Cancers

14 pages, 518 KB

Open AccessReview

Urinary Biomarkers in Bladder Cancer: FDA-Approved Tests and Emerging Tools for Diagnosis and Surveillance

by Zhenyun Yang, Fengyu Song and Jin Zhong

Cancers 2025, 17(21), 3425; https://doi.org/10.3390/cancers17213425 (registering DOI) - 25 Oct 2025

Bladder cancer is a prevalent malignancy with high morbidity and mortality, particularly when diagnosed at an advanced stage. Early detection is critical, as it significantly improves prognosis and the patient’s outcomes. Bladder cancer also has a high recurrence rate, necessitating long-term surveillance. While [...] Read more.

Bladder cancer is a prevalent malignancy with high morbidity and mortality, particularly when diagnosed at an advanced stage. Early detection is critical, as it significantly improves prognosis and the patient’s outcomes. Bladder cancer also has a high recurrence rate, necessitating long-term surveillance. While cystoscopy remains the gold standard for diagnosis and monitoring, it is invasive and costly. Urine cytology, though widely used, has high specificity for detecting high-grade urothelial carcinoma but suffers from low sensitivity and limited effectiveness as a stand-alone diagnostic tool. Urinary biomarkers offer a promising, noninvasive alternative for early detection and disease surveillance. This review examines FDA-approved urinary biomarker tests, including NMP 22, UroVysion, and BTA, highlighting their clinical utility and limitations. Additionally, we explore emerging biomarkers such as DNA methylation assays, genomic alterations, and proteomic signatures as well as advanced technologies like next-generation sequencing and machine learning-based platforms. These innovations have the potential to enhance diagnostic accuracy, risk stratification, and recurrent monitoring, ultimately improving early detection and long-term disease management. By evaluating both established and emerging urinary biomarkers, this review aims to provide clinicians and researchers with insights into evolving tools for bladder cancer diagnosis and surveillance. Full article

(This article belongs to the Special Issue Systematic Reviews and Meta-Analyses of Genitourinary Cancers (2nd Edition))

26 pages, 43386 KB

Open AccessArticle

Single-Cell Heterogeneity of Epigenetic Factor Regulation Deciphers Alteration of RNA Metabolism During Proliferative SHH-Medulloblastoma

by Raquel Francés, Jenny Bonifacio-Mundaca, Íñigo Casafont, Christophe Desterke and Jorge Mata-Garrido

Cancers 2025, 17(21), 3424; https://doi.org/10.3390/cancers17213424 (registering DOI) - 24 Oct 2025

Abstract

Background: Medulloblastoma is an aggressive pediatric brain tumor characterized by marked molecular heterogeneity, which significantly impacts prognosis. The low frequency of genomic mutations in medulloblastoma suggests that alternative mechanisms, such as epigenetic regulation, may play a critical role in its pathogenesis. Methods: Using [...] Read more.

Background: Medulloblastoma is an aggressive pediatric brain tumor characterized by marked molecular heterogeneity, which significantly impacts prognosis. The low frequency of genomic mutations in medulloblastoma suggests that alternative mechanisms, such as epigenetic regulation, may play a critical role in its pathogenesis. Methods: Using the EpiFactors database, we investigated the expression of epigenetic regulators in two independent RNA sequencing cohorts [Pediatric Brain Tumor Atlas (PBTA) and Williamson], stratified by molecular subgroups and clinical outcomes. We further analyzed expression heterogeneity at the single-cell level in malignant medulloblastoma cells using single-cell RNA sequencing. Results: Members of the SWI/SNF superfamily were dysregulated across all four molecular subtypes of medulloblastoma. Subtype-specific alterations were also observed: the acetyltransferase complex was shared between Group 3 (with SMARCD3 as a potential marker) and Group 4 (with RBM24 as a potential marker); SWR1, β-catenin/TCF, and protein–DNA complexes were specifically enriched in SHH-MB (with EYA1 and SATB2 as SHH markers); and RSC-type, PRC1, DNA polymerase complexes, and X-chromosome-related factors were enriched in WNT-MB (with FOXA1 and PIWIL4 as WNT markers). An epigenetic score (epi-score), linked to RNA metabolism and S-adenosyl-L-methionine pathways, was developed and identified as an independent adverse prognostic factor. High epi-scores were associated with proliferative, stem-like SHH malignant cells (characterized by G2/M phase, low pseudotime, and high entropy), exhibiting alterations in RNA splicing, DNA recombination, and nuclear division. Conclusions: Expression heterogeneity of epigenetic regulators is closely associated with molecular subgroups and clinical outcomes in medulloblastoma. These findings highlight the role of epigenetic dysregulation in RNA metabolism and tumor progression, particularly in SHH-driven proliferative cells. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Malignant Nervous System Cancers)

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21 pages, 2499 KB

Open AccessArticle

High-Dose Stereotactic Re-Irradiation of Recurrent High-Grade Gliomas: Clinical Outcome and Experience with AI-Based Target Volume Simulation

by Anton Früh, Franziska Loebel, Bohdan Bodnar, Larissa Kilian, Martin Misch, Goda Kalinauskaite, Anne Kluge, Chiara Eitner, Julia Onken, Kerstin Rubarth, Daniel Zips, Peter Vajkoczy, Carolin Senger and Güliz Acker

Cancers 2025, 17(21), 3423; https://doi.org/10.3390/cancers17213423 (registering DOI) - 24 Oct 2025

Abstract

Background/Objectives: Despite multimodal therapeutic concepts, treatment of recurrent malignant gliomas remains challenging. Stereotactic radiosurgery (SRS) may be a possible safe and effective non-invasive salvage treatment. In this study, we aim to investigate the SRS treatment outcomes using partly 18F-Fluorethylthyrosine (FET)-PET-imaging sequences for SRS [...] Read more.

Background/Objectives: Despite multimodal therapeutic concepts, treatment of recurrent malignant gliomas remains challenging. Stereotactic radiosurgery (SRS) may be a possible safe and effective non-invasive salvage treatment. In this study, we aim to investigate the SRS treatment outcomes using partly 18F-Fluorethylthyrosine (FET)-PET-imaging sequences for SRS treatment planning focusing on overall survival, event-free survival, and the incidence and factors influencing radiation necrosis (RN) occurrence. Additionally, we evaluated the potential application of AI-based tumor segmentation. Methods: We conducted a retrospective analysis of patients with recurrent malignant glioma treated with single-fraction or hypofractionated SRS at our institution. The outcomes assessed included local control, overall survival (OS), and local event-free survival (LEFS, defined as the interval until tumor recurrence or the onset of RN). We also performed a simulation analysis to assess the potential of AI-based tumor segmentation. Results: The study included 27 patients with a median age of 57 years and 41 lesions. The median OS post-SRS was 9.6 months and an LEFS of 5.2 months. Factors positively influencing OS and LEFS included the gross tumor volume (GTV) of the lesions before SRS therapy, presence of an IDH mutation, and lomustine treatment post-SRS. The incidence of RN post-SRS was 31.7%. RN was confirmed histopathologically in 15.4%, based on MRI in 46.2% and by FET-PET in 38.5% of lesions. In a simulation analysis, AI-based tumor segmentation reliably delineated all lesions, requiring only minimal manual adjustments to define target volumes. Conclusions: High-dose SRS is a feasible salvage treatment for small-volume recurrent high-grade gliomas, achieving local control and survival outcomes comparable to other re-irradiation strategies. IDH mutation, smaller tumor volume, and lomustine therapy were associated with improved survival. RN occurred frequently, particularly in periventricular lesions. AI-based tumor segmentation showed promise in well-defined satellite recurrences, but remains limited in cavity-adjacent lesions, underlining the need for expert review and ¹⁸FET-PET imaging. Full article

(This article belongs to the Special Issue Radiosurgery for Brain Tumors)

15 pages, 907 KB

Open AccessArticle

Prognostic Impact of Postoperative Systemic Immune-Inflammation Index Changes in Epithelial Ovarian Cancer

by Young Eun Chung, E Sun Paik, Minji Kim, Na-Hyun Kim, Seongyun Lim, Jun-Hyeong Seo, Chel Hun Choi, Tae-Joong Kim, Jeong-Won Lee and Yoo-Young Lee

Cancers 2025, 17(21), 3422; https://doi.org/10.3390/cancers17213422 (registering DOI) - 24 Oct 2025

Abstract

Background: Epithelial ovarian cancer is an aggressive malignancy with poor prognosis despite advances in multimodal treatment. The systemic immune-inflammation index (SII) has emerged as a prognostic biomarker in various cancers; however, the impact of surgery-induced inflammatory changes remains unclear. Methods: This study evaluated [...] Read more.

