Dissertations / Theses on the topic 'Coefficient de Diffusion Apparent (ADC)'

Nous avons développé un système de diagnostic assisté par ordinateur (CAD) basé sur des régions d'intérêt pour caractériser le cancer de la prostate avec un grade de l'International Society of Urological Pathology (ISUP) ≥2 lors d'une IRM multiparamétrique (IRM-mp). Les paramètres de l'image provenant de 2 jeux de données multi-constructeurs de 265 IRM pré-prostatectomie et 112 IRM pré-biopsie ont été combinés en utilisant la régression logistique. Les meilleurs modèles contenaient le 2e percentile d’ADC (ADC2) et le taux de rehaussement normalisé (WI) dans la zone périphérique (ZP) et le 25e percentile d'ADC (ADC25) dans la zone de transition (ZT). Ils ont été associés dans le système CAD. Le CAD a été évalué rétrospectivement sur 2 jeux de données multi-constructeurs contenant respectivement 158 et 105 IRM pré-biopsie de notre institution (test interne) et d'une autre institution (test externe). Deux radiologues ont indépendamment décrit les lésions ciblées par la biopsie. Le score PI-RADSv2 (Prostate Imaging-Reporting and Data System version 2) attribué prospectivement lors de la biopsie et le score CAD ont été comparés aux résultats de la biopsie. A l’échelle des patients, les aires sous la courbe Receiver Operating Characteristic (AUC) du score PI-RADSv2 étaient de 82% (IC 95% : 74-87) et 85% (IC 95% : 79-91) dans les jeux de données de test interne et externe respectivement. Pour les deux radiologues, le score CAD avait des AUC similaires dans les jeux de données interne (82%, IC 95% : 76-89, p=1 ; 84%, IC 95% : 78-91, p=1) et externe (82%, IC 95% : 76-89, p=0.82 ; 86%, IC 95% : 79-93, p=1). La combinaison du PI-RADSv2 et du CAD aurait pu éviter 41 à 52% des biopsies tout en manquant 6 à 10% des cancers ISUP≥2. Le système CAD a confirmé sa robustesse dans une étude multicentrique impliquant 22 scanners et des protocoles d'imagerie très hétérogènes. Dans l'analyse par patient, le CAD et le PI-RADSv2 avaient des performances similaires en termes d’AUC (76%, IC 95% : 70-82 contre 79%, IC 95% : 73-86 ; p=0.34) et de sensibilité (86%, IC 95% : 76-96 contre 89%, IC 95% : 79-98 pour le PI-RADSv2≥4). La spécificité du CAD (62%, IC 95% : 53-70 contre 49% ; IC 95% : 39-59 pour le PI-RADSv2≥4) permettait une complémentarité avec le score PI-RADSv2 pour potentiellement éviter 50% des biopsies, tout en manquant 13% des cancers ISUP≥2. Ces résultats étaient similaires à ceux rapportés dans les cohortes de test issues d’un unique centre et ont ouvert la voie à de nouvelles applications du CAD. Le CAD a d’abord permis une bonne discrimination des cancers ISUP≥2 chez des patients placés en surveillance active. Son AUC (80% ; IC 95% : 74-86) était similaire à celle du score PI-RADSv2 attribué prospectivement par des uro-radiologues spécialisés (81%, IC 95% : 74-87 ; p=0.96). Le CAD était plus spécifique que les scores PI-RADS≥3 (p<0.001) et PI-RADS≥4 (p<0.001). Il pourrait offrir une solution pour sélectionner les patients pouvant éviter sans risque une biopsie de confirmation ou de suivi dans le cadre de leur surveillance active (25%). Il manquerait alors 5% des cancers ISUP≥2. Le CAD a enfin été confronté aux IRM-mp pré-prostatectomie de 56 patients japonais, issus d’une population qui est géographiquement éloignée de sa population d’entraînement et qui intéresse de par ses faibles taux d’incidence et de mortalité du cancer de la prostate. Son AUC était alors similaire au score PI-RADSv2 attribué par un radiologue expérimenté dans la ZP (80%, IC 95% : 71-90 contre 80%, IC 95% : 71-89 ; p=0.886) et dans la ZT (79%, IC 95% : 66-90 contre 93%, 95%CI : 82-96 ; p=0.051). Ces résultats prometteurs et robustes sur des jeux de données hétérogènes suggèrent que le CAD pourrait être utilisée dans la routine clinique quotidienne comme un second lecteur pour aider à sélectionner les patients pouvant éviter la biopsie en toute sécurité. Ce CAD pourrait aider les lecteurs moins expérimentés à caractériser les lésions de la prostate
We developed a region of interest-based (ROIs) computer-aided diagnosis system (CAD) to characterize International Society of Urological Pathology grade (ISUP) ≥2 prostate cancers at multiparametric MRI (mp-MRI). Image parameters from two multi-vendor datasets of 265 pre-prostatectomy and 112 pre-biopsy MRIs were combined using logistic regression. The best models used the ADC 2nd percentile (ADC2) and normalized wash-in rate (WI) in the peripheral zone (PZ) and the ADC 25th percentile (ADC25) in the transition zone (TZ). They were combined in the CAD system. The CAD was retrospectively assessed on two multi-vendor datasets containing respectively 158 and 105 pre-biopsy MRIs from our institution (internal test dataset) and another institution (external test dataset). Two radiologists independently outlined lesions targeted at biopsy. The Prostate Imaging-Reporting and Data System version 2 (PI-RADSv2) score prospectively assigned at biopsy and the CAD score were compared to biopsy findings. At patient level, the areas under the Receiver Operating Characteristic curve (AUC) of the PI-RADSv2 score were 82% (95% CI: 74-87) and 85% (95% CI: 79-91) in the internal and external test datasets respectively. For both radiologists, the CAD score had similar AUC results in the internal (82%, 95% CI: 76-89, p=1; 84%, 95% CI: 78-91, p=1) and external (82%, 95% CI: 76-89, p=0.82; 86%, 95% CI: 79-93, p=1) test datasets. Combining PI-RADSv2 and CAD findings could have avoided 41-52% of biopsies while missing 6-10% of ISUP≥2 cancers. The CAD system confirmed its robustness showing good discrimination of ISUP ≥2 cancers in a multicentric study involving 22 different scanners with highly heterogeneous image protocols. In per patient analysis, the CAD and the PI-RADSv2 had similar AUC values (76%, 95% CI: 70-82 vs 79%, 95% CI: 73-86; p=0.34) and sensitivities (86%, 95% CI: 76-96 vs 89%, 95% CI: 79-98 for PI-RADSv2 ≥4). The specificity of the CAD (62%, 95% CI: 53-70 vs 49%, 95% CI: 39-59 for PI-RADSv2 ≥4) could be used to complement the PI-RADSv2 score and potentially avoid 50% of biopsies, while missing 13% of ISUP ≥2 cancers. These findings were very similar to those reported in the single center test cohorts. Given its robustness, the CAD could then be exploited in more specific applications. The CAD first provided good discrimination of ISUP ≥2 cancers in patients under Active Surveillance. Its AUC (80%, 95% CI: 74-86) was similar to that of the PI-RADS score prospectively assigned by specialized uro-radiologists at the time of biopsy (81%, 95% CI: 74-87; p=0.96). After dichotomization, the CAD was more specific than the PI-RADS ≥3 (p<0.001) and the PI-RADS ≥4 scores (p<0.001). It could offer a solution to select patients who could safely avoid confirmatory or follow-up biopsy during Active Surveillance (25%), while missing 5% of ISUP≥2 cancers. Finally, the CAD was tested with the pre-prostatectomy mp-MRIs of 56 Japanese patients, from a population which is geographically distant from its training population and which is of interest because of its low prostate cancer incidence and mortality. The CAD obtained an AUC similar to the PI-RADSv2 score assigned by an experience radiologist in the PZ (80%, 95% CI: 71-90 vs 80%, 95% CI: 71-89; p=0.886) and in the TZ (79%, 95% CI: 66-90 vs 93%, 95%CI: 82-96; p=0.051). These promising and robust results across heterogeneous datasets suggest that the CAD could be used in clinical routine as a second opinion reader to help select the patients who could safely avoid biopsy. This CAD may assist less experience readers in the characterization of prostate lesions

