Clinical Features and Risk Factors of Adrenal Insufficiency in Patients With Cancer Admitted to the Hospitalist-Managed Medical Unit.

BACKGROUND: The symptoms of adrenal insufficiency (AI) overlap with the common effects of advanced cancer and chemotherapy. Considering that AI may negatively affect the overall prognosis of cancer patients if not diagnosed in a timely manner, we analyzed the incidence, risk factors, and predictive methods of AI in cancer patients. METHODS: We retrospectively analyzed the medical records of 184 adult patients with malignancy who underwent a rapid adrenocorticotrophic hormone stimulation test in the medical hospitalist units of a tertiary hospital. Their baseline characteristics and clinical features were evaluated, and the risk factors for AI were identified using logistic regression analysis. RESULTS: Of the study patients, 65 (35%) were diagnosed with AI, in whom general weakness (63%) was the most common symptom. Multivariate logistic regression showed that eosinophilia (adjusted odds ratio [aOR], 4.28; 95% confidence interval [CI], 1.10-16.63; P = 0.036), history of steroid use (aOR, 2.37; 95% CI, 1.10-5.15; P = 0.028), and history of megestrol acetate use (aOR, 2.71; 95% CI, 1.38-5.33; P = 0.004) were associated with AI. Baseline cortisol levels of 6.2 µg/dL and 12.85 µg/dL showed a specificity of 95.0% and 95.4% for AI diagnosis, respectively. CONCLUSION: AI was found in about one-third of patients with cancer who showed general symptoms that may be easily masked by cancer or chemotherapy, suggesting that clinical suspicion of AI is important while treating cancer patients. History of corticosteroids or megestrol acetate were risk factors for AI and eosinophilia was a pre-test predictor of AI. Baseline cortisol level appears to be a useful adjunct marker for AI.

The value of preoperative antithyroidperoxidase antibody as a novel predictor of recurrence in papillary thyroid carcinoma.

The link between chronic lymphocytic thyroiditis (CLT) and papillary thyroid carcinoma (PTC) is widely recognized. Considering the strong association between raised antithyroidperoxidase antibody (TPOAb) and CLT, we postulated that the preoperative TPOAb can predict the prognosis of PTC, particularly for recurrence. A total of 2,070 patients who underwent total thyroidectomy for classical type PTC with tumor size ≥1 cm and with available data on preoperative TPOAb and TgAb were enrolled to compare disease-free survival (DFS) according to the presence of preoperative TPOAb, TgAb, and coexistent CLT. Patients with positive preoperative TPOAb had a significantly better DFS compared to patients without positive preoperative TPOAb (hazard ratio (HR) 0.53; 95% confidence interval (CI) 0.30-0.94, p = 0.028) while no difference in DFS was found according to preoperative TgAb status. Positive preoperative TPOAb was an independent prognostic factor for structural persistent/recurrent disease after adjustment for major preoperative risk factors such as age, sex, and tumor size (HR 0.52, 95% CI 0.28-0.99, p = 0.048). Although the coexistence of CLT lowered the risk for structural persistence/recurrence in univariate analysis (HR 0.52, 95% CI 0.31-0.86, p = 0.012), it was not an independent favorable prognostic factor by multivariate analysis (HR 0.65, 95% CI 0.38-1.10, p = 0.106). However, when coexistent CLT was combined with positive preoperative TPOAb, it indicated an independent protective role in structural persistent/recurrent disease (HR 0.39, 95% CI 0.16-0.98, p = 0.045). Our study clearly showed that presence of preoperative TPOAb can be a novel prognostic factor in predicting structural persistence/recurrence of PTC.

Serum thyroid-stimulating hormone levels and smoking status: Data from the Korean National Health and Nutrition Examination Survey VI.

