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Radioiodine (RAI) is selectively recommended for intermediate-risk differentiated thyroid carcinomas (DTC). The information gleaned from pretherapy stimulated thyroglobulin levels (sTg) and diagnostic 131I whole-body scans (DxWBS) to guide therapy remains controversial. The present study aimed at evaluating the impact of preablation sTg and DxWBS in the management of intermediate-risk DTC. A retrospective analysis of 301 intermediate-risk DTC patients submitted to total thyroidectomy and RAI therapy was performed. Pretherapy sTg and DxWBS and post-therapy WBS (RxWBS) findings were analyzed and compared to outcomes. Fifty-two patients (17.3%) had metastases diagnosed by DxWBS and/or RxWBS. The DxWBS identified 10.6% of patients with functioning metastases, including unexpected distant metastases. If combined with SPECT-CT, DxWBS detected RAI-avid metastases more frequently, particularly lymph node metastases (13.1% vs 4.2% planar WBS, P = 0.015). The DxWBS findings modified patient management in 8.3%. A pretherapy sTg

Scarce data are available on the quality of life and psychosocial distress of patients with multiple endocrine neoplasia type 2 (MEN2), a genetic cancer syndrome caused by RET germline mutations. Carriers of RET mutations can face several challenges, including fear for the future, guilt for transmission of a germline mutation to an offspring, side effects of cancer treatment, coping behaviors in the face of a chronic and frequently incurable cancer, and difficulties in access to adequate health care. We have addressed the effects of genetic testing on the quality of life of patients with MEN2 and the lifelong physical and psychosocial challenges experienced by these patients. We have also suggested strategies to minimize the burden of living with this chronic condition and the perspectives on future studies to improve the health-related quality of life of the patients.

PURPOSE: To compare the (18)F-NaF PET/CT studies ((18)F-NaF) with other imaging methods in the detection of skeletal metastases (SM) in patients with medullary thyroid cancer (MTC). METHODS: We retrospectively analyzed 31 patients with MTC who performed (18)F-NaF to assess SM. The results of the (18)F-NaF were compared with other imaging methods performed for metastasis detection: (99)Tc-MDP bone scan (BS), magnetic resonance imaging (MRI), contrast-enhanced CT (CT), and (68)Ga-Dotatate and (18)F-FDG PET/CT studies. A qualitative analysis comparing the (18)F-NaF findings with the ones of the other methods was performed, and the results were classified as superior (>), equal (=), and inferior ( BS and in 3 (18)F-NaF = BS), 1 performed (18)F-FDG ((18)F-NaF > (18)F-FDG), 4 performed (68)Ga-Dotatate (in 2 (18)F-NaF > (68)Ga-Dotatate and in 2 (18)F-NaF = (68)Ga-Dotatate), 20 performed CT of at least one body segment (in 15 (18)F-NaF = CT and in 5 (18)F-NaF > CT), and 16 performed MRI of at least one body segment, and in all of them, the (18)F-NaF was equal to the MRI. Beside this, the (18)F-NaF detected SM in body segments not routinely scanned in MRI and CT. CONCLUSION: In patients with MTC, the (18)F-NaF seems to be equal or superior to other imaging modalities in the detection of SM and allows the analysis of the whole skeletal in a single study.

Purpose The aim of the study was to assess the association between the burden of metastatic bone disease measured on F-NaF PET/computed tomography (CT) studies and the overall survival (OS) of patients with medullary thyroid cancer (MTC). Methods We retrospectively analyzed 31 patients with MTC who performed 18F-NaF PET/CT studies to assess skeletal metastases. The outcomes of the patients (dead or alive) were established based on the last information available on their files. In the studies considered positives for skeletal metastases, the burden of metastatic bone disease was established calculating the fluoride tumor volume (FTV). The FTV was defined using isocontour thresholds based on percentages of maximal standardized uptake values (SUVmax) in the lesions. These percentages varied from lesion to lesion and were established by visual analysis. The patients were divided into three groups as follows: without skeletal metastases (n = 11), with low FTV (≤50 cm; n = 11) and with high FTV (>50cm; n = 9). The Kaplan-Meier curves were used to analyze the OS in the three groups of patients and the log-rank test was used to determine the statistical significance of the difference between the groups. Results There were statistically significant differences in the OS between the group with high FTV and the groups of patients with low FTV (P = 0.036) and without skeletal metastases (P = 0.001). There was not a statistically significant difference between the groups of patients with low FTV and without skeletal metastases (P = 0.147). Conclusion In patients with MTC, the burden of metastatic bone disease is associated with OS.

Background: The morbidity of papillary thyroid carcinoma (PTC) is primarily related to locoregional recurrences and distant metastases. The definition of minimal extrathyroidal extension (mETE) has...

Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant genetic disease caused by RET gene germline mutations that is characterized by medullary thyroid carcinoma (MTC) associated with other endocrine tumors. Several reports have demonstrated that the RET mutation profile may vary according to the geographical area. In this study, we collected clinical and molecular data from 554 patients with surgically confirmed MTC from 176 families with MEN2 in 18 different Brazilian centers to compare the type and prevalence of RET mutations with those from other countries. The most frequent mutations, classified by the number of families affected, occur in codon 634, exon 11 (76 families), followed by codon 918, exon 16 (34 families: 26 with M918T and 8 with M918V) and codon 804, exon 14 (22 families: 15 with V804M and 7 with V804L). When compared with other major published series from Europe, there are several similarities and some differences. While the mutations in codons C618, C620, C630, E768 and S891 present a similar prevalence, some mutations have a lower prevalence in Brazil, and others are found mainly in Brazil (G533C and M918V). These results reflect the singular proportion of European, Amerindian and African ancestries in the Brazilian mosaic genome.

Treatment of advanced medullary thyroid carcinoma (MTC) was recently improved with the approval of vandetanib and cabozantinib. However, there is still a need to explore sequential therapy with more than one tyrosine kinase inhibitor (TKI) and to explore alternative therapies when vandetanib and cabozantinib are not available. This study reports the authors' experience with sorafenib as a treatment for advanced MTC.This is a retrospective longitudinal study of 13 patients with progressive metastatic MTC treated with sorafenib 400 mg twice daily between December 2011 and January 2015. The primary endpoints were to evaluate response and progression-free survival (PFS) in patients treated with sorafenib outside a clinical trial. The secondary endpoint was an assessment of the toxicity profile. One patient was excluded because of a serious allergic skin rash one week after starting sorafenib.The analysis included 12 patients with metastatic MTC (median age 48 years), 10 with sporadic and 2 with hereditary disease. The median duration of treatment was 11 months, and the median follow-up was 15.5 months. At data cutoff, 2/12 (16%) patients were still on treatment for 16 and 34 months. According to Response Evaluation Criteria in Solid Tumors analysis, 10 (83.3%) patients showed stable disease, and two (16.6%) had progression of disease; no partial response was observed. The median PFS was nine months. However, three patients with extensive and rapidly progressive disease died within three months of sorafenib treatment. The median PFS excluding these three patients was 12 months. Adverse events (AE) occurred in nine (75%) patients. The main AEs were skin toxicity, weight loss, and fatigue. Five (41.6%) patients needed dose reduction, and one patient discontinued treatment because of toxicity.Treatment with sorafenib in progressive metastatic MTC is well tolerated and resulted in disease control and durable clinical benefit in 75% of patients. Sorafenib treatment could be considered when vandetanib and cabozantinib are not available or after failing these drugs.

Context Persistent disease after surgery is common in medullary thyroid cancer (MTC), requiring lifelong radiological surveillance. Staging workup includes imaging of neck, chest, abdomen, and bones. A study integrating all sites would be ideal. Despite the established use of gallium-68 (68Ga) positron emission tomography (PET)/CT with somatostatin analogues in most neuroendocrine tumors, its efficacy is controversial in MTC. Objective Evaluate the efficacy of 68Ga PET/CT in detecting MTC lesions and evaluate tumor expression of somatostatin receptors (SSTRs) associated with 68Ga PET/CT findings. Methods Prospective study evaluating 30 patients with MTC [group 1 (n = 16), biochemical disease; group 2 (n = 14), metastatic disease]. Patients underwent 68Ga PET/CT, bone scan, CT and ultrasound of the neck, CT of the chest, CT/MRI of the abdomen, and MRI of the spine. 68Ga PET/CT findings were analyzed by disease site as positive or negative and as concordant or discordant with conventional studies. Sensitivity and specificity were calculated using pathological or cytological analysis or unequivocal identification by standard imaging studies. Immunohistochemical analysis of SSTRs was compared with 68Ga PET/CT findings. Results In both groups, 68Ga PET/CT was inferior to currently used imaging studies except for bone scan. In group 2, 68Ga PET/CT sensitivities were 56%, 57%, and 9% for detecting neck lymph nodes, lung metastases, and liver metastases, respectively, and 100% for bone metastases, superior to the bone scan (44%). Expression of SSTRs, observed in 44% of tumors, was not associated with 68Ga-DOTATATE uptake. Conclusions 68Ga PET/CT does not provide optimal whole-body imaging as a single procedure in patients with MTC. However, it is highly sensitive in detecting bone lesions and could be a substitute for a bone scan and MRI.

