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Cancers
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Brain Tumors
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Brain Tumors

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

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 61993

Special Issue Editors

Dr. Giuseppe Minniti

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Guest Editor
Radiation Oncology Unit, UPMC Hillman Cancer Center, San Pietro Hospital FBF, 00189 Rome, Italy
Interests: brain tumors; stereotactic radiosurgery; radiation therapy; gliomas; brain metastases; benign brain tumors
Special Issues, Collections and Topics in MDPI journals
Dr. Piera Navarria

E-Mail Website
Guest Editor
Radiotherapy and Radiosurgery Department, Humanitas Cancer Center and Research Hospital, Rozzano, Italy
Interests: brain tumors; stereotactic radiosurgery; radiation therapy; gliomas; brain metastases; benign brain tumors
Special Issues, Collections and Topics in MDPI journals
Dr. Claudia Scaringi

E-Mail Website
Guest Editor
Radiation Oncology Unit, UPMC Hillman Cancer Center, San Pietro Hospital, Via Cassia 600, Rome, Italy
Interests: brain tumors; stereotactic radiosurgery; radiation therapy; gliomas; brain metastases; benign brain tumors

Special Issue Information

Dear Colleagues,

Brain tumors are a heterogeneous group of diseases which include either primary or secondary brain tumors. In recent years, significant improvement has been made to identify tumor molecular markers that can predict survival and treatment response, leading to the updated World Health Organization (WHO) classification of brain tumors in 2016. Novel therapeutic approaches, developed on the basis of cancer biology, are increasingly being used, with promising results on tumor outcome.

The last few decades have seen some of the most important technological advances in all aspects of radiation treatments. Modern radiation techniques allow for more precise radiation dose delivery, while reducing the volume of healthy brain tissue irradiated to high doses. Magnetic resonance imaging (MRI) and positron emission tomography (PET) are now integrated into radiation therapy planning to improve treatment accuracy in target delineation and to decrease normal tissue toxicity. Recent advances in the knowledge of the immunostimulatory effects of irradiation have provided evidence that radiation therapy can induce direct anti-tumor immune response. In addition, the potential efficacy of combining radiation and targeted agents in patients with brain tumors is under evaluation.

This Special Issue will cover all aspects of primary and secondary brain tumors, including advanced imaging for diagnosis and response assessment, molecular mechanisms of response, and current treatment options. Together with original research articles, comprehensive up-to-date reviews to these topics are encouraged to summarize and understand the current status and future directions.

Dr. Giuseppe Minniti
Dr. Piera Navarria
Dr. Claudia Scaringi
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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

  • primary brain tumors
  • brain metastases (BMs)
  • radiotherapy (RT)
  • stereotactic radiosurgery (SRS)
  • immunotherapy
  • targeted therapies
  • magnetic resonance imaging (MRI)
  • positron emission tomography (PET)

Published Papers (16 papers)

