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Abstract Context Thyroid dysfunction occurs commonly following immune checkpoint inhibition. The etiology of thyroid immune-related adverse events (irAEs) remains unclear and clinical presentation can be variable. Objective This study sought to define thyroid irAEs following immune checkpoint inhibitor (ICI) treatment and describe their clinical and biochemical associations. Methods We performed a retrospective cohort study of thyroid dysfunction in patients with melanoma undergoing cytotoxic T-lymphocyte antigen-4 (CTLA-4) and/or programmed cell death protein-1 (PD-1) based ICI treatment from November 1, 2009, to December 31, 2019. Thyroid function was measured at baseline and at regular intervals following the start of ICI treatment. Clinical and biochemical features were evaluated for associations with ICI-associated thyroid irAEs. The prevalence of thyroid autoantibodies and the effect of thyroid irAEs on survival were analyzed. Results A total of 1246 patients were included with a median follow-up of 11.3 months. Five hundred and eighteen (42%) patients developed an ICI-associated thyroid irAE. Subclinical thyrotoxicosis (n = 234) was the most common thyroid irAE, followed by overt thyrotoxicosis (n = 154), subclinical hypothyroidism (n = 61), and overt hypothyroidism (n = 39). Onset of overt thyrotoxicosis occurred a median of 5 weeks (interquartile range [IQR] 2-8) after receipt of a first dose of ICI. Combination immunotherapy was strongly associated with development of overt thyrotoxicosis (odds ratio [OR] 10.8, 95% CI 4.51-25.6 vs CTLA-4 monotherapy; P < .001), as was female sex (OR 2.02, 95% CI 1.37-2.95; P < .001) and younger age (OR 0.83 per 10 years, 95% CI 0.72-0.95; P = .007). By comparison, median onset of overt hypothyroidism was 14 weeks (IQR 8-25). The frequency of overt hypothyroidism did not differ between different ICI types. The strongest associations for hypothyroidism were higher baseline thyroid-stimulating hormone (OR 2.33 per mIU/L, 95% CI 1.61-3.33; P < .001) and female sex (OR 3.31, 95% CI 1.67-6.56; P = .01). Overt thyrotoxicosis was associated with longer progression free survival (hazard ratio [HR] 0.68, 95% CI 0.49-0.94; P = .02) and overall survival (HR 0.57, 95% CI 0.39-0.84; P = .005). There was no association between hypothyroidism and cancer outcomes. Conclusion Thyroid irAEs are common and there are multiple distinct phenotypes. Different thyroid irAE subtypes have unique clinical and biochemical associations, suggesting potentially distinct etiologies for thyrotoxicosis and hypothyroidism arising in this context.

In the 9 years since the publication of our 2011 review of targeted treatment of thyroid cancer with multikinase inhibitors, much has changed in the landscape of this heterogeneous disease. New multikinase and selective inhibitor treatments for medullary thyroid cancer, radioiodine-refractory thyroid cancer and anaplastic thyroid cancer have completed trials and improved progression-free survival. Many physicians are concerned by dose-limiting adverse effects of these drugs and are wary to begin treatment in patients who are systemically well but have marked disease burden, which makes the timing of treatment initiation challenging. Published mechanistic data on tyrosine kinase inhibitors (TKIs) have helped guide our understanding of how to dose effectively with these drugs. A major goal in TKI therapy is to optimize inhibition of oncogenic kinase drivers while maintaining patient quality of life. Real-world data have now been published on how TKIs have fared outside the clinical trial environment. In this Review, we provide a summary of published data on the efficacy of TKIs in clinical practice, to provide clinicians with a more realistic view of how their patients will manage and respond to TKI therapy. Furthermore, we review the data on mechanisms of inhibition, outcomes and adverse effects of TKIs and provide an update on targeted treatment of thyroid cancer, focusing on optimizing the timing of treatment initiation.This Review summarizes the evidence from clinical trials for the efficacy of tyrosine kinase inhibitors in the treatment of thyroid cancer. The data from the experience with these drugs in clinical practice are also discussed, and factors that can help clinicians decide when to start or whether to continue tyrosine kinase inhibitor therapy are considered.

