Thyroidectomy without Radioiodine in Patients with Low-Risk Thyroid Cancer.

BACKGROUND: In patients with low-risk differentiated thyroid cancer undergoing thyroidectomy, the postoperative administration of radioiodine (iodine-131) is controversial in the absence of demonstrated benefits. METHODS: In this prospective, randomized, phase 3 trial, we assigned patients with low-risk differentiated thyroid cancer who were undergoing thyroidectomy to receive ablation with postoperative administration of radioiodine (1.1 GBq) after injections of recombinant human thyrotropin (radioiodine group) or to receive no postoperative radioiodine (no-radioiodine group). The primary objective was to assess whether no radioiodine therapy was noninferior to radioiodine therapy with respect to the absence of a composite end point that included functional, structural, and biologic abnormalities at 3 years. Noninferiority was defined as a between-group difference of less than 5 percentage points in the percentage of patients who did not have events that included the presence of abnormal foci of radioiodine uptake on whole-body scanning that required subsequent treatment (in the radioiodine group only), abnormal findings on neck ultrasonography, or elevated levels of thyroglobulin or thyroglobulin antibodies. Secondary end points included prognostic factors for events and molecular characterization. RESULTS: Among 730 patients who could be evaluated 3 years after randomization, the percentage of patients without an event was 95.6% (95% confidence interval [CI], 93.0 to 97.5) in the no-radioiodine group and 95.9% (95% CI, 93.3 to 97.7) in the radioiodine group, a difference of -0.3 percentage points (two-sided 90% CI, -2.7 to 2.2), a result that met the noninferiority criteria. Events consisted of structural or functional abnormalities in 8 patients and biologic abnormalities in 23 patients with 25 events. Events were more frequent in patients with a postoperative serum thyroglobulin level of more than 1 ng per milliliter during thyroid hormone treatment. Molecular alterations were similar in patients with or without an event. No treatment-related adverse events were reported. CONCLUSIONS: In patients with low-risk thyroid cancer undergoing thyroidectomy, a follow-up strategy that did not involve the use of radioiodine was noninferior to an ablation strategy with radioiodine regarding the occurrence of functional, structural, and biologic events at 3 years. (Funded by the French National Cancer Institute; ESTIMABL2 ClinicalTrials.gov number, NCT01837745.).

RADTHYR: an open-label, single-arm, prospective multicenter phase II trial of Radium-223 for the treatment of bone metastases from radioactive iodine refractory differentiated thyroid cancer.

PURPOSE: This is the first prospective trial evaluating the efficacy of alpha emitter Radium-223 in patients with bone metastases from radioactive iodine (RAI) refractory (RAIR) differentiated thyroid cancer. METHODS: RADTHYR is a multicenter, single-arm prospective Simon two-stage phase II trial (NCT02390934). The primary objective was to establish the efficacy of three administrations of 55 kBq/kg of Radium-223 by 18F-FDG PET/CT according to PERCIST criteria. Secondary objectives were to establish the efficacy of six administrations of Radium-223 by 18F-FDG PET/CT, 99mTc-HMDP bone scan and 18FNa PET/CT, clinical benefits, changes in serum bone markers, thyroglobulin levels, and safety. RESULTS: Ten patients were enrolled between July 2015 and December 2017 (4 M; median age 74 years). Prior to Radium-223 administration, patients received a median RAI cumulative activity of 15 GBq (7.4-35.6), external radiation therapy (n = 9), bone surgery (n = 8), cimentoplasty (n = 5), and cryoablation (n = 2). 18F-FDG PET/CT showed stable disease (SD) in 4/10 and progressive disease (PD) in 6/10 cases after three administrations and SD in 4/10, PD in 5/10 cases, and 1/10 non-evaluable (NE) case after six administrations. After six injections, 99mTc-HMDP bone scan showed SD in 9 cases and was NE in 1 case; 18FNa PET/CT showed SD in 8 cases, partial response (PR) in 1 case, and was NE in 1 case. No significant clinical benefits were reported during the study. A skeletal event occurred in 6 patients (median time without skeletal event of 12.1 months). Seventy-seven adverse events were reported during treatment (7 of grade 3-4). Three patients developed an acute myeloid, a promyelocytic, and a chronic myeloid leukemia after the last Radium-223 administration considered as drug-related. CONCLUSION: The trial was stopped after interim analysis for lack of response of bone metastases from RAIR thyroid cancer to Radium-223. Severe hematological toxicity was observed in patients heavily pretreated with RAI and external radiation. TRIAL REGISTRATION NUMBER: NCT02390934. Registration date 18.03.2015.