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13 pages, 1183 KiB  
Article
Pulsed-Reduced Dose Rate (PRDR) Radiotherapy for Recurrent Primary Central Nervous System Malignancies: Dosimetric and Clinical Results
by Tugce Kutuk, Ranjini Tolakanahalli, Nicole C. McAllister, Matthew D. Hall, Martin C. Tom, Muni Rubens, Haley Appel, Alonso N. Gutierrez, Yazmin Odia, Alexander Mohler, Manmeet S. Ahluwalia, Minesh P. Mehta and Rupesh Kotecha
Cancers 2022, 14(12), 2946; https://doi.org/10.3390/cancers14122946 - 15 Jun 2022
Cited by 4 | Viewed by 1800
Abstract
Purpose: The objective was to describe PRDR outcomes and report EQD2 OAR toxicity thresholds. Methods: Eighteen patients with recurrent primary CNS tumors treated with PRDR at a single institution between April 2017 and September 2021 were evaluated. The radiotherapy details, cumulative OAR doses, [...] Read more.
Purpose: The objective was to describe PRDR outcomes and report EQD2 OAR toxicity thresholds. Methods: Eighteen patients with recurrent primary CNS tumors treated with PRDR at a single institution between April 2017 and September 2021 were evaluated. The radiotherapy details, cumulative OAR doses, progression-free survival (PFS), overall survival (OS), and toxicities were collected. Results: The median PRDR dose was 45 Gy (range: 36–59.4 Gy); the median cumulative EQD2 prescription dose was 102.7 Gy (range: 93.8–120.4 Gy). The median cumulative EQD2 D0.03cc for the brain was 111.4 Gy (range: 82.4–175.2 Gy). Symptomatic radiation necrosis occurred in three patients, for which the median EQD2 brain D0.03cc was 115.9 Gy (110.4–156.7 Gy). The median PFS and OS after PRDR were 6.3 months (95%CI: 0.9–11.6 months) and 8.6 months (95%CI: 4.9–12.3 months), respectively. The systematic review identified five peer-reviewed studies with a median cumulative EQD2 prescription dose of 110.3 Gy. At a median follow-up of 8.7 months, the median PFS and OS were 5.7 months (95%CI: 2.1–15.4 months) and 6.7 months (95%CI: 3.2–14.2 months), respectively. Conclusion: PRDR re-irradiation is a relatively safe and feasible treatment for recurrent primary CNS tumors. Despite high cumulative dose to OARs, the risk of high-grade, treatment-related toxicity within the first year of follow-up remains acceptable. Full article
(This article belongs to the Special Issue Brain Tumors)
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16 pages, 1972 KiB  
Article
Gamma Irradiation Triggers Immune Escape in Glioma-Propagating Cells
by Nicola Hoppmann, Nora Heinig, Ute Distler, Ella Kim, Volker Lennerz, Yvonne Krauß, Ulrike Schumann, Alf Giese, Stefan Tenzer, Lynn Bitar and Mirko H. H. Schmidt
Cancers 2022, 14(11), 2728; https://doi.org/10.3390/cancers14112728 - 31 May 2022
Cited by 1 | Viewed by 2062
Abstract
Glioblastoma multiforme is the most common and devastating form of brain tumor for which only palliative radio- and chemotherapy exists. Although some clinical studies on vaccination approaches have shown promising efficacy due to their potential to generate long-term immune surveillance against cancer cells, [...] Read more.
Glioblastoma multiforme is the most common and devastating form of brain tumor for which only palliative radio- and chemotherapy exists. Although some clinical studies on vaccination approaches have shown promising efficacy due to their potential to generate long-term immune surveillance against cancer cells, the evasion mechanisms preventing therapy response are largely uncharacterized. Here, we studied the response of glioblastoma-propagating cells (GPCs) to clinically relevant doses of γ radiation. GPCs were treated with 2.5 Gy of γ radiation in seven consecutive cellular passages to select for GPCs with increased colony-forming properties and intrinsic or radiation-induced resistance (rsGPCs). Quantitative proteomic analysis of the cellular signaling platforms of the detergent-resistant membranes (lipid rafts) in GPCs vs. rsGPCs revealed a downregulation of the MHC class I antigen-processing and -presentation machinery. Importantly, the radio-selected GPCs showed reduced susceptibility towards cytotoxic CD8+ T-cell-mediated killing. While previous studies suggested that high-dose irradiation results in enhanced antigen presentation, we demonstrated that clinically relevant sub-lethal fractionated irradiation results in reduced expression of components of the MHC class I antigen-processing and -presentation pathway leading to immune escape. Full article
(This article belongs to the Special Issue Brain Tumors)
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19 pages, 1361 KiB  
Article
Prognostic and Predictive Value of Integrated Qualitative and Quantitative Magnetic Resonance Imaging Analysis in Glioblastoma
by Maikel Verduin, Sergey Primakov, Inge Compter, Henry C. Woodruff, Sander M. J. van Kuijk, Bram L. T. Ramaekers, Maarten te Dorsthorst, Elles G. M. Revenich, Mark ter Laan, Sjoert A. H. Pegge, Frederick J. A. Meijer, Jan Beckervordersandforth, Ernst Jan Speel, Benno Kusters, Wendy W. J. de Leng, Monique M. Anten, Martijn P. G. Broen, Linda Ackermans, Olaf E. M. G. Schijns, Onno Teernstra, Koos Hovinga, Marc A. Vooijs, Vivianne C. G. Tjan-Heijnen, Danielle B. P. Eekers, Alida A. Postma, Philippe Lambin and Ann Hoebenadd Show full author list remove Hide full author list
Cancers 2021, 13(4), 722; https://doi.org/10.3390/cancers13040722 - 10 Feb 2021
Cited by 27 | Viewed by 4069
Abstract
Glioblastoma (GBM) is the most malignant primary brain tumor for which no curative treatment options exist. Non-invasive qualitative (Visually Accessible Rembrandt Images (VASARI)) and quantitative (radiomics) imaging features to predict prognosis and clinically relevant markers for GBM patients are needed to guide clinicians. [...] Read more.
