Cancers

10 pages, 783 KB

Open AccessArticle

The Prognostic Value of High-Sensitive Troponin T Rise Within the Upper Reference Limit in Breast Cancer: A Prospective Pilot Study

by Sergey Kozhukhov and Nataliia Dovganych

Cancers 2025, 17(14), 2412; https://doi.org/10.3390/cancers17142412 - 21 Jul 2025

Viewed by 527

Abstract

Background: We investigated the role of a high-sensitive cardiac troponin T (hsTnT) increase below the upper limit of normal (ULN) in patients with breast cancer (BC). hsTnT assays accurately quantify very low plasma troponin concentrations and enable the early detection of cardiomyocyte injury [...] Read more.

Background: We investigated the role of a high-sensitive cardiac troponin T (hsTnT) increase below the upper limit of normal (ULN) in patients with breast cancer (BC). hsTnT assays accurately quantify very low plasma troponin concentrations and enable the early detection of cardiomyocyte injury before a drop in the left ventricular ejection fraction (LVEF). The increase in hsTnT below the ULN in response to chemotherapy has not previously been studied. Method: This was an open-label pilot study. Female patients with newly diagnosed BC scheduled to receive systemic cancer treatment were recruited. Blood sampling and echocardiography were performed at baseline, at 3 and 6 months of cancer treatment. hsTnT concentrations were measured using the Elecsys TnT hs assay (Roche Diagnostics). The limit of blank and 99th percentile cutoff values for the hsTnT assay were 3 and 14 ng/L. We calculated the rise in hsTnT (ΔhsTnT) by the difference (%) between its baseline level and during follow-up (FU) in each patient. Results: Among eligible subjects, we excluded 4 patients before the start of treatment and 17 patients during the follow-up with values for the hsTnT >14 ng/L. Finally, 60 women with a median age of 48.6 ± 1.3 years were included in the study. The median baseline hsTnT concentration was 5.5 ± 1.4 ng/L. During 6 months of cancer treatment, hsTnT increased in all patients by up to 10–305% from baseline, with an average of 94.2%. LV EF was normal at baseline and decreased significantly compared to the value before cancer treatment (61.9 ± 3.3% vs. 56.3 ± 7.0%; p < 0.045). We correlated the hsTnT rise with a drop in LV EF ≥ 10% from its baseline level. Logistic regression analysis showed that Δ hsTnT has a good predictive value for LV dysfunction, 0.78 (p = 0.05), 95% CI (0.67–0.90). The increase in hsTnT > 81% was determined as the optimal threshold value for detecting early biochemical cardiotoxicity. Conclusion: It was investigated that hsTnT rise within the cutoff < 14 ng/L can be used as a marker of early biochemical cardiotoxicity and is valuable for predicting LV drop in 6 months of FU. We conclude that BC patients with increased hsTnT plasma concentration > 81% from the baseline value should be considered as high-risk patients for cardiotoxicity and need more precise cardiac monitoring and early preventive medical intervention strategies. Full article

(This article belongs to the Section Cancer Biomarkers)

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24 pages, 7718 KB

Open AccessArticle

Integration of Single-Cell Analysis and Bulk RNA Sequencing Data Using Multi-Level Attention Graph Neural Network for Precise Prognostic Stratification in Thyroid Cancer

by Langping Tan, Zhenjun Huang, Yongjian Chen, Zehua Wang, Zijia Lai, Xinzhi Peng, Cheng Zhang, Ruichong Lin, Wenhao Ouyang, Yunfang Yu and Miaoyun Long

Cancers 2025, 17(14), 2411; https://doi.org/10.3390/cancers17142411 - 21 Jul 2025

Viewed by 821

Abstract

Background: The prognosis management of thyroid cancer remains a significant challenge. This study highlights the critical role of T cells in the tumor microenvironment and aims to improve prognostic precision by integrating bulk RNA-seq and single-cell RNA-seq (scRNA-seq) data, providing a more comprehensive [...] Read more.

Background: The prognosis management of thyroid cancer remains a significant challenge. This study highlights the critical role of T cells in the tumor microenvironment and aims to improve prognostic precision by integrating bulk RNA-seq and single-cell RNA-seq (scRNA-seq) data, providing a more comprehensive view of tumor biology at the single-cell level. Method: 15 thyroid cancer scRNA-seq samples were analyzed from GEO and 489 patients from TCGA. A multi-level attention graph neural network (MLA-GNN) model was applied to integrate T-cell-related differentially expressed genes (DEGs) for predicting disease-free survival (DFS). Patients were divided into training and validation cohorts in an 8:2 ratio. Result: We systematically characterized the immune microenvironment of metastatic thyroid cancer by using single-cell transcriptomics and identified the important role of T-cell subtypes in the development of thyroid cancer. T-cell-based DEGS between tumor tissues and normal tissues were also identified. Subsequently, T-cell-based risk signatures were selected for establishing a risk model using MLA-GNN. Finally, our MLA-GNN-based model demonstrated an excellent ability to predict the DFS of thyroid cancer patients (1-year AUC: 0.965, 3-years AUC: 0.979, and 5-years AUC: 0.949 in training groups, and 1-year AUC: 0.879, 3-years AUC: 0.804, and 5-years AUC: 0.804 in validation groups). Conclusions: Risk features based on T-cell genes have demonstrated the effectiveness in predicting the prognosis of thyroid cancer. By conducting a comprehensive characterization of T-cell features, we aim to enhance our understanding of the tumor’s response to immunotherapy and uncover new strategies for the treatment of cancer. Full article

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

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20 pages, 1400 KB

Open AccessReview

Novel Therapeutics and the Path Toward Effective Immunotherapy in Malignant Peripheral Nerve Sheath Tumors

by Joshua J. Lingo, Elizabeth C. Elias and Dawn E. Quelle

Cancers 2025, 17(14), 2410; https://doi.org/10.3390/cancers17142410 - 21 Jul 2025

Viewed by 754

Abstract

Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are a deadly subtype of soft tissue sarcoma for which effective therapeutic options are lacking. Currently, the best treatment for MPNSTs is complete surgical resection with wide negative margins, but this is often complicated by the tumor [...] Read more.

Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are a deadly subtype of soft tissue sarcoma for which effective therapeutic options are lacking. Currently, the best treatment for MPNSTs is complete surgical resection with wide negative margins, but this is often complicated by the tumor size and location and/or the presence of metastases. Radiation or chemotherapy may be combined with surgery, but patient responses are poor. Targeted treatments, including small-molecule inhibitors of oncogenic proteins such as mitogen-activated protein kinase kinase (MEK), cyclin-dependent kinases 4 and 6 (CDK4/6), and Src-homology 2 domain-containing phosphatase 2 (SHP2), are promising therapeutics for MPNSTs, especially when combined together, but they have yet to gain approval. Immunotherapeutic approaches have been revolutionary for the treatment of some other cancers, but their utility as single agents in sarcoma is limited and not approved for MPNSTs. The immunosuppressive niche of MPNSTs is thought to confer inherent treatment resistance, particularly to immunotherapies. Remodeling an inherently “cold” tumor microenvironment into a “hot” immune milieu to bolster the anti-tumor activity of immunotherapies is of great interest throughout the cancer community. This review focuses on novel therapeutics that target dysregulated factors and pathways in MPNSTs, as well as different types of immunotherapies currently under investigation for this disease. We also consider how certain therapeutics may be combined to remodel the MPNST immune microenvironment and thereby generate a durable anti-tumor immune response to immunotherapy. Full article

(This article belongs to the Special Issue Next-Generation Cancer Therapies)

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28 pages, 1528 KB

Open AccessReview

Is Human Chorionic Gonadotropin a Reliable Marker for Testicular Germ Cell Tumor? New Perspectives for a More Accurate Diagnosis

by Nunzio Marroncelli, Giulia Ambrosini, Andrea Errico, Sara Vinco, Elisa Dalla Pozza, Giulia Cogo, Ilaria Cristanini, Filippo Migliorini, Nicola Zampieri and Ilaria Dando

Cancers 2025, 17(14), 2409; https://doi.org/10.3390/cancers17142409 - 21 Jul 2025

Viewed by 664

Abstract

Testicular germ cell tumors (TGCTs) are the most common malignancies affecting young men between the ages of 14 and 44, accounting for about 95% of all testicular cancers. Despite being relatively rare compared to other cancers (~3.0 cases per 100,000 population, with high [...] Read more.

