The potential role of mechanotransduction in the management of pediatric calvarial bone flap repair.

Pediatric patients suffering traumatic brain injuries may require a decompressive craniectomy to accommodate brain swelling by removing a portion of the skull. Once the brain swelling subsides, the preserved calvarial bone flap is ideally replaced as an autograft during a cranioplasty to restore protection of the brain, as it can reintegrate and grow with the patient during immature skeletal development. However, pediatric patients exhibit a high prevalence of calvarial bone flap resorption post-cranioplasty, causing functional and cosmetic morbidity. This review examines possible solutions for mitigating pediatric calvarial bone flap resorption by delineating methods of stimulating mechanosensitive cell populations with mechanical forces. Mechanotransduction plays a critical role in three main cell types involved with calvarial bone repair, including mesenchymal stem cells, osteoblasts, and dural cells, through mechanisms that could be exploited to promote osteogenesis. In particular, physiologically relevant mechanical forces, including substrate deformation, external forces, and ultrasound, can be used as tools to stimulate bone repair in both in vitro and in vivo systems. Ultimately, combating pediatric calvarial flap resorption may require a combinatorial approach using both cell therapy and bioengineering strategies.

Healthcare transition in pediatric neurosurgery: lessons learned from a pilot program for patients with hydrocephalus and spina bifida.

OBJECTIVE: The pediatric neurosurgical community has increasingly recognized the importance of healthcare transition, the process of moving a patient from a pediatric to an adult model of care. However, surveys of pediatric neurosurgeons have revealed that few institutions have formal transition programs. Here, the authors share their preliminary experience with the development of a formal transition pilot program for patients with spina bifida and/or hydrocephalus. METHODS: Patients 18 years of age or older with a diagnosis of spina bifida and/or hydrocephalus who were followed by a pediatric neurosurgeon at Connecticut Children's from January 2017 to December 2023 and were recommended to transition to an adult neurosurgeon were retrospectively reviewed. Patients in the informal transition program (ITP) cohort (i.e., the recommendation to transition was made before the formal transition program [FTP] was developed in early 2020) were compared with those in the FTP cohort. RESULTS: Twenty-two patients met inclusion criteria with 7 (31.8%) in the ITP cohort and 15 (68.2%) in the FTP cohort. The median age at the time of the recommendation to transition was similar in both ITP and FTP cohorts (24 [IQR 20-35] years vs 25 [IQR 24-27] years, respectively). Four (57.1%) patients in the ITP cohort had a confirmed visit with an adult neurosurgeon, compared with 13 (86.7%) patients in the FTP cohort (p = 0.274). One patient in the ITP cohort with a failed transition returned to pediatric neurosurgical care, and 1 patient in the FTP cohort required a shunt revision by an adult neurosurgeon within 1 year of the recommendation to transition. CONCLUSIONS: Healthcare transition is recognized as a priority within pediatric neurosurgery, but structured, formal transition programs remain underdeveloped. The authors' preliminary experience with a pilot transition program demonstrated that patients who underwent a formal transition were more likely to successfully establish care with an adult neurosurgeon and trended toward less resource utilization.

Pediatric Moyamoya Revascularization Perioperative Care: A Modified Delphi Study.

