBRT alone. Age and Karnofsky performance scale (KPS) were the only independent prognostic factors. Patients who received WBRT alone or in combination with HDAC had higher rates of neurotoxicity.Consolidation treatment with WBRT, HDAC, or both does not appear to improve survival in patients who achieved a CR with induction MTX-based therapy. Age, KPS, and risk of delayed neurotoxicity must be considered in the choice of consolidation regimens.

  View details for DOI 10.1002/cncr.23670

  View details for PubMedID 18618509

• Fungal encephalitis following bone marrow transplantation: clinical findings and prognosis. Journal of postgraduate medicine Teive, H., Carsten, A. L., Iwamoto, F. M., Almeida, S. M., Munhoz, R. P., Werneck, L. C., Medeiros, C. R., Pasquini, R. 2008; 54 (3): 203-5

  Abstract

  Central nervous system fungal infections (FI) are important complications and a cause of mortality in patients who receive hematopoietic stem cell transplantation (HSCT).To study the clinical aspects of fungal encephalitis (FE).The study was carried out at the HSCT Center of the Hospital de Clínicas, Federal University of Paraná, Curitiba, Brazil.Clinical records and autopsy reports from patients submitted to HSCT with a diagnosis of FE.Twelve patients were diagnosed with FE presenting with lowered level of consciousness, hemiparesis and seizures. We were able to identify two subgroups regarding susceptibility to FE: (1) patients with early onset FI and severe leucopenia, and (2) patients with later onset FI with graft-versus-host disease using immunosuppressive drugs. Eleven of the patients died directly due to the neurological complication, all had post-mortem confirmation of the diagnosis of FI.These clinical, paraclinical and temporal patterns may provide the opportunity for earlier diagnosis and interventions.

  View details for DOI 10.4103/0022-3859.41802

  View details for PubMedID 18626168

• Clinical relevance of 1p and 19q deletion for patients with WHO grade 2 and 3 gliomas. Journal of neuro-oncology Iwamoto, F. M., Nicolardi, L., Demopoulos, A., Barbashina, V., Salazar, P., Rosenblum, M., Hormigo, A. 2008; 88 (3): 293-8

  Abstract

  To assess the frequency of chromosomes 1p and 19q deletions in gliomas and to correlate 1p deletion with prognosis in patients with grade 2 and grade 3 gliomas independently of histologic subtype.We retrospectively evaluated 208 patients with WHO grade 2 and 3 gliomas who had 1p/19q molecular studies performed between 2000 and 2004. DNA was extracted from tumor tissue and germline material and evaluated by PCR using microsatellite markers for each chromosome.There were 113 men and 95 women with a median age at diagnosis of 40. Thirty-eight patients had a low-grade astrocytoma (A2), 58 low-grade oligodendroglioma (O2), 31 low-grade oligoastrocytoma (OA2), 21 anaplastic astrocytoma (A3), 37 anaplastic oligodendroglioma (O3), and 23 had an anaplastic oligoastrocytoma (OA3). Chromosome 1p analysis was performed in all patients and showed deletions in 105 patients (76% of O2, 42% of OA2, 21% of A2, 89% of O3, 17% of AO3, and 14% of A3). Chromosome 19q studies were performed in 118 patients and showed deletions in 46 (56% of O2, 45% of OA2, 27% of A2, 76% of O3, 11% of OA3 and 0% of A3). On multivariate analyses, chromosome 1p was a prognostic factor for prolonged PFS (HR = 1.75, P = 0.03) and OS (HR = 3.59, P = 0.02) in grade 2 gliomas but not for grade 3 (HR = 0.81, P = 0.7 for PFS; HR = 1.31, P = 0.7 for OS).Chromosome 1p deletion is a significant positive prognostic marker in diffuse, grade 2 gliomas regardless of histologic subtype.

