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太赫兹技术在胶质瘤诊疗中的应用: 从组织分级到分子分型

穆宁 杨川艳 马康 全玉莲 王诗 赖颖 李飞 王与烨 陈图南 徐德刚 冯华

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太赫兹技术在胶质瘤诊疗中的应用: 从组织分级到分子分型

穆宁, 杨川艳, 马康, 全玉莲, 王诗, 赖颖, 李飞, 王与烨, 陈图南, 徐德刚, 冯华

Terahertz technology applications in glioma diagnosis: From histological classification to molecular typing

Mu Ning, Yang Chuan-Yan, Ma Kang, Quan Yu-Lian, Wang Shi, Lai Ying, Li Fei, Wang Yu-Ye, Chen Tu-Nan, Xu De-Gang, Feng Hua
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  • 太赫兹波(terahertz, THz)是位于微波和红外之间介观尺度波长的电磁波, 因其低电离性和指纹性的特点, 在生物医学领域有着巨大的应用潜力, 尤其是在肿瘤的术中定位定性诊断方面. 而对于定位定性诊断需求最迫切的肿瘤为胶质瘤, 因其侵袭性和异质性, 切除后极易复发且对临近脑区神经功能有显著影响, 快速确定瘤体边界以及肿瘤病理学特征, 是开展胶质瘤精准诊疗和临床研究的重要前提. 本文总结了胶质瘤诊断的生物物理技术, 梳理了太赫兹波这一新兴技术在胶质瘤诊断方面所取得的研究成果. 进一步, 基于胶质瘤组织病理和分子病理整合诊断研究进展, 提出不同分子分型肿瘤组织在太赫兹波段可能具有不同 “特异性蛋白组成”的太赫兹肿瘤亚型识别机制假说, 结合脑组织生物学特点与体液中胶质瘤标志物检测潜力, 全面设想了未来太赫兹波在胶质瘤临床诊疗中的应用模式和发展前景.
    Terahertz wave is an electromagnetic wave, whose wavelength is located between microwave wavelength and infrared wavelength. Based on low ionization and fingerprint characteristics, it has great potential applications in biomedical field, especially in the intraoperative localization and qualitative diagnosis of tumors. Glioma is the most urgent tumor for positioning qualitative diagnosis. Owing to its invasiveness and heterogeneity, it is easy to relapse after resection and has a significant influence on the nerve function of adjacent brain regions. Therefore, rapid determination of tumor boundary and pathological characteristics is an important prerequisite for accurate diagnosis, treatment and clinical research of glioma. Here, we summarize the biophysical technology of glioma diagnosis, and expound the new technique of terahertz wave and its research results in diagnosis of glioma. Furthermore, based on the research progress of integrated diagnosis of glioma histopathology and molecular pathology, we propose a hypothesis that different molecular subtypes of tumor tissue may have a consistent 'differential terahertz wave protein composition' of terahertz tumor subtype recognition mechanism. Finally, combining the biological characteristics of brain tissue and the potential of glioma marker detection in body fluids, we discuss the clinical application model and prospects of terahertz technologies in glioma detection.
      通信作者: 王与烨, yuyewang@tju.edu.cn ; 陈图南, ctn@tmmu.edu.cn
    • 基金项目: 国家自然科学基金(批准号: 82173388)、国家重点基础研究发展计划(批准号: 2015CB755405)和陆军军医大学人才培养方案(批准号: 2019MPRC021/XZ-2019-505-051)资助的课题.
      Corresponding author: Wang Yu-Ye, yuyewang@tju.edu.cn ; Chen Tu-Nan, ctn@tmmu.edu.cn
    • Funds: Project supported by the National Natural Science Foundation of China (Grant No. 82173388), the National Basic Research Program of China (Grant No. 2015CB755405), and the Talents Training Program of Army Military Medical University, China (Grant No. 2019MPRC021/XZ-2019-505-051).
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  • 图 1  基于“组织病理”和“分子病理”联合诊断标准 (a) 肿瘤细胞形态学特征; (b) 胶质瘤分子分型

    Fig. 1.  Based on a combination of histopathology and molecular pathology: (a) Morphological characteristics of tumor cells; (b) molecular typing of gliomas.

    图 2  胶质瘤诊断方法

    Fig. 2.  Diagnostic methods for glioma.

    图 3  太赫兹光谱检测技术 (a) 透射式太赫兹光谱系统; (b) 反射式太赫兹光谱系统; (c)衰减全反射太赫兹光谱系统

    Fig. 3.  Terahertz spectral detection technology: (a) Transmitted THz spectral system; (b) reflected THz spectral system; (c) attenuated total reflection THz spectral system.

