[Systemic therapies for advanced thyroid cancer - an update]. / Systemtherapien bei metastasierten Schilddrüsenkarzinomen ­ ein Update.

Based on phase III clinical studies, four multi-kinase inhibitors (MKI) are approved for the treatment of progressive radioiodine-refractory differentiated thyroid carcinoma (rrDTC) and medullary thyroid carcinoma (MTC) in Germany. Only recently, based on the randomized trial COSMIC-311, Cabozantinib has been approved as a second-line treatment option in advanced rrDTC. As first in-label selective RET-Inhibitor, Selpercatinib showed promising efficacy in advanced MTC (first line) with RET mutations and rrDTC (second line) with RET fusions along with fewer side effects. Changes and new approaches for the treatment of ATC have been summarised in the current ATA guidelines.

Teprotumumab Efficacy, Safety, and Durability in Longer-Duration Thyroid Eye Disease and Re-treatment: OPTIC-X Study.

PURPOSE: To evaluate teprotumumab safety/efficacy in patients with thyroid eye disease (TED) who were nonresponsive or who experienced a disease flare. DESIGN: The Treatment of Graves' Orbitopathy to Reduce Proptosis with Teprotumumab Infusions in an Open-Label Clinical Extension Study (OPTIC-X) is a teprotumumab treatment and re-treatment trial following the placebo-controlled teprotumumab Phase 3 Treatment of Graves' Orbitopathy (Thyroid Eye Disease) to Reduce Proptosis with Teprotumumab Infusions in a Randomized, Placebo-Controlled, Clinical Study (OPTIC) trial. PARTICIPANTS: Patients who previously received placebo (n = 37) or teprotumumab (n = 14) in OPTIC. METHODS: OPTIC nonresponders or those who flared (≥2-mm increase in proptosis, ≥2-point increase in clinical activity score [CAS], or both) during follow-up were treated for the first time (previous placebo patients) or re-treated with teprotumumab in OPTIC-X with 8 infusions over 24 weeks. MAIN OUTCOME MEASURES: Proptosis response and safety. Secondary outcomes included proptosis, CAS, subjective diplopia, and quality-of-life. RESULTS: Thirty-three of 37 placebo-treated OPTIC patients (89.2%) became proptosis responders (mean ± standard deviation, -3.5 ± 1.7 mm) when treated with teprotumumab in OPTIC-X. The responses were equivalent to the OPTIC study. In these responders, proptosis, CAS of 0 or 1, and diplopia responses were maintained in 29 of 32 patients (90.6%), 20 of 21 patients (95.2%), and 12 of 14 patients (85.7%), respectively, at follow-up week 48. The median TED duration was 12.9 months versus 6.3 months in those treated with teprotumumab in the OPTIC study. Of the 5 OPTIC teprotumumab nonresponders re-treated in OPTIC-X, 2 responded, 1 showed a proptosis reduction of 1.5 mm from OPTIC baseline, and 2 discontinued treatment early. Of the OPTIC teprotumumab responders who experienced flare, 5 of 8 patients (62.5%) responded when re-treated (mean proptosis reduction, 1.9 ± 1.2 mm from OPTIC-X baseline and 3.3 ± 0.7 mm from OPTIC baseline). Compared with published double-masked trials and their integrated follow-up, no new safety signals were identified. Mild hearing impairment was reported; 4 events occurred during the first course of treatment, and 2 events reoccurred after re-treatment. CONCLUSIONS: Patients with TED of longer disease duration responded similarly to those treated earlier in the disease course. Patients with an insufficient initial response or flare may benefit from additional teprotumumab therapy. No new safety risk was identified; however additional postmarketing pharmacovigilance is ongoing.

Predicting the Course of Graves' Orbitopathy Using Serially Measured TSH-Receptor Autoantibodies by Automated Binding Immunoassays and the Functional Bioassay.

