Abstract Objectives Axillary lymph node (ALN) status is a crucial prognostic factor in breast cancer. Accurate, non-invasive methods for evaluating axillary lymph node metastasis after neoadjuvant therapy (NAT) are needed to optimize surgical decisions and minimize patient morbidity. Fibroblast activation protein inhibitor (FAPI) PET/CT targets cancer-associated fibroblasts and may improve diagnostic accuracy. This study aims to assess the diagnostic performance and clinical utility of 18 F-FAPI PET/CT in detecting ALN metastasis after NAT in breast cancer patients. Methods This prospective, single-center study will enroll breast cancer patients with cT1-4N0-1M0 stage before NAT, who will undergo pre-surgical 18 F-FAPI PET/CT followed by sentinel lymph node biopsy (SLNB) or axillary lymph node dissection (ALND) guided by protocol stratification based on FAPI PET/CT and clinical findings. The primary endpoint is the diagnostic accuracy of 18 F-FAPI PET/CT for ALN metastasis vs. pathology. Secondary endpoints include false-negative rates (FNR) of SLNB, lymphedema rates, and long-term outcomes such as local recurrence and survival rates. Discussion This study will provide evidence on the efficacy of 18 F-FAPI PET/CT in accurately assessing ALN status post-NAT, potentially enabling de-escalation and reducing complications, thereby advancing personalized breast cancer care. Trial registration ClinicalTrials.gov, identification number: NCT07012707.
Abstract Loss or downregulation of MHC-I is a frequent mechanism of immune evasion in central nervous system (CNS) cancers, partially driven by an immunologically cold microenvironment. In this short commentary, we issue a call to action for exploring therapeutic strategies of MHC-I expression restoration in brain cancers to improve patient outcomes. We discuss several potential strategies, including targeting the immunosuppressive microenvironment, epigenetic modulation, and gene therapy approaches. We argue that effective MHC-I restoration may require a combinatorial approach that simultaneously boosts both antigen processing and presentation and remodels the tumor microenvironment. Overcoming CNS-specific barriers, such as the blood-brain barrier, is critical for success. We propose that combining MHC-I re-expression with immunotherapy, chemotherapy, and radiotherapy could provide new therapeutic windows for CNS malignancies.
Immune checkpoint inhibition has revolutionized the management of microsatellite instability–high (MSI-H)/mismatch repair–deficient (dMMR) metastatic colorectal cancer (mCRC), a biologically distinct subgroup characterized by high tumor mutational burden, neoantigen richness, and marked immune infiltration. Programmed death-1 (PD-1) inhibitors, such as pembrolizumab and nivolumab, have demonstrated durable responses and improved outcomes compared with historical chemotherapy, including in the first-line setting. Nevertheless, a clinically relevant proportion of patients exhibit primary resistance or early progression on PD-1 monotherapy. This unmet need has driven interest in dual immune checkpoint blockade combining PD-1 and cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) inhibition. Mechanistically, CTLA-4 blockade enhances T-cell priming and repertoire diversification, complementing PD-1–mediated reinvigoration of tumor-infiltrating effector T cells. Clinical studies indicate that nivolumab plus ipilimumab is associated with higher objective response rates and longer progression-free survival compared to PD-1 monotherapy. Recent randomized data from the Checkmate 8HW trial suggest a clinically meaningful trend toward improved overall survival with combination therapy; however, overall survival data are not yet mature and definitive conclusions regarding survival benefit cannot be drawn.
