Pat Zanzonico

Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer

BACKGROUND Metastatic thyroid cancers that are refractory to radioiodine (iodine-131) are associated with a poor prognosis. In mouse models of thyroid cancer, selective mitogen-activated protein kinase (MAPK) pathway antagonists increase the expression of the sodium-iodide symporter and uptake of iodine. Their effects in humans are not known. METHODS We conducted a study to determine whether the MAPK kinase (MEK) 1 and MEK2 inhibitor selumetinib (AZD6244, ARRY-142886) could reverse refractoriness to radioiodine in patients with metastatic thyroid cancer. After stimulation with thyrotropin alfa, dosimetry with iodine-124 positron-emission tomography (PET) was performed before and 4 weeks after treatment with selumetinib (75 mg twice daily). If the second iodine-124 PET study indicated that a dose of iodine-131 of 2000 cGy or more could be delivered to the metastatic lesion or lesions, therapeutic radioiodine was administered while the patient was receiving selumetinib. RESULTS Of 24 patients screened for the study, 20 could be evaluated. The median age was 61 years (range, 44 to 77), and 11 patients were men. Nine patients had tumors with BRAF mutations, and 5 patients had tumors with mutations of NRAS. Selumetinib increased the uptake of iodine-124 in 12 of the 20 patients (4 of 9 patients with BRAF mutations and 5 of 5 patients with NRAS mutations). Eight of these 12 patients reached the dosimetry threshold for radioiodine therapy, including all 5 patients with NRAS mutations. Of the 8 patients treated with radioiodine, 5 had confirmed partial responses and 3 had stable disease; all patients had decreases in serum thyroglobulin levels (mean reduction, 89%). No toxic effects of grade 3 or higher attributable by the investigators to selumetinib were observed. One patient received a diagnosis of myelodysplastic syndrome more than 51 weeks after radioiodine treatment, with progression to acute leukemia. CONCLUSIONS Selumetinib produces clinically meaningful increases in iodine uptake and retention in a subgroup of patients with thyroid cancer that is refractory to radioiodine; the effectiveness may be greater in patients with RAS-mutant disease. (Funded by the American Thyroid Association and others; ClinicalTrials.gov number, NCT00970359.).

Biologic bypass with the use of adenovirus-mediated gene transfer of the complementary deoxyribonucleic acid for vascular endothelial growth factor 121 improves myocardial perfusion and function in the ischemic porcine heart☆☆☆★

OBJECTIVES Vascular endothelial growth factor (VEGF), a potent angiogenic mediator, can be delivered to targeted tissues by means of a replication-deficient adenovirus (Ad) vector. We hypothesized that direct administration of Ad vector expressing the VEGF121 complementary deoxyribonucleic acid (AdGVVEGF121.10) into regions of ischemic myocardium would enhance collateral vessel formation and improve regional perfusion and function. METHODS Yorkshire swine underwent thoracotomy and placement of an Ameroid constrictor (Research Instruments & MFG, Corvallis, Ore.) on the circumflex coronary artery. Three weeks later, myocardial perfusion and function were assessed by single photon emission computed tomography imaging (SPECT) with 99mTc-labeled sestamibi and by echocardiography during rest and stress. AdGVVEGF121.10 (n = 7) or the control vector, AdNull (n = 8), was administered directly into the myocardium at 10 sites in the circumflex distribution (10(8) pfu/site). Four weeks later, these studies were repeated and ex vivo angiography was performed. RESULTS SPECT imaging 4 weeks after vector administration demonstrated significant reduction in the ischemic area at stress in AdGVVEFG121.10-treated animals compared with AdNull control animals (p = 0.005). Stress echocardiography at the same time demonstrated improved segmental wall thickening in AdGVVEGF121.10 animals compared with AdNull control animals (p = 0.03), with AdGVVEGF121.10 animals showing nearly normalized function in the circumflex distribution. Collateral vessel development assessed by angiography was also significantly greater in AdGVVEGF121.10 animals than in AdNull control animals (p = 0.04), with almost complete reconstitution of circumflex filling in AdGVVEGF121.10 animals. CONCLUSIONS An Ad vector expressing the VEGF121 cDNA induces collateral vessel development in ischemic myocardium and results in significant improvement in both myocardial perfusion and function. Such a strategy may be useful in patients with ischemic heart disease in whom complete revascularization is not possible.