The aim of the study was to investigate the use of serial measurements of TSH-receptor autoantibodies (TRAb) with the newest available assay technology to predict the course of Graves' Orbitopathy (GO) during the first 24 months from disease onset. Serial serum samples from patients with GO (103 mild/135 severe) were collected between 2007 and 2017 and retrospectively analyzed. The course of GO were classified into mild/severe 12 months after manifestation (severe: NOSPECS≥5; mild<5). TRAb were measured with automated binding immunoassays (IU/l): TRAb Elecsys (Cobas, Roche), TRAb bridge assay (IMMULITE, Siemens), and a cell-based bioassay (percent of specimen to reference ratio - SRR%) (Thyretain, Quidel). Variable cut off levels of measured TRAb were calculated at specificity of 90% from receiver operator curve (ROC) analysis for several timepoints during the course of GO. To select one: 5-8 months after first GO symptoms, which is the timepoint for usual referals for treatment mild course could be predicted at cut offs of 1.5 IU/l (Elecsys), 0.8 IU/l (Immulite) and 402% SRR (Thyretain) and the risc of severe course has to be anticipated if TRAb are above 11.6 IU/l (Elecsys), 6.5 IU/l (Thyretain), and 714% SRR (Thyretain). The Thyretain bioassay showed the highest diagnostic sensitivity (using the commercial cut off's) over the entire follow up period. TRAb measurements during the 24-month follow up of GO provide added value to the GO clinical activity and severity scores and should be used especially in the event of an unclear decision-taking situation with regard to therapy.

Predicting the Relapse of Hyperthyroidism in Treated Graves' Disease with Orbitopathy by Serial Measurements of TSH-Receptor Autoantibodies.

The aim of this study was to investigate the potential of the new TSH-receptor antibody (TRAb) assays to predict remission or relapse of hyperthyroidism in patients with Graves' disease (GD) and Graves' orbitopathy (GO). TRAbs were measured retrospectively in sera from a cohort of GD patients with GO (n=117; remission n=38 and relapse n=79-Essen GO biobank) with automated binding immunoassays: TRAb Elecsys (Cobas Roche) and TRAb bridge assay (IMMULITE, Siemens), and the TSAb (thyroid stimulating Ab) cell-based bioassay (Thyretain, Quidel Corp.). To identify relapse risk/remission of hyperthyroidism patients were followed up at least 10 months after the end of antithyroid drug therapy (ATD) therapy. ROC plot analysis was performed to calculate cut-off levels of TRAb and TSAb for prediction of relapse and remission of hyperthyroidism. Cut-off serum levels are provided for timepoints around 3, 6, 10, and 15 months after the beginning of ATD. Repeated measurements of TRAb increase the rate of relapses predictions to 60% (Elecsys), 70% (IMMULITE), and 55% (Thyretain). Patients with remission have consistently TRAb levels below the cut off for relapse in repeated measurements. The cell-based bioassay was the most sensitive - and continued to be positive during follow up [at 15 months: 90% vs. 70% (IMMULITE) and 65% (Elecsys)]. Identification of relapsing hyperthyroidism is possible with automated immunoassays and cell-based bioassay especially with serial TRAb measurements during the course of ATD therapy. Patient who need eye surgery may profit from an early decision towards definitive treatment.

Analysis of risk factors and prognosis in differentiated thyroid cancer with focus on minimal extrathyroidal extension.

AIMS: In contrast to all prior AJCC/TNM classifications for differentiated thyroid cancer (DTC) the 8th edition does not take minimal extrathyroidal extension (M-ETE) into consideration for local tumor staging. We therefore aimed to retrospectively assess the specific impact of M-ETE on the outcome of M-ETE patients treated in our clinic. METHODS: DTC patients with M-ETE and a follow-up time of ≥ 5 years were included and matched with an identical number of patients without M-ETE, but with equal histopathological tumor subtype and size. The frequency of initially metastatic disease among groups was compared using Fisher's exact test, the recurrence rate by virtue of log-rank test. Fisher's exact test and multivariate analysis were used to account for the presence of confounding risk factors. RESULTS: One hundred sixty patients (80 matching pairs) were eligible. With other confounding risk factors being equal, the prevalence of N1-/M1-disease at initial diagnosis was comparable among groups (M-ETE: 42.5 %; no M-ETE: 32.5 %; p = 0.25). No differences with regard to the recurrence rate were shown. However, M-ETE patients were treated with external beam radiation therapy more often (16.3 % vs. 1.3 %; p = 0.004) and received higher median cumulative activities of 131I (10.0 vs. 8.0 GBq; p < 0.001). DISCUSSION: Although having played a pivotal role for local tumor staging of DTC for decades M-ETE did not increase the risk for metastases at initial diagnosis and the recurrence rate in our cohort. Patients with M-ETE had undergone intensified treatment, which entails a possible confounding factor that warrants further investigation in randomized controlled trials.

