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）是男同性恋、双性恋、变性人和其他与男性发生性关系的男性（MSM）的健康危机，患病风险比美国所有男性高20 - 40倍。9 - 12高危型HPV（高危型HPV）是导致女性浸润性宫颈癌（ICC）的主要原因，也可能是导致大多数IAC的主要原因。持续性感染及其相关的高度发育不良强烈预测ICC。14 - 17最近的数据表明，我们对男性HPV感染的了解很少，特别是在IAC风险最高的MSM中。18 - 25使用巴氏染色进行宫颈细胞学检查（巴氏试验）显着减少ICC开始在20世纪50年代中期;细胞学标本目前是用细胞刷收集的，这是一种不适合肛门取样的工具。26，27专家现在建议每1 - 2年对MSM进行一次肛门巴氏试验，使用涤纶拭子盲法通过肛缘。28涤纶细胞学标本仅勉强够用，且需要对任何检测到的异常进行诊断性随访，这一阈值低于宫颈细胞学。我们的初步数据显示，使用尼龙植绒拭子，肛门细胞学预测HG-AIN的灵敏度和特异性提高了1.5倍，但特异性仅提高了1.3倍，达到73%。虽然大多数IAC使用PCR检测HPV阳性，但无癌症的MSM中感染的高患病率使HPV PCR基因分型成为特异性较差的筛查测试，阳性预测值（PPV）较低。高阈值，核酸HPV检测（分子HPV检测）进行校准，以更好地预测高级别的宫颈不典型增生的老年女性没有子宫颈癌和分流妇女阴道镜与非典型鳞状细胞的细胞学;他们没有校准IAC筛查。检测病毒DNA和mRNA的两种分子HPV检测可能与IAC筛查相关：HPV-杂交捕获II（HC-2）和-APTIMA。这两种检测方法都能检测13种最高风险的HPV; APTIMA还能检测HPV66。HC-2检测HPV-DNA> 1 pg/mL。29 HPV E6/E7通常在HPV整合到人类DNA中的较高水平检测到，这是癌症的标志。30分子HPV检测显著减少了对细胞学不明确的女性的诊断随访转诊，限制了昂贵和侵入性的程序，而这些检测提高了原位和ICC的检测，它们还没有被探索作为IAC筛查的连续性测试。此外，还没有足够的重视，以提高肛门巴氏试验标本的质量。本研究旨在评估两种巴氏试验收集方案和分子HPV检测，作为生物标志物检测，使用在单次检查访视和随机对照研究设计中收集的标本。优化生物标志物测定和细胞学的序列以预测HG-AIN将降低发病率和死亡率，并降低昂贵和侵入性诊断测试的使用。我们将评估分子HPV检测在同时或连续阳性检测（有或没有（肛门）细胞学检查）用于预测HG-AIN时的贡献。将评估肛门癌筛查算法的敏感性、特异性和PPV及其预防浸润性肛门癌的成本效益，以告知实践。

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.