Isolated calvarial aneurysmal bone cyst in a pediatric patient: illustrative case.

BACKGROUND: Aneurysmal bone cysts (ABCs) are benign, osteolytic lesions that can occur in long bones, vertebrae, or rarely, the skull. Here the authors present the case of a 15-year-old male with a primary ABC of the left frontoparietal skull along with a review of the literature to provide insight into the nature of this rare disease. OBSERVATIONS: An otherwise healthy 15-year-old male presented with a tense, painful lesion of the left frontoparietal scalp. He could not identify any inciting trauma, but first noted the lesion less than 2 weeks prior to presentation with progressive enlargement. Cranial imaging revealed a lytic skull lesion with fluid-fluid levels suggestive of ABC. Curative therapy was provided via wide excision of the lesion and calvarial reconstruction of the resultant skull defect. This was performed without complication, and histopathological evaluation confirmed the diagnosis of primary ABC. LESSONS: ABCs of the skull are rare entities and most often arise in the skull base versus the calvaria. Typically, these lesions are associated with an underlying bone pathology (secondary ABCs) but can be rarely seen as isolated lesions (primary ABCs). Clinical management consists of excision and adjuvant therapy for underlying pathology where appropriate.

Mechanism of chronic iatrogenic CSF leak following dural puncture-ventral dural leak: case report.

BACKGROUND: Postdural puncture headache has been traditionally viewed as benign, self-limited, and highly responsive to epidural blood patching (EBP) when needed. A growing body of data from patients experiencing unintended dural puncture (UDP) in the setting of attempted labor epidural placement suggests a minority of patients will have more severe and persistent symptoms. However, the mechanisms accounting for the failure of EBP following dural puncture remain obscure. An understanding of these potential mechanisms is critical to guide management decisions in the face of severe and persistent cerebrospinal fluid (CSF) leak. CASE PRESENTATION: We report the case of a peripartum patient who developed a severe and persistent CSF leak unresponsive to multiple EBPs following a UDP during epidural catheter placement for labor analgesia. Lumbar MRI revealed a ventral rather than dorsal epidural fluid collection suggesting that the needle had crossed the thecal sac and punctured the ventral dura, creating a puncture site not readily accessible to blood injected in the dorsal epidural space. The location of this persistent ventral dural defect was confirmed with digital subtraction myelography, permitting a transdural surgical exploration and repair of the ventral dura with resolution of the severe intracranial hypotension. CONCLUSIONS: A ventral rather than dorsal dural puncture is one mechanism that may contribute to both severe and persistent spinal CSF leak with resulting intracranial hypotension following a UDP.

Approach, complications, and outcomes for 37 consecutive pediatric patients undergoing laser ablation for medically refractory epilepsy at Stanford Children's Health.

OBJECTIVE: The objective of this study was to better understand the safety and efficacy of laser interstitial thermal therapy (LITT) for children with medically refractory epilepsy. METHODS: Thirty-seven consecutive pediatric epilepsy patients at a single pediatric center who underwent LITT ablation of epileptogenic foci between May 2017 and December 2021 were retrospectively reviewed. Patient demographics, medication use, seizure frequency, prior surgical interventions, procedural details, and pre- and postoperative seizure history were analyzed. RESULTS: Thirty-seven pediatric patients (24 male, 13 female) with severe medically refractory epilepsy were included; all underwent stereo-electroencephalography (SEEG) prior to LITT. The SEEG electrode placement was based on the preoperative workup and tailored to each patient by the epileptologist and neurosurgeons working together to identify the epileptic network and hopefully quiet borders. Seizure onset was at a mean age of 2.70 ± 2.82 years (range 0.25-12 years), and the mean age at the time of LITT was 9.46 ± 5.08 years (range 2.41-17.86 years). Epilepsy was lesional in 23 patients (18 tuberous sclerosis, 4 focal cortical dysplasia, 1 gliosis) and nonlesional in 14. Eighteen patients had prior surgical interventions including open resections (n = 13: 11 single and 2 multiple), LITT (n = 4), or both (n = 1). LITT targeted a region adjacent to the previous target in 5 cases. The median number of lasers placed during the procedure was 3 (range 1-5). Complications occurred in 14 (37.8%) cases, only 3 (8.11%) of which resulted in a permanent deficit: 1 venous hemorrhage requiring evacuation following laser ablation, 1 aseptic meningitis, 2 immediate postoperative seizures, and 10 neurological deficits (7 transient and 3 permanent). Postoperatively, 22 (59.5%) patients were seizure free at the last follow-up (median follow-up 18.35 months, range 7.40-48.76 months), and the median modified Engel class was I (Engel class I in 22 patients, Engel class II in 2, Engel class III in 2, and Engel class IV in 11). Patients having tried a greater number of antiseizure medications before LITT were less likely to achieve seizure improvement (p = 0.046) or freedom (p = 0.017). Seizure improvement following LITT was associated with a shorter duration of epilepsy prior to LITT (p = 0.044), although postoperative seizure freedom was not associated with a shorter epilepsy duration (p = 0.667). Caregivers reported postoperative neurocognitive improvement in 17 (45.9%) patients. CONCLUSIONS: In this large single-institution cohort of pediatric patients with medically refractory seizures due to various etiologies, LITT was a relatively safe and effective surgical approach for seizure reduction and seizure freedom at 1 year of follow-up.

