Cancers

25 pages, 2153 KiB

Open AccessSystematic Review

The Roles of Tripartite Motif Proteins in Urological Cancers: A Systematic Review

by Yuta Yamada, Naoki Kimura, Kazuki Maki, Yuji Hakozaki, Fumihiko Urabe, Shoji Kimura, Tetsuya Fujimura, Satoshi Inoue and Haruki Kume

Cancers 2025, 17(14), 2367; https://doi.org/10.3390/cancers17142367 (registering DOI) - 16 Jul 2025

Abstract

We aimed to investigate the roles of tripartite motif (TRIM) proteins in urological cancers. Methods: A systematic review was conducted to investigate the oncological role of tripartite motif proteins in urological cancers. Results: A total of 84 articles were identified for [...] Read more.

We aimed to investigate the roles of tripartite motif (TRIM) proteins in urological cancers. Methods: A systematic review was conducted to investigate the oncological role of tripartite motif proteins in urological cancers. Results: A total of 84 articles were identified for the final analysis (26 articles on kidney cancers, 19 on bladder cancers, 37 on prostate cancers, and 1 on testicular cancers). In total, 27 TRIM family proteins were involved in kidney cancer, of which 9 were associated with tumor-promoting findings (TRIM24, TRIM27, TRIM37, TRIM44, TRIM46, TRIM47, TRIM59, TRIM63, and TRIM65) and of which 9 TRIM proteins were tumor-suppressive (TRIM2, TRIM7, TRIM8, TRIM13, TRIM21, TRIM26, TRIM28, TRIM33, and TRIM58). Fourteen TRIM family proteins were associated with bladder cancer (tumor-promoting: TRIM9, TRIM25, TRIM26, TRIM28, TRIM29, TRIM59, TRIM65, and TRIM66; tumor-suppressive: TRIM19 and TRIM38). Ten TRIM family proteins were associated with prostate cancer (tumor-promoting: TRIM11, TRIM24, TRIM28, TRIM33, TRIM44, TRIM59, TRIM63, TRIM66, and TRIM68; tumor-suppressive: TRIM32 and TRIM36). Twenty-eight TRIM family proteins were identified to be associated with prostate cancer (tumor-promoting: TRIM11, TRIM24, TRIM28, TRIM33, TRIM44, TRIM59, TRIM63, TRIM66, and TRIM68; tumor-suppressive: TRIM32 and TRIM36). TRIM proteins regulate urological cancers by ubiquitination or modulation of oncologic pathways. Conclusions: This review identifies TRIM proteins that are involved in urological cancers. Some of these proteins have the potential to be the therapeutic target. Full article

(This article belongs to the Section Systematic Review or Meta-Analysis in Cancer Research)

► Show Figures

Graphical abstract

21 pages, 2238 KiB

Open AccessReview

Cell-Free DNA as a Prognostic Biomarker in Oral Carcinogenesis and Oral Squamous Cell Carcinoma: A Translational Perspective

by Pietro Rigotti, Alessandro Polizzi, Vincenzo Quinzi, Andrea Blasi, Teresa Lombardi, Eleonora Lo Muzio and Gaetano Isola

Cancers 2025, 17(14), 2366; https://doi.org/10.3390/cancers17142366 (registering DOI) - 16 Jul 2025

Abstract

Oral squamous cell carcinoma (OSCC) remains one of the most common malignancies in the head and neck region, often preceded by a spectrum of oral potentially malignant disorders (OPMDs). Despite advances in diagnostic methods, reliable and non-invasive biomarkers for early detection and prognostic [...] Read more.

Oral squamous cell carcinoma (OSCC) remains one of the most common malignancies in the head and neck region, often preceded by a spectrum of oral potentially malignant disorders (OPMDs). Despite advances in diagnostic methods, reliable and non-invasive biomarkers for early detection and prognostic stratification are still lacking. In recent years, circulating cell-free DNA (cfDNA) has emerged as a promising liquid biopsy tool in several solid tumors, offering insights into tumor burden, heterogeneity, and molecular dynamics. However, its application in oral oncology remains underexplored. This study aims to review and discuss the current evidence on cfDNA quantification and mutation analysis (including TP53, NOTCH1, and EGFR) in patients with OPMDs and OSCC. Particular attention is given to cfDNA fragmentation patterns, methylation signatures, and tumor-specific mutations as prognostic and predictive biomarkers. Moreover, we highlight the challenges in standardizing pre-analytical and analytical workflows in oral cancer patients and explore the potential role of cfDNA in monitoring oral carcinogenesis. Understanding cfDNA dynamics in the oral cavity might offer a novel, minimally invasive strategy to improve early diagnosis, risk assessment, and treatment decision-making in oral oncology. Full article

(This article belongs to the Special Issue Cell-Free DNA as Prognostic and Predictive Biomarker in Solid Cancers (2nd Edition))

► Show Figures

Figure 1

23 pages, 3053 KiB

Open AccessArticle

MICA+ Tumor Cells Modulate Macrophage Phenotype and Function via PPAR/EHHADH-Mediated Fatty Acid Metabolism in Hepatocellular Carcinoma (HCC)

by Jingquan Huang, Yumeng Teng, Peng Yan, Yan Yang, Shixun Lin, Qiulin Wu, Qiang Du, Xicai Li, Ming Yao, Jianjun Li, Yubin Huang, Xiaoyong Cai, David A. Geller and Yihe Yan

Cancers 2025, 17(14), 2365; https://doi.org/10.3390/cancers17142365 (registering DOI) - 16 Jul 2025

Abstract

Background: Tumor-associated macrophages (TAMs) play a crucial role in the tumor microenvironment (TME), and the metabolic activities of both tumor cells and TAMs have an impact on the TME. Moreover, the expression of MICA in tumor cells is closely associated with immune cells [...] Read more.

