Ovarian cancer is one of the five most common causes of cancer death in women in the USA and UK. It is usually diagnosed when it is well established beyond the ovary in the peritoneum. Intravenous injection of cisplatin is a common palliative therapy for ovarian cancer patients. Intraperitoneal therapy has been shown to improve survival for patients. Poly(lactide-co-glycolide) (PLGA) is a biodegradable polyester which has been proven safe for medical implantation. PLGA microspheres or fibres have been considered in this work as depots for delivering intraperitoneal cisplatin directly to the tumour site. The aims of this work were (1) to develop microsphere depot formulations with improved drug release profiles compared to previous work; (2) Novel cisplatin containing solid and hollow fibres were to be developed and investigated as alternative structures for depot devices; (3) The drug release profiles were to be examined using mathematical models to allow rational comparison of the devices. It was found that cisplatin containing PLGA 65:35 solid and hollow fibres represent a novel, reproducible formulation for encapsulating higher amounts of cisplatin for an equivalent mass of excipient than other polymer formulations. The fibres developed in this study were able to maintain elevated concentrations of unbound cisplatin in the presence of a biological matrix for approximately 100 hours in vitro.

O trabalho propõe a discussão sobre a construção do vocabulário político moderno utilizado na província do Rio Grande e na Banda Oriental durante o processo de formação das Cortes de Portugal, no processo de independência brasileiro, durante a elaboração da constituição nacional, na anexação da Província Cisplatina ao território brasileiro e no início da guerra de independência em relação ao Brasil. Termos como povo, nação, constituição e soberania, além de outros como opinião pública e autonomia política são considerados à luz dos eventos políticos no território brasileiro e oriental entre os anos de 1821 e 1825. Também a relação que se estabeleceu entre o império brasileiro e a condição da Província Cisplatina, principalmente sobre a relativa autonomia política, são consideradas nessa pesquisa. / The paper proposes a discussion on the construction of modern political vocabularies used in the province of Rio Grande and Eastern Band during the process of formation of the Cortes of Portugal, the Brazilian independence process during the drafting of the national constitution, the annexation of cisplatin province to Brazil and at the beginning of the war of independence in relation to Brazil. Terms such as people, nation, constitution and sovereignty, as well as opinion public and political autonomy are considered in the light of political events in Brazil and eastern territory between the years 1821 and 1825. Also the relationship established between the Brazilian Empire and the condition of cisplatin province manly on the relative political autonomy is considered in this research.

INTRODUÇÃO: A combinação de radioterapia e altas doses de cisplatina no tratamento do meduloblastoma tem se mostrado causa de importante ototoxicidade. Com a introdução da técnica de intensidade modulada do feixe (IMRT), tornou-se possível diminuir a dose média de radiação no aparelho auditivo. OBJETIVOS: O objetivo é determinar se com a radioterapia com reforço de dose com IMRT, é possível atingir índices menores de perda auditiva e se há um limite de dose no ouvido para a mesma. Analisar também se o volume de ouvido contornado durante o planejamento inverso influencia o resultado. MÉTODO: Quarenta e um pacientes com meduloblastoma (idade mediana, 10 anos) com audição normal ao início da radioterapia com IMRT foram avaliados retrospectivamente. O último seguimento e a última audiometria realizada após o término da radioterapia foram considerados. A função auditiva foi graduada em uma escala de 0 a 4 de acordo com os critérios de toxicidade do Pediatric Oncology Group (POG). As doses mínima, máxima, média e mediana recebidas pelo