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author:("sulkin, Barry")
1.  The Role of PET/CT in Assessing Pulmonary Nodules in Children With Solid Malignancies 
AJR. American journal of roentgenology  2013;201(6):W900-W905.
The purpose of this article is to assess the feasibility and utility of PET/ CT in distinguishing benign from malignant pulmonary nodules in patients with solid childhood malignancies.
This prospective study was conducted between March 2008 and August 2010. We enrolled 25 subjects 21 years old or younger with solid childhood malignancies and at least one pulmonary nodule measuring 0.5–3.0 cm. PET/CT was performed within 3 weeks of diagnostic chest CT. Three panels of three reviewers each reviewed diagnostic CT only (panel 1), PET/CT only (panel 2), or diagnostic CT and PET/CT concurrently (panel 3) and predicted each nodule’s histologic diagnosis as benign, malignant, or indeterminate. Interreviewer agreement was assessed with the kappa statistic. Using nodule biopsy or clinical follow-up as reference standards, the sensitivity, specificity, and accuracy for each panel was assessed. Logistic regression was used to assess the nodule’s maximum standardized uptake value (SUVmax) association with its histologic diagnosis.
There were 75 nodules with a median size of 0.74 cm (range, 0.18–2.38 cm); 48 nodules were malignant. Sensitivity was 85% (41/48) for panel 1, 60% (29/48) for panel 2, and 67% (32/48) for panel 3. All panels had poor specificities. Interreviewer agreement was moderate for panel 1 (0.43) and poor for panels 2 (0.22) and 3 (0.33). SUVmax was a significant predictor of histologic diagnosis (p = 0.004).
PET/CT assessment of pulmonary nodules is feasible in children with solid malignancies but may not reliably improve our ability to predict a nodule’s histologic diagnosis. The SUVmax may improve the performance of PET/CT in this setting.
PMCID: PMC4276039  PMID: 24261397
children; CT; PET; pulmonary nodules; solid malignancies
2.  Comparison of PET-CT and Conventional Imaging in Staging Pediatric Rhabdomyosarcoma 
Pediatric blood & cancer  2012;60(7):1128-1134.
To compare PET-CT to conventional imaging (CI) in staging pediatric rhabdomyosarcoma (RMS).
Subjects and Methods
Thirty subjects with RMS, median age 7.3 years, underwent PET-CT before therapy. PET-CTs and CI were independently reviewed by two radiologists and two nuclear medicine physician to determine the presence of nodal, pulmonary, bone, bone marrow and other sites of metastasis. Accuracy, sensitivity and specificity of PET-CT for detecting metastases was compared to CI using biopsy and clinical follow-up as reference standards. Maximum standardized uptake values (SUVmax) of primary tumors, lymph nodes and pulmonary nodules were measured.
Primary tumors had an average SUVmax of 7.2 (range, 2.5-19.2). Accuracy rates for 17 subjects with nodal disease were 95% for PET-CT and 49% for CI. PET-CT had 94% sensitivity and 100% specificity for nodal disease. Of 7 pulmonary nodules detected by CI, 3 were not identified by PET-CT, 2 were indeterminate by PET-CT, and 1 was malignant with a SUVmax (3.4) > twice that of benign nodules. Two subjects had bone disease; both were identified by PET-CT but only 1 by CI. Four subjects had bone marrow disease, 2 had positive PET-CTs but none had positive CI. Two subjects had soft tissue metastases detected by PET-CT but not CI.
PET-CT performed better than CI in identifying nodal, bone, bone marrow, and soft tissue disease in children with RMS. CI remains essential for detection of pulmonary nodules. We recommend PET-CT for routine staging of children with RMS. CI with Tc99m bone scan can be eliminated.
PMCID: PMC4266929  PMID: 23255260
3.  Evaluation of the Biodistribution of [11C]Methionine in Children and Young Adults 
The purpose of this study was to evaluate the biodistribution of carbon-11–labeled methionine in non–tumor-involved organs in pediatric patients studied for malignant diseases.
Ninety-three children and young adults with known or suspected malignancies underwent [11C]methionine positron emission tomography (PET) and computed tomography (CT) scans. Imaging began 5–15 min after injection of 740 MBq (20 mCi) per 1.7 m2 of body surface area. Images were acquired from the top of the head through the mid-thighs. Standardized uptake values were determined using regions of interest drawn on the CT and transferred to the corresponding transverse PET slice.
