Thyroid®

Total thyroidectomy (TT) and hemithyroidectomy (HT) are acceptable surgical options for the treatment of low-risk differentiated thyroid cancer (DTC). While previous data suggest similar disease-free and disease-specific survival regardless of initial surgical treatment, the effect of the extent of surgery on health-related quality of life (HRQOL) is less clear. This systematic review aimed to examine HRQOL in low-risk DTC survivors after TT compared with HT.

A search of PubMed, CINAHL, Cochrane, PsycINFO, and Scopus databases was conducted to identify studies published between January 1, 2011, and December 31, 2022, that assessed HRQOL predominantly in patients with low-risk DTC who underwent open thyroid surgery. Covidence™ software was used to apply the inclusion criteria, and a validated instrument was used to assess study quality.

Sixteen of the 1402 identified studies were included: 5 prospective and 11 retrospective cohort studies. The majority of included studies were of good quality (n = 14) and were from Asia and the Middle East (n = 11). Overall, six studies concluded that HT led to a better HRQOL than TT, two concluded that HT only resulted in better HRQOL compared with TT with central neck dissection (CND), and two concluded HT resulted in better short-term HRQOL that dissipated by 6 months postoperatively. The HRQOL domains found across all studies to be most consistently improved after HT included physical health, psychological/emotional, and social function. Factors found to be associated with HRQOL in more than one study included age, stage, and marital status.

Differences in HRQOL after HT and TT tended to favor HT particularly when measured <6 months after surgery or when compared with TT with CND. Additional prospective and ideally randomized data are needed to fully determine the impact of the extent of surgery on HRQOL in patients with low-risk thyroid cancer.

Rearranged during transfection (RET) alterations are targetable oncogenic drivers in thyroid cancer. Primary data from the open-label, phase 1/2 ARROW study demonstrated clinical activity and manageable safety with pralsetinib, a selective RET inhibitor, in patients with advanced/metastatic RET-altered thyroid cancer. We present an updated analysis with more patients and longer follow-up.

Adult patients with advanced/metastatic RET-mutant medullary thyroid cancer (MTC) or RET fusion-positive thyroid cancer who initiated oral pralsetinib at 400 mg once daily were included. Primary endpoints were overall response rate (ORR) by blinded independent central review (per RECIST v1.1) and safety. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), and overall survival. Responses were assessed in three cohorts of patients with baseline measurable disease: patients with RET-mutant MTC who had received prior cabozantinib and/or vandetanib (C/V), treatment-naïve patients with RET-mutant MTC, and patients with previously treated RET fusion-positive thyroid cancer. Patient-reported outcomes (PROs) were an exploratory endpoint.

As of October 18, 2021, the measurable disease population comprised of 61 patients with RET-mutant MTC and prior C/V, 62 treatment-naïve patients with RET-mutant MTC, and 22 patients with RET fusion-positive thyroid cancer who had received prior systemic therapy, including radioactive iodine. The ORR was 55.7% [confidence interval; 95% CI: 42.4–68.5] in patients with RET-mutant MTC and prior C/V, 77.4% [95% CI: 65.0–87.1] in treatment-naïve patients with RET-mutant MTC, and 90.9% [95% CI: 70.8–98.9] in patients with previously treated RET fusion-positive thyroid cancer. Median DoR and median PFS were both 25.8 months in patients with RET-mutant MTC and prior C/V, not reached in treatment-naïve patients with RET-mutant MTC, and 23.6 and 25.4 months, respectively, in patients with previously treated RET fusion-positive thyroid cancer. In the RET-altered thyroid cancer safety population (N = 175), 97.1% of patients reported a treatment-related adverse event (TRAE); these led to discontinuation in 5.7% and dose reduction in 52.6% of patients. There was one death (0.6%) due to a TRAE. PROs improved or remained stable after pralsetinib treatment.

In this updated analysis of the ARROW study, pralsetinib continued to show deep and durable clinical activity and a manageable safety profile in patients with advanced/metastatic RET-altered thyroid cancer. Clinical Trial Registration: NCT03037385

An accurate preoperative workup of cytologically indeterminate thyroid nodules (ITN) may rule out malignancy and avoid diagnostic surgery for benign nodules. This study assessed the performance of molecular diagnostics (MD) and 2-[¹⁸F]fluoro-2-deoxy-d-glucose ([¹⁸F]FDG)-positron emission tomography/computed tomography (PET/CT) in ITN, including their combined use, and explored whether molecular alterations drive the differences in [¹⁸F]FDG uptake among benign nodules.

