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Biomedical subjects

Richard G Ellenbogen

Publications and source records attributed to Richard G Ellenbogen.

At least 19 recordsLinked to original sources
PubMed2007

Magnesium sulfate for neuroprotection after traumatic brain injury: a randomised controlled trial.

BACKGROUND: Traumatic brain injuries represent an important and costly health problem. Supplemental magnesium positively affects many of the processes involved in secondary injury after traumatic brain injury and consistently improves outcome in animal models. We aimed to test whether treatment with magnesium favourably affects outcome in head-injured patients. METHODS: In a double-blind trial, 499 patients aged 14 years or older admitted to a level 1 regional trauma centre between August, 1998, and October, 2004, with moderate or severe traumatic brain injury were randomly assigned one of two doses of magnesium or placebo within 8 h of injury and continuing for 5 days. Magnesium doses were targeted to achieve serum magnesium ranges of 1.0-1.85 mmol/L or 1.25-2.5 mmol/L. The primary outcome was a composite of mortality, seizures, functional measures, and neuropsychological tests assessed up to 6 months after injury. Analyses were done according to the intention-to-treat principle. This trial is registered with , number . FINDINGS: Magnesium showed no significant positive effect on the composite primary outcome measure at the higher dose (mean=55 average percentile ranking on magnesium vs 52 on placebo, 95% CI for difference -7 to 14; p=0.70). Those randomly assigned magnesium at the lower dose did significantly worse than those assigned placebo (48 vs 54, 95% CI -10.5 to -2; p=0.007). Furthermore, there was higher mortality with the higher magnesium dose than with placebo. Other major medical complications were similar between groups, except for a slight excess of pulmonary oedema and respiratory failure in the lower magnesium target group. No subgroups were identified in which magnesium had a significantly positive effect. INTERPRETATION: Continuous infusions of magnesium for 5 days given to patients within 8 h of moderate or severe traumatic brain injury were not neuroprotective and might even have a negative effect in the treatment of significant head injury.

Adolescent↗
PubMed2006

Vagus nerve stimulation for intractable seizures in children.

Forty-three children less than 12 years of age having intractable seizures were treated with vagus nerve stimulation. Five children were monitored for <12 months, 16 children for 12 to 17 months, and 22 children for > or =18 months with overall median seizure reduction of 55%. Thirty-seven percent had at least 90% reduction. Vagus nerve stimulation was effective in children with generalized, mixed, and partial medically refractory seizures.

Age Factors↗
PubMed2006

Cisplatin-based chemotherapy followed by focal, reduced-dose irradiation for pediatric primary central nervous system germinomas.

The objective of this study was to evaluate retrospectively one institution's experience treating pediatric central nervous system (CNS) pure germinomas with platinum-based chemotherapy followed by focal, reduced-dose irradiation. Eight patients were identified with localized, pure CNS germinomas from 1993 to 2004 at the authors' institution. The median age at diagnosis was 13 years (range 7-19). The median follow-up was 40 months (range 8-141). The tumor location was suprasellar in four, the pineal region in three, and the third ventricle in one. Irradiation was started a median of 20 weeks (range 17-22) from diagnosis and consisted of conformal fields to the primary site as determined by the initial diagnostic MR plus a 1.5- to 2-cm margin. Six of the eight patients received a dose of 3,060 cGy; two patients received 3,600 cGy. The 5-year actuarial event free survival was 71% (56-86%, 95% CI). Two patients suffered marginal (at field edge) failures and both were salvaged using reinduction platinum-based chemotherapy followed by cranial spinal irradiation and a boost to the primary tumor. The 5-year actuarial overall survival was 100%. There were no spinal failures. These data suggest that a reduction in both volume and dose (30.6-36 Gy) retains the excellent survival rates for patients with localized, pure germinomas of the CNS. A higher rate of ventricular relapse rate is observed, although salvage of those patients is feasible.

Adolescent↗
PubMed2005

Apurinic/apyrimidinic endonuclease activity is associated with response to radiation and chemotherapy in medulloblastoma and primitive neuroectodermal tumors.