BACKGROUND: Surgical revascularization decreases the long-term risk of stroke in children with moyamoya arteriopathy but can be associated with an increased risk of stroke during the perioperative period. Evidence-based approaches to optimize perioperative management are limited and practice varies widely. Using a modified Delphi process, we sought to establish expert consensus on key components of the perioperative care of children with moyamoya undergoing indirect revascularization surgery and identify areas of equipoise to define future research priorities. METHODS: Thirty neurologists, neurosurgeons, and intensivists practicing in North America with expertise in the management of pediatric moyamoya were invited to participate in a three-round, modified Delphi process consisting of a 138-item practice patterns survey, anonymous electronic evaluation of 88 consensus statements on a 5-point Likert scale, and a virtual group meeting during which statements were discussed, revised, and reassessed. Consensus was defined as ≥ 80% agreement or disagreement. RESULTS: Thirty-nine statements regarding perioperative pediatric moyamoya care for indirect revascularization surgery reached consensus. Salient areas of consensus included the following: (1) children at a high risk for stroke and those with sickle cell disease should be preadmitted prior to indirect revascularization; (2) intravenous isotonic fluids should be administered in all patients for at least 4 h before and 24 h after surgery; (3) aspirin should not be discontinued in the immediate preoperative and postoperative periods; (4) arterial lines for blood pressure monitoring should be continued for at least 24 h after surgery and until active interventions to achieve blood pressure goals are not needed; (5) postoperative care should include hourly vital signs for at least 24 h, hourly neurologic assessments for at least 12 h, adequate pain control, maintaining normoxia and normothermia, and avoiding hypotension; and (6) intravenous fluid bolus administration should be considered the first-line intervention for new focal neurologic deficits following indirect revascularization surgery. CONCLUSIONS: In the absence of data supporting specific care practices before and after indirect revascularization surgery in children with moyamoya, this Delphi process defined areas of consensus among neurosurgeons, neurologists, and intensivists with moyamoya expertise. Research priorities identified include determining the role of continuous electroencephalography in postoperative moyamoya care, optimal perioperative blood pressure and hemoglobin targets, and the role of supplemental oxygen for treatment of suspected postoperative ischemia.

Incorporation of a biparietal narrowing metric to improve the ability of machine learning models to detect sagittal craniosynostosis with 2D photographs.

OBJECTIVE: Sagittal craniosynostosis is the most common form of craniosynostosis and typically results in scaphocephaly, which is characterized by biparietal narrowing, compensatory frontal bossing, and an occipital prominence. The cephalic index (CI) is a simple metric for quantifying the degree of cranial narrowing and is often used to diagnose sagittal craniosynostosis. However, patients with variant forms of sagittal craniosynostosis may present with a "normal" CI, depending on the part of the suture that is closed. As machine learning (ML) algorithms are developed to assist in the diagnosis of cranial deformities, metrics that reflect the other phenotypic features of sagittal craniosynostosis are needed. In this study the authors sought to describe the posterior arc angle (PAA), a measurement of biparietal narrowing that is obtained with 2D photographs, and elucidate the role of PAA as an adjuvant to the CI in characterizing scaphocephaly and the potential relevance of PAA in new ML model development. METHODS: The authors retrospectively reviewed 1013 craniofacial patients treated during the period from 2006 to 2021. Orthogonal top-down photographs were used to calculate the CI and PAA. Distribution densities, receiver operating characteristic (ROC) curves, and chi-square analyses were used to describe the relative predictive utility of each method for sagittal craniosynostosis. RESULTS: In total, 1001 patients underwent paired CI and PAA measurements and a clinical head shape diagnosis (sagittal craniosynostosis, n = 122; other cranial deformity, n = 565; normocephalic, n = 314). The area under the ROC curve (AUC) for the CI was 98.5% (95% confidence interval 97.8%-99.2%, p < 0.001), with an optimum specificity of 92.6% and sensitivity of 93.4%. The PAA had an AUC of 97.4% (95% confidence interval 96.0%-98.8%, p < 0.001) with an optimum specificity of 94.9% and sensitivity of 90.2%. In 6 of 122 (4.9%) cases of sagittal craniosynostosis, the PAA was abnormal while the CI was normal. This means that adding a PAA cutoff branch to a partition model increases the detection of sagittal craniosynostosis. CONCLUSIONS: Both CI and PAA are excellent discriminators for sagittal craniosynostosis. Using an accuracy-optimized partition model, the addition of the PAA to the CI increased model sensitivity compared to using the CI alone. Using a model that incorporates both CI and PAA could assist in the early identification and treatment of sagittal craniosynostosis via automated and semiautomated algorithms that utilize tree-based ML models.

Anticoagulation for the treatment of septic cerebral venous sinus thrombosis in the setting of pediatric sinogenic and otogenic intracranial infections.

