Increasing time trends in the recorded incidence of childhood cancer have been reported in many different settings. The extent to which these trends reflect real changes in incidence, rather than improvements in methods for diagnosis and registration, is controversial. Using data from the National Registry of Childhood Tumours (NRCT), this thesis investigates time trends in cancer diagnosed under age 15 in residents of Britain during 1966-2005 (54650 cases), and considers potential sources of artefact in detail. Several different methods are used to estimate completeness of NRCT registration. The history of methods for diagnosis and registration of childhood cancers in Britain is described, and predictions are made for effects on recorded incidence. For each of the 12 main diagnostic groups, Poisson regression is used to fit continuous time trends and ‘step’ models to the annual age-sex-standardised rates by year of birth and year of diagnosis. Age-specific rates by period, and quinquennial standardised rates for diagnostic subgroups, are shown graphically. For three broad groups (leukaemia, CNS tumours and other cancer), geographical variation is compared by period of diagnosis. The results of these analyses are discussed in relation to the predicted artefacts. The evidence for a positive association between affluence and recorded incidence of childhood leukaemia is briefly reviewed. A special form of diagnostic artefact, the ‘fatal infection’ hypothesis, is proposed as an explanation of both this association and the leukaemia time trend. This hypothesis is examined in a novel test based on clinical data. The recorded incidence of childhood cancer in Britain increased in each of 12 diagnostic groups during 1966-2005 (from 0.5% per year for bone cancer to 2.5% for hepatic cancer, with 0.7% for leukaemia). Evidence presented here suggests that these increases are probably artefacts of diagnosis and registration. The potential implications for epidemiological studies of childhood cancer should be considered.

SOCIAL WORK / MA(SS) (SOCIAL WORK)

Cervical cancer is reported to be the first among the five leading cancers affecting women in South Africa and the leading cancer among Black females. There is a high incidence and mortality rate among underserved and under-screened women presenting with cervical cancer as they are often unable to access screening facilities. Very little has been done to establish the factors in private health care provision that influence the implementation of cervical screening programmes. The study investigates factors influencing cervical cancer screening programme implementation among private medical practitioners in Soshanguve to establish whether private practitioners assume their roles in cervical screening. The intention is to provide guidelines for a screening programme that could be implemented in private health facilities. The study is qualitative, explorative, descriptive and contextual, using interviews and observation as the main data-collection methods. Lack of awareness and interest, failure to inform patients about cervical screening, age and gender of medical practitioners were among the factors identified. The study concluded that awareness programmes about cervical screening and materials containing information on cervical cancer and predisposing factors should be designed. The utilization of cheaper laboratory service providers could increase participation by making the test affordable and accessible to cash patients. The establishment of a private Pap clinic within medical practices or even as an independent entity is also recommended. / Health Studies / M.A. (Public Health)

Cervical cancer is reported to be the first among the five leading cancers affecting women in South Africa and the leading cancer among Black females. There is a high incidence and mortality rate among underserved and under-screened women presenting with cervical cancer as they are often unable to access screening facilities. Very little has been done to establish the factors in private health care provision that influence the implementation of cervical screening programmes. The study investigates factors influencing cervical cancer screening programme implementation among private medical practitioners in Soshanguve to establish whether private practitioners assume their roles in cervical screening. The intention is to provide guidelines for a screening programme that could be implemented in private health facilities. The study is qualitative, explorative, descriptive and contextual, using interviews and observation as the main data-collection methods. Lack of awareness and interest, failure to inform patients about cervical screening, age and gender of medical practitioners were among the factors identified. The study concluded that awareness programmes about cervical screening and materials containing information on cervical cancer and predisposing factors should be designed. The utilization of cheaper laboratory service providers could increase participation by making the test affordable and accessible to cash patients. The establishment of a private Pap clinic within medical practices or even as an independent entity is also recommended. / Health Studies / M.A. (Public Health)

SOCIAL WORK / MA(SS) (SOCIAL WORK)

