放射性内耳损伤临床分析及黑色素在放射性内耳损伤中的保护作用研究
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摘要
一鼻咽癌IMRT技术下放化疗患者放射性内耳损伤临床分析
背景和目的
我国是鼻咽癌高发国,放射治疗是目前最有效的治疗手段,同时,放射治疗也是其他头颈部恶性肿瘤的主要治疗方式之一[1]。近年来,头颈部肿瘤治疗后五年生存率有了明显提高,但随之而来的远期副反应也越来越被认识,其中放射性耳病发病率居晚期并发症的第二位[2]。放疗后感音神经性聋(Sensori-neural hearing loss,SNHL)是鼻咽癌放射治疗后的常见后遗症,尤其是联合化疗的患者更为常见,此种损害特点为延迟发生、进行性加重、不可逆的听力下降,而目前尚无有效的预防及治疗方法[3]。因此,在放疗患者中对内耳损伤的保护就显得尤为重要。随着放疗物理和放射生物的进展,调强放疗已成为鼻咽癌的标准放疗技术,放疗计划制定和实施中对内耳进行剂量限值成为可能。我们拟通过对骨导4K Hz电测听值作相关回顾性分析,了解鼻咽癌IMRT技术中化疗患者年龄、剂量等因素对SNHL发生率的影响,并尝试寻找耳蜗放疗剂量限定值,提供放疗计划制定中耳蜗剂量限值参考。
材料与方法
共有2009-2011年中29例(58耳)放化疗方案完全一致的病例进入此项研究。所有病例均为病理证实的初治鼻咽癌,行IMRT放射治疗和PF方案化疗。所有病例年龄≤55岁(以减少老年性SNHL对听力测试结果的影响),放疗前听力水平均正常(检测显示为正常电测听),在随访时均无肿瘤局部和区域复发及全身转移,有完整的体检记录及听力学检测资料包括耳鼓膜描述、电测听、声阻抗测试。入组时,我们排除放疗前后声阻抗鼓室图为B型的分泌性中耳炎患者(中耳积液有可能影响骨导测听值)。放疗前、放疗结束、放疗后3个月、放疗后6个月、放疗后1年、放疗后2年均随访电测听和声阻抗的情况,入组患者截止时点至少为放疗后12个月。以骨导4K Hz电测听值(阈值增大≥lOdB认为有意义)作相关线性回归分析、logistic分析和odds ratio分析,分析放射性内耳损伤相关因素,确定内耳剂量限定值。
结果
58耳符合电测听分析条件,放疗后25.8%耳恶化。1.多元线性回归分析发现：放疗剂量(p=0.01,评估值0.46)、年龄(p=0.002,评估值0.47)均与SNHL发病率有统计学上的相关性。2.1ogistic回归分析发现：放疗剂量(p=0.02,评估值0.76)、年龄(p=0.005,评估值0.14)均与SNHL发病率有统计学上的相关性。3.OddsRatio分析发现：剂量评估值为1.001,年龄评估值为1.151,两者均是SNHL发病率的危险因素。4.对剂量与放疗后SNHL的发生率相关性的研究发现：良好组和恶化组之间剂量比较差异有统计学上的意义(良好组剂量36.87Gy,恶化组剂量39.43Gy,P=0.0492),我们推荐在放射治疗计划制定中耳蜗剂量应限值在37Gy以下。
结论
鼻咽癌IMRT技术下的放化疗患者,无论是线性回归模型、logstic回归模型还是Odds Ratio分析得出的结论一致。耳蜗照射剂量、年龄都与放疗后SNHL的发生率具有统计学上的相关性。为了预防IMRT技术下鼻咽癌放化疗患者SNHL的发生,推荐剂量值保持在37Gy以下。
背景和目的
我们的前期研究显示,鼻咽癌放化疗患者耳蜗放射剂量限制在37Gy可以预防SNHL的发生。以往研究报道,当耳蜗剂量达41-50Gy时,SNHL的发病率达31%,60-90Gy时更高达62%[4]。为保证鼻咽部肿瘤靶区的剂量,耳蜗剂量限定值以47Gy为宜[5],过低剂量限值可能影响肿瘤靶区剂量。因此,有必要寻找更多的内耳放射损伤保护方法。
黑色素广泛分布于哺乳动物包括人的内耳中,如前庭暗细胞区、耳蜗血管纹、内淋巴囊等处的黑素细胞中[6]。大量文献证实,黑色素在噪音损伤、耳毒性药物和老年性耳聋中均有保护作用[7.8]。由于黑色素具有螯合金属阳离子的能力、氧化自由基清除能力,能量储存和转化能力[9],可能对耳蜗放射性损伤具有保护作用,但迄今为止尚未见相关报导。现有研究表明：杂色动物前庭、耳蜗和内淋巴囊内均有酪氨酸酶活性表达,因此杂色动物内耳黑素细胞能主动合成黑色素。白化动物则由于酪氨酸酶的遗传性缺陷,体内不能合成黑色素,因此白化动物内耳黑素细胞中没有黑色素分布[10]。由于白化和杂色豚鼠的内耳存在着上述差异,因此可以利用白化和杂色豚鼠相对比来研究黑色素在内耳中的功能。我们拟建造10Gy、15Gy、20Gy的豚鼠内耳损伤照射模型,然后通过比较两种豚鼠在三种剂量梯度下,在24小时和2周这两个时间截点上内耳损伤的差异,来探讨黑色素在放射性内耳损伤中是否具有保护作用。
材料和方法
将56只豚鼠分为杂色组和白化组,分别给予不照光、1000cGy、1500cGy、2000cGy照射,于照射后24小时和照射后2周断头处死,进行耳蜗铺片和制作冰冻切片,观察毛细胞、血管纹和螺旋韧带的损伤情况。1.选取第三回耳蜗基底膜进行耳蜗铺片,四氮唑蓝染色,镜下观察毛细胞排列情况,并进行细胞计数,计算缺失率。2.常规冰冻切片,HE染色,计量第三回血管纹的厚度,细胞密度,毛细血管数和螺旋韧带厚度及细胞密度。3.结果进行相关统计分析。
