Bevacizumab at recurrence in high-grade glioma

Bevacizumab has been introduced in the management of high-grade gliomas after preliminary studies that showed an acceptable safety and a marked increase in clinico-radiological responses in comparison with second-line chemotherapy. The objective is to synthetically review the present use of bevacizumab--alone or in combination--in the context of recurrent high-grade glioma and highlight the future developments. The methodology of this study is to analyse and discuss relevant literature studies using bevacizumab in recurrent high-grade glioma. Bevacizumab may be used as single-agent therapy in recurrent high-grade glioma, with good clinico-radiological responses having little effect on survival. The open questions and developments include new MRI criteria for evaluation of response to anti-angiogenic agents, the identification of putative factors predicting response/failure of bevacizumab and the introduction of bevacizumab in first-line management of high-grade glioma.     

Recurrent high-grade glioma: a diagnostic and therapeutic challenge

The management of recurrent high-grade gliomas with conventional, as well as targeted, therapies is problematic owing to several confounding issues. First, the diagnosis of recurrence using MRI is not straightforward, making the assessment of images in daily routines, as well as in clinical trials, challenging. While chemotherapies with cytotoxic agents have demonstrated initial treatment response, most tumors recur quickly. Second, targeted therapy itself is confounded by the heterogeneous expression of drug targets and nonlinear signaling effects, with functional redundancy and sidestream feedback mechanisms resulting in treatment failure; however, several active agents have been identified, most notably, bevacizumab (an antibody that sequesters VEGF), cilengitide (an inhibitor of integrin αvβ3/5 signaling) and cediranib (an oral tyrosine kinase inhibitor targeting PDGF receptor, c-Kit and all VEGF receptor subtypes). All of these agents have undergone multiple clinical trials and have demonstrated benefits and progression-free survival prolongation in recurrent disease. Given these advances, it is likely that tailored therapies for tumors harboring specific signaling defects will become more efficient and successful in the management of glioblastoma.     

92例高级别胶质瘤患者术后生存分析

目的探讨影响高级别胶质瘤术后生存的因素。方法对2014年1月至2016年8月首诊确定为高级别胶质瘤(WHO III-IV级)的92例患者采用Kaplan-Meier法分析生存率,Log-rank检验进行单因素分析,Cox回归模型进行多因素分析。结果中位生存期为15个月,中位无进展生存期为8个月,肿瘤全切率为72. 83%,1年、2年、3年、4年的生存率分别为56. 5%,35. 9%,30. 4%,25. 4%。Log-rank单因素分析表明高级别胶质瘤预后与年龄、术前生活质量评分、肿瘤大小、数目、是否累及多个皮层脑叶或者运动功能区、切除程度、病理级别、异柠檬酸脱氢酶基因是否突变、O-6-甲基鸟嘌呤DNA甲基转移酶基因启动子是否甲基化、Ki 67指数、术后是否进行放疗和/或化疗以及所进行的放化疗的方式、复发后是否积极治疗相关(P 0. 05)。引入检验水准(α=0. 01),COX多因素分析表明年龄、肿瘤切除程度、术后是否进行放疗和/或化疗是影响高级别胶质瘤预后的独立危险因素(P 0. 01)。结论发病年龄65岁、肿瘤全切除、术后进行同步放化疗和辅助化疗的高级别胶质瘤患者预后较好。     

Hypericin uptake: a prognostic marker for survival in high-grade glioma.

Currently adjuvant chemotherapy for glioblastoma patients can prolong survival time relative to patients who receive only surgery and radiotherapy. Despite these improvements and experimental and clinical efforts the prognosis for glioblastoma patients remains poor. At present, interest is focused on individual prognostic factors influencing patient responses to therapy. Photodynamic therapy may be a promising therapeutic option in the treatment of glioblastoma. In this investigation we examined whether uptake of hypericin (HY), a fluorescent photosensitization agent, by ex vivo glioblastoma cell lines correlates with prognosis of the individual from which the cell lines were derived. Twelve primary human glioma cell cultures were incubated with 20 micromol HY. Fluorescence intensity was measured using fluorescence microscopy. Three patients suffered from an anaplastic astrocytoma, WHO grade III, nine had a glioblastoma, WHO grade IV. In 6/12 patients complete tumour resection was possible. The mean survival time of the six patients in whom complete tumour resection was performed was 26 months, compared with 5 months for those who underwent incomplete resection. Eleven patients received radiation therapy. The five patients who received chemotherapy survived for a mean duration of 26 months, compared with the seven patients who survived for a mean duration of 5 months without chemotherapy. Statistical analysis using a parametric survival model based on the Weibull distribution showed that fluorescence intensity was the variable with the lowest p-value associated with survival (p=0.0225). An increase of 553 arbitrary units of fluorescence intensity is predicted to double survival time. Uptake of HY, a lipophilic molecule, is assumed to be related to low-density lipoprotein (LDL) uptake and metabolism. Cell proliferation is associated with a high turnover of cholesterol and membrane growth, which is related to cholesterol uptake by LDL. In summary, HY uptake by ex vivo glioblastoma cell cultures seems to be positively associated with survival of patients with malignant glioma.     

