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Fuchs, Herbert Edgar

Overview:

Clinical neuro-oncology research including collaborations studying molecular genetics of childhood brain tumors.
Potential role of the free electron laser in surgery of pediatric brain tumors. Current work includes animal models with human brain tumor xenografts in preclinical studies.
Collaboration with the neurooncology laboratory of Dr. Darell Bigner in preclinical studies of new therapeutic agents.

Positions:

Professor in Neurosurgery

Neurosurgery
School of Medicine

Assistant Professor of Pathology

Pathology
School of Medicine

Assistant Professor of Pediatrics

Pediatrics
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1984

M.D. — Duke University

Ph.D. 1984

Ph.D. — Duke University

Grants:

Research Training In Neuro-Oncology

Administered By
Neurosurgery, Neuro-Oncology
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 1998
End Date
August 31, 2016

Linkage and candidate gene analysis in non-syndromic Chiari type I

Administered By
Duke Molecular Physiology Institute
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
June 01, 2009
End Date
March 31, 2015

Research Training In Neuro-Oncology

Administered By
Neurosurgery, Neuro-Oncology
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
September 15, 2005
End Date
August 31, 2010

Src On Primary And Matastatic Tumors Of The Cns

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
May 01, 1994
End Date
March 31, 1999

Src On Primary And Metastatic Tumors Of The Cns

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
March 01, 1997
End Date
February 28, 1999

Src On Malignant Human Gliomas And Medulloblastomas

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
April 01, 1993
End Date
March 31, 1994
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Publications:

Rhabdomyomatous mesenchymal hamartoma presenting as a sacral skin tag in two neonates with spinal dysraphism.

Rhabdomyomatous mesenchymal hamartoma (RMH) is a rare congenital malformation involving the dermis and subcutaneous tissue, of which there were 62 reported cases through 2014. We report RMH in two neonates presenting as a sacral skin tag. In both cases, magnetic resonance imaging (MRI) of the spine showed evidence of spinal dysraphism, including a lipomyelomeningocele and a tethered cord. Surgical repair of the defects was performed. Histopathologic examination of the skin tags showed a haphazard arrangement of mature skeletal muscle fibers and adnexal elements, consistent with RMH. The second patient also had a hemangioma on the sacrum and was diagnosed with LUMBAR (lower body hemangioma and other cutaneous defects, urogenital anomalies/ulceration, myelopathy, bony deformities, anorectal/arterial anomalies, and renal anomalies) syndrome, an association between cutaneous infantile hemangiomas of the lower body and regional congenital anomalies. The apparent association of paraspinal RMH with spinal dysraphism suggests that aberrant migration of mesodermally derived tissues (including skeletal muscle fibers) during neural tube development may be responsible for the pathologic findings in the skin. Additional study of patients with spinal dysraphism and congenital cutaneous lesions may further support this hypothesis.

Authors
McKinnon, EL; Rand, AJ; Selim, MA; Fuchs, HE; Buckley, AF; Cummings, TJ
MLA Citation
McKinnon, EL, Rand, AJ, Selim, MA, Fuchs, HE, Buckley, AF, and Cummings, TJ. "Rhabdomyomatous mesenchymal hamartoma presenting as a sacral skin tag in two neonates with spinal dysraphism." Journal of cutaneous pathology 42.10 (October 2015): 774-778.
PMID
25989364
Source
epmc
Published In
Journal of Cutaneous Pathology
Volume
42
Issue
10
Publish Date
2015
Start Page
774
End Page
778
DOI
10.1111/cup.12538

Ex vivo generation of dendritic cells from cryopreserved, post-induction chemotherapy, mobilized leukapheresis from pediatric patients with medulloblastoma.

Generation of patient-derived, autologous dendritic cells (DCs) is a critical component of cancer immunotherapy with ex vivo-generated, tumor antigen-loaded DCs. An important factor in the ability to generate DCs is the potential impact of prior therapies on DC phenotype and function. We investigated the ability to generate DCs using cells harvested from pediatric patients with medulloblastoma for potential evaluation of DC-RNA based vaccination approach in this patient population. Cells harvested from medulloblastoma patient leukapheresis following induction chemotherapy and granulocyte colony stimulating factor mobilization were cryopreserved prior to use in DC generation. DCs were generated from the adherent CD14+ monocytes using standard procedures and analyzed for cell recovery, phenotype and function. To summarize, 4 out of 5 patients (80%) had sufficient monocyte recovery to permit DC generation, and we were able to generate DCs from 3 out of these 4 patient samples (75%). Overall, we successfully generated DCs that met phenotypic requisites for DC-based cancer therapy from 3 out of 5 (60%) patient samples and met both phenotypic and functional requisites from 2 out of 5 (40%) patient samples. This study highlights the potential to generate functional DCs for further clinical treatments from refractory patients that have been heavily pretreated with myelosuppressive chemotherapy. Here we demonstrate the utility of evaluating the effect of the currently employed standard-of-care therapies on the ex vivo generation of DCs for DC-based clinical studies in cancer patients.

Authors
Nair, SK; Driscoll, T; Boczkowski, D; Schmittling, R; Reynolds, R; Johnson, LA; Grant, G; Fuchs, H; Bigner, DD; Sampson, JH; Gururangan, S; Mitchell, DA
MLA Citation
Nair, SK, Driscoll, T, Boczkowski, D, Schmittling, R, Reynolds, R, Johnson, LA, Grant, G, Fuchs, H, Bigner, DD, Sampson, JH, Gururangan, S, and Mitchell, DA. "Ex vivo generation of dendritic cells from cryopreserved, post-induction chemotherapy, mobilized leukapheresis from pediatric patients with medulloblastoma." Journal of neuro-oncology 125.1 (October 2015): 65-74.
PMID
26311248
Source
epmc
Published In
Journal of Neuro-Oncology
Volume
125
Issue
1
Publish Date
2015
Start Page
65
End Page
74
DOI
10.1007/s11060-015-1890-2

Prognostic marker analysis in pediatric intracranial ependymomas.

Histologic grading methods dependent upon H&E staining review have not been shown to reliably predict survival in children with intracranial ependymomas due to the subjectivity of the analytical methods. We hypothesized that the immunohistochemical detection of MIB-1, Tenascin C, CD34, VEGF, and CA IX may represent objective markers of post-operative survival (Progression Free and Overall Survival; PFS, OS) in these patients. Intracranial ependymomas from patients aged 22 years or less were studied. The original histologic grade was recorded, H&E sections were reviewed for vascular proliferation status, and immunohistochemistry was used to determine MIB-1, Tenascin C, CD34, VEGF, and CA IX status. Based upon the World Health Organization (WHO) grading system, 3 Grade I, 18 Grade II and 9 Grade III ependymomas were studied. Median follow-up time was 9.0 years; median PFS was, 6.1 years. Original WHO grade did not correlate with PFS or OS. Peri-necrotic CA IX localization correlated with PFS (Log rank = 0.0181) and OS (Log rank p = 0.0015). All patients with a CA IX ≤ 5 % total area localization were alive at last follow-up. Perinecrotic CA IX staining was also associated with vascular proliferation (p = 0.006), though not with VEGF expression score. MIB-1 labeling index (LI) correlated with OS (HR 1.06, 95 % CI 1.01, 1.12) and PFS (HR 1.08, 95 % CI 1.02, 1.14). MIB-1 LI and perinecrotic CA IX individually correlated with PFS. The effect of perinecrotic CA IX remained when grade was added to a Cox model predicting PFS. Immunodetection of CA IX and MIB-1 expression are predictive biomarkers for survival in children with posterior fossa ependymomas. These markers represent objective indicators of survival that supplement H&E grading alone.

Authors
McLendon, RE; Lipp, E; Satterfield, D; Ehinger, M; Austin, A; Fleming, D; Perkinson, K; Lefaivre, M; Zagzag, D; Wiener, B; Gururangan, S; Fuchs, H; Friedman, HS; Herndon, JE; Healy, P
MLA Citation
McLendon, RE, Lipp, E, Satterfield, D, Ehinger, M, Austin, A, Fleming, D, Perkinson, K, Lefaivre, M, Zagzag, D, Wiener, B, Gururangan, S, Fuchs, H, Friedman, HS, Herndon, JE, and Healy, P. "Prognostic marker analysis in pediatric intracranial ependymomas." Journal of neuro-oncology 122.2 (April 2015): 255-261.
PMID
25563815
Source
epmc
Published In
Journal of Neuro-Oncology
Volume
122
Issue
2
Publish Date
2015
Start Page
255
End Page
261
DOI
10.1007/s11060-014-1711-z

Joint eQTL assessment of whole blood and dura mater tissue from individuals with Chiari type I malformation.

Expression quantitative trait loci (eQTL) play an important role in the regulation of gene expression. Gene expression levels and eQTLs are expected to vary from tissue to tissue, and therefore multi-tissue analyses are necessary to fully understand complex genetic conditions in humans. Dura mater tissue likely interacts with cranial bone growth and thus may play a role in the etiology of Chiari Type I Malformation (CMI) and related conditions, but it is often inaccessible and its gene expression has not been well studied. A genetic basis to CMI has been established; however, the specific genetic risk factors are not well characterized.We present an assessment of eQTLs for whole blood and dura mater tissue from individuals with CMI. A joint-tissue analysis identified 239 eQTLs in either dura or blood, with 79% of these eQTLs shared by both tissues. Several identified eQTLs were novel and these implicate genes involved in bone development (IPO8, XYLT1, and PRKAR1A), and ribosomal pathways related to marrow and bone dysfunction, as potential candidates in the development of CMI.Despite strong overall heterogeneity in expression levels between blood and dura, the majority of cis-eQTLs are shared by both tissues. The power to detect shared eQTLs was improved by using an integrative statistical approach. The identified tissue-specific and shared eQTLs provide new insight into the genetic basis for CMI and related conditions.

Authors
Lock, EF; Soldano, KL; Garrett, ME; Cope, H; Markunas, CA; Fuchs, H; Grant, G; Dunson, DB; Gregory, SG; Ashley-Koch, AE
MLA Citation
Lock, EF, Soldano, KL, Garrett, ME, Cope, H, Markunas, CA, Fuchs, H, Grant, G, Dunson, DB, Gregory, SG, and Ashley-Koch, AE. "Joint eQTL assessment of whole blood and dura mater tissue from individuals with Chiari type I malformation." BMC genomics 16 (January 22, 2015): 11-.
PMID
25609184
Source
epmc
Published In
BMC Genomics
Volume
16
Publish Date
2015
Start Page
11
DOI
10.1186/s12864-014-1211-8

Congenital neurosurgical problems

© Springer International Publishing Switzerland 2015.Congenital neurosurgical problems are by definition, present at birth, although they may not become symptomatic, or be detected until sometime later. Pediatric neurosurgeons deal with a variety of congenital problems, including spina bifida, tethered cord, Chiari malformations, hydrocephalus, arachnoid cysts, and craniosynostosis, often in conjunction with other specialists. Close follow up of these patients is essential, and may be required throughout the patient's lifetime. In the past, it was thought that children with congenital neurological issues would inevitably decline, and die. Through the work of a number of dedicated pediatric neurosurgeons, this idea has been refuted, and the present view is that decline is not the natural history of these patients, and any clinical deterioration should be investigated, and potentially may be treated.

Authors
Fuchs, HE
MLA Citation
Fuchs, HE. "Congenital neurosurgical problems." Emergency Approaches to Neurosurgical Conditions. January 1, 2015. 65-69.
Source
scopus
Publish Date
2015
Start Page
65
End Page
69
DOI
10.1007/978-3-319-10693-9_5

Identification of Chiari Type I Malformation subtypes using whole genome expression profiles and cranial base morphometrics.

Chiari Type I Malformation (CMI) is characterized by herniation of the cerebellar tonsils through the foramen magnum at the base of the skull, resulting in significant neurologic morbidity. As CMI patients display a high degree of clinical variability and multiple mechanisms have been proposed for tonsillar herniation, it is hypothesized that this heterogeneous disorder is due to multiple genetic and environmental factors. The purpose of the present study was to gain a better understanding of what factors contribute to this heterogeneity by using an unsupervised statistical approach to define disease subtypes within a case-only pediatric population.A collection of forty-four pediatric CMI patients were ascertained to identify disease subtypes using whole genome expression profiles generated from patient blood and dura mater tissue samples, and radiological data consisting of posterior fossa (PF) morphometrics. Sparse k-means clustering and an extension to accommodate multiple data sources were used to cluster patients into more homogeneous groups using biological and radiological data both individually and collectively.All clustering analyses resulted in the significant identification of patient classes, with the pure biological classes derived from patient blood and dura mater samples demonstrating the strongest evidence. Those patient classes were further characterized by identifying enriched biological pathways, as well as correlated cranial base morphological and clinical traits.Our results implicate several strong biological candidates warranting further investigation from the dura expression analysis and also identified a blood gene expression profile corresponding to a global down-regulation in protein synthesis.

Authors
Markunas, CA; Lock, E; Soldano, K; Cope, H; Ding, C-KC; Enterline, DS; Grant, G; Fuchs, H; Ashley-Koch, AE; Gregory, SG
MLA Citation
Markunas, CA, Lock, E, Soldano, K, Cope, H, Ding, C-KC, Enterline, DS, Grant, G, Fuchs, H, Ashley-Koch, AE, and Gregory, SG. "Identification of Chiari Type I Malformation subtypes using whole genome expression profiles and cranial base morphometrics." BMC medical genomics 7 (June 25, 2014): 39-.
PMID
24962150
Source
epmc
Published In
BMC Medical Genomics
Volume
7
Publish Date
2014
Start Page
39
DOI
10.1186/1755-8794-7-39

Clinico-pathological description of three paediatric medulloblastoma cases with MLL2/3 gene mutations

Authors
Lopez, GY; Grant, GA; Fuchs, HE; Leithe, LG; Gururangan, S; Bigner, DD; Yan, H; McLendon, RE; He, Y
MLA Citation
Lopez, GY, Grant, GA, Fuchs, HE, Leithe, LG, Gururangan, S, Bigner, DD, Yan, H, McLendon, RE, and He, Y. "Clinico-pathological description of three paediatric medulloblastoma cases with MLL2/3 gene mutations." NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY 40.2 (February 2014): 217-220.
Source
wos-lite
Published In
Neuropathology & Applied Neurobiology
Volume
40
Issue
2
Publish Date
2014
Start Page
217
End Page
220
DOI
10.1111/nan.12060

Genetic evaluation and application of posterior cranial fossa traits as endophenotypes for Chiari type I malformation.

Chiari Type I Malformation (CMI) is characterized by herniation of the cerebellar tonsils through the base of the skull. Although cerebellar tonsillar herniation (CTH) is hypothesized to result from an underdeveloped posterior cranial fossa (PF), patients are frequently diagnosed by the extent of CTH without cranial morphometric assessment. We recently completed the largest CMI whole genome qualitative linkage screen to date. Despite an initial lack of statistical evidence, stratified analyses using clinical criteria to reduce heterogeneity resulted in a striking increase in evidence for linkage. The present study focused on the use of cranial base morphometrics to further dissect this heterogeneity and increase power to identify disease genes. We characterized the genetic contribution for a series of PF traits and evaluated the use of heritable, disease-relevant PF traits in ordered subset analysis (OSA). Consistent with a genetic hypothesis for CMI, much of the PF morphology was found to be heritable and multiple genomic regions were strongly implicated from OSA, including regions on Chromosomes 1 (LOD = 3.07, p = 3 × 10(-3) ) and 22 (LOD = 3.45, p = 6 × 10(-5) ) containing several candidates warranting further investigation. This study underscores the genetic heterogeneity of CMI and the utility of PF traits in CMI genetic studies.

Authors
Markunas, CA; Enterline, DS; Dunlap, K; Soldano, K; Cope, H; Stajich, J; Grant, G; Fuchs, H; Gregory, SG; Ashley-Koch, AE
MLA Citation
Markunas, CA, Enterline, DS, Dunlap, K, Soldano, K, Cope, H, Stajich, J, Grant, G, Fuchs, H, Gregory, SG, and Ashley-Koch, AE. "Genetic evaluation and application of posterior cranial fossa traits as endophenotypes for Chiari type I malformation." Ann Hum Genet 78.1 (January 2014): 1-12.
PMID
24359474
Source
pubmed
Published In
Annals of Human Genetics
Volume
78
Issue
1
Publish Date
2014
Start Page
1
End Page
12
DOI
10.1111/ahg.12041

Stratified whole genome linkage analysis of Chiari type I malformation implicates known Klippel-Feil syndrome genes as putative disease candidates.

Chiari Type I Malformation (CMI) is characterized by displacement of the cerebellar tonsils below the base of the skull, resulting in significant neurologic morbidity. Although multiple lines of evidence support a genetic contribution to disease, no genes have been identified. We therefore conducted the largest whole genome linkage screen to date using 367 individuals from 66 families with at least two individuals presenting with nonsyndromic CMI with or without syringomyelia. Initial findings across all 66 families showed minimal evidence for linkage due to suspected genetic heterogeneity. In order to improve power to localize susceptibility genes, stratified linkage analyses were performed using clinical criteria to differentiate families based on etiologic factors. Families were stratified on the presence or absence of clinical features associated with connective tissue disorders (CTDs) since CMI and CTDs frequently co-occur and it has been proposed that CMI patients with CTDs represent a distinct class of patients with a different underlying disease mechanism. Stratified linkage analyses resulted in a marked increase in evidence of linkage to multiple genomic regions consistent with reduced genetic heterogeneity. Of particular interest were two regions (Chr8, Max LOD = 3.04; Chr12, Max LOD = 2.09) identified within the subset of "CTD-negative" families, both of which harbor growth differentiation factors (GDF6, GDF3) implicated in the development of Klippel-Feil syndrome (KFS). Interestingly, roughly 3-5% of CMI patients are diagnosed with KFS. In order to investigate the possibility that CMI and KFS are allelic, GDF3 and GDF6 were sequenced leading to the identification of a previously known KFS missense mutation and potential regulatory variants in GDF6. This study has demonstrated the value of reducing genetic heterogeneity by clinical stratification implicating several convincing biological candidates and further supporting the hypothesis that multiple, distinct mechanisms are responsible for CMI.

Authors
Markunas, CA; Soldano, K; Dunlap, K; Cope, H; Asiimwe, E; Stajich, J; Enterline, D; Grant, G; Fuchs, H; Gregory, SG; Ashley-Koch, AE
MLA Citation
Markunas, CA, Soldano, K, Dunlap, K, Cope, H, Asiimwe, E, Stajich, J, Enterline, D, Grant, G, Fuchs, H, Gregory, SG, and Ashley-Koch, AE. "Stratified whole genome linkage analysis of Chiari type I malformation implicates known Klippel-Feil syndrome genes as putative disease candidates. (Published online)" PLoS One 8.4 (2013): e61521-.
PMID
23620759
Source
pubmed
Published In
PloS one
Volume
8
Issue
4
Publish Date
2013
Start Page
e61521
DOI
10.1371/journal.pone.0061521

Inflammatory pseudotumor of the lateral ventricle in a pediatric patient.

Inflammatory pseudotumor (IP) is a benign process that most commonly occurs in the lung and orbit. Extension into the central nervous system is extremely rare, and primary intraventricular lesions of the lateral ventricles are even more infrequent with only 2 cases reported in pediatric patients to date. Here, the authors present an unusual case of IP occurring in a 16-year-old female presenting with a 2-week history of progressive headaches and vomiting, without focal neurological deficits or radiographic evidence of hydrocephalus. The patient underwent left parietal craniotomy and complete resection of the tumor, with no signs of recurrence at 3-month follow-up. Although the rarity of intraventricular IP in pediatric patients can make its initial identification difficult, IP should be considered as a potential diagnosis in this population wherein good outcomes may be achieved following surgical resection.

