Background. False-positive pulmonary radioactive iodine uptake in the followup of differentiated thyroid carcinoma has been reported in patients with certain respiratory conditions. Patient Findings. We describe a case of well-differentiated papillary thyroid carcinoma treated by total thyroidectomy and radioiodine ablation therapy. Postablation radioiodine whole body scan and subsequent diagnostic radioiodine whole body scans have shown persistent uptake in the left hemithorax despite an undetectable stimulated serum thyroglobulin in the absence of interfering thyroglobulin antibodies. Contrast-enhanced chest computed tomography has confirmed that the abnormal pulmonary radioiodine uptake correlates with focal bronchiectasis. Summary. Bronchiectasis can cause abnormal chest radioactive iodine uptake in the followup of differentiated thyroid carcinoma. Conclusions. Recognition of potential false-positive chest radioactive iodine uptake, simulating pulmonary metastases, is needed to avoid unnecessary exposure to further radiation from repeated therapeutic doses of radioactive iodine.
The purpose of using a whole-body scanning after the radioactive I-131 treatment is to screen functional residual or metastatic thyroid tissues. In whole-body scanning of some patients, false positive radioiodine I-131 uptakes may be seen in physiological uptake regions or atypical localizations.
A 54 year-old woman underwent total thyroidectomy for papillary thyroid carcinoma. A positive appearance seen in the upper postero-lateral part of the right gluteal region was determined by a post-therapy I-131 whole body scan. The colour Doppler ultrasonography, magnetic resonance imaging features and histopathological characteristics of the excised lesion were presented. The lesion was demonstrated to be a foreign body granuloma.
Unexpected positive findings in the post-therapy I-131 whole body scan should be confirmed with other imaging modalities in order to avoid unnecessary treatments. In uncertain situations, the diagnosis should be established histopathologically.
thyroid cancer; false positive radioiodine uptake; post-therapy I-131 whole body scan; colour Doppler ultrasonography; magnetic resonance imaging
Various physiological processes can cause potentially misleading appearances in radioiodine whole body scans; proper understanding of the causes of these can therefore obviate diagnostic errors. Whole-body radioiodine scintigraphy with I131 or I123 is an accurate form of imaging used for management of differentiated thyroid carcinoma. Following thyroidectomy, any residual thyroid tissue or metastatic disease is ablated with high dose I131 and diagnostic images are acquired, demonstrating residual thyroid tissue and metastatic disease. However, atypical physiological uptake of I131 can simulate metastases.
Low iodine diet (LID) is recommended in patients with differentiated thyroid cancer before radioiodine administration. Patients with increased thyroglobulin (Tg) level, but negative 131I whole body scan present diagnostic and therapeutic dilemma. This study was designed to evaluate the benefit of a two-week LID in patients with elevated serum Tg levels and negative 131I whole body scans.
Patients and methods.
For the impact assessment of two-week LID on radioiodine tissue avidity, radioiodine scans before and after LID were compared. Sixteen patients with serum Tg > 2 μg/L, negative Tg-antibodies, and negative radioiodine scans underwent two-week LID before the 131I administration. Fourteen patients underwent diagnostic scanning and two patients received radioiodine therapy. Iodine concentration in the morning urine specimens were measured in each patient, a day before and 15th day after starting LID.
Following self-managed LID, patients were able to significantly reduce their iodine body content by 50% (range 28–65%, p<0,001). 13 patients (82%) accomplished mild iodine deficiency (50-99 μg/L) and one patient (6%) achieved targeted moderate iodine deficient state (<50 μg/L). All diagnostic post-LID scans were negative. Both post-therapy 131I scans showed radioiodine accumulation outside of normal 131I distribution (neck region and diffuse hepatic uptake). This study demonstrated that two-week LID is effective way to decrease total body iodine content, although without a visible effect on post-LID diagnostic 131I scans.
