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Background: Cytopathological evaluation of thyroid fine-needle aspiration biopsy (FNAB) specimens can fail to raise preoperative suspicion of medullary thyroid carcinoma (MTC). The Afirma RNA-sequencing MTC classifier identifies MTC among FNA samples that are cytologically indeterminate, suspicious, or malignant (Bethesda categories III-VI). In this study we report the development and clinical performance of this MTC classifier. Methods: Algorithm training was performed with a set of 483 FNAB specimens (21 MTC and 462 non-MTC). A support vector machine classifier was developed using 108 differentially expressed genes, which includes the 5 genes in the prior Afirma microarray-based MTC cassette. Results: The final MTC classifier was blindly tested on 211 preoperative FNAB specimens with subsequent surgical pathology, including 21 MTC and 190 non-MTC specimens from benign and malignant thyroid nodules independent from those used in training. The classifier had 100% sensitivity (21/21 MTC FNAB specimens correctly called positive; 95% confidence interval [CI] = 83.9-100%) and 100% specificity (190/190 non-MTC FNAs correctly called negative; CI = 98.1-100%). All positive samples had pathological confirmation of MTC, while all negative samples were negative for MTC on surgical pathology. Conclusions: The RNA-sequencing MTC classifier accurately identified MTC from preoperative thyroid nodule FNAB specimens in an independent validation cohort. This identification may facilitate an MTC-specific preoperative evaluation and resulting treatment.

Item does not contain fulltext Background: The American Thyroid Association (ATA), the European Association of Nuclear Medicine, the European Thyroid Association, and the Society of Nuclear Medicine and Molecular Imaging have established an intersocietal working group to address the current controversies and evolving concepts in thyroid cancer management and therapy. The working group annually identifies topics that may significantly impact clinical practice and publishes expert opinion articles reflecting intersocietal collaboration, consensus, and suggestions for further research to address these important management issues. Summary: In 2019, the intersocietal working group identified the following topics for review and interdisciplinary discussion: (i) perioperative risk stratification, (ii) the role of diagnostic radioactive iodine (RAI) imaging in initial staging, and (iii) indicators of response to RAI therapy. Conclusions: The intersocietal working group agreed that (i) initial patient management decisions should be guided by perioperative risk stratification that should include the eighth edition American Joint Committee on Cancer staging system to predict disease specific mortality, the modified 2009 ATA risk stratification system to estimate structural disease recurrence, with judicious incorporation of molecular theranostics to further refine management recommendations; (ii) diagnostic RAI scanning in ATA intermediate risk patients should be utilized selectively rather than being considered mandatory or not necessary for all patients in this category; and (iii) a consistent semiquantitative reporting system should be used for response evaluations after RAI therapy until a reproducible and clinically practical quantitative system is validated.

Background: Gene panels are routinely used to assess predisposition to hereditary cancers by simultaneously testing multiple susceptibility genes and/or variants. More recently, genetic panels have been implemented as part of solid tumor malignancy testing assessing somatic alterations. One example is targeted variant panels for thyroid nodules that are not conclusively malignant or benign upon fine-needle aspiration (FNA). We systematically reviewed published studies from 2009 to 2018 that contained genetic data from preoperative FNA specimens on cytologically indeterminate thyroid nodules (ITNs) that subsequently underwent surgical resection. Pooled prevalence estimates per gene and variant, along with their respective positive predictive values (PPVs) for malignancy, were calculated. Summary: Our systematic search identified 540 studies that were supplemented by 18 studies from bibliographies or personal files. Sixty-one studies met all inclusion criteria and included >4600 ITNs. Overall, 26% of nodules contained at least 1 variant or fusion. However, half of them did not include details on the specific gene, variant, and/or complete fusion pair reported for inclusion toward PPV calculations. The PPVs of genomic alterations reported at least 10 times were limited to BRAFV600E (98%, 95% confidence interval [CI 96–99%]), PAX8/PPARG (55% [CI 34–78%]), HRASQ61R (45% [CI 22–72%]), BRAFK601E (42% [CI 19–68%]), and NRASQ61R (38% [CI 23–55%]). Excluding BRAFV600E, the pooled PPV for all other specified variants and fusions was 47%. Multiple variants within the same nodule were identified in ∼1% of ITN and carried a cumulative PPV of 77%. Conclusions: The chance that a genomic alteration predicts malignancy depends on the individual variant or fusion detected. Only five alterations were reported at least 10 times; BRAFV600E had a PPV of 98%, while the remaining four had individual PPVs ranging from 38% to 55%. The small sample size of most variants and fusion pairs found among ITNs, however, limits confidence in their individual PPV point estimates. Better specific reporting of genomic alterations with cytological category, histological subtype, and cancer staging would facilitate better understanding of cancer prediction, and the independent contribution of the genomic profile to prognosis.

