Introdução: A doença arterial coronariana (DAC) persiste com alta morbimortalidade. Várias modalidades diagnósticas não-invasivas estão disponíveis para sua avaliação, incluindo escore de cálcio coronariano (EC), angiotomografia coronariana (AngioTC) e tomografia por emissão de pósitrons com rubídio (PET-CT82Rb), com ótimas sensibilidade e especificidade. A integração destes métodos em um exame híbrido permite delinear extensão anatômica e funcional da aterosclerose, possibilitando diagnósticos mais corretos. Objetivo: Avaliar anatomia coronariana e perfusão miocárdica de pacientes suspeitos ou portadores de DAC com tecnologia híbrida (PETCT82Rb e AngioTC/EC), testando a hipótese da maior acurácia do método híbrido em relação aos métodos isolados, correlacionando com desfecho de IAM/óbito cardíaco após 24 meses. Métodos: Foram incluídos 54 pacientes dos ambulatórios de cardiologia do Instituto do Coração (InCor-HCFMUSP), que realizaram estudo híbrido no departamento de Medicina Nuclear do InCor entre maio e outubro de 2013. A carga aterosclerótica coronariana foi contabilizada pelo escore de cálcio; a quantidade de lesões coronarianas, o grau de redução luminal e a composição das placas foram avaliados através da AngioTC; isquemia/fibrose pelo PET-CT82Rb foi contabilizada através do SDS (summed difference score) do estresse e repouso e a reserva de fluxo coronariana (RFC) foi considerada reduzida quando menor que 2mL/min/g. Após 24 meses, foi realizado contato telefônico e avaliação do prontuário dos pacientes, sendo pesquisado infarto agudo do miocárdio/óbito cardíaco como desfecho clínico principal. Resultados: Dentre os participantes, houve predomínio de homens (61,3%), com idade média de 55,5 ± 12,3 anos. A maioria apresentava sobrepeso/obesidade (76%), hipertensão arterial sistêmica (70,4%) e/ou dislipidemia (61,1%). O protocolo durou uma média de 52,2 ± 3,5 min e a dose total média de radiação foi 12,29 ± 2,88 mSv. A média do EC total foi 127,3 ± 249,0, sendo que 24% da amostra possuíam EC maior que 100. Houve predomínio de placas de ateroma mistas (51,3%), com 13% dos pacientes apresentando lesões angiograficamente significativas ( >= 50%). Oito pacientes apresentaram resultado alterado na análise perfusional qualitativa/semiquantitativa (14,8%), metade com isquemia e metade com fibrose. A RFC estava reduzida globalmente em 18,5% dos pacientes e de forma segmentar em 5,6%. Após 24 meses, 9,3% dos pacientes apresentaram infarto, 60% destes fatais. Houve concordância no máximo moderada dos métodos avaliados com a RFC (Kappa = 0,514; p= 0,001). Quanto ao desempenho dos métodos para ocorrência de IAM em 24 meses, foi demonstrada elevada acurácia da RFC para tal finalidade, com AUROC de 0,963 (IC95% 0,912 - 1,000; p= 0,001), com melhor ponto de corte de 1,975 mL/min/g. Não foi identificada alteração na sensibilidade ou no valor preditivo negativo quando a RFC foi agregada aos outros métodos, inclusive houve redução do valor preditivo positivo e da especificidade em relação à RFC isoladamente. Conclusão: O método híbrido não apresentou maior acurácia que a RFC pelo PET-CT82Rb isoladamente na predição de IAM em dois anos de acompanhamento, todavia, a tomografia cardíaca agrega informações importantes capazes de influenciar a conduta clínica nos pacientes não isquêmicos e possivelmente modifica desfechos em médio/longo prazo / Introduction: Coronary artery disease (CAD) persists with high morbidity and mortality. Several non-invasive diagnostic imaging modalities are available for its evaluation, including coronary calcium score (CS), coronary CT angiography (AngioCT) and positron emission tomography with rubidium (82Rb PET-CT), with excellent sensitivity and specificity. The integration of these methods into a hybrid examination allows delineating the anatomical and functional impact of atherosclerosis, enabling more accurate diagnoses. Objective: To evaluate coronary anatomy and myocardial perfusion of patients with suspected or known CAD with hybrid technology (82Rb PET-CT and AngioCT/CS), testing the hypothesis of the greater accuracy of the hybrid method in relation to the isolated methods, correlating with myocardial infarction/cardiac death outcome after 24 months. Methods: Fifty-four consecutive patients referred from the Cardiology outpatient clinics of the Heart Institute (InCor-HCFMUSP) to perform CAD assessment in a hybrid study in the Department of Nuclear Medicine of InCor, between May and October 2013, were enrolled. The coronary atherosclerotic burden was accounted by CS; the amount of coronary lesions, stenosis severity and plaque composition were evaluated through AngioCT; 82Rb PET-CT perfusional analysis was evaluated through the rest and dipyridamole stress summed difference score (SDS) and the coronary flow reserve (CFR) was considered impaired when < 2mL/min/g. After 24 months, the composite outcome of myocardial infarction and cardiac death was evaluated through telephone contact and patient\'s medical records. Results: From the 54 enrolled patients, mean age was 55.5 ± 12.3 years and 61% were male. Most patients presented overwheight/obesity (76%), systemic arterial hypertension (70%) and/or dyslipidemia (61%). The protocol lasted an average of 52.2 ± 3,5 min and mean radiation dose was 12.29 ± 2,88 mSv. The mean total CS was 127.3 ± 249.0, and 24% of the patients were above 100. There was a predominance of patients with mixed atheroma plaques (51.3%) and 13% presented angiographically significant lesions ( >= 50%). Eight patients presented perfusion impairment in the qualitative/semi-quantitative perfusion analysis (14.8%), half with ischemia and half with fibrosis. The CFR was globally reduced in 18.5% of the sample and in a segmental manner in 5.6%. After 24 months of follow-up, 9.3% of the patients had a myocardium infarction, 60% of these were fatal. A maximum of moderate agreement was found between the methods and CFR (Kappa = 0.514, p= 0.001). Regarding the performance of the different methods for predicting infarction in 24 months, CFR reached high accuracy, with AUROC of 0.963 (95% CI 0.912 - 1.0; p= 0.001), with a cutoff point of 1.975 mL/min/g. No variation in neither sensitivity nor negative predictive value was identified when the other methods were added to CFR, instead, there was a reduction in positive predictive value and specificity in relation to unaided CFR. Conclusion: There was no incremental value of the hybrid method when compared to isolated CFR 82Rb PET-CT for the prediction of myocardial infarction in two years follow-up. However, cardiac CT aggregates important information capable of influencing clinical management of nonischemic patients and possibly modifies medium/long-term cardiac outcomes

