Prognostic value of postoperative anti-thyroglobulin antibody in patients with differentiated thyroid cancer.

Purpose: Postoperative thyroglobulin (Tg) generally serves as a biomarker to monitor the recurrence or persistence of differentiated thyroid cancer (DTC), whereas it constrains to interference from anti-thyroglobulin antibody (TgAb). This study aimed to determine the value of postoperative TgAb as a surrogate for monitoring tumor status in DTCs with positive TgAb after successful radioactive iodine (RAI) remnant ablation. Methods: We retrospectively enrolled DTC patients with positive (≥40 IU/mL, Roche) postoperative TgAb measurements. An index of TgAb change (ΔTgAb) was defined to describe the TgAb decrease rate. DTC status was defined as either no evidence of disease (NED) or persistent/recurrent disease (PRD). Univariate and multivariate binary logistic analyses were used to identify the independent risk factors of PRD. Receiver operating characteristic (ROC) curves were performed to determine the optimal cutoff values of each risk factor, and DeLong's test was conducted to compare their predictive powers. Kaplan-Meier curves were used to assess the impact of different TgAb trends in the first year on progression-free survival. Results: Of the 232 patients enrolled, the median diagnosis age was 34 years (range, 18-62 years), with a male-to-female ratio of 1:4.66 (41/191). Among them, after a median follow-up of 44 months (range, 4-128 months),183 (78.87%) patients were evaluated as NED, while the other 49 (21.12%) had either persistent (n = 25) or recurrent disease (n = 24). Multivariate regression showed that ΔTgAb (P < 0.001) and lymph node metastasis (LNM) rate (P = 0.009) were independently relevant to the presence of PRD, with optimal cutoff values of 47.0% and 35.1%, respectively. It is important to note that there is a high negative predictive value (96.93%) of ΔTgAb with the cutoff of 47.0%. DeLong's test showed that ΔTgAb alone and the combination of ΔTgAb and LNM rate were significantly greater than the isolated LNM rate (both P < 0.001) in predicting NED, while there was no statistical difference of the predictive power between ΔTgAb and the combination (P = 0.203). Additionally, patients with ΔTgAb >47.0% had longer progression-free survival than those with ΔTgAb ≤47.0% (not reached vs. 50 months, P < 0.001), and those with ΔTgAb >47.0% or negative conversion within the first year after RAI ablation had longer progression-free survival. Conclusion: Our study suggested that ΔTgAb could serve as a valuable indicator of disease status in DTC patients with positive TgAb. A ΔTgAb of >47.0% is conducive to identify those with NED and may help to obviate their overtreatment. The decrease rate and negative conversion of TgAb in the first year were good predictors of disease-free survival in patients.

Time Kinetics and prognosis roles of calcitonin after surgery for medullary thyroid carcinoma.

BACKGROUND: Medullary thyroid carcinoma (MTC) is a malignant tumor with low incidence. Currently, most studies have focused on the prognostic risk factors of MTC, whatever, time kinetic and risk factors related to calcitonin normalization (CN) and biochemical persistence/recurrence (BP) are yet to be elucidated. METHODS: A retrospective study was conducted for 190 MTC patients. Risk factors related to calcitonin normalization (CN) and biochemical persistence/recurrence (BP) were analyzed. The predictors of calcitonin normalization time (CNT) and biochemical persistent/recurrent time (BPT) were identified. Further, the prognostic roles of CNT and BPT were also demonstrated. RESULTS: The 5- and 10-year DFS were 86.7% and 70.2%, respectively. The 5- and 10-year OS were 97.6% and 78.8%, respectively. CN was achieved in 120 (63.2%) patients, whereas BP was presented in 76 (40.0%) patients at the last follow up. After curative surgery, 39 (32.5%) and 106 (88.3%) patients achieved CN within 1 week and 1 month. All patients who failed to achieve CN turned to BP over time and 32/70 of them developed structural recurrence. The median time of CNT and BPT was 1 month (1 day to 84 months) and 6 month (3 day to 63months), respectively. LNR > 0.23 and male gender were independent predictors for CN and BP. LNR > 0.23 (Hazard ratio (HR), 0.24; 95% CI,0.13-0.46; P < 0.01) and male gender (HR, 0.65; 95% CI, 0.42-0.99; P = 0.045) were independent predictors for longer CNT. LNR > 0.23 (HR,5.10; 95% CI,2.15-12.11; P < 0.01) was still the strongest independent predictor followed by preoperative serum Ctn > 1400ng/L (HR,2.34; 95% CI,1.29-4.25; P = 0.005) for shorter BPT. In survival analysis, primary tumor size > 2 cm (HR, 5.81; 95% CI,2.20-15.38; P < 0.01), CNT > 1 month (HR, 5.69; 95% CI, 1.17-27.61; P = 0.031) and multifocality (HR, 3.10; 95% CI, 1.45-6.65; P = 0.004) were independent predictor of DFS. CONCLUSION: Early changes of Ctn after curative surgery can predict the long-term risks of biochemical and structural recurrence, which provide a useful real-time prognostic information. LNR significantly affect the time kinetic of biochemical prognosis. Tumor burden and CNT play a crucial role in MTC survival, the intensity of follow-up must be tailored accordingly.

