Search Results (1,760)

Background and Clinical Significance: Nonbacterial thrombotic endocarditis (NBTE) is a sterile fibrin-platelet valvular condition associated with malignancy and hypercoagulable states. It produces friable vegetations prone to systemic embolization, often presenting as multifocal ischemic stroke. While modestly linked to advanced adenocarcinomas, its association with melanoma is exceedingly rare; Case Presentation: We present a 43-year-old man with recently diagnosed metastatic melanoma who presented with fever, confusion and abdominal pain. Brain magnetic resonance imaging (MRI) revealed multifocal bilateral acute infarcts. Additional imaging demonstrated splenic and bilateral renal infarcts. Transesophageal echocardiography (TEE) revealed an 8 mm × 7 mm multilobar lesion on the posterior mitral valve leaflet. Blood cultures remained persistently negative; autoimmune and infectious workup were unrevealing, and positron emission tomography-computed tomography (PET-CT) showed no cardiac hypermetabolism. Despite empiric antibiotics for suspected infective endocarditis (IE), progressive embolic infarcts occurred. After exclusion of infection, NBTE was considered, and therapeutic enoxaparin was initiated, resulting in clinical stabilization without hemorrhagic conversion; Conclusions: Distinguishing NBTE from IE remains challenging due to overlapping and nonspecific imaging findings. TEE is the preferred diagnostic modality because of its high sensitivity for detecting small valvular vegetations. Adjunctive imaging modalities such as brain MRI and PET-CT may support the diagnosis by demonstrating embolic patterns or excluding metabolically active infectious vegetations. Management primarily relies on systemic anticoagulation, while percutaneous vegetation aspiration may represent a potential diagnostic and therapeutic strategy. Clinicians should maintain high suspicion of this condition in patients with advanced melanoma and other malignancies presenting with multifocal embolic phenomena and negative cultures to enable timely anticoagulation. Full article

Upper tract urothelial carcinoma (UTUC) is a rare and aggressive malignancy, accounting for only 5–10% of all urothelial carcinomas (UCs). Lung, bone, liver, and distant lymph nodes are common sites of metastasis, while gastrointestinal metastasis is extremely rare. We present a case of a 63-year-old female who developed a descending colon lesion 19 months after left radical nephroureterectomy for high-grade ureteral UC. The diagnosis was established by computed tomography (CT), magnetic resonance imaging (MRI), colonoscopy, and biopsy, which excluded primary colorectal malignancy. First-line therapy consisted of six 21-day cycles of gemcitabine plus cisplatin, followed by two cycles of tislelizumab maintenance immunotherapy. Restaging with contrast-enhanced CT and positron emission tomography/computed tomography (PET/CT) demonstrated disease progression. Despite switching to second-line nab-paclitaxel, the patient rapidly deteriorated from tumor cachexia and ultimately succumbed to septic shock secondary to severe pulmonary infection. This represents the first reported case of descending colon metastasis from primary ureteral UC. It highlights the colon as a potential metastatic site where biopsy is essential for definitive diagnosis. Notably, although the patient initially responded to platinum-based therapy, the subsequent rapid progression underscores the need for vigilant monitoring and timely adjustment of therapeutic strategies in managing such high-risk presentations. Full article

Platelet-rich plasma (PRP) is widely used as a second-line treatment for chronic tendinopathy that persists despite structured conservative care, yet outcomes and imaging correlates remain heterogeneous. This review outlines PRP biology and preparation, summarises quantitative imaging techniques for monitoring tendon response, and presents the experience of a single centre integrating these methods into routine supraspinatus and lateral elbow PRP workflows. PRP is described as an autologous platelet concentrate with variable leukocyte and fibrin content, with leukocyte-rich formulations commonly selected for chronic tendinopathy. Quantitative approaches—including ultrasound shear-wave elastography and radiomics, MRI T2/T2* mapping, CT-based bone metrics, PET/CT, and optical techniques—offer numerical biomarkers of tendon structure, mechanics, and inflammation but are rarely implemented in PRP trials. At the authors’ centre, leukocyte-rich PRP is injected under ultrasound guidance after failed physiotherapy, and follow-up combines validated questionnaires with grey-level run-length matrix texture analysis of ultrasound and 3.0 T MRI T2 distribution profiling. A pilot ultrasound study in supraspinatus and common extensor tendinosis showed uniform short-term clinical improvement and significant changes in most texture features, with selected parameters correlating with symptom relief. A prospective supraspinatus cohort demonstrated significant six-month clinical gains in both tendinosis and small partial-thickness tears, whereas only the tendinosis group exhibited T2 profile convergence toward asymptomatic patterns. These data indicate that quantitative ultrasound radiomics and whole-length T2 profiling are feasible imaging biomarkers that capture PRP-induced tendon remodelling beyond qualitative imaging and may help tailor PRP protocols to specific tendon phenotypes. Full article

