Glioblastoma is the most common primary brain tumor in adults, and it is associated with a dismal prognosis with a median survival of 15 months. Despite treatment with chemotherapy, radiation therapy and surgery, patients inevitably have disease recurrence. Bevacizumab is a monoclonal humanized antibody that inhibits vascular endothelial growth factor signaling, and it has been shown to be effective in recurrent glioblastoma with respect to prolonging progression-free survival (PFS). The use of bevacizumab and other anti-angiogenic agents in recurrent glioblastoma have created novel challenges in interpreting magnetic resonance imaging (MRI) of patients. Furthermore, since only some patients appear to have a durable benefit from bevacizumab, there is a need for imaging biomarkers that can reliably identify this subgroup of patients. Partly due to the challenges created by anti-angiogenic agents, the Response Assessment in Neuro-Oncology (RANO) was proposed to address some of the limitations with traditional response assessment criteria. In the first part of this project, we attempted to validate the RANO criteria by performing a comparative analysis of the RANO criteria vs. the Macdonald criteria using imaging from the phase II BRAIN trial. As we hypothesized, the RANO criteria yielded a significantly decreased PFS by identifying a subset of patients who had progression of nonenhancing tumor evident on T2-weighted imaging. Additionally, response and progression as defined by the RANO criteria correlated with subsequent overall survival (OS) in landmark analyses. While this supports the implementation of RANO criteria for response assessment in glioma clinical trials, future research will be necessary to further improve response assessment by incorporating advanced techniques such as volumetric anatomic assessment, perfusion-weighted MR (PWI-MR), diffusion-weighted MR (DWI-MR), MR spectroscopy (MRS) and positron emission tomography (PET). Advanced imaging techniques are becoming increasingly recognized for their ability to provide objective, non-invasive assessment of treatment response but also to serve as predictive and prognostic biomarkers allowing for stratification of patient subgroups with better treatment outcome. In the second part of the project, we attempted to perform volumetric analysis of tumor size based on conventional MRI, as well as a histogram analysis of apparent diffusion coefficients (ADC) derived from diffusion-weighted MRI, to evaluate imaging parameters as predictors for PFS and OS in a single institution database of recurrent glioblastoma patients initiated on bevacizumab. Volumetric percentage change and absolute early post-treatment volume (3-6 weeks after initiation) of enhancing tumor can stratify survival for patients with recurrent glioblastoma receiving bevacizumab therapy. ADC histogram analysis using a multi-component curve-fitting technique within both enhancing and nonenhancing components of tumor prior to the initiation of bevacizumab can also be used to stratify OS in recurrent glioblastoma patients. While prospective studies are necessary to validate findings, future studies will increasingly incorporate multiparametric approaches to elucidate biomarkers that combine the value of conventional MRI with advanced techniques such as DWI-MR, PWI-MR, MRS and PET to obtain better predictors for PFS and OS in recurrent glioblastoma.