OBJECTIVE: Septic cerebral venous sinus thrombosis (CVST) is a recognized complication of pediatric sinogenic and otogenic intracranial infections. The optimal treatment paradigm remains controversial. Proponents of anticoagulation highlight its role in preventing thrombus propagation and promoting recanalization, while others cite the risk of hemorrhagic complications, especially after a neurosurgical procedure for an epidural abscess or subdural empyema. Here, the authors investigated the diagnosis, management, and outcomes of pediatric patients with sinogenic or otogenic intracranial infections and a septic CVST. METHODS: All patients 21 years of age or younger, who presented with an intracranial infection in the setting of sinusitis or otitis media and who underwent neurosurgical treatment at Connecticut Children's, Rady Children's Hospital-San Diego, or Ann and Robert H. Lurie Children's Hospital of Chicago from March 2015 to March 2023, were retrospectively reviewed. Demographic, clinical, and radiological data were systematically collated. RESULTS: Ninety-six patients were treated for sinusitis-related and/or otitis media-related intracranial infections during the study period, 15 (15.6%) of whom were diagnosed with a CVST. Of the 60 patients who presented prior to the COVID-19 pandemic, 6 (10.0%) were diagnosed with a septic CVST, whereas of the 36 who presented during the COVID-19 pandemic, 9 (25.0%) had a septic CVST (p = 0.050). The superior sagittal sinus was involved in 12 (80.0%) patients and the transverse and/or sigmoid sinuses in 4 (26.7%). Only 1 (6.7%) patient had a fully occlusive thrombus. Of the 15 patients with a septic CVST, 11 (73.3%) were initiated on anticoagulation at a median interval of 4 (IQR 3-5) days from the most recent neurosurgical procedure. Five (45.5%) patients who underwent anticoagulation demonstrated complete recanalization on follow-up imaging, and 4 (36.4%) had partial recanalization. Three (75.0%) patients who did not undergo anticoagulation demonstrated complete recanalization, and 1 (25.0%) had partial recanalization. None of the patients treated with anticoagulation experienced hemorrhagic complications. CONCLUSIONS: Septic CVST is frequently identified among pediatric patients undergoing neurosurgical intervention for sinogenic and/or otogenic intracranial infections and may have become more prevalent during the COVID-19 pandemic. Anticoagulation can be used safely in the acute postoperative period if administered cautiously, in a monitored setting, and with interval cross-sectional imaging. However, some patients exhibit excellent outcomes without anticoagulation, and further studies are needed to identify those who may benefit the most from anticoagulation.

Practice variability in the perioperative management of pediatric moyamoya disease in North America.

BACKGROUND: Revascularization surgery decreases the long-term risk of stroke in children with moyamoya but carries an increased risk of perioperative ischemic events. Evidence-based approaches to safe perioperative management of children with moyamoya are limited. We aimed to understand practice variability in perioperative moyamoya care. METHODS: Neurologists, neurosurgeons, and intensivists practicing in North America with expertise in perioperative pediatric moyamoya care participated in a 138-item anonymous survey focused on interdisciplinary perioperative care surrounding indirect revascularization surgery. RESULTS: Many perioperative care practices vary substantially between participants. Timing of resumption of antiplatelet therapy postoperatively, choice of sedative agents and vasopressors, goal blood pressures, rate and duration of intravenous fluid administration, and red blood cell transfusion thresholds are among the most variable practices. CONCLUSIONS: This practice variability survey highlights several important knowledge gaps and areas of equipoise that should be targets for future investigation and consensus-building efforts.

Pediatric glioblastoma: mechanisms of immune evasion and potential therapeutic opportunities.