OBJECTIVE: We aimed to evaluate differences in serum thyroid-stimulating hormone (TSH) levels according to smoking status and urine iodine concentration (UIC) in a healthy Korean population using data from the Sixth Korean National Health and Nutrition Examination Survey (KNHANES VI). STUDY DESIGN: Sixth Korean National Health and Nutrition Examination Survey (2013-2015) is a nationwide, cross-sectional survey of the Korean population. PATIENTS: Research subjects were selected by two-stage stratified cluster sampling of the population and housing census data. A total of 5639 subjects aged >18 years, who were not pregnant, and had undergone thyroid function testing during the survey period, were included. MEASUREMENT: The level of serum TSH according to smoking status, iodine intake and presence of TPOAb were evaluated. RESULTS: In the reference population, mean serum TSH level in current smokers (1.87 mIU/L, 95% CI, 0.52-5.37 mIU/L) was significantly lower than that in nonsmokers (2.33 mIU/L, 95% CI, 0.79-6.69 mIU/L, P < .001). The rate of thyroperoxidase antibody (TPOAb) positivity was higher in never smoker (7.7%) than past smokers (5.1%) and current smokers (4.7%), but sex-specific rate of TPOAb was not different according to smoking status. The lower serum TSH levels in current smokers were more apparent in iodine-deficient subjects (UIC < 100 µg/L), and this change was diminished in subjects with UICs between 100 and 299 µg/L. The difference in serum TSH levels in current smokers disappeared in subjects with UICs ≥ 300 µg/L. CONCLUSIONS: Smoking is associated with a left-shift in serum TSH level that is more apparent in iodine-deficient subjects. Smoking status is not associated with the presence of TPOAb or iodine intake. The results suggest that smoking has a direct effect on thyroid function that is not mediated by autoimmune processes in the thyroid gland.

Influence of coexistent Hashimoto's thyroiditis on the extent of cervical lymph node dissection and prognosis in papillary thyroid carcinoma.

OBJECTIVE: Previous studies did not focus on the differences in the extent of cervical lymph node (LN) dissection according to coexistent Hashimoto's thyroiditis (HT) in patients with papillary thyroid carcinoma (PTC) and its clinical impact. We aimed to determine whether extensive cervical LN dissection is responsible for favourable clinical outcomes in PTC patients with HT and whether the coexistence of HT itself has an independent protective effect regardless of LN status. DESIGN: Retrospective cohort study. PATIENTS: 1369 patients with PTC who underwent total thyroidectomy with central compartment neck dissection. MEASUREMENTS: Metastatic LN ratio, defined as number of metastatic LNs divided by number of removed LNs, was used to evaluate the extent of LN dissection as well as the status of LN metastasis. Disease-free survival and dynamic risk stratification were compared for clinical outcomes. RESULTS: Presence of HT did not lower the risk of cervical LN metastasis (61.6% in patients with HT vs 65.1% in patients without HT, P = .292). Patients with HT had significantly larger numbers of removed LNs than patients without HT (11 vs 8, respectively, P < .001). Accordingly, metastatic LN ratio was smaller in patients with HT (P = .002), which was independently associated with structural persistent/recurrent disease (hazard ratio [HR] 2.33, 95% confidence interval [CI] 1.30-4.16, P = .004). HT itself was negatively associated with structural persistent/recurrent disease after adjustment for other clinicopathological factors (HR 0.39, 95% CI 0.18-0.87, P = .020). CONCLUSIONS: Coexistence of HT itself is an independent factor associated with favourable outcome in PTC patients, regardless of the extent of LN dissection.

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.

Association between urinary sodium levels and iodine status in Korea.

BACKGROUND/AIMS: To evaluate the association between the urinary sodium concentration and iodine status in different age groups in Korea. METHODS: This nationwide, population-based, cross-sectional study used data from the Korean National Health and Nutrition Examination Survey (VI 2-3, 2014 to 2015). We included 3,645 subjects aged 10 to 75 years with normal kidney function and without a history of thyroid disease. Adequate iodine intake was defined as a urinary iodine/creatinine (I/Cr) ratio of 85 to 220 µg/g. The urinary sodium/ creatinine (Na/Cr) ratios were classified as low (< 47 mmol/g), intermediate (47 to 114 mmol/g), or high (> 114 mmol/g). RESULTS: The median urinary iodine concentration (UIC) was 292 µg/L (interquartile range [IQR], 157 to 672), and the median urinary I/Cr ratio was 195 µg/g (IQR, 104 to 478). Iodine deficiency (< 100 µg/L) and iodine excess (> 300 µg/L) were observed in 11.3% and 49.0% of subjects, respectively. The UIC was significantly associated with the urinary sodium concentration, and the urinary I/Cr ratio was significantly correlated with the urinary Na/Cr ratio (both p < 0.001). The distributions of UIC, urinary I/Cr ratio, and Na/Cr ratio varied among age groups. Low urinary I/Cr and Na/Cr ratios were most common in young adults (age, 19 to 29 years), while high urinary I/Cr and Na/Cr ratios were most common in elderly people (age, 60 to 75 years). CONCLUSION: Iodine intake was significantly associated with sodium intake in the Korean population. Our study suggested that an adequately low salt intake might be helpful for preventing iodine excess in Korea.

