S. Ted Treves

Cardiovascular Status in Long-Term Survivors of Hodgkin's Disease Treated With Chest Radiotherapy

PURPOSE Cardiovascular status was assessed in 48 Hodgkins disease (HD) survivors at a median of 14.3 years (range, 5.9 to 27.5 years) after diagnosis because they may be at increased risk for cardiovascular abnormalities. PATIENTS AND METHODS Patients completed the Short-Form 36 quality-of-life instrument and were screened by echocardiography, exercise stress testing, and resting and 24-hour ECG. RESULTS All patients received mediastinal irradiation (median, 40.0 Gy; range, 27.0 to 51.7 Gy) at a median age of 16.5 years (range, 6.4 to 25.0 years). Four patients received an anthracycline. Although every patient described their health as good or better, and none had symptomatic heart disease at screening, all but one had cardiac abnormalities on screening. Restrictive cardiomyopathy was suggested by reduced average left ventricular (LV) dimension (P < .001) and mass (P < .001), without increased LV wall thickness. Significant valvular defects were present in 42%; 75% had conduction defects. One survivor developed complete heart block shortly after the study visit. Autonomic dysfunction was suggested by a monotonous heart rate in 57%, persistent tachycardia in 31%, and blunted hemodynamic responses to exercise in 27%. Peak oxygen uptake (VO2max) during exercise, a predictor of mortality in heart failure, was significantly reduced (< 20 mL/kg/m2) in 30% of survivors. VO2max was correlated with increasing fatigue, increasing shortness of breath (both, r = -0.35; P =. 02), and decreasing physical component score on the SF-36 (r = 0.554; P = .00017). CONCLUSION A variety of unsuspected, clinically significant cardiovascular abnormalities are common in long-term survivors of HD who are treated at a young age with mediastinal irradiation. We recommend serial, comprehensive cardiac screening of HD survivors who fit this profile.

Skeletal PET with 18F-Fluoride: Applying New Technology to an Old Tracer

Although 18F-labeled NaF was the first widely used agent for skeletal scintigraphy, it quickly fell into disuse after the introduction of 99mTc-labeled bone-imaging agents. Recent comparative studies have demonstrated that 18F-fluoride PET is more accurate than 99mTc-diphosphonate SPECT for identifying both malignant and benign lesions of the skeleton. Combining 18F-fluoride PET with other imaging, such as CT, can improve the specificity and overall accuracy of skeletal 18F-fluoride PET and probably will become the routine clinical practice for 18F-fluoride PET. Although 18F-labeled NaF and 99mTc-diphosphonate have a similar patient dosimetry, 18F-fluoride PET offers shorter study times (typically less than 1 h), resulting in a more efficient workflow, improved patient convenience, and faster turnarounds of reports to the referring physicians. With the widespread availability of PET scanners and the improved logistics for the delivery of 18F radiopharmaceuticals, prior limitations to the routine use of 18F-fluoride bone imaging have largely been overcome. The favorable imaging performance and the clinical utility of 18F-fluoride PET, compared with 99mTc-diphosphonate scintigraphy, support the reconsideration of 18F-fluoride as a routine bone-imaging agent.

Patient-specific seizure onset detection

This work presents an automated, patient-specific method for the detection of epileptic seizure onsets from noninvasive EEG. We adopt a patient-specific approach to exploit the consistency of an individual patients seizure and non-seizure EEG. Our method uses a wavelet decomposition to construct a feature vector that captures the morphology and spatial distribution of an EEG epoch, and then determines whether that vector is representative of a patients seizure or non-seizure EEG using the support-vector machine classification algorithm. Our completely automated method was tested on non-invasive EEG from thirty-six pediatric subjects suffering from a variety of seizure types. It detected 131 of 139 seizure events within 8.0/spl plusmn/3.2 seconds following electrographic onset, and declared 15 false-detections in 60 hours of clinical EEG. Our patient-specific method can be used to initiate delay-sensitive clinical procedures following seizure onset; for example, the injection of an imaging radiopharmaceutical or stimulation of the vagus nerve.

