Radioiodine For Thyroid Cancer Research Articles

A Positive Feedback Loop Between DICER1 and Differentiation Transcription Factors Is Important for Thyroid Tumorigenesis.

Background: DICER1 plays a central role in microRNA biogenesis and functions as a tumor suppressor in thyroid cancer, which is the most frequent endocrine malignancy with a rapidly increasing incidence. Thyroid cancer progression is associated with loss of cell differentiation and reduced expression of thyroid differentiation genes and response to thyrotropin (TSH). Here we investigated whether a molecular link exists between DICER1 and thyroid differentiation pathways.Methods: We used bioinformatic tools to search for transcription factor binding sites in the DICER1 promoter. DICER1, NKX2-1, PAX8, and CREB expression levels were evaluated by gene and protein expression in vitro and by interrogation of The Cancer Genome Atlas (TCGA) thyroid cancer data. Transcription factor binding and activity were assayed by chromatin immunoprecipitation, band-shift analysis, and promoter–reporter gene activity. Gene-silencing and overexpression approaches were used to elucidate the functional link between DICER1 and differentiation.Results: We identified binding sites for NKX2-1 and CREB within the DICER1 promoter and found that both transcription factors are functional in thyroid cells. TSH induced DICER1 expression in differentiated thyroid cells, at least in part, through the cAMP/PKA/CREB pathway. TCGA analysis revealed a significant positive correlation between CREB and DICER1 expression in human thyroid tumors. NKX2-1 overexpression increased DICER1 promoter activity and expression in vitro, and this was significantly greater in the presence of CREB and/or PAX8. Gain- and loss-of-function assays revealed that DICER1 regulates NKX2-1 expression in thyroid tumor cells and vice versa, thus establishing a positive feedback loop between both proteins. We also found a positive correlation between NKX2-1 and DICER1 expression in human thyroid tumors. DICER1 silencing decreased PAX8 expression and, importantly, the expression and activity of the sodium iodide symporter, which is essential for the diagnostic and therapeutic use of radioiodine in thyroid cancer.Conclusions: The differentiation transcription factors NKX2.1, PAX8, and CREB act in a positive feedback loop with DICER1. As the expression of these transcription factors is markedly diminished in thyroid cancer, our findings suggest that DICER1 downregulation in this cancer is mediated, at least partly, through impairment of its transcription.

Eighty per cent more patients in 10 years of UK molecular radiotherapy: Internal Dosimetry Users Group survey results from 2007 to 2017.

The Internal Dosimetry Users Group has surveyed UK molecular radiotherapy (MRT) activity for cancer treatment in the UK. Data are presented here spanning 10 years of MRT activity across 31 UK centres, one from Northern Ireland, one from Wales, two from Scotland and 27 from England. Results were compiled from a survey of 2007 activity by the British Institute of Radiology Molecular Radiotherapy Working Party 1, subsequent matched surveys by Internal Dosimetry Users Group of data from 2011, 2012, 2013, 2014 and 2015 which have previously been presented 2,3 and new data from 2016 and 2017. The 2011 and 2012 surveys were carried out online using a dedicated webpage and subsequent surveys were distributed by email, all being publicized widely within the nuclear medicine and medical physics communities. Centres were asked a range of questions about MRT but presented here are data on the number of patients and treatments for each therapy type, activity regimens and trial participation. Treatments identified were Na131I radioiodine (RAI) for thyroid cancer, 131I-metaiodobenzylguanidine (131I-mIBG) and peptide receptor radionuclide therapy (PRRT) for neuroendocrine tumours (NETs), 89Sr-chloride, 153Sm-EDTMP and 223Ra-chloride (Xofigo; Bayer, Leverkusen, Germany) for bone metastases, MRT for haematological malignancies and selective internal radionuclide therapy (SIRT) for liver metastases.

Still Perfecting Radioiodine in Thyroid Cancer, After All These Years.