The highest concentrations of [11C]methionine were found in the pancreas and liver. Less intense uptake was seen in other regions, such as salivary glands, tonsils, and bone marrow. There was very little uptake in lungs, fat (including brown adipose tissue), and muscle. Uptake in bone marrow, parotid glands, and tonsils was slightly but statistically significantly higher in males than females. Testicular, bone marrow, and left ventricular uptake increased with age. There was little variability statistically between comparisons of uptake change and groupings of age, race, sex, and patients studied at the time of diagnosis versus previously treated patients.
High uptake of [11C]methionine is reliably found in the pancreas and liver, consistent with the anabolic functions of these organs. Low uptake in the brain, neck, chest, pelvis, and extremities will facilitate tumor localization in those areas. However, intense uptake in the upper abdomen may limit the diagnostic utility of [11C]methionine in that area.
PMCID: PMC3924715  PMID: 24050936
PET/CT; carbon-11; methionine; pediatric; tumor
4.  Evaluation of children with craniopharyngioma using carbon-11 methionine PET prior to proton therapy 
Neuro-Oncology  2013;15(4):506-510.
Fluorine-18 (18F) fluorodeoxyglucose (FDG) positron emission tomography (PET) is limited in its evaluation of brain tumors due to the high basal activity of the cerebral cortex and white matter. Carbon-11 methionine (11C MET) has little uptake under normal conditions. We prospectively investigated the uptake of 18F FDG and 11C MET PET in patients with craniopharyngioma prior to proton therapy.
Ten patients newly diagnosed with craniopharyngioma underwent PET imaging using 18F FDG and 11C MET. PET and MRI studies were registered to help identify tumor volume. Measurements of maximum standardized uptake value (SUVmax) were taken of the tumor and compared with noninvolved left frontal background white matter using a paired t-test. Uptake was graded using a 4-point scale.
Median patient age was 9 years (range 5–19). Seven patients were diagnosed by pathology, 1 by cyst fluid aspiration, and 2 by neuroimaging. Median FDG SUVmax for tumor and background were 2.65 and 3.2, respectively. Median MET SUVmax for tumor and background were 2.2 and 1, respectively. There was a significant difference between MET tumor SUVmax and MET background SUVmax (P = .0001). The difference between FDG tumor SUVmax and FDG background SUVmax was not significant (P = .3672).
11C MET PET uptake is significantly greater within the tumor compared with noninvolved background white matter, making it more useful than FDG PET in identifying active tumor in patients with craniopharyngioma. Future work will focus on using 11C MET PET to discriminate between active and inactive tumor after irradiation.
PMCID: PMC3607263  PMID: 23408862
craniopharyngioma; fluorodeoxyglucose; FDG; methionine; positron emission tomography; proton therapy
5.  Positron emission tomography-computed tomography for staging and follow-up of pediatric nasopharyngeal carcinoma 
While evaluations of FDG PET-CT in adult patients with NPC have documented advantages and disadvantages of the technique compared with conventional imaging, to our knowledge, no such studies have been performed with pediatric patients. In this investigation, we studied the utility of FDG PET-CT in children with NPC.
Eighteen children with biopsy-proven NPC who underwent FDG PET-CT and MRI were studied (total 38 pairs of imagings). All baseline and follow-up FDG PET-CT and MRI studies were independently reviewed for restaging of disease.
The concordance between FDG PET-CT and MRI in T, N, and overall staging was 29%, 64%, and 43%, respectively. Compared with MRI, FDG PET-CT yielded lower T and overall staging and showed less cervical and retropharyngeal lymphadenopathy. The concordance between follow-up FDG PET-CT and MRI was 79% overall and 100% 9 months after therapy. In patients who achieved complete remission, FDG PET-CT showed disease clearance 3-6 months earlier than MRI. There were no false positive or false negative FDG PET-CT scans during follow-up.
FDG PET-CT may underestimate tumor extent and regional lymphadenopathy compared with MRI at the time of diagnosis, but it helps to detect metastasis and clarify ambiguous findings. FDG PET-CT is sensitive and specific for follow-up and enables earlier determination of disease remission. FDG PET-CT is a valuable imaging modality for the evaluation of and monitoring NPC in pediatric patients.
PMCID: PMC3531235  PMID: 22532252
positron emission tomography; magnetic resonance imaging; nasopharyngeal carcinoma; child
6.  PET-CT of the Normal Spinal Cord in Children 
Academic radiology  2009;16(7):881-885.
Rationale and Objectives
To assess the correlation between age and spinal cord metabolic activity in children using positron emission tomography-computed tomography.
