The ghrelin receptor (GhrR) is a widely investigated target in several diseases. However, the current knowledge of its role and distribution in the brain is limited. Recently, the small and non-peptidic compound (S)-6-(4-bromo-2-fluorophenoxy)-3-((1-isopropylpiperidin-3-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4(3H)-one ((S)-9) has been described as a GhrR ligand with high binding affinity. Here, we describe the synthesis of fluorinated derivatives, the in vitro evaluation of their potency as partial agonists and selectivity at GhrRs, and their physicochemical properties. These results identified compounds (S)-9, (R)-9, and (S)-16 as suitable parent molecules for 18F-labeled positron emission tomography (PET) radiotracers to enable future investigation of GhrR in the brain.

<p>The scintillation crystal is a critical component in positron emission tomography (PET) systems. It impacts a number of PET system performance parameters, including spatial, energy, and time resolution. Our goal is to develop a new simulation tool to achieve improved accuracy by addressing several limitations in the existing packages, including more advanced surface treatments, temporal dependency of photon arrival, and rigorous experimental validations. The comparison of preliminary Monte Carlo simulation results and analytical calculations for specular reflection suggest that the simulation model is working well. The time-resolved light output was studied for various crystal surface treatment configurations. The measured energy resolutions are in the range of approximately 10% to 15%, which are in good agreement with published literatures. Based on the simulation and experimental results, the polished surface treatment, used together with an external specular reflector, is able to provide the best energy resolution and timing resolution for a LYSO (3x3x20 mm³) and SiPM assembly we tested. The AsCut surface with external diffusion reflector is not desired due to its inferior energy and timing resolutions. The direction and recommendation of improvements of simulation regarding surface models and wavelength dependency, as well as potential optimization of experiment such as timing pickoff methods, are discussed.</p> / Master of Science (MSc)

Using a tailored dose distribution for personalized radiotherapy with the help of positron emission tomography (PET) might give an edge for successful tumour elimination. One of the main determinants for tumour radioresistance in several solid tumours has been investigated as hypoxia, including head and neck cancer (HNC). Using novel methods of converting radiotracer uptake into partial oxygen pressure distribution in the form of partial pressure maps, it is possible to delineate the hypoxic region of a target to further escalate the treatment dose there, aiming at an increase in tumour control. However, the registration between functional and structural images may have an impact on the effectiveness of dose escalation, and choosing the correct registration method could be imperative. In this master’s thesis, the impact of choosing rigid or deformable image registration between planning-CT and PET/CT images on the characterization of the hypoxic compartment, as well as on the treatment evaluation in terms of tumour control and normal tissue complication, was assessed. This was achieved by, using hypoxic patients of a cohort of 22 HNC patients, creating a separate plan for each registration method, for each patient, and comparing them quantitatively. The results showed that both methods would yield distinctly different dose distributions when planned using the same objectives and constraints in terms of dose level and shape. Furthermore, they both give a distribution of similar quality. However, using rigid registration together with the deformed PET did not render lower results overall in tumour control. Thus, no advantage could be seen in choosing deformable registration over rigid registration when aiming at tumour control.

