Η λεμφαγγειογένεση η σχετιζόμενη με όγκους πρόσφατα έχει θεωρηθεί σαν ένας νέος μηχανισμός εξάπλωσης του καρκίνου. Όμως υπάρχει μεγάλη ετερογένεια στα αποτελέσματα των μελετών που συσχετίζουν την έκφραση λεμφαγγειακών δεικτών στο ενδοθήλιο των λεμφαγγείων με κλινικοπαθολογοανατομικές παραμέτρους των όγκων και με την πρόγνωση των ασθενών. Επίσης ένα μεγάλο θέμα διαφωνίας είναι το ποια είναι η σημασία των περιογκικών σε σχέση με τα ενδοογκικά λεμφαγγεία για την μετάσταση των όγκων. Στην παρούσα μελέτη διερευνήσαμε την έκφραση και την πιθανή προγνωστική σημασία των δεικτών του λεμφαγγειακού ενδοθηλίου, VEGFR-3, Ρodoplanin και LYVE-1 σε διηθητικά καρκινώματα εκ πλακώδους επιθηλίου του τραχήλου της μήτρας . Υλικά και Μέθοδοι: Το υλικό της μελέτης αποτέλεσαν 51 παρασκευάσματα υστερεκτομών με διηθητικό καρκίνωμα εκ πλακώδους επιθηλίου τραχήλου. Με την μέδοδο της Ανοσοϊστοχημείας εξετάσθηκε η πρωτεϊνική έκφραση των δεικτών CD31, VEGFR-3, Ρodoplanin και LYVE-1.Ο έλεγχος της παρουσίας ανοσοθετικών αγγείων για όλα τα ανωτέρω μόρια έγινε σε όλη την έκταση της ιστολογικής τομής, μέσα στο παρέγχυμα και σε όλη την περιφέρεια του όγκου με μικρή μεγέθυνση φωτονικού μικροσκοπίου( x 4 ).Η αγγειακή πυκνότης εκτιμήθηκε στις περιοχές με την μεγαλύτερη αγγειοβρίθεια (hot spots) σε πέντε συνεχόμενα μεγάλα οπτικά πεδία (HPF=. x 400) και ορίσθηκε ως ο μέσος όρος του αριθμού των αγγείων στα πεδία αυτά. Χρησιμοποιήθηκε στατιστικό πρόγραμμα ανάλυσης SPSS for windows με σκοπό την εκτίμηση της πιθανής συσχέτισης μεταξύ του βαθμού της αγγειακής πυκνότητας και κλινικοπαθολογοανατομικών παραμέτρων όπως είναι ο βαθμός κακοηθείας ,το στάδιο του όγκου και η παρουσία λεμφαδενικών μεταστάσεων.. Αποτελέσματα: Η Ρodoplanin και LYVE-1 εκφράσθηκαν στο ενδοθήλιο των λεμφαγγείων ενώ έκφραση του VEGFR-3 παρατηρήθηκε στα λεμφαγγεία αλλά και στα αιμοφόρα αγγεία.. Η αγγειακή πυκνότης με βάση την έκφραση του VEGFR3 συσχετίσθηκε στατιστικά σημαντικά με την αγγειακή πυκνότητα με βάση την έκφραση του CD31 .Η αγγειακή πυκνότης όπως αναδείχθηκε με την έκφραση του VEGFR3 σχετίσθηκε σημαντικά με όγκους αυξημένου βαθμού κακοηθείας .Αυξημένη ενδοογκική λεμφαγγειακή πυκνότης όπως αναδείχθηκε με την έκφραση LYVE-1 σχετίσθηκε επίσης στατιστικά σημαντικά με όγκους προχωρημένου σταδίου. Όμως δεν παρατηρήθηκε συσχέτιση της έκφρασης των λεμφαγγειακών δεικτών με την παρουσία λεμφαδενικών μεταστάσεων. Συμπέρασμα: Τα αποτελέσματα αυτής της μελέτης δηλώνουν ότι ο VEGFR-3 δεν αποτελεί πιθανόν ένα ειδικό δείκτη λεμφαγγείων αλλά φαίνεται να εμπλέκεται και στην αγγειογένεση των όγκων .Ο VEGFR3 και LYVE-1 αλλά όχι η Ρodoplanin συσχετίσθηκαν με προγνωστικές παραμέτρους του καρκινώματος του τραχήλου όπως είναι ο βαθμός κακοηθείας και το στάδιο της νόσου. Αυτό το γεγονός υποδηλώνει ότι η χρήση πολλαπλών λεμφαγγειακών δεικτών είναι απαραίτητη για την εκτίμηση της προγνωστικής σημασίας της λεμφαγγειογένεσης που σχετίζεται με όγκους .Λόγω του ότι δεν βρέθηκε συσχέτιση μεταξύ της λεμφαγγειακής πυκνότητος και της μετάστασης σε λεμφαδένες , η σχετιζόμενη με όγκους λεμφαγγειογένεση πιθανόν να αποτελεί μία επιπλέον οδό καρκινικής διασποράς αλλά όχι απαραίτητη προϋπόθεση για την μετάσταση του καρκίνου του τραχήλου της μήτρας. / Tumor-associated lymphangiogenesis has now been firmly established as a novel mechanism of cancer progression. However, results regarding correlation of lymphatic markers expression to clinicopathological tumor parameters and prognosis of cancer patients are heterogenous. In the present study we assessed the expression and prognostic significance of the lymphatic endothelial markers VEGFR-3, podoplanin and LYVE-1 and the panendothelial marker CD31 in invasive squamous cell carcinoma (SCC) of the uterine cervix. Design. The study comprised of 51 hysterectomy specimens with invasive SCC of the uterine cervix. Protein expression of