Predictors of timely diagnostic follow-up after an abnormal Pap test among Hispanic women seeking care in El Paso, Texas.

BACKGROUND: Diagnostic follow-up of women with an abnormal Pap test is necessary to resolve the risk developing cervical cancer. The purpose of this study is to describe patient characteristics associated with timely receipt of a diagnostic colposcopy after an abnormal Pap test among Hispanic women in El Paso, a Texas-Mexico border city. METHODS: We conducted a retrospective chart review of Hispanic patients seen at an academic colposcopy clinic following an abnormal Pap test. An optimal diagnostic interval to colposcopy was based on a National Breast and Cervical Cancer Early Detection Program (NBCCEDP) quality indicator and was defined as receipt of colposcopy within 90 days or less from the date of an abnormal Pap test. Risk ratios (RR) were calculated by building a generalized linear model fit using a Poisson distribution, log link, and robust variance. RESULTS: Overall, 177 of the 270 women (65.6%) received follow-up within an optimal diagnostic interval. After adjusting for other variables in the model, women who were 30 years of age or older were 32% more likely to have an optimal interval than younger women (adjusted RR = 1.32, P < 0.01). High school graduates were less likely than more educated women to have an optimal interval (adjusted RR = 0.68, P < 0.01). Participation in the NBCCEDP was not associated with receipt of follow-up within an optimal diagnostic interval. CONCLUSIONS: Compared with women with greater educational attainment, high school graduates were less likely to receive follow-up within an optimal diagnostic interval, as were younger (≤ 30 years) women compared with older women. Participation in the NBCCEDP was not associated with receipt of care within an optimal diagnostic interval.

Racial/ethnic variation in the prevalence of vaccine-related human papillomavirus genotypes.

Objective: There are currently three licensed human papillomavirus (HPV) vaccines that protect against cervical cancer. Here we compare the prevalence of bi-, quadri-, and nonavalent vaccine-related HPV genotypes in a multi-ethnic sample of non-Hispanic white, non-Hispanic black, Hispanic, and Asian women. Design: Patients in this analysis (n = 419) represent a subset of women with a previous abnormal Pap test participating in a clinical trial. HPV genotyping was conducted using the Roche Linear Array. Prevalent HPV genotypes were grouped according to their inclusion in each of the vaccines: bivalent (16, 18), quadrivalent (16, 18, 6, 11), and nonavalent (16, 18, 31, 33, 45, 52, 58, 6, 11). Results: The prevalence of HPV genotypes covered by the bi-/quadrivalent vaccines was lowest among non-Hispanic black (15%) and Hispanic women (20%), compared to non-Hispanic white (38%) and Asian women (38%). Across all racial/ethnic groups, a large proportion of infections (38%-49%) were with genotypes included in the nonavalent vaccine. However, the prevalence of HPV genotypes not covered by any vaccine was significantly higher among non-Hispanic black (36%) and Hispanic women (42%), compared to non-Hispanic white (24%) and Asian women (16%) (p < 0.001). Racial/ethnic differences in HPV genotype prevalence were observed when controlling for demographic and sexual behavior characteristics, as well as when restricting the analysis to women with CIN 2+. Conclusion: Our data suggest racial/ethnic differences in the prevalence of vaccine-related HPV genotypes. In particular, non-Hispanic black and Hispanic women had the lowest prevalence of HPV genotypes covered by the bi-/quadrivalent vaccines. While a large proportion of their infections were covered by the nonavalent vaccine, non-Hispanic black and Hispanic women also had the highest prevalence of HPV genotypes not covered by any vaccine.

Quantification of confocal fluorescence microscopy for the detection of cervical intraepithelial neoplasia.

