Katherine E Warren

National Institutes of Health, Maryland, United States

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Publications (53)208.19 Total impact

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    ABSTRACT: A phase I trial of veliparib (ABT-888), an oral poly(ADP-ribose) polymerase (PARP) inhibitor, and temozolomide (TMZ) was conducted in children with recurrent brain tumors to (i) estimate the maximum tolerated doses (MTDs) or recommended phase II doses (RP2Ds) of veliparib and TMZ; (ii) describe the toxicities of this regimen; and (iii) evaluate the plasma pharmacokinetic parameters and extent of PARP inhibition in peripheral blood mononuclear cells (PBMCs) following veliparib.
    Neuro-Oncology 06/2014; · 6.18 Impact Factor
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    ABSTRACT: Diffuse intrinsic pontine glioma (DIPG) is a malignant pediatric brain tumor associated with dismal outcome. Recent high-throughput molecular studies have shown a high frequency of mutations in histone-encoding genes (H3F3A and HIST1B) and distinctive epigenetic alterations in these tumors. Epigenetic alterations described in DIPG include global DNA hypomethylation. In addition to the generally repressive methylcytosine DNA alteration, 5-hydroxymethylation of cytosine (5hmC) is recognized as an epigenetic mark associated with active chromatin. We hypothesized that in addition to alterations in DNA methylation, that there would be changes in 5hmC. To test this hypothesis, we performed immunohistochemical studies to compare epigenetic alterations in DIPG to extrapontine adult and pediatric glioblastoma (GBM) and normal brain. A total of 124 tumors were scored for histone 3 lysine 27 trimethylation (H3K27me3) and histone 3 lysine 9 trimethylation (H3K9me3) and 104 for 5hmC and 5-methylcytosine (5mC). An H-score was derived by multiplying intensity (0-2) by percentage of positive tumor nuclei (0-100%).
    Acta neuropathologica communications. 06/2014; 2(1):59.
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    ABSTRACT: Purpose. To evaluate tumor structure in children with diffuse intrinsic pontine glioma (DIPG) using histogram analyses of mean diffusivity (MD), determine potential treatment and corticosteroid-related effects on MD, and monitor changes in MD distributions over time. Materials and Methods. DTI was performed on a 1.5T GE scanner. Regions of interest included the entire FLAIR-defined tumor. MD data were used to calculate histograms. Patterns in MD distributions were evaluated and fitted using a two-normal mixture model. Treatment-related effects were evaluated using the R (2) statistic for linear mixed models and Cox proportional hazards models. Results. 12 patients with DIPG underwent one or more DTI exams. MD histogram distributions varied among patients. Over time, histogram peaks became shorter and broader (P = 0.0443). Two-normal mixture fitting revealed large lower curve proportions that were not associated with treatment response or outcome. Corticosteroid use affected MD histograms and was strongly associated with larger, sharper peaks (R (2) = 0.51, P = 0.0028). Conclusions. MD histograms of pediatric DIPG show significant interpatient and intratumoral differences and quantifiable changes in tumor structure over time. Corticosteroids greatly affected MD and must be considered a confounding factor when interpreting MD results in the context of treatment response.
    BioMed Research International 01/2014; 2014:647356. · 2.71 Impact Factor
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    ABSTRACT: Research has suggested that autopsy in pediatrics is a valued way for parents to better understand and process their child's death, yet physicians often express hesitancy in discussing this topic with parents. To better assist clinicians with initiating discussion about this often sensitive topic, the current study examined bereaved parents' preferences about the timing and content of the autopsy discussion as well as reasons for considering autopsy. This study explored the views of 30 parents who lost a child to a variety of malignancies between 6 months and 6 years ago. Results showed that 36.7% of parents recalled having a discussion about autopsy, and the vast majority of those who did not recall a discussion (89.5%) would have considered an autopsy if it had been discussed. The majority of participants in this study indicated their preference to have the first conversation about autopsy when it becomes clear that cure is no longer possible. Findings suggest that educating parents about the clinical, emotional, and potential research benefits of autopsy and tissue procurement will ultimately help them make informed decisions and understand the importance of autopsy in medical progress. The future research and clinical implications of these findings are discussed.
