Radioimmunoscintigraphy and Pretreatment Dosimetry of 131I-Omburtamab for Planning Treatment of Leptomeningeal Disease.

Radiolabeled antibody treatment with 131I-omburtamab, administered intraventricularly into the cerebrospinal fluid (CSF) space, can deliver therapeutic absorbed doses to sites of leptomeningeal disease. Assessment of distribution and radiation dosimetry is a key element in optimizing such treatments. Using a theranostic approach, we performed pretreatment 131I-omburtamab imaging and dosimetric analysis in patients before therapy. Methods: Whole-body planar images were acquired 3 ± 1, 23 ± 2, and 47 ± 2 h after intracranioventricular administration of 75 ± 5 MBq of 131I-omburtamab via an Ommaya reservoir. Multiple blood samples were also obtained for kinetic analysis. Separate regions of interest (ROIs) were manually drawn to include the lateral ventricles, entire spinal canal CSF space, and over the whole body. Count data in the ROIs were corrected for background and physical decay, converted to activity, and subsequently fitted to an exponential clearance function. The radiation absorbed dose was estimated to the CSF, separately to the spinal column and ventricles, and to the whole body and blood. Biodistribution of the injected radiolabeled antibody was assessed for all patients. Results: Ninety-five patients were included in the analysis. Biodistribution showed prompt localization in the ventricles and spinal CSF space with low systemic distribution, noted primarily as hepatic, renal, and bladder activity after the first day. Using ROI analysis, the effective half-lives were 13 ± 11 h (range, 5-75 h) for CSF in the spinal column, 8 ± 3 h (range, 3-17 h) for ventricles, and 41 ± 11 (range, 23-81 h) for the whole body. Mean absorbed doses were 0.63 ± 0.38 cGy/MBq (range, 0.24-2.25 cGy/MBq) for CSF in the spinal column, 1.03 ± 0.69 cGy/MBq (range, 0.27-5.15 cGy/MBq) for the ventricular CSF, and 0.45 ± 0.32 mGy/MBq (range, 0.05-1.43 mGy/MBq) for the whole body. Conclusion: Pretherapeutic imaging with 131I-omburtamab allows assessment of biodistribution and dosimetry before the administration of therapeutic activity. Absorbed doses to the CSF compartments and whole body derived from the widely applicable serial 131I-omburtamab planar images had acceptable agreement with previously reported data determined from serial 124I-omburtamab PET scans.

Enhancing Radioiodine Incorporation in BRAF-Mutant, Radioiodine-Refractory Thyroid Cancers with Vemurafenib and the Anti-ErbB3 Monoclonal Antibody CDX-3379: Results of a Pilot Clinical Trial.