Bone is a remarkable multifunctional tissue with the ability to regenerate and remodel without generating any scar tissue. However, bone loss due to injury or diseases can be a great challenge and affect the patient significantly. Transplanting bone graft from one site in the patient to the site of fracture or bone void, i.e. autologous bone grafting is commonly used throughout the world. The transplanted bone not only fills voids, but is also bone inductive, housing the particular cells that are needed for bone regeneration. Nevertheless, a regenerative complement to autograft is of great interest and importance because the benefits from an off-the-shelf product with as good of healing capacity as autograft will circumvent most of the drawbacks with autograft. With a regenerative-medicine approach, the use of biomaterials loaded with bioactive molecules can avoid donor site morbidity and the problem of limited volume of material. Two such regenerative products that utilize bone morphogenetic protein 7 and 2 have been used for more than a decade in the clinic. However, some severe side effects have been reported, such as severe swelling due to inflammation and ectopic bone formation. Additionally, the products require open surgery, use of supra physiological doses of the BMPs due to poor localization and retention of the growth factors. The purpose of this thesis was to harness the strong inductive capability of the BMP-2 by optimizing the carrier of this bioactive protein, thereby minimizing the side effects that are associated with the clinical products and facilitating safe and localized bone regeneration at the desired site. We focused on an injectable hyaluronan-based carrier. The strategy was to use the body’s own regenerative pathway to stimulate and enhance bone healing in a manner similar to the natural bone-healing process. The hyaluronan-based carrier has a similar composition to the natural extracellular matrix and is degraded by resident hyaluronidase enzymes. Earlier studies have shown a more controlled release and improved mechanical properties when adding a weight of 25 percent of hydroxyapatite, a calcium phosphate that constitutes the inorganic part of the bone matrix. In Paper I, the aim was to improve the carrier by adding other forms of calcium phosphate. The results indicated that the bone formation was enhanced when using nano-sized hydroxyapatite. We wished to further develop the carrier system but were lacking an animal model with high output and easy access. We also wanted to provide paired data and were committed to the 3 Rs of refinement, reduction and replacement. To meet these challenges, we developed and refined an animal model, and this is described in Paper II. In Paper III, we characterized and optimized the handling properties of the carrier. In Paper IV, we discovered the importance of crushing the material, thus enhancing permeability and enlarging the surface area. In Paper V, we sought to further optimize biomaterial properties of the hydrogel through covalently bonding of bisphosphonates to the hyaluronan hydrogel. The results demonstrated exceptional retention of the growth factor BMP-2. In Paper VI, the in vivo response related to the release of the growth factor was examined by combining a SPECT/PET/µCT imaging method to visualize both the retention of the drug, and the in-vivo response in terms of mineralization.

Introdução: A doença arterial coronariana (DAC) persiste com alta morbimortalidade. Várias modalidades diagnósticas não-invasivas estão disponíveis para sua avaliação, incluindo escore de cálcio coronariano (EC), angiotomografia coronariana (AngioTC) e tomografia por emissão de pósitrons com rubídio (PET-CT82Rb), com ótimas sensibilidade e especificidade. A integração destes métodos em um exame híbrido permite delinear extensão anatômica e funcional da aterosclerose, possibilitando diagnósticos mais corretos. Objetivo: Avaliar anatomia coronariana e perfusão miocárdica de pacientes suspeitos ou portadores de DAC com tecnologia híbrida (PETCT82Rb e AngioTC/EC), testando a hipótese da maior acurácia do método híbrido em relação aos métodos isolados, correlacionando com desfecho de IAM/óbito cardíaco após 24 meses. Métodos: Foram incluídos 54 pacientes dos ambulatórios de cardiologia do Instituto do Coração (InCor-HCFMUSP), que realizaram estudo híbrido no departamento de Medicina Nuclear do InCor entre maio e outubro de 2013. A carga aterosclerótica coronariana foi contabilizada pelo escore de cálcio; a quantidade de lesões coronarianas, o grau de redução luminal e a composição das placas foram avaliados através da AngioTC; isquemia/fibrose pelo PET-CT82Rb foi contabilizada através do SDS (summed difference score) do estresse e repouso e a reserva de fluxo coronariana (RFC) foi considerada reduzida quando menor que 2mL/min/g. Após 24 meses, foi realizado contato telefônico e avaliação do prontuário dos pacientes, sendo pesquisado infarto agudo do miocárdio/óbito cardíaco como desfecho clínico principal. Resultados: Dentre os participantes, houve predomínio de homens (61,3%), com idade média de 55,5 ± 12,3 anos. A maioria apresentava sobrepeso/obesidade (76%), hipertensão arterial