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Biomedical subjects

I F Pollack

Publications and source records attributed to I F Pollack.

At least 55 records · Page 3Linked to original sources
PubMed1998

Application of signal transduction inhibition as a therapeutic strategy for central nervous system tumors.

During the last decade, rapid progress has been made in understanding the molecular pathways underlying the proliferation of both normal and neoplastic cells. The processes by which messages to initiate protein synthesis, cell cycle progression, and even cell death are transmitted from the cell surface or the cytoplasm to the nucleus are broadly referred to as 'signal transduction'. These multistep pathways involve a host of proteins that interact with other proteins in overlapping cascades that flow downstream in a stepwise fashion from the cell membrane to the nucleus. Inappropriate overactivation or underactivation of various components of such signaling pathways can contribute to pathological processes, such as neoplasia. Conversely, molecular and pharmacological interventions that target and attempt to reverse the aberrant state of activation can potentially be of therapeutic benefit. The present article provides a background for understanding the contribution of signal transduction pathways to the proliferation of normal and neoplastic cells and describes ways in which targetted inhibition of selected signaling pathway components has been exploited to inhibit tumor growth in vitro and in vivo. Because most studies to date involving central nervous system (CNS) tumors have focused on gliomas, in view of their frequency in both the pediatric and adult age groups, the discussion of therapeutic applications for CNS neoplasia will deal primarily with these lesions. However, the basic concepts presented are generalizable to most tumor types and have been successfully applied in vitro in medulloblastomas as well. Ultimately, the translation of such strategies to the treatment of patients with malignant brain tumors may provide novel approaches for improving the poor outlook associated with these neoplasms.

Animals↗
PubMed1998

Management of encephaloceles and craniofacial problems in the neonatal period.

Although craniofacial problems are commonly detected during the neonatal period, only a selected subgroup of lesions require early intervention. Such lesions are characterized either by their potential for causing early neurologic impairment, infection, or other severe sequelae if treatment is delayed or by the fact that the therapeutic outcome is more favorable with early intervention. An overriding consideration in the decision to treat any of these problems during the neonatal period is the risk of major blood loss, which can pose a life-threatening problem. Accordingly, meticulous surgical technique and close monitoring of hemodynamic status are crucial to optimizing therapeutic outcome. Herein, we present therapeutic caveats and operative techniques for the neurosurgical management of craniofacial lesions commonly encountered during the neonatal period.

Birth Injuries↗
PubMed1997

Incidence of postlaminectomy kyphosis after Chiari decompression.

STUDY DESIGN: In this retrospective study, a 5-year series of a pediatric population undergoing Chiari decompressions is reviewed. OBJECTIVES: To review the experience with children treated with suboccipital craniectomy and uni- or multilevel cervical laminectomy for Chiari malformation, to determine the incidence of kyphosis and to identify factors predictive of cervical instability. SUMMARY OF BACKGROUND INFORMATION: Upper cervical laminectomy in the pediatric population has a significant risk of postoperative kyphosis. To decrease the incidence of this complication, a concerted effort was made to avoid violation of the facet joint during cervical laminectomy. METHODS: Thirty-two patients (mean age 4.9 years, range 1 day to 18 years) had surgical decompression of Chiari I or II malformations throughout a 5-year period (1989-1994). Radiographs and operative records were analyzed to determine the number of cervical levels decompressed and extent of laminectomy. RESULTS: Mean follow-up was 3.7 years (range 9 months to 7 years). Only one patient had clinical and radiographic evidence of kyphosis and required C2-C3 fusion. Two others had radiographic signs of mild cervical kyphosis but remained asymptomatic. These three patients had two-level complete laminectomies. Twenty-nine patients had no clinical or radiographic evidence of cervical instability. A mean of three cervical levels were decompressed (range 0-4), including partial laminectomies, complete laminectomies, and one osteoplastic laminotomy to drain a lower cervical syrinx. The overall frequency of kyphosis in this series (9%) was substantially lower than in previous reports. Although the number of cervical levels decompressed did not correlate with cervical instability, the one patient with clinical instability had inadvertent violation of the facet joint, suggesting that overaggressive laminectomy may be a critical factor that predisposes patients to postoperative kyphosis. CONCLUSION: Cervical kyphosis after Chiari decompression is a recognized complication of cervical laminectomy in children, the frequency of which may be decreased by careful attention to operative technique.

