123I-mIBG scintigraphy in neuroblastoma: development of a SIOPEN semi-quantitative reporting ,method by an international panel.

PURPOSE: A robust method is required to standardise objective reporting of diagnostic 123I-mIBG images in neuroblastoma. Prerequisites for an appropriate system are low inter- and intra-observer error and reproducibility across a broad disease spectrum. We present a new reporting method, developed and tested for SIOPEN by an international expert panel. METHOD: Patterns of abnormal skeletal 123I-mIBG uptake were defined and assigned numerical scores [0-6] based on disease extent within 12 body segments. Uptake intensity was excluded from the analysis. Data sets from 82 patients were scored independently by six experienced specialists as unblinded pairs (pre- and post-induction chemotherapy) and in random order as a blinded study. Response was defined as ≥50 % reduction in post induction score compared with baseline. RESULTS: In total, 1968 image sets were reviewed individually. Response rates of 88 % and 82 % were recorded for patients with baseline skeletal scores ≤23 and 24-48 respectively, compared with 44 % response in patients with skeletal scores >48 (p = 0.02). Reducing the number of segments or extension scale had a small but statistically negative impact upon the number of responses detected. Intraclass correlation coefficients [ICCs] calculated for the unblinded and blinded study were 0.95 at diagnosis and 0.98 and 0.99 post-induction chemotherapy, respectively. CONCLUSIONS: The SIOPEN mIBG score method is reproducible across the full spectrum of disease in high risk neuroblastoma. Numerical assessment of skeletal disease extent avoids subjective evaluation of uptake intensity. This robust approach provides a reliable means with which to examine the role of 123I mIBG scintigraphy as a prognostic indicator in neuroblastoma.

Assessing vascular effects of adding bevacizumab to neoadjuvant chemotherapy in osteosarcoma using DCE-MRI.

BACKGROUND: The purpose of this study was to assess the impact of bevacizumab alone and in combination with cytotoxic therapy on tumour vasculature in osteosarcoma (OS) using DCE-MRI. METHODS: Six DCE-MRI and three (18)F-FDG PET examinations were scheduled in 42 subjects with newly diagnosed OS to monitor the response to antiangiogenic therapy alone and in combination with cytotoxic therapy before definitive surgery (week 10). Serial DCE-MRI parameters (K(trans), v(p), and v(e)) were examined for correlation with FDG-PET (SUV(max)) and association with drug exposure, and evaluated with clinical outcome. RESULTS: K(trans) (P=0.041) and v(p) (P=0.001) significantly dropped from baseline at 24 h after the first dose of bevacizumab alone, but returned to baseline by 72 h. Greater exposure to bevacizumab was correlated with larger decreases in v(p) at day 5 (P=0.04) and week 10 (P=0.02). A lower K(trans) at week 10 was associated with greater percent necrosis (P=0.024) and longer event-free survival (P=0.034). CONCLUSIONS: This is the first study to demonstrate significant changes of the plasma volume fraction and vascular leakage in OS with bevacizumab alone. The combination of demonstrated associations between drug exposure and imaging metrics, and imaging metrics and patient survival during neoadjuvant therapy, provides a compelling rationale for larger studies using DCE-MRI to assess vascular effects of therapy in OS.

Criteria for evaluation of disease extent by (123)I-metaiodobenzylguanidine scans in neuroblastoma: a report for the International Neuroblastoma Risk Group (INRG) Task Force.

BACKGROUND: Neuroblastoma is an embryonic tumour of the sympathetic nervous system, metastatic in half of the patients at diagnosis, with a high preponderance of osteomedullary disease, making accurate evaluation of metastatic sites and response to therapy challenging. Metaiodobenzylguanidine (mIBG), taken into cells via the norepinephrine transporter, provides a sensitive and specific method of assessing tumour in both soft tissue and bone sites. The goal of this report was to develop consensus guidelines for the use of mIBG scans in staging, response assessment and surveillance in neuroblastoma. METHODS: The International Neuroblastoma Risk Group (INRG) Task Force, including a multidisciplinary group in paediatric oncology of North and South America, Europe, Oceania and Asia, formed a subcommittee on metastatic disease evaluation, including expert nuclear medicine physicians and oncologists, who developed these guidelines based on their experience and the medical literature, with approval by the larger INRG Task Force. RESULTS: Guidelines for patient preparation, radiotracer administration, techniques of scanning including timing, energy, specific views, and use of single photon emission computed tomography are included. Optimal timing of scans in relation to therapy and for surveillance is reviewed. Validated semi-quantitative scoring methods in current use are reviewed, with recommendations for use in prognosis and response evaluation. CONCLUSIONS: Metaiodobenzylguanidine scans are the most sensitive and specific method of staging and response evaluation in neuroblastoma, particularly when used with a semi-quantitative scoring method. Use of the optimal techniques for mIBG in staging and response, including a semi-quantitative score, is essential for evaluation of the efficacy of new therapy.

