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Background and AimsTyrosine kinase inhibitors (TKIs) are now readily considered in the management of advanced and metastatic thyroid cancer. However, a key limiting factor are their adverse events (AEs), which can impair quality of life and influence patient acceptance of treatment. Prior systematic reviews have assessed the efficacy and safety of TKIs by reviewing both retrospective and prospective studies and further Phase III randomised controlled trials (RCTs) have since been published. We therefore plan to conduct a systematic review and meta-analysis of only prospective phase III and IV RCTs including the most recently published trials to investigate the efficacy and AEs of TKIs in patients with advanced and metastatic thyroid cancer compared to placebo.Review methodsThe Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, OVID Medline, Embase and PubMed databases will be electronically searched. Grey literature will be searched throughClinicaltrials.govandwww.ISRCTN.com. Expert informants will be contacted. We will include Phase III and IV randomised controlled trials that investigate the efficacy and AEs of TKIs in adults with advanced or metastatic thyroid cancer compared to placebo. Two authors will extract and assess for risk of bias using the Cochrane Risk of Bias Tool. Data extraction will include outcomes for objective response rate (ORR), progression free survival (PFS) and AEs, including diarrhoea, nausea, hypertension, proteinuria, palmar-plantar erythrodysaesthesia (PPE) and grade 3+ AEs, with a subgroup analysis on medullary vs differentiated thyroid cancer, TKI type and history of prior TKI or other systemic therapy. Pooled effect sizes will be meta-analysed using Review Manager 5 software through a random effects model. The study will be reported in line with the PRISMA guidelines.DiscussionThis will be the first systematic review to be conducted on the safety and efficacy of TKIs in advanced or metastatic thyroid cancer to meta-analyse phase III and IV RCT level data and include the most recently published trials. This review aims to highlight the balance between the therapeutic effect and toxicity of TKIs, and guide future studies that may be required in exploring different dosing and timing of TKI therapy.

Context Management of sporadic medullary thyroid microcarcinoma smaller than 1 cm (micro-MTC) is controversial because of conflicting reports of prognosis. As these cancers are often diagnosed incidentally, they pose a management challenge when deciding on further treatment and follow-up. Objective We report the outcomes of surgically managed sporadic micro-MTC in a specialist endocrine surgery and endocrinology unit and identify associations for recurrence and disease-specific survival in this population. Methods Micro-MTCs were identified from a prospectively maintained surgery database, and slides were reviewed to determine pathological grade. The primary end points were recurrence, time to recurrence and disease-specific survival. Prognostic factors assessed included size, grade, lymph node metastasis (LNM), and postoperative calcitonin. Results From 1995 to 2022, 64 patients were diagnosed with micro-MTC with 22 excluded because of hereditary disease. The included patients had a median age of 60 years, tumor size of 4 mm, and 28 (67%) were female. The diagnosis was incidental in 36 (86%) with 4 (10%) being high grade, 5 (12%) having LNM and 9 (21%) having elevated postoperative calcitonin. Over a 6.6-year median follow-up, 5 (12%) developed recurrence and 3 (7%) died of MTC. High grade and LNM were associated with 10-year survival estimates of 75% vs 100% for low grade and no LNM (hazard ratio = 831; P < .01). High grade, LNM, and increased calcitonin were associated with recurrence (P < .01). Tumor size and type of surgery were not statistically significantly associated with recurrence or survival. No patients with low grade micro-MTC and normal postoperative calcitonin developed recurrence. Conclusion Most sporadic micro-MTCs are detected incidentally and are generally associated with good outcomes. Size is not significantly associated with outcomes. Using grade, LNM, and postoperative calcitonin allows for the identification of patients at risk of recurrence to personalize management.