Modified Transverse-Vertical Gross Examination: a Better Method for the Detection of Definite Capsular Invasion in Encapsulated Follicular-Patterned Thyroid Neoplasms.

The diagnosis of encapsulated follicular-patterned thyroid carcinoma (EFPTC) is challenging, and the detection of capsular invasion and/or vascular invasion is essential in distinguishing benign lesions from malignant lesions. In this study, we present a modified transverse-vertical gross examination method with additional vertical cuts at the upper and lower ends of thyroid nodules. In addition, we compared the clinicopathological characteristics of patients with EFPTC between conventional and modified methods. The diagnostic rate of follicular thyroid carcinoma and invasive encapsulated follicular variant of papillary thyroid carcinoma was higher with the modified method (p = 0.003 and p = 0.028, respectively). Furthermore, the paraffin block number and the number of capsular invasion per centimeter were significantly higher with the modified method (p < 0.001 and p = 0.007, respectively). However, vascular invasion was not significantly different between the two methods (p = 0.771). The possibility of identifying capsular invasion was around two times higher with the modified method (odds ratio = 1.91, 95% confidence interval = 1.20-3.07, p = 0.007). A total of 38 samples (23%) in the modified transverse-vertical group had capsular and/or vascular invasion in the additional vertical cuts of the upper/lower ends of the tumor. Our modified transverse-vertical gross examination method was more effective than the conventional transverse examination method for the detection of capsular invasion in EFPTC. This modified gross examination method might allow a better differential diagnosis among various encapsulated micro-follicular proliferative lesions.

Tumor Volume Doubling Time in Active Surveillance of Papillary Thyroid Carcinoma.

Background: Tumor volume (TV) of papillary thyroid carcinoma (PTC) increases exponentially during active surveillance, and the growth rate differs for each patient. TV doubling time (TVDT) is considered a strong dynamic marker for the prediction of the growth rate and progression of the tumor. Methods: This cohort study analyzed 273 PTC patients who underwent active surveillance for more than one year rather than immediate thyroid surgery. TVDT was calculated in each patient, and patients were divided into two groups: rapid-growing (TVDT <5 years) and stable (TVDT ≥5 years). Clinical and initial ultrasonography (US) features between the two groups were compared. Results: The median patient age was 51.1 years (interquartile range [IQR] 42.2-61.0 years), and 76% of the patients were women. The initial TV of PTC was 62.1 mm3 (IQR 28.1-122.8 mm3). During a median of 42 months (IQR 29-61 months) of active surveillance, 10.3% of the patients had a TVDT of less than two years, 5.1% had a TVDT between two and three years, 6.2% had a TVDT between three and four years, 6.6% had a TVDT between four and five years, and 71.8% had a TVDT of five years or more. Patients in the rapid-growing group (77 patients; 28.2%) were significantly younger (p = 0.004) than those in the stable group (196 patients; 71.8%). Being younger than 50 years of age was significantly associated with rapid tumor growth of PTC (odds ratio = 2.31 [confidence interval 1.30-4.31], p = 0.004) in multivariate analysis. In ultrasound findings, macrocalcification was independently associated with rapid tumor growing of PTCs (odds ratio = 4.98 [confidence interval 2.19-11.69], p < 0.001). Conclusions: TVDT is a good indicator for presenting the growing velocity of PTCs during active surveillance. Younger age and macrocalcification in the initial US were associated with rapid-growing PTCs. Determination of TVDT during the early phase of active surveillance may be helpful for the prediction of rapidly progressing PTCs and deciding whether to adopt an early surgical approach.

Low Lymphocyte-to-Monocyte Ratios Are Associated with Poor Overall Survival in Anaplastic Thyroid Carcinoma Patients.