Background: Tumor-associated macrophages (TAMs) play a crucial role in the tumor microenvironment (TME), and the metabolic activities of both tumor cells and TAMs have an impact on the TME. Moreover, the expression of MICA in tumor cells is closely associated with immune cells in hepatocellular carcinoma (HCC). However, it remains unclear whether MICA expression correlates with TAMs and influences the switch in macrophage phenotype by mediating metabolic alterations. Methods: Various biostatistical tools, qPCR, and IHC staining experiments were utilized to analyze data from The Cancer Genome Atlas (TCGA) and collected HCC tumor tissues. Single-cell RNA sequencing (scRNA-seq) analyses and a co-culture model of HCC cells with macrophages were performed to validate the findings from the biostatistical analyses. Results: Through the intersection of differentially expressed genes (DEGs), metabolism-related genes (MRGs), and co-expression genes (CEGs) with MICA in HCC, the EHHADH gene was identified. Gene set enrichment analyses were conducted to further confirm the role of EHHADH. EHHADH expression is decreased in HCC tumors and can serve as a prognostic biomarker for HCC. Expressions of MICA and EHHADH exhibited significant correlations with various phenotypic macrophages and exerted opposing effects on M1-like and M2-like macrophages infiltrating HCC. The underlying metabolic and molecular mechanisms revealed that MICA in tumor cells induced M2-like polarization through the PPAR/EHHADH pathway, which regulates the fatty acid oxidation (FAO) in macrophages. Conclusions: The metabolic gene EHHADH, which is associated with MICA, led to alterations in M2-like macrophages by promoting heightened fatty acid uptake and augmenting levels of FAO within macrophages. Full article

(This article belongs to the Section Tumor Microenvironment)

► Show Figures

Figure 1

20 pages, 1063 KiB

Open AccessReview

ANGPTL4: A Comprehensive Review of 25 Years of Research

by Pedro Ramos, Qiongyu Shi, Jeremy Kleberg, Chandra K. Maharjan, Weizhou Zhang and Ryan Kolb

Cancers 2025, 17(14), 2364; https://doi.org/10.3390/cancers17142364 - 16 Jul 2025

Abstract

Angiopoietin-like 4 (ANGPTL4) is a secreted glycoprotein that was discovered in 2000 by three independent laboratories. In the ensuing two and a half decades, extensive work has been conducted to determine its physiological and pathological functions. ANGPTL4 has been shown to be involved [...] Read more.

Angiopoietin-like 4 (ANGPTL4) is a secreted glycoprotein that was discovered in 2000 by three independent laboratories. In the ensuing two and a half decades, extensive work has been conducted to determine its physiological and pathological functions. ANGPTL4 has been shown to be involved in many biological processes, including glucose and lipid metabolism, angiogenesis, and wound healing, with implications in diseases such as type 2 diabetes, cardiovascular (e.g., atherosclerosis) and renal diseases, and cancer. For instance, ANGPTL4 is upregulated in several cancers, including renal cell carcinoma, breast cancer, and colorectal cancer. Interestingly, ANGPTL4 has been shown to exhibit both pro-tumor—promoting tumor growth, cell survival, angiogenesis and metastasis—as well as anti-tumor activities, underscoring its complex roles in cancer biology. This review examines the comprehensive biological functions of ANGPTL4 and its contributions to disease mechanisms with a specific emphasis on cancer, as well as its potential as a therapeutic target across different types of human cancers. Full article

(This article belongs to the Section Molecular Cancer Biology)

► Show Figures

Figure 1

23 pages, 2406 KiB

Open AccessArticle

Ex Vivo Drug Sensitivity of Pleural Effusion-Derived Cells from Lung Cancer and Pleural Mesothelioma Patients Is Linked to Clinical Response

by Rita Hutyra-Gram Ötvös, Hanna Krynska, Greta Gudoityte, Marcus Skribek, Anca Oniscu, Olena Berkovska, Katharina Strauß, Jenny Zipprick, David Tamborero, Andrey Alexeyenko, Annica Karin Britt Gad, Brinton Seashore-Ludlow and Katalin Dobra

Cancers 2025, 17(14), 2363; https://doi.org/10.3390/cancers17142363 - 16 Jul 2025

Abstract

Background: Tumors of the pleura, such as metastatic lung cancer and mesothelioma, are amongst the most lethal and therapy-resistant tumors. The first manifestation of the disease is often pleural effusion, the first available material for diagnosis. The five-year survival rate is exceptionally low, [...] Read more.

Background: Tumors of the pleura, such as metastatic lung cancer and mesothelioma, are amongst the most lethal and therapy-resistant tumors. The first manifestation of the disease is often pleural effusion, the first available material for diagnosis. The five-year survival rate is exceptionally low, around 10–20%, and only a small proportion of patients harbor mutations that allow targeted treatments. Almost all patients develop resistance to treatment, which is often palliative. There is therefore an urgent need to refine the selection of drugs and patients for personalized treatment. Methods: We isolated and cultured cells from pleural effusions in 3D cell aggregates and compared their drug sensitivity ex vivo to the clinical response to the same chemotherapeutic agents, combined with targeted sequencing and network analysis. Results: The ex vivo drug response showed a positive correlation with the treatment response and survival of patients in the clinic, with a stronger link to overall survival than to progression-free survival. Cryopreserved cells showed a similar response to freshly collected cells from the clinic. Conclusions: The findings advance the field of ex vivo screening and present an opportunity to combine strategies for functional precision medicine with comprehensive characterization of disease for improved treatment and future management of lung cancer. Full article