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Abstract: Today, the incidence of prostate cancer is considered high, however, unlike other malignant tumours, there is an expressive number of cases in which prostate cancer does not progress to clinical disease. The management of patients with prostate cancer should be individually fitted due to the broad behaviour spectrum of this cancer, ranging from low grade tumours with low aggressive biological characteristics to high grade tumours with metastatic capacity. The possibility of predicting the future behavior of the disease allows the selection of the most appropriate conduct for each case. Studies have shown that mpMRI (multiparametric Magnetic Resonance Imaging) has a high negative predictive value for clinically significant prostate cancer, indicating that its application as a screening method and as assessment method of disease progression is promising. To standardize the protocols and reports of prostate mpMRI, the PI-RADS v2 (Prostate Imaging Reporting and Data System version 2) was launched in 2015. Multiparametric Magnetic Resonance Imaging standardized by PI-RADSv2 has been taking a prominent place in the management of prostate cancer, but the specificity and positive predictive value still need to be improved. Purpose: To assess whether the ADC (Apparent diffusion coefficient) value and tumour ADC ratio associated with PI-RADS v2 may increase accuracy in predicting clinically significant prostate cancer. Materials and methods: 91 individuals with suspected prostate cancer were retrospectively studied through mpMRI imaging standardized by PI-RADS v2, obtaining the ADC value from the tumour and the contralateral tissue. The findings were correlated to anatomopathological study (biopsy, prostatectomy or transurethral resection). Results: Accuracy, sensitivity, specificity, positive predictive value and negative predictive value for the consensus between the two reviewers using PI-RADS v2, category 3 associated with categories 4 and 5 for the detection of clinically significant cancer were 70.3%, 97.4%, 50.9%, 58.7% and 96.4% (p <0.001), respectively. The association of the ADC value (<0.795x10-3) to categories 3, 4 and 5 of the PI-RADSv2, in turn, demonstrated accuracy, specificity and positive predictive value of 78.9%, 84.9% and 76.5%; and the association with the tumour ADC ratio (<0.62) presented 77.5%, 86.5% and 77.4% of accuracy, specificity and positive predictive value, respectively. Conclusion: The association of the ADC value and the tumour ADC ratio to the PI-RADS v2 in mpMRI increases the accuracy, specificity and positive predictive value in the detection of aggressive prostate cancer, and may help in the screening of individuals who would undergo invasive procedures and radical therapy, or conservative management, as active surveillance or watchful waiting.
Introdu??o: ? considerada alta a incid?ncia de c?ncer de pr?stata na atualidade, contudo, diferentemente de outras neoplasias, existe um n?mero expressivo de casos em que o c?ncer de pr?stata n?o evolui para a doen?a cl?nica. Por este motivo, o manejo dos pacientes com neoplasia prost?tica deve ser moldado individualmente face ao amplo espectro que varia desde tumores de baixo grau, com caracter?sticas biol?gicas de baixa agressividade, a tumores de alto grau, com capacidade metast?tica. A possibilidade de prever o comportamento futuro da doen?a permite a sele??o da conduta mais adequada para cada caso. Estudos vem comprovando que a Resson?ncia Magn?tica multiparam?trica (RMmp) apresenta um alto valor preditivo negativo para o c?ncer de pr?stata com signific?ncia cl?nica, indicando que sua aplica??o como m?todo de triagem e na avalia??o da progress?o da doen?a ? promissora. Para padronizar os protocolos e os relat?rios da RMmp da pr?stata foi lan?ado em 2015 o PI-RADS v2 (?Prostate Imaging Reporting and Data System? vers?o 2). A RMmp padronizada pelo PI-RADS v2 vem assumindo um lugar de destaque no manejo do c?ncer de pr?stata, contudo, ainda s?o considerados baixos a Especificidade e o Valor Preditivo Positivo. Objetivos: Avaliar se o valor de ADC (?Apparent diffusion coefficient? = Coeficiente de Difus?o Aparente) e a raz?o tumoral do ADC associados ao PI-RADS v2 podem aumentar a acur?cia da RMmp na predi??o do c?ncer de pr?stata com signific?ncia clinica. Materiais e m?todos: Foram estudados retrospectivamente 91 indiv?duos com suspeita de c?ncer de pr?stata, submetidos a RMmp padronizada pelo PI-RADS v2, obtendo-se o ADC quantitativo da les?o e do tecido contralateral. Os achados foram correlacionados ao estudo anatomopatol?gico (bi?psia, prostatectomia ou ressec??o transuretral). Resultados: A acur?cia, sensibilidade, especificidade, valor preditivo positivo e valor preditivo negativo para o consenso entre os dois avaliadores utilizando a RMmp padronizada pelo PI-RADS v2, com a categoria 3 associada as categorias 4 e 5 para a detec??o do c?ncer com signific?ncia cl?nica foram 70,3%; 97,4%; 50,9%; 58,7% e 96,4% (p<0,001), respectivamente. A associa??o do valor do ADC (<0,795x10-3) ?s categorias 3, 4 e 5 do PI-RADS v2, por sua vez, demonstrou acur?cia, especificidade e valor preditivo positivo de 78,9%; 84,9% e 76,5%; e a associa??o com a raz?o tumoral do ADC (< 0,62), apresentou 77,5%; 86,5% e 77,4% de acur?cia, especificidade e valor preditivo positivo, respectivamente. Conclus?o: A associa??o do valor do ADC e da raz?o tumoral do ADC ao PI-RADS v2 na RMmp aumenta a acur?cia, especificidade e valor preditivo positivo na detec??o do c?ncer agressivo da pr?stata, podendo auxiliar na triagem dos indiv?duos e na decis?o entre a conduta agressiva, com procedimentos invasivos e terapia radical, ou a conduta conservadora, com vigil?ncia ativa ou observa??o.

Radiological imaging already has a key role in the detection and management of patients with metastatic colorectal cancer (mCRC). With the evolution of personalised medicine there is a need for non-invasive imaging biomarkers that can detect early tumour response to targeted therapies. Translation from bench to bedside requires a multicentre approach that follows an agreed development roadmap to ensure that the proposed biomarker is precise (reproducible/ repeatable) and accurate in its characterisation of a meaningful physiological, pathological or post treatment response. The following thesis (organized in the alternative format with experimental studies written as individual complete manuscripts) investigates methods to improve precision and accuracy of the Apparent Diffusion Coefficient (ADC), a proposed quantitative imaging biomarker with a potential role in characterisation of post treatment responses in mCRC. The first objective was to establish baseline multicentre reproducibility (n=20) for ADC. A change in ADC greater than 21.1% was required to determine a post treatment response. Using a statistical error model, the dominating factors that influenced reproducibility were motion artefact and tumour volume. In the second study these factors were addressed using a single centre cohort with pre and post treatment data. Correcting for errors due to motion and tumour volume improved sensitivity from 30.3% to 1.7%, so a post treatment response was detected in 6/12 tumours compared to 0/12 using the baseline approach. In the third study, motion correction was implemented and the statistical error model was applied successfully to a multicentre cohort of 15 patients (1.9% sensitivity). The results of this thesis highlights that with careful consideration and correction of factors that negatively influence sensitivity, ADC is a potential imaging biomarker for use in post treatment response for patients with mCRC.

Cancer is one of the major causes of worldwide mortality. Imaging plays a vital role in the staging, follow-up, and evaluation of therapeutic response in cancer patients. Whole-body (WB) magnetic resonance imaging (MRI), as a non-ionizing imaging technique, is a promising procedure to assess tumor spreading in a single examination. New MRI technological developments now enable the application of diffusion-weighted imaging (DWI) of the entire body. DWI reflects the random motion of water molecules and provides functional information of body tissues. DWI can be quantified with the use of the apparent diffusion coefficient (ADC). The aim of this dissertation was to demonstrate the value of WB MRI including DWI in cancer patients. WB MRI including DWI, 18F-NaF PET/CT, and bone scintigraphy was performed on 49 patients with newly diagnosed, high-risk prostate cancer, for the purpose of detecting bone metastases. WB DWI showed higher specificity, but lower sensitivity compared to 18F-NaF PET/CT. In addition, WB MRI including DWI, and CT of the chest and abdomen was performed in 23 patients with malignant melanoma. We concluded that WB MRI could not completely supplant CT for the staging of malignant melanoma, especially with respect to the detection of lesions in the chest region. In this study, WB MRI and DWI were able to detect more bone lesions compared to CT, and showed several lesions outside the CT field of view, reinforcing the advantage of whole-body examination. WB MRI, including DWI, was performed in 71 patients with testicular cancer. This modality demonstrated its feasibility for use in the follow-up of such patients. WB MRI, including DWI, and 18F-FDG PET-CT, were carried out in 50 patients with malignant lymphoma. Both these imaging modalities proved to be promising approaches for predicting clinical outcomes and discriminating between different subtypes of lymphomas. In conclusion, WB MRI, including DWI, is an evolving technique that is continuing to undergo technical refinement. Standardization of image acquisition and analysis will be invaluable, allowing for more accurate comparison between studies, and widespread application of this technique in clinical practice. Both WB MRI, including DWI and PET/CT, have their particular strengths and weaknesses in the evaluation of metastatic disease. DWI and PET/CT are different functional techniques, so that combinations of these techniques may provide complementary and more comprehensive information of tumor tissue.

Ce travail de thèse consiste en l’étude de la prédiction du handicap à l’aide de la séquence IRM pondérée en diffusion (DWI). Dans un premier temps, nous nous sommes intéressés à la prédiction du volume final de l’infarctus grâce à un algorithme d’analyse d’images basé sur le traitement de la cartographie du coefficient apparent de diffusion (ADC) sur 216 patients (<6H). La croissance prédite et réelle de l’infarctus étaient significativement corrélées (0,478, p<0,0001). La méthode distinguait les « infarctus stables » des « infarctus en évolution » avec une sensibilité de 77 % et une spécificité de 80 %. La relation croissance prédite - croissance réelle était modifiée par la recanalisation artérielle et la glycémie, deux facteurs connus pour influer sur le devenir de la pénombre. Dans un deuxième temps, nous avons cherché à prédire directement le handicap des patients (n=79) à 3 mois en combinant les valeurs d’ADC dans les 6 premières heures (H6) et le lendemain (J1) à une information de localisation anatomique (les structures motrices). Les valeurs d’ADC étaient significativement plus basses chez les patients dépendants (score de Rankin 3-5) dans le faisceau cortico-spinal (FCS) et le putamen à H6 et à J1 ainsi que dans le cortex moteur primaire. A l’échelle individuelle, le putamen à H6 et le FCS à J1 étaient les régions qui permettaient la meilleure classification des patients selon le pronostic (74% et 75% de précision respectivement). Ce travail souligne le rôle des voies de substance blanche par rapport au cortex dans le pronostic et l’importance de la localisation de la lésion comme facteur essentiel dans la prédiction du handicap des AIC carotidiens.

This is a non-final version of an article published in final form in International Journal of Gynecological Cancer. Final publication is available at http://journals.lww.com/ijgc/Pages/default.aspx
Kyoto University (京都大学)
0048
新制・課程博士
博士(医学)
甲第19557号
医博第4064号
新制||医||1013(附属図書館)
32593
京都大学大学院医学研究科医学専攻
(主査)教授 武藤 学, 教授 平岡 眞寛, 教授 古川 壽亮
学位規則第4条第1項該当

Nous présentons une nouvelle approche à la prédiction de la croissance finale de l'infarctus ischémique humaine en phase aiguë basée sur l'analyse de l'imagerie de résonance magnétique du coefficient apparent diffusion (ADC) en phase aiguë. Les cartographies d'ADC sont susceptibles d'indiquer des régions du cerveau appartenant à la pénombre ischémique, c'est-à-dire, des zones à risque qui pourraient être affectées par l'infarctus à très court terme. Dans ce contexte d'urgence absolue, l'imagerie IRM a pris une place considérable dans la décision thérapeutique de thrombolyse éventuelle. Cette dernière présente des risques hémorragiques secondaires importants et ne peut donc être administrée que chez les patientss dont l'infractus est susceptible de croître et d'atteindre des régions fonctionnelles cruciales. Nous avons donc développé dans ce travail de thèse des techniques d'analyse d'images automatiques en IRM de diffusion. La méthodologie sous-jacente repose sur un modèle de croissance de région qui va segmenter les régions cérébrables exposée à l'infarctus. Une étude rétrospective sur 77 patients a montré que la technique proposée possédait des performances supérieures à celles des techniques alternatives actuellement étudiées
We introduce a new approach to the prediction of the final infarct growth in human acute ischemic stroke based on image analysis of the Apparent Diffusion Coefficient (ADC) MR maps acquired in the acute stage. The ADC maps are likely to reveal brain regions belonging to the ischemic penumbra, that is, areas that will certainly may be affected by the infarction in the following next few hours. In a context where “time is brain”, and contrarily to the much explored – though still-debated – perfusion-diffusion mismatch approach, the ADC MR sequences are fast to acquire and do not necessitate injection of a contrast agent. Image analysis consists of the segmentation of the ischemic penumbra using a fast 3D region-growing infarct approach. Retrospective evaluation on 77 patients has shown that our methodlology is superior to the alternative techniques with much less practical constraints to the clinical environment

