【~（18）F】-FDG-PET/CT可对骨髓、肝脏、小肠的放射后损伤进行快速分层诊断并评估预后
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摘要
研究背景和目的
机体遭受不同程度的电离辐射(医源性及意外性辐射接触及核事故)后,各组织器官均会出现不同程度的损伤,其损伤程度主要取决于照射剂量及组织脏器对电离辐射的敏感性。不同的组织器官对辐射的敏感性并不相同,其辐射敏感性主要取决于细胞周期的长短及分化速度。因此,作为具有快速分化及复制特性的造血系统,对电脑辐射高度敏感。此外,既往研究表明小肠对辐射同样具有高度敏感性,而肝脏则被认为其对辐射具有一定耐受性,是一种具有中度辐射敏感性的脏器。虽然目前牙釉质的电子自旋谐振分析及热释发光剂量计评估技术可在辐射后任何时候段对电离辐射的剂量进行评估,但这种单纯的辐射剂量评估并不等于机体各组织脏器的实际受照剂量,亦不是以反应机体在受照后的功能变化并指导临床诊断、制定治疗方案及评估预后。根据美国国家战略储备委员会辐射工作组于2004年颁布的指南：快速、灵敏、精确的对各组织脏器实际受照剂量、机体损伤程度、后续损伤效应进行评估对于患者的预后、治疗方案的选择至关重要。
日前临床上针对于受照剂量常规方法主要有1)症状观察、2)外周血淋巴细胞动力学变化、：3)染色体核型评分。然而,这些方法在诊断时间、实用性及特异性方面均存有不足。1)症状观察往往缺乏特异性,约有50—80%的患者在受照后悔出现腹痛、恶心呕吐等症状,然而这些症状主要与受照部位相关,且易受其他因素的干扰,与受照剂量往往缺乏直接联系；2)外周血淋巴细胞动力学需持续检测至少7天以上,且诊断剂量范围为2-8Gy；3)染色体核型评分至少需要孵育72小时,且易受人为因素干扰及诊断剂量范围相对较小(2-4Gy)；4)上述三种方法均不能用以反映患者的健康状况及判定脏器受照后的功能变化。
18-氟代葡萄糖正电子发射断层扫描术/计算机层析X射线摄影法([18F]-FDG-PHT/CT)是一种先进的分子成像诊断技术,其在临床肿瘤诊断、疗效检测方而的应用已得到广泛的公认。此外,越来越多的研究表明其可用于其他非肿瘤性疾病。然而,关于[18F]-FDG-PET/CT在急性辐射损伤中的应用报道较少。既往研究表明18-氟代葡萄糖([18F]-FDG)的摄取具有组织特异性。此外,其摄取主要与下列三个因素相关：①局部细胞密度；②表达于细胞膜表面的糖转运分子活性；③周围组织的代谢活性。理论上,机体遭受不同程度的电离辐射后,上述指标均会发生不同程度的改变,且这种改变必将导致[18F]FDG的摄取发生变化。但电离辐射诱导的这种[18F]-fdg摄取的变化是否具有规性?是否可用于快速诊断受照剂量并反映机体受损程度?
有鉴于此,本研究以西藏小型猪为模型,通过予小型猪2、5、8、11、14Gy的单剂量全身照射(TBI)以诱导不同程度的全身多系统-器官性急性辐射损伤并在放射后72小时内对其进行多指标观察用以探讨：①[18f]-fdg-pet/ct示踪剂18氟代葡萄糖([18F]-FUG)在骨髓、肝脏、小肠中的标准摄取值(SUV)的变化规律；②[18F]-FDG是否可反映上述脏器的损伤程度及脏器功能。通过上述研究,可有助于进一步了解18-氟代葡萄糖正电子发射断层扫描术/计算机层析X射线摄影法在急性辐射损伤中的诊断价值并为其未来的临床应用提供实验依据。
方法
18-氟代葡萄糖正电子发射断层扫描术/计算机层析X射线摄影法在全身照射诱导的急性造血系统损伤中的诊断价值
选用未去势雄性西藏小型猪为动物模型(n=18),辐射组用直线加速器分别予2、5、8、11、14Gy单次剂量照射(n=3/组),剂量率均统一为255cGy/min。对照组未予照射。分别于照射后6、24、72小时予西藏小型猪[18F]-FDG-PHT/CT扫描并分别在相同时段于小型猪右髂后上嵴进行骨髓活检并抽吸骨髓2ml用以骨髓组织病理学检查及骨髓有核细胞计数。数据经统计学处理后用以分析[18F]-FDG SUV值及其与骨髓活检、骨髓有核细胞计数、照射剂量的相关性。
18-氟代葡萄糖正电子发射断层扫描术/计算机层析x射线摄影法在全身照射诱导的急性肝损伤中的诊断价值
选用未去势雄性西藏小型猪为动物模型(n=48),辐射组用直线加速器分别予2、5、8、11、14Gy单次剂量照射(n=9/组),剂量率均统一为255cGy/mino对照组未予照射(n=3)。分别于照射后6、24、72小时予西藏小型猪[18F]-FDG-PET/CT扫描并通过耳静脉收集静脉血用以酶学及肝脏功能各项指标检测。分别在相同时段处死小型猪并取肝脏组织用于病理学检查。
18-氟代葡萄糖正电子发射断层扫描术/计算机层析x射线摄影法在全身照射诱导的急性小肠损伤中的诊断价值
选用未去势雄性西藏小型猪为动物模型(n=48),辐射组用直线加速器分别予2、5、8、11、14Gy单次剂量照射(n=9/组),剂量率均统一为255cGy/min。对照组未予照射(n=3)。分别于照射后6、24、72小时予西藏小型猪[18F]-FDG-PET/CT扫描。分别于相同时段处死小型猪并取小肠组织用于病理学检查。
结果
18-氟代葡萄糖正电子发射断层扫描术／计算机层析x射线摄影法在全身照射诱导的急性造血系统损伤中的诊断价值
2.1.1骨髓[18F]-FDG摄取在不同辐射剂量及不同时间点的变化
辐射剂量因素及时间因素对骨髓[18F]-FDG摄取的影响具有显著性。时间主效应、剂量主效应及两者的交互效应P值均小于0.05。通过固定时间因素并分析骨髓FDG摄取在各辐射剂量组间的变化可知：①辐射后6小时,2、5、8、11Gy组的骨髓[18F]-FDG摄取与对照组相比无显著统计学差异,仅在14Gy组时,骨髓[18F]-FDG摄取值较对照组有所增加；②辐射后24小时,[18F]-FDG摄取在2、5、8、组时均较对照组显著升高,11、14Gy时骨髓[18F]-FDG摄取较对照组显著降低,且骨髓[18F]-FDG摄取在2-11Gy剂量范围内随辐射剂量的增加而降低；③辐射后72小时的[18F]-FDG摄取变化趋势与24小时相同,但变化幅度小于辐射后24小时。当固定剂量因素单独分析骨髓[18r]-FDG摄取在辐射后6、24、72小时的变化时可知：①辐射剂量为2、5、8Gy时,骨髓[18F]-FDG摄取在辐射后24及72小时均高于辐射后6小时。其变化趋势为辐射后24小时[18F]-FDG摄取>72小时>6小时。辐射剂量为11、14Gy时,[18F]-FDG摄取随观察时间的延长而进行性降低。
2.1.2骨髓活检结果
2Gy组辐射后6小时镜下可见血窦和小血管扩张及充血,造血细胞核固缩及坏死的核碎片；2Gy组辐射后24小时镜下可见核碎片几乎被清除；2Gy组辐射后72小时除了能轻易辨认非造血细胞外未见到造血细胞的再生。5-8Gy组上述变化较2Gy组显著加重,且呈剂量依赖效应。11Gv-14Gv造血细胞几乎消失怡尽,非造血细胞也显著减少,血窦结构几乎完全崩解。通过对骨髓增生程度评估可知：1)辐射后6小时,2、5Gy组小型猪骨髓增生程度为增生正常；8、11、14Gy组小型猪骨髓增生程度为增生减低。辐射后24小时,2Gy组小型猪骨髓增生程度为增生正常；5、8Gy组小型猪骨髓增生程度为增生减低；11、14Gy组小型猪骨髓增生程度为增生极度减低。辐射后72小时,2、5Gy组小型猪骨髓增生程度为增生减低；8、11、14Gy组小型猪骨髓增生程度为增生极度减低。总体而言,西藏小型猪骨髓增生程度在接受不同剂量的X线全身照射后,呈辐射剂量-时间依赖性降低。
2.1.3骨髓有核细胞计数在不同辐射剂量及不同时间点的变化
辐射剂量因素及时间因素对骨髓有核细胞计数的影响具有显著性。时间主效应、剂量主效应及两者的交互效应P值均小于0.05。通过固定时间因素并分析骨髓有核细胞计数在辐射后6、24、72小时时间点各辐射剂量组间的变化可知：①辐射后6小时,2、5Gy组的骨髓有核细胞计数与对照组无统计学差异,8、11、14Gy组的骨髓有核细胞计数较对照组显著降低,但11、14Gy组骨髓有核细胞无统计学差异；②辐射后24小时,2Gy组骨髓有核细胞计数与对照组相比无统计学差异；5、8、11、14Gy组骨髓有核细胞计数显著低于对照组,但8、11、14Gy组骨髓有核细胞记数无统计学差异：③辐射后72小时,2、5、8、11、14Gv组骨髓有核细胞记数均显著低于对照组,且骨髓有核细胞计数在28Gy组剂量范围内随辐射剂量的增加而降低,8、11、14Gy组骨髓有核细胞记数无统计学差异。当固定剂量因素单独分析骨髓FDG摄取在辅射后6、24、72小时的变化时可知：所有辐射组骨髓有核细胞计数均随观察时间的延长而降低。18-氟代葡萄糖正电子发射断层扫描术/计算机层析X射线摄影法在全身照射诱导的急性肝损伤中的诊断价值
2.2.1肝[18F]-FDG摄取在不同辐射剂量及不同时间点的变化
辐射剂量因素及时间因素对肝[8F]-FDG摄取的影响具有显著性。时间主效应、剂量主效应及两者的交互效应P值均小于0.05。通过固定时间因素并分析肝[[8F]-FDG摄取在辐射后6、24、72小时时间点各辐射剂量组间的变化可知：①辐射后6小时,2、5、8、11Gy组肝[18F]-FDG摄取较对照组升高,14Gy组肝[18F]-FDG摄取与对照组相比无统计学差异;②辐射后24小时,所有辐射组肝[18F]-FDG摄取均较对照组显著升高,[18F]-FDG摄取在2-5Gy范围内随辐射剂量增加而增加,在8-14Gy范围内[18F]-FDG摄取则随辐射剂量的增加而降低；③辐射后72小时[18F]-FDG摄取变化趋势与辐射后24小时相似,但变化幅度小于辐射后24小时。当固定剂量因素单独分析肝[18F]-FDG摄取在辐射后6、24、72小时的变化时可知：不同辐射剂量下,各时间点的肝(?)18F]-FDG摄取变化无显著规律性。