Text in English / Cervical cancer remains the leading cause of cancer mortality among women worldwide, a burden in the developing countries and commonly detected through symptoms at later invasive stages. The study aimed at establishing knowledge and awareness of the importance of cervical cancer screening in the Makhuduthamaga Sub-district by exploring the perceptions of women and professional nurses and through the review of the National Cervical Cancer Screening Policy (2013). Recommendations to address the gap in knowledge and to inform the National Cervical Cancer Screening Policy were developed based on the study findings. A mixed-method approach was used in this study through a sequential explanatory design, which is quantitatively driven was used. Quantitative data were obtained by using a researcher developed checklist. The checklist was developed from variables stated in the National Cervical Cancer Screening Policy and was used to review its implementation. Qualitative data was obtained through in-depth interviews with individual women and focus group discussions with professional nurses. The study was conducted in ten randomly selected clinics of Makhuduthamaga Sub-district. Purposive sampling was done to obtain qualitative data. An average score of 9.7 was obtained for all ten clinics that participated in the study with regard to the evaluation of the implementation of the National Cervical Cancer Screening Policy. Only 6 (60%) clinics implemented the policy whereas 4 (40%) clinics did not implement the policy. Women and professional nurses perceived cervical cancer screening as important. Lack of knowledge among women regarding cervical cancer screening contributed to the majority of women not screening for cervical cancer. Lack of resources, the 10 year interval of normal cervical cancer screening, the use of disposable vaginal speculums and brushes, lack of standardized cervical cancer screening training, centralization of cytology laboratories came out as factors that negatively influence the uptake of cervical cancer screening. Cervical cancer screening awareness campaigns, availability of resources and standardized in-service trainings on cervical cancer screening were recommended to enhance the cervical cancer screening uptake. Key concepts: / Health Studies / D. Litt. et Phil. (Health Studies)

<div> Advancements in cancer treatments have increased rapidly in recent years, but cures remain elusive. Surgical tumor resection is a central treatment for many solid malignancies. Residual tumor at surgical margins leads to tumor recurrence. Novel tools for assessing residual tumor at surgical margins could improve surgical outcomes by helping to maximize the extent of resection. Ambient ionization-mass spectrometry (MS) methods generate and analyze ions from minimally prepared samples in near-real-time (e.g. seconds to minutes). These methods leverage the high sensitivity and specificity of mass spectrometry for analyzing gas phase ions and generating those ions quickly and with minimal sample preparation. Recent work has shown that differential profiles of ions, corresponding to phospholipids and small metabolites, are detected from cancerous and their respective normal tissue with ambient ionization-MS methods. When properly implemented, ambient ionization-MS could be used to assess for tumor at surgical margins and provide a molecular diagnosis during surgery. </div><div><br></div><div>The research herein reports efforts in developing rapid intraoperative ambient ionization-MS methods for the molecular assessment of cancerous tissues. Touch spray (TS) ionization and desorption electrospray ionization (DESI) were utilized to analyze kidney cancer and brain cancer.</div><div><br></div><div> As a demonstration of the applicability of TS-MS to provide diagnostic information from fresh surgical tissues, TS-MS was used to rapidly analyze renal cell carcinoma and healthy renal tissue biopsies obtained from human subjects undergoing nephrectomy surgery. Differential phospholipid profiles were identified using principal component analysis (PCA), and the significant ions were characterized using multiple stages of mass spectrometry and high resolution/exact mass MS. The same TS-MS analyzed renal tissues were subsequently analyzed with DESI-MS imaging to corroborate the TS-MS results, and the significant DESI-MS ions were also characterized with MS.</div><div><br></div><div>Significant efforts were made in developing and evaluating a standalone intraoperative DESI-MS system for analyzing brain tissue biopsies during brain tumor surgery. The intraoperative DESI-MS system consists of a linear trap quadrupole mass spectrometer placed on a custom-machined cart that contains all hardware for operating the mass spectrometer. This instrument was operated in the neurosurgical suites at Indiana University School of Medicine to rapidly analyze brain tissue biopsies obtained from glioma resection surgeries. A DESI-MS library of normal brain tissue and glioma was used to statistically classify the brain tissue biopsies collected in the operating room. Multivariate statistical methodologies were employed to predict the disease state and tumor cell percentage of the samples. A DESI-MS assay for detecting 2-hydroxyglutarate (2HG), the oncometabolic product of the isocitrate dehydrogenase (IDH) mutation (a key glioma prognostic marker), was developed and applied to determine the IDH mutation status during the surgical resection. The strengths, weaknesses, and areas of future work in this field are discussed. </div><div><br></div>

MCur / Department of Advanced Nursing Science / Historically, cancer is regarded as a disease with very devastating effects on human beings because it leads to many deaths across the world, compared to AIDS, tuberculosis and malaria collectively. Cancer diagnosis has impacted negatively on patients and their immediate families and has caused unbearable consequences. Unlike other chronic diseases, cancer patients undergo different types of treatments which affect their well-being and as a result they tend to have different experiences to those of other chronic diseases sufferers. The study design used was a quantitative cross sectional survey. The purpose was to investigate the impact of cancer diagnosis on cancer patients in Vhembe district. The target population included all patients in the Vhembe District of Limpopo, South Africa who have been diagnosed with cancer in the past six months. Using a probability simple random, a sample of 207 patients diagnosed with cancer, from seven selected hospitals in Vhembe District were selected as respondents and a self -administered questionnaire was used to collect data. Data was analysed using a software package for descriptive statistics (SPSS version 23). Graphs, tables and charts were used to display the results visually and chi-square to compare variables. Ethical principles of privacy, anonymity, informed consent were considered. The findings revealed that cancer diagnosis has negative outcomes as patients experience physical hardship, psychological stress, financial difficulties, as well as interference with family and social life. The study recommended that cancer patients and their families, be supported through the cancer journey. / NRF