Testicular germ cell tumors (TGCTs) are the most common malignancies affecting young men between the ages of 14 and 44, accounting for about 95% of all testicular cancers. Despite being relatively rare compared to other cancers (~3.0 cases per 100,000 population, with high worldwide variability), TGCTs’ incidence is increasing, particularly in industrialized countries. The initial phase of TGCT diagnosis is performed by detecting in the blood the presence of three proteins, i.e., alpha-fetoprotein (AFP), lactate dehydrogenase (LDH), and human chorionic gonadotropin (hCG). Despite these proteins being defined as markers of TGCTs, they present limitations in specificity. Indeed, AFP is not elevated in pure seminomas; LDH serum levels can be elevated in other conditions, such as liver disease or tissue damage, and hCG can be elevated in both seminomas and non-seminomas, reducing its ability to differentiate between tumor types. However, the existence of hCG variants, characterized by distinct glycosylation profiles that are differentially expressed in TGCT types and subtypes, may increase the diagnostic and prognostic potential of this hormone. Furthermore, emerging molecular biomarkers, including miRNAs and tumor cells-related epigenetic status, may offer new promising alternatives to improve diagnostic accuracy. Nonetheless, standardized diagnostic protocols still need to be implemented. Finally, understanding the biological roles of hCG isoforms and their “canonical” (e.g., LHCGR) and “non-canonical” (e.g., TGF-βR) receptor interactions may help in understanding tumor biology and therapeutic targeting. Full article

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

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4 pages, 3729 KB

Open AccessCorrection

Correction: Afjei et al. A New Nrf2 Inhibitor Enhances Chemotherapeutic Effects in Glioblastoma Cells Carrying p53 Mutations. Cancers 2022, 14, 6120

by Rayhaneh Afjei, Negar Sadeghipour, Sukumar Uday Kumar, Mallesh Pandrala, Vineet Kumar, Sanjay V. Malhotra, Tarik F. Massoud and Ramasamy Paulmurugan

Cancers 2025, 17(14), 2408; https://doi.org/10.3390/cancers17142408 - 21 Jul 2025

Viewed by 307

Abstract

In the original publication [...] Full article

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19 pages, 3009 KB

Open AccessArticle

PD-1-Positive CD8+ T Cells and PD-1-Positive FoxP3+ Cells in Tumor Microenvironment Predict Response to Neoadjuvant Chemoimmunotherapy in Gastric Cancer Patients

by Liubov A. Tashireva, Anna Yu. Kalinchuk, Elena O. Shmakova, Elisaveta A. Tsarenkova, Dmitriy M. Loos, Pavel Iamschikov, Ivan A. Patskan, Alexandra V. Avgustinovich, Sergey V. Vtorushin, Irina V. Larionova and Evgeniya S. Grigorieva

Cancers 2025, 17(14), 2407; https://doi.org/10.3390/cancers17142407 - 21 Jul 2025

Viewed by 604

Abstract

Background/Objectives: In gastric cancer, only a subset of patients benefit clinically from neoadjuvant chemoimmunotherapy, underscoring the need for robust biomarkers that can predict treatment responses and guide personalized immunotherapy. This study aimed to characterize the immune microenvironment of gastric tumors and identify predictive [...] Read more.

Background/Objectives: In gastric cancer, only a subset of patients benefit clinically from neoadjuvant chemoimmunotherapy, underscoring the need for robust biomarkers that can predict treatment responses and guide personalized immunotherapy. This study aimed to characterize the immune microenvironment of gastric tumors and identify predictive markers associated with therapeutic efficacy. Methods: We prospectively enrolled 16 patients with histologically confirmed, PD-L1–positive (CPS ≥ 1) gastric adenocarcinoma (T_2–4N_0–1M₀). All patients received eight cycles of FLOT chemotherapy combined with pembrolizumab. Treatment response was assessed by Mandard tumor regression grading. Spatial transcriptomic profiling (10x Genomics Visium) and multiplex immunofluorescence were used to evaluate tumor-infiltrating immune cell subsets and PD-1 expression at baseline and after treatment. Results: Transcriptomic analysis differentiated the immune landscapes of responders from non-responders. Responders exhibited elevated expression of IL1B, CXCL5, HMGB1, and IFNGR2, indicative of an inflamed tumor microenvironment and type I/II interferon signaling. In contrast, non-responders demonstrated upregulation of immunosuppressive genes such as LGALS3, IDO1, and CD55, along with enrichment in oxidative phosphorylation and antigen presentation pathways. Multiplex immunofluorescence confirmed a higher density of FoxP3⁺ regulatory T cells in non-responders (median 5.36% vs. 2.41%; p = 0.0032). Notably, PD-1⁺ CD8⁺ T cell and PD-1⁺ FoxP3⁺ Treg frequencies were significantly elevated in non-responders, suggesting that PD-1 expression within cytotoxic and regulatory compartments may contribute to immune evasion. No substantial differences were observed in PD-L1 CPS or PD-1⁺ B cells and PD-1⁺ macrophages. Conclusions: Our findings identify PD-1⁺ CD8⁺ T cells and PD-1⁺ FoxP3⁺ Tregs as potential biomarkers of resistance to neoadjuvant chemoimmunotherapy in gastric cancer. Transcriptional programs centered on IL1B/CXCL5 and LGALS3/IDO1 define distinct immune phenotypes that may guide future combination strategies targeting both effector and suppressive arms of the tumor immune response. Full article

(This article belongs to the Special Issue Advances in the Diagnosis and Treatment of Solid and Hematologic Neoplasms)

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9 pages, 221 KB

Open AccessPerspective

Definitions of, Advances in, and Treatment Strategies for Breast Cancer Oligometastasis

by Tadahiko Shien, Shogo Nakamoto, Yuki Fujiwara, Maya Kosaka, Yuki Narahara, Kento Fujii, Reina Maeda, Shutaro Kato, Asuka Mimata, Ryo Yoshioka, Chihiro Kuwahara, Takahiro Tsukioki, Yuko Takahashi, Tsuguo Iwatani and Maki Tanioka

Cancers 2025, 17(14), 2406; https://doi.org/10.3390/cancers17142406 - 21 Jul 2025

Viewed by 645

Abstract

Oligometastasis represents a clinically relevant state of limited metastatic disease that could be amenable to selected local therapies in carefully chosen patients. Although initial trials such as SABR-COMET demonstrated a survival benefit with aggressive local treatment, breast cancer was underrepresented. Subsequent breast cancer-specific [...] Read more.

Oligometastasis represents a clinically relevant state of limited metastatic disease that could be amenable to selected local therapies in carefully chosen patients. Although initial trials such as SABR-COMET demonstrated a survival benefit with aggressive local treatment, breast cancer was underrepresented. Subsequent breast cancer-specific trials, including NRG-BR002, failed to show a clear survival benefit, highlighting uncertainties and the need for further refinement in patient selection and integration with systemic approaches. The definitions of oligometastasis continue to evolve, incorporating radiological, clinical, and biological features. Advances in imaging and molecular profiling suggest that oligometastatic breast cancer might represent a distinct biological subtype, with potential biomarkers including PIK3CA mutations and YAP/TAZ expression. Organ-specific strategies using stereotactic radiotherapy, surgery, and proton therapy have shown favorable local control in certain settings, though their impact on the overall survival remains under investigation. Emerging techniques, including circulating tumor DNA (ctDNA) analysis, are being explored to improve patient selection and disease monitoring. Ongoing trials may provide further insight into the role of local therapy, particularly in hormone receptor-positive or HER2-positive subtypes. Local and systemic strategies need to be carefully coordinated to optimize the outcomes. This review summarizes the current definitions of and evidence and therapeutic considerations for oligometastatic breast cancer and outlines potential future directions. Full article

(This article belongs to the Special Issue New Insights into Oligo-Recurrence of Various Cancers (2nd Edition))

12 pages, 1396 KB

Open AccessArticle

Lateral Flow Assay to Detect Carbonic Anhydrase IX in Seromas of Breast Implant-Associated Anaplastic Large Cell Lymphoma

by Peng Xu, Katerina Kourentzi, Richard Willson, Honghua Hu, Anand Deva, Christopher Campbell and Marshall Kadin

Cancers 2025, 17(14), 2405; https://doi.org/10.3390/cancers17142405 - 21 Jul 2025

Viewed by 483

Abstract

Background/Objective: Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) has affected more than 1700 women with textured breast implants. About 80% of patients present with fluid (seroma) around their implant. BIA-ALCL can be cured by surgery alone when confined to the seroma and lining [...] Read more.

Background/Objective: Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) has affected more than 1700 women with textured breast implants. About 80% of patients present with fluid (seroma) around their implant. BIA-ALCL can be cured by surgery alone when confined to the seroma and lining of the peri-implant capsule. To address the need for early detection, we developed a rapid point of care (POC) lateral flow assay (LFA) to identify lymphoma in seromas. Methods: We compared 28 malignant seromas to 23 benign seromas using both ELISA and LFA. LFA test lines (TL) and control lines (CL) were visualized and measured with imaging software and the TL/CL ratio for each sample was calculated. Results: By visual exam, the sensitivity for detection of CA9 was 93% and specificity 78%, while the positive predictive value was 84% and negative predictive value 90%. Quantitative image analysis increased the positive predictive value to 96% while the negative predictive value reduced to 79%. Conclusions: We conclude that CA9 is a sensitive biomarker for detection and screening of patients for BIA-ALCL in patients who present with seromas of unknown etiology. The CA9 LFA can potentially replace ELISA, flow cytometry and other tests requiring specialized equipment, highly trained personnel, larger amounts of fluid and delay in diagnosis of BIA-ALCL. Full article

(This article belongs to the Special Issue Pre-Clinical Studies of Personalized Medicine for Cancer Research)

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17 pages, 1342 KB

Open AccessReview

Esophageal Squamous Papilloma and Papillomatosis: Current Evidence of HPV Involvement and Malignant Potential

by Miriana Mercurio, Roberto de Sire, Paola Campagnoli, Marco Dal Fante, Linda Fazzini, Luciano Guerra, Massimo Primignani, Maria Giuseppina Tatarella, Mauro Sollai, Sandro Ardizzone and Roberta Maselli

Cancers 2025, 17(14), 2404; https://doi.org/10.3390/cancers17142404 - 20 Jul 2025

Viewed by 846

Abstract

Human papillomavirus (HPV) is a recognized oncogenic agent in several epithelial malignancies, though its role in esophageal squamous lesions remains unclear. Esophageal squamous papilloma and papillomatosis are rare, often benign lesions, but increasing evidence suggests possible associations with high-risk HPV genotypes and a [...] Read more.

