Search Results (122,182)

Cancer therapies are increasingly reliant on immunotherapeutic interventions; however, the persistent emergence of primary, adaptive, and acquired resistance severely limits durable clinical efficacy. Circular RNAs (circRNAs), distinguished by their extreme structural stability and covalently closed loops, have recently been established as potent orchestrators of this immune evasion. This review systematically synthesizes current advancements detailing how circRNAs undermine anti-tumor immunity across diverse malignancies. Specifically, we delineate their critical roles in post-transcriptionally upregulating immune checkpoint molecules (e.g., PD-L1), mediating intercellular immunosuppression via exosomal transfer, and metabolically reprogramming the tumor microenvironment to drive CD8+ T-cell exhaustion and macrophage polarization. Ultimately, we conclude that translating these molecular insights into clinical practice is paramount. Beyond serving as predictive biomarkers, engineering circRNA-targeted therapies and exploiting tumor-specific circRNAs to develop novel anti-tumor vaccines represent essential, paradigm-shifting strategies to definitively overcome immune checkpoint inhibitor resistance. Full article

Background/Objectives: We developed a telehealth-enabled fiber-bundle endomicroscopy platform and evaluated its preclinical feasibility for targeted fluorescence imaging in cervical cancer models. Methods: The platform integrates a portable fiber-bundle endomicroscopy (FBE) system, fluorescein isothiocyanate (FITC)-labeled candidate peptides, and a secure web-based telehealth platform for remote consultation. The FBE probe achieved a field of view of 1,700 µm and a lateral resolution of 4 µm, enabling cellular-level fluorescence imaging in a compact, portable format. Four FITC-labeled peptides (SHS1*, SHS2*, FPP*, and CRL*) were evaluated in A549, SiHa, and CaSki cell lines. Ex vivo testing was performed on commercial cervical tissue-array samples. The telehealth platform was assessed for secure medical-image/video transmission and end-to-end latency in a simulated remote-consultation setting. Results: Among the tested probes, FPP*-FITC and CRL*-FITC showed higher fluorescence-positive fractions in the p16-overexpressing cervical cancer cell lines than in the A549 comparator line, with the strongest signals observed in CaSki cells. In ex vivo testing, CRL*-FITC generated higher fluorescence intensity in malignant cervical tissue-array samples than in non-malignant comparator tissues, with a reported 4.6- to 7.4-fold difference in mean signal intensity (p < 0.001). The telehealth platform supported the secure transmission of medical images and video and demonstrated an end-to-end latency of <500 ms in a simulated remote consultation setting. Conclusions: These results support the technical and preclinical feasibility of integrating targeted fluorescence imaging, portable fiber-bundle endomicroscopy, and telehealth into a single platform. This study should therefore be interpreted as a preclinical feasibility study evaluating optical, molecular, and telehealth integration, rather than as a clinically validated cervical cancer screening test. Full article

Background/Objectives: High-risk prostate cancer patients undergoing radical prostatectomy remain at significant risk of biochemical recurrence and metastasis. Immediate adjuvant external beam radiotherapy (EBRT) has been proposed to improve outcomes, but its role compared to observation remains debated due to potential toxicity and uncertain overall survival benefit. To evaluate the efficacy and safety of immediate adjuvant EBRT versus observation following radical prostatectomy in men with high-risk prostate cancer. Methods: A meta-analysis was conducted according to PRISMA guidelines. We sought to include both randomized controlled trials (RCTs) and observational studies published between 2005 and 2025; however, no observational studies meeting the predefined criteria were identified. Therefore, only RCTs comparing immediate adjuvant EBRT with observation in patients with adverse pathological features and undetectable postoperative PSA were included. Primary outcomes were biochemical recurrence-free survival (BCR-FS), metastasis-free survival (MFS), and overall survival (OS). Secondary outcomes included toxicity and quality of life (QoL). Data were pooled using Mantel–Haenszel and inverse variance methods, and heterogeneity was assessed with I² statistics. Results: Four RCTs (n = 1987) met the inclusion criteria. Adjuvant EBRT significantly improved progression-free survival (PFS) (HR = 0.38; 95% CI: 0.20–0.74; p = 0.004) and metastasis-free survival (HR = 0.70; 95% CI: 0.54–0.92; p = 0.01). However, OS benefit was not statistically significant (HR = 0.88; 95% CI: 0.59–1.32; p = 0.55). Heterogeneity was substantial for some outcomes (I² up to 71%). Adjuvant EBRT was associated with higher genitourinary and gastrointestinal toxicity compared to observation. Conclusions: Immediate adjuvant EBRT after radical prostatectomy improves PFS and MFS in high-risk prostate cancer but does not confer a clear OS advantage. Treatment decisions should be individualized, balancing disease-control benefits against toxicity risks. Observation with early salvage RT remains a reasonable alternative in selected patients. Full article

