High grade gliomas are always the research focus in the field of neurosurgery due to their poor prognosis despite the current standard therapeutic regimen of surgical resection followed by radiation therapy and chemot...High grade gliomas are always the research focus in the field of neurosurgery due to their poor prognosis despite the current standard therapeutic regimen of surgical resection followed by radiation therapy and chemotherapy. Alkylating agent temozolomide has been established as the standard chemotherapy while its resistance inevitable during treatment. This phenomenon seriously influences the prognosis of patients suffering from high grade gliomas. This review aims to elucidate temozolomide chemoresistance mechanisms through three chapters including O^6-methylguanine-DNA methyltransferase(MGMT) methylation, mismatch repair mutation and epigenetic regulation consisting of p21, chromatin and histone, Y-box binding protein-1 and micro RNAs.展开更多
The last fifteen years have seen the application of the cancer stem cell hypothesis to tumors of the central nervous system,in particular to high grade glioma(HGG),the most aggressive and common brain cancer in adults...The last fifteen years have seen the application of the cancer stem cell hypothesis to tumors of the central nervous system,in particular to high grade glioma(HGG),the most aggressive and common brain cancer in adults.Seminal studies have shown that cancer stem cells(alternatively named tumor-initiating cells)are capable of self-renew and multipotency,similar to their normal counterpart.More importantly they give rise to tumors that closely mimic the phenotype and genotype of human HGG.The identification of neurogenic niches in adult rodent and human brain has further reinforced the hypothesis that HGG might derive from the malignant transformation occurring in these areas,especially in the sub-ventricular zone(SVZ),the largest and most well characterised stem cell niche.Following from evidence of animal model studies supporting this hypothesis,recently we investigated the role of the SVZ in neuro-oncogenesis using tissue material derived from HGG patients.We also described response to conventional chemo-therapies of cancer stem cells isolated from the SVZ and the tumor mass(T)of the same patients and reconstructed tumor evolution.In this review,such findings will be discussed in the context of the current literature on the biology of the SVZ in the normal and disease brain.展开更多
The current standards in radiotherapy of high-grade gliomas(HGG) are based on anatomic imaging techniques, usually computed tomography(CT) scanning and magnetic resonance imaging(MRI). The guidelines vary depending on...The current standards in radiotherapy of high-grade gliomas(HGG) are based on anatomic imaging techniques, usually computed tomography(CT) scanning and magnetic resonance imaging(MRI). The guidelines vary depending on whether the HGG is a histological grade 3 anaplastic glioma(AG) or a grade 4 glioblastoma multiforme(GBM). For AG, T2-weighted MRI sequences plus the region of contrast enhancement in T1 are considered for the delineation of the gross tumor volume(GTV), and an isotropic expansion of 15 to 20 mm is recommended for the clinical target volume(CTV). For GBM, the Radiation Therapy Oncology Group favors a two-step technique, with an initial phase(CTV1) including any T2 hyperintensity area(edema) plus a 20 mm margin treated with up to 46 Gy in 23 fractions, followed by a reduction in CTV2 to the contrast enhancement region in T1 with an additional 25 mm margin. The European Organisation of Research and Treatment of Cancer recommends a single-phase technique with a unique GTV, which comprises the T1 contrast enhancement region plus a margin of 20 to 30 mm. A total dose of 60 Gy in 30 fractions is usually delivered for GBM, and a dose of 59.4 Gy in 33 fractions is typically given for AG. As more than 85% of HGGs recur in field, dose-escalation studies have shown that 70 to 75 Gy can be delivered in 6 weeks with relevant toxicities developing in < 10% of the patients. However, the only randomized dose-escalation trial, in which the boost dose was guided by conventional MRI, did not show any survival advantage of this treatment over the reference arm. HGGs are amongst the most infiltrative and heterogeneous tumors, and it was hypothesized that the most highly aggressive areas were missed; thus, better visualization of these high-risk regions for radiation boost could decrease the