Palliative radiotherapy (PRT) is proven to be effective in palliation of symptoms for end-stage cancer patients. However, little is known about its utilization at the end of life. This research aims to examine the utilization and the practice patterns of PRT at the end of life for cancer patients in British Columbia using population-based data. The pattern observed for PRT1Y dose-fractionation practice in BC are in line with published clinical guidelines and evidence from the literature, which advises “proper” use of PRT in BC as delivered to cancer patients at the end of life. However, after controlling for age, primary cancer site, and survival time, geographic access is found to be significantly associated with PRT1Y utilization. Variations found in PRT1Y rates by geographic access, which is operationalized by the Health Services Delivery Area (HSDA) and travel time, suggests potential underutilization of PRT1Y for patients with suboptimal access. / Graduate / 0992 / 0769 / 0574 / jinhuang@uvic.ca

In the past several years, cancer treatments using FDA approved immune checkpoint inhibitors have become more popular than common chemotherapeutic agents. However, the costs, risks, and benefits associated with these treatments are still being assessed. Currently, new therapies are being tested that utilize oncolytic viruses to treat solid tumor and metastatic cancers. Reovirus is a non-enveloped virus with a double capsid structure and a genome consisting of 10 segments of double-stranded RNA encoding eleven proteins, which has been shown to have effective oncolytic activity. There are various different strains of reoviruses that can produce cytopathic effects in mammalian host cells. Moreover, several studies have shown that reovirus can be administered in multiple ways and that administration may depend on the cancer type. This investigation examined the type 3 dearing strain of reovirus and whether different types of tumors would benefit from having a specific administration appropriate to their type such as intratumoral injections for solid tumors and intravenous administration for blood/metastatic cancers. Various clinical trials were assessed in which reovirus was administered intratumorally, intravenously at a maximum dose of 3x1010 TCID50, and in combinations with other cancer therapeutics. Reovirus was shown to be safe and well-tolerated across a variety of administrations and cancer morphologies. Moreover, along with its cytopathic effects, reovirus was shown to have potent immune system stimulating effects. Overall, intratumoral administration was preferred effective for solid tumor cancers while intravenous administration was preferred for blood and metastatic cancers.

Metastatic cancer is more dangerous and difficult to treat than pre-metastatic cancer. Ninety percent of cancer-related deaths are caused by metastatic cancer. When cells go through metastases, they go through changes that allow them to break away from the primary tumor and invade secondary tissues. These changes, in lipid membrane composition and cellular glycocalyx, make the cell more resistant to therapeutics. Actin cytoskeleton contractility plays a major role in these changes, as increased contractility has been linked to upregulation of phosphoinositides and production of glycoproteins. Light induced molecular adsorption of proteins (LIMAP) was used to control the actin arrangement and cell shape in order to mimic and study metastatic cells. Negatively charged proteins electrostatically adhere to the surface in order to create patterns for the cells to stick. Neutravidin was conjugated to poly(glutamic acid) to improve attachment to the surface. We observed differences in cell shape and phosphoinositide behavior based on LIMAP patterning. Additionally, expression of key glycoproteins related to cancer metastasis increased with increased actin contractility. The actin cytoskeleton was the main driver of changes to the cell membrane and glycocalyx.

Sarcoidosis is a multisystem granulomatous disease commonly involving the lungs and mediastinal lymph nodes with the exact etiology being unclear. The simultaneous presence of malignant disease such as breast cancer and sarcoidosis has been reported. Sarcoidosis preceding a diagnosis of malignancy and that occurring years after treatment of malignant disease has been noted in the past. The presence of sarcoidosis in the setting of malignant disease carries a high risk of misdiagnosis. In this article, we report the case of a 45-year-old female with stage IA invasive ductal carcinoma of left breast that was in remission for 2 years; however, radiological imaging including magnetic resonance imaging of thoracic spine and positron emission tomography–computed tomography scanning were highly suspicious for malignant disease metastasis versus lymphoma with the widespread lymphadenopathy. Multiple tissue biopsies with histopathological evaluation allowed us to definitively exclude malignant disease metastasis and to correctly diagnose her atypical presentation of sarcoidosis.