Pediatric glioblastoma is relatively rare compared with its adult counterpart but is associated with a similarly grim prognosis. Available data indicate that pediatric glioblastomas are molecularly distinct from adult tumors, and relatively little is known about the pediatric glioblastoma tumor microenvironment (TME). Cancer immunotherapy has emerged as a new pillar of cancer treatment and is revolutionizing the care of patients with many advanced solid tumors, including melanoma, non-small cell lung cancer, head and neck cancer, and renal cell carcinoma. Unfortunately, attempts to treat adult glioblastoma with current immunotherapies have had limited success to date. Nevertheless, the immune milieu in pediatric glioblastoma is distinct from that found in adult tumors, and evidence suggests that pediatric tumors are less immunosuppressive. As a result, immunotherapies should be specifically evaluated in the pediatric context. The purpose of this review is to explore known and emerging mechanisms of immune evasion in pediatric glioblastoma and highlight potential opportunities for implementing immunotherapy in the treatment of these devastating pediatric brain tumors.

Solid-variant aneurysmal bone cysts in the craniofacial skeleton: the role of genomic analysis.

BACKGROUND: Solid variant aneurysmal bone cysts (SVABCs) are a rare but well-described subtype of ABCs. While classic ABCs are readily identified radiographically, SVABCs lack these characteristic radiographic features and thus have a wide differential diagnosis on presentation (including Ewing sarcoma, Langerhans cell histiocytosis, osteosarcoma, metastasis, and giant cell tumor). Genomic/molecular analyses are often necessary for the diagnosis of SVABCs, with USP6 rearrangements being a characteristic finding. We present two cases in which genomic analysis was critical in the diagnosis of SVABCs and revealed unique gene fusions that may provide insight into SVABC pathogenesis. CASE DESCRIPTIONS: Two 13-year old male children presented to our institution with new mass lesions involving the craniofacial skeleton. Magnetic resonance imaging (MRI) in both cases revealed predominantly solid, avidly enhancing masses, one of the squamous portion of the temporal bone, and the other arising from the sphenopalatine foramen with extension into the ipsilateral maxillary and ethmoid sinuses. Histopathology displayed predominantly solid morphology, and next generation sequencing (NGS) revealed a FAT1-USP6 gene fusion in the temporal lesion, and a MIR22HG-USP6 gene fusion in the maxillofacial lesion, the latter of which was not identified on fluorescence in situ hybridization (FISH). These findings were most consistent with a diagnosis of SVABC in each case. CONCLUSIONS: These two cases highlight novel gene fusions in atypically located SVABCs and emphasize the ability of NGS to more accurately and consistently identify USP6 gene fusions, particularly in SVABCs that may otherwise be indistinguishable from alternative pathologies.

Family-acquired photographs for the evaluation of pediatric head shape via telemedicine: an analysis of photograph quality.

OBJECTIVE: Telemedicine can be an effective tool for the evaluation of the pediatric patient with a cranial deformity, but it increases the reliance of neurosurgical providers on data provided by patients and families. Family-acquired photographs, in particular, can be used to augment the evaluation of pediatric head shape abnormalities via telemedicine, but photographs of sufficient quality are necessary. Here, the authors systematically reviewed the quality and utility of family-acquired photographs for patients referred to their pediatric neurosurgery clinic for telemedicine-based head shape evaluations. METHODS: All telemedicine encounters that were completed for head shape abnormalities at the authors' institution between May 2020 and December 2021 were retrospectively reviewed. Instructions were sent to families prior to each visit with examples of ideal photographs. Three orthogonal views of the patient's head-frontal, lateral, and vertex-were requested. Data were collected regarding demographics, diagnosis, follow-up, and photograph quality. Quality variables included orthogonality of each requested view, appropriate distance, appropriate lighting, presence of distracting elements, and whether hair obscured the head shape. RESULTS: Overall, 565 patients had 892 visits during the study period. A total of 1846 photograph requests were made, and 3335 photographs were received for 829 visits. Of 2676 requested orthogonal views, 1875 (70%) were received. Of these, 1826 (97%) had adequate lighting, 1801 (96%) had appropriate distance, and 1826 (97%) had no distracting features. Hair did not obscure the head shape on the vertex view in 557 visits with orthogonal vertex views (82%). In-person follow-up was requested for further medical evaluation in 40 visits (5%). CONCLUSIONS: The family-acquired photographs in this series demonstrated high rates of adequate lighting and distance, without distracting features. Lack of orthogonality and obscuration of the head shape by hair, however, were more common issues. Family education prior to the visit may improve the quality of family-acquired photographs but requires an investment of time by medical staff. Efforts to further improve photographic quality will facilitate efforts to perform craniometric evaluations through telemedicine visits.

