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Victor M. Lu, David J. Daniels, Dawit T. Haile, and Edward S. Ahn

OBJECTIVE

Pediatric Chiari I malformation decompression is a common neurosurgical procedure. Liposomal bupivacaine (LB) is a novel formulation that can have an impact on postoperative recovery for particular procedures, but its potential role in pediatric neurosurgery is largely unexplored. The authors sought to describe and assess their initial experience with LB in pediatric Chiari I malformation decompression to better define its potential role as an analgesic agent in a procedure for which the postoperative course is often remarkably painful.

METHODS

A retrospective review of all pediatric Chiari procedures performed at the authors’ institution between 2018 and 2020 was conducted. Patients were divided into those who were treated with a single intraoperative dose of LB (LB group) and those who were not (control group). Comparisons of total opioid use and pain control were made using chi-square and Wilcoxon rank-sum tests.

RESULTS

A total of 18 patients were identified, 9 (50%) in the LB group and 9 (50%) in the control group. Overall, there were 13 (72%) female and 5 (28%) male patients with a mean age of 15.9 years. No surgical complications were observed over a mean length of stay of 2.7 days. Within the first 24 hours after surgery, the LB group had significantly lower total opioid use than the control group (17.5 vs 47.9 morphine milligram equivalents, respectively; p = 0.03) as well as lower mean pain scores reported by patients using a 10-point visual analog scale (3.6 vs 5.5 for the LB vs control groups, p = 0.04). However, from the first 24 postoperative hours to discharge, total opioid use (p = 0.51) and mean pain scores (p = 0.09) were statistically comparable between the two groups. There were 2/9 (22%) LB patients versus 0/9 (0%) control patients who did not require opioid analgesia at any point during hospitalization.

CONCLUSIONS

The use of a single intraoperative dose of LB in pediatric Chiari I malformation surgery appears to be safe and has the potential to reduce pain scores and opioid use when administered during the first 24 postoperative hours. From that time period to discharge, however, there may be no significant difference in total opioid use or pain scores.

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Victor M. Lu, Mohammed A. Alvi, Kerrie L. McDonald, and David J. Daniels

OBJECTIVE

Pediatric high-grade gliomas (pHGGs), including diffuse intrinsic pontine glioma, present a prognostic challenge given their lethality and rarity. A substitution mutation of lysine for methionine at position 27 in histone H3 (H3K27M) has been shown to be highly specific to these tumors. Data are accumulating regarding the poor outcomes of patients with these tumors; however, the quantification of pooled outcomes has yet to be done, which could assist in prioritizing management. The aim of this study was to quantitatively pool data in the current literature on the H3K27M mutation as an independent prognostic factor in pHGG.

METHODS

Searches of seven electronic databases from their inception to March 2018 were conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Data were extracted and pooled using a meta-analysis of proportions. Meta-regression was used to identify potential sources of heterogeneity.

RESULTS

Six observational studies satisfied the selection criteria for inclusion. They reported the survival outcomes of a pooled cohort of 474 pHGG patients, with 258 (54%) and 216 (46%) patients positive and negative, respectively, for the H3K27M mutation. Overall, the presence of the mutation was independently and significantly associated with a worse prognosis (HR 3.630, p < 0.001). Overall survival was significantly shorter (by 2.300 years; p = 0.008) when the H3K27M mutation was present in pHGG. Meta-regression did not identify any study covariates of heterogeneous concern.

CONCLUSIONS

According to the current literature, pHGG patients positive for the H3K27M mutation are more than 3 times more susceptible to succumbing to this disease by more than 2 years, compared to patients negative for the mutation. More robust outcome data are required to improve our quantitative understanding of this pathological entity in order to assist in prioritizing clinical management. Future larger prospective studies are required to overcome inherent biases in the current literature to validate the quantitative findings of this study.