  View details for DOI 10.1007/s11060-008-9563-z

  View details for PubMedID 18345516

• 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

• Study of radiolabeled indium-111 and yttrium-90 ibritumomab tiuxetan in primary central nervous system lymphoma. Cancer Iwamoto, F. M., Schwartz, J., Pandit-Taskar, N., Peak, S., Divgi, C. R., Zelenetz, A. D., Humm, J., Abrey, L. E. 2007; 110 (11): 2528-34

  Abstract

  Therapeutic options for refractory or recurrent primary central nervous system lymphoma (PCNSL) are limited. The blood-brain barrier makes many agents used in systemic lymphomas ineffective in CNS lymphomas. The objective of this study was to determine whether intravenous radioimmunotherapy using anti-CD20 antibody can be delivered to PCNSL.This was a single-institution prospective study. Indium-111 ibritumomab tiuxetan was used for imaging and dosimetry. Yttrium-90 ibritumomab tiuxetan at doses of 0.3 to 0.4 mCi/kg were subsequently given for the treatment of recurrent or refractory PCNSL. 111In data were used to estimate radiation doses to lesions delivered by 90Y ibritumomab tiuxetan therapy.Six patients (4 men, 2 women) with a median age of 60 years and median Karnofsky performance status of 70 received both indium-111 and yttrium-90 ibritumomab tiuxetan. The median absorbed dose delivered to the CNS lymphoma was 701 cGy compared with 70 cGy to normal brain. The median progression-free and overall survival times were 6.8 weeks and 14.3 weeks, respectively.The results from this study suggest that it may be feasible to deliver radiolabeled monoclonal anti-CD20 antibodies as a component of therapy for PCNSL.

  View details for DOI 10.1002/cncr.23077

  View details for PubMedID 17932895

• An update on primary central nervous system lymphoma. Hematology/oncology clinics of North America Iwamoto, F. M., DeAngelis, L. M. 2006; 20 (6): 1267-85

  Abstract

  The most important recent advance in treatment of primary central nervous system lymphoma has been the introduction of high-dose methotrexate-based chemotherapy. Convincing data demonstrate that the regimens of such chemotherapy improve survival compared with historical controls treated with radiotherapy alone. However, the optical treatment approach is still unclear and therapy can be associated with long-term neurotoxicity. Current research focuses on maximizing survival while minimizing neurologic sequelae.

  View details for DOI 10.1016/j.hoc.2006.09.002

  View details for PubMedID 17113462

• An update on therapy of primary central nervous system lymphoma. Hematology. American Society of Hematology. Education Program Deangelis, L. M., Iwamoto, F. M. 2006: 311-6

  Abstract

  The most important advance in primary central nervous system (CNS) lymphoma treatment has been the convincing data that high-dose methotrexate-based chemotherapy regimens improve survival compared to historical controls treated with radiotherapy alone. However, the optimal treatment approach is still unclear and therapy can be associated with long-term neurotoxicity. Current research focuses on maximizing survival while minimizing neurologic sequelae.

  View details for DOI 10.1182/asheducation-2006.1.311

  View details for PubMedID 17124077

• Primary dural lymphomas: a clinicopathologic study of treatment and outcome in eight patients. Neurology Iwamoto, F. M., DeAngelis, L. M., Abrey, L. E. 2006; 66 (11): 1763-5

  Abstract

  The authors report eight patients with primary dural lymphoma (PDL). All patients had extra-axial masses on MRI that diffusely enhanced after gadolinium. Pathology revealed low-grade non-Hodgkin lymphoma (marginal zone lymphoma of MALT [mucosa-associated lymphoid tissue] type) in all patients. All patients underwent radiation therapy, and three received chemotherapy. Complete response was achieved in 100% of patients, but three developed systemic relapse.