Early experience with targeted therapy as a first-line adjuvant treatment for pediatric low-grade glioma.

OBJECTIVE: Pediatric low-grade gliomas (pLGGs) frequently exhibit dysregulation of the mitogen-activated protein kinase (MAPK) pathway. Targeted therapies, including mutant BRAF inhibitors (dabrafenib) and MEK inhibitors (trametinib), have shown promise in patients in whom conventional chemotherapy has failed. However, few studies have investigated the use of targeted therapy as a first-line treatment for pLGG. Here, the authors reviewed their institutional experience with using a personalized medicine approach to patients with newly diagnosed pLGGs. METHODS: All pediatric patients at the authors' institution who had been treated with dabrafenib or trametinib for pLGG without first receiving conventional chemotherapy or radiation were retrospectively reviewed. Demographic, clinical, and radiological data were collected. RESULTS: Eight patients underwent targeted therapy as a first-line treatment for pLGG. Five patients had a BRAF alteration (1 with a BRAFV600E mutation, 4 with a KIAA1549:BRAF fusion), and 3 patients had an NF1 mutation. One of the 8 patients was initially treated with dabrafenib, and trametinib was added later. Seven patients were initially treated with trametinib; of these, 2 later transitioned to dual therapy, whereas 5 continued with trametinib monotherapy. Six patients (75%) demonstrated a partial response to therapy during their treatment course, whereas stable disease was identified in the remaining 2 patients (25%). One patient experienced mild disease progression after completing a course of trametinib monotherapy, but ultimately stabilized after a period of close observation. Another patient experienced tumor progression while on dabrafenib, but subsequently responded to dual therapy with dabrafenib and trametinib. The most common adverse reactions to targeted therapy were cutaneous toxicity (100%) and diarrhea (50%). CONCLUSIONS: Targeted therapies have the potential to become a standard treatment option for pLGG due to their favorable toxicity profile and oral route of administration. This case series provides preliminary evidence that targeted therapies can induce an early disease response as a first-line adjuvant treatment; however, large-scale studies are required to assess long-term durability and safety.

Telehealth in Pediatric Surgical Subspecialties: Rapid Adoption in the Setting of COVID-19.

Background/Purpose: Telehealth has evolved over the past several decades to address varying medical needs. Most recently, it has been widely utilized as a result of the COVID-19 pandemic. Most previous studies have not performed in-depth analyses of patient satisfaction with telehealth technologies. This project investigated patient satisfaction with the abrupt implementation of telemedicine within pediatric surgical subspecialties during the COVID-19 pandemic. Materials and Methods: We conducted a single-center review to determine patients' satisfaction with telemedicine during the early stages of the pandemic. Surveys were distributed to patients who completed a telemedicine video visit within a pediatric surgical subspecialty at Connecticut Children's Medical Center between March 16 and May 16, 2020. Results: A total of 1,608 patients were contacted, with 457 surveys completed (28.4%). Of all respondents, 95.6% were "very satisfied" or "satisfied" with their overall telemedicine appointment. Seventy-three percent reported no difficulty with completing their visit. Eighty-seven percent would consider another telemedicine visit again in the future. No significant difference was found between the payor mix for telemedicine and in-person appointments. Conclusions: The implementation of telemedicine at Connecticut Children's Medical Center during the COVID-19 pandemic was successful despite numerous barriers to use. Families not only showed high rates of satisfaction with the overall visit and provider interaction, but also an overwhelming openness to future use of telehealth.

Postnatal diagnosis of single-suture craniosynostosis with cranial ultrasound: a systematic review.