Authors
Choi, BD; Hodges, TR; Grant, GA; Fuchs, HE; Cummings, TJ; Muh, CR
MLA Citation
Choi, BD, Hodges, TR, Grant, GA, Fuchs, HE, Cummings, TJ, and Muh, CR. "Inflammatory pseudotumor of the lateral ventricle in a pediatric patient." Pediatr Neurosurg 48.6 (2012): 374-378.
PMID
23948719
Source
pubmed
Published In
Pediatric neurosurgery
Volume
48
Issue
6
Publish Date
2012
Start Page
374
End Page
378
DOI
10.1159/000353609

Complications following decompression of Chiari malformation Type I in children: dural graft or sealant?

OBJECT: Posterior fossa decompression with duraplasty for Chiari malformation Type I (CM-I) is a common pediatric neurosurgery procedure. Published series report a complication rate ranging from 3% to 40% for this procedure. Historically, many dural substitutes have been used, including bovine grafts, human cadaveric pericardium, synthetic dura, and autologous pericranium. The authors hypothesized that a recently observed increase in complications was dependent on the graft used. METHODS: Between January 2004 and January 2008, 114 consecutive patients ≤ 18 years old underwent primary CM-I decompression using duraplasty. Records were retrospectively reviewed for short- and intermediate-term complications and operative technique, focusing on the choice of duraplasty graft with or without application of a tissue sealant. RESULTS: The average age of the patients was 8.6 years. The dural graft used was variable: 15 were treated with cadaveric pericardium, 12 with Durepair, and 87 with EnDura. Tisseel was used in 75 patients, DuraSeal in 12, and no tissue sealant was used in 27 patients. The overall complication rate was 21.1%. The most common complications included aseptic meningitis, symptomatic pseudomeningocele, or a CSF leak requiring reoperation. The overall complication rates were as follows: cadaveric pericardium 26.7%, Durepair 41.7%, and EnDura 17.2%; reoperation rates were 13%, 25%, and 8.1%, respectively. Prior to adopting a different graft product, the overall complication rate was 18.1%; following the change the rate increased to 35%. Complication rates for tissue sealants were 14.8% for no sealant, 18.7% for Tisseel, and 50% for DuraSeal. Nine patients were treated with the combination of Durepair and DuraSeal and this subgroup had a 56% complication rate. CONCLUSIONS: Complication rates after CM-I decompression may be dependent on the dural graft with or without the addition of tissue sealant. The complication rate at the authors' institution approximately doubled following the adoption of a different graft product. Tissue sealants used in combination with a dural substitute to augment a duraplasty may increase the risk of aseptic meningitis and/or CSF leak. The mechanism of the apparent increased inflammation with this combination remains under investigation.

Authors
Parker, SR; Harris, P; Cummings, TJ; George, T; Fuchs, H; Grant, G
MLA Citation
Parker, SR, Harris, P, Cummings, TJ, George, T, Fuchs, H, and Grant, G. "Complications following decompression of Chiari malformation Type I in children: dural graft or sealant?." J Neurosurg Pediatr 8.2 (August 2011): 177-183.
PMID
21806360
Source
pubmed
Published In
Journal of neurosurgery. Pediatrics
Volume
8
Issue
2
Publish Date
2011
Start Page
177
End Page
183
DOI
10.3171/2011.5.PEDS10362

CLINICAL PATHOLOGIC DESCRIPTION OF THREE PEDIATRIC MEDULLOBLASTOMA CASES WITH MLL2/3 GENE MUTATIONS

Authors
He, Y; Lopez, G; Grant, G; Fuchs, H; Leithe, L; Gururangan, S; Bigner, D; Yan, H; Mclendon, R
MLA Citation
He, Y, Lopez, G, Grant, G, Fuchs, H, Leithe, L, Gururangan, S, Bigner, D, Yan, H, and Mclendon, R. "CLINICAL PATHOLOGIC DESCRIPTION OF THREE PEDIATRIC MEDULLOBLASTOMA CASES WITH MLL2/3 GENE MUTATIONS." May 2011.
PMID
23659599
Source
wos-lite
Published In
Neuro-Oncology
Volume
13
Publish Date
2011
Start Page
I30
End Page
I30

CA-MRSA brain abscess in a healthy infant

We report the first case of a previously healthy term 5 week old infant with no known risk factors who developed a frontal lobe abscess from community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA). To date, only 16 cases of invasive CA-MRSA with central nervous system involvement have been previously described, but the incidence of CA-MRSA has surged within the last decade, creating a growing impact on public health. Increasing numbers of invasive infections caused by CA-MRSA in previously healthy individuals is of particular concern, and the highest rates of these infections are in children. As CA-MRSA continues to spread and develop further antibiotic resistance, cases of invasive diseases as described in this report may become more common. © 2011 IOS Press and the authors. All rights reserved.

Authors
Stack, A; Peterson-Carmichael, SL; Yin, DE; Marti, M; Fuchs, H; Jhaveri, R; Turner, DA
MLA Citation
Stack, A, Peterson-Carmichael, SL, Yin, DE, Marti, M, Fuchs, H, Jhaveri, R, and Turner, DA. "CA-MRSA brain abscess in a healthy infant." Journal of Pediatric Infectious Diseases 6.1 (2011): 71-75.
Source
scival
Published In
Journal of Pediatric Infectious Diseases
Volume
6
Issue
1
Publish Date
2011
Start Page
71
End Page
75
DOI
10.3233/JPI-2011-0290

Clinical outcome of cerebrospinal fluid shunting for communicating hydrocephalus in mucopolysaccharidoses I, II, and III: a retrospective analysis of 13 patients.

BACKGROUND: Intracranial pathology is a well-documented feature of mucopolysaccharidoses (MPSs), including communicating hydrocephalus (CH). Neither the success nor the complications of cerebrospinal fluid shunting in MPS patients have been well documented. OBJECTIVE: To retrospectively analyze 13 children with communicating hydrocephalus and MPS at our institution between 1998 and 2006. METHODS: Thirteen patients diagnosed with MPS I, II, or III presenting for stem cell transplantation were retrospectively analyzed. Patients underwent a rigorous pretransplantation workup, including magnetic resonance imaging of the brain. If imaging revealed ventriculomegaly, a lumbar puncture was performed. If intracranial pressure was >20 cm H20 or the patient demonstrated clinical signs of hydrocephalus or evidence of clinical decline with increasing ventricular size on imaging, a ventriculoperitoneal shunt (VPS) was placed. Clinical outcomes were analyzed after dividing the patients into 2 groups: patients who underwent VPS before (group A) and after (Group B) stem cell transplantation. RESULTS: There were 8 patients in group A and 5 in group B. Group B patients developed more severe complications, including 2 patients who required VPS early after transplantation, one who died secondary to intracerebral hemorrhage and another who developed a subdural empyema. Of the 8 patients in group A, 5 had complications, including 2 shunt infections, a punctate intracerebral hematoma, shunt tube migration, and 3 shunt failures. CONCLUSION: This is the largest review of MPS patients with communicating hydrocephalus. It demonstrates that VPS is an effective treatment. MPS patients need to be evaluated for hydrocephalus before stem cell transplantation because pretransplantation shunting appears to have the most favorable risk/benefit ratio.

Authors
Aliabadi, H; Reynolds, R; Powers, CJ; Grant, G; Fuchs, H; Kurtzberg, J
MLA Citation
Aliabadi, H, Reynolds, R, Powers, CJ, Grant, G, Fuchs, H, and Kurtzberg, J. "Clinical outcome of cerebrospinal fluid shunting for communicating hydrocephalus in mucopolysaccharidoses I, II, and III: a retrospective analysis of 13 patients." Neurosurgery 67.6 (December 2010): 1476-1481.
PMID
21107178
Source
pubmed
Published In
Neurosurgery
Volume
67
Issue
6
Publish Date
2010
Start Page
1476
End Page
1481
DOI
10.1227/NEU.0b013e3181f8c11d

Endodermal cyst of the oculomotor nerve.

Authors
Karikari, IO; Grant, G; Cummings, TJ; Petrella, J; Fuchs, HE
MLA Citation
Karikari, IO, Grant, G, Cummings, TJ, Petrella, J, and Fuchs, HE. "Endodermal cyst of the oculomotor nerve." Pediatr Neurosurg 46.2 (August 2010): 155-156.
PMID
20689348
Source
pubmed
Published In
Pediatric neurosurgery
Volume
46
Issue
2
Publish Date
2010
Start Page
155
End Page
156
DOI
10.1159/000319562

Single-stage bilateral choroid plexectomy for choroid plexus papilloma in a patient presenting with high cerebrospinal fluid output.

Cerebrospinal fluid overproduction resulting in communicating hydrocephalus is observed in patients who have choroid plexus papilloma or choroid plexus carcinoma. Less often, patients with these conditions have diffuse villous hyperplasia. Prior studies report CSF production greater than 3 L per day in these patients. These patients are treated with CSF shunting or by either unilateral choroid plexectomy or staged bilateral choroid plexectomy. The authors present a patient who had a number of congenital anomalies and a karyotype that revealed balanced translocations, 5 to 7 and 9 to 11. She presented with hydrocephalus and had CSF production of 5 L per day, greater output than ever previously reported. She was treated with a single-stage bilateral choroid plexectomy. Histopathological analysis revealed a bilateral choroid plexus papilloma. Postoperatively, the patient responded well clinically and showed radiographic improvement of her hydrocephalus. Bilateral choroid plexus papilloma has been reported in the literature as a cause for neonatal and congenital hydrocephalus. It can result in high CSF output and can be successfully treated with a single-stage bilateral choroid plexectomy. Further studies are ongoing to identify genes involved in embryogenesis of the choroid plexus.

Authors
Nimjee, SM; Powers, CJ; McLendon, RE; Grant, GA; Fuchs, HE
MLA Citation
Nimjee, SM, Powers, CJ, McLendon, RE, Grant, GA, and Fuchs, HE. "Single-stage bilateral choroid plexectomy for choroid plexus papilloma in a patient presenting with high cerebrospinal fluid output." J Neurosurg Pediatr 5.4 (April 2010): 342-345.
PMID
20367337
Source
pubmed
Published In
Journal of neurosurgery. Pediatrics
Volume
5
Issue
4
Publish Date
2010
Start Page
342
End Page
345
DOI
10.3171/2009.10.PEDS08454

Disappearing bone disease and Chiari I malformation.

Gorham's disease is a rare disorder in which massive osteolysis occurs within bone, and therefore earns its historical name: disappearing bone disease. We describe a case of Chiari I malformation in a patient with this rare disorder, with treatment consisting of a suboccipital craniectomy, C1 laminectomy, and duraplasty for Chiari decompression.

Authors
Hughes, BD; Grant, GA; Cummings, TJ; Fuchs, HE
MLA Citation
Hughes, BD, Grant, GA, Cummings, TJ, and Fuchs, HE. "Disappearing bone disease and Chiari I malformation." Pediatr Neurosurg 46.1 (2010): 58-61.
PMID
20516742
Source
pubmed
Published In
Pediatric neurosurgery
Volume
46
Issue
1
Publish Date
2010
Start Page
58
End Page
61
DOI
10.1159/000315005

Spontaneous intrauterine "ping-pong" fracture: review and case illustration.

We report a case of a closed outer-table parietal "ping-pong" skull fracture occurring in a 4 190-gram female infant born at 39 weeks and 5 days gestation after an uneventful Cesarean section (Apgar scores of 9 and 9 at one and five minutes). There was no maternal history of abdominal trauma during pregnancy and there were no complications or difficulties with Cesarean section delivery. Neurological examination was normal. Computed tomography with three-dimensional reconstruction images showed a 4 x 5 cm depression in the right parietal bone with a medial lucency consistent with a fracture of the superior margin of the skull and leftward deviation of the sagittal suture and sinus. Spontaneous resolution did not occur by one month of age and the skull fracture was repaired with excellent cosmetic results. Rarely has a case of spontaneous intrauterine skull fracture been reported in an atraumatic Cesarean delivery. We believe this fracture resulted from a chronic in utero process without associated trauma as evidenced by deviation of the sagittal suture and sinus.

Authors
Aliabadi, H; Miller, J; Radnakrishnan, S; Mehta, AI; Thomas, K; Selznick, L; Goldberg, R; Grant, G; Fuchs, H
MLA Citation
Aliabadi, H, Miller, J, Radnakrishnan, S, Mehta, AI, Thomas, K, Selznick, L, Goldberg, R, Grant, G, and Fuchs, H. "Spontaneous intrauterine "ping-pong" fracture: review and case illustration." Neuropediatrics 40.2 (April 2009): 73-75. (Review)
PMID
19809935
Source
pubmed
Published In
Neuropediatrics
Volume
40
Issue
2
Publish Date
2009
Start Page
73
End Page
75
DOI
10.1055/s-0029-1234108

Spontaneous resolution of a 13-mm Chiari malformation Type I in relation to differential growth of the posterior fossa volume.

The case of a 3-year-old patient with tuberous sclerosis and a 13-mm Chiari malformation Type I that spontaneously disappeared over the course of 4 years is presented. Using morphometric measurements of the posterior fossa and cerebellum in this patient, the authors show that the volume of the posterior fossa at the time of initial evaluation was consistent with that reported as normal in the literature (180.24 cm3; normal volume 132-198 cm3). Moreover, the patient showed a normal rate of growth of his posterior fossa over the period of observation (201.05 cm3; normal range 153-230 cm3). Cerebellar volumes were found to increase only minimally during this time period, which is compatible with observations in healthy controls. The posterior fossa volume, on the other hand, was shown to increase significantly more than that of the cerebellum (p=0.0185). This differential growth may permit the tonsils to ascend back up into the posterior fossa. Therefore, pediatric patients with normal posterior fossa volumes and normal development may have a spontaneous resolution of their asymptomatic Chiari malformation Type I.

Authors
Waldau, B; Domeshek, LF; Leigh, FA; Lum, KC; Fuchs, HE; Marcus, JR; Mukundan, S; Grant, GA
MLA Citation
Waldau, B, Domeshek, LF, Leigh, FA, Lum, KC, Fuchs, HE, Marcus, JR, Mukundan, S, and Grant, GA. "Spontaneous resolution of a 13-mm Chiari malformation Type I in relation to differential growth of the posterior fossa volume." J Neurosurg Pediatr 3.2 (February 2009): 110-114.
PMID
19278309
Source
pubmed
Published In
Journal of neurosurgery. Pediatrics
Volume
3
Issue
2
Publish Date
2009
Start Page
110
End Page
114
DOI
10.3171/2008.10.PEDS08200

Few isolated neurons in hypothalamic hamartomas may cause gelastic seizures.

Hypothalamic hamartomas (HHs) are congenital, benign masses in the hypothalamus and tuber cinereum that may cause central precocious puberty and gelastic seizures. Nodules of small neurons are thought to be a universal feature of the microarchitecture of HH lesions associated with epilepsy. Here we describe the case of a 5-year-old boy with gelastic seizures who underwent resection of a HH that contained nodules of glial cells, but only few, randomly distributed neurons. HHs that contain few or no neurons have only been reported thus far in cases associated with precocious puberty. This case demonstrates that few solitary neurons in HHs can drive the development of gelastic seizures, and nodules of small neurons may not be a universal feature of HHs associated with epilepsy. This finding is clinically important since hypothalamic hamartomas with rare neurons can easily be misdiagnosed as pilocytic astrocytomas or subependymomas if their presence is overlooked. A neuronal stain is helpful in making the correct diagnosis in these cases.

Authors
Waldau, B; McLendon, RE; Fuchs, HE; George, TM; Grant, GA
MLA Citation
Waldau, B, McLendon, RE, Fuchs, HE, George, TM, and Grant, GA. "Few isolated neurons in hypothalamic hamartomas may cause gelastic seizures." Pediatr Neurosurg 45.3 (2009): 225-229.
PMID
19521137
Source
pubmed
Published In
Pediatric neurosurgery
Volume
45
Issue
3
Publish Date
2009
Start Page
225
End Page
229
DOI
10.1159/000224620

Efficacy of high-dose chemotherapy or standard salvage therapy in patients with recurrent medulloblastoma.

The efficacy of high-dose chemotherapy (HDC) or standard salvage therapy was evaluated in patients with recurrent medulloblastoma (MBL) using retrospective chart review of all patients with recurrent MBL treated at Duke University Medical Center between 1995 and 2005 and who had undergone HDC with or without radiotherapy (RT) or standard salvage therapy after relapse. A total of 30 patients were diagnosed with recurrent MBL after standard RT alone or chemotherapy with RT. Nineteen patients (7 who received no RT before recurrence [group A] and 12 who received definitive RT before recurrence [group B]) underwent surgery and/or induction chemotherapy followed by HDC plus autologous stem-cell rescue. Eleven patients (group C) underwent standard salvage therapy. Six of seven group A patients also received standard RT just before or after recovery from HDC, and 5 of 12 group B patients received adjuvant palliative focal RT post-HDC. At a median follow-up of 28 months, three of seven patients in group A are alive and disease-free at >or=34, >or=110, and >or=116 months, respectively, post-HDC. All patients in groups B and C have died of tumor, at a median of 35 months and 26 months from HDC and standard salvage therapy, respectively. HDC or standard salvage therapy was ineffective in our patients with recurrent MBL who had received standard RT before recurrence. The favorable impact of HDC on disease control in the two long-term survivors cannot be clearly established due to the cofounding effect of definitive RT postrecurrence.

Authors
Gururangan, S; Krauser, J; Watral, MA; Driscoll, T; Larrier, N; Reardon, DA; Rich, JN; Quinn, JA; Vredenburgh, JJ; Desjardins, A; McLendon, RE; Fuchs, H; Kurtzberg, J; Friedman, HS
MLA Citation
Gururangan, S, Krauser, J, Watral, MA, Driscoll, T, Larrier, N, Reardon, DA, Rich, JN, Quinn, JA, Vredenburgh, JJ, Desjardins, A, McLendon, RE, Fuchs, H, Kurtzberg, J, and Friedman, HS. "Efficacy of high-dose chemotherapy or standard salvage therapy in patients with recurrent medulloblastoma." Neuro Oncol 10.5 (October 2008): 745-751.
PMID
18755919
Source
pubmed
Published In
Neuro-Oncology
Volume
10
Issue
5
Publish Date
2008
Start Page
745
End Page
751
DOI
10.1215/15228517-2008-044

Craniosynostosis and rickets.

Authors
Inman, PC; Mukundan, S; Fuchs, HE; Marcus, JR
MLA Citation
Inman, PC, Mukundan, S, Fuchs, HE, and Marcus, JR. "Craniosynostosis and rickets." Plast Reconstr Surg 121.4 (April 2008): 217e-218e.
PMID
18349605
Source
pubmed
Published In
Plastic and Reconstructive Surgery
Volume
121
Issue
4
Publish Date
2008
Start Page
217e
End Page
218e
DOI
10.1097/01.prs.0000305381.61117.2f

Development of an acquired Chiari malformation Type I in the setting of an untreated lipomyelomeningocele. Case report.

The authors present the case of a child with an untreated lipomyelomeningocele who developed an acquired Chiari malformation Type I (CM-I) with a large syrinx over the course of 3 years. To the best of the authors' knowledge, this is the first report to document a case in which an acquired CM-I evolved in a patient with an untreated tethered cord.

Authors
Waldau, B; Grant, G; Fuchs, H
MLA Citation
Waldau, B, Grant, G, and Fuchs, H. "Development of an acquired Chiari malformation Type I in the setting of an untreated lipomyelomeningocele. Case report." J Neurosurg Pediatr 1.2 (February 2008): 164-166.
PMID
18352791
Source
pubmed
Published In
Journal of neurosurgery. Pediatrics
Volume
1
Issue
2
Publish Date
2008
Start Page
164
End Page
166
DOI
10.3171/PED/2008/1/2/164

Dynamic contrast-enhanced magnetic resonance angiography of vascular malformations in pediatric patients. Case report.

