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ABSTRACT: PURPOSE: Glioblastoma (GBM) demonstrate down-regulated expression of Human Leukocyte Antigen (HLA) Class I, thereby escaping from cytotoxic T cells and limiting the efficacy of immunotherapy. LOH of HLA Class I (6p21) and/or Beta-2 microglobulin (B2m) (15q21) regions represent irreversible down-regulation. In this study, we examined the prevalence of these LOH events and their relations with overall survival in GBM. EXPERIMENTAL DESIGN: In a cross-sectional analysis on 60 adult GBM patients, DNA from formalin-fixed paraffin-embedded specimens were evaluated for ten microsatellite regions of HLA Class I, B2m, HLA Class II, HLA Class III, and 6q by PCR as well as immunohistochemical evaluation of HLA Class I expression and CD8+ T cell infiltration. RESULTS: LOH in HLA Class I, B2m, HLA Class II, HLA Class III, and 6q regions were present in 41.4%, 18.2%, 9.4%, 77.8%, and 36.0% of informative cases, respectively. LOH of HLA Class I was associated with shorter overall survival (HR = 4.89, p = 0.0078). HLA Class I was down-regulated in 22 to 43% of cases based on immunohistochemistry. Cases that displayed negative staining were significantly younger. HLA Class I expression correlated with intratumoral CD8+ T cell infiltration. CONCLUSION: LOH in the HLA Class I region is frequent in adult GBMs. The association of shorter survival with LOH in this region suggest a crucial role for these genes in immunosurveillance.
Clinical Cancer Research 02/2013; · 7.74 Impact Factor
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ABSTRACT: Despite surgery and radiotherapy, as many as 50 % of children with ependymomas will suffer from tumor recurrences that will ultimately lead to death. Our group's initial peptide-based glioma vaccine targeting EphA2, IL-13Rα2, and Survivin, which are overexpressed in pediatric gliomas, has shown promise in its initial phase of testing. We therefore investigated whether EphA2, IL-13Rα2, Survivin, and, additionally, Wilms' Tumor 1 (WT1), are overexpressed in pediatric ependymomas to determine if a similar immunotherapy approach could be applicable. Immunohistochemistry was performed using antibodies specific for EphA2, IL-13Rα2, Survivin, and WT1 on paraffin-embedded specimens from 19 pediatric and 13 adult ependymomas. Normal brain and ependyma were used for background staining controls. Negative staining was defined as no staining or staining equaling the background intensity in normal brain tissues. In the 19 pediatric cases, 18 (95 %) demonstrated positive staining for EphA2, 16 (84 %) for IL-13Rα2, 18 (95 %) for Survivin, and only 7 (37 %) for WT1. Only 3 of 19 cases were positive for two or fewer tumor-associated antigens (TAAs); 16 of 19 cases were positive for three or more TAAs. In the 13 adult cases, all 13 demonstrated positive staining for EphA2, IL-13Rα2, and Survivin. Only 2 of 13 cases (15 %) demonstrated positive staining for WT1. All adult specimens were positive for three or more TAAs. Some ependymomas showed patchy variability in intensity. Pediatric and adult ependymomas frequently express EphA2, IL-13Rα2, and Survivin. This provides the basis for the utilization of an established multiple peptide vaccine for ependymoma in a clinical trial setting.
Journal of Neuro-Oncology 11/2012; · 3.21 Impact Factor
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Journal of Clinical Oncology 11/2012; · 18.37 Impact Factor
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ABSTRACT: PURPOSE: To evaluate the effects on 1-year event-free survival (EFS) and overall survival (OS) of combining motexafin and gadolinium (MGd), a potent radiosensitizer, with daily fractionated radiation therapy in children with newly diagnosed intrinsic pontine gliomas. METHODS AND MATERIALS: Patients with newly diagnosed intrinsic pontine glioma were treated with MGd daily for 5 consecutive days each week, for a total of 30 doses. Patients received a 5- to 10-min intravenous bolus of MGd, 4.4 mg/kg/day, given 2 to 5 h prior to standard dose irradiation. Radiation therapy was administered at a daily dose of 1.8 Gy for 30 treatments over 6 weeks. The total dose was 54 Gy. RESULTS: Sixty eligible children received MGd daily, concurrent with 6 weeks of radiation therapy. The estimated 1-year EFS was 18% ± 5%, and the estimated 1-year OS was 53% ± 6.5%. The most common grade 3 to 4 toxicities were lymphopenia, transient elevation of liver transaminases, and hypertension. CONCLUSIONS: Compared to historical controls, the addition of MGd to a standard 6-week course of radiation did not improve the survival of pediatric patients with newly diagnosed intrinsic pontine gliomas.