Human papillomavirus (HPV) is a recognized oncogenic agent in several epithelial malignancies, though its role in esophageal squamous lesions remains unclear. Esophageal squamous papilloma and papillomatosis are rare, often benign lesions, but increasing evidence suggests possible associations with high-risk HPV genotypes and a non-negligible risk of dysplasia and malignant transformation. This narrative review summarizes current evidence on epidemiology, clinical features, histopathology, and diagnostic approaches, emphasizing advanced endoscopic imaging techniques that improve lesion detection and characterization. Management relies primarily on complete endoscopic resection with histological and virological evaluation. While small, non-dysplastic solitary lesions may not require routine surveillance, multifocal or high-risk HPV-positive cases warrant closer follow-up. Standardized HPV testing and long-term prospective studies are needed to better define the oncogenic potential and inform surveillance and treatment strategies. Full article

(This article belongs to the Special Issue Technical Advances in Esophageal Cancer Treatment)

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13 pages, 464 KB

Open AccessArticle

Short-Term Outcomes in Planned Versus Unplanned Surgery for Spinal Metastases

by Ali Haider Bangash, Sertac Kirnaz, Rose Fluss, Victoria Cao, Alexander Alexandrov, Liza Belman, Yaroslav Gelfand, Saikiran G. Murthy, Reza Yassari and Rafael De la Garza Ramos

Cancers 2025, 17(14), 2403; https://doi.org/10.3390/cancers17142403 - 20 Jul 2025

Viewed by 547

Abstract

Background/Objectives: Metastatic spine disease (MSD) affects a significant proportion of patients with advanced malignancies and often necessitates surgical intervention to preserve neurological function, alleviate pain, and maintain spinal stability. While oncologic spine surgery is ideally performed in a planned, semi-elective setting, a substantial [...] Read more.

Background/Objectives: Metastatic spine disease (MSD) affects a significant proportion of patients with advanced malignancies and often necessitates surgical intervention to preserve neurological function, alleviate pain, and maintain spinal stability. While oncologic spine surgery is ideally performed in a planned, semi-elective setting, a substantial number of patients require unplanned (urgent or emergent) surgery due to acute deterioration. The impact of surgical planning status on postoperative outcomes following metastatic spine tumor surgery remains underexplored. This study aimed to compare the patient characteristics and short-term outcomes of those undergoing planned versus unplanned surgery for spinal metastases. Methods: We conducted a retrospective cohort study using the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database from 2018 to 2023. Patients with disseminated cancer undergoing tumor surgery were identified. Case types were grouped into planned (elective) and unplanned (urgent or emergent). The primary endpoint was failure to rescue (FTR); secondary endpoints included 30-day major complications, 30-day mortality, and length of hospital stay. Univariable and multivariable regression analyses were performed. Results: A total of 2147 patients met our inclusion criteria, out of whom 60% (n = 1284) underwent planned and 40% (n = 863) underwent unplanned surgery. Patients in the unplanned surgery group had a significantly higher prevalence of severe hypoalbuminemia, severe anemia, and ASA class IV status (p ≤ 0.001 for all). For our primary endpoint, a multivariable analysis showed a significant association between unplanned surgery and FTR (OR 2.11 [95% CI 1.24 to 3.56]; p = 0.005). Significant associations were also found with 30-day mortality (OR 1.84 [95% CI 1.25 to 2.72]; p = 0.002) and length of hospital stay (β 2.7 [95% CI 1.97 to 3.43]; p < 0.001). However, unplanned surgery could not independently predict 30-day major complications (OR 1.21 [95% CI 0.97 to 1.51]; p = 0.08). Conclusions: Our study found that unplanned surgery for spinal metastases was associated with significantly higher rates of FTR, 30-day mortality, and extended hospital stay, independent of other covariates. These findings highlight the importance of the timely identification of patients requiring surgery and the potential benefits of semi-elective care. Full article

(This article belongs to the Special Issue Surgical Advances in Cancer Treatments: Exploring Innovative Approaches and Emerging Perspectives)

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18 pages, 9009 KB

Open AccessArticle

Cancer-Associated Fibroblasts Establish Spatially Distinct Prognostic Niches in Subcutaneous Colorectal Cancer Mouse Model

by Zhixian Lin, Jinmeng Wang, Yixin Ma, Yanan Zhu, Yuhan Li, Zhengtao Xiao and Wei Zhao

Cancers 2025, 17(14), 2402; https://doi.org/10.3390/cancers17142402 - 19 Jul 2025

Viewed by 693

Abstract

Background/Objectives: Subcutaneous tumor models are widely used in colorectal cancer (CRC) research due to their experimental accessibility; however, the spatial organization and regulatory mechanisms of their tumor microenvironment remain poorly understood. Methods: Here, we applied spatial transcriptomics to systematically characterize spatial heterogeneity within [...] Read more.

Background/Objectives: Subcutaneous tumor models are widely used in colorectal cancer (CRC) research due to their experimental accessibility; however, the spatial organization and regulatory mechanisms of their tumor microenvironment remain poorly understood. Methods: Here, we applied spatial transcriptomics to systematically characterize spatial heterogeneity within MC38 subcutaneous tumors in a syngeneic mouse model. Results: We identified two spatially distinct tumor zones, partitioned by cancer-associated fibroblasts (CAFs), that differ markedly in cellular composition, oncogenic signaling, immune infiltration, and metabolic states. One zone exhibited features of TGF-β-driven extracellular matrix remodeling, immune exclusion, and hyperproliferative metabolism, while the other was enriched for immunosuppressive macrophages, metabolic reprogramming via PPAR and AMPK pathways, and high-risk cell populations. Spatially resolved cell–cell communication networks further revealed zone-specific ligand–receptor interactions—such as ANGPTL4–SDC2 and PROS1–AXL—that underpin stromal remodeling and immune evasion and are associated with patient prognosis. Conclusions: Collectively, our study uncovers how region-specific cellular ecosystems and intercellular crosstalk establish prognostically divergent niches within subcutaneous CRC tumors, offering insights into spatially guided therapeutic strategies. Full article

(This article belongs to the Section Tumor Microenvironment)

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21 pages, 5260 KB

Open AccessReview

Disrupting Cell Cycle Machinery: CREPT Is an Emerging Target in Cancer Therapy

by Umar Farooq, Jun Li and Zhijie Chang

Cancers 2025, 17(14), 2401; https://doi.org/10.3390/cancers17142401 - 19 Jul 2025

Viewed by 824

Abstract

The transcriptional co-factor cell-cycle-related and expression-elevated protein in tumors (CREPT) has emerged as a critical driver of the cell cycle and a significant contributor to tumorigenesis. The aberrant expression or upregulation of CREPT boosts multiple signaling pathways, including Wnt/β-catenin, STAT3 and NF-κB/TNFR2, which [...] Read more.

The transcriptional co-factor cell-cycle-related and expression-elevated protein in tumors (CREPT) has emerged as a critical driver of the cell cycle and a significant contributor to tumorigenesis. The aberrant expression or upregulation of CREPT boosts multiple signaling pathways, including Wnt/β-catenin, STAT3 and NF-κB/TNFR2, which are frequently dysregulated in various cancers and are associated with poor overall survival. In preclinical studies, CREPT knockdown via shRNA has demonstrated sustained tumor growth regression. Recent researches have uncovered additional functions of CREPT, including roles in metabolic regulation, tissue repair, and microenvironmental remodeling, further establishing it as a pleiotropic transcriptional regulator. Currently, there is no therapeutic agent that directly inhibits CREPT expression in clinic. However, miRNAs and other methods have been used to target CREPT, which have yielded useful results in inhibiting tumor growth. In this review, we discuss the role of CREPT in the hallmarks of cancer and propose that targeting CREPT will reverse tumor growth and may improve the immune checkpoint inhibitors in combination in CREPT-driven cancers. Full article

(This article belongs to the Section Cancer Therapy)

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16 pages, 1088 KB

Open AccessArticle

Impact of Neoadjuvant Chemotherapy on Survival Outcomes in Gastric Signet-Ring Cell Carcinoma

by Salvatore Sorrenti, Silvia Malerba, Eleonora Lori, Daniele Pironi, Karol Polom, Jaroslaw Skokowski, Sergii Girnyi, Tomasz Cwalinski, Francesco Paolo Prete, Yogesh K. Vashist, Mario Testini and Luigi Marano

Cancers 2025, 17(14), 2400; https://doi.org/10.3390/cancers17142400 - 19 Jul 2025

Viewed by 758

Abstract

Background: Gastric signet-ring cell carcinoma (GSRCC) is an aggressive gastric cancer subtype with limited evidence supporting the role of neoadjuvant chemotherapy (NAC). This study evaluated the impact of NAC on overall survival (OS) in a large, population-based cohort. Methods: We analyzed [...] Read more.