Adolescent↗
PubMed1997

Proliferation index as a predictor of prognosis in malignant gliomas of childhood.

BACKGROUND: The prognosis for children with high grade gliomas remains somewhat unpredictable because histologic features alone provide an imperfect assessment of the biologic behavior of a given lesion. Whereas some patients experience prolonged disease control after surgery and adjuvant therapy, others with lesions that appear comparable exhibit rapid disease progression and death. METHODS: Because proliferative activity may provide a potential correlate of biologic aggressiveness, the authors examined the relationship between MIB-1 labeling index and outcome in a series of 29 archival pediatric malignant nonbrainstem gliomas from patients treated consecutively at the study institution between 1975 and 1992, in which clinical, histologic, diagnostic, and therapeutic parameters were previously defined. Three patients who died perioperatively were excluded from outcome analyses. All tumors were rereviewed by two neuropathologists and classified as Grade 3 or 4 lesions based on contemporary guidelines. RESULTS: Among the specimens from the 26 patients who survived the perioperative period, a striking difference in outcome was apparent between tumors with MIB-1 indices < 12 (n = 10) and those with indices > 12 (n = 16). Median progression free survival was >48 months in the low MIB-1 group compared with only 6 months in the high MIB-1 group (P = 0.014, rank-sum test). Median overall survival was >48 months in the low MIB-1 group compared with only 16 months in the high MIB-1 group (P = 0.012). MIB-1 index remained associated with survival after taking into account the effect of resection extent, which also correlated strongly with outcome in this cohort. Although MIB-1 index was associated with histopathologic grade (Grade 3: 11.9 +/- 9.7 vs. Grade 4: 27.3 +/- 19.0; P = 0.015, Fisher's exact test), it proved to be a much stronger predictor of outcome than histology. CONCLUSIONS: MIB-1 index may supplement routine histologic classification as a means for improving the accuracy of predicting the biologic behavior of childhood malignant gliomas and may provide a basis for stratifying patients in future malignant glioma studies and refining therapeutic decision-making.

Antibodies, Monoclonal↗
PubMed1997

The relationship between TP53 mutations and overexpression of p53 and prognosis in malignant gliomas of childhood.

The prognosis for children with high-grade gliomas remains somewhat unpredictable. Although prolonged disease control is sometimes achieved after surgery, radiotherapy, and chemotherapy, most patients exhibit rapid disease progression. Because p53-dependent apoptosis mechanisms are involved in the cytotoxic effects of irradiation and chemotherapy, we questioned whether p53 status might be associated with outcome in childhood malignant gliomas. Therefore, we examined p53 status, both immunohistochemically and by direct sequencing of exons 5-8, in a series of 29 archival pediatric malignant non-brainstem gliomas treated consecutively at our institution between 1975 and 1992. Eighteen tumors had dense p53 staining in the majority of cells, although only 11 had mutations of the p53 gene (TP53). On univariate analysis, there was a significant association between p53 overexpression and a shorter progression-free survival (PFS) and overall survival (OS; P = 0.019 and 0.013, respectively; rank sum test). In addition, there was a significant association between TP53 mutations and a poorer PFS (P = 0.04), and a strong trend toward a shorter OS among patients with TP53 mutations (P = 0.06). Median PFS and OS for patients with TP53-mutated tumors were 6 months and 16 months, respectively, and for those with p53 overexpression 5.5 months and 14 months, respectively, versus 16 months and 25 months, respectively, for those without TP53 mutations and 25 months and >4 years, respectively, for those without p53 overexpression. The percentage of patients in this series with TP53 mutations (37.9%) was substantially higher than in previous studies of childhood gliomas and comparable to the frequency of mutations noted in adult gliomas. However, both TP53 mutation and p53 overexpression were significantly less frequent in tumors from children younger than 4 than from older children (P = 0.02 and 0.01, respectively). These results indicate that p53 mutation and expression status may be associated with prognosis in childhood malignant gliomas, and thus may provide a basis for stratifying patients biologically in future malignant glioma studies.