Cranial vault suspension for basilar invagination in patients with open cranial sutures: technique and long-term follow-up. Illustrative case.

BACKGROUND: Hajdu-Cheney syndrome (HCS) is an extremely rare genetic disorder characterized by severe osteoporosis, scoliosis, and persistent open cranial sutures (POCSs). Neurological complications include hydrocephalus, Chiari I malformations, and basilar invagination (BI). Surgical intervention in HCS is challenging due to severe osteoporosis, ligamentous laxity, POCSs, and extreme skeletal deformities. Herein, the authors present a case of BI repair in a patient with HCS and POCSs, requiring a novel technique of cranial vault suspension, with long-term follow-up. OBSERVATIONS: A 20-year-old female with HCS and progressive symptomatic BI, initially managed with posterior fossa decompression and occipital to cervical fusion, subsequently required cranial vault expansion due to symptomatic shifting of her cranium secondary to POCS. This custom construct provided long-term stabilization and neurological improvement over a follow-up duration of 9.5 years. A literature review performed revealed three other cases of surgical intervention for BI in patients with HCS and clinicopathological characteristics of each case was compared to the present illustrative case. LESSONS: POCSs in patients with BI complicate traditional surgical approaches, necessitating more invasive techniques to secure all mobile cranial parts for optimal outcomes. Using this cranial vault suspension and fusion technique results in lasting neurological improvement and construct stability.

Internal Auditory Canal Glioneural Hamartoma: A Rare Mass Masquerading as a Vestibular Schwannoma.

Glioneural hamartomas are exceedingly rare lesions. When localized to the internal auditory canal (IAC), they can cause symptoms referrable to seventh and eighth cranial nerve compression. Here, the authors present a rare case of an IAC glioneural hamartoma. A 57-year-old male presented for evaluation of presumed intracanalicular vestibular schwannomas found on work-up of dizziness and progressive right-sided hearing loss. Surgical intervention pursued progressive symptoms and new onset headaches. The patient underwent uncomplicated retrosigmoid craniectomy for gross total resection. Histopathological evaluation revealed a glioneural hamartoma. A MEDLINE database search used the terms' cerebellopontine angle' OR 'internal auditory canal' AND 'hamartoma' OR 'heterotopia'. Clinicopathological characteristics and outcomes of the present case were compared to those in the literature. The literature review yielded nine articles describing 11 cases (eight females, three males; median age 40 years, range 11-71) of intracanalicular glioneural hamartomas. Patients most commonly presented with hearing loss and were presumed to have a diagnosis of vestibular schwannoma before histologic diagnosis. Glioneural hamartomas are rare lesions that may be found in the IAC. Although benign, they may be safely resected for cranial nerve function preservation goals with a low risk of recurrence.

Transverse Split Laminoplasty: A Novel Anatomy Preserving Technique.