Background: The lymphocyte-to-monocyte ratio (LMR), which reflects the tumor-infiltrating immune cell status and host immunity, has been reported as a prognostic marker in various cancers. The aim of the present study was to evaluate the role of the LMR as a prognostic marker in predicting the survival of patients with anaplastic thyroid carcinoma (ATC). Methods: This study retrospectively included 35 ATC patients with available complete blood cell count data. The primary outcome was the overall survival (OS) of patients with ATC. Results: There were no significant differences between the LMR of the baseline and that of the follow-up complete blood cell count data (p = 0.53). The patients were divided into two groups based on their baseline LMR: a low LMR group (<4; n = 23, 66%) and a high LMR group (≥4; n = 12, 34%). The proportion of cervical lymph node metastasis in the low LMR group was significantly higher than that in the high LMR group (p = 0.021). The OS curves were significantly different based on the LMR values, and the median OS of the low and high LMR groups were 3.0 and 9.5 months, respectively (p = 0.004). In multivariate analysis, a low LMR was also an independent risk factor for all-cause mortality in patients with ATC (hazard ratio = 2.55 [confidence interval 1.08-6.00], p = 0.032) after adjusting for sex, tumor size, and distant metastasis. Conclusions: A low LMR is associated with poor survival in patients with ATC. The LMR could be a simple and stable prognostic biomarker reflecting host immunity in patients with ATC. Further studies are needed to confirm the prognostic role of the LMR in ATC.

A Relook at the T Stage of Differentiated Thyroid Carcinoma with a Focus on Gross Extrathyroidal Extension.

BACKGROUND: The recently published eighth edition of the American Joint Committee on Cancer (AJCC) staging system has emphasized the importance of gross extrathyroidal extension (gETE) while classifying the tumor (T) stage in differentiated thyroid carcinoma (DTC). However, the clinical impact of gETE invading only the strap muscles or the recurrent laryngeal nerve (RLN) remains unclear due to scarce and conflicting data. METHODS: A retrospective cohort study was carried out in patients with DTC who underwent thyroid surgery from 1996 to 2005. In total, 3104 patients were included, and disease-specific survival (DSS) was compared according to the degree of gETE, with a median follow-up duration of 10 years. RESULTS: Patients with gETE invading only the strap muscles and with a tumor size ≤4 cm (T3b [≤4 cm]) showed no difference in DSS compared to patients with T2 stage disease (hazard ratio [HR] = 0.81 [confidence interval (CI) 0.24-2.77]; p = 0.737) but rather showed a better DSS than patients with T3a disease (HR = 0.19 [CI 0.05-0.72]; p = 0.014). Conversely, patients with gETE invading to the posterior direction showed significantly poorer DSS than patients with T3 stage disease, even when only the RLN was invaded (HR = 7.78 [CI 3.41-17.75]; p < 0.001). However, there was no difference in DSS between gETE invading only the RLN and that invading other posterior organs beyond the RLN (p = 0.563). A modified T classification was suggested to downgrade patients with T3b (≤4 cm) disease to the T2 stage, which revealed higher predictability of survival than the T classification according to the eighth edition of the American Joint Committee on Cancer tumor-node-metastasis staging system (proportion of variation explained: 3.6% vs. 2.65%). CONCLUSIONS: gETE invading only the strap muscles did not significantly affect DSS, while that invading the posterior organs significantly affected DSS, even when only the RLN was invaded. The data support the applicability of downgrading patients with T3b (≤4 cm) disease to the T2 stage for a better predictability of survival.

Individualized Follow-Up Strategy for Patients with an Indeterminate Response to Initial Therapy for Papillary Thyroid Carcinoma.

