<p>Targeted radionuclide therapy (TRT) holds great promise for the treatment of cancer. In TRT, radioactive nuclides are delivered specifically to tumours by molecules that recognise and bind to structures overexpressed by, or specific to, cancer cells. Human epidermal growth factor receptor like protein 2 (HER-2) is an oncogene product overexpressed in e.g. urological, breast, or ovarian cancers that have been correlated to poor prognosis and resistance to hormonal therapy. There is also evidence that tumour cells retain their HER-2 overexpression in metastases.</p><p>Trastuzumab and pertuzumab are two humanised monoclonal antibodies targeting different parts of HER-2. This thesis describes the radiolabelling of these antibodies for use in TRT and diagnostics. The thesis also investigates possible methods for modifying uptake and retention of radioactivity delivered with antibodies binding to HER-2. Modification of the cellular retention of ¹²⁵I by using polyhedral boron anion based linker molecules (DABI and NBI) is investigated, and it is shown that linking ¹²⁵I to trastuzumab using DABI increases cellular accumulation of radioactivity by 33%. It is also shown that trastuzumab can be efficiently coupled to the positron emitter ⁷⁶Br by using NBI. Furthermore, it is shown that cellular uptake of ¹²⁵I can be modified by stimulating EGFR (HER-1) with EGF.</p><p>When labelled with the alpha emitter ²¹¹At, trastuzumab could specifically kill cells in vitro. This cell killing effect could be prevented by saturating the receptors of the target cells with non-radiolabelled trastuzumab.</p><p>Pertuzumab was radiolabelled with the low energy beta emitter ¹⁷⁷Lu without losing affinity or immunocompetence. [¹⁷⁷Lu]pertuzumab was specific to HER-2 in vitro and in vivo. This targeting conjugate was shown to increase median time to tumour progression in mice bearing xenografts of the radioresistant SKOV-3 cell line. </p><p>In conclusion, antibodies against HER-2, especially pertuzumab radiolabelled with ¹⁷⁷Lu, show promise as TRT agents.</p>

Targeted radionuclide therapy (TRT) holds great promise for the treatment of cancer. In TRT, radioactive nuclides are delivered specifically to tumours by molecules that recognise and bind to structures overexpressed by, or specific to, cancer cells. Human epidermal growth factor receptor like protein 2 (HER-2) is an oncogene product overexpressed in e.g. urological, breast, or ovarian cancers that have been correlated to poor prognosis and resistance to hormonal therapy. There is also evidence that tumour cells retain their HER-2 overexpression in metastases. Trastuzumab and pertuzumab are two humanised monoclonal antibodies targeting different parts of HER-2. This thesis describes the radiolabelling of these antibodies for use in TRT and diagnostics. The thesis also investigates possible methods for modifying uptake and retention of radioactivity delivered with antibodies binding to HER-2. Modification of the cellular retention of 125I by using polyhedral boron anion based linker molecules (DABI and NBI) is investigated, and it is shown that linking 125I to trastuzumab using DABI increases cellular accumulation of radioactivity by 33%. It is also shown that trastuzumab can be efficiently coupled to the positron emitter 76Br by using NBI. Furthermore, it is shown that cellular uptake of 125I can be modified by stimulating EGFR (HER-1) with EGF. When labelled with the alpha emitter 211At, trastuzumab could specifically kill cells in vitro. This cell killing effect could be prevented by saturating the receptors of the target cells with non-radiolabelled trastuzumab. Pertuzumab was radiolabelled with the low energy beta emitter 177Lu without losing affinity or immunocompetence. [177Lu]pertuzumab was specific to HER-2 in vitro and in vivo. This targeting conjugate was shown to increase median time to tumour progression in mice bearing xenografts of the radioresistant SKOV-3 cell line. In conclusion, antibodies against HER-2, especially pertuzumab radiolabelled with 177Lu, show promise as TRT agents.

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 5 uppsatser.