Spontaneous and Treatment-Related Changes of Serum Calcitonin in Medullary Thyroid Cancer: Long-Term Experience in a Patient With Multiple Endocrine Neoplasia Type 2B.

PURPOSE: Medullary thyroid carcinoma (MTC) in MEN2B syndrome is associated with germline RET mutation. Patients harboring de novo mutations are usually diagnosed at more advanced disease stages. We present a young woman with Met918Th mutation diagnosed with stage IV MTC at age 10 years. METHODS: The disease progressed despite total thyroidectomy and multiple surgical interventions for cervical lymph node recurrences, leading to distant metastases in the fifth year after the initial diagnosis. Subsequently, she underwent five different types of tyrosine kinase inhibitor (TKI) treatments. The 17-year disease course was divided into periods defined by four surgical interventions and sequential treatment intervals with four multikinase (sunitinib, vandetanib, cabozantinib, and lenvatinib) and one RET-selective TKI (selpercatinib). Tumor growth for different phases of spontaneous development and drug treatment intervals was characterized by changes in serial log-transformed calcitonin measurements (n = 114). RESULTS: Three operations (one for calcitonin-producing adrenal pheochromocytoma) were associated with drops in calcitonin levels. All of the nonselective TKIs were stopped due to adverse effects. As reflected by the negative calcitonin doubling rate, the best treatment response was observed with selpercatinib, which was associated with an initial large drop followed by a decreasing calcitonin trajectory over 514 days without any major side effects. CONCLUSION: This case of MEN2B medullary thyroid cancer with long-term survival presents how the effectiveness of different treatment modalities can be estimated using log-transformed calcitonin levels. Furthermore, our experience supports the view that serial calcitonin measurements may be more sensitive than radiological follow-up in advanced MTC. Our patient also represents a new case of rarely reported calcitonin-producing pheochromocytomas.

The clinical value of iodine-125 seed implantation in the treatment of iodine-refractory differentiated thyroid carcinoma.

