Endocrine disrupting chemical mixture exposure and risk of papillary thyroid cancer in U.S. military personnel: A nested case-control study.

Single-pollutant methods to evaluate associations between endocrine disrupting chemicals (EDCs) and thyroid cancer risk may not reflect realistic human exposures. Therefore, we evaluated associations between exposure to a mixture of 18 EDCs, including polychlorinated biphenyls (PCBs), brominated flame retardants, and organochlorine pesticides, and risk of papillary thyroid cancer (PTC), the most common thyroid cancer histological subtype. We conducted a nested case-control study among U.S. military servicemembers of 652 histologically-confirmed PTC cases diagnosed between 2000 and 2013 and 652 controls, matched on birth year, sex, race/ethnicity, military component (active duty/reserve), and serum sample timing. We estimated mixture odds ratios (OR), 95% confidence intervals (95% CI), and standard errors (SE) for associations between pre-diagnostic serum EDC mixture concentrations, overall PTC risk, and risk of histological subtypes of PTC (classical, follicular), adjusted for body mass index and military branch, using quantile g-computation. Additionally, we identified relative contributions of individual mixture components to PTC risk, represented by positive and negative weights (w). A one-quartile increase in the serum mixture concentration was associated with a non-statistically significant increase in overall PTC risk (OR = 1.19; 95% CI = 0.91, 1.56; SE = 0.14). Stratified by histological subtype and race (White, Black), a one-quartile increase in the mixture was associated with increased classical PTC risk among those of White race (OR = 1.59; 95% CI = 1.06, 2.40; SE = 0.21), but not of Black race (OR = 0.95; 95% CI = 0.34, 2.68; SE = 0.53). PCBs 180, 199, and 118 had the greatest positive weights driving this association among those of White race (w = 0.312, 0.255, and 0.119, respectively). Findings suggest that exposure to an EDC mixture may be associated with increased classical PTC risk. These findings warrant further investigation in other study populations to better understand PTC risk by histological subtype and race.

Organochlorine pesticides and risk of papillary thyroid cancer in U.S. military personnel: a nested case-control study.

BACKGROUND: The effects of organochlorine pesticide (OCP) exposure on the development of human papillary thyroid cancer (PTC) are not well understood. A nested case-control study was conducted with data from the U.S. Department of Defense Serum Repository (DoDSR) cohort between 2000 and 2013 to assess associations of individual OCPs serum concentrations with PTC risk. METHODS: This study included 742 histologically confirmed PTC cases (341 females, 401 males) and 742 individually-matched controls with pre-diagnostic serum samples selected from the DoDSR. Associations between categories of lipid-corrected serum concentrations of seven OCPs and PTC risk were evaluated for classical PTC and follicular PTC using conditional logistic regression, adjusted for body mass index category and military branch to compute odds ratios (OR) and 95% confidence intervals (CIs). Effect modification by sex, birth cohort, and race was examined. RESULTS: There was no evidence of associations between most of the OCPs and PTC, overall or stratified by histological subtype. Overall, there was no evidence of an association between hexachlorobenzene (HCB) and PTC, but stratified by histological subtype HCB was associated with significantly increased risk of classical PTC (third tertile above the limit of detection (LOD) vs.

A Phase 2 Study of Encorafenib in Combination with Binimetinib in Patients with Metastatic BRAF-Mutated Thyroid Cancer in Japan.

