Radioiodine Uptake In Patients Research Articles

A Case for Lithium Pretreatment Prior to Radioactive Iodine Ablation in Grave’s Disease

Radioactive iodine ablation (RAIA) therapy with Iodine-131 (I-131) is an established treatment for grave’s thyrotoxicosis. However, there is 10 to 20% chance of treatment failure. Lithium, a drug used to treat bipolar disorder, has significant effects on thyroid function. The most clinically relevant is the inhibition of thyroid hormone release. It is also known to inhibit colloid formation, and is involved in blocking organic iodine as well as thyroid hormone release from the thyroid gland without an effect on radioiodine uptake. This leads to increased radioiodine retention in the thyroid gland. Here, we present a case which exemplifies this action of lithium. A 46 year old male with a history of atrial fibrillation and grave’s disease presented to the endocrine clinic. TSH was <0.01 and FT4 was 36. RAI uptake (RAIU) scan showed diffusely increased uptakes with 4 and 24 hour values of 61.2 and 54.6 %. He subsequently underwent RAI ablation with 18 mCi of I 131. He then presented three years later with persistent hyperthyroid symptoms. TSH <0.01 and FT4 4.3. RAIU showed 24-h thyroid uptake of 41%. Patient opted for a second treatment with RAIA and was treated with 30 millicuries of I 131. He however continued to have clinical and biochemical evidence of thyrotoxicosis and was started on methimazole (MMI). Although he was biochemically euthyroid on MMI, he continued to complain of hyperthyroid symptoms such as palpitations, tremors and weight loss. When methimazole was briefly held six months after initiation, TSH was undetectable and FT4 had increased from 0.83 to 1.42. He subsequently underwent a third RAIU off MMI which showed normal 4 and 24 hour uptake, measuring 15.7% and 28% respectively. Patient subsequently opted for third trial of RAI ablation with lithium pretreatment. He declined surgery. He was started on lithium 900mg/day for 6 days, starting on the day of RAI ablation. He underwent RAI ablation with 45 mCi I-131. Patient tolerated the procedure well with subsequent tests indicating hypothyroidism requiring levothyroxine supplementation. Patient’s hyperthyroid symptoms resolved. Several factors affect the efficacy of radioiodide therapy for hyperthyroidism including the short persistence of radioiodide in the thyroid gland. In hyperthyroid Graves’ patients, radioactive iodide uptake is enhanced due to presence of TSH receptor antibody, however, radioiodide is also rapidly discharged because of its increased turnover. Lithium can significantly reduce the release of iodine from the thyroid gland and thus increase iodine retention. There is evidence to suggest that adjuvant lithium can increase thyroidal radioiodine uptake in patients with a low baseline RAIU (< 30%). This case demonstrate that lithium can be used safely prior to RAI therapy in cases of RAI ablation failure even with low baseline RAIU.

In Memoriam: Marvin A. Van Dilla: 1919-2019.

© 2020 International Society for Advancement of Cytometry.

Abstract 920: p97/VCP: A novel interactor of the sodium iodide symporter, which can be pharmacologically targeted to increase radioiodine uptake in thyroid and breast cancer cells

