Ce travail de thèse avait pour objectif d’évaluer l’accessibilité, l’efficacité et les difficultés opérationnelles de la prise en charge antirétrovirale précoce des enfants infectés par le VIH en Afrique de l’Ouest : en Côte d’Ivoire, au Mali et au Burkina Faso. Cette région est particulièrement marquée par un faible accès à la prise en charge des enfants infectés par le VIH. Nos travaux ont montré qu’à coté de l’offre de soins qui est insuffisante dans cette région, le retard aux soins chez ces enfants était particulièrement influencé par la faible acceptabilité parentale du dépistage pédiatrique précoce, avec un rôle clé du père dans la décision de soins de l’enfant. Les enfants débutent le traitement antirétroviral très tardivement, à un stade très avancé de la maladie et sévèrement immunodéprimé. Après douze mois de traitement antirétroviral, on observe un échec clinique ou immunologique au traitement chez plus de la moitié des enfants, en particulier chez ceux qui avaient débuté le traitement antirétroviral avec un mauvais état clinique et immunologique. Après cinq ans de traitement, près de la moitié des enfants présentent un échec virologique. Les interventions de prévention de la transmission mère-enfant ne semblent pas associées à l’échec au traitement des enfants dans cette région. Toutefois, l’observance au traitement antirétroviral chez le jeune enfant est bonne dans cette région. Ces résultats sont en faveur de la nécessité d’une prise en charge précoce des enfants infectés par le VIH, à un stade moins avancé de la maladie. Cela passe nécessairement par l’amélioration du dépistage pédiatrique précoce, à travers l’implication des pères, le renforcement du plateau technique pour le dépistage et le suivi des enfants, et la formation du personnel soignant. Aussi, les études de cohorte sur les facteurs pronostiques de l’échec au traitement dans le contexte opérationnel ouest africain sont nécessaires pour approfondir la question de la réponse au traitement antirétroviral chez ces enfants. / This thesis aimed to assess the accessibility, the efficiency and operational difficulties of treatment and care of HIV infected children in West Africa: Cote d’Ivoire, Mali and Burkina Faso. This region is particularly marked by poor access to care for HIV infected children. Our work has show that besides the insufficient provision of care in this region, the delay to care for these children was particularly influenced by the low acceptability of HIV early infant diagnosis, with a key role of the father in the decision making for the care of the child. Children begin antiretroviral treatment very late, at a very advanced stage of disease and severely immunocompromised. After twelve months of antiretroviral therapy, there was a clinical or immunological treatment failure in more than half of all children, especially among those who had started antiretroviral therapy with poor clinical and immunological status. Interventions to prevent mother to child transmission do not seem related to children treatment failure in this region. However, adherence to antiretroviral therapy in young children is good in this region. These results support the need for early antiretroviral treatment for HIV infected children at an earlier stage of the disease. This necessarily requires improved early infant diagnosis, through the involvement of fathers, the strengthening of the technical platform for screening and monitoring of children, and training of health staff. Also, cohort studies on prognostic factors for treatment failure in West African context are needed to investigate the issue of antiretroviral treatment response in these children.

Objective: The primary objective of this real-world study was to describe the response to fampridine and changes of gait parameters in multiple sclerosis (MS) patients’ walking disability (Expanded Disability Status Scale (EDSS): 4–7) after treatment with fampridine for 2 weeks as recommended by the European Medicines Agency (EMA) and compare it with the overall physician’s judgement. Methods: A total of 211 adult MS patients were analyzed using a multimodal gait assessment including the timed 25-foot walk test (T25FW), 2-minute walking test (2-MWT), 12-item Multiple Sclerosis Walking Scale (MSWS-12), the GAITRite electronic walkway system, and the patients’ clinical global impression (CGI). Multimodal gait assessment was compared with the clinician’s impression of overall improvement after 2 weeks. Results: In total, 189 subjects were included, of which 133 (70.37%) were responders to fampridine (RF), according to physician’s judgement. Looking at independent multimodal gait assessment, RFs showed improvement of 12.60% in the T25FW, 19.25% in the 2-MWT, 21.12% in the MSWS-12, and 6.54% in their Functional Ambulation Profile (FAP) score. The combination of the T25FW and the MSWS-12 would offer the best sensitivity and specificity for determining response to fampridine according to both neurologists’ and patients’ classification. Conclusion: This study provides new information on the use of fampridine in a real-world setting with a large patient sample on the potential benefit of using more definitive responder criteria to fampridine for the clinical setting.