sistêmica (70,4%) e/ou dislipidemia (61,1%). O protocolo durou uma média de 52,2 ± 3,5 min e a dose total média de radiação foi 12,29 ± 2,88 mSv. A média do EC total foi 127,3 ± 249,0, sendo que 24% da amostra possuíam EC maior que 100. Houve predomínio de placas de ateroma mistas (51,3%), com 13% dos pacientes apresentando lesões angiograficamente significativas ( >= 50%). Oito pacientes apresentaram resultado alterado na análise perfusional qualitativa/semiquantitativa (14,8%), metade com isquemia e metade com fibrose. A RFC estava reduzida globalmente em 18,5% dos pacientes e de forma segmentar em 5,6%. Após 24 meses, 9,3% dos pacientes apresentaram infarto, 60% destes fatais. Houve concordância no máximo moderada dos métodos avaliados com a RFC (Kappa = 0,514; p= 0,001). Quanto ao desempenho dos métodos para ocorrência de IAM em 24 meses, foi demonstrada elevada acurácia da RFC para tal finalidade, com AUROC de 0,963 (IC95% 0,912 - 1,000; p= 0,001), com melhor ponto de corte de 1,975 mL/min/g. Não foi identificada alteração na sensibilidade ou no valor preditivo negativo quando a RFC foi agregada aos outros métodos, inclusive houve redução do valor preditivo positivo e da especificidade em relação à RFC isoladamente. Conclusão: O método híbrido não apresentou maior acurácia que a RFC pelo PET-CT82Rb isoladamente na predição de IAM em dois anos de acompanhamento, todavia, a tomografia cardíaca agrega informações importantes capazes de influenciar a conduta clínica nos pacientes não isquêmicos e possivelmente modifica desfechos em médio/longo prazo / Introduction: Coronary artery disease (CAD) persists with high morbidity and mortality. Several non-invasive diagnostic imaging modalities are available for its evaluation, including coronary calcium score (CS), coronary CT angiography (AngioCT) and positron emission tomography with rubidium (82Rb PET-CT), with excellent sensitivity and specificity. The integration of these methods into a hybrid examination allows delineating the anatomical and functional impact of atherosclerosis, enabling more accurate diagnoses. Objective: To evaluate coronary anatomy and myocardial perfusion of patients with suspected or known CAD with hybrid technology (82Rb PET-CT and AngioCT/CS), testing the hypothesis of the greater accuracy of the hybrid method in relation to the isolated methods, correlating with myocardial infarction/cardiac death outcome after 24 months. Methods: Fifty-four consecutive patients referred from the Cardiology outpatient clinics of the Heart Institute (InCor-HCFMUSP) to perform CAD assessment in a hybrid study in the Department of Nuclear Medicine of InCor, between May and October 2013, were enrolled. The coronary atherosclerotic burden was accounted by CS; the amount of coronary lesions, stenosis severity and plaque composition were evaluated through AngioCT; 82Rb PET-CT perfusional analysis was evaluated through the rest and dipyridamole stress summed difference score (SDS) and the coronary flow reserve (CFR) was considered impaired when < 2mL/min/g. After 24 months, the composite outcome of myocardial infarction and cardiac death was evaluated through telephone contact and patient\'s medical records. Results: From the 54 enrolled patients, mean age was 55.5 ± 12.3 years and 61% were male. Most patients presented overwheight/obesity (76%), systemic arterial hypertension (70%) and/or dyslipidemia (61%). The protocol lasted an average of 52.2 ± 3,5 min and mean radiation dose was 12.29 ± 2,88 mSv. The mean total CS was 127.3 ± 249.0, and 24% of the patients were above 100. There was a predominance of patients with mixed atheroma plaques (51.3%) and 13% presented angiographically significant lesions ( >= 50%). Eight patients presented perfusion impairment in the qualitative/semi-quantitative perfusion analysis (14.8%), half with ischemia and half with fibrosis. The CFR was globally reduced in 18.5% of the sample and in a segmental manner in 5.6%. After 24 months of follow-up, 9.3% of the patients had a myocardium infarction, 60% of these were fatal. A maximum of moderate agreement was found between the methods and CFR (Kappa = 0.514, p= 0.001). Regarding the performance of the different methods for predicting infarction in 24 months, CFR reached high accuracy, with AUROC of 0.963 (95% CI 0.912 - 1.0; p= 0.001), with a cutoff point of 1.975 mL/min/g. No variation in neither sensitivity nor negative predictive value was identified when the other methods were added to CFR, instead, there was a reduction in positive predictive value and specificity in relation to unaided CFR. Conclusion: There was no incremental value of the hybrid method when compared to isolated CFR 82Rb PET-CT for the prediction of myocardial infarction in two years follow-up. However, cardiac CT aggregates important information capable of influencing clinical management of nonischemic patients and possibly modifies medium/long-term cardiac outcomes

Introdução: O câncer do esôfago é uma das neoplasias do aparelho digestivo com maior gravidade e que apresenta grande morbimortalidade, mesmo quando o diagnóstico é precoce. A maioria dos pacientes é diagnosticado nos estágios avançados. O tratamento depende do estadiamento da neoplasia que avalia a profundidade de invasão do tumor (T), a disseminação linfonodal (N) e a presença de metástases a distância (M) e segue as orientações da União Internacional Contra o Câncer (UICC). Nas últimas décadas o estadiamento era realizado convencionalmente pela tomografia computadorizada (TC) e atualmente com a utilização de equipamentos que avaliam o metabolismo glicolítico do tumor como o 18F-FDG-PET e o PET-CT. Este estudo teve como Objetivo avaliar a relação entre a tomografia computadorizada e os métodos metabólicos como o 18F-FDG-PET e PET-CT, no estadiamento e tratamento do Adenocarcinoma e do Carcinoma Espinocelular (CEC) do esôfago. Método: Foram avaliados 331 pacientes com diagnóstico de Adenocarcinoma e CEC do esôfago entre 