recurrence rate. Innovations in imaging and linear accelerators(LINAC) could help deliver the right doses of radiation to the right subvolumes according to the dose-painting concept. Advanced imaging techniques provide functional information on cellular density(diffusion MRI), angiogenesis(perfusion MRI), metabolic activity and cellular proliferation [positron emission tomography(PET) and magnetic resonance spectroscopy(MRS)]. All of these non-invasive techniques demonstrated good association between the images and histology, with up to 40% of HGGs functionally presenting a high activity within the non- contrast-enhanced areas in T1. New LINAC technologies, such as intensity-modulated and stereotactic radiotherapy, help to deliver a simultaneous integrated boost(SIB) > 60 Gy. Trials delivering a SIB into a biological GTV showed the feasibility of this treatment, but the final results, in terms of clinical benefits for HGG patients, are still pending. Many issues have been identified: the variety of MRI and PET machines(and amino-acid tracers), the heterogeneity of the protocols used for image acquisition and post-treatment, the geometric distortion and the unreliable algorithms for co-registration of brain anatomy with functional maps, and the semi-quiescent but highly invasive HGG cells. These issues could be solved by the homogenization of the protocols and software applications, the simultaneous acquisition of anatomic and functional images(PET-MRI machines), the combination of complementary imaging tools(perfusion and diffusion MRI), and the concomitant addition of some ad hoc targeted drugs against angiogenesis and invasiveness to chemoradiotherapy. The integration of these hybrid data will construct new synthetic metrics for fully individualized treatments.展开更多
In this issue of the Chinese Journal of Cancer, European experts review current standards, trends, and future prospects in the difficult domain of high-grade glioma. In all fields covered by the different authors, the...In this issue of the Chinese Journal of Cancer, European experts review current standards, trends, and future prospects in the difficult domain of high-grade glioma. In all fields covered by the different authors, the progress has been impressive. For example, discoveries at the molecular level have already impacted imaging, surgery, radiotherapy, and systemic therapies, and they are expected to play an increasing role in the management of these cancers. The European Organization for Research and Treatment of Cancer(EORTC) has pioneered new treatment strategies and contributed to new standards. The articles in this issue will cover basic molecular biological principles applicable today, novel surgical approaches, innovations in radiotherapy planning and delivery, evidence-based standards for radiotherapy alone or combined with chemotherapy, current standards and novel approaches for systemic treatments, and the important but often neglected field of health-related quality of life. Despite the advances described in these articles, the overall prognosis of high-grade glioma, especially glioblastoma, remains poor, and more research is needed to address this problem.展开更多
The current World Health Organization classification system of primary brain tumors is solely based on morphologic criteria. However, there is accumulating evidence that tumors with similar histology have distinct mol...The current World Health Organization classification system of primary brain tumors is solely based on morphologic criteria. However, there is accumulating evidence that tumors with similar histology have distinct molecular signatures that significantly impact treatment response and survival. Recent practice-changing clinical trials have defined a role for routine assessment of O-6-methylguanine-DNA methyltransferase(MGMT) promoter methylation in glioblastoma patients, especially in the elderly, and 1p and 19q codeletions in patients with anaplastic glial tumors. Recently discovered molecular alterations including mutations in IDH-1/2, epidermal growth factor receptor(EGFR), and BRAF also have the potential to become targets for future drug development. This article aims to summarize current knowledge on the molecular biology of high-grade gliomas relevant to daily practice.展开更多