Materials and Methods
The cohort included 128 children imaged from January 2003 through April 2007, excluding those with spinal disease. Using axial images we subjectively graded as minimal, moderate or intense, the fluorodeoxyglucose activity in the pons and three cervical, three thoracic, and two lumbar spinal cord levels. From regions of interest at each level, we determined the maximum standardized uptake value. Patients were grouped by age: Group 1, < 5 years; Group 2, ≥ 5 to < 10 years; Group 3, ≥10 to <15 years; and Group 4, ≥15 < 22 years. We compared subjective grade and standardized uptake values at each level and for each level between age groups. Alpha was set at 0.0046 based on the Bonferroni correction for multiple comparisons.
There were 16 patients in Group 1, 19 in Group 2, 33 in Group 3, and 60 in Group 4. Subjective grade and standardized uptake values were higher in the pons, mid cervical and low thoracic areas than elsewhere in all age groups. Subjective grade significantly increased with age in the cervical and thoracic cord (P <0.0005). Standardized uptake values in the pons and all cord levels significantly increased with increasing age (P≤0.0008).
In children, metabolic activity of the spinal cord increases with age. On positron emission tomography, the cord can appear intensely avid in the mid cervical and low thoracic areas.
PMCID: PMC3680129  PMID: 19427802
positron emission tomography-computed tomography; spinal cord; children
7.  Role of lymphoscintigraphy and sentinel lymph node biopsy in the management of pediatric melanoma and sarcoma 
Pediatric surgery international  2012;28(6):571-578.
The purpose of this study was to describe the use of lymphoscintigraphy and sentinel lymph node biopsy for the management of children with melanoma and sarcomas. We report the experience of two children’s hospitals that utilize this technique to identify sentinel lymph nodes for lymph node biopsy and dissection.
We identified 56 patients (median age 10.8 years) who underwent 58 lymphoscintigraphy procedures. There were 33 patients with melanoma and melanocytic lesions, and 23 with sarcomas.
Of 58 lymphoscintigraphy procedures, sentinel lymph nodes were identified in 52 (90% success rate). Using the combination of intraoperative blue dye injection and lymphoscintigraphy, the success rate was 95% (55/58). Metastatic disease was found in 14 sentinel lymph nodes (13 patients with melanoma and melanocytic lesions, and 1 patient with rhabdomyosarcoma).
We have found that lymphoscintigraphy with sentinel lymph node biopsy is an effective method to identify patients who may benefit from more extensive lymph node dissection and to identify those patients who are unlikely to benefit from further lymph node exploration.
PMCID: PMC3608674  PMID: 22526545
lymphoscintigraphy; sentinel node; melanoma; sarcoma; pediatric
8.  Evaluation of 18F-FDG PET and MRI Associations in Pediatric Diffuse Intrinsic Brain stem Glioma: A Report from the Pediatric Brain Tumor Consortium 
To assess 18F-labeled 2-fluoro-2-deoxy-D-glucose (18F-FDG) uptake in children with a newly diagnosed diffuse intrinsic brainstem glioma (BSG) and to investigate associations with progression-free survival (PFS), overall survival (OS) and MRI indices.
Two Pediatric Brain Tumor Consortium (PBTC) therapeutic trials in children with newly diagnosed BSG were designed to test radiation therapy combined with molecularly targeted agents (PBTC-007: Phase I/II study of gefitinib; PBTC-014: Phase I/II study of tipifarnib). Baseline brain 18F-FDG PET scans were obtained in 40 children in these trials. Images were evaluated by consensus of two PET experts for intensity and uniformity of tracer uptake. Associations of 18F-FDG uptake intensity and uniformity with both PFS and OS were evaluated as well as associations with tumor MRI indices at baseline (tumor volume on FLAIR, baseline intratumoral enhancement, diffusion and perfusion values.
In the majority of children, BSG 18F-FDG uptake was less than gray matter uptake. Survival was poor irrespective of intensity of 18F-FDG uptake, with no association between intensity of 18F-FDG uptake and PFS or OS. However, hyperintense 18F-FDG uptake in tumor compared to gray matter suggested poorer survival rates. Patients with 18F-FDG uptake in ≥ 50% of the tumor had shorter PFS and OS compared to patients with 18F-FDG uptake in < 50% of tumor. There was some evidence that tumors with higher 18F-FDG uptake were more likely to show enhancement; and when the diffusion ratio was lower the uniformity of 18F- FDG uptake appeared higher.
Children with BSG where 18F-FDG uptake involves at least half the tumor appear to have inferior survival compared to children with uptake in <50% of tumor. A larger independent study is needed to verify this hypothesis. Intense tracer uptake in the tumors compared to gray matter suggests decreased survival. Higher 18F-FDG uptake within the tumor was associated with enhancement on MRI. Increased tumor cellularity as reflected by restricted MR diffusion may be associated with increased 18F-FDG uniformity throughout the tumor.