Background: Gastric signet-ring cell carcinoma (GSRCC) is an aggressive gastric cancer subtype with limited evidence supporting the role of neoadjuvant chemotherapy (NAC). This study evaluated the impact of NAC on overall survival (OS) in a large, population-based cohort. Methods: We analyzed data from the SEER database (2011–2018), identifying patients aged 20–80 years with primary gastric tumors (C16.0–C16.9) and signet-ring cell histology who underwent curative-intent gastrectomy. Patients with metastatic disease, non-curative surgery, clinical Stage I, incomplete staging, or unknown survival were excluded. OS was assessed using Kaplan–Meier analysis and multivariable Cox regression. Subgroup analyses evaluated the interaction of NAC with tumor location and clinical stage. Results: A total of 978 patients met inclusion criteria; 436 (44.6%) received NAC. The 3- and 5-year OS rates were 43.9% and 38.3%, respectively. NAC was not associated with improved OS compared to surgery alone (5-year OS: 39.7% vs. 37.2%; log-rank p = 0.34) and was not an independent prognostic factor in multivariable analysis (p = 0.651). Independent predictors of worse OS included larger tumor size, advanced stage, positive nodal status, and Black race (all p < 0.05). Subgroup analysis indicated a survival benefit from NAC in patients with mid or distal gastric tumors (p < 0.001 for interaction). Conclusions: In this SEER-based analysis, NAC did not improve OS in the overall GSRCC population. However, selected subgroups may derive benefit, supporting a personalized approach to neoadjuvant therapy in GSRCC. Full article

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

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19 pages, 2501 KB

Open AccessArticle

Genes Encoding Multiple Modulators of the Immune Response Are Methylated in the Prostate Tumor Microenvironment of African Americans

by Vinay Kumar, Tara Sinta Kartika Jennings, Lucas Ueta, James Nguyen, Liankun Song, Michael McClelland, Weiping Chu, Michael Lilly, Michael Ittmann, Patricia Castro, Arash Rezazadeh Kalebasty, Dan Mercola, Omid Yazdanpanah, Xiaolin Zi and Farah Rahmatpanah

Cancers 2025, 17(14), 2399; https://doi.org/10.3390/cancers17142399 - 19 Jul 2025

Viewed by 579

Abstract

Background/Objectives: Prostate cancer (PCa) is diagnosed at an earlier median age, more advanced stage, and has worse clinical outcomes in African American (AA) men compared to European Americans (EA). Methods: To investigate the role of aberrant DNA methylation in tumor-adjacent stroma [...] Read more.

Background/Objectives: Prostate cancer (PCa) is diagnosed at an earlier median age, more advanced stage, and has worse clinical outcomes in African American (AA) men compared to European Americans (EA). Methods: To investigate the role of aberrant DNA methylation in tumor-adjacent stroma (TAS), methyl binding domain sequencing (MBD-seq) was performed on AA (n = 17) and EA (n = 15) PCa patients. This was independently confirmed using the long interspersed nuclear element-1 (LINE-1) assay. Pathway analysis was performed on statistically significantly differentially methylated genes for AA and EA TAS. DNA methylation profiles of primary cultured AA and EA carcinoma-associated fibroblasts (CAFs) were compared with AA and EA TAS. AA and EA CAFs were treated with demethylating agent 5-Azacytidine (5-AzaC). Results: AA TAS exhibited higher global DNA methylation than EA TAS (p-value < 0.001). Of the 3268 differentially methylated regions identified (DMRs, p-value < 0.05), 85% (2787 DMRs) showed increased DNA methylation in AA TAS, comprising 1648 genes, of which 1379 were protein-coding genes. Based on DNA methylation levels, two AA subgroups were identified. Notably, AA patients with higher DNA methylation were predominantly those with higher Gleason scores. Pathway analysis linked methylated genes in AA TAS to several key signaling pathways (p-value < 0.05), including immune response (e.g., IL-1, IL-15, IL-7, IL-8, IL-3, and chemokine), Wnt/β-catenin, androgen, PTEN, p53, TGF-β, and circadian clock regulation. A total of 168 concordantly methylated genes were identified, with 109 genes (65%) showing increased methylation in AA CAFs and TAS (p-value < 0.05). Treatment with 5-AzaC significantly reduced DNA methylation of concordant genes in AA CAFs (p-value < 0.001). Conclusions: These findings suggest a distinct stromal methylome in AA, providing a foundation for integrating demethylating agents into standard therapies. This approach targets the tumor microenvironment, potentially addressing PCa disparities in AA men. Full article

(This article belongs to the Section Tumor Microenvironment)

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18 pages, 984 KB

Open AccessArticle

Optimizing Belantamab Mafodotin in Relapsed or Refractory Multiple Myeloma: Impact of Dose Modifications on Adverse Events and Hematologic Response in a Real-World Retrospective Study

by Lina Zoe Rüsing, Jakob Schweighofer, Julia Aschauer, Georg Jeryczynski, Lea Vospernik, Heinz Gisslinger, Armin Marcus Bumberger, Julia Cserna, Julia Riedl, Hermine Agis and Maria-Theresa Krauth

Cancers 2025, 17(14), 2398; https://doi.org/10.3390/cancers17142398 - 19 Jul 2025

Viewed by 700

Abstract

Background: Belantamab mafodotin (belamaf) is a BCMA-targeting antibody–drug conjugate used in triple-class refractory multiple myeloma. Despite its efficacy, keratopathy remains a significant dose-limiting toxicity. Following its withdrawal from the U.S. market in 2022, its use in Austria is limited to clinical trials [...] Read more.

Background: Belantamab mafodotin (belamaf) is a BCMA-targeting antibody–drug conjugate used in triple-class refractory multiple myeloma. Despite its efficacy, keratopathy remains a significant dose-limiting toxicity. Following its withdrawal from the U.S. market in 2022, its use in Austria is limited to clinical trials or compassionate use. Methods: In this real-world, retrospective study, we analyzed 36 relapsed/refractory, BCMA-naïve multiple myeloma patients treated at the University Hospital of Vienna (January 2020–June 2024); 42% received a reduced dose (1.9 mg/kg) throughout all treatment cycles. The primary objective was to assess adverse events, particularly keratopathy, and the impact of dose modifications on toxicity and efficacy. Results: The overall response rate was 64%, with responders having significantly fewer prior therapy lines (median 3 vs. 4.5, p = 0.015). Median PFS was 7.3 months, significantly longer in responders (11.1 vs. 1.6 months, p < 0.0001); median OS was 20.1 months, also longer in responders (not reached vs. 18 months, p = 0.031). Keratopathy occurred in 75% of patients; 33% experienced grade 3–4 events. Dose reduction significantly decreased grade 3–4 keratopathy (7% vs. 52%, p = 0.004) and thrombocytopenia (33% vs. 67%, p = 0.048) without compromising efficacy. Conclusions: Belamaf dose reductions improved tolerability without loss of efficacy, supporting reduced dosing in practice. Full article

(This article belongs to the Special Issue Advances in the Treatment of Relapsed and Refractory Multiple Myeloma: Novel Agents, Immunotherapies and Beyond: 2nd Edition)

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16 pages, 691 KB

Open AccessReview

Engineering Innate Immunity: Recent Advances and Future Directions for CAR-NK and CAR–Macrophage Therapies in Solid Tumors

by Behzad Amoozgar, Ayrton Bangolo, Charlene Mansour, Daniel Elias, Abdifitah Mohamed, Danielle C. Thor, Syed Usman Ehsanullah, Hadrian Hoang-Vu Tran, Izage Kianifar Aguilar and Simcha Weissman

Cancers 2025, 17(14), 2397; https://doi.org/10.3390/cancers17142397 - 19 Jul 2025

Cited by 1 | Viewed by 1091

Abstract

Adoptive cell therapies have transformed the treatment landscape for hematologic malignancies. Yet, translation to solid tumors remains constrained by antigen heterogeneity, an immunosuppressive tumor microenvironment (TME), and poor persistence of conventional CAR-T cells. In response, innate immune cell platforms, particularly chimeric antigen receptor–engineered [...] Read more.