Laminoplasty is a technique often used in spine surgery as a way of restoring a patient's normal anatomy and posterior tension band (PTB). In pediatric patients, this is an important consideration given their intrinsic relative ligamentous laxity and significant potential for future growth. Conventional laminoplasty re-approximates the bone removed at each vertebral segment, relying on the lamina to heal through osteogenesis and the soft tissue of the PTB to heal from a sharp division. Ligamentous healing of the PTB constitutes the formation of a scar that is biologically and biomechanically inferior to the tissue it has replaced. Herein, the authors present two pediatric cases in which the novel technique of transverse split laminoplasty was used to approach intradural pathology and subsequently reconstruct the spine, while maximizing preservation of the PTB, with excellent post-surgical outcomes.

Cephalohematomas, an occult nidus for infection and inflammation: A case report and review of the literature.

Background: Cephalohematomas (CH) are benign neonatal fluid collections that arise between the periosteum and skull due to birth trauma, and usually resolve spontaneously without intervention. CH may rarely become infected. Case Description: The authors report a case of sterile CH requiring surgical evacuation in a persistently febrile neonate treated with intravenous (IV) antibiotics for Escherichia coli urosepsis. Diagnostic tap of the CH yielded no pathogens, but given the persistence of fevers, surgical evacuation was performed. The patient demonstrated clinical improvement postoperatively. Conclusion: A systematic review of literature was conducted through a MEDLINE search using the keyword "cephalohematoma." Articles were screened for cases of infected CH and their subsequent management. Clinicopathological characteristics and outcomes of the present case were reviewed and compared to those in the literature. Infected CH were reported in 25 articles describing 58 patients. Common pathogens included E. coli and Staphylococcal species. Treatment included a course of IV antibiotics (10 days-6 weeks) and often included percutaneous aspiration (n = 47) for diagnostic and therapeutic purposes. Surgical evacuation was performed in 23 cases. To the authors' knowledge, the present case is the first documented report in which evacuation of a culture-negative CH resulted in resolution of the patient's clinical symptoms of sepsis that persisted despite appropriate antibiotic treatment. This suggests that patients with CH should be evaluated through diagnostic tap of the collection if there are signs of local or persistent systemic infection. Surgical evacuation may be indicated if percutaneous aspiration does not result in clinical improvement.

Spinal epidural lipomatosis in a pediatric patient with a malignant brain tumor: illustrative case.

BACKGROUND: Spinal epidural lipomatosis (SEL) in pediatric patients with concomitant malignant brain neoplasms is rare and can present with rapid deterioration in neurological function. OBSERVATIONS: A 4-year-old boy with SEL became paraplegic 4 months after completion of chemoradiation for his previously resected, intracranial atypical teratoid rhabdoid tumor. The patient presented with rapid deterioration in lower extremity sensory and motor function, which, given his oncological history, was concerning for disease progression. Of note, 8 months prior, the patient was started on corticosteroid therapy for respiratory dysfunction. Magnetic resonance imaging revealed significant progression of lumbosacral SEL requiring surgical decompression with subsequent neurological improvement. LESSONS: When evaluating pediatric patients with primary or metastatic brain tumors with new or worsening myelopathy and motor or sensory deficits, it is important to consider SEL.

Neurosurgical management of vertebral lesions in pediatric chronic recurrent multifocal osteomyelitis: patient series.

BACKGROUND: Chronic recurrent multifocal osteomyelitis (CRMO) is a rare pediatric autoinflammatory disorder involving 2 or more inflammatory bone lesions separated in time and space associated with pathological vertebral fractures. There are no current guidelines for the role of pediatric spine surgeons in the management of this condition. The authors demonstrate the importance of close and early involvement of neurosurgeons in caring for patients with CRMO with vertebral involvement. OBSERVATIONS: Fifty-six pediatric patients with clinical and radiographic evidence of CRMO were identified and clinical, radiographic, laboratory, and histopathological data were reviewed. All were evaluated via Jansson and Bristol CRMO diagnostic criteria. Ten had radiographic evidence of vertebral involvement (17.9%). Nine of these had multifocal disease. Five patients had multiple vertebrae affected. Six patients were evaluated for possible surgical intervention and one required intervention due to vertebra plana leading to a progressive kyphotic deformity and significant spinal canal stenosis. LESSONS: In conjunction with management by the primary pediatric rheumatology team using nonsteroidal anti-inflammatory drugs, disease-modifying anti-rheumatic drugs, immunotherapies, and bisphosphonates, given the risk of pathological fractures and potential resulting long-term neurological deficits, the authors recommend close monitoring and management by pediatric spine surgeons for any patient with CRMO with vertebral lesions.

