The problem investigated Four studies investigated the phenomenon of cancer-related fatigue (CRF) in women who had received adjuvant treatment for early-stage breast cancer, with a view to reducing the diagnostic uncertainty surrounding the syndrome and thus facilitating progress in both clinical management and aetiological research. Procedures and results A cross-sectional study of 109 women compared a ???cancer-specific??? self-report questionnaire (FACT-F) (canvassing fatigue symptoms) and a more generic questionnaire (SPHERE) (identifying depression and fatigue). Thirty-seven percent of women reported fatigue. Overall in 20%, fatigue was associated with psychological distress. Seventeen percent of women had fatigue but no depression. A qualitative study utilised focus groups to identify and compare the distinctive features of CRF with those of women with chronic fatigue syndrome (CFS). A similar set of symptoms was found in both groups, including overwhelming fatigue, un-refreshing sleep and subjective concentration problems. However, women with CFS also reported myalgia and arthralgia. Using the Structured Clinical Interview for Neurasthenia- SCIN, the third study compared the symptoms of three groups of women with fatigue: those with CRF, CFS or major depression. The detailed ???interviewer guide??? provided explicit directions for evaluating and classifying symptoms. This study confirmed the core symptom of ???profound fatigue unrelieved by rest???, and additional features that distinguished between the clinical diagnoses. The fourth study compared features of the evolution of clinically-identified fatigue syndromes in women from two prospective cohort studies; women with post-cancer fatigue (PCF) and women with post-infective fatigue syndrome (PIFS). Major conclusions A syndrome of PCF, present at least six months following adjuvant treatment and unexplained by medical or psychiatric disorder was investigated. The characteristics of PCF and those of CFS are very similar, with the fatigue state having indistinguishable descriptors. Longitudinal evaluation of the symptom complexes of PCF and PIFS suggests divergent pathways may be relevant. Co-morbid features like sleep disturbance; physical deconditioning and mood disturbance may be implicated as factors in the evolution and prolongation of PCF. These studies provide a basis for a more uniform and rigorous classification system - a necessary first step towards advancing the field both in investigating aetiology and new intervention strategies.

The problem investigated Four studies investigated the phenomenon of cancer-related fatigue (CRF) in women who had received adjuvant treatment for early-stage breast cancer, with a view to reducing the diagnostic uncertainty surrounding the syndrome and thus facilitating progress in both clinical management and aetiological research. Procedures and results A cross-sectional study of 109 women compared a ???cancer-specific??? self-report questionnaire (FACT-F) (canvassing fatigue symptoms) and a more generic questionnaire (SPHERE) (identifying depression and fatigue). Thirty-seven percent of women reported fatigue. Overall in 20%, fatigue was associated with psychological distress. Seventeen percent of women had fatigue but no depression. A qualitative study utilised focus groups to identify and compare the distinctive features of CRF with those of women with chronic fatigue syndrome (CFS). A similar set of symptoms was found in both groups, including overwhelming fatigue, un-refreshing sleep and subjective concentration problems. However, women with CFS also reported myalgia and arthralgia. Using the Structured Clinical Interview for Neurasthenia- SCIN, the third study compared the symptoms of three groups of women with fatigue: those with CRF, CFS or major depression. The detailed ???interviewer guide??? provided explicit directions for evaluating and classifying symptoms. This study confirmed the core symptom of ???profound fatigue unrelieved by rest???, and additional features that distinguished between the clinical diagnoses. The fourth study compared features of the evolution of clinically-identified fatigue syndromes in women from two prospective cohort studies; women with post-cancer fatigue (PCF) and women with post-infective fatigue syndrome (PIFS). Major conclusions A syndrome of PCF, present at least six months following adjuvant treatment and unexplained by medical or psychiatric disorder was investigated. The characteristics of PCF and those of CFS are very similar, with the fatigue state having indistinguishable descriptors. Longitudinal evaluation of the symptom complexes of PCF and PIFS suggests divergent pathways may be relevant. Co-morbid features like sleep disturbance; physical deconditioning and mood disturbance may be implicated as factors in the evolution and prolongation of PCF. These studies provide a basis for a more uniform and rigorous classification system - a necessary first step towards advancing the field both in investigating aetiology and new intervention strategies.

