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Maryam Fouladi

Publications and source records attributed to Maryam Fouladi.

At least 19 recordsLinked to original sources
PubMed2006

Phase II study of oxaliplatin in children with recurrent or refractory medulloblastoma, supratentorial primitive neuroectodermal tumors, and atypical teratoid rhabdoid tumors: a pediatric brain tumor consortium study.

BACKGROUND: An open-label Phase II study of oxaliplatin was conducted to evaluate its safety and efficacy in children with recurrent or refractory medulloblastoma (MB), supratentorial primitive neuroectodermal tumors (SPNET), and atypical teratoid rhabdoid tumor (ATRT). METHODS: Patients were stratified as follows: stratum IA, first recurrence MB with measurable disease; IB, recurrent MB with only cerebral spinal fluid (CSF) positivity or linear leptomeningeal disease (LLD); IC, MB > or =second recurrence; stratum II, recurrent SPNET; stratum III, recurrent ATRT. Patients received oxaliplatin, 130 mg/m(2) intravenously over 2 hours every 3 weeks. The primary objective was to estimate the sustained response rate in stratum 1A. Plasma ultrafiltrate platinum pharmacokinetics were evaluated. RESULTS: A total of 43 patients with a median age of 8.5 years (range, 0.6-18.9 years) were enrolled. In stratum 1A, 2 of 15 had partial responses (PRs, 1 sustained PR). No responses were observed in other strata. The most frequent Grade 3 and 4 toxicities included thrombocytopenia (25.6%), neutropenia (16.3%), leukopenia (12%), increase in serum alanine transaminase (ALT) (7%), vomiting (4.7%), and sensory neuropathy (4.7%). No severe ototoxicity or nephrotoxicity was reported. Plasma ultrafiltrate platinum pharmacokinetic parameters were similar to adults, with a median clearance of 12.2 L/hr (range, 4.4-30 L/hr) and median area under the curve (AUC(0-infinity)) of 9.4 microg/mL/hr (range, 6.2-13.9 microg/mL/hr). CONCLUSIONS: Oxaliplatin was well tolerated in children but has limited activity in children with recurrent CNS embryonal tumors previously treated with platinum compounds.

Adolescent↗
PubMed2006

Phase I study of depsipeptide in pediatric patients with refractory solid tumors: a Children's Oncology Group report.

PURPOSE: To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetic profile, and pharmacodynamics of the histone deacetylase inhibitor, depsipeptide, in children with refractory or recurrent solid tumors. PATIENTS AND METHODS: Depsipeptide was administered as a 4-hour infusion weekly for 3 consecutive weeks every 28 days at dose levels of 10 mg/m2, 13 mg/m2, 17 mg/m2, and 22 mg/m2. Pharmacokinetics and histone acetylation studies were performed in the first course. The levels of H3 histone and acetyl-H3 histone were evaluated in peripheral blood mononuclear cells (PBMC) using immunofluorescence techniques. RESULTS: There were 24 patients, and 18 who were assessable were enrolled. DLTs included reversible, asymptomatic T-wave inversions, without any associated changes in troponin levels or evidence of ventricular dysfunction, in the inferior leads in two patients at 22 mg/m2 and in the lateral leads in one patient at 13 mg/m2 (n = 1), and transient asymptomatic sick sinus syndrome and hypocalcemia in one patient at 17 mg/m2. At the MTD (17 mg/m2), the median depsipeptide clearance was 6.8 L/h/m(2) with an area under the plasma depsipeptide concentration-time curve from 0 to infinity of 2,414 ng/mL/h, similar to adults. Accumulation of acetylated H3 histones was seen in all patients in a dose independent manner, with maximal accumulation at a median of 4 hours, (range, 0 hours to 20 hours) after the end of the infusion. No objective tumor responses were observed. CONCLUSION: Depsipeptide is well tolerated in children with recurrent or refractory solid tumors when administered weekly for 3 consecutive weeks every 28 days and inhibits histone deacetylase activity in PBMC in a dose-independent manner. The recommended phase II dose in children with solid tumors is 17 mg/m2.