International journal of radiation oncology, biology, physics 10/2012; · 4.59 Impact Factor
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ABSTRACT: Object Previous studies of systemic and intralesional administration of nonpegylated interferon have shown efficacy against craniopharyngioma. Pegylaion of interferon-α-2b (PI) prolongs the half-life, allowing sustained exposure of the drug over time, and enhances efficacy. The authors report the results of the use of PI in 5 children with recurrent craniopharyngiomas. Methods Five children, ranging in age from 9 to 15 years, with recurrent craniopharyngiomas were treated for up to 2 years with subcutaneous injections of PI at a dose of 1-3 μg/kg/week. Tumor response was assessed using MRI. Results All patients had stable disease or better in response to PI. One patient experienced a recurrence after gross-total resection (GTR). She initially showed an increase in the predominantly cystic tumor after 3 months of treatment, followed by a complete response. She required no further intervention and remains without evidence of disease 10 years after starting treatment. Another patient experienced recurrence 3.3 years after subtotal resection (STR) and radiation therapy. He had complete disappearance of the predominantly cystic component after 4 months of treatment, and a small residual calcified mass remains 5 years later. The third patient experienced recurrence after 3 GTRs. He had a complete response after 7 months of treatment and remains without evidence of disease 19 months after starting treatment. The fourth patient experienced recurrence after 2 STRs. He had a 30% decrease in tumor size after 4 months of treatment, which was maintained for 12 months at which point the cyst began to increase in size. The final patient experienced recurrence after GTR and has stable disease 6 months after starting treatment with PI. Conclusions The use of PI in children with recurrent craniopharyngiomas can result in significant and durable responses and potentially delay or avoid the need for radiation therapy.
Journal of Neurosurgery Pediatrics 10/2012; · 1.53 Impact Factor
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ABSTRACT: Patients with constitutional mismatch repair-deficiency (CMMR-D) caused by the biallelic deletions of mismatch repair (MMR) genes have a high likelihood of developing malignancies of the bone marrow, bowel, and brain. Affected individuals often have phenotypic features of neurofibromatosis type 1 (NF-1), including café-au-lait spots. Optic pathway gliomas (OPGs), a common manifestation of NF-1, have not been reported. We report the case of a 3-year-old male with an extensive OPG who met the diagnostic criteria for NF-1. He was subsequently found to have multiple colonic polyps and bi-allelic loss of PMS2. Testing for NF-1 was negative. Pediatr Blood Cancer © 2012 Wiley Periodicals, Inc.
Pediatric Blood & Cancer 07/2012; · 1.89 Impact Factor
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Regina I Jakacki,
Peter C Burger,
Tianni Zhou,
Emiko J Holmes,
Mehmet Kocak,
Arzu Onar,
Joel Goldwein,
Minesh Mehta,
Roger J Packer,
Nancy Tarbell,
Charles Fitz,
Gilbert Vezina,
Joanne Hilden,
Ian F Pollack
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ABSTRACT: We evaluated the feasibility of administering carboplatin as a radiosensitizer during craniospinal radiation therapy (CSRT) to patients with high-risk medulloblastomas (MBs) and supratentorial primitive neuroectodermal tumors, and we report the outcome in the subset with metastatic (M+) MB.
After surgery, patients received 36 Gy CSRT with boosts to sites of disease. During radiation, patients received 15 to 30 doses of carboplatin (30-45 mg/m(2)/dose), along with vincristine (VCR) once per week for 6 weeks. Patients on regimen A received 6 months of maintenance chemotherapy (MC) with cyclophosphamide and VCR. Once the recommended phase II dose (RP2D) of carboplatin was determined, cisplatin was added to the MC (regimen B).