BACKGROUND: Cervical cancer remains a major health problem, especially in developing countries. Colposcopic examination is used to detect high-grade lesions in patients with a history of abnormal pap smears. New technologies are needed to improve the sensitivity and specificity of this technique. We propose to test the potential of fluorescence confocal microscopy to identify high-grade lesions. METHODS: We examined the quantification of ex vivo confocal fluorescence microscopy to differentiate among normal cervical tissue, low-grade Cervical Intraepithelial Neoplasia (CIN), and high-grade CIN. We sought to (1) quantify nuclear morphology and tissue architecture features by analyzing images of cervical biopsies; and (2) determine the accuracy of high-grade CIN detection via confocal microscopy relative to the accuracy of detection by colposcopic impression. Forty-six biopsies obtained from colposcopically normal and abnormal cervical sites were evaluated. Confocal images were acquired at different depths from the epithelial surface and histological images were analyzed using in-house software. RESULTS: The features calculated from the confocal images compared well with those features obtained from the histological images and histopathological reviews of the specimens (obtained by a gynecologic pathologist). The correlations between two of these features (the nuclear-cytoplasmic ratio and the average of three nearest Delaunay-neighbors distance) and the grade of dysplasia were higher than that of colposcopic impression. The sensitivity of detecting high-grade dysplasia by analysing images collected at the surface of the epithelium, and at 15 and 30 µm below the epithelial surface were respectively 100, 100, and 92 %. CONCLUSIONS: Quantitative analysis of confocal fluorescence images showed its capacity for discriminating high-grade CIN lesions vs. low-grade CIN lesions and normal tissues, at different depth of imaging. This approach could be used to help clinicians identify high-grade CIN in clinical settings.

A statistical model for removing inter-device differences in spectroscopy.

We are investigating spectroscopic devices designed to make in vivo cervical tissue measurements to detect pre-cancerous and cancerous lesions. All devices have the same design and ideally should record identical measurements. However, we observed consistent differences among them. An experiment was designed to study the sources of variation in the measurements recorded. Here we present a log additive statistical model that incorporates the sources of variability we identified. Based on this model, we estimated correction factors from the experimental data needed to eliminate the inter-device variability and other sources of variation. These correction factors are intended to improve the accuracy and repeatability of such devices when making future measurements on patient tissue.

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 50ng 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.

Association of traffic-related hazardous air pollutants and cervical dysplasia in an urban multiethnic population: a cross-sectional study.

BACKGROUND: Human papillomavirus (HPV) infection is a necessary cause in the development of cervical cancer; however, not all women infected with HPV develop cervical cancer indicating that other risk factors are involved. Our objective was to determine the association between exposure to ambient levels of common traffic-related air toxics and cervical dysplasia, a precursor lesion for cervical cancer. METHODS: The study sample consisted of women enrolled in a Phase II clinical trial to evaluate diagnostic techniques for cervical disease in Houston, Texas. The current assessment is a secondary data analysis in which cases were defined as women diagnosed with cervical dysplasia, while those without cervical dysplasia served as controls. Residential census tract-level estimates of ambient benzene, diesel particulate matter (DPM), and polycyclic aromatic hydrocarbons (PAHs) were used to assess exposure. Census tract-level pollutant estimates were obtained from the United States Environmental Protection Agency. Multivariable logistic regression was used to estimate prevalence odds ratios (aOR) and 95% confidence intervals (CI) adjusted for age, race/ethnicity, education, smoking status, and HPV status. RESULTS: Women in the highest residential exposure categories for benzene and DPM had an increased prevalence of cervical dysplasia compared to the lowest exposure category (Benzene: aOR [95% CI] for high exposure = 1.97[1.07-3.62], very high exposure = 2.30[1.19-4.46]. DPM: aOR [95% CI] for high exposure = 2.83[1.55-5.16], very high exposure = 2.10[1.07-4.11]). Similarly, women with high residential exposure to PAHs had an increased prevalence of cervical dysplasia (aOR [95% CI] = 2.46[1.35-4.48]). The highest PAH exposure category was also positively associated with cervical dysplasia prevalence but was not statistically significant. Assessment of the combined effect of HAP exposure indicates that exposure to high levels of more than one HAP is positively associated with cervical dysplasia prevalence (p for trend = 0.004). CONCLUSIONS: Traffic-related HAPs, such as benzene, DPM, and PAHs, are not as well-regulated and monitored as criteria air pollutants (e.g., ozone), underscoring the need for studies evaluating the role of these toxicants on disease risk. Our results suggest that exposure to traffic-related air toxics may increase cervical dysplasia prevalence.

Nativity disparities in late-stage diagnosis and cause-specific survival among Hispanic women with invasive cervical cancer: an analysis of Surveillance, Epidemiology, and End Results data.