<p>My research has focused on the development and translation of ambient ionization mass spectrometry (MS)-based platforms in clinical and surgical settings, specifically in the area of brain cancer diagnostics and surgical decision making. Ambient ionization MS methods, such as those described herein, generate and analyze gas phase ions with high sensitivity and specificity from minimally prepared samples in near-real-time, on the order of seconds to minutes, rendering them well suited to point-of-care applications. We used ambient ionization MS methods, specifically desorption electrospray ionization mass spectrometry (DESI-MS) and extraction nanoelectrospray ionization mass spectrometry (nESI-MS) to molecularly characterize brain cancer biopsies. The characterization was made using diagnostic compounds identified as markers of disease state, tissue composition, tumor type, and genotype in human brain tissue. Methods were developed and validated offline in the laboratory and translated to clinical and surgical settings, thereby generating chemical information on prognostic features intraoperatively and providing valuable information that would be otherwise unavailable. We believe that, with approval, the methodologies described can assist physicians and improve patient outcomes by providing analytical tools and molecular information that can inform surgical decision making and adjuvant treatment strategies, complementing and not interfering with standard of care protocols.</p> <p><br></p> <p>We have successfully demonstrated the use of desorption electrospray ionization mass spectrometry (DESI-MS) for the expedient molecular assessment of human glioma tissue biopsies based on lipid profiles and prognostic metabolites, both at the tumor core and near surgical margins, in two small-scale, clinical studies. Maximal surgical resection of gliomas that avoids non-infiltrated tissue is associated with survival benefit in patients with glioma. The infiltrative nature of gliomas, as well as their morphological and genetic diversity, renders treatment difficult and demands an integrated imaging and diagnostic approach during surgery to guide clinicians in achieving maximal tumor resection. Further, the estimation of tumor cell percentage (TCP), a measure of tumor infiltration at surgical margins, is not routinely assessed intraoperatively. </p> <p>We have previously shown that rapid, offline molecular assessment of tumor infiltration in tissue biopsies is possible and believe that the same assessment performed intraoperatively in biopsied tissue near surgical margins could improve resection and better inform patient management strategies, including postoperative radiotherapy. Using a DESI-MS spectral library of normal brain tissue and glioma biopsies to generate a statistical model to classify brain tissue biopsies intraoperatively, multivariate statistical approaches were used to predict the disease state and tumor cell percentage (TCP) of each biopsy, thereby providing an measure of tumor infiltration at surgical margins via molecular indicators. In addition to assessment of tumor infiltration, we have developed DESI-MS assays for detecting the oncometabolite 2-Hydroxyglutarate (2HG) to detect isocitrate dehydrogenase (IDH) mutations in gliomas intraoperatively. Knowledge of IDH genotypes at the time of surgical resection could improve patient outcomes, as more aggressive tumor resection of IDH-mutated gliomas is associated with increased survival. While assessments of IDH genotype are typically not available until days after surgery, we have demonstrated the ability to provide this information is less than five minutes. An intraoperative DESI-MS system has successfully been used in a proof-of-concept clinical study and intraoperative performance validation of this platform is ongoing. The findings of these two studies as well as strengths, weaknesses, and areas of improvement for upcoming future iterations of the research are discussed.</p> <p><br></p> <p>Point-of-care applications necessitate the adaptation of MS methodologies to smaller devices. Miniature mass spectrometers (Mini MS) boast small footprints, simple operation, and low power consumption, noise levels, and cost, making them attractive candidates for point-of-care use. In a small-scale clinical study, we demonstrated the first application of a Mini MS for determination of IDH mutation status in gliomas intraoperatively. This study paves a path forward for the application of Mini MS in the OR. With its small footprint and low power consumption and noise level, this application of miniature mass spectrometers represents a simple and cost-effective platform for an important intraoperative measurement. </p> <p><br></p> <p>While MS-based methods of tissue analysis can detect molecular features of interest and rapidly produce large quantities of data, their inherent speed is rarely utilized because they are traditionally coupled with time-consuming separation techniques (e.g., chromatography). Ambient ionization MS, specifically DESI-MS, is well suited for high-throughput applications due to its lack of sample preparation and purification techniques. In an attempt to rapidly characterize microarrays of tissue biopsies, we developed a high-throughput DESI-MS (HT-DESI-MS) method for the rapid characterization of disease state, human brain tumor type, glioma classification, and detection of IDH mutations in tissue microarrays (TMA) of banked and fresh human brain tissue biopsies. We anticipate that HT-DESI-MS analysis of TMAs could become a standard tool for the generation of spectral libraries for sample classification, the identification of biomarkers through large-scale studies, the correlation of molecular features with anatomical features when coupled to digital pathology, and the assessment of drug efficacy. </p>

