Background: Hypothyroidism is a common hormone deficiency condition. Regenerative medicine approaches, such as a bioengineered thyroid, have been proposed as potential therapeutic alternatives for patients with hypothyroidism. This study demonstrates a novel approach to generate thyroid grafts using decellularized rat thyroid matrix. Methods: Isolated rat thyroid glands were perfused with 1% sodium dodecyl sulfate to generate a decellularized thyroid scaffold. The rat thyroid scaffold was then recellularized with rat thyroid cell line to reconstruct the thyroid by perfusion seeding technique. As a pilot study, the decellularized rat thyroid scaffold was perfused with human-derived thyrocytes and parathyroid cells. Results: The decellularization process retained the intricate three-dimensional microarchitecture with a perfusable vascular network and native extracellular matrix components, allowing efficient reseeding of the thyroid matrix with the FRTL-5 rat thyroid cell line generating three-dimensional follicular structures in vitro. In addition, the recellularized thyroid showed successful cellular engraftment and thyroid-specific function, including synthesis of thyroglobulin and thyroid peroxidase. Moreover, the decellularized rat thyroid scaffold could further be recellularized with human-derived thyroid cells and parathyroid cells to reconstruct a humanized bioartificial endocrine organ, which maintained expression of critical genes such as thyroglobulin, thyroid peroxidase, and parathyroid hormone. Conclusion: These findings demonstrate the utility of a decellularized thyroid extracellular matrix scaffold system for the development of functional, bioengineered thyroid tissue, which could potentially be used to treat hypothyroidism.
Background: Radioiodine (I-131) remnant ablation (RRA) has become a key step in the postoperative treatment of differentiated thyroid cancer (DTC). However, inadequate or excessive I-131 is common using fixed activities. This study was designed to explore the feasibility of radioiodine uptake and thyroglobulin (RAIU-Tg)-guided RRA. Methods: A total of 277 patients were randomized to the RAIU-Tg-based activity group or a fixed activity of 3.7 GBq group at a ratio of 4:1. The RAIU-Tg-based activity was established based on four levels of RAIU (<= 2%, 2-5%, 5-15%, and >15%) and Tg levels (<= 2, 2-5, 5-10, and >10 ng/mL). Based on this, I-131 activities of 1.1, 1.85, 3.7, and 5.55 GBq were administered. If the levels for RAIU and Tg were not in the same category, the higher activity determined by either RAIU or Tg was administered. Successful RRA was defined as negative diagnostic whole-body scan and Tg <1 ng/mL (anti-Tg antibody negative) or negative diagnostic whole-body scan (anti-Tg antibody positive) under thyrotropin stimulation six months or more post RRA. Results: There was no statistically significant difference in baseline characteristics between the RAIU-Tg-based activity group (n = 207) and the fixed activity group (n = 58). The activity of I-131 used in the RAIU-Tg-based activity group (3.26 +/- 1.54 GBq) was significantly lower than that used in the fixed activity group (p < 0.0001), whereas the rate of successful RRA in the RAIU-Tg-based activity group was significantly higher than the rate in the fixed activity group (94.2% vs. 70.7%; p < 0.0001). The rates of successful RRA in the four subgroups of the RAIU-Tg-based activity group were comparable (p = 0.543). Although there was no statistically significant difference in the incidence of total/short-term adverse effects between the RAIU-Tg-based activity group and the fixed activity group, a significantly lower incidence of intermediate adverse effects, which predominantly consisted of xerostomia, was reported in the RAIU-Tg-based activity group. Conclusions: Compared to a fixed activity of 3.7 GBq, RAIU-Tg-guided dosimetry can improve the success rate and decrease the incidence of intermediate side effects of RRA in postoperative patients with DTC.