BACKGROUND: The concept of a dynamic risk-stratification scheme has been suggested for individualized management of patients with papillary thyroid carcinoma (PTC). However, there is no specified follow-up strategy for patients with an indeterminate response. METHODS: This study evaluated 403 PTC patients who had an indeterminate response during the first 12-24 months after initial therapy. All patients underwent total thyroidectomy with radioactive iodine remnant ablation. Patients were further classified into three groups based on risk of structural persistence/recurrence: a Tg+ group (detectable thyroglobulin [Tg], regardless of antithyroglobulin antibody [TgAb] or imaging findings; 196 patients), a TgAb+ group (positive results for TgAb with undetectable Tg, regardless of imaging findings; 46 patients), and an Image+ group (nonspecific findings on neck ultrasonography or faint uptake in the thyroid bed on whole-body scan, with undetectable Tg and negative results for TgAb; 161 patients). RESULTS: With a median of 9.6 years (interquartile range 7.7-11.2 years) of follow-up, 56 (14%) PTC patients had structural persistent/recurrent disease: 50 (89%) at locoregional sites and six (11%) at distant sites. The recurrence rate in Tg+, TgAb+, and Image + groups were 26.5%, 8.7%, and 0%, respectively. The median time to detection of structural persistent/recurrent disease from the initial thyroid surgery was 3.7 years (interquartile range 2.5-6.3 years). The optimal cutoff stimulated Tg level to predict structural persistent/recurrent disease was 3.1 ng/mL in the Tg+ group. This classification system revealed higher predictability of structural persistent/recurrent disease than the tumor-node-metastasis staging system and American Thyroid Association risk stratification (proportion of variation explained: 15.7% vs. 2.4% and 0.9%, respectively). Six (3%) patients with distant metastatic disease were all classified in the Tg+ group, and all had lung metastasis. CONCLUSIONS: The findings suggest a more individualized follow-up strategy for patients with an indeterminate response. More careful evaluation, including early evaluation of distant metastasis, is necessary in patients with elevated Tg levels. However, for patients testing positive for TgAb or those with only nonspecific imaging findings, regular follow-ups of Tg and TgAb levels and neck ultrasonography are sufficient.

When should antithyroid drug therapy to reduce the relapse rate of hyperthyroidism in Graves' disease be discontinued?

OBJECTIVE: The use of antithyroid drug (ATD) therapy in patients with Graves' disease (GD) hyperthyroidism has been increasing, but ATD therapy is associated with a higher relapse rate. We aimed to evaluate clinical factors for predicting relapse of GD after ATD therapy. METHODS: Patients (n = 149) with newly diagnosed GD who achieved remission of hyperthyroidism after ATD therapy (≥6 months) were followed up for >18 months after ATD withdrawal. We evaluated the predictive factors of relapse during a median of 6.9 years of follow-up. RESULTS: Disease relapse occurred in 52 patients (34.9%). By multivariate analyses, a duration of the minimum maintenance dose therapy (MMDT) of <6 months was a significant factor in disease relapse (hazard ratio [HR], 2.58; 95% confidence interval [CI], 1.47-4.52; p < 0.001), and a T3/free T4 (fT4) ratio > 120 at ATD withdrawal was significantly more frequent in patients with relapse (HR 2.43; 95% CI, 1.36-4.34; p = 0.002). In the prediction-of-relapse model, the likelihood of relapse was greater in the high-risk group, which had a short MMDT duration and a T3/fT4 ratio ≥120 (HR, 5.81; 95% CI, 2.52-13.39; p < 0.001) and the intermediate-risk group, which had a short MMDT duration or a T3/fT4 ratio < 120 (HR, 2.77; 95% CI, 1.26-6.13; p < 0.001), than in the low-risk group, which had a long MMDT duration and a T3/fT4 ratio < 120. CONCLUSION: An MMDT longer than 6 months and a high T3/fT4 ratio at ATD withdrawal were independent predictors of relapse in patients who achieved initial remission after ATD for GD. These factors could be used to determine the optimal time to withdraw ATD during the treatment of GD hyperthyroidism.

Sex-Dependent Association between Weight Change and Thyroid Dysfunction: Population-Level Analysis Using the Korean National Health and Nutrition Examination Survey.

BACKGROUND: Although body weight change (BWC) is a common manifestation of thyroid dysfunction, solid evidence for whether to perform or on whom to perform thyroid function test in subjects complaining of BWC is lacking. OBJECTIVE: To evaluate the association between thyroid dysfunction and BWC using a nationwide survey. METHOD: Data was obtained from the Korea National Health and Nutrition Examination Survey VI 2013-2015 and 5,456 subjects without previous thyroid disease were included. Serum thyroid-stimulating hormone (TSH), free T4, and self-reported BWC during the previous year were used for the evaluation. Weight loss or gain was defined as weight change of at least 3 kg. RESULTS: In total, 1,017 men (37.3%) and 1,175 women (43.0%) reported BWCs during the previous year. The overall weighted prevalence of thyroid dysfunction was not significantly associated with the extent of BWC in men (p = 0.705) or women (p = 0.094). However, when the impact of TSH levels on weight change was separately evaluated for weight gain and loss after adjusting for age and body mass index in each sex, weight loss in women was significantly associated with TSH levels (hazard ratio 0.64, 95% CI 0.47-0.85, p = 0.03). No association of thyroid dysfunction was observed for weight gain in women (p = 0.23) or any changes in men (p = 0.875 in weight gain, p = 0.923 in weight loss). CONCLUSIONS: This study highlights the necessity of performing thyroid function testing in women who complain of weight loss, but such testing may be less vital in women with weight gain or men with any changes in weight.

