Les progrès technologiques considérables réalisés dans le secteur aéronautique militaire ont donné naissance à des avions atteignant des niveaux d'accélération importants (9 Gz sur le Rafale). Ces accélérations, à l'origine de lésions cervicales aigües et chroniques, placent plus que jamais les tolérances biomécaniques des pilotes de chasse au centre des préoccupations. Dans le contexte de protection des personnels navigants, l'Institut de Recherche Biomédicale des Armées (IRBA) coordonne, avec le soutien de la Délégation Générale à l'Armement (DGA), un programme de recherche visant entre autres à mieux comprendre les mécanismes lésionnels impliqués. Les modèles en éléments finis constituent des outils particulièrement propices à l'analyse des risques lésionnels dans la mesure où ils offrent une information quantitative des niveaux de sollicitation des tissus. Néanmoins, aucun modèle ne permet à l'heure actuelle de prendre en compte à la fois les variabilités morphologiques interindividuelles et les tissus musculaires. Le but de cette étude est par conséquent de contribuer à l'étude des mécanismes lésionnels en proposant une approche de modélisation géométrique paramétrée et personnalisée. La méthode consiste à générer automatiquement des maillages du complexe musculo-squelettique du rachis cervical à partir de données issues d'imagerie médicale. Enrichis par des lois de comportement mécanique, ces maillages sont utilisés pour la construction de modèles en éléments finis dont les mobilités segmentaires sont validées dans un premier temps. Une étude préliminaire vise ensuite à mettre en évidence les effets de la morphologie et des tissus musculaires dans le cas des sollicitations en compression axiale qui sont récurrentes sous facteur de charge.

<p>A previous model of morphological pathogenesis assumed that cervical carcinoma is of monoclonal origin and progresses through multiple steps from normal epithelium via CINS into invasive carcinomas. The aim of this study was to investigate the molecular mechanism of pathogenesis of cervical neoplasia. </p><p>In the clonality study, we found that 75% (6/8) of informative cases of cervical carcinoma had identical patterns of loss of heterozygosity (LOH) in the multiple synchronous lesions, while the remaining cases had different LOU patterns. In an extensively studied "golden case", the multiple carcinoma and cervical intraepithelial neoplasia (CIN) lesions could be divided into several different clonal groups by the X-chromosome inactivation patterns, HPV 16 mutations and LOH patterns. The biggest clonal family included one CIN II, one CIN III and four carcinoma samples, while four other monoclonal families of carcinoma did not include CIN lesions. These results suggested that cervical carcinoma can be either monoclonal or polygonal and contains clones developing either directly or via multiple steps. In the study of HPV types and HPV16 variations, the results confirmed that specific HPV types are the cause of cervical carcinoma but failed to support the previous opinion that HPV16 E6 variants are more malignant than the prototype. We established a novel classification called oncogene lineage of HPV16, and found that additional variations of HPV 16 oncogenes might be a weak further risk factor for cervical carcinoma. In the study of LOH, we found that interstitial deletion of two common regions of chromosome 3p, i.e., 3p2l.1-3p2l.3, and 3p22, was an early event in the development of cervical carcinoma. The results showed that the hMLH1 gene, located in 3p22 and showing LOH in 43% of the studied cases, was not involved in the development of cervical carcinoma because neither the expression level of protein nor the gene sequence was altered in these cases. </p><p>In summary, a suggested model of molecular pathogenesis of cervical carcinoma is as follows. Specific types of HPV infect one or more committed stem cells in the basal layer of the epithelium. Fully efficient LOH events turn one (monoclonal origin) or more (polyclonal origin) HPV-infected stem cells into carcinoma cells without CIN steps. Less efficient LOH events would lead to CIN steps where some other unknown factors require to be added to facilitate the formation of carcinoma. In the absence of LOH events no carcinoma develops from the HPV-infected stem cells.</p>

<p>The study aimed to describe the knowledge and awareness of HPV infection and vaccine of female university students and to determine the predictors of vaccine acceptability.&nbsp / The study found that 70% of the participants were sexually active. Awareness and knowledge on HPV/vaccine were poor / with only 22% being aware of HPV and that a HPV vaccine was available in South Africa. A greater proportion (80%) reported willingness to be vaccinated. Being aware of the existence of a pap smear, higher knowledge about HPV, higher perceived vaccine effectiveness and higher perceived severity of HPV infection were significantly associated with increased willingness to be vaccinated.</p>

