Novel Therapeutic and Diagnostic Options in Patients with Diffuse Gliomas

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Clinical Neurology".

Deadline for manuscript submissions: closed (1 April 2021) | Viewed by 19649

Special Issue Editors


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Guest Editor
Department of Clinical Neuroscience at Institute of Neuroscience and Physiology, Göteborg, Sweden
Interests: spinal surgery; brain tumor surgery; registry based research; glioma treatment studies; quality of life research; medical technology including imaging techniques

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Guest Editor
Department of Neurosurgery, Karolinska University Hospital, Stockholm, Sweden
Interests: brain tumor surgery;clinical-and translational brain tumor research

Special Issue Information

Dear Colleagues,

Diffuse gliomas remain a challenge in neuro-oncology. The classification according to WHO 2016 and later consensus statements have embraced integrated diagnosis with the use of molecular markers to supplement histopathology, which has fueled the concept of personalized medicine. Currently, there are no curative treatments despite broad efforts to develop them. In this Special Issue, our goal is to stimulate continued work to improve diagnostic opportunities, care, and ultimately outcomes for patients with diffuse gliomas. There has been ever-evolving improvement in imaging and image analyses, and liquid biopsies have the potential to assist in diagnosis and improve follow-up. In addition, new treatment opportunities have recently emerged in surgery (e.g., LITT), diagnostics (e.g., prognostic or predictive biomarkers and methylation arrays), and oncological treatment (e.g., proton radiotherapy, targeted therapy, tumor treating fields, and immunotherapy), all of which need further evaluation.

The focus of this Special Issue is to highlight advances in the diagnostic, prognostic, and treatment factors in patients with diffuse glioma. 

Assoc. Prof. Dr. Asgeir Store Jakola
Dr. Jiri Bartek
Guest Editors

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Keywords

  • supportive care
  • rehabilitation
  • radiomics
  • immunotherapy
  • proton radiotherapy
  • image-guided surgery
  • minimal invasive surgery
  • brain mapping
  • biomarkers
  • personalized medicine
  • liquid biopsies

Published Papers (8 papers)