Strategies of radioiodine ablation in patients with low-risk thyroid cancer.

BACKGROUND: It is not clear whether the administration of radioiodine provides any benefit to patients with low-risk thyroid cancer after a complete surgical resection. The administration of the smallest possible amount of radioiodine would improve care. METHODS: In our randomized, phase 3 trial, we compared two thyrotropin-stimulation methods (thyroid hormone withdrawal and use of recombinant human thyrotropin) and two radioiodine ((131)I) doses (i.e., administered activities) (1.1 GBq and 3.7 GBq) in a 2-by-2 design. Inclusion criteria were an age of 18 years or older; total thyroidectomy for differentiated thyroid carcinoma; tumor-node-metastasis (TNM) stage, ascertained on pathological examination (p) of a surgical specimen, of pT1 (with tumor diameter ≤1 cm) and N1 or Nx, pT1 (with tumor diameter >1 to 2 cm) and any N stage, or pT2N0; absence of distant metastasis; and no iodine contamination. Thyroid ablation was assessed 8 months after radioiodine administration by neck ultrasonography and measurement of recombinant human thyrotropin-stimulated thyroglobulin. Comparisons were based on an equivalence framework. RESULTS: There were 752 patients enrolled between 2007 and 2010; 92% had papillary cancer. There were no unexpected serious adverse events. In the 684 patients with data that could be evaluated, ultrasonography of the neck was normal in 652 (95%), and the stimulated thyroglobulin level was 1.0 ng per milliliter or less in 621 of the 652 patients (95%) without detectable thyroglobulin antibodies. Thyroid ablation was complete in 631 of the 684 patients (92%). The ablation rate was equivalent between the (131)I doses and between the thyrotropin-stimulation methods. CONCLUSIONS: The use of recombinant human thyrotropin and low-dose (1.1 GBq) postoperative radioiodine ablation may be sufficient for the management of low-risk thyroid cancer. (Funded by the French National Cancer Institute [INCa] and the French Ministry of Health; ClinicalTrials.gov number, NCT00435851; INCa number, RECF0447.).

¹8F-FDG PET predicts survival after pretargeted radioimmunotherapy in patients with progressive metastatic medullary thyroid carcinoma.

PURPOSE: PET is a powerful tool for assessing targeted therapy. Since (18)F-FDG shows a potential prognostic value in medullary thyroid carcinoma (MTC), this study evaluated (18)F-FDG PET alone and combined with morphological and biomarker evaluations as a surrogate marker of overall survival (OS) in patients with progressive metastatic MTC treated with pretargeted anti-CEA radioimmunotherapy (pRAIT) in a phase II clinical trial. METHODS: Patients underwent PET associated with morphological imaging (CT and MRI) and biomarker evaluations, before and 3 and 6 months, and then every 6 months, after pRAIT for 36 months. A combined evaluation was performed using anatomic, metabolic and biomarker methods. The prognostic value of the PET response was compared with demographic parameters at inclusion including age, sex, RET mutation, time from initial diagnosis, calcitonin and CEA concentrations and doubling times (DT), SUVmax, location of disease and bone marrow involvement, and with response using RECIST, biomarker concentration variation, impact on DT, and combined methods. RESULTS: Enrolled in the study were 25 men and 17 women with disease progression. The median OS from pRAIT was 3.7 years (0.2 to 6.5 years) and from MTC diagnosis 10.9 years (1.7 to 31.5 years). After pRAIT, PET/CT showed 1 patient with a complete response, 4 with a partial response and 24 with disease stabilization. The combined evaluation showed 20 responses. For OS from pRAIT, univariate analysis showed the prognostic value of biomarker DT (P = 0.011) and SUVmax (P = 0.038) calculated before pRAIT and impact on DT (P = 0.034), RECIST (P = 0.009), PET (P = 0.009), and combined response (P = 0.004) measured after pRAIT. PET had the highest predictive value with the lowest Akaike information criterion (AIC 74.26) as compared to RECIST (AIC 78.06), biomarker variation (AIC 81.94) and impact on DT (AIC 79.22). No benefit was obtained by combining the methods (AIC 78.75). This result was confirmed by the analysis of OS from MTC diagnosis. CONCLUSION: (18)F-FDG PET appeared as the most potent and simplest prognostic method to predict survival in patients with progressive MTC treated with pRAIT. Biomarker DT before pRAIT also appeared as an independent prognostic factor, but no benefit was found by adding morphological and biomarker evaluation to PET assessment.