O 153Sm-EDTMP é um radiofármaco utilizado em medicina nuclear com resultados promissores no alívio da dor metastática. No entanto, pouco se sabe sobre os efeitos do 153Sm-EDTMP em nível celular. O presente trabalho foi conduzido com o intuito de avaliar os efeitos citogenéticos do 153Sm-EDTMP em linfócitos periféricos de pacientes com metástases ósseas (com e sem radio e/ou quimioterapias anteriores) pela da técnica de detecção de aberrações cromossômicas, tanto in vivo como in vitro. Para tanto, as amostras sangüíneas foram coletadas antes e 1 hora após a administração endovenosa do 153Sm- EDTMP (atividade média de 42,53 + 5,31 MBq/kg de peso corpóreo), levando-se em consideração o rápido clearance sangüíneo. Os principais tipos de aberrações cromossômicas estruturais encontrados foram os gaps e quebras, fragmentos acêntricos, anéis cêntricos, double minutes e dicêntricos. A análise estatística mostrou que o único grupo de pacientes que apresentou uma diferença significativa na freqüência de aberrações cromossômicas 1 hora após o tratamento foi o que recebeu prévio tratamento radio e quimioterápico antes da terapia com 153Sm-EDTMP. Quanto a averiguação do número modal de cromossomos e da cinética do ciclo celular, a análise estatística mostrou que não houve diferença significativa entre os grupos analisados, sugerindo que o tratamento com 153Sm-EDTMP não influenciou nesses parâmetros. A molécula carreadora, EDTMP, não teve qualquer influência na indução de aberrações cromossômicas. Em relação aos ensaios in vitro, os dados obtidos de linfócitos periféricos submetidos às diferentes concentrações radioativas de 153Sm-EDTMP (0,046 – 1,110 MBq/mL) de doadores sadios e de pacientes sem prévio tratamento se ajustaram melhor ao modelo de regressão linear (Y=A+BX). O dano cromossômico induzido pelo 153Sm-EDTMP observado in vitro foi cerca de 2 vezes maior do que o encontrado in vivo para o grupo de pacientes sem prévio tratamento. Os dados obtidos mostraram que a terapia com 153Sm-EDTMP induziu uma pequena quantidade de danos citogenéticos em linfócitos periféricos de pacientes 1 hora após sua administração, embora, teoricamente, um efeito estocástico a longo prazo não possa ser descartado. / The 153Sm-EDTMP is a radiopharmaceutical used in nuclear medicine with promising results for the relief of metastatic pain. Therefore, there are few knowledge about the effects of 153Sm-EDTMP at cellular level. The present study was conducted with the aim of evaluating the cytogenetic effects of 153Sm-EDTMP in peripheral lymphocytes from patients with bone metastasis (with and without previous radio and/or chemotherapy) by the chromosome aberration technique, either in vivo or in vitro. For that, the blood samples were collected before and one hour after the endovenous administrations of 153Sm-EDTMP (mean activity of 42.53 + 5.31 MBq/kg body weight), taking into account the rapid blood clearance. The principal types of structural chromosome aberrations found gaps and breaks, acentric fragments centric rings, double minutes and dicentrics. The statistical analysis showed that the group submitted to previous radio and chemotherapy before153Sm-EDTMP administration showed significant difference in chromosome aberrations frequency one hour after the treatment. The analysis of the chromosome modal number and the kinetics of cellular cycle showed no statistical difference among the groups, suggesting that the treatment with 153Sm-EDTMP, did not influence these parameters. The carrier molecule, EDTMP, did not influence the induction of chromosome aberration. In relation to the in vitro assays, the obtained data of peripheral lymphocytes of healthy donors and patients with no previous treatment exposed to different radioactive concentration of 153Sm-EDTMP (0.046 – 1.110 MBq/mL) were better adjusted by linear regression model (Y=A+BX). The chromosome damage induced by 153Sm-EDTMP observed in vitro was about 2 fold higher than that found in vivo for the group of patients with no previous treatment. The obtained data showed that the therapy with 153Sm- EDTMP induced a few quantity of cytogenetic damages in peripheral lymphocytes one hour after its administration in patients, although, theoretically, a long term stochastic effect cannot be disregarded.