PURPOSE: Apurinic/apyrimidinic endonuclease (Ap endo) is a key DNA repair activity that confers resistance to radiation- and alkylator-induced cytotoxic abasic sites in human cells. We assayed apurinic/apyrimidinic endonuclease activity in medulloblastomas and primitive neuroectodermal tumors (PNET) to establish correlates with tumor and patient characteristics and with response to adjuvant radiation plus multiagent chemotherapy. EXPERIMENTAL DESIGN: Ap endo activity was assayed in 52 medulloblastomas and 10 PNETs from patients 0.4 to 21 years old. Ape1/Ref-1, the predominant human Ap endo activity, was measured in 42 medulloblastomas by immunostaining. Cox proportional hazards regression models were used to analyze the association of activity with time to tumor progression (TTP). RESULTS: Tumor Ap endo activity varied 180-fold and was significantly associated with age and gender. Tumor Ape1/Ref-1 was detected almost exclusively in nuclei. In a multivariate model, with Ap endo activity entered as a continuous variable, the hazard ratio for progression after adjuvant treatment in 46 medulloblastomas and four PNETs increased by a factor of 1.073 for every 0.01 unit increase in activity (P < or = 0.001) and was independent of age and gender. Suppressing Ap endo activity in a human medulloblastoma cell line significantly increased sensitivity to 1,3-bis(2-chlororethyl)-1-nitrosourea and temozolomide, suggesting that the association of tumor activity with TTP reflected, at least in part, abasic site repair. CONCLUSIONS: Our data (a) suggest that Ap endo activity promotes resistance to radiation plus chemotherapy in medulloblastomas/PNETs, (b) provide a potential marker of treatment outcome, and (c) suggest clinical use of Ap endo inhibitors to overcome resistance.

Adolescent↗
PubMed2005

O6-methylguanine-DNA methyltransferase, O6-benzylguanine, and resistance to clinical alkylators in pediatric primary brain tumor cell lines.

PURPOSE: Primary brain tumors are the leading cause of cancer death in children. Our purpose is (a) to assess the contribution of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) to the resistance of pediatric brain tumor cell lines to clinical alkylating agents and (b) to evaluate variables for maximal potentiation of cell killing by the MGMT inhibitor O6-benzylguanine, currently in clinical trials. Few such data for pediatric glioma lines, particularly those from low-grade tumors, are currently available. EXPERIMENTAL DESIGN: We used clonogenic assays of proliferative survival to quantitate cytoxicity of the chloroethylating agent 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and the methylating agent temozolomide in 11 glioma and five medulloblastoma lines. Twelve lines are newly established and characterized here, nine of them from low-grade gliomas including pilocytic astrocytomas. RESULTS: (a) MGMT is a major determinant of BCNU resistance and the predominant determinant of temozolomide resistance in both our glioma and medulloblastoma lines. On average, O(6)-benzylguanine reduced LD10 for BCNU and temozolomide, 2.6- and 26-fold, respectively, in 15 MGMT-expressing lines. (b) O6-Benzylguanine reduced DT (the threshold dose for killing) for BCNU and temozolomide, 3.3- and 138-fold, respectively. DT was decreased from levels higher than, to levels below, clinically achievable plasma doses for both alkylators. (c) Maximal potentiation by O6-benzylguanine required complete and prolonged suppression of MGMT. CONCLUSIONS: Our results support the use of O6-benzylguanine to achieve full benefit of alkylating agents, particularly temozolomide, in the chemotherapy of pediatric brain tumors.

Adolescent↗
PubMed2005

Biomarkers: mining the biofluid proteome.

Proteomics has brought with it the hope of identifying novel biomarkers for diseases such as cancer. This hope is built on the ability of proteomic technologies, such as mass spectrometry (MS), to identify hundreds of proteins in complex biofluids such as plasma and serum. There are many factors that make this research very challenging beginning with the lack of standardization of sample collection and continuing through the entire analytical process. Fortunately the advances made in the characterization of biofluids using proteomic techniques have been rapid and suggest that these mainly discovery driven approaches will lead to the development of highly specific platforms for diagnosing diseases and monitoring responses to different treatments in the near future.

Biomarkers↗
PubMed2005

Endoscopic management of cerebrospinal fluid leak associated with the use of bone wax in skull-base surgery.

OBJECTIVE: To alert otolaryngologists to consider the possibility that bone wax may be associated with cerebrospinal fluid leaks that occur immediately after skull-base craniotomy approaches. STUDY DESIGN AND SETTING: Clinical report from surgical experience in a tertiary care setting. RESULTS: Three patients presented with brisk cerebrospinal fluid leak after craniotomy. Sinus endoscopy revealed bone wax within a small parasphenoid defect in all 3 cases. CONCLUSIONS: Bleeding from areas of the skull base adjacent to the paranasal sinuses during craniotomy can signal a small breach of the skull base. Bone wax may control bleeding from edges of transected bone but also stent the skull-base defect open, preventing fibrin deposition and spontaneous healing and closure. SIGNIFICANCE: Otolaryngologists repairing a cerebrospinal fluid leak after a skull-base craniotomy approach should consider the possibility of encountering bone wax and be able to identify it to better treat their patient.