PURPOSE: While cervical cancer screening and risk behaviors have been found to vary among US- and foreign-born Hispanic women, many cancer epidemiology studies have conceptualized Hispanics as a homogenous group. Here, we examine differences in cervical cancer stage at diagnosis and survival among Hispanic women by nativity. METHODS: We use data from the Surveillance, Epidemiology, and End Results program, 1998-2008. Nativity was based on place of birth and was categorized as US versus foreign born. Distant and regional tumors were classified as late stage, while local tumors were classified as early stage. RESULTS: Forty-seven percent of cases of invasive cervical cancer among Hispanics were diagnosed at a late stage, and over half of invasive cervical cancer cases were among foreign-born women. Foreign-born Hispanic women were significantly more likely than US-born Hispanics to have late-stage diagnosis, after adjusting for age at diagnosis and tumor histology (adjusted odds ration = 1.09, p value = 0.003). There was heterogeneity in the association between nativity and survival by stage at diagnosis. Among cases with early-stage diagnosis, survival was poorer among foreign-born versus US-born Hispanics after adjusting for age at diagnosis, histology, and cancer-directed therapy [adjusted hazard ratios (HR) = 1.31, p value = 0.030]. However, among cases with late-stage diagnosis, survival was better among foreign-born Hispanics (adjusted HR = 0.81, p value < 0.001). CONCLUSIONS: We hypothesize that nativity differences in survival may be indicative of diverse risk, screening, and treatment profiles. Given such differences, it may be inappropriate to aggregate Hispanics as a single group for cervical cancer research.

Polymorphisms in the Nonhomologous End-joining DNA Repair Pathway are Associated with HPV Integration in Cervical Dysplasia.

Previous evidence indicates that human papillomavirus (HPV) integration status may be associated with cervical cancer development and progression. However, host genetic variation within genes that may play important roles in the viral integration process is understudied. The aim of this study was to examine the association between HPV16 and HPV18 viral integration status and SNPs in nonhomologous-end-joining (NHEJ) DNA repair pathway genes on cervical dysplasia. Women enrolled in two large trials of optical technologies for cervical cancer detection and positive for HPV16 or HPV18 were selected for HPV integration analysis and genotyping. Associations between SNPs and cytology (normal, low-grade, or high-grade lesions) were evaluated. Among women with cervical dysplasia, polytomous logistic regression models were used to evaluate the effect of each SNP on viral integration status. Of the 710 women evaluated [149 high-grade squamous intraepithelial lesion (HSIL), 251; low-grade squamous intraepithelial lesion (LSIL, 310 normal)], 395 (55.6%) were positive for HPV16 and 192 (27%) were positive for HPV18. Tag-SNPs in 13 DNA repair genes, including RAD50, WRN, and XRCC4, were significantly associated with cervical dysplasia. HPV16 integration status was differential across cervical cytology, but overall, most participants had a mix of both episomal and integrated HPV16. Four tag-SNPs in the XRCC4 gene were found to be significantly associated with HPV16 integration status. Our findings indicate that host genetic variation in NHEJ DNA repair pathway genes, specifically XRCC4, are significantly associated with HPV integration, and that these genes may play an important role in determining cervical cancer development and progression. PREVENTION RELEVANCE: HPV integration in premalignant lesions and is thought to be an important driver of carcinogenesis. However, it is unclear what factors promote integration. The use of targeted genotyping among women presenting with cervical dysplasia has the potential to be an effective tool in assessing the likelihood of progression to cancer.

Classifying tissue samples from measurements on cells with within-class tissue sample heterogeneity.

We consider here the problem of classifying a macro-level object based on measurements of embedded (micro-level) observations within each object, for example, classifying a patient based on measurements on a collection of a random number of their cells. Classification problems with this hierarchical, nested structure have not received the same statistical understanding as the general classification problem. Some heuristic approaches have been developed and a few authors have proposed formal statistical models. We focus on the problem where heterogeneity exists between the macro-level objects within a class. We propose a model-based statistical methodology that models the log-odds of the macro-level object belonging to a class using a latent-class variable model to account for this heterogeneity. The latent classes are estimated by clustering the macro-level object density estimates. We apply this method to the detection of patients with cervical neoplasia based on quantitative cytology measurements on cells in a Papanicolaou smear. Quantitative cytology is much cheaper and potentially can take less time than the current standard of care. The results show that the automated quantitative cytology using the proposed method is roughly equivalent to clinical cytopathology and shows significant improvement over a statistical model that does not account for the heterogeneity of the data.