O 153Sm-EDTMP é um radiofármaco utilizado em medicina nuclear com resultados promissores no alívio da dor metastática. No entanto, pouco se sabe sobre os efeitos do 153Sm-EDTMP em nível celular. O presente trabalho foi conduzido com o intuito de avaliar os efeitos citogenéticos do 153Sm-EDTMP em linfócitos periféricos de pacientes com metástases ósseas (com e sem radio e/ou quimioterapias anteriores) pela da técnica de detecção de aberrações cromossômicas, tanto in vivo como in vitro. Para tanto, as amostras sangüíneas foram coletadas antes e 1 hora após a administração endovenosa do 153Sm- EDTMP (atividade média de 42,53 + 5,31 MBq/kg de peso corpóreo), levando-se em consideração o rápido clearance sangüíneo. Os principais tipos de aberrações cromossômicas estruturais encontrados foram os gaps e quebras, fragmentos acêntricos, anéis cêntricos, double minutes e dicêntricos. A análise estatística mostrou que o único grupo de pacientes que apresentou uma diferença significativa na freqüência de aberrações cromossômicas 1 hora após o tratamento foi o que recebeu prévio tratamento radio e quimioterápico antes da terapia com 153Sm-EDTMP. Quanto a averiguação do número modal de cromossomos e da cinética do ciclo celular, a análise estatística mostrou que não houve diferença significativa entre os grupos analisados, sugerindo que o tratamento com 153Sm-EDTMP não influenciou nesses parâmetros. A molécula carreadora, EDTMP, não teve qualquer influência na indução de aberrações cromossômicas. Em relação aos ensaios in vitro, os dados obtidos de linfócitos periféricos submetidos às diferentes concentrações radioativas de 153Sm-EDTMP (0,046 – 1,110 MBq/mL) de doadores sadios e de pacientes sem prévio tratamento se ajustaram melhor ao modelo de regressão linear (Y=A+BX). O dano cromossômico induzido pelo 153Sm-EDTMP observado in vitro foi cerca de 2 vezes maior do que o encontrado in vivo para o grupo de pacientes sem prévio tratamento. Os dados obtidos mostraram que a terapia com 153Sm-EDTMP induziu uma pequena quantidade de danos citogenéticos em linfócitos periféricos de pacientes 1 hora após sua administração, embora, teoricamente, um efeito estocástico a longo prazo não possa ser descartado. / The 153Sm-EDTMP is a radiopharmaceutical used in nuclear medicine with promising results for the relief of metastatic pain. Therefore, there are few knowledge about the effects of 153Sm-EDTMP at cellular level. The present study was conducted with the aim of evaluating the cytogenetic effects of 153Sm-EDTMP in peripheral lymphocytes from patients with bone metastasis (with and without previous radio and/or chemotherapy) by the chromosome aberration technique, either in vivo or in vitro. For that, the blood samples were collected before and one hour after the endovenous administrations of 153Sm-EDTMP (mean activity of 42.53 + 5.31 MBq/kg body weight), taking into account the rapid blood clearance. The principal types of structural chromosome aberrations found gaps and breaks, acentric fragments centric rings, double minutes and dicentrics. The statistical analysis showed that the group submitted to previous radio and chemotherapy before153Sm-EDTMP administration showed significant difference in chromosome aberrations frequency one hour after the treatment. The analysis of the chromosome modal number and the kinetics of cellular cycle showed no statistical difference among the groups, suggesting that the treatment with 153Sm-EDTMP, did not influence these parameters. The carrier molecule, EDTMP, did not influence the induction of chromosome aberration. In relation to the in vitro assays, the obtained data of peripheral lymphocytes of healthy donors and patients with no previous treatment exposed to different radioactive concentration of 153Sm-EDTMP (0.046 – 1.110 MBq/mL) were better adjusted by linear regression model (Y=A+BX). The chromosome damage induced by 153Sm-EDTMP observed in vitro was about 2 fold higher than that found in vivo for the group of patients with no previous treatment. The obtained data showed that the therapy with 153Sm- EDTMP induced a few quantity of cytogenetic damages in peripheral lymphocytes one hour after its administration in patients, although, theoretically, a long term stochastic effect cannot be disregarded.

