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With the emergence of immune-modulating therapies, brain tumors present significant diagnostic imaging challenges. These challenges include planning personalized treatment and adjudicating accurate monitoring approaches and therapeutically specific response criteria. This has been due, in part, to the reliance on nonspecific imaging metrics, such as gadolinium-contrast-enhanced MRI or FDG PET, and rapidly evolving biologic understanding of neuroinflammation. The importance of the tumor-immune interaction and ability to therapeutically augment inflammation to improve clinical outcomes necessitates that the radiologist develop a working knowledge of the immune system and its role in clinical neuroimaging. In this article, we review relevant biologic concepts of the tumor microenvironment of primary and metastatic brain tumors, these tumors' interactions with the immune system, and MRI and PET methods for imaging inflammatory elements associated with these malignancies. Recognizing the growing fields of immunotherapeutics and precision oncology, we highlight clinically translatable imaging metrics for the diagnosis and monitoring of brain tumor neuroinflammation. Practical guidance is provided for implementing iron nanoparticle imaging, including imaging indications, protocol, interpretation, and pitfalls. A comprehensive understanding of the inflammatory mechanisms within brain tumors and their imaging features will facilitate the development of innovative non-invasive prognostic and predictive imaging strategies for precision oncology.

Chemotherapeutics play a significant role in the management of most brain tumors. First pass effect, systemic toxicity, and more importantly, the blood-brain barrier pose significant challenges to the success of chemotherapy. Over the last 80 years, different techniques of intraarterial chemotherapy delivery have been performed in many studies but failed to become standard of care. The purpose of this article is to review the history of intraarterial drug delivery and osmotic blood-brain barrier disruption, identify the challenges for clinical translation, and identify future directions for these approaches.

Response assessment after immunotherapy remains a major challenge in glioblastoma due to an expected increased incidence of pseudoprogression. Gadolinium-enhanced magnetic resonance imaging (MRI) is the standard for monitoring therapeutic response, however, is markedly limited in characterizing pseudoprogression. Given that hypoxia is an important defining feature of glioblastoma regrowth, we hypothesized that [18F]-fluoromisonidazole (FMISO) positron emission tomography (PET) could provide an additional physiological measure for the diagnosis of immunotherapeutic failure. Six patients with newly diagnosed glioblastoma who had previously received maximal safe resection followed by Stupp protocol CRT concurrent with pembrolizumab immunotherapy were recruited for FMISO PET and Gd-MRI at the time of presumed progression. The hypoxic fraction was defined as the ratio of hypoxic volume to T1-weighted gadolinium-enhancing volume. Four patients diagnosed with pseudoprogression demonstrated a mean hypoxic fraction of 9.8 ± 10%. Two with recurrent tumor demonstrated a mean hypoxic fraction of 131 ± 66%. Our results, supported by histopathology, suggest that the noninvasive assessment of hypoxic fraction by FMISO PET/MRI is clinically feasible and may serve as a biologically specific metric of therapeutic failure.

Overexpression of O6-methylguanine DNA methyltransferase (MGMT) contributes to resistance to chemo-radiation therapy (CRT) in brain tumors. We previously demonstrated that non-ablative radiation improved delivery of anti-MGMT morpholino oligonucleotides (AMONs) to reduce MGMT levels in subcutaneous tumor xenografts. We evaluate this approach to enhance CRT efficacy in rat brain tumor xenograft models. The impact of radiation on targeted delivery was evaluated using fluorescent oligonucleotides (f-ON). In vitro, f-ON was localized to clathrin-coated vesicles, endosomes, and lysosomes using confocal microscopy in T98G glioma cells. In vivo, fluorescence was detected in pre-radiated, but not non-radiated Long Evans (non-tumor bearing) rat brains. Cranial radiation (2 Gy) followed by AMONs (intravenous, 10.5 mg/kg) reduced MGMT expression by 50% in both orthotopic cerebellar D283 medulloblastoma and intracerebral H460 non-small cell lung carcinoma (NSCLC) xenograft models. To evaluate the efficacy, AMONs concurrent with CRT (2 Gy radiation plus oral 20 mg/kg temozolomide ×4 days) reduced tumor volumes in the medulloblastoma model (p = 0.012), and a similar trend was found in the NSCLC brain metastasis model. We provide proof of concept for the use of non-ablative radiation to guide and enhance the delivery of morpholino oligonucleotides into brain tumor xenograft models to reduce MGMT levels and improve CRT efficacy.

BackgroundIntra-arterial administration of chemotherapy with or without osmotic blood–brain barrier disruption enhances delivery of therapeutic agents to brain tumors. The aim of this study is to evaluate the safety of these procedures.MethodsRetrospectively collected data from a prospective database of consecutive patients with primary and metastatic brain tumors who received intra-arterial chemotherapy without osmotic blood–brain barrier disruption (IA) or intra-arterial chemotherapy with osmotic blood–brain barrier disruption (IA/OBBBD) at Oregon Health and Science University (OHSU) between December 1997 and November 2018 is reported. Chemotherapy-related complications are detailed per Common Terminology Criteria for Adverse Events (CTCAE) guidelines. Procedure-related complications are grouped as major and minor.Results4939 procedures (1102 IA; 3837 IA/OBBBD) were performed on 436 patients with various pathologies (primary central nervous system lymphoma [26.4%], glioblastoma [18.1%], and oligodendroglioma [14.7%]). Major procedure-related complications (IA: 12, 1%; IA/OBBBD: 27, 0.7%; P = .292) occurred in 39 procedures including 3 arterial dissections requiring intervention, 21 symptomatic strokes, 3 myocardial infarctions, 6 cervical cord injuries, and 6 deaths within 3 days. Minor procedure-related complications occurred in 330 procedures (IA: 41, 3.7%; IA/OBBBD: 289, 7.5%; P = .001). Chemotherapy-related complications with a CTCAE attribution and grade higher than 3 was seen in 359 (82.3%) patients.ConclusionsWe provide safety and tolerability data from the largest cohort of consecutive patients who received IA or IA/OBBBD. Our data demonstrate that IA or IA/OBBBD safely enhance drug delivery to brain tumors and brain around the tumor.

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.

OBJECTIVE. The goal of this intraindividual comparison study was to investigate whether ferumoxytol-enhanced MRI is as effective as standard-of-care gadolinium-enhanced MRI in detecting intracranial metastatic disease. MATERIALS AND METHODS. We retrospectively reviewed all patients who underwent imaging as part of two ongoing ferumoxytol-enhanced and gadolinium-enhanced MRI protocol studies to compare the number and size of enhancing metastatic lesions. Two neuroradiologists independently measured enhancing metastases on ferumoxytol-enhanced MR images and on control gadolinium-enhanced MR images. The number and size of metastases were compared on an intraindividual basis. Primary diagnoses were recorded. A linear mixed-effects model was used to compare differences in cubic root of volume between gadolinium-enhanced and ferumoxytol-enhanced MRI. A signed rank test was used to evaluate differences between reviewers. RESULTS. MR images from 19 patients with brain metastases were analyzed (seven with lung cancer, three with breast cancer, three with melanoma, two with ovarian cancer, one with colon cancer, one with renal cell carcinoma, one with carcinoid tumor, and one with uterine cancer). Reviewer 1 identified 77 masses on ferumoxytol-enhanced MRI and 72 masses on gadolinium-enhanced MRI. Reviewer 2 identified 83 masses on ferumoxytol-enhanced MRI and 78 masses on gadolinium-enhanced MRI. For reviewer 1, ferumoxytol-enhanced MRI showed a mean tumor size measuring 1.1 mm larger in each plane compared with gadolinium-enhanced MRI (p = 0.1887). For reviewer 2, ferumoxytol-enhanced MRI showed a mean tumor size measuring 1.0 mm larger in each plane (p = 0.2892). No significant differences in number of metastases or tumor sizes were observed between contrast agents or reviewers. CONCLUSION. Intracranial metastatic disease detection with ferumoxytol-enhanced MRI was not inferior to detection with gadolinium-enhanced MRI. Ferumoxytol-enhanced MRI could improve workup and monitoring of patients with brain metastases if gadolinium-enhanced MRI is contraindicated.

