Endometriosis is a reproductive disease affecting women in their prime reproductive years characterized by the presence of endometrial glands and stroma in ectopic locations. Animal models have been proven to be indispensable not only for the study of the disease but also to develop better non-invasive diagnostic imaging modalities. A major limitation with the diagnosis of endometriosis is the lack of a specific and sensitive non-invasive diagnostic test. Our objective was to develop a domestic animal model of endometriosis suitable for serial diagnostic imaging procedures and assessment of therapies. Two major studies were conducted to achieve this objective. First study involved in vitro whole tissue-explant culture and surgical induction of endometriosis in dog, pig and sheep to choose the most suitable model. For in vitro co-culture, dog, pig and sheep endometrium was placed on visceral peritoneum for 24 to 72 h to assess the degree of attachment and adhesion characteristics of endometrium (epithelium, glandular and stromal cells). Surgical induction of endometriosis was tested in dog, sheep (n=5 each) and pig (n=4) using autologous endometrial (n=4 grafts per animal) and fat grafts sutured to visceral (urinary bladder surface in dog and pig, uterus in sheep) and parietal (abdominal wall) peritoneum. Sham surgeries were performed in control group animals (dog and sheep n=5, pig n=3) using fat grafts alone. Animals were euthanized between 80-110 days post-surgery. Size, gross characteristics and histopathologic features of endometriotic lesions were recorded. During in vitro explant culture, surface epithelial, stromal and glandular cells of endometrium were capable of attaching to visceral peritoneum within 24 hours with and without an intact layer of mesothelial lining in dog, pig and sheep. The proportion of successful endometrial attachments were greater at 24h compared to 72h (15/18 vs. 7/18, p=0.008; data combined among species) with intermediate attachment at 48h (12/15). Following surgical induction, there was no difference (p>0.05) in proportion of successful tissue grafts placed on serosal surface of visceral vs. parietal peritoneum in dog (10/10 vs. 10/10), pig (7/8 vs. 8/8) or sheep (7/10 vs. 8/10). A variety of outcomes (endometriotic cysts with sero-sangunous fluid, solid lesions, vesicles, absence of lesions) were found. The proportion of cystic lesions was greater (p<0.01) in dog (19/20 grafts) than in pig (8/16) and sheep (5/20). Further, the area of endometriotic lesions at euthanasia was larger (0.89 ± 0.11 cm2) compared to that at the time of surgery (0.50 ± 0.09 cm2) in dog, whereas, the size of lesions decreased by half or more (p<0.05) in pig and sheep. Combined among grafting sites (visceral and parietal peritoneum) and species, a greater proportion (p=0.015) of surgical sites had adhesions in treatment (12/14) versus control group animals (5/13). The wall of majority of endometrial cysts in dogs were characterized by simple cuboidal/columnar epithelium, endometrial glands (normal, dilated and cystic), subepithelial capillary network and presence of stromal and smooth muscle cells. Hemorrhage and/or hemosiderin-laden macrophages were observed in the cystic lesions in dog. Development of a greater proportion of growing lesions in the form of endometriotic cysts in dogs compared to sheep and pig led us to conclude dog as a better suitable domestic animal model for endometriosis than sheep and pig. Second study involved assessing the usefulness and limitations of ultrasonography, magnetic resonance imaging (MRI) and positron emission tomography-computed tomography (PET-CT) in detecting cystic endometriotic lesions in dog and sheep. Surgical induction of endometriois was performed in dogs (n=5) and sheep (n=5) using autologous endometrial grafts (n=4 grafts per animal) and fat grafts sutured to visceral peritoneum (urinary bladder in dogs, uterus in sheep) and parietal peritoneum (ventral abdominal wall). Weekly ultrasonography was performed from Week 1-9 post-surgery and day of euthanasia (Week 14-15). T1 and T2 weighted weighted MRI images (n=2 each for dog and sheep) and PET-CT (n=3 dog, n=1 sheep) using 18F-fluorodeoxyglucose (18F-FDG) as radiolabel was performed between Week 13-15 post-surgery in dog and sheep. Gray-scale B-mode ultrasonography was able to detect endometriotic cysts (0.25-1.75cm) on urinary bladder and abdominal wall in dogs; endometrial grafts Week 1 post-surgery appeared as a homogenous, hypoechoic masses, following which they grew larger with evidence of cyst formation by Week 5. Cysts were undetectable from Week 10-13, whereas they appeared as homogenous masses with a hypoechoic fluid-filled cavity with diffuse hyperechoic echoes and low vascularisation (Color-Doppler imaging) by Week 14-15. In sheep, endometrial grafts were detected as hypoechoic masses Week 1 post-surgery that became smaller until no detectable lesions were visible beyond Week 6-7. Cysts in dogs and sheep appeared hyperintense on T2 and hypointense on T1 weighted images. 18F -FDG PET-CT did not show hypermetabolic activity in endometriotic cysts in dogs and sheep. In conclusion, MRI appeared to provide the most definitive diagnostic images of endometriotic cysts in dogs and sheep, particularly for lesions in sheep which were not evident by ultrasonography. However, ultrasonography was sufficient to characterize most endometriotic cysts in dogs. Further research needs to be carried out to develop specific PET tracers for endometriosis.