Lobectomy Is Feasible for 1-4 cm Papillary Thyroid Carcinomas: A 10-Year Propensity Score Matched-Pair Analysis on Recurrence.

BACKGROUND: Current guidelines allow lobectomy as treatment for 1-4 cm papillary thyroid carcinomas (PTCs), as previous studies reported no clear survival advantages for total thyroidectomy (TT). However, data on recurrence based on surgical extent are limited. METHODS: This study enrolled 2345 patients with 1-4 cm PTC. Those with lateral cervical lymph node metastasis or initial distant metastasis were excluded. Disease-free survival (DFS) was compared after 1:1 propensity score matching by age, sex, tumor size, extrathyroidal extension, multifocality, and cervical lymph node metastasis. RESULTS: Lobectomy was performed in 383 (16.3%) and TT in 1962 (83.7%) patients. In the matched-pair analysis (381 patients in each group), no significant difference in DFS was observed during the median follow-up of 9.8 years (hazard ratio [HR] = 1.35 [confidence interval (CI) 0.40-1.36], p = 0.33). When stratified by tumor size, DFS did not differ between the group with 1-2 cm tumors and that with 2-4 cm tumors (HR = 1.57 [CI 0.75-3.25], p = 0.228; HR = 0.93 [CI 0.30-2.89], p = 0.902, respectively). Multivariate analysis showed that the surgical extent did not play an independent role in structural persistent/recurrent disease development (HR = 1.43 [CI 0.72-2.83], p = 0.306). CONCLUSION: Patients with 1-4 cm PTCs who underwent lobectomy exhibited DFS rates similar to those who underwent TT after controlling for major prognostic factors. This supports the feasibility of lobectomy as initial surgical approach for these patients and emphasizes that tumor size should not be an absolute indication for TT.

Time trends of thyroglobulin antibody in ablated papillary thyroid carcinoma patients: Can we predict the rate of negative conversion?

OBJECTIVES: Persistence of thyroglobulin antibody (TgAb) in patients with papillary thyroid carcinoma (PTC) years after total thyroidectomy (TT) followed by ablation occurs even without any evidence of structural disease. Few studies have studied the natural course of TgAb positivity and factors that may influence this course. The present study evaluated the time trends of TgAb in ablated PTC patients and aimed to identify the predictive factors for the rate of negative conversion of TgAb. MATERIALS AND METHODS: Overall, 1279 patients who underwent TT and subsequent ablation for PTC, with available data on thyroid peroxidase Ab (TPOAb) and TgAb prior to surgery (preop-) and ablation (abl-) were enrolled. Patients with initial distant metastasis or recurrence during follow-up were excluded. RESULTS AND CONCLUSION: Preop-TgAb was positive in 24.9% of patients (n = 319), whereas abl-TgAb positivity decreased to 12.8% (n = 164). In 164 patients positive for abl-TgAb, TgAb in patients with higher abl-TgAb levels decreased more gradually than those observed in patients with lower abl-TgAb levels (p < 0.001). Furthermore, in patients within the same range of abl-TgAb levels, patients positive for abl-TPOAb had a higher rate of negative conversion of TgAb compared with negative patients for abl-TPOAb (log rank p < 0.001). TPOAb significantly increased the rate of negative conversion in multivariate analysis adjusted for abl-TgAb (odds ratio 1.59, 95% confidence interval 1.11-2.28, p = 0.011). This study clearly showed that abl-TgAb titers and abl-TPOAb status can predict the rate of negative conversion. These findings can guide the optimal timing for additional examination in patients positive for TgAb during follow-up.

Extended Real-World Observation of Patients Treated with Sorafenib for Radioactive Iodine-Refractory Differentiated Thyroid Carcinoma and Impact of Lenvatinib Salvage Treatment: A Korean Multicenter Study.