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Victor M. Lu, Erica A. Power, Liang Zhang, and David J. Daniels

Diffuse intrinsic pontine glioma (DIPG), otherwise known as diffuse midline glioma with H3K27M mutation, is a devastating brainstem glioma without a cure. Efforts are currently underway to better optimize molecular diagnoses through biological sampling, which today remains largely limited to surgical biopsy sampling. Surgical intervention is not without its risks, and therefore a preference remains for a less invasive modality that can provide biological information about the tumor. There is emerging evidence to suggest that a liquid biopsy, targeting biofluids such as CSF and blood plasma, presents an attractive alternative for brain tumors in general. In this update, the authors provide a summary of the progress made to date regarding the use of liquid biopsy to diagnose and monitor DIPG, and they also propose future development and applications of this technique moving forward, given its unique histone biology.

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Victor M. Lu, Kevin Phan, Sean P. Crowley, and David J. Daniels

OBJECTIVE

Surgery is the definitive treatment of Chiari malformation Type I (CM-I). It involves posterior fossa decompression, which can be performed along with C-1 laminectomy, reconstructive duraplasty, or tonsil shrinkage. The aim of this study was to provide an updated systematic review and meta-analysis of the latest available evidence regarding posterior fossa decompression only (PFDO) versus posterior fossa decompression with duraplasty (PFDD) in the treatment of CM-I in children.

METHODS

A literature search was performed in compliance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines for article identification, screening, eligibility, and inclusion. Relevant articles were identified from 6 electronic databases from their inception to April 2016. These articles were screened against established criteria for inclusion into this study.

RESULTS

From 12 relevant studies identified, 1492 pediatric patients treated via PFDD were compared with 1963 pediatric patients treated by PFDO for CM-I. PFDD was associated with greater overall clinical improvement (p = 0.009), along with longer length of stay (p < 0.0001) and more postoperative complications (p = 0.0001) compared with PFDO. No difference was observed between PFDD and PFDO in terms of revision surgery incidence (p = 0.13), estimated blood loss (p = 0.14), syrinx improvement (p = 0.09), or scoliosis improvement (p = 0.95).

CONCLUSIONS

It appears that the addition of duraplasty to posterior decompression in the definitive treatment of CM-I in children may alter surgical and performance outcomes. In particular, parameters of overall clinical improvement, length of stay, and postoperative complication may differ between children undergoing PFDD and those undergoing PFDO. Current evidence in the literature is of low to very low quality that, as of yet, has not been able to completely control for inherent selection bias both in study design and surgeon preference. Future, large prospective registries and randomized controlled trials are warranted to validate the findings of this study.

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Victor M. Lu, Ashish H. Shah, Frederic A. Vallejo, Daniel G. Eichberg, Evan M. Luther, Sumedh S. Shah, Ricardo J. Komotar, and Michael E. Ivan

OBJECTIVE

Adult glioblastoma (GBM) has proven refractory to decades of innovation. Oncolytic viral therapy represents a novel therapy that uses viral vectors as both a delivery and therapeutic mechanism to target GBM cells. Despite the growing body of basic science data supporting the feasibility of viral therapy to treat GBM, the reporting of clinical trial results is heterogeneous. Correspondingly, the aim of this study was to present a contemporary summary of the progress all clinical trials have made to date.

METHODS

The ClinicalTrials.gov database was reviewed in August 2020 for all possible interventional clinical trials involving viral vector–based therapy to treat adult GBM. These were then screened against selection criteria to identify pertinent clinical trials.

RESULTS

A total of 29 oncolytic viral therapy trials treating adult GBM were identified. The median start and expected completion years were 2014 and 2020, respectively. At the time of this writing, 10 (35%) trials were reported to have completed recruitment, whereas 7 (24%) were actively recruiting. The median target enrollment number was 36 (range 13–108), with the majority of trials being phase I (n = 18, 62%), and involving secondary GBM among other malignant glioma (n = 19, 66%). A total of 10 unique viral vectors were used across all trials, with the most common being adenovirus (n = 16, 55%). Only 2 (7%) phase I trials to date have reported outcomes on the ClinicalTrials.gov portal. Results of 12 additional clinical trials were found in academic publications, with median progression-free and overall survival times of 3 and 15 months, respectively, after the first viral dose at recurrence. The coordination of the large majority of trials originated from the US (n = 21, 72%), and the median number of testing sites per trial was 1 (range 1–15), via industry funding (n = 18 trials, 62%).