A previous model of morphological pathogenesis assumed that cervical carcinoma is of monoclonal origin and progresses through multiple steps from normal epithelium via CINS into invasive carcinomas. The aim of this study was to investigate the molecular mechanism of pathogenesis of cervical neoplasia. In the clonality study, we found that 75% (6/8) of informative cases of cervical carcinoma had identical patterns of loss of heterozygosity (LOH) in the multiple synchronous lesions, while the remaining cases had different LOU patterns. In an extensively studied "golden case", the multiple carcinoma and cervical intraepithelial neoplasia (CIN) lesions could be divided into several different clonal groups by the X-chromosome inactivation patterns, HPV 16 mutations and LOH patterns. The biggest clonal family included one CIN II, one CIN III and four carcinoma samples, while four other monoclonal families of carcinoma did not include CIN lesions. These results suggested that cervical carcinoma can be either monoclonal or polygonal and contains clones developing either directly or via multiple steps. In the study of HPV types and HPV16 variations, the results confirmed that specific HPV types are the cause of cervical carcinoma but failed to support the previous opinion that HPV16 E6 variants are more malignant than the prototype. We established a novel classification called oncogene lineage of HPV16, and found that additional variations of HPV 16 oncogenes might be a weak further risk factor for cervical carcinoma. In the study of LOH, we found that interstitial deletion of two common regions of chromosome 3p, i.e., 3p2l.1-3p2l.3, and 3p22, was an early event in the development of cervical carcinoma. The results showed that the hMLH1 gene, located in 3p22 and showing LOH in 43% of the studied cases, was not involved in the development of cervical carcinoma because neither the expression level of protein nor the gene sequence was altered in these cases. In summary, a suggested model of molecular pathogenesis of cervical carcinoma is as follows. Specific types of HPV infect one or more committed stem cells in the basal layer of the epithelium. Fully efficient LOH events turn one (monoclonal origin) or more (polyclonal origin) HPV-infected stem cells into carcinoma cells without CIN steps. Less efficient LOH events would lead to CIN steps where some other unknown factors require to be added to facilitate the formation of carcinoma. In the absence of LOH events no carcinoma develops from the HPV-infected stem cells.

Cervical cancer is the second most common malignancy in women worldwide and one of the leading causes of cancer mortality globally. In patients with invasive cervical cancer prognostic factors are of value for the choice of treatment, monitoring of treatment and follow-up. The most important clinical prognostic factors are stage, tumor volume, parametrial infiltration, vascular invasion, lymph node metastases, and distant metastases. An improved estimation of the prognosis of cervical cancer is desirable, especially in early cancer stages. The aim of this research was to study possible associations between tumor markers, female sex steroids, smoking, S-phase fraction (SPF), and prognosis in invasive squamous cell cervical cancer (SCC). The study comprised 190 patients with SCC, stages IB-IV, admitted to the Department of Gynecologic Oncology at Norrland University Hospital in Umeå between September 1984 and October1990. Ten year mortality was estimated. In study I, of a total of 103 patients, it was found that increased tumor growth, measured by the DNA SPF, was associated with elevated serum progesterone and smoking in the premenopasual patients and with aneuploidy in the whole group. In study II, comprising 128 patients, survival length related to hormone levels and SPF was evaluated in women who died of cervical cancer. In both pre- and postmenopausal women, who died of cervical cancer, SPF at or above 12% was correlated with reduced survival. There was significant positive correlation between a low serum estradiol/progesterone ratio and short survival in those premenopausal women who died of cancer (p=0.02). In study III, ten-year follow-up results in 128 women were compared with the expression of ten relevant tumor markers, assessed by immunohistochemistry. The overall ten-year survival rate in patients with low COX-2 and high CD4+ expression was 76%, versus 53% in the remaining women. The survival rate with absent p53 and high COX-2 expression in the tumors was 42%, versus 71%, while the corresponding figure for the combination of high COX-2 intensity and expression of c-myc was 27%, versus 62%. None of the single markers correlated significantly with outcome in the final Cox regression analyses, while five combinations did. Study IV addressed possible associations between selected tumor markers and cofactors in SCC. Ten tumor markers were examined in 128 patients. Smoking habits and previous oral contraceptive use were recorded. Serum estradiol and progesterone levels were evaluated in 80 women. Highly significant associations were found between strong c-myc staining and increased progesterone, low EGFR staining and high serum estradiol, and absence of p53 staining and smoking. There was an association between absence of p53 and high serum progesterone. In study V, LRIG1 expression was studied in 128 patients and was compared with expression of nine other tumor markers, smoking history, hormone levels, and prognosis. LRIG1 appears to be a significant prognostic predictor in early stage SCC, independent of the other tumor markers that were studied.  Diminished expression in advanced cancer stages and the inverse correlation to serum progesterone and smoking indicate that LRIG1 is a tumor suppressor in squamous cell cervical cancer. Conclusion: The results of these studies support a role of progesterone as a promoter of cervical cancer and indicate that smoking is associated with tumor progression. A combination of tumor markers might be of help in prognostic prediction. LRIG1 acts as a tumor suppressor. These findings might contribute towards greater understanding of prognostic prediction of squamous cell cervical cancer.