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Research

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10 pages, 18451 KiB  
Article
Prediction of Intraoperative Fluorescence of Brain Gliomas: Correlation between Tumor Blood Flow and the Fluorescence
by Artem I. Batalov, Sergey A. Goryaynov, Natalya E. Zakharova, Kristina D. Solozhentseva, Alexandra V. Kosyrkova, Alexander A. Potapov and Igor N. Pronin
J. Clin. Med. 2021, 10(11), 2387; https://doi.org/10.3390/jcm10112387 - 28 May 2021
Cited by 4 | Viewed by 2069
Abstract
Introduction: The prediction of the fluorescent effect of 5-aminolevulinic acid (5-ALA) in patients with diffuse gliomas can improve the selection of patients. The degree of enhancement of gliomas has been reported to predict 5-ALA fluorescence, while, at the same time, rarer cases of [...] Read more.
Introduction: The prediction of the fluorescent effect of 5-aminolevulinic acid (5-ALA) in patients with diffuse gliomas can improve the selection of patients. The degree of enhancement of gliomas has been reported to predict 5-ALA fluorescence, while, at the same time, rarer cases of fluorescence have been described in non-enhancing gliomas. Perfusion studies, in particular arterial spin labeling perfusion, have demonstrated high efficiency in determining the degree of malignancy of brain gliomas and may be better for predicting fluorescence than contrast enhancement. The aim of the study was to investigate the relationship between tumor blood flow, measured by ASL, and intraoperative fluorescent glow of gliomas of different grades. Materials and methods: Tumoral blood flow was assessed in 75 patients by pCASL (pseudo-continuous arterial spin labeling) within 1 week prior to surgery. In all cases of tumor removal, 5-ALA had been administered preoperatively. Maximum values of tumoral blood flow (TBF max) were measured, and normalized tumor blood flow (nTBF) was calculated. Results: A total of 76% of patients had significant contrast enhancement, while 24% were non-enhancing. The histopathology revealed 17 WHO grade II gliomas, 12 WHO grade III gliomas and 46 glioblastomas. Overall, there was a relationship between the degree of intraoperative tumor fluorescence and ASL-TBF (Rs = 0.28, p = 0.02 or the TBF; Rs = 0.34, p = 0.003 for nTBF). Non-enhancing gliomas were fluorescent in 9/18 patients, with nTBF in fluorescent gliomas being 54.58 ± 32.34 mL/100 mg/s and in non-fluorescent gliomas being 52.99 ± 53.61 mL/100 g/s (p > 0.05). Enhancing gliomas were fluorescent in 53/57 patients, with nTBF being 170.17 ± 107.65 mL/100 g/s in fluorescent and 165.52 ± 141.71 in non-fluorescent gliomas (p > 0.05). Conclusion: Tumoral blood flow levels measured by non-contrast ASL perfusion method predict the fluorescence by 5-ALA; however, the additional value beyond contrast enhancement is not clear. ASL is, however, useful in cases with contraindication to contrast. Full article
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25 pages, 4088 KiB  
Article
Role of Preoperative Assessment in Predicting Tumor-Induced Plasticity in Patients with Diffuse Gliomas
by Francesco Latini, Hans Axelson, Markus Fahlström, Malin Jemstedt, Åsa Alberius Munkhammar, Maria Zetterling and Mats Ryttlefors
J. Clin. Med. 2021, 10(5), 1108; https://doi.org/10.3390/jcm10051108 - 07 Mar 2021
Cited by 12 | Viewed by 2360
Abstract
When diffuse gliomas (DG) affect the brain’s potential to reorganize functional networks, patients can exhibit seizures and/or language/cognitive impairment. The tumor–brain interaction and the individual connectomic organization cannot be predicted preoperatively. We aimed to, first, investigate the relationship between preoperative assessment and intraoperative [...] Read more.
When diffuse gliomas (DG) affect the brain’s potential to reorganize functional networks, patients can exhibit seizures and/or language/cognitive impairment. The tumor–brain interaction and the individual connectomic organization cannot be predicted preoperatively. We aimed to, first, investigate the relationship between preoperative assessment and intraoperative findings of eloquent tumors in 36 DG operated with awake surgery. Second, we also studied possible mechanisms of tumor-induced brain reorganization in these patients. FLAIR-MRI sequences were used for tumor volume segmentation and the Brain-Grid system (BG) was used as an overlay for infiltration analysis. Neuropsychological (NPS) and/or language assessments were performed in all patients. The distance between eloquent spots and tumor margins was measured. All variables were used for correlation and logistic