A Phase II Redifferentiation Trial with Dabrafenib-Trametinib and 131I in Metastatic Radioactive Iodine Refractory BRAF p.V600E-Mutated Differentiated Thyroid Cancer.

PURPOSE: To evaluate the efficacy and safety of dabrafenib-trametinib-131I for the treatment of radioactive iodine refractory metastatic differentiated thyroid cancer (DTC) with a BRAF p.V600E mutation. PATIENTS AND METHODS: A prospective phase II trial including patients with RECIST progression within 18 months and no lesion > 3 cm. Following a baseline recombinant human (rh)TSH-stimulated diagnostic whole-body scan (dc1-WBS), dabrafenib and trametinib were given for 42 days. A second rhTSH-stimulated dc WBS (dc2-WBS) was done at day 28 and 131I (5.5 GBq-150 mCi after rhTSH) was administered at day 35. Primary endpoint was the 6-month RECIST objective response rate. In case of partial response (PR) at 6 or 12 months, a second treatment course could be given. Among 24 enrolled patients, 21 were evaluable at 6 months. RESULTS: Abnormal 131I uptake was present on 5%, 65%, and 95% of the dc1-WBS, dc2-WBS, and post-therapy scans, respectively. At 6 months, PR was achieved in 38%, stable disease in 52%, and progressive disease (PD) in 10%. Ten patients received a second treatment course: one complete response and 6 PRs were observed at 6 months. The median progression-free survival (PFS) was not reached. The 12- and 24-month PFS were 82% and 68%, respectively. One death due to PD occurred at 24 months. Adverse events (AE) occurred in 96% of the patients, with 10 grade 3-4 AEs in 7 patients. CONCLUSIONS: Dabrafenib-trametinib is effective in BRAF p.V600E-mutated DTC patients for restoring 131I uptake with PR observed 6 months after 131I administration in 38% of the patients.

Amino Acid Solutions for 177Lu-Oxodotreotide Premedication: A Tolerance Study.

Background: The co-infusion of amino acid solutions during peptide receptor radionuclide therapy reduces the tubular reabsorption of 177Lu-oxodotreotide, thus minimizing nephrotoxicity. In our nuclear medicine department, the patients received two different types of amino acid perfusion over time: a commercial solution (CS) containing 10% amino acids, and a 2.5% lysine−arginine (LysArg) hospital preparation, produced by a referral laboratory. The aim of the present study was to analyze the tolerance of the two amino acid solutions. Methods: The patient files were analyzed and double-checked. The study parameters comprised the gender, age, primary tumor site, type of amino acid perfusion, adverse events (AE) and WHO AE grades, antiemetic premedication, creatinine, and serum potassium level. Results: From February 2016 to February 2019, 76 patients were treated, for a total 235 cycles. AEs occurred in 71% of the CS cycles (n = 82/116), versus 18% (n = 21/119) in the LysArg group (p < 0.0001). In the CS group, the AEs were mostly WHO grade 4 (n = 24/82), and mostly grade 1 in the LysArg group (n = 13/21). Poisson regression showed a higher risk of AE overall and of grades 3 and 4 in the females and with CS. The mean creatinine clearance was identical before and after the PRRT cycles, whichever amino acid perfusion was used. Conclusions: The lysine−arginine preparation showed better tolerance than the commercial solution. The change to LysArg reduced the antiemetic premedication from four molecules to one.

Prognostic Impact of Microscopic Extra-Thyroidal Extension (mETE) on Disease Free Survival in Patients with Papillary Thyroid Carcinoma (PTC).