A more stringent dietary protocol and longer iodine restriction period are probably needed to achieve targeted moderate iodine deficiency in patients preparing for 131I administration. This might result in higher radioiodine avidity of thyroid remnant/metastases.
low iodine diet; urine iodine concentration; differentiated thyroid cancer; radioiodine
Measurement of serum thyroglobulin (Tg) concentrations and whole-body radioiodine scan were performed simultaneously during follow-up of 32 patients with differentiated thyroid cancer who had undergone thyroid ablation by operation and radioiodine. Almost all patients in whom serum Tg was undetectable had normal scans. Concentrations exceeding 50 ng/ml were invariably associated with residual or metastatic tumour uptake in the scan. Out of 21 observations of detectable values below 50 ng/ml, 14 were in patients whose scans showed subclinical or sub-radiological tumour uptake and seven in patients with normal scans. The sensitivity of serum Tg as a tumour marker compared favourably to that of the whole-body scan. A scan is unnecessary when serum Tg is undetectable, but in patients with detectable serum Tg concentrations, particularly if these are below 50 ng/ml, a scan is important to assess and localise tumour uptake of iodine before advising treatmet with iodine-131.
Various studies have demonstrated the safety and efficacy of recombinant human thyroid-stimulating hormone (rhTSH) for radioiodine remnant ablation. On this basis, rhTSH was approved in Europe for the radioiodine ablation of low-risk differentiated thyroid cancer (DTC) during thyroid hormone therapy with L-thyroxine (L-T4). Moreover, in December 2007, the US Federal Drug Administration approved the use of rhTSH for adjuvant treatment with radioiodine in patients with DTC without evidence of metastatic thyroid cancer. Quality of life was found to be better with rhTSH preparation than with L-thyroxine withdrawal, thereby resulting in benefits for society as a whole. Furthermore, rhTSH for radioiodine remnant ablation results in a longer effective radioiodine half-life within remnant thyroid tissue and a lower specific absorbed dose in the blood and exposure of bone marrow to X-rays. More studies are required to establish the amount of radioiodine to be administered especially in high-risk patients.
thyroid cancer; thyrotropin; radioiodine (131I) remnant ablation (RRA); quality of life; ray exposure
The management protocol for differentiated thyroid cancer includes whole body iodine-131 imaging, to detect residual thyroid tissue and distant metastasis, after thyroidectomy. However, the diagnostic dose of radioiodine may fail to detect the non-functioning or poorly functioning metastasis. We present a case where hybrid single photon-emission computed tomographic and computed tomographic (SPECT-CT) fusion imaging, using a diagnostic dose of iodine-131, was able to detect both functioning as well as non-functioning pulmonary metastases, prior to high-dose radioiodine therapy.
Carcinoma; hybrid imaging; iodine-131; SPECT-CT; thyroid
The patient with a history of bone pain and muscle weakness, was thought to have oncogenic osteomalacia as a result of biochemical investigations and directed to Nuclear Medicine Department for a whole-body bone scintigraphy and 111In-octreotide scintigraphy. There was no focal pathologic tracer uptake, but generalized marked increase in skeletal uptake on bone scintigraphy. Octreotide scintigraphy showed accumulation of octreotide in the region of the left lobe of the thyroid gland in the neck. Thereafter, parathyroid scintigraphy was performed with technetium-99m labeled metroxy-isobutyl-isonitryl (99mTc-MIB) and MIBI scan demonstrated radiotracer uptake at the same location with octreotide scintigraphy. The patient underwent left inferior parathyroidectomy and histopathology confirmed a parathyroid adenoma. Somatostatin receptor positive parathyroid adenoma may show octreotide uptake. Octreotide scintigraphy may be promising and indicate a possibility of using somatostatin analogues for the medical treatment of somatostatin receptor positive
Conflict of interest:None declared.
Parathyroid adenoma; indium-111-octreotide; somatostatin
In patients, who underwent thyroid surgery or treated with I-131 radioiodine previously for differentiated thyroid cancer, a second surgical intervention carries higher risks due to distortion of the natural anatomy and development of fibrotic/cicatricial tissue. In addition, accurate assessment of current status about extent of the disease is important in terms of success of the surgery. In this case report, we present the positive contribution of intraoperative gamma probe used for lesion detectability and for surgical safety in a patient operated for several times and administered high cumulative dose of radioiodine therapy for diffentiated thyroid carcinoma previously.
Conflict of interest:None declared.
technetium Tc 99m sestamibi; thyroidectomy; local neoplasm recurrence; thyroid cancer; Scintillation Counting
In 30–50% of patients with metastatic non-medullary thyroid cancer the metastases are not radioiodine-avid and so there is no effective treatment. Retinoids have demonstrated inhibition of thyroid tumor growth and induction of radioiodine uptake. The aim of our study was to assess benefits of the retinoic acid (RA) treatment to re-differentiate non-functional NMTC metastases.
