Publications by authors named "Matthias Holdhoff"

82 Publications

CloneRetriever: An Automated Algorithm to Identify Clonal B and T Cell Gene Rearrangements by Next-Generation Sequencing for the Diagnosis of Lymphoid Malignancies.

Clin Chem 2021 Sep 7. Epub 2021 Sep 7.

Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD.

Background: Clonal immunoglobulin and T-cell receptor rearrangements serve as tumor-specific markers that have become mainstays of the diagnosis and monitoring of lymphoid malignancy. Next-generation sequencing (NGS) techniques targeting these loci have been successfully applied to lymphoblastic leukemia and multiple myeloma for minimal residual disease detection. However, adoption of NGS for primary diagnosis remains limited.

Methods: We addressed the bioinformatics challenges associated with immune cell sequencing and clone detection by designing a novel web tool, CloneRetriever (CR), which uses machine-learning principles to generate clone classification schemes that are customizable, and can be applied to large datasets. CR has 2 applications-a "validation" mode to derive a clonality classifier, and a "live" mode to screen for clones by applying a validated and/or customized classifier. In this study, CR-generated multiple classifiers using 2 datasets comprising 106 annotated patient samples. A custom classifier was then applied to 36 unannotated samples.

Results: The optimal classifier for clonality required clonal dominance ≥4.5× above background, read representation ≥8% of all reads, and technical replicate agreement. Depending on the dataset and analysis step, the optimal algorithm yielded sensitivities of 81%-90%, specificities of 97%-100%, areas under the curve of 91%-94%, positive predictive values of 92-100%, and negative predictive values of 88%-98%. Customization of the algorithms yielded 95%-100% concordance with gold-standard clonality determination, including rescue of indeterminate samples. Application to a set of unknowns showed concordance rates of 83%-96%.

Conclusions: CR is an out-of-the-box ready and user-friendly software designed to identify clonal rearrangements in large NGS datasets for the diagnosis of lymphoid malignancies.
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http://dx.doi.org/10.1093/clinchem/hvab141DOI Listing
September 2021

Pembrolizumab for patients with leptomeningeal metastasis from solid tumors: efficacy, safety, and cerebrospinal fluid biomarkers.

J Immunother Cancer 2021 Aug;9(8)

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA.

Background: The benefit of immune checkpoint inhibitors (ICIs) in patients with leptomeningeal metastases (LMM) is unknown.

Methods: We undertook a phase II trial of pembrolizumab in patients with LMM from solid tumors. Eligible patients had radiologic/cytologic LMM and Eastern Cooperative Oncology Group performance status 0-1. Pembrolizumab was administered intravenously at 200 mg q3W until disease progression/unacceptable toxicity. The primary endpoint was central nervous system (CNS) response after four cycles, defined radiologically/cytologically/clinically. Serial cerebrospinal fluid (CSF) was assessed for tumor-derived DNA (t-DNA) aneuploidy and cytokines.

Results: Thirteen of a planned 16 patients were treated between April 2017 and December 2019. The study closed early for poor accrual. Median age was 57 years (range: 22-79). Sixty-two percent of patients had tumors not traditionally ICI-responsive (hormone-receptor (HR)-positive breast carcinoma=39%; high-grade glioma=23%), while 38% had ICI-responsive tumors (non-small cell lung cancer (NSCLC)=23%, head and neck carcinoma=8%, cutaneous squamous carcinoma (CSC)=8%). CNS response was observed in 38% of patients at 12 weeks (95% CI 13.9% to 68.4%) by pre-defined criteria and LM-RANO, and 2 achieved durable complete responses (CSC=1, overall survival (OS) 3+ years; NSCLC=1, OS 9 months). Median CNS progression-free survival and OS was 2.9 months (95% CI 1.3 to NR) and 4.9 months (95% CI 3.7 to NR), respectively. Grade 3+ treatment-related adverse events occurred in 15% of patients. Sensitivity for LMM detection by t-DNA and cytopathology was 84.6% (95% CI 54.6% to 98.1%) and 53.9% (95% CI 25.1% to 80.8%), respectively. Pre-therapy and on-therapy CSF cytokine analysis demonstrated complete responders clustered together.

Conclusions: Pembrolizumab conferred a 38% CNS response rate in patients with LMM, a tolerable safety profile, and deep responses in selected patients with ICI-responsive tumors. CSF t-DNA may be sensitive for LMM detection, and immunologic subsets of CNS response warrant further study.

Trial Registration Number: NCT03091478.
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http://dx.doi.org/10.1136/jitc-2021-002473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8359453PMC
August 2021

Allogeneic Blood or Marrow Transplantation with Nonmyeloablative Conditioning and High-Dose Cyclophosphamide-Based Graft-versus-Host Disease Prophylaxis for Secondary Central Nervous System Lymphoma.

Transplant Cell Ther 2021 Jul 20. Epub 2021 Jul 20.

Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Secondary central nervous system (CNS) lymphoma is a rare and often fatal complication of non-Hodgkin lymphoma (NHL). Treatment options include radiation therapy, high-dose systemic chemotherapy, intrathecal chemotherapy, and high-dose chemotherapy with autologous stem cell rescue, but outcomes remain poor. Allogeneic blood or marrow transplantation (alloBMT) is widely used in patients with relapsed/refractory systemic NHL. We sought to understand whether a graft-versus-lymphoma effect could maintain remission in CNS disease. We reviewed outcomes in 20 consecutive patients with secondary CNS lymphoma who underwent alloBMT with nonmyeloablative conditioning using fludarabine, cyclophosphamide, and 200 cGy total body irradiation. For graft-versus-host disease prophylaxis, all patients received post-transplantation cyclophosphamide, mycophenolate mofetil, and a calcineurin inhibitor. With a median follow up of 4.1 years, the median overall survival for the entire cohort was not reached. Median progression-free survival was 3.8 years (95% confidence interval [CI], 5.3 months to not reached). The cumulative incidence of relapse was 25% (95% CI, 5% to 45%), and nonrelapse mortality was 30% (95% CI, 5% to 54%) at 4 years. Of the 5 patients who relapsed, 2 were CNS only, 1 was systemic only, and 2 were combined CNS/systemic. The use of alloBMT in CNS lymphoma merits further investigation.
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http://dx.doi.org/10.1016/j.jtct.2021.07.015DOI Listing
July 2021

IDH-mutant brainstem gliomas in adolescent and young adult patients: Report of three cases and review of the literature.

Brain Pathol 2021 Jul 7;31(4):e12959. Epub 2021 May 7.

Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA, USA.

Isocitrate dehydrogenase (IDH) mutations are rare in pediatric and adolescent gliomas. We recently identified three adolescent/young adult (AYA) patients with IDH-mutant low grade gliomas of the brainstem with several key clinicopathologic and molecular features in common. We discuss these three cases and review the current literature.
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http://dx.doi.org/10.1111/bpa.12959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8412065PMC
July 2021

Methylated markers accurately distinguish primary central nervous system lymphomas (PCNSL) from other CNS tumors.

Clin Epigenetics 2021 May 5;13(1):104. Epub 2021 May 5.

Departments of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA.

Background: Definitive diagnosis of primary central nervous system lymphoma (PCNSL) requires invasive surgical brain biopsy, causing treatment delays. In this paper, we identified and validated tumor-specific markers that can distinguish PCNSL from other CNS tumors in tissues. In a pilot study, we tested these newly identified markers in plasma.

Results: The Methylation Outlier Detector program was used to identify markers in TCGA dataset of 48 diffuse large B-cell lymphoma (DLBCL) and 656 glioblastomas and lower-grade gliomas. Eight methylated markers clearly distinguished DLBCL from gliomas. Marker performance was verified (ROC-AUC of ≥ 0.989) in samples from several GEO datasets (95 PCNSL; 2112 other primary CNS tumors of 11 types). Next, we developed a novel, efficient assay called Tailed Amplicon Multiplexed-Methylation-Specific PCR (TAM-MSP), which uses two of the methylation markers, cg0504 and SCG3 triplexed with ACTB. FFPE tissue sections (25 cases each) of PCNSL and eight types of other primary CNS tumors were analyzed using TAM-MSP. TAM-MSP distinguished PCNSL from the other primary CNS tumors with 100% accuracy (AUC = 1.00, 95% CI 0.95-1.00, P < 0.001). The TAM-MSP assay also detected as few as 5 copies of fully methylated plasma DNA spiked into 0.5 ml of healthy plasma. In a pilot study of plasma from 15 PCNSL, 5 other CNS tumors and 6 healthy individuals, methylation in cg0504 and SCG3 was detectable in 3/15 PCNSL samples (20%).

Conclusion: The Methylation Outlier Detector program identified methylated markers that distinguish PCNSL from other CNS tumors with accuracy. The high level of accuracy achieved by these markers was validated in tissues by a novel method, TAM-MSP. These studies lay a strong foundation for a liquid biopsy-based test to detect PCNSL-specific circulating tumor DNA.
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http://dx.doi.org/10.1186/s13148-021-01091-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097855PMC
May 2021

Mebendazole and temozolomide in patients with newly diagnosed high-grade gliomas: results of a phase 1 clinical trial.

Neurooncol Adv 2021 Jan-Dec;3(1):vdaa154. Epub 2020 Nov 12.

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Background: Mebendazole is an anthelmintic drug introduced for human use in 1971 that extends survival in preclinical models of glioblastoma and other brain cancers.

Methods: A single-center dose-escalation and safety study of mebendazole in 24 patients with newly diagnosed high-grade gliomas in combination with temozolomide was conducted. Patients received mebendazole in combination with adjuvant temozolomide after completing concurrent radiation plus temozolomide. Dose-escalation levels were 25, 50, 100, and 200 mg/kg/day of oral mebendazole. A total of 15 patients were enrolled at the highest dose studied of 200 mg/kg/day. Trough plasma levels of mebendazole were measured at 4, 8, and 16 weeks.

Results: Twenty-four patients (18 glioblastoma and 6 anaplastic glioma) were enrolled with a median age of 49.8 years. Four patients (at 200 mg/kg) developed elevated grade 3 alanine aminotransferase (ALT) and/or aspartate transaminase (AST) after 1 month, which reversed with lower dosing or discontinuation. Plasma levels of mebendazole were variable but generally increased with dose. Kaplan-Meier analysis showed a 21-month median overall survival with 41.7% of patients alive at 2 years and 25% at 3 and 4 years. Median progression-free survival (PFS) from the date of diagnosis for 17 patients taking more than 1 month of mebendazole was 13.1 months (95% confidence interval [CI]: 8.8-14.6 months) but for 7 patients who received less than 1 month of mebendazole PFS was 9.2 months (95% CI: 5.8-13.0 months).

Conclusion: Mebendazole at doses up to 200 mg/kg demonstrated long-term safety and acceptable toxicity. Further studies are needed to determine mebendazole's efficacy in patients with malignant glioma.
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http://dx.doi.org/10.1093/noajnl/vdaa154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817892PMC
November 2020

Challenges in the Treatment of Newly Diagnosed and Recurrent Primary Central Nervous System Lymphoma.