Adult, euthyroid patients with a Bethesda III or IV thyroid nodule were prospectively included in this multicenter study. They all underwent MD and an [¹⁸F]FDG-PET/CT scan of the neck. MD was performed using custom next-generation sequencing panels for somatic mutations, gene fusions, and copy number alterations and loss of heterozygosity. Sensitivity, specificity, negative and positive predictive value (NPV, PPV), and benign call rate (BCR) were assessed for MD and [¹⁸F]FDG-PET/CT separately and for a combined approach using both techniques.

In 115 of the 132 (87%) included patients, MD yielded a diagnostic result on cytology. Sensitivity, specificity, NPV, PPV, and BCR were 80%, 69%, 91%, 48%, and 57% for MD, and 93%, 41%, 95%, 36%, and 32% for [¹⁸F]FDG-PET/CT, respectively. When combined, sensitivity and specificity were 95% and 44% for a double-negative test (i.e., negative MD plus negative [¹⁸F]FDG-PET/CT) and 68% and 86% for a double-positive test, respectively. Concordance was 63% (82/130) between MD and [¹⁸F]FDG-PET/CT. There were more MD-positive nodules among the [¹⁸F]FDG-positive benign nodules (25/59, 42%, including 11 (44%) isolated RAS mutations) than among the [¹⁸F]FDG-negative benign nodules (7/30, 19%, p = 0.02). In oncocytic ITN, the BCR of [¹⁸F]FDG-PET/CT was mere 3% and MD was the superior technique.

MD and [¹⁸F]FDG-PET/CT are both accurate rule-out tests when unresected nodules that remain unchanged on ultrasound follow-up are considered benign. It may vary worldwide which test is considered most suitable, depending on local availability of diagnostics, expertise, and cost-effectiveness considerations. Although complementary, the benefits of their combined use may be confined when therapeutic consequences are considered, and should therefore not routinely be recommended. In nononcocytic ITN, sequential testing may be considered in case of a first-step MD negative test to confirm that withholding diagnostic surgery is oncologically safe. In oncocytic ITN, after further validation studies, MD might be considered.

This trial is registered with ClinicalTrials.gov: NCT02208544 (August 5, 2014), https://clinicaltrials.gov/ct2/show/NCT02208544.

The criteria for determining technical efficacy of thermal ablation for papillary thyroid carcinoma (PTC) are not clearly defined. We analyzed the involution process of the ablation zone with clear pathologic results on core-needle biopsy (CNB) to clarify the relationship between sonographic changes and pathologic findings.

This retrospective cohort study included 382 patients with unifocal T1N0M0 PTC who underwent radiofrequency ablation (RFA) between May 2014 and August 2021. Patients with a single ablation zone biopsy (recommended at 3 or 6 months for T1a and 6 or 12 months for T1b) and regular neck ultrasound (US)/contrast-enhanced ultrasound imaging follow-up at 1, 3, 6, and 12 months and every 6–12 months thereafter after RFA were included. Patients also underwent yearly chest computed tomography. CNB was performed in the target lesion ablation zone's central, peripheral, and surrounding thyroid parenchyma to detect the presence of tumor cells. If the thyrotropin (TSH) was >2 mU/L, levothyroxine was prescribed with the intention of keeping the TSH 0.5–2 mU/L. Technical efficacy was defined as tumor disappearance by imaging follow-up together with the pathologically confirmed absence of tumor cells in the ablation zone.

During the mean follow-up period of 67.8 ± 18.2 months (22–110 months), the overall incidence of persistent disease and the technical efficacy rate were 3.9% (15/382; 2.9% of T1a, and 12.2% of T1b) and 96.1%, respectively. Tumor size (p = 0.03) and subcapsular location (p = 0.04) were risk factors associated with persistent disease. The technical success rate was 100%. Of the 367 ablation zones with benign CNB results, 336 (91.6%) showed tumor disappearance on US and no re-emergence of imaging-visible tumors during follow-up. Male sex (p = 0.006), age <40 years (p = 0.003), T1a tumor (p < 0.01), and energy per milliliter (p < 0.03) were significantly associated with tumor disappearance.

