基于ClinicalTrials.gov剖析我国口腔癌临床注册研究困境及对策

口腔癌是最常见的头颈部恶性肿瘤,多年来,我国在口腔癌诊治研究领域积累了大量宝贵经验,为口腔癌诊治进步做出很大贡献,但循证医学最佳证据主要参考随机对照试验为主的注册研究结论,中国临床注册研究与国外相比开展仍不普遍.我国人口基数大,口腔癌患者绝对数量多,但对临床及转化医学研究普遍重视不足,造成大量珍贵病例资料流失,难以获得有说服力的循证医学证据.当前,开展口腔癌的前瞻性注册研究是我国科研成果和临床经验获得国际公认的前提,然而我国口腔癌临床注册研究起步晚,实际开展过程中容易遇到瓶颈问题.本文拟通过美国临床试验注册平台ClinicalTrials.gov,分析口腔癌临床注册研究现状、存在问题及对策.     

口腔专业临床试验机构备案现状的分析

随着临床试验机构备案制的实施,口腔专业临床试验机构得到了进一步发展,释放了更多临床资源服务于临床试验。本文通过对口腔专业备案机构数量、备案区域、备案亚专业、备案主要研究者等进行分析,发现目前存在备案机构地域分布不均衡、主要研究者资质不符、口腔相关药物/医疗器械研发动力不足等问题。针对这些问题剖析原因并提出相应的探索性改进建议,意在推动口腔专业临床试验的发展和整体研究及管理水平的提高。     

心理干预对头颈部恶性肿瘤患者负性情绪及生活质量影响的meta分析

目的: 系统分析和评价心理干预对头颈部恶性肿瘤(HNC)患者负性情绪及生活质量的影响,为开展HNC心理干预提供依据。方法: 计算机检索PubMed、Central、Embase、clinicaltrials.gov、ICTRP、Web of Science、CBM、CNKI、VIP、万方等网站有关HNC患者心理干预的随机对照临床试验(RCT)。检索时间从数据库建立到2021年5月15日,经过筛选、质量评价和数据提取,采用RevMan 5.4软件进行meta分析。结果: 最终纳入RCT 18项,包括2 097例受试者。与对照组常规护理相比,试验组加入心理干预降低了HNC患者的焦虑评分[SMD=-2.33,95%CI（-2.96,-1.70）,P<0.000 01]、抑郁评分[SMD=-2.26,95%CI（-2.78,-1.74）,P<0.000 01],生活质量评分提高[SMD=6.04,95%CI（1.53,10.56）,P=0.009]及症状自评量表评分[MD=29.99,95%CI（-36.22,-23.76）,P<0.000 01]提高。结论: 心理干预能有效缓解HNC患者的焦虑、抑郁情绪,促进HNC患者的心理健康和生活质量。但受纳入RCT质量的限制,需要更多设计严谨、方法学质量较高的研究进行验证。     

口腔专业人员开展临床研究的现状调查与分析

目的: 了解口腔专业人员对临床研究的知识、态度、行为及临床研究培训的需求,探讨影响临床研究知识水平的相关因素。方法: 采用自行设计的问卷,对国家口腔疾病临床研究中心（上海交通大学医学院附属第九人民医院）及其协同创新网络成员单位的口腔专业人员进行在线调查,内容包括调查对象的基本情况,对临床研究的知识、态度、行为及培训需求。采用SAS 9.4软件包对数据进行统计学分析。结果: 281名口腔专业人员参与调查,大部分调查对象对临床研究持积极态度,80%的调查对象曾经有开展临床研究的想法,但最终实施者较少（22.8%）。制约口腔专业人员开展临床研究的三大主要原因为时间少（68.3%）、团队不足（63.7%）及缺少经费支持（60.9%）。调查对象临床研究知识平均分为（13.72±7.20）分（总分38分）,经多元线性回归,医院类型、近5年主持或参与临床研究情况、近1次项目是否有流行病或统计学专家参与是调查对象知识水平高低的相关因素。结论: 口腔专业人员对临床研究态度积极,但行为与知识水平较为薄弱。加强临床研究的顶层设计离不开临床医师临床研究能力的培养。国家临床医学研究中心应发挥“国家队”使命,加快建立专业化、常态化、规模化的临床研究培训模式,为协同创新网络单位提供培训机会。     