Recent progress in magnetic resonance imaging (MRI) has opened the way for micron-scale resolution, and thus for imaging biological cells. In this thesis work, we performed magnetic resonance microscopy (MRM) on the nervous system of Aplysia californica, a model particularly suited due to its simplicity and to its very large neuronal cell bodies, in the aim of studying cellular-scale processes with various MR contrasts. Experiments were performed on a 17.2 Tesla horizontal magnet, at resolutions down to 25 µm isotropic. Initial work consisted in conceiving and building radiofrequency microcoils adapted to the size of single neurons and ganglia. The first major part of the project consisted in using the manganese ion (Mn2+) as neural tract tracer in the buccal ganglia of Aplysia. Manganese is an MR contrast agent that enters neurons via voltage-gated calcium channels. We performed the mapping of axonal projections from motor neurons into the peripheral nerves of the buccal ganglia. We also confirmed the existence of active Mn2+ transport inside the neural network upon activation with the neurotransmitter dopamine. In the second major part of the project, we tested the potential of two diffusion MRI sequences for microscopy. On the one hand, we explored a very original mechanism for diffusion weighting, DESIRE (Diffusion Enhancement of SIgnal and REsolution), particularly suited for small samples. The two-dimensional DESIRE sequence was implemented and successfully tested on phantoms. The measured enhancement was consistent with theoretical predictions. Using this sequence to produce diffusion weighted images with an unprecedented contrast in biological tissue remains a challenge. On the other hand, a more "standard" sequence was implemented to measure the apparent diffusion coefficient (ADC) in nervous tissue with MRM. This sequence was a three-dimensional DP-FISP (Diffusion Prepared Fast Imaging with Steady-state free Precession), which met criteria for high resolution in a short acquisition time, with minimal artifacts. Using this sequence, we studied the changes in water ADC at different scales in the nervous system, triggered by cellular challenges. The challenges were hypotonic shock or exposure to ouabain. ADC measurements were performed on single isolated neuronal bodies and on ganglia tissue, before and after challenge. Both types of stress produced an ADC increase inside the cell and an ADC decrease at tissue level. The results favor the hypothesis that the increase in membrane surface area associated with cell swelling is responsible for the decrease of water ADC in tissue, typically measured in ischemia or other conditions associated with cell swelling.

Magnetinio rezonanso tomografija (MRT) yra optimalus diagnostikos metodas vertinant gimdos kaklelio vėžio išplitimą. Pasaulyje pastaraisiais metais atlikta nedaug mokslinių tyrimų, kuriuose vertinamas gimdos kaklelio vėžys difuzinės MRT metodu. Daugumoje jų dalyvavo nedidelis tiriamųjų skaičius. Šis klinikinis tyrimas yra pirmasis Lietuvoje, kuriuo vertinamas gimdos kaklelio vėžys minėtu metodu, todėl jis turi nemažą mokslinę vertę optimizuojant MRT panaudojimo galimybes gimdos kaklelio vėžio diagnostikoje. Darbo tikslas – nustatyti konvencinės ir difuzinės MRT reikšmę vertinant gimdos kaklelio vėžio išplitimą ir chemospindulinio gydymo efektyvumą. Darbo uždaviniai: 1. Įvertinti konvencinės MRT metodu nustatytų gimdos kaklelio vėžio prognozės veiksnių tarpusavio ryšį su klinikinio ir histologinio tyrimų duomenimis. 2. Apskaičiuoti konvencinės MRT diagnostinės vertės parametrus gimdos kaklelio piktybiniam augliui ir liekamajam po chemospindulinio gydymo naviko audiniui. 3. Palyginti tariamojo difuzijos koeficiento (ADC) skaitinės reikšmės vidurkį sveikame gimdos kaklelyje, vėžio pažeistame ir po chemospindulinio gydymo. Nustatyti gimdos kaklelio vėžiui būdingą ADC skaitinės reikšmės ribą. Įvertinti ADC skaitinės reikšmės tarpusavio ryšį su įvairiais klinikinio ir histologinio tyrimų duomenimis. 4. Apskaičiuoti konvencinės ir difuzinės MRT derinio diagnostinės vertės parametrus gimdos kaklelio piktybiniam augliui ir liekamajam po chemospindulinio gydymo naviko audiniui.
Magnetic resonance imaging (MRI) is the optimal method for evaluation of spread of cervical cancer. Only a few diffusion–weighted (DW) MRI studies in the field of cervical cancer have been accomplished around the world. Most of them included a small number of subjects. This is the first clinical study in Lithuania that assesses the cervical cancer by DW–MRI and it has the scientific value in optimizing the use of MRI potential in the evaluation of the diagnostics and treatment efficiency of the mentioned illness. The aim – to identify the significance of conventional and DW–MRI in the assessment of the outspread of cervical cancer and of the efficiency of chemoradiation therapy. The objectives: 1. To assess the interrelationship of prognostic factors of cervical cancer detected by conventional MRI with clinical and histological findings. 2. To calculate the diagnostic value parameters of conventional MRI for the malignant cervical tumor and for the residual tumor tissue after chemoradiation therapy. 3. To compare the mean value of apparent diffusion coefficient (ADC) in a healthy, cancer affected cervix and the cervix after chemoradiation therapy. To identify the value range of ADC typical for cervical cancer. To evaluate the correlation of ADC with the various clinical and histological findings. 4. To calculate the diagnostic value parameters of conventional and DW–MRI combination for the malignant cervical tumor and for the residual tumor tissue after chemoradiation therapy... [to full text]

La spectroscopie par résonance magnétique nucléaire (RMN) est un outil puissant permettant d’acquérir des profils biochimiques du cerveau et de quantifier de nombreux paramètres cellulaires in vivo. Au cours de ce travail de thèse, nous nous sommes intéressés à trois techniques : (i) la spectroscopie RMN du 1H pondérée en diffusion, (ii) la spectroscopie RMN du carbone-13 (13C) et (iii) de l’oxygène-17 (17O) pour étudier la microstructure et la fonction cellulaire in vivo.Les métabolites cérébraux sont des traceurs endogènes spécifiques d’un type cellulaire (neurones et astrocytes) dont la diffusion dépend des nombreuses propriétés cellulaires (par exemple la viscosité du cytosol et la restriction intracellulaire). L’étude de la dépendance du coefficient de diffusion (ADC) aux temps de diffusion (td) permet de quantifier chacun de ces paramètres. En particulier, la mesure de l’ADC aux td longs permet d’évaluer la compartimentation des métabolites. Dans une première étude, nous avons mesuré l’ADC de plusieurs métabolites neuronaux et astrocytaires sur une large gamme de td (de ~80 ms à ~1 s) dans un large voxel dans le cerveau du macaque. Aucune dépendance de l’ADC de l’ensemble des métabolites au td n’a été observée suggérant que les métabolites diffusent majoritairement dans les prolongements neuronaux (axones, dendrites) et astrocytaires et ne sont pas confinés dans le corps cellulaire ou les organelles (mitochondries, noyau). La grande taille du voxel, liée à la sensibilité de détection limitée, ne nous a pas permis d’étudier la compartimentation des métabolites dans la substance blanche (SB) et la substance grise (SG). C’est pourquoi, une nouvelle étude a été réalisée dans le cerveau de l’Homme. Les résultats montrent que les métabolites diffusent dans des structures fibrillaires dans la SG et la SB. Enfin, une dernière étude, avec une gamme de td jusqu’à 2 s chez le macaque, nous a permis d’estimer, à l’aide de modèles analytiques simples mimant la structure cellulaire, la longueur des fibres neuronales (~110 μm) et astrocytaires (~70 μm). L’oxydation du glucose au sein des mitochondries permet de produire l’ATP (adénosine triphosphate), la principale source d’énergie de l’organisme. La spectroscopie du 13C permet de mesurer la vitesse de dégradation du glucose dans le cycle de Krebs (VTCA). Cette méthode est largement reconnue pour l’étude du métabolisme. Néanmoins, de nombreuses limitations, en termes de modélisation des données en détection indirecte ou de puissance émise dans le contexte du découplage hétéronucléaire en détection directe, ont été rencontrées sur notre scanner IRM. C’est pourquoi, la spectroscopie du 17O a ensuite été développée afin de quantifier la vitesse de consommation de l’oxygène pendant la phosphorylation oxydative (CMRO2). Des développements méthodologiques et technologiques ont été nécessaires et sont encore en cours pour mettre en place et valider cette technique qui n’a encore jamais été utilisée chez le macaque
Magnetic Resonance Spectroscopy is a unique tool that allows acquiring brain biochemical profiles and quantifying many cellular parameters in vivo. During this thesis, three different techniques have been developed: (i) 1H diffusion-weighted, (ii) carbone-13 (13C) and (iii) oxygen-17 (17O) NMR spectroscopy to study brain structure and function in vivo. Brain metabolites are cell-specific endogeneous tracers of the intracellular space whose translational diffusion depends on many cellular properties (e.g.: cytosol vicosity and intracellular restriction). Studying the variation of the diffusion coefficient (ADC) as a function of diffusion time (td) allows untangling and quantifying those parameters. In particular, measuring metabolites ADC at long diffusion times gives information about the metabolites compartmentation in cells. In a first study, we measured neuronal and astrocytic metabolites ADC over a large time window (from ~80 ms to ~1 s) in a large voxel in the macaque brain. No dependence of all metabolites ADC on td was observed suggesting that metabolites primarily diffuse in neuronal (dendrites and axons) and astrocytic processes and are not confined inside the cell body and organelles (nucleus, mitochondria). The large size of the voxel, due to low detection sensitivity, did not allow us to study metabolites compartmentation in pure white (WM) and grey matters (GM). Therefore, we performed a new study in the human brain. Results showed that in both WM and GM metabolites diffuse in fiber-like cell structure. Finally, using an even larger time window (up to 2 s) in the macaque brain and analytical models mimicking the cell structure, we estimated the length of neuronal (~110 μm) and astrocytic (~70 μm) processes. ATP (adenosine triphosphate), the main source of energy in the organism, is produced thanks to glucose oxidation inside the mitochondria. 13C NMR spectroscopy is a well-known technique to study brain energy metabolism and can be used to estimate the rate of glucose degradation within the Krebs cycle (VTCA). However, many limitations, concerning data modeling when performing indirect detection or power deposition due to heteronuclear decoupling during direct detection, were encountered on our MRI scanner. Therefore, 17O NMR spectroscopy was developed to quantify the rate of oxygen consumption during oxidative phosphorylation (CMRO2). Methodological and technological developments were necessary and are still ongoing to validate this technique, which has never been used with macaque

