Search Results (55)

Advanced-stage classic Hodgkin lymphoma (cHL) represents one of the major success stories in modern oncology, with long-term survival now exceeding 80% for most patients. In this review, we examine the evolution of frontline therapy for advanced-stage cHL, tracing the transition from empiric combination chemotherapy to contemporary, biologically informed treatment strategies. We begin by revisiting the early development of multiagent chemotherapy regimens, including MOPP and ABVD. These regimens established, for the first time, that advanced lymphoma could be cured with systemic therapy. We then discuss efforts to improve outcomes through treatment intensification, which culminated in the development of BEACOPP-based approaches that improved disease control at the cost of substantial acute and long-term toxicity. Subsequently, the incorporation of functional imaging ushered in the era of PET-adapted therapy, enabling dynamic treatment modification based on early response and providing a framework to better balance efficacy with toxicity reduction. Finally, we review the integration of novel agents, including brentuximab vedotin and PD-1 blockade, which have reshaped the frontline treatment landscape and further improved outcomes for high-risk patients while challenging historical chemotherapy paradigms. Collectively, the treatment history of advanced-stage cHL reflects a broader evolution in oncology: from maximizing cytotoxic intensity toward increasingly personalized strategies designed to optimize cure while minimizing long-term harm. Ongoing efforts focused on biomarker-driven risk stratification and the utilization of circulating tumor DNA are poised to further refine this balance in the coming decade. Full article

Neuroinflammation is increasingly recognized as a key modulator of therapeutic response and adverse events in Alzheimer’s disease (AD), especially during anti-amyloid-β (Aβ) monoclonal antibody (Aβ-mAb) treatment. We applied longitudinal translocator protein (TSPO) positron emission tomography (PET) to evaluate TSPO-associated neuroinflammatory responses to chronic Aβ-mAb therapy and their modulation by the peroxisome proliferator-activated receptor γ (PPARγ) agonist pioglitazone. App^NL-G-F knock-in mice underwent TSPO-PET and Aβ-PET imaging at 5, 7.5, and 10 months of age across four treatment arms: placebo, Aβ-mAb, pioglitazone, and combination therapy. TSPO-PET detected early and progressive neuroinflammatory responses to Aβ-mAb that appeared lower with pioglitazone co-treatment. Both mono- and combination therapy were associated with altered temporal and spatial dynamics of the TSPO-PET signal. In addition, we applied a previously validated microglia desynchronization index based on TSPO-PET connectivity, which captured individual variation in regional TSPO-PET organization and correlated with cognitive performance. Together, TSPO-PET and its regional synchronicity can quantify longitudinal, region-specific treatment effects, which may help differentiate harmful from adaptive neuroinflammatory responses. These findings highlight the potential of TSPO-PET as a stratification biomarker to optimize therapeutic interventions. TSPO-PET therefore enables in vivo tracking of treatment-associated neuroinflammatory responses during anti-Aβ immunotherapy and provides a non-invasive framework for evaluating combination strategies targeting amyloid pathology and immune regulation in AD. Full article

Prostate cancer (PCa) progression and treatment resistance are driven by tumor-intrinsic mechanisms and adaptive remodeling of the tumor microenvironment, in which cancer-associated fibroblasts (CAFs) play a crucial role. Although CAF biology is increasingly recognized, a major translational gap remains: CAFs are highly heterogeneous, and comprise distinct functional states with divergent effects on disease progression, immune regulation, and therapeutic resistance. To bridge this gap, we synthesize evidence from single-cell and spatial transcriptomic studies, tissue-based pathology, liquid biopsy assays, and molecular imaging to construct an evidence-tiered, decision-oriented translational framework that connects stromal mechanisms, translational measurement strategies, and therapeutic interventions in PCa. Single-cell and spatial transcriptomic analyses have consistently identified multiple CAF programs, including matrix-remodeling, inflammatory, immunoregulatory, antigen-presenting, and therapy-imprinted states, each with distinct functional outputs and clinical correlates. Tissue-based readouts, including reactive stromal grade (RSG) and fibroblast activation protein (FAP) immunohistochemistry, provide practical proxies for stromal activation and correlate with disease-specific mortality and imaging phenotypes. Circulating CAFs (cCAFs) represent an emerging liquid biopsy modality for longitudinal stromal monitoring, although technical standardization is required before clinical implementation. FAP-targeted PET imaging and emerging dual prostate-specific membrane antigen (PSMA)/FAP-targeted theranostic strategies provide noninvasive tools for patient selection and response assessment, particularly in PSMA-discordant or tracer-heterogeneous disease. Androgen receptor (AR)-targeted therapy can reprogram stromal states toward resistance-promoting circuits, highlighting the dynamic and plastic nature of the CAF compartment. A state-based CAF framework organizes stromal biology into testable translational hypotheses rather than immediate clinical standards. RSG and FAP-based tissue or imaging readouts are practical markers of stromal activation, whereas spatial CAF-immune signatures and cCAF assays remain investigational and require assay harmonization and prospective validation. Future trials should pre-specify stromal biomarkers as enrichment or pharmacodynamic variables when matched to the intervention and should avoid treating CAFs as a uniform therapeutic target. 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