2008 e 2014. Destes, 55 pacientes (16,6%) apresentaram Adenocarcinoma e 276 (83,4%) apresentaram CEC. A idade variou de 38 a 92 anos, com média de 62,9 (+/- 9,8) anos. Inicialmente foram submetidos ao estadiamento com TC e proposta de conduta cirúrgica curativa ou tratamento paliativo. Posteriormente foram avaliados com a inclusão do 18F-FDG-PET ou do PET-CT e foi definida a conduta final. Resultados: A proporção de linfonodos positivos (N+) na tomografia foi de 71%, enquanto que nos métodos metabólicos foi de 70,1% (p=0,834), contudo, com pequena concordância (Kappa=0,339). A proporção de metástases (M1) encontradas na TC foi de 44,1% e no PET-CT 47,1%. Para metástases, o teste Kappa mostrou que os dois métodos apresentam uma concordância regular (0,452), apresentando mudanças de estadiamento em 36,5% dos indivíduos, sendo 19,3% com sobre estadiamento e 17,2% com subestadiamento. Entretanto, apenas 63 pacientes (19%) apresentaram mudança de conduta final e esta foi maior nos pacientes com sobre estadiamento (67,2%) (p < 0,005). Nos pacientes com Adenocarcinoma, observou-se um número maior de subestadiamento (32,7%), comparado àqueles com CEC (15,4%) (p < 0,0001), entretanto, sem apresentar diferença estatisticamente significativa quando avaliada a mudança de conduta. Avaliando individualmente os 140 pacientes estadiados com 18F-FDG-PET, 52,9% apresentaram linfonodos positivos (N+), valor semelhante à tomografia (p=0,053), entretanto com concordância pequena, cerca de 32,9% destes com metástases (M1) (p=0,749) e com concordância regular entre os métodos. Após o estadiamento, ocorreu uma mudança de conduta de 23,6% quando avaliado por equipe multidisciplinar. Com o uso do PET-CT, a proporção de tumores T4 foi de 27,2% (p=0,071), porém, com concordância boa com a tomografia (Kappa=0,616). A proporção de linfonodos positivos (N+) foi de 82,7%, com pequena concordância com a tomografia (Kappa=0,392). A proporção de metástases (M1) no PET-CT foi de 57,6%, com concordância regular (Kappa=0,465). Apresentaram mudança de estadiamento 34% dos indivíduos, sendo 19,3% com sobre estadiamento e 14,7% com subestadiamento. Entretanto, dos 191 pacientes, apenas 30 (15,7%) apresentaram mudança de conduta final, sendo que 67,6% ocorreu nos casos com sobre estadiamento, quando comparada aos casos com subestadiamento (17,9%) (p < 0,005). Pacientes com Adenocarcinoma apresentaram um número maior de subestadiamento (30%), comparado àqueles com CEC (11,8%), (p < 0,0001), entretanto, sem apresentar diferença estatisticamente significativa. A sobrevida global, quando avaliados com PET-CT, foi em torno de 30% após 30 meses, sendo semelhante tanto no grupo de pacientes em que houve mudança de conduta quanto no grupo em que esta mudança de conduta não ocorreu. Conclusão: Conclui-se, portanto, que no estadiamento tomográfico com 18F-FDG-PET e com PET-CT foi identificado um número expressivo de pacientes em estágios avançados, entretanto estes achados muitas vezes diferem entre si. A mudança de conduta ocorre em número expressivo de pacientes e geralmente nos casos em que ocorre sobre estadiamento. Embora o Adenocarcinoma apresente um número maior de casos de subestadiamento que o CEC, esta mudança de estadiamento não se reflete na mudança de conduta quando comparados. Torna-se importante, portanto, a avaliação multiprofissional em serviço de excelência no momento de decisão sobre a melhor terapêutica. Por fim, observamos a mesma curva de sobrevida entre aqueles pacientes em que há certeza da conduta a ser tomada e aqueles em que a conduta foi mudada após o uso do PET-CT, o que corrobora a necessidade da utilização em conjunto desses dois métodos / Introduction: Esophagus cancer is one of the most serious neoplasms of the digestive tract that presents great morbidity and mortality even in early diagnosis. Most patients are diagnosed in advanced stages. Treatment depends on tumor staging, which evaluates the depth of tumor invasion (T), lymph node spread (N) and the presence of distant metastases (M) and follow the guidelines of Union for International Cancer Control (UICC). In the last decades, staging was performed conventionally by computed tomography (CT) and currently with the use of equipments that evaluates tumor glycolytic metabolism such as 18F-FDG-PET and PET-CT. This study has as main Objective to evaluate the relationship between computed tomography and metabolic methods such as 18F-FDG-PET and PET-CT in the staging and treatment of Adenocarcinoma and Spinocellular Carcinoma (SCC) of the esophagus. Method: A total of 331 patients diagnosed with adenocarcinoma and esophageal SCC were evaluated between 2008 and 2014. 55 of these patients (16.6%) had adenocarcinoma and 276 (83.4%) had CPB, ranging from 38 to 92 years, mean age of 62.9 (+/- 9.8) years. Initially they underwent staging with CT and it was proposed a curative surgical management or palliative treatment. Lately they were evaluated with the inclusion of 18F-FDG-PET or PET-CT and then the final management was defined. Results: The proportion of positive lymph nodes (N +) on the CT scan was 71%, whereas in the metabolic methods it was 70.1% (p=0.834), however, with a fair agreement (Kappa=0.339). The proportion of metastases (M1) found in CT was 44.1% and in PET-CT, 47.1%. For metastases, the Kappa test showed that the two methods presented a moderate agreement (0.452), presenting staging changes in 36.5% of subjects, being 19.3% with upstaging and 17.2% with downstaging. However, only 63 patients (19%) showed changes in the final management and this was higher in upstaging patients (67,2%) (p < 0,005). In patients with Adenocarcinoma, a greater number of downstaging was observed (32.7%), compared to those with CPB (15.4%) (p < 0.0001), however, without any statistically significant difference when the change of management was evaluated. Evaluating individually the 140 patients staged with 18F-FDG-PET, 52.9% presented positive lymph nodes (N +), data similar to tomography (p = 0.053), however with fair agreement, about 32.9% of these had metastases (M1) (P=0.749) and with moderate agreement between the methods. After the staging, a conduct change of 23.6% occurred when evaluated by a multidisciplinary team. With the use of PET-CT, the proportion of T4 tumors was 27.2% (p = 0.071), but with good agreement with tomography (Kappa=0.616). The proportion of positive lymph nodes (N+) was 82.7%, with fair agreement with the tomography (Kappa=0.392). The proportion of metastases (M1) in PET-CT was 57.6%, with moderate agreement (Kappa=0.465). 