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Background We aimed to investigate the detection rate of body CT or PET/CT for sites of extracranial disease in patients with a new pathological diagnosis of CNS DLBCL and to identify factors associated with sites of extracranial disease. Methods An international multicenter cohort study of consecutive immunocompetent patients with a new diagnosis of CNS DLBCL confirmed by brain biopsy who underwent CT and/or PET/CT to evaluate for sites of extracranial disease between 1998 and 2019. The primary outcome was the detection rate of extracranial lymphoma by CT or PET/CT. Subgroup analyses according to age and EBV status were also performed. Logistic regression analyses were performed to determine factors related to sites of extracranial disease. Detection rates of CT and PET/CT were compared. Results One thousand and forty-three patients were included. The overall detection rate of CT or PET/CT was 2.6% (27/1043). The treatment approach was adjusted in 74% of these patients. Multivariable analysis demonstrated that age >61 years (OR, 3.10; P = .016) and EBV positivity (OR, 3.78; P = .045) were associated with greater odds of extracranial lymphoma. There was no statistically significant difference in detection rate between CT and PET/CT (P = .802). In patients ≤61 years old, the false-referral rates were significantly higher than the detection rates (P < .001). Conclusion Our results showed increased odds of extracranial lymphoma in patients with older age or EBV-positive lymphoma. Treatment was adjusted in a majority of patients diagnosed with extracranial lymphoma, thereby supporting the current guidelines for the use of contrast-enhanced body CT or PET/CT in patients with newly diagnosed CNS DLBCL.

Advanced molecular and pathophysiologic characterization of primary central nervous system lymphoma (PCNSL) has revealed insights into promising targeted therapeutic approaches. Medical imaging plays a fundamental role in PCNSL diagnosis, staging, and response assessment. Institutional imaging variation and inconsistent clinical trial reporting diminishes the reliability and reproducibility of clinical response assessment. In this context, we aimed to: (1) critically review the use of advanced positron emission tomography (PET) and magnetic resonance imaging (MRI) in the setting of PCNSL; (2) provide results from an international survey of clinical sites describing the current practices for routine and advanced imaging, and (3) provide biologically based recommendations from the International PCNSL Collaborative Group (IPCG) on adaptation of standardized imaging practices. The IPCG provides PET and MRI consensus recommendations built upon previous recommendations for standardized brain tumor imaging protocols (BTIP) in primary and metastatic disease. A biologically integrated approach is provided to addresses the unique challenges associated with the imaging assessment of PCNSL. Detailed imaging parameters facilitate the adoption of these recommendations by researchers and clinicians. To enhance clinical feasibility, we have developed both “ideal” and “minimum standard” protocols at 3T and 1.5T MR systems that will facilitate widespread adoption.

Background ONC201 is a dopamine receptor D2 (DRD2) antagonist that penetrates the blood–brain barrier. ONC201 efficacy has been shown in glioblastoma animal models and is inversely correlated with dopamine receptor DRD5 expression. ONC201 is well tolerated in adult recurrent glioblastoma patients with dosing every 3 weeks and has achieved an objective radiographic response in a patient harboring the H3 K27M mutation. Methods In a window-of-opportunity arm, 6 adult subjects initiated ONC201 prior to re-resection of recurrent glioblastoma with intratumoral concentrations as the primary endpoint. An additional 20 adults with recurrent glioblastoma received single agent weekly oral ONC201 at 625 mg, with progression-free survival at 6 months (PFS6) by Response Assessment in Neuro-Oncology (RANO) criteria as the primary endpoint. Results The window-of-opportunity arm achieved its primary endpoint with intratumoral ONC201 concentrations at ~24 hours following the second weekly dose ranging from 600 nM to 9.3 µM. Intratumoral pharmacodynamics assessed by activating transcriptional factor 4, death receptor 5, and apoptosis induction relative to archival samples were observed with the strongest intensity and uniformity among patients with low DRD5 tumor expression. The primary endpoint of PFS6 by RANO was not achieved at 5% in this molecularly unselected cohort; however, 1 of 3 patients enrolled with the H3 K27M mutation had a complete regression of enhancing multifocal lesions that remained durable for >1.5 years. No treatment modifications or discontinuations due to toxicity were observed, including in those who underwent re-resection. Conclusions Weekly ONC201 is well tolerated, and meaningful intratumoral concentrations were achieved. ONC201 may be biologically active in a subset of adult patients with recurrent glioblastoma.

Background Targeted gene NGS testing is available through many academic institutions and commercial entities and is increasingly incorporated in practice guidelines for glioblastoma (GBM). This single-center retrospective study aimed to evaluate the clinical utility of incorporating NGS results in the management of GBM patients at a clinical trials-focused academic center. Methods We identified 1011 consecutive adult patients with pathologically confirmed GBM (IDHwt or IDHmut) who had somatic tumor sequencing (Oncopanel, ~500 cancer gene panel) at DFCI from 2013–2019. Clinical records of all IDHwt GBM patients were reviewed to capture clinical trial enrollment and off-label targeted therapy use based on NGS results. Results Of the 557 IDHwt GBM patients with sequencing, 182 entered clinical trials at diagnosis (32.7%) and 213 (38.2%) entered after recurrence. Sequencing results for 130 patients (23.3%) were utilized for clinical trial enrollment for either targeted therapy indications (6.9 % upfront and 27.7% at recurrent clinical trials and 3.1% for off-label targeted therapy) or exploratory studies (55.4% upfront and 6.9% recurrent clinical trials). Median overall survival was 20.1 months with no survival difference seen between patients enrolled in clinical trials compared to those who were not, in a posthoc analysis. Conclusions While NGS testing has become essential for improved molecular diagnostics, our study illustrates that targeted gene panels remain underutilized for selecting therapy in GBM-IDHwt. Targeted therapy and clinical trial design remain to be improved to help leverage the potential of NGS in clinical care.

Background Longitudinal measurement of glioma burden with MRI is the basis for treatment response assessment. In this study, we developed a deep learning algorithm that automatically segments abnormal fluid attenuated inversion recovery (FLAIR) hyperintensity and contrast-enhancing tumor, quantitating tumor volumes as well as the product of maximum bidimensional diameters according to the Response Assessment in Neuro-Oncology (RANO) criteria (AutoRANO). Methods Two cohorts of patients were used for this study. One consisted of 843 preoperative MRIs from 843 patients with low- or high-grade gliomas from 4 institutions and the second consisted of 713 longitudinal postoperative MRI visits from 54 patients with newly diagnosed glioblastomas (each with 2 pretreatment “baseline” MRIs) from 1 institution. Results The automatically generated FLAIR hyperintensity volume, contrast-enhancing tumor volume, and AutoRANO were highly repeatable for the double-baseline visits, with an intraclass correlation coefficient (ICC) of 0.986, 0.991, and 0.977, respectively, on the cohort of postoperative GBM patients. Furthermore, there was high agreement between manually and automatically measured tumor volumes, with ICC values of 0.915, 0.924, and 0.965 for preoperative FLAIR hyperintensity, postoperative FLAIR hyperintensity, and postoperative contrast-enhancing tumor volumes, respectively. Lastly, the ICCs for comparing manually and automatically derived longitudinal changes in tumor burden were 0.917, 0.966, and 0.850 for FLAIR hyperintensity volume, contrast-enhancing tumor volume, and RANO measures, respectively. Conclusions Our automated algorithm demonstrates potential utility for evaluating tumor burden in complex posttreatment settings, although further validation in multicenter clinical trials will be needed prior to widespread implementation.