    Journal of Pediatric Hematology/Oncology 12/2013; · 0.97 Impact Factor
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    ABSTRACT: Treatment of pediatric diffuse intrinsic pontine glioma (DIPG) remains challenging, and reliable biomarkers of response are lacking. Radiographic response is a primary endpoint in many investigational studies of brain tumors, but there is no standard method of tumor measurement for DIPG, significant inter-observer variability exists given the invasive nature of these tumors, and tumor measurements are not predictive of outcome. Because DIPGs involve a significant portion of the pons, we evaluated the reliability and prognostic value of one-dimensional (1D) and two-dimensional (2D) pons measurements using anatomical landmarks rather than tumor boundaries. Patients with DIPG (n = 75) were evaluated longitudinally at our institution using MRI. Four readers independently performed 1D and 2D measurements of the pons using FLAIR images. Agreement and inter-reader variability were evaluated using differences among the six reader pairs and the coefficient of variation (CV). Prognostic value of pons measurements was calculated using Cox proportional hazards models, where relative hazard (RH) represents risk of death. Readers evaluated 384 exams. Agreement of readers' 1D and 2D measurements was strong (median difference between reader pairs 3.1 and 5.4 %, respectively), with low inter-reader variability (median CV = 3.1 % and median CV = 4.8 %, respectively). Increases in 1D and 2D pons measurements over time indicated poorer prognosis (RH = 2.29, p = 0.0025 and RH = 1.13, p = 0.0016, respectively), with shorter overall survival. Pons measurements had low inter-reader variability compared to previously reported tumor measurement techniques and correlated with outcome in children with DIPG. Measurements of the pons (as opposed to direct measurements of tumor) are a viable in vivo biomarker for DIPG.
    Journal of Neuro-Oncology 10/2013; · 3.12 Impact Factor
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    ABSTRACT: The incidence and spectrum of acute toxicities related to the use of bevacizumab (BVZ)-containing regimens in children are largely unknown. This report describes the adverse events in a recently completed large phase 2 trial of BVZ plus irinotecan (CPT-11) in children with recurrent central nervous system tumors. Pediatric Brain Tumor Consortium trial-022 evaluated the efficacy and toxicity of BVZ (10 mg/kg administered intravenously) as a single agent for 2 doses given 2 weeks apart and then combined with CPT-11 every 2 weeks (1 course = 4 weeks) in children with recurrent central nervous system tumors. Children were treated until they experienced progressive disease, unacceptable toxicity or completed up to a maximum of 2 years of therapy. Toxicities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0. Patients who received at least 1 dose of BVZ were included for toxicity assessment. Between October 2006 and June 2010, 92 patients evaluable for toxicity were enrolled and received 687 treatment courses. The most common toxicities attributable to BVZ included grade I-III hypertension (38% of patients), grade I-III fatigue (30%), grade I-II epistaxis (24%), and grade I-IV proteinuria (22%). Twenty-two patients (24%) stopped therapy due to toxicity. The combination of BVZ and CPT-11 was fairly well-tolerated, and most severe BVZ-related toxicities were rare, self-limiting, and manageable. Cancer 2013;. © 2013 American Cancer Society.