¹⁸F-fluorodeoxyglucose (FDG) PET/CT is widely used for the evaluation of pulmonary lesions but lacks specificity, as increased FDG uptake is frequently observed in inflammatory and reparative processes. This limitation may lead to false-positive interpretations and unnecessary surgical resections. This study aimed to evaluate the immunohistochemical expression of integrin α_vβ₆ in 18 surgically resected pulmonary lesions that were falsely classified as malignant on FDG PET/CT, in order to find out if ⁶⁸Ga-Trivehexin PET/CT could have superior preoperative diagnostic specificity. Histopathological examination classified all lesions as non-neoplastic inflammatory processes of varying etiologies. Integrin α_vβ₆ expression was detected in all immunohistochemically examined tissue specimens (18/18 cases (100%)), with moderate membranous overexpression in 2/18 cases (11.11%) and strong membranous overexpression in 16/18 cases (88.89%) observed in the alveolar and bronchial epithelium of inflammatory lung lesions. Our findings indicate that integrin α_vβ₆ is upregulated not only in neoplastic lung tissue but also in inflammatory lesions, suggesting that integrin α_vβ₆ may have limited specificity for distinguishing primary neoplastic from inflammatory pulmonary lesions when used alone. Its interpretation requires integration with other clinical imaging modalities and histopathological data. Full article

Lung cancer remains the leading cause of cancer-related mortality worldwide, and although immunotherapy has transformed the treatment landscape of advanced non-small cell lung cancer (NSCLC), durable benefit is limited to a subset of patients. PD-L1 immunohistochemistry and tumor mutational burden, while clinically utilized, demonstrate imperfect predictive capacity, underscoring the need for more robust biomarkers. This review highlights emerging multimodal biomarkers—including circulating tumor DNA (ctDNA), the gut microbiome, and artificial intelligence (AI)-driven radiomics—as promising tools to enhance the prediction of immunotherapy response. Longitudinal ctDNA monitoring offers a minimally invasive method to assess tumor burden dynamics, detect early molecular response, distinguish pseudo-progression from true progression, and stratify risk, with ctDNA clearance correlating with improved survival outcomes. The gut microbiome has also been associated with ICI efficacy, as specific bacterial taxa and composite scoring systems correlate with treatment response, though methodological heterogeneity limits clinical translation. Radiomic analyses leveraging CT and PET imaging extract quantitative tumor features that, when integrated with clinical and molecular data, demonstrate improved predictive performance compared to single-modality approaches. Despite promising advances, challenges including assay standardization, external validation, data harmonization, interpretability of AI models, and infrastructure requirements remain barriers to widespread adoption. Multimodal integration of genomic, microbiome, and imaging biomarkers represents a critical step toward precision immuno-oncology, with prospective validation needed to translate these approaches into improved outcomes for patients with advanced NSCLC. Full article