Adult↗
PubMed2005

Surgical site infections after pediatric intracranial surgery for craniofacial malformations: frequency and risk factors.

OBJECTIVE: Surgical site infections (SSIs) after pediatric intracranial surgery for craniofacial malformations are relatively common and potentially serious nosocomial infections. Despite this, few studies have been published on this topic. We performed a retrospective study to determine the incidence of and factors associated with SSIs after intracranial surgery for craniofacial malformations at a single multidisciplinary craniofacial center during a 6-year period. METHODS: Retrospective chart review was performed on 254 patients who underwent 281 intracranial procedures during a 6-year period. Patients with SSIs (cases) were compared with those without SSIs (controls). National Nosocomial Infection Surveillance System criteria were used to identify cases of SSI. RESULTS: SSIs occurred in 9 (3.2%) of 281 intracranial procedures that took place during the study period. Factors associated with an SSI included a complicated diagnosis comprising a diagnosis of syndromic craniosynostosis, frontonasal dysplasia, or oblique facial cleft (odds ratio [OR], 13.0; 95% confidence interval [CI], 2.6-64.4); duration of surgery longer than 426 minutes (OR, 12.1; 95% CI, 2.4-59.9); closure of skin under tension (OR, 12.5; 95% CI, 3.0-52.6); use of bovine pericardium (OR and 95% CI undefined); more than four surgeons present during surgery (OR, 6.3; 95% CI, 1.2-32); pediatric intensive care unit stay longer than 2 days (OR, 10.8; 95% CI, 2.2-53.3); and use of a ventilator after surgery (OR, 4.8; 95% CI, 1.2-18.6). CONCLUSION: In this study, the presence of a complicated diagnosis and a number of other factors were associated with an SSI after pediatric intracranial surgery for craniofacial malformations. We speculate that a complicated diagnosis may be a marker for other factors that contribute to the risk of an SSI. Future studies investigating SSIs after intracranial surgery should consider these factors.

Child↗
PubMed2005

Early composite cranioplasty in infants with severe aplasia cutis congenita: a report of two cases.

OBJECTIVE: Severe cutis aplasia congenita has traditionally been treated with initial soft tissue coverage and delayed cranioplasty. We advocate the technique of early composite reconstruction of both bone and soft tissues. METHODS: Two cases of cutis aplasia congenita with large skull defects (6 x 10 cm, 8 x 8 cm) of superficial layers, skull, and dura are presented. In each case, composite reconstruction was undertaken before 2 weeks of age with restoration of bony and soft tissue coverage through autologous, full-thickness cranial bone grafts and scalp flaps. Both children have been followed up over 2 years with clinical examination and computed tomography (CT) scans. RESULTS: In both cases, defects were completely repaired postoperatively and remained closed 2 years later. Complete regeneration of calvarial bone graft donor sites were documented by CT scan. Head shape and circumference were normal at 2-year follow up.

Bone Transplantation↗
PubMed2005

MDCT diagnosis of the child with posterior plagiocephaly.

OBJECTIVE: In this article, we review the normal anatomy and development of the posterior skull base and describe distinguishing imaging features of the two most common causes of posterior plagiocephaly: posterior deformational plagiocephaly and unilateral lambdoid synostosis. We also describe three unusual cases of posterior plagiocephaly, including asymmetric premature fusion of the anterior and posterior intraoccipital synchondroses, with diagnoses enabled by volume-reformatted MDCT. CONCLUSION: Three-dimensional reformatted MDCT enables accurate diagnosis of common and rare causes of posterior plagiocephaly in children.

Child, Preschool↗
PubMed2005

Temporal lobectomy for refractory epilepsy in the U.S. military.

OBJECTIVES: To determine the characteristics, seizure outcomes, and quality-of-life outcomes for military beneficiaries undergoing partial temporal lobectomy for refractory epilepsy at the only U.S. military medical center with a comprehensive epilepsy surgery program. METHODS: The records of all 84 patients treated with partial temporal lobectomy between 1986 and 2000 at Walter Reed Army Medical Center were retrospectively reviewed. Outcome measures included seizure frequency according to the Engel classification system, driving, employment, anticonvulsant use, and military service. RESULTS: The study cohort consisted of 72 military dependents, 10 active duty military members, and 2 military retirees. Two years after surgery, 65 (92%) of 71 patients had seizure improvement (Engel classes I-III) and 46 (66%) of 71 had seizure remission (Engel class I). Driving and employment rates increased after surgery, whereas anticonvulsant use decreased. Five (50%) of 10 active duty patients achieved seizure remission postoperatively and continued to serve in the Armed Forces. Active duty patients had a later age of seizure onset, shorter duration of epilepsy, and greater proportion of lesional epilepsy, compared with nonactive duty patients. CONCLUSIONS: Epilepsy surgery outcomes in the U.S. military are similar to those reported from nonmilitary centers, with the majority of patients experiencing seizure remission and improvements in quality-of-life measures. Complete seizure remission after successful anterior temporal lobectomy enables some active duty military members to continue service in the U.S. Armed Forces.

