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Introduction: Human Herpes Virus-6 (HHV-6) is a ubiquitous virus but can lead to deleterious clinical manifestations due to its predilection for the pediatric central nervous system. Despite significant literature describing its common clinical course, it is rarely considered as a causative agent in CSF pleocytosis in the setting of craniotomy and external ventricular drainage device. Identification of a primary HHV-6 infection allowed for timely treatment with an antiviral agent along with earlier discontinuation of antibiotic regimen and expedited placement of a ventriculoperitoneal shunt. Case Presentation: A two-year-old girl presented with 3 months of progressive gait disturbance and intranuclear ophthalmoplegia. Following craniotomy for removal of 4th ventricular pilocytic astrocytoma and decompression of hydrocephalus, she suffered a prolonged clinical course due to persistent fevers and worsening CSF leukocytosis despite multiple antibiotic regimens. The patient was admitted to the hospital during the COVID-19 pandemic and isolated with her parents in the intensive care unit with strict infection control measures. FilmArray Meningitis/Encephalitis (FAME) panel ultimately detected HHV-6. Clinical confirmation of HHV-6-induced meningitis was proposed given improvement in CSF leukocytosis and fever reduction following the initiation of antiviral medications. Pathologic analysis of brain tumor tissue failed to show HHV-6 genome positivity, suggesting a primary peripheral etiology of infection. Discussion/Conclusion: Here, we present the first known case of HHV-6 infection detected by FAME following intracranial tumor resection. We propose a modified algorithm for persistent fever of unknown origin which may decrease symptomatic sequelae, minimize additional procedures, and shorten length of ICU stay.

Study Design Retrospective cohort study Objectives To describe the common types of complications and their risk factors during spine surgery in patients with achondroplasia. Methods A retrospective review was performed of medical records of adult achondroplasia patients who underwent spine surgery at our institution between 2007 and 2021. Inclusion criteria were achondroplasia and age >16 years. Surgical encounters were evaluated for durotomy, postoperative neurologic deficit, wound compromise, medical complications, and return to the operating room. Statistical analysis included evaluation of relationships across complications and fisher exact test applied to bivariate/categorical variables and t-test/ANOVA for continuous variables. Multivariable analysis using logistic regression was performed to account for patient characteristics Results Fifty-five patients with achondroplasia underwent 95 surgeries. Forty-nine percent of the surgeries involved a complication. These included durotomy (33.7%), neurologic deficit (11.6%), wound compromise (6.3%), and other medical complications (6.3%). Thirteen percent of surgeries required return to the operating room. The greatest number of complications occurred in thoracolumbar region (60.0%) compared to cervicothoracic (18.2%) and craniocervical junction (33.3%). Chronologically later surgical encounters had decreased complications and durotomies only occurred in thoracolumbar surgeries (45.7%). Conclusions Adult patients with achondroplasia undergoing surgery chronologically later in this set of consecutive patients were at a decreased risk for complications. Thoracolumbar surgeries were at the greatest risk for durotomies. Male sex was a risk factor for durotomy, while age was a risk factor for neurologic deficit. The potential for adverse surgical events should be considered when evaluating patients with achondroplasia for spine surgery.

Graphical abstract, Neurosurgery as one of the most technologically demanding medical fields rapidly adapts the newest developments from multiple scientific disciplines for treating brain tumors. Despite half a century of clinical trials, survival for brain primary tumors such as glioblastoma (GBM), the most common primary brain cancer, or rare ones including primary central nervous system lymphoma (PCNSL), is dismal. Cancer therapy and research have currently shifted toward targeted approaches, and personalized therapies. The orchestration of novel and effective blood–brain barrier (BBB) drug delivery approaches, targeting of cancer cells and regulating tumor microenvironment including the immune system are the key themes of this review. As the global pandemic due to SARS-CoV-2 virus continues, neurosurgery and neuro-oncology must wrestle with the issues related to treatment-related immune dysfunction. The selection of chemotherapeutic treatments, even rare cases of hypersensitivity reactions (HSRs) that occur among immunocompromised people, and number of vaccinations they have to get are emerging as a new chapter for modern Nano neurosurgery.