The authors report the first clinical use of 3-tesla dynamic contrast-enhanced magnetic resonance (MR) angiography for the diagnosis of a vascular malformation in a pediatric patient. The supply and drainage of an arteriovenous malformation were accurately demonstrated on MR angiography, which was performed without sedating the patient. This lesion was confirmed on catheter angiography, and definitive treatment via embolization was undertaken in a single session. The patient's therapeutic response will be followed with surveillance dynamic MR imaging.

Authors
Mukundan, S; Fuchs, H; Alexander, MJ; Grant, GA
MLA Citation
Mukundan, S, Fuchs, H, Alexander, MJ, and Grant, GA. "Dynamic contrast-enhanced magnetic resonance angiography of vascular malformations in pediatric patients. Case report." J Neurosurg 107.3 Suppl (September 2007): 228-231.
PMID
17918531
Source
pubmed
Published In
Journal of neurosurgery
Volume
107
Issue
3 Suppl
Publish Date
2007
Start Page
228
End Page
231
DOI
10.3171/PED-07/09/228

Tethered cord due to spina bifida occulta presenting in adulthood: a tricenter review of 61 patients.

OBJECT: Children with spina bifida occulta require early surgery to prevent neurological deficits. The treatment of patients with a congenitally tethered cord who present in adulthood remains controversial. METHODS: The authors studied the medical records of 61 adult patients who underwent surgical untethering for spina bifida occulta at three institutions between 1994 and 2003. Patients who had undergone prior myelomeningocele repair or tethered cord release surgery were excluded. The most common intraoperative findings were lipomyelomeningocele (41%) and a tight terminal filum (36%). The follow-up duration ranged from 10.8 to 149.5 months. Of the 34 patients with back pain, status improved in 65%, worsened in 3%, remained unchanged in 18%, and improved and later recurred in 15%. Lower-extremity pain improved in 16 patients (53%), remained unchanged in 23%, improved and then recurred in 17%, and worsened in 7%. Lower-extremity weakness improved in 47%, remained unchanged in 47%, and improved and then recurred in 5%. Finally, of the 17 patients with lower-extremity sensory changes, status improved in 35%, remained unchanged in 35%, and the information on five patients was unavailable. Surgical complications included three wound infections, one cerebrospinal fluid leak, and two pseudomeningoceles requiring surgical revision. One patient developed acute respiratory distress syndrome and sepsis postoperatively and died several days later. CONCLUSIONS: Adult-age presentation of a congenital tethered cord is unusual. Despite a slight increase in postoperative neurological injury in adults, surgery has relatively low risk and offers good potential for neurological improvement or stabilization. As they do in children, the authors recommend early surgery in adults with this disorder. The decision to undertake surgery, however, should be modulated by other factors such as a patient's general medical condition and risk posed by anesthesia.

Authors
Rajpal, S; Tubbs, RS; George, T; Oakes, WJ; Fuchs, HE; Hadley, MN; Iskandar, BJ
MLA Citation
Rajpal, S, Tubbs, RS, George, T, Oakes, WJ, Fuchs, HE, Hadley, MN, and Iskandar, BJ. "Tethered cord due to spina bifida occulta presenting in adulthood: a tricenter review of 61 patients." J Neurosurg Spine 6.3 (March 2007): 210-215.
PMID
17355019
Source
pubmed
Published In
Journal of neurosurgery. Spine
Volume
6
Issue
3
Publish Date
2007
Start Page
210
End Page
215
DOI
10.3171/spi.2007.6.3.210

Craniosynostosis Secondary to Rickets: Manifestations on Computed Tomography

Authors
Wang, PI; Marcus, JR; Fuchs, HE; Mukundan, S
MLA Citation
Wang, PI, Marcus, JR, Fuchs, HE, and Mukundan, S. "Craniosynostosis Secondary to Rickets: Manifestations on Computed Tomography." Radiology Case Reports 2.3 (2007): 43-43.
Source
crossref
Published In
Radiology Case Reports
Volume
2
Issue
3
Publish Date
2007
Start Page
43
End Page
43
DOI
10.2484/rcr.v2i3.43

Chronic subdural hematoma of the neonate: report of two cases and literature review.

We report the cases of 2 infants who were born with macrocephaly and bulging fontanelles and were subsequently found to have chronic subdural hematomas on imaging studies. The etiology of 1 infant was likely due to an inherent coagulopathy, while no etiology could be found for the other. The subdural hematomas were managed by craniotomy in 1 infant and serial subdural taps in the other. There are currently only 8 other case reports of chronic subdural hematoma of the neonate in the literature. Our cases and a brief review of the literature are presented.

Authors
Powers, CJ; Fuchs, HE; George, TM
MLA Citation
Powers, CJ, Fuchs, HE, and George, TM. "Chronic subdural hematoma of the neonate: report of two cases and literature review." Pediatr Neurosurg 43.1 (2007): 25-28. (Review)
PMID
17190984
Source
pubmed
Published In
Pediatric neurosurgery
Volume
43
Issue
1
Publish Date
2007
Start Page
25
End Page
28
DOI
10.1159/000097521

Cerebellopontine angle craniopharyngioma: case report and literature review.

The authors report an unusual case of adamantinomatous craniopharyngioma occurring in isolation in the cerebellopontine angle of a 12-year-old female. The patient presented with a 1-year history of nausea, vomiting, and headache. MRI revealed a left cerebellopontine angle tumor without connection to the suprasellar space. Following near-total resection, histological review confirmed the lesion as an adamantinomatous craniopharyngioma. This is only the third published report of craniopharyngioma occurring in isolation in the cerebellopontine angle. The case report and a brief review of the literature are presented.

Authors
Powers, CJ; New, KC; McLendon, RE; Friedman, AH; Fuchs, HE
MLA Citation
Powers, CJ, New, KC, McLendon, RE, Friedman, AH, and Fuchs, HE. "Cerebellopontine angle craniopharyngioma: case report and literature review." Pediatr Neurosurg 43.2 (2007): 158-163. (Review)
PMID
17337933
Source
pubmed
Published In
Pediatric neurosurgery
Volume
43
Issue
2
Publish Date
2007
Start Page
158
End Page
163
DOI
10.1159/000098394

Constipation as a reversible cause of ventriculoperitoneal shunt failure. Report of two cases.

Ventriculoperitoneal (VP) shunt failure is a common problem encountered by pediatric neurosurgeons. The majority of such failures are due to obstruction of the device. Conditions in which intraabdominal pressure is chronically elevated, such as pregnancy, have been associated with shunt failure. Chronic constipation may also result in abnormally elevated intraabdominal pressure and may be an underrecognized cause of distal VP shunt failure. The authors describe the cases of two children who presented with clinical and imaging evidence of VP shunt failure and who were also severely constipated. Treatment of their constipation resulted in both clinical and imaging-documented resolution of their shunt failure.

Authors
Powers, CJ; George, T; Fuchs, HE
MLA Citation
Powers, CJ, George, T, and Fuchs, HE. "Constipation as a reversible cause of ventriculoperitoneal shunt failure. Report of two cases." J Neurosurg 105.3 Suppl (September 2006): 227-230.
PMID
16970237
Source
pubmed
Published In
Journal of neurosurgery
Volume
105
Issue
3 Suppl
Publish Date
2006
Start Page
227
End Page
230
DOI
10.3171/ped.2006.105.3.227

Relationship of cine phase-contrast magnetic resonance imaging with outcome after decompression for Chiari I malformations.

OBJECTIVE: Many patients with symptomatic Chiari I malformations experience symptom recurrence after surgical decompression. Identification of predictors of outcome is needed to better select patients most likely to benefit from surgical intervention. We examined whether or not cerebrospinal fluid (CSF) flow dynamics assessed by cine phase contrast magnetic resonance imaging could independently predict response to posterior fossa decompression for Chiari I malformations. METHODS: Pre- and postoperative CSF flow dynamics were assessed by cine phase-contrast magnetic resonance imaging in 130 consecutive patients receiving posterior fossa decompression for a Chiari I malformation between 1997 and 2003. CSF flow was classified as "abnormal" if biphasic flow was either absent or decreased through the aqueduct, fourth ventricle and its outlets, the foramen magnum, or ventral or dorsal to the cervical spinal cord. If no evidence of decreased flow was noted, CSF flow was classified as "normal." The association between preoperative CSF flow dynamics, all recorded variables, and long-term outcome was assessed using multivariate proportional hazards regression analysis. RESULTS: All patients had tonsil herniation more than 5 mm below the foramen magnum (average, 11 +/- 5 mm). Abnormal hindbrain CSF flow was observed in 81% of patients (43% complete obstruction, 38% reduced flow). Normal CSF flow was observed in 19% of patients. In multivariate analysis, patients with normal preoperative hindbrain CSF flow were 4.8-fold more likely to experience symptom recurrence after surgery (relative risk, 4.85; 95% confidence interval, 1.88-12.5; P < 0.001) regardless of degree of tonsillar ectopia or presence of syringomyelia. Isolated frontal headache (relative risk, 4.16; 95% confidence interval, 1.7-9.8; P < 0.05) and scoliosis (relative risk, 9.2; 95% confidence interval, 1.7-10.5; P < 0.001) also were independent risk factors for symptom recurrence. CONCLUSION: Normal preoperative hindbrain CSF flow was an independent risk factor for treatment failure after decompression for Chiari I malformation regardless of the degree of tonsillar ectopia. Cine phase-contrast magnetic resonance imaging may be a valuable tool in identifying patients who are less likely to respond to surgical decompression for Chiari I malformation.

Authors
McGirt, MJ; Nimjee, SM; Fuchs, HE; George, TM
MLA Citation
McGirt, MJ, Nimjee, SM, Fuchs, HE, and George, TM. "Relationship of cine phase-contrast magnetic resonance imaging with outcome after decompression for Chiari I malformations." Neurosurgery 59.1 (July 2006): 140-146.
PMID
16823310
Source
pubmed
Published In
Neurosurgery
Volume
59
Issue
1
Publish Date
2006
Start Page
140
End Page
146
DOI
10.1227/01.NEU.0000219841.73999.B3

Intracranial Ewing sarcoma.

The occurrence of primary extraosseous Ewing sarcoma (EES) of the central nervous system (CNS) has only rarely been reported in the literature. It is important to distinguish this entity from the more common central primitive neuroectodermal tumor (PNET) of brain, since the management of these tumors is different from that of EES. We present the clinical, radiologic, and pathologic features of two cases of EES occurring in the brain. The diagnosis was further confirmed by detection of a rearrangement of the FLI1 and/or EWS gene loci in tumors from both patients using fluorescent in situ hybridization (FISH). Although rare, the possibility of EES should be considered particularly when tumors that arise near the meningeal surface of the brain and have the pathologic appearance of a PNET. Demonstration of t(11;22)(q24;q12) by molecular analysis essentially confirms the diagnosis and enables the oncologist to choose appropriate therapy.

Authors
Mazur, MA; Gururangan, S; Bridge, JA; Cummings, TJ; Mukundan, S; Fuchs, H; Larrier, N; Halperin, EC
MLA Citation
Mazur, MA, Gururangan, S, Bridge, JA, Cummings, TJ, Mukundan, S, Fuchs, H, Larrier, N, and Halperin, EC. "Intracranial Ewing sarcoma." Pediatr Blood Cancer 45.6 (November 2005): 850-856.
PMID
15929128
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
45
Issue
6
Publish Date
2005
Start Page
850
End Page
856
DOI
10.1002/pbc.20430

[18F]fluorodeoxyglucose-positron emission tomography in patients with medulloblastoma.

OBJECTIVE: We evaluated the [(18)F]fluorodeoxyglucose (FDG) accumulation during positron emission tomography (PET) in patients with medulloblastoma and examined the relationship of intensity of uptake with patient outcome after the initial scan. METHODS: Magnetic resonance imaging and FDG-PET scans of brain and spine were used to assess FDG uptake by visual grade (qualitative analysis) and metabolic activity ratios (T(max)/G(mean) and T(max)/W(mean)). Patients were divided into two groups based on either confirmation of tumor by biopsy and/or death resulting from progressive disease after the initial FDG-PET scan (Group A) or no intervention for the suspected lesion shown on magnetic resonance imaging after the initial FDG-PET scan but currently alive without evidence of disease (Group B). RESULTS: Twenty-two patients with either recurrent (n = 21) or newly diagnosed (n = 1) medulloblastoma underwent brain (n = 18) or whole-body (n = 4) FDG-PET scans after magnetic resonance imaging evidence of suspected tumor. The median qualitative analysis was 3 (range, 0-4) in 17 Group A patients compared with 0 (range, 0-1) in 5 Group B patients (P = 0.0003). The mean T(max)/G(mean) and T(max)/W(mean) ratios for 16 Group A patients were 1.3 (range, 0.1-3.8) and 2.10 (range, 0.4-5.2), respectively, compared with 0.80 (range, 0.20-1.5) and 1.3 (range, 0.5-1.9) in 5 Group B patients (P = 0.2 for both parameters, not significant). There was a significant negative correlation between increased FDG uptake and survival. Higher qualitative analysis and T(max)/W(mean) were associated with significantly poorer 2-year overall survival after the initial scan (71% versus 15% for qualitative analysis grade of <3 versus > or =3, P = 0.001; 46% versus 0% for T(max)/W(mean) < or =2.5 versus >2.5, P = 0.004). CONCLUSION: Increased FDG uptake is observed in medulloblastoma and is correlated negatively with survival.

Authors
Gururangan, S; Hwang, E; Herndon, JE; Fuchs, H; George, T; Coleman, RE
MLA Citation
Gururangan, S, Hwang, E, Herndon, JE, Fuchs, H, George, T, and Coleman, RE. "[18F]fluorodeoxyglucose-positron emission tomography in patients with medulloblastoma." Neurosurgery 55.6 (December 2004): 1280-1288.
PMID
15574210
Source
pubmed
Published In
Neurosurgery
Volume
55
Issue
6
Publish Date
2004
Start Page
1280
End Page
1288

Comparison of Tc99m-DTPA and indium-111 DTPA studies of baclofen pump function.

Authors
O'Connell, M; Wong, TZ; Forkheim, KE; Jain, M; Shipes, SW; Fuchs, HE
MLA Citation
O'Connell, M, Wong, TZ, Forkheim, KE, Jain, M, Shipes, SW, and Fuchs, HE. "Comparison of Tc99m-DTPA and indium-111 DTPA studies of baclofen pump function." Clin Nucl Med 29.9 (September 2004): 578-580.
PMID
15311132
Source
pubmed
Published In
Clinical Nuclear Medicine
Volume
29
Issue
9
Publish Date
2004
Start Page
578
End Page
580

The pathology of extracranial scalp and skull masses in young children.

OBJECTIVE: Extracranial subcutaneous masses involving the scalp and/or skull in young children are uncommon lesions that get excised by the neurosurgeon. Although the most common reported lesion is the dermoid cyst, our experience suggests that the spectrum of pathology in these lesions can present diagnostic challenges to the pathologist. MATERIAL: We reviewed 30 consecutive extracranial masses from 29 patients between July 1998 and June 2003. METHOD: Hematoxylin and eosin-stained sections were reviewed in all cases, and immunohistochemistry was performed in select cases. RESULTS: Twenty-three were within the scalp, 5 involved the scalp and skull and 2 were within the limits of the inner and outer tables of the skull. There were 8 dermoid cysts, 2 epidermoid cysts, 6 post-traumatic lesions including 3 calcified cephalhematomas and 3 pseudocysts, 5 vascular lesions including 3 capillary hemangiomas, 1 venous angioma and 1 lymphangioma, 2 cases of cranial fasciitis and 1 case each of benign teratoma, deep granuloma annulare, benign fibrous histiocytoma, congenital melanocytic nevus, hamartoma with ectopic meningothelial elements, cutaneous hyalinised ectopic meningioma and a meningocele with a fibrohistiocytic reaction. No lesions have recurred or exhibited malignant features. CONCLUSIONS: Surgical pathologists and neuropathologists should be aware that the differential diagnosis of "lumps and bumps on babie's heads" is quite varied and can be histologically challenging.

Authors
Cummings, TJ; George, TM; Fuchs, HE; McLendon, RE
MLA Citation
Cummings, TJ, George, TM, Fuchs, HE, and McLendon, RE. "The pathology of extracranial scalp and skull masses in young children." Clin Neuropathol 23.1 (January 2004): 34-43.
PMID
14986932
Source
pubmed
Published In
Clinical neuropathology
Volume
23
Issue
1
Publish Date
2004
Start Page
34
End Page
43

High-dose chemotherapy with autologous stem-cell rescue in children and adults with newly diagnosed pineoblastomas.

PURPOSE: We evaluated the usefulness of a treatment regimen that included high-dose chemotherapy (HDC) with autologous stem-cell rescue (ASCR) in patients with newly diagnosed pineoblastoma (PBL). PATIENTS AND METHODS: Twelve patients with PBL were initially treated with surgery and induction chemotherapy. All but two patients underwent radiotherapy. Subsequently, all patients received HDC using cyclophosphamide (CTX) + melphalan (MEL) or busulfan (Bu) + MEL regimens and ASCR. RESULTS: A total of six children and six adults with median ages of 4.2 (range, 0.3 to 19.8 years) and 23 years (range, 23 to 43.7 years), respectively, were treated according to this strategy. Four patients had metastatic disease confined to the neuraxis. Five of 12 patients (42%) had a complete tumor resection at diagnosis. Ten patients received radiotherapy at median doses of 36.0 and 59.4 Gy to the neuraxis and pineal region, respectively. Eleven patients received HDC with CTX + MEL, and one patient received BU + MEL followed by ASCR. Nine patients are alive with no evidence of disease recurrence at a median of 62 months from diagnosis (range, 28 to 125 months), including three patients with metastatic disease and two infants who did not receive any radiotherapy. Three patients have died of progressive disease at 19, 32, and 37 months from diagnosis, respectively. The actuarial 4-year progression-free and overall survivals are 69% (95% confidence interval [CI], 39% to 99%) and 71% (95% CI, 43% to 99%), respectively. CONCLUSION: The use of HDC in addition to radiotherapy seems to be an effective treatment for patients with newly diagnosed pineoblastoma.

Authors
Gururangan, S; McLaughlin, C; Quinn, J; Rich, J; Reardon, D; Halperin, EC; Herndon, J; Fuchs, H; George, T; Provenzale, J; Watral, M; McLendon, RE; Friedman, A; Friedman, HS; Kurtzberg, J; Vredenbergh, J; Martin, PL
MLA Citation
Gururangan, S, McLaughlin, C, Quinn, J, Rich, J, Reardon, D, Halperin, EC, Herndon, J, Fuchs, H, George, T, Provenzale, J, Watral, M, McLendon, RE, Friedman, A, Friedman, HS, Kurtzberg, J, Vredenbergh, J, and Martin, PL. "High-dose chemotherapy with autologous stem-cell rescue in children and adults with newly diagnosed pineoblastomas." J Clin Oncol 21.11 (June 1, 2003): 2187-2191.
PMID
12775745
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
21
Issue
11
Publish Date
2003
Start Page
2187
End Page
2191
DOI
10.1200/JCO.2003.10.096

Comparison of revision rates following endoscopically versus nonendoscopically placed ventricular shunt catheters.