RAS mutations are common in the available mutational analysis of cytologically indeterminate (Cyto-I) thyroid nodules. However, their reported positive predictive value (PPV) for cancer is widely variable. The reason for this variability is unknown, and it causes clinical management uncertainty. A systematic review was performed, evaluating the PPV for cancer in RAS mutation positive Cyto-I nodules, and variables that might affect residual heterogeneity across the different studies were considered.PubMed was searched through February 22, 2017, including studies that evaluated at least one type of RAS mutation in Cyto-I nodules, including any (or all) of the Bethesda III/IV/V categories or their equivalents and where the histological diagnosis was available. The PPV residual heterogeneity was investigated after accounting for Bethesda classification, blindedness of the histopathologist to the RAS mutational status, Bethesda category-specific cancer prevalence for each study, and which RAS genes and codons were tested. This was studied using five meta-regression models fit to different sets of Bethesda classification categories: Bethesda III, IV, or V (III/IV/V); Bethesda III or IV (III/IV); Bethesda III only; Bethesda IV only; and Bethesda V only.Of 1831 studies, 23 were eligible for data inclusion. Wide ranges of PPV were found at 0-100%, 28-100%, and 0-100% in Bethesda III, IV, and V, respectively. Residual heterogeneity remained moderately high for PPV after accounting for the above moderators for Bethesda III/IV/V (21 studies; IThe PPV of RAS mutations in Bethesda III and IV categories is quite heterogeneous across different studies, creating low confidence in the accuracy of a single estimate of PPV. Clinicians must appreciate this wide variability when managing a RAS-mutated Cyto-I nodule. Future studies should seek to resolve this unexplained variability.

The aim of this study was to demonstrate the analytical validity of an RNA classifier for medullary thyroid carcinoma (MTC).Fresh-frozen tissue specimens were obtained from commercial sources, and MTC diagnoses were confirmed by histopathology review. De-identified patient fine-needle aspiration biopsies (FNABs) and whole blood from normal donors were obtained. Total RNA was extracted, amplified, and hybridized to custom microarrays for gene expression analysis. Gene expression data were normalized and classified via a machine learning algorithm. Positive control materials were produced from MTC tissues and tested across multiple experiments and laboratories. Twenty-seven MTC tissue specimens were used to evaluate the sensitivity of the MTC classifier. Gene expression data from tissues and FNABs were used to model classifier response to mixtures of MTC samples with normal thyroid tissue, a benign thyroid nodule, a Hürthle cell adenoma, and whole blood. Select mixture conditions were confirmed in vitro. Assay tolerance to RNA input variation (5-25 ng) and genomic DNA contamination (30% by mass) was evaluated. The intra- and inter-run reproducibility and inter-laboratory accuracy of MTC classifier results were characterized.The MTC classifier sensitivity of 96.3% [confidence interval 81.0-99.9%] was determined retrospectively using 27 MTC confirmed tissue specimens. One false-negative result in a necrotic tissue implicated sample necrosis in reduced classifier sensitivity. Dilution modeling of MTC samples with normal or benign tissues showed consistent detection of MTC down to 20% sample proportions, with in vitro confirmation of 20% analytical sensitivity. Classifier tolerance to RNA input variation (5-25 ng), genomic DNA contamination (30% by mass), and an interfering substance (blood) was demonstrated with 100% accurate classifier results under all tested conditions. The maximum observed run-to-run score difference for a single FNAB sample was ∼1 unit compared with the average score difference between 38 MTC and non-MTC FNABs of ∼32 units. MTC classifier results for 20 tissues processed from total RNA in two different laboratories showed 100% concordance.The MTC classifier, offered as part of the routine molecular testing of cytology-indeterminate thyroid nodules, demonstrates robust analytical sensitivity, specificity, accuracy, and reproducibility.