regression analyses. Eloquent tumors were detected in 75% of the patients with no single variable able to predict this finding. Impaired NPS functions correlated with invasive tumors, crucial location (A4C2S2/A3C2S2-voxels, left opercular-insular/sub-insular region) and higher risk of eloquent tumors. Epilepsy was correlated with larger tumor volumes and infiltrated A4C2S2/A3C2S2 voxels. Language impairment was correlated with infiltrated A3C2S2 voxel. Peritumoral cortical eloquent spots reflected an early compensative mechanism with age as possible influencing factor. Preoperative NPS impairment is linked with high risk of eloquent tumors. A systematic integration of extensive cognitive assessment and advanced neuroimaging can improve our comprehension of the connectomic brain organization at the individual scale and lead to a better oncological/functional balance. Full article
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13 pages, 3020 KiB  
Article
Preoperative Patient-Reported Outcomes in Suspected Low-Grade Glioma: Markers of Disease Severity and Correlations with Molecular Subtypes
by Dongni Buvarp, Isabelle Rydén, Katharina S. Sunnerhagen, Thomas Olsson Bontell, Tomás Gómez Vecchio, Anja Smits and Asgeir Store Jakola
J. Clin. Med. 2021, 10(4), 645; https://doi.org/10.3390/jcm10040645 - 08 Feb 2021
Cited by 1 | Viewed by 1824
Abstract
This prospective study aims to determine the overall health-related quality of life (HRQoL), functioning, fatigue, and psychological distress preoperatively in patients with suspected diffuse low-grade glioma (dLGG). We were particularly interested if these parameters differed by molecular tumor subtypes: oligodendroglioma, IDHmut astrocytoma [...] Read more.
This prospective study aims to determine the overall health-related quality of life (HRQoL), functioning, fatigue, and psychological distress preoperatively in patients with suspected diffuse low-grade glioma (dLGG). We were particularly interested if these parameters differed by molecular tumor subtypes: oligodendroglioma, IDHmut astrocytoma and IDHwt astrocytoma. Fifty-one patients answered self-assessed questionnaires prior to operation (median age 51 years; range 19–75; 19 females [37%]). Thirty-five (69%) patients had IDH-mutated tumors, of which 17 were 1p/19q codeleted (i.e., oligodendroglioma) and 18 non-1p/19q codeleted (i.e., IDHmut astrocytoma). A lower overall generic HRQoL was associated with a high level of fatigue (rs = −0.49, p < 0.001), visual disorder (rs = −0.5, p < 0.001), motor dysfunction (rs = −0.51, p < 0.001), depression (rs = −0.54, p < 0.001), and reduced functioning. Nearly half of the patients reported high fatigue (23 out of 51 patients) and anxiety (26/51 patients). Patients with IDHwt had worse generic HRQoL, worse functioning, and more severe fatigue, though differences were not statistically significant between the molecular subtypes. In conclusion, fatigue and anxiety are prominent self-assessed symptoms of patients with suspected dLGG in a preoperative setting, but do not seem to be a reliable method to make assumptions of underlying biology or guide treatment decisions. Full article
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13 pages, 3025 KiB  
Article
Neuropsychological Function and Quality of Life after Resection of Suspected Lower-Grade Glioma in the Face Primary Motor Area
by Mattias Stålnacke, Tommy Bergenheim and Rickard L. Sjöberg
J. Clin. Med. 2021, 10(4), 580; https://doi.org/10.3390/jcm10040580 - 04 Feb 2021
Cited by 6 | Viewed by 1732
Abstract
The negative side effects of neurosurgical resection of the lower third of the primary motor cortex (M1) are often described as relatively mild. However, detailed descriptions of how these resections affect neurocognitive function, speech, mental health and quality of life (QoL) are sparse. [...] Read more.
The negative side effects of neurosurgical resection of the lower third of the primary motor cortex (M1) are often described as relatively mild. However, detailed descriptions of how these resections affect neurocognitive function, speech, mental health and quality of life (QoL) are sparse. In the present study, seven patients with suspected lower-grade glioma (WHO II-III) in the inferior M1 were assessed for facial motor function, cognitive function, anxiety and QoL before and after awake surgical resections. The main finding was that after surgery, six of the seven patients experienced a mild facial motor dysfunction, mainly affecting the mouth, tongue and throat. At the group level, we were also able to observe a significant postoperative decline in maximum verbal speed, whereas no negative effects on measures of word production (i.e., verbal fluency) were seen. Self-reported QoL data suggest that some patients experienced increased social isolation postoperatively but do not lend support to the interpretation that this was caused by direct neurological side effects of the surgery. The results appear to support the general notion that awake surgery in the lower M1 can be performed safely and with postoperative deficits that are most often perceived by the patient as tolerable. Full article
