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Biomedical subjects

R J Packer

Publications and source records attributed to R J Packer.

At least 127 records · Page 7Linked to original sources
PubMed1990

Localized 31P magnetic resonance spectroscopy of large pediatric brain tumors.

Fourteen children aged 1 week to 16 years, with a variety of large or superficial brain tumors, underwent localized in vivo 31P magnetic resonance spectroscopy of their tumor. Quantitative spectral analysis was performed by measuring the area under individual peaks using a computer algorithm. In eight patients with histologically benign tumors the spectra were considered to be qualitatively indistinguishable from normal brain. The phosphocreatine/inorganic phosphate ratio (PCr/Pi) averaged 2.0. Five patients had histologically malignant tumors; qualitatively, four of these were considered to have abnormal spectra, showing a decrease in the PCr peak. The PCr/Pi ratio for this group averaged 0.85, which was significantly lower than that seen in the benign tumor group (p less than 0.05). No difference between the two groups was seen in adenosine triphosphate or phosphomonoesters. It is concluded that a specific metabolic "fingerprint" for childhood brain tumors may not exist, but that some malignant tumors show a pattern suggestive of ischemia.

Adenosine Triphosphate↗
PubMed1990

Monosomy 22 in rhabdoid or atypical tumors of the brain.

Cytogenetic studies of three rare childhood brain tumors were performed. Two children presented with pure rhabdoid tumors. The third child had a tumor composed of a mixture of rhabdoid elements with neuroepithelial, epithelial, and mesenchymal tissue - an atypical teratoid tumor. All three tumors demonstrated monosomy 22 as the only cytogenetic abnormality. The cytogenetic findings suggest that loss of a gene or genes on chromosome 22 may be involved in the initiation or progression of these malignant tumors. Further studies on additional fresh tumor specimens are warranted; however, it is possible that cytogenetic studies may be used as an additional means of diagnosing rhabdoid or atypical teratoid tumors of the brain.

Brain Neoplasms↗
PubMed1990

Medulloblastomas.

It is obvious that the past decade has witnessed considerable progress in the management of children with medulloblastoma. Better surgical technique has led to more aggressive surgery with less morbidity. The use of staging has led to reduction in radiation therapy doses in some patients and will, it is hoped, lead to better neuropsychological outcome. The use of adjuvant chemotherapy in high-risk patients is delaying recurrence. It remains unknown, however, whether the patient with a medulloblastoma is ever "cured." Certainly, in the future, control of this tumor will depend on new therapeutic modalities, which will be developed on the basis of a better understanding of the biology of these primitive tumors. A better understanding of tumor immunology, cytogenetics, and biochemistry is a goal for the future.

Adolescent↗
PubMed1990

Primitive neuroectodermal tumors of the central nervous system. Patterns of expression of neuroendocrine markers, and all classes of intermediate filament proteins.

Snap-frozen samples from 22 primitive neuroectodermal tumors (PNETs) primary in the central nervous system were studied with antibodies to synaptophysin, bombesin, somatostatin, substance P, vasoactive intestinal polypeptide, all classes of intermediate filaments, and desmoplakins I and II. Frozen sections were immunostained by the avidin-biotin peroxidase complex and indirect immunofluorescence microscopy methods. Selected cases were also studied by double and triple label immunofluorescence microscopy, and by two-dimensional gel electrophoresis and immunoblot analysis. We found that all 22 PNETs expressed synaptophysin extensively. Focal expression of 2 or more neuropeptides was noted in 10 samples studied. All PNETs expressed vimentin, 21 of 22 expressed glial filament protein (GFP), 16 of 22 expressed neurofilament proteins (NFP), 4 of 22 expressed desmin, and 3 of 22 expressed cytokeratins. In only one case were focal and questionable reactions with desmoplakin antibodies seen. Immunoblots confirmed the presence of desmin. Double and triple immunofluorescence revealed a number of antigenic coexpressions in individual cells including: synaptophysin with vimentin, GFP, NFP and desmin, vimentin-GFP, vimentin-NFP, vimentin-cytokeratin, vimentin-desmin and desmin-NFP; similarly, combinations of vimentin-GFP-NFP, vimentin-GFP-desmin, and vimentin-GFP-cytokeratin were found. The consistent expression of synaptophysin and 2 or more neuropeptides indicates that central nervous system PNETs have significant phenotypic features in common with neuroendocrine tumors. Their complex and variable intermediate filament complement patterns combined with their consistent expression of specific neuroendocrine differentiation markers, suggest that central nervous system PNETs comprise a distinct, albeit heterogeneous group of neoplasms.