INTRODUCTION Gliomas are considered immunologically “cold” tumors that mask themselves from the immune system. Immunotherapy, a breakthrough for cancer treatment, remains inefficient for gliomas. H3K27M mutant diffuse midline glioma has poor survival. Using our innovative mosaic analysis with dual recombinases technology (Cell 2019), we further created a novel murine model of H3K27M glioma with an inducible expression of LAG3 and TGFBR2 to make the tumor recognizable by the immune system. This allows studying molecular mechanisms of “perfect” immunotherapy in pediatric gliomas with histone H3.3 mutations. METHODS To make a novel murine model, H3K27M plasmids with doxycycline-inducible expression for TGFBR2 and LAG3 were designed, sequenced, and replicated. For in vitro validation, murine neuronal stem cells were nucleofected with these plasmids, grown and sorted. Doxycycline was added to the experimental group in vitro to induce expression. The plasmids were then electroporated into neonatal MGMT mice (n=21) of both genders. Control mice were used on a standard diet (n=9) and experimental mice (n=12) were given doxycycline in food to induce TGFBR2 and LAG3 expression in vivo. Mice were followed up for survival. RESULTS Plasmid sequencing validation demonstrated their high purity. In vitro nucleofected neuronal stem cells showed significant increase in TGFBR2 and LAG3 expression by immunofluorescent staining after addition of doxycycline. The mouse survival study showed a significant benefit with treatment group surviving 46% longer (135 ± 41.9 days vs. 92.6 ± 32.7 days in the control group, p=0.030). Conclusion and Future Directions: We have successfully modified H3K27M glioma to have inducible expression of TGFBR2 and LAG3 to simulate “perfect” immunotherapy. The survival study showed a significant survival benefit. The development of organoid transplants for more uniform testing and next-generation sequencing is ongoing. This can lead to the emergence of novel immune therapies and uncover novel mechanisms of tumor response to treatment.

Growth promoting variants in PIK3CA cause a spectrum of developmental disorders, depending on the developmental timing of the mutation and tissues involved. These phenotypically heterogeneous entities have been grouped as PIK3CA-Related Overgrowth Spectrum disorders (PROS). Deep sequencing technologies have facilitated detection of low-level mosaic, often necessitating testing of tissues other than blood. Since clinical management practices vary considerably among healthcare professionals and services across different countries, a consensus on management guidelines is needed. Clinical heterogeneity within this spectrum leads to challenges in establishing management recommendations, which must be based on patient-specific considerations. Moreover, as most of these conditions are rare, affected families may lack access to the medical expertise that is needed to help address the multi-system and often complex medical issues seen with PROS. In March 2019,macrocephaly-capillary malformation (M-CM) patient organizations hosted an expert meeting in Manchester, United Kingdom, to help address these challenges with regards to M-CM syndrome. We have expanded the scope of this project to cover PROS and developed this consensus statement on the preferred approach for managing affected individuals based on our current knowledge.

