Association between exercise habits and incident type 2 diabetes mellitus in patients with thyroid cancer: nationwide population-based study.

BACKGROUND: We investigated the association between exercise habits before or after thyroidectomy and incident type 2 diabetes mellitus (T2DM) in patients with thyroid cancer. METHODS: An observational cohort study of 69,526 thyroid cancer patients who underwent thyroidectomy for the treatment of thyroid cancer between 2010 and 2016 was performed using the Korean National Health Information Database. Regular exercise was defined as mid-term or vigorous exercise at least 1 day in a week based on a self-reported questionnaire. Patients were divided into four groups according to exercise habits before and after thyroidectomy: persistent non-exercisers, new exercisers, exercise dropouts, and exercise maintainers. RESULTS: During a median follow-up of 4.5 years, 2,720 (3.91%) patients developed T2DM. The incidence of T2DM per 1,000 person years was lower in patients who performed regular exercise before or after thyroidectomy than in persistent non-exercisers (10.77 in persistent non-exerciser group, 8.28 in new exerciser group, 8.59 in exercise dropout group, and 7.61 in exercise maintainer group). Compared with the persistent non-exerciser group, the new exerciser group (hazard ratio [HR] 0.87, 95% confidence interval [CI] 0.78-0.97), the exercise dropout group (HR 0.81, 95% CI 0.72-0.91), and the exercise maintainer group (HR 0.84, 95% CI 0.76-0.93) had lower risks of incident T2DM. Exercising < 1,500 MET-minutes/week in the exercise maintainer group was associated with a lower risk of incident T2DM compared with persistent non-exercisers (< 500: HR 0.80, 95% CI 0.67-0.96, P = 0.002; 500 to < 1,000: HR 0.81, 95% CI 0.71-0.93, P < 0.001; 1,000 to < 1,500: HR 0.81, 95% CI 0.69-0.94, P < 0.001). CONCLUSIONS: Regular exercise before or after thyroidectomy was associated with a lower risk of incident T2DM in patients with thyroid cancer.

Comprehensive Analysis of the Transcriptional and Mutational Landscape of Follicular and Papillary Thyroid Cancers.

Follicular thyroid carcinoma (FTC) and benign follicular adenoma (FA) are indistinguishable by preoperative diagnosis due to their similar histological features. Here we report the first RNA sequencing study of these tumors, with data for 30 minimally invasive FTCs (miFTCs) and 25 FAs. We also compared 77 classical papillary thyroid carcinomas (cPTCs) and 48 follicular variant of PTCs (FVPTCs) to observe the differences in their molecular properties. Mutations in H/K/NRAS, DICER1, EIF1AX, IDH1, PTEN, SOS1, and SPOP were identified in miFTC or FA. We identified a low frequency of fusion genes in miFTC (only one, PAX8-PPARG), but a high frequency of that in PTC (17.60%). The frequencies of BRAFV600E and H/K/NRAS mutations were substantially different in miFTC and cPTC, and those of FVPTC were intermediate between miFTC and cPTC. Gene expression analysis demonstrated three molecular subtypes regardless of their histological features, including Non-BRAF-Non-RAS (NBNR), as well as BRAF-like and RAS-like. The novel molecular subtype, NBNR, was associated with DICER1, EIF1AX, IDH1, PTEN, SOS1, SPOP, and PAX8-PPARG. The transcriptome of miFTC or encapsulated FVPTC was indistinguishable from that of FA, providing a molecular explanation for the similarly indolent behavior of these tumors. We identified upregulation of genes that are related to mitochondrial biogenesis including ESRRA and PPARGC1A in oncocytic follicular thyroid neoplasm. Arm-level copy number variations were correlated to histological and molecular characteristics. These results expanded the current molecular understanding of thyroid cancer and may lead to new diagnostic and therapeutic approaches to the disease.

Rare Manifestations of Anaplastic Thyroid Carcinoma: the Role of BRAF Mutation Analysis.

