Shortened telomere length in peripheral blood leukocytes is associated with cumulative radioactive iodine doses in patients with differentiated thyroid carcinoma.

BACKGROUND: Telomere length is associated with cancer risk and cancer aggressiveness. Radioactive iodine (RAI) therapy for thyroid cancer has raised concerns for second primary malignancy (SPM) in patients with high cumulative doses. The association between RAI dose and peripheral blood leukocyte telomere length was examined. METHODS: A total of 425 patients were included who underwent total thyroidectomy and were followed up for at least 1 year with or without RAI treatment. The relative telomere length (RTL) of the patients was assessed via a quantitative polymerase chain reaction amplification method. RAI doses were divided into five groups on the basis of cumulative dose, and a comparison was made among these groups. RESULTS: The number of patients with RAI treatment was 287 (67.5%), and the cumulative RAI dose was 3.33 GBq (range, 1.11-131.35 GBq). The mean RTL was significantly shorter in the highest RAI group (>22.2 GBq) compared to both the no-RAI and lower dose groups. The association between RAI dose and RTL was positive in the lower RAI group (1.1-3.7 GBq) and negative in the highest RAI group in both univariate and multivariate analyses. We observed 59 (13.9%) SPMs and 20 (4.7%) mortalities, and RTL did not show a significant risk effect for all-cause, thyroid cancer-specific, or SPM-specific mortality. CONCLUSIONS: In patients with thyroid cancer who underwent total thyroidectomy, peripheral blood leukocyte telomere length exhibited a significant association with cumulative RAI dose higher than 22.2 GBq. These results suggest the possibility of telomere length shortening in patients who undergo high-dose RAI treatment.

Surgical Outcomes in Patients With Low-risk Papillary Thyroid Microcarcinoma From MAeSTro Study: Immediate Operation Versus Delayed Operation After Active SurveillanceA Multicenter Prospective Cohort Study.

OBJECTIVE: To investigate surgical, and clinical outcomes in patients with low-risk papillary thyroid microcarcinoma (PTMC) according to treatment options [immediate operation (IOP) vs delayed operation after active surveillance (AS) (DOP)]. BACKGROUND: AS has been adopted as an alternative to immediate surgery in patients with low-risk PTMC. Although some patients undergo surgery during AS, there is little information on surgical, and clinical outcomes after delayed operation after AS. METHODS: A multicenter prospective cohort study including 1177 patients was conducted at 3 tertiary hospitals in Korea from June 2016 to January 2020. Patients with low-risk PTMC were enrolled. The participants were self-assigned into AS or IOP, and during AS, the patients underwent surgery if there were signs of disease progression or if the patient's choice changed. RESULTS: A total of 516 patients underwent operation; 384 (74.4%) in the IOP group and 132 (25.6%) in the DOP group. Compared with the IOP group, the DOP group was significantly associated with a larger tumor size ( P =0.002), higher rates of lymphatic invasion ( P =0.002), and multifocality ( P =0.008). However, the rates of total thyroidectomy, postoperative hypoparathyroidism and vocal cord palsy did not differ significantly between the groups ( P = 0.283, P =0.184, and P =0.284, respectively). Of the 132 patients in the DOP group, disease progression was present in 39 (29.5%) patients. The DOP group with disease progression had a significantly higher rate of lymph node metastasis ( P =0.021) and radioiodine therapy ( P =0.025) than the DOP group without disease progression. CONCLUSIONS: These results suggest that AS might be considered an alternative treatment option for patients with low-risk PTMC regarding the extent of thyroidectomy and postoperative complications in the DOP group. To assess oncologic outcomes, long-term follow-up will be needed. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02938702.

US Predictors of Papillary Thyroid Microcarcinoma Progression at Active Surveillance.

