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1. Routine use of low-dose glucarpidase following high-dose methotrexate in adult patients with CNS lymphoma: an open-label, multi-center phase I study

Author

Lauren R. Schaff, Mina Lobbous, Dean Carlow, Ryan Schofield, Igor T. Gavrilovic, Alexandra M. Miller, Jacqueline B. Stone, Anna F. Piotrowski, Ugur Sener, Anna Skakodub, Edward P. Acosta, Kevin J. Ryan, Ingo K. Mellinghoff, Lisa M. DeAngelis, Louis B. Nabors, and Christian Grommes

Subjects
CNS lymphoma, Methotrexate, Glucarpidase, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background High-dose methotrexate (HD-MTX) has broad use in the treatment of central nervous system (CNS) malignancies but confers significant toxicity without inpatient hydration and monitoring. Glucarpidase is a bacterial recombinant enzyme dosed at 50 units (u)/kg, resulting in rapid systemic MTX clearance. The aim of this study was to demonstrate feasibility of low-dose glucarpidase to facilitate MTX clearance in patients with CNS lymphoma (CNSL). Methods Eight CNSL patients received HD-MTX 3 or 6 g/m2 and glucarpidase 2000 or 1000u 24 h later. Treatments repeated every 2 weeks up to 8 cycles. Results Fifty-five treatments were administered. Glucarpidase 2000u yielded > 95% reduction in plasma MTX within 15 min following 33/34 doses (97.1%) and glucarpidase 1000u yielded > 95% reduction following 15/20 doses (75%). Anti-glucarpidase antibodies developed in 4 patients and were associated with MTX rebound. In CSF, glucarpidase was not detected and MTX levels remained cytotoxic after 1 (3299.5 nmol/L, n = 8) and 6 h (1254.7 nmol/L, n = 7). Treatment was safe and well-tolerated. Radiographic responses in 6 of 8 patients (75%) were as expected following MTX-based therapy. Conclusions This study demonstrates feasibility of planned-use low-dose glucarpidase for MTX clearance and supports the hypothesis that glucarpidase does not impact MTX efficacy in the CNS. Clinical trial registration NCT03684980 (Registration date 26/09/2018).

Published
2022
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2. Sequencing and curation strategies for identifying candidate glioblastoma treatments

Author

Mayu O. Frank, Takahiko Koyama, Kahn Rhrissorrakrai, Nicolas Robine, Filippo Utro, Anne-Katrin Emde, Bo-Juen Chen, Kanika Arora, Minita Shah, Heather Geiger, Vanessa Felice, Esra Dikoglu, Sadia Rahman, Alice Fang, Vladimir Vacic, Ewa A. Bergmann, Julia L. Moore Vogel, Catherine Reeves, Depinder Khaira, Anthony Calabro, Duyang Kim, Michelle F. Lamendola-Essel, Cecilia Esteves, Phaedra Agius, Christian Stolte, John Boockvar, Alexis Demopoulos, Dimitris G. Placantonakis, John G. Golfinos, Cameron Brennan, Jeffrey Bruce, Andrew B. Lassman, Peter Canoll, Christian Grommes, Mariza Daras, Eli Diamond, Antonio Omuro, Elena Pentsova, Dana E. Orange, Stephen J. Harvey, Jerome B. Posner, Vanessa V. Michelini, Vaidehi Jobanputra, Michael C. Zody, John Kelly, Laxmi Parida, Kazimierz O. Wrzeszczynski, Ajay K. Royyuru, and Robert B. Darnell

Subjects
Internal medicine, RC31-1245, Genetics, QH426-470
Abstract

Abstract Background Prompted by the revolution in high-throughput sequencing and its potential impact for treating cancer patients, we initiated a clinical research study to compare the ability of different sequencing assays and analysis methods to analyze glioblastoma tumors and generate real-time potential treatment options for physicians. Methods A consortium of seven institutions in New York City enrolled 30 patients with glioblastoma and performed tumor whole genome sequencing (WGS) and RNA sequencing (RNA-seq; collectively WGS/RNA-seq); 20 of these patients were also analyzed with independent targeted panel sequencing. We also compared results of expert manual annotations with those from an automated annotation system, Watson Genomic Analysis (WGA), to assess the reliability and time required to identify potentially relevant pharmacologic interventions. Results WGS/RNAseq identified more potentially actionable clinical results than targeted panels in 90% of cases, with an average of 16-fold more unique potentially actionable variants identified per individual; 84 clinically actionable calls were made using WGS/RNA-seq that were not identified by panels. Expert annotation and WGA had good agreement on identifying variants [mean sensitivity = 0.71, SD = 0.18 and positive predictive value (PPV) = 0.80, SD = 0.20] and drug targets when the same variants were called (mean sensitivity = 0.74, SD = 0.34 and PPV = 0.79, SD = 0.23) across patients. Clinicians used the information to modify their treatment plan 10% of the time. Conclusion These results present the first comprehensive comparison of technical and machine augmented analysis of targeted panel and WGS/RNA-seq to identify potential cancer treatments.

Published
2019
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3. EGFR feedback-inhibition by Ran-binding protein 6 is disrupted in cancer

Author

Barbara Oldrini, Wan-Ying Hsieh, Hediye Erdjument-Bromage, Paolo Codega, Maria Stella Carro, Alvaro Curiel-García, Carl Campos, Maryam Pourmaleki, Christian Grommes, Igor Vivanco, Daniel Rohle, Craig M. Bielski, Barry S. Taylor, Travis J. Hollmann, Marc Rosenblum, Paul Tempst, John Blenis, Massimo Squatrito, and Ingo K. Mellinghoff

Subjects
Science
Abstract

The epidermal growth factor receptor (EGFR) signalling is regulated at multiple levels. Here the authors show that the importin RanBP6 acts as a tumor suppressor in Glioblastoma and regulates EGFR signalling through promoting translocation of STAT3 to the nuclei and repressing EGFR transcription.

Published
2017
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4. Retrospective review of safety and efficacy of programmed cell death-1 inhibitors in refractory high grade gliomas

Author

Samantha N. Reiss, Prakirthi Yerram, Lisa Modelevsky, and Christian Grommes

Subjects
Glioblastoma, Immune checkpoint, High-grade glioma, PD-1, PD-L1, Pembrolizumab, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Programmed cell death ligand-1 (PD-L1) expression has been reported in up to 61% of high grade gliomas (HGG). The purpose of this study was to describe safety and efficacy of PD-1 inhibition in patients with refractory HGGs. Methods This Institutional Review Board approved single center retrospective study included adult patients with pathologically confirmed HGG who received a PD-1 inhibitor from 9/2014–10/2016 outside of a clinical trial at Memorial Sloan Kettering Cancer Center. Results Twenty five HGG patients received pembrolizumab as part of a compassionate use program. Median age was 50 years (range 30–72); 44% were men; 13 had glioblastoma (52%), 7 anaplastic astrocytoma (28%), 2 anaplastic oligodendroglioma (8%), 2 unspecified HGG (8%), and 1 gliosarcoma (4%). Median prior lines of treatments were 4 (range 1–9). Nineteen (76%) previously failed bevacizumab. Median KPS was 80 (range 50–100). Concurrent treatment included bevacizumab in 17 (68%) or bevacizumab and temozolomide in 2 (8%) patients. Median number of doses administered was 3 (range 1–14). Outcomes were assessed in 24 patients. PD-1 inhibitor related adverse events included LFT elevations, hypothyroidism, diarrhea, myalgias/arthralgias, and rash. Best radiographic response was partial response (n = 2), stable disease (n = 5), and progressive disease (n = 17). Median progression free survival (PFS) was 1.4 months (range 0.2–9.4) and median overall survival (OS) was 4 months (range 0.5–13.8). Three-month PFS was 12% and 6-month OS was 28%. Conclusion While response rates are low, a few patients had a prolonged PFS. Pembrolizumab was tolerated with few serious toxicities, even in patients receiving concomitant therapy.

