Thyroid Carcinoma Research Articles

Molecular Profiling and Surgical Outcomes in Indeterminate Thyroid Nodules: Experience from a Tertiary Care Center

Abstract Introduction/Objective This study examines molecular results(MR) and surgical follow-up(SFU) of cytologically- indeterminate thyroid nodules. Methods/Case Report Atypia-of-undetermined significance/suspicious-for-follicular-neoplasm cases that underwent Quest/ThyroSeq molecular testing between 2015-2022 were analyzed for MR, SFU and lymph node metastasis(LNM). Results (if a Case Study enter NA) 417 cases(Quest=192, ThyroSeq=225). 59% had SFU. 43% malignancy rate.SFU for Quest(49%): non-neoplastic(NNP)=20%, neoplastic(NP)=80%. MR in these cases:NRAS=48, HRAS=19, BRAF=15, KRAS=8, RET/PTC=3, PAX8=2. SFU: papillary thyroid carcinoma(PTC)=35, non-invasive-follicular-thyroid- papillary-neoplasm with papillary-like nuclear features(NIFTP)=20, thyroid nodular follicular disease(TFND)=18, follicular adenoma(FA)=10, follicular carcinoma(FC)=5, oncocytic carcinoma(OC)=1, lymphocytic thyroiditis(LT)=1. Surgical-molecular correlation(SMC): PTC in 3/3 RET/PTC-mutated, 14/15 BRAF-mutated cases. 1 TFND was BRAF- positive. RAS-mutated category: NIFTP=20,PTC=18,TFND=17,FA=9, OA=5, FC=5, LT=1. In RAS-mutated PTCs, NRAS was most common(n=13), followed by HRAS(n=4) and KRAS(n=1). 2 PAX8-mutated cases showed FA and OC. 9/41 malignant cases, all PTC, had LNM, MR:BRAF=6, HRAS=2, RET/PTC=1.SFU for ThyroSeq(68%): NN=10%, NNP=90%. MR:NRAS=34, copy number alterations(CNAs)=25, HRAS=14, BRAF=13, KRAS=11, gene expression alterations(GEA)=7, THADA+IGF2BP3=7, CNAs Hurthle cell type(HCT)=6, EIF1AX=6, DICER1=4, PAX8- PPARG fusion=4, CNAs+GEA=3, NTRK3=3, TERT=2, RAS+EIF1AX=2, TERT+CNAs=2, EIF1AX=1, EZH1=1, RET/PTC1 fusion=1, ALK=1, BRAF K601E=1,RAS+TERT=1, RAS+TERT+PTEN+EIF1AX=1, TERT+BRAF=1, TERT+EIF1AX=1,TP53+CNAs=1. SFU:PTC=39, NIFTP=31, OA=21, FA=20, papillary microcarcinoma(PMiC)=13, TFND=10, OC=7, LT=6, FC=5, poorly differentiated carcinoma(PdC)=1.10/13 BRAF-mutated cases were PTC, other 3 PMiC. SFU of RAS-mutated cases(n=59):TFND=6, LT=4, NIFTP=19, FA=8, OA=4, PTC=13, PMiC=2, FC=2. RAS mutations in PTC: KRAS=6, HRAS=4, NRAS=3. SFU of CNAs-HCT: OA=3, OC=2, TFND=1. Infrequently detected mutations with SFU of PTC:RET/PTC(1/1), ALK(1/1), RAS+TERT(1/1), TERT+BRAF(1/1), BRAF K601E(1/1), RAS+EIF1AX(1/2). SFU of RAS+TERT+PTEN+EIF1AX:PdC. 11/65 malignant cases, all PTC had LNM:BRAF=5, KRAS=3, CNAs=1, EIF1AX=1, TERT+BRAF=1. Conclusion Substantial proportion of cases with positive MR underwent surgical resection. BRAF-positive and CNAs- HCT correlated with PTC and oncocytic neoplasms, respectively. BRAF-positive PTCs had a higher incidence of LNM compared to wild-type cases(46% vs.18%).