Background: Adrenalectomy is standard of care for phaeochromocytomas, but for bilateral phaeochromocytoma, the recommendations are inconsistent. However, large studies systematically investigating long-term outcomes for total adrenalectomies compared to those for patients with adrenal-sparing operations are lacking. Methods: A multi-center consortium-based registry was established to study clinical, genetic and surgical data in 623 patients with bilateral phaeochromocytomas. Findings: Of 623 patients, median age at diagnosis was 30 (range 3-79) years and 48% were female. Synchronous bilateral phaeochromocytomas were diagnosed in 396 patients and metachronousphaeochromocytomas in 227 (36%); interval to second operations were up to 40 (median 6) years. In 96% of tested patients germline mutations were detected in the genes RET (56%), VHL (34%), and others (10%). Of 849 operations, 385 (45%) surgeries in 326 patients were planned as adrenal-sparing which was successful in 251. 372 patients became steroid-dependent. Follow-up was up to 53 (median 11) years. Adrenal crises developed in 67 patients (18%) during follow-up, and 49 (13%) had manifestations of iatrogenic Cushing syndrome. Of the steroid-independent patients, 34 (14%) had developed another phaeochromocytoma within the remnant adrenal after up to 27, median 8 years, all treated with removal of the new phaeochromocytoma. Overall survival was mainly influenced by non-phaeochromocytoma comorbidities, whereas only 1% died of metastatic phaeochromocytoma. Cortical-sparing operations did not affect survival. Interpretation: Cortical-sparing operations avert lifelong steroid-dependency without affecting survival. Preoperative genetic testing is recommended even in unilateral phaeochromocytoma presentations to identify patients at heritable risk, to guide surgical approach, and inform for gene-specific extra-adrenal morbidities. Funding Statement: Supported in part by the grant AZV 16-32665A to Sarka Dvorakova and Petr Vlcek, and the Blank Foundation to Charis Eng. Declaration of Interests: None of the authors have relevant conflicts of interest. Ethics Approval Statement: The institutional review boards for human subjects’ protection or ethical committees of all participating centers approved this study. Patients provided written informed consent according to the protocols of respective institutional review boards. In The Netherlands data were collected anonymously, and no further Institutional Review Board approval is required.

Herein, we report a case of a 19-year-old man with multiple endocrine neoplasia type 2B (MEN2B) and medullary thyroid carcinoma (MTC) diagnosed when he was 12 years of age. The patient had previously undergone total thyroidectomy, cervical radiotherapy, and chemotherapy. He progressed with known bone, pulmonary, and lymph node metastases and was scanned with (18)F-fluoride ((18)F-NaF) and (68)Ga-dotatate whole-body positron emission tomography/computed tomography (PET/CT) for metastatic disease monitoring. We found that the MTC bone metastases and soft tissue calcified metastases were better characterized on (18)F-NaF PET/CT than on (68)Ga-dotatate PET/CT. This case illustrates that the (18)F-NaF PET/CT could be helpful not only to the detection of bone metastases but also to the detection of calcified soft tissue metastases in patients with MTC.

Thyroid cancer is the most common endocrine malignancy, but due to its rare occurrence in the pediatric population, the cancer risk of childhood thyroid nodules is incompletely defined, and optimal management of children with suspected nodules is debated.The aim was to study the presenting features and cancer risk of sporadic childhood thyroid nodules using a standardized clinical assessment and management plan.Boston Children's Hospital and Brigham and Women's Hospital collaborated to create a multidisciplinary pediatric thyroid nodule clinic and implement a standardized assessment plan. Upon referral for a suspected nodule, serum TSH was measured and hypothyrotropinemic patients underwent (123)I scintigraphy. All others underwent thyroid ultrasonography, and if this confirmed nodule(s) ≥ 1 cm, ultrasound-guided fine-needle aspiration was performed. Medical records were retrospectively reviewed and compared to a control population of 2582 adults evaluated by identical methods.Of 300 consecutive children referred for the initial evaluation of suspected thyroid nodules from 1997 to 2011, 17 were diagnosed with autonomous nodules by scintigraphy. Neck ultrasonography performed in the remainder revealed that biopsy was unnecessary in over half, either by documenting only sub-centimeter nodules or showing that no nodule was present. A total of 125 children met criteria for thyroid biopsy, which was performed without complication. Their rate of cancer was 22%, significantly higher than the adult rate of 14% (P = .02).Neck ultrasonography and biopsy were key to the evaluation of children with suspected thyroid nodules. Although the relative cancer prevalence of sonographically confirmed nodules ≥ 1 cm is higher in pediatric patients than adults, most children referred for suspected nodules have benign conditions, and efforts to avoid unnecessary surgery in this majority are warranted.

In a retrospective analysis of childhood thyroid nodules, 18% were radiographic incidentalomas and 41% were discovered by a clinician's palpation; 40% were discovered by patients' families. The latter group had the largest nodules and highest rates of thyroid cancer metastasis, suggesting opportunities for earlier detection through annual well-child visits.