CD31, VEGFR-3, podoplanin and LYVE-1 was examined by means of immunohistochemistry.Vessel counting was performed in whole tumor histologic section as well as in inner tumor areas and invasive tumor fronts separately. Vessel density scores were evaluated in areas of higher vascularization (hot spots). Statistical analysis was performed using SPSS v.12 to evaluate potential correlation between vessel density scores and clinicopathological parameters such as tumor grade, presence of lymph node metastases and disease stage. Results. While podoplanin and LYVE-1 was mainly expressed in lymphatic endothelium VEGFR-3 expression was observed in both lymphatic and blood vessels. Intratumoral vessel density for all markers used was significantly higher in intratumoral compared with peritumoral areas. There was a significant correlation between vessel density scores as assessed by VEGFR3 and CD31 (p<0.001, r=0.5). Intratumoral and peritumoral VEGFR3 vessel density significantly correlated with advancing tumor grade (p=0.001 and p=0.035 respectively). Intratumoral LVD (lymph vessel density) as assessed by LYVE-1 immunostaining was also significantly higher in high stage tumors (p=0.008). However there was no correlation of lymphatic markers expression with nodal metastases. Conclusions. Our results suggest that VEGFR-3 does not probably represent a specific lymphatic marker but it is also implicated in tumor angiogenesis. VEGFR3 and LYVE-1 but not podoplanin correlated with prognostic parameters of cervical carcinomas such as grade and stage, suggesting that the use of multiple lymphatic markers is required for the evaluation of the prognostic significance of tumor associated lymphangiogenesis. While both intratumoral and peritumoral VEGFR3 correlated with grade only intratumoral LVD for LYVE-1 correlated with stage suggesting that the relative significance of intartumoral versus peritumoral lymphatics remains a matter of debate. Finally, since there was no correlation between LVD scores and nodal status, tumor associated lymphatics should be regarded as an additional pathway rather than a necessity for lymph node metastasis in cervical cancer.

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Screening for breast and cervical cancers can reduce morbidity and mortality through early detection, yet many women are not getting regular lifesaving screenings as recommended. 2 The National Breast and Cervical Detection Program (NBCCEDP) was established in 1990 in order to provide low-income, uninsured, and underserved women access to breast and cervical cancer screening and diagnostic services. Georgia’s participation in the NBCCEDP led to the development of The Breast and Cervical Cancer Program (BCCP), which provides cancer screening to women 40 to 64 years of age who are uninsured and/or underinsured and at or below 200% poverty level. Deaths from breast and cervical cancers could be avoided if screening rates increased among women at risk. In order to better eliminate barriers to screening, Georgia’s Breast and Cervical Cancer Program uses client navigators to communicate with minority populations. The purpose of my thesis study was to assess the effectiveness of the Client Navigator Program utilized to enhance breast and cervical cancer screening rates for women throughout Georgia. Evaluation findings demonstrated that personal characteristics of Client Navigators, internal characteristics of the program itself, resources provided by the program, and program partnerships were the areas of greatest program strength. Funding was repeatedly listed as the greatest program threat. Findings from this study provide insights for how the overall program can be improved in the future, and thus, improving health outcomes for women who are at greatest risk of breast and cervical cancer throughout the state.

