Familial medullary thyroid cancer (MTC) and its precursor, C cell hyperplasia (CCH), is associated with germline RET mutations causing multiple endocrine neoplasia type 2. However, some rare families ...with apparent MTC/CCH predisposition do not have a detectable RET mutation. To identify novel MTC/CCH predisposition genes we undertook exome resequencing studies in a family with apparent predisposition to MTC/CCH and no identifiable RET mutation. We identified a novel ESR2 frameshift mutation, c.948delT, which segregated with histological diagnosis following thyroid surgery in family members and demonstrated loss of ESR2-encoded ERβ expression in the MTC tumour. ERα and ERβ form heterodimers binding DNA at specific oestrogen-responsive elements (EREs) to regulate gene transcription. ERβ represses ERα-mediated activation of the ERE and the RET promoter contains three EREs. In vitro, we showed that ESR2 c.948delT results in unopposed ERα mediated increased cellular proliferation, activation of the ERE and increased RET expression. In vivo, immunostaining of CCH and MTC using an anti-RET antibody demonstrated increased RET expression. Together these findings identify germline ESR2 mutation as a novel cause of familial MTC/CCH and provide important insights into a novel mechanism causing increased RET expression in tumourigenesis.
Sir Felix Semon established the Semon Lecture series in 1913 to advance the specialty of laryngology. The annual lectures continue to the present day (there have been 95 to date).
This review ...illustrates how instrumental these lectures have been in shaping otolaryngology.
The period 1913-1970 preceded subspecialisation, and so forms the background of laryngology (as well as rhinology and otology) as we know it today. This era forms the focus of the article.
Changes came about by a standardisation of practices and research, and in the treatment of conditions. The initial period was crucial.
Many lectures highlight the specialty's growth. Now, another vital resource, a dedicated website (semonlectures.org), has made this information more accessible to the wider public.
Thyroid disease is common, thyroid cancer is uncommon. Most goitres are investigated using blood tests, fine needle aspiration cytology together with ultrasound. Surgery usually entails either ...lobectomy or total thyroidectomy, and for malignancy, patients may need a neck dissection. Recently, significant advances have been made regarding mechanisms involved in both thyroid growth and function (goitrogenesis) and carcinogenesis at a molecular level.
In the study cohort, 1113 patients had benign disease and 387 malignancy. For benign disease, 716 patients had lobectomy or isthmusectomy, 44 had near-total thyroidectomy and 318 a total thyroidectomy. For malignancy, patients received initial lobectomy (180) or total thyroidectomy (152). One hundred and eleven had completion surgery. Thirty patients had extensive surgery. Thyroid growth and function was investigated using 500 human thyroid cell primary cultures obtained at surgery, as well as in three animal models. The role of pituitary tumour transforming gene (PTTG), PTTG binding factor (PBF) and sodium iodide symporter (NIS) in thyroid cell function was then evaluated.
Temporary and permanent recurrent laryngeal nerve palsy rates were 2.4% and 0.4%. Other complications included temporary (21%) and permanent (3%) hypoparathyroidism, wound infection (1.2%), haematoma (1.2%) and poor scar (0.8%). Six patients have died. Regarding thyroid growth and function, TSH represents (either directly or indirectly) the main factor mediating thyroid follicular cell growth. For carcinogenesis, over-expression of the proto-oncogenes PTTG and PBF induces tumours in nude mice, and PTTG can induce proliferation of human thyroid cells and, in addition, both repress expression and function of NIS.
Pituitary tumor transforming gene (PTTG)-binding factor (PBF or PTTG1IP) is a little characterized proto-oncogene that has been implicated in the etiology of breast and thyroid tumors. In this study, ...we created a murine transgenic model to target PBF expression to the thyroid gland (PBF-Tg mice) and found that these mice exhibited normal thyroid function, but a striking enlargement of the thyroid gland associated with hyperplastic and macrofollicular lesions. Expression of the sodium iodide symporter (NIS), a gene essential to the radioiodine ablation of thyroid hyperplasia, neoplasia, and metastasis, was also potently inhibited in PBF-Tg mice. Critically, iodide uptake was repressed in primary thyroid cultures from PBF-Tg mice, which could be rescued by PBF depletion. PBF-Tg thyroids exhibited upregulation of Akt and the TSH receptor (TSHR), each known regulators of thyrocyte proliferation, along with upregulation of the downstream proliferative marker cyclin D1. We extended and confirmed findings from the mouse model by examining PBF expression in human multinodular goiters (MNG), a hyperproliferative thyroid disorder, where PBF and TSHR was strongly upregulated relative to normal thyroid tissue. Furthermore, we showed that depleting PBF in human primary thyrocytes was sufficient to increase radioiodine uptake. Together, our findings indicate that overexpression of PBF causes thyroid cell proliferation, macrofollicular lesions, and hyperplasia, as well as repression of the critical therapeutic route for radioiodide uptake.
Adenoid Cystic Carcinoma of Trachea Varghese, Ashish; Suneha, Swati; Watkinson, John C.