Background: Driver mutations at BRAF V600 are frequently identified in papillary thyroid cancer and anaplastic thyroid cancer (ATC), in which BRAF inhibitors have shown clinical effectiveness. This Japanese phase 2 study evaluated the efficacy and safety of a BRAF inhibitor, encorafenib, combined with an MEK inhibitor, binimetinib, in patients with BRAF V600-mutated thyroid cancer. Methods: This phase 2, open-label, uncontrolled study was conducted at 10 institutions targeted patients with BRAF V600-mutated locally advanced or distant metastatic thyroid cancer not amenable to curative treatment who became refractory/intolerant to ≥1 previous vascular endothelial growth factor receptor-targeted regimen(s) or were considered ineligible for those. The primary endpoint was centrally assessed objective response rate (ORR). The secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Results: We enrolled 22 patients with BRAFV600E-mutated thyroid cancer: 17 had differentiated thyroid cancer (DTC), and 5 had ATC. At data cutoff (October 26, 2022), the median follow-up was 11.5 (range = 3.4-19.0) months. The primary endpoint of centrally assessed ORR was 54.5% (95% confidence interval [CI] 32.2-75.6; partial response in 12 patients and stable disease in 10). The ORRs in patients with DTC and ATC were 47.1% (8 of 17) and 80.0% (4 of 5), respectively. The medians for DOR and PFS by central assessment and for OS were not reached in the overall population, the DTC subgroup, or the ATC subgroup. At 12 months, the rate of ongoing response was 90.9%, and the PFS and OS rates were 78.8% and 81.8%, respectively. All patients developed ≥1 adverse events (AEs): grade 3 AEs in 6 patients (27.3%). No patients developed grade 4-5 AEs. The most common grade 3 AE was lipase increased (4 patients [18.2%]). Those toxicities were mostly manageable with appropriate monitoring and dose adjustment. Conclusions: Treatment with encorafenib plus binimetinib met the primary endpoint criteria and demonstrated clinical benefit in patients with BRAFV600E-mutated thyroid cancer regardless of its histological type, such as DTC or ATC, with no new safety concerns identified. Encorafenib plus binimetinib could thus be a new treatment option for BRAF V600-mutated thyroid cancer. Clinical Trial Registration number: Japan Registry of Clinical Trials: jRCT2011200018.

Elucidating the link between thyroid cancer and mercury exposure: a review and meta-analysis.

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.

Association Between Antibiotic Exposure and Thyroid Cancer: A Nationwide Cohort Study in South Korea.

Background: Although recent studies have introduced antibiotics as a potential risk factor for thyroid cancer, further studies are necessary. We examined the association between long-term antibiotic usage and thyroid cancer risk. Methods: This nationwide cohort study investigated 9,804,481 individuals aged 20 years or older who participated in health screening (2005-2006) with follow-up ending on December 31, 2019, using the Korean National Health Insurance Service database. Multivariable Cox proportional hazards regression was used to estimate adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for thyroid cancer risk according to the cumulative days of antibiotic prescription and the number of antibiotic classes, respectively. A 1:1 propensity score (PS) matching was also performed for analysis. Results: Compared with nonusers of antibiotics, participants prescribed ≥365 days of antibiotics showed an increased risk of thyroid cancer (aHR, 1.71; CI, 1.66-1.78) after adjusting for covariates including age, smoking status, comorbidities including thyroid-related diseases, and the number of head and neck computed tomography scans. Participants prescribed ≥365 days of antibiotics also had a significantly increased risk of thyroid cancer (aHR, 1.37; CI, 1.34-1.40) compared with participants prescribed 1-14 days of antibiotics. Association remained significant in the 1:1 PS-matched cohort. Moreover, compared with nonusers of antibiotics, the 5 or more antibiotic class user group had a higher thyroid cancer risk (aHR, 1.71; CI, 1.65-1.78). Conclusions: Long-term antibiotic prescriptions and an increasing number of antibiotic classes may be associated with a higher risk of thyroid cancer in a duration-dependent manner. The effects of long-term antibiotic exposure on thyroid cancer should be further investigated.

Glucagon-like peptide-1 receptor agonists and risk of thyroid cancer: A systematic review and meta-analysis of randomized controlled trials.