Anaplastic thyroid carcinoma (ATC) is difficult to distinguish from other cancers, especially when its pathological features are atypical for ATC or when the tumor is totally undifferentiated and occurs after a considerable lapse of time, in an area remote from the original site of the tumor. Here, we present two patients (68-year-old man and 56-year-old woman) with rare manifestations of ATC, which were initially thought to be other malignancies. Immunohistochemical tests, using various markers, failed to provide information about the origin of these tumors. However, both patients had a history of papillary thyroid carcinoma (PTC) from several years ago and BRAF mutations were observed in the undifferentiated tumors, as well as in the previous PTCs. Therefore, we could make a diagnosis of ATC derived from PTC. As such, BRAF mutation analysis may serve as a useful tool for ATC diagnosis in challenging ATC cases.

Prognostic effects of TERT promoter mutations are enhanced by coexistence with BRAF or RAS mutations and strengthen the risk prediction by the ATA or TNM staging system in differentiated thyroid cancer patients.

BACKGROUND: Recent reports suggest that mutations in the promoter of the gene encoding telomerase reverse transcriptase (TERT) affect thyroid cancer outcomes. METHODS: In all, 551 patients with differentiated thyroid cancer (DTC) enrolled in this study. The median follow-up duration was 4.8 years (interquartile range, 3.4-10.6 years). RESULTS: TERT promoter mutations were detected in 25 DTCs (4.5%): 2.8% in neither BRAF-mutated nor RAS-mutated tumors, 4.8% in BRAF-mutated tumors, and 11.3% in RAS-mutated tumors. Moreover, they were frequently observed in American Thyroid Association (ATA) high-risk and TNM stage III/IV groups (9.1% and 12.9%, respectively). The coexistence of BRAF or RAS with TERT promoter mutations increased aggressive clinicopathologic features, recurrence (hazard ratio [HR] for BRAF, 4.64; 95% confidence interval [CI], 1.42-15.18; HR for RAS, 5.36; 95% CI, 1.20-24.02), and mortality (HR for BRAF, 15.13; 95% CI, 1.55-148.23; HR for RAS, 14.75; 95% CI, 1.30-167.00), even after adjustments for the age at diagnosis and sex, although the significance was lost after additional adjustments for pathologic characteristics. Furthermore, TERT promoter mutations significantly increased the risk of both recurrence and mortality in the ATA high-risk (HR for recurrence, 5.79; 95% CI, 2.07-16.18; HR for mortality, 16.16; 95% CI, 2.10-124.15) and TNM stage III/IV groups (HR for recurrence, 3.60; 95% CI, 1.19-10.85; HR for mortality, 9.06; 95% CI, 2.09-39.26). CONCLUSIONS: The coexistence of BRAF or RAS mutations enhanced the prognostic effects of TERT promoter mutations. Furthermore, TERT promoter mutations strengthened the predictions of mortality and recurrence by the ATA and TNM staging systems, particularly for high-risk patients with DTC. Cancer 2016;122:1370-1379. © 2016 American Cancer Society.

Risk of Subsequent Primary Cancers in Thyroid Cancer Survivors according to the Dose of Levothyroxine: A Nationwide Cohort Study.

BACKGRUOUND: Current research has not investigated the effect of thyroid-stimulating hormone suppression therapy with levothyroxine on the risk for developing subsequent primary cancers (SPCs). This study aimed to investigate the association between levothyroxine dosage and the risk for SPCs in thyroid cancer patients. METHODS: We conducted a nationwide population-based retrospective cohort study form Korean National Health Insurance database. This cohort included 342,920 thyroid cancer patients between 2004 and 2018. Patients were divided into the non-levothyroxine and the levothyroxine groups, the latter consisting of four dosage subgroups according to quartiles. Cox proportional hazard models were performed to evaluate the risk for SPCs by adjusting for variables including cumulative doses of radioactive iodine (RAI) therapy. RESULTS: A total of 17,410 SPC cases were observed over a median 7.3 years of follow-up. The high-dose levothyroxine subgroups (Q3 and Q4) had a higher risk for SPC (adjusted hazard ratio [HR], 1.14 and 1.27; 95% confidence interval [CI], 1.05-1.24 and 1.17- 1.37; respectively) compared to the non-levothyroxine group. In particular, the adjusted HR of stomach (1.31), colorectal (1.60), liver and biliary tract (1.95), and pancreatic (2.48) cancers were increased in the Q4 subgroup. We consistently observed a positive association between high levothyroxine dosage per body weight and risk of SPCs, even after adjusting for various confounding variables. Moreover, similar results were identified in the stratified analyses according to thyroidectomy type and RAI therapy, as well as in a subgroup analysis of patients with good adherence. CONCLUSION: High-dose levothyroxine use was associated with increased risk of SPCs among thyroid cancer patients regardless of RAI therapy.

