Stan Sidhu

Purpose: The prognostic importance of RET and RAS mutations and their relationship to clinicopathologic parameters and outcomes in medullary thyroid carcinoma (MTC) needs to be clarified. Experimental design: A multicenter retrospective cohort study was performed utilizing data from 290 patients with MTC. The molecular profile was determined and associations were examined with clinicopathologic data and outcomes. Results: RET germline mutations were detected in 40 patients (16.3%). Somatic RET and RAS mutations occurred in 135 (46.9%) and 57 (19.8%) patients respectively. RETM918T was the most common somatic RET mutation (n=75). RET somatic mutations were associated with male sex, larger tumor size, advanced AJCC stage, vascular invasion (VI), and high IMTCGS grade. When compared with other RET somatic mutations, RETM918T was associated with younger age, AJCC (8th edition) IV, vascular invasion, extrathyroidal extension, and positive margins. RET somatic or germline mutations were significantly associated with reduced distant metastasis free survival on univariate analysis but there were no significant independent associations on multivariable analysis, after adjusting for tumor grade and stage. There were no significant differences in outcomes between RET somatic and RET germline mutations, or between RETM918T and other RET mutations. Other recurrent molecular alterations included TP53 (4.2%), ARID2 (2.9%), SETD2 (2.9%), KMT2A (2.9%), and KMT2C (2.9%). Among them, TP53 mutations were associated with decreased overall and disease-specific survival, independently of tumor grade and AJCC stage. Conclusions: RET somatic mutations were associated with high-grade, aggressive primary tumor characteristics, and decreased distant metastatic-free survival but this relationship was not significant after accounting for tumor grade and disease stage . RETM918T was associated with aggressive primary tumors but was not independently associated with clinical outcomes. TP53 mutation may represent an adverse molecular event associated with decreased overall and disease-specific survival in MTC but its prognostic value needs to be confirmed in future studies.

Adrenocortical Carcinoma (ACC) is a rare but aggressive malignancy with poor prognosis and limited response to available systemic therapies. Although complete surgical resection gives the best chance for long-term survival, ACC has a two-year recurrence rate of 50%, which poses a therapeutic challenge. High throughput analyses focused on characterizing the molecular signature of ACC have revealed specific micro-RNAs (miRNAs) that are associated with aggressive tumor phenotypes. MiRNAs are small non-coding RNA molecules that regulate gene expression by inhibiting mRNA translation or degrading mRNA transcripts and have been generally implicated in carcinogenesis. This review summarizes the current insights into dysregulated miRNAs in ACC tumorigenesis, their known functions, and specific targetomes. In addition, we explore the possibility of particular miRNAs to be exploited as clinical biomarkers in ACC and as potential therapeutics.

The incidence of thyroid cancer is rapidly increasing, mostly due to the overdiagnosis and overtreatment of differentiated thyroid cancer (TC). The increasing use of potent preclinical models, high throughput molecular technologies, and gene expression microarrays have provided a deeper understanding of molecular characteristics in cancer. Hence, molecular markers have become a potent tool also in TC management to distinguish benign from malignant lesions, predict aggressive biology, prognosis, recurrence, as well as for identification of novel therapeutic targets. In differentiated TC, molecular markers are mainly used as an adjunct to guide management of indeterminate nodules on fine needle aspiration biopsies. In contrast, in advanced thyroid cancer, molecular markers enable targeted treatments of affected signalling pathways. Identification of the driver mutation of targetable kinases in advanced TC can select treatment with mutation targeted tyrosine kinase inhibitors (TKI) to slow growth and reverse adverse effects of the mutations, when traditional treatments fail. This review will outline the molecular landscape and discuss the impact of molecular markers on diagnosis, surveillance and treatment of differentiated, poorly differentiated and anaplastic follicular TC.

Adrenocortical carcinoma (ACC) has high recurrence rates and poor prognosis with limited response to conventional cancer therapy. Recent contributions of high-throughput transcriptomic profiling identified microRNA-497 (miR-497) as significantly underexpressed, while lncRNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) as overexpressed in ACC. miR-497 is located in the chromosomal region 17p13.1, in which there is a high frequency of loss of heterozygosity in ACC. We aim to investigate the interaction of miR-497 and MALAT1 in ACC and its functional roles in the process of tumourigenesis. In this study, we demonstrated miR-497 post-transcriptionally repressed MALAT1 while MALAT1 also competes for miR-497 binding to its molecular target, EIF4E (eukaryotic translation initiation factor 4E). We showed that overexpression of miR-497 and silencing of MALAT1 suppressed cellular proliferation and induced cell cycle arrest through downregulation of EIF4E expression. Furthermore, MALAT1 directly binds to SFPQ (splicing factor proline and glutamine rich) protein, indicating its multifaceted roles in ACC pathophysiology. This is the first study to identify the feedback axis of miR-497-MALAT1/EIF4E in ACC tumourigenesis, providing novel insights into the molecular functions of noncoding RNAs in ACC.

