Cancers

17 pages, 270 KB

Open AccessEditor’s ChoiceReview

Single-Port vs. Multi-Port Robotic Surgery in Urologic Oncology: A Comparative Analysis of Current Evidence and Future Directions

by Stamatios Katsimperis, Lazaros Tzelves, Georgios Feretzakis, Themistoklis Bellos, Konstantinos Douroumis, Nikolaos Kostakopoulos and Andreas Skolarikos

Cancers 2025, 17(17), 2847; https://doi.org/10.3390/cancers17172847 - 29 Aug 2025

Cited by 3 | Viewed by 1876

Abstract

The evolution of robotic surgery in urologic oncology has led to the emergence of single-port (SP) robotic systems as a potential alternative to the widely adopted multi-port (MP) platforms. This narrative review provides a comprehensive comparison between SP and MP robotic systems, the [...] Read more.

The evolution of robotic surgery in urologic oncology has led to the emergence of single-port (SP) robotic systems as a potential alternative to the widely adopted multi-port (MP) platforms. This narrative review provides a comprehensive comparison between SP and MP robotic systems, the former of which received FDA approval in 2018 and CE marking in 2024, focusing on their application across radical prostatectomy, partial and radical nephrectomy, and radical cystectomy. Drawing from the most current literature, we examine perioperative outcomes, oncologic efficacy, postoperative recovery, and complication rates. The review highlights the technical challenges unique to SP surgery, including restricted triangulation, limited instrumentation, and a defined learning curve, while also emphasizing innovations such as transvesical prostatectomy and the Supine Anterior Retroperitoneal Access (SARA) approach. Additionally, we explore the potential impact of emerging technologies—such as artificial intelligence, augmented reality, and telesurgery—on the future of SP platforms. Despite early limitations, SP systems have demonstrated comparable safety and effectiveness in selected cases and may offer unique advantages in specific anatomical scenarios. Continued innovation, structured training, and robust long-term outcome data will be essential for the broader adoption and integration of SP robotic surgery in clinical practice. Full article

(This article belongs to the Special Issue Robot-Assisted Surgery for Urologic Cancer)

25 pages, 1461 KB

Open AccessEditor’s ChoiceReview

Anti-EGFR Therapy in Metastatic Colorectal Cancer: Identifying, Tracking, and Overcoming Resistance

by Luís Felipe Leite, Mariana Macambira Noronha, Junior Samuel Alonso de Menezes, Lucas Diniz da Conceição, Luiz F. Costa Almeida, Anelise Poluboiarinov Cappellaro, Marcos Belotto, Tiago Biachi de Castria, Renata D’Alpino Peixoto and Thais Baccili Cury Megid

Cancers 2025, 17(17), 2804; https://doi.org/10.3390/cancers17172804 - 27 Aug 2025

Cited by 7 | Viewed by 8612

Abstract

Epidermal growth factor receptor (EGFR) inhibitors remain a cornerstone in the treatment of metastatic colorectal cancer with RAS and BRAF wild-type cancer. Yet, primary and acquired resistance limit their benefit for many patients. A growing body of evidence reveals that resistance is not [...] Read more.

Epidermal growth factor receptor (EGFR) inhibitors remain a cornerstone in the treatment of metastatic colorectal cancer with RAS and BRAF wild-type cancer. Yet, primary and acquired resistance limit their benefit for many patients. A growing body of evidence reveals that resistance is not random but rather driven by a complex network of molecular alterations that sustain tumor growth independent of EGFR signaling. These include amplification of ERBB2 (HER2) and MET, activation of the PI3K and AKT pathways, EGFR extracellular domain mutations, and rare kinase fusions. The concept of negative hyperselection has emerged as a powerful strategy to refine patient selection by excluding tumors with these resistance drivers. Multiple clinical trials have consistently shown that patients who are hyperselected based on comprehensive molecular profiling achieve significantly higher response rates and improved survival compared to those selected by RAS and BRAF status alone. Liquid biopsy through circulating tumor DNA has further transformed this landscape, offering a noninvasive tool to capture tumor heterogeneity, monitor clonal evolution in real time, and guide rechallenge strategies after resistance emerges. Together, negative hyperselection, ctDNA-guided monitoring, and emerging therapeutics define a precision-oncology framework for identifying, tracking, and overcoming resistance to anti-EGFR therapy in mCRC, moving the field toward more effective and individualized care. Looking ahead, the development of innovative therapeutics such as bispecific antibodies, antibody drug conjugates, and RNA-based therapies promises to further expand in this challenging clinical scenario. These advances move precision oncology in colorectal cancer from concept to clinical reality, reshaping the standard of care through molecular insights. Full article

(This article belongs to the Special Issue The Advance of Biomarker-Driven Targeted Therapies in Cancer)

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21 pages, 861 KB

Open AccessEditor’s ChoiceReview

Bispecific Antibodies and Antibody–Drug Conjugates in Relapsed/Refractory Aggressive Non-Hodgkin Lymphoma, Focusing on Diffuse Large B-Cell Lymphoma

by Santino Caserta, Chiara Campo, Gabriella Cancemi, Santo Neri, Fabio Stagno, Donato Mannina and Alessandro Allegra

Cancers 2025, 17(15), 2479; https://doi.org/10.3390/cancers17152479 - 26 Jul 2025

Cited by 4 | Viewed by 3555

Abstract

Relapsed/refractory diffuse large B-cell lymphoma and other non-Hodgkin lymphomas represent significant clinical challenges, particularly in patients who have exhausted standard immunochemotherapy and cellular therapies. Bispecific antibodies and antibody–drug conjugates have emerged as promising treatments, offering targeted and more effective treatment options compared to [...] Read more.

Relapsed/refractory diffuse large B-cell lymphoma and other non-Hodgkin lymphomas represent significant clinical challenges, particularly in patients who have exhausted standard immunochemotherapy and cellular therapies. Bispecific antibodies and antibody–drug conjugates have emerged as promising treatments, offering targeted and more effective treatment options compared to current standards. Bispecific antibodies, including epcoritamab and glofitamab, third-line therapies for diffuse large B-cell lymphoma, are recombinant immunoglobulins engineered to recognize two distinct antigens or epitopes simultaneously. This capability enhances therapeutic precision by bridging immune effector cells and tumor cells and modulating multiple signaling pathways involved in the pathogenesis of non-Hodgkin lymphoma. In the context of new therapies, antibody–drug conjugates, such as loncastuximab tesirine, are therapies composed of monoclonal antibodies linked to cytotoxic agents, in which the antibody selectively binds to tumor-associated antigens, delivering the cytotoxic payload directly to cancer cells while minimizing off-target effects. They combine the specificity of antibodies with the potency of chemotherapy, offering enhanced efficacy and safety in hematological malignancies. Ongoing clinical trials are investigating other molecules like odronextamab and the use of bispecific antibodies in combination regimens and earlier lines of therapy. The aim of this review is to explore actual therapies in relapsed/refractory diffuse large B-cell lymphoma, focusing on bispecific antibodies and antibody–drug conjugates. Full article

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

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34 pages, 2332 KB

Open AccessEditor’s ChoiceReview

Treatment of KRAS-Mutated Pancreatic Cancer: New Hope for the Patients?

by Kamila Krupa, Marta Fudalej, Emilia Włoszek, Hanna Miski, Anna M. Badowska-Kozakiewicz, Dominika Mękal, Michał P. Budzik, Aleksandra Czerw and Andrzej Deptała

Cancers 2025, 17(15), 2453; https://doi.org/10.3390/cancers17152453 - 24 Jul 2025

Cited by 5 | Viewed by 8013

Abstract

Pancreatic cancer, specifically pancreatic ductal adenocarcinoma (PDAC), ranks among the most lethal malignancies, with a 5-year survival rate of under 10%. The most prevalent KRAS mutations occur in three hotspot residues: glycine-12 (G12), glycine-13 (G13), and glutamine-61 (Q61), leading to the constant activation [...] Read more.

Pancreatic cancer, specifically pancreatic ductal adenocarcinoma (PDAC), ranks among the most lethal malignancies, with a 5-year survival rate of under 10%. The most prevalent KRAS mutations occur in three hotspot residues: glycine-12 (G12), glycine-13 (G13), and glutamine-61 (Q61), leading to the constant activation of the Ras pathway, making them the primary focus in oncologic drug development. Selective KRAS G12C inhibitors (e.g., sotorasib, adagrasib) have demonstrated moderate efficacy in clinical trials; however, this mutation is infrequent in PDAC. Emerging therapies targeting KRAS G12D and G12V mutations, such as MRTX1133, PROTACs, and active-state inhibitors, show promise in preclinical studies. Pan-RAS inhibitors like ADT-007, RMC-9805, and RMC-6236 compounds provide broader coverage of mutations. Their efficacy and safety are currently being investigated in several clinical trials. A major challenge is the development of resistance mechanisms, including secondary mutations and pathway reactivation. Combination therapies targeting the RAS/MAPK axis, SHP2, mTOR, or SOS1 are under clinical investigation. Immunotherapy alone has demonstrated limited effectiveness, attributed to an immunosuppressive tumor microenvironment, although synergistic effects are noted when paired with KRAS-targeted agents. Furthermore, KRAS mutations reprogram cancer metabolism, enhancing glycolysis, macropinocytosis, and autophagy, which are being explored therapeutically. RNA interference technologies have also shown potential in silencing mutant KRAS and reducing tumorigenicity. Future strategies should emphasize the combination of targeted therapies with metabolic or immunomodulatory agents to overcome resistance and enhance survival in KRAS-mutated PDAC. Full article

(This article belongs to the Special Issue Targeted Therapies in Pancreatic Cancer—Current Landscape and Future Directions)

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22 pages, 1820 KB

Open AccessEditor’s ChoiceArticle

Supercharged Natural Killer (sNK) Cells Inhibit Melanoma Tumor Progression and Restore Endogenous NK Cell Function in Humanized BLT Mice

by Kawaljit Kaur, Paytsar Topchyan and Anahid Jewett

Cancers 2025, 17(15), 2430; https://doi.org/10.3390/cancers17152430 - 23 Jul 2025

Cited by 5 | Viewed by 1590

Abstract

Background: We have previously shown the remarkable impact of a single infusion of supercharged NK cells (sNK) in preventing and eliminating oral, pancreatic, and uterine cancers implanted in humanized BLT (hu-BLT) mice. Objective: In this report, we extended the studies to melanoma tumors [...] Read more.

