Search Results (94)

DICER1 syndrome is a hereditary cancer predisposition syndrome, characterized by a large range of benign and malignant neoplasms. Patients with DICER1 syndrome have a broad phenotype, with pleuropulmonary blastoma, Sertoli–Leydig cell tumor, cystic nephroma, cervical embryonal rhabdomyosarcoma, cystic lung lesions, and thyroid follicular nodular disease being the most prevalent manifestations. The syndrome is caused by loss-of-function germline variants in the DICER1 gene, and DICER1-related tumors are characterized by second somatic hotspot variants in the RNase IIIb domain of DICER1. DICER1 encodes an endoribonuclease, which is important for RNA interference. This review describes the molecular mechanism of DICER1 function and the pathogenetic mechanisms of tumorigenesis. The purpose of this review is to describe the pathogenesis, genotype–phenotype correlation and tissue specificity of DICER1 syndrome. We conclude that there is a lack of knowledge about the exact molecular mechanisms of DICER1 function and more research is needed to determine the exact role of this altered protein in relation to pathogenesis. Full article

Follicular lymphoma (FL) is one of the most common types of non-Hodgkin’s lymphomas. The tumor is characterized by a wide range of clinical manifestations, ranging from indolent forms to early transformation and progression with a poor prognosis. The search for clinically significant genetic changes is essential for personalized risk assessment and treatment selection. The CREBBP gene is frequently mutated in this type of lymphoma, with changes occurring at the level of the earliest tumor precursor cells. However, the prognostic and diagnostic significance of the CREBBP gene mutation status in FL has not been fully established. In this study, we analyzed sequencing data of exons 22–30 of the CREBBP gene in 86 samples from patients with different grades of FL (1–3B), including those in the 3A–3B subgroup without the t(14;18) translocation. We also investigated the prognostic significance of CREBBP gene mutations in relation to the treatment options, namely high-dose chemotherapy with autologous hematopoietic stem cell transplantation (HDCT/auto-HSCT) and conventional chemotherapy programs (CCT). It was found that FL patients with a single missense mutation in the KAT domain of the CREBBP gene experienced an extremely low number of early adverse events related to lymphoma and had better long-term survival rates, regardless of treatment option. In contrast, when comparing patients with FL without a missense mutation in the KAT domain or those with multiple mutations in the CREBBP gene, overall and progression free survival were worse, and early progression and histological transformation were more common. Compared to standard therapy, patients who underwent HDCT/auto-HSCT in the FL 1–3B (14;18)-positive group without a single missense mutation in the KAT domain had better survival rates and lower rates of transformation and early progression. In addition, among patients with FL 3A–3B (14;18)-negative, we found that there were no cases of a missense mutation in the KAT domain of the CREBBP gene. This suggests that a single missense mutation in the CREBBP gene may be a feature that discriminates 14;18-positive FL with a favorable prognosis from a high-risk disease. FL 3A–3B (14;18)-negative may represent a distinct variant with different biology and underlying mechanisms of development compared to classical FL. Full article

Thyroid cancer (TC) is a significant global health issue that exhibits notable heterogeneity in incidence and outcomes. In low-resource settings such as Africa, delayed diagnosis and limited healthcare access exacerbate mortality rates. Among follicular cell-derived thyroid cancers—including papillary (PTC), follicular (FTC), anaplastic (ATC), and poorly differentiated (PDTC) subtypes—the role of CD44 variants has emerged as a critical factor influencing tumor progression and multidrug resistance (MDR). CD44, a transmembrane glycoprotein, and its splice variants (CD44v) mediate cell adhesion, migration, and survival, contributing to cancer stem cell (CSC) maintenance and therapy resistance. Differential expression patterns of CD44 isoforms across TC subtypes have shown diagnostic, prognostic, and therapeutic implications. Specifically, CD44v6 expression in PTC has been correlated with metastasis and aggressive tumor behavior, while in FTC, its expression aids in distinguishing malignant from benign lesions. Furthermore, CD44 contributes to MDR through enhanced drug efflux via ABC transporters, apoptosis evasion, and CSC maintenance via the Wnt/β-catenin and PI3K/Akt pathways. Targeted therapies against CD44 such as monoclonal antibodies, hyaluronic acid-based nanocarriers, and gene-editing technologies hold promise in overcoming MDR. However, despite the mounting evidence supporting CD44-targeted strategies in various cancers, research on this therapeutic potential in TC remains limited. This review synthesizes existing knowledge on CD44 variant expression in follicular cell-derived thyroid cancers and highlights potential therapeutic strategies to mitigate MDR, particularly in high-burden regions, thereby improving patient outcomes and survival. Full article