Background: Therapy with radioactive iodine (I-131) is a well established treatment method for postsurgical differentiated thyroid carcinoma (DTC). A fixed discharge time is generally set, regardless of individual differences in residual body radioactivity (RBA). This study aimed to investigate the RBA of each patient to find the attenuation law and to identify underlying factors in order to predict the time point for a safe, scientifically sound discharge plan. Methods: A total of 231 DTC patients undergoing I-131 treatment were all treated with 3.7 GBq (100 mCi) of I-131. RBA was estimated by measuring the external body dose rate (EDR) at a distance of 1 m from the body surface between 0 and 72 hours after oral administration of I-131. Data from each patient were used to establish a time-EDR value (h-mu Sv/h) curve. Software was developed to predict the time when a patient's dose equivalent meets the national safety standard by including six time points between 40 and 60 hours. Several factors that might affect that time were analyzed. Results: The EDR attenuation law in patients could be described with a double exponential decay model, and the cutoff value was set as 23.3 mu Sv/h, upon which the predictive software was developed. Student's t-test showed there was no statistical difference between predicted values and the actual measured values (p > 0.05). Correlation analysis found that serum thyroglobulin, total triiodothyronine, total thyroxine, free triiodothyronine, free thyroxine, thyrotropin, 2- and 24-hour iodine uptake rate of the thyroid, scores of Tc-99m-pertechnetate thyroid scan, scores of I-131 whole-body scan, scores of ultrasound scan, and gastrointestinal residues were associated with attenuation speed. A further multiple linear regression analysis found that 24-hour iodine uptake (X-1), residual thyroid grading by I-131 whole-body scan (X-2), blood free triiodothyronine (X-3) and free thyroxine (X-4) predominantly influenced the decline of the EDR. The regression equation was ; = 2.091X(1) + 6.370X(2) + 4.529X(3) + 2.466X(4) - 8.614 (F = 44.03, p < 0.01). Conclusions: An effective and convenient method was created to measure and predict the individual safety time for discharge. This could play a significant role not only for scientific hospital discharge planning, rational use of medical resources, and better individualized management, but also in public radiation protection.
y Background: The thyroid hormone triiodothyronine (T3) is critical for vertebrate development and affects the function of many adult tissues and organs. Its genomic effects are mediated by thyroid hormone nuclear receptors (TRs) present in all vertebrates. The discovery of patients with resistance to thyroid hormone (RTH beta) >50 years ago and subsequent identification of genetic mutations in only the THRB gene in these patients suggest that mutations in the THRA gene may have different pathological manifestations in humans. Indeed, the recent discovery of a number of human patients carrying heterozygous mutations in the THRA gene (RTH alpha) revealed a distinct phenotype that was not observed in RTH patients with THRB gene mutations (RTH beta). That is, RTH alpha patients have constipation, implicating intestinal defects caused by THRA gene mutations. Methods: To determine how TR alpha 1 mutations affect the intestine, this study analyzed a mutant mouse expressing a strong dominantly negative TR alpha 1 mutant (denoted TR alpha 1PV; Thra1(PV) mice). This mutant mouse faithfully reproduces RTH alpha phenotypes observed in patients. Results: In adult Thra1(PV/+) mice, constipation was observed just like in patients with TR alpha mutations. Importantly, significant intestinal defects were discovered, including shorter villi and increased differentiated cells in the crypt, accompanied by reduced stem-cell proliferation in the intestine. Conclusions: The findings suggest that further analysis of this mouse model should help to reveal the molecular and physiological defects in the intestine caused by TR alpha mutations and to determine the underlying mechanisms.
Background: The iodine nutritional status of the Chinese population has been greatly improved in recent years. Therefore, the reference values for thyroid volume (Tvol) in children with sufficient iodine intake need to be updated. The study aimed to update the reference values for Tvol in children with sufficient iodine intake in order to define goiter in the context of sustained iodine sufficiency. Methods: A cross-sectional study was conducted in children with sufficient iodine intake in China. Twice-repeated 24-hour urine samples were collected from each child to estimate habitual daily iodine intake. Serum thyroid function tests were measured. Tvol was assessed by ultrasound. From the sample of euthyroid children with sufficient iodine intakes, the 50th and 97th percentiles for Tvol by age and body surface area (BSA) were calculated using quantile regression. Results: A total of 679 children aged 8-13 years with sufficient iodine intake (188 mu g/day [145-235 mu g/day]) were included in the analysis. The mean Tvol of the children was 4.1 +/- 1.6 mL, and no differences were found between boys and girls in any age or BSA group. Quantile regression models demonstrated that BSA was a strong positive predictor of Tvol (p < 0.0001), while age only had a significant effect on median Tvol (p = 0.013). Sex was not a significant predictor of Tvol in children. Conclusions: The reference values for Tvol in Chinese children have been updated. This study indicates that the upper limit of (97th percentile) Tvol was dependent on BSA, while the median Tvol was determined by both age and BSA.