Value of Progression of Coronary Artery Calcification for Risk Prediction of Coronary and Cardiovascular Events: Result of the HNR Study (Heinz Nixdorf Recall).

BACKGROUND: Computed tomography (CT) allows estimation of coronary artery calcium (CAC) progression. We evaluated several progression algorithms in our unselected, population-based cohort for risk prediction of coronary and cardiovascular events. METHODS: In 3281 participants (45-74 years of age), free from cardiovascular disease until the second visit, risk factors, and CTs at baseline (b) and after a mean of 5.1 years (5y) were measured. Hard coronary and cardiovascular events, and total cardiovascular events including revascularization, as well, were recorded during a follow-up time of 7.8±2.2 years after the second CT. The added predictive value of 10 CAC progression algorithms on top of risk factors including baseline CAC was evaluated by using survival analysis, C-statistics, net reclassification improvement, and integrated discrimination index. A subgroup analysis of risk in CAC categories was performed. RESULTS: We observed 85 (2.6%) hard coronary, 161 (4.9%) hard cardiovascular, and 241 (7.3%) total cardiovascular events. Absolute CAC progression was higher with versus without subsequent coronary events (median, 115 [Q1-Q3, 23-360] versus 8 [0-83], P<0.0001; similar for hard/total cardiovascular events). Some progression algorithms added to the predictive value of baseline CT and risk assessment in terms of C-statistic or integrated discrimination index, especially for total cardiovascular events. However, CAC progression did not improve models including CAC5y and 5-year risk factors. An excellent prognosis was found for 921 participants with double-zero CACb=CAC5y=0 (10-year coronary and hard/total cardiovascular risk: 1.4%, 2.0%, and 2.8%), which was for participants with incident CAC 1.8%, 3.8%, and 6.6%, respectively. When CACb progressed from 1 to 399 to CAC5y≥400, coronary and total cardiovascular risk were nearly 2-fold in comparison with subjects who remained below CAC5y=400. Participants with CACb≥400 had high rates of hard coronary and hard/total cardiovascular events (10-year risk: 12.0%, 13.5%, and 30.9%, respectively). CONCLUSIONS: CAC progression is associated with coronary and cardiovascular event rates, but adds only weakly to risk prediction. What counts is the most recent CAC value and risk factor assessment. Therefore, a repeat scan >5 years after the first scan may be of additional value, except when a double-zero CT scan is present or when the subjects are already at high risk.

Validation of the Tuebingen CD-25 Inventory as a Measure of Postoperative Health-Related Quality of Life in Patients Treated for Cushing's Disease.

BACKGROUND: To evaluate the construct and criterion validity of the Tuebingen Cushing's disease quality of life inventory (Tuebingen CD-25) for application in patients treated for Cushing's disease (CD). METHODS: A total of 176 patients with adrenocorticotropin hormone-dependent CD (144 of them female, overall mean age 46.1 ± 13.7 years) treated at 3 large tertiary referral centers in Germany were studied. Construct validity was assessed by hypothesis testing (self-perceived symptom reduction assessment) and contrasted groups (patients with vs. without hypercorticolism). For this purpose, already existing data from 55 CD patients was used, representing the hypercortisolemic group. Criterion validity (concurrent validity) was assessed in relation to the Cushing's quality of life questionnaire (CushingQoL), the Short Form 36 health survey (SF-36), and the body mass index (BMI). RESULTS: Patients with self-perceived remarkable symptom reduction had significant lower Tuebingen CD-25 scores (i.e. better health-related quality of life) than patients with self-perceived insufficient symptom reduction (p < 0.05). Similarly, the mean scores of the Tuebingen CD-25 scales were lower in patients without hypercortisolism (total score 27.0 ± 17.2) compared to those with hypercortisolism (total score 45.3 ± 22.1; each p < 0.05), providing evidence for construct validity. Criterion validity was confirmed by the correlations between the Tuebingen CD-25 total score and the CushingQoL (Spearman's coefficient -0.733), as well as all scales of the SF-36 (Spearman's coefficient between -0.447 and -0.700). CONCLUSION: The analyses presented in this large-sample study provide robust evidence for the construct and criterion validity of the Tuebingen CD-25.

