Effect of TSH stimulation protocols on adequacy of low-iodine diet for radioiodine administration.

Low-iodine diet (LID) is a crucial preparation for radioactive iodine (RAI) treatment or scan in thyroid cancer. The aim of this study is to analyze the influence of thyroid stimulating hormone (TSH) stimulation protocols and other clinical factors on LID adequacy. Thyroid cancer patients who underwent LID for RAI scan or treatment were retrospectively analyzed. Patients were guided to have LID for 2 weeks before RAI administration and urine iodine/creatinine ratio (UICR, µg/g Cr) was measured. TSH stimulation was conducted using either thyroid hormone withdrawal (THW) or recombinant human TSH (rhTSH) injection. Adequacy of LID was classified by UICR as 'excellent (< 50)', 'adequate (50-100)', 'inadequate (101-250)' and 'poor (> 250)'. A total of 1715 UICR measurements from 1054 patients were analyzed. UICR was significantly higher in case of rhTSH use than THW (72.4 ± 48.1 vs. 29.9 ± 45.8 µg/g Cr, P < 0.001). In patients who underwent LID twice using both TSH stimulation protocols alternately, UICR was higher in case of rhTSH than THW regardless of the order of method. Among clinical factors, female, old-age, and the first LID were significant factors to show higher UICR. Although the adequacy of LID was 'adequate' or 'excellent' in most patients, multivariate analysis demonstrated that THW method, male, young age, and prior LID-experience were significant determinants for achieving 'excellent' adequacy of LID. In conclusion, UICR was higher and the proportion of 'excellent' LID adequacy was lower with rhTSH than with THW. UICR was higher also in women, old-age, and LID-naïve patients. Further researches are required to suggest effective methods to reduce body iodine pool in case of rhTSH use and to validate the efficacy of such methods on outcomes of RAI treatment.

Major dietary patterns and differentiated thyroid cancer.

BACKGROUND: Differentiated Thyroid Cancer (DTC) is the most common endocrine cancer with an increasing trend worldwide. Dietary pattern as a modifiable factor may be associated with DTC. OBJECTIVE: The present study aimed to evaluate the association between major dietary patterns and risk of DTC. METHODS: A case control study was conducted among 309 clinic-based participants in northeast of Iran. Dietary data were then collected by a validated Food Frequency Questionnaire (FFQ). Further, codified data were analyzed by factor analysis and logistic regression analysis to identify the dietary patterns and to examine the association between dietary patterns and DTC, respectively. RESULTS: According to our results, four major dietary patterns including western dietary pattern, traditional dietary pattern, transitional dietary pattern, and healthy dietary pattern were identified. The western dietary pattern was associated with increased odds of DTC after adjustment for potential confounders (OR = 2.79, 95% CI: 1.01-7.74). However, there was no association between other dietary patterns and DTC after adjustment. CONCLUSIONS: In conclusion, the findings showed that western dietary pattern might be associated with DTC. Further studies are recommended to provide more conclusive evidences about the association between dietary patterns and DTC.

Phase I/II Trial of Vandetanib and Bortezomib in Adults with Locally Advanced or Metastatic Medullary Thyroid Cancer.

