Cervicothoracic ventral-dorsal rhizotomy for treatment of brachial hypertonia in cerebral palsy.

PURPOSE: Cervicothoracic ventral-dorsal rhizotomy (VDR) is a potential treatment of medically refractory hypertonia in patients who are not candidates for intrathecal baclofen, particularly in cases of severe upper limb hypertonia with limited to no function. A longitudinal cohort was identified to highlight our institutional safety and efficacy using cervicothoracic VDR for the treatment of hypertonia. METHODS: Retrospective data analysis was performed for patients that underwent non-selective cervicothoracic VDR between 2022 and 2023. Non-modifiable risk factors, clinical variables, and operative characteristics were collected. RESULTS: Six patients (three female) were included. Four patients underwent a bilateral C6-T1 VDR, one patient underwent a left C7-T1 VDR, and another underwent a left C6-T1 VDR. Three patients had quadriplegic mixed hypertonia, one patient had quadriplegic spasticity, one patient had triplegic mixed hypertonia, and one patient had mixed hemiplegic hypertonia. The mean difference of proximal upper extremity modified Ashworth scale (mAS) was - 1.4 ± 0.55 (p = 0.002), and - 2.2 ± 0.45 (p < 0.001) for the distal upper extremity. Both patients with independence noted quality of life improvements as well as increased ease with dressing and orthotics fits. Caregivers for the remaining four patients noted improvements in caregiving provision, mainly in dressing, orthotics fit, and ease when transferring. CONCLUSION: Cervicothoracic VDR is safe and provides tone control and quality of life improvements in short-term follow-up. It can be considered for the treatment of refractory hypertonia. Larger multicenter studies with longer follow-up are necessary to further determine safety along with long-term functional benefits in these patients.

Nonselective lumbosacral ventral-dorsal rhizotomy for the management of lower-limb hypertonia in nonambulatory children with cerebral palsy.

OBJECTIVE: Children with cerebral palsy (CP) often experience medically refractory hypertonia, for which there are surgical therapies including neuromodulation and rhizotomy. Traditional surgical treatment for medically refractory mixed hypertonia or dystonia includes intrathecal baclofen pumps and selective dorsal rhizotomy. A nonselective lumbosacral ventral-dorsal rhizotomy (VDR; ventral and dorsal roots lesioned by 80%-90%) has the potential to address the limitations of traditional surgical options. The authors highlighted the institutional safety and efficacy of nonselective lumbosacral VDR for palliative tone management in nonambulatory patients with more severe CP. METHODS: The authors performed a retrospective analysis of patients who had undergone lumbosacral VDR between 2022 and 2023. Demographic factors, clinical variables, and operative characteristics were collected. The primary outcomes of interest included tone control and quality of life improvement. Secondary outcome measures included, as a measure of safety, perioperative events such as paresthesias. Postoperative complications were also noted. RESULTS: Fourteen patients (7 female) were included in the study. All patients had undergone a T12-L2 osteoplastic laminoplasty and bilateral L1-S1 VDR. Nine patients had quadriplegic mixed hypertonia, 4 had quadriplegic spasticity, and 1 had generalized secondary dystonia. Following VDR, there was a significant decrease in both lower-extremity modified Ashworth Scale (mAS) scores (mean difference [MD] -2.77 ± 1.0, p < 0.001) and upper-extremity mAS scores (MD -0.71 ± 0.76, p = 0.02), with an average follow-up of 3 months. In the patient with generalized dystonia, the lower-extremity Barry-Albright Dystonia Scale score decreased from 8 to 0, and the overall score decreased from 32 to 13. All parents noted increased ease in caregiving, particularly in terms of positioning, transfers, and changing. The mean daily enteral baclofen dose decreased from 47 mg preoperatively to 24.5 mg postoperatively (p < 0.001). Three patients developed wound dehiscence, 2 of whom had concurrent infections. CONCLUSIONS: Lumbosacral VDR is safe, is effective for tone control, and can provide quality of life improvements in patients with medically refractory lower-limb mixed hypertonia. Lumbosacral VDR can be considered for palliative tone control in nonambulatory patients with more severe CP. Larger studies with longer follow-ups are necessary to further determine safety and long-term benefits in these patients.

Public reporting of black participation in anti-hypertensive drug clinical trials.

