Eval of Efficacy and Mechs of Anti-inflammatory Interven

口腔炎的定义是口腔和口咽粘膜的炎症，以组织红斑、水肿和萎缩为特征，通常进展为溃疡。口腔炎是一种生物学上复杂的、多因素的、与治疗相关的口腔疾病，许多肿瘤患者都会经历这种情况，它通常会导致一连串的负面后遗症，包括口咽部疼痛、严重的治疗改变或停止治疗，以及生活质量下降。口腔炎的最佳治疗策略尚未确定。在随机对照临床试验中，迫切需要使用有效和可靠的口腔炎评估工具来检查口腔炎和相关急性口咽痛的发病机制并评估干预措施，以促进癌症治疗相关口腔毒性的科学研究，并改善患者护理。因此，这项随机对照临床试验的目的是通过测试一种新型的肿瘤坏死因子(TNF)融合蛋白etanercept(Enbrel？，免疫公司，西雅图，华盛顿州)对口腔炎的发病率和严重程度的影响来阐明炎症在口腔炎中的作用。这种融合蛋白特异性地与肿瘤坏死因子结合，阻止其与细胞受体的相互作用，并改变炎症级联反应，可能有助于深入了解炎症在口腔炎中的作用。依那西普效应被定义为预防或改善口腔炎和急性口咽疼痛和/或组织介质水平的变化。如果口腔炎主要是粘膜炎症反应的结果，那么我们假设这种口腔疾病将对肿瘤坏死因子-α的结合产生反应。阐明与口腔炎相关的炎症细胞信号转导的作用和肿瘤坏死因子-α的作用，可能会阐明口腔炎的发病机制和其他粘膜状况。 计划接受口腔化疗和自体造血干细胞移植(HSCT)的患者，年龄在16岁或以上，将被邀请参加这项研究，他们将在国家牙科和颅面研究牙科诊所定期安排的治疗前访问期间参与这项研究，或通过位于南卡罗来纳州格林维尔癌症中心的国家癌症研究所赞助的社区临床肿瘤学计划的既定招募战略参与这项研究。将获得所有参与者的书面知情同意。患者将随机接受依那西普漱口水或安慰剂，这两种药物都将按协议时间表给药。口腔炎和口咽疼痛将在基线和特定的化疗后时间点进行测量，这些时间点与预测的口腔炎发病、高峰和愈合时间进程相对应。通过实时聚合酶链式反应技术分析口腔黏膜中的肿瘤坏死因子-α水平，并在基线和特定的化疗后时间点测量促炎症细胞因子、生长因子和炎症介质的血液水平，这些时间点与预测的口腔炎发病、高峰和愈合时间进程相对应。NINR数据和安全监测委员会已经批准了数据和安全监测计划。 这项干预研究的初步研究旨在评估计划中的实验室技术在该人群中检测唾液、血浆和口腔粘膜中的肿瘤坏死因子-α的适宜性，并评估成年HSCT患者的口咽部疼痛。使用口腔粘膜炎评定量表和PainmeterO评估CT前后口咽部疼痛的当前总强度、24小时内最差强度、感觉和情感维度。用双抗体夹心法测定唾液和血浆中的肿瘤坏死因子-α浓度，用定量聚合酶链式反应测定口腔粘膜中的肿瘤坏死因子-α浓度。男性和女性受试者(N=24)，平均年龄46岁，主要是高加索人，被诊断为晚期癌症，接受了五种HCT方案之一。CT后发生口腔炎18例，平均5.26例，红斑17例，溃疡9例。受试者(n=9)主要报告持续的、轻微的总体口腔疼痛(平均值=1.4)，吞咽时疼痛程度较高(平均值=2.38；范围=0至10)。口腔炎的严重程度与口腔疼痛总强度(p&lt；.05)、最差强度(p&lt；.001)、口腔疼痛总强度和吞咽最差强度(p&lt；.001)呈显著正相关。吞咽疼痛的感觉描述包括灼热和尖锐(23%)；情感描述令人讨厌(2%)和痛苦(18%)。溃疡与感觉性疼痛呈显著正相关(p&lt；0.05)。CT后唾液中高水平的肿瘤坏死因子-α与未升高的血浆肿瘤坏死因子-α水平相比(EL ISA；明尼苏达州明尼阿波利斯的R&D系统公司)提示口腔炎的局部炎症病因。口腔刷检标本用TRIzol(tri-O)(46例)和RLT-TRIzol(RLT-tri)(24例)处理。实时定量聚合酶链式反应，使用完全对照和参考质粒，在RLT-TRI组中，人肿瘤坏死因子-α的表达低于检测阈值。配对的tri-O样本的mRNA拷贝数在10^2~10^4之间，提示tri-O是口腔RNA的首选方法。颊粘膜肿瘤坏死因子-α的表达范围为42~15300拷贝。14名受试者在CT扫描后通过tri-O法可测量到肿瘤坏死因子-α的表达增加。肿瘤坏死因子-α浓度与疼痛维度呈显著正相关：总强度(p&lt；.05)；最差强度(p&lt；.01)；总体(p&lt；.05)和最差吞咽强度(p&lt；.01)。一种独特、灵敏的口腔刷牙基因表达检测方法的有效性被证明。这些数据证明了分子技术在这项临床试验中的适用性。

Stomatitis is defined as inflammation of the mucous membranes of the oral cavity and oropharynx characterized by tissue erythema, edema, and atrophy, often progressing to ulceration. Stomatitis is a biologically complex, multifactorial, treatment-related oral condition experienced by many oncology patients, which often leads to a cascade of negative sequelae including oropharyngeal pain, critical treatment alterations or cessation, and decreased quality of life. The optimal treatment strategies for stomatitis have not been established. There is a critical need to examine the pathogenesis of and to evaluate interventions for stomatitis and related acute oropharyngeal pain in the randomized controlled clinical trial setting using valid and reliable stomatitis assessment tools to both advance the science of cancer treatment-related oral toxicities and improve patient care. Therefore, the purpose of this randomized controlled clinical trial is to elucidate the role of inflammation in stomatitis by testing the effects of a novel tumor necrosis factor (TNF) fusion protein etanercept, (Enbrel ?, Immunex Corporation, Seattle, WA) on the incidence and severity of stomatitis. The actions of this fusion protein, which binds specifically to TNF preventing its interaction with cellular receptors and altering the inflammatory cascade, may provide insight into the role of inflammation in stomatitis. An etanercept effect is defined as a prevention or amelioration of stomatitis and acute oropharyngeal pain and/or changes in levels of tissue mediators. If stomatitis is primarily a consequence of a mucosal inflammatory response, then we hypothesize that this oral condition will be responsive to binding of TNF-alpha. Elaboration of the role of inflammatory cell signalling associated with stomatitis and the effect of TNF-alpha may elucidate the mechanisms related to the pathogenesis of stomatitis and to other mucosal conditions. Patients who are scheduled to receive