Published
2017
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5. Correction to: Sequencing and curation strategies for identifying candidate glioblastoma treatments

Author

Mayu O. Frank, Takahiko Koyama, Kahn Rhrissorrakrai, Nicolas Robine, Filippo Utro, Anne-Katrin Emde, Bo-Juen Chen, Kanika Arora, Minita Shah, Heather Geiger, Vanessa Felice, Esra Dikoglu, Sadia Rahman, Xiaolan Fang, Vladimir Vacic, Ewa A. Bergmann, Julia L. Moore Vogel, Catherine Reeves, Depinder Khaira, Anthony Calabro, Duyang Kim, Michelle F. Lamendola-Essel, Cecilia Esteves, Phaedra Agius, Christian Stolte, John Boockvar, Alexis Demopoulos, Dimitris G. Placantonakis, John G. Golfinos, Cameron Brennan, Jeffrey Bruce, Andrew B. Lassman, Peter Canoll, Christian Grommes, Mariza Daras, Eli Diamond, Antonio Omuro, Elena Pentsova, Dana E. Orange, Stephen J. Harvey, Jerome B. Posner, Vanessa V. Michelini, Vaidehi Jobanputra, Michael C. Zody, John Kelly, Laxmi Parida, Kazimierz O. Wrzeszczynski, Ajay K. Royyuru, and Robert B. Darnell

Subjects
Internal medicine, RC31-1245, Genetics, QH426-470
Abstract

Following publication of the original article [1], it was reported that the given name of the fourteenth author was incorrectly published. The incorrect and the correct names are given below.

Published
2019
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6. Combination Olaparib and Temozolomide for the Treatment of Glioma: A Retrospective Case Series

Author

Lauren R Schaff, Marina Kushnirsky, Andrew L Lin, Subhiksha Nandakumar, Christian Grommes, Alexandra Michelle Miller, Igor T Gavrilovic, Craig Nolan, Elena Pentsova, Ingo K Mellinghoff, and Thomas J Kaley

Subjects
Clinical/Scientific Note, Neurology (clinical)
Abstract

Objectives:To report on the tolerability and efficacy of olaparib with temozolomide (TMZ) for gliomaMethods:Single-center retrospective series of glioma patients treated with olaparib/TMZ September 2018-December 2021Results:Twenty patients (median age: 42, median Karnofsky Performance Status: 90) received olaparib/TMZ for diagnoses of IDH-mutant oligodendroglioma (n=5), IDH-mutant astrocytoma grade 2-3 (n=4), IDH-mutant astrocytoma grade 4 (n=7), or IDH-wildtype glioma (n=4). One patient was treated upfront and 19 at recurrence (median=3). Olaparib 150mg was administered three times/week concurrent with TMZ 50-75mg/m2 daily. Fatigue, gastrointestinal symptoms, and hematologic toxicity were common. 6/20 patients required dose reduction (n=4) or discontinuation (n=2) due to toxicity. Radiographic response was evaluable in 16 and observed (complete + partial) in 4/8 with IDH-mutant grade 2-3 glioma. No responses were seen in patients with grade 4 IDH-mutant astrocytomas (0/5) or IDH-wildtype gliomas (0/3). Progression-free survival was 7.8, 1.3, and 2.0 months, respectively.Discussion:Olaparib/TMZ resulted in objective radiographic response in 50% of evaluable patients with recurrent IDH-mutant grade 2-3 gliomas with encouraging PFS and manageable toxicity. This supports a prospective trial of olaparib/TMZ for this population.Classification of Evidence:This case series provides Class IV evidence that treatment with olaparib/TMZ may result in radiographic response in patients with glioma.

Published
2022

7. Consensus recommendations for MRI and PET imaging of primary central nervous system lymphoma: guideline statement from the International Primary CNS Lymphoma Collaborative Group (IPCG)

Author

Maciej M. Mrugala, Edward A. Neuwelt, Heiko Schöder, Benjamin M. Ellingson, C. Chad Quarles, Gerald Illerhaus, Tracy T. Batchelor, Timothy J. Kaufmann, Andrés J.M. Ferreri, James L. Rubenstein, Christopher P. Fox, Nicoletta Anzalone, Christian Grommes, Leland S. Hu, Letterio S. Politi, Ovidiu C. Andronesi, Dorothee P. Auer, Jerrold L. Boxerman, Motoo Nagane, Ramon F. Barajas, Prakash Ambady, Barajas, R. F., Politi, L. S., Anzalone, N., Schoder, H., Fox, C. P., Boxerman, J. L., Kaufmann, T. J., Quarles, C. C., Ellingson, B. M., Auer, D., Andronesi, O. C., Ferreri, A. J. M., Mrugala, M. M., Grommes, C., Neuwelt, E. A., Ambady, P., Rubenstein, J. L., Illerhaus, G., Nagane, M., Batchelor, T. T., and Hu, L. S.

Subjects
Central Nervous System, Cancer Research, Lymphoma, Central Nervous System Neoplasms, 0302 clinical medicine, hemic and lymphatic diseases, Cancer, medicine.diagnostic_test, Primary central nervous system lymphoma, imaging, Hematology, Guideline Statement, Magnetic Resonance Imaging, Oncology, Positron emission tomography, 030220 oncology & carcinogenesis, Biomedical Imaging, Patient Safety, 4.2 Evaluation of markers and technologies, MRI, medicine.medical_specialty, Consensus, Oncology and Carcinogenesis, Brain tumor, Context (language use), 03 medical and health sciences, Rare Diseases, Clinical Research, medicine, Medical imaging, AcademicSubjects/MED00300, Humans, Medical physics, Oncology & Carcinogenesis, PCNSL, primary central nervous system lymphoma, business.industry, Neurosciences, Reproducibility of Results, Magnetic resonance imaging, Guideline, medicine.disease, Clinical trial, PET, Positron-Emission Tomography, AcademicSubjects/MED00310, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

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

Published
2021

8. CTNI-61. PILOT STUDY OF REPEATED PLANNED GLUCARPIDASE FOLLOWING HIGH DOSE METHOTREXATE (HD-MTX) IN CNS LYMPHOMA (CNSL)

Author

Alexandra Miller, Anna Skakodub, Dean Carlow, Lauren Schaff, Edward P. Acosta, Ugur Sener, Juli Madzsar, Christian Grommes, Jacqueline B. Stone, Lisa M. DeAngelis, Kevin J. Ryan, Alyssa Schumpp, Igor T. Gavrilovic, Louis B. Nabors, Anna F. Piotrowski, and Mina Lobbous

Subjects
Oncology, musculoskeletal diseases, Cancer Research, medicine.medical_specialty, Glucarpidase, business.industry, Complete remission, Clinical Trials: Non-Immunologic, medicine.disease, High dose methotrexate, Lymphoma, Internal medicine, Troponin I, medicine, Methotrexate, Rituximab, Neurology (clinical), business, Anaphylaxis, medicine.drug
Abstract

