Critical reviews in oncology/hematology最新文献

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, driven largely by metastatic progression and therapeutic resistance. Despite advances in early detection and systemic treatment, a substantial proportion of patients develop disease that is refractory to conventional therapies. Epithelial-mesenchymal transition (EMT) is a dynamic and reversible cellular program that critically shapes CRC progression. Rather than functioning as a binary switch, EMT in CRC is increasingly understood as epithelial-mesenchymal plasticity (EMP), in which tumor cells occupy partial or hybrid epithelial/mesenchymal states. These intermediate phenotypes retain epithelial features while activating mesenchymal programs, enabling collective invasion, stem-like behavior, immune evasion, and resistance to therapy. This review provides a comprehensive analysis of the molecular drivers of EMT and EMP in CRC, including EMT-associated transcription factors (e.g., SNAIL, ZEB1), key signaling pathways (e.g., TGF-β, Wnt/β-catenin, Notch), and epigenetic regulators such as DNA methylation, histone modifications, and noncoding RNAs. The role of the tumor microenvironment, particularly cancer-associated fibroblasts and tumor-associated macrophages, in stabilizing hybrid EMT states through paracrine signaling and metabolic crosstalk is examined in detail. Importantly, EMP and hybrid EMT states are highlighted as central contributors to resistance across chemotherapy, targeted therapy, radiotherapy, and immunotherapy, driven by phenotypic flexibility rather than irreversible mesenchymal conversion. Emerging therapeutic strategies targeting EMT-associated signaling, epigenetic plasticity, and EMT-immune interactions are discussed, alongside the potential of liquid biopsy approaches to dynamically monitor EMT states during treatment. A refined understanding of epithelial-mesenchymal plasticity and hybrid EMT states is essential for the development of rational combination therapies and biomarker-guided strategies aimed at overcoming therapeutic resistance and limiting metastatic progression in colorectal cancer.

Background: A distinct subpopulation of tumour cells, known as breast cancer stem cells (BCSCs), plays a critical role in driving poor therapeutic outcomes due to its high proliferative capacity, metastatic potential and resistance to treatment. MicroRNAs (miRNAs) have emerged as a promising focus of research owing to their stability and ability to modulate tumour biology. However, the role of miRNAs in regulating BCSC characteristics remains insufficiently understood. This systematic review aims to synthesise evidence from in vitro and in vivo studies to evaluate the potential of miRNA-based strategies in targeting BCSCs to suppress their proliferation, metastasis potential, and treatment resistance.

Methods: A systematic search of major scientific databases was conducted for studies published from 2015 to 2024. Studies investigating the effects of microRNAs on BCSCs were screened based on predefined inclusion criteria.

Key findings: Twenty studies met the inclusion criteria, identifying 16 miRNAs with reported regulatory effects on BCSCs. Most miRNAs demonstrated tumour-suppressive functions by reducing proliferation, stemness marker expression, metastatic potential, or treatment resistance, whereas a smaller subset displayed oncogenic activity. miR-7 was the most consistently studied tumour-suppressive miRNA and exhibited multifunctional inhibitory effects.

Conclusion: miRNAs represent promising therapeutic candidates for targeting BCSCs through coordinated regulation of proliferation, resistance, and metastatic behaviour. However, the translational advancement of miRNA-based strategies requires more standardized experimental frameworks, expanded in vivo studies, and deeper mechanistic investigation to ensure safety and efficacy across breast cancer subtypes.

Introduction: In the majority of very high-risk and selected high-risk cases of clinically non-muscle-invasive bladder cancer (NMIBC), radical cystectomy (RC) may be performed. However, the necessity of pelvic lymph node dissection (PLND) in this clinical scenario is debated. The aim of this review was to evaluate how the presence and extent of PLND influence survival outcomes.

Materials and methods: A systematic literature search was performed on July 6^th, 2025, without language or time restrictions. Studies were considered eligible if they compared oncological outcomes between various extents of PLND during RC for NMIBC. The primary endpoint was overall survival (OS); secondary endpoints included cancer-specific survival (CSS) and recurrence-free survival (RFS).

Results: Nine retrospective studies comprising 20,806 patients were included. Pathological upstaging to muscle-invasive disease was observed in 19.1%-42.0% of patients. Seven studies evaluated OS, three CSS, and four RFS. Most studies demonstrated OS benefit associated with PLND, particularly in patients with cT1 tumors. Greater lymph node yield - especially the removal of ≥10 or >20 nodes - was consistently associated with improved OS. Extended PLND was linked to better CSS and RFS in several studies. However, findings for recurrence-related outcomes were heterogeneous and endpoint definitions varied.

Conclusions: PLND during RC for clinically NMIBC may be associated with improved survival, especially in patients with cT1 disease. Higher lymph node yield may further enhance oncologic benefit. These findings support the consideration of at least limited PLND during RC for clinically NMIBC. Prospective randomized studies are needed to establish definitive recommendations.