US-guided RFA is an effective treatment for small low-risk PTC. Tumor disappearance on US after RFA may suggest an excellent prognosis and confirm complete ablation of the macroscopic tumor, but this sonographic finding is generally late and requires histological confirmation.

The impact of near-infrared autofluorescence (NIRAF) imaging on postthyroidectomy hypocalcemia is controversial. As patients with Graves' disease are at increased risk, our aim was to compare postoperative parathyroid function in these patients undergoing total thyroidectomy (TT) with or without NIRAF imaging.

This was a retrospective “before and after” study, comparing outcomes of patients who underwent TT without or with NIRAF imaging at a single center. Primary outcome was the incidence of temporary hypocalcemia and secondary outcomes, rates of incidental parathyroidectomy on final specimens and permanent hypocalcemia. Analyses were performed using Mann-Whitney U and chi-Square tests. Continuous data are expressed as median (interquartile range).

There were 85 patients in NIRAF and 100 patients in non-NIRAF group. Groups were comparable regarding age, gender, body-mass index, and thyroid weight. Number of parathyroid glands identified intraoperatively was 3 in both groups (p = 0.47). Intraoperative parathyroid implantation rate was 16.5% in NIRAF and 6% in non-NIRAF group (p = 0.02). Incidental parathyroidectomy rate on final pathology was 12.9% in NIRAF and 32% in non-NIRAF group (p = 0.002). The rates of temporary (11.7% vs. 16%) and permanent hypocalcemia (2.4% vs. 2%) were similar between the two groups, respectively (p = 0.66).

To our knowledge, this is the first comparative study investigating the impact of NIRAF on postoperative parathyroid function after thyroidectomy for Graves' disease. The rate of incidental parathyroidectomy on final pathology was lower with use of NIRAF, without an impact on temporary or permanent hypocalcemia rates compared to conventional technique.

Redifferentiation therapy (RDT) can restore radioactive iodine (RAI) uptake in differentiated thyroid cancer (DTC) cells to enable salvage ¹³¹I therapy for previously RAI refractory (RAIR) disease. This study evaluated the clinical outcomes of patients who underwent RDT and identified clinicopathologic characteristics predictive of RAI restoration following RDT.

This is a retrospective case series of 33 patients with response evaluation criteria in solid tumors (RECIST)-progressive metastatic RAIR-DTC who underwent RDT between 2017 and 2022 at the Mayo Clinic (Rochester, MN). All patients underwent genomic profiling and received MEK, RET or ALK inhibitors alone, or combination BRAF-MEK inhibitors for 4 weeks. At week 3, those with increased RAI avidity in metastatic foci received high-dose ¹³¹I therapy. Baseline and clinicopathologic outcomes were comprehensively reviewed.

Of the 33 patients, 57.6% had restored RAI uptake following RDT (Redifferentiated subgroup). 42.1% (8/19) with papillary thyroid cancers (PTC), 100% (4/4) with invasive encapsulated follicular variant PTCs (IEFV-PTCs), and 100% (7/7) with follicular thyroid cancers (FTC) redifferentiated. All (11/11) RAS mutant tumors redifferentiated compared with 38.9% (7/18) with BRAF mutant disease (6 PTC and 1 IEFV-PTC). 76.5% (13/17) of redifferentiated and 66.7% (8/12) of non-redifferentiated patients achieved a best overall RECIST response of stable disease (SD) or non-complete response/non-progressive disease. Both subgroups had a median 12% tumor shrinkage at 3 weeks on drug(s) alone. The redifferentiated subgroup, following high-dose ¹³¹I therapy, achieved an additional median 20% tumor reduction at 6 months after RDT. There were no statistically significant differences between both groups in progression free survival (PFS), time to initiation of systemic therapy, and time to any additional therapy. Of the entire cohort, 6.1% (2/33) experienced histologic transformation to anaplastic thyroid cancer, 15.1% (5/33) died, and all had redifferentiated following RDT and received ¹³¹I therapy.

RDT has the potential to restore RAI avidity and induce RECIST responses following ¹³¹I therapy in select patients with RAIR-DTC, particularly those with RAS-driven “follicular” phenotypes. In patients with PTC, none of the evaluated clinical outcomes differed statistically between the redifferentiated and non-redifferentiated subgroups. Further studies are needed to better characterize the long-term survival and/or safety outcomes of high-dose RAI following RDT, particularly whether it could be associated with histologic anaplastic transformation.