研究结果
在放射性内耳损伤模型中,研究结果如下：1.黑色素：白化组无论照射与否,均未见黑色素；杂色组随着照射剂量增加和照射后时间延长,黑色素有递增趋势,照射后2周黑色素增加更明显。2.毛细胞状况：随着照射时间延长和照射剂量的增加,两组豚鼠毛细胞紊乱和缺失率都有增加,但在同等剂量和时间条件下,白化组比杂色组排列更紊乱,缺失率更高。3.血管纹状况：随着照射剂量增加和照射后时间延长,白化组血管纹厚度减少,而杂色组基本不变,甚至有增厚趋势；照射后24小时,血管纹细胞数计数差别不明显。照射后2周,无论白化组还是杂色组,有核细胞都减少,白化组比杂色组减少更明显。4.毛细血管状况：照射后,两组豚鼠毛细血管数都增加,但两组之间差异不明显。5.螺旋韧带状况：随着照射剂量增加和照射后时间延长,两组豚鼠螺旋韧带纤维细胞均有减少的趋势,白化组比杂色组更明显。
结论
内耳黑色素量与内耳血管纹细胞、螺旋韧带细胞及基底膜毛细胞损伤变化呈负相关,此种相关性在照射后2周比照射后24小时更明显,但黑色素与血管纹微循环关系不明显。
在放射性内耳损伤中,内耳黑色素与放射后SNHL的发生可能具有相关性,值得进一步研究。
I Clinical Analysis of Radiation-induced Inner Ear Damages on Patients by Radio-chemotherapy under Nasopharyngeal Carcinoma IMRT Technology
Background and Purpose
Our country is the highly NPC prone country. At present, radiotherapy is the most effective therapy for nasopharyngeal carcinoma as well as one of the main therapies for other malignant tumors of head and neck. In recent years,5-year-survival rate upon treatment of tumors of head and neck has been improved obviously, however, the subsequent long-term side effects are also been acquired more and more, in which radiation-induced ear disease incidence ranks second among the advanced complications. Sensorineural Hearing Loss (SNHL) upon radiotherapy is a common sequela for patients by NPC radiotherapy, especially for the patients combined with chemotherapy. Characteristics of this damage are delayed occurrence, progressive severity and irreversible hearing reduction, while there is no effective prevention and treatment currently. Therefore, the protection for inner ear damages on patients by chemotherapy is becoming especially important. With the development of radiotherapeutical physics and radiation biology, IMRT has become the standard radiotherapy technology and dose limit for inner ear is possible for plan formulation and implementation of radiotherapy. We plan, through the value of bone conduction4K Hz electro audiometry, to conduct related retrospective analysis, acquire the effects of the factors such as age, dose of patients by chemotherapy under NPC IMRT technology on the incidence of SNHL, try to find out the limit value of radiotherapeutic dose for cochlea and provide reference limit value of inner ear dose for the formulation of radiotherapy plan.