L'objectif principal de cette thèse est de faire progresser le domaine de l'imagerie quantitative par ultrasons (QUS) et de la viscoélastographie par ondes de cisaillement (SWVE) pour l'évaluation du cancer du foie, en particulier pour différencier les lésions bénignes et malignes. Cet objectif est atteint grâce à trois études ciblées. La première étude améliore les capacités de diagnostic de QUS en développant des cartes de pente du coefficient d'atténuation local (LACS) régularisées sans fantôme (PF-R). Les méthodes traditionnelles nécessitant des fantômes de référence sont limitées par l'hypothèse de vitesses sonores comparables entre les fantômes et les tissus et par l'inconvénient d'acquérir des données à partir des deux. La méthodologie PF-R proposée élimine le besoin de fantômes d'étalonnage, normalise la fréquence et la profondeur sans sacrifier la précision et étend l'applicabilité aux tissus non homogènes. Les principales modifications comprennent l'interpolation linéaire du spectre de puissance, l'assouplissement des hypothèses de diffraction et la restriction adaptative de fréquence. Testée sur divers fantômes imitant les tissus et sur des ensembles de données hépatiques humaines, la méthode démontre sa robustesse et son potentiel pour améliorer la précision diagnostique de la stéatose hépatique et des tumeurs. La deuxième étude aborde les limites de l'échographie en mode B (US) dans la détection et la différenciation des nodules hépatiques en utilisant l'imagerie QUS LACS. L'échographie en mode B traditionnelle est souvent confrontée à une faible sensibilité en présence de foie gras ou de cirrhose. L'imagerie LACS, fournissant une caractérisation tissulaire supplémentaire sans agents de contraste, améliore la visibilité des nodules et les performances diagnostiques. L'étude a été menée sur 97 patients (âge : 62 ans ± 13) présentant 100 nodules hépatiques focaux (57% malins et 43% bénins). L'imagerie LACS a démontré un rapport contraste-bruit (CNR) supérieur à celui de l'US en mode B (12.3 dB, p<0.0001). Avec un seuil LACS de 0.94 dB/cm/MHz, la technique a atteint une sensibilité de 0.83 (IC – intervalle de confiance : 0.74-0.89) et une spécificité de 0.82 (IC : 0.73-0.88). Les valeurs moyennes du LACS étaient significativement plus élevées dans les nodules malins (1.28 ± 0.27 dB/cm/MHz) que dans les nodules bénins (0.98 ± 0.19 dB/cm/MHz, p<0.0001), permettant une classification plus précise avec une aire sous la courbe caractéristique (AUC) de 0.93 pour les nodules malins (IC : 0.88-0.97). La troisième étude examine l'application du SWVE au diagnostic du cancer du foie, en se concentrant sur la vitesse des ondes de cisaillement (SWS) et l'atténuation des ondes de cisaillement (SWA). Bien que le SWVE se soit révélé prometteur dans l'évaluation de la fibrose et de la stéatose hépatique, son utilisation dans la caractérisation des lésions hépatiques focales est sous-explorée. Cette étude évalue le SWS et le SWA chez 73 patients présentant 75 nodules hépatiques focaux, en utilisant l'IRM et l'histopathologie comme références. Les résultats indiquent que le SWS moyen était significativement plus élevé dans les nodules malins (2.35 ± 0.62 m/s) que dans les nodules bénins (1.89 ± 0.88 m/s, p<0.001), tandis que le SWA était significativement plus faible dans les nodules malins (0.59 ± 0.31 Np/m/Hz) que dans les nodules bénins (0.93 ± 0.49 Np/m/Hz, p<0.001). Un seuil de 2.43 m/s pour le SWS a fourni une sensibilité de 0.54 (IC : 0.38-0.69) et une spécificité de 0.84 (IC : 0.72-0.94), tandis qu'un seuil SWA de 0.81 Np/m/Hz a atteint une sensibilité de 0.83 (IC : 0.69-0.92) et une spécificité de 0.71 (IC : 0.55-0.83). La combinaison du SWS et du SWA par le biais d'une analyse discriminante linéaire (LDA) a permis d’améliorer la précision de la classification, avec une sensibilité de 0.84 (IC : 0.69-0.92) et une spécificité de 0.87 (IC : 0.73-0.94). La combinaison du SWS et du SWA par l’analyse LDA améliore la précision de la classification, soulignant le potentiel du SWVE pour affiner le diagnostic du cancer