Familial adenomatous polyposis gene MUTYH mutations are identified in anaplastic thyroid carcinoma

Abstract Introduction/Objective Anaplastic thyroid carcinoma (ATC) is a rare aggressive disease unresponsive to treatment. Next-Generation Sequencing (NGS) allows identification of targets for precision therapies, such as BRAF, with implications in treating ATC. Our prior work identified ATC clusters with characteristic gene mutations and multiple previously unreported mutations. One of these is MUTYH, which is associated with colon (CRC), ovarian, breast, bladder, and duodenal carcinomas in MUTYH-associated polyposis (MAP). Its association with ATC is not defined. Methods/Case Report Exploratory analysis of pathogenic mutations in 727 ATC cases using a 324-gene panel (FoundationOneCDx) and an interactive visualization of association rules was conducted for informative maximal frequent patterns among mutated gene combinations to identify gene clusters including genes not commonly associated with ATC. TCGA database was reviewed for frequency of MUTYH mutations. My Cancer Genome and the Drug-Gene Interaction Database were used to identify potential targeted drugs for MUTYH gene-mutated cancers. Results (if a Case Study enter NA) NGS showed MUTYH short-variant mutations in 17 cases (2.34%). Germline MUTYH variants incidence is 1.43% in normal samples. 5 cases harbored only Y165C and 7 had only G382D, with 1 case having both Y165C and G382D. The other 4 cases contained sporadic truncating events in MUTYH. All instances of Y165C and G382D were predicted to be germline. 6 patients (35%) had BRAF co-mutations, correlating with expected frequency of ATC thought to transform from papillary carcinoma (PC). One case had only MUTYH mutation while a second had MUTYH with TERT and TP53. TCGA database contained 6(0.2%) cases of PC with MUTYH mutations (total 2871 MUTYH-mutated carcinomas), but no cases of ATC or other thyroid tumors were described. Conclusion MUTYH is a DNA repair enzyme linked to CRC and other cancers. MUTYH mutations occur in 6.7% of MAP patients and 1–2.2% of sporadic CRC cases that are mutually exclusive of BRAF mutations. While MAP increases the lifetime risk of CRC by over 60%, the link of MUTYH mutations to PC has only been observed in MAP and not been described outside of it. To our knowledge this is the first description of MUTYH mutations in ATC, especially without concurrent BRAF mutation (11 cases), suggesting MUTYH may independently contribute to pathogenesis of ATC. PARP inhibitors, PD-1/PD-L1 inhibitors, and ATR inhibitors demonstrate promising results in clinical trials of MUTYH-mutated cancers, warranting further research.

Expression of CLDN1 and EGFR in PTC

Papillary thyroid carcinoma (PTC) involves complex genetic mechanisms, notably involving CLDN1 and EGFR. This study investigates the expression and variations of these genes and their effects on tumor behavior and patient outcomes. Meta-analysis of CLDN1 and EGFR expression in TCGA–PTC patients and GEO datasets was conducted. cBioPortal was used for clinical analysis. GSEA, GO, KEGG, Hallmark pathways, and cibersort analysis were applied. Cell proliferation, migration, invasion, and apoptosis were assessed in vitro. Co-culturing with CD8+ T cells, MTT assay, ELISA, subcutaneous tumor models, and immunohistochemistry were performed. TGF-β pathway-related proteins were analyzed via Western blot. CLDN1 and EGFR were overexpressed in PTC tumors, correlating with higher-risk patients and reduced CD8+ T cell infiltration. Silencing these genes inhibited tumor cell functions and enhanced CD8+ T cell activity, both in vitro and in vivo. CLDN1 and EGFR are crucial in PTC, linked to tumor invasiveness, EMT, and immune suppression, presenting them as potential therapeutic targets.