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 1,000 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 4,864 biopsies were obtained from the sites measured, including abnormal and normal colposcopic areas. The gold standard was the histologic report of biopsies, read 2 to 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.

Impact of type 2 diabetes on adenoma detection in screening colonoscopies performed in disparate populations.

BACKGROUND: The Black/African Ancestry (AA) population has a higher prevalence of type 2 diabetes mellitus (T2DM) and a higher incidence and mortality rate for colorectal cancer (CRC) than all other races in the United States. T2DM has been shown to increase adenoma risk in predominantly white/European ancestry (EA) populations, but the effect of T2DM on adenoma risk in Black/AA individuals is less clear. We hypothesize that T2DM has a significant effect on adenoma risk in a predominantly Black/AA population. AIM: To investigate the effect of T2DM and race on the adenoma detection rate (ADR) in screening colonoscopies in two disparate populations. METHODS: A retrospective cohort study was conducted on ADR during index screening colonoscopies (age 45-75) performed at an urban public hospital serving a predominantly Black/AA population (92%) (2017-2018, n = 1606). Clinical metadata collected included basic demographics, insurance, body mass index (BMI), family history of CRC, smoking, diabetes diagnosis, and aspirin use. This dataset was combined with a recently reported parallel retrospective cohort data set collected at a suburban university hospital serving a predominantly White/EA population (87%) (2012-2015, n = 2882). RESULTS: The ADR was higher in T2DM patients than in patients without T2DM or prediabetes (35.2% vs 27.9%, P = 0.0166, n = 981) at the urban public hospital. Multivariable analysis of the combined datasets showed that T2DM [odds ratio (OR) = 1.29, 95% confidence interval (CI): 1.08-1.55, P = 0.0049], smoking (current vs never OR = 1.47, 95%CI: 1.18-1.82, current vs past OR = 1.32, 95%CI: 1.02-1.70, P = 0.0026), older age (OR = 1.05 per year, 95%CI: 1.04-1.06, P < 0.0001), higher BMI (OR = 1.02 per unit, 95%CI: 1.01-1.03, P = 0.0003), and male sex (OR = 1.87, 95%CI: 1.62-2.15, P < 0.0001) were associated with increased ADR in the combined datasets, but race, aspirin use and insurance were not. CONCLUSION: T2DM, but not race, is significantly associated with increased ADR on index screening colonoscopy while controlling for other factors.

Using Laddering Interviews and Hierarchical Value Mapping to Gain Insights Into Improving Patient Experience in the Hospital: A Systematic Literature Review.

Hospitals are continuously facing pressures to mitigate the gap between patient's expectations and the quality of services provided. Now with Medicare reimbursements tied to Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) scores, institutions are attempting interventions to increase satisfaction scores. However, a standard framework to understand patient values and perceptions and subsequently translate it into reliable measures of patient satisfaction does not exist, particularly in the inpatient settings. This article highlights opportunity for the addition of qualitative customer value research to augment the information providers gain from HCAHPS scores and provide additional indicators that can be used in improving the patient experience. In this article, patient laddering interviews and hierarchical value mapping are reviewed as methodologies to understand patient core satisfaction values during their hospital stay. A systematic literature search was performed to identify articles addressing laddering interviews and hierarchical value mapping as applied to health care. Inclusion criteria involved studies relating to health care and using laddering interviews. Exclusion criteria included non-health-care studies. Only 3 studies were found eligible for this review. Our systematic review of literature revealed only few studies which may help to guide us to improve patient experience using laddering interviews. These interviews can help compose a personalized bedside survey which may be more meaningful than current widely used HCAHPS survey.

Analysis of count data in the setting of cervical cancer detection.