PMCID: PMC3526809  PMID: 21233173
pediatric; brainstem glioma; 18F-FDG PET; MRI; diffusion; enhancement; perfusion; brain tumor
9.  Phase II study of oral capsular 4-hydroxyphenylretinamide (4-HPR/fenretinide) in pediatric patients with refractory or recurrent neuroblastoma: A report from the Children’s Oncology Group NSC #374551; IND# 40294 
To determine the response rate to oral capsular fenretinide in children with recurrent or biopsy proven refractory high-risk neuroblastoma.
Experimental Design
Patients received 7 days of fenretinide: 2475 mg/m2/day divided TID (<18 years) or 1800 mg/m2/day divided BID (≥18 years) every 21 days for a maximum of 30 courses. Patients with stable or responding disease after course 30 could request additional compassionate courses. Best response by course 8 was evaluated in Stratum 1 (measurable disease on CT/MRI +/− bone marrow and/or MIBG avid sites) and Stratum 2 (bone marrow and/or MIBG avid sites only).
Sixty-two eligible patients, median age 5 years (range 0.6–19.9), were treated in Stratum 1 (n=38) and Stratum 2 (n=24). One partial response (PR) was seen in Stratum 2 (n=24 evaluable). No responses were seen in Stratum 1 (n=35 evaluable). Prolonged stable disease (SD) was seen in 7 patients in Stratum 1 and 6 patients in Stratum 2 for 4–45+ (median 15) courses. Median time to progression was 40 days (range 17–506) for Stratum 1 and 48 days (range 17–892) for Stratum 2. Mean 4-HPR steady state trough plasma concentrations were 7.25 µM (coefficient of variation 40–56%) at day 7 course 1. Toxicities were mild and reversible.
Although neither stratum met protocol criteria for efficacy, 1 PR + 13 prolonged SD occurred in 14/59 (24%) of evaluable patients. Low bioavailability may have limited fenretinide activity. Novel fenretinide formulations with improved bioavailability are currently in pediatric Phase I studies.
PMCID: PMC3207022  PMID: 21908574
fenretinide; neuroblastoma; Phase II; ANBL0321
10.  Retrospective Evaluation of PET-MRI Registration Algorithms 
Journal of Digital Imaging  2010;24(3):485-493.
The purpose of this study is to evaluate the accuracy of registration positron emission tomography (PET) head images to the MRI-based brain atlas. The [18F]fluoro-2-deoxyglucose PET images were normalized to the MRI-based brain atlas using nine registration algorithms including objective functions of ratio image uniformity (RIU), normalized mutual information (NMI), and normalized cross correlation (CC) and transformation models of rigid-body, linear, affine, and nonlinear transformations. The accuracy of normalization was evaluated by visual inspection and quantified by the gray matter (GM) concordance between normalized PET images and the brain atlas. The linear and affine registration based on the RIU provided the best GM concordance (average similarity index of 0.71 for both). We also observed that the GM concordances of linear and affine registration were higher than those of the rigid and nonlinear registration among the methods evaluated.
PMCID: PMC3092046  PMID: 20437075
Normalization; PET; MR; brain; tissue concordance
11.  FDG PET Imaging of Childhood Sarcomas 
Pediatric blood & cancer  2010;54(2):222-227.
Positron-emission tomography (PET) imaging using [18F]fluorodeoxyglucose (FDG) is useful for detection, staging, and monitoring a variety of malignancies, including lymphoma, in adults, but its utility in sarcomas, especially soft tissue sarcomas (STS), in children and young adults is not clear.
To evaluate the potential utility of FDG PET in the care of STS in children and young adults, we analyzed 46 PET scans in 25 patients acquired over 12 years. Scans were interpreted by two imaging physicians blinded to findings from other imaging studies and clinical information. Results were compared with computed tomography and magnetic resonance imaging, biopsy results, where available, and clinical follow-up of at least 12 months.
For a total of 46 scans in 25 patients, there were 25 true positive scans, 3 false positive scans, 12 true negative scans, and 6 false negative scans. The sensitivity of the PET scan was 86%, specificity was 80%, positive predictive value was 89%, and negative predictive value was 67%.
FDG PET may be a useful imaging modality in the management of children and young adults with STS, although prospective studies are needed to establish its true utility.
PMCID: PMC2794959  PMID: 19890901
fluorodeoxyglucose; FDG; PET; Ewing; rhabdomyosarcoma; pediatric

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