Lymph nodes are vital immunological organs, yet nodal surgery-including sentinel lymph node biopsy and completion lymph node dissection-is routinely performed in many solid tumors. Importantly, nodal surgery remains clinically valuable in selected settings, particularly for pathological staging and treatment decision-making, and in some contexts for regional disease control. We address a central paradox in surgical oncology: while lymph node dissection aims to control regional metastasis, emerging immunology suggests that intact tumor-draining regional lymph nodes can support antitumor immunity during immune checkpoint blockade. Although the immunological principles discussed may be relevant across a range of solid tumors, the most direct evidence to date comes from immunotherapy-treated settings-particularly tumor types with established checkpoint inhibitor activity-and from studies of regional, non-metastatic (tumor-draining) lymph nodes; whether these observations extend to immunotherapy-refractory tumors or metastatic nodes remains to be determined. Emerging evidence from preclinical models and correlative human studies suggests that tumor-infiltrating immune responses can be seeded from tumor-draining regional lymph nodes, supported by intratumoral tertiary lymphoid structures (ectopic lymphoid aggregates within tumors) and tumor-associated high endothelial venules (specialized venules that facilitate lymphocyte entry). With advances in imaging and drug-delivery platforms, even metastatic lymph nodes may also be addressed via non-surgical strategies. We propose the "Lymph Node Catalyst" hypothesis as an integrative, testable framework: preserved nodal-vascular circuits act as immunological reservoirs that may enhance responses to immunotherapy. This perspective reframes lymph nodes from solely metastatic waystations to context-dependent immune hubs in the immunotherapy era.

Approximately 15-30% of patients with colorectal cancer (CRC) present with metastases at diagnosis, while up to 50% will develop metastases during follow-up. The integration of targeted drugs into standard chemotherapy has significantly improved clinical outcomes, with anti-EGFR monoclonal antibodies playing a crucial role in the treatment of RAS wild-type metastatic CRC. In this context, high-quality RAS testing is essential. A national survey was carried out among 60 Italian laboratories to assess the state of the art for RAS testing. Based on the reported frequency of RAS mutations, laboratories were classified as "in range" (n. 35; RAS mutation frequency >42% and <56%) or "outliers" (n. 25; ≤42% or ≥56%). Considering the type of institutions, in Community Hospitals the percentage of 'outliers' is significantly higher than in Universities and National Cancer Institutes. Among the laboratories processing fewer than 150 samples per year, 'outliers' are more frequently detected in the group using Next generation sequencing (NGS) as prevalent methodology (n=10) than in the real time PCR (RT-PCR) group (n=4). In contrast, within laboratories processing more than 150 samples per year, the number of 'within range' laboratories (n=19) is more than twice that of 'outliers' (n=8) in the NGS group. The survey underscores the need for continuous training of stakeholders involved in molecular testing and a multidisciplinary approach to patient management. The authors suggest a similar evaluation in other European countries noting that beyond infrastructure and technology, personnel training and improved communication skills are essential for optimizing biomarker testing and personalized treatment approaches.

Glioblastoma (GBM) is characterized by a highly immunosuppressive microenvironment that is enriched with myeloid cell populations. Historically, these myeloid cells, particularly GBM-associated microglia/macrophages (GAMs) and myeloid-derived suppressor cells (MDSCs), were considered as pro-tumorigenic due to limitations in genomic technologies. However, advances in single-cell and spatial omics have revolutionized our understanding of the GBM immune landscape, uncovering extensive heterogeneity within the myeloid compartment. Studies utilizing murine models and patient-derived samples have demonstrated that GAMs and MDSCs exist along a spectrum of activation states, with both tumor-promoting and tumor-suppressive roles. These findings challenge the conventional view of myeloid cells in GBM and highlight their dynamic and context-dependent functions. This review summarizes key findings from single-cell and spatial-omics studies utilizing human GBM patient samples and highlighting the discovery of novel myeloid cell subsets, immunomodulatory programs, and tumor-niche specific myeloid subpopulations that have reshaped our understanding of the GBM immune landscape. We discuss how specific subpopulations interact with other cellular components of the tumor microenvironment to support tumor invasion, drive immunosuppression, and contribute to therapeutic resistance. Finally, we discuss therapeutic strategies informed by these insights, including subset-directed myeloid reprogramming, stimulating innate immune signaling and phagocytosis, and rational combinations of myeloid-targeted agents with chimeric antigen receptor (CAR) T-cell and other immune therapies to improve clinical outcomes in GBM.

