Steven Brem - Profile on Academia.edu (original) (raw)

Papers by Steven Brem

American Journal of Neuroradiology, Apr 1, 2002

Isolated neurosarcoidosis involving the optic nerve meninges is extremely rare and is often indis... more Isolated neurosarcoidosis involving the optic nerve meninges is extremely rare and is often indistinguishable from a meningioma in its anatomic site and MR imaging presentation. Characteristic findings include enhanced perineural encasement and thickening of the affected optic nerve on contrast-enhanced T1-weighted cranial MR imaging studies. We present the case report of a patient with isolated necrotizing neurosarcoidosis of the left optic nerve, with clinical and MR imaging findings strongly suggestive of a preoperative diagnosis of a meningioma.

Cell Reports, Dec 1, 2017

Highlights d Single-mitochondrion sequencing shows singlemitochondrion heteroplasmy d The distrib... more Highlights d Single-mitochondrion sequencing shows singlemitochondrion heteroplasmy d The distribution of SNV loci suggests inheritance of variants across generations

Neuro-oncology advances, Aug 1, 2023

iii15 NEURO-ONCOLOGY ADVANCES • AUGUST 2023 18 F-fluciclovine injection for the first seven enrol... more iii15 NEURO-ONCOLOGY ADVANCES • AUGUST 2023 18 F-fluciclovine injection for the first seven enrolled patients (9 lesions) who completed baseline imaging, and five patients (7 lesions) who completed the treatment course (SSRS). Patients underwent a baseline (pre-treatment) 18 F-fluciclovine PET/CT and contrast-enhanced treatment planning brain MRI before 1 st SSRS (15 Gy), repeated after 4 weeks (interim; before 2 nd SSRS [15 Gy]), and 8 weeks after treatment completion (first follow-up after 2 nd SSRS). The median age was 72 years and 57% were female. All lesions exhibited baseline increased 18 F-fluciclovine uptake compared to normal contralateral brain. The median baseline lesion diameters and volumes were 2.16 cm (1.76-3.22 cm) and 4.71cc (2.24-10.21 cc). The median baseline SUVmax, SUVpeak, and SUVmean values were 5.78 (2.16-8.79), 3.33 (0.5-2.72), and 1.75 (1.22-5.16), respectively. The median relative changes in diameter and volume were both -2% (-23% to +13% and -60% to +30%, respectively) at the interim scans, and -30% (-44% to +0.2%) and -43% (-94% to +13%), respectively, at first follow-up. Corresponding median relative changes values for SUVmax, SUVpeak, and SUVmean at interim scan were -20% (-73% to +174%), -9% (-75% to +99%), and -14% (-69% to +36%), and at first follow-up -59% (-87% to -21%), -41% (-86% to +11%), and -21% (-79% to +44%), respectively. In conclusion, this proofof-concept interim study reports 18 F-fluciclovine metrics for patients with large BMs, demonstrating interval reduction in PET metrics after SSRS, more than anatomical measurements alone, highlighting the potential of this as an imaging biomarker.

Cancer Control, May 1, 2004

Neurosurgery, Mar 16, 2017

BACKGROUND: Diffuse low-grade gliomas (DLGGs) represent several pathological entities that infilt... more BACKGROUND: Diffuse low-grade gliomas (DLGGs) represent several pathological entities that infiltrate and invade cortical and subcortical structures in the brain. OBJECTIVE: To describe methods for rapid prototyping of DLGGs and surgically relevant anatomy. METHODS: Using high-definition imaging data and rapid prototyping technologies, we were able to generate 3 patient DLGGs to scale and represent the associated white matter tracts in 3 dimensions using advanced diffusion tensor imaging techniques. RESULTS: This report represents a novel application of 3-dimensional (3-D) printing in neurosurgery and a means to model individualized tumors in 3-D space with respect to subcortical white matter tract anatomy. Faculty and resident evaluations of this technology were favorable at our institution. CONCLUSION: Developing an understanding of the anatomic relationships existing within individuals is fundamental to successful neurosurgical therapy. Imaging-based rapid prototyping may improve on our ability to plan for and treat complex neuro-oncologic pathology.