Diffuse sclerosing variant (DSV) of papillary thyroid carcinomais a rare form of thyroid cancer that demonstrates more aggressive histopathology than classical papillary thyroid carcinoma (c-PTC); however, if this leads to worse survival is debated. Many DSVs are driven by fusion events which are of recent clinical importance due to the advent of targeted RET inhibitors. A systematic search and meta-analysis of the literature was performed to compare outcomes of disease-specific mortality (DSM), metastatic and recurrent disease and the incidence of fusion events between DSV and c-PTC to July 2022. The Newcastle–Ottawa Quality Assessment studies was used to assess quality. An odds ratio (OR) was utilised to measure outcomes with 95% CIs. The Preferred Reporting Items for Systematic Reviews and Meta-analysis guideline was followed. Seventeen studies were included with 874 DSV patients compared to 76,013 c-PTC patients. DSV patients had worse DSM (OR=2.50, 95% CI 1.39–4.51) and presented with a higher rate of metastatic lymph nodes (OR = 5.85, 95% CI 2.73–12.53) and more distant metastases (OR = 3.83, 95% CI 2.17–6.77). DSV patients had higher odds of recurrent disease (OR = 3.23, 95% CI 2.00–5.23) and overall distant metastasis (OR = 2.70, 95% CI 1.74–4.17). Rates of RET fusion alterations for DSV ranged from 25 to 83%. DSV has a worse prognosis than c-PTC with higher rates of recurrent disease and distant metastasis. The high prevalence of RET fusions offers the potential to improve outcomes for patients with DSV.

ContextThyroid hormone (TH) abuse for performance enhancement in sport remains controversial and it is not prohibited in sports under the World Anti-Doping Code. However, the prevalence of TH usage in athletes is not known.ObjectiveWe investigated TH use among Australian athletes undergoing antidoping tests for competition in World Anti-Doping Agency (WADA)–compliant sports by measuring TH in serum and surveying mandatory doping control form (DCF) declarations by athletes of all drugs used in the week prior to the antidoping test.MethodsSerum thyroxine (T4), triiodothyronine (T3), and reverse T3 were measured by liquid chromatography–mass spectrometry and serum thyrotropin, free T4, and free T3 by immunoassays in 498 frozen serum samples from antidoping tests together with a separate set of 509 DCFs.ResultsTwo athletes had biochemical thyrotoxicosis giving a prevalence of 4 per 1000 athletes (upper 95% confidence limit [CL] 16). Similarly, only 2 of 509 DCFs declared usage of T4 and none for T3, also giving a prevalence of 4 (upper 95% CL 16) per 1000 athletes. These estimates were consistent with DCF analyses from international competitions and lower than the estimated T4 prescription rates in the age-matched Australian population.ConclusionThere is minimal evidence for TH abuse among Australian athletes being tested for competing in WADA-compliant sports.

Genomic deletions in medullary thyroid cancer (MTC) are rare. Selpercatinib is a highly selective RET inhibitor for treatment of metastatic RET-altered MTC. We report a case of a 35 year old male with an aggressive metastatic MTC harboring p.632_633del RET poorly responsive to RET kinase inhibitor selpercatinib. Objective Understand the clinical phenotype of p.632_633del RET in MTC in context of novel RET kinase inhibitor treatment.Wild-type and p.632_633del RET sequences were modeled using a lighter version of the AlphaFold2 (AF2) software. Functional studies were performed on transfected HEK 293 cells (pCMV6-Entry, pCMV6-RET or pCMV6-RET(p.632_633del) treated with inhibitors for 24 hours and analysed on luciferase assays.Structural modeling revealed the paucity of disulfide bridge between Cys630-Cys634 in p.632_633del RET sequences, apparent in wild-type, while forming an intermolecular disulfide bridge between two Cys656. Proximity of juxtamembrane segments of each dimer may impede Tyr687 phosphorylation and stable conformation of intracellular RET that hosts selpercatinib. In vitro experiments confirmed a reduction in efficacy of selpercatinib upon p.632_633del RET compared with wild-type RET control.Clinical presentation together with structural modeling and functional studies suggest p.632_633del RET results inpoor response to selpercatinib.