Background: Epithelial ovarian cancer is an aggressive malignancy with poor prognosis despite advances in multimodal treatment. The systemic immune-inflammation index (SII) has emerged as a prognostic biomarker in various cancers; however, the impact of surgery-induced inflammatory changes remains unclear. Methods: This study evaluated the prognostic significance of postoperative changes in SII among patients with epithelial ovarian cancer undergoing primary surgery. Data from 374 patients treated at Samsung Medical Center and Kangbuk Samsung Hospital between 2016 and 2021 were retrospectively reviewed. SII was calculated from complete blood counts obtained within one month before surgery and on postoperative day 1. The percentage change in SII was analyzed, and the optimal cutoff was determined using receiver operating characteristic curve analysis. Survival outcomes were assessed using Kaplan–Meier and multivariable Cox regression models. Results: Patients with a postoperative SII increase > 98.4% (Group 2) had significantly poorer overall (HR = 1.86, p = 0.009) and progression-free survival (HR = 1.30, p = 0.112) compared with those with smaller changes (Group 1). Discussion: High-grade histology, serous subtype, and greater intraoperative blood loss were associated with higher postoperative SII. A marked postoperative increase in SII independently predicted poor survival, suggesting that dynamic inflammatory responses rather than static baseline levels provide additional prognostic information. Conclusions: Perioperative SII monitoring, easily obtainable from routine blood tests, may help identify high-risk patients who could benefit from intensified surveillance or adjuvant treatment. Prospective multicenter studies are warranted to validate these findings and explore whether perioperative modulation of systemic inflammation can improve outcomes. Full article

(This article belongs to the Special Issue Research on Surgical Treatment for Ovarian Cancer)

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19 pages, 1330 KB

Open AccessArticle

P-POSSUM Falls Short: Predicting Morbidity in Ovarian Cancer (OC) Cytoreductive Surgery

by Michail Sideris, Mark R. Brincat, Oleg Blyuss, Samuel George Oxley, Jacqueline Sia, Ashwin Kalra, Xia Wei, Caitlin T. Fierheller, Subhasheenee Ganesan, Rowan E. Miller, Fatima El-Khouly, Mevan Gooneratne, Tom Abbott, Ching Ling Pang, Parvesh Verma, Seema Shah, Alexandra Lawrence, Arjun Jeyarajah, Elly Brockbank, Saurabh Phadnis, James Dilley and Ranjit Manchanda Show full author list Hide full author list

Cancers 2025, 17(21), 3421; https://doi.org/10.3390/cancers17213421 (registering DOI) - 24 Oct 2025

Abstract

Objective: The P-POSSUM scale is widely used in predicting perioperative morbidity and mortality. Evidence on the performance of P-POSSUM in predicting outcomes after cytoreductive surgery (CRS) for ovarian cancer (OC) is limited. In this study, we assess how well P-POSSUM predicts morbidity in [...] Read more.

Objective: The P-POSSUM scale is widely used in predicting perioperative morbidity and mortality. Evidence on the performance of P-POSSUM in predicting outcomes after cytoreductive surgery (CRS) for ovarian cancer (OC) is limited. In this study, we assess how well P-POSSUM predicts morbidity in OC CRS and explore whether incorporating additional clinical variables can enhance its predictive accuracy. We retrospectively collected data on consecutive patients undergoing OC CRS within a tertiary gynaecologic oncology network. The collected information included demographic characteristics, P-POSSUM morbidity and mortality scores, Edmonton Frail Scale (EFS) scores, preoperative serum albumin levels, and observed 30-day postoperative morbidity and mortality, classified using the Clavien–Dindo (CD) scale. The predictive performance of P-POSSUM was evaluated using receiver operating characteristic (ROC) curves to calculate sensitivity and specificity. A stepwise regression analysis was then applied to identify additional variables that could improve model performance, incorporating preoperative covariates. The final model incorporated parameters chosen through bootstrap investigation of the model variability (stepAIC). Predicted versus observed morbidity was calibrated and performance compared between P-POSSUM and the final model. Results: Of 161 sequential OC patients, 95 (59%) underwent primary, 45 (28%) interval, and 21 (13%) delayed CRS. The mean age was 66.4 (95%CI: 60–75) and duration of surgery was 223 mins (95%CI: 142–279). Sixty-five (40.3%) patients had ≥1 postoperative complication. Two deaths were reported. Among the observed complications, 4 patients (6.1%) experienced CD4, 10 patients (15.3%) CD3, 38 patients (58.5%) CD2, and 11 patients (16.9%) CD1 events. The mean P-POSSUM-predicted morbidity and mortality were 59.5% (95%CI: 56.7–62.3%) and 5.86% (95%CI: 5.02–6.70%), respectively. The area under the curve (AUC) for P-POSSUM in predicting morbidity and mortality was 0.539 (p = 0.401) and 0.569 (p = 0.137), respectively. Given the small number of deaths, no robust conclusions regarding mortality are possible. EFS and BMI emerged as significant predictors of observed morbidity using a stepwise-model selection process. The AIC of this final model was 211.44. Our final model of PPOSSUM + EFS + BMI had AUC = 0.6551 (Delong’s Z = 1.8845, p-value = 0.05949). Conclusions: The P-POSSUM scale shows poor performance for predicting morbidity in OC CRS. New validated and accurate model(s) are necessary for predicting surgical morbidity. Our proposed model incorporates additional variables to improve P-POSSUM’s performance. This requires further development and validation. Full article

(This article belongs to the Special Issue Advancements in Surgical Approaches for Gynecological Cancers)

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17 pages, 2850 KB

Open AccessArticle

Repurposing Carfilzomib as a Promising Drug for Targeted Therapy in Gastric Cancer

by Emma Mathilde Kurstjens, Kristin E. Cox, Prerna Bali, Siamak Amirfakhri, Jonathan Hernandez, Ivonne Lozano-Pope, Christopher Benner, Michael Bouvet and Marygorret Obonyo

Cancers 2025, 17(21), 3420; https://doi.org/10.3390/cancers17213420 (registering DOI) - 24 Oct 2025

Abstract

Background/Objectives: Identifying novel targets to treat gastric cancer (GC) has become a focus of research in recent years. Our accelerated Helicobacter-induced gastric cancer mouse model allowed us to identify several differentially expressed genes (DEGs), including Psmb8 (proteasome subunit beta type 8, [...] Read more.

Background/Objectives: Identifying novel targets to treat gastric cancer (GC) has become a focus of research in recent years. Our accelerated Helicobacter-induced gastric cancer mouse model allowed us to identify several differentially expressed genes (DEGs), including Psmb8 (proteasome subunit beta type 8, also called Lmp7), which was also found to be elevated in GC patient samples. PSMB8 encodes one of the immune subunits of the immunoproteasome, which has been associated with disease severity in multiple cancers. Methods: We identified carfilzomib from a public database as a potential drug targeting PSMB8; it effectively halts immunoproteasome activity, leading to apoptosis. We tested carfilzomib’s efficacy against gastric cancer by subcutaneously implanting nude mice with human gastric epithelial-derived tumors and treating them with carfilzomib, either alone or in combination with 5-fluorouracil (5-FU), a standard-of-care drug. The effectiveness of drug treatment was measured by tumor growth, cell proliferation, and apoptosis. Results: We observed that carfilzomib retarded tumor growth, inhibited cell proliferation, and induced apoptosis. Conclusions: These results strongly suggest that PSMB8 is a suitable candidate for targeted therapy. Moreover, with carfilzomib having robust anti-tumor activity, it has potential as a treatment option for cancers where high levels of PSMB8 are associated with poor overall survival. Full article

(This article belongs to the Section Cancer Drug Development)

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20 pages, 554 KB

Open AccessReview

AI-Based Cancer Models in Oncology: From Diagnosis to ADC Drug Prediction

by Navid Sobhani, Fernanda G. Kugeratski, Sergio Venturini, Raheleh Roudi, Tristan Nguyen, Alberto D’Angelo and Daniele Generali

Cancers 2025, 17(21), 3419; https://doi.org/10.3390/cancers17213419 (registering DOI) - 24 Oct 2025

Abstract

Introduction Artificial intelligence (AI) has been influencing the way oncology has been practiced. Major issues constituting a bottleneck are the lack of data for training purposes, confidentiality preventing development, or the absence of transparency in clarifying how models operate to generate decisions. Novel [...] Read more.

Introduction Artificial intelligence (AI) has been influencing the way oncology has been practiced. Major issues constituting a bottleneck are the lack of data for training purposes, confidentiality preventing development, or the absence of transparency in clarifying how models operate to generate decisions. Novel Models With explainable AI, trust and utilization barriers among clinicians, researchers, and patients can be removed. With the implementation of federated learning, multiple institutions could contribute to crucial dataset’s learning information. Precise diagnosis and prescription of the right drug are essential in preventing unnecessary life losses, and economic burden to the underling system. Focus This review focuses on new AI models that could make medical diagnosis more precise, quicker and convenient, as well as help with the discovery of new drugs and better selection of certain cancer therapies, in particular for those drugs whose results have been inconsistent across different groups of patients. We then speculate on the transformative role AI could play in predicting ADC therapy efficacy. This would ultimately bestow the medical field of an impeccable selection tool. Such colossal methodology, coupled with seeming monitoring of treatment and recovery, may be granting remedies that have been so longed, and deemed necessary. Full article

(This article belongs to the Section Methods and Technologies Development)

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12 pages, 548 KB

Open AccessArticle

The Prognostic Role of Para-Aortic Lymph Node Metastasis in Patients with Resected Pancreatic Adenocarcinoma

by Maximilian Brunner, Lena Kitzke, Anke Mittelstädt, Susanne Merkel, Georg F. Weber, Robert Grützmann and Christian Krautz

Cancers 2025, 17(21), 3418; https://doi.org/10.3390/cancers17213418 (registering DOI) - 24 Oct 2025

Abstract

Background: This study aimed to evaluate the prognostic significance of para-aortic lymph node dissection (PALND) during pancreatic head resection and the impact of para-aortic lymph node metastasis (PALN+) on survival outcomes in patients with resected pancreatic ductal adenocarcinoma (PDAC). Methods: A retrospective analysis [...] Read more.