Adoptive cell therapies have transformed the treatment landscape for hematologic malignancies. Yet, translation to solid tumors remains constrained by antigen heterogeneity, an immunosuppressive tumor microenvironment (TME), and poor persistence of conventional CAR-T cells. In response, innate immune cell platforms, particularly chimeric antigen receptor–engineered natural killer (CAR-NK) cells and chimeric antigen receptor–macrophages (CAR-MΦ), have emerged as promising alternatives. This review summarizes recent advances in the design and application of CAR-NK and CAR-MΦ therapies for solid tumors. We highlight key innovations, including the use of lineage-specific intracellular signaling domains (e.g., DAP12, 2B4, FcRγ), novel effector constructs (e.g., NKG7-overexpressing CARs, TME-responsive CARs), and scalable induced pluripotent stem cell (iPSC)-derived platforms. Preclinical data support enhanced antitumor activity through mechanisms such as major histocompatibility complex (MHC)-unrestricted cytotoxicity, phagocytosis, trogocytosis, cytokine secretion, and cross-talk with adaptive immunity. Early-phase clinical studies (e.g., CT-0508) demonstrate feasibility and TME remodeling with CAR-MΦ. However, persistent challenges remain, including transient in vivo survival, manufacturing complexity, and risks of off-target inflammation. Emerging combinatorial strategies, such as dual-effector regimens (CAR-NK⁺ CAR-MΦ), cytokine-modulated cross-support, and bispecific or logic-gated CARs, may overcome these barriers and provide more durable, tumor-selective responses. Taken together, CAR-NK and CAR-MΦ platforms are poised to expand the reach of engineered cell therapy into the solid tumor domain. Full article

(This article belongs to the Special Issue Cell Therapy in Solid Cancers: Current and Future Landscape)

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13 pages, 1056 KB

Open AccessArticle

Diagnostic Accuracy and Interrater Agreement of FDG-PET/CT Lymph Node Staging in High-Risk Endometrial Cancer: The SENTIREC-Endo Study

by Jorun Holm, André Henrique Dias, Oke Gerke, Annika Loft, Kirsten Bouchelouche, Mie Holm Vilstrup, Sarah Marie Bjørnholt, Sara Elisabeth Sponholtz, Kirsten Marie Jochumsen, Malene Grubbe Hildebrandt and Pernille Tine Jensen

Cancers 2025, 17(14), 2396; https://doi.org/10.3390/cancers17142396 - 19 Jul 2025

Viewed by 518

Abstract

Background/Objectives: The SENTIREC-endo study identified a safe sentinel lymph node mapping algorithm combined with PET-positive node dissection, matching radical pelvic and paraaortic lymphadenectomy in high-risk endometrial cancer. The present study evaluated the diagnostic accuracy of FDG-PET/CT for lymph node metastases in the same [...] Read more.

Background/Objectives: The SENTIREC-endo study identified a safe sentinel lymph node mapping algorithm combined with PET-positive node dissection, matching radical pelvic and paraaortic lymphadenectomy in high-risk endometrial cancer. The present study evaluated the diagnostic accuracy of FDG-PET/CT for lymph node metastases in the same population based on location, size, and Standardised Uptake Value (SUV), in addition to assessing interrater agreement across three Danish centres. Methods: This prospective multicentre study included women with high-risk endometrial cancer from the Danish SENTIREC study database (2017–2023). All patients underwent preoperative FDG-PET/CT. Diagnostic accuracy was evaluated against a pathology-confirmed reference standard. Interrater agreement was evaluated between trained specialists in Nuclear Medicine. Results: Among 227 patients, 52 patients (23%) had lymph node metastases. FDG-PET/CT identified lymph node metastases with 56% sensitivity (95% CI: 42–68) and 91% specificity (95% CI: 86–94). Positive and negative predictive values were 64% and 87%, respectively. Specificity for paraaortic nodes was high (97%), though sensitivity remained limited (56%). Lymph node size and SUVmax had moderate diagnostic value (AUC-ROC ~0.7). Interrater proportion of agreement was 95% and Cohen’s Kappa κ = 0.84 (95% CI: 0.73–0.94), the latter of which was ‘almost perfect’. Conclusions: FDG-PET/CT had limited sensitivity in lymph node staging in high-risk EC, and the diagnostic accuracy of FDG-PET/CT remains complementary to the sentinel node procedure. Due to its high specificity and strong interrater reliability, FDG-PET/CT is recommended for clinical implementation in combination with the sensitive sentinel node biopsy for the targeted dissection of PET-positive lymph nodes, particularly in paraaortic regions. Full article

(This article belongs to the Special Issue Lymph Node Dissection for Gynecologic Cancers)

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25 pages, 3050 KB

Open AccessReview

REG3A: A Multifunctional Antioxidant Lectin at the Crossroads of Microbiota Regulation, Inflammation, and Cancer

by Jamila Faivre, Hala Shalhoub, Tung Son Nguyen, Haishen Xie and Nicolas Moniaux

Cancers 2025, 17(14), 2395; https://doi.org/10.3390/cancers17142395 - 19 Jul 2025

Viewed by 766

Abstract

REG3A, a prominent member of the human regenerating islet-derived (REG) lectin family, plays a pivotal and multifaceted role in immune defense, inflammation, and cancer biology. Primarily expressed in gastrointestinal epithelial cells, REG3A reinforces barrier integrity, orchestrates mucosal immune responses, and regulates host–microbiota interactions. [...] Read more.

REG3A, a prominent member of the human regenerating islet-derived (REG) lectin family, plays a pivotal and multifaceted role in immune defense, inflammation, and cancer biology. Primarily expressed in gastrointestinal epithelial cells, REG3A reinforces barrier integrity, orchestrates mucosal immune responses, and regulates host–microbiota interactions. It also functions as a potent non-enzymatic antioxidant, protecting tissues from oxidative stress. REG3A expression is tightly regulated by inflammatory stimuli and is robustly induced during immune activation, where it limits microbial invasion, dampens tissue injury, and promotes epithelial repair. Beyond its antimicrobial and immunomodulatory properties, REG3A contributes to the resolution of inflammation and the maintenance of tissue homeostasis. However, its role in cancer is highly context-dependent. In some tumor types, REG3A fosters malignant progression by enhancing cell survival, proliferation, and invasiveness. In others, it acts as a tumor suppressor, inhibiting growth and metastatic potential. These opposing effects are likely dictated by a combination of factors, including the tissue of origin, the composition and dynamics of the tumor microenvironment, and the stage of disease progression. Additionally, the secreted nature of REG3A implies both local and systemic effects, further modulated by organ-specific physiology. Experimental variability may also reflect differences in methodologies, analytical tools, and model systems used. This review synthesizes current knowledge on the pleiotropic functions of REG3A, emphasizing its roles in epithelial defense, immune regulation, redox homeostasis, and oncogenesis. A deeper understanding of REG3A’s pleiotropic effects could open up new therapeutic avenues in both inflammatory disorders and cancer. Full article

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

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11 pages, 250 KB

Open AccessArticle

Adherence to General Medical Screenings, Cancer-Specific Screenings, and Management of Chronic Diseases in Cancer Survivors: Focus on Five-Year Survivors

by EunKyo Kang, HyeWon Lee, Juyoung Choi and HyoRim Ju

Cancers 2025, 17(14), 2394; https://doi.org/10.3390/cancers17142394 - 19 Jul 2025

Viewed by 419

Abstract

Background: Cancer survivors may continue to experience health issues that affect their quality of life and raise the risk of other chronic diseases. Methods: This study aimed to assess adherence to general health check-ups, cancer-specific screenings, and chronic disease management among five-year cancer [...] Read more.

Background: Cancer survivors may continue to experience health issues that affect their quality of life and raise the risk of other chronic diseases. Methods: This study aimed to assess adherence to general health check-ups, cancer-specific screenings, and chronic disease management among five-year cancer survivors using nationally representative data from the Korea National Health and Nutrition Examination Survey (KNHANES) conducted between 2013 and 2021. A total of 2597 cancer survivors and 2458 matched non-cancer controls were selected via 1:1 propensity score matching based on demographic and lifestyle characteristics. We analyzed health behaviors (smoking and alcohol use), participation in general and cancer-specific screenings, and medication adherence for hypertension, diabetes, and dyslipidemia. Results: Compared to controls, cancer survivors, especially those diagnosed more than five years ago, were significantly less likely to participate in recommended cancer screenings (adjusted OR: 0.82, p = 0.014) and had lower adherence to treatment for hypertension (adjusted OR: 1.84, p = 0.004) and dyslipidemia (adjusted OR: 1.42, p = 0.026). However, cancer survivors were less likely to smoke or consume alcohol. Conclusions: These findings underscore the need for comprehensive survivorship care policies that integrate both cancer surveillance and chronic disease management. Full article

(This article belongs to the Special Issue Feature Papers in Section “Cancer Survivorship and Quality of Life” in 2024–2025)

23 pages, 949 KB

Open AccessArticle

Anticancer Effect of Nature-Inspired Indolizine-Based Pentathiepines in 2D and 3D Cellular Model

by Roberto Tallarita, Federica Randisi, Lukas Manuel Jacobsen, Emanuela Marras, Mattia Riva, Giulia Modoni, Johannes Fimmen, Siva Sankar Murthy Bandaru, Carola Schulzke and Marzia Bruna Gariboldi

Cancers 2025, 17(14), 2393; https://doi.org/10.3390/cancers17142393 - 19 Jul 2025

Viewed by 597

Abstract

Background: 1,2,3,4,5-pentathiepines (PTEs) are compounds originally identified in marine ascidians and are currently under investigation for their promising pharmacological properties, particularly as potential antineoplastic agents. Objectives: In this study, we investigated the antineoplastic properties of a series of ten indolizine-based PTEs, comprising eight [...] Read more.