Background: Treatment for patients with radioactive iodine (RAI)-refractory differentiated thyroid carcinoma (DTC) is challenging. Recently, two tyrosine kinase inhibitors (sorafenib and lenvatinib) have been approved and showed benefits for progression-free survival with tolerable adverse events. Methods: This is an extension study of a previous multicenter, retrospective cohort study of real-world experience in treating 98 patients with progressive RAI-refractory DTC with sorafenib. The primary endpoint was overall survival (OS). The efficacy of lenvatinib as salvage therapy after disease progression on first-line sorafenib was evaluated by comparing outcomes in 32 patients who were treated with lenvatinib with 41 patients who were not and therefore served as a no salvage treatment group. Results: The median OS of all 98 patients treated with sorafenib was 41.5 months, and the median progression-free survival was 13.5 months. Patients without disease-related symptoms before sorafenib treatment had better OS than those with symptoms (hazard ratio [HR] = 0.56 [95% confidence interval, CI 0.31-0.99], p = 0.048). Larger tumor size was associated with a minimally increased risk of death (HR = 1.02 [CI 1.00-1.03], p = 0.049). Best tumor response was not associated with OS (p = 0.490). Lenvatinib salvage treatment significantly improved OS in patients receiving it compared with those who did not (HR = 0.28 [CI 0.15-0.53], p < 0.001). The median OS from the time of disease progression after first-line sorafenib treatment was 4.9 months in no salvage treatment group, whereas it was not reached in the lenvatinib salvage group. Conclusions: The absence of disease-related symptoms and smaller tumor burden was associated with survival benefits of first-line sorafenib treatment in patients with progressive RAI-refractory DTC. Lenvatinib salvage therapy was effective in improving OS in patients with disease progression after first-line sorafenib.

A Follow-Up Strategy for Patients with an Excellent Response to Initial Therapy for Differentiated Thyroid Carcinoma: Less Is Better.

BACKGROUND: The risk of recurrence in patients with differentiated thyroid cancer (DTC) can be estimated based on their response to initial therapy. The aim of this study was to evaluate an adequate follow-up strategy for DTC patients with an excellent response by assessing the characteristics of structural recurrence. METHODS: This historical cohort study included 1359 DTC patients who had excellent response to total thyroidectomy with radioactive iodine remnant ablation. RESULTS: Among 1359 patients, 703 (54%) patients were classified as stage I according to the seventh tumor node metastasis staging system, and 987 (73%) patients were classified as intermediate risk according to the American Thyroid Association's risk stratification after initial therapy. During a median of 8.7 years of follow-up, only 13 (1%) patients were confirmed to have structural recurrence. All of the recurrences were locoregional disease, and there were no distant metastases. Recurrences were detected late at a median of 5.5 years after the initial surgery (range 3.6-10.7 years). All structural recurrences were detected on neck ultrasonography. Non-stimulated serum thyroglobulin (Tg) was detectable (≥0.2 ng/mL) in four (31%) patients, and serum anti-Tg antibodies were positive in one (8%) patient. However, non-stimulated serum Tg levels were stably low (<0.2 ng/mL) in eight (62%) patients when recurrences were detected. In addition to these 13 patients, 14 patients also presented with biochemical persistent disease at the end of follow-up. CONCLUSIONS: Recurrences of DTC in patients with an excellent response to initial therapy were detected relatively late. The intensity and frequency of follow-up of neck ultrasonography as well as serum Tg and anti-Tg antibody measurements should be reduced, especially within five years of the initial therapy, in DTC patients who have an excellent response.

Comparison of Immunohistochemistry and Direct Sanger Sequencing for Detection of the BRAF(V600E) Mutation in Thyroid Neoplasm.