Patients and Methods
In this prospective study, 53 patients with radioiodine non avid metastatic disease (45) or hyperthyroglobulinemia (8) were treated with 13-cis-retinoic acid (13-CRA) [1.0 mg/kg/day over 1st week and then 1.5 mg/kg] for six weeks prior to I-131 treatment performed under rhTSH stimulation. The re-differentiating effect of RA was evaluated by serum thyroglobulin (Tg) monitoring before and after cessation of RA treatment and by qualitative analysis of iodine uptake on the post-therapeutic whole body scan (rxWBS).
13-CRA induced radioiodine uptake in 9 (17%) of patients. In the univariate analysis neither the patient's gender, age, tumor histopathology, uptake in thyroid bed nor time since thyroid cancer diagnosis was associated with results of rxWBS.
41 (77%) patients were evaluable for Tg response before and after to 13-CRA treatment. There was a statistically significant increase in median Tg level (60 v. 90 ng/ml, p < 0.05). There was no difference in Tg increase between scintigraphic responders and non-responders.
13-CRA and RIT was repeated at least once in 8 of 9 scintigraphic responders. None of them showed tumor regression by radiological imaging within 12 months after the first treatment, 4/9 (44%) of them had disease progression.
13-CRA treatment was well-tolerated. All but one patient complained of at least one side effect the most prevalent being lip dryness (98%). All side effects were transient and resolved within 2 weeks after 13-CRA cessation.
Our results show that in patients with non-functional metastases from NMTC, 13-CRA is able to exert some re-differentiation effect by induction of radioiodine uptake in <20% of patients and increase of Tg serum level in about 30% of them. Nevertheless, this does not transfer into clinical benefit as it neither induces measurable tumor response nor prevents disease progression.
An 80-year-old male with recurrent thyroid cancer and a percutaneous endoscopic gastrostomy (PEG) tube in situ was referred for radioiodine therapy and was administered 5510 MBq I-131 sodium iodide intravenously. Sequential whole-body images taken over the subsequent 7 days for dosimetric evaluation revealed an area of persistent high uptake in the abdomen. Delayed imaging with single photon emission CT/CT at 15 days post administration revealed this uptake to be at the junction of the PEG tube with the anatomically normal stomach wall. We hypothesise that the PEG tube became contaminated by radioiodine secreted in the gastric mucosa during therapy and this radioactivity subsequently decayed with an increased effective half-life relative to the stomach, leading to the apparent hot spot.
The incidence of thyroid cancer is low, but when it occurs, it is mainly of the papillary histopathological type. Although PET/CT has a limited role in the diagnosis, it plays a significant role in the overall post-surgery management of a patient with thyroid cancer. This follow-up role is important, especially in patients with elevated serum thyroglobulin, but negative radioiodine whole body scans. There is increasing evidence that PET/CT should be a part of routine care in the Tg positive Radioiodine scan negative patient.
Thyroid cancer; thyroglobulin; radioiodine scan; PET/CT
We report the case of a patient diagnosed with a struma ovarii with lymphocytic thyroiditis of her ectopic thyroid tissue. We believe that this case presents an unusual variation of a struma ovarii and a rare presentation of subclinical hyperthyroidism.
A 17-year-old Caucasian female patient who had undergone an ovariectomy and been diagnosed with a struma ovarii was subsequently found to have persistent subclinical hyperthyroidism with a low radioiodine uptake. Abdominal magnetic resonance imaging and iodine-131 whole body scanning showed no residue or recurrence and a thyroid ultrasonography was normal. Laboratory and histopathological findings suggested Hashimoto's thyroiditis as the cause of the subclinical thyrotoxicosis, which had presumably started at the ectopic tissue.
Struma ovarii is a rare cause of thyrotoxicosis, and can be difficult to diagnose in the presence of co-existing thyroid disorders. In patients with a struma ovarii who have not undergone thyroidectomy, there is no common consensus on management in terms of residue, recurrence or metastasis. Autoimmune thyroiditis must be kept in mind for a differential diagnosis.