Background: This study aimed to evaluate the prognostic significance of para-aortic lymph node dissection (PALND) during pancreatic head resection and the impact of para-aortic lymph node metastasis (PALN+) on survival outcomes in patients with resected pancreatic ductal adenocarcinoma (PDAC). Methods: A retrospective analysis was conducted on 198 patients who underwent primary pancreatic head resection for PDAC at the University Hospital Erlangen between 2003 and 2022. Patients were stratified based on the presence or absence of PALND and PALN metastases, and their clinicopathological characteristics and survival outcomes were compared. Results: Of the 198 patients, 113 (57%) underwent additional PALND. PALND itself had no significant impact on overall survival (OS) or disease-free survival (DFS) compared to those without PALND. Among patients who underwent PALND, 17 (15%) had PALN metastases (PALN+). PALN+ patients exhibited significantly worse pathological features, including a higher rate of regional lymph node metastases (pN+), lymphovascular invasion (L1) and vascular invasion (V1). Survival analysis showed that PALN+ was associated with significantly poorer OS (8.7 vs. 29.3 months, p < 0.001) and DFS (3.8 vs. 17.0 months, p < 0.001). In multivariate analysis, PALN+ was confirmed as an independent prognostic factor for both OS (HR 1.9 [1.0–3.6], p = 0.035) and DFS (HR 2.2 [1.2–4.0], p = 0.006). Conclusions: While PALND does not impact survival outcomes in PDAC, it plays a crucial role in identifying PALN+ patients, who have significantly worse prognoses. PALN status should be integrated into clinical decision-making, particularly when considering intensified adjuvant therapy. Full article

(This article belongs to the Section Cancer Survivorship and Quality of Life)

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13 pages, 881 KB

Open AccessArticle

Radiomics and Deep Learning Interplay for Predicting MGMT Methylation in Glioblastoma: The Crucial Role of Segmentation Quality

by Francesca Lizzi, Sara Saponaro, Alessia Giuliano, Cinzia Talamonti, Leonardo Ubaldi and Alessandra Retico

Cancers 2025, 17(21), 3417; https://doi.org/10.3390/cancers17213417 (registering DOI) - 24 Oct 2025

Abstract

Background/Objectives: Glioblastoma (GBM) is the most malignant subtype of glioma and shows the poorest prognosis with a median survival time of 15 months. The methylation status of the Methylguanine-DNA Methyltransferase (MGMT) was proven to be a crucial factor in selecting the most appropriate [...] Read more.

Background/Objectives: Glioblastoma (GBM) is the most malignant subtype of glioma and shows the poorest prognosis with a median survival time of 15 months. The methylation status of the Methylguanine-DNA Methyltransferase (MGMT) was proven to be a crucial factor in selecting the most appropriate therapy. Currently, it is assessed through brain biopsy, which is a highly invasive and very expensive technique. For these reasons, in recent years, the possibility of inferring this information from multi-parametric Magnetic Resonance Imaging (mpMRI) has been widely explored. However, substantial differences in performance are reported in the literature. Methods: In this study, we developed several models based on either radiomic or deep learning approaches and a mixture of them using mpMRI for the MGMT status assessment using the public dataset UPENN-GBM, available on The Cancer Imaging Archive. Despite the tests performed using all MRI acquisitions and different methodological approaches, we did not obtain sufficiently reliable performance to direct the therapeutic path of patients. We thus investigated the impact of segmentation quality on MGMT status prediction since the UPENN-GBM dataset contains both automatic and manual refined segmentation masks. Results: We found that performance obtained through radiomic features computed on manually segmented tumors was significantly higher compared to that obtained using automatic segmentation, even when the differences between segmentation masks, measured in terms of Dice Similarity Coefficient (DSC), is not significantly different. Conclusion: This could be the reason why very different MGMT classification performance is typically reported and suggests the creation of a benchmark dataset, with high-quality segmentation masks. Full article

(This article belongs to the Special Issue The Development and Application of Imaging Biomarkers in Cancer)

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14 pages, 537 KB

Open AccessArticle

Risk of Esophageal and Gastric Cancer by Histologic Subtype in Steatotic Liver Disease: A UK Biobank Study

by Donghoon Kang, Ji Won Han, Kenneth R. Muir, Artitaya Lophatananon and Jongin Lee

Cancers 2025, 17(21), 3416; https://doi.org/10.3390/cancers17213416 - 24 Oct 2025

Abstract

Aim: The recently updated steatotic liver disease (SLD) nomenclature provides a refined classification accounting for both metabolic dysfunction and alcohol exposure. However, the relationship between SLD subtypes and upper gastrointestinal (UGI) cancer risk remains unclear. Methods: We analyzed 456,367 UK Biobank participants, categorizing [...] Read more.

Aim: The recently updated steatotic liver disease (SLD) nomenclature provides a refined classification accounting for both metabolic dysfunction and alcohol exposure. However, the relationship between SLD subtypes and upper gastrointestinal (UGI) cancer risk remains unclear. Methods: We analyzed 456,367 UK Biobank participants, categorizing them into non-SLD, metabolic dysfunction-associated steatotic liver disease with no alcohol (MASLD1), MASLD with minimal alcohol use (MASLD2), metabolic dysfunction-associated alcohol-related liver disease (MetALD), and alcohol-associated liver disease (ALD) groups. Cox proportional hazards models estimated cancer risks over a median 13-year follow-up, with histologic subtype-specific analyses. Results: Compared to non-SLD, esophageal cancer risk was significantly elevated in all SLD groups with any alcohol consumption (MASLD2, MetALD, and ALD), but not in purely metabolic SLD without alcohol (MASLD1). This association was driven by adenocarcinoma subtype, with hazard ratios ranging from 1.67 to 1.80 in alcohol-exposed SLD groups. For gastric cancer, elevated risk was observed primarily in ALD and MetALD groups, affecting intestinal-type cancers. Squamous cell esophageal cancer and non-intestinal gastric cancer showed no significant associations. Conclusions: Upper GI cancer risk in SLD patients is significantly modified by alcohol consumption, with combined metabolic dysfunction and alcohol exposure conferring the highest risks for esophageal adenocarcinoma and intestinal-type gastric cancer. Clinically, these findings suggest that SLD patients with any level of alcohol consumption require heightened cancer surveillance. Even minimal alcohol intake substantially increases cancer risk in metabolically compromised individuals, supporting alcohol reduction as a key preventive strategy. Full article

(This article belongs to the Special Issue Clinical Epidemiology and Risk Prediction for Gastrointestinal Cancers)

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25 pages, 1227 KB

Open AccessReview

FLT3: A 35-Year Voyage from Discovery to the Next Generation of Targeted Therapy in AML

by Maria-Camelia Stancioaica, Daniel Coriu and Gabriel Ghiaur

Cancers 2025, 17(21), 3415; https://doi.org/10.3390/cancers17213415 - 23 Oct 2025

Abstract

FMS-like tyrosine kinase 3 (FLT3) is a crucial regulator of normal hematopoiesis, with high expression in hematopoietic stem and progenitor cells. Beyond its role in stem cell survival and proliferation, FLT3 signaling is essential for immune regulation, particularly dendritic cell differentiation and NK [...] Read more.