Thyroid hormone is a master regulator of differentiation and growth, and its action is terminated by the enzymatic removal of an inner-ring iodine catalyzed by the selenoenzyme type 3 deiodinase (dio3). Our studies of the zebrafish reveal that the dio3 gene is duplicated in this species and that embryonic deiodination is an important determinant of embryo size. Although both dio3 paralogs encode enzymatically active proteins with high affinity for thyroid hormones, their anatomic patterns of expression are markedly divergent and only embryos with knockdown of dio3b, a biallelically expressed selenoenzyme expressed in the developing central nervous system, manifest severe thyroid hormone-dependent growth restriction at 72 hours post fertilization. This indicates that the embryonic deficiency of dio3, once considered only a placental enzyme, causes microsomia independently of placental physiology and raises the intriguing possibility that fetal abnormalities in human deiodination may present as intrauterine growth retardation. By mapping the gene structures and enzymatic properties of all four zebrafish deiodinases, we also identify dio3b as the first multiexon dio3 gene, containing a large intron separating its open reading frame from its selenocysteine insertion sequence (SECIS) element.

Type 3 deiodinase (D3), the physiologic inactivator of thyroid hormones, is induced during tissue injury and regeneration. This has led to the hypotheses that D3 impacts injury tolerance by reducing local T3 signaling and contributes to the fall in serum triiodothyronine (T3) observed in up to 75% of sick patients (termed the low T3 syndrome). Here we show that a novel mutant mouse with hepatocyte-specific D3 deficiency has normal local responses to toxin-induced hepatonecrosis, including normal degrees of tissue necrosis and intact regeneration, but accelerated systemic recovery from illness-induced hypothyroxinemia and hypotriiodothyroninemia, demonstrating that peripheral D3 expression is a key modulator of the low T3 syndrome.

Because of its large mass, relatively high metabolic activity and responsiveness to thyroid hormone, skeletal muscle contributes significantly to energy expenditure. Despite the presence of mRNA encoding the type 2 iodothyronine-deiodinase (D2), an enzyme that activates T4 to T3, very low or undetectable activity has been reported in muscle homogenates of adult humans and mice. With a modified D2 assay, using microsomal protein, overnight incubation and protein from D2 knockout mouse muscle as a tissue-specific blank, we examined slow- and fast-twitch mouse skeletal muscles for D2 activity and its response to physiological stimuli. D2 activity was detectable in all hind limb muscles of 8- to 12-wk old C57/BL6 mice. Interestingly, it was higher in the slow-twitch soleus than in fast-twitch muscles (0.40 ± 0.06 vs. 0.076 ± 0.01 fmol/min · mg microsomal protein, respectively, P < 0.001). These levels are greater than those previously reported. Hypothyroidism caused a 40% (P < 0.01) and 300% (P < 0.001) increase in D2 activity after 4 and 8 wk treatment with antithyroid drugs, respectively, with no changes in D2 mRNA. Neither D2 mRNA nor activity increased after an overnight 4 C exposure despite a 10-fold increase in D2 activity in brown adipose tissue in the same mice. The magnitude of the activity, the fiber specificity, and the robust posttranslational response to hypothyroidism argue for a more important role for D2-generated T3 in skeletal muscle physiology than previously assumed.

Summary Context A GHR-exon 3 polymorphism has been reported to influence the growth response to hGH therapy in short stature children. None of these studies provided data on IGF-1 generation test. Objective To evaluate the influence of the GHR-exon 3 polymorphism on the generation test in children with idiopathic short stature (ISS). Design and patients A total of 45 prepubertal ISS children were submitted to IGF-1 and IGFBP-3 generation test (4 days of hGH 33 µg/kg/day). Children were genotyped for GHR-exon 3: full-length (fl) and exon 3-deleted (d3) alleles. Measurements IGF-1 and IGFBP-3 increment as absolute values and standard deviation scores (SDS). Results Basal clinical and laboratory data were similar among patients with different genotypes (fl/fl vs. fl/d3 or d3/d3). All patients presented IGF-1 increase ≥ 15 µg/l at generation test. Children with GHRd3 allele, as a group, presented a statistically significant higher IGF-1 SDS increase at generation test than children homozygous for GHRfl allele (1·0 ranging from 0·1 to 3·7 for fl/fl vs. 1·2 ranging from 0·3 to 4·4 for fl/d3 and d3/d3; P = 0·037). Multiple linear regression found a positive association between increase in IGF-1 SDS with chronological age (P = 0·007) and GHR genotype (P = 0·027), which together explain 24% of the variability of IGF-1 SDS increment at generation test. There was no difference in IGFBP-3 generation test between the two genotype groups. Conclusion This study demonstrates that ISS children carrying the GHRd3 allele, as a group, present a slightly higher GH sensitivity regarding short-term IGF-1 generation during hGH stimulus than children homozygous for GHRfl allele.