Thyroid Lesion with a Novel Concurrent ETV6-NTRK3 Translocation and DICER1 Mutation

Abstract Introduction/Objective Understanding of the behavior of thyroid tumors expand as the basis of their classification gradually move from morphologic to molecular/genetic. The use of molecular methods in detecting mutations in fine needle aspiration (FNA) specimens further helped in tailoring patient management. Here, we describe a case of a thyroid lesion which was diagnosed with atypia of undetermined significance (AUS) on FNA and discovered to have an unreported concurrent mutation pattern. Methods/Case Report The patient is a 26 year-old female with long standing history of prominent anterior neck mass. New onset of neck pain prompted sonographic analysis which revealed a 1.1 cm hypoechoic left thyroid nodule with microcalcification. FNA was done, and was signed out as AUS which initiated molecular genetic testing. The lesion was found to have both ETV6/NTRK3 translocation and DICER1 p.P375R mutation. Existing literature on NTRK3 rearrangements in thyroid tumors confer a >95% risk of malignancy. It is commonly associated with BRAF-negative papillary thyroid carcinomas (PTC) with both in BRAF-like behavior in terms of nodal metastases and extrathyroidal extension. On the other hand, there are no existing literature specifying the malignancy risk of the exact DICER1 mutation identified since it has been linked to follicular neoplasms in general. Furthermore, isolated DICER1 mutations in the thyroid showed RAS-like behavior. Subsequent resection of the thyroid revealed that the tumor is morphologically a PTC, with lymphovascular invasion. Results (if a Case Study enter NA) NA Conclusion Molecular testing in thyroid lesions with morphologically indeterminable features on FNA significantly aided in prognostication of patients and prediction of malignancy risk. In this case with a previously unreported combination of mutations, existing literature helped in describing the probable behavior of the patient’s tumor. Thus, the researchers emphasize the importance of databases of identified mutations in tumors and their associated characteristics such as The Cancer Genomic Atlas (TCGA) and The Catalogue of Somatic Mutations in Cancer (COSMIC).

Regional distribution of anaplastic thyroid cancer in the United States

Abstract Introduction/Objective Anaplastic thyroid cancer (ATC) is an aggressive rare malignancy found in less than 2% of thyroid cancer patients. Its low occurrence rate presents challenges for collecting sufficiently large cohorts at a single institution, making statistical analysis about the disease’s spread, geographical distribution, and prevalence difficult. Nationwide data lakes such as Oracle EHR Real-World Data (ORWD, formerly Cerner Real World Data) offer a boost in cohort sizes and an opportunity to study ATC’s geographical distribution and assess regional differences. Methods/Case Report We searched ATC distribution across US regions defined by ZIP codes recorded in ORWD using multiple coding parameters, including ICD9, ICD10, and SNOMED as well as direct text searches for “anaplastic thyroid carcinoma”. We analyzed the geographical associations defined by ORWD (region) with sex, race, and age of ATC onset using the Fisher’s exact test. We combined 10 regions into 4 representative groups because of the small sample size. The groups are West Coast including the Rockies, Midwest from North Dakota to Texas, East Coast, and New England. Results (if a Case Study enter NA) Search for ATC condition codes in ORWD produced only 200 region-coded patient records across the US using multiple methods to try and identify cases. The mid-section of the US and coastal regions shows the highest numbers of ATC patients while New England and South regions show the lowest. While more women have ATC overall, the East Coast group has significantly more males (p value = 0.04). ATC is a predominantly white disease (79.8% overall) with black population increasing in East Coast group and other races (Asian/Undeclared) in West Coast (p-value < 0.001). There appears to be no significant association between age of ATC onset and the geographical groups. Conclusion The data shows geographic differences in distribution of ATC although this preliminary analysis neither explains the nature of these differences nor allows for a clearer view. The rarity of the disease complicates data analysis. This study was also limited by number of cases retrievable from the database itself and lack of granularity in coding available for ATC to find cases of interest, highlighting the difficulty of accurate tumor classifications in large data lakes. Further research into geographical distribution and environmental factors (radioactivity, pollution) of thyroid cancer using more advanced tools, such as GeoSpark, are planned.

