Understanding the importance of quality control and quality assurance in preclinical PET/CT imaging

The fundamental principle of experimental design is to ensure efficiency and efficacy of the performed experiments. Therefore, it behoves the researcher to gain knowledge of the technological equipment to be used. This should include an understanding of the instrument quality control and assurance requirements to avoid inadequate or spurious results due to instrumentation bias whilst improving reproducibility. Here, the important role of preclinical positron emission tomography/computed tomography and the scanner's required quality control and assurance is presented along with the suggested guidelines for quality control and assurance. There are a multitude of factors impeding the continuity and reproducibility of preclinical research data within a single laboratory as well as across laboratories. A more robust experimental design incorporating validation or accreditation of the scanner performance can reduce inconsistencies. Moreover, the well-being and welfare of the laboratory animals being imaged is prime justification for refining experimental designs to include verification of instrumentation quality control and assurance. Suboptimal scanner performance is not consistent with the 3R principle (Replacement, Reduction, and Refinement) and potentially subjects animals to unnecessary harm. Thus, quality assurance and control should be of paramount interest to any scientist conducting animal studies. For this reason, through this work, we intend to raise the awareness of researchers using PET/CT regarding quality control/quality assurance (QC/QA) guidelines and instil the importance of confirming that these are routinely followed. We introduce a basic understanding of the PET/CT scanner, present the purpose of QC/QA as well as provide evidence of imaging data biases caused by lack of QC/QA. This is shown through a review of the literature, QC/QA accepted standard protocols and our research. We also want to encourage researchers to have discussions with the PET/CT facilities manager and/or technicians to develop the optimal designed PET/CT experiment for obtaining their scientific objective. Additionally, this work provides an easy gateway to multiple resources not only for PET/CT knowledge but for guidelines and assistance in preclinical experimental design to enhance scientific integrity of the data and ensure animal welfare

Absorbed dose maps of patients submitted to 68Ga-PSMA-11 PET/CT

Although nuclear medicine (NM) procedures are highly effective diagnostic tools, they have been contributing significantly, together with other medical diagnostic and therapeutic methodologies, to the increase in exposure to ionizing radiation in recent years. There is an urgent need to opti mize NM techniques, to maintain diagnostic quality at a minimum possible radiation absorbed dose. 68Ga-prostate-specific membrane antigen positron emission tomography/computed tomog raphy (68Ga-PSMA-11 PET/CT) imaging has rapidly gained notoriety in the NM field and, at the same time, personalized dosimetry studies using voxel-based methods have been performed. This study aimed to calculate the absorbed dose at the voxel level in the kidneys, liver, spleen, and red bone marrow, compare the results with other studies and draw conclusions regarding the safety of using 68Ga-PSMA-11 in NM clinics. Whole-body PET/CT images from six patients were acquired after a single 68Ga-PSMA 11 injection. After registration of the CT and PET images, the target organs were manually seg mented in the CT and resampled to the PET voxel size. Voxel S-values were computed for spe cific tissues using the Monte-Carlo N-Particle transport 6.1 code. The absorbed dose rates were obtained by convolution of the PET activity images with the specific S-values of each tissue. A time integral was then applied to each distribution to account for all 68Ga decay. Statistical dose values were computed and compared with the available literature. Considering all the patients included in this study, the kidneys received the highest radi ation, with a mean overall absorbed dose of 0.0561 mGy/MBq and a median overall absorbed dose of 0.0499 mGy/MBq. In contrast, the red bone marrow received the lowest absorbed dose values (mean dose: 0.0015 mGy/MBq, median dose: 0.0013 mGy/MBq). The present study showed lower dosimetry values than the literature, resulting in deviations ranging from -38.1% (in the liver) to -91.3% (in the red bone marrow). The present study employs a voxel-based approach, which considers a non-uniform bio distribution of the radiopharmaceutical in the organs and leads to dosimetry estimates closer to the real ones. The reasonable low absorbed doses in the four organs herein studied is an argument in favor of using 68Ga-PSMA-11 in NM clinics. In the Future Work chapter, a more specific dynamic NM imaging methodology, taking into consideration the radiopharmaceutical pharma cokinetics, is presented

Selection and Evaluation of a Silver Nanoparticle Imaging Agent for Dual-Energy Mammography