Syftet med denna studie var att undersöka hur användningen av bedömningsmetoden cervikal auskultation (CA) ser ut hos dysfagilogopeder i Sverige. Våra frågeställningar var: Hur utspridd är metoden inom logopedkåren? Hur utspridd är metoden i landet? Vilka åsikter finns kring metoden bland logopeder i Sverige? Vilka undersökningsmetoder vid dysfagi används mest bland logopeder i Sverige? Totalt deltog 82 personer i studien. Data samlades in genom en webbenkät. Frågorna i enkäten var blandat öppna och slutna. Resultaten visade att 18 % av de svarande använde CA. Det fanns ett signifikant samband mellan hur ofta man använde metoden och hur säker man kände sig i bedömningen. Signifikans hittades också mellan hur ofta man använde CA och hur stor vikt man lade vid det man kom fram till med metoden när man gjorde sin totala bedömning. Större vikt tillskrevs även CA:s resultat av dem som kände sig säkra i att bedöma med CA. Resultaten visade också att ju fler år man hade använt metoden desto säkrare kände man sig i att göra bedömningar med den. Majoriteten av de som använde CA var självlärda eller hade lärt sig metoden genom kollegor. En tanke som uppkom var om logopeder i Sverige eventuellt tror att CA är menat att användas som enskild bedömningsmetod och därmed ersätta icke-instrumentell bedömning. CA tycks inte användas så frekvent i Sverige främst på grund av brister i evidens och tillförlitlighet men många ser fördelar som skulle motivera användning av CA som en del i icke-instrumentell bedömning. / The purpose of this study was to investigate the use of the assessment method cervical auscultation (CA) amongst speech and language pathologists (SLPs) in Sweden working with dysphagia. We wanted to find out: How widespread is the method in the SLP profession? How widespread is the method in the country? What opinions are there about the method amongst SLP´s in Sweden? What assessment methods within dysphagia are mostly used among SLP´s in Sweden? A total of 82 SLPs participated in the study. Data were collected through an online survey. The survey questions were of both quantitative and qualitative nature. The results showed that 18% of the respondents used CA. There was a significant correlation between the frequency of use of the method and how confident SLPs felt in the assessment. Significance was also found between the frequency of use of CA and how much importance SLPs assigned to what was discovered with the method when making the overall assessment. More importance was also ascribed to the results of CA from those who felt confident in assessing with the method. The results also showed that the longer SLPs had used the method, the more confident they felt in assessing with it. The majority of those who used CA were self-taught or had learned the method through colleagues. A thought that arose was whether the SLPs in Sweden possibly believe that CA is meant to be used as the sole method of assessment, replacing non-instrumental assessment. CA does not seem to be used frequently in Sweden, mainly because of lack of evidence and reliability but many see benefits that would justify the use of CA as part of the clinical assessment.

Die in der Bundesrepublik Deutschland übliche Therapie für das Zervixkarzinom der FIGO-Stadien IB-IIB ist die Wertheim-Meigs-Operation. Bei bestimmten Risikofaktoren wird häufig eine adjuvante Bestrahlung, gegebenenfalls eine postoperative Radioche-motherapie angeschlossen. Die Folge können zahlreiche Einschränkungen der gesund-heitsbezogenen Lebensqualität sein. Zur Verbesserung der postoperativen gesund-heitsbezogenen Lebensqualität wurde eine neue nervenschonende Operationsmetho-de, die totale mesometriale Resektion (TMMR), von Höckel und Kollegen der Universi-tätsfrauenklinik Leipzig entwickelt. Die vorliegende retrospektive Querschnittsstudie untersucht erstmals die Auswirkungen der TMMR im Vergleich zur Wertheim-Meigs-Operation in Bezug auf die postoperative gesundheitsbezogene Lebensqualität. Dazu wurden 110 Zervixkarzinompatientinnen mit der Hilfe der Fragebögen EORTC-QLQ-C30 und EORTC-QLQ-CX24 befragt. Die Ergebnisse dieser Pilotstudie deuten daraufhin, dass Patientinnen nach einer TMMR-Operation im Vergleich zu Frauen nach einer Wert-heim-Meigs-Operation in einigen Teilaspekten eine bessere Lebensqualität haben. So fanden sich bezüglich der postoperativen körperlichen Funktionsfähigkeit und der Rol-lenfunktion sowie der postoperative Ausprägung der Symptome Fatigue, Schmerzen, Diarrhö, Appetitlosigkeit und Dyspnoe in der vorliegenden Untersuchung signifikant bessere Werte in der Gruppe der mittels TMMR operierten Frauen im Vergleich zur Wertheim-Meigs-Gruppe. Dies kann zum Anlass genommen werden große multizentri-sche prospektive Studien durchzuführen.