Background: 1,2,3,4,5-pentathiepines (PTEs) are compounds originally identified in marine ascidians and are currently under investigation for their promising pharmacological properties, particularly as potential antineoplastic agents. Objectives: In this study, we investigated the antineoplastic properties of a series of ten indolizine-based PTEs, comprising eight previously reported compounds and two newly synthesized derivatives. Methods: These compounds were evaluated against a panel of human cancer cell lines of diverse tissue origins, as well as, for the first time, on non-cancerous CR9 fibroblasts to assess their cytotoxic selectivity. In addition, their effects were tested on 3D spheroid models, providing preliminary insights into their potential in vivo efficacy. Initial screening focused on cell viability, followed by a more detailed characterization of the most active compounds in terms of their ability to induce apoptosis, necrosis, cell cycle arrest, and reactive oxygen species (ROS) generation. The anti-migratory activity of PTEs and a newly adapted assay to confirm sulfur species release in the cells were also performed for the first time. Results and Conclusions: Our findings reveal that four PTEs bearing hydrophilic, hydrogen-bonding functional groups, particularly the two inspired by natural analogs, exhibited the most potent anticancer activity. Full article

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

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16 pages, 2015 KB

Open AccessSystematic Review

Immunotherapy and Advanced Vulvar Cancer: A Systematic Review and Meta-Analysis of Survival and Safety Outcomes

by Mauro Francesco Pio Maiorano, Vera Loizzi, Gennaro Cormio and Brigida Anna Maiorano

Cancers 2025, 17(14), 2392; https://doi.org/10.3390/cancers17142392 - 19 Jul 2025

Viewed by 806

Abstract

Background: Advanced and recurrent vulvar squamous cell carcinoma (VSCC) presents a major therapeutic challenge with limited treatment options and poor outcomes. Immune checkpoint inhibitors (ICIs) have shown efficacy in other HPV-associated malignancies, but their role in VSCC remains poorly defined due to [...] Read more.

Background: Advanced and recurrent vulvar squamous cell carcinoma (VSCC) presents a major therapeutic challenge with limited treatment options and poor outcomes. Immune checkpoint inhibitors (ICIs) have shown efficacy in other HPV-associated malignancies, but their role in VSCC remains poorly defined due to the rarity of the disease and limited clinical trial data. Methods: We conducted a systematic review and meta-analysis following PRISMA guidelines and registered in PROSPERO (CRD420251067565). A comprehensive literature search identified prospective clinical trials evaluating ICIs in patients with advanced, unresectable, recurrent, or metastatic VSCC. The primary outcomes included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Risk of bias was assessed using the MINORS tool. Meta-analyses were performed using random-effects models, with subgroup analyses based on PD-L1 status and treatment regimens (monotherapy vs. combination therapy). Results: Six non-randomized single-arm trials involving 181 patients were included. The pooled ORR was 21%, with higher response rates observed in combination therapy (46%) compared to monotherapy (11%), though not statistically significant. Median PFS and OS were 2.2 months and 6.4 months, respectively. ORRs were similar between PD-L1-positive and PD-L1-negative subgroups. A safety analysis showed treatment-related adverse events (AEs) in 73% of patients and grade ≥ 3 AEs in 23%. The incidence of treatment-related death was 3%. Conclusions: ICIs demonstrate modest but durable efficacy and an acceptable safety profile in advanced VSCC. The current evidence supports their use in selected patients. However, response variability and the lack of reliable predictive biomarkers, such as PD-L1 or HPV status, underscore the need for biomarker-driven clinical trials and improved patient selection strategies. Full article

(This article belongs to the Topic New Advancements in Innate Immunity and Cancer Immunotherapy)

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24 pages, 850 KB

Open AccessReview

Platelets in Hepatocellular Carcinoma—From Pathogenesis to Targeted Therapy

by Natalia Kluz, Hanna Grabowska, Paulina Chmiel, Kornelia Rynkiewicz, Alicja Skrobucha, Ewa Wysokińska, Łukasz Szymański, Piotr Tomasz Wysocki, Aleksandra Semeniuk-Wojtaś and Leszek Kraj

Cancers 2025, 17(14), 2391; https://doi.org/10.3390/cancers17142391 - 18 Jul 2025

Viewed by 625

Abstract

Hepatocellular carcinoma (HCC) is a malignancy with a complex pathogenesis, course, and prognosis with increasing incidence. The most significant contributing factor to the development of HCC is the chronic process of inflammation and remodeling of the cirrhotic liver, in which the interaction between [...] Read more.

Hepatocellular carcinoma (HCC) is a malignancy with a complex pathogenesis, course, and prognosis with increasing incidence. The most significant contributing factor to the development of HCC is the chronic process of inflammation and remodeling of the cirrhotic liver, in which the interaction between the tumor microenvironment (TME) and cancer cells plays a pivotal role. In recent years, increasing focus has been directed toward the role of platelets (PLTs) in mediating interactions between tumor cells and the TME and in the progression and spread of HCC, as well as other cancers. Due to their abundance in the bloodstream and intracellular granules rich in mediators facilitating their ability to modulate the immune system, PLTs play a significant role in carcinogenesis. In the context of HCC, the role of PLTs in the healing and regeneration processes of the liver has been recognized for some time. In recent years, there has been an increasing utilization of PLTs in prognostic models for patients with HCC. Given their role and the availability of clinical options that block PLTs’ action, clinical trials of platelet blockers in the adjunctive treatment of HCC are becoming increasingly common. However, further research, both preclinical and clinical, is necessary to fully elucidate the role of PLTs in HCC and their potential use as a therapeutic target. In this literature review, we summarize the current knowledge on PLTs in HCC and focus on their potential use in everyday clinical practice. Full article

(This article belongs to the Special Issue Treatment Response Biomarkers in Hepatocellular Carcinoma: From Basic Science to Clinical Validation)

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19 pages, 1536 KB

Open AccessArticle

Enhancing Hepatocellular Carcinoma Surveillance: Comparative Evaluation of AFP, AFP-L3, DCP and Composite Models in a Biobank-Based Case-Control Study

by Coskun O. Demirtas, Sehnaz Akin, Demet Yilmaz Karadag, Tuba Yilmaz, Ugur Ciftci, Javid Huseynov, Tugba Tolu Bulte, Yasemin Armutcuoglu Kaldirim, Feyza Dilber, Osman Cavit Ozdogan and Fatih Eren

Cancers 2025, 17(14), 2390; https://doi.org/10.3390/cancers17142390 - 18 Jul 2025

Viewed by 525

Abstract

Background/Objectives: Biomarkers such as lens agglutinin-reactive alpha-fetoprotein and des-gamma-carboxy prothrombin, as well as biomarker- and/or clinical-parameter-derived composite models (GALAD, GAAP, ASAP, aMAP, Doylestown), may improve detection in addition to alpha-fetoprotein, yet comparative data across diverse populations remain limited. Methods: In this [...] Read more.

Background/Objectives: Biomarkers such as lens agglutinin-reactive alpha-fetoprotein and des-gamma-carboxy prothrombin, as well as biomarker- and/or clinical-parameter-derived composite models (GALAD, GAAP, ASAP, aMAP, Doylestown), may improve detection in addition to alpha-fetoprotein, yet comparative data across diverse populations remain limited. Methods: In this biobank-based case–control study, we evaluated 562 adults (120 healthy controls, 277 chronic liver disease, 165 hepatocellular carcinoma) from January 2019 to 2024. Diagnostic performance for any-stage and early-stage hepatocellular carcinoma was assessed across three thresholds: Youden-index-derived optimal cut-offs, research-established cut-offs, and cut-offs ensuring 90% specificity. Receiver operating characteristic analysis was performed. Subgroup analyses were stratified by etiology and alpha-fetoprotein status. Results: At optimal cut-offs, GALAD showed the highest sensitivity for any-stage (90.3%) and early-stage (89.1%) hepatocellular carcinoma, with 70–80% specificity. Using established cut-offs, GALAD retained the highest sensitivity for any-stage (75.8%) and early-stage (57.8%) hepatocellular carcinoma, with 93.5% specificity. GALAD demonstrated the best performance in non-viral hepatocellular carcinomas (area under the curve 0.872), whereas GAAP and ASAP showed similarly high area under the curve values in viral etiology (area under the curve 0.955–0.960). Conclusions: Our results demonstrate the consistent performance of the GALAD score across diverse populations and underscore its superiority over individual biomarkers and other composite models. Notably, the GAAP and ASAP scores—which use one less biomarker (AFP-L3)—exhibited comparable performance, particularly in viral etiology. These findings support the integration of the composite biomarker models into tailored hepatocellular carcinoma surveillance strategies. Full article

(This article belongs to the Special Issue Recent Advances in Hepatobiliary Cancers: From Diagnosis to Treatment (2nd Edition))

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14 pages, 830 KB

Open AccessArticle

Metastatic Patterns of Apical Lymph Node and Prognostic Analysis in Rectal and Sigmoid Colon Cancer—A Multicenter Retrospective Cohort Study of 2809 Cases

by Mingguang Zhang, Fuqiang Zhao, Aiwen Wu, Xiaohui Du, Lei Zhou, Shiwen Mei, Fangze Wei, Shidong Hu, Xinzhi Liu, Hua Yang, Lai Xu, Yi Xiao, Xishan Wang, Qian Liu and on behalf of the Chinese Apical Lymph Node Study Consortium

Cancers 2025, 17(14), 2389; https://doi.org/10.3390/cancers17142389 - 18 Jul 2025

Viewed by 516

Abstract

Background/Objectives: The metastatic patterns of apical lymph node (ALN) in rectal and sigmoid colon cancer are currently unclear, and there is no consensus on the indications for dissection of ALN. This study aimed to analyze the impact of ALN metastasis on prognosis, [...] Read more.