2.2.2肝脏病理结果
病理结果表明2、5Gy组镜下肝脏肝小叶结构尚完整,可见沿肝中央静脉周围肝窦扩张充血,肝细胞核固缩、细胞肿胀、嗜酸小体形成。8、11、14Gy组镜下可见显著的肝细胞凋亡、肝索结构破坏、肝窦及肝内血管扩张、充血.、局部或散在出血及多小叶同时受累。病理类型分析及HAI积分表明肝脏病理损伤随时间的延长及辐射剂量的增加而加重。
2.2.3肝细胞及双核细胞计数结果
辐射剂量因素及时间因素对肝细胞、双核肝细胞计数的影响具有显著性。时间主效应、剂量主效应及两者的交互效应P值均小于0.05。通过固定时间因素并分析肝细胞记数在各辐射剂量组间的变化可知：①辐射后6小时,2Gy组肝细胞计数与对照组相比无统计学差异,5、8、11、14Gy组肝细胞计数低于对照组,但8、11、14Gy组肝细胞计数无统计学差异；②辐射后24小时,2Gy组肝细胞计数与对照组相比无统计学差异；5、8、11、14Gy组肝细胞计数低于对照组；肝细胞计数在2-11Gy剂量范围内随辐射剂量的增加而降低；3)辐射后72小时肝细胞计数变化趋势与辐射后6小时相似,但变化幅度大于辐射后6小时。固定剂量因素单独分析肝FDG摄取在辐射后6、24、72小时的变化时可知：2、5Gy肝细胞计数在辐射后6、24、72小时时间点无显著变化,8Gy组肝细胞计数在在三时间点的变化趋势为在21小时升高后再下降,至72小时达最低,11、14Gy组肝细胞计数在辐射后6、24小时时间点无显著变化,至72小时时则显著降低。放射后6小时,双核肝细胞计数仅在11、14Gy时升高；放射后24、72小时,双核肝细胞计数在2、5Gy时显著升高,且随放射剂量的增加而增加；至8、11、14Gy剂量时,双核肝细胞值随放射剂量的增加而呈降低趋势；固定剂量因素可知：双核肝细胞在2Gy时随观察时间点的延长而延长；5Gy时在放射后24小时显著升高,72小时时则降低,但仍高于放射后6小时；8、11、14Gy时双核肝细胞在三时间点的变化不具统计学差异。
2.2.4肝功能结果
血清白蛋白辐射后各时间点及各剂量组间无统计差异。总胆红素、国际标准化比率、谷丙转氨酶、谷草转氨酶及两者比值均仅在较大剂量辐射后(8、11、14Gy)较对照组显著升高且辐射后24小时变化最为显著。
2.2.5肝脏SUV与病理积分、双核肝细胞相关性分析
本研究结果表明肝脏SUV值与病理严重程度在辐射后6、72小时无相关性(SUV6h vs HAI积分6h,R=0.256,P=0.061,SUV72h vs HAI积分72h,R=-0.55,P=0.537),在辐射后24小时呈正相关,但相关性弱(R=0.315,P=0.020)。此外,放射后6小时肝脏SUV值与双核肝细胞计数无相关性(SUV6hvs双核肝细胞计数：r=-0.33,P=0.815)；放射后24、72小时双核肝细胞计数与肝脏SUV值呈正相关,SLV24h vs双核肝细胞计数：r=0.541,P=0.000；SUV72h vs双核肝细胞计数：r=0.434,P=0.001)。
18-氟代葡萄糖正电子发射断层扫描术/计算机层析X射线摄影法在全身射诱导的急性小肠损伤中的诊断价值
2.3.1小肠[18F]-FDG摄取在不同辐射剂量及不同时间点的变化
辐射剂量因素及时间因素对小肠[18F]FDG摄取的影响具有显著性。时间主效应、剂量主效应及两者的交互效应P值均小于0.05。通过固定时间因素并分析小肠[18F]-FDG摄取在各辐射剂量组间的变化可知：①辐射后6小时,2、5、14Gy组小肠[18F]-FDG摄取与对照组相比无统计学差异,8、11Gy组小肠[18F]-FDG摄取较对照组升高。2)辐射后24小时,2Gy组小肠FDG摄取与对照组无差异；5、8、11Gy组FDG摄取较对照组升高：14Gy组FDG摄取较对照组降低；此二时间点小肠FDG在2、5、8Gy均随剂量增加而增加；至11Gy及其后的剂量组则逐渐降至对照组水平(辐射后6小时)或低于对照组(辐射后24小时)。3)辐射后72小时2、5、8、11Gy组FDG摄取显著高于对照组,且FDG摄取在2-8Gy剂量范围内随辐射剂量增加而增加,至14Gy时则突然降低至正常值以下。固定剂量因素单独分析小肠FDG摄取在辐射后6、24、72小时的变化时可知：2、5、8Gy剂量组小肠FDG摄取随时间的延长而增加；11、14Gy剂量组小肠FDG摄取随时间的延长而降低。
2.3.2病理结果
辐射后6、24、72小时2、5Gy组肠壁结构完整。辐射后6小时,2、5Gv组可见固有层、粘膜下层水肿,无或偶见炎性细胞；辐射后24、72小时2、5Gy组可见固有层、粘膜下层水肿较辐射后6小时加重,可见小血管充血水肿,可见小肠绒毛稀疏、隐窝上皮细胞坏死、偶见细胞嗜酸性变。辐射后6小时8、11、14Gy组可见粘膜结构破坏,浅表性粘膜糜烂、固有膜粘膜炎性细胞浸润；辐射后24、72小时8、11、14Gy组可见严重的粘膜结构破坏、肠壁变薄、上皮细胞坏死、粘膜及粘膜下层允血、出血。总体而苦,小肠病理积分病理损伤随辐射剂量的增加及观察时间的延长而增加。炎症评分表明炎性细胞浸润在辐射后72小时最显著；其在辐射剂量为2—11Gy范围内随辐射剂量的增加而增加,至14Gy则突然降低。
2.3.3小肠[18F]-FDG摄取与病理积分及炎性评分的相关性
辐射后6小时小肠[18F]-FDG摄取与病理积分呈正相关,但相关关系不强；辐射后24、72小时小肠[18F]-FDG摄取均与炎性积分呈正相关
结论
1、[18F]-FDG-PFT/CT可用于骨髓受照剂量的快速评估(辐射后24小时)其评估范围为2-11Gy
2、[18F]-FDG-PET/CT可用于早期评估电离辐射对造血系统的损伤后果
3、骨髓[18F]-FDG摄取至少部分程度上与骨髓有核细胞数量相关
4、骨髓、肝脏、小肠病理损伤程度均呈辐射剂量-时间依赖性增加
5、[18F]-FDG-PET/CT可间接反映急性辐射性肝损伤的程度,有助于临床对于急性辐射性肝损伤的预后、病变严重程度快速评估及预测
6、传统的Child-Pugh积分系统及酶学检查并不适用于急性辐射性肝损伤
7、小肠[18F]-FDG摄取在辐射前后的变化主要与小肠炎性细胞浸润相关；其在辐射后24、72小时的异常降低往往预示者患者接受过大剂量照射及预后不良。
Background and Objection:
Accidental or intended radiation exposure may cause the different degree of injury to the body. The radiosensivity of organs was determined by their cell cycle and differentiation. Therefore, hematopoietic system is ranked as the organ most sensitive to radiation exposure attributed to its rapid differentiation, proliferation and cellular circle. In addition, lots of previous study revealed that small intestine is sensitive to radiation as well. In contrast, liver was regarded as the relatively radioresistance organ. Radiation dose can be determined at any time by analysis of electron spin resonance of tooth enamel or by conventional thennoluminescent dosimeters. However, simply absorbed dose determination is not enough to guide diagnosis, prognosis and selecting therapeutic approach. Instead, according to guideline published by Strategic National Stockpile Radiation Working Group in2004, a sensitive, timely and accurate assay for assessing the severity of the effect of dose on or damage sustained by critical organ system is essential to determine an appropriate medical countermeasure.