LESSONS LEARNED: Vandetanib at a dose of 300 mg orally every day plus bortezomib 1.3 mg/m2 intravenously on days 1, 4, 8, and 11 could be administered safely.Assessing outcomes in 17 patients with medullary thyroid cancer, investigators considered the combination to be more difficult to administer than single-agent vandetanib and that achieving better outcomes was unlikely. Consequently, a planned phase II study was terminated early. BACKGROUND: The proto-oncogene RET (REarranged during Transfection) has a critical role in the pathogenesis of medullary thyroid cancer (MTC). Vandetanib (V), a multitargeted tyrosine kinase inhibitor approved for the treatment of MTC, is thought to inhibit RET in MTC. Supported by preclinical studies demonstrating that bortezomib (B) administration lowered RET mRNA and protein levels, we conducted a phase I study in advanced solid tumors of vandetanib in combination with bortezomib. The goal was to establish an RP2D (recommended phase II dose) for the combination of vandetanib plus bortezomib, a regimen envisioned as a dual strategy for targeting RET in MTC. METHODS: Patients with advanced solid tumors were treated with escalating doses of bortezomib or vandetanib to assess the safety and tolerability of daily oral vandetanib and intravenous (IV) bortezomib administered on days 1, 4, 8, and 11 of a 28-day cycle. Intrapatient dose escalation was allowed. RESULTS: Twenty-two patients were enrolled and received escalating mg/m2 bortezomib and mg vandetanib (number of patients) at initial doses of 1 and 100 (3), 1.3 and 100 (6), 1.3 and 200 (6), and 1.3 and 300 (7), respectively. Patients received a median of four cycles of bortezomib/vandetanib (range: 1-10), with 13 patients escalating to 1.3/200 and 10 to 1.3/300. G3 toxicities occurring in more than one patient included hypertension (24%), fatigue (19%), thrombocytopenia (10%), diarrhea (10%), and arthralgia (10%). There were no drug-related G4/5 toxicities. There was one dose-limiting toxicity, G3 thrombocytopenia, at bortezomib/vandetanib doses of 1.3/200 in cycle 2 that resolved without intervention. Four patients with a diagnosis of MTC (27%) had a partial response (PR). CONCLUSION: The MTD of the combination was established as bortezomib, 1.3 mg/m2 IV days 1, 4, 8, and 11 with vandetanib 300 mg p.o. daily. RECIST responses were observed in patients with a diagnosis of MTC.

Predictive factors for the outcomes of initial I-131 low-dose ablation therapy to Japanese patients with differentiated thyroid cancer.

OBJECTIVE: To identify prognostic factors associated with a low-iodine diet (LID) and the amount of remnant thyroid tissue in Japanese patients with differentiated thyroid cancer (DTC) who received initial I-131 remnant ablation (RAI) using a fixed low dose of I-131 (1110 MBq). PATIENTS AND METHODS: In this prospective study, we enrolled 45 patients. Patients were classified into a self-managed LID group and a strict LID group. We measured the urinary iodine concentration on the day of RAI after patients consumed LID for 2 weeks. Thyroid-stimulating hormone-induced thyroglobulin (Tg) levels and I-131 uptake by the remnant thyroid tissue were also evaluated. A response-evaluation whole-body scan (WBS) was performed 6-8 months after RAI to determine the outcome of the therapy. RESULTS: Post-LID urinary iodine levels of the strict LID group tended to be lower than those of the self-managed LID group. Twenty-five cases (56%) showed absence of uptake, whereas 20 cases (44%) showed residual uptake on the response-evaluation WBS. There were no significant differences between "absence" and "residual" groups in urinary iodine concentrations and Tg levels (p = 0.253 and p = 0.234, respectively). However, significant differences were observed in I-131 uptake by the thyroid bed (p = 0.035). CONCLUSIONS: For patients following the current Japanese method of a 2-week LID, the urinary iodine concentration was not a predictive factor for the successful outcome of RAI. In contrast, low I-131 uptake by the thyroid bed, revealed by the scintigram after RAI, may serve as a favorable predictive factor.

Inhibition of the AKT/mTOR Pathway Augments the Anticancer Effects of Sorafenib in Thyroid Cancer.