Background: This article provides a comprehensive overview of recent advancements in artificial intelligence (AI) and deep-learning technologies for breast cancer (BC) diagnosis across various imaging modalities. Methods: A systematic review was conducted in strict adherence to the PRISMA guidelines, incorporating a comparative analysis of 65 peer-reviewed studies published between 2018 and 2024. The evaluation focused on diagnostic performance, architectural developments, and clinical integration strategies. Results: The review synthesizes primary findings on convolutional neural networks (CNNs), emerging architectures including graph neural networks, and hybrid models, with diagnostic accuracy, risk prediction, and personalized screening strategies identified as the leading research domains. Notable achievements include CNNs attaining up to 98.5% accuracy in mammography and Vision Transformers reaching 96% in histopathological analysis. Furthermore, the implementation of explainable AI methodologies, such as SHAP, LIME, and Grad-CAM, is emphasized for maintaining transparency, trust, and accountability in clinical decision-making. Conclusions: AI constitutes a pivotal factor in facilitating early BC diagnosis and optimizing treatment outcomes. Nevertheless, significant challenges persist, including dataset heterogeneity, model generalizability, standardization of imaging protocols, computational resource limitations, and the seamless integration of these technologies into established clinical workflows. Future research must prioritize robust multi-dataset validation and standardized implementation frameworks to overcome existing limitations and advance successful BC diagnostic practices. Full article

Background/Objectives. Head and neck mucosal melanoma (HNMM) is a rare, aggressive malignancy with poor outcomes and limited evidence to guide prognostication and treatment. A detailed assessment of long-term survival and prognostic factors is needed to inform clinical management and staging. This work aimed to describe outcomes and prognostic factors in HNMM patients treated over 45 years. Methods. This was a retrospective observational cohort study of consecutive patients treated at a tertiary referral center in Italy from 1975 to 2020. Random-forest-based screening informed covariate selection for Cox models. Endpoints were overall survival (OS), disease-free survival (DFS), and post-recurrence DFS (prDFS). Associations with clinical and pathological variables were evaluated using Kaplan–Meier estimates, log-rank tests, and multivariable Cox regression. Results. Among 112 patients (median follow-up, 121.1 months), 3-/5-year OS was 42.8%/28.0%, DFS 20.5%/13.2%, and 1-/3-year prDFS 36.7%/10.9%. Ulceration was associated with worse OS (HR 2.12; 95% CI 1.05–4.26) and DFS (HR 2.23; 95% CI 1.16–4.28). Male sex showed a trend toward poorer OS and DFS. Regional lymph-node treatment correlated strongly with OS and prDFS (overall p < 0.001), with neck dissection indicating unfavorable risk (OS HR 5.22; 95% CI 2.39–11.40). Conclusions. HNMM remains a high-mortality disease with frequent recurrence. Ulceration and nodal involvement were key adverse prognostic factors, while surgery was associated with improved survival. The findings support incorporating ulceration into future staging and highlight the potential for durable control through salvage surgery. Further investigation of treatment intensification, biomarkers, and multimodal strategies is warranted. Full article

