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Background and Objective In the USA, cabozantinib was approved for the treatment of patients aged ≥ 12 years with radioiodine-refractory differentiated thyroid cancer (DTC) who progressed on prior vascular endothelial growth factor (VEGFR)-targeted therapy based on the Phase 3 COSMIC-311 trial, which evaluated cabozantinib 60 mg/day versus placebo. Approved dosing is 60 mg/day for adults and for pediatric patients aged ≥ 12 years with body surface area (BSA) ≥ 1.2 m 2 , and 40 mg/day for pediatric patients aged ≥ 12 years with BSA < 1.2 m 2 . This report describes a population pharmacokinetic (PopPK) and exposure–response analysis of COSMIC-311. Methods A PopPK model was developed using concentration-time data from COSMIC-311 and 6 other cabozantinib studies. The final (full) PopPK model was used to simulate the effect of sex, body weight, race, and patient population. For exposure–response analysis, derived datasets from COSMIC-311 were constructed for time-to-event analyses of progression-free survival (PFS) and safety endpoints. Results The PopPK analysis included 4746 cabozantinib PK samples from 1745 patients and healthy volunteers. Body weight had minimal impact on cabozantinib exposure but increasing body weight was associated with increased apparent volume of distribution. Based on model-based simulation, adolescents < 40 kg had higher maximum plasma concentration at steady state of cabozantinib 60 mg/day compared to adults. Allometric scaling simulation in adolescents < 40 kg demonstrated higher exposure with 60 mg/day relative to adults receiving the same dose, while exposure with 40 mg/day in adolescents < 40 kg was similar to 60 mg/day in adults. The exposure–response analysis included 115 patients. There was no clear relationship between PFS or dose modification and cabozantinib exposure. A statistically significant relationship was demonstrated for cabozantinib exposure and hypertension (Grade ≥ 3) and fatigue/asthenia (Grade ≥ 3). Conclusions These results support the dosing strategy implemented in COSMIC-311 and the BSA-based label recommendations for adolescents. The cabozantinib dose should be reduced to manage adverse events as indicated.

AbstractObjectiveTo investigate whether use of glucagon-like peptide 1 (GLP1) receptor agonists is associated with increased risk of thyroid cancer.DesignScandinavian cohort study.SettingDenmark, Norway, and Sweden, 2007-21.ParticipantsPatients who started GLP1 receptor agonist treatment were compared with patients who started dipeptidyl peptidase 4 (DPP4) inhibitor treatment, and in an additional analysis, patients who started sodium-glucose cotransporter 2 (SGLT2) inhibitor treatment.Main outcome measuresThyroid cancer identified from nationwide cancer registers. An active-comparator new user study design was used to minimise risks of confounding and time related biases from using real world studies of drug effects. Cox regression was used to estimate hazard ratios, controlling for potential confounders with propensity score weighting.ResultsThe mean follow-up time was 3.9 years (standard deviation 3.5 years) in the GLP1 receptor agonist group and 5.4 years (standard deviation 3.5 years) in the DPP4 inhibitor group. 76 of 145 410 patients (incidence rate 1.33 events per 10 000 person years) treated with GLP1 receptor agonists and 184 of 291 667 patients (incidence rate 1.46 events per 10 000 person years) treated with DPP4 inhibitors developed thyroid cancer. GLP1 receptor agonist use was not associated with increased risk of thyroid cancer (hazard ratio 0.93, 95% confidence interval 0.66 to 1.31; rate difference −0.13, 95% confidence interval −0.61 to 0.36 events per 10 000 person years). The hazard ratio for medullary thyroid cancer was 1.19 (0.37 to 3.86). In the additional analysis comparing the GLP1 receptor agonist group with the SGLT2 inhibitor group, the hazard ratio for thyroid cancer was 1.16 (0.65 to 2.05).ConclusionsIn this large cohort study using nationwide data from three countries, GLP1 receptor agonist use was not associated with a substantially increased risk of thyroid cancer over a mean follow-up of 3.9 years. In the main analysis comparing GLP1 receptor agonists with DPP4 inhibitors, the upper limit of the confidence interval was consistent with no more than a 31% increase in relative risk.

