Zinc-Based Early Detection of Prostate Cancer

描述(由申请人提供)：在第一阶段，我们对前列腺液中游离锌的测量是前列腺癌的一个有前途的临床指标。事实上，在我们的两项先导性研究和之前发表的一项研究中，前列腺液锌评分给出了受试者工作曲线(AUROC)下的区域，分别为0.79、0.92和0.99，用于检测经活检证实的前列腺癌。我们的测试是非侵入性的，只需要在直肠前列腺检查中从尿道口获得几滴前列腺液，并进行短暂的前列腺按摩。锌的测量具有快速、廉价、简便和精准的特点。我们的第二阶段研究包括两个部分。在IIA研究中，我们将增加样本量，以更好地估计我们测试的敏感性和特异性。我们将从精心挑选的大约100名预计患有前列腺癌的男性和大约100名预计没有癌症的男性中收集前列腺液样本。在所有男性均经组织病理学证实为腺癌或不存在腺癌后，将进行受试者工作曲线分析，以确定通过测量前列腺液中的锌来检测腺癌的敏感性、特异性和曲线下总面积(AUROC)。这项研究将展示锌测试在前列腺癌检测中的作用。这项研究的对象将是(I)计划进行前列腺摘除的男性(Ii)计划进行膀胱前列腺摘除的男性(Iii)计划进行饱和(核心)针吸活检的男性和(Iv)计划进行常规活检的男性。在研究IIB中，我们将确定哪些前列腺疾病伴随着锌的隔离和分泌的丧失。因此，我们将从研究IIA中的受试者的前列腺组织切片中，用H&E和(在某些情况下)对疾病定义蛋白的抗体进行染色。在切片的数字图像上标记PIA(增生性炎性萎缩)、PIN(前列腺上皮内瘤变)或腺癌等前列腺特异性病变区域，然后在X射线荧光和锌组织荧光显微镜下对相邻切片进行成像，分别显示元素锌和游离锌的分布。将经典组织学与数字叠加的锌图谱进行比较，将显示锌的隔离(从而分泌)在每一种不同类型和不同的病理阶段中的变化。文献中的数据表明，锌的固存和分泌在PIN中受到抑制，在靠近腺癌的健康外观的腺泡中也受到抑制，这表明存在场效应。如果我们的工作证实了这一点，这将解释为什么即使是相对较小的腺癌也会显著抑制腺体锌的分泌。在美国，每年约有1500,000例前列腺活检，仅发现约300,000例癌症。尽管如此，仍有大约3万名男性死于晚期癌症，无法进行有效的治疗。我们相信，我们的锌测试可以更早、更确定地检测出潜在的侵袭性癌症，从而挽救生命。公共卫生NARAVTIVE：这项第二阶段的SBIR旨在确定前列腺癌锌试验的敏感性和特异性。这项测试测量按摩前列腺液中的锌，只需大约60秒就能获得液体，在台式仪器上进行测量只需要大约60秒，售价5000美元。这项测试旨在补充其他测试，包括PSA和DRE。由于锌在癌症中下降，但在良性前列腺增生症中不下降，锌测试有可能区分这两种情况。

DESCRIPTION (provided by applicant): In Phase I we showed that our measurement of free zinc in expressed prostatic fluid is a promising clinical indicator of prostate cancer. Indeed, in our two pilot studies and one prior published study, prostatic fluid zinc scores gave areas under the receiver operating curve (AUROC) of .79, .92, and .99 for detecting biopsy-confirmed prostatic adenocarcinoma. Our test is non-invasive, requiring only a few drops of prostatic fluid obtained from the urethral meatus during a rectal prostate examination with brief prostate massage. The zinc measurement is fast, cheap, easy, and exquisitely accurate. Our Phase II study has two components. In Study IIA we will increase our sample size to better estimate the sensitivity and specificity of our test. We will collect samples of prostatic fluid from a carefully selected sample of approximately 100 men expected to have prostate adenocarcinoma and approximately 100 men expected to be cancer free. Upon histopathological confirmation of adenocarcinoma or the absence of adenocarcinoma in all men, a receiver operating curve analysis will be conducted to determine the sensitivity, specificity and overall area under the curve (AUROC) for the detection of adenocarcinoma by the measurement of zinc in prostatic fluid. This study will show how useful the zinc test is for detecting prostate cancer. The subjects in this study will be (i) men scheduled for prostatectomy (ii) men scheduled for cysto-prostatectomy (iii) men scheduled for saturation (64 core) needle biopsy and (iv) men scheduled for conventional biopsy. In Study IIB we will establish which prostatic disease conditions are accompanied by the loss of zinc sequestering and secretion. Thus, we will take tissue sections from the prostate glands of the subjects in Study IIA, stain them with H&E and (in some cases) antibodies to disease- defining proteins. Regions with specific prostatic pathology such as PIA (proliferative inflammatory atrophy), PIN (prostatic intraepithelial neoplasia) or adenocarcinoma will be marked on digital images of the sections, then adjacent sections will be imaged in X-RAY fluorescence and zinc histofluorescence microscopy to show the distribution of elemental and free zinc , respectively. Comparison of the classical histology with the zinc maps by digitally superimposing them will show how zinc sequestration (and therefore secretion) changes in each of the different types and stages of pathology. Data in the literature indicate that zinc sequestration and secretion are suppressed in PIN and suppressed in healthy-appearing acini that are near an adenocarcinoma, suggesting a field effect. If confirmed by our work, this would explain how even relatively small adenocarcinomas markedly suppress zinc secretion of the gland. Every year in the US about 1,500,000 prostate biopsies are done, revealing only about 300,000 cancers. Still, about 30,000 men die from cancers too advanced for effective treatment. We believe our zinc test could allow earlier and more certain detection of potentially aggressive cancers, thus saving lives. PUBLIC HEALTH NARAVTIVE: This Phase II SBIR is designed to determine the sensitivity and specificity of a zinc test for prostate cancer. The test measures zinc in massage-expressed prostatic fluid, and it only takes about 60 sec to get the fluid and about 60 sec to make the measurement on a table-top, $5000 instrument. The test is intended to supplement other tests, including the PSA and DRE. Because the zinc falls in cancer but does not fall in BPH, the zinc tests has the potential to distinguish these two conditions.