The problem investigated Four studies investigated the phenomenon of cancer-related fatigue (CRF) in women who had received adjuvant treatment for early-stage breast cancer, with a view to reducing the diagnostic uncertainty surrounding the syndrome and thus facilitating progress in both clinical management and aetiological research. Procedures and results A cross-sectional study of 109 women compared a ???cancer-specific??? self-report questionnaire (FACT-F) (canvassing fatigue symptoms) and a more generic questionnaire (SPHERE) (identifying depression and fatigue). Thirty-seven percent of women reported fatigue. Overall in 20%, fatigue was associated with psychological distress. Seventeen percent of women had fatigue but no depression. A qualitative study utilised focus groups to identify and compare the distinctive features of CRF with those of women with chronic fatigue syndrome (CFS). A similar set of symptoms was found in both groups, including overwhelming fatigue, un-refreshing sleep and subjective concentration problems. However, women with CFS also reported myalgia and arthralgia. Using the Structured Clinical Interview for Neurasthenia- SCIN, the third study compared the symptoms of three groups of women with fatigue: those with CRF, CFS or major depression. The detailed ???interviewer guide??? provided explicit directions for evaluating and classifying symptoms. This study confirmed the core symptom of ???profound fatigue unrelieved by rest???, and additional features that distinguished between the clinical diagnoses. The fourth study compared features of the evolution of clinically-identified fatigue syndromes in women from two prospective cohort studies; women with post-cancer fatigue (PCF) and women with post-infective fatigue syndrome (PIFS). Major conclusions A syndrome of PCF, present at least six months following adjuvant treatment and unexplained by medical or psychiatric disorder was investigated. The characteristics of PCF and those of CFS are very similar, with the fatigue state having indistinguishable descriptors. Longitudinal evaluation of the symptom complexes of PCF and PIFS suggests divergent pathways may be relevant. Co-morbid features like sleep disturbance; physical deconditioning and mood disturbance may be implicated as factors in the evolution and prolongation of PCF. These studies provide a basis for a more uniform and rigorous classification system - a necessary first step towards advancing the field both in investigating aetiology and new intervention strategies.

The problem investigated Four studies investigated the phenomenon of cancer-related fatigue (CRF) in women who had received adjuvant treatment for early-stage breast cancer, with a view to reducing the diagnostic uncertainty surrounding the syndrome and thus facilitating progress in both clinical management and aetiological research. Procedures and results A cross-sectional study of 109 women compared a ???cancer-specific??? self-report questionnaire (FACT-F) (canvassing fatigue symptoms) and a more generic questionnaire (SPHERE) (identifying depression and fatigue). Thirty-seven percent of women reported fatigue. Overall in 20%, fatigue was associated with psychological distress. Seventeen percent of women had fatigue but no depression. A qualitative study utilised focus groups to identify and compare the distinctive features of CRF with those of women with chronic fatigue syndrome (CFS). A similar set of symptoms was found in both groups, including overwhelming fatigue, un-refreshing sleep and subjective concentration problems. However, women with CFS also reported myalgia and arthralgia. Using the Structured Clinical Interview for Neurasthenia- SCIN, the third study compared the symptoms of three groups of women with fatigue: those with CRF, CFS or major depression. The detailed ???interviewer guide??? provided explicit directions for evaluating and classifying symptoms. This study confirmed the core symptom of ???profound fatigue unrelieved by rest???, and additional features that distinguished between the clinical diagnoses. The fourth study compared features of the evolution of clinically-identified fatigue syndromes in women from two prospective cohort studies; women with post-cancer fatigue (PCF) and women with post-infective fatigue syndrome (PIFS). Major conclusions A syndrome of PCF, present at least six months following adjuvant treatment and unexplained by medical or psychiatric disorder was investigated. The characteristics of PCF and those of CFS are very similar, with the fatigue state having indistinguishable descriptors. Longitudinal evaluation of the symptom complexes of PCF and PIFS suggests divergent pathways may be relevant. Co-morbid features like sleep disturbance; physical deconditioning and mood disturbance may be implicated as factors in the evolution and prolongation of PCF. These studies provide a basis for a more uniform and rigorous classification system - a necessary first step towards advancing the field both in investigating aetiology and new intervention strategies.

