Elevation of Depressed Skull Fracture in Neonates Using a Breast Pump and a Custom-Molded Flange.

BACKGROUND AND IMPORTANCE: "Ping-pong fractures" (PPF) can occur in neonates and result in cosmetic deformity and local mass effect. Standard treatment involves surgical elevation of the depressed bone when the indentation is considerable or cosmetically apparent. Surgical correction of PPF subjects patients to the risks of surgery and general anesthesia. This article and corresponding video demonstrate a novel means of correcting PPF at bedside without surgery or anesthesia. We used a hospital-grade breast pump connected to a custom-fabricated flange to successfully elevate PPF in two neonates. CLINICAL PRESENTATION: Two moderately preterm infants were noted at birth to have large parietal PPF. To avoid surgical intervention, elevation using a suction device was attempted. A hospital-grade breast pump was used to provide suction. A custom device was fabricated out of a breast pump flange and molded Coloplast Brava® protective seal rings. This device was carefully applied to the skull to exactly match the diameter of the PPF and contour of the bone. Brief (15-30 seconds) periods of suction were applied several times until the PPF was successfully elevated as documented on subsequent computed tomography scans. Both infants achieved excellent cosmetic results with no adverse effects over 24- and 9-month follow-ups, respectively. DISCUSSION: This technique eliminates the risks of open surgical correction and corrected the PPF without general anesthesia or adverse effects to the infant. While there may be limitations due to patient age and/or location of the PPF, the use of widely available and inexpensive custom-fitted materials with a hospital grade breast pump achieves maximal efficacy without requiring higher negative pressure suction application. CONCLUSION: Elevation of PPF can be safely achieved in some neonates using readily available equipment: a hospital-grade breast pump, flange, and moldable adherent material. This technique is reasonable to attempt in lieu of surgical elevation.

Progressive vascular tumor in infant: A case report and literature review of PIK3CA vascular malformation.

PURPOSE: Vascular anomalies are classified as either vascular tumors or vascular malformations. Vascular malformations can be difficult to diagnose and treat in the pediatric population and can masquerade as malignant processes. Understanding the genetics behind vascular malformations can lead to identification of specific mutations which can be treated with targeted immunotherapy. METHODS: Our case presents a pediatric patient with progressively enlarging vascular malformation despite multiple surgical resections and systemic medical treatments who underwent genetic evaluation and was found to have PIK3CA mutation. RESULTS: After identification of PIK3CA mutation, our patient was successfully treated with the p110ɑ-specific inhibitor, alpelisib, with both shrinkage of malformation on follow-up imaging as well as gains in her developmental milestones. CONCLUSION: Progressive vascular malformations in the pediatric population can be hard to diagnose and treat and are thought to arise from somatic mutations. Our case highlights a patient with progressive malformation despite multiple surgical resections who was successfully treated with targeted immunotherapy after proper identification of genetic mutation.

Engineering subarachnoid trabeculae with electrospun poly(caprolactone) (PCL) scaffolds to study leptomeningeal metastasis in medulloblastoma.

Leptomeningeal metastasis (LM) occurs when cancer cells infiltrate the subarachnoid space (SAS) and metastasize to the fibrous structures that surround the brain and spinal cord. These structures include the leptomeninges (i.e., the pia mater and arachnoid mater), as well as subarachnoid trabeculae, which are collagen-rich fibers that provide mechanical structure for the SAS, support resident cells, and mediate flow of cerebrospinal fluid (CSF). Although there is a strong expectation that the presence of fibers within the SAS influences LM to be a major driver of tumor progression and lethality, exactly how trabecular architecture relates to the process of metastasis in cancer is poorly understood. This lack of understanding is likely due in part to the difficulty of accessing and manipulating this tissue compartment in vivo. Here, we utilized electrospun polycaprolactone (PCL) to produce structures bearing remarkable morphological similarity to native SAS fiber architecture. First, we profiled the native architecture of leptomeningeal and trabecular fibers collected from rhesus macaque monkeys, evaluating both qualitative and quantitative differences in fiber ultrastructure for various regions of the CNS. We then varied electrospinning parameters to produce a small library of PCL scaffolds possessing distinct architectures mimicking the range of fiber properties observed in vivo. For proof of concept, we studied the metastasis-related behaviors of human pediatric medulloblastoma cells cultured in different fiber microenvironments. These studies demonstrated that a more open, porous fiber structure facilitates DAOY cell spread across and infiltration into the meningeal mimic. Our results present a new tissue engineered model of the subarachnoid space and affirm the expectation that fiber architecture plays an important role in mediating metastasis-related behaviors in an in vitro model of pediatric medulloblastoma.