Background/Objectives: The metastatic patterns of apical lymph node (ALN) in rectal and sigmoid colon cancer are currently unclear, and there is no consensus on the indications for dissection of ALN. This study aimed to analyze the impact of ALN metastasis on prognosis, determine the metastatic patterns of ALN and provide evidence for indications of ALN dissection in rectal and sigmoid colon cancer. Methods: In this multicenter, retrospective cohort study, patients from five centers with stage I-III rectal or sigmoid colon cancer who underwent laparoscopic radical surgery with ALN dissection without neoadjuvant treatment from January 2015 to December 2019 were enrolled. Results: Among 2809 patients, the positive rate of ALN was 1.9%. The 5-year overall survival and cancer-specific survival rate for patients with metastatic ALN were 37.5% and 41.0%, respectively. ALN metastasis was the independent risk factor for poor prognosis. Tumor size ≥5 cm (OR = 2.32, 95% CI: 1.30–4.13, p = 0.004), signet ring cell cancer/mucinous adenocarcinoma (vs. poor differentiated adenocarcinoma, OR = 0.19, 95% CI: 0.08–0.45, p < 0.001; vs. moderate to well differentiated adenocarcinoma, OR = 0.22, 95% CI: 0.11–0.42, p < 0.001), T4 stage (OR = 1.93, 95% CI: 1.05–3.55, p = 0.034), N2 stage (OR = 8.86, 95% CI: 4.45–17.65, p < 0.001) and radiologic evidence of extramural venous invasion (OR = 1.88, 95% CI: 1.03–3.42, p = 0.040) were independent risk factors for ALN metastasis. The nomogram model developed by these factors achieved a good predictive performance. Conclusions: This research offered insights into the incidence, risk factors, and prognostic significance of apical lymph node metastasis in cases of rectal and sigmoid colon cancer. Additionally, the study furnished empirical support for the criteria guiding ALN dissection. Furthermore, a pragmatic risk assessment model was developed to predict ALN metastasis. Full article

(This article belongs to the Section Cancer Metastasis)

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19 pages, 577 KB

Open AccessReview

Co-Occurring Genomic Alterations in NSCLC: Making Order into a Crowded List

by Ilaria Attili, Federico Pio Fabrizio and Filippo de Marinis

Cancers 2025, 17(14), 2388; https://doi.org/10.3390/cancers17142388 - 18 Jul 2025

Viewed by 872

Abstract

Worldwide, lung cancer is one of the most common cancers, with non-small cell lung cancer (NSCLC) including up to 80–85% of all lung cancer diagnoses. The landscape of NSCLC is characterized by a heterogeneous spectrum of gene alterations, with tyrosine kinase inhibitors (TKIs) [...] Read more.

Worldwide, lung cancer is one of the most common cancers, with non-small cell lung cancer (NSCLC) including up to 80–85% of all lung cancer diagnoses. The landscape of NSCLC is characterized by a heterogeneous spectrum of gene alterations, with tyrosine kinase inhibitors (TKIs) and targeted treatments that significantly improve survival outcomes for patients with oncogene-addicted NSCLC, offering superior efficacy, and often favorable safety and tolerability profiles compared to chemotherapy-based treatments. However, the complexity of NSCLC extends to co-occurring genomic alterations or amplifications in tumor suppressors and other oncogenes, such as TP53, STK11, KEAP1, PIK3CA, RB1, and others, that significantly influence disease progression, therapeutic resistance, and clinical outcomes. These co-mutations often contribute to the development of primary and acquired resistance to targeted therapies, complicating decision-making strategies. This review provides a timely and comprehensive synthesis of current insights into co-mutations in NSCLC, with a particular focus on their clinical implications, and offers a novel perspective by integrating recent molecular insights with therapeutic challenges, addressing existing knowledge gaps through a more integrative and clinically oriented analysis of co-mutations. Advances in next-generation sequencing (NGS) and molecular profiling have enabled the identification of these co-alterations, paving the way for more personalized therapeutic approaches. However, challenges remain in interpreting the functional interplay of co-mutations and translating these insights into effective clinical interventions. This review also highlights the significance of co-mutations in shaping NSCLC biology, and discusses their impact on current therapeutic paradigms, emphasizing the need for integrative biomarker-driven approaches to improve outcomes in NSCLC. Full article

(This article belongs to the Special Issue Current Status and Clinical Developments in Lung Cancer: What to Expect from Emerging Drugs? (2nd Edition))

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9 pages, 258 KB

Open AccessEditorial

Acute Myeloid Leukemia: Updates on Diagnosis, Treatment and Management

by Francesco Lanza, Michela Rondoni and Giovanni Marconi

Cancers 2025, 17(14), 2387; https://doi.org/10.3390/cancers17142387 - 18 Jul 2025

Viewed by 651

Abstract

This Special Issue of Cancers, entitled “Acute Myeloid Leukemia (AML): Updates on Diagnosis, Treatment and Management”, will be a forum for stimulating discussions and thought-provoking debates, featuring cutting-edge scientific manuscripts on the most relevant topics related to the diagnosis and therapeutic advances [...] Read more.

This Special Issue of Cancers, entitled “Acute Myeloid Leukemia (AML): Updates on Diagnosis, Treatment and Management”, will be a forum for stimulating discussions and thought-provoking debates, featuring cutting-edge scientific manuscripts on the most relevant topics related to the diagnosis and therapeutic advances for the management of AML [...] Full article

(This article belongs to the Special Issue Acute Myeloid Leukemia: Updates on Diagnosis, Treatment and Management)

15 pages, 2610 KB

Open AccessArticle

CT-Based Radiomics for a priori Predicting Response to Chemoradiation in Locally Advanced Lung Adenocarcinoma

by Erika Z. Chung, Laurentius O. Osapoetra, Patrick Cheung, Ian Poon, Alexander V. Louie, May Tsao, Yee Ung, Mateus T. Cunha, Ines B. Menjak and Gregory J. Czarnota

Cancers 2025, 17(14), 2386; https://doi.org/10.3390/cancers17142386 - 18 Jul 2025

Viewed by 447

Abstract

The standard treatment for patients with locally advanced non-small cell lung cancer (NSCLC) is concurrent chemoradiation. However, clinical responses are heterogeneous and generally not known until after the completion of therapy. Multiple studies have investigated imaging predictors (radiomics) for different cancer histologies, but [...] Read more.

The standard treatment for patients with locally advanced non-small cell lung cancer (NSCLC) is concurrent chemoradiation. However, clinical responses are heterogeneous and generally not known until after the completion of therapy. Multiple studies have investigated imaging predictors (radiomics) for different cancer histologies, but little exists for NSCLC. The objective of this study was to develop a multivariate CT-based radiomics model to a priori predict responses to definitive chemoradiation in patients with lung adenocarcinoma. Methods: Patients diagnosed with locally advanced unresectable lung adenocarcinoma who had undergone chemoradiotherapy followed by at least one dose of maintenance durvalumab were included. The PyRadiomics Python library was used to determine statistical, morphological, and textural features from normalized patient pre-treatment CT images and their wavelet-filtered versions. A nested leave-one-out cross-validation was used for model building and evaluation. Results: Fifty-seven patients formed the study cohort. The clinical stage was IIIA-C in 98% of patients. All but one received 6000–6600 cGy of radiation in 30–33 fractions. All received concurrent platinum-based chemotherapy. Based on RECIST 1.1, 20 (35%) patients were classified as responders (R) to chemoradiation and 37 (65%) patients as non-responders (NR). A three-feature model based on a KNN k = 1 machine learning classifier was found to have the best performance, achieving a recall, specificity, accuracy, balanced accuracy, precision, negative predictive value, F1-score, and area under the curve of 84%, 70%, 80%, 77%, 84%, 70%, 84%, and 0.77, respectively. Conclusions: Our results suggest that a CT-based radiomics model may be able to predict chemoradiation response for lung adenocarcinoma patients with estimated accuracies of 77–84%. Full article

(This article belongs to the Section Cancer Therapy)

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20 pages, 12298 KB

Open AccessArticle

Impact of Metastatic Microenvironment on Physiology and Metabolism of Small Cell Neuroendocrine Prostate Cancer Patient-Derived Xenografts

by Shubhangi Agarwal, Deepti Upadhyay, Jinny Sun, Emilie Decavel-Bueff, Robert A. Bok, Romelyn Delos Santos, Said Al Muzhahimi, Rosalie Nolley, Jason Crane, John Kurhanewicz, Donna M. Peehl and Renuka Sriram

Cancers 2025, 17(14), 2385; https://doi.org/10.3390/cancers17142385 - 18 Jul 2025

Viewed by 572

Abstract

Background: Potent androgen receptor pathway inhibitors induce small cell neuroendocrine prostate cancer (SCNC), a highly aggressive subtype of metastatic androgen deprivation-resistant prostate cancer (ARPC) with limited treatment options and poor survival rates. Patients with metastases in the liver have a poor prognosis relative [...] Read more.