INTRODUCTION: The optimal protocol for diagnostic workup of craniosynostosis and the role of specific imaging modalities remain controversial. Skull X-rays and 3-dimensional head CTs are options when physical exam is equivocal but involve ionizing radiation. Ultrasound has emerged as an alternative modality for visualization of cranial sutures, but its use is not widespread. METHODS: The authors performed a systematic review of the literature on the use of ultrasound for the diagnosis of craniosynostosis. RESULTS: A total of 12 studies involving 1062 patients were included. Overall, 300 patients (28.2%) were diagnosed with craniosynostosis. A total of 369 (34.7%) patients had their diagnosis (craniosynostosis vs. patent sutures) confirmed with another imaging modality in addition to ultrasound. Among studies, the specificity of ultrasound ranged from 86 to 100%, and the sensitivity from 71 to 100%. CONCLUSIONS: Ultrasonography of cranial sutures is a feasible and accurate tool for the diagnosis of single-suture craniosynostosis when physical exam findings are insufficient. Although technical aspects of ultrasonography and its interpretation have an associated learning curve, ultrasound can achieve high sensitivity and specificity among patients with suspected craniosynostosis.

Juvenile myelomonocytic leukemia presenting in an infant with a subdural hematoma.

BACKGROUND: Juvenile myelomonocytic leukemia (JMML) is a rare childhood hematopoietic disorder typically presenting with hepatosplenomegaly, lymphadenopathy, pallor, fever, and cutaneous findings. The authors report the first case, to our knowledge, of JMML presenting in a pediatric patient with a subdural hematoma. CASE DESCRIPTION: A 7-month old male with recurrent respiratory infections and a low-grade fever presented with a full fontanelle and an increasing head circumference and was found to have chronic bilateral subdural collections. Abusive head trauma, infectious, and coagulopathy workups were unremarkable, and the patient underwent bilateral burr holes for evacuation of the subdural collections. The postoperative course was complicated by the development of thrombocytopenia, anemia, and an acute subdural hemorrhage which required evacuation. Cytologic analysis of the subdural fluid demonstrated atypical cells, which prompted flow cytometric analysis, a bone marrow biopsy, and ultimately a diagnosis of JMML. Following chemotherapy, the patient's counts improved, and he subsequently underwent a hematopoietic stem cell transplant. CONCLUSION: Subdural collections may rarely represent the first presenting sign of hematologic malignancies. In patients with a history of recurrent infections and a negative workup for abusive head trauma, clinicians should include neoplastic etiologies in the differential for chronic subdural collections and have a low threshold for fluid analysis.

Changes in Gene Expression in Space and Time Orchestrate Environmentally Mediated Shaping of Root Architecture.

Shaping of root architecture is a quintessential developmental response that involves the concerted action of many different cell types, is highly dynamic, and underpins root plasticity. To determine to what extent the environmental regulation of lateral root development is a product of cell-type preferential activities, we tracked transcriptomic responses to two different treatments that both change root development in Arabidopsis thaliana at an unprecedented level of temporal detail. We found that individual transcripts are expressed with a very high degree of temporal and spatial specificity, yet biological processes are commonly regulated, in a mechanism we term response nonredundancy. Using causative gene network inference to compare the genes regulated in different cell types and during responses to nitrogen and a biotic interaction, we found that common transcriptional modules often regulate the same gene families but control different individual members of these families, specific to response and cell type. This reinforces that the activity of a gene cannot be defined simply as molecular function; rather, it is a consequence of spatial location, expression timing, and environmental responsiveness.

Predictors of an Extended Length of Stay following an Elective Craniotomy in Children and Young Adults.