In all, 161 eligible patients (median age, 8.7 years; range, 3.1 to 21.6 years) were enrolled. Myelosuppression was dose limiting and 35 mg/m(2)/dose × 30 was determined to be the RP2D of carboplatin. Twenty-nine (36%) of 81 patients with M+ MB had diffuse anaplasia. Four patients were taken off study within 11 months of completing radiotherapy for presumed metastatic progression and are long-term survivors following palliative chemotherapy. Excluding these four patients, 5-year overall survival ± SE and progression-free survival ± SE for M+ patients treated at the RP2D on regimen A was 82% ± 9% and 71% ± 11% versus 68% ± 10% and 59% ± 10% on regimen B (P = .36). There was no difference in survival by M stage. Anaplasia was a negative predictor of outcome.
The use of carboplatin as a radiosensitizer is a promising strategy for patients with M+ MB. Early progression should be confirmed by biopsy.
Journal of Clinical Oncology 06/2012; 30(21):2648-53. · 18.37 Impact Factor
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Ian F. Pollack,
Ronald L. Hamilton,
Robert W. Sobol,
Marina N. Nikiforova,
Maureen A. Lyons-Weiler,
William A. LaFramboise,
Peter C. Burger,
Daniel J. Brat,
Marc K. Rosenblum,
Emiko J. Holmes,
Tianni Zhou, Regina I. Jakacki,
for the Children’s Oncology Group
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ABSTRACT: PurposeRecent studies have demonstrated a high frequency of IDH mutations in adult “secondary” malignant gliomas arising from preexisting lower grade lesions, often in young adults, but
not in “primary” gliomas. Because pediatric malignant gliomas share some molecular features with adult secondary gliomas,
we questioned whether a subset of these tumors also exhibited IDH mutations.
Experimental designWe examined the frequency of IDH mutations, using real-time polymerase chain reaction and sequencing analysis, in a cohort of 43 pediatric primary malignant
gliomas treated on the Children’s Oncology Group ACNS0423 study. The relationship between IDH mutations and other molecular and clinical factors, and outcome, was evaluated.
Results
IDH1 mutations were observed in 7 of 43 (16.3%) tumors; no IDH2 mutations were observed. A striking age association was apparent in that mutations were noted in 7 of 20 tumors (35%) from
children ≥14years, but in 0 of 23 (0%) younger children (p = 0.0024). No association was observed with clinical factors other than age. One-year event-free survival was 86 ± 15% in
the IDH-mutated group versus 64 ± 8% in the non-mutated group (p = 0.03, one-sided logrank test). One-year overall survival was 100% in patients with mutations versus 81 ± 6.7% in those
without mutations (p = 0.035, one-sided logrank test).
Conclusions
IDH1 mutations are common in malignant gliomas in older children, suggesting that a subset of these lesions may be biologically
similar to malignant gliomas arising in younger adults and may be associated with a more favorable prognosis.
KeywordsAnaplastic glioma–Childhood–Glioblastoma–IDH
Child s Nervous System 04/2012; 27(1):87-94. · 1.54 Impact Factor
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ABSTRACT: Both carboplatin and vinblastine have demonstrated single-agent activity in children with low-grade gliomas. A phase 1 trial evaluating 2 different schedules of these 2 agents in combination was performed: (1) Schedule A = carboplatin (140 mg/m(2)) weekly × 3 + vinblastine (4.5 or 3.5 mg/m(2)) weekly × 6, every 6 weeks; (2) Schedule B = carboplatin (300, 400, or 500 mg/m(2)) on day 1 + vinblastine (4.0 mg/m(2)) weekly × 3, every 4 weeks. Twenty-six patients, median (range) age 4.4 (0.7-14.8) years, were enrolled. Four of 9 patients enrolled on Schedule A had recurrent grade 4 neutropenia, suggesting that this schedule was not feasible. Seventeen patients were enrolled on Schedule B. At the 500 mg/m(2) carboplatin dose level, 2 of 3 patients developed dose-limiting toxicity (elevated alkaline phosphatase, neutropenia). At the 400 mg/m(2) carboplatin dose level, none of the 6 patients had dose-limiting toxicity. Ten of 16 patients who received treatment on Schedule B completed the prescribed 12 courses. Of the 21 patients evaluable for response, central review confirmed 1 partial response and 6 minor responses. Eleven patients had stable disease (>3 months) and 3 developed progressive disease. Seven of 9 patients with visual pathway tumors and acute visual changes prior to enrollment had documented improvement. The recommended phase 2 dose and schedule is carboplatin, 400 mg/m(2)/dose on day 1, and vinblastine, 4 mg/m(2)/dose, weekly × 3, repeated every 4 weeks. Further study of this regimen in patients with low-grade glioma is warranted.