Frontiers in Neuroscience, Jun 16, 2022

The lateral habenula (LHb) is an epithalamic nucleus associated with negative valence and affecti... more The lateral habenula (LHb) is an epithalamic nucleus associated with negative valence and affective disorders. It receives input via the stria medullaris (SM) and sends output via the fasciculus retroflexus (FR). Here, we use tractography to reconstruct and characterize this pathway. Methods: Multi-shell human diffusion magnetic resonance imaging (dMRI) data was obtained from the human connectome project (HCP) (n = 20, 10 males) and from healthy controls (n = 10, 6 males) scanned at our institution. We generated LHb afferents and efferents using probabilistic tractography by selecting the pallidum as the seed region and the ventral tegmental area as the output target. Results: We were able to reconstruct the intended streamlines in all individuals from the HCP dataset and our dataset. Our technique also aided in identification of the LHb. In right-handed individuals, the streamlines were significantly more numerous in the left hemisphere (mean ratio 1.59 ± 0.09, p = 0.04). In left-handed individuals, there was no hemispheric asymmetry on average (mean ratio 1.00 ± 0.09, p = 1.0). Additionally, these streamlines were significantly more numerous in females than in males (619.9 ± 159.7 vs. 225.9 ± 66.03, p = 0.04). We developed a method to reconstruct the SM and FR without manual identification of the LHb. This technique enables targeting of these fiber tracts as well as the LHb. Furthermore, we have demonstrated that there are sex and hemispheric differences in streamline number. These findings may have therapeutic implications and warrant further investigation.

NIMG-82. Radiogenomic Signatures of Key Driver Genes in GBM Reveal Molecular Heterogeneity of the Tumor Microenvironment Linked to Spatial Distribution: Impact on the Trajectory of Glioma Evolution

Neuro-oncology, Nov 1, 2022

Somatic genomic alterations acquired during GBM growth enhance adaptation of tumor cells to their... more Somatic genomic alterations acquired during GBM growth enhance adaptation of tumor cells to their microenvironment and give rise to molecular heterogeneity. Radiogenomics could facilitate exploration of the underlying pathobiology of tumor growth in specific microenvironments and thereby, promote precision medicine for the patients. We derived radiogenomic signatures of key driver genes and evaluated molecular compositions of tumor groups with predisposition to specific brain regions. Pre-operative multiparametric conventional MRI scans of 357 IDH-wildtype GBM patients with available targeted NGS data were jointly segmented and registered into a common template. We constructed spatial distribution atlases for tumors harboring mutations in driver genes and identified four distinct groups of tumor locations with predilection to the left frontal cingulate region (Group1), right temporal (Group2), right parietal (Group3), and occipital pole (Group4). Evaluation of the differences in molecular features of the tumor groups included: (1) exploring similarities of genomic profiles across all four groups by evaluating cosine similarity metric (CSM) between mutational signatures; (2) quantification of molecular heterogeneity based on Mutant Allele Tumor Heterogeneity (MATH) scores; and (3) inference of the evolutionary trajectories. Groups 1 and 4 were the most different, and Groups 2 and 3 were the most similar tumors, molecularly. The mutational signatures between Groups 1 and 4 revealed a CSM of 0.35. Group1 showed significantly lower MATH score (less heterogeneity) compared to Group4 (p< 0.05). Evaluation of evolutionary patterns suggested NF1 mutation as an early event in Group1, without subsequent gain of function or mutation in EGFR. In contrast, in Group4, EGFR mutations were early events triggering PTEN mutations later in the evolutionary trajectory. Radiogenomic signatures revealed distinct molecular underpinnings for the tumors with predilection towards specific brain regions that may suggest existence of different tumor microenvironments in different brain regions that cause intra- and inter-patient heterogeneity in the molecular tumor composition.

