The World Health Organization published in 2004 a bulletin addressing the gap between research, technology, and its implementation in the health systems of different countries (Haines, Kuruvilla, & Borchert, 2004). Among the barriers described for the implementation of new knowledge in the medical practice is the lack of connection between research results and policy makers. This happens in different subfields within the medical field. The focus of this project is to analyze the differences in implementation of radionuclide therapy technology between the EU and the US. The hypothesis is that this technology has been implemented in the EU earlier and more often than in the US, and that this variation can be connected to the differences in the policies relevant to nuclear medicine. Nuclear medicine is a unique field because of the way radioactive material is used to create diagnostic images and treat illnesses (mostly cancer). Although radiation is used every day in radiotherapy and radiology, the main difference between these two fields and nuclear medicine is the type of radiation used. Radiotherapy and radiology use closed sources of radiation, or particle accelerators that produce radiation, while nuclear medicine uses open sources of radiation that are injected into the patient’s body. This is an important difference because the accelerators used in radiotherapy and radiology can be turned on and off unlike the open sources of radiation used for nuclear medicine. If not handled properly, open sources of radiation may cause radiation contamination. Additionally, the radioactive material must be supplied on a daily basis. With nuclear medicine is possible to create diagnostic images of the body, and to record bodily functions all the way down to the molecular level. It is also possible to treat certain illnesses, such as some types of cancer, in a targeted manner. This is possible because the radioactive material is “connected” with a chemical compound (or drug) that carries the radioactive atoms to a desired location in the body; this is called targeted therapy. It is also possible to inject the radioactive material directly into the organ or region of interest. The targeted therapy and injected techniques are two processes that are part of radionuclide therapy technology. In order to check the status of the implementation of radionuclide therapy I used the practice guidelines published on the websites of the European Association of Nuclear Medicine (EANM) and the Society of Nuclear Medicine (SNM) in the US. Assuming that the practice guidelines are evidence of well-established and implemented techniques in the regions, these documents were evaluated according to their content and publication date. The content analysis was focused on the type of practices described: diagnostic, general, or therapy, as well as the type of radioactive material (or radioactive isotopes) used in such practices. The practice guidelines evaluation was done in Nvivo, a text analysis software. In addition to the analysis of practice guidelines, a bibliometric analysis of four databases (Pubmed, Medline, Biosis, and ISI Web of Science) was conducted in four databases. The keywords used for the search were (“radionuclide therapy” AND case AND report) OR (radioinmunotherapy AND case AND report). Case reports are publications that expose the day-to-day practice of physicians, and allow medical personnel to take a detail look into a specific case. The records from these sources were analyzed in Vantage Point, a bibliometric analysis software. From the policy landscape, three main types of policies were studied in relation to the practice of nuclear medicine: first, the education standards for the different professionals involved; second, the policies related to the approval of radiopharmaceuticals in the different drug administration entities; and finally, the policies concerning the production of radionuclide therapies in the two regions. The main finding of this project is that Europe and US have different policy approaches that affect, directly or indirectly, the nuclear medicine field. The main differences are in the standards of education for nuclear medicine specialist that is divided between radiologist and nuclear medicine specialists in the US; the production of radioactive material, which is commercially supplied by a very few reactors in the world, none of them in the US; and the drug administration institutions, which have very different approaches approving new drugs. Aditionally, Europe has implemented more radionuclide therapy technologies than US. From the practice guidelines analysis, it was evident that the US started publishing guidelines for nuclear medicine several years before Europe. The US published its first guideline in 1994, while the EU’s first guideline was published in 2000. However, as of July 2013, the European association had published more guidelines with 54 unique ones versus 49 from the US. EU also leads in the number of guidelines in regards to therapy, with 13 versus 2 from the US. Additionally, there is more variety in the radioisotopes used in therapy than the ones in diagnostics, and all the radioisotopes are mentioned in the European guidelines, while the US doesn’t have guidelines that mention Lu-177, Re-186, and Y-90 isotopes. From the bilbiometric analysis it was evident that Europe had published case reports for more time and more frequently than the US regarding radionuclide therapy. The first case report record from Europe was published in 1988, almost a decade before the first case report in the US. Additionally, the US has only 10 publications that match the keywords while the EU has 37. In conclusion, the EU has more practice guidelines on radionuclide therapies regarding more types of illnesses and more radioisotopes, and Europeans have published more case reports on these therapies, which indicates that the EU has implemented radionuclide therapy technology more fully than has the US. The differences in the policies and standards in education for Nuclear Medicine may influence this difference, because EU has a more standardized education and a more unified professional field than US. While the EU has a proposed syllabus for nuclear medicine practitioners, medical physicists, and radiopharmacists, in the US the education is neither standardized nor unified. Two different boards can certify physicians specializing in nuclear medicine: the American Board of Radiology and The American Board of Nuclear Medicine. The first one does a Nuclear Radiology certification for which the physicians are not required or allowed to conduct radionuclide therapies, while the American Board of Nuclear Medicine requires more nuclear medicine training and involves diagnostics and therapy. These differences are important in the implementation of radionuclide therapy techniques, because not all the nuclear medicine physicians in the US are trained on this aspect or allowed to practice it. For that reason a fraction of the professionals may not be interested or informed about these techniques, leaving the field of nuclear medicine in the US behind its EU counterpart. The policies that involve the production of radioisotopes and the market for this good deeply affects the status of the field in both regions. Since most of the radionuclide materials for therapies are produced in nuclear reactors, this is a very complex topic. Nuclear reactors are recognized for their capability to produce nuclear energy and not frequently associated with medicine. The precautionary approach that some regions apply to this topic may affect the availability of the radioisotopes in local markets. The EU has more nuclear reactors capable of the production of materials for radionuclide therapies, while the production of radioisotopes in the US is less and it focused on research. Therefore, the EU has a more stable and reliable supply of radioisotopes, which allows them to use the technology in everyday practice. Finally, the drug administration entities seem to differ in the clarity of their procedures for the approval of radiopharmaceuticals. The EU tools for approval are clear and easy to find, which may encourage European researchers to work on new radiopharmaceuticals and to carry their findings to the application level. The European Medicines Agency has a Radiopharmaceutical Drafting Group that supports the creation and approval of radiopharmaceuticals. In addition, one of the practice guidelines from the European Association of Nuclear Medicine (EANM) is about the approval of new drugs. This is not replicated in the US; although the Food and Drug Administration (FDA) has a special group that works with radiation therapies and devices, there are no references to a group that relates to radiopharmaceuticals, or the information is not as easy to find. It also looks like the Society of Nuclear Medicine (SNM) is focusing more on research and approval of Positron Emission Tomography (PET) radiopharmaceuticals than on therapy based ones. This is understandable since the radioactive material for PET images is produced in cyclotrons available at many clinics and hospitals around the world. In conclusion, nuclear medicine is a very diverse field that is capable of important contributions to medicine. However, the radioactive nature of the material needed for the development of new radionuclide therapies presents a barrier to the development of new drugs. The availability of the drug and the personnel trained in these matters are the most important factors for the successful use of this technology. Although the US and the EU have been collaborating more and more in the creation of standardized procedures for nuclear medicine, it is evident that the EU has more experience in the day to day application of the technology, and the technology is also more accessible in the EU by the physicians interested in it. A trained and informed group of professionals can raise awareness in the public and influence the policy making by monitoring agencies to create clearer paths for drug approvals, and pushing for laws that approve the research and production of alternatives for radioisotopes production such as Low Enriched Uranium reactors.