Adolescent↗
PubMed1990

Acute mental status changes in children with systemic cancer.

Acute changes in mental status (AMS) develop in children with cancer from a multitude of cancer- and treatment-related complications. To determine the incidence, etiology, and outcome of children with cancer who had AMS, the medical records of all children under 18 years of age with systemic cancer (excluding primary central nervous system tumors) who had AMS in our institution during the years 1981 through 1987 were reviewed. AMS developed in 89 of 815 children at risk (11%). The AMS was caused by seizures in 53 (60%), an encephalopathy in 24 (27%), and a stroke syndrome in 12 (13%). AMS occurred in 42 of 305 (14%) with leukemia, 16 of 139 (12%) with lymphoma, 14 of 136 (10%) with sarcoma, 10 of 104 (9%) with neuroblastoma, and 7 of 104 (5%) with other malignancies. Children with acute lymphocytic leukemia were more prone to having seizures (61%), while children with nonacute lymphocytic leukemia were almost equally likely to have encephalopathies, strokes, or seizures. Children with lymphoma were admitted for treatment most often with an encephalopathy (44%). Etiologies for AMS were evaluated vigorously, and one or more etiologies were identified in 80 of 89 (89%) patients. Dependent on the type of tumor, the anticancer treatment used and, timing during the course of illness AMS occurred, specific diagnoses were more likely. Neurologic morbidity and mortality were dependent on the cause of AMS. Children with seizures that were initially difficult to control were more likely to require long-term anticonvulsant therapy.

Acute Disease↗
PubMed1989

Neurologic complications in children with soft tissue and osseous sarcoma.

From 1980 to 1987, 162 consecutive children with soft tissue and osseous sarcoma were reviewed to determine the frequency and types of neurologic complications seen. Neurologic complications occurred in 43 of 162 (26.5%) patients. Children with poorly differentiated sarcomas and rhabdomyosarcoma were more likely to have neurologic complications, which occurred in 39% of patients at risk. The types of complications seen included: metastatic spinal cord compression (11%); symptomatic peripheral neuropathy (10%); intracranial metastatic disease (7.5%); seizures (6%); and acute and chronic methotrexate-related neurologic dysfunction (2.5%). Spinal cord compression frequently occurred early in disease whereas brain metastases was almost always a late finding. Symptomatic peripheral neuropathy occurred primarily in children with rhabdomyosarcoma and Ewing's sarcoma. The advent of increasingly successful therapies for children with sarcoma and the frequency of severe neurologic complications indicate that a heightened level of surveillance for neurologic compromise is required.

Adolescent↗
PubMed1989

Phase I trial and pharmacokinetic evaluation of fazarabine in children.

A phase I trial of fazarabine (1-beta-D-arabinofuranosyl-5-azacytosine, NSC 281272) administered as a 24-h continuous infusion was performed in 16 children with refractory malignancies. Dose-limiting toxicity consisting of reversible granulocytopenia and thrombocytopenia was observed in 4 of 4 solid tumor patients treated at the starting dose of 20 mg/m2/h. Subsequent patients were treated at a dose of 15 mg/m2/h which was determined to be the maximum tolerated dose. Moderate nausea and vomiting were the only other toxicities observed. Plasma steady-state concentrations of fazarabine were attained by 2-4 h in all patients and were 1.8 and 2.5 microM at the 15- and 20-mg/m2/h doses, respectively. The total body clearance of fazarabine was 571 and 550 ml/min/m2 at the 15- and 20-mg/m2/h doses, respectively. In three of four patients evaluated, fazarabine was detectable in the cerebrospinal fluid (CSF). Steady-state CSF concentrations ranged from 0.29 to 0.74 microM in these three individuals and the steady-state CSF:plasma ratios ranged from 0.22-0.25. Both the plasma and CSF steady-state concentrations were within the 0.1 to 1 microM range reported to be cytotoxic in vitro against the Molt-4 human T-lymphoblastic leukemia cell line. Based on the above, the optimal dose for phase II trials of fazarabine administered as a 24-h infusion is 15 mg/m2/h (360 mg/m2/day).