    Cancer 09/2013; · 5.20 Impact Factor
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    ABSTRACT: Tumors of the central nervous system are the second most common malignancy in children. In particular, diffuse intrinsic pontine gliomas (DIPGs) are aggressive tumors with poor prognosis and account for 10% to 25% of pediatric brain tumors. The majority of DIPGs are astrocytic, infiltrative, and localized to the pons. Studies have shown median survival times of less than a year, with 90% of children dying within 2 years. We built multitissue arrays with 24 postmortem DIPG samples and analyzed the morphology and expression of several proteins (p53, EGFR, GFAP, MIB1, BMI1, β-catenin, p16, Nanog, Nestin, OCT4, OLIG2, SOX2) with the goal of identifying potential treatment targets and improving our understanding of the biology of these tumors. The majority of DIPGs were high-grade gliomas (22), with 18 cases having features of glioblastoma (World Health Organization [WHO] grade IV) and 4 cases with high-grade features consistent with anaplastic astrocytoma (WHO grade III). One case was low grade (WHO grade II), and 1 case showed intermediate features between a grade II and grade III glioma (low mitotic rate but increased cellularity and cell atypia), being difficult to grade precisely. The majority of the tumors were positive for GFAP (24/24), MIB1 (23/24), OLIG2 (22/24), p16 (20/24), p53 (20/24), SOX2 (19/24), EGFR (16/24), and BMI1 (9/24). Our results suggest that dysregulation of EGFR and p53 may play an important role in the development of DIPGs. The majority of DIPGs express stem cell markers such as SOX2 and OLIG2, consistent with a role for tumor stem cells in the origin and maintenance of these tumors. Targeted therapies against these proteins could be beneficial in treatment.
    The American journal of surgical pathology 09/2013; 37(9):1357-64. · 4.06 Impact Factor
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    ABSTRACT: Criteria for new drug approval include demonstration of efficacy. In neuro-oncology, this is determined radiographically utilizing tumor measurements on MRI scans. Limitations of this method have been identified where drug activity is not reflected in decreased tumor size. The RANO (Response Assessment in Neuro-Oncology) working group was established to address limitations in defining endpoints for clinical trials in adult neuro-oncology and to develop standardized response criteria. RAPNO was subsequently established to address unique issues in pediatric neuro-oncology. The aim of this paper is to delineate response criteria issues in pediatric clinical trials as a basis for subsequent recommendations. Pediatr Blood Cancer 2013;9999:XX-XX. © 2013 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 04/2013; · 2.35 Impact Factor
  • Jason Fangusaro, Katherine E Warren
    Journal of Neuro-Oncology 03/2013; · 3.12 Impact Factor
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    ABSTRACT: Pediatric diffuse intrinsic pontine gliomas are aggressive brainstem tumors that fail to respond to treatment. We hypothesize that the protective features of the pons may hinder chemotherapeutic agents from entering pontine tissue compared with cortical brain tissue. To test this hypothesis, we developed a unique nonhuman primate model using microdialysis, a continuous in vivo extracellular sampling technique, to compare drug exposure concurrently in pontine tissue, cortical tissue, CSF, and plasma after intravenous administration of chemotherapeutic agents. The surgical coordinates and approach for microdialysis cannula-probe placement were determined in 5 adult male rhesus monkeys (Macaca mulatta) by using MRI. Microdialysis cannulas-probes were implanted stereotactically in the brain, retrodialysis was performed to measure relative recovery, and a 1-h intravenous infusion of temozolomide was administered. Continuous microdialysis samples were collected from the pons and cortex over 4 h with concurrent serial plasma and CSF samples. Postsurgical verification of microdialysis cannula-probe placement was obtained via MRI in 3 macaques and by gross pathology in all 5 animals. The MRI-determined coordinates and surgical methodologies resulted in accurate microdialysis probe placement in the pons and cortex in 4 of the 5 macaques. Histologic examination from these 4 animals revealed negligible tissue damage to the pontine and cortical tissue from microdialysis. One macaque was maintained for 8 wk and had no deficits attributed to the procedure. This animal model allows for the determination of differences in CNS penetration of chemotherapeutic agents in the pons, cortex, and CSF after systemic drug administration.