Adaptive radiation therapy re-optimizes treatment plans based on updated tumor geometries from magnetic resonance imaging scans. However, the imaging process is costly in labor and equipment. In this study, we develop a mathematical model that describes tumor evolution based on a Markov assumption. We then extend the model to predict tumor evolution with any level of information from a new patient: weekly MRI scans are used to estimate transition probabilities when available, otherwise historical MRI scans are used. In the latter case, patients in the historical data are clustered into two groups, and the model relates the new patient's behavior to the existing two groups. The models are evaluated with 33 cervical cancer patients from Princess Margaret Cancer Centre. The result indicates that our models outperform the constant volume model, which replicates the current clinical practice.

Adaptive radiation therapy re-optimizes treatment plans based on updated tumor geometries from magnetic resonance imaging scans. However, the imaging process is costly in labor and equipment. In this study, we develop a mathematical model that describes tumor evolution based on a Markov assumption. We then extend the model to predict tumor evolution with any level of information from a new patient: weekly MRI scans are used to estimate transition probabilities when available, otherwise historical MRI scans are used. In the latter case, patients in the historical data are clustered into two groups, and the model relates the new patient's behavior to the existing two groups. The models are evaluated with 33 cervical cancer patients from Princess Margaret Cancer Centre. The result indicates that our models outperform the constant volume model, which replicates the current clinical practice.

Aisha Kamilah O. Lofters Cervical Cancer Screening Among Ontario’s Urban Immigrants Doctor of Philosophy, 2012 Institute of Health Policy, Management and Evaluation University of Toronto Background: The majority of cervical cancers can be prevented because of the highly effective screening tool, the Papanicolaou (Pap) test. Relevant guidelines recommend routine screening for nearly all adult women. However, inequities in screening exist in Ontario. This dissertation, consisting of three studies, uses administrative data to advance knowledge on barriers to cervical cancer screening for Ontario’s urban immigrant population. Methods: First, we developed and validated a billing code-based algorithm for cervical cancer screening. We then implemented this algorithm to examine screening rates in Ontario among women with various sociodemographic characteristics for 2003-2005. Second, we compared the prevalence of appropriate cervical cancer screening in Ontario in 2006-2008 among immigrant women from all major geographic regions of the world and Canadian-born women. Third, we used a stratified multivariate analysis to determine if the independent effects of various factors that could serve as screening barriers were modified by region of origin for immigrant women for 2006-2008. Results: Our first study showed that our algorithm was 99.5% sensitive and 85.7% specific, and that screening inequities in Ontario’s urban areas are largest among women 50 years and older, living in the lowest-income neighbourhoods and new to the province. In our second study, we determined that immigrant women had significantly lower screening rates than their peers, with the most pronounced differences seen for South Asian women aged 50 years and above. In the final study, we demonstrated that living in the lowest-income neighbourhoods, being younger than 35 years or older than 49 years, not being enrolled in a primary care enrolment model, having a male provider, and having a provider from the same region of the world each significantly influenced screening for immigrant women regardless of region of origin. Conclusion: These results add to the literature on health equity in cancer screening. Our findings demonstrate that Ontario’s urban immigrant women experience significant inequities in cervical cancer screening, and may offer guidance toward targeted patient and physician interventions to decrease screening gaps.

Aisha Kamilah O. Lofters Cervical Cancer Screening Among Ontario’s Urban Immigrants Doctor of Philosophy, 2012 Institute of Health Policy, Management and Evaluation University of Toronto Background: The majority of cervical cancers can be prevented because of the highly effective screening tool, the Papanicolaou (Pap) test. Relevant guidelines recommend routine screening for nearly all adult women. However, inequities in screening exist in Ontario. This dissertation, consisting of three studies, uses administrative data to advance knowledge on barriers to cervical cancer screening for Ontario’s urban immigrant population. Methods: First, we developed and validated a billing code-based algorithm for cervical cancer screening. We then implemented this algorithm to examine screening rates in Ontario among women with various sociodemographic characteristics for 2003-2005. Second, we compared the prevalence of appropriate cervical cancer screening in Ontario in 2006-2008 among immigrant women from all major geographic regions of the world and Canadian-born women. Third, we used a stratified multivariate analysis to determine if the independent effects of various factors that could serve as screening barriers were modified by region of origin for immigrant women for 2006-2008. Results: Our first study showed that our algorithm was 99.5% sensitive and 85.7% specific, and that screening inequities in Ontario’s urban areas are largest among women 50 years and older, living in the lowest-income neighbourhoods and new to the province. In our second study, we determined that immigrant women had significantly lower screening rates than their peers, with the most pronounced differences seen for South Asian women aged 50 years and above. In the final study, we demonstrated that living in the lowest-income neighbourhoods, being younger than 35 years or older than 49 years, not being enrolled in a primary care enrolment model, having a male provider, and having a provider from the same region of the world each significantly influenced screening for immigrant women regardless of region of origin. Conclusion: These results add to the literature on health equity in cancer screening. Our findings demonstrate that Ontario’s urban immigrant women experience significant inequities in cervical cancer screening, and may offer guidance toward targeted patient and physician interventions to decrease screening gaps.

