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Thyroid tumors occur in many domestic species, but are most common in the dog, in which they are classified as follicular or medullary. During 2012–2016, we received tissue specimens or whole carcasses of 4 dogs with variable enlargement of the thyroid glands. The 2 males and 2 females were of mixed (mongrel) inbreeding, 3–4.5-y-old. All tumors had lobulated architecture forming follicular structures variably containing colloid. On immunohistochemistry of the tumors from 3 of the dogs, 2 were thyroglobulin positive, and all 3 were negative for calcitonin, confirming follicular thyroid carcinoma in 2 of the dogs. Thyroid carcinomas have not been reported previously in related mongrel dogs, to our knowledge. [ABSTRACT FROM AUTHOR]

Background: Conceptually, thyroid tumor desmoplasia may be better suited for excluding node metastases in sporadic MTC than preoperative serum calcitonin levels. Methods: This analysis included 181 patients with unilateral sporadic MTC graded on the 7‐grade desmoplasia scale after thyroidectomy and neck dissection. Results: When thyroid tumor desmoplasia reached 1% and ≥50%, node metastases increased from 0% to 7% (median of 0 metastases) and 83% (median of 7.5 metastases), microscopic lymphatic invasion from 0% to 3% and 35%, extrathyroid extension from 0% to 5% and 22%, and extranodal growth from 0% to 0% and 44%, whereas biochemical cure declined from 100% to 95% and 25%. Thyroid tumor diameters and basal calcitonin overlapped widely among the seven desmoplasia groups, precluding differentiation by thyroid tumor size or serum calcitonin levels. Conclusions: Thyroid tumor desmoplasia, unlike serum calcitonin levels, discriminates extremely well between node‐negative and node‐positive sporadic MTC, opening new avenues for precision surgery. [ABSTRACT FROM AUTHOR]

Background: With the rising incidence of breast cancer (BC) and neoplasms of the thyroid gland, a potential link between the two has drawn increasing attention. However, the causal relationship remains unclear due to various confounding factors. This study aims to investigate the causality between BC and thyroid tumors using Mendelian Randomization (MR) analysis. Methods: We conducted a bidirectional two-sample MR analysis, utilizing breast cancer-associated single nucleotide polymorphisms (SNPs) from the Breast Cancer Association Consortium (BCAC) and thyroid tumor-related SNPs from the FinnGen (https://www.finngen.fi/) database. First, we performed univariable MR (UVMR) to assess the causal relationship between BC and both malignant and benign thyroid tumors, followed by reverse causality analysis. To account for potential confounders, we applied multivariable MR (MVMR). The inverse-variance weighted (IVW) method was primarily used, with secondary analyses performed using the weighted median and MR-Egger regression approaches. Results: UVMR analysis revealed a significant positive causal relationship between BC and malignant thyroid tumors (odds ratio [OR] and 95% confidence interval [CI]: 1.291, 1.143-1.458, P = 3.90x10-5). No causal relationship was found between BC and benign thyroid tumors. The MVMR analysis, adjusting for confounding factors such as smoking, drinking, and body mass index (BMI), confirmed the robustness of the results. Conclusion: This study provides genetic evidence supporting a causal relationship between BC and malignant thyroid tumors. These findings highlight the importance of thyroid cancer screening in BC patients. However, further MR studies or randomized controlled trials (RCTs) are necessary to assess small effects accurately. [ABSTRACT FROM AUTHOR]

Background: The effects of physical activity on the development of different types of cancers have not been comprehensively studied. This nationwide, population-based cohort study investigated the effects of leisure-time physical activity (LTPA) on the development of different types of cancer in Taiwanese adults. A total of 67,890 adult participants (≥ 18 y old) from five rounds (2001, 2005, 2009, 2013, and 2017) of the Taiwan National Health Interview Survey were included. LTPA was measured as the metabolic equivalent of task (MET) expenditure per week and was classified as inactive (< 1 MET-h), low (1-7.49 MET-h), or high (≥ 7.5 MET-h). The LTPA and other covariates were collected through in-person interviews at baseline. New-onset cancer was ascertained from histopathological reports. The Fine-Gray sub-distribution method, with death as a competing risk, was used to determine the impact of LTPA on incident cancer risk. Results: During the 844,337 person-years of follow-up, 4,435 individuals developed cancer. Compared to inactive adults, individuals engaging in high levels of LTPA (≥ 7.5 MET-h/week) were significantly associated with a reduced risk of developing cancer (adjusted hazard ratio [aHR] = 0.93; 95% confidence interval [CI] = 0.87–0.99). However, those with low levels of LTPA (1-7.49 MET-h/week) did not exhibit a significant association with a reduced risk of developing cancer (aHR = 1.00; 95% CI = 0.92–1.10). When considering specific types of cancers, participants with high levels of LTPA (≥ 7.5 MET-h/week) had a significantly lower risk of developing bladder cancer (aHR = 0.68; 95% CI = 0.47–0.99), cervical cancer (aHR = 0.48; 95% CI = 0.24–0.95), and thyroid cancer (aHR = 0.64; 95% CI = 0.44–0.93). Conclusions: Our findings suggest that high LTPA (≥ 7.5 MET-h/week) is significantly associated with a low risk of incident bladder, cervical, and thyroid cancers. Key points: This prospective cohort study with a mean follow-up of 12.4 years found that high leisure-time physical activity (≥ 7.5 MET-h/week) was significantly associated with a lower risk of incident cancer, including bladder, cervical, and thyroid cancer. Healthcare professionals should encourage inactive adults to perform leisure-time physical activities to reduce cancer risk. [ABSTRACT FROM AUTHOR]

Background: The objective of the following retrospective review was to perform a cost-effectiveness analysis of the use of molecular testing of indeterminate thyroid nodules compared to current management practices in Nova Scotia, Canada. Methods: All cases of cytologically indeterminate thyroid nodules from January 1st, 2014 to December 31st, 2018 were reviewed. All interventions related to an indeterminate thyroid nodule were recorded. Patients were excluded if less than 18 years old if no further information regarding medical management was electronically available beyond the diagnosis of an indeterminate thyroid nodule, history of radiation, or previous thyroid surgery prior to diagnosis of an indeterminate thyroid nodule in the remaining lobe. Microcosting was performed to determine the cost of all relevant interventions including repeat fine needle aspiration biopsy, ultrasound, thyroid surgery(s), and molecular testing. Institution-specific transition state probabilities were calculated and used to build a cost-effectiveness analysis model. Model output was an incremental cost-effectiveness ratio, defined as the ratio of cost difference to effectiveness difference between routine molecular testing and the current management strategy, yielding cost per surgery avoided. Results: The mean effectiveness of the current management of indeterminate thyroid nodules in Nova Scotia based on the American Thyroid Association guidelines is 64% at a mean cost of $6431, while the simulated mean effectiveness of routine molecular testing is 89% at a mean cost of $8414. Differences in management strategies generated an incremental cost-effectiveness ratio of $7876 per surgery avoided. Conclusion: Routine molecular testing is the more effective strategy for the appropriate management of indeterminate thyroid nodules; however, it comes at a higher mean cost compared to the current management strategy. As the cost of molecular testing continues to decrease, and the cost of OR resources continues to rise, molecular testing is likely to become the optimal strategy in Nova Scotia. [ABSTRACT FROM AUTHOR]

Introduction: The optimal strategy for differentiated thyroid cancer (DTC) patients treated with radioiodine (RAI) following thyroidectomy remains controversial. Multi-centre clinical studies are essential to identify strategies to improve patient outcomes while minimising treatment-induced toxicity. Materials and Methods: The INSPIRE clinical trial (ClinicalTrials.gov Identifier: NCT04391244) aims to investigate patient-specific dosimetry for DTC patients and to determine the range of absorbed doses delivered to target and nontarget tissues and their relationship with treatment outcome and toxicity. Results: We report here initial results of the first 30 patients enrolled onto the INSPIRE trial. A large range of absorbed doses are observed for both thyroid remnants and salivary glands, with median values of 4.8 Gy (Range 0.2 -- 242 Gy) and 0.3 Gy (Range 0.1 to 1.7 Gy), respectively. Discussion: The preliminary study results are encouraging and could help to improve our understanding of absorbed doses to thyroid remnants and normal organs following RAI therapy. Such knowledge could potentially enable patient specific treatment planning with improved clinical outcomes and quality-of-life of patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Medullary thyroid carcinoma (MTC) is a rare but aggressive form of thyroid cancer accounting for over 10% of deaths related to thyroid malignancies. MTC can be either hereditary or sporadic. Although it can be cured if it is detected early and completely removed, most patients with MTC are diagnosed when the cancer has already spread beyond the thyroid gland, making it difficult to treat. Managing MTC is complex, despite the availability of newer treatment options like targeted therapy, which works in less than 30% of cases and can lead to severe side effects in some patients. MTC behaves differently in each patient, making the selection of appropriate treatments challenging, even for multidisciplinary teams of experts. This article aims to describe the challenges faced during the diagnostic workup and management of MTC patients. It highlights how holomics, which is an integrated approach combining various biological data types, and artificial intelligence (AI) can assist in improving patient outcomes. By simultaneously analyzing and integrating findings from biochemical, radiological, and histological investigations, genetic studies, and other sources, along with the personal information of a patient, AI can enhance decision-making processes. This innovative approach has the potential to personalize and optimize treatment strategies, leading to better management and improved outcomes for patients with MTC. Background/Objective: Medullary thyroid carcinoma (MTC) is a rare yet aggressive form of thyroid cancer comprising a disproportionate share of thyroid cancer-related mortalities, despite its low prevalence. MTC differs from other differentiated thyroid malignancies due to its heterogeneous nature, presenting complexities in both hereditary and sporadic cases. Traditional management guidelines, which are designed primarily for papillary thyroid carcinoma (PTC), fall short in providing the individualized care required for patients with MTC. In recent years, the sheer volume of data generated from clinical evaluations, radiological imaging, pathological assessments, genetic mutations, and immunological profiles has made it humanly impossible for clinicians to simultaneously analyze and integrate these diverse data streams effectively. This data deluge necessitates the adoption of advanced technologies to assist in decision-making processes. Holomics, which is an integrated approach that combines various omics technologies, along with artificial intelligence (AI), emerges as a powerful solution to address these challenges. Methods: This article reviews how AI-driven precision oncology can enhance the diagnostic workup, staging, risk stratification, management, and follow-up care of patients with MTC by processing vast amounts of complex data quickly and accurately. Articles published in English language and indexed in Pubmed were searched. Results: AI algorithms can identify patterns and correlations that may not be apparent to human clinicians, thereby improving the precision of personalized treatment plans. Moreover, the implementation of AI in the management of MTC enables the collation and synthesis of clinical experiences from across the globe, facilitating a more comprehensive understanding of the disease and its treatment outcomes. Conclusions: The integration of holomics and AI in the management of patients with MTC represents a significant advancement in precision oncology. This innovative approach not only addresses the complexities of a rare and aggressive disease but also paves the way for global collaboration and equitable healthcare solutions, ultimately transforming the landscape of treatment and care of patients with MTC. By leveraging AI and holomics, we can strive toward making personalized healthcare accessible to every individual, regardless of their economic status, thereby improving overall survival rates and quality of life for MTC patients worldwide. This global approach aligns with the United Nations Sustainable Development Goal 3, which aims to ensure healthy lives and promote well-being at all ages. [ABSTRACT FROM AUTHOR]