Effect of Stent Porosity, Platelet Function Test Usage, and Dual Antiplatelet Therapy Duration on Clinical and Radiographic Outcomes After Stenting for Cerebral Aneurysms: A Meta-Analysis.

BACKGROUND: The use of stents with various porosities for treating cerebral aneurysms requires dual antiplatelet therapy (DAPT) without clear guidelines on the utility of platelet function tests (PFTs) and the duration of DAPT. We sought to determine the effects of stent porosity, PFT usage, and DAPT duration on the radiographic and clinical outcomes after stenting of cerebral aneurysms. METHODS: PubMed was searched on March 29, 2021 for studies of cerebral aneurysm stenting that had specified the stent type and DAPT duration. A random effects meta-analysis was used to measure the prevalence of nonprocedural thrombotic and hemorrhagic events, clinical outcomes, aneurysm occlusion, and in-stent stenosis stratified by stent porosity, PFT usage, and DAPT duration. RESULTS: The review yielded 105 studies (89 retrospective and 16 prospective) with 117 stenting cohorts (50 high porosity, 17 intermediate porosity, and 50 low porosity). In the high-, intermediate-, and low-porosity stenting cohorts, PFT usage was 26.0%, 47.1%, and 62.0% and the mean DAPT duration was 3.51 ± 2.33, 3.97 ± 1.92, and 5.18 ± 2.27 months, respectively. The intermediate-porosity stents showed a reduced incidence of hemorrhagic events (π = 0.32%) compared with low-porosity stents (π = 1.36%; P = 0.01) and improved aneurysm occlusion (π = 6.18%) compared with high-porosity stents (π = 14.42%; P = 0.001) and low-porosity stents (π = 11.71%; P = 0.04). The prevalence of in-stent stenosis was lower for the intermediate-porosity (π = 0.57%) and high-porosity (π = 1.51%) stents than for the low-porosity stents (π = 3.30%; P < 0.05). PFT use had resulted in fewer poor clinical outcomes (π = 3.54%) compared with those without PFT use (π = 5.94%; P = 0.04). The DAPT duration had no effect on the outcomes. CONCLUSIONS: In the present meta-analysis, which had selected for studies of cerebral aneurysm stenting that had reported the DAPT duration, intermediate-porosity stents and PFT use had resulted significantly improved outcomes. No effect of DAPT duration could be detected.

"The Circle" Predicts Extent of Fusion for Surgical Correction of Cervical Spinal Kyphotic Deformities: Proof of Concept.

BACKGROUND: Correction of kyphotic deformities of the spine is a common problem faced by spine surgeons. Unfortunately, there are no clear published guidelines available regarding the extent of spinal fusion required to achieve and maintain lasting deformity correction. We aim to share a set of novel radiographic parameters ("the Circle") that can be used as a guideline for determining the extent of fusion required in surgical correction of spinal kyphotic deformity. METHODS: A Google forms survey was distributed among spine surgeons and trainees to evaluate differences in recommended extent of posterior-approach fusions for cervical spinal kyphotic deformities before and after introduction to the Circle. Extent of fusion before and after use of the Circle were qualitatively and quantitatively analyzed. Data were anonymized and stored in a secure database. RESULTS: Twenty-seven neurosurgical attendings (n = 14), residents (n = 9), and fellows (n = 3) responded to the survey. Variance between predicted upper and lower instrumented vertebrae, and length of construct, was statistically significantly decreased after application of the Circle in almost all cases. Respondents rated the ease of use of the Circle an average of 4.2 out of 5 (5 = the most ease). The majority of participants (92 [6%]; n = 25 of 27) stated that they would or would likely use the Circle as a radiographic tool in the surgical planning for correction of cervical spinal kyphotic deformities in the future. CONCLUSIONS: The Circle is a novel set of radiographic parameters that may be used to educate and guide surgical plans and extent of fusion when aiming to correct spinal kyphotic deformities.