This study explores the repeated use of glucarpidase following HD-MTX in patients with CNSL. HD-MTX requires aggressive hydration and inpatient monitoring to prevent toxicity. Glucarpidase 50 units(u)/kg for delayed MTX clearance results in a reduction of systemic MTX levels without crossing the blood brain barrier. This study explores the use of 1000 or 2000 units of glucarpidase following repeated cycles of MTX 3–8 g/m2. Eligible adult patients had isolated CNSL, CrCl ≥ 60 mL/min, and KPS ≥ 50. Rituximab with MTX was administered for eight cycles. Glucarpidase was given 24 hours after each MTX infusion. MTX concentrations were monitored in serum and cerebrospinal fluid (CSF). Twelve patients enrolled to date and data are available for 50 doses of MTX (3 g/m2 (20), 6 g/m2 (21), 8 g/m2 (9)). Glucarpidase 1000u (14) or 2000u (36) resulted in at least a 95% reduction in serum MTX levels within 15 minutes following 49/50 doses. A 93% decrease was seen with the remaining dose. Glucarpidase was not detected in the CSF of 7 patients analyzed. Potentially cytotoxic MTX concentrations (10–6 M) were observed in CSF 1 hour (7/7) and 6 hours (4/7) after glucarpidase administration. Radiographic responses are evaluable in 9 patients: complete response (5), partial response (2), stable disease (1), and progressive disease (1). No grade 3 events were attributed to glucarpidase; one grade 4 event of anaphylaxis occurred. Anti-glucarpidase antibodies were detected in 2/5 patients analyzed. In summary, administration of low-dose glucarpidase 24 hours after MTX 3–8 g/m2 results in a reproducible rapid reduction in serum MTX levels in non-renally impaired patients. CSF MTX levels remain therapeutic and clinical response expected from MTX-based therapy does not appear compromised. Anti-glucarpidase antibodies may develop though significance remains unclear. Study is ongoing. Future directions will explore glucarpidase use for reduction of inpatient stay with HD-MTX.

Published
2020

9. BIOM-53. DIFFUSION MR IMAGING DERIVED APPARENT DIFFUSION COEFFICIENT AS A POTENTIAL BIOMARKER OF CLINICAL OUTCOME IN RECURRENT CENTRAL NERVOUS SYSTEM LYMPHOMA

Author

Christian Grommes, Robert J. Young, Anton Nosov, and Ka-wai Ho

Subjects
Cancer Research, Pathology, medicine.medical_specialty, medicine.diagnostic_test, business.industry, Central nervous system, Magnetic resonance imaging, medicine.disease, Lymphoma, body regions, Cerebrospinal fluid, medicine.anatomical_structure, Oncology, medicine, Medical imaging, Effective diffusion coefficient, Neurology (clinical), Progression-free survival, business, Biomarkers, Diffusion MRI
Abstract

BACKGROUND Studies have shown that diffusion-weighted imaging (DWI) derived apparent diffusion coefficient (ADC) measurements inversely correlate with tumor cell density and may have prognostic value in newly-diagnosed CNS lymphoma patients. This study characterizes ADC measurements in a relapsed/refractory CNS lymphoma population and describes the potential prognostic value of ADC measurements in these patients. METHODS ADC measurements were assessed in immunocompetent patients enrolled on a prospective clinical trial studying ibrutinib-based treatment in recurrent/refractory CNS lymphoma (NCT02315326; 42 treated with single agent ibrutinib and 15 with an ibrutinib containing combination). Measurements were normalized to values contralateral to the lesion to generate an ADC measurement ratio. Imaging and clinical variables were correlated with treatment response. High-quality lesions were defined as areas with clear delineation from preserved brain parenchyma ≥ 10mm in maximal transverse dimension. Cerebral spinal fluid (CSF) was collected at time of MR imaging in all patients. RESULTS Thirty-nine out of 57 patients had lesions with measurable ADC of which 17 (44%) were high-quality ADC lesions. The median ADCmean ratio was 0.909 (range 0.497–1.444). There was no association between ADC ratios and tumor volume, CSF cell count, or CSF protein. The high-quality lesions had a median ADCmean ratio of 0.774 (range 0.497–1.051). These patients with a high ADCmean ratio (≥ 0.774) had increased rates of partial and complete responses (p=0.057) as well as a longer progression free survival (PFS; median not reached) compared to those with low ADCmean ratios (< 0.774; median PFS=1.5 months, p=0.016). CONCLUSION ADC ratios in the recurrent CNS population do not correlate with tumor size, cell count, or protein in the CSF. In high-quality DWI measurements, ADC might be a prognostic marker in relapsed/refractory CNS lymphoma patients treated with ibrutinib.

Published
2020

10. CMET-21. A PHASE IB STUDY OF PROTON CRANIOSPINAL IRRADIATION FOR THE TREATMENT OF SOLID TUMOR LEPTOMENINGEAL METASTASES

Author

Elena Pentsova, Christian Grommes, T. Jonathan Yang, Andrew Lin, Robert J. Young, Anna F. Piotrowski, Josh Yamada, Lauren Schaff, Michelle Mehallow, Suzanne L. Wolden, Jacqueline B. Stone, Adrienne Boire, Anna Skakodub, Bianca Santomasso, and Igor T. Gavrilovic

Subjects
Cancer Research, CNS Metastasis, Palliative care, business.industry, medicine.medical_treatment, Treatment outcome, Craniospinal Irradiation, Radiation therapy, Circulating tumor cell, Oncology, Medicine, Neurology (clinical), Progression-free survival, Nuclear medicine, business, Solid tumor, Carcinomatous meningitis
Abstract

Leptomeningeal metastases (LM) is associated with limited survival and treatment options for patients with solid tumor malignancies. While focal radiotherapy is effective for local palliation, it lacks durability due to cerebrospinal fluid (CSF) tumor cells reseeding. Craniospinal irradiation (CSI) in contrast treats the entire central nervous system (CNS) compartment thus potentially improves disease control. We performed a phase IB study of proton CSI using 30CGE in 10 fractions for treating solid tumor LM (NCT03520504). The primary end point is dose-liming toxicity (DLT) within 1 month of treatment. Clinical outcomes and CSF circulating tumor cells (CTCs) by CellSearch® were evaluated. Overall (OS) and progression-free survival (PFS) were assessed using Kaplan-Meier estimates. Of the 24 patients enrolled, 4 were excluded from analysis: 3 did not complete treatment due to CNS or systemic disease progression (PD), and 1 completed treatment outside study window. The majority of patients had metastatic lung (55%) and breast (30%) malignancies. At this submission, the median follow-up was 2.8 months (0.5–9.4 months). No DLT was observed. Treatment-related grade 2+ toxicities were: fatigue (G2=43%), anorexia (G2=5%), anemia (G2=10%), thrombocytopenia (G3=5%, G2=10%), and leukopenia (G3=14%, G2=14%). Median survival is not reached with 17 patients (85%) alive with stable/improved LM including 2 with durable CNS control for >9 months, 1 patient alive with CNS and systemic PD at 3.7 months, 2 patients died at 3.6 and 5.1 months with CNS and systemic PD. At 3-month, OS and PFS were 100% and 90% (95% CI 100–72%), respectively. In the 13 patients with CSF CTCs evaluation, decreased quantifiable CTCs at 1-month after proton CSI correlated significantly with improved CNS PFS (log-rank p=0.014). These early findings suggest that proton CSI is a safe and potentially effective treatment for patients with solid tumor LM. CSF biomarkers assessment is needed to better elucidate predictors of response.