FMS-like tyrosine kinase 3 (FLT3) is a crucial regulator of normal hematopoiesis, with high expression in hematopoietic stem and progenitor cells. Beyond its role in stem cell survival and proliferation, FLT3 signaling is essential for immune regulation, particularly dendritic cell differentiation and NK cell expansion. In acute myeloid leukemia (AML), FLT3 mutations—most commonly internal tandem duplications (FLT3-ITD) and tyrosine kinase domain (FLT3-TKD) substitutions—are among the most frequent genetic alterations, driving constitutive activation of proliferative and antiapoptotic pathways and conferring adverse prognosis. The clinical development of FLT3 inhibitors has been a decades-long endeavor. Early multikinase agents established proof-of-concept but were hampered by off-target effects and incomplete efficacy. The subsequent generation of potent and selective inhibitors has transformed outcomes, culminating in FDA approvals of midostaurin, quizartinib, and gilteritinib. Together with allogeneic transplantation, these agents have reshaped the treatment paradigm for FLT3-mutant AML, converting a historically high-risk subset into one with realistic prospects for long-term survival. Despite these advances, challenges remain. Resistance emerges through cell-intrinsic mechanisms such as acquisition of secondary TKD or RAS pathway mutations, metabolic reprogramming, and antiapoptotic shifts, as well as cell-extrinsic mechanisms mediated by the bone marrow microenvironment, including cytokine support, stromal CYP3A4 metabolism, and retinoid inactivation. These pathways sustain measurable residual disease (MRD), the key predictor of relapse. Rational combination strategies and MRD-directed approaches are therefore essential to fully realize the curative potential of FLT3 inhibition. Full article

(This article belongs to the Special Issue From Bench to Bedside: Novel Molecular Targets and Therapeutic Strategies in AML)

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30 pages, 1351 KB

Open AccessReview

Testosterone and Androgen Receptor in Cancers with Significant Sex Dimorphism in Incidence Rates and Survival

by Jianjian Lin, Jingwen Zhu, Jay Fowke, Ramesh Narayanan and Feng Liu-Smith

Cancers 2025, 17(21), 3414; https://doi.org/10.3390/cancers17213414 - 23 Oct 2025

Abstract

Several major cancer types exhibit significant sex dimorphism in incidence and survival. Whether and how sex as a biological factor impacts tumorigenesis, progression, and survival warrants full investigation, as such knowledge may lead to novel, precise prevention and treatment strategies. We reviewed epidemiological [...] Read more.

Several major cancer types exhibit significant sex dimorphism in incidence and survival. Whether and how sex as a biological factor impacts tumorigenesis, progression, and survival warrants full investigation, as such knowledge may lead to novel, precise prevention and treatment strategies. We reviewed epidemiological and molecular data on sex differences in cancers of the esophagus, bladder, head and neck, lung, liver, kidney, stomach, and skin melanoma, as well as the potential role of androgens and androgen receptor (AR) activity in these cancers. The potential molecular mechanisms are briefly discussed. Elevated testosterone (T) levels seemed to be associated with increased liver cancer and cutaneous melanoma incidences, and with reduced esophageal cancer risk. AR activity does not always correlate with T levels in tumorigenesis and progression. Higher AR expressions are associated with poorer survival in ESCC, whereas the role of AR in the survival of HNSCC and melanoma patients is inconsistent. The molecular impact of AR in liver cancer, kidney cancer, melanoma, and lung cancer is controversial. However, AR is likely to promote tumor growth and/or progression in esophagus, bladder, head and neck, and stomach cancers, and thus is associated with poor survival. Patients diagnosed with a tumor in this latter group could potentially benefit from therapeutic approaches targeting AR. Overall, the research on sex hormone androgens and AR in these cancers is limited. Further research is needed to determine a possible U-shaped relationship of T with cancer risk, and to decipher the role of testosterone and AR in some of these tumors to facilitate our understanding of sex dimorphism and to explore novel T/AR-based treatment options. Full article

(This article belongs to the Special Issue Feature Paper in Section ‘Cancer Epidemiology and Prevention’ in 2025)

30 pages, 2059 KB

Open AccessReview

Thrombotic Risk and Coagulation Imbalance in Cirrhosis and Hepatocellular Carcinoma: Clinical Implications and Management

by Leonardo Stella, Matteo De Siati, Rosa Talerico, Maria Pallozzi, Lucia Cerrito, Silvia Sorrentino, Antonio Gasbarrini, Erica De Candia, Roberto Pola and Francesca Romana Ponziani

Cancers 2025, 17(21), 3413; https://doi.org/10.3390/cancers17213413 - 23 Oct 2025

Abstract

Hepatocellular carcinoma (HCC) is characterized by a complex disruption of hemostatic balance, increasing the risk of both thrombotic and hemorrhagic events. Thrombotic complications, most notably portal vein thrombosis (PVT) and venous thromboembolism (VTE), have a significant impact on clinical outcomes and therapeutic strategies. [...] Read more.

Hepatocellular carcinoma (HCC) is characterized by a complex disruption of hemostatic balance, increasing the risk of both thrombotic and hemorrhagic events. Thrombotic complications, most notably portal vein thrombosis (PVT) and venous thromboembolism (VTE), have a significant impact on clinical outcomes and therapeutic strategies. Cirrhosis contributes to the precarious equilibrium between pro- and anticoagulant forces through impaired synthesis of coagulation factors, endothelial dysfunction, and systemic inflammation. In the presence of HCC tumor-driven mechanisms, such as tissue factor expression, extracellular vesicle release, platelet activation, and suppression of fibrinolysis exacerbate this prothrombotic state. In this scenario, advanced diagnostic tools such as thrombin generation assay (TGA) and rotational thromboelastometry (ROTEM) offer a more accurate assessment of coagulation dynamics than conventional tests, enabling better risk stratification especially for therapeutic purposes. Anticoagulant therapy has demonstrated clinical benefit in selected cases of non-malignant PVT and VTE, particularly when liver function is preserved. While prophylactic strategies are still under investigation, data suggest they may be safely implemented in selected surgical patients. In the setting of immunotherapy, especially regimens involving anti-VEGF agents, anticoagulation may be considered with careful management of bleeding risk due to portal hypertension. An individualized approach to anticoagulation, supported by functional coagulation testing, is gaining acceptance as a means to safely reduce thrombotic burden and potentially improve outcomes in patients with HCC. Full article

(This article belongs to the Special Issue Novel Insights into Mechanisms of Cancer-Associated Thrombosis)

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25 pages, 800 KB

Open AccessReview

Radioligand Therapy in Cancer Management: A Global Perspective

by Gaia Ninatti, Sze Ting Lee and Andrew M. Scott

Cancers 2025, 17(21), 3412; https://doi.org/10.3390/cancers17213412 - 23 Oct 2025

Abstract

Radioligand therapy (RLT) is a targeted treatment modality that combines a tumour-specific ligand with a therapeutic radionuclide. Once administered, the radiopharmaceutical binds selectively to cancer-associated targets, delivering cytotoxic radiation directly to tumour cells while sparing surrounding tissues. Two RLT agents, [¹⁷⁷Lu]Lu-DOTA-TATE [...] Read more.

Radioligand therapy (RLT) is a targeted treatment modality that combines a tumour-specific ligand with a therapeutic radionuclide. Once administered, the radiopharmaceutical binds selectively to cancer-associated targets, delivering cytotoxic radiation directly to tumour cells while sparing surrounding tissues. Two RLT agents, [¹⁷⁷Lu]Lu-DOTA-TATE (Lutathera^®) and [¹⁷⁷Lu]Lu-PSMA-617 (Pluvicto^®), have received regulatory approval for the treatment of advanced gastroenteropancreatic neuroendocrine tumours and metastatic castration-resistant prostate cancer, respectively. As of July 2025, more than 400 clinical trials are registered, exploring novel molecular targets such as FAP, CAIX, and GRPR, as well as alternative radionuclides and combination regimens in both solid and haematologic malignancies. In this review, we describe the design principles and mechanisms of action of RLT, summarise clinical evidence for approved and emerging radiopharmaceuticals, and discuss current global disparities in access and availability. Finally, we outline the main clinical challenges, including fixed dosing regimens, resistance, toxicity, and variability in patient selection and response assessment. Continued research to optimise radiopharmaceutical design, together with investment in infrastructure, workforce capacity, and international collaboration, will be essential to expand access and realise the full potential of RLT as a leading treatment strategy in modern oncology. Full article

(This article belongs to the Special Issue Cancer Treatment: Present and Future of Radioligand Therapy)

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24 pages, 3314 KB

Open AccessArticle

Targeted Hyaluronan Degradation Enhanced Tumor Growth Inhibition in Gastrointestinal Cancer Models

by Fulai Zhou, Guangmao Mu, Honglei Bi, Limin Chen, Zhengxia Zha, Ying Jin and Mark L. Chiu

Cancers 2025, 17(21), 3411; https://doi.org/10.3390/cancers17213411 - 23 Oct 2025

Abstract

Background. The dense hyaluronan (HA)-rich stroma in solid tumors can prevent effective tumor growth inhibition by hindering drug delivery and immune cell infiltration. However, the degradation of HA alone by systemic delivery of hyaluronidase has not shown significant improvement of tumor growth inhibition. [...] Read more.

