ABSTRACT
Rapid, serial, and humane collection of cerebrospinal fluid (CSF) in nonhuman primates (NHP) is an essential element of numerous research studies and is currently accomplished via two different models. The CSF reservoir model (FR) combines a catheter in the 4th ventricle with a flexible silastic reservoir to permit circulating CSF flow. The CSF lateral port model (LP) consists of a lateral ventricular catheter and an IV port that provides static access to CSF and volume restrictions on sample collection. The FR model is associated with an intensive, prolonged recovery and frequent postsurgical hydrocephalus and nonpatency, whereas the LP model is associated with an easier recovery. To maximize the advantages of both systems, we developed the CSF lateral reservoir model (LR), which combines the beneficial features of the 2 previous models but avoids their limitations by using a reservoir for circulating CSF flow combined with catheter placement in the lateral ventricle. Nine adult male rhesus monkeys were utilized in this study. Pre-surgical MRI was performed to determine the coordinates of the lateral ventricle and location of choroid plexus (CP). The coordinates were determined to avoid the CP and major blood vessels. The predetermined coordinates were 100% accurate, according to MRI validation. The LR system functioned successfully in 67% of cases for 221 d, and 44% remain functional at 426 to 510 d postoperatively. Compared with established models, our LR model markedly reduced postoperative complications and recovery time. Development of the LR model was successful in rhesus macaques and is a useful alternative to the FR and LP methods of CSF collection from nonhuman primates.
Subject(s)
Catheterization/methods , Cerebrospinal Fluid/chemistry , Macaca mulatta , Models, Animal , Specimen Handling/methods , Animals , Lateral Ventricles/surgery , Magnetic Resonance Imaging , MaleABSTRACT
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.
Subject(s)
Brain Stem Neoplasms/diagnosis , Diffusion Tensor Imaging/methods , Glioma/diagnosis , Adrenal Cortex Hormones/therapeutic use , Brain Stem Neoplasms/drug therapy , Brain Stem Neoplasms/pathology , Child , Child, Preschool , Female , Glioma/drug therapy , Glioma/pathology , Humans , Male , Time FactorsABSTRACT
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.
Subject(s)
Brain Stem Neoplasms/diagnosis , Glioma/diagnosis , Pons/pathology , Adolescent , Brain Stem Neoplasms/mortality , Child , Child, Preschool , Female , Glioma/mortality , Humans , Image Processing, Computer-Assisted , Kaplan-Meier Estimate , Magnetic Resonance Imaging , Male , Predictive Value of Tests , Proportional Hazards Models , Retrospective StudiesABSTRACT
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.
Subject(s)
Brain Stem/metabolism , Cerebral Cortex/metabolism , Dacarbazine/analogs & derivatives , Macaca mulatta , Microdialysis/methods , Models, Animal , Animals , Dacarbazine/pharmacokinetics , Magnetic Resonance Imaging , Male , TemozolomideABSTRACT
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.
Subject(s)
Brain Neoplasms/diagnostic imaging , Brain Neoplasms/metabolism , Molecular Imaging/methods , Adolescent , Child , Child, Preschool , Female , Fluorodeoxyglucose F18 , Humans , Image Interpretation, Computer-Assisted , Magnetic Resonance Imaging , Male , Positron-Emission Tomography , Radiopharmaceuticals , Young AdultABSTRACT
PURPOSE: 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. METHODS AND MATERIALS: 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. RESULTS: 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. CONCLUSIONS: 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.
Subject(s)
Brain Stem Neoplasms/metabolism , Glioma/metabolism , Magnetic Resonance Spectroscopy/methods , Adolescent , Aspartic Acid/analogs & derivatives , Aspartic Acid/metabolism , Brain Stem Neoplasms/diagnosis , Child , Child, Preschool , Choline/metabolism , Creatine/metabolism , Feasibility Studies , Glioma/diagnosis , Humans , Infant , Longitudinal Studies , Prospective Studies , Statistics, NonparametricABSTRACT
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.
Subject(s)
Brain Stem Neoplasms/pathology , Brain Stem Neoplasms/radiotherapy , Magnetic Resonance Imaging , Pons/pathology , Adolescent , Basilar Artery/pathology , Brain Stem Neoplasms/complications , Cerebral Hemorrhage/diagnosis , Child , Child, Preschool , Constriction, Pathologic/pathology , Constriction, Pathologic/radiotherapy , Dose Fractionation, Radiation , Female , Fourth Ventricle/pathology , Humans , Hydrocephalus/pathology , Male , Organs at Risk , Prospective Studies , Time Factors , Tumor Burden/radiation effectsABSTRACT
Noninvasive evaluation using MRI is the primary means to routinely assess children with diffuse intrinsic pontine gliomas (DIPGs). However, no standard MR sequence has correlated with outcome in these patients. In this study, patients with DIPGs were assessed to determine the combined prognostic value via dynamic susceptibility contrast (DSC) MRI, single-voxel spectroscopy (SVS), multivoxel MR spectroscopy (MRS), and T1-weighted post-gadolinium imaging. Eligible patients had clinical and radiographic findings consistent with a DIPG. Imaging studies were acquired on a 1.5T MRI at various time points during each patient's course. Data were evaluated using a Cox proportional hazard model, a time-dependent covariant Cox model, a Wald test, and a Kaplan-Meier analysis. Ninety-eight studies were performed on 34 patients of median age 5.5 years. Median survival from diagnosis was 468 days. At baseline imaging only, increased ratio of choline to n-acetylaspartate (Cho:NAA) on SVS and increased perfusion on DSC-MRI each predicted shorter survival (relative risk [RR] = 1.48, P = .015 and RR = 4.91, P = .0012, respectively). When analyzing all subsequent time points, increased maximum Cho:NAA on MRS (RR = 1.45, P = .042), increased Cho:NAA on SVS (RR = 1.69, P = .003), increased perfusion (RR = 4.68, P = .0016), and the presence of enhancement (RR = 5.69, P = .022) each predicted shorter survival. Kaplan-Meier analysis showed shorter survival associated with increased perfusion at baseline (P = .0004). Increased perfusion at any time point predicts a significantly shorter survival in children with DIPG. In addition, enhancement, increased Cho:NAA on SVS, and increased maximum Cho:NAA on chemical shift imaging are predictive of shorter survival over time. Routine baseline and subsequent imaging for children with DIPG should, at minimum, incorporate DSC-MRI and SVS.