aparelho auditivo, bem como o volume contornado no planejamento do IMRT foram correlacionados com o grau de função auditiva. Foi realizada análise univariada e multivariada dos dados. RESULTADOS: O seguimento mediano foi de 41 meses (12,8 a 71) para avaliação audiométrica e 44 meses (14-72) para a sobrevida global. As doses medianas mínima, máxima, média e mediana recebidas pelo aparelho auditivo foram respectivamente de: 3785 (589,4 a 4758,2), 4832,5 (3724 a 5447,9), 4366,5 (2808,5 a 5097,3) e 4360,5 (2878 a 5031,1). Sete pacientes (17%) apresentaram perda auditiva graus 3 e 4. A análise univariada entre as variáveis não mostrou diferença com significância estatística, exceto para a dose de cisplatina (P < 0,03). Na análise multivariada com regressão logística, a dose mediana no aparelho auditivo foi um fator significativo para a perda auditiva graus 3 e 4 (P < 0,01), ao passo que a dose cumulativa de cisplatina apresentou tendência à perda graus 3 e 4 (P = 0,075). Não houve correlação entre o volume contornado no planejamento a perda auditiva. Perda auditiva graus 3 e 4 foi incomum com dose mediana no aparelho auditivo menor que 42 Gy (P = 0,063) e dose cumulativa de cisplatina abaixo de 375 mg/m² (P < 0,01). Nenhum paciente que recebeu carboplatina em substituição à cisplatina apresentou perda auditiva grave. Não houve associação, com significância estatística, entre as variáveis analisadas e a ototoxicidade, quando estes pacientes foram excluídos da análise. Quatro pacientes morreram e dois apresentaram recidiva no momento do estudo, levando a uma sobrevida global de 90% e uma sobrevida livre de doença de 85% em 44 meses. CONCLUSÕES: Os resultados mostram que o tratamento com IMRT leva a uma baixa taxa de perda auditiva grave, mesmo com um seguimento maior, o que é consistente com outros estudos. Acreditamos ser seguro contornar somente a cóclea e que uma dose mediana para a mesma deve ser mantida abaixo de 42 Gy. A quimioterapia com cisplatina continua a ter um papel importante no tratamento, no entanto a dose cumulativa não deve exceder 375 mg/m². A sobrevida foi impressionante neste estudo, uma vez que 21 (51,2%) foram classificados como alto risco / INTRODUCTION: The combination of radiation therapy and cisplatin chemotherapy for the treatment of medulloblastoma is a known cause of important ototoxicity. With the introduction of intensity-modulated radiation therapy (IMRT), it became possible to deliver less radiation to the auditory apparatus. PURPOSE: To determine if boost radiotherapy with IMRT can achieve a lower rate of hearing loss and if theres a cutoff dose for it. Also, to analyze whether the auditory apparatus volume contoured in inverse planning influences the outcome. METHODS: Forty-one pediatric medulloblastoma patients (median age, 10 years) with normal hearing at the time of radiation with IMRT were retrospectively evaluated. The last audiogram and follow-up from the completion of radiation were considered. Hearing function was graded on a scale 0 to 4 according to Pediatric Oncology groups toxicity criteria. Minimum, maximum, mean and median doses to the inner ear and its volume contoured in IMRT planning, as well the cisplatin dose were recorded and correlated with hearing function. Univariate and multivariate data analysis were performed. RESULTS: The median follow-up was 41 months (range 12.8-71.0 months) for audiometric evaluation and 44 months (range 14-72 months) for survival. Median doses for minimum, maximum, mean and median in the inner ear were respectively: 3785 (range, 589.4 to 4758.2), 4832.5 (range 3724 to 5447.9), 4366.5 (range 2808.5 to 5097,3) and 4360,5 (range 2878 to 5031,1). Seven patients (17%) have experienced Grade 3 or 4 hearing loss. Univariate analysis showed no difference among the variables with statistical significance, except for cisplatin dose (P < 0.03). In multivariate analysis with logistic regression, median dose in inner ear was a significant factor for hearing loss grade 3 or 4 (P < 0,01), meanwhile cisplatin dose had a trend to hearing loss