Orientadores: Celso Darío Ramos, Elizabeth João Pavin / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-17T05:19:39Z (GMT). No. of bitstreams: 1 Oki_GlauciaCelesteRossatto_M.pdf: 1462381 bytes, checksum: fcc4e95fbf2ec65e6d9cf04335c52034 (MD5) Previous issue date: 2010 / Resumo: Introdução: A doença arterial coronariana (DAC) é frequentemente assintomática em pacientes diabéticos, o que faz os testes não-invasivos serem uma ferramenta essencial para a detecção precoce da doença. O objetivo deste estudo foi avaliar a perfusão miocárdica de pacientes com diabetes mellitus tipo 1 (DM1) e tipo 2 (DM2) assintomáticos, sem diagnóstico prévio de DAC ou acidente vascular cerebral. Materiais e métodos: Cinqüenta e nove pacientes consecutivos assintomáticos (16 DM1, 43 DM2) foram submetidos a cintilografia de perfusão miocárdica com sestamibi- 99mTc (CPM). Eles foram avaliados quanto ao índice de massa corpórea (IMC), controle metabólico do diabetes, dislipidemia, tipo de terapia para o diabetes, hipertensão arterial sistêmica, nefropatia, retinopatia, neuropatia periférica, tabagismo e história familiar de DAC. Resultados: CPM foi anormal em 25,4%: 12 com alterações de perfusão (2 DM1, 10 DM2) e 3 com disfunção ventricular esquerda isolada (3 DM2). Os mais fortes preditores de perfusão miocárdica anormal foram: idade igual ou maior a 60 anos (p = 0,017, OR = 6,0), neuropatia periférica (p = 0,028, OR = 6,1), nefropatia (p = 0,031, OR = 5,6) e ECG de esforço positivo para isquemia (p = 0,049, OR = 4,08). Conclusão: A isquemia miocárdica silenciosa ocorre em mais de um em cada cinco diabéticos assintomáticos. Os mais fortes preditores de isquemia foram: idade avançada, neuropatia periférica, nefropatia, retinopatia e ECG de esforço positivo para isquemia / Abstract: Introduction: Coronary artery disease (CAD) is often asymptomatic in diabetic patients, which makes non-invasive tests an essential tool for early detection of the disease. This study was aimed to evaluate myocardial perfusion in asymptomatic patients with type 1 (DM1) and type 2 diabetes mellitus (DM2) without previous diagnoses of CAD or stroke. Methods: Fifty nine consecutive asymptomatic patients (16 DM1, 43 DM2) underwent myocardial perfusion scintigraphy with 99mTc-sestamibi (MPS). They were evaluated for body mass index (BMI), metabolic control of DM, type of therapy, systemic arterial hypertension, dyslipidemia, nephropathy, retinopathy, peripheral neuropathy, smoking, and familial history of CAD. Results: MPS was abnormal in 15 patients (25.4%): 12 (20,3%) with perfusion abnormalities (2 DM1, 10 DM2), and 3 with isolated left ventricular dysfunction (3 DM2). The strongest predictors for abnormal myocardial perfusion were: age 60 years and above (p=0.017; OR=6.0), peripheral neuropathy (p=0.028; OR=6.1), nephropathy (p=0.031; OR=5.6), and stress ECG positive for ischemia (p=0.049; OR=4.08). Conclusions: Silent myocardial ischemia occurs in more than one in five asymptomatic diabetic patients. The strongest predictors of ischemia in this study were: patient age, peripheral neuropathy, nephropathy, retinopathy and a stress ECG positive for ischemia / Mestrado / Clinica Medica / Mestre em Clinica Medica

The well-known neurological disturbances associated with caudal displacement of the cerebellar tonsils through the fora men magnum (Chiari malformation) have lead to many radiological studies of the region. With MRI, routine sagittal and parasagittal views of the craniovertebral junction have shown that the position of the cerebellar tonsils is variable, and in many otherwise healthy individuals, the inferior tonsillar margins lie within the fora men magnum itself. In some cases, this topography is associated with little signal from the surrounding cerebra-spinal fluid (CSF), indicating reduction of the cerebellomedullary cistern and, therefore, crowding of neural structures within the confines of the fora men. The objective of this study has been to examine the spatial relationship between the contents of the foramen magnum ie. the medulla and cerebellar tonsils, using a normal sample comprising 120 volunteers. Instead of the conventional measurements of distance, a ratio, the Foramen Magnum Index (FMI), has been determined, derived from the relative surface areas (pixels) of neural parenchyma and CSF, over axially and sagittaly-defined boundaries of the fora men. The FMI, with a 95th centile of 0.77, exhibits appropriate statistical correlation with tonsillar position below the level of the foramen, and is therefore considered specific. As a quantitative means of assessing the cerebellomedullary cistern, the FMI also identifies certain subjects whose tonsils are at the foramen, in whom the cistern is small with resultant neural crowding.