J Natl Compr Canc Netw 2020 11 2;18(11):1571-1578. Epub 2020 Nov 2.

Center for CNS Lymphoma, Dana-Farber Cancer Institute, Boston, Massachusetts.

Primary central nervous system lymphomas (PCNSLs) are rare cancers of the central nervous system (CNS) and are predominantly diffuse large B-cell lymphomas of the activated B-cell (ABC) subtype. They typically present in the sixth and seventh decade of life, with the highest incidence among patients aged >75 years. Although many different regimens have demonstrated efficacy in newly diagnosed and relapsed or refractory PCNSL, there have been few randomized prospective trials, and most recommendations and treatment decisions are based on single-arm phase II trials or even retrospective studies. High-dose methotrexate (HD-MTX; 3-8 g/m2) is the backbone of preferred standard induction regimens. Various effective regimens with different toxicity profiles can be considered that combine other chemotherapies and/or rituximab with HD-MTX, but there is currently no consensus for a single preferred regimen. There is controversy about the role of various consolidation therapies for patients who respond to HD-MTX-based induction therapy. For patients with relapsed or refractory PCNSL who previously experienced response to HD-MTX, repeat treatment with HD-MTX-based therapy can be considered depending on the timing of recurrence. Other more novel and less toxic regimens have been developed that show efficacy in recurrent disease, including ibrutinib, or lenalidomide ± rituximab. There is uniform agreement to delay or avoid whole-brain radiation therapy due to concerns for significant neurotoxicity if a reasonable systemic treatment option exists. This article aims to provide a clinically practical approach to PCNSL, including special considerations for older patients and those with impaired renal function. The benefits and risks of HD-MTX or high-dose chemotherapy with autologous stem cell transplantation versus other, better tolerated strategies are also discussed. In all settings, the preferred treatment is always enrollment in a clinical trial if one is available.
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http://dx.doi.org/10.6004/jnccn.2020.7667DOI Listing
November 2020

Central Nervous System Cancers, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw 2020 11 2;18(11):1537-1570. Epub 2020 Nov 2.

5The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins.

The NCCN Guidelines for Central Nervous System (CNS) Cancers focus on management of adult CNS cancers ranging from noninvasive and surgically curable pilocytic astrocytomas to metastatic brain disease. The involvement of an interdisciplinary team, including neurosurgeons, radiation therapists, oncologists, neurologists, and neuroradiologists, is a key factor in the appropriate management of CNS cancers. Integrated histopathologic and molecular characterization of brain tumors such as gliomas should be standard practice. This article describes NCCN Guidelines recommendations for WHO grade I, II, III, and IV gliomas. Treatment of brain metastases, the most common intracranial tumors in adults, is also described.
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http://dx.doi.org/10.6004/jnccn.2020.0052DOI Listing
November 2020

Systemic Approach to Recurrent Primary CNS Lymphoma: Perspective on Current and Emerging Treatment Strategies.

Onco Targets Ther 2020 20;13:8323-8335. Epub 2020 Aug 20.

Lymphoid Malignancies Branch, National Cancer Institute, Bethesda, Maryland, USA.

There is no uniform standard of care for the treatment of refractory or recurrent primary central nervous lymphoma (r/r PCNSL). Many different systemic treatment regimens have been studied, but available data are based on small prospective or retrospective reports. There have been no randomized controlled trials in r/r PCNSL to date. Here, we provide an overview of published systemic regimens for the treatment of r/r PCNSL, as well as therapies that are under investigation. In addition, based on available data, we propose strategies of how to approach choice of therapy for different groups of patients in this disease setting. Patients can be mainly divided into three groups: 1) patients suitable for a re-challenge with high-dose methotrexate (HD-MTX)-based regimens and that may or may not be candidates for consolidation with high-dose chemotherapy with autologous stem cell transplant, 2) patients refractory to HD-MTX or that had early relapse, but suitable for an aggressive treatment strategy with re-induction with non-MTX-based therapy, possibly followed by high-dose chemotherapy with autologous transplant, and 3) patients not suitable for re-treatment with HD-MTX and that are not candidates for aggressive therapy. As PCNSL is a rare disease and as there is urgent need for better outcomes in r/r PCNSL, clinical trial participation is encouraged, especially in elderly or frail patients who are not candidates for high-dose chemotherapy and transplant.
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http://dx.doi.org/10.2147/OTT.S192379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7445492PMC
August 2020

Clinical Trial Design and Development Work Group Within the Quantitative Imaging Network.

Tomography 2020 06;6(2):60-64

Irving Medical Center, Columbia University, New York Presbyterian Hospital, New York, NY.

The Clinical Trial Design and Development Working Group within the Quantitative Imaging Network focuses on providing support for the development, validation, and harmonization of quantitative imaging (QI) methods and tools for use in cancer clinical trials. In the past 10 years, the Group has been working in several areas to identify challenges and opportunities in clinical trials involving QI and radiation oncology. The Group has been working with Quantitative Imaging Network members and the Quantitative Imaging Biomarkers Alliance leadership to develop guidelines for standardizing the reporting of quantitative imaging. As a validation platform, the Group led a multireader study to test a semi-automated positron emission tomography quantification software. Clinical translation of QI tools cannot be possible without a continuing dialogue with clinical users. This article also highlights the outreach activities extended to cooperative groups and other organizations that promote the use of QI tools to support clinical decisions.
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http://dx.doi.org/10.18383/j.tom.2019.00022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289239PMC
June 2020

Ivosidenib in Isocitrate Dehydrogenase 1Mutated Advanced Glioma.

J Clin Oncol 2020 10 12;38(29):3398-3406. Epub 2020 Jun 12.

Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Purpose: Diffuse gliomas are malignant brain tumors that include lower-grade gliomas (LGGs) and glioblastomas. Transformation of low-grade glioma into a higher tumor grade is typically associated with contrast enhancement on magnetic resonance imaging. Mutations in the isocitrate dehydrogenase 1 () gene occur in most LGGs (> 70%). Ivosidenib is an inhibitor of mutant IDH1 (mIDH1) under evaluation in patients with solid tumors.

Methods: We conducted a multicenter, open-label, phase I, dose escalation and expansion study of ivosidenib in patients with m solid tumors. Ivosidenib was administered orally daily in 28-day cycles.

Results: In 66 patients with advanced gliomas, ivosidenib was well tolerated, with no dose-limiting toxicities reported. The maximum tolerated dose was not reached; 500 mg once per day was selected for the expansion cohort. The grade ≥ 3 adverse event rate was 19.7%; 3% (n = 2) were considered treatment related. In patients with nonenhancing glioma (n = 35), the objective response rate was 2.9%, with 1 partial response. Thirty of 35 patients (85.7%) with nonenhancing glioma achieved stable disease compared with 14 of 31 (45.2%) with enhancing glioma. Median progression-free survival was 13.6 months (95% CI, 9.2 to 33.2 months) and 1.4 months (95% CI, 1.0 to 1.9 months) for the nonenhancing and enhancing glioma cohorts, respectively. In an exploratory analysis, ivosidenib reduced the volume and growth rates of nonenhancing tumors.

Conclusion: In patients with m advanced glioma, ivosidenib 500 mg once per day was associated with a favorable safety profile, prolonged disease control, and reduced growth of nonenhancing tumors.
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http://dx.doi.org/10.1200/JCO.19.03327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527160PMC
October 2020

Hemophagocytic Lymphohistiocytosis Secondary to PD-1 and IDO Inhibition in a Patient with Refractory Glioblastoma.

Case Rep Oncol 2020 May-Aug;13(2):508-514. Epub 2020 May 12.

Department of Oncology, The Johns Hopkins University School of Medicine and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA.

Immune checkpoint inhibition (ICI)-based approaches have transformed the treatment landscape of numerous solid tumors. Glioblastoma (GBM) is an aggressive and almost universally fatal disease which is in need of novel treatment options, and combinations of immune checkpoint inhibitors, including dual agent therapy, are starting to be explored in refractory GBM. Growing adoption of ICI-based approaches in solid tumors has been met with improved understanding of immune-related adverse events (IRAEs), including primary hematologic adverse events. Although management guidelines for multiple hematologic IRAEs have been established, the emergence of hemophagocytic lymphohistiocytosis (HLH) secondary to ICI therapy has only rarely been described, and its pathogenesis and optimal management are incompletely understood. We present the case of a 74-year-old male with a history of refractory GBM treated with PD-1 and indoleamine-pyrrole 2,3-dioxygenase (IDO) inhibition who experienced acute liver injury, followed by progressive fevers, altered mental status, and cytopenias. Serum studies and examination of spleen and bone marrow pathology were consistent with HLH, which was refractory to steroids and ultimately resulted in his rapid clinical decline. Here, we review prior cases of HLH secondary to ICI therapy across solid tumors, and explore potential mechanisms contributing to the rapid onset and refractory nature of our patient's HLH syndrome. We hope to further highlight HLH as an emerging hematologic IRAE secondary to ICI therapy, and suggest that new practice guidelines begin to recognize HLH as a characteristic hematologic IRAE in patients treated with PD-1 and other immune checkpoint inhibitors.
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http://dx.doi.org/10.1159/000507281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265705PMC
May 2020

Patterns of bevacizumab use in patients with glioblastoma: an online survey among experts in neuro-oncology.

Neurooncol Pract 2020 Jan 6;7(1):52-58. Epub 2019 Jul 6.

Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: Bevacizumab (BEV) received accelerated FDA approval in 2009 for the treatment of recurrent glioblastoma (rGBM). Unfortunately, prospective randomized controlled phase 3 studies (AVAglio and Radiation Therapy Oncology Group 0825 in newly diagnosed, European Organisation for Research and Treatment of Cancer 26101 in rGBM) failed to show an overall survival benefit with BEV added to standard therapy. In light of these data, we aimed to capture current utilization patterns and perceived value of BEV in the treatment of GBM among experts in the field.

Methods: An online questionnaire comprising 14 multiple choice questions was sent out in spring 2017 to 207 oncologists/neuro-oncologists treating patients with GBM at all National Cancer Institute-designated cancer centers in the United States.

Results: Sixty-two of 207 (30%) invitees responded (by training, 70% neuro-oncologists, 20% medical oncologists, 10% pediatric oncologists/neuro-oncologists). Participants reported use of BEV most frequently in rGBM for control of edema (85% of respondents) and/or when no other treatment options were available (68%). BEV is rarely used in newly diagnosed GBM (<5% of cases by 78% respondents and in 5% to 10% cases by 15% respondents). Sixty-six percent of participants indicated that they thought BEV improved symptoms, 30% that it improved symptoms and survival, 3% that it had no benefit in GBM patients.

Conclusion: In this cross-sectional online survey we found that among neuro-oncology experts in the United States in 2017, BEV is predominantly utilized in select patients with rGBM, and is only rarely used in a small subgroup of patients with newly diagnosed GBM for control of edema. The low response rate may have introduced a nonresponse bias.
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http://dx.doi.org/10.1093/nop/npz022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7104881PMC
January 2020

alterations in anaplastic ependymoma progression to ependymosarcoma.