In most randomised controlled trials (RCTs), a large number of patients need to be followed over many years, for the clinical benefit of the drug to be accurately quantified (1). Using an early proxy, or a surrogate endpoint, in place of the direct endpoint of overall survival (OS) could theoretically shorten the duration of RCTs and minimise the exposure of patients to ineffective or toxic treatments (2, 3). This thesis examined the relationship between surrogate endpoints and OS in metastatic colorectal cancer (CRC), advanced non-small cell lung cancer (NSCLC) and metastatic breast cancer (MBC). A review of the literature identified 144 RCTs in metastatic CRC, 189 in advanced NSCLC and 133 in MBC. The publications were generally of poor quality with incomplete reporting on many key variables, making comparisons between studies difficult. The introduction of the CONSORT statement was associated with improvements in the quality of reporting. For CRC (337 arms), NSCLC (429 arms) and MBC (290 arms) there were strong relationships between OS and progression free survival (PFS), time to progression (TTP), disease control rate (DCR), response rate (RR) and partial response (PR). Correlation was also demonstrated between OS and complete response (CR) in CRC and duration of response (DOR) in MBC. However, while strong relationships were found, the proportion of variance explained by the models was small. Prediction bands constructed to determine the surrogate threshold effect size indicated that large improvements in the surrogate endpoints were needed to predict overall survival gains. PFS and TTP showed the most promise as surrogates. The gain in PFS and TTP required to predict a significant gain in overall survival was between 1.2 and 7.0 months and 1.8 and 7.7 months respectively, depending on trial size and tumour type. DCR was a better potential predictor of OS than RR. The results of this study could be used to design future clinical trials with particular reference to the selection of surrogate endpoint and trial size.

In most randomised controlled trials (RCTs), a large number of patients need to be followed over many years, for the clinical benefit of the drug to be accurately quantified (1). Using an early proxy, or a surrogate endpoint, in place of the direct endpoint of overall survival (OS) could theoretically shorten the duration of RCTs and minimise the exposure of patients to ineffective or toxic treatments (2, 3). This thesis examined the relationship between surrogate endpoints and OS in metastatic colorectal cancer (CRC), advanced non-small cell lung cancer (NSCLC) and metastatic breast cancer (MBC). A review of the literature identified 144 RCTs in metastatic CRC, 189 in advanced NSCLC and 133 in MBC. The publications were generally of poor quality with incomplete reporting on many key variables, making comparisons between studies difficult. The introduction of the CONSORT statement was associated with improvements in the quality of reporting. For CRC (337 arms), NSCLC (429 arms) and MBC (290 arms) there were strong relationships between OS and progression free survival (PFS), time to progression (TTP), disease control rate (DCR), response rate (RR) and partial response (PR). Correlation was also demonstrated between OS and complete response (CR) in CRC and duration of response (DOR) in MBC. However, while strong relationships were found, the proportion of variance explained by the models was small. Prediction bands constructed to determine the surrogate threshold effect size indicated that large improvements in the surrogate endpoints were needed to predict overall survival gains. PFS and TTP showed the most promise as surrogates. The gain in PFS and TTP required to predict a significant gain in overall survival was between 1.2 and 7.0 months and 1.8 and 7.7 months respectively, depending on trial size and tumour type. DCR was a better potential predictor of OS than RR. The results of this study could be used to design future clinical trials with particular reference to the selection of surrogate endpoint and trial size.

