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Biomedical subjects

R Packer

Publications and source records attributed to R Packer.

At least 19 recordsLinked to original sources
PubMed2006

Phase II trial of intravenous lobradimil and carboplatin in childhood brain tumors: a report from the Children's Oncology Group.

BACKGROUND: [corrected] Lobradimil is a synthetic bradykinin analog that rapidly and transiently increases the permeability of the blood-brain barrier (BBB). The combination of lobradimil and carboplatin was studied in pediatric patients with primary brain tumors in a phase II trial, the primary endpoints of which were to estimate the response rate and time to disease progression. PATIENTS AND METHODS: Patients were stratified by histology into five cohorts: brainstem glioma, high-grade glioma, low-grade glioma, medullobastoma/primitive neuroectodermal tumor (PNET), and ependymoma. Patients received carboplatin adaptively dosed to achieve a target AUC of 3.5 mg min/ml per day (7 mg.min/ml/cycle) intravenously over 15 min on 2 consecutive days and lobradimil 600 ng/kg ideal body weight/day on 2 consecutive days each 28 day cycle. RESULTS: Forty-one patients, age 2-19 years, were enrolled; 38 patients, including 1 patient ultimately determined to have atypical neurocytoma, were evaluable for response. No objective responses were observed in the brainstem glioma (n=12) and high-grade glioma (n = 9) cohorts, although two patients with high-grade glioma had prolonged disease stabilization (>6 months). The study was closed for commercial reasons prior to achieving the accrual goals for the ependymoma (n = 8), medulloblastoma/PNET (n = 6) and low-grade glioma (n = 2) cohorts, although responses were observed in 1 patient with PNET and 2 patients with ependymoma. CONCLUSION: The combination of lobradimil and carboplatin was inactive in childhood high-grade gliomas and brainstem gliomas.

Adolescent↗
PubMed2001

Intellectual outcome after reduced-dose radiation therapy plus adjuvant chemotherapy for medulloblastoma: a Children's Cancer Group study.

PURPOSE: To investigate the intellectual outcomes of children with medulloblastomas/primitive neuroectodermal tumors (MB/PNET) treated with reduced-dose craniospinal radiotherapy (RT) plus adjuvant chemotherapy. PATIENTS AND METHODS: Forty-three children with average-risk posterior fossa MB/PNETs underwent longitudinal intelligence testing. All had been treated with a reduced-dose craniospinal RT regimen (23.4 Gy to the neuraxis, 32.4-Gy boost to the posterior fossa) and adjuvant chemotherapy. RESULTS: The estimated rate of change from baseline was significant for Full Scale Intelligence Quotient (FSIQ), Verbal IQ (VIQ), and Nonverbal IQ (NVIQ) (P <.001 for all three outcomes). The rate of change was estimated to be -4.3 FSIQ points per year, -4.2 VIQ points per year, and -4.0 NVIQ points per year. Females were more subject to VIQ decline than were males (P =.008), and young children (< 7 years of age) were more negatively affected than were older children, with a significant decline in NVIQ (P =.016). Finally, patients with higher baseline evaluations suffered greater declines in IQ than did those with lower baseline scores. CONCLUSION: This study represents the largest series of patients with average-risk MB/PNETs treated with a combination of reduced-dose RT and adjuvant chemotherapy whose intellectual development has been followed prospectively. Intellectual loss was substantial but suggestive of some degree of intellectual preservation compared with effects associated with conventional RT doses. However, this conclusion remains provisional, pending further research.

Adolescent↗
PubMed1998

A phase I-II trial of lovastatin for anaplastic astrocytoma and glioblastoma multiforme.

Malignant gliomas are thought to be highly dependent on the mevalonate pathway for cell growth. Lovastatin, a cholesterol-lowering drug, inhibits not only the rate-limiting step in the mevalonate pathway (hepatic hydroxymethyl glutaryl coenzyme A reductase), but also the prenylation of several key regulatory proteins including ras and the small guanosine triphosphate binding proteins. Therefore, from August 1994 through March 1996, 18 patients with either anaplastic glioma or glioblastoma multiforme were entered into a trial testing the safety of high-dose lovastatin with or without radiation. Although the response data is too premature to evaluate activity, the fact that high doses of lovastatin are well tolerated with concurrent radiation suggests that central nervous system toxicity will not be a significant limiting toxicity as more selective farnesyltransferase inhibitors are brought into the clinic as radiation sensitizers.

Adult↗
PubMed1996

Association of a suprasellar mass and intraocular retinoblastoma: a variant of pineal trilateral retinoblastoma?

