Reena Thomas, MD PhD

All Publications

• Underrepresented in Medicine Trainees' Sense of Belonging and Professional Identity Formation after Participation in the Leadership Education in Advancing Diversity Program. Academic pediatrics Yemane, L., Powell, C., Edwards, J., Shumba, T., Alvarez, A., Bandstra, B., Brooks, M., Brown-Johnson, C., Caceres, W., Dunn, T., Johnson, C., Perez, F. D., Reece-Nguyen, T., Thomas, R. P., Watkins, A. C., Blankenburg, R. 2024

  Abstract

  There are persistent structural barriers that threaten inclusion and retention of underrepresented in medicine (UIM) residents and fellows (trainees) as future faculty in academic medicine. We developed the Leadership Education in Advancing Diversity (LEAD) Program at a single, academic institution, to address these barriers through a 10-month longitudinal curriculum across GME for trainees to develop leadership and scholarship skills in DEI.Explore how participation in LEAD impacted UIM trainees' sense of belonging and professional identity formation in academic medicine; as well as perceptions about pursuing a career in academic medicine and future leadership roles.IRB-approved qualitative study in August 2020-August 2021 with individual, semi-structured interviews of UIM LEAD graduates from the first 4 cohorts (2017-2021). Data were analyzed by two authors using modified grounded theory.14 UIM trainees were interviewed; seven themes emerged. Critical aspects of the program: (1) Creation of a community of shared DEI values (2) Mentorship (3) Role of allies. Results of the program: (4) Deepened appreciation of personal and professional identity as UIM (5) Fostered belonging in academic medicine (6) Appreciation of different careers in academic medicine and how to integrate DEI interests (7) Inspired trainees to pursue leadership roles.LEAD can serve as a model for other institutions that seek to support UIM trainees' sense of belonging, professional identity formation, and perceptions about pursuing careers in academic medicine and future leadership roles.

  View details for DOI 10.1016/j.acap.2024.08.003

  View details for PubMedID 39117029

• Extraction of Unstructured Electronic Health Records to Evaluate Glioblastoma Treatment Patterns. JCO clinical cancer informatics Swaminathan, A., Ren, A. L., Wu, J. Y., Bhargava-Shah, A., Lopez, I., Srivastava, U., Alexopoulos, V., Pizzitola, R., Bui, B., Alkhani, L., Lee, S., Mohit, N., Seo, N., Macedo, N., Cheng, W., Wang, W., Tran, E., Thomas, R., Gevaert, O. 2024; 8: e2300091

  Abstract

  Data on lines of therapy (LOTs) for cancer treatment are important for clinical oncology research, but LOTs are not explicitly recorded in electronic health records (EHRs). We present an efficient approach for clinical data abstraction and a flexible algorithm to derive LOTs from EHR-based medication data on patients with glioblastoma multiforme (GBM).Nonclinicians were trained to abstract the diagnosis of GBM from EHRs, and their accuracy was compared with abstraction performed by clinicians. The resulting data were used to build a cohort of patients with confirmed GBM diagnosis. An algorithm was developed to derive LOTs using structured medication data, accounting for the addition and discontinuation of therapies and drug class. Descriptive statistics were calculated and time-to-next-treatment (TTNT) analysis was performed using the Kaplan-Meier method.Treating clinicians as the gold standard, nonclinicians abstracted GBM diagnosis with a sensitivity of 0.98, specificity 1.00, positive predictive value 1.00, and negative predictive value 0.90, suggesting that nonclinician abstraction of GBM diagnosis was comparable with clinician abstraction. Of 693 patients with a confirmed diagnosis of GBM, 246 patients contained structured information about the types of medications received. Of them, 165 (67.1%) received a first-line therapy (1L) of temozolomide, and the median TTNT from the start of 1L was 179 days.We described a workflow for extracting diagnosis of GBM and LOT from EHR data that combines nonclinician abstraction with algorithmic processing, demonstrating comparable accuracy with clinician abstraction and highlighting the potential for scalable and efficient EHR-based oncology research.

  View details for DOI 10.1200/CCI.23.00091

  View details for PubMedID 38857465

• A phase II study of plerixafor combined with whole brain radiation therapy (WBRT) for patients with newly diagnosed glioblastoma Cao, T., Gu, Y., Yagmurlu, B., Yerraballa, H., Bertrand, S., Naya, L., Miller, K., Iv, M., Soltys, S. G., Patel, C. B., Nagpal, S., Thomas, R., Brown, M., Recht, L. LIPPINCOTT WILLIAMS & WILKINS. 2024

  View details for Web of Science ID 001275557400433

• Tumor treating fields increases blood-brain barrier permeability and relative cerebral blood volume in patients with glioblastoma. The neuroradiology journal Iv, M., Naya, L., Sanan, S., Van Buskirk, S. L., Nagpal, S., Thomas, R. P., Recht, L. D., Patel, C. B. 2023: 19714009231207083

  Abstract

  200 kHz tumor treating fields (TTFields) is clinically approved for newly-diagnosed glioblastoma (nGBM). Because its effects on conventional surveillance MRI brain scans are equivocal, we investigated its effects on perfusion MRI (pMRI) brain scans.Each patient underwent institutional standard pMRI: dynamic contrast-enhanced (DCE) and dynamic susceptibility contrast (DSC) pMRI at three time points: baseline, 2-, and 6-months on-adjuvant therapy. At each timepoint, the difference between T1 pre- versus post-contrast tumor volume (ΔT1) and these pMRI metrics were evaluated: normalized and standardized relative cerebral blood volume (nRCBV, sRCBV); fractional plasma volume (Vp), volume of extravascular extracellular space (EES) per volume of tissue (Ve), blood-brain barrier (BBB) permeability (Ktrans), and time constant for gadolinium reflux from EES back into the vascular system (Kep). Between-group comparisons were performed using rank-sum analysis, and bootstrapping evaluated likely reproducibility of the results.Among 13 pMRI datasets (11 nGBM, 2 recurrent GBM), therapies included temozolomide-only (n = 9) and temozolomide + TTFields (n = 4). No significant differences were found in patient or tumor characteristics. Compared to temozolomide-only, temozolomide + TTFields did not significantly affect the percent-change in pMRI metrics from baseline to 2 months. But during the 2- to 6-month period, temozolomide + TTFields significantly increased the percent-change in nRCBV (+26.9% [interquartile range 55.1%] vs -39.1% [37.0%], p = 0.049), sRCBV (+9.5% [39.7%] vs -30.5% [39.4%], p = 0.049), Ktrans (+54.6% [1768.4%] vs -26.9% [61.2%], p = 0.024), Ve (+111.0% [518.1%] vs -13.0% [22.5%], p = 0.048), and Vp (+98.8% [2172.4%] vs -24.6% [53.3%], p = 0.024) compared to temozolomide-only.Using pMRI, we provide initial in-human validation of pre-clinical studies regarding the effects of TTFields on tumor blood volume and BBB permeability in GBM.

  View details for DOI 10.1177/19714009231207083

  View details for PubMedID 37931176

• Selective prediction for extracting unstructured clinical data. Journal of the American Medical Informatics Association : JAMIA Swaminathan, A., Lopez, I., Wang, W., Srivastava, U., Tran, E., Bhargava-Shah, A., Wu, J. Y., Ren, A. L., Caoili, K., Bui, B., Alkhani, L., Lee, S., Mohit, N., Seo, N., Macedo, N., Cheng, W., Liu, C., Thomas, R., Chen, J. H., Gevaert, O. 2023

  Abstract

  While there are currently approaches to handle unstructured clinical data, such as manual abstraction and structured proxy variables, these methods may be time-consuming, not scalable, and imprecise. This article aims to determine whether selective prediction, which gives a model the option to abstain from generating a prediction, can improve the accuracy and efficiency of unstructured clinical data abstraction.We trained selective classifiers (logistic regression, random forest, support vector machine) to extract 5 variables from clinical notes: depression (n = 1563), glioblastoma (GBM, n = 659), rectal adenocarcinoma (DRA, n = 601), and abdominoperineal resection (APR, n = 601) and low anterior resection (LAR, n = 601) of adenocarcinoma. We varied the cost of false positives (FP), false negatives (FN), and abstained notes and measured total misclassification cost.The depression selective classifiers abstained on anywhere from 0% to 97% of notes, and the change in total misclassification cost ranged from -58% to 9%. Selective classifiers abstained on 5%-43% of notes across the GBM and colorectal cancer models. The GBM selective classifier abstained on 43% of notes, which led to improvements in sensitivity (0.94 to 0.96), specificity (0.79 to 0.96), PPV (0.89 to 0.98), and NPV (0.88 to 0.91) when compared to a non-selective classifier and when compared to structured proxy variables.We showed that selective classifiers outperformed both non-selective classifiers and structured proxy variables for extracting data from unstructured clinical notes.Selective prediction should be considered when abstaining is preferable to making an incorrect prediction.

  View details for DOI 10.1093/jamia/ocad182

  View details for PubMedID 37769323

• Patterns of Progression in Patients with Newly Diagnosed Glioblastoma Treated with 5 mm Margins on a Phase I/II Trial of 5 Fraction Stereotactic Radiosurgery with Concurrent and Adjuvant Temozolomide. Practical radiation oncology Mendoza, M. G., Azoulay, M., Chang, S. D., Gibbs, I. C., Hancock, S. L., Pollom, E. L., Adler, J. R., Harraher, C., Li, G., Gephart, M. H., Nagpal, S., Thomas, R. P., Recht, L. D., Jacobs, L. R., Modlin, L. A., Wynne, J., Seiger, K., Fujimoto, D., Usoz, M., von Eyben, R., Choi, C. Y., Soltys, S. G. 2023

  Abstract

  BACKGROUND: In patients with newly diagnosed glioblastoma (GBM), tumor margins of at least 20 mm are the standard of care. We sought to determine the pattern of tumor progression in patients treated with 5 fraction stereotactic radiosurgery (SRS) with 5 mm margins.METHODS: Thirty adult patients with newly diagnosed GBM were treated with 5 fraction SRS in escalated doses from 25 Gy to 40 Gy with a 5 mm total treatment margin. Progression was scored as 'in-field' if the recurrent tumor was within or contiguous with the 5 mm margin, 'marginal' if between 5 and 20 mm, and 'distant' if entirely occurring greater than 20 mm. As geometric patterns of progression do not reflect the biologic dose received, we calculated the minimum equieffective dose in 2 Gy per day (EQD2) at the site of tumor recurrence. Progression was 'dosimetrically in-field' if covered by a minimum EQD2 of 48 Gy10.RESULTS: From 2010 to 2016, 27 patients had progressed. Progression was in-field in 17 (63%), marginal in 3 (11%) and distant in 7 (26%) patients. In the 3 patients with marginal progression, the minimum EQD2 to recurrent tumor were 48 Gy10, 56 Gy10 (both considered dosimetrically in-field) and 7 Gy10 (i.e., dosimetrically out-of-field). Median overall survival (OS) was 12.1 months for in-field (95%CI 8.9-17.6), 15.1 months (95%CI 10.1-not achieved) for marginal and 21.4 months (95%CI 11.2-33.5) for distant progression. Patients with radiation necrosis were less likely to have in-field progression (1 of 7; 14%) compared to those without radiation necrosis (16 of 20; 80%; p = 0.003); those with necrosis had a median overall survival of 27.2 months (95%CI 11.2-48.3) compared to 11.7 months (95%CI 8.9-17.6) for patients with no necrosis (p = 0.077).CONCLUSION: In patients with newly diagnosed GBM treated with a 5 mm CTV margin, 3 patients (11%) had marginal progression within 5-20 mm; only 1 patient (4%) may have dosimetrically benefitted from conventional 20 mm margins. Radiation necrosis was associated with in-field tumor control.