Background In patients with high-grade glioma (HGG), true disease progression and treatment-related changes often appear similar on magnetic resonance imaging (MRI), making it challenging to evaluate therapeutic response. Dynamic susceptibility contrast (DSC) MRI has been extensively studied to differentiate between disease progression and treatment-related changes. This systematic review evaluated and synthesized the evidence for using DSC MRI to distinguish true progression from treatment-related changes. Methods We searched Ovid MEDLINE and the Ovid MEDLINE in-process file (January 2005–October 2019) and the reference lists. Studies on test performance of DSC MRI using relative cerebral blood volume in HGG patients were included. One investigator abstracted data, and a second investigator confirmed them; two investigators independently assessed study quality. Meta-analyses were conducted to quantitatively synthesize area under the receiver operating curve (AUROC), sensitivity, and specificity. Results We screened 1177 citations and included 28 studies with 638 patients with true tumor progression, and 430 patients with treatment-related changes. Nineteen studies reported AUROC and the combined AUROC is 0.85 (95% CI, 0.81–0.90). All studies contributed data for sensitivity and specificity, and the pooled sensitivity and specificity are 0.84 (95% CI, 0.80–0.88), and 0.78 (95% CI, 0.72–0.83). Extensive subgroup analyses based on study, treatment, and imaging characteristics generally showed similar results. Conclusions There is moderate strength of evidence that relative cerebral blood volume obtained from DSC imaging demonstrated “excellent” ability to discriminate true tumor progression from treatment-related changes, with robust sensitivity and specificity.

Purpose High dose corticosteroids are an effective tool for rapidly alleviating neurologic symptoms caused by intracranial mass lesions. However, there is concern that preoperative corticosteroids limit the ability to obtain a definitive pathologic diagnosis, particularly if imaging features suggest primary central nervous system lymphoma (PCNSL). Methods To explore the impact of preoperative corticosteroids in newly diagnosed PCNSL patients, from 2009 to 2018 treated at our institution. Results We identified 54 patients; 18 had received corticosteroids prior to biopsy or resection. Only in one case did the patient have a prior non-diagnostic biopsy, requiring a second procedure. The cumulative doses of preoperative dexamethasone ranged from 4 mg to 120 mg (mean 32 mg, median 24 mg), given over 1–14 days (mean 2 days, median 1 day), and the majority had received corticosteroids for only 1–2 days. There was a trend for a larger diameter of lesional T1 contrast enhancement for patients who received steroids (39 mm vs. 34 mm, p = 0.11). In this series of cases with pathologically and clinically proven PCNSL, preoperative corticosteroids had been given in a third of cases, suggesting that they may be given for symptomatic relief without compromising pathologic diagnosis. Conclusions Despite the commonly held tenet that preoperative corticosteroids can obscure the pathologic diagnosis in PCNSL, this is likely not the case in the majority of patients who receive a short course preoperatively. Obtaining a second stereotactic scan to confirm continued presence of the lesion prior to tissue sampling may also mitigate these concerns.

INTRODUCTION There is consensus that high-dose methotrexate-based (HD-MTX) chemotherapy is the first line treatment for primary central nervous system lymphoma (PCNSL) but there is no consensus on drug dosing and duration. Area under the curve of Methotrexate (MTX-AUC) is a measure of exposure, and we hypothesize that a high MTX-AUC is associated with improved overall survival (OS) and progression free survival (PFS).Method: This retrospective study was approved by the institutional review board. HIV negative PCNSL patients who received Rituximab and HD-MTX at our institution from 2002-2020 were included. HD-MTX dose ranged from 1.2 gm/m2-8 gm/m2 based on creatinine clearance. MTX-AUC was calculated using mtxpk.org. OS and PFS were analyzed using Kaplan-Meier method and Cox proportional hazard regression. Result: 34 PCNSL patient’s charts (mean age: 67 yrs ± 15, 22F/12M) were reviewed. The mean MTX dose (5313 mg/m2) strongly correlated with the mean MTX-AUC (3648 μmol*l−1h, range: 698 – 6634). Patients with MTX-AUC < 3648 μmol*l−1h median PFS is 44.6 months (95% CI: 3.8– non-estimable), not significantly different from patient with MTX-AUC > 3648μmol*l−1h (PFS: 53.2 months, 95% CI: 4.3– non-estimable; P = 0.96). Results were similar after adjusting for patient characteristics in the Cox regression with hazard ratio (HR): 0.84; 95% CI: 0.29–2.43; P = 0.75). The median OS was 44.6 months (95% CI, 12.5– non-estimable) for patients with MTX AUC < 3648 μmol*l−1h and not estimable for patients with MTX-AUC > 3648 μmol*l−1h , HR of 0.43 (95% CI: 0.08–2.33; P = 0.33). Higher KPS prior to chemotherapy was associated with improved PFS/OS with HR: 0.95 (95% CI: 0.93–0.98; P = 0.0006) and HR: 0.91 (95% CI: 0.87–0.96; P = 0.0005) respectively. CONCLUSION Our patients PFS and OS is improved compared to historical control but our data suggests that there is no statistically significant association with MTX-AUC in PCNSL.

With the emergence of immune-modulating therapies, brain tumors present important diagnostic imaging challenges. These challenges include planning personalized treatment and adjudicating accurate monitoring approaches and therapeutically specific response criteria. The challenges have been due, in part reliance on nonspecific imaging metrics, such as gadolinium contrast-enhanced MRI or FDG PET, and rapidly evolving biologic understanding of neuroinflammation. The importance of the tumor immune interaction and ability to therapeutically augment inflammation to improve clinical outcomes make it necessary for radiologists to develop a working knowledge of the immune system and its role in clinical neuroimaging. The purpose of this article is to review relevant biologic concepts of the tumor microenvironment of primary and metastatic brain tumors, the interactions between the tumors and the immune system, and MRI and PET methods for imaging inflammatory elements associated with these malignancies. In recognition of the growing fields of immunotherapeutics and precision oncology, clinically translatable imaging metrics for the diagnosis and monitoring of brain tumor neuroinflammation are highlighted. Practical guidance is provided for implementing iron nanoparticle imaging, including imaging indications, protocols, interpretation, and pitfalls. A comprehensive understanding of the inflammatory mechanisms within brain tumors and their imaging features will facilitate the development of innovative noninvasive prognostic and predictive imaging strategies for precision oncology.