Objective: To explore the clinical benefits of 125I seed implantation for iodine-refractory differentiated thyroid cancer (RAIR-DTC). Methods: A retrospective analysis was conducted on 36 patients with RAIR-DTC who underwent radioactive 125I seed implantation from January 2015 to February 2022, involving 73 lesions. Prescription dose: 80~120 Gy. All cases were followed up at 1, 3, and 5 months postoperatively to monitor changes in tumor size, serum thyroglobulin (Tg), and serum anti-thyroglobulin antibody levels in thyrotropin-inhibited states, pain scores, and postoperative adverse reactions. The data were processed and analyzed using IBM SPSS 26.0. LER (Local Effective Rate) and LCR (Local Control Rate) were expressed as n (%), tumor diameter, Tg, and pain scores were represented as Median (Q1, Q3). Pairwise comparisons were conducted using the Wilcoxon signed-rank test, and a p-value of less than 0.05 indicated statistical significance. Results: Tumor size was significantly reduced after treatment (all P < 0.001): tumor length diameters were 32.67 (17.70, 45.72) mm, 27.45 (12.30, 39.98) mm, 20.70 (11.98, 37.58) mm, and 20.39 (10.56, 33.20) mm in the preoperative, 1-, 3-, and 5-months postoperative periods, respectively. Additionally, two consecutive post-treatment results were more minor and statistically significant than the previous results (P < 0.001). The LER at 1-, 3-, and 5-months post-surgery was 23.73%, 38.98%, and 52.54%, respectively, while the LCR at the same time points was 98.31%, 96.61%, and 94.92%, respectively. Patients' serum Tg levels decreased significantly after surgery. (P < 0.001). Serum Tg levels were measured before surgery and 1-, 3-, and 5-months post-surgery. The results showed that serum Tg levels were 249.45 (79.39, 4718.75) ng/ml, 193.40 (44.53, 2829.00) ng/ml, 192.10 (25.58, 1758.00) ng/ml, and 136.25 (16.57, 1553.25) ng/ml, respectively. Two consecutive post-treatment results were more minor and statistically significant than the previous results (P < 0.001). The patients' pain symptoms were significantly relieved after 125I brachytherapy (P < 0.001). The pain scores before 125I seed implantation and at 1, 3, and 5 months after the operation were 5.00 (4.00, 6.00), 3.00 (2.25, 4.00), 2.00 (2.00, 3.00), and 2.00 (1.00, 3.00), respectively. Conclusion: Most lesions treated with 125I seed implantation in RAIR-DTC patients showed shrinkage and improved pain symptoms. Clinical trial registration: https://www.clinicaltrials.gov, identifier NCT06362772.

Thyroid cancer and endocrine disruptive chemicals: a case-control study on per-fluoroalkyl substances and other persistent organic pollutants.

Objective: The aim was to evaluate the possible association between some endocrine disruptive chemicals and thyroid cancer (TC) in an Italian case-control cohort. Methods: We enrolled 112 TC patients and 112 sex- and age-matched controls without known thyroid diseases. Per- and poly-fluoroalkyl substances (PFAS), poly-chlorinated biphenyls (PCBs), and dichlorodiphenyltrichloroethane (4,4'-DDT and 4,4'-DDE) were measured in the serum by liquid or gas chromatography-mass spectrometry. Unconditional logistic regression, Bayesan kernel machine regression and weighted quantile sum models were used to estimate the association between TC and pollutants' levels, considered individually or as mixture. BRAFV600E mutation was assessed by standard methods. Results: The detection of perfluorodecanoic acid (PFDA) was positively correlated to TC (OR = 2.03, 95% CI: 1.10-3.75, P = 0.02), while a negative association was found with perfluorohexanesulfonic acid (PFHxS) levels (OR = 0.63, 95% CI: 0.41-0.98, P = 0.04). Moreover, perfluorononanoic acid (PFNA) was positively associated with the presence of thyroiditis, while PFHxS and perfluorooctane sulfonic acid (PFOS) with higher levels of presurgical thyroid-stimulating hormone (TSH). PFHxS, PFOS, PFNA, and PFDA were correlated with less aggressive TC, while poly-chlorinated biphenyls (PCB-105 and PCB-118) with larger and more aggressive tumors. Statistical models showed a negative association between pollutants' mixture and TC. BRAF V600E mutations were associated with PCB-153, PCB-138, and PCB-180. Conclusion: Our study suggests, for the first time in a case-control population, that exposure to some PFAS and PCBs associates with TC and some clinical and molecular features. On the contrary, an inverse correlation was found with both PFHxS and pollutants' mixture, likely due to a potential reverse causality.

Using haematological indices to predict impaired liver function in DTC patients.