In patients with high grade gliomas (HGGs), progression after treatment can be difficult to diagnose due to treatment-related effects, which overlap in appearance with tumour progression on conventional magnetic reson...In patients with high grade gliomas (HGGs), progression after treatment can be difficult to diagnose due to treatment-related effects, which overlap in appearance with tumour progression on conventional magnetic resonance imaging (MRI) sequences. Specialised imaging methods have been studied for this purpose, though most institutions currently use histopathology or clinicoradiological follow-up for diagnosis. This publication aims to review the evidence for perfusion MRI techniques. The databases of Pubmed, MEDLINE, EMBASE and Scopus were searched using combinations of the subject headings high grade glioma and MRI perfusion. 41 articles fulfilled the inclusion criteria. Dynamic Susceptibility Contrast (DSC) MRI was the most extensively studied, with several studies achieving high sensitivities and specificities. Other techniques exhibiting potential include Dynamic Contrast Enhanced (DCE) MRI, Arterial Spin Labelling (ASL). However, these techniques are not widely used or available for clinical practice. Composite measures combining results from multiple techniques tended to achieve higher accuracies. Some publications compared processing software used or looked at machine learning with relative success. An issue common to the literature is the lack of standardisation in the reference standard and acquisition/processing methods. Furthermore, many had small sample sizes, and further consideration needs to be given with regards to timing of imaging, and treatment regimens received in such studies.展开更多
目的本研究旨在结合传统MRI序列及增强检查,提取多模态高通量影像组学特征并联合语义特征,使用不同的机器学习分类器构建不同的模型并绘制列线图来鉴别高级别胶质瘤(high-grade glioma,HGG)和单发性脑转移瘤(solitary brain metastasis,...目的本研究旨在结合传统MRI序列及增强检查,提取多模态高通量影像组学特征并联合语义特征,使用不同的机器学习分类器构建不同的模型并绘制列线图来鉴别高级别胶质瘤(high-grade glioma,HGG)和单发性脑转移瘤(solitary brain metastasis,SBM)。材料与方法本研究对101名患者的多参数MR图像进行了回顾性分析,由两位资深医师标定肿瘤感兴趣区,然后对每个序列分别提取影像组学特征后进行组合,共提取428组影像组学特征。为消除人为标定差异,进行组内相关系数一致性检验,并运用最大相关最小冗余算法选取最具相关性的特征,然后进一步通过最小绝对收缩和选择算子算法筛除冗余特征。本研究采用支持向量机、逻辑回归、随机森林及K近邻四种算法建立分类模型。结合放射科医生评估的七项语义特征,通过卡方检验和多因素分析去除差异无统计学意义的语义特征。然后结合组学特征建立综合模型并绘制列线图。最终,评价各模型的诊断能力,以确定最优分类器。结果HGG及SBM患者建立的影像组学模型中LR的受试者工作特征曲线下面积(area under the curve,AUC)值最高,训练集与测试集分别为0.90和0.90。语义特征建立的模型中随机森林模型性能最好,训练集和测试集AUC分别为0.82和0.87。语义特征联合影像组学评分后采用逻辑回归建立的模型性能最好,训练集和测试集AUC分别为0.91和0.92。结论本研究使用影像组学机器学习分类器并联合其他图像语义特征绘制列线图对HGG及SBM进行鉴别,这是一种非侵入性方法,具有较好的准确性,为临床决策和实践提供了较大的帮助。展开更多
基金Scientific Research Project of Science and Technology Committee of Shanghai Municipality, 14DZ1930303
文摘High grade gliomas are always the research focus in the field of neurosurgery due to their poor prognosis despite the current standard therapeutic regimen of surgical resection followed by radiation therapy and chemotherapy. Alkylating agent temozolomide has been established as the standard chemotherapy while its resistance inevitable during treatment. This phenomenon seriously influences the prognosis of patients suffering from high grade gliomas. This review aims to elucidate temozolomide chemoresistance mechanisms through three chapters including O^6-methylguanine-DNA methyltransferase(MGMT) methylation, mismatch repair mutation and epigenetic regulation consisting of p21, chromatin and histone, Y-box binding protein-1 and micro RNAs.
文摘The last fifteen years have seen the application of the cancer stem cell hypothesis to tumors of the central nervous system,in particular to high grade glioma(HGG),the most aggressive and common brain cancer in adults.Seminal studies have shown that cancer stem cells(alternatively named tumor-initiating cells)are capable of self-renew and multipotency,similar to their normal counterpart.More importantly they give rise to tumors that closely mimic the phenotype and genotype of human HGG.The identification of neurogenic niches in adult rodent and human brain has further reinforced the hypothesis that HGG might derive from the malignant transformation occurring in these areas,especially in the sub-ventricular zone(SVZ),the largest and most well characterised stem cell niche.Following from evidence of animal model studies supporting this hypothesis,recently we investigated the role of the SVZ in neuro-oncogenesis using tissue material derived from HGG patients.We also described response to conventional chemo-therapies of cancer stem cells isolated from the SVZ and the tumor mass(T)of the same patients and reconstructed tumor evolution.In this review,such findings will be discussed in the context of the current literature on the biology of the SVZ in the normal and disease brain.