AIM: To conduct a meta-analysis of randomized clinical trials (RCTs) to investigate whether there is an association between glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment and thyroid cancer. MATERIALS AND METHODS: In this meta-analysis of RCTs, we included studies comparing a GLP-1RA with any comparator, lasting at least 52 weeks, and reporting the incidence of adverse events independently of the principal endpoint and population. All cases of thyroid cancer were collected. RESULTS: We retrieved 64 trials, 26 of which reported at least one incident case of thyroid cancer. GLP-1RA treatment was associated with a significant increase in the risk of overall thyroid cancer (Mantel-Haenzel odds ratio [MH-OR] 1.52 [95% confidence interval {CI} 1.01, 2.29]; P = 0.04, I2 = 0%), with a fragility index of 1, and a 5-year number needed to harm of 1349. The association remained significant when including only trials lasting at least 104 weeks (MH-OR 1.76 [95% CI 1.00, 3.12]; P = 0.05). No significant association was found for papillary thyroid cancer (MH-OR 1.54 [95% CI 0.77, 3.06]; P = 0.22) or medullary thyroid cancer (MH-OR 1.44 [95% CI 0.23, 9.16]; P = 0.55). CONCLUSIONS: Our meta-analysis showed that GLP-1RA treatment could be associated with a moderate increase in relative risk for thyroid cancer in clinical trials, with a small increase in absolute risk. Studies of longer duration are required to assess the clinical implications of this finding.

Association between different water iodine exposures and thyroid cancer: A retrospective study of high water iodine areas in China from 2009 to 2020.

In recent years, the incidence of thyroid cancer has been on a significant rise worldwide, and a number of environmental factors have been suspected to be risk factors for thyroid cancer, especially the relationship between iodine intake and thyroid cancer has attracted attention. In this study, we want to assess the relationship between different water iodine exposures and thyroid cancer incidence before and after water alteration in areas with high water iodine in China. Thyroid cancer patients (2009-2020) were enrolled at two hospitals, both in Heze City, Shandong Province, an area with high water iodine levels. According to the criteria of the study, 5826 cases out of 8785 cases were selected for inclusion in the study. Before and after water alteration, the incidence of thyroid cancer was highest in areas with water iodine concentrations of 200-300 µg/L in high iodine areas. In areas where water iodine decreased to adequate iodine levels, there was a strong negative correlation between the decreased level of water iodine and the incidence of thyroid cancer. In addition, in cases with pathology reports, we found that the greater the decrease in water iodine values, the markedly smaller the maximum diameter of the thyroid cancer lesions. Taken together, these findings suggest that we should continue to monitor the incidence of thyroid cancer in areas with high water iodine and continue to optimize population iodine intake to reduce the incidence of thyroid cancer.

[Associations of a mixture of eleven endocrine disruptors in human urine with the risk of papillary thyroid cancer].

OBJECTIVE: To examine the associations of human exposure to a mixture of 11 endocrine disruptors(EDCs) with the risk of papillary thyroid cancer(PTC), and to identify the priority of these EDCs. METHODS: EDCs were determined in fasting urine specimens to represent human exposure. Logistics regressions were performed to examine the associations between individual EDC and PTC risk. Bayes kernel machine regression was applied to examine the associations between the mixture of EDCs and PTC risk. Weighted quantile sum(WQS) regression and LASSO regression were performed to identify the main contributor. RESULTS: In the multivariate logistic regression model, after adjusting for a series of variables, 11 endocrine disruptors were statistically significantly correlated with the risk of PTC(P<0.05). In BKMR models, the mixture of EDCs was positively correlated with the risk of PTC(P<0.05). The weight and coefficient of mono(2-ethyl-5-hydroxyhexyl) phthalate(MEHHP) was 0.62 and 1.58 in WQS and LASSO models, respectively, which were much higher than those of the other EDCs. CONCLUSION: Combined exposure to o a variety of EDCs might promote the risk of PTC, and MEHHP was identified as the main contributor.

Assessment of five typical environmental endocrine disruptors and thyroid cancer risk: a meta-analysis.