68Ga-DOTATOC PET/CT in the localization of metastatic extra-adrenal paraganglioma and pheochromocytoma compared with 18F-DOPA PET/CT. / Comparación entre la PET/TC con 18F-DOPA y la PET/TC con 68Ga-DOTATOC para la localización del paraganglioma maligno extra-adrenal y el feocromocitoma.

OBJECTIVE: 18F-Fluoro-L-dihydroxyphenylalanine (18F-DOPA) PET offers high sensitivity and specificity in the imaging of non-malignant extra-adrenal paraganglioma (PGL) and pheochromocytoma (PHEO) but lower sensitivity in metastatic disease. These tumours are of neuroendocrine origin and can be detected by 68Ga-DOTA-Tyr3-octreotide (68Ga-DOTA-TOC) PET. Therefore, we compared 68Ga-DOTA-TOC and 18F-DOPA as radiolabels for PET/CT imaging for the diagnosis of metastatic extra-adrenal PGL and PHEO. Combined cross-sectional imaging was the reference standard. METHODS: A total of 6 men and 4 women (age range 22-72 years) with anatomical and/or histologically proven metastatic PGL and PHEO were included in this study. Of these patients, 2 male patients suffered from PHEO, while the remaining 8 patients were diagnosed as metastatic extra-adrenal PGL disease. Comparative evaluation included morphological imaging with CT and functional imaging with 68Ga-DOTA-TOC and 18F-DOPA PET. The imaging results were analyzed on a per-lesion basis. The maximum standardized uptake value (SUVmax) of each functional imaging modality in concordant tumour lesions was measured. RESULTS: Compared with anatomical imaging, the per-lesion detection rate of 68Ga-DOTA-TOC was 100% (McNemar, P<0.01), and that of 18F-DOPA PET was 82.3% (McNemar, P<0.8) in metastatic extra-adrenal PGL and PHEO. Overall, 68Ga-DOTA-TOC PET identified 67 lesions; anatomical imaging identified 62 lesions, and 18F-DOPA PET identified 56 lesions. The SUVmax (mean±SD) of all concordant lesions was 29.3±19.9 for 68Ga-DOTA-TOC PET and 12.3±9.1 for 18F-DOPA PET (Mann-Whitney U test, P<0.0001). CONCLUSION: 68Ga-DOTA-TOC PET offers the highest detection rate in metastatic extra-adrenal PGL and PHEO compared to 18F-DOPA PET and even to diagnostic CT, particularly in bone lesions. Combined functional/anatomical imaging (68Ga-DOTA-TOC PET/CT) enables exact tumour extension to be detected in these rare tumour entities, especially in the case of unclear anatomical correlation.

Lymphoscintigraphy in melanoma: initial evaluation of a low protein dose monoclonal antibody cocktail.