ANATOMICAL AND FUNCTIONAL STUDY OF THE PENUMBRA REGION IN AN IN VITRO MODEL OF FOCAL CEREBRAL ISCHEMIA Experimental data have shown that the ischemic brain region is characterized by a highly damaged core surrounded by a rim of reversibly altered tissue, commonly referred to as the ischemic penumbra. The core region is characterized by a severely compromised CBF, whereas in the penumbra CBF is reduced but cellular metabolism is still preserved (Hossmann, 2008). One possible approach to identify core and penumbra is based on the evaluation of both metabolism and perfusion of the cerebral tissue. In principle, MRI could be utilized to solve this issue. Still, the significance of the MRI changes observed in the early phase of focal cerebral ischemia is a matter of discussion (Neumann-Hafelin et al., 2000; Kidwell et al., 2003; Rivers et al., 2006). Understanding the functional and structural correlates of MRI findings will help to characterize the pathological status of brain tissue that continuously change during the early few hours that follow an ischemic stroke. The model of the isolated brain facilitates these objectives because permits to induce a highly reproducible infarction by the simple ligation of the MCA and allows to perform multiple fine electrophysiological recordings before, during and after occlusion. In the guinea pig the medial cerebral artery (MCA) supplies the entire piriform cortex (PC), the Olfactory Tubercle (OT) is perfused, also, by collaterals of the anterior cerebral artery, especially in its medial part. This vascular condition puts the lateral Olfactory Tubercle (l-OT) as an area of watershed between the ischemic core and the normally perfused tissue. We analyzed and correlated neurophysiological, morphological and MRI changes induced by transient (30-60 minutes) and permanent occlusion of the medial cerebral artery (MCAo) in the isolated guinea pig brain. Multi-site extracellular recordings demonstrated prolonged ischemic depolarizations (ID) and the abolition of evoked responses in the piriform cortex served by MCA, but not in the olfactory tubercle, supplied by the anterior cerebral artery. Here evoked responses were transiently reduced and brief peri-infarctual depolarizations (PID) could be observed during the transient MCA occlusion. Diffusion weighted images performed on brains fixed 4 hours after transient ischemia and immunostaining for a microtubule-associated protein, MAP-2, showed overlapping changes due to acute brain injury, restricted to the piriform cortex. Our compared analysis of neurophysiological, MR and anatomical data demonstrate that DW-MRI sequences underestimate the extension of brain tissue damage induced by focal ischemia and do not include the area of PIDs generation, namely the penumbra region Hence the penumbra is a region that maintains the capability to be excited. Hypothetically the ionic imbalance successive to the ischemic condition may prelude to a seizure that is frequent consequence of a stroke. In a consecutive study we verified whether anoxic ischemia per se, without intracranial hemorrhagic complication and in the absence of blood-borne elements responsible for brain infarction, is able to induce early changes in excitability that may prelude to the generation of seizures, and, ultimately could prime epileptogenesis. We used the multimodal approach herein described to identify the penumbra region in the very acute post-ischemic phase. To evaluate the effect of ischemia on cortical excitability we focused on ventral cortical structures (PC and OT) that have been extensively analyzed in this preparation (Biella & de Curtis, 1995; Carriero et al., 2009). The major input to these olfactory-limbic regions is carried by the lateral olfactory tract (LOT) that originates from neurons in the olfactory bulb (Haberly & Price, 1978). LOT is supplied by the medial cerebral artery (MCA). Since we aimed at evaluating synaptic excitability changes that occur acutely after ischemia, we needed to preserve the LOT as source of stimulation to evoke field responses in the olfactory cortex. Therefore, we chose to perform permanent bilateral occlusion of the anterior cerebral arteries (ACAo). We recorded, in olfactory cortices, slow potentials and evoked responses using specific patterns of stimulation in order to evaluate excitability changes in the acute phase after ischemia. The ACAo induces a core area located in the shell of nucleus accumbens and a region of penumbra in the underlying olfactory cortices, where characteristic slow potential shifts (i.e PIDs), but no reduction of diffusion tensor MR signal and MAP-2 immunostaining (typical of ischemic core) were observed. Recording of responses evoked by low- and high-frequency stimulations of the lateral olfactory tract showed no excitability changes in the early hours that follow ischemia in the olfactory cortical areas supplied by ACA. The absence of early hyperexcitability changes in an isolated whole brain model of ischemia, strongly suggests that brain anoxia per se does not contribute to the generation of early seizures. These findings support the view that blood-borne events (such as hemorrhage and inflammation) may play a major role in early post-ischemic seizures.

La pomme (Malus Domestica Borkh.), fruit largement répandu dans les pays tempérés est beaucoup consommée. Elle représente une source importante en composés phénoliques. Cette étude s’est intéressée aux polyphénols des tissus du parenchyme. La problématique s’oriente sur les effets de la texture sur la diffusion de ces molécules. L’originalité de l’approche repose sur l’association de la texture, de la pression osmotique et la diffusion des polyphénols. Les méthodes de caractérisations physiques et biochimiques ont permis de mesurer les changements à l´échelle macroscopique et les modifications chimiques qui s’opèrent dans les matrices végétales. Les résultats de l’étude du transfert de matière ont permis de mettre en évidence les différents facteurs pouvant influer sur les valeurs des coefficients de diffusion. La texture, l’épaisseur, la variété du fruit et la pression du milieu diffusant, constituent des facteurs pouvant influencer le transfert de matière. L’étude de l’évolution de composant de la paroi a montré des changements qui s’opèrent au cours de la diffusion. Des analyses microscopiques ont relevé les modifications à l’échelle cellulaire de la diffusion de procyanidines, polyphénols majoritaires et des interactions avec les composants pariétaux
Apple (Malus domestica Borkh. ) fruit widespread in temperate countries, is much consumed.It represents an important source of phenolic compounds. This study was interestedin polyphenol content of apple tissue parenchyma. The problem concerns effects of texturedegradation on the diffusion of polyphenols molecules. The originality of the approach isbased on the combination of texture, osmotic pressure and polyphenol leaching. Physicaland biochemical methods were used to measure changes at macroscopic scale and chemicalchanges occurring in the parenchymateous tissue . The study of mass transfer highlightedvarious factors that may affect apparent coefficient diffusion. The result showed that thedisintegration of texture , thickness, apple variety and osmotic pressure of leaching mediacan influence mass transfer yield. The study of the Cell walls components showed changesthat occur during leaching process. Light microscopic analysis revealed changes at cellularscale, procyanidins the major polyphenols, leaching phenomena and also interactionswith cell walls matrix

Toward the objective to create or to replace impaired tissues, it is essential to establish a culture process allowing tissue growth in vitro . The Petri dish culture or the traditional 2D culture has only a limited potential, mainly caused by a poor oxygen mass transfer to feed larger tissue constructs. In this project, an autonomous and complete bioprocess has been built to fullfill these needs. The developed reactor is versatile because many cell culture chamber designs can be connected to it. Two proportional-integral algorithms (PI) can control the dissolved oxygen concentration and the pH. The pressure, the temperature and mass flow rate are recorded in real time. An actuator allows mimicking the cardiac output flow. In this mémoire , it will be demonstrated how the reactor has been optimized to reduce the risk of bioburden. Also, the procedures to develop the control tools of the PI algorithm will be detailed. To characterize the reactor, a RTD study will be presented. To characterize the cell culture chamber, a permeability analysis using fluorescent microscopy and magnetic resonance imaging (MRI) will be exposed. Finally, two cell culture chamber designs to orient microvessel formation have been tested and these results will be presented.

As imagens de ressonância magnética (RM) ponderadas em Difusão são conhecidas como uma técnica funcional capaz de refletir alterações estruturais e celulares de neoplasias. No câncer de mama, a difusão e sua quantificação através dos valores do coeficiente de difusão aparente (CDA) têm sido utilizados para avaliar resposta tumoral após quimioterapia neoadjuvante (QTN). Os variados desfechos clínicos do câncer de mama, incluindo as diferentes respostas ao tratamento quimioterápico podem estar relacionados à heterogeneidade da doença. A presença das células tronco tumorais (CTT) é uma das hipóteses aceitas para explicar os diferentes comportamentos biológicos dos tumores. Este estudo buscou avaliar uma possível associação entre os valores de CDA nas neoplasias invasivas da mama e a presença de marcadores de CTT e os principais marcadores prognósticos da doença em pacientes tratadas com QTN. Foram avaliadas prospectiva e consecutivamente as imagens de RM pré-tratamento de 27 pacientes com câncer da mama que realizaram QTN seguida de cirurgia. Os valores de CDA média, p10, p25 e p50 foram obtidos através de duas mensurações, uma com único ROI e outra com múltiplos ROIs envolvendo toda extensão tumoral. Esses valores de CDA foram correlacionados: à quantificação por citometria de fluxo de CTT com fenótipos ESA+/CD44+/CD24-, células ESA+ com alta atividade ALDH1 e células ESA+/ABCG2+, à capacidade de formação de mamoesferas, e aos principais fatores prognósticos do câncer de mama, incluindo estágio clínico, doença axilar linfonodal, grau tumoral, receptores de estrógeno (RE), receptores de progesterona (RP) e superexpressão do HER2. Também foi realizada correlação dos valores de CDA com a resposta patológica completa após QTN. A presença de CTT, a capacidade de formação de mamoesferas e a resposta patológica completa não se correlacionaram aos valores de CDA. Para ambas as medidas e todos os parâmetros avaliados de CDA (x10-3mm2/s), os valores foram significantemente menores nos tumores com estágio clínico III e IV vs II (0,90±0,16; 1,02±0,18); com doença linfonodal após QTN vs axila livre (0,89±0,16; 1,01±0,17); RE+ vs RE- (0,90±0,16; 1,00±0,18); RP+ vs RP- (0,91±0,16; 0,98±0,18) e HER2+ vs HER2- (0,92±0,17;0,97±0,18). Tumores grau 1 apresentaram CDA com valores significativamente maiores em relação aos tumores grau 2 (diferença 0,18; CI: 0,03-0,33, p=0,02). Os valores de CDA dos tumores de mama pré-QTN não predizem a presença de CTT, a capacidade de formação de mamoesferas ou a resposta patológica completa, porém se correlacionam com o estágio clínico da doença, doença linfonodal axilar após QTN, grau tumoral e expressão das proteínas RE, RP e HER2, sendo um promissor marcador de agressividade tumoral
The diffusion-weighted magnetic resonance imaging (DWMRI) is a functional technique able to reflect structural and cellular changes in the tumors. In the breast cancer, the diffusion-weighted images and its numeric value known as the apparent diffusion coefficient (ADC) has been applied to evaluate pathologic response in patients treated with neoadjuvant chemotherapy (NC). The difference in the clinical results after breast cancer treatment, including different rates of responses to the NC has been associated to the heterogeneity of the disease. The presence of the breast cancer stem cells (BCSC) is an accepted hypothesis to explain the different biologic breast cancers behaviors. The aim of this study was to correlate the ADC value of invasive breast cancer with the presence of cancer stem cells markers and the major prognostic factors in patients treated with neoadjuvant chemotherapy. Prospectively, the MRI pre-treatment of twenty-seven consecutive patients with invasive breast cancer posteriorly treated with NC followed by surgery were evaluated. The ADC values mean, 10th percentile, 25th percentile, 50th percentile were obtained from two measurements, one of them with a unique ROI and the other with multiple ROIs encompassing the entire lesion. The ADC values were correlated to: presence of BCSCs (cell surface markers CD44+/CD24-, ABCG2 and ALDH1) identified by flow cytometric analysis, tumor grade, breast cancer staging, lymph nodal involvement, expression of estrogen receptors (ER), expression of progesterone receptors (PR) and expression of HER2. The assay mammospheres (Mammocult ®) were analyzed in 18 samples. Additionally, the ADC values were correlated to the pathologic complete response after QN treatment. There were no correlations between ADC values and breast cancer stem cells markers or mammospheres formation efficiency. For all parameters calculated, the ADC values (x10- 3 mm 2 /s) were lower in: breast cancer stage III and IV than stage II (0,90±0,16; 1,02±0,18), tumors with lymph node metastasis than without lymph node metastasis (0,89±0,16; 1,01±0,17), ER expression than ER negative (0,90±0,16; 1,00±0,18), PR expression than PR 10 negative (0,91±0,16; 0,98±0,18) and HER2 expression than HER2 negative (0,92±0,17; 0,97±0,18). The ADC values were significantly higher in grade-1 tumors (difference 0,18; CI: 0,03-0,33) compared to grade-2 tumors (p=0,02). The tumors values of ADC pretreatment were not correlated to the pathologic complete response after NC. The ADC values in pre-treatment invasive breast cancers are not a predictor of BCSC presence, mammospheres formation efficiency or pathologic complete response to QN. However it is correlated to the tumor grade, breast cancer staging, lymph nodal involvement, expression of ER, PR and HER2 and may represent a promising marker of tumor aggressiveness