Background: We have previously shown the remarkable impact of a single infusion of supercharged NK cells (sNK) in preventing and eliminating oral, pancreatic, and uterine cancers implanted in humanized BLT (hu-BLT) mice. Objective: In this report, we extended the studies to melanoma tumors to observe whether there were differences in response to sNK cells. Methods: We investigated the safety and tissue biodistribution profile of sNK cells in hu-BLT mice. This included the effect of sNK cell therapy on the peripheral blood-derived PBMCs, bone marrow, and spleen of hu-BLT mice. Results: Our investigation showed promising outcomes, as sNK cell infusions effectively inhibited melanoma tumor growth in hu-BLT mice. These potent cells not only traversed through the peripheral blood, spleen, and bone marrow but also infiltrated the tumor site, triggering in vivo differentiation of melanoma tumors. Moreover, the infusion of sNK cells increased the percentages of NK cells in the peripheral blood of hu-BLT mice, restoring cytotoxicity and IFN-γ secretion within the peripheral blood, spleen, and bone marrow of melanoma-bearing mice. Conclusions: This therapeutic approach not only reversed tumor progression but also revitalized the functionality of endogenous NK cells, potentially reversing the immunosuppressive effects induced by tumor cells in cancer patients. Full article

(This article belongs to the Special Issue New Insights into Cancer Immunotherapy: From Immune Cell to Clinical Practice)

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16 pages, 691 KB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 8 | Viewed by 4120

Abstract

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

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

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

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14 pages, 362 KB

Open AccessEditor’s ChoiceReview

Recent Advances in Immunotherapy for Melanoma: Perspectives on the Development of Novel Treatments: A Mini Review

by Yusuke Muto, Taku Fujimura and Yoshihide Asano

Cancers 2025, 17(13), 2265; https://doi.org/10.3390/cancers17132265 - 7 Jul 2025

Cited by 4 | Viewed by 3000

Abstract

It has been more than a decade since anti-PD-1 and anti-CTLA-4 antibodies were first introduced for the treatment of unresectable melanoma. The advent of these immunotherapies has dramatically transformed the treatment landscape. In recent years, anti-PD-1 antibodies have become the cornerstone of melanoma [...] Read more.

It has been more than a decade since anti-PD-1 and anti-CTLA-4 antibodies were first introduced for the treatment of unresectable melanoma. The advent of these immunotherapies has dramatically transformed the treatment landscape. In recent years, anti-PD-1 antibodies have become the cornerstone of melanoma therapy, and the development of new treatment regimens has advanced rapidly in both Eastern and Western countries. However, clinical practice has revealed lower response rates in East Asian melanoma patients compared to Caucasian populations. This discrepancy may be partially attributed to T cell immune exhaustion within the tumor microenvironment, although the detailed mechanisms remain unclear. Moreover, there is currently no established treatment for BRAF wild-type melanoma that is resistant to anti-PD-1 antibodies. This review discusses the currently available therapeutic strategies for advanced melanoma and addresses the aforementioned challenges, highlighting recent efforts in both Eastern and Western regions. Full article

(This article belongs to the Special Issue Immunotherapy for Skin Cancers)

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18 pages, 543 KB

Open AccessEditor’s ChoiceReview

The PI3K/Akt/mTOR Signaling Pathway in Triple-Negative Breast Cancer: A Resistance Pathway and a Prime Target for Targeted Therapies

by Ali Hassan and Corinne Aubel

Cancers 2025, 17(13), 2232; https://doi.org/10.3390/cancers17132232 - 3 Jul 2025

Cited by 8 | Viewed by 5679

Abstract

Triple-negative breast cancer is the most aggressive subtype of breast cancer and is associated with the worst prognosis. Conventional chemotherapy remains the gold standard treatment for this disease but is associated with a high relapse rate, highlighting the urgent need for effective targeted [...] Read more.

Triple-negative breast cancer is the most aggressive subtype of breast cancer and is associated with the worst prognosis. Conventional chemotherapy remains the gold standard treatment for this disease but is associated with a high relapse rate, highlighting the urgent need for effective targeted therapies. The PI3K/Akt/mTOR pathway, dysregulated in nearly 60% of these cancers, appears to be a prime target. It involves a signaling cascade beginning with PI3K activation followed by activating phosphorylation of Akt and then mTOR complex, which activates oncogenic processes by enhancing protein synthesis, inhibiting apoptosis, dysregulating autophagy and promoting DNA repair that supports tumor cell survival. Moreover, the PI3K/Akt/mTOR pathway plays a central role in the development of chemoresistance. Numerous alterations (activating the mutation of PIK3CA or the loss of tumor suppressor PTEN) may lead to its overactivation. Targeted inhibitors of PI3K, Akt and mTOR have been developed to counteract this dysregulation. However, numerous cancer resistance mechanisms have emerged, reducing their efficacy, for example, reactivation of Akt following mTOR blockade, reactivation of the pathway by insulin signaling or activation of compensatory pathways such as the MAPK pathway, thus limiting their integration into routine practice. To counteract these resistances, combination therapies currently being investigated in clinical trials aim to improve clinical outcomes of PI3K/Akt/mTOR pathway inhibition. The aim of this review was to summarize current therapies developed to target this pathway in TNBC, with a focus on the resistance mechanisms that limit their effectiveness. Full article

(This article belongs to the Special Issue PI3K Pathway in Cancer)

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12 pages, 1341 KB

Open AccessEditor’s ChoiceArticle

Prognostic Value of PLR, SIRI, PIV, SII, and NLR in Non-Muscle Invasive Bladder Cancer: Can Inflammatory Factors Influence Pathogenesis and Outcomes?

by Francesco Pio Bizzarri, Marco Campetella, Pierluigi Russo, Giuseppe Palermo, Seyed Koosha Moosavi, Francesco Rossi, Lorenzo D’Amico, Antonio Cretì, Filippo Gavi, Enrico Panio, Simona Presutti, Fabrizio Bellavia, Mauro Ragonese, Chiara Ciccarese, Roberto Iacovelli, Maria Chiara Sighinolfi, Marco Racioppi, Emilio Sacco and Bernardo Rocco

Cancers 2025, 17(13), 2189; https://doi.org/10.3390/cancers17132189 - 28 Jun 2025

Cited by 9 | Viewed by 1447

Abstract

Background/Objectives: Given the increasing interest in the predictive role of inflammation in oncology, we aimed to assess the association between inflammatory factors (IFs) and the histopathological characteristics of bladder cancer (BC). Our objective was to correlate some of these IFs with BC progression [...] Read more.

Background/Objectives: Given the increasing interest in the predictive role of inflammation in oncology, we aimed to assess the association between inflammatory factors (IFs) and the histopathological characteristics of bladder cancer (BC). Our objective was to correlate some of these IFs with BC progression and recurrence, identifying possible new diagnostic tools. Methods: We retrospectively analyzed 285 patients (79.8% male, 20.4% female; median age 73) who underwent transurethral resection of the bladder (TURB) between January 2016 and January 2022. The preoperative neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), pan-immune-inflammation value (PIV), systemic inflammation response index (SIRI), and standard clinical variables were collected one month before TURB and evaluated as predictors of recurrence and progression. Patients were stratified using the Youden Index and ROC analysis. Cox regression models were applied to identify independent predictors. Results: High-grade tumors were present in 74.6% of cases, and 34% were recurrent. Carcinoma in situ was found in 5%. After 72 months, 53% underwent radical cystectomy, and 13.7% died within 5 years. The optimal cutoffs were PLR 139, SIRI 1.12, PIV 248.49, NLR 2, SII 327. Smoking, primary MIBC, age, and lymph node status were significantly associated with recurrence. Elevated PLR correlated with recurrence and T2 progression (p = 0.004). Higher SIRI, PIV, and PLR levels were significantly associated with lymphovascular invasion and nodal metastasis (p < 0.05). PLR was linked to recurrence in tumors ≥ 3 cm post-BCG (p = 0.004); high SIRI predicted recurrence within 48 months (p = 0.05). Conclusions: High PLR and SIRI levels were associated with recurrence. Our findings support the emerging role of IFs in predicting BC outcomes and suggest their potential inclusion in future prognostic models. Full article

(This article belongs to the Special Issue New Advances in Urothelial Cancer: Diagnosis, Therapy and Prognosis (2nd Edition))

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28 pages, 7186 KB

Open AccessEditor’s ChoiceReview

Advances and Challenges in Prostate Cancer Diagnosis: A Comprehensive Review

by Emil Kania, Maciej Janica, Miłosz Nesterowicz, Wojciech Modzelewski, Mateusz Cybulski and Jacek Janica

Cancers 2025, 17(13), 2137; https://doi.org/10.3390/cancers17132137 - 25 Jun 2025

Cited by 5 | Viewed by 5547

Abstract

Prostate cancer is the most commonly diagnosed malignancy in men and continues to be a leading cause of cancer-related mortality. Accurate and timely diagnosis is essential for distinguishing clinically significant tumors from indolent lesions and for informing treatment decisions. Multiparametric magnetic resonance imaging [...] Read more.

Prostate cancer is the most commonly diagnosed malignancy in men and continues to be a leading cause of cancer-related mortality. Accurate and timely diagnosis is essential for distinguishing clinically significant tumors from indolent lesions and for informing treatment decisions. Multiparametric magnetic resonance imaging (mpMRI) has revolutionized prostate cancer detection by enabling precise lesion localization, risk stratification, and improved biopsy targeting. Fusion biopsy, which combines mpMRI findings with real-time transrectal ultrasonography (TRUS), has emerged as a highly effective method for sampling suspicious lesions. This review provides an integrated anatomical, epidemiological, technical, and clinical overview that highlights the evolving role of fusion biopsy in contemporary prostate cancer diagnostics. We also explore emerging strategies such as penumbra-targeted sampling, discuss ongoing clinical challenges, and examine the impact of biopsy underestimation and lack of standardization. Compared to conventional systematic biopsy, mpMRI-TRUS fusion biopsy improves the detection of clinically significant prostate cancer while reducing the overdiagnosis of low-risk tumors. To our knowledge, few recent reviews have comprehensively synthesized current clinical guidelines, emerging biopsy techniques, and future directions within a single narrative. mpMRI-TRUS-guided fusion biopsy represents a major advancement in the prostate cancer diagnostic pathway, promoting precision oncology by reducing overtreatment and facilitating individualized patient care. This review aims to assist clinicians in adopting biopsy innovations that enhance diagnostic accuracy and improve patient outcomes. Full article

(This article belongs to the Special Issue Overcoming Pitfalls in the Detection and Definition of Clinically Significant Prostate Cancer: Strategies to Improve Screening and Diagnosis)

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26 pages, 306 KB

Open AccessEditor’s ChoiceReview

Screening for Cervical Cancer: A Comprehensive Review of Guidelines

by Evgenia Zampaoglou, Eirini Boureka, Evdoxia Gounari, Polyxeni-Natalia Liasidi, Ioannis Kalogiannidis, Zoi Tsimtsiou, Anna-Bettina Haidich, Ioannis Tsakiridis and Themistoklis Dagklis

Cancers 2025, 17(13), 2072; https://doi.org/10.3390/cancers17132072 - 20 Jun 2025

Cited by 4 | Viewed by 9554

Abstract

Cervical cancer remains one of the main causes of female mortality, especially in middle- and low-income countries, despite efforts towards the implementation of global vaccination against human papillomavirus (HPV). The aim of this study was to review and compare the most recently published [...] Read more.