grade 3 or 4 (P = 0.075). There was no relationship between the auditory apparatus volume contoured in planning and hearing loss. Grade 3 or 4 hearing loss were uncommon with median dose to the inner ear bellow 42 Gy (P = 0.063) and cisplatin dose less than 375 mg/m² (P < 0.01). None of the patients who received carboplatin in lieu of cisplatin had severe hearing loss. There was no statistically significant association between ototoxicity and the variables, when these patients were excluded from the analysis. Four patients died and two have recurred at the time of the study with a 90% overall survival rate and 85% disease free survival in 44 months. CONCLUSIONS: Our findings shows that IMRT treatment leads to a low rate of serious hearing loss even with a longer follow-up, which is consistent with others trials. We believe that is safe to contour only the cochlea and that a median dose to it should be kept below 42Gy. Cisplatin chemotherapy continues to have an important role in treatment, however doses should not exceed 375 mg/m². Survival rates were impressing in this trial given the fact that 21 (51.2%) patients were classified as high risk

Orientador: Marisa Aparecida Cabrini Gabrielli / Resumo: A maioria dos pacientes submetidos a tratamentos de câncer bucal são impossibilitados de receber reabilitação com próteses dentais convencionais. Assim, a confecção de próteses suportadas por implantes dentários osseointegráveis tem sido considerada uma alternativa. Apesar dos elevados índices de sucesso destes tratamentos, pode haver um inconveniente em se reabilitar esses pacientes. Alguns quimioterápicos, como a Cisplatina, apresentam efeitos colaterais como redução na remodelação óssea e/ou alteração na nutrição desse tecido, o que pode interferir com a osseointegração dos implantes. O presente estudo avaliou, em ratos, o efeito da terapia em longo prazo com Cisplatina sobre o processo de reparo e mineralização óssea ao redor de implantes e sobre as propriedades mecânicas do tecido ósseo. Para isso, 43 ratos foram distribuídos aleatoriamente em 2 grupos: cisplatina (CIS, n=23), no qual os animais receberam administração intraperitoneal de cisplatina uma vez a cada semana durante 4 semanas, totalizando 4 administrações, e controle (CTL, n=20), no qual os animais receberam administração a cada 1 semana de placebo, durante todo o período experimental. Após 28 dias do início do tratamento, um implante de titânio foi instalado na metáfise tibial, em ambas as pernas. Os animais foram sacrificados 30 e 60 dias após a instalação dos implantes, sendo retirados os fêmures e as tíbias. Os fêmures foram submetidos aos testes mecânicos de força máxima (N), força de ruptura (N), força ... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Most of patients undergoing oral cancer treatments are unable to receive rehabilitation with conventional dental prostheses. Thus, the use of prostheses supported by osseointegrated implants has been considered as an alternative. Despite the high rate of success of the dental treatments, there may be an inconvenience to rehabilitate these patients. Some chemotherapeutic agents as Cisplatin exhibit undesirable side effects, such as the reduction in bone remodeling and/or changes in nutrition of tissue, which can interfere with the osseointegration of implants. This study evaluated, in rats, the effect of the long-term therapy with Cisplatin on bone healing and mineralization around implants and on the mechanical properties of bone tissue. Forty-three rats were randomly divided into two groups: Cisplatin (CIS, n=23), in which the animals received subcutaneous administration of Cisplatin once a week for 4 weeks (a total of 4 administrations) and control (CTL, n=20), in which the animals received a placebo solution once a week throughout the trial period. After 28 days of treatment initiation, a titanium implant were installed in the tibial metaphysis, on both legs. The animals from each group were sacrificed 30 and 60 days after the implant placement, and their femurs and tibias removed. Femurs were subjected to mechanical tests of maximum strength (N), maximum rupture force (N), maximum strength (mm), and rupture (mm). The tibias with the implants were assessed for removal torq... (Complete abstract click electronic access below) / Doutor