Background: Cervical cancer is the second most common cancer among women worldwide and its incidence is higher for certain ethnic groups in Canada, compared to White Canadians. As more women immigrate to Canada, the potential for prevention increases. Failure to prevent cervical cancer is partly due to non-participation in regular screening. The objectives of the research were to (1) explore whether there are cervical cancer screening differences between non-immigrant and immigrant women; (2) explore cervical cancer screening decision-making among immigrant women; and (3) explore the influence of acculturation on cervical cancer screening. Methods: This research consisted of two studies. The first study consisted of quantitative analysis of the 2007-2008 Canadian Community Health Survey (CCHS). Univariate analyses, cross-tabulations, and logistic regression modeling were conducted. Analyses were restricted to women aged 18-69 years old living in Ontario with no history of hysterectomy. Sample weights were applied and bootstrapping was performed. Analyses were conducted on the full Ontario sample (unweighted n=13,549) and the immigrant sample (unweighted n=2,904), the latter of which was stratified into two groups based on self-reported cultural/racial background: immigrant women more likely to report a time-appropriate Pap test (low risk) and those less likely to report a time-appropriate Pap test (high risk). The second study consisted of interviews conducted with 22 older (aged 50-69 years) South Asian immigrant women from Waterloo and Toronto, Ontario. The descriptive qualitative study was informed by grounded theory methodology. Interviews were audio-recorded and transcribed. Results: The first study identified that almost 17% of women reported not having a time-appropriate Pap test. Immigrant women were more likely to report not having a time-appropriate Pap test (21.73%) compared to non-immigrants (14.22%). Among immigrant women, almost 17% of White, Black, and other women (low-risk group) did not report a recent Pap test, compared to 28.67% of Chinese, South Asian, and other Asian women (high-risk group). Among the full Ontario sample, not having a time-appropriate Pap test was associated with being 50-69 years old, single, having low education and income, not having a regular doctor, being of Asian (Chinese, South Asian, other Asian) cultural/racial background, perceiving having less than excellent health, and being a recent immigrant. Among women in the low-risk group, not having a recent Pap test was associated with older age, lower household income, not having a regular doctor, and a lower proportion of life spent in Canada. Among women in the high-risk group, not having a time-appropriate Pap test was associated with lower education and not having a regular doctor. Within the second study, various themes emerged exploring cervical cancer screening decision-making among the sample. Six major categories emerged: (1) the influence of others, (2) health beliefs and knowledge, (3) responsibility over health, (4) experiences in healthcare, (5) components of culture, and (6) the process of acculturation. The influence of doctors on cervical cancer screening decision-making emerged as a strong theme within interviews. Conclusion: Results provide insight into the inequities that still exist in terms of who is participating in cervical cancer screening, as well as the factors involved in screening decision-making and the relationships between them. This research provides an updated overview of Pap test participation in Ontario, as well as advancing our understanding of the influence of factors on screening decision-making among immigrant women. Through this research, it becomes clear that targeted efforts must be directed towards those less likely to get a Pap test.

