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1.  Microinvasive cervical squamous cell carcinoma in Slovenia during the period 2001–2007 
Radiology and Oncology  2014;48(3):282-288.
Microinvasive squamous cell carcinoma (MISCC) comprises a significant portion of all cervical cancers in Slovenia. Criteria of carcinomatous invasion are well described in the literature, however histopathological assessment of MISCC is difficult, because morphological characteristics can overlap with cervical intraepithelial neoplasia grade 3 (CIN 3) and other pathological changes. The aim of our study was to evaluate the reliability of the histopathological diagnosis of MISCC in Slovenia during the period from 2001 to 2007.
Materials and methods.
Data on patients with a histopathological diagnosis of cervical MISCC (FIGO stage IA) in the period of 2001 to 2007 were obtained from the Cancer Registry of Slovenia. Histological slides were obtained from the majority of pathology laboratories in Slovenia. We received 250 cases (69% of all MISCC) for the review; 30 control cases with CIN 3 and invasive squamous cell carcinoma FIGO stage IB were intermixed. The slides were coded and reviewed.
Among 250 cases originally diagnosed as MISCC, there was an agreement with MISCC diagnosis in 184 (73.6%) cases (of these 179/184 (97.3%) cases were FIGO stage IA1 and 5/184 (2.7%) cases were FIGO stage IA2). Among 179 FIGO stage IA1 cases 117 (65.4%) showed only early stromal invasion.
The retrospective review of cases diagnosed as MISCC during the period 2001–2007 in Slovenia showed a considerable number of overdiagnosed cases. Amongst cases with MISCC confirmed on review, there was a significant proportion with early stromal invasion (depth of invasion less than 1 mm).
PMCID: PMC4110084  PMID: 25177242
cervical cancer; cervical squamous cell carcinoma; microinvasive squamous cell carcinoma; cervical intraepithelial neoplasia
2.  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
3.  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
4.  Prevalence and type distribution of human papillomavirus in 5,000 British Columbia women—implications for vaccination 
Cancer Causes & Control   2009;20(8):1387-1396.
Human papilloma virus (HPV) prevalence studies performed in different regions and population groups across Canada would inform public health decisions regarding implementation of anti-HPV vaccines.
A total of 8,700 liquid-based specimens from 8,660 women aged 13–86 from throughout British Columbia were collected. DNA was isolated from 4,980 of these samples and assessed for HPV prevalence and type distribution. HPV was detected by PCR analysis using tagged GP5+/6+ consensus primers to amplify the L1 region of HPV; typing was done by bi-directional sequencing of PCR products.
Overall HPV prevalence was 16.8% (age adjusted 15.5%). Prevalence of high-risk HPV was 13.9, and 10.7% of samples contained HPV16. HPV prevalence was highest in the youngest group of women (<20 years). One-third of HPV positive samples contained more than one HPV type. Percentages of low-grade (LGIL) and high-grade intraepithelial lesions (HGIL) containing high-risk HPV are 52.3 and 79.4%, respectively.
Overall HPV prevalence in this study is within the range of estimates from other studies. The prevalence of HPV16 is higher than what is found in other Canadian and international studies. HPV16 and HPV18 compose a majority of the high-risk virus in this study. Use of current HPV vaccines could considerably reduce HPV-related conditions including cervical cancer and procedures such as colposcopy.
Electronic supplementary material
The online version of this article (doi:10.1007/s10552-009-9365-4) contains supplementary material, which is available to authorized users.
PMCID: PMC2746887  PMID: 19475481
HPV; Typing; Prevalence; Canada
5.  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
6.  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
7.  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
8.  Cervical cleaning improves Pap smear quality 
Cervical Papanicolaou (Pap) smear screening is an effective method of detecting cytological changes in the cervix before they lead to cervical cancer. However, the quality of a Pap smear can be compromised by inflammatory exudate, inadequate cellularity or failure to sample the transformation zone. We evaluated the effect of routine cervical cleaning on Pap smear quality.
In a primary care setting, we compared the quality of Pap smears obtained after cervical cleaning (with a dry, oversized cotton swab) with the quality of historical control slides obtained from the same women without prior cervical cleaning. The results for both groups were then compared with statistical averages for the province of British Columbia.
Inflammatory exudate was reported in 1 (0.3%) of the 334 study smears and 72 (11.0%) of the 652 control smears (p < 0.001). Inadequate endocervical or metaplastic squamous cells were reported in 11 (3.3%) of the study smears and 90 (13.8%) of the control smears (p < 0.001). Inadequate cellularity was reported in 13 (3.9%) of the study smears and 9 (1.4%) of the control smears (p = 0.01). There were similar statistical differences between the study group and provincial averages. The results for the control group did not differ significantly from provincial averages (inflammatory exudate, 11.3%; inadequate endocervical cells, 14.7%; and poor cellularity, 2.7%).
Prior cervical cleaning with an oversized cotton swab was associated with a lower frequency of smears with inflammatory exudate or inadequate endocervical cells and, to a lesser degree, a higher frequency of smears with inadequate cellularity.
PMCID: PMC202283  PMID: 14517124
9.  Organisation and results of the cervical cytology screening programme in British Columbia, 1955-85 
A screening programme to detect preinvasive carcinoma of the cervix was started in British Columbia in 1949. Since 1970 the number of women who have been screened at least once has been maintained at about 85% of the population at risk. More than 500 000 cervical smears are being examined each year in the central laboratory. There has been an appreciable increase in the number of cases and rates of carcinoma in situ seen since 1970, particularly in women between 20 and 30 years of age. Since the programme started over 26 000 cases of squamous carcinoma in situ have been detected and treated. The incidence of clinically invasive squamous carcinoma of the cervix has fallen by 78% during the period under review, and mortality from squamous carcinoma of the cervix has fallen by 72%. A colposcopy programme, introduced throughout British Columbia over the past 12 years, has been important in reducing the problems of managing preinvasive lesions, particularly in younger women.
It is concluded that the reduction in morbidity and mortality from invasive squamous cancer of the cervix in British Columbia over the past 30 years is directly attributable to the province wide screening programme and that a large potential increase in invasive cervical cancer rates among younger women is being prevented.
PMCID: PMC2545443  PMID: 3129115

Results 1-9 (9)