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1. Endocrinology. 2016 Jun 2:en20152046. [Epub ahead of print] Thyroid Hormone Receptor β (TRβ) Mediates Runt-Related Transcription Factor 2 (Runx2) Expression in Thyroid Cancer Cells: A novel signaling pathway in thyroid cancer. Carr FE(1), Tai PW(2), Barnum MS(1), Gillis NE(1), Evans KG(1), Taber TH(1), White JH(1), Tomczak JA(1), Jaworski DM(3), Zaidi SK(2), Lian JB(2), Stein JL(2), Stein GS(2). Author information: (1)Departments of Pharmacology. (2)Biochemistry. (3)Neurological Sciences, College of Medicine, University of Vermont, 89 Beaumont Ave, Burlington Vermont 05405. Dysregulation of the thyroid hormone receptor β (TRβ) is common in human cancers. Restoration of functional TRβ delays tumor progression in models of thyroid and breast cancers implicating TRβ as a tumor suppressor. Conversely, aberrant expression of the runt-related transcription factor 2 (Runx2) is established in the progression and metastasis of thyroid, breast and other cancers. Silencing of Runx2 diminishes tumor invasive characteristics. With TRβ as a tumor suppressor and Runx2 as a tumor promoter, a compelling question is whether there is a functional relationship between these regulatory factors in thyroid tumorigenesis. Here, we demonstrated that these proteins are reciprocally expressed in normal and malignant thyroid cells; TRβ is high in normal cells and Runx2 is high in malignant cells. T3 induced a time and concentration dependent decrease in Runx2 expression. Silencing of TRβ by siRNA knock-down resulted in a corresponding increase in Runx2 and Runx2-regulated genes indicating that TRβ levels directly impact Runx2 expression and associated EMT molecules. TRβ specifically bound to three putative thyroid hormone response element (TRE) motifs within the Runx2-P1 promoter ((-)105/(+)133) as detected by electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP). TRβ suppressed Runx2 transcriptional activities thus confirming TRβ regulation of Runx2 at functional TREs. Significantly, these findings indicate that a ratio of the tumor-suppressor TRβ and tumor-promoting Runx2 may reflect tumor aggression and serve as biomarkers in biopsy tissues. The discovery of this TRβ-Runx2 signaling supports the emerging role of TRβ as a tumor suppressor and reveals a novel pathway for intervention. PMID: 27253998 [PubMed - as supplied by publisher] 2. Lancet. 2016 May 27. pii: S0140-6736(16)30172-6. doi: 10.1016/S0140-6736(16)30172-6. [Epub ahead of print] Thyroid cancer. Cabanillas ME(1), McFadden DG(2), Durante C(3). Author information: (1)Department of Endocrine Neoplasia and Hormonal Disorders, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: [email protected]. (2)Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA. (3)Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy. Thyroid cancer is the fifth most common cancer in women in the USA, and an estimated over 62 000 new cases occurred in men and women in 2015. The incidence continues to rise worldwide. Differentiated thyroid cancer is the most frequent subtype of thyroid cancer and in most patients the standard treatment (surgery followed by either radioactive iodine or observation) is effective. Patients with other, more rare subtypes of thyroid cancer-medullary and anaplastic-are ideally treated by physicians with experience managing these malignancies. Targeted treatments that are approved for differentiated and medullary thyroid cancers have prolonged progression-free survival, but these drugs are not curative and therefore are reserved for patients with progressive or symptomatic disease. Copyright © 2016 Elsevier Ltd. All rights reserved. PMID: 27240885 [PubMed - as supplied by publisher] 3. J Clin Endocrinol Metab. 