Neuro-Oncology 08/2011; 13(8):910-5. · 5.72 Impact Factor
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ABSTRACT: Brain tumors are the most common solid tumors in children. With the increasingly widespread availability of MRI, the incidence of childhood brain tumors seemed to rise in the 1980s, but has subsequently remained relatively stable. However, management of brain tumors in children has evolved substantially during this time, reflecting refinements in classification of tumors, delineation of risk groups within histological subsets of tumors, and incorporation of molecular techniques to further define tumor subgroups. Although considerable progress has been made in the outcomes of certain tumors, prognosis in other childhood brain tumor types is poor. Among the tumor groups with more-favorable outcomes, attention has been focused on reducing long-term morbidity without sacrificing survival rates. Studies for high-risk groups have examined the use of intensive therapy or novel, molecularly targeted approaches to improve disease control rates. In addition to reviewing the literature and providing an overview of the complexities in diagnosing childhood brain tumors, we will discuss advances in the treatment and categorization of several tumor types in which progress has been most apparent, as well as those in which improvements have been lacking. The latest insights from molecular correlative studies that hold potential for future refinements in therapy will also be discussed.
Nature Reviews Neurology 07/2011; 7(9):495-506. · 12.46 Impact Factor
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ABSTRACT: Genomic instability in cancer leads to abnormal genome copy number alterations (CNA) as a mechanism underlying tumorigenesis. Using microarrays and other technologies, tumor CNA are detected by comparing tumor sample CN to normal reference sample CN. While advances in microarray technology have improved detection of copy number alterations, the increase in the number of measured signals, noise from array probes, variations in signal-to-noise ratio across batches and disparity across laboratories leads to significant limitations for the accurate identification of CNA regions when comparing tumor and normal samples.
To address these limitations, we designed a novel "Virtual Normal" algorithm (VN), which allowed for construction of an unbiased reference signal directly from test samples within an experiment using any publicly available normal reference set as a baseline thus eliminating the need for an in-lab normal reference set.
The algorithm was tested using an optimal, paired tumor/normal data set as well as previously uncharacterized pediatric malignant gliomas for which a normal reference set was not available. Using Affymetrix 250K Sty microarrays, we demonstrated improved signal-to-noise ratio and detected significant copy number alterations using the VN algorithm that were validated by independent PCR analysis of the target CNA regions.
We developed and validated an algorithm to provide a virtual normal reference signal directly from tumor samples and minimize noise in the derivation of the raw CN signal. The algorithm reduces the variability of assays performed across different reagent and array batches, methods of sample preservation, multiple personnel, and among different laboratories. This approach may be valuable when matched normal samples are unavailable or the paired normal specimens have been subjected to variations in methods of preservation.
BMC Medical Genomics 01/2011; 4:14. · 3.69 Impact Factor
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Ian F Pollack,
Ronald L Hamilton,
Robert W Sobol,
Marina N Nikiforova,
Maureen A Lyons-Weiler,
William A LaFramboise,
Peter C Burger,
Daniel J Brat,
Marc K Rosenblum,
Emiko J Holmes,
Tianni Zhou, Regina I Jakacki
[show abstract]
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ABSTRACT: Recent studies have demonstrated a high frequency of IDH mutations in adult "secondary" malignant gliomas arising from preexisting lower grade lesions, often in young adults, but not in "primary" gliomas. Because pediatric malignant gliomas share some molecular features with adult secondary gliomas, we questioned whether a subset of these tumors also exhibited IDH mutations.
We examined the frequency of IDH mutations, using real-time polymerase chain reaction and sequencing analysis, in a cohort of 43 pediatric primary malignant gliomas treated on the Children's Oncology Group ACNS0423 study. The relationship between IDH mutations and other molecular and clinical factors, and outcome, was evaluated.