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

► Show Figures

Figure 1

2 pages, 142 KiB

Open AccessCorrection

Correction: Jarahian et al. Re-Expression of Poly/Oligo-Sialylated Adhesion Molecules on the Surface of Tumor Cells Disrupts Their Interaction with Immune-Effector Cells and Contributes to Pathophysiological Immune Escape. Cancers 2021, 13, 5203

by Mostafa Jarahian, Faroogh Marofi, Marwah Suliman Maashi, Mahnaz Ghaebi, Abdolrahman Khezri and Martin R. Berger

Cancers 2025, 17(14), 2362; https://doi.org/10.3390/cancers17142362 - 16 Jul 2025

Abstract

There was an error in the original publication [...] Full article

(This article belongs to the Special Issue Feature Paper from Journal Reviewers)

14 pages, 1999 KiB

Open AccessArticle

Synergistic Efficacy of WST11-VTP and P-Selectin-Targeted Nanotherapy in a Preclinical Prostate Cancer Model

by Lucas Nogueira, Ricardo Alvim, Hanan Baker, Karan Nagar, Jasmine Thomas, Laura Alvim, Kwanghee Kim, Daniel A. Heller, Augusto Reis, Avigdor Scherz and Jonathan Coleman

Cancers 2025, 17(14), 2361; https://doi.org/10.3390/cancers17142361 - 16 Jul 2025

Abstract

Objective: Radical therapies are associated with significant morbidity in patients with localized prostate cancer (PCa). While advances in nuclear magnetic resonance techniques have enabled the development of focal ablation procedures that can selectively destroy tumors, preserve the gland and surrounding structures, and minimize [...] Read more.

Objective: Radical therapies are associated with significant morbidity in patients with localized prostate cancer (PCa). While advances in nuclear magnetic resonance techniques have enabled the development of focal ablation procedures that can selectively destroy tumors, preserve the gland and surrounding structures, and minimize side effects, existing vascular-targeted photodynamic therapy (VTP) and nanodrug therapies often face limitations, such as recurrence and insufficient drug concentration at the tumor site. This study investigated a novel approach that combines VTP with systemic treatment using drug-loaded nanoparticles in a murine model, demonstrating substantial advancements beyond current monotherapies. Methods: SCID (severe combined immunodeficiency) mice were engrafted with androgen-sensitive prostate tumor cells (LNCaP-AR) and treated with a combination of VTP and two different drugs linked to fucoidan nanoparticles (Enzalutamide and Paclitaxel). Experiments were performed using different cohorts: the evaluation of oncological effect, the administration time and concentration of systemic therapy, a comparison of efficacy between VTP and radiotherapy, and the induction of the abscopal effect in untreated synchronous tumors. Results: The groups that received combination therapy showed better tumor control. After eight weeks, the recurrence-free survival rates were 87.5%, 62.5%, and 50% in the VTP + N-PAC, VTP + N-ENZ, and VTP monotherapy groups, respectively (p < 0.05). There was a significant difference in the intra-tumoral concentration of nanodrugs between the groups with combined treatment and monotherapy. After two weeks, the monotherapy groups showed almost total elimination of the drugs, whereas in the combined therapy groups, this concentration remained high, starting to decrease after three weeks (p < 0.05). Treatment with nanodrugs associated with VTP showed superior oncological benefits compared to radiotherapy alone or in combination with other therapies. The abscopal effect on synchronous tumors was not demonstrated with VTP alone or in combination with nanodrugs. Conclusions: Combining vascular photodynamic therapy with nanodrugs was highly effective in treating a prostate tumor model, leading to increased survival and a reduced risk of tumor recurrence. This approach significantly advances beyond existing VTP and nanodrug therapies by improving tumor control, ensuring sustained intra-tumoral drug concentration, and yielding superior oncological outcomes. Our results suggest that this therapy is a potential treatment option for prostate tumors treated with VTP in future clinical trials. Full article

(This article belongs to the Special Issue Advancements in Molecular Research of Prostate Cancer)

► Show Figures

Figure 1

13 pages, 388 KiB

Open AccessArticle

Effectiveness of Surgical Treatment on Survival of Patients with Malignant Pleural Mesothelioma

by Renata Báez-Saldaña, María Esther Marmolejo-Torres, Marco Antonio Iñiguez-García, Aída Jiménez-Corona and Juan Alberto Berrios-Mejía

Cancers 2025, 17(14), 2360; https://doi.org/10.3390/cancers17142360 - 16 Jul 2025

Abstract

Background: The benefit of surgery for malignant pleural mesothelioma is highly debated, as few robust clinical trials show its effectiveness. Objective: To examine the long-term survival of patients with malignant pleural mesothelioma who underwent surgical treatment combined with neoadjuvant chemotherapy versus those who [...] Read more.

