Steven Brem | University of Pennsylvania (original) (raw)

Papers by Steven Brem

bioRxiv (Cold Spring Harbor Laboratory), May 9, 2023

Visualization of fiber tracts around the tumor is critical for neurosurgical planning and preserv... more Visualization of fiber tracts around the tumor is critical for neurosurgical planning and preservation of crucial structural connectivity during tumor resection. Biophysical modeling approaches estimate fiber tract orientations from differential water diffusivity information of diffusion MRI. However, the presence of edema and tumor infiltration presents a challenge to visualize crossing fiber tracts in the peritumoral region. Previous approaches proposed free water modeling to compensate for the effect of water diffusivity in edema, but those methods were limited in estimating complex crossing fiber tracts. We propose a new cascaded multi-compartment model to estimate tissue microstructure in the presence of edema and pathological contaminants in the area surrounding brain tumors. In our model (COMPARI), the isotropic components of diffusion signal, including free water and hindered water, were eliminated, and the fiber orientation distribution (FOD) of the remaining signal was estimated. In simulated data, COMPARI accurately recovered fiber orientations in the presence of extracellular water. In a dataset of 23 patients with highly edematous brain tumors, the amplitudes of FOD and anisotropic index distribution within the peritumoral region were higher with COMPARI than with a recently proposed multi-compartment constrained deconvolution model. In a selected patient with metastatic brain tumor, we demonstrated COMPARI's ability to effectively model and eliminate water from the peritumoral region. The white matter bundles reconstructed with our model were qualitatively improved compared to those of other models, and allowed the identification of crossing fibers. In conclusion, the removal of isotropic components as proposed with COMPARI improved the bio-physical modeling of dMRI in edema, thus providing information on crossing fibers, thereby enabling improved tractography in a highly edematous brain tumor. This model may improve surgical planning tools to help achieve maximal safe resection of brain tumors. .

Research Square (Research Square), Mar 28, 2023

Treatment e cacy with chimeric antigen receptor (CAR) T cell therapy in glioblastoma (GBM) is und... more Treatment e cacy with chimeric antigen receptor (CAR) T cell therapy in glioblastoma (GBM) is undermined by an immunosuppressive tumor microenvironment (TME). We previously showed that CAR T cell therapy targeting epidermal growth factor receptor variant III (EGFRvIII) produces anti-tumor activity against recurrent GBM and causes upregulation of programmed death-ligand 1 (PD-L1) in the TME. Here, we conducted a phase I trial to study the impact of CART-EGFRvIII cells administered concomitantly with the PD-1 inhibitor pembrolizumab in patients (n = 7) with newly diagnosed, EGFRvIII + GBM. Treatment was well tolerated without incidence of dose-limiting toxicity. However, no signal of e cacy was detected with a median progression-free survival of 5.2 months (90% CI, 2.9-6.0 months) and median overall survival of 11.8 months (90% CI, 9.2-14.2 months). In addition, PD-1 expression in the CART-EGFRvIII infusion product did not correlate with outcomes, and peripheral CAR T cell engraftment was relatively short-lived. Together, these ndings show the safety of combining CAR T cells and PD-1 inhibition in GBM but given the lack of e cacy, also indicate a need to consider alternative combinatorial strategies. ClinicalTrials.gov registration: NCT03726515.

