Pathoplasticity of neuromuscular fatigue induced by exercise in breast cancer patients treated with chemotherapy : central and peripheral mechanisms

Si la fatigue associée au cancer du sein est reconnue comme le symptôme majeur, sa dimension neuromusculaire était mal caractérisée. Plus précisément, l’étiologie de la fatigue neuromusculaire, à travers ses composantes centrales et périphériques, restait à investiguer. Par le biais d’une étude longitudinale menée sur 100 patientes et d’une étude transversale menée sur 15 patientes comparées à 15 femmes contrôles, nous avons mis en évidence une réduction des capacités d’exercice expliquée majoritairement par une exacerbation de la fatigue centrale, alors que la fatigue périphérique était similaire au groupe contrôle, mais pour un niveau de force initial diminué. La mise en place de l’exercice, aujourd’hui considéré comme l’intervention la plus efficace pour contrecarrer la fatigue associée au cancer, a ainsi fait l’objet de la troisième étude de cette thèse. En identifiant le pédalage excentrique comme modalité adaptée au profil de ces patientes, la caractérisation des réponses neuromusculaires et cardiorespiratoires de ce type de pédalage chez 9 patientes atteintes d’un cancer du sein a permis d’envisager la mise en place de ce type d’exercice au cours de la chimiothérapie afin de contrecarrer les altérations neuromusculaires.If cancer-related fatigue is a major symptom in patients with breast cancer, the neuromuscular component remained unknown. More precisely, the etiology of neuromuscular fatigue, i.e. central or peripheral component, needs to be investigated. With a longitudinal study conducted on 100 patients and a transversal study conducted on 15 patients compared to 15 healthy controls, we first reported a substantial reduction in exercise capacity, mainly explained by an exacerbated central fatigue, while peripheral fatigue was similar than the control group, but with a lower initial force level. The implementation of exercise, currently considered as the most effective intervention to counteract cancer-related fatigue, was integrated in the third study of this thesis. As eccentric cycling appears as an adapted modality for patients with breast cancer, we characterized the neuromuscular and cardiorespiratory responses in 9 patients before the implementation of eccentric cycling during breast cancer chemotherapy

Pathoplasticité de la fatigue neuromusculaire à l’exercice chez la patiente atteinte d’un cancer du sein traité par chimiothérapie : mécanismes centraux et périphériques

If cancer-related fatigue is a major symptom in patients with breast cancer, the neuromuscular component remained unknown. More precisely, the etiology of neuromuscular fatigue, i.e. central or peripheral component, needs to be investigated. With a longitudinal study conducted on 100 patients and a transversal study conducted on 15 patients compared to 15 healthy controls, we first reported a substantial reduction in exercise capacity, mainly explained by an exacerbated central fatigue, while peripheral fatigue was similar than the control group, but with a lower initial force level. The implementation of exercise, currently considered as the most effective intervention to counteract cancer-related fatigue, was integrated in the third study of this thesis. As eccentric cycling appears as an adapted modality for patients with breast cancer, we characterized the neuromuscular and cardiorespiratory responses in 9 patients before the implementation of eccentric cycling during breast cancer chemotherapy.Si la fatigue associée au cancer du sein est reconnue comme le symptôme majeur, sa dimension neuromusculaire était mal caractérisée. Plus précisément, l’étiologie de la fatigue neuromusculaire, à travers ses composantes centrales et périphériques, restait à investiguer. Par le biais d’une étude longitudinale menée sur 100 patientes et d’une étude transversale menée sur 15 patientes comparées à 15 femmes contrôles, nous avons mis en évidence une réduction des capacités d’exercice expliquée majoritairement par une exacerbation de la fatigue centrale, alors que la fatigue périphérique était similaire au groupe contrôle, mais pour un niveau de force initial diminué. La mise en place de l’exercice, aujourd’hui considéré comme l’intervention la plus efficace pour contrecarrer la fatigue associée au cancer, a ainsi fait l’objet de la troisième étude de cette thèse. En identifiant le pédalage excentrique comme modalité adaptée au profil de ces patientes, la caractérisation des réponses neuromusculaires et cardiorespiratoires de ce type de pédalage chez 9 patientes atteintes d’un cancer du sein a permis d’envisager la mise en place de ce type d’exercice au cours de la chimiothérapie afin de contrecarrer les altérations neuromusculaires

