Low Prevalence of Clinically Significant Hyponatremia following Cranial Vault Reconstruction for Single-Suture Craniosynostosis.

BACKGROUND: Patients are commonly monitored for hyponatremia after intracranial procedures, yet the prevalence of hyponatremia after cranial vault reconstruction (CVR) remains unclear. The purpose of this study is to define the prevalence, risk factors, and complications of hyponatremia after CVR to optimize postoperative sodium surveillance protocols. METHODS: Patients with nonsyndromic, single-suture craniosynostosis who underwent primary CVR between 2009 and 2020 at Michigan Medicine were included (n = 231). Demographic, intraoperative, and postoperative characteristics were compared by postoperative hyponatremia status at P < 0.05 significance. Hyponatremia was defined as mild (<135 mEq/L), moderate (<130 mEq/L), or severe (<125 mEq/L) based on the lowest postoperative laboratory draw. RESULTS: Twenty-three patients (10.0%) developed mild postoperative hyponatremia. No patient developed moderate or severe postoperative hyponatremia. On multivariable regression, decreased preoperative sodium level (P = 0.03) and decreased preoperative weight (P = 0.02) were significantly associated with mild postoperative hyponatremia. No patient developed complications or required hospital readmission because of hyponatremia. CONCLUSIONS: This large retrospective cohort study of patients with nonsyndromic single-suture craniosynostosis demonstrated a 10% prevalence of mild, clinically inconsequential hyponatremia and 0% prevalence of moderate or severe, clinically significant hyponatremia after primary CVR. Patients with low preoperative sodium level or weight were at increased risk for developing mild postoperative hyponatremia. The results suggest that patients with preoperative sodium greater than 140 mEq/L or preoperative weight greater than 10 kg may be candidates for limited postoperative sodium surveillance; however, future prospective studies are warranted before implementation. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

Influence of socioeconomic status on clinical outcomes of diffuse midline glioma and diffuse intrinsic pontine glioma.

OBJECTIVE: Given the lack of a definitive treatment and the poor prognosis of patients with diffuse midline glioma (DMG) and diffuse intrinsic pontine glioma (DIPG), socioeconomic status (SES) may affect treatment access and therefore survival. Therefore, this study aimed to examine the relationship between SES and treatment modalities, progression-free survival (PFS), and overall survival (OS) in children with DMG/DIPG. METHODS: A retrospective, single-institution review was conducted of medical records of patients ≤ 18 years of age who had DMG or DIPG that was diagnosed between 2000 and 2022. Patient demographics, surgical interventions, chemotherapy, radiation therapy, clinical trial enrollment, and medical care-related travel were extracted. SES variables (education and mean income) for associated patient census tracts were collected and stratified. Statistical analysis using unpaired t-tests, chi-square analysis, and log-rank tests was conducted. RESULTS: Of the 96 patients who met the inclusion criteria, the majority were female (59%) and non-Hispanic White (57%). The median PFS, median OS, and time from diagnosis to treatment did not differ between races/ethnicities or sex. Ninety-one of 96 patients had census tract data available. Patients from higher-income census tracts (> 50% of families with annual household income greater than $50,000) had a longer median OS (480 vs 235 days, p < 0.001) and traveled significantly longer distances for medical care (1550 vs 1114 miles, p = 0.048) than families from lower-income census tracts. Patients from the highest education quartile traveled significantly farther for treatment than the lowest education quartile (mean 2964 vs 478 miles, p = 0.047). Patients who received both oral and intravenous chemotherapy were more likely to be from higher-income census tracts than those who received intravenous or no chemotherapy. Duration of PFS, rates of clinical trial enrollment, biopsy rates, H3K27 mutation status, ventriculoperitoneal shunt placement rates, and radiotherapy rates were not associated with SES variables. CONCLUSIONS: Patients from families from higher-income census tracts experienced longer OS and traveled farther for treatment. Patients from families from higher-education-level census tracts traveled more often for treatment. The authors' findings suggest that SES influences DMG and DIPG OS. More studies should be done to understand the role of SES in the outcomes of children with DMG/DIPG.

A road map for the treatment of pediatric diffuse midline glioma.

Recent clinical trials for H3K27-altered diffuse midline gliomas (DMGs) have shown much promise. We present a consensus roadmap and identify three major barriers: (1) refinement of experimental models to include immune and brain-specific components; (2) collaboration among researchers, clinicians, and industry to integrate patient-derived data through sharing, transparency, and regulatory considerations; and (3) streamlining clinical efforts including biopsy, CNS-drug delivery, endpoint determination, and response monitoring. We highlight the importance of comprehensive collaboration to advance the understanding, diagnostics, and therapeutics for DMGs.

Combined cytotoxic and immune-stimulatory gene therapy for primary adult high-grade glioma: a phase 1, first-in-human trial.