Antimetabolites, Antineoplastic↗
PubMed1989

Phase I and pharmacokinetic evaluation of thiotepa in the cerebrospinal fluid and plasma of pediatric patients: evidence for dose-dependent plasma clearance of thiotepa.

A Phase I trial of thiotepa (TT) administered as an i.v. bolus was performed in 19 children with refractory malignancies. The starting dose was 25 mg/m2 with escalations to 50, 65, and 75 mg/m2. Seven additional patients were treated with 8-h infusions at 50 or 65 mg/m2. The maximum tolerated bolus dose was 65 mg/m2. Reversible myelosuppression was the dose-limiting toxicity. The plasma and cerebrospinal fluid (CSF) pharmacokinetic parameters of TT and its major active metabolite tepa (TP) were also evaluated. When the bolus or infusion methods of TT administration were compared, there was little difference observed in any pharmacokinetic parameter for either TT or TP. The plasma disappearance of TT was rapid and biphasic with half-lives of 0.14 to 0.32 and 1.34 to 2.0 h. Dose-dependent pharmacokinetics was demonstrated by steadily declining plasma clearance with increasing TT dose. Clearance values declined from 28.6 liters/m2/h at the 25-mg/m2 dose to 11.9 liters/m2/h at the 75-mg/m2 dose. The half-life of TP was longer than that of TT and ranged between 4.3 and 5.6 h. There was evidence of the saturation of TP production. TT and TP both exhibited excellent penetration into the CSF, producing lumbar and ventricular concentrations which were nearly identical to simultaneous plasma concentrations. In one patient with a Rickham reservoir, the CSF:plasma area under the (concentration x time) curve ratios for TT and TP were 1.01 and 0.95, respectively. The above data indicate that TT can be safely administered to pediatric patients at doses higher than conventionally used. The favorable CSF penetration of TT and TP suggests that Phase II studies of TT be considered in patients with central nervous system tumors.

Adolescent↗
PubMed1989

Suprasellar germinomas in childhood. A reappraisal.

Germinomas in childhood may arise in both the suprasellar and pineal region, and outcome has been reported to be worse for suprasellar germinomas with a 5-year survival rate of 20% as compared to 60% for pineal germinoma. To determine the factors impacting on outcome, the results of a uniform treatment approach were evaluated and included primary surgical debulking (PSD) and systemic craniospinal axis radiation (CSRT) for suprasellar germinomas. Between 1976 and 1985 ten consecutive patients (seven females, three males) with the pathologically confirmed diagnosis of suprasellar germinoma were treated. Outcome was compared to four male patients with pineal germinoma treated over the same time period and series of patients reported in the literature. At diagnosis the mean age of patients with suprasellar germinoma was 13.9 years (range, 8.9 to 9.4 years). Symptoms were present for a mean of 18 months (range, 2 to 72 months) prior to diagnosis and included diabetes insipidus, anterior pituitary dysfunction, decreased vision, headache, vomiting, and diplopia. Staging studies, including myelography (n = 4) and cerebrospinal fluid cytology (n = 7), disclosed dissemination in only one child. Surgical treatment included biopsy in three cases, partial resection in five, and total resection in two; no permanent postsurgical complications were noted. The mean radiation therapy dose to the tumor site was 4953 cGy (range, 4400 to 5250 cGy) and to the spine 3354 cGy (range, 3000 to 4000 cGy). Patients were followed for a mean period of 5.1 years (range, 1.9 to 10.5 years). One patient with SG who did not receive treatment initially developed a pineal tumor after diagnosis; she was treated with PSD and CSRT and is asymptomatic 5 years later. All the remaining patients are alive and remain disease-free. Surgical resection and CSRT results in excellent disease control for children with suprasellar germinomas, and outcome is similar to those patients with pineal germinoma.

