Plasticity of language pathways in patients with low-grade glioma A diffusion tensor imaging study

Knowledge of the plasticity of language pathways neurosurgeons to achieve maximum resection wh n patients with low-grade glioma is important for e preserving neurological function. The current study sought to investigate changes in the ventral language pathways in patients with low-grade glioma located in regions likely to affect the dorsal language pathways. The results revealed no significant difference in fractional anisotropy values in the arcuate fasciculus between groups or between hemispheres. However, fractional anisotropy and lateralization index values in the left inferior longitudinal fasciculus and lateralization index values in the left inferior fronto-occpital fasciculus were higher in patients than in healthy subjects. These results indicate plasticity of language pathways in patients with low-grade glioma. The ventral language pathways may perform more functions in patients than in healthy subjects. As such, it is important to protect the ventral language pathways intraoperatively.

Impacts of Nutlin-3a and exercise on murine double minute 2-enriched glioma treatment

Recent research has demonstrated the impact of physical activity on the prognosis of glioma patients,with evidence suggesting exercise may reduce mortality risks and aid neural regeneration.The role of the small ubiquitin-like modifier(SUMO)protein,especially post-exercise,in cancer progression,is gaining attention,as are the potential anti-cancer effects of SUMOylation.We used machine learning to create the exercise and SUMO-related gene signature(ESLRS).This signature shows how physical activity might help improve the outlook for low-grade glioma and other cancers.We demonstrated the prognostic and immunotherapeutic significance of ESLRS markers,specifically highlighting how murine double minute 2(MDM2),a component of the ESLRS,can be targeted by nutlin-3.This underscores the intricate relationship between natural compounds such as nutlin-3 and immune regulation.Using comprehensive CRISPR screening,we validated the effects of specific ESLRS genes on low-grade glioma progression.We also revealed insights into the effectiveness of Nutlin-3a as a potent MDM2 inhibitor through molecular docking and dynamic simulation.Nutlin-3a inhibited glioma cell proliferation and activated the p53 pathway.Its efficacy decreased with MDM2 overexpression,and this was reversed by Nutlin-3a or exercise.Experiments using a low-grade glioma mouse model highlighted the effect of physical activity on oxidative stress and molecular pathway regulation.Notably,both physical exercise and Nutlin-3a administration improved physical function in mice bearing tumors derived from MDM2-overexpressing cells.These results suggest the potential for Nutlin-3a,an MDM2 inhibitor,with physical exercise as a therapeutic approach for glioma management.Our research also supports the use of natural products for therapy and sheds light on the interaction of exercise,natural products,and immune regulation in cancer treatment.

Adaptability of language-related brain network in a low-grade glioma patient

Because functional magnetic resonance imaging can be used for dynamic observation of functional cortical changes after brain injuries, we followed up functional magnetic resonance imaging manifestations of a language-related brain network in a low-grade glioma patient. Disease progression and therapy during a 3-year period were followed up at different time points： before and after reoperation, after radiation therapy, and 1 year after irradiation. During the whole 3-year follow-up period, the patient exhibited no neurological deficits while functional magnetic resonance imaging revealed different topologies of the language-related brain network. During disease progression and after irradiation, the language-related brain network was extended or completely transferred to the nondominant （right） hemisphere. In addition, after reoperation and 1 year after irradiation, language areas were primarily found in the language dominant （left） hemisphere. Our results suggest a high level of adaptability of the language-related cortical network of the bilateral hemispheres in this low-grade glioma patient.

The surgical treatment of low-grade glioma with secondary epilepsy

Objective To explore the methods of surgical treatment of low-grade glioma with secondary epilepsy. Methods Video-EEG, magnetoencephalography (MEG) were performed to localizate the epileptogenic zone and domain in 13 patients,and stereotactic technology ,ultrasoumd,electrocorticogram (EcoG) were combined

A Phase II Study of Antineoplastons A10 and AS2-1 in Children with Low-Grade Astrocytomas—Final Report (Protocol BT-13)