Background: Oncogenic activation of mitogen-activated protein kinase (MAPK) signaling is associated with radioiodine refractory (RAIR) thyroid cancer. Preclinical models suggest that activation of the receptor tyrosine kinase erbB-3 (HER3) mitigates the MAPK pathway inhibition achieved by BRAF inhibitors in BRAFV600E mutant thyroid cancers. We hypothesized that combined inhibition of BRAF and HER3 using vemurafenib and the human monoclonal antibody CDX-3379, respectively, would potently inhibit MAPK activation and restore radioactive iodine (RAI) avidity in patients with BRAF-mutant RAIR thyroid cancer. Methods: Patients with BRAFV600E RAIR thyroid cancer were evaluated by thyrogen-stimulated iodine-124 (124I) positron emission tomography-computed tomography (PET/CT) at baseline and after 5 weeks of treatment with oral vemurafenib 960 mg twice daily alone for 1 week, followed by vemurafenib in combination with 1000 mg of intravenous CDX-3379 every 2 weeks. Patients with adequate 124I uptake on the second PET/CT then received therapeutic radioactive iodine (131I) with vemurafenb+CDX-3379. All therapy was discontinued two days later. Treatment response was monitored by serum thyroglobulin measurements and imaging. The primary endpoints were safety and tolerability of vemurafenib+CDX-3379, as well as the proportion of patients after vemurafenb+CDX-3379 therapy with enhanced RAI incorporation warranting therapeutic 131I. Results: Seven patients were enrolled; six were evaluable for the primary endpoints. No grade 3 or 4 toxicities related to CDX-3379 were observed. Five patients had increased RAI uptake after treatment; in 4 patients this increased uptake warranted therapeutic 131I. At 6 months, 2 patients achieved partial response after 131I and 2 progression of disease. Next-generation sequencing of 5 patients showed that all had co-occurring telomerase reverse transcriptase promoter alterations. A deleterious mutation in the SWItch/Sucrose Non-Fermentable (SWI/SNF) gene ARID2 was discovered in the patient without enhanced RAI avidity after therapy and an RAI-resistant tumor from another patient that was sampled off-study. Conclusions: The endpoints for success were met, providing preliminary evidence of vemurafenib+CDX-3379 safety and efficacy for enhancing RAI uptake. Preclinical data and genomic profiling in this small cohort suggest SWI/SNF gene mutations should be investigated as potential markers of resistance to redifferentiation strategies. Further evaluation of vemurafenib+CDX-3379 as a redifferentiation therapy in a larger trial is warranted (ClinicalTrials.gov: NCT02456701).

Biodistribution and Dosimetry of Intraventricularly Administered 124I-Omburtamab in Patients with Metastatic Leptomeningeal Tumors.

Radiation dose estimations are key for optimizing therapies. We studied the role of 124I-omburtamab (8H9) given intraventricularly in assessing the distribution and radiation doses before 131I-omburtamab therapy in patients with metastatic leptomeningeal disease and compared it with the estimates from cerebrospinal fluid (CSF) sampling. Methods: Patients with histologically proven malignancy and metastatic disease to the central nervous system or leptomeninges who met eligibility criteria for 131I-omburtamab therapy underwent immuno-PET imaging with 124I-8H9 followed by 131I-8H9 antibody therapy. Patients were imaged with approximately 74 MBq of intraventricular 124I-omburtamab via an Ommaya reservoir. Whole-body PET images were acquired at approximately 4, 24, and 48 h after administration and analyzed for dosimetry calculations. Peripheral blood and CSF samples were obtained at multiple time points for dosimetry estimation. Results: Forty-two patients with complete dosimetry and therapy data were analyzed. 124I-omburtamab PET-based radiation dosimetry estimations revealed mean (±SD) absorbed dose to the CSF for 131I-8H9 of 0.62 ± 0.40 cGy/MBq, compared with 2.22 ± 2.19 cGy/MBq based on 124I-omburtamab CSF samples and 1.53 ± 1.37 cGy/MBq based on 131I-omburtamab CSF samples. The mean absorbed dose to the blood was 0.051 ± 0.11 cGy/MBq for 124I-omburtamab samples and 0.07 ± 0.04 cGy/MBq for 131I-omburtamab samples. The effective whole-body radiation dose for 124I-omburtamab was 0.49 ± 0.27 mSv/MBq. The mean whole-body clearance half-time was 44.98 ± 16.29 h. Conclusion: PET imaging with 124I-omburtamab antibody administered intraventricularly allows for noninvasive estimation of dose to CSF and normal organs. High CSF-to-blood absorbed-dose ratios are noted, allowing for an improved therapeutic index to leptomeningeal disease and reduced systemic doses. PET imaging-based estimates were less variable and more reliable than CSF sample-based dosimetry.

Vemurafenib Redifferentiation of BRAF Mutant, RAI-Refractory Thyroid Cancers.

