Improving screening tools to better predict high-grade anal dysplasia for MSM

描述(申请人提供)：侵袭性肛门癌(IAC)是同性恋、双性恋、变性人和其他男男性行为者(MSM)的健康危机，这些疾病的风险现在是所有美国男性的20-40倍。9-12 13种人类乳头状瘤病毒(高危HPV)导致大多数女性侵袭性宫颈癌(ICC)，可能导致大多数IAC。13高危HPV感染是在伴侣之间性传播的。持续感染，与其相关的高度不典型增生，强烈预测ICC。14-17最近的数据表明，我们对男性中的HPV感染了解很少，特别是在MSM中，他们是IAC.18-25的最高风险人群。18-25宫颈细胞学使用巴氏染色(巴氏试验)从1950年中期开始显著降低ICC‘S；26，27名专家现在建议对男男性接触者进行一次每1-2年一次的肛门巴氏检查，使用涤纶拭子盲目穿过肛门边缘。28份涤纶细胞学标本略有不足，需要对任何检测到的异常进行诊断随访，这一门槛低于宫颈细胞学。我们的初步数据显示，使用尼龙绒毛拭子，肛门细胞学预测HG-AIN的灵敏度和特异度提高了1.5倍，但特异度仅提高了1.3倍至73%。虽然大多数IAC用聚合酶链式反应检测HPV呈阳性，但在没有癌症的MSM中感染的高流行率使得HPVPCR基因分型不是一种特异性很差的筛查试验，阳性预测值(PPV)很低。高阈值、核酸HPV检测(分子HPV检测)被校准，以更好地预测无异型性的老年女性的高度宫颈异型增生，并对妇女进行细胞学上非典型鳞状细胞阴道镜检查；它们没有被校准为IAC筛查。两种检测病毒DNA和-mRNA的分子HPV试验可能与IAC筛查有关：HPV-杂交捕获II(HC-2)和-APTIMA。这两种检测都检测到了13种最高风险的HPV；APTIMA还检测到了HPV66。HC-2检测HPV-DNA&GT；1 pg/ml29 HPV E6/E7通常在HPV整合到人类DNA的较高水平上检测到，这是癌症的一个特征。30分子HPV检测极大地减少了细胞学可疑妇女的诊断随访转诊，限制了昂贵的侵入性检查程序，尽管这些测试提高了原位和ICC的检测，但它们尚未被探索作为IAC筛查的辅助测试。此外，对提高肛门巴氏试验标本的质量也没有给予足够的重视。这项研究试图评估两种巴氏试验收集方案&分子HPV试验，作为生物标志物分析，使用在一次检查访问中收集的标本&随机对照研究设计。优化生物标记物分析和细胞学序列以预测HG-AIN将减少发病率和死亡率，并减少昂贵和侵入性诊断测试的使用。我们将评估分子HPV检测的贡献，当同时或连续阳性检测，有或没有(肛门)细胞学，被用来预测HG-AIN。将评估肛门癌筛查算法的敏感性、特异性和PPV，以及它们预防浸润性肛门癌的成本效益，为实践提供参考。

DESCRIPTION (provided by applicant): Invasive anal cancer (IAC) is a health crisis for gay, bisexual, transgender & other men who have sex with men (MSM), where risk for disease is now 20-40-fold higher than all U.S. males.9-12 Thirteen human papillomaviruses (high-risk HPVs) cause most invasive cervical cancers (ICC) in women & likely cause most IACs.13 High-risk HPV infections are sexually transmitted between partners. Persistent infections, together with their associated high-grade dysplasias, strongly predict ICCs.14-17 Recent data suggests we poorly understand HPV infections in men, especially among MSM who are at highest risk for IAC.18-25 Cervical cytology using Papanicolaou's staining (Pap test) significantly reduced ICC beginning in the mid-1950's; & cytology specimens are currently collected using cytobrush, a tool poorly adapted to anal sampling.26,27 Experts now recommend anal Pap test for MSM every 1-2 years, using Dacron swab passed blindly through the anal verge.28 Dacron-cytology specimens are marginally sufficient & require diagnostic follow-up for any detected abnormalities, a lower threshold than used for cervical cytology. Our pilot data show that sensitivity & specificity of anal cytology to predict HG-AIN is improved 1.5-fold using nylon-flocked swab, but only improved specificity 1.3-fold to 73%. Although most IACs test positive for HPV using PCR, the high prevalence of infection among MSM without cancer makes HPV PCR genotyping a poorly specific screening test, with low positive predictive value (PPV). High-threshold, nucleic acid HPV assays (molecular HPV tests) are calibrated to better predict high-grade cervical dysplasia in older females without atypias & to triage women to colposcopy with atypical squamous cells on cytology; they are not calibrated for IAC screening. Two molecular HPV tests that detect viral DNA & -mRNA may be relevant for IAC screening: HPV-Hybrid-capture II (HC-2) & -APTIMA. Both tests detect the 13 highest-risk HPVs; APTIMA detects HPV66, additionally. HC-2 detects HPV-DNA >1 pg/mL.29 HPV E6/E7 are often detected at higher levels where HPV is integrated into human DNA, a hallmark of cancer.30 Molecular HPV tests significantly reduce diagnostic follow-up referrals for women with equivocal cytology, limiting costly & invasive procedures, & while these tests improve detection of in situ & ICCs, they have not been explored as adjunctive tests for IAC screening. Also, sufficient attention has not been paid to improving the quality of anal Pap test specimens. This study seeks to evaluate two Pap test collection protocols & molecular HPV tests, as biomarker assays, using specimens collected at a single examination visit & randomized controlled study design. Optimizing the sequence of biomarker assays & cytology to predict HG- AIN will decrease morbidity & mortality, & lower use of costly & invasive diagnostic testing. We will evaluate the contribution that molecular HPV testing makes when simultaneously or sequentially positive tests, with or without (anal) cytology, are used to predict HG-AIN. Sensitivity, specificity, & PPV for anal cancer screening algorithms & their cost-effectiveness to prevent invasive anal cancer will be evaluated to inform practice.