Background: The benefit of surgery for malignant pleural mesothelioma is highly debated, as few robust clinical trials show its effectiveness. Objective: To examine the long-term survival of patients with malignant pleural mesothelioma who underwent surgical treatment combined with neoadjuvant chemotherapy versus those who received chemotherapy alone. Methods: We analyzed a historical cohort of 122 patients diagnosed with mesothelioma, confirmed through histopathological examination. We compared the clinical and laboratory characteristics of the surgery and chemotherapy groups at baseline. We calculated Kaplan–Meier survival curves and used Cox’s proportional hazards model to evaluate the relationship between surgery and mortality. Results: Surgery was performed in 16 out of 122 cases. Pleurectomy/decortication (PD) represented 8 cases, while extrapleural pneumonectomy (EPP) accounted for the remaining 8 cases. At five years, survival rates for those who underwent surgery compared to chemotherapy alone were 53% (95% CI 15–81%) versus 23% (95% CI 10–40%), respectively. Survival among those who had PD was 67%, compared to 40% for those who had EPP. Surgical treatment was associated with improved survival, with a hazard ratio (HR) of 0.34 (95% CI 0.19–0.61) after adjusting for factors such as age over 65, the duration from symptom onset to diagnosis, hemoglobin levels below 10 g, a neutrophil-to-lymphocyte ratio over 6, and ECOG scores greater than 2. Conclusions: Mesothelioma surgery, whether it be PD or EPP, enhances patients’ survival compared to chemotherapy. PD produces better outcomes than EPP. Full article

(This article belongs to the Section Cancer Therapy)

► Show Figures

Figure 1

11 pages, 1220 KiB

Open AccessArticle

The Combination of HSP90 Inhibitors and Selumetinib Reinforces the Inhibitory Effects on Plexiform Neurofibromas

by Sajjad Khan, Oluwatosin Aina, Ximei Veneklasen, Hannah Edens, Donia Alson, Li Sun, Huda Zayed, Kimani Njoya and Daochun Sun

Cancers 2025, 17(14), 2359; https://doi.org/10.3390/cancers17142359 - 16 Jul 2025

Abstract

Background/Objectives: Plexiform neurofibromas (pNFs) are one of the cardinal presentations of NF1 patients, often arising during early childhood. Since selumetinib was approved by the FDA in 2020, the long-term side effects and various responses of mitogen-activated protein kinase inhibitors (MEKi) in pediatric [...] Read more.

Background/Objectives: Plexiform neurofibromas (pNFs) are one of the cardinal presentations of NF1 patients, often arising during early childhood. Since selumetinib was approved by the FDA in 2020, the long-term side effects and various responses of mitogen-activated protein kinase inhibitors (MEKi) in pediatric patients necessitate a new strategy. We propose that combining selumetinib with heat shock protein 90 inhibitors (HSP90i) can enhance the inhibitory effects as well as reduce the dosage of selumetinib in combination. We validated the synergistic effects and the significantly improved treatment effects of the combination of selumetinib and HSP90i in pNFs. Methods: We used drug screen data mining to predict the combination of selumetinib and HSP90i. Using cell lines and in vivo mouse models for pNFs, we tested a series of combinations with different concentrations. We validated the in vivo inhibitory effects using the transplanted tumors from DhhCreNf1^f/f mouse models. Results: We demonstrated that combining selumetinib and SNX-2112 or retaspimycin can achieve better tumor inhibition with synergistic effects. The combination significantly delays the progression of mouse pNFs. Conclusions: The combination of selumetinib and HSP90i has significant synergistic effects, provides therapeutic inhibitor effects, and reduces the selumetinib dosage in combination. Full article

(This article belongs to the Special Issue Neurofibromatosis Type 1 (NF1) Related Tumors (2nd Edition))

► Show Figures

Figure 1

11 pages, 587 KiB

Open AccessArticle

Real World Outcomes of Patients with Aggressive Lymphoma and Autoimmune Disease Treated with CART

by Nicole J. Altomare, Megan M. Herr, Nisha M. Nair, Deborah M. Stephens, Jonathon B. Cohen, Narendranath Epperla, Matthew Cortese, Rahul Bhansali, Tamara K. Moyo, Vaishalee Kenkre, Thomas Ollila, Brian Hess, Lindsey Fitzgerald, Geoffrey Shouse, James A. Davis, Christy Jesme, Ari Pelcovits, Jonathan Moreira, Adam Lin, Shuo Ma, Jane N. Winter, Alexey Danilov, Stefan K. Barta, Leo I. Gordon, Jason Romancik, Natalie S. Grover and Reem Karmali Show full author list Hide full author list

Cancers 2025, 17(14), 2358; https://doi.org/10.3390/cancers17142358 - 16 Jul 2025

Abstract

Autoimmune diseases (AIDs) have been shown to be a risk factor for the development of non-Hodgkin lymphoma (NHL), with more than 15 million Americans diagnosed with AIDs between 2011 and 2022 [...] Full article

(This article belongs to the Special Issue The Development of Immunotherapies to Treat Lymphoma)

► Show Figures

Figure 1

19 pages, 2076 KiB

Open AccessArticle

Capacity for Compensatory Cyclin D2 Response Confers Trametinib Resistance in Canine Mucosal Melanoma

by Bih-Rong Wei, Vincenzo Verdi, Shuling Zhang, Beverly A. Mock, Heather R. Shive and R. Mark Simpson

Cancers 2025, 17(14), 2357; https://doi.org/10.3390/cancers17142357 - 15 Jul 2025

Abstract

Background/objective: Mucosal melanoma (MM) is a poorly responsive, rare and aggressive subtype with few cases having targetable recurrent driver mutations, although Ras/MAPK and PI3K/AKT/mTOR signaling pathway activations are common. Eventual tumor evasion of targeted therapy continues to limit treatment success. Adequate models are [...] Read more.