Neuro-oncology, Nov 1, 2018

NEURO-ONCOLOGY • NOVEMBER 2018 tracking. Confounding effects of tumor infiltration and edema resu... more NEURO-ONCOLOGY • NOVEMBER 2018 tracking. Confounding effects of tumor infiltration and edema results in significant discordance between subcortical, intraoperative electrical stimulation (IES) and preoperative fiber track visualization. We hypothesized that tracking in peritumoral zone, which includes vasogenic edema and neoplastic infiltration, could be enhanced by using a bi-compartment diffusion modeling. Due to the known tendency of primary malignant tumors, glioblastoma, to infiltrate surrounding white matter (WM), the bi-compartment model will be validated to distinguish peritumoral tissue in gliomas versus secondary brain tumors (metastases). METHODS: Patients with tumors (88 gliomas and 50 metastates) underwent 30 direction DTI and were fitted with standard tensor and Fernet, a free-water-invariant bi-compartment tensor model. Deterministic tractography was performed on each subject. Five WM tracts (corticospinal tract, inferior fronto-occipital, inferior longitudinal, arcuate and uncinate fasciculi) were extracted bilaterally in each patient using a shape-based clustering algorithm. For each subject, percentage change of edema volume was compared between standard and Fernet tensor models. RESULTS: Fernet-based tractography showed average increase in edema coverage of 87 +/-25% (t=6.9, p CONCLUSIONS: Results show fiber tractography in peritumoral region is significantly improved with better diffusion modeling of peritumoral tissue microstructure. Additionally, difference in tracking between metastases and glioblastomas is representative of tracking being affected differentially due to infiltration in peritumoral regions. CLINICAL IMPLICATIONS: Our peritumoral tissue modeling incorporates edema and infiltration, leading to superior tracking, and hence robust surgical planning. In future, the peritumoral tissue maps could be used to elucidate differences in radiological diagnosis, surgical risk stratification, response to therapy, tumor invasion and tumor genetics, and neuroplasticity.

Neuro-oncology, Nov 1, 2020

pathology-proven, amphetamine-associated CNS vasculitis resembling a tumor. A 41-year-old man pre... more pathology-proven, amphetamine-associated CNS vasculitis resembling a tumor. A 41-year-old man presented with six weeks of progressive confusion and left-sided weakness. CT head reported a right thalamic mass with vasogenic edema. Laboratory tests were unremarkable except for cannabinoids and amphetamine in urine. MRI brain showed enhancement in right frontotemporal lobe, basal ganglia, and thalamus concerning for glioblastoma multiforme. After high-dose IV dexamethasone, an initial biopsy showed reactive gliosis, perivascular lymphocytic cuffing by CD3+, rare CD20+ cells and no infection. He continued to decline. MRI 22 days after admission showed increased T2/FLAIR hyperintensity, multifocal areas of enhancement, microhemorrhages, and ischemia. High-grade glioma, lymphoma and infectious encephalitis remained on differentials. Treatment included broad-spectrum antibiotics and acyclovir. Biopsy on 23rd day showed reactive gliosis with parenchymal macrophage infiltration and perivascular cuffing with mixed inflammatory infiltrates. CSF: slightly elevated WBCs (8/µL), elevated protein (139mg/dL), normal glucose, and no infection. MRI whole spine and CT body were unremarkable. The patient was transferred to MDACC 5.5 weeks after initial presentation. He was alert with expressive aphasia, right gaze preference, left hemiplegia, and right hemiparesis. He underwent a right anterior temporal lobectomy. Pathology showed extensive cortical laminar and white matter necrosis with macrophage infiltration and microglial activation. In areas of the preserved cortex, vasculocentric lymphocytic aggregates were present and reticulin staining showed lymphocytic infiltration of the vascular walls. Immunophenotyping (CD3, CD20) showed an almost pure T-cell population. The predominance of intramural T-lymphocytes reflected a vasculitic process. The final diagnosis was cerebral vasculitis with subacute infarction. The patient died six days later. The autopsy findings were identical to the previous resection without evidence of systemic inflammation.