Simple Summary: This study explores the impact of telomerase reverse transcriptase (TERTp) molecular alterations on the behavior of thyroid nodules, exploring the differential behavior of these molecular alterations occurring alone versus with concurrent molecular alterations. By analyzing the data from thyroid cancer patients treated between 2017 and 2024, this study aimed to clarify how the genetic landscape of TERTp molecular alterations relates to severity and various clinical and histopathological features of disease. The study found that thyroid cancers harboring both TERTp and concurrent molecular alterations were more likely to be classified as high-risk and have aggressive histology in contrast to nodules with TERTp molecular alterations in isolation, which generally showed less aggressive behavior. These findings suggest that identifying concurrent molecular alterations in TERTp-positive thyroid nodules could improve cancer risk assessment and prognosis and inform more tailored treatment strategies. Background/Objectives: Molecular testing of thyroid nodules enables the detection of genetic alterations, which can help assess the risk of malignancy and tumor behavior. While telomerase reverse transcriptase (TERTp) mutations are known to be associated with aggressive disease, their exact prognostic significance when occurring alone or with other molecular alterations remains underreported. Methods: This study examined patients with thyroid cancer treated at two tertiary care hospitals from 2017 to 2024. We compared tumor behavior in patients with TERTp molecular alterations occurring alone and with concurrent molecular alterations. Aggressive histologic subtypes were defined as tall-cell, hobnail, and columnar variants of papillary carcinoma, as well as poorly differentiated and anaplastic carcinoma. High-risk disease was defined according to the 2015 ATA guidelines as gross extrathyroidal extension, lymph node metastasis >3 cm, postoperative elevated serum thyroglobulin, distant metastases, and/or positive resection margins. Statistical analysis was performed to assess differences between groups. Results: 30 patients with TERTp-positive thyroid malignancies were included. TERTp/BRAF V600E was the most prevalent mutation combination (n = 13, 43.3%), followed by TERTp alone (n = 8, 26.7%) and TERTp/RAS (n = 7, 23.4%). TERTp/EIF1AX/GNAS and TERTp/EIF1AX/PIK3CA were the least common combinations (n = 1, 3.3% each). Nodules with TERTp and concurrent mutations were significantly more likely to be classified as high-risk (p = 0.006) and were more frequently associated with aggressive histologic subtypes (p = 0.003) compared to those with TERTp mutations alone, which tended to exhibit more benign behavior. Conclusions: Thyroid carcinomas harboring both TERTp and concurrent molecular alterations are associated with more aggressive features and a higher likelihood of being classified as high-risk. In contrast, TERTp mutations occurring alone do not confer an elevated risk. [ABSTRACT FROM AUTHOR]

Background: Molecular testing can reduce the need for diagnostic thyroidectomy in cytologically indeterminate thyroid nodules. However, the health-related quality of life in patients managed with molecular testing is not well studied. Objective: The objective of this scoping review was to identify and analyze the health-related quality of life outcomes in patients with indeterminate thyroid nodules who are expected to undergo or have undergone surgery or molecular testing. Methods: A comprehensive search was conducted on PubMed, Scopus, PsychINFO, and Embase to identify relevant studies. The search terms included "thyroid neoplasms" or "thyroid nodule" and "molecular testing" or "surgery" and "quality of life". The included articles were analyzed for their main study objective, study design, participant characteristics, and main results. Results: Eight studies were included in this scoping review. Four evaluated the quality-adjusted life years for patients with indeterminate thyroid nodules. Three of these studies found that molecular testing slightly improved quality-adjusted life years compared to surgery, while one study found no difference. Two studies assessed surgical health-related quality of life outcomes and reported that patients with indeterminate thyroid nodules who were expected to undergo surgery favored surgical procedures, while those who underwent surgery experienced impaired health-related quality of life. Two studies evaluated molecular testing in patients with indeterminate thyroid nodules and found that the final molecular test result significantly impacted health-related quality of life outcomes. Patients with suspicious/positive molecular test results had worse symptoms of goiter, anxiety, and depression, while those with benign results had preserved health-related quality of life scores. Patients with benign results from molecular testing experience better health-related quality of life within the first year compared to those with benign surgical outcomes. Conclusions: This scoping review highlights the importance of considering health-related quality of life outcomes in the management of patients with indeterminate thyroid nodules. Benign molecular testing results yield better quality of life than benign surgical outcomes within the first year, suggesting molecular testing as a preferable option. Further research comparing the impact of surgery and molecular testing on health-related quality of life is needed to improve shared decision-making and patient outcomes. [ABSTRACT FROM AUTHOR]

Background/Objectives: Thyroid carcinoma, presenting as a lateral neck mass without an identifiable primary tumor within the thyroid, poses a diagnostic challenge. This comparative analysis aimed to explore the differences between metastatic thyroid carcinoma and ectopic thyroid carcinoma, as both present with a lateral neck mass without evidence of primary thyroid carcinoma. Methods: Searches were conducted for studies on thyroid carcinoma in the lateral neck without evidence of primary thyroid carcinoma. A total of 39 patients were identified from 32 reported studies. Results: Metastatic and ectopic thyroid carcinomas were found in 11 and 28 patients, respectively. Metastatic thyroid carcinoma is characterized by evidence of spontaneous primary tumor regression within the thyroid and commonly associated with multiple lymph node metastases in central and lateral neck compartments. Ectopic thyroid carcinoma is more commonly diagnosed in younger patients and is frequently identified in branchial cleft cysts. The coexistence of normal thyroid tissue adjacent to the ectopic thyroid carcinoma was confirmed, and patients with ectopic thyroid carcinoma exhibited significantly higher rates of second-stage thyroidectomy or neck dissection. When complete surgical excision was considered adequate, excision alone was chosen for patients with ectopic thyroid carcinoma. Conclusions: Identifying these differences is valuable for the differential diagnosis and development of treatment strategies for metastatic and ectopic thyroid carcinomas in lateral neck masses without evidence of primary thyroid tumor. [ABSTRACT FROM AUTHOR]

Simple Summary: Non-iodine avid differentiated thyroid cancer (DTC) may be a diagnostic problem, especially in patients with an indeterminate response to treatment (i.e., with thyroglobulin (Tg) concentration in the range of 1–10 ng/mL). PET/CT with [18F]FDG may be a useful technique for visualizing non-iodine avid DTC lesions. Presented study assessed the usefulness of using exogenous stimulation with recombinant human TSH (rhTSH) before PET/CT with [18F]FDG in detecting non-iodine avid foci of DTC in patients with elevated sTg and negative 131I WBS and the usefulness of Tg concentration in predicting a positive result of [18F]FDG PET/CT in this type of patients and to determine the optimal Tg cut-off point for obtaining a positive [18F]FDG PET/CT result. In a retrospective analysis including 73 patients with DTC suspected of having non-iodine avid recurrence or metastases there was no effect of rhTSH stimulation on the sensitivity and specificity of PET/CT, but a positive impact on the number of lesions visible in the examination was observed. Moreover, rhTSH stimulation allowed for visualization of non-iodine avid lesions with lower Tg concentration. Introduction: Non-iodine avid metastases of differentiated thyroid cancer (DTC) can be found using PET/CT with a fluorine-18-labeled glucose analog ([18F]FDG). There are ongoing discussions on the appropriateness of using exogenous thyrotropin (TSH) stimulation before this examination. Material and Methods: In a retrospective study, 73 PET/CT scans with [18F]FDG performed after exogenous stimulation with recombinant human TSH (rhTSH) and without such stimulation were analyzed. All analyzed patients were suspected of having non-iodine-avid foci of DTC. Results: The stimulation with rhTSH before the PET/CT did not affect the percentage of positive results: 37.5% (18/48) with rhTSH and 40% (10/25) without rhTSH (p = 0.83). The analysis of the ROC curves established the cut-off thyroglobulin point for a positive PET/CT result separately for both subgroups. There was no statistically significant difference between obtaining a positive PET/CT result and the baseline thyroglobulin concentration (both stimulated and unstimulated). The exogenous stimulation of TSH prior to the PET/CT had no effect on the [18F]FDG uptake in the PET/CT lesions. Conclusions: PET/CT with [18F]FDG remains a useful method for the diagnosis of non-iodine-avid DTC lesions; in the presented group, a positive effect of rhTSH stimulation on the number of DTC foci visible in the PET/CT was found, but without affecting its effectiveness. [ABSTRACT FROM AUTHOR]

Simple Summary: Routine measurement of basal calcitonin (bCt) levels is used in the preoperative workup of thyroid nodules ("Ct screening") and has been documented to facilitate the early diagnosis and treatment of patients with medullary thyroid cancer (MTC). Although clear cut-offs have been proposed, the relevance for predicting lymph node metastasis (LNM) and long-term outcomes (LOs) has so far not been tested on a large cohort of patients. In this study, 306 patients with MTC were grouped into three oncologic risk groups by clearly defined gender- and assay-specific bCt cutoffs. The rate of central LNM was 2.6% in risk Group 1 (minimal oncologic risk; recently published MTC incidence: females: 17.1%; males: 37.5%) and 6.0% in Group 2 (low oncologic risk: recently published MTC incidence 100%). Lateral LNM and distant metastasis (DMet) were not found. The overall cure rate for both groups was 95.7% and 20-year disease-specific survival (DSS) was 100%. In risk Group 3 (high oncologic risk) LNMs were found in 51.0% (thereof 88.9% also in the lateral neck compartment) and DMet in 13.5%. The cure rate dropped to 58.3% and DSS to 85.3%. Within a Ct screening program, grouping patients upon pretherapeutic bCt provides a simple risk classification system for indicating surgery and its extent, predicting LNM, and estimating LOs. Background: The clinical relevance of clearly defined pretherapeutic basal calcitonin (bCt) cut-offs for predicting lymph node metastases (LNMs) and long-term outcomes (LOs) has so far not been tested in a large cohort of patients with medullary thyroid cancer included in a Ct screening program during the initial diagnostic workup of thyroid nodules. Material and Methods: Female (f) patients with a bCt level of ≤23 pg/mL and male (m) patients with a level of ≤43 pg/mL were assigned to Group 1 (minimal oncologic risk), patients with a bCt between 24 and 84 pg/mL (f) and 44–99 pg/mL (m) to Group 2 (low oncologic risk), and those with a bCt of ≥85 pg/mL (f) and ≥100 pg/mL (m) to Group 3 (high oncologic risk). All patients underwent surgery applying a uniform surgical protocol. The median follow-up was 100 months. Results: The study included 306 patients. In 3/115 (2.6%) patients in Group 1 and in 3/50 (6.0%) in Group 2, LNM in the central but not lateral neck and no distant metastases (DMet) were documented. In both groups, the biochemical long-term cure rate was 95.7% and the disease-specific-survival (DSS) rate was 100% at 10, 15 and 20 years. Lateral LNM and DMet were diagnosed only in Group 3. The bCt levels of N0 and N1 patients showed broadly overlapping ranges, thus impeding the differentiation between those patients through bCt. Both the cure rate and DSS were significantly worse in Group 3. The overall biochemical long-term cure rate was 78.2%. Conclusions: Within a Ct screening program, grouping patients upon pretherapeutic bCt provides a simple risk classification system for indicating surgery, predicting LN involvement, and LOs. [ABSTRACT FROM AUTHOR]