  View details for DOI 10.1212/01.wnl.0000218284.23872.eb

  View details for PubMedID 16769960

• Frequency of obsessive and compulsive symptoms in patients with blepharospasm and hemifacial spasm (vol 63, pg 213, 2005) ARQUIVOS DE NEURO-PSIQUIATRIA Munhoz, R. P., Teive, H. A., Dellacolletta, M. V., Germiniani, F., Iwamoto, F. M., Camargo, C. F., Werneck, L. C. 2005; 63 (2B): 552

  View details for DOI 10.1590/S0004-282X2005000300037

  View details for Web of Science ID 000230309800037

• Primary dural lymphomas Iwamoto, F. M., Abrey, L. E., DeAngelis, L. M. LIPPINCOTT WILLIAMS & WILKINS. 2005: A49-A50

  View details for Web of Science ID 000227841500167

• Ankylosing spondylitis and central core disease: case report. Arquivos de neuro-psiquiatria Scola, R. H., Lin, K., Iwamoto, F. M., Arruda, W. O., Werneck, L. C. 2003; 61 (3A): 687-90

  Abstract

  Ankylosing spondylitis (AS) is an inflammatory disorder of unknown cause that primarily affects the axial skeleton. Neurological manifestations of AS are usually related to spinal deformities. Previous studies of the paraspinal muscles of AS patients showed muscle fiber atrophy, and core fibers. On the other hand, central core disease (CCD) is a genetic condition that primarily involves the skeletal muscles, but can present articular deformities secondary to muscular weakness. We report the case of a 45-year-old man with clinical and radiological diagnosis of AS and proximal muscular weakness in the lower limbs. Needle electromyography showed myopathic features and nerve conduction study was normal. Muscle biopsy disclosed almost complete predominance of type-1 fibers, and fibers with central cores. This is the first report of AS and CCD. Whether central core myopathy is coincidental or a new association with AS is discussed.

  View details for DOI 10.1590/s0004-282x2003000400031

  View details for PubMedID 14513182

• Botulinum toxin for treatment of Frey's syndrome: report of two cases. Arquivos de neuro-psiquiatria Teive, H. A., Troiano, A. R., Robert, F., Iwamoto, F. M., Maniglia, J. J., Mocellin, M., Werneck, L. C. 2003; 61 (2A): 256-8

  Abstract

  Frey's syndrome is a phenomenon of hemifacial flushing and sweating after gustatory stimulus, usually secondary to surgical trauma over the parotid gland, although other injury mechanisms may be seen. It is accepted as a result of aberrant regeneration of facial autonomic nerve fibers. Treatment evolved from ineffective medical and surgical approaches to botulinum toxin. We evaluate the effectiveness and safety of botulinum toxin in the treatment of this complication in two patients.

  View details for DOI 10.1590/s0004-282x2003000200017

  View details for PubMedID 12806506

• Myotonia congenita and myoadenylate deaminase deficiency: case report. Arquivos de neuro-psiquiatria Scola, R. H., Iwamoto, F. M., Camargo, C. H., Arruda, W. O., Werneck, L. C. 2003; 61 (2A): 262-4

  Abstract

  Approximately 1-2% of the population has a deficiency of the enzyme myoadenylate deaminase. Early reports suggested that patients with myoadenylate deaminase deficiency had various forms of myalgia, and exercise intolerance. However, a deficiency of the enzyme has been described in many conditions, including myopathies, neuropathies, and motor neuron disease. We report a patient with clinical diagnosis of myotonia congenita and absent myoadenylate deaminase reaction on the muscle biopsy. This is the first description of myoadenilate deaminase deficiency with myotonia congenita. Myoadenylate deaminase deficiency is the most common enzymatic deficit of muscle, and the association with other neuromuscular diseases is coincidental.

  View details for DOI 10.1590/s0004-282x2003000200019

  View details for PubMedID 12806508

• [Distal myasthenia gravis: case report]. Arquivos de neuro-psiquiatria Scola, R. H., Iwamoto, F. M., Mainardi, M. A., Della-Coletta, M. V., Carvalho, G., Zavala, J. A., Werneck, L. C. 2003; 61 (1): 119-20

  Abstract

  We report the case of a 30-year-old woman with a 7-year history of distal lower limbs weakness that evolved to upper limbs weakness. On neurological examination, she presented normal cranial nerves, bilateral quadriceps and feet interosseous atrophy, normal muscular tonus, muscular weakness more severe in dorsal feet interosseous and anterior tibial, and decreased deep tendon reflexes. Repetitive nerve stimulation of the ulnar and fibular nerves showed a decrement greater than 10% of the compound muscle action potential. Antibody against acetylcholine receptor titer was positive. Computed tomography scan of the thorax was normal. Thyroid function tests showed evidence of hyperthyroidism. Distal muscular weakness is a rare onset presentation of myasthenia gravis. However, myasthenia gravis must be considered in the differential diagnosis of distal limb weakness.