No description available.

Background Although abdominal aortic aneurysm (AAA) growth is non-linear, serial measurements of aneurysm diameter are the mainstay of aneurysm surveillance and contribute to decisions on timing of intervention. Aneurysm biology plays a key part in disease evolution but is not currently routinely assessed in clinical practice. Magnetic Resonance Imaging (MRI) and Positron Emission Tomography-Computed Tomography (PET-CT) provide insight into disease processes on a cellular or molecular level, and represent exciting new imaging biomarkers of disease activity. Macrophage-mediated inflammation may be assessed using ultrasmall superparamagnetic particles of iron oxide (USPIO) MRI and the PET radiotracer 18FSodium Fluoride (18F-NaF) identifies microcalcification which is a response to underlying necrotic inflammation. The central aim of this thesis was to investigate these imaging modalities in patients with AAA. Methods and Results USPIO MRI: MULTI-CENTRE STUDY In a prospective multi-centre observational cohort study, 342 patients (85.4% male, mean age 73.1±7.2 years, mean AAA diameter 49.6±7.7mm) with asymptomatic AAA ≥4 cm anteroposterior diameter underwent MRI before and 24-36 hours after intravenous administration of USPIO. Colour maps (depicting the change in T2* caused by USPIO) were used to classify aneurysms on the basis of the presence of USPIO uptake in the aneurysm wall, representing mural inflammation. Intra- and inter-observer agreement were found to be very good, with proportional agreement of 0.91 (kappa 0.82) and 0.83 (kappa 0.66), respectively. At 1 year, there was 29.3% discordant classification of aneurysms on repeated USPIO MRI and at 2 years, discordance was 65%, suggesting that inflammation evolves over time. In the observational study, after a mean of 1005±280 days of follow up, there were 126 (36.8%) aneurysm repairs and 17 (5.0%) ruptures. Participants with USPIO enhancement (42.7%) had increased aneurysm expansion rates (3·1±2·5 versus 2·5±2·4 mm/year; difference 0·6 [95% confidence intervals (CI), 0·02 to 1·2] mm/year, p=0·0424) and had higher rates of aneurysm rupture or repair (69/146=47·3% versus 68/191=35·6%; difference 11·7%, 95% CI 1·1 to 22·2%, p=0·0308). USPIO MRI was therefore shown to predict AAA expansion and the composite of rupture or repair, however this was not independent of aneurysm diameter (c-statistic, 0·7924 to 0·7926; unconditional net reclassification -13·5%, 95% confidence intervals -36·4% to 9·3%). 18F-NaF PET-CT: SINGLE-CENTRE STUDY A sub-group of 76 patients also underwent 18F-NaF PET-CT, which was evaluated using the maximum tissue-to-background ratio (TBRmax) in the most diseased segment (MDS), a technique that showed very good intra- (ICC 0.70-0.89) and inter-observer (ICC 0.637-0.856) agreement. Aneurysm tracer uptake was compared firstly in a case-control study, with 20 patients matched to 20 control patients for age, sex and smoking status. 18F-NaF uptake was higher in aneurysm when compared to control aorta (log2TBRmax 1.712±0.560 vs. 1.314±0.489; difference 0.398 (95% CI 0.057, 0.739), p=0.023), or to non-aneurysmal aorta in patients with AAA (log2TBRmax 1.647±0.537 vs. 1.332±0.497; difference 0.314 (95% CI 0.0685, 0.560), p=0.004). An ex vivo study was performed on aneurysm and control tissue, which demonstrated that 18F-NaF uptake on microPET-CT was higher in the aneurysm hotspots and higher in aneurysm tissue compared to control tissue. Histological analysis suggested that 18F-NaF was highest in areas of focal calcification and necrosis. In an observational cohort study, aneurysms were stratified by tertiles of TBRmax in the MDS and followed up for 510±196 days, with 6 monthly serial ultrasound measurements of diameter. Those in the highest tertile of tracer uptake expanded more than 2.5 times more rapidly than those in the lowest