Indian journal of surgery,
02/2017, Letnik:
79, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Adenoid cystic carcinoma (ACC) is the second most common primary malignant tumor of the trachea, after squamous cell carcinoma. Patients present with upper airway obstructive symptoms and signs ...including dyspnoea, cough, haemoptysis, and stridor which are often insidious, delaying diagnosis and optimal management. Described here is an unusual case of primary ACC cervical trachea with concomitant micropapillary thyroid carcinoma (microPTC) in a middle-aged lady presenting with cough and breathing difficulty since 3 months.
Re-operative thyroid surgery is a relatively uncommon procedure complicated by distorted anatomy and post-operative tissue changes. Surgery may follow initial benign or malignant pathology. Published ...outcomes vary widely in the literature. This study aims to report our outcomes from re-operative thyroid surgery. Patient demographics and complication rates for consecutive thyroidectomies performed by a single surgeon at a tertiary centre were collected between 1993 and 2013. Outcomes in re-operative surgery are analysed and compared with local and national data. Cases of re-operative surgery following benign disease are further analysed for histology, re-presenting symptoms and time between procedures. Our cohort comprised 1,657 cases including 164 re-operative procedures (101 malignant, 63 benign). Within our cohort re-operative cases were on average 4 years older (mean 49.9 vs 45.9 years,
p
= 0.001) and had a higher incidence of haematoma formation (4.3 vs 1.7 %,
p
= 0.033) and transient recurrent laryngeal nerve palsy (5.5 vs 2.5 %,
p
= 0.044) compared to primary surgery. Rates of permanent hypocalcaemia (2.4 vs 1.8 %,
p
= 0.540) and permanent RLN palsy (1.8 vs 0.4 %,
p
= 0.051) were higher in the re-operative group but did not reach significance. Comparison of complications following re-operation for benign and malignant disease revealed no significant differences. Mean interval to re-operation for benign cases was 17.4 years with 74.6 % found to have multinodular goitre at repeat procedure. Re-operative procedures comprised around 10 % of thyroid surgery at our centre. Re-operative cases experienced more complications than primary surgery but permanent rates were low. Re-operative surgery may therefore be safely considered in experienced hands.
Differentiated thyroid cancers and their metastases frequently exhibit reduced iodide uptake, impacting on the efficacy of radioiodine ablation therapy. PTTG binding factor (PBF) is a proto-oncogene ...implicated in the pathogenesis of thyroid cancer. We recently reported that PBF inhibits iodide uptake, and have now elucidated a mechanism by which PBF directly modulates sodium iodide symporter (NIS) activity in vitro. In subcellular localisation studies, PBF overexpression resulted in the redistribution of NIS from the plasma membrane into intracellular vesicles, where it colocalised with the tetraspanin CD63. Cell-surface biotinylation assays confirmed a reduction in plasma membrane NIS expression following PBF transfection compared with vector-only treatment. Coimmunoprecipitation and GST-pull-down experiments demonstrated a direct interaction between NIS and PBF, the functional consequence of which was assessed using iodide-uptake studies in rat thyroid FRTL-5 cells. PBF repressed iodide uptake, whereas three deletion mutants, which did not localise within intracellular vesicles, lost the ability to inhibit NIS activity. In summary, we present an entirely novel mechanism by which the proto-oncogene PBF binds NIS and alters its subcellular localisation, thereby regulating its ability to uptake iodide. Given that PBF is overexpressed in thyroid cancer, these findings have profound implications for thyroid cancer ablation using radioiodine.
The proto-oncogene PTTG and its binding partner PBF have been widely studied in multiple cancer types, particularly thyroid and colorectal, but their combined role in tumourigenesis is ...uncharacterised. Here, we show for the first time that together PTTG and PBF significantly modulate DNA damage response (DDR) genes, including p53 target genes, required to maintain genomic integrity in thyroid cells. Critically, DDR genes were extensively repressed in primary thyrocytes from a bitransgenic murine model (Bi-Tg) of thyroid-specific PBF and PTTG overexpression. Irradiation exposure to amplify p53 levels further induced significant repression of DDR genes in Bi-Tg thyrocytes (P=2.4 × 10
) compared with either PBF- (P=1.5 × 10
) or PTTG-expressing thyrocytes (P=NS). Consistent with this, genetic instability was greatest in Bi-Tg thyrocytes with a mean genetic instability (GI) index of 35.8±2.6%, as well as significant induction of gross chromosomal aberrations in thyroidal TPC-1 cells following overexpression of PBF and PTTG. We extended our findings to human thyroid cancer using TCGA data sets (n=322) and found striking correlations with PBF and PTTG expression in well-characterised DDR gene panel RNA-seq data. In addition, genetic associations and transient transfection identified PBF as a downstream target of the receptor tyrosine kinase-BRAF signalling pathway, emphasising a role for PBF as a novel component in a pathway well described to drive neoplastic growth. We also showed that overall survival (P=1.91 × 10
) and disease-free survival (P=4.9 × 10
) was poorer for TCGA patients with elevated tumoural PBF/PTTG expression and mutationally activated BRAF. Together our findings indicate that PBF and PTTG have a critical role in promoting thyroid cancer that is predictive of poorer patient outcome.
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