Expert Opinion on Drug Delivery, Jun 11, 2013

Introduction-Brain tumors are inherently difficult to treat in large part due to the cellular blo... more Introduction-Brain tumors are inherently difficult to treat in large part due to the cellular blood-brain barriers (BBB) that limit the delivery of therapeutics to the tumor tissue from the systemic circulation. Virtually no large-molecules, including antibody-based proteins, can penetrate the BBB. With antibodies fast becoming attractive ligands for highly specific molecular targeting to tumor antigens, a variety of methods are being investigated to enhance the access of these agents to intracranial tumors for imaging or therapeutic applications. Areas covered-This review describes the characteristics of the BBB and the vasculature in brain tumors, described as the blood-brain tumor barrier (BBTB). Antibodies targeted to molecular markers of CNS tumors will be highlighted, and current strategies for enhancing the delivery of antibodies across these cellular barriers into the brain parenchyma to the tumor will be discussed. Non-invasive imaging approaches to assess BBB/BBTB permeability and/or antibody targeting will be presented as a means of guiding the optimal delivery of targeted agents to brain tumors. Expert Opinion-Pre-clinical and clinical studies highlight the potential of several approaches in increasing brain tumor delivery across the blood-brain barrier divide. However, each carries its own risks and challenges. There is tremendous potential in using neuroimaging strategies to assist in understanding and defining the challenges to translating and optimizing molecularly-targeted antibody delivery to CNS tumors to improve clinical outcomes.

Neuro-oncology, Nov 1, 2018

NEURO-ONCOLOGY • NOVEMBER 2018 based algorithm to assess for possible glioma and to assign grade.... more NEURO-ONCOLOGY • NOVEMBER 2018 based algorithm to assess for possible glioma and to assign grade. EGFRviii and IDH1 mutations were also analyzed and compared to molecular testing from tumor specimens. RESULTS: 97.5% (39 of 40) of glioma patients were deemed to have gliomas by plasma testing. 96% of HGG patients and 67% of the LGG patients were correctly graded. Of the 10 healthy controls, 8 were concluded to be cancer-free. Two of the patients were suspicious for malignancy, of which one was possible glioma. IDH1 and EGFRviii mutation had concordance at 74 % (26/35) and 59% (12/16), respectively. CONCLUSIONS: Analysis of plasma cell free tumor derived DNA and RNA was highly sensitive for detecting glioma with high agreement in grading as well. In patients with newly diagnosed intracerebral lesions, this may be a useful screening test to determine the need for more invasive testing, i.e. biopsy/ resection. Further testing in blinded samples from brain tumor patients and healthy subjects will follow.

Nature Communications, Aug 27, 2018

Angiogenesis is a hallmark of cancer. However, most malignant solid tumors exhibit robust resista... more Angiogenesis is a hallmark of cancer. However, most malignant solid tumors exhibit robust resistance to current anti-angiogenic therapies that primarily target VEGF pathways. Here we report that endothelial-mesenchymal transformation induces glioblastoma (GBM) resistance to anti-angiogenic therapy by downregulating VEGFR-2 expression in tumor-associated endothelial cells (ECs). We show that VEGFR-2 expression is markedly reduced in human and mouse GBM ECs. Transcriptome analysis verifies reduced VEGFR-2 expression in ECs under GBM conditions and shows increased mesenchymal gene expression in these cells. Furthermore, we identify a PDGF/NF-κB/Snail axis that induces mesenchymal transformation and reduces VEGFR-2 expression in ECs. Finally, dual inhibition of VEGFR and PDGFR eliminates tumor-associated ECs and improves animal survival in GBM-bearing mice. Notably, EC-specific knockout of PDGFR-β sensitizes tumors to VEGF-neutralizing treatment. These findings reveal an endothelial plasticity-mediated mechanism that controls antiangiogenic therapy resistance, and suggest that vascular de-transformation may offer promising opportunities for anti-vascular therapy in cancer.