Materials and Methods
Totally29cases of radiochemotherapeutic plans fully in accordance between2009and2011are included in this study. All cases are proved to be NPC pathologically and treated by IMRT radiotherapy and PF chemotherapy. Ages of all cases are≤55(to decrease the effect of aged SNHL on results of hearing test). Before radiotherapy, all their hearing levels are normal, all the tumors have no local or areal recurrence and systemic transfer upon follow-up survey, and they have complete physical examination records and audiological testing data, including tympanic membrane description, electro audiometry and acoustic impedance test. When grouping, we excluded the patients with secretory otitis media (middle ear effusion may affect the value of bone conduction audiometry) whose tympanic camity chart of acoustic impedance before and after radiotherapy is Type B. Electro audiometry and acoustic impedance before radiotherapy, upon completion of radiotherapy,3months after radiotherapy,6months after radiotherapy,1year after radiotherapy and2years after radiotherapy are both followed up for survey, and the deadline of the grouped patients is at least12months after radiotherapy. The related linear regression analysis, logistic analysis and odds ratio analysis are conducted based on the value of bone conduction4K Hz electro audiometry (the increase of≥10dB of threshold value is deemed meaningful) to analyze the factors related to radiation-induced inner ear damages and determine dose limit for inner ear.
Results
Ear58conforms to the conditions of electro audiometry analysis, and25.8%ears deteriorates after radiotherapy.1. Multiple linear regression analysis finds that: both radiotherapeutic dose (p=0.01and assessment value is0.46) and age (p=0.002and assessment value is0.47) are related to the incidence of SNHL statistically.2. Logistic regression analysis finds that:both radiotherapeutic dose (p=0.02and assessment value is0,76) and age (p=0.005and assessment value is0.14) are related to the incidence of SNHL statistically.3. Odds Ratio analysis finds that:assessment value of dose is1.001and assessment value of age is1.151, both are the risk factors of the incidence of SNHL,4. The study on the relativity to incidence of SNHL after dosage and radiotherapy finds that:the comparative differences of doses between the benign group and the deteriorative group have statistical significance (Dose of the benign group is36.87Gy and that of the deteriorative group is39.43Gy, P=0.0492), therefore, we recommend that the limit value of cochlear dose shall be less than37Gy during the formulation of radiotherapy plan.
Conclusions
For patients by radio-chemotherapy under NPC IMRT technology, whether by linear regression model, logistic regression model or Odds Ratio analysis, the conclusions acquired are consistent. Both cochlea radiation dose and age are related to the incidence of SNHL after radiotherapy statistically. In order to prevent the SNHL occurrence of patients by radio-chemotherapy under NPC IMRT technology, the dose value is recommenced to be less than37Gy.
