Cancers

12 pages, 1272 KB

Open AccessArticle

Implementation and Measurement of Shared Decision Making in Gynaecological Oncology Outpatient Setting at a Tertiary Cancer Centre

by Sarah Ahmed, Benitta Mathews, David Griffiths, Yvonne Anderson, Nithya Ratnavelu and Tineke Vergeldt

Cancers 2025, 17(19), 3168; https://doi.org/10.3390/cancers17193168 (registering DOI) - 29 Sep 2025

Abstract

Background: Shared Decision-Making (SDM) is important for patient-centred care, especially in areas such as gynaecological oncology where treatment decisions are often multifaceted. This study aimed to implement and measure SDM in a gynaecological oncology outpatient clinic, specifically assessing the impact of the [...] Read more.

Background: Shared Decision-Making (SDM) is important for patient-centred care, especially in areas such as gynaecological oncology where treatment decisions are often multifaceted. This study aimed to implement and measure SDM in a gynaecological oncology outpatient clinic, specifically assessing the impact of the BRAN (Benefits, Risks, Alternatives, Nothing) tool on patient and physician perceptions. Methods: A two-phased prospective observational and survey mixed-methodology study was conducted at the tertiary Northern Gynaecological Oncology Centre (NGOC) outpatient clinic in Gateshead, United Kingdom, from October 2023 to November 2024. SDM champions provided staff training. Patient and physician perspectives were measured using the nine-item Shared Decision Making Questionnaire (SDM-Q-9). Phase one was a baseline assessment; phase two involved the implementation of BRAN posters and leaflets. Statistical analyses included the Mann–Whitney U Test and Fisher’s Exact Test. A post-implementation online staff survey was conducted. Results: A total of 207 patients and 13 physicians participated: 107 patients and 13 physicians in phase one and 100 patients and 12 physicians in phase two. Whilst no statistically significant difference in patients’ perceptions of SDM was found between phases (p = 0.73), physicians’ perceptions showed a statistically significant improvement after BRAN tool implementation (p < 0.01). The staff survey results indicated that 84% observed increased patient involvement, and 92% agreed that SDM helped achieve consultation goals. Conclusions: The implementation of SDM at the NGOC led to a statistically significant improvement in the subjective use of SDM by physicians’, despite no significant change in patients’ perceptions, possibly due to high baseline levels. Staff reported increased patient engagement and improved consultation styles. These findings support implementing SDM in gynaecological oncology outpatient settings Full article

(This article belongs to the Special Issue Gynecologic Oncology: Clinical and Translational Research)

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17 pages, 282 KB

Open AccessReview

Current Insights of Post-Infusion CAR T Expansion and Persistence for Large B-Cell Lymphoma

by Grace Wolyncewicz, Rebecca Wayte and Edward Abadir

Cancers 2025, 17(19), 3167; https://doi.org/10.3390/cancers17193167 (registering DOI) - 29 Sep 2025

Abstract

CD19 directed chimeric antigen receptor (CAR) T-cell therapy is standard of care for relapsed or refractory large B-cell lymphoma. CAR T-cell persistence and activity are associated with outcomes for patients with relapsed B-acute lymphoblastic leukaemia (B-ALL), but the association between expansion kinetics and [...] Read more.

CD19 directed chimeric antigen receptor (CAR) T-cell therapy is standard of care for relapsed or refractory large B-cell lymphoma. CAR T-cell persistence and activity are associated with outcomes for patients with relapsed B-acute lymphoblastic leukaemia (B-ALL), but the association between expansion kinetics and outcome is less clear in the setting of large B-cell lymphoma. CAR T-cell expansion and persistence have been measured in both clinical trials and real-world settings, but the clinical relevance and applicability of these measurements remain unclear. There is increasing evidence that the in vivo kinetics of CAR T-cells post-infusion do offer important predictive insights into patient outcomes; despite this, limitations remain given the heterogeneity in methodology and timing of measurement. This review will summarise methodologies utilised to measure CD19 directed CAR T-cell expansion and persistence in vivo, in addition to the clinical implications of these measurements as currently described. Full article

(This article belongs to the Special Issue Significance of CAR T-Cell Therapy in Aggressive B-Cell Lymphoma Treatment)

16 pages, 4959 KB

Open AccessArticle

Donor-Derived Vγ9Vδ2 T Cells for Acute Myeloid Leukemia: A Promising “Off-the-Shelf” Immunotherapy Approach

by Amanda Eckstrom, Anudishi Tyagi, Maryam Siddiqui, Jenny Borgman, Jieming Zeng, Adishwar Rao, Abhishek Maiti and Venkata Lokesh Battula

Cancers 2025, 17(19), 3166; https://doi.org/10.3390/cancers17193166 (registering DOI) - 29 Sep 2025

Abstract

Background: Venetoclax-based combination therapies have provided treatment options for patients with acute myeloid leukemia (AML) who are unfit for intensive chemotherapy. However, venetoclax resistance is common, and for such patients, the prognosis is dismal, and treatment approaches with different mechanisms of action are [...] Read more.