Simple Summary: Thyroid cancer is very common, with approximately 580,000 cases reported worldwide in 2020. Proper evaluation and management are necessary to ensure maximum patient care. It is important to consider the entire thyroid stimulating hormone (TSH) test results rather than the average or partial TSH test results to accurately evaluate the TSH status of patients with low-risk papillary thyroid carcinoma (PTC) after lobectomy. In patients with low-risk PTC after lobectomy, recurrence-free survival can be worse if the TSH status of patients, despite fulfilling the 2015 American Thyroid Association guideline recommendations, is maintained below a certain percentage among the total number of TSH tests during the postoperative follow-up period. Clinicians should make deliberate efforts to maintain the postoperative TSH status of patients with low-risk PTC who underwent lobectomy within an appropriate level during the postoperative follow-up period using thorough examinations. Background: The 2015 American Thyroid Association guidelines recommend the maintenance of serum thyroid stimulating hormone (TSH) levels ≤2 mIU/L in patients with low-risk papillary thyroid carcinoma (PTC) who underwent lobectomy; however, the evidence is insufficient. We investigated the association between maintaining the TSH status at ≤2 mIU/L and tumor recurrence in patients with low-risk PTC who underwent lobectomy through a 5-year landmark analysis. Methods: Between 2010 and 2016, 662 patients with low-risk PTC were included. The postoperative TSH status was determined using the 'TSH > 2 ratio', which was calculated using the TSH test results during the 5-year follow-up. The optimal cutoff value of 'TSH > 2 ratio' for tumor recurrence was determined using a receiver operating characteristic curve analysis. Recurrence-free survival (RFS) was compared between the groups using Kaplan–Meier and Cox proportional hazard regression analyses. Results: Patients with 'TSH > 2 ratio' > 0.1833 (n = 498) had a worse RFS outcome compared to patients with 'TSH > 2 ratio' ≤ 0.1833 (n = 164; p < 0.001). 'TSH > 2 ratio' > 0.1833 was a significant risk factor for tumor recurrence after the 5-year landmark (hazard ratio: 4.795, 95% confidence interval: 2.102–10.937, p < 0.001). Conclusions: Maintaining TSH levels ≤ 2 mIU/L below a certain percentage among the total TSH tests during the 5-year follow-up period has a negative impact on tumor recurrence. [ABSTRACT FROM AUTHOR]

Background: Recent studies have suggested that pathogenic variants of the DICER1 gene could be a driver of alterations in some pediatric thyroid nodules, but data are still limited. The aim of this study was to detect variants in the DICER1 gene in a large cohort of pediatric thyroid nodules and then correlate them with clinicopathological data, with a focus on the disease prognosis in patients with thyroid carcinoma. Methods: This retrospective cohort study consisted of 350 pediatric and young adult patients (aged 2–21 years) with thyroid nodules, from whom 275 fresh-frozen thyroid nodule samples and 92 fine-needle aspiration biopsy (FNAB) samples were collected. After an analysis of variants in major genetic alterations of thyroid tumors, variants in the DICER1 gene were identified using next-generation sequencing and multiplex ligation-dependent probe amplification methods. Peripheral blood was analyzed from patients with DICER1-positive tumors. The results of genetic analysis were then correlated with clinicopathological data. Results: Variants in the DICER1 gene were detected in a total of 24/350 (6.9%; 95%CI [4.4;10.0]) pediatric and young adult patients, respectively, in 10/119 (8.4%; [4.1;14.9]) patients with benign fresh-frozen tissue, in 8/141 (5.7%; [1.9;9.5]) with papillary thyroid carcinoma (PTC) and in 6/86 (7.0%; [4.1;14.6]) patients with FNAB. No other gene alteration was found in DICER1-positive samples. Germline DICER1 variants were identified in 11/24 (45.8%; [25.6;67.2]) patients. Two somatic (biallelic) variants in the DICER1 gene were found in 9/24 (37.5%; [18.8;59.4]) thyroid nodules. Somatic deletions of at least 3 Mbp long were revealed in 2/24 (8.3%; [1.0;27.0]) cases. DICER1-positive PTCs were significantly associated with the follicular subtype of PTC (p = 0.001), encapsulation (p = 0.006) and were larger in size (p = 0.035), but with no extrathyroidal extension (p = 0.039), and less frequent lymph node metastases (p = 0.003) compared with DICER1-negative PTCs. Patients with DICER1-positive PTC had an excellent response to treatment in 75% of cases. Conclusions: Variants of the DICER1 gene are frequently found in the thyroid nodules of pediatric and young adult patients. In our patients, DICER1-positive PTCs showed low invasiveness. Our findings support considering more conservative management for DICER1-positive low-risk PTCs. [ABSTRACT FROM AUTHOR]

In ACTH-dependent Cushing syndrome, identifying the source of ACTH can be challenging. A 23-year-old male presented with Cushingoid symptoms and signs to other clinics. Laboratory tests confirmed ACTH-dependent Cushing's syndrome. Imaging revealed a suspicious adenoma in the pituitary, a hypoechoic nodule in the thyroid, and pathological-appearing lymph nodes in the neck. Following a fine needle aspiration cytological examination, medullary thyroid carcinoma was diagnosed. A total thyroidectomy and lymph node dissection were subsequently performed. The pathology report confirmed medullary thyroid carcinoma. When the patient was admitted to our hospital, disease recurrence was considered, and lymph node ACTH washout was performed as an unusual method to identify the source of ACTH. The washout sample yielded a very high value of 958 pg/mL. We describe a patient who was hospitalized with severe symptoms of Cushing's syndrome resulting from medullary thyroid cancer. We employed a novel method involving lymph node ACTH washout to identify the source of ACTH production. Lymph node ACTH washout can be an effective diagnostic option to determine the origin of ACTH. [ABSTRACT FROM AUTHOR]

Background: Postoperative hypoparathyroidism is a major complication of thyroidectomy, occurring when the parathyroid glands are inadvertently damaged during surgery. Although intraoperative images are rarely used to train artificial intelligence (AI) because of its complex nature, AI may be trained to intraoperatively detect parathyroid glands using various augmentation methods. The purpose of this study was to train an effective AI model to detect parathyroid glands during thyroidectomy. Methods: Video clips of the parathyroid gland were collected during thyroid lobectomy procedures. Confirmed parathyroid images were used to train three types of datasets according to augmentation status: baseline, geometric transformation, and generative adversarial network-based image inpainting. The primary outcome was the average precision of the performance of AI in detecting parathyroid glands. Results: 152 Fine-needle aspiration-confirmed parathyroid gland images were acquired from 150 patients who underwent unilateral lobectomy. The average precision of the AI model in detecting parathyroid glands based on baseline data was 77%. This performance was enhanced by applying both geometric transformation and image inpainting augmentation methods, with the geometric transformation data augmentation dataset showing a higher average precision (79%) than the image inpainting model (78.6%). When this model was subjected to external validation using a completely different thyroidectomy approach, the image inpainting method was more effective (46%) than both the geometric transformation (37%) and baseline (33%) methods. Conclusion: This AI model was found to be an effective and generalizable tool in the intraoperative identification of parathyroid glands during thyroidectomy, especially when aided by appropriate augmentation methods. Additional studies comparing model performance and surgeon identification, however, are needed to assess the true clinical relevance of this AI model. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to compare the effectiveness of reflex molecular testing at identifying thyroid malignancy in indeterminate thyroid nodules (ITNs) since its implementation at our institution. Method: Identified all ITNs at our institution from January 2010 to October 2020. Calculated the sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) of ThyroSeq since the initiation of universal reflex testing of all first-time ITNs beginning in March 2016. Analyze effect on frequency of diagnostic surgeries. Results: Study group: March 2016 to October 2020, 378 ITNs underwent ThyroSeq (318 Bethesda III and 60 Bethesda IV). Mean age 52 years, 35.9% male, 61.1% female. 145 surgically excised with overall resection rate of 38.4% (III: 32.7%; IV 68%). Final histology: 49 malignant with overall rate of malignancy (ROM) of ITNs at 33.8% (III: 31.7%; IV: 39%). ThyroSeq sensitivity for ITNs at 84% (III 78.8%, IV 93.8%). ThyroSeq NPV for ITNs at 86% (III 84%, IV 93.3%). ThyroSeq specificity for ITNs at 52% (III 50.7%, IV 56%). ThyroSeq PPV for ITNs at 47% (III 42.6%, IV 57.7%). Control group: From January 2010 to February 2016 there were 242 ITNs (152 Bethesda III, 90 Bethesda IV). Mean age 52.6 years, 25.8% male, 74.2% female. 157 cases were surgically excised, with an overall resection rate of 64.9% (III: 57.2%; IV: 77.8%). Final histology: 32 malignant, with overall ROM of ITNs at 20.4% (III: 27.6%; IV: 11.4%). Conclusion: The initiation of universal Thyroseq (sensitivity 84% and NPV 86%) of ITNs at our institution has significantly decreased our percentage of diagnostic lobectomies, with a decreased resection rate of 26.5%. [ABSTRACT FROM AUTHOR]

Objective: To understand whether TSH suppressive therapy affect short‐term postoperative cancer‐related depression and anxiety among DTC patients. To evaluate short‐term postoperative psychological problems and its relationship with baseline parameters, fatigue, sleep quality, illness perception, and patients' quality of life. Study Design and Methods: This was a prospective, observational, single center study. This study involved 831 TC patients who consecutively admitted to the inpatient department of hospital between 1st June 2020 and 31th February 2021. Results: Mean scores of the self‐rated anxiety scale (SAS) (49.04 vs. 40.69) and self‐rated depression scale (SDS) (44.61 vs. 39.86), as well as the incidence of anxiety (41.5% vs. 22.1%) and depression (22.5% vs. 2.4%) significantly decreased 3 months after surgery. For personal and clinical characteristics, low educational background (SAS, β = 1.392; SDS, β = 1.622; and p < 0.05), without children (SAS, β = 4.068; SDS, β = 1.873, and p < 0.01), FNAC (SAS, β = −0.981; SDS, β = −2.583; and p < 0.05), and multifocal tumor (SAS, β = −1.287; SDS, β = −2.681; and p < 0.05) were the main effects for both short‐term postoperative anxiety and depression. Multiple linear regression analysis identified the serum TSH level as a significant variable associated with worse SAS (Beta = −0.695 and p = 0.043) and SDS (Beta = −3.133 and p < 0.001) scores 3 months after surgery. FT4 was independently associated with SAS scores (Beta = −0.202 and p < 0.001). Patients with middle ATA risk had a significantly higher level of SDS scores (p = 0.033). Conclusion: We confirmed that cancer‐related anxiety and depression among DTC patients significantly alleviated 3 months after surgery. TSH suppression therapy has profound effects on cancer‐related anxiety and depression, and the degree of anxiety and depression significantly deteriorated with the decrease of TSH level. [ABSTRACT FROM AUTHOR]