Background and Purpose
As shown from the previous studies, cochlear radiation dose of NPC patients treated by radiochemotherapy shall be limited to37Gy to prevent SNHL. According to reports of previous studies, when cochlear dose is higher than41-50Gy, the incidence rate of SNHL reaches31%, which will up to62%when cochlear dose is60-90Gy, therefore, in order to ensure dose in gross tumor volume of the nasopharynx, the cochlear dose is appropriately limited to47Gy, and the lower dose limit may affect dose of gross tumor volume. Therefore, it is necessary to find more protection methods of inner ear damages to prevent SNHL after radiotherapy.
Melanin is widely distributed in mammal, including inner ear of human, such as melanocyte in dark cell of human vestibular organs, stria vascularis and endolymphytic sac. Lots of literature confirmed that melanin has a protective effect on noise damages, ototoxic drugs and presbycusis. Due to capacity of melanin to chelate metallic cation, eliminate oxyradical, as well as store and transform energy, so that it has a protective effect on cochlear radiation-induced damages, but it has no related reports so far. As shown from the existing studies:there is tyrosine, enzymatic activity in vestibule, cochlea and endolymphatic sac of mottled animal so that melanocyte in their inner ear can actively synthesize melanin. Due to genetic defects of tyrosinase, albino animals can not synthesize melanin in body, therefore, it has no melanin in melanocyte of their inner ears. Due to such differences in inner ears of albino guinea pigs and mottled ones, the function of melanin in inner ears can be researched through comparison between them. It is proposed to create radiation model of guinea pigs with1OGy,15Gy,20Gy, then through comparative differences of inner ear damages between the two kinds of guinea pigs under three dose grads in two time points of24hours and2weeks to explore whether the melanin has a protective effect in radiation-induced inner ear damages.
Materials and Methods
The guinea pigs are divided into mottled group and albino group, which are given different irradiation with1000cGy,1500cGy,2000cGy, then cut off their heads after irradiation of24hours and2weeks, and do stretched preparation of cochlear and production of frozen sections to observe damages of hair cell, stria vascularis and spiral ligament.1. Select the third cochlear basilar membrane to do stretched preparation and staining of blue tetrazolium, and observe arrangement of the hair cells through microscope and calculate cells to figure out the miss rate.2. Conventional frozen sections, HE staining, measuring thickness of the third stria vascularis, cell density, number of blood capillary, as well as thickness of spiral ligament and the cell density.3. Conduct related statistical analysis to the results.
Results
In models of radiation-induced inner ear damages, the results are as follows:1. Melanin:whether the albino group is irradiated or not, it has no melanin; the melanin of mottled group is in an increasing trend with increasing of irradiation dose and prolonging of irradiation time, increasing of the melanin is more obvious after2weeks upon irradiation.2. Status of hair cell:with the extension of irradiation time and increment of irradiation dose, hair cell disorder and miss rate of the two groups of guinea pigs are both increased, but under the condition of same dose and time, disorder of arrangement and miss rate of the albino group is higher than that of the mottled group.3. Status of stria vascularis:with increment of irradiation dose and extension of time after irradiation, thickness of stria vascularis of albino group is reduced, while that of the mottled group is essentially the same, even in a thickening trend; number of cells in stria vascularis has no obvious difference after irradiation of24hours.2weeks after irradiation, karyote of the albino group and the mottled group are both reduced, while karyote of albino group is reduced more obviously than that of the mottled group.4. Status of blood capillary:after irradiation, the numbers of blood capillary of the two groups of guinea pigs are both increased, but no significant differences between the two groups.5. Status of spiral ligament:with increment of irradiation dose and extension of time after irradiation, fibrocyte of spiral ligament of the two groups of guinea pigs are on a decreasing trend, while the albino group is more obvious than the mottled group.
Conclusions
Number of melanin in inner ear is in negative correlation with damage changes of stria vascularis cells of inner ear, spiral ligament cells and basilar membrane hair cells. Such correlation is move obvious in two weeks than in24hours after irradiation, but microcirculation relationship of melanin and stria vascularis is not obvious.