Hiperplasia congênita de suprarrenal (CAH) compreende um grupo de transtornos hereditários decorrentes de erros inatos do metabolismo dos esteróides adrenais. O aumento das dimensões das glândulas suprarrenais é um marco morfológico na CAH que pode ser avaliado por métodos de imagem com signifitiva correlação com o controle hormonal dos pacientes. Porém, técnicas de imagem que forneçam informações qualitativas e quantitativas relativas à citoarquitetura das glândulas ainda não foram estabelecidas neste contexto. A difusão por ressonância magnética (DWI) é uma técnica que pode fornecer informações quantitativas dos tecidos através do valor do coeficiente de difusão aparente (ADC). O papel do ADC na avaliação de lesões tumorais adrenais já foi estudado, no entanto, o valor do ADC das glândulas suprarrenais normais ainda não foi descrito. O objetivo geral desta tese foi investigar a utilidade dos métodos de imagem na avaliação da CAH. Os objetivos específicos foram apresentar uma revisão dos métodos por imagem já estabelecidos para avaliação da CAH, validar o cálculo do ADC da glândula suprarrenal e avaliar se o ADC e as dimensões das glândulas suprarrenais poderiam auxiliar no manejo de pacientes com CAH, correlacionando-os com controle hormonal. Esta tese é baseada em artigos, nos quais estão mostrados a metodologia, resultados e discussões relativos a cada uma das etapas. O primeiro artigo, The role of imaging in congenital adrenal hyperplasia, trata de uma revisão sistemática de imagem em CAH, com ênfase em genitografia, ultrassonografia, tomografia computadorizada e ressonância magnética (MRI). O segundo artigo, Apparent Diffusion Coefficient (ADC) of the normal adrenal glands: premilinary results, teve como principal objetivo validar o método de medida do ADC das glândulas suprarrenais. No terceiro artigo, Quantitative magnetic resonance imaging in the evaluation of adrenal glands in children and young adults with congenital adrenal hyperplasia due to 21-hydroxylase deficiency, foram estudados os parâmetros quantitativos por MRI (ADC, volume e medidas lineares) das glândulas suprarrenais que poderiam estar relacionados ao controle hormonal dos pacientes com CAH. Medir o ADC das suprarrenais normais é factível e reprodutível. Em indivíduos saudáveis após a adrenarca o ADC é significativamente menor. Todavia, o ADC não foi capaz de diferenciar indivíduos controles de pacientes com CAH, assim como não apresentou correlação com o status hormonal dos pacientes. O volume e as medidas lineares das glândulas adrenais foram os melhores parâmetros quantitativos por MRI para diferenciar pacientes de indivíduos controles, com correlação positiva com o status hormonal recente dos pacientes com CAH. As dimensões das glândulas suprarrenais avaliadas por MRI podem ser utilizadas como ferramenta auxiliar no acompanhamento dos pacientes e mostrar rapidamente os efeitos da exposição a altos níveis de hormônio adrenocorticotrópico. Apesar de ocorrerem modificações celulares na CAH e de ter sido mostrado neste estudo que em pacientes sem doença hormonal conhecida o ADC é mais baixo após a adrenarca, estas alterações celulares que ocorrem na CAH não foram detectadas pelas medidas de ADC.
Congenital adrenal hyperplasia (CAH) is an autossomic recessive disorder caused by impaired steroidogenesis. A morphological hallmark in CAH is enlarged adrenal glands. Imaging studies have addressed mainly morphological aspects and dimensions of the adrenal glands, which correlate to the patients hormonal statuses. However, no imaging technique was used to evaluate changes in the adrenal glands at a cellular level in these patients. Diffusion-weighted magnetic resonance imaging (DWI) is a magnetic resonance imaging (MRI) technique with the ability to provide quantitative information about intracellular and extracellular space, given by the apparent diffusion coefficient (ADC) values. The role of ADC in evaluation of adrenal lesions has already been studied. However, ADC of the normal adrenals has not yet been described. The main purposes of this study were: to investigate the role of imaging in CAH, to validate the method of calculating ADC values of the normal adrenal glands and to assess hormonal status in patients with CAH and its correlation to quantitative MRI. This is an article-based thesis divided in three articles. The first article, The role of imaging in congenital adrenal hyperplasia, is a systematic review of imaging in congenital adrenal hyperplasia, with emphasis on genitography, ultrasonography, computed tomography and MRI. The article Apparent diffusion coefficient (ADC) of the normal adrenal glands: premilinary results aimed to validate the method of measuring ADC of the adrenal glands. The study of quantitative parameters (ADC, volume and linear measurements) of the adrenals evaluated by MRI that correlate with hormonal status in patients with CAH is described in the third article, Quantitative magnetic resonance imaging in evaluation of the adrenal glands in children and young adults with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Measuring ADC of the normal adrenal glands is feasible and reproducible. In healthy subjects, ADC values were significantly lower after adrenarche. However, neither a difference between ADC values of controls and patients, nor correlations with patients hormonal statuses were found. Volume and linear measurements of the adrenal glands were the best parameter to differentiate patients from controls. Moreover, a positive correlation was found between short-term hormonal control status and adrenal size. Adrenal size assessed by MRI might be a useful tool in the follow-up of patients with CAH. Although adrenal cell structure modifications in patients with CAH have been described, they were not detectable by DWI.

This thesis is aimed at further understanding the uppermost lipid-filled membranous layer (i.e. surface amorphous layer (SAL)) of articular cartilage and to develop a scientific framework for re-introducing lipids onto the surface of lipid-depleted articular cartilage (i.e. "resurfacing"). The outcome will potentially contribute to knowledge that will facilitate the repair of the articular surface of cartilage where degradation is limited to the loss of the lipids of the SAL only. The surface amorphous layer is of utmost importance to the effective load-spreading, lubrication, and semipermeability (which controls its fluid management, nutrient transport and waste removal) of articular cartilage in the mammalian joints. However, because this uppermost layer of cartilage is often in contact during physiological function, it is prone to wear and tear, and thus, is the site for damage initiation that can lead to the early stages of joint condition like osteoarthritis, and related conditions that cause pain and discomfort leading to low quality of life in patients. It is therefore imperative to conduct a study which offers insight into remedying this problem. It is hypothesized that restoration (resurfacing) of the surface amorphous layer can be achieved by re-introducing synthetic surface-active phospholipids (SAPL) into the joint space. This hypothesis was tested in this thesis by exposing cartilage samples whose surface lipids had been depleted to individual and mixtures of synthetic saturated and unsaturated phospholipids. The surfaces of normal, delipidized, and relipidized samples of cartilage were characterized for their structural integrity and functionality using atomic force microscope (AFM), confocal microscope (COFM), Raman spectroscopy, magnetic resonance imaging (MRI) with image processing in the MATLAB® environment and mechanical loading experiments. The results from AFM imaging, confocal microscopy, and Raman spectroscopy revealed a successful deposition of new surface layer on delipidized cartilage when incubated in synthetic phospholipids. The relipidization resulted in a significant improvement in the surface nanostructure of the artificially degraded cartilage, with the complete SAPL mixture providing better outcomes in comparison to those created with the single SAPL components (palmitoyl-oleoyl-phosphatidylcholine, POPC and dipalmitoyl-phosphatidylcholine, DPPC). MRI analysis revealed that the surface created with the complete mixture of synthetic lipids was capable of providing semipermeability to the surface layer of the treated cartilage samples relative to the normal intact surface. Furthermore, deformation energy analysis revealed that the treated samples were capable of delivering the elastic properties required for load bearing and recovery of the tissue relative to the normal intact samples, with this capability closer between the normal and the samples incubated in the complete lipid mixture. In conclusion, this thesis has established that it is possible to deposit/create a potentially viable layer on the surface of cartilage following degradation/lipid loss through incubation in synthetic lipid solutions. However, further studies will be required to advance the ideas developed in this thesis, for the development of synthetic lipid-based injections/drugs for treatment of osteoarthritis and other related joint conditions.