Subject(s)
Aspartic Acid/analogs & derivatives , Brain Neoplasms/diagnosis , Brain Stem Neoplasms/diagnosis , Choline/metabolism , Magnetic Resonance Imaging , Magnetic Resonance Spectroscopy , Pons , Adolescent , Adult , Aspartic Acid/metabolism , Brain Neoplasms/metabolism , Brain Neoplasms/radiotherapy , Brain Stem Neoplasms/metabolism , Brain Stem Neoplasms/radiotherapy , Child , Child, Preschool , Female , Humans , Longitudinal Studies , Male , Prospective Studies , Survival Rate , Treatment Outcome , Young AdultABSTRACT
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.
Subject(s)
Brain Stem Neoplasms/diagnosis , Brain Stem Neoplasms/mortality , Magnetic Resonance Spectroscopy , Pons , Protons , Adolescent , Biomarkers, Tumor/metabolism , Brain Stem Neoplasms/metabolism , Child , Child, Preschool , Disease Progression , Female , Follow-Up Studies , Humans , Infant , Magnetic Resonance Imaging , Male , Neoplasm Recurrence, Local/diagnosis , Neoplasm Recurrence, Local/metabolism , Neoplasm Recurrence, Local/mortality , Prognosis , Prospective Studies , Survival RateABSTRACT
OBJECTIVE: The study objective was to detect abnormalities and identify relationships between brain metabolic ratios determined by proton magnetic resonance spectroscopic imaging ((1)H-MRSI) and neuropsychological (NP) function in cancer patients at risk for neurotoxicity. METHODS: Thirty-two patients received (1)H-MRSI using a multi-slice, multi-voxel technique on a 1.5T magnet. Cho/NAA, NAA/Cr, and Cho/Cr ratios were identified in seven pre-determined sites without tumor involvement. A battery of age-appropriate NP tests was administered within 7 days of imaging. Relationships were examined between test scores and metabolite ratios. CONCLUSIONS: This study identifies relationships between brain metabolite ratios and cognitive functioning in cancer patients. (1)H-MRSI may be useful in early detection of neurotoxic effects, but prospective longitudinal studies in a homogeneous population are recommended to determine the prognostic value.
Subject(s)
Magnetic Resonance Imaging , Neoplasms/metabolism , Neurotoxicity Syndromes/etiology , Neurotoxicity Syndromes/metabolism , Adolescent , Adult , Aspartic Acid/analogs & derivatives , Aspartic Acid/metabolism , Child , Child, Preschool , Choline/metabolism , Creatine/metabolism , Female , Humans , Male , Neoplasms/drug therapy , Neuropsychological Tests , Neurotoxicity Syndromes/complications , ProtonsABSTRACT
Allogeneic bone marrow (BM) and cytokine mobilized peripheral blood stem cell (PBSC) transplantation can be curative for patients with malignant and nonmalignant hematologic diseases. Siblings are most often selected as a donor match; however, research on sibling donors is limited and has focused primarily on conventional BM donors. This exploratory study describes the experiences of PBSC sibling donors at a single institution. Through retrospective interviews, 14 sibling donors shared their perceived needs and concerns before and after their stem cell collection. Donors identified fears about the donation procedure, and expressed the need for more information about transplant outcome and complications. The inclusion of the sibling donors themselves, rather than the report of their parents or health-care providers and the qualitative nature of the structured design allowed sibling donors to describe their concerns and thoughts without being restrained by the beliefs of the participant's parents, researcher or sibling's medical team. Suggestions for visual educational tools, psychosocial interventions and future research are provided.
Subject(s)
Anxiety/epidemiology , Anxiety/psychology , Bone Marrow Transplantation/psychology , Hematopoietic Stem Cell Transplantation/psychology , Living Donors/psychology , Siblings/psychology , Social Adjustment , Adolescent , Anxiety/diagnosis , Attitude to Health , Child , Female , Humans , Male , National Cancer Institute (U.S.)/statistics & numerical data , Psychology , Sibling Relations , Surveys and Questionnaires , Tissue Donors/psychology , Treatment Outcome , United StatesABSTRACT
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.