Dynamic Risk Model for the Medical Treatment of Graves' Hyperthyroidism according to Treatment Duration.

Background: Changes in thyrotropin receptor antibody (TRAb) levels are associated with the clinical outcomes of Graves' hyperthyroidism. However, the effects of the patterns of TRAb changes on patient prognosis according to the treatment duration of antithyroid drugs (ATDs) are not well established. Methods: In this retrospective cohort study, 1,235 patients with Graves' hyperthyroidism who were treated with ATDs for more than 12 months were included. Patients were divided into two groups according to treatment duration: group 1 (12-24 months) and group 2 (>24 months). Risk prediction models comprising age, sex, and either TRAb levels at ATD withdrawal (model A) or patterns of TRAb changes (model B) were compared. Results: The median treatment duration in groups 1 (n=667, 54%) and 2 (n=568, 46%) was 17.3 and 37.1 months, respectively. The recurrence rate was significantly higher in group 2 (47.9%) than in group 1 (41.4%, P=0.025). Group 2 had significantly more goiter, thyroid eye disease, and fluctuating and smoldering type of TRAb pattern compared with group 1 (all P<0.001). The patterns of TRAb changes were an independent risk factor for recurrence after adjusting for other confounding factors in all patients, except in group 1. Integrated discrimination improvement and net reclassification improvement analyses showed that model B performed better than model A in all patients, except in group 1. Conclusion: The dynamic risk model, including the patterns of TRAb changes, was more suitable for predicting prognosis in patients with Graves' hyperthyroidism who underwent longer ATD treatment duration.

Tumor Growth Kinetics Based on Initial Tumor Volume Doubling Time in Active Surveillance of Low-Risk Papillary Thyroid Carcinoma.

BACKGROUND: During active surveillance (AS) of low-risk papillary thyroid carcinomas (PTCs), the majority remain stable, while some exhibit either increase or decrease in tumor diameter or tumor volume (TV). We aimed to evaluate the clinical outcomes and relevant parameters influencing tumor growth kinetics of low-risk PTCs. METHODS: This retrospective cohort study evaluated clinical parameters of 402 patients with low-risk PTC sized <2 cm, with a follow-up duration over 3 years. Changes in maximum tumor diameter, TV, and initial TV doubling time (i-TVDT) calculated within 3-year were assessed. A significant change in TV was defined as a change of 75% or more. RESULTS: Of the 402 patients with low-risk PTC, 93.3% (375/402) were diagnosed with papillary thyroid microcarcinoma. During a median follow-up of 5 years, 3.4% (14/402) of patients developed new cervical lymph node (LN) metastasis, and 8.2% (33/402) experienced maximal diameter increase of ≥3 mm. The i-TVDT of <5 years emerged as an independent risk factor for both maximal diameter growth and new LN metastasis (p<0.001 and p=0.04, respectively). Based on TV changes and i-TVDT during AS, we identified four statistically significant tumor kinetic patterns (p<0.001): Stable (±75% change in TV), Rapid growth (TV increase >75% and i- TVDT <5 years), Slow growth (TV increase >75% and i-TVDT ≥5 years), and Shrinkage (TV decrease >75%). Most of the PTCs remained stable (67.7%), but 17.2% were rapidly growing, with a median onset of growth of 2.0 years. Slowly growing PTCs, comprising 10.9%, grew at a median of 4.3 years. A minority, 4.2%, exhibited shrinkage. In total, 115 (28.6%) patients underwent delayed surgery >12 months after initiating AS. The reasons for delayed surgery included patient preference (51/115, 44.3%), disease progression (31/115, 27.0%), and suspected disease progression, which was referred to as tumor growth not meeting the criteria of an increase of ≥3 mm in maximal tumor diameter (17/115, 14.8%). CONCLUSION: An i-TVDT of <5 years serve as an important prognostic indicator for disease progression, including tumor growth and new LN metastasis. The four tumor kinetic patterns based on TV changes and i-TVDT assist in guiding personalized decisions early in AS.

Prognostic Roles of Inflammatory Biomarkers in Radioiodine-Refractory Thyroid Cancer Treated with Lenvatinib.