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7 pages, 537 KiB  
Communication
Sex Disparities in MGMT Promoter Methylation and Survival in Glioblastoma: Further Evidence from Clinical Cohorts
by Anja Smits, Malgorzata Lysiak, Andreas Magnusson, Johan Rosell, Peter Söderkvist and Annika Malmström
J. Clin. Med. 2021, 10(4), 556; https://doi.org/10.3390/jcm10040556 - 03 Feb 2021
Cited by 10 | Viewed by 1967
Abstract
Introduction: Recent studies suggest an overrepresentation of MGMT promoter methylated tumors in females with IDHwt glioblastoma (GBM) compared to males, with a subsequent better response to alkylating treatment. Methods: To reveal sex-bound associations that may have gone unnoticed in the original analysis, [...] Read more.
Introduction: Recent studies suggest an overrepresentation of MGMT promoter methylated tumors in females with IDHwt glioblastoma (GBM) compared to males, with a subsequent better response to alkylating treatment. Methods: To reveal sex-bound associations that may have gone unnoticed in the original analysis, we re-analyzed two previously published clinical cohorts. One was the multicenter Nordic trial of elderly patients with GBM, randomizing patients into three different treatment arms, including 203 cases with known MGMT promoter methylation status. The other was a population-based study of 179 patients with IDHwt GBM, receiving concomittant radiotherapy and chemotherapy with temozolomide. Cohorts were stratified by sex to test the hypothesis that female sex in combination with MGMT promoter methylation constitutes a subgroup with more favorable outcome. Results: There was a significantly larger proportion of MGMT promoter methylation and better outcome for female patients with MGMT promoter methylated tumors. Results were confirmed in 257 TCGA-derived IDHwt GBM with known sex and MGMT status. Conclusions: These results confirm that patient sex in combination with MGMT promoter methylation is a key determinant in GBM to be considered prior to treatment decisions. Our study also illustrates the need for stratification to identify such sex-bound associations. Full article
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11 pages, 1238 KiB  
Article
Information Recall in Pre-Operative Consultation for Glioma Surgery Using Actual Size Three-Dimensional Models
by Sümeyye Sezer, Vitoria Piai, Roy P.C. Kessels and Mark ter Laan
J. Clin. Med. 2020, 9(11), 3660; https://doi.org/10.3390/jcm9113660 - 13 Nov 2020
Cited by 13 | Viewed by 2065
Abstract
Three-dimensional (3D) technologies are being used for patient education. For glioma, a personalized 3D model can show the patient specific tumor and eloquent areas. We aim to compare the amount of information that is understood and can be recalled after a pre-operative consult [...] Read more.
Three-dimensional (3D) technologies are being used for patient education. For glioma, a personalized 3D model can show the patient specific tumor and eloquent areas. We aim to compare the amount of information that is understood and can be recalled after a pre-operative consult using a 3D model (physically printed or in Augmented Reality (AR)) versus two-dimensional (2D) MR images. In this explorative study, healthy individuals were eligible to participate. Sixty-one participants were enrolled and assigned to either the 2D (MRI/fMRI), 3D (physical 3D model) or AR groups. After undergoing a mock pre-operative consultation for low-grade glioma surgery, participants completed two assessments (one week apart) testing information recall using a standardized questionnaire. The 3D group obtained the highest recall scores on both assessments (Cohen’s d = 1.76 and Cohen’s d = 0.94, respectively, compared to 2D), followed by AR and 2D, respectively. Thus, real-size 3D models appear to improve information recall as compared to MR images in a pre-operative consultation for glioma cases. Future clinical studies should measure the efficacy of using real-size 3D models in actual neurosurgery patients. Full article
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Review