Histopathologic "Evolution" in Pediatric Primary Intracranial High-Grade Sarcoma - a Key that Unlocked the Correct Diagnosis.

Central nervous system (CNS) tumors are the second most common in the pediatric age group, accounting for 3.5% of overall mortality. The 2021 World Health Organization (WHO) classification of pediatric CNS tumors has given insight into their molecular biology. Correct diagnosis of high-grade intracranial sarcomas is a well-known challenge because of their histopathological variation, presence of heterologous elements, and haphazard pattern of growth. We present a case of a 13-year-old female with a right-sided frontal hemorrhagic mass. Pathological work-up revealed an intra-cranial high-grade sarcoma, not otherwise specified (NOS). Despite receiving chemo-radiation, the lesion recurred after 9 months. This time, the sarcoma had evolved, showing distinct focal rhabdomyoblastic differentiation. Next-generation sequencing (NGS) based assay revealed variants p.E1705V, p.Y1417Ter in DICER1, and other mutations in KRAS and TP53 genes. The lesion was then diagnosed as spindle cell sarcoma with rhabdomyosarcoma-like features, DICER1 mutant. We propose that upfront molecular studies in pediatric undifferentiated high-grade sarcomas are indicated for precise diagnosis and classification.

Can Craniosynostosis be Diagnosed on Physical Examination? A Retrospective Review.

Craniosynostosis is a developmental craniofacial defect in which one or more sutures of the skull fuse together prematurely. Uncorrected craniosynostosis may have serious complications including elevated intracranial pressure, developmental delay, and blindness. Proper diagnosis of craniosynostosis requires a physical examination of the head with assessment for symmetry and palpation of sutures for prominence. Often, if craniosynostosis is suspected, computed tomography (CT) imaging will be obtained. Recent literature has posited that this is unnecessary. This study aims to address whether physical examination alone is sufficient for the diagnosis and treatment planning of single suture craniosynostosis. Between 2015 and 2022, the Divisions of Pediatric Neurosurgery and Pediatric Plastic Surgery at UTHealth Houston evaluated 140 children under 36 months of age with suspected craniosynostosis by physical examination and subsequently ordered CT imaging for preoperative planning. Twenty-three patients received a clinical diagnosis of multi-sutural or syndromic craniosynostosis that was confirmed by CT. One hundred seventeen patients were diagnosed with single suture craniosynostosis on clinical examination and follow-up CT confirmed suture fusion in 109 (93.2%) patients and identified intracranial anomalies in 7 (6.0%) patients. These patients underwent surgical correction. Eight (6.8%) patients showed no evidence of craniosynostosis on CT imaging. Treatment for patients without fused sutures included molding helmets and observation alone. This evidence suggests that physical examination alone may be inadequate to accurately diagnose single suture synostosis, and surgery without preoperative CT evaluation could lead to unindicated procedures.

Characterization of recurrence patterns and outcomes of medulloblastoma in adults: The University of Texas MD Anderson Cancer Center experience.