Head and neck squamous cell carcinoma (HNSCC) remains a therapeutic challenge, with immune checkpoint inhibitors (ICIs) benefiting only a minority of patients. This review addresses the translational gap between promising preclinical results and suboptimal clinical outcomes. We critically analyze biological resistance drivers, including the immunosuppressive tumor microenvironment, TGF-β-mediated exclusion, hypoxia-driven metabolic checkpoints (e.g., adenosine signaling), and the distinct immune landscapes of HPV-positive versus HPV-negative disease. We argue that conventional models, such as 2D cell lines, syngeneic mice, and standard immunodeficient xenografts, inadequately recapitulate these human-specific mechanisms and stromal complexities. Consequently, we advocate for a paradigm shift toward high-fidelity platforms, specifically Air-Liquid Interface (ALI) autologous patient-derived organoids (PDOs) and humanized mouse models. While acknowledging technical challenges like establishment efficiency and time-to-answer constraints, we propose that integrating these avatars into biomarker-driven co-clinical trials is essential. Ultimately, integrating these high-fidelity avatars into co-clinical trials will enable precise patient stratification and the rational design of biomarker-driven trials, moving HNSCC therapy from empirical selection to data-driven clinical decision-making. Furthermore, standardizing these high-fidelity protocols to meet clinical turnaround times is the next frontier for ensuring their practical implementation in routine precision oncology for HNSCC.

Background: Tumor Treating Fields (TTFields) is a novel, non-invasive anti-tumor modality using low-intensity alternating electric fields to disrupt cancer cell division. Initially approved for glioblastoma, TTFields is now under investigation in multiple solid tumors.

Objectives: We synthesized evidence from preclinical and clinical studies, with the aim to emphasize TTFields' mechanistic insights and outcomes in various solid tumors.

Methods: We performed a comprehensive search and included original articles, review articles, case reports/series, meeting abstracts/reports and clinical trials that published, completed or conducted between January 1, 2000 and August 31, 2025. All papers reviewed and their key references are cross-checked to ensure a balanced and high-quality literature review on the subjects.

Result: Our retrieved in vitro and in vivo preclinical studies indicated that TTFields could inhibit tumor growth by interfering with mitosis, disrupting deoxyribonucleic acid (DNA) replication and repair, inducing apoptosis, activating autophagy, modulating immune response, suppressing metastasis and influencing cellular membrane permeability. Clinical studies have proven safe and efficacious in multiple solid tumors, with evidence of synergistic effects in combination with other anti-tumor treatment methods.

Conclusion: The preponderances of TTFields, which introduce an innovative dimension to solid tumor treatment, containing non-invasive anti-tumor effect, minimal systemic toxicity and superior therapeutic benefit in combination with diversified antineoplastic therapies, have been confirmed by results from preclinical studies and clinical trials. In the future, further exploration is still needed in indication expansion, new therapeutic combinations, biomarker identification and device renovation in the pursuit of better solid tumor management.

Importance: Randomized controlled trials (RCTs) establish the efficacy of new oncology drugs but often exclude older adults, patients with comorbidities, and individuals with poorer performance status. Real-world evidence (RWE) is therefore essential to determine whether trial benefits translate to the broader populations treated in routine practice.

Objective: To synthesize contemporary RWE on the effectiveness and safety of ten oncology drugs approved between 2020 and 2025 for solid tumors, focusing on studies with ≥100 patients to maximize robustness and generalizability.

Evidence review: A systematic search of PubMed/MEDLINE, Embase, Scopus, Web of Science, and major conference proceedings (ASCO, ESMO, AACR) identified observational cohorts, registries, expanded-access programs, and claims-based studies published from January 2020 to January 2025.

Findings: Twenty studies (N>3,400) met inclusion criteria: breast cancer (9), lung cancer (7), urothelial carcinoma (3), and endometrial cancer (1). In breast cancer, sacituzumab govitecan reproduced ASCENT outcomes (ORR 27-30%; PFS 4.8-5.2 months), trastuzumab deruxtecan achieved ORRs near 70% in HER2-positive disease and median PFS 7.5 months in HER2-low cohorts, and elacestrant showed real-world time-to-next-treatment of 7.9-10.8 months in ESR1-mutant ER+/HER2- disease. In NSCLC, sotorasib and adagrasib demonstrated ORRs of ~28-34% and PFS 3.5-6 months, selpercatinib provided durable disease control, and MET inhibitors (capmatinib, tepotinib) yielded PFS around 6-7 months. In urothelial carcinoma, enfortumab vedotin produced ORRs of 31-73% across datasets. In endometrial cancer, dostarlimab generated highly durable responses in dMMR/MSI-H disease.

Conclusions: RWE confirms the effectiveness and safety of multiple recently approved oncology drugs reinforcing the external validity of RCTs.

Human breast cancer (HBC) is a complex disease with several molecular subtypes, posing challenges in diagnosis and treatment. Among these subtypes, triple-negative breast cancer (TNBC) is particularly challenging due to the lack of targeted therapies and generally has a poorer prognosis than other molecular subtypes. Canine mammary carcinomas (CMCs) have been proposed as a spontaneous model of HBC and a suitable model for molecular subtypes. Notably, dogs exhibited a high prevalence of triple-negative subtypes compared to humans. This review explores the parallels between HBC and CMCs, with a special emphasis on triple-negative phenotype, through the lens of cancer hallmarks. Several similarities have been found between both species; however, challenges remain in understanding the full spectrum of cancer hallmarks in dogs and translating findings into effective therapies. The convergence of insights from the hallmarks of cancer and the unique attributes of CMCs model drives us toward future personalized medicine, offering new avenues for research in the field of comparative oncology.