CONCLUSIONS

There are multiple early-stage oncolytic viral therapy clinical trials for adult GBM currently active. To date, limited results and outcomes are promising but scarce. The authors expect this to change in the near future because many trials are scheduled to have either nearly or actually reached their expected recruitment completion time. How exactly oncolytic viral therapy will fit into the current treatment paradigms for primary and secondary GBM remains to be seen, and will not be known until safety and toxicity profiles are established by these clinical trials.

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Victor M. Lu, S. Shelby Burks, Rainya N. Heath, Tizeta Wolde, Robert J. Spinner, and Allan D. Levi

OBJECTIVE

Meralgia paresthetica is caused by entrapment of the lateral femoral cutaneous nerve (LFCN) and often presents with pain. Multiple treatment options targeting the LFCN can be pursued to treat the pain should conservative measures fail, with the most common options being injection, neurolysis, and neurectomy. However, their efficacy in causing pain relief and their clinical outcomes have yet to be directly compared. The aim of this study was to interrogate the contemporary literature and quantitatively define how these options compare.

METHODS

The electronic databases Ovid Embase, PubMed, SCOPUS, and the Cochrane Library were interrogated from inception to May 2020 following the PRISMA guidelines. Candidate articles were screened against prespecified criteria. Outcome data were abstracted and pooled by random-effects meta-analysis of proportions.

RESULTS

There were 25 articles that satisfied all criteria, reporting outcomes for a total of 670 meralgia paresthetica patients, with 78 (12%) treated by injection, 496 (74%) by neurolysis, and 96 (14%) by neurectomy. The incidence of complete pain relief was 85% (95% CI 71%–96%) after neurectomy, 63% (95% CI 56%–71%) after neurolysis, and 22% (95% CI 13%–33%) after injection, which were all statistically different (p < 0.01). The incidence of revision procedures was 12% (95% CI 4%–22%) after neurolysis and 0% (95% CI 0%–2%) after neurectomy, which were significantly lower than 81% (95% CI 64%–94%) after injection (p < 0.01). The incidences of treatment complications were statistically comparable across all three treatments, ranging from 0% to 5% (p = 0.34).

CONCLUSIONS

There are multiple treatment options to target pain in meralgia paresthetica. The incidence of complete pain relief appears to be the greatest among the 3 interventions after neurectomy, accompanied by the lowest incidence of revision procedures. These findings should help inform patient preference and expectations. Greater exploration of the anatomical rationale for incomplete pain relief after surgical intervention will assist in optimizing further surgical treatment for meralgia paresthetica.

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Juliana Rotter, Victor M. Lu, Christopher S. Graffeo, Avital Perry, Colin L. W. Driscoll, Bruce E. Pollock, and Michael J. Link

OBJECTIVE

Intracranial facial nerve schwannomas (FNS) requiring treatment are frequently recommended for surgery or stereotactic radiosurgery (SRS). The objective of this study was to compare facial nerve function outcomes between these two interventions for FNS via a systematic review and meta-analysis.

METHODS

A search of the Ovid EMBASE, PubMed, SCOPUS, and Cochrane databases from inception to July 2019 was conducted following PRISMA guidelines. Articles were screened against prespecified criteria. Facial nerve outcomes were classified as improved, stabilized, or worsened by last follow-up. Incidence was pooled by random-effects meta-analysis of proportions.

RESULTS

Thirty-three articles with a pooled cohort of 519 patients with FNS satisfied all criteria. Twenty-five articles described operative outcomes in 407 (78%) patients; 10 articles reported SRS outcomes in 112 (22%). In the surgical cohort, facial nerve function improved in 23% (95% CI 15%–32%), stabilized in 41% (95% CI 32%–50%), and worsened in 30% (95% CI 21%–40%). In the SRS cohort, facial nerve function was improved in 20% (95% CI 9%–34%), stable in 66% (95% CI 54%–78%), and worsened in 9% (95% CI 3%–16%). Compared with SRS, microsurgery was associated with a significantly lower incidence of stable facial nerve function (p < 0.01) and a significantly higher incidence of worsened facial nerve function (p < 0.01). Tumor progression and complication rates were comparable. Outcome certainty assessments were very low to moderate for all parameters.