Background/Objectives: Diffuse large B-cell lymphoma (DLBCL) is molecularly heterogeneous, and approximately 30-50% of patients fail to achieve cure with standard R-CHOP. Genotype-directed first-line therapy may improve outcomes by targeting subtype-specific oncogenic pathways. This study evaluated the feasibility, efficacy, and safety of a molecularly adapted R-CHOP-X strategy with two-year follow-up. Methods: In this single-center, prospective, non-randomized study conducted between September 2023 and the data cut-off (16 September 2025), 43 adults with newly diagnosed DLBCL (excluding high-grade B-cell lymphoma, primary immune-privileged, and primary mediastinal large B-cell lymphomas) underwent tumor genotyping using the LymphGen classification after targeted sequencing: a 19-gene Sanger panel (Cohort 1, n = 35) or an expanded 60-gene panel (Cohort 2, n = 8; proof-of-concept). All patients received one initial cycle of R-CHOP as bridge therapy pending molecular profiling results, followed by five cycles of R-CHOP-X, with the additional agent (vorinostat, acalabrutinib, decitabine, or lenalidomide) selected according to molecular subtype. Response was assessed by PET/CT per Lugano criteria; adverse events were graded per NCI CTCAE v5.0. Results: The overall study population was predominantly high-risk: 72% had an IPI of 3–5, 58% had stage III–IV disease, and 67% exhibited a non-GCB immunophenotype. Expansion from the 19-gene to the 60-gene panel reduced unclassifiable (NOS) cases from 34% to 12%. The overall response rate was 100% (43/43); complete response among patients completing therapy was 100% (35/35). At two years, overall survival was 92% (95% CI 83–100%) and progression-free survival was 94% (95% CI 86–100%). Two early relapses occurred (NOS and N1 subtypes), both resulting in death. Grade 3–4 neutropenia, thrombocytopenia, and anemia occurred in 26%, 12%, and 7% of patients, respectively; no dose reductions or treatment discontinuations were recorded. Conclusions: Molecularly adapted R-CHOP-X is feasible and associated with high response rates and favorable two-year survival in newly diagnosed DLBCL, comparing favorably with historical R-CHOP outcomes in high-risk populations. Expanded genomic panels substantially improve molecular classifiability. These findings warrant validation in larger, multicenter, randomized clinical trials. 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 and objectives: Early biomarkers that can reliably predict treatment outcomes during CDK4/6 inhibitor therapy remain an unmet clinical need in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) metastatic breast cancer (MBC). Metabolic changes on ^18F-FDG PET/CT may precede radiologic response and provide insight into tumor biology and early treatment resistance. Methods: This two-center retrospective study included 203 patients with HR+/HER2− MBC who received first-line CDK4/6 inhibitors (ribociclib or palbociclib) plus endocrine therapy between 2018 and 2024. Baseline and interim ^18F-FDG PET/CT scans performed after 2–4 cycles were evaluated. Early metabolic response was defined as a ≥30% reduction in SUVmax on the most metabolically active lesion, consistent with PERCIST 1.0. Progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan–Meier and multivariable Cox models. ROC analysis assessed the discriminative performance of ΔSUVmax for predicting disease progression. Results: Among 203 patients, 153 (75.4%) achieved a ≥30% SUVmax reduction. Responders had significantly longer PFS (median 44.4 vs. 4.8 months; p < 0.001) and OS (median not reached vs. 32.0 months; p < 0.001). Metabolic response remained independently associated with improved PFS (HR 0.24; 95% CI 0.15–0.37; p < 0.001) and OS (HR 0.37; 95% CI 0.20–0.67; p = 0.001) after adjustment for tumor grade, endocrine resistance, and visceral disease involvement. Non-responders demonstrated more aggressive baseline features, including higher rates of liver (34.0% vs. 15.0%) and brain metastasis (10.0% vs. 1.3%), as well as lower progesterone receptor expression (median 30% vs. 60%). Conclusions: Early metabolic response assessed by SUV-max on interim ^18F-FDG PET/CT is independently associated with substantially improved PFS and OS in HR+/HER2− MBC receiving treatment with CDK4/6 inhibitors. Although the predictive accuracy of ΔSUVmax alone was modest, the strong survival gradient suggests meaningful prognostic value. Prospective studies with standardized imaging time points and comprehensive metabolic metrics are warranted to define the role of PET-guided treatment adaptation: Full article