2016 May 17:jc20161440. [Epub ahead of print] Risk stratification of neck lesions detected sonographically during the follow-up of differentiated thyroid cancer. Lamartina L(1), Grani G(1), Biffoni M(2), Giacomelli L(2), Costante G(3), Lupo S(1), Maranghi M(1), Plasmati K(1), Sponziello M(1), Trulli F(1), Verrienti A(1), Filetti S(1), Durante C(1). Author information: (1)Dipartimento di Medicina Interna e Specialità Mediche, Università di Roma "Sapienza", Viale del Policlinico 155, 00161 Roma, Italy. (2)Dipartimento di Scienze Chirurgiche, Università di Roma "Sapienza", Viale del Policlinico 155, 00161 Roma, Italy. (3)Department of Internal Medicine, Institut Jules Bordet Comprehensive Cancer Center, 1000 Brussels, Belgium. CONTEXT: The European Thyroid Association (ETA) has classified post-treatment cervical ultrasound findings in thyroid cancer patients based on their association with disease persistence/recurrence. OBJECTIVE: To assess this classification's ability to predict the growth and persistence of such lesions during active post-treatment surveillance of patients with differentiated thyroid cancer (DTC). DESIGN: Retrospective, observational study Setting: Thyroid cancer center, large Italian teaching hospital. PATIENTS: Center referrals (2005-2014) were reviewed and patients selected with pathologically confirmed DTC; total thyroidectomy, with or without neck dissection and/or radioiodine remnant ablation; abnormal findings on ≥2 consecutive post-treatment neck sonograms; subsequent follow-up consisting of active surveillance. Baseline ultrasound abnormalities (thyroid bed masses, lymph nodes) were classified according to the ETA system. Patients were divided into group S (those with ≥1 lesion classified as 'suspicious') and group I ('indeterminate' lesions only). We recorded baseline and follow-up clinical data through 30 June 2015. MAIN OUTCOMES: Patients with growth (> 3 mm, largest diameter) of ≥1 lesion during follow-up, patients with ≥1 persistent lesion at the final visit. RESULTS: The cohort included 58 (9%) of the 637 DTC cases screened. A total of 113 lesions were followed (18 thyroid bed masses, 95 lymph nodes). During surveillance (median 3.7 years), group I had significantly lower rates than group S of lesion growth (8% vs. 36%, p=0.01) and persistence (64% vs. 97%, p=0.014). Median time to scan normalization: 2.9 years. CONCLUSIONS: The ETA's evidence-based classification of sonographically detected neck abnormalities can help identify PTC patients eligible for more relaxed follow-up. PMID: 27186860 [PubMed - as supplied by publisher] 4. Nat Rev Endocrinol. 2016 May 13. doi: 10.1038/nrendo.2016.64. [Epub ahead of print] NADPH oxidases: new actors in thyroid cancer? Ameziane-El-Hassani R(1,)(2), Schlumberger M(1,)(3), Dupuy C(1,)(3). Author information: (1)Institut Gustave Roussy, UMR 8200 CNRS, 114 Rue Edouard Vaillant, Villejuif F-94805, France. (2)Unité de Biologie et de Recherche Médicale, Centre National de l'Energie, des Sciences et des Techniques Nucléaires, BP 1382, Rabat M-10001, Morocco. (3)University Paris-Saclay, Orsay F-91400, France. Hydrogen peroxide (H2O2) is a crucial substrate for thyroid peroxidase, a key enzyme involved in thyroid hormone synthesis. However, as a potent oxidant, H2O2 might also be responsible for the high level of oxidative DNA damage observed in thyroid tissues, such as DNA base lesions and strand breakages, which promote chromosomal instability and contribute to the development of tumours. Although the role of H2O2 in thyroid hormone synthesis is well established, its precise mechanisms of action in pathological processes are still under investigation. The NADPH oxidase/dual oxidase family are the only oxidoreductases whose primary function is to produce reactive oxygen species. As such, the function and expression of these enzymes are tightly regulated. Thyrocytes express dual oxidase 2, which produces most of the H2O2 for thyroid hormone synthesis. Thyrocytes also express dual oxidase 1 and NADPH oxidase 4, but the roles of these enzymes are still unknown. Here, we review