Neuro-oncology, Nov 1, 2020

tumor-bearing mice had an increase in circulating granulocytic MDSC (gMDSC) frequency, and a high... more tumor-bearing mice had an increase in circulating granulocytic MDSC (gMDSC) frequency, and a high gMDSC gene signature correlated with worse outcome of female patients. However, the mechanisms underlying sexual dimorphism of MDSC heterogeneity remain understudied and can provide insights for improved immunotherapy response. Using syngeneic mouse glioma models and sequencing approaches, we show that expression of Y-chromosome-linked genes correlates with upregulation of multiple RNA transcription-related pathways specifically in male mMDSCs. Consistently, adoptive transfer of male mMDSCs but not gMDSCs worsened GBM outcome in male recipients, while the transfer of sex-matched mMDSCs did not impact survival of female mice. In contrast to this cell-intrinsic regulatory pathway, sex steroids had no impact on MDSC profile, as castration or ovariectomy failed to alter MDSC subset accumulation patterns in GBMbearing mice. Correspondingly, IL-1β, which we had identified as a femalespecific drug target, was highly expressed in female but not male gMDSCs. Single-cell sequencing revealed that circulating but not tumor-infiltrating gMDSCs were the primary source of IL-1β and that its neutralization provided a female-specific survival advantage by reducing circulating gMDSCs. This was accompanied by declines in tumor infiltration of microglia, microglia activation status and tumor cell proliferation. In vitro, IL-1β inhibition reduced viability and expression of activation markers by primary microglia. These findings highlight a peripheral gMDSC-microglia communication axis mediated by IL-1β signaling in females with GBM and indicate that expression differences in MDSC subsets represent opportunities for improved immunotherapy efficacy while accounting for sex as a biological variable.

Journal of clinical and translational science, Jun 1, 2018

This study aims to determine if pembrolizumab therapy can lead to a radiologic, cytologic or clin... more This study aims to determine if pembrolizumab therapy can lead to a radiologic, cytologic or clinical response in the CNS, in patients with LMD. METHODS/STUDY POPULATION: Patients with pathologically confirmed advanced solid tumors, and either radiologic or cytologic evidence of LMD, will be identified at a single institution. Radiologic LMD will be defined as a >4 mm area of measurable LMD on gadolinium-enhanced MRI brain/total-spine; and cytologic LMD will be defined as the presence of malignant cells on CSF cytology. Patients will be excluded if they have: active autoimmune conditions that require immunosuppression, received radiation therapy to the only area of measurable LMD within 3 months of study enrollment, have an ECOG performance status <1. Once enrolled, patients will receive pembrolizumab 200 mg intravenously every 3-weeks, until disease progression or unacceptable toxicity. Patients will have CSF sample sampling, blood draws, radiologic imaging of the body (CT), brain/total-spine (gadolinium-enhanced MRI) pre-treatment, after 2 and after 4 cycles of therapy, for response assessment and correlative studies. The primary endpoint of the study is CNS response assessed at 12 weeks/ after 4 cycles of pembrolizumab, defined either as radiologic response (reduction in size of LMD on gadolinium-enhanced MRI) and/or cytologic response (conversion of positive to negative CSF cytology on 2 consecutive samples) and/or clinical response. Secondary endpoints will include progression-free survival, overall survival, and safety. To explore the mechanisms by which pembrolizumab may affect LMD, we will assess dynamic changes in genomic and immunologic markers in the CSF and serum pre and post pembrolizumab using next-generation sequencing and multi-color flow cytometry, respectively. RESULTS/ANTICIPATED RESULTS: We will aim to accrue a total of 20 patients, allowing for a 10% drop-out rate, the final sample size will include 18 patients who have received at least 1 dose of pembrolizumab. CNS-response at 12 weeks will be assessed radiologically + / − cytologically, and the proportion of patients with CNS response and associated 95% confidence interval with be reported. CNS-progression-free survival and overall survival will be assessed using the Kaplan-Meier method. Cause of death will be recorded. Safety will be assessed as detailed above, and monitored as per an institutional Data Safety and Monitoring Plan. Exploratory endpoints will include genomic testing of tumor cells and cell-free DNA in CSF and serum, and immunologic studies of immune cells in CSF and serum at pre-defined timepoints. These data will be presented descriptively. We conservatively estimate that we will accrue 1 patient per month at our institution. Study duration will be approximately 24 months, allowing 18 months for accrual and 6 months for follow-up and data analysis. DISCUSSION/SIGNIFICANCE OF IMPACT: There are no currently FDA-approved therapies for patients with LMD from solid tumors. Anti-PD-1 immunotherapy is a promising class of agents, with known efficacy in patients with CNS metastatic disease, across tumor types. This study seeks to identify whether pembrolizumab may lead to CNS responses in patients with LMD. Additionally, genomic and immunologic analyses in CSF and blood pre and post-pembrolizumab may identify mechanisms by which immunotherapy affects the CNS in patients with LMD.