Progression of coronary artery calcification seems to be inevitable, but predictable - results of the Heinz Nixdorf Recall (HNR) study.

AIM: Coronary artery calcification (CAC), as a sign of atherosclerosis, can be detected and progression quantified using computed tomography (CT). We develop a tool for predicting CAC progression. METHODS AND RESULTS: In 3481 participants (45-74 years, 53.1% women) CAC percentiles at baseline (CACb) and after five years (CAC5y) were evaluated, demonstrating progression along gender-specific percentiles, which showed exponentially shaped age-dependence. Using quantile regression on the log-scale (log(CACb+1)) we developed a tool to individually predict CAC5y, and compared to observed CAC5y. The difference between observed and predicted CAC5y (log-scale, mean±SD) was 0.08±1.11 and 0.06±1.29 in men and women. Agreement reached a kappa-value of 0.746 (95% confidence interval: 0.732-0.760) and concordance correlation (log-scale) of 0.886 (0.879-0.893). Explained variance of observed by predicted log(CAC5y+1) was 80.1% and 72.0% in men and women, and 81.0 and 73.6% including baseline risk factors. Evaluating the tool in 1940 individuals with CACb>0 and CACb<400 at baseline, of whom 242 (12.5%) developed CAC5y>400, yielded a sensitivity of 59.5%, specificity 96.1%, (+) and (-) predictive values of 68.3% and 94.3%. A pre-defined acceptance range around predicted CAC5y contained 68.1% of observed CAC5y; only 20% were expected by chance. Age, blood pressure, lipid-lowering medication, diabetes, and smoking contributed to progression above the acceptance range in men and, excepting age, in women. CONCLUSION: CAC nearly inevitably progresses with limited influence of cardiovascular risk factors. This allowed the development of a mathematical tool for prediction of individual CAC progression, enabling anticipation of the age when CAC thresholds of high risk are reached.

Consanguineous couple with SDHD gene mutations: Diagnosis, treatment, and implications of family genetic testing.

The newly published clinical consensus guideline on the management of PGL/PCC is helpful for decision-making for diagnostics and treatment. Still, the treatment of patients with SDHD gene mutations requires an individual approach and those patients belong to multiprofessional teams. It is often assumed that spouses are genetically unrelated. However, the genetic relationships between spouses should always be examined empathetically and impartially.

Genotype-specific development of MEN 2 constituent components in 683 RET carriers.

The age-specific development of the three constituent components of multiple endocrine neoplasia type 2 (MEN 2) is incompletely characterized for many of the >30 causative rearranged during transfection (RET) mutations, which this genetic association study aimed to specify. Included in the study were 683 carriers of heterogeneous RET germline mutations: 53 carriers with 1 highest-risk mutation (codon 918); 240 carriers with 8 different high-risk mutations (codon 634); 176 carriers with 16 different intermediate-risk mutations (codon 609, 611, 618, 620, or 630); and 214 carriers with 6 different low-risk mutations (codon 768, 790, 804, or 891).There was a strong genotype-specific development of MEN 2 constituent components, with distinct age gradients from C cell disease to node negative medullary thyroid cancer (MTC), from node negative to node positive MTC, from node positive MTC to pheochromocytoma, and from pheochromocytoma to primary hyperparathyroidism. Primary hyperparathyroidism was not observed among the 53 MEN 2B patients who carried highest-risk mutations (age range: 0.5-50 years), of whom no more than 12 (23%) and 3 (6%) carriers were older than age 30 years and 35 years, respectively. The age-specific development of MTC differed significantly between the four RET risk categories, whereas the age-specific development of pheochromocytoma differed significantly only between the two strongest RET risk categories. No significant differences were noted in the development of primary hyperparathyroidism. These findings delineate age-specific disease manifestation corridors for the three constituent components of MEN 2 by RET genotype. These corridors are useful for initial risk assessment and organ-specific surveillance of newly identified RET carriers going forward.

Vandetanib in locally advanced or metastatic differentiated thyroid cancer refractory to radioiodine therapy.