  View details for DOI 10.1016/j.prro.2023.01.008

  View details for PubMedID 36736621

• Continuous EEG monitoring detects nonconvulsive seizure and Ictal-Interictal Continuum abnormalities in moderate to severe ICANS following systemic CAR-T therapy. The Neurohospitalist Satyanarayan, S., Spiegel, J., Hovsepian, D., Markert, M., Thomas, R., Muffly, L., Miklos, D., Graber, K., Scott, B. J. 2023; 13 (1): 53-60

  Abstract

  Immune Cell Effector Associated Neurotoxicity Syndrome (ICANS) is common amongst patients receiving CD19 targeted Chimeric Antigen Receptor T-cell (CAR-T) therapy. The purpose of this study is to characterize the incidence of seizures and ictal-interictal continuum (IIC) abnormalities in patients with ICANS.Retrospective review of consecutive patients treated with axicabtagene ciloleucel (axi-cel) for recurrent high-grade systemic lymphoma at Stanford Medical Center between 2/2016-6/2019. Electronic medical records (EMR) were reviewed for clinical features, treatment information, EEG data, CRS (cytokine release syndrome)/ICANS severity, and clinical outcomes.Fifty-six patients met inclusion criteria. 85.7% of patients developed CRS, and 58.9% developed ICANS. Twenty-eight patients had EEG monitoring, of whom 26 had ICANS. Median duration of EEG monitoring was 30 hours (range .5-126 hours). Four patients (7.1%) had seizures (1 patient had a clinical generalized seizure, 2 patients had clinical and nonconvulsive seizures, and 1 patient had an isolated non-convulsive seizure). Ictal-interictal continuum abnormalities were common, of which generalized periodic discharges (GPDs) with triphasic morphology and GPDs with epileptiform morphology were most frequently seen. Generalized periodic discharges with triphasic wave morphology were found across Grade 2-3 peak ICANS severity, however the majority (86%) of patients with epileptiform GPDs had Grade 3 peak ICANS severity.Among patients receiving axi-cel, seizure occurred in 7.1% of the total cohort, representing 12% of patients with ICANS. Ictal-interictal continuum abnormalities are also seen in patients with ICANS, most commonly GPDs. 75% of patients with seizures had nonconvulsive seizures supporting the use of continuous video EEG monitoring in this population.

  View details for DOI 10.1177/19418744221128852

  View details for PubMedID 36531846

  View details for PubMedCentralID PMC9755619

• Continuous EEG monitoring detects nonconvulsive seizure and Ictal-Interictal Continuum abnormalities in moderate to severe ICANS following systemic CAR-T therapy NEUROHOSPITALIST Satyanarayan, S., Spiegel, J., Hovsepian, D., Markert, M., Thomas, R., Muffly, L., Miklos, D., Graber, K., Scott, B. J. 2022

  View details for DOI 10.1177/19418744221128852

  View details for Web of Science ID 000867394200001

• Radiation Therapy for IDH-Mutant Grade 2 and Grade 3 Diffuse Glioma: An ASTRO Clinical Practice Guideline. Practical radiation oncology Halasz, L. M., Attia, A., Bradfield, L., Brat, D. J., Kirkpatrick, J. P., Laack, N. N., Lalani, N., Lebow, E. S., Liu, A. K., Niemeier, H. M., Palmer, J. D., Peters, K. B., Sheehan, J., Thomas, R. P., Vora, S. A., Wahl, D. R., Weiss, S. E., Yeboa, D. N., Zhong, J., Shih, H. A. 2022

  Abstract

  PURPOSE: This guideline provides evidence-based recommendations for adults with isocitrate dehydrogenase (IDH)-mutant grade 2 and grade 3 diffuse glioma, as classified in the 2021 World Health Organization (WHO) Classification of Tumours. It includes indications for radiation therapy (RT), advanced RT techniques, and clinical management of adverse effects.METHODS: The American Society for Radiation Oncology convened a multidisciplinary task force to address 4 key questions focused on the RT management of patients with IDH-mutant grade 2 and grade 3 diffuse glioma. Recommendations were based on a systematic literature review and created using a predefined consensus-building methodology and system for grading evidence quality and recommendation strength.RESULTS: A strong recommendation for close surveillance alone was made for patients with oligodendroglioma, IDH-mutant, 1p/19q codeleted, WHO grade 2 after gross total resection without high-risk features. For oligodendroglioma, WHO grade 2 with any high-risk features, adjuvant RT was conditionally recommended. However, adjuvant RT was strongly recommended for oligodendroglioma, WHO grade 3. A conditional recommendation for close surveillance alone was made for astrocytoma, IDH-mutant, WHO grade 2 after gross total resection without high-risk features. Adjuvant RT was conditionally recommended for astrocytoma, WHO grade 2, with any high-risk features and strongly recommended for astrocytoma, WHO grade 3. Dose recommendations varied based on histology and grade. Given known adverse long-term effects of RT, consideration for advanced techniques such as intensity modulated radiation therapy/volumetric modulated arc therapy or proton therapy were given as strong and conditional recommendations, respectively. Finally, based on expert opinion, the guideline recommends assessment, surveillance, and management for toxicity management.CONCLUSIONS: Based on published data, the American Society for Radiation Oncology task force has proposed recommendations to inform the management of adults with IDH-mutant grade 2 and grade 3 diffuse glioma as defined by WHO 2021 classification, based on the highest quality published data, and best translated by our task force of subject matter experts.

  View details for DOI 10.1016/j.prro.2022.05.004

  View details for PubMedID 35902341

• Modifiers of and Disparities in Palliative and Supportive Care Timing and Utilization among Neurosurgical Patients with Malignant Central Nervous System Tumors. Cancers Jin, M. C., Hsin, G., Ratliff, J., Thomas, R., Zygourakis, C. C., Li, G., Wu, A. 2022; 14 (10)

  Abstract

  Patients with primary or secondary central nervous system (CNS) malignancies benefit from utilization of palliative care (PC) in addition to other supportive services, such as home health and social work. Guidelines propose early initiation of PC for patients with advanced cancers. We analyzed a cohort of privately insured patients with malignant brain or spinal tumors derived from the Optum Clinformatics Datamart Database to investigate health disparities in access to and utilization of supportive services. We introduce a novel construct, "provider patient racial diversity index" (provider pRDI), which is a measure of the proportion of non-white minority patients a provider encounters to approximate a provider's patient demographics and suggest a provider's cultural sensitivity and exposure to diversity. Our analysis demonstrates low rates of PC, home health, and social work services among racial minority patients. Notably, Hispanic patients had low likelihood of engaging with all three categories of supportive services. However, patients who saw providers categorized into high provider pRDI (categories II and III) were increasingly more likely to interface with supportive care services and at an earlier point in their disease courses. This study suggests that prospective studies that examine potential interventions at the provider level, including diversity training, are needed.

  View details for DOI 10.3390/cancers14102567

  View details for PubMedID 35626171

• A Clinical PET Imaging Tracer ([18F]DASA-23) to Monitor Pyruvate Kinase M2 Induced Glycolytic Reprogramming in Glioblastoma. Clinical cancer research : an official journal of the American Association for Cancer Research Beinat, C., Patel, C. B., Haywood, T., Murty, S., Naya, L., Castillo, J. B., Reyes, S. T., Phillips, M., Buccino, P., Shen, B., Park, J. H., Koran, M. E., Alam, I. S., James, M. L., Holley, D., Halbert, K., Gandhi, H., He, J. Q., Granucci, M., Johnson, E., Liu, D. D., Uchida, N., Sinha, R., Chu, P., Born, D. E., Warnock, G. I., Weissman, I., Hayden Gephart, M., Khalighi, M. M., Massoud, T. F., Iagaru, A., Davidzon, G., Thomas, R., Nagpal, S., Recht, L. D., Gambhir, S. S. 2021

  Abstract

  PURPOSE: Pyruvate kinase M2 (PKM2) catalyzes the final step in glycolysis, a key process of cancer metabolism. PKM2 is preferentially expressed by glioblastoma (GBM) cells with minimal expression in healthy brain. We describe the development, validation, and translation of a novel positron emission tomography (PET) tracer to study PKM2 in GBM. We evaluated 1-((2-fluoro-6-[18F]fluorophenyl)sulfonyl)-4-((4-methoxyphenyl)sulfonyl)piperazine ([18F]DASA-23) in cell culture, mouse models of GBM, healthy human volunteers, and GBM patients.EXPERIMENTAL DESIGN: [18F]DASA-23 was synthesized with a molar activity of 100.47 {plus minus} 29.58 GBq/mol and radiochemical purity >95%. We performed initial testing of [18F]DASA-23 in GBM cell culture and human GBM xenografts implanted orthotopically into mice. Next we produced [18F]DASA-23 under FDA oversight, and evaluated it in healthy volunteers, and a pilot cohort of glioma patients.RESULTS: In mouse imaging studies, [18F]DASA-23 clearly delineated the U87 GBM from surrounding healthy brain tissue and had a tumor-to-brain ratio (TBR) of 3.6 {plus minus} 0.5. In human volunteers, [18F]DASA-23 crossed the intact blood-brain barrier and was rapidly cleared. In GBM patients, [18F]DASA-23 successfully outlined tumors visible on contrast-enhanced magnetic resonance imaging (MRI). The uptake of [18F]DASA-23 was markedly elevated in GBMs compared to normal brain, and it identified a metabolic non-responder within 1-week of treatment initiation.CONCLUSIONS: We developed and translated [18F]DASA-23 as a new tracer that demonstrated the visualization of aberrantly expressed PKM2 for the first time in human subjects. These results warrant further clinical evaluation of [18F]DASA-23 to assess its utility for imaging therapy-induced normalization of aberrant cancer metabolism.