Nasopharyngeal carcinoma (NPC) is a common malignant head and neck tumor originating in the nasopharynx. Its incidence exhibits distinct geographical heterogeneity. Although global incidence rates have declined in recent years, the disease remains highly prevalent in East and Southeast Asia. Early-stage NPC has a cure rate approaching 90 %; however, its insidious onset and non-specific symptoms often delay diagnosis until advanced stages. This results in limited treatment efficacy, poor prognosis, and a 5-year overall survival rate of less than 15 %. Current screening relies mainly on Epstein-Barr virus (EBV)-related markers, which show high performance in endemic regions but limited sensitivity and positive predictive value in non-endemic settings. Therefore, there is an urgent need for reliable biomarkers suitable for population screening, risk stratification, and prognostic evaluation. This review offers a systematic synthesis of recent advances in NPC diagnostic biomarkers, dividing them into six categories based on molecular characteristics: genetic, epigenetic, proteomic, microbiomic, metabolomic, and extracellular vesicles (EVs) biomarkers. These multi-omics biomarkers offer a comprehensive landscape for earlier detection and individualized management of NPC and lay the groundwork for future integrative, region-tailored screening strategies. We anticipate that this review will foster continued progress toward the development and clinical translation of more effective biomarkers for the diagnosis, prognosis, and therapeutic stratification of NPC.
Objectives Malignant transformation (MT)-associated risk in oral potentially malignant disorders (OPMDs) involves not only dysplastic epithelial changes but also local remodeling of neighboring epithelium. Nuclear factor of activated T cells 3 (NFAT3) is a stress-responsive transcription factor, yet its role in early oral carcinogenesis and field cancerization-like processes remains unclear. This study investigated whether NFAT3-high dysplastic cells remodel adjacent epithelium via an interleukin-17C (IL-17C) axis and whether NFAT3/IL-17C patterns support subtype-specific clinical stratification in OPMDs.Methods NFAT3 expression was profiled in public datasets and validated in animal model and oral epithelial cell lines. 2D/3D direct co-culture tracked time-dependent population shifts. Transcriptomics, RT-qPCR, Western blotting, and ELISA assessed IL-17C/interleukin-17 receptor E (IL-17RE) signaling and NF-kappa B activation, with functional tests using IL-17C supplementation and IL-17C-IL-17RE blockade. A supplementary Lotka-Volterra model described proportion trajectories. In the UK Biobank (UKB) OPMDs cohort (n=6,197), oral cancer diagnosis status was used for subtype-specific NFAT3/IL-17C stratification and interaction analyses.Results NFAT3 was upregulated in precancerous lesions and promoted epithelial proliferation. In direct co-culture, NFAT3-high DOK cells triggered transcriptional convergence in neighboring NFAT3-low DOK cells via an IL-17C-IL-17RE/NF-kappa B-associated paracrine program, producing local remodeling consistent with a field cancerization-like process. Clinically, NFAT3/IL-17C showed subtype-specific stratification and interaction patterns in the UK Biobank cohort, with more informative risk grouping in oral leukoplakia (OLK) and discoid lupus erythematosus (DLE).Conclusions These findings identify an NFAT3-high dysplastic clone-driven, IL-17C-mediated paracrine remodeling mechanism and support the NFAT3/IL-17C axis as a potential biomarker for subtype-specific risk stratification and early clinical intervention in OPMDs.
Abstract Brain metastasis represents one of the most devastating complications of lung adenocarcinoma (LUAD) and remains a major cause of cancer-related mortality. The metastatic spread of LUAD to the brain is not a random event but a highly coordinated, multistep process that requires tumor cells to dynamically adapt to changing microenvironments. Epithelial-mesenchymal transition (EMT) has emerged as a central driver of this phenotypic plasticity. Rather than functioning as a simple binary switch, EMT encompasses a spectrum of reversible cellular states that endow tumor cells with enhanced motility, survival in circulation, and the capacity to cross the blood-brain barrier, followed by re-acquisition of epithelial traits that support metastatic colonization. In this review, we discuss how EMT-associated plasticity shapes each stage of LUAD brain metastasis, from local invasion and systemic dissemination to intracranial adaptation and outgrowth. We further examine the regulatory networks that integrate microenvironmental cues with transcriptional and epigenetic programs to sustain these dynamic state transitions. Finally, we highlight the clinical implications of EMT-driven heterogeneity, including its impact on therapeutic resistance and disease progression, and outline emerging strategies aimed at targeting metastatic plasticity. A deeper understanding of EMT as a context-dependent and reversible process may open new avenues for the prevention and treatment of LUAD brain metastasis.