Purpose: Thyroid-stimulating hormone receptor (TSHR) is a G-protein coupled receptor that is highly expressed on benign and malignant thyroid tissues. TSHR binding and activation has long been a component of thyroid cancer molecular imaging and radiotherapy, by promoting expression of the sodium-iodide symporter (NIS) and incorporation of I-131 into thyroid hormones. Here, we report the radiosynthesis and preclinical evaluation of a Zirconium-89 (89Zr) labeled TSHR antibody to serve as a positron emission tomography (PET) diagnostic correlate for therapeutic agents targeting TSHR without reliance on NIS. Procedures: TSHR human monoclonal antibody K1-70 was conjugated to chelator desferrioxamine-p-benzyl-isothiocyanate, followed by labeling with Zr-89, yielding the radiotracer 89Zr-DFO-TSHR-Ab. The in vitro cellar uptake and binding affinity of 89Zr-DFO-TSHR-Ab were analyzed in three new TSHR stable overexpressing tumor cell lines and their corresponding wild types (WT) with low or no TSHR expression. 89Zr-DFO-TSHR-Ab PET/CT imaging of TSHR expression was evaluated in tumor mouse models bearing one TSHR-positive tumor and other negative control with or without the coinjection of antibody K1-70, and then verified by radiotracer biodistribution study and tumor immunohistochemistry (IHC). Results: The conjugate DFO-TSHR-Ab was labeled with Zr-89 at 37 °C for 60 min and purified by PD-10 column in radiochemical yields of 68.8 ± 9.9%, radiochemical purities of 98.7 ± 0.8%, and specific activities of 19.1 ± 2.7 mCi/mg (n = 5). In vitro cell studies showed 89Zr-DFO-TSHR-Ab had significantly high uptake on TSHR expressing tumor cells with nanomolar affinity and high potency. Preclinical PET/CT imaging revealed that 89Zr-DFO-TSHR-Ab selectively detected TSHR expressing thyroid tumors and displayed improved in vivo performance with the coinjection of unlabeled TSHR antibody K1-70 leading to higher uptake in TSHR expressing tumors than parental WT tumors and physiologic tissues; this observation was confirmed by the biodistribution and immunostaining analyses. Conclusions: We synthesized 89Zr-labeled antibody K1-70 as a new radiopharmaceutical for PET imaging of TSHR. 89Zr-DFO-TSHR-Ab has high radioactive uptake and retention in TSHR expressing tumors and cleared quickly from most background tissues in mouse models. Our study demonstrated that 89Zr-DFO-TSHR-Ab has the potential for PET imaging of TSHR-positive thyroid cancer and monitoring TSHR-targeted therapy. [ABSTRACT FROM AUTHOR]

Background/Objectives: The thyroid gland can represent the seat of development for giant tumors exceeding 10 cm in diameter. A retrospective analysis on 21 cases of giant thyroid tumors with comorbidities, operated in the ENT Department of the Bucharest University Emergency Hospital has been conducted. Methods: Giant benign tumors accounted for 28.57% of the cases studied and reached gigantic volumes in an average time interval of 3 years, with an average resection piece weight of 318 g. Malignant tumors accounted for 71.43%, with an average duration of evolution of 7 years, with an average resection piece weight of 581 g. Results: Dysphagia was present in all patients, dyspnea in 47.61% and dysphonia in 38.09% of cases. Total thyroidectomy is the gold standard in giant thyroid tumors, associated with radical neck dissection, extended to groups VI and VII in malignant tumors. In 10 of 11 cases of giant malignant thyroid tumors (90.90%), without anaplastic thyroid carcinoma, the survival at 5 years after multimodal oncologic treatment was favorable. Anticoagulant treatment increased the risk of postoperative reversible recurrent laryngeal nerve lesion. Conclusions: The management of giant thyroid tumors in patients with multiple comorbidities needs a multidisciplinary team including endocrinologist, radiologist, anesthesiologist, pathologist, ENT surgeon, thoracic surgeon, oncologist and radiotherapist. [ABSTRACT FROM AUTHOR]

Background: Parathyroid adenoma is the primary cause of primary hyperparathyroidism, commonly presenting with elevated parathyroid hormone (PTH) and blood calcium levels. Chronic primary hyperparathyroidism often results in bone destruction, resulting in the formation of brown tumors. The preferred clinical treatment for parathyroid adenoma is parathyroidectomy. Postoperative pancytopenia, although rare, is a critical complication that warrants further investigation into its mechanisms and management strategies. Case presentation: We present a case of a 59-year-old female patient who was admitted due to nausea and vomiting. Positron emission tomography-computed tomography (PET-CT) revealed a mass posterior to the left thyroid lobe and multiple areas of fibrocystic osteitis throughout the body. Hematological tests showed elevated serum calcium and parathyroid hormone (PTH) levels. The patient subsequently underwent parathyroidectomy, and pathological examination confirmed the presence of a parathyroid adenoma. Postoperatively, the patient developed pancytopenia and received symptomatic treatment such as correction of anemia and elevation of white blood. At the two-month follow-up, all indicators had returned to normal. Conclusions: Pancytopenia is commonly seen in bone marrow diseases, infections and immune-related disorders, nutritional deficiencies, and metabolic diseases. This case confirms that pancytopenia can also occur postoperatively in patients with parathyroid adenoma. Therefore, Clinicians should be aware of the potential for postoperative pancytopenia following parathyroidectomy and the need for prompt management. [ABSTRACT FROM AUTHOR]

Objectives: To examine the putative functions and mechanisms of lysine crotonylation (Kcr) during the development and progression of papillary thyroid cancer (PTC). Methods: Samples of thyroid cancer tissues were collected and subjected to liquid chromatography–tandem mass spectrometry. Crotonylated differentially expressed proteins (DEPs) and differentially expressed Kcr sites (DEKSs) were analyzed by Motif, dynamic expression model analysis (Mfuzz), subcellular localization, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotation, Go Ontology (GO) annotation, and protein–protein interaction analysis (PPI). Validation was performed by immunohistochemistry (IHC). Results: A total of 262 crotonylated DEPs and 702 DEKSs were quantitated. First, for the tumor/normal comparison, a dynamic expression model analysis (Mfuzz) of the DEKSs revealed that clusters 1, 3, and 4 increased with the progression of thyroid cancer; however, cluster 6 showed a dramatic increase during the transition from N0-tumor to N1-tumor. Furthermore, based on GO annotation, KEGG, and PPI, the crotonylated DEPs were primarily enriched in the PI3K-Akt signaling pathway, Cell cycle, and Hippo signaling pathway. Of note, crosstalk between the proteome and Kcr proteome suggested a differential changing trend, which was enriched in Thyroid hormone synthesis, Pyruvate metabolism, TCA cycle, Cell cycle, and Apoptosis pathways. Similarly, for the LNM comparison group, the DEKSs and related DEPs were primarily enriched in Hydrogen peroxide catabolic process and Tight junction pathway. Finally, according to The Cancer Genome Atlas Program (TCGA) database, the differential expression of Kcr DEPs were associated with the prognosis of thyroid cancer, indicating the prognostic significance of these proteins. Moreover, based on the clinical validation of 47 additional samples, Kcr was highly expressed in thyroid tumor tissues compared with normal tissue (t = 9.792, P < 0.001). In addition, a positive correlation was observed between Kcr and N-cadherin (r = 0.5710, P = 0.0015). Moreover, N-cadherin expression was higher in the relatively high Kcr expression group (χ2 = 18.966, P < 0.001). Conclusions: Higher Kcr expression was correlated with thyroid tumorigenesis and lymphatic metastasis, which may regulate thyroid cancer progression by Pyruvate metabolism, TCA cycle, Cell cycle, and other pathways. [ABSTRACT FROM AUTHOR]

Background: Glycoprotein A repetitions predominant (GARP) is a novel transmembrane protein highly expressed on the surface of regulatory T cells (Tregs), which are a subset of immunosuppressive T lymphocytes that play a major role in inhibiting the antitumor immune response. Many studies documented increased GARP expression in various tumors, which is related to a poorer prognosis, and only one single paper investigated its expression in thyroid tumors. Aim: To evaluate the immunohistochemical expression of GARP in differentiated thyroid carcinomas and their tumor-infiltrating lymphocytes (TILs) in comparison to its expression in other benign and low-risk lesions. Methods: Sixty-nine cases of different thyroid lesions were subgrouped into 37 cases of malignant thyroid neoplasms, 25 cases of benign thyroid lesions, and 7 cases of low-risk neoplasms collected from the Pathology Department Laboratories of Ain Shams University Hospitals during the period from January 2017 to December 2021 and stained immunohistochemically for GARP. Immunohistochemical (IHC) results were evaluated in thyroid epithelial cells and TILs. The expression of GARP was correlated with the different clinicopathological parameters. Results: GARP expression discloses a significant statistical difference between the three studied groups (P < 0.001). High GARP expression was detected in 89.19% of the malignant cases and in 28.57% of low-risk neoplasms, while all benign lesions exhibited low GARP expression. High GARP expression of TILs was detected in 60% of the malignant cases. Synchronous high GARP expression in tumor tissue and in the surrounding TILs was detected in 63.16% of the malignant cases, yet these results did not reach statistical significance. Conclusion: GARP is a marker of Tregs, whose high expression is increased in malignant over benign and low-risk lesions. It might be a potential novel target for anticancer immunotherapy. [ABSTRACT FROM AUTHOR]

Thyroid cancer (TC) is a malignancy that is increasing in prevalence on a global scale, necessitating the development of innovative approaches for both diagnosis and treatment. Myo-inositol (MI) plays a crucial role in a wide range of physiological and pathological functions within human cells. To date, studies have investigated the function of MI in thyroid physiology as well as its potential therapeutic benefits for hypothyroidism and autoimmune thyroiditis. However, research in the field of TC is very restricted. Metabolomics studies have highlighted the promising diagnostic capabilities of MI, recognizing it as a metabolic biomarker for identifying thyroid tumors. Furthermore, MI can influence therapeutic characteristics by modulating key cellular pathways involved in TC. This review evaluates the potential application of MI as a naturally occurring compound in the management of thyroid diseases, including hypothyroidism, autoimmune thyroiditis, and especially TC. The limited number of studies conducted in the field of TC emphasizes the critical need for future research to comprehend the multifaceted role of MI in TC. A significant amount of research and clinical trials is necessary to understand the role of MI in the pathology of TC, its diagnostic and therapeutic potential, and to pave the way for personalized medicine strategies in managing this intricate disease. [ABSTRACT FROM AUTHOR]

Background and objective: Extrathyroidal extension (ETE) is the term used to describe the growth of the primary thyroid tumor beyond the thyroid capsule. ETE is a critical prognostic marker for thyroid tumors, necessitating accurate preoperative assessment. This study aims to evaluate the diagnostic performance of computed tomography (CT)-based grading for ETE and tracheal invasion (TI) for preoperative prediction in patients with differentiated papillary thyroid carcinoma (PTC) and compare the diagnostic accuracy with ultrasound (US). Materials and methods: This retrospective study was approved by our institutional review board. Preoperative US and CT were performed for 83 patients who underwent surgery for PTC between 1 January 2010 and 31 December 2020. The US and CT features of ETE and TI of each case were retrospectively and independently investigated by two radiologists. The diagnostic performances of US and CT, including their specificity, sensitivity, positive predictive value (PPV), and negative predictive value (NPV) for ETE, and their accuracy in predicting ETE and TI were analyzed. As per the grading for ETE on USG and CT, lesions were graded into three grades and Mahajan grading was also devised on CT to predict the TI and graded into four grades. Results: The accuracy and specificity of CT are relatively good for identifying tumor infiltration into the adjacent structures and range from 82% to 87% and 95% to 98%, respectively. It, however, has a low sensitivity, between 14.3% and 77.78%, when compared to US, which suggests that in case of any doubt regarding CT evidence of tumor infiltration into surrounding structures, additional clinical examination must be performed. CT showed better sensitivity (78%) and specificity (75%) in detecting TI compared to previous studies. The diagnostic accuracy of CT Mahajan grading was 91.5% with p <0.005 in the prediction of TI. Conclusion: Preoperative US should be regarded as a first-line imaging modality for predicting minimal ETE, and CT should be additionally performed for the evaluation of maximal ETE. The specificity and PPV of CT are higher than those of US in detecting overall ETE and TI of PTC. The US- and CT-based grading systems have the potential to optimize preoperative surgical planning. [ABSTRACT FROM AUTHOR]