Background: Medulloblastoma in adults is rare and treatment decisions are largely driven from pediatric literature. We sought to characterize recurrent medulloblastoma in adults. Methods: From a single-institution dataset of 200 adult patients diagnosed with medulloblastoma during 1978-2017, those with recurrence were analyzed for clinical features, treatment, and outcome. Results: Of the 200 patients, 82 (41%) with median age of 29 years (18-59) had recurrence after a median follow-up time of 8.4 years (95% CI = 7.1, 10.3). Of these, 30 (37%) were standard-risk, 31 (38%) were high-risk, and 21 (26%) had unknown-risk diseases at the time of initial diagnosis. Forty-eight (58%) presented with recurrence outside the posterior fossa, of whom 35 (43%) had distant recurrence only. Median Progression-free survival (PFS) and OS from initial surgery were 33.5 and 62.4 months, respectively. Neither PFS nor OS from initial diagnosis differed between the standard-risk and high-risk groups in those who experience recurrence (P = .505 and .463, respectively). Median OS from first recurrence was 20.3 months, also with no difference between the standard-risk and high-risk groups (P = .518). Recurrences were treated with combinations of re-resection (20 patients; 25%), systemic chemotherapy (61 patients; 76%), radiation (29 patients; 36%), stem cell transplant (6 patients; 8%), and intrathecal chemotherapy (4 patients; 5%). Patients who received radiation at recurrence had better OS (32.9 months) than those who did not (19.2 months) (P = .034). Conclusions: Recurrent medulloblastoma in adults has a poor prognosis irrespective of initial risk stratification. Recurrence commonly arises outside the posterior fossa years after initial diagnosis.

Contrast Enhancement Patterns in Pediatric Glioblastomas.

BACKGROUND AND PURPOSE: Brain tumors are the most common cause of cancer-related deaths among the pediatric population. Among these, pediatric glioblastomas (GBMs) comprise 2.9% of all central nervous system tumors and have a poor prognosis. The purpose of this study is to determine whether the imaging findings can be a prognostic factor for survival in children with GBMs. MATERIALS AND METHODS: The imaging studies and clinical data from 64 pediatric patients with pathology-proven GBMs were evaluated. Contrast enhancement patterns were classified into focal, ring-like, and diffuse, based on preoperative postcontrast T1-weighted magnetic resonance images. We used the Kaplan-Meier method and Cox proportional hazard regression to evaluate the prognostic value of imaging findings. RESULTS: Patients with ring-enhanced GBMs who underwent gross total resection or subtotal resection were found to have a significantly shorter progression-free survival ( P = 0.03) comparing with other enhancing and nonenhancing glioblastomas. CONCLUSIONS: In this study, we analyzed survival factors in children with pediatric glioblastomas. In the group of patients who underwent gross total resection or subtotal resection, those patients with focal-enhanced GBMs had significantly longer progression-free survival ( P = 0.03) than did those with other types of enhancing GBMs (diffuse and ring-like).

Patterns of failure after radiation therapy in primary spinal high-grade gliomas: A single institutional analysis.

Background: Primary spinal high-grade gliomas (S-HGG) are rare aggressive tumors; radiation therapy (RT) often plays a dominant role in management. We conducted a single-institution retrospective review to study the clinicopathological features and management of S-HGGs. Methods: Patients with biopsy-proven S-HGG who received RT from 2001 to 2020 were analyzed for patient, tumor, and treatment characteristics. Kaplan-Meier estimates were used for survival analyses. Results: Twenty-nine patients were identified with a median age of 25.9 years (range 1-74 y). Four patients had GTR while 25 underwent subtotal resection or biopsy. All patients were IDH wildtype and MGMT-promoter unmethylated, where available. H3K27M mutation was present in 5 out of 10 patients tested, while one patient harbored p53 mutation. Median RT dose was 50.4 Gy (range 39.6-54 Gy) and 65% received concurrent chemotherapy, most commonly temozolomide. Twenty-three (79%) of patients had documented recurrence. Overall, 16 patients relapsed locally, 10 relapsed in the brain and 8 developed leptomeningeal disease; only 8 had isolated local relapse. Median OS from diagnosis was 21.3 months and median PFS was 9.7 months. On univariate analysis, age, gender, GTR, grade, RT modality, RT dose and concurrent chemotherapy did not predict for survival. Patients with H3K27M mutation had a poorer PFS compared to those without mutation (10.1 m vs 45.1 m) but the difference did not reach statistical significance (P = .26). Conclusions: The prognosis of patients with spinal HGGs remains poor with two-thirds of the patients developing distant recurrence despite chemoradiation. Survival outcomes were similar in patients ≤ 29 years compared to adults > 29 years. A better understanding of the molecular drivers of spinal HGGs is needed to develop more effective treatment options.

