Abstract：
BACKGROUND: Today, a number of methods and ways of prevention and treatment of radiation- -induced mucositis of the oral cavity and oropharynx have been developed, but the represented approaches are still not effective enough. Therefore, to increase the effectiveness of the prevention and treatment of radiation-induced mucositis, it is necessary to approach this problem comprehensively and individually, and to evaluate the factors affecting the development of mucositis.
METHODS: In this single-center prospective controlled non-randomized clinical trial, the results of clinical observation of the development of complications of radiation and chemoradiation therapy in 105 patients with a newly diagnosed squamous cell cancer of the oral cavity and oropharynx were analyzed. Factors affecting the risk of the development of grade III radiation-induced mucositis including the age, gender of the patients, their general condition before the treatment according to World Health Organisation scales, type of the treatment and its doses, additional use of immunotherapy with alpha/beta defensins, characteristic signs of the tumor process and all indices of the immune status of the patients before the treatment have been analyzed.
RESULTS: The method of construction and analysis of one-factor logistic regression models, where 24 indices were analyzed as factorial features, showed that the reduction of the risk of the development of grade III radiation-induced mucositis is predicted by several factors: immunotherapy, gender, serum concentrations of IgG and IgA. A decrease (P < 0.001) in the risk of the development of grade III radiation-induced mucositis was revealed if immunotherapy with alpha/beta defensins (with a total dose of 40 mg) was included into the treatment scheme (relative odds (RO) 0.05; 95% reference interval (RI) 0.02-0.18), in comparison with patients of the groups where it was not present or this immune agent was used in a total dose of 60 mg (P = 0.001, RO 0.06; 95% RI 0.01-0.30). The next factorial sign was gender, namely the risk of the development of grade III radiation-induced mucositis was lower for men (P = 0.003; RO 0.15; 95% RI 0.04-0.53) compared to women. An increase (P = 0.024) in the risk of the development of grade III radiation-induced mucositis with an increase in the initial level of IgG serum concentration was revealed, (RO 1.08; 95% RI 1.01-1.16) for each 1 mg/mL, as well as an increase (P = 0.044) in the possibility of the appearance of grade III radiation-induced mucositis with an increase in the serum concentration of IgA (RO 1.23; 95% RI 1.01-1.50) for every 1 mg/mL also before the beginning of the treatment. Multifactorial analysis has also confirmed that the risk of the development of grade III radiation-induced mucositis increases (P = 0.008) with a high serum IgG concentration before the treatment or with an increase in this index during therapy (RO 1.13; 95% RI 1.03-1.09) for every 1 mg/mL (when standardized by other risk factors). It was determined that when standardizing according to other factors (gender, IgG level), the risk of the development of grade III radiation-induced mucositis in the use of the immune agent alpha/beta defensins in a total dose of 40 mg per course decreases (P < 0.001; RO 0.08; 95% RI 0.02-0.27) compared to patients with oral cavity and oropharynx cancer who were not treated with immunotherapy. The risk of the development of grade III radiation-induced mucositis also decreases (P = 0.001) in the use of immunotherapy in a higher dose, i.e. 60 mg per course (RO 0.03; 95% RI 0.004-0.24 compared to patients whose treatment did not include immunotherapy (when standardized by other factors).
CONCLUSIONS: As a result of this controlled clinical study, some factors were determined in addition to the radiation as those affecting the risk of the development of grade III radiation-induced mucositis in patients with oral cavity and oropharynx cancer during special treatment. These factors comprise the inclusion of immunotherapy with alpha/beta defensins into the specific treatment; gender, and baseline levels of serum IgG and IgA concentrations suggest a pattern in which the higher the serum IgG and IgA concentrations are before the start of the treatment, the greater is the likelihood of severe radiation-induced mucositis degree during special therapy. The results of the study of humoral state of the immune system in patients with oral cavity and oropharynx cancer before the beginning of chemoradiation therapy can be used as prognostic risk factors for the development of severe gamma-irradiation-induced mucositis of the oropharyngeal area, as well as an indication for the use of immunotherapeutic agents (in particular, alpha/beta defensins) that are able to polarize the immune response towards type 1 T-helpers through their immunomodulatory action.
METHODS: In this single-center prospective controlled non-randomized clinical trial, the results of clinical observation of the development of complications of radiation and chemoradiation therapy in 105 patients with a newly diagnosed squamous cell cancer of the oral cavity and oropharynx were analyzed. Factors affecting the risk of the development of grade III radiation-induced mucositis including the age, gender of the patients, their general condition before the treatment according to World Health Organisation scales, type of the treatment and its doses, additional use of immunotherapy with alpha/beta defensins, characteristic signs of the tumor process and all indices of the immune status of the patients before the treatment have been analyzed.