Glioblastoma (GBM) is the most malignant primary brain tumor for which no curative treatment options exist. Non-invasive qualitative (Visually Accessible Rembrandt Images (VASARI)) and quantitative (radiomics) imaging features to predict prognosis and clinically relevant markers for GBM patients are needed to guide clinicians. A retrospective analysis of GBM patients in two neuro-oncology centers was conducted. The multimodal Cox-regression model to predict overall survival (OS) was developed using clinical features with VASARI and radiomics features in isocitrate dehydrogenase (IDH)-wild type GBM. Predictive models for IDH-mutation, 06-methylguanine-DNA-methyltransferase (MGMT)-methylation and epidermal growth factor receptor (EGFR) amplification using imaging features were developed using machine learning. The performance of the prognostic model improved upon addition of clinical, VASARI and radiomics features, for which the combined model performed best. This could be reproduced after external validation (C-index 0.711 95% CI 0.64–0.78) and used to stratify Kaplan–Meijer curves in two survival groups (p-value < 0.001). The predictive models performed significantly in the external validation for EGFR amplification (area-under-the-curve (AUC) 0.707, 95% CI 0.582–8.25) and MGMT-methylation (AUC 0.667, 95% CI 0.522–0.82) but not for IDH-mutation (AUC 0.695, 95% CI 0.436–0.927). The integrated clinical and imaging prognostic model was shown to be robust and of potential clinical relevance. The prediction of molecular markers showed promising results in the training set but could not be validated after external validation in a clinically relevant manner. Overall, these results show the potential of combining clinical features with imaging features for prognostic and predictive models in GBM, but further optimization and larger prospective studies are warranted. Full article
(This article belongs to the Special Issue Brain Tumors)
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15 pages, 1685 KiB  
Article
A Paravermal Trans-Cerebellar Approach to the Posterior Fossa Tumor Causes Hypertrophic Olivary Degeneration by Dentate Nucleus Injury
by Martin A. Schaller-Paule, Peter Baumgarten, Volker Seifert, Marlies Wagner, Eike Steidl, Elke Hattingen, Felix Wicke, Joachim P. Steinbach, Christian Foerch and Juergen Konczalla
Cancers 2021, 13(2), 258; https://doi.org/10.3390/cancers13020258 - 12 Jan 2021
Cited by 6 | Viewed by 2724
Abstract
Background: In brain tumor surgery, injury to cerebellar connectivity pathways can induce a neurodegenerative disease called hypertrophic olivary degeneration (HOD), along with a disabling clinical syndrome. In children, cerebellar mutism syndrome (CMS) is another consequence of damage to cerebello–thalamo–cortical networks. The goal of [...] Read more.
Background: In brain tumor surgery, injury to cerebellar connectivity pathways can induce a neurodegenerative disease called hypertrophic olivary degeneration (HOD), along with a disabling clinical syndrome. In children, cerebellar mutism syndrome (CMS) is another consequence of damage to cerebello–thalamo–cortical networks. The goal of this study was to compare paravermal trans-cerebellar to other more midline or lateral operative approaches in their risk of causing HOD on MR-imaging and CMS. Methods: We scanned our neurosurgical database for patients with surgical removal of pilocytic astrocytoma, ependymoma and medulloblastoma in the posterior fossa. Fifty patients with a mean age of 22.7 (±16.9) years were identified and analyzed. Results: HOD occurred in n = 10/50 (20%) patients within four months (median), always associated with contralateral dentate nucleus (DN)-lesions (p < 0.001). Patients with paravermal trans-cerebellar approach significantly more often developed HOD (7/11; 63.6%) when compared to other approaches (3/39; 7.7%; p < 0.001). Injury to the DN occurred more frequently after a paravermal approach (8/11 vs. 13/39 patients; p < 0.05). CMS was described for n = 12/50 patients (24%). Data indicated no correlation of radiological HOD and CMS development. Conclusions: A paravermal trans-cerebellar approach more likely causes HOD due to DN-injury when compared to more midline or lateral approaches. HOD is a radiological indicator for surgical disruption of cerebellar pathways involving the DN. Neurosurgeons should consider trajectories and approaches in the planning of posterior fossa surgery that spare the DN, whenever feasible. Full article
(This article belongs to the Special Issue Brain Tumors)
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14 pages, 4580 KiB  
Article
Subtraction Maps Derived from Longitudinal Magnetic Resonance Imaging in Patients with Glioma Facilitate Early Detection of Tumor Progression
by Nico Sollmann, Magaly Gutbrod-Fernandez, Egon Burian, Isabelle Riederer, Bernhard Meyer, Andreas Hock, Jens Gempt, Claus Zimmer and Jan S. Kirschke
Cancers 2020, 12(11), 3111; https://doi.org/10.3390/cancers12113111 - 24 Oct 2020
Cited by 8 | Viewed by 2555
Abstract
Progression of glioma is frequently characterized by increases or enhanced spread of a hyperintensity in fluid attenuated inversion recovery (FLAIR) sequences. However, changes in FLAIR signal over time can be subtle, and conventional (CONV) visual reading is time-consuming. The purpose of this monocentric, [...] Read more.
Progression of glioma is frequently characterized by increases or enhanced spread of a hyperintensity in fluid attenuated inversion recovery (FLAIR) sequences. However, changes in FLAIR signal over time can be subtle, and conventional (CONV) visual reading is time-consuming. The purpose of this monocentric, retrospective study was to compare CONV reading to reading of subtraction maps (SMs) for serial FLAIR imaging. FLAIR datasets of cranial 3-Tesla magnetic resonance imaging (MRI), acquired at two different time points (mean inter-scan interval: 5.4 ± 1.9 months), were considered per patient in a consecutive series of 100 patients (mean age: 49.0 ± 13.7 years) diagnosed with glioma (19 glioma World Health Organization [WHO] grade I and II, 81 glioma WHO grade III and IV). Two readers (R1 and R2) performed CONV and SM reading by assessing overall image quality and artifacts, alterations in tumor-associated FLAIR signal over time (stable/unchanged or progressive) including diagnostic confidence (1—very high to 5—very low diagnostic confidence), and time needed for reading. Gold-standard (GS) reading, including