Future Directions for Global Clinical Neurosurgical Training: Challenges and Opportunities.

OBJECTIVE: Expanded access to training opportunities is necessary to address 5 million essential neurosurgical cases not performed annually, nearly all in low- and middle-income countries. To target this critical neurosurgical workforce issue and advance positive collaborations, a summit (Global Neurosurgery 2019: A Practical Symposium) was designed to assemble stakeholders in global neurosurgical clinical education to discuss innovative platforms for clinical neurosurgery fellowships. METHODS: The Global Neurosurgery Education Summit was held in November 2021, with 30 presentations from directors and trainees in existing global neurosurgical clinical fellowships. Presenters were selected based on chain referral sampling from suggestions made primarily from young neurosurgeons in low- and middle-income countries. Presentations focused on the perspectives of hosts, local champions, and trainees on clinical global neurosurgery fellowships and virtual learning resources. This conference sought to identify factors for success in overcoming barriers to improving access, equity, throughput, and quality of clinical global neurosurgery fellowships. A preconference survey was disseminated to attendees. RESULTS: Presentations included in-country training courses, twinning programs, provision of surgical laboratories and resources, existing virtual educational resources, and virtual teaching technologies, with reference to their applicability to hybrid training fellowships. Virtual learning resources developed during the coronavirus disease 2019 pandemic and high-fidelity surgical simulators were presented, some for the first time to this audience. CONCLUSIONS: The summit provided a forum for discussion of challenges and opportunities for developing a collaborative consortium capable of designing a pilot program for efficient, sustainable, accessible, and affordable clinical neurosurgery fellowship models for the future.

High prevalence of gram-negative and multiorganism surgical site infections after pediatric complex tethered spinal cord surgery: a multicenter study.

OBJECTIVE: Complex tethered spinal cord (cTSC) release in children is often complicated by surgical site infection (SSI). Children undergoing this surgery share many similarities with patients undergoing correction for neuromuscular scoliosis, where high rates of gram-negative and polymicrobial infections have been reported. Similar organisms isolated from SSIs after cTSC release were recently demonstrated in a single-center pilot study. The purpose of this investigation was to determine if these findings are reproducible across a larger, multicenter study. METHODS: A multicenter, retrospective chart review including 7 centers was conducted to identify all cases of SSI following cTSC release during a 10-year study period from 2007 to 2017. Demographic information along with specific microbial culture data and antibiotic sensitivities for each cultured organism were collected. RESULTS: A total of 44 SSIs were identified from a total of 655 cases, with 78 individual organisms isolated. There was an overall SSI rate of 6.7%, with 43% polymicrobial and 66% containing at least one gram-negative organism. Half of SSIs included an organism that was resistant to cefazolin, whereas only 32% of SSIs were completely susceptible to cefazolin. CONCLUSIONS: In this study, gram-negative and polymicrobial infections were responsible for the majority of SSIs following cTSC surgery, with approximately half resistant to cefazolin. Broader gram-negative antibiotic prophylaxis should be considered for this patient population.

Back to the Beginning: An Algorithmic Approach to Neonatal Myelomeningocele Repair.

