>Magister Scientiae - MSc / This study investigated the current knowledge, perceptions, and practices of Risk-Based Monitoring (RBM) using written and verbal responses to an ethics review board approved questionnaire. Responses were collected from individuals involved in the practice, oversight, and implementation of clinical trial monitoring in the USA. RBM was viewed as a positive force with a bright future. However the results suggested that a renewed focus on change management strategies is needed to ensure RBM practices penetrate all levels of clinical trial management. The site sponsor/site operational relationship was identified as a key RBM component. Shortcomings in this relationship were identified as significant operational barriers to effective RBM practice. Respondents indicated that current RBM training efforts were lacking. Because RBM is new and its practices deviate significantly from the past total monitoring efforts, both industry and the clinic need to work harder to ensure that everyone involved in clinical trial monitoring understands these differences. Fortunately, overcoming the identified barriers will not require massive changes to current RBM practice. By refocusing efforts on the sponsor/CRO and investigative sites to attain RBM governance, develop quality control plans, institute an optimal RBM platform, and improve training, the true promise of RBM is within reach. Each of these are critical pieces to an effective RBM implementation methodology and correcting initial stumbles in their implementation can assure the RBM future is as promised.

Orientador: Eduardo Bresciani / Banca: Rebeca Di Nicoló / Banca: Taciana Marco Ferraz Caneppele / Banca: Luciana Fávaro Francisconi dos Rios / Banca: Flávio Henrique Baggio Aguiar / Resumo: Este estudo foi composto por um estudo in vitro, um estudo clínico randomizado, controlado e duplo cego e uma revisão sistemática, com objetivo de compreender e avaliar a aplicabilidade da técnica da dentina úmida por etanol (EWBT) em procedimentos restauradores. Estudo laboratorial: 48 incisivos bovinos foram divididos em 2 grupos, com a utilização ou não de etanol anterior ao sistema adesivo universal (Single Bond Universal) no modo autocondicionante. Em seguida blocos de resina composta (Filtek Z350 xt) foram confeccionados. A interface adesiva foi analisada, antes e após envelhecimento por 6 meses em água, com relação à nanodureza e módulo de elasticidade e em microscopia eletrônica de varredura (MEV) após a realização de nanoinfiltração com nitrato de prata. Os dados de nanodureza e módulo de elasticidade foram analisados estatisticamente com ANOVA e teste de Tukey (α=5%). Houve diferença estatística para as áreas avaliadas (p<0.001) e também para a aplicação do etanol (p<0.001). A dentina apresentou valores maiores de nanodureza quando comparado com a camada híbrida. EWBT foi capaz de manter as propriedades da interface adesiva mesmo após envelhecimento. Estudo clínico randomizado: Os voluntários receberam restaurações em cavidades do tipo classe V, provenientes de lesões cervicais não cariosas, com extensão e profundidade de no mínimo 1 mm. As restaurações foram realizadas aleatoriamente, de acordo com a divisão dos grupos, sendo o grupo controle sem pré-tratamento den... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: This study was composed by an in vitro study, a randomized, controlled and double blind clinical trial, and a systematic review, aiming to understand and evaluate the applicability of ethanol-wet-bonding technique (EWBT) in restorative procedures. Laboratory study: 48 bovine incisors were divided into 2 groups, according to EWBT use prior to the universal adhesive system (Single Bond Universal) in the self-etch mode. Blocks of composite resin (Filtek Z350 xt) were made. The adhesive interface was analyzed, on baseline and 6 months of water aging, by scanning electron microscopy (SEM) after nanoleakage with silver nitrate, besides the nanohardness and elastic modulus. The data of nanohardness and elastic modulus were statistically analyzed with ANOVA and Tukey test (α=5%). There was a statistically significant difference for the areas evaluated, in which dentin presented higher values, for nanohardness, than the hybrid layer (p<0.001) and for the use of ethanol (p<0.001). The use of ethanol was able to maintain the properties of the adhesive layer even after aging. Randomized clinical trial: The volunteers received restorations in class V cavities from non-carious cervical lesions (NCCL), with cavity extension and depth of at least 1 mm. The restorations were randomly performed according to group division: no ethanol dentin pretreatment (SE), with ethanol dentin pretreatment in association with 3-step (E) or 2-step (EU) or adhesive, or hydrophobic adhesive (EB). The restoratio... (Complete abstract click electronic access below) / Doutor