Cervical cancer remains one of the main causes of female mortality, especially in middle- and low-income countries, despite efforts towards the implementation of global vaccination against human papillomavirus (HPV). The aim of this study was to review and compare the most recently published international guidelines providing recommendations on cervical cancer screening strategies among average and high-risk women. Thus, a comparative review of guidelines by the US Preventive Services Task Force (USPSTF), the American Cancer Society (ACS), the American Society of Clinical Oncology (ASCO), the World Health Organization (WHO), the Canadian Task Force on Preventive Health Care (CTFPHC), the Cancer Council Australia (CCA), and the European Guidelines (EG) was conducted. There is an overall agreement regarding the suggestions made for women younger than 21 and those older than 65, with all guidelines stating against routine screening, with the exceptions of CTFPHC and CCA that expand the age group to up to 70 and 75 years, respectively. Continuation of screening in older women is also suggested in those with a history of a precancerous lesion and those with inadequate screening. Most guidelines recommend routine screening at 30–65 years, while the WHO advises that screening should be prioritized at 30–49 years. HPV DNA testing is the method of choice recommended by most guidelines, followed by cytology as an alternative, except for CTFPHC, which refers to cytology only, with self-sampling being an acceptable method by most medical societies. Agreements exist regarding recommendations for specific groups, such as women with a history of total hysterectomy for benign reasons, women with a complete vaccination against HPV, individuals from the lesbian, gay, bisexual, transgender, and queer communities and women with multiple sexual partners or early initiation of sexual activity. On the other hand, the age group of 21–29 is addressed differently by the reviewed guidelines, while differentiations also occur in the screening strategies in cases of abnormal screening results, in women with immunodeficiency, those with in utero exposure to diethylstilbestrole and pregnant women. The development of consistent practice protocols for the most appropriate cervical cancer screening programs seems to be of major importance to reduce mortality rates and safely guide everyday clinical practice. Full article

(This article belongs to the Section Cancer Causes, Screening and Diagnosis)

21 pages, 4441 KB

Open AccessEditor’s ChoiceReview

An Update on Flow Cytometry Analysis of Hematological Malignancies: Focus on Standardization

by Eda Holl, Michael Kapinsky and Anis Larbi

Cancers 2025, 17(12), 2045; https://doi.org/10.3390/cancers17122045 - 19 Jun 2025

Cited by 4 | Viewed by 4987

Abstract

Flow cytometry use has significantly increased in clinical laboratories and has significantly helped improve the diagnosis of leukemias, lymphomas, and follow-up of minimal residual disease. Mastering this technique enables the performance of multiparametric single-cell analysis and increases the odds of identifying abnormal populations. [...] Read more.

Flow cytometry use has significantly increased in clinical laboratories and has significantly helped improve the diagnosis of leukemias, lymphomas, and follow-up of minimal residual disease. Mastering this technique enables the performance of multiparametric single-cell analysis and increases the odds of identifying abnormal populations. As in many fields, there is a need to improve the quality of the data generated for accuracy, reproducibility, and trueness. The implementation of solutions reducing variability is achievable and needed, as the flow cytometry workflow involves many manual steps and items susceptible to operator bias and human error. Standardization of flow cytometry assays is sought and already implemented in many clinical hematology laboratories. However, the clinical community would highly benefit from further efforts in that direction to increase the comparability of findings across laboratories. This review covers the strengths and weaknesses of flow cytometry and focuses on the standardization approaches developed, including recent advances in the field. Full article

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

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12 pages, 229 KB

Open AccessEditor’s ChoiceReview

Surgical Management of Oligometastatic Non-Small Cell Lung Cancer

by Susana Fortich, Deniz Piyadeoglu, Nafiye Busra Celik and Mara Antonoff

Cancers 2025, 17(12), 2040; https://doi.org/10.3390/cancers17122040 - 18 Jun 2025

Cited by 4 | Viewed by 2851

Abstract

Background: Oligometastatic non-small cell lung cancer (NSCLC) represents a biologically and clinically distinct state characterized by limited metastatic spread. Increasing evidence suggests that aggressive local therapies, including surgical resection, may confer a survival benefit in this population. The objective of this review is [...] Read more.

Background: Oligometastatic non-small cell lung cancer (NSCLC) represents a biologically and clinically distinct state characterized by limited metastatic spread. Increasing evidence suggests that aggressive local therapies, including surgical resection, may confer a survival benefit in this population. The objective of this review is to evaluate the current role of surgery in the management of oligometastatic NSCLC, with emphasis on patient selection, surgical strategy, integration with systemic therapy, and ongoing clinical investigations. Methods: This narrative review synthesizes retrospective and prospective clinical data, meta-analyses, major consensus guidelines, and ongoing trials since 2012. We highlight prognostic factors, staging strategies, and the evolving role of molecular and biomarker-based stratification. Results: Multiple retrospective studies and several randomized trials have demonstrated improved progression-free and overall survival with local consolidative therapy in oligometastatic NSCLC. Prognostic factors associated with favorable outcomes include a limited number of metastases (≤3), good performance status, absence of mediastinal nodal disease, metachronous presentation, and actionable molecular alterations. The integration of surgery with systemic therapies, including targeted agents and immunotherapy, has become increasingly common in selected patients. Ongoing trials such as LONESTAR, NORTHSTAR, and BRIGHTSTAR are expected to further define the role of surgery in this setting. Conclusions: Surgery is emerging as a key component of multimodal treatment for carefully selected patients with oligometastatic NSCLC. Future efforts should focus on refining patient selection through molecular stratification and expanding prospective trial data to guide personalized biology-driven treatment strategies. Full article

(This article belongs to the Special Issue The Current Status of Treatment for Oligometastatic Lung Cancer)

14 pages, 1482 KB

Open AccessEditor’s ChoiceSystematic Review

Safety and Efficacy Outcomes of Robotic, Laparoscopic, and Laparotomic Surgery in Severe Obese Endometrial Cancer Patients: A Network Meta-Analysis

by Carlo Ronsini, Mario Fordellone, Eleonora Braca, Mariano Catello Di Donna, Maria Cristina Solazzo, Giuseppe Cucinella, Cono Scaffa, Pasquale De Franciscis and Vito Chiantera

Cancers 2025, 17(12), 2018; https://doi.org/10.3390/cancers17122018 - 17 Jun 2025

Cited by 4 | Viewed by 1694

Abstract

Background: The surgical management of endometrial cancer in severely obese patients (BMI ≥ 40) presents unique challenges. This study evaluates the outcomes of various surgical approaches in terms of safety and efficacy in lymph node retrieval. Methods: A systematic review and network meta-analysis [...] Read more.

Background: The surgical management of endometrial cancer in severely obese patients (BMI ≥ 40) presents unique challenges. This study evaluates the outcomes of various surgical approaches in terms of safety and efficacy in lymph node retrieval. Methods: A systematic review and network meta-analysis focused on intra-operative complications, post-operative complications, severe complications, and complete surgical staging rates. The analysis included 1163 patients, following a pre-specified methodology based on the PRISMA-NMA guidelines. The study was registered on PROSPERO with protocol number CRD 395959. Results: Intra-operative complications: No significant difference was found between minimally invasive surgery (MIS, 233 patients) and laparotomy (LPT) (OR 0.68 [95% CI 0.21–2.26], p = 0.18). However, robotic surgery showed a significantly lower risk (OR 0.28 [0.10–0.74]). Post-operative complications: The MIS group (457 patients) had a lower risk compared to LPT (OR 0.41 [0.26–0.64]). Network analysis: Robotic surgery had a 70.7% probability of reducing intra-operative complications compared to laparoscopy (LPS) and a 99.2% probability compared to LPT. Laparoscopy was the safest option for post-operative complications, with a 74.3% probability. Robotic surgery had an 82.4% probability of achieving complete surgical staging compared to LPT. Conclusions: Robotic surgery shows superior outcomes for complete lymph nodal staging in obese endometrial cancer patients, while LPS is favorable for post-operative complications. Further studies are needed to optimize strategies. Full article

(This article belongs to the Special Issue New Diagnostic and Therapeutic Perspectives of Gynecological Carcinomas)

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15 pages, 1416 KB

Open AccessEditor’s ChoiceArticle

Benefits from ¹⁸F-FDG PET-CT-Based Radiotherapy Planning in Stage III Non-Small-Cell Lung Cancer: A Prospective Single-Center Study

by Admir Mulita, Pipitsa Valsamaki, Eleni Bekou, Stavros Anevlavis, Christos Nanos, Athanasios Zisimopoulos, Alexandra Giatromanolaki and Michael I. Koukourakis

Cancers 2025, 17(12), 1969; https://doi.org/10.3390/cancers17121969 - 13 Jun 2025

Cited by 4 | Viewed by 1818

Abstract

Background/Objectives: Lung cancer is the leading cause of cancer-related mortality worldwide. Accurate radiotherapy (RT) planning alongside chemotherapy and immunotherapy is critical for improving treatment outcomes for inoperable non-metastatic cases. Conventional computed tomography (CT)-based planning may be inadequate for accurately identifying tumor margins and [...] Read more.

Background/Objectives: Lung cancer is the leading cause of cancer-related mortality worldwide. Accurate radiotherapy (RT) planning alongside chemotherapy and immunotherapy is critical for improving treatment outcomes for inoperable non-metastatic cases. Conventional computed tomography (CT)-based planning may be inadequate for accurately identifying tumor margins and the location of nodal disease. We investigated whether ¹⁸F-labeled fluorodeoxyglucose positron emission tomography (¹⁸F-FDG PET-CT) imaging can assist in target volume delineation for primary, nodal, and metastatic disease in the RT planning and overall therapeutic planning of patients. Methods: In this single-center, prospective study, we recruited 34 patients with histologically confirmed locally advanced non-small-cell lung carcinoma (NSCLC). All patients underwent ¹⁸F-FDG PET-CT-based RT simulation. Two sequential RT plans were created by the same radiation oncologist: one based on CT alone and the other PET-CT. Planning target volumes (PTVs) and PET-CT-guided adjustments were analyzed to assess their impact. Standardized protocols for immobilization, imaging, target delineation, and dose prescription were applied. Results: A total of 34 patients (31 males and 3 females) were recruited in the study. ¹⁸F-FDG PET-CT detected distant metastases in 7/34 (20.6%) patients, altering the overall therapeutic plan in 4/34 (11.8%) and allowing radical RT in 3 of them who had oligometastatic disease (8.8%). It modified RT planning in 26/34 (76.5%) patients and clarified malignancy in atelectatic areas. Nodal involvement was identified in 3/34 patients (8.8%) and excluded in 3/34 cases, avoiding unnecessary nodal irradiation. Additional involved nodes were revealed in 12/34 (35.3%) patients, requiring dose escalation. Overall, changes to the tumor PTV were made in 23/30 (76.6%) and to the nodal PTV in 19/30 (63.3%) cases (p < 0.0001). Primary tumor and nodal PTVs increased in 20/34 (66.7%) and 13/34 (43.3%), respectively. Conclusions: ¹⁸F-FDG PET-CT significantly improves RT planning by more precisely defining tumor and nodal volumes, identifying undetected lesions, and guiding dose adaptation. Larger long-term studies are required to confirm potential locoregional control and survival improvements. Full article

(This article belongs to the Special Issue Recent Developments in the Field of Radiotherapy Treatment for Lung Cancer)

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31 pages, 1245 KB

Open AccessEditor’s ChoiceReview

Neoantigen-Based Immunotherapy in Lung Cancer: Advances, Challenges and Prospects

by Xiong Li, Ya-Juan Zhu, Ying Xue, Ting-Ting Chen, Xiao-Ke Sun and Hong-Yang Shi

Cancers 2025, 17(12), 1953; https://doi.org/10.3390/cancers17121953 - 12 Jun 2025

Cited by 6 | Viewed by 4598

Abstract

Lung cancer ranks among the most prevalent malignant tumors, characterized by delayed diagnosis, limited treatment efficacy, and generally poor prognosis. Consequently, there is an urgent demand for effective treatments. Neoantigen-based immunotherapy emerged as a promising strategy in lung cancer treatment as ideal targets [...] Read more.