Background: TBX1 is a member of the T-box family of transcription factors characterized by a conserved DNA binding domain termed T-box. TBX1 has been reported to be downregulated in mouse skin tumors and is considered a negative regulator of tumor cell growth in mice. However, its role and exact mechanism in human cancers, including thyroid cancer, remain totally unknown. Methods: Quantitative reverse transcription polymerase chain reaction and Western blot assays were performed to evaluate the expression of investigated genes. Methylation-specific polymerase chain reaction and pyrosequencing were used to analyze TBX1 promoter methylation. The biological functions of TBX1 in thyroid cancer cells were determined by a series of in vitro and in vivo experiments. Chromatin immunoprecipitation sequencing and dual-luciferase reporter assays were used to identify its downstream targets. Results: This study demonstrates that TBX1 is frequently downregulated by promoter methylation in both papillary thyroid cancers and thyroid cancer cell lines. Ectopic expression of TBX1 in thyroid cancer cells dramatically inhibits cell viability, colony formation, and tumorigenic potential in nude mice, and induces cell-cycle arrest and apoptosis through modulating a panel of cell-cycle and apoptosis-related genes. In addition, ectopic expression of TBX1 significantly decreases the migration and invasion potential of thyroid cancer cells through inhibiting the process of epithelial-mesenchymal transition and the expression of matrix metalloproteinases. On the other hand, TBX1 knockdown markedly promotes thyroid cancer cell viability and invasiveness. Mechanistically, TBX1 exerts its tumor suppressor function in thyroid cancer cells through inhibiting phosphorylation of AKT at Ser473 and ERK via regulating its downstream targets such as RNF41, PARK2, and PHLPP2. Conclusions: The data show that TBX1 is frequently inactivated by promoter methylation and functions as a potential tumor suppressor in thyroid cancer through inhibiting the activities of the PI3K/AKT and MAPK/ERK signaling pathways.
Background: Metformin is the most-prescribed oral medication to lower blood glucose worldwide. Some data suggest that metformin may have a role in the treatment of patients with thyroid nodules, but contrasting results are reported in different settings. This study explores and critically reevaluates the knowledge on this topic. Methods: A literature search identified 250 records. Studies evaluating the size of thyroid nodules before and after metformin treatment were included. Assessed outcomes were the size of thyroid nodules, thyrotropin (TSH) level, thyroid gland volume, and insulin resistance index (HOMA-IR). After screening and full-text assessment, five studies were included in the systematic review. Random-effects meta-analyses of the standardized mean difference (SMD) were performed for the four outcomes of interest. Heterogeneity was estimated using I-2, and the quality of evidence was assessed for each outcome using the Grading of Recommendations Assessment, Development, and Evaluation guidelines. Results: A total of 189 patients were included in the final analysis. After metformin treatment, a slight but significant reduction in thyroid nodule size was found in four studies, which included a total of 167 patients (SMD 0.46 [confidence interval (CI) 0.00-0.93]; p = 0.05). Similarly, in four studies reporting on a total of 146 patients, significant reductions in TSH level (SMD 0.30 [CI 0.07-0.53]; p = 0.01) and HOMA-IR level (SMD 0.90 [CI 0.12-1.67]; p = 0.02) were reported after treatment with metformin. In two studies, which included 114 patients, no change in thyroid gland volume was discovered after treatment with metformin (SMD 0.21 [CI -0.05 to 0.47]; p = 0.11). Quality of evidence was generally assessed as low or very low. Conclusions: Metformin induces reductions in thyroid nodule size and TSH and HOMA-IR levels in patients with thyroid nodules and insulin resistance. In contrast, no change in thyroid gland volumes was found. Whether metformin treatment for thyroid nodules has clinical significance remains to be demonstrated.