In situ transgenesis methods such as virus and electroporation can create somatic transgenic mice quickly, but they lack the exquisite control over copy number, zygosity, and locus specificity. We have recently established mosaic analysis by dual recombinase-mediated cassette exchange (MADR), which permits stable labeling of mutant cells expressing transgenic elements from precisely-defined chromosomal loci. MADR provides a toolkit of elements for combinatorial labeling, inducible/reversible transgene manipulation, VCre recombinase expression, and genetic manipulation of human cells. Further, we have demonstrated the versatility of MADR by creating glioma models with mixed, reporter-identified zygosity or with “personalized” driver mutations from pediatric glioma. For example, introducing H3f3a mutation variants with MADR regulates the spatiotemporal profile of glioma, and single-cell RNA and ATAC sequencing analysis demonstrates a recapitulation of developmental hierarchy seen in K27M-mutant human glioma. Moreover, we have generated novel models of supratentorial ependymoma using patient-derived oncofusion transgenes. These models display a high degree of fidelity and we now compare these models on a single-cell level with our previous models and human tumor cell transcriptomes. In addition, we now demonstrate the ability to generalize the MADR technology to other non-CNS tissues using local plasmid delivery. Finally, we have engineered human cells to allow for MADR transgenesis and somatic transgenic organoids. These combined approaches will enable researchers to discovery disease mechanisms and test therapeutics in more physiologically relevant cancer models.MADR is extensible to thousands of existing mouse lines and can be adapted to human cells, providing a flexible platform to democratize the generation of somatic transgenic disease models. Citation Format: Gi Bum Kim, David Rincon Fernandez Pacheco, David Saxon, Amy Yang, Sara Sabat, Marina Dutra-Clarke, Rachelle Levy, Ashley Watkins, Hannah Park, Aslam Abbasi Akhtar, Paul W. Linesch, Naomi Kobritz, Swasty S. Shandra, Katie Grausam, Alberto Ayala-Sarmiento, Jessica Molina, Kristyna Sedivakova, Daniel S. Gareau, Mariella G. Filbin, Serguei Bannykh, Jie Tang, Mario L. Suva, Bin Chen, Moise Danielpour, Joshua J. Breunig. MADR: Rapid generation of somatic mosaics to model cancer in mice and human organoids [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr NG01.

In situ transgenesis methods such as virus and electroporation can create somatic transgenic mice quickly, but they lack the exquisite control over copy number, zygosity, and locus specificity. We have recently established mosaic analysis by dual recombinase-mediated cassette exchange (MADR), which permits stable labeling of mutant cells expressing transgenic elements from precisely defined chromosomal loci. MADR provides a toolkit of elements for combinatorial labeling, inducible/reversible transgene manipulation, VCre recombinase expression, and genetic manipulation of human cells. Further, we have demonstrated the versatility of MADR by creating glioma models with mixed, reporter-identified zygosity or with “personalized” driver mutations from pediatric glioma. For example, introducing H3f3a mutation variants with MADR regulates the spatiotemporal profile of glioma, and single-cell RNA and ATAC sequencing analysis demonstrates a recapitulation of developmental hierarchy seen in K27M mutant human glioma. Moreover, we have generated novel models of supratentorial ependymoma using patient-derived oncofusion transgenes. These models display a high degree of fidelity, and we now compare these models on a single-cell level with our previous models and human tumor cell transcriptomes. In addition, we now demonstrate the ability to generalize the MADR technology to other non-CNS tissues using local plasmid delivery. Finally, we have engineered human cells to allow for MADR transgenesis and somatic transgenic organoids. These combined approaches will enable researchers to discover disease mechanisms and test therapeutics in more physiologically relevant cancer models. MADR is extensible to thousands of existing mouse lines and can be adapted to human cells, providing a flexible platform to democratize the generation of somatic transgenic disease models. This abstract is also being presented as Poster B46. Citation Format: Gi Bum Kim, David Rincon Fernandez Pacheco, David Saxon, Amy Yang, Sara Sabet, Marina Dutra-Clarke, Rachelle Levy, Ashley Watkins, Hannah Park, Aslam Abbasi Akhtar, Paul W. Linesch, Naomi Kobritz, Swasty S. Chandra, Katie Grausam, Alberto Ayala- Sarmiento, Jessica Molina, Kristyna Sedivakova, Daniel S. Gareau, Mariella G. Filbin, Serguei Bannykh, Jie Tang, Mario Suva, Bin Chen, Moise Danielpour, Joshua J. Breunig. MADR: Rapid generation of somatic mosaics with locus-specific, stably integrated transgenic elements for generation of “personalized” mouse models and human organoid tumor models [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr PR11.

Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00401-018-1883-2) contains supplementary material, which is available to authorized users.