BACKGROUND: Sorafenib is a multikinase inhibitor that has been approved for the treatment of patients with advanced 131iodine (131I) refractory differentiated thyroid cancer (DTC). However, the progression-free survival of patients with advanced 131I refractory DTC is short, and most DTC patients eventually acquire resistance to sorafenib. Therefore, new therapeutic strategies need to be developed. MATERIALS AND METHODS: The thyroid cancer cell lines 8505C and FTC133 were treated with sorafenib in the presence or absence of BEZ235 or small interfering RNA (siRNA) directed against AKT. A CCK8 kit was used to evaluate cell viability. Protein expression levels of relevant genes were determined by Western blotting analysis, whereas messenger RNA expression levels were determined by real-time PCR analysis. Flow cytometry was performed to assess the number of apoptotic cells. RESULTS: The results indicate that sorafenib simultaneously inhibited the activities of the MAPK and PI3K/AKT/mTOR pathways in thyroid cancer cells. Treatment of 8505C and FTC133 cells with NVP-BEZ235, siRNA against AKT, or sorafenib induced tumor cell apoptosis and led to reduced tumor cell proliferation. Sorafenib in combination with PI3K/AKT/mTOR inhibition by NVP-BEZ235 or AKT siRNA enhanced apoptosis and proliferation suppression. CONCLUSIONS: The evidence of this study suggests that a combinatorial approach that inhibits both the MAPK and PI3K/AKT/mTOR pathways exerts a greater antitumor effect than sorafenib alone in thyroid cancer cell lines.

Low iodine diet in differentiated thyroid cancer: a review.

Radioactive iodine (RAI) ablation is a beneficial, adjuvant therapy for the management of differentiated thyroid cancer (DTC) after thyroidectomy. The goal of RAI is to destroy remnant thyroid and microscopic cancerous tissue. Radioactive iodine uptake is enhanced by elevating TSH levels and initiating a low iodine diet (LID) prior to ablation. An ideal LID should preferably not exceed 50 mcg/day of dietary iodine for 1-2 weeks, although the duration may be shortened to a week with a structured patient education programme. A pre-ablation spot urinary iodine concentration (UIC) of <100 mcg/l and/or a urinary iodine to creatinine ratio (UICR) of <100 mcg/gCr would support an adequate LID preparation. Hyponatraemia, most likely due to iatrogenic hypothyroidism, is a potential side effect associated with LID and occurs during and a few days after the LID. Although the overall incidence of hyponatraemia is low, patients at high risk (older age, female sex, use of thiazide diuretics) may benefit from serum sodium monitoring. The existing evidence on the impact of LID on RAI ablation has been largely inconsistent due to retrospective study designs and the lack of an objective measurement of urinary iodine levels. Future large prospective randomized control trials are needed to elucidate and confirm the crucial role of LID in achieving successful RAI ablation and greater disease-free survival in DTC.

Dietary flavonoid intake and thyroid cancer risk in the NIH-AARP diet and health study.

Experimental studies suggested that flavonoids may influence thyroid carcinogenesis, but epidemiologic evidence is sparse. No study has examined different classes of flavonoids in relation to thyroid cancer risk. Using data from the NIH-AARP Diet and Health Study, which enrolled 491,840 U.S. men and women, ages 50 to 71 years at baseline, we prospectively examined the risk of thyroid cancer in relation to dietary intakes of catechins, flavanones, flavonols, anthocyanidins, flavones, isoflavones, and total flavonoids. Dietary intakes were assessed using a food frequency questionnaire. Cancer cases were ascertained by linkage to state cancer registries. Multivariable-adjusted Cox proportional hazard models were used to estimate HRs and 95% confidence intervals (CI). During follow up (mean = 9 years), we identified 586 thyroid cancer cases. Thyroid cancer risk was inversely associated with dietary flavan-3-ols [HRQ5 vs. Q1 (95% CI): 0.70 (0.55, 0.91), PTrend = 0.03], but positively associated with flavanones [HRQ5 vs. Q1 (95% CI): 1.50 (1.14, 1.96), PTrend = 0.004]. Other classes of flavonoids and total flavonoids were not associated with thyroid cancer risk. Similar associations were found for papillary thyroid cancer. Our findings suggest that dietary intake of different classes of dietary flavonoids may have divergent effects on thyroid cancer risk. More studies are needed to clarify a role of flavonoids in thyroid cancer development. Results from our study suggest a potential nutritional etiology of thyroid cancer. Cancer Epidemiol Biomarkers Prev; 23(6); 1102-8. ©2014 AACR.