Background: Treatment options for patients with advanced or metastatic medullary thyroid cancer (MTC) have, in recent years, expanded with the approval of two tyrosine kinase inhibitors (TKIs): vandetanib and cabozantinib. Other agents, including TKIs, are under clinical investigation for MTC. Although patients treated with TKIs are at risk of developing dermatologic adverse events (AE), these untoward events may be mitigated through AE-driven algorithms. Summary: AE-driven algorithms combine effective nonpharmaceutical and pharmaceutical treatment modalities implemented by a multidisciplinary effort that incorporates nursing interventions, patient education, and referrals to pain-management specialists, podiatrists, and dermatologists, as appropriate. Effective AE prevention and management reduce the need for dose interruptions and modifications, allowing patients the opportunity to derive the maximal benefit from TKI therapy, while maintaining quality of life. Conclusions: Optimal use of targeted therapies in the treatment of MTC depends on careful patient selection, interdisciplinary communication, and patient education and encouragement to enhance compliance and safety, optimize consistent dosing, and maximize the use of effective therapies.

Micro-single-photon emission computed tomography (SPECT) provides a noninvasive way to evaluate the effects of genetic and/or pharmacological modulation on sodium-iodide symporter (NIS)-mediated radionuclide accumulation in mouse thyroid and salivary glands. However, parameters affecting image acquisition and analysis of mouse thyroids and salivary glands have not been thoroughly investigated. In this study, we investigated the effects of region-of-interest (ROI) selection, collimation, scan time, and imaging orbit on image acquisition and quantification of thyroidal and salivary radionuclide accumulation in mice.The effects of data window minima and maxima on thyroidal and salivary ROI selection using a visual boundary method were examined in SPECT images acquired from mice injected with (123)I NaI. The effects of collimation, scan time, and imaging orbit on counting linearity and signal intensity were investigated using phantoms filled with various activities of (123)I NaI or Tc-99m pertechnetate. Spatial resolution of target organs in whole-animal images was compared between circular orbit with parallel-hole collimation and spiral orbit with five-pinhole collimation. Lastly, the inter-experimental variability of the same mouse scanned multiple times was compared with the intra-experimental variability among different mice scanned at the same time.Thyroid ROI was separated from salivary glands by empirically increasing the data window maxima. Counting linearity within the range of 0.5-14.2 μCi was validated by phantom imaging using single- or multiple-pinhole collimators with circular or spiral imaging orbit. Scanning time could be shortened to 15 minutes per mouse without compromising counting linearity despite proportionally decreased signal intensity. Whole-animal imaging using a spiral orbit with five-pinhole collimators achieved a high spatial resolution and counting linearity. Finally, the extent of inter-experimental variability of NIS-mediated radionuclide accumulation in the thyroid and salivary glands by SPECT imaging in the same mouse was less than the magnitude of variability among the littermates.The impacts of multiple variables and experimental designs on micro-SPECT imaging and quantification of radionuclide accumulation in mouse thyroid and salivary glands can be minimized. This platform will serve as an invaluable tool to screen for pharmacologic reagents that differentially modulate thyroidal and salivary radioiodine accumulation in preclinical mouse models.

The role of prophylactic central lymph node dissection in papillary thyroid cancer (PTC) is controversial in patients who have no pre- or intraoperative evidence of nodal metastasis (clinically N0; cN0). The controversy relates to its unproven role in reducing recurrence rates while possibly increasing morbidity (permanent hypoparathyroidism and unintentional recurrent laryngeal nerve injury).We examined the design and feasibility of a multi-institutional prospective randomized controlled trial of prophylactic central lymph node dissection in cN0 PTC. Assuming a 7-year study with 4 years of enrollment, 5 years of average follow-up, a recurrence rate of 10% after 7 years, a 25% relative reduction in the rate of the primary endpoint (newly identified structural disease; i.e., persistent, recurrent, or distant metastatic disease) with central lymph node dissection and an annual dropout rate of 3%, a total of 5840 patients would have to be included in the study to achieve at least 80% statistical power. Similarly, given the low rates of morbidity, several thousands of patients would need to be included to identify a significant difference in rates of permanent hypoparathyroidism and unintentional recurrent laryngeal nerve injury.Given the low rates of both newly identified structural disease and morbidity after surgery for cN0 PTC, prohibitively large sample sizes would be required for sufficient statistical power to demonstrate significant differences in outcomes. Thus, a prospective randomized controlled trial of prophylactic central lymph node dissection in cN0 PTC is not readily feasible.