Cancer therapy-induced adverse effects on the brain are a major challenge in neuro-oncology. Brain tissue necrosis (treatment necrosis [TN]) as a consequence of brain directed cancer therapy remains an insufficiently characterized condition with diagnostic and therapeutic difficulties and is frequently associated with significant patient morbidity. A better understanding of the underlying mechanisms, improvement of diagnostic tools, development of preventive strategies, and implementation of evidence-based therapeutic practices are pivotal to improve patient management. In this comprehensive review, we address existing challenges associated with current TN-related clinical and research practices and highlight unanswered questions and areas in need of further research with the ultimate goal to improve management of patients affected by this important neuro-oncological condition.

BACKGROUND The Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) is a phase II platform trial with Bayesian adaptive randomization and deep genomic profiling to more efficiently test experimental agents in newly diagnosed glioblastoma and to prioritize therapies for late-stage testing. METHODS In the ongoing INSIGhT trial, patients with newly diagnosed MGMT-unmethylated glioblastoma are randomized to the control arm or one of three experimental therapy arms (CC-115, abemaciclib, and neratinib). The control arm therapy is radiotherapy with concomitant and adjuvant temozolomide, and primary endpoint is overall survival. Randomization has been adapted based on Bayesian estimation of biomarker-specific probability of treatment impact on progression-free survival (PFS). All tumors undergo detailed molecular sequencing, and this is facilitated with the companion ALLELE protocol. To evaluate feasibility of this approach, we assessed the status of this ongoing trial. RESULTS Since INSIGhT was activated 4.3 years ago, it has expanded to include 12 sites across the United States. A total of 247 patients have been enrolled. Randomization probabilities have been repeatedly adjusted over time based upon early PFS results to alter the randomization ratio from standard 1:1:1:1 randomization. All three arms have completed accrual and efficacy estimates are available based upon comparison to the common control arm in context of relevant biomarkers. There are 87 patients alive and in follow-up, and there are ongoing plans to add additional arms to evaluate further treatments in the future. CONCLUSION The INSIGhT trial demonstrates that a multi-center Bayesian adaptive platform trial is a feasible and effective approach to help prioritize therapies and biomarkers for newly diagnosed GBM. The trial has maintained robust accrual, and the simultaneous testing of multiple agents, sharing a common control arm and adaptive randomization serve as features to increase trial efficiency relative to traditional clinical trial designs.

Background Update 3 of the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) recognizes amplification of epidermal growth factor receptor (EGFR) as one important aberration in diffuse gliomas (World Health Organization [WHO] grade II/III). While these recommendations endorse testing, a cost-effective, clinically relevant testing paradigm is currently lacking. Here, we use real-world clinical data to propose a financially effective diagnostic test algorithm in the context of new guidelines. Methods To determine the prevalence, distribution, neuroradiographic features (Visually Accessible REMBRANDT Images [VASARI]), and prognostic relevance of EGFR amplification in lower-grade gliomas, we assembled a consecutive series of diffuse gliomas. For validation we included publicly available data from The Cancer Genome Atlas. For a cost-utility analysis we compared combined EGFR and isocitrate dehydrogenase (IDH) testing, EGFR testing based on IDH results, and no EGFR testing. Results In n = 71 WHO grade II/III gliomas, we identified EGFR amplification in 28.2%. With one exception, all EGFR amplifications occurred in IDH-wildtype gliomas. Comparison of overall survival showed that EGFR amplification denotes a significantly more aggressive subset of tumors (P 5% tumor contrast enhancement (75%, P = 0.016), and mild (not avid) enhancement (P = 0.016). The proposed testing algorithm reserves EGFR fluorescence in situ hybridization (FISH) testing for IDH-wildtype cases. Implementation would result in ~37.9% cost reduction at our institution, or about $1.3-4 million nationally. Conclusion EGFR-amplified diffuse gliomas are "glioblastoma-like" in their behavior and may represent undersampled glioblastomas, or subsets of IDH-wildtype diffuse gliomas with inherently aggressive biology. EGFR FISH after IDH testing is a financially effective and clinically relevant test algorithm for routine clinical practice.

BACKGROUND The neurologic assessment in neuro-oncology (NANO) scale was developed as a standardized metric to objectively measure neurologic function in patients with brain tumors and complement radiographic assessment in defining overall outcome. The scale has been incorporated in clinical trials. Early data is suggestive of feasibility and that NANO contributes to overall outcome assessment. However, real-world use of the NANO scale to drive clinical-decision making and the predictive value of the NANO scale to determine overall survival remains unclear in IDH-wt GBM. METHODS We report on an ongoing study using the NANO scale to evaluate neurologic function in patients with IDH-wt GBM, seen at Dana-Farber Cancer Institute (DFCI). Patient demographics, tumor histology and molecular status, treatment history and progression dates are being captured. NANO score, as collected by a built-in scale in our institutional electronic medical record (EMR), functional status (Karnofsky performance status) and corticosteroid dose are collected at prespecified time points (prior to start of therapy, and during each subsequent MRI visit). Changes in the NANO score will be correlated to overall survival. Statistical analyses including descriptive data analysis and generalized linear models will be performed using R (version 3.4.3). RESULTS Since June 2020, 50 patients have been enrolled in this study, including 42 (84%) with ≥2 follow up visits. Study accrual was initially impacted by the COVID-19 pandemic, but adaptation to a virtual platform for NANO allowed for improved recruitment and follow up of patients. Study results will be available for discussion at the 2021 SNO conference. CONCLUSIONS Evaluation of neurologic function by NANO is feasible in a virtual framework in a prospective study in patients with GBM, aided by integration of the scale in our institutional EMR. NANO is able to objectively track neurologic function throughout disease course in IDH-wt GBM.