all available clinical and imaging information, was performed by a senior reader, revealing progressive FLAIR signal in 61 patients (tumor progression or recurrence in 38 patients, pseudoprogression in 10 patients, and unclear in the remaining 13 patients). SM reading used an officially certified and commercially available algorithm performing semi-automatic coregistration, intensity normalization, and color-coding to generate individual SMs. The approach of SM reading revealed FLAIR signal increases in a larger proportion of patients according to evaluations of both readers (R1: 61 patients/R2: 60 patients identified with FLAIR signal increase vs. R1: 45 patients/R2: 44 patients for CONV reading) with significantly higher diagnostic confidence (R1: 1.29 ± 0.48, R2: 1.26 ± 0.44 vs. R1: 1.73 ± 0.80, R2: 1.82 ± 0.85; p < 0.0001). This resulted in increased sensitivity (99.9% vs. 73.3%) with maintained high specificity (98.1% vs. 98.8%) for SM reading when compared to CONV reading. Furthermore, the time needed for SM reading was significantly lower compared to CONV assessments (p < 0.0001). In conclusion, SM reading may improve diagnostic accuracy and sensitivity while reducing reading time, thus potentially enabling earlier detection of disease progression. Full article
(This article belongs to the Special Issue Brain Tumors)
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12 pages, 3135 KiB  
Article
Assessment of the Extent of Resection in Surgery of High-Grade Glioma—Evaluation of Black Blood Sequences for Intraoperative Magnetic Resonance Imaging at 3 Tesla
by Tom Finck, Jens Gempt, Sandro M. Krieg, Bernhard Meyer, Claus Zimmer, Benedikt Wiestler, Jan S. Kirschke and Nico Sollmann
Cancers 2020, 12(6), 1580; https://doi.org/10.3390/cancers12061580 - 15 Jun 2020
Cited by 6 | Viewed by 2407
Abstract
Achieving an optimal extent of resection (EOR) whilst keeping lasting neurological decline to a minimum is paramount for modern neurosurgery in patients with high-grade glioma (HGG). To improve EOR assessment, this study introduces Black Blood (BB) imaging, which uses a selective saturation pulse [...] Read more.
Achieving an optimal extent of resection (EOR) whilst keeping lasting neurological decline to a minimum is paramount for modern neurosurgery in patients with high-grade glioma (HGG). To improve EOR assessment, this study introduces Black Blood (BB) imaging, which uses a selective saturation pulse to suppress the blood signal, to 3-Tesla intraoperative magnetic resonance imaging (iMRI). Seventy-three patients (56.4 ± 13.9 years, 64.4% male) with contrast-enhancing HGGs underwent iMRI, including contrast-enhanced (CE) and non-CE 3D turbo field-echo imaging (TFE; acquisition time: 4:20 min per sequence) and CE and non-CE 3D BB imaging (acquisition time: 1:36 min per sequence). Two readers (R1 and R2) retrospectively evaluated the EOR and diagnostic confidence (1—very inconfident to 5—very confident) as well as the delineation of tumor boarders and spread of contrast-enhancing tumor components (in case of contrast-enhancing tumor residuals). Furthermore, the contrast-to-noise ratio (CNR) was measured for contrast-enhancing tumor residuals. Both BB and conventional TFE imaging allowed for the correct detection of all contrast-enhancing tumor residuals intraoperatively (considering postsurgical MRI and histopathological evaluation as the ground truth for determination of the lack/presence of contrast-enhancing tumor residuals), but BB imaging showed significantly higher diagnostic confidence (R1: 4.65 ± 0.53 vs. 3.88 ± 1.02, p < 0.0001; R2: 4.75 ± 0.50 vs. 4.25 ± 0.81, p < 0.0001). Delineation of contrast-enhancing tumor residuals and detection of their spread into adjacent brain parenchyma was better for BB imaging. Accordingly, significantly higher CNRs were noted for BB imaging (48.1 ± 32.1 vs. 24.4 ± 15.3, p < 0.0001). In conclusion, BB imaging is not inferior to conventional TFE imaging for EOR assessment, but may significantly reduce scanning time for iMRI whilst increasing diagnostic confidence. Furthermore, given the better depiction of contrast-enhancing tumor residual spread and borders, BB imaging could support achieving complete macroscopic resection in patients suffering from HGG, which is clinically relevant as an optimal EOR is correlated to prolonged survival. Full article
(This article belongs to the Special Issue Brain Tumors)
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19 pages, 5914 KiB  
Article
Risk Assessment by Presurgical Tractography Using Navigated TMS Maps in Patients with Highly Motor- or Language-Eloquent Brain Tumors
by Nico Sollmann, Haosu Zhang, Alessia Fratini, Noémie Wildschuetz, Sebastian Ille, Axel Schröder, Claus Zimmer, Bernhard Meyer and Sandro M. Krieg
Cancers 2020, 12(5), 1264; https://doi.org/10.3390/cancers12051264 - 17 May 2020
Cited by 51 | Viewed by 4307
Abstract
Patients with functionally eloquent brain lesions are at risk of functional decline in the course of resection. Given tumor-related plastic reshaping and reallocation of function, individual data are needed for patient counseling and risk assessment prior to surgery. This study evaluates the utility [...] Read more.