BACKGRUOUND: Inflammatory biomarkers, such as the neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and platelet-to-lymphocyte ratio (PLR), serve as valuable prognostic indicators in various cancers. This multicenter, retrospective cohort study assessed the treatment outcomes of lenvatinib in 71 patients with radioactive iodine (RAI)-refractory thyroid cancer, considering the baseline inflammatory biomarkers. METHODS: This study retrospectively included patients from five tertiary hospitals in Korea whose complete blood counts were available before lenvatinib treatment. Progression-free survival (PFS) and overall survival (OS) were evaluated based on the median value of inflammatory biomarkers. RESULTS: No significant differences in baseline characteristics were observed among patients grouped according to the inflammatory biomarkers, except for older patients with a higher-than-median NLR (≥2) compared to their counterparts with a lower NLR (P= 0.01). Patients with a higher-than-median NLR had significantly shorter PFS (P=0.02) and OS (P=0.017) than those with a lower NLR. In multivariate analysis, a higher-than-median NLR was significantly associated with poor OS (hazard ratio, 3.0; 95% confidence interval, 1.24 to 7.29; P=0.015). However, neither the LMR nor the PLR was associated with PFS. A higher-than-median LMR (≥3.9) was significantly associated with prolonged OS compared to a lower LMR (P=0.036). In contrast, a higher-than-median PLR (≥142.1) was associated with shorter OS compared to a lower PLR (P=0.039). CONCLUSION: Baseline inflammatory biomarkers can serve as predictive indicators of PFS and OS in patients with RAI-refractory thyroid cancer treated with lenvatinib.

Morphometric Analysis of Lateral Cervical Lymph Node Metastasis in Papillary Thyroid Carcinoma Using Digital Pathology.

Digital pathology uses digitized images for cancer research. We aimed to assess morphometric parameters using digital pathology for predicting recurrence in patients with papillary thyroid carcinoma (PTC) and lateral cervical lymph node (LN) metastasis. We analyzed 316 PTC patients and assessed the longest diameter and largest area of metastatic focus in LNs using a whole slide imaging scanner. In digital pathology assessment, the longest diameters and largest areas of metastatic foci in LNs were positively correlated with traditional optically measured diameters (R = 0.928 and R2 = 0.727, p < 0.001 and p < 0.001, respectively). The optimal cutoff diameter was 8.0 mm in both traditional microscopic (p = 0.009) and digital pathology (p = 0.016) evaluations, with significant differences in progression-free survival (PFS) observed at this cutoff (p = 0.006 and p = 0.002, respectively). The predictive area's cutoff was 35.6 mm2 (p = 0.005), which significantly affected PFS (p = 0.015). Using an 8.0-mm cutoff in traditional microscopic evaluation and a 35.6-mm2 cutoff in digital pathology showed comparable predictive results using the proportion of variation explained (PVE) methods (2.6% vs. 2.4%). Excluding cases with predominant cystic changes in LNs, the largest metastatic areas by digital pathology had the highest PVE at 3.9%. Furthermore, high volume of LN metastasis (p = 0.001), extranodal extension (p = 0.047), and high ratio of metastatic LNs (p = 0.006) were associated with poor prognosis. Both traditional microscopic and digital pathology evaluations effectively measured the longest diameter of metastatic foci in LNs. Moreover, digital pathology offers limited advantages in predicting PFS of patients with lateral cervical LN metastasis of PTC, especially those without predominant cystic changes in LNs.

Undercover active surveillance of small highly suspicious thyroid nodules without fine needle aspiration.

PURPOSE: Active surveillance (AS) is an alternative treatment approach for small, low-risk papillary thyroid microcarcinoma (PTMC). This study aimed to assess the clinical outcomes of small, highly suspicious nodules lacking initial cytological confirmation. METHODS: This study included 112 patients with highly suspicious nodules measuring ≤ 10 mm who underwent serial ultrasound at Asan Medical Center, Korea, between 2010 and 2023. RESULTS: The median participant age was 51.9 years, and 74.1% were female. The median maximal tumor diameter and tumor volume (TV) were 4.5 (interquartile range [IQR] 3.7-5.2, range 2.2-9.3) mm and 25.2 (IQR 13.1-49.2) mm3, respectively. During a median follow-up period of 4.8 years, four (3.6%) patients showed a ≥ 3 mm increase in maximal diameter, and two (1.8%) developed new lymph node (LN) metastasis. Disease progression was associated with a TV doubling time (TVDT) of < 5 years and a ≥ 75% increase in TV (p = 0.017 and p < 0.005, respectively). Furthermore, 34.8% of patients underwent fine needle aspiration (FNA), primarily at their own request, yielding 46.2%, 5.1%, 41.0%, and 12.8 % malignant, benign, indeterminate, and non-diagnostic results, respectively. Of 18 patients with PTMC, 8 (44.4%) underwent surgery and 10 continued AS, with no LN metastasis during AS and no postoperative recurrence. CONCLUSION: Small, highly suspicious nodules had a low disease progression rate during AS without FNA. Disease progression was associated with a TVDT of < 5 years and a ≥ 75% increase in TV. FNA can be performed more conservatively than it currently is in patients with highly suspicious nodules measuring ≤ 10 mm.