Pediatric Radiopharmaceutical Administered Doses: 2010 North American Consensus Guidelines

Dose reduction has been a work in progress in pediatric imaging for nearly a decade. A 1996 report indicated that the long-term risk of carcinogenesis due to ionizing radiation in atomic bomb survivors was higher than had been previously estimated. For solid tumors, representing about 75% of excess cancer mortality, the likelihood of a radiation-induced malignancy after exposure to ionizing radiation was about 1.0–1.8 times higher in a 10-y-old child than in a young adult. For leukemia, representing the remaining 25% of excess cancer mortality, the likelihood of a radiation-induced malignancy after exposure to ionizing radiation was about twice as high for a 10-y-old child as for a young adult (1). The new risk estimates led to dose-reduction efforts in pediatric imaging that initially focused on CT. Because of the increased use of CT and the relatively high effective radiation dose per study, CT had emerged as a major source of medical radiation received by children in the United States. A careful look at CT image quality and CT exposure parameters indicated that significant reductions in absorbed radiation dose per study were possible without compromising the diagnostic information or image quality of pediatric CT scans (2–6). The ALARA concept, As Low As Reasonably Achievable, was extended to pediatric diagnostic imaging and may be restated as imaging at the lowest absorbed radiation dose that is consistent with quality imaging. The need for reduced CT exposure was then publicized— in the public domain, in the pediatric radiology community, and throughout general radiology. The introduction of reduced-exposure parameters was assessed in a follow-up survey (7–9). Equipment manufacturers made improvements in CT technology that facilitated the reduction of radiation exposures in children. In addition, at this time new dose-reduction efforts are under way in pediatric interventional radiology and fluoroscopy (10). A survey conducted in 2008 revealed a wide variation of pediatric radiopharmaceutical administered doses among 13 leading pediatric hospitals in North America (11). Among the institutions surveyed, the administered activity per kilogram and the maximum administered activity in children older than 1 y varied on average by a factor of 3 and, in 1 case, by a factor of 10. Minimum administered activity varied, on the average, by a factor of 10 and as much as a factor of 20 for 1 procedure. The greatest variability in administered dose occurred in the smallest, youngest, and most at-risk patients. Because the survey included only leading pediatric institutions in North America, concern was raised that the variability among other institutions would be even greater. The survey highlighted the need for a consensus on pediatric radiopharmaceutical administered doses for nuclear medicine imaging in children. The ALARA concept may be extended to pediatric nuclear medicine and restated as the use of the lowest administered activities in children that are consistent with high-quality imaging. The response to this need for dose reduction and uniformity was the formation of a Pediatric Nuclear Medicine Dose Reduction Workgroup, consisting of pediatric nuclear medicine physicians, technologists, and physicists in North America, representing the Society of Nuclear Medicine through the Pediatric Imaging Council, the Society for Pediatric Radiology, and the American College of Radiology (Appendix). The workgroup conducted consensus workshops at annual meetings of the Society of Nuclear Medicine and the Society for Pediatric Radiology. Dose reduction was also featured in categoric courses presented at the 2009 and 2010 Society of Nuclear Medicine annual meetings. Likewise, dose reduction and image optimization in conventional and hybrid imaging were prominently featured in the Pediatric Nuclear Medicine Special Focus Session entitled “New Challenges” at the 52nd Annual Meeting of the Society for Pediatric Radiology in 2009. A symposium on pediatric radiopharmaceutical dosimetry was also held at the Society of Nuclear Medicine 2009 annual meeting. As a result of these consensus workshops, the Workgroup has achieved consensus on pediatric administered radiopharmaceutical doses for 9 commonly used radiopharmaceuticals, in terms of administered activity per kilogram Received Oct. 15, 2010; revision accepted Oct. 26, 2010. For correspondence or reprints contact: S. Ted Treves, Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Children’s Hospital Boston, Harvard Medical School, 300 Longwood Ave., PV2C12, Boston, MA 02115. E-mail: Ted.Treves@childrens.harvard.edu COPYRIGHT a 2011 by the Society of Nuclear Medicine, Inc. DOI: 10.2967/jnumed.110.084327

Positron emission tomography (PET) imaging of neuroblastoma and melanoma with 64Cu-SarAr immunoconjugates