Purpose Environmental endocrine-disrupting chemicals (EDCs) are a mixture of chemical compounds capable to interfere with endocrine axis at different levels and to which population is daily exposed. This paper aims to review the relationship between EDCs and breast, prostate, testicle, ovary, and thyroid cancer, discussing carcinogenic activity of known EDCs, while evaluating the impact on public health. Methods A literature review regarding EDCs and cancer was carried out with particular interest on meta-analysis and human studies. Results The definition of EDCs has been changed through years, and currently there are no common criteria to test new chemicals to clarify their possible carcinogenic activity. Moreover, it is difficult to assess the full impact of human exposure to EDCs because adverse effects develop latently and manifest at different ages, even if preclinical and clinical evidence suggest that developing fetus and neonates are most vulnerable to endocrine disruption. Conclusion EDCs represent a major environmental and health issue that has a role in cancer development. There are currently some EDCs that can be considered as carcinogenic, like dioxin and cadmium for breast and thyroid cancer; arsenic, asbestos, and dioxin for prostate cancer; and organochlorines/organohalogens for testicular cancer. New evidence supports the role of other EDCs as possible carcinogenic and pregnant women should avoid risk area and exposure. The relationship between EDCs and cancer supports the need for effective prevention policies increasing public awareness.

Background: Current knowledge about Chornobyl-related thyroid cancer risks comes from ecological studies based on grouped doses, case-control studies, and studies of prevalent cancers. Objective: To address this limitation, we evaluated the dose-response relationship for incident thyroid cancers using measurement-based individual iodine-131 (1-131) thyroid dose estimates in a prospective analytic cohort study. Methods: The cohort consists of individuals < 18 years of age on 26 April 1986 who resided in three contaminated oblasts (states) of Ukraine and underwent up to four thyroid screening examinations between 1998 and 2007 (n = 12,514). Thyroid doses of 1-131 were estimated based on individual radioactivity measurements taken within 2 months after the accident, environmental transport models, and interview data. Excess radiation risks were estimated using Poisson regression models. Results: Sixty-five incident thyroid cancers were diagnosed during the second through fourth screenings and 73,004 person-years (PY) of observation. The dose-response relationship was consistent with linearity on relative and absolute scales, although the excess relative risk (ERR) model described data better than did the excess absolute risk (EAR) model. The ERR per gray was 1.91 [95% confidence interval (CI), 0.43-6.34], and the EAR per 10⁴ PY/Gy was 2.21 (95% CI, 0.04-5.78). The ERR per gray varied significantly by oblast of residence but not by time since exposure, use of iodine prophylaxis, iodine status, sex, age, or tumor size. Conclusions: I-131-related thyroid cancer risks persisted for two decades after exposure, with no evidence of decrease during the observation period. The radiation risks, although smaller, are compatible with those of retrospective and ecological post-Chornobyl studies.

Environmental metals are established thyroid carcinogens, yet how their co-exposure collectively reshapes carcinogenic mechanisms remains elusive. This study used ICP-MS to quantify plasma concentrations of 18 metals in 368 thyroid cancer patients and matched controls, with free thyroxine (FT4) levels abstracted from medical records. Subsequently, we applied integrative statistical modeling comprising WQS regression, BKMR modeling, interaction analysis, and causal mediation analysis to elucidate exposure-response relationships and mediating pathways. Cases exhibited elevated plasma levels of Cr, Co, Mn, Ni, Cu, As, Cd, and Sn. WQS regression prioritized Sn, Cd, Ni, and As as risk-contributing metals demonstrating positive weight values, while Sb, Pb, and Zn showed inverse associations. BKMR modeling visualized exposure-response relationships, indicating elevated thyroid cancer risks at higher quantiles of co-exposure. A critical synergistic interaction was identified between the Cd-Sn pair. Causal mediation analysis confirmed FT4 mediates 46–69.3% of thyroid cancer risk for Sn, Cd, Ni, and As. Collectively, these findings highlight the need to incorporate metal mixture surveillance and FT4-based endocrine pathway screening into precision prevention frameworks.