Patients with diffuse midline glioma (DMG) harboring H3 K27M mutation rarely survive longer than two years and have no proven therapies following first-line radiation. ONC201, a bitopic DRD2 antagonist and allosteric ClpP agonist, has shown encouraging efficacy in early phase studies in H3 K27M-mutant DMG. In order to define response rates in H3 K27M DMG patients and to clarify the genomic, anatomic and molecular predictors of response, we performed an integrated pre-clinical and clinical analysis of ONC201 treatment. ONC201 was effective in intra-uterine electroporation (IUE)-generated H3 K27M-mutant murine glioma models with excellent CNS penetration and survival benefit. Patients with H3 K27M-mutant DMG treated with ONC201 on active clinical trials (n=50, 27 thalamic, 23 brainstem) showed an overall survival (OS) of 28.1 (range: 5.9–105) months from diagnosis (enrollment by 4/29/19, data cut-off 12/28/19), compared to historical median OS of 12 months. Median OS for non-recurrent patients has not been reached (n=16, median follow-up: 16.8 from diagnosis). For non-recurrent thalamic patients (n=8), median PFS is 20.1 (range: 9.3–27.6) months from diagnosis (median time on drug: 14.5 months). Best response for thalamic patients by RANO: 1 CR, 5 PR, 7 SD, 8 PD, 6 not reported. Decreased H3 K27M cell-free tumor DNA in plasma and CSF at 6 months correlated with long-term response. Baseline tumor gene expression profiling in patients treated with ONC201 (n=14) identified EGFR and the cortical developmental transcription factor FOXG1 as the strongest biomarkers of radiographic response to ONC201. Analysis of 541 ONC201-treated human cancer cell lines from DepMap, provided evidence for an EGFR-dependent ONC201 resistance mechanism. Analysis of 38 glioma cell lines further supports FOXG1 as a glioma-specific predictive biomarker of ONC201 response. The unprecedented survival results and radiographic responses to ONC201 in H3K27M DMG make a compelling case for later phase and combinatorial studies.

H3 K27M-mutant diffuse midline gliomas (DMG) have a dismal prognosis. We report an integrated analysis for ONC201, a DRD2 antagonist and ClpP agonist, in patients with recurrent H3 K27M DMG administered as monotherapy in 3 clinical studies (NCT03295396, n=20; NCT02525692, n=6; or expanded access, n=4) by independent, central radiology review among 30 patients. At baseline, patients had measurable contrast-enhancing disease by RANO criteria, KPS>60, and were >90 days from prior radiation. Patients with primary lesions that involved the pons or spinal cord or had evidence of leptomeningeal or cerebrospinal fluid dissemination were excluded. ONC201 was orally administered at 625 mg (scaled by body weight for patients < 18 years old) weekly in 29 patients and every 3 weeks in 1 patient. Median age was 31 years (range 8–70; two patients < 18). There were 16 women and 14 men. Tumors were predominantly thalamic (73%), with other locations including the cerebellum (5%), brainstem (non-pontine) (3%), basal ganglia (3%), and midbrain (3%). Median time from prior radiation was 7.5 months. The most frequent drug-related adverse events were low grade nausea (10%) and fatigue (10%). Nine patients (30%) had >50% regression of T1 contrast enhancement and 11 (36.7%) patients had regression of T2/FLAIR. Objective response rate and progression-free survival by RANO criteria, as well overall survival will be reported. Among 8 patients with sustained radiographic regressions, 6 were tapered off dexamethasone and 4 had improvement in KPS. Five patients (16.7%) remain on treatment with a median of 9.5 months (range 7.3–12). In conclusion, single agent ONC201 is well tolerated and clinically active in recurrent H3 K27M DMG patients.

H3 K27M-mutant gliomas often manifest as midline gliomas, have a dismal prognosis, and have no established or effective treatments at recurrence. ONC201 is the first clinical bitopic DRD2 antagonist/ClpP agonist and is under evaluation in Phase II trials for gliomas and other cancers. We previously reported in vitro studies suggesting dysregulated dopamine receptor expression and enhanced ONC201 sensitivity among H3 K27M-mutant gliomas. Following these observations, adults with midline H3 K27M-mutant glioma patients were enrolled to a dedicated Phase II clinical trial (NCT03295396), a multi-arm Phase II trial (NCT0252569), and expanded access protocols under the Sponsor’s IND. An integrated radiographic analysis with an objective response rate primary endpoint in patients who received ONC201 monotherapy with confirmed H3 K27M-mutant glioma (not primarily in the pons or spinal cord and without leptomeningeal spread) that was progressive and measurable disease by RANO criteria, >90 days from completion of prior radiation, and had KPS >60. As of December 15, 2018, 15 patients have received single agent ONC201 who meet these criteria (n=9 NCT03295396; n=5 NCT0252569; n=1 expanded access). ONC201 was orally administered at 625 mg weekly, except for one patient dosed once every 3 weeks. As midline gliomas can exhibit a mixture of contrast-enhancing and non-contrast-enhancing disease, objective response was assessed by blinded independent central review using RANO-HGG and RANO-LGG criteria for each patient. Best response to date by RANO-HGG criteria is at least 27%: 1 CR, 3 PR, 7 SD, and 4 PD; by RANO-LGG is at least 36%: 1 CR, 1 PR, 3 minor response (MR), 4 SD, 5 PD, 1 unevaluable. By RANO-HGG, median onset of response is 2.6 months (range 1.3–3.4); median duration of response has not been reached with a median follow-up of 7.7 months (range 1.8–29.8). Updated radiographic response, pharmacodynamics, safety, and other clinical outcomes will be reported.

BACKGROUND Up to 25% of all cancer patients will develop brain metastases and prognosis remains poor. In preclinical work, we discovered that more than 50% brain metastases genomically diverge from primary tumors and harbor alterations in genes involved with cell cycle regulation. We thus initiated a phase II study to evaluate the efficacy and safety of the cyclin dependent kinase (CDK) 4/6 inhibitor, palbociclib, in patients with recurrent brain metastases with alterations in the CDK pathway (NCT02896335). METHODS The primary endpoint of the trial is the rate of intracranial benefit (defined as CR, PR, or SD, per RANO) at 8 weeks after the start of palbociclib. A Simon two-stage design was used to compare the rate of intracranial benefit for a null rate of 10% against an alternative of 30%. Fifteen patients were to be enrolled in the first stage. If fewer than 2 responders were observed, then the study would stop for insufficient evidence of efficacy. If 6 or more responders were observed among the total of 30, this treatment regimen would be considered worthy of further study. CSF, blood samples and tumor samples were collected to elucidate the genomic determinants of response to CDK inhibitors in the brain. RESULTS A total of 14 patients have been accrued (5 with breast cancer, 4 with melanoma, 3 esophageal and 2 with non-small cell lung cancer) thus far. One or more grade-3 or higher adverse events at least possibly related to treatment were seen in six (42%) patients, the majority being hematologic toxicities. At the time of the data analysis, eight (57%) patients had achieved intracranial benefit. Therefore, the study met primary endpoint. CONCLUSIONS In this unique, genomically-guided brain metastasis trial, we demonstrate that the CDK 4/6 inhibitor, palbociclib, is well-tolerated and has activity in patients with brain metastases.