OBJECTIVE: In patients with normal liver function, patients with acute or chronic thyroid disease are more likely to develop liver dysfunction. Although the mechanisms underlying this process are not yet fully understood, it has been shown that hypothyroidism can lead to hepatic injury. We evaluated haematological function trends in patients with differentiated thyroid cancer (DTC) at baseline and approximately 4 weeks after l-thyroxine withdrawal before radioactive iodine ablation. SUBJECTS AND METHODS: This is a retrospective study, and 157 patients were enrolled. Logistic regression analysis was used to find significant predictors. Four weeks after LT4 withdrawal, 64 patients belonged to the group of liver injury, and 93 patients belonged to the group of normal liver function. RESULTS: Univariate analysis determined that platelet count (PC) (P=0.005), mean platelet volume (MPV) (P=0.013), platelet distribution width (PDW) (P=0.039) and absolute lymphocyte count (ALC) (P=0.008) were responsible risk factors for liver injury in DTC patients after withdrawal of levothyroxine (l-thyroxine). Multivariate analysis showed that slight increases in PC (OR: 2.243, P: 0.024) and ALC (OR: 0.398, P: 0.017) were closely associated with liver injury in DTC patients after 4 weeks LT4 withdrawal before radioactive iodine ablation. CONCLUSION: Our results suggest that PC and ALC are independent predictors of hypo-related liver injury. Our study is the first to suggest that haematological indices can be used for predicting the development and progression of hypo-related liver disorders.

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.

Comparison of pathophysiology in subclinical hyperthyroidism with different etiologies.

Subclinical hyperthyroidism (SHyper) is defined as normal levels of free thyroxine (fT4) and free triiodothyronine (fT3) with suppressed levels of TSH. Previous studies have reported the individual pathophysiology of endogenous SHyper patients and athyreotic patients receiving TSH suppression therapy with levothyroxine; however, apparently no studies have compared the two conditions. Five-hundred-forty untreated endogenous SHyper patients and 1,024 patients receiving TSH suppression therapy who underwent total thyroidectomy for papillary thyroid carcinoma were sampled. Thyroid hormone profiles and peripheral indices related to thyrotoxicosis were investigated in endogenous SHyper patients, athyreotic patients receiving TSH suppression therapy, and healthy participants. Endogenous SHyper patients showed significantly higher thyroid hormone levels (fT4 [p < 0.001] and fT3 [p < 0.001]), and peripheral indices showed a significant tendency towards thyrotoxicosis (strong TSH suppression: alkaline phosphatase [ALP, p < 0.001], creatinine [Cre, p < 0.001], pulse rate [p < 0.05]; and mild TSH suppression: Cre [p < 0.05]) than healthy participants. In contrast, athyreotic patients receiving TSH suppression therapy showed a significant tendency towards thyrotoxicosis than healthy participants only when TSH was strongly suppressed (fT3 [p < 0.001] and Cre [p < 0.001]). Endogenous SHyper patients showed significantly higher fT3 levels (p < 0.001) than athyreotic patients receiving TSH suppression therapy; however, there was a significant tendency towards thyrotoxicosis only when TSH was strongly suppressed (ALP [p < 0.05] and pulse rate [p < 0.05]). The effects of endogenous SHyper and TSH suppression therapy on target organ function are different. Although the serum thyroid hormone profile is similar to that of the thyrotoxic state, athyreotic patients receiving TSH suppression therapy with mildly suppressed serum TSH levels are not thyrotoxic.

Preoperative platelet distribution width-to-platelet ratio combined with serum thyroglobulin may be objective and popularizable indicators in predicting papillary thyroid carcinoma.

