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We explored the potential impact of HPV testing on women’s intentions to be screened for cervical cancer in a cohort of Canadian women. Participants aged 25-65 from an ongoing trial were sent a questionnaire to assess women’s intentions to be screened for cervical cancer with HPV testing instead of Pap smears and to be screened every 4 years or after 25 years of age. We created scales for attitudes about HPV testing, perceived behavioural control and direct and indirect subjective norms. Demographic data and scales that were significantly different (p<0.1) between women who intended to be screened with HPV and those who did not intend were included in a stepwise logistic regression model. Of the 2016 invitations emailed, 1538 were received, and 981 completed surveys for a response rate of 63% (981/1538). Eighty-four percent of women (826/981) responded that they intended to attend for HPV-based cervical cancer screening, which decreased to 54.2% when the screening interval was extended, and decreased further to 51.4% when screening start was delayed to age 25. Predictors of intentions to undergo screening were attitudes (OR 1.22; 95%CI 1.15, 1.30), indirect subjective norms (OR 1.02; 95%CI 1.01, 1.03) and perceived behavioural control (OR 1.16; 95% CI 1.10; 1.22). Intentions to be screened for cervical cancer with HPV testing decreased substantially when the screening interval was extended and screening started at age 25. Use of primary HPV testing may optimize the screening paradigm, but programs should ensure robust planning and education to mitigate any negative impact on screening attendance rates.
PMCID: PMC4515309  PMID: 23754203
HPV; cervical cancer screening; intention; Theory of Planned Behavior
2.  Molecular Fixative Enables Expression Microarray Analysis of Microdissected Clinical Cervical Specimens 
Formalin-fixed tissue has been a mainstay of clinical pathology laboratories, but formalin alters many biomolecules, including nucleic acids and proteins. Meanwhile, frozen tissues contain better-preserved biomolecules, but tissue morphology is affected, limiting their diagnostic utility. Molecular fixatives promise to bridge this gap by simultaneously preserving morphology and biomolecules, enabling clinical diagnosis and molecular analyses on the same specimen. While previous reports have broadly evaluated the use of molecular fixative in various human tissues, we present here the first detailed assessment of the applicability of molecular fixative to both routine histopathological diagnosis and molecular analysis of cervical tissues. Ten specimens excised via the Loop Electrosurgical Excision Procedure, which removes conical tissue samples from the cervix, were cut into alternating pieces preserved in either formalin or molecular fixative. Cervical specimens preserved in molecular fixative were easily interpretable, despite featuring more eosinophilic cytoplasm and more recognizable chromatin texture than formalin-fixed specimens. Immunohistochemical staining patterns of p16 and Ki-67 were similar between fixatives, although Ki-67 staining was stronger in the molecular fixative specimens. The RNA of molecular fixative specimens from seven cases representing various dysplasia grades was assessed for utility in expression microarray analysis. Cluster analysis and scatter plots of duplicate samples suggest that data of sufficient quality can be obtained from as little as 50 ng of RNA from molecular fixative samples. Taken together, our results show that molecular fixative may be a more versatile substitute for formalin, simultaneously preserving tissue morphology for clinical diagnosis and biomolecules for immunohistochemistry and gene expression analysis.
PMCID: PMC3988026  PMID: 24412268
cervical intraepithelial neoplasia; gene expression microarray analysis; immunohistochemistry; microdissection; molecular fixative
3.  Women’s intentions to self-collect samples for human papillomavirus testing in an organized cervical cancer screening program 
BMC Public Health  2014;14:1060.
Mounting evidence affirms HPV testing as an effective cervical cancer screening tool, and many organized screening programs are considering adopting it as primary testing. HPV self-collection has comparable sensitivity to clinician collected specimens and is considered a feasible option in hard-to-reach women. We explored women’s intentions to HPV self-collect for cervical cancer screening from a cohort participating in a Canadian randomized controlled cervical cancer screening trial.
Women aged 25–65 were invited to complete an online survey assessing intentions to be screened with HPV testing instead of the Pap smear. The survey was based in the Theory of Planned Behaviour and questions were included to assess women’s intentions to self-collect for HPV. Demographic characteristics of women who intended to self-collect were compared with those who did not. Demographic and scale variables achieving a p-value <0.1 in the univariate and bivariate analyses were included in the stepwise logistic regression model. The final model was created to predict factors associated with women’s intentions to self-collect an HPV specimen for cervical cancer. Odds ratios were calculated with 95% confidence intervals to identify variables associated with a woman’s intention to self-collect for cervical cancer screening.