Because patients with differentiated thyroid carcinoma (DTC) presenting with distant metastasis (DM) have a particularly poor prognosis, examining the prognostic factors in this group is essential. We aimed to evaluate the prognostic factors affecting cancer-specific survival (CSS) in DTC patients presenting with DM.
Of the 1227 DTC patients, 51 (4.2 %) presented with DM at diagnosis. All patients underwent a total thyroidectomy, followed by radioiodine (RAI) ablation and postablation whole body scan (WBS). Patients were considered to have an osseous metastasis if one of the metastatic sites involved a bone, while RAI avidity was determined by any visual uptake in a known metastatic site on the first WBS. Factors predictive of CSS were determined by univariate and multivariate analyses by the Cox proportional hazard model.
In univariate analysis, older age (relative risk [RR] 1.050, 95 % confidence interval [CI] 1.010–1.091, P = 0.014), DM discovered before WBS (RR 3.401, 95 % CI 1.127–10.309, P = 0.030), follicular thyroid carcinoma (RR 3.095, 95 % CI 1.168–8.205, P = 0.025), osseous metastasis (RR 4.695, 95 % CI 1.379–15.873, P = 0.013), non-RAI avidity (RR 3.355, 95 % CI 1.280–8.772, P = 0.014), and external beam radiotherapy to DM (RR 3.241, 95 % CI 1.093–9.614, P = 0.034) were significant poor prognostic factors for CSS. In the multivariate analysis, after adjusting for other factors, osseous metastasis (RR 6.849, 95 % CI 1.495–31.250, P = 0.013) and non-RAI avidity (RR 7.752, 95 % CI 2.198–27.027, P = 0.001) were the two independent poor prognostic factors for CSS. Older age almost reached statistically significance (RR 1.055, 95 % CI 0.996–1.117, P = 0.068).
DTC patients presenting with DM accounted for 4.2 % of all patients. Because osseous metastasis and RAI avidity were independent prognostic factors, future therapy should be directed at improving the treatment efficacy of osseous and/or non-RAI-avid metastases.
There is no ideal treatment for benign multinodular goitre. Besides surgery, which is recommended for large goitres or when malignancy cannot be excluded, the non-surgical treatment options are levothyroxine therapy and radioiodine (131I) therapy. Conventional 131I therapy [without recombinant human thyroid-stimulating hormone (rhTSH)] has been used for more than a decade in symptomatic non-toxic multinodular goitre, and although it does lead to significant thyroid volume reduction, relatively high activities of radioiodine are needed because of a frequent finding of a low thyroid radioiodine uptake. rhTSH, even when used in very small doses in combination with 131I therapy, enhances the thyroid volume reduction at lower 131I activities by doubling the thyroid radioiodine uptake. However, before rhTSH stimulation can be routinely used by clinicians to optimise the 131I therapy in multinodular goitre, aspects of this association, such as the cost-benefit and optimum rhTSH dose and safety, will have to be sufficiently clarified.
Radioiodine therapy has proven to be a safe and effective approach in the treatment of differentiated thyroid cancer. Similar treatment strategies have been exploited in nonthyroidal malignancies by transfecting hNIS gene into tumor cells or xenografts. However, rapid radioiodine efflux is often observed after radioiodine uptake, limiting the overall antitumor effects. In this study, we aimed at constructing multicistronic co-expression of hNIS and hTPO genes in tumor cells to enhance the radioiodine uptake and prolong the radioiodine retention. Driven by the cytomegalovirus promoter, hNIS and hTPO were simultaneously inserted into the expression cassette of adenoviral vector. An Ad5 viral vector (Ad-CMV-hTPO-T2A-hNIS) was assembled as a gene therapy vehicle by Gateway technology and 2A method. The co-expression of hNIS and hTPO genes was confirmed by a double-label immunofluorescence assay. The radioiodine (125I) uptake and efflux effects induced by co-expression of hNIS and hTPO genes were determined in transfected and non-transfected PC-3 cells. Significantly higher uptake (6.58 ± 0.56 fold, at 1 h post-incubation) and prolonged retention (5.47 ± 0.36 fold, at 1 h of cell efflux) of radioiodine (125I) were observed in hNIS and hTPO co-expressed PC-3 cells as compared to non-transfected PC-3 cells. We concluded that the new virus vector displayed favorable radioiodine uptake and retention properties in hNIS-hTPO transfected PC-3 cells. Our study will provide valuable information on improving the efficacy of hNIS-hTPO co-mediated radioiodine gene therapy.