Neuro-oncology, Nov 1, 2022

and pseudoprogression rates were similar in both arms. Exploring the hypothesis of undetected pse... more and pseudoprogression rates were similar in both arms. Exploring the hypothesis of undetected pseudoprogressions being accountable for this discrepancy, we analyzed patterns of postprogression survival (PPS) and MRI features at RANO-defined progression. METHODS: 86 CeTeG/ NOA-09 patients with progression (modified RANO criteria) and MRI evaluable for standardized T1 and FLAIR volumetry at baseline and progression were included. Patients were further subdivided to short PPS (< 24 months) or long PPS (> 24 months) and a PPS/PFS ratio was calculated. RESULTS: In the CCNU/TMZ arm, long PPS patients (n=10) tended to a shorter PFS (median 7.3 months) than short PPS patients in the same arm (n=33, 14 months, p=0.089, logrank test) and long PPS patients in the TMZ arm (n=9, 12.7 months, p=0.21). The mean PPS/PFS ratio in the long PPS group was markedly higher in the CCNU/TMZ arm (5.8) compared to the TMZ arm (3.3, p=0.043, Mann-Whitney test). Patients with long PPS of the CCNU/TMZ arm showed a nonsignificant tendency to a stronger volumetric increase in T1 enhancement (mean delta 6184,86 vs. 697.5 mm ³) and FLAIR-T1-enhancement (mean delta 42671 vs 16860 mm ³) at progression as compared to long PPS patients of the TMZ arm. CONCLUSION: Combining a substantially increased PPS/PFS ratio (long OS despite particularly short PFS according to RANO) with indications for increased contrast enhancement and FLAIR volume at progression, the patients with long PPS in the CCNU/TMZ arm appear to differ from those in the TMZ arm. These observations support the hypothesis that this group (~25% of CCNU/TMZtreated patients) contained patients with pseudoprogression undetected by modified RANO criteria.

Scientific Reports, Jul 22, 2021

Glioblastoma (GBM) has high metabolic demands, which can lead to acidification of the tumor micro... more Glioblastoma (GBM) has high metabolic demands, which can lead to acidification of the tumor microenvironment. We hypothesize that a machine learning model built on temporal principal component analysis (PCA) of dynamic susceptibility contrast-enhanced (DSC) perfusion MRI can be used to estimate tumor acidity in GBM, as estimated by pH-sensitive amine chemical exchange saturation transfer echo-planar imaging (CEST-EPI). We analyzed 78 MRI scans in 32 treatment naïve and post-treatment GBM patients. All patients were imaged with DSC-MRI, and pH-weighting that was quantified from CEST-EPI estimation of the magnetization transfer ratio asymmetry (MTR asym) at 3 ppm. Enhancing tumor (ET), non-enhancing core (NC), and peritumoral T2 hyperintensity (namely, edema, ED) were used to extract principal components (PCs) and to build support vector machines regression (SVR) models to predict MTR asym values using PCs. Our predicted map correlated with MTR asym values with Spearman's r equal to 0.66, 0.47, 0.67, 0.71, in NC, ET, ED, and overall, respectively (p < 0.006). The results of this study demonstrates that PCA analysis of DSC imaging data can provide information about tumor pH in GBM patients, with the strongest association within the peritumoral regions. Glioblastoma (GBM) is the most common malignant primary brain tumor in adults, characterized with vasular proliferation, diffuse infiltration in the adjacent brain parenchyma, and resistance to the standard therapies 1. The tumor microenvironment plays an important role in abundant infiltration of GBM tumor cells, its resistance to standard therapies, recurrence and therefore, poor patient prognosis 2. Due to rapid growth of GBM tumors and actively migrating cell population, hypercellular regions are formed typically surrounding the necrotic foci tissues and have a high metabolic demand 3. When the tumor grows, the lack of sufficient circulation compared to the cell population of the tumor results in ischemia and secretion of angiogenic factors, which in turn leads to proliferation of new vessels 4 .