Salvage angiogenesis induced by adenovirus-mediated gene transfer of vascular endothelial growth factor protects against ischemic vascular occlusion

PURPOSE Vascular endothelial growth factor (VEGF) is a potent stimulator of angiogenesis, and transgene expression from adenovirus vectors can provide in vivo delivery of proteins. On the basis of this knowledge, we hypothesized that local administration of a replication-deficient adenovirus vector expressing complementary DNA for VEGF (AdVEGF) would induce collateral vessel formation in the setting of ischemia that could protect against subsequent acute vascular occlusion. METHODS Hindlimb ischemia was induced in Sprague-Dawley rats by means of unilateral ligation of the common iliac artery immediately followed by administration of 4 x 10(9)-plaque-forming units VEGF, the control vector AdNull, or phosphate-buffered saline solution into the iliofemoral adipose tissue and thigh muscles. Untreated rats with common iliac ligation were used as an additional control group. RESULTS Local VEGF expression was observed for 5 days in AdVEGF-treated rats but not in controls. Three weeks after ligation and vector administration, the ipsilateral femoral artery was ligated for a model of an acute vascular occlusion in the setting of preexisting ischemia. Blood flow to the ischemic hindlimb relative to the contralateral hindlimb evaluated with color microspheres demonstrated significantly increased blood flow in the AdVEGF-treated rats compared with each control group (p < 0.0001). Relative blood flow assessed by means of 99mTc-sestamibi radionuclide scans also demonstrated increased blood flow to the ligated hindlimb of AdVEGF-treated rats compared with each control group (p < 0.002). AdVEGF-treated rats also demonstrated increased vascularity in the ligated limb compared with each control group as assessed by means of angiography (p < 0.0001) and histologic quantification of blood vessels less than 80 microm diameter in local adipose tissue and capillaries per muscle fiber (p < 0.0002). AdVEGF treatment prevented a rise in femoral venous lactate femoral venous concentrations 1 hour after femoral artery ligation in control rats (p < 0.04). CONCLUSIONS An adenovirus vector expressing VEGF complementary DNA is capable of stimulating an angiogenic response that protects against acute vascular occlusion in the setting of preexisting ischemia, suggesting that in vivo gene transfer of VEGF complementary DNA might be useful in prophylaxis of advancing arterial occlusive disease.

MIRD Pamphlet No. 22 (Abridged): Radiobiology and Dosimetry of α-Particle Emitters for Targeted Radionuclide Therapy

The potential of α-particle emitters to treat cancer has been recognized since the early 1900s. Advances in the targeted delivery of radionuclides and radionuclide conjugation chemistry, and the increased availability of α-emitters appropriate for clinical use, have recently led to patient trials of radiopharmaceuticals labeled with α-particle emitters. Although α-emitters have been studied for many decades, their current use in humans for targeted therapy is an important milestone. The objective of this work is to review those aspects of the field that are pertinent to targeted α-particle emitter therapy and to provide guidance and recommendations for human α-particle emitter dosimetry.

Routine Quality Control of Clinical Nuclear Medicine Instrumentation: A Brief Review

This article reviews routine quality-control (QC) procedures for current nuclear medicine instrumentation, including the survey meter, dose calibrator, well counter, intraoperative probe, organ (“thyroid”) uptake probe, γ-camera, SPECT and SPECT/CT scanner, and PET and PET/CT scanner. It should be particularly useful for residents, fellows, and other trainees in nuclear medicine, nuclear cardiology, and radiology. The procedures described and their respective frequencies are presented only as general guidelines.

Phase I Study of Targeted Radioimmunotherapy for Leptomeningeal Cancers Using Intra-Ommaya 131-I-3F8

PURPOSE Tumors metastasizing to the CNS and leptomeninges (LM) are associated with significant mortality. We tested the toxicity, pharmacokinetics, and dosimetry of intraventricular iodine-131-labeled monoclonal antibody 3F8 (131I-3F8) targeting GD2-positive CNS/LM disease in a phase I clinical trial. PATIENTS AND METHODS Adequate CSF flow was determined by pretreatment indium-111-DTPA studies. Fifteen patients received a tracer (1 to 2 mCi) and therapeutic injection (10 to 20 mCi) of intra-Ommaya 131I-3F8. 131I-3F8 pharmacokinetics were studied by serial CSF and blood samplings. Dosimetry was based on pharmacokinetics and region of interest (ROI) analyses on whole-body gamma camera scans. Tumor response was determined by clinical, radiographic, and cytologic criteria. RESULTS Total absorbed CSF dose was 1.12 to 13.00 Gy by sampling and 1.00 to 13.70 Gy by ROI data. Average dosimetry ratio (Gy/mCi) of the therapy/tracer administration was 0.88 (+/- 0.58) and 1.08 (+/- 0.66) based on CSF pharmacokinetics and ROI analysis, respectively. CSF half-life by sampling was 3 to 12.9 hours. Toxicities included self-limited headache, fever, and vomiting. Dose-limiting toxicity was reached at the 20-mCi dose, when transient elevations in intracranial pressure and chemical meningitis were seen. Three of 13 assessable patients achieved objective radiographic and/or cytologic responses. No late toxicities have been seen in two patients who remain in remission off therapy for more than 3.5 years. CONCLUSION Intra-Ommaya 131I-3F8 was generally well tolerated; the maximum-tolerated dose was 10 mCi. A high CSF-to-blood ratio was achieved. Tracer studies reliably predicted the therapeutic dose to the CSF. Radioimmunoconjugates targeting GD2 may have clinical utility in the treatment of CNS/LM malignancies.