OBJECTIVE AND IMPORTANCE: 'Trilateral retinoblastoma' designates the association of bilateral retinoblastomas with an ectopic (non-metastatic) intracranial primitive neuroectodermal tumor (PNET). Although the intracranial tumor, usually located in the pineal region, is seen 2-3 years after discovery of the bilateral ocular tumors, variant presentations do occur. The intraocular tumor can be unilateral, and the intracranial tumor can be suprasellar, presenting before the retinal lesions. CLINICAL PRESENTATION: A 4-month-old boy presented with irritability, vomiting and nystagmus. Head CT revealed a large calcified sellar-suprasellar mass. Ocular examination disclosed white macular lesions in the right fundus. He was taken to surgery where subtotal resection of the sellar-suprasellar mass was achieved. Microscopic examination showed a primitive, small, round, blue cell tumor consistent with retinoblastoma. The right ocular lesions, also consistent with retinoblastoma, were treated by cryosurgery. CONCLUSION: The appearance of a suprasellar PNET can precede the appearance of retinal masses in retinoblastoma. The literature suggests that patients with 'sellar' trilateral retinoblastoma have characteristics that differ from patients with a pineal region trilateral retinoblastoma: the intracranial mass more often presents initially; it occurs at a younger age; it is predominant in females, and is more often associated with unilateral ocular lesions. Retinal screening of patients with suprasellar PNET and other atypically located PNETs may disclose more cases of sellar 'trilateral retinoblastoma' and hereditary retinoblastomas. This will have implications on genetic counseling as siblings harboring the disease may be diagnosed and treated at an earlier stage.

Brain Neoplasms↗
PubMed1995

Central nervous system atypical teratoid/rhabdoid tumors of infancy and childhood.

Clinical and morphological features of an apparently unique, biologically aggressive central nervous system tumor in 32 infants and children are presented. This neoplasm is formed wholly or partly by rhabdoid cells, areas resembling typical primitive neuroectodermal tumor, and, less frequently, malignant mesenchymal and/or epithelial tissue. The tumor has been named atypical teratoid/rhabdoid tumor (ATT/RhT) and is regarded as a unique class of primary central nervous system (CNS) tumors. It occurs most commonly in infants less than two years of age, has often metastasized throughout the CNS at presentation, dose not respond to therapy and causes death less than a year after diagnosis. These tumors may occur in any CNS site but almost 60% are located in the cerebellum. The most common chromosomal abnormality involves chromosome 22.

Central Nervous System Neoplasms↗
PubMed1991

Recombinant interferon beta: a phase I-II trial in children with recurrent brain tumors.

A multicenter phase I-II trial of intravenous (IV) human recombinant interferon beta (rIFN-beta; Betaseron; Triton Bioscience Inc, Almeda, CA) was conducted in children with recurrent or progressive primary brain and spinal cord tumors. A total of 29 patients were enrolled: high-grade astrocytoma (12), brainstem glioma (nine), and primitive neuroectadermal tumor (three), ependymoma (two), germ cell (two), and spinal cord astrocytoma (one). Betaseron was given by IV infusion over 30 minutes 3 times per week (Monday-Wednesday-Friday [MWF]). Four dose levels were studied, and at least three patients were entered at each dose level. The treatment plan began with a three-step dose escalation for each patient over 6 weeks (initiation phase). The dose-escalation schema for the four dose levels was: 50-100-200, 100-200-400, 200-300-500, and 300-400-600 x 10(6) (M) IU/m2. Patients experiencing an objective response or stable disease after 6 weeks entered the maintenance phase at the final escalated dose, ie, 200, 400, 500, or 600 mlU/m2 (MWF). Common transient effects included chills, fever, and fatigue. Dose-limiting toxicities were hematologic, hepatic, and CNS. The maintenance maximum-tolerable dose (MTD) was 500 mlU/m2, ie, dose level 3. Response was assessed at completion of the initiation phase and at 2-month intervals during the maintenance phase. Objective partial responses were seen in patients with high-grade astrocytoma (two) and brain-stem glioma (two). Thus, four of 21 (19%) assessable patients had partial responses for a median of 4 months. Eight patients had stable disease for a median of 5+ (2 to 14+) months. Antineoplastic activity has been identified in children with high-grade astrocytomas and brainstem gliomas in a dose-intensive regimen.

Brain Neoplasms↗
PubMed1990

High-dose multi-agent chemotherapy followed by bone marrow 'rescue' for malignant astrocytomas of childhood and adolescence.