口腔黏膜黑色素瘤人源性移植瘤模型的建立及鉴定

目的 建立和鉴定口腔黏膜黑色素瘤（oral mucosal melanoma,OMM）人源性移植瘤（patient-derived xenograft,PDX）模型。方法 将4例原发性口腔黏膜黑色素瘤组织移植于免疫缺陷裸鼠皮下,观察并记录裸鼠成瘤情况,待移植瘤稳定生长后进行传代;利用H-E染色观察原发瘤和移植瘤的组织病理学特征,应用免疫组织化学染色检测黑色素瘤标志物HMB-45、Melan-A、S-100及Ki-67在两者组织的表达水平。结果 4例口腔黏膜黑色素瘤组织皮下移植成功并序列传代;H-E和免疫组织化学染色显示,移植瘤在组织病理形态和4个标志物表达情况上与原发瘤保持一致。结论 本研究成功建立4例口腔黏膜黑色素瘤人源性移植瘤模型,传代移植瘤保留了原发瘤的组织病理学和分子特征,可为口腔黏膜黑色素瘤研究提供理想的临床前动物模型。     

阿西替尼对人口腔黏膜黑色素瘤裸鼠移植瘤血管生成拟态的作用探讨

目的:探讨阿西替尼用于口腔黏膜黑色素瘤(oral mucosal melanoma, OMM）治疗的可行性。方法:取病理确诊的口腔黏膜黑色素瘤标本,构建病人源性小鼠移植瘤（patient-derived xenografts,PDX）模型。将PDX动物模型随机分为2组,分别给予阿西替尼和羧甲基纤维素钠处理,用药周期28 d。应用免疫组织化学染色和过碘酸雪夫反应双染法,检测各组肿瘤的血管拟态(vasculogenic mimicry,VM)、EphA2、MMP-2及HIF-1a等蛋白的表达。采用SPSS 23.0软件包对数据进行统计学分析。结果:与空白对照组相比,阿西替尼显著抑制肿瘤生长,VM数量、CD34⁺血管数量、EphA2及MMP-2蛋白表达水平显著降低;HIF-1a表达显著高于对照组。结论:阿西替尼对人口腔黏膜黑色素瘤小鼠具有较好的肿瘤生长抑制作用,主要机制可能为抗血管新生和VM形成。     

牙周炎和院内获得性肺炎之间的关联:观察性研究的系统评价和荟萃分析

目的:评估重症监护病房（ICU）患者的牙周炎与院内获得性肺炎之间的关联。材料和方法:本研究依据系统评价和荟萃分析的首选报告项目（PRISMA）的指南进行，并已在PROSPERO（国际前瞻性系统评价注册，英国约克大学）注册，注册号为CRD42018105124。本研究在五个数据库中进行了搜索，没有语言或出版日期的限制。在检索的560项研究中，对10篇进行了全文分析，其中五项病例对照研究符合条件，纳入荟萃分析。荟萃分析结果通过敏感性分析和异质性检验进行评价。通过比值比（OR）和95％置信区间计算简要效果量度。结果:在荟萃分析中，牙周炎与院内获得性肺炎之间存在显著相关性（OR 2.55，95％CI:1.68-3.86）。在此荟萃分析中，I2=0％。结论:证据表明牙周炎与院内获得性肺炎之间呈正相关。与没有牙周炎的患者相比，入住ICU的牙周炎患者更容易出现院内获得性肺炎。     

导航辅助射频温控热凝术中注册标记系统的改良

目的：改进导航辅助射频温控热凝术中的注册标记系统,使其更加无创,同时达到导航系统的精确要求。方法：采用热塑型塑料面罩,依照人体面部特征加热塑型,表面双侧颞部、眉弓中点和颧骨最高点安置6个塑料标记点．内部随意安置6个标记点。CT扫描获得影像学数据,输入SurgView—RFT电磁导航系统后,分别选用4个（内外各2个）、6个（内外各3个）和8个（内外各4个）标记点进行注册和配准,每组设置5种组合,每点读取3次坐标值,取平均值代入配准误差公式。采用SAS6．12软件包对数据进行t检验。结果：取4个标记点时．系统误差为f1．58_±0．25）mm;取6个标记点时,系统误差为（1．28±0．21）mm;当标记点数量达到8个时,导航系统的配准精度达（1．06±0．10）mm。4点组与6点组间有显著差异（P=0．0149）,6点组与8点组间无显著差异（P=0.1402）。结论：热塑型塑料面罩表面放置标记点可避免患者创伤,配准精度完全符合导航系统的要求和卯圆孔穿刺的特定要求,在应用中至少应有6个标记点。     