The current reference approaches such as symptoms observation (e.g. nausea or/and vomiting), peripheral lymphocyte count dynamics and scoring of unstable chromosomal-type aberrations in mitogen-stimulated peripheral blood lack the ability to correlate damage with functional capacity of critical organ systems or the general health status of the individual. Besides, these conventional diagnostic approaches have their own limitations. First, the symptoms of nausea or/and vomiting have not a precise correlation with absorbed dose. Second, chromosome must be incubated for48-72hours and the diagnostic dose range was2-4Gy. Thrid, lymphocyte count need continued repeating of the monitoring for several days after acute radiation exposure and the diagnostci dose range was2-8Gy.
2-[18F]-Fluoro-2-deoxy-D-glucose positron emission tomography with computed tomography ([18F]-FDG-PET/CT, henceforth FDG-PET/CT) has been well-estabilished in tumor diagnosis and treatment response monitoring. Besides, a long-term concern has been on its application in an increasing number of nontumorous disorders. However, there is a few reports with respect to the application of FDG-PET/CT in radiation-induced hematopoietic injury. Previous studies demonstrated that the FDG uptake was tissue-specificity. In addition, uptake of [18F]-FDG depends upon glucose transport molecules expressed in the cell membrane, the local cell density, and the metabolic activity of the surrounding tissue. We theoretically assume that above infulent factors shold be changed under different dose radiation exposure and the resultant change of FDG uptake should be present. However, the regularity of this kind of TBI-induced change of FDG uptake, as it relates to injury degree and radiation dose, remains incompletely understood.
In light of this, the Tibet minipigs were exposed to total body X-ray radiation (TBI) of various doses, and the time-point of6,24and72hours post-TBI was used for observing the regularity of this kind of TBI-induced change of FDG uptake and it relates to injury degree and radiation dose. Our present work will be help to better unsertand the diagnostic value of FDG-PET/CT in acute radiation-induced injury and provided the labrotary evidence for future clinical application.
1.1Chapter1The diagnostic value of [18F]-FDG-PET/CT in TBI-induced hemopoietic radiation toxicity
A total of18adult male Tibet minipigs were used for total body inadiation (TBI). The pigs were divided into six groups randomly. One control group (n=3) were not exposed to X-ray. Five treatment groups (n=3for each group) were irradiated with a single dose of2,5,8,11and14Gy TBI respectively using an8-MV X-ray linear accelerator, and a dose rate of255cGy/min for all experimental groups. These pigs were tested by [18F]-FDG-PET/CT and marrow nucleated cells counting on6,24and72hours post-TBI. The correlations of (standard uptake value) SUV with bone marrow nucleated cells number and biopsy and radiation dose were analyzed.
1.2Chapter2The diagnostic value of [18F]-FDG-PET/CT in TBI-induced acute hepatic radiation toxicity
A total of48adult male Tibet minipigs were used for total body irradiation (TBI). The pigs were divided into six groups randomly. One control group (n=3) were not exposed to X-ray. Five treatment groups (n=9for each group) were irradiated with a single dose of2,5,8,11and14Gy TBI respectively using an8-MV X-ray linear accelerator, and a dose rate of255cGy/min for all experimental groups. These pigs were tested by [18F]-FDG-PET/CT and collected ear-vein blood and liver tissue for liver function test and pathologic examination on6,24and72hours post-TBI.
13Chapter3The diagnostic value of [18F]-FDG-PET/CT in TBI-induced acute small-intestinal radiation toxicity
A total of48adult male Tibet minipigs were randomly divided into six groups. Five treatment groups (n=9) were irradiated with a single dose of2,5,8,11and14Gy total body irradiation respectively using an8Mv X-ray linear accelerator. Then the pigs in each group were further divided into four subgroups with3in each subgroup. Three subgroups in each experimental group were scanned by [18F]-FDG-PET/CT and then sacrified by for collecting materials at6,24and72hours of exposure, respectively.
Results
2.1.1Marrow FDG uptakes in different radiation doses and time-points.
The factors of radiation dose and time-point had significant effects on marrow FDG uptake. The main-effects of time and radiation dose and their cross-over effect were less than0.05. To the simple effect of radiation dose, at6h post-TBI, marrow FDG uptake in2,5,8and11Gy-group showed no significant difference with control group, and those in14Gy was higher than in control group. At24h post-TBI, marrow FDG uptakes in2,5and8Gy were higher than those in control group, while those in11and14Gy-group showed the marked decline compared with control group. In addition, marrow FDG uptake showed a radiation dose-dependent decrease in the dose range of2to11Gy. Compared with FDG uptake on24h post-TBI, FDG uptakes on72h post-TBI showed a similar, but smaller trend. To the simple effect of time-points, both of FDG uptakes on24and72h post-TBI were higher than those on6h post-TBI in2,5and8Gy-group. In11and14Gy group, FDG uptake decreased with the time prolonging.
2.1.2The results of marrow biopsy.
Microscopic observation showed the extention congestion of blood sinus and small vessels, and pyknosis of hemopoietic nucleus and nuclear debris in2Gy-group on6h post-TBI. However, this nuclear debris was cleared on24h post-TBI. All of these pathologic changes was also shown in5-8Gy and exhibited a radiation dose-dependent increase. In11and14Gy-group, microscopic observation showed the disappearance of hematopoietic cell and the loss of non-hematopoietic cell and the disintegration of blood sinus. The analysis of marrow hyperplasia degree showed as follows:1) at6h post-TBI, the marrow hyperplasia degree in2and5Gy-group was normal,and the moderate decrease was shown in8,11and14Gy-group;2) at24h post-TBI, the marrow hyperplasia degree in2Gy was normal,and the moderate decrease was shown in5and8Gy-group, and the marked decrease was shown in11and14Gy-group;3) at72h post-TBI, the marrow hyperplasia degree in2and5Gy-group showed moderate decrease, and the marked decrease was shown in8,11and14Gy-group respectively. In general, after receiving different x-ray TBI, marrow hyperplasia degree presented a radiation dose-time-dependent decrease.
2.1.3The change of marrow nucleated cells number in different radiation doses and time-points
The factors of radiation dose and time-point had significant effects on marrow nucleated cells number. The main-effects of time and radiation dose, and their cross-over effect were less than0.05. To the simple effect of radiation dose, at6h post-TBI, marrow nucleated cells number in2and5Gy-group showed no significance from control group, while those in8,11and14Gy-group were lower than in control group. However, there was no different between11and14Gy-group. AT24h post-TBI, there was no significant difference between2Gy-group and control group, while those in5,8,11and14Gy-group were lower than in control group. However, there was no difference among8,11and14Gy. At72h post-TBI, marrow nulceated cells number in2,5,8,11and14Gy were lower than in control group, and showed a radiation dose-dependent decrease in the dose range of2to8Gy. However, there was no significant difference among8,11and14Gy. To the simple effect of time-points, in all irradiated groups, the marrow nucleated cells number decreased with time prolonging.