Peak demand is an issue in power supply system when demand exceeds the available capacity. Continuous growth in peak demand increases the risk of power failures, and increases the marginal cost of supply. The contribution of the residential sector to the system peak is quite substantial and has been a subject of discussion internationally. For example, a study done in New Zealand in 2007 attributed about half of system peak load to the residential sector. International research has attributed a significant influence of human behaviour on households energy use. “Demand Response” is a demand side management tool aimed at achieving peak energy demand reduction by eliciting behaviour change. It encompasses energy needs analysis, information provision to customers, behaviour induction, smart metering, and new signalling and feedback concepts. Demand response is far advanced in the industrial and commercial demand sectors. In the residential sector, information barriers and a lack of proper understanding of consumers’ behaviour have impeded the development of effective response strategies and new enabling technologies in the sector. To date, efforts to understanding residential sector behaviour for the purpose of peak demand analysis has been based on pricing mechanism. However, not much is known about the significance of other factors in influencing household customers’ peak electricity demand behaviour. There is a tremendous amount of data that can be analyzed and fed back to the user to influence behaviour. These may include information about energy shortages, supply security and environmental concerns during the peak hours. This research is intended to begin the process of understanding the importance of some of these factors in the arena of peak energy consumption behaviour. Using stated preference survey and focus group discussions, information about household customers’ energy use activities during winter morning and evening peak hours was collected. Data about how customers would modify their usage behaviour when they receive enhanced supply constraint information was also collected. The thesis further explores households’ customer demand response motivation with respect to three factors: cost (price), environment (CO2-intensity) and security (risk of black-outs). Householders were first informed about the relationship between these factors and peak demand. Their responses were analyzed as multi-mode motivation to energy use behaviour change. Overall, the findings suggest that, household customers would be willing to reduce their peak electricity demand when they are given clear and enhanced information. In terms of motivation to reduce demand the results show customers response to the security factor to be on par with the price factor. The Environmental factor also produced a strong response; nearly two-thirds of that of price or security. A generic modelling methodology was developed to estimate the impact of households’ activity demand response on the load curve of the utility using a combination of published literature reviews and resources, and own research work. This modelling methodology was applied in a case study in Halswell, a small neighbourhood in Christchurch, New Zealand, with approximately 400 households. The results show that a program to develop the necessary technology and provide credible information and understandable signals about risks and consequences of peak demand could provide up to about 13% voluntary demand reduction during the morning peak hours and 8% during the evening peak hours.

No description available.

Therapeutic response assessment is a key component in adaptive image-guided radiotherapy. Conventional anatomic measures of response offer little information about the spatial distribution of tumor change. Recently developed voxel-wise response assessment methods operating on functional and biological imaging are better capable of evaluating the heterogeneity of response within the tumor, and thus may yield greater sensitivity than conventional approaches. However, voxel-wise analyses are limited by local registration uncertainties inherent to longitudinal imaging of tumors with changing morphology. A multi-resolution local histogram (LH) moment-based measure of voxel similarity was developed for the purpose of assessing the strength of correspondence between voxels of serial tumor images. This measure was first benchmarked through a series of experiments designed to establish robustness to image intensity variation and sensitivity to alterations in tissue structure through application of simulated deformations. The LH similarity method was subsequently developed as a means of mapping the spatial extent of structural change in tumors through the incorporation of an estimate of image complexity. The change maps were applied to a voxel-wise analysis of diffusion-weighted magnetic resonance imaging of patients with glioblastoma, acquired pre- and post-chemoradiotherapy. The sensitivity of the voxel-wise analysis in differentiating responding/stable patients from non-responding/progressing patients was improved by stratifying the analysis voxels according to regions of interest (ROI) based on the LH similarity-based estimate of tumor change. Meaningful correspondence relationships between evaluated voxels are essential for accurate image-based quantification of tumor structure and function with voxel-wise analysis techniques. The LH similarity methods developed here can robustly evaluate the quality of spatial and temporal voxel correspondence relationships and provide an automated tool for ROI selection and voxel change stratification. It is readily extendable to the analysis of the wide array of anatomic, functional and biological imaging currently used to characterize tumors, guide therapy and assess response.

Therapeutic response assessment is a key component in adaptive image-guided radiotherapy. Conventional anatomic measures of response offer little information about the spatial distribution of tumor change. Recently developed voxel-wise response assessment methods operating on functional and biological imaging are better capable of evaluating the heterogeneity of response within the tumor, and thus may yield greater sensitivity than conventional approaches. However, voxel-wise analyses are limited by local registration uncertainties inherent to longitudinal imaging of tumors with changing morphology. A multi-resolution local histogram (LH) moment-based measure of voxel similarity was developed for the purpose of assessing the strength of correspondence between voxels of serial tumor images. This measure was first benchmarked through a series of experiments designed to establish robustness to image intensity variation and sensitivity to alterations in tissue structure through application of simulated deformations. The LH similarity method was subsequently developed as a means of mapping the spatial extent of structural change in tumors through the incorporation of an estimate of image complexity. The change maps were applied to a voxel-wise analysis of diffusion-weighted magnetic resonance imaging of patients with glioblastoma, acquired pre- and post-chemoradiotherapy. The sensitivity of the voxel-wise analysis in differentiating responding/stable patients from non-responding/progressing patients was improved by stratifying the analysis voxels according to regions of interest (ROI) based on the LH similarity-based estimate of tumor change. Meaningful correspondence relationships between evaluated voxels are essential for accurate image-based quantification of tumor structure and function with voxel-wise analysis techniques. The LH similarity methods developed here can robustly evaluate the quality of spatial and temporal voxel correspondence relationships and provide an automated tool for ROI selection and voxel change stratification. It is readily extendable to the analysis of the wide array of anatomic, functional and biological imaging currently used to characterize tumors, guide therapy and assess response.