Clinicopathological Features and Molecular Signatures of Lateral Neck Lymph Node Metastasis in Papillary Thyroid Microcarcinoma.

BACKGRUOUND: The predictive factors for lateral neck lymph node metastasis (LLNM) in papillary thyroid microcarcinoma (PTMC) remain undetermined. This study investigated the clinicopathological characteristics, transcriptomes, and tumor microenvironment in PTMC according to the LLNM status. We aimed to identify the biomarkers associated with LLNM development. METHODS: We retrospectively reviewed the medical records of patients with PTMC from two independent institutions between 2018 and 2022 (n=597 and n=467). We compared clinicopathological features between patients without lymph node metastasis (N0) and those with LLNM (N1b). Additionally, laser capture microdissection and RNA sequencing were performed on primary tumors from both groups, including metastatic lymph nodes from the N1b group (n=30; 20 primary tumors and 10 paired LLNMs). We corroborated the findings using RNA sequencing data from 16 BRAF-like PTMCs from The Cancer Genome Atlas. Transcriptomic analyses were validated by immunohistochemical staining. RESULTS: Clinicopathological characteristics, such as male sex, multifocality, extrathyroidal extension, lymphatic invasion, and central node metastasis showed associations with LLNM in PTMCs. Transcriptomic profiles between the N0 and N1b PTMC groups were similar. However, tumor microenvironment deconvolution from RNA sequencing and immunohistochemistry revealed an increased abundance of tumor-associated macrophages, particularly M2 macrophages, in the N1b group. CONCLUSION: Patients with PTMC who have a male sex, multifocality, extrathyroidal extension, lymphatic invasion, and central node metastasis exhibited an elevated risk for LLNM. Furthermore, infiltration of M2 macrophages in the tumor microenvironment potentially supports tumor progression and LLNM in PTMCs.

Integrative Multi-omics Analysis Reveals Different Metabolic Phenotypes Based on Molecular Characteristics in Thyroid Cancer.

PURPOSE: Thyroid cancer metabolic characteristics vary depending on the molecular subtype determined by mutational status. We aimed to investigate the molecular subtype-specific metabolic characteristics of thyroid cancers. EXPERIMENTAL DESIGN: An integrative multi-omics analysis was conducted, incorporating transcriptomics, metabolomics, and proteomics data obtained from human tissues representing distinct molecular characteristics of thyroid cancers: BRAF-like (papillary thyroid cancer with BRAFV600E mutation; PTC-B), RAS-like (follicular thyroid cancer with RAS mutation; FTC-R), and ATC-like (anaplastic thyroid cancer with BRAFV600E or RAS mutation; ATC-B or ATC-R). To validate our findings, we employed tissue microarray of human thyroid cancer tissues and performed in vitro analyses of cancer cell phenotypes and metabolomic assays after inducing genetic knockdown. RESULTS: Metabolic properties differed between differentiated thyroid cancers of PTC-B and FTC-R, but were similar in dedifferentiated thyroid cancers of ATC-B/R, regardless of their mutational status. Tricarboxylic acid (TCA) intermediates and branched-chain amino acids (BCAA) were enriched with the activation of TCA cycle only in FTC-R, whereas one-carbon metabolism and pyrimidine metabolism increased in both PTC-B and FTC-R and to a great extent in ATC-B/R. However, the protein expression levels of the BCAA transporter (SLC7A5) and a key enzyme in one-carbon metabolism (SHMT2) increased in all thyroid cancers and were particularly high in ATC-B/R. Knockdown of SLC7A5 or SHMT2 inhibited the migration and proliferation of thyroid cancer cell lines differently, depending on the mutational status. CONCLUSIONS: These findings define the metabolic properties of each molecular subtype of thyroid cancers and identify metabolic vulnerabilities, providing a rationale for therapies targeting its altered metabolic pathways in advanced thyroid cancer.

Thyroid Dysfunction after Atezolizumab and Bevacizumab Is Associated with Favorable Outcomes in Hepatocellular Carcinoma.