    Comparative medicine 01/2013; 63(4):355-60. · 1.12 Impact Factor
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    ABSTRACT: Magnetic resonance spectroscopic imaging (MRSI) and (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) are non-invasive imaging techniques routinely used to evaluate tumor malignancy in adults with brain tumors. We compared the metabolic activity of pediatric brain tumors using FDG-PET and MRSI. Children (n = 37) diagnosed with a primary brain tumor underwent FDG-PET and MRSI within two weeks of each other. Tumor metabolism was classified as inactive, active or highly active using the maximum choline:N-acetyl-asparate (Cho:NAA) on MRSI and the highest tumor uptake on FDG-PET. A voxel-wise comparison was used to evaluate the area with the greatest abnormal metabolism. Agreement between methods was assessed using the percent agreement and the kappa statistic (κ). Pediatric brain tumors were metabolically heterogeneous on FDG-PET and MRSI studies. Active tumor metabolism was observed more frequently using MRSI compared to FDG-PET, and agreement in tumor classification was weak (κ = 0.16, p = 0.12), with 42 % agreement (95 % CI = 25-61 %). Voxel-wise comparison for identifying the area of greatest metabolic activity showed overlap in the majority (62 %) of studies, though exact agreement between techniques was low (29.4 %, 95 % CI = 15.1-47.5 %). These results indicate that FDG-PET and MRSI detect similar but not always identical regions of tumor activity, and there is little agreement in the degree of tumor metabolic activity between the two techniques.
    Journal of Neuro-Oncology 07/2012; 109(3):521-7. · 3.12 Impact Factor
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    ABSTRACT: BACKGROUND: The overall outcome for children with diffuse intrinsic pontine gliomas remains poor. We hypothesize that the lack of efficacy of any chemotherapy agents for this disease is related to differences in the blood-brain barrier (BBB) throughout the central nervous system, with certain areas crucial to basic functioning (such as the pons) having a more restrictive BBB. We developed a novel animal model in rhesus macaques (Macaca mulatta) using microdialysis (MD), a continuous sampling technique based on diffusion, to simultaneously measure drug penetration into the cerebral cortex, pons, and CSF. METHODS: Custom made MD probes (CMA, Solna, Sweden) were stereotactically placed into the frontal cortex and pons of 4 adult male rhesus macaques based on coordinates determined by pre-surgical MRI. After completion of in vivo retrodialysis, an intravenous infusion of temozolomide was administered. Single continuous MD samples from the pons and cortex were collected over 4 hours with concurrent serial plasma and CSF samples. Post-surgical MRI was obtained for 2 animals and post-mortem pathology was performed on all 4 animals to confirm probe placement. Temozolomide concentrations for all samples were quantified using HPLC/tandem mass spectroscopy. RESULTS: Microdialysis probe placement was tolerated in all four animals with confirmation of proper placement into the pons and cortex in 3 of 4 animals. Measurable drug quantities were present in both the pons and cerebral cortex for samples analyzed to date. CONCLUSIONS: We have developed a new animal model using MD to assess differences in drug penetration within the CNS. We were able to confirm in 3 of 4 animals proper placement of both MD probes using either MRI or gross pathology. Temozolomide drug concentrations can be quantified within the pons and cortex using microdialysis; further pharmacokinetic assessment, assay development and survival studies will be done to validate this animal model.