CONCLUSIONS

Unfavorable facial nerve function outcomes are associated with surgical treatment of intracranial FNS, whereas stable facial nerve function outcomes are associated with SRS. Therefore, SRS should be recommended to patients with FNS who require treatment, and surgery should be reserved for patients with another indication, such as decompression of the brainstem. Further study is required to definitively optimize and validate management strategies for these rare skull base tumors.

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Julian S. Rechberger, Erica A. Power, Victor M. Lu, Liang Zhang, Jann N. Sarkaria, and David J. Daniels

OBJECTIVE

Convection-enhanced delivery (CED) and osmotic pump delivery both have been promoted as promising techniques to deliver drugs to pediatric diffuse intrinsic pontine gliomas (DIPGs). Correspondingly, the aim of this study was to understand how infusate molecular weight (MW), duration of delivery, and mechanism of delivery (CED or osmotic pump) affect volume of distribution (Vd) in the brainstem, to better inform drug selection and delivery in future DIPG investigations.

METHODS

A series of in vivo experiments were conducted using rat models. CED and osmotic pump delivery systems were surgically implanted in the brainstem, and different MW fluorescent dextran beads were infused either once (acute) or daily for 5 days (chronic) in a volume infused (Vi). Brainstems were harvested after the last infusion, and Vd was quantified using serial sectioning and fluorescence imaging.

RESULTS

Fluorescence imaging showed infusate uptake within the brainstem for both systems without complication. A significant inverse relationship was observed between infusate MW and Vd in all settings, which was distinctly exponential in nature in the setting of acute delivery across the 570-Da to 150-kDa range. Chronic duration and CED technique resulted in significantly greater Vd compared to acute duration or osmotic pump delivery, respectively. When accounting for Vi, acute infusion yielded significantly greater Vd/Vi than chronic infusion. The distribution in CED versus osmotic pump delivery was significantly affected by infusate MW at higher weights.

CONCLUSIONS

Here the authors demonstrate that infusate MW, duration of infusion, and infusion mechanism all impact the Vd of an infused agent and should be considered when selecting drugs and infusion parameters for novel investigations to treat DIPGs.

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Victor M. Lu, Kendall A. Snyder, Eniola R. Ibirogba, Rodrigo Ruano, David J. Daniels, and Edward S. Ahn

OBJECTIVE

Open prenatal myelomeningocele (MMC) repair is typically associated with reversal of in utero hindbrain herniation (HBH) and has been posited to be associated with a reduction in both postoperative prenatal and immediate postnatal hydrocephalus (HCP) risks. However, the long-term postnatal risk of HCP following HBH reversal in these cases has not been well defined. The authors describe the results of a long-term HCP surveillance in a cohort of patients who underwent prenatal MMC repair at their institution.

METHODS

A retrospective review of all prenatal MMC repair operations performed at the Mayo Clinic between 2012 and 2017 was conducted. Pertinent data regarding the clinical courses of these patients before and after MMC repair were summarized. Outcomes of interest were occurrences of HBH and HCP and the need for intervention.

RESULTS

A total of 9 prenatal MMC repair cases were identified. There were 7 cases in which MRI clearly demonstrated prenatal HBH, and of these 86% (6/7) had evidence of HBH reversal after repair and prior to delivery. After a mean postnatal follow-up of 20 months, there were 3 cases of postnatal HCP requiring intervention. One case that failed to show complete HBH reversal after MMC repair required early ventriculoperitoneal shunting. The other 2 cases were of progressive, gradual-onset HCP despite complete prenatal HBH reversal, requiring endoscopic third ventriculostomy with choroid plexus cauterization at ages 5 and 7 months.

CONCLUSIONS

Although prenatal MMC repair can achieve HBH reversal in a majority of well-selected cases, the prevention of postnatal HCP requiring intervention appears not to be predicated on this outcome alone. In fact, it appears that in a subset of cases in which HBH reversal is achieved, patients can experience a progressive, gradual-onset HCP within the 1st year of life. These findings support continued rigorous postnatal surveillance of all prenatal MMC repair patients, irrespective of postoperative HBH outcome.