Patients with functionally eloquent brain lesions are at risk of functional decline in the course of resection. Given tumor-related plastic reshaping and reallocation of function, individual data are needed for patient counseling and risk assessment prior to surgery. This study evaluates the utility of mapping by navigated transcranial magnetic stimulation (nTMS) and nTMS-based diffusion tensor imaging fiber tracking (DTI FT) for individual risk evaluation of surgery-related decline of motor or language function in the clinical setting. In total, 250 preoperative nTMS mappings (100 language and 150 motor mappings) derived from 216 patients (mean age: 57.0 ± 15.5 years, 58.8% males; glioma World Health Organization (WHO) grade I & II: 4.2%, glioma WHO grade III & IV: 83.4%, arteriovenous malformations: 1.9%, cavernoma: 2.3%, metastasis: 8.2%) were included. Deterministic tractography based on nTMS motor or language maps as seed regions was performed with 25%, 50%, and 75% of the individual fractional anisotropy threshold (FAT). Lesion-to-tract distances (LTDs) were measured between the tumor mass and the corticospinal tract (CST), arcuate fascicle (AF), or other closest language-related tracts. LTDs were compared between patients and correlated to the functional status (no/transient/permanent surgery-related paresis or aphasia). Significant differences were found between patients with no or transient surgery-related deficits and patients with permanent surgery-related deficits regarding LTDs in relation to the CST (p < 0.0001), AF (p ≤ 0.0491), or other closest language-related tracts (p ≤ 0.0435). The cut-off values for surgery-related paresis or aphasia were ≤ 12 mm (LTD—CST) and ≤ 16 mm (LTD—AF) or ≤25 mm (LTD—other closest language-related tract), respectively. Moreover, there were significant associations between the status of surgery-related deficits and the LTD when considering the CST (range r: −0.3994 to −0.3910, p < 0.0001) or AF (range r: −0.2918 to −0.2592, p = 0.0135 and p = 0.0473 for 25% and 50% FAT). In conclusion, this is the largest study evaluating the application of both preoperative functional mapping and function-based tractography for motor and language function for risk stratification in patients with functionally eloquent tumors. The LTD may qualify as a viable marker that can be seamlessly assessed in the clinical neurooncological setup. Full article
(This article belongs to the Special Issue Brain Tumors)
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12 pages, 2568 KiB  
Article
Hypoxic Roadmap of Glioblastoma—Learning about Directions and Distances in the Brain Tumor Environment
by Agnieszka Bronisz, Elżbieta Salińska, E. Antonio Chiocca and Jakub Godlewski
Cancers 2020, 12(5), 1213; https://doi.org/10.3390/cancers12051213 - 13 May 2020
Cited by 11 | Viewed by 3316
Abstract
Malignant brain tumor—glioblastoma is not only difficult to treat but also hard to study and model. One of the reasons for these is their heterogeneity, i.e., individual tumors consisting of cancer cells that are unlike each other. Such diverse cells can thrive due [...] Read more.
Malignant brain tumor—glioblastoma is not only difficult to treat but also hard to study and model. One of the reasons for these is their heterogeneity, i.e., individual tumors consisting of cancer cells that are unlike each other. Such diverse cells can thrive due to the simultaneous co-evolution of anatomic niches and adaption into zones with distorted homeostasis of oxygen. It dampens cytotoxic and immune therapies as the response depends on the cellular composition and its adaptation to hypoxia. We explored what transcriptome reposition strategies are used by cells in the different areas of the tumor. We created the hypoxic map by differential expression analysis between hypoxic and cellular features using RNA sequencing data cross-referenced with the tumor’s anatomic features (Ivy Glioblastoma Atlas Project). The molecular functions of genes differentially expressed in the hypoxic regions were analyzed by a systematic review of the gene ontology analysis. To put a hypoxic niche signature into a clinical context, we associated the model with patients’ survival datasets (The Cancer Genome Atlas). The most unique class of genes in the hypoxic area of the tumor was associated with the process of autophagy. Both hypoxic and cellular anatomic features were enriched in immune response genes whose, along with autophagy cluster genes, had the power to predict glioblastoma patient survival. Our analysis revealed that transcriptome responsive to hypoxia predicted worse patients’ outcomes by driving tumor cell adaptation to metabolic stress and immune escape. Full article
(This article belongs to the Special Issue Brain Tumors)
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19 pages, 5460 KiB  
Article
Intratumoral Heterogeneity and Longitudinal Changes in Gene Expression Predict Differential Drug Sensitivity in Newly Diagnosed and Recurrent Glioblastoma
by Ella L. Kim, Maxim Sorokin, Sven Rainer Kantelhardt, Darius Kalasauskas, Bettina Sprang, Julian Fauss, Florian Ringel, Andrew Garazha, Eugene Albert, Nurshat Gaifullin, Christian Hartmann, Nicole Naumann, Sven-Ernö Bikar, Alf Giese and Anton Buzdin
Cancers 2020, 12(2), 520; https://doi.org/10.3390/cancers12020520 - 24 Feb 2020
Cited by 37 | Viewed by 5560
Abstract
Background: Inevitable recurrence after radiochemotherapy is the major problem in the treatment of glioblastoma, the most prevalent type of adult brain malignancy. Glioblastomas are notorious for a high degree of intratumor heterogeneity manifest through a diversity of cell types and molecular patterns. The [...] Read more.
Background: Inevitable recurrence after radiochemotherapy is the major problem in the treatment of glioblastoma, the most prevalent type of adult brain malignancy. Glioblastomas are notorious for a high degree of intratumor heterogeneity manifest through a diversity of cell types and molecular patterns. The current paradigm of understanding glioblastoma recurrence is that cytotoxic therapy fails to target effectively glioma stem cells. Recent advances indicate that therapy-driven molecular evolution is a fundamental trait associated with glioblastoma recurrence. There is a growing body of evidence indicating that intratumor heterogeneity, longitudinal changes in molecular biomarkers and specific impacts of glioma stem cells need to be taken into consideration in order to increase the accuracy of molecular diagnostics still relying on readouts obtained from a single tumor specimen. Methods: This study integrates a multisampling strategy, longitudinal approach and complementary transcriptomic investigations in order to identify transcriptomic traits of recurrent glioblastoma in whole-tissue specimens of glioblastoma or glioblastoma stem cells. In this study, 128 tissue samples of 44 tumors including 23 first diagnosed, 19 recurrent and 2 secondary recurrent glioblastomas were analyzed along with 27 primary cultures of glioblastoma stem