Background: Drugs targeting angiogenic pathway remain the mainstay of treatment for metastatic renal cell carcinoma (mRCC). Tyrosine Kinase Inhibitors (TKI) as Sunitinib, Pazopanib as single agents and humanised monoclonal antibody bevacizumab (Bev) in combination with Interferon- α2a (IFN) have established as the first-line therapy for mRCC. Despite improvements in treatment, there are multiple questions which remain unanswered. In the combination of Bev and IFN, the respective role of each drug and whether any additional anti-angiogenic activity is gained by adding IFN to Bev remains unknown. As the clinical benefit obtained with these cytostatic agents does not always correlate with the conventional response assessment techniques as RECIST, it is necessary to reconsider the methods by which we assess benefit from these therapies. In this thesis, I report three studies aiming to answer these questions. Methods: With the clinical trial reported here, I explore whether Bev induced changes in vascular parameters measured by Dynamic Contrast Enhanced MRI (DCE-MRI) is significantly enhanced by the addition of IFN. In a phase II, randomised, open labelled, multicentre trial, treatment naïve mRCC patients were randomised to receive Bev on its own or in combination with a low dose (3MU) or standard dose (9MU) IFN. DCE-MRI was used to assess the changes in vascularity with the primary endpoint being, changes in transfer coefficient (Ktrans) after six weeks of treatment. I also report two retrospective imaging-based studies, using contrast-enhanced CT scans, performed to improve the methodology of response assessment for these antiangiogenic therapeutics. Here I explore the use of a) combining changes in size and arterial phase contrast enhancement measured using CT scan and b) changes in CT texture as methods of therapeutic response assessment in mRCC patients treated with TKI. Results: With the phase 2 clinical trial, we faced significant difficulty in recruitment as a result of restrictions in access to treatment in NHS, other competing studies and restrictions proposed by the DCE-MRI inclusion criteria. With slow recruitment, an unplanned analysis was performed after 21 patients were recruited. Analysis of primary endpoint showed no trend in the difference between arms with no correlation found between change in Ktrans and addition of IFN to bevacizumab. Effect size analysis performed due to the small numbers recruited failed to show any significance in the observed difference in Ktrans. Change in Ktrans and Kep may identify a group of patients likely to have PFS > 6 months, but this observation needs to evaluation in a larger sample size. Measuring size and change in arterial phase enhancement retrospectively using CT, a new criterion "modified" Choi, which prerequisite a combination of a decrease in arterial phase density by 15% and a decrease in size by 10% for response was proposed. Response assessment was measured with RECIST, Choi and modified Choi individually in 20 evaluable patients retrospectively and clinical benefit compared with Kaplan-Meier statistics and Log-Rank test. Response assessment as defined by the modified Choi criteria successfully identified patients who received clinical benefit from the treatment. Time to progression (TTP) was 448 days for the partial response and 89 days for stable disease as per the new criteria which were statistically significant with a p-value of 0.002. The second retrospective analysis explored the textural changes in enhanced CT scan. Performed in collaboration with researchers from Brighton University who developed the software algorithm used to assess changes in entropy and uniformity, 87 metastases from 39 patients with mRCC were analysed at baseline and after two cycles of TKI treatment. Textural parameters and response assessment criteria were correlated with TTP. After two cycles of TKI, the decrease in tumour entropy was 3%-45%, and increase in uniformity was 5%-21%. At a threshold change of -2% with uniformity, on a coarse scale of 2.5, the textural change was able to separate responders from non-responders. With Kaplan-Meier analysis comparing all four criteria, the percentage change in uniformity was statistically more significant than for RECIST, Choi, and Modified Choi criteria. Cox regression analysis showed that texture uniformity was an independent predictor of time to progression. Discussion: With the studies reported here, I was able to demonstrate the importance of improving the methodology in assessment of therapeutic response to targeted anti-angiogenic therapy in metastatic