BACKGROUND Recurrent glioblastoma (rGBM) is rapidly fatal with current therapies. PVSRIPO is an intratumoral immunotherapy targeting CD155 on antigen-presenting and malignant cells of solid tumors. Preclinically, PVSRIPO treatment leads to systemic, tumor antigen-specific, polyfunctional T-cell–mediated anti-tumor response, predominately driven by type I/III interferons. This inflammatory signature generates anti-tumor immunity and upregulates the programmed death (PD)-1 immune checkpoint in the tumor microenvironment. Preclinical models (including GBM) have shown that PVSRIPO+anti-PD-1/L1 therapy was more efficacious than either agent alone, warranting further investigation. METHODS Adults with histologically confirmed rGBM (1-2 prior progressions), Karnofsky performance status (KPS) ≥70, and an active, supratentorial, contrast-enhancing lesion (1-5.5 cm), received PVSRIPO (5x107 TCID50) intratumorally via convection-enhanced delivery (Day 1), followed by 200 mg pembrolizumab IV at week 2, given every 3 weeks for up to 24 months, to evaluate the safety/efficacy of the combination. A safety lead-in period (n=3-6) with a minimum 21–28-day delay before treatment of subsequent patients was planned, with a data safety monitoring board (DSMB) evaluating safety/tolerability prior to expansion (up to N=30). RESULTS The first 3 patients enrolled (ages 55-60, KPS 90-100) all received PVSRIPO followed by pembrolizumab (1-5 cycles), as planned. At cutoff (26-106 days of follow-up), there were no dose-limiting toxicities, treatment-emergent (TE) serious adverse events (SAE), or TEAEs necessitating a delay in initial/subsequent pembrolizumab treatments. All patients experienced a related TEAE, all grade 1 or 2 in severity. One patient experienced an AE of special interest (peritumoral edema, resulting in headache and hemiparesis), successfully managed with low-dose bevacizumab and corticosteroids. The DSMB unanimously recommended the study proceed without modification. CONCLUSIONS Intratumoral PVSRIPO+pembrolizumab was reasonably well tolerated, warranting continued investigation of the safety and efficacy of this combination in patients with rGBM.

Background Progressive and/or unresectable pilocytic astrocytomas (PAs) carry a poor prognosis compared to typical PA. Early radiotherapy (RT) may have severe long-term neurocognitive side effects in this patient population. Intra-arterial (IA) chemotherapy is a viable alternative or addition to intravenous (IV) chemotherapy, which may be beneficial in avoidance of early RT. Objective To evaluate the safety and efficacy of IA chemotherapy in this subset of patients. Methods This is a retrospective review of medical records of PA patients who are treated with IA chemotherapy at Oregon Health & Science University from 1997 until 2019. Response to treatment was categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). Progression free survival (PFS) and overall survival (OS) are also reported. Results Twelve patients were identified. All patients experienced progression prior to initiation of IA chemotherapy. The most common grade 3 or 4 toxicities related to chemotherapy were thrombocytopenia (66%), neutropenia (66%), leukopenia (50%), anemia (33%), and lymphopenia (16%). Responses achieved were CR in 1, PR in 3, SD in 7, and PD in 1. Median PFS and median OS were 16.5 and 83.5 mo, respectively. A total of 112 procedures (IA injections) were performed and 250 arteries were catheterized. There were 3 minor and no major complications attributable to procedures. Conclusion This study demonstrates that IA chemotherapy can be safely used in patients with unresectable or progressive PA.

CNS lymphoma often presents with atypical imaging characteristics leading to delay in diagnosis and initiation of treatment. Among the most rarely reported of these is entirely nonenhancing CNS lymphoma, which is estimated at an incidence of about 1%. Here, we present three cases of nonenhancing CNS lymphoma in immune competent patients at both initial presentation and recurrence and in primary as well as secondary CNS lymphoma. Diffusion- and perfusion-weighted imaging was found helpful in diagnosis in some cases.

OBJECTIVE To identify the trend of distress over time and whether palliative care (PC) referral and visit affected distress level in glioblastoma (GBM) patients. BACKGROUND GBM patients experience significant distress due to their prognosis and neurologic involvement. All subjects in the neuro-oncology clinic at our institution routinely receive the Patient Health Questionnaire-4 (PHQ4) which is a validated screening tool that comprises a section for generalized anxiety disorder (GAD2) and a depression screen (PHQ2). DESIGN This prospective study was approved by the institutional review board. GBM patients who started radiation therapy on 1/1/2019 or later were included. Patients with a GAD2 or PHQ2 of 3 or above were categorized as present for anxiety or depression. A logistic mixed-effects model was used to test the trend of anxiety or depression over time and the impact of PC referral and visit. RESULT 131 PHQ4 questionnaires from 39 newly diagnosed GBM patients (mean age: 59.9yrs ± 15.0; 23M/16F) at the pre-radiation, post radiation and at least every 2 months thereafter were reviewed. Before radiation, 54.8% of patients reported anxiety, higher than at 1-month post radiation (23.5%), 2-3 months (41.4%), 4-6 months (20.0%), and after 6 months (25.0%). This temporal trend is significant (P = 0.0385) after adjusting for patient characteristics such as age, gender and performance status. The proportions of anxiety were not different among visits without PC referral (23.7%), with PC referral and no PC visit (42.4%), and with PC visit (32.4%, P = 0.64). We did not identify a similar temporal trend in depression. CONCLUSION Our data suggests that anxiety is more prevalent than depression in this cohort. This study identifies subjects to be at a greatest likelihood of experiencing anxiety at the pre-radiation time point. Focused interventions at this time point may help improve the patient’s overall quality of life.

BACKGROUND Intra-arterial route of drug delivery (IA) without or with osmotic blood brain barrier disruption (IA/BBBD) is one of the available techniques to overcome the blood-brain barrier and enhance drug delivery to brain tumors. We present a large single institution safety data of IA or IA/BBBD. METHODS This is a retrospective review of the electronic records, imaging and complications in patients who underwent IA or IA/BBBD in OHSU between December, 1997 and November, 2018. Procedural complications were documented prospectively and reviewed in the electronic medical records. Toxicities, attributed to chemotherapy, were reported when grade is either II or higher by Common Terminology Criteria for Adverse Events (CTCAE). RESULTS Complications related to chemotherapy and procedure were reported separately. Total of 4940 procedures (1102 IAC and 3838 oBBBD) were performed on 436 patients (190 female and 246 male). Pathologies were primary central nervous system lymphoma (PCNSL) (n=115, 26%), secondary central nervous system involvement (SCNSL) (n=37, 8%), glioblastoma (n=79, 18%), astrocytoma (grade II/III) (n=34, 7%), oligodendroglioma (n=64, 14%), pilocytic astrocytoma (n=10, 2%), metastatic (n=38, 8%), embryologic (n=37, 8%), others (n=22, 5%). Procedural complications: groin related (n=16, 0.32%), transient neurological decline (n=57, 1.15%), subintimal arterial injury (n=13, 0.26%), asymptomatic imaging changes (T2 or DWI) (n=60, 1.21%), symptomatic stroke (n=21, 0.43%), myocardial infarction (n=3, 0.37%), cervical cord injury (n=6, 0.12%), death within 3 days (n=6, 0.12%). Minor complications are 2.86%, major complications are 1.12%. Eighty-four percent (n=369) of the patients experienced grade 2 or higher toxicities attributed to chemotherapy. CONCLUSION We present the largest safety data set to date from a single institution experience using IA and IA/BBBD for brain tumors. Our results suggest that IA and IA/BBBD is safe and can be performed multiple times in the same patients with acceptable procedure related complications. Efficacy of this approach is being evaluated in prospective clinical trials.