Dunn et al. report on vemurafenib redifferentiation in BRAFV660E DTC. Tumor biopsies showed pharmacologic reprogramming. Decades after RAI was brought into the clinic, we are still perfecting its use.

A practical approach on radioprotection in the treatment of radioiodine for thyroid cancer

There are several protocols for the treatment and follow-up of differentiated thyroid cancer. All of them gather evidence on the evolution and treatment and try to establish a treatment standard. However, there are few occasions in which this issue is addressed from the standpoint of radiological protection, as the ICRP 94 and TECDOC 1608. The focus of our work is to demonstrate that simple actions in the routine of workers in the Nuclear Medicine Service interfere positively in the radiation protection of all those involved in the patient's care, also optimizing their well being during the procedure. In the current model, the patient participates in an interview with nurses, doctors and physicists, before admission, and receives written and verbal information about the treatment procedures in order to diminish his anxiety and clarify possible doubts. In all the cases under hospital care there were no instances of high exposure (above 1mSv/month or 6 mSv/year) among the staff. With the participation of all involved, there was an escalating improvement in the reduction of complications generated by the patient’s anxiety, waste decrease, providing better comfort during hospital care) and minimization of occupational hazard affecting the staff in charge of the patient’s room maintenance after hospital leave.

Controversies on the Use of Radioiodine in Thyroid Cancer: We Need More and Better Data.

> See the associated articles on pages [1187][1] and [1195][2]. Differentiated thyroid cancer is a fascinating disease—it is both frustrating and heartening to treat. As eloquently pointed out by Tuttle in this issue of The Journal of Nuclear Medicine ([1][3]), “[M]ost patients with low-risk

Absorbed dose estimation to family members of patients treated with radioiodine for thyroid cancer

Introduction Thyroid remnant ablation with radioiodine is a well-established treatment for patients with Differentiated Thyroid Carcinoma (DTC) following thyroidectomy. After 3–4 days of hospitalization, these patients return home, presenting a possible radiation hazard to their family members. Purpose This work aims at estimating the radiation burden to the cohabitants of DTC patients treated with radioiodine, after hospital release. Materials and methods 724 patients (183/541 men/women) suffering from DTC were treated with radioiodine activities ranging from 1850 to 9250MBq. Thyroid Hormone Withdrawal (THW) was applied in 305 patients (42.1%), whereas 419 (57.9%) patients were prepared with recombinant human TSH (rhTSH). Radioiodine T eff was calculated from dose rate measurements at 1 and 2 m from the patients, performed at regular time intervals throughout their hospitalization. All patients were discharged 3–4 days post-treatment and were provided with written and oral instructions about radiation protection precautions. Patients were grouped according to their family status and radiation doses to their cohabitants were estimated based on appropriate exposure scenarios. Results Mean radioiodine T eff was 15.3 h (range 1.9–37.5 h). T eff in the rhTSH group was lower than the THW group (14.5 h and 17.1 h respectively, p〈0.05). Mean absorbed doses to all family members were estimated to be well below the corresponding dose constraints. Maximum dose to any child was slightly above 0.5 mSv, whereas maximum dose to any non-relative co-traveller was Conclusion Provided necessary precautions are followed, radiation burden to the family members of DTC patients treated with radioiodine following thyroidectomy can be kept lower than the corresponding dose constraints.

Radioiodine in thyroid cancer—how to minimize side effects

Life expectancy of most patients with differentiated thyroid cancer is normal, so adverse treatment effects should be minimized. Lower activities of radioiodine for ablation of thyroid remnants are non-inferior to higher activities and quality of life can be maintained by preparation of radioiodine remnant ablation using recombinant human thyrotropin.