2.2.1Hepatic FDG uptake in different radiation doses and time-points
The factors of radiation dose and time-point had significant effects on hepatic FDG uptake. The main-effects of time and radiation dose and their cross-over effect were less than0.05. To the simple effect of radiation dose, at6h post-TBI, hepatic FDG uptake in2,5,8and11Gy-group were higher than those in control group. However,there was no significant difference between control and14Gy-group. At24h post-TBI, hepatic FDG uptakes in all irradiated groups were higher than those in control group. FDG uptake increased with the increase of radiation doses in the dose range of2to5Gy, while FDG uptake decreased with the increase of radiation doses in the dose range of8to14Gy. Compared with FDG uptake on24h post-TBI, those on72h post-TBI showed a similar, but smaller trend. To the simple effect of time-points, hepatic FDG uptake showed no regularity on entire time-course.
2.2.2The result of pathologic examination
Microscopic examination of pig liver sections from2and5Gy groups at6,24and72h post-radiation compared to the control group revealed that the structure of hepatic cord was still integrity, but the hepatic sinusoid around central veins of liver had a extension and congestion. In addition, hepatocytes presented pyknotic nucleus, cellular swelling and eosinophilic body in these doses. In contrast with the sections from2and5Gy groups, lesions were more severe in the8,11and14Gy groups at all time points including1) evidence of severe hepatic cord structure damages,2) severe and obvious extension, congestion and hemorrhage in hepatic sinusoid and inner blood vessel of liver (localized or generalized), and3) the necrosis of hepatocytes. Besides, the multiple hepatic lobules were involved and observed in these doses, we observed their specific changes at the three time-points. In short, the higher radiation doses lead to more serious severe pathologic changes and seriousness increased with observation times within72hours post-TBI. In addition, pathologic score showed a radiation dose-time-dependent increase within72hours after TBI.
2.2.3The results of hepatocyte numbers and binucleated hepatocyte numbers
The factors of radiation dose and time-point had significant effects on hypatocytes number. The main-effects of time and radiation dose and their cross-over effect were less than0.05. To the simple effect of radiation dose, at6h post-TBI, hepatocytes number showed no difference from control group, and those in5,8,11and14Gy-group were lower than in control group. However, there were no differences among8,11and14Gy-group. At24h post-TBI, hepatocytes number in2Gy-group showed no difference with control group, while those in5,8,11and14Gy-group were lower than in control group. Hypatocytes number showed a radiation dose-dependent decrease in the dose range of2to11Gy. Compared with FDG uptake on6h post-TBI, those on72h post-TBI showed a similar, but larger trend. To the simple effect of time-points, hepatocytes number in2and5Gy showed no differneces on entire time-course. Hepatocytes number in8,11and14Gy-group showed no differnece between on6and24h post-TBI, but markedly decreased on72h post-TBI. At6h post-TBI, compared with control group, binucleated hepatocytes numbers only showed the significant increases in11and14Gy-group. At24and72h post-TBI, binucleated hepatocyte numbers in2and5Gy-group were higher than those in control group and increased with the increase of radiation doses. However, the reversed trend was shown in8,11and14Gy-group. For fixing dose factor, binucleated hepatocytes numbers in2Gy-group increased with times. Those in5Gy markedly increased on24and72h post-TBI and the highest level was recorded on24h post-TBI. When the doses were fixed in8,11and14Gy-group, binucleated hepatocytes numbers showed no significant differences among three time-points.
2.2.4The results of liver function
The level of serum albumin showed no significant differences in different radiation doses and time-points.TBIL, INT, AST, ALT, AST/ALT only showed the increase trend in8,11, and14Gy and the most obvious change was shown on24h post-TBI.
2.2.5The correlation analysis of hepatic SUVs with pathologic secores and binucleated hepatocytes numbers
Our results revealed that hepatic SUVs showed no correlation with pathologic scores on6and72h post-TBI (SUV6h vs HAI6h, R=0.256, P=0.061, SUV72h vs HAI72h, R=-0.55, P=0.537) and showed poor correlation with pathologic scores on24h post-TBI (R=0.315, P=0.020). In addition, hepatic SUVs showed no correlation with binucleated hepatocyte numbers on6h post-TBI (SUV6h vs binucleated hepatocytes numbers6h:r=-0.33, P=0.815). However, hepatic SUVs showed positive correlations with binucleated hepatocyte numbers on24and72h post-TBI (SUV24h vs binucleated hepatocyte number24h:1-0.541, P=0.000, SUV72h vs binucleated hepatocytes numbers:r=0.434, P=0.001).
2.3.1Small-intestinal FDG uptake in different radiation doses and time-points
The factors of radiation dose and time-point had significant effects on small-intestinal FDG uptake. The main-effects of time and radiation dose, and their cross-over effect were less than0.05. To the simple effect of radiation dose, at6h post-TBI, small-intestinal FDG uptake in2,5and14Gy showed no difference from control group, while those in8and11Gy were higher than control group. At24h post-TBI, small-intestinal FDG uptake showed no difference between2Gy-group and control group. Those in5,8and11Gy-group were higher than control group, while those in14Gy-group was lower than control group. It should be noted that on the time-points of6and24h post-TBI, FDG uptake in2,5and8Gy increased with the increase of radiation doses, while the reverse trend were shown in the following doses. At72h post-TBI. small-intestinal FDG uptake showed a radiation dose-dependent increase in the dose range of2to8Gy, while the rapid and marked decreases were shown in11and14Gy-grooup. To the simple effect of time-points, small-intestinal FDG uptake increased with the time prolonging in2,5and8Gy-group, while the reversed trend was shown in11and14Gy-group.
2.3.2The result of pathologic examination
Macroscopic examination of pig intestine sections from2and5Gy groups at6,24and72h post-radiation compared to the control group revealed that the structure of small intestine canal was still integrity, but the lamina propria and submucosa had a edema and small blood vessels dilated hyperaemia were presented. Microscopic examination of the intestine sections from the two groups revealed a spectrum of the pathological features described as follows:1) the small intestinal villi became sparse;
2) crypt epithelial cell appeared necrosis;3) occasionally found the cytoplasm of lamina propria cells show eosinophilic changes. In contrast with the sections from2and5Gy groups, lesions were more severe in the8,11and14Gy groups at all time points including evidence of severe mucosal structure damages, thinner intestinal wall, epithelial necrosis, congestion and/or mucosa and submucosa bleeding. By the results of semi-quantitative pathological assessment, we found pathologic scores increased with the increase of radiation doses at each time point post-TBI, and tended to be worse with time. We found the most pathological change shown at the72h post-TBI. In addition, the degree of inflammatory cell infiltrate showed a dose-dependent increase in the dose range of2to11Gy, and rapidly fell down in14Gy-group.
2.3.3The correlation analysis of small-intestinal [18F]-FDG uptakes and pathologic score and imflammary score
Small-intestinal FDG uptake showed a positive correlation with pathologic score on6h post-TBI.However, the correlation was weak. Whereas, small-intestinal FDG uptake showed the positive correlation with imflammary score on24nad72h post-TBI.
Conclusion
1.[18F]-FDG-PET/CT may be used to quickly assess the radiation dose in the dose range of2to11Gy.
2. FDG PET/CT has the potential for early prognostic assessment in haematopoietic radiation toxicity.
3. FDG uptake is, at least partly, correlated with marrow nucleated cells number.
4. The pathologic lesion degree in bone marrow, small intestine and liver showed a radiation dose-time-dependent increase.
5.[18F]-FDG-PET/CT can reflect the acute radiation-induced injury degree of liver and is helpful for quick assessing the prognosis and diagnosis clinically.
6. Child-Pugh score system and enzyme labeled compound assay were inappropriate for diagnosis of acute hepatic radiation-induced injury.
7.[18F]-FDG uptake in small intestine was correlated with small-intestinal inflammatory cell infiltrate and the markedly reduction on24and72h post-TBI maybe suggested the high dose exposure and poor prognosis.