Background Active surveillance (AS) is an accepted strategy for patients with low-risk papillary thyroid microcarcinoma (PTMC). While previous studies have evaluated the prognostic value of US features, results have been inconsistent. Purpose To determine if US features can help predict tumor progression in patients with low-risk PTMC undergoing AS. Materials and Methods This prospective study enrolled 1177 participants with PTMC from three hospitals between June 2016 and January 2021. Participants were self-assigned to either immediate surgery or AS, and those with two or more US examinations in the absence of surgery were included in the analysis. A χ2 test was used to compare estimated tumor progression rate at 4 years between participants stratified according to US features. Multivariable Cox regression analysis was used to assess the association of clinical and US features with overall tumor progression and specific progression criteria. Results Among 699 participants included in the analysis, 68 (mean age, 49 years ± 12 [SD]; 40 female participants) showed tumor progression (median follow-up, 41.4 months ± 16 [SD]). Tumor progression was associated with the US features of diffuse thyroid disease (DTD) (hazard ratio [HR], 2.3 [95% CI: 1.4, 3.7]; P = .001) and intratumoral vascularity (HR, 1.7 [95% CI: 1.0, 3.0]; P = .04) and the participant characteristics of male sex (HR, 2.8 [95% CI: 1.7, 4.6]; P < .001), age less than 30 years (HR, 2.9 [95% CI: 1.2, 6.8]; P = .01), and thyroid-stimulating hormone level of 7 µU/mL or higher (HR, 6.9 [95% CI: 2.7, 17.4]; P < .001). The risk of tumor progression was higher for participants with DTD (14%, P = .001) or intratumoral vascularity (14%, P = .02) than for participants without these features (6%). DTD and intratumoral vascularity were associated with tumor enlargement (HR, 2.7 [95% CI: 1.4, 5.1]; P = .002) and new lymph node metastasis (HR, 5.0 [95% CI: 1.3, 19.4]; P = .02), respectively. Conclusion DTD and intratumoral vascularity were associated with an increased risk of tumor progression in participants with PTMC undergoing AS. Clinical trial registration no. NCT02938702 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Reuter and the review "International Expert Consensus on US Lexicon for Thyroid Nodules" by Durante et al in this issue.

Tumor doubling time predicts response to sorafenib in radioactive iodine-refractory differentiated thyroid cancer.

Sorafenib has emerged as an effective therapeutic option for radioactive iodine (RAI)-refractory, locally advanced or metastatic differentiated thyroid cancer (DTC). We investigated the efficacy and safety of sorafenib treatment in a real-world setting and unveil predictive markers of responsiveness to sorafenib. The treatment response, progression-free survival (PFS), overall survival, and adverse events (AEs) of sorafenib-treated RAI-refractory, locally advanced or metastatic DTC patients at three institutes were retrospectively reviewed, and their tumor doubling time was calculated by three investigators. Total eighty-five patients were treated with sorafenib, and seven patients discontinued sorafenib due to AEs before the first tumor assessment. The median PFS was 14.4 months, and the objective response rate was 10.3% in 78 patients who were able to evaluate the tumor response. Age, sex, histologic type, tumor location, RAI avidity, or the presence of FDG-PET uptake did not affect PFS. However, smaller tumor size (≤1.5 cm) of the target lesions in lung showed better PFS (hazard ratio [HR] 0.39, p = 0.01), and tumors with the shortest doubling time (≤6 months) had worse outcome (HR 2.70, p < 0.01). Because of AEs, dose reductions or drug interruptions were required in 64% of patients, and eventually, 23% of patients discontinued sorafenib permanently. The most common AE was hand-foot skin reaction (HFSR). Patients with severe HFSR showed better PFS, but there were no statistical significance (HR 0.65, p = 0.05). In conclusion, small tumor size and long doubling time of each target lesion can be a prognostic marker to predict the responsiveness to sorafenib in RAI-refractory DTC patients.

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.

Extent of surgery did not affect recurrence during 7-years follow-up in papillary thyroid cancer sized 1-4 cm: Preliminary results.