A low protein dose (73 +/- 10 micrograms total) 131I-labeled monoclonal antibody cocktail made of equal microgram quantities of 225.28S (IgG2a) and 763.24T (IgG1) murine monoclonal antibodies, which bind additively to a high molecular weight antigen of melanoma, was evaluated as a lymphoscintigraphic agent in 17 patients with intermediate to thick (mean Breslow depth, 3.39 +/- 0.64 mm) melanomas or clinical Stage II disease scheduled for nodal dissection. Eleven of the patients were clinically Stage I while 6 were clinically Stage II. 131I antibody cocktail, 258 +/- 10 microCi, was administered s.c. at the site of the primary melanoma or its scar following surgical removal. In eight patients, 63 +/- 8 microCi of 125I nonspecific normal sheep IgG was coadministered s.c. Gamma camera imaging was conducted beginning immediately after and continuing for several days following injection. Surgical resection, weighing, and gamma counting of the draining lymph nodes were undertaken in all patients. On gamma scans, early nodal uptake of antibody was most pronounced and of longest duration in the tumor pathologically positive patients (5 of 7 had visible nodal uptake, 4 of 7 visually stable or rising with time), with the t 1/2 of nodal clearance by gamma scan significantly (P less than 0.05) longer than in the negative patients in whom 4 of 10 showed some, although generally transient (0 of 10 stable or rising), nodal uptake. Scans were not easily interpretable when the injection site was very near the draining nodal group, in part due to the detection of scatter activity from the injection site. In several instances the scan was correct and the clinical examination was incorrect as regards nodal disease. Quantitative analysis of the surgically excised draining nodes showed significantly (P less than 0.001) more 131I anti-melanoma antibody uptake in the 21 tumor-involved nodes [0.01217% injected dose (ID)/node median] than in the 512 tumor-negative nodes (0.00051% ID/node median). Median percentage ID/g of anti-melanoma antibody in tumor-involved nodes was significantly greater (P less than 0.01) than in tumor-negative nodes (0.01984 versus 0.003215% ID/g). 125I-labeled nonspecific antibody did not accumulate significantly more in the tumor-involved nodes on a per node or per g basis in the 283 of 533 nodes studied using the dual-label approach (0.0036 versus 0.00092% ID/g). These data demonstrate that by external imaging and by tissue counting that a radiolabeled anti-melanoma monoclonal antibody cocktail can specifically accumulate to melanoma-involved lymph nodes following s.c. administration.(ABSTRACT TRUNCATED AT 400 WORDS)

Low molecular weight proteomic information distinguishes metastatic from benign pheochromocytoma.

Metastatic lesions occur in up to 36% of patients with pheochromocytoma. Currently there is no way to reliably detect or predict which patients are at risk for metastatic pheochromocytoma. Thus, the discovery of biomarkers that could distinguish patients with benign disease from those with metastatic disease would be of great clinical value. Using surface-enhanced laser desorption ionization protein chips combined with high-resolution mass spectrometry, we tested the hypothesis that pheochromocytoma pathologic states can be reflected as biomarker information within the low molecular weight (LMW) region of the serum proteome. LMW protein profiles were generated from the serum of 67 pheochromocytoma patients from four institutions and analyzed by two different bioinformatics approaches employing pattern recognition algorithms to determine if the LMW component of the circulatory proteome contains potentially useful discriminatory information. Both approaches were able to identify combinations of LMW molecules which could distinguish all metastatic from all benign pheochromocytomas in a separate blinded validation set. In conclusion, for this study set low molecular mass biomarker information correlated with pheochromocytoma pathologic state using blinded validation. If confirmed in larger validation studies, efforts to identify the underlying diagnostic molecules by sequencing would be warranted. In the future, measurement of these biomarkers could be potentially used to improve the ability to identify patients with metastatic disease.

Radioisotope diagnosis and therapy of malignant pheochromocytoma.

The availability of radiopharmaceuticals to depict primary malignant pheochromocytoma and its metastases has markedly changed the approach to these unusual cancers. Whole body screening afforded by scintigraphy allows remote tumor involvement to be identified and provides staging information necessary to guide subsequent therapy. The avid accumulation by malignant pheochromocytoma of some radiopharmaceuticals used for scanning has shown promise in therapeutic trials. In this paper, we discuss radiopharmaceuticals presently employed in malignant pheochromocytoma for both diagnostic and therapeutic uses and potential future compounds that may find their way into clinical practice in the approach to these and other related neoplasms.