Introduction: Atezolizumab and bevacizumab (Ate/Bev) combination has become the new first-line systemic therapy for unresectable hepatocellular carcinoma (HCC). Although several studies reported thyroid dysfunction after treatment with immune checkpoint inhibitors, the clinical and immunological significance of thyroid dysfunction in patients treated with Ate/Bev has not been comprehensively addressed. We aimed to comprehensively evaluate the clinical and immunological implications of thyroid dysfunction in unresectable HCC patients treated with Ate/Bev. Methods: We enrolled 208 patients with unresectable HCC treated with Ate/Bev from three Korean cancer centers. Thyroid adverse events (AEs) were reviewed, and cytokines and T cells in the blood samples were analyzed at baseline. For external validation, we analyzed clinical outcomes according to thyroid AEs in patients treated with Ate/Bev in the IMbrave150 study. Results: Forty-one (19.7%) out of 208 patients experienced thyroid dysfunction (hypothyroidism [17.3%] and thyrotoxicosis [5.8%]) after Ate/Bev treatment. Median time to onset of hypothyroidism and thyrotoxicosis after Ate/Bev treatment was 3.5 and 1.3 months, respectively. Patients with thyroid AEs demonstrated significantly better progression-free survival, overall survival, and objective response rate than those without thyroid AEs. These findings were still consistent even after adjusting for confounding factors. Furthermore, favorable survival outcomes in patients with thyroid AEs were also validated in a cohort of IMbrave150 patients. While patients with thyrotoxicosis showed a significantly lower level of baseline IL-6, those with hypothyroidism did not show significant differences in circulating cytokine levels and CD8+ T-cell fractions. Conclusions: A fraction of patients with HCC treated with Ate/Bev experienced thyroid dysfunction, and the development of thyroid AEs was associated with favorable clinical outcomes.

Estrogen-related receptor alpha promotes thyroid tumor cell survival via a tumor subtype-specific regulation of target gene networks.

Mortalin (encoded by HSPA9) is a mitochondrial chaperone often overexpressed in cancer through as-yet-unknown mechanisms. By searching different RNA-sequencing datasets, we found that ESRRA is a transcription factor highly correlated with HSPA9 in thyroid cancer, especially in follicular, but not C cell-originated, tumors. Consistent with this correlation, ESRRA depletion decreased mortalin expression only in follicular thyroid tumor cells. Further, ESRRA expression and activity were relatively high in thyroid tumors with oncocytic characteristics, wherein ESRRA and mortalin exhibited relatively high functional overlap. Mechanistically, ESRRA directly regulated HSPA9 transcription through a novel ESRRA-responsive element located upstream of the HSPA9 promoter. Physiologically, ESRRA depletion suppressed thyroid tumor cell survival via caspase-dependent apoptosis, which ectopic mortalin expression substantially abrogated. ESRRA depletion also effectively suppressed tumor growth and mortalin expression in the xenografts of oncocytic or ESRRA-overexpressing human thyroid tumor cells in mice. Notably, our Bioinformatics analyses of patient data revealed two ESRRA target gene clusters that contrast oncocytic-like and anaplastic features of follicular thyroid tumors. These findings suggest that ESRRA is a tumor-specific regulator of mortalin expression, the ESRRA-mortalin axis has higher significance in tumors with oncocytic characteristics, and ESRRA target gene networks can refine molecular classification of thyroid cancer.

Active Surveillance for Low-Risk Thyroid Cancers: A Review of Current Practice Guidelines.

The indolent nature and favorable outcomes associated with papillary thyroid microcarcinoma have prompted numerous prospective studies on active surveillance (AS) and its adoption as an alternative to immediate surgery in managing low-risk thyroid cancer. This article reviews the current status of AS, as outlined in various international practice guidelines. AS is typically recommended for tumors that measure 1 cm or less in diameter and do not exhibit aggressive subtypes on cytology, extrathyroidal extension, lymph node metastasis, or distant metastasis. To determine the most appropriate candidates for AS, factors such as tumor size, location, multiplicity, and ultrasound findings are considered, along with patient characteristics like medical condition, age, and family history. Moreover, shared decision-making, which includes patient-reported outcomes such as quality of life and cost-effectiveness, is essential. During AS, patients undergo regular ultrasound examinations to monitor for signs of disease progression, including tumor growth, extrathyroidal extension, or lymph node metastasis. In conclusion, while AS is a feasible and reliable approach for managing lowrisk thyroid cancer, it requires careful patient selection, effective communication for shared decision-making, standardized follow-up protocols, and a clear definition of disease progression.