For the treatment of cancer, Auger-electron emitting radionuclides are strongly dependent on their close proximity to DNA to utilize the local therapeutic potential of the Auger electrons. This thesis investigates a two-step targeting approach that uses targeting liposomes for the delivery of an Auger-electron emitter, 125I, coupled to a DNA-binding compound, Comp1, to the tumour-cell DNA. In the first step the liposome targets overexpressed cell-surface receptors. Receptors belonging to epidermal growth factor receptor (EGFR) family are overexpressed in a number of different cancers and are therefore suitable targets. The second step is transportation of the radionuclide to the cell nucleus utilizing a DNA-binding compound. The DNA-binder used in this thesis is a daunorubicin derivative called Comp1. Papers I and II are in vitro characterizations of the targeting liposomes. Both EGFR- and HER2-targeting liposomes delivered 125I-Comp1 receptor specifically to tumour cells, and were efficient in decreasing growth of cultured tumour cells. Paper II also included a biodistribution of 125I-Comp1 delivered by HER2-targeting liposomes in tumour-bearing mice. The results gave a time-dependent uptake in tumours differed from when non-targeting liposomes encapsulating 125I-Comp1 were given. Paper III investigates the therapeutic effect of 125I-Comp1 delivered by HER2-targeting liposomes, in an animal model that mimics a situation of disseminated tumour cells in the abdomen. 125I-Comp1 delivered by HER2-targeting liposomes effectively prolonged survival of the mice in a dose-dependent relation. Several mice in the groups receiving the highest doses were tumour-free at the end of the study. Paper IV compares different lipid compositions of the liposomes with respect to leakage, cellular uptake and therapeutic efficacy of delivered 125I-Comp1on cultured cells. Liposomes containing sphingomyelin or dihydrosphingomyelin retained drug more efficiently and exhibited more receptor specific delivery properties than distearoylglycerophosphatidylcholine (DSPC) containing liposomes. However, it was the DSPC-containing liposomes that displayed best growth inhibition on cultured tumour cells. The thesis concludes that 125I-Comp1 delivered by targeting liposomes is a promising candidate for effective radionuclide therapy.