tertile (3.10 [3.58] mm/year vs. 1.24 [2.41] mm/year, p=0.008) and were also more likely to experience repair or rupture (15.3% vs. 5.6%, log-rank p=0.043). In multivariable analyses, 18F-NaF uptake on PET-CT emerged as an independent predictor of AAA expansion (p=0.042) and rupture or repair (HR 2.49, 95% CI1.07, 5.78; p=0.034), even when adjusted for age, sex, body mass index, systolic blood pressure, current smoking and, crucially, aneurysm diameter. Conclusion These are the largest USPIO MRI and PET-CT studies in AAA disease to date and the first to investigate 18F-NaF. Both USPIO MRI and 18F-NaF PET-CT are able to predict AAA expansion and the composite of rupture and repair, with 18F-NaF PETCT emerging as the first imaging biomarker that independently predicts expansion and AAA events, even after adjustment for aneurysm diameter. This represents an exciting new predictor of disease progression that adds incremental value to standard clinical assessments. Feasibility and randomised clinical trials are now required to assess the potential of this technique to change the management and outcome of patients with AAA.

Submitted by Automa??o e Estat?stica (sst@bczm.ufrn.br) on 2016-01-27T19:01:45Z No. of bitstreams: 1 MarcosPrettoMosmann_DISSERT.pdf: 1864596 bytes, checksum: 5469813ebb21427467b5a5e041958d8a (MD5) / Approved for entry into archive by Arlan Eloi Leite Silva (eloihistoriador@yahoo.com.br) on 2016-02-02T21:54:05Z (GMT) No. of bitstreams: 1 MarcosPrettoMosmann_DISSERT.pdf: 1864596 bytes, checksum: 5469813ebb21427467b5a5e041958d8a (MD5) / Made available in DSpace on 2016-02-02T21:54:05Z (GMT). No. of bitstreams: 1 MarcosPrettoMosmann_DISSERT.pdf: 1864596 bytes, checksum: 5469813ebb21427467b5a5e041958d8a (MD5) Previous issue date: 2014-02-26 / O c?ncer tem contribu?do drasticamente em termos de morbidade, mortalidade e custos para os sistemas de sa?de no mundo. O manejo desses pacientes ? complexo e novas tecnologias t?m emergido para o seu melhor cuidado. A tomografia por emiss?o de p?sitrons associada ? tomografia computadorizada (PET/CT) ? um m?todo diagn?stico dispon?vel mais recentemente no Brasil e determinou uma mudan?a de paradigma no fluxo do acompanhamento para muitos dos pacientes com c?ncer. Nesse sentido, o objetivo desse trabalho ? avaliar o acesso ao exame 18F-FDG PET/CT Oncol?gico no Estado do Rio Grande do Norte, segundo as caracter?sticas dos usu?rios, as indica??es e as fontes de financiamento do m?todo. Trata-se de um estudo individuado, observacional e transversal. Foram inclu?dos todos os pacientes que realizaram o exame 18F-FDG PET/CT com fins oncol?gicos na Liga Norteriograndense Contra o C?ncer no per?odo de 01/05/2011 a 30/04/2013. Coletaram-se dados relativos ? data de realiza??o do exame, sexo, idade, indica??o (diagn?stico / estadiamento / monitoriza??o da resposta ao tratamento / reestadiamento / suspeita de recidiva e controle), tipo de c?ncer ou condi??o que determinou a realiza??o do exame e a fonte de financiamento (p?blico ou particular). Nos dois anos que compreenderam o per?odo de coleta de dados do estudo, foram realizados 924 exames 18F-FDG PET/CT, em 718 pacientes. A m?dia de idade foi 51,4 (19,1) anos, variando entre 4 e 88 anos. Houve maior realiza??o do exame entre as mulheres, com um total de 539 exames (58,3%). Observou-se aumento da realiza??o do exame do primeiro ano (37,4%) para o segundo ano (62,6%). Quanto ?s indica??es do exame 18F-FDG PET/CT, foram realizados 3,8% com fins de diagn?stico, 6,6% para estadiamento, 1,0% para monitoriza??o da resposta ao tratamento, 49,8% para reestadiamento e 38,9% na suspeita de recidiva/controle, ou seja, apenas 10,4% dos exames foram realizados como estrat?gia inicial (diagn?stico e estadiamento). Em rela??o ao financiamento do 18F-FDG PET/CT, a maioria dos exames foi realizada com o conv?nio firmado com a Secretaria de Estado de