Exacerbated central fatigue and reduced exercise capacity in early-stage breast cancer patients treated with chemotherapy

Purpose: The present study aimed to characterize the etiology of exercise-induced neuromuscular fatigue and its consequences on the force-duration relationship to provide mechanistic insights into the reduced exercise capacity characterizing early-stage breast cancer patients.Methods: Fifteen early-stage breast cancer patients and fifteen healthy women performed 60 maximal voluntary isometric quadriceps contractions (MVCs, 3 s of contraction, 2 s of relaxation). The critical force was determined as the mean force of the last six contractions, while W' was calculated as the force impulse generated above the critical force. Quadriceps muscle activation during exercise was estimated from vastus lateralis, vastus medialis and rectus femoris EMG. Central and peripheral fatigue were quantified via changes in pre- to postexercise quadriceps voluntary activation (ΔVA) and quadriceps twitch force (ΔQTw) evoked by supramaximal electrical stimulation, respectively.Results: Early-stage breast cancer patients demonstrated lower MVC than controls preexercise (- 15%, P = 0.022), and this reduction persisted throughout the 60-MVC exercise (- 21%, P = 0.002). The absolute critical force was lower in patients than in controls (144 ± 29N vs. 201 ± 47N, respectively, P < 0.001), while W' was similar (P = 0.546), resulting in lower total work done (- 23%, P = 0.001). This was associated with lower muscle activation in the vastus lateralis (P < 0.001), vastus medialis (P = 0.003) and rectus femoris (P = 0.003) in patients. Immediately following exercise, ΔVA showed a greater reduction in patients compared to controls (- 21.6 ± 13.3% vs. - 12.6 ± 7.7%, P = 0.040), while ΔQTw was similar (- 60.2 ± 13.2% vs. - 52.8 ± 19.4%, P = 0.196).Conclusion: These findings support central fatigue as a primary cause of the reduction in exercise capacity characterizing early-stage breast cancer patients treated with chemotherapy

Subcutaneous Administration of a Zwitterionic Chitosan‐Based Hydrogel for Controlled Spatiotemporal Release of Monoclonal Antibodies

International audienceAbstract Subcutaneous (SC) administration of monoclonal antibodies (mAbs) is a proven strategy for improving therapeutic outcomes and patient compliance. The current FDA‐/EMA‐approved enzymatic approach, utilizing recombinant human hyaluronidase (rHuPH20) to enhance mAbs SC delivery, involves degrading the extracellular matrix's hyaluronate to increase tissue permeability. However, this method lacks tunable release properties, requiring individual optimization for each mAb. Seeking alternatives, physical polysaccharide hydrogels emerge as promising candidates due to their tunable physicochemical and biodegradability features. Unfortunately, none have demonstrated simultaneous biocompatibility, biodegradability, and controlled release properties for large proteins (≥150 kDa) after SC delivery in clinical settings. Here, a novel two‐component hydrogel comprising chitosan and chitosan@DOTAGA is introduced that can be seamlessly mixed with sterile mAbs formulations initially designed for intravenous (IV) administration, repurposing them as novel tunable SC formulations. Validated in mice and nonhuman primates (NHPs) with various mAbs, including trastuzumab and rituximab, the hydrogel exhibited biodegradability and biocompatibility features. Pharmacokinetic studies in both species demonstrated tunable controlled release, surpassing the capabilities of rHuPH20, with comparable parameters to the rHuPH20+mAbs formulation. These findings signify the potential for rapid translation to human applications, opening avenues for the clinical development of this novel SC biosimilar formulation