Changes in peripheral blood immune cell population in thyroid cancer patients treated with lenvatinib.

This study evaluated changes in the peripheral blood immune cell population in patients with advanced thyroid cancer receiving lenvatinib treatment to confirm the immune-modulatory effect of lenvatinib. After obtaining informed consent from patients, we prospectively collected 20 ml of whole blood at 2-3 months intervals 2-4 times from each patient; peripheral blood mononuclear cells (PBMCs) were separated, and the Maxpar Direct Immune Profiling Assay was performed. A total of 10 patients were enrolled, and 31 blood samples were obtained. The median age of patients was 65 years, and all patients showed durable responses to the lenvatinib treatment. When we compared the PBMC profiles between the pre-treatment, on-treatment, and off-treatment samples, the peripheral natural killer (NK) cell proportion differed significantly. The proportion of NK cells among total live cells significantly increased from 9.3 ± 4.5 (%) in the pre-treatment samples to 20.8 ± 7.9 (%) in the on-treatment samples (P = 0.009) and decreased to 13.3 ± 3.1 (%) in the off-treatment samples (P = 0.07). There was a significant increase in the peripheral NK cell population with lenvatinib treatment in advanced thyroid cancer patients. This finding confirms the immune-modulatory effect of lenvatinib.

Serum thyroglobulin testing after thyroid lobectomy in patients with 1-4 cm papillary thyroid carcinoma.

BACKGROUND: The role of measuring serum thyroglobulin (Tg) levels in patients who have undergone lobectomy has not been proven. The goal of this research is to see if serum Tg levels can predict the recurrence of papillary thyroid carcinoma (PTC) after lobectomy. METHODS: The 463 patients with 1-4 cm PTC who underwent lobectomy between January 2005 and December 2012, were included in this retrospective cohort study. Postoperative serum Tg levels and neck ultrasound were evaluated every 6-12 months after lobectomy during a median 7.8-year follow-up period. The receiver operating characteristic (ROC) curve and its area under the ROC curve (AUC) was used to assess the diagnostic performance of serum Tg levels. RESULTS: During the follow-up, the structural recurrent disease was confirmed in 30 patients (6.5%). The serum Tg levels measured by initial Tg, maximal Tg, and last Tg did not differ statistically between the recurrence and non-recurrence groups. According to our findings, serial patterns of serum maximal Tg variations in 30 patients with recurrence showed no obvious trend and no rising trend toward recurrence before detecting recurrence. The AUC was 54.5% (IQR 43.1%-65.9%) in the ROC curve analysis, indicating that it was not significantly different from the random classifier. CONCLUSION: Serum Tg levels did not differ significantly between the recurrence and non-recurrence groups, and there was no tendency for the recurrence group to increase Tg levels. In patients with PTC who underwent lobectomy, monitoring Tg levels regularly provides little benefit in predicting recurrence.

Long-term follow-up result of antithyroid drug treatment of Graves' hyperthyroidism in a large cohort.

Objective: This study evaluated the efficacy of antithyroid drugs (ATDs) and risk factors associated with the recurrence of Graves' hyperthyroidism using a comprehensive retrospective cohort. Methods: We included 1829 patients newly diagnosed with Graves' hyperthyroidism, with sufficient follow-up data. Clinical outcomes of the patients and risk factors associated with recurrence-free survival, including the changes in thyrotropin receptor antibody, were evaluated. Results: The median age of the patients was 44.5 years, and 69% were female. Among the patients, 1235 had a chance to withdraw ATD after a median of 23 (interquartile range (IQR) 17.0-35.5) months of treatment. The first remission rate was 55.6% during a median of 72.7 months of follow-up. After the first recurrence, 95% of patients underwent the second course of ATD treatment for a median of 21.1 (IQR 14.8-31.7) months, and the remission rate was 54.1%. During a median of 67 months of follow-up, 7.7% of patients underwent surgery, and 10.5% underwent radioactive iodine therapy. Approximately 30% were still on ATD therapy for recurrent disease or prolonged low-dose maintenance. Younger age (<45 years), male sex, and fluctuating or smoldering of TRAb levels were independent risk factors of the first recurrence after ATD treatment. Conclusions: ATD treatment is an acceptable option for the initial treatment of Graves' hyperthyroidism as well as for recurrent disease. The optimal treatment period for ATD treatment needs to be determined using the individual risk factors of recurrence.