Assessing variability in surgical decision making among attending neurosurgeons at an academic center

Journal of Neurosurgery, Jun 1, 2020

OBJECTIVEAlthough it is known that intersurgeon variability in offering elective surgery can have... more OBJECTIVEAlthough it is known that intersurgeon variability in offering elective surgery can have major consequences for patient morbidity and healthcare spending, data addressing variability within neurosurgery are scarce. The authors performed a prospective peer review study of randomly selected neurosurgery cases in order to assess the extent of consensus regarding the decision to offer elective surgery among attending neurosurgeons across one large academic institution.METHODSAll consecutive patients who had undergone standard inpatient surgical interventions of 1 of 4 types (craniotomy for tumor [CFT], nonacute redo CFT, first-time spine surgery with/without instrumentation, and nonacute redo spine surgery with/without instrumentation) during the period 2015–2017 were retrospectively enrolled (n = 9156 patient surgeries, n = 80 randomly selected individual cases, n = 20 index cases of each type randomly selected for review). The selected cases were scored by attending neurosurgeons using a need for surgery (NFS) score based on clinical data (patient demographics, preoperative notes, radiology reports, and operative notes; n = 616 independent case reviews). Attending neurosurgeon reviewers were blinded as to performing provider and surgical outcome. Aggregate NFS scores across various categories were measured. The authors employed a repeated-measures mixed ANOVA model with autoregressive variance structure to compute omnibus statistical tests across the various surgery types. Interrater reliability (IRR) was measured using Cohen’s kappa based on binary NFS scores.RESULTSOverall, the authors found that most of the neurosurgical procedures studied were rated as “indicated” by blinded attending neurosurgeons (mean NFS = 88.3, all p values < 0.001) with greater agreement among neurosurgeon raters than expected by chance (IRR = 81.78%, p = 0.016). Redo surgery had lower NFS scores and IRR scores than first-time surgery, both for craniotomy and spine surgery (ANOVA, all p values < 0.01). Spine surgeries with fusion had lower NFS scores than spine surgeries without fusion procedures (p < 0.01).CONCLUSIONSThere was general agreement among neurosurgeons in terms of indication for surgery; however, revision surgery of all types and spine surgery with fusion procedures had the lowest amount of decision consensus. These results should guide efforts aimed at reducing unnecessary variability in surgical practice with the goal of effective allocation of healthcare resources to advance the value paradigm in neurosurgery.

Neuro-oncology, Nov 1, 2020

AI-based methods have shown great promise in a variety of biomedical research fields, including n... more AI-based methods have shown great promise in a variety of biomedical research fields, including neurooncologic imaging. For example, machine learning methods have offered informative predictions of overall survival (OS) and progression-free survival (PFS), differentiation between pseudoprogression (PsP) and progressive disease (PD), and estimation of mutational status from imaging data. Despite their promise, AI, and especially the emerging deep learning (DL) methods, are challenged by several factors, including imaging heterogeneity across scanners and lack of sufficiently large and diverse training datasets, which limits their reproducibility and general acceptance. These challenges prompted the development of the ReSPOND (Radiomics Signatures for PrecisiON Diagnostics) consortium on glioblastoma, a growing effort to bring together a community of researchers sharing imaging, demographic, clinical and (currently) limited molecular data in order to address the following aims: 1) pool and harmonize data across diverse hospitals and patient populations worldwide; 2) derive robust and generalizable AI models for prediction of (initially) OS, PFS, PsP vs. PD, and recurrence; 3) test these predictive models across multiple sites. In its first phase, ReSPOND aims to pool together approximately 3,000MRI scans (from 10institutions plus TCIA), along with demographics, KPS, and (for a subset) MGMT/IDH1 status. We present initial results testing the generalization of a previously trained model of OS on 505Penn datasets to 2independent cohorts from Case Western Reserve University and University Hospitals (N=44), and Penn (N=67). The results indicate good generalization, with correlation coefficients between OS/predicted-OS between 0.25 to 0.5, depending on variable availability, which is comparable to cross-validated accuracy previously obtained from the training set itself (N=505). Additional preliminary studies evaluating prediction of future recurrence from baseline pre-operative scans in de novo patients (Penn model applied to CWR) indicated potential for guiding targeted dose escalation and supra-total resection (excellent predictions in 6/12 patients, modest in 1/12, and poor in 5/12).