The Journal of Neuroscience, Aug 25, 2010

Alzheimer's disease (AD) is the most common form of dementia among the aging population and is ch... more Alzheimer's disease (AD) is the most common form of dementia among the aging population and is characterized pathologically by the progressive intracerebral accumulation of ␤-amyloid (A␤) peptides and neurofibrillary tangles. The level of proangiogenic growth factors and inflammatory mediators with proangiogenic activity is known to be elevated in AD brains which has led to the supposition that the cerebrovasculature of AD patients is in a proangiogenic state. However, angiogenesis depends on the balance between proangiogenic and antiangiogenic factors and the brains of AD patients also show an accumulation of endostatin and A␤ peptides which have been shown to be antiangiogenic. To determine whether angiogenesis is compromised in the brains of two transgenic mouse models of AD overproducing A␤ peptides (Tg APPsw and Tg PS1/APPsw mice), we assessed the growth and vascularization of orthotopically implanted murine gliomas since they require a high degree of angiogenesis to sustain their growth. Our data reveal that intracranial tumor growth and angiogenesis is significantly reduced in Tg APPsw and Tg PS1/APPsw mice compared with their wild-type littermates. In addition, we show that A␤ inhibits the angiogenesis stimulated by glioma cells when cocultured with human brain microvascular cells on a Matrigel layer. Altogether our data suggest that the brain of transgenic mouse models of AD does not constitute a favorable environment to support neoangiogenesis and may explain why vascular insults synergistically precipitate the cognitive presentation of AD.

CNS oncology, Nov 1, 2019

• EGFR mutations are among the most common genetic alterations in glioblastoma (GBM). • Targeted ... more • EGFR mutations are among the most common genetic alterations in glioblastoma (GBM). • Targeted therapies against EGFR have been unsuccessful in GBM due to tumor heterogeneity, poor brain penetration of most targeted therapies and inadequate enrichment for EGFR alterations in prior targeted therapy clinical trials for GBM. • Osimertinib is a highly brain-penetrant EGFR tyrosine kinase inhibitor that is approved for EGFR-mutant non-small-cell lung cancer. • We present a case of a patient with multifocal GBM harboring multiple EGFR mutations that experienced a complete response to osimertinib in one of the patient's tumor sites. • The patient ultimately progressed at a separate tumor site, highlighting tumor heterogeneity as a significant challenge to EGFR-targeted therapies in GBM. • This case report underscores the need for further clinical evaluation of osimertinib in GBM, including identification of which EGFR alterations are predictive of response to this drug. Glioblastoma(GBM) is the most common primary malignant brain tumor in adults and carries a dismal prognosis. The EGFR gene is among the most commonly deranged genes in GBM and thus an important therapeutic target. We report the case of a young female with heavily pretreated EGFR-mutated GBM, for whom we initiated osimertinib, an oral, third-generation tyrosine kinase inhibitor that irreversibly inhibits EGFR and has significant brain penetration. We then review some of the main challenges in targeting EGFR, including lack of central nervous system penetration with most tyrosine kinase inhibitors, molecular heterogeneity of GBM and the need for enhanced specificity for the EGFR mutations relevant in GBM.