Summary Precise methods for transgene regulation are important to study signaling pathways and cell lineages in biological systems where gene function is often recycled within and across lineages. We engineered a genetic toolset for flexible transgene regulation in these diverse cellular contexts. Specifically, we created an optimized piggyBac transposon-based system, allowing for the facile generation of stably transduced cell lineages in vivo and in vitro. The system, termed pB-Tet-GOI (piggyBac-transposable tetracycline transactivator-mediated flexible expression of a genetic element of interest), incorporates the latest generation of tetracycline (Tet) transactivator and reverse Tet transactivator variants—along with engineered mutants—in order to provide regulated transgene expression upon addition or removal of doxycycline (dox). Altogether, the flexibility of the system allows for dox-induced, dox-suppressed, dox-resistant (i.e., constitutive), and dox-induced/constitutive regulation of transgenes. This versatile strategy provides reversible temporal regulation of transgenes with robust inducibility and minimal leakiness., Graphical Abstract, Highlights • pB-Tet-GOI features the latest generation of Tet transactivators (tTAs) and variants • piggyBac transposition allows for genomic insertion of pb-Tet-GOI • pb-Tet-GOI provides flexible control of transgenes in vitro and in vivo • tTA variants permit reversible, constitutive, or induced constitutive expression, In this article, Breunig and colleagues describe a stable, flexible genetic system for inducible and reversible gene expression. The doxycycline-mediated system, termed pB-Tet-GOI, is non-leaky, robust, and allows for “On→Off→On,” “Off→On→Off” and inducible-constitutive temporal control (“Off→permanently On”) of transgenes in vivo and in vitro, as well as a dox-resistant variant for strong, constitutive expression of transgenes.

We have developed a simple and generalizable in vivo method for brain tumor modeling, mosaic analysis by dual recombinase-mediated cassette exchange (MADR). MADR allows for stable labeling of mutant cells expressing transgenic elements from a precisely-defined chromosomal locus. We have demonstrated the power and versatility of MADR by creating novel glioma models with mixed, reporter-defined zygosity, or with “personalized” H3. 3-containing driver mutation signatures from pediatric glioma--each manipulation altering the spatiotemporal profile of resulting tumors. Further we have generated ependymoma models by employing patient-derived fusion driver mutations. Notably, each model displays divergent spatiotemporal tumor expansion profiles and cellular phenotypes. Now, we use single-cell RNA-seq to compare these models to their cells of mutation and to human datasets to elucidate the fundamental transcriptional programs and markers within and across these tumor types. This investigation will assess and credential these models against their clinical counterparts by scrutinizing the resulting datasets and validating their clinical relevance as pre-clinical models for therapeutic discovery and testing.

Viral vectors and electroporation (EP)-mediated gene transfers are efficient means of inducing somatic mosaicism in mice, but they lack the exquisite control over transgene copy number, gene zygosity, and genomic-locus specificity that genetically engineered mouse models (GEMMs) provide. Here, we develop and demonstrate a simple and generalizable in vivo method, mosaic analysis by dual recombinase-mediated cassette ex-change (MADR). MADR allows for stable labeling of mutant cells express transgenic elements from a precisely-defined chromosomal locus. To test our method, we generated reporter-labeled lineages from stem and progenitor cells in a well-defined Rosa26mTmG mouse. We demonstrate the power and versatility MADR by creating novel glioma models with mixed, reporter-defined zygosity or with personalized driver mutations from pediatric glioma-with each manipulation altering the profile of resulting tumors. Thus, MADR provides a high-throughput genetic platform for the dissection of development and disease, and this rapid method can be ap-plied to the thousands of existing gene-trap mice.

Bent Bone Dysplasia-FGFR2 type is a relatively recently described bent bone phenotype with diagnostic clinical, radiographic, and molecular characteristics. Here we report on 11 individuals, including the original four patients plus seven new individuals with three longer-term survivors. The prenatal phenotype included stillbirth, bending of the femora, and a high incidence of polyhydramnios, prematurity, and perinatal death in three of 11 patients in the series. The survivors presented with characteristic radiographic findings that were observed among those with lethality, including bent bones, distinctive (moustache-shaped) small clavicles, angel-shaped metacarpals and phalanges, poor mineralization of the calvarium, and craniosynostosis. Craniofacial abnormalities, hirsutism, hepatic abnormalities, and genitourinary abnormalities were noted as well. Longer-term survivors all needed ventilator support. Heterozygosity for mutations in the gene that encodes Fibroblast Growth Factor Receptor 2 (FGFR2) was identified in the nine individuals with available DNA. Description of these patients expands the prenatal and postnatal findings of Bent Bone Dysplasia-FGFR2 type and adds to the phenotypic spectrum among all FGFR2 disorders. © 2016 Wiley Periodicals, Inc.