Background. The dense hyaluronan (HA)-rich stroma in solid tumors can prevent effective tumor growth inhibition by hindering drug delivery and immune cell infiltration. However, the degradation of HA alone by systemic delivery of hyaluronidase has not shown significant improvement of tumor growth inhibition. Objectives/Methods. In this study, we targeted hyaluronan degradation by using antibody–enzyme (AbEn) molecules by fusing antibodies to a recombinant human hyaluronidase (HYAL). Results. The AbEn molecules were stable, retained both antigen-binding and enzymatic activities, and demonstrated a prolonged serum half-life of 132 h in rodent models. In the HA-rich colorectal cancer model, the cancer-associated fibroblast (CAF)-directed AbEn, TAVO423 (FAP × LRRC15 × HYAL trispecific antibody) achieved greater intratumoral HA depletion resulting in superior tumor growth inhibition compared to untargeted HYAL. Furthermore, the combination of TAVO423 in combination with other solid tumor cell targeting modalities such as 5-fluorouracil (5-FU), anti-PD-L1 monoclonal antibody, a PD-L1 × CD3 bispecific T-cell engager (TCE), and a CD318-targeting antibody–drug conjugate (ADC) all demonstrated enhanced tumor growth inhibition (TGI) values of 49–67% as compared to the respective monotherapy TGI values of 1–28%. In addition, TAVO423 improved the antitumor response of a 5T4 × CD3 TCE with an increase in TGI from 73% to 92% in an in vivo HA-rich pancreatic cancer model. The CAF-targeted HA degradation mediated by TAVO423 also reversed immune exclusion by increasing the density of CD8⁺ tumor-infiltrating lymphocytes (TILs) by 6–9-fold and synergized with PD-1 blockade to enhance TGI from 33% to 51% in an in vivo immunocompetent EMT-6 breast cancer model. Conclusions. These findings demonstrated the broad potential of the modular AbEn platform for targeted HA degradation to overcome barrier entry in stromal HA-rich solid tumors. Full article

(This article belongs to the Special Issue Novel Therapeutic Approaches for Cancer Treatment)

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14 pages, 1301 KB

Open AccessArticle

Tissue Factor Expression in Penile Squamous Cell Carcinoma: A Potential Marker of HPV-Independent Disease

by Jamaal C. Jackson, Andrew C. Johns, Leticia Campos Clemente, Christopher M. Manuel, Wei Qiao, Wei Lu, Khaja Khan, Luisa M. Solis Soto, Jad Chahoud, Priya Rao, Matthew T. Campbell, Curtis A. Pettaway and Niki M. Zacharias

Cancers 2025, 17(21), 3410; https://doi.org/10.3390/cancers17213410 - 23 Oct 2025

Abstract

Background/Objectives: In a series of 33 patients with advanced penile squamous cell carcinoma (PSCC), we evaluated tissue factor (TF), TROP2, and nectin-4 protein expression as potential therapeutic targets. Expression levels of these proteins were also correlated to clinicopathological characteristics, including high-risk human [...] Read more.

Background/Objectives: In a series of 33 patients with advanced penile squamous cell carcinoma (PSCC), we evaluated tissue factor (TF), TROP2, and nectin-4 protein expression as potential therapeutic targets. Expression levels of these proteins were also correlated to clinicopathological characteristics, including high-risk human papillomavirus (HPV), CDKN2A (p16) status, and aberrant p53 expression. Methods: A tissue microarray (TMA) was constructed with three cores per patient tumor (99 total cores). Anti-TF antibody staining was performed by immunohistochemistry, and H-scores for membrane and cytoplasm staining were assessed (range 0–300). The percentage of cores and patient tumors staining positive for TF (≥10% of tumor cells with at least 1+ intensity in cytoplasm and/or membrane) and H-scores were described and compared with HPV and p16 status. The association of TF expression with tumor grade, presence of metastatic disease, lymphovascular invasion (LVI), perineural invasion (PNI), aberrant p53 expression, recurrence-free survival (RFS), and cancer-specific survival (CSS) was assessed. Nectin-4 and TROP2 staining and their association with clinical/pathological data were determined in a similar manner. Results: TF staining was evident in 26 (81.3%) of the cohort and was more prominent in HPV-negative tumors in both the membrane (H-score 69.6 vs. 18.8; p = 0.003) and cytoplasm (H-score 59.2 vs. 17.7, p = 0.007). Cytoplasmic (H-score 61.7 vs. 11.7, p < 0.001) and membrane TF staining (H-score 71.7 vs. 15.0, p < 0.001) favored p16-negative tumors. The p53 status was more likely to be aberrant in the higher TF staining samples (cytoplasm H-score 61.7 vs. 18.3, p = 0.012; membrane H-score 67.5 vs. 20.3, p = 0.006). We observed an association with TROP2 staining and positive p16 status (membrane H-score 120.3 vs. 85, p = 0.052; cytoplasmic H-score 135 vs. 107.5, p = 0.041). We observed an association of TROP2 staining with positive LVI (membrane H-score 136.7 vs. 66.7, p = 0.014; cytoplasmic H-score 110 vs. 93.3, p = 0.04). We found no association between TF, TROP2, or nectin-4 staining with CSS or RFS; however, we suspect that this was due to our small sample size. Conclusions: Our results indicate that TF was expressed in the majority of advanced PSCC with enhanced expression among HPV-independent, p53-aberrant tumors and may represent a novel therapy target in advanced PSCC. Full article

(This article belongs to the Special Issue Penile Cancer and Rare Urogenital Malignancies: From Biology to Clinical Management)

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16 pages, 3581 KB

Open AccessReview

CTRP6 in Cancer: Mechanistic Insights and Therapeutic Potential

by Muhammad Zubair Mehboob and Xia Lei

Cancers 2025, 17(21), 3409; https://doi.org/10.3390/cancers17213409 - 23 Oct 2025

Abstract

C1q/TNF-related protein 6 (CTRP6) is emerging as a critical regulator of cancer biology with direct implications for clinical outcomes. Across a wide spectrum of malignancies, CTRP6 plays a central role in coordinating key oncogenic processes and linking metabolic, inflammatory, and signaling pathways that [...] Read more.

C1q/TNF-related protein 6 (CTRP6) is emerging as a critical regulator of cancer biology with direct implications for clinical outcomes. Across a wide spectrum of malignancies, CTRP6 plays a central role in coordinating key oncogenic processes and linking metabolic, inflammatory, and signaling pathways that drive tumor progression. While CTRP6 generally promotes oncogenic behavior in cancers such as hepatocellular carcinoma, lung cancer, and clear cell renal cell carcinoma, conflicting findings have been reported in gastric cancer and oral or head and neck squamous cell carcinoma, where its tumor-promoting versus tumor-suppressive roles remain unresolved. CTRP6 has been shown to modulate fundamental processes including angiogenesis, ferroptosis, proliferation, apoptosis, migration, invasion, and inflammation. These effects are primarily mediated through activation of the PI3K/AKT and MEK/ERK signaling pathways, which are central to tumor growth, metastasis, and therapeutic resistance. Beyond its mechanistic roles, CTRP6 demonstrates potential as a diagnostic and prognostic biomarker, with altered expression patterns linked to cancer initiation, progression, and patient survival. Inhibition of CTRP6 in preclinical models enhances ferroptotic cell death and suppresses tumor progression, highlighting its promise as a therapeutic target. By consolidating current evidence from multiple cancer models, this review provides a comprehensive overview of CTRP6’s contributions to oncogenesis and underscores its dual potential as both a biomarker and a therapeutic target. Advancing a deeper understanding of CTRP6 in specific tumor contexts will be critical for unlocking its clinical utility and may open new opportunities to improve diagnosis, optimize therapeutic strategies, and ultimately enhance patient outcomes. Full article

(This article belongs to the Section Molecular Cancer Biology)

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21 pages, 584 KB

Open AccessReview

Beyond Imaging: Integrating Radiomics, Genomics, and Multi-Omics for Precision Breast Cancer Management

by Xiaorong Wu and Wei Dai

Cancers 2025, 17(21), 3408; https://doi.org/10.3390/cancers17213408 - 23 Oct 2025

Abstract

Radiomics has emerged as a promising tool for non-invasive tumour phenotyping in breast cancer, providing valuable insights into tumour heterogeneity, response prediction, and risk stratification. However, traditional radiomic approaches often rely on correlative patterns of image analysis to clinical data and lack direct [...] Read more.

Radiomics has emerged as a promising tool for non-invasive tumour phenotyping in breast cancer, providing valuable insights into tumour heterogeneity, response prediction, and risk stratification. However, traditional radiomic approaches often rely on correlative patterns of image analysis to clinical data and lack direct biological interpretability. Combining information provided by radiomics with genomics or other multi-omics data can be important to personalise diagnostic and therapeutic work up in breast cancer management. This review aims to explore the current progress in integrating radiomics with multi-omics data—genomics and transcriptomics—to establish biologically grounded, multidimensional models for precision management of breast cancer. We will review recent advances in integrative radiomics and radiogenomics, highlight the synergy between imaging and molecular profiling, and discuss emerging machine learning methodologies that facilitate the integration of high-dimensional data. Applications of radiogenomics, including breast cancer subtype and molecular mutation prediction, radiogenomic mapping of the tumour immune microenvironment, and response forecasting to immunotherapy and targeted therapies, as well as lymph nodes involvement, will be evaluated. Challenges in technical limitations including imaging modalities harmonization, interpretability, and advancing machine learning methodologies will be addressed. This review positions integrative radiogenomics as a driving force for next-generation breast cancer care. Full article

(This article belongs to the Special Issue Radiomics in Cancer)

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17 pages, 1458 KB

Open AccessArticle

Treatment Outcomes and Significance of Multimodal Treatment in Esophageal Squamous Cell Carcinoma with Synchronous Oligometastasis

by Manato Ohsawa, Yoichi Hamai, Yuta Ibuki, Tomoaki Kurokawa, Nao Kitasaki and Morihito Okada

Cancers 2025, 17(21), 3407; https://doi.org/10.3390/cancers17213407 - 23 Oct 2025

Abstract

Background/Objectives: Synchronous oligometastasis in stage IVB esophageal squamous cell carcinoma (ESCC) may represent an intermediate state in which local therapy remains effective. However, its definition is still debated, and outcome data are limited. Methods: We retrospectively analyzed 191 consecutive patients with ESCC and [...] Read more.