34% of the individuals presented staging change, 19.3% with upstaging and 14.7% with downstaging. However, only 30 (15.7%) out of 191 presented a final change of behavior, 67.6% of which occurred in cases with upstaging when compared to cases with downstaging (17.9%) (p < 0.005). Patients with adenocarcinoma had a greater number of downstaging (30%) compared to those with CPB (11.8%), (p < 0.0001), however, with no statistically significant difference. Overall survival when staged with PET-CT was around 30% after 30 months, being similar both in the group of patients where there was change of management and in the group where this change of management did not occur. Conclusion: It was concluded that in the tomographic staging with 18F-FDG-PET and with PET-CT an expressive number of patients in advanced stages was identified, however these findings often differ from each other. The change in management occurs in an expressive number of patients, and usually in cases where upstaging occurs. Although Adenocarcinoma presents a greater number of cases of downstaging than CPB, this change in staging is not reflected in the change of management when both are compared. It is important, therefore, the multiprofessional evaluation in service of excellence when deciding on the best therapeutics. Finally, we observed the same survival curve between those patients in which there is certainty of the management to be taken and those in which the management was changed after the use of PET-CT, which corroborates with the need to use these two methods together

Biomedical optical imaging is capable of providing functional information of the soft bi-ological tissues, whose applications include imaging large tissues, such breastand brain in-vivo. Biomedical optical imaging uses near infrared light (600nm-900nm) as the probing media, givin ganaddedadvantageofbeingnon-ionizingimagingmodality. The tomographic technologies for imaging large tissues encompasses diffuse optical tomogra-phyandphotoacoustictomography. Traditional image reconstruction methods indiffuse optical tomographyemploysa �2-norm based regularization, which is known to remove high frequency no is either econstructed images and make the mappearsmooth. Hence as parsity based image reconstruction has been deployed for diffuse optical tomography, these sparserecov-ery methods utilize the �p-norm based regularization in the estimation problem with 0≤ p<1. These sparse recovery methods, along with an approximation to utilizethe �0-norm, have been used forther econstruction of diffus eopticaltomographic images.The comparison of these methods was performed by increasing the sparsityinthesolu-tion. Further a model resolution matrix based framework was proposed and shown to in-duceblurinthe�2-norm based regularization framework for diffuse optical tomography. This model-resolution matrix framework was utilized in the optical imaged econvolution framework. A basis pursuitdeconvolution based on Split AugmentedLagrangianShrink-ageAlgorithm(SALSA)algorithm was used along with the Tikhonovregularization step making the image reconstruction into a two-step procedure. This new two-step approach was found to be robust with no iseandwasabletobetterdelineatethestructureswhichwasevaluatedusingnumericalandgelatinphantom experiments. Modern diffuse optical imaging systems are multi-modalin nature, where diffuse optical imaging is combined with traditional imaging modalitiessuc has Magnetic Res-onanceImaging(MRI),or Computed Tomography(CT). Image-guided diffuse optical tomography has the advantage of reducingthetota lnumber of optical parameters beingreconstructedtothenumber of distinct tissue types identified by the traditional imaging modality, converting the optical image-reconstruction problem fromunder-determined innaturetoover-determined. In such cases, the minimum required measurements might be farless compared to those of the traditional diffuse optical imaging. An approach to choose these measurements optimally based on a data-resolution matrix is proposed, and it is shown that it drastically reduces the minimum required measurements (typicalcaseof240to6) without compromising the image reconstruction performance. In the last part of the work , a model-based image reconstruction approaches in pho-toacoustic tomography (which combines light and ultra sound) arestudied as it is know that these methods have a distinct advantage compared to traditionalanalytical methods in limited datacase. These model-based methods deployTikhonovbasedregularizationschemetoreconstruct the initial pressure from the boundary acoustic data. Again a model-resolution for these cases tend to represent the blurinduced by the regularization scheme. A method that utilizes this blurringmodelandper forms the basis pursuit econ-volution to improve the quantitative accuracy of the reconstructed photoacoustic image is proposed and shown to be superior compared to other traditional methods. Moreover, this deconvolution including the building of model-resolution matrixis achievedvia the Lanczosbidiagonalization (least-squares QR) making this approach computationally ef-ficient and deployable inreal-time. Keywords Medical imaging, biomedical optical imaging, diffuse optical tomography, photoacous-tictomography, multi-modalimaging, inverse problems,sparse recovery,computational methods inbiomedical optical imaging.