Apigenin in combination with Akt inhibition significantly enhances thyrotropin-stimulated radioiodide accumulation in thyroid cells.

BACKGROUND: Selectively increased radioiodine accumulation in thyroid cells by thyrotropin (TSH) allows targeted treatment of thyroid cancer. However, the extent of TSH-stimulated radioiodine accumulation in some thyroid tumors is not sufficient to confer therapeutic efficacy. Hence, it is of clinical importance to identify novel strategies to selectively further enhance TSH-stimulated thyroidal radioiodine accumulation. METHODS: PCCl3 rat thyroid cells, PCCl3 cells overexpressing BRAF(V600E), or primary cultured tumor cells from a thyroid cancer mouse model, under TSH stimulation were treated with various reagents for 24 hours. Cells were then subjected to radioactive iodide uptake, kinetics, efflux assays, and protein extraction followed by Western blotting against selected antibodies. RESULTS: We previously reported that Akt inhibition increased radioiodine accumulation in thyroid cells under chronic TSH stimulation. Here, we identified Apigenin, a plant-derived flavonoid, as a reagent to further enhance the iodide influx rate increased by Akt inhibition in thyroid cells under acute TSH stimulation. Akt inhibition is permissive for Apigenin's action, as Apigenin alone had little effect. This action of Apigenin requires p38 MAPK activity but not PKC-δ. The increase in radioiodide accumulation by Apigenin with Akt inhibition was also observed in thyroid cells expressing BRAF(V600E) and in primary cultured thyroid tumor cells from TRß(PV/PV) mice. CONCLUSION: Taken together, Apigenin may serve as a dietary supplement in combination with Akt inhibitors to enhance therapeutic efficacy of radioiodine for thyroid cancer.

Epidemiology and histology of malignant thyroid nodules in North East Region of Romania (Moldavia) before and after alimentary salt universal iodination.

UNLABELLED: Research on the relationship between iodine exposure and thyroid cancer risk is limited and the findings are inconclusive. OBJECTIVES: Given this molecular data on iodine we decided to evaluate the changes of incidence and histology of thyroid cancer in the North-Eastern region of Romania (Moldavia) after the government decision from 2004 that introduced the universal iodination of alimentary salt. After this decision values of urinary iodine increased from 50 microg/L (2001-2002) to 117 microg/L (2006 -2008). MATERIAL AND METHODS: We compared the incidence and the histology of thyroid cancer in residents living in an area known as a mild endemic goiter region (Moldavia-Romania) between 2001-2004 with the incidence and the histology of thyroid cancer between 2005-2008 in the same region after the introduction of universal iodization of alimentary salt. RESULTS: The number of papillary cancers increased from 125 cases (2001-2004) to 276 cases (2005-2008). The number of follicular cancer decreased from 52 cases (2001-2004) to 27 cases (2005-2008). The ratio between papillary and follicular cancers increased from 4.80 / 1 (2001-2004) at 10.61 / 1 (2005-2008). The number of medullar thyroid carcinoma increased from six cases (2001-2004) to 24 cases (2005-2008). Thyroid anaplastic carcinomas number increased from 7 cases (2001-2004) to 12 cases (2005-2008). The total number of thyroid cancer has increased dramatically after the introduction of universal iodination of alimentary salt with 178% compared to 2001-2004 (from 190 cases in 2001-2004 to 339 cases in 2005-2008), despite the fact that the number thyroidectomies decreased from 1734 (2001-2004) to 1449 (2005-2008). CONCLUSION: After the introduction the universal iodination of alimentary salt starting from 2004 the total number of thyroid cancers increased comparative with the period before universal iodination of alimentary salt.

Diallyl sulfide induces growth inhibition and apoptosis of anaplastic thyroid cancer cells by mitochondrial signaling pathway.