Background/Objectives: The 2023 revision of the Bethesda System for Reporting Thyroid Cytopathology (BSRTC) simplified the subcategorization of category III into two groups: “AUS-nuclear” and “AUS-other”. The aim of this study was to investigate the risk of malignancy (ROM) of individual BSRTC categories with a particular emphasis on the “AUS-nuclear” and “AUS-other” subcategories and to check whether the low-risk follicular-cell-derived thyroid neoplasm (LRTN) interpretation or EU-TIRADS class of the nodule modify ROM. Methods: The analysis covered the FNA results of 18,225 nodules in 12,470 patients. The rate of malignancy (the upper limit of ROM) was established on the basis of the assessment of 1660 nodules treated surgically in 978 patients. Results: In the broadest variant, with all LRTNs regarded as malignant, the ROM for subsequent categories was as follows: I: 0.4–3.5%, II: 0.1–1.3%, III: 3.8–17.7%, IV: 23.3–27.8%, V: 79.6–90.1%, and VI: 86.3–100.0%. In AUS-nuclear nodules, the ROM was 10.5–28.9%, while in AUS-other nodules, it was 2.2–12.2%. The exclusion of NIFTP or all LRTNs from cancers mainly affected the ROM of AUS-nuclear nodules: 9.4–25.9% or 8.6–23.7%, respectively. EU-TIRADS 5 class increases the ROM in AUS-nuclear nodules to 78.3%, OR: 15.7 and in AUS-other to 40.7%, OR: 6.6. Conclusions: The 2023 BSRTC is a welcome step towards simplification of the way nodules are classified within category III. The AUS-nuclear subcategory is associated with a two-times-higher incidence of malignancy than the AUS-other regardless of LRTN interpretation and EU-TIRADS class of the nodule. The EU-TIRADS 5 class of the nodule is helpful in the identification of category III nodules with a high risk of malignancy. Full article

Background: Lung adenocarcinoma (LUAD) is a common histopathological variant of non-small cell lung cancer. Individuals with type 2 diabetes (T2DM) face an elevated risk of developing LUAD. We examined the common genomic characteristics between LUAD and T2DM through bioinformatics analysis. Methods: We acquired the GSE40791, GSE25724, GSE10072, and GSE71416 datasets. Differentially expressed genes (DEGs) were identified through R software, particularly its version 4.1.3 and analyzed via gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Subsequently, we analyzed the relationship between immune cell infiltration and DEGs. we constructed a protein–protein interaction network using STRING and visualized it with Cytoscape. Moreover, gene modules were identified utilizing the MCODE plugin, and hub genes were selected through the CytoHubba plugin. Additionally, we evaluated the predictive significance of hub genes using receiver operating characteristic curves and identified the final central hub genes. Finally, we forecasted the regulatory networks of miRNA and transcription factors for the central hub genes. Results: A total of 748 DEGs were identified. Analysis of immune infiltration showed a notable accumulation of effector-memory CD8 T cells, T follicular helper cells, type 1 T helper cells, activated B cells, natural killer cells, macrophages, and neutrophils in both LUAD and T2DM. Moreover, these DEGs were predominantly enriched in immune-related pathways, including the positive regulation of I-κB kinase/NF-κB signaling, positive regulation of immunoglobulin production, cellular response to interleukin-7, and cellular response to interleukin-4. The TGF-β signaling pathway was significantly important among them. Additionally, seven hub genes were identified, including ATR, RFC4, MCM2, NUP155, NUP107, NUP85, and NUP37. Among them, ATR, RFC4, and MCM2 were identified as pivotal hub genes. Additionally, hsa-mir147a, hsa-mir16-5p, and hsa-mir-1-3p were associated with LUAD and T2DM. SP1 (specific protein 1) and KDM5A (lysine-specific demethylase 5A) regulated MCM2, ATR, and RFC4. Conclusions: Our study elucidates the common mechanisms of immune response, TGF-β signaling pathway, and natural killer cells in LUAD and T2DM, and identifies ATR, RFC4, and MCM2 as key potential biomarkers and therapeutic targets for the comorbidity of these two conditions. Full article