Lung cancer ranks among the most prevalent malignant tumors, characterized by delayed diagnosis, limited treatment efficacy, and generally poor prognosis. Consequently, there is an urgent demand for effective treatments. Neoantigen-based immunotherapy emerged as a promising strategy in lung cancer treatment as ideal targets for immunotherapy interventions. Neoantigens are tumor-specific antigens produced by genetic mutations in somatic cells, which, unlike tumor-associated antigens, are found only in tumor tissue. Neoantigen immunotherapy has the advantages of high specificity, high safety and low immunotolerance, especially for lung cancer patients with a high tumor mutation load. We systematically summarize the biological characteristics, prediction and identification, mechanism of action, clinical application, risk challenges, and prospects of neoantigens as a novel precision immunotherapy method in lung cancer to provide valuable insights and references for the advancement of lung cancer treatment strategies. Full article

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

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12 pages, 1593 KB

Open AccessEditor’s ChoiceReview

Next-Generation CAR-T and TCR-T Cell Therapies for Solid Tumors: Innovations, Challenges, and Global Development Trends

by Tomomi Sanomachi, Yuki Katsuya, Tetsuya Nakatsura and Takafumi Koyama

Cancers 2025, 17(12), 1945; https://doi.org/10.3390/cancers17121945 - 11 Jun 2025

Cited by 7 | Viewed by 10162

Abstract

Chimeric antigen receptor (CAR)-T and T-cell receptor (TCR)-engineered T-cell (TCR-T) therapies have revolutionized the treatment of hematological malignancies; however, their application to solid tumors remains a formidable challenge. The immunosuppressive tumor microenvironment, antigen heterogeneity, and manufacturing complexity limit the clinical efficacy and scalability [...] Read more.

Chimeric antigen receptor (CAR)-T and T-cell receptor (TCR)-engineered T-cell (TCR-T) therapies have revolutionized the treatment of hematological malignancies; however, their application to solid tumors remains a formidable challenge. The immunosuppressive tumor microenvironment, antigen heterogeneity, and manufacturing complexity limit the clinical efficacy and scalability of these treatment modalities. This review provides a comprehensive analysis of the current clinical development strategies for CAR-T and TCR-T cell therapies for solid tumors. Herein, we discuss recent breakthroughs and highlight the potential of TCR-T cell therapy. Furthermore, innovative approaches for enhancing CAR-T cell function in solid tumors (e.g., in vivo engineering; induced pluripotent stem cell-derived allogeneic CAR-T cells; armored CAR constructs; dual-antigen targeting; and combination regimens with checkpoint inhibitors, chemotherapy, radiotherapy, and oncolytic viruses) are explored. We also present trends in global patent activity, revealing a marked acceleration in CAR-T- and TCR-T-related innovations, with the United States and China leading with respect to application volumes. This field is increasingly characterized by multidisciplinary collaborations between academia and industry, driving the development of next-generation platforms, including messenger RNA-based and off-the-shelf cell therapies. Although no CAR-T product has been approved for solid tumors, these findings underscore the accelerating momentum and translational promise of adoptive cell therapies. Addressing the unique biological and logistical challenges of solid tumors is essential for realizing the full potential of these transformative immunotherapies. Full article

(This article belongs to the Special Issue Advances in Clinical Trials: Outcome, Innovations, Challenges, and Ethical Practice in Cancer Research 2025–2026)

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11 pages, 561 KB

Open AccessEditor’s ChoiceReview

Current Progress and Future Perspectives of RNA-Based Cancer Vaccines: A 2025 Update

by Matthias Magoola and Sarfaraz K. Niazi

Cancers 2025, 17(11), 1882; https://doi.org/10.3390/cancers17111882 - 4 Jun 2025

Cited by 16 | Viewed by 16795

Abstract

RNA-based cancer vaccines have emerged as transformative immunotherapeutic platforms, leveraging advances in mRNA technology and personalized medicine approaches. Recent clinical breakthroughs, particularly the success of mRNA-4157 combined with pembrolizumab in melanoma patients, have demonstrated significant improvements in efficacy, with a 44% reduction in [...] Read more.

RNA-based cancer vaccines have emerged as transformative immunotherapeutic platforms, leveraging advances in mRNA technology and personalized medicine approaches. Recent clinical breakthroughs, particularly the success of mRNA-4157 combined with pembrolizumab in melanoma patients, have demonstrated significant improvements in efficacy, with a 44% reduction in recurrence risk compared to checkpoint inhibitor monotherapy. Breakthrough results from pancreatic cancer vaccines and novel glioblastoma treatments using layered nanoparticle delivery systems mark 2024–2025 as a pivotal period for RNA cancer vaccine development. Current RNA vaccine platforms include conventional mRNA, self-amplifying RNA, trans-amplifying RNA, and emerging circular RNA technologies, with over 120 clinical trials currently underway across various malignancies. Critical advances in delivery optimization include next-generation lipid nanoparticles with tissue-specific targeting and novel nanoengineered systems achieving rapid immune system reprogramming. Manufacturing innovations focus on automated platforms, reducing production timelines from nine weeks to under four weeks for personalized vaccines, while costs remain challenging at over $ 100,000 per patient. Artificial intelligence integration is revolutionizing neoantigen selection through advanced algorithms and CRISPR-enhanced platforms, while regulatory frameworks are evolving with new FDA guidance for therapeutic cancer vaccines. Non-coding RNA applications, including microRNA and long non-coding RNA therapeutics, represent emerging frontiers with potential for enhanced immune modulation. With over 60 candidates in clinical development and the first commercial approvals anticipated by 2029, RNA cancer vaccines are positioned to become cornerstone therapeutics in personalized oncology, offering transformative hope for cancer patients worldwide. Full article

(This article belongs to the Special Issue Advances in Drug Delivery for Cancer Therapy)

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14 pages, 3146 KB

Open AccessEditor’s ChoiceArticle

A High Performing Biomarker Signature for Detecting Early-Stage Pancreatic Ductal Adenocarcinoma in High-Risk Individuals

by Norma A. Palma, Aimee L. Lucas, Bryson W. Katona, Alcibiade Athanasiou, Natasha M. Kureshi, Lisa Ford, Thomas Keller, Stephen Weber, Ralph Schiess, Thomas King, Diane M. Simeone and Randall Brand

Cancers 2025, 17(11), 1866; https://doi.org/10.3390/cancers17111866 - 2 Jun 2025

Cited by 6 | Viewed by 3282

Abstract

Background/Objectives: Early detection of pancreatic cancer can improve patient survival, and blood-based biomarkers to aid in this are a significant need. The goal of this study was to develop and evaluate the performance of a 4- to 6-plex biomarker signature for detection of [...] Read more.

Background/Objectives: Early detection of pancreatic cancer can improve patient survival, and blood-based biomarkers to aid in this are a significant need. The goal of this study was to develop and evaluate the performance of a 4- to 6-plex biomarker signature for detection of early-stage pancreatic ductal adenocarcinoma (PDAC) that performs well in high-risk controls. Methods: Enzyme-linked immunosorbent assays were used to measure 10 previously identified serum protein biomarker candidates in Stage I and II PDAC cases (n = 128), high-risk controls (n = 465), and normal-risk controls (n = 30). Various combinations of biomarker candidates (models) were trained using machine learning and tested for robustness in differentiating cases from controls on the full cohort and in clinically relevant sub-types including those with diabetes, those ≥65 years of age, and low producers of carbohydrate antigen 19-9 (CA 19-9). Results: At 98% specificity, the top performing model, which was comprised of tissue inhibitor of metalloproteinase 1 (TIMP1), intracellular adhesion molecule 1 (ICAM1), thrombospondin 1 (THBS1), cathepsin D (CTSD), and CA 19-9, achieved 85% sensitivity in the full cohort and sensitivities of 91% in diabetics, 90% in ≥65 years of age, and 60% in low CA 19-9 producers. This model demonstrated significantly higher sensitivity in detecting PDAC in the full cohort and all sub-populations compared to CA 19-9 alone (p < 0.001). Conclusions: Our findings demonstrate the feasibility of a blood-based assay for detecting early-stage PDAC in high-risk individuals and key sub-populations, representing an important step towards improving diagnostic success for early-stage disease. Full article

(This article belongs to the Section Cancer Biomarkers)

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34 pages, 4621 KB

Open AccessEditor’s ChoiceReview

Lymphatic Metastasis of Esophageal Squamous Cell Carcinoma: The Role of NRF2 and Therapeutic Strategies

by Yahui Li, Zachary Ladd, Zhaohui Xiong, Candice Bui-Linh, Chorlada Paiboonrungruang, Boopathi Subramaniyan, Huan Li, Haining Wang, Curt Balch, David D. Shersher, Francis Spitz and Xiaoxin Chen

Cancers 2025, 17(11), 1853; https://doi.org/10.3390/cancers17111853 - 31 May 2025

Cited by 4 | Viewed by 4514

Abstract

The lethality of esophageal squamous cell carcinoma (ESCC), and other epithelial cancers, is primarily due to its aggressive nature and frequent lymphatic metastasis, both of which impact prognosis. In this review, we explore the underlying molecular mechanisms of ESCC lymphatic metastasis, specifically, the [...] Read more.

The lethality of esophageal squamous cell carcinoma (ESCC), and other epithelial cancers, is primarily due to its aggressive nature and frequent lymphatic metastasis, both of which impact prognosis. In this review, we explore the underlying molecular mechanisms of ESCC lymphatic metastasis, specifically, the functional role of NRF2 and therapeutic strategies. Current data suggest that NRF2 hyperactivation (NRF2^high) may promote lymphatic metastasis of ESCC by affecting the extracellular matrix (ECM), epithelial–mesenchymal transition (EMT), lymphangiogenesis, immune evasion, metabolic programming, and Hippo signaling. We also update the latest developments in NRF2 inhibitors, their mechanisms of action, screening strategies, and approaches for evaluating compound efficacy. Finally, we highlight the utility of animal models for mechanistic studies and therapeutic development. We believe elucidation of the functional role of NRF2 in ESCC lymphatic metastasis and developing proper NRF2 inhibitors will greatly improve the clinical prognosis of ESCC in human patients. Full article

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

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20 pages, 578 KB

Open AccessEditor’s ChoiceReview

Harnessing Artificial Intelligence in Pediatric Oncology Diagnosis and Treatment: A Review

by Mubashir Hassan, Saba Shahzadi and Andrzej Kloczkowski

Cancers 2025, 17(11), 1828; https://doi.org/10.3390/cancers17111828 - 30 May 2025

Cited by 6 | Viewed by 2622

Abstract

Artificial intelligence (AI) is rapidly transforming pediatric oncology by creating new means to improve the accuracy and efficacy of cancer diagnosis and treatment in children. This review critically examines current applications of AI technologies like machine learning (ML) and deep learning (DL) to [...] Read more.