Published
2019

11. Genomic correlates of disease progression and treatment response in prospectively characterized gliomas

Author

Juliann Chmielecki, Timothy A. Chan, Kathryn Beal, Philip H. Gutin, Elena Pentsova, Viviane Tabar, Michael E. Goldberg, Cameron Brennan, Malbora Manne, David B. Solit, Bob T. Li, Thomas Kaley, Adrienne Boire, Igor T. Gavrilovic, Shahiba Ogilvie, Michael F. Berger, Jacqueline B. Stone, Mariza Daras, Robert J. Young, Anna F. Piotrowski, Eli L. Diamond, David M. Hyman, Angela G. Arnold, Natalie DiStefano, Shweta S. Chavan, Antonio Omuro, Marc K. Rosenblum, Maryam Pourmaleki, Alexandra Miller, Ingo K. Mellinghoff, Zsofia K. Stadler, Philip Jonsson, Christian Grommes, Lisa M. DeAngelis, Andrew T. McKeown, Andrew L. Lin, Allison Hyde, Barry S. Taylor, Diana Mandelker, Marc Ladanyi, Ahmet Zehir, T. Jonathan Yang, and Craig Nolan

Subjects
0301 basic medicine, Male, Cancer Research, Somatic cell, Kaplan-Meier Estimate, medicine.disease_cause, Germline, 0302 clinical medicine, Medicine, Precision Medicine, Child, Promoter Regions, Genetic, DNA Modification Methylases, Aged, 80 and over, Mutation, Brain Neoplasms, High-Throughput Nucleotide Sequencing, Genomics, Glioma, Middle Aged, Prognosis, Phenotype, Magnetic Resonance Imaging, Treatment Outcome, Oncology, DNA methylation, Disease Progression, Female, Adult, Adolescent, DNA repair, Models, Biological, Article, 03 medical and health sciences, Young Adult, Germline mutation, Humans, Germ-Line Mutation, Aged, business.industry, Tumor Suppressor Proteins, Genetic Variation, DNA Methylation, medicine.disease, Image Enhancement, 030104 developmental biology, DNA Repair Enzymes, Cancer research, business, 030217 neurology & neurosurgery
Abstract

Purpose: The genomic landscape of gliomas has been characterized and now contributes to disease classification, yet the relationship between molecular profile and disease progression and treatment response remain poorly understood. Experimental Design: We integrated prospective clinical sequencing of 1,004 primary and recurrent tumors from 923 glioma patients with clinical and treatment phenotypes. Results: Thirteen percent of glioma patients harbored a pathogenic germline variant, including a subset associated with heritable genetic syndromes and variants mediating DNA repair dysfunctions (29% of the total) that were associated with somatic biallelic inactivation and mechanism-specific somatic phenotypes. In astrocytomas, genomic alterations in effectors of cell-cycle progression correlated with aggressive disease independent of IDH mutation status, arose preferentially in enhancing tumors (44% vs. 8%, P < 0.001), were associated with rapid disease progression following tumor recurrence (HR = 2.6, P = 0.02), and likely preceded the acquisition of alkylating therapy-associated somatic hypermutation. Thirty-two percent of patients harbored a potentially therapeutically actionable lesion, of whom 11% received targeted therapies. In BRAF-mutant gliomas, response to agents targeting the RAF/MEK/ERK signaling axis was influenced by the type of mutation, its clonality, and its cellular and genomic context. Conclusions: These data reveal genomic correlates of disease progression and treatment response in diverse types of glioma and highlight the potential utility of incorporating genomic information into the clinical decision-making for patients with glioma.

Published
2019

12. Staging Identifies Non-CNS malignancies in a Large Cohort with Newly Diagnosed Lymphomatous Brain Lesions

Author

Christian Grommes, Julia Wolfe, Rachna Malani, and Ankush Bhatia

Subjects
Adult, Male, Cancer Research, Systemic disease, Pathology, medicine.medical_specialty, Lymphoma, Biopsy, Central nervous system, Newly diagnosed, Article, Neoplasms, Multiple Primary, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Bone Marrow, Fluorodeoxyglucose F18, medicine, Humans, Aged, Neoplasm Staging, Retrospective Studies, Aged, 80 and over, business.industry, Brain Neoplasms, food and beverages, Secondary Malignancy, Hematology, Middle Aged, medicine.disease, Large cohort, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Positron-Emission Tomography, Brain lesions, Female, business, Tomography, X-Ray Computed, 030215 immunology
Abstract

Lymphomatous brain lesions can represent primary central nervous system (CNS) lymphoma or secondary involvement as part of systemic disease (SCNSL). In this study, we characterize staging evaluations in a large patient cohort with newly-diagnosed brain lymphomas, to determine the frequency of SCNSL and secondary malignancies. This retrospective review includes 262 patients with newly-diagnosed lymphomatous CNS lesions evaluated at Memorial Sloan Kettering Cancer Center between 2006 and 2018. Staging procedures included PET scans in 180 (69%) patients, CT scans of chest/abdomen/pelvis (CAP) in 195 (74%) and bone marrow biopsies (BMB) in 177 (68%). PET scans were reported as abnormal in 34 of 180 (19%), CT in 50 of 195 (26%) and BMB in 15 of 177 (8.5%). A total of 24 non-CNS malignancies were identified (11.8%; 19 systemic lymphomas and 5 secondary malignancies). Thus, in patients with new lymphomatous brain lesions, performing initial systemic staging procedures can identify systemic lymphoma and additional malignancies, highlighting the importance of staging evaluations, in particular PET and BMB.

Published
2019

13. Pretreatment dynamic contrast-enhanced MRI biomarkers correlate with progression-free survival in primary central nervous system lymphoma

Author

Vaios Hatzoglou, Jung Hun Oh, Xuling Lin, Kyung K. Peck, Olivia Buck, Robert J. Young, Behroze Vachha, Michelle Lee, Amita Shukla-Dave, Christian Grommes, and Andrei I. Holodny

Subjects
Oncology, Male, Cancer Research, medicine.medical_specialty, Time Factors, Lymphoma, Contrast Media, Article, 030218 nuclear medicine & medical imaging, Central Nervous System Neoplasms, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Effective diffusion coefficient, Humans, Progression-free survival, Radiation treatment planning, Survival analysis, Aged, Retrospective Studies, Aged, 80 and over, Receiver operating characteristic, business.industry, Primary central nervous system lymphoma, Area under the curve, Brain, Middle Aged, medicine.disease, Prognosis, Magnetic Resonance Imaging, Progression-Free Survival, Neurology, Dynamic contrast-enhanced MRI, Female, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

PURPOSE: Prediction of clinical outcomes in patients with primary central nervous system lymphoma (PCNSL) is important for optimization of treatment planning. Quantitative imaging biomarkers for PCNSL have not yet been established. This study evaluated the prognostic value of pretreatment dynamic contrast-enhanced MRI and diffusion-weighted imaging for progression-free survival (PFS) in patients with PCNSL. METHODS: Pretreatment dynamic contrast-enhanced MRI and diffusion-weighted imaging were retrospectively analyzed in 18 immunocompetent patients with PCNSL. Volumes of interest encompassing the tumors were assessed for measurements of blood plasma volume (Vp), volume transfer constant (K(trans)), and apparent diffusion coefficient. Patients were divided into short and long PFS groups based on median PFS. Imaging and clinical variables were correlated with PFS. RESULTS: Median PFS was 19.6 months. Lower Vp(mean) and K(trans)(mean) values increased risk for rapid progression (< 19.6 months). Receiver operating characteristic curve analysis demonstrated an optimal Vp(mean) cutoff value of 2.29 (area under the curve [AUC] = 0.74, sensitivity and specificity = 0.78, p = 0.023) for separating patients with short and long PFS. The optimal K(trans)(mean) cutoff was 0.08 (AUC = 0.74, sensitivity = 0.67, specificity = 0.78, p = 0.025). Kaplan–Meier survival analysis with log-rank test demonstrated significantly (p = 0.015) increased risk of rapid progression for patients with Vp(mean) < 2.29. Vp(mean) was significantly (p = 0.03) associated with PFS on univariate Cox analysis. Apparent diffusion coefficient values and clinical factors did not influence PFS. CONCLUSIONS: Pretreatment Vp and K(trans) derived from dynamic contrast-enhanced MRI may be novel prognostic quantitative imaging biomarkers of progression-free survival in patients with PCNSL. These data should be prospectively validated in larger patient cohorts.