机体遭受不同程度的电离辐射(医源性及意外性辐射接触及核事故)后,各组织器官均会出现不同程度的损伤,其损伤程度主要取决于照射剂量及组织脏器对电离辐射的敏感性。不同的组织器官对辐射的敏感性并不相同,其辐射敏感性主要取决于细胞周期的长短及分化速度。因此,作为具有快速分化及复制特性的造血系统,对电脑辐射高度敏感。此外,既往研究表明小肠对辐射同样具有高度敏感性,而肝脏则被认为其对辐射具有一定耐受性,是一种具有中度辐射敏感性的脏器。虽然目前牙釉质的电子自旋谐振分析及热释发光剂量计评估技术可在辐射后任何时候段对电离辐射的剂量进行评估,但这种单纯的辐射剂量评估并不等于机体各组织脏器的实际受照剂量,亦不是以反应机体在受照后的功能变化并指导临床诊断、制定治疗方案及评估预后。根据美国国家战略储备委员会辐射工作组于2004年颁布的指南：快速、灵敏、精确的对各组织脏器实际受照剂量、机体损伤程度、后续损伤效应进行评估对于患者的预后、治疗方案的选择至关重要。
日前临床上针对于受照剂量常规方法主要有1)症状观察、2)外周血淋巴细胞动力学变化、：3)染色体核型评分。然而,这些方法在诊断时间、实用性及特异性方面均存有不足。1)症状观察往往缺乏特异性,约有50—80%的患者在受照后悔出现腹痛、恶心呕吐等症状,然而这些症状主要与受照部位相关,且易受其他因素的干扰,与受照剂量往往缺乏直接联系；2)外周血淋巴细胞动力学需持续检测至少7天以上,且诊断剂量范围为2-8Gy；3)染色体核型评分至少需要孵育72小时,且易受人为因素干扰及诊断剂量范围相对较小(2-4Gy)；4)上述三种方法均不能用以反映患者的健康状况及判定脏器受照后的功能变化。
18-氟代葡萄糖正电子发射断层扫描术/计算机层析X射线摄影法([18F]-FDG-PHT/CT)是一种先进的分子成像诊断技术,其在临床肿瘤诊断、疗效检测方而的应用已得到广泛的公认。此外,越来越多的研究表明其可用于其他非肿瘤性疾病。然而,关于[18F]-FDG-PET/CT在急性辐射损伤中的应用报道较少。既往研究表明18-氟代葡萄糖([18F]-FDG)的摄取具有组织特异性。此外,其摄取主要与下列三个因素相关：①局部细胞密度；②表达于细胞膜表面的糖转运分子活性；③周围组织的代谢活性。理论上,机体遭受不同程度的电离辐射后,上述指标均会发生不同程度的改变,且这种改变必将导致[18F]FDG的摄取发生变化。但电离辐射诱导的这种[18F]-fdg摄取的变化是否具有规性?是否可用于快速诊断受照剂量并反映机体受损程度?
有鉴于此,本研究以西藏小型猪为模型,通过予小型猪2、5、8、11、14Gy的单剂量全身照射(TBI)以诱导不同程度的全身多系统-器官性急性辐射损伤并在放射后72小时内对其进行多指标观察用以探讨：①[18f]-fdg-pet/ct示踪剂18氟代葡萄糖([18F]-FUG)在骨髓、肝脏、小肠中的标准摄取值(SUV)的变化规律；②[18F]-FDG是否可反映上述脏器的损伤程度及脏器功能。通过上述研究,可有助于进一步了解18-氟代葡萄糖正电子发射断层扫描术/计算机层析X射线摄影法在急性辐射损伤中的诊断价值并为其未来的临床应用提供实验依据。
方法
18-氟代葡萄糖正电子发射断层扫描术/计算机层析X射线摄影法在全身照射诱导的急性造血系统损伤中的诊断价值
选用未去势雄性西藏小型猪为动物模型(n=18),辐射组用直线加速器分别予2、5、8、11、14Gy单次剂量照射(n=3/组),剂量率均统一为255cGy/min。对照组未予照射。分别于照射后6、24、72小时予西藏小型猪[18F]-FDG-PHT/CT扫描并分别在相同时段于小型猪右髂后上嵴进行骨髓活检并抽吸骨髓2ml用以骨髓组织病理学检查及骨髓有核细胞计数。数据经统计学处理后用以分析[18F]-FDG SUV值及其与骨髓活检、骨髓有核细胞计数、照射剂量的相关性。
18-氟代葡萄糖正电子发射断层扫描术/计算机层析x射线摄影法在全身照射诱导的急性肝损伤中的诊断价值
选用未去势雄性西藏小型猪为动物模型(n=48),辐射组用直线加速器分别予2、5、8、11、14Gy单次剂量照射(n=9/组),剂量率均统一为255cGy/mino对照组未予照射(n=3)。分别于照射后6、24、72小时予西藏小型猪[18F]-FDG-PET/CT扫描并通过耳静脉收集静脉血用以酶学及肝脏功能各项指标检测。分别在相同时段处死小型猪并取肝脏组织用于病理学检查。
18-氟代葡萄糖正电子发射断层扫描术/计算机层析x射线摄影法在全身照射诱导的急性小肠损伤中的诊断价值
选用未去势雄性西藏小型猪为动物模型(n=48),辐射组用直线加速器分别予2、5、8、11、14Gy单次剂量照射(n=9/组),剂量率均统一为255cGy/min。对照组未予照射(n=3)。分别于照射后6、24、72小时予西藏小型猪[18F]-FDG-PET/CT扫描。分别于相同时段处死小型猪并取小肠组织用于病理学检查。
结果
18-氟代葡萄糖正电子发射断层扫描术／计算机层析x射线摄影法在全身照射诱导的急性造血系统损伤中的诊断价值
2.1.1骨髓[18F]-FDG摄取在不同辐射剂量及不同时间点的变化
辐射剂量因素及时间因素对骨髓[18F]-FDG摄取的影响具有显著性。时间主效应、剂量主效应及两者的交互效应P值均小于0.05。通过固定时间因素并分析骨髓FDG摄取在各辐射剂量组间的变化可知：①辐射后6小时,2、5、8、11Gy组的骨髓[18F]-FDG摄取与对照组相比无显著统计学差异,仅在14Gy组时,骨髓[18F]-FDG摄取值较对照组有所增加；②辐射后24小时,[18F]-FDG摄取在2、5、8、组时均较对照组显著升高,11、14Gy时骨髓[18F]-FDG摄取较对照组显著降低,且骨髓[18F]-FDG摄取在2-11Gy剂量范围内随辐射剂量的增加而降低；③辐射后72小时的[18F]-FDG摄取变化趋势与24小时相同,但变化幅度小于辐射后24小时。当固定剂量因素单独分析骨髓[18r]-FDG摄取在辐射后6、24、72小时的变化时可知：①辐射剂量为2、5、8Gy时,骨髓[18F]-FDG摄取在辐射后24及72小时均高于辐射后6小时。其变化趋势为辐射后24小时[18F]-FDG摄取>72小时>6小时。辐射剂量为11、14Gy时,[18F]-FDG摄取随观察时间的延长而进行性降低。
2.1.2骨髓活检结果
2Gy组辐射后6小时镜下可见血窦和小血管扩张及充血,造血细胞核固缩及坏死的核碎片；2Gy组辐射后24小时镜下可见核碎片几乎被清除；2Gy组辐射后72小时除了能轻易辨认非造血细胞外未见到造血细胞的再生。5-8Gy组上述变化较2Gy组显著加重,且呈剂量依赖效应。11Gv-14Gv造血细胞几乎消失怡尽,非造血细胞也显著减少,血窦结构几乎完全崩解。通过对骨髓增生程度评估可知：1)辐射后6小时,2、5Gy组小型猪骨髓增生程度为增生正常；8、11、14Gy组小型猪骨髓增生程度为增生减低。辐射后24小时,2Gy组小型猪骨髓增生程度为增生正常；5、8Gy组小型猪骨髓增生程度为增生减低；11、14Gy组小型猪骨髓增生程度为增生极度减低。辐射后72小时,2、5Gy组小型猪骨髓增生程度为增生减低；8、11、14Gy组小型猪骨髓增生程度为增生极度减低。总体而言,西藏小型猪骨髓增生程度在接受不同剂量的X线全身照射后,呈辐射剂量-时间依赖性降低。
2.1.3骨髓有核细胞计数在不同辐射剂量及不同时间点的变化
辐射剂量因素及时间因素对骨髓有核细胞计数的影响具有显著性。时间主效应、剂量主效应及两者的交互效应P值均小于0.05。通过固定时间因素并分析骨髓有核细胞计数在辐射后6、24、72小时时间点各辐射剂量组间的变化可知：①辐射后6小时,2、5Gy组的骨髓有核细胞计数与对照组无统计学差异,8、11、14Gy组的骨髓有核细胞计数较对照组显著降低,但11、14Gy组骨髓有核细胞无统计学差异；②辐射后24小时,2Gy组骨髓有核细胞计数与对照组相比无统计学差异；5、8、11、14Gy组骨髓有核细胞计数显著低于对照组,但8、11、14Gy组骨髓有核细胞记数无统计学差异：③辐射后72小时,2、5、8、11、14Gv组骨髓有核细胞记数均显著低于对照组,且骨髓有核细胞计数在28Gy组剂量范围内随辐射剂量的增加而降低,8、11、14Gy组骨髓有核细胞记数无统计学差异。当固定剂量因素单独分析骨髓FDG摄取在辅射后6、24、72小时的变化时可知：所有辐射组骨髓有核细胞计数均随观察时间的延长而降低。18-氟代葡萄糖正电子发射断层扫描术/计算机层析X射线摄影法在全身照射诱导的急性肝损伤中的诊断价值
2.2.1肝[18F]-FDG摄取在不同辐射剂量及不同时间点的变化
辐射剂量因素及时间因素对肝[8F]-FDG摄取的影响具有显著性。时间主效应、剂量主效应及两者的交互效应P值均小于0.05。通过固定时间因素并分析肝[[8F]-FDG摄取在辐射后6、24、72小时时间点各辐射剂量组间的变化可知：①辐射后6小时,2、5、8、11Gy组肝[18F]-FDG摄取较对照组升高,14Gy组肝[18F]-FDG摄取与对照组相比无统计学差异;②辐射后24小时,所有辐射组肝[18F]-FDG摄取均较对照组显著升高,[18F]-FDG摄取在2-5Gy范围内随辐射剂量增加而增加,在8-14Gy范围内[18F]-FDG摄取则随辐射剂量的增加而降低；③辐射后72小时[18F]-FDG摄取变化趋势与辐射后24小时相似,但变化幅度小于辐射后24小时。当固定剂量因素单独分析肝[18F]-FDG摄取在辐射后6、24、72小时的变化时可知：不同辐射剂量下,各时间点的肝(?)18F]-FDG摄取变化无显著规律性。