    图 4  近10年太赫兹技术在胶质瘤诊断研究中的发文情况

    Fig. 4.  Publication of THz technology in glioma diagnosis in recent 10 years.

    图 5  THz技术在临床胶质瘤诊断方面的新模式

    Fig. 5.  New models of THz technology in clinical glioma diagnosis.

    表 1  当前胶质瘤临床诊断方法

    Table 1.  Current clinical diagnosis of glioma.

    诊断方式标记物对健康组织损伤局限性应用效果对比检测信息
    影像学
    诊断
    CT18F; 11C; 64Cu微量辐射暴露对软组织的分辨率和敏感性相对较低, 成像参数少适用于术后早期病人的检查及因手术银夹不能行MRI检查者实现定位, 部分定性
    PET-CT碘剂; 钡剂; 金辐射引起微量
    组织损伤
    辐射大、价格昂贵,
    缺乏解剖相关性
    特异性高, 具有较高阳性预测值与准确性, 阴性预测值较CT和MRI低
    SPECT放射药物辐射剂量小,
    价格低廉
    空间分辨率、特异性低可应用于判断胶质瘤恶性程度
    MRI顺磁性或超顺磁性粒子钆无创、需造影剂检查时间长、费用高, 对患者自身因素有限制敏感性高, 具有较高的诊断准确性
    病理学
    诊断
    术中冰冻病理HE试剂有创、局部组织取材局限、容易漏诊,
    图像解释具有主观性
    可用于术中胶质瘤形态观察, 确定手术范围实现定性
    术后免疫组化标记物抗体有创、病灶组织周期长、滞后为后期胶质瘤治疗提供指导建议
    分子生物学技术生物芯片、基因检测和测序依赖检测平台有创、局部病灶组织、血液准入门槛高、滞后性、
    价格昂贵
    提供药物筛查、靶向精准治疗
    其他新型技术拉曼光谱抗干扰强, 结果
    重复性好
    散射效率低, 单次检测面积小介观尺度胶质瘤病灶精准检测及分级识别可同时获取“定位定性”信息
    太赫兹波无创、非电离穿透深度低, 水敏感宏观到介观尺度病灶分布与肿瘤边界, 肿瘤组织与正常组织, 肿瘤分子分型特异性识别
    下载: 导出CSV

    表 2  近10年太赫兹技术在肿瘤诊断中的工作模式

    Table 2.  Patterns of THz technique in tumor diagnosis over the last 10 years.

    年份癌症种类辐射源工作模式参考文献
    2011肝癌(兔)脉冲式反射式光谱成像系统[46]
    2011结肠癌(人)脉冲式反射式成像系统[47]
    2011基底细胞癌(BCC)连续式光纤扫描近场显微镜透射成像系统[61]
    2011乳腺癌脉冲式透射式成像系统[38]
    2011结肠癌脉冲式反射式成像系统[48]
    2011宫颈癌脉冲式反射式成像模式[49]
    2011皮肤癌连续式透射式成像模式[41]
    2011胶质瘤脉冲式反射式成像模式[62]
    2013结肠癌连续式反射式成像模式[63]
    2013肝癌脉冲式光纤扫描近场显微镜透射成像系统[64]
    2013恶性黑色素瘤脉冲式反射式成像模式[65]
    2013乳腺癌连续式反射式成像模式[51]
    2013口腔癌脉冲式反射式成像模式[50]
    2014结肠癌连续式反射式成像模式[66]
    2014皮肤病脉冲式反射式成像模式[52]
    2014皮肤癌脉冲式反射式成像模式[67]
    2014皮肤癌连续式反射式成像模式[68]
    2014胶质瘤脉冲式反射式成像模式[69]
    2014肠癌脉冲式反射式成像模式[70]
    2014胶质瘤脉冲式透射式光谱模式[42]
    2015结肠癌组织脉冲式透射式近场成像模式[71]
    2015结肠癌组织脉冲式透射式光谱模式[39]
    2015胃癌脉冲式透射式光谱模式[72]
    2015乳腺癌脉冲式反射式成像模式[73]
    2015肝癌组织连续式透射式同轴全息成像模式[74]
    2016结肠癌连续式反射式光谱及成像模式[40]
    2015胃癌脉冲式反射式光谱及成像模式[75]
    2016NMSC组织连续式反射式成像模式[76]
    2016胶质瘤脉冲式反射式光谱模式[53]
    2016皮肤癌连续式反射式光谱及成像模式[77]
    2016胶质瘤脉冲式反射式光谱及成像模式[78]
    2016胶质瘤脉冲式反射式成像系统[79]
    2017胃癌脉冲式透射式光谱模式[43]
    2017乳腺癌脉冲式反射式成像模式[80]
    2017乳腺癌脉冲式透射式光谱及反射式成像模式[44]
    2018肝癌脉冲式反射式光谱模式[81]
    2018乳腺癌脉冲式透射式成像模式[82]
    2018乳腺癌连续式反射式成像模式[83]
    2018乳腺癌脉冲式反射式光谱及成像模式[84]
    2019胃癌脉冲式反射式光谱模式[85]
    2019胶质瘤连续式反射式成像模式[58]
    2019乳腺癌脉冲式反射式成像模式[86]
    2019胶质瘤脉冲式反射式光谱及成像模式[87]
    2020乳腺癌脉冲式反射式光谱及成像模式[88]
    2020胶质瘤组织连续式反射成像模式[59]
    2020胶质瘤组织连续式反射式成像模式[89]
    2021皮肤癌脉冲式透射式光谱模式[45]
    2021胶质瘤脉冲式[90]
    2021胶质瘤脉冲式反射式光谱及成像系统[91]
    2021胶质瘤组织连续式反射式光谱及成像系统[60]
    下载: 导出CSV