A lo largo de la última década hemos asistido a un desarrollo sin precedentes de las tecnologías de la salud. Los avances en la informatización, la creación de redes, las técnicas de imagen, la robótica, las micro/nano tecnologías, y la genómica, han contribuido a aumentar significativamente la cantidad y diversidad de información al alcance del personal clínico para el diagnóstico, pronóstico, tratamiento y seguimiento de los pacientes. Este aumento en la cantidad y diversidad de datos clínicos requiere del continuo desarrollo de técnicas y metodologías capaces de integrar estos datos, procesarlos, y dar soporte en su interpretación de una forma robusta y eficiente. En este contexto, esta Tesis se focaliza en el análisis y procesado de señales biomédicas y su uso en problemas de clasificación automática. Es decir, se focaliza en: el diseño e integración de algoritmos para el procesado automático de señales biomédicas, el desarrollo de nuevos métodos de extracción de características para señales, la evaluación de compatibilidad entre señales biomédicas, y el diseño de modelos de clasificación para problemas clínicos específicos. En la mayoría de casos contenidos en esta Tesis, estos problemas se sitúan en el ámbito de los sistemas de apoyo a la decisión clínica, es decir, de sistemas computacionales que proporcionan conocimiento experto para la decisión en el diagnóstico, pronóstico y tratamiento de los pacientes. Una de las principales contribuciones de esta tesis consiste en la evaluación de la compatibilidad entre espectros de resonancia magnética (ERM) obtenidos mediante dos tecnologías de escáneres de resonancia magnética coexistentes en la actualidad (escáneres de 1.5T y de 3T). Esta compatibilidad se evalúa en el contexto de clasificación automática de tumores cerebrales. Los resultados obtenidos en este trabajo sugieren que los clasificadores existentes basados en datos de ERM de 1.5T pueden ser aplicables a casos obtenidos con la nueva tecnolog / Fuster García, E. (2012). Biomedical signal analysis in automatic classification problems [Tesis doctoral]. Editorial Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/17176

京都大学 / 新制・課程博士 / 博士(医学) / 甲第25492号 / 医博第5092号 / 新制||医||1073(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 斎藤 通紀, 教授 浅野 雅秀, 教授 柊 卓志 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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

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

Islet transplantation is a possible curative treatment for type 1 diabetes (T1D). Currently the liver dominates as implantation site, despite the many challenges encountered at this site. Acute hypoxia in islets transplanted to muscle and omentum, two possible alternative sites, was prevailing. However, it was rapidly reversed at both implantation sites, in contrast to when islets were transplanted intraportally. At the intramuscular site hypoxia was further relieved by co-transplantation of an oxygen carrier, polymerized hemoglobin, which also improved the functional outcome. The complement system was activated after islet transplantation to muscle, but did not hamper graft function. Both mouse and human islets transplanted to omentum become well re-vascularized and have a functional blood flow and oxygenation comparable with that of endogenous islets. Animals transplanted with islets to the omentum had a superior graft function compared with animals receiving intraportal islet grafts. Alloxan-diabetic animals were cured with a low number of islets both when the islets were implanted in the omentum and muscle. The islet grafts responded adequately to both glucose and insulin and displayed a favorable mRNA gene expression profile. A challenge in diabetes research and in islet transplantation is that there are no established techniques for quantifying beta-cell mass in vivo. By using radiolabeled Exendin-4, a GLP-1 receptor agonist, beta-cell mass after transplantation to muscle of mice was quantified. The results may well be translated to the clinical setting. By comparing the pancreatic accumulation of [11C]5-hydroxy tryptophan ([11C]5-HTP) as detected by positron emission tomography (PET) in T1D patients with that of healthy controls, a 66% decrease was observed. This may in fact represent the loss of beta-cells, taking into account that other cells within the islets of Langerhans are largely unaffected in T1D.  In conclusion, the data presented support the use of alternative implantation sites for islet transplantation. In addition to improving the functional outcome this may enable more transplantations since the number of transplanted islets may be reduced. The techniques investigated for quantifying transplanted and endogenous beta-cell mass may greatly improve our knowledge of the pathophysiology of T1D and become a valuable tool for evaluation of beta-cell mass.