RESULTS: The method of construction and analysis of one-factor logistic regression models, where 24 indices were analyzed as factorial features, showed that the reduction of the risk of the development of grade III radiation-induced mucositis is predicted by several factors: immunotherapy, gender, serum concentrations of IgG and IgA. A decrease (P < 0.001) in the risk of the development of grade III radiation-induced mucositis was revealed if immunotherapy with alpha/beta defensins (with a total dose of 40 mg) was included into the treatment scheme (relative odds (RO) 0.05; 95% reference interval (RI) 0.02-0.18), in comparison with patients of the groups where it was not present or this immune agent was used in a total dose of 60 mg (P = 0.001, RO 0.06; 95% RI 0.01-0.30). The next factorial sign was gender, namely the risk of the development of grade III radiation-induced mucositis was lower for men (P = 0.003; RO 0.15; 95% RI 0.04-0.53) compared to women. An increase (P = 0.024) in the risk of the development of grade III radiation-induced mucositis with an increase in the initial level of IgG serum concentration was revealed, (RO 1.08; 95% RI 1.01-1.16) for each 1 mg/mL, as well as an increase (P = 0.044) in the possibility of the appearance of grade III radiation-induced mucositis with an increase in the serum concentration of IgA (RO 1.23; 95% RI 1.01-1.50) for every 1 mg/mL also before the beginning of the treatment. Multifactorial analysis has also confirmed that the risk of the development of grade III radiation-induced mucositis increases (P = 0.008) with a high serum IgG concentration before the treatment or with an increase in this index during therapy (RO 1.13; 95% RI 1.03-1.09) for every 1 mg/mL (when standardized by other risk factors). It was determined that when standardizing according to other factors (gender, IgG level), the risk of the development of grade III radiation-induced mucositis in the use of the immune agent alpha/beta defensins in a total dose of 40 mg per course decreases (P < 0.001; RO 0.08; 95% RI 0.02-0.27) compared to patients with oral cavity and oropharynx cancer who were not treated with immunotherapy. The risk of the development of grade III radiation-induced mucositis also decreases (P = 0.001) in the use of immunotherapy in a higher dose, i.e. 60 mg per course (RO 0.03; 95% RI 0.004-0.24 compared to patients whose treatment did not include immunotherapy (when standardized by other factors).
CONCLUSIONS: As a result of this controlled clinical study, some factors were determined in addition to the radiation as those affecting the risk of the development of grade III radiation-induced mucositis in patients with oral cavity and oropharynx cancer during special treatment. These factors comprise the inclusion of immunotherapy with alpha/beta defensins into the specific treatment; gender, and baseline levels of serum IgG and IgA concentrations suggest a pattern in which the higher the serum IgG and IgA concentrations are before the start of the treatment, the greater is the likelihood of severe radiation-induced mucositis degree