Artificial intelligence (AI) is rapidly transforming pediatric oncology by creating new means to improve the accuracy and efficacy of cancer diagnosis and treatment in children. This review critically examines current applications of AI technologies like machine learning (ML) and deep learning (DL) to the main types of pediatric cancers. However, the application of AI to pediatric oncology is prone to certain challenges, including the heterogeneity and rarity of pediatric cancer data, rapid technological development in imaging, and ethical concerns pertaining to data privacy and algorithmic transparency. Collaborative efforts and data-sharing schemes are important to surpass these challenges and facilitate effective training of AI models. This review also points to emerging trends, including AI-based radiomics and proteomics applications, and provides future directions to realize the full potential of AI in pediatric oncology. Finally, AI is a promising paradigm shift toward precision medicine in childhood cancer treatment, which can enhance the survival rates and quality of life for pediatric patients. Full article

(This article belongs to the Section Cancer Informatics and Big Data)

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13 pages, 1624 KB

Open AccessEditor’s ChoiceArticle

Proportional Correlation Between Systemic Inflammation Response Index and Gastric Cancer Recurrence Time: A Retrospective Study

by Kyungryun In, Sunhyung Kang, Hyunseok Lee, Hyuksoo Eun, Heeseok Moon, Eaumseok Lee, Seokhyun Kim, Jaekyu Sung and Byungseok Lee

Cancers 2025, 17(9), 1415; https://doi.org/10.3390/cancers17091415 - 23 Apr 2025

Cited by 3 | Viewed by 1345

Abstract

Background: Disease recurrence is the primary cause of death in patients with gastric cancer who have undergone complete surgical resection. No prognostic factors for recurrence, other than the Tumor, Node, and Metastasis stage, have been established. However, recurrence rates differ even within the [...] Read more.

Background: Disease recurrence is the primary cause of death in patients with gastric cancer who have undergone complete surgical resection. No prognostic factors for recurrence, other than the Tumor, Node, and Metastasis stage, have been established. However, recurrence rates differ even within the same Tumor, Node, and Metastasis stage. Therefore, we aimed to develop a new prognostic confidence measure for gastric cancer recurrence and demonstrate its practical utility. Methods: This was a retrospective study based on the medical records of the Chungnam National University Hospital, Republic of Korea. We enrolled patients diagnosed with stage II/III gastric cancer who underwent complete surgical resection and adjuvant chemotherapy over the past 12 years. The association between seven variables, including the systemic inflammation response index (SIRI) and gastric cancer recurrence, was analyzed. Results: A total of 296 patients were enrolled in this study. Although other factors did not exhibit significant correlations, SIRI showed a significant positive correlation with gastric cancer recurrence risk, confirmed through Cox regression testing (hazard ratio, 1.231; 95% confidence interval, 1.04–1.45). Linear regression analysis revealed a significant association between higher SIRI values and shorter recurrence time (p = 0.044; β = −0.225). Conclusions: In this study, other than SIRI, effective prognostic factors related to gastric cancer recurrence were not verified, thus indicating SIRI as a potential independent prognostic factor. Full article

(This article belongs to the Special Issue Role of Cancer Biomarkers for Diagnosis, Prognosis and Targeted Therapy in Gastrointestinal Cancers)

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27 pages, 15911 KB

Open AccessEditor’s ChoiceArticle

Pro-Inflammatory Cytokines Transactivate Glycosylated Cytokine Receptors on Cancer Cells to Induce Epithelial–Mesenchymal Transition to the Metastatic Phenotype

by Leili Baghaie, David A. Bunsick, Emilyn B. Aucoin, Elizabeth Skapinker, Abdulrahman M. Yaish, Yunfan Li, William W. Harless and Myron R. Szewczuk

Cancers 2025, 17(7), 1234; https://doi.org/10.3390/cancers17071234 - 5 Apr 2025

Cited by 2 | Viewed by 1583

Abstract

Background/Objectives: The significance of cytokine signaling on cancer progression and metastasis has raised interest in cancer research over the last few decades. Here, we analyzed the effects of three cytokines that we previously reported are significantly upregulated rapidly after the surgical removal of [...] Read more.

Background/Objectives: The significance of cytokine signaling on cancer progression and metastasis has raised interest in cancer research over the last few decades. Here, we analyzed the effects of three cytokines that we previously reported are significantly upregulated rapidly after the surgical removal of primary breast, colorectal, and prostate cancer. We also investigated the regulation of their cognate receptors. Methods: All experiments were conducted using the PANC-1, SW620, and MCF-7 cell lines, treated with three different cytokines (TGF-β1, HGF, and IL-6). The effect of these cytokines on the expression of epithelial–mesenchymal transition (EMT) cell surface markers and neuraminidase-1 activity was measured via fluorescent microscopy and image analysis software. Results: The findings show that these cytokines increase the expression of mesenchymal markers while reducing epithelial markers, corresponding to the EMT process. A strong link between cytokine receptor signaling and the Neu-1-MMP-9-GPCR crosstalk was identified, suggesting that cytokine receptor binding leads to increased Neu-1 activity and subsequent signaling pathway activation. Oseltamivir phosphate (OP) prevented sialic acid hydrolysis by neuraminidase-1 (Neu-1), leading to the downregulation of these signaling cascades. Conclusions: In concert with the previous work revealing the role of Neu-1 in regulating other glycosylated receptors implicated in cancer cell proliferation and EMT, targeting Neu-1 may provide effective treatment against a variety of malignancies. Most significantly, the treatment of patients with specific inhibitors of Neu-1 soon after primary cancer surgery may improve our ability to cure early-stage cancer by inhibiting the EMT process and disrupting the ability of any residual cancer cell population to metastasize. Full article

(This article belongs to the Special Issue Role of Cytokines in Cancer)

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21 pages, 1679 KB

Open AccessEditor’s ChoiceReview

Advances in Non-Invasive Screening Methods for Gastrointestinal Cancers: How Continued Innovation Has Revolutionized Early Cancer Detection

by Dushyant Singh Dahiya, Sheza Malik, Ruchir Paladiya, Sidra Ahsan, Haniya Wasim, Hareesha Rishab Bharadwaj, Abhishek Goel, Ali Jaan, Umar Hayat, Fariha Hasan, Sneh Sonaiya and Hassam Ali

Cancers 2025, 17(7), 1085; https://doi.org/10.3390/cancers17071085 - 24 Mar 2025

Cited by 5 | Viewed by 5995

Abstract

The early diagnosis of gastrointestinal cancers is essential for better survival and to reduce the burden of malignancies worldwide [...] Full article

(This article belongs to the Special Issue Gastrointestinal and Its Associated Malignancies: Diagnosis, Targets and Therapies)

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19 pages, 2212 KB

Open AccessEditor’s ChoiceReview

IL-10-Directed Cancer Immunotherapy: Preclinical Advances, Clinical Insights, and Future Perspectives

by Adel G. El-Shemi, Afnan Alqurashi, Jihan Abdullah Abdulrahman, Hanin Dhaifallah Alzahrani, Khawlah Saad Almwalad, Hadeel Hisham Felfilan, Wahaj Saud Alomiri, Jana Ahmed Aloufi, Ghadeer Hassn Madkhali, Sarah Adel Maqliyah, Jood Bandar Alshahrani, Huda Taj Kamal, Sawsan Hazim Daghistani, Bassem Refaat and Faisal Minshawi

Cancers 2025, 17(6), 1012; https://doi.org/10.3390/cancers17061012 - 17 Mar 2025

Cited by 6 | Viewed by 6525

Abstract

Interleukin-10 (IL-10) is a dimeric cytokine encoded by the IL-10 gene on chromosome 1 [...] Full article

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

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17 pages, 8138 KB

Open AccessEditor’s ChoiceArticle

Deep Learning Models Based on Pretreatment MRI and Clinicopathological Data to Predict Responses to Neoadjuvant Systemic Therapy in Triple-Negative Breast Cancer

by Zhan Xu, Zijian Zhou, Jong Bum Son, Haonan Feng, Beatriz E. Adrada, Tanya W. Moseley, Rosalind P. Candelaria, Mary S. Guirguis, Miral M. Patel, Gary J. Whitman, Jessica W. T. Leung, Huong T. C. Le-Petross, Rania M. Mohamed, Bikash Panthi, Deanna L. Lane, Huiqin Chen, Peng Wei, Debu Tripathy, Jennifer K. Litton, Vicente Valero, Lei Huo, Kelly K. Hunt, Anil Korkut, Alastair Thompson, Wei Yang, Clinton Yam, Gaiane M. Rauch and Jingfei Ma Show full author list Hide full author list

Cancers 2025, 17(6), 966; https://doi.org/10.3390/cancers17060966 - 13 Mar 2025

Cited by 6 | Viewed by 2943

Abstract

Purpose: To develop deep learning models for predicting the pathologic complete response (pCR) to neoadjuvant systemic therapy (NAST) in patients with triple-negative breast cancer (TNBC) based on pretreatment multiparametric breast MRI and clinicopathological data. Methods: The prospective institutional review board-approved study [NCT02276443] included [...] Read more.

Purpose: To develop deep learning models for predicting the pathologic complete response (pCR) to neoadjuvant systemic therapy (NAST) in patients with triple-negative breast cancer (TNBC) based on pretreatment multiparametric breast MRI and clinicopathological data. Methods: The prospective institutional review board-approved study [NCT02276443] included 282 patients with stage I–III TNBC who had multiparametric breast MRI at baseline and underwent NAST and surgery during 2016–2021. Dynamic contrast-enhanced MRI (DCE), diffusion-weighted imaging (DWI), and clinicopathological data were used for the model development and internal testing. Data from the I-SPY 2 trial (2010–2016) were used for external testing. Four variables with a potential impact on model performance were systematically investigated: 3D model frameworks, tumor volume preprocessing, tumor ROI selection, and data inputs. Results: Forty-eight models with different variable combinations were investigated. The best-performing model in the internal testing dataset used DCE, DWI, and clinicopathological data with the originally contoured tumor volume, the tight bounding box of the tumor mask, and ResNeXt50, and achieved an area under the receiver operating characteristic curve (AUC) of 0.76 (95% CI: 0.60–0.88). The best-performing models in the external testing dataset achieved an AUC of 0.72 (95% CI: 0.57–0.84) using only DCE images (originally contoured tumor volume, enlarged bounding box of tumor mask, and ResNeXt50) and an AUC of 0.72 (95% CI: 0.56–0.86) using only DWI images (originally contoured tumor volume, enlarged bounding box of tumor mask, and ResNet18). Conclusions: We developed 3D deep learning models based on pretreatment data that could predict pCR to NAST in TNBC patients. Full article

(This article belongs to the Special Issue Advances in Triple-Negative Breast Cancer)

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16 pages, 3685 KB

Open AccessEditor’s ChoiceArticle

ASPH Is a Metastatic Factor and Therapeutic Target in Chondrosarcoma

by Xiaojuan Sun, Jesse Hart, Ross Taliano, Janine Molino, Joseph H. Schwab, Sjoerd Nota, Katsuya Nagaoka, Songhua Zhang, Mark Olsen, Rolf Carlson, Jack Wands and Richard M. Terek

Cancers 2025, 17(6), 951; https://doi.org/10.3390/cancers17060951 - 12 Mar 2025

Cited by 3 | Viewed by 1814

Abstract

Background: Chondrosarcoma (CS) is a highly aggressive primary malignant bone tumor for which there are no effective systemic treatments. We assessed aspartate β-hydroxylase (ASPH) as a potential treatment target. ASPH is a transforming cell surface receptor, but its role in chondrosarcoma has not [...] Read more.