Beta-adrenergic antagonist inhibition of hepatic 3,5,3'-triiodothyronine production.

beta-Adrenergic antagonists provide moderate symptomatic relief for most hyperthyroid patients, although these agents have no direct antithyroid effects. Propranolol administration results in modest declines in serum T3 concentrations in both hyperthyroid and normal subjects and also inhibits T4 to T3 conversion in various tissue preparations in vitro. Other beta-adrenergic antagonists have not been shown to consistently alter serum T3 concentrations in vivo or T3 production in vitro. To evaluate the ability of beta-adrenergic antagonists to inhibit T4-5'-deiodination, we measured T3 production from T4 in rat liver homogenates (10,000 X g supernatant) using 1 microM T4 in the presence of varying concentrations of the beta-adrenergic antagonists available in the United States. Each drug inhibited T3 production, and the dose-dependent responses were linear and parallel when plotted as percent inhibition vs. log dose concentration. The calculated drug concentrations required to produce 50% inhibition were: propranolol, 1.7 mM; pindolol, 6.7 mM; timolol, 11.5 mM; atenolol, 23.2 mM; metoprolol, 30.5 mM, and nadolol, 106.1 mM. The IC50 values were similar in the presence of 4 mM dithiothreitol. In separate studies, the ability of D- and L-propranolol to inhibit T3 production was compared with that of D,L-propranolol, the common form. Both D- and L-propranolol were as effective as the racemic mixture. The propranolol metabolites 4-hydroxypropranolol, 4-methylpropranolol, propranolol glycol, and N-desisopropyl propranolol were also effective inhibitors. Thus, beta-adrenergic antagonists inhibit T3 production in vitro. This inhibition is not related to beta-adrenergic antagonism per se, but is correlated with the lipid solubility of the drugs, which may explain the effects of propranolol on serum T3 in vivo.

Preincubation of thyroxine with sulfhydryl-reducing agents does not stimulate thyroxine inner or outer ring deiodination.

Sulfhydryl reagents stimulate enzymatic conversion of T4 to T3 and rT3. A recent study suggested that such reagents stimulated T4 5'-deiodination by a direct interaction with T4. We therefore tested the ability of dithiothreitol (DTT) and other sulfhydryl reagents to enhance the susceptibility of T4 and rT3 to 5'-deiodination by liver homogenates and of T4 to 5-deiodination by placental homogenates. Preincubation of T4 with DTT in concentrations ranging from 0.5-80 mM did not result in increased T3 production from T4 in rat liver homogenates, nor was T3 production increased by preincubation of T4 with reduced glutathione or mercaptoethanol. Preincubation of rT3 with DTT also did not result in increased rT3 degradation by liver homogenates. T4 5-deiodination to rT3 by rat and human placental homogenates was not consistently increased by preincubation of T4 with DTT in concentrations ranging from 2.25-450 mM. These results do not support the hypothesis that sulfhydryl stimulation of T4 deiodination occurs as a result of sulfhydryl-T4 interaction.

Caloric restriction does not alter thyrotropin secretion in hypothyroidism.

The effect of caloric restriction, as a model of nonthyroid illness, on serum thyroid hormone and TSH concentrations in hypothyroid patients was studied to determine if pituitary-thyroid function is altered in such patients, as it is in euthyroid subjects. Serum T4, T3, and TSH concentrations and serum TSH responses to TRH were measured in 5 untreated hypothyroid patients and 10 hypothyroid patients receiving T4 replacement therapy before and after restriction of caloric intake to 500 cal daily for 7 days. In 5 untreated hypothyroid patients, the mean serum T3 concentration declined 17%, from 75 +/- 14 (+/- SE) to 62 +/- 11 ng/dl. The mean basal serum TSH concentrations were 154 +/- 67 (+/- SE) microU/ml before and 161 +/- 75 microU/ml at the end of the period of caloric restriction, and the serum TSH responses to TRH were similar on both occasions. In 10 T4-treated hypothyroid patients, the mean serum T3 concentration declined 35%, from 110 +/- 8 to 71 +/- 8 ng/dl. In this group, mean basal serum TSH concentrations were 17 +/- 5.1 microU/ml before and 18.2 +/- 7.0 microU/ml at the end of the period of caloric restriction, and as in the untreated hypothyroid patients, the serum TSH responses to TRH were similar on both occasions. Mean serum T4 concentrations and serum free T4 index values did not change in either group. These results indicate that caloric restriction in both untreated and T4-treated hypothyroid patients is accompanied by 1) reduced serum T3 concentrations, as it is euthyroid subjects, and 2) no alterations in basal or TRH-stimulated TSH secretion.

Reverse triiodothyronine does not alter pituitary-thyroid function in normal subjects.