Acetylation↗
PubMed2006

Polar spongioblastoma of the spinal cord: a case report.

"Rhythmic palisading" is a striking histologic pattern infrequently encountered in a variety of central nervous system (CNS) tumors. We present the case of an infant with a large spinal cord lesion wherein all sampled tissue showed columnar arrangements of palisaded cells, typical of polar spongioblastoma. The tumor was briskly proliferative, focally necrotic, and variably expressed S100, glial fibrillary acidic protein, neuron specific enolase, and p53 by immunohistochemistry. Fluorescence in situ hybridization failed to reveal isochromosome 17q, EGFR amplification, or deletions of 1p, 19q, 22q11.2, 10q, or p16. Despite chemotherapy and decadron, he developed lesional necrosis and intracranial metastases and died less than 1 mo from presentation. This case illustrates polar spongioblastoma as a distinctive histologic pattern that can occur in embryonal CNS tumors. Discrimination of these rare aggressive lesions from other CNS tumors with focal palisaded architecture is crucial as the treatment and prognosis of the latter may differ significantly.

Antineoplastic Agents, Hormonal↗
PubMed2006

Intratumoral hemorrhage among children with newly diagnosed, diffuse brainstem glioma.

BACKGROUND: Children with diffuse brainstem glioma (BSG) commonly undergo novel therapies because their outcome is poor with radiation therapy (RT). Although recent clinical trials using new biologic agents documented intratumoral hemorrhage (IH) among several children with BSG, to the authors' knowledge little is known regarding this phenomenon. In the current study, the authors assessed the characteristics and estimated the cumulative incidence of IH among children with BSG. METHODS: All available brain imaging studies and medical records of 48 consecutive patients with newly diagnosed BSG treated at the study institution over a 10-year interval (1992-2002) were reviewed. Treatment was comprised of RT and various regimens of conventional chemotherapy; none of these patients received biologic agents. At the time of last follow-up, all patients had died of tumor progression. RESULTS: The authors reviewed 319 imaging studies (251 magnetic resonance imaging scans and 68 computed tomography scans). IH was present in 6.25% of patients at the time of diagnosis. The 6-month and 12-month cumulative incidence estimates of IH regardless of the associated symptoms were 15.5% +/- 5.5% and 24.4% +/- 6.5%, respectively. The same estimates for symptomatic cases were 8.9% +/- 4% and 17.8% +/- 6%, respectively. All cases of IH at the time of diagnosis and 78% of symptomatic cases that developed after diagnosis were located in necrotic areas. CONCLUSIONS: Although IH is uncommon at the time of diagnosis, symptomatic IH may occur among nearly 20% of children after the diagnosis of BSG. The uniform occurrence of IH among patients treated with various chemotherapeutic regimens and its association with necrotic areas suggests that tumor biology plays a significant role in this event.

Adolescent↗
PubMed2006

Evaluation of the antitumor efficacy, pharmacokinetics, and pharmacodynamics of the histone deacetylase inhibitor depsipeptide in childhood cancer models in vivo.