Abdominal aortic aneurysm (AAA) is a common disease that develops gradually over several years and is characterised by weakening and dilatation of the aortic wall. AAAs also demonstrates a marked inflammatory infiltrate throughout the aortic wall. Chlamydophila pneumoniae (C. pneumoniae), is a common bacterium. About 50% of the population has been infected in adolescence. Thirteen studies report the presence of either C. pneumoniae or its antigens in 35-100% of AAA specimens. The overall aim of this thesis was to evaluate the possible role of C. pneumoniae in inflammatory response and expansion of AAA from a clinical point of view. In paper I, viable C. pneumoniae was detected in a majority of 26 patients with AAA having open surgery. Patients operated for AAA had higher C. pneumoniae antibodies titers than controls. In paper II, 247 patients were randomised in a double-blind trial, to evaluate the effect of azithromycin on the expansion of small AAAs. No such effect was seen and there was no correlation between C. pneumoniae antibody titers and AAA expansion. In paper III, 42 patients with AAA were compared to 100 age- and sex matched controls with normal aortas. C. pneumoniae antibodies were analysed in plasma samples obtained at screening, and in samples from a study conducted 5-15 (mean 12) years previously on the same population. There was no significant difference between the groups. In paper IV, were 211 patients were analysed, we could not find an association between levels in plasma of three markers of inflammation (IL-6, MMP-9 and CRP) and AAA expansion. A significant reduction in AAA expansion rate was found in patients treated with a combination of ASA and statins. In conclusion, viable C. pneumoniae is found at the scene of the crime, but we were unable to reverse or halt expansion of AAA with antibiotic treatment. C. pneumoniae antibody titers cannot be used, to detect small AAA, or to evaluate AAA expansion. From a clinical point of view, based on the methods and analyses used in this thesis, the role of C. pneumoniae in the inflammatory response and expansion of abdominal aortic aneurysms is limited.

As the bio-pharmaceutical industries find itself moving forward in super high speed, the more strategic move it need to take to keep it survival in the biotechnology competition.The big pharm starts to release new drug exploring,investigation,production,and marketing and try to take the contract research method to run their business.Thus the Contract Research Organization (CRO) find its wave in the bio-pharmaceutical industries. The CRO in Taiwan is a young competitor.The CRO business is a knowledge-based incentive business.It takes medical human resources and stastics experts to make it run .It needs to qualify the national regulation while the clinical trial related regulations in Taiwan needs to qualify the international good clinical trial regulations.This study focuses on the competitive forces analysis of the CRO industries in Taiwan. The study will review the lately development of CRO companies in Taiwan.The study will review the company profile and analyze it in the Diamond model by Michael Porter. The government factor plays a significant role in the Clinical trial related business.The CRO will be more flexible and competitive under preper regulations.

