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C Raffel

Publications and source records attributed to C Raffel.

At least 37 records · Page 2Linked to original sources
PubMed1998

Sporadic medulloblastomas contain oncogenic beta-catenin mutations.

The beta-catenin, glycogen synthase kinase 3beta (GSK-3beta), and adenomatous polyposis coli (APC) gene products interact to form a network that influences the rate of cell proliferation. Medulloblastoma occurs as part of Turcot's syndrome, and patients with Turcot's who develop medulloblastomas have been shown to harbor germ-line APC mutations. Although APC mutations have been investigated and not identified in sporadic medulloblastomas, the status of the beta-catenin and GSK-3beta genes has not been evaluated in this tumor. Here we show that 3 of 67 medulloblastomas harbor beta-catenin mutations, each of which converts a GSK-3beta phosphorylation site from serine to cysteine. The beta-catenin mutation seen in the tumors was not present in matched constitutional DNA in the two cases where matched DNA was available. A loss of heterozygosity analysis of 32 medulloblastomas with paired normal DNA samples was performed with four microsatellite markers flanking the GSK-3beta locus; loss of heterozygosity with at least one marker was identified in 7 tumors. Sequencing of the remaining GSK-3beta allele in these cases failed to identify any mutations. Taken together, these data suggest that activating mutations in the beta-catenin gene may be involved in the development of a subset of medulloblastomas. The GSK-3beta gene does not appear to be a target for inactivation in this tumor.

Adolescent↗
PubMed1997

Sporadic medulloblastomas contain PTCH mutations.

Nevoid basal cell carcinoma syndrome (NBCCS), or Gorlin's syndrome, is an autosomal dominant disorder that predisposes to developmental defects and various forms of cancer. PTCH was recently proposed as a candidate gene for NBCCS due to its frequent mutation in basal cell carcinomas, the cancer most often associated with this syndrome. Another NBCCS-associated cancer is medulloblastoma, a common central nervous system tumor in children. Most medulloblastomas, however, occur without indication of an inherited predisposition. We have examined 24 sporadic medulloblastomas for loss of heterozygosity (LOH) at loci flanking as well as within PTCH. In cases with LOH, single-strand conformational polymorphism and sequencing analysis were performed to determine the status of the remaining PTCH allele. Microsatellite analysis indicated LOH of PTCH in 5 of 24 tumors, and in three of these cases a mutation of the remaining allele was identified. Two of the mutations were duplication insertions, and the third consisted of a single base deletion. It is interesting that all three mutations occur in exon 17 of the PTCH gene. These data suggest that inactivation of PTCH function is involved in the development of at least a subset of sporadic medulloblastomas.

Chromosomes, Human, Pair 9↗
PubMed1997

Deletion within the D17S34 locus in a primitive neuroectodermal tumor.

Loss of heterozygosity on chromosome 17p13.3 is frequently observed in solid tumors, and the presence of a tumor suppressor gene has been predicted in this region of chromosome 17. We have analyzed a primitive neuroectodermal tumor sample exhibiting loss of heterozygosity at the D17S34 locus, a commonly used telomeric marker on the short arm of chromosome 17. The remaining allele showed a rearrangement. Cosmids spanning the D17S34 locus and probes from that region were used to demonstrate a 9-kb deletion within the D17S34 locus and were found to contain evolutionary, conserved sequences. Genetic alterations in this region may also affect expression of immediately adjacent genes, such as ABR, and could be a common mechanism in the causation of primitive neuroectodermal tumors.

Chromosomes, Human, Pair 17↗
PubMed1997

Acrylic cranioplasty with alginate molding: technical note.