  View details for DOI 10.1158/1078-0432.CCR-21-0544

  View details for PubMedID 34475101

• EGFR-targeted intraoperative fluorescence imaging detects high-grade glioma with panitumumab-IRDye800 in a phase 1 clinical trial. Theranostics Zhou, Q., van den Berg, N. S., Rosenthal, E. L., Iv, M., Zhang, M., Vega Leonel, J. C., Walters, S., Nishio, N., Granucci, M., Raymundo, R., Yi, G., Vogel, H., Cayrol, R., Lee, Y. J., Lu, G., Hom, M., Kang, W., Hayden Gephart, M., Recht, L., Nagpal, S., Thomas, R., Patel, C., Grant, G. A., Li, G. 2021; 11 (15): 7130-7143

  Abstract

  Rationale: First-line therapy for high-grade gliomas (HGGs) includes maximal safe surgical resection. The extent of resection predicts overall survival, but current neuroimaging approaches lack tumor specificity. The epidermal growth factor receptor (EGFR) is a highly expressed HGG biomarker. We evaluated the safety and feasibility of an anti-EGFR antibody, panitumuab-IRDye800, at subtherapeutic doses as an imaging agent for HGG. Methods: Eleven patients with contrast-enhancing HGGs were systemically infused with panitumumab-IRDye800 at a low (50 mg) or high (100 mg) dose 1-5 days before surgery. Near-infrared fluorescence imaging was performed intraoperatively and ex vivo, to identify the optimal tumor-to-background ratio by comparing mean fluorescence intensities of tumor and histologically uninvolved tissue. Fluorescence was correlated with preoperative T1 contrast, tumor size, EGFR expression and other biomarkers. Results: No adverse events were attributed to panitumumab-IRDye800. Tumor fragments as small as 5 mg could be detected ex vivo and detection threshold was dose dependent. In tissue sections, panitumumab-IRDye800 was highly sensitive (95%) and specific (96%) for pathology confirmed tumor containing tissue. Cellular delivery of panitumumab-IRDye800 was correlated to EGFR overexpression and compromised blood-brain barrier in HGG, while normal brain tissue showed minimal fluorescence. Intraoperative fluorescence improved optical contrast in tumor tissue within and beyond the T1 contrast-enhancing margin, with contrast-to-noise ratios of 9.5 ± 2.1 and 3.6 ± 1.1, respectively. Conclusions: Panitumumab-IRDye800 provided excellent tumor contrast and was safe at both doses. Smaller fragments of tumor could be detected at the 100 mg dose and thus more suitable for intraoperative imaging.

  View details for DOI 10.7150/thno.60582

  View details for PubMedID 34158840

  View details for PubMedCentralID PMC8210618

• Safety and Efficacy of the Combination of Nivolumab Plus Ipilimumab in Patients With Melanoma and Asymptomatic or Symptomatic Brain Metastases (CheckMate 204). Neuro-oncology Tawbi, H. A., Forsyth, P. A., Hodi, F. S., Lao, C. D., Moschos, S. J., Hamid, O., Atkins, M. B., Lewis, K., Thomas, R. P., Glaspy, J. A., Jang, S., Algazi, A. P., Khushalani, N. I., Postow, M. A., Pavlick, A. C., Ernstoff, M. S., Reardon, D. A., Puzanov, I., Kudchadkar, R. R., Tarhini, A. A., Sumbul, A., Rizzo, J. I., Margolin, K. A. 2021

  Abstract

  BACKGROUND: In patients with melanoma and asymptomatic brain metastases (MBM), nivolumab plus ipilimumab provided an intracranial response rate of 55%. Here, we present first report for patients who were symptomatic and/or required corticosteroids and updated data for asymptomatic patients.METHODS: Patients with measurable MBM, 0.5-3.0cm, were enrolled into Cohort A (asymptomatic) or Cohort B (stable neurologic symptoms and/or receiving corticosteroids). Nivolumab, 1mg/kg, and ipilimumab, 3mg/kg, were given intravenously every 3 weeks x4, followed by nivolumab, 3mg/kg, every 2 weeks until progression, unacceptable toxicity, or 24 months. The primary endpoint was intracranial clinical benefit rate (CBR; complete response [CR], partial response [PR], or stable disease ≥6 months).RESULTS: Symptomatic patients (N = 18) received a median of one nivolumab and ipilimumab combination dose, and had an intracranial CBR of 22.2%. Two of 12 patients on corticosteroids had CR; 2 responded among the 6 not on corticosteroids. Median intracranial progression-free survival (PFS) and overall survival (OS) were 1.2 and 8.7 months, respectively. In contrast, with 20.6 months of follow-up, we confirmed an intracranial CBR of 58.4% in asymptomatic patients (N = 101); median duration of response, PFS, and OS were not reached. No new safety signals were observed.CONCLUSIONS: Nivolumab plus ipilimumab provides durable clinical benefit for asymptomatic patients with MBM and should be considered for first-line therapy. This regimen has limited activity in MBM patients with neurologic symptoms and/or requiring corticosteroids, supporting the need for alternative approaches and methods to reduce the dependency on corticosteroids.

  View details for DOI 10.1093/neuonc/noab094

  View details for PubMedID 33880555

• Developing the Neurology Diversity Officer: A Roadmap for Academic Neurology Departments. Neurology Mohile, N. A., Spector, A. R., Ebong, I. M., Flippen, C. 2., Gutierrez, C., Leacock, R. O., Marulanda-Londono, E., Mejia, N. I., Thomas, R., Hamilton, R. H. 2021

  Abstract

  Academic Neurology Departments must confront the challenges of developing a diverse workforce, reducing inequity and discrimination within academia, and providing neurologic care for an increasingly diverse society. A neurology diversity officer should have a specific role and associated title within a neurology department as well as a mandate to focus their efforts on issues of equity, diversity and inclusion that affect staff, trainees and faculty. This role is expansive and works across departmental missions but it has many challenges related to structural intolerance and cultural gaps. In this review, we describe the many challenges that diversity officers face and how they might confront them. We delineate the role and duties of the neurology diversity officer and provide a guide to departmental leaders on how to assess qualifications and evaluate progress. Finally, we describe the elements necessary for success. A neurology diversity officer should have the financial, administrative and emotional support of leadership in order for them to carry out their mission and to truly have a positive influence.

  View details for DOI 10.1212/WNL.0000000000011460

  View details for PubMedID 33402439

• Outcomes From a Novel Graduate Medical Education Leadership Program in Advancing Diversity, Equity, and Inclusion Journal of Graduate Medical Education Powell, C., Yemane, L., Brooks, M., Johnson, C., Alvarez, A., Bandstra, B., Caceres, W., Dierickx, Q., Thomas, R., Blankenburg, R. 2021; 13 (6): 774–784

  View details for DOI 10.4300/JGME-D-21-00235.1

• Long-term outcomes of patients with active melanoma brain metastases treated with combination nivolumab plus ipilimumab (CheckMate 204): final results of an open-label, multicentre, phase 2 study. The Lancet. Oncology Tawbi, H. A., Forsyth, P. A., Hodi, F. S., Algazi, A. P., Hamid, O., Lao, C. D., Moschos, S. J., Atkins, M. B., Lewis, K., Postow, M. A., Thomas, R. P., Glaspy, J., Jang, S., Khushalani, N. I., Pavlick, A. C., Ernstoff, M. S., Reardon, D. A., Kudchadkar, R., Tarhini, A., Chung, C., Ritchings, C., Durani, P., Askelson, M., Puzanov, I., Margolin, K. A. 2021

  Abstract

  Combination nivolumab plus ipilimumab was efficacious in patients with asymptomatic melanoma brain metastases (MBM) in CheckMate 204, but showed low efficacy in patients with symptomatic MBM. Here, we provide final 3-year follow-up data from the trial.This open-label, multicentre, phase 2 study (CheckMate 204) included adults (aged ≥18 years) with measurable MBM (0·5-3·0 cm in diameter). Asymptomatic patients (cohort A) had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and no neurological symptoms or baseline corticosteroid use; symptomatic patients (cohort B) had an ECOG performance status of 0-2 with stable neurological symptoms and could be receiving low-dose dexamethasone. Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg was given intravenously every 3 weeks for four doses, followed by nivolumab 3 mg/kg every 2 weeks for up to 2 years, until disease progression or unacceptable toxicity. The primary endpoint was intracranial clinical benefit rate (complete responses, partial responses, or stable disease lasting ≥6 months) assessed in all treated patients. Intracranial progression-free survival and overall survival were key secondary endpoints. This study is registered with ClinicalTrials.gov, NCT02320058.Between Feb 19, 2015, and Nov 1, 2017, 119 (72%) of 165 screened patients were enrolled and treated: 101 patients were asymptomatic (cohort A; median follow-up 34·3 months [IQR 14·7-36·4]) and 18 were symptomatic (cohort B; median follow-up 7·5 months [1·2-35·2]). Investigator-assessed intracranial clinical benefit was observed in 58 (57·4% [95% CI 47·2-67·2]) of 101 patients in cohort A and three (16·7% [3·6-41·4]) of 18 patients in cohort B; investigator-assessed objective response was observed in 54 (53·5% [43·3-63·5]) patients in cohort A and three (16·7% [3·6-41·4]) patients in cohort B. 33 (33%) patients in cohort A and three (17%) patients in cohort B had an investigator-assessed intracranial complete response. For patients in cohort A, 36-month intracranial progression-free survival was 54·1% (95% CI 42·7-64·1) and overall survival was 71·9% (61·8-79·8). For patients in cohort B, 36-month intracranial progression-free survival was 18·9% (95% CI 4·6-40·5) and overall survival was 36·6% (14·0-59·8). The most common grade 3-4 treatment-related adverse events (TRAEs) were increased alanine aminotransferase and aspartate aminotransferase (15 [15%] of 101 patients each) in cohort A; no grade 3 TRAEs occurred in more than one patient each in cohort B, and no grade 4 events occurred. The most common serious TRAEs were colitis, diarrhoea, hypophysitis, and increased alanine aminotransferase (five [5%] of each among the 101 patients in cohort A); no serious TRAE occurred in more than one patient each in cohort B. There was one treatment-related death (myocarditis in cohort A).The durable 3-year response, overall survival, and progression-free survival rates for asymptomatic patients support first-line use of nivolumab plus ipilimumab. Symptomatic disease in patients with MBM remains difficult to treat, but some patients achieve a long-term response with the combination.Bristol Myers Squibb.

  View details for DOI 10.1016/S1470-2045(21)00545-3

  View details for PubMedID 34774225

• EGFR-targeted intraoperative fluorescence imaging detects high-grade glioma with panitumumab-IRDye800 in a phase 1 clinical trial Theranostics Zhou, Q., van den Berg, N. S., Rosenthal, E. L., Iv, M., Zhang, M., Vega Leonel, J. C., Walters, S., Nishio, N., Granucci, M., Raymundo, R., Yi, G., Vogel, H., Cayrol, R., Lee, Y., Lu, G., Hom, M., Kang, W., Hayden Gephart, M., Recht, L. D., Nagpal, S., Thomas, R. P., Patel, C. B., Grant, G. A., Li, G. 2021; 11 (15): 7130-7143

  View details for DOI 10.7150/thno.60582

• Recurrent Status Epilepticus in the Setting of Chimeric Antigen Receptor (CAR)-T Cell Therapy The Neurohospitalist Reveron-Thornton, R., Scott, B. J., Post, D., Finley Caulfield, A., Werbaneth, K., Hovsepian, D. A., Spiegel, J., Miklos, D., Thomas, R. P., Patel, C. B. 2021: 74-79

  Abstract

  Axicabtagene ciloleucel (AC) is an FDA-approved anti-CD19 autologous chimeric antigen receptor T-cell (CAR-T) therapy for refractory diffuse large B cell lymphoma (DLBCL). While its efficacy in DLBCL has been promising, neurotoxicity remains a significant concern. We present a case of a 22-year-old woman with chemotherapy-refractory DLBCL who exhibited Grade IV neurotoxicity in the setting of sepsis, after undergoing AC infusion. Despite prophylactic levetiracetam given per guidelines,1,2 she experienced a precipitous mental status decline on post-infusion day 8 (D8) followed by hypoxic respiratory failure in the setting of clinical status epilepticus on D11 and nonconvulsive status epilepticus (NCSE) on D18. While neuroimaging was unremarkable, EEG demonstrated diffuse slowing and 2.5-3 Hz generalized periodic discharges consistent with NCSE. Seizures were initially refractory to lorazepam, increasing doses of levetiracetam, and phenobarbital, requiring a midazolam drip titrated to 50-70% burst suppression for resolution. Methylprednisolone and tocilizumab were used to treat neurotoxicity and cytokine release syndrome, respectively. Empiric antibiotics were used for sepsis. After cessation of sedatives on D19, mental status improved to near baseline. PET/CT just prior to discharge showed a complete response of the DLBCL (Deauville 3). She was discharged on D37 with no further seizure activity. Unfortunately, a 3-month interval PET/CT demonstrated disease progression which continued through salvage pembrolizumab eventually leading to death 1.2 years post-CAR-T infusion. This case illustrates the clinical management challenges of a complex and rare neurotoxic side effect of CAR-T cell therapy, namely NCSE following status epilepticus.