BACKGROUND: Non-Hispanic Black people in the United States have the highest prevalence of essential hypertension. Unfortunately, clinical trials often underrepresent Black patients. We aim to understand whether trial sponsorship type is associated with representation of Black participants in anti-hypertensive drug clinical trials. Then, we contextualize our findings amongst current efforts to improve diversity in clinical research populations. METHODS: We searched ClinicalTrials.gov in May 2022 for antihypertensive drug trials. Of n = 408 trials in our initial search, n = 97 (23.77%) met inclusion criteria and were stratified by sponsorship type (industry vs non-industry). Standardized tests of difference were employed to compare characteristics of these trials, and linear regression was used to model change over time. RESULTS: Of 97 trials reporting results from 2010 to 2020, there were minimal differences in the percent of Black patients enrolled in anti-hypertensive clinical trials by sponsorship type. Both industry and non-industry sponsored studies had high rates of non-reporting, with slightly more non-reporting for industry (73.2%) vs non-industry (66.67%) studies. Industry funded studies reported results to ClinicalTrials.gov within 23.3 ± 15.0 months from completing studies, while non-industry funded trials reported within 18.9 ± 10.8 months. CONCLUSIONS: Despite Black Americans carrying the highest burden of disease for essential hypertension, they are underrepresented in anti-hypertension clinical trials and their overall participation has decreased between 2010 and 2020. In addition, there is major underreporting of trial participant race. We implore researchers and funders to establish clear, meaningful targets for anti-hypertensive drug trial diversity, and improve transparency in reporting of study characteristics.

Defining interventions and metrics to improve diversity in CNS clinical trial participation: A SNO and RANO effort.

Despite major strides in cancer research and therapy, these advances have not been equitable across race and ethnicity. Historically marginalized groups (HMG) are more likely to have inadequate preventive screening, increased delays in diagnosis, and poor representation in clinical trials. Notably, Black, Hispanic, and Indigenous people represent 30% of the population but only 9% of oncology clinical trial participants. As a result, HMGs lack equitable access to novel therapies, contradicting the principle of distributive justice, as enshrined in the Belmont report, which demands the equitable selection of subjects in research involving human subjects. The lack of clinical trial diversity also leads to low generalizability and potentially harmful medical practices. Specifically, patients with brain cancer face unique barriers to clinical trial enrollment and completion due to disease-specific neurologic and treatment-induced conditions. Collectively, the intersection of these disease-specific conditions with social determinants of health fosters a lack of diversity in clinical trials. To ameliorate this disparity in neuro-oncology clinical trial participation, we present interventions focused on improving engagement of HMGs. Proposals range from inclusive trial design, decreasing barriers to care, expanding trial eligibility, access to tumor profiling for personalized medical trials, setting reasonable metrics and goals for accrual, working with patient community stakeholders, diversifying the neuro-oncology workforce, and development of tools to overcome biases with options to incentivize equity. The diversification of participation amongst neuro-oncology clinical trials is imperative. Equitable access and inclusion of HMG patients with brain tumors will not only enhance research discoveries but will also improve patient care.

Ibrutinib disrupts blood-tumor barrier integrity and prolongs survival in rodent glioma model.

In malignant glioma, cytotoxic drugs are often inhibited from accessing the tumor site due to the blood-tumor barrier (BTB). Ibrutinib, FDA-approved lymphoma agent, inhibits Bruton tyrosine kinase (BTK) and has previously been shown to independently impair aortic endothelial adhesion and increase rodent glioma model survival in combination with cytotoxic therapy. Yet additional research is required to understand ibrutinib's effect on BTB function. In this study, we detail baseline BTK expression in glioma cells and its surrounding vasculature, then measure endothelial junctional expression/function changes with varied ibrutinib doses in vitro. Rat glioma cells and rodent glioma models were treated with ibrutinib alone (1-10 µM and 25 mg/kg) and in combination with doxil (10-100 µM and 3 mg/kg) to assess additive effects on viability, drug concentrations, tumor volume, endothelial junctional expression and survival. We found that ibrutinib, in a dose-dependent manner, decreased brain endothelial cell-cell adhesion over 24 h, without affecting endothelial cell viability (p < 0.005). Expression of tight junction gene and protein expression was decreased maximally 4 h after administration, along with inhibition of efflux transporter, ABCB1, activity. We demonstrated an additive effect of ibrutinib with doxil on rat glioma cells, as seen by a significant reduction in cell viability (p < 0.001) and increased CNS doxil concentration in the brain (56 ng/mL doxil alone vs. 74.6 ng/mL combination, p < 0.05). Finally, Ibrutinib, combined with doxil, prolonged median survival in rodent glioma models (27 vs. 16 days, p < 0.0001) with brain imaging showing a - 53% versus - 75% volume change with doxil alone versus combination therapy (p < 0.05). These findings indicate ibrutinib's ability to increase brain endothelial permeability via junctional disruption and efflux inhibition, to increase BTB drug entry and prolong rodent glioma model survival. Our results motivate the need to identify other BTB modifiers, all with the intent of improving survival and reducing systemic toxicities.