the structure, expression, localization and function of these enzymes. We focus on their potential role in thyroid cancer, which is characterized by increased expression of these enzymes. PMID: 27174022 [PubMed - as supplied by publisher] 5. World J Surg. 2016 May 2. [Epub ahead of print] BRAF(V600E) Mutation is Associated with Decreased Disease-Free Survival in Papillary Thyroid Cancer. Fraser S(1), Go C(2), Aniss A(2), Sidhu S(2), Delbridge L(2), Learoyd D(3), Clifton-Bligh R(3), Tacon L(3), Tsang V(3), Robinson B(3), Gill AJ(4), Sywak M(2). Author information: (1)Surgical Endocrine Unit, Royal North Shore Hospital, University of Sydney, Level 3, Acute Services Building, Reserve Road, St Leonards, NSW, 2065, Australia. [email protected]. (2)Surgical Endocrine Unit, Royal North Shore Hospital, University of Sydney, Level 3, Acute Services Building, Reserve Road, St Leonards, NSW, 2065, Australia. (3)Department of Endocrinology, Royal North Shore Hospital and Sydney Medical School, University of Sydney, St Leonards, Australia. (4)Department of Anatomical Pathology, Royal North Shore Hospital and Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, University of Sydney, St Leonards, Australia. BACKGROUND: The BRAF (V600E) mutation is a recognised molecular marker in papillary thyroid cancer (PTC), reported incidence from 30 to 80 %. BRAF(V600E) aberrantly activates the MAPK pathway, a central regulator of cell growth and proliferation. Previous studies have reported conflicting data regarding the impact of BRAF(V600E) on clinicopathological features of PTC. The study aims to determine whether BRAF(V600E) is useful as a prognostic biomarker in PTC. METHODS: A cohort study of patients undergoing surgery for PTC was undertaken. The primary outcome measure was disease-free survival. Secondary outcome measures were tumour size, nodal positivity and radioactive iodine ablation rate. All cases were re-examined to confirm PTC. Immunohistochemistry for BRAF(V600E) was performed on tissue microarrays. A single endocrine pathologist, blinded to clinicopathological data, interpreted staining. RESULTS: 496 patients with PTC were included, and 309 (62 %) were BRAF(V600E) positive. Tumour size was similar for BRAF(V600E)-positive and -negative tumours (21.3 vs. 23.2 mm, p = 0.23). BRAF(V600E)-positive patients were significantly older at first operation (mean age 45 versus 49 years, p = 0.003). BRAF(V600E)-positive PTCs had a higher rate of disease recurrence (12.9 vs. 5.6 %, p = 0.004), lymph node metastasis (44 vs. 29.4 %, p = 0.004) and extra-thyroidal extension (44 vs. 22 %, p < 0.001). Five-year disease-free survival was 89.6 % for BRAF(V600E) positive and 96.3 % for negative tumours, p < 0.001. There was no difference between groups for vascular invasion or multifocality. The mean follow-up was 57 months for both groups. CONCLUSION: BRAF(V600E) in PTC predicts an increased risk of lymph node metastasis, extra-thyroidal extension and reduced disease-free survival. It is an additional useful prognostic biomarker. PMID: 27138882 [PubMed - as supplied by publisher] 6. Br J Surg. 2016 Apr 28. doi: 10.1002/bjs.10144. [Epub ahead of print] Risk factors for recurrence in patients with papillary thyroid carcinoma undergoing modified radical neck dissection. Lee YM(1), Sung TY(1), Kim WB(2), Chung KW(1), Yoon JH(1), Hong SJ(1). Author information: (1)Department of Surgery, University of Ulsan College of Medicine, Seoul, Korea. (2)Department of Internal Medicine, Asan Medical Centre, University of Ulsan College of Medicine, Seoul, Korea. BACKGROUND: This study evaluated the impact of lymph node-related factors on the risk of and site of recurrence in patients who had papillary thyroid carcinoma with lymph node metastasis in the lateral compartment (classified as pN1b). METHODS: Patients underwent total thyroidectomy with unilateral modified radical neck dissection for classical papillary thyroid