BackgroundWe evaluated the association between smoking status and thyroid cancer risk and whether this association is mediated by body mass index (BMI) and thyroid-stimulating hormone (TSH).MethodsWe performed a cohort study of 96,855 Korean adults who were followed annually or biennially for a median of 5.9 years.ResultsDuring 511,052.9 person-years of follow-up, 1,250 participants developed thyroid cancer. In men, we observed a dose-dependent inverse association between current smoking, pack-years, and thyroid cancer. After adjustment for confounders, adjusted hazard ratios (95% confidence intervals) for thyroid cancer comparing current and former smokers to never smokers were 0.58 (0.45–0.75) and 0.93 (0.73–1.18), respectively. After further adjustment for BMI and TSH as potential mediators, this association was slightly attenuated, but remained significant. For women, current smokers tended to have a lower risk of thyroid cancer, but this association did not reach statistical significance.ConclusionsIn this cohort study, current smoking was associated with a decreased risk of incident thyroid cancer in men but not in women and this association was observed even after adjusting for TSH and BMI levels as potential mediators. Further mechanistic studies are needed to elucidate the possible effect of smoking on the pathogenesis of thyroid cancer development.

Mercury (Hg) is a widely distributed and bioavailable metal of public health concern, with many known human toxicities, but data regarding mercury's influence on thyroid cancer (TC) is scarce. Mercury is known to impact several molecular pathways implicated in carcinogenesis, and its proclivity for bioaccumulation in the thyroid suggests a potential modulatory effect. We conducted a literature/systematic review of studies between 1995–2022 intending to define better and establish relationships between these two entities, congregate the evidence for mercury's potential role in thyroid carcinogenesis, and identify populations of interest for further study. Insufficient evidence precludes definitive conclusions on dietary mercury as a TC risk factor; however, several common mechanisms affected by mercury are crucial for TC development, including biochemical, endocrine, and reactive oxygen species effects. Quantitative analysis revealed associations between TC risk and mercury exposure. In three mercury studies, average urine levels were higher in TC patients, with a mean difference of 1.86 µg/g creatinine (95% CI = 0.32–3.41). In two studies investigating exposure to elevated mercury levels, the exposed group exhibited a higher risk of developing TC, with a relative risk of 1.90 (95% CI = 1.76–2.06). In three thyroid tissue studies, mercury levels (ppm) were higher in TC patients, averaging 0.14 (0.06–0.22) in cancerous cases (N = 178) and 0.08 (0.04–0.11) in normal thyroids (N = 257). Our findings suggest an association between mercury exposure and TC risk, implying a possible predisposing factor. Further research is necessary to reveal the clinical relevance of dietary and environmental mercury exposures in TC pathogenesis.

The beginning of the atomic age marked the outset of nuclear weapons testing, which is responsible for the radioactive contamination of a large number of sites worldwide. The paper aims to analyze nuclear weapons tests conducted in the second half of the twentieth century, highlighting the impact of radioactive pollution on the atmospheric, aquatic, and underground environments. Special attention was given to the concentration of main radioactive isotopes which were released, such as ¹⁴C, ¹³⁷Cs, and ⁹⁰Sr, generally stored in the atmosphere and marine environment. In addition, an attempt was made to trace the spatial delimitation of the most heavily contaminated sites worldwide, and to note the human exposure which has caused a significantly increased incidence of thyroidal cancer locally and regionally. The United States is one of the important examples of assessing the correlation between the increase in the thyroid cancer incidence rate and the continental-scale radioactive contamination with ¹³¹I, a radioactive isotope which was released in large amounts during the nuclear tests carried out in the main test site, Nevada.