Background: Thyroid peroxidase antibody (TPOAb) positivity can attenuate gestational thyroid responses to human chorionic gonadotropin (hCG) during pregnancy, whereas the effects of thyroglobulin antibodies (TgAb) remain unknown. The aim of our study was to explore the thyroid response to hCG in women with thyrotropin (TSH) levels within the method-specific reference range under different conditions of thyroid autoimmunity. Methods: The study screened 822 women at 7-20 weeks of gestation using the pregnancy-specific reference range for TSH. Serum TSH, free thyroxine (fT4), TPOAb, TgAb, and beta-hCG levels were measured using electrochemiluminescence immunoassays. Results: The enrolled pregnant women were subdivided into four subgroups based on TPOAb/TgAb positivity: co-positive for TPOAb and TgAb (group 1), isolated TPOAb positive (group 2), isolated TgAb positive (group 3), and co-negative for TPOAb and TgAb (group 4). TSH was negatively associated with hCG in all four groups (p < 0.05). fT4 was positively associated with hCG in groups 3 and 4 (p < 0.01) but not in groups 1 (p = 0.096) and 2 (p = 0.758). Group 2 was further stratified into tertiles according to TPOAb concentrations. No negative TSH/hCG association was observed in the middle- and upper-tertile groups when TPOAb were >= 53 IU/mL (p > 0.05). There was no positive fT4/hCG association in any of the three subgroups (p > 0.05). Similarly, group 3 was further stratified into tertiles according to TgAb levels. TSH was negatively associated with hCG in the lower and middle tertiles (p < 0.01), but the association was not found in the upper tertile when TgAb was >= 356 IU/mL (p = 0.191). fT4 was positively associated with hCG in the lower tertile (p = 0.027) but not in subgroups when TgAb was >= 219 IU/mL (p > 0.05). Conclusions: When TSH was within the pregnancy-specific reference range, high concentrations of TPOAb and TgAb attenuated the fT4 stimulation and suppression of TSH by hCG. The results imply that TgAb, in addition to TPOAb, could also interfere with thyroidal responses to hCG during the first half of pregnancy.
Background: Early pregnancy fetal growth is a relevant determinant of pregnancy outcome and child health during later life. During the first trimester, fetal growth depends on the transfer of maternal thyroid hormone, and optimal thyroid hormone availability is ensured via stimulation of the maternal thyroid by human chorionic gonadotropin (hCG). The potent stimulatory effects of hCG on gestational thyroid function and its clinical relevance with early fetal growth remain unknown and need to be examined. Methods: This study comprised 46,186 mothers for whom early pregnancy thyrotropin (TSH), free thyroxine (fT4), triiodothyronine, thyroperoxidase antibodies, hCG, as well as ultrasound crown-rump length (CRL) measurements were available. Data were also available on potential confounders, including maternal age, parity, anthropometrics, and fetal sex. Results: There was a negative association of TSH with CRL and a positive association of fT4 with CRL, with effect estimates of roughly 0.1 standard deviation (SD) across the full ranges. However, when taking into account thyroid stimulation by hCG, an impaired thyroidal response to hCG stimulation was associated with up to a 0.2 SD lower CRL (high hCG with high TSH) and up to a 0.6 SD lower CRL (high hCG with low fT4). Even within the normal range of TSH and fT4, an impaired thyroidal response to hCG stimulation was associated with a lower CRL. Conclusions: Low maternal thyroid function during the first trimester is associated with a modestly lower CRL. However, an impaired thyroidal response to hCG stimulation is associated with a considerably lower CRL for which effect estimates are in the range of or even supersede those of well-known risk factors. These data can help to improve the identification of pregnancies at high risk of fetal growth restriction and adverse pregnancy or child outcomes.