BACKGROUND AND OBJECTIVE: To describe the incidence, characteristics, and risk factors of a pigmentary maculopathy in patients with primary central nervous system (CNS) lymphoma treated with blood–brain barrier disruption (BBBD) therapy. PATIENTS AND METHODS: This retrospective chart review included patients with biopsy-proven primary CNS lymphoma treated with or without BBBD therapy who underwent an ophthalmic examination after starting systemic treatment. Clinical data and all available retinal imaging were analyzed. RESULTS: Fifty-eight patients met inclusion criteria. Twenty-one of 36 patients treated with BBBD therapy had a bilateral pigmentary maculopathy. None of the 22 patients treated with conventional chemotherapy had similar changes. Additional findings in patients treated with BBBD included geographic retinal pigment epithelium atrophy, subretinal fluid, and in one case, choroidal neovascularization. Some cases of maculopathy resulted in reduced visual acuity. The presence of a pigmentary maculopathy was associated with a higher number of BBBD treatment sessions (20.1 vs 13.3, P = .016), but not vitreoretinal lymphoma involvement or intravitreal methotrexate injections. CONCLUSION: In this cohort, 58.3% of patients with primary CNS lymphoma treated with BBBD and chemotherapy were found to have a bilateral pigmentary maculopathy. This maculopathy can result in reduced visual acuity and is associated with the number of BBBD treatment sessions. [ Ophthalmic Surg Lasers Imaging Retina. 2020;51:S5–S12.]

BACKGROUND: Noninvasively differentiating therapy-induced pseudoprogression from recurrent disease in patients with glioblastoma is prospectively difficult due to the current lack of a biologically specific imaging metric. Ferumoxytol iron oxide nanoparticle MRI contrast characterizes innate immunity mediated neuroinflammation; therefore, we hypothesized that combined ferumoxytol and gadolinium enhanced MRI could serve as a biomarker of glioblastoma pseudoprogression. METHODS: In this institutional review board-approved, retrospective study, we analyzed ferumoxytol and gadolinium contrast enhanced T1-weighted 3T MRI in 45 patients with glioblastoma over multiple clinical timepoints. Isocitrate dehydrogenase 1 (IDH-1) mutational status was characterized by exome sequencing. Sum of products diameter measurements were calculated according to Response Assessment in Neuro-Oncology criteria from both gadolinium and ferumoxytol enhanced sequences. Enhancement mismatch was calculated as the natural log of the ferumoxytol to gadolinium sum of products diameter ratio. Analysis of variance and Student’s t-test assessed differences in mismatch ratios. P-value

PURPOSE Delayed ferumoxytol enhancement on T1 -weighted images appears visually similar to gadoteridol enhancement. The purpose of this study was to quantitatively compare ferumoxytol T1 enhancement to gadoteridol enhancement with an objective, semi-automated method. METHODS 206 sets of post-gadoteridol and 24 h post-ferumoxytol T1 -weighted scans from 58 high grade glioma patients were analyzed (9 pre-chemoradiation, 111 90 days post-chemoradiation, 65 post-bevacizumab scans). Enhancement volumes and signal intensities normalized to normal appearing tissue proximal to enhancement were calculated with a semi-automated method. Enhancement cube root volumes (D) and signal intensities (SI) were compared between the 2 contrast agents, and relative difference of D and SI were compared in different treatment groups with multivariate analysis. Within patient differences in D and SI before and after treatment with bevacizumab or steroid were assessed in 26 patients in each treatment group. RESULTS When compared to gadoteridol, ferumoxytol D was 13.83% smaller and SI was 7.24% lower (P 0.05). Relative difference in D and SI did not change significantly in response to bevacizumab (P = 0.5234 and P = 0.2442, respectively) or to steroid (P = 0.3774, P = 0.0741) in the within patient comparison. CONCLUSION The correlation between the 2 contrast agents' enhancement size and signal intensity and their similar behavior in response to therapy suggest that ferumoxytol can be used for revealing enhancement in high grade glioma patients. Magn Reson Med 80:224-230, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Contrast-enhanced magnetic resonance imaging is a commonly used diagnostic tool. Compared with standard gadolinium-based contrast agents, ferumoxytol (Feraheme, AMAG Pharmaceuticals, Waltham, MA), used as an alternative contrast medium, is feasible in patients with impaired renal function. Other attractive imaging features of i.v. ferumoxytol include a prolonged blood pool phaseand delayed intracellular uptake. With its unique pharmacologic, metabolic, and imaging properties, ferumoxytol may play a crucial role in future magnetic resonance imaging of the central nervous system, various organs outside the central nervous system, and the cardiovascular system. Preclinical and clinical studies have demonstrated the overall safety and effectiveness of this novel contrast agent, with rarely occurring anaphylactoid reactions. The purpose of this review is to describe the general and organ-specific properties of ferumoxytol, as well as the advantages and potential pitfalls associated with its use in magnetic resonance imaging. To more fully demonstrate the applications of ferumoxytol throughout the body, an imaging atlas was created and is available online as supplementary material.

BACKGROUND AND PURPOSE: Despite the label change and the FDA9s boxed warning added to the Feraheme (ferumoxytol) label in March 2015, radiologists have shown increasing interest in using ferumoxytol as an MR imaging contrast agent as a supplement or alternative to gadolinium. The goals of this study were to provide information regarding ferumoxytol safety as an imaging agent in a single center and to assess how the Feraheme label change may affect this potential, currently off-label indication. MATERIALS AND METHODS: This retrospective study evaluated the overall frequency of ferumoxytol-related adverse events when used for CNS MR imaging. Patients with various CNS pathologies were enrolled in institutional review board–approved imaging studies. Ferumoxytol was administered as multiple rapid bolus injections. The risk of adverse events was correlated with demographic data/medical history. RESULTS: The safety of 671 ferumoxytol-enhanced MR studies in 331 patients was analyzed. No anaphylactic, life-threatening, or fatal (grade 4 or 5) adverse events were recorded. The overall proportion of ferumoxytol-related grade 1–3 adverse events was 10.6% (8.6% occurring within 48 hours), including hypertension (2.38%), nausea (1.64%), diarrhea (1.04%), and headache (1.04%). History of 1 or 2 allergies was associated with an increased risk of adverse events (14.61% versus 7.51% [no history]; P = .007). CONCLUSIONS: The frequency of mild ferumoxytol-related adverse events was comparable with literature results, and no serious adverse event was recorded. Although the recommendations in the boxed warning should be followed, serious adverse events appear to be rare, and with proper precautions, ferumoxytol may be a valuable MR imaging agent.