  View details for DOI 10.1590/s0004-282x2003000100024

  View details for PubMedID 12715034

• [Stroke in young adults: analysis of 164 patients]. Arquivos de neuro-psiquiatria Zétola, V. H., Nóvak, E. M., Camargo, C. H., Carraro, H., Coral, P., Muzzio, J. A., Iwamoto, F. M., Coleta, M. V., Werneck, L. C. 2001; 59 (3-B): 740-5

  Abstract

  We retrospectively analyzed the epidemiological features of 164 out-clinic patients with a first-onset stroke between 15 and 49 years old. Ischemic stroke occurred in 141 patients, hemorrhagic stroke in 16 patients, and venous thrombosis in 7 patients. Forty-eight percent of ischemic strokes were atherothrombotic, but no etiology was found in 32% of patients with ischemic stroke. Systemic arterial hypertension was the most frequent etiology in the hemorrhagic stroke group. The most frequent risk factors were systemic arterial hypertension, smoking, hypercholesterolemia, alcoholism and diabetes mellitus. Although stroke in young adults deserves some specific etiological investigation, we found that ordinary risk factors such as hypertension, tobacco use, hypercholesteremia and diabetes were prevalent in our population. It seems that prevention campaigns should be the target of our work.

  View details for PubMedID 11593276

• Machado-Joseph disease versus hereditary spastic paraplegia: case report. Arquivos de neuro-psiquiatria Teive, H. A., Iwamoto, F. M., Camargo, C. H., Lopes-Cendes, I., Werneck, L. C. 2001; 59 (3-B): 809-11

  Abstract

  Machado-Joseph disease (MJD) is the most common autosomal dominant spinocerebellar ataxia and presents great phenotypic variability. MJD presenting with spastic paraparesis was recently described in Japanese patients. We report the case of 41-year-old woman with the phenotype of complicated hereditary spastic paraplegia. Her father died at the age of 56 years due to an undiagnosed progressive neurological disease that presented parkinsonism. She had an expanded allele with 66 CAG repeats and a normal allele with 22 repeats in the gene of MJD. MJD should be considered in the differential diagnosis of autosomal dominant complicated HSP. A patient with the phenotype of complicated HSP and relatives with other clinical features of a neurodegenerative disease should raise the suspicion of MJD.

  View details for DOI 10.1590/s0004-282x2001000500030

  View details for PubMedID 11593289

• [Acute cerebellitis caused by Epstein-Barr virus: case report]. Arquivos de neuro-psiquiatria Teive, H. A., Zavala, J. A., Iwamoto, F. M., Bertucci-Filho, D., Werneck, L. C. 2001; 59 (3-A): 616-8

  Abstract

  Acute cerebellitis can occur in association with varicella-zoster virus, enterovirus, mumps, mycoplasma, and other infective organisms. Acute cerebellitis is a rare complication of Epstein-Barr virus (EBV) infection. We report the case of a 21-year-old woman with a 12-day history of nausea and vomiting, gait and limbs ataxia, myoclonus, tremor of head and all four limbs, opsoclonus and cutaneous rash. Anti-EBV IgG and IgM antibodies against antiviral capsid were positive and anti-EBV against virus-associated nuclear antigen was also positive. EBV infection in association with neurological findings can occur without the classic signs and symptoms of infectious mononucleosis.