Abstract Context Checkpoint inhibitor–associated autoimmune diabetes mellitus (CIADM) is a rare illness, and little is known about its incidence, clinical features, or pathogenesis. Case Series Description Consecutive patients from a single quaternary melanoma center who developed new-onset insulin-requiring diabetes after commencing anti–programmed cell death-1 (PD-1) immunotherapy were studied to describe CIADM characteristics. Ten (1.9%) of 538 patients with metastatic melanoma treated with anti–PD-1–based immunotherapy from March 2015 to March 2018 developed CIADM. Nine patients had no history of diabetes, and one had pre-existing type 2 diabetes mellitus. Median time from immunotherapy start to CIADM diagnosis was 25 weeks [interquartile range (IQR), 17.5 to 34.5 weeks]. All patients had normal serum C-peptide shortly before CIADM onset and an inappropriately low level when measured soon after. At CIADM diagnosis, median hemoglobin A1c was 7.6% (IQR, 7.15% to 9.75%), median glucose level was 32.5 mmol/L (IQR, 21.6 to 36.7 mmol/L), and median C-peptide concentration was 0.35 nmol/L (IQR, 0.10 to 0.49 mmol/L). Type 1 diabetes (T1D)–associated autoantibodies (DAAs) were present in two patients (both of whom had anti–glutamic acid decarboxylase antibody); all were negative for insulin-associated protein 2, insulin, and ZnT8. Three patients were heterozygous for an HLA class II T1D-risk haplotype; two additional patients also carried protective haplotypes for T1D. All patients continued immunotherapy; eight (80%) had complete or partial oncological response, and all patients required ongoing insulin therapy. Conclusion CIADM is characterized by sudden permanent β-cell failure occurring after immunotherapy. It is distinct from T1D, usually lacks DAA or T1D-associated HLA-risk haplotypes, and is associated with difficult glycemic control from the onset. As such, CIADM represents a new model of auto-inflammatory β-cell failure. CIADM represents a new class and increasingly common cause of autoimmune diabetes that is distinct from T1D in onset and cause; it is characterized by sudden complete β-cell failure after immune checkpoint inhibitor therapy.

Background Tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis of patients with advanced medullary thyroid cancer (MTC). However, treatment response heterogeneity leads to challenges in predicting individual favourable response. This study evaluated the correlation between PET metrics on 68 Ga-DOTATATE and 18 F-FDG PET/CTs prior to treatment, and TKI response. Methods This study retrospectively evaluated patients with metastatic MTC who received TKIs at a tertiary care hospital and had prior 68 Ga-DOTATATE and/or 18 F-FDG PET/CT imaging. Patient demographics, treatment and PET/CT data were collected. Standardized Uptake Value (SUV) max, SUVmean, Total Lesion Activity (TLA) and Metabolic Tumor Volume (MTV) were determined per PET/CT. Results In the 25 patients, mean age at diagnosis was 48 (±15) years; 11 (44%) were female and 21 tumors harbored RET driver alterations. Thirty-six TKI treatments were administered (11 patients received two TKIs sequentially). RECIST response rates (available in 32/36 treatments) included; stable disease in 8/32 (25%), partial response in 23/32 (72%) and complete response in 1/32 (3%) treatments. In total, 30 pre-TKI PET/CTs (24 68 Ga-DOTATATE PET/CTs, 6 18 F-FDG PET/CTs) were performed. Pre-TKI 68 Ga-DOTATATE PET/CTs did not correlate with TKI treatment response. In the 18 F-FDG cohort, high MTV and TLA correlated with a better structural response ( p  < 0.001) and high SUVmean correlated with a longer time to reach optimal response ( p  = 0.037). Conclusions In a small cohort of MTC patients, MTV and TLA on 18 F-FDG PET/CT were associated with the structural response of TKI treatment, suggesting their potential utility in identifying patients who are likely to respond significantly. In contrast, TKI response showed no correlation with uptake on 68 Ga-DOTATATE PET/CT.