Between April 1986 and March 1989, ten patients under 21 years of age with histologically confirmed malignant astrocytoma, received marrow-ablative chemotherapy with either thiotepa and Etoposide (five patients) or thiotepa, Etoposide and BCNU (five patients), followed by bone marrow 'rescue'. Nine patients had glioblastoma multiforme (GBM), and one patient had an intrinsic brain stem anaplastic astrocytoma (AA). Seven patients were treated for recurrent tumor. Two patients who developed GBM as second malignancies were treated directly following surgical resection. One patient had received irradiation only for recently diagnosed cervical spinal cord GBM. Thiotepa was administered at a total dose of 600-900 mg/M2 over three days, Etoposide was administered at a total dose of 1500 mg/M2 over three days, and BCNU was administered at a total dose of 600 mg/M2 over four days. Non-hematopoietic toxicities have been mainly transient, predictable and acceptable, consisting of oropharyngeal mucositis, cutaneous hyperpigmentation, erythema and desquamation. Four patients achieved complete responses (CR), as determined by radiographic evaluation (CT and/or MRI) on day 28 post-marrow infusion. The mean remission duration of those with CR is 290+ days; two patients presently remain in remission. Two patients achieved partial responses (PR, greater than 50% tumor shrinkage) by day 28 post-marrow infusion; both developed disease progression, at day 61 and 94 post-marrow infusion, respectively. One patient, with a brain stem AA, had stable disease maintained for 13 months post-marrow infusion. With a total (CR + PR) response rate of 60%, these regimens merit evaluation in broader categories of recurrent brain tumor patients, as well as in patients with newly-diagnosed GBM.

Adolescent↗
PubMed1990

Key problems in the management of children with brain tumors.

Steady progress has been made in the clinical management of children with brain tumors. Better diagnostic methods and more efficient surgical, radiotherapeutic, and chemotherapeutic techniques have evolved singly and in various combinations. These advances have at times created problems in patient management; for example, interpretation of clinically inexplicable signal changes on magnetic resonance imaging. Equally substantive, and at a more basic level, is the fact that understanding of the nature of the various tumors remains elusive in many cases. Some lesions seem to behave more like maldevelopments than neoplasms. Specific markers for any of the several tumor types have not been identified. The isochromosome i(17q), found in some malignant pediatric brain tumors, is also present in children with other conditions, both benign and malignant. Fundamental research is hampered by the difficulty in establishing cell lines for even the medulloblastoma, the most common of the frankly malignant group. Until these problems are supervened, important advances will largely remain at the clinical and morphologic level. Close coordination and careful correlation of data among the several members of the pediatric neuro-oncology team is essential for success. Clinical trials of combined modality care especially require well-reasoned rationales and careful definition of objectives, and must include meticulous evaluation of the late effects of therapy in survivors.

Brain Neoplasms↗
PubMed1989

The role of radiation therapy in the management of childhood craniopharyngioma.

Between 1965 and 1986, 31 children were treated for craniopharyngioma at the Children's Hospital of Philadelphia. Total removal was attempted in all patients. Some patients received radiation therapy following subtotal removal. Of the patients whose first resection was subtotal, five received radiation and seven did not. Four of the 5 patients who were radiated (80%) are stable (median 89 months, range 42-155 months) and one recurred at 42 months, failed salvage with total removal, and subsequently died of disease. Of the seven who were not irradiated, all had recurrences (median 12 months, range 3-192 months) and one died of disease. Nineteen patients initially had total removal and none received adjuvant radiation. One patient died postoperatively. Of the 18 remaining patients, 6 had recurrences (median 24 months, range 7-100 months) and 12 (66%) are stable (median 42 months, range 9-133 months). One of these stable patients died of endocrine complications 24 months after initial surgery. Fourteen of the 31 patients recurred. Two died with recurrence and one required no further treatment. Eleven had second resections following initial surgical removal. Seven of these 11 went on to receive radiation and four did not. All seven who were radiated are stable (median 33 months, range 1-228 months); whereas 1 of the 4 who were not radiated recurred again at 18 months. This patient had a third resection followed by radiation therapy and is now stable at 20 months. After initial surgery (and before radiation, when given) 26 of 31 patients had panhypopituitarism, 4 had partial deficits, and 1 was normal. Severe diencephalic syndrome, loss of visual acuity, and intellectual deficits were no more frequent in patients treated with total removal, subtotal removal, and in patients who received radiation. We conclude that radiation has an important role following subtotal removal and for salvage treatment after initial surgery. Aggressive attempt at total removal does result in prolonged progression-free survival in some patients. Extensive resections may result in significant mortality and endocrine morbidity. This review suggests that subtotal removal and radiation results in outcomes at least as favorable as treatment with total removal alone.

Adolescent↗
PubMed1989

Outbreak of poliomyelitis-like paralysis associated with enterovirus 71.