Background: Chondrosarcoma (CS) is a highly aggressive primary malignant bone tumor for which there are no effective systemic treatments. We assessed aspartate β-hydroxylase (ASPH) as a potential treatment target. ASPH is a transforming cell surface receptor, but its role in chondrosarcoma has not been evaluated. Our goals were to analyze the expression of ASPH in conventional chondrosarcoma, evaluate its utility as a biomarker, and determine if ASPH inhibition diminishes tumor progression in a preclinical model. Methods: An annotated tissue microarray was constructed with conventional chondrosarcoma tissues. ASPH expression was quantified with immunohistochemistry. A small molecule inhibitor (SMI) designed to inhibit ASPH activity was evaluated in two CS cell lines with intact ASPH expression and after knockout. Cell viability, invasion, and matrix metalloproteinase (MMP) expression were measured. A mouse xenograft chondrosarcoma model was used to evaluate the effect of the SMI on tumor growth, MMP activity in tumors, and lung metastatic burden. Results: Higher ASPH scores were associated with a greater risk of death and metastasis. The SMI decreased CS cell proliferation, invasion, and secretion of MMPs in vitro, and the effects were lost after ASPH knockout. In vivo, systemic administration of the SMI decreased tumor growth, MMP activity and content in xenograft tumors, and lung metastatic burden. Conclusions: These data validate ASPH as a biomarker in CS and as a factor in the metastatic phenotype. Systemic treatment with an SMI directed against ASPH inhibits tumor progression in a preclinical model, suggesting that ASPH-targeted therapy may be a new treatment strategy for chondrosarcoma expressing ASPH. Full article

(This article belongs to the Special Issue Molecular Targeted Therapy in Cancer)

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16 pages, 6502 KB

Open AccessEditor’s ChoiceArticle

Perceived Gaps in Oncologic Emergency Care for Patients with Cancer: A Qualitative Comparison of Emergency Medicine and Oncologist Physician Perspectives

by Monica K. Wattana, Moira Davenport, Jason J. Bischof, Angela B. Lindsay, Nicholas R. Pettit, Jazmin R. Menendez, Kelsey Harper, Demis N. Lipe and Aiham Qdaisat

Cancers 2025, 17(5), 828; https://doi.org/10.3390/cancers17050828 - 27 Feb 2025

Cited by 2 | Viewed by 1767

Abstract

Objective: Providing high-quality, safe, and consistent care for patients with cancer in the emergency department (ED) poses unique challenges. To better understand these challenges, we surveyed oncologists and emergency medicine (EM) physicians across five institutions to identify key areas for improvement in oncologic [...] Read more.

Objective: Providing high-quality, safe, and consistent care for patients with cancer in the emergency department (ED) poses unique challenges. To better understand these challenges, we surveyed oncologists and emergency medicine (EM) physicians across five institutions to identify key areas for improvement in oncologic EM. Methods: In this multi-institutional, cross-sectional qualitative study, a semi-structured survey was administered to EM attending and resident physicians and medical and surgical oncologists across five institutions in 2023. We assessed the open-ended questionnaire responses using thematic analysis; codes were created and collated to generate initial themes. The themes were then reviewed according to specialty for coherence and non-repetition and finalized. Results: Of the 302 surveys accessed, 185 (61.3%) had complete responses. Three main domains of issues emerged: systems-based challenges, direct patient care-related issues, and knowledge gaps. The issues most frequently perceived by oncologist survey respondents were long delays in care (41%), variability in care (25%), and communication issues between the EM physician and oncologist (14%). The issues most frequently perceived by EM physician survey respondents were knowledge gaps in cancer therapeutics (40%) and in general oncologic emergencies (23%); physician comfort level (14%); the timing and/or location of initial discussions about goals of care (13%); and challenges with the follow-up process (12%). Conclusions: Incorporating an interdisciplinary approach to patient care in the ED, improved EM oncologic education, and the development of oncologic specialized EDs may enhance the quality, safety, and consistency of care for patients with cancer in the ED. Full article

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

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32 pages, 2615 KB

Open AccessEditor’s ChoiceReview

The Role of the Gut Microbiota in Modulating Signaling Pathways and Oxidative Stress in Glioma Therapies

by Aleksandra Krawczyk, Gabriela Elzbieta Sladowska and Barbara Strzalka-Mrozik

Cancers 2025, 17(5), 719; https://doi.org/10.3390/cancers17050719 - 20 Feb 2025

Cited by 9 | Viewed by 3329

Abstract

Tumors of the central nervous system (CNS), especially gliomas, pose a significant clinical challenge due to their aggressive nature and limited therapeutic options. Emerging research highlights the critical role of the gut microbiota in regulating CNS health and disease. The composition of the [...] Read more.

Tumors of the central nervous system (CNS), especially gliomas, pose a significant clinical challenge due to their aggressive nature and limited therapeutic options. Emerging research highlights the critical role of the gut microbiota in regulating CNS health and disease. The composition of the gut microbiota is essential for maintaining CNS homeostasis, as it modulates immune responses, oxidative status, and neuroinflammation. The microbiota–gut–brain axis, a bidirectional communication network, plays a pivotal role in cancer and CNS disease treatment, exerting its influence through neural, endocrine, immunological, and metabolic pathways. Recent studies suggest that the gut microbiota influences the solidification of the tumor microenvironment and that dysbiosis may promote glioma development by modulating systemic inflammation and oxidative stress, which contributes to tumorigenesis and CNS tumor progression. This review interrogates the impact of the gut microbiota on glioma, focusing on critical pathways such as NF-κB, MAPK, PI3K/Akt/mTOR, and Kynurenine/AhR that drive tumor proliferation, immune evasion, and therapy resistance. Furthermore, we explore emerging therapeutic strategies, including probiotics and microbiota-based interventions, which show potential in modulating these pathways and enhancing immunotherapies such as checkpoint inhibitors. By focusing on the multifaceted interactions between the gut microbiota, oxidative stress, and CNS tumors, this review highlights the potential of microbiota-targeted therapies and their manipulation to complement and enhance current treatments. Full article

(This article belongs to the Section Molecular Cancer Biology)

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15 pages, 735 KB

Open AccessEditor’s ChoiceReview

Revolutionizing MASLD: How Artificial Intelligence Is Shaping the Future of Liver Care

by Nicola Pugliese, Arianna Bertazzoni, Cesare Hassan, Jörn M. Schattenberg and Alessio Aghemo

Cancers 2025, 17(5), 722; https://doi.org/10.3390/cancers17050722 - 20 Feb 2025

Cited by 9 | Viewed by 3011

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is emerging as a leading cause of chronic liver disease. In recent years, artificial intelligence (AI) has attracted significant attention in healthcare, particularly in diagnostics, patient management, and drug development, demonstrating immense potential for application and implementation. [...] Read more.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is emerging as a leading cause of chronic liver disease. In recent years, artificial intelligence (AI) has attracted significant attention in healthcare, particularly in diagnostics, patient management, and drug development, demonstrating immense potential for application and implementation. In the field of MASLD, substantial research has explored the application of AI in various areas, including patient counseling, improved patient stratification, enhanced diagnostic accuracy, drug development, and prognosis prediction. However, the integration of AI in hepatology is not without challenges. Key issues include data management and privacy, algorithmic bias, and the risk of AI-generated inaccuracies, commonly referred to as “hallucinations”. This review aims to provide a comprehensive overview of the applications of AI in hepatology, with a focus on MASLD, highlighting both its transformative potential and its inherent limitations. Full article

(This article belongs to the Special Issue The Applications of Artificial Intelligence in Gastroenterology)

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17 pages, 1172 KB

Open AccessEditor’s ChoiceSystematic Review

Methylation Biomarkers of Lung Cancer Risk: A Systematic Review and Meta-Analysis

by Jacopo Dolcini, Manuela Chiavarini, Giorgio Firmani, Kasey J. M. Brennan, Andres Cardenas, Andrea A. Baccarelli and Pamela Barbadoro

Cancers 2025, 17(4), 690; https://doi.org/10.3390/cancers17040690 - 18 Feb 2025

Cited by 6 | Viewed by 2758

Abstract

Background: Lung cancer (LC) is the leading cause of cancer deaths worldwide among both men and women, and represents a major public health challenge. DNA methylation (DNAm) has shown potential in identifying individuals at higher risk of LC, but the overall evidence [...] Read more.

Background: Lung cancer (LC) is the leading cause of cancer deaths worldwide among both men and women, and represents a major public health challenge. DNA methylation (DNAm) has shown potential in identifying individuals at higher risk of LC, but the overall evidence has not been systematically evaluated. This review and meta-analysis aims to evaluate and summarize existing research on the association between blood DNAm levels and LC risk. Methods: Searches were conducted in PubMed, Web of Science, and Scopus for studies published until February 2024, following PRISMA and MOOSE guidelines. Eleven studies met the eligibility criteria. Results: Using a random effects model, our pooled analysis showed a significant association between increased DNAm levels and LC risk (OR 1.24, 95% CI 1.10–1.39; I² = 93.90%, p = 0.0001). Stratifying the results by study design showed a stronger association in two prospective cohort studies (OR 1.61; 95% CI 1.36–1.90; I² = 14.42%, p = 0.32), while case–control studies showed a weaker association (OR 1.05; 95% CI 0.99–1.11; I² = 70.57%, p = 0.0001). Sensitivity analyses indicated that omitting individual studies did not significantly alter the LC risk estimates. Conclusions: These findings suggest that higher blood DNAm levels are associated with an increased risk of LC, especially in long-term cohort studies. Further research is recommended to explore the potential of DNAm as a screening biomarker for LC and to clarify the role of other influencing factors. Full article

(This article belongs to the Special Issue Lung Cancer: From Mechanisms of Action and Risk Factors in Disease Onset to Management)

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25 pages, 2664 KB

Open AccessEditor’s ChoiceReview

Applications of Artificial Intelligence for the Prediction and Diagnosis of Cancer Therapy-Related Cardiac Dysfunction in Oncology Patients

by Isabel G. Scalia, Girish Pathangey, Mahmoud Abdelnabi, Omar H. Ibrahim, Fatmaelzahraa E. Abdelfattah, Milagros Pereyra Pietri, Ramzi Ibrahim, Juan M. Farina, Imon Banerjee, Balaji K. Tamarappoo, Reza Arsanjani and Chadi Ayoub

Cancers 2025, 17(4), 605; https://doi.org/10.3390/cancers17040605 - 11 Feb 2025

Cited by 4 | Viewed by 3245

Abstract

Cardiovascular diseases and cancer are the leading causes of morbidity and mortality in modern society. Expanding cancer therapies that have improved prognosis may also be associated with cardiotoxicity, and extended life span after survivorship is associated with the increasing prevalence of cardiovascular disease. [...] Read more.