BACKGROUND: Endoscopic placement of ventriculoperitoneal (VP) shunt catheters in pediatric patients has been increasingly used in an attempt to minimize the unacceptably high rates of revision. Although this procedure carries an increased expense, there is currently no evidence to support an improved long-term outcome. This paper compares the rates of revision following ventricular catheter placement for shunted hydrocephalus with and without the use of endoscopy. METHODS: We retrospectively reviewed the records of all pediatric patients who had undergone shunt placement for hydrocephalus between April 1992 and February 1998. All shunts placed before March 1995 were performed without the endoscope; all subsequent shunts were placed endoscopically. The independent effect of endoscopic versus nonendoscopic shunt placement on subsequent shunt failure was analyzed via multivariate proportional hazards regression model. Multiple logistic regression analyses were used to determine the independent effect of endoscopic placement on subsequent etiology of failure (infection, proximal obstruction, distal malfunction) in the 511 failing shunts. RESULTS: There were 447 pediatric patients who underwent a total of 965 shunt placements or revisions. Six hundred and five (63%) catheters were placed with the use of the endoscope. Three hundred and sixty (37.3%) were placed without the use of the endoscope. Neuroendoscopy did not independently affect the risk of subsequent shunt failure [Hazard Ratio (95% Confidence Interval) = 1.08 (0.84-1.41)]. Endoscopic placement independently decreased the odds [Odds Ratio (95% Confidence Interval) = 0.56 (0.32-0.93)] of proximal obstruction, increased the odds of distal malfunction [1.52 (1.02-2.72)], and was not associated with infection [1.42 (0.78-2.61)]. CONCLUSIONS: Endoscopic assisted ventricular catheter placement decreased the odds of proximal obstruction but failed to improve overall shunt survival in this 6 year experience.

Authors
Villavicencio, AT; Leveque, J-C; McGirt, MJ; Hopkins, JS; Fuchs, HE; George, TM
MLA Citation
Villavicencio, AT, Leveque, J-C, McGirt, MJ, Hopkins, JS, Fuchs, HE, and George, TM. "Comparison of revision rates following endoscopically versus nonendoscopically placed ventricular shunt catheters." Surg Neurol 59.5 (May 2003): 375-379.
PMID
12765808
Source
pubmed
Published In
World Neurosurgery
Volume
59
Issue
5
Publish Date
2003
Start Page
375
End Page
379

Risk factors for pediatric ventriculoperitoneal shunt infection and predictors of infectious pathogens.

Identification of risk factors for shunt infection and predictors of infectious pathogens may improve current methods to prevent and treat shunt infections. We reviewed data on 820 consecutive ventriculoperitoneal (VP) shunt placement procedures in 442 pediatric patients at our institution during 1992-1998. Ninety-two shunts (11%) developed infection a median of 19 days (interquartile range, 11-35 days) after insertion. Premature birth (relative risk [RR], 4.81; 95% confidence interval [CI], 2.19-10.87), previous shunt infection (RR, 3.83; 95% CI, 2.40-6.13), and intraoperative use of the neuroendoscope (RR, 1.58; 95% CI, 1.01-2.50) were independent risk factors for shunt infection. The bacterial organisms early after shunt surgery (<14 days) were the same as those late after shunt surgery (>14 days). As determined by an analysis of the 92 infected shunts, hospital stay of >3 days at the time of shunt insertion (odds ratio [OR], 5.27; 95% CI, 1.15-25.3) and prior Staphylococcus aureus shunt infection (OR, 5.91; 95% CI, 1.35-25.9) independently increased the odds that S. aureus was the causal pathogen.

Authors
McGirt, MJ; Zaas, A; Fuchs, HE; George, TM; Kaye, K; Sexton, DJ
MLA Citation
McGirt, MJ, Zaas, A, Fuchs, HE, George, TM, Kaye, K, and Sexton, DJ. "Risk factors for pediatric ventriculoperitoneal shunt infection and predictors of infectious pathogens." Clin Infect Dis 36.7 (April 1, 2003): 858-862.
PMID
12652386
Source
pubmed
Published In
Clinical Infectious Diseases
Volume
36
Issue
7
Publish Date
2003
Start Page
858
End Page
862
DOI
10.1086/368191

Comparison of total versus partial revision of initial ventriculoperitoneal shunt failures.

BACKGROUND: Optimal surgical management of patients presenting with shunt failure in the age of neuroendoscopy remains complex. The value of replacing the entire shunt system as opposed to a single shunt component has not been assessed. METHODS: We reviewed the records of all pediatric patients who underwent their first shunt revision between January 1992 and December 1998. Patients with primary shunt failure attributed solely to proximal catheter obstruction or distal catheter obstruction were included for analysis. Shunt revisions were classified as total (entire shunt replaced) or partial (only malfunctioning component replaced). Kaplan-Meier (shunt survival curves) and log rank analysis were used to compare failure rates between partially and totally revised shunts according to the underlying diagnosis and failed shunt part. Significant differences in univariate analysis were confirmed with a multivariate proportional hazards regression model. RESULTS: 301 pediatric patients underwent primary shunt revision (183 total, 118 partial revisions). All shunts utilized distal slit peritoneal catheters. In shunt failures attributed to proximal obstruction, reutilization of the distal catheter was associated with a 57% increased risk of subsequent shunt failure (hazard ratio 1.57, 95% confidence interval 1.19-3.49). In shunt failures attributed to distal obstruction, subsequent shunt survival was not affected by reutilization of the proximal catheter (p = 0.581). When stratified according to the etiology of hydrocephalus, only patients with intraventricular hemorrhage (IVH) failed to demonstrate greater survival of totally revised shunts. CONCLUSIONS: In this series, in the setting of proximal shunt catheter obstruction, reutilizing the functional distal catheter was associated with an increase in subsequent shunt failure rates compared to revising the entire shunt system. Total revision was not associated with improved shunt survival in patients with IVH.

Authors
McGirt, MJ; Wellons, JC; Nimjee, SM; Bulsara, KR; Fuchs, HE; George, TM
MLA Citation
McGirt, MJ, Wellons, JC, Nimjee, SM, Bulsara, KR, Fuchs, HE, and George, TM. "Comparison of total versus partial revision of initial ventriculoperitoneal shunt failures." Pediatr Neurosurg 38.1 (January 2003): 34-40.
PMID
12476025
Source
pubmed
Published In
Pediatric neurosurgery
Volume
38
Issue
1
Publish Date
2003
Start Page
34
End Page
40

Cerebrospinal fluid shunt survival and etiology of failures: a seven-year institutional experience.

BACKGROUND: Innovations in shunt technology and neuroendoscopy have been increasingly applied to shunt management. However, the relative life span of shunts and the etiology of shunt failure have not been characterized recently. METHODS: We reviewed the records of all shunting procedures at our institution between January 1992 and December 1998. Independent predictors of shunt failure were analyzed via multivariate Cox regression analysis in 836 shunting procedures. Independent predictors of the etiology of failure (infection, proximal obstruction, distal malfunction) were analyzed via multivariate logistic regression analysis in the 383 shunts which failed. RESULTS: A total of 353 pediatric patients underwent 308 shunt placements and 528 revisions. The risk (hazard ratio; HR) of shunt failure decreased as a function of time in both primary placements and revised shunts. In failed shunts, the odds of infection decreased 4-fold per year of shunt function, while the odds of distal malfunction increased 1.45-fold per year. Increasing number of shunt revisions (HR 1.31, p < 0.05), decreasing patient age in years (HR 1.04, p < 0.001), gestational age <40 weeks (HR 2.15, p < 0.001) but not the etiology of hydrocephalus were associated with an increased risk of shunt failure. Revisions versus primary placements, Dandy-Walker cysts and gestational age <40 weeks were independently associated with proximal, distal and infectious causes of failure, respectively. CONCLUSIONS: The long-term shunt revision rates observed here are similar to those reported over the past 2 decades. Shunt life span remains poorer in shunt revisions and in younger patients. Patient characteristics may suggest a specific risk and mechanism of failure, aiding in the long-term management of shunted hydrocephalus.

Authors
McGirt, MJ; Leveque, J-C; Wellons, JC; Villavicencio, AT; Hopkins, JS; Fuchs, HE; George, TM
MLA Citation
McGirt, MJ, Leveque, J-C, Wellons, JC, Villavicencio, AT, Hopkins, JS, Fuchs, HE, and George, TM. "Cerebrospinal fluid shunt survival and etiology of failures: a seven-year institutional experience." Pediatr Neurosurg 36.5 (May 2002): 248-255.
PMID
12053043
Source
pubmed
Published In
Pediatric neurosurgery
Volume
36
Issue
5
Publish Date
2002
Start Page
248
End Page
255

Clinical outcome differences for lipomyelomeningoceles, intraspinal lipomas, and lipomas of the filum terminale.

Failure to differentiate between the different types of lumbosacral lipomas may lead to inaccurate assumptions and inappropriate management of patients. The goal of this study was to determine whether there is a difference in clinical outcome between patients with lipomyelomeningocles, intraspinal lipomas, and lipomas of the filum terminale. One hundred and fourteen patients with spinal dysraphism were seen at Duke University Medical Center between 1995-1999. All patients who had undergone previous operative intervention for these lesions were excluded. Twenty-two patients with intradural lipomas were identified. Of these, 14 (64%) had lipomyelomeningoceles and 8 (36%) had intraspinal lipomas. Twenty-five patients had filum terminale lipomas. Operative management consisted of lumbosacral laminectomies with microsurgical resection of the lipoma and division of the fatty filum. Average age at presentation in symptomatic patients with lipomas of the filum terminale was 17.7 years, and 23 years in the symptomatic intraspinal lipoma group. Patients with lipomyelomeningoceles ranged in age from 1 day to 18 years, with the majority being younger than 2 years. After an average follow-up of 8 months all patients showed improvement in motor strength following operative intervention. Greater improvements in sensory, bladder, and pain scores were associated with filum terminale lipomas. The least improvements in these categories were seen in the lipomyelomeningocele group. Motor strength is the most likely deficit to improve following operative intervention. Lipomyelomeningoceles, intraspinal lipomas, and filum termniale lipomas have different clinical outcomes following operative intervention.

Authors
Bulsara, KR; Zomorodi, AR; Villavicencio, AT; Fuchs, H; George, TM
MLA Citation
Bulsara, KR, Zomorodi, AR, Villavicencio, AT, Fuchs, H, and George, TM. "Clinical outcome differences for lipomyelomeningoceles, intraspinal lipomas, and lipomas of the filum terminale." Neurosurg Rev 24.4 (December 2001): 192-194.
PMID
11778825
Source
pubmed
Published In
Neurosurgical Review
Volume
24
Issue
4
Publish Date
2001
Start Page
192
End Page
194

Acute abdominal symptoms and signs in children and young adults with spina bifida: ten years' experience.

BACKGROUND/PURPOSE: Diagnosis and management of the acute abdomen in patients with spina bifida (SB) can be problematic. There are at least 4 clinical factors that can predispose to the development of acute abdominal symptoms and signs, and patients with a thoracic level lesion can have a partially insensate abdomen. The authors analyzed their accumulated experience to determine the annual incidence of acute abdominal signs and symptoms in children and young adults with spina bifida, the differential diagnosis, the operative management, and the outcome. The pertinent literature was reviewed. METHODS: Cases were ascertained during a 10-year period at 1 institution and reviewed retrospectively. RESULTS: Twenty-two episodes of acute abdominal symptoms and signs in 19 children and young adults with SB were ascertained over 10 years at 1 institution, for an annual incidence of 0.74%. More patients had a thoracic level lesion (n = 12; 60%) than in the clinic population as a whole (27%; P =.04), but the gender distribution was similar (58% girls), as was the prevalence of ventriculoperitoneal shunts (VPS; 95%). The median age was 13 years (range, 1 year to 26 years). Hospitalization was necessary for 19 (86%) of the 22 episodes. The duration of symptoms before diagnosis was a median of 3 days (range, 1 to 14 days). Most patients (82%) presented with abdominal pain. Fever was present in 27%, shock in 23%, and peritoneal signs in 23%. There were 14 different final diagnoses, 10 (71%) of which were associated with a predisposing factor. Of the 22 episodes, 18 (82%) could be attributed to an underlying factor: (1) neurogenic bladder (9; 41%); (2) neurogenic bowel (3; 14%); (3) VPS (4; 18%); (4) complications from previous surgery (2; 9%). Thirteen patients (59%) underwent a total of 20 surgical procedures of 12 different kinds. Despite awareness of the complexities involved, 3 patients (14%) died: 1 from complications resulting from bladder perforation; 1 from urosepsis and shock; and 1 from peritonitis caused by VPS infection. CONCLUSION: The differential diagnosis of the acute abdomen in patients with SB is broad, conditions requiring surgery are frequently diagnosed, and the mortality rate is substantial, despite aggressive management.

Authors
Worley, G; Wiener, JS; George, TM; Fuchs, HE; Mackey, JF; Fitch, RD; Oldham, KT
MLA Citation
Worley, G, Wiener, JS, George, TM, Fuchs, HE, Mackey, JF, Fitch, RD, and Oldham, KT. "Acute abdominal symptoms and signs in children and young adults with spina bifida: ten years' experience." J Pediatr Surg 36.9 (September 2001): 1381-1386.
PMID
11528610
Source
pubmed
Published In
Journal of Pediatric Surgery
Volume
36
Issue
9
Publish Date
2001
Start Page
1381
End Page
1386
DOI
10.1053/jpsu.2001.26375

Pathology of the normal versus the tethered filum terminale.

Authors
Cummings, TJ; Bulsara, KR; McLendon, RE; Fuchs, HE; George, TM
MLA Citation
Cummings, TJ, Bulsara, KR, McLendon, RE, Fuchs, HE, and George, TM. "Pathology of the normal versus the tethered filum terminale." May 2001.
Source
wos-lite
Published In
Journal of Neuropathology and Experimental Neurology
Volume
60
Issue
5
Publish Date
2001
Start Page
553
End Page
553

Pathology of the filum terminale in the tethered spinal cord syndrome

Authors
Cummings, TJ; Fuchs, HE; George, TM
MLA Citation
Cummings, TJ, Fuchs, HE, and George, TM. "Pathology of the filum terminale in the tethered spinal cord syndrome." January 2001.
Source
wos-lite
Published In
Modern Pathology
Volume
14
Issue
1
Publish Date
2001
Start Page
6P
End Page
6P

Pathology of the filum terminale in the tethered spinal cord syndrome

Authors
Cummings, TJ; Fuchs, HE; George, TM
MLA Citation
Cummings, TJ, Fuchs, HE, and George, TM. "Pathology of the filum terminale in the tethered spinal cord syndrome." January 2001.
Source
wos-lite
Published In
Laboratory Investigation
Volume
81
Issue
1
Publish Date
2001
Start Page
6P
End Page
6P

Diagnostic markers in paediatric medulloblastoma: a Paediatric Oncology Group Study.

AIMS: We have reviewed immunohistochemically 17 paediatric medulloblastomas in order to determine if correlations exist that might be useful in subclassifying these tumours. METHODS AND RESULTS: The patient group included 11 children who had died (mean survival 13 months) and six still alive (followed for up to 10 years). Ten tumours were diffuse and six were nodular (one biopsy had only perivascular tumour). Of the 10 diffuse tumours, three were desmoplastic: of the six nodular tumours, all six were desmoplastic. All 17 tumours were synaptophysin-reactive: three nodular tumours were glial fibrillary acidic protein (GFAP)-reactive in the nodules (two of three S 100-reactive tumours were also GFAP-reactive). MIB-1 labelling indices (LI) ranged from 5 to 80%. Six tumours exhibited at least 1% LI against Tp53 (Mab D07 and/or Mab 1801). Eight cases were 100% bcl2-reactive with nine cases having an LI <80% ('low labelling'). All nine 'low labelling' bcl2 cases were TP53 non-reactive; all six Tp53-reactive cases were bcl2 100% reactive. Six of 10 patients with diffuse medulloblastomas survived 18 months or less while four of 10 are alive up to 10 years. In contrast, five of six patients with nodular neoplasms died within 48 months of diagnosis with one patient followed up for less than 1 year. CONCLUSIONS: Immunohistochemistry is a useful adjunct in characterizing subsets of paediatric medulloblastomas and confirms that larger co-operative studies may be fruitful in identifying a prognostic utility of a combined histochemical/immunohistochemical analysis on these tumours.

Authors
McLendon, RE; Friedman, HS; Fuchs, HE; Kun, LE; Bigner, SH
MLA Citation
McLendon, RE, Friedman, HS, Fuchs, HE, Kun, LE, and Bigner, SH. "Diagnostic markers in paediatric medulloblastoma: a Paediatric Oncology Group Study." Histopathology 34.2 (February 1999): 154-162.
PMID
10064395
Source
pubmed
Published In
Histopathology
Volume
34
Issue
2
Publish Date
1999
Start Page
154
End Page
162

Intrathecal busulfan treatment of human neoplastic meningitis in athymic nude rats.

The current study was designed to evaluate the toxicity and activity of Spartaject Busulfan, a microcrystalline preparation of busulfan, following its intrathecal administration into a nude rat model of human neoplastic meningitis. Animals were treated through permanent indwelling subarachnoid catheters. Human glioma D-456 MG growing in the subarachnoid space was treated with 8.1 micromol of intrathecal Spartaject Busulfan. Single-dose therapy was also subsequently compared with 4 doses of 8.1 and 2.0 micromol busulfan, respectively, against D-456 MG neoplastic meningitis. Additional experiments evaluated a saline control versus 8.1 micromol x 1, 6.2 micromol x 4 and 4.1 micromol x 4, respectively, against D-456 MG. A single dose of 8.1 micromol of intrathecal Spartaject Busulfan resulted in an increase in median survival of 61.7% compared with the saline control. In experiment 2, all busulfan treatments showed increases in median survival of 142.8% (8.1 micromol x 1), 52.3% (2.0 micromol x 4), and 23% (8.1 micromol x 4) (p < 0.001 for all groups) compared with the saline control. These results suggest that a narrow therapeutic dose range for both toxicity and activity has been defined for intrathecal busulfan in the treatment of human neoplastic meningitis in athymic nude rats. Although busulfan has only limited activity against solid tumors, the high doses achievable in the CSF following intrathecal administration coupled with the steep dose-response relationships of alkylating agents, provide rationale for further evaluation of this agent.

Authors
Archer, GE; Sampson, JH; McLendon, RE; Friedman, AH; Colvin, OM; Rose, M; Sands, H; McCullough, W; Fuchs, HE; Bigner, DD; Friedman, HS
MLA Citation
Archer, GE, Sampson, JH, McLendon, RE, Friedman, AH, Colvin, OM, Rose, M, Sands, H, McCullough, W, Fuchs, HE, Bigner, DD, and Friedman, HS. "Intrathecal busulfan treatment of human neoplastic meningitis in athymic nude rats." J Neurooncol 44.3 (1999): 233-241.
PMID
10720203
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
44
Issue
3
Publish Date
1999
Start Page
233
End Page
241

Analysis of DNA mismatch repair proteins in human medulloblastoma.

During replication, the primary function of the eukaryotic DNA mismatch repair (MMR) system is to recognize and correct mismatched base pairs within the DNA helix. Deficiencies in MMR have been reported previously in cases of hereditary nonpolyposis colorectal cancer and sporadic tumors occurring in a variety of tissues including gliomas. Furthermore, recent evidence indicates that the MMR system may be involved in mediating therapeutic sensitivity to alkylating agents. In this study, 22 neoplastic tissue samples from 22 patients who underwent surgical resection for medulloblastoma, a common cerebellar tumor of childhood, were assayed for the presence or absence of MMR polypeptides using Western blot and immunohistochemical techniques. Results from these experiments indicate that the MMR system is not commonly deficient in medulloblastoma.

Authors
Lee, SE; Johnson, SP; Hale, LP; Li, J; Bullock, N; Fuchs, H; Friedman, A; McLendon, R; Bigner, DD; Modrich, P; Friedman, HS
MLA Citation
Lee, SE, Johnson, SP, Hale, LP, Li, J, Bullock, N, Fuchs, H, Friedman, A, McLendon, R, Bigner, DD, Modrich, P, and Friedman, HS. "Analysis of DNA mismatch repair proteins in human medulloblastoma." Clin Cancer Res 4.6 (June 1998): 1415-1419.
PMID
9626457
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
4
Issue
6
Publish Date
1998
Start Page
1415
End Page
1419

Phase II study of carboplatin (CBDCA) in progressive low-grade gliomas.