Nonresectable Low-Grade Astrocytomas (LGA) can compromise function and threaten life. For the majority of patients, the most appropriate strategy is initial chemotherapy followed by Radiation Therapy (RT). Since curative treatment is not available for most of these patients, it is reasonable to conduct clinical studies to evaluate new agents. This Phase II study evaluates efficacy and safety of Antineoplastons A10 and AS2-1 (ANP) in LGA. Sixteen children diagnosed with LGA were treated. They included 12 males and 4 females, ages 1.6 - 17.4 years (median 10.6). Efficacy was evaluated in 16 patients. The majority of patients were previously treated, but 1 patient had stereotactic biopsy only. Out of the remaining 15 patients, 6 patients received chemotherapy, and 7 patients had surgery, and 2 patients received RT and chemotherapy after surgery. The patients received treatment with ANP administered daily every 4 hours (median dose of A10 was 7.71 g/kg/d and AS2-1 was 0.26 g/kg/d) until objective response or stable disease was documented and for 8 months thereafter. The duration of ANP IV ranged from 1.4 to 286 weeks with a median of 83 weeks. A complete response was documented in 25.0%, partial response in 12.5%, and stable disease in 37.5%. Overall survival was 67.7% at 5 years, and 54.2% at 10 and 15 years. Progression-free survival was 48.1%, 34.4% and 34.4% at 5, 10, and 15 years respectively. The treatment was associated with grade 3 or grade 4 Adverse Drug Experiences (ADE) in 6 patients. There were two hypernatremias of grade 4 (12%). Grade 3 ADE included urinary frequency (6%), fatigue (6%) and hypernatremia (6%). There were no chronic toxicities, and there was a high quality of survival. ANP shows efficacy with a very good toxicity profile in this cohort of children with low-grade astrocytoma.

Focus on current and emerging treatment options for glioma:A comprehensive review

This comprehensive review delves into the current updates and challenges associated with the management of low-grade gliomas(LGG),the predominant primary tumors in the central nervous system.With a general incidence rate of 5.81 per 100000,gliomas pose a significant global concern,necessitating advancements in treatment techniques to reduce mortality and morbidity.This review places a particular focus on immunotherapies,discussing promising agents such as Zotiraciclib and Lerapolturev.Zotiraciclib,a CDK9 inhibitor,has demonstrated efficacy in glioblastoma treatment in preclinical and clinical studies,showing its potential as a therapeutic breakthrough.Lerapolturev,a viral immunotherapy,induces inflammation in glioblastoma and displays positive outcomes in both adult and pediatric patients.Exploration of immunotherapy extends to Pembrolizumab,Nivolumab,and Entrectinib,revealing the challenges and variabilities in patient responses.Despite promising preclinical data,the monoclonal antibody Depatuxizumab has proven ineffective in glioblastoma treatment,emphasizing the critical need to understand resistance mechanisms.The review also covers the success of radiation therapy in pediatric LGG,with evolving techniques,such as proton therapy,showing potential improvements in patient quality of life.Surgical treatment is discussed in the context of achieving a balance between preserving the patient’s quality of life and attaining gross total resection,with the extent of surgical resection significantly influencing the survival outcomes.In addition to advancements in cancer vaccine development,this review highlights the evolving landscape of LGG treatment,emphasizing a shift toward personalized and targeted therapies.Ongoing research is essential for refining strategies and enhancing outcomes in the management of LGG.

