Primary prophylactic human papillomavirus vaccination programs: future perspective on global impact

Of the 40 types of human papillomavirus that can infect the mucosal epithelium, four types can now be prevented using prophylactic vaccination. Two of these types (high-risk types 16 and 18) cause 70% of cervical cancers, a proportion of other genital cancers and a subset of head and neck cancers. The low-risk types 6 and 11 cause 90% of genital warts and the disease recurrent respiratory papillomatosis. Thus, if primary HPV vaccination programs can be implemented effectively, the potential for a reduction in global disease burden is great. This article considers the current issues and challenges in delivering primary HPV vaccination programs effectively and the likely impact of the vaccines in both the near and more distant future.     

Incidence and clinical management of oral human papillomavirus infection in men: a series of key short messages

Oral human papillomavirus (HPV) infections are less prevalent than genital and anal infections. However, the incidence of oropharyngeal squamous cell carcinomas has increased significantly over the last 2 decades in several countries. At least 90% of these cancers are associated with oncogenic type HPV16. Oral HPV infections are notably more frequent in men than in women, and the incidence of HPV-positive oropharyngeal squamous cell carcinomas has increased, predominantly among mid-adult men. Nevertheless, little is known about the progression of oral HPV infection to cancer, and it remains unclear which medical interventions should be applied to modify the natural history of the disease. This narrative review aimed at non-experts in HPV infection provides an update on oral HPV infection and its clinical management in men. Furthermore, using the cervix as a reference anatomical site, the lessons learned from investigations on cervical HPV infection are also addressed.     

Retrospective review of serum teicoplanin concentrations in clinical trials and their relationship to clinical outcome

Twenty-five published clinical studies were reviewed in which teicoplanin serum concentrations were determined. A variety of assay methods were used, including bioassay, solid phase enzyme receptor assay, HPLC and immunoassay, and in some studies, more than 1 methodology was used. Fourteen studies gave sufficient data on the method of assay, timing of assays relative to dosage or during therapy, and route of administration of teicoplanin to be included in a detailed pharmacokinetic analysis. Since a wide range of dosing regimens were employed, the studies were grouped in order to facilitate analysis according to the teicoplanin maintenance dose, either 200 mg, 400 mg or 6 mg/kg/day. Six studies used a dose of 200 mg/day and although the mean trough concentrations varied by as much as 3-fold, they did not exceed 10 mg/L in the first 7 days of therapy. Six studies used a 400 mg/day maintenance dose and the mean trough concentrations varied from 4 to 11 mg/L on days 1–2, to 9 to 17 mg/L on days 6–7 of therapy. In 5 of these studies, the mean trough concentration was less than 10 mg/L for the first 48 hours of treatment. In 2 studies where a dose of 6 mg/kg/day was used, the mean concentrations did not exceed 10 mg/L until day 7, while in the other study they were greater than 10 mg/L beginning on day 1. A retrospective analysis of 58 clinical cases reported in the literature, 42 of whom had staphylococcal infections, indicated that serum concentrations and teicoplanin concentration/MIC ratios were related to clinical cure particularly for patients with staphylococcal infections. Trough concentrations of greater than 10 mg/L were related to favorable outcomes when all 58 patients were analyzed and trough concentrations of greater than 20 mg/L were related to cure for those who had staphylococcal infections. While retrospective in nature, this review indicates that there is considerable variation in teicoplanin pharmacokinetics in the different patient groups, only some of which is related to differences in dosing, timing of blood collection for assay or assay methodology. In addition, these data suggest that pharmacokinetic parameters such as trough and postdose teicoplanin concentrations, and phamracodynamic factors such as serum concentration MIC ratios may be related to clinical outcome with teicoplanin therapy.     

Therapeutic vaccines in metastatic castration-resistant prostate cancer: principles in clinical trial design

Although docetaxel was approved for the treatment of metastatic castration-resistant prostate cancer in 2004, additional therapies are still required. Prostate cancer is often slow-growing and expresses many tumor-associated antigens, making it a feasible target for immunotherapy. Several therapeutic cancer vaccines have been developed for prostate cancer, including antigen-presenting-cell-based, vector-based, and whole tumor cell vaccines. Initial trials demonstrated that vaccine approaches have limited toxicity. Clinical trials of targeted biologic therapies have demonstrated that patient selection is vital, and there is preliminary evidence that clinical parameters can be used to encompass metastatic prostate cancer patients who will more probably respond to vaccine treatment. In addition to appropriate patient selection, a successful clinical trial must have an appropriate primary endpoint as well. Three randomized, ‘placebo’-controlled studies in metastatic castration-resistant prostate cancer have suggested a clinically significant survival advantage in spite of a lack of improvement in time to progression, implying that overall survival is the ideal endpoint for such trials. Careful examination of data from completed immunotherapy clinical trials in prostate cancer has identified appropriate patient populations and endpoints. Those principles need to be applied to future trial design to properly evaluate prostate cancer vaccines.     