Background: Adrenocortical carcinoma (ACC) is a rare endocrine cancer with treatments limited in efficacy for metastatic disease. New molecular targeted therapies have yet to improve patient outcomes. In contrast, established treatment regimens of adrenolytics and chemotherapy have demonstrated treatment benefit, although admittedly in a minority of patients. Identification of microRNAs (miRNAs) in patients responsive to adjuvant therapy may offer a means to sensitize patients with progressive disease to existing adjuvant regimens. Materials and Methods: Samples from primary ACC tumors of 10 Stage IV patients were examined for differentially expressed miRNAs between a “sensitive” and “resistant” cohort. Candidate microRNAs were restored via transfection in two functional ACC cell lines. Gain of function and effects on apoptosis and cell cycle were assessed. Results: microRNA-431 (miR-431) was underexpressed in patients with ACC with progressive disease undergoing adjuvant therapy. Restoration of miR-431 in vitro decreased the half maximal inhibitory concentrations of doxorubicin and mitotane, with markedly increased apoptosis. We found that a reversal of epithelial-mesenchymal transition underlies the action of miR-431 with doxorubicin treatment, with Zinc Finger E-Box Binding Homeobox 1 implicated as the molecular target of miR-431 in ACC. Conclusion: This is the first report of the potential of miRNA therapy to sensitize ACC to current established adjuvant therapy regimens, which may mitigate the resistance underlying treatment failure in patients with advanced ACC. Effective and well-studied methods of targeted miRNA delivery in existence hints at the imminent translatability of these findings.

Background: Adrenocortical carcinoma is a rare and heterogeneous malignancy with poor outcomes. Recent research has suggested that outcomes may be improved by centralization of care in specialist centres. We review our evolving 21‐year experience in managing adrenocortical carcinoma with a view towards outcomes and lessons learnt.Methods: A retrospective study of patients treated in our specialist endocrine surgical unit over 21 years was undertaken.Results: Thirty‐five patients were treated from diagnosis, 29 forming a primary study cohort. Additionally, seven patients were referred to us for quaternary care, forming a secondary study cohort. The European Network for the Study of Adrenal Tumours (ENSAT) stage and immunohistochemical marker Ki‐67 index were strong prognostic indicators for survival.Conclusions: Early stage, complete resection and Ki‐67 <10% are the best prognosticators for survival. Aggressive surgical resection at index operation and of recurrent oligometastatic disease along with multimodal adjuvant treatment has led to long‐term survivors of patients with Stage 4 disease in our aggregate cohort.

Background Low‐risk differentiated thyroid cancers may, according to the American Thyroid Association (ATA) 2015 guidelines, be managed initially with lobectomy. However, definitive risk categorization requires pathological assessment of the specimen, resulting in completion thyroidectomy being recommended when discordance between preoperative and postoperative staging occurs. This study sought to establish the expected rate of completion thyroidectomy in patients with papillary thyroid cancer (PTC) treated by lobectomy. Methods Patients with PTC treated over 5 years (2013–2017 inclusive) and meeting the ATA criteria for lobectomy were identified from the prospectively developed database of a high‐volume, university department of endocrine surgery. Concordance between the ATA initial and final recommendation, and the putative rate of completion thyroidectomy were calculated. Multivariable analysis was used to assess preoperative factors as predictors of the need for total thyroidectomy. Results Of 275 patients with PTC who met ATA preoperative criteria for lobectomy there was concordance between this and the final recommendation in 158 (57·5 per cent) and discordance in 117 (43·5 per cent). Most common reasons for discordance were: angioinvasion (30·8 per cent), local invasion (23·9 per cent) or both (20·5 per cent). Four patients (1·5 per cent) had permanent hypoparathyroidism. On multivariable analysis, age, sex, tumour size and family history did not independently predict the final treatment required. Conclusion Although many patients may be treated adequately with lobectomy, just under half would require completion thyroidectomy. Further work is needed on preoperative risk stratification but, before this, total thyroidectomy remains the treatment of choice for low‐risk 1–4‐cm PTC in the hands of high‐volume thyroid surgeons who can demonstrate low complication rates.

Background Integrity of the recurrent laryngeal nerve (RLN) and the external branch of the superior laryngeal nerve (EBSLN) can be checked by intraoperative nerve monitoring (IONM) after visualization. The aim of this study was to determine the prevalence and nature of voice dysfunction following thyroid surgery with routine IONM. Methods Thyroidectomies were performed with routine division of strap muscles and nerve monitoring to confirm integrity of the RLN and EBSLN following dissection. Patients were assessed for vocal function before surgery and at 1 and 3 months after operation. Assessment included use of the Voice Handicap Index (VHI) 10, maximum phonation time, fundamental frequency, pitch range, harmonic to noise ratio, cepstral peak prominence and smoothed cepstral peak prominence. Results A total of 172 nerves at risk were analysed in 102 consecutive patients undergoing elective thyroid surgery. In 23·3 per cent of EBSLNs and 0·6 per cent of RLNs nerve identification required the assistance of IONM in addition to visualization. Nerve integrity was confirmed during surgery for 98·8 per cent of EBSLNs and 98·3 per cent of RLNs. There were no differences between preoperative and postoperative VHI‐10 scores. Acoustic voice assessment showed small changes in maximum phonation time at 1 and 3 months after surgery. Conclusion Where there is routine division of strap muscles, thyroidectomy using nerve monitoring confirmation of RLN and EBSLN function following dissection results in no clinically significant voice change.