INTRODUCTION: Myelomeningoceles are formed by prenatal failure of neural tube closure and can cause hydrocephalus, motor abnormalities, and developmental delay. Although small defects are amenable to primary closure, larger defects often require complex reconstruction. Our goal was to identify factors associated with postoperative soft tissue complications and develop a systematic approach for myelomeningocele closure. METHODS: A retrospective review was performed at the Children's Memorial Hermann Hospital from January 2013 to January 2019. Patients were identified using International Classification of Diseases, Ninth Revision/Tenth Revision , codes for myelomeningocele. Cohorts were stratified by reconstruction type and defect location. Primary outcomes were incidence of complications including cerebrospinal fluid leak, superficial and deep infection, and wound dehiscence. In addition, we developed an algorithm to standardize closure approach for patients with myelomeningoceles. RESULTS: A total of 172 patients with myelomeningocele were identified with 73 patients undergoing postnatal repair. Overall, 72% of defects were >5 cm. Defects were in the lumbar (9%), sacral (8%), and junctional (83%) regions. Overall, 30.1% patients underwent lumbar myofascial repair with 39.7% requiring fasciocutaneous flaps. Larger defects (>5 cm) were more likely to be closed with complex fasciocutaneous flaps (82.8% vs 66.0%, P = 0.11). No significant differences were observed in complication rates. CONCLUSIONS: In this series, patients with larger myelomeningoceles appear to benefit from complex flap closure. We propose a 5-layer closure for patients with myelomeningocele including the routine use of a myofascial layer. Cutaneous closure technique should be tailored based on specific defect characteristics as outlined in our algorithm. This approach streamlines myelomeningocele repair while optimizing outcomes and decreasing downstream complications.

Clinical characterization of adult medulloblastoma and the effect of first-line therapies on outcome; The MD Anderson Cancer Center experience.

BACKGROUND: Adult medulloblastoma (MB) is rare, and management guidelines are largely based on pediatric clinical trials and retrospective series. Limited data exist with respect to clinical characteristics, prognostic factors, and outcomes based on first-line treatments. METHODS: Two hundred adults with MB seen at a single institution from January 1978 to April 2017 were identified and followed for a median of 8.4 y (7.1, 10.3). RESULTS: Patient's median age at diagnosis was 29 y (18, 63). One hundred eleven (55.5%) were standard-risk, 59 (29.5%) were high-risk, and 30 (15.0%) were indeterminate. Most received post-operative radiation (RT) (184 [92.0%]), and 105 (52.5%) received first-line chemotherapy. Median overall survival (OS) was 8.8 y (7.2, 12.2) and median progression-free survival (PFS) was 6.6 y (4.9, 11.2). High-risk patients had inferior OS (Hazard ratio [HR] = 2.5 [1.5, 4.2], P = .0006) and PFS (HR = 2.3 [1.3, 3.9], P = .002) compared to standard-risk patients. Age, sex, and metastatic disease were not associated with survival. After adjusting for risk status, those who received RT plus adjuvant chemotherapy had superior PFS compared to RT plus neoadjuvant chemotherapy [HR = 0.46 (0.22, 0.95), P = .0357]. Within a subgroup for whom detailed clinical data were available, those who received RT plus adjuvant chemotherapy had improved PFS compared to RT only [HR = 0.24 (0.074-0.76), P = .016]. The substitution of cisplatin for carboplatin and the elimination of vincristine did not negatively affect outcomes. CONCLUSION: This is the largest single-institution retrospective study of adult MB to our knowledge and identifies standard-risk status, first-line RT and adjuvant chemotherapy as factors associated with improved outcomes.

Indications for Inpatient Magnetoencephalography in Children - An Institution's Experience.