The mechanism of resistance of tumor cells to chemotherapeutic agents is explored using probabilistic methods where it is assumed that resistant cells arise spontaneously with a defined frequency. The resistance process is embedded in a discrete time Markov branching process which models the growth of the tumor and contains three seperate cell types: stem, transitional and end cells. Using the asymptotic properties of such models it is shown that the proportion of each type of cell converge to constants almost surely. It is shown that the parameters relating to stem cell behaviour determine the asymptotic behaviour of the system. It is argued that for biologically likely parameter values, cure of the tumor will occur if, and only if, all stem cells are eliminated. A model is developed for the acquisition of resistance by stem cells to a single drug. Probability generating functions are derived which describe the behaviour of the process after an arbitrary sequence of drug treatments. The probability of cure, defined as the probability of ultimate extinction of the stem cell compartment, is characterised as the central quantity reflecting the success of therapeutic intervention. Expressions for this function are derived for a number of experimental situations. The effects of variation in the parameter values are examined. The model is extended to the case where two anticancer drugs are available and formulae for the probability of cure are developed. The problem of therapeutic scheduling is examined and under situations where drugs are of "equal" effectiveness, but may not be given together, it is shown that the mean number of tumor cells is minimised by sequential alternation of the drugs. The models are applied to data collected on the L1210 leukemia treated by the drugs Cyclophosphamide and Arabinosylcytosine. In both cases the analysis of the data provide evidence that resistant cells arise spontaneously with a frequency of approximately 10⁻⁷ per division. When applied to human breast cancer, the model indicates that neoadjuvant therapy is unlikely to greatly influence the likelihood that the patient will die from the growth of drug-resistant cells. / Science, Faculty of / Statistics, Department of / Graduate

The most common treatment used for cancer is chemotherapy. Chemotherapeutic agents have a greater affinity for rapidly dividing cells which is a characteristic of tumour cells. Although anti-cancer agents have their advantages in providing anti-cancer effects, they can be seen as highly toxic molecules posing a threat to normal healthy tissue within the human body. However, these toxic therapies need to be delivered to tumour sites without damaging healthy tissue. Liposomes can serve as a delivery system for these toxic molecules and be delivered to the tumour site via the EPR effect. Hence, liposomes that fuse with tumour cell line membranes are advantageous in delivering payloads of drugs directly into the tumour cell without damaging normal healthy tissue. The aim of the study was to formulate an optimised liposome preparation in order to enhance cellular uptake by MCF-7, Caco-2 and C3A cancer cell lines via membrane fusion. The optimal liposome formulation was aimed to be prepared utilising a statistical design approach in order to determine the ranges of the parameters that were furthermost optimal in formulating an ideal liposome preparation. The primary screening design was conducted using a 24-1 fractional factorial design that took into account the four parameters that were used to determine the optimisation of the liposomal preparation. The four variables used in the liposome preparation were the phospholipid type (PS or DOPE), the concentration of cholesteryl hemisuccinate (CHEMS) (10 – 40 %), the concentration of PEG2000-PE (0.5 – 4 %) and liposome size (100 or 200 nm). Liposomes were prepared using thin film hydration method and characterisation for size and zeta potential was carried out using photon correlation spectroscopy (PCS). Visual characterisation of liposome size was carried out using atomic force microscopy (AFM). Liposomes were exposed the cancer cell lines with visualisation and uptake being measured using fluorescent microscopy and flow cytometry, respectively. An optimal liposome preparation was prepared following the statistical design method. The optimal liposome preparation consisted of phospholipid type PS, 22.91 % of CHEMS, 4 % of PEG2000-PE and a liposome size of 200 nm. AFM analysis has shown that optimal liposome sizes ranged between 130 and 170 nm. Flow cytometry analysis indicated high level of liposome uptake with actual values falling below the predicted values set out by the statistical design. Fluorescence microscopy captured images of the fluorescent liposomes concentrated on the membrane of cells. The objective of the study was to determine from literature which variables would be desirable in preparing an optimal non-targeted liposome preparation. This was achieved by identifying four such variables and utilising them in a statistical design approach which was screened in order to determine the ideal parameters in preparing the optimised liposome batch. Therefore, from the results obtained it can be concluded that the aim of the study were met by preparing an optimal liposome preparation that has the ability to fuse with the tumour cell line membranes.

