[Show abstract][Hide abstract] ABSTRACT: Critical injury has been associated with reduction in innate immune function in adults, with infection risk being related to degree of immune suppression. This relationship has not been reported in critically injured children.
[Show abstract][Hide abstract] ABSTRACT: Medulloblastoma is the most common type of pediatric brain tumor. Although numerous factors influence patient survival rates, more than 30% of all cases will ultimately be refractory to conventional therapies. Current standards of care are also associated with significant morbidities, giving impetus for the development of new treatments. We have previously shown that oncolytic measles virotherapy is effective against medulloblastoma, leading to significant prolongation of survival and even cures in mouse xenograft models of localized and metastatic disease. Because medulloblastomas are known to be highly vascularized tumors, we reasoned that the addition of angiogenesis inhibitors could further enhance the efficacy of oncolytic measles virotherapy. Toward this end, we have engineered an oncolytic measles virus that express a fusion protein of endostatin and angiostatin, two endogenous and potent inhibitors of angiogenesis.
Oncolytic measles viruses encoding human and mouse variants of a secretable endostatin/angiostatin fusion protein were designed and rescued according to established protocols. These viruses, known as MV-hE:A and MV-mE:A respectively, were then evaluated for their anti-angiogenic potential and efficacy against medulloblastoma cell lines and orthotopic mouse models of localized disease.
Medulloblastoma cells infected by MV-E:A readily secrete endostatin and angiostatin prior to lysis. The inclusion of the endostatin/angiostatin gene did not negatively impact the measles virus' cytotoxicity against medulloblastoma cells or alter its growth kinetics. Conditioned media obtained from these infected cells was capable of inhibiting multiple angiogenic factors in vitro, significantly reducing endothelial cell tube formation, viability and migration compared to conditioned media derived from cells infected by a control measles virus. Mice that were given a single intratumoral injection of MV-E:A likewise showed reduced numbers of tumor-associated blood vessels and a trend for increased survival compared to mice treated with the control virus.
These data suggest that oncolytic measles viruses encoding anti-angiogenic proteins may have therapeutic benefit against medulloblastoma and support ongoing efforts to target angiogenesis in medulloblastoma.
BMC Cancer 03/2014; 14(1):206. DOI:10.1186/1471-2407-14-206 · 3.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Medulloblastoma is the most common malignant brain tumor of childhood. Although the clinical outcome for medulloblastoma patients has improved significantly, children afflicted with the disease frequently suffer from debilitating side effects related to the aggressive nature of currently available therapy. Alternative means for treating medulloblastoma are desperately needed. We have previously shown that oncolytic measles virus (MV) can selectively target and destroy medulloblastoma tumor cells in localized and disseminated models of the disease. MV-NIS, an oncolytic measles virus that encodes the human thyroidal sodium iodide symporter (NIS), has the potential to deliver targeted radiotherapy to the tumor site and promote a localized bystander effect above and beyond that achieved by MV alone.
We evaluated the efficacy of MV-NIS against medulloblastoma cells in vitro and examined their ability to incorporate radioiodine at various timepoints, finding peak uptake at 48 hours post infection. The effects of MV-NIS were also evaluated in mouse xenograft models of localized and disseminated medulloblastoma. Athymic nude mice were injected with D283med-Luc medulloblastoma cells in the caudate putamen (localized disease) or right lateral ventricle (disseminated disease) and subsequently treated with MV-NIS. Subsets of these mice were given a dose of 131I at 24, 48 or 72 hours later.
MV-NIS treatment, both by itself and in combination with 131I, elicited tumor stabilization and regression in the treated mice and significantly extended their survival times. Mice given 131I were found to concentrate radioiodine at the site of their tumor implantations. In addition, mice with localized tumors that were given 131I either 24 or 48 hours after MV-NIS treatment exhibited a significant survival advantage over mice given MV-NIS alone.
These data suggest MV-NIS plus radioiodine may be a potentially useful therapy for the treatment of medulloblastoma.
BMC Cancer 11/2012; 12(1):508. DOI:10.1186/1471-2407-12-508 · 3.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Medulloblastoma is the most common malignant brain tumor of childhood. Although the survival rate of afflicted children has improved considerably over the past several years, a subset of these patients will present with disseminated disease and face a much bleaker prognosis. In addition, patients may present with disseminated disease at recurrence. We previously demonstrated the efficacy of a recombinant oncolytic measles virus (MV) to treat localized medulloblastoma in a mouse xenograft model. In the present study, we sought to extend our findings to the treatment of disseminated disease. To this end, we developed and characterized a mouse xenograft model of disseminated medulloblastoma using serial bioluminescent imaging techniques in combination with histopathological examination. Mice injected with medulloblastoma cells into their right lateral ventricle showed tumor growth in their ventricles and in both intracranial and spinal subarachnoid spaces, closely recapitulating the human disease. Subsequent intraventricular administration of MV resulted in stabilization and shrinkage of the tumor, significantly prolonging the survival of the treated animals, compared with those treated with an inactivated virus. These data demonstrate that oncolytic MV may be of use in treating disseminated medulloblastoma. In addition, our protocol of intraventricular tumor cell injection, followed by bioluminescent imaging coupled with histopathological examination, provides a model for use in evaluating future recombinant oncolytic viruses and other preclinical therapeutic approaches for disseminated medulloblastoma.