PURPOSE: Histone acetyltransferases and histone deacetylases (HDAC) control the acetylation state of histones and other proteins regulating transcription and protein function. Several structurally diverse HDAC inhibitors have been developed as cancer therapeutic agents and in vitro have been shown to cause differentiation, cell cycle arrest, or apoptosis. Here, we have evaluated depsipeptide, a natural tetrapeptide HDAC inhibitor, against a panel of pediatric solid tumor models in vivo and evaluated pharmacokinetic and pharmacodynamic variables with tumor sensitivity. EXPERIMENTAL DESIGN: Depsipeptide was administered at the maximum tolerated dose (4.4 mg/kg administered every 7 days x 3 i.v. repeated q21d for a total of two cycles) to scid mice bearing 39 independently derived childhood tumors (9 brain tumors, 11 kidney cancers, 9 rhabdomyosarcomas, 3 neuroblastomas, and 7 osteosarcomas). Pharmacokinetic variables were determined, as were changes in histone and p53 acetylation, induction of p53 and p53 genotype, and alterations in Akt phosphorylation. RESULTS: Of 39 tumors evaluated, three showed objective tumor regressions [two brain tumors (primitive neuroectodermal tumor and atypical teratoid malignant rhabdoid tumor) and one Wilms' tumor]. Depsipeptide inhibited growth of many tumor lines but achieved stable disease (<25% increase in volume during treatment cycle 1) in only two tumor models (anaplastic astrocytoma, two rhabdomyosarcomas, and a Wilms' tumor). Pharmacokinetic analysis showed that the population estimated AUC(0-24) was 1,123 ng h/mL, similar to the exposure following 13 mg/m2 in ongoing phase I trials. Pharmacodynamic changes in histone acetylation (H2A, H2B, H3, and H4) in three depsipeptide-sensitive and three intrinsically resistant tumors followed a similar pattern; maximal increases in histone acetylation occurred at 8 hours and were elevated for up to 96 hours. In two sensitive tumor lines, IRS56 and BT27 (both wild-type p53) p53 increased in treated tumors being maximal at 8 hours and associated with induction of p21(cip1), whereas p53 was stable in tumors with mutant p53. Sensitivity to depsipeptide did not correlate with p53 genotype, p53 acetylation, cleaved poly(ADP-ribose) polymerase, or phosphorylation of Akt (Ser473). CONCLUSIONS: Our results show that depsipeptide inhibits its target in vivo causing increased histone acetylation; however, this does not correlate with drug sensitivity. The relatively low objective response rate [3 of 39 (8%) tumor lines showing greater than or equal to partial response and 4 (10%) stable disease] administered at dose levels that give clinically relevant drug exposures suggests that as a single agent depsipeptide may have limited clinical utility against pediatric solid tumors in a first-line setting.

Acetylation↗
PubMed2006

Temozolomide after radiotherapy for newly diagnosed high-grade glioma and unfavorable low-grade glioma in children.

Chemotherapy is commonly used in the treatment of children with high-grade glioma, although its usefulness is uncertain. We conducted a multi-institutional study to evaluate the efficacy of temozolomide given after radiotherapy in children with newly diagnosed high-grade glioma and unfavorable low-grade glioma (gliomatosis cerebri or bithalamic involvement). Optional window therapy of intravenous irinotecan (10 doses of 20 mg/m2 per cycle x 2) was given over 6 weeks. The 5-day schedule of temozolomide (200 mg/m2 per day) started 4 weeks after the completion of radiotherapy and continued for a total of 6 cycles. Thirty-one eligible patients (median age: 12.3 years) participated. Tumors most commonly involved cerebral hemispheres (n = 13, 42%) and thalamus (n = 14, 45%). Whereas six patients underwent radical resection, the remainder had limited surgery, including biopsy (n = 14, 45%). The predominant histologic diagnoses were glioblastoma multiforme (n = 15, 48%) and anaplastic astrocytoma (n = 10, 32%). Two patients had bithalamic grade II astrocytoma. Twenty-seven patients received radiotherapy (median dose: 59.4 Gy), including craniospinal irradiation in 3 because of leptomeningeal spread. Four patients did not receive radiotherapy in this study because of consent withdrawn (n = 2), toxicity during window therapy (n = 1), or at the physician's discretion (n = 1). Twenty-three patients received 112 cycles of temozolomide therapy. The 2-year progression-free and overall survival estimates were 11 +/- 5% and 21 +/- 7%, respectively. Although the heterogeneity of prognostic factors in our patients made assessment of treatment outcome more difficult, the addition of 6 cycles of temozolomide after radiotherapy did not seem to alter the poor outcome of these patients.

Adolescent↗
PubMed2006

Risk-adapted craniospinal radiotherapy followed by high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma (St Jude Medulloblastoma-96): long-term results from a prospective, multicentre trial.