高级别脑胶质瘤患者术后同步放化疗的临床疗效研究

目的探讨术后不同方案同步放化疗和单纯放疗对高级别脑胶质瘤患者的疗效和安全性的差异。 方法海军总医院放射肿瘤科自2004年6月至2008年6月间采用不同方案治疗经病理证实的高级别脑胶质瘤患者59例,均行三维适形放射治疗(3D-CRT),其中联合替莫唑胺(TMZ)化疗患者21例（A组,Ⅲ级13例,Ⅳ级8例）,联合尼莫司汀(ACNU)加替尼泊苷(VM-26)化疗患者26例（B组,Ⅲ级14例、Ⅳ级12例）,未联合化疗患者12例（C组,Ⅲ级8例,Ⅳ级4例）。分析比较3组患者的疗效、不良反应和生存率。 结果A、B组患者的治疗有效率均高于C组,差异有统计学意义(P＜0.05);B组血液学毒性、消化道副反应的发生率较A组高,差异均有统计学意义(P＜0.05);全组中位疾病无进展生存时间(PFS)为8个月,中位总生存时间(OS)为15个月,Log-rank检验结果显示3组患者疾病无进展生存率、生存率不同,差异有统计学意义（P＜0.05）,A、B组患者的疾病无进展生存率、生存率均高于C组,差异有统计学意义(P＜0.05)。 结论高级别脑胶质瘤患者术后同步放化疗效果显著优于单纯放疗,可提高肿瘤治疗有效率及患者的PFS和OS。化疗方案推荐使用TMZ单药化疗,其与ACNU加VM26联合化疗疗效相当,但毒副反应更低。     

合成MRI在高级别脑胶质瘤术后复发与放射性损伤鉴别中的应用

目的 探讨合成MRI技术鉴别高级别脑胶质瘤（HCG）术后复发与放射性脑损伤的应用价值。方法 收集2018年1月—2022年12月在安阳地区医院和西安医学院第二附属医院就诊的HCG术后放疗后患者41例,所有患者均接受合成MRI扫描和合成MRI对比增强扫描,并经二次手术病理证实或MRI随访确诊。测量病灶实质区、周围水肿区的增强前T1值（T1-pre）、T2值（T2-pre）和增强后T1值（T1+c）,比较复发组和损伤组间各参数的差异。并绘制ROC曲线评价各参数对复发和损伤的鉴别诊断效能。结果 最终纳入37例,其中21例为复发,16例为放射性脑损伤。复发组和脑损伤组实质区与水肿区T1-pre、T2-pre比较,差异均无统计学意义（均P＞0.05）。复发组实质区和水肿区T1+c低于损伤组,增强前后T1差值（ΔT1）、T1值变化百分比高于损伤组,差异均具有统计学意义（P＜0.05）。实质区和水肿区T1+c、ΔT1、T1值变化百分比对鉴别HCG复发和放射性脑损伤的效能均较高,诊断准确率分别为91.8%、94.6%、94.6%、97.2%和97.2%。结论 合成MRI技术在鉴别HCG术后复发和放射性脑损伤方面具有较好的效能,可辅助临床制定后续治疗方案。 [国际神经病学神经外科学杂志, 2023, 50(6): 40-46]     

视交叉胶质瘤的诊断和显微外科治疗

目的探讨视交叉胶质瘤的临床表现、诊断要点、病理及治疗方案。方法回顾性分析13例经手术和病理证实的视交叉胶质瘤。结果本组占同期鞍上胶质瘤的2l％;青少年病人占大多数。视力下降、视野改变为主要症状;MRI可良好显示病灶特点及肿瘤与邻近结构的关系。手术采用一侧冠状切口经额下入路和(或)经纵裂入路,囊内切除肿瘤,充分内减压;术后行常规放射治疗。病理证实视交叉胶质瘤多为毛细胞型星形细胞瘤。结论视交叉胶质瘤具有一定的临床特征,显微手术切除疗效好。     