  View details for DOI 10.1177/19418744211000980

  View details for PubMedCentralID PMC8689529

• Phase I study of BPM31510 and vitamin K in patients with high grade glioma recurrent after a bevacizumab-containing regimen. Nagpal, S., Thomas, R., Bertrand, S., Yerraballa, H., Iv, M., Li, G., Klotz, A., Kiebish, M. A., Narain, N. R., Sarangarajan, R., Granger, E., Recht, L. AMER SOC CLINICAL ONCOLOGY. 2020

  View details for Web of Science ID 000560368301238

• Neurological adverse effects due to programmed death 1 (PD-1) inhibitors. Journal of neuro-oncology Shi, S., Jaoube, J. A., Kanwar, R., Jin, M. C., Amorin, A., Varanasi, V., Eisinger, E., Thomas, R., Moore, J. M. 2020

  Abstract

  PURPOSE: PD-1 Immunotherapy is integral in treating multiple cancers, but has been associated with neurological adverse events (nAEs). Our study was aimed at identifying the clinical spectrum of nAEs associated with pembrolizumab and nivolumab.METHODS: We performed an IRB approved single-center retrospective cohort study on patients receiving either pembrolizumab or nivolumab. Patients that developed nAEs within 12months of treatment were identified. Descriptive statistics were conducted, and differences between groups were analyzed by the Chi-square or t test method.RESULTS: In total, 649 patients were identified. Seventeen patients (2.6%) developed nAEs. Eight of those were on pembrolizumab and nine were on nivolumab. Average age was 62.1years. Ten were males and 7 were females. Most patients had melanoma (6, 35.3%). Patients who developed nAEs more frequently had intracranial lesions at initiation of anti PD-1 therapy compared to those who did not develop nAEs (76.5% vs 27.8%; p-value<0.001). Fifteen patients (88.2%) permanently stopped PD-1 therapy. In 8 patients, treatment termination resolved symptoms attributed to immune checkpoint blockade. The majority of patients developed grade 3 or 4 nAEs (10 patients, 58.8%), and required hospitalization (11 patients, 64.7%). Eight patients died for nAEs referable causes.CONCLUSION: Pembrolizumab and nivolumab are associated with the development of nAEs associated with increased risk of permanent discontinuation of treatment, hospitalization, and death. Melanoma patients might be at a particularly high risk of such side effects. Future studies are still required to better assess which patients benefit most from such therapies, while minimizing the risk of complications.

  View details for DOI 10.1007/s11060-020-03514-8

  View details for PubMedID 32350779

• A Phase I/II Trial of 5-Fraction Stereotactic Radiosurgery with 5-mm Margins with Concurrent Temozolomide in Newly Diagnosed Glioblastoma: Primary Outcomes. Neuro-oncology Azoulay, M. n., Chang, S. D., Gibbs, I. C., Hancock, S. L., Pollom, E. L., Harsh, G. R., Adler, J. R., Harrahar, C. n., Li, G. n., Hayden Gephart, M. n., Nagpal, S. n., Thomas, R. P., Recht, L. D., Jacobs, L. R., Modlin, L. A., Wynne, J. n., Seiger, K. n., Fujimoto, D. n., Usoz, M. n., von Eyben, R. n., Choi, C. Y., Soltys, S. G. 2020

  Abstract

  We sought to determine the maximum tolerated dose (MTD) of 5-fraction stereotactic radiosurgery (SRS) with 5-mm margins delivered with concurrent temozolomide in newly diagnosed glioblastoma.We enrolled adult patients with newly diagnosed glioblastoma to 5 days of SRS in a 3+3 design on 4 escalating dose levels: 25, 30, 35, and 40 Gy. Dose limiting toxicity (DLT) was defined as CTCAE Grade 3-5 acute or late CNS toxicity, including adverse radiation effect (ARE), the imaging correlate of radiation necrosis.From 2010 to 2015, 30 patients were enrolled. The median age was 66 years (range 51-86 years). The median target volume was 60 cm3 (range 14.7-137.3 cm3). DLT occurred in 2 patients: one for post-treatment cerebral edema and progressive disease at 3 weeks (Grade 4, Dose 40 Gy); another patient died 1.5 weeks following SRS from post-operative complications (Grade 5, Dose 40 Gy). Late grade 1-2 ARE occurred in 8 patients at a median of 7.6 months (range 3.2-12.6 months). No grade 3-5 ARE occurred. With a median follow-up of 13.8 months (range 1.7-64.4 months), the median survival times were: PFS 8.2 months (95%CI 4.6-10.5), OS 14.8 months (95%CI 10.9-19.9), MGMT hypermethylated 19.9 months (95%CI 10.5-33.5) vs. 11.3 months (95%CI 8.9-17.6) for no/unknown hypermethylation (p=0.03), and 27.2 months (95%CI 11.2-48.3) if late ARE occurred vs. 11.7 months (95%CI 8.9-17.6) for no ARE (p=0.08).The per-protocol MTD of 5-fraction SRS with 5-mm margins with concurrent temozolomide was 40 Gy in 5 fractions. ARE was limited to grade 1-2 and did not statistically impact survival.

  View details for DOI 10.1093/neuonc/noaa019

  View details for PubMedID 32002547

• Intracranial Tumor Control Following Immune-Related Adverse Events and Discontinuation of Immunotherapy for Melanoma. World neurosurgery Zhang, M. n., Rodrigues, A. J., Bhambhvani, H. P., Fatemi, P. n., Pollom, E. L., Gibbs, I. C., Thomas, R. P., Soltys, S. G., Hancock, S. L., Chang, S. D., Reddy, S. A., Gephart, M. H., Li, G. n. 2020

  Abstract

  Immunotherapy for melanoma patients with brain metastasis has significantly improved outcomes; however, they have also been characterized by potentially dangerous immune-related adverse events (IRAEs). Several reports suggest these reactions can precede improved treatment responses. We sought to identify if such association exists for intracranial disease control.We conducted a retrospective chart review of melanoma patients who underwent immunotherapy treatment following diagnosis of brain metastasis. The study cohort was then stratified into two groups based on their history of developing an IRAE that prompted discontinuation of that regimen. The primary outcome variable included intracranial progression-free survival (PFS). Kaplan-Meier and Cox proportional hazard analysis were used to evaluate survival and predictors of outcomes.Fifty-two patients met inclusion criteria, seventeen of whom experienced severe IRAEs that led to discontinuation of immunotherapy. Median intracranial PFS was 19.9 vs 10.5 months (p = 0.053) in patients who did and did not experience severe IRAEs prompting discontinuation, respectively. No additional outcome benefits were identified for systemic PFS or overall survival, mean (33.1 months and 27.6 months, respectively). Multivariable analysis identified BRAF mutation status as a negative prognosticator of brain progression (p = 0.013, HR = 3.90). Initial treatment with BRAF inhibitor was also a negative predictor of all-cause mortality (p = 0.015, HR = 10.73) CONCLUSION: Immune related adverse events may signify an underlying immunogenic response that has intracranial disease control benefits. Despite their associated side effects, immunotherapies continue to demonstrate promising outcomes as a first-line agent for melanoma with brain metastasis.

  View details for DOI 10.1016/j.wneu.2020.08.124

  View details for PubMedID 32853767

• Impact of the Patient Protection and Affordable Care Act on 1-year survival in glioblastoma patients. Neuro-oncology advances Moghavem, N., Oh, D. L., Santiago-Rodriguez, E. J., Tate, W. J., Gomez, S. L., Thomas, R. 2020; 2 (1): vdaa080

  Abstract

  Background: Glioblastoma (GBM) treatment requires access to complex medical services, and the Patient Protection and Affordable Care Act (ACA) sought to expand access to health care, including complex oncologic care. Whether the implementation of the ACA was subsequently associated with changes in 1-year survival in GBM is not known.Methods: A retrospective cohort study was performed using the Surveillance, Epidemiology, and End Results (SEER) database. We identified patients with the primary diagnosis of GBM between 2008 and 2016. A multivariable-adjusted Cox proportional hazards model was developed using patient and clinical characteristics to determine the main outcome: the 1-year cumulative probability of death by state expansion status.Results: A total of 25 784 patients and 14 355 deaths at 1 year were identified and included in the analysis, 49.7% were older than 65 at diagnosis. Overall 1-year cumulative probability of death for GBM patients in non-expansion versus expansion states did not significantly worsen over the 2 time periods (2008-2010: hazard ratio [HR] 1.11, 95% confidence interval [CI] 1.04-1.19; 2014-2016: HR 1.18, 95% CI 1.09-1.27). In GBM patients younger than age 65 at diagnosis, there was a nonsignificant trend toward the poorer 1-year cumulative probability of death in non-expansion versus expansion states (2008-2010: HR 1.09, 95% CI 0.97-1.22; 2014-2016: HR 1.23, 95% CI 1.09-1.40).Conclusions: No differences were found over time in survival for GBM patients in expansion versus non-expansion states. Further study may reveal whether GBM patients diagnosed younger than age 65 in expansion states experienced improvements in 1-year survival.