文摘The current standards in radiotherapy of high-grade gliomas(HGG) are based on anatomic imaging techniques, usually computed tomography(CT) scanning and magnetic resonance imaging(MRI). The guidelines vary depending on whether the HGG is a histological grade 3 anaplastic glioma(AG) or a grade 4 glioblastoma multiforme(GBM). For AG, T2-weighted MRI sequences plus the region of contrast enhancement in T1 are considered for the delineation of the gross tumor volume(GTV), and an isotropic expansion of 15 to 20 mm is recommended for the clinical target volume(CTV). For GBM, the Radiation Therapy Oncology Group favors a two-step technique, with an initial phase(CTV1) including any T2 hyperintensity area(edema) plus a 20 mm margin treated with up to 46 Gy in 23 fractions, followed by a reduction in CTV2 to the contrast enhancement region in T1 with an additional 25 mm margin. The European Organisation of Research and Treatment of Cancer recommends a single-phase technique with a unique GTV, which comprises the T1 contrast enhancement region plus a margin of 20 to 30 mm. A total dose of 60 Gy in 30 fractions is usually delivered for GBM, and a dose of 59.4 Gy in 33 fractions is typically given for AG. As more than 85% of HGGs recur in field, dose-escalation studies have shown that 70 to 75 Gy can be delivered in 6 weeks with relevant toxicities developing in < 10% of the patients. However, the only randomized dose-escalation trial, in which the boost dose was guided by conventional MRI, did not show any survival advantage of this treatment over the reference arm. HGGs are amongst the most infiltrative and heterogeneous tumors, and it was hypothesized that the most highly aggressive areas were missed; thus, better visualization of these high-risk regions for radiation boost could decrease the recurrence rate. Innovations in imaging and linear accelerators(LINAC) could help deliver the right doses of radiation to the right subvolumes according to the dose-painting concept. Advanced imaging techniques provide functional information on cellular density(diffusion MRI), angiogenesis(perfusion MRI), metabolic activity and cellular proliferation [positron emission tomography(PET) and magnetic resonance spectroscopy(MRS)]. All of these non-invasive techniques demonstrated good association between the images and histology, with up to 40% of HGGs functionally presenting a high activity within the non- contrast-enhanced areas in T1. New LINAC technologies, such as intensity-modulated and stereotactic radiotherapy, help to deliver a simultaneous integrated boost(SIB) > 60 Gy. Trials delivering a SIB into a biological GTV showed the feasibility of this treatment, but the final results, in terms of clinical benefits for HGG patients, are still pending. Many issues have been identified: the variety of MRI and PET machines(and amino-acid tracers), the heterogeneity of the protocols used for image acquisition and post-treatment, the geometric distortion and the unreliable algorithms for co-registration of brain anatomy with functional maps, and the semi-quiescent but highly invasive HGG cells. These issues could be solved by the homogenization of the protocols and software applications, the simultaneous acquisition of anatomic and functional images(PET-MRI machines), the combination of complementary imaging tools(perfusion and diffusion MRI), and the concomitant addition of some ad hoc targeted drugs against angiogenesis and invasiveness to chemoradiotherapy. The integration of these hybrid data will construct new synthetic metrics for fully individualized treatments.
文摘In this issue of the Chinese Journal of Cancer, European experts review current standards, trends, and future prospects in the difficult domain of high-grade glioma. In all fields covered by the different authors, the progress has been impressive. For example, discoveries at the molecular level have already impacted imaging, surgery, radiotherapy, and systemic therapies, and they are expected to play an increasing role in the management of these cancers. The European Organization for Research and Treatment of Cancer(EORTC) has pioneered new treatment strategies and contributed to new standards. The articles in this issue will cover basic molecular biological principles applicable today, novel surgical approaches, innovations in radiotherapy planning and delivery, evidence-based standards for radiotherapy alone or combined with chemotherapy, current standards and novel approaches for systemic treatments, and the important but often neglected field of health-related quality of life. Despite the advances described in these articles, the overall prognosis of high-grade glioma, especially glioblastoma, remains poor, and more research is needed to address this problem.