Anaplastic thyroid carcinoma (ATC) is one of the most lethal solid tumors arising thyroid gland with dismal prognosis. One of the constituents of garlic, diallyl sulfide (DAS) was shown to inhibit chemically induced carcinogenesis in many animal models. This study examined whether DAS could induce growth inhibition and apoptosis in ATC cells. In MTT assay, DAS treatment inhibited the proliferation of ARO cells in a dose-dependent manner. Flow cytometric analysis showed that DAS treatment increased the accumulation of sub-G1 DNA and concomitant accumulation of cells in the G2/M phase in a dose-dependent manner. In addition, DAS-induced apoptosis was associated with a decrease in the level of Bcl-2 expression and an increase in the level of Bax expression, and cytochrome c was remarkably released from mitochondrial into the cytosol by DAS. Furthermore, caspase-9 and caspase-3 were activated by DAS, and DAS cleaved PARP. Taken together, DAS decreased cell proliferation and induced apoptosis via mitochondrial signaling pathway in ATC cells.

Severe hyponatremia: a danger of low-iodine diet.

Two patients who were placed on a low-iodine diet in preparation for testing and possible treatment with radio-iodine developed severe hyponatremia that required hospitalization. In elderly patients or those with risk factors for hyponatremia, serum sodium should be measured.

Reevaluation of the impact of a stringent low-iodine diet on ablation rates in radioiodine treatment of thyroid carcinoma.

Prior analyses of the impact of stringent, preablative low-iodine diets (LIDs) on ablation in patients with differentiated thyroid cancer postthyroidectomy are dated. We retrospectively reviewed first-time, short-term ablation rates for 44 LID patients and 50 patients following a regular diet (RD) who were verbally instructed to avoid salt, seafood, and multivitamins containing iodine. Patients who had undergone ablation were given between 100 and 200 mCi of 131I, depending on the presence of metastases. We found a 68.2% ablation rate for LID patients, compared to a 62.0% rate for RD patients, a nonsignificant difference (p = 0.53). We observed a dose-response relationship for both patient groups, with higher ablation rates corresponding to higher doses of radioiodine administered. We also measured iodine levels in spot urine samples from 7 matched LID patients and 7 matched RD adherents (healthy volunteers) prediet and postdiet as well as 39 healthy volunteers. LID patients had a lower mean urinary iodine level postdiet (173.9 microg/L; range, 45-1,217 microg/L; standard deviation [SD] = 127.7) than the RD patients (mean, 381.4 microg/L; range, 140-630 microg/L; SD = 196.3) or the 39 normal controls (444.0 microg/L; range, 50-1,690 microg/L; SD = 413.4). Whereas the LID lowered urinary iodine levels by 69.4% from prediet values, the RD reduced urinary iodine by 23.6%. Although differences in the reduction of urinary iodine levels between the LID and the RD were substantial, both groups experienced equivalent outcomes. The level of iodine in the American diet has progressively decreased, and may be much lower now than when prior LID studies were conducted. We suggest that prescribing a refined, less stringent diet that avoids high-iodine-containing foods would offer equivalent outcomes with increased patient convenience.

Low iodine diet in I-131 ablation of thyroid remnants.

A low-iodine diet was developed for used in decreasing iodine intake and excretion in patients undergoing evaluation with radioactive I-131 for ablation of thyroid remnants as treatment for thyroid cancer. It has been demonstrated to effectively lower iodine excretion to less than 25% of basal values. Preliminary calculations suggest that such iodine depletion may be potentially useful in increasing the radiation dose per mCi of administered activity in I-131 ablative therapy.

[Cystic degeneration of autonomous adenomas (author's transl)]. / Zystische Degeneration autonomer Adenome

Follow-up examinations in four patients with autonomous adenomas showed cystic degeneration in the autonomous adenomas 20 to 45 months after the first examination, confirmed by fine needle biopsy. Clinical improvement occurred three times with scintigraphic compensation, decompensation occurred once without clinical deterioration. In particular cases a therapeutic policy of wait and see is justified in patients with autonomous adenomas because they may remain clinically inconspicuous for a long time; on the other hand there is a possibility of a cystic degeneration.