Adolescent↗
PubMed1997

The role of protein kinase C (PKC) in the evolution and proliferation of malignant gliomas, and the application of PKC inhibition as a novel approach to anti-glioma therapy.

The present article reviews the role of the second messenger enzyme protein kinase C (PKC) in the growth regulation of high-grade gliomas, and evaluates the efficacy of therapeutic strategies directed against PKC for blocking the proliferation of these malignancies in in vitro and in vivo models. The translation of such strategies to the treatment of patients with malignant gliomas may provide a novel approach for improving the otherwise grim outlook associated with these neoplasms.

Animals↗
PubMed1997

Posterior fossa syndrome.

Transient mutism is a well-recognized sequela of posterior fossa tumor resection in children. A recent review from our institution indicated that 12 of 142 children undergoing such procedures (8.5%) exhibited transient speech impairment, the largest series of such patients reported to date. Each child had a vermian neoplasm that was approached by division of the inferior vermis (n = 10) and/or superior vermis (n = 3). Seven children had medulloblastomas, three had astrocytomas, and two had ependymomas. None of the affected children had cerebellar hemispheric lesions; in contrast, the incidence among children with vermian neoplasms was 13%. In general, mutism developed 1 to 4 days postoperatively and typically was associated with puzzling neurobehavioral abnormalities. All children had bizarre personality changes, emotional lability, and/or decreased initiation of voluntary movements; nine exhibited poor oral intake; and five had urinary retention. Detailed neuropsychological testing was performed in seven children and confirmed the presence of widespread impairments not only in speech, but also in initiation of other motor activities. These deficits generally resolved during a period of several weeks to months, although two children had residual impairment. Characteristically, affect and oral intake normalized before the speech began to improve. These deficits were noted to correlate with the presence of edema within the brachium pontis bilaterally, although this association was not absolute. The latter observation suggests that there was not a single locus underlying this disorder, but rather that the involved neural pathways may have been impaired at any one of a number of sites within the posterior fossa. Based on the results in our patients and in others described in the literature, we postulate an important role for the cerebellum and/or its afferent and efferent connections in initiating (rather than merely coordinating) speech and other complex motor activities and a potential role for these structures in influencing overall behavior and affective state.

Adolescent↗
PubMed1997

The effect of calphostin C, a potent photodependent protein kinase C inhibitor, on the proliferation of glioma cells in vitro.

Recent studies have suggested that the proliferation of malignant gliomas may result from activation of protein kinase C (PKC)-mediated pathways; conversely, inhibition of PKC may provide a strategy for blocking tumor growth. In the current studies, we examined the effect of a novel PKC inhibitor, calphostin C, which is a selective, highly potent, photo-activatable inhibitor of the PKC regulatory domain, on the proliferation and viability of three established and three low-passage malignant glioma cell lines, four low-passage low-grade glioma cell lines, and in adult human and neonatal rat non-neoplastic astrocyte cell lines in vitro. Under light-treated conditions, calphostin C consistently inhibited cell proliferation in each of the tumor cell lines and in the neonatal rat astrocyte cell line with a 50% effective concentration of 30 to 50 ng/ml (40 to 60 nm), which was comparable to the previously reported median inhibitory concentration (IC50) for PKC inhibition by calphostin C. Complete elimination of proliferation was achieved at concentrations of 50 to 100 ng/ml (60 to 125 nM). Cell viability decreased sharply with calphostin C concentrations of 100 to 300 ng/ml (125 to 380 nM). In contrast, under light-shielded conditions, calphostin C had a comparatively modest effect on cell proliferation and viability, with a median effective concentration of approximately 300 ng/ml. No significant inhibition of proliferation was noted in the non-neoplastic adult astrocyte cell line under either light-treated or light-shielded conditions. These findings provide further evidence that PKC may play an essential role in mediating the proliferation of both benign and malignant glioma cells in vitro and may also contribute to the proliferation of non-neoplastic immature astrocytes. Light-sensitive inhibition of proliferation and viability by agents such as calphostin C may provide a novel strategy for applying photodynamic therapy to the treatment of neoplastic glial cells.