BACKGROUND: High-grade gliomas have a poor prognosis and do not respond well to treatment. Effective cancer immune responses depend on functional immune cells, which are typically absent from the brain. This study aimed to evaluate the safety and activity of two adenoviral vectors expressing HSV1-TK (Ad-hCMV-TK) and Flt3L (Ad-hCMV-Flt3L) in patients with high-grade glioma. METHODS: In this dose-finding, first-in-human trial, treatment-naive adults aged 18-75 years with newly identified high-grade glioma that was evaluated per immunotherapy response assessment in neuro-oncology criteria, and a Karnofsky Performance Status score of 70 or more, underwent maximal safe resection followed by injections of adenoviral vectors expressing HSV1-TK and Flt3L into the tumour bed. The study was conducted at the University of Michigan Medical School, Michigan Medicine (Ann Arbor, MI, USA). The study included six escalating doses of viral particles with starting doses of 1×1010 Ad-hCMV-TK viral particles and 1×109 Ad-hCMV-Flt3L viral particles (cohort A), and then 1×1011 Ad-hCMV-TK viral particles and 1×109 Ad-hCMV-Flt3L viral particles (cohort B), 1×1010 Ad-hCMV-TK viral particles and 1×1010 Ad-hCMV-Flt3L viral particles (cohort C), 1×1011 Ad-hCMV-TK viral particles and 1×1010 Ad-hCMV-Flt3L viral particles (cohort D), 1×1010 Ad-hCMV-TK viral particles and 1×1011 Ad-hCMV-Flt3L viral particles (cohort E), and 1×1011 Ad-hCMV-TK viral particles and 1×1011 Ad-hCMV-Flt3L viral particles (cohort F) following a 3+3 design. Two 1 mL tuberculin syringes were used to deliver freehand a mix of Ad-hCMV-TK and Ad-hCMV-Flt3L vectors into the walls of the resection cavity with a total injection of 2 mL distributed as 0·1 mL per site across 20 locations. Subsequently, patients received two 14-day courses of valacyclovir (2 g orally, three times per day) at 1-3 days and 10-12 weeks after vector administration and standad upfront chemoradiotherapy. The primary endpoint was the maximum tolerated dose of Ad-hCMV-Flt3L and Ad-hCMV-TK. Overall survival was a secondary endpoint. Recruitment is complete and the trial is finished. The trial is registered with ClinicalTrials.gov, NCT01811992. FINDINGS: Between April 8, 2014, and March 13, 2019, 21 patients were assessed for eligibility and 18 patients with high-grade glioma were enrolled and included in the analysis (three patients in each of the six dose cohorts); eight patients were female and ten were male. Neuropathological examination identified 14 (78%) patients with glioblastoma, three (17%) with gliosarcoma, and one (6%) with anaplastic ependymoma. The treatment was well-tolerated, and no dose-limiting toxicity was observed. The maximum tolerated dose was not reached. The most common serious grade 3-4 adverse events across all treatment groups were wound infection (four events in two patients) and thromboembolic events (five events in four patients). One death due to an adverse event (respiratory failure) occurred but was not related to study treatment. No treatment-related deaths occurred during the study. Median overall survival was 21·3 months (95% CI 11·1-26·1). INTERPRETATION: The combination of two adenoviral vectors demonstrated safety and feasibility in patients with high-grade glioma and warrants further investigation in a phase 1b/2 clinical trial. FUNDING: Funded in part by Phase One Foundation, Los Angeles, CA, The Board of Governors at Cedars-Sinai Medical Center, Los Angeles, CA, and The Rogel Cancer Center at The University of Michigan.

Sports Participation and Sports-Related Neurologic Injuries in Pediatric Patients With Arachnoid Cysts.

BACKGROUND: Currently, there is no consensus recommendation regarding the safety of sports participation for pediatric patients with arachnoid cysts (ACs). OBJECTIVE: To prospectively survey patients with ACs to define the risk of sports-associated neurologic injury in untreated and treated patients. METHODS: A prospectively administered survey was given to all patients diagnosed with an AC who presented to a single pediatric neurosurgery clinic between December 2010 and December 2021. Data were recorded on demographic information, imaging characteristics, treatment, sports participation, and presence of sports-related neurologic injury. The type and date of surgery for the AC were noted if surgery was performed. RESULTS: Of the 303 patients with completed surveys, 189 patients participated in sports, and 94 patients had prospective data available. There was no significant difference in cyst location or Galassi score between patients who did and did not participate in contact vs noncontact sports and those who did and did not experience a concussion. A cumulative total of 2700.5 seasons of sports were played (2499.7 in untreated and 200.8 in treated patients). There were 44 sports-related concussions among 34 patients: 43 in untreated patients and 1 in a treated patient. For all participants, the concussion rate was 16.3 per 1000 seasons of all sports and 14.8 per 1000 seasons of contact sports. The concussion rate after AC treatment was 4.9 per 1000 seasons of all sports. Three patients experienced sports-related AC rupture or hemorrhage, none of which required surgery or resulted in lasting neurologic symptoms or deficits. CONCLUSION: The rates of sports-related concussion and cyst rupture in patients with AC in both treated and untreated populations were low. We advocate for a generally permissive posture toward sports participation in this population.