Novel insights into the pathophysiology of primary central nervous system lymphoma (PCNSL) have identified the B-cell receptor and Toll-like receptor pathway as well as immune evasion and suppressed tumor immune microenvironment as a key mechanism in the pathogenesis of PCNSL. Small molecules and novel agents targeting these aberrant pathways have been introduced into clinical trials targeting the recurrent or refractory PCNSL patient population. Agents like the Bruton tyrosine kinase (BTK) inhibitor ibrutinib or immunomodulatory drugs (IMiDs) like pomalidomide and lenalidomide have shown promising high response rates in the salvage setting. Here, we give an overview about the recent, exciting developments in PCNSL and summarize the results of clinical trials using novel agents in the recurrent and refractory salvage setting, which include immune checkpoint inhibitors, IMiDs, as well as BTK, phosphatidylinositol-3 kinase, and mammalian target of rapamycin inhibitors.

ONC201, a bitopic DRD2 antagonist and allosteric ClpP agonist, has shown encouraging efficacy in H3 K27M-mutant glioma. Given that the thalamus has the highest extra-striatal expression of DRD2, we performed an integrated preclinical and clinical analysis of ONC201 in thalamic H3 K27M-mutant glioma. ONC201 was effective in mouse intra-uterine electroporation (IUE)-generated H3 K27M-mutant gliomas, with an in vitro IC50 of 500 nM and 50% prolongation of median survival in vivo (p=0.02, n=14). We analyzed thalamic H3 K27M-mutant glioma patients treated with ONC201 on active clinical trials as of 5/22/19 enrollment (n=19 recurrent and 10 post-radiation, non-recurrent; 5–70 years old). As of 12/18/2019, PFS6 and OS12 are 26.3% and 36.8%, respectively, in the recurrent group. For non-recurrent patients, with median follow up of 21.9 months (8.6–26.6) from diagnosis, median PFS or OS have not been reached. This surpasses historical OS of 13.5 months. Best response by RANO includes 1 CR, 3 PR, 4 SD, 8 PD for recurrent patients and 2 PR, 4 SD, 1 PD for non-recurrent patients (4 on-trial patients experienced regressions that are yet unconfirmed responses). Median duration of response for recurrent patients is 14.0 months (2.0–33.1). Furthermore, H3 K27M cell-free tumor DNA in plasma and CSF correlated with MRI response. In summary, single agent ONC201 administered at recurrence, or adjuvantly following radiation, demonstrates promising clinical efficacy in thalamic H3 K27M-mutant glioma patients who currently have no effective treatments following radiation. Investigations are ongoing to assess whether micro-environmental DRD2 expression explains the early exceptional responses in thalamic H3 K27M-mutant glioma.

The authors wish to correct a mistake in Figure 1, Panel A: the label for cell SNZ308, SNZ308r1, and SNZ308r2 should be LNZ308, LNZ308r1, and LNZ308r2, respectively (Volume 20, Issue 5, doi:10.1093/neuonc/nox198).

Meningioma is the most common primary brain tumor, comprising 35% of all CNS tumors in the United States.1 Approximately 80% of meningiomas are World Health Organization (WHO) grade I and may be observed expectantly or treated successfully with surgery or radiotherapy. However, the remaining 20% are either WHO grade II (atypical) or grade III (anaplastic or “malignant”) and have high recurrence rates, exceeding 50% for atypical tumors and 80% for anaplastic tumors. Despite maximal surgical resection and radiotherapy, a subset of these patients will recur and require additional treatment, but there is no proven effective chemotherapy for patients with aggressive meningiomas. Studies investigating traditional chemotherapies (temozolomide, hydroxyurea, irinotecan, and triple therapy with cyclophosphamide + doxorubicin + vincristine), hormonal therapies (progesterone and estrogen modulators, somatostatin analogues), interferon alfa-2b, and molecularly targeted therapies, including inhibitors of platelet-derived growth factor receptors (PDGFRs; imatinib) and epidermal growth factor receptor (gefitinib and erlotinib), have all been disappointing.2–19 Although the natural history of these tumors is not well established, the 6-month progression-free survival (PFS6) rate for these patients is poor. A phase II study of imatinib in recurrent meningioma demonstrated a PFS6 of 0% in the atypical/anaplastic cohort.19 PDGF is a ubiquitous growth factor driving cell proliferation in normal development as well as numerous neoplasms, including meningiomas.20–25 Administration of PDGF-BB to meningioma cells in culture results in stimulation of tumor growth, while administration of anti–PDGF-BB antibodies inhibits proliferation.26,27 Vascular endothelial growth factor (VEGF) is upregulated in almost all meningiomas and has been associated with neovascularization, tumor growth, and the development of edema.28,29 Targeting VEGF with different agents has proved effective in several different cancers, including malignant gliomas.30,31 Targeting this pathway may have therapeutic potential in meningioma. Sunitinib malate (SU011248, Sutent, Pfizer) is an orally administered tyrosine kinase inhibitor targeting VEGF receptor (VEGFR), PDGFR, and KIT.32 Inhibiting these targets represents an attractive therapeutic approach for recurrent meningiomas. The FDA-approved and recommended dose for sunitinib in renal cell carcinoma and gastrointestinal stromal tumor is 50 mg daily for 4 of every 6 weeks. We selected this dose because meningiomas are extraparenchymal tumors. Given (i) the strong preclinical rationale for targeting PDGFR and VEGFR in meningiomas, (ii) the efficacy of sunitinib cotargeting VEGFR2 and PDGFR, and (iii) its safety in adults with other solid tumors, we investigated sunitinib in this phase II study for recurrent and progressive meningiomas that had failed prior surgery and radiation.

Anti-VEGF therapies remain controversial in the treatment of recurrent GBM. In the current study we demonstrate that recurrent GBM patients with a specific diffusion MR imaging signature have an OS advantage when treated with anti-VEGF therapy at first or second recurrence. These findings were then validated using data from a separate trial.

Oligodendroglioma (OD) is a subtype of adult diffuse glioma defined by IDH1/2 gene mutation and co-deletion of chromosomal arms 1p and 19q. Although prognosis in OD tumors is initially relatively favorable, the majority of OD develop outgrowth of a subclone that has undergone malignant transformation. Modeling the molecular mechanisms of this tumor progression is crucial to identify therapeutic targets for malignant disease. However, there are few available patient-derived OD xenograft models, which limit preclinical investigations. Here, we present novel patient derived anaplastic oligodendroglioma (AOD) xenograft models. In a panel of OD at different stages of disease, we harvested two distinct cell samples: those with and without PIK3CA mutation. From the tumor that subsequently rapidly progressed and had a PIK3CA mutation, we established a xenograft model that was lethal to the mouse and retained the PIK3CA mutation. In contrast, xenograft did not form from the other tumor that was clinically stable after resection and had wild-type PIK3CA. We confirmed AOD phenotype and the presence of IDH1 mutation and 1p/19q co-deletion in xenograft tissue, indicating successful capture of these signature OD genetic alterations. We also tested to see if PI3K/AKT/mTOR gene mutation could induce patient-derived OD xenograft formation. In our attempts to establish xenograft models, the presence of activating mutations in PI3K/AKT/mTOR pathway was consistently associated with successful xenograft establishment. OD/AOD tumors that did not form xenograft did not have mutation in the PI3K/AKT/mTOR pathway Importantly, we found progressive tumor cells that harbor mutant PIK3CA were vulnerable to alkylating agents and PIK/AKT/mTOR pathway inhibitors. These findings suggest there is a critical role of PI3K/AKT/mTOR pathway activation in driving progression and xenograft formation in oligodendroglial tumors. Our xenograft models will facilitate dissection of the mechanism of malignant transformation, contributing to the identification of optimal therapeutic strategies for patients with oligodendroglial tumors