cells by RNA sequencing. A novel algorithm was used to quantify longitudinal changes in pathway activities and model efficacy of anti-cancer drugs based on gene expression data. Results: Our study reveals that intratumor heterogeneity of gene expression patterns is a fundamental characteristic of not only newly diagnosed but also recurrent glioblastomas. Evidence is provided that glioblastoma stem cells recapitulate intratumor heterogeneity, longitudinal transcriptomic changes and drug sensitivity patterns associated with the state of recurrence. Conclusions: Our results provide a transcriptional rationale for the lack of significant therapeutic benefit from temozolomide in patients with recurrent glioblastoma. Our findings imply that the spectrum of potentially effective drugs is likely to differ between newly diagnosed and recurrent glioblastomas and underscore the merits of glioblastoma stem cells as prognostic models for identifying alternative drugs and predicting drug response in recurrent glioblastoma. With the majority of recurrent glioblastomas being inoperable, glioblastoma stem cell models provide the means of compensating for the limited availability of recurrent glioblastoma specimens. Full article
(This article belongs to the Special Issue Brain Tumors)
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19 pages, 1781 KiB  
Article
Predictors of Postoperative Seizure Outcome in Low Grade Glioma: From Volumetric Analysis to Molecular Stratification
by Tamara Ius, Giada Pauletto, Barbara Tomasino, Marta Maieron, Riccardo Budai, Miriam Isola, Daniela Cesselli, Christian Lettieri and Miran Skrap
Cancers 2020, 12(2), 397; https://doi.org/10.3390/cancers12020397 - 8 Feb 2020
Cited by 28 | Viewed by 2669
Abstract
The importance of the extent of resection (EOR) has been widely demonstrated as the main predictor for survival, nevertheless its effect on tumor related epilepsy is less investigated. A total of 155 patients were enrolled after a first-line surgery for supratentorial Diffuse Low [...] Read more.
The importance of the extent of resection (EOR) has been widely demonstrated as the main predictor for survival, nevertheless its effect on tumor related epilepsy is less investigated. A total of 155 patients were enrolled after a first-line surgery for supratentorial Diffuse Low Grade Gliomas (DLGGs). Postoperative seizure outcome was analyzed stratifying the results by tumor volumetric data and molecular markers according to 2016 WHO classification. Receiver operating characteristic (ROC) curves were computed to asses EOR, residual tumor volume, and ΔT2T1 MRI index (expressing the tumor growing pattern) corresponding to optimal seizure outcome. A total of 70.97% of patients were seizure-free 18 months after surgery. Better seizure outcome was observed in IDH1/2 mutated and 1p/19q codeleted subgroup. At multivariate analysis, age (p = 0.014), EOR (p = 0.030), ΔT2T1 MRI index (p = 0.016) resulted as independent predictors of postoperative seizure control. Optimal parameters to improve postoperative seizure outcome were EOR ≥ 85%, ΔT2T1 MRI index ≤ 18 cm3, residual tumor volume ≤ 15 cm3. This study confirms the role of EOR and tumor growing pattern on postoperative seizure outcome independently from the molecular class. Higher ΔT2T1 MRI index, representing the infiltrative component of the tumor, is associated with worse seizure outcome and strengthens the evidence of common pathogenic mechanisms underlying tumor growth and postoperative seizure outcome. Full article
(This article belongs to the Special Issue Brain Tumors)
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14 pages, 1430 KiB  
Article
Heterogeneous EGFR, CDK4, MDM4, and PDGFRA Gene Expression Profiles in Primary GBM: No Association with Patient Survival
by María González-Tablas, Daniel Arandia, María Jara-Acevedo, Álvaro Otero, Ana-Luisa Vital, Carlos Prieto, Nerea González-Garcia, Ana Belén Nieto-Librero, Herminio Tao, Daniel Pascual, Laura Ruiz, Pablo Sousa, Purificación Galindo-Villardón, Alberto Orfao and María Dolores Tabernero
Cancers 2020, 12(1), 231; https://doi.org/10.3390/cancers12010231 - 17 Jan 2020
Cited by 12 | Viewed by 3760
Abstract
Background: The prognostic impact of the expression profile of genes recurrently amplified in glioblastoma multiforme (GBM) remains controversial. Methods: We investigated the RNA gene expression profile of epidermal growth factor receptor (EGFR), cyclin-dependent kinase 4 (CDK4), murine doble minute [...] Read more.
Background: The prognostic impact of the expression profile of genes recurrently amplified in glioblastoma multiforme (GBM) remains controversial. Methods: We investigated the RNA gene expression profile of epidermal growth factor receptor (EGFR), cyclin-dependent kinase 4 (CDK4), murine doble minute 4 (MDM4), and platelet derived growth factor receptor alpha (PDGFRA) in 83 primary GBM tumors vs. 42 normal brain tissue samples. Interphase FISH (iFISH) analysis for the four genes, together with analysis of intragenic deletions in EGFR and PDGFRA, were evaluated in parallel at the DNA level. As validation cohort, publicly available RNA gene expression data on 293 samples from 10 different GBM patient series were also studied. Results: At the RNA level, CDK4 was the most frequently overexpressed gene (90%) followed by EGFR (58%) and PDGFRA (58%). Chromosome 7 copy number alterations, i.e., trisomy (49%) and polysomy (44%), showed no clear association with EGFR gene expression levels. In turn, intragenic EGFR deletions were found in 39 patients (47%), including EGFRvIII (46%) in association with EGFRvIVa (4%), EGFRvII (2%) or other EGFR deletions (3%) and PDGFRA deletion of exons 8–9 was found in only two tumors (2%). Conclusions: Overall, none of the gene expression profiles and/or intragenic EGFR deletions showed a significant impact on overall survival of GBM supporting the notion that other still unraveled features of the disease might play a more relevant prognostic role in GBM. Full article
(This article belongs to the Special Issue Brain Tumors)
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Review