Introduction: There are conflicting reports on the association between environmental endocrine disruptors (EEDs) and thyroid cancer. This meta-analysis aimed to elucidate the relationship between EEDs and thyroid cancer. Methods: We searched for epidemiological studies on EEDs and thyroid cancer published in PubMed and Web of Science up to December 2022. We then screened the articles that could extract data on EEDs concentration levels in both thyroid cancer patients and healthy controls. We excluded articles that could not calculate effect sizes, focused on other thyroid diseases, or lacked controls. Standardized mean difference (SMD) was calculated to analyze the association between EEDs and thyroid cancer. We measured the heterogeneity among the included studies using I2, assessed publication bias by Egger's and Begg's test, and evaluated article quality using the Newcastle-Ottawa Quality Score (NOS). In the end, fifteen eligible case-control studies were included. Results: Our comprehensive analysis revealed that polychlorinated biphenyls (PCBs) were negatively associated with thyroid cancer{ SMD = -0.03, 95% confidence interval (CI) = (-0.05, -0.00), P = 0.03}, while polybrominated diphenyl ethers (PBDEs), phthalates (PAEs), and heavy metals were positively associated with thyroid cancer{PBDEs: SMD = 0.14, 95%CI = (0.04, 0.23), P = 0.007; PAEs: SMD = 0.30, 95%CI = (0.02, 0.58), P = 0.04; heavy metals: SMD = 0.21, 95%CI = (0.11, 0.32), P < 0.001}. We did not find a statistically significant relationship between bisphenol A (BPA) and thyroid cancer. Most of the included studies did not show publication bias, except for those on PCBs. Discussion: Our results indicate that exposure to certain EEDs, such as PBDEs, PAEs, and heavy metals, increases the risk of thyroid cancer. However, further large-scale epidemiological studies and mechanism studies are needed to verify these potential relationships and understand the underlying biological mechanisms.

Environmental factors and incidence of thyroid cancer in the world (1990-2019): an ecological study.

Thyroid cancer (TC) is the most common endocrine malignancy. Environmental risk factors such as presence of pollutants in air as well as the combustion of fossil fuels or carbon as a cooking habit in closed environments inside houses affect thyroid hormonal homeostasis and diseases. This study aimed to estimate the association between environmental risk factors and the incidence of thyroid cancer worldwide from 1990 to 2019 including particulate pollutants coming from fossil fuels employed in closed environments. Data on the incidence of thyroid cancer and some environmental risk factors were extracted from the Global Cancer Observatory (GLOBOCAN) for 204 countries and territories from 1990 to 2019. Pearson's correlation coefficient was used to determine the correlation between the thyroid cancer incidence and environmental risk factors. Finally, a generalized additive model was fitted for modeling. R 3.5.0 was used for analysis of the data. The most relevant results showed that the age-standardized incidence rate (ASIR) of thyroid cancer has a positive and significant correlation with environmental air pollution by O3 (r=0.63, P value<0.001), by particulate matter pollution (r=0.23, P value<0.001), and by household PM2.5 air pollution (r=0.52, P value≤0.001). In contrast, the correlation between ASIR and high temperature (T>25.6°C) (r=-0.27, P value<0.001) is negative and significant. The modeling results showed that particulate matter pollution and O3 pollution and household PM2.5 air pollution which originated from solid fuels are risk factors for thyroid cancer. Therefore, more research in this field is necessary in areas with high levels of air pollution at the national and international levels.

The efficacy and safety in radioactive iodine refractory thyroid cancer patients treated with sorafenib.

Background: Sorafenib included in Chinese medical insurance is the earliest targeted drug for radioactive iodine refractory differentiated thyroid cancer (RR-DTC). This study is to further demonstrate the clinical efficacy and safety of sorafenib used in Zhujiang Hospital of Southern Medical University. Methods: RR-DTC patients treated at our Department of Nuclear Medicine in Zhujiang Hospital of Southern Medical University (October 2017-May 2020) were retrospectively analyzed. Treatment effects, progression-free survival (PFS), and adverse effects (AEs) during medication were evaluated. Results: Of the 31 patients included, 26 patients were evaluated for efficacy with a median follow-up time of 17.5 months (4.0-51.0 months). The disease control rate (DCR) was 57.7% (n = 15) and the objective response rate (ORR) was 26.9% (n = 7). Most patients with disease control had thyroglobulin decreases of more than 60% (p = 0.004), ORRs were favorable in patients with lung metastasis and lung-only metastasis (p = 0.010 and 0.001, respectively). The PFS of the 26 patients analyzed was 16.5 months (95%CI: 14.41 -23.90 months). In the subgroup analysis, female, patients with lung-only metastasis, hand-foot skin syndrome (HFS), and thyroglobulin response ≥ 60% observed longer PFS (p = 0.038, 0.045, 0.035, and 0.000, respectively), while patients with bone metastasis had lower PFS (p = 0.035). The most common toxicity profile was HFS (93.5%), followed by diarrhea (83.9%), alopecia (74.2%). All the side effects were mainly grade 1-2. Grade 3-4 adverse reactions were more common in diarrhea and HFS. Conclusions: Sorafenib has promising efficacy in RR-DTC, especially in patients with lung metastasis and lung-only metastasis. The AEs of sorafenib were generally mild, and the main AE was HFS.