The advancement of positron emission tomography (PET) depends on the development of new radiotracers that will complement 18F-FDG. Copper-64 (64Cu) is a promising PET radionuclide, particularly for antibody-targeted imaging, but the high in vivo lability of conventional chelates has limited its clinical application. The objective of this work was to evaluate the novel chelating agent SarAr (1-N-(4-aminobenzyl)-3, 6,10,13,16,19-hexaazabicyclo[6.6.6] eicosane-1,8-diamine) for use in developing a new class of tumor-specific 64Cu radiopharmaceuticals for imaging neuroblastoma and melanoma. The anti-GD2 monoclonal antibody (mAb) 14.G2a, and its chimeric derivative, ch14.18, target disialogangliosides that are overexpressed on neuroblastoma and melanoma. Both mAbs were conjugated to SarAr using carbodiimide coupling. Radiolabeling with 64Cu resulted in >95% of the 64Cu being chelated by the immunoconjugate. Specific activities of at least 10 μCi/μg (1 Ci = 37 GBq) were routinely achieved, and no additional purification was required after 64Cu labeling. Solid-phase radioimmunoassays and intact cell-binding assays confirmed retention of bioactivity. Biodistribution studies in athymic nude mice bearing s.c. neuroblastoma (IMR-6, NMB-7) and melanoma (M21) xenografts showed that 15–20% of the injected dose per gram accumulated in the tumor at 24 hours after injection, and only 5–10% of the injected dose accumulated in the liver, a lower value than typically seen with other chelators. Uptake by a GD2-negative tumor xenograft was significantly lower (<5% injected dose per gram). MicroPET imaging confirmed significant uptake of the tracer in GD-2-positive tumors, with minimal uptake in GD-2-negative tumors and nontarget tissues such as liver. The 64Cu-SarAr-mAb system described here is potentially applicable to 64Cu-PET imaging with a broad range of antibody or peptide-based imaging agents.

Myocardial perfusion, function and exercise tolerance after the arterial switch operation

OBJECTIVES This study was conducted to determine the prevalence of myocardial perfusion abnormalities at rest and exercise and to assess exercise capacity in children after the arterial switch operation. BACKGROUND There have been sporadic reports of myocardial ischemia or sudden death in children after the arterial switch operation for transposition of the great arteries, possibly related to inadequate coronary perfusion due to kinking or stenosis of the translocated coronary arteries. METHODS Myocardial perfusion at rest and peak exercise was assessed using the scintigraphic agent technetium-99m methoxyisobutyl isonitrile (sestamibi). Exercise capacity was determined with a modified Bruce protocol. Ambulatory electrocardiographic (ECG) Holter monitoring was performed. Ventricular function, contractility and wall motion were assessed echocardiographically. RESULTS Twenty-three children (aged 4.2 to 7.9 years) underwent evaluation. Abnormalities were found on the rest perfusion scans in 22 children (95.6%). The left ventricular myocardium was divided into 13 segments for analysis. Of 299 rest segments, 225 (75.3%) were normal, 11 (3.7%) showed mild defects, 45 (15%) moderate defects and 18 (6%) severe defects at rest. At peak exercise, 237 segments (79.3%) were normal, 24 (8%) showed mild defects, 33 (11%) moderate defects and 5 (1.7%) severe defects. Compared with rest studies, myocardial perfusion grade at exercise was unchanged in 246 segments (82.3%), improved in 42 (14%) and worsened in 11 (3.7%). All patients had normal exercise tolerance without symptoms or ischemic ECG changes. No ventricular tachycardia was seen on Holter monitoring. All patients had a shortening fraction > or = 27%. Left ventricular contractility was normal in 12 children in whom it was assessed. Regional wall motion was normal in 17 children with adequate echocardiographic images for this analysis. CONCLUSIONS Myocardial perfusion scan abnormalities assessed by technetium-99m sestamibi are common after an arterial switch operation. These abnormalities are of uncertain clinical significance and generally lessen with exercise. The normal exercise tolerance without symptoms or ECG changes suggests that myocardial perfusion is adequate during the physiologic stress of exercise in children up to 8 years after an arterial switch operation.

Minimizing and Communicating Radiation Risk in Pediatric Nuclear Medicine

The value of pediatric nuclear medicine is well established. Pediatric patients are referred to nuclear medicine from nearly all pediatric specialties including urology, oncology, cardiology, gastroenterology, and orthopedics. Radiation exposure is associated with a potential, small, risk of inducing cancer in the patient later in life and is higher in younger patients. Recently, there has been enhanced interest in exposure to radiation from medical imaging. Thus, it is incumbent on practitioners of pediatric nuclear medicine to have an understanding of dosimetry and radiation risk to communicate effectively with their patients and their families. This article reviews radiation dosimetry for radiopharmaceuticals and also CT given the recent proliferation of PET/CT and SPECT/CT. It also describes the scientific basis for radiation risk estimation in the context of pediatric nuclear medicine. Approaches for effective communication of risk to patients’ families are discussed. Lastly, radiation dose reduction in pediatric nuclear medicine is explicated.

Early experience with fluorine-18 sodium fluoride bone PET in young patients with back pain.