In radiation-induced inner ear damages, inner ear melanin may have a correlation with incidence of SNHL after irradiation, which deserves further study
背景和目的
我国是鼻咽癌高发国,放射治疗是目前最有效的治疗手段,同时,放射治疗也是其他头颈部恶性肿瘤的主要治疗方式之一[1]。近年来,头颈部肿瘤治疗后五年生存率有了明显提高,但随之而来的远期副反应也越来越被认识,其中放射性耳病发病率居晚期并发症的第二位[2]。放疗后感音神经性聋(Sensori-neural hearing loss,SNHL)是鼻咽癌放射治疗后的常见后遗症,尤其是联合化疗的患者更为常见,此种损害特点为延迟发生、进行性加重、不可逆的听力下降,而目前尚无有效的预防及治疗方法[3]。因此,在放疗患者中对内耳损伤的保护就显得尤为重要。随着放疗物理和放射生物的进展,调强放疗已成为鼻咽癌的标准放疗技术,放疗计划制定和实施中对内耳进行剂量限值成为可能。我们拟通过对骨导4K Hz电测听值作相关回顾性分析,了解鼻咽癌IMRT技术中化疗患者年龄、剂量等因素对SNHL发生率的影响,并尝试寻找耳蜗放疗剂量限定值,提供放疗计划制定中耳蜗剂量限值参考。
材料与方法
共有2009-2011年中29例(58耳)放化疗方案完全一致的病例进入此项研究。所有病例均为病理证实的初治鼻咽癌,行IMRT放射治疗和PF方案化疗。所有病例年龄≤55岁(以减少老年性SNHL对听力测试结果的影响),放疗前听力水平均正常(检测显示为正常电测听),在随访时均无肿瘤局部和区域复发及全身转移,有完整的体检记录及听力学检测资料包括耳鼓膜描述、电测听、声阻抗测试。入组时,我们排除放疗前后声阻抗鼓室图为B型的分泌性中耳炎患者(中耳积液有可能影响骨导测听值)。放疗前、放疗结束、放疗后3个月、放疗后6个月、放疗后1年、放疗后2年均随访电测听和声阻抗的情况,入组患者截止时点至少为放疗后12个月。以骨导4K Hz电测听值(阈值增大≥lOdB认为有意义)作相关线性回归分析、logistic分析和odds ratio分析,分析放射性内耳损伤相关因素,确定内耳剂量限定值。
结果
58耳符合电测听分析条件,放疗后25.8%耳恶化。1.多元线性回归分析发现：放疗剂量(p=0.01,评估值0.46)、年龄(p=0.002,评估值0.47)均与SNHL发病率有统计学上的相关性。2.1ogistic回归分析发现：放疗剂量(p=0.02,评估值0.76)、年龄(p=0.005,评估值0.14)均与SNHL发病率有统计学上的相关性。3.OddsRatio分析发现：剂量评估值为1.001,年龄评估值为1.151,两者均是SNHL发病率的危险因素。4.对剂量与放疗后SNHL的发生率相关性的研究发现：良好组和恶化组之间剂量比较差异有统计学上的意义(良好组剂量36.87Gy,恶化组剂量39.43Gy,P=0.0492),我们推荐在放射治疗计划制定中耳蜗剂量应限值在37Gy以下。
结论
鼻咽癌IMRT技术下的放化疗患者,无论是线性回归模型、logstic回归模型还是Odds Ratio分析得出的结论一致。耳蜗照射剂量、年龄都与放疗后SNHL的发生率具有统计学上的相关性。为了预防IMRT技术下鼻咽癌放化疗患者SNHL的发生,推荐剂量值保持在37Gy以下。
背景和目的
我们的前期研究显示,鼻咽癌放化疗患者耳蜗放射剂量限制在37Gy可以预防SNHL的发生。以往研究报道,当耳蜗剂量达41-50Gy时,SNHL的发病率达31%,60-90Gy时更高达62%[4]。为保证鼻咽部肿瘤靶区的剂量,耳蜗剂量限定值以47Gy为宜[5],过低剂量限值可能影响肿瘤靶区剂量。因此,有必要寻找更多的内耳放射损伤保护方法。
黑色素广泛分布于哺乳动物包括人的内耳中,如前庭暗细胞区、耳蜗血管纹、内淋巴囊等处的黑素细胞中[6]。大量文献证实,黑色素在噪音损伤、耳毒性药物和老年性耳聋中均有保护作用[7.8]。由于黑色素具有螯合金属阳离子的能力、氧化自由基清除能力,能量储存和转化能力[9],可能对耳蜗放射性损伤具有保护作用,但迄今为止尚未见相关报导。现有研究表明：杂色动物前庭、耳蜗和内淋巴囊内均有酪氨酸酶活性表达,因此杂色动物内耳黑素细胞能主动合成黑色素。白化动物则由于酪氨酸酶的遗传性缺陷,体内不能合成黑色素,因此白化动物内耳黑素细胞中没有黑色素分布[10]。由于白化和杂色豚鼠的内耳存在着上述差异,因此可以利用白化和杂色豚鼠相对比来研究黑色素在内耳中的功能。我们拟建造10Gy、15Gy、20Gy的豚鼠内耳损伤照射模型,然后通过比较两种豚鼠在三种剂量梯度下,在24小时和2周这两个时间截点上内耳损伤的差异,来探讨黑色素在放射性内耳损伤中是否具有保护作用。
材料和方法
将56只豚鼠分为杂色组和白化组,分别给予不照光、1000cGy、1500cGy、2000cGy照射,于照射后24小时和照射后2周断头处死,进行耳蜗铺片和制作冰冻切片,观察毛细胞、血管纹和螺旋韧带的损伤情况。1.选取第三回耳蜗基底膜进行耳蜗铺片,四氮唑蓝染色,镜下观察毛细胞排列情况,并进行细胞计数,计算缺失率。2.常规冰冻切片,HE染色,计量第三回血管纹的厚度,细胞密度,毛细血管数和螺旋韧带厚度及细胞密度。3.结果进行相关统计分析。