In this study, the authors sought to investigate the response rate and toxicity of carboplatin in patients with progressive low-grade glioma (LGG). Thirty-two patients with progressive LGG were treated with carboplatin at a dosage of 560 mg/m(2). Treatment was given at 4-week intervals and continued until the disease progressed, unacceptable toxicity supervened, or for 12 additional courses after achieving maximal response. Patients with stable disease were treated with a total of 12 cycles. All patients were treated as outpatients. Patients were evaluated for response to treatment and toxicity. All patients received a minimum of two cycles of carboplatin, and were examined for response. A partial response was achieved in nine patients (28%) and a minimal response in two (6%), for an overall response rate of 34% (11 of 32 patients). Eighteen patients (56%) had stable disease. A partial response was achieved in the nine patients after a median of six cycles (range 4-11 cycles), a minimal response was achieved in the two patients after five cycles. Glioma progression was noted in three patients after three, five, and five cycles, respectively. The 11 patients in whom some response was achieved had either an optic pathway tumor or a juvenile pilocytic astrocytoma. Twenty-six of the 32 patients had those characteristics, making the response rate in that group 42% (11 of 26 patients). Thirty-two patients received a total of 387 cycles of chemotherapy. Hematological toxicity was moderate. Twenty-one patients developed thrombocytopenia (platelet count < 50,000/microl); three patients required one platelet transfusion each. Nine patients developed neutropenia (absolute neutrophil count < 500/microl); one developed fever and required administration of antibiotic agents. One dose adjustment in each of the patients prevented further thrombocytopenia and neutropenia. Two patients with stable disease died of respiratory complications. One patient developed Grade III ototoxicity after receiving five cycles, one patient developed hypersensitivity to carboplatin, and none developed nephrotoxicity. Carboplatin given at a dosage of 560 mg/m(2) every 4 weeks has activity in patients with progressive LGG. This drug regimen is relatively simple and well tolerated. Further investigation and longer follow-up study are warranted.

Authors
Moghrabi, A; Friedman, HS; Ashley, DM; Bottom, KS; Kerby, T; Stewart, E; Bruggers, C; Provenzale, JM; Champagne, M; Hershon, L; Watral, M; Ryan, J; Rasheed, K; Lovell, S; Korones, D; Fuchs, H; George, T; McLendon, RE; Friedman, AH; Buckley, E; Longee, DC
MLA Citation
Moghrabi, A, Friedman, HS, Ashley, DM, Bottom, KS, Kerby, T, Stewart, E, Bruggers, C, Provenzale, JM, Champagne, M, Hershon, L, Watral, M, Ryan, J, Rasheed, K, Lovell, S, Korones, D, Fuchs, H, George, T, McLendon, RE, Friedman, AH, Buckley, E, and Longee, DC. "Phase II study of carboplatin (CBDCA) in progressive low-grade gliomas." Neurosurgical focus 4.4 (April 1998): e3-.
PMID
17168503
Source
epmc
Published In
Neurosurgical focus
Volume
4
Issue
4
Publish Date
1998
Start Page
e3
DOI
10.3171/foc.1998.4.4.6

Activity of high-dose cyclophosphamide in the treatment of childhood malignant gliomas.

Seventeen patients less than or equal to 20 years of age with newly diagnosed (n = 10) or recurrent (n = 7) malignant gliomas (anaplastic astrocytoma and glioblastoma multiforme) were treated with cyclophosphamide in association with hematopoietic cytokines (GM-CSF or G-CSF). Cyclophosphamide was given at a dose of 2 g/m2 daily for 2 days at 4-week intervals. Toxicity consisted of grade IV neutropenia and thrombocytopenia in 95% and 48% of cycles, respectively. There were no cyclophosphamide-related cardiac, pulmonary, or urothelial toxicities observed. Four of 10 patients with newly diagnosed disease demonstrated responses (three complete and one partial responses; one CR was only of 2 months duration). None of the seven patients with recurrent tumors demonstrated a response. We conclude that high-dose cyclophosphamide warrants further evaluation in children with newly diagnosed malignant glioma.

Authors
McCowage, GB; Friedman, HS; Moghrabi, A; Kerby, T; Ferrell, L; Stewart, E; Duncan-Brown, M; Fuchs, HE; Tien, R; McLendon, RE; Meier, L; Kurtzberg, J; Ashley, D; Colvin, OM; Longee, DC
MLA Citation
McCowage, GB, Friedman, HS, Moghrabi, A, Kerby, T, Ferrell, L, Stewart, E, Duncan-Brown, M, Fuchs, HE, Tien, R, McLendon, RE, Meier, L, Kurtzberg, J, Ashley, D, Colvin, OM, and Longee, DC. "Activity of high-dose cyclophosphamide in the treatment of childhood malignant gliomas." Med Pediatr Oncol 30.2 (February 1998): 75-80.
PMID
9403013
Source
pubmed
Published In
Pediatric Blood and Cancer
Volume
30
Issue
2
Publish Date
1998
Start Page
75
End Page
80

Solitary fibrous tumor of the meninges occurring after irradiation of a mixed germ cell tumor of the pineal gland.

Twenty-nine months after surgery, irradiation, and systemic chemotherapy for a pineal mixed germ cell tumor, an 11-year-old Caucasian male developed a 3 cm dural based nodule in the occipital lobe that proved to be a solitary fibrous tumor by immunohistochemical and ultrastructural examination. Differential diagnosis included fibrous meningioma, neurofibroma, Schwannoma, cranial fasciitis of infancy, and solitary fibrous tumor. A Masson trichrome stain revealed a prominent collagenous stroma and reticulin staining exhibited strong pericellular positivity. Immunohistochemical staining demonstrated diffuse vimentin and focal CD34 positivity of tumor cells. Ultrastructural examination revealed fibroblastic differentiation. These features are consistent with solitary fibrous tumor. Although we favor a radiation-induced origin for the neoplasm, alternative explanations for the tumor's origin include cerebrospinal fluid spread from the original germ cell tumor or a de novo neoplasm.

Authors
Slavik, T; Bentley, RC; Gray, L; Fuchs, HE; McLendon, RE
MLA Citation
Slavik, T, Bentley, RC, Gray, L, Fuchs, HE, and McLendon, RE. "Solitary fibrous tumor of the meninges occurring after irradiation of a mixed germ cell tumor of the pineal gland." Clin Neuropathol 17.1 (January 1998): 55-60.
PMID
9496542
Source
pubmed
Published In
Clinical neuropathology
Volume
17
Issue
1
Publish Date
1998
Start Page
55
End Page
60

Characterization of a spontaneous murine astrocytoma and abrogation of its tumorigenicity by cytokine secretion.

OBJECTIVE: The promise of immunotherapies developed against brain tumors in animal models has not been realized in human clinical trials. This may be because of the routine use of rodent tumors artificially induced by chemicals or viruses that do not accurately portray the intrinsic qualities of spontaneously arising human tumors and that often fail to incorporate the role of immunosuppressants, such as transforming growth factor-beta, that are secreted by human gliomas. From an astrocytoma that arose spontaneously in inbred VM/Dk mice, we have characterized a highly tumorigenic spontaneous murine astrocytoma cell line (SMA-560) that retains features of glial differentiation and naturally produces high levels of biologically active transforming growth factor-beta. We have used this model to determine whether cytokine production by tumor cells will inhibit intracerebral astrocytoma growth. METHODS: Packaging cell lines producing replication-incompetent retroviral vectors were used to transfect the SMA-560 cell line in vitro with the genes encoding the murine cytokines interleukin (IL)-2, IL-3, IL-4, IL-6, tumor necrosis factor-alpha, gamma-interferon, or granulocyte-macrophage colony-stimulating factor or the costimulatory molecule B7.1 (CD80). RESULTS: Mice challenged intracerebrally with 5000 untransfected SMA-560 cells all succumbed to tumor within 30 days, with a median survival of 25 days. In contrast, mice challenged with SMA-560 cells producing IL-2, IL-4, or tumor necrosis factor-alpha each had a more than 400% increase in median survival (P < 0.0001). In these groups, 78.3% (18 of 23 mice), 66.7% (10 of 15 mice), and 60% (6 of 10 mice) of the mice, respectively, remained alive without evidence of tumor for longer than 100 days after the initial tumor challenge. All other cytokines tested and the expression of B7.1 failed to result in an increase in median survival. CONCLUSION: Using a spontaneous astrocytoma model in an inbred mouse strain, we have shown that cytokine production by glial tumors can abrogate their tumorigenicity in vivo despite production of transforming growth factor-beta. These results predict that approaches directed at cytokine production within intracerebral astrocytomas may be efficacious in human trials and that the "immunological privilege" of the brain may not be absolute under such conditions.

Authors
Sampson, JH; Ashley, DM; Archer, GE; Fuchs, HE; Dranoff, G; Hale, LP; Bigner, DD
MLA Citation
Sampson, JH, Ashley, DM, Archer, GE, Fuchs, HE, Dranoff, G, Hale, LP, and Bigner, DD. "Characterization of a spontaneous murine astrocytoma and abrogation of its tumorigenicity by cytokine secretion." Neurosurgery 41.6 (December 1997): 1365-1372.
PMID
9402588
Source
pubmed
Published In
Neurosurgery
Volume
41
Issue
6
Publish Date
1997
Start Page
1365
End Page
1372

Chromosomal characteristics of childhood brain tumors.

In the present cytogenetic analysis of 116 pediatric brain tumors, chromosomal abnormalities were demonstrated in 44 cases, 48 cases revealed only 46,XX or 46,XY cells, and 24 cases were nonproductive. In contrast to studies of adult brain tumors in which isolated loss of one X or the Y chromosome is often encountered, 45,X,-X and 45,X-Y stemlines or sidelines were not observed in this series of childhood tumors. Among the 17 medulloblastomas with cytogenetic abnormalities, chromosome 1 was most frequently affected by structural deviations; the most prevalent specific alteration (7 of 17 tumors) was loss of 17p, through i(17)(q10) or unbalanced translocation. The majority of low grade astrocytomas had normal stemlines, although one pilocytic astrocytoma and one cerebellar astrocytoma had frequent telomeric associations and a second pilocytic astrocytoma had a clone with trisomy 11. Thirteen of 19 high-grade and recurrent astrocytic tumors had abnormal stemlines that were approximately equally divided among cases with chromosomal counts in the near-diploid, hyperdiploid, and near-triploid-tetraploid ranges. Although no consistent abnormalities were observed, subsets of cases had structural abnormalities of chromosome 3, 7q, 9q, or 17p. The cases of childhood brain tumors described here demonstrate that 45,X,-X, and 45,X,-Y stemlines or sidelines are rare in these tumors and confirm frequent loss of 17p in medulloblastomas. High-grade astrocytic tumors in children frequently have abnormal stemlines, often in the hyperdiploid and polyploid ranges, and they differ from high-grade gliomas in the adult by lacking consistent numerical and structural deviations.

Authors
Bigner, SH; McLendon, RE; Fuchs, H; McKeever, PE; Friedman, HS
MLA Citation
Bigner, SH, McLendon, RE, Fuchs, H, McKeever, PE, and Friedman, HS. "Chromosomal characteristics of childhood brain tumors." Cancer Genet Cytogenet 97.2 (September 1997): 125-134.
PMID
9283596
Source
pubmed
Published In
Cancer Genetics and Cytogenetics
Volume
97
Issue
2
Publish Date
1997
Start Page
125
End Page
134

Chronic CSF leak into the peritoneal cavity shown by radionuclide cisternography. Successful treatment with an epidural blood patch.

Authors
Ashley, DM; Coleman, RE; Fuchs, H; Dear, G; Ginsberg, B; Zalduondo, FM; Friedman, HS; Longee, D
MLA Citation
Ashley, DM, Coleman, RE, Fuchs, H, Dear, G, Ginsberg, B, Zalduondo, FM, Friedman, HS, and Longee, D. "Chronic CSF leak into the peritoneal cavity shown by radionuclide cisternography. Successful treatment with an epidural blood patch." Clin Nucl Med 22.6 (June 1997): 390-392.
PMID
9193811
Source
pubmed
Published In
Clinical Nuclear Medicine
Volume
22
Issue
6
Publish Date
1997
Start Page
390
End Page
392

False positive images in the follow-up of patients with brain tumors.

In recent years, major advances in the diagnosis and treatment of patients with brain tumors have been seen. Today, evaluation of the central nervous system almost always includes magnetic resonance imaging (MRI). The appearance of a new lesion on the MRI scan of a patient previously treated for a central nervous system (CNS) tumor raises concern for recurrent disease with the need for selection of new, potentially toxic therapy. However, the sensitivity of MRI may allow demonstration of new lesions which are not due to tumor. We now report three patients with medulloblastoma who demonstrated new enhancing lesions on MRI following treatment of their tumors with surgery (3 patients), chemotherapy (2 patients), and radiotherapy (2 patients). Two patients underwent resection of the lesion revealing gliosis. One patient had serial imaging that showed disappearance of the lesions. This suggests that not all new enhancing lesions in previously treated brain tumor patients represent tumor. Histologic proof of a suspicious lesion should be demonstrated prior to initiation of new therapy.

Authors
Moghrabi, A; Tien, R; Fuchs, H; Longee, D; McLendon, R; Friedman, HS
MLA Citation
Moghrabi, A, Tien, R, Fuchs, H, Longee, D, McLendon, R, and Friedman, HS. "False positive images in the follow-up of patients with brain tumors." Med Pediatr Oncol 28.2 (February 1997): 127-131.
PMID
8986148
Source
pubmed
Published In
Pediatric Blood and Cancer
Volume
28
Issue
2
Publish Date
1997
Start Page
127
End Page
131

Subcutaneous vaccination with irradiated, cytokine-producing tumor cells stimulates CD8+ cell-mediated immunity against tumors located in the "immunologically privileged" central nervous system.

Vaccination with cytokine-producing tumor cells generates potent immune responses against tumors outside the central nervous system (CNS). The CNS, however, is a barrier to allograft and xenograft rejection, and established tumors within the CNS have failed to respond to other forms of systemic immunotherapy. To determine what barriers the "immunologically privileged" CNS would pose to cytokine-assisted tumor vaccines and what cytokines would be most efficacious against tumors within the CNS, we irradiated B16 murine melanoma cells producing murine interleukin 2 (IL-2), IL-3, IL-4, IL-6, gamma-interferon, or granulocyte-macrophage colony stimulating factor (GM-CSF) and used these cells as subcutaneous vaccines against tumors within the brain. Under conditions where untransfected B16 cells had no effect, cells producing IL-3, IL-6, or GM-CSF increased the survival of mice challenged with viable B16 cells in the brain. Vaccination with B16 cells producing IL-4 or gamma-interferon had no effect, and vaccination with B16 cells producing IL-2 decreased survival time. GM-CSF-producing vaccines were also able to increase survival in mice with pre-established tumors. The response elicited by GM-CSF-producing vaccines was found to be specific to tumor type and to be abrogated by depletion of CD8+ cells. Unlike the immunity generated against subcutaneous tumors by GM-CSF, however, the effector responses generated against tumors in the CNS were not dependent on CD4+ cells. These data suggest that cytokine-producing tumor cells are very potent stimulators of immunity against tumors within the CNS, but effector responses in the CNS may be different from those obtained against subcutaneous tumors.

Authors
Sampson, JH; Archer, GE; Ashley, DM; Fuchs, HE; Hale, LP; Dranoff, G; Bigner, DD
MLA Citation
Sampson, JH, Archer, GE, Ashley, DM, Fuchs, HE, Hale, LP, Dranoff, G, and Bigner, DD. "Subcutaneous vaccination with irradiated, cytokine-producing tumor cells stimulates CD8+ cell-mediated immunity against tumors located in the "immunologically privileged" central nervous system." Proc Natl Acad Sci U S A 93.19 (September 17, 1996): 10399-10404.
PMID
8816812
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
93
Issue
19
Publish Date
1996
Start Page
10399
End Page
10404

Successful treatment of childhood pilocytic astrocytomas metastatic to the leptomeninges with high-dose cyclophosphamide.

Leptomeningeal dissemination of childhood pilocytic astrocytoma (PA) is a rare event with little information available regarding therapy. We report here four children with disseminated PA whom we treated with high doses of cyclophosphamide with clinical benefit. The patients were aged 2.5 to 8 years. Three patients presented with PA localized in the posterior fossa, initially treated with surgical resection (n = 3) and radiotherapy (n = 1). Leptomeningeal dissemination occurred at 32, 44, and 8 months from diagnosis, respectively. The fourth patient presented with an optic pathway tumor with leptomeningeal dissemination at diagnosis. At commencement of cyclophosphamide therapy, disease was present in the subarachnoid space (intracranial, n = 2; spinal, n = 4), cerebral ventricles (n = 2), and primary site (n = 3). Histology was identical at diagnosis and recurrence in the two biopsied cases and cerebrospinal fluid was negative in all cases. Treatment was with cyclophosphamide 4-5 g/m2/cycle given every 4 weeks for a total of two cycles (n = 1) and four cycles (n = 3). One patient achieved disease stabilization (duration 27 months at the time of publication) and three patients experienced significant reductions in tumor burden. Subsequent intrathecal therapy was administered to two patients. Two patients developed disease progression at 10 and 9 months from cessation of chemotherapy. The one re-treated patient responded to further, lower dose, cyclophosphamide. This is the first report of the use of high dose cyclophosphamide for disseminated PA. The recurrence of disease in two cases with a further response to lower dose cyclophosphamide has implications for the optimal duration of therapy for these low grade, aggressive tumors.

Authors
McCowage, G; Tien, R; McLendon, R; Felsberg, G; Fuchs, H; Graham, ML; Kurtzberg, J; Moghrabi, A; Ferrell, L; Kerby, T; Duncan-Brown, M; Stewart, E; Robertson, PL; Colvin, OM; Golembe, B; Bigner, DD; Friedman, HS
MLA Citation
McCowage, G, Tien, R, McLendon, R, Felsberg, G, Fuchs, H, Graham, ML, Kurtzberg, J, Moghrabi, A, Ferrell, L, Kerby, T, Duncan-Brown, M, Stewart, E, Robertson, PL, Colvin, OM, Golembe, B, Bigner, DD, and Friedman, HS. "Successful treatment of childhood pilocytic astrocytomas metastatic to the leptomeninges with high-dose cyclophosphamide." Med Pediatr Oncol 27.1 (July 1996): 32-39.
PMID
8614389
Source
pubmed
Published In
Pediatric Blood and Cancer
Volume
27
Issue
1
Publish Date
1996
Start Page
32
End Page
39
DOI
10.1002/(SICI)1096-911X(199607)27:1<32::AID-MPO7>3.0.CO;2-V

Torticollis acquired in late infancy due to a cerebellar gangliocytoma.

Torticollis in infancy is a common disorder and is typically benign and self-limiting. However, in some instances it is the presentation of serious disease. A critical distinction is whether the condition is congenital or acquired. We present a case of acquired late infantile torticollis caused by a cerebellar gangliocytoma that underscores the importance of making this determination prior to initiating a treatment plan. A gangliocytoma presenting with torticollis has not been previously described.

Authors
Caress, JB; Nohria, V; Fuchs, H; Boustany, RM
MLA Citation
Caress, JB, Nohria, V, Fuchs, H, and Boustany, RM. "Torticollis acquired in late infancy due to a cerebellar gangliocytoma." Int J Pediatr Otorhinolaryngol 36.1 (June 1996): 39-44.
PMID
8803690
Source
pubmed
Published In
International Journal of Pediatric Otorhinolaryngology
Volume
36
Issue
1
Publish Date
1996
Start Page
39
End Page
44

Treatment of patients with pineoblastoma with high dose cyclophosphamide.