Organochlorine pesticides and epigenetic alterations in thyroid tumors.

Purpose: Cancer incidence depends on various factors e.g., pesticide exposures which cause epigenetic alterations. The present research aimed to investigate the organochlorine pesticides (OCPs) impacts on promoter methylation of three tumor-suppressor genes and four histone modifications in thyroid nodules in 61 Papillary thyroid carcinoma (PTC) and 70 benign thyroid nodules (BTN) patients. Methods: OCPs were measured by Gas chromatography. To identify promoter methylation of TSHR, ATM, and P16 genes, the nested-methylation-specific PCR (MSP) was utilized, and histone lysine acetylation (H3K9, H4K16, and H3K18) and lysine methylation (H4K20) were detected by performing western blot analysis. Results: Further TSHR methylation and less P16 methylation were observed in PTC than in BTN. No substantial difference was detected for ATM methylation between PTC and BTN groups. Also, OCP dramatically increased the odds ratio of TSHR (OR=3.98, P=0.001) and P16 (OR=5.65, P<0.001) methylation while confounding variables reduced the chances of ATM methylation arising from 2,4-DDE and 4,4-DDT influence. Hypomethylation of H4K20 and hypo-acetylation of H3K9, H4K16, and H3K18 (P<0.001) were observed in PTC samples than BTN. Furthermore, OCPs substantially decreased the odds ratio of H3K9 (OR=3.68, P<0.001) and H4K16 (OR=6.03, P<0.001) acetylation. Conclusion: The current research indicated that OCPs could contribute to PTC progression by TSHR promoter hypermethylation and decreased acetylation of H3K9 and H4K16. In addition, in PTC patients, assessing TSHR promoter methylation and acetylation of H3K9 and H4K16 could have predictive values.

Per- and polyfluoroalkyl substances and the associated thyroid cancer risk: A case-control study in China.

The role of perfluoroalkyl and polyfluoroalkyl substances (PFAS) as thyroid carcinogens is unclear. Therefore, we intended to identify associations between each PFAS congener and their mixture with thyroid cancer risk. This case-control study of thyroid cancer was conducted in Shijiazhuang, Hebei Province, China. Three hundred participants were recruited from January to May 2022 and were matched according to sex and age. Twelve PFAS were assessed using ultra-high-performance liquid chromatography-tandem mass spectrometry. Associations between PFAS congeners and thyroid cancer risk were considered under conditional logistic regression analysis and a restricted cubic spline model. Mixture effects were also assessed with quantile g-computation and a Bayesian kernel machine regression model. Compared to the first tertile, third tertile PFOA, PFNA, PFHxS, PFDA, and PFUnDA concentrations were associated with lower thyroid cancer risk (ORPFOA: 0.32, 95% confidence interval (CI): 0.15-0.69; ORPFNA: 0.18, 95% CI: 0.07-0.46; ORPFHxS: 0.37, 95% CI: 0.15-0.92; ORPFDA: 0.07, 95% CI: 0.02-0.23; ORPFUnDA: 0.12, 95% CI: 0.05-0.30) after adjusting for confounding factors. PFNA, PFDA, and PFUnDA had a negative dose-response relationship with thyroid cancer risk. Mixture analysis also showed that thyroid cancer risk is negatively associated with the overall mixture and carboxylates. In the overall mixture, PFOS and PFDA contributed most to positive and negative changes in thyroid cancer risk, respectively. However, PFOS, PFNA, PFDA, and PFUnDA were of equally high importance. This study is the first to confirm the effects of the PFAS mixture on thyroid cancer, and further large-scale prospective studies are still warranted to test these inverse associations.