Sa?de P?blica (45% dos exames). Os principais tipos de c?ncer encaminhados para o exame foram o linfoma (36,7%), c?ncer colorretal (10,6%), pulm?o (9,7%) e mama (8,5%). Foram realizados poucos exames PET/CT em alguns tipos de c?ncer, em especial es?fago (0,4%), p?ncreas (0,9%), est?mago (1,2%) e cabe?a e pesco?o (2,1%). De todos os exames em pacientes classificados como estrat?gia inicial, apenas 21% tiveram acesso ao exame pelo sistema p?blico, o que denota a pouca realiza??o do 18F-FDG PET/CT Oncol?gico no estado para esse fim. Para os sistemas de sa?de, ? fundamental promover o uso racional desse m?todo / Cancer has contributed dramatically in terms of morbidity, mortality and costs for healthcare systems in the world. The management of these patients is complex and new technologies have emerged for their best care. Positron emission tomography associated with computed tomography (PET/CT) is a diagnostic method available more recently in Brazil and led to a paradigm shift in the management for many cancer patients. Therefore, the aim of this study is to analyse the access to the exam 18F-FDG PET/CT in Oncology in the State of Rio Grande do Norte, according to the users characteristics, indications and sources of funding. This is an individual, observational and transversal study. All patients who underwent 18FFDG PET-CT examinations for oncologic purposes at Liga Norteriograndense contra o C?ncer from 01/05/2011 to 30/04/2013 were included. Data on the date of the examination, sex, age, indication (diagnosis / staging / monitoring response to treatment / restaging / suspected recurrence and control), type of cancer or condition that determined the exam and the source financing (public or private) were collected. During the two years that comprised the period of data collection for the study, 924 18F-FDG PET/CT exams were performed in 718 patients. The mean age was 51.4 (19.1) years, ranging from 4 to 88 years. There were more exams among women with a total of 539 examinations (58.3%). Increases were observed in the exams from the first year (37.4%) for the second year (62.6%). Accordingly, the 18F-FDG PET/CT indications were: 3.8% for diagnostic purposes, 6.6% for staging, 1.0% for monitoring response to treatment, 49.8% for restaging and 38.9% in suspected recurrence/control, only 10.4% of the exams were performed as initial strategy (diagnosis and staging). Regarding the financing of 18F-FDG PET/CT, the majority of tests were carried out with the agreement signed with the State Department of Public Health (45% of the exams). The main types of cancer referred for examination were lymphoma (36.7%), colorectal cancer (10.6%), lung (9.7%) and breast (8.5%). Few PET/CT studies were performed in some cancers, especially oesophagus (0.4%), pancreas (0.9%), stomach (1.2%) and head and neck (2.1%). Among those patients classified as initial strategy, only 21% had access to the exam by the public system, which demonstrates the low access of 18F-FDG PET/CT in Oncology in the state for this purpose. For health systems, it is essential to promote the rational use of this method.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / The positron emission tomography (PET), associated with computed tomography (CT) is a diagnostic technique from nuclear medicine called PET/CT. It is possible to estimate conversion coefficient for absorbed doses in PET/CT by means of computational simulations by Monte Carlo method. The main purpose of this work was, using the MCNPX code, to study the absorbed doses in internal organs of patients due PET/CT exams. For this, anthropomorphic computational phantoms with more realistic representation of adult and pediatric patients and their internal structures were employed. These phantoms were incorporated in scenarios of radiation of two PET/CT equipment, a Discovery VCT (GE) and Biograph (Siemens). Six