Cardiovascular diseases and cancer are the leading causes of morbidity and mortality in modern society. Expanding cancer therapies that have improved prognosis may also be associated with cardiotoxicity, and extended life span after survivorship is associated with the increasing prevalence of cardiovascular disease. As such, the field of cardio-oncology has been rapidly expanding, with an aim to identify cardiotoxicity and cardiac disease early in a patient who is receiving treatment for cancer or is in survivorship. Artificial intelligence is revolutionizing modern medicine with its ability to identify cardiac disease early. This article comprehensively reviews applications of artificial intelligence specifically applied to electrocardiograms, echocardiography, cardiac magnetic resonance imaging, and nuclear imaging to predict cardiac toxicity in the setting of cancer therapies, with a view to reduce early complications and cardiac side effects from cancer therapies such as chemotherapy, radiation therapy, or immunotherapy. Full article

(This article belongs to the Section Cancer Causes, Screening and Diagnosis)

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15 pages, 566 KB

Open AccessEditor’s ChoiceArticle

The Impact of Preoperative Radiotherapy and Chemotherapy on Autologous Breast Reconstruction Outcomes—A Retrospective Single-Center Study

by Caterina M. Nava, Jérôme Martineau, Edward T. C. Dong, Gauthier Zinner and Carlo M. Oranges

Cancers 2025, 17(3), 512; https://doi.org/10.3390/cancers17030512 - 4 Feb 2025

Cited by 3 | Viewed by 2091

Abstract

Background: While radiotherapy (RT) and chemotherapy (CT) significantly improve breast cancer outcomes, they may affect breast reconstruction by causing vascular damage and delayed wound healing. This retrospective study evaluates how preoperative RT, CT, or the combination of both impacts intraoperative and postoperative outcomes [...] Read more.

Background: While radiotherapy (RT) and chemotherapy (CT) significantly improve breast cancer outcomes, they may affect breast reconstruction by causing vascular damage and delayed wound healing. This retrospective study evaluates how preoperative RT, CT, or the combination of both impacts intraoperative and postoperative outcomes in immediate or delayed deep inferior epigastric perforator (DIEP) flap breast reconstructions. Methods: We conducted a single-center review of all patients undergoing autologous DIEP flap reconstruction after mastectomy between 2018 and 2024. Patients were divided into four groups: RT only, CT only, a combination of RT and CT, and a control group with no preoperative therapies. Intraoperative and postoperative outcomes were then compared among these groups, with statistical significance defined as p < 0.05. Results: We included 114 patients representing 141 DIEP-flap breast reconstructions. Flap survival rate was 98.5%. In the univariate analysis, total microvascular recipient site complications were significantly higher in the RT + CT group (14.0%, p = 0.021). Donor-site complication rates differed significantly among the four groups (p = 0.025), with the highest rate observed in the RT + CT group (44.7%). In the logistic regression analysis, ischemia time was found as an independent risk factor for total recipient site complications, but not for microvascular complications (OR = 1.019, 95%-CI = 1.004–1.035, p = 0.014). Conclusions: Combined RT + CT significantly increased microsurgical complications. Ischemia time correlated with higher odds of total recipient site complications. Individualized patient management and diminished ischemia time are likely to improve flap survival. Full article

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

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19 pages, 1624 KB

Open AccessEditor’s ChoiceArticle

A New Blood-Based Epigenetic Diagnostic Biomarker Test (EpiSwitch^®® NST) with High Sensitivity and Positive Predictive Value for Colorectal Cancer and Precancerous Polyps

by Ewan Hunter, Heba Alshaker, Cicely Weston, Mutaz Issa, Shekinah Bautista, Abel Gebregzabhar, Anya Virdi, Ann Dring, Ryan Powell, Jayne Green, Roshan Lal, Vamsi Velchuru, Kamal Aryal, Muhammad Radzi Bin Abu Hassan, Goh Tiong Meng, Janisha Suriakant Patel, Shameera Pharveen Mohamed Gani, Chun Ren Lim, Thomas Guiel, Alexandre Akoulitchev and Dmitri Pchejetski Show full author list Hide full author list

Cancers 2025, 17(3), 521; https://doi.org/10.3390/cancers17030521 - 4 Feb 2025

Cited by 4 | Viewed by 3274

Abstract

Background/Objectives: Colorectal cancer (CRC) arises from the epithelial lining of the colon or rectum, often following a progression from benign adenomatous polyps to malignant carcinoma. Screening modalities such as colonoscopy, faecal immunochemical tests (FIT), and FIT-DNA are critical for early detection and prevention, [...] Read more.

Background/Objectives: Colorectal cancer (CRC) arises from the epithelial lining of the colon or rectum, often following a progression from benign adenomatous polyps to malignant carcinoma. Screening modalities such as colonoscopy, faecal immunochemical tests (FIT), and FIT-DNA are critical for early detection and prevention, but non-invasive methods lack sensitivity to polyps and early CRC. Chromosome conformations (CCs) are potent epigenetic regulators of gene expression. We have previously developed an epigenetic assay, EpiSwitch^®®, that employs an algorithmic-based CCs analysis. Using EpiSwitch^®® technology, we have shown the presence of cancer-specific CCs in peripheral blood mononuclear cells (PBMCs) and primary tumours of patients with melanoma and prostate cancer. EpiSwitch^®®-based commercial tests are now available to diagnose prostate cancer with 94% accuracy (PSE test) and response to immune checkpoint inhibitors across 14 cancers with 85% accuracy (CiRT test). Methods/Results/Conclusions: Using blood samples collected from n = 171 patients with CRC, n = 44 patients with colorectal polyps and n = 110 patients with a ‘clear’ colonoscopy we performed whole Genome DNA screening for CCs correlating to CRC diagnosis. Our findings suggest the presence of two eight-marker CC signatures (EpiSwitch^®® NST) in whole blood that allow diagnosis of CRC and precancerous polyps, respectively. Independent validation cohort testing demonstrated high accuracy in identifying colorectal polyps and early versus late stages of CRC with an exceptionally high sensitivity of 79–90% and a high positive prediction value of 60–84%. Linking the top diagnostic CCs to nearby genes, we have built pathways maps that likely underline processes contributing to the pathology of polyp and CRC progression, including TGFβ, cMYC, Rho GTPase, ROS, TNFa/NFκB, and APC. Full article

(This article belongs to the Special Issue New Biomarkers in Cancers 2nd Edition)

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21 pages, 4327 KB

Open AccessEditor’s ChoiceArticle

Interval Analysis-Based Optimization: A Robust Model for Intensity-Modulated Radiotherapy (IMRT)

by Andrés Camilo Sevilla-Moreno, María Eugenia Puerta-Yepes, Niklas Wahl, Rafael Benito-Herce and Gonzalo Cabal-Arango

Cancers 2025, 17(3), 504; https://doi.org/10.3390/cancers17030504 - 3 Feb 2025

Cited by 1 | Viewed by 2492

Abstract

Background: Cancer remains one of the leading causes of mortality worldwide, with radiotherapy playing a crucial role in its treatment. Intensity-modulated radiotherapy (IMRT) enables precise dose delivery to tumors while sparing healthy tissues. However, geometric uncertainties such as patient positioning errors and [...] Read more.

Background: Cancer remains one of the leading causes of mortality worldwide, with radiotherapy playing a crucial role in its treatment. Intensity-modulated radiotherapy (IMRT) enables precise dose delivery to tumors while sparing healthy tissues. However, geometric uncertainties such as patient positioning errors and anatomical deformations can compromise treatment accuracy. Traditional methods use safety margins, which may lead to excessive irradiation of healthy organs or insufficient tumor coverage. Robust optimization techniques, such as minimax approaches, attempt to address these uncertainties but can result in overly conservative treatment plans. This study introduces an interval analysis-based optimization model for IMRT, offering a more flexible approach to uncertainty management. Methods: The proposed model represents geometric uncertainties using interval dose influence matrices and incorporates Bertoluzza’s metric to balance tumor coverage and organ-at-risk (OAR) protection. The

θ

parameter allows controlled robustness modulation. The model was implemented in matRad, an open-source treatment planning system, and evaluated on five prostate cancer cases. Results were compared against traditional Planning Target Volume (PTV) and minimax robust optimization approaches. Results: The interval-based model improved tumor coverage by 5.8% while reducing bladder dose by 4.2% compared to PTV. In contrast, minimax robust optimization improved tumor coverage by 25.8% but increased bladder dose by 23.2%. The interval-based approach provided a better balance between tumor coverage and OAR protection, demonstrating its potential to enhance treatment effectiveness without excessive conservatism. Conclusions: This study presents a novel framework for IMRT planning that improves uncertainty management through interval analysis. By allowing adjustable robustness modulation, the proposed model enables more personalized and clinically adaptable treatment plans. These findings highlight the potential of interval analysis as a powerful tool for optimizing radiotherapy outcomes, balancing treatment efficacy and patient safety. Full article

(This article belongs to the Special Issue The Future of Radiation Research in Cancers, 2nd Edition)

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17 pages, 3414 KB

Open AccessEditor’s ChoiceArticle

TLR2-Bound Cancer-Secreted Hsp70 Induces MerTK-Mediated Immunosuppression and Tumorigenesis in Solid Tumors

by Ahmet Kaynak, Subrahmanya D. Vallabhapurapu, Harold W. Davis, Eric P. Smith, Petr Muller, Borek Vojtesek, Robert S. Franco, Wen-Hai Shao and Xiaoyang Qi

Cancers 2025, 17(3), 450; https://doi.org/10.3390/cancers17030450 - 28 Jan 2025

Cited by 5 | Viewed by 2471

Abstract

Background: A hallmark of cancer is the presence of an immunosuppressive tumor microenvironment (TME). Immunosuppressive M2 macrophages (MΦs) in the TME facilitate escape from immune surveillance and promote tumor growth; therefore, TME-induced immunosuppression is a potent immunotherapeutic approach to treating cancer. Methods [...] Read more.

Background: A hallmark of cancer is the presence of an immunosuppressive tumor microenvironment (TME). Immunosuppressive M2 macrophages (MΦs) in the TME facilitate escape from immune surveillance and promote tumor growth; therefore, TME-induced immunosuppression is a potent immunotherapeutic approach to treating cancer. Methods: Cancer cell-secreted proteins were detected by using liquid chromatography–mass spectrometry (LC-MS). Neutralizing antibodies (nAbs) were used to assess which proteins were involved in MΦs polarization and differentiation. The protein–protein interaction was characterized using co-immunoprecipitation and immunofluorescence assays. Cancer-secreted heat shock protein 70 (Hsp70) protein was quantified using an enzyme-linked immunosorbent assay (ELISA). MΦ polarization and tumor growth were assessed in vivo with subcutaneous LLC-GFP tumor models and toll-like receptor 2 (TLR2) knockout mice; in vitro assessments were conducted using TLR2 knockout and both LLC-GFP and LN227 lentiviral-mediated knockdown (KD) cells. Results: Cancer cells released a secreted form of Hsp70 that acted on MΦ TLR2 to upregulate Mer receptor tyrosine kinase (MerTK) and induce MΦ M2 polarization. Hsp70 nAbs led to a reduction in CD14 expression by 75% in THP-1 cells in response to Gli36 EMD-CM. In addition, neutralizing TLR2 nAbs resulted in a 30% and 50% reduction in CD14 expression on THP-1 cells in response to MiaPaCa-2 and Gli36 exosome/microparticle-depleted conditioned media (EMD-CMs), respectively. Hsp70, TLR2, and MerTK formed a protein complex. Tumor growth and intra-tumor M2 MΦs were significantly reduced upon cancer cell Hsp70 knockdown and in TLR2 knockout mice. Conclusions: Cancer-secreted Hsp70 interacts with TLR2, upregulates MerTK on MΦs, and induces immunosuppressive MΦ M2 polarization. This previously unreported action of secreted Hsp70 suggests that disrupting the Hsp70-TLR2-MerTK interaction could serve as a promising immunotherapeutic approach to mitigate TME immunosuppression in solid cancers. Full article

(This article belongs to the Special Issue Heat Shock Proteins in Cancers)

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30 pages, 1104 KB

Open AccessEditor’s ChoiceReview

Heterogeneity in Cancer

by William J. MacDonald, Connor Purcell, Maximilian Pinho-Schwermann, Nolan M. Stubbs, Praveen R. Srinivasan and Wafik S. El-Deiry

Cancers 2025, 17(3), 441; https://doi.org/10.3390/cancers17030441 - 28 Jan 2025

Cited by 16 | Viewed by 10322

Abstract

Cancer heterogeneity is a major challenge in oncology, complicating diagnosis, prognostication, and treatment. The clinical heterogeneity of cancer, which leads to differential treatment outcomes between patients with histopathologically similar cancers, is attributable to molecular diversity manifesting through genetic, epigenetic, transcriptomic, microenvironmental, and host [...] Read more.