文摘The current World Health Organization classification system of primary brain tumors is solely based on morphologic criteria. However, there is accumulating evidence that tumors with similar histology have distinct molecular signatures that significantly impact treatment response and survival. Recent practice-changing clinical trials have defined a role for routine assessment of O-6-methylguanine-DNA methyltransferase(MGMT) promoter methylation in glioblastoma patients, especially in the elderly, and 1p and 19q codeletions in patients with anaplastic glial tumors. Recently discovered molecular alterations including mutations in IDH-1/2, epidermal growth factor receptor(EGFR), and BRAF also have the potential to become targets for future drug development. This article aims to summarize current knowledge on the molecular biology of high-grade gliomas relevant to daily practice.
文摘In patients with high grade gliomas (HGGs), progression after treatment can be difficult to diagnose due to treatment-related effects, which overlap in appearance with tumour progression on conventional magnetic resonance imaging (MRI) sequences. Specialised imaging methods have been studied for this purpose, though most institutions currently use histopathology or clinicoradiological follow-up for diagnosis. This publication aims to review the evidence for perfusion MRI techniques. The databases of Pubmed, MEDLINE, EMBASE and Scopus were searched using combinations of the subject headings high grade glioma and MRI perfusion. 41 articles fulfilled the inclusion criteria. Dynamic Susceptibility Contrast (DSC) MRI was the most extensively studied, with several studies achieving high sensitivities and specificities. Other techniques exhibiting potential include Dynamic Contrast Enhanced (DCE) MRI, Arterial Spin Labelling (ASL). However, these techniques are not widely used or available for clinical practice. Composite measures combining results from multiple techniques tended to achieve higher accuracies. Some publications compared processing software used or looked at machine learning with relative success. An issue common to the literature is the lack of standardisation in the reference standard and acquisition/processing methods. Furthermore, many had small sample sizes, and further consideration needs to be given with regards to timing of imaging, and treatment regimens received in such studies.
文摘目的本研究旨在结合传统MRI序列及增强检查,提取多模态高通量影像组学特征并联合语义特征,使用不同的机器学习分类器构建不同的模型并绘制列线图来鉴别高级别胶质瘤(high-grade glioma,HGG)和单发性脑转移瘤(solitary brain metastasis,SBM)。材料与方法本研究对101名患者的多参数MR图像进行了回顾性分析,由两位资深医师标定肿瘤感兴趣区,然后对每个序列分别提取影像组学特征后进行组合,共提取428组影像组学特征。为消除人为标定差异,进行组内相关系数一致性检验,并运用最大相关最小冗余算法选取最具相关性的特征,然后进一步通过最小绝对收缩和选择算子算法筛除冗余特征。本研究采用支持向量机、逻辑回归、随机森林及K近邻四种算法建立分类模型。结合放射科医生评估的七项语义特征,通过卡方检验和多因素分析去除差异无统计学意义的语义特征。然后结合组学特征建立综合模型并绘制列线图。最终,评价各模型的诊断能力,以确定最优分类器。结果HGG及SBM患者建立的影像组学模型中LR的受试者工作特征曲线下面积(area under the curve,AUC)值最高,训练集与测试集分别为0.90和0.90。语义特征建立的模型中随机森林模型性能最好,训练集和测试集AUC分别为0.82和0.87。语义特征联合影像组学评分后采用逻辑回归建立的模型性能最好,训练集和测试集AUC分别为0.91和0.92。结论本研究使用影像组学机器学习分类器并联合其他图像语义特征绘制列线图对HGG及SBM进行鉴别,这是一种非侵入性方法,具有较好的准确性,为临床决策和实践提供了较大的帮助。