INTRODUÇÃO: A insuficiência respiratória acomete grande parte dos pacientes oncológicos levando a altos índices de mortalidade. A ventilação não invasiva (VNI) pode auxiliar seu manejo, mas seus efeitos ainda são pouco conhecidos sobre os mecanismos de defesa pulmonar. OBJETIVOS: Observar o efeito da VNI com máscara facial usando-se geradores de fluxo com pressão positiva contínua (CPAP) e ventilador microprocessado no modo pressão de suporte + pressão positiva ao final da expiração (PSV + PEEP), a fim de verificar impacto nas propriedades viscoelásticas do muco respiratório e o conforto proporcionado ao paciente. MÉTODOS: A VNI foi instalada após diagnóstico de insuficiência respiratória em dezenove pacientes, admitidos nas unidades de tratamento intensivo do Hospital A. C. Camargo, sendo nove submetidos ao CPAP e dez com PSV + PEEP. Foram colhidos antes e após uma hora de VNI: os dados clínicos, secreção nasal, gasometria, e o grau de conforto através de uma escala visual. As propriedades físicas do muco (transportabilidade in vitro, adesividade e wettabilidade ou hidrofobicidade) foram avaliadas respectivamente no palato de rã, máquina da tosse e ângulo de contato. RESULTADOS: Os grupos eram homogêneos entre si em relação à idade, sexo, tipo e estadiamento do tumor e SAPS II. Em relação às propriedades físicas do muco, houve um aumento da transportabilidade in vitro do muco nasal com o sistema PSV + PEEP (p = 0,04) e um aumento na wettabilidade no grupo CPAP (p = 0,06). Os dois sistemas foram eficazes em melhorar significativamente os sinais vitais, a PaO2/FiO2, o padrão e o conforto respiratório e em evitar a intubação traqueal nas primeiras 24 horas (p < 0,05). Entretanto, independentemente do tipo de sistema de VNI usado, foram encontrados altos índices de intubação endotraqueal e mortalidade no seguimento destes pacientes. CONCLUSÃO: As propriedades físicas do muco (transportabilidade in vitro e wettabilidade) se alteraram após uma hora de uso da VNI e parecem ser dependentes da temperatura e umidificação dentro da máscara. A VNI mostrou-se útil em reverter a insuficiência respiratória em pacientes selecionados, ou pelo menos em trazer conforto para pacientes hipoxêmicos que a princípio recusam a intubação endotraqueal / INTRODUCTION: Respiratory failure is a common situation among cancer patients leading to high rates of mortality. Noninvasive ventilation (NIV) can help its management, but its effects are still unknown regarding the pulmonary defense mechanisms. OBJECTIVES: Observe the effect of NIV with facial mask using a flow generator with continuous positive pressure (CPAP) and standard intensive care unit ventilator using pressure support ventilation + positive end expiratory pressure (PSV + PEEP), to verify impact on the physical properties of respiratory mucus and the comfort provided to the patient. METHODS: NIV was started after diagnosis of respiratory failure in nineteen patients, admitted in the intensive care unit of the A. C. Camargo Hospital. Nine patients were submitted to CPAP and ten to PSV + PEEP. Nasal mucus, blood gases, and the degree of comfort through a visual scale were accessed before and after one hour. The physical properties of nasal mucus (transportabilility in vitro, adhesivity and wettability or hydrofobicity) were evaluated respectively by frog palate, cough machine and contact angle. RESULTS: Groups had similar characteristics about age, sex, tumor and SAPS II score. Regarding the physical properties of the mucus, there was an increase in mucus transportability (by the frog palate model) with the system PSV + PEEP (p = 0.04) and an increase in the contact angle in the CPAP groupo (p = 0.06). The two systems were effective in improving the vital signs, the PaO2/FiO2, the respiratory pattern and comfort and avoiding endotracheal intubation in the first 24 hours (p < 0.05). However, regardless of the type of NIV system used, high rates of endotracheal intubation and mortality were found. CONCLUSION: The physical properties of the mucus (transportability in vitro and wettability) changed after an hour of use of the NIV as a result of temperature and humidification into the mask. NIV was useful in reversing the respiratory failure in selected patients, or at least in bringing comfort for those who refuse endotracheal intubation