Background/objective: Mucosal melanoma (MM) is a poorly responsive, rare and aggressive subtype with few cases having targetable recurrent driver mutations, although Ras/MAPK and PI3K/AKT/mTOR signaling pathway activations are common. Eventual tumor evasion of targeted therapy continues to limit treatment success. Adequate models are necessary to address therapeutic resistance. The relatively greater incidence of naturally occurring MM in dogs, as well as its comparable clinical and pathological characteristics to human MM, represents an opportunity for study as a human MM patient surrogate. Resistance-promoting crosstalk between Ras/MAPK and PI3K/AKT/mTOR signaling under trametinib inhibition of MEK was studied in canine MM. Emphasis was placed on the suppressive effect of trametinib on cell cycle entry and its potential role in drug resistance. Methods: D-type cyclins were investigated following trametinib treatment of five MM cell lines exhibiting differential drug sensitivities. Signaling pathway activation, proliferation, survival, cell death, and cell cycle were analyzed in the context of D-type cyclin expression. Cyclin D2 expression was manipulated using siRNA knockdown or inducible recombinant overexpression. Results: Trametinib diminished cyclin D1 in all cell lines. While relatively trametinib-resistant MM cells exhibited capacity to upregulate cyclin D2, which promoted proliferation, sensitive MM cells lacked similar cyclin D2 compensation. Inhibition of the compensatory cyclin D2 in resistant cells conferred sensitivity. Induced cyclin D2 overexpression in otherwise trametinib-sensitive MM cells promoted survival. Upregulated PI3K/AKT/mTOR signaling under trametinib treatment was suppressed by mTORC1/2 inhibition, which similarly diminished cyclin D2 response. Conclusions: The compensatory switch from preferential reliance on cyclin D1 to D2 plays a role in MM resistance to MEK inhibition. Full article

(This article belongs to the Special Issue Molecular Insights into Drug Resistance in Cancer)

► Show Figures

Figure 1

47 pages, 1236 KiB

Open AccessReview

Cancer Vaccination and Immune-Based Approaches in Pancreatic Cancer

by Matthew Bloom, Ali Raza Shaikh, Zhengyang Sun, Babar Bashir and Adam E. Snook

Cancers 2025, 17(14), 2356; https://doi.org/10.3390/cancers17142356 - 15 Jul 2025

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with high recurrence rates even after curative resection and adjuvant chemotherapy. Although immunotherapeutic approaches, such as immune checkpoint blockade (ICB), have revolutionized the treatment of some solid tumor malignancies, this has not been the case [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with high recurrence rates even after curative resection and adjuvant chemotherapy. Although immunotherapeutic approaches, such as immune checkpoint blockade (ICB), have revolutionized the treatment of some solid tumor malignancies, this has not been the case for PDAC. Several characteristics of PDAC, including its distinctive desmoplastic tumor microenvironment (TME), intratumor heterogeneity, and poor antigenicity and immune cell infiltration, contribute to its dismal immunotherapeutic landscape. Cancer vaccines offer one approach to overcoming these barriers, particularly in the resectable or borderline resectable settings, where tumor burden is low and immunosuppression is less pronounced. Various vaccination platforms have been tested in the clinical setting, from off-the-shelf peptide-based vaccines (e.g., AMPLFIFY-201 study, where over 80% of participants exhibited T-cell and biomarker responses) to personalized neoantigen mRNA vaccine approaches (e.g., autogene cevumeran, with significant responders experiencing longer median recurrence-free survival (RFS)). The key considerations for enhancing the efficacy of vaccination include combinations with chemotherapy, radiotherapy, and/or ICBs, as well as selecting appropriate immunomodulators or adjuvants. Recent results suggest that with continued mechanistic advancement and novel therapeutic development, cancer vaccines may finally be poised for clinical success in PDAC. Full article

(This article belongs to the Special Issue Pancreatic Cancer: Clinical Standards, Unmet Needs and Future Directions)

► Show Figures

Figure 1

22 pages, 2398 KiB

Open AccessReview

Intravascular Lymphoma: A Unique Pattern Underlying a Protean Disease

by Mario Della Mura, Joana Sorino, Filippo Emanuele Angiuli, Gerardo Cazzato, Francesco Gaudio and Giuseppe Ingravallo

Cancers 2025, 17(14), 2355; https://doi.org/10.3390/cancers17142355 - 15 Jul 2025

Abstract

Intravascular lymphoma (IVL) is a rare, aggressive subtype of non-Hodgkin lymphoma (NHL) characterized by the selective proliferation of neoplastic lymphoid cells within small and medium-sized blood vessels, most frequently of B-cell origin (IVLBCL). Its protean clinical presentation, lack of pathognomonic findings, and absence [...] Read more.

Intravascular lymphoma (IVL) is a rare, aggressive subtype of non-Hodgkin lymphoma (NHL) characterized by the selective proliferation of neoplastic lymphoid cells within small and medium-sized blood vessels, most frequently of B-cell origin (IVLBCL). Its protean clinical presentation, lack of pathognomonic findings, and absence of tumor masses or lymphadenopathies often lead to diagnostic delays and poor outcomes. IVLBCL can manifest in classic, hemophagocytic syndrome-associated (HPS), or cutaneous variants, with extremely variable organ involvement including the central nervous system (CNS), skin, lungs, and endocrine system. Diagnosis requires histopathologic identification of neoplastic intravascular lymphoid cells via targeted or random tissue biopsies. Tumor cells are highly atypical and display a non-GCB B-cell phenotype, often expressing CD20, MUM1, BCL2, and MYC; molecularly, they frequently harbor mutations in MYD88 and CD79B, defining a molecular profile shared with ABC-type DLBCL of immune-privileged sites. Therapeutic approaches are based on rituximab-containing chemotherapy regimens (R-CHOP), often supplemented with CNS-directed therapy due to the disease’s marked neurotropism. Emerging strategies include autologous stem cell transplantation (ASCT) and novel immunotherapeutic approaches, potentially exploiting the frequent expression of PD-L1 by tumor cells. A distinct but related entity, intravascular NK/T-cell lymphoma (IVNKTCL), is an exceedingly rare EBV-associated lymphoma, showing unique own histologic, immunophenotypic, and molecular features and an even poorer outcome. This review provides a comprehensive overview of the current understandings about clinicopathological, molecular, and therapeutic landscape of IVL, emphasizing the need for increased clinical awareness, standardized diagnostic protocols, and individualized treatment strategies for this aggressive yet intriguing malignancy. Full article