stomatogenic chemotherapy with autologous hematopoietic stem cell transplantation (HSCT), ages 16 years or older, will be invited to participate in this study during a regularly scheduled pre-treatment visit in the National Institute of Dental and Craniofacial Research Dental Clinic, or through established recruitment strategies at a National Cancer Institute sponsored Community Clinical Oncology Program located at the Cancer Centers of the Carolinas, Greenville, SC. Written informed consent will be obtained from all participants. Patients will be randomized to receive either etanercept mouthwash or placebo, which will both be administered by protocol schedule. Stomatitis and oropharyngeal pain will be measured at baseline and at specified post-chemotherapy time points corresponding with the predicted stomatitis onset, peak, and healing time course. TNF-alpha levels in buccal mucosa, analyzed by real time polymerase chain reaction techniques, and blood levels of pro-inflammatory cytokines, growth factors, and inflammatory mediators will also be measured at baseline and at specified post-chemotherapy time points corresponding with the predicted stomatitis onset, peak, and healing time course. The data and safety monitoring plan has been approved by the NINR Data and Safety Monitoring Board. The pilot study for this intervention study was designed to assess appropriateness of planned laboratory techniques to measure TNF-alpha in saliva, plasma, and buccal mucosa in this population, and to assess oropharyngeal pain in adult HSCT patients. Present overall intensity, worst intensity within 24 hours, sensory, and affective dimensions of oropharyngeal pain were assessed pre/post CT using the Oral Mucositis Assessment Scale and PainometerO. TNF-alpha concentrations were measured in saliva and plasma using ELISA, and in buccal mucosa using QPCR. Male and female subjects (N = 24), mean age 46 years, primarily Caucasian, with late stage cancer diagnoses, received one of five HCT protocols. Post-CT stomatitis was observed in 18 subjects (mean = 5.26); erythema (n=17) and ulcerations (n = 9). Subjects (n = 9) reported primarily continuous, mild overall intensity of oral pain (mean = 1.4), and higher pain levels on swallowing (n = 10) (mean = 2.38; range = 0 to 10). Stomatitis severity significantly positively correlated with oral pain overall intensity (p < .05), worst intensity (p < .001), and oral pain overall intensity and worst intensity with swallowing (p < .001). Pain with swallowing sensory descriptors included burning and sharp (23%); affective descriptors were annoying (2%), and miserable (18%). Ulceration significantly positively correlated with sensory pain (p < .05). Elevated post-CT salivary TNF-alpha concentrations compared with non-elevated plasma TNF-alpha levels (ELISA; R & D Systems, Inc., Minneapolis, MN) suggest a local inflammatory etiology of stomatitis. Buccal brush biopsy samples were processed by TRIzol only (TRI-O) (N = 46), and RLT-TRIzol (RLT-TRI) (N = 24). Real time PCR, employing complete controls and reference plasmids, for human TNF-alpha showed expression below detection threshold in the RLT-TRI group. Matched TRI-O samples showed mRNA copy numbers of 10^2 to 10^4, suggesting that TRI-O is the preferred method for buccal RNA. Buccal mucosa TNF-alpha expression ranged from 42 to 15300 copies. Fourteen subjects had measurable increases in TNF-alpha expression post CT via TRI-O method. Significant positive correlations were seen between TNF-alpha concentrations and pain dimensions: overall intensity (p < .05); worst intensity (p < .01); and overall (p < .05) and worst intensity with swallowing (p < .01).Validity of a unique, sensitive assay for gene expression from buccal brushing was demonstrated. These data demonstrate appropriateness of molecular techniques for this clinical trial.