Objective: Preoperative diagnosis for follicular thyroid cancer (FTC) remains challenging. The purpose of this study was to explore the maximum intensity projection (MIP) features, which can be utilized for reconstructing and characterizing the structure of microvascular in tissue, associated with FTC, and to explore the independent risk factors for FTC in combination with multimodal ultrasonography and blood indicators. Methods: This single-center, prospective, single-blind, observational study included patients with suspected follicular thyroid carcinoma based on preoperative ultrasonography findings. All patients underwent routine ultrasonography, contrast-enhanced ultrasonography (CEUS), and correlated blood indexes tests. Offline MIP reconstruction of the CEUS images was performed. The tumor was histologically diagnosed postoperatively. Multivariable logistics regression was utilized for analyzing MIP characteristics combined with multimodal ultrasonography and preoperative blood indicators to identify independent risk factors for FTC. Results: In this study, 61 thyroid nodules were finally included according to the atretic criteria. (1) Compared with traditional color profile ultrasonography and CEUS, MIP technology can provide more information regarding microvascular characteristics inside thyroid tumors. The short, rod-like, crossed, curved and firework-like features of MIP images revealed statistically significant differences between the benign and malignant groups. (2) Multivariable logistic regression analysis indicated that the firework-like MIP characteristics of microvascular, thyroglobulin (Tg) level and vessel intensity (VI) value were independent risk factors for malignancy. Conclusion: (1) MIP technology has potential applications in the differential diagnosis of follicular thyroid carcinoma from benign lesions. (2) Firework MIP microvascular characteristics, Tg values and VI values can serve as parameters for the differential diagnosis of follicular thyroid carcinoma from benign lesions. This study provides a novel approach idea for preoperative multimodal differentiation of follicular thyroid carcinoma from benign lesions. [ABSTRACT FROM AUTHOR]

Objective. Hashimoto's thyroiditis (HT), also known as chronic lymphocytic thyroiditis, represents the most prevalent autoimmune thyroid disorder globally. The potential influence of HT on the clinical and pathological attributes, as well as the clinical outcomes of differentiated thyroid carcinoma (DTC), remains a point of ongoing debate within the medical community. The central focus of this study was to analyze the influence of HT on clinico‐pathological characteristics and its prognostic impact in a large cohort of DTC from Middle Eastern ethnicity. Design, Patients, Measurements. An extensive analysis involving 1822 DTC patients was conducted to determine the association with clinico‐pathological characteristics as well as prognosis, using Chi‐square tests and Kaplan‐Meier curves. Results. 23.9% (435/1822) of DTC patients were diagnosed with HT. Univariate analysis revealed a positive correlation between presence of HT and clinico‐pathological factors such as female gender, younger age, and early stage tumor. In contrast, HT demonstrated a negative association with several aggressive clinical features, including extrathyroidal extension, distant metastasis, recurrent/persistent disease and high‐risk categorization by the American Thyroid Association (ATA) guidelines. Despite HT being associated with favorable clinico‐pathological features in Middle Eastern DTC patient, our study found no significant influence on overall survival or recurrence‐free survival. Conclusion. The finding of an association between HT and favorable clinico‐pathological characteristics, but lack of impact on prognosis, underscores the complexity of HT‐DTC relationship, necessitating further comprehensive research to fully understand these interactions. [ABSTRACT FROM AUTHOR]

Background: Several case reports and a few studies have reported that hypothyroid patients have elevated serum potassium levels. However, hypothyroidism has not been widely accepted as a cause of hyperkalemia. Objectives: This study aims to evaluate the incidence of hyperkalemia and factors influencing serum potassium levels in thyroid cancer patients with hypothyroidism during thyroid hormone withdrawal before radioactive iodine (RAI) treatment. Methods: We conducted a retrospective review of electronic medical records from January 2017 to June 2021, involving 956 thyroid cancer patients post-thyroidectomy and undergoing RAI. Laboratory parameters, including serum potassium levels, were collected in both euthyroid (<1 year prior to RAI) and hypothyroid states. Results: Among 508 patients (mean age 52 years, 79.3% female), hyperkalemia (potassium ⩾ 5.0 mEq/L) occurred in 2.8%, without severe hyperkalemia (potassium ⩾ 6.5 mEq/L). The hypothyroid state exhibited significantly higher serum potassium than the euthyroid state [4.16 (IQR, 3.94-4.41) vs 4.10 (IQR, 3.90-4.35) mEq/L, P <.01]. The mean change in potassium levels between the euthyroid and hypothyroid state was 0.05 ± 0.17 mEq/L. Pre-thyroid hormone withdrawal (euthyroid state) factors associated with serum potassium levels in the hypothyroid state included age, use of angiotensin-converting enzyme inhibitors, diabetes mellitus, serum BUN/creatinine, serum potassium levels, hemoglobin A1c (positive correlation); and thiazide use and eGFR (negative correlation). In the hypothyroid state, hyperkalemia was more likely in patients with serum potassium ⩾4.2 mEq/L (OR 9.36, P <.01) or free T4 ⩾1.38 ng/dL (OR 7.05, P <.01) during the euthyroid state. Conclusions: The incidence of hyperkalemia was low in our hypothyroid cohorts. However, physicians should remain vigilant for cases with risk factors for developing hyperkalemia. Plain Language Summary: Serum Potassium in Hypothyroid Patients A retrospective cohort study of thyroid cancer patients undergoing radioactive iodine therapy found a low incidence of hyperkalemia (2.8%) during hypothyroidism. Patients exhibited higher serum potassium levels, influenced by factors included age, medication use (ACEI), diabetes mellitus, and initial potassium levels. Elevated initial potassium and thyroid hormone levels were associated with higher risk of hypothyroid-related hyperkalemia. Physicians should remain vigilant for hyperkalemia in these patients, particularly those with predisposing factors, warranting further mechanistic studies and broader validations. [ABSTRACT FROM AUTHOR]

Background: The European Thyroid Association Thyroid Imaging Data and Reporting Systems (EU-TIRADS) is widely used in the risk stratification of thyroid nodule malignancy. However, data on the subject in Sub-Saharan Africa are limited. The objective of this study is to evaluate the clinical, sonographic and histopathological concordance of thyroid nodules in the diagnosis of thyroid cancer. Methods: This was an analytical cross-sectional study that examined the clinical, ultrasound and pathological data of 61 patients from 4 hospitals in the city province of Kinshasa over a period of 24 months, from June 01, 2020 to May 31, 2022. Results: Of the 61 patients, their mean age was 47.38 ± 8.8 years. The mean clinical score of the patients was 3.4 ± 0.84 with the extremes ranging from 1 to 5. The majority of the patients were classified as having an intermediate risk, ie 85.2% of the cases. It was noted that 41% of the nodules had a high risk according to the EU-TIRADS score and 8.2% of the nodules were malignant after histopathological analysis. The ROC curves reported at the diagnosis of malignancy show an area under the curve of 0.709 with 95% CI (0.486–0.931), a Youden index of 0.769 for the clinical score, and an area under the curve of 0.830 with 95% CI (0.605–0.995), a Youden index of 0.772 for the EU-TIRADS score. Conclusion: In a low-income country, a well-performed thyroid ultrasound and the well-applied clinical score could be an important tool in the selection of thyroid nodules suspected of malignancy and requiring histopathological examination to avoid excessive acts in the patient. [ABSTRACT FROM AUTHOR]

While activating RET fusions are identified in various cancers, lung cancer represents the most common RET fusion-positive tumor. The clinical drug development of RET inhibitors in RET fusion-positive lung cancers naturally began after RET fusions were first identified in patient tumor samples in 2011, and thereafter paralleled drug development in RET fusion-positive thyroid cancers. Multikinase inhibitors were initially tested with limited efficacy and substantial toxicity. RET inhibitors were then designed with improved selectivity, central nervous system penetrance, and activity against RET fusions and most RET mutations, including resistance mutations. Owing their success to these rationally designed features, the first-generation selective RET tyrosine kinase inhibitors (TKIs) had higher response rates, more durable disease control, and an improved safety profile compared to the multikinase inhibitors. This led to lung and thyroid cancer, and later tumor-agnostic regulatory approvals. While next-generation RET TKIs were designed to abrogate uncommon on-target (e.g., solvent front mutation) resistance to selpercatinib and pralsetinib, many of these drugs lacked the selectivity of the first-generation TKIs, raising the question of what the future holds for drug development in RET-dependent cancers. [ABSTRACT FROM AUTHOR]

Background: Diagnostic classification of thyroid malignancy is primarily accomplished through examination of histomorphological features and may be substantiated and clarified by molecular data. Individual molecular drivers show relatively robust and specific associations with histological subtypes of thyroid malignancy, including BRAF sequence variants and kinase gene fusions in papillary thyroid carcinoma, predominantly RAS variants in follicular-patterned neoplasia, and additional "late" mutations affecting TERT promoter, TP53, and the PI3K/AKT/PTEN pathway in high-grade malignancies. Given the oncogenic role of FGFR, particularly FGFR1-3, the goal of this study was to explore the role of FGFR in thyroid carcinoma biology. Methods: We completed a multicenter retrospective observational study for thyroid carcinomas with pathogenic alterations in the FGFR gene family. We performed this study by querying the molecular data accumulated for thyroid carcinomas from each center. Results: Overall, 5030 sequenced thyroid malignancies were reviewed, yielding 17 tumors with FGFR alterations, including 11 where FGFR was the primary molecular driver and 6 where FGFR was a secondary pathogenic alteration, with a subset for which there was available clinical follow-up data. Of the 11 carcinomas with an FGFR driver, 9 were gene fusions involving FGFR2:VCL (4 tumors), TG::FGFR1 (3 tumors), FGFR2::CIT, and FGFR2::SHTN1, and the remaining 2 were driven by FGFR1 amplification. In the 6 tumors where a canonical driver of thyroid neoplasia was present (5 cases) or no clear primary driver was detected (1 case), sequencing detected secondary FGFR2 p.W290C, p.Y375C, and p.N549K, as well as FGFR1 p.N546K in the respective tyrosine kinase domains, some at subclonal variant allele frequencies. Conclusions: This study presents the first description of a collection of thyroid carcinomas grouped by primary driver alterations in FGFR, as well as a cohort of thyroid tumors with secondary alterations that potentially lead to tumor progression or resistance to targeted therapy. Given the availability of small molecular inhibitors targeting oncogenic FGFR, this study emphasizes the significant implications for patients from identification of FGFR alterations as they are currently under-recognized in the literature and, most importantly, have potential novel treatment options. [ABSTRACT FROM AUTHOR]