研究结果
在放射性内耳损伤模型中,研究结果如下：1.黑色素：白化组无论照射与否,均未见黑色素；杂色组随着照射剂量增加和照射后时间延长,黑色素有递增趋势,照射后2周黑色素增加更明显。2.毛细胞状况：随着照射时间延长和照射剂量的增加,两组豚鼠毛细胞紊乱和缺失率都有增加,但在同等剂量和时间条件下,白化组比杂色组排列更紊乱,缺失率更高。3.血管纹状况：随着照射剂量增加和照射后时间延长,白化组血管纹厚度减少,而杂色组基本不变,甚至有增厚趋势；照射后24小时,血管纹细胞数计数差别不明显。照射后2周,无论白化组还是杂色组,有核细胞都减少,白化组比杂色组减少更明显。4.毛细血管状况：照射后,两组豚鼠毛细血管数都增加,但两组之间差异不明显。5.螺旋韧带状况：随着照射剂量增加和照射后时间延长,两组豚鼠螺旋韧带纤维细胞均有减少的趋势,白化组比杂色组更明显。
结论
内耳黑色素量与内耳血管纹细胞、螺旋韧带细胞及基底膜毛细胞损伤变化呈负相关,此种相关性在照射后2周比照射后24小时更明显,但黑色素与血管纹微循环关系不明显。
在放射性内耳损伤中,内耳黑色素与放射后SNHL的发生可能具有相关性,值得进一步研究。
I Clinical Analysis of Radiation-induced Inner Ear Damages on Patients by Radio-chemotherapy under Nasopharyngeal Carcinoma IMRT Technology
Background and Purpose
Our country is the highly NPC prone country. At present, radiotherapy is the most effective therapy for nasopharyngeal carcinoma as well as one of the main therapies for other malignant tumors of head and neck. In recent years,5-year-survival rate upon treatment of tumors of head and neck has been improved obviously, however, the subsequent long-term side effects are also been acquired more and more, in which radiation-induced ear disease incidence ranks second among the advanced complications. Sensorineural Hearing Loss (SNHL) upon radiotherapy is a common sequela for patients by NPC radiotherapy, especially for the patients combined with chemotherapy. Characteristics of this damage are delayed occurrence, progressive severity and irreversible hearing reduction, while there is no effective prevention and treatment currently. Therefore, the protection for inner ear damages on patients by chemotherapy is becoming especially important. With the development of radiotherapeutical physics and radiation biology, IMRT has become the standard radiotherapy technology and dose limit for inner ear is possible for plan formulation and implementation of radiotherapy. We plan, through the value of bone conduction4K Hz electro audiometry, to conduct related retrospective analysis, acquire the effects of the factors such as age, dose of patients by chemotherapy under NPC IMRT technology on the incidence of SNHL, try to find out the limit value of radiotherapeutic dose for cochlea and provide reference limit value of inner ear dose for the formulation of radiotherapy plan.