Published
2018

14. Genomic Heterogeneity Underlies Mixed Response to Tropomyosin Receptor Kinase Inhibition in Recurrent Glioma

Author

Bethany Hanusch, Alison M. Schram, Robert J. Young, Philip Jonsson, Nora Ku, Alexander Drilon, Thomas Kaley, David M. Hyman, Ryma Benayed, Barry S. Taylor, Tejus Bale, Christian Grommes, and Jaclyn F. Hechtman

Subjects
0301 basic medicine, Cancer Research, biology, business.industry, medicine.medical_treatment, Cancer, PDGFRA, Recurrent Glioma, medicine.disease, Receptor tyrosine kinase, Article, Targeted therapy, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, Trk receptor, Glioma, Cancer research, biology.protein, Medicine, business, ATRX
Abstract

Glioblastoma is the most common malignant primary brain tumor in adults. Despite aggressive initial treatment, recurrence is inevitable and almost always fatal. Treatment options for recurrent disease are limited and do not substantially improve survival. In recent years, molecular characterization of gliomas has revealed recurrent somatic mutations, structural rearrangements, and epigenetic alterations. These genomic alterations have implications for prognosis and response to treatment. IDH1/2 mutations are associated with a more favorable prognosis among glioblastomas, whereas tumors with MGMT promoter hypermethylation are more likely to respond to treatment with alkylating agents.1,2 The pattern of genomic alterations can also provide insight into the origin and evolution of the tumor. For example, the presence of coexistent mutations in IDH1 and ATRX suggest a secondary glioma that has progressed from a lower-grade glioma.3-5 In addition to informing prognosis and diagnostic classification, some genomic alterations in glioma represent potential therapeutic targets. Specifically, recurrent alterations in one of several receptor tyrosine kinases (RTKs), including EGFR, PDGFRA, MET, and FGFR1/2/3, have been observed in the majority of glioblastomas.6 Unfortunately, efforts to develop genomically targeted therapy for the treatment of glioblastoma have been unsuccessful to date.7 It remains unknown the extent to which the lack of activity of targeted therapy may be attributed to so-called key alterations that do not represent true clonal drivers that are critical to tumor growth and progression compared with the simple inability of existing drugs to achieve therapeutic exposures within the CNS. In addition to these more common genomic alterations, less common fusions that involve the kinase domain of tropomyosin receptor kinases (TRKs; A/B/C) encoded by the genes, NTRK1, NTRK2, and NTRK3 have also been identified in gliomas.8-11 In other cancer types, selective inhibition of these TRK fusions has resulted in remarkable efficacy12; however, it remains unknown whether this therapeutic strategy is effective in primary brain tumors. Here, we report the case of a young woman with recurrent glioblastoma treated with larotrectinib, a first-in-class, potent, highly selective TRK inhibitor. To our knowledge, this is the first report of the use of a TRK inhibitor in a patient with a TRK fusion–positive glioblastoma.

Published
2018

15. SL3 PRIMARY CNS LYMPHOMA: CURRENT CONCEPTS AND THERAPEUTIC PERSPECTIVES

Author

Christian Grommes

Subjects
business.industry, Primary central nervous system lymphoma, medicine.disease, Signal pathway, chemotherapy regimen, Abstracts, Electrical current, Primary CNS Lymphoma, hemic and lymphatic diseases, Medicine, Current (fluid), Signal transduction, salvage therapy, business, B-cell receptor signaling pathway, Neuroscience, Invited Lectures, Primary Central Nervous System Lymphoma
Abstract

The lecture will summaries current standards of disease staging and treatment of Primary Central Nervous System Lymphoma (PCNSL). Concepts underlying the current first-line treatment regimen will be presented and current controversies in the treatment of PCNSL, including choice of induction regimen, choice of consolidation, and the roles of surgery/radiation/intrathecal therapy, will be discussed. In additional, the presentation will summarize novel insights into the pathophysiology of PCNSL, particularly the B-cell receptor signaling pathway (BCR). Results of completed and ongoing clinical trials targeting the BCR will be presented. The treatment standards in the recurrent setting will be summarized and additional novel therapeutic avenues, eg. immune checkpoint inhibition will be discussed. Furthermore, novel combinational clinical trials in recurrent/refractory setting will be discussed. Moreover, the diagnostic and prognostic value of novel, genomic testing and their integration into clinical trial development and clinical decision making will be discussed.

Published
2019

16. Correction to: Sequencing and curation strategies for identifying candidate glioblastoma treatments

Author

Catherine Reeves, Robert B. Darnell, Michael C. Zody, Christian Grommes, Laxmi Parida, Mayu O. Frank, Anne-Katrin Emde, Cameron Brennan, Stephen J. Harvey, Phaedra Agius, Andrew B. Lassman, Cecilia Esteves, Kazimierz O. Wrzeszczynski, Vanessa V. Michelini, Christian Stolte, Alexis Demopoulos, Dimitris G. Placantonakis, Bo-Juen Chen, Anthony Calabro, Ewa A. Bergmann, Vaidehi Jobanputra, Peter Canoll, Vladimir Vacic, Minita Shah, Mariza Daras, Elena Pentsova, Antonio Omuro, John Anthony Kelly, Jerome B. Posner, Dana E. Orange, Sadia Rahman, Depinder Khaira, Ajay K. Royyuru, Michelle F. Lamendola-Essel, Duyang Kim, Julia L. Moore Vogel, Kanika Arora, Xiaolan Fang, Heather Geiger, Vanessa Felice, Kahn Rhrissorrakrai, Filippo Utro, Takahiko Koyama, Jeffrey N. Bruce, John G. Golfinos, Eli L. Diamond, Nicolas Robine, John A. Boockvar, and Esra Dikoglu

Subjects
0301 basic medicine, lcsh:Internal medicine, lcsh:QH426-470, Published Erratum, MEDLINE, Computational biology, Biology, medicine.disease, Given name, Human genetics, 03 medical and health sciences, lcsh:Genetics, 030104 developmental biology, 0302 clinical medicine, 030220 oncology & carcinogenesis, Genetics, medicine, DNA microarray, lcsh:RC31-1245, Genetics (clinical), Glioblastoma
Abstract

Following publication of the original article [1], it was reported that the given name of the fourteenth author was incorrectly published. The incorrect and the correct names are given below.

