RESUMEN
Introduction: Deep brain stimulation (DBS) is utilized to treat pediatric refractory dystonia and its use in pediatric patients is expected to grow. One important question concerns the impact of hope and unrealistic optimism on decision-making, especially in "last resort" intervention scenarios such as DBS for refractory conditions. Objective: This study examined stakeholder experiences and perspectives on hope and unrealistic optimism in the context of decision-making about DBS for childhood dystonia and provides insights for clinicians seeking to implement effective communication strategies. Materials and Methods: Semi-structured interviews with clinicians (n = 29) and caregivers (n = 44) were conducted, transcribed, and coded. Results: Using thematic content analysis, four major themes from clinician interviews and five major themes from caregiver interviews related to hopes and expectations were identified. Clinicians expressed concerns about caregiver false hopes (86%, 25/29) and desperation (68.9%, 20/29) in light of DBS being a last resort. As a result, 68.9% of clinicians (20/29) expressed that they intentionally tried to lower caregiver expectations about DBS outcomes. Clinicians also expressed concern that, on the flip side, unrealistic pessimism drives away some patients who might otherwise benefit from DBS (34.5%, 10/29). Caregivers viewed DBS as the last option that they had to try (61.3%, 27/44), and 73% of caregivers (32/44) viewed themselves as having high hopes but reasonable expectations. Fewer than half (43%, 19/44) expressed that they struggled setting outcome expectations due to the uncertainty of DBS, and 50% of post-DBS caregivers (14/28) expressed some negative feelings post treatment due to unmet expectations. 43% of caregivers (19/44) had experiences with clinicians who tried to set low expectations about the potential benefits of DBS. Conclusion: Thoughtful clinician-stakeholder discussion is needed to ensure realistic outcome expectations.
RESUMEN
Chemotherapy-induced cognitive dysfunction (chemobrain) is an important adverse sequela of chemotherapy. Chemobrain has been identified by the National Cancer Institute as a poorly understood problem for which current management or treatment strategies are limited or ineffective. Here, we show that chemotherapy treatment with doxorubicin (DOX) in a breast cancer mouse model induced protein kinase A (PKA) phosphorylation of the neuronal ryanodine receptor/calcium (Ca2+) channel type 2 (RyR2), RyR2 oxidation, RyR2 nitrosylation, RyR2 calstabin2 depletion, and subsequent RyR2 Ca2+ leakiness. Chemotherapy was furthermore associated with abnormalities in brain glucose metabolism and neurocognitive dysfunction in breast cancer mice. RyR2 leakiness and cognitive dysfunction could be ameliorated by treatment with a small molecule Rycal drug (S107). Chemobrain was also found in noncancer mice treated with DOX or methotrexate and 5-fluorouracil and could be prevented by treatment with S107. Genetic ablation of the RyR2 PKA phosphorylation site (RyR2-S2808A) also prevented the development of chemobrain. Chemotherapy increased brain concentrations of the tumor necrosis factor-α and transforming growth factor-ß signaling, suggesting that increased inflammatory signaling might contribute to oxidation-driven biochemical remodeling of RyR2. Proteomics and Gene Ontology analysis indicated that the signaling downstream of chemotherapy-induced leaky RyR2 was linked to the dysregulation of synaptic structure-associated proteins that are involved in neurotransmission. Together, our study points to neuronal Ca2+ dyshomeostasis via leaky RyR2 channels as a potential mechanism contributing to chemobrain, warranting further translational studies.