BACKGROUND: Isocitrate dehydrogenase (IDH) mutant tumors represent a distinct subtype among diffuse gliomas, with improved prognosis compared to grade-matched IDH wild-type tumors. As a basis for clinical trial design of IDH-targeting drugs, we sought to describe outcomes exclusively within the glioma subgroup defined by IDH1 mutation. METHODS: We retrospectively analyzed 275 IDH mutant glioma patients (48.7% grade II and 51.3% grade III tumors; 65.5% astrocytic and 34.5% oligodendroglial tumors) treated at our institution. We calculated progression and survival statistics, including median time to second progression event following first episode of recurrence, using the method of Kaplan-Meier. Estimated survival proportions were correlated with molecular, histologic and clinical factors. RESULTS: During a median follow-up of 6.4 years, 44 deaths (7.6%) and 149 first progression events (54.1%) were observed, with estimated median PFS of 5.7 years (95% CI 4.7–6.4) and median OS of 18.7 years (95% CI 12.2 years - not reached). We validated the effect of grade, molecular diagnosis and treatment paradigms on PFS in our cohort and found results consistent with existing literature. Following the first episode of progressive disease, 79 second progression events occurred during a median follow-up period of 4.1 years. The estimated PFS following first progressive event (PFS-2nd) is 3.0 years (95% CI 2.1–4.1). CONCLUSION: This well-characterized cohort of IDH mutant glioma patients demonstrate progression and survival outcomes reflecting published literature and serves as a reasonable historical control population. Notably, the PFS interval accelerates during disease course, with interval between first to second recurrence (3.0 years) shorter than time from diagnosis to first recurrence (5.7 years). The novel survival statistic PFS-2nd offers an accurate and relevant surrogate outcome for the design of clinical trials investigating experimental drug efficacy at recurrence. These findings highlight that inappropriate comparison to historical baseline PFS may result in prematurely abandoning promising agents.

BACKGROUND: H3 K27M-mutant gliomas have a dismal clinical prognosis and no proven curative therapy. We report the updated clinical experience with ONC201, the first cancer-specific DRD2 antagonist, in adult and pediatric H3 K27M-mutant gliomas. METHODS: As of May 28, 2018, 26 patients with H3 K27M-mutant glioma have been treated with ONC201: 9 pediatric (18 years old). Twelve patients had recurrent disease and 14 had previously-treated stable disease prior to initiating ONC201. Patients had 1–4 prior lines of therapy and all received prior radiation. Ten adult patients were enrolled on clinical trials and the other 16 were on compassionate use. ONC201 was orally administered at 625 mg to adults and scaled by body weight for pediatric patients. All patients, except one, were dosed weekly. RESULTS: Fourteen of 26 patients (54%) remain progression-free on ONC201 with a median follow up of 3.6 (range 1.6–24.5) months. No dose modifications or discontinuation due to toxicity have occurred. Among the 12 adult patients with recurrent disease who received single agent ONC201, the estimated PFS6 is 36.5%. Seven patients have experienced radiographic and/or clinical benefit (neurological stabilization or improvement). Among the 5 adults with recurrent thalamic glioma, three have experienced durable complete regression of their thalamic tumors, including the first H3 K27M-mutant glioma patient treated with ONC201 who has experienced 96% regression of her recurrent disease and continues single agent ONC201 for >2 years. Two DIPG pediatric patients who initiated single agent ONC201 6–8 weeks after radiation have experienced radiographic and neurological improvements and exhibited PFS of >13 months from diagnosis. CONCLUSIONS: Emerging clinical data suggest that ONC201 exhibits clinical activity for some patients with H3 K27M-mutant glioma.

BACKGROUND: Patients with malignant gliomas have a poor prognosis and high symptom burden. Caregivers of these patients face significant challenges due to the impact of the cancer on their loved ones neurological and mental faculties. We have previously shown that rates of clinically significant anxiety symptoms in caregivers of this population are high (50%). We sought to evaluate whether caregiving burden was associated with anxiety symptoms in caregivers of patients with malignant gliomas. METHODS: We conducted a prospective study in patients with newly diagnosed malignant gliomas and their caregivers, collecting caregivers self-report data within 6 weeks of diagnosis. We assessed caregivers anxiety symptoms with the Hospital Anxiety and Depression Scale, with subscale scores >7 considered clinically significant. We evaluated caregiving burden using the Caregiver Reaction Assessment (CRA) subscales, with the following domains: impact on schedule, caregivers esteem, lack of family support, impact on health, and impact on finances. We used a linear regression model to identify associations between the CRA subscales and anxiety symptoms. RESULTS: Fifty percent (38/76) of caregivers experienced clinically significant anxiety symptoms. Caregiving burden was significantly associated with anxiety symptoms F(5, 69)=11.525, p

BACKGROUND: Glioblastoma and tumor endothelial cells express phosphatidylserine, a highly immunosuppressive membrane phospholipid. Bavituximab a chimeric monoclonal antibody binds to 2-glycoprotein 1 (2-GP1) to form a complex of 2-GP1 with phosphatidylserine, resulting in immune activation against tumor cells and anti-angiogenic effects. Phase I/II trials in other solid cancers have demonstrated response rates up to 85% when bavituximab was given with cytotoxic chemotherapy. Pre-clinical data in glioblastoma models suggested synergistic effects of phosphatidylserine blockade, radiation, and temozolomide (TMZ). METHODS: In this ongoing phase II trial (NCT03139916), adult patients with IDH-wild-type newly diagnosed glioblastoma receive 6 weeks of chemoradiation, followed by 6 cycles of adjuvant TMZ (C1-C6 aTMZ). Bavituximab (3 mg/kg) is given weekly, starting week 1 of chemoradiation, for 18 weeks with the option to continue if tolerated. Physiologic MRIs are performed pre-treatment, pre-C1, pre-C3, and pre-C5 aTMZ. Within the enhancing tumor region, we measured median tumor Ktrans (reflecting vascular permeability) and relative cerebral blood volume (rCBV). Median percent changes during treatment were compared to pre-treatment values. RESULTS: To date, 25 of 36 anticipated patients have enrolled (10 with MGMT promoter methylation). All patients underwent pre-treatment scans. 13 have evaluable pre-C1 and 8 pre-C3 aTMZ scans. On the pre-C1 MRIs, enhancing volume decreased by 39% and median tumor Ktrans and rCBV did not change significantly. On the pre-C3 MRIs, enhancing volume decreased by 11% and Ktrans and rCBV decreased by 17% and 21%, respectively. Five patients experienced radiographic disease progression after a median of 2.6 months and 1 patient died 76 days after diagnosis due to disease progression. Bavituximab was generally well tolerated. CONCLUSIONS: Combining bavituximab with radiation and temozolomide results in decreased enhancing tumor volume, permeability, and cerebral perfusion. Continued patient accrual and imaging marker evaluation are underway to investigate the correlation between bavituximab, MRI changes, and survival.