Dysregulation of pseudouridylation in small RNAs contributes to papillary thyroid carcinoma metastasis

BackgroundPrevious studies have indicated that ψ-modified small RNAs play crucial roles in tumor metastasis. However, the ψ-modified small RNAs during metastasis of PTC are still unclear.MethodsWe compared the pseudouridine synthase 7 (PUS7) alteration between metastatic and non-metastatic PTCs, and investigated its correlation with clinicopathological features. Additionally, we employed a small RNA ψ modification microarray to examine the small RNA ψ modification profile in both metastatic and non-metastatic PTCs, as well as paired paracancerous tissues. The key molecule involved in ψ modification, pre-miR-8082, was identified and found to regulate the expression of CD47. Experiments in vitro were conducted to further investigate the function of PUS7 and CD47 in PTC.ResultsOur results demonstrated that PUS7 was down-regulated in PTC and was closely associated with metastasis. Moreover, the ψ modification of pre-miR-8082 was found to be decreased, resulting in down-expression of pre-miR-8082 and miR-8082, leading to the loss of the inhibitory effect on CD47, thereby promoting tumor migration.ConclusionsOur study demonstrates that PUS7 promotes the inhibition of CD47 and inhibits metastasis of PTC cells by regulating the ψ modification of pre-miR-8082. These results suggest that PUS7 and ψ pre-miR-8082 may serve as potential targets and diagnostic markers for PTC metastasis.

Approach to the patient with thyroid nodules: considering GLP-1 receptor agonists.

Glucagon-like peptide 1 receptor agonists (GLP1RA) have rapidly changed the landscape of diabetes and obesity treatment. Enthusiasm for their use is tempered with concerns regarding their risk for inducing C-cell tumors based on preclinical studies in rodents. A black-box warning from the United States Food and Drug Administration (USFDA) recommends against using GLP1RA in patients with a personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2A or 2B (MEN2), providing clear guidance regarding this cohort of patients. However, emerging data also suggest an increased incidence of differentiated thyroid cancer (DTC) in patients treated with these agents. Other studies, though, have not confirmed an association between GLP1RA and DTC. With conflicting results concerning thyroid cancer risk, there is no clear consensus regarding the optimal approach to screening patients prior to initiating the medications and/or evaluating for thyroid cancer during GLP1RA treatment. Within the context of patient cases, this review will summarize the existing data, describe ongoing controversies, and outline future areas for research regarding thyroid cancer risk with GLP1RA use.

Aggressive Types of Malignant Thyroid Neoplasms.

Differentiated thyroid cancer (DTC) includes many subtypes, which demonstrate favorable to aggressive behavior. During the past decades, efforts have been made to describe aggressive thyroid cancers. Within DTC, aggressive variants constitute rare entities with unique histopathological features and compromised survival, as local and distant metastatic disease is frequent. In recent years, the distinct category of poorly differentiated thyroid cancer was introduced in 2004 and the type of differentiated high-grade thyroid carcinoma was recently added in the 2022 WHO classification of thyroid neoplasms. Finally, anaplastic thyroid cancer exhibits a rapid, resistant to therapy, progression and confers the shortest survival. In this review, we will present the characteristics of these thyroid cancer types and also discuss the treatment, management, and follow-up of these difficult cases. Emphasis was given to recent bibliography of the last decade.

The Prevalence and Prognostic Implications of BRAF K601E Mutations in Thyroid Neoplasms: A Systematic Review and Meta-Analysis.

Activating mutations in the BRAF oncogene occur in 45% of papillary thyroid carcinomas (PTCs). Though less studied, K601E may identify a clinically distinct subset of thyroid neoplasms. A bioinformatics assessment was conducted using the COSMIC database and in silico data analysis. A systematic search was conducted through August 2024 to identify studies reporting BRAF mutation in thyroid neoplasms. Pooled prevalence, histopathological subtype distribution, extrathyroidal extension, lymph node metastasis, recurrence, and survival were extracted/analyzed from 32 studies (13 191 patients). In the COSMIC database, BRAF K601E was found in various tissue types but mainly in the thyroid. In silico data analysis revealed a structural and functional basis for differences between K601E and V600E. Upon systematic review, the BRAF K601E mutation was identified in 2.8% of PTCs compared to 22% with V600E. The stratified analysis revealed geographical differences, with higher rates in Italy (5.23%) and the United States of America (3.31%). The K601E mutant was enriched for follicular-patterned variants like NIFTP (11.2% of cases). Meta-analysis demonstrated significantly reduced extrathyroidal extension for K601E versus V600E mutants (RR = 0.22, 95% CI = 0.10-0.50, p = 0.0003). K601E-mutated neoplasms could be a unique clinicopathological entity associated with low-risk histology and reduced extrathyroidal extension, consistent with a more indolent course than V600E mutants. Although detecting K601E may potentially guide conservative management, further prospective studies are needed.