during special therapy. The results of the study of humoral state of the immune system in patients with oral cavity and oropharynx cancer before the beginning of chemoradiation therapy can be used as prognostic risk factors for the development of severe gamma-irradiation-induced mucositis of the oropharyngeal area, as well as an indication for the use of immunotherapeutic agents (in particular, alpha/beta defensins) that are able to polarize the immune response towards type 1 T-helpers through their immunomodulatory action.
摘要：
背景：今天，已经开发了许多预防和治疗辐射引起的口腔和口咽部粘膜炎的方法和途径，但是代表的方法仍然不够有效。因此,为了提高预防和治疗辐射引起的粘膜炎的有效性，有必要全面和单独地解决这个问题，并评估影响黏膜炎发展的因素。
方法：在这项单中心前瞻性对照非随机临床试验中，分析了105例新诊断的口腔和口咽鳞状细胞癌患者放疗和放化疗并发症的临床观察结果。影响III级放射性粘膜炎发展风险的因素，包括年龄，患者的性别,根据世界卫生组织的标准，他们在治疗前的一般状况，治疗类型及其剂量，额外使用α/β防御素的免疫疗法，分析了治疗前患者的肿瘤过程特征和免疫状态的所有指标。
结果：单因素logistic回归模型的构建和分析方法，其中24个指数作为阶乘特征分析，表明，降低III级辐射诱导的粘膜炎的发展的风险是由几个因素预测：免疫疗法，性别,IgG和IgA的血清浓度。如果将α/β防御素（总剂量为40mg）的免疫疗法纳入治疗方案（相对赔率（RO）0.05;95％参考区间（RI）0.02-0.18），则显示出III级放射诱发的粘膜炎的风险降低（P＆lt;0.001），与不存在或使用总剂量为60mg（P=0.001，RO0.06；95％RI0.01-0.30）的患者相比。下一个阶乘符号是性别，即与女性相比,男性发生III级放射性粘膜炎的风险较低(P=0.003;RO0.15;95%RI0.04-0.53).随着IgG血清浓度初始水平的增加，III级辐射诱导的粘膜炎的发展风险增加（P=0.024）。（RO1.08；95%RI1.01-1.16），每1mg/mL，以及在开始治疗之前，随着血清IgA浓度（RO1.23;95％RI1.01-1.50）的增加，出现III级放射性粘膜炎的可能性增加（P=0.044）。多因素分析还证实，随着治疗前血清IgG浓度升高或治疗期间该指数增加（RO1.13;95％RI1.03-1.09），发生III级放射性粘膜炎的风险增加（P=0.008）每1mg/mL（按其他风险因素标准化时）。确定在根据其他因素(性别、IgG水平),与未接受免疫疗法治疗的口腔癌和口咽癌患者相比,每疗程总剂量为40mg的免疫剂α/β防御素发生III级放射诱发的粘膜炎的风险降低(P<0.001;RO0.08;95%RI0.02-0.27).在使用较高剂量的免疫疗法时，发生III级辐射诱发的粘膜炎的风险也降低（P=0.001），即每疗程60mg(RO0.03;95%RI0.004-0.24与治疗不包括免疫治疗的患者相比(当通过其他因素标准化时)。
结论：作为这项对照临床研究的结果，除放疗外,我们还确定了一些影响特殊治疗期间口腔癌和口咽癌患者发生III级放射性黏膜炎风险的因素.这些因素包括将α/β防御素免疫疗法纳入特定治疗；性别，血清IgG和IgA浓度的基线水平表明，在治疗开始之前血清IgG和IgA浓度越高，在特殊治疗期间发生严重放射性粘膜炎程度的可能性更大。在开始放化疗之前，对口腔和口咽癌患者的免疫系统的体液状态进行研究的结果可作为严重的γ射线辐射引起的口咽区粘膜炎发展的预后危险因素，以及使用免疫治疗剂的适应症(特别是，α/β防御素）能够通过其免疫调节作用使1型T辅助者的免疫应答极化。
方法：在这项单中心前瞻性对照非随机临床试验中，分析了105例新诊断的口腔和口咽鳞状细胞癌患者放疗和放化疗并发症的临床观察结果。影响III级放射性粘膜炎发展风险的因素，包括年龄，患者的性别,根据世界卫生组织的标准，他们在治疗前的一般状况，治疗类型及其剂量，额外使用α/β防御素的免疫疗法，分析了治疗前患者的肿瘤过程特征和免疫状态的所有指标。
结果：单因素logistic回归模型的构建和分析方法，其中24个指数作为阶乘特征分析，表明，降低III级辐射诱导的粘膜炎的发展的风险是由几个因素预测：免疫疗法，性别,IgG和IgA的血清浓度。如果将α/β防御素（总剂量为40mg）的免疫疗法纳入治疗方案（相对赔率（RO）0.05;95％参考区间（RI）0.02-0.18），则显示出III级放射诱发的粘膜炎的风险降低（P＆lt;0.001），与不存在或使用总剂量为60mg（P=0.001，RO0.06；95％RI0.01-0.30）的患者相比。下一个阶乘符号是性别，即与女性相比,男性发生III级放射性粘膜炎的风险较低(P=0.003;RO0.15;95%RI0.04-0.53).随着IgG血清浓度初始水平的增加，III级辐射诱导的粘膜炎的发展风险增加（P=0.024）。（RO1.08；95%RI1.01-1.16），每1mg/mL，以及在开始治疗之前，随着血清IgA浓度（RO1.23;95％RI1.01-1.50）的增加，出现III级放射性粘膜炎的可能性增加（P=0.044）。多因素分析还证实，随着治疗前血清IgG浓度升高或治疗期间该指数增加（RO1.13;95％RI1.03-1.09），发生III级放射性粘膜炎的风险增加（P=0.008）每1mg/mL（按其他风险因素标准化时）。确定在根据其他因素(性别、IgG水平),与未接受免疫疗法治疗的口腔癌和口咽癌患者相比,每疗程总剂量为40mg的免疫剂α/β防御素发生III级放射诱发的粘膜炎的风险降低(P<0.001;RO0.08;95%RI0.02-0.27).在使用较高剂量的免疫疗法时，发生III级辐射诱发的粘膜炎的风险也降低（P=0.001），即每疗程60mg(RO0.03;95%RI0.004-0.24与治疗不包括免疫治疗的患者相比(当通过其他因素标准化时)。
结论：作为这项对照临床研究的结果，除放疗外,我们还确定了一些影响特殊治疗期间口腔癌和口咽癌患者发生III级放射性黏膜炎风险的因素.这些因素包括将α/β防御素免疫疗法纳入特定治疗；性别，血清IgG和IgA浓度的基线水平表明，在治疗开始之前血清IgG和IgA浓度越高，在特殊治疗期间发生严重放射性粘膜炎程度的可能性更大。在开始放化疗之前，对口腔和口咽癌患者的免疫系统的体液状态进行研究的结果可作为严重的γ射线辐射引起的口咽区粘膜炎发展的预后危险因素，以及使用免疫治疗剂的适应症(特别是，α/β防御素）能够通过其免疫调节作用使1型T辅助者的免疫应答极化。
