Search Results (181)

Objectives: The response to radioiodine therapy (RAI) in differentiated thyroid cancer (DTC) patients is one of the most important factors that determines the treatment outcome and overall prognosis. The objective of this study is to determine the correlation between BRAF^V600E and TERT promoter (TERTp) mutation in tumor samples of DTC patients with the response to RAI as well as correlation with clinical and pathohistological features. Methods: Samples of 110 DTC patients (80 with intermediate and high risk of disease recurrence-IHR and 30 with distant metastases) were analyzed for BRAF^V600E and TERTp mutation (BRAF/TERT) and 89 patients were assessed for the response to RAI. Results: Sixty-one (55.5%) patients had BRAF^V600E mutation, 30 (27.3%) had TERTp mutation, while 21 (19.1%) patients had both mutations. In the IHR group, the study showed a statistically significant association between genotype BRAF/TERTp and treatment outcome (p = 0.04). IHR DTC patients with BRAF-/TERT- finding showed in general an excellent response to RAI, while patients with BRAF/TERT co-mutation had a predominantly incomplete or indeterminate response. In DTC patients with BRAF/TERT co-mutation that presented with distant metastases, a tendency to a higher frequency of RAI-refractory (RAI-R) disease was recorded, but without statistical significance. The pathohistological and clinical features that significantly correlated with BRAF/TERT status are age at diagnosis, locoregional lymph node involvement, the largest positive lymph node diameter, tumor angioinvasion and the presence of distant metastases. Conclusions: BRAF/TERT co-mutation may be associated with a less favorable disease course and poorer response to RAI. However, findings in patients with distant metastases should be considered exploratory due to the limited sample size. Full article

Brain tumors in older adults are difficult to diagnose and manage due to nonspecific symptoms, overlapping with neurodegenerative diseases such as dementia, and significant tumor heterogeneity. Although molecular markers such as IDH1/2 mutations, MGMT promoter methylation, TERT alterations, and 1p/19q co-deletion have improved glioma classification and prognostic assessment, current care still relies on invasive tissue biopsies, which limit longitudinal monitoring and may not fully capture tumor complexity because of sampling bias, assay variability, and limited accessibility. Liquid biopsy offers a promising alternative that enables the detection of tumor-derived DNA, RNA, proteins, and extracellular vesicles, supporting earlier diagnosis and real-time monitoring of disease progression and treatment response. However, liquid biopsy for brain tumors is not yet clinically definitive due to low biomarker abundance, lack of standardization, and limited validation, and therefore, it cannot replace tissue diagnosis. Ongoing research focuses on multi-analyte biomarker panels, improved assay standardization, and integration with imaging and tissue-based data. In parallel, artificial intelligence and machine learning are advancing the field by integrating multi-omics and radiomic data to enhance detection, classify tumors, and predict key molecular alterations, supporting the emerging framework of radiogenomics. Together, these developments are driving a shift toward more precise and dynamic approaches to brain tumor diagnosis and management, with relevance for improving outcomes in older adults with brain cancer. Full article

IDH-wildtype glioblastoma remains the most aggressive primary brain tumor, with a median overall survival (OS) of 14–16 months despite maximal treatment. A small subset of patients, however, survive beyond 30 months, suggesting distinct underlying biological features. The aim of this pilot study was to explore whether selected molecular alterations detectable by FISH show differing distribution patterns between patients with prolonged and poor survival in IDH-wildtype glioblastoma. We retrospectively analyzed 20 patients with newly diagnosed primary IDH-wildtype glioblastoma who underwent gross-total resection followed by standard radiotherapy and temozolomide treatment between 2016 and 2022. Patients were categorized into two predefined groups according to survival outcomes: long-term survivors (OS > 30 months) and short-term survivors (OS < 10 months). Fluorescence in situ hybridization (FISH) was used to evaluate alterations in ATRX, BRAF, and PIK3CA. MGMT promoter methylation, EGFR amplification, and TERT promoter mutation status were obtained from routine diagnostic reports. Because survival groups were intentionally pre-selected as extreme phenotypes, time-to-event analysis was not appropriate. Therefore, statistical comparisons were performed using Fisher’s exact test and multivariable logistic regression with long-term versus short-term survival as a binary outcome. Short-term survivors had a significantly higher median age (57.5 vs. 46.5 years, p = 0.043) and a higher rate of EGFR amplification (100% vs. 50%, p = 0.033). Strikingly, combined BRAF and PIK3CA alterations (predominantly polysomy) were detected in 8 out of 10 (80%) long-term survivors, compared to 0 out of 10 (0%) short-term survivors (p = 0.0007). In multivariable logistic regression adjusted for age and MGMT promoter methylation, BRAF/PIK3CA alteration remained strongly associated with long-term survival, though the effect size was mathematically inflated due to perfect separation (0 events in Group B). BRAF and PIK3CA copy number alterations were observed exclusively in long-term survivors in this small exploratory cohort, suggesting a possible association with prolonged survival. However, given the limited sample size, the selection of extreme survival groups, and the predominance of chromosomal polysomy detected by FISH, these findings should be interpreted as hypothesis-generating only. Further validation in larger cohorts using high-resolution genomic methods is warranted. Full article