Antiangiogenic therapy is associated with increased radiographic responses in glioblastomas, but tumors invariably recur. Because tumor-associated macrophages have been shown to mediate escape from antiangiogenic therapy in preclinical models, we examined the role of macrophages in patients with recurrent glioblastoma. We compared autopsy brain specimens from 20 patients with recurrent glioblastoma who received antiangiogenic treatment and chemoradiation with 8 patients who received chemotherapy and/or radiotherapy without antiangiogenic therapy or no treatment. Tumor-associated macrophages were morphologically and phenotypically analyzed using flow cytometry and immunohistochemistry for CD68, CD14, CD163, and CD11b expression. Flow cytometry showed an increase in macrophages in the antiangiogenic-treated patients. Immunohistochemical analysis demonstrated an increase in CD68+ macrophages in the tumor bulk (P < .01) and infiltrative areas (P = .02) in antiangiogenic-treated patients. We also observed an increase in CD11b+ cells in the tumor bulk (P < .01) and an increase in CD163+ macrophages in infiltrative tumor (P = .02). Of note, an increased number of CD11b+ cells in bulk and infiltrative tumors (P = .05 and P = .05, respectively) correlated with poor overall survival among patients who first received antiangiogenic therapy at recurrence. In summary, recurrent glioblastomas showed an increased infiltration in myeloid populations in the tumor bulk and in the infiltrative regions after antiangiogenic therapy. Higher numbers of CD11b+ cells correlated with poor survival among these patients. These data suggest that tumor-associated macrophages may participate in escape from antiangiogenic therapy and may represent a potential biomarker of resistance and a potential therapeutic target in recurrent glioblastoma.

Sorafenib is an inhibitor of multiple kinases that has demonstrated antiproliferative and antiangiogenic activity in a number of in vitro and in vivo model systems. A phase I study was conducted to determine the maximum tolerated dose (MTD) of sorafenib in patients with recurrent malignant glioma. Sorafenib was given orally, twice a day (BID), continuously in 28-day cycles. The dose was escalated in 2 groups of patients stratified by use of enzyme-inducing antiseizure drugs (± EIASDs). Dose-limiting toxicity (DLT) was defined as any grades 3-4 nonhematological toxicity, grade 4 hematological toxicity, and febrile neutropenia. The number of evaluable patients enrolled in the +EIASD and -EIASD arms were 23 and 24, respectively. DLTs were predominantly dermatological and gastrointestinal effects, as observed in previous clinical trials of sorafenib. The MTD was 600 mg BID for patients receiving EIASDs and 800 mg BID for those who were not. The plasma pharmacokinetics of sorafenib were not significantly affected by the concurrent administration of EIASDs. The MTD of sorafenib given orally BID on a continuous basis was established as 600 mg BID in patients with malignant glioma who were concurrently receiving EIASDs and 800 mg BID in those who were not. Further evaluation is warranted of sorafenib at the recommended MTD against recurrent or progressive malignant glioma in combination with other molecularly targeted drugs or in the newly diagnosed setting concurrent with chemoradiation.

Insights into the molecular pathogenesis of glioblastoma have not yet resulted in relevant clinical improvement. With standard therapy, which consists of surgical resection with concomitant temozolomide in addition to radiotherapy followed by adjuvant temozolomide, the median duration of survival is 12–14 months. Therefore, the identification of novel molecular targets and inhibitory agents has become a focus of research for glioblastoma treatment. Recent results of bevacizumab may represent a proof of principle that treatment with targeted agents can result in clinical benefits for patients with glioblastoma. This review discusses limitations in the existing therapy for glioblastoma and provides an overview of current efforts to identify molecular targets using large-scale screening of glioblastoma cell lines and tumor samples. We discuss preclinical and clinical data for several novel molecular targets, including growth factor receptors, phosphatidylinositol-3 kinase, SRC-family kinases, integrins, and CD95 ligand and agents that inhibit these targets, including erlotinib, enzastaurin, dasatinib, sorafenib, cilengitide, AMG102, and APG101. By combining advances in tumor screening with novel targeted therapies, it is hoped that new treatment options will emerge for this challenging tumor type.

Agents targeting the vascular endothelial growth factor (VEGF) pathway are being used with increasing frequency in patients with recurrent high-grade glioma. The effect of more than one antiangiogenic therapy given in succession has not been established. We reviewed the efficacy of bevacizumab, a VEGF-A monoclonal antibody, in patients who progressed following prior therapy with VEGF receptor tyrosine kinase inhibitors (R-TKi). Seventy-three patients with recurrent high-grade gliomas received VEGF R-TKi (cediranib, sorafenib, pazopanib, or sunitinib) as part of phase I or II clinical trials. Twenty-four of these patients with glioblastoma progressed and received bevacizumab-containing regimens immediately after R-TKi. Those who stopped R-TKi therapy for reasons other than disease progression, or received a treatment that did not include bevacizumab, were excluded from the analysis. The efficacy of bevacizumab-containing regimens in these 24 patients was evaluated. During R-TKi therapy, 6 of 24 patients (25%) had a partial response (PR) to treatment. The 6-month progression-free survival (APF6) was 16.7% and median time-to-progression (TTP) was 14.3 weeks. Grade III/IV toxicities were seen in 13 of 24 patients (54%). Subsequently with bevacizumab salvage therapy, 5 of 24 patients (21%) had a PR, the APF6 was 12.5%, and the median TTP was 8 weeks. Five of 24 patients had grade III/IV toxicities (21%). The median overall survival (OS) from the start of R-TKi therapy was 9.2 months (range: 2.8-34.1+), whereas the median OS after bevacizumab was 5.2 months (range: 1.3-28.9+). Bevacizumab retains modest activity in high-grade glioma patients who progress on R-TKi. However, the APF6 of 12.5% in this cohort of patients indicates that durable tumor control is not achieved for most patients.