Published
2019
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17. NEURO/MEDICAL ONCOLOGY

Author

Irene Helenowski, Naoya Hashimoto, Jan J. Heimans, Toshiki Yoshimine, Johan A F Koekkoek, Evelyne Emery, José L. Asencio, Andrea Chamczuck, Carly Bridge, Gilbert Faure, Barbara-Ann Millar, Arthur Rosiello, Michela Casanova, John Freymann, Giulio Bertani, Jun-ich Adachi, Christian LaFougere, Julianne Bloom, Paul Vincent Opinaldo, Tobey J. McDonald, Alexander Khandji, Maciej M. Mrugala, Agnieszka Kowalska, Clifford G. Robinson, Josef Pichler, Jayesh Mehta, Lisa M. DeAngelis, Katie Slusarz, Rachel Grossman, Juan Armando Mejía, Sadhana Kannan, In Ah Kim, Pierre Soubeyran, Nabil Ahmed, Matthew J. Matasar, David A. Reardon, Marie-Laure Tanguy, Andrea Pace, Vani Santosh, Tackeun Kim, Adrienne C. Lahti, John E. Donahue, Pavlina Poloskova, Marc H. A. Jansen, Nilanjana Banerji, Margaret Schwartz, Matthias Kirsch, Robert Jeraj, Guus A.M.S. van Dongen, Samuel Singer, Tom J. Snijders, Santosh Kesari, Riccardo Soffetti, Takashi Sasayama, Diana Ly, Kaoru Kurisu, Carsten Friedrich, Shinji Kawabata, Cedric Revil, Michael A. Jacobs, Ryuichi Hirayama, Wan-Soo Yoon, Kathleen Lupica, Christopher Reilly, Takuichiro Hideo, Miguel Gil, Josep Garcia, Ming Zheng, Edward K. Avila, Mairéad G McNamara, Hartmut Uschmann, Jeffrey S. Weinberg, Craig H. Moskowitz, Jörg Hense, Manmeet Ahluwalia, Georg Bjarnason, David Corwin, Shakti Ramkissoon, Jad Alshami, Eric C. Leuthardt, Paul Dilfer, Margaret Patton, Lindsey Heathcock, Cees van Montfort, Rakesh Kumar Gupta, Akihiko Yoshida, Carmine Maria Carapella, Guy K. Mckhann, Marian Hajduch, Meinhard Nevinny-Stickel, Patricia Bruns, Ashish Suri, Hernán Carranza, David A. Gutman, Carlos Yepes, Patrick Y. Wen, T. Cloughesy, Anna Kaltenboeck, Carlos Bartels, Paul D. Brown, Lisa Fichtel, Lorenzo Giammattei, Steven Hamilton, Nobuyuki Takayama, Nan Lin, Jan Drappatz, Roland Eils, Akihiro Tsuboi, Patrick Urban, Minesh P. Mehta, Remy Gressin, Zarnie Lwin, Clarence Eng, Ian F. Dunn, Sin-Soo Jeun, Alva B. Weir, Elisa Trevisan, silviya Meletath, Fumiyuki Yamasaki, Scott N. Hwang, Navya Nambudiri, Timothy F. Cloughesy, Paolo Rampini, Kathryn J. Ruddy, Justin Kirby, Marc C. Huisman, Normand Laperriere, Abajo Guijarro, Alberto González-Aguilar, David M. Peereboom, Antoine F. Carpentier, Steven M. Greenberg, Chikashi Ishioka, Sarah C. Gaffey, Sneha Arya, Guy M. McKhann, Richard Curry, Takashi Watanabe, Keishi Makino, Radek Trojanec, Hideo Takeshima, Joseph F. Megyesi, Jasmina I. Ivanova, Victor Rodriguez Berrocal, Marcel Kool, Eric Burton, Sandra K. Johnston, Hideyuki Arita, Konstantina Karabatsou, Robert C. Rostomily, Sean Grimm, Ralph G. Dacey, Karl Olson, Sonia Gómez, Harry C. Schouten, Christof M. Kramm, Fred H. Hochberg, Darren Hargrave, Kazuhiko Sugiyama, Wilhelm Boogerd, Stefano Tiziani, Christine McCluskey, Albert H. Kim, Tejpal Gupta, Ida Martinelli, Friedrich-Wilhelm Kreth, Lennea Coombs, Keith L. Ligon, J. Manuel Sarmiento, David R. Macdonald, Holly Dickinson, Cristian Massacesi, Basile Wittwer, Jung-Il Lee, Volker Hovestadt, Mark Smolkin, Sampath Somanna, Ingo K. Mellinghoff, Nancy Ann Oberheim Bush, Sanjeev Francis, Roland Goldbrunner, Jai Ho Choi, John Sampson, Roy Allan Dominique Torcuator, Kathleen R. Lamborn, Simon V. Liubinas, Daniel J. Sargent, Christina K. Cramer, Francine Armentano, Heather Leeper, Stefan Rutkowski, Prakash Shetty, Arivazhagan Arimappamagan, Alicia Ortega, Enrique Jiménez, Kazuhiro Tanaka, Kolette D. Fly, Seunggu Han, Nicolas U. Gerber, David Schiff, Antonella Castellano, Isabel Arrillaga-Romany, Robert J. Wechsler-Reya, Sophie Taillibert, Macarena de la Fuente, Wolfgang Wick, Monica Bennett, Francesco Cognetti, John de Groot, Michael Gonzales, Leon D. Ortiz, Yoshiaki Shiokawa, George Sachs, Ivo Tremont, Charles A. Conrad, Michael D. Taylor, Igor J. Barani, Shannon Langmead, Lisa Sturla, Doosik Kong, Rebecca D. Folkerth, Garrett Riggs, Yoon-La Choi, Carole Soussain, Calvin Soh, Peter Canoll, Mariza Daras, Melissa Hoag, James Rigas, Dana Cernea, Liu Diane, Kenji Wakiya, Sandra Silberman, Ivan A. Reveles, Jeffrey S. Wefel, Wenting Wu, Marie Blonski, MA Majaid, Vanessa A. Nestor, Maurits W.C.B. Sanders, Cynthia Harrison, Ruxandra Costa, Andrea Hawkins-Daarud, Mark R. Gilbert, Ruth Katz, Masayuki Kanamori, Tomek Janicki, Aaron C. Spalding, Dong-Sup Chung, Lauren Foresman, Fateme Salehi, Allan H. Friedman, Eric P. Winer, Robert Kwiecien, Joachim Kuehl, Motoo Nagane, Stanislaw Burzynski, Tomokazu Aoki, Gregory N. Fuller, Nina Paleologos, Darell D. Bigner, Max Wintermark, Adam E. Flanders, Eiichi Ishikawa, Subramanian Hariharan, Doreen Pachow, Glen Stevens, Ulrich Schüller, Jennifer Lycette, Jennifer Garst, Jeffery T. Williams, Gordana Vlahovic, Tjeerd J. Postma, Tribhwan Vats, Isabel Arrilaga, Krista Follmer, Henry S. Friedman, Kenneth Schwartz, James Perry, Jonas M. Sheehan, Christian Grommes, Annette M. Molinaro, Seung-Ho Yang, Peter Lichter, Naoki Kagawa, Trish Whitcomb, Monica Loghin, Amanda L. Bergner, Miroslav Vaverka, Jayashree Kalpathy-Cramer, Chitra Sarkar, Thomas Davidson, Nithya Ramnath, Leland Rogers, Roberta Rudà, Steven A. Toms, Martin Gore, Khê Hoang-Xuan, Emmanuel Gyan, Hani Malone, Jun-ichi Adachi, Jennifer Rifenburg, Stefan M. Pfister, Luis Carlos Mayor, Vanja Vaccaro, Hannah E. Goldstein, Karen Fink, Eva Dombi, Timothy Cloughsey, Sabina Eigenbrod, Jiri Ehrmann, Li Li, Pamela R. Jackson, Makoto Ohno, Craig Nolan, Gerald P. Linette, Tatjana Seute, Eric Bouffet, Patricia M. M. B. Soetekouw, David J. Pisapia, Marc Remke, Susan Snodgras, David Tran, Keiichi Kobayashi, Warren P. Mason, Setsu Sakamoto, Chiara Bosa, Gabriele Schackert, Alfred Yung, David Cachia, Toshihiko Kuroiwa, María Ángeles Vaz Salgado, F. Lonnqvist, Francesca Piludu, Alvina Acquaye, Keisuke Ueki, Jung Ho Han, Kathy Newell, Mythili Shastry, Yoon Jae Cho, Marco Riva, Laura M. Fayad, Kristin Diefes, André O. von Bueren, Ina Ly, Beatrix Lutiger, Hiroyoshi Suzuki, Jeanette K. Doorduijn, Eiji Kohmura, Olivier Chinot, Ichiyo Shibahara, Nathalie Jansen, Marta Del Álamo de Pedro, Scott L. Pomeroy, Andreas Zwergal, Terri S. Armstrong, Elmar Kirches, Daniel P. Cahill, Howard A. Fine, Cezary Szczylik, Stéphane Oudard, Gregg C. Shepard, Mark G. Kris, Andrea Milbourne, Dominique Jennings, Marco Locatelli, Dereck Amakye, Takumi Kudo, Simon Bailey, Alessandra Fabi, Taketoshi Maehara, Soumen Khatua, Caroline Houllier, Klaus J. Müller, Jaishri O. Blakeley, Karen Kelly, Jonathon Yun, Thomas Gergel, Diane Liu, Eric T. Wong, Alin Borha, Brian J. Williams, Rakesh Jalali, Birgit Geoerger, Naosuke Nonoguchi, Julie Walker, Jasmin Jo, Manmohan Singh, Mary Noel, Denise Lally-Goss, Tracy T. Batchelor, Andrea Falini, Maximilian Niyazi, Jeffrey Raizer, Martin J. van den Bent, Aleksandra Gruslova, Phioanh L. Nghiemphu, Kristin R. Swanson, Maaike J. Vos, Jethro Hu, Rebeca Alcalce Pampliega, Craig S. Sauter, Leena Ketonen, Michael A. Vogelbaum, Donald Picker, Robert Hawkins, Chris Halpin, Otto S. Hoekstra, Elizabeth Vera-Bolanos, Ahmad Awada, Sawan Kumar, Alexandra Benouaich-Amiel, Joseph Pernicone, Noriyuki Kawabata, Andrew H. Kaye, David Brachman, Kurt A. Jaeckle, Cameron J. Nowell, Maria Carlo, Tom Mikkelsen, Jorg Dietrich, Tomonari Suzuki, Kohei Fukuoka, Philippe Aftimos, Christine