BACKGROUND: Length of stay (LOS) is now a generally accepted clinical metric within the USA. An extended LOS following an elective craniotomy can significantly impact overall costs. Few studies have evaluated predictors of an extended LOS in pediatric neurosurgical patients. OBJECTIVE: The aim of the study was to determine predictors of an extended hospital LOS following an elective craniotomy in children and young adults. METHODS: All pediatric patients and young adults undergoing an elective craniotomy between January 1, 2010, and April 1, 2019, were retrospectively identified using a prospectively maintained database. Demographic, clinical, radiological, and surgical data were collected. The primary outcome was extended LOS, defined as a postsurgical stay greater than 7 days. Bivariate and multivariable analyses were performed. RESULTS: A total of 1,498 patients underwent 1,720 elective craniotomies during the study period over the course of 1,698 hospitalizations with a median LOS of 4 days (interquartile range 3-6 days). Of these encounters, 218 (12.8%) had a prolonged LOS. Multivariable analysis demonstrated that non-Caucasian race (OR = 1.9 [African American]; OR = 1.6 [other]), the presence of an existing shunt (OR = 1.8), the type of craniotomy (OR = 0.3 [vascular relative to Chiari]), and the presence of a postoperative complication (OR = 14.7) were associated with an extended LOS. CONCLUSIONS: Inherent and modifiable factors predict a hospital stay of more than a week in children and young adults undergoing an elective craniotomy.

Design, characterization and evaluation of a laser-guided focused ultrasound system for preclinical investigations.

BACKGROUND: The clinical applications of transcranial focused ultrasound continue to expand and include ablation as well as drug delivery applications in the brain, where treatments are typically guided by MRI. Although MRI-guided focused ultrasound systems are also preferred for many preclinical investigations, they are expensive to purchase and operate, and require the presence of a nearby imaging center. For many basic mechanistic studies, however, MRI is not required. The purpose of this study was to design, construct, characterize and evaluate a portable, custom, laser-guided focused ultrasound system for noninvasive, transcranial treatments in small rodents. METHODS: The system comprised an off-the-shelf focused ultrasound transducer and amplifier, with a custom cone fabricated for direct coupling of the transducer to the head region. A laser-guidance apparatus was constructed with a 3D stage for accurate positioning to 1 mm. Pressure field simulations were performed to demonstrate the effects of the coupling cone and the sealing membrane, as well as for determining the location of the focus and acoustic transmission across rat skulls over a range of sizes. Hydrophone measurements and exposures in hydrogels were used to assess the accuracy of the simulations. In vivo treatments were performed in rodents for opening the blood-brain barrier and to assess the performance and accuracy of the system. The effects of varying the acoustic pressure, microbubble dose and animal size were evaluated in terms of efficacy and safety of the treatments. RESULTS: The simulation results were validated by the hydrophone measurements and exposures in the hydrogels. The in vivo treatments demonstrated the ability of the system to open the blood-brain barrier. A higher acoustic pressure was required in larger-sized animals, as predicted by the simulations and transmission measurements. In a particular sized animal, the degree of blood-brain barrier opening, and the safety of the treatments were directly associated with the microbubble dose. CONCLUSION: The focused ultrasound system that was developed was found to be a cost-effective alternative to MRI-guided systems as an investigational device that is capable of accurately providing noninvasive, transcranial treatments in rodents.

Management of Chiari malformations: opinions from different centers-a review.

PURPOSE: Surgical decision-making in Chiari malformation type I (CM-I) patients tends to depend on the presence of neurological signs and symptoms, syringomyelia, and/or scoliosis, but significant variability exists from center to center. Here, we review the symptoms of CM-I in children and provide an overview of the differences in opinion regarding surgical indications, preferred surgical techniques, and measures of outcome. METHODS: A review of the literature was performed to identify publications relevant to the surgical management of pediatric CM-I patients. RESULTS: Most surgeons agree that asymptomatic patients without syringomyelia should not undergo prophylactic surgery, while symptoms of brainstem compression and/or lower cranial nerve dysfunction warrant surgery. Patients between these extremes, however, remain controversial, as does selection of the most appropriate surgical technique. CONCLUSIONS: The optimal surgical procedure for children with CM-I remains a point of contention, and widespread variability exists between and within centers.

Differential expression of the TWEAK receptor Fn14 in IDH1 wild-type and mutant gliomas.