BACKGROUND: Current treatment for medulloblastoma, which includes postoperative radiotherapy and 1 year of chemotherapy, does not cure many children with high-risk disease. We aimed to investigate the effectiveness of risk-adapted radiotherapy followed by a shortened period of dose-intense chemotherapy in children with medulloblastoma. METHODS: After resection, patients were classified as having average-risk medulloblastoma (< or = 1.5 cm2 residual tumour and no metastatic disease) or high-risk medulloblastoma (> 1.5 cm2 residual disease or metastatic disease localised to neuraxis) medulloblastoma. All patients received risk-adapted craniospinal radiotherapy (23.4 Gy for average-risk disease and 36.0-39.6 Gy for high-risk disease) followed by four cycles of cyclophosphamide-based, dose-intensive chemotherapy. Patients were assessed regularly for disease status and treatment side-effects. The primary endpoint was 5-year event-free survival; we also measured overall survival. This study is registered with ClinicalTrials.gov, number NCT00003211. FINDINGS: Of 134 children with medulloblastoma who underwent treatment (86 average-risk, 48 high-risk), 119 (89%) completed the planned protocol. No treatment-related deaths occurred. 5-year overall survival was 85% (95% CI 75-94) in patients in the average-risk group and 70% (54-84) in those in the high-risk group (p=0.04); 5-year event-free survival was 83% (73-93) and 70% (55-85), respectively (p=0.046). For the 116 patients whose histology was reviewed centrally, histological subtype correlated with 5-year event-free survival (p=0.04): 84% (74-95) for classic histology, 77% (49-100) for desmoplastic tumours, and 57% (33-80) for large-cell anaplastic tumours. INTERPRETATION: Risk-adapted radiotherapy followed by a shortened schedule of dose-intensive chemotherapy can be used to improve the outcome of patients with high-risk medulloblastoma.

Adolescent↗
PubMed2006

Chromosome 17 abnormalities in pediatric neuroblastic tumor with abundant neuropil and true rosettes.

Although as a group, embryonal central nervous system tumors share a common background of primitive round cells, numerous distinctive histologic features allow for further subclassification. One tumor with a unique microscopic appearance is the recently described pediatric neuroblastic tumor with abundant neuropil and true rosettes (PNTANTR). We report 2 additional cases of this unusual tumor; both arose in 4-year-old children, one a midpontine tumor and the other a large cerebral lesion. The tumors contained hypercellular sheets of undifferentiated cells, broad zones of neuropil, and scattered perivascular, Homer Wright, and multilayered ependymoblastic-like rosettes. Isochromosome 17q was detected in multiple samples from one tumor, while the other tumor showed polysomy 17. No deletions of INI1 or amplifications of MYC or MYCN were detected. This report adds 2 cases to our experience of PNTANTR and is the first to demonstrate isochromosome 17q, a molecular alteration typical of medulloblastomas.

Brain↗
PubMed2005

Determination of lapatinib (GW572016) in human plasma by liquid chromatography electrospray tandem mass spectrometry (LC-ESI-MS/MS).

A sensitive method for the determination of lapatinib (GW572016) in human plasma was developed using high-performance liquid chromatographic separation with tandem mass spectrometric detection. Plasma samples (100 microL) were prepared using solid phase extraction (SPE) columns, and 6.0 microL of the reconstituted eluate was injected onto a Phenomenex CuroSil-PFP 3 mu analytical column (50 mm x 2.0mm) with an isocratic mobile phase. Analytes were detected with a PE SCIEX API-365 LC-MS/MS system at unit (Q1) and low (Q3) resolution in positive multiple reaction monitoring mode (m/z 581 (precursor ion) to m/z 364 (product ion) for lapatinib). The mean recovery for lapatinib was 75% with a lower limit of quantification of 15 ng/mL (S/N=11.3, CV< or =14%). This method was validated over a linear range of 100-10,000 ng/mL, and results from a 5-day validation study demonstrated good within-day and between-day precision and accuracy. This method has been used to measure plasma lapatinib concentrations in a Phase I study in children with cancer.

Child↗
PubMed2005

Intellectual and functional outcome of children 3 years old or younger who have CNS malignancies.