Survival outcomes for childhood acute lymphoblastic leukaemia (cALL) in Malaysia have improved markedly, with survival rates of >90 % in the best-risk groups reported recently. However, long-term survivorship remains challenged by a high burden of late effects, with many survivors developing severe – and in some cases life-threatening – health complications within two decades of diagnosis. This narrative review discusses the potential main driver of these comorbidities, which is chronic inflammation or ‘inflammaging’, as well as the potential deregulation of the CD38-NAD-Sirtuins axis, as a consequence of treatment-related insults. Thus, there is an urgent need for effective, evidence-based interventions to mitigate chronic health conditions in this growing population of young adult survivors of childhood cancer. We examine the potential role of dietary flavonoids, which are bioactive compounds abundant in fruits, vegetables, and common daily foods, in reducing long-term treatment-related complications due to their established anti-inflammatory and antioxidant properties. Specifically, we focus on five flavonoids of interest, namely apigenin, quercetin, fisetin, epigallocatechin gallate, and luteolin, and summarise current evidence regarding their mechanistic actions and potential utility as adjunctive strategies to alleviate late effects in childhood cancer survivors.
Tongue squamous cell carcinoma (TSCC) presents unique clinical challenges characterized by intricate lingual musculature, early perineural invasion, and a high propensity for occult cervical lymph node metastasis. Despite significant therapeutic advancements, the attrition rate for novel pharmacological agents remains high, largely attributed to the disconnect between preclinical models and clinical reality. Adhering to PRISMA-ScR guidelines, this study aims to systematically map recent advancements in preclinical TSCC models and evaluate their biological fidelity to provide a strategic framework for optimal model selection.
Metastatic castration-resistant prostate cancer (mCRPC) causes over 375,000 deaths annually. Genomic heterogeneity, androgen receptor (AR) signaling dysregulation, DNA damage repair (DDR) deficiencies, and diverse resistance mechanisms limit conventional therapies, underscoring the need for individualized precision approaches.
Exosomes secreted by tumor-associated macrophages (TAMs) function as pivotal mediators of intercellular communication within tumor microenvironments (TME). These vesicles actively accelerate cancer progression through multiple pathways: driving tumor cell proliferation and metastasis, reprogramming tumor metabolism, inducing angiogenesis to support nutrient supply, facilitating immune evasion, enhancing resistance to therapies, and sustaining cancer stem cell populations. In breast and gynecological malignancies specifically, TAM-derived exosomes (TDEs) demonstrate broad functional impact across these critical processes. Beyond their pathological roles, these exosomes show promise as both diagnostic biomarkers and therapeutic targets. This review not only summarizes the functional roles of TDEs but also delves into the underlying molecular mechanisms governing their biogenesis, secretion, and uptake, including the ESCRT-dependent and -independent pathways, the regulatory roles of Rab GTPases (e.g., Rab27a) in exosome release, the selective packaging of oncogenic miRNAs mediated by RNA-binding proteins (e.g., hnRNPA2B1), and the modulation of these processes by hypoxic and metabolic cues within the TME. Furthermore, we outline promising future research directions aimed at translating this knowledge into improved prevention and treatment strategies for female-specific cancers.
Cisplatin remains a cornerstone chemotherapeutic agent for advanced gastric cancer; however, the development of drug resistance substantially limits its clinical benefit and is frequently associated with poor prognosis. Recent studies suggest functional interactions between MYBL2, CLSPN and CHK1 genes and multiple DNA repair pathways, indicating that they may contribute to tumor cell tolerance of cisplatin-induced genotoxic stress. MYBL2 has been implicated in transcriptional regulation of cell cycle and DNA repair–associated genes, CLSPN functions as a mediator of ATR-dependent checkpoint activation, and CHK1 coordinates cell cycle arrest and repair signaling under replication stress conditions. This review aims to examine emerging evidence regarding the roles of MYBL2, CLSPN and CHK1 in cisplatin resistance in gastric cancer, with particular emphasis on their potential involvement in DNA damage response and replication stress pathways. We further outline a working model in which enhanced proliferative drive and replication stress may increase reliance on checkpoint-mediated repair mechanisms during cisplatin exposure. It should be noted that much of the available evidence is derived from in vitro models or extrapolated from other tumor types, and direct in vivo and clinical validation in gastric cancer remains limited. These findings suggest a regulatory network that may drive cisplatin resistance and reveal potential therapeutic vulnerabilities. Clarifying the context-dependent contribution of this network may ultimately inform biomarker-guided strategies and combination approaches for improving treatment response in gastric cancer.