Surgical correction of pediatric spinal deformities with coexisting intraspinal pathology: A case report and literature review.

BACKGROUND: Surgical correction of spinal deformities with coexisting intraspinal pathology (SDCIP) requires special consideration to minimize risks of further injury to an already abnormal spinal cord. However, there is a paucity of literature on this topic. Here, the authors present a pediatric patient with a residual pilocytic astrocytoma and syringomyelia who underwent surgical correction of progressive postlaminectomy kyphoscoliosis. Techniques employed are compared to those in the literature to compile a set of guidelines for surgical correction of SDCIP. METHODS: A systematic MEDLINE search was conducted using the following keywords; "pediatric," "spinal tumor resection," "deformity correction," "postlaminectomy," "scoliosis correction," "intraspinal pathology," "tethered cord," "syringomyelia," or "diastematomyelia." Recommendations for surgical technique for pediatric SDCIP correction were reviewed. RESULTS: The presented case demonstrates recommendations that primarily compressive forces on the convexity of the coronal curve should be used when performing in situ correction of SDCIP. Undercorrection is favored to minimize risks of traction on the abnormal spinal cord. The literature yielded 13 articles describing various intraoperative techniques. Notably, seven articles described use of compressive forces on the convex side of the deformity as the primary mode of correction, while only five articles provided recommendations on how to safely and effectively surgically correct SDCIP. CONCLUSION: The authors demonstrated with their case analysis and literature review that there are no clear current guidelines regarding the safe and effective techniques for in situ correction and fusion for the management of pediatric SDCIP.

Rigid versus flexible neuroendoscopy: a systematic review and meta-analysis of endoscopic third ventriculostomy for the management of pediatric hydrocephalus.

OBJECTIVE: Endoscopic third ventriculostomy (ETV), with or without choroid plexus cauterization (±CPC), is a technique used for the treatment of pediatric hydrocephalus. Rigid or flexible neuroendoscopy can be used, but few studies directly compare the two techniques. Here, the authors sought to compare these methods in treating pediatric hydrocephalus. METHODS: A systematic MEDLINE search was conducted using combinations of keywords: "flexible," "rigid," "endoscope/endoscopic," "ETV," and "hydrocephalus." Inclusion criteria were as follows: English-language studies with patients 2 years of age and younger who had undergone ETV±CPC using rigid or flexible endoscopy for hydrocephalus. The primary outcome was ETV success (i.e., without the need for further CSF diversion procedures). Secondary outcomes included ETV-related and other complications. Statistical significance was determined via independent t-tests and Mood's median tests. RESULTS: Forty-eight articles met the study inclusion criteria: 37 involving rigid endoscopy, 10 involving flexible endoscopy, and 1 propensity scored-matched comparison. A cumulative 560 patients had undergone 578 rigid ETV±CPC, and 661 patients had undergone 672 flexible ETV±CPC. The flexible endoscopy cohort had a significantly lower average age at the time of the procedure (0.33 vs 0.53 years, p = 0.001) and a lower preoperatively predicted ETV success score (median 40, IQR 32.5-57.5 vs 62.5, IQR 50-70; p = 0.033). Average ETV success rates in the rigid versus flexible groups were 54.98% and 59.65% (p = 0.63), respectively. ETV-related complication rates did not differ significantly at 0.63% for flexible endoscopy and 3.46% for rigid endoscopy (p = 0.30). There was no significant difference in ETV success or complication rate in comparing ETV, ETV+CPC, and ETV with other concurrent procedures. CONCLUSIONS: Despite the lower expected ETV success scores for patients treated with flexible endoscopy, the authors found similar ETV success and complication rates for ETV±CPC with flexible versus rigid endoscopy, as reported in the literature. Further direct comparison between the techniques is necessary.

Anaplastic Hemangiopericytoma of the Jugular Foramen: Case Report and Systematic Review.