Background: Surveillance of non-muscle-invasive bladder cancer (NMIBC) relies on cystoscopy and urine cytology, both of which have well-recognised limitations. Molecular urine assays have been developed to reduce the burden of invasive surveillance, yet their real-world clinical utility remains uncertain. Uromonitor^® is a quantitative PCR-based assay targeting hotspot variants in the TERT promoter, FGFR3, and KRAS, which are frequently altered in urothelial carcinoma. We evaluated the performance of Uromonitor^® in routine clinical practice and assessed its technical reproducibility. Methods: Uromonitor^® diagnostic test accuracy was retrospectively calculated from samples from patients undergoing investigation for suspected bladder cancer (n = 64) or surveillance (n = 30) following a prior diagnosis at a tertiary referral centre between 2021 and 2023. Uromonitor^® results were compared with histology where available (n = 49, 52%), or with contemporaneous cystoscopy and urine cytology findings (n = 45, 48%). This pragmatic dual reference standard reflects routine clinical practice but may introduce some heterogeneity in diagnostic accuracy verification. A prospective in-house verification cohort was used to assess inter-laboratory reproducibility. Discordant cases underwent orthogonal next-generation sequencing (NGS) analysis. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy were calculated for the Uromonitor^® against the standard of care. Results: Ninety-four patients were included in the clinical performance analysis. Overall sensitivity, specificity, PPV, NPV and overall accuracy for Uromonitor^® were 38%, 88%, 63%, 72% and 70%, respectively. Sensitivity was higher in the diagnostic setting (47%; 95% CI 27.3–68.3%) than during surveillance (23%; 95% CI 8.2–50.2%). Several false-negative cases in the verification cohort harboured variants either detectable by NGS at variant allele frequencies below or slightly above the assay’s limit of detection or variants not covered by the assay hotspot design. Inter-laboratory reproducibility was excellent, with 100% concordance observed in the verification cohort. Conclusions: In a real-world clinical setting, Uromonitor^® demonstrated high specificity but limited sensitivity for detection of bladder cancer, particularly during surveillance. A negative result does not reliably exclude recurrence. Assay sensitivity thresholds and restricted variant coverage appear to be key contributors to false-negative results. These findings highlight the need for cautious clinical integration of Uromonitor^®. It is unclear whether this approach has sufficient sensitivity in surveillance to safely reduce cystoscopy frequency. This underscores the need for further refinement of urine-based molecular assays, including a need for enhanced sensitivity and broader mutational coverage before routine clinical adoption. Full article