INTRODUÇÃO: A insuficiência respiratória acomete grande parte dos pacientes oncológicos levando a altos índices de mortalidade. A ventilação não invasiva (VNI) pode auxiliar seu manejo, mas seus efeitos ainda são pouco conhecidos sobre os mecanismos de defesa pulmonar. OBJETIVOS: Observar o efeito da VNI com máscara facial usando-se geradores de fluxo com pressão positiva contínua (CPAP) e ventilador microprocessado no modo pressão de suporte + pressão positiva ao final da expiração (PSV + PEEP), a fim de verificar impacto nas propriedades viscoelásticas do muco respiratório e o conforto proporcionado ao paciente. MÉTODOS: A VNI foi instalada após diagnóstico de insuficiência respiratória em dezenove pacientes, admitidos nas unidades de tratamento intensivo do Hospital A. C. Camargo, sendo nove submetidos ao CPAP e dez com PSV + PEEP. Foram colhidos antes e após uma hora de VNI: os dados clínicos, secreção nasal, gasometria, e o grau de conforto através de uma escala visual. As propriedades físicas do muco (transportabilidade in vitro, adesividade e wettabilidade ou hidrofobicidade) foram avaliadas respectivamente no palato de rã, máquina da tosse e ângulo de contato. RESULTADOS: Os grupos eram homogêneos entre si em relação à idade, sexo, tipo e estadiamento do tumor e SAPS II. Em relação às propriedades físicas do muco, houve um aumento da transportabilidade in vitro do muco nasal com o sistema PSV + PEEP (p = 0,04) e um aumento na wettabilidade no grupo CPAP (p = 0,06). Os dois sistemas foram eficazes em melhorar significativamente os sinais vitais, a PaO2/FiO2, o padrão e o conforto respiratório e em evitar a intubação traqueal nas primeiras 24 horas (p < 0,05). Entretanto, independentemente do tipo de sistema de VNI usado, foram encontrados altos índices de intubação endotraqueal e mortalidade no seguimento destes pacientes. CONCLUSÃO: As propriedades físicas do muco (transportabilidade in vitro e wettabilidade) se alteraram após uma hora de uso da VNI e parecem ser dependentes da temperatura e umidificação dentro da máscara. A VNI mostrou-se útil em reverter a insuficiência respiratória em pacientes selecionados, ou pelo menos em trazer conforto para pacientes hipoxêmicos que a princípio recusam a intubação endotraqueal / INTRODUCTION: Respiratory failure is a common situation among cancer patients leading to high rates of mortality. Noninvasive ventilation (NIV) can help its management, but its effects are still unknown regarding the pulmonary defense mechanisms. OBJECTIVES: Observe the effect of NIV with facial mask using a flow generator with continuous positive pressure (CPAP) and standard intensive care unit ventilator using pressure support ventilation + positive end expiratory pressure (PSV + PEEP), to verify impact on the physical properties of respiratory mucus and the comfort provided to the patient. METHODS: NIV was started after diagnosis of respiratory failure in nineteen patients, admitted in the intensive care unit of the A. C. Camargo Hospital. Nine patients were submitted to CPAP and ten to PSV + PEEP. Nasal mucus, blood gases, and the degree of comfort through a visual scale were accessed before and after one hour. The physical properties of nasal mucus (transportabilility in vitro, adhesivity and wettability or hydrofobicity) were evaluated respectively by frog palate, cough machine and contact angle. RESULTS: Groups had similar characteristics about age, sex, tumor and SAPS II score. Regarding the physical properties of the mucus, there was an increase in mucus transportability (by the frog palate model) with the system PSV + PEEP (p = 0.04) and an increase in the contact angle in the CPAP groupo (p = 0.06). The two systems were effective in improving the vital signs, the PaO2/FiO2, the respiratory pattern and comfort and avoiding endotracheal intubation in the first 24 hours (p < 0.05). However, regardless of the type of NIV system used, high rates of endotracheal intubation and mortality were found. CONCLUSION: The physical properties of the mucus (transportability in vitro and wettability) changed after an hour of use of the NIV as a result of temperature and humidification into the mask. NIV was useful in reversing the respiratory failure in selected patients, or at least in bringing comfort for those who refuse endotracheal intubation