Diffuse optical tomography uses near infrared (NIR) light as the probing media to recover the distributions of tissue optical properties. It has a potential to become an adjunct imaging modality for breast and brain imaging, that is capable of providing functional information of the tissue under investigation. As NIR light propagation in the tissue is dominated by scattering, the image reconstruction problem (inverse problem) tends to be non-linear and ill-posed, requiring usage of advanced computational methods to compensate this. Traditional image reconstruction methods in diffuse optical tomography employ l2 –norm based regularization, which is known to remove high frequency noises in the re-constructed images and make them appear smooth. The recovered contrast in the reconstructed image in these type of methods are typically dependent on the iterative nature of the method employed, in which the non-linear iterative technique is known to perform better in comparison to linear techniques. The usage of non-linear iterative techniques in the real-time, especially in dynamical imaging, becomes prohibitive due to the computational complexity associated with them. In the rapid dynamic diffuse optical imaging, assumption of a linear dependency in the solutions between successive frames results in a linear inverse problem. This new frame work along with the l1–norm based regularization can provide better robustness to noise and results in a better contrast recovery compared to conventional l2 –based techniques. Moreover, it is shown that the proposed l1-based technique is computationally efficient compared to its counterpart(l2 –based one). The proposed framework requires a reasonably close estimate of the actual solution for the initial frame and any suboptimal estimate leads to erroneous reconstruction results for the subsequent frames. Modern diffuse optical imaging systems are multi-modal in nature, where diffuse optical imaging is combined with traditional imaging modalities such as MRI, CT, and Ultrasound. A novel approach that can more effectively use the structural information provided by the traditional imaging modalities in these scenarios is introduced, which is based on prior image constrained- l1 minimization scheme. This method has been motivated by the recent progress in the sparse image reconstruction techniques. It is shown that the- l1 based frame work is more effective in terms of localizing the tumor region and recovering the optical property values both in numerical and gelatin phantom cases compared to the traditional methods that use structural information.

Over a decade ago, it was discovered that the earth’s natural seismic wavefields, propagating as seismic noise, can be processed using correlation methods to produce surface waves, similar to those generated by earthquakes. This discovery represents a paradigm shift in seismology and has led to several tomographic studies of earth structures, at different scales and resolutions, in previously difficult-to-study areas around the world. This PhD dissertation presents research results on multi-scale and multi-purpose applications of ambient seismic noise wavefields under three topics: (1) Imaging of sedimentary basins and sub-basin structures in eastern and western Canada using ambient seismic noise, (2) Combining measurements from ambient seismic noise with earthquake datasets for imaging crustal and mantle structures, and (3) Temporal variation in cultural seismic noise and noise correlation functions (NCFs) during the COVID-19 lockdown in Canada. The first topic involved imaging the sedimentary basins in eastern and western Canada using shear wave velocities derived from ambient noise group velocities. The results show that the basins are characterized by varying depths, with maximums along the studied cross-sections in excess of 10 km, in eastern and western Canada. Characteristics of accreted terranes in eastern and western Canada are also revealed in the results. A seismically distinct basement is imaged in eastern Canada and is interpreted to be a vestige of the western African crust trapped beneath eastern Canada at the opening of the Atlantic Ocean. In western Canada, the 3D variation of the Moho and sedimentary basin depths is imaged. The thickest sediments in eastern Canada are found beneath the Queen Charlotte, Williston and the Alberta Deep basins, while the Moho is the deepest beneath the Williston basin and parts of Alberta basin and northern British Columbia. For the second topic, I worked on improving the seismological methodology to construct broadband (period from 2 to 220 s) dispersion curves by combining the dispersion measurements derived from ambient seismic noise with those from earthquakes. The broadband dispersion curves allow for imaging earth structures spanning the shallow crust to the upper mantle. For the third topic, I used ambient seismic data from the earlier stages of the COVID-19 pandemic to study the temporal variation of seismic power spectra and the potential impacts of COVID-19 lockdown on ambient NCFs in four cities in eastern and western Canada. The results show mean seismic power drops of 24% and 17% during the lockdown in eastern Canada, near Montreal and Ottawa respectively and reductions of 27% and 17% near Victoria and Sidney respectively. NCF signal quality within the secondary microseism band reached maximum before the lockdown, minimum during lockdown and at intermediate levels during the gradual reopening phase for the western Canada station pair. / Graduate

No description available.

