Jeffrey Leonard

Oncolytic Herpes Virus rRp450 Shows Efficacy in Orthotopic Xenograft Group 3/4 Medulloblastomas and Atypical Teratoid/Rhabdoid Tumors

Pediatric brain tumors including medulloblastoma and atypical teratoid/rhabdoid tumor are associated with significant mortality and treatment-associated morbidity. While medulloblastoma tumors within molecular subgroups 3 and 4 have a propensity to metastasize, atypical teratoid/rhabdoid tumors frequently afflict a very young patient population. Adjuvant treatment options for children suffering with these tumors are not only sub-optimal but also associated with many neurocognitive obstacles. A potentially novel treatment approach is oncolytic virotherapy, a developing therapeutic platform currently in early-phase clinical trials for pediatric brain tumors and recently US Food and Drug Administration (FDA)-approved to treat melanoma in adults. We evaluated the therapeutic potential of the clinically available oncolytic herpes simplex vector rRp450 in cell lines derived from medulloblastoma and atypical teratoid/rhabdoid tumor. Cells of both tumor types were supportive of virus replication and virus-mediated cytotoxicity. Orthotopic xenograft models of medulloblastoma and atypical teratoid/rhabdoid tumors displayed significantly prolonged survival following a single, stereotactic intratumoral injection of rRp450. Furthermore, addition of the chemotherapeutic prodrug cyclophosphamide (CPA) enhanced rRp450’s in vivo efficacy. In conclusion, oncolytic herpes viruses with the ability to bioactivate the prodrug CPA within the tumor microenvironment warrant further investigation as a potential therapy for pediatric brain tumors.

SHH desmoplastic/nodular medulloblastoma and Gorlin syndrome in the setting of Down syndrome: case report, molecular profiling, and review of the literature

IntroductionIndividuals with Down syndrome (DS) have an increased risk of acute leukemia compared to a markedly decreased incidence of solid tumors. Medulloblastoma, the most common malignant brain tumor of childhood, is particularly rare in the DS population, with only one published case. As demonstrated in a mouse model, DS is associated with cerebellar hypoplasia and a decreased number of cerebellar granule neuron progenitor cells (CGNPs) in the external granule cell layer (EGL). Treatment of these mice with sonic hedgehog signaling pathway (Shh) agonists promote normalization of CGNPs and improved cognitive functioning.Case reportWe describe a 21-month-old male with DS and concurrent desmoplastic/nodular medulloblastoma (DNMB)—a tumor derived from Shh dysregulation and over-activation of CGNPs. Molecular profiling further classified the tumor into the new consensus SHH molecular subgroup. Additional testing revealed a de novo heterozygous germ line mutation in the PTCH1 gene encoding a tumor suppressor protein in the Shh pathway.DiscussionThe developmental failure of CGNPs in DS patients offers a plausible explanation for the rarity of medulloblastoma in this population. Conversely, patients with PTCH1 germline mutations experience Shh overstimulation resulting in Gorlin (Nevoid Basal Cell Carcinoma) syndrome and an increased incidence of malignant transformation of CGNPs leading to medulloblastoma formation. This represents the first documented report of an individual with DS simultaneously carrying PTCH1 germline mutation.ConclusionWe have observed a highly unusual circumstance in which the PTCH1 mutation appears to “trump” the effects of DS in causation of Shh-activated medulloblastoma.

Comparison of Prenatal and Postnatal Management of Patients with Myelomeningocele

Myelomeningocele (MMC) is a costly lifetime disease with many comorbidities, including sensory and motor lower limb disability, bladder/bowel dysfunction, scoliosis, club foot, and hydrocephalus. MMC treatment options have changed over time because routine use of fetal ultrasonography and MRI has provided prenatal diagnosis and the potential for fetal surgery. There is still no consensus on how to treat the MMC diagnoses prenatally, mainly related to the infrastructure required to operate on pregnant patients. This article provides an overview of prenatal and postnatal MMC repair and the features in the prenatal diagnosis.