Systemic sclerosis (SSc) is a complex autoimmune connective tissue disease characterized by microvascular dysfunction, immune activation, and progressive fibrosis affecting multiple organs, including the heart. Myocardial involvement represents an important but frequently underrecognized manifestation of SSc and may develop even in the absence of overt clinical symptoms. Cardiac manifestations include ventricular dysfunction, arrhythmias, conduction abnormalities, and heart failure, contributing substantially to morbidity and mortality. The underlying pathophysiology involves coronary microvascular dysfunction, immune-mediated myocardial inflammation, and progressive myocardial fibrosis, which often precede clinically apparent cardiac disease. This review aims to summarize the current understanding of myocardial involvement in SSc and to provide a comprehensive overview of contemporary multimodality cardiovascular imaging techniques for its detection, characterization, and risk stratification. A comprehensive overview of the current literature was conducted focusing on established and emerging cardiovascular imaging modalities for the evaluation of myocardial involvement in SSc. Particular attention was given to echocardiography, cardiac magnetic resonance (CMR), nuclear imaging techniques including positron emission tomography (PET) and single-photon emission computed tomography (SPECT), and cardiac computed tomography (CT). Recent advances in imaging biomarkers, parametric mapping, myocardial strain analysis, and emerging technologies such as artificial intelligence (AI), radiomics, and molecular imaging were also considered. Multimodality cardiovascular imaging plays a central role in the early detection and comprehensive assessment of myocardial involvement in SSc. Advanced imaging techniques enable improved identification of subclinical myocardial dysfunction, microvascular impairment, inflammation, and fibrosis. An integrated imaging approach combining echocardiography, CMR, nuclear imaging, and CT may facilitate earlier diagnosis, enhance risk stratification, and ultimately improve cardiovascular outcomes in patients with SSc. Full article

Background/Objectives: Assessing treatment response in neuroendocrine tumors (NETs) remains challenging. The multifactorial mechanism of action of peptide receptor radionuclide therapy (PRRT) further complicates response evaluation, particularly in the absence of standardized criteria. This study aimed to compare different imaging-based response assessment methods after PRRT and to explore their relationship with clinical outcomes, particularly progression-free survival (PFS). Methods: In this single-center retrospective study, we analyzed NET patients treated with PRRT between 2020 and 2024 who underwent [⁶⁸Ga]Ga-DOTATOC PET/CT before and after therapy, with a minimum follow-up of 12 months. Five response criteria were evaluated: (a) Krenning Score changes; (b) adapted PERCIST criteria (MORE); (c) ZP-normalized parameter; (d) qualitative visual PET assessment; and (e) RECIST-based morphological response on contrast-enhanced CT. Imaging findings were correlated with clinical outcomes. Nonparametric analyses were performed using the MedCalc^® software. Results: Thirty-one patients (median age 63 years; 17 males) with NET were evaluated after PRRT. Post-PRRT PET/CT was performed at a median of 3 months. Response rates varied across methods, with higher rates noted using functional imaging (MORE 66%, Visual PET 68%, ZP 70%) compared to RECIST (40%) and Krenning score (21%). After a median follow-up of 37 months, 58% of patients experienced disease progression. Although no significant association was found between the response criteria and progression (p > 0.05), functional imaging showed a trend toward better correlation with longer progression-free survival. Conclusions: Functional PET-based responsecriteria suggest association with progression-free survival compared to RECIST criteria and Krenning score changes. However, given the exploratory nature of the study and its methodological limitations, these observations should be considered hypothesis-generating only. They do not provide definitive evidence of superiority over established assessment methods and therefore should not be interpreted as practice-changing. Full article

Advances in medical imaging modalities such as multiparametric and functional MRI, PET, and CT/CBCT, together with complementary innovations such as radiomics, artificial intelligence (AI), adaptive radiotherapy, and theranostics, have expanded the role of imaging from anatomical guidance to biologically informed treatment planning, adaptation, and response assessment. In this review, we provide a comprehensive overview of the technical foundations of imaging biomarkers in radiotherapy (RT), spanning functional and molecular imaging techniques and data-driven analytic approaches. We synthesize current clinical evidence across major disease sites, highlighting how imaging biomarkers are being used to refine target delineation, guide dose painting and functional avoidance, predict and monitor treatment response, and support adaptive and personalized RT strategies. We also critically examine key challenges to clinical translation and implementation, including standardization and reproducibility, validation and generalizability, interpretability of AI-driven models, regulatory and ethical considerations, issues of data sharing, reimbursement, and equity. Finally, we propose a multi-stage translational roadmap to guide the development, validation, and clinical deployment of imaging biomarkers in radiotherapy. Collectively, this review underscores the central role of imaging biomarkers in advancing biologically adaptive and precision radiotherapy and outlines priorities for their responsible and equitable integration into routine clinical practice. Full article