Serum rT3 concentrations are often increased in patients with nonthyroid illness. Such elevations could be responsible for some of the alterations in pituitary-thyroid function that occur in such patients, particularly since rT3 is a potent inhibitor of extrathyroidal T3 production in vitro. To evaluate the role of serum rT3 elevations in the regulation of the hypothalamic-pituitary-thyroid axis, 10 normal subjects were given 3 mg rT3, orally, in divided doses for 4 days. Serum rT3 concentrations were elevated at least 10-fold by the end of the first day of treatment. Mean serum T4 and T3 concentrations did not change, nor was there any change in basal or TRH-stimulated serum TSH concentrations. There was, likewise, no change in serum binding of T3 or T4. These results show that rT3, given orally, has no detectable activity in normal subjects, and hence, elevations in serum rT3 concentrations per se do not contribute to other abnormalities in thyroid function found in patients with nonthyroid illness.

A "pheo" lurks: novel approaches for locating occult pheochromocytoma.

Most, but not all, pheochromocytomas can be localized by computed tomography or magnetic resonance imaging. Here we introduce two novel approaches for localization of pheochromocytoma in a patient in whom conventional imaging modalities failed to show the tumor. First, we establish that measurements of plasma free metanephrines coupled with vena caval sampling are useful for localizing occult pheochromocytoma, particularly when elevations in plasma catecholamines are slight or intermittent. Second, we show that positron emission tomographic scanning using the imaging agent 6-[18F]fluorodopamine as a substrate for the norepinephrine transporter offers a highly effective method for tumor localization. These novel approaches may be of value in difficult cases, where biochemical and clinical evidence of pheochromocytoma is compelling, yet conventional imaging modalities fail to locate the tumor.

Use of [11C]aminocyclohexanecarboxylate for the measurement of amino acid uptake and distribution volume in human brain.

A quantitative positron emission tomographic (PET) method to measure amino acid blood-brain barrier (BBB) transport rate and tissue distribution volume (DV) has been developed using 11C-labeled aminocyclohexanecarboxylate (ACHC), a nonmetabolized amino acid analogue. Dynamic PET data were acquired as a series of 15 scans covering a total of 60 min and analyzed by means of a two-compartment, two-parameter model. Functional images were calculated for the amino acid transport rate constants across the BBB and the amino acid DV in the brain. Results show [11C]ACHC to have an influx rate constant in gray matter of approximately 0.03-0.04 ml g-1 min-1, indicating a single-pass extraction fraction of approximately 5-7%. The intersubject coefficient of variation was approximately 15% while intrasubject variability of repeat scans was only slightly greater than 5%. Studies were performed in 15 young normal volunteer control subjects, 5 elderly controls, 7 patients with probable Alzheimer's disease, and one patient with phenylketonuria. Results indicate that [11C]-ACHC will serve as the basis of a method for measuring amino acid transport rate and DV in the normal and pathological human brain.

Pheochromocytoma, polycythemia, and venous thrombosis.

Polycythemia is rarely associated with pheochromocytoma. A patient with a 22-year history of malignant pheochromocytoma is presented in whom major complications developed as a result of long-standing polycythemia, apparently due to secretion of erythropoietin by the tumors. Despite attempts to reduce tumor burden by surgery, chemotherapy, and large doses of I-131-metaiodobenzylguanidine, polycythemia persisted. Extensive venous thrombosis developed requiring hospitalization and anticoagulation. Thus, polycythemia itself may be a cause of major morbidity in patients with pheochromocytoma, and prophylactic measures may be warranted. Review of the 130 patients with benign and malignant pheochromocytoma studied since the introduction of I-131-metaiodobenzylguanidine in 1980 revealed another six patients with hematocrits over 50 but only one had a hematocrit greater than 55 and required regular phlebotomy. In contrast, anemia (hematocrit less than 35) due to variety of causes was present in 18 cases.

The role of imaging tests in the diagnosis of thyroid carcinoma.

Many noninvasive high-quality imaging tests are widely available to assist in the evaluation of thyroid nodules. These include thyroid scans, computed tomography, ultrasonography, and magnetic resonance imaging. These procedures and other less commonly performed tests are reviewed. Their routine role in the diagnosis of thyroid carcinoma, however, has been, for the most part, obviated by the convenience and accuracy of fine needle aspiration cytology. Special situations in which imaging tests are most useful are discussed.