Thesis (MScMedSc (Medical Imaging and Clinical Oncology. Nuclear Medicine))--University of Stellenbosch, 2007. / Introduction: Whole body bone scintigraphy with Tc-99m MDP is able to provide a survey of the entire skeleton. The question arises if it is mandatory to perform a whole body bone scan in all patients, irrespective of the clinical indication. The aim of this study is to determine the implications of performing limited imaging in patients who had whole body bone scan for various clinical patholgy with Tc-99m MDP, in order to determine if limited imaging would be acceptable in selected pathologies. This may enable gamma camera time to be optimally utilized in units with limited facilities. Materials and Methods: Reports of 3015 patients with various clinical pathologies who had whole body bone scans with Tc-99m MDP in our department from January 2002 to December 2004 were retrospectively reviewed. The presence of pathologic radiotracer uptake was analyzed in order to establish the pattern of distribution. Clinically significant skeletal lesions were classified according to the anatomical regions where they were located viz; skull (including the neck), axial skeleton (including the pelvis and shoulders) and limbs. Results: Our results showed that in patients with lung cancer, soft tissue sarcoma, and myeloma, there was an error in more than 25% of patients when limited imaging was performed. In patients with cancer of the breast, prostate, kidney, gastrointestinal system, and reproductive system and lymphoma there is an error in less than 5% of patients when limited imaging is employed. For iv patients with more localized musculoskeletal disorders such as suspected stress fractures, complicated joint prosthesis and avascular necrosis of the femur head, regional imaging of the area of pathology showed a percentage error of less than 6%.

Thesis (MSc)--Stellenbosch University, 2003. / ENGLISH ABSTRACT: Planar bone scintigraphy is highly sensitive but it may not be sensitive enough to detect subtle lesions in complex bony structures such as the spine. The accurate anatomic localisation of lesions in regions such as this is also limited using planar images. Single Photon Emission Computed Tomography (SPECT) results in a higher lesion contrast resulting in an improved sensitivity for the detection of subtle lesions. SPECT also enables improved lesion localisation, often valuable in distinguishing benign from malignant disease in the spine. A number of previous studies have demonstrated that the addition of SPECT of the spine significantly enhances the value of bone scintigraphy for the detection of bone metastases compared to planar imaging alone. These studies were however not done in the African context where patients typically present with more advanced disease. In a retrospective study of 576 patients with known primary tumors sent to our institution for bone scintigraphy for the diagnosis of bone metastases, we evaluated 119 patients in whom both planar imaging and SPECT were obtained. The studies were graded for the probability of metastatic disease, and the number of spinal lesions was determined with and without SPECT. The influence of adding SPECT on the interpretation of the study was determined in terms of the reported probability of metastatic disease, the exclusion and confirmation of metastatic disease, the decisiveness of interpretation, and the number of spinal lesions. The addition of SPEeT resulted in a statistically significant change in the interpretation of studies, although the actual numbers of patients affected were relatively small. SPEeT resulted in a more decisive interpretation of bone scintigraphy. There was a significant increase in the number of spinal lesions detected after the addition of SPEeT. It was concluded that although the use of SPEeT is ideal, acceptable results could be achieved using planar imaging alone in this patient population. This is particularly relevant in the African context, where SPEeT is often unavailable or scarce and in great demand. / AFRIKAANSE OPSOMMING: Planare beenflikkergrafie is hoogs sensitief, maar moontlik nie sensitief genoeg om subtiele letsels in ingewikkelde beenstrukture soos die werwelkolom aan te toon nie. Akkurate anatomiese lokalisasie van letsels in die genoemde strukture is beperk wanneer slegs planare beelde gebruik word. Enkelfoton-uitstraling Rekenaartomografie (EFERT) lewer 'n hoër letsel kontras, wat 'n verbeterde sensitiwiteit vir die opsporing van subtiele letsels tot gevolg het. EFERT lei ook tot verbeterde letsel lokalisasie, wat dikwels van waarde is om onderskeid tussen benigne en maligne siekte in die werwelkolom te tref. Reeds met 'n aantal vorige studies is aangetoon dat die toevoeging van EFERT van die werwelkolom die waarde van beenflikkergrafie in die opsporing van beenmetastases beduidend verhoog bo dié van planare beelding alleenlik. Hierdie studies is egter nie in omstandighede eie aan Afrika gedoen nie, waar pasiënte kenmerkend met gevorderde siekte voordoen. In In terugskouende studie van 576 pasiënte met bekende primêre tumore, wat na ons instelling verwys is vir beenflikkergrafie om beenmetastases op te spoor, het ons 119 pasiënte, wat beide planare beelding en EFERT ondergaan het, ge-evalueer. Die studies is gegradeer volgens die waarskynlikheid vir metastatiese siekte, en die hoeveelheid werwelkolom letsels, met en sonder EFERT, is bepaal. Die invloed van EFERT op die vertolking van die studie is bepaal in terme van die waarskynlikheid van metastatiese siekte, die bevestiging en uitskakeling daarvan, die beslistheid van vertolking, en die hoeveelheid werwelkolom letsels. Die toevoeging van EFERT het tot 'n statisties beduidende verandering in die vertolking van studies gelei, alhoewel die werklike getal pasiënte wat hierdeur geraak is, relatief min was. EFERT het 'n meer besliste vertolking van beenflikkergrafie tot gevolg gehad. Daar was 'n beduidende toename in die hoeveelheid werwelkolom letsels wat opgespoor is na die toevoeging van EFERT. Daar is tot die slotsom gekom dat, alhoewel die gebruik van EFERT wenslik is, aanvaarbare resultate met slegs die gebruik van planare beelding in hierdie pasiënt bevolkingsgroep verkry kan word. Dit is veral van belang in Afrikaomstandighede, waar EFERT dikwels onbeskikbaar of skaars is, en ook in groot aanvraag is.