Remifentanil for Sedation of Children With Traumatic Brain Injury

Objective: To determine whether remifentanil would provide adequate sedation while allowing frequent and reproducible neurologic assessments in children admitted to the pediatric intensive care unit (PICU) with traumatic brain injury (TBI) during mechanical ventilation. Design: Retrospective review. Setting: Tertiary care PICU. Patients: Thirty-eight patients over a 30-month period. Measurements and Main Results: Median age was 9 years (interquartile range [IQR] 2.25-12 years). The median Glasgow Coma Scale (GCS) was 9 (IQR: 8-10). All patients were tracheally intubated and receiving mechanical ventilation. A continuous infusion of remifentanil was started at 0.1 μg/kg/min, and bolus doses of 0.25 to 1 μg/kg were administered every 3 to 5 minutes as needed to reach the desired sedation level. Infusions were stopped at least hourly to perform neurologic examinations. The median remifentanil dose was 0.25 μg/kg/min with an IQR of 0.1 and 0.6 μg/kg/min. The maximum dose for any patient in the cohort was 2 μg/kg/min. Median duration of therapy with remifentanil was 20 hours (IQR: 8-44 hours). Adequate sedation was achieved with sedation scores (State Behavioral Scale) meeting target levels with a median value of 100% of the time (IQR: 79%-100%). Neurologic examinations were able to be performed within a median of 9 minutes (IQR: 5-14 minutes) of pausing the infusion. No serious safety events occurred. In 68% of the patients, neurologic examinations remained reassuring during remifentanil infusion, and patients were extubated. The remaining patients were transitioned to traditional sedative agents for long-term management of their traumatic injuries once the neurologic status was deemed stable. Conclusion: This data suggest that remifentanil is a suitable sedative agent for use in children with TBI. It provides a rapid onset of sedation with recovery that permits reliable and reproducible clinical examination.

Chiari I Malformation: Adult and Pediatric Considerations

ic s. co m Chiari type I malformation (CM-1) is encountered across the full spectrum of neurosurgical practice, affecting patients from infancy through adulthood. As with any neurosurgical disorder, understanding the pathophysiology, clinical presentation, and radiographic findings is paramount in determining the appropriate management approach for any given patient with CM-1. The objective of this issue of Neurosurgery Clinics of North America, titled “Chiari I Malformation,” is to provide this critical information in a single, concise volume with up-todate reports from leading experts in the field of CM-1. While there is general acknowledgment that CM-1 is characterized by cerebellar tonsillar ectopia, there remains no consensus definition of the disorder. Indeed, large institutional studies have shown that w3% of children and 1% of adults demonstrate radiographic evidence of CM-1, yet the conditions under which such radiographic findings translate to clinically significant CM-1 are unclear. Furthermore, tonsillar ectopia also may be associated with any number of developmental and acquired disorders (eg, craniofacial syndromes, hydrocephalus, posterior fossa tumors). Thus, a clear understanding of the clinical presentation of CM-1 in both pediatric and adult patients has direct bearing on both patient selection and the approach for operative management.

A descriptive model for a multidisciplinary unit for colorectal and pelvic malformations

INTRODUCTION Patients with anorectal malformations (ARM), Hirschsprung disease (HD), and colonic motility disorders often require care from specialists across a variety of fields, including colorectal surgery, urology, gynecology, and GI motility. We sought to describe the process of creating a collaborative process for the care of these complex patients. METHODS We developed a model of a devoted center for these conditions that includes physicians, psychologists, social workers, nurses, and advanced practice nurses. Our weekly planning strategy includes a meeting with representatives of all specialties to review all patients prior to evaluation in our multidisciplinary clinic, followed by combined exams under anesthesia or surgical intervention as needed. RESULTS There are 31 people working directly in the Center at present. From the Centers start in 2014 until 2017, 1258 patients were cared for from all 50 United States and 62 countries. 360 patients had an ARM (110 had a cloacal malformation, 11 had cloacal exstrophy), 223 presented with HD, 71 had a spinal malformation or injury causing neurogenic bowel, 321 had severe functional constipation or colonic dysmotility, and 162 had other diagnoses including familial polyposis, Crohns disease, or ulcerative colitis. We have had 170 multidisciplinary meetings, 170 multispecialty outpatient, and 52 nurse practitioner clinics. In our bowel management program we have seen a total of 514 patients in 36 sessions. CONCLUSION This is the first report describing the design of a multidisciplinary team approach for patients with colorectal and complex pelvic malformations. We found that approaching these patients in a collaborative way allows for combined medical and surgical decisions with many providers simultaneously, facilitates therapy, and can potentially improve patient outcomes. We hope that this model will help establish new-devoted centers in other locations to encourage centralized care for these rare malformations. LEVEL OF EVIDENCE IV.

Pygopagus Conjoined Twins: A Neurophysiologic Intraoperative Monitoring Schema.

Conjoined twins occur in up to 1 in 50,000 live births with approximately 18% joined in a pygopagus configuration at the buttocks. Twins with this configuration display symptoms and carry surgical risks during separation related to the extent of their connection which can include anorectal, genitourinary, vertebral, and neural structures. Neurophysiologic intraoperative monitoring for these cases has been discussed in the literature with variable utility. The authors present a case of pygopagus twins with fused spinal cords and imperforate anus where the use of neurophysiologic intraoperative monitoring significantly impacted surgical decision-making in division of these critical structures.