Pharmacokinetic Assessment of the Uptake of 16β-18F-Fluoro-5α-Dihydrotestosterone (FDHT) in Prostate Tumors as Measured by PET

The aim of this study was to develop a clinically applicable noninvasive method to quantify changes in androgen receptor (AR) levels based on 18F-16β-fluoro-5α-dihydrotestosterone (18F-FDHT) PET in prostate cancer patients undergoing therapy. Methods: Thirteen patients underwent dynamic 18F-FDHT PET over a selected tumor. Concurrent venous blood samples were acquired for blood metabolite analysis. A second cohort of 25 patients injected with 18F-FDHT underwent dynamic PET of the heart. These data were used to generate a population-based input function, essential for pharmacokinetic modeling. Linear compartmental pharmacokinetic models of increasing complexity were tested on the tumor tissue data. Four suitable models were applied and compared using the Bayesian information criterion (BIC). Model 1 consisted of an instantaneously equilibrating space, followed by a unidirectional trap. Models 2a and 2b contained a reversible space between the instantaneously equilibrating space and the trap, into which metabolites were excluded (2a) or allowed (2b). Model 3 built on model 2b with the addition of a second reversible space preceding the unidirectional trap and from which metabolites were excluded. Results: The half-life of the 18F-FDHT in blood was between 6 and 7 min. As a consequence, the uptake of 18F-FDHT in prostate cancer lesions reached a plateau within 20 min as the blood-borne activity was consumed. Radiolabeled metabolites were shown not to bind to ARs in in vitro studies with CWR22 cells. Model 1 produced reasonable and robust fits for all datasets and was judged best by the BIC for 16 of 26 tumor scans. Models 2a, 2b, and 3 were judged best in 7, 2, and 1 cases, respectively. Conclusion: Our study explores the clinical potential of using 18F-FDHT PET to estimate free AR concentration. This process involved the estimation of a net uptake parameter such as the ktrap of model 1 that could serve as a surrogate measure of AR expression in metastatic prostate cancer. Our initial studies suggest that a simple body mass–normalized standardized uptake value correlates reasonably well to model-based ktrap estimates, which we surmise may be proportional to AR expression. Validation studies to test this hypothesis are underway.

Imaging hNET Reporter Gene Expression with 124I-MIBG

The norepinephrine transporter (NET) has recently been suggested as a useful reporter gene. We have extended this effort by constructing an internal ribosomal entry site (IRES)-linked hNET-green fluorescent protein (GFP) hybrid reporter gene for both nuclear and optical imaging. Methods: A retroviral vector pQCXhNET-IRES-GFP was constructed and used to generate several reporter cell lines and xenografts. Transduced cells were sorted by fluorescence-activated cell sorting based on GFP expression and used for both in vitro and in vivo imaging studies. Results: The transduced reporter cells accumulated 123I- or 124I-labeled metaiodobenzylguanidine (MIBG) to high levels compared with the wild-type parent cell lines. Differences in MIBG accumulation between cell lines were primarily due to differences in influx (K1) rather than efflux (k2). The estimated MIBG distribution volumes (Vd) for transduced Jurkat, C6, and COS-7 cells were 572 ± 13, 754 ± 25, and 1,556 ± 38 mL/g, respectively. A correlation between radiotracer accumulation (K1) and GFP fluorescence intensity was also demonstrated. Sequential imaging studies of mice bearing pQCXhNET-IRES-GFP transduced and wild-type C6 xenografts demonstrated several advantages of 124I-MIBG small-animal PET compared with 123I-MIBG γ-camera/SPECT. This was primarily due to the longer half-life of 124I and to the retention and slow clearance (half-time, 63 ± 6 h) of MIBG from transduced xenografts compared with that from wild-type xenografts (half-time, 12 ± 1 h) and other organs (half-time, 2.6–21 h). Very high radioactivity ratios were observed at later imaging times; at 73 h after 124I-MIBG injection, the C6/hNET-IRES-GFP xenograft-to-muscle ratio was 293 ± 48 whereas the C6 xenograft-to-muscle ratio was 0.71 ± 0.19. Conclusion: These studies demonstrate the potential for a wider application of hNET reporter imaging and the future translation to patient studies using radiopharmaceuticals that are currently available for both SPECT and PET.