OBJECTIVES: The incidence of papillary thyroid carcinoma (PTC) has increased more rapidly than that of any other cancer type in China. Early indicators with high sensitivity and specificity during diagnosis are required. To date, there has been a paucity of studies investigating the relationship between preoperative platelet distribution width-to-platelet count ratio (PPR) and PTC. This study thus aimed to assess the diagnostic value of PPR combined with serum thyroglobulin (Tg) in patients with PTC. METHODS: A total of 1001 participants were included in our study. 876 patients who underwent surgery for nodular goiter were divided into the PTC group or benign thyroid nodule (BTN) group according to pathology reports, and 125 healthy controls (HCs) were included. Preoperative hemogram parameters and serum Tg levels were compared among three groups. Receiver operating characteristic (ROC) curve was used to evaluate the value of PPR combined with serum Tg for diagnosing PTC. RESULTS: Platelet distribution width (PDW) and PPR levels were higher in the PTC group than in the BTN and HC groups (both p < 0.05) but did not significantly differ between the BTN and HC groups. PDW and PPR levels significantly differed in the presence/absence of lymph node metastasis, the presence/absence of capsule invasion (p = 0.005), and TNM stages (p < 0.001). Multivariable analyses indicated that high serum Tg levels [adjusted odds ratio (OR), 1.007; 95% confidence interval (CI), 1.004-1.009; p < 0.001], high neutrophil-to-lymphocyte ratio (NLR,adjusted OR, 1.928; 95% CI, 1.619-2.295; p < 0.001), and high PPR (adjusted OR, 1.378; 95% CI, 1.268-1.497; p < 0.001) were independent risk factors for PTC. In ROC analysis, the areas under the curves (AUCs) of serum Tg, PDW, PPR, and NLR for predicting PTC were 0.603, 0.610, 0.706, and 0.685, respectively. PPR combined with serum Tg (PPR + Tg) had a higher diagnostic value (AUC, 0.738; sensitivity, 60%; specificity, 74.7%) compared with PDW + Tg (AUC, 0.656; sensitivity, 64.4%; specificity, 59.9%) and NLR + Tg (AUC, 0.714; sensitivity, 61.6%; specificity, 71.1%). CONCLUSIONS: Preoperative PPR combined with serum Tg may be objective and popularizable indicators for effective predicting PTC.

Preoperative Serum Calcitonin Level and Ultrasonographic Characteristics Predict the Risk of Metastatic Medullary Thyroid Carcinoma: Functional Analysis of Calcitonin-Related Genes.

Background: Early cervical lymph node (LN) metastasis is an important cause of poor survival in patients with medullary thyroid cancer (MTC). This study evaluated whether the preoperative serum calcitonin level in combination with ultrasonographic features of MTC can be used to assess the LN status as well as predict the risk of metastasis in patients with MTC. Methods: We retrospectively analyzed the clinical data of 95 patients with MTC, and a nomogram model was constructed and validated. Using integrated database analysis of The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx), we mined pathways wherein CALCA is involved, identified calcitonin-related genes, and analyzed their functions. Results: Correlation analysis revealed a significant association between the infiltrating range, diameter, calcification, blood flow, the preoperative serum calcitonin level, and metastasis. The metastasis risk-prediction model showed great accuracy in determining the risk of metastasis in MTC (area under the curve of the receiver operating characteristic [ROC] curve: 0.979 [95% confidence interval 0.946-1.000]). Decision curve analysis (DCA) showed that the model has excellent clinical utilization potential. Significantly, CALCA, the mRNA for calcitonin, was highly expressed in thyroid cancer tissues and associated with the cytokine-cytokine receptor and neuroactive ligand-receptor interaction pathways as well as the cell-adhesion molecules. ROC curve indicated that the CNTFR, CD27, GDF6, and TSLP genes, which are related to the cytokine-cytokine receptor interaction pathway, could indicate the risk of metastasis in MTC. Conclusions: The preoperative serum calcitonin level, in combination with ultrasonographic features, can be used to predict the risk of metastasis in patients with MTC and constitute a noninvasive accurate method for preoperative diagnosis of MTC.

Clinical Significance of Circulating Tumor Cells (CTCs) and Survivin on Predicting Prognosis in Thyroid Cancer Patients.