(This article belongs to the Special Issue Advances in Pathology of Lymphoma and Leukemia)

19 pages, 743 KiB

Open AccessReview

Drivers of Pancreatic Cancer: Beyond the Big 4

by Laura M. Porcza, Rafael Ballesteros-Cillero, Lok To Lam, Cristina Maiello and Nicholas R. Leslie

Cancers 2025, 17(14), 2354; https://doi.org/10.3390/cancers17142354 - 15 Jul 2025

Abstract

Background: Pancreatic cancer is frequently identified as the cancer type with the shortest probable survival time after diagnosis, and efforts to develop successful treatments have had a very limited impact in the clinic. One reason for the limited therapeutic options is the lack [...] Read more.

Background: Pancreatic cancer is frequently identified as the cancer type with the shortest probable survival time after diagnosis, and efforts to develop successful treatments have had a very limited impact in the clinic. One reason for the limited therapeutic options is the lack of appealing drug targets. The great majority of pancreatic cancers are classified as Pancreatic Ductal Adenocarcinoma (PDAC), in which the genetic landscape is dominated by four genes: KRAS, TP53, CDKN2A, and SMAD4. However, despite extensive knowledge of these genetic drivers, the development of effective therapies has seen only very limited success. Methods: Existing evidence indicates that mutations in the tumour suppressor gene PTEN are uncommon in PDAC (<10% cases). However, the loss of PTEN function through non-genetic mechanisms may be much more common and have a strong impact. We therefore summarise and review a large body of immunohistochemical studies that address the loss of PTEN in PDAC as well as a smaller number of studies addressing other implicated proteins, including KDM6A and ARID1A. Results: These studies show some loss of PTEN protein in more than half of PDAC cases. Furthermore, although genetic changes in genes including KDM6A/UTX and ARID1A are also uncommon, reduced expression of their encoded proteins is observed in many, perhaps most, cases of PDAC. Conclusions: These analyses, which go beyond genetics, highlight the broader set of cellular functions that are dysregulated in many pancreatic cancers and provide broader opportunities for treatment strategies. This review highlights the emerging importance of other drivers in PDAC, which are less well-studied in this context. Full article

(This article belongs to the Special Issue PTEN: Regulation, Signalling and Targeting in Cancer)

► Show Figures

Figure 1

16 pages, 1070 KiB

Open AccessArticle

Validation of the HFA-ICOS Score for Carfilzomib-Induced Cardiotoxicity in Multiple Myeloma: A Real-Life Perspective Study

by Anna Astarita, Giulia Mingrone, Lorenzo Airale, Anna Colomba, Cinzia Catarinella, Marco Cesareo, Fabrizio Vallelonga, Arianna Paladino, Giulia Bruno, Dario Leone, Francesca Gay, Sara Bringhen, Franco Veglio and Alberto Milan

Cancers 2025, 17(14), 2353; https://doi.org/10.3390/cancers17142353 - 15 Jul 2025

Abstract

Background: Despite the inference about the cardiotoxicity induced by Carfilzomib, no validated risk prediction models for adverse cardiovascular events in a real-life population are available. Objectives: The aim of this study was to evaluate the performance of the risk stratification score for Carfilzomib-induced [...] Read more.

Background: Despite the inference about the cardiotoxicity induced by Carfilzomib, no validated risk prediction models for adverse cardiovascular events in a real-life population are available. Objectives: The aim of this study was to evaluate the performance of the risk stratification score for Carfilzomib-induced cardiotoxicity of the Heart Failure Association of the European Society of Cardiology and the International Cardio-Oncology Society (HFA-ICOS) in patients with multiple myeloma (MM). Methods: This is a prospective, real-world study including MM patients consecutively enrolled prior to starting Carfilzomib, divided into levels of risk according to the HFA-ICOS proforma. Results: Of 169 patients, 11.8% were classified as ‘low risk’, 38.5% as ‘medium risk’, 45.6% as ‘high risk’ and 4.1% as ‘very high risk’ at baseline. A total of 89 (52.7%) patients experienced one of the following events: 36 (21.3%) had at least one cardiovascular event and 77 (45.6%) had almost one hypertension-related event. No significant differences were observed for the incidence of any cardiovascular events between the different levels of risk (p > 0.05), even considering the HFA-ICOS score as a continuous variable. The integration of the score with the baseline systolic blood pressure and pulse wave velocity enhanced the accuracy of the score (AUC 0.557 vs. 0.736). Conclusions: The HFA-ICOS score did not discriminate between patients at low, medium and high risk, showing a limited discriminatory power in predicting the risk of events in our population. The integration of other parameters in the HFA-ICOS score, such as systolic blood pressure and pulse wave velocity, improved the performance of the score. Full article

(This article belongs to the Special Issue Cardio-Oncology: An Emerging Paradigm in Modern Medicine: 2nd Edition)

► Show Figures

Figure 1

25 pages, 1297 KiB

Open AccessSystematic Review

The Diagnostic Yield of Cerebrospinal Fluid Analysis for the Diagnosis of Primary Central Nervous System Lymphoma: A Systematic Review

by Josephus van Rooij, Tom Snijders, Prerana Bhande, Tatjana Seute, Monique Minnema and Peter Wessels

Cancers 2025, 17(14), 2352; https://doi.org/10.3390/cancers17142352 - 15 Jul 2025

Abstract

Background: The gold standard for diagnosing primary central nervous system lymphoma (PCNSL) is brain biopsy, an invasive procedure with significant risks. The role of cerebrospinal fluid (CSF) examination, limited to cytology and flow cytometry in current practice, is acknowledged as a less invasive [...] Read more.