2.2.2肝脏病理结果
病理结果表明2、5Gy组镜下肝脏肝小叶结构尚完整,可见沿肝中央静脉周围肝窦扩张充血,肝细胞核固缩、细胞肿胀、嗜酸小体形成。8、11、14Gy组镜下可见显著的肝细胞凋亡、肝索结构破坏、肝窦及肝内血管扩张、充血.、局部或散在出血及多小叶同时受累。病理类型分析及HAI积分表明肝脏病理损伤随时间的延长及辐射剂量的增加而加重。
2.2.3肝细胞及双核细胞计数结果
辐射剂量因素及时间因素对肝细胞、双核肝细胞计数的影响具有显著性。时间主效应、剂量主效应及两者的交互效应P值均小于0.05。通过固定时间因素并分析肝细胞记数在各辐射剂量组间的变化可知：①辐射后6小时,2Gy组肝细胞计数与对照组相比无统计学差异,5、8、11、14Gy组肝细胞计数低于对照组,但8、11、14Gy组肝细胞计数无统计学差异；②辐射后24小时,2Gy组肝细胞计数与对照组相比无统计学差异；5、8、11、14Gy组肝细胞计数低于对照组；肝细胞计数在2-11Gy剂量范围内随辐射剂量的增加而降低；3)辐射后72小时肝细胞计数变化趋势与辐射后6小时相似,但变化幅度大于辐射后6小时。固定剂量因素单独分析肝FDG摄取在辐射后6、24、72小时的变化时可知：2、5Gy肝细胞计数在辐射后6、24、72小时时间点无显著变化,8Gy组肝细胞计数在在三时间点的变化趋势为在21小时升高后再下降,至72小时达最低,11、14Gy组肝细胞计数在辐射后6、24小时时间点无显著变化,至72小时时则显著降低。放射后6小时,双核肝细胞计数仅在11、14Gy时升高；放射后24、72小时,双核肝细胞计数在2、5Gy时显著升高,且随放射剂量的增加而增加；至8、11、14Gy剂量时,双核肝细胞值随放射剂量的增加而呈降低趋势；固定剂量因素可知：双核肝细胞在2Gy时随观察时间点的延长而延长；5Gy时在放射后24小时显著升高,72小时时则降低,但仍高于放射后6小时；8、11、14Gy时双核肝细胞在三时间点的变化不具统计学差异。
2.2.4肝功能结果
血清白蛋白辐射后各时间点及各剂量组间无统计差异。总胆红素、国际标准化比率、谷丙转氨酶、谷草转氨酶及两者比值均仅在较大剂量辐射后(8、11、14Gy)较对照组显著升高且辐射后24小时变化最为显著。
2.2.5肝脏SUV与病理积分、双核肝细胞相关性分析
本研究结果表明肝脏SUV值与病理严重程度在辐射后6、72小时无相关性(SUV6h vs HAI积分6h,R=0.256,P=0.061,SUV72h vs HAI积分72h,R=-0.55,P=0.537),在辐射后24小时呈正相关,但相关性弱(R=0.315,P=0.020)。此外,放射后6小时肝脏SUV值与双核肝细胞计数无相关性(SUV6hvs双核肝细胞计数：r=-0.33,P=0.815)；放射后24、72小时双核肝细胞计数与肝脏SUV值呈正相关,SLV24h vs双核肝细胞计数：r=0.541,P=0.000；SUV72h vs双核肝细胞计数：r=0.434,P=0.001)。
18-氟代葡萄糖正电子发射断层扫描术/计算机层析X射线摄影法在全身射诱导的急性小肠损伤中的诊断价值
2.3.1小肠[18F]-FDG摄取在不同辐射剂量及不同时间点的变化
辐射剂量因素及时间因素对小肠[18F]FDG摄取的影响具有显著性。时间主效应、剂量主效应及两者的交互效应P值均小于0.05。通过固定时间因素并分析小肠[18F]-FDG摄取在各辐射剂量组间的变化可知：①辐射后6小时,2、5、14Gy组小肠[18F]-FDG摄取与对照组相比无统计学差异,8、11Gy组小肠[18F]-FDG摄取较对照组升高。2)辐射后24小时,2Gy组小肠FDG摄取与对照组无差异；5、8、11Gy组FDG摄取较对照组升高：14Gy组FDG摄取较对照组降低；此二时间点小肠FDG在2、5、8Gy均随剂量增加而增加；至11Gy及其后的剂量组则逐渐降至对照组水平(辐射后6小时)或低于对照组(辐射后24小时)。3)辐射后72小时2、5、8、11Gy组FDG摄取显著高于对照组,且FDG摄取在2-8Gy剂量范围内随辐射剂量增加而增加,至14Gy时则突然降低至正常值以下。固定剂量因素单独分析小肠FDG摄取在辐射后6、24、72小时的变化时可知：2、5、8Gy剂量组小肠FDG摄取随时间的延长而增加；11、14Gy剂量组小肠FDG摄取随时间的延长而降低。
2.3.2病理结果
辐射后6、24、72小时2、5Gy组肠壁结构完整。辐射后6小时,2、5Gv组可见固有层、粘膜下层水肿,无或偶见炎性细胞；辐射后24、72小时2、5Gy组可见固有层、粘膜下层水肿较辐射后6小时加重,可见小血管充血水肿,可见小肠绒毛稀疏、隐窝上皮细胞坏死、偶见细胞嗜酸性变。辐射后6小时8、11、14Gy组可见粘膜结构破坏,浅表性粘膜糜烂、固有膜粘膜炎性细胞浸润；辐射后24、72小时8、11、14Gy组可见严重的粘膜结构破坏、肠壁变薄、上皮细胞坏死、粘膜及粘膜下层允血、出血。总体而苦,小肠病理积分病理损伤随辐射剂量的增加及观察时间的延长而增加。炎症评分表明炎性细胞浸润在辐射后72小时最显著；其在辐射剂量为2—11Gy范围内随辐射剂量的增加而增加,至14Gy则突然降低。
2.3.3小肠[18F]-FDG摄取与病理积分及炎性评分的相关性
辐射后6小时小肠[18F]-FDG摄取与病理积分呈正相关,但相关关系不强；辐射后24、72小时小肠[18F]-FDG摄取均与炎性积分呈正相关
结论
1、[18F]-FDG-PFT/CT可用于骨髓受照剂量的快速评估(辐射后24小时)其评估范围为2-11Gy
2、[18F]-FDG-PET/CT可用于早期评估电离辐射对造血系统的损伤后果
3、骨髓[18F]-FDG摄取至少部分程度上与骨髓有核细胞数量相关
4、骨髓、肝脏、小肠病理损伤程度均呈辐射剂量-时间依赖性增加
5、[18F]-FDG-PET/CT可间接反映急性辐射性肝损伤的程度,有助于临床对于急性辐射性肝损伤的预后、病变严重程度快速评估及预测
6、传统的Child-Pugh积分系统及酶学检查并不适用于急性辐射性肝损伤
7、小肠[18F]-FDG摄取在辐射前后的变化主要与小肠炎性细胞浸润相关；其在辐射后24、72小时的异常降低往往预示者患者接受过大剂量照射及预后不良。
Background and Objection:
Accidental or intended radiation exposure may cause the different degree of injury to the body. The radiosensivity of organs was determined by their cell cycle and differentiation. Therefore, hematopoietic system is ranked as the organ most sensitive to radiation exposure attributed to its rapid differentiation, proliferation and cellular circle. In addition, lots of previous study revealed that small intestine is sensitive to radiation as well. In contrast, liver was regarded as the relatively radioresistance organ. Radiation dose can be determined at any time by analysis of electron spin resonance of tooth enamel or by conventional thennoluminescent dosimeters. However, simply absorbed dose determination is not enough to guide diagnosis, prognosis and selecting therapeutic approach. Instead, according to guideline published by Strategic National Stockpile Radiation Working Group in2004, a sensitive, timely and accurate assay for assessing the severity of the effect of dose on or damage sustained by critical organ system is essential to determine an appropriate medical countermeasure.