Adolescent↗
PubMed1989

Clinical, cytogenetic, and pedigree findings in 18 cases of Aicardi syndrome.

Eighteen girls with Aicardi syndrome were identified through a survey of neurologists, geneticists, and ophthalmologists. All had infantile seizures, developmental delay, agenesis of the corpus callosum (complete: 72%, partial: 28%), and characteristic chorioretinal lacunar lesions. Costovertebral defects including hemivertebrae, scoliosis, and absent or malformed ribs were present in 39%, cortical heterotopias were present in 50%, and microphthalmia was identified in a third. Cytogenetic investigation was carried out in all families. An unbalanced X;3 translocation, 46,X,der(X)t(X;3)(p22.3;p23)mat, was discovered in a girl with chorioretinal lacunar lesions characteristic of Aicardi syndrome, developmental delay, and infantile seizures. However, this child had a normal appearing corpus callosum on CT and magnetic resonance imaging scans and therefore did not meet the criteria for inclusion in the study. Chromosomes of all other patients and parents were normal. Findings at birth, age of seizure onset, treatment, and prognosis are discussed. The pedigree data from these 18 families demonstrated an unaffected male:female sib ratio of 1:1.7 and a 14% spontaneous abortion rate. The findings of this study support the contention that Aicardi syndrome is an X-linked dominant disorder with early embryonic lethality in hemizygous males and that all cases represent new mutations.

Abnormalities, Multiple↗
PubMed1989

Isochromosome 17q in primitive neuroectodermal tumors of the central nervous system.

We have prepared karyotypes from 22 primitive neuroectodermal tumors (PNETs) from pediatric patients ranging in age from 10 months to 16 years. Twenty-one cases were newly diagnosed, primary, posterior fossa tumors. One case was a recurrent tumor in a patient previously treated with radiation. Cytogenetic results were obtained from direct preparations and/or short-term (1-10 day) culture. Three tumors had apparently normal karyotypes. Nineteen tumors demonstrated numerical and/or structural abnormalities. The most frequent structural chromosomal changes were deletions and nonreciprocal translocations. Four tumors contained double minutes. Several chromosomes appear to be nonrandomly involved in PNETs. These include chromosomes 5, 6, 11, 16, 17, and a sex chromosome. The most consistent change, however, was an i(17q), present in one-third (8/22) of the cases. Strikingly, in three of these eight tumors, the i(17q) was the only structural abnormality observed. An i(17q) is not specific for pediatric PNETs, as it is also seen in leukemias and other solid tumors. However, in PNETs it may be a primary change related to tumor development and/or progression. Clinically, there was no correlation of the cytogenetic findings with histologic features of the tumors, size of the tumor, extent of metastasis, or surgical resection.

Adolescent↗
PubMed1989

An animal model to detect the neuropsychological toxicity of anticancer agents.

The unexpected discovery that certain chemotherapeutic agents used in the treatment of childhood cancers have neurocognitive side effects has prompted a search for techniques that identify those medications that place children at risk. An animal model for the assessment of resultant neurocognitive toxicity is described which makes use of simple classical conditioning. We have shown that rats learn about environmental events more slowly following neonatal administration of methotrexate. The changes after methotrexate exposure are not related to stimulus characteristics or to perceptual abilities, but rather to damage to the neural systems involved in acquisition, retention, or recall. Similar problems with learning have been observed in children treated with methotrexate. An effective animal model such as the one described here may help detect and avoid antineoplastic agents that produce severe cognitive defects in childhood cancer patients.

Animals↗
PubMed1989

Gadolinium-DTPA-enhanced magnetic resonance imaging in childhood brain tumors.