Ο γενικός σκοπός της παρούσας μελέτης ήταν να προτείνει μια νέα μέθοδο για την πλήρη περιγραφή των χαρακτηριστικών ποιότητας εικόνας και την βελτιστοποίηση της Τομογραφίας Εκπομπής Ποζιτρονίων (PET) αναπτύσσοντας ένα μοντέλο Monte Carlo. Υλικά και Μέθοδοι: Η μέθοδος αναπτύχθηκε χρησιμοποιώντας τον κώδικα Monte Carlo (GEANT4 Application For Tomographic Emissions) του GEANT4 με το πακέτο λογισμικού GATE που αναπτύχθηκε από την Open-GATE collaboration. Για την ανακατασκευή των εικόνων χρησιμοποιήθηκε το λογισμικό STIR και για τη λήψη των δεδομένων της ανακατασκευής, από το GATE, χρησιμοποιήθηκε μια συστοιχία από 12 επεξεργαστές Dual Core Intel (R) Xeon (TM) 3.00GHz (Supermicro SuperServer 6015B-UR/NTR, Αγγλία). Ο σαρωτής PET που προσομοιώθηκε σε αυτή τη μελέτη ήταν ο General Electric Discovery-ST (ΗΠΑ). Το μοντέλο GATE πιστοποιήθηκε μέσω της σύγκρισης των αποτελεσμάτων που ελήφθησαν με δημοσιευμένα αποτελέσματα (Bettinardi et al 2004, Mawlawi et al 2004) τα οποία ακολουθούν το πρωτόκολλο της NEMA-NU-2 2001. Οι εικόνες ανακατασκευάστηκαν με τρεις μεθόδους, αρχικά με τη 2D φιλτραρισμένη οπισθοπροβολή (FBP2D), στη συνέχεια με τη μέθοδο της 3D φιλτραρισμένης οπισθοπροβολής (FPB3DRP), των Kinahan και Rogers, και τέλος με χρήση επαναληπτικών αλγορίθμων (MLE-OSMAPOSL). Αρχικά έγινε προσδιορισμός της Συνάρτησης Μεταφοράς Διαμόρφωσης (MTF) για την αξιολόγηση της ποιότητας εικόνας συστημάτων PET. Η αξιολόγηση έγινε μέσω της προσομοίωσης μιας νέας επίπεδης πηγής Λεπτού Χρωματογραφικού Φιλμ (Thin Layer Chromatography-TLC) το οποίο αποτελείται από ένα στρώμα Διοξειδίου του Πυριτίου και υποστρώματα φύλλου Αλουμινίου, εμβαπτισμένο σε 18F-FDG με ενεργότητα 44.4MBq. Η αξιολόγηση της MTF έγινε μέσω των ανακατασκευασμένων εικόνων της επίπεδης πηγής κάνοντας χρήση του λογισμικού STIR. Η αξιολόγηση της MTF πραγματοποιήθηκε επίσης: α) σε τρεις διαστάσεις (3D), τοποθετώντας την επίπεδη πηγή σε οριζόντια και σε κάθετη κατεύθυνση (διαστάσεις πηγής οριζόντια και κάθετα 5x10 εκατοστά), β) με σάρωση πηγής μεγαλύτερου πλάτους, ανακατασκευάζοντας την εγκάρσια τομή της (διαστάσεις 18x10cm) και γ) από ανακατασκευασμένες εικόνες σημειακής πηγής. Να τονίσουμε εδώ ότι η παρούσα μελέτη είχε ως στόχο να συγκρίνει την προτεινόμενη μέθοδο (αξιολόγηση της MTF μέσω επίπεδης πηγής) με την πιο παραδοσιακή τεχνική που βασίζεται σε σημειακές πηγές. Στη συνέχεια έγινε προσδιορισμός της Ανιχνευτικής Κβαντικής Αποδοτικότητας (DQE) για την εκτίμηση της συνολικής απόδοσης του συστήματος PET, μέσω υπολογισμού της Συνάρτησης Μεταφοράς Διαμόρφωσης και του Κανονικοποιημένου Φάσματος Ισχύος Θορύβου (NNPS). Οι καμπύλες της MTF υπολογίστηκαν από την ανακατασκευή των εγκάρσιων τομών της επίπεδης πηγής (1 MBq), ενώ το NNPS υπολογίστηκε από τις αντίστοιχες στεφανιαίες τομές. Οι εικόνες ανακατασκευάστηκαν εφαρμόζοντας επαναληπτικούς αλγόριθμους (MLE-OSMAPOSL), χρησιμοποιώντας διάφορα υποσύνολα των προβολών (subsets) (3 έως 21) και επαναλήψεων (iterations) (1 έως 20). Επιπλέον, η αξιολόγηση της DQE έγινε μέσω διερεύνησης της επίδρασης διαφόρων κρυστάλλων σπινθηριστών στην διακριτική ικανότητα (MTF) και τον θόρυβο (NNPS) των ανακατασκευασμένων εικόνων του PET. Σε αυτή την περίπτωση, ο αλγόριθμος ανακατασκευής της εικόνας MLE-OSMAPOSL, υλοποιήθηκε χρησιμοποιώντας 15 subsets και 3 iterations. Αποτελέσματα και Συζήτηση: Τα αποτελέσματα της πιστοποίησης μέσω σύγκρισης με δημοσιευμένα αποτελέσματα είναι τα ακόλουθα: Η Διακριτική Ικανότητα (Spatial Resolution, SR) στο Πλήρες Εύρος στο Ήμιση του Μέγιστου (Full Width at Half Maximum - FWHM) βρέθηκε να έχει απόκλιση μικρότερη από 3,29% σε