The current reference approaches such as symptoms observation (e.g. nausea or/and vomiting), peripheral lymphocyte count dynamics and scoring of unstable chromosomal-type aberrations in mitogen-stimulated peripheral blood lack the ability to correlate damage with functional capacity of critical organ systems or the general health status of the individual. Besides, these conventional diagnostic approaches have their own limitations. First, the symptoms of nausea or/and vomiting have not a precise correlation with absorbed dose. Second, chromosome must be incubated for48-72hours and the diagnostic dose range was2-4Gy. Thrid, lymphocyte count need continued repeating of the monitoring for several days after acute radiation exposure and the diagnostci dose range was2-8Gy.
2-[18F]-Fluoro-2-deoxy-D-glucose positron emission tomography with computed tomography ([18F]-FDG-PET/CT, henceforth FDG-PET/CT) has been well-estabilished in tumor diagnosis and treatment response monitoring. Besides, a long-term concern has been on its application in an increasing number of nontumorous disorders. However, there is a few reports with respect to the application of FDG-PET/CT in radiation-induced hematopoietic injury. Previous studies demonstrated that the FDG uptake was tissue-specificity. In addition, uptake of [18F]-FDG depends upon glucose transport molecules expressed in the cell membrane, the local cell density, and the metabolic activity of the surrounding tissue. We theoretically assume that above infulent factors shold be changed under different dose radiation exposure and the resultant change of FDG uptake should be present. However, the regularity of this kind of TBI-induced change of FDG uptake, as it relates to injury degree and radiation dose, remains incompletely understood.
In light of this, the Tibet minipigs were exposed to total body X-ray radiation (TBI) of various doses, and the time-point of6,24and72hours post-TBI was used for observing the regularity of this kind of TBI-induced change of FDG uptake and it relates to injury degree and radiation dose. Our present work will be help to better unsertand the diagnostic value of FDG-PET/CT in acute radiation-induced injury and provided the labrotary evidence for future clinical application.
1.1Chapter1The diagnostic value of [18F]-FDG-PET/CT in TBI-induced hemopoietic radiation toxicity
A total of18adult male Tibet minipigs were used for total body inadiation (TBI). The pigs were divided into six groups randomly. One control group (n=3) were not exposed to X-ray. Five treatment groups (n=3for each group) were irradiated with a single dose of2,5,8,11and14Gy TBI respectively using an8-MV X-ray linear accelerator, and a dose rate of255cGy/min for all experimental groups. These pigs were tested by [18F]-FDG-PET/CT and marrow nucleated cells counting on6,24and72hours post-TBI. The correlations of (standard uptake value) SUV with bone marrow nucleated cells number and biopsy and radiation dose were analyzed.
1.2Chapter2The diagnostic value of [18F]-FDG-PET/CT in TBI-induced acute hepatic radiation toxicity
A total of48adult male Tibet minipigs were used for total body irradiation (TBI). The pigs were divided into six groups randomly. One control group (n=3) were not exposed to X-ray. Five treatment groups (n=9for each group) were irradiated with a single dose of2,5,8,11and14Gy TBI respectively using an8-MV X-ray linear accelerator, and a dose rate of255cGy/min for all experimental groups. These pigs were tested by [18F]-FDG-PET/CT and collected ear-vein blood and liver tissue for liver function test and pathologic examination on6,24and72hours post-TBI.
13Chapter3The diagnostic value of [18F]-FDG-PET/CT in TBI-induced acute small-intestinal radiation toxicity
A total of48adult male Tibet minipigs were randomly divided into six groups. Five treatment groups (n=9) were irradiated with a single dose of2,5,8,11and14Gy total body irradiation respectively using an8Mv X-ray linear accelerator. Then the pigs in each group were further divided into four subgroups with3in each subgroup. Three subgroups in each experimental group were scanned by [18F]-FDG-PET/CT and then sacrified by for collecting materials at6,24and72hours of exposure, respectively.
Results
2.1.1Marrow FDG uptakes in different radiation doses and time-points.
The factors of radiation dose and time-point had significant effects on marrow FDG uptake. The main-effects of time and radiation dose and their cross-over effect were less than0.05. To the simple effect of radiation dose, at6h post-TBI, marrow FDG uptake in2,5,8and11Gy-group showed no significant difference with control group, and those in14Gy was higher than in control group. At24h post-TBI, marrow FDG uptakes in2,5and8Gy were higher than those in control group, while those in11and14Gy-group showed the marked decline compared with control group. In addition, marrow FDG uptake showed a radiation dose-dependent decrease in the dose range of2to11Gy. Compared with FDG uptake on24h post-TBI, FDG uptakes on72h post-TBI showed a similar, but smaller trend. To the simple effect of time-points, both of FDG uptakes on24and72h post-TBI were higher than those on6h post-TBI in2,5and8Gy-group. In11and14Gy group, FDG uptake decreased with the time prolonging.
2.1.2The results of marrow biopsy.
Microscopic observation showed the extention congestion of blood sinus and small vessels, and pyknosis of hemopoietic nucleus and nuclear debris in2Gy-group on6h post-TBI. However, this nuclear debris was cleared on24h post-TBI. All of these pathologic changes was also shown in5-8Gy and exhibited a radiation dose-dependent increase. In11and14Gy-group, microscopic observation showed the disappearance of hematopoietic cell and the loss of non-hematopoietic cell and the disintegration of blood sinus. The analysis of marrow hyperplasia degree showed as follows:1) at6h post-TBI, the marrow hyperplasia degree in2and5Gy-group was normal,and the moderate decrease was shown in8,11and14Gy-group;2) at24h post-TBI, the marrow hyperplasia degree in2Gy was normal,and the moderate decrease was shown in5and8Gy-group, and the marked decrease was shown in11and14Gy-group;3) at72h post-TBI, the marrow hyperplasia degree in2and5Gy-group showed moderate decrease, and the marked decrease was shown in8,11and14Gy-group respectively. In general, after receiving different x-ray TBI, marrow hyperplasia degree presented a radiation dose-time-dependent decrease.
2.1.3The change of marrow nucleated cells number in different radiation doses and time-points
The factors of radiation dose and time-point had significant effects on marrow nucleated cells number. The main-effects of time and radiation dose, and their cross-over effect were less than0.05. To the simple effect of radiation dose, at6h post-TBI, marrow nucleated cells number in2and5Gy-group showed no significance from control group, while those in8,11and14Gy-group were lower than in control group. However, there was no different between11and14Gy-group. AT24h post-TBI, there was no significant difference between2Gy-group and control group, while those in5,8,11and14Gy-group were lower than in control group. However, there was no difference among8,11and14Gy. At72h post-TBI, marrow nulceated cells number in2,5,8,11and14Gy were lower than in control group, and showed a radiation dose-dependent decrease in the dose range of2to8Gy. However, there was no significant difference among8,11and14Gy. To the simple effect of time-points, in all irradiated groups, the marrow nucleated cells number decreased with time prolonging.