Gene therapy; prostate cance; hNIS; hTPO; gateway cloning system
Expression of the sodium iodide symporter (NIS) is required for efficient iodide uptake in thyroid and lactating breast. Since most differentiated thyroid cancer expresses NIS, β-emitting radioactive iodide is routinely utilized to target remnant thyroid cancer and metastasis after total thyroidectomy. Stimulation of NIS expression by high levels of thyroid-stimulating hormone is necessary to achieve radioiodide uptake into thyroid cancer that is sufficient for therapy. The majority of breast cancer also expresses NIS, but at a low level insufficient for radioiodine therapy. Retinoic acid is a potent NIS inducer in some breast cancer cells. NIS is also modestly expressed in some non-thyroidal tissues, including salivary glands, lacrimal glands and stomach. Selective induction of iodide uptake is required to target tumors with radioiodide. Iodide uptake in mammalian cells is dependent on the level of NIS gene expression, but also successful translocation of NIS to the cell membrane and correct insertion. The regulatory mechanisms of NIS expression and membrane insertion are regulated by signal transduction pathways that differ by tissue. Differential regulation of NIS confers selective induction of functional NIS in thyroid cancer cells, as well as some breast cancer cells, leading to more efficient radioiodide therapy for thyroid cancer and a new strategy for breast cancer therapy. The potential for systemic radioiodide treatment of a range of other cancers, that do not express endogenous NIS, has been demonstrated in models with tumor-selective introduction of exogenous NIS.
Sodium iodide symporter; thyroid cancer; breast cancer; Transcriptional regulation; Posttranslational regulation
The Na+/I- symporter (NIS) is a transmembrane glycoprotein that mediates iodide uptake into thyroid follicular cells and serves as the molecular basis of radioiodine imaging and therapy for thyroid cancer patients. The finding that NIS protein is present in 80-90% of breast tumors suggests that breast cancer patients may also benefit from NIS-mediated radionuclide imaging and targeted therapy. However, only 17-25% of NIS-positive breast tumors have detectable radionuclide uptake activity. The discrepancy between NIS expression and radionuclide uptake activity is most likely contributed by variable cell surface NIS protein levels. Apart from the prevalent view that NIS cell surface trafficking impairments account for the variability, our current study proposes that differential levels of NIS expression may also account for variable cell surface NIS levels among breast tumors. We address the need to confirm the identity of intracellular NIS staining to reveal the mechanisms underlying variable cell surface NIS levels. In addition, we warrant a quantitative correlation between cell surface NIS levels and radionuclide uptake activity in patients such that the cell surface NIS levels required for radionuclide imaging can be defined and the defects impairing NIS activity can be recognized.
Breast cancer; glycoprotein; iodide uptake; radionuclide imaging and therapy; sodium iodide symporter (NIS)
Currently, there is no consensus on the necessity of repeated radioiodine therapy (RAI) in patients who show iodine uptake in the thyroid bed on a diagnostic whole-body scan (DxWBS) despite undetectable thyroglobulin (Tg) levels after remnant ablation. The present study investigated the clinical outcomes of scan-positive, Tg-negative patients (WBS+Tg-) who did or did not receive additional RAI.
We retrospectively reviewed 389 differentiated thyroid carcinoma patients who underwent a total thyroidectomy and received high-dose RAI from January 2003 through December 2005. The patients were classified according to surveillance DxWBS findings and TSH-stimulated Tg levels 6 to 12 months after the initial RAI.
Forty-four of the 389 patients (11.3%) showed thyroid bed uptake on a DxWBS despite negative Tg levels (WBS+Tg-). There was no difference in clinical and pathological parameters between WBS+Tg- and WBS-Tg- patients, except for an increased frequency of thyroiditis in the WBS+Tg- group. Among the 44 WBS+Tg- patients, 27 subjects were treated with additional RAI; 25 subjects showed no uptake in subsequent DxWBS. Two patients were evaluated only by ultrasonography (US) and displayed no persistent/recurrent disease. The other 17 patients received no further RAI; Eight patients and two patients showed no uptake and persistent uptake, respectively, on subsequent DxWBS. Six patients presented negative subsequent US findings, and one was lost to follow-up. Over the course of 53.2 ± 10.1 months, recurrence/persistence was suspicious in two patients in the treatment group.