OBJECTIVE: There is debate whether hemithyroidectomy is sufficient for patients with papillary thyroid cancer (PTC) sized 1-4 cm. Therefore, we investigated whether hemithyroidectomy affects recurrence rate compared with thyroidectomy in patients with PTC sized 1-4 cm. DESIGN: Retrospective observational study. PATIENTS: We included 147 patients with 1-4 cm PTC who underwent hemithyroidectomy between 2004 and 2008. They were matched with 298 patients who underwent thyroidectomy, comparing age, sex, tumour size, multiplicity, extrathyroidal extension status and lymph node (LN) metastasis status. MEASUREMENTS: Recurrence-free survival (RFS) was compared between hemithyroidectomy and thyroidectomy groups. RESULTS: Median follow-up length was 7 years, during which there were nine (6.1%) and 17 (5.7%) recurrences in hemithyroidectomy and thyroidectomy groups, respectively. Recurrence-free survival in the hemithyroidectomy group was not different from that in the thyroidectomy group regardless of variant, multifocality, LN metastasis and radioactive iodine treatment. However, in subgroup analysis, hemithyroidectomy significantly increased the risk of recurrence in patients with contralateral nodules on the preoperative imaging. CONCLUSIONS: Recurrence after hemithyroidectomy was not different from that after thyroidectomy during a median follow-up of 7 years. However, because thyroidectomy might be favoured in patients with contralateral nodules at preoperative evaluation, a thorough evaluation of the contralateral thyroid lobe is necessary.

Radiofrequency ablation of low-risk small papillary thyroidcarcinoma: preliminary results for patients ineligible for surgery.

PURPOSE: The purpose of this study is to retrospectively evaluate the outcomes of radiofrequency ablation (RFA) of low-risk small papillary thyroid carcinomas (PTCs) in patients who were ineligible for surgery. MATERIALS AND METHODS: Between 2005 and 2009, six PTCs (mean diameter, 0.92 cm; range, 0.6-1.3 cm) in six patients were treated with RFA by three radiologists in two hospitals. The inclusion criteria for this study were (1) pathologically confirmed PTC without cytological aggressiveness, (2) single PTC without extrathyroidal extension, (3) no metastatic tumours and (4) ineligibility for surgery. RFA was performed using a radiofrequency generator and an 18-gauge internally cooled electrode. The medical records were reviewed and analysed, focussing on the procedural profiles of RFA, symptoms and complications during and after RFA, and changes in tumours on follow-up ultrasonography. RESULTS: Before and after RFA, the results of thyroid function tests were normal in all patients. During 48.5 ± 12.3 months (range, 36-65 months) of follow-up, along with a significant reduction in the mean volume (98.5 ± 3.3%), four ablation zones (4/6, 66.7%) completely disappeared. Two ablation zones exhibited only small calcified residues with nearly complete disappearance of the corresponding non-calcified solid portions, and in one of them, malignant cells were absent as assessed by fine-needle aspiration and core-needle biopsy. Transient hypertension with mild headache (n = 1) and mild neck pain (n = 1) developed during the procedure and subsided without any treatment. CONCLUSION: Besides surgery and active surveillance, which are conflicting currently used management plans, RFA might represent an effective and a safe alternative for managing low-risk small PTCs, especially in patients ineligible for surgery.

A genome-wide association study on thyroid function and anti-thyroid peroxidase antibodies in Koreans.

Genetic factors are thought to be an important determinant of thyroid function and autoimmunity. However, there are limited data on genetic variants in Asians. In this study, we performed a genome-wide association study on plasma thyroid-stimulating hormone (TSH) and free thyroxine (fT4) concentration and anti-thyroid peroxidase (anti-TPO) antibody positivity in 4238 Korean subjects. In the Stage 1 genome scan, 3396 participants from the Ansung cohort were investigated using 1.42 million genotyped or imputed markers. In the Stage 2 follow-up, 10 markers were genotyped in 842 participants from the Korean Longitudinal Study on Health and Aging cohort. An intronic variant in VAV3, rs12126655, which has been reported in Europeans, was significantly associated with plasma TSH concentration in the joint Stages 1 and 2 analyses (P = 2.2 × 10(-8)). We observed that a novel variant, rs2071403, located 75 bp proximal to the translational start site of TPO was significantly associated with plasma anti-TPO antibody positivity in the joint Stages 1 and 2 analyses (P = 1.3 × 10(-10)). This variant had a marginal sex-specific effect, and its association was more significant in females. Subjects possessing the rs2071403A allele, associated with an absence of the anti-TPO antibody, had decreased TPO mRNA expression in their thyroid tissue. Another intronic variant of HLA-DPB2, rs733208, had a suggestive association with anti-TPO antibody positivity (P = 4.2 × 10(-7)). In conclusion, we have identified genetic variants that are strongly associated with TSH level and anti-TPO antibody positivity in Koreans. Further replications and meta-analysis are required to confirm these findings.