carcinoma. Risk factors for recurrence were evaluated according to the pattern of recurrence. RESULTS: A total of 324 patients were included in the study. The median follow-up was 63 (range 14-181) months. Recurrence was detected in 47 patients (14·5 per cent). In the multivariable analysis, a maximum diameter of metastatic lymph nodes larger than 2·0 cm (hazard ratio (HR) 1·15, 95 per cent c.i. 1·06 to 1·25; P = 0·033) and a central compartment metastatic lymph node ratio of more than 0·42 (HR 3·35, 1·65 to 6·79; P < 0·001) were identified as independent risk factors for locoregional recurrence. Age 45 years or older (HR 5·69, 1·24 to 26·12; P = 0·025) and extranodal extension of metastasis (HR 12·71, 1·64 to 98·25; P = 0·015) were risk factors for distant metastasis. In subgroup analysis of locoregional recurrence, several lymph node-related factors affected the risk of recurrence according to the specific site of metastasis. CONCLUSION: Lymph node-related factors are of importance for the risk of recurrence in patients with classical papillary thyroid carcinoma classified as pN1b. © 2016 BJS Society Ltd Published by John Wiley & Sons Ltd. PMID: 27121346 [PubMed - as supplied by publisher] 7. Lancet Oncol. 2016 Apr 21. pii: S1470-2045(16)30089-4. doi: 10.1016/S1470-2045(16)30089-4. [Epub ahead of print] Thyroid cancer subtype downgraded to non-cancer. Tanday S. PMID: 27118318 [PubMed - as supplied by publisher] 8. Lancet Diabetes Endocrinol. 2016 Apr 21. pii: S2213-8587(16)00076-0. doi: 10.1016/S2213-8587(16)00076-0. [Epub ahead of print] Explaining geographical variation in the presentation of primary hyperparathyroidism. Minisola S(1), Pepe J(2), Scillitani A(3), Cipriani C(2). Author information: (1)Department of Internal Medicine and Medical Disciplines, Sapienza University of Rome, 00161 Rome, Italy. Electronic address: [email protected]. (2)Department of Internal Medicine and Medical Disciplines, Sapienza University of Rome, 00161 Rome, Italy. (3)Unit of Endocrinology, Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Foggia, Italy. PMID: 27117882 [PubMed - as supplied by publisher] 9. Nat Rev Endocrinol. 2016 Jun;12(6):313-4. doi: 10.1038/nrendo.2016.48. Epub 2016 Mar 29. Thyroid function: Thyroid dysfunction and breast cancer risk - an unfinished story. Chaker L(1), Visser TJ(2). Author information: (1)Rotterdam Thyroid Center; the Department of Internal Medicine; and the Department of Epidemiology, Erasmus University Medical Center, PO Box 2040, 3000 CA, Rotterdam, Netherlands. (2)Department of Internal Medicine, Erasmus University Medical Center, PO Box 2040, 3000 CA, Rotterdam, Netherlands. PMID: 27020258 [PubMed - in process] 10. Endocrinology. 2016 May;157(5):2182-95. doi: 10.1210/en.2015-2066. Epub 2016 Mar 16. Targeted Foxe1 Overexpression in Mouse Thyroid Causes the Development of Multinodular Goiter But Does Not Promote Carcinogenesis. Nikitski A(1), Saenko V(1), Shimamura M(1), Nakashima M(1), Matsuse M(1), Suzuki K(1), Rogounovitch T(1), Bogdanova T(1), Shibusawa N(1), Yamada M(1), Nagayama Y(1), Yamashita S(1), Mitsutake N(1). Author information: (1)Departments of Radiation Medical Sciences (A.N., M.M., K.S., S.Y., N.M.), Radiation Molecular Epidemiology (V.S., S.Y.), Molecular Medicine (M.S., Y.N.), Global Health, Medicine and Welfare (T.R.), and Department of Tumor and Diagnostic Pathology (M.N.), Atomic Bomb Disease Institute, Nagasaki University; Nagasaki University Graduate School of Biomedical Sciences (A.N.); and Nagasaki University Research Centre for Genomic Instability and Carcinogenesis (N.M.), Nagasaki 852-8523, Japan; Laboratory of Morphology of Endocrine System (T.B.), State Institution V.P. Komisarenko Institute of Endocrinology and Metabolism of Academy of Medical Sciences of Ukraine, Kyiv 254114, Ukraine; and Department of Medicine and Molecular Science (N.S., M.Y.), Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan. Recent