nÃo hà / O cÃncer de mama foi descrito hà muitos anos e documentado, pela primeira vez, por Imhotep, mÃdico, astrÃlogo e arquiteto egÃpcio, nascido em 2.650 antes de Cristo (a.C.) que recomendava Ãquela Ãpoca, como tratamento, a cauterizaÃÃo do tecido doente. Tamoxifeno à o fÃrmaco mais prescrito no tratamento do cÃncer de mama. Sua utilizaÃÃo à principalmente na modalidade adjuvante, em pacientes prà ou pÃs menopausadas, receptor de estrÃgeno e/ou progesterona positivos. à tambÃm utilizado no tratamento da doenÃa localmente avanÃada e metastÃtica e em menor proporÃÃo nas pacientes com contra-indicaÃÃo formal de cirurgia ou que se recusam a se submeter a esta modalidade de tratamento. Na neo-adjuvÃncia à utilizada apenas em ensaios clÃnicos. O tamoxifeno tambÃm diminui, na adjuvÃncia por cinco anos, a probabilidade de recidiva em 47% e de morte por cÃncer de mama em 26% e os dois principais efeitos colaterais, apesar de raros, sÃo aumento da prevalÃncia de cÃncer de endomÃtrio e de fenÃmenos tromboembÃlicos. Este estudo teve como objetivo principal avaliar as pacientes portadoras de cÃncer de mama, no Instituto do CÃncer do CearÃ, tratadas com tamoxifeno de forma adjuvante, no perÃodo de janeiro de 1993 a 1996, com relaÃÃo aos principais benefÃcios e efeitos colaterais, bem como anÃlise de sobrevivÃncia. ProntuÃrios de setecentos e quarenta e duas pacientes foram analisados no que diz respeito aos dados sÃcio- demogrÃficos, idade, status menopausal, estadiamento clÃnico e patolÃgico, dosagem de receptores de estrÃgeno e progesterona, casos de cÃncer de endomÃtrio, principais sÃtios de metÃstases, modalidade de tratamento cirÃrgico, radioterÃpico e quimioterÃpico, causas de Ãbito, tipo histolÃgico, status dos linfonodos axilares e anÃlise de sobrevivÃncia de acordo com o estadiamento. Concluiu-se que a maioria dos dados estÃo de acordo com a literatura e que o prejuÃzo da anÃlise foi resultante da qualidade dos registros realizados nos prontuÃrios, devendo cada vez mais os mÃdicos serem estimulados a documentar, de forma clara e legÃvel, o maior nÃmero de informaÃÃes possÃveis, nÃo apenas as positivas, mas todas aquelas que, mais freqÃentemente, possam ter relaÃÃo com a utilizaÃÃo de qualquer medicamento prescrito. / O cÃncer de mama foi descrito hà muitos anos e documentado, pela primeira vez, por Imhotep, mÃdico, astrÃlogo e arquiteto egÃpcio, nascido em 2.650 antes de Cristo (a.C.) que recomendava Ãquela Ãpoca, como tratamento, a cauterizaÃÃo do tecido doente. Tamoxifeno à o fÃrmaco mais prescrito no tratamento do cÃncer de mama. Sua utilizaÃÃo à principalmente na modalidade adjuvante, em pacientes prà ou pÃs menopausadas, receptor de estrÃgeno e/ou progesterona positivos. à tambÃm utilizado no tratamento da doenÃa localmente avanÃada e metastÃtica e em menor proporÃÃo nas pacientes com contra-indicaÃÃo formal de cirurgia ou que se recusam a se submeter a esta modalidade de tratamento. Na neo-adjuvÃncia à utilizada apenas em ensaios clÃnicos. O tamoxifeno tambÃm diminui, na adjuvÃncia por cinco anos, a probabilidade de recidiva em 47% e de morte por cÃncer de mama em 26% e os dois principais efeitos colaterais, apesar de raros, sÃo aumento da prevalÃncia de cÃncer de endomÃtrio e de fenÃmenos tromboembÃlicos. Este estudo teve como objetivo principal avaliar as pacientes portadoras de cÃncer de mama, no Instituto do CÃncer do CearÃ, tratadas com tamoxifeno de forma adjuvante, no perÃodo de janeiro de 1993 a 1996, com relaÃÃo aos principais benefÃcios e efeitos colaterais, bem como anÃlise de sobrevivÃncia. ProntuÃrios de setecentos e quarenta e duas pacientes foram analisados no que diz respeito aos dados sÃcio- demogrÃficos, idade, status menopausal, estadiamento clÃnico e patolÃgico, dosagem de receptores de estrÃgeno e progesterona, casos de cÃncer de endomÃtrio, principais sÃtios de metÃstases, modalidade de tratamento cirÃrgico, radioterÃpico e quimioterÃpico, causas de Ãbito, tipo histolÃgico, status dos linfonodos axilares e anÃlise de sobrevivÃncia de acordo com o estadiamento. Concluiu-se que a maioria dos dados estÃo de acordo com a literatura e que o prejuÃzo da anÃlise foi resultante da qualidade dos registros realizados nos prontuÃrios, devendo cada vez mais os mÃdicos serem estimulados a documentar, de forma clara e legÃvel, o maior nÃmero de informaÃÃes possÃveis, nÃo apenas as positivas, mas todas aquelas que, mais freqÃentemente, possam ter