The purpose of this Thesis is to present a Bayesian analysis of oncological data sets with particular focus on cervical carcinomas and ovarian cancers. Bayesian methods of data analysis have a very long history, and have been used with great success in many disciplines, from Physics to Econometrics. Nonetheless, they remain very controversial among statisticians who belong to the orthodox - i.e, frequentist school, and are not well known by the medical community. To help in that direction, we reviewed in the introductory chapter the basic philosophical and practical differences between the two schools, and in the second chapter, we briefly reviewed the history of Bayesian methodology, from the early efforts of Thomas Bayes and of Pierre Simon de Laplace to the modern contributions of Harold Jeffreys, Richard Cox, and Edwin Jaynes. In many aspects of medical research, we deal with experimental data from which a certain proposition or hypothesis is validated. Unlike in physics, where we have strong and solid foundations such as Newton's law of motion, Snell's optical laws, Kirchoff's laws, Einstein's relativity theory, and many more, we do not have such privileges in medical research. Hence, many hypotheses are constantly tested as new evidence becomes available. One of the actively-researched medical areas is cancer research about which our understanding is still in its infancy. Numerous experiments (both in vivo and in vitro) and clinical trials have been conducted to further our knowledge; thus, Bayesian methodology finds its place to aid us in obtaining scientific inferences about certain propositions or hypotheses from available data and resources. In this work, we use data given to us by our medical collaborators at the Princess Margaret Hospital (PMH) in Toronto to carry out two main projects: Firstly, to make an inference about the oxygenation status (oxygen partial pressure, pO$_2$) within human cervical carcinomas and secondly, an inference about the effectiveness of various molecularly-targeted agents (MTAs) in phase II clinical trials of relapsed ovarian cancer patients. In the first problem, we address the challenges of tumor hypoxia - a state of oxygen deprivation in tumors. Currently, there are two methods to obtain tumor oxygen status, namely the direct Eppendorf needle electrode and the indirect immunohistochemical assay of a protein marker, Carbonic Anhydrase IX (CAIX). In this project, we introduce Bayesian probability theory to obtain inferences about tumor oxygenation from each technique and the concordance between the two techniques. From this study, we conclude that under certain conditions, two biopsies are sufficient to infer the tumor oxygenation level based on the immunohistochemical assays of CAIX. Additionally, there is a fair concordance between the direct and the indirect measurements of tumor oxygenation. In the latter problem, ovarian cancer is the topic of study. Ovarian cancer has the highest mortality rate among gynecological cancers and one that is known to relapse. CA-125 is still the most inexpensive biomarker for monitoring ovarian cancers. From the phase II clinical trial data, we demonstrate the survival advantage of CA-125 responsive group of patients by means of a non-parametric Kaplan-Meier statistic.