IDH1 mutations were observed in 7 of 43 (16.3%) tumors; no IDH2 mutations were observed. A striking age association was apparent in that mutations were noted in 7 of 20 tumors (35%) from children ≥14 years, but in 0 of 23 (0%) younger children (p = 0.0024). No association was observed with clinical factors other than age. One-year event-free survival was 86 ± 15% in the IDH-mutated group versus 64 ± 8% in the non-mutated group (p = 0.03, one-sided logrank test). One-year overall survival was 100% in patients with mutations versus 81 ± 6.7% in those without mutations (p = 0.035, one-sided logrank test).
IDH1 mutations are common in malignant gliomas in older children, suggesting that a subset of these lesions may be biologically similar to malignant gliomas arising in younger adults and may be associated with a more favorable prognosis.
Child s Nervous System 01/2011; 27(1):87-94. · 1.54 Impact Factor
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Ian F Pollack,
Ronald L Hamilton,
Robert W Sobol,
Marina N Nikiforova,
Yuri E Nikiforov,
Maureen A Lyons-Weiler,
William A LaFramboise,
Peter C Burger,
Daniel J Brat,
Marc K Rosenblum,
Floyd H Gilles,
Allan J Yates,
Tianni Zhou,
Kenneth J Cohen,
Jonathan L Finlay, Regina I Jakacki
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ABSTRACT: Alkylating agents are commonly used in the treatment of childhood malignant gliomas. Overexpression of O(6)-methylguanine-DNA methyltransferase (MGMT) constitutes an important mechanism for resistance to such agents, and MGMT status has been associated with outcome in several recent trials. Deficiency in mismatch repair (MMR) function has been implicated in preclinical studies as an additional potential mechanism of resistance to methylating agents, such as temozolomide, independent of tumor MGMT status. However, the frequency of this abnormality as a clinical resistance mechanism in childhood malignant gliomas has not been well characterized.
To address this issue, we examined the frequency of microsatellite instability (MSI), a marker of defective MMR, in a series of 68 tumors, derived from newly diagnosed patients treated on the Children's Cancer Group 945 study, and the Children's Oncology Group ACNS0126 and 0423 studies. MSI was assessed using a panel of six microsatellite markers, including BAT-25, BAT-26, CAT-25, D2S123, D5S346, and D17S250. MGMT immunoreactivity was assessed in parallel to allow comparison of the relative incidence of MGMT overexpression and MSI.
Only three tumors had high-level MSI involving three or more markers; the remainder had no MSI at any of the loci examined. These children did not have unusual features in terms of their outcome. In contrast to the infrequency of MSI, 25 tumors (37%) exhibited MGMT overexpression as assessed by immunohistochemistry. None of the tumors with MSI exhibited overexpression of MGMT.
MMR deficiency is an infrequent contributor to initial alkylator resistance in children with malignant gliomas.
Pediatric Blood & Cancer 12/2010; 55(6):1066-71. · 1.89 Impact Factor
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Ian F Pollack,
Ronald L Hamilton,
Peter C Burger,
Daniel J Brat,
Marc K Rosenblum,
Geoffrey H Murdoch,
Marina N Nikiforova,
Emiko J Holmes,
Tianni Zhou,
Kenneth J Cohen, Regina I Jakacki
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ABSTRACT: Aberrant activation of Akt is a common finding in adult malignant gliomas, resulting in most cases from mutations or deletions involving PTEN, which allows constitutive Akt phosphorylation. In contrast, we have previously reported that pediatric malignant gliomas, which are morphologically similar to lesions arising in adults, have a substantially lower incidence of genomic alterations of PTEN. The objective of this study was to determine whether Akt activation was also an uncommon finding in childhood malignant gliomas and whether this feature was associated with survival. To address this issue, we examined the frequency of Akt activation, determined by overexpression of the activated phosphorylated form of Akt (Se(473)) on immunohistochemical analysis, in a series of 53 childhood malignant gliomas obtained from newly diagnosed patients treated on the Children's Oncology Group ACNS0126 and 0423 studies. The relationship between Akt activation and p53 overexpression, MIB1 labeling, and tumor histology was evaluated. The association between Akt activation and survival was also assessed. Overexpression of activated Akt was observed in 42 of 53 tumors, far in excess of the frequency of PTEN mutations we have previously observed. There was no association between Akt activation and either histology, p53 overexpression, or MIB1 proliferation indices. Although tumors that lacked Akt overexpression had a trend toward more favorable event-free survival and overall survival (p = 0.06), this association reflected that non-overexpressing tumors were significantly more likely to have undergone extensive tumor removal, which was independently associated with outcome. Activation of Akt is a common finding in pediatric malignant gliomas, although it remains uncertain whether this is an independent adverse prognostic factor. In view of the frequency of Akt activation, the evaluation of molecularly targeted therapies that inhibit this pathway warrants consideration for these tumors.