Over the past decade, contrast-enhanced (CE) dual-energy (DE) x-ray breast imaging has emerged as an exciting, new modality to provide high quality anatomic and functional information of the breast. The combination of these data in a single imaging procedure represents a powerful tool for the detection and diagnosis of breast cancer. The most widely used implementation of CEDE imaging is k-edge imaging, whereby two x-ray spectra are placed on either side of the k-edge of the contrast material. Currently, CEDE imaging is performed with iodinated contrast agents. The lower energies used in clinical DE breast imaging systems compared to imaging systems for other organs suggest that an alternative material may be better suited. We developed an analytical model to compare the contrast of various elements in the periodic table. The model predicts that materials with atomic numbers from 42 to 52 should provide the best contrast in DE breast imaging while still providing high-quality anatomical images. Upon consideration, silver was chosen for more detailed study. Through simulation and experimental validation, we determined that not only does silver perform better than iodine when imaged at their respective optimal conditions, but silver is able to provide higher levels of contrast than iodine when imaged with current protocols that are optimal for iodine. Therefore, a silver agent could be translated to the clinic without modification of existing imaging systems or techniques. A prototype silver agent was designed. The agent consists of (i) a silver core for DE contrast, (ii) a silica shell to prevent the release of toxic silver cations, and (iii) a polyethylene glycol layer to improve the biocompatibility of the entire nanostructure. DE imaging with the particles showed a 9-fold increase in contrast when injected into mice, while displaying no acutely toxic effects. The prototype silica-silver nanoparticles represent a first step in developing a biologically stable contrast agent that is specifically suited for DE breast imaging