T follicular helper (Tfh) and T follicular regulatory cells (Tfr) are required for antibody production and are dysregulated in SLE. Genetic variants within or near interferon regulatory factor 5 (IRF5) are associated with SLE risk. We previously reported higher plasma cells and autoantibodies in healthy IRF5-SLE homozygous risk carriers. Here, we report the dysregulation of circulating Tfh and Tfr in both SLE patients and presymptomatic IRF5-SLE homozygous risk carriers. Full article

The pediatric common variable immunodeficiency (CVID) is the most frequent symptomatic antibody production defect characterized by infectious and non-infectious autoimmune, inflammatory, and lymphoproliferative complications. The background for CVID-related organ-specific immunopathology is associated with immune dysregulation and immunophenotypic biomarkers with expansion of CD21low B cells, and dysfunctional memory B cell, follicular T cell, and regulatory T cell compartments. The ever-increasing progress in immunogenetics shows the heterogeneity of genetic background for CVID related to the complexity of clinical phenotypes. Multiple systemic modulatory pathways are determined by variants in such genes as TACI or TNFRSF13B gene encoding for BAFF-R, CTLA-4, LRBA, NFKB1 and NFKB2, and PIK3CD or PIK3R1. The organ-specific immunopathology encompasses a spectrum of disorders associated with immune dysregulation, such as granulomatous interstitial lung disease, hepatocellular nodular regenerative hyperplasia, enteropathy, neuropathy, endocrinopathies, and dermatoses. This review is aimed to define and delineate the organ-specific immunopathology in pediatric CVID. It is also conducted to gather data facilitating a better understanding of complex and heterogeneous immunophenotypes in the context of immune dysregulation mechanisms and genetic background determining manifestations of the disease and implicating personalized targeted therapies with biological agents. Full article

Background: Methods such as cytogenetics and immunocytology/immunohistology provide essential diagnostic insights but may be limited in ambiguous cases of mature B-cell lymphoma. Next-generation sequencing (NGS) has emerged as a potential tool to improve diagnostics. Methods: We validated the analytical performance of a lymphoid customized NGS panel. Clinical validation was conducted in 226 patients with suspected mature B-cell lymphoma with potential bone marrow involvement across multiple clinically relevant scenarios. Results: NGS (1) achieved 100% sensitivity and specificity with high reproducibility (r = 0.995), confirming its analytical performance. (2) It reliably detected WHO-classified markers, including BRAF mutations in all hairy cell leukemia cases, MYD88/CXCR4 mutations in lymphoplasmacytic lymphoma, and absence of BRAF mutations in splenic B-cell lymphoma with prominent nucleoli. (3) In lymphoma exclusion diagnostics, NGS identified mutations in previously undiagnosed cases, including a BCORL1 mutation leading to reclassification as marginal zone lymphoma. (4) Among 105 confirmed lymphomas, 65% harbored mutations, with detection rates highest in HCL and LPL (100%) and CLL (62%), while follicular lymphoma showed no detectable mutations. (5) In cases with non-interpretable cytogenetics, NGS detected pathogenic variants in 61% of patients, compensating for inconclusive findings. (6) In cases with limited morphological assessment, NGS identified relevant mutations in 70%, outperforming cytogenetics (30%; p = 0.0256, OR = 5.44). Conclusions: NGS enhances the diagnostic accuracy of mature B-cell lymphomas by complementing traditional methods, refining WHO-classified subtypes, and improving detection in cases with inconclusive cytogenetics or morphology. NGS may reduce the need for unnecessary bone marrow re-punctures by providing additional information in ambiguous cases. Full article