Magnetoencephalography (MEG) is recognized as a valuable non-invasive clinical method for localization of the epileptogenic zone and critical functional areas, as part of a pre-surgical evaluation for patients with pharmaco-resistant epilepsy. MEG is also useful in localizing functional areas as part of pre-surgical planning for tumor resection. MEG is usually performed in an outpatient setting, as one part of an evaluation that can include a variety of other testing modalities including 3-Tesla MRI and inpatient video-electroencephalography monitoring. In some clinical circumstances, however, completion of the MEG as an inpatient can provide crucial ictal or interictal localization data during an ongoing inpatient evaluation, in order to expedite medical or surgical planning. Despite well-established clinical indications for performing MEG in general, there are no current reports that discuss indications or considerations for completion of MEG on an inpatient basis. We conducted a retrospective institutional review of all pediatric MEGs performed between January 2012 and December 2020, and identified 34 cases where MEG was completed as an inpatient. We then reviewed all relevant medical records to determine clinical history, all associated diagnostic procedures, and subsequent treatment plans including epilepsy surgery and post-surgical outcomes. In doing so, we were able to identify five indications for completing the MEG on an inpatient basis: (1) super-refractory status epilepticus (SRSE), (2) intractable epilepsy with frequent electroclinical seizures, and/or frequent or repeated episodes of status epilepticus, (3) intractable epilepsy with infrequent epileptiform discharges on EEG or outpatient MEG, or other special circumstances necessitating inpatient monitoring for successful and safe MEG data acquisition, (4) MEG mapping of eloquent cortex or interictal spike localization in the setting of tumor resection or other urgent neurosurgical intervention, and (5) international or long-distance patients, where outpatient MEG is not possible or practical. MEG contributed to surgical decision-making in the majority of our cases (32 of 34). Our clinical experience suggests that MEG should be considered on an inpatient basis in certain clinical circumstances, where MEG data can provide essential information regarding the localization of epileptogenic activity or eloquent cortex, and be used to develop a treatment plan for surgical management of children with complicated or intractable epilepsy.

Posttreatment Maturation of Medulloblastoma into Gangliocytoma: Report of 2 Cases.

INTRODUCTION: We report 2 cases of medulloblastoma maturing into gangliocytoma after receiving multimodal therapy. Here we present 2 cases of diagnosed medulloblastoma which on re-resection were noted to be gangliocytoma without heterogeneity, which is an extremely rare occurrence. CASE PRESENTATION: The first patient, an 11-year-old boy diagnosed with high-risk (non-WNT, non-SHH) medulloblastoma, was treated with near-total surgical resection followed by craniospinal radiation therapy with weekly vincristine. He then received maintenance chemotherapy with vincristine, cyclophosphamide, and cisplatin. On surveillance MR imaging studies residual tumor in the lateral aspect of the tumor bed was noted to be slowly growing, eliciting gross-total resection of the residual tumor. Histopathology showed benign gangliocytoma without residual medulloblastoma. The second patient, a 3-year-old girl, was diagnosed with medulloblastoma, desmoplastic nodular variant. She was initially treated with gross total resection and chemotherapy with etoposide, carboplatin, and high-dose methotrexate. At 4 months off therapy, she was noted to have local recurrence along the resection cavity. Second-line therapy was started with irinotecan and temozolomide, but MRI assessment during treatment showed further disease progression. She then received craniospinal radiation. Eleven months off therapy, further radiographic progression was noted, and the patient underwent second-look surgery, with pathology showing gangliocytoma and treatment-related gliosis. DISCUSSION/CONCLUSION: The maturation of medulloblastoma into a ganglion cell-rich lesion is very rare, with few well-characterized previous reports. Given the rare nature of this entity, it would be of great value to understand the process of posttreatment maturation and the genetic and treatment factors which contribute to this phenomenon.

High-dose MTX110 (soluble panobinostat) safely administered into the fourth ventricle in a nonhuman primate model.