PURPOSE: To evaluate the impact of tumor location, clinical parameters, and therapy on neurocognitive, neuroendocrine, and functional outcomes in children < or = 3 years old with intracranial CNS malignancies who survived at least 2 years after diagnosis. PATIENTS AND METHODS: Records were retrospectively reviewed for 194 children diagnosed from 1985 to 1999 at St Jude Children's Research Hospital (Memphis, TN). RESULTS: The median age at diagnosis was 1.8 years (range, 0.1 to 3.5 years). Median follow-up was 7.64 years (2.0 to 19.4 years). Tumors were infratentorial (102), diencephalic (53), and hemispheric (39); 47% required ventriculoperitoneal shunts, 36% developed seizure disorders, and 20% developed severe ototoxicity. Therapy included no radiation therapy (RT) in 57 (30%), local RT in 87 (45%), and craniospinal irradiation (CSI) in 49 (25%). Overall survival at 10 years was 78 +/- 4%. In a longitudinal analysis of 126 patients with at least one neurocognitive evaluation (NE), the mean rate of intelligence quotient (IQ) change for patients who received CSI (-1.34 points per year) and local RT (-0.51 points per year) was significantly different from the no RT group (0.91 points per year; P = .005 and P = .036, respectively). Patients with hemispheric tumors had a significantly greater IQ decline (-1.52 points per year) than those with midline tumors (0.59 points per year; P = .038). Among those with NE > or = 5 years after diagnosis, 71.4% of CSI recipients compared with 23% of local RT recipients had IQ less than 70 (P = .021). Patients undergoing CSI were more likely to develop endocrinopathies (P < .0001) and to require special education (P = .0007). CONCLUSION: In young children with CNS tumors, CSI and hemispheric location are associated with significant declines in IQ scores.

Age of Onset↗
PubMed2005

End-of-life care preferences of pediatric patients with cancer.

PURPOSE: The viewpoint of the terminally ill child at the time of an end-of-life decision has not been formally investigated. We identified the preferences of children and adolescents with advanced cancer about their end-of-life care and the factors that influenced their decisions. PATIENTS AND METHODS: Pediatric patients 10 or more years of age were interviewed within 7 days of participating in one of the following three end-of-life decisions: enrollment onto a phase I trial (n = 7), adoption of a do not resuscitate order (n = 5), or initiation of terminal care (n = 8). The patient, a parent, and the primary pediatric oncologist were interviewed separately by using open-ended interview questions. RESULTS: Twenty patients, aged 10 to 20 years (mean, 17 years and 4 months), with a refractory solid tumor (n = 12), brain tumor (n = 4), or leukemia (n = 4) participated. Eighteen patients (90%) accurately recalled all of their treatment options and identified their own death as a consequence of their decision. The factors that were most frequently identified included the following: for patients, caring about others (n = 19 patients); for parents, the child's preferences (n = 18 parents); and for physicians, the patient's prognosis and comorbid conditions (n = 14 physicians). CONCLUSION: These children and adolescents with advanced cancer realized that they were involved in an end-of-life decision, understood the consequences of their decision, and were capable of participating in a complex decision process involving risks to themselves and others. The decision factors most frequently reported by patients were relationship based; this finding is contrary to existing developmental theories.

Adolescent↗
PubMed2005

Atypical teratoid/rhabdoid tumors (ATRT): improved survival in children 3 years of age and older with radiation therapy and high-dose alkylator-based chemotherapy.

