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14 pages, 1800 KiB

Open AccessArticle

MGMT Promoter Methylation: Prognostication beyond Treatment Response

J. Pers. Med. 2023, 13(6), 999; https://doi.org/10.3390/jpm13060999 - 14 Jun 2023

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MGMT promoter methylation is related to the increased sensitivity of tumour tissue to chemotherapy with temozolomide (TMZ) and thus to improved patient survival. However, it is unclear how the extent of MGMT promoter methylation affects outcomes. In our study, a single-centre retrospective study, [...] Read more.

MGMT promoter methylation is related to the increased sensitivity of tumour tissue to chemotherapy with temozolomide (TMZ) and thus to improved patient survival. However, it is unclear how the extent of MGMT promoter methylation affects outcomes. In our study, a single-centre retrospective study, we explore the impact of MGMT promoter methylation in patients with glioblastoma who were operated upon with 5-ALA. Demographic, clinical and histology data, and survival rates were assessed. A total of 69 patients formed the study group (mean age 53.75 ± 15.51 years old). Positive 5-ALA fluorescence was noted in 79.41%. A higher percentage of MGMT promoter methylation was related to lower preoperative tumour volume (p = 0.003), a lower likelihood of 5-ALA positive fluorescence (p = 0.041) and a larger extent of resection EoR (p = 0.041). A higher MGMT promoter methylation rate was also related to improved progression-free survival (PFS) and overall survival (OS) (p = 0.008 and p = 0.006, respectively), even when adjusted for the extent of resection (p = 0.034 and p = 0.042, respectively). A higher number of adjuvant chemotherapy cycles was also related to longer PFS and OS (p = 0.049 and p = 0.030, respectively). Therefore, this study suggests MGMT promoter methylation should be considered as a continuous variable. It is a prognostic factor that goes beyond sensitivity to chemotherapy treatment, as a higher percentage of methylation is related not only to increased EoR and increased PFS and OS, but also to lower tumour volume at presentation and a lower likelihood of 5-ALA fluorescence intraoperatively. Full article

(This article belongs to the Special Issue Precision Medicine in Neurooncology and Neurosurgery for the 21st Century)

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14 pages, 2485 KiB

Open AccessArticle

Neurosurgical Management of Central Nervous System Lymphoma: Lessons Learnt from a Neuro-Oncology Multidisciplinary Team Approach

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Maria Alexandra Velicu

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J. Pers. Med. 2023, 13(5), 783; https://doi.org/10.3390/jpm13050783 - 30 Apr 2023

Cited by 1 | Viewed by 966

Abstract

Central nervous system lymphoma (CNSL) represents one of the most aggressive forms of extranodal lymphoma. The gold standard for CNSL diagnosis remains the stereotactic biopsy, with a limited role for cytoreductive surgery that has not been supported by historical data. Our study aims [...] Read more.

Central nervous system lymphoma (CNSL) represents one of the most aggressive forms of extranodal lymphoma. The gold standard for CNSL diagnosis remains the stereotactic biopsy, with a limited role for cytoreductive surgery that has not been supported by historical data. Our study aims to provide a comprehensive overview of neurosurgery’s role in the diagnosis of systemic relapsed and primary CNSL, with an emphasis on the impact on management and survival. This is a single center retrospective cohort study with data collected between August 2012 and August 2020, including patients referred with a potential diagnosis of CNSL to the local Neuro-oncology Multidisciplinary Team (MDT). The concordance between the MDT outcome and histopathological confirmation was assessed using diagnostic statistics. A Cox regression is used for overall survival (OS) risk factor analysis, and Kaplan–Meier statistics are performed for three prognostic models. The diagnosis of lymphoma is confirmed in all cases of relapsed CNSL, and in all but two patients who underwent neurosurgery. For the relapsed CNSL group, the highest positive predictive value (PPV) is found for an MDT outcome when lymphoma had been considered as single or topmost probable diagnosis. Neuro-oncology MDT has an important role in establishing the diagnosis in CNSL, not only to plan tissue diagnosis but also to stratify the surgical candidates. The MDT outcome based on history and imaging has good predictive value for cases where lymphoma is considered the most probable diagnosis, with the best prediction for cases of relapsed CNSL, questioning the need for invasive tissue diagnosis in the latter group. Full article