Effects of time of administration and dietary iodine levels on potassium iodide (KI) blockade of thyroid irradiation by 131I from radioactive fallout.

Abstract—Radioiodines, particularly 131I, may be released into the environment in breach-of-containment nuclear reactor accidents and localize in and irradiate the thyroid with an attendant risk of neoplastic growth and other adverse health effects. Pharmacologic thyroid blockade by oral potassium iodide (KI) (50–100 mg in adults) can substantially reduce thyroid uptake of and irradiation by internalized radioiodine. In the current analysis, computer modeling of iodine metabolism has been used to systematically elucidate the effects of two practically important but highly variable factors on the radioprotective effect of KI: the time of administration relative to exposure to radioiodine and the dietary level of iodine. In euthyroid adults receiving iodine-sufficient diets (250 &mgr;g d−1 in the current analysis), KI administered up to 48 h before 131I exposure can almost completely block thyroid uptake and therefore greatly reduce the thyroid absorbed dose. However, KI administration 96 h or more before 131I exposure has no significant protective effect. In contrast, KI administration after exposure to radioiodine induces a smaller and rapidly decreasing blockade effect. KI administration 16 h or later after 131I exposure will have little effect on thyroid uptake and absorbed dose and therefore little or no protective effect. The 131I thyroid absorbed dose is two-fold greater with insufficient levels of dietary iodine, 2,900 cGy/37 MBq, than with sufficient levels of dietary iodine, 1,500 cGy/37 MBq. When KI is administered 48 h or less before 131I intake, the thyroid absorbed doses (in cGy/37 MBq) are comparably low with both sufficient and insufficient dietary iodine levels. When KI is administered after 131I intake, however, the protective effect of KI is less and decreases more rapidly with insufficient than with sufficient dietary iodine. For example, KI administration 2 and 8 h after 131I intake yields protective effects of 80 and 40%, respectively, with iodine-sufficient diets, but only 65 and 15% with iodine-deficient diets. In conclusion, whether exposed populations receive sufficient or insufficient dietary iodine, oral KI is an effective means of reducing thyroid irradiation from environmentally dispersed radioiodine but is effective only when administered within 2 d before to ∼8 h after radioiodine intake.

124 I-huA33 Antibody PET of Colorectal Cancer

Humanized A33 (huA33) is a promising monoclonal antibody that recognizes A33 antigen, which is present in more than 95% of colorectal cancers and in normal bowel. In this study, we took advantage of quantitative PET to evaluate 124I huA33 targeting, biodistribution, and safety in patients with colorectal cancer. We also determined the biodistribution of 124I-huA33 when a large dose of human intravenous IgG (IVIG) was administered to manipulate the Fc receptor or when 124I-huA33 was given via hepatic arterial infusion (HAI). Methods: We studied 25 patients with primary or metastatic colorectal cancer; 19 patients had surgical exploration or resection. Patients received a median of 343 MBq (44.4–396 MBq) and 10 mg of 124I-huA33. Nineteen patients received the antibody intravenously and 6 patients via HAI, and 5 patients also received IVIG. Results: Ten of 12 primary tumors were visualized in 11 patients. The median concentration in primary colon tumors was 0.016% injected dose per gram, compared with 0.004% in normal colon. The PET-based median ratio of hepatic tumor uptake to normal-liver uptake was 3.9 (range, 1.8–22.2). Quantitation using PET, compared with well counting of serum and tissue, showed little difference. Prominent uptake in bowel hindered tumor identification in some patients. Pharmacokinetics showed that patients receiving IVIG had a significantly shorter serum half-time (41.6 ± 14.0 h) than those without (65.2 ± 9.8 h). There were no differences in clearance rates among the intravenous group, IVIG group, and HAI group, nor was there any difference in serum area under the curve, maximum serum concentration, or volume of distribution. Weak titers of human–antihuman antibodies were observed in 6 of 25 patients. No acute side effects or significant toxicities were associated with huA33. Conclusion: Good localization of 124I-huA33 in colorectal cancer with no significant toxicity has been observed. PET-derived 124I concentrations agreed well with those obtained by well counting of surgically resected tissue and blood, confirming the quantitative accuracy of 124I-huA33 PET. The HAI route had no advantage over the intravenous route. No clinically significant changes in blood clearance were induced by IVIG.