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10 pages, 1143 KiB  
Review
MRI-Based Radiomics and Radiogenomics in the Management of Low-Grade Gliomas: Evaluating the Evidence for a Paradigm Shift
by Ahmed Habib, Nicolina Jovanovich, Meagan Hoppe, Murat Ak, Priyadarshini Mamindla, Rivka R. Colen and Pascal O. Zinn
J. Clin. Med. 2021, 10(7), 1411; https://doi.org/10.3390/jcm10071411 - 01 Apr 2021
Cited by 23 | Viewed by 3703
Abstract
Low-grade gliomas (LGGs) are tumors that affect mostly adults. These neoplasms are comprised mainly of oligodendrogliomas and diffuse astrocytomas. LGGs remain vexing to current management and therapeutic modalities although they exhibit more favorable survival rates compared with high-grade gliomas (HGGs). The specific genetic [...] Read more.
Low-grade gliomas (LGGs) are tumors that affect mostly adults. These neoplasms are comprised mainly of oligodendrogliomas and diffuse astrocytomas. LGGs remain vexing to current management and therapeutic modalities although they exhibit more favorable survival rates compared with high-grade gliomas (HGGs). The specific genetic subtypes that these tumors exhibit result in variable clinical courses and the need to involve multidisciplinary teams of neurologists, epileptologists, neurooncologists and neurosurgeons. Currently, the diagnosis of an LGG pivots mainly around the preliminary radiological findings and the subsequent definitive surgical diagnosis (via surgical sampling). The introduction of radiomics as a high throughput quantitative imaging technique that allows for improved diagnostic, prognostic and predictive indices has created more interest for such techniques in cancer research and especially in neurooncology (MRI-based classification of LGGs, predicting Isocitrate dehydrogenase (IDH) and Telomerase reverse transcriptase (TERT) promoter mutations and predicting LGG associated seizures). Radiogenomics refers to the linkage of imaging findings with the tumor/tissue genomics. Numerous applications of radiomics and radiogenomics have been described in the clinical context and management of LGGs. In this review, we describe the recently published studies discussing the potential application of radiomics and radiogenomics in LGGs. We also highlight the potential pitfalls of the above-mentioned high throughput computerized techniques and, most excitingly, explore the use of machine learning artificial intelligence technologies as standalone and adjunct imaging tools en route to enhance a personalized MRI-based tumor diagnosis and management plan design. Full article
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10 pages, 1938 KiB  
Review
Laser Interstitial Thermal Therapy in Patients with Newly Diagnosed Glioblastoma: A Systematic Review
by Ilaria Viozzi, Alis Guberinic, Christiaan G. Overduin, Maroeska M. Rovers and Mark ter Laan
J. Clin. Med. 2021, 10(2), 355; https://doi.org/10.3390/jcm10020355 - 19 Jan 2021
Cited by 15 | Viewed by 2944
Abstract
Background: Laser interstitial thermal therapy (LITT) is a minimal invasive neurosurgical technique for the treatment of brain tumors. Results of LITT have been reported in a case series of patients with deep seated and/or recurrent glioblastoma or cerebral metastases. With this review we [...] Read more.
Background: Laser interstitial thermal therapy (LITT) is a minimal invasive neurosurgical technique for the treatment of brain tumors. Results of LITT have been reported in a case series of patients with deep seated and/or recurrent glioblastoma or cerebral metastases. With this review we aim to summarize the currently available evidence regarding safety and effectiveness of LITT in patients with newly diagnosed glioblastoma (nGBM). Methods: A literature search was performed using electronic databases (PubMed and Embase). Papers were assessed for the methodological quality using the Risk Of Bias In Non- randomised Studies - of Interventions (ROBINS-I) tool, and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) was used to assess the quality of the evidence. Results: We identified 835 papers of which only 11 articles were eligible for our review. All papers suffered from serious or critical risk of bias, and the quality of evidence was graded as very low according to the GRADE criteria. None of the studies was randomized and reporting of confounders and other parameters was poor. Median overall survival (OS) ranged from 4.1 to 32 months and progression free survival (PFS) from 2 to 31 months. The mean complication rate was 33.7%. No quality of life or cost-effectiveness data were reported. Conclusions: Due to the low quality of the studies, it is not possible to draw firm conclusions regarding the (cost) effectiveness of LITT in patients with newly diagnosed glioblastoma. The low quality of evidence shows the need for a well-designed prospective multicenter randomized controlled trial. Full article
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