(This article belongs to the Special Issue Precision Medicine in Neurooncology and Neurosurgery for the 21st Century)

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12 pages, 1501 KiB

Open AccessArticle

Tractography-Enhanced Biopsy of Central Core Motor Eloquent Tumours: A Simulation-Based Study

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Harishchandra Lalgudi Srinivasan

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Jose Pedro Lavrador

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Kantharuby Tambirajoo

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J. Pers. Med. 2023, 13(3), 467; https://doi.org/10.3390/jpm13030467 - 03 Mar 2023

Viewed by 751

Abstract

Safe Trajectory planning for navigation guided biopsy (nBx) of motor eloquent tumours (METs) is important to minimise neurological morbidity. Preliminary clinical data suggest that visualisation of the corticospinal tract (CST) and its relation to the tumour may aid in planning a safe trajectory. [...] Read more.

Safe Trajectory planning for navigation guided biopsy (nBx) of motor eloquent tumours (METs) is important to minimise neurological morbidity. Preliminary clinical data suggest that visualisation of the corticospinal tract (CST) and its relation to the tumour may aid in planning a safe trajectory. In this article we assess the impact of tractography in nBx planning in a simulation-based exercise. This single centre cross-sectional study was performed in March 2021 including 10 patients with METs divided into 2 groups: (1) tractography enhanced group (T-nBx; n = 5; CST merged with volumetric MRI); (2) anatomy-based group (A-nBx; n = 5; volumetric MRI only). A biopsy target was chosen on each tumour. Volunteer neurosurgical trainees had to plan a suitable biopsy trajectory on a Stealth S8^® workstation for all patients in a single session. A trajectory safety index (TSI) was devised for each trajectory. Data collection and analysis included a comparison of trajectory planning time, trajectory/lobe changes and TSI. A total of 190 trajectories were analysed based on participation from 19 trainees. Mean trajectory planning time for the entire cohort was 225.1 ± 21.97 s. T-nBx required shorter time for planning (p = 0.01). Mean trajectory changes and lobe changes made per biopsy were 3.28 ± 0.29 and 0.45 ± 0.08, respectively. T-nBx required fewer trajectory/lobe changes (p = 0.01). TSI was better in the presence of tractography than A-nBx (p = 0.04). Neurosurgical experience of trainees had no significant impact on the measured parameters despite adjusted analysis. Irrespective of the level of neurosurgical training, surgical planning of navigation guided biopsy for METs may be achieved in less time with a safer trajectory if tractography imaging is available. Full article

(This article belongs to the Special Issue Precision Medicine in Neurooncology and Neurosurgery for the 21st Century)

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7 pages, 1238 KiB

Open AccessCommunication

Supratotal Resection of Glioblastoma: Better Survival Outcome than Gross Total Resection

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J. Pers. Med. 2023, 13(3), 383; https://doi.org/10.3390/jpm13030383 - 22 Feb 2023

Cited by 2 | Viewed by 1628

Abstract

Objective: Supratotal resection (SupTR) of glioblastoma allows for a superior long-term disease control and increases overall survival. On the other hand, aggressive conventional approaches, including gross total resections (GTR), are limited by the impairment risk of adjacent eloquent areas, which may cause severe [...] Read more.