Clin Neuropathol 2020 Jul/Aug;39(4):179-187

Ependymosarcomas are rare, biphasic tumors composed of ependymal and sarcomatous components. Due to their rarity, their biologic basis is not well understood. We report the case of a 38-year-old male with anaplastic ependymoma (WHO grade III) that progressed to ependymosarcoma in less than 2 years after multiple resections, chemoradiotherapy, and anti-PD1 immunotherapy. Next-generation sequencing was performed on both high-grade anaplastic ependymoma and ependymosarcoma samples to detect small base changes, insertions, and deletions in exons and splice junctions from a panel of over 400 genes. We identify genetic variants in the tumor suppressors , , and in these samples and discuss the potential significance of an additional genetic variant in the progression to ependymosarcoma.
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http://dx.doi.org/10.5414/NP301240DOI Listing
April 2021

Optimizing eligibility criteria and clinical trial conduct to enhance clinical trial participation for primary brain tumor patients.

Neuro Oncol 2020 05;22(5):601-612

Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

Building on an initiative to enhance clinical trial participation involving the Society for Neuro-Oncology, the Response Assessment in Neuro-Oncology Working Group, patient advocacy groups, clinical trial cooperative groups, and other partners, we evaluate the impact of eligibility criteria and trial conduct on neuro-oncology clinical trial participation. Clinical trials often carry forward eligibility criteria from prior studies that may be overly restrictive and unnecessary and needlessly limit patient accrual. Inclusion and exclusion criteria should be evaluated based on the goals and design of the study and whether they impact patient safety and/or treatment efficacy. In addition, we evaluate clinical trial conduct as a barrier to accrual and discuss strategies to minimize such barriers for neuro-oncology trials.
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http://dx.doi.org/10.1093/neuonc/noaa015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229255PMC
May 2020

Cerebellar Melanoneurons: An Overlooked and Potentially Important Cell Population.

J Neuropathol Exp Neurol 2020 02;79(2):242-243

Department of Pathology, Johns Hopkins University, Baltimore, Maryland.

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http://dx.doi.org/10.1093/jnen/nlz127DOI Listing
February 2020

White matter changes in primary central nervous system lymphoma patients treated with high-dose methotrexate with or without rituximab.

J Neurooncol 2019 Dec 16;145(3):461-466. Epub 2019 Oct 16.

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.

Purpose: White matter changes (WMCs) can develop following systemic chemotherapy in patients with primary central nervous system lymphomas (PCNSLs), but the frequency and extent of these changes is not well characterized. This single center retrospective semi-quantitative study was performed to determine the rate, timing and grade of WMC on MRI in adult patients with newly-diagnosed radiotherapy-naïve PCNSL undergoing treatment with high-dose methotrexate (HD-MTX) with or without the addition of rituximab (-R).

Methods: Serial MRI scans of consecutive adult PCNSL patients treated with HD-MTX ± R were assessed for WMC comparing the pre-treatment to post-treatment scans utilizing a 0-to-8-point severity scoring system.

Results: Forty-seven PCNSL patients treated with either HD-MTX-R (n = 34; median age 66, 50% male) or HD-MTX (n = 13; median age 53, 54% male) were included in the analysis. WMC were detected in 62% (95% CI 46-76%) overall, in 68% of the HD-MTX-R, and in 46% of the HD-MTX group. Among patients with WMC (n = 29), WMC were first detected at an average of 2.8 months from beginning of therapy in the HD-MTX-R versus at 10.7 months in the HD-MTX group. Average WMC non-zero scores when first detected following the start of treatment were 2.5 (± 1.1) in HD-MTX-R and 1.5 (± 0.6) in HD-MTX.

Conclusions: Development of WMC in PCNSL patients treated with MTX and MTX-R is common. WMC changes appear to be more frequent, occur earlier and are more extensive in patients treated with HD-MTX-R compared to HD-MTX. Prospective studies are required to determine whether WMC correlate with survival or neurocognitive outcomes.
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http://dx.doi.org/10.1007/s11060-019-03279-9DOI Listing
December 2019

Immune-Related Adverse Events Requiring Hospitalization: Spectrum of Toxicity, Treatment, and Outcomes.

J Oncol Pract 2019 09 6;15(9):e825-e834. Epub 2019 Aug 6.

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD.

Purpose: Immune checkpoint inhibitors (ICIs) cause immune-related adverse events (irAEs). The proportion of patients who are hospitalized for irAEs and their spectrum, management, and outcomes are not well described.

Methods: We report the proportion of hospitalized patients in an academic center who were treated with ICIs from May to December 2017. Patient characteristics, toxicities, management, and outcomes for confirmed irAE admissions are reported. Associations between patient features and irAE hospitalizations are examined.

Results: Twenty-three percent (n = 100) of 443 patients who were admitted to an academic oncology center over 6 months had ever received ICIs. Of these patients, 41% were admitted for suspected irAEs and 23% were confirmed irAEs. IrAEs accounted for 5% of all oncology hospitalizations (n = 23). Ninety-one percent of patients with confirmed irAEs prompted a medicine subspecialist consultation, most commonly gastroenterology (22%). Fifteen patients (65%) had their irAEs improve/resolve, seven (30%) had worsening irAEs, and three (13%) died of their irAEs. The majority of patients (n = 20; 87%) discontinued ICIs after discharge. Among ICI-treated patients who required admission, an increased likelihood of irAE-related hospitalization was associated with patient age older than 65 years (odds ratio, 5.4; 95% CI, 1.6 to 17.8) and receipt of combination immunotherapy (OR, 6.8; 95% CI, 2.0 to 23.2).