CONTEXT: BRAFV600E mutant thyroid cancers are often refractory to radioiodine (RAI). OBJECTIVES: To investigate the utility and molecular underpinnings of enhancing lesional iodide uptake with the BRAF inhibitor vemurafenib in patients with RAI-refractory (RAIR). DESIGN: This was a pilot trial that enrolled from June 2014 to January 2016. SETTING: Academic cancer center. PATIENTS: Patients with RAIR, BRAF mutant thyroid cancer. INTERVENTION: Patients underwent thyrotropin-stimulated iodine-124 (124I) positron emission tomography scans before and after ~4 weeks of vemurafenib. Those with increased RAI concentration exceeding a predefined lesional dosimetry threshold (124I responders) were treated with iodine-131 (131I). Response was evaluated with imaging and serum thyroglobulin. Three patients underwent research biopsies to evaluate the impact of vemurafenib on mitogen-activated protein kinase (MAPK) signaling and thyroid differentiation. MAIN OUTCOME MEASURE: The proportion of patients in whom vemurafenib increased RAI incorporation to warrant 131I. RESULTS: Twelve BRAF mutant patients were enrolled; 10 were evaluable. Four patients were 124I responders on vemurafenib and treated with 131I, resulting in tumor regressions at 6 months. Analysis of research tumor biopsies demonstrated that vemurafenib inhibition of the MAPK pathway was associated with increased thyroid gene expression and RAI uptake. The mean pretreatment serum thyroglobulin value was higher among 124I responders than among nonresponders (30.6 vs 1.0 ng/mL; P = 0.0048). CONCLUSIONS: Vemurafenib restores RAI uptake and efficacy in a subset of BRAF mutant RAIR patients, probably by upregulating thyroid-specific gene expression via MAPK pathway inhibition. Higher baseline thyroglobulin values among responders suggest that tumor differentiation status may be a predictor of vemurafenib benefit.

A recommendation for revised dose calibrator measurement procedures for 89Zr and 124I.

Because of their chemical properties and multiday half lives, iodine-124 and zirconium-89 are being used in a growing number of PET imaging studies. Some aspects of their quantitation, however, still need attention. For (89)Zr the PET images should, in principle, be as quantitatively accurate as similarly reconstructed 18F measurements. We found, however, that images of a 20 cm well calibration phantom containing (89)Zr underestimated the activity by approximately 10% relative to a dose calibrator measurement (Capintec CRC-15R) using a published calibration setting number of 465. PET images of (124)I, in contrast, are complicated by the contribution of decays in cascade that add spurious coincident events to the PET data. When these cascade coincidences are properly accounted for, quantitatively accurate images should be possible. We found, however, that even with this correction we still encountered what appeared to be a large variability in the accuracy of the PET images when compared to dose calibrator measurements made using the calibration setting number, 570, recommended by Capintec. We derive new calibration setting numbers for (89)Zr and (124)I based on their 511 keV photon peaks as measured on an HPGe detector. The peaks were calibrated relative to an 18F standard, the activity level of which was precisely measured in a dose calibrator under well-defined measurement conditions. When measuring (89)Zr on a Capintec CRC-15R we propose the use of calibration setting number 517. And for (124)I, we recommend the use of a copper filter surrounding the sample and the use of calibration setting number 494. The new dose calibrator measurement procedures we propose will result in more consistent and accurate radioactivity measurements of (89)Zr and (124)I. These and other positron emitting radionuclides can be accurately calibrated relative to 18F based on measurements of their 511 keV peaks and knowledge of their relative positron abundances.

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.).

Quantitative modeling of Cerenkov light production efficiency from medical radionuclides.

There has been recent and growing interest in applying Cerenkov radiation (CR) for biological applications. Knowledge of the production efficiency and other characteristics of the CR produced by various radionuclides would help in accessing the feasibility of proposed applications and guide the choice of radionuclides. To generate this information we developed models of CR production efficiency based on the Frank-Tamm equation and models of CR distribution based on Monte-Carlo simulations of photon and ß particle transport. All models were validated against direct measurements using multiple radionuclides and then applied to a number of radionuclides commonly used in biomedical applications. We show that two radionuclides, Ac-225 and In-111, which have been reported to produce CR in water, do not in fact produce CR directly. We also propose a simple means of using this information to calibrate high sensitivity luminescence imaging systems and show evidence suggesting that this calibration may be more accurate than methods in routine current use.