Adolescent↗
PubMed2004

The misdiagnosis of acute cervical spine injuries and fractures in infants and children: the 12-year experience of a level I pediatric and adult trauma center.

OBJECTIVE: The objective was to determine the frequency of acute cervical spine injuries and fractures that were misdiagnosed in infants and children (< or =14 years) initially evaluated at a pediatric and adult urban level I trauma center. METHODS AND RESULTS: This was a retrospective, single-institution, case series of pediatric cervical spine injuries and fractures that were misdiagnosed during initial emergency room imaging evaluation. "Misdiagnosed" cases were those cases whose imaging studies initially obtained in the emergency room were misinterpreted based on reevaluation by a senior trauma radiologist blinded to the initial results. Nineteen percent (7 out of 37) were misdiagnosed on initial emergency room imaging evaluation. Five percent were true "missed" fractures, and 14% were "normal and/or developmental variants" read as fractures or dislocation. CONCLUSIONS: The error rate for infants and children < or =8 years was 24%, and for children > or =9 years was 15%. The occiput to C2 region was the most common site of diagnostic error. The most common factors predisposing to misdiagnosis were unfamiliarity with pediatric cervical spine anatomy, failure to recognize normal variants seen during growth and development, and suboptimal conventional film techniques.

Adolescent↗
PubMed2004

The SmoA1 mouse model reveals that notch signaling is critical for the growth and survival of sonic hedgehog-induced medulloblastomas.

To develop a genetically faithful model of medulloblastoma with increased tumor incidence compared with the current best model we activated the Sonic Hedgehog (Shh) pathway by transgenically expressing a constitutively active form of Smoothened in mouse cerebellar granule neuron precursors (ND2:SmoA1 mice). This resulted in early cerebellar granule cell hyper-proliferation and a 48% incidence of medulloblastoma formation. Gene expression studies showed an increase in the known Shh targets Gli1 and Nmyc that correlated with increasing hyperplasia and tumor formation. Notch2 and the Notch target gene, HES5, were also significantly elevated in Smoothened-induced tumors showing that Shh pathway activation is sufficient to induce Notch pathway signaling. In human medulloblastomas reverse transcription-PCR for Shh and Notch targets revealed activation of both of these pathways in most tumors when compared with normal cerebellum. Notch pathway inhibition with soluble Delta ligand or gamma secretase inhibitors resulted in a marked reduction of viable cell numbers in medulloblastoma cell lines and primary tumor cultures. Treatment of mice with D283 medulloblastoma xenografts with a gamma secretase inhibitor resulted in decreased proliferation and increased apoptosis, confirming that Notch signaling contributes to human medulloblastoma proliferation and survival. Medulloblastomas in ND2:SmoA1 mice and humans have concomitant increase in Shh and Notch pathway activities, both of which contribute to tumor survival.

Adolescent↗
PubMed2004

Concurrent chemotherapy and reduced-dose cranial spinal irradiation followed by conformal posterior fossa tumor bed boost for average-risk medulloblastoma: efficacy and patterns of failure.