重庆地区人乳头瘤病毒各亚型感染情况的临床分析

目的了解重庆地区人乳头瘤病毒(HPV)各亚型感染的分布情况,为重庆地区HPV分子流行病学研究提供依据。方法采用导流杂交技术,同时检测21种HPV亚型,其中高危型HPV 13种,低危型HPV 5种和中国人群常见型HPV 3种。结果 3 884例临床标本共检出阳性1 144例(29.45%,1 144/3 884),单一HPV亚型感染750例(19.31%,750/3 884),复合感染394例(10.14%,394/3 884),其中高危型HPV 515例(13.26%,515/3 884,不含复合感染);21种HPV亚型均被检出,其中HPV52、16、58、33、68是最常见的高危型;58例男性标本中检出31例(53.45%)阳性,主要为复合型和HPV6型。结论 HPV各亚型检测对于HPV感染的诊断、治疗及宫颈癌的早期干预和预防具有重要意义。     

临床试验与临床试验中心

临床试验指的是在人体进行的药物或其他干预措施的研究,其目的是确定试验用药品或其他干预措施的疗效与安全性。由于其对象是人,试验中不可避免地涉及社会、心理、伦理和可行性等复杂问题。世界各国已共同认识到必须推行规范化的临床试验,才能保证研究工作的客观、科学和高效。其核心问题就是:既要考虑到以人为对象的特殊性与复杂性,又要保证实验研究的科学性。根据临床科研设计的要求,临床试验应遵循随机化、设立对照、盲法、符合伦理道德等原则。中国临床试验存在的问题是:存在发表偏倚,中国的临床试验尤其是中医药领域的试验得不到国际承认,中国缺乏国际认可的临床试验中心,在随机临床试验的设计、进行、管理和监测、报告等方面存在问题,临床试验的技术方法与质量有待提高。中国循证医学中心正对以往的中文医学文献进行手工检索以建立临床试验数据库,为系统评价和卫生技术评估奠定基础。我国临床研究的水平尚有待提高,应尽可能采用随机对照实验或双盲设计,多中心、大规模的协作研究值得提倡。介绍临床试验的定义和特点、中国临床试验发展的历史、药物临床试验的分期、临床试验管理规范、临床试验研究存在的问题和注意事项等。还介绍了临床试验中心的定义、背景、目标与任务和提供的服务。     

Synthetic genes: a tool for identifying human papillomavirus genotypes by hybridization and polymerase chain reaction-based assays

Obtaining positive polymerase chain reaction (PCR) controls for human papillomavirus (HPV) diagnostic tests has been difficult because of prevalence variation in different geographic regions of each high-risk viral type. Overlapping oligonucleotides were designed for HPV-18, HPV-31, HPV-45, and HPV-58 type-specific (TS) sequences. Synthetic HPV viral genes were constructed by 2-step assembly PCR for accurately diagnosing TS HPV infection.     

Discovery of Therapeutic Approaches for Polyglutamine Diseases: A Summary of Recent Efforts

Polyglutamine (PolyQ) diseases are a group of neurodegenerative disorders caused by the expansion of cytosine–adenine–guanine (CAG) trinucleotide repeats in the coding region of specific genes. This leads to the production of pathogenic proteins containing critically expanded tracts of glutamines. Although polyQ diseases are individually rare, the fact that these nine diseases are irreversibly progressive over 10 to 30 years, severely impairing and ultimately fatal, usually implicating the full‐time patient support by a caregiver for long time periods, makes their economic and social impact quite significant. This has led several researchers worldwide to investigate the pathogenic mechanism(s) and therapeutic strategies for polyQ diseases. Although research in the field has grown notably in the last decades, we are still far from having an effective treatment to offer patients, and the decision of which compounds should be translated to the clinics may be very challenging. In this review, we provide a comprehensive and critical overview of the most recent drug discovery efforts in the field of polyQ diseases, including the most relevant findings emerging from two different types of approaches—hypothesis‐based candidate molecule testing and hypothesis‐free unbiased drug screenings. We hereby summarize and reflect on the preclinical studies as well as all the clinical trials performed to date, aiming to provide a useful framework for increasingly successful future drug discovery and development efforts.     