The VERIFY study aimed to determine the efficacy of vandetanib in patients with differentiated thyroid cancer (DTC) that is either locally advanced or metastatic and refractory to radioiodine (RAI) therapy. Specifically, VERIFY is a randomized, double-blind, multicenter phase III trial aimed to determine the efficacy and safety of vandetanib in tyrosine kinase inhibitor-naive patients with locally advanced or metastatic RAI-refractory DTC with documented progression (NCT01876784). Patients were randomized 1:1 to vandetanib or placebo. The primary endpoint was progression-free survival (PFS). Secondary endpoints included best objective response rate, overall survival (OS), safety, and tolerability. Patients continued to receive randomized treatment until disease progression or for as long as they were receiving clinical benefit unless criteria for treatment discontinuation were met. Following randomization, 117 patients received vandetanib, and 118 patients received a placebo. Median PFS was 10.0 months in the vandetanib group and 5.7 months in the placebo group (hazard ratio: 0.75; 95% CI: 0.55-1.03; P = 0.080). OS was not significantly different between treatment arms. Common Terminology Criteria for Adverse Events (CTCAE) of grade ≥3 were reported in 55.6% of patients in the vandetanib arm and 25.4% in the placebo arm. Thirty-three deaths (28.2%; one related to study treatment) occurred in the vandetanib arm compared with 16 deaths (13.6%; two related to treatment) in the placebo arm. No statistically significant improvement was observed in PFS in treatment versus placebo in patients with locally advanced or metastatic, RAI-refractory DTC. Moreover, active treatment was associated with more adverse events and more deaths than placebo, though the difference in OS was not statistically significant.

Patients' Persistent Symptoms, Clinician Demographics, and Geo-Economic Factors Are Associated with Choice of Therapy for Hypothyroidism by European Thyroid Specialists: The "THESIS" Collaboration.

Background: Hypothyroidism is common, however, aspects of its treatment remain controversial. Our survey aimed at documenting treatment choices of European thyroid specialists and exploring how patients' persistent symptoms, clinician demographics, and geo-economic factors relate to treatment choices. Methods: Seventeen thousand two hundred forty-seven thyroid specialists from 28 countries were invited to participate in an online questionnaire survey. The survey included respondent demographic data and treatment choices for hypothyroid patients with persistent symptoms. Geo-economic data for each country were included in the analyses. Results: The response rate was 32.9% (6058 respondents out of 17,247 invitees). Levothyroxine (LT4) was the initial treatment preferred by the majority (98.3%). Persistent symptoms despite normal serum thyrotropin (TSH) while receiving LT4 treatment were reported to affect up to 10.0% of patients by 75.4% of respondents, while 28.4% reported an increasing such trend in the past 5 years. The principal explanations offered for patients' persistent symptoms were psychosocial factors (77.1%), comorbidities (69.2%), and unrealistic patient expectations (61.0%). Combination treatment with LT4+liothyronine (LT3) was chosen by 40.0% of respondents for patients who complained of persistent symptoms despite a normal TSH. This option was selected more frequently by female thyroid specialists, with high-volume practice, working in countries with high gross national income per capita. Conclusions: The perception of patients' dissatisfaction reported by physicians seems lower than that described by hypothyroid patients in previous surveys. LT4+LT3 treatment is used frequently by thyroid specialists in Europe for persistent hypothyroid-like symptoms even if they generally attribute such symptoms to nonendocrine causes and despite the evidence of nonsuperiority of the combined over the LT4 therapy. Pressure by dissatisfied patients on their physicians for LT3-containing treatments is a likely explanation. The association of the therapeutic choices with the clinician demographic characteristics and geo-economic factors in Europe is a novel information and requires further investigation.

[Systemic therapies for advanced thyroid cancer - an update]. / Systemtherapien bei metastasierten Schilddrüsenkarzinomen ­ ein Update.

Based on phase III clinical studies, four multi-kinase inhibitors (MKI) are approved for the treatment of progressive radioiodine-refractory differentiated thyroid carcinoma (rrDTC) and medullary thyroid carcinoma (MTC) in Germany. Only recently, based on the randomized trial COSMIC-311, Cabozantinib has been approved as a second-line treatment option in advanced rrDTC. As first in-label selective RET-Inhibitor, Selpercatinib showed promising efficacy in advanced MTC (first line) with RET mutations and rrDTC (second line) with RET fusions along with fewer side effects. Changes and new approaches for the treatment of ATC have been summarised in the current ATA guidelines.