Acute suppurative thyroiditis (AST) resulting from a bacterial infection is an infrequent but potentially life-threatening endocrine emergency. Traditional management of this disease has been surgery in conjunction with targeted antibiotic therapy. Recent nonrandomized reports of small series have demonstrated good outcomes using less invasive approaches. No randomized clinical trials have been performed. Here, we provide a review of the literature and an approach to this problem based on expert opinion.The literature was reviewed utilizing PubMed, and a representative case of AST was presented to a panel of experts. Endocrinology, surgery, and infectious disease experts responded to a series of questions regarding diagnosis, management, prognosis, and harm.Combining a broad spectrum of clinical expertise and the published literature, the authors suggest a clinical algorithm as a guide to management, addressing both diagnosis and acute and long-term management.Published studies indicate a trend toward less invasive management during active inflammation and infection and regarding definite therapy. Remaining questions are presented to foster an evidence-based approach to this disease. Ideally, future randomized, controlled trials will provide data to improve the therapy and outcome of AST.

Background: Thyroid nodules are a common clinical problem, and differentiated thyroid cancer is becoming increasingly prevalent. Since the publication of the American Thyroid Association's guidelines for the management of these disorders was published in 2006, a large amount of new information has become available, prompting a revision of the guidelines. Methods: Relevant articles through December 2008 were reviewed by the task force and categorized by topic and level of evidence according to a modified schema used by the United States Preventative Services Task Force. Results: The revised guidelines for the management of thyroid nodules include recommendations regarding initial evaluation, clinical and ultrasound criteria for fine-needle aspiration biopsy, interpretation of fine-needle aspiration biopsy results, and management of benign thyroid nodules. Recommendations regarding the initial management of thyroid cancer include those relating to optimal surgical management, radioiodine remnant ablation, a...

Background: The primary goals of this interdisciplinary consensus statement are to review the relevant anatomy of the central neck compartment, to identify the nodal subgroups within the central compartment commonly involved in thyroid cancer, and to define a consistent terminology relevant to the central compartment neck dissection. Summary: The most commonly involved central lymph nodes in thyroid carcinoma are the prelaryngeal (Delphian), pretracheal, and the right and left paratracheal nodal basins. A central neck dissection includes comprehensive, compartment-oriented removal of the prelaryngeal and pretracheal nodes and at least one paratracheal lymph node basin. A designation should be made as to whether a unilateral or bilateral dissection is performed and on which side (left or right) in unilateral cases. Lymph node “plucking” or “berry picking” implies removal only of the clinically involved nodes rather than a complete nodal group within the compartment and is not recommended. A therapeutic cen...

Adenoviral gene therapy represents a novel approach for the treatment of aggressive thyroid carcinomas. Both coxsackie-adenovirus receptor (CAR) and integrins have been shown to be the major determinants for adenoviral infectivity in many types of cancer cells, yet conflicting results have been reported. In this report we examine these factors mediating adenoviral infection in thyroid cells and to evaluate CAR expression in various types of thyroid cancer. We found that neither expression levels of CAR nor integrins are solely predictive of adenoviral infectivity in thyroid cells. However, the absence of CAR was associated with poor adenoviral infectivity in immortalized rat FRTL-5 cells. Moreover, preincubation with alpha-CAR antibody decreased infectivity in FTC 238 cells, a human thyroid tumor line. These results indicate that CAR does play a role in adenoviral infection of thyroid cells. Immunohistochemical analysis revealed that CAR is expressed at the cell surface in the majority of malignant thyroid tumors. We further show that adenoviral infectivity in some thyroid cancer cells can be improved by poly-L-lysine. Our study warrants a functional method to evaluate adenoviral infectivity should be developed and instituted prior to clinical trials of adenoviral gene therapy in patients with advanced thyroid cancer.

