Context Germline CDKN1B pathogenic variants result in multiple endocrine neoplasia type 4 (MEN4), an autosomal dominant hereditary tumor syndrome variably associated with primary hyperparathyroidism, pituitary adenoma, and duodenopancreatic neuroendocrine tumors. Objective To report the phenotype of 3 unrelated cases each with a unique germline CDKN1B variant (of which 2 are novel) and compare these cases with those described in the current literature. Design/Methods Three case studies, including clinical presentation, germline, and tumor genetic analysis and family history. Setting Two tertiary University Hospitals in Sydney, New South Wales, and 1 tertiary University Hospital in Canberra, Australian Capital Territory, Australia. Outcome Phenotype of the 3 cases and their kindred; molecular analysis and tumor p27^kip1 immunohistochemistry. Results Family A: The proband developed multiglandular primary hyperparathyroidism, a microprolactinoma and a multifocal nonfunctioning duodenopancreatic neuroendocrine tumor. Family B: The proband was diagnosed with primary hyperparathyroidism from a single parathyroid adenoma. Family C: The proband was diagnosed with a nonfunctioning pituitary microadenoma and ectopic Cushing’s syndrome from an atypical thymic carcinoid tumor. Germline sequencing in each patient identified a unique variant in CDKN1B, 2 of which are novel (c.179G > A, p.Trp60*; c.475G > A, p.Asp159Asn) and 1 previously reported (c.374_375delCT, p.Ser125*). Conclusions Germline CDKN1B pathogenic variants cause the syndrome MEN4. The phenotype resulting from the 3 pathogenic variants described in this series highlights the heterogenous nature of this syndrome, ranging from isolated primary hyperparathyroidism to the full spectrum of endocrine manifestations. We report the first described cases of a prolactinoma and an atypical thymic carcinoid tumor in MEN4.

Liquid biopsies are a novel technique to assess for either circulating tumor cells (CTC) or circulating tumor DNA (ctDNA and microRNA (miRNA)) in peripheral blood samples of cancer patients. The diagnostic role of liquid biopsy in oncology has expanded in recent years, particularly in lung, colorectal and breast cancer. In thyroid cancer, the role of liquid biopsy in either diagnosis or prognosis is beginning to translate from the lab to the clinic. In this review, we describe the evolution of liquid biopsies in detecting CTC, ctDNA and miRNA in thyroid cancer patients, together with its limitations and future directions in clinical practice.

Objective: We propose a new scoring system (I‐PET) combining whole body scan (WBS) and FDG findings to identify patients who have or are likely to become refractory to radioactive iodine.Design: Retrospective analysis of 142 patients age >18 with differentiated thyroid cancer who had a F‐18 labelled fluoro‐2‐deoxyglucose (¹⁸F‐FDG) positron emission tomography (PET) and WBS within a 6‐month period between 2010 and 2020. Pairs of ¹⁸F‐FDG PET and WBS were reviewed by three independent nuclear medicine physicians and an I‐PET score was assigned: I‐PET [0]: Iodine −ve/FDG −ve, I‐PET [1]: Iodine +ve/FDG −ve, I‐PET [2]: Iodine +ve/FDG +ve and I‐PET [3]: Iodine −ve/FDG +ve. Patients with FDG +ve lesions (I‐PET [2] and I‐PET [3]) were further classified into groups A and B if SUVmax was ≤5 or >5, respectively. Follow‐up data were obtained by chart review. Progression was defined as structural progression as per RECIST 1.1 or further surgical intervention; or biochemical progression as unstimulated thyroglobulin increasing >20% from baseline.Results: Of 142 patients included in the study 121 patients had follow‐up data available for review. At baseline, 49 patients were classified as I‐PET [0], 10 as I‐PET [1], 16 as I‐PET [2] and 46 as I‐PET [3]. Progression was seen in 11/49 (22%) of I‐PET [0], 4/10 (40%) of I‐PET [1], 10/16 (63%) of I‐PET [2] and 34/46 (74%) of I‐PET [3] (p < 0.001). I‐PET [2B] and I‐PET [3B] had a progression rate of 88% (7/8) and 78% (25/32), respectively. I‐PET [3B] were 9.6 times more likely to commence multikinase inhibitor therapy (p = 0.001) and had 8 times greater mortality (p = 0.003) than patients in other I‐PET groups combined.Conclusion: I‐PET is a simple readily acquired imaging biomarker that potentially enhances the dynamic risk stratification and guide treatment in thyroid cancer.

Objective: Our study aimed to analyse temporal trends in radioactive iodine (RAI) treatment for thyroid cancer over the past decade; to analyse key factors associated with clinical decisions in RAI dosing; and to confirm lower activities of RAI for low-risk patients were not associated with an increased risk of recurrence. Methods: Retrospective analysis of 1,323 patients who received RAI at a quaternary centre in Australia between 2008 and 2018 was performed. Prospectively collected data included age, gender, histology, and American Joint Committee on Cancer stage (7th ed). American Thyroid Association risk was calculated retrospectively. Results: The median activities of RAI administered to low-risk patients decreased from 3.85 GBq (104 mCi) in 2008–2016 to 2.0 GBq (54 mCi) in 2017–2018. The principal driver of this change was an increased use of 1 GBq (27 mCi) from 1.3% of prescriptions in 2008–2011 to 18.5% in 2017–2018. In patients assigned as low risk per ATA stratification, lower activities of 1 GBq or 2 GBq (27 mCi or 54 mCi) were not associated with an increased risk of recurrence. In patients assigned to intermediate- or high-risk categories who received RAI as adjuvant therapy, there was no difference in risk of recurrence between 4 GBq (108 mCi) and 6 GBq (162 mCi). Conclusions: Our data demonstrate an evolution of RAI activities consistent with translation of ATA guidelines into clinical practice. Use of lower RAI activities was not associated with an increase in recurrence in low-risk thyroid cancer patients. Our data also suggest lower RAI activities may be as efficacious for adjuvant therapy in intermediate- and high-risk patients.

Summary: Background: Noise, an unwanted variability in judgment, is ubiquitous in medicine, including in the prescription of radioactive iodine (RAI). Building upon our recently developed predictive risk model, we created an online clinical support tool to facilitate the translation of our model into clinical practice. The aim of this study is to assess the utility of an online clinical support tool to reduce noise in the treatment for patients with differentiated thyroid cancer (DTC). Methods: The tool was accessible via weblink or a QR code. Activity recommendations were applied to the calculator’s four risk categories: 0 GBq for very low risk, 1 GBq for low risk, 4 GBq for intermediate risk, and 6 GBq for high risk. The tool was applied prospectively to 103 patients who received RAI at Royal North Shore Hospital between 2021 and 2022 and retrospectively to 393 patients treated with RAI between 2017 and 2021. Results: A significant difference was observed in administered activity between the 2021–2022 and 2017–2021 cohorts in patients stratified as intermediate risk (median activity 3.95 GBq, interquartile range 2.03–4.04 vs 4 GBq, 4–4) and high risk (4.07 GBq, 3.95–5.7 vs 6 GBq, 6–6) with P-values of 0.01 and <0.01, respectively. No difference was seen in low-risk patients (2.01 GBq, 1.03–3.98 vs 1 GBq, 1–4, P = 0.30). Additionally, no clinically significant recurrence was observed between the two cohorts (6.6% vs 4.5%; P = 0.628). Conclusion: Optimal risk classification and activity recommendation continue to be established. Our data suggest that providing risk stratification and activity recommendation in an easy-to-access online tool can reduce noise and variability in activity prescription for patients with DTC.