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to evaluate the yield of electroencephalography and structural and functional neuroimaging in children having resective epilepsy surgery before 5 years of age. Charts of all 28 children (54% male) having resective surgery before 60 months of age at the Mayo Clinic between January 2002 and June 2009 were reviewed. Mean age at seizure onset was 9.6 months (S.D. 12.7); mean age at surgery was 28.8 months (S.D. 17.7). Sixteen children (57%) had partial-onset seizures, 8 (29%) had partial-onset seizures and spasms, and 4 (14%) had spasms alone. Initial surgery type was hemispherectomy in 6 cases, multilobar resection in 8, temporal in 7, and extratemporal in 7. Only 10 of the 25 children (40%) with recorded seizures preoperatively had a well-localized, single ictal focus. Ictal discharge was generalized in 8/25 cases (32%), both generalized and focal in 1 case (4%), hemispheric in 4 cases (16%), and absent in 1 case (4%). Findings from magnetic resonance imaging were abnormal in 27 cases, and revealed focal pathology in 20. Surgical outcome was favorable, with 18 of the 27 survivors (67%) being free, or nearly free, of disabling seizures. In summary, electroencephalography frequently failed to indicate a single ictal focus in young children having epilepsy surgery. In contrast, magnetic resonance imaging was more helpful, revealing focal abnormalities in 74% of patients.
[Show abstract][Hide abstract] ABSTRACT: The use of fetal MR imaging for the in utero evaluation of pathological conditions of the CNS is widely accepted as an adjunct to fetal ultrasonography studies. Magnetic resonance imaging is thought to characterize CNS anomalies better, and to provide a more exact diagnosis and accurate prognosis. The purpose of this study was to determine the role of and indications for fetal MR imaging in evaluating fetuses with different CNS abnormalities that were seen initially on prenatal sonograms.
Over a 3-year period, fetuses with prior sonographic evidence of CNS abnormalities who consequently received prenatal MR imaging at Columbus Nationwide Children's Hospital within 2 weeks of the fetal ultrasonography study were included in this study. For each patient, radiological reports from both studies were reviewed, analyzed, and compared with the findings at postnatal imaging or physical examination. Results of the 2 modalities were then compared in terms of diagnostic accuracy.
Twenty-six fetuses were included in this study on the basis of an in utero sonogram showing a CNS anomaly. Their gestational age ranged from 17 to 35 weeks, with a mean of 25 weeks at the time of fetal ultrasonography. Hydrocephalus was identified in 16 fetuses, 6 had evidence of a spinal dysraphic defect, 2 had holoprosencephaly, 1 had an encephalocele, and 1 had multiple body abnormalities requiring detailed CNS evaluation. Twenty-five of the fetuses were correctly evaluated as having abnormal CNS findings on both fetal ultrasonography and fetal MR imaging. Fetal ultrasonography provided a correct prenatal diagnosis in 20 cases, whereas fetal MR imaging was correct in 22 cases. There were 9 cumulative false-positive results for fetal ultrasonography and 7 for fetal MR imaging, whereas for false-negative results there were a total of 34 and 19, respectively.
Fetal MR imaging is more sensitive in detecting fetal CNS abnormalities, but its ability to provide a correct prenatal diagnosis is only marginally superior to fetal ultrasonography. Moreover, fetal MR imaging is not exempt from misdiagnosis, and still shows a significantly high rate of false-negative results. Particularly for spinal dysraphic defects, fetal MR imaging does not seem to add important diagnostic or prognostic details when compared with fetal ultrasonography.