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17 pages, 1200 KiB  
Review
The Management of Brain Metastases—Systematic Review of Neurosurgical Aspects
by Martin A. Proescholdt, Petra Schödel, Christian Doenitz, Tobias Pukrop, Julius Höhne, Nils Ole Schmidt and Karl-Michael Schebesch
Cancers 2021, 13(7), 1616; https://doi.org/10.3390/cancers13071616 - 31 Mar 2021
Cited by 20 | Viewed by 3052
Abstract
The multidisciplinary management of patients with brain metastases (BM) consists of surgical resection, different radiation treatment modalities, cytotoxic chemotherapy, and targeted molecular treatment. This review presents the current state of neurosurgical technology applied to achieve maximal resection with minimal morbidity as a treatment [...] Read more.
The multidisciplinary management of patients with brain metastases (BM) consists of surgical resection, different radiation treatment modalities, cytotoxic chemotherapy, and targeted molecular treatment. This review presents the current state of neurosurgical technology applied to achieve maximal resection with minimal morbidity as a treatment paradigm in patients with BM. In addition, we discuss the contribution of neurosurgical resection on functional outcome, advanced systemic treatment strategies, and enhanced understanding of the tumor biology. Full article
(This article belongs to the Special Issue Brain Tumors)
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30 pages, 3474 KiB  
Review
Advanced Imaging Techniques for Radiotherapy Planning of Gliomas
by Antonella Castellano, Michele Bailo, Francesco Cicone, Luciano Carideo, Natale Quartuccio, Pietro Mortini, Andrea Falini, Giuseppe Lucio Cascini and Giuseppe Minniti
Cancers 2021, 13(5), 1063; https://doi.org/10.3390/cancers13051063 - 3 Mar 2021
Cited by 32 | Viewed by 5471
Abstract
The accuracy of target delineation in radiation treatment (RT) planning of cerebral gliomas is crucial to achieve high tumor control, while minimizing treatment-related toxicity. Conventional magnetic resonance imaging (MRI), including contrast-enhanced T1-weighted and fluid-attenuated inversion recovery (FLAIR) sequences, represents the current standard imaging [...] Read more.
The accuracy of target delineation in radiation treatment (RT) planning of cerebral gliomas is crucial to achieve high tumor control, while minimizing treatment-related toxicity. Conventional magnetic resonance imaging (MRI), including contrast-enhanced T1-weighted and fluid-attenuated inversion recovery (FLAIR) sequences, represents the current standard imaging modality for target volume delineation of gliomas. However, conventional sequences have limited capability to discriminate treatment-related changes from viable tumors, owing to the low specificity of increased blood-brain barrier permeability and peritumoral edema. Advanced physiology-based MRI techniques, such as MR spectroscopy, diffusion MRI and perfusion MRI, have been developed for the biological characterization of gliomas and may circumvent these limitations, providing additional metabolic, structural, and hemodynamic information for treatment planning and monitoring. Radionuclide imaging techniques, such as positron emission tomography (PET) with amino acid radiopharmaceuticals, are also increasingly used in the workup of primary brain tumors, and their integration in RT planning is being evaluated in specialized centers. This review focuses on the basic principles and clinical results of advanced MRI and PET imaging techniques that have promise as a complement to RT planning of gliomas. Full article
(This article belongs to the Special Issue Brain Tumors)
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25 pages, 6133 KiB  
Review
Advancements in Neuroimaging to Unravel Biological and Molecular Features of Brain Tumors
by Francesco Sanvito, Antonella Castellano and Andrea Falini
Cancers 2021, 13(3), 424; https://doi.org/10.3390/cancers13030424 - 23 Jan 2021
Cited by 21 | Viewed by 4734
Abstract
In recent years, the clinical assessment of primary brain tumors has been increasingly dependent on advanced magnetic resonance imaging (MRI) techniques in order to infer tumor pathophysiological characteristics, such as hemodynamics, metabolism, and microstructure. Quantitative radiomic data extracted from advanced MRI have risen [...] Read more.
In recent years, the clinical assessment of primary brain tumors has been increasingly dependent on advanced magnetic resonance imaging (MRI) techniques in order to infer tumor pathophysiological characteristics, such as hemodynamics, metabolism, and microstructure. Quantitative radiomic data extracted from advanced MRI have risen as potential in vivo noninvasive biomarkers for predicting tumor grades and molecular subtypes, opening the era of “molecular imaging” and radiogenomics. This review presents the most relevant advancements in quantitative neuroimaging of advanced MRI techniques, by means of radiomics analysis, applied to primary brain tumors, including lower-grade glioma and glioblastoma, with a special focus on peculiar oncologic entities of current interest. Novel findings from diffusion MRI (dMRI), perfusion-weighted imaging (PWI), and MR spectroscopy (MRS) are hereby sifted in order to evaluate the role of quantitative imaging in neuro-oncology as a tool for predicting molecular profiles, stratifying prognosis, and characterizing tumor tissue microenvironments. Furthermore, innovative technological approaches are briefly addressed, including artificial intelligence contributions and ultra-high-field imaging new techniques. Lastly, after providing an overview of the advancements, we illustrate current clinical applications and future perspectives. Full article