  View details for DOI 10.1093/noajnl/vdaa080

  View details for PubMedID 32743549

• Evaluating Surgical Resection Extent and Adjuvant Therapy in the Management of Gliosarcoma. Frontiers in oncology Jin, M. C., Liu, E. K., Shi, S. n., Gibbs, I. C., Thomas, R. n., Recht, L. n., Soltys, S. G., Pollom, E. L., Chang, S. D., Hayden Gephart, M. n., Nagpal, S. n., Li, G. n. 2020; 10: 337

  Abstract

  Introduction: Gliosarcomas are clinically aggressive tumors, histologically distinct from glioblastoma. Data regarding the impact of extent of resection and post-operative adjuvant therapy on gliosarcoma outcomes are limited. Methods: Patients with histologically confirmed gliosarcoma diagnosed between 1999 and 2019 were identified. Clinical, molecular, and radiographic data were assembled based on historical records. Comparisons of categorical variables used Pearson's Chi-square and Fisher's exact test while continuous values were compared using the Wilcoxon signed-rank test. Survival comparisons were assessed using Kaplan-Meier statistics and Cox regressions. Results: Seventy-one gliosarcoma patients were identified. Secondary gliosarcoma was not associated with worse survival when compared to recurrent primary gliosarcoma (median survival 9.8 [3.8 to 21.0] months vs. 7.6 [1.0 to 35.7], p = 0.7493). On multivariable analysis, receipt of temozolomide (HR = 0.02, 95% CI 0.001-0.21) and achievement of gross total resection (GTR; HR = 0.13, 95% CI 0.02-0.77) were independently prognostic for improved progression-free survival (PFS) while only receipt of temozolomide was independently associated with extended overall survival (OS) (HR = 0.03, 95% CI 0.001-0.89). In patients receiving surgical resection followed by radiotherapy and concomitant temozolomide, achievement of GTR was significantly associated with improved PFS (median 32.97 [7.1-79.6] months vs. 5.45 [1.8-26.3], p = 0.0092) and OS (median 56.73 months [7.8-104.5] vs. 14.83 [3.8 to 29.1], p = 0.0252). Conclusion: Multimodal therapy is associated with improved survival in gliosarcoma. Even in patients receiving aggressive post-operative multimodal management, total surgical removal of macroscopic disease remains important for optimal outcomes.

  View details for DOI 10.3389/fonc.2020.00337

  View details for PubMedID 32219069

  View details for PubMedCentralID PMC7078164

• Macrophage exclusion after radiation therapy (MERT): A new and effective way to increase the therapeutic ratio of radiotherapy. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology Brown, J. M., Thomas, R., Nagpal, S., Recht, L. 2019; 144: 159–64

  Abstract

  Here we review a variety of preclinical studies and a first-in-human clinical trial of newly diagnosed glioblastoma (GBM) patients that have investigated the significance of the influx of tumor associated macrophages (TAMs) into tumors after irradiation. We summarize the effects on the response of the tumors and normal tissues to radiation of various agents that either reduce the influx of TAMs into tumors after radiation or change their M1/M2 polarization. The studies show that following irradiation there is an accumulation of bone marrow derived TAMs in the irradiated tumors. These TAMs stimulate the resumption of blood flow in the irradiated tumors thereby promoting recurrence of the tumors. A key mechanism for this accumulation of TAMs is driven by the SDF-1/CXCR4 chemokine pathway though other pathways could also be involved for some tumors. Blocking this pathway to prevent the TAM accumulation in the tumors both enhances tumor response to radiation and protects irradiated tissues. A clinical trial in which the CXCR4 antagonist plerixafor was added to standard therapy of glioblastoma validated the preclinical findings by demonstrating i) reduced blood flow in the irradiated site, and ii) significantly improved tumor local control compared to GBM patients not treated with plerixafor. We conclude that macrophage exclusion after radiation therapy (MERT) is an effective way both to enhance the tumor response to radiation and to protect the irradiated normal tissues. Further clinical trials are warranted.

  View details for DOI 10.1016/j.radonc.2019.11.020

  View details for PubMedID 31812931

• EVALUATION OF [18F]DASA-23 FOR NON-INVASIVE MEASUREMENT OF ABERRANTLY EXPRESSED PYRUVATE KINASE M2 IN GLIOMA: FIRST-IN-HUMAN STUDY Patel, C., Beinat, C., Haywood, T., Murty, S., Xie, Y., Recht, L., Nagpal, S., Thomas, R., Khalighi, M., Gandhi, H., Holley, D., Gambhir, S. OXFORD UNIV PRESS INC. 2019: 169

  View details for Web of Science ID 000509478704010

• A PHASE 1 STUDY OF BPM31510 PLUS VITAMIN K IN SUBJECTS WITH HIGH-GRADE GLIOMA THAT HAS RECURRED ON A BEVACIZUMAB-CONTAINING REGIMEN Recht, L., Thomas, R., Bertrand, S., Yerballa, P., Li, G., Iv, M., Narain, N., Sarangarajan, R., Granger, E., Nagpal, S. OXFORD UNIV PRESS INC. 2019: 27

  View details for Web of Science ID 000509478700102

• Efficacy and safety of the combination of nivolumab (NIVO) plus ipilimumab (IPI) in patients with symptomatic melanoma brain metastases (MBM; CheckMate 204) Tawbi, H., Forsyth, P., Hodi, F., Lao, C., Moschos, S., Hamid, O., Atkins, M. B., Lewis, K., Thomas, R. P., Glaspy, J. A., Jang, S., Algazi, A., Khushalani, N. I., Postow, M. A., Pavlick, A. C., Ernstoff, M., Reardon, D. A., Balogh, A., Rizzo, J., Margolin, K. NATURE PUBLISHING GROUP. 2019: 20

  View details for Web of Science ID 000505173600055

• Rooting out racial stereotypes in Neurology (R) A commentary on "Lucky and the root doctor" NEUROLOGY Hamilton, R. H., McClean, J. C., Greicius, M. D., Gamaldo, C. E., Burrus, T. M., Charleston, L., Correa, D. J., Ebong, I. M., Hamilton, R., Lewis, S., Thomas, R. P., Vargas, A., Flippen, C. C. 2019; 92 (22): 1029–32

  View details for DOI 10.1212/WNL.0000000000007578

  View details for Web of Science ID 000480769900016

• Efficacy and safety of the combination of nivolumab (NIVO) plus ipilimumab (IPI) in patients with symptomatic melanoma brain metastases (CheckMate 204). Tawbi, H., Forsyth, P. J., Hodi, F., Lao, C. D., Moschos, S. J., Hamid, O., Atkins, M. B., Lewis, K. D., Thomas, R., Glaspy, J. A., Jang, S., Algazi, A., Khushalani, N. I., Postow, M. A., Pavlick, A. C., Ernstoff, M. S., Reardon, D. A., Balogh, A., Rizzo, J. I., Margolin, K. AMER SOC CLINICAL ONCOLOGY. 2019

  View details for DOI 10.1200/JCO.2019.37.15_suppl.9501

  View details for Web of Science ID 000487345806555

• Rooting out racial stereotypes in Neurology: A commentary on "Lucky and the root doctor". Neurology Hamilton, R. H., McClean, J. C., Greicius, M. D., Gamaldo, C. E., Burrus, T. M., Charleston, L. 4., Correa, D. J., Ebong, I. M., Hamilton, R., Lewis, S., Thomas, R. P., Vargas, A., Flippen, C. C. 2019

  View details for PubMedID 31053666

• Melanoma central nervous system metastases: An update to approaches, challenges, and opportunities PIGMENT CELL & MELANOMA RESEARCH Eroglu, Z., Holmen, S. L., Chen, Q., Khushalani, N. I., Amaravadi, R., Thomas, R., Ahmed, K. A., Tawbi, H., Chandra, S., Markowitz, J., Smalley, I., Liu, J. C., Chen, Y., Najjar, Y. G., Karreth, F. A., Abate-Daga, D., Glitza, I. C., Sosman, J. A., Sondak, V. K., Bosenberg, M., Herlyn, M., Atkins, M. B., Kluger, H., Margolin, K., Forsyth, P. A., Davies, M. A., Smalley, K. M. 2019; 32 (3): 458–69

  View details for DOI 10.1111/pcmr.12771

  View details for Web of Science ID 000465607700014

• EEG Findings in Chimeric Antigen Receptor T-Cell (CAR-T) Related Encephalopathy Syndrome Satyanarayan, S., Markert, M., Hovsepian, D., Post, D., Muffly, L., Miklos, D., Thomas, R., Scott, B. LIPPINCOTT WILLIAMS & WILKINS. 2019

  View details for Web of Science ID 000475965900243

• Neurological Adverse Effects Due to Programmed Death (PD-1) Inhibitors Shi, S., Kanwar, R., Varanasi, V., Eisinger, E., Thomas, R., Moore, J. LIPPINCOTT WILLIAMS & WILKINS. 2019

  View details for Web of Science ID 000475965900259

• Melanoma central nervous system metastases: An update to approaches, challenges, and opportunities. Pigment cell & melanoma research Eroglu, Z., Holmen, S. L., Chen, Q., Khushalani, N. I., Amaravadi, R., Thomas, R., Ahmed, K. A., Tawbi, H., Chandra, S., Markowitz, J., Smalley, I., Liu, J. K., Ann Chen, Y., Najjar, Y. G., Karreth, F. A., Abate-Daga, D., Glitza, I. C., Sosman, J. A., Sondak, V. K., Bosenberg, M., Herlyn, M., Atkins, M. B., Kluger, H., Margolin, K., Forsyth, P. A., Davies, M. A., Smalley, K. S. 2019

  Abstract

  In February 2018, theMelanomaResearch Foundation and the Moffitt Cancer Center hosted the Second Summit onMelanomaCentral Nervous System (CNS) Metastases in Tampa, Florida. In this white paper we outline the current status of basic science, translational and clinical research into melanoma brain metastasis development and therapeutic management. We further outline the important challenges that remain for the field and the critical barriers that need to be overcome for continued progress to be made in this clinically difficult area. This article is protected by copyright. All rights reserved.

  View details for PubMedID 30712316

• Macrophage Exclusion after Radiation Therapy (MERT): A First in Human Phase I/II Trial using a CXCR4 Inhibitor in Glioblastoma. Clinical cancer research : an official journal of the American Association for Cancer Research Thomas, R. P., Nagpal, S. n., Iv, M. n., Soltys, S. G., Bertrand, S. n., Pelpola, J. S., Ball, R. L., Yang, J. n., Sundaram, V. n., Lavezo, J. L., Born, D. E., Vogel, H. n., Brown, J. M., Recht, L. n. 2019

  Abstract

  Preclinical studies have demonstrated that post-irradiation tumor revascularization is dependent on a stromal cell-derived factor-1 (SDF-1)/C-X-C chemokine receptor type 4 (CXCR4)-driven process in which myeloid cells are recruited from bone marrow. Blocking this axis results in survival improvement in preclinical models of solid tumors, including glioblastoma (GBM). We conducted a phase I/II study to determine the safety and efficacy of Macrophage Exclusion after Radiation Therapy (MERT) using the reversible CXCR4 inhibitor plerixafor in newly diagnosed glioblastoma patients.We enrolled 9 patients to the phase I study and an additional 20 patients to phase II using a modified toxicity probability interval (mTPI) design. Plerixafor was continuously infused intravenously via PICC line for four consecutive weeks beginning at day 35 of conventional treatment with concurrent chemo-radiation. Blood serum samples were obtained for pharmacokinetic analysis. Additional studies included relative cerebral blood volume (rCBV) analysis using MRI and histopathology analysis of recurrent tumors.Plerixafor was well tolerated with no drug-attributable grade 3 toxicities observed. At the maximum dose of 400 µg/kg/day, biomarker analysis found suprathreshold plerixafor serum levels and an increase in plasma SDF-1 levels. Median overall survival was 21.3 months (95% Confidence Interval (CI) 15.9, NA) with a progression-free survival of 14.5 months (95% CI 11.8, NA). MRI and histopathology support the mechanism of action to inhibit post-irradiation tumor revascularization.Infusion of the CXCR4 inhibitor plerixafor was well tolerated as an adjunct to standard chemo-irradiation in newly diagnosed GBM patients and improves local control of tumor recurrences.