Background: This study assessed the risk of reduced disease-free survival (DFS) and poor clinical outcome in patients with papillary thyroid carcinomas (PTC) with microscopic extra-thyroidal extension (mETE), as compared to PTC patients without mETE. Methods: Retrospective analysis of a prospective database of patients treated by total thyroidectomy and radioactive iodine (RAI) with a five-year follow-up and tumors < 40 mm. In total, 303 patients were analyzed: 30.7% presented tumors with mETE, and 69.3% without. mETE was defined as extra-thyroidal invasion without skeletal muscle involvement. The primary outcome, DFS, was defined as the interval between initial treatment and any subsequent PTC-related treatment. The second outcome was the clinical status at five years. Results: In univariate analyses, the five-year DFS was significantly lower for tumors with mETE (62.4% versus 88.1%, p < 0.001). In multivariate analysis, mETE and massive lymph node involvement (LNI) were independent prognostic factors, associated respectively with a hazard ratio of 2.55 (95% CI 1.48−4.40) and 8.94 (95% CI 4.92−16.26). mETE was significantly associated with a pejorative clinical outcome at five years, i.e., biochemical/indeterminate response and structural persistence (Respectively OR 1.83 (95% CI 0.83; 4.06) and OR 4.92 (95% CI 1.87; 12.97)). Conclusion: Our results suggest that mETE is an independent poor prognosis factor of reduced DFS and predictive of poor clinical outcome.

Results of combined treatment of anaplastic thyroid carcinoma (ATC).

BACKGROUND: Anaplastic thyroid carcinoma (ATC) is among the most aggressive human malignancies. It is associated with a high rate of local recurrence and with poor prognosis. METHODS: We retrospectively reviewed 44 consecutive patients treated between 1996 and 2010 at Leon Berard Cancer Centre, Lyon, France. The combined treatment strategy derived from the one developed at the Institut Gustave Roussy included total thyroidectomy and cervical lymph-node dissection, when feasible, combined with 2 cycles of doxorubicin (60 mg/m2) and cisplatin (100 mg/m2) Q3W, hyperfractionated (1.2 Gy twice daily) radiation to the neck and upper mediastinum (46-50 Gy), and then four cycles of doxorubicin-cisplatin. RESULTS: Thirty-five patients received the three-phase combined treatment. Complete response after treatment was achieved in 14/44 patients (31.8%). Eight patients had a partial response (18.2%). Twenty-two (50%) had progressive disease. All patients with metastases at diagnosis died shortly afterwards. Thirteen patients are still alive. The median survival of the entire population was 8 months. CONCLUSION: Despite the ultimately dismal prognosis of ATC, multimodality treatment significantly improves local control and appears to afford long-term survival in some patients. There is active ongoing research, and results obtained with new targeted systemic treatment appear encouraging.

Safety and Efficacy of Peptide-Receptor Radionuclide Therapy in Elderly Neuroendocrine Tumor Patients.

Peptide receptor radionuclide therapy (PRRT) is a well-established treatment in somatostatin receptor-expressing neuroendocrine tumours (NETs). The safety and efficacy of PRRT in >79 years old patients (EP) have not been systematically investigated. All patients with inoperable/metastatic/progressive G1/G2 NET, >79 years (EP), treated with PRRT at the University Hospital of Basel between 2006 and 2018, were enrolled in this retrospective matched cohort study. Each patient was manually matched with ≥1 younger patient (YP = 60-70 years). The primary endpoint was toxicity. Toxicity (subacute, long-term) was graded according to the criteria for adverse events (CTCAE) v5.0. All toxicity grades ≥ 3, or whose delta (Δ) to baseline were ≥2, were considered significant. The odds ratio (OR) for developing toxicity was tested for non-inferiority of EP vs. YP. Clinical response to PRRT and overall survival (OS) were assessed as secondary outcome measures. Forty-eight EP and 68 YP were enrolled. Both cohorts were balanced regarding median time since diagnosis, tumour location, grading, treatment scheme, and baseline biochemical parameters, except for eGFR (EP: 61 ± 16 vs. YP: 78 ± 19; mL/min/1.73 m2). Twenty-two grade ≥ 3 or Δ ≥ 2 subacute hematotoxicities occurred in 10 EP (10.3% of cycles) and 37 in 19 YP (11.6% of cycles; p = NS). Long-term grade ≥ 3 renal toxicity occurred in 7 EP and 2 YP (p = NS). The median OS was 3.4 years (EP) vs. 6.0 years (YP), HR: 1.50 [0.75, 2.98], p = NS. PRRT is a valid therapeutic option in elderly NET patients with similar toxicity and non-inferior survival compared to matched younger patients.