Health outcomes of children fathered by patients treated with radioiodine for thyroid cancer

Health outcomes of children fathered by patients treated with radioiodine for thyroid cancer

Health outcomes of children fathered by patients treated with radioiodine for thyroid cancer

Radiation is known to be mutagenic. The present study analyses birth outcomes and the health of offspring from men previously exposed to (131) I treatment for thyroid carcinoma. Data on 493 pregnancies (356 from 173 untreated fathers, 23 from 17 patients who have undergone surgery alone and 114 from 63 fathers who received (131) I) were obtained by interviewing male patients treated for thyroid carcinoma who had not received significant external radiation to the testes. Among these pregnancies, 73 were conceived from fathers who had received more than 370 MBq. The mean activity for the 114 pregnancies fathered by 63 patients was 3993 MBq leading to an estimated radiation dose of 9.2 cGy to the testes (MIRD committee coefficient). No significant differences between untreated and treated fathers were found for any adverse outcome. There was no evidence that exposure to radioiodine affects the outcome of subsequent pregnancies and offspring, whatever the event considered. As our study is underpowered, the question of whether testicular irradiation, fractionated or not, is linked to impaired fertility or consequences on offspring remains to be established.

Reciprocal immunohistochemical expression of sodium/iodide symporter and hexokinase I in primary thyroid tumors with synchronous cervical metastasis

Sodium/iodide symporter (NIS) is a glycoprotein which is related to the concentration of radioiodine in thyroid cancer. Glucose transporter-1 (Glut-1) and hexokinases (HK) are glycoproteins related to glucose metabolism (i.e., uptake and phosphorylation) in various cancers. The aim of this study was to determine the immunohistochemical patterns of expression and mutual relationships between NIS, Glut-1, HK I, and HK II in primary thyroid tumors and synchronous cervical metastatic tumors. Retrospective experimental study. Nine cases of follicular carcinomas, sixteen cases of papillary carcinomas, and four cases of anaplastic carcinomas were included. The immunohistochemical staining intensities were categorized (scored) as negative (0), weak (1), positive (2), or strongly positive (3) and dichotomized as a negative/weak (scores 0 or 1) or positive expression (scores 2 or 3). NIS had a positive expression in good prognostic types of thyroid carcinomas, such as follicular carcinomas, more often, while having a positive expression in poor prognostic types of thyroid carcinomas, such as anaplastic carcinomas (P = .033) less often; HK I had the opposite pattern of expression (P = .033). Primary thyroid tumors and corresponding synchronous cervical metastatic tumors had a similar pattern of expression for NIS, HK I, and HK II. NIS had a reciprocal relationship with HK I as compared to Glut-1 with respect to staining intensity on each primary tumor (P = .040). Reciprocal staining pattern of NIS and HK I on primary tumors is related to the staining pattern of NIS and HK I on synchronous as well as occult cervical metastatic tumors.

Evaluation of the reticulocyte micronucleus assay in patients treated with radioiodine for thyroid cancer

In the case of accidental radiation exposure, biological dosimetry has an important role. Previous studies have indicated that the flow cytometric micronucleus (MN) assay in human transferrin receptor positive reticulocytes ( Tf-Ret) in blood could be a sensitive biomarker for chromosome damage. In the present investigation, the utility and sensitivity of this method was studied in 44 young patients from Belarus, who were treated with 131I for thyroid cancer. Red marrow (RM) is the critical organ in radioiodine therapy (RIT). In our patients, it was exposed to 100–700 mSv low-dose rate irradiation within 2–4 days. About 3 days after 131I administration, the frequency of micronucleated- Tf-Ret ( f( MN- Tf- Ret)) increases within 1 day to a maximum and declines in the following 2–5 days to its value before treatment. A total dose of 100 mSv was easily detectable. The sensitivity of the assay after acute irradiation may be 50 mSv. The method should be useful for monitoring individuals after a radiation accident, provided blood samples can be obtained within a few days after exposure. The time-course of f( MN-Tf-Ret) is interpreted using a model, which considers the exponential exposure of red marrow in RIT as well as the kinetics of erythroblast maturation and reticulocyte migration into the peripheral circulation. Similar modelling was done on published data of MN in immature mouse erythrocytes. Striking similarities in the kinetic and in the yield of MN-induction were found between these two species. This lends support for the use of the mouse as a model for the MN-induction in humans.