relaÃÃo com a utilizaÃÃo de qualquer medicamento prescrito. / Breast cancer is a disease that was described many years ago and has been documented, for the first time, by Imhotep, physician, astrologer and Egyptian architect, born in 2.650 before Christ (b.C.), who recommended, at that time, as a way of treatment, cauterization of the diseased tissue. Tamoxifen is the drug more prescribed in the treatment of breast cancer. Itâs use is mainly in the adjuvant modality, in pre or post menopaused patients positive estrogen and/or progesteron receptors. Itâs used in the treatment of locally advanced and metastatic disease and in smaller proportion in patients with formal contraindication of surgery or that refuse to submit this treatment modality. In the neoadjuvancy it is just used in clinical research. The tamoxifen also reduces in the adjuvant modality during five years, the probability of recurrence in 47% and deaths caused by breast cancer in 26% and the two main side effects, in spite of rare, are the increase of the prevalence of endometrial cancer and of thromboembolic phenomenas. This study had as main objective to evaluate the patients, breast cancer bearers, in the Institute of Cancer of CearÃ, treated with tamoxifen in the adjuvant form in the period of 1993 to 1996 regarding the main benefits and side effects, as well as survival analysis. Seven hundred forty-two patientsâprontuaries were analyzed in respect to the demographic datas, age, menopausal status, clinical and pathological staging, dosage of estrogen and/or progesterone receptors, cases of endometrial cancer, main local metastasis, modality of surgical treatment, radiotherapy and chemotherapy, death causes, histological type, status of the axillary lymph nodes and survival analysis in agreement with the staging. We concluded that most of the data is in agreement with the literature and that the demage of the analysis was resulting from the quality accomplished found in the prontuaries. Also, doctors should be more and more stimulated to document, in a clear and readable way, the largest number of possible information, not just the positive ones, but all those that more frequently can have relationships with the use of any prescribed medicine. / Breast cancer is a disease that was described many years ago and has been documented, for the first time, by Imhotep, physician, astrologer and Egyptian architect, born in 2.650 before Christ (b.C.), who recommended, at that time, as a way of treatment, cauterization of the diseased tissue. Tamoxifen is the drug more prescribed in the treatment of breast cancer. Itâs use is mainly in the adjuvant modality, in pre or post menopaused patients positive estrogen and/or progesteron receptors. Itâs used in the treatment of locally advanced and metastatic disease and in smaller proportion in patients with formal contraindication of surgery or that refuse to submit this treatment modality. In the neoadjuvancy it is just used in clinical research. The tamoxifen also reduces in the adjuvant modality during five years, the probability of recurrence in 47% and deaths caused by breast cancer in 26% and the two main side effects, in spite of rare, are the increase of the prevalence of endometrial cancer and of thromboembolic phenomenas. This study had as main objective to evaluate the patients, breast cancer bearers, in the Institute of Cancer of CearÃ, treated with tamoxifen in the adjuvant form in the period of 1993 to 1996 regarding the main benefits and side effects, as well as survival analysis. Seven hundred forty-two patientsâprontuaries were analyzed in respect to the demographic datas, age, menopausal status, clinical and pathological staging, dosage of estrogen and/or progesterone receptors, cases of endometrial cancer, main local metastasis, modality of surgical treatment, radiotherapy and chemotherapy, death causes, histological type, status of the axillary lymph nodes and survival analysis in agreement with the staging. We concluded that most of the data is in agreement with the literature and that the demage of the analysis was resulting from the quality accomplished found in the prontuaries. Also, doctors should be more and more stimulated to document, in a clear and readable way, the largest number of possible information, not just the positive ones, but all those that more frequently can have relationships with the use of any prescribed medicine.