Cancer poses a serious threat to human life and health, and the number of new cancer and death cases worldwide is substantial, of which breast cancer is the most common among women. p-QM-1h is an organic small molecule with excellent anti-cancer activity, but it has low solubility and requires a high dosage, and it is not a targeted anti-tumor drug. In this study, p-QM-1h was loaded into a nanostructured lipid carrier (NLC) using the thin-film dispersion method to construct p-QM-1h-NLC, and its surface was modified with cetuximab (CTX) to construct CTX-p-QM-1h-NLC, which was tested for activity in 4T1 cells and tumor-bearing mice. The construction of CTX-p-QM-1h-NLC used Miglyol 812N as a liquid lipid, which effectively improved the solubility and encapsulation efficiency of p-QM-1h. Nanoparticles were uniform, well dispersed, and had good stability, and the CTX modification of p-QM-1h-NLC exhibited high connection efficiency and ensured antibody integrity. CTX-p-QM-1h-NLC exhibited effective anti-tumor activity in both 4T1 cells and tumor-bearing mice. The construction of CTX-p-QM-1h-NLC effectively improved the solubility of p-QM-1h, enhanced its therapeutic efficacy and reduced its drug dosage. It also had a certain targeting ability, increasing drug aggregation in tumor tissues. Flow cytometry and Western blot results showed that CTX-p-QM-1h-NLC could effectively inhibit the expression of TrxR and increase the expression of Bax and caspase 3 in vivo, which was consistent with the increase in ROS levels and the induction of apoptosis in 4T1 cells. These results indicated that the construction of CTX-p-QM-1h-NLC is worthy of further investigation. Full article

Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited treatment options. Patients are treated with DNA damaging chemotherapies which act by inducing DNA damage in rapidly dividing tumor cells. Unfortunately, these tumors frequently develop treatment resistance, underscoring the need to understand resistance mechanisms in order to develop better treatment strategies. DNA damage response (DDR) detects and repairs DNA damage, and the DDR pathway has been shown to contribute to chemoresistance. Another factor known to drive chemoresistance in PDAC is the dense stroma, composed of extracellular matrix proteins secreted by cancer-associated fibroblasts (CAFs). Our recent work identified a CAF-induced resistance mechanism involving N-myc downstream regulated gene 1 (NDRG1). CAF-induced signaling resulted in the phosphorylation of NDRG1 and NDRG1-dependent DNA repair and protection from chemotherapies. Loss of NDRG1 resulted in increased chemotherapy-induced DNA damage and decreased replication fork speed and recovery. Methods: To gain insight into the molecular mechanism of NDRG1-mediated DNA repair and replication, we performed a BioID screen to identify binding partners of NDRG1. We further assessed the mechanistic roles of the identified interaction partners on DNA repair using DNA replication and repair assays such as the Comet assay and DNA fiber assays. Results: Our BioID screen identified meiotic recombination 11 (MRE11) protein, a nuclease involved in DDR, as a putative NDRG1 interacting protein. Interaction between MRE11 and NDRG1 was enriched during the late S/early G2 cell cycle phases and under replication stress. However, this interaction is likely indirect as the interaction only occurred in a cellular context and not with in vitro purified proteins. Blocking NDRG1 phosphorylation or blocking MRE11 exonuclease activity both resulted in protection of newly synthesized DNA at stalled replication forks. In NDRG1 knockout cells, blocking MRE11 led to decreased protection of nascent DNA, suggesting that NDRG1 and MRE11 may be acting in the same pathway and that NDRG1 is required for MRE11’s activity at stalled forks. Conclusions: In summary, our work has uncovered a protein complex between NDRG1 and MRE11 that may play a key role in chemoresistance due to its role in the processing of stalled replication forks. Full article