Background Glioblastoma is a rapidly fatal brain cancer that exhibits extensive intra- and intertumoral heterogeneity. Improving survival will require the development of personalized treatment strategies that can stratify tumors into subtypes that differ in therapeutic vulnerability and outcomes. Glioblastoma stratification has been hampered by intratumoral heterogeneity, limiting our ability to compare tumors in a consistent manner. Here, we develop methods that mitigate the impact of intratumoral heterogeneity on transcriptomic-based patient stratification. Methods We accessed open-source transcriptional profiles of histological structures from 34 human glioblastomas from the Ivy Glioblastoma Atlas Project. Principal component and correlation network analyses were performed to assess sample inter-relationships. Gene set enrichment analysis was used to identify enriched biological processes and classify glioblastoma subtype. For survival models, Cox proportional hazards regression was utilized. Transcriptional profiles from 156 human glioblastomas were accessed from The Cancer Genome Atlas to externally validate the survival model. Results We showed that intratumoral histologic architecture influences tumor classification when assessing established subtyping and prognostic gene signatures, and that indiscriminate sampling can produce misleading results. We identified the cellular tumor as a glioblastoma structure that can be targeted for transcriptional analysis to more accurately stratify patients by subtype and prognosis. Based on expression from cellular tumor, we created an improved risk stratification gene signature. Conclusions Our results highlight that biomarker performance for diagnostics, prognostics, and prediction of therapeutic response can be improved by analyzing transcriptional profiles in pure cellular tumor, which is a critical step toward developing personalized treatment for glioblastoma.

BACKGROUND AND PURPOSE: Glioblastoma-associated macrophages are a major constituent of the immune response to therapy and are known to engulf the iron-based MR imaging contrast agent, ferumoxytol. Current ferumoxytol MR imaging techniques for localizing macrophages are confounded by contaminating intravascular signal. The aim of this study was to assess the utility of a newly developed MR imaging technique, segregation and extravascular localization of ferumoxytol imaging, for differentiating extravascular-from-intravascular ferumoxytol contrast signal at a delayed 24-hour imaging time point. MATERIALS AND METHODS: Twenty-three patients with suspected post-chemoradiotherapy glioblastoma progression underwent ferumoxytol-enhanced SWI. Segregation and extravascular localization of ferumoxytol imaging maps were generated as the voxelwise difference of the delayed (24 hours) from the early (immediately after administration) time point SWI maps. Continuous segregation and extravascular localization of ferumoxytol imaging map values were separated into positive and negative components. Image-guided biologic correlation was performed. RESULTS: Negative segregation and extravascular localization of ferumoxytol imaging values correlated with early and delayed time point SWI values, demonstrating that intravascular signal detected in the early time point persists into the delayed time point. Positive segregation and extravascular localization of ferumoxytol imaging values correlated only with delayed time point SWI values, suggesting successful detection of the newly developed extravascular signal. CONCLUSIONS: Segregation and extravascular localization of ferumoxytol MR imaging improves on current techniques by eliminating intrinsic tissue and intravascular ferumoxytol signal and may inform glioblastoma outcomes by serving as a more specific metric of macrophage content compared with uncorrected T1 and SWI techniques.

Despite recent therapeutic progress and improved survival for many patients with primary central nervous system lymphoma (PCNSL), up to 50% of patients will experience refractory or relapsed disease following first-line treatment with high dose methotrexate (HD-MTX) based regimens. The majority of such events occur within 2 years of diagnosis although, unlike their systemic counterpart, the risk of PCNSL relapse remains, even for patients in radiologic complete response at 10 years following diagnosis. Currently, there are no approved therapies, and no widely accepted 'standard-of-care' approaches for the treatment of refractory or recurrent primary central nervous system lymphoma (rrPCNSL). Re-treatment with HD-MTX based regimens, use of non-cross resistant chemotherapy regimens, high-dose chemotherapy and autologous stem cell transplantation (HDT-ASCT), and brain irradiation all remain important therapeutic approaches for rrPCNSL. However, the survival outcomes for patients with rrPCNSL remain extremely poor and the vast majority of patients will die of their disease. Increasingly, novel treatment approaches are being investigated in early phase clinical studies. Importantly, such therapies need to be evaluated in the context of both refractory and relapsed disease; in older patients and those with co-morbid conditions; and those with neurocognitive dysfunction. A deeper understanding of the molecular genetic mechanisms underpinning rrPCNSL and its unique tumor microenvironment is urgently needed to inform biologically rational and effective therapies. rrPCNSL remains a clear unmet clinical need and a high priority area for clinical research that will require national and international collaborative studies with embedded translational science in order to improve outcomes for patients.

Background: The prognosis for patients (pts) with recurrent (r) glioblastoma (GBM) is poor, with no highly effective approved therapies. Treatment failure may result from poor penetration of drugs through the blood-brain barrier and the immunosuppressive nature of the tumor microenvironment (TME). PVSRIPO, a recombinant poliovirus (PV):rhinovirus chimera, is a novel, non-neurovirulent, intratumoral immunotherapy. Trial results in rGBM pts showed greater long-term survival with PVSRIPO monotherapy (21%, 36-60 months [mos]) vs. criteria-matched external controls (4%, 36 mos; 2%, 60 mos; Desjardins 2018 NEJM). PVSRIPO targets CD155 (PV receptor), expressed on solid tumors and APC. PVSRIPO IT infection results in inflammatory-mediated destruction of tumor cells but non-lethal lingering infection in TME APC. This leads to a type-I/III interferon-dominant inflammation and ultimately, tumor antigen-specific T cell activation and recruitment (Brown 2017 Sci Transl Med), which is potentiated by immunologic recall to intratumoral replicating virus via prior vaccination. Induction of type-1 IFN dominant inflammation and compensatory activation of the PD-1:PD-L1 immune checkpoint (IC) pathway support investigation of PVSRIPO in combination with PD-1/L1 IC inhibitors. Immunologically cold mouse glioma models showed PVSRIPO+anti-PD-1 therapy resulted in greater anti-tumor response than either agent. Trial design/objectives: LUMINOS-101 (NCT04479241) is a phase 2, multicenter, open-label, single-arm study of intratumoral infusion of PVSRIPO (day 1: 5×107 TCID50) followed by the anti-PD-1 monoclonal antibody pembrolizumab (200mg IV q3w) in adult pts with rGBM. The trial objective is to evaluate the anti-tumor activity, safety, and tolerability of the combination. Eligibility criteria: Pts ≥18 years who had prior PV and boost IPOL® immunizations, histologically confirmed supratentorial rGBM, infusible 1 to ≤5.5cm enhancing disease, confirmed disease progression following prior therapies, and KPS ≥70 will be enrolled. Key exclusion criteria include multifocal disease; discontinuation of prior anti-PD-1/L1 agent for toxicity; prior intratumoral therapy, immunotherapy, or radiotherapy within 12 weeks; high-dose systemic corticosteroids; chemotherapy, anti-VEGF, or TTF therapy ≤1-6 weeks depending on the therapy; serious cerebral herniation syndrome; extensive leptomeningeal, subependymal, or ≥1cm enhancing disease crossing the midline; and severe active comorbidities. Endpoints: Primary endpoints are objective response rate, duration of response, and safety. Secondary endpoints include overall and progression-free survival and disease control rate and duration. Exploratory endpoints include assessment of tumor and blood for biomarkers of response. The study is currently enrolling in the US, and results will inform the design of a randomized phase 3 trial. Citation Format: Andrea True Kelly, Prakash Ambady, Michael Brown, Nicholas Butowski, Robert Cavaliere, William Curry, Annick Desjardins, Lisa Franklin, Henry Friedman, Matthias Gromeier, LeAnn Jackson, Lori Mixson, Shirley Ong, Dina Randazzo, Andrew Sloan, Patrick Wen, Garrett Nichols. LUMINOS-101: Phase 2 study of PVSRIPO with pembrolizumab in recurrent glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT240.