102 AI-Based Molecular Classification of Diffuse Gliomas using Rapid, Label-Free Optical Imaging.

INTRODUCTION: Molecular classification has transformed the management of brain tumors by enabling more accurate prognostication and personalized treatment. Access to timely molecular diagnostic testing for brain tumor patients is limited, complicating surgical and adjuvant treatment and obstructing clinical trial enrollment. METHODS: By combining stimulated Raman histology (SRH), a rapid, label-free, non-consumptive, optical imaging method, and deep learning-based image classification, we are able to predict the molecular genetic features used by the World Health Organization (WHO) to define the adult-type diffuse glioma taxonomy, including IDH-1/2, 1p19q-codeletion, and ATRX loss. We developed a multimodal deep neural network training strategy that uses both SRH images and large-scale, public diffuse glioma genomic data (i.e. TCGA, CGGA, etc.) in order to achieve optimal molecular classification performance. RESULTS: One institution was used for model training (University of Michigan) and four institutions (NYU, UCSF, Medical University of Vienna, and University Hospital Cologne) were included for patient enrollment in the prospective testing cohort. Using our system, called DeepGlioma, we achieved an average molecular genetic classification accuracy of 93.2% and identified the correct diffuse glioma molecular subgroup with 91.5% accuracy within 2 minutes in the operating room. DeepGlioma outperformed conventional IDH1-R132H immunohistochemistry (94.2% versus 91.4% accuracy) as a first-line molecular diagnostic screening method for diffuse gliomas and can detect canonical and non-canonical IDH mutations. CONCLUSIONS: Our results demonstrate how artificial intelligence and optical histology can be used to provide a rapid and scalable alternative to wet lab methods for the molecular diagnosis of brain tumor patients during surgery.

Metabolomic Profiles of Human Glioma Inform Patient Survival.

Aims: Targeting tumor metabolism may improve the outcomes for patients with glioblastoma (GBM). To further preclinical efforts targeting metabolism in GBM, we tested the hypothesis that brain tumors can be stratified into distinct metabolic groups with different patient outcomes. Therefore, to determine if tumor metabolites relate to patient survival, we profiled the metabolomes of human gliomas and correlated metabolic information with clinical data. Results: We found that isocitrate dehydrogenase-wildtype (IDHwt) GBMs are metabolically distinguishable from IDH mutated (IDHmut) astrocytomas and oligodendrogliomas. Survival of patients with IDHmut gliomas was expectedly more favorable than those with IDHwt GBM, and metabolic signatures can stratify IDHwt GBMs subtypes with varying prognoses. Patients whose GBMs were enriched in amino acids had improved survival, while those whose tumors were enriched for nucleotides, redox molecules, and lipid metabolites fared more poorly. These findings were recapitulated in validation cohorts using both metabolomic and transcriptomic data. Innovation: Our results suggest the existence of metabolic subtypes of GBM with differing prognoses, and further support the concept that metabolism may drive the aggressiveness of human gliomas. Conclusions: Our data show that metabolic signatures of human gliomas can inform patient survival. These findings may be used clinically to tailor novel metabolically targeted agents for GBM patients with different metabolic phenotypes. Antioxid. Redox Signal. 39, 942-956.

Subclonal evolution and expansion of spatially distinct THY1-positive cells is associated with recurrence in glioblastoma.

PURPOSE: Glioblastoma(GBM) is a lethal disease characterized by inevitable recurrence. Here we investigate the molecular pathways mediating resistance, with the goal of identifying novel therapeutic opportunities. EXPERIMENTAL DESIGN: We developed a longitudinal in vivo recurrence model utilizing patient-derived explants to produce paired specimens(pre- and post-recurrence) following temozolomide(TMZ) and radiation(IR). These specimens were evaluated for treatment response and to identify gene expression pathways driving treatment resistance. Findings were clinically validated using spatial transcriptomics of human GBMs. RESULTS: These studies reveal in replicate cohorts, a gene expression profile characterized by upregulation of mesenchymal and stem-like genes at recurrence. Analyses of clinical databases revealed significant association of this transcriptional profile with worse overall survival and upregulation at recurrence. Notably, gene expression analyses identified upregulation of TGFß signaling, and more than one-hundred-fold increase in THY1 levels at recurrence. Furthermore, THY1-positive cells represented <10% of cells in treatment-naïve tumors, compared to 75-96% in recurrent tumors. We then isolated THY1-positive cells from treatment-naïve patient samples and determined that they were inherently resistant to chemoradiation in orthotopic models. Additionally, using image-guided biopsies from treatment-naïve human GBM, we conducted spatial transcriptomic analyses. This revealed rare THY1+ regions characterized by mesenchymal/stem-like gene expression, analogous to our recurrent mouse model, which co-localized with macrophages within the perivascular niche. We then inhibited TGFBRI activity in vivo which decreased mesenchymal/stem-like protein levels, including THY1, and restored sensitivity to TMZ/IR in recurrent tumors. CONCLUSIONS: These findings reveal that GBM recurrence may result from tumor repopulation by pre-existing, therapy-resistant, THY1-positive, mesenchymal cells within the perivascular niche.