Background: Venetoclax-based combination therapies have provided treatment options for patients with acute myeloid leukemia (AML) who are unfit for intensive chemotherapy. However, venetoclax resistance is common, and for such patients, the prognosis is dismal, and treatment approaches with different mechanisms of action are urgently needed. γδ T cells are a promising candidate owing to their good safety profile and cytotoxic effects in various types of cancers but are mostly unstudied in AML. Methods: Here we used flow cytometry to profile the subtype and memory phenotype of peripheral blood γδ T cells in AML patients and investigate the feasibility of using donor-derived Vγ9Vδ2 T cells to treat AML as both a single agent and in combination with venetoclax. Additionally, we used bioluminescence imaging to examine the effect of donor-derived Vγ9Vδ2 T cells on AML xenograft models alone and in combination with venetoclax. Results: We observed that Vδ2 T cells were less abundant and the TEMRA (terminally differentiated effector memory) phenotype was more prevalent as compared with that of healthy donors, suggesting that replenishing patients with Vδ2 T cells may be an effective treatment option. We found that donor-derived Vγ9Vδ2 T cells that Vγ9Vδ2 T cells efficiently induced apoptosis in AML cells from eight cell lines and three primary cultures in an effector-to-target cell ratio-dependent manner. Moreover, Vγ9Vδ2 T cells showed potent cytotoxicity against the venetoclax-resistant OCI-AML3 cell line and remained potent in the presence of venetoclax. Treatment with Vγ9Vδ2 T cells significantly extended survival in two AML xenograft models established with the aggressive Molm-13 and the venetoclax-resistant OCI-AML3 cell lines. An additive effect of venetoclax and Vγ9Vδ2 T cells was observed in the latter model. Conclusions: Overall, these findings suggest Vγ9Vδ2 T cells as a promising “off-the-shelf” immunotherapy approach for AML patients, especially for patients with venetoclax-resistant disease. Full article

(This article belongs to the Section Cancer Immunology and Immunotherapy)

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31 pages, 1529 KB

Open AccessReview

Artificial Intelligence-Enhanced Liquid Biopsy and Radiomics in Early-Stage Lung Cancer Detection: A Precision Oncology Paradigm

by Swathi Priya Cherukuri, Anmolpreet Kaur, Bipasha Goyal, Hanisha Reddy Kukunoor, Areesh Fatima Sahito, Pratyush Sachdeva, Gayathri Yerrapragada, Poonguzhali Elangovan, Mohammed Naveed Shariff, Thangeswaran Natarajan, Jayarajasekaran Janarthanan, Samuel Richard, Shakthidevi Pallikaranai Venkatesaprasath, Shiva Sankari Karuppiah, Vivek N. Iyer, Scott A. Helgeson and Shivaram P. Arunachalam

Cancers 2025, 17(19), 3165; https://doi.org/10.3390/cancers17193165 (registering DOI) - 29 Sep 2025

Abstract

Background: Lung cancer remains the leading cause of cancer-related mortality globally, largely due to delayed diagnosis in its early stages. While conventional diagnostic tools like low-dose CT and tissue biopsy are routinely used, they suffer from limitations including invasiveness, radiation exposure, cost, and [...] Read more.

Background: Lung cancer remains the leading cause of cancer-related mortality globally, largely due to delayed diagnosis in its early stages. While conventional diagnostic tools like low-dose CT and tissue biopsy are routinely used, they suffer from limitations including invasiveness, radiation exposure, cost, and limited sensitivity for early-stage detection. Liquid biopsy, a minimally invasive alternative that captures circulating tumor-derived biomarkers such as ctDNA, cfRNA, and exosomes from body fluids, offers promising diagnostic potential—yet its sensitivity in early disease remains suboptimal. Recent advances in Artificial Intelligence (AI) and radiomics are poised to bridge this gap. Objective: This review aims to explore how AI, in combination with radiomics, enhances the diagnostic capabilities of liquid biopsy for early detection of lung cancer and facilitates personalized monitoring strategies. Content Overview: We begin by outlining the molecular heterogeneity of lung cancer, emphasizing the need for earlier, more accurate detection strategies. The discussion then transitions into liquid biopsy and its key analytes, followed by an in-depth overview of AI techniques—including machine learning (e.g., SVMs, Random Forest) and deep learning models (e.g., CNNs, RNNs, GANs)—that enable robust pattern recognition across multi-omics datasets. The role of radiomics, which quantitatively extracts spatial and morphological features from imaging modalities such as CT and PET, is explored in conjunction with AI to provide an integrative, multimodal approach. This convergence supports the broader vision of precision medicine by integrating omics data, imaging, and electronic health records. Discussion: The synergy between AI, liquid biopsy, and radiomics signifies a shift from traditional diagnostics toward dynamic, patient-specific decision-making. Radiomics contributes spatial information, while AI improves pattern detection and predictive modeling. Despite these advancements, challenges remain—including data standardization, limited annotated datasets, the interpretability of deep learning models, and ethical considerations. A push toward rigorous validation and multimodal AI frameworks is necessary to facilitate clinical adoption. Conclusion: The integration of AI with liquid biopsy and radiomics holds transformative potential for early lung cancer detection. This non-invasive, scalable, and individualized diagnostic paradigm could significantly reduce lung cancer mortality through timely and targeted interventions. As technology and regulatory pathways mature, collaborative research is crucial to standardize methodologies and translate this innovation into routine clinical practice. Full article

(This article belongs to the Special Issue The Genetic Analysis and Clinical Therapy in Lung Cancer: 2nd Edition)

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24 pages, 9143 KB

Open AccessArticle

M2 Macrophage Polarization Mediated by Complement C3 from Hedgehog-Activated Fibroblasts Establishes an Immunosuppressive Niche in Gastric Cancer

by Jiaheng Lou, Jingcheng Zhang, Zhiyuan Song, Shuo Zhang, Sicheng Zhao, Yunhai Wei, Guiping Chen, Tao Jiang and Guangji Zhang

Cancers 2025, 17(19), 3164; https://doi.org/10.3390/cancers17193164 - 29 Sep 2025

Abstract

Introduction: The Hedgehog (Hh) signaling pathway is aberrantly activated in various types of cancer and plays a critical regulatory role. However, its biological significance in gastric cancer remains unclear. In this study, the mechanism underlying the role of Hh in gastric cancer [...] Read more.