Identification of potential biomarkers of papillary thyroid carcinoma.

This study aimed to identify candidate biomarkers for papillary thyroid carcinoma using an integrative analysis of bioinformatics and machine learning (ML). The PTC datasets GSE6004, GSE3467, and GSE33630 (species: Homo sapiens) were downloaded from NCBI and analyzed using the limma package to obtain DEGs. Once DEGs were identified, GO and KEGG enrichment analyses were performed as the first step in the bioinformatics process. Subsequently, a protein-protein interaction (PPI) network was constructed according to the common genes in bioinformatics and machine learning using STRING to elucidate the important genes involved in PTC pathogenesis. In machine learning, finding genes entails feature selection to identify the key genes that distinguish biological states. Hybrid feature selection will be used for this. In the second step, the original data sets were preprocessed to detect and correct missing and noisy data; after that, all data were merged. Following performing Linear and Discriminative Hybrid Feature Selection (LDHFS) on the processed dataset, machine learning algorithms such as Random Forest (RF), Naive Bayes (NB), and Support Vector Machines (SVM) are utilized. Bioinformatics and machine learning analyses indicate that the genes RXRG, CDH2, ETV5, QPCT, LRP4, FN1, and LPAR5 are integral to the progression of thyroid cancer. This study attained the highest accuracy utilizing the RF algorithm, achieving an accuracy rate of 94.62%, a Kappa value of 91.36%, and an AUC value of 96.13%. These results offer additional evidence and confirmation for the genetic alterations of these genes. These findings may accelerate the development of prospective therapeutic and diagnostic methods in future research. Bioinformatics and machine learning techniques identified the common genes "RXRG, CDH2, ETV5, QPCT, LRP4, FN1, and LPAR5" as PTC biomarkers, providing novel reference markers for the diagnosis and treatment of PTC patients. The model is anticipated to possess significant predictive value and assist in the early diagnosis and screening of clinical PTC. These insights enhance the field of PTC management and offer guidance for future research.

Does The Diagnostic Performance Of The Pathologist On The Indeterminate Categories Of The Bethesda System For Reporting Thyroid Cytopathology Vary Between Pediatric And Adult Patients?

The objectives of this study were to investigate the variation in the use of indeterminate categories of The Bethesda System for reporting thyroid cytopathology across age groups, particularly focusing on 'atypia of undetermined significance (AUS) category, and discern the potential role of a bias in pathologist's interpretation when dialing with pediatric patients. To highlight a more refined diagnostic pattern, thyroid fine-needle aspirations reported by a single pathologist over a span of 10 years enrolled to the study. A total of 8827 cases from patients aged between 2 and 89 were categorized for each decades of ages. For the AUS category, AUS to malignant (AUS:M) ratio was calculated, and variations in distinct age groups and across the years were noted. The rate of indeterminate categories was 19% for the pediatric cases and 11% for the adults. When compared to adults, AUS diagnosis was more common in pediatric patients (14% vs. 9%), with rates of malignancy (ROM) 54% and 45%, respectively. The AUS:M ratio during the study period ranged between 0.5 and 2.3 (mean 1.4). AUS:M ratio was highest in children below the age 11. Among AUS subtypes, AUS-nuclear predominated in both age groups, and papillary thyroid carcinoma emerged as the most common malignancy after resection. Follicular neoplasia category was higher in pediatric patients than adults (4% vs.1%), with similar ROMs (29% vs. 32%). Indeterminate cytology diagnosis and subsequent ROM is higher in pediatric patients, which might be attributable to a slightly higher use of AUS diagnosis in the youngest children.

"Long-Term Active Surveillance for Patients with Low- Risk Papillary Thyroid Carcinoma in Bulgaria"

"Long-Term Active Surveillance for Patients with Low- Risk Papillary Thyroid Carcinoma in Bulgaria"

Clinicopathological Findings of 220 Pediatric, Adolescent, and Young Adult Patients with Thyroid Cancer in Fukushima Medical University Hospital.