Molecular markers of papillary thyroid carcinoma (PTC) are relatively unknown. Recently, the CITED1 gene was reported to be greatly upregulated in PTC relative to normal thyroid. The CITED1 protein, a 27-kd transcriptional transactivator nuclear protein is expressed in PTC, melanocytes, breast epithelial cells, and several embryonic tissues. However, its expression in other thyroid masses and non-thyroid tumors is not known. We evaluated CITED1 protein expression in tissue microarrays comprising various thyroid and nonthyroid tissues by immunohistochemistry using a polyclonal anti-CITED1 antibody. CITED1 expression was seen in 63 of 68 PTC (93%), 3 of 12 follicular carcinomas (25%), 2 of 7 Hürthle cell carcinomas (28%), 2 of 21 adenomas (10%), 2 of 6 follicular neoplasms of undetermined malignant behavior (33%), and 2 of 24 nodular goiters (8%). Normal thyroids (n = 27), thyrotoxic hyperplasias (n = 14), and anaplastic thyroid carcinomas (n = 5) did not express CITED1. Among nonthyroid tumors, 6 of 23 melanomas (26%), 11 of 65 prostatic carcinomas (17%), 3 of 25 glioblastomas (12%), 4 of 67 breast carcinomas (6%), 1 of 49 lymphomas (2%), 1 of 65 lung carcinomas (2%), 1 of 68 colon carcinomas (2%), and none of 49 ovarian carcinomas (0%) expressed CITED1. The accuracy of CITED1 in differentiating PTC from benign thyroid nodules, other thyroid carcinomas, and nonthyroid carcinomas was 93%, 89%, and 94%, respectively. CITED1 is preferentially expressed in PTC and may be used as a diagnostic marker of it.

Fetuses whose mothers are treated with radioiodine after approximately 10–12 weeks of pregnancy are at high risk of developing iatrogenic hypothyroidism (1). Other than this well-documented occurrence, there is no evidence of harm to others from radiation originating from patients treated with radioiodine. Given that radioiodine is concentrated in breast milk and radioiodine has been documented to be taken up by the thyroid in nursing newborns whose mothers were given diagnostic activities of radioiodine (2), discontinuing lactation before radioiodine therapy and avoiding breastfeeding after radioiodine treatment is justified despite the lack of a case report of infantile hypothyroidism ascribed to radioiodine ingestion from breastfeeding. Aside from circumstances relating to pregnancy and lactation, the harm that a radioiodine-treated patient could inflict upon another person while following common sense instructions appears to be low. Patients, who themselves receive a much higher dose of radiation because they ingest the full radioiodine treatment, suffer relatively few side effects. For the most part these occur in tissues that actively take up the radionuclide, and the adverse effects occur in a dose-dependent manner (3). This provides some reassurance that the small amount of radiation exposure to the public from those who receive radioiodine treatment is unlikely to cause harm, even if the treated patients ignore nearly all of the radiation safety instructions they receive. On the other hand, it is known that thyroidal exposure to higher levels of radiation, especially in children, can result in harm (4) and by extrapolation with a linear no-threshold dose–response relationship, one may assume that exposure to low levels of radiation might result in some harm. Thus, this theoretical possibility of increased harm at any increase of radiation exposure beyond background radiation, combined with no evidence of benefit of radiation exposure to the public, has led to the practice of keeping radiation exposure to others As Low As Reasonably Achievable (ALARA). High levels of radiation exposure are dangerous. It has been estimated that half of the people receiving a dose to the whole body over a few minutes to a few hours of between 3500 and 5000 mSv would die within 30 days (multiple mSv by 100 to convert to mrem). Similarly, high-dose exposure (starting somewhere between 100 and 1000 mSv) over a relatively short period of time, is associated with the development of a number of malignancies. Conversely, the average yearly radiation exposure from natural sources to an individual in the United States is approximately 3 mSv. Radon gas accounts for two thirds of this exposure, while cosmic, terrestrial, and internal radiation account for the remainder. No adverse health effects have been demonstrated from these levels of natural radiation exposure. In addition, artificial sources of radiation from medical, commercial, and industrial activities contribute another 0.6 mSv, for a total average yearly radiation exposure of 3.6 mSv. Doses (in mSv) from common medical imaging procedures include the following: bitewing dental x-ray, 0.004; chest x-ray (posterior-anterior), 0.02; lateral lumbar spine x-ray, 0.3; mammography, 0.7; lung ventilation/perfusion scan, 1.5; barium swallow, 1.5; technetium-99m bone scan, 4.4; barium enema, 7; 2-deoxy2[F-18]fluoro-d-glucose positron emission tomography scan, 7; chest or abdominal computed tomography scan, 8-10; and coronary angiogram, 5–16. A personalized annual radiation dose estimate can be calculated at the website http:// www.epa.gov/radiation/understand/calculate.html. Although radiation may cause cancers at high doses and dose rates, currently there are no data that unequivocally establish the occurrence of cancer following exposure to low doses or dose rates (e.g., below about 100 mSv). People living in areas with high levels of background radiation (>10 mSv per year) such as Denver, Colorado, have shown no adverse biological effects. Keep these millisievert values in mind as you read the next paragraph. Effective May 29, 1997, and updated on July 29, 2009, the Nuclear Regulatory Commission (NRC) revised Federal Regulation 10 CFR 35.75, which permits NRC-licensed facilities to release a patient treated with radioiodine from their control if the total effective dose equivalent to any other individual from exposure to the released individual is not likely to exceed 5 mSv. Further, a licensee must provide the released individual, or the individual’s parent or guardian, with instructions (including written instructions) on actions