OBJECTIVE: Chemotherapy infusions directly into the fourth ventricle may play a role in treating malignant fourth-ventricular tumors. This study tested the safety and pharmacokinetics of short-term and long-term administration of MTX110 (soluble panobinostat; Midatech Pharma) into the fourth ventricle of nonhuman primates. METHODS: Four rhesus macaque monkeys underwent posterior fossa craniectomy and catheter insertion into the fourth ventricle. In group I (n = 2), catheters were externalized and lumbar drain catheters were placed simultaneously to assess CSF distribution after short-term infusions. MTX110 (0.5 ml of 300 µM panobinostat solution) was infused into the fourth ventricle daily for 5 consecutive days. Serial CSF and serum panobinostat levels were measured. In group II (n = 2), fourth-ventricle catheters were connected to a subcutaneously placed port for subsequent long-term infusions. Four cycles of MTX110, each consisting of 5 daily infusions (0.5 ml of 300 µM panobinostat solution), were administered over 8 weeks. Animals underwent detailed neurological evaluations, MRI scans, and postmortem histological analyses. RESULTS: No neurological deficits occurred after intraventricular MTX110 infusions. MRI scans showed catheter placement within the fourth ventricle in all 4 animals, with extension to the cerebral aqueduct in 1 animal and into the third ventricle in 1 animal. There were no MRI signal changes in the brainstem, cerebellum, or elsewhere in the brains of any of the animals. Histologically, normal brain cytoarchitecture was preserved with only focal mild postsurgical changes in all animals. Panobinostat was undetectable in serum samples collected 2 and 4 hours after infusions in all samples in both groups. In group I, the mean peak panobinostat level in the fourth-ventricle CSF (6242 ng/ml) was significantly higher than that in the lumbar CSF (9 ng/ml; p < 0.0001). In group II, the mean peak CSF panobinostat level (11,042 ng/ml) was significantly higher than the mean trough CSF panobinostat level (33 ng/ml; p < 0.0001). CONCLUSIONS: MTX110 can be safely infused into the fourth ventricle in nonhuman primates at supratherapeutic doses. Postinfusion CSF panobinostat levels peak immediately in the fourth ventricle and then rapidly decrease over 24 hours. Panobinostat is detectable at low levels in CSF measured from the lumbar cistern up to 4 hours after infusions. These results will provide background data for a pilot clinical trial in patients with recurrent medulloblastoma.

Outcomes and prognostic factors of pediatric patients with a Glasgow Coma Score of 3 after blunt head trauma.

PURPOSE: This study aims to assess outcomes of pediatric patients with blunt traumatic brain injury (TBI) with a presenting Glasgow Coma Score (GCS) of 3. METHODS: After local institutional review board approval, we identified patients ages 0 to15 years with blunt TBI and a reported GCS of 3 between 2007 and 2017 from a pediatric level 1 trauma center prospective registry. Exclusion criteria were cardiac death on arrival and penetrating injury. We recorded clinical variables from patients with a non-pharmacologic GCS of 3 and pupillary exam documented by a neurosurgical attending or resident. The original Glasgow Outcome Scale (GOS) was used to compare with other studies. Importance of variables to survival was calculated. RESULTS: A total of 88 patients (mean age 6.9 years) were included with a mortality rate of 68%. Twelve percent had a poor long-term outcome (GOS 2 or 3) while 20% had a good long-term outcome (GOS 4 or 5). Median follow-up was 1.8 years. Initial group comparison revealed patients in group 1 (survivors) had less hypotension on arrival (14% SBP < 90 mmHg vs. 66%, p < 0.0001), higher temperatures on arrival (36.3 °C vs 34.9 °C, p = 0.0002), lower ISS (29.7 vs 39.5, p = 0.003), less serious injury to other major organs (34% vs 61%, p = 0.02), more epidural hematomas (24% vs 7%, p = 0.04), and less evidence of brain ischemia on CT (7% vs 39%, p = 0.002) or brainstem infarct, hemorrhage, or herniation (0% vs 27%, p = 0.002). Differences between the 2 groups in age, sex, race, MOI, AIS score, presence of midline shift > 5 mm, or time from injury to hospital arrival or time to surgery were not statistically significant. Classification tree analysis showed that the most important variable for survival was pupillary exam; mortality was 92% in presence of bilateral, fixed dilated pupils. The relative importance of initial temperature, MOI, and hypotension to survivability was 0.79, 0.75, and 0.47, respectively. CONCLUSION: Twenty percent of our pediatric non-pharmacologic GCS 3 cohort had a good functional outcome. Lack of bilaterally fixed and dilated pupils was the most important factor for survival. Temperature, MOI, and hypotension also correlated with survival. The data support selective aggressive management for these patients.