Simple Summary: Total thyroidectomy and dissection of cervical lymph node compartments, depending on serum calcitonin levels and ultrasound findings, is standard treatment for patients with medullary thyroid cancer. The aim of this study was to evaluate whether pre-operative calcitonin and CEA levels can be useful as biomarkers of the extent of lymph node metastases at diagnosis. Results indicate that pre-operative serum calcitonin and CEA levels can predict presence, number, and site of lymph node metastases and, more specifically, values of 90 pg/mL for calcitonin and 17 ng/mL for CEA accurately indicate the N1b status. Since surgery is the only curative treatment for medullary thyroid cancer and there is not a strong indication regarding the extent of lymphadenectomy, these findings may help in the choice of the extent of neck dissection. Background: In medullary thyroid cancer (MTC), lymph node metastases are often present at diagnosis and the extent of surgery is usually based upon pre-operative calcitonin and CEA levels as well as ultrasound findings. The aim of this study was to evaluate the role of pre-operative calcitonin and CEA levels as predictive markers of the burden of lymph node metastases at diagnosis. Methods: we conducted a retrospective study analyzing 87 MTC patients. Results: The median levels of calcitonin and CEA were 88.4 pg/mL and 7.0 ng/mL, respectively, in patients with no lymph nodes metastases; 108.0 pg/mL and 9.6 ng/mL, respectively, in patients with metastases to 1–5 lymph nodes; 520.5 pg/mL and 43.2 ng/mL, respectively, in patients with metastases to >5 lymph nodes. There were no significant differences in pre-operative calcitonin and CEA values between N0 and N1a patients, whereas they were significantly higher in N1b patients. Pre-operative cut-off levels distinguishing N0/N1a from N1b patients were 90 pg/mL for calcitonin (sensitivity 100%, specificity 59.3%, AUC = 0.82) and 17 ng/mL for CEA (sensitivity 100%, specificity 75%, AUC = 0.89). Conclusions: in patients with MTC, pre-operative serum calcitonin and CEA levels may drive the decision-making process to better define the extent of surgery. [ABSTRACT FROM AUTHOR]

Simple Summary: The use of radioactive iodine (RAI) for the treatment of patients with thyroid cancer at intermediate risk of recurrence is controversial. Evidence to date has not conclusively proven that there are benefits of this strategy to survival or recurrence after surgery for thyroid cancer. We describe key elements that can help clinicians decide when to prescribe RAI to this group of patients. These include a thorough discussion of the purpose of RAI therapy, better prediction of recurrence risk, the use of tumor markers after surgery, the use of the genetic profile of the tumor when available, and a detailed evaluation of the adverse effects of RAI, patient medical problems, and patient preferences. Integration of these variables will ensure a more comprehensive assessment of the risks and benefits of RAI treatment with the ultimate goal of avoiding overtreatment and reducing harm. The use of radioactive iodine (RAI) after total thyroidectomy for patients at the American Thyroid Association (ATA) who are at intermediate risk of recurrence is controversial. This is due to the lack of prospective randomized trials proving a benefit to recurrence or survival of RAI therapy in this group. In the absence of such evidence, clinicians struggle to recommend for or against this therapeutic approach which frequently results in overtreatment. This review describes key elements in the decision-making process that help clinicians more comprehensively evaluate the need for RAI therapy in patients with thyroid cancer at intermediate risk of recurrence. A clear definition of the purpose of RAI therapy should be conveyed to patients. In this sense, adjuvant RAI therapy intends to decrease recurrence, and ablation therapy is used to facilitate surveillance. Better stratification of the intermediate risk category into a low–intermediate subgroup and an intermediate–high-risk subgroup results in less heterogeneity and a more precise prediction of recurrence risk. The evaluation of post-operative thyroglobulin levels may prevent the overtreatment of low–intermediate-risk patients when their thyroglobulin level is <2.5 ng/mL. the integration of tumor genomics (when available) alongside pathologic features can enhance the ability of the clinician to predict iodine concentration in thyroid cancer cells. Finally, a detailed consideration of the adverse effects of RAI, patients' comorbidities, and patient preferences will result in a patient-centered personalized approach. Systematic examination of these variables will ultimately provide a framework for making more educated decisions on the use of RAI in patients at intermediate risk of recurrence that will prevent overtreatment and minimize harm. [ABSTRACT FROM AUTHOR]

Dyshormonogenesis (DG) is the failure of thyroid hormone production due to a defect in thyroid hormonogenesis. Loss-of-function mutations in the thyroglobulin (TG) gene are a cause of DG, leading to gland stimulation by thyroid-stimulating hormone (TSH), resulting in goiter. We report a mitotically active follicular nodule in an 11-year-old female with a novel mutation in the TG gene. The patient had been under follow-up for congenital hypothyroidism (CH) since the neonatal period, and she had normal TSH levels on replacement therapy. Genetic test revealed a novel compound heterogeneous mutation [c.2149C>T (p.R717*) (P.Arg717Ter) / c.5361_5362delCCinsG (p.H1787Qfs*3) (p.His1787GlnfsTer3)] in the TG gene. She underwent total thyroidectomy for a thyroid nodule that was reported as Bethesda IV on fine needle aspiration biopsy (FNAB) and noted as suspicious for noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). Pathological examination revealed a 16 mm, well-demarcated follicular nodule with a solid/insular pattern. Mitotic activity and Ki67 proliferation index were unusually high (10 mitoses/mm2 and 10%, respectively). Marked cellular pleomorphism and nuclear atypia are well-known diagnostic pitfalls in patients with dyshormonogenetic goiter. However, high mitotic activity is a feature that is less commonly reported in dyshormonogenetic goiter and may raise suspicion of poorly differentiated carcinoma when observed together with a solid pattern. The absence of signs of invasion, history of CH, and awareness of the presence of mutations compatible with dyshormonogenetic goiter can prevent the overinterpretation of such lesions. The risk of cancer development in the dyshormonogenetic thyroid gland is possible in childhood. The close follow-up is life-saving and prevents morbidities and possible mortality. [ABSTRACT FROM AUTHOR]

Objective: Differentiated thyroid cancer (DTC) is the most common pediatric endocrine cancer but studies are scarce. Latest recommendations advocate for an individualized risk-based approach to select patients for additional therapy. Lymphovascular invasion is not considered, despite being a well-known risk factor in the adult population. The aim of this study was to describe the outcomes of a cohort of DTC patients diagnosed at pediatric age and to evaluate the impact of lymphovascular invasion on the risk of persistence/ recurrence. Methods: A retrospective study of patients diagnosed with DTC at pediatric age from 2010 to 2022 at a single center was performed. All patients had total thyroidectomy. Radioactive iodine therapy (RAI) was used in selected patients. The response to therapy and occurrence of persistent/recurrent disease were evaluated. Results: A total of 21 DTC were diagnosed, mostly papillary thyroid carcinoma (PTC) (81.0%, n=17). Six patients (28.6%) had nodal involvement and one (4.8%) had lung metastasis at the time of the diagnosis. Lymphovascular invasion was present in 11 patients (52.4%). After surgery, 13 patients (61.9%) underwent RAI. The mean follow-up time was 5.7±3.1 years. In total, 6 patients (31.6%) experienced persistent/recurrent disease during the follow-up time. Among PTC patients, persistent/recurrent disease was more frequent in the presence of lymphovascular invasion [55.6% (5/9) vs. 0.0% (0/6), p=0.031]. Conclusion: An individualized risk-based approach is recommended. Our study suggests that lymphovascular invasion may be associated with a higher risk of persistence/recurrence and should therefore be considered for decision making in children and adolescents with PTC. [ABSTRACT FROM AUTHOR]

Background: Women are three times more likely to be diagnosed with thyroid cancer than men, with incidence rates per 100,000 in the United States of 20.2 for women and 7.4 for men. Several reproductive and hormonal factors have been proposed as possible contributors to thyroid cancer risk, including age at menarche, parity, age at menopause, oral contraceptive use, surgical menopause, and menopausal hormone therapy. Our study aimed to investigate potential reproductive/hormonal factors in a multiethnic population. Methods: Risk factors for thyroid cancer were evaluated among female participants (n = 118,344) of the Multiethnic Cohort Study. The cohort was linked to Surveillance, Epidemiology, and End Results cancer incidence and statewide death certificate files in Hawaii and California, with 373 incident papillary thyroid cancer cases identified. Exposures investigated include age at menarche, parity, first pregnancy outcome, birth control use, and menopausal status and type. Multivariable Cox proportional hazards models were used to obtain relative risk (RR) of papillary thyroid cancer and their 95% confidence intervals (CI). Covariates included age, race and ethnicity, reproductive history, body size, smoking, and alcohol consumption. Results: We observed a statistically significant increased risk of papillary thyroid cancer for oophorectomy (adjusted RR 1.58, 95% CI: 1.26, 1.99), hysterectomy (adjusted RR 1.65, 95% CI: 1.33, 2.04), and surgical menopause (adjusted RR 1.55, 95% CI: 1.22, 1.97), and decreased risk for first live birth at ≤20 years of age versus nulliparity (adjusted RR 0.66, 95% CI: 0.46, 0.93). These associations did not vary by race and ethnicity (p het > 0.44). Conclusion: The reproductive risk factors for papillary thyroid cancer reported in the literature were largely confirmed in all racial and ethnic groups in our multiethnic population, which validates uniform obstetric and gynecological practice. [ABSTRACT FROM AUTHOR]

Early onset medullary thyroid carcinoma, later pheochromocytomas, and nonspecific extra-endocrine features (hypermobility and persistent constipation) are part of the clinical phenotype of Multiple Endocrine Neoplasia type 2B (MEN2B). A de novo pathogenic M918T variant in the rearranged during transfection proto-oncogene is usually identified. Affected children are often seen by multiple clinicians over a long period before consideration of a diagnosis of MEN2B, with metastatic medullary thyroid carcinoma often the precipitator. We describe the clinical presentation and course of 5 children ultimately diagnosed with MEN2B in New South Wales and the Australian Capital Territory, Australia between 1989 and 2021. All cases had intestinal ganglioneuromatosis that could have prompted an earlier diagnosis. Population wide newborn genomic screening for rare diseases is on the horizon. We propose that MEN2B genomic screening should be included in newborn screening programs and that careful exclusion of intestinal ganglioneuromatosis would allow earlier identification leading to improved clinical outcomes. [ABSTRACT FROM AUTHOR]

Introduction: Medullary thyroid carcinoma constitutes 5% to 10% of all thyroid cancers. Metastatic adenopathies may pose challenges in intricate anatomical locations, such as the parapharyngeal space. A rare case of metastatic medullary thyroid carcinoma in the parapharyngeal space has been treated in our unit using combined trans-cervical trans-oral robotic surgery. Our objective was to provide a detailed description of the surgery performed on this patient. Method: We reported a singular case report worth of interest. Result: A 42-year-old woman was addressed in our unit for the management of a medullary thyroid carcinoma adenopathy located in the right parapharyngeal space. A parapharyngeal 40.0 mm × 25.0 mm × 12.0 mm adenopathy was removed using a combined trans-cervical and trans-oral robotic approach without sacrifice or injury of vascular or nervous structure. Neither the tracheostomy nor the feeding tube was implemented. Feeding was resumed on postoperative day 1 and hospitalization spanned 7 days. Conclusion: An innovative combined trans-cervical and trans-oral robotic surgery approach was conducted to address a metastatic medullary thyroid carcinoma in the parapharyngeal space. This surgical technique allowed us to circumvent the need for a trans-mandibular approach, tracheostomy, and feeding tube and enabling successful tumor removal without fragmentation. Postoperative care was significantly eased. The sole complication observed was dysphonia, likely resulting from intra-operative stretching of the vagus nerve during the dissection of the carotid artery. [ABSTRACT FROM AUTHOR]

