Download 1. Endocrinology. 2016 Jun 2:en20152046. [Epub ahead of print

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]