Abstract Magnetic targeting systems integrate external magnetic fields with functionalized magnetic nanoparticles to enable precise intervention at tumor sites, addressing well-recognized limitations of conventional chemotherapy and immunotherapy, including insufficient intratumoral drug enrichment, systemic toxicity, and an immunosuppressive tumor microenvironment. This review systematically maps the evolution of this field from fundamental physical principles to intelligent closed-loop theranostics, and proposes a conceptual framework that positions magnetic targeting as a potential spatiotemporally precise mediator for tumor immune modulation. It examines the interplay between magnetic force and hemodynamic drag, the impact of nanoparticle physicochemical properties on in vivo fate, and compares engineering advances in static and dynamic magnetic systems. Therapeutic strategies – including magnetic hyperthermia combined with immune checkpoint inhibitors, magnetically targeted drug/nucleic acid delivery, cell therapy navigation, and magnetically driven ferroptosis – are analyzed for their immunoregulatory potential. The integration of real-time imaging guidance and artificial intelligence (AI)-driven optimization for theranostic closed-loop systems is also discussed, along with representative clinical trials and translational challenges. Despite persistent hurdles, magnetic targeting systems are evolving into enabling platforms for precise, individualized cancer therapy.
Abstract Magnesium (Mg 2+ ) is a divalent cation that functions as a cofactor for numerous enzymes and plays a critical role in essential cellular processes, including proliferation, migration, and apoptosis. Over the past decade, Mg 2+ has gained increasing attention as a potential protective factor against colorectal cancer (CRC), as higher dietary Mg 2+ intake has been associated with a reduced risk of disease development. Emerging evidence also suggests that Mg 2+ supplementation may modulate the gut microbiome and enhance vitamin D synthesis, which could further contribute to CRC prevention. In addition, some in vitro studies suggest that Mg 2+ may reduce the survival of human colon cancer cells, supporting a potential antitumor role. Conversely, dysregulation of Mg 2+ channels and transporters has been reported in CRC and has been associated with chemoresistance, metastasis, tumor progression, and poorer clinical prognosis. Clinically, hypomagnesemia is frequently observed in CRC patients, particularly in those receiving anti-EGFR therapies, and has been proposed as a potential, although still debated, biomarker of treatment response and prognosis. This mini-review summarizes current knowledge regarding Mg 2+ homeostasis in the large intestine and discusses the potential implications of Mg 2+ transporters and channels in CRC development, progression, and clinical outcomes.
Objectives: Acute myeloid leukemia (AML) is a heterogenous hematologic malignancy affecting both children and adults, characterized by diverse molecular alterations and variable clinical outcomes. Identifying subtype-specific gene markers is therefore important for improving disease characterization and guiding personalized therapeutic strategies. In this study, we aimed to identify potential genes involved in AML using a graph-based clustering method and to evaluate their differential expression across AML subtypes. Methods: A protein-protein interaction network (PPIN) was constructed and analyzed using the DPClusOST clustering algorithm to identify protein clusters at densities ranging from 0.1 to 1.0. Cluster significance was evaluated using a significance score (SScore) based on Fisher's exact test, and clusters containing AML gene panels were assessed through receiver operating characteristic (ROC) analysis. The cluster density with the highest area under the curve (AUC) was subsequently subjected to differential gene expression and pathway enrichment analyses. Results: At a clustering density of 1.0, 32 clusters were identified, including 16 novel AML-associated genes that exhibited significant differential expression across AML subtypes (e.g., PML-RAR alpha and CD34; |log(2)FC| >= 1, adjusted p<0.05). Pathway enrichment analysis further demonstrated significant involvement in AML-related biological processes (p-value <0.05), including PI3K/AKT signaling and hematopoietic dysregulation, such as refractory macrocytosis, abnormalities of bone marrow stromal cells, and multiple lineage myelodysplasia, inferring the potential involvement of the newly discovered genes in the clonal, acquired stem cell disorder characterization of AML. Conclusions: These findings demonstrate that graph-based clustering can effectively identify novel AML-associated genes with potential relevance for subtype characterization.