Introduction: The Hedgehog (Hh) signaling pathway is aberrantly activated in various types of cancer and plays a critical regulatory role. However, its biological significance in gastric cancer remains unclear. In this study, the mechanism underlying the role of Hh in gastric cancer progression and prognosis was investigated through bioinformatics analysis as well as in vitro and in vivo experiments. Methods: In this study, a systematic analysis of scRNA-seq datasets and bulk RNA-seq datasets from gastric cancer patients derived from the GEO database and TCGA database was performed by us, which revealed the activation characteristics of Hh in different cell types within the gastric cancer tumor microenvironment (TME). Furthermore, through conducting multiplex immunofluorescence staining experiments on clinical gastric cancer samples, we clarified the association mechanism between fibroblasts with highly activated Hh and the gastric cancer tumor immunosuppressive microenvironment. Finally, by means of in vitro and in vivo experiments, we elucidated the key molecular mechanism by which fibroblasts with highly activated Hh remodel the gastric cancer tumor immunosuppressive microenvironment. Results: We identified a distinct subpopulation of fibroblasts, designated MMP1 + FIB, in the gastric cancer tumor microenvironment. Studies revealed that this subpopulation can significantly activate Hh, suggesting it may play a crucial role in the regulation of the TME. Subsequent mechanistic investigations further confirmed that MMP1 + FIB exhibits a significant correlation with the immunosuppressive state of the TME (R = 0.29, p = 2.5 × 10^−0.8). In terms of the specific functions, the complement system in this fibroblast subpopulation is significantly activated (p < 0.05); further studies demonstrated that MMP1 + FIB can induce the polarization of macrophages toward the M2 subtype (an immunosuppressive phenotype) by specifically secreting complement C3 protein. Collectively, these processes contribute to the establishment of an immunosuppressive TME and ultimately promote the proliferation and metastasis of gastric cancer cells. Discussion: Aberrant activation of the Hh signaling pathway promotes gastric cancer progression via the MMP1 + FIB–C3–macrophage axis, providing a potential therapeutic strategy for targeting the tumor microenvironment. Full article

(This article belongs to the Section Cancer Immunology and Immunotherapy)

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16 pages, 296 KB

Open AccessReview

Novel Therapeutic Approaches for Cutaneous Angiosarcoma, Particularly Focusing on Immune Checkpoint Inhibitors

by Yasuhiro Fujisawa

Cancers 2025, 17(19), 3163; https://doi.org/10.3390/cancers17193163 - 29 Sep 2025

Abstract

Background/Objectives: Cutaneous angiosarcoma (CAS) is a rare and aggressive endothelial malignancy with a high rate of local recurrence and distant metastasis. In advanced cases, where surgical resection is not feasible, systemic therapy remains the cornerstone of treatment. This review aims to summarize [...] Read more.

Background/Objectives: Cutaneous angiosarcoma (CAS) is a rare and aggressive endothelial malignancy with a high rate of local recurrence and distant metastasis. In advanced cases, where surgical resection is not feasible, systemic therapy remains the cornerstone of treatment. This review aims to summarize the current landscape of systemic therapies for unresectable or metastatic CAS and discuss emerging strategies, particularly focusing on immune checkpoint inhibitors (ICIs). Methods: A comprehensive review of the literature was conducted, including clinical trials, retrospective studies, and case series focusing on systemic treatments for advanced CAS. Therapeutic approaches covered include cytotoxic chemotherapy, molecular targeted therapies, and ICIs, as well as combination strategies. Special attention was given to biomarker studies and ongoing clinical trials. Results: Taxane-based chemotherapy, particularly paclitaxel, has demonstrated clinical activity and remains a standard option. Molecular targeted agents such as pazopanib have yielded modest efficacy. Recent trials of ICIs, including the SWOG S1609 DART and AngioCheck studies, have shown encouraging results in select subgroups, especially tumors from sun-exposed regions associated with high tumor mutational burden (TMB). Although AngioCheck did not meet its predefined response criteria, a subset of patients achieved disease control. Biomarkers such as TMB, PD-L1 expression, and tumor-infiltrating lymphocytes are under investigation to guide patient selection. Combination therapies with ICIs and tyrosine kinase inhibitors (TKIs) are being actively explored. Conclusions: While systemic therapies for CAS remain limited in efficacy, ICIs—particularly in combination with TKIs—represent a promising avenue. Future trials should emphasize biomarker-driven, CAS-specific strategies to improve clinical outcomes in this challenging malignancy. Full article

(This article belongs to the Special Issue New Strategies for the Treatment of Melanoma and Non-Melanoma Skin Cancer)

11 pages, 538 KB

Open AccessArticle

Real-Life Use Patterns of Androgen Receptor Pathway Inhibitors (ARPIs): A Nationwide Register-Based Study in Finland During 2012–2023

by Terhi Kurko, Pekka Heino, Pirkko-Liisa Kellokumpu-Lehtinen, Kati Sarnola, Hanna Koskinen and Maarit Bärlund

Cancers 2025, 17(19), 3162; https://doi.org/10.3390/cancers17193162 - 29 Sep 2025

Abstract

Background and Objective: Prostate cancer (PC) is the most common cancer among males in the Western World. Androgens are key growth regulators both in normal and malignant prostate growth. Several new types of androgen pathway inhibitors (ARPIs) have been developed for the treatment [...] Read more.

Background and Objective: Prostate cancer (PC) is the most common cancer among males in the Western World. Androgens are key growth regulators both in normal and malignant prostate growth. Several new types of androgen pathway inhibitors (ARPIs) have been developed for the treatment of PC. Despite the lack of evidence, sequential use of ARPIs has been adopted into everyday clinical practice. This study aimed to assess real-life ARPI use patterns, especially sequential use and treatment costs, in Finland. Methods: Nationwide register data on all ARPI (enzalutamide, apalutamide, darolutamide, abiraterone) purchases recorded in the National Health Insurance scheme register maintained by the Social Insurance Institution of Finland from January 2012 to December 2023 were used. The data included patient demographics and medicine purchase details, which were descriptively analysed. Results: During the study period, 8369 patients initiated ARPIs. The median age of the users was 75.1 years. Of these, 32.1% (n = 2685) used at least two ARPIs sequentially. The proportion of treatment initiations leading to sequential use increased from 36% in 2012 to 56% in 2017, then decreased to 14% in 2022. The total cost of sequential use was €43.8 million. Limitations include the unrecorded phase of PC. The study’s strength is its inclusion of all reimbursed ARPI purchases nationwide. Conclusions: Despite the lack of evidence, sequential ARPI use was initially prevalent but declined after the introduction of new guidelines. Randomised trials are needed to guide the sequential use of these medicines. Patient summary: Androgen pathway inhibitors (ARPIs) are widely used in prostate cancer in Finland. One-third of patients use at least two ARPIs sequentially to inhibit testosterone effect. However, there are no large clinical trials published demonstrating the benefits of sequential treatment. More evidence is needed to justify sequential use. Full article