This project considers the diffusion of water molecules through a cellular medium in which the cells are modeled by square compartments placed symmetrically in a square domain. We assume the diffusion process is governed by the 2D diffusion equations and the solution is provided by implementing the Crank-Nicolson scheme. These results are verified and illustrated to agree well with the finite element method using the Comsol Multiphysics package. The model is used to compute the values of the apparent diffusion coefficient, (ADC) which is a measure that is derived from diffusion weighted MRI data and can be used to identify, e.g., regions of ischemia in the brain. With our model, it is possible to examine how the value of the apparent diffusion coefficient is affected whenever the extracellular space is varied. We observe that the average distance that the water molecules travel in a definite time is highly dependent on the geometrical properties of the cellular media.
UOIT

Breast cancer is a major global health problem and the most common form of cancer among women. Major advances in the technologies of imaging provide improved detection and sensitivity with fewer unnecessary biopsies. Commonly used imaging modalities include mammography, ultrasonography, magnetic resonance imaging (MRI), scintimammography, single photon emission computed tomography (SPECT) and positron emission tomography (PET). The current study is focused on breast MRI imaging, especially one of the most promising recent techniques, i.e. the Diffusion Weighted Imaging breast MRI (DWI). DWI is an unenhanced MRI technique, based on volume sequences on various b values (the b value identifies the measurement's sensitivity to diffusion and determines the strength and duration of the diffusion gradients) measuring the mobility of water molecules (Brownian motion) in vivo (in tissues) and provides different and potentially complementary information to Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) technique. As DWI based on the diffusive properties of water molecules, reflects their random motion resulting from thermal agitation. Water diffusion on breast can be quantified by measuring the mean diffusivity, which is the average of Apparent Diffusion Coefficient (ADC). The ADC can be calculated by making measurements at a low b factor, b1, and a higher b factor, b2. DWI allows the mapping of the diffusion process of molecules by the ADC map. ADC maps are calculated by collecting images with at least 2 different values, b1 and b2, of the b factor. The ADC map is a parametric image whose color scale or gray scale represents the ADC values of the voxels and is usually generated by proprietary or in house software. DWI apart from the 3D anatomical information, provides a noninvasive investigation of tissue vascularity, a novel contrast mechanism in MRI and has a high sensitivity in the detection of changes in the local biologic environment due to a pathologic process. Therefore, in addition to contrast enhancement-based characterization (DCE-MRI), measurement of the motion of water molecules in DWI provides an additional feature for lesion characterization that may further increase the specificity of MRI for classifying breast lesions. The diagnostic task that the current study deals with, accounts for the diagnosis of mass-like lesions in Diffusion Weighed Magnetic Resonance Imaging, based on low ADC values compared to high once in case of benign versus normal tissue. The hypothesis is that diffusivity of water molecules is restricted in environments of high cellularity, intracellular and extracellular edema, high viscosity, and fibrosis, such as malignant tumors, because these conditions become barriers to the movement of water molecules. Therefore, most of breast cancers show low ADC values compared with benign and normal tissue. Many studies have revealed the usefulness of ADC values in the differential diagnosis of breast lesions; however, the clinical effect remains limited because of the substantial overlap between benign and malignant lesions, which presents challenges for implementing a useful diagnostic ADC threshold. The majority of studies, similar to the current study, determined optimal cutoff levels of the ADC value between malignant and benign lesions by using ROC analysis, and ranged from 0.90 to 1.76 × 10-3 mm2/s while the sensitivity and specificity ranged from 63% to 100% and 46% to 97%, respectively. In addition, the methods for measuring ADC differ among reported studies, with the most representative method being the mean value of ADC (mean ± standard deviation) over a Region Of Interest representative of the breast lesion. The purpose of this study was to investigate the ability of histogram characteristics of Apparent Diffusion Coefficient (Apparent Diffusion Coefficient-ADC) to differentiate malignant from benign breast lesions in breast DWI. To this end the ADC maps of representative lesion ROIs were subjected to first order statistics analysis by calculating five first order textural features: Mean value, Standard Deviation, Kurtosis, Skewness and Entropy. This approach is intended to offer a more complete assessment of tumor texture and heterogeneity. The dataset analyzed is comprised of 92 histologically verified breast lesions, originating from 69 women with mammographically and/or ultrasonographically detected or palpable findings. Histology revealed 53 malignant lesions originating from 45 women and 39 benign lesions originating from 26 women. All of the breast MR examinations were performed with a 3T MR scanner, for b= 0, 900 s/mm2. Diagnostic performances of these parameters were compared by receiver operating characteristic (ROC) curve analysis. The mean of ADC of benign lesions [(1.470 ± 0.342) × 10-3 mm2/s] was found to be significantly higher than that of malignant tumours, [(0.965 ± 0.268) × 10-3 mm2/s, (p<0.00001)]. The standard deviation of ADC of benign lesions [(0.184 ± 0.999) × 10-3 mm2/s] was not significantly different from that of malignant tumours, [(0.192 ± 0.151) × 10-3 mm2/s, (p=0.6581)]. The skewness of ADC of benign [-0.303 ± 0.584] was significantly different than that of malignant tumours, 0.210 ± 0.725. (p = 0.0008)]. The kurtosis of ADC of benign [3.003 ± 1.065] was not significantly different from that of malignant tumours, [3.337 ± 1.334. (p=0.0987)]. The entropy of ADC of benign [4.794 ± 0.665] was significantly lower than that of malignant tumours, [5.569 ± 0.649, (p<0.00001)] The corresponding area under the empirical receiver operating characteristic curve was: 0.862 ± 0.042 (95% confidence interval: 0.754, 0.925) for mean of ADC, 0.705 ± 0.054 (95% confidence interval: 0.589, 0.800) for skeweness of ADC, 0.800 ± 0.046 (95% confidence interval: 0.691, 0.874) for entropy of ADC, resulting a good diagnostic performance of DWI for these parameters. On the other hand, an AUC of 0.527 ± 0.063 (95% confidence interval: 0.393, 0.640) and 0.601 ± 0.061 (95% confidence interval: 0.470, 0.707) for Standard deviation and kurtosis respectively, suggests a degree of overlap in ADC values between benign and malignant tumors. In an effort to identify optimal threshold values for differentiating benign versus malignant lesions these were selected to correspond to the points of highest accuracy of the ROC curves. In our study, we obtained two threshold values of mean ADC, both with an accuracy of 83.15%: 1.21 x 10-3 mm2/s with a sensitivity of 86.27% and specificity of 78.95%; and 1.32 x 10-3 mm2/s with a sensitivity of 92.16% and specificity of 71.05%. The threshold value of skeweness was -0.06 with an accuracy of 68.54%, a sensitivity of 66.03% and specificity of 66.67%. Finally, we found two threshold values of entropy, both with an accuracy of 76.40%: 5.17 with a sensitivity of 75.47% and specificity of 71.80%; and 5.21 with a sensitivity of 73.59% and specificity of 74.36%. In conclusion, results of the current study suggest the contribution of texture analysis methods in Diffusion-weighted MRI breast imaging for the quantification of tissue heterogeneity, providing important information for breast cancer diagnosis. Histogram analysis of ADC values in breast cancer has potential for differentiating benign and malignant tumors, providing information about the entire tumor. The mean, skewness and entropy of ADC are valuable parameters that are correlated with pathologic characterization of breast tumors. These 3 ADC parameters significantly elevated the quantitative diagnostic performance of breast DWI and would be effective parameters in distinguishing between malignant and benign breast lesions. Finally, future efforts will also focus on investigating the correlation of extracted texture features with histopathological findings, in order to verify the potential of the proposed texture analysis of ADC map in providing non-invasive prognostic factors of breast cancer.
Ο καρκίνος του μαστού είναι ένα σημαντικό παγκόσμιο πρόβλημα υγείας και η πιο διαδεδομένη μορφή καρκίνου στον γυναικείο πληθυσμό. Η ολοένα και πιο έγκαιρη διάγνωση του καρκίνου του μαστού έχει οδηγήσει σε σημαντική βελτίωση του ρυθμό θεραπείας της νόσου. Σημαντικές πρόοδοι στην τεχνολογία της απεικόνισης παρέχουν τη βελτιωμένη ανίχνευση και ευαισθησία του καρκίνου και οδηγούν σε όλο ένα και λιγότερες περιττές βιοψίες. Οι πιο συνηθισμένες μέθοδοι απεικόνισης, που χρησιμοποιούνται, περιλαμβάνουν την Μαστογραφία, την Υπερηχογραφία, την Μαγνητική Τομογραφία (MRI), την σπινθηρομαστογραφία, την Τομογραφία Εκπομπής Φωτονίων (SPECT) και την Τομογραφία Εκπομπής Ποζιτρονίων (PET). Η παρούσα μελέτη επικεντρώνεται στην τεχνολογία της Απεικόνισης Μαγνητικού Συντονισμού ειδικά σε μία πρόσφατη και ελπιδοφόρα τεχνική απεικόνισης του καρκίνου του μαστού, που ονομάζεται Απεικόνιση Σταθμισμένης Διάχυσης στη Τομογραφία Πυρηνικού Μαγνητικού Συντονισμού (Diffusion Weighted Imaging breast MRI (DWI)). Η DWI είναι μια MRI ακολουθία χωρίς χρήση σκιαγραφικής ουσίας, η οποία βασίζεται σε αλληλουχίες για διάφορες τιμές του παράγοντα διάχυσης b (η τιμή b προσδιορίζει την διαχυτότητα και καθορίζει την ένταση και τη διάρκεια των βαθμωτών πεδίων διάχυσης). Η DWI ποσοστικοποιεί την κινητικότητα των μορίων του νερού (Brownian κίνηση) in vivo (σε ιστούς) και παρέχει διαφορετικές και ενδεχομένως συμπληρωματικές πληροφορίες στην μαστογραφία μαγνητικής τομογραφίας με χρήση σκιαγραφικού (Dynamic Contrast-Enhanced Magnetic Resonance Imaging: DCE-MRI). Η DWI με βάση τις ιδιότητες διάχυσης των μορίων του νερού, αντανακλά την τυχαία κίνησής τους λόγω της θερμικής τους ενέργειας. Η διάχυση του νερού στον μαστό μπορεί να ποσοτικοποιηθεί με τη μέτρηση της μέσης διαχυτότητας, η οποία αναφέρεται ως Φαινόμενος Συντελεστής Διάχυσης (Apparent Diffusion Coefficient-ΑDC). Ο ADC υπολογίζεται ύστερα από μετρήσεις για δυο b τιμές, μια χαμηλή b1 και μια υψηλότερη b2 τιμή. Η DWI επιτρέπει την χαρτογράφηση της διάχυσης των μορίων του νερού μέσω του ADC χάρτη. Ο ADC χάρτης είναι μια παραμετρική εικόνα της οποίας η κλίμακα χρωμάτων ή κλίμακα των τόνων του γκρι, αντιπροσωπεύει τις ADC τιμές των voxels και συνήθως παράγεται από λογισμικό. Οι παραμετρικοί ADC χάρτες απεικόνισης DWI αναπαριστούν τη μικροδομή των ιστών για διάφορους συνδυασμούς τιμών της παραμέτρου b. Η DWI εκτός από 3D ανατομική πληροφορία, παρέχει μια μη επεμβατική διερεύνηση της αγγειοβρίθειας του ιστού, έναν νέο μηχανισμό αντίθεσης στην MRI, και χαρακτηρίζεται από υψηλή ευαισθησία στην ανίχνευση ενδεχόμενων αλλαγών στο τοπικό βιολογικό περιβάλλον, οι οποίες οφείλονται σε παθολογία. Ως εκ τούτου, εκτός από τον χαρακτηρισμό αλλοιώσεων βάση σκιαγραφικής ενίσχυσης (DCE - MRI), η ποσοτικοποίηση της κίνησης των μορίων του νερού στην DWI παρέχει επιπλέον στοιχεία για τον χαρακτηρισμό της αλλοίωσης, κάτι το οποίο μπορεί να αυξήσει περαιτέρω την ειδικότητα της MRI για την ταξινόμηση των αλλοιώσεων του μαστού. Το διαγνωστικό πρόβλημα το οποίο αντιμετώπισε/εστίασε η παρούσα διπλωματική εργασία, αφορά στο χαρακτηρισμό/διάγνωση χωροκατακτητικών αλλοιώσεων (mass-like) του μαστού στην Απεικονιση Μαγνητικου Συντονισμου Σταθμισμενης Διαχυσης (DWI) και την ποσοτικη αναλυση του Φαινομενου Συντελεστη Διαχυσης (ADC) για διαγνωση καρκινου του μαστου. Η ικανότητα διάχυσης των μορίων του νερού περιορίζεται σε περιβάλλον υψηλής κυτταροβρίθιας, ενδοκυττάριων και εξωκυττάριων οιδημάτων, υψηλού ιξώδους και ίνωσης, όπως συμβαίνει στους κακοήθεις όγκους, διότι οι παράγοντες αυτοί εμποδίζουν την κυκλοφορία των μορίων του νερού. Αποτέλεσμα αυτού είναι οι περισσότεροι καρκίνοι του μαστού να παρουσιάζουν χαμηλές ADC τιμές σε σύγκριση με τους καλοήθεις όγκους ή τον φυσιολογικό ιστό. Πολλές μελέτες έχουν δείξει τη χρησιμότητα των ADC τιμών στη διαφορική διάγνωση των αλλοιώσεων του μαστού. Εν τούτοις, το κλινικό αποτέλεσμα παραμένει περιορισμένο λόγω της σημαντικής επικάλυψης καλοήθων και κακοήθων αλλοιώσεων, γεγονός που αποτελεί πρόκληση για την εφαρμογή ενός χρήσιμου διαγνωστικού ορίου της μέσης ADC. Στη πλειοψηφία των μελετών, όπως και στη παρούσα μελέτη, τα βέλτιστα επίπεδα αποκοπής της ADC μεταξύ κακοήθων και καλοήθων αλλοιώσεων προσδιορίστηκαν με τη χρήση ROC ανάλυσης. Στις μέχρι τώρα μελέτες τα διαγνωστικά όρια της μέσης ADC κυμαίνονται από 0.90 έως 1.76 × 10-3 mm2 / s, με ευαισθησία και ειδικότητα να κυμαίνονται από 63% έως 100% και 46% έως 97%, αντίστοιχα. Γεγονός αποτελεί, επίσης, η διαφορετική μέθοδος υπολογισμού της ADC που ακολουθεί η κάθε μελέτη, με πιο συχνή μέθοδο, ο υπολογισμός της μέσης τιμής της ADC (μέση τιμή ± τυπική απόκλιση) σε μια περιοχή ενδιαφέροντος (ROI) μιας αλλοίωσης του μαστού. Σκοπός της παρούσας μεταπτυχιακής διπλωματικής εργασίας ήταν να διερευνηθεί η ικανότητα των χαρακτηριστικών ιστογράμματος του Φαινόμενου Συντελεστή Διάχυσης (Apparent Diffusion Coefficient-ADC) να διαφοροποιούν κακοήθεις από καλοήθεις αλλοιώσεις του μαστού στην Απεικόνιση Μαγνητικού Συντονισμού Σταθμισμένης Διάχυσης (Diffusion Weighted MRI-DWI). Για το σκοπό αυτό, δημιουργήθηκε ο ADC παραμετρικός χάρτης ο οποίος αποτέλεσε τη βάση για την εφαρμογή μεθόδου ανάλυσης υφής εικόνας, και τον υπολογισμό πέντε χαρακτηριστικών υφής πρώτης τάξης: την μέση τιμή, την τυπική απόκλιση, την κύρτωση, την λοξότητα και την εντροπία. Η προσέγγιση αυτή θεωρήθηκε ότι θα προσφέρει μια πιο ολοκληρωμένη αξιολόγηση της υφής του όγκου και της ετερογένειας. Η προσέγγιση εφαρμόσθηκε σε κλινικό δείγμα 92 ιστολογικά αποδεδειγμένων αλλοιώσεων του μαστού, οι οποίες προέρχονται από 69 γυναίκες οι οποίες είχαν νωρίτερα ανιχνευθεί μέσω μαστογραφίας ή/και υπερηχογραφίας ή από ψηλαφητά ευρήματα. Η ιστολογική εξέταση αποκάλυψε 53 κακοήθεις αλλοιώσεις που προέρχονταν από 45 γυναίκες και 39 καλοήθεις αλλοιώσεις από 26 γυναίκες. Όλες οι εξετάσεις μαγνητικής τομογραφίας του μαστού έγιναν με σύστημα MRI 3T και για b=0 και 900 s/mm2. Η διαγνωστική απόδοση/επίδοση των παραμέτρων αυτών συγκρίθηκε με την ανάλυση λειτουργικού χαρακτηριστικού δέκτη (ROC analysis). Τα αποτελέσματα υποδεικνύουν τον σημαντικό ρόλο της ανάλυσης ADC ιστογράμματος χρησιμοποιώντας τα 5 παραπάνω χαρακτηριστικά υφής για την ταυτοποίηση των αλλοιώσεων του μαστού. Οι μετρήσεις της μέσης τιμής, της λοξότητας και της εντροπία της ADC των καλοήθων και κακοήθων αλλοιώσεων του μαστού είχαν στατιστικώς σημαντική διαφορά. Ειδικότερα, η μέση ADC τιμή των καλοήθων όγκων [(1.470 ± 0.342) × 10-3 mm2/s] ήταν σημαντικά υψηλότερη από εκείνη των κακοήθων, [(0.965 ± 0.268) × 10-3 mm2/s, (ρ < 0.00001)]. Η λοξότητα της ADC των καλοήθων όγκων [-0.303 ± 0.584], διέφερε σημαντικά από εκείνη των κακοήθων, [0.210 ± 0.725. (ρ= 0.0008)]. Και η εντροπία της ADC των καλοήθων όγκων [4.794 ± 0.665], ήταν σημαντικά χαμηλότερη από εκείνη των κακοήθων, [5.569 ± 0.649, (ρ < 0.00001)]. Ωστόσο, η τυπική απόκλιση και η κύρτωση της ADC των καλοήθων και κακοήθων αλλοιώσεων του μαστού δεν είχαν στατιστικώς σημαντική διαφορά. Συγκεκριμένα, η τυπική απόκλιση της ADC των καλοήθων όγκων ήταν [(0.184 ± 0.999) × 10-3 mm2/s] ενώ των κακοήθων ήταν [(0.192 ± 0.151) × 10-3 mm2/s, (ρ = 0.6581)] και η κύρτωση της ADC των καλοήθων όγκων ήταν [3.003 ± 1.065] ενώ των κακοήθων ήταν [3.337 ± 1.334, (ρ = 0.0987)]. Η περιοχή κάτω από την ROC καμπύλη (AUC) για τη μέση ADC τιμή ήταν 0.862 ± 0.042 (95% διάστημα εμπιστοσύνης: 0.754, 0.925), για την λοξότητα της ADC ήταν 0.705 ± 0.054 (95% διάστημα εμπιστοσύνης: 0.589, 0.800) και για η εντροπία της ADC ήταν 0.800 ± 0.046 (95% διάστημα εμπιστοσύνης: 0.691, 0.874), και είχαν ως αποτέλεσμα μια καλή διαγνωστική απόδοση/ επίδοση της DWI για τις παραμέτρους αυτές. Από την άλλη πλευρά, η AUC με 0.527 ± 0.063 (95% διάστημα εμπιστοσύνης: 0.393, 0.640) και με 0.601 ± 0.061 (95% διάστημα εμπιστοσύνης: 0.470, 0.707) για την τυπική απόκλιση και την κύρτωση, αντίστοιχα, υποδηλώνει ένα βαθμό επικάλυψης στις ADC τιμές μεταξύ καλοήθων και κακοήθων όγκων. Τα βέλτιστα κατώφλια αποκοπής για διαφοροποίηση καλοήθων έναντι κακοήθων αλλοιώσεων καθορίστηκαν με τον εντοπισμό των σημείων όπου η ακρίβεια ήταν μέγιστη στις καμπύλες ROC. Από τη συγκεκριμένη μελέτη, προέκυψαν δύο τιμές κατωφλίου αποκοπής της μέσης ADC, με την ίδια ακρίβεια 83.15%. Το πρώτο κατώφλι με τιμή 1.21 x 10-3 mm2/s χαρακτηρίζεται με ευαισθησία 86.27% και ειδικότητα 78.95%. Και το δεύτερο κατώφλι με τιμή 1.32 x 10-3 mm2/s χαρακτηρίζεται με ευαισθησία 92.16% και ειδικότητα 71.05%. Το κατώφλι για την λοξότητα της ADC ήταν στα -0.06 με ακρίβεια 68.54%, ευαισθησία 66.03% και ειδικότητα 66.67%. Τέλος, προέκυψαν δύο τιμές κατωφλίου αποκοπής της εντροπίας της ADC με την ίδια ακρίβεια ακρίβεια 76.40%. Το πρώτο κατώφλι με τιμή 5.17 χαρακτηρίζεται με ευαισθησία 75.47% και ειδικότητα 71.80%. Και το δεύτερο κατώφλι με τιμή 5.21 χαρακτηρίζεται με ευαισθησία 73.59% και ειδικότητα 74.36%. Συμπερασματικά, τα αποτελέσματα της παρούσας μελέτης δείχνουν τη συνεισφορά των μεθόδων ανάλυσης υφής εικόνας στη Απεικονιση Μαγνητικου Συντονισμου Σταθμισμενης Διαχυσης (DWI) του μαστού για την ποσοτικοποίηση της ετερογένειας του ιστού, παρέχοντας σημαντικές πληροφορίες για τη διάγνωση του καρκίνου του μαστού. Η ανάλυση ιστογράμματος των ADC τιμών στον καρκίνο του μαστού έχει τη δυνατότητα διαφοροποίησης καλοήθων και κακοήθων όγκων, παρέχοντας πληροφορίες για το σύνολο του όγκου. Η μέση τιμή, η λοξότητα και η εντροπία του ADC είναι πολύτιμες παράμετροι που συσχετίζονται με παθολογικό χαρακτηρισμό των όγκων του μαστού. Αυτές οι 3 ADC παράμετροι αύξησαν σημαντικά την ποσοτική διαγνωστική απόδοση της DWI του μαστού και πιθανότατα να είναι αποτελεσματικές παράμετροι όσον αφορά τη διάκριση μεταξύ καλοήθων και κακοήθων αλλοιώσεων του μαστού Μελλοντικές προσπάθειες πρόκειται να εστιάσουν στη διερεύνηση της συσχέτισης των εξαχθέντων χαρακτηριστικών υφής με ιστοπαθολογικούς δείκτες, με σκοπό την περαιτέρω επιβεβαίωση των προτεινόμενων προσεγγίσεων και ενδεχομένως την χρήση συγκεκριμένων χαρακτηριστικών υφής ως μη επεμβατικών προγνωστικών δεικτών καρκίνου του μαστού.

