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.

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.

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

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18128号 / 医博第3848号 / 新制||医||1001(附属図書館) / 30986 / 京都大学大学院医学研究科医学専攻 / (主査)教授 福山 秀直, 教授 戸井 雅和, 教授 平岡 眞寛 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DGAM

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第12945号 / 論医博第2097号 / 新制||医||1010(附属図書館) / 32204 / (主査)教授 髙橋 良輔, 教授 富樫 かおり, 教授 髙橋 淳 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

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 / 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 / Doctor of Medical Science / Kyoto University / DFAM

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]

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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.

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