Clinical presentation of MEN 2A in index vs. non-index patients.

PURPOSE: Differences in syndromic manifestations of multiple endocrine neoplasia 2 A (MEN2A) between index and non-index patients are ill-defined. METHODS: Cross-sectional analysis of 602 REarranged during Transfection (RET) carriers (156 index and 446 non-index patients) who underwent thyroidectomy, adrenalectomy, and/or parathyroidectomy between 1985 and 2022, stratified by mutational risk. RESULTS: Index patients were 5.8-13.9 years older at thyroidectomy than non-index patients, at which point they had developed 10.6-14.4 mm larger medullary thyroid cancers. Correlations between index status and primary tumor size (ρ = 0.489-0.544) were stronger than correlations between index status and age at thyroidectomy (ρ = 0.359-0.438). For pheochromocytoma and primary hyperparathyroidism, no significant differences were noted. When stratified by time of surgery before vs. in the new millennium, age at thyroidectomy fell significantly only for non-index patients in the new millennium: from 28.6 to 21.2 years (moderate-high risk mutations; P = 0.049) and from 23.1 to 12.3 years (high-risk mutations; P < 0.001). All other inter-millennium comparisons did not reach statistical significance. CONCLUSION: These findings imply that differences between index and non-index patients impact the first syndromic manifestation without extending to subsequent syndromic manifestations. Because they exhibited similar age and tumor characteristics for the secondary and tertiary manifestations of MEN2A, screening for these syndromic components remains an integral element of MEN2A management in index and non-index patients alike. Wider use of population genomic screening may work to diminish the observed disparities between index and non-index patients going forward.

Modification of TSH-related genetic effects by indicators of socioeconomic position.

Objective: Thyroid-stimulating hormone (TSH) is influenced by genetic and environmental factors such as socioeconomic position (SEP). However, interactions between TSH-related genetic factors and indicators of SEP have not been investigated to date. The aim of the study was to determine whether education and income as SEP indicators may interact with TSH-related genetic effect allele sum scores (GESTSH_2013 and GESTSH_2020) based on two different GWAS meta-analyses that affect TSH values in a population-based study. Methods: In 4085 participants of the Heinz Nixdorf Recall Study associations between SEP indicators, GESTSH and TSH were quantified using sex- and age-adjusted linear regression models. Interactions between SEP indicators and GESTSH were assessed by GESTSH × SEP interaction terms, single reference joint effects and calculating genetic effects stratified by SEP group. Results: Participants within the highest education group showed the strongest genetic effect with on average 1.109-fold (95% CI: 1.067-1.155) higher TSH values per GESTSH_2013 SD, while in the lowest education group, the genetic effect was less strong (1.061-fold (95% CI: 1.022-1.103)). In linear regression models including interaction terms, some weak indication for a positive GESTSH_2013 by education interaction was observed showing an interaction effect size estimate of 1.005 (95% CI: 1.000-1.010) per year of education and GESTSH_2013 SD. No indication for interaction was observed for using income as SEP indicator. Using the GESTSH_2020, similar results were observed. Conclusion: Our results gave some indication that education may affect the expression of TSH-related genetic effects. Stronger genetic effects in high-education groups may be explained by environmental factors that have an impact on gene expression and are more prevalent in high SEP groups.

The Changing Face of Multiple Endocrine Neoplasia 2A: From Symptom-Based to Preventative Medicine.