The TNF receptor superfamily member Fn14 is overexpressed by many solid tumor types, including glioblastoma (GBM), the most common and lethal form of adult brain cancer. GBM is notable for a highly infiltrative growth pattern and several groups have reported that high Fn14 expression levels can increase tumor cell invasiveness. We reported previously that the mesenchymal and proneural GBM transcriptomic subtypes expressed the highest and lowest levels of Fn14 mRNA, respectively. Given the recent histopathological re-classification of human gliomas by the World Health Organization based on isocitrate dehydrogenase 1 (IDH1) gene mutation status, we extended this work by comparing Fn14 gene expression in IDH1 wild-type (WT) and mutant (R132H) gliomas and in cell lines engineered to overexpress the IDH1 R132H enzyme. We found that both low-grade and high-grade (i.e., GBM) IDH1 R132H gliomas exhibit low Fn14 mRNA and protein levels compared to IDH1 WT gliomas. Forced overexpression of the IDH1 R132H protein in glioma cells reduced Fn14 expression, while treatment of IDH1 R132H-overexpressing cells with the IDH1 R132H inhibitor AGI-5198 or the DNA demethylating agent 5-aza-2'-deoxycytidine increased Fn14 expression. These results support a role for Fn14 in the more aggressive and invasive phenotype associated with IDH1 WT tumors and indicate that the low levels of Fn14 gene expression noted in IDH1 R132H mutant gliomas may be due to epigenetic regulation via changes in DNA methylation.

Surgical treatment of a type IV cystic sacrococcygeal teratoma with intraspinal extension utilizing a posterior-anterior-posterior approach: a case report.

Type IV sacrococcygeal teratoma with intraspinal involvement is rare and to our knowledge has not been reported previously in the literature. The authors present the case of a 2-month-old infant with a type IV sacrococcygeal teratoma diagnosed on prenatal ultrasound. Postnatal MRI revealed intraspinal extension through an enlarged sacral neuroforamina on the right side. On surgical exploration, the authors discovered a dorsal cystic tumor involving the sacral spine that extended through an enlarged S4 foramen to a large presacral component. The tumor was successfully removed to achieve a complete en bloc surgical resection. The authors review the epidemiology, pathophysiology, and treatment of sacrococcygeal teratomas with intraspinal extension.

Instrumented fusion for spinal deformity after laminectomy or laminoplasty for resection of intramedullary spinal cord tumors in pediatric patients.

OBJECTIVE Spinal deformity has become a well-recognized complication of intramedullary spinal cord tumor (IMSCT) resection. In particular, laminectomy can result in biomechanical instability caused by loss of the posterior tension band. Therefore, laminoplasty has been proposed as an alternative to laminectomy. Here, the authors describe the largest current series of pediatric patients who have undergone laminoplasty for IMSCT resection and investigate the need for surgical fusion after both laminectomy and laminoplasty. METHODS The medical records of pediatric patients who underwent resection of an IMSCT at a single institution between November 2003 and May 2014 were reviewed retrospectively. Demographic, clinical, radiological, surgical, histopathological, and follow-up data were collected. RESULTS Sixty-six consecutive patients underwent resection of an IMSCT during the study period. Forty-three (65%) patients were male. The patients had a median age of 12.9 years (interquartile range [IQR] 7.2-16.5 years) at the time of surgery. Patients typically presented with a tumor that involved the cervical and/or thoracic spine. Nineteen (29%) patients underwent laminectomy, and 47 (71%) patients underwent laminoplasty. Patients in each cohort had a similar rate of postoperative deformity. Overall, 10 (15%) patients required instrumented spinal fusion for spinal deformity. Four patients required revision of the primary fusion. CONCLUSIONS These findings show that among pediatric patients with an IMSCT, postoperative surgical fusion rates remain high, even after laminoplasty. Known risk factors, such as the age of the patient, location of the tumor, and the number of involved levels, might play a larger role than replacement of the laminae in determining the rate of surgical fusion after IMSCT resection.