Orientador: Carlos Roberto Daleck / Banca: José Jurandir Fagliari / Banca: Duvaldo Eurides / Resumo: A cisplatina é um fármaco antineoplásico utilizado como adjuvante no tratamento de diversas neoplasias. Neste estudo foram avaliados o hemograma e os teores de sódio, potássio, magnésio, cálcio e fósforo do soro sanguíneo de cães submetidos à terapia com cisplatina. Foram utilizados oito cães, machos, sem raça definida, com 10 a 15 kg de peso, clinicamente sadios. Os cães foram distribuídos em dois grupos, contendo 4 animais cada, sendo que os animais do grupo 1 receberam cisplatina e aqueles do grupo 2 não receberam cisplatina. Os cães do grupo 1 receberam quimioterapia e protocolo de diurese para proteção renal, já o grupo controle 2 não recebeu a cisplatina, estando sujeito apenas aos fatores ambientais. Os animais do grupo 1 foram submetidos a quatro sessões de quimioterapia com cisplatina na dose de 70mg/mø, administrada por via intravenosa, durante 20 minutos, no intervalo de 21 dias. Antes da administração da cisplatina, realizou-se fluidoterapia com solução fisiológica a 0,9% na dose de 25mL/kg/hora, por via intravenosa, durante duas horas, e depois por mais uma hora. Todos os animais receberam metoclopramida na dose de 2mg/kg, por via intravenosa, 15 minutos antes da administração da cisplatina e furosemida na dose de 2 mg/kg, por via intravenosa, 5 minutos após administração de metoclopramida. As amostras foram processadas e analisadas antes de cada sessão de quimioterapia. Os resultados mostraram que não houve diferença significativa entre os grupos para as contagens de hemácias, concentração de hemoglobina, hematócrito e contagem de leucócitos, mesmo assim as concentrações séricas de eletrólitos mantiveram-se dentro dos padrões da normalidade. Os resultados obtidos podem ser indicativos de que o protocolo empregado para o grupo 1 se mostrou efetivo para manter as características do hemograma e a concentração sérica dos eletrólitos. / Abstract: The cisplatin is an antineoplasic drug used like adjunct treatment of various neoplasms. In this study, one evaluated the hemogram and sodium, potassium, magnesium, calcium and phosphorus levels in the dogs' blood under administration of cisplatin. One used 8 male dogs, with no definite race, weighing from 10 to 15 kilograms, and clinically healthy. The dogs were divided into two groups of 4 animals each, being group 1 treated with cisplatin and group 2 with no cisplatin. Group 1 received chemotherapy and the diurese protocol for kidney protection, group 2 did not receive cisplatin, being exposed only to the environmental factors. The animals from group 1 were submitted to four chemotherapy sessions with cisplatin 70mg/m2 administered intravenously for 20 minutes, in a 21 days interval before the cisplatin administration, one carried out a fluidotherapy with physiologic solution 0,9% on a dosage of 25mg/kg/hour intravenously during 2 hours, and posteriorly for one more hour. All the animals received methoclopramid intravenously on a dosage of 2mg/kg, 15 minutes before the cisplatin and furosemide administration on a 2mg/kg dosage, 5 minutes before the cisplatin infusion. The evaluation of the hemogram and the electrolytes levels above mentioned were done before each chemotherapy session. The results demonstrate that there were no significant differences among the groups for red blood cells counting, hemoglobin concentration, hematocrit and leucocytes counting, but still, the electrolytes seric concentration maintained itself in a normal standard. The results obtained may indicate that the protocol employed for group 1 showed efficiency to maintain the characteristics of the hemogram and the electrolytes seric concentration. / Mestre