Background: Cervical cancer is the second most common cancer among women worldwide and its incidence is higher for certain ethnic groups in Canada, compared to White Canadians. As more women immigrate to Canada, the potential for prevention increases. Failure to prevent cervical cancer is partly due to non-participation in regular screening. The objectives of the research were to (1) explore whether there are cervical cancer screening differences between non-immigrant and immigrant women; (2) explore cervical cancer screening decision-making among immigrant women; and (3) explore the influence of acculturation on cervical cancer screening. Methods: This research consisted of two studies. The first study consisted of quantitative analysis of the 2007-2008 Canadian Community Health Survey (CCHS). Univariate analyses, cross-tabulations, and logistic regression modeling were conducted. Analyses were restricted to women aged 18-69 years old living in Ontario with no history of hysterectomy. Sample weights were applied and bootstrapping was performed. Analyses were conducted on the full Ontario sample (unweighted n=13,549) and the immigrant sample (unweighted n=2,904), the latter of which was stratified into two groups based on self-reported cultural/racial background: immigrant women more likely to report a time-appropriate Pap test (low risk) and those less likely to report a time-appropriate Pap test (high risk). The second study consisted of interviews conducted with 22 older (aged 50-69 years) South Asian immigrant women from Waterloo and Toronto, Ontario. The descriptive qualitative study was informed by grounded theory methodology. Interviews were audio-recorded and transcribed. Results: The first study identified that almost 17% of women reported not having a time-appropriate Pap test. Immigrant women were more likely to report not having a time-appropriate Pap test (21.73%) compared to non-immigrants (14.22%). Among immigrant women, almost 17% of White, Black, and other women (low-risk group) did not report a recent Pap test, compared to 28.67% of Chinese, South Asian, and other Asian women (high-risk group). Among the full Ontario sample, not having a time-appropriate Pap test was associated with being 50-69 years old, single, having low education and income, not having a regular doctor, being of Asian (Chinese, South Asian, other Asian) cultural/racial background, perceiving having less than excellent health, and being a recent immigrant. Among women in the low-risk group, not having a recent Pap test was associated with older age, lower household income, not having a regular doctor, and a lower proportion of life spent in Canada. Among women in the high-risk group, not having a time-appropriate Pap test was associated with lower education and not having a regular doctor. Within the second study, various themes emerged exploring cervical cancer screening decision-making among the sample. Six major categories emerged: (1) the influence of others, (2) health beliefs and knowledge, (3) responsibility over health, (4) experiences in healthcare, (5) components of culture, and (6) the process of acculturation. The influence of doctors on cervical cancer screening decision-making emerged as a strong theme within interviews. Conclusion: Results provide insight into the inequities that still exist in terms of who is participating in cervical cancer screening, as well as the factors involved in screening decision-making and the relationships between them. This research provides an updated overview of Pap test participation in Ontario, as well as advancing our understanding of the influence of factors on screening decision-making among immigrant women. Through this research, it becomes clear that targeted efforts must be directed towards those less likely to get a Pap test.

Human Papillomavirus (HPV) is one of the most common causes of sexually transmitted disease worldwide. Infections by high-risk HPVs, such as HPV-18, have been associated etiologically with cervical cancer. The successful development of HPV vaccines may be beneficial to the HPV-na??ve population, but women that have already been exposed to the virus are still at risk of developing HPV-associated malignancies. A need for a systemic cure for HPV-infection therefore still exists. Gene therapies using tissue-specific promoters have been reported to be a promising tool for treating cancers; however, few studies have explored this possibility for cervical cancer. The aim of this project is to construct a gene expression vector that can specifically target HPV-infected cervical cancer cells, by making use of the activity and selectivity of the P105 promoter which is determined by transcription control elements within the HPV-18 long control region (LCR). The first part of this study involved the construction of LCR deletion plasmids, and examining the subsequent level of gene expression induced within different mammalian cell lines. The results suggest the LCR to be capable in achieving cervical cancer-specific gene expression. The 3′-end of the viral L1 gene upstream of the LCR appeared to have a repressive effect on the promoter and therefore should be excluded for maximum LCR promoter activity. The second part of the project involved site-directed mutagenesis studies performed on selected transcription factor binding sites with an attempt to further increase the level of LCR promoter activity and specificity towards HPV-infected cervical cancer cells. The results suggest that a GRE/YY1 mutation may significantly enhance promoter activity. In terms of promoter regulation, the E2BSs appeared to be responsible for promoter activation in the absence of viral E2 proteins. The findings of this study suggest a possible gene therapy approach towards the treatment of cervical cancer. By making use of the activity and specificity of the HPV-18 P105 promoter to induce cervical carcinoma-specific expression of appropriate therapeutic genes, suicidal phenotypes can be introduced selectively within HPV-positive cervical cancer cells while normal HPV-negative cells are unaffected.