[Show abstract][Hide abstract] ABSTRACT: Although treatment of medulloblastoma has improved, at least 30% of patients with this tumor die of progressive disease. Unfortunately, many of the children who survive suffer long-term treatment-related morbidity. Previous studies have demonstrated the efficacy of using oncolytic viruses to eradicate brain tumors. The objective of this study was to test the efficacy of measles virus in treating medulloblastoma. To determine whether medulloblastoma cells are susceptible, 5 different human medulloblastoma cell lines were analyzed for the expression of the measles virus receptor CD46. Fluorescence-activated cell-sorting analysis confirmed expression of CD46 on all cell lines tested, with UW288-1 having the most prominent expression and D283med displaying the lowest expression. CD46 expression was also demonstrated, using immunohistochemistry, in 13 of 13 medulloblastoma tissue specimens. All 5 medulloblastoma cell lines were examined for their susceptibility to measles virus killing in vitro. A measles virus containing the green fluorescent protein (GFP) gene as a marker for infection (MV-GFP) was used. All cell lines exhibited significant killing when infected with MV-GFP, all formed syncytia with infection, all showed fluorescence, and all allowed viral replicaton after infection. In an intracerebral murine xenograft model, a statistically significant increase in survival was seen in animals treated with the active measles virus compared with those treated with inactivated virus. These data demonstrate that medulloblastoma is susceptible to measles virus killing and that the virus may have a role in treating this tumor in the clinical setting.
[Show abstract][Hide abstract] ABSTRACT: Arteriovenous malformation (AVM) is the most common cause of spontaneous intraparenchymal hemorrhage in children, excluding hemorrhages of prematurity and early infancy. Because most children diagnosed with an AVM undergo initial treatment emergently, the natural history of AVMs in the pediatric population is not well understood. Most pediatric AVMs do not come to clinical attention unless they hemorrhage. Therefore, their optimal management remains controversial. Children with intracranial AVMs represent a special challenge in that they harbor unacceptable lifelong risks of hemorrhage and potential neurologic deficits. Patients should be evaluated on a case-by-case basis to determine the best multidisciplinary treatment regimen that can be used to preserve neurologic function and eradicate the AVM with the lowest risk of mortality. Successful treatment depends on the location and size of the AVM, its hemodynamic properties, the clinical condition of the patient, and the treatment modality selected. The armamentarium for AVM management has grown with technological advances and now includes microsurgical resection, endovascular embolization, radiosurgery, or any combination of these modalities. Microsurgical resection remains the gold standard for treatment of accessible pediatric AVMs, especially in cases that present with intracranial hemorrhage. Newer modalities, such as embolization and radiosurgery, have provided additional tools to help children with large or deep-seated lesions that would be deemed unresectable with microsurgical techniques alone. Long-term follow-up with repeated diagnostic imaging is important despite complete obliteration of the lesion to rule out the small possibility of AVM recurrence.
Neurosurgery clinics of North America 07/2010; 21(3):443-56. DOI:10.1016/j.nec.2010.03.012 · 1.44 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Ependymomas are rare tumors of neuroectodermal origin and the third most common pediatric brain tumor following astrocytoma
and medulloblastoma. They arise from radial glial-like stem cells in the cerebral subven-tricular zone (SVZ), lining the fourth
ventricle, and within the spinal cord.
The typical location of these tumors is different in adults and children. Most childhood ependymomas are intracranial, while
in adults they more commonly occur in the spinal cord. They locate infratentorially in 65% of pediatric cases, most often
arising from the floor of the fourth ventricle. The remaining 35% of ependymo-mas in children occur equally divided between
the spinal cord and supratentorial intracranial space.
[Show abstract][Hide abstract] ABSTRACT: Large dural arteriovenous malformations (DAVMs) accompanied by cardiac failure usually carry a poor prognosis with a high risk of morbidity and death. The authors report on the case of a male neonate with a massive DAVM who presented at birth with macrocephaly and high-output cardiac failure. The child initially underwent treatment with surgical clipping of the large main feeding artery. Hydrocephalus, thought to be due to venous hypertension, developed when the boy was 8 months old. The condition resolved after interventional embolization treatment. The patient did not require placement of a ventriculoperitoneal shunt. At 21 months of age, the child had near normal development without any focal neurological deficits.
[Show abstract][Hide abstract] ABSTRACT: Intracranial subdural grid monitoring is a useful diagnostic technique for surgical localization in patients with intractable partial epilepsy. The rationale for the present study was to assess the morbidity of intracranial recordings and the surgical outcomes.
We retrospectively reviewed the clinical data for 189 unique patients undergoing 198 intracranial subdural grid monitoring sessions between 1996 and 2004 at a tertiary epilepsy center.
The mean age of patients undergoing monitoring was 28 +/- 14 years. An average of 63 +/- 23 electrodes were inserted. The mean duration of monitoring was 8 +/- 4 days. Localization of an epileptogenic zone occurred in 156 sessions (79%) resulting in 136 resections (69%). There were 13 major complications (6.6%), including five infections and six hematomas. Three patients (1.5%) developed permanent deficits related to implantation. Sixty-two (47%) of 136 patients undergoing resection were seizure-free after resection. An additional 38 patients (28%) had a significant reduction in seizures. The mean follow-up was 51 +/- 30 months. The duration of monitoring, bone flap replacement, number of electrodes, and perioperative corticosteroids were not associated with infection or complication.