Background and Objectives: The incidence of colorectal cancer (CRC) in developed Western countries is constantly growing. CRC represents the third most common cancer and the second leading cancer-related cause of death worldwide. Innate and adaptive immunity play a pivotal role in the tumor response, but many of these interactions are still not well understood. Granulysin (GNLY) is an effector, cytolytic molecule, present in human cytotoxic granules of different lymphocyte subpopulations, mainly in cytotoxic T cells and NK cells. Pore-forming proteins GNLY, perforin and granzymes play a key role in cell-mediated immune responses against tumors and infections. Materials and Methods: We aimed to analyze perforin and GNLY-mediated cytotoxicity in the peripheral blood of patients with CRC by flow cytometry. Simultaneously, the cells were labeled with monoclonal antibodies against perforin, GNLY and different surface antigens (CD3, CD4, CD8 and CD56). Phenotypes of lymphocyte subpopulation and expression of perforin and GNLY were analyzed using intracellular and surface immunofluorescence. Results: Total perforin and GNLY expressions in peripheral blood mononuclear cells (PBMC) were significantly lower than in the control group. Statistically significant differences were observed in the distribution of perforin and GNLY expression in different stages of tumors classified according to Dukes’, indicating that the percentage of total perforin and GNLY was significantly diminished in accordance with tumor progression. Perforin and GNLY expression were significantly reduced in NK and NKT cells, accompanied by reduced cytolytic potential in patients with CRC and a consequent reduction in their ability to eliminate tumors and infected cells. Conclusions: The determination of cytotoxic potential may provide a valuable assessment of a patient’s immune status and represent a novel therapeutic target. Patients with CRC exhibit markedly impaired perforin- and GNLY-mediated cytotoxicity that correlates with disease progression. Assessment and restoration of cytolytic potential may therefore serve as indicators of immune competence and promising therapeutic strategies to improve perioperative and oncologic outcomes. Full article

Introduction: Antipsychotic (AP) medications are widely prescribed beyond psychotic disorders, yet their long-term safety profile regarding breast cancer (BC) risk remains uncertain. Methods: We conducted a systematic review and meta-analysis of observational studies evaluating the association between AP exposure and incident BC. Eligible studies reported adjusted odds ratios (ORs) with 95% confidence intervals for any AP, prolactin-increasing antipsychotics (PIAPs), or prolactin-sparing antipsychotics (PSAPs). Study quality was assessed using the modified Newcastle-Ottawa Scale (mNOS), and certainty of evidence was graded with the GRADE framework. Random-effect models were used to pool effect estimates by exposure category, duration, and cumulative Defined Daily Dose (DDD). Results: Nine high-quality observational studies encompassing 108 effect estimates were included. Most studies achieved mNOS scores of 9, yet GRADE certainty ranged from very low to moderate, with the overall body of evidence graded as low certainty due primarily to residual confounding. Any AP exposure was associated with a modestly increased BC risk, particularly with long-term use: use for >5 years yielded pooled ORs around 1.5–1.6, while short-to-medium duration (1–5 years) showed smaller increases (pooled ORs in the range 1.2–1.3). For PIAPs, both longer duration (>5 years) and higher cumulative exposure (>1000–2000 DDDs) were consistently associated with ORs/HRs in the 1.3–1.6 range, suggesting a possible dose–response pattern. Histological analyses indicated stronger associations for ductal than lobular BC, and elevated risks were observed across age strata, including women aged <55 and ≥70 years. Discussion: This meta-analysis suggests that chronic exposure to prolactin-increasing antipsychotics is associated with a potentially clinically relevant increase in BC risk, whereas prolactin-sparing agents do not show a clear signal of harm. However, the certainty of this association is limited by inconsistently measured confounders and by the observational nature of the data. These findings support a cautious, individualized approach in which clinicians preferentially consider PSAPs when appropriate, discuss BC risk as part of shared decision-making, and integrate tailored screening strategies for women requiring long-term PIAP therapy. Further high-quality pharmacoepidemiologic studies with better confounder control and mechanistic integration are needed to refine risk estimates and inform preventive neuropsychopharmacology. Full article