CONTEXT: Early genetic association studies yielded too high risk estimates for multiple endocrine neoplasia (MEN2A), suggesting a need for extended surgery. OBJECTIVE: The objective was to delineate temporal changes in MEN2A presentation by birth cohort analyses. METHODS: Birth cohort analyses (10-year increments; ≤1950 to 2011-2020) of carriers of rearranged during transfection (RET) mutations who underwent surgery for MEN2A. RESULTS: Included in this study were 604 carriers (155 index, 445 nonindex, 4 additional patients), with 237 carriers harboring high-risk mutations, 165 carriers moderate-high risk mutations, and 202 carriers low-moderate risk mutations. With increasing recency of birth cohorts, there was a continual decline in index patients from 41-74% to 0% (P < .001) and of medullary thyroid cancer (MTC) from 96-100% to 0-33% (P < .001). Node metastases diminished from 62-70% to 0% (P ≤ .001; high and low-moderate risk mutations), whereas biochemical cure after thyroidectomy surged from 17-33% to 100% (P ≤ .019; high and low-moderate mutations). Surgical interventions for MEN2A-related tumors were performed increasingly earlier, causing median carrier age to fall: from 51-63 to 3-5 years at thyroidectomy (P < .001); from 46-51 to 24-25 years at first adrenalectomy (P ≤ .013; high and moderate-high risk mutations); and from 43.5-66 to 16.5-32 years at parathyroidectomy. MTC diameters were more effectively decreased from 14-32 to 1-4 mm (P ≤ 002) than pheochromocytoma diameters (nonsignificant). CONCLUSION: These insights into MEN2A presentation, adjusted by birth year, illustrate the shift from reactive to preventative medicine, enabling less extensive risk-reducing surgery.

Molecular Markers Are Associated with Onset of Radioiodine Refractoriness in Patients with Papillary Thyroid Carcinoma.

The onset of radioiodine-refractory thyroid carcinoma (RR-TC) is a negative predictor of survival and has been linked to the presence of BRAFV600E mutations in papillary thyroid cancer. We aimed to identify further genetic alterations associated with RR-TC. Methods: We included 38 patients with papillary thyroid cancer who underwent radioiodine imaging and 18F-FDG PET/CT after total thyroidectomy. The molecular profile was assessed by next-generation sequencing. The time to the onset of RR-TC for different genetic alterations was compared using the log-rank test. Results: The median onset to RR-TC was 0.7 and 19.8 mo in patients with and without, respectively, telomerase reverse transcriptase promoter mutations (P = 0.02) and 1.7 and 19.8 mo in patients with and without, respectively, a tumor protein 53 mutation (P < 0.01). This association was not observed for BRAFV600E mutations (P = 0.49). Conclusion: Our data show a significant association between the onset of RR-TC and mutations in telomerase reverse transcriptase promoter and tumor protein 53, indicating the need for a more extensive diagnostic workup in these patients. Certain genetic changes put patients with thyroid cancer at risk of developing cancer spread that does not respond to radioiodine therapy.

Sporadic noninvasive medullary thyroid neoplasm: A desmoplasia-negative unifocal nonmetastatic tumor cured by hemithyroidectomy.

BACKGROUND: The absence of primary tumor desmoplasia, a marker of node metastases, on frozen section may help reduce the extent of surgery without compromising the biochemical cure. We aimed to clarify whether hemithyroidectomy with diagnostic ipsilateral central neck dissection can replace total thyroidectomy with routine central neck dissection in patients with sporadic medullary thyroid cancer. METHODS: We retrospectively evaluated data collected from patients who had undergone primary neck surgery for hypercalcitoninemic sporadic medullary thyroid cancer between January 2017 and December 2022 at one institution. RESULTS: Of the 25 patients we examined, 19 had desmoplasia-negative and 6 desmoplasia-positive primary thyroid tumors on frozen section. The desmoplasia-negative patients had undergone less surgery with fewer nodes removed than the desmoplasia-positive patients (medians of 6 vs 31 nodes, P < .001). The desmoplasia-negative patients had predominantly undergone hemithyroidectomy with ipsilateral central neck dissection. None of the desmoplasia-negative tumors was multifocal (0 of 19 desmoplasia-negative vs 2 of 6 desmoplasia-positive or 0% vs 33%, P = .050) or node-positive (0 of 19 vs 6 of 6 patients or 0% vs 100%; medians of 0 vs 3.5 node metastases; both P < .001). Despite limited surgery, all desmoplasia-negative patients attained and maintained biochemical cure. CONCLUSION: Hemithyroidectomy combined with diagnostic ipsilateral central neck dissection is a viable risk-reducing and curative strategy for desmoplasia-negative and node-negative, nonmetastatic unifocal tumors, for which we propose the term sporadic noninvasive medullary thyroid neoplasm (SNMTP).