Objective: Although many studies have shown the relationship between type 1 diabetes mellitus (T1DM) and autoimmune thyroid diseases, few studies have conducted a morphological evaluation of the thyroid gland in T1DM without thyroid disease. This study aimed to compare thyroid ultrasonography findings of the healthy control group with the T1DM group without thyroid disease and examine the relationship between β-cell autoantibodies and the presence of thyroid nodules. Methods: This cross-sectional study included 119 patients with T1DM and 105 healthy controls. Thyroid function tests, thyroid volume, and presence of thyroid nodules were compared between the two groups. Patients with T1DM were divided into two groups according to the presence of thyroid nodules, and risk factors that may affect the development of thyroid nodules were tried to be determined. Results: No significant difference was found between the control group and the T1DM group in terms of thyroid function tests, thyroid volume, and presence of thyroid nodules. In the T1DM group, the number of female patients and the islet cell antibody (ICA) positivity rate were higher in the presence of thyroid nodules. As a result of regression analysis, ICA positivity in the T1DM group increased threefold the risk of having thyroid nodules. Conclusion: A relationship was observed between ICA positivity and thyroid nodules in T1DM. Thus, cases with ICA positivity may have a higher probability of nodules in the thyroid gland, and neck examinations should be performed more frequently. [ABSTRACT FROM AUTHOR]

Context.--Oncocytic thyroid tumors displaying a papillary growth pattern are rare and may cause diagnostic problems. Objective.--To examine the clinicopathologic features of a series of 32 follicular cell-derived tumors composed of cells with oncocytic cytoplasm and displaying papillary architecture. Design.--Thirty-two cases were collected and studied to assess clinicopathologic features, including immunohistochemical and molecular testing for BRAF V600E. Results.--The patients were 26 women and 6 men, aged 17 to 77 years. The nodules ranged from 0.3 to 6.0 cm. Eighteen cases showed features of oncocytic hyper- plastic nodules and were identified against a background of thyroid follicular nodular disease; 4 cases showed features of oncocytic follicular adenoma; and 10 cases corresponded to carcinomas with oncocytic and papillary features. Nuclear features of papillary thyroid carcinoma were absent or exceedingly rare. All cases were negative for HBME-1 and cytokeratin 19 (CK19) and wild type for BRAF V600E. Follow-up in 25 patients showed that all patients with hyperplastic nodules and oncocytic follicular adenomas were alive and well and free of disease from 7 to 20 years. One patient with oncocytic follicular carcinoma showed metastases and died of tumor at 16 months; 2 patients with carcinoma had metastases and recurrence at 6 and 7 years; and 5 patients with invasive tumors were free of disease from 5 to 10 years. Conclusions.--Oncocytic thyroid tumors with papillary features can span a spectrum from benign hyperplastic, to encapsulated neoplastic, to invasive malignant lesions. Owing to their papillary features, it is important not to confuse them for other types of thyroid tumors, such as oncocytic papillary thyroid carcinoma. [ABSTRACT FROM AUTHOR]

Squamous cell carcinomas (SCC) account for over 90% of oral cancers. Over the last few decades, there has been a significant increase in the number of cases. Metastasis of oral cancer to the thyroid is extremely rare. Rarer still are tumours metastasizing from the tongue to the thyroid. We present a case of a patient who presented to her dentist with a tongue SCC. Despite radical curative treatment, the tumour metastasized to the thyroid and the patient succumbed to the metastatic disease. We, additionally, highlight the importance of thorough lymph node and neck examination in the dental setting to help identify pathology in patients. CPD/Clinical Relevance: The importance of a thorough lymph node and neck examination at routine dental check-ups is highlighted. [ABSTRACT FROM AUTHOR]

Objective: To investigate the expression of eight subunits of chaperonin containing t-complex 1 (CCT) in thyroid cancer (TC) tissues and their correlation with TC staging, patient prognosis, immune cell infiltration, immune checkpoint expression, and chemotherapy drug sensitivity. Methods: Data from The Cancer Genome Atlas (TCGA) database were used to analyze the expression of each CCT subunit in TC tissues and para-cancerous tissues as well as their relationship with the prognosis of TC patients. The biological function of each CCT subunit was analyzed by the Gene Set Enrichment Analysis (GSEA). Data from the TCGA and TIMER2.0 databases were used to analyze the correlations between the expression of each CCT subunit and the tumor microenvironment, infiltration of immune cells, chemotherapeutic drug sensitivity, and immune checkpoint expression. Results: Database analysis showed high mRNA expression of CCT3, CCT7, and CCT8 and low mRNA expression of CCT1, CCT2, CCT5, and CCT6B in TC tissues (P < 0.01 or P < 0.001). CCT3, CCT6B, and CCT8 mRNA expression were correlated with T staging (P < 0.05 or P < 0.01); CCT6B mRNA expression was associated with lymph node metastasis (P < 0.01); CCT5 mRNA expression was associated with distant metastasis (P < 0.05); and CCT6B may serve as an independent prognostic biomarker for overall survival (OS) in TC patients. CCT subunit expression was primarily enriched in signaling pathways such as graft rejection, complement, and interferongamma.Low expression groups of CCT subunits demonstrated significantly higher TC stromal score, immune infiltration score and composite score than the high expression groups (P < 0.05 or P < 0.01 or P < 0.001), displaying a negative correlation between the expression of each CCT subunit and TC stromal, immune infiltration and composite scores (all P < 0.01). The mRNA expression of each CCT subunit was positively correlated with CD8+ T cell and macrophage infiltration (all P < 0.05), the mRNA expression of most CCT subunits (except CCT6B and CCT7) was positively correlated with neutrophil infiltration (P < 0.05 or P < 0.01 or P < 0.001), whereas the mRNA expression of CCT3, 4, 7, and 8 was negatively correlated with CD4+ T-cell infiltration (all P < 0.05). Compared to the low-expression group, patients with high mRNA expression of most CCT subunit had significantly higher IC50 for chemotherapeutic agents such as sorafenib, levatinib, darafenib, trametinib, vandetanib, and cabozantinib (all P < 0.05 or P < 0.01 or P < 0.001). CCT subunit expression in TC tissues was significantly correlated with the expression of PD-1, PD-L1, PD-L2, CTLA4, CD80, and CD86 (P < 0.05 or P < 0.01 or P < 0.001). Conclusion: CCT complexes may promote TC development by affecting the tumor microenvironment thus impacting patient prognosis, potentially serving as a target for the diagnosis and immunotherapy of refractory TC. [ABSTRACT FROM AUTHOR]

Objective: To explore how germacrone regulates the proliferation, migration and chemoresistance of human thyroid cancer BCPAP cells and doxorubicin (DOX) resistant BCPAP cells (BCPAP/DOX) through the forkhead box O3 (FOXO3)-FOX subclass M1 transcription factor (FOXM1) signaling pathway. Methods: BCPAP cells were cultured routinely and used to construct BCPAP/DOX cells. MTT method was applied to detect the effects of different concentrations of germacrone on the proliferation of BCPAP and BCPAP/DOX cells. BCPAP and BCPAP/DOX cells were divided into control group (Ctrl), negative control group (NC, transfected with sh-NC plasmid), low concentration germacrone group (0.10 mmol/L), high concentration germacrone group (0.15 mmol/L), high concentration germacrone (0.15 mmol/L) + sh-FOXO3 group (transfected with sh-FOXO3 plasmid). The sh-NC plasmid and sh-FOXO3 plasmid were transfected into the corresponding BCPAP and BCPAP/DOX cells with transfection reagents. The proliferation and migration of the cells were detected using CCK-8 assay and scratching healing assay, and the expression of FOXO3, FOXM1, BAX, MMP-9 and multi-drug resistant-1 (MDR-1) was detected using WB assay. Results: The expression of FOXO3 was successfully knocked down in BCPAP and BCPAP/DOX cells. Both low and high concentrations of germacrone could significantly inhibit the proliferation and migration of BCPAP and BCPAP/DOX cells, reduce the protein expression of FOMX1, MMP-9 or MDR-1 (in BCPAP/ DOX cells), and increase the protein expression of FOXO3 and BAX (all P < 0.05). Notably, the effects were more significant with high concentration germacrone compared to that of low concentration (all P < 0.05). Knockdown of FOXO3 partially reversed the effects of germacrone on these cells (all P < 0.05). Conclusion: Germacrone may regulate the proliferation and migration of BCPAP and BCPAP/DOX cells and reduce chemotherapy resistance of BCPAP/DOX cells through the FOXO3/FOXM1 signaling pathway. [ABSTRACT FROM AUTHOR]

Aim: Differentiated thyroid cancer (DTC) is a common type of cancer that originates in the thyroid gland. This study aimed to predict the recurrence of differentiated thyroid carcinoma, in patient with well-DTC, using explainable machine learning (XAI) models. Material and Method: The study utilized a dataset from the UCI Machine Learning Repository, which included 383 patients and 13 candidate predictors. After a variable selection process using distance correlation, only four predictors (Response, Risk, T, and N) were retained for model building. Two XAI models, Fast Interpretable Greedy-Tree Sums (FIGS) and Explainable Boosting Machines (EBM), were employed. Results: The EBM model slightly outperformed the FIGS model in terms of accuracy. The study found that the most influential predictors of Well-DTC recurrence were the response to DTC treatment, risk status according to the American Thyroid Association classification, tumor size (T), and lymph node metastasis (N). Conclusion: In conclusion, this study successfully identified key risk factors for DTC recurrence using XAI models, providing interpretable insights for clinical decision-making and potential for personalized treatment strategies. [ABSTRACT FROM AUTHOR]

Background The prognostic significance of lymph node metastasis (LNM) in papillary thyroid carcinoma (PTC) remains controversial. Notably, there is evidence suggesting an association between tissue stiffness and the aggressiveness of the disease. We therefore aimed to explore the effect of tissue stiffness on LNM-related invasiveness in PTC patients. Method A total of 2492 PTC patients from 3 hospitals were divided into an LNM group and a non-LNM group based on their pathological results. The effects of interior lesion stiffness (E) and peri-cancerous tissue stiffness (Eshell) on the LNM-related recurrence rate and mortality in each patient with PTC subgroup were analyzed. The activation of cancer-associated fibroblasts (CAFs) and extracellular matrix component type 1 collagen (COL-I) in the lesion were compared and analyzed across different subgroups. The underlying biological basis of differences in each subgroup was identified using RNA sequencing (RNA-seq) data. Results The Eshell value and Eshell/E in the LNM group were significantly higher than those in the non-LNM group of patients with PTC (Eshell: 72.72 ± 5.63 vs 66.05 ± 4.46; Eshell/E: 1.20 ± 1.72 vs 1.09 ± 1.10, P  < .001). When Eshell/E > 1.412 and LNM were both present, the recurrence rate and mortality were significantly increased compared to those of group of patients with LNM (91.67% and 7.29%, respectively). The CAF activation and COL-I content in the Eshell/E+ group were significantly higher than those in the Eshell/E− group (all P  < .001), and the RNA-seq results revealed significant extracellular matrix (ECM) remodeling in the LNM-Eshell/E+ group. Conclusions Stiff peri-cancerous tissue induced CAF activation, COL-I deposition, and ECM remodeling, resulting in a poor prognosis for PTC patients with LNM. [ABSTRACT FROM AUTHOR]