Thyroglobulin measurement in fine-needle aspirates of lymph nodes in patients with differentiated thyroid cancer: a simple definition of the threshold value, with emphasis on potential pitfalls of the method.

BACKGROUND: Thyroglobulin measurements in fine-needle aspirate (FNA-Tg) is an accurate method for the diagnosis of lymph node metastasis in differentiated thyroid carcinoma. The goal of this study is to determine the most appropriate diagnostic threshold value for FNA-Tg. METHODS: Ultrasound-guided fine-needle aspiration-cytology (FNA-C) and FNA-Tg were performed on suspicious lymph nodes in 114 consecutive patients with thyroid cancer prior to thyroidectomy (n=13) or during follow-up (n=93), and in 16 control subjects. Functional sensitivity of the thyroglobulin assay was 0.7 ng/mL. Sensitivity and specificity of FNA-Tg and FNA-C were determined for different cut-off values within a range of 0.69-1.34 nanogram/punction (ng/p) using receiver operating characteristic curve analysis. RESULTS: The FNA-Tg cut-off value of 0.93 ng/p offers the best diagnostic performances: 94.2% sensitivity, 97.8% specificity. FNA-C showed 100% specificity in diagnostic samples, but low sensitivity of 71% due primarily to inadequate samples. Combining FNA-C and FNA-Tg resulted in 98% sensitivity and 100% specificity. CONCLUSIONS: A unique threshold of 0.93 ng/p gives high sensitivity and specificity, even in non-thyroidectomized patients. However, since false negative results may be observed in poorly differentiated thyroid cancer, FNA-C should remain combined to FNA-Tg.

TERT promoter mutations identify a high-risk group in metastasis-free advanced thyroid carcinoma.

BACKGROUND: TERT promoter mutations are associated with adverse clinicopathological characteristics in thyroid carcinomas and considered as a major indicator of poor outcomes. Nevertheless, most studies have pooled heterogeneous types of thyroid carcinomas and have been conducted retrospectively. We investigated the association between TERT promoter mutations and recurrence in a prospective series of 173 intermediate- to high-risk patients with thyroid cancer. PATIENTS: Patients referred for radioiodine treatment after thyroidectomy for intermediate- to high-risk differentiated thyroid carcinoma were included in a prospective observational study and tested for TERT promoter, BRAF, and RAS mutations of their primary tumours. We analysed the relationship between TERT promoter mutations and outcomes. RESULTS: The prevalence of TERT promoter mutations was 20.2% (35/173) in the total population. It was significantly higher in tumours harbouring aggressive histological features (poorly differentiated carcinoma, tall cell variant of papillary cancer or widely invasive follicular cancer) than in non-aggressive tumours: 32.7% (16/49) versus 15.3% (19/124; p = 0.020). TERT promoter mutations were also strongly associated with age ≥45 years (p = 0.005), pT4 stage (p = 0.015), metastatic disease (p = 0.014), and extrathyroidal extension (p = 0.002). TERT promoter mutations were associated with poor outcomes in the total population (p < 0.001) but not in the subgroup of non-metastatic patients (p = 0.051). However, they were associated with a worse outcome in patients both free of metastases and devoid of aggressive histological features. Neither BRAF nor RAS mutations were associated with event-free survival in non-metastatic patients. CONCLUSION: Although their prognostic value does not seem to overcome that of histology, TERT promoter mutations may help to better define the prognosis of localized thyroid cancer patients without aggressive histology.

Recombinant Thyrotropin vs Levothyroxine Withdrawal in 131I Therapy of N1 Thyroid Cancer: A Large Matched Cohort Study (ThyrNod).