Background: This narrative review introduces the “From Plaque to Perfusion” framework, a clinically pragmatic approach that maps multimodality imaging technologies to critical decision points in the acute coronary syndrome (ACS) patient journey. By integrating non-invasive assessment, invasive procedural guidance, and post-event tissue characterisation, this framework provides a structured pathway for deep phenotyping of ACS. Artificial intelligence (AI) is highlighted as an essential enabling layer that enhances diagnostic precision, automates quantification, and supports scalable, data-driven care. Contemporary ACS management pathways, while effective, often leave residual clinical uncertainty. The diagnostic objective has evolved beyond confirming myocardial injury to comprehensively phenotyping the entire ACS cascade: defining the plaque substrate, identifying the culprit mechanism, and quantifying the myocardial consequence. This requires a systematic integration of advanced imaging modalities. Methods: This narrative review is based on a comprehensive literature search of major medical databases (PubMed/MEDLINE, Scopus, Embase, Google Scholar) for high-level evidence, including randomized controlled trials, meta-analyses, and international expert consensus documents published between January 2010 and February 2026. Results: The “From Plaque to Perfusion” framework consists of three core stages. First, non-invasive assessment with coronary computed tomography angiography (CCTA), fractional flow reserve (FFR-CT), and PET-CT defines plaque substrate and vascular inflammation. Second, invasive precision in the catheterization laboratory, guided by optical coherence tomography (OCT) and intravascular ultrasound (IVUS), resolves the culprit mechanism and optimizes percutaneous coronary intervention (PCI). Third, post-event tissue characterization with cardiac magnetic resonance (CMR) quantifies myocardial injury and refines prognosis. AI-driven platforms are shown to enhance each stage by automating analysis, standardizing interpretation, and providing actionable metrics for clinical decisions, including complex scenarios like Myocardial Infarction with Non-Obstructive Coronary Arteries (MINOCA). Conclusions: The “From Plaque to Perfusion” framework, enabled by AI, reframes ACS imaging as an integrated, mechanism-driven pathway. This approach moves beyond isolated test interpretation toward a scalable model of precision, phenotype-led care that promises to improve diagnostic certainty and personalize patient management. Full article

Background and Objectives: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive technique widely used for mediastinal staging and diagnosis in patients with lung cancer and extrathoracic malignancies. This study aimed to evaluate patient and procedural factors associated with malignant histopathological outcomes in individuals undergoing EBUS-TBNA for intrathoracic lymphadenopathy across three malignancy groups: primary lung cancer, extrathoracic solid organ malignancy, and hematological malignancy. Materials and Methods: This retrospective descriptive study included patients who underwent EBUS-TBNA at Ankara Bilkent City Hospital between March 2019 and December 2023. Demographic characteristics, histopathological findings, procedural details, additional sampling techniques, and imaging parameters, including FDG SUVmax values from pre-procedural PET-CT, were recorded. Histopathological outcomes were categorized as malignant or non-malignant. Binary and multinomial logistic regression analyses were performed to identify independent predictors of malignancy and to differentiate between malignancy groups and lung cancer subtypes. Results: A total of 776 patients underwent EBUS-TBNA, and 667 were included after excluding non-diagnostic samples. Malignancy was detected in 274 patients, including primary lung cancer (n = 213, 77.7%), extrathoracic malignancy (n = 43, 15.7%), and hematological malignancy (n = 18, 6.6%). Of the included patients, 426 (63.9%) were male; the median age was 63 (IQR = 16) years. Older age (OR = 1.03, 95% CI = 1.02–1.05, p < 0.001), male sex (OR = 2.05, 95% CI = 1.43–2.93, p < 0.001), and larger lymph node size (OR = 1.09, 95% CI = 1.06–1.11, p < 0.001) were independently associated with malignant outcomes. Younger age, female sex, and smaller lymph node size were associated with extrathoracic malignancy compared to primary lung cancer, while younger age was the only predictor of hematological malignancy. Larger lymph node size was inversely associated with adenocarcinoma and squamous cell carcinoma compared with small cell lung cancer. Conclusions: Older age, male sex, and larger lymph node size independently predict malignant EBUS-TBNA outcomes. Younger age and female sex favor extrathoracic malignancy, whereas small cell lung cancer is associated with more extensive nodal involvement. Additional bronchoscopic techniques may enhance diagnostic accuracy in selected patients. Full article