Clinical protocol: Feasibility of evaluating abemaciclib neuropharmacokinetics of diffuse midline glioma using intratumoral microdialysis.

Diffuse midline gliomas (DMG) are the most aggressive brain tumors of childhood and young adults, with documented 2-year survival rates <10%. Treatment failure is due in part to the function of the BBB. Intratumoral microdialysis sampling is an effective tool to determine brain entry of varied agents and could help to provide a better understanding of the relationship of drug permeability to DMG treatment responsivity. This is a non-randomized, single-center, phase 1 clinical trial. Up to seven young adult (18-39 years) patients with recurrent high-grade or diffuse midline glioma will be enrolled with the goal of 5 patients completing the trial over an anticipated 24 months. All patients will take abemaciclib pre-operatively for 4.5 days at twice daily dosing. Patients will undergo resection or biopsy, placement of a microdialysis catheter, and 48 hours of dialysate sampling coupled with timed plasma collections. If intratumoral tumor or brain dialysate sampling concentrations are >10nmol/L, or tumor tissue studies demonstrate CDK inhibition, then restart of abemaciclib therapy along with temozolomide will be administered for maintenance therapy and discontinued with evidence of radiologic or clinical disease progression. The poor survival associated with diffuse midline gliomas underscore the need for improved means to evaluate efficacy of drug delivery to tumor and peritumoral tissue. The findings of this novel study, will provide real-time measurements of BBB function which have the potential to influence future prognostic and diagnostic decisions in such a lethal disease with limited treatment options. Trial registration: Clinicaltrials.gov, NCT05413304. Registered June 10, 2022, Abemaciclib Neuropharmacokinetics of Diffuse Midline Glioma Using Intratumoral Microdialysis.

Survival and neurological outcomes after stereotactic biopsy of diffuse intrinsic pontine glioma: a systematic review.

OBJECTIVE: Diffuse intrinsic pontine gliomas (DIPGs) are aggressive and malignant tumors of the brainstem. Stereotactic biopsy can obtain molecular and genetic information for diagnostic and potentially therapeutic purposes. However, there is no consensus on the safety of biopsy or effect on survival. The authors aimed to characterize neurological risk associated with and the effect of stereotactic biopsy on survival among patients with DIPGs. METHODS: A systematic review was performed in accordance with PRISMA guidelines to identify all studies examining pediatric patients with DIPG who underwent stereotactic biopsy. The search strategy was deployed in PubMed, Embase, and Scopus. The quality of studies was assessed using the Grading of Recommendations, Assessment, Development and Evaluation system, and risk of bias was evaluated with the Cochrane Risk of Bias in Nonrandomized Studies-of Interventions tool. Bibliographic, demographic, clinical, and outcome data were extracted from studies meeting inclusion criteria. RESULTS: Of 2634 resultant articles, 13 were included, representing 192 patients undergoing biopsy. The weighted mean age at diagnosis was 7.5 years (range 0.5-17 years). There was an overall neurosurgical complication rate of 13.02% (25/192). The most common neurosurgical complication was cranial nerve palsy (4.2%, 8/192), of which cranial nerve VII was the most common (37.5%, 3/8). The second most common complication was perioperative hemorrhage (3.6%, 7/192), followed by hemiparesis (2.1%, 4/192), speech disorders (1.6%, 3/192) such as dysarthria and dysphasia, and movement disorders (1.0%, 2/192). Hydrocephalus was less commonly reported (0.5%, 1/192), and there were no complications relating to wound infection/dehiscence (0%, 0/192) or CSF leak (0%, 0/192). No mortality was specifically attributed to biopsy. Diagnostic yield of biopsy revealed a weighted mean of 97.4% (range 91%-100%). Of the studies reporting survival data, 37.6% (32/85) of patients died within the study follow-up period (range 2 weeks-48 months). The mean overall survival in patients undergoing biopsy was 9.73 months (SD 0.68, median 10 months, range 6-13 months). CONCLUSIONS: Children with DIPGs undergoing biopsy have mild to moderate rates of neurosurgical complications and no excessive morbidity. With reasonably acceptable surgical risk and high diagnostic yield, stereotactic biopsy of DIPGs can allow for characterization of patient-specific molecular and genetic features that may influence prognosis and the development of future therapeutic strategies.

A scoping review of pediatric microdialysis: A missed opportunity for microdialysis in the pediatric neuro-oncology setting.

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. 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 18 yo. Results: Of the 1171 articles screened, 49 were included. The 49 studies included 472 pediatric patients (age range 0-17 years old), in the brain (21), abdominal (16), and musculoskeletal (12) regions. Intracerebral microdialysis was performed in 64 collective patients, with a median age of 11 years old, 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.