Lower Thyroid Cancer Mortality in Patients Detected by Screening: A Meta-Analysis.

BACKGRUOUND: Thyroid cancer screening has contributed to the skyrocketing prevalence of thyroid cancer. However, the true benefit of thyroid cancer screening is not fully understood. This study aimed to evaluate the impact of screening on the clinical outcomes of thyroid cancer by comparing incidental thyroid cancer (ITC) with non-incidental thyroid cancer (NITC) through a meta-analysis. METHODS: PubMed and Embase were searched from inception to September 2022. We estimated and compared the prevalence of high-risk features (aggressive histology of thyroid cancer, extrathyroidal extension, metastasis to regional lymph nodes or distant organs, and advanced tumor-node-metastasis [TNM] stage), thyroid cancer-specific death, and recurrence in the ITC and NITC groups. We also calculated pooled risks and 95% confidence intervals (CIs) of the outcomes derived from these two groups. RESULTS: From 1,078 studies screened, 14 were included. In comparison to NITC, the ITC group had a lower incidence of aggressive histology (odds ratio [OR], 0.46; 95% CI, 0.31 to 0.7), smaller tumors (mean difference, -7.9 mm; 95% CI, -10.2 to -5.6), lymph node metastasis (OR, 0.64; 95% CI, 0.48 to 0.86), and distant metastasis (OR, 0.42; 95% CI, 0.23 to 0.77). The risks of recurrence and thyroid cancer-specific mortality were also lower in the ITC group (OR, 0.42; 95% CI, 0.25 to 0.71 and OR, 0.46; 95% CI, 0.28 to 0.74) than in the NITC group. CONCLUSION: Our findings provide important evidence of a survival benefit from the early detection of thyroid cancer compared to symptomatic thyroid cancer.

Different Molecular Phenotypes of Progression in BRAF- and RAS-Like Papillary Thyroid Carcinoma.

BACKGRUOUND: Papillary thyroid carcinoma (PTC) can be classified into two distinct molecular subtypes, BRAF-like (BL) and RASlike (RL). However, the molecular characteristics of each subtype according to clinicopathological factors have not yet been determined. We aimed to investigate the gene signatures and tumor microenvironment according to clinicopathological factors, and to identify the mechanism of progression in BL-PTCs and RL-PTCs. METHODS: We analyzed RNA sequencing data and corresponding clinicopathological information of 503 patients with PTC from The Cancer Genome Atlas database. We performed differentially expressed gene (DEG), Gene Ontology, and molecular pathway enrichment analyses according to clinicopathological factors in each molecular subtype. EcoTyper and CIBERSORTx were used to deconvolve the tumor cell types and their surrounding microenvironment. RESULTS: Even for the same clinicopathological factors, overlapping DEGs between the two molecular subtypes were uncommon, indicating that BL-PTCs and RL-PTCs have different progression mechanisms. Genes related to the extracellular matrix were commonly upregulated in BL-PTCs with aggressive clinicopathological factors, such as old age (≥55 years), presence of extrathyroidal extension, lymph node metastasis, advanced tumor-node-metastasis (TNM) stage, and high metastasis-age-completeness of resection- invasion-size (MACIS) scores (≥6). Furthermore, in the deconvolution analysis of tumor microenvironment, cancer-associated fibroblasts were significantly enriched. In contrast, in RL-PTCs, downregulation of immune response and immunoglobulin-related genes was significantly associated with aggressive characteristics, even after adjusting for thyroiditis status. CONCLUSION: The molecular phenotypes of cancer progression differed between BL-PTC and RL-PTC. In particular, extracellular matrix and cancer-associated fibroblasts, which constitute the tumor microenvironment, would play an important role in the progression of BL-PTC that accounts for the majority of advanced PTCs.

Risk of Subsequent Primary Cancer in Thyroid Cancer Survivors: A Nationwide Population-Based Study.