Schmid-Tannwald, Vera Wenter, Valeria Conte, Scott Turner, Brian J A Gill, John D. Cullen, Jiayi Huang, Saurabh Dahiya, Vincent Delwail, Lien Bekaert, Priya Kumthekar, Roberta Seidman, Scott R. Plotkin, Priya Deshpande, Christopher Zalewski, Vaibhav Patel, Peter Kurniali, Martha Nowosielski, Zvi Ram, Susan M. Chang, Dannis G. van Vuurden, Stuart A. Grossman, Vaishali Suri, Rajan Jain, Christine Carico, Ying Yuan, Yoji Yamashita, Bojana Milojkovic-Kerklaan, Yannick Kerloeguen, Michael B. Sisti, Rameen Beroukhim, Andrea Artoni, Frances McSherry, John J. Evans, Mark E. Shaffrey, Lauren E. Abrey, Akshal S. Patel, Laura Bernal-Vaca, Rolf-Dieter Kortmann, Robert Grubb, Mimi Lee, Jörg-Christian Tonn, Shinobu Yamada, Andrés Quintero, Kazuhiko Mishima, Ania Marszalek, Stephen Gancher, Amal Melhem-Bertrandt, Takamitsu Fujimaki, Monika Warmuth-Metz, George Avgeropoulos, Rifaquat Rahman, Franck Bourdeaut, Frank Feleppa, Jennifer Clarke, Meredith A. Reid, Maria Werner-Wasik, Andrew D. Norden, Kenneth D. Swanson, Jeffrey N. Bruce, Chae-Yong Kim, Steven S. Rosenfeld, Haiyan Jiang, Oliver Schnell, Toshihiro Kumabe, Michael J. Sullivan, W. Gladdines, Glenn J. Lesser, Chang-Ho Yun, Epari Sridhar, Sophie Lebouvier-Sadot, Andrea Baldwin, Chirag G. Patil, Thomas Smith, Shin-Ichi Miyatake, Renato LaRocca, Kent C. Shih, Russell C. Rockne, Katsu Mizukawa, Antonio Omuro, Ryuta Saito, Mohamed H. Hamza, Eunju Hurh, Silke Soucek, Michel Lacroix, Brian J. Scott, Thomas Kaley, Tetsuya Yamamoto, Gregory J. Zipfel, Andrew Lin, Elena Pentsova, Carlos Emilio Restrepo, Utkarsh Bhagat, Masao Matsutani, Andrew B. Lassman, Stephanie L. Pugh, Yasuji Miyakita, Manabu Kinoshita, Christian Hagel, D. Brandsma, Jorge M. Otero, Marco Timmer, Ke Zhang, S. Altintas, Thierry Lamy, Hirofumi Hirano, Mehar Chand Sharma, Wafik S. El-Deiry, Peter A. Sims, Evanthia Galanis, Yong-Kil Hong, Terence J. O'Brien, Haruo Sugiyama, Dieta Brandsma, Loretta Barron, Joshua J. Jacobs, Roger Henriksson, Albert Lai, David White, Xiao-Tang Kong, John D. Hainsworth, Petronella J Lugtenburg, Paul A. Northcott, Maryline Barrie, Kenneth J. Cohen, Tanuj Saaraswat, Xiaobu Ye, Sandra Ruland, Diana M. Haninger, Surasak Phuphanich, Marc C. Chamberlain, Kenneth Aldape, Ewa Matczak, Phyo Kim, Peter Bartenstein, Lumir Hrabalek, Howard Y. Chang, Donatella Tampieri, Fumi Higuchi, Katherine S. Panageas, Allicia C. Girvan, Majid Khan, Stevie Threatt, Tareq Juratli, Mitchel S. Berger, Linda Dirven, Michele Nikolai, Emmanuelle DiTomaso, Sarah Leary, Jan H.M. Schellens, Chuanlu Jiang, Michael Glantz, Harald Sontheimer, Michael D. Prados, Mauricio Lema, Marie-Christine Guiot, Shesh N. Rai, Minhee Won, Carlos Vargas, Eva Galanis, Kazunori Arita, David I. Sandberg, Gianluca Ardolino, Sylvain Choquet, Ondrej Kalita, Michael Rytting, Lorenzo Bello, Luis Ley Urzaiz, Martin J.B. Taphoorn, Kourosh Jafari-Khouzani, Alfred Rademaker, Juan Martinez San Millan, Isabelle Aerts, Sergio Bracarda, John Norton, Mark D. Anderson, Barbara Zarino, Jun Ichi Kuratsu, Nicholas Butowski, Derek R. Johnson, James E. Herndon, Diana Giannarelli, Debra LaFrankie, Filippo Cogiamanian, Yasuyoshi Chiba, Hideo Nakamura, Agnes Jager, Caroline Chung, Paula Warren, Frans S. S. Leijten, Peter Hau, Yusuke Oji, Yuichi Hirose, Kathryn Gilliland, Sadao Kaneko, W. K. Alfred Yung, Roger Stupp, Amy Chung, Yutaka Hata, Mary Frances McAleer, Hee-Won Jung, Miloslava Zlevorová, Brendan Killory, Raymond Sawaya, Anita Chawla, John Trusheim, H. Ian Robins, Judy Lima, Prakash Ambady, Barbara O'Brien, Sonia Bermúdez, Howard Colman, Matthias Gromeier, Jean-Sébastien Guillamo, Maria C. Pietanza, Antonello Vidiri, Laura Guyman, Kristin Swanson, Paul Rosenblatt, Joshua L. Dowling, Lakshmi Nayak, Ashlee Drawz, Yu Jung Kim, Mikael L. Rinne, Shlomit Yust-Katz, Jessi Stevens, Katharine J. Drummond, Patricia Wing, Sarah Taylor, Joshua E. Allen, Ron Schaafsma, John DeGroot, Shigetoshi Yano, Paula Rauschkolb, Anupam Kumar, Soichiro Shibui, M. E. van Linde, Shirish M. Gadgeel, Yoshitaka Narita, Nicholas G. Avgeropoulos, Luca Bertero, Hongjun Wang, Jason K. Rockhill, Suriya Jeyapalan, Yukihiko Sonoda, Hikaru Sasaki, Shirley L. Markant, Masamitsu Nishihara, Daniel J. Brat, Alexandra Flowers, Monica Sierra del Rio, Morgan Prust, Adam M. Sonabend, Pierre A. Robe, James J. Dignam, Julia C. Chisholm, Gregory J. Riely, Mary Gerard, Sajeel Chowdhary, Natalie Jäger, Giovanna M. D'Abaco, James J. Culhane, Tatsunori Okamura, Erik P. Sulman, L. Adriana Esparza, Ivo W. Tremont-Lukats, Emily Porensky, Yoshihiro Oka, Marcelo De Carvalho, Brigitte C. Widemann, Stacey Kalambakas, Rolf D. Kortmann, Stewart Goldman, Jaap C. Reijneveld, Andrew Brenner, Jacob Mandel, Riccardo Draghi, Yunus Arik, Shinji Yamashita, Torsten Pietsch, Tanweer Zaidi, Dawid Schellingerhout, Marta Penas-Prado, Veronica Villani, Adriana Olar, Vanessa L. Merker, Matthias Holdhoff, Joke W. Baars, Katrina H. Smith, Arnab Chakravarti, Giorgio Carrabba, Gertjan J.L. Kaspers, Susan Boulton, Peter A. Forsyth, David T.W. Jones, Anne Baldock, Meier Hsu, Soham Dasgupta, Jeremy Rudnick, Arun Rai, Jessica Sun, Naoki Shinojima, Christian Mawrin, Eita Uchida, Jaswinder Jutla, Koichi Ichimura, Alona Muzikansky, Jean Philippe Maire, Louis B. Nabors, Yuko Matsushita, Emilie Le Rhun, Annick Desjardins, Magali Lecavalier-Barsoum, Laurie Rice, Bradford A. Moffat, Kelly Hempfling, Andrew A. Kanner, Mark W. Kieran, Stephanie M. Robert, Hervé Ghesquières, Alba A. Brandes, E. Sander Connolly, Jingxia Liu, David T. Dicker, Katherine B. Peters, Gregory S. Burzynski, Charles Sweeley, Deborah T. Blumenthal, Nicolás Useche, Tulika Ranjan, Thierry Muanza, Mercedes Garcia Villanueva, Fernando Hakim, Yana Krutoshinskaya, Shintaro Fukushima, Ryo Nishikawa, Damien C. Weber, Michael R. Chicoine, Motomasa Furuse, André Busson, Joseph R. Simpson, Gabriele Röhn, Susanne Koeppen, Arjun Sahgal, Fabio M. Iwamoto, Leland Graves, Sarah Iglseder, Taro Yanagawa, Michael Lahn, Ramaswamy Govindan, Eduardo Roberts Cervantes, Eric S. Wong, Nadine Kliese, Feng Tai, Katja von Hoff, Vincenzo Anelli, Trevor J. Pugh, Andrés F. Cardona, Gebra Cuyun Carter, Yuko Watanabe, Bogdana Suchorska, Manuela Caroli, José Luis Asencio, Eudocia Q. Lee, John Floyd, Lucas Moreno, Samantha J Mills, Jun-ichiro Kuroda, Susan Chi, David N. Louis, Aanchal Kakkar, Elizabeth R. Gerstner, Annika Schlamann, Robert Cavaliere, John L. Villano, Asha Das, Petr Kavan, Takaaki Yanagisawa, Luc Taillandier, Jonathan Fratkin, Günther Stockhammer, Tomasz Janicki, Sherese Fralin, Wafik Zaky, Lisa Scarpace, Kazunari Yoshida, Magalie Hilton, Andrey Korshunov, Aliasgar Moiyadi, Alexandra Gorelick, Alfredo Carrato Mena, Yuya Nishiyama, Riccardo Soffietti, Marina Donativi, Andrew S. Chi, Lauren Schaff, Andrew P. Morokoff, Sophie E. M. Veldhuijzen van Zanten, Hans-Joachim Reimers, John G. Stewart, Clare Ferrigno, Jackson Hamilton, Do-Hyun Nam, Samantha Hammond, Regina Krel, Mika Watanabe, Anna K. Nowak, Elina Tsyvkin, Michael W. McDermott, Jacoline E C Bromberg, Teiji Tominaga, Laila M. Poisson, Lisa Doherty, Alessia Lodi, Vino Apok, Magdalena Kneblova, Michelle Bell, Carl Jaffe, Sunita Dahr, Maria Koh, Pedro Garciarena, J. Gregory Cairncross, Ana Gómez Rueda, Augustus Perez, Ho Jun Seol, Frank Saran, Camillo Porta, Grace Elzinga, Michael Cloney, and Charles P. Hart

