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Meningioma: Genomic Discoveries and Recent Therapeutic Advances

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (15 November 2020) | Viewed by 22713

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Special Issue Editors

Dr. Hiroaki Wakimoto

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Guest Editor

Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02215, USA
Interests: neuro-oncology; glioblastoma; meningioma; oncolytic virus; herpes simplex virus; gene therapy
Special Issues, Collections and Topics in MDPI journals

Dr. Tareq A. Juratli

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Guest Editor

Department of Neurosurgery, Faculty of Medicine and University Hospital Carl Gustav Carus, Technischen Universität Dresden, Dresden, Germany
Translational Neuro-Oncology Laboratory, Department of Neurosurgery, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA
Interests: central nervous system tumors; meningioma; glioma; genomics and personilized medicine; biomarkers; drug discovery

Special Issue Information

Dear Colleagues,

Meningioma are the most common primary intracranial tumor, representing up to 35% of all central nervous system neoplasms. Initial standard-of-care therapy for meningioma is surgical resection, followed by radiation in recurrent, atypical, or malignant meningioma. Nevertheless, the post-treatment clinical course of the disease is remarkably heterogeneous; while most low-grade meningiomas do not recur after resection, recurrence in atypical and anaplastic meningioma is frequent.

The evidence base for traditional chemotherapeutics is poor, and securing durable, long-term disease control in this setting has been challenging. Therefore, there is an unmet need to better identify patients who are at risk to develop progressive meningioma with an aggressive clinical course. Recent genomic and epigenmoic discoveries have provided us with an improved understanding of the molecular drivers in meningioma and novel approaches to their treatment, while also redefining the role of genomic screening for meningioma classification and prognostic stratification. On the other hand, the role of the tumor microenvironment and immune surveilance in meningioma biology is poorly understood.

This Special Issue therefore covers new original research articles and timely reviews from experts in the field of menigioma in basic, translational, and clinical research arenas. Emphasis will be on genomic discoveries and recent therapeutic advancements in meningioma. However, cutting-edge research in other areas, such as novel biomarkers, diagnostic modalities, the tumor microenvironment, and immunology, is also welcome.

Dr. Hiroaki Wakimoto
Dr. Tareq A. Juratli
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Meningioma
classification
genomics
epigenomics
biomarkers
molecular targets
surgery
radiation
targeted therapy
immunotherapy

Published Papers (7 papers)

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Research

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12 pages, 1938 KiB

Open AccessArticle

CNS Invasion in Meningioma—How the Intraoperative Assessment Can Improve the Prognostic Evaluation of Tumor Recurrence

by Felix Behling, Christina Fodi, Irina Gepfner-Tuma, Kathrin Machetanz, Mirjam Renovanz, Marco Skardelly, Antje Bornemann, Jürgen Honegger, Ghazaleh Tabatabai, Marcos Tatagiba and Jens Schittenhelm

Cancers 2020, 12(12), 3620; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12123620 - 03 Dec 2020

Cited by 13 | Viewed by 1749

Abstract

The detection of the infiltrative growth of meningiomas into CNS tissue has been integrated into the WHO classification as a stand-alone marker for atypical meningioma. However, its prognostic impact has been questioned. Infiltrative growth can also be detected intraoperatively. The prognostic impact of the intraoperative detection of the central nervous system tissue invasion of meningiomas was analyzed and compared to the histopathological assessment. The clinical data of 1517 cases with follow-up data regarding radiographic recurrence was collected. Histopathology and operative reports were reviewed and invasive growth was seen during resection in 23.7% (n = 345) while histopathology detected it in 4.8% (n = 73). The histopathological and intraoperative assessments were compatible in 63%. The prognostic impact of histopathological and intraoperative assessment was significant in the univariate but not in the multivariate analysis. Both methods of assessment combined reached statistical significance in the multivariate analysis (p = 0.0409). A score including all independent prognostic factors divided the cohort into three prognostic subgroups with a risk of recurrence of 33.8, 64.7 and 88.5%, respectively. The intraoperative detection of the infiltrative growth of primary meningiomas into the central nervous system tissue can complement the histopathological assessment of CNS invasion. The combined assessment is an independent prognostic factor regarding tumor recurrence and allows a risk-adapted tumor stratification. Full article

