Lu, Victor M.

Abstract Systematic reviews and meta-analyses in the neurosurgical literature have surged in popularity over the last decade. It is our concern that, without a renewed effort to critically interpret and appraise these studies as high or low quality, we run the risk of the quality and value of evidence-based medicine in neurosurgery being misinterpreted. Correspondingly, we have outlined 4 major domains to target in interpreting neurosurgical systematic reviews and meta-analyses based on the lessons learned by a collaboration of clinicians and academics summarized as 4 pearls. The domains of (1) heterogeneity, (2) modeling, (3) certainty, and (4) bias in neurosurgical systematic reviews and meta-analyses were identified as aspects in which the authors’ approaches have changed over time to improve robustness and transparency. Examples of how and why these pearls were adapted were provided in areas of cranial neuralgia, spine, pediatric, and neuro-oncology to demonstrate how neurosurgical readers and writers may improve their interpretation of these domains. The incorporation of these pearls into practice will empower neurosurgical academics to effectively interpret systematic reviews and meta-analyses, enhancing the quality of our evidence-based medicine literature while maintaining a critical focus on the needs of the individual patients in neurosurgery.

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 (V d ) 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 (V i ). Brainstems were harvested after the last infusion, and V d 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 V d 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 V d compared to acute duration or osmotic pump delivery, respectively. When accounting for V i , acute infusion yielded significantly greater V d /V i 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 V d of an infused agent and should be considered when selecting drugs and infusion parameters for novel investigations to treat DIPGs.

Abstract BACKGROUND Diffuse intrinsic pontine glioma (DIPG) is a pediatric brain tumor with dismal prognosis despite initial radiation therapy (RT). The clinical consequences of attempting reirradiation (reRT) in these patients to alleviate both symptomatology and improve prognosis are currently unclear. Thus, the aim of this systematic review and meta-analysis was to clarify the efficacy and safety of reRT in DIPG. METHODS Searches of 7 electronic databases from inception to January 2019 were conducted following the appropriate guidelines. Articles were screened against pre-specified criteria. The incidence and duration of clinical outcomes were then extracted and pooled by means of meta-analysis from the included studies. RESULTS A total of 7 studies satisfied all criteria, describing 90 cases of DIPG in which reRT was attempted 11.8–14 months after initial RT. Based on a random-effects model, the incidences of clinical improvement and radiologic response following reRT were 87% (95% CI, 78–95%) and 69% (95% CI, 52–84%) respectively. The incidence of acute serious toxicity was 0% (95% CI, 0–4%). Pooled overall survivals from initial diagnosis, and time of reRT, were 18.0 months (95% CI, 14.2–21.7) and 6.2 months (95% CI, 5.5–7.0) respectively. CONCLUSIONS Based on these results, the clinical consequences of reRT for DIPG when administered appropriately and safely at first progression appear acceptable, and potentially favorable, based on the limited evidence in the current literature. Concerns regarding acute serious toxicity were not realized. It is likely a sub-cohort of all DIPG diagnoses will be most amenable to improved prognosis with reRT, and greater investigation is required to identify their characteristics.

Abstract BACKGROUND High-grade gliomas (HGGs) of the brainstem represent a rarer subtype of central nervous system tumors compared to their supratentorial counterpart. Predictors of survival and patterns of care have not yet been established on a national, multi-institutional scale. METHODS The National Cancer Database was queried for adult cases surgically diagnosed with brainstem high-grade glioma. An array of patient demographics, comorbidities, tumor characteristics and treatment parameters were captured. Predictors of survival were investigated using multivariable Cox proportional hazards regression analysis adjusting for age, insurance status, Charlson comorbidity score, tumor grade, tumor size and type of treatment. RESULTS A total of 422 patients (median 51 years, 60% males) were analyzed. Two hundred eighty one received postoperative radiation with chemotherapy (66.6%), thirty-nine had radiation alone (9.2%), while the remaining had no adjuvant treatment (24.2%). Median radiation dosage was 54Gy. Overall median survival was 9.8 months (95% CI 8.8–12). Survival was significantly longer (p< .001) in the chemotherapy+radiation group (median: 14.2 months, 95% CI 11.7–17.1) compared to radiation alone (median: 5.7 months, 95% CI 3.7–12) and no adjuvant treatment (median:1.8 months, 95% CI 1.4–4). In multivariable analysis, increasing age (HR 1.87, 95% CI 1.47–2.37, p< .001) was associated with worse survival, whereas radiation with chemotherapy (HR 0.67, 95% CI 0.46–0.98, p=0.038) were associated with lower hazards of death compared to radiation alone. In subgroup analysis, the effect of adjuvant chemotherapy with radiation remained significant for grade IV (HR 0.46, 95% CI 0.28–0.76, p=0.003), but not for grade III tumors (HR 0.87, 95% CI 0.48–1.58, p=0.65). CONCLUSION Findings of the present analysis demonstrate the effectiveness of radiation with chemotherapy for adult patients with high-grade brainstem gliomas, particularly grade IV. Further research should aim on identifying specific patient profiles and molecular subgroups that are more likely to benefit from multimodality therapy.