PURPOSE: To describe clinical features, therapeutic approaches, and prognostic factors in pediatric patients with atypical teratoid/rhabdoid tumors (ATRT) treated at St Jude Children's Research Hospital (SJCRH). PATIENTS AND METHODS: Primary tumor samples from patients diagnosed with ATRT at SJCRH between July 1984 and June 2003 were identified. Pathology review included histologic, immunohistochemical analysis, and fluorescence in situ hybridization for SMARCB1 (also known as hSNF5/INI1) deletion. Clinical records of patients with pathologic confirmation of ATRT were reviewed. RESULTS: Thirty-seven patients were diagnosed with ATRT at SJCRH during the 19-year study interval. Six patients were excluded from this clinical review based on pathologic or clinical criteria. Of the remaining 31 patients, 22 were younger than 3 years. Posterior fossa primary lesions and metastatic disease at diagnosis were more common in younger patients with ATRT. All patients underwent surgical resection; 30 received subsequent chemotherapy. The majority of patients aged 3 years or older received postoperative craniospinal radiation. Two-year event-free (EFS) and overall survival (OS) of children aged 3 years or older (EFS, 78% + 14%; OS, 89% +/- 11%) were significantly better than those for younger patients (EFS, 11% +/- 6%; OS, 17% +/- 8%); EFS, P = .009 and OS, P = .0001. No other clinical characteristics were predictive of survival. Three of four patients 3 years or older with progressive disease were successfully rescued with ifosfamide, carboplatin, and etoposide therapy. CONCLUSION: Children presenting with ATRT before the age of 3 years have a dismal prognosis. ATRT presenting in older patients can be cured using a combination of radiation and high-dose alkylating therapy. Older patients with relapsed ATRT can have salvage treatment using ICE chemotherapy.

Central Nervous System Neoplasms↗
PubMed2005

Role of temozolomide after radiotherapy for newly diagnosed diffuse brainstem glioma in children: results of a multiinstitutional study (SJHG-98).

BACKGROUND: The role of chemotherapy in the treatment of children with newly diagnosed diffuse brainstem glioma is uncertain. In the current study, the authors tested the efficacy of temozolomide treatment after radiotherapy (RT) in this setting. METHODS: Patients ages 3-21 years were eligible for the current multiinstitutional study. An optional window therapy regimen consisting of 2 cycles of intravenous irinotecan (10 doses of 20 mg/m2 per day separated by 2 days of rest per cycle) was delivered over 6 weeks and was followed by conventionally fractionated RT. The 5-day schedule of temozolomide (200 mg/m2 per day) was initiated 4 weeks after RT and was continued for a total of 6 cycles. The pharmacokinetics of temozolomide and its active metabolite, 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (MTIC), were analyzed during Cycles 1 and 3. RESULTS: Thirty-three patients (median age at diagnosis, 6.4 years) were enrolled. Of the 16 patients who received window therapy, 6 had irinotecan treatment discontinued due to clinical progression (n=5) or toxicity (n=1); the remaining 10 experienced disease stabilization after 2 cycles. All patients completed RT (median dose, 55.8 gray). Twenty-nine patients received a combined total of 125 cycles of temozolomide. Grade 3/4 neutropenia and thrombocytopenia occurred in 33% and 29% of all temozolomide cycles, respectively. In approximately one-third of the cycles, dose reduction was required due to myelosuppression. No correlation was demonstrated between temozolomide/MTIC exposure and myelosuppression at the conclusion of Cycle 1. All patients died of disease progression (median survival, 12 months). The estimated 1-year survival rate was 48% (standard error, 8%). CONCLUSIONS: The administration of temozolomide after RT did not alter the poor prognosis associated with newly diagnosed diffuse brainstem glioma in children.

Administration, Oral↗
PubMed2005

Ependymoma: new therapeutic approaches including radiation and chemotherapy.

Recent advances in neuroimaging, neurosurgery and radiation therapy have improved disease control and functional outcomes for children with ependymoma, including children under the age of 3 years. The rate of gross-total resection has been increased to 85% in some series and 3 year progression-free survival after radiation therapy as high as 75% has been reported along with significant reductions in neurologic, endocrine and cognitive deficits. Based on these advances and renewed interest in radiation therapy as a frontline treatment modality, attention has been refocused on disease control instead of radiotherapy avoidance. Future research in the treatment of this tumor, that afflicts fewer than 200 children in the US each year, will focus on molecular biology, clarifying risk factors for tumor control and late effects, and testing novel agents.