genome-wide association studies have identified several single nucleotide polymorphisms in the forkhead box E1 gene (FOXE1) locus, which are strongly associated with the risk for thyroid cancer. In addition, our recent work has demonstrated FOXE1 overexpression in papillary thyroid carcinomas. To assess possible contribution of Foxe1 to thyroid carcinogenesis, transgenic mice overexpressing Foxe1 in their thyroids under thyroglobulin promoter (Tg-Foxe1) were generated. Additionally, Tg-Foxe1 mice were exposed to x-rays at the age of 5 weeks or crossed with Pten(+/-) mice to examine the combined effect of Foxe1 overexpression with radiation or activated phosphatidylinositol-3-kinase/Akt pathway, respectively. In 5- to 8-week-old Tg-Foxe1 mice, severe hypothyroidism was observed, and mouse thyroids exhibited hypoplasia of the parenchyma. Adult 48-week-old mice were almost recovered from hypothyroidism, their thyroids were enlarged, and featured colloid microcysts and multiple benign nodules of macrofollicular-papilloid growth pattern, but no malignancy was found. Exposure of transgenic mice to 1 or 8 Gy of x-rays and Pten haploinsufficiency promoted hyperplastic nodule formation also without carcinogenic effect. These results indicate that Foxe1 overexpression is not directly involved in the development of thyroid cancer and that proper Foxe1 dosage is essential for achieving normal structure and function of the thyroid. PMID: 26982637 [PubMed - in process] 11. Nat Rev Endocrinol. 2016 Jun;12(6):312. doi: 10.1038/nrendo.2016.41. Epub 2016 Mar 11. Thyroid cancer: Incidence trends in the USA. Holmes D. PMID: 26965379 [PubMed - in process] 12. J Clin Endocrinol Metab. 2016 May;101(5):2196-200. doi: 10.1210/jc.2016-1211. Epub 2016 Mar 10. Association of Mutations in SLC12A1 Encoding the NKCC2 Cotransporter With Neonatal Primary Hyperparathyroidism. Li D(1), Tian L(1), Hou C(1), Kim CE(1), Hakonarson H(1), Levine MA(1). Author information: (1)The Center for Applied Genomics (D.L., L.T., C.H., C.E.K., H.H.), The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104; Department of Pediatrics (H.H., M.A.L.), University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104; and Division of Endocrinology and Diabetes and the Center for Bone Health (M.A.L.), The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104. CONTEXT: Primary hyperparathyroidism with hypercalciuria has not been described in the newborn period. OBJECTIVE: Our objectives are to identify the genetic basis for neonatal primary hyperparathyroidism in a family with 2 affected children. SUBJECTS: An African American boy presenting with mild neonatal primary hyperparathyroidism and hypercalciuria was evaluated at The Children's Hospital of Philadelphia. His older brother with neonatal primary hyperparathyroidism had died in infancy of multiple organ failure. METHODS: We collected clinical and biochemical data and performed exome sequencing analysis on DNA from the patient and his unaffected mother after negative genetic testing for known causes of primary hyperparathyroidism. RESULTS: Exome sequencing followed by Sanger sequencing disclosed 2 heterozygous mutations, c.1883C>A, p.(A628D) and c.2786_2787insC, p.(T931fsX10), in the SLC12A1 gene, which was previously implicated in antenatal type 1 Bartter syndrome. Sanger sequencing confirmed the 2 mutations in the proband and his deceased brother; both parents were heterozygous for different mutations and an unaffected sister was homozygous for wild-type alleles. CONCLUSIONS: These results demonstrate a previously unrecognized association between neonatal primary hyperparathyroidism and mutation of SLC12A1, the cause of antenatal Bartter syndrome type 1, and suggest that the loss of sodium-potassium-chloride cotransporter-2 cotransporter activity influences parathyroid gland function. PMCID: PMC4870850 [Available on 2017-05-01] PMID: 26963954 [PubMed - in process] 13. J Clin Endocrinol Metab. 