Objective Patients with radioiodine-refractory (RAIR) differentiated thyroid carcinoma (DTC; RAIR-DTC) have a poor prognosis. The aim of this study was to provide new insights and possibilities for the diagnosis and treatment of RAIR-DTC. Methods The metabolomics of 24 RAIR-DTC and 18 non-radioiodine-refractory (NonRAIR) DTC patients samples were analyzed by liquid chromatograph-mass spectrometry. Cellular radioiodine uptake was detected with γ counter. Sodium iodide symporter (NIS) expression and thyroid stimulating hormone receptor (TSHR) were measured by Western blot analysis. CCK8 and colony formation assays were used to measure cellular proliferation. Scratch and transwell assays were performed to assess cell migration and invasion. Annexin V/PI staining was used to detect cell apoptosis. Cell growth in vivo was evaluated by a tumor xenograft model. The acetoacetate (AcAc) level was measured by ELISA. Pathological changes, Ki67, NIS, and TSHR expression were investigated by immunohistochemistry. Results The metabolite profiles of RAIR could be distinguished from those of NonRAIR, with AcAc significantly lower in RAIR. The significantly different metabolic pathway was ketone body metabolism. AcAc increased NIS and TSHR expression and improved radioiodine uptake. AcAc inhibited cell proliferation, migration, and invasion, and as well promoted cell apoptosis. Ketogenic diet (KD) elevated AcAc levels and significantly suppressed tumor growth, as well as improved NIS and TSHR expression. Conclusion Significant metabolic differences were observed between RAIR and NonRAIR, and ketone body metabolism might play an important role in RAIR-DTC. AcAc improved cellular iodine uptake and had antitumor effects for thyroid carcinoma. KD might be a new therapeutic strategy for RAIR-DTC. [ABSTRACT FROM AUTHOR]

Background: Medullary thyroid cancer (MTC) is a rare neuroendocrine tumor that originates from the parafollicular C cells of thyroid gland. Understanding the fundamental pathophysiology of MTC is essential for clinical management. Single-cell RNA sequencing (scRNA-seq) technology is a powerful tool for identifying distinct cell types, offering a new biological foundation for comprehending the MTC ecosystem and developing precise treatment. Methods: Formalin fixed and paraffin-embedded (FFPE) samples of primary and adjacent non-cancerous tissues of three MTC cases were collected, and single-cell transcriptome data of MTC were obtained by using scRNA-seq technology. Annotated cell subpopulations were categorized and functionally enriched by principal component analysis, differential gene expression, and cell clustering analysis, to explore the biological process of tumor evolution that may be involved in each cell subpopulation. The copy number variation (CNV) profile was used to distinguish the malignancy of parafollicular thyroid cells, and the evolutionary trajectories of normal cells and tumor cells were revealed by the proposed time series analysis. The highly expressed genes in each cell subpopulation were analyzed by the FindAllMarker function of Seurat software, and verified by immunohistochemistry and fluorescence in situ hybridization. The prognostic value of specific cell subtypes was validated using large-scale public datasets. Results: A total of 32,544 cells were obtained from the MTC tissue samples and 11,751 cells from the adjacent non-cancerous samples, which were classified into 7 heterogenous subpopulations by using R package of Seurat module. Copy number variations (CNVs) were significantly higher in tumor tissues than in adjacent non-tumor samples, predominantly enriched in subtypes C2 and C4. In addition, the pseudo-time for trajectory analysis suggested that the evolution of MTC tumor cells might begin with the C2 subtype, then transition to the early cancer subgroup C3, and further differentiate into four major malignant cell subpopulations C0, C1, C5 and C6. Survival analysis of a thyroid cancer cohort using the TCGA dataset revealed that high expression of genes linked to the C0 subcluster was correlated with poorer overall survival compared to low expression. Immunohistochemical staining showed that MAP3K4 was highly expressed in MTC tissues compared to adjacent non-cancerous tissues. Fluorescence in situ hybridization also confirmed the amplification of these two genes in MTC samples. Conclusions: By conducting scRNA-seq on FFPE samples, we mapped the single-cell transcriptome of MTC, uncovering the tumor heterogeneity and unique biological features of each cellular subpopulation. The biological roles of identified tumor cell subpopulations such as C0 and C3 subtypes of parafollicular cells suggested the potential to discover new therapeutic targets and biomarkers for MTC, providing valuable insights for future translational and clinical research. [ABSTRACT FROM AUTHOR]

Simple Summary: The study analyzed income disparities in 5-year survival rates (5YSR) among cancer patients in South Korea from 2002 to 2018. Overall, 5YSR improved from 2002–2006 to 2014–2018, particularly for lung, liver, and stomach cancers. The Slope Index of Inequality (SII) indicated significant income-related disparities, with higher survival rates associated with higher incomes, notably for lung and liver cancers. The SII for lung, liver, and stomach cancer increased, while that of thyroid, breast, cervical, prostate, and colorectal cancer decreased over the study period. The findings highlight persistent income-related gaps in cancer survival despite overall improvements, emphasizing the need for targeted interventions to address socioeconomic inequalities in cancer care outcomes. Background: The overall survival rates among cancer patients have been improving. However, the increase in survival is not uniform across socioeconomic status. Thus, we investigated income disparities in the 5-year survival rate (5YSR) in cancer patients and the temporal trends. Methods: This study used a national cancer cohort from 2002 to 2018 that was established by linking the Korea Central Cancer Registry and the National Health Insurance Service (NHIS) claim database to calculate the cancer survival rate by income level in the Republic of Korea. Survival data were available from 2002 onward, and the analysis was based on the actuarial method. We compared the survival of the earliest available 5-year period of 2002–2006 and the latest available 5-year period of 2014–2018, observing until 31 December 2021. Income level was classified into six categories: Medical Aid beneficiaries and five NHIS subtypes according to insurance premium. The slope index of inequality (SII) and relative index of inequality were used to measure absolute and relative differences in 5YSR by income, respectively. Results: The 5YSR between the 2002–2006 and 2014–2018 periods for all cancers improved. A significant improvement in 5-year survival rates (5YSR) over the study period was observed in lung, liver, and stomach cancer. The SII of survival rates for lung (17.5, 95% confidence interval (CI) 7.0–28.1), liver (15.1, 95% CI 10.9–19.2), stomach (13.9, 95% CI 3.2–24.7), colorectal (11.4, 95% CI 0.9–22.0), and prostate (10.7, 95% CI 2.5–18.8) cancer was significantly higher, implying higher survival rates as income levels increased. The SII for lung, liver, and stomach cancer increased, while that of thyroid, breast, cervical, prostate, and colorectal cancer decreased over the study period. Conclusions: Although substantial improvement in the 5YSR was observed across cancer types and income levels from 2002 to 2018, this increase was not uniformly distributed across income levels. Our study revealed persistent income disparities in the survival of cancer patients, particularly for lung and liver cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Postoperative hypoparathyroidism (HypoPTH) is the most common complication following total thyroidectomy, but the literature still lacks clear risk and protective factors. This study aimed to evaluate and compare the risk factors for post-surgical HypoPTH in a large series of patients at a tertiary academic high-volume center undergoing total thyroidectomy for both benign and malignant diseases. It also focused on identifying risk and protective factors for persistent HypoPTH. Background: Postoperative hypoparathyroidism (HypoPTH) is the most common complication following total thyroidectomy. Several risk factors have been identified, but data on postoperative follow-up are scarce. Methods: The study focused on 1965 patients undergoing surgery for benign and malignant thyroid diseases at a tertiary-level academic center. Anamnestic, biochemical, surgical, pathological, and follow-up data were evaluated. HypoPTH was defined by a serum concentration of PTH < 10 pg/mL on the first or the second post-operative day. Persistent HypoPTH was defined by the need for calcium/active vitamin D treatment > 12 months after surgery. Results: Postoperative HypoPTH occurred in 542 patients. Multivariate analysis identified the association of central lymph-nodal dissection, reduced preoperative PTH levels, a lower rate of parathyroid glands preserved in situ, and longer duration of surgery as independent risk factors. At a median follow-up of 47 months, HypoPTH regressed in 443 patients (more than 6 months after surgery in 7%) and persisted in 53 patients. Patients receiving a lower dose of calcium/active vitamin D treatment at discharge (HR 0.559; p < 0.001) or undergoing prolonged, tailored, and direct follow-up by the operating endocrine surgeon team had a significantly lower risk of persistent HypoPTH (2.4% compared to 32.8% for other specialists) (HR 2.563; p < 0.001). Conclusions: Various patient, disease, and surgeon-related risk factors may predict postoperative HypoPTH. Lower postoperative calcium/active vitamin D treatment and prolonged, tailored follow-up directly performed by operating endocrine surgeons may significantly reduce the rate of persistent HypoPTH. [ABSTRACT FROM AUTHOR]

Objective: The accurate diagnosis of thyroid nodules is crucial for effective management and the detection of malignancy. Fine-needle aspiration biopsy (FNAB) and fine-needle non-aspiration biopsy (FNNAB) are widely used techniques for evaluating thyroid nodules. In this study, we aimed to investigate the impact of anthropometric parameters and sonographic characteristics on the choice between FNAB and FNNAB in terms of diagnostic yield. Material and Methods: This retrospective and cross-sectional analysis involved 188 cases with a total of 225 thyroid nodules. Each nodule initially underwent either FNAB or FNNAB and if the initial biopsy did not yield a diagnostic result, the nodule was re-biopsied using the alternate technique. Ultrasound was used to evaluate the nodules, with a focus on echogenicity, calcifications, size, vascularity, and the presence of a halo sign. Both FNAB and FNNAB were performed using a 25-gauge needle, with the only difference being the application of suction. Results: FNAB demonstrated a higher diagnostic rate for nodules with a taller-than-wide shape (anteroposteriorto-transverse ratio ≥1), nodules sized 10–40 mm, nodules with volumes <0.5 cc, and hypoechoic nodules (P < 0.001 for all). FNAB also outperformed FNNAB in the assessment of the right-sided, inferior, and posterior nodules (P < 0.001), nodules with and without calcification (P = 0.041 and P = 0.020, respectively), and nodules with type 1 and type 2 vascularity patterns (P = 0.006 and P = 0.017, respectively). FNAB was effective in obese individuals (Body mass index ≥40 kg/m2), males with a waist circumference of <94 cm, females with a waist circumference of ≥80 cm, and females with a neck circumference of ≥34 cm (P = 0.011, P = 0.044, P = 0.029, and P = 0.008, respectively). Conclusion: Anthropometric parameters and sonographic characteristics influenced the diagnostic yield of FNAB and FNNAB, with FNAB generally demonstrating superior results. Given the importance of obtaining an accurate diagnostic result from fine-needle biopsy, clinicians should consider both the sonographic features of the nodule and the anthropometric measurements of the patient when selecting a biopsy technique. [ABSTRACT FROM AUTHOR]