BACKGROUND: Clinical significance of circulating tumor cell (CTC) count, mesenchymal CTCs (MCTCs), and survivin in patients with thyroid cancer remains unclear. We evaluated the relationship between the expression of different CTC subtypes or survivin and the prognosis in patients with thyroid cancer. Patients and Methods. This study enrolled 164 patients with thyroid cancer who were diagnosed from January 2013 to September 2020 in our hospital. Among these patients, there were 73 cases with papillary thyroid cancer (PTC), 60 cases with follicular thyroid cancer (FTC), 12 medullary thyroid cancers (MTC), 10 poorly differentiated thyroid cancers (PDTC), 9 anaplastic thyroid cancers, and 10 control patients with nonmalignant thyroid nodules based on their histopathological characteristics. Only 5 milliliters (mL) of peripheral blood from the patients with thyroid cancer and control was used to detect the CTC cell number via CanPatrol capture technique before treatments. We also isolated mononuclear cells (MNC) from the peripheral blood and performed quantity reverse transcriptase polymerase chain reaction (qPCR) for survivin gene expression among these patients. RESULTS: The overall positive rates of CTC at diagnosis were 56.1%. The relapse and metastasis rates in PTC and FTC patients with more than 6 CTCs and positive MCTCs were significantly higher than those in the patients with 6 or less than 6 CTCs and MCTCs. It was also found that these patients with >6 CTCs and MCTCs had shorter progression-free survival (PFS). Additionally, the survivin level of the patients with thyroid cancer was strongly relative to differentiation grades of thyroid cancers. CONCLUSIONS: The detection of more than six of total CTCs and positive MCTCs in the patients with differentiated thyroid cancer is an excellent biomarker for predicting the prognosis of patients. Survivin also is a good biomarker for thyroid cancer differentiation.

Short NK- and Naïve T-Cell Telomere Length Is Associated with Thyroid Cancer in Childhood Cancer Survivors: A Report from the Childhood Cancer Survivor Study.

BACKGROUND: Survivors of childhood cancer are at risk for therapy-related subsequent malignant neoplasms (SMN), including thyroid SMN. Telomere length (TL) is associated with cancer risk, but the relationship between TL and SMN risk among survivors is less clear. METHODS: We conducted a nested, matched case-control study of radiation-exposed 15-year+ adult survivors of childhood cancer with thyroid SMN (cases) and without SMN (controls). Forty-six cases were matched to 46 controls by primary diagnosis, chemotherapy (yes/no), radiation field, and follow-up duration. Lymphocyte TL (LTL) was measured by telomere flow-FISH cytometry using blood samples banked at a mean of 38.9 years (cases), 39.2 years (controls). Genetic variation in telomere genes was assessed by whole genome sequencing. Point estimates for LTL <10th percentile were determined for cases and controls. RESULTS: Cases had shorter median LTL than controls in three out of four leukocyte subsets. Cases were more likely to have NK cell LTL <10th percentile (P = 0.01), and 2.8-fold more likely to have naïve T-cell LTL <10th percentile than controls (CI, 1.07-8.78). Five out of 15 cases with a rare indel or missense variant had naïve T-cell LTL <10th percentile, compared with one out of eight controls. CONCLUSIONS: Long-term survivors have shorter than expected LTL, a finding that is more pronounced among survivors with thyroid SMN. IMPACT: The long-term impact of childhood cancer treatment on immune function is poorly understood. Our findings support immune function studies in larger survivor cohorts to assess long-term deficits in adaptive and innate immunity that may underlie SMN risk.

Clinical challenges with calcitonin-negative medullary thyroid carcinoma: three case reports and a review of the literature.

Medullary thyroid carcinoma (MTC) is relatively rare, and has the main feature of calcitonin (Ct) secretion. However, a few cases of MTC with negative serum calcitonin have been reported in the literature, so the diagnosis and follow up of Ct-negative MTCs are still a challenge. Here we present three cases of Ct-negative MTCs, illustrating the rarity of the disease and challenges in managing it, together with a review of the literature of 39 MTCs with negative serum Ct.

Preoperative calcitonin testing improves the diagnosis of medullary thyroid carcinoma in female and male patients.

AIM: Calcitonin (Ctn) measurement in patients with thyroid disease could potentially increase the detection rates of medullary thyroid carcinoma (MTC) but remains a controversial issue. The aim of this study was to evaluate routine preoperative Ctn measurements. METHODS: All patients with thyroid surgery documented in the prospective StuDoQ|Thyroid registry between March 2017 and September 2020 were included. Cutoff levels for Ctn were determined with receiver-operating characteristic analyses to assess the preoperative diagnosis of MTC in subgroups for females and males. FINDINGS: In 29 590 of 39 679 patients (75%) participating in the registry, routine preoperative Ctn testing was performed. In 357 patients (227 females and 130 males), histopathology confirmed MTC with a mean tumor size of 14.7 mm (±12.43). Biochemical cure was achieved in 71.4% of the patients. Ctn levels between 11 and 20 pg/mL were seen in 2.6% of the patients, and only 0.7% of the patients had Ctn levels above 21 pg/mL. Cutoff levels for the diagnosis of MTC were 7.9 pg/mL for females and 15 pg/mL for males (P < 0.001). The sensitivity and specificity for females were 95 and 98%, and 96 and 97% for males, respectively. CONCLUSION: Routine Ctn testing is a reliable predictor for MTC and provides the opportunity for earlier thyroidectomy before lymph node metastases occur, resulting in a better prognosis. Females with Ctn levels >7.9 pg/mL and males >15 pg/mL without any other extrathyroidal sources for an elevated Ctn should be monitored. Thyroid surgery should be considered if Ctn levels are increasing or ultrasound detects suspicious thyroid lesions.