Review: insights gained from modelling high-grade glioma in the mouse

High-grade gliomas (HGGs) are devastating primary brain tumours with poor outcomes. Advances towards effective treatments require improved understanding of pathogenesis and relevant model systems for preclinical testing. Mouse models for HGG provide physiologically relevant experimental systems for analysis of HGG pathogenesis. There are advantages and disadvantages to the different methodologies used to generate such models, including implantation, genetic engineering or somatic gene transfer approaches. This review highlights how mouse models have provided insights into the contribution of specific mutations to tumour initiation, progression and phenotype, the influence of tumour micro-environment, and the analysis of cell types that can give rise to glioma. HGGs are a heterogeneous group of tumours, and the complexity of diverse mutations within common signalling pathways as well as the developmental and cell-type context of transformation contributes to the overall diversity of glioma phenotype. Enhanced understanding of the mutations and cell types giving rise to HGG, along with the ability to design increasingly complex mouse models that more closely simulate the process of human gliomagenesis will continue to provide improved experimental systems for dissecting mechanisms of disease pathogenesis and for preclinical testing.     

5-aminolevulinic acid and neuronavigation in high-grade glioma surgery: results of a combined approach

In high-grade glioma surgery, several techniques are used to achieve the maximum cytoreductive treatment preserving neurological functions. However, the effectiveness of all the methods used alone is reduced by specific limitations of each. We assessed the reliability of a multimodal strategy based on 5-aminolevulinic acid (5-ALA) and neuronavigation. We prospectively studied 18 patients with suspected, non eloquent-area malignant gliomas amenable for complete resection. Conventional illumination was used until the excision appeared complete. The cavity was then systematically inspected in violet-blue light to identify any residual tumour. Multiple biopsies of both fluorescent and non-fluorescent tissue were performed in all cases. Each specimen was labelled according to the sampling location (inside or outside the boundary set by the neuronavigator). The samples were analysed by a neuropathologist blinded to the intraoperative classification. We reviewed the results of both methods, either singly or in combination. Individual analysis showed higher 5-ALA reliability compared to neuronavigation. However, several false-negative fluorescent specimens were detected. With the combined use of fluorescence and neuroimaging, only 1 sample (negative for both 5-ALA and navigation) was tumoral tissue. In our experience, the combined approach showed the best sensitivity and it is recommended in cases of lesions involving non-eloquent areas.     

A symptomatic large subependymoma with neuroradiological features mimicking a high-grade glioma: A case report

A subependymoma is a benign primary brain tumor classified as a World Health Organization grade I tumor; it is asymptomatic in most cases. We present the case of a 66-year-old Japanese man with a complaint of recurrent vomiting that led to the discovery of a large mass with hemorrhage, peritumoral edema, and a midline shift in the posterior horn of the right lateral ventricle. The patient was pathologically diagnosed with subependymoma after undergoing total tumor resection; a year after the surgery, he was free from tumor recurrence. Although symptomatic subependymomas are rare, they tend to show hemorrhage with peritumoral edema on neuroradiological tests and tend to be confused with high-grade brain tumors. In the present case, we highlight the importance of the appropriate diagnosis for subependymomas showing neuroradiological features that mimic high-grade gliomas. This diagnosis will help in providing suitable treatment for subependymomas.     

Prognosis of pediatric high-grade gliomas with temozolomide treatment: a retrospective, multicenter study

Purpose

We analyzed the usefulness of initial or recurrent treatment of temozolomide (TMZ) in pediatric high-grade gliomas (HGGs).

Methods

Between 2002 and 2010, we performed surgery on 35 patients with 17 glioblastomas, 14 anaplastic astrocytomas, 3 anaplastic oligodendrogliomas, and 1 anaplastic oligoastrocytoma. The male-to-female ratio was 21:14, and the median age was 13?years (range, 3–18?years). The mean follow-up period was 15.9 (±1.8) months. As the TMZ treatment, 22 patients received the initial treatment and 13 patients at recurrence. We analyzed the prognostic significance of TMZ treatment, tumor location, extent of removal, pathology, and recurrence pattern.