2016 May;101(5):2185-95. doi: 10.1210/jc.2015-3442. Epub 2016 Mar 10. Familial Hypocalciuric Hypercalcemia Types 1 and 3 and Primary Hyperparathyroidism: Similarities and Differences. Vargas-Poussou R(1), Mansour-Hendili L(1), Baron S(1), Bertocchio JP(1), Travers C(1), Simian C(1), Treard C(1), Baudouin V(1), Beltran S(1), Broux F(1), Camard O(1), Cloarec S(1), Cormier C(1), Debussche X(1), Dubosclard E(1), Eid C(1), Haymann JP(1), Kiando SR(1), Kuhn JM(1), Lefort G(1), Linglart A(1), Lucas-Pouliquen B(1), Macher MA(1), Maruani G(1), Ouzounian S(1), Polak M(1), Requeda E(1), Robier D(1), Silve C(1), Souberbielle JC(1), Tack I(1), Vezzosi D(1), Jeunemaitre X(1), Houillier P(1). Author information: (1)Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou (R.V.-P., L.M.-H., C.Tra., C.Sim., C.Tre., X.J.), Service de Génétique, Paris, France; INSERM, UMR970 (R.V.-P., L.M.-H., C.Tre., S.R.K., X.J.), Paris-Centre de Recherche Cardiovasculaire, Paris, France; Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte (R.V.-P., J.-P.B., V.B., M.-A.M., X.J., P.H.), Paris, France; Faculté de Médecine (L.M.-H., S.Bar., J.-P.B., X.J., P.H.), Université Paris Descartes, Paris, France; Département de Physiologie (S.Bar., J.-P.B., G.M., P.H.), Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France; Service de Néphrologie (V.B., M.-A.M.), Assistance Publique-Hôpitaux de Paris, Hôpital Robert Debré, Paris, France; Service d'Endocrinologie (S.Bel.), Centre Hospitalier de Vienne, Vienne, France; Département de Pédiatrie (F.B.), Centre Hospitalier Universitaire de Rouen, Rouen, France; Service de Pédiatrie (O.C., D.R.), Centre Hospitalier de Niort, Niort, France; Département de Néphrologie (S.C.), Centre Hospitalier Universitaire de Tours, Tours, France; Département de Rhumatologie A (C.C.), Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Paris, France; Service d'endocrinologie (X.D.), Centre hospitalier Felix Guyon, St Denis de la Réunion, France; Service de Médicine Interne (E.D.), Centre Hospitalier Henri Mondor d'Aurillac, Aurillac, France; Service d'Endocrinologie (C.D.), Centre Hospitalier de Perpignan, Perpignan, France; Département de Physiologie (J.-P.H.), Assistance Publique-Hôpitaux de Paris, Hôpital Tenon, Paris, France; Département d'Endocrinologie (J.-M.K.), Centre Hospitalier Universitaire de Rouen, Rouen, France; Service d'Endocrinologie (G.L.), Centre Hospitalier de Niort, Niort, France; Assistance Publique-Hôpitaux de Paris, Service d'Endocrinologie Pédiatrique (A.L.), Hôpital Kremlin Bicêtre, Le Kremlin-Bicêtre, France; Service d'Endocrinologie CONTEXT: Familial hypocalciuric hypercalcemia (FHH) is a genetically heterogeneous condition resembling primary hyperparathyroidism (PHPT) but not curable by surgery; FHH types 1, 2, and 3 are due to loss-of-function mutations of the CASR, GNA11, or AP2S1 genes, respectively. OBJECTIVE: This study aimed to compare the phenotypes of patients with genetically proven FHH types 1 or 3 or PHPT. DESIGN, SETTING, AND PATIENTS: This was a mutation analysis in a large cohort, a cross-sectional comparison of 52 patients with FHH type 1, 22 patients with FHH type 3, 60 with PHPT, and 24 normal adults. INTERVENTION: There were no interventions. MAIN OUTCOME MEASURES: Abnormalities of the CASR, GNA11, and AP2S1 genes, blood calcium, phosphate, and PTH concentrations, urinary calcium excretion were measured. RESULTS: In 133 families, we detected 101 mutations in the CASR gene, 68 of which were previously unknown, and in 19 families, the three recurrent AP2S1 mutations. No mutation was detected in the GNA11 gene. Patients with FHH type 3 had higher plasma calcium concentrations than patients with FHH type 1, despite having similar PTH concentrations and urinary calcium excretion. Renal tubular calcium reabsorption levels were higher in patients with FHH type 3 than in those with FHH type 1. Plasma calcium concentration was higher whereas PTH concentration and urinary calcium excretion were lower in FHH patients than in PHPT patients. In patients with FHH or PHPT, all data groups partially overlapped. CONCLUSION: In our population, AP2S1 mutations affect calcium homeostasis more severely than CASR mutations. Due to overlap, the risk of confusion between FHH and PHPT is high. PMID: 26963950 [PubMed - in process] 14. J Clin Endocrinol Metab. 