Diagnostic RET genetic testing in 1,058 index patients: A UK centre perspective.

OBJECTIVE: Diagnostic germline RET analysis is offered to all patients with a diagnosis of medullary thyroid carcinoma (MTC), or other conditions associated with multiple endocrine neoplasia type 2 (MEN2) in the United Kingdom. Here, we report the experience of a single centre's germline RET analysis over a 21-year period. DESIGN: Retrospective case-note review. PATIENTS: All index patients referred to the Exeter Genomics Laboratory for diagnostic germline RET analysis between 1997 and 2018, and unaffected family members, undergoing predictive testing. MEASUREMENTS: The rate and nature of pathogenic variant detection were recorded, as well as the indication for testing. RESULTS: 1,058 index patients and 551 unaffected family members were tested. The overall rate of pathogenic variant detection was 10.2% amongst index patients and 29% amongst unaffected family members. The commonest indication was isolated MTC, and amongst the 690 patients with isolated MTC, 68 (9.9%) were found to harbour a RET pathogenic variant. Of those with presumed sporadic MTC, 8.5% were found to harbour germline RET pathogenic variants, compared with 36.4% of those with a family history of MEN2-associated conditions. Pathogenic variants were identified in 3.6% and 0% of patients with isolated phaeochromocytoma and primary hyperparathyroidism, respectively. CONCLUSIONS: Although the detection rate of RET germline pathogenic variants in patients with presumed sporadic MTC was significant, the overall detection rate in those with MTC was lower than expected in this series. Advances in RET analysis in response to reports of new variants over the last two decades are likely to have improved the pick-up rate in recent years.

The role of molecular genetics in the clinical management of sporadic medullary thyroid carcinoma: A systematic review.

BACKGROUND: The significant variation in the clinical behaviour of sporadic medullary thyroid carcinoma (sMTC) causes uncertainty when planning the management of these patients. Several tumour genetic and epigenetic markers have been described, but their clinical usefulness remains unclear. The aim of this review was to evaluate the evidence for the use of molecular genetic and epigenetic profiles in the risk stratification and management of sMTC. METHODS: MEDLINE and Embase databases were searched using the MeSH terms "medullary carcinoma", "epigenetics", "molecular genetics", "microRNAs"; and free text terms "medullary carcinoma", "sporadic medullary thyroid cancer", "sMTC", "RET", "RAS" and "miR". Articles containing less than ten subjects, not focussing on sMTC, or not reporting clinical outcomes were excluded. Risk of bias was assessed using a modified version of the Newcastle-Ottawa Scale. RESULTS: Twenty-three studies met the inclusion criteria, and key findings were summarized in themes according to the genetic and epigenetic markers studied. There is good evidence that somatic RET mutations predict higher rates of lymph node metastasis and persistent disease, and worse survival. There are also several good quality studies demonstrating associations between certain epigenetic markers such as tumour miR-183 and miR-375 expression and higher rates of lymph node and distant metastasis, and worse survival. CONCLUSIONS: There is a growing body of evidence that tumour genetic and epigenetic profiles can be used to risk stratify patients with sMTC. Further research should focus on the clinical applicability of these findings by investigating the possibility of tailoring management to an individual's tumour mutation profile.

Controversies in the surgical management of sporadic medullary thyroid carcinoma.

PURPOSE OF REVIEW: Medullary thyroid carcinoma (MTC) represents a wide spectrum of tumours with differing biology, behaviour and natural history. The only current available curative treatment is surgery in the form of thyroidectomy with or without ipsilateral or bilateral neck dissection. There is a lack of consensus in the available published guidelines on the optimum extent of initial surgery, and there is significant variation in clinical practice. This review focuses on the most recently published evidence. RECENT FINDINGS: Many patients with limited disease do not receive total thyroidectomy and central neck compartment dissection as recommended by international guidelines. Despite this, 5-year disease-specific survival is over 90% in those without distant metastases at presentation. Over 20% of patients may harbour occult lateral compartment nodal metastases, and baseline calcitonin alone (>1000 pg/ml) is not a good predictor of nodal metastasis. Although delayed lateral neck compartment dissection results in similar survival outcomes to prophylactic neck dissection for clinically node-negative patients, there is an underappreciated psychological effect of having biochemical evidence of persistent disease following limited surgery. SUMMARY: No single currently available prognostic indicator is sufficient to predict disease behaviour and evidence of occult nodal metastases. In clinically ad radiologically node-negative patients, the extent of neck dissection at initial operation, therefore, needs to be planned and executed on an individual patient basis.