Creatine monohydrate supplementation is widely used by athletes in high-intensity, power-based sports due to its ability to enhance short-term performance by increasing intramuscular phosphocreatine (PCr) stores, which aid in ATP resynthesis during intense muscle contractions. However, emerging evidence suggests that creatine monohydrate offers benefits beyond athletic performance. This narrative review explores the literature supporting the advantages of creatine supplementation in women, vegans, and clinical populations. In women, who typically have lower baseline intramuscular creatine levels, supplementation may help alleviate fatigue-related symptoms associated with the menstrual cycle, particularly during the early follicular and luteal phases. For vegans and vegetarians, who often have reduced creatine stores due to the absence of creatine-rich animal products in their diet, supplementation can improve both physical and cognitive performance while supporting adherence to plant-based diets. Additionally, creatine supplementation holds potential for various clinical populations. It may mitigate muscle wasting in conditions such as sarcopenia and cachexia, support neuroprotection in neurodegenerative diseases such as Parkinson’s and Huntington’s, improve exercise capacity in cardiovascular diseases, and enhance energy metabolism in chronic fatigue syndrome. Creatine may also aid recovery from traumatic brain injury by promoting brain energy metabolism and reducing neuronal damage. In conclusion, creatine monohydrate supplementation can enhance physical performance, cognitive function, and overall health in women, vegans, and clinical populations by addressing creatine deficiencies, improving energy metabolism, and supporting recovery from physical and neurological challenges. Most available evidence supports the effectiveness of creatine monohydrate, which should be considered the preferred form of creatine supplementation over other variants. Additionally, proper creatine dosing is essential to maximize benefits and minimize potential adverse effects that may arise from chronic ingestion of excessively high doses. Full article

Paraneoplastic pemphigus (PNP) is a rare autoimmune disorder associated with underlying neoplasms, predominantly Non-Hodgkin Lymphomas, affecting adults aged 45 to 70. This review analyzed 87 articles from MEDLINE/PubMed, Ovid and Scopus focusing on patients with oral manifestations of PNP, emphasizing histological and serological aspects and discussing recent updates on pathogenetic options. Key findings revealed that PNP is often diagnosed before the neoplasm, with Follicular variant Non-Hodgkin Lymphoma and Castleman Disease being the most common associations. Histopathological analysis showed suprabasal acantholysis and inflammation, and serological tests identify a comprehensive autoantibody panel, underscoring the need for standardized diagnostic criteria and improved serological testing. Full article