Journal of Neuro-Oncology 09/2010; 99(2):155-63. · 3.21 Impact Factor
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ABSTRACT: The term “optic glioma” encompasses a diverse group of tumors that can arise anywhere along the visual pathway from the globe
to the optic radiations. A particularly challenging subgroup of these tumors involves the hypothalamus in conjunction with
the optic chiasm. Because complete resection of such lesions is not feasible without excessive morbidity, a variety of adjuvant
management options have been explored. The success of low-intensity outpatient chemotherapy regimens in the treatment of chiasmatic-hypothalamic
gliomas has led to dramatic changes in management algorithms for these tumors during the last decade. A second factor that
has come to influence management in recent years is the recognition that optic pathway tumors in children with neurofibromatosis
type 1 (NF1) typically behave in a substantially more indolent manner than in those without this disorder, necessitating a
correspondingly more conservative approach to intervention.
12/2009: pages 395-404;
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ABSTRACT: We conducted a phase I and pharmacokinetic study of the epidermal growth factor receptor (EGFR) inhibitor erlotinib as a single agent and in combination with temozolomide in children with refractory solid tumors.
Erlotinib was administered orally once daily to cohorts of three to six children for a single 28-day course. Patients then received the combination of daily erlotinib and temozolomide daily for 5 days for all subsequent 28-day courses. An oral erlotinib solution was administered during the dose-finding phase and a tablet formulation was subsequently studied at the maximum-tolerated dose (MTD). Pharmacokinetic studies and ERBB-receptor expression and signaling studies were performed.
Forty-six patients, median age 11.5 years, received erlotinib at doses of 35, 50, 65, 85, or 110 mg/m(2)/d. At 110 mg/m(2)/d, two of four patients had dose-limiting toxicity (DLT) consisting of rash and hyperbilirubinemia, whereas one of six patients developed dose-limiting rash at 85 mg/m(2)/d. The most frequent non-DLTs included diarrhea, rash, and hyperbilirubinemia. The combination of erlotinib and temozolomide was well tolerated. The median apparent erlotinib clearance was 3.1 L/h/m(2) and the median terminal half-life was 8.7 hours. One patient with a neurocytoma had stable disease for 19 months, two patients with neuroblastoma remained on study for 23 and 24 months, and one patient with myoepithelioma had a mixed response.
The recommended phase II dose of erlotinib in recurrent pediatric solid tumors is 85 mg/m(2)/d, either alone or in combination with temozolomide.
Journal of Clinical Oncology 10/2008; 26(30):4921-7. · 18.37 Impact Factor
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ABSTRACT: Neurocytomas are rare tumors of the central nervous system that are typically located in the ventricular system. The authors report a case of a child with neurofibromatosis Type 1 (NF1) who had a tumor of the optic nerves and chiasm with signal abnormality extending through the diencephalon, as well as an occipital lobe mass, which was presumed to be part of the visual pathway neoplasm. Because the occipital lobe lesion slowly increased in size over time, while the other areas remained stable, a biopsy was performed. Pathological evaluation revealed an extraventricular neurocytoma of extraventricular neurocytoma. To the authors' knowledge, neurocytomas have not been previously reported in patients with NF1. Because visual pathway gliomas are extremely common in children with NF1, they are often treated empirically as low-grade gliomas without histological confirmation. The importance of obtaining a biopsy in lesions that have atypical imaging features is highlighted.