The overall survey response rate was 63.8% (981/1538) with 447 (45.6%) reporting they intended to self-collect, versus 534 (54.4%) reporting they did not. In the univariate analysis, women with more than high school education were more likely to self-collect. Women who intended to receive HPV testing versus the Pap smear were 1.94 times as likely to be in favour of self-collection and those who intended to self-collect had significantly higher attitudinal scores towards HPV self-collection. The adjusted odds ratio and 95% confidence interval from the multivariate analysis demonstrated attitude towards self-collection was the only significant variable predicting a woman’s intention to self-collect (OR 1.25; 95% CI: 1.22, 1.29).
The primary predictor of a woman’s intention to HPV self-collect for cervical cancer screening was her attitude towards the procedure. From a program planning perspective, these results indicate that education and awareness may be significant contributing factors to improving acceptance of self-collection and subsequently, improving screening attendance rates.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2458-14-1060) contains supplementary material, which is available to authorized users.
PMCID: PMC4203923  PMID: 25303975
Human papillomavirus (HPV); Cervical cancer screening; Self-collection; Intention; Theory of planned behaviour
4.  Evaluation of HPV Infection and Smoking Status Impacts on Cell Proliferation in Epithelial Layers of Cervical Neoplasia 
PLoS ONE  2014;9(9):e107088.
Accurate cervical intra-epithelial neoplasia (CIN) lesion grading is needed for effective patient management. We applied computer-assisted scanning and analytic approaches to immuno-stained CIN lesion sections to more accurately delineate disease states and decipher cell proliferation impacts from HPV and smoking within individual epithelial layers. A patient cohort undergoing cervical screening was identified (n = 196) and biopsies of varying disease grades and with intact basement membranes and epithelial layers were obtained (n = 261). Specimens were sectioned, stained (Mib1), and scanned using a high-resolution imaging system. We achieved semi-automated delineation of proliferation status and epithelial cell layers using Otsu segmentation, manual image review, Voronoi tessellation, and immuno-staining. Data were interrogated against known status for HPV infection, smoking, and disease grade. We observed increased cell proliferation and decreased epithelial thickness with increased disease grade (when analyzing the epithelium at full thickness). Analysis within individual cell layers showed a ≥50% increase in cell proliferation for CIN2 vs. CIN1 lesions in higher epithelial layers (with minimal differences seen in basal/parabasal layers). Higher rates of proliferation for HPV-positive vs. -negative cases were seen in epithelial layers beyond the basal/parabasal layers in normal and CIN1 tissues. Comparing smokers vs. non-smokers, we observed increased cell proliferation in parabasal (low and high grade lesions) and basal layers (high grade only). In sum, we report CIN grade-specific differences in cell proliferation within individual epithelial layers. We also show HPV and smoking impacts on cell layer-specific proliferation. Our findings yield insight into CIN progression biology and demonstrate that rigorous, semi-automated imaging of histopathological specimens may be applied to improve disease grading accuracy.
PMCID: PMC4161429  PMID: 25210770
5.  Optical Technologies and Molecular Imaging for Cervical Neoplasia: A Program Project Update 
Gender Medicine  2011;9(1 Suppl):S7-S24.
There is an urgent global need for effective and affordable approaches to cervical cancer screening and diagnosis. For developing nations, cervical malignancies remain the leading cause of cancer death in women. This reality is difficult to accept given that these deaths are largely preventable; where cervical screening programs are implemented, cervical cancer deaths decrease dramatically. In the developed world, the challenges with respect to cervical disease stem from high costs and over-treatment. We are presently eleven years into a National Cancer Institute-funded Program Project (P01 CA82710) that is evaluating optical technologies for their applicability to the cervical cancer problem. Our mandate is to create new tools for disease detection and diagnosis that are inexpensive, require minimal expertise to use, are more accurate than existing modalities, and will be feasibly implemented in a variety of clinical settings. Herein, we update the status of this work and explain the long-term goals of this project.