Subjects
Cancer Research, medicine.medical_specialty, business.industry, 010403 inorganic & nuclear chemistry, 01 natural sciences, 0104 chemical sciences, 03 medical and health sciences, Abstracts, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, medicine, Medical physics, Neurology (clinical), business
Published
2013

20. Evaluating Cancer of the Central Nervous System Through Next-Generation Sequencing of Cerebrospinal Fluid.

Author

Pentsova EI, Shah RH, Tang J, Boire A, You D, Briggs S, Omuro A, Lin X, Fleisher M, Grommes C, Panageas KS, Meng F, Selcuklu SD, Ogilvie S, Distefano N, Shagabayeva L, Rosenblum M, DeAngelis LM, Viale A, Mellinghoff IK, and Berger MF

Subjects
Adult, Aged, Brain Neoplasms genetics, Cell-Free System, Female, Humans, Male, Middle Aged, Mutation, Brain Neoplasms cerebrospinal fluid, DNA, Neoplasm cerebrospinal fluid, High-Throughput Nucleotide Sequencing methods
Abstract

Purpose: Cancer spread to the central nervous system (CNS) often is diagnosed late and is unresponsive to therapy. Mechanisms of tumor dissemination and evolution within the CNS are largely unknown because of limited access to tumor tissue., Materials and Methods: We sequenced 341 cancer-associated genes in cell-free DNA from cerebrospinal fluid (CSF) obtained through routine lumbar puncture in 53 patients with suspected or known CNS involvement by cancer., Results: We detected high-confidence somatic alterations in 63% (20 of 32) of patients with CNS metastases of solid tumors, 50% (six of 12) of patients with primary brain tumors, and 0% (zero of nine) of patients without CNS involvement by cancer. Several patients with tumor progression in the CNS during therapy with inhibitors of oncogenic kinases harbored mutations in the kinase target or kinase bypass pathways. In patients with glioma, the most common malignant primary brain tumor in adults, examination of cell-free DNA uncovered patterns of tumor evolution, including temozolomide-associated mutations., Conclusion: The study shows that CSF harbors clinically relevant genomic alterations in patients with CNS cancers and should be considered for liquid biopsies to monitor tumor evolution in the CNS., (© 2016 by American Society of Clinical Oncology.)

Published
2016
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