Background: Despite obtaining a good prognosis and long life expectancy, survivors of thyroid cancer can nevertheless develop subsequent primary cancer (SPC). We investigated the risk and types of SPC in patients with thyroid cancer and compared them with subjects without thyroid cancer history (controls). Methods: We conducted a nationwide, population-based, retrospective cohort study based on the Korean National Health Insurance Database. A total of 432,654 patients diagnosed with thyroid cancer between 2004 and 2019 were 1:1 matched with controls for age, sex, income, and region of residence. The hazard ratios (HR) and 95% confidence intervals (CI) of SPC were estimated using Cox proportional hazard models. Results: In total, 78,584 (18.2%) patients with thyroid cancer and 49,979 (11.6%) controls were diagnosed with SPCs over a mean follow-up of 6.9 years. Patients with thyroid cancer had a higher risk of SPC at any site (adjusted HR, 1.62; 95% CI, 1.60-1.64) than the controls. The risk of SPCs was particularly high for patients diagnosed with thyroid cancer at a younger age (<40 years) and within 5 years. Conclusions: Medical caregivers should consider the long-term follow-up of patients with thyroid cancer and discuss the risk of SPC, especially if they complain of cancer-related symptoms.

Postprandial Free Fatty Acids at Mid-Pregnancy Increase the Risk of Large-for-Gestational-Age Newborns in Women with Gestational Diabetes Mellitus.

BACKGROUND: To investigate the association between free fatty acid (FFA) level at mid-pregnancy and large-for-gestational-age (LGA) newborns in women with gestational diabetes mellitus (GDM). METHODS: We enrolled 710 pregnant women diagnosed with GDM from February 2009 to October 2016. GDM was diagnosed by a 'two-step' approach with Carpenter and Coustan criteria. We measured plasma lipid profiles including fasting and 2-hour postprandial FFA (2h-FFA) levels at mid-pregnancy. LGA was defined if birthweights of newborns were above the 90th percentile for their gestational age. RESULTS: Mean age of pregnant women in this study was 33.1 years. Mean pre-pregnancy body mass index (BMI) was 22.4 kg/m2. The prevalence of LGA was 8.3% (n=59). Levels of 2h-FFA were higher in women who delivered LGA newborns than in those who delivered non-LGA newborns (416.7 µEq/L vs. 352.5 µEq/L, P=0.006). However, fasting FFA was not significantly different between the two groups. The prevalence of delivering LGA newborns was increased with increasing tertile of 2h-FFA (T1, 4.3%; T2, 9.8%; T3, 10.7%; P for trend <0.05). After adjustment for maternal age, pre-pregnancy BMI, and fasting plasma glucose, the highest tertile of 2h-FFA was 2.38 times (95% confidence interval, 1.11 to 5.13) more likely to have LGA newborns than the lowest tertile. However, there was no significant difference between groups according to fasting FFA tertiles. CONCLUSION: In women with GDM, a high 2h-FFA level (but not fasting FFA) at mid-pregnancy is associated with an increasing risk of delivering LGA newborns.

FGM-based remote intervention for adults with type 1 diabetes: The FRIEND randomized clinical trial.

Background: The use of flash glucose monitoring (FGM) in conjunction with proper education has been reported to improve glycemic control in people with diabetes on insulin therapy. However, there are still few randomized controlled trials on the educational effect, and an ideal educational model has not been established. This study aimed to estimate the efficacy of remote intervention for glycemic control in adults with type 1 diabetes using FGM. Methods: In this single-center, randomized controlled trial, we enrolled adults with type 1 diabetes (HbA1c ≥7.0%). The participants were randomly assigned (1:1) to either FGM use with remote intervention (intervention group) or FGM use only (control group). Changes in glycemic outcomes such as HbA1c levels and continuous glucose monitoring metrics were evaluated at 12 weeks. Results: Among 36 randomized participants (mean age, 44.3 years; mean baseline HbA1c, 8.9%), 34 completed the study. The remote intervention did not significantly reduce HbA1c levels. FGM use significantly improved HbA1c levels by -1.4% and -0.8% in both groups with and without remote intervention, respectively (P=0.003 and P=0.004, respectively). However, the intervention group showed significant increases in time with glucose in the range of 70-180 mg/dL (TIR; from 49.8% to 60.9%, P=0.001) and significant decreases in time with hyperglycemia (P=0.002) and mean glucose (P=0.017), but the control group did not. Moreover, the TIR (P=0.019), time with hyperglycemia >250 mg/dL (P=0.019), and coefficient of variation (P=0.018) were significantly improved in the intervention group compared to the control group. In particular, the CGM metrics improved gradually as the remote intervention was repeated. Furthermore, the intervention group reported higher treatment satisfaction (P=0.016). Conclusions: Ongoing, personalized education during FGM use may lead to amelioration of glycemic control in adults with type 1 diabetes, even remotely. Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT04936633, identifier NCT04936633.