Gadolinium DTPA (Gd-DTPA) is a paramagnetic blood-brain barrier contrast agent for MRI that has been used primarily in adults. During May through October 1987, 17 children between the ages of 3 and 18 years with brain tumors underwent MRI examinations, before and after Gd-DTPA (11 gliomas, 4 medulloblastomas, 1 craniopharyngioma, and 1 child with neurofibromatosis and no pathologic diagnosis). We compared T1 and T2 Gd-DTPA-enhanced MRI with concurrent unenhanced MRI and enhanced CT, and then correlated this with the clinical and pathologic findings. Gd-DTPA enhanced tumors in all 7 patients with newly diagnosed tumors and enhanced tumors in 7 of 10 patients without clinical evidence of progressive disease at the time of the study. In the 7 new patients, Gd-DTPA defined tumor margins in all, and demonstrated internal tumor architecture (vessels, necrosis, and cysts) in 5. Areas believed to represent surgical scars showed varying degrees of enhancement. Leptomeningeal tumor spread, including spinal, not seen on pre-Gd-DTPA MRI or on contrast CT, was evident in 2 patients. Gd-DTPA enhancement obscured hemorrhage within the tumor (methemoglobin) in 2 patients. There were no significant side effects. These results suggest that Gd-DTPA-enhanced MRI (1) is safe in children, (2) demonstrates the extent and character of tumors better than unenhanced MRI and enhanced CT, and (3) may allow for noninvasive imaging of leptomeningeal disease, including the spine, not previously demonstrated by any other noninvasive neuroimaging technique.

Adolescent↗
PubMed1989

A prospective study of cognitive function in children receiving whole-brain radiotherapy and chemotherapy: 2-year results.

As survival rates have risen for children with malignant primary brain tumors, so has the concern that many survivors have significant permanent cognitive deficits. Cranial irradiation (CRT) has been implicated as the major cause for cognitive dysfunction. To clarify the etiology, incidence, and severity of intellectual compromise in children with brain tumors after CRT, a prospective study was undertaken comparing the neuropsychological outcome in 18 consecutive children with malignant brain tumors treated with CRT to outcome in 14 children harboring brain tumors in similar sites in the nervous system who had not received CRT. Children with cortical or subcortical brain tumors were not eligible for study. Neuropsychological testing was performed after surgery prior to radiotherapy, after radiotherapy, and at 1- and 2-year intervals thereafter. Children who had received CRT had a mean full-scale intelligence quotient (FSIQ) of 105 at diagnosis which fell to 91 by Year 2. Similar declines were noted in their performance intelligence quotient (IQ) and verbal IQ. After CRT, patients demonstrated a statistically significant decline from baseline in FSIQ (p less than 0.02) and verbal IQ (p less than 0.04). Children who had not received CRT did not demonstrate a fall in any cognitive parameter over time. The decline between baseline testing and testing performed at Year 2 in patients who had CRT was inversely correlated with age (p less than 0.02), as younger children demonstrated the greatest loss of intelligence. Children less than 7 years of age at diagnosis had a mean decline in FSIQ of 25 points 2 years posttreatment. No other clinical parameter correlated with the overall IQ or decline in IQ. After CRT, children demonstrated a wide range of dysfunction including deficits in fine motor, visual-motor, and visual-spatial skills and memory difficulties. After CRT, children with brain tumors also demonstrated a fall in a wide range of achievement scores and an increased need, over time, for special help in school. The 2-year results of this study suggest that children with brain tumors treated with CRT are cognitively impaired and that these deficits worsen over time. The younger the child is at the time of treatment, the greater is the likelihood and severity of damage. These children, although not retarded, have a multitude of neurocognitive deficits which detrimentally affects school performance. New treatment strategies are needed for children with malignant brain tumors.

Adolescent↗
PubMed1989

Molecular markers of primitive neuroectodermal tumors and other pediatric central nervous system tumors. Monoclonal antibodies to neuronal and glial antigens distinguish subsets of primitive neuroectodermal tumors.