2016 May;101(5):2031-9. doi: 10.1210/jc.2015-3290. Epub 2016 Mar 10. Pediatric Differentiated Thyroid Carcinoma in The Netherlands: A Nationwide Follow-Up Study. Klein Hesselink MS(1), Nies M(1), Bocca G(1), Brouwers AH(1), Burgerhof JG(1), van Dam EW(1), Havekes B(1), van den Heuvel-Eibrink MM(1), Corssmit EP(1), Kremer LC(1), Netea-Maier RT(1), van der Pal HJ(1), Peeters RP(1), Schmid KW(1), Smit JW(1), Williams GR(1), Plukker JT(1), Ronckers CM(1), van Santen HM(1), Tissing WJ(1), Links TP(1). Author information: (1)Departments of Endocrinology (M.S.K.H., M.N., T.P.L.), Nuclear Medicine and Molecular Imaging (A.H.B.), Epidemiology (J.G.M.B.), and Surgical Oncology (J.T.M.P.), University of Groningen, University Medical Center Groningen, and Departments of Pediatric Endocrinology (G.B.) and Pediatric Oncology (W.J.E.T.), Beatrix Children's Hospital, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, The Netherlands; Department of Internal Medicine (E.W.C.M.v.D.), VU University Medical Center, 1007 MB Amsterdam, The Netherlands; Department of Internal Medicine (B.H.), Division of Endocrinology, Maastricht University Medical Center, 6202 AZ Maastricht, The Netherlands; Department of Pediatric Oncology (M.M.v.d.H.-E.), Sophia Children's Hospital, Erasmus Medical Center, 3000 CB Rotterdam, The Netherlands; Department of Internal Medicine (E.P.M.C.), Division of Endocrinology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands; Department of Pediatric Oncology (L.C.M.K., H.J.H.v.d.P., C.M.R.), Emma Children's Hospital, Academic Medical Center, 1100 DD Amsterdam, The Netherlands; Department of Internal Medicine (R.T.N.-M., J.W.A.S.), Division of Endocrinology, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands; Department of Medical Oncology (H.J.H.v.d.P.), Academic Medical Center, 1100 DD Amsterdam, The Netherlands; Department of Internal Medicine (R.P.P.) and Rotterdam Thyroid Center (R.P.P.), Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands; Institute of Pathology (K.W.S.), University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany; Department of Medicine (G.R.W.), Imperial College London, London SW7 2AZ, United Kingdom; and Department of Pediatrics (H.M.v.S.), Wilhelmina Children's Hospital, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands. INTRODUCTION: Treatment for differentiated thyroid carcinoma (DTC) in pediatric patients is based mainly on evidence from adult series due to lack of data from pediatric cohorts. Our objective was to evaluate presentation, treatment-related complications, and long-term outcome in patients with pediatric DTC in The Netherlands. PATIENTS AND METHODS: In this nationwide study, presentation, complications, and outcome of patients with pediatric DTC (age at diagnosis ≤18 y) treated in The Netherlands between 1970 and 2013 were assessed using medical records. RESULTS: We identified 170 patients. Overall survival was 99.4% after a median follow-up of 13.5 years (range 0.3-44.7 y). Extensive follow-up data were available for 105 patients (83.8% women), treated in 39 hospitals. Median age at diagnosis was 15.6 years (range 5.8-18.9 y). At initial diagnosis, 43.8% of the patients had cervical lymph node metastases; 13.3% had distant metastases. All patients underwent total thyroidectomy. Radioiodine was administered to 97.1%, with a median cumulative activity of 5.66 GBq (range 0.74-35.15 GBq). Life-long postoperative complications (permanent hypoparathyroidism and/or recurrent laryngeal