In the summer of 1987 five children were seen at The Children's Hospital of Philadelphia because of acute onset of flaccid paralysis of an arm or leg(s). Although there were documented exposures to oral poliovirus vaccine and coxsackievirus B3 in some of the cases, the clinical, epidemiologic and laboratory findings indicate that enterovirus 71 was the common etiologic agent for this unusual outbreak of poliomyelitis-like paralysis. Of the five children three recovered completely; the other two had residual paralysis with weakness and muscle wasting. Imaging studies of the spinal cord in the two children with residual paralysis revealed defects in the ventral aspect of the spinal cord. This series of paralytic cases attributed to enterovirus 71 is the largest reported in the United States.

Child↗
PubMed1988

Focal cortical dysplasia on magnetic resonance imaging: a case report.

A case report of an 11 years old boy with new onset of a seizure disorder is presented. A computed tomography scan demonstrated a noncalcified, nonenhancing focal region of abnormal cortex. A magnetic resonance imaging scan delineated both an isointense area of abnormally thickened gyri and linear areas of abnormal high signal intensity in the subjacent white matter. A review of the radiologic and pathologic literature suggests that this lesion represents the entity focal cortical dysplasia as described by Taylor, et al. This abnormality is part of a spectrum of disorders including hamartomas (of tuberous sclerosis), focal cortical dysplasia and heterotopias.

Astrocytes↗
PubMed1985

Resistive NMR of brain stem gliomas.

The NMR and CT findings in 22 patients with primary brain stem tumors were compared to determine the value of each study in identifying, and delineating the extent and relationships of the tumor to brain anatomy. NMR was found to be distinctly superior to CT in showing involvement of the medulla and upper cervical cord. NMR eliminates the need for intrathecal enhanced metrizamide CT, and in the future should be the only initial diagnostic test needed for the evaluation of intrinsic brain stem tumors.

Adolescent↗
PubMedDate not supplied

A multi-institutional retrospective study of intracranial ependymoma in children: identification of risk factors.

PURPOSE: The goal of this multi-institutional retrospective study of children with intracranial ependymoma was to identify risk factors associated with unfavorable overall survival (OS) and event-free survival (EFS). PATIENTS AND METHODS: Clinical data, including demographics, tumor location, spread, histology, details of surgery, radiation treatment, and chemotherapy were collected. Clinical characteristics and univariate and multivariate analyses of risk factors for OS and EFS are presented. RESULTS: Eleven U.S. institutions contributed 83 patients treated from 1987 to 1991. The OS at 5 and 7 years was 57% and 46%, and EFS at 5 and 7 years was 42% and 33%. Patients 3 years of age or younger differed from the older group by more common infratentorial location, less common gross total resection (GTR), and postoperative use of chemotherapy rather than radiation. This younger group of patients had worse survival (P < 0.01) than the older age group. Other than young age, less than GTR and World Health Organization (WHO) II grade 3 histology were significant adverse risk factors for EFS in univariate and multivariate analyses. OS shared the same adverse risk factors except for histology in multivariate analysis, which was only of borderline significance (P = 0.05). Progression at the original tumor location, present in 89% of patients, was the major pattern of tumor recurrence. Adjuvant chemotherapy in the group older than 3 years or craniospinal radiation in M0 patients did not significantly change EFS. CONCLUSIONS: Adverse outcome in childhood intracranial ependymoma is related to age (3 years or younger), histology (grade 3), and degree of surgical resection (less than GTR). New approaches, particularly for local tumor control in younger patients, are needed to improve survival.

Brain Neoplasms↗
PubMedDate not supplied

Prognostic factors in childhood ependymomas.

Between 1975 and 1989, 45 children with newly diagnosed intracranial ependymomas were treated at the authors' institution. Patients were managed with aggressive surgical resection, followed by postoperative CT or MRI scans to evaluate the extent of resection. Most patients received involved-field radiation therapy, however 10 were treated with craniospinal axis irradiation for disseminated disease, or malignant histology. Beginning in 1983, all patients were also treated with adjuvant chemotherapy with 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), vincristine, and cisplatinum. Four patients died in the immediate postoperative period for an operative mortality of 8.8%. The 5-year progression-free survival for the remaining 41 patients was 36%. Tumor location had little effect on survival, as the 5-year PFS for supratentorial tumors was 26%, compared with 40% for the posterior fossa lesions (ns). Neither histologic degree of malignancy, nor use of adjuvant chemotherapy impacted on survival. The extent of surgical resection, as determined by operative reports and postoperative imaging studies, was a major determinant of outcome, as patients with total or near-total resections experienced a 5-year PFS of 60%, compared with 21% for children with partial resection or biopsy (p less than 0.01). It is concluded that the use of adjuvant chemotherapy with CCNU, vincristine, and cisplatinum does not improve progression-free survival in childhood ependymoma, and that the extent of surgical resection is a major determinant of outcome in this disease.

Adolescent↗