Diagnostic Accuracy of Non-Invasive Thermal Evaluation of Ventriculoperitoneal Shunt Flow in Shunt Malfunction: A Prospective, Multi-Site, Operator-Blinded Study.

BACKGROUND: Thermal flow evaluation (TFE) is a non-invasive method to assess ventriculoperitoneal shunt function. Flow detected by TFE is a negative predictor of the need for revision surgery. Further optimization of testing protocols, evaluation in multiple centers, and integration with clinical and imaging impressions prompted the current study. OBJECTIVE: To compare the diagnostic accuracy of 2 TFE protocols, with micropumper (TFE+MP) or without (TFE-only), to neuro-imaging in patients emergently presenting with symptoms concerning for shunt malfunction. METHODS: We performed a prospective multicenter operator-blinded trial of a consecutive series of patients who underwent evaluation for shunt malfunction. TFE was performed, and preimaging clinician impressions and imaging results were recorded. The primary outcome was shunt obstruction requiring neurosurgical revision within 7 d. Non-inferiority of the sensitivity of TFE vs neuro-imaging for detecting shunt obstruction was tested using a prospectively determined a priori margin of -2.5%. RESULTS: We enrolled 406 patients at 10 centers. Of these, 68/348 (20%) evaluated with TFE+MP and 30/215 (14%) with TFE-only had shunt obstruction. The sensitivity for detecting obstruction was 100% (95% CI: 88%-100%) for TFE-only, 90% (95% CI: 80%-96%) for TFE+MP, 76% (95% CI: 65%-86%) for imaging in TFE+MP cohort, and 77% (95% CI: 58%-90%) for imaging in the TFE-only cohort. Difference in sensitivities between TFE methods and imaging did not exceed the non-inferiority margin. CONCLUSION: TFE is non-inferior to imaging in ruling out shunt malfunction and may help avoid imaging and other steps. For this purpose, TFE only is favored over TFE+MP.

Phase I study of intraventricular infusions of autologous ex vivo expanded NK cells in children with recurrent medulloblastoma and ependymoma.

BACKGROUND: Recurrent pediatric medulloblastoma and ependymoma have a grim prognosis. We report a first-in-human, phase I study of intraventricular infusions of ex vivo expanded autologous natural killer (NK) cells in these tumors, with correlative studies. METHODS: Twelve patients were enrolled, 9 received protocol therapy up to 3 infusions weekly, in escalating doses from 3 × 106 to 3 × 108 NK cells/m2/infusion, for up to 3 cycles. Cerebrospinal fluid (CSF) was obtained for cellular profile, persistence, and phenotypic analysis of NK cells. Radiomic characterization on pretreatment MRI scans was performed in 7 patients, to develop a non-invasive imaging-based signature. RESULTS: Primary objectives of NK cell harvest, expansion, release, and safety of 112 intraventricular infusions of NK cells were achieved in all 9 patients. There were no dose-limiting toxicities. All patients showed progressive disease (PD), except 1 patient showed stable disease for one month at end of study follow-up. Another patient had transient radiographic response of the intraventricular tumor after 5 infusions of NK cell before progressing to PD. At higher dose levels, NK cells increased in the CSF during treatment with repetitive infusions (mean 11.6-fold). Frequent infusions of NK cells resulted in CSF pleocytosis. Radiomic signatures were profiled in 7 patients, evaluating ability to predict upfront radiographic changes, although they did not attain statistical significance. CONCLUSIONS: This study demonstrated feasibility of production and safety of intraventricular infusions of autologous NK cells. These findings support further investigation of locoregional NK cell infusions in children with brain malignancies.