CONTEXT: Recombinant human thyrotropin (rhTSH) has been shown to be an effective stimulation method for radioactive iodine (RAI) therapy in differentiated thyroid cancer, including in those with nodal metastases (N1 DTC). OBJECTIVES: To demonstrate the noninferiority of rhTSH vs thyroid hormone withdrawal (THW) in preparation to RAI regarding disease status at the first evaluation in the real-life setting in patients with N1 DTC. DESIGN: This was a French multicenter retrospective study. Groups were matched according to age (<45/≥45 years), number of N1 nodes (≤5/>5 lymph nodes), and stage (pT1-T2/pT3). RESULTS: The cohort consisted of 404 patients pT1-T3/N1/M0 DTC treated with rhTSH (n = 205) or THW (n = 199). Pathological characteristics and initially administrated RAI activities (3.27 ± 1.00 GBq) were similar between the two groups. At first evaluation (6 to 18 months post-RAI), disease-free status was defined by thyroglobulin levels below threshold and a normal ultrasound. Disease-free rate was not inferior in the rhTSH group (75.1%) compared with the THW group (71.9%). The observed difference between the success rates was 3.3% (-6.6 to 13.0); rhTSH was therefore considered noninferior to THW because the upper limit of this interval was <15%. At the last evaluation (29.7 ± 20.7 months for rhTSH; 36.7 ± 23.8 months for THW), 83.5% (rhTSH) and 81.5% (THW) of patients achieved a complete response. This result was not influenced by any of the known prognostic factors. CONCLUSIONS: A preparation for initial RAI treatment with rhTSH was noninferior to that with THW in our series of pT1-T3/N1/M0-DTC on disease-free status outcomes at the first evaluation and after 3 years.

Evaluation of gene expression profiles in thyroid nodule biopsy material to diagnose thyroid cancer.

CONTEXT: Detection of thyroid cancer among benign nodules on fine-needle aspiration biopsies (FNAB), which presently relies on cytological examination, is expected to be improved by new diagnostic tests set up from genomic data. OBJECTIVE: The aim of the study was to use a set of genes discriminating benign from malignant tumors, on the basis of their expression levels, to build tumor classifiers and evaluate their capacity to predict malignancy on FNAB. DESIGN: We analyzed the level of expression of 200 potentially informative genes in 56 thyroid tissue samples (benign or malignant tumors and paired normal tissue) using nylon macroarrays. Gene expression data were subjected to a weighted voting algorithm to generate tumor classifiers. The performances of the classifiers were evaluated on a series of 26 sham FNAB, i.e. FNAB carried out on thyroid nodules after surgical resection. RESULTS: A series of 19 genes with a similar expression in follicular adenomas and normal tissue and discriminating follicular adenomas+normal tissue from the following: 1) follicular thyroid carcinomas (FTCs), 2) papillary thyroid carcinomas (PTCs), or 3) both FTCs and PTCs. These were used to generate four classifiers, the FTCs, PTCs, common (FTC+PTCs), and global classifiers. In 23 of the 26 sham FNAB, the four classifiers yielded a diagnosis in agreement with the diagnosis of the pathologist used as reference; in the three other cases, the correct diagnosis was given by three of four classifiers. CONCLUSIONS: We developed a procedure of molecular diagnosis of benign vs. malignant tumors applicable to the material collected by FNAB. The molecular test complied with a preclinical validation stage; it must be now evaluated on ultrasound-guided FNAB in a large-scale prospective study.

131I effective half-life and dosimetry in thyroid cancer patients.

UNLABELLED: (131)I treatment in thyroid cancer patients may induce side effects, including extrathyroidal cancer and leukemia. There are still some uncertainties concerning parameters that may influence the effective half-life of (131)I and the absorbed doses by extrathyroidal organs. METHODS: Whole-body retention of radioiodine was measured in 254 patients, and repeated quantitative whole-body scans and measurements of the urinary excretion of (131)I were performed on 30 of these patients. RESULTS: The mean effective half-life (10.5 h) was shorter by 31%, with little difference between patients, in the 36 patients who received recombinant human thyroid-stimulating hormone than in the 218 patients who underwent thyroid hormone withdrawal (15.7 h). The residence times in the stomach and in the rest of the body were significantly shorter in patients who received recombinant human thyroid-stimulating hormone than in patients who underwent withdrawal, but the residence times were similar in the colon and bladder. CONCLUSION: In patients who undergo thyroid hormone withdrawal, the longer mean effective half-life is mainly due to delayed renal excretion of (131)I and results in dose estimates higher than the data in report 53 of the International Commission on Radiological Protection, which were obtained from healthy, euthyroid subjects.

Graves' disease and pregnancy.