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

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10 pages, 217 KB

Open AccessArticle

Middle East Deployment and Lymphoid Malignancies in US Veterans: A Matched Case-Control Analysis

by Helen Ma and Pankaj Gupta

Cancers 2025, 17(19), 3161; https://doi.org/10.3390/cancers17193161 - 29 Sep 2025

Abstract

Background/Objective: US military personnel deployed to the Middle East were potentially subjected to harmful exposures, such as carcinogens from burn pits, which may increase the risk of lymphoid malignancies. Our objective was to determine the association between deployment and the risk of developing [...] Read more.

Background/Objective: US military personnel deployed to the Middle East were potentially subjected to harmful exposures, such as carcinogens from burn pits, which may increase the risk of lymphoid malignancies. Our objective was to determine the association between deployment and the risk of developing lymphoid malignancies. Methods: This was a retrospective nested matched case-control study from a cohort of 3.5 million veterans who enlisted in the military after September 2001 and were followed until death or last follow up through September 2024. Cases of lymphoid malignancies were identified by the VA Central Cancer Registry and controls were randomly selected from the same base cohort, matched by year of birth, year of enlistment, sex, race, and ethnicity. Exposure was defined as deployment to the Middle East as determined by identification on the VA Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) roster with confirmed dates of deployment or paystubs. Results: There were 1037 cases of lymphoid malignancies and 3572 matched controls. Deployment was not associated with a higher risk of developing lymphoid malignancies compared to non-deployment. Exposure to OEF/OIF was not associated with a higher risk of developing certain types of lymphoid malignancies. Conclusions: In this large, matched case-control study of US veterans, deployment to the Middle East was not associated with increased risk of developing lymphoid malignancies. While these findings do not support an increased lymphoid malignancy risk, important limitations remain, including the absence of detailed exposure and potential confounding variables. Prospective monitoring of specific types and doses of exposures during military deployment, development of lymphoid and other malignancies, and their underlying pathophysiology is indicated. Full article

(This article belongs to the Special Issue Chronic Lymphocytic Leukemia: From Genetics to Therapy)

38 pages, 1612 KB

Open AccessReview

Microengineered Breast Cancer Models: Shaping the Future of Personalized Oncology

by Tudor-Alexandru Popoiu, Anca Maria Cimpean, Florina Bojin, Simona Cerbu, Miruna-Cristiana Gug, Catalin-Alexandru Pirvu, Stelian Pantea and Adrian Neagu

Cancers 2025, 17(19), 3160; https://doi.org/10.3390/cancers17193160 - 29 Sep 2025

Abstract

Background: Breast cancer remains the most prevalent malignancy in women worldwide, characterized by remarkable genetic, molecular, and clinical heterogeneity. Traditional preclinical models have significantly advanced our understanding of tumor biology, yet consistently fall short in recapitulating the complexity of the human tumor [...] Read more.

Background: Breast cancer remains the most prevalent malignancy in women worldwide, characterized by remarkable genetic, molecular, and clinical heterogeneity. Traditional preclinical models have significantly advanced our understanding of tumor biology, yet consistently fall short in recapitulating the complexity of the human tumor microenvironment (TME), immune, and metastatic behavior. In recent years, breast cancer-on-a-chip (BCOC) have emerged as powerful microengineered systems that integrate patient-derived cells, stromal and immune components, and physiological stimuli such as perfusion, hypoxia, and acidic milieu within controlled three-dimensional microenvironments. Aim: To comprehensively review the BCOC development and application, encompassing fabrication materials, biological modeling of key subtypes (DCIS, luminal A, triple-negative), dynamic tumor–stroma–immune crosstalk, and organotropic metastasis to bone, liver, brain, lungs, and lymph nodes. Methods: We selected papers from academic trusted databases (PubMed, Web of Science, Google Scholar) by using Breast Cancer, Microfluidic System, and Breast Cancer on a Chip as the main search terms. Results: We critically discuss and highlight how microfluidic systems replicate essential features of disease progression—such as epithelial-to-mesenchymal transition, vascular invasion, immune evasion, and therapy resistance—with unprecedented physiological relevance. Special attention has been paid to the integration of liquid biopsy technologies within microfluidic platforms for non-invasive, real-time analysis of circulating tumor cells, cell-free nucleic acids, and exosomes. Conclusions: In light of regulatory momentum toward reducing animal use in drug development, BCOC platforms stand at the forefront of a new era in precision oncology. By bridging biological fidelity with engineering innovation, these systems hold immense potential to transform cancer research, therapy screening, and personalized medicine. Full article

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

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10 pages, 383 KB

Open AccessArticle

Venetoclax–Rituximab and Emerging Treatment Strategies After c-BTKi Exposure in Relapsed/Refractory CLL: A Real-World Cohort and Literature Overview

by Maria Dimou, Rodanthi Fioretzaki, Calliope Zerzi, Eliana Konstantinou, John V. Asimakopoulos, Maria Arapaki, Alexia Piperidou, Alexandros Machairas, Anastasia Kopsaftopoulou, Athanasios Liaskas, Aikaterini Bitsani, Marina Belia, Fotios Panitsas, Aikaterini Benekou, Panagiota Petsa, Eleni Plata, Panagiotis Tsaftaridis, Marina Siakantaris, Theodoros P. Vassilakopoulos, Panayiotis Panayiotidis and Maria K. Angelopoulou Show full author list Hide full author list

Cancers 2025, 17(19), 3159; https://doi.org/10.3390/cancers17193159 - 29 Sep 2025

Abstract

Background: Fixed-duration venetoclax plus rituximab (VR) is a standard therapy for relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). However, evidence supporting its use after covalent BTK inhibitor (c-BTKi) therapy is scarce in clinical trials and limited in real-world settings. Objectives: To assess the efficacy [...] Read more.