    15th International Symposium on Pediatric Neuro-Oncology; 06/2012
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    ABSTRACT: PURPOSE: Diagnosis and management of DIPG relies upon assessment of changes on magnetic resonance imaging (MRI). However, heterogeneous radiographic appearance and interobserver variability in tumor measurement complicate interpretation of tumor response and progression. This study evaluated the prognostic value of pontine measurements rather than tumor measurements in patients with DIPG. METHODS: Patients (< 21 years) with newly diagnosed, refractory or progressive DIPG underwent MRI evaluation according to their treatment protocol or as clinically indicated. Two experienced readers evaluated scans independently using axial pre- and post-contrast fluid attenuated inversion recovery (FLAIR) images and consistent anatomical landmarks to determine maximum diameter (1D) and maximal bidimensional measurements (2D) of the pons. Variability between readers was estimated using the coefficient of variation. The prognostic value of averaged 1D- and 2D-measurements from the two readers was evaluated using a univariate Cox proportional hazards model. RESULTS: Seventy-five patients (median=6 years, range=2 - 17 years)were evaluated; 63 died during the follow-up period. Median survival from the first scan was 38 weeks (range = 2 - 502+ weeks). Readers evaluated 386 scans. Variability between readers for 1D and 2D-measurements was 3.1% and 1.2%, respectively. 2D-measurements obtained at the first scan were predictive of survival (relative hazard, RH = 2.62, p=0.007). Increases over time in both 1D- and 2D-measurements predicted shorter overall survival (RH = 1.85, p = 0.0085 and RH = 3.29, p = 0.0047, respectively). CONCLUSIONS: Pontine measurements were obtained with low variability between readers compared to previous studies of tumor measurements. The size of the pons, rather than tumor measurement only, was predictive of outcome. As expected, patients with increases in either 1D or 2D pontine measurements over time had an increased risk of death. Incorporation of pontine measurements over the course of treatment is warranted to decrease interobserver variability in measurement and to further evaluate the prognostic value of this technique.
    15th International Symposium on Pediatric Neuro-Oncology; 06/2012
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    ABSTRACT: BACKGROUND: MRSI and DTI are noninvasive techniques used to investigate the characteristics of brain tumors. MRSI evaluates tissue metabolism, typically elevated in active tumors, while DTI reflects tissue microstructure with lower mean diffusivity (MD) observed in regions of higher cellularity, such as high-grade tumor. We explored the relationship between MRSI and DTI in children with DIPG. METHODS: Patients with DIPG underwent longitudinal MRI evaluations including MRSI and DTI. Pre-contrast axial fluid attenuated inversion recovery (FLAIR) images were used to co-register MD and MRSI maps. Regions of interest included the entire tumor identified on FLAIR. Voxels with the maximum choline:N-acetylaspartate (Cho:NAA) and minimum MD value were identified, presumably corresponding to areas of highest metabolic activity and highest cellularity, respectively. MRSI and DTI were considered co-localized if max Cho:NAA and minimum MD were from the same or adjacent voxels. The relationship between MRSI and DTI was evaluated using percent co-localization and repeated measures analysis of variance. RESULTS:Thirty patients (median = 5.4 yrs, range = 1.8-14.1 yrs) were evaluated, with a total of 64 scans. Max Cho:NAA ranged from 0.7 to 7.9 (median = 2.0). Minimum MD ranged from 0.8 to 1.4 x 102 6mm2/s (median = 1.0 x 102 6mm2/s). Co-localization between max Cho:NAA and minimum MD voxels was 53%. Correlation between Max Cho:NAA and minimum MD was not significant (p = 0.27). CONCLUSIONS: Maximum Cho:NAA and minimum MD values did not co-localize well. Tumor areas with greatest metabolic activity determined by MRSI typically did not correspond to regions of minimum MD determined by DTI. In addition, all minimum MD values were greater than that of normal tissue, indicating a broad influence of edema that may mask areas of increased cellularity. Max Cho:NAA and minimum MD do not seem to provide complementary information about DIPG. Further investigation is needed to understand the relationship of results from these modalities in patients with DIPG.