Navigation system based in motion tracking sensor for percutaneous renal access

Tese de Doutoramento em Engenharia BiomédicaMinimally-invasive kidney interventions are daily performed to diagnose and treat several renal diseases. Percutaneous renal access (PRA) is an essential but challenging stage for most of these procedures, since its outcome is directly linked to the physician’s ability to precisely visualize and reach the anatomical target. Nowadays, PRA is always guided with medical imaging assistance, most frequently using X-ray based imaging (e.g. fluoroscopy). Thus, radiation on the surgical theater represents a major risk to the medical team, where its exclusion from PRA has a direct impact diminishing the dose exposure on both patients and physicians. To solve the referred problems this thesis aims to develop a new hardware/software framework to intuitively and safely guide the surgeon during PRA planning and puncturing. In terms of surgical planning, a set of methodologies were developed to increase the certainty of reaching a specific target inside the kidney. The most relevant abdominal structures for PRA were automatically clustered into different 3D volumes. For that, primitive volumes were merged as a local optimization problem using the minimum description length principle and image statistical properties. A multi-volume Ray Cast method was then used to highlight each segmented volume. Results show that it is possible to detect all abdominal structures surrounding the kidney, with the ability to correctly estimate a virtual trajectory. Concerning the percutaneous puncturing stage, either an electromagnetic or optical solution were developed and tested in multiple in vitro, in vivo and ex vivo trials. The optical tracking solution aids in establishing the desired puncture site and choosing the best virtual puncture trajectory. However, this system required a line of sight to different optical markers placed at the needle base, limiting the accuracy when tracking inside the human body. Results show that the needle tip can deflect from its initial straight line trajectory with an error higher than 3 mm. Moreover, a complex registration procedure and initial setup is needed. On the other hand, a real-time electromagnetic tracking was developed. Hereto, a catheter was inserted trans-urethrally towards the renal target. This catheter has a position and orientation electromagnetic sensor on its tip that function as a real-time target locator. Then, a needle integrating a similar sensor is used. From the data provided by both sensors, one computes a virtual puncture trajectory, which is displayed in a 3D visualization software. In vivo tests showed a median renal and ureteral puncture times of 19 and 51 seconds, respectively (range 14 to 45 and 45 to 67 seconds). Such results represent a puncture time improvement between 75% and 85% when comparing to state of the art methods. 3D sound and vibrotactile feedback were also developed to provide additional information about the needle orientation. By using these kind of feedback, it was verified that the surgeon tends to follow a virtual puncture trajectory with a reduced amount of deviations from the ideal trajectory, being able to anticipate any movement even without looking to a monitor. Best results show that 3D sound sources were correctly identified 79.2 ± 8.1% of times with an average angulation error of 10.4º degrees. Vibration sources were accurately identified 91.1 ± 3.6% of times with an average angulation error of 8.0º degrees. Additionally to the EMT framework, three circular ultrasound transducers were built with a needle working channel. One explored different manufacture fabrication setups in terms of the piezoelectric materials, transducer construction, single vs. multi array configurations, backing and matching material design. The A-scan signals retrieved from each transducer were filtered and processed to automatically detect reflected echoes and to alert the surgeon when undesirable anatomical structures are in between the puncture path. The transducers were mapped in a water tank and tested in a study involving 45 phantoms. Results showed that the beam cross-sectional area oscillates around the ceramics radius and it was possible to automatically detect echo signals in phantoms with length higher than 80 mm. Hereupon, it is expected that the introduction of the proposed system on the PRA procedure, will allow to guide the surgeon through the optimal path towards the precise kidney target, increasing surgeon’s confidence and reducing complications (e.g. organ perforation) during PRA. Moreover, the developed framework has the potential to make the PRA free of radiation for both patient and surgeon and to broad the use of PRA to less specialized surgeons.Intervenções renais minimamente invasivas são realizadas diariamente para o tratamento e diagnóstico de várias doenças renais. O acesso renal percutâneo (ARP) é uma etapa essencial e desafiante na maior parte destes procedimentos. O seu resultado encontra-se diretamente relacionado com a capacidade do cirurgião visualizar e atingir com precisão o alvo anatómico. Hoje em dia, o ARP é sempre guiado com recurso a sistemas imagiológicos, na maior parte das vezes baseados em raios-X (p.e. a fluoroscopia). A radiação destes sistemas nas salas cirúrgicas representa um grande risco para a equipa médica, aonde a sua remoção levará a um impacto direto na diminuição da dose exposta aos pacientes e cirurgiões. De modo a resolver os problemas existentes, esta tese tem como objetivo o desenvolvimento de uma framework de hardware/software que permita, de forma intuitiva e segura, guiar o cirurgião durante o planeamento e punção do ARP. Em termos de planeamento, foi desenvolvido um conjunto de metodologias de modo a aumentar a eficácia com que o alvo anatómico é alcançado. As estruturas abdominais mais relevantes para o procedimento de ARP, foram automaticamente agrupadas em volumes 3D, através de um problema de optimização global com base no princípio de “minimum description length” e propriedades estatísticas da imagem. Por fim, um procedimento de Ray Cast, com múltiplas funções de transferência, foi utilizado para enfatizar as estruturas segmentadas. Os resultados mostram que é possível detetar todas as estruturas abdominais envolventes ao rim, com a capacidade para estimar corretamente uma trajetória virtual. No que diz respeito à fase de punção percutânea, foram testadas duas soluções de deteção de movimento (ótica e eletromagnética) em múltiplos ensaios in vitro, in vivo e ex vivo. A solução baseada em sensores óticos ajudou no cálculo do melhor ponto de punção e na definição da melhor trajetória a seguir. Contudo, este sistema necessita de uma linha de visão com diferentes marcadores óticos acoplados à base da agulha, limitando a precisão com que a agulha é detetada no interior do corpo humano. Os resultados indicam que a agulha pode sofrer deflexões à medida que vai sendo inserida, com erros superiores a 3 mm. Por outro lado, foi desenvolvida e testada uma solução com base em sensores eletromagnéticos. Para tal, um cateter que integra um sensor de posição e orientação na sua ponta, foi colocado por via trans-uretral junto do alvo renal. De seguida, uma agulha, integrando um sensor semelhante, é utilizada para a punção percutânea. A partir da diferença espacial de ambos os sensores, é possível gerar uma trajetória de punção virtual. A mediana do tempo necessário para puncionar o rim e ureter, segundo esta trajetória, foi de 19 e 51 segundos, respetivamente (variações de 14 a 45 e 45 a 67 segundos). Estes resultados representam uma melhoria do tempo de punção entre 75% e 85%, quando comparados com o estado da arte dos métodos atuais. Além do feedback visual, som 3D e feedback vibratório foram explorados de modo a fornecer informações complementares da posição da agulha. Verificou-se que com este tipo de feedback, o cirurgião tende a seguir uma trajetória de punção com desvios mínimos, sendo igualmente capaz de antecipar qualquer movimento, mesmo sem olhar para o monitor. Fontes de som e vibração podem ser corretamente detetadas em 79,2 ± 8,1% e 91,1 ± 3,6%, com erros médios de angulação de 10.4º e 8.0 graus, respetivamente. Adicionalmente ao sistema de navegação, foram também produzidos três transdutores de ultrassom circulares com um canal de trabalho para a agulha. Para tal, foram exploradas diferentes configurações de fabricação em termos de materiais piezoelétricos, transdutores multi-array ou singulares e espessura/material de layers de suporte. Os sinais originados em cada transdutor foram filtrados e processados de modo a detetar de forma automática os ecos refletidos, e assim, alertar o cirurgião quando existem variações anatómicas ao longo do caminho de punção. Os transdutores foram mapeados num tanque de água e testados em 45 phantoms. Os resultados mostraram que o feixe de área em corte transversal oscila em torno do raio de cerâmica, e que os ecos refletidos são detetados em phantoms com comprimentos superiores a 80 mm. Desta forma, é expectável que a introdução deste novo sistema a nível do ARP permitirá conduzir o cirurgião ao longo do caminho de punção ideal, aumentado a confiança do cirurgião e reduzindo possíveis complicações (p.e. a perfuração dos órgãos). Além disso, de realçar que este sistema apresenta o potencial de tornar o ARP livre de radiação e alarga-lo a cirurgiões menos especializados.The present work was only possible thanks to the support by the Portuguese Science and Technology Foundation through the PhD grant with reference SFRH/BD/74276/2010 funded by FCT/MEC (PIDDAC) and by Fundo Europeu de Desenvolvimento Regional (FEDER), Programa COMPETE - Programa Operacional Factores de Competitividade (POFC) do QREN