New biomarker:the gene HLA-DRA associated with low-grade glioma prognosis

Background:Low-grade gliomas(LGG)are WHO grade II tumors presenting as the most common primary malignant brain tumors in adults.Currently,LGG treatment involves either or a combination of surgery,radiation therapy,and chemotherapy.Despite the knowledge of constitutive genetic risk factors contributing to gliomas,the role of single genes as diagnostic and prognostic biomarkers is limited.The aim of the current study is to discover the predictive and prognostic genetic markers for LGG.Methods:Transcriptome data and clinical data were obtained from The Cancer Genome Atlas(TCGA)database.We first performed the tumor microenvironment(TME)survival analysis using the Kaplan-Meier method.An analysis was undertaken to screen for differentially expressed genes.The function of these genes was studied by Gene Ontology(GO)enrichment analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analysis.Following which a protein-protein interaction network(PPI)was constructed and visualized.Univariate and multivariate COX analyses were performed to obtain the probable prognostic genes.The key genes were selected by an intersection of core and prognostic genes.A clinical correlation analysis of single-gene expression was undertaken.GSEA enrichment analysis was performed to identify the function of key genes.Finally,a single gene-related correlation analysis was performed to identify the core immune cells involved in the development of LGG.Results:A total of 529 transcriptome data and 515 clinical samples were obtained from the TCGA.Immune cells and stromal cells were found to be significantly increased in the LGG microenvironment.The top five core genes intersected with the top 38 prognostically relevant genes and two key genes were identified.Our analysis revealed that a high expression of HLA-DRA was associated with a poor prognosis of LGG.Correlation analysis of immune cells showed that HLA-DRA expression level was related to immune infiltration,positively related to macrophage M1 phenotype,and negatively related to activation of NK cells.Conclusions:HLA-DRA may be an independent prognostic indicator and an important biomarker for diagnosing and predicting survival in LGG patients.It may also be associated with the immune infiltration phenotype in LGG.

Risk factors for early progression of diffuse low-grade glioma in adults

Background:To explore the risk factors for early progression of diffuse low-grade glioma in adults.Methods:A retrospective analysis of pathologic and clinical data of patients diagnosed with diffuse low-grade gliomas at Southwest Hospital between January 2010 and December 2014.The progression-free survival(PFS)less than 60 months was classified as the early progress group,and the PFS greater than 60 months was the control group for comparative analysis.Results:A total of 138 patients were included in this study,including 94 cases of astrocytoma and 44 cases of oligodendroglioma.There were 63 cases with 100%resection,56 cases with 90-100%resection degree,and 19 cases with resection degree<90%.The average follow-up time was 60 months,of which 80 patients progressed and 58 patients did not progress.The average progression-free survival was 61 months.The median progression-free survival was 60 months.There were 68 patients with PFS≤60 months and 70 patients with PFS>60 months.The two groups were compared for statistical analysis.In univariate analysis,there were significant differences in tumor subtype(p=0.005),range(p=0.011),volume(p=0.005),location(p=0.000),and extent of resection(p=0.000).Multifactor analysis shows tumor location(HR=4.549,95%CI:1.324-15.634,p=0.016)and tumor subtype(HR=3.347,95%CI=1.373-8.157,p=0.008),and imcomplete resection is factors influencing early progression of low-grade glioma.Conclusions:Low-grade gliomas involving deep location such as basal ganglia,inner capsule,and corpus callosum are more likely to progress early,while incomplete resection is a risk factor in early progression of astrocytoma.

偶发低级别胶质瘤的手术效果及生存预后的影响因素分析

目的探讨偶发低级别胶质瘤的手术效果及生存预后的影响因素。方法回顾性分析2010年1月1日至2017年12月31日手术治疗的75例成人大脑半球偶发低级别胶质瘤的临床资料。结果75例中,出现临床症状之前手术49例(无症状组),出现症状之后手术26例(症状组)。肿瘤全切除59例(78.7%),次全切除13例(17.3%),部分切除3例(4%);术后病理检查结果显示弥漫性星形细胞瘤44例(58.7%),少突胶质细胞瘤31例(41.3%)。症状组术后功能障碍发生率(11.5%,2/26)明显高于无症状组(0%;P<0.05)。59例(无症状组33例,症状组26例)术前接受MRI随访12~60个月,平均(30±10)个月;其中症状组术前随访18~60个月,平均(35±10)个月;无症状组术前随访12~38个月,平均(25±7)个月。59例肿瘤生长速率1~5 mm/年,平均(2.7±0.9)mm/年;无症状组生长速率1~5 mm/年,平均(2.9±0.9)mm/年;症状组生长速率1~4 mm/年,平均(2.5±0.7)mm/年;两组肿瘤生长速率无显著差别(P>0.05)。多因素Cox回归分析显示肿瘤切除程度、病理性质是病人总生存期(OS)、无症状生存期(PFS)及恶性进展期(MPFS)的独立影响因素,生存曲线分析显示肿瘤全切除病人的中位OS、PFS和MPFS均明显优于肿瘤未全切除病人(P<0.05),少突胶质细胞瘤病人的中位OS、PFS、MPFS均显著优于弥漫性星形细胞瘤病人(P<0.05)。结论偶发低级别胶质瘤是一类恶性度较低、呈缓慢进展的疾病。肿瘤全切除有助于改善病人的生存预后,因此,手术时机的抉择应充分考虑利于肿瘤全切除,以延长病人生存期同时兼顾功能保护的目的。