BACKGROUND: The BRAF(V600E) mutation is the most common genetic alteration identified in papillary thyroid carcinoma (PTC). Because of its costs effectiveness and sensitivity, direct Sanger sequencing has several limitations. The aim of this study was to evaluate the efficiency of immunohistochemistry (IHC) as an alternative method to detect the BRAF(V600E) mutation in preoperative and postoperative tissue samples. METHODS: We evaluated 71 patients who underwent thyroid surgery with the result of direct sequencing of the BRAF(V600E) mutation. IHC staining of the BRAF(V600E) mutation was performed in 49 preoperative and 23 postoperative thyroid specimens. RESULTS: Sixty-two patients (87.3%) had PTC, and of these, BRAF(V600E) was confirmed by direct sequencing in 57 patients (91.9%). In 23 postoperative tissue samples, the BRAF(V600E) mutation was detected in 16 samples (70%) by direct sequencing and 18 samples (78%) by IHC. In 24 fine needle aspiration (FNA) samples, BRAF(V600E) was detected in 18 samples (75%) by direct sequencing and 16 samples (67%) by IHC. In 25 core needle biopsy (CNB) samples, the BRAF(V600E) mutation was detected in 15 samples (60%) by direct sequencing and 16 samples (64%) by IHC. The sensitivity and specificity of IHC for detecting the BRAF(V600E) mutation were 77.8% and 66.7% in FNA samples and 99.3% and 80.0% in CNB samples. CONCLUSION: IHC could be an alternative method to direct Sanger sequencing for BRAF(V600E) mutation detection both in postoperative and preoperative samples. However, application of IHC to detect the BRAF(V600E) mutation in FNA samples is of limited value compared with direct sequencing.

BRAF and RAS Mutational Status in Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features and Invasive Subtype of Encapsulated Follicular Variant of Papillary Thyroid Carcinoma in Korea.

BACKGROUND: Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is an indolent thyroid tumor previously known as noninvasive subtype of encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC). The absence of BRAFV600E mutations has been considered characteristic of NIFTPs. However, a recent study from Korea found that 28.6% of NIFTPs harbored a BRAF mutation. This study evaluated BRAF and RAS mutations in NIFTPs and invasive subtype of EFVPTCs. METHODS: This study enrolled 32 patients with NIFTP and 48 with invasive EFVPTC. BRAF, NRAS, HRAS, and KRAS mutations were evaluated by direct sequencing using DNA from fresh-frozen tissues and formalin-fixed, paraffin-embedded tissue samples. RESULTS: The primary tumor size of NIFTP was smaller than that of invasive EFVPTC (median 2.8 cm vs. 3.2 cm; p = 0.03). Cervical lymph node metastases were found in only four (8%) patients with invasive EFVPTC. There was no BRAF mutation in NIFTPs, whereas invasive EFVPTCs had three (6%) BRAFV600E mutations and one (2%) BRAFK601E mutation. RAS mutations were detected in 15 (47%) NIFTPs and 22 (46%) invasive EFVPTCs. NRAS mutations in codon 61 were the most common mutations in NIFTPs (34%) and invasive EFVPTCs (27%). There was no significant difference in the frequency of RAS mutations between the two groups. CONCLUSIONS: There was no BRAF mutation in any of the NIFTPs. RAS mutations, particularly mutations in codon 61 of NRAS, were the most common mutations in both NIFTPs and invasive EFVPTCs. The presence of a RAS mutation is not helpful for preoperative differentiation between NIFTPs and invasive EFVPTCs.

Association Between Thyroid Dysfunction and Lipid Profiles Differs According to Age and Sex: Results from the Korean National Health and Nutrition Examination Survey.

BACKGROUND: Lipid profiles of men and women change differently during the aging process. Guidelines recommend that dyslipidemia patients should consider screening for hypothyroidism without consideration of age or sex. METHODS: Data from the sixth Korean National Health and Nutrition Examination Survey were used. A total of 4275 participants without thyroid disease and without a past history of dyslipidemia or dyslipidemia medication were evaluated. The association between thyroid dysfunction and lipid profiles (total cholesterol [TC], low-density lipoprotein cholesterol [LDLC], and triglycerides [TG]) was analyzed by age and sex. RESULTS: The prevalence of thyroid dysfunction was significantly different according to TC and LDLC levels (p = 0.003 and p = 0.021, respectively). In women, the weighted prevalence of thyroid dysfunction was significantly different according to levels of TC, LDLC, and TG (p = 0.007, p = 0.016, and p = 0.044, respectively). However, in men, no association was found in any of the lipid profiles. Female participants were divided into two groups using a cutoff age of 55 years. In younger women, the weighted prevalence of thyroid dysfunction was different according to the levels of TC, LDLC, and TG (p = 0.013, p = 0.007, and p = 0.007, respectively). However, in older women, no association was found for any of the lipid profiles. CONCLUSIONS: The prevalence of thyroid dysfunction was significantly different according to lipid profiles, and this association differed by age and sex.