Phyllodes tumours (PTs) of the breast are rare fibroepithelial neoplasms with potentially aggressive behaviour, characterised by rapid growth, a significant risk of local recurrence, and occasional metastatic spread. Optimal management remains controversial, particularly regarding surgical margins, adjuvant radiotherapy, and the relevance of molecular markers in predicting tumour behaviour. A PRISMA 2020-guided qualitative systematic review was conducted of studies published between January 2000 and December 2024 in PubMed/MEDLINE, Scopus, and Web of Science. Eligible studies included malignant PTs of the breast and addressed at least one of the following domains: molecular pathology, surgical margins and local recurrence, adjuvant radiotherapy, or predictors of recurrence and metastasis. A clinical case of malignant PT treated at our institution is presented as an illustrative study. Thirty-four studies met the inclusion criteria. Evidence suggests that margin status, stromal proliferative activity, and selected molecular markers influence recurrence risk. Several retrospective studies suggest that adjuvant radiotherapy may improve local control in selected high-risk malignant PTs, although the evidence remains heterogeneous, retrospective, and potentially affected by treatment-selection bias, and no consistent survival benefit has been demonstrated. Molecular alterations, including MED12 mutations, TERT promoter mutations, TP53 alterations, and increased Ki-67 expression, have been associated with tumour progression and aggressive behaviour. A 44-year-old woman presented with a 2.4 cm left breast mass on radiological examination. Lumpectomy revealed a malignant PT with stromal hypercellularity, nuclear atypia, and a mitotic index of 20/10 HPF with close margins. Immunohistochemistry showed positivity for CD99, Bcl-2, and CD34 with a Ki-67 proliferation index of 20%. The patient underwent wide local re-excision followed by adjuvant radiotherapy (60 Gy), and at 24-month follow-up, the patient remained disease-free. Evidence synthesis highlights the importance of complete surgical excision, multidisciplinary management, and consideration of adjuvant radiotherapy in selected malignant PTs. Emerging molecular profiling may contribute to improved biological understanding and future risk stratification of malignant PTs, although its routine clinical utility remains to be validated in prospective studies. Full article

Signal transducers and activators of transcription (STAT) proteins, which operate via canonical and non-canonical mechanisms, are critically implicated in thyroid tumorigenesis. This review integrates their multifaceted roles in thyroid cancer. STAT3 acts as a “double-edged sword”: hyperactive STAT3 drives metastasis and BRAF inhibitor resistance in advanced carcinomas, yet paradoxically acts as a tumor suppressor by restraining the Warburg effect via non-canonical mitochondrial localization. Clinically, preserved nuclear STAT3 independently predicts a favorable prognosis and is inversely correlated with TERT promoter mutations, offering a biological modifier for clinical risk stratification. Furthermore, STAT1 regulates differentiation via the IGF2BP2-m⁶A axis, STAT5 drives proliferation upon release from TRβ suppression, and STAT6 confers chemoresistance. While novel direct STAT3 inhibitors (e.g., TTI-101) and rational combinations with immune checkpoint inhibitors or STING agonists show promise in overcoming refractory disease, the intricate dual functionality of STAT family proteins demands rigorous biomarker-guided precision medicine approaches. Full article

Background: Extracranial metastasis (EM) from glioblastoma (GB), IDH-wildtype (WHO CNS 2021 grade 4) is rare and often under-recognized, yet it has immediate implications for staging and management. We report a case series integrating advanced neuroimaging, whole-body imaging, and pathology/biomarkers to characterize imaging–pathology correlates of EM and highlight practical clinical triggers that should prompt systemic evaluation. Case presentation: We report three patients with adult-type, IDH-wildtype GB who developed EM confirmed by cytology/histology and/or concordant multimodality imaging. Brain MRI (1.5T/3T) demonstrated aggressive primary tumors with qualitative elevation of DSC-perfusion and frequent tumor–surface contact (dural, ependymal/leptomeningeal contact). Intratumoral susceptibility signal reached grade 3 where assessed. All patients underwent surgical resection followed by temozolomide-based chemoradiation; two received fotemustine and bevacizumab, and one underwent re-irradiation. EM presented with clinical triggers including severe axial/back pain, palpable cervical masses, and/or cytopenias. Initial EM sites were bone marrow/vertebrae (n = 1) and cervical lymph nodes (n = 2); staging revealed additional osseous disease in both nodal cases and a small pulmonary nodule in one. Nodal and osseous lesions were FDG-avid on 18F-FDG PET/CT. OLIG2-positive cytology confirmed cervical nodal metastases, and bone marrow aspiration with GFAP/OLIG2 positivity confirmed medullary infiltration. All tumors shared a molecular profile of TERT-promoter mutation, ATRX wild-type, TP53 mutation, and MGMT-promoter methylation. Despite attempts at second- and third-line therapies, disease progression was rapid, and all patients succumbed within 8–16 months of diagnosis. Discussion: This series underscores that EM can occur despite MGMT-promoter methylation and supports the concept of heterogeneous metastatic phenotypes in GB. Our cases reinforce that new axial/back pain or hematologic abnormalities may signal osseous or marrow involvement, and necrotic cervical lymphadenopathy in GB patients warrants dedicated imaging and tissue confirmation with glial markers. Integrating brain MRI features (high perfusion, surface contact, susceptibility burden) with FDG-PET/CT and targeted cytology/pathology can expedite diagnosis and inform multidisciplinary care. Conclusions: EM can arise despite MGMT-promoter methylation in IDH-wildtype GBM. Imaging red flags (high perfusion, surface contact, necrotic/FDG-avid cervical nodes) and clinical cues (axial pain, cytopenias, neck masses) should prompt early systemic staging (CT/PET-CT) and targeted tissue confirmation to advance management. Full article