The outcome for patients with pineoblastoma has historically been very poor, with most patients dying of disseminated disease despite irradiation. Furthermore, the low incidence of this tumor has hindered progress toward defining better treatment strategies. Here we report the activity and toxicity of cyclophosphamide administered as a single agent at a dose schedule of 2 g/m2/day for 2 successive days at monthly intervals for a maximum of four courses. Eight patients were evaluated, six newly diagnosed and two recurrent. Amongst the six newly diagnosed patients, there were three patients demonstrating partial responses, and three had stable disease throughout the cyclophosphamide treatment period. All six patients are alive and disease free after further therapy. One patient with recurrent disease demonstrated tumor progression on cyclophosphamide, and the other had stable disease throughout the cyclophosphamide treatment period. Both patients subsequently died of progressive disease. The major toxicity of high dose cyclophosphamide was hematopoietic, with one patient requiring a dose reduction after three courses due to prolonged thrombocytopenia. One patient was also withdrawn from treatment with cyclophosphamide due to impaired pulmonary function. This study demonstrates the activity of high dose cyclophosphamide in the treatment of pineoblastoma and may serve as basis for the design of future studies of this tumor.

Authors
Ashley, DM; Longee, D; Tien, R; Fuchs, H; Graham, ML; Kurtzberg, J; Casey, J; Olson, J; Meier, L; Ferrell, L; Kerby, T; Duncan-Brown, M; Stewart, E; Colvin, OM; Pipas, JM; McCowage, G; McLendon, R; Bigner, DD; Friedman, HS
MLA Citation
Ashley, DM, Longee, D, Tien, R, Fuchs, H, Graham, ML, Kurtzberg, J, Casey, J, Olson, J, Meier, L, Ferrell, L, Kerby, T, Duncan-Brown, M, Stewart, E, Colvin, OM, Pipas, JM, McCowage, G, McLendon, R, Bigner, DD, and Friedman, HS. "Treatment of patients with pineoblastoma with high dose cyclophosphamide." Med Pediatr Oncol 26.6 (June 1996): 387-392.
PMID
8614374
Source
pubmed
Published In
Pediatric Blood and Cancer
Volume
26
Issue
6
Publish Date
1996
Start Page
387
End Page
392
DOI
10.1002/(SICI)1096-911X(199606)26:6<387::AID-MPO3>3.0.CO;2-D

Microsatellite analysis of childhood brain tumors.

Loss of heterozygosity at specific chromosomal locations has been taken as evidence of a tumor suppressor gene located in that area. We performed a genomic allelotyping study on 46 childhood brain tumors of different histopathological types in order to identify and confirm common areas of deletion in different tumor types. Two hundred microsatellite DNA probes equally distributed over the 22 autosomes were applied, covering the genome in steps of approximately 25 cM. Our results confirm frequent loss of heterozygosity of chromosome arms 9q, 10q, 11p, 11q, 16q, and 22q in high-grade gliomas, medulloblastomas, and ependymomas. In addition, we found a new region of loss on chromosome segment 2p21-23 affected predominantly in high-grade gliomas and medulloblastomas.

Authors
Blaeker, H; Rasheed, BK; McLendon, RE; Friedman, HS; Batra, SK; Fuchs, HE; Bigner, SH
MLA Citation
Blaeker, H, Rasheed, BK, McLendon, RE, Friedman, HS, Batra, SK, Fuchs, HE, and Bigner, SH. "Microsatellite analysis of childhood brain tumors." Genes Chromosomes Cancer 15.1 (January 1996): 54-63.
PMID
8824726
Source
pubmed
Published In
Genes, Chromosomes and Cancer
Volume
15
Issue
1
Publish Date
1996
Start Page
54
End Page
63
DOI
10.1002/(SICI)1098-2264(199601)15:1<54::AID-GCC8>3.0.CO;2-3

Efficacy of compartmental administration of immunotoxin LMB-1 (B3-LysPE38) in a rat model of carcinomatous meningitis.

LMB-1 (B3-LysPE38) is an immunotoxin composed of the tumor-reactive monoclonal antibody B3 and a genetically engineered form of Pseudomonas exotoxin. Monoclonal antibody B3 reacts with a carbohydrate epitope that is found on a number of solid tumors (e.g., breast, ovarian, and lung carcinomas) that frequently invade the intrathecal space, causing neoplastic meningitis. The Pseudomonas exotoxin has been engineered to remove the binding domain to eliminate nonspecific binding. A model of human neoplastic meningitis using rats bearing the human epidermoid carcinoma A431 was used for therapeutic studies of immunotoxin LMB-1. Therapy was initiated 3 days after injection of the tumor cells, which was one third of the median survival time of untreated rats. A single intrathecal injection of 40 microgram increased median survival from 9 days with saline injection to 16 days (78%, P < 0.001), and a single dose of 200 microgram increased median survival to 25 days (188%, P < 0. 001). Three doses of 40 or 200 microgram given on days 3, 6, and 8 significantly increased the median survival of 9.5 days associated with saline injection to 40.5 days (326% increase) and 33.0 days (247% increase), respectively, with two long-term survivors (191-day survival) in each treatment group. LMB-1 had no therapeutic effect on the treatment of two B3 antigen-negative neoplastic meningitis models. Treatment of the antigen-positive A431 neoplastic meningitis with B3 alone or a nonspecific monoclonal, MOPC, coupled to the engineered Pseudomonas exotoxin produced no survival effects. Nontumor-bearing athymic rats showed no toxicity with a single dose of either 40 microgram or 200 microgram, or 3 doses of 40 microgram. However, when they were given three doses of 200 microgram, these rats showed weight loss and loss of neurological function, and two of eight animals died. These studies indicate that, in the range of the most therapeutically effective dosage, the immunotoxin LMB-1 is tolerated in the intrathecal space and should be considered for human intrathecal trials.

Authors
Bigner, DD; Archer, GE; McLendon, RE; Friedman, HS; Fuchs, HE; Pai, LH; Herndon, JE; Pastan, IH
MLA Citation
Bigner, DD, Archer, GE, McLendon, RE, Friedman, HS, Fuchs, HE, Pai, LH, Herndon, JE, and Pastan, IH. "Efficacy of compartmental administration of immunotoxin LMB-1 (B3-LysPE38) in a rat model of carcinomatous meningitis." Clin Cancer Res 1.12 (December 1995): 1545-1555.
PMID
9815955
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
1
Issue
12
Publish Date
1995
Start Page
1545
End Page
1555

MRI of papillary meningiomas in children.

We report two cases of papillary meningioma in children. The MRI appearance of this special type of meningioma is described for the first time. Both lesions were dura based and associated with cystic components. We review the literature pertaining to this type of meningioma and discuss the differential diagnosis of the MRI appearance. Because this is a malignant type of meningioma, early diagnosis and surgical intervention are important in the management of patients.

Authors
Lirng, JF; Enterline, DS; Tien, RD; Fuchs, H; Friedman, HS; Ellington, KS; McLendon, RP
MLA Citation
Lirng, JF, Enterline, DS, Tien, RD, Fuchs, H, Friedman, HS, Ellington, KS, and McLendon, RP. "MRI of papillary meningiomas in children." Pediatr Radiol 25 Suppl 1 (November 1995): S9-13.
PMID
8577564
Source
pubmed
Published In
Pediatric Radiology
Volume
25 Suppl 1
Publish Date
1995
Start Page
S9
End Page
13

Intraarterial administration of melphalan for treatment of intracranial human glioma xenografts in athymic rats.

Malignant gliomas will affect 15,000-17,000 Americans each year and carry a dismal prognosis. Adjuvant chemotherapy is hampered by inadequate drug delivery, systemic toxicity, and a markedly variable biological sensitivity. Intraarterial (i.a.) therapy may enhance selectivity by improving tumor drug delivery and reducing systemic toxicity. Using melphalan given i.a., we studied the therapy of intracranial human glioma xenografts in male athymic nude rats (mean weight, 300 g) which were inoculated intracerebrally with D-54 MG and D-456 MG. On Days 6 and 7 (D-54 MG) or Days 9 and 10 (D-456 MG), rats randomized by body weight and treated with single-dose melphalan given i.a. at 0.5 or 0.75 mg produced significantly higher median survival (D-54 MG, Days 33 and 32; D-456 MG, Days 52 and 54, respectively) compared with i.a. saline (D-54 MG, Day 14, P < 0.001; D-456 MG, Day 24, P = 0.000) or melphalan given i.v. at 0.75 mg and 0.9 mg (D-54 MG only; Day 19, P < 0.001; Day 23, P < 0.001, respectively) and at 0.5 and 0.75 mg (D-456 MG only; Day 26 for both doses, P = 0.00). Although a dose-dependent increase in median survival (D-54 MG, 0.25 mg, Day 18; 0.5 mg, Day 28.5; 0.75 mg, Day 32.5) was observed with i.a. administered melphalan, no significant difference was apparent between 0.5 and 0.75 mg in either tumor model (D-54 MG, P = 0.15; D-456 MG, P = 0.37). Toxicity studies in nontumor-bearing athymic rats yielded a maximum tolerated dose of 0.8 mg for i.a. administered melphalan. This dosage was superior in spite of different xenograft permeabilities (apparent mean blood-to-tissue transport [K] values for alpha-aminoisobutyric acid, 5.8 for D-54 MG and 1.3 for D-456 MG). Pharmacokinetic experiments demonstrated a significant first pass advantage for i.a. (versus i.v.) melphalan. The short plasma half-life, marked antiglioma activity, and lack of requirement for metabolic activation indicate that i.a. melphalan holds considerable promise for human glioma therapy.

Authors
Kurpad, SN; Friedman, HS; Archer, GE; McLendon, RE; Petros, WM; Fuchs, HE; Guaspari, A; Bigner, DD
MLA Citation
Kurpad, SN, Friedman, HS, Archer, GE, McLendon, RE, Petros, WM, Fuchs, HE, Guaspari, A, and Bigner, DD. "Intraarterial administration of melphalan for treatment of intracranial human glioma xenografts in athymic rats." Cancer Res 55.17 (September 1, 1995): 3803-3809.
PMID
7641197
Source
pubmed
Published In
Cancer Research
Volume
55
Issue
17
Publish Date
1995
Start Page
3803
End Page
3809

Cyclophosphamide in combination with sargramostim for treatment of recurrent medulloblastoma.

Thirteen patients with recurrent medulloblastoma were treated with cyclophosphamide in association with Sargramostim. Cyclophosphamide was given at doses ranging between 1.0-2.5 g/m2 daily for two doses. Sargramostim was given at a fixed dose of 250 micrograms/m2 subcutaneously twice a day beginning 24 hours after the second cyclophosphamide dose and continuing through the leukocyte nadir until the ANC was more than 1,000 cells/microliters for two consecutive days. A total of 33 courses were given with toxicity consisting of grade 4 neutropenia in all courses and grade 3-4 thrombocytopenia in 10 of 13 patients. There were no deaths related to infection or bleeding. Four patients were taken off study because of prolonged myelosuppression. Three of these patients were at the 2.5 g/m2 level, and of these three, two developed lung toxicity (grades 2 and 4, respectively). One patient developed an allergic reaction following the first injection of Sargramostim and was also taken off study. Of 10 evaluable patients, there were 9 PR and 1 SD. We conclude that cyclophosphamide at a dose of 2.0 g/m2/day x 2 days q 4 weeks in association with Sargramostim demonstrates marked activity with acceptable toxicity in patients with recurrent medulloblastoma.

Authors
Moghrabi, A; Fuchs, H; Brown, M; Schold, SC; Graham, M; Kurtzberg, J; Tien, R; Felsberg, G; Lachance, DH; Colvin, OM
MLA Citation
Moghrabi, A, Fuchs, H, Brown, M, Schold, SC, Graham, M, Kurtzberg, J, Tien, R, Felsberg, G, Lachance, DH, and Colvin, OM. "Cyclophosphamide in combination with sargramostim for treatment of recurrent medulloblastoma." Med Pediatr Oncol 25.3 (September 1995): 190-196.
PMID
7623728
Source
pubmed
Published In
Pediatric Blood and Cancer
Volume
25
Issue
3
Publish Date
1995
Start Page
190
End Page
196

Chromosome 10 deletion mapping in human gliomas: a common deletion region in 10q25.

The high incidence of loss of chromosome 10 alleles in glioblastoma multiforme suggests the presence on this chromosome of a tumor suppressor gene that is important in glioma tumorigenesis and progression. Our initial deletion mapping studies using restriction fragment length polymorphism markers indicated a common deletion region in 10q24-qter. In an attempt to localize the deleted region further, we screened a panel of 117 gliomas for loss of heterozygosity for chromosome 10 loci using 10 microsatellite markers. Seventeen tumors showed partial loss of a copy of chromosome 10 and were further analysed using 28 additional microsatellite markers. Of these, 10 had terminal deletion in the q arm, three had deletions in both p and q arms, two contained interstitial deletion in 10q and two carried deletions in 10p. In the 15 tumors with deletions in 10q, the minimal overlapping deletion region was in distal 10q between markers D10S587 and D10S216. Loci D10S587 and D10S216 are approximately mapped to a 5 cM region in 10q25.1.

Authors
Rasheed, BK; McLendon, RE; Friedman, HS; Friedman, AH; Fuchs, HE; Bigner, DD; Bigner, SH
MLA Citation
Rasheed, BK, McLendon, RE, Friedman, HS, Friedman, AH, Fuchs, HE, Bigner, DD, and Bigner, SH. "Chromosome 10 deletion mapping in human gliomas: a common deletion region in 10q25." Oncogene 10.11 (June 1, 1995): 2243-2246.
PMID
7784070
Source
pubmed
Published In
Oncogene: Including Oncogene Reviews
Volume
10
Issue
11
Publish Date
1995
Start Page
2243
End Page
2246

SYNCHRONOUS EPENDYMO-GLIOMAS

Authors
MCLENDON, RE; FRIEDMAN, HS; LONGEE, DC; FUCHS, HE; HESSLER, RB
MLA Citation
MCLENDON, RE, FRIEDMAN, HS, LONGEE, DC, FUCHS, HE, and HESSLER, RB. "SYNCHRONOUS EPENDYMO-GLIOMAS." May 1995.
Source
wos-lite
Published In
Journal of Neuropathology and Experimental Neurology
Volume
54
Issue
3
Publish Date
1995
Start Page
422
End Page
422
DOI
10.1097/00005072-199505000-00062

Dose escalation trial of cyclophosphamide with Sargramostim in the treatment of central nervous system (CNS) neoplasms.

We conducted a dose escalation trial of cyclophosphamide plus Sargramostim in the therapy of patients with newly diagnosed or recurrent central nervous system tumors. Cyclophosphamide was administered at doses ranging between 1.0 and 2.5 g/m2 daily for two doses. Sargramostim was administered at a fixed dose of 250 micrograms/m2 subcutaneously twice a day beginning 24 hours after the second cyclophosphamide dose and continuing through the leukocyte nadir until the absolute neutrophil count (ANC) was > 1,000 cells/microliters for two consecutive days. The MTD for patients who had not received any prior chemotherapy and who had received either no radiotherapy or radiotherapy confined to the cranium was 2.0 g/m2 daily for two doses. The MTD for patients previously treated with chemotherapy or neuraxis radiotherapy was also 2.0 g/m2 daily for two doses. Responses were seen in patients with medulloblastoma (8/9), glioblastoma multiforme (2/13), germinoma (1/1), and pineoblastoma (1/2).

Authors
Lachance, DH; Oette, D; Schold, SC; Brown, M; Kurtzberg, J; Graham, ML; Tien, R; Felsberg, G; Colvin, OM; Moghrabi, A
MLA Citation
Lachance, DH, Oette, D, Schold, SC, Brown, M, Kurtzberg, J, Graham, ML, Tien, R, Felsberg, G, Colvin, OM, and Moghrabi, A. "Dose escalation trial of cyclophosphamide with Sargramostim in the treatment of central nervous system (CNS) neoplasms." Med Pediatr Oncol 24.4 (April 1995): 241-247.
PMID
7700169
Source
pubmed
Published In
Pediatric Blood and Cancer
Volume
24
Issue
4
Publish Date
1995
Start Page
241
End Page
247

Intrathecal administration of single-chain immunotoxin, LMB-7 [B3(Fv)-PE38], produces cures of carcinomatous meningitis in a rat model.

LMB-7 [B3(Fv)-PE38] is a single-chain immunotoxin constructed from the murine monoclonal antibody B3 and a truncated from of Pseudomonas exotoxin PE38. Antibody B3 recognizes a carbohydrate epitope found on solid tumors that frequently invade the intrathecal space and cause neoplastic meningitis. We tested the therapeutic value of intrathecally administered LMB-7 by using a model of human neoplastic meningitis in athymic rats. This model is representative of a clinical situation in that antibody B3 cross-reacts with a number of normal tissues that can be used to monitor potential systemic toxicity. Treatment was begun 3 days after A431 tumor implantation. Without treatment, the animals median survival was 10 days. Intrathecal administration of 10 micrograms of LMB-7 in 40 microliters on days 3, 5, and 7 produced 4 of 10 and 8 of 10 long-term survivors (> 170 days) in two experiments. Of the long-term survivors, 2 of 4 and 7 of 8 survivors had no microscopic evidence of tumor and were considered histologic cures. Lack of significant toxicity in the effective dose range and specificity make LMB-7 an excellent candidate for intrathecal treatment of neoplastic meningitis in humans.

Authors
Pastan, IH; Archer, GE; McLendon, RE; Friedman, HS; Fuchs, HE; Wang, QC; Pai, LH; Herndon, J; Bigner, DD
MLA Citation
Pastan, IH, Archer, GE, McLendon, RE, Friedman, HS, Fuchs, HE, Wang, QC, Pai, LH, Herndon, J, and Bigner, DD. "Intrathecal administration of single-chain immunotoxin, LMB-7 [B3(Fv)-PE38], produces cures of carcinomatous meningitis in a rat model." Proc Natl Acad Sci U S A 92.7 (March 28, 1995): 2765-2769.
PMID
7708720
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
92
Issue
7
Publish Date
1995
Start Page
2765
End Page
2769

Post-traumatic epidermoid cyst: CT appearance.

We report development of an intracranial epidermoid cyst 2 years after a depressed skull fracture. The epidermoid cyst is presumed to be the result of introduction of epidermal elements at the time of trauma. Post-traumatic intracranial epidermoid cysts are rare and appear to be less common than those occurring in the spine.

Authors
Lee, VS; Provenzale, JM; Fuchs, HE; Osumi, A; McLendon, RE
MLA Citation
Lee, VS, Provenzale, JM, Fuchs, HE, Osumi, A, and McLendon, RE. "Post-traumatic epidermoid cyst: CT appearance." J Comput Assist Tomogr 19.1 (January 1995): 153-155.
PMID
7822537
Source
pubmed
Published In
Journal of Computer Assisted Tomography
Volume
19
Issue
1
Publish Date
1995
Start Page
153
End Page
155

Prognostic implications of chromosome 17p deletions in human medulloblastomas.

DNA derived from medulloblastoma biopsies was analyzed to determine if deletions of the 17p region, mutations of the TP53 gene, or amplification of the c-myc, N-myc, EGFR (epidermal growth factor receptor), or MDM2 (murine double-minute-2) genes was indicative of a poor prognosis. Loss of heterozygosity for 17p, observed in 8/28 (29%) paired samples, was associated with a shortened survival period (p = 0.045 by the logrank test). TP53 mutations occurred in 2/46 (4.3%) tumor samples. c-myc Amplification was seen in 3/43 (6.9%) cases, while none of the tumors contained amplified N-myc, EGFR, or MDM2 genes. These results demonstrate that, while only rare medulloblastomas contain TP53 gene mutations or amplification of the c-myc gene, loss of heterozygosity on chromosome 17p is indicative of a significantly worse prognosis among patients with these tumors. Further, these results provide a strong impetus for a prospective analysis of loss of heterozygosity in a cooperative group setting, which would include tumor staging, a selection of treatment modalities, and multivariate analyses.