Animals↗
PubMed1997

Growth factors in gliomas: antisense and dominant negative mutant strategies.

Antisense and dominant negative mutant strategies were developed as 'magic bullets' to suppress the function of a particular gene while preserving the remaining cellular activities. While experience with these techniques has dispelled some of the 'magic', these strategies remain useful for understanding the function of particular gene products. Antisense strategies involve the administration of either a synthetic oligodeoxynucleotide or a plasmid construct which produces a sequence that is complementary to the DNA or mRNA of the gene of interest. Antisense binding should inhibit transcription or translation of the gene, and thus decrease synthesis of the protein for which the gene encodes. Conversely, dominant negative mutations inhibit activity of a gene product by encoding for a second protein which suppresses the function of the gene of interest. For example, a single mutant subunit in a multimeric protein might allow normal assembly of the protein while inhibiting its activity. The use of these techniques for investigating the role of various growth factor pathways in glial neoplasia and their potential therapeutic applications are reviewed below.

Animals↗
PubMed1997

Frameless stereotactic guidance for surgery of the upper cervical spine.

OBJECTIVE: The goal was to evaluate and describe the use of a frameless, computed tomography-guided, stereotactic technique in complex procedures involving the craniocervical junction. METHODS: Eleven procedures, including transoral odontoid resection, posterior atlantoaxial fusion with transarticular C1-C2 screw fixation, and spinal tumor resection, were performed in the preceding 26 months. In each case, frameless stereotaxy was used to plan the incision, to define resection margins, and to determine the appropriate orientation of instrumentation. RESULTS: There were no intraoperative complications noted. Each patient underwent adequate resection of the pathological lesion and satisfactory placement of instrumentation. The stereotactic system provided detailed anatomic visualization, which increased the confidence of the surgeon during the procedure. The system limited the need for extensive surgical exposure, reduced fluoroscopy time, and decreased the risk of neurovascular injury. CONCLUSION: Frameless stereotaxy provided the surgeon with intraoperative information regarding the extent of bone and soft tissue resection. It provided a multidimensional view of anatomic relationships in the operative field, which significantly increased surgical accuracy and safety.

Adult↗
PubMed1997

The molecular biology of ependymomas.

Intracranial ependymomas are the third most common primary brain tumor in the pediatric population. Although an anaplastic variant is recognized, numerous studies examining the prognostic implications of histological features, such as necrosis, endothelial proliferation and mitoses, have yielded contradictory results. In order to improve outcome prediction in affected patients and to refine therapeutic decision-making, there is a strong need for identifying relevant biological correlates of tumor behavior. The molecular biology of tumors is a rapidly expanding field and includes investigations into cytogenetics, oncogenes, growth factors, growth factor receptors, hormonal receptors, proliferation markers, apoptosis, cell cycle genes and cell adhesion molecules, as well as factors potentially related to therapeutic resistance, such as the multidrug resistance gene. The molecular biology of astrocytic tumors in adults has been the subject of many studies; however, relatively few studies have been focused on ependymomas. Herein we review potential oncological markers in ependymomas that have been identified to date and highlight the limitations of our current knowledge as a basis for defining areas for future investigation.

Brain Neoplasms↗
PubMed1997

Neurofibromatosis 1 and 2.