Immune checkpoint blockade is a treatment option for patients with melanoma brain metastases (MBM). This single institutional analysis investigated the optimal management for patients with MBM undergoing surgical resection and immunotherapy. An IRB-approved, retrospective study identified 142 MBM patients treated with immune checkpoint blockade between 2010 and 2015. Overall survival (OS) was calculated from the date of diagnosis of MBM until death from any cause. Model building included a prognostic model of OS and the effect of immunotherapy and surgical sequencing on OS. Parallel model-building techniques were used to address the potential for guarantee-time bias. The 2-year OS for patients treated with CTLA-4, PD-1 or combinatorial blockade were 19%, 54%, and 57%, respectively. Accounting for the time-dependent covariate of surgery, factors associated with increased hazard of death included abnormal LDH, presence of extracranial disease at time of brain metastasis diagnosis, and greater than 3 brain metastases. The sequence of therapy was associated with a 2.1-fold increase in the hazard of death amongst patients initially undergoing immunotherapy +/- subsequent surgery compared to surgical patients who went on to receive immunotherapy (HR: 2.1, 95% CI: 1.2 to 3.9, P=0.01). The observed increase in risk is primarily reflected in the subgroup of patients undergoing immunotherapy prior to brain metastases diagnosis +/- surgery, who had a statistically significant, 2.3-fold increase in the hazard of death (HR: 2.29, 95% CI: 1.2 to 4.4, P=0.04). In conclusion, the sequence of surgery and immunotherapy is associated with OS and surgical resection should be considered prior to commencing immunotherapy. A prospective, randomized trial comparing the sequence of surgery and immunotherapy for treatment-naïve MBM is warranted.

Mutant IDH1 suppresses normal IDH1 activity and alters the cellular metabolic microenvironment. We have previously identified that steady-state NAD+ level is decreased in endogenous IDH1 mutant cancers. Additionally, we found that inhibitors of the NAD+ biosynthesis enzyme nicotinamide phosphoribosyltransferase (NAMPT) potently depleted NAD+ and selectively induced cytotoxicity in IDH1 mutant cancers. Here, we investigated strategies to further perturb NAD+ metabolism to enhance NAMPT inhibitor efficacy in IDH1 mutant cancers. One major source of intracellular NAD+ consumption is mediated by distinct enzyme complexes of poly(ADP-ribose) polymerase (PARP). We found that temozolomide (TMZ), a commonly-used alkylating chemotherapeutic agent, transiently and potently reduced NAD+ to enhance NAMPT inhibitor efficacy in IDH1 mutant cancers. Mechanistically, TMZ stimulates an acute burst of NAD+ consumption by PARP via activation of DNA damage repair, and as a result, selectively potentiated NAD+ depletion-induced cytotoxicity in IDH mutant cells. In an in vivo IDH1 mutant cancer model, combined treatment with TMZ and NAMPT inhibitor enhanced efficacy compared to each agent alone. Thus, we find chemotherapy induces metabolic stress in IDH1 mutant cancers which can be exploited for therapeutic gain. Targeting of NAD+ homeostasis via convergent metabolic pathways could improve responses to metabolic therapy.

INTRODUCTION Histone H3 K27M mutations distinguish a subgroup of midline gliomas in children and young adults with devastating prognosis for which there are no effective medical therapies. In a recent phase 2 trial in adult recurrent glioblastoma with ONC201, a small molecule selective antagonist of the dopamine receptor D2 (DRD2) and D3 (DRD3), a 22 year old female with recurrent H3 K27M mutant glioblastoma had tumor regression of 92% that has persisted >15 months. Furthermore, antiseizure medication was discontinued and no ONC201 side effects were observed. Based on this exceptional response, we tested whether H3 K27M mutant gliomas were selectively sensitive to ONC201-induced apoptosis.

The prognostic significance of residual contrast enhancing tumor volume after initial surgery to predict OS in newly diagnosed GBM remains poorly understood and not controlled for in prospective clinical trials. In the current study we pooled imaging data in >1,400 newly diagnosed GBM patients from international multicenter clinical trials, single institution databases, and multicenter clinical trial consortiums identify relationships between clinical parameters, MGMT methylation status, treatment, and residual enhancing tumor volume on OS.

Although anti‐angiogenic therapy for high-grade glioma (HGG) is promising, responses are not durable. The SDF-1/CXCR4 axis may help mediate resistance to VEGFR inhibition. Plerixafor is a reversible CXCR4 inhibitor that has demonstrated growth inhibition in glioblastoma xenografts. We conducted a Phase I study to determine the safety and tolerability of plerixafor in combination with bevacizumab in recurrent HGG. Part 1 of the study enrolled 23 patients and was a 3 x 3 dose escalation design to a maximum planned dose level of plerixafor 320 µg/kg on Days 1–21 and bevacizumab 10 mg/kg on Days 1 and 15 of each 28 day cycle. Dose-limiting toxicities (DLTs) were determined during the initial 4 weeks of therapy. CSF and concomitant plasma samples were obtained to determine pharmacokinetic (PK) data. Part 2 of the study enrolled 3 patients and was a surgical study to determine if plerixafor penetrates tumor tissue. Patients were pre-treated with plerixafor 320 µg/kg for 5–9 days before surgery. For all 26 patients enrolled on study, the median age is 59 (23–72), median KPS 90 (70–100), 11 women (42.3%). In Part 1, no DLTs were seen at the maximum planned dose level of plerixafor + bevacizumb. Treatment was well tolerated with one grade 3 hypophosphatemia and one grade 3 rectal fistula. Serum PK data on plerixafor in this study compares well with historical PK data. At a plerixafor dose of 320 µg/kg, the average CSF concentration was 26.8 ng/mL (SD +/- 19.6). Circulating biomarker data suggests that plerixafor + bevacizumab induces rapid and persistent increases in plasma SDF1 and PlGF. Plerixafor concentration in resected tumor tissue from patients pre-treated with plerixafor was 1000–1200 ng/mL. Combination treatment with bevacizumab and plerixafor was well tolerated in HGG patients. Plerixafor distributes to both the CSF and brain tumor tissue.

The prognostic significance of tumor location in newly diagnosed GBM (NDGBM) remains provocative and poorly understood. In this study we pooled imaging data in >1,400 NDGBM patients from international multicenter clinical trials, single institution databases, and multicenter clinical trial consortiums to identify relationships between tumor location on OS, independent of clinical and genetic or molecular characteristics.

The introduction of methotrexate (MTX)-based chemotherapy has improved median survival for patients with primary CNS lymphoma (PCNSL). Older age is a negative prognostic marker in patients with PCNSL and may increase the likelihood of MTX toxicity. We studied the response and adverse effects of intravenous high-dose MTX in patients who were 70 or more years of age at the time of diagnosis. We identified 31 patients at our institution diagnosed with PCNSL at ageor =70 years (median, 74 years) who were treated with high-dose MTX (3.5-8 g/m(2)) as initial therapy from 1992 through 2006. The best response to MTX was determined by contrast-enhanced MRI. Toxicity was analyzed by chart review. These 31 patients received a total of 303 cycles of MTX (median, eight cycles per patient). Overall, 87.9% of the cycles required dose reduction because of impaired creatinine clearance. In 30 evaluable patients, the overall radiographic response rate was 96.7%, with 18 complete responses (60%) and 11 partial responses (36.7%). Progression-free survival and overall survival were 7.1 months and 37 months, respectively. Grade I-IV toxicities were observed in 27 of 31 patients and included gastrointestinal disturbances in 58% (3.2% grade III), hematological complications in 80.6% (6.5% grade III), and renal toxicity in 29% (0% grade III/IV). High-dose MTX is associated with a high proportion of radiographic responses and a low proportion of grade III/IV toxicity in patients 70 or more years of age. High-dose MTX should be considered as a feasible treatment option in elderly patients with PCNSL.