Introduction: Acute ischemic stroke demands interventions that restore perfusion and protect neurons within a narrow therapeutic window. We propose a unified theranostic platform that couples adaptive imaging, topology-aware decision-making, and immediate neuroprotective and micro-dosimetric intervention. Methods: The platform integrates three components. First, a topology-preserving MR–PET engine employs adaptive Poisson-disc sampling, partial Fourier constraints, and structured Hankel low-rank priors in a closed loop. Persistent-homology metrics quantify vascular graph uncertainty and guide subsequent k-space and PET projections, reducing acquisition time while preserving collateral topology. Second, immediate post-reperfusion delivery of glycolic acid attenuates glutamate-driven calcium influx and stabilizes mitochondrial function. Third, trace doses of sol–gel-derived, neutron-activated ⁹⁰Y₂O₃ microspheres provide sharply confined beta irradiation for micro-scale metabolic modulation. Results: In a porcine stroke model replicating the human recanalization workflow, the imaging engine maintained vascular Betti-number invariants within three percent of fully sampled reference scans while reducing acquisition time by nearly half. Glycolic acid reduced glutamate-induced intracellular calcium rise by approximately sixty percent in vitro and decreased infarct volume by thirty-eight percent in vivo. Micro-dosimetry confirmed a mean perivascular beta dose of twenty-eight grays, and histology demonstrated a forty-two percent increase in NeuN-positive neuronal survival compared with standard recanalization. Conclusions: These results demonstrate that intelligent compressed-sensing MR–PET, targeted micro-radioembolization, and glycolic acid neuroprotection can act synergistically to bridge diagnostic imaging and immediate intervention. By coupling imaging, decision-making, and therapy in a closed-loop manner and elevating topological fidelity from a reconstruction byproduct to a control variable, the proposed platform reframes MR–PET from passive diagnostics into an active, decision-driven theranostic system and establishes a foundation for future human trials. Full article

Background: In triple-negative breast cancer (TNBC), the addition of immunotherapy has significantly improved outcomes. Immune-related adverse events (irAEs) can be accelerated in patients with pre-existing autoimmune (AI) conditions. The treatment-response standardized protocol used in clinical care raises concerns about the need for right-sizing strategies. As the use of immunotherapy expands, recognizing toxicity from recurrence and optimizing response-adapted approaches are essential to balance cure with quality of survival. Case Presentation: A 38-year-old pregnant woman with a distant history of uveitis and psoriasis was discovered to have pregnancy-associated TNBC. Postnatally, she was treated with neoadjuvant chemotherapy and pembrolizumab, followed by wire-guided left breast wide local excision and sentinel lymph node biopsy of the left axilla. After surgery, residual cancer was noted. She continued adjuvant pembrolizumab and adjuvant radiotherapy 40.05 Gy/15 fr to the breast and nodes, followed by a 13.35 Gy/5 fr boost to the tumour bed (breast). Despite a persistent residual tumour, pembrolizumab was continued as per protocol in a response-agnostic manner. At the end of one year of adjuvant pembrolizumab, she developed progressive numbness and weakness in the ipsilateral arm, initially raising suspicion for local recurrence. Comprehensive MRI and PET-CT imaging did not identify recurrent tumour or new metastatic disease. Electromyography confirmed a lower-trunk brachial plexopathy without a structural cause. An immune-mediated process was diagnosed by a process of elimination. Despite treatment with 1st-line high-dose corticosteroids and 2nd-line intravenous immunoglobulin (IVIG), improvement was limited. Therapeutic plasmapheresis led to marked functional recovery and symptom resolution 20 months later. Discussion: Four main challenges are identified: (1) the diagnostic difficulty in identifying local recurrence or radiation injury from immune-related neuropathy; (2) the emerging therapeutic role of plasmapheresis in steroid-refractory irAEs; (3) the possible inconsistencies between rare toxicities observed in clinical trials vs. clinical practice; and (4) the limitations in response in adjuvant therapy, particularly in patients with coexisting AI conditions. Conclusions: Early recognition and accurate distinction from tumour recurrence, as well as support for plasmapheresis as a potential option in steroid-refractory presentations, have been shown to improve patient survival and symptom reduction. With increasing use of immunotherapy, real-world toxicity data, predictive biomarkers, and personalized treatment strategies are urgently needed to balance cure with long-term functional outcomes. Full article