Dose response for T-cell receptor (TCR) mutants in patients repeatedly treated with [formula omitted] for thyroid cancer

The T-cell receptor mutant frequency (TCR- Mf) was measured in 53 young adults, who were treated with radioiodine for thyroid cancer. Patients came from the southern part of Belarus. This region had suffered the most from the Chernobyl Disaster. TCR- Mf was determined by flow cytometry before and after 1 to maximal 10 treatments. Before treatment, TCR- Mf of patients was 2.0×10 −4. This Mf value is in the same range as that of young healthy students. After radioiodine therapy (RIT), TCR- Mf increases within about half a year to a maximum. The increase per one mGy to red marrow was 8.7×10 −7. After the maximum TCR- Mf declines exponentially. The half-life of TCR mutants was found to be 3.2 years. On the basis of these data, a calibration curve for the use of TCR- Mf as a biological dosimeter is given.

Prognosis for fertility and ovarian function after treatment with radioiodine for thyroid cancer

The aim of this study was to review the outcome of ablative radioiodine treatment on ovarian function in young women treated for differentiated thyroid carcinoma. Of 1398 patients with differentiated...

Improved determination of variant erythrocytes at the glycophorin A (GPA) locus and variant frequency in patients treated with radioiodine for thyroid cancer.

Red blood cells from individuals with the blood group MN express each form of the allelic GPA protein (GPAM and GPAN) on their cell surface. Variant cells have lost one form of the protein. Their frequency is about 10(-5) in blood from unexposed persons. The BR6 assay is currently the most widely used assay to determine variant frequency (VF) by immunolabelling and flow cytometry. The precision of the BR6 assay is mainly limited by the Poisson error because only small numbers of variant cells are detected in each assay. The BR6 assay has been improved by magnetic cell separation (MACS) of variant erythrocytes prior to their determination by this assay. This new version of the assay is named 'MACS-BR6'. It allows enumeration of variant cells from 2 x 10(8) or more blood cells instead of 5 x 10(6) in the BR6 assay with a precision which is about 5 times higher than that of the BR6 assay. The MACS-BR6 assay was used to determine the VF of GPAN/0 and GPAN/N variant cells in 12 healthy adults and 11 patients treated with radioiodine for thyroid cancer 2 to 16 years before. The average red bone marrow dose was 347 mGy. In healthy adults the mean VF of GPAN/0 and GPAN/N variant cells was 16.1 x 10(6) and 5.3 x 10(-6) respectively. In patients the corresponding mean VF was 25.4 x 10(6) and 11.9 x 10(-6), respectively. The patients GPAN/0 VF was significantly higher than that of controls. In patients VF increases linearly with the dose. The linear regression parameters of VF were 16.6 x 10(-6) (intercept), 23.7 x 10(-6) GY-1 (slope) and 6.3 x 10(-6) (intercept), 12.9 x 10(-6) Gy-1 (slope) for GPAN/0 and GPAN/N variant cells, respectively.

Salivary and lacrimal gland involvement in a patient who had undergone a thyroidectomy and was treated with radioiodine for thyroid cancer

A patient with bilateral, insidiously developing enlargement of the parotid glands that started 1 year after a total thyroidectomy and ablative radioiodine therapy (200 mCi I 131) for papillary carcinoma is presented. The patient displayed prolonged periods of hypothyroidism accompanied by hypercholesterolinemia, notwithstanding hormone replacement therapy. Three years after surgery, parotid and lacrimal gland functions were reduced and fatty degeneration of the parotid parenchyma was demonstrated histologically. The submandibular and sublingual glands were preserved. It is suggested that the hormonal and metabolic derangements are responsible for the glandular dysfunction, rather than a direct effect of iodine on the glands.