BACKGROUND: Hemangiopericytomas (HPCs) and solitary fibrous tumors (SFTs) are rare tumors of mesenchymal origin. Here, the authors present a rare case of anaplastic HPC in the jugular foramen (JF). The authors also conduct a systematic review of the literature to examine the current fund of knowledge on JF HPC/SFTs. METHODS: A systematic MEDLINE search was conducted using key words "hemangiopericytoma" OR "solitary fibrous tumor" AND "jugular foramen" OR "extracranial" OR "skull base." Clinicopathologic characteristics and outcomes of the present case were reviewed and compared with those in the literature. RESULTS: A 41-year-old male, who had undergone stereotactic radiation therapy 6 years ago for a presumed glomus jugulare tumor, presented to our institution with worsening dysphagia, hoarseness, persistent tongue weakness, and radiographic evidence of tumor progression. The patient underwent uncomplicated gross total resection with sacrifice of the infiltrated hypoglossal nerve. Histopathologic evaluation revealed anaplastic HPC/SFT (World Health Organization grade III). Review of the literature yielded 9 additional cases of JF HPC/SFT in 5 males (56%) and 4 females (44%), with a mean age of 49.6 years old. Patients commonly presented with pain (37.5%) and lower cranial nerve deficits (100%). Preoperative diagnoses included glomus jugulare (n = 2) or JF schwannomas (n = 3). All patients underwent microsurgical resection of the lesion, except for 1 who refused all treatment after diagnostic biopsy. CONCLUSION: The authors present the only reported case of anaplastic HPC of the JF. The illustrative case and those found on systematic review of the literature highlight the importance of tissue diagnosis and appropriate management.

Primary Intradural Extramedullary Sporadic Spinal Hemangioblastomas: Case Report and Systematic Review.

BACKGROUND: Hemangioblastomas are benign vascular neoplasms of the central nervous system that may occur sporadically or in association with Von Hippel-Lindau disease. A minority of these lesions can occur in the spine, mostly as intramedullary masses. The authors present a rare case of primary sporadic spinal hemangioblastoma occurring as an intradural extramedullary (IDEM) lesion. Diagnostic workup and surgical management of the patient are described. METHODS: A systematic MEDLINE search was conducted using the keywords "hemangioblastoma" and "intradural extramedullary," "extramedullary," or "cauda equina." Clinicopathological characteristics and outcomes of the present case were reviewed and compared with those in the literature. RESULTS: A 72-year-old man was found to have an IDEM lesion in his cervical spine after presenting with neck and shoulder pain. Gross total resection was successfully performed with sacrifice of an involved dorsal nerve rootlet. Screening for Von Hippel-Lindau was negative. Thirty-three additional patients with sporadic IDEM hemangioblastomas are reported in the literature. There was a slight male preponderance (54%) with a median age of 52 years. Patients presented with pain (54%), radiculopathy (33%), or myelopathy (32%). The majority of lesions were located in the lumbosacral spine (56%). All patients underwent maximal safe resection with stable or improved clinical status. CONCLUSION: Primary IDEM hemangioblastomas are a rare entity. Differential diagnosis includes other IDEM lesions, such as schwannomas, meningiomas, or some vascular malformations. Resection of these sporadic tumors can be safely performed and result in improvement of neurologic deficits associated with mass effect from the tumor with low likelihood of recurrence.

Transsphenoidal Resection of Pituitary Tumors in the United States, 2009 to 2011: Effects of Hospital Volume on Postoperative Complications.