different types of positron-emitting radionuclides are simulated. Variations in morphology due to the gravitational effect were also considered for the adult phantoms. The second objective was to construct a physical phantom for the validation of dosimetric irradiation scenarios using optically stimulated luminescence technique. The collimation and filtration models of beams were experimentally determined, and later implemented in MCNPX code. Using the computed tomography dose index (CTDI) quantities the irradiation scenarios have been validated for the CT. The estimated effective doses in the adult anthropomorphic computational phantoms due to CT are responsible for 9.0% and 20.2% considering GE and Siemens PET/CT equipments, respectively. For the 18F-FDG, specifically, these dose coefficients for absorbed doses showed an increase of 30% compared to values from ICRP 106. In children, the effective dose due to CT increased by 23.6% when compared to the results of the literature. Considering the same 18F-FDG, the results showed variations of 0.1%, 8.2% and 5.2% for 1 year, 5 and 10 years, respectively, compared to the values in ICRP 106. For children it necessary a special attention to the parameters protocol in PET/CT scans to ensure minimum effective doses to each age. The physical phantom proved be effective to validation of computational scenarios, despite limitations in regard to absorbed doses determination in the source region but also in the amount of available sources (only one). / A tomografia por emissão de pósitrons (PET), associada à tomografia computadorizada (CT), é uma técnica diagnóstica da medicina nuclear chamada de PET/CT. É possível estimar coeficientes de conversão para dose absorvida em PET/CT por meio de simulações computacionais realizadas com o método de Monte Carlo. A proposta principal deste trabalho foi, utilizando o código MCNPX, estudar as doses absorvidas em órgãos internos de pacientes em decorrência de exames de PET/CT. Para isso, foram empregados simuladores antropomórficos computacionais com representação dos órgãos e estruturas internas realistas de pacientes adultos e pediátricos incorporados em cenários de radiação de dois equipamentos PET/CT, modelos Discovery VCT (GE) e Biograph (Siemens). Foram considerados seis diferentes tipos de radionuclídeos emissores de pósitrons. Variações morfológicas devido ao efeito gravitacional foram também levados em conta para os simuladores adultos. O segundo objetivo foi construir um objeto simulador físico para validação dosimétrica dos cenários de irradiação com a técnica de luminescência opticamente estimulada. Foram determinados experimentalmente modelos de colimação e filtração dos feixes, implementados posteriormente no código MCNPX. Utilizando a grandeza índice de dose em tomografia computadorizada os cenários das irradiações foram validados para o feixe de CT. As doses efetivas estimadas nos simuladores computacionais antropomórficos adultos devido à CT são responsáveis por 14,2% e 26,3% nos equipamentos GE e Siemens, respectivamente. Devido ao 18F-FDG, os coeficientes de dose para dose absorvida apresentaram um acréscimo de 30% em relação aos valores da ICRP 106. Em crianças, as doses efetivas devido ao CT aumentaram em até 23,6%, comparadas a resultados da literatura. Considerando-se o 18F-FDG, os resultados mostraram variações de 0,1%, 8,2% e 5.2% para simuladores de 1, 5 e 10 anos, respectivamente, comparados aos valores da ICRP 106. Para as crianças há necessidade de atenção especial nos protocolos em exames de PET/CT, a fim de garantir valores mínimos de dose efetivas para cada idade. O objeto simulador físico construído mostrou-se eficaz na validação dos cenários computacionais, apesar de limitações no que refere à determinação das doses absorvidas na região fonte, como também na quantidade de regiões fontes disponíveis (apenas uma).