Women consuming oral contraceptives containing cyproterone acetate and ethinylestradiol show a higher risk of thyroid cancer than nonusers.

This study explored whether the risk of thyroid cancer in Asian women is associated with consumption of oral contraceptives (Diane-35). We conducted a population-based, retrospective cohort study using the Taiwan National Health Insurance Research Database. From the database, 9865 women aged 18 to 65 years who were prescribed Diane-35 between 2000 and 2012 were included in the Diane-35 group, and 39,460 women who were not prescribed Diane-35 were included in the comparison group and were frequency-matched by age and index year. Both groups were followed until 2013 to calculate the incidence of thyroid cancer. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox proportional hazard model. The median (standard deviation) follow-up duration was 7.08 (3.63) and 7.04 (3.64) years in the Diane-35 and the comparison group, respectively. The incidence of thyroid cancer was 1.80-fold higher in the Diane-35 group than in the comparison group (2.72 vs 1.51 per 10,000 person-years). The cumulative incidence of thyroid cancer was significantly higher in the Diane-35 group than in the comparison group (log-rank test, P = .03). An elevated hazard ratio of thyroid cancer was observed in the Diane-35 group than in the comparison group (HR: 1.91, 95% CI: 1.10-3.30). In subgroup analysis, patients aged 30 to 39 years showed a higher hazard ratio of developing thyroid cancer after consuming Diane-35 than those in the comparison group (HR: 5.58, 95% CI: 1.84-16.91). The study provides evidence that women aged 30 to 39 years consuming Diane-35 are at increased risk of thyroid cancer. Nevertheless, a larger population with a longer follow-up may be necessary to confirm causality.

Population Pharmacokinetics and Exposure-Response Analysis for the Phase 3 COSMIC-311 Trial of Cabozantinib for Radioiodine-Refractory Differentiated Thyroid Cancer.

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 m2, and 40 mg/day for pediatric patients aged ≥ 12 years with BSA < 1.2 m2. 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.

Human 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure and thyroid cancer risk.

Thyroid cancer incidence has been steadily rising since the 1970s and exposure to environmental pollutants, including persistent organic pollutants such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other dioxins, has emerged as a potential explanation for this increase. This study aimed to summarize available human studies on the association between TCDD exposure and thyroid cancer. A systematic review of the literature was performed searching the National Library of Medicine and National Institutes of Health PubMed, Embase, and Scopus databases, through January 2022, using the following keywords: "thyroid", "2,3,7,8-tetrachlorodibenzo-p-dioxin", "TCDD", "dioxin", and "Agent Orange". Six studies were included in this review. Three studies evaluated the acute exposure to the chemical factory accident in Seveso, Italy, and found a non-significant increase in the risk of thyroid cancer. Two studies investigating Agent Orange exposure among United States Vietnam War veterans found a significant risk of thyroid cancer following exposure. No association was found in one study evaluating TCDD exposure through herbicides. The current study highlights the limited information on the potential association between TCDD exposure and thyroid cancer and thus the need for future human studies, especially considering the persistent human exposure to dioxins in the environment.

Association between urinary iodine concentration and the risk of papillary thyroid cancer by sex and age: a case-control study.