We have developed a simple and generalizable in vivo method for brain tumor modeling, mosaic analysis by dual recombinase-mediated cassette exchange (MADR). MADR allows for stable labeling of mutant cells expressing transgenic elements from a precisely-defined chromosomal locus. We have demonstrated the power and versatility of MADR by creating novel glioma models with mixed, reporter-defined zygosity, or with “personalized” H3.3-containing driver mutation signatures from pediatric glioma--each manipulation altering the spatiotemporal profile of resulting tumors. Further we have generated ependymoma models by employing patient-derived fusion driver mutations. Notably, each model displays divergent spatiotemporal tumor expansion profiles and cellular phenotypes. Now, we use single-cell RNA-seq to compare these models to their cells of mutation and to human datasets to elucidate the fundamental transcriptional programs and markers within and across these tumor types. This investigation will assess and credential these models against their clinical counterparts by scrutinizing the resulting datasets and validating their clinical relevance as pre-clinical models for therapeutic discovery and testing.

SummaryAs the list of putative driver mutations in glioma grows, we are just beginning to elucidate the effects of dysregulated developmental signaling pathways on the transformation of neural cells. We have employed a postnatal, mosaic, autochthonous glioma model that captures the first hours and days of gliomagenesis in more resolution than conventional genetically engineered mouse models of cancer. We provide evidence that disruption of the Nf1-Ras pathway in the ventricular zone at multiple signaling nodes uniformly results in rapid neural stem cell depletion, progenitor hyperproliferation, and gliogenic lineage restriction. Abolishing Ets subfamily activity, which is upregulated downstream of Ras, rescues these phenotypes and blocks glioma initiation. Thus, the Nf1-Ras-Ets axis might be one of the select molecular pathways that are perturbed for initiation and maintenance in glioma.

The past decade has seen the identification of several mutations associated with low grade pediatric glioma—notably those to the v-raf murine sarcoma viral oncogene homolog B1 (BRAF). Further, next generation sequencing has recently led to the discovery of a wide variety of recurrent somatic mutations associated with low grade gliomas as well as elucidating the landscape of genetic alterations in low and high grade glioma. We have employed a novel methodology, postnatal electroporation coupled with piggyBac transposition in order to rapidly interrogate the causality of these mutations in tumorigenesis. Introduction of somatic mutation to tumor cells lining the ventricular zone led to a characteristic hyperplasia denoted by dramatic overgrowth of mutant cells. However, the cells rapidly senesced. In the minority of cases, tumors transition into invasive high grade glioblastoma. Co-introduction of additional tumor suppressor targeting elements (shRNA against p16/p19, Trp53 shRNA) increased tumor grade. Here, we discuss findings from our functional investigations of these putative low grade driver mutations.

We have created a novel method for studying glioma initiation, progression, and recurrence with in vivo-postnatal electroporation combined with piggyBac transposition. Electroporation allows for rapid addition of transgenes, simply by the inclusion of plasmid DNA in the initial injection. Thus, we have created a toolkit for interrogating the resulting tumor cells in vivo. Specifically, we have created piggyBac plasmids expressing a spectrum of transgenes or elements for modeling recently discovered and previously identified pediatric driver mutations, including H3.3, Atrx, Trp53, Nf1, and Pdgfra . Here we detail the use of these elements with additional transgenes for non-invasive imaging and inducible cell ablation. Further, we are investigating the use of novel methods for genetically labeling quiescent and recurrent cells, including inducible and reversible transgenic systems. Here we discuss these methodologies and their use in the context of our novel pediatric glioma models with a focus on emergent properties from different driver gene combinations.