Nasolacrimal duct obstruction (NLDO) is an adverse effect of high dose radioactive iodine (RAI) therapy for thyroid carcinoma. There are currently no established preventive measures. This study assesses whether preservative free artificial tears (PFATs) can decrease the ¹³¹I sodium iodide (¹³¹I) activity in the tears of patients following RAI therapy for thyroid carcinoma, and potentially serve as a preventive measure for RAI-associated NLDO.

This non-randomized prospective pilot clinical trial recruited contact-lens wearing patients undergoing RAI therapy for thyroid cancer to self-administer PFATs into the right eye for four days starting on the day of RAI ingestion. Left eyes were the controls. While wearing contacts, patients self-administered PFATs per the following—Day 1: every 15 minutes for 2 hours, then every 30 minutes until bedtime, day 2: every hour for at least 12 hours, day 3: four times a day, and day 4: two times a day. Contact lenses were changed daily, and all lenses were collected one week later. Levels of ¹³¹I activity were measured by a well counter, decay-corrected, and converted to units of becquerel. Statistical analyses were performed to compare the ¹³¹I activities of the experimental and control eyes.

Sixteen eyes of eight patients treated with an average of 145.7 mCi (range 108–159) of ¹³¹I for papillary thyroid cancer were included. On day 1, artificial tears decreased the geometric mean ¹³¹I activity by 26% in the experimental eyes (p = 0.008). Artificial tears also decreased the geometric mean area under the curve over four days by 23% (p = 0.002).

¹³¹I is present in the tears following RAI therapy for thyroid carcinoma. Frequent PFATs starting on the day of RAI ingestion may decrease the level of ¹³¹I in the tears. This finding could have implications for lowering the risk of NLDO. Future multi-center clinical trials are needed to determine whether the use of artificial tears after RAI therapy may decrease the risk of NLDO.

NCT04327999

Risk stratification systems for thyroid nodules are limited by low specificity. The fine-needle aspiration (FNA) biopsy size thresholds and stratification criteria are based on evidence from the literature and expert consensus. Our aims were to investigate the optimal FNA biopsy size thresholds in the American College of Radiology (ACR) Thyroid Imaging Reporting and Data System (TI-RADS) and artificial intelligence (AI) TI-RADS and to revise the stratification criteria in AI TI-RADS.

A total of 2596 thyroid nodules (in 2511 patients) on ultrasound examination with definite pathological diagnoses were retrospectively identified from January 2017 to September 2021 in 6 participating Chinese hospitals. The modified criteria for ACR TI-RADS were as follows: (1) no FNA for TR3; (2) FNA threshold for TR4 increased to 2.5 cm. The modified criteria for AI TI-RADS were as follows: (1) 6-point nodules upgraded to TR5; (2) no FNA for TR3; (3) FNA threshold for TR4 increased to 2.5 cm. The diagnostic performance and the unnecessary FNA rate (UFR) of modified versions were compared with the original ACR TI-RADS.

Compared with the original ACR TI-RADS, the modified ACR (mACR) TI-RADS yielded higher specificity (73% vs. 46%), accuracy (74% vs. 51%), area under the receiver operating characteristic curve (AUC; 0.80 vs. 0.70), and lower UFR (25% vs. 48%; all p < 0.001), although the sensitivity was slightly decreased (87% vs. 93%, p = 0.057). Compared with the original ACR TI-RADS, the modified AI (mAI) TI-RADS yielded higher specificity (73% vs. 46%), accuracy (75% vs. 51%), AUC (0.81 vs. 0.70), and lower UFR (24% vs. 48%; all p < 0.001), although the sensitivity tended to be slightly decreased (89% vs. 93%, p = 0.13). There was no significant difference between the mACR TI-RADS and mAI TI-RADS in the diagnostic performance and UFR (all p > 0.05).

The revised FNA thresholds and the stratification criteria of the mACR TI-RADS and mAI TI-RADS may be associated with improvements in specificity and accuracy, without significantly sacrificing sensitivity for malignancy detection.

Previous studies have reported gut microbiome alterations in Hashimoto's autoimmune thyroiditis (HT) patients. Yet, it is unknown whether an aberrant microbiome is present before clinical disease onset in participants susceptible to HT or whether it reflects the effects of the disease itself. In this study, we report for the first time a comprehensive characterization of the taxonomic and functional profiles of the gut microbiota in euthyroid seropositive and seronegative participants. Our primary goal was to determine taxonomic and functional signatures of the intestinal microbiota associated with serum thyroid peroxidase antibodies (TPOAb). A secondary aim was to determine whether different ethnicities warrant distinct reference intervals for accurate interpretation of serum thyroid biomarkers.