Purpose: Skeletal positron emission tomography (PET) with fluorine-18 (18F) sodium fluoride (18F NaF) is an alternative to technetium-99m (99mTc)methylene diphosphonate (MDP) scintigraphy. Experience with pediatric PET is sparse, primarily in oncology. This study assesses the role of 18F NaF in evaluating young patients with back pain. Methods: Ninety-four 18F NaF PET scans were performed in 94 patients (27 males, 67 females; mean age, 15 years; range, 4-26 years) with back pain. Three-dimensional PET acquisition was performed 30 minutes after administration of 18F NaF (2.1 MBq/kg; maximum, 148 MBq). Radiation doses are presented for 18F NaF and 99mTc MDP. Results: 18F NaF PET revealed a possible cause of back pain in 55% (52/94). Fifteen patients had 2 or more potential sources of back pain. Diagnoses by PET were pars interarticularis/pedicle stress (34%), spinous process injury (16%), vertebral body ring apophyseal injury (14%), stress at a transitional vertebra-sacral articulation (7%), and sacroiliac joint inflammation/stress (3%). Comparing 18F NaF PET with 99mTc MDP scintigraphy, time between injection and scanning was shorter (0.5 hours vs 3 hours), radiation dosimetry was similar (3.5 mGy vs 2.8 mGy effective dose for a 55-kg patient for 18F NaF and 99mTc MDP, respectively), and cost of radiopharmaceutical was higher. Conclusions: 18F NaF bone PET can detect a variety of skeletal abnormalities in young patients with back pain. Relative to 99mTc MDP, images are of higher resolution. Total time from tracer administration to completion is shorter, and radiation dosimetry is similar. Higher cost for 18F NaF may be offset by enhanced patient throughput.

Isolated Peripheral Pulmonary Artery Stenoses in the Adult

BACKGROUND Isolated peripheral pulmonary artery stenosis (PPS) in the adult is rare and frequently unsuspected. We review in this article our experience with 12 adult patients with isolated PPS, half of whom had been previously diagnosed with chronic pulmonary thromboembolic disease. METHODS AND RESULTS The presentation, evolution, and management of 12 adults with isolated PPS, 17 to 51 years of age (mean, 36.2 +/- 9.7 years), were evaluated. Presenting symptoms were dyspnea and fatigue. Three patients had New York Heart Association (NYHA) functional class III or greater. Lung perfusion scans revealed multiple segmental abnormalities in flow distribution in all patients. Oxygen desaturation at rest was present in 4 patients. At catheterization, right ventricular (RV) pressure was suprasystemic in 2 patients, systemic in 1, and more than half-systemic in 7. All had multiple bilateral non-uniform stenoses in segmental and subsegmental arteries. Balloon pulmonary angioplasty (BPA) to decrease RV hypertension and improve pulmonary flow distribution was performed in 11 patients. After BPA, vessel diameter increased > 50% in 10 patients, distal pulmonary artery pressure increased > or = 30% in 6, and RV pressure decreased > 30% in 5. One patient died shortly after BPA as a result of pulmonary hemorrhage. Immediate procedural success was achieved in 9 of 11 patients. At a mean follow-up period of 52 +/- 32 months, 7 patients had sustained symptomatic improvement (NYHA class I-II). CONCLUSIONS We describe a severe syndrome of isolated PPS in the adult that mimics chronic pulmonary thromboembolic disease. Pulmonary hemodynamics and angiography are required for definitive diagnosis. BPA may offer these patients successful short-term reduction in RV hypertension and alleviation of symptomatology.

The pediatric pulmonary and cardiovascular complications of vertically transmitted human immunodeficiency virus (P2C2 HIV) infection study: Design and methods

The P2C2 HIV Study is a prospective natural history study initiated by the National Heart, Lung, and Blood Institute in order to describe the types and incidence of cardiovascular and pulmonary disorders that occur in children with vertically transmitted HIV infection (i.e., transmitted from mother to child in utero or perinatally). This article describes the study design and methods. Patients were recruited from five clinical centers in the United States. The cohort is composed of 205 infants and children enrolled after 28 days of age (Group I) and 612 fetuses and infants of HIV-infected mothers, enrolled prenatally (73%) or postnatally at age < 28 days (Group II). The maternal-to-infant transmission rate in Group II was 17%. The HIV-negative infants in Group II (Group IIb) serves as a control group for the HIV-infected children (Group IIa). The cohort is followed at specified intervals for clinical examination, cardiac, pulmonary, immunologic, and infectious studies and for intercurrent illnesses. In Group IIa, the cumulative loss-to-follow-up rate at 3 years was 10.5%, and the 3-year cumulative mortality rate was 24.9%. The findings will be relevant to clinical and epidemiologic aspects of HIV infection in children.