    15th International Symposium on Pediatric Neuro-Oncology; 06/2012
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    ABSTRACT: PURPOSE: Diagnosis and management of children with diffuse intrinsic pontine glioma (DIPG) is reliant upon MRI, as biopsy tissue rarely is obtained. Diffusion tensor imaging (DTI) provides noninvasive analysis of the tissue microstructure and has been shown to be useful in evaluating response to therapy in some cancers. Studies of DTI in DIPG have reported increased diffusivity compared to normal tissue and other brain tumors. The global diffusion metrics used in most studies provide a limited view of the tumor structure, whereas histogram analyzes may provide more specific information of diffusion properties throughout the lesion. This study evaluated pediatric DIPGs over the course of treatment using global metrics and histogram analysis of DTI parameters. MATERIALS & METHODS: Diffusion tensor imaging was acquired at 2.5 mm isotropic voxels with 60 diffusion directions and b-value = 1100 s/mm2 in 10 pediatric patients (range = 4 - 8 years, median = 5 years) enrolled in a clinical study of Pegylated Interferon Alfa-2b (PEG-Intron®) for treatment of DIPG following radiation therapy. Scans were performed prior to disease progression at multiple time points over the course of treatment, with a median of 18 weeks from the initial scan to progression (range = 5 - 59.9 wks). Mean diffusivity (MD) was evaluated in a region of interest (ROI) that encompassed the entire tumor, as identified by signal abnormality on T2 fluid attenuated inversion recovery (FLAIR) images. Tumor histograms were calculated from MD values. Histogram characteristics including the mean, median, and kurtosis were evaluated with time to progression. RESULTS As seen in Figure 1A, mean MD values at initial scan (range = 0.89 - 1.15x10-3 mm2/s) were higher than normal tissue (normal brain tissue = 0.7x10-3 mm2/s) and were found to significantly increase during treatment (p< 0.05). However, mean MD was not predictive of time to progression. The range of initial mean MD was quite broad, thus the histogram of ROI values was analyzed in an attempt to find common features. Shape of the MD histograms was heterogeneous (median kurtosis = 8, range 2.2 - 34.7) with no clear pattern of MD distribution (Figure 1B). CONCLUSION: While global measures of MD showed increased tumor diffusivity in all patients, the range of values was large. Mean diffusivity histograms revealed diverse diffusion characteristics in DIPG. These findings illustrate the vastly heterogeneous structure of these tumors, which can confound evaluation of treatment response.
    ASNR 50th Anniversary Annual Meeting; 04/2012
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    ABSTRACT: Background: We developed a nonhuman primate model using rhesus macaques (Macaca mulatta) to compare drug exposure in cortical brain, pontine tissue, and cerebrospinal fluid (CSF) during systemic administration of chemotherapeutic agents by microdialysis (MD), a continuous in vivo extracellular sampling technique. Pediatric diffuse intrinsic pontine gliomas are aggressive brainstem tumors that respond minimally to chemotherapy. We hypothesize that, because of its role in maintaining basic life-sustaining functions, the protective features of the pons, including the blood brain barrier and the blood-cerebrospinal fluid barrier, may further limit antitumor agents from entering the pons compared to cortical brain tissue. Methods: The coordinates and surgical approach for probe placement were determined using 3T MRI (Philips Healthcare, Best Netherlands) and OsiriX imaging software (v 3.9.4) in 4 adult male rhesus macaques (Macaca mulatta). Custom MD cannulas and probes (CMA, Solna, Sweden) were stereotactically implanted in the brain. The pontine MD cannula (34 mm) was implanted superior to the pons, and the MD probe (34 mm shaft plus 8 mm membrane) was then lowered through the cannula, into the pons. The cortical MD cannula (10 mm) was implanted in frontal cortex and a MD probe (10 mm shaft plus 8 mm membrane) was lowered through the cannula. The MD probe inlet/outlet capillaries were connected to a MD infusion pump (CMA 106, flow rate 0.3 µL/min). Retrodialysis was performed to assess in vivo recovery. A systemic intravenous (IV) drug infusion of temozolomide was then administered over 1hr. Single continuous MD samples were collected from both the pons and cortex over 4 hours with concurrent serial plasma and CSF samples (via a subarachnoid or lumbar catheter). Post-surgical MRI verification of MD probe placement was obtained in 2 of 4 animals. Verification of probe placement was obtained via gross pathology and histology in all 4 animals. Results: MRI-determined coordinates and surgical approach for MD probe placement and sample collection in the pons and cerebral cortex was successful in 3 of 4 animals. Surgical monitoring for heart and respiration rates, ETCO2 and SPO2 remained normal in all animals during probe placement and sample collection. Conclusions: MRI-determined coordinates and surgical methodologies resulted in accurate placement of a MD probe in the pons and cerebral cortex of a rhesus macaque allowing for MD sampling from these sites, in conjunction with CSF and plasma sampling, following systemic drug administration. This new animal model allows for the determination of differences in penetration of chemotherapeutic agents in pons, cerebrum, and CSF following systemic drug administration. Additionally, this model provides the foundation for a subcutaneous, semi-permanent, closed system for CNS MD probe placement and continuous sampling in rhesus macaques.