Background: Fixed-duration venetoclax plus rituximab (VR) is a standard therapy for relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). However, evidence supporting its use after covalent BTK inhibitor (c-BTKi) therapy is scarce in clinical trials and limited in real-world settings. Objectives: To assess the efficacy and safety of VR in a real-world cohort of patients with R/R CLL, including cBTKi-pretreated individuals, and to contextualize outcomes alongside published real-world studies and registrational trials of alternative therapies. Methods: We retrospectively analyzed 37 patients with R/R CLL treated with VR at our center between April 2018 and November 2024. Baseline characteristics, treatment responses, minimal residual disease (MRD), and adverse events were recorded. Survival was estimated using the Kaplan–Meier method. A structured review of relevant real-world evidence and pirtobrutinib clinical trials was also conducted. Results: Median age was 67 years; 35.1% had prior cBTKi exposure. The overall response rate (ORR) was 91.7% (22/24 evaluable patients), with 66.7% achieving complete remission (CR). Among evaluable c-BTKi-pretreated patients, the ORR was 87.5% (7/8) and the CR rate was 62.5%. Undetectable MRD (uMRD) rates were 78.6% in peripheral blood and 71.4% in bone marrow. Thirty-month progression-free survival (PFS), time to next treatment (TTNT), and overall survival (OS) were >90% for the whole cohort and for c-BTKi-pretreated patients. The most frequent adverse event was neutropenia grade ≥ 3, especially during combination therapy, which is easily managed with GCSF support. Conclusions: Our real-world evidence shows that VR is an effective and well-tolerated option even after c-BTKi therapy in R/R CLL. These data complement evidence from emerging therapies and inform post-c-BTKi treatment selection in clinical practice. Full article

(This article belongs to the Special Issue Chronic Lymphocytic Leukemia: From Genetics to Therapy)

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29 pages, 415 KB

Open AccessGuidelines

Diagnosis and Therapy of Soft Tissue Sarcomas: Spanish Group for Research in Sarcomas (GEIS) Guidelines

by Maria Angeles Vaz-Salgado, Claudia Valverde-Morales, Rosa Alvarez, Jose Manuel Asencio, Erica Collado, Enrique de Alava, Roberto Diaz Beveridge, M. Carmen Gómez-Mateo, Isidro Gracia Alegria, Gloria Marquina, Javier Martin Broto, Javier Martínez-Trufero, José Antonio Narváez García, Andres Redondo, Ana Sebio, Ramona Verges, Joan Maria Viñals and Xavier García del Muro

Cancers 2025, 17(19), 3158; https://doi.org/10.3390/cancers17193158 - 29 Sep 2025

Abstract

Soft tissue sarcomas (STSs) are a rare and highly heterogeneous group of tumours originating from mesenchymal cells, characterized by significant clinical and biological diversity. Due to this complexity, STSs present considerable challenges in both diagnosis and treatment, requiring an expert, multidisciplinary, and coordinated [...] Read more.

Soft tissue sarcomas (STSs) are a rare and highly heterogeneous group of tumours originating from mesenchymal cells, characterized by significant clinical and biological diversity. Due to this complexity, STSs present considerable challenges in both diagnosis and treatment, requiring an expert, multidisciplinary, and coordinated approach. To address these challenges, a multidisciplinary team of experts from the Spanish Group for Research in Sarcomas (GEIS) has developed a comprehensive, evidence-based consensus guideline that incorporates the latest advancements in biology, imaging techniques, and treatment options. The primary objective of this guideline is to provide clear and practical, up-to-date recommendations addressing the key questions that arise in the management of STSs. This approach aims to support therapeutic decision-making, enhance overall patient management, and ultimately improve clinical outcomes for patients affected by STSs. Key recommendations include the use of MRI as the preferred imaging modality prior to biopsy and ensuring that all patients are referred to specialised sarcoma centres with a multidisciplinary team for diagnosis and treatment. Full article

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

18 pages, 1488 KB

Open AccessArticle

Moderate Immune-Related Liver Injury Is a Good Factor in Patients with Hepatoma Under Atezolizumab Plus Bevacizumab

by Tai-Chi Wu, Po-Ting Lin, Wei Teng, Eric Yi-Liang Shen, Chung-Wei Su, Yi-Chung Hsieh, Wei-Ting Chen, Tsung-Han Wu, Chen-Chun Lin, Shi-Ming Lin and Chun-Yen Lin

Cancers 2025, 17(19), 3157; https://doi.org/10.3390/cancers17193157 - 28 Sep 2025

Abstract

Background: Atezolizumab plus bevacizumab is the standard first-line therapy for unresectable hepatocellular carcinoma (uHCC). Immune-related liver injury (IrLI) is common; however, the association between IrLI severity and patient outcomes remains unknown. This study aimed to investigate the prognostic value of irLI in such [...] Read more.