  View details for PubMedID 11588648

• Hereditary spastic paraplegia associated with thin corpus callosum. Arquivos de neuro-psiquiatria Teive, H. A., Iwamoto, F. M., Della Coletta, M. V., Camargo, C. H., Bezerra, R. D., Minguetti, G., Werneck, L. C. 2001; 59 (3-B): 790-2

  Abstract

  Autosomal recessive hereditary spastic paraplegia (AR-HSP) associated with thin corpus callosum was recently described in Japan, and most families were linked to chromosome 15 q13-15. We report two patients from two different Brazilian families with progressive gait disturbance starting at the second decade of life, spastic paraparesis, and mental deterioration. One patient presented cerebellar ataxia. Magnetic resonance imaging (MRI) of the head of both patients showed a thin corpus callosum. AR-HSP with a thin corpus callosum is a rare disorder, mainly described in Japanese patients. We found only 4 Caucasian families with AR-HSP with thin corpus callosum described in the literature. Further studies including additional Caucasian families of AR-HSP with thin corpus callosum are required to delineate the genetic profile of this syndrome in occidental countries.

  View details for DOI 10.1590/s0004-282x2001000500025

  View details for PubMedID 11593284

• The G209A mutation in the alpha-synuclein gene in Brazilian families with Parkinson's disease. Arquivos de neuro-psiquiatria Teive, H. A., Raskin, S., Iwamoto, F. M., Germiniani, F. M., Baran, M. H., Werneck, L. C., Allan, N., Quagliato, E., Leroy, E., Ide, S. E., Polymeropoulos, M. H. 2001; 59 (3-B): 722-4

  Abstract

  A missense G209A mutation of the alpha-synuclein gene was recently described in a large Contursi kindred with Parkinson's disease (PD). The objective of this study is to determine if the mutation G209A of the alpha-synuclein gene was present in 10 Brazilian families with PD. PD patients were recruited from movement disorders clinics of Brazil. A family history with two or more affected in relatives was the inclusion criterion for this study. The alpha-synuclein G209A mutation assay was made using polymerase chain reaction and the restriction enzyme Tsp45I. Ten patients from 10 unrelated families were studied. The mean age of PD onset was 42.7 years old. We did not find the G209A mutation in our 10 families with PD. Our results suggest that alpha-synuclein mutation G209A is uncommon in Brazilian PD families.

  View details for DOI 10.1590/s0004-282x2001000500013

  View details for PubMedID 11593272

• [Contributions of Charcot and Marsden to the development of movement disorders in the 19th and 20th centuries]. Arquivos de neuro-psiquiatria Teive, H. A., Zavala, J. A., Iwamoto, F. M., Sá, D., Carraro, H., Werneck, L. C. 2001; 59 (3-A): 633-6

  Abstract

  Charcot described many neurological diseases in the 19th century, particularly in movement disorders. Charcot contributed in the clinical description of Parkinson's disease, and introduced its first pharmacological treatment. He also studied the hyperkinesias, e.g. of Tourette syndrome, differential diagnosis of tremors, dystonias, choreas and startle disease. Marsden, who died recently, was an exponent in the study of Movement Disorders, with many publications in this field in the 20th century. His most important contributions are definitions and classifications of movement disorders, such as Parkinson's disease, dystonia, myoclonus, essential tremor, the description of the syndromes "Painful Legs Moving Toes", "Gait Ignition Failure" and "Primary Writing Tremor". The contributions of Charcot in the 19th century and Marsden in the 20th century to the movement disorders allow us to conclude that both of them were the most representative icons in this field in the past two centuries.

  View details for PubMedID 11588652

• Symptomatic muscle involvement in neurosarcoidosis: a clinicopathological study of 5 cases. Arquivos de neuro-psiquiatria Scola, R. H., Werneck, L. C., Prevedello, D. M., Greboge, P., Iwamoto, F. M. 2001; 59 (2-B): 347-52

  Abstract

  We report on the clinical course and histopathologic muscle alterations of five patients diagnosed with neurosarcoidosis, who underwent biopsy due to their muscle manifestations. The five patients were females and only one was less than 40 years of age. Proximal muscle weakness was presented by all and only two patients complained of myalgia. Only normal values of serum muscle enzymes were detected. Electromyography revealed diverse findings such as normal, myopathic and neuropathic patterns. Granuloma was not present in one muscle biopsy. Two patients thoroughly recovered by taking only prednisone and one patient required a methotrexate addition for 3 months before becoming asymptomatic. The other two patients received azathioprine, one due to steroid side effects but without a satisfactory evolution, and the other to strengthen the prednisone régime, with excellent results.