Abstract By exploiting the canonical function of the sodium iodide symporter (NIS), ablative radioiodine therapy is an effective treatment for papillary thyroid cancer (PTC). Unfortunately, ~25% of PTC patients are unable to accumulate therapeutically sufficient radioiodine due to diminished expression and/or altered plasma membrane localization of NIS. Patients with radioiodine-refractory PTC have reduced mean survival times. Radioiodine therapy has been proposed as a viable treatment for breast cancer but is hampered by low levels of membranous NIS localization. Currently, however, the regulation of NIS membrane localization remains ill-defined. Mass spectrometry identified the protein p97/VCP as a novel NIS interactor, which was validated through co-immunoprecipitation and proximity ligation assays. p97 siRNA depletion increased NIS-mediated radioiodine uptake by 97% and 141% in the lentivirally-expressing NIS MDA-MB-231 breast and TPC1 thyroid cancer cell lines respectively (p&amp;lt;0.05), and significantly boosted endogenous NIS function in human primary thyrocytes (p&amp;lt;0.05). Conversely, p97 overexpression significantly repressed NIS function in all cell systems, accompanied by lowered membranous NIS localization (p&amp;lt;0.05), as quantified via cell surface biotinylation assays. We next identified five different allosteric p97 inhibitors - Eeyarestatin-1, NMS-873, Astemizole, Clotrimazole and Ebastine - which were all able to overcome p97 inhibition of NIS function in TPC1 and MDA-MB-231 cell lines lentivirally-expressing NIS, significantly increasing NIS function by at least 100%. TCGA analyses of matched PTCs revealed p97 mRNA expression is highly upregulated in PTC compared to matched normal thyroid (n=58, p&amp;lt;0.05), providing a putative explanation for repressed NIS function. In a wider cohort of 413 PTC patients, high tumoral p97 expression was associated with a worse disease-free survival when compared to low p97 expression (p&amp;lt;0.01, hazard ratio (HR): 2.924 (95% CI, 1.280-6.683)). Strikingly, in patients that did not receive radioiodine, high tumoral p97 expression had no significant effect on disease-free survival (n=136, p=NS, HR: 0.020 (95% CI, 0.000013-31.192)), whereas in patients who received radioiodine, high tumoral p97 expression resulted in a markedly worse disease-free survival (n=194, p&amp;lt;0.01, HR: 6.043 (95% CI, 1.749-20.879)). This is indicative that high p97 expression correlates with a worse response to radioiodine therapy. Our data therefore highlight a new pathway of NIS regulation. Critically, two of these p97 inhibitors are already FDA-approved, highlighting a novel potential therapeutic strategy for enhancing radioiodine uptake in patients with radioiodine-refractory PTC and increasing the feasibility of radioiodine therapy in breast cancer via the transient inhibition of p97 activity. Citation Format: Alice Fletcher, Martin L. Read, Vikki L. Poole, Vicki E. Smith, Christopher J. McCabe. p97/VCP: A novel interactor of the sodium iodide symporter, which can be pharmacologically targeted to increase radioiodine uptake in thyroid and breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 920.

Dabrafenib Induced Radioiodine Uptake in Patients with Metastatic Thyroid Cancer Containing the BRAF Mutation

Clinical ThyroidologyVol. 27, No. 3 SummariesDabrafenib Induced Radioiodine Uptake in Patients with Metastatic Thyroid Cancer Containing the BRAF MutationJerome M. HershmanJerome M. HershmanSearch for more papers by this authorPublished Online:16 Mar 2015https://doi.org/10.1089/ct.2015;27.54-55AboutSectionsView articleView Full TextPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View article"Dabrafenib Induced Radioiodine Uptake in Patients with Metastatic Thyroid Cancer Containing the BRAF Mutation." Clinical Thyroidology, 27(3), pp. 54–55FiguresReferencesRelatedDetails Volume 27Issue 3Mar 2015 InformationCopyright 2015 American Thyroid Association, Inc.To cite this article:Jerome M. Hershman.Dabrafenib Induced Radioiodine Uptake in Patients with Metastatic Thyroid Cancer Containing the BRAF Mutation.Clinical Thyroidology.Mar 2015.54-55.http://doi.org/10.1089/ct.2015;27.54-55Published in Volume: 27 Issue 3: March 16, 2015PDF download

Redifferentiation of iodine-refractory BRAF V600E-mutant metastatic papillary thyroid cancer with dabrafenib.

To determine whether the selective BRAF inhibitor, dabrafenib, can stimulate radioiodine uptake in BRAF V600E-mutated unresectable or metastatic iodine-refractory papillary thyroid cancer (PTC). Ten patients with BRAF V600E-mutant iodine-refractory PTC were enrolled. Absence of radioiodine uptake on iodine-131 whole body scan obtained within 14 months of study entry was required. Each patient received dabrafenib (150 mg twice daily) for 25 days before thyrotropin α-stimulated iodine-131 whole body scan (4 mCi/148 MBq). Patients whose scan showed new sites of radioiodine uptake remained on dabrafenib for 17 more days, and then were treated with 150 mCi (5.5 GBq) iodine-131. The primary endpoint of the study was the percentage of patients with new radioiodine uptake after treatment with dabrafenib. Six of 10 patients (60%) demonstrated new radioiodine uptake on whole body scan after treatment with dabrafenib. All 6 were treated with 5.5 GBq iodine-131. Two patients had partial responses and 4 patients had stable disease on standard radiographic restaging at 3 months. Thyroglobulin decreased in 4 of 6 treated patients. One patient developed squamous cell carcinoma of the skin. There were no other significant adverse events attributed to dabrafenib. Dabrafenib can stimulate radioiodine uptake in patients with metastatic BRAF V600E-mutant iodine-refractory PTC, representing a potential new therapeutic approach for these patients.