Background: High-grade vaginal intraepithelial neoplasia (VaIN 2+) is a rare condition with limited evidence to guide optimal management. This study aimed to evaluate the efficacy of various treatment strategies and identify clinical risk factors associated with treatment failure. Methods: A systematic literature search in PubMed, Scopus, Web of Science, and Cochrane databases was performed following PRISMA guidelines. The meta-analysis included 15 retrospective studies including patients treated for VaIN 2+. Pooled risk ratios (RRs) with 95% confidence intervals (CIs) were calculated for treatment modalities (laser ablation, surgical excision, topical therapy) and clinical risk factors (prior hysterectomy, multifocality, immunosuppression, HPV16 infection and history of cervical intraepithelial neoplasia (CIN)). Results: Immunosuppression was significantly associated with a higher risk of treatment failure (RR = 2.01; 95% CI 1.12–3.60; p = 0.030). Topical therapies were found to have a significantly higher risk of treatment failure compared to laser ablation (RR = 1.92; 95% CI 1.34–2.92; p = 0.009). No statistically significant difference in recurrence risk was found between laser ablation and surgical excision, and between surgical excision and topical therapy. Factors such as prior hysterectomy, multifocality, and history of CIN did not show a statistically significant association with recurrence in the pooled models. Conclusions: Immunosuppression is a critical risk factor for VaIN 2+ recurrence, highlighting the need for individualized management and closer surveillance in this population. Surgical and ablative methods appear superior to topical agents in controlling high-grade disease. Given the retrospective nature of current data, standardized prospective studies are required to refine treatment algorithms. Full article

Background/Objectives: The clinical challenges of PARP inhibitors in ovarian cancer include the lack of effective maintenance regimens for homologous recombination proficiency (HRP) patients and the emergence of acquired resistance in initially responsive homologous recombination deficiency (HRD) patients. This study aims to explore the synergistic effect and molecular mechanism of the bispecific tyrosine phosphorylation-regulated kinase 1B (DYRK1B) inhibitor AZ191 combined with the PARP inhibitor Niraparib on high-grade serous ovarian cancer (HGSOC). Methods: This study first explored the expression and prognostic significance of DYRK1B in ovarian cancer through bioinformatics analysis. Subsequently, the therapeutic effect of the DYRK1B inhibitor AZ191 combined with Niraparib on HGSOC cells and organoids was evaluated by MTT examination. Flow cytometry and Western blot were used to investigate the synergistic mechanism between the two agents. Results: Bioinformatics analysis shows that the high expression of DYRK1B in serous ovarian cancer is associated with poor prognosis of the patients. The experiments in vitro have shown that the DYRK1B inhibitor AZ191 can enhance the therapeutic effect of Niraparib on HGSOC cells and organoids, whether HRD-positive or not. Mechanistic studies have shown that the combination of AZ191 and Niraparib can synergistically increase the accumulation of DNA damage, thereby intensifying the apoptosis of HGSOC cells. In addition, the combination therapy induces ferroptosis by inhibiting the Nrf2/SLC7A11/GPX4 axis, thereby exerting cytotoxic effects. Conclusions: Our results uncover a novel mechanism by which inhibiting DYRK1B enhances the anti-HGSOC efficacy of Niraparib and may offer a promising treatment strategy to improve the maintenance therapy in both HRD and HRP ovarian cancer patients. Full article