Background: The gold standard for diagnosing primary central nervous system lymphoma (PCNSL) is brain biopsy, an invasive procedure with significant risks. The role of cerebrospinal fluid (CSF) examination, limited to cytology and flow cytometry in current practice, is acknowledged as a less invasive diagnostic method. We aimed to summarize available data concerning the efficacy and actual use of current standard CSF diagnostics in the diagnosis of PCNSL. Methods: A systematic review and meta-analysis of 144 studies (n = 9493 patients) was conducted, assessing detection rates of cytology and flow cytometry and the proportion of diagnoses based on CSF analysis. The QUADAS-2 tool was used to evaluate study quality and bias. Results: Meta-analysis showed an 18% pooled detection rate for positive CSF results, with 17% for cytology and 20% for flow cytometry. Only 8% of diagnoses were made using CSF analysis. Most studies had a high risk of bias. Conclusions: Despite its established role in guidelines, CSF analysis remains underutilized for diagnosing PCNSL, with room to improve its clinical impact. Novel techniques, such as chemokines and circulating tumor DNA (cfDNA) analysis, hold promise to unlock the untapped potential of CSF diagnostics, offering significant advancements in non-invasive PCNSL diagnosis. Full article

(This article belongs to the Section Systematic Review or Meta-Analysis in Cancer Research)

► Show Figures

Figure 1

16 pages, 769 KiB

Open AccessArticle

[¹⁷⁷Lu]Lu-PSMA-617 in Patients with Progressive PSMA+ mCRPC Treated With or Without Prior Taxane-Based Chemotherapy: A Phase 2, Open-Label, Single-Arm Trial in Japan

by Kouji Izumi, Ryuji Matsumoto, Yusuke Ito, Seiji Hoshi, Nobuaki Matsubara, Toshinari Yamasaki, Takashi Mizowaki, Atsushi Komaru, Satoshi Nomura, Toru Hattori, Hiroya Kambara, Shaheen Alanee, Makoto Hosono and Seigo Kinuya

Cancers 2025, 17(14), 2351; https://doi.org/10.3390/cancers17142351 - 15 Jul 2025

Abstract

Background: This Phase 2 trial evaluated the efficacy, tolerability, and safety of [¹⁷⁷Lu]Lu-PSMA-617 (¹⁷⁷Lu-PSMA-617) in patients with ≥1 measurable lesion and progressive prostate-specific membrane antigen-positive (PSMA+) metastatic castration-resistant prostate cancer (mCRPC) in Japan. Methods: This study comprises four parts; [...] Read more.

Background: This Phase 2 trial evaluated the efficacy, tolerability, and safety of [¹⁷⁷Lu]Lu-PSMA-617 (¹⁷⁷Lu-PSMA-617) in patients with ≥1 measurable lesion and progressive prostate-specific membrane antigen-positive (PSMA+) metastatic castration-resistant prostate cancer (mCRPC) in Japan. Methods: This study comprises four parts; data from three parts are presented here. Part 1 evaluated safety and tolerability; Parts 2 (post-taxane) and 3 (pre-taxane/taxane-naive) assessed the overall response rate (ORR; primary endpoint), overall survival (OS), radiographic progression-free survival (rPFS), disease control rate (DCR), PFS, and safety; and Part 4 is the expansion part. Patients received 7.4 GBq (±10%) ¹⁷⁷Lu-PSMA-617 Q6W for up to six cycles. Results: Of the 35 patients who underwent a [⁶⁸Ga]Ga-PSMA-11 (⁶⁸Ga-PSMA-11) PET/CT scan, 30 received ¹⁷⁷Lu-PSMA-617 (post-taxane, n = 12; pre-taxane, n = 18). No dose-limiting toxicity was noted in Part 1 (n = 3). Post- and pre-taxane patients had a median of three and five cycles, respectively. The primary endpoint, ORR, met the pre-specified threshold, with the lower limit of the 90% confidence interval (CI) above the threshold of 5% for post-taxane and 12% for pre-taxane. Post- and pre-taxane patients had an ORR of 25.0% (90% CI: 7.2–52.7) and 33.3% (90% CI: 15.6–55.4), respectively. In post- and pre-taxane patients, the DCR was 91.7% and 83.3%, the median rPFS was 3.71 and 12.25 months, and the median PFS was 3.71 and 5.59 months, respectively. The median OS was 14.42 and 12.94 months in post- and pre-taxane patients, respectively. The most common adverse events were constipation, decreased appetite, decreased platelet count, anemia, and nausea. Conclusions: The primary endpoint (ORR) was met. The safety profile of ¹⁷⁷Lu-PSMA-617 was consistent with the VISION and PSMAfore studies, with no new safety signals in the Japanese patients with mCRPC. Full article

(This article belongs to the Section Cancer Therapy)

► Show Figures

Figure 1

14 pages, 1509 KiB

Open AccessArticle

A Multi-Modal Deep Learning Approach for Predicting Eligibility for Adaptive Radiation Therapy in Nasopharyngeal Carcinoma Patients

by Zhichun Li, Zihan Li, Sai Kit Lam, Xiang Wang, Peilin Wang, Liming Song, Francis Kar-Ho Lee, Celia Wai-Yi Yip, Jing Cai and Tian Li

Cancers 2025, 17(14), 2350; https://doi.org/10.3390/cancers17142350 - 15 Jul 2025

Abstract

Background: Adaptive radiation therapy (ART) can improve prognosis for nasopharyngeal carcinoma (NPC) patients. However, the inter-individual variability in anatomical changes, along with the resulting extension of treatment duration and increased workload for the radiologists, makes the selection of eligible patients a persistent challenge [...] Read more.