Efficacy and Safety of Selumetinib Compared with Current Therapies for Advanced Cancer: a Meta-analysis

Selumetinib is a promising and interesting targeted therapy agent as it may reverse radioiodine uptake in patients with radioiodine-refractory differentiated thyroid cancer. We conduct this meta- analysis to compare the efficacy and safety of selumetinib with current therapies in patients with advanced cancer. An electronic search was conducted using PubMed/ Medicine, EMBASE and Cochrane library databases. Statistical analyses were carried out using either random-effects or fixed-effects models according to the heterogeneity of eligible studies. Six eligible trials involved 601 patients were identified. Compared with current therapies, treatment schedules with selumetinib did not improve progression free survival (hazard ratio, 0.91; 95%CI 0.70-1.17, P= 0.448), but did identify better clinical benefits (odds ratio, 1.24; 95%CI 0.69- 2.24, P = 0.472) and less disease progression (hazard ratio, 0.72; 95%CI 0.51-1.00, P = 0.052) though its impact was not statistically significant. Sub-group analysis resulted in significantly improved progression free survival (hazard ratio, 0.61; 95%CI 0.49-0.57, P = 0.00), clinical benefits (odds ratio, 3.04; 95%CI 1.60-5.77, P = 0.001) and reduced disease progression (hazard ratio, 0.35; 95%CI 0.18-0.67, P = 0.001) in patients administrated selumetinib. Dermatitis acneiform (risk ratio, 9.775; 95%CI 3.143-30.395, P = 0.00) and peripheral edema (risk ratio, 2.371; 95%CI 1.690-3.327, P = 0.00) are the most frequently observed adverse effects associated with selumetinib. Compared with current chemotherapy, selumetinib has modest clinical activity as monotherapy in patients with advanced cancer, but combinations of selumetinib with cytotoxic agents in patients with BRAF or KRAS mutations hold great promise for cancer treatment. Dermatitis acneiform and peripheral edema are the most frequently observed adverse effects in patients with selumetinib.

Recombinant Human Thyrotropin in Veterinary Medicine: Current Use and Future Perspectives

Recombinant human thyrotropin (rhTSH) was developed after bovine thyrotropin (bTSH) was no longer commercially available. It was approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) as an aid to diagnostic follow-up of differentiated thyroid carcinoma in humans and for thyroid remnant ablation with radioiodine. In addition, rhTSH is used in human medicine to evaluate thyroid reserve capacity and to enhance radioiodine uptake in patients with metastatic thyroid cancer and multinodular goiter. Likewise, rhTSH has been used in veterinary medicine over the last decade. The most important veterinary use of rhTSH is thyroidal functional reserve testing for the diagnosis of canine hypothyroidism. Recent pilot studies performed at Ghent University in Belgium have investigated the use of rhTSH to optimize radioiodine treatment of canine thyroid carcinoma and feline hyperthyroidism. Radioiodine treatment optimization may allow a decreased therapeutic dosage of radioiodine and thus may improve radioprotection. This review outlines the current uses of rhTSH in human and veterinary medicine, emphasizing research performed in dogs and cats, as well as potential future applications.

Level VI Lymph Node Dissection Does Not Decrease Radioiodine Uptake in Patients Undergoing Radioiodine Ablation for Differentiated Thyroid Cancer

