Emilie A. Steffen-Smith

Hematopoietic stem cell donation in children: a review of the sibling donor experience.

Abstract Hematopoietic Stem Cell Transplant (HSCT) represents the second most frequent major organ transplant in the United States. Compared with other family members, siblings are more likely to be immunologically matched with the recipient and therefore are often the most suitable donors. Due to a dearth of information on the positive and adverse effects of HSCT on pediatric sibling donors, we sought to examine available data. Eight published reports assessing the pediatric sibling donor experience were identified in the literature. Studies were predominately small (n < 44) and cross-sectional. Results suggest a range of psychological distress responses with higher distress in pediatric donor than non-donor siblings. Recommendations include future longitudinal research on sibling donor psychosocial adjustment, identification of sibling donors at high risk for maladaptive responses, and development of educational and psychosocial interventions for this overlooked pediatric population.

Proton magnetic resonance spectroscopy predicts survival in children with diffuse intrinsic pontine glioma

Patients with diffuse intrinsic pontine glioma (DIPG) face a grim prognosis with limited treatment options. Many patients will enroll on investigational trials though the role of chemotherapy or immunotherapy is unclear. Radiographic changes on conventional MRI are used to evaluate tumor response and progression, but are not predictive of outcome in these patients. More sensitive measures of tumor biology are needed to improve patient management. We evaluated changes in magnetic resonance spectroscopy (MRS) biomarkers in patients with DIPG. Thirty-eight patients were enrolled prospectively on an IRB-approved protocol, which included standard MRI, single voxel spectroscopy (SVS) and multi-slice multi-voxel spectroscopy (MRSI). Scans were performed at multiple time points during each patient’s clinical course, with a total of 142 scans. The prognostic values of Choline:N-acetylaspartate (Cho:NAA), Cho:Creatine (Cho:Cr) and the presence of lactate and lipids (+Lac/Lip) were evaluated. Cho:NAA and variance in Cho:NAA values among different voxels within a tumor were each predictive of shorter survival. This prospective study shows that MRS can be used to identify high-risk patients and monitor changes in tumor metabolism, which may reflect changes in tumor behavior.

Diffusion tensor histogram analysis of pediatric diffuse intrinsic pontine glioma.

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.

Role of early postradiation magnetic resonance imaging scans in children with diffuse intrinsic pontine glioma.

PURPOSE To determine optimal timing of assessing postradiation radiographic response on magnetic resonance imaging (MRI) scans in pediatric patients with diffuse intrinsic pontine glioma (DIPG). METHODS AND MATERIALS 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. RESULTS 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. CONCLUSIONS 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.

Abstract 3789: Development of an animal model for microdialysis sampling of pons and cerebral cortex in rhesus macaques

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. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3789. doi:1538-7445.AM2012-3789