  View details for DOI 10.1158/1078-0432.CCR-19-1421

  View details for PubMedID 31537527

• Nodular Leptomeningeal Disease - A Distinct Pattern of Recurrence After Post-Resection Stereotactic Radiosurgery for Brain Metastases: A Multi-Institutional Study of Inter-Observer Reliability. International journal of radiation oncology, biology, physics Turner, B. E., Prabhu, R. S., Burri, S. H., Brown, P. D., Pollom, E. L., Milano, M. T., Weiss, S. E., Iv, M. n., Fischbein, N. n., Soliman, H. n., Lo, S. S., Chao, S. T., Cox, B. W., Murphy, J. D., Li, G. n., Gephart, M. H., Nagpal, S. n., Atalar, B. n., Azoulay, M. n., Thomas, R. n., Tillman, G. n., Durkee, B. Y., Shah, J. L., Soltys, S. G. 2019

  Abstract

  For brain metastases, surgical resection with postoperative stereotactic radiosurgery (SRS) is an emerging standard of care. Postoperative cavity SRS is associated with a specific, under-recognized pattern of intracranial recurrence, herein termed nodular leptomeningeal disease (nLMD), which is distinct from classical leptomeningeal disease (cLMD). We hypothesized that there is poor consensus regarding the definition of LMD, and that a formal, self-guided training module will improve inter-rater reliability (IRR) and validity in diagnosing LMD.Twenty-two physicians at 16 institutions, including 15 physicians with central nervous system (CNS) expertise, completed a two-phase survey that included MRI imaging and treatment information for 30 patients. In the "pre-training" phase, physicians labeled cases using 3 patterns of recurrence commonly reported in prospective studies: local recurrence (LR), distant parenchymal recurrence (DR), and LMD. After a self-directed training module, participating physicians completed the "post-training" phase and relabeled the 30 cases using the 4 following labels: LR, DR, cLMD, nLMD.Inter-rater reliability (IRR) increased 34% after training (Fleiss' Kappa K=0.41 to K=0.55, p<0.001). IRR increased most among non-CNS specialists (+58%, p<0.001). Prior to training, IRR was lowest for LMD (K=0.33). After training, IRR increased across all recurrence subgroups and increased most for LMD (+67%). After training, ≥27% of cases initially labeled LR or DR were later recognized as nLMD.This study highlights the large degree of inconsistency among clinicians in recognizing nLMD. Our findings demonstrate that a brief self-guided training module distinguishing nLMD can significantly improve IRR across all patterns of recurrence, and particularly in nLMD. To optimize outcomes reporting, prospective trials in brain metastases should incorporate central imaging review and investigator training.

  View details for DOI 10.1016/j.ijrobp.2019.10.002

  View details for PubMedID 31605786

• Perfusion MRI-Based Fractional Tumor Burden Differentiates between Tumor and Treatment Effect in Recurrent Glioblastomas and Informs Clinical Decision-Making. AJNR. American journal of neuroradiology Iv, M. n., Liu, X. n., Lavezo, J. n., Gentles, A. J., Ghanem, R. n., Lummus, S. n., Born, D. E., Soltys, S. G., Nagpal, S. n., Thomas, R. n., Recht, L. n., Fischbein, N. n. 2019

  Abstract

  Fractional tumor burden better correlates with histologic tumor volume fraction in treated glioblastoma than other perfusion metrics such as relative CBV. We defined fractional tumor burden classes with low and high blood volume to distinguish tumor from treatment effect and to determine whether fractional tumor burden can inform treatment-related decision-making.Forty-seven patients with high-grade gliomas (primarily glioblastoma) with recurrent contrast-enhancing lesions on DSC-MR imaging were retrospectively evaluated after surgical sampling. Histopathologic examination defined treatment effect versus tumor. Normalized relative CBV thresholds of 1.0 and 1.75 were used to define low, intermediate, and high fractional tumor burden classes in each histopathologically defined group. Performance was assessed with an area under the receiver operating characteristic curve. Consensus agreement among physician raters reporting hypothetic changes in treatment-related decisions based on fractional tumor burden was compared with actual real-time treatment decisions.Mean low fractional tumor burden, high fractional tumor burden, and relative CBV of the contrast-enhancing volume were significantly different between treatment effect and tumor (P = .002, P < .001, and P < .001), with tumor having significantly higher fractional tumor burden and relative CBV and lower fractional tumor burden. No significance was found with intermediate fractional tumor burden. Performance of the area under the receiver operating characteristic curve was the following: high fractional tumor burden, 0.85; low fractional tumor burden, 0.7; and relative CBV, 0.81. In comparing treatment decisions, there were disagreements in 7% of tumor and 44% of treatment effect cases; in the latter, all disagreements were in cases with scattered atypical cells.High fractional tumor burden and low fractional tumor burden define fractions of the contrast-enhancing lesion volume with high and low blood volume, respectively, and can differentiate treatment effect from tumor in recurrent glioblastomas. Fractional tumor burden maps can also help to inform clinical decision-making.

  View details for DOI 10.3174/ajnr.A6211

  View details for PubMedID 31515215

• Quantification of Macrophages in High-Grade Gliomas by Using Ferumoxytol-enhanced MRI: A Pilot Study. Radiology Iv, M. n., Samghabadi, P. n., Holdsworth, S. n., Gentles, A. n., Rezaii, P. n., Harsh, G. n., Li, G. n., Thomas, R. n., Moseley, M. n., Daldrup-Link, H. E., Vogel, H. n., Wintermark, M. n., Cheshier, S. n., Yeom, K. W. 2018: 181204

  Abstract

  Purpose To investigate ferumoxytol-enhanced MRI as a noninvasive imaging biomarker of macrophages in adults with high-grade gliomas. Materials and Methods In this prospective study, adults with high-grade gliomas were enrolled between July 2015 and July 2017. Each participant was administered intravenous ferumoxytol (5 mg/kg) and underwent 3.0-T MRI 24 hours later. Two sites in each tumor were selected for intraoperative sampling on the basis of the degree of ferumoxytol-induced signal change. Susceptibility and the relaxation rates R2* (1/T2*) and R2 (1/T2) were obtained by region-of-interest analysis by using the respective postprocessed maps. Each sample was stained with Prussian blue, CD68, CD163, and glial fibrillary acidic protein. Pearson correlation and linear mixed models were performed to assess the relationship between imaging measurements and number of 400× magnification high-power fields with iron-containing macrophages. Results Ten adults (four male participants [mean age, 65 years ± 9 {standard deviation}; age range, 57-74 years] and six female participants [mean age, 53 years ± 12 years; age range, 32-65 years]; mean age of all participants, 58 years ± 12 [age range, 32-74 years]) with high-grade gliomas were included. Significant positive correlations were found between susceptibility, R2*, and R2' and the number of high-power fields with CD163-positive (r range, 0.64-0.71; P < .01) and CD68-positive (r range, 0.55-0.57; P value range, .01-.02) iron-containing macrophages. No significant correlation was found between R2 and CD163-positive (r = 0.33; P = .16) and CD68-positive (r = 0.24; P = .32) iron-containing macrophages. Similar significance results were obtained with linear mixed models. At histopathologic analysis, iron particles were found only in macrophages; none was found in glial fibrillary acidic protein-positive tumor cells. Conclusion MRI measurements of susceptibility, R2*, and R2' (R2* - R2) obtained after ferumoxytol administration correlate with iron-containing macrophage concentration, and this shows their potential as quantitative imaging markers of macrophages in malignant gliomas. © RSNA, 2018 Online supplemental material is available for this article.

  View details for PubMedID 30398435

• Combined Nivolumab and Ipilimumab in Melanoma Metastatic to the Brain. The New England journal of medicine Tawbi, H. A., Forsyth, P. A., Algazi, A., Hamid, O., Hodi, F. S., Moschos, S. J., Khushalani, N. I., Lewis, K., Lao, C. D., Postow, M. A., Atkins, M. B., Ernstoff, M. S., Reardon, D. A., Puzanov, I., Kudchadkar, R. R., Thomas, R. P., Tarhini, A., Pavlick, A. C., Jiang, J., Avila, A., Demelo, S., Margolin, K. 2018; 379 (8): 722–30

  Abstract

  BACKGROUND: Brain metastases are a common cause of disabling neurologic complications and death in patients with metastatic melanoma. Previous studies of nivolumab combined with ipilimumab in metastatic melanoma have excluded patients with untreated brain metastases. We evaluated the efficacy and safety of nivolumab plus ipilimumab in patients with melanoma who had untreated brain metastases.METHODS: In this open-label, multicenter, phase 2 study, patients with metastatic melanoma and at least one measurable, nonirradiated brain metastasis (tumor diameter, 0.5 to 3 cm) and no neurologic symptoms received nivolumab (1 mg per kilogram of body weight) plus ipilimumab (3 mg per kilogram) every 3 weeks for up to four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks until progression or unacceptable toxic effects. The primary end point was the rate of intracranial clinical benefit, defined as the percentage of patients who had stable disease for at least 6 months, complete response, or partial response.RESULTS: Among 94 patients with a median follow-up of 14.0 months, the rate of intracranial clinical benefit was 57% (95% confidence interval [CI], 47 to 68); the rate of complete response was 26%, the rate of partial response was 30%, and the rate of stable disease for at least 6 months was 2%. The rate of extracranial clinical benefit was 56% (95% CI, 46 to 67). Treatment-related grade 3 or 4 adverse events were reported in 55% of patients, including events involving the central nervous system in 7%. One patient died from immune-related myocarditis. The safety profile of the regimen was similar to that reported in patients with melanoma who do not have brain metastases.CONCLUSIONS: Nivolumab combined with ipilimumab had clinically meaningful intracranial efficacy, concordant with extracranial activity, in patients with melanoma who had untreated brain metastases. (Funded by Bristol-Myers Squibb and the National Cancer Institute; CheckMate 204 ClinicalTrials.gov number, NCT02320058 .).