In patients with well-differentiated thyroid cancer, the incidence of pathologic central compartment lymph node metastases is reported to be approximately 50%. Recently level VI lymph node dissection has been advocated as a means of reducing recurrence rates in these patients, even if there are no clinically apparent nodal metastases. This study investigates whether level VI lymph node dissection decreases the percent radioiodine uptake when patients undergo radioiodine ablation. All thyroid cancer patients entered into the endocrine surgery database at a tertiary care center from 2006 to 2010 were reviewed. Those treated with radioactive iodine were analyzed with respect to performance of a central compartment lymph node dissection and the percent uptake of radioiodine ((131)I) on the preablation scan at 72h. There were 277 patients with well-differentiated thyroid cancer who underwent radioiodine ablation. In all, 75% were female, and the mean age was 47.7years. A total of 87 patients underwent total thyroidectomy and level VI lymph node dissection (TT+LVIND). The mean number of level VI nodes resected was 6 (1-27), and 60.9% of patients had nodal metastases. Altogether, 190 had a total thyroidectomy (TT) only, and the median number of nodes resected was 0 (0-10). The percent uptake of radioiodine on the preablation scan was 0.93% in patients who had undergone TT+LVIND and 1.2% in those with TT alone (p=0.17). The median number of radioactive foci noted within the thyroid bed was two in both groups (p=0.64). The mean preablation thyroglobulin levels, measured after thyroxine withdrawal or thyrogen stimulation, were 4.0ng/ml in the TT+LVIND group versus 4.7ng/ml in the TT group (p=0.07). The average ablative dose of (131)I was 111.8mCi in the dissection group and 98.5mCi in the TT-only group. There is no evidence that uptake of (131)I is reduced by performance of a central neck dissection in patients with well-differentiated thyroid cancer. Preablation thyroglobulin levels were not altered by level VI lymph node dissection.

Serum thyroxine and age — rather than thyroid volume and serum TSH — are determinants of the thyroid radioiodine uptake in patients with nodular goiter

Radioiodine (131I) therapy is widely used for treatment of non-toxic goiters. A limitation for this treatment is a low thyroid radioiodine uptake (RAIU), often encountered in these patients. To estimate the impact of various factors on the thyroid RAIU. We examined prospectively 170 patients (146 females; age range: 22-87 yrs) with nodular goiter (median 64 ml, range: 20-464 ml) selected for 131I therapy. Serum TSH was sub-normal in 42.4%. None were treated with anti-thyroid drugs. The thyroid RAIU was determined at 24h and 96 h. The goiter volume was measured by ultrasound (no.=127), or by magnetic resonance imaging (no.=43). The 24h and the 96 h RAIU were 34.2 ± 9.8(SD)% (range: 11.4-66.0%) and 34.0 ± 10.0% (range: 10.5-60.9%), respectively. Sixty-one patients had a 24h RAIU <30% and these individuals were older than patients with a 24h RAIU ≥ 30% (median 58 vs 51 yrs, p=0.02). These two subgroups did not differ significantly in other variables. Overall, the 24h RAIU was positively correlated to the serum (s) free T4-index (r=0.20, p=0.01), and negatively to age (r=-0.18, p=0.02), but not significantly related to serum TSH or thyroid volume. Age correlated positively with thyroid volume (r=0.31, p < 0.001). In a regression analysis, s-free T4-index and age remained as the only determinants of the 24h and the 96 h RAIU. In patients with a symptomatic nodular goiter, serum T4 and age are the major determinants of the thyroid RAIU. A sub-normal serum TSH is not a marker of a compromised thyroid RAIU but reflects that the iodine is confined to a few 'hot spots'.

Recombinant Human Thyrotropin-Assisted Radioiodine Therapy for Patients with Metastatic Thyroid Cancer Who Could Not Elevate Endogenous Thyrotropin or Be Withdrawn from Thyroxine

The value of recombinant human thyrotropin (rhTSH) as preparation for radioiodine therapy was assessed in 115 patients with metastatic thyroid cancer. Patients who were either unable to elevate endogenous TSH during thyroxine withdrawal, or in whom thyroxine withdrawal was contraindicated for medical reasons were eligible. Their physicians requested rhTSH as part of the Thyrogen Compassionate Use Program. This is a retrospective summary of the nonrandomized uncontrolled experience. We assessed the ability of rhTSH to elevate the serum TSH; to avoid the complications of hypothyroidism; to stimulate radioiodine uptake; and to stimulate the serum thyroglobulin. Disease response and adverse events were also assessed. After rhTSH, the serum TSH levels rose to >or=25mU/L in every patient in whom levels were measured (n = 112). Hypothyroid complications were avoided in 22 of 25 patients who had experienced them in the past, and in 47 of 51 patients who were at high risk for hypothyroid complications. Radioiodine uptake was present on whole-body scans (WBS) in 105 of the 115 patients. Serum thyroglobulin levels were lower than baseline in 73% of patients assessed at 12 months. Cancer-related symptoms were improved in approximately 25%. Two patients had serious adverse events that were thought to be related to rhTSH. rhTSH elevates serum TSH and facilitates radioiodine uptake in patients who cannot produce endogenous TSH or who cannot tolerate hypothyroidism.