Authors
Batra, SK; McLendon, RE; Koo, JS; Castelino-Prabhu, S; Fuchs, HE; Krischer, JP; Friedman, HS; Bigner, DD; Bigner, SH
MLA Citation
Batra, SK, McLendon, RE, Koo, JS, Castelino-Prabhu, S, Fuchs, HE, Krischer, JP, Friedman, HS, Bigner, DD, and Bigner, SH. "Prognostic implications of chromosome 17p deletions in human medulloblastomas." J Neurooncol 24.1 (1995): 39-45.
PMID
8523074
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
24
Issue
1
Publish Date
1995
Start Page
39
End Page
45

Diagnosis and management of astrocytomas occurring in the posterior fossa

The posterior fossa is a common site of occurrence of astrocytic tumors in the pediatric population. The two distinct subgroups comprising these tumors are cerebellar astrocytomas and brainstem gliomas. The cerebellar astrocytoma commonly presents with signs and symptoms of increased intracranial pressure. These tumors are generally amenable to total surgical resection, and carry an excellent prognosis. Brainstem gliomas are a heterogeneous group of tumors of which the diffuse pontine glioma is the most common. These tumors are inevitably glioblastoma multiforme, and carry a dismal prognosis. In recent years, subgroups of brainstem tumors have been identified, which are more focal in nature, are of a more benign histology, and carry a better prognosis. These tumors may be amenable to surgical resection.

Authors
Fuchs, HE; McLone, DG
MLA Citation
Fuchs, HE, and McLone, DG. "Diagnosis and management of astrocytomas occurring in the posterior fossa." Neurosurgery Quarterly 5.3 (1995): 168-178.
Source
scival
Published In
Neurosurgery Quarterly
Volume
5
Issue
3
Publish Date
1995
Start Page
168
End Page
178

Intrathecal melphalan therapy of human neoplastic meningitis in athymic nude rats.

We report the activity and toxicity of intrathecal melphalan in the treatment of human neoplastic meningitis in the subarachnoid space of athymic nude rats. Animals received injections via chronic indwelling subarachnoid catheters with 5 x 10(5) or 5 x 10(6) TE-671 human rhabdomyosarcoma cells or 5 x 10(6) D-54 MG human glioma cells and were treated with melphalan on days 8, 5, or 5, respectively. Melphalan toxicity in nontumor-bearing rats was assessed at single doses of a 2.0, 3.0, 4.0, or 5.0 mM solution, with clinical and histological evidence of neurotoxicity observed at the 4.0 and 5.0 mM levels. Multiple-dose toxicity studies using a dosing schedule of twice a week for two weeks with a 0.25, 0.5, 0.75, 1.0, 1.5, or 2 mM solution revealed dose-dependent clinical and histological evidence for toxicity at all dosages. Treatment of TE-671 with a single dose of 2.0 mM intrathecal melphalan produced an increase in median survival of 442% compared with saline controls (P < 0.003). Comparison of a single dose of 1.0 or 2.0 mM melphalan with a multiple dose regimen at 0.25 or 0.5 mM melphalan in the treatment of TE-671 revealed increases in median survival of 50% for 1.0 mM, 57% for 2.0 mM, 79% for 0.5 mM, and 111% for 0.25 mM concentrations. Comparison of a single dose of 1 mM melphalan with multiple doses of 0.25 mM melphalan in the treatment of D-54 MG revealed an increase in median survival of 475+% for each of the regimens. Intrathecal melphalan may be an important new addition in the treatment of neoplastic meningitis and is currently being evaluated clinically in a Phase 1 trial.

Authors
Friedman, HS; Archer, GE; McLendon, RE; Schuster, JM; Colvin, OM; Guaspari, A; Blum, R; Savina, PA; Fuchs, HE; Bigner, DD
MLA Citation
Friedman, HS, Archer, GE, McLendon, RE, Schuster, JM, Colvin, OM, Guaspari, A, Blum, R, Savina, PA, Fuchs, HE, and Bigner, DD. "Intrathecal melphalan therapy of human neoplastic meningitis in athymic nude rats." Cancer Res 54.17 (September 1, 1994): 4710-4714.
PMID
8062269
Source
pubmed
Published In
Cancer Research
Volume
54
Issue
17
Publish Date
1994
Start Page
4710
End Page
4714

Surgery, hyperfractionated craniospinal irradiation, and adjuvant chemotherapy in the management of supratentorial embryonal neuroepithelial neoplasms in children.

Supratentorial embryonal neuroepithelial tumors are undifferentiated neoplasms. We have used this term in preference to the controversial classification primitive neuroectodermal tumors (PNET). These lesions in children are malignant neoplasms which are usually fatal within 2 years of diagnosis in spite of therapy with surgery, radiotherapy, and chemotherapy. We have adopted an aggressive approach to the treatment of these tumors with surgical resection, hyperfractionated craniospinal irradiation of 30.6-43.9 Gy followed by a tumor boost to a total dose of 50-63.7 Gy, and adjuvant chemotherapy with cyclophosphamide, vincristine, and cis-platinum. We have treated five children, aged 4-18 years, with this approach. In contrast to the results reported in the literature, four children are alive without evidence of tumor from 4.3 to 8.0 years following diagnosis. One has suffered a tumor relapse at 2.3 years following diagnosis but remains alive. The basis of our therapeutic strategy for childhood supratentorial embryonal neuroepithelial tumors and the implications of our clinical results are discussed.

Authors
Halperin, EC; Friedman, HS; Schold, SC; Fuchs, HE; Oakes, WJ; Hockenberger, B; Burger, PC
MLA Citation
Halperin, EC, Friedman, HS, Schold, SC, Fuchs, HE, Oakes, WJ, Hockenberger, B, and Burger, PC. "Surgery, hyperfractionated craniospinal irradiation, and adjuvant chemotherapy in the management of supratentorial embryonal neuroepithelial neoplasms in children." Surg Neurol 40.4 (October 1993): 278-283.
PMID
8211637
Source
pubmed
Published In
World Neurosurgery
Volume
40
Issue
4
Publish Date
1993
Start Page
278
End Page
283

Intraarterial therapy of human glioma xenografts in athymic rats using 4-hydroperoxycyclophosphamide.

The addition of chemotherapy, notably using nitrosoureas, in the treatment of patients with glioblastoma multiforme has resulted in only modest improvements in long-term patient survival over the use of surgical intervention and irradiation alone. Intraarterial (i.a.) chemotherapy offers the potential benefit of increasing tumor drug delivery because of first-pass drug uptake, while minimizing systemic drug levels and toxicity. We have now investigated the i.a. therapy of intracerebral human glioma xenografts in athymic rats with 4-hydroperoxycyclophosphamide (4-HC), a preactivated derivative of cyclophosphamide. Athymic male rats were given intracerebral injections of the human glioma line D-54 MG. On Day 5 after injection, the rats were randomized (n = 8-10) by body weight (mean weight, approximately 300 g). In one set of experiments, each group received either i.v. saline, i.a. saline, 6 mg i.a. 4-HC, 6 mg i.v. 4-HC (6 mg), or 12 mg i.v. 4-HC. Intraarterial 4-HC produced significant increases in median survival (Day 24) compared with i.a. saline controls (140% increase), equivalent doses given i.v. (71% increase), and twice the equivalent dose given i.v. (50% increase) (by Wilcoxon rank sum analysis, P < 0.05 is statistically significant). The i.a. maximum tolerated dose was subsequently determined to be approximately 12.5 mg in non-tumor-bearing rats. Further experiments demonstrated a dose-response increase in survival for i.a. dosages of 6, 9, and 12.5 mg with significant improvement when compared with saline controls and 12.5 mg i.v. Pharmacokinetic experiments also demonstrated a significant first-pass uptake advantage for i.a. (versus i.v.) administered 4-HC. The short plasma half-life and marked antiglioma activity of 4-HC, without the need for hepatic activation, suggest a therapeutic application of this drug in the i.a. treatment of brain tumors.

Authors
Schuster, JM; Friedman, HS; Archer, GE; Fuchs, HE; McLendon, RE; Colvin, OM; Bigner, DD
MLA Citation
Schuster, JM, Friedman, HS, Archer, GE, Fuchs, HE, McLendon, RE, Colvin, OM, and Bigner, DD. "Intraarterial therapy of human glioma xenografts in athymic rats using 4-hydroperoxycyclophosphamide." Cancer Res 53.10 Suppl (May 15, 1993): 2338-2343.
PMID
8485721
Source
pubmed
Published In
Cancer Research
Volume
53
Issue
10 Suppl
Publish Date
1993
Start Page
2338
End Page
2343

MRI of gangliocytoma of cerebellum and spinal cord.

Gangliocytomas are rare CNS tumors that occur in children and young adults. We present a case of a cerebellar gangliocytoma with invasion of the cervical spinal cord demonstrated on MR. Radiographic differentiation of gangliocytomas from other ganglion cell tumors--ganglioglioma, dysplastic gangliocytoma of Lhermitte-Duclos, and desmoplastic infantile ganglioglioma--is discussed.

Authors
Furie, DM; Felsberg, GJ; Tien, RD; Friedman, HS; Fuchs, H; McLendon, R
MLA Citation
Furie, DM, Felsberg, GJ, Tien, RD, Friedman, HS, Fuchs, H, and McLendon, R. "MRI of gangliocytoma of cerebellum and spinal cord." J Comput Assist Tomogr 17.3 (May 1993): 488-491.
PMID
8491919
Source
pubmed
Published In
Journal of Computer Assisted Tomography
Volume
17
Issue
3
Publish Date
1993
Start Page
488
End Page
491

NEUROPATHOLOGY OF MULTIPLE VERSUS SINGLE-DOSE INTRATHECAL MELPHALAN IN RATS

Authors
ARCHER, GE; SCHUSTER, JM; FUCHS, HE; GUASPARI, A; BIGNER, DD; FRIEDMAN, HS; MCLENDON, RE
MLA Citation
ARCHER, GE, SCHUSTER, JM, FUCHS, HE, GUASPARI, A, BIGNER, DD, FRIEDMAN, HS, and MCLENDON, RE. "NEUROPATHOLOGY OF MULTIPLE VERSUS SINGLE-DOSE INTRATHECAL MELPHALAN IN RATS." May 1993.
Source
wos-lite
Published In
Journal of Neuropathology and Experimental Neurology
Volume
52
Issue
3
Publish Date
1993
Start Page
298
End Page
298

Activity of intrathecal 4-hydroperoxycyclophosphamide in a nude rat model of human neoplastic meningitis.

Neoplastic meningitis can result from leptomeningeal dissemination of a variety of cancers. We now report the development of animal models of human neoplastic meningitis and activity of intrathecal 4-hydroperoxycyclophosphamide (4-HC) against the human rhabdomyosarcoma cell line TE-671 and the human glioma cell line D-54 MG grown in the subarachnoid space of athymic rats. The injection of 5 x 10(5) TE-671 or D-54 MG cells resulted in leptomeningeal tumor growth from the base of the brain to the cauda equina. Daily weights and neurological examinations revealed progressive neurological deficits and weight loss, with death occurring between Days 21 and 27 for TE-671 and Days 14 and 26 for D-54 MG. 4-HC toxicity in non-tumor-bearing rats was assessed at dose levels of 2.0, 10.0, 15.0, and 20.0 mM, with clinical and histological evidence of neurotoxicity observed at the 2 highest dose levels. Intrathecal treatment with 4-HC on Day 8 following injection of TE-671 resulted in an increase in median survival of 20% (P = 0.04) at 1.0 mM 4-HC and 41% (P less than 0.001) at 2.5 mM 4-HC. Intrathecal treatment with 4-HC (2.5 mM) on Day 5 following injection of D-54 MG resulted in an increase in median survival of 23% (P = 0.009). These studies show the usefulness of the athymic rat model of human neoplastic meningitis and demonstrate the efficacy in vivo of intrathecally administered 4-HC against a human glioma and a human rhabdomyosarcoma cell line and the lack of toxicity at therapeutic levels of 4-HC in normal athymic rats.

Authors
Fuchs, HE; Archer, GE; Colvin, OM; Bigner, SH; Schuster, JM; Fuller, GN; Muhlbaier, LH; Schold, SC; Friedman, HS; Bigner, DD
MLA Citation
Fuchs, HE, Archer, GE, Colvin, OM, Bigner, SH, Schuster, JM, Fuller, GN, Muhlbaier, LH, Schold, SC, Friedman, HS, and Bigner, DD. "Activity of intrathecal 4-hydroperoxycyclophosphamide in a nude rat model of human neoplastic meningitis." Cancer Res 50.6 (March 15, 1990): 1954-1959.
PMID
2306744
Source
pubmed
Published In
Cancer Research
Volume
50
Issue
6
Publish Date
1990
Start Page
1954
End Page
1959

A NUDE RAT MODEL OF LEPTOMENINGEAL TUMOR DISSEMINATION (LTD) OF HUMAN MEDULLOBLASTOMA

Authors
FUCHS, HE; ARCHER, GE; SCHUSTER, JM; COLVIN, OM; BIGNER, SH; MUHLBAIER, LH; FRIEDMAN, HS; BIGNER, DD
MLA Citation
FUCHS, HE, ARCHER, GE, SCHUSTER, JM, COLVIN, OM, BIGNER, SH, MUHLBAIER, LH, FRIEDMAN, HS, and BIGNER, DD. "A NUDE RAT MODEL OF LEPTOMENINGEAL TUMOR DISSEMINATION (LTD) OF HUMAN MEDULLOBLASTOMA." May 1989.
Source
wos-lite
Published In
Journal of Neuropathology and Experimental Neurology
Volume
48
Issue
3
Publish Date
1989
Start Page
356
End Page
356
DOI
10.1097/00005072-198905000-00173

Immunology of transplantation in the central nervous system.

The brain has long been considered an immunologically privileged site. Tissue transplanted to the central nervous system (CNS) is immunologically better tolerated than grafts to other regions of the body. With improved graft survival, tissue transplantation may provide new treatment options for previously incurable CNS disorders. The normal immune response is reviewed, followed by a discussion of the factors responsible for graft rejection. The modification of these factors to allow successful CNS transplantation is discussed.

Authors
Fuchs, HE; Bullard, DE
MLA Citation
Fuchs, HE, and Bullard, DE. "Immunology of transplantation in the central nervous system." Appl Neurophysiol 51.6 (1988): 278-296. (Review)
PMID
3048211
Source
pubmed
Published In
Applied Neurophysiology
Volume
51
Issue
6
Publish Date
1988
Start Page
278
End Page
296

Specificity of alpha 2-macroglobulin covalent cross-linking for the active domain of proteinases.

The reaction of alpha 2-macroglobulin (alpha 2M) with the two-chain enzyme plasma kallikrein results in covalent bond formation between the catalytic subunit and the inhibitor. We have recently published a model of alpha 2M which suggests that this phenomenon may be a general mechanism when multisubunit proteinases are inactivated by alpha 2M. In order to test this hypothesis, we studied the reactions of factor Xa, plasmin, streptokinase-plasmin and alpha-thrombin with alpha 2M. In the case of factor Xa the catalytic heavy chain demonstrated greater than 99% covalent incorporation while over 97% of the light chain failed to crosslink to the inhibitor. Preferential binding of the catalytic light chains of plasmin (70% covalent incorporation) and plasmin in complex with streptokinase (79% covalent incorporation) was also observed. Finally, 82% covalent incorporation of the catalytic heavy chain of alpha-thrombin was found. These studies demonstrate that in the case of multisubunit proteinases, the chain containing the active site demonstrates preferential binding as predicted by the model supporting placement of the site of covalent binding close to the "bait region" of alpha 2M.

Authors
Pizzo, SV; Rajagopalan, S; Roche, PA; Fuchs, HE; Feldman, SR; Gonias, SL
MLA Citation
Pizzo, SV, Rajagopalan, S, Roche, PA, Fuchs, HE, Feldman, SR, and Gonias, SL. "Specificity of alpha 2-macroglobulin covalent cross-linking for the active domain of proteinases." Biol Chem Hoppe Seyler 367.11 (November 1986): 1177-1182.
PMID
2434119
Source
pubmed
Published In
Biological Chemistry Hoppe-Seyler
Volume
367
Issue
11
Publish Date
1986
Start Page
1177
End Page
1182

The macrophage-mediated regulation of hepatocyte synthesis of antithrombin III and alpha 1-proteinase inhibitor.

Antithrombin III (ATIII) is an anticoagulant protein which binds and inactivates thrombin and other serine proteinases. Little is known about regulation of its synthesis. We confirm that ATIII is synthesized by isolated rat hepatocytes, and that its synthesis is not altered by direct feedback of its complexes with proteinases. Neither is hepatocyte synthesis of ATIII altered by supernatants from macrophages cultured in the presence of ATIII-proteinase complexes. However, culture of macrophages with fibrinogen fragment D results in production of a factor(s) in the macrophage supernatants which stimulates hepatic fibrinogen synthesis, as previously described, and also stimulates the synthesis of ATIII and alpha 1-proteinase inhibitor (alpha 1PI). Synthesis of albumin and rat alpha 2-macroglobulin (alpha 2M) is not (alpha 2M) is not altered. Culture of macrophages in the presence of bacterial endotoxin also results in release of a factor(s) into the medium which stimulates the same changes in hepatocyte protein synthesis. These results show for the first time a mechanism by which synthesis of ATIII can be regulated during coagulation and fibrinolysis.

Authors
Hoffman, M; Fuchs, HE; Pizzo, SV
MLA Citation
Hoffman, M, Fuchs, HE, and Pizzo, SV. "The macrophage-mediated regulation of hepatocyte synthesis of antithrombin III and alpha 1-proteinase inhibitor." Thromb Res 41.5 (March 1, 1986): 707-715.
PMID
3485835
Source
pubmed
Published In
Thrombosis Research
Volume
41
Issue
5
Publish Date
1986
Start Page
707
End Page
715

Release of tissue plasminogen activator and its fast-acting inhibitor in defective fibrinolysis.

Releasable tissue plasminogen activator (t-PA) and the fast inhibitor of t-PA were measured in 18 controls and a pedigree with venous thrombosis. The functional assay was performed by a technique that destroys the t-PA inhibitor when blood is drawn. It was found that activator and inhibitor levels varied widely in the control group. One patient demonstrated inhibitor levels, on two different occasions, of 2.82 and 3.54 IU of t-PA per milliliter of plasma, as compared with a releasable activator level of 1.87 IU/mL. The t-PA antigen levels of this patient and the remainder of the pedigree were essentially normal for all seven subjects. Thus, it is suggested that the previously reported fibrinolytic disorder in this pedigree represents an imbalance between activator and inhibitor levels rather than an actual deficiency of t-PA.

Authors
Pizzo, SV; Fuchs, HE; Doman, KA; Petruska, DB; Berger, H
MLA Citation
Pizzo, SV, Fuchs, HE, Doman, KA, Petruska, DB, and Berger, H. "Release of tissue plasminogen activator and its fast-acting inhibitor in defective fibrinolysis." Arch Intern Med 146.1 (January 1986): 188-191.
PMID
2935105
Source
pubmed
Published In
Archives of internal medicine
Volume
146
Issue
1
Publish Date
1986
Start Page
188
End Page
191

Releasable vascular plasminogen activator and thrombotic strokes.

Releasable vascular plasminogen activator was measured in 28 patients (14 males and 14 females) with a history of thrombotic strokes documented by computed tomographic scanning. Levels were compared with those in a control population of 126 healthy subjects with no history of thromboembolic disease. The patient population tended to have higher levels of activator than the control population, 0.53 Committee on Thrombolytic Agents (CTA) units/ml of plasma for patients versus 0.21 CTA units/ml for control subjects; however, there was a wide distribution of values, as reported in all previous populations. Since plasminogen activator levels distribute in a non-Gaussian manner, patient values and control values were stratified into deciles. By this approach, the distribution among the patient was not significantly different from that among the control subjects except in females, who demonstrated skewing to higher deciles (p = 0.019). It is concluded that thrombotic strokes are not associated with low levels of releasable vascular plasminogen activator, and in fact, these patients may present with levels considerably above the mean for normal subjects.