There were no remarkable differences in clinical outcomes between observation and treatment groups of WBS+Tg- patients. Observation without repeated RAI may be an alternative management option for WBS+Tg- patients.
Iodine radioisotopes; Thyroglobulin; Thyroid neoplasms; Whole body scan
Radioiodine is regularly used in the treatment of thyroid cancer to eliminate residual malignant tissue after thyroidectomy and to treat metastasis. Because of the low dose of radioiodine used to treat thyroid cancer patients, leukemia is an uncommon complication of exposure to radioiodine. Here, we present a patient who developed therapy-related acute myeloid leukemia with inv(16)(p13.1q22);CBFβ-MYH11, eosinophilia, and K-ras mutation and who had been treated with very low-dose radioiodine following total thyroidectomy.
Radioiodine; Thyroid cancer; Acute myeloid leukemia; CBFβ-MYH11; Eosinophilia; K-ras
Radioiodine (RAI) ablation following thyroidectomy is standard of care treatment for patients with intermediate or high risk differentiated thyroid cancer. Traditionally, this has been achieved by forgoing thyroid hormone replacement postoperatively, allowing endogenous thyroid stimulating hormone (TSH) levels to rise. This rise in TSH provides the stimulus for RAI uptake by the thyroid remnant, but is associated with clinical hypothyroidism and its associated morbidities. Recombinant human TSH (rhTSH, thyrotropin alfa [Thyrogen®], Genzyme Corporation, Cambridge, MA, USA) was developed to provide TSH stimulation without withdrawal of thyroid hormone and clinical hypothyroidism. Phase III studies reported equivalent detection of recurrent or residual disease when rhTSH was used compared with thyroid hormone withdrawal (THW). These trials led to its approval as an adjunctive diagnostic tool for serum thyroglobulin (Tg) testing with or without RAI imaging in the surveillance of patients with differentiated thyroid cancer. Recently, rhTSH was given an indication for adjunctive preparation for thyroid remnant ablation after phase III studies demonstrated comparable outcomes for rhTSH preparation when compared with THW. Importantly, rhTSH stimulation has been found to be safe, well tolerated, and to result in improved quality of life. Here, we review the efficacy and tolerability studies leading to the approval for the use of rhTSH in well-differentiated thyroid cancer management.
recombinant human thyroid stimulating hormone; thyroid cancer; radioiodine; ablation; Thyrogen®; thyrotropin alfa
Recovery of iodide uptake in thyroid cancer cells by means of obtaining the functional expression of the sodium/iodide symporter (NIS) represents an innovative strategy for the treatment of poorly differentiated thyroid cancer. However, the NIS gene expression alone is not always sufficient to restore radioiodine concentration ability in these tumour cells.
In this study, the anaplastic thyroid carcinoma ARO cells were stably transfected with a Pax8 gene expression vector. A quantitative RT-PCR was performed to assess the thyroid specific gene expression in selected clones. The presence of NIS protein was detected by Western blot and localized by immunofluorescence. A iodide uptake assay was also performed to verify the functional effect of NIS induction and differentiation switch.
The clones overexpressing Pax8 showed the re-activation of several thyroid specific genes including NIS, Pendrin, Thyroglobulin, TPO and TTF1. In ARO-Pax8 clones NIS protein was also localized both in cell cytoplasm and membrane. Thus, the ability to uptake the radioiodine was partially restored, associated to a high rate of efflux. In addition, ARO cells expressing Pax8 presented a lower rate of cell growth.
These finding demonstrate that induction of Pax8 expression may determine a re-differentiation of thyroid cancer cells, including a partial recovery of iodide uptake, fundamental requisite for a radioiodine-based therapeutic approach for thyroid tumours.
Dedifferentiation of thyroid follicular cells renders radioiodine therapy ineffective in patients of differentiated thyroid cancer (DTC). An alternative therapy to treat the disease or reinduce radioiodine uptake is necessary.