PMCID: PMC3289763  PMID: 21944317
6.  Accuracy of optical spectroscopy for the detection of cervical intraepithelial neoplasia: testing a device as an adjunct to colposcopy 
Testing emerging technologies involves the evaluation of biologic plausibility, technical efficacy, clinical effectiveness, patient satisfaction, and cost-effectiveness. The objective of this study was to select an effective classification algorithm for optical spectroscopy as an adjunct to colposcopy and obtain preliminary estimates of its accuracy for the detection of CIN 2 or worse. We recruited 1000 patients from screening and prevention clinics and 850 patients from colposcopy clinics at two comprehensive cancer centers and a community hospital. Optical spectroscopy was performed and 4864 biopsies were obtained from the sites measured, including abnormal and normal colposcopic areas. The gold standard was the histologic report of biopsies, read 2–3 times by histopathologists blinded to the cytologic, histopathologic, and spectroscopic results. We calculated sensitivities, specificities, receiver operating characteristic (ROC) curves, and areas under the ROC curves. We identified a cutpoint for an algorithm based on optical spectroscopy that yielded an estimated sensitivity of 1.00 [95% confidence interval (CI) = 0.92 – 1.00] and an estimated specificity of 0.71 [95% CI = 0.62 – 0.79] in a combined screening and diagnostic population. The positive and negative predictive values were 0.58 and 1.00, respectively. The area under the ROC curve was 0.85 (95% CI 0.81 – 0.89). The per-patient and per-site performance were similar in the diagnostic and poorer in the screening settings. Like colposcopy, the device performs best in a diagnostic population. Alternative statistical approaches demonstrate that the analysis is robust and that spectroscopy works as well as or slightly better than colposcopy for the detection of CIN 2 to cancer.
PMCID: PMC3015005  PMID: 20830707
sensitivity and specificity; diagnosis; early detection of cancer; uterine cervical neoplasms; cervical intraepithelial neoplasia
7.  A randomized controlled trial of Human Papillomavirus (HPV) testing for cervical cancer screening: trial design and preliminary results (HPV FOCAL Trial) 
BMC Cancer  2010;10:111.
In the HPV FOCAL trial, we will establish the efficacy of hr-HPV DNA testing as a stand-alone screening test followed by liquid based cytology (LBC) triage of hr-HPV-positive women compared to LBC followed by hr-HPV triage with ≥ CIN3 as the outcome.
HPV-FOCAL is a randomized, controlled, three-armed study over a four year period conducted in British Columbia. It will recruit 33,000 women aged 25-65 through the province's population based cervical cancer screening program. Control arm: LBC at entry and two years, and combined LBC and hr-HPV at four years among those with initial negative results and hr-HPV triage of ASCUS cases; Two Year Safety Check arm: hr-HPV at entry and LBC at two years in those with initial negative results with LBC triage of hr-HPV positives; Four Year Intervention Arm: hr-HPV at entry and combined hr-HPV and LBC at four years among those with initial negative results with LBC triage of hr-HPV positive cases
To date, 6150 participants have a completed sample and epidemiologic questionnaire. Of the 2019 women enrolled in the control arm, 1908 (94.5%) were cytology negative. Women aged 25-29 had the highest rates of HSIL (1.4%). In the safety arm 92.2% of women were hr-HPV negative, with the highest rate of hr-HPV positivity found in 25-29 year old women (23.5%). Similar results were obtained in the intervention arm HPV FOCAL is the first randomized trial in North America to examine hr-HPV testing as the primary screen for cervical cancer within a population-based cervical cancer screening program.
Trial Registration
International Standard Randomised Controlled Trial Number Register, ISRCTN79347302
PMCID: PMC2858109  PMID: 20334685
8.  Up regulation in gene expression of chromatin remodelling factors in cervical intraepithelial neoplasia 
BMC Genomics  2008;9:64.
The highest rates of cervical cancer are found in developing countries. Frontline monitoring has reduced these rates in developed countries and present day screening programs primarily identify precancerous lesions termed cervical intraepithelial neoplasias (CIN). CIN lesions described as mild dysplasia (CIN I) are likely to spontaneously regress while CIN III lesions (severe dysplasia) are likely to progress if untreated. Thoughtful consideration of gene expression changes paralleling the progressive pre invasive neoplastic development will yield insight into the key casual events involved in cervical cancer development.
In this study, we have identified gene expression changes across 16 cervical cases (CIN I, CIN II, CIN III and normal cervical epithelium) using the unbiased long serial analysis of gene expression (L-SAGE) method. The 16 L-SAGE libraries were sequenced to the level of 2,481,387 tags, creating the largest SAGE data collection for cervical tissue worldwide. We have identified 222 genes differentially expressed between normal cervical tissue and CIN III. Many of these genes influence biological functions characteristic of cancer, such as cell death, cell growth/proliferation and cellular movement. Evaluation of these genes through network interactions identified multiple candidates that influence regulation of cellular transcription through chromatin remodelling (SMARCC1, NCOR1, MRFAP1 and MORF4L2). Further, these expression events are focused at the critical junction in disease development of moderate dysplasia (CIN II) indicating a role for chromatin remodelling as part of cervical cancer development.