No description available.

Orientador: Sonia Marta Moriguchi / Resumo: Introdução: A doença falciforme (DF) é a doença monogênica herdada mais comum no mundo. Acometimentos cardiopulmonares de caráter progressivo associados à vaso oclusão e fenômenos embólicos assim como, as exacerbações de sintomas respiratórios são causas recorrentes de internações nessa população. A cintilografia de perfusão é método de imagem sensível e consagrado para avaliação hipoperfusão pulmonar, notadamente em processos embólicos. A semi-quantiticação da porcentagem de obstrução vascular de perfusão (POVF) apresenta relação segura com a angiografia. Objetivo: 1) Verificar a correlação entre os sintomas clínicos (Classes funcionais) versus Porcentagem de defeitos perfusionais (POVF%) em portadores de DF e 2) Verificar a associação entre POVF% e espirometria, avaliada pela porcentagem da capacidade vital forçada do predito (CVF%). Casuística e Metodologia Trata-se de estudo transversal observacional descritivo de 22 portadores de Doença Falciforme (DF), com coleta retrospectiva de dados clínicos e de espirometria, no período de 2017-2019 e semi-quantificação da cintilografia de perfusão pulmonar (POVF%), CF de I a IV e CVF% Análise estatística descritiva e inferenciais (Coeficiente de correlação – CC), com nível de significância com p<0,05. Resultados: Foram observados cinco subtipos de DF: SS (n=13), BSB0 (n=04), SS+alfatalassemia (n=02), SS+ fetal elevada (n=02) e SC (n=1). A cintilografia de perfusão pulmonar foi sensível identificando defeitos perfusionais em 91% da ... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: INTRODUCITON: Sickle cell disease (SCD) is the most common inherited monogenic disease in the world. Cardiopulmonary complications of a progressive character, associated with vessel occlusion and embolic phenomena, such as, exacerbations of respiratory symptoms are recurrent causes of hospitalization in this population. Perfusion scintigraphy is a sensitive and conspicuous imaging method for evaluating pulmonary hypoperfusion, especially in embolic processes. The semi-quantification of the percentage of vascular perfusion obstruction (POVF) presents a safe relationship with angiography. Objective: 1) To verify the correlation between clinical symptoms (functional classes- FC) versus percentage of perfusion defects (POVF%) in patients with CSD and 2) to verify the association between POVF% and spirometry, evaluated by the percentage of forced vital capacity predicted VCF%). MATERIALS AND METHODOLOGY This was a descriptive, observational cross-sectional study of 22 patients with SCD, with retrospective collection of clinical data and spirometry data for the period 2017-2019 and semi-quantification of pulmonary perfusion scintigraphy (POVF%) , FC from I to IV and VCF% Descriptive and inferential statistical analysis (Coefficient of correlation - CC), with level of significance with p <0.05. Results: Five subtypes of SCD: SS (n = 13), BSB0 (n = 04), SS + alphatassemia (n = 02), high fetal SS + (n = 02) and SC (n = 1) were observed. Pulmonary perfusion scintigraphy was sensitive b... (Complete abstract click electronic access below) / Mestre