Toxoplasma vaccines: appropriate end points and sample size in future human clinical trials

Rabies remains a serious endemic disease in animal populations in many European countries. Oral vaccination by use of rabies vaccine baits has proved to be durably efficient for controlling and eliminating terrestrial rabies. However, the recurrence of rabies in some countries highlights the fragility of rabies-free country status and the need for continuous surveillance. In Eastern and Southern countries, the rabies control programmes for foxes should be accompanied by stray dog management measures in view of the high populations of strays in certain areas. Alerts of rabies in pets imported from enzootic countries are regularly reported in Europe, threatening the rabies-free status of terrestrial animals. New variants of rabies virus have been recently discovered in autochthonous bats, implying research studies to assess the efficacy of the current vaccines against those strains and the possible crossing of the species barrier in terrestrial mammals. The incidence of the disease in humans is very low, with cases contracted in Europe or in enzootic countries. Sustainable strategies of vaccination programmes in animals and improvement of public awareness, particularly for travelers, regarding rabies risks and legislation for pet movements would render accessible the elimination of rabies in Europe.     

人乳头瘤病毒基因亚型与宫颈病变的相关性及临床意义

目的探讨人乳头瘤病毒(HPV)基因亚型与宫颈病变的相关性及临床意义。方法选取2019年在济南市天桥人民医院妇科就诊患者864例作为研究对象,采集患者宫颈细胞进行HPV基因检测并实施宫颈病理活检,组织切片取样行病理学检查,比较HPV基因亚型与病理诊断结果并进行相关性分析。结果864例患者中,正常或炎症宫颈620例,宫颈上皮内瘤变(CIN)Ⅰ级58例,CINⅡ级36例,CINⅢ级88例,宫颈癌62例。HPV阳性检出率随宫颈病变程度不断加重而升高,差异均有统计学意义(P<0.05)。伴随病情不断发展,HPV 16型在不同宫颈病变中的阳性检出率逐渐升高,在宫颈癌患者中同样也是HPV 16型阳性检出优势明显,为77.4%(48/62)。HPV多重感染在不同宫颈病变中的检出情况:正常及炎症11.3%,CINⅠ级17.2%,CINⅡ级27.8%,CINⅢ级29.5%,宫颈癌9.7%;宫颈癌中HPV多重感染占比明显更少,更多的是单一HPV基因型感染,且感染类型全部为高危型。结论随着宫颈病变程度不断加重,HPV阳性检出率随之逐渐升高;宫颈癌中HPV基因亚型主要包括:HPV 16、33、52型。     

NSABP breast cancer clinical trials: recent results and future directions

Over the past 40 years, the National Surgical Adjuvant Breast and Bowel Project (NSABP) has conducted several large, randomized clinical trials evaluating various aspects of surgical and adjuvant therapy in patients with operable breast cancer. Results from these trials have contributed significantly in reducing the extent of surgical procedures and in improving the outcome of patients with early-stage breast cancer. Furthermore, they have helped to establish standards of care for the surgical management of invasive and non-invasive disease and for the use of adjuvant hormonal therapy and adjuvant chemotherapy for patients with negative as well as for those with positive axillary nodes. More recent trials are evaluating several new classes of promising drugs such as the aromatase inhibitors in postmenopausal women with invasive or intraductal breast cancer, the taxanes for patients with positive nodes and in the neoadjuvant setting and other targeted molecular therapies such as trastuzumab and bisphosphonates. Results from these ongoing and recently completed trials could improve outcomes and quality of life for patients with early-stage breast cancer.     

Surrogate endpoints in randomized cardiovascular clinical trials

Surrogate endpoints predict the occurrence and timing of a clinical endpoint of interest (CEI). Substitution of a surrogate endpoint for a CEI can dramatically reduce the time and cost necessary to complete a Phase III clinical trial. However, assurance that use of a surrogate endpoint will result in a correct conclusion regarding treatment effect on a CEI requires prior rigorous validation of the surrogate. Surrogate endpoints can also be of substantial use in Phase I and II studies to assess whether the intended therapeutic pathway is operative, thus providing assurance regarding the reasonableness of proceeding to a Phase III trial. This paper discusses the uses and validation of surrogate endpoints.     