λειτουργία 2D και μικρότερη από 2,51% σε λειτουργία 3D, σε σχέση με δημοσιευμένα πειραματικά αποτελέσματα (Mawlawi et al 2004), αντιστοίχως. Οι τιμές 2D, για την Ευαισθησία (Sensitivity), το Ποσοστό Σκέδασης (Scatter Fraction-SF) και την Απόδοση του Ρυθμού Μέτρησης (Count-Rate), τα οποία ελήφθησαν ακολουθώντας το πρωτόκολλο της NEMA NU 2-2001, βρέθηκαν να διαφέρουν λιγότερο από 0,46%, 4,59% και 7,86%, αντίστοιχα με τα δημοσιευμένα πειραματικά αποτελέσματα (Mawlawi et al 2004). Ακολούθως, οι αντίστοιχες τιμές σε λειτουργία 3D βρέθηκαν να διαφέρουν λιγότερο από 1,62%, 2,85% και 9,13%, αντίστοιχα, με τα δημοσιευμένα πειραματικά αποτελέσματα (Mawlawi et al 2004). Η ευαισθησία επιπλέον εκτιμήθηκε χωρίς την παρουσία υλικού εξασθένησης, προσομοιώνοντας απευθείας μια ιδανική πηγή. Οι διαφορές που προέκυψαν μεταξύ της ιδανικής πηγής και της μεθοδολογίας κατά NEMA-NU-2 2001 κυμαίνονται από 0,04% έως 0,82% (ακτινική θέση R = 0cm) σε λειτουργία 2D και από 0,52% έως 0,67% σε λειτουργία 3D (ακτινικές θέσεις R = 10cm). Συνεπώς κάνοντας χρήση αυτής της μεθόδου, η ευαισθησία μπορεί να προσδιοριστεί με πιο απλοποιημένη και γρήγορη διαδικασία. Οι τιμές του Ρυθμού Μέτρησης Ισοδύναμου Θορύβου (Noise Equivalent Count Rate-NECR) που προέκυψαν ήταν 94.31kcps σε 2D και 66.9kcps σε 3D στα 70 και 15kBq/mL αντίστοιχα, σε σύγκριση με τα δημοσιευμένα αποτελέσματα τα οποία ήταν 94.08kcps σε 2D και 70.88kcps σε 3D στα 54.6kBq/mL και 14kBq/mL αντίστοιχα. Οι τιμές για την ποιότητα εικόνας βρέθηκαν σε εξαιρετική συμφωνία με τα δημοσιευμένα αποτελέσματα. Αφού ολοκληρώθηκε η πιστοποίηση του μοντέλου έγινε υπολογισμός της MTF. Οι τιμές MTF που προέκυψαν από την ανακατασκευή με τον αλγόριθμο FBP2D βρέθηκαν σε εξαιρετική συμφωνία με αυτές που προέκυψαν από την ανακατασκευή με τον αλγόριθμο FBP3DRP, ενώ οι αντίστοιχες τιμές μέσω του αλγόριθμου MLE-OSMAPOSL ήταν σε όλο το φάσμα των χωρικών συχνοτήτων υψηλότερες σε σχέση με τους αλγόριθμους οπισθοπροβολής (FBP). Η προσομοίωση της μεγάλης επίπεδης πηγής με αλγορίθμους οπισθοπροβολής έδειξε ότι οι τιμές της MTF ελαττώνονται σταδιακά από το κέντρο προς τα άκρα του οπτικού πεδίου (Field Of View-FOV). H MTF, της κάθετης τομής, διέφερε ελάχιστα σε σχέση με την οριζόντια. Η σύγκριση της επίπεδης πηγής με τη σημειακή πηγή έδειξε ότι η πρώτη είναι λιγότερη ευαίσθητη στο θόρυβο (SD = 0,0031 και 0,0203, αντίστοιχα). Η αξιολόγηση της DQE μέσω επαναληπτικών αλγορίθμων MLE-OSMAPOSL έδειξε ότι η απόδοση του συστήματος βελτιώνεται όσο αυξάνεται ο αριθμός των επαναλήψεων μέχρι μια μέγιστη τιμή (12 iterations) και παρέμενε αναλλοίωτη από εκεί και έπειτα. Επιπλέον, η μεταβολή του αριθμού των subsets δεν είχε επίδραση στην MTF, για ίσο αριθμό επαναλήψεων. Αντίστοιχα τα επίπεδα θορύβου (NNPS) μειώθηκαν με την αύξηση του αριθμού των iterations και των subsets. Με βάση τα προηγούμενα οι τιμές της DQE επηρεάστηκαν τόσο από την MTF όσο και από το NNPS και βρέθηκαν να αυξάνουν με την αντίστοιχη αύξηση του αριθμού των iterations και των subsets. Τέλος, ο ανιχνευτής PET στον οποίο τοποθετήθηκαν κρύσταλλοι LuAP, παρείχε τις βέλτιστες τιμές MTF σε οπισθοπροβολή 2D και 3D ενώ η αντίστοιχη διαμόρφωση με κρυστάλλους BGO παρείχε τις βέλτιστες τιμές MTF μετά την ανακατασκευή με MLE-OSMAPOSL. Αντίστοιχα, ο ανιχνευτής με κρυστάλλους BGO είχε τα χαμηλότερα επίπεδα θορύβου και τις υψηλότερες τιμές DQE μετά από την εφαρμογή όλων των αλγόριθμων ανακατασκευής. Συμπερασματικά: Η παρούσα μελέτη έδειξε ότι η συνολική απόδοση συστημάτων PET μπορεί να χαρακτηριστεί πλήρως, να βελτιωθεί περαιτέρω και να γίνει πιο απλή με τη διερεύνηση των διαφόρων στοιχείων