Subdural grid monitoring for identification an epileptogenic focus is high yield, revealing a focus in 79% of monitoring sessions. Complications rarely result in permanent morbidity (1.5%). Surgical outcome indicated that 74% of patients experienced a favorable reduction in seizure tendency.
[Show abstract][Hide abstract] ABSTRACT: Gliomas have a dismal prognosis, with the median survival of patients with the most common histology, glioblastoma multiforme, being only 12-15 months. Development of novel therapeutic agents is urgently needed. We have previously demonstrated that oncolytic measles virus strains derived from the Edmonston vaccine lineage have significant antitumor activity against gliomas [Phuong, L.K., Allen, C., Peng, K.W., Giannini, C., Greiner, S., Teneyck, C.J., Mishra, P.K., Macura, S.I., Russell, S.J., Galanis, E.C. (2003). Cancer. Res. 63, 2462-2469]. MV-CEA is an Edmonston vaccine lineage measles virus strain engineered to express the marker peptide carcinoembryonic antigen (CEA): CEA levels can serve as a correlate of viral gene expression. In support of a phase I clinical trial of intratumoral and resection cavity administration of MV-CEA to patients with recurrent gliomas, we assessed the neurotoxicity of MV-CEA in adult immune male rhesus macaques (Macaca mulatta). The animals ' immune status and administration schedule mimicked the trial population and proposed administration schema. Macaca mulatta represents the prototype animal species for assessment of measles neurotoxicity. The animals were stereotactically administered either vehicle (n = 1) or MV-CEA at 2 x 10(5)or 2 x 10(6) TCID(50) (each, n = 2) in the right frontal lobe in two injections on days 1 and 5. Macaques were closely monitored clinically for neurotoxicity. Body weight, temperature, complete blood count, CEA, clinical chemistries, coagulation, complement levels, immunoglobulin, measles antibody titers, viremia, and shedding (buccal swabs) were tested at multiple time points. Furthermore, cisterna magna spinal taps were performed on day 9 and 1 year after the first viral dose administration, and samples were analyzed for protein, glucose, cell differential, and presence of MV-CEA. Magnetic resonance imaging (MRI) was performed between 4 and 5 months after article administration to assess for subclinical neurotoxicity. To date, 36+ months from study initiation there has been no clinical or biochemical evidence of toxicity, including lack of neurological symptoms, fever, or other systemic symptoms and lack of immunosuppression. Quantitative RT-PCR analysis of blood, buccal swabs, and cerebrospinal fluid (CSF) was negative for MV-CEA at all time points, with the exception of viral genome deletion in the blood of one asymptomatic animal at the 2 x 10(6) TCID(50) dose level on day 85. Vero cell overlays of CSF cells and supernatant were negative for viral recovery. There was no detection of CEA in serum or CSF at any time point. MRI scans were negative for imaging abnormalities and showed no evidence of encephalitis. Our results support the safety of CNS administration of MV-CEA in glioma patients. A clinical trial of intratumoral and resection cavity administration of MV-CEA in patients with recurrent glioblastoma multiforme is currently ongoing.
Human gene therapy 08/2008; 19(7):690-8. DOI:10.1089/hum.2008.035 · 3.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We describe the clinical manifestations, radiographic features, and management options of an extensive spontaneous spinal epidural hematoma in a 7-month boy who had severe hemophilia that had not been previously diagnosed, despite a baseline factor VIII level less than 1% of normal. We believe this to be the youngest reported case of a symptomatic spontaneous spinal epidural hemorrhage in an infant subsequently initially establishing a diagnosis of hemophilia.
[Show abstract][Hide abstract] ABSTRACT: Bovine tissues are now routinely used for dural closure in cranial and spinal surgery. The authors report the case of an 18-year-old woman with a history of myelomeningocele who had symptoms of tethered cord syndrome and presented to a regional hospital. At that hospital she underwent a cord untethering procedure. The spinal dura was closed with Durepair, a dural substitute derived from fetal bovine skin. Her postoperative course was complicated by a cerebrospinal fluid leak that was surgically repaired. Following this, she developed erythroderma, intermittent fevers, eosinophilia, and marked elevation in serum immunoglobulin E. She was then transferred to the authors' institution. A skin antigen test to beef was administered, which revealed a positive reaction. A radioallergosorbent test to beef also yielded positive results. She was taken to the operating room for removal of the bovine graft due to concern for an allergic reaction to the graft. The graft material showed evidence of eosinophilic infiltration. Her clinical symptoms and laboratory values all improved after surgery. To the authors' knowledge this is the first reported case of an allergic reaction to bovine-based dural substitutes.