This section deals with the specificities of managing Graves' disease during pregnancy. Graves' disease incurs risks of fetal, neonatal and maternal complications that are rare but may be severe: fetal hyper- or hypothyroidism, usually first showing as fetal goiter, neonatal dysthyroidism, premature birth and pre-eclampsia. Treatment during pregnancy is based on antithyroid drugs alone, without association to levothyroxine. An history of Graves' disease, whether treated radically or not, with persistent maternal anti-TSH-receptor antibodies must be well identified. Fetal monitoring should be initiated in a multidisciplinary framework that should be continued throughout pregnancy. Neonatal monitoring is also crucial if the mother still shows anti-TSH-receptor antibodies at end of pregnancy or underwent antithyroid treatment. The risk of recurrence of hyperthyroidism in the weeks following delivery requires maternal monitoring. The long-term neuropsychological progression of children of mothers with Graves' disease is poorly known.

Outcome after ablation in patients with low-risk thyroid cancer (ESTIMABL1): 5-year follow-up results of a randomised, phase 3, equivalence trial.

BACKGROUND: In ESTIMABL1, a randomised phase 3 trial of radioactive iodine (131I) administration after complete surgical resection in patients with low-risk thyroid cancer, 92% of patients had complete thyroid ablation at 6-10 months, defined as a recombinant human thyroid-stimulating hormone (rhTSH)-stimulated serum thyroglobulin concentration of 1 ng/mL or less and normal findings on neck ultrasonography. Equivalence was shown between low-activity (1·1 GBq) and high-activity (3·7 GBq) radioactive iodine and also between the use of rhTSH injections and thyroid hormone withdrawal. Here, we report outcomes after 5 years of follow-up. METHODS: This multicentre, randomised, open-label, equivalence trial was done at 24 centres in France. Between March 28, 2007, and Feb 25, 2010, we randomly assigned (1:1:1:1) adults with low-risk differentiated thyroid carcinoma who had undergone total thyroidectomy to one of four strategies, each combining one of two methods of thyrotropin stimulation (rhTSH or thyroid hormone withdrawal) and one of two radioactive iodine activities (1·1 GBq or 3·7 GBq). Randomisation was by computer-generated sequence, with variable block size. Follow-up consisted of a yearly serum thyroglobulin measurement on levothyroxine treatment. Measurement of rhTSH-stimulated thyroglobulin and neck ultrasonography were done at the discretion of the treating physician. No evidence of disease was defined as serum thyroglobulin of 1 ng/mL or less on levothyroxine treatment and normal results on neck ultrasonography, when performed. This study was registered with ClinicalTrials.gov, number NCT00435851. FINDINGS: 726 patients (97% of the 752 patients originally randomised) were followed up. At a median follow-up since randomisation of 5·4 years (range 0·5-9·2), 715 (98%) had no evidence of disease. The other 11 had either structural disease (n=4), raised serum thyroglobulin concentration (n=5), or indeterminate findings on neck ultrasonography (n=2). At ablation, six of these patients had received 1·1 GBq radioactive iodine (five after rhTSH and one after withdrawal) and five had received 3·7 GBq (two after rhTSH and three after withdrawal). TSH-stimulated (either after rhTSH injections or thyroid hormone withdrawal according to the treatment group) thyroglobulin concentration measured at the time of ablation was prognostic for structural disease status at ablation, ablation status at 6-10 months, and the final outcome. INTERPRETATION: Our findings suggest that disease recurrence was not related to the strategy used for ablation. These data validate the use of 1·1 GBq radioactive iodine after rhTSH for postoperative ablation in patients with low-risk thyroid cancer. FUNDING: French National Cancer Institute (INCa), French Ministry of Health, and Sanofi Genzyme.

Effect of Buparlisib, a Pan-Class I PI3K Inhibitor, in Refractory Follicular and Poorly Differentiated Thyroid Cancer.