Neuro-oncology, Nov 1, 2018

NEURO-ONCOLOGY • NOVEMBER 2018 expansion of CD11b+ Gr-1+ myeloid cells compared to wtIDH1 tumors ... more NEURO-ONCOLOGY • NOVEMBER 2018 expansion of CD11b+ Gr-1+ myeloid cells compared to wtIDH1 tumors (%MDSC/CD45+: 67.0% vs. 45.06%; P<0.05). Interestingly, CD11b+ Gr-1+ myeloid cells (MDSCs) from mIDH1 tumor expressed lower levels of immunosuppressive markers such as PD-L1 and CD80 which are involved in T-cell checkpoint inhibition. Consistent with this, TME-derived CD11b+ Gr-1+ myeloid cells from mIDH1 tumors didn't inhibit tumor antigen specific T-cells' expansion. Further analysis indicated that mIDH1 MDSCs also express lower levels of maturation markers suggesting that MDSCs from mIDH1 are at earlier maturation/differentiation stage. Interestingly, MDSCs depletion did not improve efficacy of immunotherapy in mIDH1; whilst in wtIDH1 bearing animals, survival increased to 70% when MDSCs depletion was combined with immunotherapy. In conclusion, mIDH1 expression in glioma cells impact the myeloid cells' compartment possibly by changing the cytokine's repertoire secreted by the tumor cells. This leads to reprogramming of myeloid cells within the TME which exhibit a non-immunosuppressive phenotype. 1.

In this paper, we present a tractography paradigm that addresses the challenge of tracking throug... more In this paper, we present a tractography paradigm that addresses the challenge of tracking through edema as well as regions of complex white matter. It involves the fitting of a multi-compartment model to a multi-shell acquisition, with one compartment pertaining to free water that characterizes the edema, and the second compartment, a higher order diffusion model that captures the underlying fiber structure. This is then incorporated into a probabilistic streamline tracking algorithm. This paradigm has been validated using cortical stimulation data acquired on patients. We applied the tracking paradigm to the datasets of the MICCAI Tractography Challenge. As the data comprised four shells, b = 200, 500, 1000 and 3000 s/mm 2 respectively, we were able to successfully fit a two-compartment model to the data that combines edema correction with a fiber orientation distribution (FOD) scheme to create a new higher order diffusion model. We then used this higher order diffusion model for tracking the cortico-spinal tract (CST) in the two patients with brain tumor. The tract was reconstructed using inclusion regions in the cerebral peduncle provided with the Challenge data, as well as regions defining the motor cortex segmented in the two subjects using an atlas. The results of fiber tracking showed that we were able to track through the edema, as well as complex white matter to reconstruct the CST, obtaining not only the main trunk of the CST, but also the lateral fibers to the hand and face regions. The results on the Challenge data were evaluated for anatomical correctness by two neurosurgeons, as well as for overlap with the motor strip provided with the Challenge data.

Late-Breaking Abstracts

Background T lymphocytes reactive to melanoma antigens can cause regression of advanced melanoma ... more Background T lymphocytes reactive to melanoma antigens can cause regression of advanced melanoma and mediate long-term immunologic memory. However, immune control of melanoma depends on the ability of T cells to infiltrate sites of melanoma deposits. The objective of this study was to determine whether 6 synthetic melanoma helper peptides (6MHP) vaccine plus pembrolizumab increased infiltration of vaccineinduced T cells into tumor metastases compared to 6MHP vaccine alone. Methods Patients in Mel64 (NCT02515227) received 6MHP vaccines on days 1/8/15/43/64/85. Pembrolizumab was administered intravenously every three weeks, beginning on day 1. Patients also provided blood samples, and sentinel immunized node (SINs) biopsies if available, at specific time points for immune analyses. Tumor biopsies were collected on days 1 (pre-treatment) and 22. Patients in a prior trial, Mel41 (NCT00089219), served as controls, who received 6MHP vaccines on days 1/8/15/29/36/43. Tumor biopsies were collected pre-vaccination and post-vaccination at time of tumor recurrence (figure ). Across both trials, DNA was extracted from peripheral blood mononuclear cells (PBMCs) pre-treatment, and PBMCs/SINs at time of peak T cell response to 6MHP. These were submitted for high throughput T cell receptor (TCR) sequencing to assess for T cell clonotypes that were significantly increased in number post-treatment or novel clonotypes evident de novo post-treatment. Tumor biopsies were sampled, from which DNA was extracted and submitted for TCR sequencing. These sequences were cross referenced against those in PBMCs/SINs for those that overlapped and were present in tumor post-treatment, but not pre-treatment. Results Patients across both trials (Mel41 n = 5; Mel64 n = 4) had expanded circulating vaccine-induced T lymphocytes in PBMCs/SINs post-treatment compared to pre-treatment (figure ). All patients had novel T cell clonotypes in tumor posttreatment compared to pre-treatment, with Mel64 patients having upward trends of the number of vaccine-induced tumor infiltrating T cell clonotypes compared to Mel41 patients (figure ). The fraction of vaccine-induced tumor infiltrating lymphocytes (VITILs) of total tumor infiltrating lymphocytes (TILs) was significantly increased in Mel64 patients compared to that in Mel41 patients (p = 0.0159) (figure ).