Background/Objectives: Synchronous oligometastasis in stage IVB esophageal squamous cell carcinoma (ESCC) may represent an intermediate state in which local therapy remains effective. However, its definition is still debated, and outcome data are limited. Methods: We retrospectively analyzed 191 consecutive patients with ESCC and synchronous oligometastases treated between 2006 and 2022. Oligometastasis was defined as ≤5 distant metastatic lesions. Patients received systemic therapy (chemotherapy and/or immunotherapy), local therapy (surgery or radiotherapy), or combined systemic and local therapy (surgery following preoperative therapy or chemoradiotherapy). Survival outcomes and prognostic factors were assessed. Results: The median overall survival (OS) was 25.1 months, with a 3-year OS rate of 41.0%. Multivariate analysis identified performance status, number of organ metastases, and treatment type as independent prognostic factors. Patients with single-organ metastasis had superior outcomes compared with those with multiple metastases (3-year OS: 44.3% vs. 0%; progression-free survival [PFS]: 23.5% vs. 0%). Combined systemic and local therapy yielded the best outcomes, with 3-year OS and PFS rates of 49.8% and 29.3%, respectively, compared with 20.0% and 18.1% for local therapy and 20.1% and 0% for systemic therapy alone. Conclusions: Patients with multiple-organ metastases have a very poor prognosis, indicating that their metastases may not represent true oligometastases. Long-term survival can be achieved in some patients using multimodal strategies that integrate systemic and local therapies. These findings demonstrate better treatment outcomes for stage IVB ESCC and provide a reference for future developments relating to oligometastatic disease. Full article

(This article belongs to the Section Cancer Therapy)

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16 pages, 4636 KB

Open AccessArticle

Radiomics for Dynamic Lung Cancer Risk Prediction in USPSTF-Ineligible Patients

by Morteza Salehjahromi, Hui Li, Eman Showkatian, Maliazurina B. Saad, Mohamed Qayati, Sherif M. Ismail, Sheeba J. Sujit, Amgad Muneer, Muhammad Aminu, Lingzhi Hong, Xiaoyu Han, Simon Heeke, Tina Cascone, Xiuning Le, Natalie Vokes, Don L. Gibbons, Iakovos Toumazis, Edwin J. Ostrin, Mara B. Antonoff, Ara A. Vaporciyan, David Jaffray, Fernando U. Kay, Brett W. Carter, Carol C. Wu, Myrna C. B. Godoy, J. Jack Lee, David E. Gerber, John V. Heymach, Jianjun Zhang and Jia Wu Show full author list Hide full author list

Cancers 2025, 17(21), 3406; https://doi.org/10.3390/cancers17213406 - 23 Oct 2025

Abstract

Background: Non-smokers and individuals with minimal smoking history represent a significant proportion of lung cancer cases but are often overlooked in current risk assessment models. Pulmonary nodules are commonly detected incidentally—appearing in approximately 24–31% of all chest CT scans regardless of smoking [...] Read more.

Background: Non-smokers and individuals with minimal smoking history represent a significant proportion of lung cancer cases but are often overlooked in current risk assessment models. Pulmonary nodules are commonly detected incidentally—appearing in approximately 24–31% of all chest CT scans regardless of smoking status. However, most established risk models, such as the Brock model, were developed using cohorts heavily enriched with individuals who have substantial smoking histories. This limits their generalizability to non-smoking and light-smoking populations, highlighting the need for more inclusive and tailored risk prediction strategies. Purpose: We aimed to develop a longitudinal radiomics-based approach for lung cancer risk prediction, integrating time-varying radiomic modeling to enhance early detection in USPSTF-ineligible patients. Methods: Unlike conventional models that rely on a single scan, we conducted a longitudinal analysis of 122 patients who were later diagnosed with lung cancer, with a total of 622 CT scans analyzed. Of these patients, 69% were former smokers, while 30% had never smoked. Quantitative radiomic features were extracted from serial chest CT scans to capture temporal changes in nodule evolution. A time-varying survival model was implemented to dynamically assess lung cancer risk. Additionally, we evaluated the integration of handcrafted radiomic features and the deep learning-based Sybil model to determine the added value of combining local nodule characteristics with global lung assessments. Results: Our radiomic analysis identified specific CT patterns associated with malignant transformation, including increased nodule size, voxel intensity, textural entropy, as indicators of tumor heterogeneity and progression. Integrating radiomics, delta-radiomics, and longitudinal imaging features resulted in the optimal predictive performance during cross-validation (concordance index [C-index]: 0.69), surpassing that of models using demographics alone (C-index: 0.50) and Sybil alone (C-index: 0.54). Compared to the Brock model (67% accuracy, 100% sensitivity, 33% specificity), our composite risk model achieved 78% accuracy, 89% sensitivity, and 67% specificity, demonstrating improved early cancer risk stratification. Kaplan–Meier curves and individualized cancer development probability functions further validated the model’s ability to track dynamic risk progression for individual patients. Visual analysis of longitudinal CT scans confirmed alignment between predicted risk and evolving nodule characteristics. Conclusions: Our study demonstrates that integrating radiomics, sybil, and clinical factors enhances future lung cancer risk prediction in USPSTF-ineligible patients, outperforming existing models and supporting personalized screening and early intervention strategies. Full article

(This article belongs to the Special Issue Artificial Intelligence and Machine Learning in Lung Cancer Screening: Current Applications and Future Directions)

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20 pages, 1908 KB

Open AccessArticle

The Clinical Utility of Selected Coagulation Parameters in Predicting the Risk of Venous Thromboembolism in Neuroendocrine Tumours: A Prospective, Single-Centre Study

by Monika Wójcik-Giertuga, Anna Malczewska-Herman, Arkadiusz Orzeł and Beata Kos-Kudła

Cancers 2025, 17(21), 3405; https://doi.org/10.3390/cancers17213405 - 22 Oct 2025

Abstract

The incidence of venous thromboembolism (VTE) markedly increases mortality in cancer patients, potentially by as much as fourfold [...] Full article

(This article belongs to the Section Clinical Research of Cancer)

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29 pages, 3572 KB

Open AccessReview

Fifty Shades of PSMA-Avid Rib Lesions: A Comprehensive Review

by Amirreza Shamshirgaran, Mohammad Hadi Samadi, Michael Saeed, Sara Harsini, Pegah Sahafi, Ghasemali Divband, Gholamreza Mohammadi, Narjess Ayati, Ramin Sadeghi, Alessio Rizzo, Giorgio Treglia and Emran Askari

Cancers 2025, 17(21), 3404; https://doi.org/10.3390/cancers17213404 - 22 Oct 2025

Abstract

Background: While prostate-specific membrane antigen (PSMA)-targeted imaging has revolutionized metastatic detection, unspecific bone uptake (UBU)—particularly in the ribs—is a common but diagnostically challenging finding in prostate cancer (PCa) patients. This review aims to synthesize current evidence on PSMA-avid rib lesions in PCa and [...] Read more.

Background: While prostate-specific membrane antigen (PSMA)-targeted imaging has revolutionized metastatic detection, unspecific bone uptake (UBU)—particularly in the ribs—is a common but diagnostically challenging finding in prostate cancer (PCa) patients. This review aims to synthesize current evidence on PSMA-avid rib lesions in PCa and to propose a structured approach for differentiating true metastases from benign mimics. Methods: A comprehensive literature search across PubMed, EMBASE, Scopus, and Web of Science identified relevant studies on PSMA imaging interpretation, tracer-specific patterns, rib lesion morphology, and clinical correlates. Data on uptake intensity, CT features, lesion number, location, tracer type, patient-specific risk factors, and follow-up behavior were extracted and analyzed. Results: Most solitary rib lesions are benign, particularly in low-risk patients or when located in the anterior/lateral arcs. Metastatic lesions are more likely to present as multiple foci, show cortical destruction on CT, exhibit high uptake intensity, and occur in patients with elevated PSA, high Gleason score, or ongoing androgen deprivation. ¹⁸F-PSMA-1007 is especially prone to UBU in the ribs compared to ⁶⁸Ga-PSMA-11. Based on these variables, we propose a clinical decision tree to guide interpretation of PSMA-avid rib lesions. Conclusions: Accurate interpretation of rib lesions on PSMA PET/CT requires a multimodal, context-sensitive approach. Our diagnostic decision tree guides precise differentiation of benign versus metastatic rib lesions, enhancing staging accuracy and clinical decision-making. Biomarker-guided therapies offer potential for personalized treatment, though rib-specific validation remains a critical need. Full article

(This article belongs to the Special Issue Systematic Reviews and Meta-Analyses of Genitourinary Cancers (2nd Edition))

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15 pages, 253 KB

Open AccessArticle

Characteristics of Participants and Findings of the National Breast Cancer Early Detection Program in Saudi Arabia

by Fatina Al Tahan, Shaker A. Alomary, Hani Tamim, Mohammad Alkaiyat, Haifa Nassri, Khaled Alkattan and Abdul Rahman Jazieh

Cancers 2025, 17(21), 3403; https://doi.org/10.3390/cancers17213403 - 22 Oct 2025

Abstract

Globally, around 2 [...] Full article

(This article belongs to the Special Issue Cancer Screening and Primary Care)

19 pages, 1273 KB

Open AccessReview

Proton Beam Therapy and the AYA Sarcoma Patient Journey: Highlighting Needs from Diagnosis to Survivorship

by Margaret M. Harris and Safia K. Ahmed

Cancers 2025, 17(21), 3402; https://doi.org/10.3390/cancers17213402 - 22 Oct 2025

Abstract

Background: Adolescents and young adults (15–39 years of age at time of diagnosis: AYA) with sarcoma are a unique patient population. The objective of this review is to examine the literature outlining the benefits of proton beam therapy (PBT) for treatment of [...] Read more.