Neurosurgery residency and fellowship education in the United States: 2 decades of system development by the One Neurosurgery Summit organizations.

The purpose of this report is to chronicle a 2-decade period of educational innovation and improvement, as well as governance reform, across the specialty of neurological surgery. Neurological surgery educational and professional governance systems have evolved substantially over the past 2 decades with the goal of improving training outcomes, patient safety, and the quality of US neurosurgical care. Innovations during this period have included the following: creating a consensus national curriculum; standardizing the length and structure of neurosurgical training; introducing educational outcomes milestones and required case minimums; establishing national skills, safety, and professionalism courses; systematically accrediting subspecialty fellowships; expanding professional development for educators; promoting training in research; and coordinating policy and strategy through the cooperation of national stakeholder organizations. A series of education summits held between 2007 and 2009 restructured some aspects of neurosurgical residency training. Since 2010, ongoing meetings of the One Neurosurgery Summit have provided strategic coordination for specialty definition, neurosurgical education, public policy, and governance. The Summit now includes leadership representatives from the Society of Neurological Surgeons, the American Association of Neurological Surgeons, the Congress of Neurological Surgeons, the American Board of Neurological Surgery, the Review Committee for Neurological Surgery of the Accreditation Council for Graduate Medical Education, the American Academy of Neurological Surgery, and the AANS/CNS Joint Washington Committee. Together, these organizations have increased the effectiveness and efficiency of the specialty of neurosurgery in advancing educational best practices, aligning policymaking, and coordinating strategic planning in order to meet the highest standards of professionalism and promote public health.

Targeting integrated epigenetic and metabolic pathways in lethal childhood PFA ependymomas.

Childhood posterior fossa group A ependymomas (PFAs) have limited treatment options and bear dismal prognoses compared to group B ependymomas (PFBs). PFAs overexpress the oncohistone-like protein EZHIP (enhancer of Zeste homologs inhibitory protein), causing global reduction of repressive histone H3 lysine 27 trimethylation (H3K27me3), similar to the oncohistone H3K27M. Integrated metabolic analyses in patient-derived cells and tumors, single-cell RNA sequencing of tumors, and noninvasive metabolic imaging in patients demonstrated enhanced glycolysis and tricarboxylic acid (TCA) cycle metabolism in PFAs. Furthermore, high glycolytic gene expression in PFAs was associated with a poor outcome. PFAs demonstrated high EZHIP expression associated with poor prognosis and elevated activating mark histone H3 lysine 27 acetylation (H3K27ac). Genomic H3K27ac was enriched in PFAs at key glycolytic and TCA cycle­related genes including hexokinase-2 and pyruvate dehydrogenase. Similarly, mouse neuronal stem cells (NSCs) expressing wild-type EZHIP (EZHIP-WT) versus catalytically attenuated EZHIP-M406K demonstrated H3K27ac enrichment at hexokinase-2 and pyruvate dehydrogenase, accompanied by enhanced glycolysis and TCA cycle metabolism. AMPKα-2, a key component of the metabolic regulator AMP-activated protein kinase (AMPK), also showed H3K27ac enrichment in PFAs and EZHIP-WT NSCs. The AMPK activator metformin lowered EZHIP protein concentrations, increased H3K27me3, suppressed TCA cycle metabolism, and showed therapeutic efficacy in vitro and in vivo in patient-derived PFA xenografts in mice. Our data indicate that PFAs and EZHIP-WT­expressing NSCs are characterized by enhanced glycolysis and TCA cycle metabolism. Repurposing the antidiabetic drug metformin lowered pathogenic EZHIP, increased H3K27me3, and suppressed tumor growth, suggesting that targeting integrated metabolic/epigenetic pathways is a potential therapeutic strategy for treating childhood ependymomas.

Longitudinal scoliosis behavior in Chiari malformation with and without syringomyelia.