nerve injury) were present in 32.4% of the patients. At last known follow-up, 8.6% of the patients had persistent disease and 7.6% experienced a recurrence. TSH suppression was not associated with recurrences (odds ratio 2.00, 95% confidence interval 0.78-5.17, P = .152). CONCLUSIONS: Survival of pediatric DTC is excellent. Therefore, minimizing treatment-related morbidity takes major priority. Our study shows a frequent occurrence of life-long postoperative complications. Adverse effects may be reduced by the centralization of care, which is crucial for children with DTC. PMID: 26963949 [PubMed - in process] 15. J Clin Endocrinol Metab. 2016 May;101(5):1970-9. doi: 10.1210/jc.2015-3960. Epub 2016 Mar 1. Pediatric Thyroid Cancer: Postoperative Classifications and Response to Initial Therapy as Prognostic Factors. Lazar L(1), Lebenthal Y(1), Segal K(1), Steinmetz A(1), Strenov Y(1), Cohen M(1), Yaniv I(1), Yackobovitch-Gavan M(1), Phillip M(1). Author information: (1)The Jesse Z. and Sara Lea Shafer Institute for Endocrinology and Diabetes, National Center for Childhood Diabetes (L.L., Y.L., M.Y.-G., M.P.), Department of Pediatric Hematology-Oncology (I.Y.), Schneider Children's Medical Center of Israel, Petah Tikva 49202, Israel; Departments of Otolaryngology and Head and Neck Surgery (K.S.), Nuclear Medicine (A.S), and Imaging (M.C.), and Institute of Pathology (Y.S.), Rabin Medical Center, Beilinson Campus, Petah Tikva 49100, Israel; and Sackler Faculty of Medicine (L.L., Y.L., K.S., M.C., I.Y., M.P.) Tel Aviv University, Tel Aviv 69978, Israel. CONTEXT: Prognostic factors for pediatric differentiated thyroid cancer (DTC) are not well established. OBJECTIVE: The objective of the study was to retrospectively compare the postoperative risk-stratification systems: American Thyroid Association (ATA) risk categories, Schneider Children's Medical Center of Israel (SCMCI) score, and the response to initial therapy as predictors for disease outcome. PATIENTS AND METHODS: Fifty-four DTC patients, median age at diagnosis 13.9 years (range 1.9-17 y), followed up for a median of 8.8 years (range 2.6-20.5 y) were stratified into prepubertal (n = 9), pubertal (n = 25), and postpubertal (n = 20) groups. All patients underwent total/near-total thyroidectomy; 48 received radioiodine therapy. The extent of DTC was evaluated by applying the ATA risk categories and the novel SCMCI score. Postoperative risk stratifications (low/intermediate/high) were determined using histopathological, laboratory, and imaging findings. Response to initial therapy (complete/acceptable/incomplete) was based on stimulated thyroglobulin and imaging results during the first 2 years of follow-up. RESULTS: The risk for recurrent/persistent disease, as assessed by the postoperative ATA risk-stratification system and the SCMCI score and by the response to initial therapy, was higher in the prepubertal group (P < .001, P = .002, and P = .02, respectively). Outcome prediction by the risk-stratification systems was applicable: ATA risk categories, P = .014, R(2) = 0.247, predictive ability 80.4%; SCMCI score, P < .001, R(2) = 0.435, predictive ability 86.3%; and response to initial therapy stratification, P < .001, R(2) = 0.789, predictive ability 96.1%. The proportion of variance explained by the ATA risk categories (0.25), SCMCI score (0.44), and response to initial therapy (0.79) indicated that the latter was the most precise predictor and that the SCMCI score reflected the disease outcome better than ATA risk categories. CONCLUSIONS: Our data confirm that the postoperative pediatric ATA stratification system and the novel SCMCI score are suitable for predicting the risk of recurrent/persistent disease in this population. The response to initial therapy classification performed 1-2 years after the initial therapy may be more appropriate for guiding surveillance recommendations. PMID: 26930182 [PubMed - in process]