(This article belongs to the Special Issue Brain Tumors)
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36 pages, 2065 KiB  
Review
Predicting Survival in Glioblastoma Patients Using Diffusion MR Imaging Metrics—A Systematic Review
by Valentina Brancato, Silvia Nuzzo, Liberatore Tramontano, Gerolama Condorelli, Marco Salvatore and Carlo Cavaliere
Cancers 2020, 12(10), 2858; https://doi.org/10.3390/cancers12102858 - 4 Oct 2020
Cited by 17 | Viewed by 2642
Abstract
Despite advances in surgical and medical treatment of glioblastoma (GBM), the medium survival is about 15 months and varies significantly, with occasional longer survivors and individuals whose tumours show a significant response to therapy with respect to others. Diffusion MRI can provide a [...] Read more.
Despite advances in surgical and medical treatment of glioblastoma (GBM), the medium survival is about 15 months and varies significantly, with occasional longer survivors and individuals whose tumours show a significant response to therapy with respect to others. Diffusion MRI can provide a quantitative assessment of the intratumoral heterogeneity of GBM infiltration, which is of clinical significance for targeted surgery and therapy, and aimed at improving GBM patient survival. So, the aim of this systematic review is to assess the role of diffusion MRI metrics in predicting survival of patients with GBM. According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, a systematic literature search was performed to identify original articles since 2010 that evaluated the association of diffusion MRI metrics with overall survival (OS) and progression-free survival (PFS). The quality of the included studies was evaluated using the QUIPS tool. A total of 52 articles were selected. The most examined metrics were associated with the standard Diffusion Weighted Imaging (DWI) (34 studies) and Diffusion Tensor Imaging (DTI) models (17 studies). Our findings showed that quantitative diffusion MRI metrics provide useful information for predicting survival outcomes in GBM patients, mainly in combination with other clinical and multimodality imaging parameters. Full article
(This article belongs to the Special Issue Brain Tumors)
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27 pages, 1353 KiB  
Review
The Emerging Roles of RNA Modifications in Glioblastoma
by Zhen Dong and Hongjuan Cui
Cancers 2020, 12(3), 736; https://doi.org/10.3390/cancers12030736 - 20 Mar 2020
Cited by 86 | Viewed by 8288
Abstract
Glioblastoma (GBM) is a grade IV glioma that is the most malignant brain tumor type. Currently, there are no effective and sufficient therapeutic strategies for its treatment because its pathological mechanism is not fully characterized. With the fast development of the Next Generation [...] Read more.
Glioblastoma (GBM) is a grade IV glioma that is the most malignant brain tumor type. Currently, there are no effective and sufficient therapeutic strategies for its treatment because its pathological mechanism is not fully characterized. With the fast development of the Next Generation Sequencing (NGS) technology, more than 170 kinds of covalent ribonucleic acid (RNA) modifications are found to be extensively present in almost all living organisms and all kinds of RNAs, including ribosomal RNAs (rRNAs), transfer RNAs (tRNAs) and messenger RNAs (mRNAs). RNA modifications are also emerging as important modulators in the regulation of biological processes and pathological progression, and study of the epi-transcriptome has been a new area for researchers to explore their connections with the initiation and progression of cancers. Recently, RNA modifications, especially m6A, and their RNA-modifying proteins (RMPs) such as methyltransferase like 3 (METTL3) and α-ketoglutarate-dependent dioxygenase alkB homolog 5 (ALKBH5), have also emerged as important epigenetic mechanisms for the aggressiveness and malignancy of GBM, especially the pluripotency of glioma stem-like cells (GSCs). Although the current study is just the tip of an iceberg, these new evidences will provide new insights for possible GBM treatments. In this review, we summarize the recent studies about RNA modifications, such as N6-methyladenosine (m6A), N6,2′O-dimethyladenosine (m6Am), 5-methylcytosine (m5C), N1-methyladenosine (m1A), inosine (I) and pseudouridine (ψ) as well as the corresponding RMPs including the writers, erasers and readers that participate in the tumorigenesis and development of GBM, so as to provide some clues for GBM treatment. Full article
(This article belongs to the Special Issue Brain Tumors)
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