du foie et la planification du traitement. Dans l'ensemble, cette recherche fait progresser les techniques d'échographie non invasives, fournit de nouveaux biomarqueurs et améliore la précision du diagnostic du cancer du foie, favorisant ainsi une meilleure prise de décision clinique et de meilleurs résultats pour les patients. / The primary aim of this thesis is to advance the field of quantitative ultrasound (QUS) imaging and shear wave viscoelastography (SWVE) for liver cancer assessment, specifically in differentiating benign and malignant nodules. This objective is achieved through three focused studies. The first study enhances QUS diagnostic capabilities by developing phantom-free regularized (PF-R) local attenuation coefficient slope (LACS) maps. Traditional methods requiring reference phantoms are limited by the assumption of comparable sound speeds between phantoms and tissues and the inconvenience of acquiring data from both. The proposed PF-R methodology eliminates the need for calibration phantoms, normalizes frequency and depth without sacrificing accuracy, and extends applicability to nonhomogeneous tissues. Key modifications include linear interpolation of the power spectrum, relaxation of diffraction assumptions, and adaptive frequency restriction. Tested on various tissue-mimicking phantoms and human liver datasets, the method demonstrates robustness and potential for improved diagnostic accuracy in liver steatosis and tumors. The second study addresses the limitations of B-mode ultrasound (US) in detecting and differentiating liver nodules by employing QUS LACS imaging. Traditional B-mode US often struggles with low sensitivity in the presence of fatty liver or cirrhosis. LACS imaging, providing additional tissue characterization without contrast agents, improves nodule visibility and diagnostic performance. The study was conducted on 97 patients (age: 62 years ± 13) with 100 focal liver nodules (57% malignant and 43% benign). LACS imaging demonstrated superior contrast-to-noise ratio (CNR) compared to B-mode US (12.3 dB, p<0.0001). With a LACS threshold of 0.94 dB/cm/MHz, the technique achieved a sensitivity of 0.83 (CI – confidence interval: 0.74-0.89) and a specificity of 0.82 (CI: 0.73-0.88). LACS mean values were significantly higher in malignant nodules (1.28 ± 0.27 dB/cm/MHz) compared to benign nodules (0.98 ± 0.19 dB/cm/MHz, p<0.0001), providing a more accurate classification with an area under the receiver operating characteristic curve (AUC) of 0.93 for malignant nodules (CI: 0.88-0.97). The third study investigates the application of SWVE in liver cancer diagnosis, focusing on shear wave speed (SWS) and shear wave attenuation (SWA). While SWVE has shown promise in assessing liver fibrosis and steatosis, its use in characterizing focal liver nodules is underexplored. This study evaluates SWS and SWA in 73 patients with 75 focal liver nodules, using MRI and histopathology as references. Results indicate that mean SWS was significantly higher in malignant nodules (2.35 ± 0.62 m/s) than in benign nodules (1.89 ± 0.88 m/s, p<0.001), while SWA was significantly lower in malignant nodules (0.59 ± 0.31 Np/m/Hz) compared to benign nodules (0.93 ± 0.49 Np/m/Hz, p<0.001). A threshold of 2.43 m/s for SWS provided a sensitivity of 0.54 (CI: 0.38-0.69) and a specificity of 0.84 (CI: 0.72-0.94), whereas a SWA threshold of 0.81 Np/m/Hz achieved a sensitivity of 0.83 (CI: 0.69-0.92) and a specificity of 0.71 (CI: 0.55-0.83). Combining SWS and SWA through linear discriminant analysis (LDA) further improved classification accuracy, achieving a sensitivity of 0.84 (CI: 0.69-0.92) and a specificity of 0.87 (CI: 0.73-0.94). Combining SWS and SWA through the LDA improves classification accuracy, highlighting the potential of SWVE in refining liver cancer diagnosis and treatment planning. Overall, this research advances noninvasive ultrasound techniques, providing new biomarkers and enhancing the diagnostic accuracy for liver cancer, thereby supporting better clinical decision-making and patient outcomes.