    2012 Annual Meeting of the American Association for Cancer Research; 03/2012
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    ABSTRACT: To determine the feasibility of two magnetic resonance spectroscopy (MRS) techniques for treating pediatric patients with diffuse intrinsic pontine gliomas (DIPGs) and to evaluate the relationship of metabolic profiles determined by each technique. Utility of each technique for improving patient management is also discussed. Children with DIPG (n = 36) were evaluated using single-voxel spectroscopy (SVS) and magnetic resonance spectroscopic imaging (MRSI) during the same imaging session. Patients were followed longitudinally (n = 150 total studies). Technical feasibility was defined by sufficient water and lipid suppression for detection of metabolites. Correlation of metabolic data obtained by SVS and MRSI was determined using the Spearman rank method. Metabolite ratios, including choline:N-acetyl-aspartate (Cho:NAA) and Cho:creatine (Cho:Cr), were obtained from SVS and MRSI. SVS and MRSI acquisitions were feasible in >90% of studies. Maximum Cho:NAA and Cho:Cr from MRSI analysis were strongly associated with Cho:NAA and Cho:Cr obtained by SVS (r = 0.67 and 0.76, respectively). MRSI Cho:NAA values were more heterogeneous than Cho:Cr values within the same lesion, and a strong linear relationship between the range and maximum Cho:NAA values was observed. SVS and MRSI acquisitions were feasible, with a strong correlation in metabolic data. Both techniques may improve diagnostic evaluation and management of DIPG. SVS is recommended for global assessment of tumor metabolism before and after therapy. MRSI showed heterogeneous patterns of metabolic activity within these tumors and is recommended for planning and monitoring targeted therapies and evaluating nearby tissue for tumor invasion.
    International journal of radiation oncology, biology, physics 03/2012; 84(3):774-9. · 4.59 Impact Factor
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    ABSTRACT: To estimate the sustained (≥8 weeks) objective response rate in pediatric patients with recurrent or progressive high-grade gliomas (HGG, Stratum A) or brainstem gliomas (BSG, Stratum B) treated with the combination of O6-benzylguanine (O6BG) and temozolomide(®) (TMZ). Patients received O6BG 120 mg/m(2)/d IV followed by TMZ 75 mg/m(2)/d orally daily for 5 consecutive days of each 28-day course. The target objective response rate to consider the combination active was 17%. A two-stage design was employed. Forty-three patients were enrolled; 41 were evaluable for response, including 25 patients with HGG and 16 patients with BSG. The combination of O6BG and TMZ was tolerable, and the primary toxicities were myelosuppression and gastrointestinal symptoms. One sustained (≥8 weeks) partial response was observed in the HGG cohort; no sustained objective responses were observed in the BSG cohort. Long-term (≥6 courses) stable disease (SD) was observed in 4 patients in Stratum A and 1 patient in Stratum B. Of the 5 patients with objective response or long-term SD, 3 underwent central review with 2 reclassified as low-grade gliomas. The combination of O6BG and TMZ did not achieve the target response rate for activity in pediatric patients with recurrent or progressive HGG and BSG.