SAMMANFATTNING Bakgrund: Livmoderhalscancer orsakas av humant papillomvirus (HPV). De flesta fallen inträffar bland kvinnor som inte deltar i preventionsprogram mot livmoderhalscancer. Syfte: Att undersöka invandrarkvinnors inställning till prevention av livmoderhalscancer. Metod: En explorativ kvalitativ studie. The Health Belief Model har använts som teoretisk modell. Fem fokusgruppintervjuer med 32 kvinnor ålder 18-54 år, som studerade svenska för invandrare. Data analyserades med latent innehållsanalys. Resultat: De temata som kunde urskiljas var svårigheterna med kommunikation med sjukvården, positiva till hälso- kontroll, behov av information för att fatta beslut samt ojämlikhet mellan könen. Kvinnorna i studien var mycket positiva till prevention av livmoderhalscancer och hade hög tilltro till det svenska sjukvårdssystemet. De poängterade i synnerhet kontakten med barnmorska. Deltagarna hade överlag svårigheter med information från sjukvården och saknade kunskap och information om HPV för att kunna fatta beslut om prevention av livmoderhalscancer med HPV- vaccin. Det framkom även att kulturella skillnader och ojämlikhet mellan könen påverkade inställning till prevention av livmoderhalscancer. Slutsats: Informanterna var positiva till prevention av livmoderhalscancer och vill få adekvat kunskap och information om sjukdomen men de har svårigheter med kontakten med sjukvården. Sjukvårdspersonal behöver beakta att kulturella normer påverkar kvinnors inställning till deltagande i det nationella preventionsprogrammet av livmoderhalscancer. / ABSTRACT Background: Cervical cancer is caused by Human papillomavirus (HPV). Most cases occur among women who don’t attend prevention programs. Objective: To explore immigrant women’s attitude towards prevention of cervical cancer. Method: An exploratory qualitative study. The Health Belief Model (HBM) has been used as a theoretical model. Five focus groups interviews with 32 women age 18-54, who studied Swedish for immigrants. Data was analyzed with content analysis. Results: Four main themes were found: difficulties to communicate with healthcare, positive to health control, the need of information to make a decision and inequalities among genders. The informants were positive to prevention of cervical cancer and had high confidence in the Swedish health care system. They appreciated in particular the meeting with the midwife. They had difficulty understanding the information from health care and had inadequate knowledge about HPV to make decisions about prevention of cervical cancer. Cultural differences and inequalities among genders were also related to prevention of cervical cancer. Conclusion: The informants were positive to prevention of cervical cancer and want to have adequate information about the disease. Healthcare professionals should consider that difficulties in contact with healthcare as well as inequalities in gender and cultural aspects have an impact on immigrant women’s attitude to prevention of cervical cancer. / HPV-projektet

The purpose of this Thesis is to present a Bayesian analysis of oncological data sets with particular focus on cervical carcinomas and ovarian cancers. Bayesian methods of data analysis have a very long history, and have been used with great success in many disciplines, from Physics to Econometrics. Nonetheless, they remain very controversial among statisticians who belong to the orthodox - i.e, frequentist school, and are not well known by the medical community. To help in that direction, we reviewed in the introductory chapter the basic philosophical and practical differences between the two schools, and in the second chapter, we briefly reviewed the history of Bayesian methodology, from the early efforts of Thomas Bayes and of Pierre Simon de Laplace to the modern contributions of Harold Jeffreys, Richard Cox, and Edwin Jaynes. In many aspects of medical research, we deal with experimental data from which a certain proposition or hypothesis is validated. Unlike in physics, where we have strong and solid foundations such as Newton's law of motion, Snell's optical laws, Kirchoff's laws, Einstein's relativity theory, and many more, we do not have such privileges in medical research. Hence, many hypotheses are constantly tested as new evidence becomes available. One of the actively-researched medical areas is cancer research about which our understanding is still in its infancy. Numerous experiments (both in vivo and in vitro) and clinical trials have been conducted to further our knowledge; thus, Bayesian methodology finds its place to aid us in obtaining scientific inferences about certain propositions or hypotheses from available data and resources. In this work, we use data given to us by our medical collaborators at the Princess Margaret Hospital (PMH) in Toronto to carry out two main projects: Firstly, to make an inference about the oxygenation status (oxygen partial pressure, pO$_2$) within human cervical carcinomas and secondly, an inference about the effectiveness of various molecularly-targeted agents (MTAs) in phase II clinical trials of relapsed ovarian cancer patients. In the first problem, we address the challenges of tumor hypoxia - a state of oxygen deprivation in tumors. Currently, there are two methods to obtain tumor oxygen status, namely the direct Eppendorf needle electrode and the indirect immunohistochemical assay of a protein marker, Carbonic Anhydrase IX (CAIX). In this project, we introduce Bayesian probability theory to obtain inferences about tumor oxygenation from each technique and the concordance between the two techniques. From this study, we conclude that under certain conditions, two biopsies are sufficient to infer the tumor oxygenation level based on the immunohistochemical assays of CAIX. Additionally, there is a fair concordance between the direct and the indirect measurements of tumor oxygenation. In the latter problem, ovarian cancer is the topic of study. Ovarian cancer has the highest mortality rate among gynecological cancers and one that is known to relapse. CA-125 is still the most inexpensive biomarker for monitoring ovarian cancers. From the phase II clinical trial data, we demonstrate the survival advantage of CA-125 responsive group of patients by means of a non-parametric Kaplan-Meier statistic.