HPV-positive OPSCC shows a favourable prognosis, prompting evaluation of de-escalated and adaptive strategies. Quantitative imaging may provide scalable biomarkers to individualise care. Quantitative imaging can support baseline risk stratification, early on-treatment decision-making, and posttreatment surveillance in HPV-positive OPSCC. Real-world translation requires standardised reporting, calibration/harmonisation across centres, rigorous model validation, and workflow integration with radiotherapy planning. Quantitative MRI, CT, and PET, augmented by radiomics and AI, show convergent promise as non-invasive biomarkers to enable safe individualisation of therapy in HPV-positive OPSCC, contingent on methodological rigour and prospective, externally validated studies. Despite this promise, clinical translation faces substantial barriers, including limited external validation, heterogeneous methodologies, and the need for standardised, prospectively validated pipelines. Full article

Background/Objectives: In men with biochemical recurrence (BCR) after a radical prostatectomy (RP), salvage radiotherapy (SRT) is commonly recommended when imaging shows no metastases. The optimal management for patients with negative prostate-specific membrane antigen (PSMA) PET/CT findings at BCR remains uncertain. This study evaluated outcomes of patients with BCR and negative PSMA PET/CT to identify who may be safely observed and who may benefit from early SRT. Methods: This retrospective multicentre cohort study included 89 patients with BCR and negative PSMA PET/CT findings after a RP (2015–2022) who were managed with observation. The exclusion criteria were PSA levels ≥ 0.8 ng/mL at baseline, prior SRT, or prior or ongoing hormonal therapy. Minimum follow-up was 3 years. Biochemical progression (PSA rise > 0.2 ng/mL above baseline or initiation of additional treatment) and radiological progression (local or metastatic disease on follow-up PSMA PET/CT) were assessed. Patients were stratified by EAU BCR-risk classification. Multivariable Cox regression included age, biochemical persistence (BCP) after a RP, pathological tumour stage (pT), pathological ISUP grade group (pISUP), node status (pN), margin status (R), and PSA doubling time (PSAdt). Results: The median age was 66 years (IQR 60–69) and the median PSA measurement at BCR was 0.2 ng/mL (IQR 0.2–0.3). A total of 27/89 (30%) patients were EAU BCR low-risk and 62/89 (70%) were high-risk. At three years, biochemical progression occurred in 14/27 (52%) low-risk vs. 51/62 (83%) high-risk patients, with time to progression being 21 vs. 12 months (p = 0.01). A pISUP grade group ≥ 4 (HR 2.04 [95%-CI 1.11–3.74]; p = 0.022) and a PSAdt < 20 months (HR 5.72 [95%-CI 2.41–13,56]; p < 0.01) independently predicted biochemical progression. Radiological progression occurred in 43/68 (66%) rescanned patients, with 32/43 (74%) showing disease outside the prostatic fossa. Conclusions: Nearly half of patients with BCR and negative PSMA PET/CT findings who were classified as EAU BCR low-risk remained progression-free at three years. These results support a risk-adapted approach, indicating that SRT may be deferred in selected low-risk patients. Full article