Background: Atezolizumab plus bevacizumab is the standard first-line therapy for unresectable hepatocellular carcinoma (uHCC). Immune-related liver injury (IrLI) is common; however, the association between IrLI severity and patient outcomes remains unknown. This study aimed to investigate the prognostic value of irLI in such patients. Methods: One hundred and sixteen patients who fulfilled the IMBrave150 inclusion criteria were enrolled. IrLI was defined as an increase in serum ALT and/or AST levels attributed to treatment and was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0. Results: A total of 61 patients (52.6%) developed any grade of irLI, with a median onset time of 1.7 months. Multivariate analysis revealed that grade II ALBI (hazard ratio [HR] = 2.003, p = 0.028) and BCLC stage C (HR = 3.876, p = 0.016) were associated with worse OS and PFS (HR = 1.327, p = 0.044 and HR = 1.790, p = 0.039, respectively), whereas grade 2 irLI was associated with better OS (HR = 0.223, p = 0.046) and PFS (HR = 0.244, p = 0.011). Patients with grade 2 irLI showed better median OS (not reached) than those without irLI (16.7 months), those with grade 1 (17.5 months), and those with grade ≥ 3 (7.3 months) (overall log-rank p = 0.037). Furthermore, patients with grade 2 irLI demonstrated significantly enhanced PFS (not reached) compared to those without irLI (5.7 months), grade 1 (4.6 months), or grade ≥ 3 (2.3 months), with an overall log-rank p = 0.010. In addition, patients with grade 2 irLI had the highest disease control rate (overall p = 0.053). Conclusion: In patients with uHCC treated with Ate/Bev, moderate elevation of liver enzymes (grade 2 irLI) was associated with significantly improved survival and tumor control. Full article

(This article belongs to the Section Cancer Immunology and Immunotherapy)

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35 pages, 4243 KB

Open AccessReview

Proline Metabolism in Cancer: Emerging Roles in Redox Homeostasis and Therapeutic Opportunities

by Tyrell C. Rossman, Gunjan Purohit, Oseeyi I. Daudu and Donald F. Becker

Cancers 2025, 17(19), 3156; https://doi.org/10.3390/cancers17193156 - 28 Sep 2025

Abstract

Cancer is a complex disease characterized by uncontrolled proliferation and progression toward metastasis. The activation and maintenance of these processes demand increased energy production. Traditional cancer therapies often target broad energy-generating mechanisms to inhibit cancer growth. However, the field of oncology is increasingly [...] Read more.

Cancer is a complex disease characterized by uncontrolled proliferation and progression toward metastasis. The activation and maintenance of these processes demand increased energy production. Traditional cancer therapies often target broad energy-generating mechanisms to inhibit cancer growth. However, the field of oncology is increasingly shifting toward more potent, precise, and personalized treatment strategies. This shift has fueled interest in novel cancer metabolic pathway targets. This review focuses on proline metabolism, an amino acid pathway that has been observed to be altered across various cancer subtypes. Proline has emerged as one of the most consistently deregulated non-essential amino acids in cancer biology. Proline metabolism is intimately linked to mitochondria function and energy regulation through mechanisms such as reactive oxygen species, ATP production, and interactions with the tumor microenvironment. Due to its dichotomous nature, proline metabolism functions are highly context dependent, varying across cancer subtypes. While this provides a potential novel therapeutic target, it also presents unique challenges and knowledge gaps. Full article

(This article belongs to the Section Cancer Pathophysiology)

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22 pages, 1013 KB

Open AccessArticle

“We Just Get Whispers Back”: Perspectives of Primary and Hospital Health Care Providers on Between-Service Communication for Aboriginal People with Cancer in the Northern Territory

by Emma V. Taylor, Amy Elson, Bronte Avishai, Philip Mayo, Christine Sanderson and Sandra C. Thompson

Cancers 2025, 17(19), 3155; https://doi.org/10.3390/cancers17193155 - 28 Sep 2025

Abstract

Background/Objectives: Cancer is a leading cause of death for Aboriginal and Torres Strait Islander people, with remoteness increasing the risk for poorer outcomes. Primary health care (PHC) clinics have an important role in cancer screening, diagnosis, and post-discharge cancer care, particularly in remote [...] Read more.

Background/Objectives: Cancer is a leading cause of death for Aboriginal and Torres Strait Islander people, with remoteness increasing the risk for poorer outcomes. Primary health care (PHC) clinics have an important role in cancer screening, diagnosis, and post-discharge cancer care, particularly in remote communities, so accurate, timely communication between hospitals, specialists and PHC clinics is vital. This paper analyses the perspectives of Northern Territory health care professionals on communication between PHC and hospital services related to providing care for Aboriginal people with cancer and recommends strategies for improving communication between services. Methods: A qualitative study was undertaken in which semi-structured interviews were conducted with fifty staff from 15 health services (8 regional, remote, and very remote PHC clinics; 3 hospitals; one cancer centre and 3 cancer support services) between 2016 and 2019. Transcripts were thematically analysed, with findings categorized into barriers and enablers to communication. Results: Deficiencies in communication impeded patient care and support. A major barrier was fragmented, inefficient information systems; IT systems across health services were unable to interface, resulting in delayed/missing patient information that impacted discharge and follow up. Other barriers included PHC staff with limited knowledge of cancer, high turnover of PHC staff and tertiary hospital staff with limited understanding of remote health care challenges. Individuals used workarounds to overcome system failures and made substantial efforts around individual patients to improve communication. Specific roles and the use of telehealth between services and centralised cancer care services supported better between-service communication. Conclusions: Communication between hospital services and remote PHC clinics is essential to care for Aboriginal cancer patients; our research identified communication as inadequate in terms of consistency and timeliness. Commitment to more timely communication, health care IT systems that facilitate sharing information, designated staff in PHC clinics to support patients with cancer, dedicated Aboriginal cancer roles and additional resourcing to coordinate telehealth appointments could improve communication and sharing of patient information between services. Full article

(This article belongs to the Special Issue Health Services Research in Cancer Care)

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15 pages, 3621 KB

Open AccessArticle

Role of Hyaluronic Acid and Chondroitin Sulphate in Protecting Urinary Epithelium in Patients Operated for Differentiated Thyroid Cancer Undergoing Ablation Therapy with Iodine-131

by Giuseppe Campagna, Chiara Lauri, Tiziana Lanzolla, Anna Festa, Luciano Carideo and Alberto Signore

Cancers 2025, 17(19), 3154; https://doi.org/10.3390/cancers17193154 - 28 Sep 2025

Abstract

Background: It is not clear if the administration of iodine-131 in patients with differentiated thyroid cancers induces relevant cystitis and lower urinary tract infections (UTIs). The aim of this study was to evaluate the impact of oral administration of hyaluronic acid and chondroitin [...] Read more.