碩士
元培醫事科技大學
醫學影像暨放射技術系碩士班
106
Glioma is the most common malignant brain tumor. According to its degree of malignancy, the World Health Organization divided it into four levels, and there are differences in tumor invasion trends between different levels, suggesting different prognosis and treatment options. The histopathology of tumor standard examination generally gave sampling errors. Therefore, magnetic resonance imaging (MRI) has been widely used in brain tumor evaluation in recent years, providing non-invasive and high-resolution brain imaging, assisting clinical identification and classification, and as a therapeutic evaluation and long-term evaluation. The MRI images of patients with gliomas confirmed by pathological section were collected in this retrospective study of Taipei Veterans General Hospital since April 2010 for eight years. These images were obtained using the GE 1.5 T system. Patients were aged 30 to 64 years old and there are 70 cases in total. According to the tumor levels, the patient's apparent diffusion coefficient map (ADC map) and the pre-operative magnetic resonance spectrum (MRS) were combined with gender, age, height, weight, body mass index and body surface area for statistical analysis. Alpha reliability, one way-ANOVA, receiver operating characteristic curve (ROC) and Pearson’s correlation analysis on differential staging showed that the diagnostic benefit of MRS was better than ADC map, and the differential diagnoses were highly or moderately correlated with most of the MRS metabolites and ADC. An ADC map (p < 0.05) with 120% tumor area preoperatively selected was more appropriate determined by multivariate analysis. In addition, the ADC map has excellent tracking benefit in the paired sample t-test. By the way, the ADCs of preoperative/postoperative lesions (p ≦ 0.001, r = 0.23) and preoperative disease/health ratio to postoperative disease/health ratio (p ≦ 0.001, r = 0.45) showed low and medium correlation, respectively. Finally, the ROC test is used to calculate the thresholds and analyze the diagnostic efficacy. It is found that the MRS metabolites ratio are more suitable for disease diagnoses, while the MRS single metabolite concentrations are more suitable for identifying the tumor stage. Overall, MRS has better sensitivity, while ADC has better specificity. These two techniques complement with each other, which can effectively improve the diagnostic value and implement precise treatment goals.