机会发现的低级别胶质瘤

目的机会发现的低级别胶质瘤（LGG）是指患者不具备常见的LGG症状,在并非以发现肿瘤为目的而行的头颅影像学检查中发现的、经病理证实的LGG。本研究通过对解放军总医院近年相关病例的回顾,加深对这种少见LGG的认识和理解。方法回顾分析在2010年2月1日-2012年9月30日收入解放军总医院并初次行颅脑手术的LGG患者,将其中机会发现的LGG定为试验组,其他有LGG明显相关症状的定为对照组。对机会发现的LGG特点进行组间对比研究。结果试验组共入组35例,对照组入组231例。机会发现LGG最常见原因为头痛（40.0%）,其次为健康体检（22.9%）与外伤（20.0%）。相较于对照组,此类LGG特点：试验组女性比例较高（57.1%,P=0.0414）,更好发于额叶（P=0.0130）,对功能区累计较少（P=0.0002）,肿瘤体积小（P=0.0009）,手术全切率更高（82.9%vs 74.8%）,而且不论其手术并发症（11.4%vs 15.8%）还是术后1年生存率（97.1%vs 94.0%）及LGG患者生活质量评分（91.4分vs 84.2分）上都要更好。结论相对于有症状的LGG,机会发现的LGG手术安全性更高,手术疗效与预后更好。

Fractionated resection on low grade gliomas involving Broca＇s area and insights to brain plasticity

Background Resent advances on functional mapping have enabled us to conduct surgery on gliomas within the eloquent area. The objective of the article is to discuss the feasibility of a planned fractionated strategy of resection on low-grade gliomas （LGGs） involving Broca＇s area. We report the first surgical series of planned fractionated resections on LGGs within Broca＇s area, focusing on language functional reshaping. Methods Four patients were treated with fractionated operations for LGGs involving Broca＇s area. All cases underwent conventional magnetic resonance （MR） scanning, language functional MR and diffusion tensor imaging （DTI） before operation. The resections were then performed on patients under awake anesthesia using intraoperative electrical stimulation （IES） for functional mapping. Pre- and post-operative neuro-psychological examinations were evaluated.Results Total resections were achieved in all cases as confirmed by the postoperative control MR. After transient language worsening, all patients recovered to normal 3-6 months later. Language functional MR scannings have shown language functional cortical and subcortical pathway reorganization （in the perilesion or contra-lateral hemisphere） after the operation. All patients returned to a normal socioprofessional life. Conclusions By utilizing the dynamic interaction between brain plasticity and fractionated resections, we can totally remove the tumor involving Broca＇s structure without inducing permanent postoperative deficits and even improve the quality of life.

Concise review of radiosurgery for contemporary management of pilocytic astrocytomas in children and adults

Pilocytic astrocytoma(PA)may be seen in both adults and children as a distinct histologic and biologic subset of low-grade glioma.Surgery is the principal treatment for the management of PAs;however,selected patients may benefit from irradiation particularly in the setting of inoperability,incomplete resection,or recurrent disease.While conventionally fractionated radiation therapy has been traditionally utilized for radiotherapeutic management,stereotactic irradiation strategies have been introduced more recently to improve the toxicity profile of radiation delivery without compromising tumor control.PAs may be suitable for radiosurgical management due to their typical appearance as well circumscribed lesions.Focused and precise targeting of these well-defined lesions under stereotactic immobilization and image guidance may offer great potential for achieving an improved therapeutic ratio by virtue of radiosurgical techniques.Given the high conformality along with steep dose gradients around the target volume allowing for reduced normal tissue exposure,radiosurgery may be considered a viable modality of radiotherapeutic management.Another advantage of radiosurgery may be the completion of therapy in a usually shorter overall treatment time,which may be particularly well suited for children with requirement of anesthesia during irradiation.Several studies have addressed the utility of radiosurgery particularly as an adjuvant or salvage treatment modality for PA.Nevertheless,despite the growing body of evidence supporting the use of radiosurgery,there is need for a high level of evidence to dictate treatment decisions and establish its optimal role in the management of PA.Herein,we provide a concise review of radiosurgery for PA in light of the literature.