TPS2065 Background: The prognosis for patients (pts) with recurrent (r) glioblastoma (GBM) is poor, with no highly effective approved therapies. Treatment failure may result from poor penetration of drugs through the blood-brain barrier and the immunosuppressive nature of the tumor microenvironment (TME). PVSRIPO, a recombinant poliovirus (PV):rhinovirus chimera, is a novel, non-neurovirulent, intratumoral immunotherapy. Trial results in rGBM pts show greater long-term survival with PVSRIPO monotherapy (21%, 36-60 months [mos]) vs criteria-matched external controls (4%, 36 mos; 2%, 60 mos; Desjardins 2018 NEJM). PVSRIPO targets CD155 (PV receptor), expressed on solid tumors and on APC. PVSRIPO infection results in inflammatory-mediated destruction of tumor cells but non-lethal lingering infection in TME APC. This leads to type I/III interferon-dominant inflammation and, ultimately, tumor antigen-specific T cell activation and recruitment (Brown 2017 Sci Transl Med), which is potentiated by immunologic recall to intratumoral replicating virus via prior vaccination. Induction of type 1 IFN dominant inflammation and compensatory activation of the PD-1:PD-L1 immune checkpoint (IC) pathway support investigation of PVSRIPO in combination with PD-1/L1 IC inhibitors. Immunologically cold mouse glioma models show PVSRIPO+anti-PD-1 therapy resulted in greater anti-tumor response than either agent. Methods: LUMINOS-101 is a phase 2, multicenter, open-label, single-arm study of intratumoral infusion of PVSRIPO (Day 1: 5x107 TCID50) followed by the anti-PD-1 monoclonal antibody pembrolizumab (200mg IV q3w) in adult pts with rGBM. The trial objective is to evaluate anti-tumor activity and safety and tolerability of the combination. Eligibility criteria include pts ≥18 years who had prior PV and boost IPOL® immunizations, histologically confirmed supratentorial rGBM, infusible 1 to ≤5.5cm enhancing disease, confirmed disease progression following prior therapies, and KPS ≥70. Key exclusion criteria include multifocal disease; discontinuation of prior anti-PD-1/L1 agent for toxicity; prior intratumoral therapy, immunotherapy, or radiotherapy within 12 weeks; high-dose systemic corticosteroids; chemotherapy, anti-VEGF, or TTF therapy ≤1-6 weeks depending on the therapy; serious cerebral herniation syndrome; extensive leptomeningeal, subependymal, or ≥1cm enhancing disease crossing the midline; and severe active comorbidities. Primary endpoints are objective response rate, duration of response, and safety. Secondary endpoints include overall and progression-free survival and disease control rate and duration. Exploratory endpoints include assessment of tumor and blood for biomarkers of response. The initially planned safety lead-in period is now fully enrolled. Recruitment is ongoing in the US, and results will inform the design of a randomized phase 3 trial. Clinical trial information: NCT04479241.

Primary central nervous system lymphoma (PCNSL) is a rare disease of the brain, spine, cerebrospinal fluid (CSF) and/or vitreoretinal space. PCNSL is chemo and radiosensitive but relapse is common even years after initial treatment. Outside of consensus regarding the use of high-dose methotrexate (HD-MTX) for first line treatment, there is little uniformity in the management of newly diagnosed or relapsed PCNSL. The lack of consensus is driven by a paucity of randomized trials in this disease. Prospective studies are troubled by low enrollment, the lack of a standard induction regimen, and a varied approach to consolidation strategies. Moreover, the PCNSL patient population is heterogeneous and includes a high proportion of elderly or frail patients and consists of patients manifesting disease in varied compartments of the central nervous system (CNS). As a result, current treatment strategies vary widely and are often dictated by physician and institutional preference or regional practice. This review provides an overview of recently completed and ongoing therapeutic studies for patients with newly diagnosed and recurrent or refractory PCNSL. It discusses the existing evidence behind common approaches to induction and consolidation or maintenance regimens as well as the recent data regarding management of recurrent disease. Finally, it highlights the complexity of trial design in this disease and provides a framework for the design of future studies, which are needed to identify patient populations likely to benefit from specific induction, consolidation, or maintenance therapies.

Importance Blood-brain barrier disruption (BBBD) is a systemic therapy for malignant central nervous system (CNS) tumors that has been linked to poorly understood pigmentary maculopathy. Objectives To examine the rate of and risk factors for the development of BBBD-associated maculopathy and to assess whether there can be visually significant progression after completion of systemic therapy. Design, setting, and participants In this retrospective case series, data from February 1, 2006, through December 31, 2019, were collected from patients treated with osmotic BBBD at a single tertiary referral center who had subsequent ophthalmic evaluation. Exposures Treatment with BBBD therapy for any malignant CNS tumor. Main outcomes and measures Rate and potential risk factors for developing BBBD-associated maculopathy and changes in visual acuity and retinal imaging characteristics after completion of BBBD therapy. Results Of 283 patients treated with BBBD and chemotherapy for a CNS malignant neoplasm, 68 (mean [SD] age, 46.0 [17.9] years; 25 [38.5%] female) had an ophthalmic examination after starting systemic therapy. After excluding 3 patients because of bilateral media opacities, pigmentary maculopathy was present in 32 of 65 patients (49.2%) treated with BBBD. The number of BBBD treatment sessions, but not age, CNS malignant cancer type, or systemic chemotherapy agent, was associated with maculopathy development (odds ratio, 1.30; 95% CI, 1.12-1.50; P = .001). After completion of BBBD therapy, progressive enlargement of geographic atrophy occurred in 5 eyes of 3 patients, and choroidal neovascularization developed in 1 eye. Conclusions and relevance In this case series, an association was found between BBBD-related maculopathy and the number of BBBD treatment sessions, suggesting a dose-dependent effect. In some cases, maculopathy progression, including enlargement of geographic atrophy, occurred years after completion of systemic therapy. These findings may have important implications for patient education and ophthalmic monitoring.