OBJECTIVE: The objective of this study was to understand the natural history of scoliosis in patients with Chiari malformation type I (CM-I) with and without syringomyelia. METHODS: A retrospective review of data was conducted. Patients with CM-I were identified from a cohort of 14,118 individuals age 18 years or younger who had undergone MRI over an 11-year period at the University of Michigan. Patients eligible for study inclusion had a coronal curve ≥ 10° on radiography, associated CM-I with or without syringomyelia, and at least 1 year of clinical follow-up prior to any surgery. Curve magnitude at initial diagnosis, prior to posterior fossa decompression (PFD; if applicable), and at the last follow-up (prior to any surgical correction of scoliosis) was recorded, and clinical and radiographic characteristics were noted. The change in curve magnitude by 10° was defined as curve progression (increase by 10°) or regression (decrease by 10°). RESULTS: Forty-three patients met the study inclusion criteria and were analyzed. About one-third (35%) of the patients presented with symptoms attributed to their CM-I. The mean degree of scoliosis at presentation was 32.6° ± 17.7°. Twenty-one patients (49%) had an associated syrinx. The mean tonsil position below the level of the foramen magnum was 9.8 ± 5.8 mm. Patients with a syrinx were more likely to have a curve > 20° (86% vs 41%, p = 0.002). Curve magnitude remained stable (≤ ±10°) in 77% of patients (33/43), progressed in 16% (7/43), and regressed in 7% (3/43). Mean age was higher (14.8 ± 0.59 years) among patients with regressed curves (p = 0.026). All regressed curves initially measured ≤ 20° (mean 14° ± 5.3°), and none of the patients with regressed curves had a syrinx. The change in curve magnitude was statistically similar in patients with (7.32° ± 17.7°) and without (5.32° ± 15.8°) a syrinx (p = 0.67). After a mean follow-up of 3.13 ± 2.04 years prior to surgery, 27 patients (63%) ultimately underwent posterior fossa or scoliosis correction surgery. For those who eventually underwent PFD only, the rate of change in curve magnitude prior to surgery was 0.054° ± 0.79°. The rate of change in curve magnitude was statistically similar before (0.054° ± 0.79°) and after (0.042° ± 0.33°) surgery (p = 0.45) for patients who underwent PFD surgery only. CONCLUSIONS: The natural history of scoliosis in the presence of CM-I is variable, though most curves remained stable. All curves that regressed were ≤ 20° at initial diagnosis, and most patients in such cases were older at scoliosis diagnosis. Patients who underwent no surgery or PFD only had similar profiles for the change in curve magnitude, which remained relatively stable overall, as compared to patients who underwent PFD and subsequent fusion, who demonstrated curve progression. Among the patients with a syrinx, no curves regressed, most remained stable, and some progressed. Understanding this variability is a first step toward building a prediction model for outcomes for these patients.

Management of Calcified Cephalohematoma of Infancy: The University of Michigan 25-Year Experience.

BACKGROUND: Cephalohematoma of infancy is the result of a subperiosteal blood collection that usually forms during birth-related trauma. A small proportion of cephalohematomas can calcify over time, causing a permanent calvarial deformity that is only correctable with surgery. The authors present a technique for the excision and reconstruction of calcified cephalohematoma and their management experience over the past 25 years. METHODS: All patients with a diagnosis of calcified cephalohematoma between 1994 and 2019 were identified. Patients were included if the diagnosis was confirmed by a pediatric plastic surgeon or a neurosurgeon. All patients underwent surgical evaluation followed by surgical intervention or observation. Patient demographics and potential risk factors for both surgical and nonsurgical groups were compared using chi-square or Fisher's exact test. Additional data were collected for the surgical cohort. RESULTS: Of 160 infants diagnosed with cephalohematoma, 72 met inclusion criteria. Thirty patients underwent surgical treatment. There was no significant difference in demographics, baseline characteristics, or potential risk factors between the operative and nonoperative groups. Mean age at the time of surgery was 8.6 months. Twenty-one surgical patients (70 percent) required inlay bone grafting. All surgery patients had improvement in calvarial shape. The main risk of surgery was blood loss requiring transfusion [eight patients (26.7 percent)]. Thirteen percent of patients experienced minor complications. CONCLUSIONS: This series of 72 children with calcified cephalohematomas, 30 of whom required surgical intervention, is one of the largest to date. The technique presented herein demonstrated excellent surgical outcomes by restoring normal cranial contours and was associated with a low complication profile. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Children's Oncology Group Phase III Trial of Reduced-Dose and Reduced-Volume Radiotherapy With Chemotherapy for Newly Diagnosed Average-Risk Medulloblastoma.