Objective: Supratotal resection (SupTR) of glioblastoma allows for a superior long-term disease control and increases overall survival. On the other hand, aggressive conventional approaches, including gross total resections (GTR), are limited by the impairment risk of adjacent eloquent areas, which may cause severe postoperative functional morbidity. This study aimed to analyze institutional cases with respect to the potential survival benefits of additional resection, including lobectomy, as a paradigm for SupTR in patients of glioblastoma. Methods: Between 2014 and 2018, 15 patients with glioblastoma underwent SupTR (GTR and additional lobectomy) at the authors’ institution. The postoperative Karnofsky performance score (KPS), progression-free survival (PFS), and overall survival (OS) were analyzed for the patients. Results: Patients with SupTR showed significantly prolonged PFS and OS. The median PFS and OS values for the entire study group were 33.5 months (95% confidence intervals (CI): 18.5–57.3 months) and 49.1 months (95% CI: 24.7–86.6 months), respectively. Multivariate analysis revealed that the O6-DNA-methylguanine methyltransferase (MGMT) promoter methylation status was the only predictor for both superior PFS (p = 0.03, OR 5.7, 95% CI 1.0–49.8) and OS (p = 0.04, OR 6.5, 95% CI 1.1–40.2). There was no significant difference between the pre- and postoperative KPS scores. Conclusions: Our results suggest that SupTR with lobectomy allows for a superior PFS and OS without negatively affecting patient performance. However, due to the small number of patients, further studies that include more patients are needed. Full article

(This article belongs to the Special Issue Precision Medicine in Neurooncology and Neurosurgery for the 21st Century)

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11 pages, 1528 KiB

Open AccessFeature PaperArticle

Presurgical Language Mapping: What Are We Testing?

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Roelien Bastiaanse

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Ann-Katrin Ohlerth

J. Pers. Med. 2023, 13(3), 376; https://doi.org/10.3390/jpm13030376 - 21 Feb 2023

Viewed by 1227

Abstract

Gliomas are brain tumors infiltrating healthy cortical and subcortical areas that may host cognitive functions, such as language. If these areas are damaged during surgery, the patient might develop word retrieval or articulation problems. For this reason, many glioma patients are operated on [...] Read more.

Gliomas are brain tumors infiltrating healthy cortical and subcortical areas that may host cognitive functions, such as language. If these areas are damaged during surgery, the patient might develop word retrieval or articulation problems. For this reason, many glioma patients are operated on awake, while their language functions are tested. For this practice, quite simple tests are used, for example, picture naming. This paper describes the process and timeline of picture naming (noun retrieval) and shows the timeline and localization of the distinguished stages. This is relevant information for presurgical language testing with navigated Magnetic Stimulation (nTMS). This novel technique allows us to identify cortical involved in the language production process and, thus, guides the neurosurgeon in how to approach and remove the tumor. We argue that not only nouns, but also verbs should be tested, since sentences are built around verbs, and sentences are what we use in daily life. This approach’s relevance is illustrated by two case studies of glioma patients. Full article

(This article belongs to the Special Issue Precision Medicine in Neurooncology and Neurosurgery for the 21st Century)

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19 pages, 1609 KiB

Open AccessArticle

A Prospective Study of Longitudinal Risks of Cognitive Deficit for People Undergoing Glioblastoma Surgery Using a Tablet Computer Cognition Testing Battery: Towards Personalized Understanding of Risks to Cognitive Function

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J. Pers. Med. 2023, 13(2), 278; https://doi.org/10.3390/jpm13020278 - 31 Jan 2023

Viewed by 1146

Abstract

Glioblastoma and the surgery to remove it pose high risks to the cognitive function of patients. Little reliable data exist about these risks, especially postoperatively before radiotherapy. We hypothesized that cognitive deficit risks detected before surgery will be exacerbated by surgery in patients [...] Read more.