Brain Tumor Segmentation in Multimodal MRI Using U-Net Layered Structure

The brain tumour is the mass where some tissues become old or damaged,but they do not die or not leave their space.Mainly brain tumour masses occur due to malignant masses.These tissues must die so that new tissues are allowed to be born and take their place.Tumour segmentation is a complex and time-taking problem due to the tumour’s size,shape,and appearance variation.Manually finding such masses in the brain by analyzing Magnetic Resonance Images(MRI)is a crucial task for experts and radiologists.Radiologists could not work for large volume images simultaneously,and many errors occurred due to overwhelming image analysis.The main objective of this research study is the segmentation of tumors in brain MRI images with the help of digital image processing and deep learning approaches.This research study proposed an automatic model for tumor segmentation in MRI images.The proposed model has a few significant steps,which first apply the pre-processing method for the whole dataset to convert Neuroimaging Informatics Technology Initiative(NIFTI)volumes into the 3D NumPy array.In the second step,the proposed model adopts U-Net deep learning segmentation algorithm with an improved layered structure and sets the updated parameters.In the third step,the proposed model uses state-of-the-art Medical Image Computing and Computer-Assisted Intervention(MICCAI)BRATS 2018 dataset withMRI modalities such as T1,T1Gd,T2,and Fluidattenuated inversion recovery(FLAIR).Tumour types in MRI images are classified according to the tumour masses.Labelling of these masses carried by state-of-the-art approaches such that the first is enhancing tumour(label 4),edema(label 2),necrotic and non-enhancing tumour core(label 1),and the remaining region is label 0 such that edema(whole tumour),necrosis and active.The proposed model is evaluated and gets the Dice Coefficient(DSC)value for High-grade glioma(HGG)volumes for their test set-a,test set-b,and test set-c 0.9795, 0.9855 and 0.9793, respectively. DSC value for the Low-gradeglioma (LGG) volumes for the test set is 0.9950, which shows the proposedmodel has achieved significant results in segmenting the tumour in MRI usingdeep learning approaches. The proposed model is fully automatic that canimplement in clinics where human experts consumemaximumtime to identifythe tumorous region of the brain MRI. The proposed model can help in a wayit can proceed rapidly by treating the tumor segmentation in MRI.

A Phase II Study of Antineoplastons A10 and AS2-1 in Adult Patients with Primary Brain Tumors—Final Report (Protocol BT-09)

Antineoplastons A10 and AS2-1 (ANP) are synthetic derivatives of glutamine, isoglutamine, and phenylacetic acid. In 1993, a phase II clinical trial program began according to protocols based on the initial protocol, BT-06, which was transferred from the National Institutes of Health (NIH). Protocol BT-09 was designed for different types of primary brain tumors in adults that were not curable by standard treatment. The study was designed as a single arm, two-stage, phase II trial of ANP as a monotherapy in a high-risk, poor-prognosis population. The total number of registered subjects was 40. The majority of patients were diagnosed with high-grade tumors (N = 33). In this group, 12 patients carried diagnosis of anaplastic astrocytoma (AA) and 11 patients of glioblastoma. In the group of low-grade tumors (N = 7), there were 6 cases of low-grade glioma, and 1 neurocytoma grade 2. A group of 12 patients did not receive any prior treatment, 12 patients had surgical resection only, 5 patients received radiation therapy (RT) only, and 11 patients received both RT and chemotherapy. The median duration of ANP was 16.6 weeks. The median dosage of A10 was 7.16 g/kg/d and AS2-1 was 0.27 g/kg/d. Responses were accessed by gadolinium-enhanced magnetic resonance imaging (MRI). Objective responses (OR) in all patients were 22.5% and in the AA group were 41.7% of patients. The median progression-free survival (PFS) in the AA group was 5.4 months. The median overall survival (OS) was 12.7 months and OS at 1 and 2 years was 54.5% and 45.5% correspondingly. The treatment was well-tolerated with reversible grade 3 and 4 toxicities in 35% of all patients (N = 40). In conclusion, the study reached efficacy endpoint and ANP was well-tolerated and compared favorably to the current treatment of AA.