renal cell carcinoma. Even though the clinical trial, terminated early due to slow recruitment, did not reach its primary endpoint, changes in other vascular parameters as Kep combined with changes Ktrans showed tendency towards identifying a group of patients who derived clinical benefit of >6months with these therapies. This is particularly exciting as given the vascular stabilisation effect proposed for bevacizumab, the effusion parameter Kep may be a better tool in assessing response rather than Ktrans and warrants further assessment in a larger cohort. Modified choi criterion and textural analysis are two important methodological improvements in response assessment of cytostatic anti-angiogenic therapy. In the analyses reported here, both techniques have shown superiority over RECIST in response assessment and differentiating mRCC patients who is likely to gain clinical benefit by TKI therapy. Validation of these criteria on a larger patient cohort is important. As these criterions are assessed on standard enhanced CT scans, incorporating these criteria, especially modified choi criterion, as part of standard CT assessment could be performed and will provide a real world validation. Retrospective assessment using larger cohort of patients from previous phase 3 trials or inclusion of these parameters prospectively in phase 3 trials would also help us in evaluating these modalities further.

[ES] Los tumores cerebrales son una de las enfermedades más devastadoras en la actualidad por el importante deterioro cognitivo que sufren los pacientes, la elevada tasa de mortalidad y el mal pronóstico. Los astrocitomas de grado 4 conllevan una supervivencia de cinco años en aproximadamente el 5% de los pacientes diagnosticados, siendo los tumores más agresivos y letales del Sistema Nervioso Central (SNC). Los astrocitomas de grado 4 siguen siendo un problema médico complejo aún sin resolver. A pesar de representar más del 60% de los tumores cerebrales malignos en adultos, estos tumores tienen una baja prevalencia relativa y se consideran una enfermedad huérfana, lo que dificulta el desarrollo de nuevos fármacos o tratamientos que puedan beneficiar a los pacientes. La agresividad de estos tumores se debe a diferentes características, como la fuerte angiogénesis, la necrosis, la microproliferación vascular, la capacidad de invasión e infiltración de las células tumorales y un microambiente inmunológico particular. Además, debido a la rápida progresión de los astrocitomas de grado 4, en la zona de la lesión coexisten diferentes regiones específicas que cambian con el tiempo. Esta naturaleza compleja, junto con la marcada heterogeneidad interpaciente, intratumoral y longitudinal, complica el éxito de un único tratamiento eficaz para todos los pacientes. La imagen de resonancia magnética (MRI) supone una técnica útil para caracterizar la morfología y la vascularidad del tumor. El uso de métodos avanzados y robustos para analizar las imágenes de MR recogidas en las fases iniciales del tratamiento de los pacientes permite la delimitación de las diferentes regiones de los astrocitomas de grado 4, convirtiéndose en herramientas útiles para investigadores, radiólogos y neurocirujanos. Además, el cálculo de biomarcadores vasculares de imagen, como los propuestos en esta tesis, facilitaría la caracterización del tumor, la estimación del pronóstico y los enfoques de tratamiento más personalizados. Esta tesis propone cuatro pilares fundamentales para avanzar en el manejo de los astrocitomas de grado 4. Estos incluyen I) la caracterización multinivel del tumor para mejorar las clasificaciones de los gliomas de alto grado del SNC; II) la búsqueda y desarrollo de biomarcadores robustos para estimar el pronóstico de los pacientes desde el momento prequirúrgico; III) así como para evaluar la respuesta a los tratamientos y la selección de los pacientes que pueden beneficiarse de terapias específicas; y IV) el diseño e implementación de estudios clínicos y protocolos para la recogida de datos a largo plazo de cohortes de pacientes notables a nivel internacional. Para abordar estos cuatro pilares, se ha utilizado un enfoque interdisciplinario que combina el análisis de imágenes médicas, técnicas avanzadas de inteligencia artificial y variables moleculares, histopatológicas y clínicas. En conclusión, hemos abordado la influencia de la heterogeneidad interpaciente e intratumoral del astrocitoma de grado 4 para la caracterización y clasificación del tumor, la estimación del pronóstico del paciente y la predicción de las respuestas al tratamiento. Además, se han diseñado