Background: Adolescents and young adults (15–39 years of age at time of diagnosis: AYA) with sarcoma are a unique patient population. The objective of this review is to examine the literature outlining the benefits of proton beam therapy (PBT) for treatment of AYA sarcoma patients, barriers to PBT, evaluation of AYA-specific considerations and challenges, and exploration of future opportunities for improvements in care. Methods: An electronic search was conducted using databases and online search engines, primarily PubMed. The search criteria included studies and reviews completed from 2015 to 2025. Results: 57 articles were reviewed and categorized into sections: PBT for the treatment of the AYA patient, barriers to PBT, AYA-specific considerations and challenges, and future directions for the care of an AYA patient. Conclusions: Through this review, PBT can be deemed necessary when treating AYA sarcoma patients with radiation therapy to decrease long-term therapy-related toxicities. Furthermore, considerations for caring for an AYA sarcoma patient must extend beyond evidence-based treatment plans and must embrace the patient as a whole person through acknowledgement of the challenging impact on physical, mental, and social well-being from symptoms to diagnosis, diagnosis to treatment, and treatment to survivorship. Full article

(This article belongs to the Special Issue Radiotherapy for Sarcoma)

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17 pages, 2196 KB

Open AccessArticle

Diagnostic Models for Predicting Follicular Thyroid Carcinomas Using Circulating Plasma MicroRNAs

by Sin Woo Kang, Ji Min Kim, Sung-Chan Shin, Yong-Il Cheon, Bo Hyun Kim, Mijin Kim, Sang Soo Kim and Byung-Joo Lee

Cancers 2025, 17(21), 3401; https://doi.org/10.3390/cancers17213401 - 22 Oct 2025

Abstract

Background: Follicular thyroid carcinoma (FC) accounts for 10–15% of all thyroid cancers. FC is challenging to diagnose using fine-needle aspiration (FNA), making diagnostic thyroidectomy the standard approach. Recent studies have explored the use of circulating microRNAs for thyroid cancer diagnosis. This study evaluated [...] Read more.

Background: Follicular thyroid carcinoma (FC) accounts for 10–15% of all thyroid cancers. FC is challenging to diagnose using fine-needle aspiration (FNA), making diagnostic thyroidectomy the standard approach. Recent studies have explored the use of circulating microRNAs for thyroid cancer diagnosis. This study evaluated the diagnostic value of circulating miRNAs in plasma for FC to potentially reduce unnecessary thyroidectomies and repeat invasive procedures. Methods: This study was a retrospective observational study, and included consecutively selected 90 patients who underwent thyroidectomy at Pusan National University Hospital between January 2013 and February 2024 and were diagnosed with FC (49 patients) or follicular thyroid adenoma (FA) (41 patients) on final histopathology. Of these, 58 patients were enrolled in the utility assessment and 32 patients were included in the validation test. Among the 58 patients included in the utility assessment, microarray analysis was conducted on 15 patients who were randomly selected to identify novel plasma miRNAs. Next, TaqMan qRT-PCR was performed to evaluate the diagnostic utility of five plasma miRNAs and to develop a predictive model capable of predicting FC from FA using logistic regression as the utility assessment on 58 patients. Finally, in the validation test, TaqMan qRT-PCR and statistical analysis were conducted again on 32 patients and the constructed predictive models, verifying the accuracy of the predictive model. Results: Using microarray analysis, a novel miRNA, miR-6085, was identified for its distinguishing capability between FC and FA. In the utility assessment, miR-6085, miR-146b-5p, miR-221, and miR-222 were significantly upregulated in the FC group. A predictive model combining these four miRNAs showed strong diagnostic value for FC, with an AUC of 0.928 (0.843, 1.000), sensitivity of 94.7% (84.2, 100), specificity of 86.4% (68.2, 100). The accuracy of this model was 76.2% (52.8, 91.8) in the validation test. Conclusions: A model combining four miRNAs (miR-6085, miR-146b-5p, miR-221, and miR-222) demonstrated high sensitivity, specificity, and accuracy, suggesting that it could be a useful tool for differentiating FC from FA. Full article

(This article belongs to the Section Cancer Biomarkers)

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13 pages, 481 KB

Open AccessArticle

Serum Iodine Levels and 8-Year Survival in Patients After Kidney Cancer Diagnosis

by Elżbieta Złowocka-Perłowska, Piotr Baszuk, Adam Kiljańczyk, Wojciech Marciniak, Róża Derkacz, Aleksandra Tołoczko-Grabarek, Andrzej Sikorski, Marcin Słojewski, Adam Gołąb, Artur Lemiński, Michał Soczawa, Magdalena Marciniak, Rodney J. Scott, Jacek Gronwald and Jan Lubiński

Cancers 2025, 17(21), 3400; https://doi.org/10.3390/cancers17213400 - 22 Oct 2025

Abstract

Background/Objectives: The aim of this study was to evaluate the association between serum iodine (I) levels and kidney cancer mortality. The role of serum iodine levels in relation to 8-year survival rates in survivors of kidney cancer has not previously been established. In [...] Read more.

Background/Objectives: The aim of this study was to evaluate the association between serum iodine (I) levels and kidney cancer mortality. The role of serum iodine levels in relation to 8-year survival rates in survivors of kidney cancer has not previously been established. In this prospective study, we analyzed 284 consecutive, unselected survivors of kidney cancer and determined their 8-year survival in relation to iodine levels. Methods: Micronutrient levels were measured using inductively coupled plasma mass spectrometry (ICP-MS). Each survivors of kidney cancer was assigned to one of four groups based on the quartile distribution of iodine levels, ranked in ascending order. The multivariable models included covariates such as age at diagnosis, sex, smoking status, type of surgery, histopathological classification and serum levels of selenium, zinc, copper and the zinc-to-copper ratio. Results: We observed that survivors of kidney cancer with serum iodine levels in quartiles III and IV had significantly higher all-cause mortality compared to those in quartile II (reference quartile) (HR = 2.83; p = 0.012; HR = 2.64; p = 0.017). Furthermore, multivariable analysis revealed a significant association between serum iodine levels (quartiles III and IV vs. quartile II) and mortality due to kidney cancer progression (HR = 4.17; p = 0.031; HR = 3.94; p = 0.038, respectively). This association was significant only among men in quartile IV (HR = 16.5; p = 0.027). Additionally a positive association was observed between iodine levels in quartile IV and all-cause mortality from non–kidney cancer–related deaths (HR = 5.41; p = 0.05). Conclusions: To our knowledge, this study is the first investigation of relationship between serum iodine levels and survival of survivors of kidney cancer. Full article

(This article belongs to the Special Issue Advancements in “Cancer Biomarkers” for 2025–2026)

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16 pages, 6261 KB

Open AccessArticle

Spatial Organisation and Invasive Behaviour of Metastatic Cutaneous Squamous Cell Carcinoma-Derived Multicellular Spheroids Reflect Tumour Cell Phenotype

by Benjamin Genenger, Jessica Conley, Chelsea Penney, Luke McAlary, Jay R. Perry, Bruce Ashford and Marie Ranson

Cancers 2025, 17(21), 3399; https://doi.org/10.3390/cancers17213399 - 22 Oct 2025

Abstract

Background/Objectives: Cutaneous squamous cell carcinoma (cSCC) is a very common skin malignancy of the head and neck area, with a propensity to spread to local lymph nodes. Epithelial-to-mesenchymal transition (EMT) and cancer-associated fibroblasts (CAFs) play a well-documented role in the progression of [...] Read more.