Introduction Higher surgical volumes correlate with superior patient outcomes for various surgical pathologies, including transnasal transsphenoidal (TNTS) pituitary tumor resection. With the introduction of endoscopic approaches, there have been nationwide shifts in technique with relative declines in microsurgery. We examined the volume-outcome relationship (VOR) for TNTS pituitary tumor surgery in an era of increasingly prevalent endoscopic approaches. Methods Patients who underwent TNTS pituitary tumor resection between 2009 and 2011 were retrospectively identified in the State Inpatient Database subset of the Healthcare Cost and Utilization Project. Generalized linear mixed-effect models were used to assess odds of various outcome measures. Institutions were grouped into quartiles by case volume for analysis. Results A total of 6,727 patients underwent TNTS pituitary tumor resection between 2009 and 2011. White or Asian American patients and those with private insurance were more likely to receive care at higher volume centers (HVC). Patients treated at HVC (>60 cases/year) were less likely to have nonroutine discharges (3.9 vs. 1.9%; p = 0.002) and had shorter length of stay (LOS; 4 vs. 2 days; p = 0.001). Overall, care at HVC trended toward lower rates of postoperative complications, for example, a 10-case/year increase correlated with a 10% decrease in the rate of iatrogenic panhypopituitarism (odds ratio [OR] = 0.90, 95% confidence interval [CI]: 0.81-0.99; p = 0.04) and 5% decrease in likelihood of diabetes insipidus (OR = 0.95, 95% CI: 0.90-0.99; p = 0.04) on multivariable analysis. Conclusions Our analysis shows that increased case volume is related to superior perioperative outcomes for TNTS pituitary tumor resections. Despite the recent adoption of newer endoscopic techniques and concerns of technical learning curves, this VOR remains undisturbed.

Standardization of the liquid biopsy for pediatric diffuse midline glioma using ddPCR.

Diffuse midline glioma (DMG) is a highly morbid pediatric brain tumor. Up to 80% of DMGs harbor mutations in histone H3-encoding genes, associated with poor prognosis. We previously showed the feasibility of detecting H3 mutations in circulating tumor DNA (ctDNA) in the liquid biome of children diagnosed with DMG. However, detection of low levels of ctDNA is highly dependent on platform sensitivity and sample type. To address this, we optimized ctDNA detection sensitivity and specificity across two commonly used digital droplet PCR (ddPCR) platforms (RainDance and BioRad), and validated methods for detecting H3F3A c.83A > T (H3.3K27M) mutations in DMG CSF, plasma, and primary tumor specimens across three different institutions. DNA was extracted from H3.3K27M mutant and H3 wildtype (H3WT) specimens, including H3.3K27M tumor tissue (n = 4), CSF (n = 6), plasma (n = 4), and human primary pediatric glioma cells (H3.3K27M, n = 2; H3WT, n = 1). ctDNA detection was enhanced via PCR pre-amplification and use of distinct custom primers and fluorescent LNA probes for c.83 A > T H3F3A mutation detection. Mutation allelic frequency (MAF) was determined and validated through parallel analysis of matched H3.3K27M tissue specimens (n = 3). We determined technical nuances between ddPCR instruments, and optimized sample preparation and sequencing protocols for H3.3K27M mutation detection and quantification. We observed 100% sensitivity and specificity for mutation detection in matched DMG tissue and CSF across assays, platforms and institutions. ctDNA is reliably and reproducibly detected in the liquid biome using ddPCR, representing a clinically feasible, reproducible, and minimally invasive approach for DMG diagnosis, molecular subtyping and therapeutic monitoring.

Safety of Ventricular Reservoir Sampling in Pediatric Posthemorrhagic Hydrocephalus Patients: Institutional Experience and Review of the Literature.

ABSTRACT: INTRODUCTION: Posthemorrhagic hydrocephalus (PHH) is a common disease process encountered in neonates. Management often includes cerebrospinal fluid (CSF) aspiration through ventricular access devices (VADs). However, a common concern surrounding serial access of implanted subcutaneous reservoirs includes introduction of infection. In addition, there is great variability in aseptic technique. Therefore, the authors sought to evaluate the incidence of VAD access-associated infections in the literature and compare them with the rate of infection found at our institution. We also highlight the use of a preassembled VAD access kit and standardized access protocol, as well as the role of provider education, in maintaining safety and sterility during serial VAD access. METHODS: A single-institution retrospective review was performed for PHH patients younger than 1 year old undergoing serial CSF aspirations via implanted VADs (2009-2019). Patients were excluded if they had a ventriculoperitoneal shunt placed as primary intervention. MEDLINE search for reports of serial VAD access in PHH was also performed. Reports were excluded if they did not include full-text articles in the English literature. RESULTS: At our institution, subcutaneous reservoirs were placed in 37 neonates with PHH for serial CSF aspiration. No infections occurred after a total of 630 taps (average, 17 taps per reservoir; range, 0-83) and 10 420 collective reservoir days (average, 282 per patient; range, 6-3700). Only 2 reservoirs required revision for malfunction. Serial VAD taps for PHH were described in 14 articles in the medical literature, with 7.9% (n = 47/592) of patients reported with tap-related infectious complications. CONCLUSION: A standardized VAD access kit, along with stringent adherence to access protocol, can significantly minimize risk of infection associated with serial VAD access. These principles can be generalized to percutaneous aspiration of CSF from subcutaneous reservoirs placed for other indications to promote safety and sterility of this common procedure.

