e While urine-based sampling for human papillomavirus (HPV) is being explored as a simple and noninvasive approach for cervical cancer screening, data comparing HPV genotyping in urine and those in cellular sampling of the cervix and vulva, and their correlation with rigorously confirmed cervical disease status, are sparse. We performed HPV genotyping on voided-urine and clinician-collected vulvar and cervical samples from 72 women undergoing colposcopy. Although urine-based HPV carcinogenic HPV detection was lower (58.3%) than cervical (73.6%) and vulvar (72.1%) detection (P ‫؍‬ 0.05 and 0.07, respectively), the agreement of urine HPV with cervical and vulvar HPV was moderate (kappa ‫؍‬ 0.55) and substantial (kappa ‫؍‬ 0.62), respectively. Urine-based carcinogenic HPV detection had a clinical sensitivity of 80.8% (95% confidence interval [CI] ‫؍‬ 60.7 to 93.5) and a specificity of 53.3% (95% CI ‫؍‬ 37.9 to 68.3) for diagnosing cervical intraepithelial neoplasia grades 2/3 (CIN2/3) on histology; 90.0% of CIN3 was positive for urine HPV. The corresponding sensitivity and specificity values for vulvar sampling were 92% (95% CI ‫؍‬ 74 to 99) and 40.5% (95% CI ‫؍‬ 25.6 to 56.7), and those for cervical sampling were 96.2% (95% CI ‫؍‬ 80.4 to 99.9) and 40% (95% CI ‫؍‬ 25.7 to 55.7), respectively. HPV16 was the most common carcinogenic genotype detectable in 25% of urine, 33.8% of vulvar, and 31.9% of cervical samples overall, with prevalence increasing with cervical disease grade, regardless of the sampling method. Stronger cervical HPV PCR signal strengths were associated with increased frequency of urine HPV detection. In summary, the relatively lower detection rates but comparable clinical performance of urine-based HPV sampling underscore the need for larger studies to evaluate urine-based sampling for cervical cancer screening, epidemiologic studies, and postvaccination HPV disease surveillance. Human papillomavirus (HPV)-based primary screening or cotesting is being increasingly implemented as an alternative to cytology-based screening (1). Unlike cytology, HPV testing is amenable to simplified approaches for sample collection, including self-collected vaginal samples and urine-based sampling. These approaches may offer alternatives to clinic-based screening and improve access to care, particularly for hard-to-reach populations (2-11). While urine-based screening offers simplicity in sample collection, there are few studies of clinical performance of urine-based sampling and HPV genotypes detectable by this approach compared to that of cervical and external genital sampling in relation to rigorously confirmed cervical disease status. To expand the evidence in this area, we conducted a pilot study in a colposcopy referral population to evaluate HPV detection in voided urine samples, compare it to clinician-collected external genital (vulvar) and cervical sampling, and correlate results against histologically confirmed cervical disease ascertainment. MATERIALS AND METHODSThe study was nested within the National Ca...

The epithelial component of normal and non-invasive breast tissues is normally surrounded by a layer of myoepithelial (ME) cells, whose absence or disruption is an absolute prerequisite for tumor invasion and metastasis [1]. ME cells are not easily identifiable in hematoxylin/eosin (H&E)-stained breast tissue sections, as they are often indistinguishable from subjacent myofibroblastic cells in the stroma. Immunohistochemical staining for smooth muscle actin (SMA) has been routinely used to assist in the identification of ME cells [2]. However, we and others have repeatedly noted that about 4-6% of morphologically recognizable ME cells in H&E-stained sections fail to display SMA immunoreactivity [3,4]. We attempted to assess whether these SMA-negative cells also lack the expression of eight additional markers that are supposed to present exclusively or preferentially at ME cells. Materials and methods Case selectionFormalin-fixed, paraffin-embedded tissue blocks from female patients with breast lesions were retrieved from files of the Armed Forces Institute of Pathology. Consecutive sections at 4-5 µm thickness were cut and placed on CK = cytokeratin; ER = estrogen receptor; H&E = hematoxylin/eosin; ME = myoepithelial; SMA = smooth muscle actin; SM-MHC = smooth muscle myosin heavy chain; WT-1 = Wilms' tumor-1. (Print ISSN 1465-5411; Online ISSN 1465-542X). This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL. AbstractIntroduction: Immunostaining for smooth muscle actin (SMA) is commonly used to elucidate mammary myoepithelial (ME) cells, whose presence or absence is a reliable criterion for differentiating in situ and invasive carcinomas. However, some morphologically distinct ME cells fail to stain for SMA. This study intended to assess whether these SMA-negative cells also lack the expression of other ME cell markers.