PURPOSE: Children with average-risk medulloblastoma (MB) experience survival rates of ≥ 80% at the expense of adverse consequences of treatment. Efforts to mitigate these effects include deintensification of craniospinal irradiation (CSI) dose and volume. METHODS: ACNS0331 (ClinicalTrials.gov identifier: NCT00085735) randomly assigned patients age 3-21 years with average-risk MB to receive posterior fossa radiation therapy (PFRT) or involved field radiation therapy (IFRT) following CSI. Young children (3-7 years) were also randomly assigned to receive standard-dose CSI (SDCSI; 23.4 Gy) or low-dose CSI (LDCSI; 18 Gy). Post hoc molecular classification and mutational analysis contextualized outcomes according to known biologic subgroups (Wingless, Sonic Hedgehog, group 3, and group 4) and genetic biomarkers. Neurocognitive changes and ototoxicity were monitored over time. RESULTS: Five hundred forty-nine patients were enrolled on study, of which 464 were eligible and evaluable to compare PFRT versus IFRT and 226 for SDCSI versus LDCSI. The five-year event-free survival (EFS) was 82.5% (95% CI, 77.2 to 87.8) and 80.5% (95% CI, 75.2 to 85.8) for the IFRT and PFRT regimens, respectively, and 71.4% (95% CI, 62.8 to 80) and 82.9% (95% CI, 75.6 to 90.2) for the LDCSI and SDCSI regimens, respectively. IFRT was not inferior to PFRT (hazard ratio, 0.97; 94% upper CI, 1.32). LDCSI was inferior to SDCSI (hazard ratio, 1.67%; 80% upper CI, 2.10). Improved EFS was observed in patients with Sonic Hedgehog MB who were randomly assigned to the IFRT arm (P = .018). Patients with group 4 MB receiving LDCSI exhibited inferior EFS (P = .047). Children receiving SDCSI exhibited greater late declines in IQ (estimate = 5.87; P = .021). CONCLUSION: Reducing the radiation boost volume in average-risk MB is safe and does not compromise survival. Reducing CSI dose in young children with average-risk MB results in inferior outcomes, possibly in a subgroup-dependent manner, but is associated with better neurocognitive outcome. Molecularly informed patient selection warrants further exploration for children with MB to be considered for late-effect sparing approaches.

Weighing In on the Controversy: Preoperative Imaging in Unicoronal Craniosynostosis Leads to Strategic Changes in Surgical Care.

BACKGROUND: Clinical findings in children with unilateral coronal craniosynostosis are characteristic, and therefore clinicians have questioned the need for confirmatory imaging. Preoperative computed tomographic imaging is a powerful tool for diagnosing associated anomalies that can alter treatment management and surgical planning. The authors' aim was to determine whether and how routine preoperative imaging affected treatment management in unilateral coronal craniosynostosis patients within their institution. METHODS: A retrospective, single-center review of all patients who underwent cranial vault remodeling for unilateral coronal craniosynostosis between 2006 and 2014 was performed. Patient data included demographics, age at computed tomographic scan, age at surgery, results of the radiographic evaluation, and modification of treatment following radiologic examination. RESULTS: Of 194 patients diagnosed with single-suture craniosynostosis, 29 were diagnosed with unilateral coronal craniosynostosis. Additional radiographic anomalies were found in 19 unilateral coronal craniosynostosis patients (65.5 percent). These included severe deviation of the anterior superior sagittal sinus [n = 12 (41.4 percent)], Chiari I malformation [n = 1 (3.4 percent)], and benign external hydrocephalus [n = 2 (6.9 percent)]. The radiographic anomalies resulted in a change in management for 48.3 percent of patients. Specifically, alteration in frontal craniotomy design occurred in 12 patients (41.4 percent), and two patients (6.9 percent) required further radiographic studies. CONCLUSIONS: Although clinical findings in children with unilateral coronal craniosynostosis are prototypical, preoperative computed tomographic imaging is still of great consequence and continues to play an important role in surgical management. Preoperative imaging enabled surgeons to alter surgical management and avoid inadvertent complications such as damage to a deviated superior sagittal sinus. Imaging findings of Chiari malformation and hydrocephalus also permitted judicious follow-up. CLINICAL QUESTIONS/LEVEL OF EVIDENCE: Therapeutic, IV.

Computed Tomography in Patients With Craniosynostosis: A Survey to Ascertain Practice Patterns Among Craniofacial Surgeons.

BACKGROUND: In patients with craniosynostosis, imaging remains up to the discretion of the plastic surgeon or neurosurgeon. To inform best practice guidelines, we sought to obtain data surrounding the frequency at which craniofacial surgeons order computed tomography (CT), as well as indications. We hypothesized that we would identify considerable variation in both imaging and associated indications. METHODS: We surveyed members of the American Society of Maxillofacial Surgeons and the American Society of Craniofacial Surgeons to measure the frequency of preoperative and postoperative head CTs, as well as indications. Initial items were piloted with 2 craniofacial surgeons and 1 neurosurgeon, using interviews to ensure content validity. χ2 Tests were used to measure associations between operative volume, years in practice, and imaging. RESULTS: Eighty-five craniofacial surgeons responded (13.8% response rate), with the majority (63.5%) having performed a craniosynostosis operation in the last month. Only 9.4% of surgeons never order preoperative CTs. Of those who do, the most common indications included diagnosis confirmation (31.2%) and preoperative planning (27.3%). About 25% of surgeons always obtain postoperative head CTs, usually to evaluate surgical outcomes (46.7%). Only 13.3% of respondents order 2 or more postoperative scans. Higher operative volume was associated with a lower likelihood of ordering preoperative head CTs (P = 0.008). CONCLUSIONS: The majority of surgeons obtain preoperative head CTs, whereas only 25% obtain CTs postoperatively, often to evaluate outcomes. Because outcomes may be evaluated clinically, this is a poor use of resources and exposes children to radiation. Consensus guidelines are needed to create best practices and limit unnecessary studies.