Utilizing the circulating tumor markers in diagnosis and management of medullary thyroid cancer.

Medullary thyroid cancer (MTC) is the third frequent subtype of thyroid cancer-driving from thyroid C-cells. The first-line strategy to treat MTC is surgery, but tumor recurrence and patients' mortality rate have still been demonstrated in approximately 4-10% of MTC cases. Therefore, to treat and prevent the progressive form of the disease, the early diagnosis of MTC is assumed to play a critical role. In this regard, recently, circulating biomarkers have drawn researchers' attention for their nonaggressive manners in the sample collection. In this systematic review, we aimed to focus on circulating biomarkers and their applications in MTC diagnosis, prognosis and follow-up, and we discussed their clinical application and how they can affect clinical decision making in the future. A literature search (from 2000 to 2021) was accomplished on MTC circulating biomarkers in different databases, and only English articles were evaluated. We found that calcitonin (CT) and carcinoembryonic antigen (CEA) are the most important circulating biomarkers in the MTC diagnosis. Other circulating biomarkers included pro-calcitonin (Pro-CT), pro-Gastrin releasing peptide (Pro-GRP), carbohydrate antigen 19-9 (CA 19-9) and chromogranin A (CgA). Some novel circulating biomarkers comprised vaspin and retinol-binding protein-4 (RBP4), myostatin, tumor cells (CTCs), RET M918T mutated cfDNA, circulating tumor DNA (ctDNA), miR-375 and Alu83 and Alu244 cfDNAs. Several circulating biomarkers have been identified to optimize the accuracy of diagnosis and offer new prognostic criteria, which should be verified before any clinical application. Although different circulating biomarkers contributed to MTC have been discovered, a few of them could be used in clinical diagnosis. In many cases, the application of each marker may not be useful lonely; therefore, a combination of two or more biomarkers could open a new avenue in the diagnosis, prognosis and prediction of MTC.

Markedly elevated serum preoperative thyroglobulin predicts radioiodine-refractory thyroid cancer.

BACKGROUND: Repeated radiotherapy brings limited benefits and significant side effects for differentiated thyroid cancer patients (DTC) with radioiodine refractory (RAIR). However, the prognostic role of preoperative thyroglobulin (pre-Tg) in predicting RAIR is unclear. METHODS: In the present study, data were retrospectively reviewed from 5173 patients who underwent radiotherapy in the Jiangyuan Hospital from January 2006 to December 2020. RESULTS: A total of 1,102 patients with or without repeated radiotherapy were compared (repeated vs. single radiotherapy; n = 199 vs. n = 903). Pre-Tg was significantly elevated in patients with repeated radiotherapy. After the classification of RAIR (non-RAIR, n = 786 vs. RAIR, n = 90), elevated pre-Tg was also correlated with RAIR after univariate and multivariate analyses. According to the receiver operating characteristic curve analysis, elevated pre-Tg well predicted RAIR (AUC = 0.76, CI: 0.71-0.82, p < 0.0001). To control the selection bias, the propensity score matching was used. Pre-Tg level was found to be an independent predictor of RAIR (p < 0.001, HR = 7.25, CI: 2.55-20.62). CONCLUSION: Our results indicate that markedly elevated pre-Tg level can be served as an independent predictor of RAIR-DTC, which can guide a more precise treatment strategy and/or an active surveillance during surgery and follow-ups.