Karenitecin is a highly lipophilic camptothecin analogue with a lactone ring that is relatively resistant to inactivating hydrolysis under physiologic conditions. This phase I clinical trial was conducted to determine the maximum tolerated dose (MTD) of karenitecin in adults with recurrent malignant glioma (MG), to describe the effects of enzyme-inducing antiseizure drugs (EIASDs) on its pharmacokinetics, and to obtain preliminary evidence of activity. Karenitecin was administered intravenously over 60 min daily for 5 consecutive days every 3 weeks to adults with recurrent MG who had no more than one prior chemotherapy regimen. The continual reassessment method was used to escalate doses, beginning at 1.0 mg/m(2)/day, in patients stratified by EIASD use. Treatment was continued until disease progression or treatment-related dose-limiting toxicity (DLT). Plasma pharmacokinetics was determined for the first daily dose of karenitecin. Thirty-two patients (median age, 52 years; median KPS score, 90) were accrued. Seventy-eight percent had glioblastoma, and 22% had anaplastic glioma. DLT was reversible neutropenia or thrombocytopenia. The MTD was 2.0 mg/m(2) in daggerEIASD patients and 1.5 mg/m(2) in -EIASD patients. The mean (+/-SD) total body clearance of karenitecin was 15.9 +/- 9.6 liters/h/m(2) in daggerEIASD patients and 10.2 +/- 3.5 liters/h/m(2) in -EIASD patients (p = 0.02). No objective responses were observed in 11 patients treated at or above the MTD. The total body clearance of karenitecin is significantly enhanced by the concurrent administration of EIASDs. This schedule of karenitecin, a novel lipophilic camptothecin analogue, has little activity in recurrent MG.

We conducted a phase II study of the combination of temozolomide and angiogenesis inhibitors for treating adult patients with newly diagnosed glioblastoma. Patients who had stable disease following standard radiation therapy received temozolomide for 5 days in 28-day cycles, in combination with daily thalidomide and cele-coxib. Patients were treated until tumor progression or development of unacceptable toxicity. Four-month progression-free survival (PFS) from study enrollment was the primary end point, and overall survival (OS) was the secondary end point. In addition, we sought to correlate response with O6-methylguanine-DNA methyl-transferase promoter methylation status and serum levels of angiogenic peptides. Fifty patients with glioblastoma were enrolled (18 women, 32 men). Median age was 54 years (range, 29–78) and median KPS score was 90 (range, 70–100). From study enrollment, median PFS was 5.9 months (95% confidence interval [CI]: 4.2–8.0) and 4-month PFS was 63% (95% CI: 46%–75%). Median OS was 12.6 months (95% CI: 8.5–16.4) and 1-year OS was 47%. Of the 47 patients evaluable for best response, none had a complete response, five (11%) had partial response, four (9%) had minor response, 22 (47%) had stable disease, and 16 (34%) had progressive disease. Analysis of serial serum samples obtained from 47 patients for four angiogenic peptides failed to show a significant correlation with response or survival for three of the peptides; higher vascular endothelial growth factor levels showed a trend toward correlation with decreased OS (p = 0.07) and PFS (p = 0.09). The addition of celecoxib and thalidomide to adjuvant temozolomide was well tolerated but did not meet the primary end point of improvement of 4-month PFS from study enrollment.

Methotrexate (MTX) is a widely used chemotherapeutic agent that can cause acute, subacute, and chronic neurological complications. Subacute MTX neurotoxicity is manifest by abrupt onset of focal cerebral dysfunction occurring days to weeks after MTX administration, usually in children. We describe the neuroimaging features of an adult patient with primary CNS lymphoma who presented with transient aphasia and right hemiparesis 12 days after receiving intravenous high-dose MTX (8 g/m2) chemotherapy. Imaging within 1 h of symptom onset showed bilateral symmetrical restricted diffusion involving white matter of the cerebral hemispheres. CT angiogram and dynamic susceptibility MRI showed no evidence of vasospasm or perfusion defect. MRI five days later showed near-complete resolution of the abnormalities. MRI 3(1/2) months later showed normal diffusion but new hyperintense T2-weighted signal changes in the subcortical white matter corresponding to previous areas of restricted diffusion. The absence of vascular or perfusion abnormalities suggests that transient cytotoxic edema in white matter may explain the syndrome of subacute MTX neurotoxicity.

A 38-year-old woman presented with an infiltrative tumor of the right frontal lobe and genu of the corpus callosum that was deemed only partially resectable. A stereotactic biopsy was performed, which revealed a right frontal oligoastrocytoma that had some anaplastic features as well as allelic loss of chromosome arms 1p and 19q. The patient was treated with temozolomide for 24 months. The partial response of the tumor to chemotherapy rendered the lesion amenable to gross total resection, which was performed subsequently. The patient remains alive and well without evidence of recurrence 7 months after resection and 48 months after initial diagnosis. Thus, preoperative chemotherapy decreased tumor mass to a degree that subsequently enabled a gross total resection. This treatment strategy, although common in the treatment of other solid tumors, is rarely utilized in adult neuro-oncology and raises another potential role for chromosome testing in oligodendroglial tumor management.

The primary objective of this study was to determine the proportion of patients exhibiting a radiographic response in a cohort of patients with recurrent malignant glioma who were treated with irinotecan. Secondary objectives were to determine progression-free survival, overall survival, and toxicity. The trial was terminated after the first 18 patients were enrolled in this multicenter, 2-stage, phase 2 study. Twelve patients received concurrent enzyme-inducing antiepileptic drugs, and 6 did not. Each cycle consisted of a 90-min i.v. infusion of irinotecan every week for 4 consecutive weeks, followed by 2 weeks off. One patient had a complete response, 5 patients had stable disease, 5 patients had radiographic progression, 6 patients were removed from the study because of toxicity, and 1 patient refused further therapy and was removed from the study. The response rate in this study was 6% (1/18), and 28% (5/18) of these patients progressed while receiving irinotecan. Dose-limiting toxicities consisted of diarrhea in 5 patients, neutropenia in 1 patient, infection in 1 patient, and respiratory failure in 1 patient. Irinotecan had minimal efficacy in this cohort of 18 patients with recurrent malignant glioma. Toxicity was significant but similar to that reported in other patient populations.