病人源性头颈部黏膜恶性黑色素瘤细胞模型的构建及鉴定

目的：构建及鉴定头颈部黏膜恶性黑色素瘤（mucosal melanoma of head and neck, HNMM）病人源性肿瘤细胞（patient derived tumor cell, PDC）模型。方法：通过肿瘤组织块原代培养、分离肿瘤细胞,利用免疫荧光染色鉴定分离的肿瘤细胞;以PDC皮下成瘤,通过组织切片染色和免疫组织化学染色对比病人原发灶和PDC成瘤组织的细胞学形态。结果：头颈黏膜恶性黑色素瘤患者移植瘤组织块分离出的细胞细胞膜和细胞质HMB-45和Melan-A免疫荧光染色呈阳性。PDC可以在裸鼠皮下成瘤,成瘤组织与患者组织细胞形态一致。结论：头颈部黏膜恶性黑色素瘤构建的PDC模型能够反映患者的组织学特征,PDC模型能够为头颈部黏膜恶性黑色素瘤的研究提供可靠的模型。     

中国人口腔黏膜黑色素瘤临床诊治专家共识

头颈黏膜黑色素瘤（HNMM）是一类高度恶性的实体肿瘤,5年生存率长期徘徊在20%左右,其致病因素、驱动基因、临床表现及治疗手段等与皮肤黑色素瘤差异较大。2015年,国内首个头颈黏膜黑色素瘤诊治专家共识建立,经过6年多的推广应用, HNMM临床诊治规范性有了很大提高。随着黏膜黑色素瘤临床与基础研究的不断深入,HNMM的诊治与预后在近些年发生了较大变化,特别是头颈部各分支学科的蓬勃发展,口腔、鼻腔鼻窦、眼部等黏膜黑色素瘤各自发展出独特的诊治模式,该共识已不能满足当前临床的实际需求。对此,专家组认为头颈部黏膜包含的解剖范围较广,涉及的临床科室较多,不同学科之间黑色素瘤诊疗模式差异明显,临床亟须符合个体化治疗及精准治疗的更加专科化的诊治共识。为了进一步提高口腔黏膜黑色素瘤（OMM）的远期生存率和生存质量,让共识更好地指导临床工作,专家组聚焦 OMM,深入讨论,基于循证医学证据和经验医学,完成专家共识的制定。考虑到患者的个体化差异,本共识可作为OMM临床实践的参考。     

Clinical studies in orthodontics An overview of NIDR-sponsored clinical orthodontic studies in the US

A number of clinical trials sponsored by the National Institutes of Health (NIH) use rigorous methods of data acquisition and analysis previously developed in fundamental biology and the physical sciences. The naive expectation that these trials would lead relatively rapidly to definitive answers concerning the therapeutic strategies and techniques under study is dispelled. This presentation focuses on delineating differences between the study of central tendencies and individual variation, more specifically on the strategy to study this variation: measure additional sources of variance within each patient at more timepoints and perhaps with greater precision. As rigorous orthodontic research is still in its infancy, the problem of defining the proper mix between prospective and retrospective trials is discussed. In view of the high costs of prospective clinical trials, many of the questions germane to orthodontics can be answered by well-conducted retrospective trials, assuming that properly randomized sampling procedures are employed. Definitive clinical trials are likely to require better theoretical constructs, better instrumentation, and better measures than now available. Reasons for concern are the restricted resources available and the fact that current mensurational approaches may not detect many of the individual differences. The task of constructing sharable databases and record bases stored in digital form and available either remotely from servers, or locally from CD-ROMs or optical disks, is crucial to the optimization of future investigations.     

Clinical studies in orthodontics--an overview of NIDR-sponsored clinical orthodontic studies in the US.

A number of clinical trials sponsored by the National Institutes of Health (NIH) use rigorous methods of data acquisition and analysis previously developed in fundamental biology and the physical sciences. The naive expectation that these trials would lead relatively rapidly to definitive answers concerning the therapeutic strategies and techniques under study is dispelled. This presentation focuses on delineating differences between the study of central tendencies and individual variation, more specifically on the strategy to study this variation: measure additional sources of variance within each patient at more timepoints and perhaps with greater precision. As rigorous orthodontic research is still in its infancy, the problem of defining the proper mix between prospective and retrospective trials is discussed. In view of the high costs of prospective clinical trials, many of the questions germane to orthodontics can be answered by well-conducted retrospective trials, assuming that properly randomized sampling procedures are employed. Definitive clinical trials are likely to require better theoretical constructs, better instrumentation, and better measures than now available. Reasons for concern are the restricted resources available and the fact that current mensurational approaches may not detect many of the individual differences. The task of constructing sharable databases and record bases stored in digital form and available either remotely from servers, or locally from CD-ROMs or optical disks, is crucial to the optimization of future investigations.     