Age Factors↗
PubMed2004

White matter lesions detected by magnetic resonance imaging after radiotherapy and high-dose chemotherapy in children with medulloblastoma or primitive neuroectodermal tumor.

PURPOSE: White matter lesions (WMLs) have been described as a delayed effect of cranial irradiation in children with brain tumors, or a transient subacute effect characterized by an intralesional or perilesional reaction. We report the occurrence of subacute WMLs detected by magnetic resonance imaging (MRI) in children treated for medulloblastoma or primitive neuroectodermal tumor (PNET) and document the associated clinical, radiologic, and neurocognitive findings. PATIENTS AND METHODS: Among 134 patients with medulloblastoma or supratentorial PNET treated prospectively with risk-adjusted craniospinal irradiation and conformal boost to the tumor bed, followed by four high-dose chemotherapy (HDC) cycles with stem-cell rescue, 22 developed WMLs on T1-weighted imaging with and without contrast and/or T2-weighted imaging on MRI. Patients had > or = 12 months of follow-up. Neurocognitive assessments included intelligence quotient (IQ) tests and tests of academic achievement. RESULTS: Twenty-two patients developed WMLs at a median of 7.8 months after starting therapy (range, 1.9 to 13.0 months). Lesions were predominantly in the pons (n = 8) and cerebellum (n = 6). Sixteen patients (73%) had WML resolution at a median of 6.2 months (range, 1.68 to 23.5 months) after onset; two patients developed necrosis and atrophy. Three developed persistent neurologic deficits. Cumulative incidence of WMLs at 1 year was 15% +/- 3%. Patients with WMLs had a significant decline in estimated IQ (-2.5 per year; P = .03) and math (-4.5 per year; P = .003) scores. CONCLUSION: WMLs in medulloblastoma or PNET patients treated with conformal radiotherapy and HDC are typically transient and asymptomatic, and may mimic early tumor recurrence. A minority of patients with WMLs develop permanent neurologic deficits and imaging changes. Overall, the presence of WMLs is associated with greater neurocognitive decline.

Adolescent↗
PubMed2004

Medullomyoblastoma: a radiographic and clinicopathologic analysis of six cases and review of the literature.

BACKGROUND: Medullomyoblastoma (MMB) is a rare cerebellar embryonal neoplasm that occurs almost exclusively in children. It is biphasic by microscopy, containing myoblastic and primitive neuroectodermal components. METHODS: The authors conducted a retrospective review of the radiographic and pathologic characteristics, treatment, and clinical outcomes of six children with MMB who were treated at St. Jude Children's Research Hospital (Memphis, TN) between 1984 and 2003. Fluorescence in situ hybridization (FISH) data were available for four children. A literature review also was conducted and focused on imaging and pathologic findings. RESULTS: The median age at diagnosis was 4.5 years (range, 0.83-7.5 years). Radiographically, all tumors were cerebellar and exhibited variable enhancement, and 50% of tumors had necrotic foci. Three tumors contained discrete, magnetic resonance imaging (MRI) T2-weighted-hypointense/computed tomography (CT)-hyperdense enhancing regions and separate hyperintense/hypodense nonenhancing regions, which correlated microscopically with geographic islands of primitive neuroectodermal and rhabdomyoblastic cells. Large cell/anaplastic (five tumors), nodular/desmoplastic (two tumors), and classic (two tumors) medulloblastoma histologies were encountered either alone (five tumors) or in combination with each other (two tumors). All 4 tumors that were tested exhibited alterations in chromosome 17 or c-myc amplification. All patients underwent macroscopic total resection and subsequently received chemotherapy and craniospinal (five patients) or local conformal (one patient) radiotherapy. At a median follow-up of 92 months (range, 23-187 months), 3 patients remain alive with no evidence of disease, 2 patients have died of disease, and 1 patient has died of secondary acute lymphocytic leukemia. CONCLUSIONS: The results of the current study demonstrated the frequent correlation of biphasic nodularity (as determined by MRI or CT) with discrete rhabdomyoblastic and primitive neuroectodermal islands (as revealed by microscopy) in MMB. These results also support the view that MMB and medulloblastoma may have common tumorigenic origins, given their similar histologic and molecular features.