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.

Recombinant human thyrotropin-stimulated thyroglobulin level at the time of radioactive iodine ablation is an independent prognostic marker of differentiated thyroid carcinoma in the setting of prophylactic central neck dissection.

OBJECTIVE: We investigated the value of the stimulated thyroglobulin (Tg) level at the time of recombinant human thyrotropin (rhTSH)-aided remnant ablation for predicting disease status 1 year later in patients with DTC who underwent total thyroidectomy with central neck dissection (CND). DESIGN, SETTING, AND PARTICIPANT: This was a prospective observational study of 253 consecutive patients with DTC who underwent rhTSH-aided RAI ablation after total thyroidectomy and prophylactic CND. Patients with evidence of initial distant metastasis or positive Tg antibodies were excluded. MAJOR OUTCOME MEASURE: We compared rhTSH-stimulated Tg level at RAI ablation according to the disease status at 1 year and evaluated optimal cut-off value of rhTSH-stimulated Tg. Binary logistic regression analysis was performed to investigate the independent predictive factors for disease status 1 year after ablation. RESULTS: Among study participants, 228 (90·1%) were considered disease free at 1 year after remnant ablation. Patients with persistent or recurrent disease were more likely to be aged ≥45 years, and to have N1b stage, TNM stage III or IV, and higher rhTSH-stimulated Tg level at RAI ablation. The optimal cut-off of rhTSH-stimulated Tg for predicting persistent or recurrent disease was 1·79 ng/ml, with a negative predictive value of 99·5%. A serum rhTSH-stimulated Tg level ≥1·79 at the time of ablation was independently associated with persistent or recurrent disease 1 year later. N1b stage tended to be associated with persistent or recurrent disease. CONCLUSION: A low stimulated serum Tg level at rhTSH-aided RAI ablation may be a favourable prognostic marker in the setting of prophylactic CND.

Postoperative biochemical remission of serum calcitonin is the best predictive factor for recurrence-free survival of medullary thyroid cancer: a large-scale retrospective analysis over 30 years.

CONTEXT: The increase in thyroid screening in the general population may lead to earlier detection of medullary thyroid carcinoma (MTC). OBJECTIVE: We aimed to evaluate secular trends in clinicopathological characteristics and long-term prognosis of MTC and its prognostic factors. DESIGN: This was a retrospective analysis from 1982 to 2012. PATIENTS: Three hundred and thirty-one patients with MTC were included and grouped based on the year of diagnosis (1982-2000, 2001-2005, 2006-2010 and 2011-2012). MEASUREMENTS: These included recurrence and mortality as well as biochemical remission (BCR) of serum calcitonin. RESULTS: Mean tumour size (from 2·5 cm to 1·7 cm, P < 0·001) and percentage of extrathyroidal extension (from 52·0% to 26·0%, P = 0·026) decreased. The percentage of patients achieving BCR within six postoperative months (po-BCR) increased with time (from 39·6% to 76·1%, P < 0·001). The 5-year overall recurrence rate significantly decreased in 2006-2012 compared to 1982-2005 (10% vs 18%, respectively, P = 0·031), although the 5-year survival rate did not improve (92% vs 92%, P = 0·929). Failure to achieve po-BCR was the strongest predictive factor associated with recurrence (hazard ratio [HR] = 58·04, 95% CI 7·14-472·11; P < 0·001). Male gender (HR = 3·18, 95% CI 1·18-8·56; P = 0·022), tumour size >2 cm (HR = 18·33, 95% CI 2·35-143·06; P = 0·006) and distant metastasis (HR = 4·00, 95% CI 1·31-12·21; P = 0·015) were significant prognostic factors for mortality. CONCLUSIONS: Clinicopathological characteristics and recurrence of MTC improved with time. Po-BCR was the best predictive factor for recurrence-free survival.