Thesis (MMed)--Stellenbosch University, 2013. / ENGLISH ABSTRACT: Background: Hybrid imaging using single photon emission computed tomography/low dose (x-ray) computed tomography (SPECT/LDCT) is of benefit in preoperative scintigraphy of primary hyperparathyroidism. The role of SPECT/LDCT in preoperative assessment of renal hyperparathyroidism has not yet been examined. The aim of the study was to determine whether SPECT/LDCT conferred any benefit over SPECT alone in terms of detection and/or localization of hyperfunctioning parathyroid tissue in this patient group. Methods: A retrospective study of patients with renal hyperparathyroidism and positive planar and SPECT scintigraphy was undertaken. All patients underwent planar scintigraphy using 99mTc-pertechnetate immediately followed by 99mTc-sestamibi as well as SPECT/LDCT 60 min after sestamibi injection and a delayed static image to assess for differential washout at 2-3 hours. Planar subtraction images were generated. For each patient, two nuclear physicians reported on planar+ SPECT images followed by planar + SPECT/LDCT images (assisted by a radiologist). Confidence for the presence of hyperfunctioning parathyroid tissue as well as confidence of location was scored on a Likert-type scale. Interpretation of planar + SPECT was compared with interpretation of planar + SPECT/LDCT. The impact of LDCT on equivocal lesions and number of ectopic lesions detected was also assessed. Results: Twenty patients (M:13; F:7) imaged between February 2008 and June 2011 were included [mean age: 40 years (24 – 55)]. Mean creatinine was 687 μmol/l (169-1213), mean corrected calcium: 2.55 mmol/l (1.95-3.33) and median PTH 167 pmol/l (2.4 - >201). Thirty-five lesions were detected on planar and SPECT and this was unchanged after assessment of the LDCT data. Confidence for the presence of parathyroid pathology changed in 5 patients (5 lesions) with the addition of LDCT. LDCT changed the mean confidence of parathyroid pathology from 3.17 to 3.29 (p=0.16). Addition of LDCT reduced the number of equivocal lesions from 18 (14 patients) to 14 (10 patients) (p=0.13). The addition of LDCT changed localization in 4 lesions (3 patients). Confidence in localization of pathology changed in 9 lesions (7 patients) and the mean localization confidence score was improved from 4.2 to 4.46 (p=0.002) with LDCT. The number of lesions classified as ectopic increased from 5 (on planar+SPECT) to 8 (with addition of LDCT) (p=0.25). Conclusion: In renal hyperparathyroidism SPECT/LDCT altered localization of lesions detected on planar and SPECT alone and improved reader confidence of localization accuracy. SPECT/LDCT conferred no additional benefit over SPECT in terms of detection, confidence of parathyroid pathology or ability to distinguish equivocal from non-equivocal parathyroid lesions. The addition of LDCT did not detect significantly more ectopic lesions. Whereas the minor improvement in reader confidence of localization (with addition of LDCT) was of questionable clinical significance, we speculate that the changed and presumably improved localization of lesions on SPECT/LDCT had potential clinical impact in a significant proportion of patients. On this basis we recommend the use of hybrid SPECT/LDCT in imaging of renal hyperparathyroidism when surgery is considered. / AFRIKAANSE OPSOMMING: Agtergrond: Hibriedbeelding met enkelfoton emissie rekenaartomografie / lae dosis rekenaartomografie (EFERT/LDRT) is voordelig in pre-operatiewe beelding van primêre hiperparatiroïedisme. Die rol van EFERT/RT in pre-operatiewe evaluering van renale hiperparatiroïedisme is nog nie ondersoek nie. Die doel van hierdie studie was om in hierdie pasiëntgroep te bepaal of EFERT/RT 'n voordeel bo EFERT alleen verleen. Metode: 'n Retrospektiewe studie van pasiënte met renale hiperparatiroïedisme en positiewe planare en EFERT flikkergrafie is onderneem. Na die toediening van 99mTc-pertegnetaat is planare beelding op alle pasiënte gedoen, onmiddellik gevolg deur 99mTc-sestamibi sowel as EFERT/RT beelding 60 min na sestamibi inspuiting en 'n laat statiese beeld vir differensiële uitwas op 2-3 uur. Planare subtraksiebeelde is verkry. Twee kerngeneeskundiges het die planare + EFERT beelde van elke pasiënt gerapporteer, waarna die planare + EFERT/RT beelde met die hulp van 'n radioloog gerapporteer is. Sekerheid oor die teenwoordigheid van hiperfunksionerende paratiroïedweefsel sowel as die sekerheid oor die lokalisering daarvan, is op 'n Likert-tipe skaal verkry. Interpretasie van planare + EFERT is vergelyk met die interpretasie van planare + EFERT/RT. Die impak van LDRT op twyfelagtige letsels en die aantal ektopiese letsels waargeneem, is ook bepaal. Resultate: Twintig pasiënte (M:13; F:7) met beelding tussen Februarie 2008 en Junie 2011 is ingesluit [gemiddelde ouderdom: 40 jaar (24-55)] . Die gemiddelde kreatinien was 687 μmol/l (169-1213), gemiddelde gekorrigeerde kalsium 2.55 mmol/l (1.95-3.33) en mediaan PTH 167 pmol/l (2.4->201). Vyf en dertig letsels is op planare en EFERT beelde waargeneem en was onveranderd na assessering van die LDRT-data. Sekerheid oor die teenwoordigheid van paratiroïedpatologie het verander in 5 pasiënte (5 letsels) met die toevoeging van LDRT. LDRT het die gemiddelde sekerheid van paratiroïedpatologie van 3.17 tot 3.29 verander (p = 0.16). Toevoeging van LDRT het die aantal twyfelagtige letsels van 18 (14 pasiënte) tot 14 (10 pasiënte) verminder (p = 0.13). Die byvoeging van LDRT het die lokalisering in 4 letsels (3 pasiënte) verander. Sekerheid oor die lokalisering van patologie is in 9 letsels (7 pasiënte) verander en die gemiddelde lokalisering betroubaarheidswaarde is verbeter van 4.2 tot 4.46 (p = 0.002) met LDRT. Met die byvoeging van LDRT het die aantal letsels geklassifiseer as ektopies van 5 tot 8 (p = 0.25) toegeneem. Gevolgtrekking: In renale hiperparatiroïedisme het EFERT/RT die lokalisering van letsels wat op planare + EFERT beelding alleen waargeneem is, verander en die leser se vertroue om akkuraat te lokaliseer verbeter. EFERT/LDRT het geen bykomende voordeel bo EFERT in terme van die opsporing, sekerheid van paratiroïedpatologie of onderskeidingsvermoë tussen twyfelagtige teenoor nie-twyfelagtige paratiroïedletsels verleen nie. Met die byvoeging van LDRT is nie beduidend meer ektopiese letsels gevind nie. Terwyl die geringe verbetering in die sekerheid van lokalisering (met die byvoeging van LDRT) van twyfelagtige kliniese betekenis was, spekuleer ons dat die verandering en vermoedelik verbeterde lokalisering van letsels op EFERT/LDRT ʼn potensiële kliniese impak het in 'n beduidende aantal pasiënte. Die gebruik van EFERT/LDRT in die beelding van renale hiperparatiroïedisme wanneer chirurgie oorweeg word, word dus vir bogenoemde rede aanbeveel.