Background: Although high initial response rates have been reported, fewer than 50% of newly diagnosed primary CNS lymphoma (PCNSL) patients remain disease free 2 yrs after high-dose (HD) methotrexate (MTX)-based regimens. Treatment options at relapse including HD chemotherapy with or without autologous stem cell transplantation and/or whole brain radiotherapy can lead to considerable toxicity and are not ideal especially for elderly and high-risk patients. New approaches to prolong disease control and response duration in PCNSL are needed. Maintenance rituximab has increased response duration in follicular and mantle cell lymphomas. Several reports (Ney and Abrey [2009]; Ambady et al [2020]) suggest that maintenance rituximab after achieving complete response (CR) to MTX-based chemotherapy, will prolong disease control in PCNSL. We designed a randomized study to evaluate the effect of maintenance obinutuzumab on CR duration in CD20+ B-cell PCNSL patients who attain CR to first-line HD MTX-based chemotherapy. We report adverse events (AEs) to-date in the maintenance group. Methods:This was a multicenter, non-blinded, randomized phase II study, with an estimated sample size of 120 patients randomly assigned to maintenance obinutuzumab or observation. Patients in the maintenance group received obinutuzumab (1000 mg) every 60 days for 2 yrs. Eligible patients were within 75 days of completing first-line MTX-based regimen, and in CR. The primary endpoint was CR duration. Lab tests and safety assessments were performed throughout the study until 60 days after the patient's last obinutuzumab infusion. We graded AEs according to NCI CTCAE v4, and summarized AEs descriptively. Clinical Trial Information: NCT02498951. Results: As of July 1, 2020, 24 patients were enrolled at 11 U.S. centers. Twelve patients (5F, 7M) with median age of 68 yrs (range: 39 - 82), median KPS 90 (range: 80 - 100) were in the maintenance group. Seven of the 12 patients were older than 65 yrs. The 12 patients received 87 obinutuzumab infusions (median 7 [range 2 - 12]). The only grade (Gr) 3 AEs attributable to study drug were nausea, vomiting and skin infection (1 patient [8%] each). The most frequent Gr 2 AEs were respiratory infection and diarrhea (2 patients [17%] each). Gr 2 nausea, vomiting and skin infection occurred in 1 patient (8%, each). Gr 1 dizziness and flushing during cycle 1 infusion occurred in 3 patients (25%). Conclusions: Maintenance obinutuzumab was well tolerated with an encouraging safety profile in PCNSL patients in remission. However, enrollment closed prematurely due to slow accrual made worse by the coronavirus pandemic. Thus the role of maintenance obinutuzumab in prolonging CR duration in this patient population remains unknown. Disclosures Barth: Sanofi:Membership on an entity's Board of Directors or advisory committees.

Overexpression of O6-methylguanine DNA methyltransferase (MGMT) contributes to brain tumor chemo-resistance. Previously we found that non-cytotoxic radiation improved anti-MGMT Morpholino Oligonucleotides (AMONs) delivery to reduce MGMT levels in subcutaneous tumor xenografts. Here we evaluated if radiation enhanced the delivery of intravenous (IV) AMONs to rat brain and improved chemo-radiation therapy (CRT) efficacy using rat models of human brain tumors. Athymic nude rats bearing orthotopic cerebellar D283 medulloblastoma or intracerebral H460 non-small cell lung carcinoma (NSCLC) brain metastasis xenografts were used. The impact of cranial radiation on delivery of IV 3’-carboxyfluorescein labeled oligonucleotides across the neurovascular unit was evaluated using confocal microscopy. We found that high brain parencymal fluorescence in radiated compared to non-radiated rats. MGMT protein silencing was assessed by immunoblot in tumor-bearing rats 3 d after 2 Gy cranial radiation alone or followed in 1 d by IV AMONs (10.5 mg/kg). Radiation followed by AMONs reduced MGMT expression by 50% in both xenograft models. To evaluate efficacy, tumor-bearing rats received one dose of 2 Gy radiation plus oral temozolomide (20 mg/kg x 4d) with or without IV AMONs. AMONs concurrent with CRT reduced tumor volumes in the medulloblastoma model (p=0.012), and a similar trend was found in the NSCLC brain metastasis model. In conclusion, we demonstrate the use of a single clinically relevant radiation dose fraction to guide and enhance the delivery of oligonucleotides into brain tumor xenograft models to reduce MGMT levels and improve CRT efficacy.

The exploratory endpoint for our prospective single-arm study (NCT 03347617) evaluated longitudinal changes in immune cell sub-populations (B-cells, T-cells, NK cells, monocytes, and myeloid cells) in 25 newly diagnosed glioblastoma patients who received standard of care chemoradiation with concurrent pembrolizumab after maximal safe resection. Patient demographics included the following: 15 males, 10 females, age range 25-72 years old, mean age 52 years old, 8 MGMT unmethylated, 17 MGMT methylated, 7 IDH1 mutant, and 18 IDH1 wild-type. Flow cytometry was performed on blood collected at predetermined timepoints (pre-treatment, post-radiation, suspected progression, and confirmed progression) and immune cell sub-populations were evaluated as covariates in survival analysis using Cox proportional hazards regression in R. CD5+ CD19+ B-cell count was significantly associated with progression-free survival at pre-treatment (hazard ratio (HR)= 0.76; likelihood ratio test (LRT) p=0.029) and post-radiation (HR = 0.16; LRT p=0.004) timepoints. No association with progression-free survival was found in 25 other immune cell sub-populations evaluated. The study will continue to monitor for progression. Results of imaging, tissue histology, overall survival analysis and functional studies in animal models are pending. Investigations of the immunological mechanisms underlying the potential anti-tumor activity of CD5+ B-cells are ongoing and include detection and characterization of anti-tumor antibodies, T cell-dependence of the response, and whether it is triggered by pembrolizumab. Modulating CD5+ B-cells, or the antibodies they produce, may have therapeutic implications in improving checkpoint inhibition in glioblastoma. Citation Format: Cheryl J. Claunch, Claire Diaz, Riley A. Roth-Carter, Lauren Popp, Rochelle Fu, Amy E. Huddleston, Dana L. Moussalli, Julie Peterson, Kutluay Uluc, Laszlo Szidonya, Guang Fan, Ferdinando Pucci, Ramon F. Barajas, Leslie L. Muldoon, Edward A. Neuwelt, Prakash Ambady. CD5+ B-cell count is a favorable prognostic factor associated with progression-free survival in glioblastoma patients receiving chemoradiation and pembrolizumab [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT183.

Primary central nervous system lymphoma (PCNSL) is an extemely rare, CD20+ non-germinal center B cell lymphoma (diffuse large cell type) in a bed of T-cell rich tumor microenvironment. The prognost...

Radiation (RT), temozolomide (TMZ), and dexamethasone in newly diagnosed high grade gliomas (HGG) produces severe treatment-related lymphopenia (TRL) that is associated with early cancer-related deaths. This TRL may result from inadvertent radiation to circulating lymphocytes. This study reinfused lymphocytes, harvested before chemo-radiation, and assessed safety, feasibility, and trends in lymphocyte counts. Patients with newly diagnosed HGG and total lymphocyte counts (TLC) ≥ 1000 cells/mm(3) underwent apheresis. Cryopreserved autologous lymphocytes were reinfused once radiation was completed. Safety, feasibility, and trends in TLC, T cell subsets and cytokines were studied. Serial TLC were also compared with an unreinfused matched control group. Ten patients were harvested (median values: age 56 years, dexamethasone 3 mg/day, TLC/CD4 1980/772 cells/mm(3)). After 6 weeks of RT/TMZ, TLC fell 69 % (p 0.0001) with similar reductions in CD4, CD8 and NK cells but not Tregs. Eight patients received lymphocyte reinfusions (median = 7.0 × 10(7) lymphocytes/kg) without adverse events. A post-reinfusion TLC rise of ≥300 cells/mm(3) was noted in 3/8 patients at 4 weeks and 7/8 at 14 weeks which was similar to 23 matched controls. The reduced CD4/CD8 ratio was not restored by lymphocyte reinfusion. Severe lymphopenia was not accompanied by elevated serum interleukin-7 (IL-7) levels. This study confirms that severe TRL is common in HGG and is not associated with high plasma IL-7 levels. Although lymphocyte harvesting/reinfusion is feasible and safe, serial lymphocyte counts are similar to unreinfused matched controls. Studies administering higher lymphocyte doses and/or IL-7 should be considered to restore severe treatment-related lymphopenia in HGG.