(This article belongs to the Special Issue Meningioma: Genomic Discoveries and Recent Therapeutic Advances)

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16 pages, 3147 KiB

Open AccessFeature PaperArticle

Image-Guided Multisession Radiosurgery of Skull Base Meningiomas

by Alfredo Conti, Antonio Pontoriero, Giuseppe Iatì, Salvatore M. Cardali, Anna Brogna, Filippo Friso, Vittoria Rosetti, Matteo Zoli, Silvana Parisi, Alberto Cacciola, Sara Lillo, Stefano Pergolizzi and Diego Mazzatenta

Cancers 2020, 12(12), 3569; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12123569 - 29 Nov 2020

Cited by 7 | Viewed by 2181

Abstract

Background: The efficacy of single-session stereotactic radiosurgery (sSRS) for the treatment of intracranial meningioma is widely recognized. However, sSRS is not always feasible in cases of large tumors and those lying close to critically radiation-sensitive structures. When surgery is not recommended, multi-session stereotactic radiosurgery (mSRS) can be applied. Even so, the efficacy and best treatment schedule of mSRS are not yet established. The aim of this study is to validate the role of mSRS in the treatment of skull base meningiomas. Methods: A retrospective analysis of patients with skull base meningiomas treated with mSRS (two to five fractions) at the University of Messina, Italy, from 2008 to 2018, was conducted. Results: 156 patients met the inclusion criteria. The median follow-up period was 36.2 ± 29.3 months. Progression-free survival at 2-, 5-, and 10- years was 95%, 90%, and 80.8%, respectively. There were no new visual or motor deficits, nor cranial nerves impairments, excluding trigeminal neuralgia, which was reported by 5.7% of patients. One patient reported carotid occlusion and one developed brain edema. Conclusion: Multisession radiosurgery is an effective approach for skull base meningiomas. The long-term control is comparable to that obtained with conventionally-fractionated radiotherapy, while the toxicity rate is very limited. Full article

(This article belongs to the Special Issue Meningioma: Genomic Discoveries and Recent Therapeutic Advances)

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22 pages, 3224 KiB

Open AccessArticle

Integration and Comparison of Transcriptomic and Proteomic Data for Meningioma

by Jemma Dunn, Vasileios P. Lenis, David A. Hilton, Rolf Warta, Christel Herold-Mende, C. Oliver Hanemann and Matthias E. Futschik

Cancers 2020, 12(11), 3270; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12113270 - 05 Nov 2020

Cited by 8 | Viewed by 3997

Abstract

Meningioma are the most frequent primary intracranial tumour. Management of aggressive meningioma is complex, and development of effective biomarkers or pharmacological interventions is hampered by an incomplete knowledge of molecular landscape. Here, we present an integrated analysis of two complementary omics studies to investigate alterations in the “transcriptome–proteome” profile of high-grade (III) compared to low-grade (I) meningiomas. We identified 3598 common transcripts/proteins and revealed concordant up- and downregulation in grade III vs. grade I meningiomas. Concordantly upregulated genes included FABP7, a fatty acid binding protein and the monoamine oxidase MAOB, the latter of which we validated at the protein level and established an association with Food and Drug Administration (FDA)-approved drugs. Notably, we derived a plasma signature of 21 discordantly expressed genes showing positive changes in protein but negative in transcript levels of high-grade meningiomas, including the validated genes CST3, LAMP2, PACS1 and HTRA1, suggesting the acquisition of these proteins by tumour from plasma. Aggressive meningiomas were enriched in processes such as oxidative phosphorylation and RNA metabolism, whilst concordantly downregulated genes were related to reduced cellular adhesion. Overall, our study provides the first transcriptome–proteome characterisation of meningioma, identifying several novel and previously described transcripts/proteins with potential grade III biomarker and therapeutic significance. Full article