2.2.1Hepatic FDG uptake in different radiation doses and time-points
The factors of radiation dose and time-point had significant effects on hepatic FDG uptake. The main-effects of time and radiation dose and their cross-over effect were less than0.05. To the simple effect of radiation dose, at6h post-TBI, hepatic FDG uptake in2,5,8and11Gy-group were higher than those in control group. However,there was no significant difference between control and14Gy-group. At24h post-TBI, hepatic FDG uptakes in all irradiated groups were higher than those in control group. FDG uptake increased with the increase of radiation doses in the dose range of2to5Gy, while FDG uptake decreased with the increase of radiation doses in the dose range of8to14Gy. Compared with FDG uptake on24h post-TBI, those on72h post-TBI showed a similar, but smaller trend. To the simple effect of time-points, hepatic FDG uptake showed no regularity on entire time-course.
2.2.2The result of pathologic examination
Microscopic examination of pig liver sections from2and5Gy groups at6,24and72h post-radiation compared to the control group revealed that the structure of hepatic cord was still integrity, but the hepatic sinusoid around central veins of liver had a extension and congestion. In addition, hepatocytes presented pyknotic nucleus, cellular swelling and eosinophilic body in these doses. In contrast with the sections from2and5Gy groups, lesions were more severe in the8,11and14Gy groups at all time points including1) evidence of severe hepatic cord structure damages,2) severe and obvious extension, congestion and hemorrhage in hepatic sinusoid and inner blood vessel of liver (localized or generalized), and3) the necrosis of hepatocytes. Besides, the multiple hepatic lobules were involved and observed in these doses, we observed their specific changes at the three time-points. In short, the higher radiation doses lead to more serious severe pathologic changes and seriousness increased with observation times within72hours post-TBI. In addition, pathologic score showed a radiation dose-time-dependent increase within72hours after TBI.
2.2.3The results of hepatocyte numbers and binucleated hepatocyte numbers
The factors of radiation dose and time-point had significant effects on hypatocytes number. The main-effects of time and radiation dose and their cross-over effect were less than0.05. To the simple effect of radiation dose, at6h post-TBI, hepatocytes number showed no difference from control group, and those in5,8,11and14Gy-group were lower than in control group. However, there were no differences among8,11and14Gy-group. At24h post-TBI, hepatocytes number in2Gy-group showed no difference with control group, while those in5,8,11and14Gy-group were lower than in control group. Hypatocytes number showed a radiation dose-dependent decrease in the dose range of2to11Gy. Compared with FDG uptake on6h post-TBI, those on72h post-TBI showed a similar, but larger trend. To the simple effect of time-points, hepatocytes number in2and5Gy showed no differneces on entire time-course. Hepatocytes number in8,11and14Gy-group showed no differnece between on6and24h post-TBI, but markedly decreased on72h post-TBI. At6h post-TBI, compared with control group, binucleated hepatocytes numbers only showed the significant increases in11and14Gy-group. At24and72h post-TBI, binucleated hepatocyte numbers in2and5Gy-group were higher than those in control group and increased with the increase of radiation doses. However, the reversed trend was shown in8,11and14Gy-group. For fixing dose factor, binucleated hepatocytes numbers in2Gy-group increased with times. Those in5Gy markedly increased on24and72h post-TBI and the highest level was recorded on24h post-TBI. When the doses were fixed in8,11and14Gy-group, binucleated hepatocytes numbers showed no significant differences among three time-points.
2.2.4The results of liver function
The level of serum albumin showed no significant differences in different radiation doses and time-points.TBIL, INT, AST, ALT, AST/ALT only showed the increase trend in8,11, and14Gy and the most obvious change was shown on24h post-TBI.
2.2.5The correlation analysis of hepatic SUVs with pathologic secores and binucleated hepatocytes numbers
Our results revealed that hepatic SUVs showed no correlation with pathologic scores on6and72h post-TBI (SUV6h vs HAI6h, R=0.256, P=0.061, SUV72h vs HAI72h, R=-0.55, P=0.537) and showed poor correlation with pathologic scores on24h post-TBI (R=0.315, P=0.020). In addition, hepatic SUVs showed no correlation with binucleated hepatocyte numbers on6h post-TBI (SUV6h vs binucleated hepatocytes numbers6h:r=-0.33, P=0.815). However, hepatic SUVs showed positive correlations with binucleated hepatocyte numbers on24and72h post-TBI (SUV24h vs binucleated hepatocyte number24h:1-0.541, P=0.000, SUV72h vs binucleated hepatocytes numbers:r=0.434, P=0.001).
2.3.1Small-intestinal FDG uptake in different radiation doses and time-points
The factors of radiation dose and time-point had significant effects on small-intestinal FDG uptake. The main-effects of time and radiation dose, and their cross-over effect were less than0.05. To the simple effect of radiation dose, at6h post-TBI, small-intestinal FDG uptake in2,5and14Gy showed no difference from control group, while those in8and11Gy were higher than control group. At24h post-TBI, small-intestinal FDG uptake showed no difference between2Gy-group and control group. Those in5,8and11Gy-group were higher than control group, while those in14Gy-group was lower than control group. It should be noted that on the time-points of6and24h post-TBI, FDG uptake in2,5and8Gy increased with the increase of radiation doses, while the reverse trend were shown in the following doses. At72h post-TBI. small-intestinal FDG uptake showed a radiation dose-dependent increase in the dose range of2to8Gy, while the rapid and marked decreases were shown in11and14Gy-grooup. To the simple effect of time-points, small-intestinal FDG uptake increased with the time prolonging in2,5and8Gy-group, while the reversed trend was shown in11and14Gy-group.
2.3.2The result of pathologic examination
Macroscopic examination of pig intestine sections from2and5Gy groups at6,24and72h post-radiation compared to the control group revealed that the structure of small intestine canal was still integrity, but the lamina propria and submucosa had a edema and small blood vessels dilated hyperaemia were presented. Microscopic examination of the intestine sections from the two groups revealed a spectrum of the pathological features described as follows:1) the small intestinal villi became sparse;
2) crypt epithelial cell appeared necrosis;3) occasionally found the cytoplasm of lamina propria cells show eosinophilic changes. In contrast with the sections from2and5Gy groups, lesions were more severe in the8,11and14Gy groups at all time points including evidence of severe mucosal structure damages, thinner intestinal wall, epithelial necrosis, congestion and/or mucosa and submucosa bleeding. By the results of semi-quantitative pathological assessment, we found pathologic scores increased with the increase of radiation doses at each time point post-TBI, and tended to be worse with time. We found the most pathological change shown at the72h post-TBI. In addition, the degree of inflammatory cell infiltrate showed a dose-dependent increase in the dose range of2to11Gy, and rapidly fell down in14Gy-group.
2.3.3The correlation analysis of small-intestinal [18F]-FDG uptakes and pathologic score and imflammary score
Small-intestinal FDG uptake showed a positive correlation with pathologic score on6h post-TBI.However, the correlation was weak. Whereas, small-intestinal FDG uptake showed the positive correlation with imflammary score on24nad72h post-TBI.
Conclusion
1.[18F]-FDG-PET/CT may be used to quickly assess the radiation dose in the dose range of2to11Gy.
2. FDG PET/CT has the potential for early prognostic assessment in haematopoietic radiation toxicity.
3. FDG uptake is, at least partly, correlated with marrow nucleated cells number.
4. The pathologic lesion degree in bone marrow, small intestine and liver showed a radiation dose-time-dependent increase.
5.[18F]-FDG-PET/CT can reflect the acute radiation-induced injury degree of liver and is helpful for quick assessing the prognosis and diagnosis clinically.
6. Child-Pugh score system and enzyme labeled compound assay were inappropriate for diagnosis of acute hepatic radiation-induced injury.
7.[18F]-FDG uptake in small intestine was correlated with small-intestinal inflammatory cell infiltrate and the markedly reduction on24and72h post-TBI maybe suggested the high dose exposure and poor prognosis.
引文
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[7]Egarni MI, Segreto C, Kerbauy J, Juliano Y. Effects of whole-body X-irradiation on the peripheral blood of primate Cebus apella. Braz J Med Biol Res.1991.24(3):271-4.
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[9]Radu CG, Shu CJ, Shelly SM, Phelps ME, Witte ON. Positron emission tomography with computed tomography imaging of neuroinflammation in experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A.2007. 104(6):1937-42.
[10]Cheng MF, Wu YW, Liu KL. et al. Diagnostic value of 18F-FDG-PET/CT in indeterminate infiltrative hepatic lesions in an endemic area of viral hepatitis. Nucl Med Commun.2011.32(4):252-9.
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[14]McGuire SM, Menda Y, Boles PLL, Gross B, Buatti J, Bayouth JE. 3'-deoxy-3'-[(1)F]fluorothymidine PET quantification of bone marrow response to radiation dose. Int J Radiat Oncol Biol Phys.2011.81(3):888-93.
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