Background: Ultrasound (US) examination is helpful in the differential diagnosis of thyroid nodules (malignant vs. benign), but its accuracy relies heavily on examiner experience. Therefore, the aim of this study was to develop a less subjective diagnostic model aided by machine learning. Methods: A total of 2064 thyroid nodules (2032 patients, 695 male; M-age = 45.25 +/- 13.49 years) met all of the following inclusion criteria: (i) hemi- or total thyroidectomy, (ii) maximum nodule diameter 2.5 cm, (iii) examination by conventional US and real-time elastography within one month before surgery, and (iv) no previous thyroid surgery or percutaneous thermotherapy. Models were developed using 60% of randomly selected samples based on nine commonly used algorithms, and validated using the remaining 40% of cases. All models function with a validation data set that has a pretest probability of malignancy of 10%. The models were refined with machine learning that consisted of 1000 repetitions of derivatization and validation, and compared to diagnosis by an experienced radiologist. Sensitivity, specificity, accuracy, and area under the curve (AUC) were calculated. Results: A random forest algorithm led to the best diagnostic model, which performed better than radiologist diagnosis based on conventional US only (AUC = 0.924 [confidence interval (CI) 0.895-0.953] vs. 0.834 [CI 0.815-0.853]) and based on both conventional US and real-time elastography (AUC = 0.938 [CI 0.914-0.961] vs. 0.843 [CI 0.829-0.857]). Conclusions: Machine-learning algorithms based on US examinations, particularly the random forest classifier, may diagnose malignant thyroid nodules better than radiologists.
Background: Little is known about annual hazard rates of cancer mortality and recurrence for papillary thyroid cancer (PTC). This study investigated the time-varying pattern of cancer death and recurrence from PTC and independent prognostic factors for cause-specific mortality (CSM) and recurrence of PTC. Methods: This retrospective chart review enrolled 466 patients diagnosed with PTC who underwent curative initial surgery between April 1981 and December 1991 with a median follow-up of 18.4 years. Clinical characteristics, cancer mortality (primary endpoint), and recurrence (secondary endpoint) were ascertained. The failure rates of either death or recurrence were estimated using the Kaplan-Meier methods, and annual death/recurrence hazard was depicted using hazard function. Results: In this Japanese cohort where only 1.5% of patients received radioactive iodine therapy, the 10-, 20-, and 30-year CSM rates were 2.7%, 6.2%, and 8.6%, respectively. Eleven (44.0%) cases of death occurred within the first 10 years, whereas 10 (40.0%) and 4 (16.0%) cases occurred within 10-20 and 20-30 years after surgery, respectively. The 10-, 20-, and 30-year recurrence rates were 11.3%, 21.8%, and 29.4%, respectively. Forty-six (54.8%) cases of recurrence occurred within the first 10 years, predominantly within the first five years (31 cases; 36.9%), whereas 29 (34.5%), 7 (8.3%), and 2 (2.4%) cases occurred within 10-20, 20-30, and >= 30 years after surgery, respectively. Age >= 55 years was the only independent prognostic factor for CSM. Age >= 55 years, male, tumor size > 4 cm, extranodal extension, and positive pathological lymph node metastasis were independent prognostic factors for recurrence. The annual hazard curve of cancer mortality presented a double-peaked distribution, with a first peak at the 10th year, and the second peak reaching the maximum at the 20th year after surgery for the entire population. The annual hazard curve of recurrence showed a triple-peaked pattern, with surges at about 12, 22, and 29 years after surgery. Conclusions: Patients with PTC harboring at least one of the prognostic characteristics may be at persistent risk of cancer mortality and recurrence even 10 or more years after initial treatment. Understanding the hazard rate of PTC is key to creating more tailored treatment and surveillance.