Salivary gland side effects commonly develop several weeks after initial radioactive iodine ablation.

UNLABELLED: Salivary gland side effects (SSEs) can be a source of significant morbidity in thyroid cancer patients receiving radioactive iodine (RAI) for remnant ablation or therapy. However, the incidence, time course, and ultimate resolution of SSEs that develop in the first few months after a single administered activity of RAI for remnant ablation has not be adequately defined. METHODS: We retrospectively reviewed the clinical records of patients after RAI remnant ablation (RRA) to determine the incidence of salivary gland-related side effects reported within the first year of RRA, the dose-response relationship between administered activity and specific SSEs, and the incidence of specific SSEs based on the method of preparation for remnant ablation (recombinant human thyroid-stimulating hormone [rhTSH] vs. traditional thyroid hormone withdrawal [THW]). RESULTS: SSEs were reported within the first year of RAI ablation in 39% of a cohort of 262 patients (66% women, 93% papillary thyroid cancer; median dose, 5,217 MBq [141 mCi]). Persistent side effects were noted after a median of 7 y in 5% or less of the entire cohort. However, when side effects developed in patients during the first year, the incidence of persistence of the symptom at last follow-up ranged from 5% to 13%. A statistically significant dose response was seen between administered activity of RAI and development of salivary gland swelling (P = 0.001, logistic dose-response curve) but not with dry mouth (P = 0.63), altered taste (P = 0.27), or salivary gland pain (P = 0.152). SSEs developed in 14% of patients receiving administered activities of 1,110 MBq (30 mCi); administered activities of 2,775 MBq (75 mCi) or more were associated with symptoms in 40% of patients (P = 0.046). Despite receiving a statistically higher administered activity (5,661 +/- 2,997 MBq [153 +/- 81 mCi] for THW vs. 4,958 +/- 2,294 MBq [134 +/- 62 mCi] for rhTSH), THW was associated with a lower rate of salivary gland swelling than the rhTSH preparation (20% vs. 10%; P = 0.017), without differences in the development of dry mouth, altered taste, or salivary gland pain. CONCLUSION: Although SSEs occurred in 39% of patients after routine RRA, they were usually transient, so that the overall incidence of persistent side effects at a median follow-up of 7 y was only 5%. Even though the risk for persistent side effects is rather small, these data do emphasize the need to select patients carefully for RRA who are thought to be at moderate to high risk for recurrence and to use the minimally effective dose of RAI activity, in an attempt to maximize the potential benefit while minimizing the risk for adverse events for an individual patient.

Prediction of absorbed dose to normal organs in thyroid cancer patients treated with 131I by use of 124I PET and 3-dimensional internal dosimetry software.

UNLABELLED: The objective of this work was to determine normal organ (131)I dosimetry in patients undergoing radioiodide therapy for thyroid cancer by use of serial scanning with (124)I PET. METHODS: A total of 26 patients who had papillary and follicular metastatic thyroid cancer and who were already enrolled in a Memorial Sloan-Kettering Cancer Center (131)I thyroid cancer protocol were selected for this study. Imaging before (131)I therapy consisted of multiple, whole-body (124)I PET studies over a period of 2-8 d, an (18)F-FDG PET scan and, for some, a diagnostic CT scan. With a set of in-house-developed software tools (3-dimensional internal dosimetry [3D-ID] and Multiple Image Analysis Utility [MIAU]), the following procedures were performed: all PET emission and transmission and CT image sets were aligned; half-life-corrected tomographic images of (131)I activity were integrated voxel by voxel to produce cumulated (131)I activity images; and the latter images were, in turn, convolved with a (131)I electron-photon point kernel to produce images of (131)I dose distribution. Cumulated activity values and calculated residence times obtained from our patient-specific dosimetry software (3D-ID) were used as inputs to OLINDA, and volume difference-adjusted comparisons were made between the mean dose estimates. RESULTS: With 3D-ID, dose volume histograms and mean doses were calculated for 14 organs, and results were expressed in Gy/GBq. The highest mean dose, 0.26 Gy/GBq, was seen in the right submandibular gland, whereas the lowest mean dose, 0.029 Gy/GBq, was seen in the brain. CONCLUSION: This is the first comprehensive study of normal organ dosimetry in patients by use of a quantitative tomographic imaging modality.