    表 3  当前基于太赫兹技术研究胶质瘤的结果

    Table 3.  Current results of glioma studies using the terahertz techniques.

    参考文献年份样本类型THz 技术研究特点生物学对照机理解释
    组织[62]2011SD大鼠胶质瘤模型反射式太赫兹脉冲成像系统首次开展THz胶质瘤成像MRI, 可见光水含量
    [69]2014SD大鼠胶质瘤及瘤旁
    (石蜡3 μm)
    反射式太赫兹脉冲成像系统解释THz波生物组织成像机制MRI, HE除水含量外, 细胞密度、髓鞘分布
    [42]2014C57小鼠胶质瘤模型, 大脑组织石蜡1—2.5 mm透射式太赫兹脉冲光谱系统测量了石蜡包埋的脑胶质瘤和正常脑组织的折射率、吸收系数和复介电常数, 分析最佳太赫兹频率脑胶质瘤具有更高的折射率、吸收系数和介电常数
    [78]2016SD大鼠胶质瘤模型(新鲜、石蜡)反射式太赫兹脉冲光谱系统定量解释THz光谱检测胶质瘤可行性HE细胞密度、含水量增加肿瘤折射率
    [76]2016SD大鼠胶质瘤模型(新鲜)反射式太赫兹脉冲光谱成像系统探究利用复折射率值获得太赫兹图像检测脑肿瘤的可能性HE水含量、细胞密度
    [79]2016Balb裸鼠原位异种移植、临床新鲜标本反射式太赫兹脉冲成像系统回答TRI解决临床组织移动性及无标记成像可能性HE, 核磁水、脂质
    [87]2019临床人脑胶质瘤(明胶包埋)反射式太赫兹脉冲光谱成像系统应用于临床分级组织HE水、细胞密度、血肿成分
    [58]2019C57胶质瘤组织反射连续波太赫兹成像系统反射连续波太赫兹成像系统应用与胶质瘤成像可能性MRI, HE血管、坏死碎片、水肿、细胞密度
    [59]2020大鼠/小鼠胶质瘤组织衰减全反射连续波太赫兹成像系统提高成像有效面积HE水、细胞密度、血管密度
    [89]2020大鼠胶质瘤反射连续波太赫兹成像系统提高分辨率HE水、细胞密度、血管密度
    [91]2021SD大鼠胶质瘤模型(新鲜)反射式太赫兹脉冲光谱系统胶质瘤异质性HE微血管生成、组织异质性
    [60]2021SD小鼠胶质瘤组织反射式连续性太赫兹光谱成像系统提高分辨率及扫描面积HE、MRI细胞、血管密度、组织坏死
    [90]2021临床胶质瘤样品(明胶包埋)脉冲太赫兹光谱系统验证介电常数的物理模型可靠性
    细胞系[98]2021胶质瘤细胞系透射式太赫兹脉冲光谱系统首次提出THz检测不同分子分型细胞形态、大小、分子分型
    [97]2019神经胶质细胞和胶质瘤细胞衰减全反射太赫兹脉冲式光谱系统从细胞系角度解释THz可区分肿瘤组织形态、含水量
    分子
    标记物
    [99]2019GABA/COC 1:15—1:18透射式太赫兹脉冲光谱系统率先推进了太赫兹神经递质检测
    [101]2016A-GLU/b-Glu太赫兹时域光谱系统区分不同构型谷氨酸
    [37]20162-HG及其异构体太赫兹时域光谱系统区分不同构型代谢物碳链质子转移
    [102]2021EGFR抗体结合太赫兹时域光谱系统提升EGFR检测灵敏性
    下载: 导出CSV
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  • 收稿日期:  2021-12-29
  • 修回日期:  2022-01-26
  • 上网日期:  2022-08-16
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