Malignant melanoma (MM) is the deadliest skin cancer with an ever-increasing incidence. New treatments have improved the prognosis for patients with advanced MM. Still, most patients do not respond, and the side effects can be severe, underlining the need for better therapies. The overall aim of this thesis was to evaluate new means to improve the treatment for patients with advanced MM. Immunostimulatory gene therapy (AdCD40L) was evaluated in a clinical study and BRAF-inhibitory treatment in rare cases of BRAF-mutated MM. Due to its immunogenicity, MM is an attractive target for immunostimulatory gene therapy. AdCD40L is an adenovirus carrying the human gene for CD40 ligand, which in different ways can stimulate the immune system to combat cancer. We conducted a Phase I/IIa study with AdCD40L in patients with metastatic MM having received established treatments. In cohort 1 (n=6), four weekly, intratumoural AdCD40L injections were given. In cohort 2 (n=9), low dose cyclophosphamide was added to increase the immune response. Since irradiation may act synergistically with immunotherapy, patients in cohort 3 (n=9) also received a single fraction of radiotherapy (8 Gy). This fraction was given towards the lesion selected for injections. The primary objectives were to assess the feasibility and safety of AdCD40L-treatment and secondarily its anti-tumour effects. Patients were thoroughly assessed for toxicity. The anti-tumour response was evaluated by imaging techniques (FDG-PET/CT, DW-MRI scans), tumour biopsies and blood tests. Plasma protein markers were measured with a multiplex platform. Another objective was to evaluate the potential of DW-MRI and FDG-PET/CT for prediction of AdCD40L treatment response, in terms of overall survival (OS). AdCD40L was well tolerated with mild transient reactions. Local and distant responses in PET/CT scans along with a significantly better 6-month survival in the cohorts that received cyclophosphamide conditioning were observed. Effector lymphocyte responses were elicited. All patients had an increased T effector/T regulatory-cell ratio and death receptors were significantly up-regulated post therapy. Inflammatory cytokines and other plasma proteins were altered in favourable ways by the AdCD40L treatment. The analyses support that the functional DWI parameters may be better early predictors of OS than the established metabolic and morphologic criteria of FDG-PET/CT and CT/MRI, respectively. In conclusion, the stimulation of the CD40 pathway to initiate anti-tumour immunity is a promising treatment alternative for MM patients. However, further studies with developed treatment schemes are warranted. In the first report ever on treatment of a pregnant patient with a BRAF-inhibitor, the therapy was initiated in the second trimester. The treatment with vemurafenib enabled prolonged gestation, hence reducing the risk of immaturity-related complications. Further, we report the first case worldwide of a patient with metastatic conjunctival melanoma who benefitted from treatment with vemurafenib. Additional studies are needed to assess the efficacy of BRAF -inhibitors in the different subtypes of ocular melanoma.

Respiratory motion during PET acquisition degrades image quality. It is mainly the area around the thorax and abdomen which is affected. External devices do provide respiratory gating solutions but are time-consuming to set up on patients and may not always be available. A data-driven gating (DDG) method based on principal component analysis (PCA) was found to provide a reliable respiratory gating signal, discriminating the need for external gating systems with FDG, but it remains to be investigated how well it performs with other PET tracers. The HER2-targeting radiotracer 68Ga-ABY-025 is currently in phase 3 development and is aimed to develop methods to select breast cancer patients that benefit from HER2-targeted treatment. Hence, absolute quantification is important. Respiratory motion correction will be important for improved quantitative accuracy since many patients have metastases in the lower part of the lungs or the liver.  DDG was applied to PET/CT list mode data retrospectively using quiescent period gating. Gated images were then compared to reconstructions without gating with a matched number of coincidences. Two iterative reconstructions were evaluated, TOF OSEM (3 iterations, 16 subsets, and a 5 mm gaussian postprocessing filter) and TOF BSREM β 400. Images were evaluated for standardized uptake value (SUV) changes for well-defined lesions in thorax and abdomen where respiratory motion is prevalent. Respiratory motion was detected in a mean 2.1 bed positions per examination. DDG application resulted in a mean increase of 12.7% in SUVmax for TOF OSEM reconstruction (p=0.0156).

A 28-year-old female patient with active and difficult-to-treat systemic lupus erythematosus (SLE) was diagnosed with liver-dominant diffused large B-cell lymphoma. Repeated response 18F-FDG-PET studies showed persistently high, and, despite intensified immunochemotherapy, further increasing metabolic activity of one of the hepatic lymphoma residuals, whereas all other initial lymphoma manifestations had achieved complete metabolic remission. As biopsy of the 18F-FDG-PET-positive liver residual turned out to be inconclusive, complete resection was performed. Subsequent histopathological examination, however, revealed only necrotic tissue. Thus, no further lymphoma treatment was scheduled. The patient undergoes regular surveillance and is disease-free 13 months after resection. Similarly, treatment of SLE is no longer required due to lack of activity already after the first two cycles of lymphoma treatment. The case shows how closely SLE and diffused large B-cell lymphoma can be connected and stresses the importance of interdisciplinary treatment approaches. In the future, artificial intelligence may help to further classify 18F-FDG-PET-positive lymphoma residuals. This could lead to an increase of the positive predictive value of interim- and end-of-treatment 18F-FDG-PET. The patient’s point of view enables another instructive perspective on the course of treatment, which often remains hidden to treating physicians due to lack of time in clinical routine.