Efficacy and Safety of Radiofrequency Ablation for Treatment of Locally Recurrent Thyroid Cancers Smaller than 2 cm.

PURPOSE: To evaluate the efficacy and safety of radiofrequency ablation (RFA) for localized small recurrent thyroid cancers less than 2 cm by comparing them with those at repeat surgery. MATERIALS AND METHODS: This retrospective study was institutional review board-approved, and informed consent was waived. From December 2008 to December 2011, this study evaluated 73 patients (17 men and 56 women; age, 50.3 years ± 13.6) with recurrent thyroid cancer who had been treated with RFA (n = 27) or repeat surgery (n = 46) who met the following criteria: (a) three or fewer recurrences or lesions with high probability of recurrence at ultrasonography; (b) no tumor other than the target tumors; and (c) at least 1 year of follow-up. RFA was recommended and performed in cases of surgical ineligibility, such as patient refusal and poor medical condition. Recurrence-free survival rates and posttreatment complication rates (eg, hoarseness and hypocalcemia) were compared between RFA and reoperation groups after adjustment with weighted analysis by using inverse probability of treatment weights. RESULTS: After this adjustment, the 1- and 3-year recurrence-free survival rates were comparable (P = .681) for RFA (96.0% and 92.6%, respectively) and reoperation (92.2% and 92.2%, respectively) groups. The posttreatment hoarseness rate did not differ between the RFA (7.3% [1.8 of 24]) and reoperation (9.0% [3.6 of 39.5]) groups (P = .812), and posttreatment hypocalcemia occurred exclusively in the reoperation group (11.6% [4.6 of 39.5]) but not in the RFA group (0% [0 of 24]) (P = .083). CONCLUSION: RFA may be an effective and safe alternative to repeat surgery in patients with locally recurrent small thyroid cancers.

Factors Affecting the Locoregional Recurrence of Conventional Papillary Thyroid Carcinoma After Surgery: A Retrospective Analysis of 3381 Patients.

BACKGROUND: Papillary thyroid carcinoma (PTC) does recur, despite its favorable long-term outcome. The incidence of thyroid cancer in South Korea increased during the 1990s, then increased rapidly after the turn of the century. In 2011, the rate of thyroid cancer diagnoses was 15 times that observed in 1993. The present study aimed to identify factors associated with the locoregional recurrence of recently increasing conventional PTC. METHODS: The records of 3381 patients with conventional PTC were reviewed for this retrospective cohort study. Between January 2004 and January 2012, these patients underwent ultrasonography, computed tomography, and preoperative and total thyroidectomy with central neck dissection. Disease recurrence was defined as structural evidence of disease following the remission period. RESULTS: Median length of follow-up was 5.6 (range 2.1-10.1) years. Of 3381 patients, 75 (2.2 %) experienced recurrence. The univariate analysis suggested that locoregional recurrence was associated with tumor size, multifocality, extrathyroidal extension (ETE), lymph node metastasis, lymphatic invasion, vascular invasion, and positive surgical margin. However, multivariate analysis showed that only tumor size (p < 0.001), bilaterality (p < 0.001), gross ETE (p = 0.049), lymph node metastasis (p < 0.001), and vascular invasion (p = 0.013) were independently associated with locoregional recurrence. CONCLUSIONS: Tumor size, bilaterality, gross ETE, lymph node metastasis, and vascular invasion were associated with locoregional recurrence. Evaluation of these prognostic factors appears to help identify patients who require close monitoring.

The risk of second primary malignancy is increased in differentiated thyroid cancer patients with a cumulative (131)I dose over 37 GBq.