Journal of Neurosurgery Pediatrics 08/2008; 2(1):63-7. · 1.53 Impact Factor
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ABSTRACT: A phase I trial was conducted to determine the maximum tolerated dose (MTD) of temozolomide given in combination with lomustine in newly diagnosed pediatric patients with high-grade gliomas. Response was assessed following two courses of therapy at the MTD. Temozolomide was administered to cohorts of patients at doses of 100, 125, 160, or 200 mg/m(2) on days 1-5, along with 90 mg/m(2) lomustine on day 1. Two courses of lomustine/temozolomide were given prior to radiation therapy (RT) and up to six courses were administered afterward. Thirty-two patients were enrolled. Dose-limiting myelosuppression was seen in two of three patients enrolled at the 200 mg/m(2) dose level. One of 14 patients in the expanded MTD cohort (160 mg/m(2)) experienced dose-limiting thrombocytopenia. After two courses at the MTD, one patient with a 5-mm enhancing nodule postoperatively had a complete response, one patient with a large residual temporal lobe glioblastoma had a partial response, and eight patients had stable disease. Several patients developed transient radiographic worsening after completing RT. Median 1- and 2-year overall survivals at the MTD were 60% +/- 13% and 40% +/- 13% with a median of 17.6 months. Thirteen of 20 patients (65%) who underwent MRI scans within 6 months prior to death developed metastatic disease. In conclusion, when administered with 90 mg/m(2) lomustine on day 1, the MTD of temozolomide is 160 mg/m(2)/day x 5. Radiographic changes following RT make determination of early tumor progression difficult. Metastatic disease is common prior to death.
Neuro-Oncology 06/2008; 10(4):569-76. · 5.72 Impact Factor
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Ian F Pollack, Regina I Jakacki,
Susan M Blaney,
Michael L Hancock,
Mark W Kieran,
Peter Phillips,
Larry E Kun,
Henry Friedman,
Roger Packer,
Anu Banerjee,
J Russell Geyer,
Stewart Goldman,
Tina Young Poussaint,
Matthew J Krasin,
Yanfeng Wang,
Michael Hayes,
Anthony Murgo,
Susan Weiner,
James M Boyett
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ABSTRACT: This study estimated the maximum tolerated dose (MTD) of imatinib with irradiation in children with newly diagnosed brainstem gliomas, and those with recurrent malignant intracranial gliomas, stratified according to use of enzyme-inducing anticonvulsant drugs (EIACDs). In the brainstem glioma stratum, imatinib was initially administered twice daily during irradiation, but because of possible association with intratumoral hemorrhage (ITH) was subsequently started two weeks after irradiation. The protocol was also amended to exclude children with prior hemorrhage. Twenty-four evaluable patients received therapy before the amendment, and three of six with a brainstem tumor experienced dose-limiting toxicity (DLT): one had asymptomatic ITH, one had grade 4 neutropenia and, one had renal insufficiency. None of 18 patients with recurrent glioma experienced DLT. After protocol amendment, 3 of 16 patients with brainstem glioma and 2 of 11 patients with recurrent glioma who were not receiving EIACDs experienced ITH DLTs, with three patients being symptomatic. In addition to the six patients with hemorrhages during the DLT monitoring period, 10 experienced ITH (eight patients were symptomatic) thereafter. The recommended phase II dose for brainstem gliomas was 265 mg/m(2). Three of 27 patients with brainstem gliomas with imaging before and after irradiation, prior to receiving imatinib, had new hemorrhage, excluding their receiving imatinib. The MTD for recurrent high-grade gliomas without EIACDs was 465 mg/m(2), but the MTD was not established with EIACDs, with no DLTs at 800 mg/m(2). In summary, recommended phase II imatinib doses were determined for children with newly diagnosed brainstem glioma and recurrent high-grade glioma who were not receiving EIACDs. Imatinib may increase the risk of ITH, although the incidence of spontaneous hemorrhages in brainstem glioma is sufficiently high that this should be considered in studies of agents in which hemorrhage is a concern.
Neuro-Oncology 05/2007; 9(2):145-60. · 5.72 Impact Factor
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Regina I Jakacki
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ABSTRACT: Primitive neuroectodermal tumors (PNETs) are malignant tumors with a high propensity to disseminate throughout the cerebrospinal fluid. Current treatment guidelines are largely determined by clinically based prognostic factors, the most important of which are tumor location and the extent of tumor spread. Although the cure rate for high-risk PNETs has improved, the irreversible sequelae of craniospinal axis radiation treatment in patients who survive have motivated researchers to investigate more fully which patients can safely receive less treatment. The author reviews the literature, describes currently available treatment options for patients with high-risk PNETs, and discusses strategies aimed at improving outcome and refining prognosis that are currently being explored.
Journal of Neurosurgery 02/2005; 102(1 Suppl):44-52. · 2.96 Impact Factor