  View details for DOI 10.1590/s0004-282x2001000300007

  View details for PubMedID 11460177

• Congenital contractural arachnodactyly with neurogenic muscular atrophy: case report. Arquivos de neuro-psiquiatria Scola, R. H., Werneck, L. C., Iwamoto, F. M., Ribas, L. C., Raskin, S., Correa Neto, Y. 2001; 59 (2-A): 259-62

  Abstract

  We report the case of a 3-(1/2)-year-old girl with hypotonia, multiple joint contractures, hip luxation, arachnodactyly, adducted thumbs, dolichostenomelia, and abnormal external ears suggesting the diagnosis of congenital contractural arachnodactyly (CCA). The serum muscle enzymes were normal and the needle electromyography showed active and chronic denervation. The muscle biopsy demonstrated active and chronic denervation compatible with spinal muscular atrophy. Analysis of exons 7 and 8 of survival motor neuron gene through polymerase chain reaction did not show deletions. Neurogenic muscular atrophy is a new abnormality associated with CCA, suggesting that CCA is clinically heterogeneous.

  View details for DOI 10.1590/s0004-282x2001000200022

  View details for PubMedID 11400038

• Progressive multifocal leukoencephalopathy Medlink Neurology Mattson, D. H., Iwamoto, F. M. 2001
• Acquired slow-channel syndrome. Muscle & nerve Scola, R. H., Werneck, L. C., Iwamoto, F. M., Comerlato, E. A., Kay, C. K. 2000; 23 (10): 1582-5

  Abstract

  We report the case of a 37-year-old man with clinical and electrophysiological features of hereditary slow-channel syndrome (SCS) and antibodies against acetylcholine receptors (AChR-Abs). He presented with weakness of shoulder and hand muscles. A supramaximal single stimulus to the motor nerves disclosed a double compound muscle action potential (CMAP). Repetitive stimulation of ulnar, suprascapular, and median nerves showed a CMAP decrement greater than 10%. The patient responded to pyridostigmine. This report confirms the importance of AChR-Ab titers in suspected cases of hereditary SCS because patients with positive AChR-Abs may have a better response to available treatments.

  View details for DOI 10.1002/1097-4598(200010)23:10<1582::aid-mus16>3.0.co;2-h

  View details for PubMedID 11003795

• Diagnosis of dermatomyositis and polymyositis: a study of 102 cases. Arquivos de neuro-psiquiatria Scola, R. H., Werneck, L. C., Prevedello, D. M., Toderke, E. L., Iwamoto, F. M. 2000; 58 (3B): 789-99

  Abstract

  Patients with dermatomyositis (DM) or polymyositis (PM) were studied retrospectively. The patients were divided into four groups: definite PM 24, probable PM 19, definite DM 34 and mild-early DM 25 cases. PM patients complained more often proximal muscle weakness [p <0.01]. DM patients complained more arthralgia [p <0.05], dysphagia [p <0.03] and weight loss [p <0.04]. Five patients had a malignant neoplasm and 9 had other connective-tissue disease. DM presented higher ESR than PM [p <0.002]. PM presented more significant increase in creatine kinase (CK) [p <0.02] and in alanine aminotransferase (ALT) [p <0.001] levels. Electromyography showed myopathic pattern in 76%. Muscle biopsy was the definitive test. Perifascicular atrophy was more frequent in definite DM than in mild-early DM group [p <0.03].A small association with connective-tissue diseases and neoplasms was found. DM and PM are clinically different. DM presents systemic involvement affecting the skin, developing more severe arthralgia, dysphagia and weight loss and presenting higher values of ESR. PM presents a restricted and more significant involvement of muscles generating more weakness complaints and higher levels of serum muscle enzymes.