BACKGROUND: The aim of this study was to investigate the risk factors for second primary malignancy (SPM) diagnosed after differentiated thyroid cancer (DTC). METHODS: A total of 2468 DTC patients who underwent thyroidectomy were reviewed. SPM was defined as a non-thyroidal malignancy, diagnosed at least 1 year after the diagnosis of thyroid cancer. Patients were divided into five groups according to cumulative (131)I dose: very high-activity (≥ 37.0 GBq), high-activity (22.3-36.9 GBq), intermediate-activity (5.56-22.2 GBq), low-activity (1.1-5.55 GBq) and no RAI. RESULTS: Among the 2468 patients, 61 (2.5%) had SPMs during 7.0 (1.0-33.0) years of median follow-up. Age above 40 years, male sex and very high-activity RAI were independent risk factors for the development of SPM. SPM-related mortality was highest in the very high-activity group, while DTC-related mortality was highest in the high-activity group. The overall mortality both from SPM and DTC was highest in the high-activity group. CONCLUSION: A cumulative (131)I dose <37.0 GBq did not increase the risk of SPM. A cumulative (131) I dose ≥ 37.0 GBq increased the risk of SPM and SPM-related mortality and decreased the DTC-specific mortality, resulting in a similar all-cause mortality compared with the low-activity RAI group. Using repeated high-dose RAI for treating RAI-responsive but persistent DTC patients needs careful consideration of the individual benefits from RAI vs the risk of developing SPM.

The role of ultrasound findings in the management of thyroid nodules with atypia or follicular lesions of undetermined significance.

BACKGROUND: Atypia or follicular lesions of undetermined significance (AUS/FLUS) is a broad cytological category in the Bethesda system for classifying thyroid cytology. This study investigated the diagnostic accuracy of ultrasound (US) analysis of thyroid nodules with AUS/FLUS. PATIENTS AND METHODS: Of 5062 subjects with nodules subjected to fine-needle aspiration cytology (FNACs) at our institution from January 2010 through May 2012, 383 met the Bethesda criteria for AUS/FLUS. After excluding subjects who had a history of thyroid cancer, who only underwent repeat FNA or who underwent no further examinations, we selected 249 subjects who had subsequently undergone a core-needle biopsy and/or surgery. Of these, 100 were found to have malignant nodules (40·2%), 122 had benign nodules (49%), and 27 had nodules with indeterminate status (10·8%). We compared specific US parameters, including size, location, content, shape, margin, echogenicity, echotexture and calcification across these subject groups. RESULTS: Multivariate analysis revealed that malignancy was associated with taller-than-wide shape (TDW) (OR = 8·43, P = 0·002), ill-defined margin (OR = 3·23, P = 0·002) and marked hypoechogenicity. (OR = 3·61, P = 0·001). The specificity and positive predictive values of TDW were 98% and 90·6%,respectively. The specificity and positive predictive values of 'TDW and marked hypoechogenicity' were both 100%. CONCLUSION: US findings play a complementary role in the diagnosis of thyroid nodules with AUS/FLUS. In case of highly suspicious US findings such as 'TDW and marked hypoechogenicity', could be very helpful in the diagnosis of malignancy.

Diagnostic Accuracy of Preoperative Radiologic Findings in Papillary Thyroid Microcarcinoma: Discrepancies with the Postoperative Pathologic Diagnosis and Implications for Clinical Outcomes.