Telomerase reverse transcriptase (TERT) plays a key role in tumorigenesis by maintaining telomere length, promoting chromosomal stability, and enabling cells to evade replicative senescence. TERT promoter mutations have been detected in various types of tumor; however, their prevalence in ameloblastoma has not been verified. This study aimed to determine the frequency of TERT promoter mutations in ameloblastoma. This retrospective study included formalin-fixed, paraffin-embedded (FFPE) tissue specimens and corresponding medical records from patients who underwent surgical treatment for jaw ameloblastoma at the Department of Oral and Maxillofacial Surgery, Kyungpook National University (Daegu, Republic of Korea) between January 2011 and December 2024. Clinical data were reviewed through January 2026. Of the 49 patients included, genomic DNA was extracted from two 5 μm thick FFPE tissue sections using the PANAMAX™ FFPE Plus DNA Extraction Kit (HLB PANAGENE, Daejeon, Republic of Korea), according to the manufacturer’s instructions. Hotspot TERT promoter mutations (C228T and C250T) were analyzed using the PNAClamp™ TERT Mutation Detection Kit (HLB PANAGENE, Daejeon, Republic of Korea). From a total of 73 TERT promoter mutation analyses performed in 49 patients, one of the recurrent cases harbored both C228T and C250T hotspot mutations. In the non-recurrent group, one case exhibited a C250T mutation. These findings indicate that TERT promoter mutations are rare in ameloblastoma. Full article

The sodium/iodide symporter (NIS/SLC5A5) is a major determinant of radioiodine therapy efficacy in differentiated thyroid cancer (DTC). This narrative review examines the molecular mechanisms underlying NIS dysregulation and radioiodine refractoriness in DTC. Reduced NIS expression or function in radioiodine-refractory DTC is associated with multiple mechanisms, including transcriptional suppression linked to MAPK/ERK and PI3K/AKT pathway activation and disruption of thyroid differentiation programs; epigenetic silencing involving SLC5A5 regulatory regions; impaired protein trafficking and membrane localization; and post-transcriptional regulation by microRNAs such as miR-221-3p, miR-222-3p, miR-146b-3p, and miR-204-5p. Genetic alterations including BRAF V600E and TERT promoter mutations are associated with dedifferentiated tumor phenotypes and poor radioiodine response. Redifferentiation approaches using MAPK pathway inhibitors such as selumetinib and dabrafenib can restore iodine uptake in selected patients, although the overall clinical applicability of these strategies remains under evaluation. A better understanding of these mechanisms may support improved biologic stratification and more selective therapeutic decision-making in radioiodine-refractory DTC. Full article