<p>Kolorektalni karcinom je treća po redu maligna bolest po broju novoobolelih u svetskoj populaciji, posle karcinoma pluća i dojke. Petogodi&scaron;nje preživljavanje od kolorektalnog karcinoma u SAD-u je 59-66%, u zemljama Zapadne Evrope oko 60% a u Autonomnoj Pokrajuni Vojvodini 27%. U razvijenim zemljama se sprovode skrining programi koji omogućavaju rano otkrivanje malignih bolesti, međutim, u Srbiji takav program ne postoji. Stoga je potrebno iznaći nove načine u inicijalnom menadžmentu obolelih od ove bolesti, koji će indirektno povećati njihovo preživljavanje. Jedan od načina je primena &scaron;to savremenijih dijagnostičkih metoda koji će precizno definisati stadijum. PET-CT je imidžing metoda koja poslednjih godina zauzima značajno mesto u određivanju stadijuma malignih bolesti i dijagnostikovanju recidiva. Fuzionisanjem skenova PET-a i CT-a dobija se PET-CT slika koja prikazuje funkcionalno stanje pojedinih tkiva i organa (PET) sa anatomskim detaljima (CT). Cilj istraživanja je bio da se utvrdi vrednost PET-CT pregleda u određivanju stadijuma KRK kao i u planiranju radioterapije. Nakon pregleda, pacijenti su ili operisani ili podvrgnuti planiranju radioterapije. Kod operisanih pacijenata poredilo se određivanje stadijuma PET-CT pregledom i PH metodom.Utvrđeno je da kod određivanja T stadijuma ne postoji statistički značajna razlika u<br />određivanju stadijuma KRK između navedene dve metode odnosno da je senzitivnost za ovaj parameter 90,7%. PET-CT pregled ima nisku senzitivnost za procenjivanje proboja mezorektalne fascije koja iznosi 77,3%. U određivanju N stadijuma, PET-CT pregled se pokazao kao visokosenzitivan (85,8%). Od 4 pacijenta kod kojih su dijagnostikovane metastatske lezije jetre, kod svih su one i patohistolo&scaron;ki verifikovane &scaron;to predstavlja 100% tačnost. Kod poređenja planiranja radioterapije na osnovu PET-CT pregleda i samo CT simulatora, za GTV meru, ova vrednost je u grupi pacijenata kod kojih je planiranje vr&scaron;eno nakon fuzije CT i PET-CT slike bila za 65,5% manja u odnosu na retrospektivnu grupu kod koje je planiranje vr&scaron;eno samo na osnovu CT pregleda. Za CTV volumene, dobijena je statistički značajna razlika u poređenju prospektivne i retrospektivne grupe u smislu manjih volumena u prvoj grupi. Kod poređenja PTV volumena, nije dobijena statistički značajna razlika. Takođe, kada se poredila doza zračenja koju su primili organi od rizika (m.be&scaron;ika i glave femura), dobijeno je da su statistički značajno manje doze primili navedeni organi u prospektivnoj grupi, kada se planirnaje vr&scaron;ilo pomoću PET-CT slajsova. Na&scaron;i rezultati pokazuju da bi kod dve trećine pacijenata do&scaron;lo do promene u terapijskom modalitetu kada bi svaki pacijent inicijalno, pre bilo kakve terapije bio podvrgnut PET-CT pregledu. Istraživanjem je potvrđena hipoteza da primena PET-CT pregleda ima značaja u inicijalnom određivanju stadijuma KRK kod većine pacijenata (96,3% pacijenata). Takođe je potvrđeno da ova metoda ima veliku vrednost u planiranju radioterapije smanjujući ozračivanje zdravih tkiva i pobolj&scaron;avajući kvalitet terapije tumora.</p> / <p>Colorectal carcinoma is third malignant disease by the frequency of appearance worldwide, following lung and breast cancer. Five-year survival from colorectal cancer is 59-66% in the USA, 60% in Western Europe and 27% in Region of Vojvodina. In developed countries, screening programs that provide early detection of the malignancies are in use, but in Serbia such program doesn&rsquo;t exsist.Therefore, upgrading of the initial colorectal cancer management is necessary in order of survival benefit. Accurate preoperative staging is essential in determining the optimal therapeutic procedures and planning for individual patients. Advances in imaging technology have raised interest in the potential role of PET-CT examination for staging of colorectal cancer. By PET and CT scan fusion, functional and anatomical informations are both provided. Aim of this study was to evaluate PET-CT examination in colorectal cancer staging and radiotherapy planning. After examination, patients underwent surgery or radiotherapy. In operated group, histopathological examination was the reference standard. Analysing the use of PET-CT in T stage evaluation our results showed high sensitivity of 90,7%. PET-CT examination has low sensitivity in analyzing mesorectal fascia involvement (77,3%). It was showed that PET-CT is very sensitive in N staging (85,8%). Four of the patients had liver metastases on PET-CT, and all of them were histopathologicaly confirmed, so the accuracy of M staging was 100%. In radiotherapy planning comparison, for GTV measure, we concluded that PET-CT planning provide 65,5% less tumor irradiated volume compared with CT planning. For CTV volumes, our results show that there is statistically significant difference between prospective and retrospective group with smaller volumes in the first group. In PTV volume comparison, the difference wasn&rsquo;t statistically significant. Also, when we compared doses that received organs of risk (bladder, femoral heads), we got statistically significant differences which means that less doses patients received in prospective group where planning was performed with PET-CT scans. Our results show that after initial PET-CT examination therapy modality changes in two thirds of the patients. This study confirmed the hypothesis that PET-CT has an impact on initial colorectal cancer staging in most of the patients (96,3% of the patients). Also, this examination has a great value in radiotherapy planning because it decriases radiation of the healty tissue and provides better quality of tumor therapy.</p>