BACKGRUOUND: The diagnostic accuracy of preoperative radiologic findings in predicting the tumor characteristics and clinical outcomes of papillary thyroid microcarcinoma (PTMC) was evaluated across all risk groups. METHODS: In total, 939 PTMC patients, comprising both low-risk and non-low-risk groups, who underwent surgery were enrolled. The preoperative tumor size and lymph node metastasis (LNM) were evaluated by ultrasonography within 6 months before surgery and compared with the postoperative pathologic findings. Discrepancies between the preoperative and postoperative tumor sizes were analyzed, and clinical outcomes were assessed. RESULTS: The agreement rate between radiological and pathological tumor size was approximately 60%. Significant discrepancies were noted, including an increase in tumor size in 24.3% of cases. Notably, in 10.8% of patients, the postoperative tumor size exceeded 1 cm, despite being initially classified as 0.5 to 1.0 cm based on preoperative imaging. A postoperative tumor size >1 cm was associated with aggressive pathologic factors such as multiplicity, microscopic extrathyroidal extension, and LNM, as well as a higher risk of distant metastasis. In 30.1% of patients, LNM was diagnosed after surgery despite not being suspected before the procedure. This group was characterized by smaller metastatic foci and lower risks of distant metastasis or recurrence than patients with LNM detected both before and after surgery. CONCLUSION: Among all risk groups of PTMCs, a subset showed an increase in tumor size, reaching 1 cm after surgery. These cases require special consideration due to their association with adverse clinical outcomes, including an elevated risk of distant metastasis.

Plasma FGF21 levels are increased in patients with hypothyroidism independently of lipid profile.

Thyroid hormone is a potent regulator of metabolic and energy homeostasis implicated in various metabolic diseases. Fibroblast growth factor 21(FGF21) is a systemic metabolic regulator known to modulate various biological functions similar to the actions of thyroid hormone. We investigated the differences in plasma FGF21 concentrations in patients with varying thyroid function. Ninety drug-naïve subjects who underwent thyroid evaluation at Seoul National University Bundang Hospital were enrolled and classified into euthyroid, subclinical hypothyroid, and overtly hypothyroid groups. Biochemical markers and plasma FGF21 levels were measured and analyzed. The mean age of the subjects was 42.6 ± 9.1 years. The mean body mass index (BMI), waist circumference, and fasting glucose concentrations were similar between groups. Overtly hypothyroid subjects exhibited significantly higher concentrations of total cholesterol, triglyceride, and LDL-cholesterol than the other groups (p<0.01). Mean plasma FGF21 concentrations in euthyroid, subclinical hypothyroid and overtly hypothyroid groups were 43.2 ± 39.2 pg/mL, 63.6 ± 73.6 pg/mL, and 101.5 ± 74.9 pg/mL, respectively (p<0.01 between groups). Plasma FGF21 concentrations remained significantly higher in overtly hypothyroid subjects after adjusting for serum triglyceride concentrations (p<0.005). Multivariate analysis revealed a significant positive linear relationship between serum TSH concentrations and plasma FGF21 concentrations (ß = 0.192, p = 0.002) and a significant negative linear relationship between free T4 and plasma FGF21 concentrations (ß = -0.382, p = 0.037) after adjusting for gender, BMI and serum concentrations of triglycerides and glucose. Plasma FGF21 levels were significantly increased in patients with hypothyroidism independently of BMI, or lipid or glucose metabolism.

The association between vitamin D supplementation and the long-term prognosis of differentiated thyroid cancer patients: a retrospective observational cohort study with propensity score matching.

Objective: Benefits of vitamin D in various cancers have been reported, but its effects on differentiated thyroid cancer (DTC) have not been established. We aimed to analyze the effect of vitamin D supplementation on the prognosis of DTC. Methods: A retrospective observational cohort study was conducted on 9,739 DTC patients who underwent thyroidectomy from January 1997 to December 2016. Mortality was classified as all-cause, cancer-related, or thyroid cancer-related. Patients were divided into the "VD group" (supplemented with vitamin D) and the "control group" (without vitamin D supplementation). Propensity score matching was performed in a 1:1 ratio according to age, sex, tumor size, extrathyroidal extension (ETE), and lymph node metastasis (LNM) status, and 3,238 patients were assigned to each group. Kaplan-Meier curves, log-rank test and Cox proportional hazards regression analysis were performed. Results: The follow-up period was 10.7 ± 4.2 years. Clinicopathological variables between two groups were similar except for all-cause (p<0.001) and total cancer death (p=0.001). From the Kaplan-Meier curve and log-rank test, "VD group" had significantly favorable all-cause (p<0.001) and total cancer mortality (p=0.003), but similar thyroid cancer mortality (p=0.23). In Cox regression, vitamin D intake reduced the risk of all-cause (hazard ratio [HR], 0.617, p=0.001) and total cancer mortality (HR, 0.668, p=0.016) but had no effect on thyroid cancer mortality. Discussion/conclusion: Vitamin D supplementation was positively associated with all-cause and total cancer mortality in DTC and might be a modifiable prognostic factor for improved survival. Further research will be needed to clarify the effect of vitamin D supplementation on DTC.