Background: It is not clear if the administration of iodine-131 in patients with differentiated thyroid cancers induces relevant cystitis and lower urinary tract infections (UTIs). The aim of this study was to evaluate the impact of oral administration of hyaluronic acid and chondroitin sulphate (HA&CS) on the frequency of UTIs induced by iodine-131. Methods: In this study, 166 female patients with a surgical diagnosis of differentiated thyroid cancer who were hospitalized in Sant ’Andrea Hospital of Rome to undergo the first cycle of therapy with iodine-131 for thyroid remnant ablation were evaluated. Sixty-one patients were treated with HA&CS for 8 days, and thirty-nine patients were treated with HA&CS for 17 days. Sixty-six patients were not treated with HA&CS and were used as control subjects. Patients underwent urinalysis at different time points: immediately before ¹³¹I therapy, two days later, and one week later. Patients were divided in six groups based on whether they received the treatment with HA&CS, its duration, and whether they developed a UTI: group A, n = 51 patients who did not receive HA&CS and did not develop UTI; group B1, n = 37 patients treated with HA&CS for 8 days and did not develop UTI; group B2, n = 29 patients treated with HA&CS for 17 days and did not develop UTI; group C, n = 15 patients who did not receive HA&CS and developed UTI; group D1, n = 24 patients treated with HA&CS for 8 days and developed UTI; group D2, n = 10 patients treated with HA&CS for 17 days and developed UTI. Results: The bacteria count, red blood cells and white blood cells did not change when group A was compared to both group B1 and group B2, while pH and epithelial cells showed a decrease over time when comparing group A and group B2 (p = 0.01 and p < 0.0001, respectively). Comparing group C with group D1 and group D2, patients who did not receive HA&CS (group C) showed a higher bacteria and epithelial cell count compared to those who were pre-treated with HA&CS. Conclusions: HA&CS could be an effective supportive therapy to prevent and mitigate UTIs in patients treated with ¹³¹I. Full article

(This article belongs to the Special Issue Updates on Thyroid Cancer)

20 pages, 420 KB

Open AccessReview

Immunotherapy-Induced Complete Response in dMMR Rectal Cancer—A Surgical Dilemma?

by Panagiotis Loufopoulos, Konstantinos Perivoliotis, Danai Chatziathanasiou, Maximos Frountzas, Anisha Sukha, Abdullah Alrebdi, Mohammad Mahmoud Rajab Eddama, Christos Kontovounisios, Shengyang Qiu, Paris Tekkis and Shahnawaz Rasheed

Cancers 2025, 17(19), 3153; https://doi.org/10.3390/cancers17193153 - 28 Sep 2025

Abstract

Background: Deficient mismatch repair rectal cancer represents approximately 10% of rectal malignancies and demonstrates exceptional responsiveness to immune checkpoint inhibitors, achieving unprecedented complete response rates approaching 100%. This creates a novel clinical dilemma: should patients achieving complete response undergo standard surgical resection or [...] Read more.

Background: Deficient mismatch repair rectal cancer represents approximately 10% of rectal malignancies and demonstrates exceptional responsiveness to immune checkpoint inhibitors, achieving unprecedented complete response rates approaching 100%. This creates a novel clinical dilemma: should patients achieving complete response undergo standard surgical resection or pursue organ preservation through watch-and-wait management? Methods: We conducted a comprehensive literature review of clinical trials and retrospective studies published through 2025, focusing on response assessment strategies, decision-making frameworks, oncological outcomes, and quality of life assessments. Results: Landmark studies demonstrated remarkable efficacy with dostarlimab achieving 100% clinical complete response, while surgical cohorts achieved 68–92% pathological complete response rates. Response assessment challenges included pseudoprogression and pseudoresidue phenomena that complicated conventional imaging interpretation and required specialised multimodal evaluation protocols. Comparative analyses suggest equivalent oncological outcomes between surgical and non-surgical approaches in complete responders, achieving 100% disease-free survival at 2–3 years across multiple studies. The watch-and-wait approach offered significant advantages by preserving organ integrity and avoiding surgical morbidity, including permanent colostomy (15.4%) and perioperative complications (19.3%). Conversely, surgical management provided distinct benefits through definitive tissue confirmation and anxiety relief from intensive surveillance requirements and potential recurrence concerns. Conclusions: The surgery versus watch-and-wait dilemma represents a choice between equally effective oncological approaches with different quality of life implications. Evidence supports individualised decision-making weighing functional preservation benefits against patient preferences and institutional capabilities in this evolving therapeutic landscape. Full article

(This article belongs to the Special Issue Surgical Treatment of Abdominal Tumors)

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28 pages, 730 KB

Open AccessReview

by Silvia Belloni, Rosamaria Virgili, Rosario Caruso, Cristina Arrigoni, Arianna Magon, Gennaro Rocco and Maddalena De Maria

Cancers 2025, 17(19), 3152; https://doi.org/10.3390/cancers17193152 - 28 Sep 2025

Abstract

Objectives: We conducted a systematic review of clinical trials and case reports analyzing the safety of the currently approved BRAF and MEK inhibitors in adults with cutaneous melanoma (CM), and a meta-analysis to estimate the pooled prevalence of treatment-related adverse events (TRAEs). [...] Read more.

