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

描述（由申请人提供）：浸润性肛门癌（IAC）是男同性恋、双性恋、变性人和其他男男性行为者（MSM）的健康危机，其患病风险现在比所有美国男性高20-40倍。13种人类乳头瘤病毒（高危hpv）导致女性中大多数侵袭性宫颈癌（ICC），并可能导致大多数iacs高危HPV感染是性伴侣之间的性传播。持续感染及其相关的高度发育不良强烈预测icc。最近的数据表明，我们对男性HPV感染的了解甚少，特别是在iac风险最高的MSM人群中。18-25从20世纪50年代中期开始，使用巴氏染色法（Pap试验）的宫颈细胞学显著降低了ICC；目前使用细胞刷收集细胞学标本，这是一种不适合肛门取样的工具专家现在建议男男性接触者每1-2年做一次肛门巴氏试验，用涤纶棉签盲目地穿过肛门边缘涤纶细胞学标本是勉强足够的，需要诊断随访任何检测到的异常，一个较低的阈值比用于宫颈细胞学。我们的试点数据显示，肛门细胞学预测HG-AIN的敏感性和特异性使用尼龙棉签提高了1.5倍，但特异性仅提高了1.3倍，达到73%。尽管大多数IACs使用PCR检测HPV呈阳性，但在没有癌症的MSM中感染的高患病率使得HPV PCR基因分型是一种特异性较差的筛查试验，阳性预测值（PPV）较低。校准高阈值核酸HPV检测（分子HPV检测），以更好地预测无异型的老年女性的高级别宫颈发育不良，并在细胞学上对具有非典型鳞状细胞的女性进行阴道镜检查；它们没有针对IAC筛查进行校准。两种检测病毒DNA和mrna的HPV分子检测可能与IAC筛查相关：HPV- hybrid -capture II （HC-2）和-APTIMA。两种检测方法都能检测出13种高危hpv；此外，APTIMA还检测HPV66。HC-2检测HPV-DNA >1 pg/ mlHPV E6/E7通常在HPV整合到人类DNA（癌症的标志）的较高水平被检测到分子HPV检测显著减少了细胞学不明确的妇女的诊断随访转诊，限制了昂贵和侵入性的手术，虽然这些检测提高了原位和icc的检测，但它们尚未被探索作为IAC筛查的辅助检测。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。本研究旨在评估两种巴氏试验收集方案和分子HPV检测，作为生物标志物分析，使用单次检查访问收集的标本和随机对照研究设计。优化生物标志物检测和细胞学序列来预测HG- AIN将降低发病率和死亡率，并减少昂贵的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）用于预测HG-AIN时的贡献。肛门癌筛查算法的敏感性、特异性和PPV及其预防侵袭性肛门癌的成本效益将被评估，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.