Background Environmental exposure to per- and polyfluoroalkyl substances (PFAS) has been related to some adverse health effects. An increasing number of people are suffering from nodular goiter (NG) and papillary thyroid carcinoma (PTC), the specific types of thyroid tumors with the highest prevalence. In vivo and in vitro studies have indicated that exposure to PFAS can disrupt thyroid homeostasis and exhibit apparent endocrine-disrupting toxicity, including the decreased thyroid hormone levels and abnormal expression of thyroid-related genes. However, epidemiological evidence supporting the cause-effect relationship between PFAS exposure and the risk of NG and PTC is still lacking. Methods We enrolled 290 participants to explore the relationship between PFAS exposure and NG/PTC risk. 21 urinary PFAS were detected by ultra-high performance liquid chromatography-triple quadrupole mass spectrometry (UPLC-MS/MS). Logistic regression, restricted cubic spline (RCS), Bayesian Kernel Machine Regression (BKMR) and quantile g-computation (qgcomp) models were adopted to examine effects of single and mixed PFAS exposure on NG/PTC risk. Results Our data showed that perfluoroheptane sulfonate (PFHpS) ( P  = 0.033) and perfluorohexane sulfonate (PFHxS) ( P  = 0.003) levels in NG cases and perfluoroheptanoic acid (PFHpA) ( P  = 0.008) levels in PTC cases were significantly higher than those in the controls. After adjustment for confounders, PFHxS was significantly related to higher NG/PTC risk (all P for trend < 0.05). A remarkable non-linear association was found between PFHpA exposure and PTC risk ( P -overall < 0.001, P -non-linear = 0.001). The BKMR model indicated that PFAS mixtures significantly increased NG risk, with PFHxS contributing the most (groupPIP: 0.886, condPIP: 0.658). In stratified analyses, PFAS mixtures were positively associated with NG/PTC risk in females and normal-weight subjects. Conclusion Our results suggest that environmental exposure to PFAS mixtures may be associated with increased NG/PTC risk, and each PFAS may contribute to NG/PTC risk in very different ways. To the best of our knowledge, this is the first epidemiological study to examine effects of PFAS exposure on NG/PTC risk.

Pediatric thyroid cancer incidence has been increasing globally, with environmental exposures being a hypothesized risk factor. We evaluated the association between pediatric thyroid cancer risk and perinatal exposure to ambient fine particulate matter (PM) with aerodynamic diameter ( ) and outdoor artificial light at night (O-ALAN). Both are considered environmental carcinogens with evidence of thyroid function disruption, reported associations with thyroid cancer in adults, and concerns of distributive inequity. O-ALAN may also serve as a proxy for other outdoor air pollutants or urbanization. We conducted a case-control study of papillary thyroid cancer nested within a California birth cohort that included 736 cases diagnosed at 0-19 y of age and born in 1982-2011 and 36,800 controls frequency-matched on birth year. We assigned individual-level exposures for residence at birth for ambient concentrations from a validated, ensemble-based prediction model and O-ALAN using the New World Atlas of Artificial Night Sky Brightness. We calculated odds ratios (OR) and 95% confidence intervals (CI) using logistic regression adjusting for potential confounders and stratified by age and race/ethnicity. We observed statistically significant associations between exposure and papillary thyroid cancer risk overall (OR per increase in , 95% CI: 1.01, 1.14), among the 15-19 y age group ( ; 95% CI: 1.00, 1.16), and among Hispanic children ( ; 95% CI: 1.02, 1.24). For O-ALAN, we observed statistically significantly increased odds of papillary thyroid cancer in higher exposure tertiles in comparison with the reference tertile in the overall population (tertile 2: , 95% CI: 1.04, 1.50; tertile 3: , 95% CI: 1.02, 1.50) and when modeled as a continuous variable ( per ). In age-stratified analyses, significant associations were observed among the 15-19 y age group, but not the 0-14 y age group. No significant differences were found by race/ethnicity. This study provides new evidence suggesting associations between early-life exposure to and O-ALAN and pediatric papillary thyroid cancer. Given that O-ALAN may also represent other air pollutants or broader urbanization patterns, further research and refinements to exposure metrics are needed to disentangle these factors. https://doi.org/10.1289/EHP14849.