Background: Thyroid cancer (TC) remains a significant clinical challenge worldwide, with a subset of patients facing aggressive disease progression and therapeutic resistance. Immune checkpoint inhibitors targeting programmed death-ligand 1 (PD-L1) have emerged as promising therapeutic approaches for various malignancies, yet their efficacy in TC remains uncertain. The objective of this study was to investigate PD-L1 expression in aggressive TC and its association with histological subtypes, molecular mutation, and progression-free survival. Methods: This is a retrospective study of patients with advanced TC seen in two tertiary health care centers. Included in this study were patients with advanced TC with recurrence or progression on therapy for whom tumor molecular profiling and PD-L1 status were available. Kaplan–Meier estimators were utilized to analyze the progression-free survival (PFS) between patients with PD-L1 positive and negative status in Anaplastic TC (ATC) subgroup. Results: A total of 176 patients with advanced thyroid cancer were included (48.9% female). Of the patients, 13 had ATC, 11 Medullary TC (MTC), 81 Papillary TC Classic Variant (PTCCV), 20 Follicular TC (FTC), 8 Oncocytic TC (OTC), 10 Poorly Differentiated TC (PDTC), and 30 had the Papillary TC Follicular Variant (PTCFV). BRAF mutation was present in 41%, TERT in 30%, RAS in 19%, TP53 in 10%, and RET in 8.6% of patients. PD-L1 positivity was significantly different across different TC types and histological subtypes (p < 0.01): Patients with OTC had the highest frequency of PD-L1 positivity (71%), followed by ATC (69%), PTCCV (28.5%), and FTC (11%). Patients with MTC and PTCFV did not exhibit any PD-L1 positivity. TP53 mutation was positively associated with PD-L1 expression (21.6% vs. 7.5%, p = 0.03), and RAS mutation was negatively associated with PD-L1 expression (8.1% vs. 24.2% p = 0.04). Among patients with ATC, positive PD-L1 expression was associated with lower PFS (p = 0.002). Conclusions: PD-L1 expression varies across different TC types and histological subtypes and may be modulated by the mutational landscape. PD-L1 expression in ATC is associated with shorter PFS. Follow up studies are warranted to elucidate the molecular mechanism driving the observed differences in immune pathways, potentially paving the way for the development of more effective and personalized immune therapies for patients with aggressive TC. Full article

Background: Oncocytic thyroid carcinoma (OTC) was previously considered a variant of follicular thyroid carcinoma (FTC) but has recently been reclassified as a separate form of thyroid cancer. This study aimed to demonstrate that FTC and OTC are fundamentally distinct entities that can potentially be differentiated preoperatively through cytology and/or molecular testing. Methods: A retrospective chart review of patients diagnosed with FTC and OTC operated upon at two university health centers from January 2016 to September 2023 (n = 3219) was conducted. Molecular testing results were correlated with histopathologic diagnosis. Results: Fifty patients met the inclusion criteria. FTC was identified in 27 (54.0%) patients, and OTC in 23 (46.0%) patients. Patients with OTC were older (61.8 years) than FTC patients (51.2 years) (p = 0.013). Moreover, aggressive tumors were found in 39.1% (9/23) of OTCs compared to 11.1% (3/27) of FTCs (p = 0.021). Amongst Bethesda category III and IV nodules, 17 out of 20 (85.0%) OTC cytology reports demonstrated an oncocytic subtype compared to only 5 out of 24 FTC cytology reports (20.8%) (p = 0.002). On molecular testing, the EIF1AX alteration was exclusively present in OTCs while the PAX8/PPARy and PTEN alterations were exclusively found in FTCs. Copy number alterations (CNAs) were found to be more prevalent in OTC (66.7%) compared to FTC (33.3%), and they were not indicative of tumor aggressiveness. Within the OTC group, all three patients who had a TP53 alteration were diagnosed with aggressive cancer. Lastly, the OTCs exhibited a higher frequency of multiple alterations on molecular testing (66.7%) compared to FTCs (33.3%). Conclusion: To our knowledge, this is the largest study to date comparing the clinical application of abnormalities found on molecular testing for FTC and OTC. It further demonstrates the distinct clinicopathological and molecular characteristics of OTC. Full article