A Simplified Approach to Myelomeningocele Defect Repair.

BACKGROUND: Repair of the soft tissue defect in myelomeningoceles remains challenging. The literature currently lacks a systematic approach, reporting high rates of complications. We present outcomes from the largest series to date and describe a simplified approach that minimizes morbidity and streamlines decision making. METHODS: Patients 1 year or younger who underwent myelomeningocele repair between 2008 and 2018 were reviewed. Flap types were categorized by tissue composition. Complications were dichotomized into early and late (<30 days and >30 days postoperative, respectively). Logistic regression was used to measure the impact of flap tissue composition and skin closure technique on odds of postoperative complications. RESULTS: Ninety-seven patients met inclusion criteria. Reoperation was required in only 3 (3.0%) patients-1 for wound dehiscence and 2 for surgical site infections. Zero cases of tethered cord or cerebrospinal fluid leak occurred. The most common minor complications were early wound complications (n = 18, 18.6%) and early infection (n = 5, 5.2%). Fascia-only flaps and muscle + other tissue flaps were not associated with higher odds of complications compared with muscle-only flaps (odds ratio [OR], 2.13; 95% confidence interval [CI], 0.53-8.50, P = 0.29; OR = 2.87, 95% CI 0.66-12.51, P = 0.16, respectively). Rhomboid flaps for skin closure were associated with higher odds of complications (OR, 4.47; 95% CI, 1.00-19.97; P = 0.05). CONCLUSIONS: Our approach to myelomeningocele repair demonstrated no cases of secondary tethered cord or cerebrospinal fluid leak, and reoperative rates were extremely low. Because complications were unrelated to flap type, we recommend a simplified approach using any tissue type for dural coverage and 2-layer primary closure of the skin.

Electronic DNA Analysis of CSF Cell-free Tumor DNA to Quantify Multi-gene Molecular Response in Pediatric High-grade Glioma.

PURPOSE: Pediatric high-grade glioma (pHGG) diagnosis portends poor prognosis and therapeutic monitoring remains difficult. Tumors release cell-free tumor DNA (cf-tDNA) into cerebrospinal fluid (CSF), allowing for potential detection of tumor-associated mutations by CSF sampling. We hypothesized that direct, electronic analysis of cf-tDNA with a handheld platform (Oxford Nanopore MinION) could quantify patient-specific CSF cf-tDNA variant allele fraction (VAF) with improved speed and limit of detection compared with established methods. EXPERIMENTAL DESIGN: We performed ultra-short fragment (100-200 bp) PCR amplification of cf-tDNA for clinically actionable alterations in CSF and tumor samples from patients with pHGG (n = 12) alongside nontumor CSF (n = 6). PCR products underwent rapid amplicon-based sequencing by Oxford Nanopore Technology (Nanopore) with quantification of VAF. Additional comparison to next-generation sequencing (NGS) and droplet digital PCR (ddPCR) was performed. RESULTS: Nanopore demonstrated 85% sensitivity and 100% specificity in CSF samples (n = 127 replicates) with 0.1 femtomole DNA limit of detection and 12-hour results, all of which compared favorably with NGS. Multiplexed analysis provided concurrent analysis of H3.3A (H3F3A) and H3C2 (HIST1H3B) mutations in a nonbiopsied patient and results were confirmed by ddPCR. Serial CSF cf-tDNA sequencing by Nanopore demonstrated correlation of radiological response on a clinical trial, with one patient showing dramatic multi-gene molecular response that predicted long-term clinical response. CONCLUSIONS: Nanopore sequencing of ultra-short pHGG CSF cf-tDNA fragments is feasible, efficient, and sensitive with low-input samples thus overcoming many of the barriers restricting wider use of CSF cf-tDNA diagnosis and monitoring in this patient population.

Pregnancy and parental leave among neurosurgeons and neurosurgical trainees.