της αλυσίδας απεικόνισης μέσω μεθόδων Monte Carlo. Η μέθοδος αξιολόγησης ανιχνευτών ΡΕΤ, βασιζόμενη σε επίπεδη πηγή TLC, απαιτεί υλικά που είναι συνηθισμένα στο κλινικό περιβάλλον, μπορεί να εφαρμοστεί πειραματικά και να χρησιμοποιηθεί στην κλινική πράξη. Σε αυτή τη μελέτη χρησιμοποιήθηκε για την εκτίμηση και βελτιστοποίηση της ποιότητας εικόνας, αλλά μπορεί να είναι επίσης χρήσιμη στον τομέα της έρευνας για περαιτέρω ανάπτυξη συστημάτων ΡΕΤ και SPECT, μέσω προσομοιώσεων με το πακέτο λογισμικού GATE. Οι ανακατασκευασμένες εικόνες από το λογισμικό STIR μπορούν επίσης να χρησιμοποιηθούν για την εκτίμηση της κατανομής του ραδιοφαρμάκου, καθώς και την απευθείας λήψη της δοσιμετρικής κατανομής, με αντίστοιχο όφελος στους πυρηνικούς γιατρούς. / The overall purpose of this study was to propose a novel method for the complete image quality characterization and optimization of Positron Emission Tomography (PET) scanners with Monte-Carlo (MC) methods. Α model was developed using the Monte Carlo package of Geant4 Application for Tomographic Emission (GATE) and the software for tomographic image reconstruction (STIR) with cluster computing to obtain reconstructed images. The PET scanner used in this study was the General Electric Discovery-ST (US). The GATE model was validated by comparing results obtained in accordance with the National Electrical Manufacturers Association NEMA-NU-2-2001 protocol (Bettinardi et al 2004, Mawlawi et al 2004). Validation images were reconstructed with the commonly used 2D Filtered Back Projection (FBP2D) and the Kinahan and Rogers FPB3DRP Reprojection Algorithms. Image quality, in terms of the Modulation Transfer Function (MTF), was initially assessed with a novel plane source consisting of a Thin Layer Chromatography (TLC) plate, simulated by a layer of Silica gel on Aluminium foil substrates immersed in Fluorodeoxyglucose (18F-FDG) bath solution (44.4MBq). MTF was assessed from the evaluated STIR digital reconstructed images of the plane source. MTF was also assessed a) in three dimensions, in lines passing through the central axis of the PET scanner, by placing the plane source only horizontally and vertically (5x10cm), b) by scanning 18cm of the transaxial Field Of View (FOV) through the simulation of a horizontal large plane source (18x10cm) and c) by evaluating reconstructed point source images. Furthermore, the study aimed to compare the proposed method with the more traditional technique based on a line source. The complete image quality characterization was assessed in terms of the Detective Quantum Efficiency (DQE) by estimating the MTF and the Normalized Noise Power Spectrum (NNPS) of the 18F-FDG TLC plane source (1 MBq). MTFs curves were estimated from transverse reconstructed images of the plane source, whereas the NNPS data were estimated from the corresponding coronal images. Images were reconstructed by the Maximum Likelihood Estimation (MLE)-OSMAPOSL reprojection algorithm by using various subsets (3 to 21) and iterations (1 to 20). Additionally, the influence of different scintillating crystals on PET scanner’s image quality, in terms of the MTF, the NNPS and the DQE, was also investigated. In this case, OSMAPOSL image reconstruction was assessed by using 15 subsets and 3 iterations. The simulated spatial resolution in terms of Full Width at Half Maximum (FWHM) agreed with published data of Mawlawi et al (2004), within less than 3.29% in 2D and less than 2.51% in 3D with published data of others, respectively. The 2D values for the sensitivity, the scatter fraction and the count-rate