Purpose. Interstitial fibrosis in papillary thyroid microcarcinoma is a subject which is under-investigated. The aim of this study is to determine the relationship between interstitial fibrosis, the subtypes of papillary microcarcinoma, and the established prognostic factors. Material and Methods. A total of 75 patients diagnosed with papillary microcarcinoma of the thyroid from January 2011 to December 2020 have been evaluated retrospectively, using demographic features, tumor size, subtype of the tumor, surgical margin status, unifocality, lymphovascular invasion, extracapsular spread and lymph node metastasis as parameters. Hematoxylin and eosin slides were reviewed for interstitial fibrosis. Results. The study includes 13 males and 62 females, in a total of 75 patients. There were 51 patients (68%) with interstitial fibrosis and 24 (32%) patients without interstitial fibrosis. Among them, 45 (60%) were classic, 27 (36%) were follicular variant and 3 (4%) were other subtypes. Interstitial fibrosis is significantly associated with bilaterality (p = 0.023), multifocality (p = 0.004), capsule invasion (p < 0.001) and lymph node metastasis (p = 0.043). Evaluation of tumor sub groups showed significant increased risk of lymphovascular invasion in the follicular variant (p = 0.019). Conclusion. Although the relationship of interstitial fibrosis and prognosis of other cancer types has been discussed, there are few studies in the literature regarding its effect on the prognosis of papillary microcarcinoma. Our results show that interstitial fibrosis can be used as a risk factor. However, new studies are needed to clearly reveal the physiopathology of interstitial fibrosis and its effect on tumorigenesis. Full article

Thyroid cancer (TC) represents a significant health burden globally, with follicular thyroid cancer (FTC) posing diagnostic challenges despite advancements. This pilot study aimed to evaluate the utility of a liquid biopsy with cell-free DNA (cfDNA) in patients with FTC. Blood samples were collected from 13 patients diagnosed with FTC, DNA extraction was performed, and cfDNA was analyzed using the Illumina’s TruSight Oncology 500 High-Throughput panel. The results revealed low tumor mutational burden and minimal pathogenic variants in cfDNA, indicating challenges such as low DNA yield and poor material quality despite adequate coverage. Our findings indicate that cfDNA as an add-on diagnostic tool in patients with FTC might not be a useful supplement. Full article

We aimed to analyze the management of the ectopic mediastinal thyroid (EMT) with respect to EMT-related cancer and non-malignant findings related to the pathological report, clinical presentation, imaging traits, endocrine profile, connective tissue to the cervical (eutopic) thyroid gland, biopsy or fine needle aspiration (FNA) results, surgical techniques and post-operatory outcome. This was a comprehensive review based on revising any type of freely PubMed-accessible English, full-length original papers including the keywords “ectopic thyroid” and “mediastinum” from inception until March 2024. We included 89 original articles that specified EMTs data. We classified them into four main groups: (I) studies/case series (n = 10; N = 36 EMT patients); (II) malignant EMTs (N = 22 subjects; except for one newborn with immature teratoma in the EMT, only adults were reported; mean age of 62.94 years; ranges: 34 to 90 years; female to male ratio of 0.9). Histological analysis in adults showed the following: papillary (N = 11/21); follicular variant of the papillary type (N = 2/21); Hürthle cell thyroid follicular malignancy (N = 1/21); poorly differentiated (N = 1/21); anaplastic (N = 2/21); medullary (N = 1/21); lymphoma (N = 2/21); and MALT (mucosa-associated lymphoid tissue) (N = 1/21); (III) benign EMTs with no thyroid anomalies (N = 37 subjects; mean age of 56.32 years; ranges: 30 to 80 years; female to male ratio of 1.8); (IV) benign EMTs with thyroid anomalies (N = 23; female to male ratio of 5.6; average age of 52.1 years). This panel involved clinical/subclinical hypothyroidism (iatrogenic, congenital, thyroiditis-induced, and transitory type upon EMT removal); thyrotoxicosis (including autonomous activity in EMTs that suppressed eutopic gland); autoimmune thyroiditis/Graves’s disease; nodules/multinodular goiter and cancer in eutopic thyroid or prior thyroidectomy (before EMT detection). We propose a 10-item algorithm that might help navigate through the EMT domain. To conclude, across this focused-sample analysis (to our knowledge, the largest of its kind) of EMTs, the EMT clinical index of suspicion remains low; a higher rate of cancer is reported than prior data (18.8%), incident imagery-based detection was found in 10–14% of the EMTs; surgery offered an overall good outcome. A wide range of imagery, biopsy/FNA and surgical procedures is part of an otherwise complex personalized management. Full article