A 4-year-old girl with history of polydactyly and imperforate anus surgeries presented with short stature. Brain MRI revealed a large hypothalamic hamartoma (figure). Pallister-Hall syndrome (PHS) was diagnosed. Biopsy was not indicated given stable and typical tumoral appearance. Annual evaluations, hormonal replacement, and medical genetics consult were recommended. Compared to sporadic hypothalamic hamartoma, patients with PHS tend to be less symptomatic and have minimal tumor growth.1 The etiology is an autosomal dominant or de novo GLI3 gene mutation.2 Neurologists and neuroradiologists should be familiar with PHS characteristics, surveillance, and symptomatic therapy as neurosurgery is not usually recommended.

Viral vectors and electroporation (EP)-mediated gene transfers are efficient means of inducing somatic mosaicism in mice, but they lack the exquisite control over transgene copy number, gene zygosity, and genomic-locus speci-ficity that genetically engineered mouse models (GEMMs) provide. Here, we develop and demonstrate a simple and generalizable in vivo method, mosaic analysis by dual recombinase-mediated cassette exchange (MADR). MADR allows for stable labeling of mutant cells express transgenic elements from a precisely-defined chromosomal locus. To test our method, we generated reporter-labeled lineages from stem and progenitor cells in a well-defined Rosa26mTmG mouse. We demonstrate the power and versatility of MADR by creating novel glioma models with mixed, reporter-defined zygosity or with “personalized,” H3.3-containing driver mutation signatures from pediatric glioma-each manipulation altering the profile of resulting tumors. Thus, MADR provides a high-throughput genetic platform for the dissection of development and disease, and this rapid method can be applied to the thousands of existing gene-trap mice.

Pediatric gliomas, a type of brain tumor which arises from uncontrolled growth of glial cells, are the most common type of CNS tumor in children. As the list of putative driver mutations in glioma grows, we are just beginning to elucidate the combined effects of unhinged signaling pathways on the transformation of CNS cells. While the oncogenic role of ETV5 in various cancers is well-established, its role in high-grade pediatric gliomas has yet to be elucidated. We have created a mosaic, autochthonous, glioma model that captures the first hours and days of gliomagenesis in more resolution than conventional mouse models of cancer. Our various models of pediatric glioma have indicated a fundamental role for Etv5 in tumor cells. We show that ETV5 is highly expressed in our glioma models and primary pediatric glioma cells. We are currently pursuing an omics approach to identifying the mechanisms regulating ETV5 in high-grade glioma. Additionally, we are employing a novel single-site conditional system to identify ETV5 genomic targets in patient tumors and to explore the results of ETV5 manipulation on cell fate. Taken together, we provide evidence that Etv5 is necessary for tumor initiation and regulates the exuberant gliogenesis observed in these tumors.

Cancer cell secretion of TGF-β is a potent mechanism for immune evasion. However, little is known about how central nervous system tumors guard against immune eradication. We sought to determine the impact of T-cell TGF-β signaling blockade on progression of medulloblastoma (MB), the most common pediatric brain tumor. Genetic abrogation of T-cell TGF-β signaling mitigated tumor progression in the smoothened A1 (SmoA1) transgenic MB mouse. T regulatory cells were nearly abolished and antitumor immunity was mediated by CD8 cytotoxic T lymphocytes. To define the CD8 T-cell subpopulation responsible, primed CD8 T cells were adoptively transferred into tumor-bearing immunocompromised SmoA1 recipients. This led to generation of CD8(+)/killer cell lectin-like receptor G1 high (KLRG1(hi))/IL-7R(lo) short-lived effector cells that expressed granzyme B at the tumor. These results identify a cellular immune mechanism whereby TGF-β signaling blockade licenses the T-cell repertoire to kill pediatric brain tumor cells.

Over the past several years the pial surface has been identified as a germinal niche of importance during embryonic, perinatal and adult neuro- and gliogenesis, including after injury. However, methods for genetically interrogating these progenitor populations and tracking their lineages had been limited owing to a lack of specificity or time consuming production of viruses. Thus, progress in this region has been relatively slow with only a handful of investigations of this location. Electroporation has been used for over a decade to study neural stem cell properties in the embryo, and more recently in the postnatal brain. Here we describe an efficient, rapid, and simple technique for the genetic manipulation of pial surface progenitors based on an adapted electroporation approach. Pial surface electroporation allows for facile genetic labeling and manipulation of these progenitors, thus representing a time-saving and economical approach for studying these cells.