Screening Leads to Overestimated Associations of Thyroid Dysfunction and Thyroiditis with Thyroid Cancer Risk.

We aimed to assess the relationships of functional thyroid disease and thyroiditis with subsequent thyroid cancer, which is controversial due to various confounders, and the effect of thyroid disease workup on this association. We used the cohort data from 2002 to 2015 (Study I, n = 28,330) and the entire data from 2002 to 2019 (Study II, n = 883,074) of the Korean National Health Insurance Service database, and performed logistic regression and subgroup analyses with various covariates. In Study I, hypothyroidism, thyroiditis, autoimmune thyroiditis, hyperthyroidism, and Graves' disease showed positive associations with thyroid cancer. In Study II, after adjustment for covariates including the number of thyroid function tests, the ORs for thyroid cancer were significantly reduced in all thyroid diseases. Hypothyroidism, thyroiditis, and autoimmune thyroiditis were positively associated (adjusted odds ratio, OR (95% confidence interval, CI) 1.28 (1.25-1.32), 1.36 (1.31-1.42), and 1.17 (1.11-1.24), respectively), whereas hyperthyroidism and Graves' disease were negatively associated with thyroid cancer (adjusted OR (95% CI) 0.80 (0.77-0.83) and 0.69 (0.65-0.74), respectively). Multiple subgroup analyses in both studies showed consistent results. In this large population-based, nationwide study, we confirmed that thyroid disease workup leads to overestimation of associations of thyroid dysfunction and thyroiditis with thyroid cancer risk.

Analyses of the Relation between BPPV and Thyroid Diseases: A Nested Case-Control Study.

BACKGROUND: This study investigated relationship between multiple thyroid disorders and benign paroxysmal positional vertigo (BPPV), adjusting for levothyroxine medication. METHODS: The Korean National Health Insurance Service-Health Screening Cohort data from 2002 to 2015 were used. A total of 19,071 patients with BPPV were matched with 76,284 participants of a control group in a ratio of 1:4 for age, sex, income, and region of residence. The previous histories of thyroid disorders such as goiter, hypothyroidism, thyroiditis, hyperthyroidism, and autoimmune thyroiditis were investigated in both the BPPV and control groups. The odds ratios (ORs) for BPPV in thyroid diseases were calculated using conditional logistic regression analyses. RESULTS: The histories of goiter (5.5% vs. 4.1%), hypothyroidism (4.7% vs. 3.7%), thyroiditis (2.1% vs. 1.6%), and hyperthyroidism (3.1% vs. 2.5%) were higher in the BPPV group than in the control group (all p < 0.001). Goiter, hypothyroidism, thyroiditis, and hyperthyroidism were associated with BPPV (adjusted OR = 1.28 (95% CI = 1.17-1.39) for goiter, 1.23 (95% CI = 1.10-1.37) for hypothyroidism, 1.13 (95% CI = 1.02-1.26) for hyperthyroidism, each p < 0.05). CONCLUSIONS: BPPV was associated with thyroid disorders such as goiter, hypothyroidism, thyroiditis, and hyperthyroidism.

DEHP Down-Regulates Tshr Gene Expression in Rat Thyroid Tissues and FRTL-5 Rat Thyrocytes: A Potential Mechanism of Thyroid Disruption.