Materials and Methods
Totally29cases of radiochemotherapeutic plans fully in accordance between2009and2011are included in this study. All cases are proved to be NPC pathologically and treated by IMRT radiotherapy and PF chemotherapy. Ages of all cases are≤55(to decrease the effect of aged SNHL on results of hearing test). Before radiotherapy, all their hearing levels are normal, all the tumors have no local or areal recurrence and systemic transfer upon follow-up survey, and they have complete physical examination records and audiological testing data, including tympanic membrane description, electro audiometry and acoustic impedance test. When grouping, we excluded the patients with secretory otitis media (middle ear effusion may affect the value of bone conduction audiometry) whose tympanic camity chart of acoustic impedance before and after radiotherapy is Type B. Electro audiometry and acoustic impedance before radiotherapy, upon completion of radiotherapy,3months after radiotherapy,6months after radiotherapy,1year after radiotherapy and2years after radiotherapy are both followed up for survey, and the deadline of the grouped patients is at least12months after radiotherapy. The related linear regression analysis, logistic analysis and odds ratio analysis are conducted based on the value of bone conduction4K Hz electro audiometry (the increase of≥10dB of threshold value is deemed meaningful) to analyze the factors related to radiation-induced inner ear damages and determine dose limit for inner ear.
Results
Ear58conforms to the conditions of electro audiometry analysis, and25.8%ears deteriorates after radiotherapy.1. Multiple linear regression analysis finds that: both radiotherapeutic dose (p=0.01and assessment value is0.46) and age (p=0.002and assessment value is0.47) are related to the incidence of SNHL statistically.2. Logistic regression analysis finds that:both radiotherapeutic dose (p=0.02and assessment value is0,76) and age (p=0.005and assessment value is0.14) are related to the incidence of SNHL statistically.3. Odds Ratio analysis finds that:assessment value of dose is1.001and assessment value of age is1.151, both are the risk factors of the incidence of SNHL,4. The study on the relativity to incidence of SNHL after dosage and radiotherapy finds that:the comparative differences of doses between the benign group and the deteriorative group have statistical significance (Dose of the benign group is36.87Gy and that of the deteriorative group is39.43Gy, P=0.0492), therefore, we recommend that the limit value of cochlear dose shall be less than37Gy during the formulation of radiotherapy plan.
Conclusions
For patients by radio-chemotherapy under NPC IMRT technology, whether by linear regression model, logistic regression model or Odds Ratio analysis, the conclusions acquired are consistent. Both cochlea radiation dose and age are related to the incidence of SNHL after radiotherapy statistically. In order to prevent the SNHL occurrence of patients by radio-chemotherapy under NPC IMRT technology, the dose value is recommenced to be less than37Gy.