Objectives: Despite clinical advancements, challenges persist in breast cancer (BRCA) management, particularly regarding the ubiquitin-proteasome system. This study aims to comprehensively investigate the diagnostic, prognostic, and therapeutic roles of UBE2C. Methods: Multi-omics data from 1,097 TCGA-BRCA samples were analyzed using subtype-stratified survival analyses. The tumor-immune microenvironment was profiled via deconvolution algorithms. Biological mechanisms were investigated using GSEA and DepMap functional genomic screens. Pharmacogenetic profiling and molecular docking were employed to identify targeted therapeutic vulnerabilities. Results: UBE2C was significantly overexpressed in tumor tissues, demonstrating exceptional discriminatory power (AUC: 0.972). High expression correlated positively with genomic instability markers, including tumor mutation burden (TMB) and microsatellite instability. Clinically, elevated UBE2C predicted worse overall and relapse-free survival, particularly in advanced-stage tumors and low-TMB patients. At the transcriptomic and functional-genomic level, UBE2C is critical for cell viability, and its overexpression is associated with cell cycle dysregulation and TSC/mTOR pathway activation; genetic knockout resulted in growth inhibition. Furthermore, UBE2C overexpression is strongly associated with an immunosuppressive microenvironment, correlating negatively with anti-tumor effector cells and positively with regulatory T cells and checkpoints like PD-1, PD-L1, and CTLA4. Pharmacogenetic analysis indicated that UBE2C overexpression is associated with increased sensitivity to the JAK1/2 inhibitor Ruxolitinib. Molecular docking simulations revealed a structural basis for this vulnerability, showing that Ruxolitinib occupies a binding pocket within the UBE2C protein structure, stabilized by a critical hydrogen bond with residue ILE113. This structural stability suggests a potential therapeutic vulnerability associated with UBE2C overexpression and JAK1/2 inhibition. Conclusions: UBE2C is a robust diagnostic and prognostic biomarker. Its observational association with aggressive tumour biology, immune evasion gene signatures, and candidate therapeutic vulnerability to Ruxolitinib suggests a hypothesis-generating framework for future experimental and clinical investigation.
Objectives: While biomarkers related to nutrition and inflammation have been widely recognized as reliable prognostic indicators for esophageal squamous cell carcinoma (ESCC), their combined predictive efficacy in unresectable ESCC patients undergoing first-line immunotherapy has not been fully verified. Moreover, there is still a shortage of simple and specialized combined prognostic scoring tools for these patients. This study aims to construct a novel modified nutrition-inflammation index to predict the clinical prognosis of patients with unresectable ESCC treated with first-line immunotherapy. Methods: A total of 330 individuals were included in this retrospective analysis. The random forest algorithm was applied to assess the prognostic significance of baseline nutritional and inflammatory markers, facilitating the development of a comprehensive nutritional-inflammation score (NIS). Differences in overall survival (OS) across risk groups were evaluated using Kaplan-Meier survival analysis with log-rank tests. Subsequently, the prognostic performance of the NIS across various clinical subgroups was further examined. Cox hazard model was utilized to verify the predictive impact of the NIS on OS, followed by the construction of a nomogram based on significant independent predictors to systematically evaluate its predictive ability. Results: Patients with a high NIS demonstrated significantly prolonged OS in both the overall cohort and all predefined subgroups. Multivariate analysis identified Eastern Cooperative Oncology Group Performance Status (ECOG PS) score, distant organ metastasis, immunotherapy modality, and NIS as independent prognostic factors (all p<0.001). The nomogram exhibited robust predictive performance, yielding a C-index of 0.734 (95 % CI: 0.688-0.780). Conclusions: The novel NIS serves as an effective prognostic indicator for patients with unresectable ESCC undergoing first-line immunotherapy.