Previous studies on dietary iodine intake and the risk of papillary thyroid cancer (PTC) have demonstrated inconsistent results. We aimed to evaluate the association between urinary iodine concentration (UIC), a surrogate biomarker for dietary iodine intake, and the risk of thyroid cancer stratified by sex and age in an iodine-sufficient area. A hospital-based case-control study was conducted in Seoul, South Korea. A total of 492 cases of newly diagnosed PTC and 595 controls were included. Compared with the lowest quartile of creatine-adjusted UIC (< 159.3 µg/gCr), the highest quartile (≥ 1037.3 µg/gCr) showed an increased risk of PTC (odds ratio [OR] 1.49, 95% confidence interval [CI] 1.04-2.13), especially in those who were < 45 years old (ptrend = 0.01) compared with those who were ≥ 45 years old (ptrend = 0.48). For those who were < 45 years old, a positive association between creatinine-adjusted UIC and the risk of PTC was observed in both men (q4 vs. q1, OR 4.27, 95% CI 1.14-18.08) and women (OR 1.97, 95% CI 1.04-3.78). For those who were ≥ 45 years old, no association was found in any sex. Creatinine-adjusted UIC was positively associated with the risk of PTC, especially in those who were younger than 45 years for both men and women.

Efficacy of methimazole before the administration of radioactive iodine in the management of Graves' disease: a systematic review and meta-analysis.

BACKGROUND: The efficacy of anti-thyroid drugs in conjunction with radioactive iodine therapy in the management of Graves' disease is still controversial. OBJECTIVE: To compare the efficacy of pretreatment with methimazole before the administration of radioactive iodine for the treatment of Graves' disease. DESIGN AND SETTING: A systematic review and meta-analysis was conducted at a teaching/tertiary hospital in Ibadan, Nigeria. METHODS: A systematic search of the PubMed, Embase, Cochrane Library, and Web of Science databases was performed from inception to December, 2021. RESULTS: Five studies with 297 participants were included. There was no difference in the risk of persistent hyperthyroidism when radioactive iodine was used in conjunction with methimazole compared with when radioactive iodine was used alone (relative risk: 1.02, 95% confidence interval, CI: 0.62-1.66; P = 0.95, I2 = 0%). Subgroup analysis based on the duration between discontinuation of methimazole and the administration of radioactive iodine showed a lower risk of persistent hyperthyroidism when methimazole was discontinued within 7 days before radioactive iodine use, although this did not reach statistical significance (risk ratio: 0.85, CI: 0.28-2.58). CONCLUSIONS: The use of methimazole before radioactive iodine administration was not associated with an increased risk of persistent hyperthyroidism. Concerns about medication toxicity and adverse effects should be considered when clinicians make decisions on combination therapies for the treatment of Graves' disease. PROSPERO REGISTRATION: CRD42020150013, https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=150013.

Thyroid Function: A Target for Endocrine Disruptors, Air Pollution and Radiofrequencies.

Thyroid diseases, including congenital hypothyroidism, thyroiditis, and childhood thyrotoxicosis, are progressively increasing. The incidence of thyroid cancer in children and adolescents has also increased in recent decades, mirroring the trends observed in adults. These epidemiologic trends develop in parallel with the rising costs associated with diagnosis and treatment of thyroid diseases. Both genetic and environmental factors are involved in these diseases, and a number of widely diffused toxic chemicals of anthropogenic origin can impair thyroid function and make thyroid cancer worse. Synthetic substances persistently contaminate environmental matrices (i.e., air, soil, water) and the food chain and bio-accumulate in humans, starting from in utero life. Environmental toxins such as air pollutants, endocrine disruptors, and high-frequency electromagnetic fields can act on common targets through common pathways, combined mechanisms, and with trans-generational effects, all of which contribute to thyroid damage. Both experimental and epidemiologic observations show that mechanisms of damage include: modulation of synthesis; transportation and metabolism of thyroid hormones; direct interference with hormone receptors: modulation of gene expression; and autoimmunity. We should not underestimate the available evidence linking environmental pollutants with thyroid disease, cancer included, since toxic substances increasingly diffuse and thyroid hormones play a key role in maintaining systemic metabolic homeostasis during body development. Thus, primary prevention measures are urgently needed in particular to protect children, the most exposed and vulnerable subjects.

Endocrine-disrupting chemicals (EDCs) and cancer: new perspectives on an old relationship.

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.