Background and Objectives: Melanoma is the leading cause of skin cancer-related mortality due to its high propensity for early metastasis, although survival rates have improved with the advent of targeted and immune-based therapies. Accurate detection of targetable mutations and assessment of tumor mutational burden are essential for informed therapeutic decision-making. Mutation profiling is routinely performed using next-generation sequencing (NGS). The Oncomine Focus Assay (OFA) detects common alterations in 52 genes across various tumor entities, whereas MelArray is a melanoma-specific NGS panel covering mutations in 190 melanoma-relevant genes and providing a genome-wide copy number analysis. Moreover, tumor mutational burden is being assessed. Materials and Methods: In this retrospective study, we analyzed the phenotypic characteristics of 100 patients with cutaneous melanoma who underwent NGS testing using either OFA or MelArray. The aims were to compare the diagnostic yield of the two panels and to investigate potential associations between mutational profiles and clinicopathological features of melanoma. Results: Tumor location, ulceration, and Breslow thickness showed significant correlations with the melanoma subtypes. BRAF mutations were the most frequent driver alterations across all cutaneous melanoma subtypes; however, no significant correlation between specific driver mutations and phenotypic characteristics was identified. MelArray detected a notably high number of alterations in the TERT promoter and CDKN2A genes, which were not captured by OFA and are of potential therapeutic relevance. Conclusions: In conclusion, MelArray enables a more comprehensive molecular characterization of cutaneous melanoma compared with a small generic cancer panel and may support more personalized therapeutic decision-making. Full article

Undifferentiated melanoma (UM) is a rare and diagnostically challenging subtype of malignant melanoma that often lacks traditional histological features and immunophenotypic expression. We report the case of a 58-year-old man with a history of a previously excised melanoma in-situ (lentigo maligna type) of the scalp who later developed a painful chest wall mass. Subsequent workup revealed a high-grade malignant neoplasm with only focal weak S100P positivity while molecular analysis with next-generation sequencing (NGS) revealed an ultra-high TMB tumor mutational burden (>150 mut/Mb), NF1 mutation, TERT promoter mutation, TP53 mutations, PTPRD mutations, and a UV mutational signature (100% SBS7a), supportive of a diagnosis of UM. This case highlights the diagnostic value of comprehensive molecular testing in UM and its role in informing immunotherapy decisions. Full article

Cellular senescence is a stress-induced cell-cycle arrest that constrains expansion of ultraviolet-damaged keratinocytes yet can remodel the microenvironment. This systematic review evaluated histological and genetic or epigenetic senescence markers in actinic keratosis (AK), cutaneous squamous cell carcinoma (cSCC), and basal cell carcinoma (BCC). PubMed, Scopus, and Web of Science were searched (January 2005–May 2025); 34 human studies were included. AK showed an early senescent signature with frequent cyclin-dependent kinase inhibitor p21 (p21CIP1) expression (82.1%) and DNA damage signaling, including phosphorylated histone H2AX (gamma-H2AX) positivity (77%). In invasive cSCC, p21^CIP1 fell to 43.9% and tumor suppressor p53 immunoreactivity often declined, whereas cyclin-dependent kinase inhibitor p16 (p16INK4a) commonly accumulated without arrest, including cytoplasmic staining at invasion fronts. Reported escape pathways involved c-Jun N-terminal kinase 2 activity and long noncoding RNA PVT1–dependent repression of p21. Telomerase reverse transcriptase (TERT) promoter mutations were prevalent in cSCC (about 50%) and BCC (up to 78%) but uncommon in AK, consistent with late telomerase activation. Study heterogeneity, variable antibody scoring, and limited assessment of senescence-associated beta-galactosidase and secretory mediators restricted cross-study comparability. Standardized, spatially resolved profiling may refine risk stratification and support senescence-targeted prevention and therapy in keratinocyte cancers. Full article

This study evaluated the reliability of droplet digital polymerase chain reaction (ddPCR) for detecting TERT promoter (pTERT) mutations in formalin-fixed, paraffin-embedded (FFPE) thyroid cancer samples and examined their association with clinicopathological features. A retrospective cohort of 296 postoperative patients with papillary thyroid carcinoma (PTC) was analyzed. DNA extracted from archived FFPE thyroidectomy specimens was examined for TERT promoter mutations using ddPCR. pTERT mutations were detected in 14 cases (4.7%). Tumors harboring pTERT mutations were significantly larger than wild-type tumors (1.5 ± 1.3 cm vs. 1.0 ± 0.7 cm, p = 0.012) and showed higher frequencies of extrathyroidal extension (78.6% vs. 55.0%, p = 0.028), capsular invasion (85.7% vs. 63.1%, p = 0.036), and lymph node metastasis (64.3% vs. 44.0%, p = 0.012). Multivariate analysis demonstrated that increasing age (odds ratio (OR), 1.07; 95% confidence interval (CI), 1.01–1.13; p = 0.015), tumor size (OR, 1.86; 95% CI, 1.12–3.08; p = 0.016), and lymph node metastasis (OR, 3.50; 95% CI, 1.09–6.53; p = 0.026) were independently associated with pTERT mutations. ddPCR enables sensitive detection of pTERT mutations in archived FFPE thyroid cancer specimens and identifies tumors with aggressive clinicopathological features, supporting its utility for postoperative risk stratification in clinical practice. Full article