Effect of Thyroid-Stimulating Hormone Suppression on Muscle Function After Total Thyroidectomy in Patients With Thyroid Cancer.

Context: Thyroid-stimulating hormone (TSH) suppression is recommended to reduce tumor recurrence following surgery for differentiated thyroid cancer (DTC). However, prolonged subclinical hyperthyroidism caused by levothyroxine treatment has deleterious effects on various organs. Objective: To evaluate the relationships of TSH concentration with muscle mass, muscle strength, and physical performance related to sarcopenia in patients with DTC undergoing TSH suppression following surgery. Methods: We studied 134 patients of >60 years who were undergoing TSH suppression therapy following surgery for DTC. We evaluated muscle mass and muscle function-related parameters and diagnosed sarcopenia using the threshold for Asian people. Results: The participants were 68.3 ± 7.2 years old and 36/134 (26.9%) were diagnosed with sarcopenia. They were allocated to high-TSH and low-TSH groups using a threshold concentration of 0.40 µU/mL, and grip strength was significantly lower in the low-TSH group. The data were further analyzed according to age and sex, and in the low-TSH group, male participants and those of <70 years were found to have significantly lower grip strength. Conclusions: Low-TSH concentrations is associated with low grip strength, and this is most pronounced in individuals of <70 years of age. Therefore, muscle function should be considered an adverse effect of TSH suppression in patients with DTC who undergo TSH suppression therapy, especially in men of <70 years.

The prognostic value of plasma complement factor B (CFB) in thyroid carcinoma.

Stromal and immune cells are major components of tumor microenvironment (TME) and affect the growth and development of thyroid carcinoma (THCA). However, data on the exact mechanisms that define the relationship between the TME and THCA remain scant. We calculated stromal and immune cells scores and the proportion of tumor-infiltrating immune cells (TICs) by CIBERSORT and ESTIMATE based on the THCA gene expression data from the Cancer Genome Atlas (TCGA). In addition, we evaluated differentially expressed genes (DEGs) from high- and low-score groups and performed functional enrichment analysis. Furthermore, our data show a significant correlation between plasma complement factor B (CFB) and PTC development and prognosis. Gene Set Enrichment Analysis (GSEA) demonstrated that the CFB was mainly enriched in immune response pathways. The expression of CFB was positively correlated with T cells CD8, Macrophages M1, Plasma cells, T cells CD4 memory activated, T cells follicular helper and T cells regulatory (Tregs), whereas negatively correlated with Eosinophils, Macrophages M0, Macrophages M2, Mast cells resting, T cells CD4 memory resting in the TME. Finally, the expression level of CFB was verified by other cohorts from Gene Expression Omnibus (GEO) database and quantitative Real-Time PCR (qRT-PCR) analyses, which was consistent with the results of bioinformatic analysis. Taken together, our data demonstrated that the CFB could be a prognostic marker for THCA and its expression influences the infiltration of immune cells.

Preoperative thyroid-stimulating hormone associated risk of differentiated thyroid cancer in patients with thyroid nodules.

In an assessment of risk for differentiated thyroid cancer (DTC) in individuals with human papillary thyroid cancer (PTC) and thyroid nodules a cohort prospective study was undertaken to establish the significance of preoperative thyroid-stimulating hormone (TSH) levels. Confirmed histologically PTC cases in one tertiary care center, and matched healthy individuals were tested for TSH, T3, T4 and T4 free total. The ORs and 95% confidence intervals have been calculated using conditional logistic regression models (CI). The blood TSH levels were related to the higher risk of PTC for men (OR,0,09; 95% Ci, 04-0,21, 95% CI and women) compared with the middle tertile of the TSH levels in the normal range (OR,0,07; 95 percent CI, 0,04-0,1). Over the normal range of TSH levels, an elevated PTC risks were connected amongst women (OR 0,09; 95% CI, 0,04-0,21) but not amongst men (OR,0,07; 95% CI, 0,04-0,1). With an increase in TSH level in the normal range between men and women, the risk for PTC reduced (Ptrend=0.041 and 0.0001). The risk of PTC related to TSH levels has been dramatically elevated above  the normal range for men  and TSH values below the normal range for women.