BACKGROUND: Di-2-ethylhexyl phthalate (DEHP) is known to disrupt thyroid hormonal status. However, the underlying molecular mechanism of this disruption is unclear. Therefore, we investigated the direct effects of DEHP on the thyroid gland. METHODS: DEHP (vehicle, 50 mg/kg, and 500 mg/kg) was administered to Sprague-Dawley rats for 2 weeks. The expression of the thyroid hormone synthesis pathway in rat thyroid tissues was analyzed through RNA sequencing analysis, quantitative reverse transcription-polymerase chain reaction (RT-PCR), and immunohistochemical (IHC) staining. DEHP was treated to FRTL-5 rat thyroid cells, and an RT-PCR analysis was performed. A reporter gene assay containing the promoter of thyroid stimulating hormone receptor (TSHR) in Nthy-ori 3-1 human thyroid cells was constructed, and luciferase activity was determined. RESULTS: After DEHP treatment, the free thyroxine (T4) and total T4 levels in rats significantly decreased. RNA sequencing analysis of rat thyroid tissues showed little difference between vehicle and DEHP groups. In the RT-PCR analysis, Tshr expression was significantly lower in both DEHP groups (50 and 500 mg/kg) compared to that in the vehicle group, and IHC staining showed that TSHR expression in the 50 mg/kg DEHP group significantly decreased. DEHP treatment to FRTL-5 cells significantly down-regulated Tshr expression. DEHP treatment also reduced luciferase activity in a reporter gene assay for TSHR. CONCLUSION: Although overall genetic changes in the thyroid hormone synthesis pathway are not clear, DEHP exposure could significantly down-regulate Tshr expression in thyroid glands. Down-regulation of Tshr gene appears to be one of potential mechanisms of thyroid disruption by DEHP exposure.

Evaluation of the relationship between previous statin use and thyroid cancer using Korean National Health Insurance Service-Health Screening Cohort data.

The association of thyroid cancer with statin use is controversial. This study aimed to investigate the association of previous statin use with thyroid cancer in the ≥ 40-year-old population in the Korean National Health Insurance Service-Health Screening Cohort. The 5501 patients in the thyroid cancer group were matched with the 22,004 patients in the non-thyroid cancer group for age, sex, income, and region of residence. Previous statin use during the 2 years before the diagnosis of thyroid cancer was examined. The odds ratios (ORs) with 95% confidence intervals (CIs) of previous statin use for thyroid cancer were estimated using conditional logistic regression analyses. Additionally, subgroup analyses were conducted. The thyroid cancer group showed more days of previous statin use than the non-thyroid cancer group (72.3, standard deviation [SD] = 181.2 days vs. 64.3, SD = 174.4 days, P = 0.003). Although the odds of previous statin use for thyroid cancer were high in the crude model (OR = 1.10, 95% CI 1.04-1.17, P = 0.002), they were low in the fully adjusted model (OR = 0.89, 95% CI 0.82-0.95, P = 0.001). According to age and sex subgroups, the younger (< 60 years old) male group showed lower odds for thyroid cancer according to previous statin use (adjusted OR = 0.70, 95% CI 0.55-0.88, P = 0.003), but this finding was not observed in other subgroups of older men or in any groups of women. Thyroid cancer was negatively associated with statin use in the previous 2 years in the adjusted model.

Increased expression of thyroid hormone receptor alpha and estrogen receptor alpha in breast cancer associated with thyroid cancer.

INTRODUCTION: Breast cancer co-occurred with thyroid cancer might be associated with thyroid hormone receptor (TR) and estrogen receptor (ER), but few have been reported. We aimed to investigate the expression and prognostic significance of ERs and TRs in such settings. MATERIAL AND METHODS: Tissue microarrays were constructed from 75 patients with breast and thyroid cancer (BC + TC) who were retrospectively recruited between 1999 and 2012 and 147 with breast cancer only (BC controls). The ERα, ERß, TRα, and TRß expression levels were analyzed by immunohistochemistry. RESULTS: TRα expression was more frequently observed in the BC + TC group than the BC control group both in the normal (51.5% vs 23.3%, respectively, p = 0.009) and cancer tissues (21.6% vs 6.8%, respectively, p = 0.001). The BC + TC group showed greater ERα-positivity in the cancer tissues (79.7% vs 58.7%, respectively, p = 0.002) than the BC control group. The degree of ERα- and TRα-positivity was unchanged by radioactive treatment or serum thyroid stimulating hormone levels. In the BC + TC group, ERα-positivity was associated with earlier disease stage I/IIA (81.0% vs 50.0%; p = 0.031) and lower recurrence rates (8.5% vs 40.0%; p = 0.002). TRα-positivity alone was not associated with any recurrence-free survival-related differences, and ERα- and TRα-negativity were associated with significantly shorter recurrence-free survival (p < 0.001). CONCLUSION: Enhanced ERα and TRα expression in breast cancer is associated with thyroid cancer occurrence, and the observed association with prognosis suggests the possible role of ERs and TRs in the link between breast cancer and thyroid cancer.