Neurofibromatosis (NF) 1 and 2 are multisystem disorders associated with a variety of neoplastic and non-neoplastic manifestations that typically progress in severity during the lifetime of the affected patient. The importance of appropriately diagnosing these disorders stems from the fact that the natural history of an associated neoplasm, such as a peripheral nerve tumor or an optic glioma, may be significantly different depending on whether or not the lesion arises in a person with NF. In addition, the indications for therapeutic intervention, hierarchy of treatment options and long-term management goals may differ substantially for patients with NF-related versus sporadic tumors. Finally, recognition of the diagnosis comprises an essential step for providing appropriate multidisciplinary evaluation and counseling to affected patients and their families. This article addresses the principal manifestations of these disorders and provides a contemporary review of the diagnostic and therapeutic issues that arise in children with NF1 and NF2.

Humans↗
PubMed1997

Follow-up of children with shunted hydrocephalus.

In order to determine if routine yearly evaluations of children with shunted hydrocephalus were likely to diagnose shunt malfunction, we reviewed the medical records of the last 100 children who had such routine evaluations. Only 4 children had symptoms that were potentially referable to malfunction; none were subsequently found to have malfunction and no child had signs of malfunction. We also reviewed the medical records of the last 100 children who had shunt revisions to determine if any of them were diagnosed during routine follow-up examinations. Four were: 2 with clinical signs of malfunction and 2 with evidence of malfunction on routine scans. Only 1 child in either group had signs or symptoms of malfunction if they had a functioning shunt in place for longer than 1 year. Although yearly follow-up visits are common practice, we conclude that such examinations are unlikely to detect shunt malfunction. Follow-up at intervals of 2 years is probably appropriate after 2 years of age if the child has had a functional shunt for 1 year and has had a scan that indicates a functioning shunt.

Child↗
PubMed1997

Vestibular compensation in a patient with a cerebellar infarction.

We report the case of a 67-year-old man who suffered a traumatic unilateral peripheral vestibular injury subsequent to an unrelated prior cerebellar infarction that occurred at least 2 years earlier. The patient's clinical course was marked by poor compensation for his peripheral vestibular loss. Four months after his vestibular injury, his symptoms of dizziness had not resolved. He had a spontaneous vestibular nystagmus, and laboratory testing indicated an asymmetric semicircular canal-ocular reflex. The otolith-ocular reflex, tested using off-vertical axis rotation, also was asymmetric but had a preserved modulation component. Visual-vestibular interaction and semicircular canal-otolith interaction were normal. An MRI indicated preservation of the flocculo-nodular lobe but infarction of the pyramis and uvula. Taken together, the findings in this case suggest that despite structural and functional preservation of the flocculo-nodular lobe, an anatomic region often labeled the "vestibulo-cerebellum", a lesion of the cerebellum that can impair CNS compensation for a unilateral peripheral lesion in humans.

Adaptation, Physiological↗
PubMed1997

Diagnosis and management of posterior plagiocephaly.

OBJECTIVE: The management of infants with posterior plagiocephaly has been controversial both because of widely differing estimates in the literature of the relative frequencies of true lambdoidal synostosis vs positional molding and because of divergent approaches to treating this problem in different institutions. Based on our experience, we hypothesized that the vast majority of children with posterior plagiocephaly did not have true synostosis and that the cosmetic impairment in such patients could be effectively treated with nonsurgical modalities. METHODS: Between 1992 and 1995, we prospectively applied in 71 infants a consistent management philosophy for these malformations that has incorporated a detailed evaluation of sutural anatomy as the basis for a physiologic approach to treatment. This approach has been directed at distinguishing true synostosis from deformational plagiocephaly and at avoiding surgery for patients with deformational abnormalities by using a combination of nonsurgical modalities to restore normal cranial growth dynamics. All children first underwent skull radiographs to determine whether the lambdoidal sutures were patent. In equivocal cases, computed tomography was also performed. Patients without true synostosis were enrolled on a course of positional therapy. In patients that did not improve after 2 to 3 months, a custom-fitted orthoplastic molding helmet was applied to facilitate passive skull recontouring. RESULTS: Forty children had patent sutures based on skull radiographs, and 29 others, in whom the radiographs were equivocal, had open sutures based on computed tomography, thus establishing the diagnosis of deformational plagiocephaly in 69. Predisposing factors for this deformity included a strong positioning preference during early infancy (n = 67), torticollis (n = 10), prematurity (n = 6), and developmental delay (n = 2). Only two patients had true lambdoidal synostosis; in each case, this was associated with synostosis of the posterior sagittal suture and was managed effectively with cranial reconstructive surgery. Thirty-five patients with deformational plagiocephaly had a dramatic improvement in their cranial contour with positional therapy alone; 34 patients failed to improve and were treated with molding helmets. All but five children, each of whom was more than 6 months old at initial intervention (P < .025), developed a normal or nearly normal head shape with these measures. CONCLUSION: The vast majority of children with posterior plagiocephaly do not have true synostosis and can be effectively managed by nonsurgical means. The impact of positional preference on the development of this process is discussed.