  View details for PubMedID 30134131

• Conditional Probability of Survival as a Proposed Endpoint for Future Single-Arm Clinical Trials in Glioblastoma Patel, C. B., Thomas, R. P., Nagpal, S., Recht, L. D. WILEY. 2017: S206–S207

  View details for Web of Science ID 000413198700445

• Anti-PD-1-associated inflammatory-demyelinating lesions in patients with brain metastases Samghabadi, P., Makar, S., Thomas, R., Pelpola, J., Reddy, S., Tranvinh, E., Spence, A., Vogel, H., Born, D., Sobel, R. OXFORD UNIV PRESS INC. 2017: 500–501

  View details for Web of Science ID 000404906900045

• Phase 1/2 Trial of 5-Fraction Stereotactic Radiosurgery With 5-mm Margins With Concurrent and Adjuvant Temozolomide in Newly Diagnosed Supratentorial Glioblastoma: Health-Related Quality of Life Results. International journal of radiation oncology, biology, physics Pollom, E. L., Fujimoto, D., Wynne, J., Seiger, K., Modlin, L. A., Jacobs, L. R., Azoulay, M., von Eyben, R., Tupper, L., Gibbs, I. C., Hancock, S. L., Li, G., Chang, S. D., Adler, J. R., Harsh, G. R., Harraher, C., Nagpal, S., Thomas, R. P., Recht, L. D., Choi, C. Y., Soltys, S. G. 2017; 98 (1): 123-130

  Abstract

  We report a longitudinal assessment of health-related quality of life (HRQOL) in patients with glioblastoma (GBM) treated on a prospective dose escalation trial of 5-fraction stereotactic radiosurgery (25-40 Gy in 5 fractions) with concurrent and adjuvant temozolomide.HRQOL was assessed using the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire core-30 (QLQ-C30) general, the EORTC quality of life questionnaire-brain cancer specific module (QLQ-BN20), and the M.D. Anderson Symptom Inventory-Brain Tumor (MDASI-BT). Questionnaires were completed at baseline and at every follow-up visit after completion of radiosurgery. Changes from baseline for 9 predefined HRQOL measures (global quality of life, physical functioning, social functioning, emotional functioning, motor dysfunction, communication deficit, fatigue, insomnia, and future uncertainty) were calculated at every time point.With a median follow-up time of 10.4 months (range, 0.4-52 months), 139 total HRQOL questionnaires were completed by the 30 patients on trial. Compliance with HRQOL assessment was 76% at 12 months. Communication deficit significantly worsened over time, with a decline of 1.7 points per month (P=.008). No significant changes over time were detected in the other 8 scales of our primary analysis, including global quality of life. Although 8 patients (27%) experienced adverse radiation effects (ARE) on this dose escalation trial, it was not associated with a statistically significant decline in any of the primary HRQOL scales. Disease progression was associated with communication deficit, with patients experiencing an average worsening of 13.9 points per month after progression compared with 0.7 points per month before progression (P=.01).On this 5-fraction dose escalation protocol for newly diagnosed GBM, overall HRQOL remained stable and appears similar to historical controls of 30 fractions of radiation therapy. Tumor recurrence was associated with worsening communication deficit, and ARE did not correlate with a decline in HRQOL.

  View details for DOI 10.1016/j.ijrobp.2017.01.242

  View details for PubMedID 28586949

• Response of metastatic glioma to vemurafenib. Neuro-oncology practice Leaver, K. E., Zhang, N., Ziskin, J. L., Vogel, H., Recht, L., Thomas, R. P. 2016; 3 (4): 268-271

  Abstract

  Extraneural metastatic disease of glioma is rare and poses unique therapeutic challenges. Increasingly, the ability to sequence genetic alterations in tumors has allowed for the identification of common oncogenic signatures such as the activating BRAFV600E mutation and may be useful in therapeutic decision making. We report two patients with widespread aggressive gliomas whose tumors were found to express the BRAFV600E mutation and then responded robustly albeit transiently when exposed to vemurafenib. Although both patients succumbed to their disease, our results suggest that targeting BRAF might be appropriate for patients with aggressive gliomas that express this mutation.

  View details for DOI 10.1093/nop/npv054

  View details for PubMedID 31386052

  View details for PubMedCentralID PMC6657395

• Melanoma central nervous system metastases: current approaches, challenges, and opportunities PIGMENT CELL & MELANOMA RESEARCH Cohen, J. V., Tawbi, H., Margolin, K. A., Amravadi, R., Bosenberg, M., Brastianos, P. K., Chiang, V. L., de Groot, J., Glitza, I. C., Herlyn, M., Holmen, S. L., Jilaveanu, L. B., Lassman, A., Moschos, S., Postow, M. A., Thomas, R., Tsiouris, J. A., Wen, P., White, R. M., Turnham, T., Davies, M. A., Kluger, H. M. 2016; 29 (6): 627-642

  Abstract

  Melanoma central nervous system metastases are increasing, and the challenges presented by this patient population remain complex. In December 2015, the Melanoma Research Foundation and the Wistar Institute hosted the First Summit on Melanoma Central Nervous System (CNS) Metastases in Philadelphia, Pennsylvania. Here, we provide a review of the current status of the field of melanoma brain metastasis research; identify key challenges and opportunities for improving the outcomes in patients with melanoma brain metastases; and set a framework to optimize future research in this critical area.

  View details for DOI 10.1111/pcmr.12538

  View details for PubMedID 27615400

• Phase II pilot study of single-agent etirinotecan pegol (NKTR-102) in bevacizumab-resistant high grade glioma JOURNAL OF NEURO-ONCOLOGY Nagpal, S., Recht, C. K., Bertrand, S., Thomas, R. P., Ajlan, A., Pena, J., Gershon, M., Coffey, G., Kunz, P. L., Li, G., Recht, L. D. 2015; 123 (2): 277-282

  Abstract

  Patients with recurrence of high-grade glioma (HGG) after bevacizumab (BEV) have an extremely poor prognosis. Etirinotecan pegol (EP) is the first long-acting topoisomerase-I inhibitor designed to concentrate in and provide continuous tumor exposure throughout the entire chemotherapy cycle. Here we report results of a Phase 2, single arm, open-label trial evaluating EP in HGG patients who progressed after BEV. Patients age >18 with histologically proven anaplastic astrocytoma or glioblastoma (GB) who previously received standard chemo-radiation and recurred after BEV were eligible. A predicted life expectancy >6 weeks and KPS ≥ 50 were required. The primary endpoint was PFS at 6-weeks. Secondary endpoint was overall survival from first EP infusion. Response was assessed by RANO criteria. Single agent EP was administered IV every 3 weeks at 145 mg/m2. Patients did not receive BEV while on EP. 20 patients (90 % GB) were enrolled with a median age of 50 and median KPS of 70. Three patients with GB (16.7 % of GB) had partial MRI responses. 6-week PFS was 55 %. Median and 6-month PFS were 2.2 months (95 % CI 1.4-3.4 months) and 11.2 % (95 % CI 1.9-28.9 %) respectively. Median overall survival from first EP infusion was 4.5 months (95 % CI 2.4-5.9). Only one patient had grade 3 toxicity (diarrhea with dehydration) attributable to EP. Hematologic toxicity was mild. Three patients had confirmed partial responses according to RANO criteria. These clinical data combined with a favorable safety profile warrant further clinical investigation of this agent in HGG.

  View details for DOI 10.1007/s11060-015-1795-0

  View details for PubMedID 25935109

• Treatment options for optic pathway gliomas. Current treatment options in neurology Thomas, R. P., Gibbs, I. C., Xu, L. W., Recht, L. 2015; 17 (2): 333-?

  Abstract

  Gliomas that affect the optic pathways are for the most part low-grade neoplasms that often, but not always, have good prognoses. Optimal treatment and management of optic pathway gliomas remains unclear and the decision hinges upon several factors including patient age, tumor location, and visual symptoms. We favor a treatment approach that is dependent on the location of tumor within anterior, chiasmal or posterior/hypothalamic visual pathways. In children who are minimally or not symptomatic, we recommend observation rather than early treatment intervention. Most of these patients will have neurofibromatosis type 1 (NF1) based on the natural history and their pilocytic astrocytoma histology. Serial magnetic resonance imaging studies and formal neuro-ophthalmology testing should enable close observation of these patients, with intervention being reserved for when tumor progression results in significant visual loss or proptosis. Chemotherapy is an accepted first line treatment, and a number of effective medications are available, although no agent has proven clearly superior. If progression is accompanied by the complete loss of vision, surgery can be utilized to help alleviate structural issues (ie, proptosis). Minimally symptomatic chiasmal or hypothalamic tumors that arise in the setting of NF1 can also be observed initially because of their favorable prognosis. Children with NF1 and chiasmal or posterior visual tumors who progress either on imaging or clinical grounds (ie, development of significant visual deficits) should be treated first with chemotherapy rather than radiation therapy to minimize the effects on the developing central nervous system. Individuals without NF1 presenting with a chiasmal or hypothalamic mass are candidates for biopsy to determine the underlying pathology of the lesion. Symptomatic patients with pilocytic astrocytoma should first receive chemotherapy. In contrast, other histologies including malignant optic pathway gliomas should be treated similar to other gliomas that occur in other locations with appropriate doses of radiation and chemotherapy.

  View details for DOI 10.1007/s11940-014-0333-2

  View details for PubMedID 25619537

• Treatment Options for Optic Pathway Gliomas CURRENT TREATMENT OPTIONS IN NEUROLOGY Thomas, R. P., Gibbs, I. C., Xu, L. W., Recht, L. 2015; 17 (2)

  View details for DOI 10.1007/s11940-014-0333-2

  View details for Web of Science ID 000351159000001

  View details for PubMedID 25619537

• ARE WE USING TOO MUCH BEVACIZUMAB IN OUR GBM PATIENTS? Ajlan, A., Thomas, P., Thomas, R., Nagpal, S., Recht, L. OXFORD UNIV PRESS INC. 2014

  View details for DOI 10.1093/neuonc/nou238.1

  View details for Web of Science ID 000350452200002

• COMPLETE RESPONSE TO VEMURAFINIB IN A PATIENT WITH METASTATIC ANAPLASTIC XANTHROASTROCYTOMA Thomas, R., Ajlan, A., Ziskin, J., Soltys, S., Reddy, S., Recht, L., Nagpal, S. OXFORD UNIV PRESS INC. 2014

  View details for DOI 10.1093/neuonc/nou265.32

  View details for Web of Science ID 000350452200661

• Simultaneous perfusion and permeability measurements using combined spin- and gradient-echo MRI. Journal of cerebral blood flow and metabolism Schmiedeskamp, H., Andre, J. B., Straka, M., Christen, T., Nagpal, S., Recht, L., Thomas, R. P., Zaharchuk, G., Bammer, R. 2013; 33 (5): 732-743

  Abstract

  The purpose of this study was to estimate magnetic resonance imaging-based brain perfusion parameters from combined multiecho spin-echo and gradient-echo acquisitions, to correct them for T1-, T2-, and -related contrast agent (CA) extravasation effects, and to simultaneously determine vascular permeability. Perfusion data were acquired using a combined multiecho spin- and gradient-echo (SAGE) echo-planar imaging sequence, which was corrected for CA extravasation effects using pharmacokinetic modeling. The presented method was validated in simulations and brain tumor patients, and compared with uncorrected single-echo and multiecho data. In the presence of CA extravasation, uncorrected single-echo data resulted in underestimated CA concentrations, leading to underestimated single-echo cerebral blood volume (CBV) and mean transit time (MTT). In contrast, uncorrected multiecho data resulted in overestimations of CA concentrations, CBV, and MTT. The correction of CA extravasation effects resulted in CBV and MTT estimates that were more consistent with the underlying tissue characteristics. Spin-echo perfusion data showed reduced large-vessel blooming effects, facilitating better distinction between increased CBV due to active tumor progression and elevated CBV due to the presence of cortical vessels in tumor proximity. Furthermore, extracted permeability parameters were in good agreement with elevated T1-weighted postcontrast signal values.