Background/Objectives: Atypical skull base osteomyelitis (ASBO) is a rare disease, typically involving the basisphenoid and basiocciput. Diagnosis consists of clinical examination, imaging methods such as PET-CT scans and MRI, microbiological testing, and possibly native tissue samples. Long-term intravenous antibiotic therapy is the treatment of choice. Methods/Case Report: We present a case of ASBO of the clivus initially suspected to be a malignant lesion due to malignant melanoma in the patient’s history. Several tissue biopsies were taken, and microbiological testing of native tissue biopsies in combination with PET-CT and MRI imaging led to the diagnosis of ASBO. The patient received long-term antibiotic therapy with meropenem and drastically improved in his overall health. Discussion and Conclusions: This case highlights the challenges encountered in the diagnosis and management of ASBO, especially with relevant possible differential diagnoses. Full article

Background/Objectives: Peptide receptor radionuclide therapy (PRRT) is an established treatment for metastatic neuroendocrine tumors (NETs), yet long-term disease control occurs only in a subset of patients. Predicting progression-free survival (PFS) could support individualized treatment planning. This study evaluates laboratory, imaging, and multimodal deep learning models for PFS prediction in PRRT-treated patients. Methods: In this retrospective, single-center study 116 patients with metastatic NETs undergoing [177Lu]Lu-DOTATOC were included. Clinical characteristics, laboratory values, and pretherapeutic somatostatin receptor positron emission tomography/computed tomographies (SR-PET/CTs) were collected. Seven models were trained to classify low- vs. high-PFS groups, including unimodal (laboratory, SR-PET, or CT) and multimodal fusion approaches. Performance was assessed via repeated 3-fold cross-validation with area under the receiver operating characteristic curve (AUROC) and area under the precision–recall curve (AUPRC). Explainability was evaluated by feature importance analysis and gradient based saliency maps. Results: Forty-two patients (36%) displayed short PFS (≤1 year) and 74 patients displayed long PFS (>1 year). Groups were similar in most characteristics, except for higher baseline chromogranin A (p = 0.003), elevated $\gamma$-GT (p = 0.002), and fewer PRRT cycles (p < 0.001) in short-PFS patients. The Random Forest model trained only on laboratory biomarkers reached an AUROC of 0.59 ± 0.02. Unimodal three-dimensional convolutional neural networks using SR-PET or CT performed worse (AUROC 0.42 ± 0.03 and 0.54 ± 0.01, respectively). A multimodal fusion model integrating laboratory values, SR-PET, and CT—augmented with a pretrained CT branch—achieved the best results (AUROC 0.72 ± 0.01, AUPRC 0.80 ± 0.01). Explainability analyses provided insights into model predictions, with explainability patterns in the fusion model appearing physiologically plausible and predominantly tumor-focused. Conclusions: Multimodal deep learning combining SR-PET, CT, and laboratory biomarkers outperformed unimodal approaches for PFS prediction after PRRT. Upon external validation, such models may support risk-adapted follow-up strategies. Full article