Current concepts on the diagnostic use of MIBG in children.

Metaiodobenzylguanidine (MIBG) was developed 18 yr ago for scintigraphic imaging of the adrenomedullary tumors pheochromocytoma and neuroblastoma. Many studies have shown the usefulness of this agent for the management of patients with neuroblastoma or pheochromocytoma, and the 131I-labeled form was recently approved by the Food and Drug Administration for use in the U.S. This article summarizes our current concepts on the diagnostic use of MIBG in children. The radioisotopes available for labeling of MIBG and related compounds, the dosimetry, metabolism and mechanisms of uptake and retention are discussed. Our protocols for imaging both 131I-MIBG and 123I-MIBG, along with the normal distribution of these compounds, are reviewed. The use of MIBG for the management of neuroblastoma, and comparisons with other radiotracers available for imaging neuroblastomas are also addressed.

Iodine-131-metaiodobenzylguanidine and bone scintigraphy for the detection of neuroblastoma.

The purpose of this study was to compare the utility of bone and metaiodobenzylguanidine (MIBG) scintigraphy for the detection of primary and metastatic deposits of neuroblastoma. 99mTc methylene diphosphonate (MDP) bone and 131I-MIBG scans performed within 1 mo of each other in 85 patients with known or suspected neuroblastoma were evaluated for evidence of skeletal and extraskeletal disease. In 77 of 77 patients with confirmed neuroblastoma, the MDP and MIBG scans were concordant for the presence or absence of skeletal disease. A nearly twofold greater number of skeletal lesions were evident on MIBG scanning. No patients with normal bone scans had MIBG studies indicating bone involvement. In patients with histologic evidence of bone marrow involvement, each study suggested skeletal lesions in approximately 70%. In patients with extraskeletal disease demonstrated by CT, there was soft-tissue uptake of MIBG in 80% and MDP in 39%. We conclude that both MIBG and MDP are useful for the detection of skeletal neuroblastoma. MIBG is the better agent for characterizing the extent of disease, and MDP is a valuable adjunctive agent that provides skeletal landmarks for comparison. MIBG is clearly superior for the detection of extraskeletal neuroblastoma.

Iodine-131 MIBG scintigraphy of the extremities in metastatic pheochromocytoma and neuroblastoma.

Iodine-131 MIBG scintigraphy may be used to determine the presence or absence of metastases to the appendicular skeleton in malignant pheochromocytoma and neuroblastoma. Normal bones show no uptake of [131I]MIBG and the joints are seen as photon-deficient areas surrounded by background muscle activity. Discrete concentrations of radioactivity in bone are often seen in patients with malignant pheochromocytoma and neuroblastoma. Bone marrow involvement in neuroblastoma may be indicated by diffuse uptake of [131I]MIBG or focal accumulation at the metaphyses. Uncommonly, bone involvement may not be displayed by the [131I]MIBG images. Since conventional bone scanning agents may also fail to detect these tumors, skeletal scintigraphy with both [131I]MIBG and [99mTc]MDP is necessary to reliably stage malignant pheochromocytoma and neuroblastoma.

The use of indium-111 oxine platelet scintigraphy and survival studies in pediatric patients with thrombocytopenia.

We have utilized 111In-labeled heterologous platelets to investigate the mechanism of thrombocytopenia in ten children. From the scintigraphic findings, platelet survival times, and clinical information, thrombocytopenia was ascribed to decreased production or to increased destruction. Two patients were found to have bone marrow production defects. Two patients with hemangiomas were studied. In one, the hemangioma was shown not to be the cause of thrombocytopenia. In the second, the hemangioma was proven the source of platelet destruction, but was much more extensive than clinically evident. In both, surgical manipulation of the hemangioma was avoided. Six additional patients had thrombocytopenia due to accelerated destruction. In four, the spleen was shown responsible. In two, however, the spleen was shown not to be responsible for the low platelet counts, and splenectomy was avoided. Thus, 111In-platelet scintigraphy and survival studies are valuable in the classification and management of childhood thrombocytopenia. We believe that this study should be performed, when possible, in any child with thrombocytopenia where the mechanism is unclear or the therapeutic intervention involves splenectomy or resection of a hemangioma.