Authors
Pizzo, SV; Petruska, DB; Doman, KA; Soong, SJ; Fuchs, HE
MLA Citation
Pizzo, SV, Petruska, DB, Doman, KA, Soong, SJ, and Fuchs, HE. "Releasable vascular plasminogen activator and thrombotic strokes." Am J Med 79.4 (October 1985): 407-411.
PMID
3931468
Source
pubmed
Published In
The American Journal of Medicine
Volume
79
Issue
4
Publish Date
1985
Start Page
407
End Page
411

Catabolism of human tissue plasminogen activator in mice.

The catabolism of human tissue plasminogen activator (t-PA) was studied in mice. The clearance of t-PA labeled with iodine 125 was rapid (t1/2). The clearance of phenylmethylsulfonyl-125I-t-PA, which is active site-inhibited, was identical to the active enzyme. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) demonstrated that the vast majority of 125I-t-PA injected into the circulation was present as free enzyme and not in a complex with inhibitors. The clearance of 125I-t-PA was unaltered by large molar excesses of several ligands of known clearance specificities, including macroalbumin, asialoorosomucoid, and diisopropylphosphorylthrombin and was also not altered in the presence of a 1,000-fold molar excess of unlabeled t-PA. Organ distribution studies demonstrated that the early rapid clearance of 125I-t-PA occurred in hepatocytes, followed by a later renal phase of clearance. The clearance of 125I-urokinase (UK) also was studied and was very similar in all aspects to the clearance of 125I-t-PA. These results suggest that both t-PA and UK are cleared from the circulation by unique nonsaturable processes localized in the liver that are independent of the proteinase active site.

Authors
Fuchs, HE; Berger, H; Pizzo, SV
MLA Citation
Fuchs, HE, Berger, H, and Pizzo, SV. "Catabolism of human tissue plasminogen activator in mice." Blood 65.3 (March 1985): 539-544.
PMID
4038613
Source
pubmed
Published In
Blood
Volume
65
Issue
3
Publish Date
1985
Start Page
539
End Page
544

Regulation of factor IXa in vitro in human and mouse plasma and in vivo in the mouse. Role of the endothelium and the plasma proteinase inhibitors.

The regulation of human Factor IXa was studied in vitro in human and mouse plasma and in vivo in the mouse. In human plasma, approximately 60% of the 125I-Factor IXa was bound to antithrombin III (ATIII) by 2 h, with no binding to alpha 2-macroglobulin or alpha 1-proteinase inhibitor, as assessed by gel electrophoresis and IgG- antiproteinase inhibitor-Sepharose beads. In the presence of heparin, virtually 100% of the 125I-Factor IXa was bound to ATIII by 1 min. The distribution of 125I-Factor IXa in mouse plasma was similar. The clearance of 125I-Factor IXa was rapid (50% clearance in 2 min) and biphasic and was inhibited by large molar excesses of ATIII-thrombin and alpha 1-proteinase inhibitor-trypsin, but not alpha 2-macro-globulin-trypsin; it was also inhibited by large molar excesses of diisopropylphosphoryl - (DIP-) Factor Xa, DIP-thrombin, and Factor IX, but not by prothrombin or Factor X. The clearance of Factor IX was also rapid (50% clearance in 2.5 min) and was inhibited by a large molar excess of Factor IX, but not by large molar excesses of Factor X, prothrombin, DIP-Factor Xa, or DIP-thrombin. Electrophoresis and IgG- antiproteinase inhibitor-Sepharose bead studies confirmed that by 2 min after injection into the murine circulation, 60% of the 125I-Factor IXa was bound to ATIII. Organ distribution studies with 125I-Factor IXa demonstrated that most of the radioactivity was in the liver. These studies suggest that Factor IXa binds to at least two classes of binding sites on endothelial cells. One site apparently recognizes both Factors IX and IXa, but not Factor X, Factor Xa, prothrombin, or thrombin. The other site recognizes thrombin, Factor Xa, and Factor IXa, but not the zymogen forms of these clotting factors. After this binding, Factor IXa is bound to ATIII and the complex is cleared from the circulation by hepatocytes.

Authors
Fuchs, HE; Trapp, HG; Griffith, MJ; Roberts, HR; Pizzo, SV
MLA Citation
Fuchs, HE, Trapp, HG, Griffith, MJ, Roberts, HR, and Pizzo, SV. "Regulation of factor IXa in vitro in human and mouse plasma and in vivo in the mouse. Role of the endothelium and the plasma proteinase inhibitors." J Clin Invest 73.6 (June 1984): 1696-1703.
PMID
6202716
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
73
Issue
6
Publish Date
1984
Start Page
1696
End Page
1703
DOI
10.1172/JCI111377

Hepatocyte uptake of alpha 1-proteinase inhibitor-trypsin complexes in vitro: evidence for a shared uptake mechanism for proteinase complexes of alpha 1-proteinase inhibitor and antithrombin III.

In vivo clearance studies have indicated that the clearance of proteinase complexes of the homologous serine proteinase inhibitors alpha 1-proteinase inhibitor and antithrombin III occurs via a specific and saturable pathway located on hepatocytes. In vitro hepatocyte-uptake studies with antithrombin III-proteinase complexes confirmed the hepatocyte uptake and degradation of these complexes, and demonstrated the formation of a disulfide interchange product between the ligand and a cellular protein. We now report the results of in vitro hepatocyte uptake studies with alpha 1-proteinase inhibitor-trypsin complexes. Trypsin complexes of alpha 1-proteinase inhibitor were prepared and purified to homogeneity. Uptake of these complexes by hepatocytes was time and concentration-dependent. Competition experiments with alpha 1-proteinase inhibitor, alpha 1-proteinase inhibitor-trypsin, and antithrombin III-thrombin indicated that the proteinase complexes of these two inhibitors are recognized by the same uptake mechanism, whereas the native inhibitor is not. Uptake studies were performed at 37 degrees C with 125I-alpha 1-proteinase inhibitor-trypsin and analyzed by sodium dodecyl sulfate-gel electrophoresis in conjunction with autoradiography. These studies demonstrated time-dependent uptake and degradation of the ligand to low molecular weight peptides. In addition, there was a time-dependent accumulation of a high molecular weight complex of ligand and a cellular protein. This complex disappeared when gels were performed under reducing conditions. The sole cysteine residue in alpha 1-proteinase inhibitor was reduced and alkylated with iodoacetamide. Trypsin complexes of the modified inhibitor were prepared and purified to homogeneity. Uptake and degradation studies demonstrated no differences in the results obtained with this modified complex as compared to unmodified alpha 1-proteinase inhibitor-trypsin complex. In addition, the high molecular weight disulfide interchange product was still present on sodium dodecyl sulfate-polyacrylamide gel electrophoresis of solubilized cells. Clearance and clearance competition studies with alpha 1-proteinase inhibitor-trypsin, alkylated alpha 1-proteinase inhibitor-trypsin, antithrombin III-thrombin, and anti-thrombin III-factor IXa further demonstrated the shared hepatocyte uptake mechanism for all these complexes.

Authors
Fuchs, HE; Michalopoulos, GK; Pizzo, SV
MLA Citation
Fuchs, HE, Michalopoulos, GK, and Pizzo, SV. "Hepatocyte uptake of alpha 1-proteinase inhibitor-trypsin complexes in vitro: evidence for a shared uptake mechanism for proteinase complexes of alpha 1-proteinase inhibitor and antithrombin III." J Cell Biochem 25.4 (1984): 231-243.
PMID
6334690
Source
pubmed
Published In
Journal of Cellular Biochemistry
Volume
25
Issue
4
Publish Date
1984
Start Page
231
End Page
243
DOI
10.1002/jcb.240250405

Hepatocyte receptors for antithrombin III-proteinase complexes.

The in vivo clearance of antithrombin III-proteinase complexes occurs via a specific and saturable pathway located on hepatocytes. We now report studies of the catabolism of antithrombin III-proteinase complexes in vitro using rat hepatocytes in primary culture. Antithrombin III-thrombin and trypsin complexes were prepared and purified to homogeneity. Ligand uptake by hepatocytes was concentration, temperature, and time dependent. Initial rate studies were performed to characterize the maximum rate of uptake, V, and apparent Michaelis constant Kapp. These studies yielded a V of 12.8 fmol/mg cell protein/min and a Kapp of 144 nM for antithrombin-trypsin complexes. Competition experiments with antithrombin III, antithrombin III-proteinase complexes, alpha 2-macroglobulin-methylamine, asialoorosomucoid and the neoglycoproteins, fucosyl-bovine serum albumin (BSA), N-acetylglucosaminyl-BSA, and mannosyl-BSA indicated that only antithrombin III-proteinase complexes were recognized by the hepatocyte receptor. Uptake studies were performed at 37 degrees C with 125I-antithrombin III-trypsin and analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) in conjunction with autoradiography. These studies demonstrate time-dependent uptake and degradation of the ligand to low molecular weight peptides. In addition, there was a time-dependent accumulation of a high molecular weight complex of ligand and a cellular protein. This complex disappeared when gels were performed under reducing conditions.

Authors
Fuchs, HE; Shifman, MA; Michalopoulos, G; Pizzo, SV
MLA Citation
Fuchs, HE, Shifman, MA, Michalopoulos, G, and Pizzo, SV. "Hepatocyte receptors for antithrombin III-proteinase complexes." J Cell Biochem 24.3 (1984): 197-206.
PMID
6330134
Source
pubmed
Published In
Journal of Cellular Biochemistry
Volume
24
Issue
3
Publish Date
1984
Start Page
197
End Page
206
DOI
10.1002/jcb.240240302

SYNTHESIS OF ANTITHROMBIN-III BY CULTURED RAT HEPATOCYTES

Authors
HOFFMAN, MR; FUCHS, HE; PIZZO, SV
MLA Citation
HOFFMAN, MR, FUCHS, HE, and PIZZO, SV. "SYNTHESIS OF ANTITHROMBIN-III BY CULTURED RAT HEPATOCYTES." 1984.
Source
wos-lite
Published In
Laboratory Investigation
Volume
50
Issue
1
Publish Date
1984
Start Page
A26
End Page
A26

Regulation of factor Xa in vitro in human and mouse plasma and in vivo in mouse. Role of the endothelium and plasma proteinase inhibitors.

The regulation of human Factor Xa was studied in vitro in human and mouse plasma, and in vivo in mouse. In human plasma, 125I-Factor Xa bound to alpha 1-proteinase inhibitor, antithrombin III, and alpha 2-macroglobulin in a ratio of 4.9:1.9:1 as determined by gel electrophoresis and by adsorption to IgG-(antiproteinase inhibitor)-Sepharose beads. The distribution of Factor Xa in mouse plasma was similar. The clearance of Factor Xa in mice was rapid (50% clearance in 3 min) and biphasic. alpha 1-Proteinase inhibitor-trypsin, even at a 2,000-fold molar excess, failed to inhibit the clearance of Factor Xa, while alpha 2-macroglobulin-trypsin inhibited only the later phase of clearance. The plasma clearance of diisopropylphosphoryl-Factor Xa was more rapid than native Factor Xa (50% clearance in 2.5 min), and the clearance was blocked by diisopropylphosphoryl-thrombin. Electrophoresis experiments confirmed that by 2 min after injection into the murine circulation, 90% of the bound Factor Xa was on alpha 2-macroglobulin, in marked contrast to the in vitro results. Organ distribution studies at 3 and 15 min with 125I-Factor Xa demonstrated that the majority of radioactivity was in the liver, with significant radioactivity also present in lung and kidney. Autopsies performed 30 s after injection of 125I-Factor Xa also demonstrated significant binding to the aorta and vena cava. These studies indicate that Factor Xa binds to specific thrombin-binding sites on endothelial cells, and that this binding alters its proteinase inhibitor specificity. Factor Xa binds to alpha 2-macroglobulin in vivo, whereas the predominant in vitro inhibitor of Factor Xa is alpha 1-proteinase inhibitor.

Authors
Fuchs, HE; Pizzo, SV
MLA Citation
Fuchs, HE, and Pizzo, SV. "Regulation of factor Xa in vitro in human and mouse plasma and in vivo in mouse. Role of the endothelium and plasma proteinase inhibitors." J Clin Invest 72.6 (December 1983): 2041-2049.
PMID
6196377
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
72
Issue
6
Publish Date
1983
Start Page
2041
End Page
2049
DOI
10.1172/JCI111169

Catabolism of antithrombin III-protease complexes.

Authors
Fuchs, HE; Pizzo, SV
MLA Citation
Fuchs, HE, and Pizzo, SV. "Catabolism of antithrombin III-protease complexes." Thromb Res 32.2 (October 15, 1983): 253-254. (Letter)
PMID
6658716
Source
pubmed
Published In
Thrombosis Research
Volume
32
Issue
2
Publish Date
1983
Start Page
253
End Page
254

THE CATABOLISM OF HUMAN FACTOR-XA IN A MOUSE MODEL

Authors
FUCHS, HE; PIZZO, SV
MLA Citation
FUCHS, HE, and PIZZO, SV. "THE CATABOLISM OF HUMAN FACTOR-XA IN A MOUSE MODEL." 1983.
Source
wos-lite
Published In
The FASEB Journal
Volume
42
Issue
4
Publish Date
1983
Start Page
1030
End Page
1030

A unique pathway for the plasma elimination of alpha 2-antiplasmin-protease complexes in mice.

Radiolabeled alpha 2-antiplasmin cleared slowly from the circulation of mice. Complex formation with either plasmin or trypsin resulted in a significant increase in the plasma elimination rate of the protease inhibitor. Approximately 20 min and 14 min were required for 50% of the injected alpha 2-antiplasmin-plasmin and alpha 2-antiplasmin-trypsin to clear from the circulation, respectively. Significant competition was observed when radiolabeled alpha 2-antiplasmin-plasmin was cleared in the presence of a large molar excess of unlabeled alpha 2-antiplasmin-plasmin. alpha 1-Antitrypsin-trypsin failed to complete with radiolabeled alpha 2-antiplasmin-plasmin even when present at 2000 fold molar excess. Organ distribution studies localized the major site of alpha 2-antiplasmin-plasmin clearance in the liver. Microscopic autoradiography data suggested that the cell responsible for the clearance pathway was the hepatocyte.

Authors
Gonias, SL; Fuchs, HE; Pizzo, SV
MLA Citation
Gonias, SL, Fuchs, HE, and Pizzo, SV. "A unique pathway for the plasma elimination of alpha 2-antiplasmin-protease complexes in mice." Thromb Haemost 48.2 (October 29, 1982): 208-210.
PMID
6758181
Source
pubmed
Published In
Thrombosis and haemostasis
Volume
48
Issue
2
Publish Date
1982
Start Page
208
End Page
210

In vivo catabolism of alpha 1-proteinase inhibitor-trypsin, antithrombin III-thrombin and alpha 2-macroglobulin-methylamine.

The clearances of 125I-labeled alpha 1-proteinase inhibitor-trypsin, antithrombin III-thrombin and alpha 2-macroglobulin-methylamine (CH3NH2) were compared in our previously described mouse model. alpha 1-Proteinase inhibitor-trypsin cleared with a t 1/2 of 20 min, antithrombin III-thrombin of 7 min and 125I-labeled alpha 2-macroglobulin-methylamine of 2 min. Competition studies were performed to determine whether one or several pathways clear these three ligands. The clearance of 125I-labeled alpha 1-proteinase inhibitor-trypsin and 125I-labeled antithrombin III-thrombin was blocked by large molar excesses of either ligand, but not by alpha 2-macroglobulin-methylamine. The clearance of 125I-labeled alpha 2-macroglobulin-methylamine can be blocked by a large molar excesses of unlabeled alpha 2-macroglobulin-methylamine but not by alpha 1-proteinase inhibitor-trypsin. These studies demonstrate that the clearance of alpha 1-proteinase inhibitor-trypsin complexes is independent of alpha 2-macroglobulin-methylamine and utilizes the same pathway which is involved in the clearance of antithrombin III-thrombin complexes.

Authors
Fuchs, HE; Shifman, MA; Pizzo, SV
MLA Citation
Fuchs, HE, Shifman, MA, and Pizzo, SV. "In vivo catabolism of alpha 1-proteinase inhibitor-trypsin, antithrombin III-thrombin and alpha 2-macroglobulin-methylamine." Biochim Biophys Acta 716.2 (May 27, 1982): 151-157.
PMID
6178438
Source
pubmed
Published In
Biochimica et Biophysica Acta: international journal of biochemistry and biophysics
Volume
716
Issue
2
Publish Date
1982
Start Page
151
End Page
157

Three-dimensional structures of C-phycocyanin and B-phycoerythrin at 5-A resolution.

Single crystal x-ray diffraction studies are proceeding on two phycobiliproteins: C-Phycocyanin from Anabaena variabilis and B-Phycoerythrin from Porphyridium cruentum. C-Phycocyanin consists of six alpha and six beta subunits. A three-dimensional x-ray diffraction study of this light-harvesting protein (P6(3); a = b = 154.1 A, c = 40.1 A) at 5-A resolution shows that the molecule is 110 A in diameter, 40 A thick, with a 20-A diameter central channel. It can be divided into three separate domains related by the crystallographic 3 and contains long, columnar regions of density, presumed to represent alpha helix. B-Phycoerythrin is composed of 6 alpha, 6 beta, and a gamma subunit. A 5.25-A resolution study of this protein (R3, a = b = 189 A, c = 60 A) indicates that the molecule is 107 A in diameter and 55 A thick, has 32-D3 symmetry, and can be divided into six regions. The gamma chain lies on a crystallographic 3 and undergoes symmetric disordering. A region of low and unstructured density in the center of the molecule is presumably occupied by this gamma chains. These two low resolution structures are compared with regard to differences in quaternary structure.

Authors
Fisher, RG; Woods, NE; Fuchs, HE; Sweet, RM
MLA Citation
Fisher, RG, Woods, NE, Fuchs, HE, and Sweet, RM. "Three-dimensional structures of C-phycocyanin and B-phycoerythrin at 5-A resolution." J Biol Chem 255.11 (June 10, 1980): 5082-5089.
PMID
6768730
Source
pubmed
Published In
The Journal of biological chemistry
Volume
255
Issue
11
Publish Date
1980
Start Page
5082
End Page
5089

Preliminary crystallographic investigations of two phycobiliproteins.

Single crystal x-ray diffraction investigations are in progress on two phycobiliproteins. C-phycocyanin from Anabaena variabilis crystallizes in space group P63 with a = b = 154 A and c = 40 A. The crystallographic asymmetric unit is (alphabeta)2 with a total molecular mass of 7.0-10(4) daltons. B-phycoerythrin from Porphyridium cruentum crystallizes in space group R3 with a = b = 189 A and c = 60 A. This molecule has the unusual molecular stoichiometry (alphabeta)6gamma and the crystallographic asymmetric unit is (alphabeta)2gamma1/3. This requires that the gamma chain undergo a perfect 3-fold disordering about the crystallographic 3 axis, i.e. the gamma chain must occupy three symmetry-equivalent positions, each with an occupancy of one-third.

Authors
Sweet, RM; Fuchs, HE; Fisher, RG; Glazer, AN
MLA Citation
Sweet, RM, Fuchs, HE, Fisher, RG, and Glazer, AN. "Preliminary crystallographic investigations of two phycobiliproteins." J Biol Chem 252.22 (November 25, 1977): 8258-8260.
PMID
410813
Source
pubmed
Published In
The Journal of biological chemistry
Volume
252
Issue
22
Publish Date
1977
Start Page
8258
End Page
8260
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