Background Recent findings have indicated the presence of a progenitor domain at the marginal zone/layer 1 of the cerebral cortex, and it has been suggested that these progenitors have neurogenic and gliogenic potential. However, their contribution to the histogenesis of the cortex remains poorly understood due to difficulties associated with genetically manipulating these unique cells in a population-specific manner. Results We have adapted the electroporation technique to target pial surface cells for rapid genetic manipulation at postnatal day 2. In vivo data show that most of these cells proliferate and progressively differentiate into both neuronal and glial subtypes. Furthermore, these cells localize to the superficial layers of the optic tectum and cerebral cortex prior to migration away from the surface. Conclusions We provide a foundation upon which future studies can begin to elucidate the molecular controls governing neural progenitor fate, migration, differentiation, and contribution to cortical and tectal histogenesis. Furthermore, specific genetic targeting of such neural progenitor populations will likely be of future clinical interest.

The authors describe a 9 month old female with recurrent atypical central neurocytoma and leptomeningeal spread treated with high dose chemotherapy, autologous stem cell rescue, and adjuvant therapy. She had a complete response to therapy and was disease free at 4 years of age until a recurrence 6 months later. The use of intensive chemotherapy followed by autologous stem cell rescue for atypical neurocytoma may be considered as an adjunct to surgical therapy in young patients with atypical neurocytoma not amenable to radiation therapy.

Vein of Galen malformations are rare congenital intracranial vascular malformations. Based on reports in the literature, spontaneous thrombosis or regression of these lesions is rare. Patients have variable outcomes from an asymptomatic course to death. The reasons behind spontaneous thrombosis are not entirely understood. Here the authors present a case of an infant diagnosed with a vein of Galen malformation in utero that subsequently went on to thrombose or regress. A review of the published cases on this phenomenon and the potential causality are discussed.

Here, we report the neuroimaging findings and neurological changes in 17 unpublished patients with Macrocephaly-Capillary Malformation (M-CM). This syndrome has been traditionally known as Macrocephaly-Cutis Marmorata Telangiectatica Congenita (M-CMTC), but we explain why M-CM is a more accurate term for this overgrowth syndrome. We analyzed the 17 patients with available brain MRI or CT scans and compared their findings with features identified by a comprehensive review of published cases. White matter irregularities with increased signal on T2-weighted images were commonly observed findings. A distinctive feature in more than half the patients was cerebellar tonsillar herniation associated with rapid brain growth and progressive crowding of the posterior fossa during infancy. In four such cases, we confirmed that the tonsillar herniation was an acquired event. Concurrently, with the development of these findings, ventriculomegaly (frequently obstructive) and dilated dural venous sinuses were observed in conjunction with prominent Virchow-Robin spaces in many of those in whom cerebellar tonsil herniation had developed. We postulate that this constellation of unusual features suggests a dynamic process of mechanical compromise in the posterior fossa, perhaps initiated by a rapidly growing cerebellum, which leads to congestion of the venous drainage with subsequently compromised cerebrospinal fluid reabsorption, all of which increases the posterior fossa pressure and leads to acquired tonsillar herniation. We make a distinction between congenital Chiari I malformation and acquired cerebellar tonsil herniation in this syndrome. We also observed numerous examples of abnormal cortical morphogenesis, including focal cortical dysplasia, polymicrogyria which primarily involved the perisylvian and insular regions, and cerebral and/or cerebellar asymmetric overgrowth. Other findings included a high frequency of cavum septum pellucidum or vergae, thickened corpus callosum, prominent optic nerve sheaths and a single case of venous sinus thrombosis. One patient was found to have a frontal perifalcine mass resembling a meningioma at age 5 years. This is the second apparent occurrence of this specific tumor in M-CM.