Women with an abnormal Pap smear are often referred to colposcopy, a procedure during which endocervical curettage (ECC) may be performed. ECC is a scraping of the endocervical canal lining. Our goal was to compare the performance of a naïve Poisson (NP) regression model with that of a zero-inflated Poisson (ZIP) model when identifying predictors of the number of distress/pain vocalizations made by women undergoing ECC. Data on women seen in the colposcopy clinic at a medical school in El Paso, Texas, were analyzed. The outcome was the number of pain vocalizations made by the patient during ECC. Six dichotomous predictors were evaluated. Initially, NP regression was used to model the data. A high proportion of patients did not make any vocalizations, and hence a ZIP model was also fit and relative rates (RRs) and 95% CIs were calculated. AIC was used to identify the best model (NP or ZIP). Of the 210 women, 154 (73.3%) had a value of 0 for the number of ECC vocalizations. NP identified three statistically significant predictors (language preference of the subject, sexual abuse history and length of the colposcopy), while ZIP identified one: history of sexual abuse (yes vs no; adjusted RR=2.70, 95% CI 1.47 to 4.97). ZIP was preferred over NP. ZIP performed better than NP regression. Clinicians and epidemiologists should consider using the ZIP model (or the zero-inflated negative binomial model) for zero-inflated count data.

Imaging intracellular motion with dynamic micro-optical coherence tomography.

This paper describes a new technology that uses 1-µm-resolution optical coherence tomography (µOCT) to obtain cross-sectional images of intracellular dynamics with dramatically enhanced image contrast. This so-called dynamic µOCT (d-µOCT) is accomplished by acquiring a time series of µOCT images and conducting power frequency analysis of the temporal fluctuations that arise from intracellular motion on a pixel-per-pixel basis. Here, we demonstrate d-µOCT imaging of freshly excised human esophageal and cervical biopsy samples. Depth-resolved d-µOCT images of intact tissue show that intracellular dynamics provides a new contrast mechanism for µOCT that highlights subcellular morphology and activity in epithelial surface maturation patterns.

Cervical cytology reproducibility and associated clinical and demographic factors.

BACKGROUND: Although the Pap test has been the standard screening method for cervical precancer/cancer detection, it has been criticized for having a relatively low sensitivity and a low reproducibility between pathologists. There is limited knowledge about inter-rater agreement and what clinical and demographic factors are associated with disagreements between pathologists reading the same Pap smear. METHODS: This study aimed to assess inter- and intra- rater agreement of the Pap smear in 1619 cytologic slides with biopsy confirmation, using kappa statistics. Clinical and demographic factors associated with higher odds of inter-rater agreement were also examined and stratified by histologic diagnosis grade. RESULTS: Using a five grade classification system, the overall kappa statistics for total, inter-rater, and intra-rater samples were 0.62, 0.57, and 0.88 (unweighted) and 0.83, 0.81, and 0.95 (weighted), respectively. In stratified analyses by histologic grade, total kappas ranged from 0.40 (atypia) to 0.64 (human papilloma virus/CIN 1). Factors such as referral for abnormal Pap test (diagnostic vs screening population), recruiting site, and parity were found to be associated with higher agreement between the two cytologic readings. CONCLUSIONS: We observed relatively higher levels of agreement compared with other studies. However, variability was considerable and agreement was generally moderate, suggesting that cervical screening test accuracy and reproducibility needs to be improved.

Confounders in Adenoma Detection at Initial Screening Colonoscopy: A Factor in the Assessment of Racial Disparities as a Risk for Colon Cancer.

BACKGROUND AND AIMS: The incidence and mortality of colorectal cancer is persistently highest in Black/African-Americans in the United States. While access to care, barriers to screening, and poverty might explain these findings, there is increased interest in examining biological factors that impact the colonic environment. Our group is examining biologic factors that contribute to disparities in development of adenomas prospectively. In preparation for this and to characterize a potential patient population, we conducted a retrospective review of initial screening colonoscopies in a cohort of patients. METHODS: A retrospective review was performed on initial average risk screening colonoscopies on patients (age 45-75 years) during 2012 at three institutions. Descriptive statistics and multivariable logistic regression models were used to examine the relationship between potential risk factors and the detection of adenomas. RESULTS: Of the 2225 initial screening colonoscopies 1495 (67.2%) were performed on Black/African-Americans and 566 (25.4%) on Caucasians. Multivariable logistic regression revealed that older age, male sex, current smoking and teaching gastroenterologists were associated with higher detection of adenomas and these were less prevalent among Black/African-Americas except for age. Neither race, ethnicity, BMI, diabetes mellitus, HIV nor insurance were associated with adenoma detection. CONCLUSION: In this sample, there was no association between race and adenoma detection. While this may be due to a lower prevalence of risk factors for adenomas in this sample, our findings were confounded by a lower detection rate by consultant gastroenterologists at one institution. The study allowed us to rectify the problem and characterize patients for future trials.