    Journal of Neuro-Oncology 02/2012; 106(3):643-9. · 3.12 Impact Factor
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    ABSTRACT: To determine optimal timing of assessing postradiation radiographic response on magnetic resonance imaging (MRI) scans in pediatric patients with diffuse intrinsic pontine glioma (DIPG). Patients were treated on a prospective study at the National Cancer Institute (Protocol #06-C-0219) evaluating the effects of radiotherapy (RT). Standard RT was administered in standard fractionation over 6 weeks. Postradiation MRI scans were performed at 2 and 6-8 weeks. Eleven patients with DIPG were evaluated. Median age was 6 years (range, 4-13 years). Patients were treated with external-beam RT to 55.8 Gy (n = 10) or 54 Gy (n = 1), with a gross tumor volume to planning target volume expansion of 1.8-2.0 cm. All patients received prescribed dose and underwent posttreatment MRI scans at 2 and 6-8 weeks. Pretreatment imaging revealed compression of fourth ventricle (n = 11); basilar artery encasement (n = 9); tumor extension outside the pons (n = 11); and tumor hemorrhage (n = 2). At the 2-week scan, basilar artery encasement improved in 7 of 9 patients, and extent of tumor was reduced in 5 of 11 patients. Fourth ventricle compression improved in 6 of 11 patients but worsened in 3 of 11 patients. Presumed necrosis was observed in 5 of 11 patients at 2 weeks and in 1 additional patient at 6-8 weeks. There was no significant difference in mean anteroposterior and transverse diameters of tumor between the 2- and 6-8-week time points. Six of 11 patients had increasing ventricular size, with no evidence of obstruction. There is no significant difference in tumor size of DIPG patients who have received standard RT when measured at 2 weeks vs. 6-8 weeks after RT. The majority of patients had the largest change in tumor size at the 2-week post-RT scan, with evolving changes documented on the 6-8-week scan. Six of 11 patients had progressive ventriculomegaly without obstruction, suggestive of communicating hydrocephalus. To the best of our knowledge, this is the first documentation of this phenomenon in this cohort of patients.
    International journal of radiation oncology, biology, physics 01/2012; 83(4):1252-6. · 4.59 Impact Factor
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    Katherine E Warren
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    ABSTRACT: Diffuse intrinsic pontine gliomas (DIPGs) are amongst the most challenging tumors to treat. Surgery is not an option, the effects of radiation therapy are temporary, and no chemotherapeutic agent has demonstrated significant efficacy. Numerous clinical trials of new agents and novel therapeutic approaches have been performed over the course of several decades in efforts to improve the outcome of children with DIPG, yet without success. The diagnosis of DIPG is based on radiographic findings in the setting of a typical clinical presentation, and tissue is not routinely obtained as the standard of care. The paradigm for treating children with these tumors has been based on that for supratentorial high-grade gliomas in adults as the biology of these lesions were presumed to be similar. However, recent pivotal studies demonstrate that DIPGs appear to be their own entity. Simply identifying this fact releases a number of constraints and opens opportunities for biologic investigation of these lesions, setting the stage to move forward in identifying DIPG-specific treatments. This review will summarize the current state of knowledge of DIPG, discuss obstacles to therapy, and summarize results of recent biologic studies.
    Frontiers in Oncology 01/2012; 2:205.

Publication Stats

430 Citations
208.19 Total Impact Points

Institutions

  • 2001–2014
    • National Institutes of Health
      • • Branch of Pediatric Oncology
      • • Branch of Radiation Oncology
      • • Branch of Neuro-Oncology
      Maryland, United States
  • 2013
    • Ann & Robert H. Lurie Children's Hospital of Chicago
      Chicago, Illinois, United States
  • 2000–2013
    • National Cancer Institute (USA)
      • • Pediatric Oncology Branch
      • • Neuro-Oncology Branch
      Maryland, United States
  • 2008–2012
    • National Cancer Institute
      Μπογκοτά, Bogota D.C., Colombia