We have been investigating the effects of immune system modulation on brain tumor survival in animal models of pediatric malignancies. For example, TGF-β is produced by various tumor types and dampens the response of the immune system, preventing recognition of tumor cells. Thus, we crossed mice with T-cell-specific TGF-β blockade (CD4-TGFβRII-DNR) with a mouse model of medulloblastoma (SmoA1 transgenic mice) and analyzed offspring. We noted dramatic infiltration of T cells into the tumor and coincident improvement in survival of these mice. Furthermore, there was a striking change in T cell phenotype—notably a large increase in memory T cells in double transgenic mice, which are in principle able to mount anti-tumor immunity. We've been employing a novel piggyBac model of forebrain glioma to rapidly generate tumors from patient driver genes. Interestingly, using genome-wide analysis, many members of the TGF-β ligand family are upregulated by tumor cells and these secreted ligands appear to be the principle immunosuppressive molecules expressed by the tumor propagating population. Given the survival-promoting role of T cell TGF-β signaling blockade in our medulloblastoma model, we have generated de novo tumors in CD4-TGFβRII-DNR mice using our in vivo piggyBac system and are investigating the applicability of this strategy in pediatric forebrain glioma.

Hypothesis Experimental work raises the possibility that in utero repair of myelomeningocele (mmc) may improve lower extremity, bladder, and bowel function, ameliorate the arnold-chiari malformation, and decrease the need for postnatal shunting. Design We previously developed fetal lamb models to create and reverse lower extremity damage and the arnold-chiari malformation in utero. we then applied our extensive experience with fetal surgery, including fetal endoscopic (fetoscopic) surgical manipulation, to develop techniques for mmc repair. Setting A tertiary referral center. Patients All patients treated between 1998 and 2002 for a prenatally diagnosed mmc. Interventions Either fetoscopic mmc repair, fetoscopic patch repair, or limited maternal hysterotomy and microsurgical 3-layered fetal mmc repair was performed. Main outcome measures Gestational age at delivery, survival, neurologic outcome, and need for ventricular shunting at 1 year. Results Complete fetoscopic repair was accomplished in 1 fetus. two other fetuses underwent partial fetoscopic procedures. the remaining 10 patients underwent limited maternal hysterotomy and microsurgical 3-layered fetal mmc repair. four of 13 patients died, and the mean gestational age at delivery of 11 fetuses born alive was 31 weeks. five of 9 required ventricular shunting by age 1 year. in 2 patients, lower extremity function improved by more than 2 vertebral levels compared with prenatal ultrasonography. five of 10 patients who lived longer than 3 weeks required postnatal wound revision within 7 days after birth. Conclusions Fetoscopic repair, although feasible, does not yet yield optimal surgical results. open surgical repair before 22 weeks' gestation is physiologically sound and technically feasible. one third of patients appear to be spared the need for a shunt at age 1 year, but improvement in distal neurologic function is less clear. additionally, fetal mortality is associated with this procedure. our results complement the data published by groups at children's hospital of philadelphia, in pennsylvania, and vanderbilt university, nashville, tenn. a national institutes of health–sponsored prospective randomized trial is now underway at these 3 centers to compare fetal repair with postnatal repair.

Object Positional plagiocephaly (PP) has been on the rise in recent years. In this review, the authors' aim was to assess the effectiveness of current recommendations to parents on this exceedingly common problem through a comprehensive literature search. Additionally, the current treatment options and the most recent studies on PP are reviewed. Methods A search of the existing literature was conducted to obtain all relevant studies on guidelines, recommendations, parental and clinician practices, and epidemiological aspects. Results Although the incidence and risk factors for PP have been well delineated, there continues to be debates on its management and association with developmental delays. Current guidelines and recommendations on prevention set by the American Association of Pediatrics may not be easily followed by both parents and clinicians. There is also evidence that certain populations, including those with lower education, socioeconomic status, and in particular geographic regions may be more affected by the condition. Additionally, the marketing and financial aspects of PP treatments exist and should be addressed. Conclusions Better awareness and education are necessary to inform the population as a whole, although certain populations should be given special attention. Additionally, current guidelines and recommendations can be modified to foster a better grasp of the condition by both parents and clinicians. Adjusting current recommendations, introducing initiatives, and offering elaborate educational campaigns would help deliver these aims. Educating parents on PP as early as possible through clearer guidelines and close monitoring is central to preventing and managing this common condition.