Background: Thyroid ultrasound examinations (TUEs), conducted as part of the Fukushima Health Management Survey (FHMS), were initiated to monitor the health status of residents after the Fukushima Daiichi Nuclear Power Plant accident owing to concerns regarding the increased incidence of thyroid cancer among children, as observed after the Chernobyl Nuclear Power Plant accident. This study reported the clinicopathological characteristics of patients with thyroid cancer diagnosed through the FHMS and treated at the Fukushima Medical University Hospital. Methods: Data regarding the clinicopathological characteristics of patients with thyroid cancer were collected and evaluated in this descriptive study. Results: Among the 263 patients diagnosed with thyroid cancer as of September 2021, 220 patients with cytologically diagnosed thyroid cancer were treated as referrals from the FHMS. The median (interquartile range) age at the time of diagnosis was 18.6 (16.2-20.3) years. The median maximum tumor diameter was 13.0 (10.4-18.0) mm. To reduce surgical invasiveness, 199 patients (90.1%) underwent unilateral lobectomy. Pathological findings were suggestive of papillary thyroid carcinomas (PTC) in 216 (98.2%) patients; among them, 205 patients had PTC of the classical type. In addition, 216 (98.2%) patients had stage I disease. Cancer cell extension in the sternothyroid muscle or perithyroidal soft tissues and microscopic lymphovascular invasion were observed in 112 (50.9%) and 123 (55.9%) patients, respectively. No differences were observed between the two age groups (<18.6 years and ≥18.6 years) in terms of the clinical or pathological characteristics of thyroid cancer: risk classification (p = 0.69) and American Thyroid Association pediatric risk level (p = 0.24). Compared with those from previous reports, few surgical complications were observed. Conclusions: Patients with thyroid cancer diagnosed with TUEs underwent safe and minimally invasive operations, and careful postoperative follow-up was provided. The pathological findings of the detected thyroid cancers indicated that the majority were classical papillary carcinomas, and approximately half of the patients had extrathyroidal or lymphovascular invasion. No differences were observed between the two age groups in terms of the clinical or pathological characteristics of thyroid cancer.

Reproductive life and differentiated thyroid carcinoma in women: reciprocal influences on their respective outcome.

To analyze the reciprocal influences between female reproductive life and DTC management. Data on pregnancy outcome in DTC patients indicate that after conceiving, these women may need an increased L-T4 dose to maintain suppressed serum TSH levels. Nevertheless, this does not determine major harm in terms of pregnancy outcome. Analogously, the most recent findings obtained with the propensity score matching approach have confirmed that pregnancy does not significantly affect DTC clinical course and eventually tumor prognosis. A recent metanalysis and a large case-control study excluded a significant effect of radioactive iodine treatment (RAIT) on several reproductive variables in DTC patients, providing reassuring evidence that the current recommendations on RAIT for women of childbearing age are sufficiently well tolerated and do not affect fertility nor pregnancy rate. Overall, the most recent studies have provided sufficiently reassuring evidence that the occurrence of pregnancy and DTC management are of no reciprocal harm for adverse outcome in affected women of childbearing age. Thus, female DTC patients should be managed according to the individual response to treatment before pregnancy. When DTC diagnosis is made after conception, delaying surgery does not represent a harm in most patients.

Holomics and Artificial Intelligence-Driven Precision Oncology for Medullary Thyroid Carcinoma: Addressing Challenges of a Rare and Aggressive Disease.

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.

USP4 promotes PTC progression by stabilizing LDHA and activating the MAPK and AKT signaling pathway.

Ubiquitin-specific protease 4 (USP4) has been identified as a promising oncogenic factor implicated in various human malignancies. However, the exact biological functions and underlying mechanisms of USP4 in the progression of papillary thyroid carcinoma (PTC) remain elusive. In this study, we observed a marked upregulation of USP4 expression in PTC tumor tissues. Elevated levels of USP4 were significantly correlated with aggressive clinicopathological features and poor prognosis. Functional assays for loss-of-function demonstrated that silencing USP4 hindered the proliferation of PTC cells. Furthermore, our investigation revealed a specific interaction between USP4 and lactate dehydrogenase A (LDHA), wherein USP4 played a crucial role in stabilizing LDHA protein levels via deubiquitination in PTC cells. Notably, this study demonstrated that USP4 promotes PTC proliferation by modulating the MAPK and AKT signaling pathways. In summary, our findings elucidate the critical involvement of the USP4/LDHA axis in driving PTC progression through the modulation of MAPK and AKT pathways, thereby identifying USP4 as a potential therapeutic target for the treatment of PTC.