[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

Drug combination therapies for cancer treatment show high efficacy but often induce severe side effects, resulting in dose or cycle number reduction. We investigated the impact of neoadjuvant chemotherapy (neoCTx) adaptions on treatment outcome in 59 patients with pancreatic ductal adenocarcinoma (PDAC). Resections with tumor-free margins were significantly more frequent when full-dose neoCTx was applied. We determined if patient-derived organoids (PDOs) can be used to personalize poly-chemotherapy regimens by pharmacotyping of treatment-naïve and post-neoCTx PDAC PDOs. Five out of ten CTx-naïve PDO lines exhibited a differential response to either the FOLFIRINOX or the Gem/Pac regimen. NeoCTx PDOs showed a poor response to the neoadjuvant regimen that had been administered to the respective patient in 30% of cases. No significant difference in PDO response was noted when comparing modified treatments in which the least effective single drug was removed from the complete regimen.Drug testing of CTx-naïve PDAC PDOs and neoCTx PDOs may be useful to guide neoadjuvant and adjuvant regimen selection, respectively. Personalizing poly-chemotherapy regimens by omitting substances with low efficacy could potentially result in less severe side effects, thereby increasing the fraction of patients receiving a full course of neoadjuvant treatment.

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

Prolonged-release (PR) fampridine is the only approved medication to improve walking in multiple sclerosis (MS), having been shown to produce a clinically meaningful improvement in walking ability in the subset of MS patients with Expanded Disability Status Scale 4–7. Recent responder subgroup analyses in the phase III ENHANCE study show a large effect size in terms of an increase of 20.58 points on the patient-reported 12-item MS Walking Scale in the 43% of patients classified as responders to PR-fampridine, corresponding to a standardized response mean of 1.68. Use of PR-fampridine in clinical practice varies across Europe, depending partly on whether it is reimbursed. A group of European MS experts met in June 2017 to discuss their experience with using PR-fampridine, including their views on the patient population for treatment, assessment of treatment response, re-testing and retreatment, and stopping criteria. This article summarizes the experts’ opinions on how PRfampridine can be used in real-world clinical practice to optimize the benefits to people with MS with impaired walking ability.

No description available.

The self-organizing maps portraying has been proven to be a powerful approach for analysis of transcriptomic, genomic, epigenetic, single-cell, and pathway-level data as well as for “multi-omic” integrative analyses. However, the SOM method has a major disadvantage: it requires the retraining of the entire dataset once a new sample is added, which can be resource- and timedemanding. It also shifts the gene landscape, thus complicating the interpretation and comparison of results. To overcome this issue, we have developed two approaches of transfer learning that allow for extending SOM space with new samples, meanwhile preserving its intrinsic structure. The extension SOM (exSOM) approach is based on adding secondary data to the existing SOM space by “meta-gene adaptation”, while supervised SOM portrayal (supSOM) adds support vector machine regression model on top of the original SOM algorithm to “predict” the portrait of a new sample. Both methods have been shown to accurately combine existing and new data. With simulated data, exSOM outperforms supSOM for accuracy, while supSOM significantly reduces the computing time and outperforms exSOM for this parameter. Analysis of real datasets demonstrated the validity of the projection methods with independent datasets mapped on existing SOM space. Moreover, both methods well handle the projection of samples with new characteristics that were not present in training datasets.