Online adaptive radiotherapy (ART) is rapidly transforming clinical radiation oncology by enabling adaptation of treatment plans based on patient-specific anatomical and biological changes. However, most medical physics training programs lack structured education in ART. To address this critical gap, the Medical Physics Adaptive Radiotherapy (MPART) Fellowship was established at our center to train post-residency or practicing physicists in advanced adaptive technologies and workflows. The MPART Fellowship is a two-year program that provides immersive, platform-specific training in CBCT-guided (Varian Ethos), MR-guided (Elekta Unity), and PET-guided (RefleXion X1) radiotherapy. Fellows undergo modular clinical rotations, hands-on training, and dedicated research projects. The curriculum incorporates competencies in imaging, contouring, online planning, quality assurance, and team-based decision-making. Evaluation is based on the Accreditation Council for Graduate Medical Education competency domains and includes milestone tracking, mentor reviews, and structured presentations. The fellowship attracted applicants from both domestic and international institutions, reflecting strong demand for formal ART training. Out of 22 applications, two fellows have been successfully recruited into the program since 2024. Fellows actively participate in all phases of adaptive workflows and are expected to function at near-attending levels by the second year of their training. Each fellow also leads at least one translational or operational research project aimed at improving ART delivery. Fellows contribute to clinical coverage and lead developmental projects, resulting in presentations and publications at the national and international levels. The MPART Fellowship addresses a vital educational need by equipping medical physicists with the advanced competencies necessary for implementing and leading ART. This program offers a replicable framework for other institutions seeking to advance precision radiation therapy through structured post-residency training in adaptive radiotherapy. As this fellowship program is still in its early phase of establishment, the primary goal of this paper is to introduce the structure, framework, and implementation model of the program. Comprehensive outcome analyses—such as quantitative assessments, fellow feedback, and longitudinal competency evaluations—will be incorporated in future work as additional cohorts complete training. Full article

Glioblastoma (GBM) is one of the most common and aggressive primary malignant tumors of the central nervous system, accounting for about half of all gliomas in adults. Despite intensive research and advances in molecular biology, genomics, and modern neuroimaging techniques, the prognosis for patients with GBM remains extremely poor. Despite the implementation of multimodal treatment involving surgery, radiotherapy, and chemotherapy with temozolomide, the average survival time of patients is only about 15 months. This is primarily due to the complex biology of this cancer, which involves numerous genetic and epigenetic abnormalities, as well as a highly heterogeneous tumor structure and the presence of glioblastoma stem cells with self renewal capacity. Mutations and abnormalities in genes such as IDH-wt, EGFR, PTEN, TP53, TERT, and CDKN2A/B are crucial in the pathogenesis of GBM. In particular, IDH-wt status (wild-type isocitrate dehydrogenase) is one of the most important identification markers distinguishing GBM from other, more favorable gliomas with IDH mutations. Frequent EGFR amplifications and TERT gene promoter mutations lead to the deregulation of tumor cell proliferation and increased aggressiveness. In turn, the loss of function of suppressor genes such as PTEN or CDKN2A/B promotes uncontrolled cell growth and tumor progression. The immunosuppressive tumor microenvironment also plays an important role, promoting immune escape and weakening the effectiveness of systemic therapies, including immunotherapy. The aim of this review is to summarize the current state of knowledge on the epidemiology, classification, pathogenesis, diagnosis, and treatment of glioblastoma multiforme, as well as to discuss the impact of recent advances in molecular and imaging diagnostics on clinical decision-making. A comprehensive review of recent literature (2018–2025) was conducted, focusing on WHO CNS5 classification updates, novel biomarkers (IDH, TERT, MGMT, EGFR), and modern diagnostic techniques such as liquid biopsy, radiogenomics, and next-generation sequencing (NGS). The results of the review indicate that the introduction of integrated histo-molecular diagnostics in the WHO 2021 classification has significantly increased diagnostic precision, enabling better prognostic and therapeutic stratification of patients. Modern imaging techniques, such as advanced magnetic resonance imaging (MRI), positron emission tomography (PET), and radiomics and radiogenomics tools, allow for more precise assessment of tumor characteristics, prediction of response to therapy, and monitoring of disease progression. Contemporary molecular techniques, including DNA methylation profiling and NGS, enable in-depth genomic and epigenetic analysis, which translates into a more personalized approach to treatment. Despite the use of multimodal therapy, which is based on maximum safe tumor resection followed by radiotherapy and temozolomide chemotherapy, recurrence is almost inevitable. GBM shows a high degree of resistance to treatment, which results from the presence of stem cell subpopulations, dynamic clonal evolution, and the ability to adapt to unfavorable microenvironmental conditions. Promising preclinical and early clinical results show new therapeutic strategies, including immunotherapy (cancer vaccines, checkpoint inhibitors, CAR-T therapies), oncolytic virotherapy, and Tumor Treating Fields (TTF) technology. Although these methods show potential for prolonging survival, their clinical efficacy still needs to be confirmed in large studies. The role of artificial intelligence in the analysis of imaging and molecular data is also increasingly being emphasized, which may contribute to the development of more accurate predictive models and therapeutic decisions. Despite these advancements, GBM remains a major therapeutic challenge due to its high heterogeneity and treatment resistance. The integration of molecular diagnostics, artificial intelligence, and personalized therapeutic strategies that may enhance survival and quality of life for GBM patients. Full article