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Malignant brain tumors, especially malignant gliomas, have a poor prognosis, a fact which has remained unchanged over the last decades despite the employment of multimodal therapeutic approaches. Malignant gliomas are among the most vascularized tumors known and the amount of vascularization has been correlated to their prognosis. Since tumor growth is dependent on concomitant vascularization, recent experimental studies have focused on the use of anti-angiogenic molecules as a novel strategy in brain tumor therapy. Angiogenesis inhibitors target at proliferating endothelial cells and suppress the formation of a sufficient vascular bed. Inhibitors such as TNP-470, suramin and angiostatin have shown their therapeutic potential in experimental studies. In a clinical setting, they could be applied for the treatment of multiple tumors or postsurgically as an adjuvant therapy to prevent recurrence. This article discusses presently available anti-angiogenic agents, emphasizing on substances already in clinical trials. / Maligne Hirntumoren, insbesondere die malignen Gliome, haben trotz multimodaler Therapieansätze eine unverändert schlechte Prognose. Diese Aggressivität korreliert mit der Tatsache, daß maligne Gliome zu den gefäßreichsten Tumoren zählen, die wir kennen. Die Quantifizierung der Gefäßdichte in diesen Tumoren erlaubte die Korrelation zur Überlebenszeit der Patienten. Da das Tumorwachstum von einer begleitenden Neovaskularisierung abhängt, wurden erste experimentelle Therapieansätze durchgeführt, um das Tumorwachstum durch Inhibierung der Neovaskularisierung zu verhindern. Inhibitoren der Angiogenese, z.B. TNP-470, Suramin und Angiostatin hemmen die Proliferation von Endothelzellen und die Ausbildung eines funktionsfähigen Gefäßbettes. Erste experimentelle Ansätze haben ihre tumorstatische Wirksamkeit in vivo bewiesen. Zur klinischen Behandlung wären diese Substanzen in Verbindung mit bestehenden Therapien einsetzbar, insbesondere für die Behandlung multipler Tumoren und zur postoperativen Therapie. Diese Übersichtsarbeit beschreibt die neuesten anti-angiogenen Therapiekonzepte besonders mit Hinblick auf Substanzen, die in ersten klinischen Studien eingesetzt werden. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Nowell (1976) first proposed that unless cytotoxic cancer therapy eradicates all tumor cells, genetic or heritable variation within heterogeneous tumors will inevitably lead to the evolution of chemotherapeutic resistance through clonal selection. This evolutionary hypothesis was formalized by Goldie and Coldman (1979), who developed one of the earliest mathematical kinetic models of resistance evolution in neoplasms. Their model predicted that the likelihood of response and cure would be increased in combination vs single agent cytotoxic therapies. In a later study, Gardner (2002) developed a computational kinetic model to predict chemotherapeutic combinations, doses, and schedules most likely to result in patient response and prolonged life. This model predicts that combination therapy involving both cytotoxic and cytostatic drugs will be more effective than combination therapy involving only cytotoxic drugs. Thus far, no systematic evaluation of the Goldie and Coldman and Gardner hypotheses have been conducted in the metastatic clinical trial setting. Here I test these hypotheses using the results of over 700 phase II, III and II/III clinical trials. I show that, as predicted by Goldie and Coldman, both overall response rate and overall survival were greater in combination arms. Moreover, median duration of response – the key indicator of the rate of resistance evolution - was also greater in combination vs single agent arms. These results suggest that generally combination chemotherapy is more effective than single agent therapy for advanced solid tumors as predicted by Goldie and Coldman (1979) hypothesis and that, at least in the metastatic setting, the potential disadvantages of combination therapy with respect to accelerated resistance evolution are outweighed by the greater waiting times for resistance mutations to arise. By contrast, although combination cytotoxic and cytostatic therapy is associated with a greater average overall response rate than multi agent cytotoxic therapy, this is not the case for both median duration of response and overall survival. Hence, there is no evidence that, in contrast to the predictions of the Gardner (2002) model, combination cytotoxic and cytostatic therapy decreases the rate of resistance evolution relative to that obtaining under combination cytotoxic therapy.

A prospective study was performed to evaluate a biological medication in the treatment of digital dermatitis (DD) in dairy cattle. The study was divided into four parts; i) on farm evaluation of DD and treatment effects and comparison between the biological ointment and OTC-spray, ii) statistical evaluation, iii) histological examination using FISH and iv) microbiological examination and culture if bacteria found in biopsies from infected skin.

The aims of this thesis were to investigate the utility of in vitro drug sensitivity testing to optimize the use of cancer chemotherapy and to assess the properties of a new cancer drug in a phase I clinical trial. Tumour cells from patients were analysed with the short-term Fluorometric Microculture Cytotoxicity Assay (FMCA). In samples from a wide spectrum of tumour types, the effect of the drug combination FEC (5Fu-epirubicin-cyclophosphamide) was generally appropriately predicted from the effect of the best component drug. However, of samples intermediately sensitive to the best single drug, 45% converted to sensitive when testing the combination. Thus, combination testing may identify advantageous interactions and improve in vitro test performance. In tumour samples from peritoneal carcinomatosis, significant differences in drug sensitivity between diagnoses were observed, cross-resistance between most drugs was modest or absent, and the concentration-effect relationships for two drugs in individual samples varied considerably. Thus, for optimal selection of drugs for intraperitoneal chemotherapy, differences in drug sensitivity at the diagnosis and individual patient level should be considered. In samples from patients with ovarian carcinoma, drug sensitivity was related to tumour grade, histologic subtype and patient treatment status. In a homogeneous subset of patients, the FMCA predicted individual patient tumour response with high sensitivity and specificity. Thus, if carefully interpreted in the context of important clinical variables, in vitro testing could be of value for individualizing chemotherapy in ovarian cancer. Employing a once weekly dosing schedule in a phase I trial, the mechanistically new and preclinically promising NAD depleting drug CHS 828 produced dose limiting thrombocytopenia and gastrointestinal toxicity without clear evidence of anti-tumour efficacy. It is concluded that in vitro drug sensitivity testing could be a way to optimize the use of chemotherapy and that successful development of new cancer drugs needs improved strategies.