Cerebellar Neoplasms↗
PubMed2004

Results of a phase II upfront window of pharmacokinetically guided topotecan in high-risk medulloblastoma and supratentorial primitive neuroectodermal tumor.

PURPOSE: To assess the antitumor efficacy of pharmacokinetically guided topotecan dosing in previously untreated patients with medulloblastoma and supratentorial primitive neuroectodermal tumors, and to evaluate plasma and CSF disposition of topotecan in these patients. PATIENTS AND METHODS: After maximal surgical resection, 44 children with previously untreated high-risk medulloblastoma were enrolled, of which 36 were assessable for response. The topotecan window consisted of two cycles, administered initially as a 30-minute infusion daily for 5 days, lasting 6 weeks. Pharmacokinetic studies were conducted on day 1 to attain a topotecan lactone area under the plasma concentration-time curve (AUC) of 120 to 160 ng/mL.h. After 10 patients were enrolled, the infusion was modified to 4 hours, with dosage individualization. RESULTS: Of 36 assessable patients, four patients (11.1%) had a complete response and six (16.6%) showed a partial response, and disease was stable in 17 patients (47.2%). Toxicity was mostly hematologic, with only one patient experiencing treatment delay. The target plasma AUC was achieved in 24 of 32 studies (75%) in the 30-minute infusion group, and in 58 of 93 studies (62%) in the 4-hour infusion group. The desired CSF topotecan exposure was achieved in seven of eight pharmacokinetic studies when the topotecan plasma AUC was within target range. CONCLUSION: Topotecan is an effective agent against pediatric medulloblastoma in patients who have received no therapy other than surgery. Pharmacokinetically guided dosing achieved the target plasma AUC in the majority of patients. This drug warrants testing as part of standard postradiation chemotherapeutic regimens. Furthermore, these results emphasize the importance of translational research in drug development, which in this case identified an effective drug.

Adolescent↗
PubMed2003

Clear cell ependymoma: a clinicopathologic and radiographic analysis of 10 patients.

BACKGROUND: Clear cell ependymoma (CCE) is an uncommon central nervous system tumor with a predilection for the supratentorial region in children. Histologically, it may mimic oligodendroglioma, central neurocytoma, hemangioblastoma, and renal cell carcinoma. METHODS: The authors reviewed the clinical, radiographic, and pathologic features, therapy, and outcome in 10 children with CCE who were treated at St. Jude Children's Research Hospital (1984-2003). Fluorescence in situ hybridization (FISH) was performed using 1p/1q, 19p/19q, CEP18/DAL1, and bcr/NF2 probe pairs. RESULTS: The median patient age at diagnosis was 7.5 years (range, 1-19 years). Tumors occurred supratentorially in 9 of 10 patients. All tumors had rounded nuclei with surrounding, clear halos and at least focal perivascular pseudorosettes. Seven tumors had anaplastic features. No deletions involving 1p, 19q, or NF2 were detected. The tumors from 5 of 7 patients, all with anaplasia, had losses of both CEP18 and DAL-1. Radiographically, all tumors were enhanced, and 9 tumors had associated cysts with enhancing walls. Seven patients underwent gross total resection, which was near total in one patient and subtotal in two patients. Five patients received immediate postoperative local radiotherapy. Three patients were diagnosed initially with pilocytic astrocytoma (one patient) and oligodendroglioma (two patients) and were observed. The progression-free survival and overall survival rates at 5 years were 34% +/- 20% and 75% +/- 19%, respectively. The median follow-up was 37 months (range, 5-239 months). Five patients developed local recurrence within a median of 9 months after diagnosis. Two patients developed extracranial soft tissue and lymph node metastases. CONCLUSIONS: CCEs were found to have a predilection for extraneural metastases and early recurrence and demonstrate characteristic radiographic features, anaplastic histologic features, and chromosome 18 losses. The authors recommend resection followed by local radiotherapy as the treatment of choice in children.

Adolescent↗