Background and Purpose
As shown from the previous studies, cochlear radiation dose of NPC patients treated by radiochemotherapy shall be limited to37Gy to prevent SNHL. According to reports of previous studies, when cochlear dose is higher than41-50Gy, the incidence rate of SNHL reaches31%, which will up to62%when cochlear dose is60-90Gy, therefore, in order to ensure dose in gross tumor volume of the nasopharynx, the cochlear dose is appropriately limited to47Gy, and the lower dose limit may affect dose of gross tumor volume. Therefore, it is necessary to find more protection methods of inner ear damages to prevent SNHL after radiotherapy.
Melanin is widely distributed in mammal, including inner ear of human, such as melanocyte in dark cell of human vestibular organs, stria vascularis and endolymphytic sac. Lots of literature confirmed that melanin has a protective effect on noise damages, ototoxic drugs and presbycusis. Due to capacity of melanin to chelate metallic cation, eliminate oxyradical, as well as store and transform energy, so that it has a protective effect on cochlear radiation-induced damages, but it has no related reports so far. As shown from the existing studies:there is tyrosine, enzymatic activity in vestibule, cochlea and endolymphatic sac of mottled animal so that melanocyte in their inner ear can actively synthesize melanin. Due to genetic defects of tyrosinase, albino animals can not synthesize melanin in body, therefore, it has no melanin in melanocyte of their inner ears. Due to such differences in inner ears of albino guinea pigs and mottled ones, the function of melanin in inner ears can be researched through comparison between them. It is proposed to create radiation model of guinea pigs with1OGy,15Gy,20Gy, then through comparative differences of inner ear damages between the two kinds of guinea pigs under three dose grads in two time points of24hours and2weeks to explore whether the melanin has a protective effect in radiation-induced inner ear damages.
Materials and Methods
The guinea pigs are divided into mottled group and albino group, which are given different irradiation with1000cGy,1500cGy,2000cGy, then cut off their heads after irradiation of24hours and2weeks, and do stretched preparation of cochlear and production of frozen sections to observe damages of hair cell, stria vascularis and spiral ligament.1. Select the third cochlear basilar membrane to do stretched preparation and staining of blue tetrazolium, and observe arrangement of the hair cells through microscope and calculate cells to figure out the miss rate.2. Conventional frozen sections, HE staining, measuring thickness of the third stria vascularis, cell density, number of blood capillary, as well as thickness of spiral ligament and the cell density.3. Conduct related statistical analysis to the results.
Results
In models of radiation-induced inner ear damages, the results are as follows:1. Melanin:whether the albino group is irradiated or not, it has no melanin; the melanin of mottled group is in an increasing trend with increasing of irradiation dose and prolonging of irradiation time, increasing of the melanin is more obvious after2weeks upon irradiation.2. Status of hair cell:with the extension of irradiation time and increment of irradiation dose, hair cell disorder and miss rate of the two groups of guinea pigs are both increased, but under the condition of same dose and time, disorder of arrangement and miss rate of the albino group is higher than that of the mottled group.3. Status of stria vascularis:with increment of irradiation dose and extension of time after irradiation, thickness of stria vascularis of albino group is reduced, while that of the mottled group is essentially the same, even in a thickening trend; number of cells in stria vascularis has no obvious difference after irradiation of24hours.2weeks after irradiation, karyote of the albino group and the mottled group are both reduced, while karyote of albino group is reduced more obviously than that of the mottled group.4. Status of blood capillary:after irradiation, the numbers of blood capillary of the two groups of guinea pigs are both increased, but no significant differences between the two groups.5. Status of spiral ligament:with increment of irradiation dose and extension of time after irradiation, fibrocyte of spiral ligament of the two groups of guinea pigs are on a decreasing trend, while the albino group is more obvious than the mottled group.
Conclusions
Number of melanin in inner ear is in negative correlation with damage changes of stria vascularis cells of inner ear, spiral ligament cells and basilar membrane hair cells. Such correlation is move obvious in two weeks than in24hours after irradiation, but microcirculation relationship of melanin and stria vascularis is not obvious.
In radiation-induced inner ear damages, inner ear melanin may have a correlation with incidence of SNHL after irradiation, which deserves further study
引文
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