  View details for DOI 10.1590/s0004-282x2000000500001

  View details for PubMedID 11018813

• [True neurogenic outlet syndrome: report of 2 cases]. Arquivos de neuro-psiquiatria Scola, R. H., Werneck, L. C., Iwamoto, F. M., Maegawa, G. H., Faoro, L. N., Caldeira, F. H. 1999; 57 (3A): 659-65

  Abstract

  True neurogenic thoracic outlet syndrome is caused by compression of the lower trunk of the brachial plexus usually by a cervical rib, fibrous band or an elongated transverse process of C7. We describe two cases of female patients (23 and 19 years old) with pain in the right superior limb and progressive muscular weakness and atrophy of the intrinsic muscles of hand. Electrodiagnostic studies showed reduced amplitude of compound muscle action potential of median nerve and decreased amplitude of ulnar sensory nerve action potential. Motor and sensory nerve conduction velocities were normal in both patients. Needle electromyography were findings compatible with chronic denervation in the intrinsic muscles of the right hand of both patients. Radiological investigation showed cervical ribs in one case and elongated transverse process of C7 in the other. A discussion about the clinical and electrophysiological features and the treatment of the syndrome was performed.

  View details for DOI 10.1590/s0004-282x1999000400020

  View details for PubMedID 10667293

• Neurofibromatosis, stroke and basilar impression. Case report. Arquivos de neuro-psiquiatria Piovesan, E. J., Scola, R. H., Werneck, L. C., Zétola, V. H., Nóvak, E. M., Iwamoto, F. M., Piovesan, L. M. 1999; 57 (2B): 484-8

  Abstract

  Neurofibromatosis type 1 (NF1) can virtually affect any organ, presenting most frequently with "cafe au lait" spots and neurofibromas. Vasculopathy is a known complication of NF1, but cerebrovascular disease is rare. We report the case of a 51-year-old man admitted to the hospital with a history of stroke four months before admission. On physical examination, he presented various "cafe au lait" spots and cutaneous neurofibromas. Neurologic examination demonstrated right-sided facial paralysis, right-sided hemiplegia, and aphasia. Computed tomography scan of head showed hypodense areas in the basal ganglia and centrum semiovale. Radiographs of cranium and cervical spine showed basilar impression. Angiography revealed complete occlusion of both vertebral and left internal carotid arteries, and partial stenosis of the right internal carotid artery. A large network of collateral vessels was present (moyamoya syndrome). It is an uncommon case of occlusive cerebrovascular disease associated with NF1, since most cases described in the literature are in young people, and tend to spare the posterior cerebral circulation. Basilar impression associated with this case may be considered a pure coincidence, but rare cases of basilar impression and NF1 have been described.

  View details for DOI 10.1590/s0004-282x1999000300022

  View details for PubMedID 10450358

• [Immunocytochemical analysis of the inflammatory infiltrate in inclusion body myositis and other neuromuscular disorders with rimmed vacuoles]. Arquivos de neuro-psiquiatria Scola, R. H., Werneck, L. C., Iwamoto, F. M., de Messias, I. T., Tsuchiya, L. V. 1998; 56 (3A): 388-97

  Abstract

  Among 1400 muscle biopsies, we found 16 cases with rimmed vacuoles whose diagnosis were sporadic inclusion body myositis (IBM) (4 cases), juvenile spinal muscular atrophy (6 cases), distal myopathies (3 cases), limb-girdle muscular dystrophy (2 cases), and peripheral neuropathy (1 case). Monoclonal antibodies reactive for T lymphocytes and subsets, B lymphocytes, macrophages, natural killer cells, immunoglobulins, and complement were used to analyze the inflammatory infiltrate. The analysis was quantitative and according to the site of accumulation (interstitial, endomysial, and perivascular). The immunocytochemical analysis showed CD8+ lymphocytes in the interstitial in most cases, occasionally inside of muscle fibers, and rarely in the perivascular region. The IBM cases had an increased number of CD8+ lymphocytes comparing with the other diseases. CD8+/CD4+ ratio was increased in IBM compared with the other diseases. Macrophages were frequent in IBM, distal myopathy, and one case of limb-girdle muscular dystrophy. Natural killer cells were frequent at interstitial.