Neuro-oncology, Nov 1, 2022

November 00 oped a workflow for annotation of images and development of volumetric segmentations ... more November 00 oped a workflow for annotation of images and development of volumetric segmentations in neuroradiology clinical workflow. Material: 1990 patients from Yale Radiation Oncology Registry (2012-2019) were identified. Segmentations were performed using a UNETR algorithm trained on BRaTS 2021 and an internal dataset of manually segmented tumors. Segmentations were validated by a board-certified neuro-radiologist and natively embedded PyRadiomics in PACS was used for feature extraction. RESULTS: In 7 Months (05/2021-08/2021, 03/2022-05/2022) segmentations and annotations were performed in 835 patients (322 female, 467 male, 46 unknown, mean age 53 yrs). Dataset includes 275 Grade 4 Gliomas (54 Grade 3, 100 Grade 2, 31 Grade 1, 375 unknown). Molecular subtypes include IDH (113 mutated, 498 wildtype, 2 Equivocal, 222 unknown), 1p/19q (87 deleted or co-deleted, 122 intact, 626 unknown), MGMT promotor (182 methylated, 95 partially methylated, 275 unmethylated, 283 unknown), EGFR (76 amplified, 177 not amplified, 582 unknown), ATRX (40 mutated, 157 retained, 638 unknown), Ki-67 (616 known, 219 unknown) and p53 (549 known, 286 unknown). Classification of gliomas between grade 3/4 and grade 1/2, yielded AUC of 0.85. CONCLUSION: We developed a method for incorporation of volumetric segmentation, feature extraction, and classification that is easily incorporated into neuroradiology workflow. These tools allowed us to annotate over 100 gliomas per month, thus establishing a proof of concept for rapid development of annotated imaging database for AI applications.

Neuro-oncology, Nov 1, 2022

detailed lesion delineation, while neuronavigation often overestimated lesion size. CONCLUSION: A... more detailed lesion delineation, while neuronavigation often overestimated lesion size. CONCLUSION: Augmented reality provides a faster and more accurate alternative for resection planning. Lesion delineation was more intuitive while retaining high accuracy. Future research should focus on further intraoperative implementations.

Journal of The National Comprehensive Cancer Network, 2023

In support of improving patient care, National Comprehensive Cancer Network (NCCN) is jointly acc... more In support of improving patient care, National Comprehensive Cancer Network (NCCN) is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team. Physicians: NCCN designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit TM. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Nurses: NCCN designates this educational activity for a maximum of 1.0 contact hour. Pharmacists: NCCN designates this knowledge-based continuing education activity for 1.0 contact hour (0.1 CEUs) of continuing education credit. UAN: JA4008196-0000-23-001-H01-P PAs: NCCN has been authorized by the American Academy of PAs (AAPA) to award AAPA Category 1 CME credit for activities planned in accordance with AAPA CME Criteria. This activity is designated for 1.0 AAPA Category 1 CME credit. Approval is valid until January 10, 2024. PAs should only claim credit commensurate with the extent of their participation. All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: (1) review the educational content; (2) take the posttest with a 66% minimum passing score and complete the evaluation at https://education. nccn.org/node/92887; and (3) view/print certificate. Pharmacists: You must complete the posttest and evaluation within 30 days of the activity. Continuing pharmacy education credit is reported to the CPE Monitor once you have completed the posttest and evaluation and claimed your credits. Before completing these requirements, be sure your NCCN profile has been updated with your NAPB e-profile ID and date of birth. Your credit cannot be reported without this information. If you have any questions, please email

Neuro-oncology, Nov 1, 2019

Carolina Digital Repository (University of North Carolina at Chapel Hill), 2013

BACKGROUND: Neurosurgical resection and whole-brain radiation therapy (WBRT) are accepted treatme... more BACKGROUND: Neurosurgical resection and whole-brain radiation therapy (WBRT) are accepted treatments for single and oligometastatic cancer to the brain. To avoid the decline in neurocognitive function (NCF) linked to WBRT, the authors conducted a prospective, multicenter, phase 2 study to determine whether surgery and carmustine wafers (CW), while deferring WBRT, could preserve NCF and achieve local control (LC). METHODS: NCF and LC were measured in 59 patients who underwent resection and received CW for a single (83%) or dominant (oligometastatic, 2 to 3 lesions) metastasis and received stereotactic radiosurgery (SRS) for tiny nodules not treated with resection plus CW. Preservation of NCF was defined as an improvement or a decline 1 standard deviation from baseline in 3 domains: memory, executive function, and fine motor skills, evaluated at 2-month intervals. RESULTS: Significant improvements in executive function and memory occurred throughout the 1-year follow-up. Preservation or improvement of NCF occurred in all 3 domains for the majority of patients at each of the 2-month intervals. NCF declined in only 1 patient. The chemowafers were well tolerated, and serious adverse events were reversible. There was local recurrence in 28% of the patients at 1-year follow-up. CONCLUSIONS: Patients with brain metastases had improvements in their cognitive trajectory, especially memory and executive function, after treatment with resection plus CW. The rate of LC (78%) was comparable to historic rates of surgery with WBRT and superior to reports of WBRT alone. For patients who undergo resection for symptomatic or large-volume metastasis or for tissue diagnosis, the addition of CW can be considered as an option.