Cardiac function in acute hypothyroidism.

It has been established that chronic hypothyroidism may affect cardiac function by several mechanisms. It is not known how long the patient has to be hypothyroid for cardiac involvement to develop. This study was undertaken to assess the effect of a short period of hypothyroidism (10 days) on cardiac function. Nine patients who had had total thyroidectomy, had received ablative radioiodine for thyroid cancer and were euthyroid on replacement therapy were studied while both euthyroid and hypothyroid. Cardiac assessment was performed by X-ray, ECG, echocardiography and gated blood-pool scans. After 10 days of hypothyroidism, the left-ventricular ejection fraction failed to rise after exercise in 4 of the 9 patients studied, which was significant (P less than 0.002). No significant changes in cardiac size or function at rest were detected. This functional abnormality in the absence of any demonstrable change in cardiac size and the absence of pericardial effusion with normal basal function suggest that short periods of hypothyroidism may reduce cardiac reserve, mostly because of alterations in metabolic function.

The future of radioiodines

As early as 1934 FERMI 1 produced 128I using a radium-beryllium source. Soon longer-lived isotopes of iodine, 13~ and 131I, became availbale. The latter was discovered in t983 by LIVINGOOD and SEABORG who were specifically looking for a medically useful radioisotope of this element, and it became the most widely used isotope of iodine. HERTZ 2 and HAMILTON 3 undertook therapy of hyperthyroidism at about the same time. The understanding of radioiodine in thyroid cancer came shortly after the first clinical studies in other diseases. 4 In 1946 SEIDLIN s reported the first thyroid cancer patient successfully trated with radioiodine. More recently the advantages o f other radioisotopes of iodine, such as 1211, 123I, and 125I, have been explored. MYERS, 6 along with other investigators, has contributed significantly to the exploration and application of these isotopes. The short half-life and good gamma energy of 1231 motivated MYERS 6 to advocate its use long ago. Inasmuch as iodine chemistry is relatively well understood, and radiochemists have a longstanding experience in labeling methods with the radioiodine racionuclides 131I and, more recently, 125 I, it has been relatively simple to extend to 123I all the procedures used for the other radionuclidesofiodine. Surprisingly, however the list of 1231-labeled radiopharmaceuticals in actual practice has been limited due in part to the substantial cost difference between 123I and other radionuclides of iodine, such as 131 I. One problem that remains is the relatively avoidable contamination of t23I with the longer-lived 124I and 12sI. Most methods of direct production result in 124I contamination, whereas 123i produced by 123Xe decay is usually contaminated with 1251 at the time of delivery. When first appraised of The International Symposium, on Radioiodines I was intrigued with the prospect in view of several earlier, excellent radioiodine conferences. As reflected by these proceedings, Published on Volume 65, No 1-2 of the Joural of the Radioanalytical Chemistry, Drs. NOUJAIM and WlEBE have shown great wisdom in assembling a symposium of such breadth and quality. I have been asked to address the future of radioiodines, and in deing so must consider their

Radioiodine for Thyroid Cancer

Radioiodine for Thyroid Cancer

The treatment of thyroid carcinoma by radioiodine.

Where a subject is still in an elementary stage of evolution it is all too easy prematurely to crystallise the state of affairs by setting them down in a paper. It is important therefore to keep in mind that this subject of radioiodine treatment of thyroid carcinoma is still very much in a state of flux. The ideas which I propose to outline now are merely a description of our present theories in Manchester of how this new method of treatment should be explored and no more than that. The first point to be emphasised is that this use of radioiodine in thyroid cancer represents a completely new principle of therapy—the principle of systemic ingestion with, thereafter, selective absorption of a drug carrying a radioactive element in it and resulting in a zone of localised high radiation dosage in the selective absorption tissues. Because it is based on new principles we have to start and think out our own basic principles of therapeutic use from scratch and to try and avoid assumption that those principles we...