Introduction A well-known 'flip flop' phenomenon exists between whole-body scans (WBS) and 18FFDG PET imaging in differentiated thyroid cancer (DTC) such that cancer progression is typically associated with reduced iodine uptake and increased FDG avidity. Patients with FDG avidity have a poor clinical outcome while those with iodine avid lesions are more responsive to radioactive iodine therapy (RAI) and have a better prognosis. A spectrum however exists, as thyroid cancers become less well differentiated, when they will be both iodine and FDG avid. Current scoring systems in thyroid cancer are limited to a single imaging data set. We propose a new scoring system (I-PET) combining WBS and FDG findings to identify patients more likely to be refractory to RAI, and who may be ideal candidates for 're-differentiation' before RAI treatment. Methods Retrospective analysis of 142 patients age > 18 with differentiated thyroid cancer who had a 18FFDG PET and WBS within a 6 month period of each other between 2010 and 2020. Initial pair of 18F FDG PET and WBS were reviewed by two independent nuclear medicine physicians and an IPET score was assigned: IPET [0]: Iodine –ve, FDG –ve, IPET [1]: Iodine +ve, FDG –ve, IPET [2]: Iodine +ve, FDG +ve and IPET [3]: Iodine –ve, FDG +ve. Patients with FDG +ve lesions (I-PET 2 and I-PET 3) were further classified into group 'a' and 'b' if SUVmax was less than or greater than 5 respectively. Follow-up data was obtained by chart review. Progression was defined as either structural recurrence as per RECIST 1.1 or equivalent clinical assessment, or biochemical incomplete response with an unstimulated Tg > 1ug/L. The study was approved by IRB (ETH00674/ STE01494). Results Of the 142 patients included in the study 121 patients had follow up data available for review. At baseline, 49 patients were classified as IPET [0], 10 as IPET [1], 16 as IPET [2] and 46 as IPET [3]. Progression was identified in 49% (59/121) patients; of which 54 were structural and 5 biochemical. Patients classified as [2b] and [3b] had a recurrence rate of 88% (7/8) and 78% (25/32) respectively, while IPET [0] patients had 22% (11/49) recurrence (p < 0.001). Patients classified as IPET [3b] were 10.4 times more likely to commence on tyrosine kinase inhibitor therapy (p=0.005) and had a 8.1 times greater mortality rate (p=0.02) than patients in the other IPET groups. Conclusion IPET score is a novel scoring system incorporating WBS and 18FFDG PET imaging which predicts progression and death in patients with FDG avid thyroid cancer. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Saturday, June 11, 2022 1:48 p.m. - 1:53 p.m.

Papillary thyroid carcinoma (PTC) accounts for the vast majority of thyroid cancer cases. Cerebellar metastasis is rarely the presenting feature. We report a patient presenting with a cerebellar lesion which demonstrated metastatic PTC upon resection, with unusual features including incidental medullary thyroid microcarcinoma without PTC in the main thyroidectomy specimen.

Context Metastatic medullary thyroid carcinoma (MTC) and radioactive iodine–refractory differentiated thyroid carcinoma (RAI-R DTC) have poor prognosis and limited treatment options. Selpercatinib (LOXO-292), a selective kinase inhibitor targeting the RET gene, has shown a 69% to 79% objective response rate in this cohort with benefits in other tumors including lung cancer harboring the same oncogenic driver. Published reports describe only 17% of patients experiencing gastrointestinal (GI) adverse effects (AEs), which is in contrast to our local experience. Objective Here we characterize the AEs and correlate them with radiological and histopathological findings. Methods Sequential patients enrolled in LIBRETTO-001 at Royal North Shore Hospital, Sydney, Australia, with available imaging (n = 22) were recruited. Patients had regular visits with AEs documented and computed tomography (CT) scans every 3 months. CT at screening, at time of GI AE, and at most recent follow-up were reviewed and scored. Endoscopic examination was performed in 5 patients. Results Of 22 patients in this cohort, the majority had somatic RET alterations (n = 18), most commonly p.Met918Thr (n = 14). Ten patients (50%) developed GI AEs. Dose reduction was required in 8 of the 10 patients, but none discontinued therapy. The majority had stable disease (n = 17). Gastric and small-bowel edema was evident in symptomatic patients after a median time of 67 weeks’ treatment. Histological correlation in 5 patients revealed mucosal edema correlating with radiological evidence of congestion and edema. Conclusion GI AEs with selpercatinib may be more common than previously described. Most are self-limiting but often require dose adjustments. Histological evidence of mucosal edema observed in conjunction with the radiological findings of congestion and wall thickening suggest bowel-wall edema is a predominant mechanism of abdominal pain in these patients.