Made available in DSpace on 2017-07-10T14:17:06Z (GMT). No. of bitstreams: 1 Ademar Cunha Junior.pdf: 5907577 bytes, checksum: d4f5656226f906835cfbc7f0cb6c2a2a (MD5) Previous issue date: 2014-02-14 / Acute kidney injury (AKI) in patients receiving cisplatin is common, therefore the evaluation of renal function in patients on use of nephrotoxic drugs is fundamental. Objective: To evaluate the incidence of AKI and the role of lipocalin associated to neutrophil gelatinase (NGAL) in the monitoring of renal function in patients with head and neck cancer (HNC) who received cisplatin. Methods: We prospectively studied 50 patients with HNC treated with three sessions of cisplatin. Blood and urine were collected 24 h before cisplatin, 24 h after infusion, 48 h after each application and 35 days after the end of treatment (urine NGAL, C-reactive protein, creatinine, glomerular filtration rate, plasma lactate dehydrogenase and magnesium). Results: AKI was observed in 78 % of patients. There was increase in creatinina, and decrease in GFR after each cycle of cisplatin, and increased urine NGAL. Positive association was observed between the levels of NGAL, creatinine and C-reactive protein. It was observed an increase in creatinine, NGAL, C-reactive protein and decreased GFR in AKI patients compared to patients without AKI. Conclusion: AKI was noted in 78 % of patients with HNC treated with cisplatin and showed the correlation of NGAL with creatinine and GFR in demonstrating renal injury. NGAL levels may be elevated compared to baseline levels, even before the use of cisplatin / A injúria renal aguda (IRA) em pacientes que recebem a cisplatina é comum. Portanto, a avaliação da função renal em pacientes que utilizam drogas nefrotóxicas é fundamental. Objetivo: Avaliar a incidência da IRA e o papel da lipocalina associada à gelatinase neutrofílica (NGAL) na avaliação da função renal em pacientes com câncer de cabeça e pescoço (CCP) que receberam a cisplatina. Métodos: Foram avaliados prospectivamente 50 pacientes com CCP, tratados com três sessões de cisplatina. Foram coletados sangue e urina 24 h antes da cisplatina, 24 h após a infusão, 48 h após cada aplicação e 35 dias após o término do tratamento (NGAL urinária, proteína C reativa, creatinina e taxa de filtração glomerular, desidrogenase lática e magnésio plasmáticos). Resultados: A IRA foi observada em 78% dos pacientes. Houve aumento na creatinina, ureia e queda na TFG após cada ciclo de cisplatina, e aumento da NGAL urinária. Foi observada associação positiva entre os níveis de NGAL e a creatinina e PCR. Evidenciou-se um aumento dos níveis de creatinina, NGAL, PCR e diminuição da TFG nos pacientes com IRA em relação aos pacientes sem IRA. Conclusão: Observamos IRA em 78% dos pacientes avaliados com CCP tratados com a cisplatina e ao final do estudo 32% ainda apresentavam TFG abaixo de 60ml/min com potencial para cronificação do quadro. Observamos correlação da NGAL com a creatinina e a TFG em demonstrar lesão renal e sua concentração esteve elevada em relação a concentração basal, mesmo antes da utilização da cisplatina

The p53 tumour suppressor protein lies at the hub of a very complex network of cellular pathways including apoptosis, cell cycle arrest, DNA repair and cellular senescence. However, the mechanism of why and how p53 switches between apoptosis and cell cycle arrest, thereby determining a cell’s fate, remains a mystery to us. To enable us to investigate this ability of p53 to switch between cell cycle arrest and apoptosis, we developed a model which demonstrates similar p53 expression patterns but different functional outcomes. Treating cells with Cisplatin (a common chemotherapeutic drug) and Nutlin-3 (an MDM-2 inhibitor) results in similar high levels of p53 accumulation but different cellular responses. Cisplatin-treated cells undergo apoptosis while Nutlin-treated cells enter cell cycle arrest. Using this model, we explored the localization of p53 and in particular a C-terminal Ser 392 moiety in an attempt to identify how p53 is able to preferentially activate cell cycle arrest or apoptotic pathway.