A phase II study using retinoids as redifferentiation agents to increase iodine uptake in metastatic thyroid cancer

Radio-iodine is effective in treating metastatic differentiated thyroid cancers. In 20% of cases, however, these tumours fail to take up radio-iodine, and treatment options are then limited. Failure of iodine uptake might be reversible using redifferentiating agents. Retinoids redifferentiate a variety of cell types and increase iodine uptake in thyroid tumour cells in vitro. The aim of this study was to assess whether oral isotretinoin could increase radio-iodine uptake in patients with iodine-uptake-negative metastatic thyroid cancer. Patients who had iodine-uptake-negative metastatic papillary or follicular thyroid cancers were selected from the thyroid database at The Royal Marsden Hospital and enrolled to an open-label, non-randomised phase II trial. Sites of metastatic disease were assessed using computed tomography or magnetic resonance imaging, and absence of iodine uptake was confirmed using a diagnostic radio-iodine scan before study entry. In eligible patients, isotretinoin was prescribed at 1.5 mg/kg/day orally for 8 weeks. Response was assessed within 2 weeks of completing treatment with repeat radio-iodine scan. All patients were reviewed every 2 weeks during treatment for assessment of toxicity. Sixteen patients were treated with isotretinoin between January 2001 and July 2002: nine with metastatic papillary thyroid cancer, five with metastatic follicular cancer and two with Hurthle cell carcinoma. Median age was 57 years. All patients tolerated 8 weeks of oral isotretinoin. Mucocutaneous side-effects and minor changes in biochemical or lipid profiles were documented in most patients. In one patient, radio-iodine uptake increased after retinoid administration; however, this was not large enough to permit a significant dose of iodine to be given to sites of metastatic disease. In the other 15 patients, no radio-iodine uptake was documented. Treatment with isotretinoin does not reliably increase radio-iodine uptake in patients with metastatic thyroid cancer. This treatment alone does not enable radio-iodine to be used for further treatment.

Recombinant Human Thyroid-Stimulating Hormone

The major functions of pituitary thyroid-stimulating hormone (TSH) are to maintain the biosynthesis and secretion of the thyroid hormones L-thyroxine (T4) and L-3,5,3'triidothyronine (T3). The TSH core contains two apoproteins, the alpha and beta subunits. The alpha subunit is identical to that of pituitary follitropin, pituitary lutropin and placental chorionic gonadotropin, whereas the beta subunit is unique. TSH is a glycoprotein; the glycoprotein components of the alpha and beta subunits account for more than 10% of their mass and are essential for normal thyrotropic action and intravascular kinetics. The hypothalamic tripeptide, TSH-releasing hormone (TRH) is required for optimum TSH biosynthesis, particularly as far as addition of the glycoprotein components is concerned. TRH deficiency is associated with secretion of TSH molecules that are appropriately measured in most assays but have reduced bioactivity. In previous years the TSH used in clinical practice was obtained and purified from bovine pituitaries. Bovine TSH was used to test thyroid function and to augment the uptake of radioiodine in patients with thyroid cancer. Bovine TSH has been largely abandoned as a clinical agent because of adverse immune reactions. A recombinant human TSH (rhTSH; Thyrogen), has been approved by the US FDA for diagnostic use in patients with thyroid cancer. The alpha and beta subunits of Thyrogen are identical to those of human pituitary TSH. Thyrogen has a specific activity of approximately 4 IU/mg and is a potent stimulator of T4, T3 and thyroglobulin (Tg) secretion in healthy volunteers. It also increases thyroid iodide uptake in patients with thyroid cancer or multinodular goitre and in volunteers, even those exposed to large amounts of stable iodide. Thyroid cancer patients who have been treated by thyroidectomy and radioiodine ablation but are at risk of harbouring residual thyroid cancer are candidates for Thyrogen administration to prepare them for whole body iodide scans and serum Tg measurements. In thyroidectomised thyroid cancer patients who are unable to secrete pituitary TSH upon thyroid hormone withdrawal, Thyrogen is the only acceptable method to prepare them for these procedures. Thyrogen has been used on a compassionate basis to prepare patients for radioiodine ablation. rhTSH, in addition to being useful in the management of patients with thyroid cancer, is potentially useful to test thyroid reserve and to aid in thyroid-related nuclear medicine procedures. In the future, TSH analogues that have superagonist or antagonist properties may become available as therapeutic agents.