The Role of Iodine-124-Positron Emission Tomography Imaging in the Management of Patients with Thyroid Cancer.

Molecular imaging is the visualization, characterization, and measurement of biologic processes at the molecular and cellular levels in human beings and other living systems. In thyroid cancer, this includes imaging iodine transport, which is active in about 80% of well-differentiated thyroid malignancies. Iodine-124 imaging with positron emission tomography (I-124-PET) is ideal for this purpose because PET provides tomographic images with spatial and contrast resolution. Because iodine-131 is the mainstay for therapy in thyroid cancer, and because success or failure of therapy depends on the degree of iodine uptake by the tumor cells, I-124-PET imaging will increasingly act as a surrogate for this treatment. This approach may serve as a model for individualized therapeutic interventions for many other malignant and nonmalignant diseases.

PET-based radiation dosimetry in man of 18F-fluorodihydrotestosterone, a new radiotracer for imaging prostate cancer.

UNLABELLED: 16 beta-fluoro-5 alpha-dihydrotestosterone (FDHT) is a promising new PET radiopharmaceutical for the imaging of prostate cancer. A recent clinical trial provided the opportunity for refinement of normal-tissue radiation-absorbed dose estimates based on quantitative PET. The objective of the current study was to derive estimates of normal-tissue absorbed doses for (18)F-FDHT administered to patients with advanced prostate cancer. METHODS: Absorbed dose estimates were derived from 10 (18)F-FDHT PET studies (administered activity, 111-407 MBq) of 7 prostate cancer patients. Activity concentrations in plasma and red marrow (assuming a plasmacrit of 0.58, an extracellular fluid fraction of 0.40, and equilibration of activity between plasma and marrow extracellular fluid) were measured ex vivo from a peripheral blood sample. Liver, spleen, urinary bladder contents, and total-body activities were measured by region-of-interest analysis of quantitative whole-body studies acquired with a dedicated PET scanner. Total organ activities and residence times were calculated from the respective PET scan-derived activity concentrations assuming standard (70 kg) man organ masses. Urinary excretion was corrected for hepatobiliary excretion (liver activity), and a first-order adjustment was made for the bladder-wall mass based on the patient's total-body mass. Mean organ absorbed doses were calculated with the MIRD formalism and the standard man model using the MIRDOSE3 software program. RESULTS: The absorbed doses (mean +/- SD) ranged from 0.00057 +/- 0.000281 cGy/MBq (to skin) to 0.00868 +/- 0.00481 cGy/MBq (to bladder wall) (voiding intervals, 1-2 h), and the effective dose equivalent was 0.00177 +/- 0.000152 cSv/MBq. CONCLUSION: The maximum absorbed dose among all tissues in all 10 studies, 0.0151 cGy/MBq, occurred for the urinary bladder wall (with hydration and 1- to 2-h voiding intervals). To ensure that the maximum normal-tissue absorbed dose is kept below the recommended maximum permissible dose of 5 cGy per single administration, a maximum administered activity of 331 MBq (5 cGy/[0.0151 cGy/MBq]) is recommended for (18)F-FDHT.

Patient-specific dosimetry for 131I thyroid cancer therapy using 124I PET and 3-dimensional-internal dosimetry (3D-ID) software.