Craniofacial Abnormalities↗
PubMed1997

Continuous intraoperative electromyographic monitoring of cranial nerves during resection of fourth ventricular tumors in children.

The authors reviewed the results of continuous intraoperative electromyographic (EMG) monitoring of muscles innervated by cranial nerves in 17 children whose preoperative imaging studies showed compression or infiltration of the fourth ventricular floor by tumor to determine how intraoperative EMG activity correlated with postoperative cranial nerve morbidity. Bilateral lateral rectus (sixth) and facial (seventh) nerve musculatures were monitored in all children. Cranial nerve function was documented immediately postoperatively and at 1 year. Of the 68 nerves monitored, nine new neuropathies occurred in six children (sixth nerve in four children and seventh nerve in five). In five new neuropathies, intraoperative EMG activity could be correlated in one of four sixth nerve injuries and four of five seventh nerve injuries. Electromyographic activity could not be correlated in four children with new neuropathies. Of 59 cranial nerves monitored that remained unchanged, 47 had no EMG activity. Twelve cranial nerves (three sixth nerves and nine seventh nerves) had EMG activity but no deficit. Of four children with lateral rectus EMG activity, three had new seventh nerve injuries. Lateral rectus EMG activity did not predict postoperative abducens injury. The absence of lateral rectus EMG activity did not assure preserved abducens function postoperatively. Likely because of the close apposition of the intrapontine facial nerve to the abducens nucleus, lateral rectus EMG activity was highly predictive of seventh nerve injury. Although facial muscle EMG activity was not an absolute predictor of postoperative facial nerve dysfunction, the presence of facial muscle EMG activity was associated statistically with postoperative facial paresis. The absence of facial muscle EMG activity was rarely associated with facial nerve injury. The authors speculate that EMG activity in the facial muscles may have provided important intraoperative information to the surgeon so as to avoid facial nerve injury.

Adolescent↗
PubMed1997

Upper cervical spine fusion in the pediatric population.

The outcomes of 25 pediatric patients who underwent upper cervical or occipitocervical fusion at the authors' institution since 1983 were reviewed. At a mean age of 9 years, the patients presented with spinal instability that was associated with os odontoideum in 11 cases, rotatory subluxation in five cases, odontoid fracture in two cases, atlantooccipital dislocation in two cases, and congenital atlantoaxial instability in five patients, four of whom had Down's syndrome (trisomy 21). Ten children had abnormal findings on neurological examination preoperatively; however, nine experienced improvement or resolution of deficits as of their latest follow-up evaluation (mean 17 months). Fusion was achieved with the first operation in 21 of 25 patients; eventually it was attained in all but one. Four patients exhibited persistent spinal instability after an initial procedure. This was caused by erosion of a multistranded cable through the intact arch of C-2 in two cases, by pin site infection necessitating early halo removal in one case, and by slippage in a halo following a Gallie procedure, which was revised with a Brooks fusion in one case. This series, the largest yet published, shows that with appropriate surgical management, posterior upper cervical fusion in the pediatric population is highly successful. Careful attention to halo pin site care and caution in using multistranded cable in young patients may improve results.

Adolescent↗