Glioblastoma and the surgery to remove it pose high risks to the cognitive function of patients. Little reliable data exist about these risks, especially postoperatively before radiotherapy. We hypothesized that cognitive deficit risks detected before surgery will be exacerbated by surgery in patients with glioblastoma undergoing maximal treatment regimens. We used longitudinal electronic cognitive testing perioperatively to perform a prospective, longitudinal, observational study of 49 participants with glioblastoma undergoing surgery. Before surgery (A1), the participant risk of deficit in 5/6 cognitive domains was increased compared to normative data. Of these, the risks to Attention (OR = 31.19), Memory (OR = 97.38), and Perception (OR = 213.75) were markedly increased. These risks significantly increased in the early period after surgery (A2) when patients were discharged home or seen in the clinic to discuss histology results. For participants tested at 4–6 weeks after surgery (A3) before starting radiotherapy, there was evidence of risk reduction towards A1. The observed risks of cognitive deficit were independent of patient-specific, tumour-specific, and surgery-specific co-variates. These results reveal a timeframe of natural recovery in the first 4–6 weeks after surgery based on personalized deficit profiles for each participant. Future research in this period could investigate personalized rehabilitation tools to aid the recovery process found. Full article

(This article belongs to the Special Issue Precision Medicine in Neurooncology and Neurosurgery for the 21st Century)

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13 pages, 3973 KiB

Open AccessArticle

Simultaneous Motor and Visual Intraoperative Neuromonitoring in Asleep Parietal Lobe Surgery: Dual Strip Technique

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J. Pers. Med. 2022, 12(9), 1478; https://doi.org/10.3390/jpm12091478 - 09 Sep 2022

Viewed by 1280

Abstract

Background: The role played by the non-dominant parietal lobe in motor cognition, attention and spatial awareness networks has potentiated the use of awake surgery. When this is not feasible, asleep monitoring and mapping techniques should be used to achieve an onco-functional balance. [...] Read more.

Background: The role played by the non-dominant parietal lobe in motor cognition, attention and spatial awareness networks has potentiated the use of awake surgery. When this is not feasible, asleep monitoring and mapping techniques should be used to achieve an onco-functional balance. Objective: This study aims to assess the feasibility of a dual-strip method to obtain direct cortical stimulation for continuous real-time cortical monitoring and subcortical mapping of motor and visual pathways simultaneously in parietal lobe tumour surgery. Methods: Single-centre prospective study between 19 May–20 November of patients with intrinsic non-dominant parietal-lobe tumours. Two subdural strips were used to simultaneously map and monitor motor and visual pathways. Results: Fifteen patients were included. With regards to motor function, a large proportion of patients had abnormal interhemispheric resting motor threshold ratio (iRMTr) (71.4%), abnormal Cortical Excitability Score (CES) (85.7%), close distance to the corticospinal tract—Lesion-To-Tract Distance (LTD)—4.2 mm, Cavity-To-Tract Distance (CTD)—7 mm and intraoperative subcortical distance—6.4 mm. Concerning visual function, the LTD and CTD for optic radiations (OR) were 0.5 mm and 3.4 mm, respectively; the mean intensity for positive subcortical stimulation of OR was 12 mA ± 2.3 mA and 5/6 patients with deterioration of VEPs > 50% had persistent hemianopia and transgression of ORs. Twelve patients remained stable, one patient had a de-novo transitory hemiparesis, and two showed improvements in motor symptoms. A higher iRMTr for lower limbs was related with a worse motor outcome (p = 0.013) and a longer CTD to OR was directly related with a better visual outcome (p = 0.041). At 2 weeks after hospital discharge, all patients were ambulatory at home, and all proceeded to have oncological treatment. Conclusion: We propose motor and visual function boundaries for asleep surgery of intrinsic non-dominant parietal tumours. Pre-operative abnormal cortical excitability of the motor cortex, deterioration of the VEP recordings and CTD < 2 mm from the OR were related to poorer outcomes. Full article

(This article belongs to the Special Issue Precision Medicine in Neurooncology and Neurosurgery for the 21st Century)

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Review

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14 pages, 8235 KiB

Open AccessFeature PaperReview

Nanoparticle-Based Treatment in Glioblastoma

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Diogo Roque

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Nuno Cruz

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Hugo Alexandre Ferreira

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Catarina Pinto Reis

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Nuno Matela

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Manuel Herculano-Carvalho

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Rita Cascão

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Claudia C. Faria

J. Pers. Med. 2023, 13(9), 1328; https://doi.org/10.3390/jpm13091328 - 29 Aug 2023

Viewed by 903

Abstract

Glioblastoma (GB) is a malignant glioma associated with a mean overall survival of 12 to 18 months, even with optimal treatment, due to its high relapse rate and treatment resistance. The standardized first-line treatment consists of surgery, which allows for diagnosis and cytoreduction, [...] Read more.