Background: Adaptive radiation therapy (ART) can improve prognosis for nasopharyngeal carcinoma (NPC) patients. However, the inter-individual variability in anatomical changes, along with the resulting extension of treatment duration and increased workload for the radiologists, makes the selection of eligible patients a persistent challenge in clinical practice. The purpose of this study was to predict eligible ART candidates prior to radiation therapy (RT) for NPC patients using a classification neural network. By leveraging the fusion of medical imaging and clinical data, this method aimed to save time and resources in clinical workflows and improve treatment efficiency. Methods: We collected retrospective data from 305 NPC patients who received RT at Hong Kong Queen Elizabeth Hospital. Each patient sample included pre-treatment computed tomographic (CT) images, T1-weighted magnetic resonance imaging (MRI) data, and T2-weighted MRI images, along with clinical data. We developed and trained a novel multi-modal classification neural network that combines ResNet-50, cross-attention, multi-scale features, and clinical data for multi-modal fusion. The patients were categorized into two labels based on their re-plan status: patients who received ART during RT treatment, as determined by the radiation oncologist, and those who did not. Results: The experimental results demonstrated that the proposed multi-modal deep prediction model outperformed other commonly used deep learning networks, achieving an area under the curve (AUC) of 0.9070. These results indicated the ability of the model to accurately classify and predict ART eligibility for NPC patients. Conclusions: The proposed method showed good performance in predicting ART eligibility among NPC patients, highlighting its potential to enhance clinical decision-making, optimize treatment efficiency, and support more personalized cancer care. Full article

(This article belongs to the Special Issue Image-Guided Adaptive Radiation Therapy (IGART): Advancing Precision Oncology)

► Show Figures

Figure 1

19 pages, 2357 KiB

Open AccessArticle

Chimeric Element-Regulated MRI Reporter System for Mediation of Glioma Theranostics

by Qian Hu, Jie Huang, Xiangmin Zhang, Haoru Wang, Xiaoying Ni, Huiru Zhu and Jinhua Cai

Cancers 2025, 17(14), 2349; https://doi.org/10.3390/cancers17142349 - 15 Jul 2025

Abstract

Background and Purpose: Glioblastoma remains a therapeutic challenge with a poor prognosis despite multimodal treatments. Reporter-based magnetic resonance imaging (MRI) offers a promising approach for tumor visualization, but its efficacy depends on sufficient reporter gene expression. This study aimed to develop a [...] Read more.

Background and Purpose: Glioblastoma remains a therapeutic challenge with a poor prognosis despite multimodal treatments. Reporter-based magnetic resonance imaging (MRI) offers a promising approach for tumor visualization, but its efficacy depends on sufficient reporter gene expression. This study aimed to develop a chimeric element-regulated ferritin heavy chain 1 (FTH1) reporter system to enhance MRI-based glioma detection while enabling targeted therapy via transferrin receptor (TfR)-mediated drug delivery. Methods: Using gene cloning techniques, we constructed a chimeric FTH1 expression system comprising tumor-specific PEG3 promoter (transcriptional control), bFGF-2 5′UTR (translational enhancement), and WPRE (mRNA stabilization). Lentiviral vectors delivered constructs to U251 glioblastoma cells and xenografts. FTH1/TfR expression was validated by Western blot and immunofluorescence. Iron accumulation was assessed via Prussian blue staining and TEM. MRI evaluated T2 signal changes. Transferrin-modified doxorubicin liposomes (Tf-LPD) were characterized for size and drug loading and tested for cellular uptake and cytotoxicity in vitro. In vivo therapeutic efficacy was assessed in nude mouse models through tumor volume measurement, MR imaging, and histopathology. Results: The chimeric system increased FTH1 expression significantly over PEG3-only controls (p < 0.01), with an increase of nearly 1.5-fold compared to the negative and blank groups and approximately a two-fold increase relative to the single promoter group, with corresponding TfR upregulation. Enhanced iron accumulation reduced T2 relaxation times significantly (p < 0.01), improving MR contrast. Tf-LPD (115 nm, 70% encapsulation) showed TfR-dependent uptake, inducing obvious apoptosis in high-TfR cells compared with that in controls. In vivo, Tf-LPD reduced tumor growth markedly in chimeric-system xenografts versus controls, with concurrent MR signal attenuation. Conclusions: The chimeric regulatory strategy overcomes limitations of single-element systems, demonstrating significant potential for integrated glioma theranostics. Its modular design may be adaptable to other reporter genes and malignancies. Full article

(This article belongs to the Section Cancer Therapy)

► Show Figures

Figure 1

Journal Description

Cancers

Latest Articles

Journal Menu

Journal Browser

Highly Accessed Articles

Latest Books

E-Mail Alert

News

Topics

Conferences

Special Issues

Topical Collections

Further Information

Guidelines

MDPI Initiatives

Follow MDPI