OBJECTIVE: Despite recently heightened advocacy efforts relating to pregnancy and family leave policies in multiple surgical specialties, no studies to date have described female neurosurgeons' experiences with childbearing. The AANS/CNS Section of Women in Neurosurgery created the Women and Pregnancy Task Force to ascertain female neurosurgeons' experiences with and attitudes toward pregnancy and the role of family leave policies. METHODS: A voluntary online 28-question survey examined the pregnancy experiences of female neurosurgeons and perceived barriers to childbearing. The survey was developed and electronically distributed to all members of the American Association of Neurological Surgeons and Congress of Neurological Surgeons who self-identified as female in February 2016. Responses from female resident physicians, fellows, and current or retired practicing neurosurgeons were analyzed. RESULTS: A total of 126 women (20.3%) responded to the survey; 57 participants (49%) already had children, and 39 (33%) planned to do so. Participants overwhelmingly had or planned to have children during the early practice and senior residency years. The most frequent obstacles experienced or anticipated included insufficient time to care for newborns (47% of women with children, 92% of women planning to have children), discrimination by coworkers (31% and 77%, respectively), and inadequate time for completion of board requirements (18% and 51%, respectively). There was substantial variability in family leave policies, and a minority of participants (35%) endorsed the presence of any formal policy at their institution. Respondents described myriad unique challenges associated with pregnancy and family leave. CONCLUSIONS: Pregnancy and family leave pose significant challenges to the recruitment, retention, and advancement of women in neurosurgery. It is thus imperative to promote clear family leave policies for trainees and practitioners, address discrimination surrounding these topics, and encourage forethought and flexibility to tackle obstacles inherent in pregnancy and the early stages of child rearing.

Near real-time intraoperative brain tumor diagnosis using stimulated Raman histology and deep neural networks.

Intraoperative diagnosis is essential for providing safe and effective care during cancer surgery1. The existing workflow for intraoperative diagnosis based on hematoxylin and eosin staining of processed tissue is time, resource and labor intensive2,3. Moreover, interpretation of intraoperative histologic images is dependent on a contracting, unevenly distributed, pathology workforce4. In the present study, we report a parallel workflow that combines stimulated Raman histology (SRH)5-7, a label-free optical imaging method and deep convolutional neural networks (CNNs) to predict diagnosis at the bedside in near real-time in an automated fashion. Specifically, our CNNs, trained on over 2.5 million SRH images, predict brain tumor diagnosis in the operating room in under 150 s, an order of magnitude faster than conventional techniques (for example, 20-30 min)2. In a multicenter, prospective clinical trial (n = 278), we demonstrated that CNN-based diagnosis of SRH images was noninferior to pathologist-based interpretation of conventional histologic images (overall accuracy, 94.6% versus 93.9%). Our CNNs learned a hierarchy of recognizable histologic feature representations to classify the major histopathologic classes of brain tumors. In addition, we implemented a semantic segmentation method to identify tumor-infiltrated diagnostic regions within SRH images. These results demonstrate how intraoperative cancer diagnosis can be streamlined, creating a complementary pathway for tissue diagnosis that is independent of a traditional pathology laboratory.

Syringomyelia in children with closed spinal dysraphism: long-term outcomes after surgical intervention.

OBJECTIVE: The nature of the relationship between spinal cord syrinx and tethered cord is not well known. It is unclear if surgical cord untethering results in resolution or improvement of an associated syrinx. The objective of this study was to report the response of spinal cord syrinx to surgical cord untethering. METHODS: The authors retrospectively reviewed all patients with a syrinx and tethered cord who presented to a single institution over an 11-year interval. Patients with open neural tube defects were excluded. Thirty-one patients were identified, 25 of whom had both clinical and imaging follow-up after surgery. Patients were grouped according to etiology of the tethered cord. Clinical outcomes and syrinx characteristics were recorded. RESULTS: Of the 25 patients with tethered cord, 68% (n = 17) were male. The average age at presentation was 2.5 years (0-10.1 years) and age at surgery was 3.7 years (range 1 day to 17 years). Etiologies of tethered cord were lipomyelomeningocele (n = 8), thickened/fatty filum (n = 7), intradural lipoma (n = 5), myelocystocele (n = 2), meningocele (n = 2), and diastematomyelia (n = 1). Twenty-three of the patients underwent primary untethering, whereas 2 patients had received untethering previously at another institution. The average syrinx length and width prior to surgery were 4.81 vertebral levels (SD 4.35) and 5.19 mm (SD 2.55 mm), respectively. Conus level ranged from L1 to S3. Patients were followed for an average of 8.4 years (1.35-15.85 years). Overall there was no significant change in syrinx length or width postoperatively; the average syrinx length increased by 0.86 vertebral levels (SD 4.36) and width decreased by 0.72 mm (SD 2.94 mm). Seven of 25 patients had improvement in at least one presenting symptom, including scoliosis, weakness, bowel/bladder dysfunction, and pain. Eight patients had stable presenting symptoms. Six patients were asymptomatic and 5 patients had new or worsening symptoms, which included scoliosis, pain, or sensory changes. CONCLUSIONS: Although some syrinxes improved after surgery for tethered cord, radiological improvement was not consistent and did not appear to be associated with change in clinical symptoms. The decision to surgically untether a cord should be focused on the clinical symptoms and not the presence of a syrinx alone. Further studies are needed to confirm this finding.