e implementado diferentes estudios clínicos que permiten la recogida de datos multinivel de cohortes internacionales de pacientes con astrocitoma de grado 4. / [CA] Els tumors cerebrals són una de les malalties més devastadores en l'actualitat per la important deterioració cognitiva que pateixen els pacients, l'elevada taxa de mortalitat i el mal pronòstic. Els astrocitomes de grau 4 comporten una supervivència de cinc anys en aproximadament el 5% dels pacients diagnosticats, sent els tumors més agressius i letals del Sistema Nerviós Central (SNC). Els astrocitomes de grau 4 continuen sent un problema mèdic complex encara sense resoldre. Malgrat representar més del 60% dels tumors cerebrals malignes en adults, aquests tumors tenen una baixa prevalença relativa i es consideren una malaltia òrfena, la qual cosa dificulta el desenvolupament de nous fàrmacs o tractaments que puguen beneficiar als pacients. L'agressivitat d'aquests tumors es deu a diferents característiques, com la forta angiogènesis, la necrosi, la microproliferació vascular, la capacitat d'invasió i infiltració de les cèl·lules tumorals i un microambient immunològic particular. A més, a causa de la ràpida progressió dels astrocitomes de grau 4, en la zona de la lesió coexisteixen diferents regions específiques que canvien amb el temps. Aquesta naturalesa complexa, juntament amb la marcada heterogeneïtat interpacient, intratumoral i longitudinal fa que es complique l'èxit d'un únic tractament eficaç per a tots els pacients. L'imatge de ressonància magnètica (MRI) suposa una tècnica útil per a caracteritzar la morfologia i la vascularitat del tumor. L'ús de mètodes avançats i robustos per a analitzar les imatges de MR recollides en les fases inicials del tractament dels pacients permet la delimitació de les diferents regions dels astrocitomes de grau 4, convertint-se en eines útils per a investigadors, radiòlegs i neurocirugians. A més, el càlcul de biomarcadors vasculars d'imatge, com els proposats en aquesta tesi, facilitaria la caracterització del tumor, l'estimació del pronòstic i els enfocaments de tractament més personalitzats. Aquesta tesi proposa quatre pilars fonamentals per a avançar en el maneig dels astrocitomes de grau 4. Aquests inclouen I) la caracterització multinivell del tumor per a millorar les classificacions dels gliomes d'alt grau del SNC; II) la cerca i desenvolupament de biomarcadors robustos per a estimar el pronòstic dels pacients des del moment prequirúrgic; III) així com per a avaluar la resposta als tractaments i la selecció dels pacients que poden beneficiar-se de teràpies específiques; i IV) el disseny i implementació d'estudis clínics i protocols per a la recollida de dades a llarg termini de cohorts de pacients notables a nivell internacional. Per a abordar aquests quatre pilars, s'ha utilitzat un enfocament interdisciplinari que combina l'anàlisi d'imatges mèdiques, tècniques avançades d'intel·ligència artificial i variables moleculars, histopatològiques i clíniques. En conclusió, hem abordat la influència de l'heterogeneïtat interpacient i intratumoral del astrocitoma de grau 4 per a la caracterització i classificació del tumor, l'estimació del pronòstic del pacient i la predicció de les respostes al tractament. A més, s'han dissenyat i implementat diferents estudis clínics que permeten la recollida de dades multinivell de cohorts internacionals de pacients amb astrocitoma de grau 4. / [EN] Brain tumors are one of the most devastating diseases today because of the significant cognitive impairment suffered by patients, high mortality rates, and poor prognosis. Astrocytomas grade 4 bring five-year survival in approximately 5% of diagnosed patients, being the most aggressive and lethal tumors of the Central Nervous System (CNS). Astrocytomas grade 4 continue to be an unresolved complex medical problem. Despite accounting for more than 60% of malignant brain tumors in adults, these tumors have a low relative prevalence and are considered an orphan disease, making difficult developing new drugs or treatments that might benefit patients. The aggressiveness of these tumors is due to different characteristics, such as strong angiogenesis, necrosis, vascular microproliferation, the capacity of the tumor cells to invade and infiltrate, and a particular immune microenvironment. In addition, due to the rapid progression of astrocytomas grade 4, different specific regions coexist in the lesion area which change over time. This complex nature, along with the marked interpatient, intratumor, and longitudinal heterogeneity, makes complicate the success of a