Background: There is growing evidence that sphingosine-1-phosphate (S1P), a pleiotropic bioactive sphingolipid metabolite synthesized intracellularly by two closely related sphingosine kinases (SphKs), SphK1 and SphK2, is involved in inflammation. However, the role of SphKs/S1P/S1P receptors (S1PRs) in autoimmune thyroiditis (AIT) has not been studied to date. Methods: This study examined whether SphK1/S1P/S1PR1 signaling is aberrantly altered in thyroid tissues and serum of both AIT patients and a spontaneously autoimmune thyroiditis (SAT) mouse model. Murine CD4+T cells were employed to further investigate the downstream signaling of SphK1/S1P/S1PR1. Furthermore, a total of 102 NOD.H-2(h4) mice, randomly divided into different groups, were used to investigate the therapeutic effect of S1PR1 blockade and its potential mechanism. Results: We found that components of the SphK1/S1P/S1PR1 pathway were abnormally expressed in patients with Hashimoto thyroiditis and in a SAT mouse model. In addition, S1P could activate signal transducer and activator of transcription 3 (STAT3) through S1PR1 and its downstream signaling pathways in CD4+T cells of NOD.H-2(h4) mice. Furthermore, an in vivo study demonstrated that blocking S1PR1 by FTY720 administration could reduce the incidence and severity of thyroiditis and goiter in SAT mice in a time-dependent manner. The proportions of STAT3-related and inflammation-related cell subtypes, such as T helper 1, T helper 17, and follicular T helper cells, were elevated in the SAT group when compared to the control group, and these cell subtypes decreased after FTY720 administration. Furthermore, the downstream inflammatory cytokines of STAT3 were also downregulated after FTY720 administration. Conclusion: The present study shows that blocking Sphk1/S1P/S1PR1 signaling can ameliorate the severity of AIT, providing evidence of a promising therapeutic target for AIT.
Background: Anaplastic thyroid carcinoma (ATC) is one of the most aggressive malignancies, with no effective treatment currently available. The molecular mechanisms of ATC carcinogenesis remain poorly understood. The objective of this study was to investigate the mechanisms and functions of super-enhancer (SE)-driven oncogenic transcriptional addiction in the progression of ATC and identify new drug targets for ATC treatments. Methods: High-throughput chemical screening was performed to identify new drugs inhibiting ATC cell growth. Cell viability assay, colony formation analysis, cell-cycle analysis, and animal study were used to examine the effects of drug treatments on ATC progression. Chromatin immunoprecipitation sequencing was conducted to establish a SE landscape of ATC. Integrative analysis of RNA sequencing, chromatin immunoprecipitation sequencing, and CRISPR/Cas9-mediated gene editing was used to identify THZ1 target genes. Drug combination analysis was performed to assess drug synergy. Patient samples were analyzed to evaluate candidate biomarkers of prognosis in ATC. Results: THZ1, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7), was identified as a potent anti-ATC compound by high-throughput chemical screening. ATC cells, but not papillary thyroid carcinoma cells, are exceptionally sensitive to CDK7 inhibition. An integrative analysis of both gene expression profiles and SE features revealed that the SE-mediated oncogenic transcriptional amplification mediates the vulnerability of ATC cells to THZ1 treatment. Combining this integrative analysis with functional assays led to the discovery of a number of novel cancer genes of ATC, including PPP1R15A, SMG9, and KLF2. Inhibition of PPP1R15A with Guanabenz or Sephin1 greatly suppresses ATC growth. Significantly, the expression level of PPP1R15A is correlated with CDK7 expression in ATC tissue samples. Elevated expression of PPP1R15A and CDK7 are both associated with poor clinical prognosis in ATC patients. Importantly, CDK7 or PPP1R15A inhibition sensitizes ATC cells to conventional chemotherapy. Conclusions: Taken together, these findings demonstrate transcriptional addiction in ATC pathobiology and identify CDK7 and PPP1R15A as potential biomarkers and therapeutic targets for ATC.