Up regulation in gene expression of chromatin remodelling factors in cervical intraepithelial neoplasia.

BACKGROUND: 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. RESULTS: 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. CONCLUSION: 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.

The performance of human papillomavirus high-risk DNA testing in the screening and diagnostic settings.

OBJECTIVE: We sought to evaluate the performance of the human papillomavirus high-risk DNA test in patients 30 years and older. MATERIALS AND METHODS: Screening (n=835) and diagnosis (n=518) groups were defined based on prior Papanicolaou smear results as part of a clinical trial for cervical cancer detection. We compared the Hybrid Capture II (HCII) test result with the worst histologic report. We used cervical intraepithelial neoplasia (CIN) 2/3 or worse as the reference of disease. We calculated sensitivities, specificities, positive and negative likelihood ratios (LR+ and LR-), receiver operating characteristic (ROC) curves, and areas under the ROC curves for the HCII test. We also considered alternative strategies, including Papanicolaou smear, a combination of Papanicolaou smear and the HCII test, a sequence of Papanicolaou smear followed by the HCII test, and a sequence of the HCII test followed by Papanicolaou smear. RESULTS: For the screening group, the sensitivity was 0.69 and the specificity was 0.93; the area under the ROC curve was 0.81. The LR+ and LR- were 10.24 and 0.34, respectively. For the diagnosis group, the sensitivity was 0.88 and the specificity was 0.78; the area under the ROC curve was 0.83. The LR+ and LR- were 4.06 and 0.14, respectively. Sequential testing showed little or no improvement over the combination testing. CONCLUSIONS: The HCII test in the screening group had a greater LR+ for the detection of CIN 2/3 or worse. HCII testing may be an additional screening tool for cervical cancer in women 30 years and older.

Accuracy of colposcopy in the diagnostic setting compared with the screening setting.

OBJECTIVE: To estimate the accuracy of colposcopy to identify cervical precancer in screening and diagnostic settings. METHODS: As part of a larger clinical trial to evaluate the diagnostic accuracy of optical spectroscopy, we recruited 1,850 patients into a diagnostic or a screening group depending on their history of abnormal findings on Papanicolaou tests. Colposcopic examinations were performed and biopsies specimens obtained from abnormal and normal colposcopic sites for all patients. The criterion standard of test accuracy was the histologic report of biopsies. We calculated sensitivities, specificities, likelihood ratios, receiver operating characteristic curves, and areas under the receiver operating characteristic curves. RESULTS: The prevalence of high-grade squamous intraepithelial lesions (HSIL) or cancer was 29.0% for the diagnostic group and 2.2% for the screening group. Using a disease threshold of HSIL, colposcopy had a sensitivity of 0.983 and a specificity of 0.451 in the diagnostic group when the test threshold was low-grade squamous intraepithelial lesions (LSIL), and a sensitivity of 0.714 and a specificity of 0.813 when the test threshold was HSIL. Using the same HSIL disease threshold, in the screening group, colposcopy had a sensitivity of 0.286 and a specificity of 0.877 when the test threshold was LSIL, and a sensitivity of 0.191 and a specificity of 0.961 when the threshold was HSIL. The colposcopy area under the receiver operating characteristic curve was 0.821 (95% confidence interval 0.79-0.85) in the diagnostic setting compared with 0.587 (95% confidence interval 0.56-0.62) in the screening setting. Changing the disease threshold to LSIL demonstrated similar patterns in the tradeoff of sensitivity and specificity and measure of accuracy. CONCLUSION: Colposcopy performs well in the diagnostic setting and poorly in the screening setting. Colposcopy should not be used to screen for cervical intraepithelial neoplasia. LEVEL OF EVIDENCE: II.