Background: Potent androgen receptor pathway inhibitors induce small cell neuroendocrine prostate cancer (SCNC), a highly aggressive subtype of metastatic androgen deprivation-resistant prostate cancer (ARPC) with limited treatment options and poor survival rates. Patients with metastases in the liver have a poor prognosis relative to those with bone metastases alone. The mechanisms that underlie the different behavior of ARPC in bone vs. liver may involve factors intrinsic to the tumor cell, tumor microenvironment, and/or systemic factors, and identifying these factors is critical to improved diagnosis and treatment of SCNC. Metabolic reprogramming is a fundamental strategy of tumor cells to colonize and proliferate in microenvironments distinct from the primary site. Understanding the metabolic plasticity of cancer cells may reveal novel approaches to imaging and treating metastases more effectively. Methods: Using magnetic resonance (MR) imaging and spectroscopy, we interrogated the physiological and metabolic characteristics of SCNC patient-derived xenografts (PDXs) propagated in the bone and liver, and used correlative biochemical, immunohistochemical, and transcriptomic measures to understand the biological underpinnings of the observed imaging metrics. Results: We found that the influence of the microenvironment on physiologic measures using MRI was variable among PDXs. However, the MR measure of glycolytic capacity in the liver using hyperpolarized ¹³C pyruvic acid recapitulated the enzyme activity (lactate dehydrogenase), cofactor (nicotinamide adenine dinucleotide), and stable isotope measures of fractional enrichment of lactate. While in the bone, the congruence of the glycolytic components was lost and potentially weighted by the interaction of cancer cells with osteoclasts/osteoblasts. Conclusion: While there was little impact of microenvironmental factors on metabolism, the physiological measures (cellularity and perfusion) are highly variable and necessitate the use of combined hyperpolarized ¹³C MRI and multiparametric (anatomic, diffusion-, and perfusion- weighted) ¹H MRI to better characterize pre-treatment tumor characteristics, which will be crucial to evaluate treatment response. Full article

(This article belongs to the Special Issue Magnetic Resonance in Cancer Research)

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14 pages, 1865 KB

Open AccessArticle

Plasma WFDC2 (HE4) as a Predictive Biomarker for Clinical Outcomes in Cancer Patients Receiving Anti-PD-1 Therapy: A Pilot Study

by Makoto Watanabe, Katsuaki Ieguchi, Takashi Shimizu, Ryotaro Ohkuma, Risako Suzuki, Emiko Mura, Nana Iriguchi, Tomoyuki Ishiguro, Yuya Hirasawa, Go Ikeda, Masahiro Shimokawa, Hirotsugu Ariizumi, Kiyoshi Yoshimura, Atsushi Horiike, Takuya Tsunoda, Mayumi Tsuji, Shinichi Kobayashi, Tatsunori Oguchi, Yuji Kiuchi and Satoshi Wada

Cancers 2025, 17(14), 2384; https://doi.org/10.3390/cancers17142384 - 18 Jul 2025

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Abstract

Background/Objectives: Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy; however, reliable biomarkers of therapeutic efficacy remain limited. We investigated the clinical utility of plasma WFDC2 levels in patients receiving anti-PD-1 antibody treatment. Methods: Twenty-one patients with non-small cell lung, gastric, or [...] Read more.

Background/Objectives: Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy; however, reliable biomarkers of therapeutic efficacy remain limited. We investigated the clinical utility of plasma WFDC2 levels in patients receiving anti-PD-1 antibody treatment. Methods: Twenty-one patients with non-small cell lung, gastric, or bladder cancer received nivolumab or pembrolizumab. Plasma WFDC2 concentrations were measured by ELISA before ICI treatment (pre-ICI) and after two and four treatment cycles. Associations between WFDC2 expression changes and overall survival (OS), progression-free survival (PFS), and tumor progression were assessed. ROC curve analyses compared the predictive performance of WFDC2, soluble PD-L1 (sPD-L1), soluble PD-1 (sPD-1), and their combinations, with the area under the curve (AUC) evaluating predictive accuracy. Results: Levels of WFDC2 pre-ICI and those after two cycles were significantly higher than levels in healthy donors. However, no significant differences in WFDC2 levels were found between the time points during treatment. Greater increases in WFDC2 levels were significantly correlated with shorter OS (p = 0.002), shorter PFS (p = 0.037), and tumor progression (p = 0.003). ROC analysis revealed that WFDC2 achieved a higher AUC (0.700) than sPD-L1 (0.538) or sPD-1 (0.650). Combining biomarkers improved the predictive accuracy, with sPD-L1 plus WFDC2 showing the highest AUC (0.825). Conclusions: Serial increases in plasma WFDC2 are associated with poor clinical outcomes, highlighting its potential as a biomarker. Baseline plasma WFDC2 outperformed sPD-L1 and sPD-1 diagnostically. These findings should be interpreted as exploratory and hypothesis-generating, requiring confirmation in larger, tumor-specific cohorts with multivariate adjustment. WFDC2 represents a promising minimally invasive biomarker for the early identification of patients unlikely to benefit from ICI therapy. Full article

(This article belongs to the Special Issue Cancer Immunotherapy: Focus on Immune Checkpoint Inhibitors and Immune Modulators)

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Open AccessArticle

Radiotherapy Upregulates the Expression of Membrane-Bound Negative Complement Regulator Proteins on Tumor Cells and Limits Complement-Mediated Tumor Cell Lysis

by Yingying Liang, Lixin Mai, Jonathan M. Schneeweiss, Ramon Lopez Perez, Michael Kirschfink and Peter E. Huber

Cancers 2025, 17(14), 2383; https://doi.org/10.3390/cancers17142383 - 18 Jul 2025

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Abstract

Background/Objectives: Radiotherapy (RT) is a mainstay of clinical cancer therapy that causes broad immune responses. The complement system is a pivotal effector mechanism in the innate immune response, but the impact of RT is less well understood. This study investigates the interaction [...] Read more.

Background/Objectives: Radiotherapy (RT) is a mainstay of clinical cancer therapy that causes broad immune responses. The complement system is a pivotal effector mechanism in the innate immune response, but the impact of RT is less well understood. This study investigates the interaction between RT and the complement system as a possible approach to improve immune responses in cancer treatment. Methods: Human solid cancer (lung, prostate, liver, breast cancer), lymphoma, and leukemia cells were irradiated using X-rays and treated with polyclonal antibodies or anti-CD20 monoclonal antibodies, respectively. Chromium release assay was applied to measure cell lysis after radiation with or without complement-activating antibody treatment. The expression of membrane-bound complement regulatory proteins (mCRPs; CD46, CD55, CD59), which confer resistance against complement activation, CD20 expression, apoptosis, and radiation-induced DNA double-strand breaks (γH2AX), was measured by flow cytometry. The radiosensitivity of tumor cells was assessed by colony-forming assay. Results: We demonstrate that RT profoundly impacts complement function by upregulating the expression of membrane-bound complement regulatory proteins (mCRPs) on tumor cells in a dose- and time-dependent manner. Impaired complement-mediated tumor cell lysis could thus potentially contribute to radiotherapeutic resistance. We also observed RT-induced upregulation of CD20 expression on lymphoma and leukemic cells. Notably, complement activation prior to RT proved more effective in inducing RT-dependent early apoptosis compared to post-irradiation treatment. While complement modulation does not significantly alter RT-induced DNA-damage repair mechanisms or intrinsic radiosensitivity in cancer cells, our results suggest that combining RT with complement-based anti-cancer therapy may enhance complement-dependent cytotoxicity (CDC) and apoptosis in tumor cells. Conclusions: This study sheds light on the complex interplay between RT and the complement system, offering insights into potential novel combinatorial therapeutic strategies and a potential sequential structure for certain tumor types. Full article

(This article belongs to the Special Issue Combination Immunotherapy for Cancer Treatment)

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Cancers, Volume 17, Issue 14 (July-2 2025) – 145 articles

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