Objectives: We conducted a systematic review of clinical trials and case reports analyzing the safety of the currently approved BRAF and MEK inhibitors in adults with cutaneous melanoma (CM), and a meta-analysis to estimate the pooled prevalence of treatment-related adverse events (TRAEs). Methods: We systematically searched six databases for studies published since 2009. The TRAE absolute frequencies reported in primary studies were aggregated using the Metaprop command in Stata 17, which calculates 95% confidence intervals (CIs) incorporating the Freeman–Tukey double arcsine transformation of proportions to stabilize variances within random-effect models. Methodological quality was assessed using the RoB 2 tool for randomized controlled trials (RCTs) and the ROBINS-I tool for non-randomized studies. Results: Twelve RCTs, thirteen prospective cohort studies (PCSs), and ten case reports were included. Meta-analysis was feasible for two regimens: vemurafenib 960 mg monotherapy and dabrafenib 150 mg twice daily plus trametinib 1–2 mg daily. The most common TRAEs during vemurafenib treatment were musculoskeletal and connective-tissue disorders (24%, 95% CI: 6–41%, p = 0.01), with arthralgia as the most prevalent (44%, 95% CI: 29–59%, p < 0.001), followed by rash (39%, 95% CI: 22–56%, p < 0.001). The most common TRAEs during dabrafenib plus trametinib were constitutional toxicities (classified in CTCAE as ‘General disorders and administration site conditions’; 25%, 95% CI: 14–37%, p < 0.001), with fatigue as the most prevalent (47%, 95% CI: 38–56%, p < 0.001), followed by pyrexia (40%, 95% CI: 26–54%, p < 0.001). Squamous cell carcinoma and keratoacanthoma were among the most frequent grade ≥ 3 cutaneous adverse events observed with vemurafenib therapy. Conclusions: Although additional large-scale studies are needed to corroborate these findings, each treatment has a distinct toxicity profile that should be considered when developing personalized risk-stratified treatment plans and in guiding healthcare resource allocation in melanoma care. Full article

(This article belongs to the Section Cancer Therapy)

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11 pages, 863 KB

Open AccessArticle

Seven-Year PSA ≤ 0.2 ng/mL After High-Dose-Rate Brachytherapy Indicates Eligibility for Discontinuing PSA Surveillance in Prostate Cancer

by Tomoyuki Makino, Takayuki Sakurai, Shigeyuki Takamatsu, Ryunosuke Nakagawa, Taiki Kamijima, Hiroshi Kano, Renato Naito, Hiroaki Iwamoto, Hiroshi Yaegashi, Kazuyoshi Shigehara, Takahiro Nohara, Kouji Izumi and Atsushi Mizokami

Cancers 2025, 17(19), 3151; https://doi.org/10.3390/cancers17193151 - 28 Sep 2025

Abstract

Background: We evaluated the long-term treatment outcomes of patients with clinically localized and locally advanced prostate cancer (PC) who underwent high-dose-rate brachytherapy (HDR-BT) combined with external beam radiotherapy (EBRT). The primary objective was to identify the optimal timing for discontinuing prostate-specific antigen (PSA) [...] Read more.

Background: We evaluated the long-term treatment outcomes of patients with clinically localized and locally advanced prostate cancer (PC) who underwent high-dose-rate brachytherapy (HDR-BT) combined with external beam radiotherapy (EBRT). The primary objective was to identify the optimal timing for discontinuing prostate-specific antigen (PSA) monitoring after HDR-BT. Methods: This analysis included 338 patients with PC who received HDR-BT combined with EBRT between 2006 and 2022 and had a minimum follow-up of 5 years. The patients were stratified based on their PSA levels, and factors associated with recurrence were identified. Results: The median observation period was 8.9 years (range, 5.0–19.0 years). The 10-year recurrence-free survival rate was 92.0%, with 26 recurrences. PSA levels at 5 and 7 years were significantly correlated with oncological outcomes after HDR-BT. Multivariate analysis revealed that a PSA level of >0.2 ng/mL at 5 years was an independent poor prognostic factor for recurrence (hazard ratio, 117.57; 95% confidence interval, 6.22–2223.37; p = 0.001). No patient with a PSA level of ≤0.2 ng/mL at 7 years developed recurrences. Conclusions: Based on our long-term data, we propose that PSA monitoring may be safely discontinued in patients with a PSA level of ≤0.2 ng/mL 7 years after HDR-BT because the risk of recurrence beyond this point is exceedingly low. Full article

(This article belongs to the Special Issue Clinical Treatment and Prognostic Factors of Urologic Cancer)

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14 pages, 531 KB

Open AccessReview

Sexual Dysfunction in Female Rectal and Anal Cancer Survivors: Pathophysiology, Clinical Management, and Integration into Survivorship Care

by Denise Drittone, Monia Specchia, Eva Mazzotti and Federica Mazzuca

Cancers 2025, 17(19), 3150; https://doi.org/10.3390/cancers17193150 - 28 Sep 2025

Abstract

Background: Female Sexual dysfunction (FSD) is a common but under-recognized outcome of rectal and anal cancer treatment. While survival has improved, sexual health remains insufficiently addressed in survivorship care, warranting a multidisciplinary perspective. Methods: A narrative review of studies published between [...] Read more.

Background: Female Sexual dysfunction (FSD) is a common but under-recognized outcome of rectal and anal cancer treatment. While survival has improved, sexual health remains insufficiently addressed in survivorship care, warranting a multidisciplinary perspective. Methods: A narrative review of studies published between 2000 and 2025 was conducted, including clinical trials, cohort studies, and guideline documents addressing female sexual dysfunction after anorectal cancer treatment. Articles that were not pertinent to the research topic, outdated, or methodologically inadequate were excluded from the analysis. Results: Over 60% of female survivors experience FSD, including decreased libido, vaginal dryness, dyspareunia, and arousal difficulties. Causes include hormonal deficiency, nerve injury, and radiation fibrosis, compounded by psychological distress, altered body image, stoma-related stigma, and communication issues. The FSFI is commonly applied but lacks specificity for this population. Geographic disparities persist, with greater stigma and limited care access in low- and middle-income countries. Emerging therapies, such as immunotherapy, may mitigate FSD risk, though evidence is scarce. Conclusions: FSD after anorectal cancer is highly prevalent and significantly impacts quality of life, yet remains under-assessed in follow-up care. Multidisciplinary, culturally sensitive strategies integrating screening, psychosexual support, and tailored rehabilitation are urgently needed. Future research should address sexual outcomes more systematically, particularly in novel treatment contexts. Full article

(This article belongs to the Special Issue Long-Term Cancer Survivors: Rehabilitation and Quality of Life)

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