Background In the treatment of head and neck cancers (HNCs), radiotherapy (RT) has the advantage of organ preservation compared to surgery. However, treatment toxicities associated with RT can affect important functions for everyday life, both in the acute and late stage. RT to macroscopic tumour in HNC is commonly combined with elective RT to cervical lymph nodes at risk of microscopic involvement. The resulting risk reduction of the elective treatment based on dose-volume parameters is sparsely evaluated. So is the relationship between the elective treatment and treatment toxicity. The present thesis addresses these aspects. A strategy aimed at improving the outcome of RT is accelerated fractionation (AF). AF strives to shorten total treatment time to minimise proliferation of the tumour tissue during the RT period. We have investigated the impact of AF on both disease control and toxicity. Methods In the ARTSCAN study, 750 patients with localised HNC were randomised between AF (68 Gy in 4.5 weeks) and conventional fractionation (CF) (68 Gy in 7 weeks). The elective treatment volume was prescribed 46 Gy with CF in both treatment arms. The thesis is based on four individual papers, investigating the issues above in the whole study population or in sub-populations. Results No difference in disease control or late toxicity between CF and AF was observed at five years. However, there was an increased acute toxicity with AF. Weight loss was associated with treatment volume, independent of tumour stage. The elective treatment volume was found to be an independent risk factor for late aspiration, as well as mean dose to the pharyngeal constrictor muscles, neck dissection, and age at randomisation. There was a significant risk reduction for node relapses in volumes treated to an elective dose. Only a relapse in volumes treated to >60 Gy affected the survival. Conclusion The present thesis questions the benefit of AF in definitive RT as well as extensive elective treatment of the cervical nodes.

Background: The use of chemotherapy and endocrine therapies in the treatment of pre-menopausal women with breast cancer may result in menopausal symptoms, permanent infertility or the need to delay pregnancy. This series of studies investigates the fertility- and menopause-related information needs of pre-menopausal women with a diagnosis of early breast cancer (Studies 1 and 2) and the benefits women need to make undergoing adjuvant endocrine therapies worthwhile (Study 3). Method: Study 1 is a qualitative study of 24 women and Study 2 a survey study amongst 228 women. Study 3 included a subset of 102 women from the sample involved in Study 2 who had been treated with endocrine therapies for a minimum of three months. To be eligible, women had to be aged 40 years or younger (Study 2 and 3) when diagnosed with early stage breast cancer, and be 6-60 months post-diagnosis at the time of participation. For Study 2, participants completed a mailed self-report questionnaire that included a fertility- and menopause-related information needs survey, and standardized measures of distress, quality-of-life, menopausal symptoms and information preferences. For Study 3, participants were asked to complete a face-to-face interview. Results: Study 1 showed that many women thought that the information they had received in the past about fertility and menopausal symptoms was either insufficient or unavailable. Some women felt that, while information on fertility and menopause issues had not been paramount at the time of diagnosis, it became increasingly important after diagnosis. Study 2 showed that 71% of participants discussed fertility-related issues with a health professional as part of their breast cancer treatment and 86% discussed menopause-related issues. Consultation with a fertility or menopause specialist was the most preferred method of obtaining this information. Study 3 demonstrated that the majority of participants considered adjuvant endocrine therapy worthwhile for a 2% absolute gain in survival rates and for a 6-month gain in life expectancy. Conclusions: The results of this series of studies suggest that younger women have unmet needs for fertility- and menopause-related information. Women with early breast cancer who had received adjuvant endocrine therapies judged modest survival gains sufficient to make adjuvant endocrine therapy worthwhile.

Access to abstract restricted until 05/2016. / Access to thesis restricted until 05/2016. / Department of Physics and Astronomy