  View details for DOI 10.1038/jcbfm.2013.10

  View details for PubMedID 23462570

• The incidence and significance of multiple lesions in glioblastoma JOURNAL OF NEURO-ONCOLOGY Thomas, R. P., Xu, L. W., Lober, R. M., Li, G., Nagpal, S. 2013; 112 (1): 91-97

  Abstract

  The location and distribution of glioblastoma (GBM) within the brain parenchyma plays an important role in surgical and radiation planning. Prior studies have reported incidences of multiple lesions at the time of diagnosis ranging from 0.5 to 20 %. Multiple lesions can be further categorized as multifocal (multiple areas involved, but with a clear path of spread from one lesion to another) or multicentric (multiple lesions, no clear path of spread). In this retrospective study, we reviewed our experience with GBM and found the incidence of multiple lesions at time of diagnosis was 35 %, much higher than previously suggested in the literature. Patients with single lesions had an improved overall survival when compared to patients with multiple lesions (18 vs. 10 months). Patients with multicentric lesions fared the worst, with average survival of 3 months. However, the difference between single and multiple lesions (multifocal or multicentric) was no longer significant when taking into consideration age, Karnofsky performance score (KPS) and extent of resection by multivariate analysis. Age, KPS, gross total resection, and MGMT status were independent predictors of outcome. Multiple lesions did not independently confer a worse outcome, but were associated with lower KPS scores and inability to perform gross total resection. These findings suggest that single, multiple and multicentric imaging exams represent a spectrum of presentations of a single disease. The rate of multiple lesions reported here may be the result of improved imaging technology, suggesting that incidence of multiple lesions will continue to increase as imaging technology advances.

  View details for DOI 10.1007/s11060-012-1030-1

  View details for PubMedID 23354652

• Advances in the management of glioblastoma: the role of temozolomide and MGMT testing. Clinical pharmacology : advances and applications Thomas, R. P., Recht, L., Nagpal, S. 2013; 5: 1-9

  Abstract

  Glioblastoma (GB) is one of the most lethal forms of cancer, with an invasive growth pattern that requires the use of adjuvant therapies, including chemotherapy and radiation, to prolong survival. Temozolomide (TMZ) is an oral chemotherapy with a limited side effect profile that has become the standard of care in GB treatment. While TMZ has made an impact on survival, tumor recurrence and TMZ resistance remain major challenges. Molecular markers, such as O6-methylguanine-DNA methyltransferase methylation status, can be helpful in predicting tumor response to TMZ, and therefore guides clinical decision making. This review will discuss the epidemiology and possible genetic underpinnings of GB, how TMZ became the standard of care for GB patients, the pharmacology of TMZ, the practical aspects of using TMZ in clinic, and how molecular diagnostics - particularly the use of O6-methylguanine-DNA methyltransferase status - affect clinical management.

  View details for DOI 10.2147/CPAA.S26586

  View details for PubMedID 23293540

• PRELIMINARY RESULTS UTILIZING VESSEL SIZE IMAGING AS A METRIC OF RESPONSE IN GLIOBLASTOMA MULTIFORME 17th Annual Scientific Meeting and Education Day of the Society-for-Neuro-Oncology (SNO) Andre, J. B., Schmiedeskamp, H., Thomas, R. P., Feroze, A., Nagpal, S., Zaharchuk, G., Straka, M., Recht, L., Bammer, R. OXFORD UNIV PRESS INC. 2012: 127–127

  View details for Web of Science ID 000310971300503

• THE INCIDENCE AND SIGNIFICANCE OF MULTIPLE LESIONS IN GLIOBLASTOMA Xu, L. W., Thomas, R. P., Lober, R. M., Nagpal, S., Li, G. OXFORD UNIV PRESS INC. 2012: 120

  View details for Web of Science ID 000310971300475

• Tumor-derived chemokine MCP-1/CCL2 is sufficient for mediating tumor tropism of adoptively transferred T cells JOURNAL OF IMMUNOLOGY Brown, C. E., Vishwanath, R. P., Aguilar, B., Starr, R., Najbauer, J., Aboody, K. S., Jensen, M. C. 2007; 179 (5): 3332-3341

  Abstract

  To exert a therapeutic effect, adoptively transferred tumor-specific CTLs must traffic to sites of tumor burden, exit the circulation, and infiltrate the tumor microenvironment. In this study, we examine the ability of adoptively transferred human CTL to traffic to tumors with disparate chemokine secretion profiles independent of tumor Ag recognition. Using a combination of in vivo tumor tropism studies and in vitro biophotonic chemotaxis assays, we observed that cell lines derived from glioma, medulloblastoma, and renal cell carcinoma efficiently chemoattracted ex vivo-expanded primary human T cells. We compared the chemokines secreted by tumor cell lines with high chemotactic activity with those that failed to elicit T cell chemotaxis (Daudi lymphoma, 10HTB neuroblastoma, and A2058 melanoma cells) and found a correlation between tumor-derived production of MCP-1/CCL2 (> or =10 ng/ml) and T cell chemotaxis. Chemokine immunodepletion studies confirmed that tumor-derived MCP-1 elicits effector T cell chemotaxis. Moreover, MCP-1 is sufficient for in vivo T cell tumor tropism as evidenced by the selective accumulation of i.v. administered firefly luciferase-expressing T cells in intracerebral xenografts of tumor transfectants secreting MCP-1. These studies suggest that the capacity of adoptively transferred T cells to home to tumors may be, in part, dictated by the species and amounts of tumor-derived chemokines, in particular MCP-1.

  View details for Web of Science ID 000248991800076

  View details for PubMedID 17709550

• A quantitative high-throughput chemotaxis assay using bioluminescent reporter cells JOURNAL OF IMMUNOLOGICAL METHODS Vishwanath, R. P., Brown, C. E., Wagner, J. R., Meechoovet, H. B., Naranjo, A., Wright, C. L., Olivares, S., Qian, D., Cooper, L. J., Jensen, M. C. 2005; 302 (1-2): 78-89

  Abstract

  Here we report on a novel biophotonic assay system for the detection and quantitation of chemotaxis, the directed movement of cells in response to chemokine concentration gradients. Our assay employs a firefly luciferase (ffLuc)-generated biophotonic signal to quantify cellular migration in 96-well microplate chemotaxis instruments. When compared to direct cell enumeration, the biophotonic reporter method is superior in accuracy, reproducibility, and sensitivity. As a proof-of-concept, we demonstrate the utility of this assay for quantifying the chemotactic response of ex vivo expanded ffLuc(+) primary human T-cells to recombinant human chemokines MCP-1, RANTES, and IP-10. The 96-well microplate format and in situ biophotonic detection of cells are amenable to high-throughput screening of peptides and small molecule libraries to identify agonists and antagonists of cellular chemotaxis, to analyze biological fluids for chemotactic activity, and to study chemotaxis in a variety of cell types.

  View details for DOI 10.1016/j.jim.2005.04.021

  View details for Web of Science ID 000231490600007

  View details for PubMedID 15987642

• Biophotonic cytotoxicity assay for high-throughput screening of cytolytic killing JOURNAL OF IMMUNOLOGICAL METHODS Brown, C. E., Wright, C. L., Naranjo, A., Vishwanath, R. P., Chang, W. C., Olivares, S., Wagner, J. R., Bruins, L., Raubitschek, A., Cooper, L. J., Jensen, M. C. 2005; 297 (1-2): 39-52

  Abstract

  We have developed a highly sensitive biophotonic luciferase assay as an alternative to (51)Cr-release for assessment of cell-mediated cytotoxicity. The luciferin/ATP-dependent luminescent signal of target cells stably or transiently transfected with a firefly luciferase reporter gene (fLuc:Zeo) linearly correlates with viable target cell number. Upon incubation of fLuc:Zeo(+) target cells with CD8(+) CTLs, a rapid decrease in bioluminescence was detected that correlated with antigen-specific target cell lysis. The levels of specific lysis measured by (51)Cr-release assays correlated with the attenuation in biophotonic target cell signal, thus validating this approach as a sensitive and accurate method for the measurement of cytolysis. We show that this luminescent-based cytolytic assay (LCA) is amenable for high-throughput screening of effector cell cytolytic activity, allows for the rate of cytolysis to be measured in a single micro-plate, and permits the multiplexing of cytolytic killing with other lymphocyte functional assays such as cytokine release. Importantly, this method accurately measures the cytolytic killing of target cells that are either stably or transiently transfected with a fLuc reporter gene, and thus is ideal for monitoring cytolysis of both primary autologous and immortalized target cell lines. The versatility of the non-radioactive, high-throughput, biophotonic cytolytic assay should make this method an attractive alternative to chromium-release for quantifying effector cell cytolytic activity.

  View details for DOI 10.1016/j.jim.2004.11.021

  View details for Web of Science ID 000228301700004

  View details for PubMedID 15777929

• Quantification of chemotherapeutic target gene mRNA expression in human breast cancer biopsies: Comparison of real-time reverse transcription-PCR vs. relative quantification reverse transcription-PCR utilizing DNA sequencer analysis of PCR products JOURNAL OF CLINICAL LABORATORY ANALYSIS Juhasz, A., Frankel, P., Cheng, C., Rivera, H., Vishwanath, R., Chiu, A., Margolin, K., Yen, Y., Newman, E. M., Synold, T., Wilczynski, S., Lenz, H. J., Gandara, D., Albain, K. S., Longmate, J., Doroshow, J. H. 2003; 17 (5): 184-194

  Abstract

  The solid tumor mRNA expression of genes related to the mechanism of action of certain antineoplastic agents is often predictive of clinical efficacy. We report here on the development of a rapid and practical real-time RT-PCR method to quantify genetic expression in solid tumors. The genes examined are related to the intracellular pharmacology of gemcitabine and cisplatin, two drugs that are used in the treatment of several types of advanced cancer. We evaluated target gene mRNA levels from breast tumor samples using two quantitative RT-PCR methods: 1) an improved relative RT-PCR method using fluorescence-labeled primers, automated PCR set up, and GeneScan analysis software; and 2) real-time RT-PCR with redesigned primers using an ABI 7900HT instrument, with additional postprocessing of the data to adjust for efficiency differences across the target genes. Using these methods, we quantified mRNA expression levels of deoxycytidine kinase (dCK), deoxycytidylate deaminase (dCDA), the M1 and M2 subunits of ribonucleotide reductase (RRM1, RRM2), and excision cross complementation group 1 (ERCC1) in 35 human "fresh" frozen breast cancer biopsies. While both assay methods were substantially more rapid than traditional RT-PCR, real-time RT-PCR appeared to be superior to the amplification end-point measurement in terms of precision and high throughput, even when a DNA sequencer was used to assess fluorescence-labeled PCR products. This reproducible, highly sensitive real-time RT-PCR method for the detection and quantification of the mRNAs for dCK, dCDA, RRM1, RRM2, and ERCC1 in human breast cancer biopsies appears to be more informative and less time-consuming than either classical radioisotope-dependent RT-PCR or the technique utilizing GeneScan analysis described herein. By allowing the measurement of intratumoral target gene expression, these new methods may prove useful in predicting the clinical utility of gemcitabine- and platinum-containing chemotherapy programs in patients with solid tumors.

  View details for DOI 10.1002/jcla.10091

  View details for Web of Science ID 000186284100008

  View details for PubMedID 12938148