Glioblastoma (GB) is a malignant glioma associated with a mean overall survival of 12 to 18 months, even with optimal treatment, due to its high relapse rate and treatment resistance. The standardized first-line treatment consists of surgery, which allows for diagnosis and cytoreduction, followed by stereotactic fractionated radiotherapy and chemotherapy. Treatment failure can result from the poor passage of drugs through the blood–brain barrier (BBB). The development of novel and more effective therapeutic approaches is paramount to increasing the life expectancy of GB patients. Nanoparticle-based treatments include epitopes that are designed to interact with specialized transport systems, ultimately allowing the crossing of the BBB, increasing therapeutic efficacy, and reducing systemic toxicity and drug degradation. Polymeric nanoparticles have shown promising results in terms of precisely directing drugs to the brain with minimal systemic side effects. Various methods of drug delivery that pass through the BBB, such as the stereotactic injection of nanoparticles, are being actively tested in vitro and in vivo in animal models. A significant variety of pre-clinical studies with polymeric nanoparticles for the treatment of GB are being conducted, with only a few nanoparticle-based drug delivery systems to date having entered clinical trials. Pre-clinical studies are key to testing the safety and efficacy of these novel anticancer therapies and will hopefully facilitate the testing of the clinical validity of this promising treatment method. Here we review the recent literature concerning the most frequently reported types of nanoparticles for the treatment of GB. Full article

(This article belongs to the Special Issue Precision Medicine in Neurooncology and Neurosurgery for the 21st Century)

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20 pages, 757 KiB

Open AccessReview

A Personalized Longitudinal Strategy in Low-Grade Glioma Patients: Predicting Oncological and Neural Interindividual Variability and Its Changes over Years to Think One Step Ahead

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Hugues Duffau

J. Pers. Med. 2022, 12(10), 1621; https://doi.org/10.3390/jpm12101621 - 01 Oct 2022

Cited by 1 | Viewed by 1682

Abstract

Diffuse low-grade glioma (LGG) is a rare cerebral cancer, mostly involving young adults with an active life at diagnosis. If left untreated, LGG widely invades the brain and becomes malignant, generating neurological worsening and ultimately death. Early and repeat treatments for this incurable [...] Read more.

Diffuse low-grade glioma (LGG) is a rare cerebral cancer, mostly involving young adults with an active life at diagnosis. If left untreated, LGG widely invades the brain and becomes malignant, generating neurological worsening and ultimately death. Early and repeat treatments for this incurable tumor, including maximal connectome-based surgical resection(s) in awake patients, enable postponement of malignant transformation while preserving quality of life owing to constant neural network reconfiguration. Due to considerable interindividual variability in terms of LGG course and consecutive cerebral reorganization, a multistage longitudinal strategy should be tailored accordingly in each patient. It is crucial to predict how the glioma will progress (changes in growth rate and pattern of migration, genetic mutation, etc.) and how the brain will adapt (changes in patterns of spatiotemporal redistribution, possible functional consequences such as epilepsy or cognitive decline, etc.). The goal is to anticipate therapeutic management, remaining one step ahead in order to select the optimal (re-)treatment(s) (some of them possibly kept in reserve), at the appropriate time(s) in the evolution of this chronic disease, before malignization and clinical worsening. Here, predictive tumoral and non-tumoral factors, and their ever-changing interactions, are reviewed to guide individual decisions in advance based on patient-specific markers, for the treatment of LGG. Full article

(This article belongs to the Special Issue Precision Medicine in Neurooncology and Neurosurgery for the 21st Century)

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