(This article belongs to the Special Issue Meningioma: Genomic Discoveries and Recent Therapeutic Advances)

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13 pages, 2304 KiB

Open AccessArticle

Midline Meningiomas of the Anterior Skull Base: Surgical Outcomes and a Decision-Making Algorithm for Classic Skull Base Approaches

by Amir Kaywan Aftahy, Melanie Barz, Philipp Krauss, Arthur Wagner, Nicole Lange, Alaa Hijazi, Benedikt Wiestler, Bernhard Meyer, Chiara Negwer and Jens Gempt

Cancers 2020, 12(11), 3243; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12113243 - 03 Nov 2020

Cited by 13 | Viewed by 5744

Abstract

(1) Background: Midline meningiomas such as olfactory groove (OGMs), planum sphenoidale (PSMs), or tuberculum sellae meningiomas (TSMs) are challenging, and determining the appropriate approach is important. We propose a decision algorithm for choosing suitable transcranial approaches. (2) Methods: A retrospective chart review between 06/2007 and 01/2020. Clinical outcomes, radiographic findings, and postoperative complication rates were analyzed with respect to operative approaches. (3) Results: We included 88 patients in the analysis. Of these, 18.2% (16/88) underwent an interhemispheric approach, 72.7% (64/88) underwent a pterional/frontolateral/supraorbital approach, 2.3% (2/88) underwent a unilateral subfrontal approach, and 6.8% (6/88) underwent a bifrontal approach. All OGMs underwent median approaches, along with one PSM. All of the other PSMs and TSMs were resected via lateral approaches. The preoperative tumor volume was ∅20.2 ± 27.1 cm³. Median approaches had significantly higher tumor volume but also higher rates of Simpson I resection (75.0% vs. 34.4%). An improvement of visual deficits was observed in 34.1% (30/88). The adverse event rate was 17.0%. Median follow-up was 15.5 months (range 0–112 months). (4) Conclusions: Median approaches provides satisfying results for OGMs, lateral approaches enable sufficient exposure of the visual apparatus for PSMs and TSMs. In proposing a simple decision-making algorithm, the authors found that satisfactory outcomes can be achieved for midline meningiomas. Full article

(This article belongs to the Special Issue Meningioma: Genomic Discoveries and Recent Therapeutic Advances)

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15 pages, 2651 KiB

Open AccessArticle

The Potential of MLN3651 in Combination with Selumetinib as a Treatment for Merlin-Deficient Meningioma

by Jade Lyons Rimmer, Emanuela Ercolano, Daniele Baiz, Mahindra Makhija, Allison Berger, Todd Sells, Steve Stroud, David Hilton, Claire L. Adams and C Oliver Hanemann

Cancers 2020, 12(7), 1744; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12071744 - 30 Jun 2020

Cited by 1 | Viewed by 2809

Abstract

Meningioma is the most common primary intracranial tumour, and surgical resection is the main therapeutic option. Merlin is a tumour suppressor protein that is frequently mutated in meningioma. The activity of the E3 ubiquitin ligase complex, CRL4-DCAF1, and the Raf/MEK/ERK scaffold protein Kinase suppressor of Ras 1 (KSR1) are upregulated in Merlin-deficient tumours, which drives tumour growth. Identifying small molecules that inhibit these key pathways may provide an effective treatment option for patients with meningioma. We used meningioma tissue and primary cells derived from meningioma tumours to investigate the expression of DDB1 and Cullin 4-associated factor 1 (DCAF1) and KSR1, and confirmed these proteins were overexpressed. We then used primary cells to assess the therapeutic potential of MLN3651, a neddylation inhibitor which impacts the activity of the CRL family of E3 ubiquitin ligases and the MAPK/ERK kinase (MEK1/2) inhibitor selumetinib. MLN3651 treatment reduced proliferation and activated apoptosis, whilst increasing Raf/MEK/ERK pathway activation. The combination of MLN3651 and the MEK1/2 inhibitor selumetinib prevented the increase in Raf/MEK/ERK activity, and had an additive effect compared with either treatment alone. Therefore, the combined targeting of CRL4-DCAF1 and Raf/MEK/ERK activity represents an attractive novel strategy in the treatment of Merlin-deficient meningioma. Full article