Abstract Context Carriers of germline pathogenic variants (PVs) in succinate dehydrogenase type B (SDHB) are at increased risk of developing pheochromocytomas and paragangliomas (PPGLs). Understanding their outcomes can guide recommendations for risk assessment and early detection. Objective We performed a systematic review and meta-analysis of the following outcomes in SDHB PV carriers: age-specific risk of developing tumors, metastatic progression, second primary tumor development, and mortality. Methods PubMed, MEDLINE, and EMBASE were searched. Sixteen studies met the inclusion criteria and were sorted into 4 outcome categories: age-specific penetrance, metastatic disease, risk of second tumor, and mortality. We assessed heterogeneity and performed a meta-analysis across studies using a random-effects model with the DerSimonian and Laird method. Results Penetrance of PPGLs for nonproband/nonindex SDHB PV carriers by age 20 was 4% (95% CI, 3%-6%), 11% (95% CI, 8%-15%) by age 40, 24% (95% CI, 19%-31%) by age 60%, and 35% (95% CI, 25%-47%) by age 80. The overall risk of metastatic disease for nonproband/nonindex carriers with PPGLs was 9% (95%, CI 5%-16%) per lifetime. In all affected cases (combining both proband/index and nonproband/nonindex carriers with tumors), the risk of a second tumor was 24% (95% CI, 18%-31%) and all-cause 5-year mortality was 18% (95% CI, 6%-40%). Conclusion Penetrance for PPGLs in SDHB PV carriers increases linearly with age. Affected carriers are at risk of developing and dying of metastatic disease, or of developing second tumors. Lifelong surveillance is appropriate.

PurposeHypophysitis develops in up to 19% of melanoma patients treated with ipilimumab, a cytotoxic T-lymphocyte antigen-4 antibody. Early detection may avert life-threatening hypopituitarism. We aimed to assess the incidence of ipilimumab-induced hypophysitis (IH) at a quaternary melanoma referral centre, and to determine whether cortisol or thyroid stimulating hormone (TSH) monitoring could predict IH onset.MethodsWe performed a retrospective cohort study of ipilimumab-treated patients at a quaternary melanoma referral centre in Australia. The inclusion criteria were patients with metastatic or unresectable melanoma treated with ipilimumab monotherapy, and cortisol and TSH measurements prior to ≥ 2 infusions. The main outcomes were IH incidence and TSH and cortisol patterns in patients who did and did not develop IH.ResultsOf 78 ipilimumab-treated patients, 46 met the study criteria and 9/46 (20%) developed IH at a median duration of 13.0 weeks (range 7.7–18.1) following ipilimumab initiation. All patients whose TSH fell ≥ 80% compared to baseline developed IH, and, in 5/9 patients with IH, TSH fell prior to cortisol fall and IH diagnosis. Pre-cycle-4 TSH was significantly lower in those who developed IH (0.31 vs. 1.73 mIU/L, P = 0.006). TSH fall was detected at a median time of 9.2 (range 7.7–16.4) weeks after commencing ipilimumab, and a median of 3.6 (range of − 1.4 to 9.7) weeks before IH diagnosis. There was no difference in TSH between the groups before cycles 1–3 or in cortisol before cycles 1–4.ConclusionsTSH fall ≥ 80% may be an early marker of IH. Serial TSH measurement during ipilimumab therapy may be an inexpensive tool to expedite IH diagnosis.

Tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis of patients with advanced medullary thyroid cancer (MTC). However, treatment response heterogeneity leads to challenges in predicting individual favourable response. This study evaluated the correlation between PET metrics on Ga-DOTATATE and F-FDG PET/CTs prior to treatment, and TKI response. This study retrospectively evaluated patients with metastatic MTC who received TKIs at a tertiary care hospital and had prior Ga-DOTATATE and/or F-FDG PET/CT imaging. Patient demographics, treatment and PET/CT data were collected. Standardized Uptake Value (SUV) max, SUVmean, Total Lesion Activity (TLA) and Metabolic Tumor Volume (MTV) were determined per PET/CT. In the 25 patients, mean age at diagnosis was 48 (±15) years; 11 (44%) were female and 21 tumors harbored RET driver alterations. Thirty-six TKI treatments were administered (11 patients received two TKIs sequentially). RECIST response rates (available in 32/36 treatments) included; stable disease in 8/32 (25%), partial response in 23/32 (72%) and complete response in 1/32 (3%) treatments. In total, 30 pre-TKI PET/CTs (24 Ga-DOTATATE PET/CTs, 6 F-FDG PET/CTs) were performed. Pre-TKI Ga-DOTATATE PET/CTs did not correlate with TKI treatment response. In the F-FDG cohort, high MTV and TLA correlated with a better structural response (p < 0.001) and high SUVmean correlated with a longer time to reach optimal response (p = 0.037). In a small cohort of MTC patients, MTV and TLA on F-FDG PET/CT were associated with the structural response of TKI treatment, suggesting their potential utility in identifying patients who are likely to respond significantly. In contrast, TKI response showed no correlation with uptake on Ga-DOTATATE PET/CT.