Scientific Reports, Jul 14, 2021

water volume fraction map (FW-VF), and free water corrected fractional anisotropy (FW-FA), axial ... more water volume fraction map (FW-VF), and free water corrected fractional anisotropy (FW-FA), axial diffusivity (FW-AX) and radial diffusivity (FW-RAD), for every patient from their pre-processed dMRI data 28 .

Scientific Reports, May 24, 2022

Multi-omic data, i.e., clinical measures, radiomic, and genetic data, capture multi-faceted tumor... more Multi-omic data, i.e., clinical measures, radiomic, and genetic data, capture multi-faceted tumor characteristics, contributing to a comprehensive patient risk assessment. Here, we investigate the additive value and independent reproducibility of integrated diagnostics in prediction of overall survival (OS) in isocitrate dehydrogenase (IDH)-wildtype GBM patients, by combining conventional and deep learning methods. Conventional radiomics and deep learning features were extracted from pre-operative multi-parametric MRI of 516 GBM patients. Support vector machine (SVM) classifiers were trained on the radiomic features in the discovery cohort (n = 404) to categorize patient groups of high-risk (OS < 6 months) vs all, and low-risk (OS ≥ 18 months) vs all. The trained radiomic model was independently tested in the replication cohort (n = 112) and a patient-wise survival prediction index was produced. Multivariate Cox-PH models were generated for the replication cohort, first based on clinical measures solely, and then by layering on radiomics and molecular information. Evaluation of the high-risk and low-risk classifiers in the discovery/replication cohorts revealed area under the ROC curves (AUCs) of 0.78 (95% CI 0.70-0.85)/0.75 (95% CI 0.64-0.79) and 0.75 (95% CI 0.65-0.84)/0.63 (95% CI 0.52-0.71), respectively. Cox-PH modeling showed a concordance index of 0.65 (95% CI 0.6-0.7) for clinical data improving to 0.75 (95% CI 0.72-0.79) for the combination of all omics. This study signifies the value of integrated diagnostics for improved prediction of OS in GBM. Glioblastoma (GBM) is the most common and aggressive primary brain neoplasm in adults with a dismal prognosis. Standard treatment consists of maximal safe surgical resection followed by radiation therapy concomitant with temozolomide (TMZ) chemotherapy, which yields a median overall survival (OS) of 14.6-16.7 months 1. While GBM is nearly always fatal, there is overwhelming evidence that the prognosis of patients with GBM

bioRxiv (Cold Spring Harbor Laboratory), May 9, 2023

Research Square (Research Square), Mar 28, 2023

Neuro-oncology, Nov 1, 2018

Neuro-oncology, Nov 1, 2020

Expert Opinion on Drug Delivery, Jun 11, 2013

Neuro-oncology, Nov 1, 2018

Nature Communications, Aug 27, 2018

Neuro-oncology, Nov 1, 2020

Journal of clinical and translational science, Jun 1, 2018

Neuro-oncology, Nov 1, 2022

Scientific Reports, Jul 22, 2021

The Journal of Neuroscience, Aug 25, 2010

CNS oncology, Nov 1, 2019

Neuro-oncology, Nov 1, 2022

Journal of The National Comprehensive Cancer Network, 2023

Neuro-oncology, Nov 1, 2019

Carolina Digital Repository (University of North Carolina at Chapel Hill), 2013

Scientific Reports, Jul 14, 2021

Scientific Reports, May 24, 2022