Seventy-one tumors of the central nervous system in children were studied immunohistologically. Thirty-seven were classified histologically as PNETs, of which 35 were located in the cerebellum (medulloblastomas), one in the cerebrum, and one in the spinal cord. The 34 non-PNETs included five ependymomas, seven gangliogliomas, 15 astrocytomas, and seven tumors of other histology. We used monoclonal antibodies specific for neurofilament (NF) triplet proteins, for microtubule associated protein 2 and tau protein and for glial fibrillary acidic protein (GFAP) and myelin basic protein. In addition, a monoclonal antibody to epithelial membrane antigen was applied. The presence or absence of these antigens defined four major groups of PNETs: 1) PNETs not otherwise specified (10 cases), 2) PNETs with neuronal differentiation (eight cases), 3) PNETs with astrocytic differentiation (six cases), and 4) PNETs with both neuronal and astrocytic differentiation (12 cases). One case showed ependymal differentiation. The pattern of expression of NF isoforms in PNETs was reminiscent of that seen during normal mammalian development, such that phosphorylated NF-H was only present in combination with NF-M and NF-L. Among the other central nervous system tumors, all astrocytomas and gangliogliomas were positive for GFAP, and the gangliogliomas also expressed all NF isoforms. Three atypical teratoid tumors and two rhabdoid tumors showed strong positivity for epithelial membrane antigen and also for GFAP. We conclude that the differentiation antigens described here serve to distinguish PNETs from other pediatric central nervous system tumors and to identify subsets of PNETs. Accordingly, PNETs represent a heterogeneous group of pediatric brain tumors capable of neuronal and glial differentiation.

Adolescent↗
PubMed1988

Late recurrence of primitive neuroectodermal tumor/medulloblastoma.

The period of risk for recurrence of primitive neuroectodermal tumor/medulloblastoma (PNET/MB) is not clearly defined. With current treatment since more than 50% of children with PNET/MB can be expected to survive for at least 5 years after diagnosis, determining the evidence of "late" recurrence is of increasing concern. Collins has stated that patients with embryonal tumors who survive, disease free, for a period of time equal to the age at diagnosis plus 9 months can be declared cured. This, so-called Collins' law has been applied to patients with PNET/MB. To determine the incidence of "late" recurrence, factors which impact on recurrence and applicability of Collins' law, the authors studied all patients diagnosed with PNET/MB at the Children's Hospital of Philadelphia, Hospital of the University of Pennsylvania, Philadelphia, and Geisinger Medical Center, Danville, Pennsylvania, between 1970 and 1984. For the 44 patients in this study, the disease-free survival at 5, 10, and 12 years was 54%, 41% and 30%, respectively. For children surviving 5 years, the actuarial survival at 10 years was 75% and at 12 years, 51%. Age, sex, dose of radiotherapy, chemotherapy, or extent of surgery were not predictive of late relapse. Recurrence in three of seven patients (43%) occurred outside the "period of risk" as predicted by Collins. It appears that the "period of risk" for recurrent central nervous system tumors after PNET/MB is as yet undefined and probably indefinite.

Actuarial Analysis↗
PubMed1988

A pediatric phase I and pharmacokinetic study of spirohydantoin mustard.

A pediatric Phase I and pharmacokinetic study of the lipophilic alkylating agent spirohydantoin mustard (SHM) was conducted in 23 patients. The dose-limiting toxicity of SHM was neurological with disorientation, delirium, or hallucinations occurring in 9 of 23 patients. These symptoms were partially reversible and preventable with physostigmine. In 17 patients who were evaluable for response to treatment (14 of whom had central nervous system malignancies), no objective tumor responses were observed. Pharmacokinetic evaluation of SHM revealed a t1/2 alpha of 1.7 +/- 0.7 min, t1/2 beta of 16 +/- 8.3 min, and total body clearance of 2134 +/- 735 ml/min/m2. Measureable peak plasma levels were less than 40% of that which produces cytotoxicity in vitro against monolayer cultures of rat 9L brain tumor. Over 90% of SHM was protein bound, greatly limiting the free drug available for central nervous system penetration. SHM cerebrospinal fluid to plasma ratios were less than 0.047. The above suggests that in spite of its lipophilicity, SHM may not reach clinically significant levels in the central nervous system at clinically tolerable doses.

Adolescent↗