single efficient treatment for all patients. Magnetic Resonance Imaging (MRI) represents a useful technique to characterize tumor morphology and vascularity. Using advanced and robust methods to analyze MR images collected from initial stages of patient management allows the delineation of different regions of astrocytomas grade 4, becoming useful tools for researchers, radiologists and neurosurgeons. In addition, the calculation of imaging vascular biomarkers, such as those proposed in this thesis, would facilitate tumor characterization, prognosis estimation and more personalized treatment approaches. This thesis proposes four fundamental pillars to advance the management of astrocytomas grade 4. These include I) the multilevel characterization of the tumor to improve classifications of high-grade CNS gliomas; II) the search and development of robust biomarkers for estimating patient prognosis from the presurgical moment; III) as well as for evaluating the response to treatments and the selection of patients who may benefit from specific therapies; and IV) the design and implementation of clinical studies and protocols for long-term collecting data from internationally remarkable cohorts of patients. To address these four pillars, an interdisciplinary approach has been used that combines medical imaging analysis, advanced artificial intelligence techniques, and molecular, histopathological, and clinical variables. Concluding, we have addressed the influence of both interpatient and intratumor heterogeneity of astrocytoma grade 4 for tumor characterization and classification, patient prognosis estimation and predicting treatment responses. In addition, different clinical studies have been designed and implemented allowing the collection of multilevel data from international cohorts of patients with astrocytoma grade 4. / Álvarez Torres, MDM. (2022). Characterization of vascular heterogeneity of astrocytomas grade 4 for supporting patient prognosis estimation, and treatment response assessment [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/188957

Trois aspects principaux de l'imagerie fonctionnelle corps entier dans les hémopathies lymphoïdes ont été étudiés dans ma thèse. Nous avons d'abord démontré en étudiant 92 patients avec un lymphome B à grandes cellules que 14 patients (15%) considérés positifs sur l'analyse visuelle du FDG-TEP après deux cycles de chimiothérapie, auraient pu être reclassés comme des bons répondeurs si le pourcentage de réduction du SUVmax avait été mesuré. Dans un sous groupe de 80 patients, une deuxième étude a permis de montrer qu'après 4 cycles, l'analyse visuelle et l'analyse semi-quantitative SUV étaient équivalentes. Nous avons ensuite développé un protocole d'IRM fonctionnelle corps entier, utilisant une injection dynamique de Gadolinium et 5 stations d'acquisition. Cela a permis de mesurer les courbes signal-temps du rehaussement de la moelle osseuse et des lésions focales. Notre étude a permis d'optimiser un protocole d'imagerie dynamique corps entier après injection de Gadolinium, et de montrer que nous avions pu explorer avec succès 21 patients présentant un myélome multiple sous traitement, nous avons montré que cette nouvelle méthode d'IRM fonctionnelle corps entier avec injection de Gadolinium pouvait être utilisée pour évaluer la réponse du traitement. De plus, cette technique a aidé à détecter les lésions résiduelles actives de myélome après traitement alors qu'aucun signe clinique ou une immunoglobine monoclonale minime n'était présent. Le troisième aspect a été d'optimiser un protocole d'IRM fonctionnelle corps entier utilisant l'imagerie de diffusion avec asservissement respiratoire. Le but est de pouvoir mesurer le coefficient de diffusion apprent des lésions disséminées. L'étude pilote a été réalisée chez 15 patients avec un lymphome B à grandes cellules avant traitement. Nous avons aussi pu montrer les changements d'ADC après 4 cycles de chimiothérapie en considérant l'imagerie FDG-TEP/scanner comme imagerie de référence / Three components regarding whole-body functional imaging in lymphoid malignancies have been studies in this thesis. We first demonstrated retrospectively in a series of 92 patients with diffuse large B-cell lymphoma (DLBCL) that 14 patients (15%) considered as positive on visual analysis on FDG-PET after only 2 cycles of chemotherapy could have been correctly re-classified as good responders by measuring the percentage reduction of maximum standardized uptake value (SUVmax); in a subgroup of 80 patients, SUV-based assessment was equivalent to visual analysis at 4 cycles