Abstract Diffuse midline gliomas harboring the H3K27M mutation, previously known as diffuse intrinsic pontine gliomas (DIPG), are rare and aggressive pediatric brain tumors without cure. One of the major challenge sin DIPG treatment is the effective delivery of therapeutic agents across the blood-brain barrier (BBB) to the tumor and surrounding infiltrating cells. Therefore, strategies that enhance drug delivery to the brain are of great interest. Convection-enhanced delivery (CED) is a technique that bypasses the BBB and increases drug distribution by applying hydraulic pressure to deliver compounds directly and evenly into a target region. However, knowledge in CED pharmacology and convective kinetics is still lacking. In an effort to characterize the feasibility, safety, and distribution in the brain based on molecular size of the delivered agent, we performed infusions of FITC-dextran (range 3,000 Da–150,000 Da) comparing CED and osmotic pump-based delivery into the brainstem of rodents. We calculated the area and volume of distribution (Vd) of the FITC-dextran throughout the brain. Our data showed that the Vd decreased exponentially with increased molecular weight of the FITC-dextran. Interestingly, the Vdcan maintain linearity at lower molecular weights. Maximal cross-sectional area and craniocaudal extension of fluorescence also decreased when lowering the infusate size. In addition, we developed a patient-derived DIPG orthotopic xenograft model and performed an image-guided CED cannula installation in the tumor bed. Using 3D bioluminescence imaging and computed tomography, we determined the tumor volume and the positioning of the cannula in the bulk tumor. The summation of these results supports CED as a promising technique for treating DIPG tumors. A better understanding of how drugs distribute by convection will allow us to optimize treatment regimens and, ultimately, offers hope to patients and families with this devastating disease.

Abstract BACKGROUND Although rare, the propensity for pediatric low-grade glioma (pLGG) to recur despite upfront intervention presents a management conundrum for clinicians. One novel salvage option is anti-angiogenic bevacizumab, however, its safety and efficacy in this specific demographic is poorly defined. Correspondingly, our aim was to pool systematically-identified metadata in the literature to substantiate the clinical relevance of bevacizumab in treating recurrent pLGG. METHODS Searches of 7 electronic databases from inception to June 2019 were conducted following PRISMA guidelines. Articles were screened against pre-specified criteria. The incidence of loss was then pooled by random-effects meta-analysis of proportions. RESULTS Six pertinent studies described the outcomes of 110 recurrent pLGG patients managed with bevacizumab. While on-treatment, the rate of clinical response was 58% (95% CI, 43–72%), and the rate of radiographic response was 80% (95% CI, 58–96%). Additionally, the rate of serious adverse events (Grade 3 and above) was 11% (95% CI, 5–18%), with proteinuria the most common of those events. By the time patients were off-treatment, the rate of progression was estimated to be 51% (95% CI, 28–74%). Certainty of these results ranged from very low to low. CONCLUSIONS The use of bevacizumab as therapy for recurrent pLGG appears to confer appreciable clinical and radiographic response with relatively low serious adverse events risk while on-treatment. However, the long-term off-treatment benefits of this therapy have yet to be consolidated. Traditional clinical heterogeneity concerns preclude the formalization of any recommendations until larger, more standardized investigations can be performed.

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.

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.

OBJECTIVEDelayed cerebral ischemia (DCI) and aneurysm rebleeding contribute to morbidity and mortality in aneurysmal subarachnoid hemorrhage (aSAH); however, the relationship between their impacts on overall functional outcome is incompletely understood.METHODSThe authors conducted a cohort study of all aSAH during the study period from 2001 to 2016. Primary end points were overall functional outcome and ischemic aSAH sequelae, defined as delayed cerebral ischemia (DCI), DCI with infarction, symptomatic vasospasm (SV), and global cerebral edema (GCE). Outcomes were compared between the rebleed and nonrebleed cohorts overall and after propensity-score matching (PSM) for risk factors and treatment modality. Univariate and multivariate ordered logistic regression analyses for functional outcomes were performed in the PSM cohort to identify predictors of poor outcome.RESULTSFour hundred fifty-five aSAH cases admitted within 24 hours of aneurysm rupture were included, of which 411 (90%) experienced initial aneurysm ruptures only, while 44 (10%) had clinically confirmed rebleeding. In the overall cohort, rebleeding was associated with significantly worse functional outcome, longer intensive care unit length of stay (LOS), and GCE (all p < 0.01); treatment modality, overall LOS, DCI, DCI with infarction, and SV were nonsignificant. In the PSM analysis of 43 matched rebleed and 43 matched nonrebleed cases, only poor functional outcome and GCE remained significantly associated with rebleeding (p < 0.01 and p = 0.02, respectively). Multivariate regression identified that both rebleeding (HR 21.5, p < 0.01) and DCI (HR 10.1, p = 0.01) independently predicted poor functional outcome.CONCLUSIONSRebleeding and DCI after aSAH are highly morbid and potentially deadly events after aSAH, which appear to have independent negative impacts on overall functional outcome. Early rebleeding did not significantly affect the risk of delayed ischemic complications.

Background Endoscopic resection (ER) for uncommon sinonasal malignancies (SNMs) has been reported to confer superior surgical outcomes compared to open resection (OR) based on indirect comparisons of limited evidence. Objective The aim of this study was to pool all direct comparative studies in the literature to validate this potential superior association. Methods Systematic searches of 7 electronic databases from their inception to April 2019 were conducted following Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. There were 1001 articles identified for screening. Outcomes of interest were pooled as risk ratios (RRs) and mean difference (MD) and analyzed using a random-effects model. Results There were 10 studies included in this meta-analysis, with 900 SNM patients in total where ER and OR were utilized in 399 (44%) and 501 (56%) cases, respectively. Compared to OR, random-effects (RE) modeling indicated ER resulted in statistically comparable complications (RR = 0.68; P-effect = .12) and recurrence (RR = 0.84; P-effect = .35). ER was associated with significantly shorter length of stay (LOS) compared to OR (MD = −2.9 days; P-effect <.01). Conclusions The use of ER to manage SNM was associated with significantly favorable reduction in LOS compared to OR. However, with respect to other surgical outcomes and recurrence, the current literature does not indicate either ER or OR as statistically superior. Therefore, until greater validation of these associations can be proven, expectations that ER for SNMs confers superior surgical outcomes compared to OR should be tempered.