OBJECTIVE: Acrylic cranioplasty for cranial defects is a common neurosurgical procedure that is performed when the original bone flap becomes infected or is unusable for other reasons. We developed a simple technique to produce a complete copy of the original bone flap from acrylic, using alginate impression material as a mold. METHODS: Alginate impression material was used to form a mold of the patient's original bone flap. Methylmethacrylate was then placed inside the mold to create an exact duplicate of the bone flap. The acrylic flap was sterilized with gamma irradiation and used for cranioplasty. Two patients who had cranial defects secondary to infections of their craniotomy bone flaps underwent cranioplasty with this technique. RESULTS AND CONCLUSION: A perfect copy of the patient's original bone flap was easily and quickly created with this technique, and excellent cosmetic results were obtained. Operative time was shortened because the prosthesis was preformed before the operation. This technique can also be used to mold large or complex cranial defects as long as the original bone flap is available and there is no major cranial remodeling around the defect.

Alginates↗
PubMed1997

Effective chemotherapy for advanced CNS embryonal tumors in adults.

PURPOSE: Embryonal tumors of the CNS include, among others, medulloblastoma, cerebral neuroblastoma, pineoblastoma, and primitive neuroectodermal tumors (PNETs). Almost all data on the treatment of embryonal CNS tumors are derived from the pediatric population, since these tumors are uncommon in adulthood. The purpose of this study was to examine the rate and duration of response to chemotherapy of advanced embryonal CNS tumors in adults. PATIENTS AND METHODS: We retrospectively studied all adult (> 18 years of age) patients with advanced embryonal tumors of the CNS who received chemotherapy at our institution between 1976 and 1994. Seventeen consecutive patients were treated with regimens that contained either nitrosourea or cisplatin or both sequentially, with no patients having received the combination of nitrosourea and cisplatin concurrently. RESULTS: In patients who received cisplatin-based chemotherapy, responses were observed in 84.5% (26% complete response [CR] rate), 10.5% remained stable, and 5% progressed. The median time to progression was 18 months for patients who had a CR, 6 months for those with partial response (PR), and 10 months for stable patients. Among patients who received nitrosourea-based chemotherapy, PR was observed in 27%, 36.5% remained stable, and 36.5% progress. The median time to progression was 6 months for patients who had a PR and 6.5 months for stable patients. CONCLUSION: In adults with advanced embryonal CNS tumors, conventional-dose intravenous cisplatin-based chemotherapy regimens are able to produce responses in the majority of the patients (84.5%), even as second- or third-line regimens. Nitrosourea-based regimens less frequently produce responses (27%).

Adolescent↗
PubMed1997

Surgical treatment of craniosynostosis: outcome analysis of 250 consecutive patients.

OBJECTIVE: Surgery for craniosynostosis has evolved rapidly over the past two decades, with increased emphasis on early, extensive operations. Older published series may not accurately reflect more recent experience. Our study was designed to analyze outcome in a large series of consecutive patients treated recently at a single center. METHODS: We reviewed 250 consecutive patients who underwent surgical treatment of craniosynostosis between January 1, 1987 and December 31, 1992. They were divided into nine groups by suture involvement: sagittal, unilateral coronal, bilateral coronal, unilateral lambdoid, bilateral lambdoid, metopic, multiple suture, the Klee-blattschädel deformity (cloverleaf skull), and acquired craniosynostosis. Outcome was analyzed in terms of residual deformities and irregularities, complications, mortality, as well as the need for additional surgery. RESULTS: There were 157 males (62. 8%) and 93 females (37.2%), with most of the male preponderance accounted for by the large sagittal synostosis group, which consisted of 82 males and 25 females. Median age at first operation was 147 days. A named syndrome was present in 23 patients (9.2%) and was more common than expected with bilateral and unilateral coronal synostosis, the Kleeblattschädel deformity, and multiple suture synostosis. There were two deaths (0.8%), both with Klee-blattschädel patients, and 17 other complications (6.8%). Morbidity and mortality were significantly associated with secondary vs primary operations and syndromic vs nonsyndromic patients. Outcome analysis revealed the best surgical results with metopic synostosis and significantly less good results with the Kleeblattschädel deformity, multiple suture synostosis, and bilateral coronal synostosis. CONCLUSIONS: Using modern surgical techniques, craniosynostosis can be corrected with good outcomes and relatively low morbidity and mortality, particularly for otherwise healthy, nonsyndromic infants.