Background/Objectives: Cutaneous squamous cell carcinoma (cSCC) is a very common skin malignancy of the head and neck area, with a propensity to spread to local lymph nodes. Epithelial-to-mesenchymal transition (EMT) and cancer-associated fibroblasts (CAFs) play a well-documented role in the progression of the disease. In this study, we developed and characterised multicellular tumour spheroids (MCTS) composed of patient-derived metastatic cSCC cell lines—each exhibiting distinct phenotypes—combined with either dermal- or lymph node-derived fibroblasts. We aimed to investigate how these cellular combinations influence MCTS formation, spatial architecture, and invasive behaviour. We hypothesised that the interplay between different cSCC and fibroblast cell combinations would differentially influence spheroid formation and invasion. Methods: Using live-cell microscopy we assessed the spatial architectures specific to each cell line-fibroblast combination and evaluated the expression of EMT and CAF markers. Furthermore, we utilised MCTS in invasion models to investigate associations between the mode of invasion and the EMT phenotype of the cancer cell line. Results: We show that metastatic cSCC/fibroblast MCTS self-organise into distinct spatial architectures. They also invade through collagen in a manner influenced by fibroblasts but dominated by the EMT status of the originating cancer cells. Conclusions: These findings highlight the physiological relevance and utility of MCTS as models for investigating tumour–stroma interactions and invasion dynamics in metastatic cSCC. Full article

(This article belongs to the Special Issue Multicellular 3D Models of Cancer)

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11 pages, 829 KB

Open AccessArticle

Artificial Intelligence for Lymph Node Detection and Malignancy Prediction in Endoscopic Ultrasound: A Multicenter Study

by Belén Agudo Castillo, Miguel Mascarenhas Saraiva, António Miguel Martins Pinto da Costa, João Ferreira, Miguel Martins, Francisco Mendes, Pedro Cardoso, Joana Mota, Maria João Almeida, João Afonso, Tiago Ribeiro, Marcos Eduardo Lera dos Santos, Matheus de Carvalho, María Morís, Ana García García de Paredes, Daniel de la Iglesia García, Carlos Estebam Fernández-Zarza, Ana Pérez González, Khoon-Sheng Kok, Jessica Widmer, Uzma D. Siddiqui, Grace E. Kim, Susana Lopes, Pedro Moutinho Ribeiro, Filipe Vilas-Boas, Eduardo Hourneaux de Moura, Guilherme Macedo and Mariano González-Haba Ruiz Show full author list Hide full author list

Cancers 2025, 17(21), 3398; https://doi.org/10.3390/cancers17213398 - 22 Oct 2025

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Abstract

Background/Objectives: Endoscopic ultrasound (EUS) is crucial for lymph node (LN) characterization, playing a key role in oncological staging and treatment guidance. EUS criteria for predicting malignancy are imprecise, and histologic diagnosis may have limitations. This multicenter study aimed to evaluate the effectiveness [...] Read more.

Background/Objectives: Endoscopic ultrasound (EUS) is crucial for lymph node (LN) characterization, playing a key role in oncological staging and treatment guidance. EUS criteria for predicting malignancy are imprecise, and histologic diagnosis may have limitations. This multicenter study aimed to evaluate the effectiveness of a novel artificial intelligence (AI)–based system in predicting LN malignancy from EUS images. Methods: This multicenter study included EUS images from nine centers. Lesions were labeled (“malignant” or “benign”) and delimited with bounding boxes. Definitive diagnoses were based on cytology/biopsy or surgical specimens and, if negative, a minimum six-month clinical follow-up. A convolutional neural network (CNN) was developed using the YOLO (You Only Look Once) architecture, incorporating both detection and classification modules. Results: A total of 59,992 images from 82 EUS procedures were analyzed. The CNN distinguished malignant from benign lymph nodes with a sensitivity of 98.8% (95% CI: 98.5–99.2%), specificity of 99.0% (95% CI: 98.3–99.7%), and precision of 99.0% (95% CI: 98.4–99.7%). The negative and positive predictive values for malignancy were 98.8% and 99.0%, respectively. Overall diagnostic accuracy was 98.3% (95% CI: 97.6–99.1%). Conclusions: This is the first study evaluating the performance of deep learning systems for LN assessment using EUS imaging. Our AI-powered imaging model shows excellent detection and classification capabilities, emphasizing its potential to provide a valuable tool to refine LN evaluation with EUS, ultimately supporting more tailored, efficient patient care. Full article

(This article belongs to the Special Issue Application of Artificial Intelligence-Based Approaches in Cancer Diagnosis, Treatment and Prognosis)

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18 pages, 1088 KB

Open AccessReview

Challenges in the Evolving Role of Calreticulin as a Promising Target for Precision Medicine in Myeloproliferative Neoplasms

by Alessandro Costa and Massimo Breccia

Cancers 2025, 17(21), 3397; https://doi.org/10.3390/cancers17213397 - 22 Oct 2025

Viewed by 33

Abstract

More than a decade after its discovery, advances have been made in understanding the oncogenic role of mutant CALR in BCR::ABL1-negative myeloproliferative neoplasms (MPNs). Disease biology has proven to be distinct from other MPN subtypes, with meaningful differences that have created opportunities [...] Read more.

More than a decade after its discovery, advances have been made in understanding the oncogenic role of mutant CALR in BCR::ABL1-negative myeloproliferative neoplasms (MPNs). Disease biology has proven to be distinct from other MPN subtypes, with meaningful differences that have created opportunities for therapeutic targeting of CALR-mutant clones. Among the approaches under investigation, immunotherapy has advanced furthest into clinical development and holds promise. Several strategies are now being explored, including monoclonal antibodies directed against the CALR neoepitope, T-cell–redirecting bispecific antibodies, precision antibody–drug conjugates, vaccination approaches, and CAR T-cell therapies. Early-phase clinical trials with fully human anti-CALR monoclonal antibodies (e.g., INCA033989) have shown very promising hematologic and molecular responses with manageable toxicity. In preclinical models, bispecific antibodies and CAR T-cell therapy offer additional avenues to exploit the selective cell-surface localization of mutant CALR. By contrast, vaccination strategies have so far demonstrated limited clinical efficacy, and their potential in clinical practice remains challenging. At the same time, the complexity of CALR-driven disease raises key questions, including whether anti-CALR therapies can shift treatment goals beyond thrombotic risk reduction, how best to monitor clonal burden, and how to address immune escape. In this review, we highlight the latest therapeutic advances in CALR-mutated MPNs while outlining the critical unmet needs that will shape the future of care for these patients. Full article

(This article belongs to the Special Issue Insights from the Editorial Board Member)

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27 pages, 1843 KB

Open AccessArticle

Oncological Outcomes of De-Escalation of Axillary Surgery in Breast Cancer Patients at a Referral Cancer Center in Colombia

by Sandra Esperanza Díaz-Casas, Andres Augusto Reyes-Agudelo, Oscar Alberto Vergara-Gamarra, Ximena Briceño-Morales, Luis Guzmán-AbiSaab, Daniel Contreras-Perez, Carlos Lehmann-Mosquera, Javier Ángel-Aristizábal, Mauricio García-Mora, Carlos Duarte-Torres, Iván Mariño-Lozano, Raúl Suárez-Rodríguez and Marcela Núñez-Lemus

Cancers 2025, 17(21), 3396; https://doi.org/10.3390/cancers17213396 - 22 Oct 2025

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Abstract

Background/Objectives: De-escalation of axillary surgery with sentinel lymph node biopsy (SLNB) has been shown to decrease morbidity in breast cancer patients without affecting oncological outcomes. However, there are very few reports on its applicability in real-world clinical practice, especially in middle-income countries. [...] Read more.

Background/Objectives: De-escalation of axillary surgery with sentinel lymph node biopsy (SLNB) has been shown to decrease morbidity in breast cancer patients without affecting oncological outcomes. However, there are very few reports on its applicability in real-world clinical practice, especially in middle-income countries. Methods: A retrospective historical cohort study was conducted, including 787 patients with clinical stage I–IIIA breast cancer treated from 2013 to 2023 at the INC in Colombia. Two groups were analyzed based on the timing of the axillary procedure: patients undergoing SLNB as initial surgery (Upfront SLNB) and those receiving neoadjuvant chemotherapy (Post-NACT SLNB). Results: The overall sentinel lymph node (SLN) identification rate was 99.3%. SLN positivity was 32% in Upfront SLNB and 13.1% in Post-NACT SLNB. Axillary lymph node dissection (ALND) was omitted in 56% of patients with node-positive Upfront SLNB; it was avoided in 86.8% of the Post-NACT group with complete axillary response (ypN0). Regional recurrence rates were 2.33%. In multivariate analysis, the main factors linked to recurrence and mortality were triple-negative and luminal B HER2-negative biological subtypes, histological grade 2, and tumor size ≥ 2 cm. At 60 months of follow-up, 91.4% (95% CI: 88.9–93.9) of patients remained recurrence-free (time-recurrence (TR)), and overall survival (OS) was 96.1% (95% CI: 94.5–97.7), with no differences observed based on the axillary surgical strategy. Conclusions: Sentinel lymph node biopsy (SLNB) is an oncologically safe procedure for patients with early-stage and locally advanced breast cancer with an adequate response to neoadjuvant systemic treatment. Full article

(This article belongs to the Section Cancer Therapy)

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Cancers, Volume 17, Issue 21 (November-1 2025) – 30 articles

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