(This article belongs to the Special Issue Meningioma: Genomic Discoveries and Recent Therapeutic Advances)

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15 pages, 58301 KiB

Open AccessFeature PaperArticle

Protein Kinase A Distribution in Meningioma

by Antonio Caretta, Luca Denaro, Domenico D’Avella and Carla Mucignat-Caretta

Cancers 2019, 11(11), 1686; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11111686 - 29 Oct 2019

Cited by 3 | Viewed by 2195

Abstract

Deregulation of intracellular signal transduction pathways is a hallmark of cancer cells, clearly differentiating them from healthy cells. Differential intracellular distribution of the cAMP-dependent protein kinases (PKA) was previously detected in cell cultures and in vivo in glioblastoma and medulloblastoma. Our goal is to extend this observation to meningioma, to explore possible differences among tumors of different origins and prospective outcomes. The distribution of regulatory and catalytic subunits of PKA has been examined in tissue specimens obtained during surgery from meningioma patients. PKA RI subunit appeared more evenly distributed throughout the cytoplasm, but it was clearly detectable only in some tumors. RII was present in discrete spots, presumably at high local concentration; these aggregates could also be visualized under equilibrium binding conditions with fluorescent 8-substituted cAMP analogues, at variance with normal brain tissue and other brain tumors. The PKA catalytic subunit showed exactly overlapping pattern to RII and in fixed sections could be visualized by fluorescent cAMP analogues. Gene expression analysis showed that the PKA catalytic subunit revealed a significant correlation pattern with genes involved in meningioma. Hence, meningioma patients show a distinctive distribution pattern of PKA regulatory and catalytic subunits, different from glioblastoma, medulloblastoma, and healthy brain tissue. These observations raise the possibility of exploiting the PKA intracellular pathway as a diagnostic tool and possible therapeutic interventions. Full article

(This article belongs to the Special Issue Meningioma: Genomic Discoveries and Recent Therapeutic Advances)

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Review

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16 pages, 1198 KiB

Open AccessReview

Boron Neutron Capture Therapy and Photodynamic Therapy for High-Grade Meningiomas

by Yukiko Nakahara, Hiroshi Ito, Jun Masuoka and Tatsuya Abe

Cancers 2020, 12(5), 1334; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12051334 - 23 May 2020

Cited by 12 | Viewed by 3230

Abstract

Meningiomas are the most common type of intracranial brain tumors in adults. The majority of meningiomas are benign with a low risk of recurrence after resection. However, meningiomas defined as grades II or III, according to the 2016 World Health Organization (WHO) classification, termed high-grade meningiomas, frequently recur, even after gross total resection with or without adjuvant radiotherapy. Boron neutron capture therapy (BNCT) and photodynamic therapy (PDT) are novel treatment modalities for malignant brain tumors, represented by glioblastomas. Although BNCT is based on a nuclear reaction and PDT uses a photochemical reaction, both of these therapies result in cellular damage to only the tumor cells. The aim of this literature review is to investigate the possibility and efficacy of BNCT and PDT as novel treatment modalities for high-grade meningiomas. The present review was conducted by searching PubMed and Scopus databases. The search was conducted in December 2019. Early clinical studies of BNCT have demonstrated activity for high-grade meningiomas, and a phase II clinical trial is in progress in Japan. As for PDT, studies have investigated the effect of PDT in malignant meningioma cell lines to establish PDT as a treatment for malignant meningiomas. Further laboratory research combined with proper controlled trials investigating the effects of these therapies is warranted. Full article

(This article belongs to the Special Issue Meningioma: Genomic Discoveries and Recent Therapeutic Advances)

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