Craniosynostoses↗
PubMed1997

Prognostic significance of chromosome 17p deletions in childhood primitive neuroectodermal tumors (medulloblastomas) of the central nervous system.

Deletions in the short arm of chromosome 17 (17p) are the most common genetic abnormality in primitive neuroectodermal tumors of the posterior fossa/medulloblastoma (PNET/Mb). The biological consequences of these deletions are not known for children with PNET/Mb; however, the presence of a tumor suppressor gene located in 17p, distinct from p53, has been implicated in tumorigenesis. Two recent studies suggest that 17p deletions in PNET/Mb are associated with a poor prognosis. To address this question, we identified deletions of chromosome 17p by cytogenetic and/or molecular biology methods in tumor biopsy samples from 56 patients with PNET/Mb. Associations between clinical characteristics or survival outcomes and 17p status were examined by multivariate analysis. Forty-one percent of PNET/Mb cases had a deletion of 17p. No significant association was found between 17p deletion and shorter survival duration or higher metastatic stage. Multivariate analysis did not find independent prognostic significance for 17p deletions after accounting for the effects of significant clinical variables. A larger study of the prognostic value of 17p deletion should be considered; however, clinical use of this factor to distinguish high-risk from standard-risk PNET/Mb populations is not warranted at this time.

Age Factors↗
PubMed1996

Gene therapy for PNET.

A new era has been reached in cancer therapeutics in which the techniques of molecular biology can be applied to human brain tumors. Ongoing studies are determining the best vector system with which to deliver genes to cells. Choices include the retroviral, adenoviral, and Herpes simplex virus vector systems. The optimum mode of delivering the vector specifically to the tumor is being explored through intravenous, intraarterial, and direct intra-tumoral injections. Finally, efforts to achieve adequate vector expression throughout an entire tumor are being realized with our greater understanding of vector design and gene expression. The PNET may be amenable in the future to gene therapy strategies because of its rapid proliferative potential, its tendency to spread within the CSF pathways, and its high recurrence rate. In this regard, a number of novel strategies for treating PNET are described herein.

Adenoviridae↗
PubMed1996

The scintigraphic appearance of childhood moyamoya disease on cerebral perfusion imaging.

OBJECTIVE: This study was performed to evaluate the role of single photon emission computed tomography (SPECT) perfusion imaging in the evaluation of patients with moyamoya disease. MATERIALS AND METHODS: Five patients (four female, one male) were studied utilizing iodine-123 iodoamphetamine or technetium-99m hexamethylpropyleneamine oxime SPECT. The data were reconstructed into axial, coronal and sagittal sections for review, and compared with CT, MR and/or angiographic images. RESULTS: All five patients had significant perfusion defects. These areas of vascular compromise were seen to cross normal vascular territories, and were greater in number and extent than seen on anatomic sectional imaging. CONCLUSION: Patients with moyamoya disease have a recognizable pattern of scintigraphic perfusion deficits which should be identified by pediatric imaging physicians. SPECT perfusion studies should be performed in conjunction with other imaging modalities (CT, MR or angiography).

Adolescent↗
PubMed1996

Usefulness of [18F]fluorodeoxyglucose positron emission tomography in pediatric epilepsy surgery.

We sought to analyze our experience with pediatric epilepsy surgery patients to determine the place of [18F]fluorodeoxyglucose (FDG) positron emission tomography (FDG-PET) in the preoperative evaluation of such children relative to chronic invasive intracranial monitoring. Fifty-six children who received an interictal FDG-PET as part of a phase 1 epilepsy surgery evaluation were compared with 44 children who did not have this study in a retrospective analysis of 100 patients accrued over a 4-year period. There was no significant difference between the two groups of children in terms of age or follow-up or was there a significant difference between the FDG-PET group and the no-FDG-PET group in regard to the numbers of children who had surgery, the type of procedure done, whether chronic invasive intracranial monitoring was performed, or outcome. The hypometabolic area demonstrated on interictal FDG-PET was concordant with that of the epileptogenic zone as mapped out with ictal recordings from subdural electrodes in 2 of 13 patients in whom a complete data set was available for comparison. In the other 11 children there was either poor agreement between interictal FDG-PET and ictal electrocorticographic data or the interictal FDG-PET was normal in the face of an epileptogenic focus which was successfully mapped by invasive electrophysiologic techniques and excised. We conclude that one cannot exclude a child with intractable partial seizures from surgical consideration because the interictal FDG-PET is normal; nor is there sufficient correlation between the interictal hypometabolic area on FDG-PET and the epileptogenic zone in terms of anatomic location and size to justify forgoing chronic invasive intracranial monitoring in children with intractable partial seizures being evaluated for epilepsy surgery unless there is absolute concordance between all neuroimaging, clinical, and video-electroencephalographic data.