Background: Particulate matter (PM) air pollution is an environmental risk to public health. The prevalence of thyroid disease during pregnancy has increased rapidly in recent decades, but the available data on the relationships among air pollution, thyroid function, and birth outcomes in pregnant women, particularly in China, are scarce. We aimed to evaluate the association between maternal exposure to PM2.5 and its components and maternal and neonatal thyroid function and to investigate whether thyroid function acts as a mediator between air pollution and birth weight. Methods: In this prospective birth cohort study, the levels of maternal exposure to PM2.5 and its components during the first trimester were assessed in 433 pregnant women in Nanjing, China, enrolled during 2014-2015. We evaluated the levels of maternal exposure to PM2.5 and its six main constituents-organic matter (OM), black carbon (BC), sulfate (SO42-), nitrate (NO3-), ammonium (NH4+), and soil dust-using the V4.CH.02 product of the Dalhousie University Atmospheric Composition Analysis Group. The maternal serum-free thyroxine (fT4), thyrotropin (TSH), and thyroid peroxidase antibody (TPOAb) levels during the second trimester were measured through electrochemiluminescent microparticle immunoassays. The neonatal TSH levels were detected using an AutoDELFIA Neonatal TSH kit within 72 hours after birth, and the birth weight Z-score of each newborn was estimated. Results: Higher exposure to maternal PM2.5 and some components (BC and NH4+) decreased the maternal fT4 level (p < 0.05), and the birth weight Z-score was decreased (p < 0.05) by higher exposure to maternal PM2.5 and some components (OM, BC, NO3-, and NH4+). A mediation analysis clarified that the maternal fT4 levels explained 15.9%, 18.4%, and 20.9% of the associations of maternal PM2.5, BC, and NH4+ exposure with the birth weight Z-score, respectively (p < 0.05). After additional sensitivity analyses including only nonpreterm participants (n = 418) and non-TPOAb-positive participants (n = 415), the models remained stable. Conclusions: Our results suggest an inverse association between maternal exposure to PM2.5 and its components and the maternal fT4 levels. Maternal fT4 might act as a mediator between exposure to PM2.5 and its components and birth weight.
Background: Expression of the programmed death-ligand 1 (PD-L1) in medullary thyroid carcinoma (MTC) has been rarely reported. In this study, we evaluated PD-L1 positivity in MTC and analyzed its correlation with clinicopathological characteristics, structural recurrence (SR), and biochemical recurrence/persistent disease (BcR/BcPD). We also evaluated the prevalence of PD-L1 expression in patients developing distant or unresectable locoregional recurrence. Methods: In total, 201 consecutive MTC patients who underwent initial surgery in our institution from January 2006 to December 2015 were included. PD-L1 expression was evaluated by immunohistochemical staining and was considered positive in case of a combined positive score >= 1. The association of PD-L1 positivity with clinicopathological characteristics, structural recurrence-free survival (SRFS), and BcR/BcPD was retrospectively investigated. Results: The median follow-up length of the entire cohort was 73 months. We observed positive PD-L1 staining in 29 (14.4%) patients who were more likely to have a larger tumor size (p = 0.002), lymph node metastases (p = 0.036), and advanced TNM staging (p = 0.019). The five-year SRFS of the PD-L1-negative and PD-L1-positive groups was 85.4% and 57.9% (p = 0.001). Multivariate Cox analysis showed that PD-L1 positivity was independently associated with SR (hazard ratio = 2.19 [95% confidence interval (CI) 1.01-4.77], p = 0.047). Furthermore, multivariate logistic analysis showed that PD-L1 positivity was significantly associated with BcR/BcPD (odds ratio = 3.16 [CI 1.16-8.66], p = 0.025). During the study period, 20 patients developed distant or unresectable locoregional recurrence, among whom 8 (40%) were PD-L1 positive, which was much higher than in the entire MTC population. Conclusions: Using a large cohort of MTC patients, we demonstrate that PD-L1 positivity is associated with aggressive clinicopathological features and is independently predictive of SR and BcR/BcPD. Furthermore, a higher rate of PD-L1 expression in patients with incurable recurrence has been observed. Therefore, immune checkpoint inhibitors targeting the programmed cell death-1 (PD-1)/PD-L1 pathway may be a potential therapeutic strategy to treat advanced MTC.