Background/Objectives: Fibroblast activation protein (FAP) has emerged as a promising target for oncologic molecular imaging due to its high expression in cancer-associated fibroblasts and low presence in healthy tissues. Among available FAP ligands, [⁶⁸Ga]Ga-FAPi-46 has shown rapid tumor accumulation, low background uptake, and broad tumor applicability. This study reports the successful translation of [⁶⁸Ga]Ga-FAPi-46 from preclinical development to routine clinical radiopharmacy practice, detailing automated synthesis, quality control performance, radiochemical stability, and the first clinical imaging results. Methods: Automated radiolabeling of FAPi-46 with gallium-68 was performed using a synthesis module. Quality control included radiochemical purity assessments by iTLC, SPE, and RP-HPLC (pH, appearance, endotoxin levels, and membrane integrity testing). Radiochemical stability was evaluated in saline (up to 6 h) and human serum (up to 90 min). In vitro characterization included the partition coefficient and serum protein binding determination. A clinical evaluation was conducted in a woman with newly diagnosed lung adenocarcinoma who underwent both [¹⁸F]FDG PET/CT and [⁶⁸Ga]Ga-FAPi-46 PET/CT. Results: Automated synthesis of [⁶⁸Ga]Ga-FAPi-46 achieved a high radiochemical yield (87.9 ± 1.3%) and radiochemical purity greater than 98%. All batches met release specifications for sterility, apyrogenicity, and physicochemical parameters. The radiotracer demonstrated high stability in saline and human serum, with radiochemical purity consistently above 95% at all evaluated time points. The compound showed a hydrophilic profile (LogP = −3.32 ± 0.14) and 40–60% serum protein binding. Clinically, [⁶⁸Ga]Ga-FAPi-46 PET/CT provided superior lesion delineation compared to [¹⁸F]FDG, revealing additional mediastinal, supraclavicular, and brain metastases. Conclusions: [⁶⁸Ga]Ga-FAPi-46 can be reliably synthesized using automated procedures under routine radiopharmacy conditions, meeting regulatory quality standards and demonstrating excellent stability. Its enhanced lesion detectability compared with [¹⁸F]FDG in the first patient case supports its potential value for oncological staging and clinical implementation. Full article

Background and Objectives: Bladder cancer is one of the most common malignancies of the urinary tract and poses a significant clinical challenge due to its biological heterogeneity and high rates of recurrence and progression. Urothelial carcinoma represents the predominant histological subtype, ranging from non-muscle-invasive disease with relatively favorable outcomes to aggressive muscle-invasive and metastatic forms associated with poor prognosis. Accurate diagnosis, staging, prognostic stratification, and assessment of treatment response are therefore essential for optimal patient management. The objective of this review is to summarize and critically evaluate the current evidence on the role of positron emission tomography/computed tomography (PET/CT) in bladder cancer, with particular emphasis on [¹⁸F]FDG PET/CT and non-FDG radiotracers. Materials and Methods: A narrative review of the available literature was performed, focusing on clinical studies, review articles, and guideline documents addressing the use of PET/CT in bladder cancer. The literature search included articles published between 2000 and 2025, while earlier landmark studies were selectively included if considered historically important for understanding the development of PET/CT imaging in bladder cancer. The initial search yielded over 500 records; after screening titles and abstracts, more than 100 articles were selected for full-text evaluation. The analyzed evidence encompasses the clinical applications of [¹⁸F]FDG PET/CT and alternative radiotracers, including choline-, acetate-, methionine-, and sodium fluoride-based tracers, and fibroblast activation protein inhibitors (FAPI), across different stages of disease and clinical settings. Results: Conventional imaging modalities, such as computed tomography and magnetic resonance imaging, provide important anatomical information but remain limited in the evaluation of lymph node involvement, early metastatic disease, treatment response, and disease recurrence. Despite limitations related to physiological urinary excretion, [¹⁸F]FDG PET/CT has demonstrated clinical value in selected scenarios, particularly for staging, prognostic assessment, detection of recurrence, and response evaluation. To overcome FDG-related constraints, several non-FDG radiotracers have been investigated. Among these, FAPI PET/CT has emerged as a promising modality due to its ability to target the tumor stroma, potentially improving lesion detectability and tumor-to-background contrast. Conclusions: This review summarizes and critically evaluates current evidence on the role of PET/CT in bladder cancer, with a focus on [¹⁸F]FDG PET/CT and non-FDG radiotracers. The discussed studies highlight their applications in primary diagnosis, staging, prognostic assessment, detection of recurrence, and evaluation of treatment response, as well as their respective advantages and limitations. Furthermore, potential future directions for PET/CT imaging in clinical practice are outlined, emphasizing the need for further research to clarify the optimal use of established and emerging radiotracers. 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