for patient outcome prediction. We secondly developed a whole-body 5-station dynamic contrast- enhanced MR protocol and time-signal intensity curves for the bone marrow and the focal lesions were successfully obtaines in 21 patients with plasma cell disorders included in the feasibility study; later in a pilot prospective study with 30 patients with multiple myeloma who received systemic therapy, we showed that this novel whole-body functional MR technique can be used to assess treatment response and helps to delect residual active disease after completion of therapy when clinically no or only minimum monoclonal protein can be identified. We thirdly optimized a whole-body diffusion-weighted MR protocol with respiratory gating in order to determine apparent diffusion coefficient (ADC) value on a whole-body scale. Pilot study was performed in 15 patients with DLBCL for both staging and response assessment at 4 cycles of chemotherapy, with FDG PET/CT as the standard of reference

Outputs of dose–response assessments can be used as benchmarks that help to identify the need for risk management measures to reduce population health risks associated with exposure to chemicals. Various approaches can be used to facilitate the incorporation of chemical- or scenario-specific data into dose–response analyses, as a means of replacing or influencing default assumptions and extrapolations. The goal of the first part of this thesis was to examine the evolution of approaches to the incorporation of chemical- and scenario-specific data in dose–response assessments in regulatory settings, and identify contextual factors that serve as barriers and facilitators to the use of approaches. A main focus of the investigation was on physiological modelling, which is the most commonly-used category of approaches enabling extrapolations that depart from default assumptions. Evaluations of the dose–response applications of physiological modelling in the peer-reviewed scientific literature and in regulatory reports were conducted. Similarities between the scientific literature databases and regulatory reports were observed with respect to the evolution of physiological modelling in dose–response assessments, notably related to the timing, quantity, and annual frequency of publications. These similarities indicate that a factor in the low dose–response application of physiological modelling, relative to the overall production of physiological models, is an absence of data. However, variability in adoption of physiological modelling in regulatory dose–response assessments was observed among—and even within—organizations faced with the same data, indicating that other factors influence regulatory uptake of physiological modelling. Analysis of a survey indicated that factors acting as barriers or facilitators to regulatory risk assessors’ incorporation of increasingly data-informed approaches originated in both external and internal contexts. The external context was composed of the regulatory environment, domestic and international alignment, availability of external expertise, background of peer reviewers and stakeholders, availability and accessibility of software and tools, and chemical-dependent factors. The internal context was influenced by problem formulation, time and financial resources, organizational and management support, and training. A conceptual framework demonstrating how these factors impact a risk assessor’s ability to incorporate chemical- and scenario-specific data in dose–response analysis was developed, and subsequently used to provide recommendations on actions that could be taken to increase regulatory adoption of increasingly data-informed approaches. The second part of the thesis focused on the development of a knowledge translation tool designed to assist risk managers in the evaluation of dose–response analyses. The tool was focused on occupational exposure limits (OELs), and provides a guide to occupational hygienists in evaluating the relevance and reliability of individual OELs. When occupational hygienists are faced with multiple varying OELs for a chemical of interest, these evaluations can support the selection of the most appropriate OEL for a given situation. The usefulness of the tool was demonstrated for the selection of OELs for an OEL-rich compound (n-hexane), an OEL-poor compound (methamphetamine), and one additional compound (manganese). Such a tool can improve occupational hygienists’ understanding of the basis of OELs and the levels of protection afforded by each, which can contribute to more informed risk management decisions.