氯诺昔康控制智牙拔除术后疼痛的系统评价

目的：评价氯诺昔康在智牙拔除术后疼痛控制中的效果及安全性。方法：计算机检索Medline（Ovid,1950-2010.7）、CENTRAL（2010年第7期）、EMBASE（1980-2010.7）、WHOICTRP（至2010.7）及CBM（1978-2010.7）并手工检索17种中文口腔医学杂志,按照纳入和排除标准选择相关研究,提取数据,进行质量评价,采用Revman5.0予以Meta分析。结果：共纳入6篇文献。将其中4个关于氯诺昔康与安慰剂比较的研究进行Meta分析。结果显示,4mg、8mg、16mg氯诺昔康在最大疼痛缓解程度方面均好于安慰剂（P〈0.05）,患者对8mg、16mg氯诺昔康的总体评价优于安慰剂（P〈0.05）,2个剂量组（除4mg组外）的不良反应与安慰剂组相比均无显著差异。疼痛缓解方面,8mg的氯诺昔康优于布洛芬（P=0.004）和10mg与20mg的硫酸吗啡（P=0.002,P=0.001）,但较酮咯酸和阿司匹林并无明显优势;其不良反应与其余NSAIDs比较无显著差异,但优于10mg与20mg的硫酸吗啡（P〈0.05）。结论：目前有限的证据表明,氯诺昔康可作为智牙拔除术后安全有效的镇痛药物。     

Dental education in the developing countries and the role of WHO.

The present picture of Dental Manpower in the world is reviewed. The Dentist/Population ratio in 1972 in each of the WHO regions was as follows: African Region 1:96,391, American Region 1:2892, Eastern Mediterranean Region 1:26,188, European Region 1:2948, South East Asia Region 1:81,606, Western Pacific Region 1:4533. There was wide variation of this ratio between individual countries within each region. The present approach to the dental education of all types of dental personnel in the developing countries is described. The activity of WHO in organizing seminars and conference on the needs of the regions in relation to types of dental personnel and their training is discussed. Attention is drawn to the strong recommendation of WHO to plan the dental health manpower training in close conformity with a country's Oral Health needs. The importance of integration of the training programmes for the various categories of dental personnel is stressed.     

口腔粘膜原发恶性黑色素瘤的临床病理学研究

目的　研究口腔粘膜原发恶性黑色素瘤的临床病理特点及其与预后的关系。方法　采用回顾性分析的方法对73例口腔粘膜原发恶性黑色素瘤进行了临床病理学研究并对有随访资料的患者进行Kaplan-meier生存曲线及Log rank检验的统计学分析。结果　口腔粘膜原发恶性黑色素瘤多发于40~60岁的男性,腭部和牙龈多见。临床分期以I期最多;病理分型中结节型多见,其次是雀斑样型和表浅扩散型;按细胞形态分型以混合细胞型最为多见,其次是上皮样细胞型和梭形细胞型。有随访资料的43例患者3年生存率为19·86%,5年生存率为11·91%;淋巴结转移、浸润深度、临床分期、病理分型和治疗方法与预后有关(P<0·05)。黑斑与病理分型有关(P<0·05),黑斑多见于雀斑样型口腔粘膜原发恶性黑色素瘤,且预后较好。结论　口腔粘膜恶性黑色素瘤是一种预后差的恶性肿瘤;有无黑斑和淋巴结转移、浸润深度、临床分期、病理分型、治疗方法等与预后有关。     

Effect of reducing the number of items of the Oral Health Impact Profile on responsiveness, validity and reliability in edentulous populations