Does Obesity Cause Thyroid Cancer? A Mendelian Randomization Study.

BACKGROUND: The incidence of thyroid cancer is rising, and relatively little is known about modifiable risk factors for the condition. Observational studies have suggested a link between adiposity and thyroid cancer; however, these are subject to confounding and reverse causality. Here, we used data from the UK Biobank and Mendelian randomization approaches to investigate whether adiposity causes benign nodular thyroid disease and differentiated thyroid cancer. METHODS: We analyzed data from 379 708 unrelated participants of European ancestry in the UK Biobank and identified 1812 participants with benign nodular thyroid disease and 425 with differentiated thyroid carcinoma. We tested observational associations with measures of adiposity and type 2 diabetes mellitus. One and 2-sample Mendelian randomization approaches were used to investigate causal relationships. RESULTS: Observationally, there were positive associations between higher body mass index (odds ratio [OR], 1.15; 95% confidence interval [CI], 1.08-1.22), higher waist-hip ratio (OR, 1.16; 95% CI, 1.09-1.23), and benign nodular thyroid disease, but not thyroid cancer. Mendelian randomization did not support a causal link for obesity with benign nodular thyroid disease or thyroid cancer, although it did provide some evidence that individuals in the highest quartile for genetic liability of type 2 diabetes had higher odds of thyroid cancer than those in the lowest quartile (OR, 1.45; CI, 1.11-1.90). CONCLUSIONS: Contrary to the findings of observational studies, our results do not confirm a causal role for obesity in benign nodular thyroid disease or thyroid cancer. They do, however, suggest a link between type 2 diabetes and thyroid cancer.

Clinical outcomes following Cochlear™ BIA300 bone anchored hearing aid implantation in children.

OBJECTIVE: Bone anchored hearing implants (BAHI) have been in use for over 30 years, and are commonly implanted in children for a range of indications. The Cochlear™ BIA300 system was launched in 2010 and used at The Birmingham Children's Hospital from 2011. Here we report the long-term outcomes of children implanted with the Cochlear™ BIA300 BAHI system in our centre. METHODS: A retrospective case note analysis was performed to identify outcomes in all children who underwent BIA300 implantation between 2011 and 2013. RESULTS: 52 children with a total of 78 implants were included. Mean age at implantation was 8.7 years. Mean follow-up was 43.5 months. Overall, 60 (77%) implants developed soft tissue complications requiring treatment. Forty-eight (62%) required topical treatment; 27 (35%) required systemic treatment; and 27 (35%) required surgical soft tissue revision under general anaesthesia. CONCLUSIONS: The Cochlear™ BIA300 system appears to be associated with higher than expected rates of soft tissue reaction in children, with late as well as early soft tissue complications requiring both medical and surgical treatment.

Thyroid-stimulating hormone suppression therapy for differentiated thyroid cancer: The role for a combined T3/T4 approach.

BACKGROUND: In the management of differentiated thyroid carcinoma, surgery with or without postoperative radioiodine, and thyroid-stimulating hormone (TSH) suppression is the standard of care in most patients. Levothyroxine is recommended for long-term TSH suppression. For some patients, this may be difficult to tolerate due to adverse effects, such as impaired cognitive function. METHODS: This article reviews the evidence for the role of combination treatment with triiodothyronine (T3) and levothyroxine (T4) in these patients. RESULTS: The evidence for combination T3 and T4 treatment comes mainly from studies on hypothyroidism, and research into its use for TSH suppression is limited. CONCLUSION: Although the evidence base is not strong, there is a small group of patients who may benefit from combination T3 and T4 treatment due to difficulty tolerating thyroxine. Until further evidence is available, a case-by-case approach is recommended.