Background and purpose The radiologic features and patterns of primary central nervous system lymphoma (PCNSL) at initial presentation are well described. High response rates can be achieved with first-line high-dose methotrexate (HD-MTX) based regimens, yet many relapse within 2 years of diagnosis. We describe the pattern of relapse and review the potential mechanisms involved in relapse. Methods We identified 78 consecutive patients who attained complete radiographic response (CR) during or after first-line treatment for newly diagnosed PCNSL (CD20+, diffuse large B cell type). Patients were treated with HD-MTX based regimen in conjunction with blood–brain barrier disruption (HD-MTX/BBBD); 44 subsequently relapsed. Images and medical records of these 44 consecutive patients were retrospectively reviewed. The anatomical location of enhancing lesions at initial diagnosis and at the time of relapse were identified and compared. Results 37/44 patients fulfilled inclusion criteria and had new measureable enhancing lesions at relapse; the pattern and location of relapse of these 37 patients were identified. At relapse, the new enhancement was at a spatially distinct site in 30 of 37 patients. Local relapse was found only in seven patients. Discussion Unlike gliomas, the majority of PCNSL had radiographic relapse at spatially distinct anatomical locations within the brain behind a previously intact neurovascular unit (NVU), and in few cases outside, the central nervous system (CNS). This may suggest either (1) reactivation of occult reservoirs behind an intact NVU in the CNS (or ocular) or (2) seeding from bone marrow or other extra CNS sites. Conclusion Recognizing patterns of relapse is key for early detection and may provide insight into potential mechanisms of relapse as well as help develop strategies to extend duration of complete response.

OBJECTIVE Personalized treatment strategies in Glioblastoma multiforme (GBM) has been hampered by intra-tumoral heterogeneity. The goals of this study were to (1) determine the impact of intra-tumoral heterogeneity on established predictive and prognostic transcriptional signatures in human GBM, and (2) develop methods to mitigate the impact of tissue heterogeneity on transcriptomic-based patient stratification. METHODS We analyzed transcriptional profiles of GBM histological structures from the open-source Ivy Glioblastoma Atlas Project. To generate these data, infiltrative tumor, leading edge, cellular tumor [CT], perinecrotic zones, pseudopalisading cells, hyperplastic blood vessels and microvascular proliferation were microdissected from 34 newly diagnosed GBM and underwent RNA sequencing. Data from The Cancer Genome Atlas were used for validation. Principle component analysis, network analysis and gene set enrichment analysis were used to probe gene expression patterns. RESULTS Distinct biological networks were enriched in each tumor histological structure. Classification of patients into GBM molecular subtypes varied based on the structure assessed, with many patients classified as every subtype depending on the structure analyzed. Using only CT to classify subtypes, we identified biologically unique patterns suggesting that proneural and mesenchymal tumors may be more sensitive to chemoradiotherapy and immunotherapy, respectively. Survival outcome predicted by an established multigene panel was confounded by histologic structure. Utilizing CT transcriptomics we developed a novel survival prediction gene signature that identified the highest-risk GBM patients in both CT and bulk tissue gene expression profiles. CONCLUSIONS Histologic structures contribute to intra-tumoral heterogeneity in GBM. Using mixed-structure biopsy samples could incorrectly subtype tumors and produce invalid patient stratification. Limiting transcriptomic analysis to the CT allowed us to develop a new survival prediction gene signature that appears accurate even in mixed tissue samples. The biological patterns uncovered in the subtypes and risk-stratified groups have important implications for guiding the development of precision medicine in GBM.

SUMMARY MRI remains the backbone of measuring disease burden and treatment response in individuals with malignant gliomas. Traditional radiographic approaches, however, are largely limited to depicting anatomic changes and are not a direct measure of disease burden. For example, contrast enhancement is related to blood–brain barrier integrity rather than actual tumor size. Without accurate measures of disease, common clinical dilemmas include ‘pseudo-progression‘ (e.g., after chemoradiation) or ‘pseudo-response‘ (e.g., with steroid treatment and antiangiogenic agents), which can lead to delays in therapy, premature discontinuation of successful treatments and to unnecessary surgical procedures. This overview focuses on novel, minimally invasive approaches in the area of imaging and blood-based biomarkers that aim to more accurately determine disease status and response to treatment in malignant brain tumors.

Intra-arterial (IA) infusion of hypertonic mannitol transiently opens the blood-brain barrier (BBB) to improve drug delivery to intracerebral tumors. The aim of this study was to evaluate the safety of osmotic BBB disruption (BBBD) followed by administration of IA chemotherapy. We performed a retrospective chart review of all malignant brain tumor patients who underwent BBBD on six IRB approved treatment protocols or off protocol at Oregon Health and Science University between 1997 and 2017. Toxicities and adverse events (AEs), including death within 30 days of treatment, were assessed. A total of 4018 BBBD procedures were performed on 268 patients (mean 15 BBBD procedures per patient). The most common pathologies were primary central nervous system lymphoma (32%) and anaplastic oligodendroglioma (12%). Most AEs were chemotherapy-related. Only 5% of AEs were attributable to the BBBD procedure, and only 0.42% of these were associated with permanent neurological damage (Grade 3 or 4 SAE). Four SAEs were due to ischemia as detected on magnetic resonance imaging and had minimal impact on quality of life. Four SAEs were due to anterior cord syndrome subsequent to iatrogenic laminar flow of the chemotherapy and were partially responsive to steroids. Subsequently this toxicity was eliminated by procedures to avoid laminar flow. Focal seizures, largely responsive to medical intervention, occurred within 24 hours after 257 (6.4%) BBBD procedures. Most seizures (229, 89%) followed IA administration of methotrexate and were transient and without sequelae. Five patient deaths occurred within 30 days; 1 due to a brain stem stroke related to BBBD, 1 due to a pulmonary embolus, and 3 due to disease progression. We conclude that although the BBBD procedure is invasive, permanent toxicities or death are rare. These results show that osmotic BBBD can be performed safely in brain tumor patients.

e22203Background: Glioblastomas (GBMs) are primary malignant brain tumors that, in spite of aggressive treatment, carry a poor prognosis and a significant emotional and socioeconomic burden. Early ...

e14056Background: Osmotic blood brain barrier disruption (BBBD) can increase drug delivery up to 100 fold in brain tumors when compared to IV delivery. The aim of this study was to evaluate the saf...

Treatment of patients with newly diagnosed primary CNS lymphomas using high dose methotrexate regimens is reported to yield about 30% long term survivors with minimal neurotoxicity. As in other systemic large cell lymphomas, it is generally assumed that most relapses occur within 5 years of diagnosis. A retrospective review of the Johns Hopkins experience in 52 patients treated between 1995 and 2008 yielded 19 patients (37%) who achieved a complete response and were followed for over 5 years. Four of these patients remained progression-free for over 10 years. However, two of these long-term survivors have now relapsed over 10 years after their initial diagnosis. An analysis of progression and overall survival does not reveal a plateau suggesting that even patients who have not recurred for over 10 years remain at high risk for relapse after treatment with single agent high dose methotrexate.