Adolescent↗
PubMed1996

Two primitive neuroectodermal tumor cell lines require an activated insulin-like growth factor I receptor for growth in vitro.

OBJECTIVE: To determine the expression of the insulin-like growth factors (IGFs) and the IGF-I receptor in primitive neuroectodermal tumor cell lines and to assess the importance of these proteins in the growth of cell lines in vitro. METHODS: Ribonucleic acid blotting and reverse transcriptase-polymerase chain reaction were used for detection of IGF and IGF-I expression. Ribonucleic acid blotting was used for detection of up-regulation of c-fos in the presence of exogenous growth factor. Immunoprecipitation was used to demonstrate autophosphorylation of the receptor in the presence of exogenous growth factor. Ligand binding analysis was used to determine the binding affinity of the receptor and the number of receptors per cell. Growth of curves in the presence of monoclonal antibody that blocks binding of ligand to receptor was measured to determine the requirement for an activated receptor during growth. RESULTS: Expression of IGF-II was identified in one cell line. No expression of IGF-I was seen in any cell line. Expression of IGF-I receptor was detected in all three cell lines. Immunoprecipitation experiments demonstrated autophosphorylation of the receptor after addition of IGF-I to growing cells. Ligand binding analysis revealed 9.2 x 10(4) and 4 x 10(4) receptors per cell in the Daoy and PFSK cell lines, respectively. Addition of either IGF alone or in combination to serum-starved cells was not able to restore growth of the cell lines. A blocking monoclonal antireceptor antibody decreased growth of Daoy and PFSK cells in a dose-dependent fashion. Complete arrest of growth occurred at 1 microgram/ml antibody in both cell lines. CONCLUSION: The IGF-I receptor is expressed by primitive neuroectodermal tumor cell lines in vitro. An activated receptor is important for cell proliferation in vitro. Additional work will establish the importance of these findings for tumors in vivo.

Antibodies↗
PubMed1996

Giant intracranial aneurysm and fibromuscular dysplasia in an adolescent with alpha 1-antitrypsin deficiency.

Recent studies have suggested that a deficiency of alpha 1-antitrypsin may be a genetic risk factor for the development of intracranial aneurysms and arterial fibromuscular dysplasia. The authors report a 16-year-old girl with a history of lung disease who suffered a cerebral hemorrhage due to the rupture of a giant intracranial aneurysm arising from the middle cerebral artery. This fusiform aneurysm was associated with fibromuscular dysplasia of the intimal type. She was found to have an unusual alpha 1-antitrypsin deficiency (PiMP phenotype). This case provides further evidence of an underlying arteriopathy in alpha 1-antitrypsin deficiency.

Adolescent↗
PubMed1996

Surveillance imaging in children with primitive neuroectodermal tumors.

Controversy surrounds the benefits of routine surveillance magnetic resonance or computed tomographic imaging for monitoring children after resection of primitive neuroectodermal tumors. A recent study suggested that serial imaging studies detect only a small minority of tumor recurrences in patients with symptoms. The authors concluded that even in patients with recurrence documented by imaging, no patient with a recurrence survived long (average, 5 mo) and that surveillance scanning is of little clinical value in children with primitive neuroectodermal tumors. We reviewed our experience with 25 patients (28% of our total series) who presented to the Children's Hospital Los Angeles, Los Angeles, CA, from 1985 to 1993 with recurrent tumors after surgery and adjuvant therapy. Recurrent tumors were detected on routine imaging in 19 asymptomatic patients (76%) and in 6 symptomatic patients (24%). Recurrences were documented 15 months (mean) after the initial diagnosis in asymptomatic children and 5 months (mean) after the initial diagnosis in children with symptoms of recurrent tumor (P < or = 0.01). Asymptomatic patients with recurrence documented on serial imaging had prolonged survival when compared with those who were symptomatic (P < or = 0.05). The surviving patients with recurrence remained alive for more than 24 months after documentation of recurrence. Early detection of local tumor recurrence by surveillance scanning may provide a critical therapeutic window for successful treatment with aggressive or novel therapies.