人乳头状瘤病毒核酸检测试剂盒用于宫颈癌及癌前病变筛查的临床价值

目的分析人乳头状瘤病毒(HPV)杂交捕获-化学发光法核酸检测试剂盒(DH3)用于宫颈癌及癌前病变筛查的临床价值。方法收集480例妇科门诊妇女宫颈脱落细胞样本,分别采用DH3、TCT和HPV-PCR检测,对TCT≥ASC-US者行阴道镜下病理检测,以病理学结果为金标准,分析DH3诊断价值。结果病理学结果显示,正常者370例(77.08%),良性病变者(≤CINⅠ)59例(12.29%),高危者(≥CINⅡ)51例(10.63%);TCT、HPV-PCR和DH3诊断阳性率分别为26.04%、32.08%和27.08%;DH3与TCT检测一致率为94.79%(P0.01),与HPV-PCR检测一致率为93.13%(P0.01);DH3灵敏度98.18%,特异度87.57%,阳性预测值70.13%,阴性预测值99.39%,准确率为90%,检出高危型(≥CINⅡ)的ROC曲线面积Z=0.887(95%CI为0.785~0.918,P0.01)。结论 DH3试剂盒与TCT、HPV-PCR在检出HPV宫颈癌及癌前病变具有高度一致性,灵敏度、特异度和准确率高,操作便捷,临床筛查意义显著。     

Principles of recruitment and retention in clinical trials

Efficient and effective recruitment and retention of participants is the largest single component of the study workload and forms an essential component in the conduct of clinical trials. In this paper, we present five principles to guide the processes of both recruitment and retention. These principles include the selection of an appropriate population to adequately answer the research question, followed by the establishment of a sampling process that accurately represents that population. Creation of systematic and effective recruitment mechanisms should be supported by implementation of follow-up mechanisms that promote participant retention. Finally, all activities related to recruitment and retention must be conducted within the framework of ethics and privacy regulations. Adherence to these principles will assist the researcher in achieving the goals of the study within the available resources.     

Anti-angiogenic drugs: from bench to clinical trials

Angiogenesis, the generation of new capillaries through a process of pre-existing microvessel sprouting, is under stringent control and normally occurs only during embryonic and post-embryonic development, reproductive cycle, and wound repair. However, in many pathological conditions (solid tumor progression, metastasis, diabetic retinopathy, hemangioma, arthritis, psoriasis and atherosclerosis among others), the disease appears to be associated with persistent upregulated angiogenesis. The development of specific anti-angiogenic agents arises as an attractive therapeutic approach for the treatment of cancer and other angiogenesis-dependent diseases. The formation of new blood vessels is a complex multi-step process. Endothelial cells resting in the parent vessels are activated by an angiogenic signal and stimulated to synthesize and release degradative enzymes allowing endothelial cells to migrate, proliferate and finally differentiate to give rise to capillary tubules. Any of these steps may be a potential target for pharmacological intervention. In spite of the disappointing results obtained initially in clinical trials with anti-angiogenic drugs, recent reports with positive results in phases II and III trials encourage expectations in their therapeutic potential. This review discusses the current approaches for the discovery of new compounds that inhibit angiogenesis, with emphasis on the clinical developmental status of anti-angiogenic drugs.     

Hsp-based tumor vaccines: state-of-the-art and future directions

Hsp-based tumor vaccines, autologous tumor-derived Hsp-peptide complexes, have been applied to cancer immunotherapy for the treatment of cancer patients with a variety of advanced malignancies. Data from clinical trials, including those from phase III, have so far demonstrated that the immunization strategy can induce significant tumor-specific immune responses. Some improved clinical outcomes have also been observed but the clinical utility of this strategy awaits further investigations. In addition, preclinical studies have been conducted to design a variety of novel Hsp-based tumor vaccines with improved therapeutic potentials. These approaches include development of Hsp fusion proteins and genetic vaccines using plasmid DNA and adenoviruses. Successful cancer immunotherapy with Hsp-based tumor vaccines will depend on the results obtained from both clinical trials and preclinical studies.