Prostate-specific membrane antigen (PSMA) is a type II transmembrane glycoprotein that has become central to prostate cancer (PCa) diagnostics and treatment. Beyond its enzymatic role in folate and glutamate metabolism, PSMA is upregulated in advanced PCa, where it contributes to angiogenesis, tumour progression, and therapeutic resistance. This review integrates current understanding of PSMA biology with an emphasis on the role of PSMA expression and the hallmarks of cancer-proliferative signalling, metabolic adaptation, and evasion of cell death. While PSMA has revolutionised theranostic strategies in PCa, its utility as a sole biomarker is limited in select cases such as neuroendocrine differentiation and discordant disease biology. To address these challenges, we highlight emerging biomarkers and novel imaging markers that complement PSMA, including genomic alterations, circulating tumour markers, and exosomal microRNAs. Advances in radiomics and dual-tracer positron emission tomography (PET) further refine patient selection by capturing aggressive low-PSMA phenotypes. Furthermore, PSMA-PET is showing promise in other malignancies, including renal cell carcinoma (RCC) and glioblastoma multiforme (GBM), where neovasculature expression may extend its theranostic applications beyond PCa. By situating PSMA within this broader biomarker landscape, we outline opportunities for theranostic integration, including predictive models, combination therapies and expansion into non-prostate malignancies. Understanding the biology of PSMA in conjunction with novel biomarkers provides a framework for optimising theranostic applications and advancing personalised cancer care. Full article

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer mortality, with therapeutic resistance posing the primary barrier to durable outcomes. Beyond genetic and epigenetic alterations, amino acid transporter-driven metabolic reprogramming—mediated by LAT1 (SLC7A5), ASCT2 (SLC1A5), and xCT (SLC7A11)—supports tumor proliferation, redox homeostasis, and immune escape. Their preferential expression in NSCLC highlights their potential as therapeutic targets and predictive biomarkers. In parallel, α-particle therapy has gained attention for its capacity to eradicate resistant clones through densely clustered, irreparable DNA double-strand breaks. Astatine-211 (²¹¹At) combines a clinically relevant half-life, high linear energy transfer, and predictable decay scheme, positioning it as a unique candidate among α-emitters. Preclinical studies of ²¹¹At-labeled transporter ligands, particularly LAT1-targeted conjugates, demonstrate potent tumor suppression and synergy with targeted therapy, chemotherapy, radiotherapy, immunotherapy, and ferroptosis inducers. Advances in radiochemistry, delivery systems (antibodies, peptides, and nanocarriers), and PET tracers such as [¹⁸F]FAMT and [¹⁸F]FSPG collectively support a theranostic framework for patient stratification and adaptive dosing. By linking transporter biology with α-particle delivery, ²¹¹At-based theranostics offer a mechanistically orthogonal strategy to overcome resistance and heterogeneity in NSCLC. Successful translation will depend on precise dosimetry, scaffold stabilization, and biomarker-guided trial design, enabling progression toward first-in-human studies and future integration into multimodal NSCLC therapy. Full article