Background: Electrochemotherapy enhances the intracellular delivery of anticancer agents through electroporation but is traditionally limited to cytotoxic drugs associated with significant side effects. Vitamin C (ascorbic acid) exhibits selective anticancer activity when accumulated at high intracellular concentrations; however, its therapeutic application is restricted by poor membrane permeability and rapid systemic clearance. Methods: In this study, we investigated whether reversible electroporation, applied using a custom-designed variable plate electrode system designed to deliver a uniform electric field, could potentiate the antitumor efficacy of low-dose vitamin C. Numerical simulations were performed to optimize electrode spacing and stimulation voltage, suggesting homogeneous electric field coverage throughout the tumor volume. The proposed approach was evaluated in vitro using MDA-MB-231 and 4T1 breast cancer cell lines and in vivo in a 4T1 murine breast cancer model. Results: Low-dose vitamin C alone produced minimal cytotoxic effects, whereas its combination with electroporation significantly reduced cell viability and increased apoptotic and necrotic cell death in vitro. In vivo, vitamin C–assisted electrochemotherapy resulted in pronounced tumor growth suppression, with tumor volumes reduced to approximately 0.34-fold of baseline by day 15, accompanied by decreased proliferation and marked tissue disruption. Conclusions: These findings demonstrate that uniform-field reversible electroporation markedly enhances the intracellular delivery and antitumor activity of low-dose vitamin C, supporting this technology-driven strategy as a promising, low-toxicity alternative to conventional chemotherapeutic agents in electrochemotherapy for solid tumors. Full article

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies, characterized by early metastasis, dense desmoplastic stroma and a profoundly immunosuppressive, lymphocyte-depleted tumor microenvironment that severely limits the efficacy of current systemic and immunotherapeutic approaches. Oncolytic viruses (OVs), which selectively replicate in and lyse malignant cells while activating antitumor immunity, have emerged as attractive candidates to convert this “cold” tumor into a more inflamed and therapeutically responsive disease. In this review, we summarize clinical evidence on the main OV platforms evaluated in PDAC, including adenovirus, herpes simplex virus, vaccinia virus, parvovirus and reovirus, with a focus on clinical trials. Across these classes of viruses, intratumoral administration has consistently proven feasible and generally well tolerated, with frequent evidence of viral replication, microenvironmental remodeling and immune activation, but only modest and often transient antitumor responses in small, early-phase cohorts. We then discuss key biological and translational challenges that currently limit OV impact in PDAC, such as systemic delivery in the context of pre-existing antiviral immunity and rapid clearance, penetration through the fibrotic stroma, and rational selection of encoded transgenes to reshape myeloid cell-driven, pro-tumoral inflammation and enhance T-cell recruitment. Finally, we outline future directions for the field, including carrier-cell–based systemic delivery, stroma-targeting or cytokine-armed constructs, and combinatorial strategies with chemotherapy and immune checkpoint blockade, arguing that design refinement, innovative combinations and mechanism-driven trial designs will be essential to unlock the full therapeutic potential of oncolytic virotherapy in PDAC. Full article

Background/Objectives: Malnutrition and nutritional vulnerability are common in patients with cancer and are associated with adverse clinical outcomes, particularly among hospitalised patients. However, data specifically describing nutritional risk in patients admitted to medical oncology departments remain limited. This study aimed to estimate the prevalence of nutritional risk at hospital admission and to evaluate factors associated with nutritional risk and its clinical consequences. Methods: The REGIO registry is a national multicentre prospective cohort including adult patients with solid tumours admitted to medical oncology departments in 17 Spanish hospitals between February 2024 and January 2025. Nutritional risk was assessed within the first working day of hospitalisation using the Malnutrition Screening Tool (MST), with a score ≥ 2 indicating nutritional risk. Multivariable logistic regression models were used to identify factors associated with nutritional risk and its association with prolonged hospital stay and mortality. Results: A total of 1229 patients were included (median age 67.8 years; 59% male; 64% metastatic disease). Nutritional risk was identified in 53% of patients. In multivariable analysis, poorer functional status, tumour progression, recent exposure to cytotoxic chemotherapy, and tumour types with higher nutritional impact were independently associated with nutritional risk. Patients at nutritional risk had longer hospital stays (median 10 vs. 7 days; p < 0.001), a higher likelihood of prolonged hospitalisation (adjusted OR 1.38), and increased mortality at 30 days (adjusted OR 1.63) and 60 days after discharge (adjusted OR 1.53). Conclusions: In this large multicentre cohort, nutritional risk was highly prevalent and independently associated with worse clinical outcomes, supporting the clinical relevance of systematic nutritional screening at hospital admission in patients with cancer. Full article