The association of the BRAF(V600E) mutation with prognostic factors and poor clinical outcome in papillary thyroid cancer: a meta-analysis.

BACKGROUND: The effects of the BRAF(V600E) mutation on prognostic factors and poor clinical outcomes in papillary thyroid cancer (PTC) have not been fully quantified. The authors performed comprehensive meta-analysis to assess the strength of associations between these conditions and the BRAF(V600E) mutation. METHODS: The authors identified the clinical studies that examined the association of the BRAF(V600E) mutation in surgical specimens with clinicopathologic outcomes between January 2003 and October 2010 using the Medline database. One hundred thirty-one relevant studies were hand-searched. The authors selected 27 studies that included 5655 PTC patients. They calculated the pooled odds ratios (ORs) or risk ratios with 95% confidence intervals (CIs) for each study using a random effect model. RESULTS: The average prevalence rate of the BRAF(V600E) mutation was 49.4%. In 26 studies, compared with the patients who had the wild-type BRAF genes, the PTC patients with the BRAF(V600E) mutation had increased ORs of an extrathyroidal invasion (OR, 2.14; 95% CI, 1.68-2.73), a lymph node metastasis (OR, 1.54; 95% CI, 1.21-1.97), and an advanced TNM stage (OR, 2.00; 95% CI, 1.61-2.49). In 8 studies, patients with the mutation had 2.14-fold increased risk of recurrent and persistent disease (95% CI, 1.67-2.74). The associations were generally consistent across the different study populations. CONCLUSIONS: This meta-analysis demonstrates that the BRAF(V600E) mutation is closely related to the high-risk clinicopathological factors and poorer outcome of PTC. The results obtained here suggest that the BRAF(V600E) mutation should be considered as a poor prognostic marker in PTC and may lead to better management for individual patients.

Opposing regulation of cytochrome P450 expression by CAR and PXR in hypothyroid mice.

Clinical hypothyroidism affects various metabolic processes including drug metabolism. CYP2B and CYP3A are important cytochrome P450 drug metabolizing enzymes that are regulated by the xenobiotic receptors constitutive androstane receptor (CAR, NR1I3) and pregnane X receptor (PXR, NR1I2). We evaluated the regulation of the hepatic expression of CYPs by CAR and PXR in the hypothyroid state induced by a low-iodine diet containing 0.15% propylthiouracil. Expression of Cyp3a11 was suppressed in hypothyroid C57BL/6 wild type (WT) mice and a further decrement was observed in hypothyroid CAR-/- mice, but not in hypothyroid PXR-/- mice. In contrast, expression of Cyp2b10 was induced in both WT and PXR-/- hypothyroid mice, and this induction was abolished in CAR-/- mice and in and CAR-/- PXR-/- double knockouts. CAR mRNA expression was increased by hypothyroidism, while PXR expression remained unchanged. Carbamazepine (CBZ) is a commonly used antiepileptic that is metabolized by CYP3A isoforms. After CBZ treatment of normal chow fed mice, serum CBZ levels were highest in CAR-/- mice and lowest in WT and PXR-/- mice. Hypothyroid WT or PXR-/- mice survived chronic CBZ treatment, but all hypothyroid CAR-/- and CAR-/- PXR-/- mice died, with CAR-/-PXR-/- mice surviving longer than CAR-/- mice (12.3±3.3 days vs. 6.3±2.1 days, p=0.04). All these findings suggest that hypothyroid status affects xenobiotic metabolism, with opposing responses of CAR and PXR and their CYP targets that can cancel each other out, decreasing serious metabolic derangement in response to a xenobiotic challenge.