Trabalho final de mestrado integrado em Medicina área científica de Imagiologia, apresentado á Faculdade de Medicina da Universidade de Coimbra
Purpose: To measure apparent diffusion coefficient (ADC) values of liver parenchyma and focal hepatic lesions (FHL), investigate the utility of ADC for the differential diagnosis of hepatic findings, and determine the influence of region of interest (ROI) characteristics in the overall ADC measurements. Materials and Methods: Ninety-three patients (47 men, 46 women; mean age, 58 years) with at least one FHL ≥ 10 mm, or parenchyma abnormalities, were retrospectively evaluated. Reference standard for diagnosis was obtained from histopathologic data, consensus between imaging methods, follow-up imaging and patient clinical history. A total of 90 lesions were evaluated: 14 hepatocellular carcinomas (HCC), 18 metastases, 10 focal nodular hyperplasias (FNH), 4 adenomas, 30 hemangiomas and 14 cysts. Respiratory-Triggered (RT) DWI was performed using b-values of 50 and 700 s/mm2. ADC was measured in hepatic parenchyma by placing ROIs in four different segments, and in FHL by using three circular 1 cm2 ROIs and one ROI encompassing all lesion volume. Data was statistically compared in SPSS software using the Mann-Whitney and Friedman tests. Wilcoxon test was used to confirm ROI influence and receiver operating characteristic (ROC) curve was analyzed to evaluate the utility of ADC for diagnosis of malignancy. P<0.05 was significant. Results: Mean ADCs (×10−3mm2/s) were 1.45, 1.28 and 1.25 for normal, cirrhotic and steatotic liver parenchyma and 1.16, 1.18, 1.30, 1.64, 1.89 and 2.77 for metastases, HCCs, adenomas, FNHs, hemangiomas and cysts, respectively. Parenchyma ADCs in segment II were significantly higher than in any other region. ADCs of malignant lesions were significantly lower than those of benign lesions (p<0.001). Individually, ADCs of Cysts were significantly higher than all other lesions except hemangiomas. There was significant overlap between benign solid lesions and malignant lesions and between HCCs and cirrhotic parenchyma. The area under the curve for diagnosis of malignancy was 0.939, with sensitivity of 89.7% and specificity of 90.6%, using a cutoff ADC of 1.43×10−3 mm2/s. No significant difference was found between the different ROI sampling methods, but only homogeneous lesions were studied. Conclusion: We concluded that (a) quantitative measurements of ADC can be useful in differentiating normal from pathological liver parenchyma and in the characterization of focal hepatic lesions, (b) left hepatic lobe is more subject to cardiac motion artifacts, and (c) the size of ROI does not influence ADC measurements in homogeneous lesions
Objectivo: Medir o coeficiente de difusão aparente (ADC) do parênquima hepático e de lesões hepáticas focais (LHF), investigar a utilidade do ADC no diagnóstico diferencial de lesões hepáticas e determinar a influência das características da região de interesse (ROI) nos valores de coeficiente obtidos. Materiais e Métodos: Noventa e três doentes (47 homens, 46 mulheres; idade média, 58 anos) com pelo menos uma LHF maior ou igual que 10 mm, ou parênquima patológico, foram retrospectivamente avaliados. Confirmação diagnóstica foi obtida por histopatologia, concordância entre métodos de imagem, follow-up e historial do doente. No total, 90 lesões foram avaliadas: 14 carcinomas hepatocelulares (CHC), 18 metástases, 10 hiperplasias nodular focais (HNF), 4 adenomas, 30 hemangiomas e 14 quistos. Foi efectuado estudo ponderado em difusão com trigger respiratório (valores b de 50 e 700 s/mm2). Medições de ADC foram efectuadas no parênquima através de ROIs colocadas em quarto segmentos hepáticos e, nas LHF, através de três ROIs de 1 cm2 e uma ROI englobando toda a lesão. O tratamento estatístico foi efectuado, através do software SPSS, pelos testes Mann-Whitney e Friedman. O teste Wilcoxon foi utilizado para confirmar a influência do ROI e uma curva ROC foi analisada para avaliar o ADC como ferramenta diagnóstica de malignidade. P<0.05 foi considerado significativo. Resultados: ADCs médios (×10−3mm2/s) foram 1.45, 1.28 e 1.25 para parênquima normal, cirrótico e esteatótico, e 1.16, 1.18, 1.30, 1.64, 1.89 e 2.77 para metástases, CHCs, adenomas, HNFs, hemangiomas e quistos, respectivamente. ADCs medidos (×10−3mm2/s) no parênquima do segmento II foram significativamente mais altos do que em qualquer outro segmento. Lesões malignas apresentaram ADCs significativamente mais baixos que lesões benignas (p<0.001). Individualmente, os ADCs de quistos foram significativamente maiores do que os de outras lesões, exceptuando hemangiomas. Verificou-se uma sobreposição significativa entre lesões sólidas benignas e leso+es malignas, e entre CHCs e parênquima cirrótico. A área sobre a curva para diagnóstico de malignidade foi 0.939, com um ADC limiar de 1.43×10−3 mm2/s (sensibilidade de 89.7% e especificidade de 90.6%). Não foi encontrada diferença significativa entre as medições efectuadas com as ROIs de diferentes tamanhos. Conclusão: Concluímos que (a) medições quantitativas de ADC são úteis na distinção entre parênquima normal e patológico e na caracterização de LHF, (b) o lobo hepático esquerdo é mais susceptível a artefactos cardíacos, e (c) o tamanho da ROI não influencia o valor do ADC calculado.

Trabalho final de mestrado integrado em Medicina, apresentado à Faculdade de Medicina da Universidade de Coimbra.
Purpose: To assess the relevance of diffusion-weighted imaging (DWI) in the hepatocellular carcinoma (HCC) detection as a stand-alone procedure or in combination to conventional magnetic resonance imaging (MRI). Methods: Medical records from nineteen patients with pathological confirmation of HCC, who have been submitted to conventional MRI and DWI in a time frame 3 months prior and 3 months after diagnosis, were retrospectively reviewed. For each patient, apparent diffusion coefficient (ADC) values were measured in the HCC lesion, in the liver parenchyma and in the spleen. Tumor ADC and parenchyma ADC, obtained with and without normalization, were compared through paired-samples t-test. Tumor ADC was analyzed according to lobe, size category and acquisition system using the Mann-Whitney test. For sensitivity assessment of DWI and conventional MRI, individually and combined, a contingency table was made. Results: The calculated DWI sensitivity for HCC detection (47.4%) was lower than conventional MRI sensitivity (68.4%). The highest sensitivity was obtained with the combined reading of both techniques (78.9%). A statistically significant difference between tumor ADC and parenchymal ADC was found, both for normalized and non-normalized values, with lower values for the HCC lesions. Comparison of tumor ADC values according to lobe, size and acquisition system did not show a statistically significant difference. Conclusions: For HCC detection in the setting of liver cirrhosis the use of DWI increases tumor detection compared to conventional MR alone and its use is recommended. This result corroborates other literature reports regarding the added value of DWI in HCC diagnosis, irrespective of the magnetic field strength. Due to the small patient sample of the current series further investigation may be warranted.
Objectivo: Determinar a relevância da ressonância magnética ponderada em difusão (DWI) no diagnóstico do carcinoma hepatocelular (CHC) a título individual e enquanto complemento à ressonância magnética (RM) convencional. Métodos: Registos médicos de dezanove pacientes com confirmação anatomopatológica de CHC, que tinham sido submetidos a RM convencional e DWI na faixa temporal 3 meses antes e 3 meses depois do diagnóstico, foram revistos retrospectivamente. Para cada paciente foram medidos os valores do coeficiente de difusão aparente (ADC) na lesão tumoral, no parênquima hepático e no baço. O ADC do tumor e o ADC do parênquima, com e sem normalização, foram comparados através do t-teste para amostras emparelhadas e o ADC do tumor foi analisado de acordo com lobo, categoria dimensional e sistema de aquisição utilizando o teste de Mann-Whitney. Para determinação da sensibilidade da DWI e da RM convencional, individualmente e em conjunto, foi feita uma tabela de contingência. Resultados: A sensibilidade calculada da DWI (47.4%) foi inferior à da RM convencional (68.4%). Contudo, a sensibilidade calculada quando ambos os métodos foram combinados (78.9%) revelou-se superior. Foi encontrada uma diferença estatisticamente significativa entre o ADC do tumor e o ADC do parênquima hepático, tanto para os valores não normalizados como para os normalizados, com valores menores registados para as lesões tumorais. Após comparação dos ADC tumorais de acordo com lobo, categoria dimensional e sistema de aquisição, não foi encontrada uma diferença estatisticamente significativa. Conclusões: Os resultados do nosso estudo estão em concordância com a literatura mais recente que sustenta o valor adicional da DWI no diagnóstico do CHC. No entanto, as limitações que reconhecemos ao presente trabalho sugerem a necessidade de mais investigação nesta área.