In this cross-sectional study, euthyroid participants with (N = 159) and without (N = 1309) TPOAb were selected from the multiethnic (European Dutch, Moroccan, and Turkish) HEalthy Life In an Urban Setting (HELIUS) cohort. Fecal microbiota composition was profiled using 16S rRNA sequencing. Differences between the groups were analyzed based on the overall composition (alpha and beta diversity), as well as differential abundance (DA) of microbial taxa and functional pathways using multiple DA tools.

Overall composition showed a substantial overlap between the two groups (p > 0.05 for alpha-diversity; p = 0.39 for beta-diversity), indicating that TPOAb-seropositivity does not significantly differentiate gut microbiota composition and diversity. Interestingly, TPOAb status accounted for only a minor fraction (0.07%) of microbiome variance (p = 0.545). Further exploration of taxonomic differences identified 138 taxa nominally associated with TPOAb status. Among these, 13 taxa consistently demonstrated nominal significance across three additional DA methods, alongside notable associations within various functional pathways. Furthermore, we showed that ethnicity-specific reference intervals for serum thyroid biomarkers are not required, as no significant disparities in serum thyroid markers were found among the three ethnic groups residing in an iodine-replete area (p > 0.05 for thyrotropin, free thyroxine, and TPOAb).

These findings suggest that there is no robust difference in gut microbiome between individuals with or without TPOAb in terms of alpha and beta-diversity. Nonetheless, several taxa were identified with nominal significance related to TPOAb presence. Further research is required to determine whether these changes indeed imply a higher risk of overt HT.

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.

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.

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).

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.

Graves' disease has been associated with adverse pregnancy, labor and delivery, and neonatal outcomes. Thyroid function levels, assessed during newborn screening (NBS), can serve as indicators of the adaptation in the hypothalamic–pituitary–thyroid axis. We utilized data from the national thyroid NBS program to investigate the characteristics of the mother–infant dyad of term infants born to mothers with past or active Graves' disease.

The dataset of the Israeli NBS for thyroid function was linked with the electronic records of a tertiary medical center to generate a unified database of mothers and their term infants born between 2011 and 2021. The MDClone big data platform extracted maternal, pregnancy, disease course, labor and delivery, and neonatal characteristics of the mother-infant dyads.

Out of 103,899 registered mother–infant dyads, 292 (0.3%) mothers had past or active Graves' disease. A forward multivariate linear regression demonstrated that Graves' disease did not significantly affect NBS total thyroxine (tT4) levels (p = 0.252). NBS tT4 levels in infants born to mothers with active Graves' disease were higher than those observed in the general Israeli population (p < 0.001). Mothers with Graves' disease more frequently used assisted reproductive technology (12.7% vs. 9.0%, respectively, p = 0.012; odds ratio [OR] = 1.46 [CI 1.03–2.07], p = 0.031), and had more gestational hypertension (3.9% vs. 1.1%, p < 0.001; OR = 3.53 [CI 1.92–6.47], p < 0.001), proteinuria (2.5% vs. 0.9%, p < 0.001; OR = 3.03 [CI 1.43–6.45], p = 0.004), cesarean sections (26.4% vs. 19.7%, p = 0.029; OR = 1.46 [CI 1.13–1.90], p = 0.004), prelabor rupture of membranes (15.4% vs. 4.1%, p < 0.001; OR = 4.3 [CI 3.13–5.91], p < 0.001), and placental abnormalities (5.1% vs. 2.0%, p < 0.001; OR = 2.64 [CI 1.57–4.44]; p < 0.001). Their infants had lower adjusted birthweight z-scores (−0.18 ± 0.94 vs. −0.03 ± 0.90, p = 0.007) and were more likely to be small for gestational age (12.0% vs. 8.1%, p = 0.005; OR = 1.54 [CI 1.08–2.19], p = 0.018).

Neonatal thyroid function levels were affected by maternal Graves' disease only when the disease was active during gestation. Moreover, maternal Graves' disease was also associated with an increased risk of adverse outcomes for the mother–infant dyad.