PURPOSE: To review the efficacy and patterns of failure in average-risk medulloblastoma patients treated with concurrent chemotherapy and reduced-dose cranial spinal irradiation and a conformal tumor bed boost. METHODS AND MATERIALS: Thirty-three patients with average risk (defined as < or =1.5 cm(2) of residual tumor after resection, age >3 years, and no involvement of the cerebrospinal fluid or spine [M0]) medulloblastoma were diagnosed at our institution between January 1994 and December 2001. They were enrolled in an institutional pilot protocol consisting of concurrent chemotherapy (vincristine), reduced-dose cranial spinal irradiation (2340 cGy), a conformal primary tumor bed boost (3240 cGy), followed by eight cycles of chemotherapy (vincristine, cisplatin, and lomustine or cyclophosphamide). The median age at diagnosis of the 33 patients was 7 years (range, 3-21 years). The male/female patient ratio was 2.4:1. The median follow-up of the entire group was 37 months (range, 6-96 months), and the median follow-up of the survivors was 44 months (range, 10-96 months). RESULTS: The 5-year estimated disease-free survival rate, as determined by Kaplan-Meier plots, was 86% (+/-12.6%, 95% confidence interval). The 5-year estimated disease-free posterior fossa control and primary tumor bed control rates were both 94% (+/-8.2%, 95% confidence interval). The patterns of failure included 2 patients with distant central nervous system failure only, 1 patient who developed local primary tumor bed failure, posterior fossa failure, and diffuse leptomeningeal spread simultaneously, and 1 patient with failure in the high-dose, primary tumor bed field. No patient experienced isolated posterior fossa failure outside the high-dose boost region. CONCLUSION: The treatment of average-risk medulloblastoma with chemotherapy, reduced-dose cranial spinal irradiation, and a conformal tumor bed boost results in survival rates and local control rates comparable to those in contemporary studies. A reduction in the amount of posterior fossa treated to the high dose is possible. These results need to be corroborated in a large, cooperative group study.

Adolescent↗
PubMed2004

Differential diagnosis of the trapezoid-shaped head.

OBJECTIVE: To recognize several conditions that result in a trapezoid head shape and review and contrast their various physical findings. METHODS: A detailed review of all patients seen in the Craniofacial Clinic at the Children's Hospital and Regional Medical Center in Seattle, Washington, over a 10-year period from 1991 to 2001, with the diagnosis of craniosynostosis and plagiocephaly was performed. During this period, 690 patients had a surgical correction of craniosynostosis, and 1537 patients had posterior plagiocephaly. RESULTS AND CONCLUSIONS: The shape of the head when viewed from the vertex position in an axial plane can be a significant diagnostic aid when evaluating a patient with plagiocephaly. Positional molding causes the vast majority of plagiocephaly. This deformational change results in a parallelogram-shaped head. A much more rare cause of plagiocephaly is lambdoid synostosis. With premature fusion of one of the lambdoid sutures, the head takes on a very characteristic trapezoid shape when viewed from the vertex. Unilateral coronal synostosis that occurs on the same side as either posterior positional molding or unilateral lambdoid synostosis will also result in the trapezoid head shape. Furthermore, on the rare occasion when anterior and posterior deformational plagiocephaly occurs on the same side, the trapezoid head shape may be the consequence. The choice of appropriate treatment modality requires systematic evaluation of the patient with a trapezoid-shaped head to determine the etiology of the deformation.

Craniosynostoses↗
PubMed2004

Failure of autologous bone-assisted cranioplasty following decompressive craniectomy in children and adolescents.

OBJECT: The authors have routinely performed primary autologous cranioplasty to repair skull defects after decompressive craniectomy. The high rates of subsequent bone resorption occurring in children prompted this study. METHODS: In an institutional review, the authors identified 40 (32 male and eight female) children and adolescents ranging from 4 months to 19 years of age in whom autologous cranioplasty was performed after decompressive craniectomy. The defect surface area ranged from 14 to 147 cm2. In all cases, the bone was fresh frozen at the time of the decompression. Symptomatic bone resorption subsequently occurred in 20 children (50%) in all of whom reoperation was required. The incidence of bone resorption significantly correlated with an increased skull defect area (p < 0.025). No significant correlation was found with age, sex, or anatomical location of the skull defect, number of fractured bone fragments, presence of a shunt, cause for decompressive craniectomy, method of duraplasty, or interval between the craniectomy and the cranioplasty. Reoperation to repair the resorbed autologous bone was performed 2 to 76 months after the initial procedure. CONCLUSIONS: The use of autologous bone to reconstruct skull defects in pediatric patients after decompressive craniectomy is associated with a high incidence of bone resorption. The use of autologous bone should be reevaluated in light of the high rate of reoperation in this pediatric population.

Adolescent↗
PubMed2004

Severe posttraumatic craniocervical instability in the very young patient. Report of three cases.

Children younger than 3 years of age represent a distinct subpopulation of patients at particular risk for high cervical and craniovertebral injuries. There are few descriptions of survivors of severe craniocervical trauma among the very young, and scarce data exist regarding management after initial emergency stabilization. The authors describe three children, age 1 to 32 months, who presented with craniocervical junction injuries. Variable neurological findings were observed at presentation (cranial nerve deficits, obtundation, and moderate-to-severe quadriparesis). All three were treated with prolonged immobilization and have recovered with minimal to no neurological deficit.

Child, Preschool↗