UNLABELLED: Compared with conventional, whole-organ, S-factor-based dosimetry, 3-dimensional (3D), patient-specific dosimetry better accounts for radionuclide distribution and anatomic patient variability. Its accuracy, however, is limited by the quality of the cumulated activity information that is provided as input. This input has typically been obtained from SPECT and planar imaging studies. The objective was to implement and evaluate PET-based, patient-specific, 3D dosimetry for thyroid cancer patients. METHODS: Three to 4 PET imaging studies were obtained over a 7-d period in 15 patients with metastatic thyroid carcinoma after administration of (124)I-NaI. Subsequently, patients were treated with (131)I on the basis of established clinical parameters. Retrospective dosimetry was performed using registered (124)I PET images that were corrected for the half-life difference between (124)I and (131)I. A voxel-by-voxel integration, over time, of the resulting (131)I-equivalent PET-derived images was performed to provide a single 3D dataset representing the spatial distribution of cumulated activity values for each patient. Image manipulation and registration were performed using Multiple Image Analysis Utility (MIAU), a software package developed previously. The software package, 3D-Internal Dosimetry (3D-ID), was used to obtain absorbed dose maps from the cumulated activity image sets. RESULTS: Spatial distributions of absorbed dose, isodose contours, dose-volume histograms (DVHs), and mean absorbed dose estimates were obtained for a total of 56 tumors. Mean absorbed dose values for individual tumors ranged from 1.2 to 540 Gy. The absorbed dose distribution within individual tumors was widely distributed ranging from a minimum of 0.3 to a maximum of 4,000 Gy. CONCLUSION: (124)I PET-based, patient-specific 3D dosimetry is feasible, and sequential PET can be used to obtain cumulated activity images for 3D dosimetry.

Quantitative imaging of bromine-76 and yttrium-86 with PET: a method for the removal of spurious activity introduced by cascade gamma rays.

Positron Emission Tomography of bromine-76 and yttrium-86 results in the detection of coincident events that are not strictly associated with annihilation photon pairs. Instead, these coincidences occur because prompt gamma rays emitted by these nuclides result in cascades of photons that are emitted within the timing window of the PET scanner. Pairs of detected photons from these cascades are not angularly correlated and therefore contain little information regarding the location of their source. Furthermore, these coincidences are not removed by correction procedures (e.g., randoms, scatter) routinely applied to PET data. If left uncorrected, the cascade coincidences will result in spurious apparent activity within the PET images. A correction, applied within projection space, that removes the cascade coincidence signal from septa-in (i.e., two-dimensional) datasets is proposed and tested on phantom data.

A retrospective review of the effectiveness of recombinant human TSH as a preparation for radioiodine thyroid remnant ablation.

UNLABELLED: Radioiodine remnant ablation (RRA) is frequently used after a thyroidectomy for differentiated thyroid carcinoma because it has been reported to reduce the number of local recurrences and to increase overall survival. Although the traditional method of preparation for RRA is thyroid hormone withdrawal, several physicians at our medical center have offered the option of having RRA after preparation by recombinant human thyroid-stimulating hormone (thyrotropin; TSH) over the past 2 y. During this same time period, other patients at our center were prepared for RRA by hormone withdrawal. METHODS: We took this opportunity to retrospectively review the rate of complete remnant ablation in patients having RRA after hormone withdrawal compared with those having RRA after recombinant human TSH. Only patients who had RRA after January 1, 1999, and follow-up diagnostic studies at our medical center, were included in the analysis. A successful ablation was defined as no visible radioiodine uptake on the follow-up diagnostic scans, performed with 185 MBq (5 mCi) (131)I. The 2 groups had comparable patient and tumor characteristics and received similar ablative activities of (131)I. RESULTS: We found that 84% of those prepared by recombinant human TSH, and 81% of those prepared by hormone withdrawal, had complete resolution of visible thyroid bed uptake after RRA (P = not significant). CONCLUSION: Given the biases that exist in retrospective studies, we cannot yet recommend RRA preparation by recombinant human TSH for routine use. However, these preliminary findings are favorable enough to support the design of a prospective randomized trial comparing RRA success rates after preparation by either thyroid hormone withdrawal or recombinant human TSH.