Adolescent↗
PubMed1995

MDR1 gene expression in brain of patients with medically intractable epilepsy.

Why some patients with seizures are successfully treated with antiepileptic drugs (AEDs) and others prove medically intractable is not known. Inadequate intraparenchymal drug concentration is a possible mechanism of resistance to AEDs. The multiple drug resistance gene (MDR1) encodes P-glycoprotein, an energy-dependent efflux pump that exports planar hydrophobic molecules from the cell. If P-glycoprotein is expressed in brain of some patients with intractable epilepsy and AEDs are exported by P-glycoprotein, lower intraparenchymal drug concentrations could contribute to lack of drug response in such patients. Eleven of 19 brain specimens removed from patients during operation for intractable epilepsy had MDR1 mRNA levels > 10 times greater than those in normal brain, as determined by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) method. Immunohistochemistry for P-glycoprotein from 14 of the patients showed increased staining in capillary endothelium in samples from epileptic patients as compared with staining in normal brain samples. In epileptic brain specimens with high MDR1 mRNA levels, expression of P-glycoprotein in astrocytes also was identified. Last, steady-state intracellular phenytoin (PHT) concentrations in MDR1 expressing neuroectodermal cells was one fourth that in MDR1-negative cells. MDR1 expression is increased in brain of some patients with medically intractable epilepsy, suggesting that the patients' lack of response to medication may be caused by inadequate accumulation of AED in brain.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Pediatric traumatic intracranial aneurysms.

During the past 17 years, 7 children have been treated at Children's Hospital Los Angeles (CHLA) for traumatic intracranial aneurysms. These patients presented with subarachnoid or intraparenchymal hemorrhage (5 cases), growing fracture (1 case), and behavioral change (1 case). All patients were managed with surgery, and no patient died or was made neurologically worse as a result of such management. The existence of a traumatic aneurysm should be considered when new neurological symptoms develop in a patient with a history of head injury.

Adolescent↗
PubMed1995

The multiple tumor suppressor 1/cyclin-dependent kinase inhibitor 2 gene in human central nervous system primitive neuroectodermal tumor.

The recently described multiple tumor suppressor 1/cyclin-dependent kinase inhibitor 2 (MTS1/CDKN2) gene, encoding the cyclin-dependent kinase 4 inhibitor p16, is mutated in a wide variety of tumor cell lines, including gliomas. To investigate the possible role of this gene in the genesis of the central nervous system primitive neuroectodermal tumor (PNET), four established PNET cell lines and 18 PNET surgical specimens were studied for deletions and mutations of the MTS1/CDKN2 gene. One of the four cell lines had homozygous deletion of the gene. No mutation in any of the three MTS1/CDKN2 exons was detected in the other three cell lines by single strand conformational polymorphism analysis. Eighteen surgical PNET specimens were studied for allelic and homozygous deletion at chromosome 9p21, the location of the MTS1/CDKN2 gene. No loss of heterozygosity was noted in 11 of the tumors, and no homozygous loss was noted in any tumor. Single strand conformational polymorphism analysis of the entire coding region of the MTS1/CDKN2 gene revealed no mutation within MTS1/CDKN2 in any tumor. Although deletion of MTS1/CDKN2 may occur in some PNET cell lines, neither deletion nor mutation of the gene is found in tumors before culture. The genesis of the human central nervous system PNET does not involve deletion or mutation of the MTS1/CDKN2 gene.

Base Sequence↗