We previously reported a synergistic anticancer action of clioquinol and docosahexaenoic acid (DHA) in human cancer cells. However, clioquinol has been banned from the clinic due to its neurotoxicity. This study identified disulfiram (DSF) as a substitute compound to clioquinol, acting in concert with DHA to more effectively kill cancer cells and suppress tumor growth. Treatment with DSF and DHA induced greater apoptotic cell death and suppression of tumor growth in vitro and in vivo, as compared to DSF and DHA used alone. Mechanistic studies demonstrated that DSF enhances DHA-induced cellular oxidative stress as evidenced by up-regulation of Nrf2-mediated heme oxygenase 1 (HO-1) gene transcription. On the other hand, DHA was found to enhance DSF-induced suppression of mammosphere formation and stem cell frequency in a selected cancer model system, indicating that alterations to cancer cell stemness are involved in the combinatory anticancer action of DSF and DHA. Thus, DHA and DSF, both clinically approved drugs, act in concert to more effectively kill cancer cells. This combinatory action involves an enhancement of cellular oxidative stress and suppression of cancer cell stemness.

BACKGROUND: Recent proposals to lengthen the interval in cervical cancer screening highlight the importance of the accurate interpretation of screening tests. Tumor debris present in Papanicolaou (Pap) tests from women with invasive cancer is known to hamper interpretation. The current study evaluated limiting factors in Pap tests from women with invasive cervical cancer. METHODS: A total of 3003 women with the spectrum of cervical lesions who had ThinPrep (Hologic Inc, Marlborough, Mass) Pap and human papillomavirus (HPV) genotyping tests performed were grouped by their most severe histologic diagnosis. Cytologic and HPV results were analyzed by cross-sectional analysis. RESULTS: The unsatisfactory rate of cytology specimens from patients with cancer (3.1%) was significantly higher than those from patients with cervical intraepithelial neoplasia of type 3 or less (0.8%) (P <.001). The percentage of samples with qualified adequacy was 34.8% in specimens from patients with cancer compared with only 3.6% from specimens from those without cancer (P <.001). The unsatisfactory and qualified adequacy rates were higher in squamous cancers compared with adenocarcinomas. However, adenocarcinomas were identified less frequently than squamous cancers (37.0% vs 61.7%) in the Pap tests. HPV tests were positive in 84.4% of unsatisfactory cases including 8 of 9 cancer cases, although 8.5% of cancers tested negative for HPV. CONCLUSIONS: Unsatisfactory and suboptimal ThinPrep Pap tests were increased in cancer cases compared with lesser histologic diagnoses. This was found to be particularly true for squamous cancers.Specimens from adenocarcinomas had fewer adequacy problems but were less frequently recognized as malignant. HPV tests were positive in the majority of unsatisfactory Pap tests in women with carcinoma, suggesting that HPV testing in women aged > 30 years can help to identify high-risk women with unsatisfactory Pap tests. Cancer (Cancer Cytopathol) 2014;122:694-701.

Tumor microenvironments (TMEs) are composed of cancer cells, fibroblasts, extracellular matrix, microvessels, and endothelial cells. Two prolyl endopeptidases, fibroblast activation protein (FAP) and prolyl oligopeptidase (POP), are commonly overexpressed by epithelial-derived malignancies, with the specificity of FAP expression by cancer stromal fibroblasts suggesting FAP as a possible therapeutic target. Despite overexpression in most cancers and having a role in angiogenesis, inhibition of POP activity has received little attention as an approach to quench tumor growth. We developed two specific and highly effective pseudopeptide inhibitors, M83, which inhibits FAP and POP proteinase activities, and J94, which inhibits only POP. Both suppressed human colon cancer xenograft growth > 90% in mice. By immunohistochemical stains, M83- and J94-treated tumors had fewer microvessels, and apoptotic areas were apparent in both. In response to M83, but not J94, disordered collagen accumulations were observed. Neither M83- nor J94-treated mice manifested changes in behavior, weight, or gastrointestinal function. Tumor growth suppression was more extensive than noted with recently reported efforts by others to inhibit FAP proteinase function or reduce FAP expression. Diminished angiogenesis and the accompanying profound reduction in tumor growth suggest that inhibition of either FAP or POP may offer new therapeutic approaches that directly target TMEs.