Background Brain microdialysis is a minimally invasive technique for monitoring analytes, metabolites, drugs, neurotransmitters, and/or cytokines. Studies to date have centered on adults with traumatic brain injury, with a limited number of pediatric studies performed. Objective This scoping review details past use of brain microdialysis in children and identifies potential use for future neuro-oncology trials. Methods In December 2020, Cochrane Library: CENTRAL, Embase, PubMed, Scopus, and Web of Science: Core Collection were searched. Two reviewers screened all articles by title and abstract review and then full study texts, using microdialysis in patients less than 18yo. Results Of the 1,171 articles screened, 49 were included. The 49 studies included 472 pediatric patients (age range 0–17yo), in the brain (21), abdominal (16), and musculoskeletal (12) regions. Intracerebral microdialysis was performed in 64 collective patients, with a median age of 11yo, and predominance in metabolic evaluations. Conclusion Historically, pediatric microdialysis was safely performed within the brain in varied neurologic conditions, except neuro-oncology. Adult brain tumor studies using intratumoral/peritumoral microdialysis sampling can inform future pediatric studies to advance diagnosis and treatment options for such aggressive tumors.
Objective: Over 40,000 infants are born annually with a heart defect; 25% require surgery and of those 20% result in hospital readmissions. We sought to identify risk factors for short- and long-term readmission following pediatric congenital heart surgery (CHS) to reduce avoidable future admissions. Methods: A systematic approach was used to search four electronic databases and retrieve articles published through 05/2020. We included observational and experimental studies that observed factors associated with 30-day or 1-year readmission after CHS. Studies with a composite outcome of readmission and death were excluded. For each independent risk factor, we assessed the pooled effect size and heterogeneity using a random-effects model. Risk of bias was assessed via the Newcastle-Ottawa scale. Results: After removing 970 duplicates, we screened 5,084 studies; 17 were included in the systematic review and 15 (N= 82,794; 9,856 readmitted) in the meta-analysis. Hospital readmission was significantly and positively associated with gestational age, non-white race, Hispanic ethnicity, government insurance, genetic abnormality, renal dysfunction, failure to thrive, mechanical ventilation, intraoperative ventricular dysfunction, RACHS score, STAT mortality score, cross clamp time, gastroesophageal reflux disease, postoperative arrhythmia, valve regurgitation, feeding difficulties, and ICU and hospital length of stay (LOS). Readmission definition (i.e., 1-yr vs 30-day) and LOS dichotomization (i.e., ≥ 10 or ≥ 14) resulted in significant subgroup differences for age at surgery and LOS. Five studies had higher potential for risk of bias. Conclusions: This is the first meta-analysis to identify patient and clinical factors associated with short and long-term readmission after pediatric CHS. Findings may support clinical decisions before undergoing surgery and identify patients that may benefit from receiving more aggressive care transitions prior to discharge to reduce avoidable hospital readmissions.
BACKGROUND The blood-brain barrier (BBB), among malignant gliomas limits certain agents from impairing tumor growth. Thus, identifying agents that can transiently increase BBB permeability may prove useful in enhancing glioma treatment response. Previous ibrutinib studies showed it independently disrupted gut epithelial integrity and hampered glioma growth through BMX (bone marrow x-linked tyrosine kinase) inhibition. We propose BMX inhibition via ibrutinib disrupts BBB integrity while impairing glioma progression. METHODS To evaluate ibrutinib’s effect on brain endothelium, we evaluated electrical cell-cell impedance, junctional/cytoskeletal expression, downstream protein expression and functional ABC transporter activity; monitoring changes over time (0 to 8h) and at varied drug concentrations (1-10μM ibrutinib). Using rat glioma cells (S635) in vitro and in models, we examined cytotoxicity, apoptosis, model survival, and drug concentrations with ibrutinib alone or combined with poorly permeable Abcb1 substrate doxorubicin. RESULTS Ibrutinib dose-dependently decreased brain endothelial cell-cell impedance by 60% at 2h, without affecting cell viability. We observed decreased ZO-1 junctions, actin cytoskeletal rearrangement, and downstream pErk and pMek decreased expression optimally 2h (10μM ibrutinib). Dose-dependently ibrutinib inhibited Abcb1 efflux activity, further favoring a more permeable endothelium. Synergy with doxorubicin was seen in rat glioma cells treated with ibrutinib via increased apoptosis and cytotoxicity. However, while combined treatment resulted in decreased systemic doxorubicin concentrations, no differences in brain:plasma or tumor:plasma concentrations were evident. Combination therapy also did not increase rodent glioma model survival nor decrease tumor size. CONCLUSION Our results suggest that while ibrutinib induces brain endothelial permeability by junctional/cytoskeletal disruption and inhibition of Abcb1 efflux, no sustained effect can be seen in rodent glioma models in combination with a cytotoxic agent. Additional studies exploring similar agents that can enhance BBB permeability while slowing glioma growth are warranted, so as to improve upon current bleak malignant glioma treatment options.
Despite major strides in cancer research, care, and therapy, these advances have not been equitable across race and ethnicity. Groups underrepresented in medicine (URM) are more likely to have inadequate preventive screening, increased delays in diagnosis, and poor representation in clinical trials. Notably, Black and Latino Americans represent 29% of the population but only reflect 8% of oncology clinical trial participants. Recent studies have shown that this disparity is also present in neuro-oncology as women, Black, and Latino Americans remain under-accrued in clinical trials. Brain tumor patients already face unique barriers to clinical trial enrollment and completion due to disease-specific conditions–such as impaired motor function, cognition, language deficits, and caregiver dependency–which pose additional difficulties in clinical trial consent, enrollment, and adherence. As part of this collaborative initiative, we evaluated the impact of how a lack of diversity in cancer research is detrimental to scientific discovery and propose interventions focused on improving URM engagement with clinical research. Recommendations include the creation of inclusive trial design at the onset, decreasing barriers to care, expanding trial eligibility, and equitable access to tumor profiling for personalized medical trials. Additionally, setting reasonable metrics and goals for accrual and engagement with patient and community stakeholders will ultimately help to diversify trial participants. Lastly, diversification and inclusion practices within the neuro-oncology workforce, including all personnel involved in clinical research, will help to minimize bias, promote concordant care, and assist with developing sustainable solutions. The diversification of participation in neuro-oncology clinical trials is imperative. The lack of diversity in clinical trials can contribute to improper generalizability of treatment efficacy, resulting in potentially harmful practices. Equitable access and inclusion of URM brain tumor patients will not only enhance research discoveries but will also result in improved patient care for all cancer patients.
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