One of the main objectives of combining radiation treatment and chemotherapy is to obtain a therapeutic gain by an improved tumour control with less or no enhancement of normal tissue toxicity. The optimal schedule for the combined treatment of cisplatin-radiation is still under investigation. Neither the optimal time interval, nor the most adequate sequence of administration of cisplatin and radiation are known. The results of the trials are also inconclusive. Some trials showed a supra-additive effect from the administration of cisplatin before radiotherapy, others, on contrary, from the injection of drug after radiotherapy. The present work encompasses the major challenges brought by the combined modality treatment: cisplatin-radiotherapy. The major goal of this work was to investigate the optimal treatment sequencing between cisplatin and radiotherapy and also the optimal schedule for head and neck carcinomas. Therefore, a computer-based tumour model with literature-given biological parameters has been developed which has allowed the simulation of treatment with radiation and chemotherapy. Radiotherapy has been simulated on the virtual tumour and the effects of radiotherapy on tumour regression and regrowth have been analyzed. Also, the mechanisms of cisplatin's action on tumour have been implemented, and the phenomena of drug resistance and tumour repopulation during chemotherapy studied. Finally, the combined modality treatment has been simulated, and the effect of drug-radiation interaction on tumour behaviour evaluated. The current investigation has shown that cisplatin administered immediately before radiation gives similar tumour control to the post-radiation sequencing of the drug. Furthermore, the killing effect of the combined modality treatment on tumour increases with the increase in cell recruitment. The individual cell kill produced by cisplatin and radiation leads to an additive-only tumour response when the treatments are given concurrently, and for a synergistic effect cisplatin must potentiate the effect of radiation. The final conclusion, by which cisplatin administered on a daily basis leads to a better tumour control than cisplatin administered weekly, is in accordance with the latest trial results on head and neck cancers. Therefore, treatment regimens that correlate better with the pharmacokinetics and the radiobiological properties of the therapeutic agents result in better outcomes. / Thesis (Ph.D.)--School of Chemistry and Physics, 2004.

<p>Cancer therapy operates by inflicting damage in malignant cells. The most lethal target is the genomic DNA. As a single double strand DNA break has the potential to kill the cell, mechanisms have evolved to detect and block propagation of the damage. Genes and their products function in a highly connected network-structure with ample cross-talk between different pathways. This interplay can be studied by genome-wide experiments, such as expression profiling. The aim of this thesis is to study the cellular effects of DNA damaging agents.</p><p>A theoretical framework is explored to improve understanding of expression profiling results. To analyse large datasets, computational methods were developed to model the data. Further, the response to DNA damage was investigated in different cellular systems. As late radiation toxicity is a severe limitation of radiotherapy of cancer patients, patients were enrolled in a study to search for a molecular signature to identify high-risk patients. Ex vivo irradiation of lymphocytes revealed a signature of functionally related gene sets that were capable to separate patients with regard to toxicity status. </p><p>The gene set analysis was also applied to a dataset where mouse embryonic stem cells had been exposed to various doses of cisplatin. At several time-points after administration of the drug, expression profiles were determined. In addition to the expected increase of genes related to apoptosis and cell cycle progression, damaged cells also seemed to have embarked upon a p53-dependent differentiation programme. Finally, in a study of cardiac rodent cells, the genotoxic treatment with irradiation was compared to the mechanical stress induced in heart tissue.</p><p>In conclusion, this thesis presents evidence for the advantage of using functionally related sets of genes in analysis and interpretation of genome-wide experiments. This strategy may improve clinical understanding of the effects of DNA damaging agents used for cancer therapeutics.</p>

The invasive nature and undesirable side-effects related to conventional cancer therapy, such as surgery and chemotherapy, have led to the development of novel drug delivery systems (DDS). A minimally invasive DDS using near-infrared (NIR) light as a trigger for drug release is investigated to reduce the adverse side-effects triggered by systemic delivery of chemotherapeutic drugs. The low tissue absorbance in the NIR region, λ = 650–2500 nm, allows the irradiation to penetrate through tissues to release cisplatin from a NIR-sensitive nanocomposite of Au-Au₂S. Our laboratory has recently shown that cisplatin can be effectively released from Au-Au₂S upon NIR irradiation. Cisplatin was loaded onto Au-Au₂S through its adsorption on COOH-functionalized alkanethiols coated on Au-Au₂S. The current work focuses on the development of methods to control the release of cisplatin. Drug release is controlled by either the irradiation parameters or the type of coatings. The effect of different coatings on NIR sensitivity and drug release is investigated. Molecular layers of HS-(CH₂)n-COOH and HS-CH₂-COO-CH₂(CH₂CH₂O)xCH₂-COOH have been successfully coated onto Au-Au₂S. The effect of different surface layers on drug adsorption is being examined. In addition, a mathematical model has been developed to describe the thermal effects of different irradiation parameters on soft tissues. / Singapore-MIT Alliance (SMA)