O objetivo deste estudo foi avaliar o uso da cintilografia de perfusão miocárdica planar de repouso para o diagnóstico de insuficiência coronariana aguda em pacientes com dor torácica e eletrocardiograma sem alterações sugestivas de isquemia. Foram estudados 71 pacientes com idades entre 34 e 87 (média 58, desvio-padrão 12) anos; 44 (62%) eram do sexo masculino e 27 (38%) do feminino. Os pacientes com dor torácica foram avaliados na unidade de emergência com anamnese, exame físico e eletrocardroqrarna de 12 derivações. Pacientes com dor torácica de duração superior a 20 minutos, em vigência da dor ou sem dor, mas que sofreram dor torácica até seis horas anies do atendimento e com eletrocardioqrarna sem alterações sugestivas de isquemia miocárdica, foram submetidos à cintilografia planar de perfusão miocárdica de repouso quando solicitada pelo médico assistente. O tempo médio entre o início da dor toràcica e a Injeção do radiotraçador foi de três horas e seis minutos. Treze pacientes apresentavam dor torácica no momento da injeção. Foram colhidas amostras sanguineas para dosagens de atividade da creatinoquinase-MB (CK-MB), CK-MB massa, troponina I e mioglobina, seis horas após o início da dor torácica. O diagnóstico de insuficiência coronariana aguda foi feito em pacientes com angina de repouso, infarto agudo do miocárdio, pacientes submetidos à revascularização miocárdica, presença de lesões coronarianas significativas na angiografia (>- 70% estenose em artérias coronárias ou seus ramos ou .- 50% em tronco de artéria coronária esquerda) realizada durante a inernação e morte cardíaca foram considerados eventos cardíacos maiores. As cintilografias com defeito de captação foram consideradas sugestivas de isquemia miocárdica e foram comparadas com o diagnóstico clínico e com a ocorrência de eventos cardíacos maiores até três meses após a alta.Pacientes sem insuficiência coronariana aguda, dispensados da unidade de emergência, foram encaminhados para realização ambulatorial de cintilografia de perfusão miocárdica tomográfica de esforço ou com dipiridamol. Vinte e um pacientes (29,6%) tiveram o diagnóstico de insuficiência coronariana aguda e em 15 (21,1%) ocorreram eventos cardíacos maiores (oito com infarto agudo do miocárdio e sete foram submetidos à revascularização miocárdica). A cintilografia planar de perfusão miocárdica demonstrou defeitos de captação em 21 (29,6%) pacientes, dos quais 16 (76,2%) tiveram o diagnóstico de insuficiência coronariana aguda, 12 (80%) apresentaram eventos cardíacos maiores e 7 (87,5%) infarto agudo do miocárdio. O valor preditivo negativo da cintilografia planar de perfusão miocárdica foi de 90% para o diagnóstico de insuficiência coronariana aguda e de 94% para detecção de eventos cardíacos maiores. Portanto a cintilografia planar de perfusão miocárdica foi eficaz para o diagnóstico de insuficiência coronariana aguda em pacientes com dor torácica e electrocardiograma sem alterações sugestivas de isquemia / The objective of the study was to evaluate the usefulness of rest scintigraphic planar myocardial perfusion imaging in patients with acute chest pain suspected of myocardial ischemia and nondiagnostic ECG in the diagnosis of acute coronary syndromes and to predict adverse cardiac outcomes. Patients within 6 hours of chest pain onset and nondiagnostic ECGs underwent planar myocardial perfusion imaging with Technetium-99m sestamibi and measurements of serum creatine kinase-MB, creatine kinase-MB mass. troponin and myoglobin 6 hours after the onset of symptoms. Studies showing perfusion defects were considered suggestive of acute coronary syndromes and were compared to the diagnosis made by the attending cardiologist. Clinical diagnosis of acute coronary syndromes was made In patients with rest angina admitted to the hospital, acute myocardial Infarction, myocardial revascularization, demonstration of significant coronary artery disease on angiography or cardiac death. Acute myocardial revascularization and cardiac death were considered major cardiac events. Patients discharged without acute coronary syndromes were scheduled for outpatient stress myocardial perfusion imaging. A total of 71 patients underwent planar myocardial perfusion imaging. The mean age was 58 +- 12 years, 44 (62%) were male and 27 (38%) female. The mean time between chest pain onset and radiotracer injection was 3 hours and 6 minutes, thirteen patients had chest pain at the moment of iniection. Twenty-one (29,6%) patients had acute coronary syndromes, 15 (21,1 %) had major cardiac events (8 myocardial infarction and 7 underwent myocardial revascularization). Planar perfusion imaging demonstrated perfusion defects in 21 patients, 16 (76,2%) patients with acute coronary syndromes, 12 (80%) patients who had major cardiac events and in 7 (87,5%) patients with myocardial infarction. The negative predictive value of planar perfusion image was 90% for diagnosis of acute coronary syndromes and 94% for detecting major cardiac events. In conclusion, early planar perfusion imaging allowed for a rapid and accurate risk stratification of emergency departments patients with possible myocardial ischemia and nondiagnostic ECGs