Prostate cancer (PCa) is the most common non-skin malignancy of men in developed countries. In spite of treatment with curative intent up to 30-40% of patients have disease recurrence after treatment, resulting from any combination of lymphatic, hematogenous, or contiguous local spread. The concept of early detection of PCa offer benefits in terms of reduced mortality, but at the cost of over-diagnosis and overtreatment of indolent disease. This is largely due to the random nature of conventional biopsies, with a risk of missing significant cancer and randomly hitting indolent disease. In the present thesis, diagnostic performance of MRI DWI and 11C Acetate PET/CT lymph node staging of intermediate and high risk PCa, was investigated, and additionally, predictive factors of regional lymph node metastases were evaluated. Further, additional value of targeted biopsies to conventional biopsies, for detection of clinically significant PCa, was investigated. In paper one and two, 53 and 40 patients with predominantly high risk PCa underwent 11C Acetate PET/CT and 3T MRI DWI, respectively, for lymph node staging, before extended pelvic lymph node dissection (ePLND). The sensitivity and specificity for PET/CT was 38% and 96% respectively. The sensitivity and specificity for MRI DWI was 55% and 90% respectively. In paper three, 53 patients with newly diagnosed PCa were included. All patients underwent multi-parametric MRI, followed by two cognitive targeted biopsies. Five more clinically significant cancers were detected by adding targeted biopsies to conventional biopsies. In paper four the value of quantitative and qualitative MRI DWI and 11C Acetate PET/CT parameters, alone and in combination, in predicting regional lymph node metastases were examined. ADCmean in lymph nodes and T-stage on MRI were independent predictors of lymph node metastases in multiple logistic regression analysis. In conclusion the specificity of diffusion weighted MRI and 11C Acetate PET/CT for lymph node staging was high, although the sensitivity was low. Predictive factors of regional lymph node metastases could be retrieved from diffusion weighted MRI and 11C Acetate PET/CT. By combining targeted biopsies with conventional biopsies the detection rate of clinically significant PCa could be increased.

Le facteur pronostic majeur des cancers du col localement avancés (LACC) est le statut ganglionnaire lombo-aortique. Notre travail de thèse a été d'évaluer la lymphadénectomie lombo-aortique (qui représente la technique de référence pour obtenir cette information) à l'ère de la tomographie par émission de positron (TEP) et de la chirurgie par une seule incision (LESS). Les résultats publiés de cette thèse sont: la lymphadénectomie lombo-aortique extrapéritonéale par LESS est faisable. Nous en avons décrit et codifié la technique pour la première fois par une incision iliaque gauche unique ; cette technique que nous avons mise au point est sure, reproductible et équivalente sur le plan carcinologique et ergonomique à la laparoscopie conventionnelle ; la lymphadénectomie lombo-aortique de staging est indispensable dans les LACC compte tenu du taux de faux négatif du TEP-TDM retrouvé dans ce travail de thèse (12% s'élevant à 22 % en cas de fixations ganglionnaires pelviennes suspectes). Nous avons également démontré sur la plus large de la série de littérature que la lymphadénectomie lombo-aortique associée à l'extension des champs d'irradiation en lombo-aortique lors de la radio-chimiothérapie apporte aux patientes présentant des micrométastases une survie identique à celle des patientes négatives histologiquement au niveau lombo-aortique. En revanche, en cas d'atteinte macrométastatique le pronostic demeure péjoratif et nécessite de proposer d'autres options thérapeutiques / In locally advanced cervical cancer (LACC) the most important predictor of disease recurrence is para-aortic nodal status. The aim of our thesis was to evaluate the role of para-aortic lymphadenectomy (the current gold standard to assess para-aortic nodal status) in the era of positron emission tomography (PET) and single incision surgery (LESS). The published results of this thesis are: extraperitoneal para-aortic lymphadenectomy by LESS is feasible and we have described and codified the technique for the first time by a single left iliac incision; the technique we have developed is safe, reproducible and oncologically and ergonomically equivalent to conventional laparoscopy; para-aortic LAD staging is essential in LACC given the false negative rate of PET-CT found in this work (12% increasing to 22% if PET-CT reveals suspicious pelvic lymph nodes). We have also demonstrated, in the largest case series published to date, that para-aortic lymphadenectomy followed by chemoradiation including the pelvis and para-aortic lymph nodes for patients with micrometastatic para-aortic nodal involvement provides an overall survival that is identical to the overall survival of LACC with histologically negative para-aortic lymph nodes. However, in case of macrometastatic disease prognosis remains pejorative and requires other treatment options