Amyloid Goiter, Papillary Thyroid Carcinoma, and Diffuse Thyroid Lipomatosis: A Case Report of a Rare Association

Amyloid Goiter, Papillary Thyroid Carcinoma, and Diffuse Thyroid Lipomatosis: A Case Report of a Rare Association

Clinical and Histopathological Features of Thyroid Cancer with TERT Promoter Molecular Alterations in Isolation Versus with Concurrent Molecular Alterations: A Multicenter Retrospective Study

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 &gt;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.

Características genéticas y manifestaciones fenotípicas extracolónicas en pacientes con poliposis adenomatosa familiar

IntroductionFamilial adenomatous polyposis (FAP) is a hereditary disease caused by mutations in the APC gene, which is also associated with extracolonic manifestations. The objective was to characterize the extracolonic manifestations in a cohort of patients with classic FAP and the possible genotype-phenotype association. Materials and methodsThe study design was observational and descriptive. Demographic, clinical, and genetic variables were collected based on the type of mutation (frameshift, nonsense, splicing, rearrangement, and others). ResultsWe included 45 patients with FAP (mean age 47years, range 21-78; 51% female), belonging to 21 families, with a median of 2 (range 0-6) manifestations per patient. Eighty percent (n=36) had upper digestive tract involvement, with duodenal adenomas (73%), fundic gland polyposis (56%), and ampullary adenoma (36%) being the most frequent findings. The most common extraintestinal manifestations were desmoid tumors (16%) and papillary thyroid carcinoma (13%). Thirty eight percent of the patients presented an aggressive phenotype (SpigelmanIII-IV, high-grade dysplasia, invasive neoplasia, desmoid tumor, and papillary thyroid carcinoma). The most common genetic mutations were frameshift (56%), nonsense (26%), and splicing (16%), primarily located in exon15 (50%). No significant correlation was found between the type of genetic mutation and the severity or location of phenotypic manifestations. ConclusionsOne-third of patients with FAP present an aggressive phenotype, without a demonstrated correlation between the type of genetic alteration and the phenotypic manifestations.

MAPK pathway and NIS in B-CPAP human papillary thyroid carcinoma cells treated with resveratrol

BackgroundResveratrol, a herbal phytoalexin, is known to have anti-tumor effects in several tumors including thyroid cancer cells. AimThe aim of this study was to determine the effects of resveratrol on the expression of BRAF, ERK and NIS mRNA levels and protein expression in B-CPAP human thyroid papillary cancer cell line. MethodsB-CPAP cells were treated with resveratrol at concentrations of 10–100 μM for 24–48–72 h. Cell viability was assessed by XTT Cell Proliferation Assay. BRAF, ERK and NIS mRNA levels were evaluated by rt-PCR method. Protein expressions were evaluated by Western Blot method. ResultsResveratrol was found to inhibit cell proliferation in a time and dose dependent manner. The IC50 values of resveratrol were 18.7 μM and 56.8 μM after 48 h and 72 h respectively. Resveratrol treatment of B-CPAP cells resulted in up to 1.5-fold reduction in BRAF mRNA and up to 5.5 fold reduction in ERK mRNA levels. NIS mRNA levels showed up to 3-fold increase. Western Blot studies confirmed the rt- PCR results with a decrease in BRAF and ERK, and increase in NIS protein expressions. ConclusionThis study demonstrated that resveratrol inhibits thyroid papillary carcinoma cell proliferation and reduces poor prognostic BRAF and ERK mRNA and protein expressions, while increasing NIS mRNA and protein expression suggesting a redifferentiating effect. More studies are needed to evaluate resveratrol as a novel therapeutic agent in the treatment of papillary thyroid cancer.