Conclusion: A notable proportion of ICI-treated patients are hospitalized for irAEs, and these patients have a high demand for multidisciplinary management. Older age and combination ICI treatment were associated with an increased risk of irAE-related hospitalization. Whereas these data are from an academic center and include patients in clinical trials, with expanding use of ICIs, these data have important implications for inpatient service planning and risk stratification.
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http://dx.doi.org/10.1200/JOP.18.00703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6743220PMC
September 2019

prophylaxis in patients treated for high-grade gliomas: a survey among neuro-oncologists.

Neurooncol Pract 2019 Jul 29;6(4):321-326. Epub 2018 Nov 29.

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland.

Background: pneumonia (PJP) is a known complication in patients with high-grade gliomas (HGGs) who are treated with radiation and chemotherapy. PJP prophylaxis is commonly recommended, but there are currently no clear guidelines regarding duration of treatment and choice of drugs. This study aimed to assess current practice patterns of PJP prophylaxis among neuro-oncologists.

Methods: An online survey of 14 multiple choice questions was sent to 207 neuro-oncologists and medical oncologists treating brain cancers at all National Cancer Institute-designated cancer centers in the United States. Recipients were identified via a search of the cancer centers' websites.

Results: Sixty-one invited experts completed the survey (response rate 29%; of these, 72% were neuro-oncologists, 18% were medical oncologists, and 10% were pediatric neuro- or medical oncologists). Seventy percent of respondents stated that they routinely prescribe PJP prophylaxis, while 7% do not provide prophylaxis. Eighty-one percent of respondents use absolute lymphocyte count (ALC) to assess lymphopenia and 13% also monitor CD4 lymphocyte counts during prophylaxis. The most commonly used first-line agent is trimethoprim-sulfamethoxazole (88% of respondents), followed by pentamidine (6%). Discontinuation of PJP prophylaxis is determined by the following: count recovery (33% by ALC; 18% by CD4 lymphocyte counts), radiation completion (23%), and chemotherapy completion (7%). Glucose-6-phosphate dehydrogenase levels were routinely checked by only 13% of respondents.

Conclusions: PJP prophylaxis is commonly used in HGG patients, but there are large variations in practice patterns, including the duration of prophylaxis. As consideration for PJP prophylaxis affects all patients with HGG, standardization of prophylaxis should be formally addressed.
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http://dx.doi.org/10.1093/nop/npy049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6660813PMC
July 2019

Discovery of predictive biomarkers in malignant gliomas.

Neuro Oncol 2019 09;21(9):1089-1090

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland.

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http://dx.doi.org/10.1093/neuonc/noz120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594562PMC
September 2019

Evolving Treatments for Primary Central Nervous System Lymphoma.

Am Soc Clin Oncol Educ Book 2019 Jan 17;39:454-466. Epub 2019 May 17.

4 University of California, San Francisco, CA.

Primary central nervous system (CNS) lymphoma (PCNSL) is an aggressive form of non-Hodgkin lymphoma that remains confined to the CNS neuroaxis during its natural history of disease and is therefore considered stage IE disease. PCNSL is diffuse large B-cell lymphoma (DLBCL) morphology in more than 95% of patients and is designated primary diffuse large B-cell lymphoma of the CNS on the basis of the 2017 World Health Organization classification of hematopoietic and lymphoid tumors. Rapidly evolving therapeutic paradigms have been linked to evidence of progress in PCNSL, a disease long considered to be incurable. Increasing evidence supports the need for efficient diagnosis, staging, and initiation of therapy, ideally at centers with experience with this type of brain cancer. High-dose methotrexate (MTX) remains a cornerstone of induction regimens, and most data support the use of rituximab. However, clinical research challenges must address key questions, including the development of ever more effective and less toxic induction regimens and the selection of the most appropriate and effective consolidation approaches, as well as the fact that, increasingly, PCNSL affects older patients who do not tolerate strong genotoxic irradiation or high-dose chemotherapy (HDC)-based strategies. Maintenance therapy, immunotherapy, and the implementation of targeted agents on the basis of the molecular and biologic properties of the disease create opportunities for precision medicine and the potential for long-term disease-free survival and cure, with minimal treatment-related neurotoxicity, for a greater fraction of patients.
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http://dx.doi.org/10.1200/EDBK_242547DOI Listing
January 2019

Validation of the Coronary Artery Calcium Data and Reporting System (CAC-DRS): Dual importance of CAC score and CAC distribution from the Coronary Artery Calcium (CAC) consortium.

J Cardiovasc Comput Tomogr 2020 Jan - Feb;14(1):12-17. Epub 2019 Mar 28.

Johns Hopkins Ciccarone Center for Prevention of Heart Disease, Baltimore, MD, United States; Department of Medicine, The Johns Hopkins Hospital, Baltimore, MD, United States. Electronic address:

Background: The Coronary Artery Calcium Data and Reporting System (CAC-DRS), which takes into account the Agatston score category (A) and the number of calcified vessels (N) has not yet been validated in terms of its prognostic significance.

Methods: We included 54,678 patients from the CAC Consortium, a large retrospective clinical cohort of asymptomatic individuals free of baseline cardiovascular disease (CVD). CAC-DRS groups were derived from routine, cardiac-gated CAC scans. Cox proportional hazards regression models, adjusted for traditional CVD risk factors, were used to assess the association between CAC-DRS groups and CHD, CVD, and all-cause mortality. CAC-DRS was then compared to CAC score groups and regional CAC distribution using area under the curve (AUC) analysis.