Materials and Methods:
We evaluated the role of retinoic acid therapy in 13 cases of DTC with raised thyroglobulin and/or clinically evident disease. Retinoic acid was given in a dose of 1.5 mg/kg for a period ranging between 1.5 and 18 months.
Age of the patients was between 18 and 65 years with a median of 49 years. Ten patients had papillary while two had follicular and one patient had mixed papillary and follicular thyroid cancer. Mean radioiodine given before starting retinoic acid was 164 mCi. Mean duration of therapy was 6.4 months. Thyroglobulin decreased in 2 patients and increased in 11 patients at the end of therapy. Radioiodine uptake was demonstrable in six patients, though faintly, while 7 cases showed no uptake. Based on the clinical and biochemical parameters, four patients had progressive disease, eight had stable disease and one patient showed partial response. Of the six patients with reinduction of radioiodine uptake, three had biochemical progression and the other three had stable disease.
Our findings suggest that retinoic acid therapy may induce radioiodine uptake and reduce serum thyroglobulin levels in some patients with DTC, but whether this results in clinically significant response can only be ascertained on long-term follow-up.
Radioiodine; redifferentiation; retinoic acid; thyroglobulin
The selective increase of Na+/I− symporter (NIS)-mediated active iodide uptake in thyroid cells allows the use of radioiodine I131 for diagnosis and targeted treatment of thyroid cancers. However, NIS-mediated radioiodine accumulation is often reduced in thyroid cancers due to decreased NIS expression/function. As PI3K signaling is overactivated in many thyroid tumors, we investigated the effects of inhibitors for PI3K, Akt, or mTORC1 as well as their interplay on NIS modulation in thyroid cells under chronic TSH stimulation. PI3K inhibition by LY294002 increased NIS-mediated radioiodide uptake (RAIU) mainly through upregulation of NIS expression, however, mTORC1 inhibition by Rapamycin did not increase NIS-mediated RAIU despite increased NIS protein levels. In comparison, Akt inhibition by Akti-1/2 did not increase NIS protein levels, yet markedly increased NIS-mediated RAIU by decreasing iodide efflux rate and increasing iodide transport rate and iodide affinity of NIS. The effects of Akti-1/2 on NIS-mediated RAIU are not detected in nonthyroid cells, implying that Akti-1/2 or its derivatives may represent potential pharmacological reagents to selectively increase thyroidal radioiodine accumulation and therapeutic efficacy.
Radioiodine is a routine therapy for differentiated thyroid cancers. Non-thyroid cancers may be treated with radio-iodine following transfection with the human sodium/iodide symporter (hNIS) gene. The glial fibrillary acidic protein (GFAP) promoter is an effective tumor-specific promoter for gene expression and thus may be useful in targeted gene therapy of malignant glioma. The present study used GFAP promoter-modulated expression of the hNIS gene in an experimental model of radioiodine-based treatment for malignant glioma. Cells were transfected using a recombination adeno-virus and evaluated in cells by studying the transfected transgene expression through western blot analysis, 125I uptake and efflux, clonogenicity following 131I treatment and radioiodine therapy using a U87 xenograft nude mouse model. Following transfection with the hNIS gene, the cells showed 95–70-fold higher 125I uptake compared with the control cells transfected with Ad-cytomegalovirus (CMV)-enhanced green fluorescent protein (EGFP). The western blotting revealed bands of ∼70, 49 and 43 kDa, consistent with the hNIS, GFAP and β-actin proteins. The clonogenic assay indicated that, following exposure to 500 μCi of 131I-iodide for 12 h, >90% of cells transfected with the hNIS gene were killed. Ad-GFAP-hNIS-transfected and 2 mCi 131I-injected U87 xenograft nude mice survived the longest of the three groups. The hNIS-expressing tumor tissue accumulated 99mTcO4 rapidly within 30 min of it being intraperitoneally injected. The experiments demonstrated that effective 131I therapy was achieved in the malignant glioma cell lines following the induction of tumor-specific iodide uptake activity by GFAP promoter-directed hNIS gene expression in vitro and in vivo. 131I therapy retarded Ad-GFAP-hNIS transfected-tumor growth following injection with 131I in U87 xenograft-bearing nude mice.
malignant glioma; sodium iodide symporter; glial fibrillary acidic protein promoter; radioiodine therapy