  View details for DOI 10.1590/s0004-282x1998000300007

  View details for PubMedID 9754419

• Lambert-Eaton myasthenic syndrome. Report of two cases. Arquivos de neuro-psiquiatria Scola, R. H., Iwamoto, F. M., Ramos, C. S., Sanderson, A. M., Lopardo, D., Cantarelli, A., Watanabe, M., Horta, W., Werneck, L. C. 1998; 56 (3A): 457-64

  Abstract

  Two cases of Lambert-Eaton myasthenic syndrome, in female patients whose neoplasm investigation was negative, are reported. Repetitive stimulation of ulnar nerve showed an incremental response (+187% and +198%). Needle EMG was normal in one of them, however, the other patient showed fibrillation potentials, positive sharp waves, potentials of low amplitude and short duration. The authors discuss the clinical, electrophysiological, and pathological features of the disease, as well as some aspects of the treatment and follow-up of these patients.

  View details for DOI 10.1590/s0004-282x1998000300017

  View details for PubMedID 9754429

• [Ossification of the posterior longitudinal ligament in the cervical spine: case report]. Arquivos de neuro-psiquiatria Scola, R. H., Werneck, L. C., Iwamoto, F. M., Cabral, N. L., Maegawa, G. H., Rogacheski, E. 1998; 56 (3A): 480-5

  Abstract

  Ossification of the posterior longitudinal ligament (OPLL) is an uncommon cause of compressive myelopathy in the Caucasian population. A case of spastic paraparesis in a Caucasian man whose radiological investigation showed OPLL is presented. The radiographs of the cervical spine showed a strip of bony density posterior to the vertebral bodies, extending from C2 to T1. Computerized tomography (CT) and CT myelography showed OPLL at the same level. Magnetic resonance showed an area of increased signal on T2-weighted sequences at C7-T1 level suggestive of myelomalacia. The patient underwent an open-door laminoplasty (C2 to C7) with improvement of the paraparesis. OPLL should be included in the differential diagnosis of cervical myelopathy. It can be easily detected by plain radiographs and CT of the cervical spine. A review of the clinical and radiological features and the treatment of OPLL is presented.

  View details for DOI 10.1590/s0004-282x1998000300021

  View details for PubMedID 9754433

• [Congenital muscular dystrophy and merosin deficiency]. Arquivos de neuro-psiquiatria Werneck, L. C., Scola, R. H., Iwamoto, F. M. 1997; 55 (4): 780-7

  Abstract

  Merosin alpha 2 chain, an extracellular matrix protein, is deficient in a proportion of patients with classical congenital muscular dystrophy (CMD). A study of clinical, laboratory and histopathological features of 18 patients with CMD was performed in relation to the merosin expression in muscle biopsy. Immunohistochemistry study showed that merosin was deficient in 11 patients and present in 7. None of the 9 merosin-deficient patients evaluated achieved walking. In contrast, 4 of 7 merosin-positive patients achieved independent ambulation. Creatine kinase levels were higher in merosin-deficient patients, but this difference was not statistically significant. Motor nerve conduction study was carried out on 12 children. All 4 merosin-positive patients had normal exams whereas 2 out 8 merosin-deficient patients presented decreased motor nerve conduction velocity. Among 69 histopathological features studied, we did not find any significant difference between merosin-deficient and merosin-positive patients. These results suggest that merosin status evaluation is important in the determination of the prognostic, since merosin-positive patients can achieve independent walking. This study also suggests that there is no relation between absence of merosin and histopathological features.

  View details for DOI 10.1590/s0004-282x1997000500015

  View details for PubMedID 9629338