Results: The study population had a mean age of 54.2 ± 10.7, 34.4% female, and mean ASCVD score 7.3% ± 9.0. Over a mean follow-up of 12 ± 4 years, a total of 2,469 deaths (including 398 CHD deaths and 762 CVD deaths) were recorded. There was a graded risk for CHD, CVD and all-cause mortality with increasing CAC-DRS groups ranging from an all-cause mortality rate of 1.2 per 1,000 person-years for A0 to 15.4 per 1,000 person-years for A3/N4. In multivariable-adjusted models, those with CAC-DRS A3/N4 had significantly higher risk for CHD mortality (HR 5.9 (95% CI 3.6-9.9), CVD mortality (HR4.0 (95% CI 2.8-5.7), and all-cause mortality a (HR 2.5 (95% CI 2.1-3.0) compared to CAC-DRS A0. CAC-DRS had higher AUC than CAC score groups (0.762 vs 0.754, P < 0.001) and CAC distribution (0.762 vs 0.748, P < 0.001).

Conclusion: The CAC-DRS system, combining the Agatston score and the number of vessels with CAC provides better stratification of risk for CHD, CVD, and all-cause death than the Agatston score alone. These prognostic data strongly support new SCCT guidelines recommending the use CAC-DRS scoring.
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http://dx.doi.org/10.1016/j.jcct.2019.03.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6765460PMC
July 2020

Surgical Resection for Primary Central Nervous System Lymphoma: A Systematic Review.

World Neurosurg 2019 Jun 20;126:e1436-e1448. Epub 2019 Mar 20.

Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. Electronic address:

Background: Primary central nervous system lymphomas (PCNSLs) account for 1%-2% of primary central nervous system tumors. Until recently, treatment has centered on biopsy, radiotherapy, and high-dose methotrexate, without a clear role for cytoreductive surgery. The objective of this article is to compare the impact of biopsy versus cytoreductive surgery in outcomes of patients with PCNSL, including postoperative complications and survival.

Methods: We performed a systematic review of literature published from January 1, 1968 to May 2, 2018 related to PCNSL treatment in patients undergoing biopsy or resection. Data on morbidity, progression-free survival, and overall survival were extracted and analyzed.

Results: A total of 1291 nonduplicate citations were identified, with 244 articles selected for full-text review. Twenty-four articles were included for data abstraction including 2 level IIb studies, 4 level IIIb studies, and the remaining 18 articles representing level IVb studies. Of these articles, 15 failed to show benefit with cytoreductive surgery; most of these articles included relatively small sample sizes and predated standardization of high-dose systemic methotrexate treatment. Larger, more recent series included 9 articles providing evidence in support of cytoreductive surgery. Patient age, functional status, and treatment with chemotherapy and/or radiation were associated with improved survival across studies.

Conclusions: The treatment of PCNSL is challenging and ever-evolving. Earlier, smaller studies failed to show the benefit of cytoreductive surgery over biopsy in patients with PCNSL. Larger, more recent series seem to show the possible benefit of cytoreductive surgery in PCNSL. Future well-designed prospective studies may help further elucidate the role of resection in the modern treatment of PCNSL.
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http://dx.doi.org/10.1016/j.wneu.2019.02.252DOI Listing
June 2019

Aquaporin-4 Expression Patterns in Glioblastoma Pre-Chemoradiation and at Time of Suspected Progression.

Cancer Invest 2019 15;37(2):67-72. Epub 2019 Mar 15.

c Department of Oncology , Johns Hopkins University , Baltimore , MD , USA.

There has been controversy about the presence and potential role of aquaporin-4 (AQP4) in glioblastoma (GBM). We analyzed tissue from 22 patients with newly-diagnosed GBM as well as matching tissue from 17 of these cases who underwent repeat resection for suspected recurrence and performed immunohistochemical analysis for AQP-4 expression. While some degree of AQP4 expression was detected in all 22 cases (39 samples), there was no clear relationship between staining pattern and disease status (active versus inactive GBM) between baseline and time of repeat biopsy. In addition, there was no clear relationship between AQP4 expression and degree of edema.
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http://dx.doi.org/10.1080/07357907.2018.1564927DOI Listing
March 2019

Incidence and clinicopathologic features of H3 K27M mutations in adults with radiographically-determined midline gliomas.

J Neurooncol 2019 May 12;143(1):87-93. Epub 2019 Mar 12.

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 201 North Broadway, Viragh Building, 9th floor, Post Box 3, Baltimore, MD, 21287, USA.

Purpose: H3 K27 mutations, most commonly in H3F3A, are common in diffuse midline glioma. The exact frequency of these mutations in adults with gliomas in the midline location is unknown. This study was conducted to define the incidence of H3 K27M mutations in this location and to compare clinicopathological features with those of patients who do not harbor this mutation.

Methods: Consecutive glioma cases from 2007 to 2017 were screened for gliomas in the midline location. Immunohistochemistry was performed on all available tissue for mutations of H3 K27M, IDH1, and ARTX.

Results: Of 850 gliomas screened, 163 cases had midline glioma on MRI. Sufficient FFPE tissue was available for 123 cases (75%). H3 K27M mutation was identified in 18 of 123 cases (15%). All except one H3 K27M-mutant tumors were WHO grade III or IV on histology, while non-mutant tumors encompassed all four grades. The most common midline locations for H3 K27M-mutated tumors were midbrain (2/3; 67%), pons (4/11; 36%), and cerebellum (6/24; 25%). As compared to H3 K27M-wildtype tumors, there were no differences in age at diagnosis, sex, tumor grade, contrast enhancement on MRI, extent of resection, or treatment received. In this cohort, median survival was longer for patients with H3 K27M-mutated tumors (n = 18; 17.6 months) compared with high-grade wildtype tumors (n = 74; 7.7 months, p = 0.03).