Journal of Clinical Oncology

2015 Background: Glioblastoma (GBM) is associated with a high rate of venous thromboembolism (VTE... more 2015 Background: Glioblastoma (GBM) is associated with a high rate of venous thromboembolism (VTE), but there is little data to guide anticoagulation in GBM patients, in whom the risks of VTE must be balanced against the risk of intracranial hemorrhage (ICH). Methods: We performed a single-institution retrospective cohort study of patients with GBM diagnosed with VTE from 2014-2021 who were treated with low molecular weight heparin (LMWH) or a direct oral anticoagulant (DOAC). The cumulative incidence of ICH was compared between the LMWH and DOAC groups. The primary outcome was clinically relevant ICH within the first 30 days of anticoagulation, defined as any ICH that was fatal, symptomatic, required surgical intervention, and/or led to cessation of anticoagulation. Key secondary outcomes included clinically relevant ICH within 6 months, fatal ICH within 30 days and 6 months, any bleeding within 30 days and 6 months, and recurrent VTE within 6 months. Fisher’s exact test was used f...

Medical Image Computing and Computer Assisted Intervention – MICCAI 2018, 2018

In this work, we propose an edema-informed anatomically constrained tractography paradigm that en... more In this work, we propose an edema-informed anatomically constrained tractography paradigm that enables reconstructing larger spatial extent of white matter bundles as well as increased cortical coverage in the presence of edema. These improvements will help surgeons maximize the extent of the resection while minimizing the risk of cognitive deficits. The new paradigm is based on a segmentation of the brain into gray matter, white matter, corticospinal fluid, edema and tumor regions which utilizes a tumor growth model. Using this segmentation, a valid tracking domain is generated and, in combination with anatomically constrained particle filter tractography, allows streamlines to cross the edema region and reach the cortex. Using subjects with brain tumors, we show that our edema-informed anatomically constrained tractography paradigm increases the cortico-cortical connections that cross edemacontaminated regions when compared to traditional fractional anisotropy thresholded tracking.

Commentary: “Zooming in” on Glioblastoma: Understanding Tumor Heterogeneity and Its Clinical Implications in the Era of Single-Cell Ribonucleic Acid Sequencing

Neurosurgery, 2021

This article has been withdrawn due to an error that caused the article to be duplicated. The def... more This article has been withdrawn due to an error that caused the article to be duplicated. The definitive version of this article is published under DOI 10.1093/neuros/nyab288.

Effect of Vocimagene Amiretrorepvec in Combination With Flucytosine vs Standard of Care on Survival Following Tumor Resection in Patients With Recurrent High-Grade Glioma

JAMA Oncology, 2020

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

Assays examining the open-chromatin landscape in single cells require isolation of the nucleus, r... more Assays examining the open-chromatin landscape in single cells require isolation of the nucleus, resulting in the loss of spatial/microenvironment information. Here we describe CHEX-seq (CHromatin EXposed) for identifying single-stranded open-chromatin DNA regions in paraformaldehyde-fixed single cells. CHEX-seq uses light-activated DNA probes that binds to single-stranded DNA in open chromatin. In situ laser activation of the annealed probes’ 3’-Lightning Terminator™ in selected cells permits the probe to act as a primer for in situ enzymatic copying of single-stranded DNA that is then sequenced. CHEX-seq is benchmarked with human K562 cells and its utility is demonstrated in dispersed primary mouse and human brain cells, and immunostained cells in mouse brain sections. Further, CHEX-seq queries the openness of mitochondrial DNA in single cells. Evaluation of an individual cell’s chromatin landscape in its tissue context enables “spatial chromatin analysis”.One Sentence SummaryA new...

Glioblastoma: Translating Scientific Advances to Innovative Therapy

Glioblastoma, 2016