Thesis (Ph. D.)--University of Missouri-Columbia, 1996. / "m in ⁹⁹mTc on short title page is supercript." Typescript. Vita. Includes bibliographical references (leaves 131-136). Also available on the Internet.

Thesis (Ph. D.)--University of Missouri-Columbia, 1996. / "M in ⁹⁹mTc on short title page is supercript." Typescript. Vita. Includes bibliographical references (leaves 131-136). Also available on the Internet.

Thesis (doctoral)--Rijksuniversiteit te Utrecht.

Thesis (doctoral)--Katholieke Universiteit te Nijmegen.

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Orientador: Gláucia Maria Bovi Ambrosano / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba / Made available in DSpace on 2018-08-17T23:08:34Z (GMT). No. of bitstreams: 1 Santos_LuisAntonioNogueirados_D.pdf: 2779322 bytes, checksum: 13f963d0d475b047589e806517aa9a48 (MD5) Previous issue date: 2011 / Resumo: A Displasia fibrosa (DF) é uma condição benigna caracterizada pela substituição do tecido ósseo por tecido fibroso desorganizado e osso imaturo. A lesão é resultante de uma mutação pós-zigótica do gene GNAS 1, que codifica a proteína Gs?, localizada no cromossomo 20q13.2, e possui expressão fenotípica variável. Sua classificação ainda é, porém, controversa e motivo de diversas pesquisas. O manejo da DF pode ser tornar um problema em função de tamanho, extensão da lesão e envolvimento anatômico. Exames imaginológicos comumente empregados para o diagnóstico e controle da DF são a radiografia convencional e a tomografia computadorizada. No presente estudo, realizamos uma analise clinica, radiográfica e cintilográfica da DF. A cintilografia óssea foi utilizada para avaliar a taxa de metabolismo ósseo da lesão e o padrão de distribuição do radiofármaco em portadores de DF monostótica. Assim, foram estudados 17 casos de DF, e sua taxa de metabolismo ósseo foi calculada de acordo com o proposto por Kaban et al, 1995. Dos casos estudados, 94.11% apresentaram imagem hipercaptante restrita à maxila ou mandíbula e todos possuíam elevado metabolismo ósseo. Não houve relação entre o fator de atividade óssea com a idade do paciente e localização anatômica. O aspecto radiográfico mais comum foi forma esclerótica, 47%, seguido do aspecto misto, 35.3%, e a forma lítica com 17.6%. Não foi possível estabelecer relação entre padrão de imagem cintilográfica e imagem radiográfica, entretanto o método foi útil para diferenciar lesões maduras e lesões ativas / Abstract: Fibrous dysplasia (FD) is benign bone disease characterized by maturation disorder of the bone forming mesenchyma where the lamellar bone marrow is replaced with abnormal fibrous-osseous tissue. This type of lesion results in a postzygotic mutation of GNAS 1, which encodes the Gs? protein and can be found on the 20q13.2 chromosome, and presents variable phenotypic expressions. The classification of this lesion is controversial and has been the aim of many studies. The management of FD can cause problems, depending on its size, extent of injury, and anatomic involvement. Plain film and computed tomography are commonly employed imaging studies for the diagnosis and control of FD. In the present study, bone scintigraphy was used to assess the rate of bone metabolism and the standard of radionuclide distribution in patients with monostotic FD. Radionuclide bone scans were performed in 17 cases of histopathologically proven FD. In addition, the rate of bone metabolism was calculated according to that proposed by Kaban et al. 1995. In 94.11% of the cases, images of increased uptake to the maxilla or mandible could be observed, all of which presented a high bone turnover. No significant relationship could be determined between bone activity and patient age or anatomic site. The studied lesions constituted casual radiological findings, including sclerotic lesions (47%), mixed aspects (35.3%), and lytic appearances (17.6%). The present study was unable to establish a relationship between the bone scan standard and radiological findings. Nevertheless, this method is still a helpful parameter for the diagnosis of both mature and active lesions / Doutorado / Radiologia Odontologica / Doutor em Radiologia Odontológica

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