were found to agree within less than 0.46%, 4.59% and 7.86%, respectively with corresponding published values. Accordingly, the corresponding 3D values were found to agree to less than 1.62%, 2.85% and 9.13%, respectively with Mawlawi et al (2004) published values. Sensitivity, which was also estimated in the absence of attenuation material by simulating an ideal source, showed differences between the extrapolated and the ideal source values (with and without attenuation) ranging in 2D from 0.04% to 0.82% (radial location R=0cm) in 2D and from 0.52% to 0.67% in 3D mode (radial locations R=10cm). By using this model, sensitivity can be obtained in a more simplified procedure. The simulated noise equivalent count rate was found to be 94.31kcps in 2D and 66.9kcps in 3D at 70 and 15kBq/mL respectively, compared to 94.08kcps in 2D and 70.88kcps in 3D at 54.6kBq/mL and 14kBq/mL respectively, from the published by others values. The simulated image quality was found in excellent agreement with these published values. The MTFs obtained using the FBP2D were in close agreement to those obtained by the FBP3DRP, whereas the MTFs of the OSMAPOSL show, in all cases, that higher frequencies are preserved than in the case of the FBP. FBP reconstructed images obtained from the large horizontal plane source showed that the MTF was found to degrade gradually as we move towards the edge of the FOV. The MTFs of the FBP images along the vertical direction were slightly lower than the corresponding horizontal ones. In addition, the plane source method is less prone to noise than the conventional line source method (sd=0.0031 and 0.0203, respectively). In the case of DQE investigation, MTF values assessed from the evaluated STIR digital reconstructed images, of the TLC based plane source, were found to improve as the number of iterations increased up to 12 and remain almost constant thereafter. Furthermore, variation in the number of subsets didn’t show any effect on the MTF, for equal number of iterations. The noise levels, in terms of the NNPS, in the reconstructed PET image, were found to decrease with the corresponding increase of both the number of iterations and subsets. DQE values were influenced by both MTF and NNPS and were found to increase with the corresponding increase in both number of iterations and subsets. Finally, the PET scanner configuration, incorporating LuAP crystals, provided the optimum MTF values in both 2D and 3DFBP whereas the corresponding configuration with BGO crystals was found with the higher MTF values after OSMAPOSL. The scanner incorporating BGO crystals were also found with the lowest noise levels and the highest DQE values after all image reconstruction algorithms. In conclusion, our study showed that the imaging performance of PET scanners can be fully characterized, further improved and simplified by investigation of the imaging chain components through MC methods. The simulated PET evaluation method, based on a TLC plane source, requires materials commonly found in a clinical environment and can be experimentally implemented and used in clinical practice. In this study it was used for the image quality assessment and optimization, but it can be also useful in research for the further development of PET and SPECT (Single Photon Emission Tomography) scanners though GATE simulations. Reconstructed images by STIR can be also used to obtain radiopharmaceutical distribution of images and direct dose maps, quite useful to nuclear medicine practitioners.

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