Background: Melanoma outcomes have improved in recent years as a result of modern systemic therapies. A major molecular feature of melanoma is abnormal telomerase activation; this is most often caused by telomerase reverse transcriptase (TERT) promoter mutations, which occur in 50–82% of cases and are the most common noncoding alteration in this cancer. Telomerase maintains telomere length, allowing melanoma cells to avoid senescence and continue dividing. However, how telomerase activity influences melanoma cell doubling time remains unclear, and the pathways linking TERT expression to faster cell-cycle progression require further study. Although telomerase inhibitors show promise in preclinical models, their clinical use is limited by delayed cytotoxicity and resistance. Materials and Methods: A scoping review was conducted using Scopus, ScienceDirect, MEDLINE/PubMed, and CINAHL (Cumulative Index to Nursing and Allied Health Literature). Keywords included “telomerase,” “melanoma,” “cancer,” “cell proliferation,” and “doubling time,” using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results: Telomerase-related biomarkers were found to correlate with disease stage and survival. Suggested therapeutic strategies include enzyme inhibitors, cytotoxic nucleotide incorporation, telomere destabilization, and immunotherapies such as peptide or dendritic cell vaccines, etc. Conclusions: Understanding both telomere-dependent and -independent TERT functions is essential for developing effective biomarkers and therapies that overcome resistance and slow melanoma progression. Full article

Background: Urine cytology remains widely used for surveillance of non-muscle-invasive bladder cancer despite well-known limitations in sensitivity, especially for low-grade tumors. Uromonitor^®, a molecular assay detecting TERT promoter, FGFR3, and KRAS mutations in voided urine, has emerged as a promising adjunct. To evaluate its suitability for routine use, a consolidated assessment of diagnostic performance and a direct comparison with urine cytology are needed. Methods: We conducted a prospectively registered systematic review (PROSPERO CRD420251173244), synthesizing all available studies that evaluated Uromonitor^® for the detection of urothelial carcinoma of the bladder (UCB). Methodological quality was assessed using the QUADAS-2 framework, and certainty of evidence was evaluated following GRADE for diagnostic tests. Sensitivity was prespecified as the primary endpoint. Comparative datasets were identified, and random-effects meta-analyses were performed for sensitivity, specificity, accuracy, and predictive values (PVs). Results: Across eight cohorts evaluating Uromonitor^®, 832 of 3196 patients (26.0%) had histologically confirmed UCB. Aggregated sensitivity was 0.55 (95% CI 0.52–0.58). Specificity was 0.95 (0.94–0.96). Accuracy was 0.85 (0.83–0.86). PPV was 0.79 (0.76–0.82), and NPV was 0.86 (0.84–0.87). Across seven paired datasets, urine cytology demonstrated a sensitivity of 0.42, a specificity of 0.91, an accuracy of 0.78, a PPV of 0.64, and an NPV of 0.81. Pooled odds ratio for sensitivity was 3.16 (0.73–13.76), while diagnostic accuracy yielded 1.71 (1.01–2.90). Differences in specificity and NPV were not statistically significant, whereas the PPV favored Uromonitor^®, reaching statistical significance in pooled analyses. Conclusions: Uromonitor^® demonstrates higher sensitivity and improved accuracy compared with urine cytology, although current performance remains insufficient for stand-alone surveillance. The sensitivity estimate showed very low certainty due to pronounced heterogeneity, underscoring the need for careful interpretation. With advancing DNA recovery methods, incorporation of droplet digital PCR, and rigorous evaluations in prospective multicenter studies, Uromonitor^® may become an integral element of risk-adapted follow-up strategies. Full article