Conclusions: H3 K27M mutations are common in midline gliomas in adults and can present in all midline locations. Survival comparison between H3 K27M-mutant and wildtype midline gliomas suggests that survival may be similar or possibly improved if the mutation is present.
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http://dx.doi.org/10.1007/s11060-019-03134-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6482123PMC
May 2019

Widely metastatic IDH1-mutant glioblastoma with oligodendroglial features and atypical molecular findings: a case report and review of current challenges in molecular diagnostics.

Diagn Pathol 2019 Feb 9;14(1):16. Epub 2019 Feb 9.

Brain Cancer Program, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 1550 Orleans Street, 1M16, Baltimore, MD, 21287, USA.

Background: Gliomas with 1p/19q-codeletion as well as mutation of isocitrate dehydrogenase (IDH) 1 are typically characterized as oligodendrogliomas with comparatively good response to treatment with radiation and chemotherapy.

Case Presentation: We present the case of a 28-year-old man with an IDH1 and TP53 mutant high grade glioma with abnormalities in chromosomes 1 and 19 suggestive of anaplastic oligodendroglioma that rapidly progressed to widespread metastatic disease. Biopsy of a liver lesion confirmed metastasis of the patient's known brain primary and chemotherapy with temozolomide was initiated. The patient's rapidly growing tumor burden with fulminant liver failure and tumor lysis led to multisystem failure of which the patient died. Further molecular testing illustrated features more consistent with glioblastoma: multiple large chromosomal aberrations including loss of whole chromosome 1 and 2q; gain/amplification of MYCN, MET, and CDK4; loss of CDKN2A/B; and an ATRX mutation.

Conclusion: This case illustrates the importance of higher level molecular diagnostic testing for patients with particularly aggressive disease progression that is not concordant with standard prognoses. Additional data on cases with atypical alterations of 1p and 19q are needed to better understand the distinct biology of these cancers so that appropriate therapies can be developed.
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http://dx.doi.org/10.1186/s13000-019-0793-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6368694PMC
February 2019

L265P mutation and loss are early mutational events in primary central nervous system diffuse large B-cell lymphomas.

Blood Adv 2019 02;3(3):375-383

Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA.

The genetic alterations that define primary central nervous system lymphoma (PCNSL) are incompletely elucidated, and the genomic evolution from diagnosis to relapse is poorly understood. We performed whole-exome sequencing (WES) on 36 PCNSL patients and targeted sequencing on a validation cohort of 27 PCNSL patients. We also performed WES and phylogenetic analysis of 3 matched newly diagnosed and relapsed tumor specimens and 1 synchronous intracranial and extracranial relapse. Immunohistochemistry (IHC) for programmed death-1 ligand (PD-L1) was performed on 43 patient specimens. Combined WES and targeted sequencing identified mutation in 67% (42 of 63) of patients, biallelic loss in 44% (16 of 36), and mutation in 61% (22 of 36). Copy-number analysis demonstrated frequent regions of copy loss (ie, ), with few areas of amplification. mutations were associated with improved progression-free and overall survival. We did not identify amplification at the / loci. IHC for PD-L1 revealed membranous expression in 30% (13 of 43) of specimens. Phylogenetic analysis of paired primary and relapsed specimens identified mutation and loss as early clonal events. PCNSL is characterized by frequent mutations within the B-cell receptor and NF-κB pathways. The lack of amplifications, along with membranous PD-L1 expression in 30% of our cohort, suggests that PD-1/PD-L1 inhibitors may be useful in a subset of PCNSL. WES of PCNSL provides insight into the genomic landscape and evolution of this rare lymphoma subtype and potentially informs more rational treatment decisions.
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http://dx.doi.org/10.1182/bloodadvances.2018027672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373750PMC
February 2019

The consistency of neuropathological diagnoses in patients undergoing surgery for suspected recurrence of glioblastoma.

J Neurooncol 2019 Jan 9;141(2):347-354. Epub 2018 Nov 9.

Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Purpose: Clinical factors and neuro-imaging in patients with glioblastoma who appear to progress following standard chemoradiation are unable to reliably distinguish tumor progression from pseudo-progression. As a result, surgery is commonly recommended to establish a final diagnosis. However, studies evaluating the pathologists' agreement on pathologic diagnoses in this setting have not been previously evaluated.

Methods: A hypothetical clinical history coupled with images of histological sections from 13 patients with glioblastoma who underwent diagnostic surgery for suspected early recurrence were sent to 101 pathologists from 50 NCI-designated Cancer Centers. Pathologists were asked to provide a final diagnosis (active tumor, treatment effect, or unable to classify) and to report on percent active tumor, treatment effect, and degree of cellularity and degree of mitotic activity.

Results: Forty-eight pathologists (48%) from 30 centers responded. In three cases > 75% of pathologists diagnosed active tumor. In two cases > 75% diagnosed treatment effect. However, in the remaining eight cases the disparity in diagnoses was striking (maximum agreement on final diagnosis ranged from 36 to 68%). Overall, only marginal agreement was observed in the overall assessment of disease status [kappa score 0.228 (95% CI 0.22-0.24)].

Conclusions: Confidence in any clinical diagnostic assay requires that very similar results are obtained from identical specimens evaluated by sophisticated clinicians and institutions. The findings of this study illustrate that the diagnostic agreement between different cases of repeat resection for suspected recurrent glioblastoma can be variable. This raises concerns as pathological diagnoses are critical in directing standard and experimental care in this setting.
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http://dx.doi.org/10.1007/s11060-018-03037-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6342857PMC
January 2019
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