We have created a valuable publically available resource for the study of gene expression in precancerous cervical lesions. Our results indicate deregulation of the chromatin remodelling complex components and its influencing factors occur in the development of CIN lesions. The increase in SWI/SNF stabilizing molecule SMARCC1 and other novel genes has not been previously illustrated as events in the early stages of dysplasia development and thus not only provides novel candidate markers for screening but a biological function for targeting treatment.
PMCID: PMC2277413  PMID: 18248679
9.  Using LongSAGE to Detect Biomarkers of Cervical Cancer Potentially Amenable to Optical Contrast Agent Labelling 
Biomarker Insights  2007;2:447-461.
Sixteen longSAGE libraries from four different clinical stages of cervical intraepithelial neoplasia have enabled us to identify novel cell-surface biomarkers indicative of CIN stage. By comparing gene expression profiles of cervical tissue at early and advanced stages of CIN, several genes are identified to be novel genetic markers. We present fifty-six cell-surface gene products differentially expressed during progression of CIN. These cell surface proteins are being examined to establish their capacity for optical contrast agent binding. Contrast agent visualization will allow real-time assessment of the physiological state of the disease process bringing vast benefit to cancer care. The data discussed in this publication have been submitted to NCBIs Gene Expression Omnibus (GEO, and are accessible through GEO Series accession number GSE6252.
PMCID: PMC2717845  PMID: 19662225
longSAGE; cervical cancer; biomarker; optical imaging
10.  Comprehensive serial analysis of gene expression of the cervical transcriptome 
BMC Genomics  2007;8:142.
More than half of the approximately 500,000 women diagnosed with cervical cancer worldwide each year will die from this disease. Investigation of genes expressed in precancer lesions compared to those expressed in normal cervical epithelium will yield insight into the early stages of disease. As such, establishing a baseline from which to compare to, is critical in elucidating the abnormal biology of disease. In this study we examine the normal cervical tissue transcriptome and investigate the similarities and differences in relation to CIN III by Long-SAGE (L-SAGE).
We have sequenced 691,390 tags from four L-SAGE libraries increasing the existing gene expression data on cervical tissue by 20 fold. One-hundred and eighteen unique tags were highly expressed in normal cervical tissue and 107 of them mapped to unique genes, most belong to the ribosomal, calcium-binding and keratinizing gene families. We assessed these genes for aberrant expression in CIN III and five genes showed altered expression. In addition, we have identified twelve unique HPV 16 SAGE tags in the CIN III libraries absent in the normal libraries.
Establishing a baseline of gene expression in normal cervical tissue is key for identifying changes in cancer. We demonstrate the utility of this baseline data by identifying genes with aberrant expression in CIN III when compared to normal tissue.
PMCID: PMC1899502  PMID: 17543121
11.  Randomized clinical evaluation of self-screening for anal cancer precursors in men who have sex with men 
CytoJournal  2006;3:4.
Self-collection of anorectal swab specimens could greatly facilitate the completion of prerequisite studies and future implementation of anal cancer screening among men who have sex with men (MSM). We therefore compared self- versus clinician- collection procedures with respect to specimen adequacy for cytological evaluation, concordance of paired cytological results, and concordance of cytological with biopsy results.
Paired self- and clinician- collected anorectal Dacron® swabs for liquid-based (Thin Prep®) cytological evaluation were collected in random sequence from a mostly HIV-1 seronegative cohort of young MSM in Vancouver. Slides were reviewed by one cytopathologist. Presence of any cytological abnormality (atypical squamous cells of uncertain significance, ASCUS, or above) prompted referral for high-resolution anoscopy and possible biopsy.
Among 222 patient-clinician specimen pairs, most were adequate for cytological evaluation, though self-collected specimens were less likely to be so (83% versus 92%, McNemar's test p < 0.001). Cytological abnormalities, noted in 47 (21%) of self-collected and 47 (21%) of clinician-collected specimens (with fair agreement, kappa = 0.414) included, respectively: ASCUS (5%, 5%), and low-grade (13%, 13%) and high-grade (3%, 3%) squamous intraepithelial lesions. Among 12 men with biopsy-confirmed high-grade neoplasia, most had abnormal cytological results (including 6 patient and 9 clinician swabs) but few (2 patient and 1 clinician swab) were high-grade.
Self-collection of anorectal swab specimens for cytologic screening in research and possibly clinical settings appears feasible, particularly if specimen adequacy can be further improved. The severity of biopsy-confirmed anorectal disease is seriously underestimated by cytological screening, regardless of collector.
PMCID: PMC1435770  PMID: 16549010

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