High-dose radiation associated with improved survival in IDH-wildtype lowgrade glioma

Background:As molecular advances have deepened the knowledge on low-grade glioma(LGG),we investigated the effect of higher radiation dose on the survival of IDH-wildtype(IDHwt)LGG.Methods:In the current study,52 IDHwt LGG patients who received radiotherapy were enrolled from the Chinese Glioma Genome Atlas dataset.Radiation doses>54 Gy were defined as high-dose,whereas doses≤54 Gy were defined as low-dose.We performed univariate and multivariate survival analyses to examine the prognostic role of high-dose radiotherapy.Results:In total,the radiation dose ranged from 48.6 Gy to 61.2 Gy,with a median of 55.8 Gy,and 31 patients were grouped into high-dose radiation.Univariate survival analysis indicated that high-dose radiotherapy(p=0.015),tumors located in the frontal lobe(p=0.009),and pathology of astrocytoma(p=0.037)were significantly prognostic factors for overall survival.In multivariate survival analysis,high-dose radiotherapy(p=0.028)and tumors located in the frontal lobe(p=0.016)were independently associated with better overall survival.Conclusions:In conclusion,high-dose radiotherapy independently improved the survival of IDHwt LGG.This can guide treatments for glioma with known molecular characteristics.

Gliomatosis cerebri: a monocentric real-life experience

Aim:Gliomatosis cerebri(GC)is defined as a rare pattern of growth of diffuse gliomas involving three or more cerebral lobes.Given its rarity,it is difficult to define prognostic factors and standard of treatment.We retrospectively analyzed patients(PT)with GC from a single institution with the aim of identifying the main prognostic factors and to assess optimal management.Methods:Medical records were reviewed of patients≥18 years with a histological and/or radiological diagnosis of GC(with no contrast enhancement)occurring between 2006 and 2017.Median progression free survival(PFS)and overall survival(OS)were calculated by the Kaplan-Meier method.Results:We analyzed 33 PT,22 males and 11 females;Eastern Cooperative Oncology Group(ECOG)performance status(PS)was 0-1 in 21 of the patients.Twenty-two PT underwent biopsy:16 were astrocytomas and 6 oligodendrogliomas.O6-methylguanin-DNA-methyltransferase(MGMT)was detected in 14 cases,and it was methylated in eight cases.Isocitrate dehydrogenase 1(IDH1)was analyzed in 16 PT,and it had mutated in 10 of them.Nine PT(27%)were treated with radiation therapy(RT)plus concurrent temozolomide(TMZ),22 PT(67%)received TMZ alone,and 2 PT(6%)underwent RT alone.We reported“complete response”in 1 patient(3%),partial response in 9 PT(27%),and stable disease in 15 PT(45%),while 8 PT(25%)had a progressive disease.For all PT,PFS and OS were 19.1 and 30.7 months,respectively.For ECOG PS 0-1 and≥2,PFS was 34.6 months vs.3.4 months(P<0.0001)and OS was 42 months vs.8.9 months(P<0.0001),respectively.Methylated MGMT was associated with longer PFS(41.6 months vs.8.9 months,P=0.05)and OS(52.7 months vs.14.6 months,P=0.009);PFS for IDH1 mutation and IDH wild-type was 52.7 months vs.8.9 months(P=0.006)and OS was 52.7 months vs.41.7 months(P=0.02),respectively.No significant difference was detected as regards treatments.With regard to histological subtype,OS was 42.0 months vs.52.7 months(P=0.8)and PFS was 41.6 months vs.28.6 months(P=0.7)for astrocytoma vs.oligodendroglioma,respectively.PT with treatment response showed a longer OS.PT receiving second-line treatment had a longer OS of 30.7 months vs.6.5 months(P=0.04).Conclusion:ECOG PS,MGMT methylation,and IDH1 mutational status seem to have an important prognostic significance,while the type of treatment does not seem to affect survival.Treatment response could be a surrogate marker for survival.