Objectives: Growth hormone-secreting pituitary adenomas (GHPAs) can exhibit highly aggressive oncological behaviors, characterized by local invasion, high recurrence rates, and resistance to standard multimodal therapies including surgery and radiotherapy. While these refractory tumors drive the systemic syndrome of acromegaly, early identification of their aggressive phenotype remains a major clinical challenge. To overcome the limitations of conventional morphological markers, this study aimed to develop a deep learning model using multi-sequence MRI to predict aggressive GHPAs preoperatively by capturing complex tumor image features. Methods: In this single-center retrospective study, 102 patients with GHPAs were included, of which 38 exhibited aggressive, treatment-refractory behavior. Model inputs comprised multi-sequence pituitary MRIs: coronal contrast-enhanced T1-weighted (CE-T1), sagittal CE-T1, and coronal T2-weighted imaging. We implemented a hierarchical multiple instance learning framework to construct a multi-sequence residual fusion network (PTNet). This architecture featured shared-weight feature extraction, slice-level attention aggregation, and sequence-level residual fusion to automatically learn high-dimensional oncological imaging phenotypes from patient-level labels. Model performance was evaluated via 5fold cross-validation, alongside decision curve and calibration analyses. Results: During 5-fold cross-validation, PTNet achieved an area under the curve (AUC) of 0.9126, an accuracy of 0.8922, and a sensitivity of 0.8684 in identifying aggressive tumors, outperforming both single-sequence models and fusion models based on simple concatenation. Notably, patients in the aggressive group also exhibited significantly higher oncological proliferation markers, such as the Ki-67 index. Decision curve analysis demonstrated a favorable net clinical benefit across relevant risk thresholds, while calibration analysis indicated good agreement between predicted and observed probabilities. Conclusions: The deep learning-based integration of multi-sequence MRI effectively captures latent imaging phenotypes associated with aggressive GHPAs. Although requiring external validation, this approach shows strong potential as a preoperative neuro-oncological tool to identify patients at high risk of refractoriness, thereby facilitating individualized multimodal interventions such as targeted surgical and adjuvant radiotherapy planning.
Objectives: Procalcitonin (PCT) is widely used as a biomarker of bacterial infection and sepsis, but its specificity decreases substantially in patients with advanced malignancy. Case presentation: We report a 55-year-old woman with surgically resected lung adenocarcinoma who subsequently underwent multiple systemic treatments, Gamma Knife radiosurgery for central nervous system metastases, immunotherapy, and KRAS G12C-targeted therapy. After disease progression, biopsy of a liver metastasis demonstrated histologic transformation to dominant small-cell lung carcinoma (SCLC) with neuroendocrine phenotype, including diffuse CD56 and synaptophysin positivity, thyroid transcription factor-1 (TTF-1) positivity, Napsin A loss, Ki-67 approximately 80 %, and focal retinoblastoma (RB) loss. The patient was admitted with markedly elevated inflammatory markers and persistently extreme PCT values above 20 ng/mL, while serum calcitonin was profoundly elevated (2,409 pg/mL). Extensive infectious evaluation showed three negative sets of blood cultures obtained before antibiotic therapy, a sterile urine culture, negative Aspergillus and Candida serology, negative mannan, galactomannan, and beta-D-glucan assays, and no radiological evidence of pneumonia, abscess, or intra-abdominal infection on contrast-enhanced computed tomography of the chest, abdomen, and pelvis. She remained afebrile and clinically stable, with no improvement attributable to broad-spectrum antimicrobial therapy; subjective improvement followed a packed red blood cell transfusion. Conclusion: This case is clinically distinctive because persistent extreme PCT elevation occurred in parallel with histologically confirmed adenocarcinoma-to-SCLC transformation, marked hypercalcitoninemia, extensive tumor necrosis, and a consistently negative infectious workup, closely mimicking severe bacterial sepsis. In this setting, extreme PCT elevation was more consistent with a tumor-related inflammatory phenomenon than with bacterial infection.