Abstract – Background: The 49‐item Oral Health Impact Profile (OHIP) has shown strong responsiveness, reliability and validity. However, the large number of items included may limit its use in clinical trials, clinical practice and surveys. Objective: The main objective of this study is to assess the effect of reducing the number of items in each domain, one at a time, on responsiveness, reliability and validity of the OHIP in edentulous populations. Materials and methods: Data used in this study were obtained from two randomized clinical trials comparing mandibular implant overdentures and conventional dentures among 102 subjects between 35 and 65 years of age, and 60 subjects over the age of 65 years. Participants were edentulous individuals who wished to replace their current prostheses. Subjects in both trials were asked to complete the 49‐item OHIP prior to treatment and at 2 months post‐treatment. Within the study, effect sizes were computed at each stage of item reduction using the impact method. Intraclass correlation coefficients and Pearson's correlation coefficients were also assessed at each stage of item reduction. In addition, receiver‐operating characteristic (ROC) curves were used to indicate the accuracy with which measurement changes corresponded to judgements of important changes in Oral Health Related Quality of Life (OHRQL). Results: The results indicated that, in general, domain responsiveness was not affected by the reduction of the number of items used per domain. However, there was a decrease in reliability, especially within the ‘psychological’ and ‘social’ disabilities and ‘handicap’ domains (35‐ to 65‐year group). In addition, there was a decrease in construct validity of the ‘physical pain’, ‘psychological’ and ‘social disabilities’ domains (35‐ to 65‐year group), as well as on ‘physical pain’, ‘psychological discomfort’, ‘physical’ and ‘psychological’ disabilities in the 65‐year and older group. This occurred primarily, when reducing from two to one item per domain. Among the 35‐ to 65‐year group, there were consistencies in patients’ ratings of the importance of similarly measured changes in oral health. Conclusion: The results indicate that although the 49‐item OHIP responsiveness could be maintained with item reduction, this will lead to compromises in reliability and validity.     

Quality assessment of randomised controlled trials in oral and maxillofacial surgery

Randomised controlled trials are the best way to study the evaluation of treatments. We have evaluated the quantity and quality of clinical trials in three of the main journals in the specialty of oral and maxillofacial surgery between January 2010 and December 2016, using a scientometric analysis, and evaluation by the Jadad scale. In this period, 303 randomised controlled trials (5% of the total) were identified; the largest number of studies were from Asia (45%) followed by Europe (32%). The subgroup that concerned most studies was oral surgery. The mean score on the Jadad scale was 3.06 points, which means that 32% of the total studies had a low risk of bias. Studies that declared funding and adherence to Consolidated Standards of Reporting Trials (CONSORT) were given significantly higher scores (p < 0.001) than studies that did not. We conclude that randomised controlled trials in oral maxillofacial surgery have evolved in both quality and quantity since previous surveys were published. The quality of trials was related to the presence of funding and adherence to CONSORT.     

Primary malignant melanoma of the oral mucosa.

PURPOSE: To present our experience on the epidemiology, clinical features, management, and survival of patients with oral malignant melanoma. PATIENTS AND METHODS: Records of patients with a histologic diagnosis of primary oral mucosal malignant melanoma seen over a 23-year period were retrospectively reviewed. RESULTS: There were 6 females and 2 males, ranging in age from 18 to 60 years; 4 cases in the maxilla, 2 in the mandible, 1 on the lower lip, and 1 on the buccal mucosa. Local recurrences developed in 2 patients who eventually died with clinical metastatic cervical nodal disease. Follow-up ranged from 6 months to 16 years 3 months. Surgery was the only treatment available. CONCLUSION: Primary oral mucosal melanoma is rare, with a 3 to 1 female to male ratio and an average age of 41.7 years at presentation. It is most common in the maxilla and has poor prognosis despite apparent adequate local surgical control.     

230例手术治疗的口腔黏膜恶性黑色素瘤患者预后的多因素分析

目的：探讨影响口腔黏膜恶性黑色素瘤患者生存率的因素.方法：单纯手术治疗的口腔黏膜恶性黑色素瘤患者230例,男141例,女89例.TNM分期：Ⅰ期,34例;Ⅱ期,87例;Ⅲ期,109例.采用Cox比例风险模型进行预后因素筛选,Kaplan-Meier法进行影响因素及生存率的分析.Log rank法比较不同生存分布的差异.结果：肿瘤厚度、淋巴结转移、肿瘤有无溃破及原发部位是影响生存率的相对独立因素,其P值与RR值依次分别为：P＜0.001、1.868,P＜0.001、1.685,P＜0.001、1.411,P=0.008、0.747.各因素不同水平间统计学差异明显.资料未显示年龄（P=0.136）、性别（P=0.721）及所用手术方法（P=0.944）对生存率有显著影响.结论：影响口腔黏膜恶性黑色素瘤的预后因素与皮肤部位发病者类似.各因素间无明显相互作用.单纯手术治疗并非最佳治疗措施.