BACKGROUND: Dysregulation of the phosphatidylinositol 3-kinase (PI3K) pathway is frequent in advanced follicular (FTC) and poorly differentiated thyroid (PDTC) carcinomas and has been implicated in oncogenesis and tumor progression. This study investigated the efficacy and safety of buparlisib, a pan-PI3K inhibitor in radioiodine refractory FTC and PDTC. METHODS: The primary endpoint of this open-label, multicenter, phase 2 pilot study was progression-free survival (PFS) at 6 months. The sample size was determined considering that a PFS ≤50% at 6 months would denote an absence of benefits (null hypothesis). Secondary endpoints were objective response rate, PFS at 12 months, overall survival at 6 and 12 months, and safety based on the frequency and severity of adverse events (AEs). RESULTS: Forty-three patients (19M/24 F; median age: 67 years) with metastatic, radioiodine refractory, progressive disease received buparlisib, 100 mg, daily. Histology was PDTC in 25 (58%), FTC in 17 (40%), and Hürthle cell carcinoma in 1 (2%). RAS mutation was found in 44% (12/27) and activation of the PI3K pathway in 35% (8/23) of tested tumors. The probability of PFS was 41.7% [95% confidence interval (CI) 7.7-55.5] at 6 months and 20.9% [CI 0-35.7] at 12 months, lower than the 50% expected PFS. At 6 months, 25.6% patients had stable disease, 48.8% were progressive and 25.6% had stopped treatment due to AE. The response to therapy was not influenced by age, sex, histology, or genetic alterations. The overall survivals at 6 and 12 months were 85.9% [CI 76-97] and 78.7 % [CI 67-92], respectively. The mean tumor growth rate decreased from 3.78 mm/month [CI 2.61-4.95] before treatment to 0.8 mm/month [CI -0.2-1.88] during treatment (p < 0.02). Severe grade 3-4 AEs occurred in 27 patients (63%), including hepatitis (25%), hyperglycemia (21%), mood disorders (12%), and skin toxicity (12%), with favorable outcome after temporary or permanent treatment discontinuation or dose reduction. CONCLUSIONS: Buparlisib did not result in significant efficacy in advanced FTC and PDTC. However, the decrease in tumor growth rate may suggest incomplete inhibition of oncogenic pathways and/or escape mechanisms. This should lead to evaluate combined therapy associating inhibitors of both the PI3K and mitogen-activated protein kinase pathways.

Sensitivity and prognostic value of positron emission tomography with F-18-fluorodeoxyglucose and sensitivity of immunoscintigraphy in patients with medullary thyroid carcinoma treated with anticarcinoembryonic antigen-targeted radioimmunotherapy.

CONTEXT: Patients with progressive medullary thyroid carcinoma (MTC) undergo multiple imaging procedures for diagnosis of relapse and staging. OBJECTIVE: Our objective was to assess the sensitivity and prognostic value of 18F-2-fluoro-2-deoxy-d-glucose (FDG) positron emission tomography (PET)/computed tomography (CT), and the imaging sensitivity of pretargeted iodine-131-radioimmunotherapy (RIT) in patients with progressive MTC. DESIGN/SETTING/PATIENTS: We performed a prospective multicenter study in high-risk patients with rapidly progressing MTC enrolled in a phase-II pretargeted RIT study, as documented by short serum calcitonin (Ct) or carcinoembryonic antigen (CEA) doubling time (DT). INTERVENTIONS/MAIN OUTCOME MEASURES: Patients underwent neck-thoracic-abdominal CT, spine and pelvic magnetic resonance imaging, whole-body post-RIT immunoscintigraphy (IS) with iodine-131, and whole-body 18F-FDG-PET/CT imaging. Imaging sensitivity and the correlation between FDG uptake and biomarkers DT were evaluated. RESULTS: A total of 33 patients with mean CEA and Ct DTs of 1.90 yr (range 0.21-8.50) and 1.52 yr (range 0.09-6.01), respectively, were evaluated. Sensitivity of FDG-PET/CT was 83% for neck, 85% for mediastinal, 75% for lung, 60% for liver, and 67% for bone metastases; overall sensitivity was 76%. Median standardized uptake value (SUVmax) was 5.23 (2.06-13.90). SUVmax correlated significantly with Ct DT (P = 0.011) and minimal DT (minimal value between CEA DT and Ct DT) (P = 0.027). Overall sensitivity of post-RIT IS, CT, and bone magnetic resonance imaging were 94, 74, and 85%, respectively. CONCLUSIONS: These results demonstrate the value of FDG-PET/CT for staging of patients with progressive MTC, especially in the neck and mediastinum, with possible prognostication by SUV quantification. Post-RIT IS was the most sensitive of the imaging modalities studied prospectively.