Ventricular Cerebrospinal Fluid Sampling in Pediatric Diffuse Midline Glioma Patients: Institutional Experience and Review of the Literature.

Purpose: Increasing evidence suggests that circulating biomarkers may serve diagnostic and longitudinal monitoring purposes in pediatric neuro-oncology. Mutant tumor DNA is detectable in the cerebrospinal fluid (CSF) of pediatric diffuse midline glioma (DMG) patients and quantity can reflect disease burden. CSF sampling ("liquid biopsy") via a CSF access device could therefore play a role in DMG management. Therefore, we set to evaluate the incidence of hydrocephalus (HCP) in DMG patients, and to characterize ventricular reservoir placement and access practices. Methods: A single institution retrospective review of DMG patients ≤21-years-old was performed (1984-2019). MEDLINE searches for reports of ventricular reservoir or shunt placement in DMG, and reservoir access for intraventricular chemotherapy (IVC) were performed. Results: At our institution, 62.6% of DMG patients (67/108) required intervention for HCP: 19.4% provided transient CSF access (ETV alone n = 3, EVD n = 8, unspecified n = 2), and 80.6% permanent CSF access (ETV + reservoir n = 13, shunt n = 41). Further, 22/34 patients with initially transient CSF devices required conversion to a permanent device. Five devices were revised for malfunction, one for infection. Seventeen articles cited HCP in 22 to 100% of DMG patients. IVC administration was described in 632 patients (seven articles), with 42 infectious and 63 non-infectious complications. Conclusions: Management of HCP is often necessary in children with DMG. Given the low rate of clinical risk associated with VAD placement and access, and the potential utility of longitudinal disease monitoring via CSF analysis, VAD placement could be considered in future clinical trials to guide DMG treatment.

Histone tail analysis reveals H3K36me2 and H4K16ac as epigenetic signatures of diffuse intrinsic pontine glioma.

BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) is an aggressive pediatric brainstem tumor. Most DIPGs harbor a histone H3 mutation, which alters histone post-translational modification (PTM) states and transcription. Here, we employed quantitative proteomic analysis to elucidate the impact of the H3.3K27M mutation, as well as radiation and bromodomain inhibition (BRDi) with JQ1, on DIPG PTM profiles. METHODS: We performed targeted mass spectrometry on H3.3K27M mutant and wild-type tissues (n = 12) and cell lines (n = 7). RESULTS: We found 29.2 and 26.4% of total H3.3K27 peptides were H3.3K27M in mutant DIPG tumor cell lines and tissue specimens, respectively. Significant differences in modification states were observed in H3.3K27M specimens, including at H3K27, H3K36, and H4K16. In addition, H3.3K27me1 and H4K16ac were the most significantly distinct modifications in H3.3K27M mutant tumors, relative to wild-type. Further, H3.3K36me2 was the most abundant co-occurring modification on the H3.3K27M mutant peptide in DIPG tissue, while H4K16ac was the most acetylated residue. Radiation treatment caused changes in PTM abundance in vitro, including increased H3K9me3. JQ1 treatment resulted in increased mono- and di-methylation of H3.1K27, H3.3K27, H3.3K36 and H4K20 in vitro. CONCLUSION: Taken together, our findings provide insight into the effects of the H3K27M mutation on histone modification states and response to treatment, and suggest that H3K36me2 and H4K16ac may represent unique tumor epigenetic signatures for targeted DIPG therapy.