Results

The median progression-free survival (PFS) and overall survival (OS) were 9.7 (±1.4) and 17.8 (±2.5) months, respectively. Based on univariate analysis, the median PFS was 9.9 (±1.6) months in the tumors located in the cerebral hemisphere and 5.6 (±1.3) months in the diencephalon (p?=?0.03). Median PFS was 12.5 (±1.7) months in the initial treatment and 6.8 (±0.8) months in the recurrent treatment (p?=?0.03). The median OS was 14.9 (±2.3) months in glioblastomas and 24.4 (±4.1) months in tumors with an anaplastic pathology (p?=?0.01). The median OS was 12.1 (±3.7) months in patients with cerebrospinal fluid (CSF) dissemination and 18.2 (±2.9) months in patients without CSF dissemination (p?=?0.02). Grades 3 and 4 treatment-related toxicity occurred in 7.7–9?% of the patients.

Conclusions

Initial or recurrent TMZ treatment in pediatric HGGs was safe and tolerable. Initial treatment showed improved PFS compared to recurrent treatment, and both showed similar OS.     

基于多灶性胶质母细胞瘤整合基因组分析脑胶质瘤复发相关生物标志物的研究

目的 基于多灶性胶质母细胞瘤（M-GBM）基因组分析脑胶质瘤复发相关生物标志物,为了解潜在的发病机制和制订针对性的治疗策略提供依据。方法 选择中国脑胶质瘤基因组图谱（CGGA）中 1 例胶质母细胞瘤患者的原发性和非同步性肿瘤样本的基因组进行高通量测序,并通过单核苷酸变异（SNV）和基因组重排进行验证。对差异基因进行筛选,并将所测序数据的差异基因纳入 CGGA_325和 CGGA_693 两个数据库中进行 Kaplan-Meier 生存曲线分析。结果 在原发性和非同步性肿瘤中分别检测到 14 322、16 464 个 SNV,其中 4 744 个（33.1%）SNV 是共有的。1 组基因重排存在于原发性和非同步性肿瘤中,3 组基因重排存在于原发性肿瘤中但不存在于非同步性肿瘤中,1 组重排存在于非同步性肿瘤中但不存在于原发性肿瘤中。生存曲线分析结果显示,总生存期和无进展生存期的差异有统计学意义（P＜ 0.01）,低风险组患者的生存优于高风险组。结论 祖先克隆的子代细胞可能较早发生分化,然后平行进化产生M-GBM,尽管在重排全景图上存在总体差异,但两个病变有共同的祖先。一组生物标志物可能与M-GBM 的复发和级别进展相关。临床可根据靶向治疗策略独立分析 M-GBM 患者不同位置的病变,指导精准治疗。     

Contribution of DNA repair mechanisms to determining chemotherapy response in high-grade glioma.

Despite the existence of a well described, succinct pathological grading system for gliomas, tumour behaviour between individual patients varies widely. In addition, predictors of response to treatment in glioblastoma multiforme are lacking. The majority of chemotherapeutic agents currently employed exert their effect on DNA. As our understanding of DNA repair mechanisms improves and predictive markers are elucidated, this may allow treating clinicians to individualise treatment based on molecular markers. This review examines important DNA repair mechanisms and their application to glioblastoma multiforme. By improving understanding of these mechanisms, and particularly the variations that occur between tumours and individuals, it may be possible to adapt treatment to maximise effectiveness and minimise toxicity.     

Risk factors for the occurrence and recurrence of acute cerebellar ataxia: a retrospective observational study

Neurological Sciences - There is little evidence to support a correlation between abdominal surgery and acute cerebellar ataxia (ACA). We reviewed the records of children with ACA treated at our...     

Delayed traumatic CSF-fistulas: a retrospective analysis

Immediate posttraumatic CSF-fistulas are a well known entity after severe head injury. Delayed onset of rhinorrhea is considered to be rare. In the last 5 years 7 patients were treated in our department, who developed rhinorrhea 2-25 years after trauma. All patients went through episodes of meningitis. In 4 cases intermittent rhinorrhea was reported. In all cases a bony defect of the anterior skull base was detected by coronal bone window CT-scan. In three of them an encephalocele was revealed by MR-scanning. Treatment consisted in reconstruction of anterior skull base with a pedicled galeal-pericranial flap via a bifrontal craniotomy and went out without any complications. Delayed rhinorrhea after severe head injury is not a rare curiosity. In cases of bony defects after head injury reconstruction of anterior skull base is recommended to prevent episodes of recurrent meningitis.