The optimal healthy ranges of thyroid function defined by the risk of cardiovascular disease and mortality: systematic review and individual participant data meta-analysis.

BACKGROUND: Reference intervals of thyroid-stimulating hormone (TSH) and free thyroxine (FT4) are statistically defined by the 2·5-97·5th percentiles, without accounting for potential risk of clinical outcomes. We aimed to define the optimal healthy ranges of TSH and FT4 based on the risk of cardiovascular disease and mortality. METHODS: This systematic review and individual participant data (IPD) meta-analysis identified eligible prospective cohorts through the Thyroid Studies Collaboration, supplemented with a systematic search via Embase, MEDLINE (Ovid), Web of science, the Cochrane Central Register of Controlled Trials, and Google Scholar from Jan 1, 2011, to Feb 12, 2017 with an updated search to Oct 13, 2022 (cohorts found in the second search were not included in the IPD). We included cohorts that collected TSH or FT4, and cardiovascular outcomes or mortality for adults (aged ≥18 years). We excluded cohorts that included solely pregnant women, individuals with overt thyroid diseases, and individuals with cardiovascular disease. We contacted the study investigators of eligible cohorts to provide IPD on demographics, TSH, FT4, thyroid peroxidase antibodies, history of cardiovascular disease and risk factors, medication use, cardiovascular disease events, cardiovascular disease mortality, and all-cause mortality. The primary outcome was a composite outcome including cardiovascular disease events (coronary heart disease, stroke, and heart failure) and all-cause mortality. Secondary outcomes were the separate assessment of cardiovascular disease events, all-cause mortality, and cardiovascular disease mortality. We performed one-step (cohort-stratified Cox models) and two-step (random-effects models) meta-analyses adjusting for age, sex, smoking, systolic blood pressure, diabetes, and total cholesterol. The study was registered with PROSPERO, CRD42017057576. FINDINGS: We identified 3935 studies, of which 53 cohorts fulfilled the inclusion criteria and 26 cohorts agreed to participate. We included IPD on 134 346 participants with a median age of 59 years (range 18-106) at baseline. There was a J-shaped association of FT4 with the composite outcome and secondary outcomes, with the 20th (median 13·5 pmol/L [IQR 11·2-13·9]) to 40th percentiles (median 14·8 pmol/L [12·3-15·0]) conveying the lowest risk. Compared with the 20-40th percentiles, the age-adjusted and sex-adjusted hazard ratio (HR) for FT4 in the 80-100th percentiles was 1·20 (95% CI 1·11-1·31) for the composite outcome, 1·34 (1·20-1·49) for all-cause mortality, 1·57 (1·31-1·89) for cardiovascular disease mortality, and 1·22 (1·11-1·33) for cardiovascular disease events. In individuals aged 70 years and older, the 10-year absolute risk of composite outcome increased over 5% for women with FT4 greater than the 85th percentile (median 17·6 pmol/L [IQR 15·0-18·3]), and men with FT4 greater than the 75th percentile (16·7 pmol/L [14·0-17·4]). Non-linear associations were identified for TSH, with the 60th (median 1·90 mIU/L [IQR 1·68-2·25]) to 80th percentiles (2·90 mIU/L [2·41-3·32]) associated with the lowest risk of cardiovascular disease and mortality. Compared with the 60-80th percentiles, the age-adjusted and sex-adjusted HR of TSH in the 0-20th percentiles was 1·07 (95% CI 1·02-1·12) for the composite outcome, 1·09 (1·05-1·14) for all-cause mortality, and 1·07 (0·99-1·16) for cardiovascular disease mortality. INTERPRETATION: There was a J-shaped association of FT4 with cardiovascular disease and mortality. Low concentrations of TSH were associated with a higher risk of all-cause mortality and cardiovascular disease mortality. The 20-40th percentiles of FT4 and the 60-80th percentiles of TSH could represent the optimal healthy ranges of thyroid function based on the risk of cardiovascular disease and mortality, with more than 5% increase of 10-year composite risk identified for FT4 greater than the 85th percentile in women and men older than 70 years. We propose a feasible approach to establish the optimal healthy ranges of thyroid function, allowing for better identification of individuals with a higher risk of thyroid-related outcomes. FUNDING: None.