Radioiodine-concentrating activity in thyroid tissues has allowed the use of radioiodine as a diagnostic and therapeutic agent for patients with thyroid disorders such as well-differentiated thyroid cancer. However, some extrathyroidal tissues also take up radioiodine, contributing to unwanted side effects of radioiodine therapy. Now that the molecule that mediates radioiodine uptake, the sodium iodide symporter (NIS), has been cloned and characterized, it may be possible to develop novel strategies to differentially modulate NIS expression and/or activity, enhancing it in target tissues and impeding it in others. In addition to restoring NIS expression/activity to ensure sufficient radioiodine uptake for the diagnosis and treatment of advanced thyroid cancers, we envision that it may be possible to selectively increase or confer NIS expression/activity in tumors of nonthyroidal tissues to facilitate the use of radioiodine in their diagnosis and treatment. We also consider the molecular basis of thyroid and nonthyroid disorders that may be complicated by NIS deregulation. Finally, we explore the use of NIS as an imaging reporter gene to monitor the expression profile of the transgene in transgenic mouse animal models and in patients undergoing gene therapy clinical trials.

Mortality rates from thyroid cancer have fallen significantly in recent decades, almost certainly as the result of earlier diagnosis and improved treatment of differentiated (papillary and follicular) thyroid cancer. Enhanced survival is likely a result of early diagnosis and therapy applied at a disease stage when treatment is most effective. In the United States and Europe, most patients at high risk for relapse and death from thyroid cancer are treated with total or near-total thyroidectomy and receive radioiodine ablation of residual normal or malignant thyroid tissue, followed by treatment with thyroid hormone, a strategy that cures more than 80% of patients. Still, some die of the disease and nearly 15% have local recurrences, while another 5% to 10% develop distant metastases. Over 50% of recurrences appear in the first five years, but distant metastases may surface years, and sometimes decades, after initial therapy. Much has been learned about risk stratification to predict recurrence and death from thyroid cancer but individual patients continue to have adverse outcomes not always foreseen by a low tumor stage. Follow-up must accordingly be meticulous and prolonged. The National Cancer Center Network (NCCN) has recently established consensus practice guidelines that give explicit advice about the diagnosis and management of benign and malignant thyroid tumors, including paradigms for long-term follow-up and the treatment of recurrent disease. The guidelines confirm that diagnostic scanning with 131I and measurement of serum thyroglobulin (Tg) levels are the mainstay of follow-up, offering the opportunity to detect recurrent or persistent cancer at very early stages. These guidelines advocate TSH-stimulated serum Tg measurements, done either during thyroid hormone withdrawal or stimulation with recombinant human TSH (rhTSH, Thyrogen), that often identify the presence of cancer well before diagnostic whole-body scanning or other imaging studies can spot the tumor, which offers the opportunity to treat recurrent disease at an early stage. The use of rhTSH adds a new dimension to long-term follow-up that avoids putting patients through the symptoms of hypothyroidism, and offers the opportunity to follow some patients with rhTSH-stimulated serum Tg levels without performing 131I whole-body scans. A multicenter international study has shown that serum Tg measurements alone are not as sensitive in the identification of patients with persistent or recurrent tumor as are rhTSH-stimulated serum Tg determinations. Although not yet approved for preparation of patients for 131I therapy, rhTSH has been used successfully in a compassionate use program for this purpose in a relatively large number of patients. Formal clinical investigations now planned to provide guidelines for the use of rhTSH for therapeutic 131I portend a new set of effective therapeutic paradigms for the management of differentiated thyroid cancer.