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Robert J. Rothrock, Victor M. Lu, and Allan D. Levi

OBJECTIVE

Syringomyelia is a debilitating, progressive disease process that can lead to loss of neurological function in patients already experiencing significant compromise. Syringosubarachnoid, syringoperitoneal, and syringopleural shunts are accepted treatment options for patients with persistent syringomyelia, but direct comparisons have been lacking to date. The authors conducted a systematic review of the literature and meta-analysis to compare clinical outcomes between these three syrinx shunt modalities.

METHODS

Utilizing PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines for systematic reviews, Ovid Embase, PubMed, Scopus, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, American College of Physicians Journal Club, and Database of Abstracts of Review of Effectiveness were searched to identify all potentially relevant studies published from inception until July 2020. Data were extracted and analyzed using meta-analysis of proportions. The primary study outcome was the rate of reoperation based on the initial shunt modality. Secondary outcomes included clinical improvement, clinical deterioration, and complications following shunt placement.

RESULTS

A total of 22 articles describing 27 distinct treatment cohorts published between 1984 and 2019 satisfied the inclusion criteria. This captured 473 syrinx shunt procedures, 193 (41%) by syringosubarachnoid shunt, 153 (32%) by syringoperitoneal shunt, and 127 (27%) by syringopleural shunt, with an overall median clinical follow-up of 44 months. The pooled incidences of revision surgery were estimated as 13% for syringosubarachnoid, 28% for syringoperitoneal, and 10% for syringopleural shunts, respectively (p-interaction = 0.27). The rate of clinical improvement was estimated as 61% for syringosubarachnoid, 64% for syringoperitoneal, and 71% for syringopleural shunts. The rate of clinical deterioration following placement was estimated as 13% for syringosubarachnoid, 13% for syringoperitoneal, and 10% for syringopleural shunts.

CONCLUSIONS

The preferred modality of syrinx shunting remains a controversial topic for symptomatic syringomyelia. This study suggests that while all three modalities offer similar rates of clinical improvement and deterioration after placement, syringoperitoneal shunts have a greater rate of malfunction requiring surgical revision. These data also suggest that syringopleural shunts may offer the best rate of clinical improvement with the lowest rate of reoperation.

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Roberto J. Perez-Roman, Wendy Gaztanaga, Victor M. Lu, and Michael Y. Wang

OBJECTIVE

Lumbar stenosis treatment has evolved with the introduction of minimally invasive surgery (MIS) techniques. Endoscopic methods take the concepts applied to MIS a step further, with multiple studies showing that endoscopic techniques have outcomes that are similar to those of more traditional approaches. The aim of this study was to perform an updated meta-analysis and systematic review of studies comparing the outcomes between endoscopic (uni- and biportal) and microscopic techniques for the treatment of lumbar stenosis.

METHODS

Following PRISMA guidelines, a systematic search was performed using the Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Ovid Embase, and PubMed databases from their dates of inception to December 14, 2020. All identified articles were then systematically screened against the following inclusion criteria: 1) studies comparing endoscopic (either uniportal or biportal) with minimally invasive approaches, 2) patient age ≥ 18 years, and 3) diagnosis of lumbar spinal stenosis. Bias was assessed using quality assessment criteria and funnel plots. Meta-analysis using a random-effects model was used to synthesize the metadata.

RESULTS

From a total of 470 studies, 14 underwent full-text assessment. Of these 14 studies, 13 comparative studies were included for quantitative analysis, totaling 1406 procedures satisfying all criteria for selection. Regarding postoperative back pain, 9 studies showed that endoscopic methods resulted in significantly lower pain scores compared with MIS (mean difference [MD] −1.0, 95% CI −1.6 to −0.4, p < 0.01). The length of stay data were reported by 7 studies, with endoscopic methods associated with a significantly shorter length of stay versus the MIS technique (MD −2.1 days, 95% CI −2.7 to −1.4, p < 0.01). There was no significant difference with respect to leg visual analog scale scores, Oswestry Disability Index scores, blood loss, surgical time, and complications, and there were not any significant quality or bias concerns.

CONCLUSIONS

Both endoscopic and MIS techniques are safe and effective methods for treating patients with symptomatic lumbar stenosis. Patients who undergo endoscopic surgery seem to report less postoperative low-back pain and significantly reduced hospital stay with a trend toward less perioperative blood loss. Future large prospective randomized trials are needed to confirm the findings in this study.

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Nickalus R. Khan, Victor M. Lu, Turki Elarjani, Michael A. Silva, Aria M. Jamshidi, Iahn Cajigas, and Jacques J. Morcos

OBJECTIVE

Cerebral extracranial-intracranial (EC-IC) direct bypass is a commonly used procedure for ischemic vasculopathy. A previously described variation of this technique is to utilize one donor artery to supply two recipient arteries, which the authors designate as 1D2R. The purpose of this study is to present a single surgeon’s series of 1D2R direct bypasses for moyamoya and ischemia using detailed clinical, angiographic, and intraoperative blood flow measurement data. To the authors’ knowledge, this is the largest series reported to date.

METHODS

Hospital, office, and radiographic imaging records for all patients who underwent cerebral revascularization using a 1D2R bypass by the senior author were reviewed. The patients’ demographic information, clinical presentation, associated medical conditions, intraoperative information, and postoperative course were obtained from reviewing the medical records.

RESULTS

A total of 21 1D2R bypasses were performed in 19 patients during the study period. Immediate bypass patency was 100% and was 90% on delayed follow-up. The mean initial cut flow index (CFI(i)) was 0.64 ± 0.33 prior to the second anastomosis and the mean final value (CFI(f)) was 0.94 ± 0.38 after the second anastomosis (p < 0.001). The overall bypass flow increased on average by 50% (mean 17.9 ml/min, range −10 to 40 ml/min) with the addition of the second anastomosis. There was no significant difference in the overall flow measurements when the end-to-side anastomosis or side-to-side anastomosis was performed first. There was a statistically significant difference in the proportion of patients with a modified Rankin Scale (mRS) score of 0 or 1 postoperatively compared to preoperatively (p < 0.01). Through the application of Poiseuille’s law, the authors analyzed flow dynamics, deduced the component vascular resistances based on an analogy to electrical circuits and Ohm’s law, and introduced the new concepts of “second anastomosis relative augmentation” and “second anastomosis sink index” in the evaluation of 1D2R bypasses.

CONCLUSIONS

The application of the 1D2R technique in a series of 19 consecutive patients undergoing direct EC-IC bypass for flow augmentation demonstrated high patency rates, statistically significantly higher CFIs compared to 1D1R, and improved mRS scores at last clinical follow-up. Additionally, the technique allows a shorter dissection time and preserves blood flow to the scalp. The routine utilization of intraoperative volumetric flow measurements in such surgeries allows a deeper understanding of the hemodynamic impact on individual patients.

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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, 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, 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, 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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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.