Cancer heterogeneity is a major challenge in oncology, complicating diagnosis, prognostication, and treatment. The clinical heterogeneity of cancer, which leads to differential treatment outcomes between patients with histopathologically similar cancers, is attributable to molecular diversity manifesting through genetic, epigenetic, transcriptomic, microenvironmental, and host biology differences. Heterogeneity is observed between patients, individual metastases, and within individual lesions. This review discusses clinical implications of heterogeneity, emphasizing need for personalized approaches to overcome challenges posed by cancer’s diverse presentations. Understanding of emerging molecular diagnostic and analytical techniques can provide a view into the multidimensional complexity of cancer heterogeneity. With over 90% of cancer-related deaths associated with metastasis, we additionally explore the role heterogeneity plays in treatment resistance and recurrence of metastatic lesions. Molecular insights from next-generation sequencing, single-cell transcriptomics, liquid biopsy technology, and artificial intelligence will facilitate the development of combination therapy regimens that can potentially induce lasting and even curative treatment outcomes. Full article

(This article belongs to the Special Issue Molecular and Cellular Heterogeneity in an Evolving Tumor Landscape: When Diversity Gives Rise to Aggressive and Drug Resistant Cells)

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34 pages, 1418 KB

Open AccessEditor’s ChoiceReview

Advances in the Repurposing and Blood–Brain Barrier Penetrance of Drugs in Pediatric Brain Tumors

by Julian S. Rechberger, Stephanie A. Toll, Subhasree Biswas, Hyo Bin You, William D. Chow, Nicholas Kendall, Pournima Navalkele and Soumen Khatua

Cancers 2025, 17(3), 439; https://doi.org/10.3390/cancers17030439 - 27 Jan 2025

Cited by 3 | Viewed by 6110

Abstract

Central nervous system (CNS) tumors are the leading cause of cancer-related mortality in children, with prognosis remaining dismal for some of these malignancies. Though the past two decades have seen advancements in surgery, radiation, and targeted therapy, major unresolved hurdles continue to undermine [...] Read more.

Central nervous system (CNS) tumors are the leading cause of cancer-related mortality in children, with prognosis remaining dismal for some of these malignancies. Though the past two decades have seen advancements in surgery, radiation, and targeted therapy, major unresolved hurdles continue to undermine the therapeutic efficacy. These include challenges in suboptimal drug delivery through the blood–brain barrier (BBB), marked intra-tumoral molecular heterogeneity, and the elusive tumor microenvironment. Drug repurposing or re-tasking FDA-approved drugs with evidence of penetration into the CNS, using newer methods of intracranial drug delivery facilitating optimal drug exposure, has been an area of intense research. This could be a valuable tool, as most of these agents have already gone through the lengthy process of drug development and the evaluation of safety risks and the optimal pharmacokinetic profile. They can now be used and tested in clinics with an accelerated and different approach. Conclusions: The next-generation therapeutic strategy should prioritize repurposing oncologic and non-oncologic drugs that have been used for other indication, and have demonstrated robust preclinical activity against pediatric brain tumors. In combination with novel drug delivery techniques, these drugs could hold significant therapeutic promise in pediatric neurooncology. Full article

(This article belongs to the Special Issue Advances in Drug Repurposing to Overcome Cancers)

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20 pages, 2817 KB

Open AccessEditor’s ChoiceSystematic Review

Fluorescence-Guided Surgery to Detect Microscopic Disease in Ovarian Cancer: A Systematic Review with Meta-Analysis

by Evrim Erdemoglu, Carrie L. Langstraat, Amanika Kumar, Stuart A. Ostby, Marlene E. Girardo, Andrea Giannini and Kristina A. Butler

Cancers 2025, 17(3), 410; https://doi.org/10.3390/cancers17030410 - 26 Jan 2025

Cited by 1 | Viewed by 2681

Abstract

Background: The objective in epithelial ovarian cancer is to reach maximal cytoreduction with no visible residual tumor. Tumor detection during cytoreductive surgery depends on visual inspection, palpation, or blind biopsy, methods that lack reliability for identifying microscopic disease. Although the importance of [...] Read more.

Background: The objective in epithelial ovarian cancer is to reach maximal cytoreduction with no visible residual tumor. Tumor detection during cytoreductive surgery depends on visual inspection, palpation, or blind biopsy, methods that lack reliability for identifying microscopic disease. Although the importance of microscopic disease in epithelial ovarian cancer is controversial, it may harbor chemoresistant cells and explain the high recurrence rates. Fluorescence-guided surgery (FGS) is an emerging approach. However, the potential in ovarian cancer remains underexplored; the majority of the existing evidence pertains to gastrointestinal tumors and a limited group of ovarian cancer patients. Their comparative effectiveness is still uncertain. Objective: To systematically review and evaluate the role of fluorescence-guided surgical techniques in detecting microscopic disease in ovarian cancer and compare their efficacy to total peritonectomy. Data Sources: A systematic search was made in three databases (PubMed, Web of Science, and Embase). The search was conducted from 1975 to 2024, including randomized controlled trials, observational studies, and conference abstracts in the last 25 years. Study Selection: Clinical studies published in English involving ovarian cancer patients undergoing FGS or total peritonectomy were included. Case reports, reviews, animal studies, and studies involving mixed cancer populations without ovarian cancer-specific data were excluded. Two independent reviewers screened 631 studies, yielding 12 eligible studies for final analysis. Data Extraction and Synthesis: Data were extracted and synthesized in accordance with PRISMA and MOOSE guidelines, using random-effects models for independent analysis. Sensitivity, specificity, positive predictive value (PPV), and odds ratios (ORs) were grouped, accompanied by subgroup analyses based on the fluorescence agent employed. For quality assessment, we utilized the NIH quality tool. Main Outcome(s) and Measure(s): The primary outcome was the rate of change in surgical management due to fluorescence guidance or total peritonectomy. Secondary outcomes comprised lesion-level sensitivity, specificity, and PPV. Safety outcomes included adverse events associated with fluorescence agents. Results: There were 12 studies involving 429 ovarian cancer patients. FGS improved the detection of microscopic disease compared to standard visualization methods, with a pooled sensitivity of 0.77. Folate receptor-targeted agents had high sensitivity (84%) but low specificity (26%). Aminolevulinic acid (5-ALA) showed superior diagnostic accuracy with a sensitivity of 84% and a specificity of 96%. Total peritonectomy showed no significant advantage over FGS for detecting microscopic disease. The adverse events were mild, with no serious events reported. We observed a high heterogeneity across studies and methodologies. Conclusions and Relevance: Fluorescence-guided surgery utilizing fluorescence tracers demonstrates potential in improving the detection of microscopic disease and may change surgical management in epithelial ovarian cancer, particularly with 5-ALA. Variability in performance and limited data on survival outcomes necessitates additional research. Total peritonectomy does not offer further advantage in the detection of microscopic disease. Future trials should focus on standardizing methodology and evaluating the effects of microscopic disease removal on survival outcomes. Registration: The study was registered to PROSPERO as CRD42024578274. Full article

(This article belongs to the Special Issue Paradigm Shifts in Gynaecological Oncology Surgery)

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21 pages, 1715 KB

Open AccessEditor’s ChoiceReview

Exploring Artificial Intelligence Biases in Predictive Models for Cancer Diagnosis

by Aref Smiley, C. Mahony Reategui-Rivera, David Villarreal-Zegarra, Stefan Escobar-Agreda and Joseph Finkelstein

Cancers 2025, 17(3), 407; https://doi.org/10.3390/cancers17030407 - 26 Jan 2025

Cited by 16 | Viewed by 3307

Abstract

The American Society of Clinical Oncology (ASCO) has released the principles for the responsible use of artificial intelligence (AI) in oncology emphasizing fairness, accountability, oversight, equity, and transparency. However, the extent to which these principles are followed is unknown. The goal of this [...] Read more.

The American Society of Clinical Oncology (ASCO) has released the principles for the responsible use of artificial intelligence (AI) in oncology emphasizing fairness, accountability, oversight, equity, and transparency. However, the extent to which these principles are followed is unknown. The goal of this study was to assess the presence of biases and the quality of studies on AI models according to the ASCO principles and examine their potential impact through citation analysis and subsequent research applications. A review of original research articles centered on the evaluation of predictive models for cancer diagnosis published in the ASCO journal dedicated to informatics and data science in clinical oncology was conducted. Seventeen potential bias criteria were used to evaluate the sources of bias in the studies, aligned with the ASCO’s principles for responsible AI use in oncology. The CREMLS checklist was applied to assess the study quality, focusing on the reporting standards, and the performance metrics along with citation counts of the included studies were analyzed. Nine studies were included. The most common biases were environmental and life-course bias, contextual bias, provider expertise bias, and implicit bias. Among the ASCO principles, the least adhered to were transparency, oversight and privacy, and human-centered AI application. Only 22% of the studies provided access to their data. The CREMLS checklist revealed the deficiencies in methodology and evaluation reporting. Most studies reported performance metrics within moderate to high ranges. Additionally, two studies were replicated in the subsequent research. In conclusion, most studies exhibited various types of bias, reporting deficiencies, and failure to adhere to the principles for responsible AI use in oncology, limiting their applicability and reproducibility. Greater transparency, data accessibility, and compliance with international guidelines are recommended to improve the reliability of AI-based research in oncology. Full article

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

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38 pages, 2883 KB

Open AccessEditor’s ChoiceReview

Hepatic Iron Overload and Hepatocellular Carcinoma: New Insights into Pathophysiological Mechanisms and Therapeutic Approaches

by Elena Chatzikalil, Konstantinos Arvanitakis, Georgios Kalopitas, Matilda Florentin, Georgios Germanidis, Theocharis Koufakis and Elena E. Solomou

Cancers 2025, 17(3), 392; https://doi.org/10.3390/cancers17030392 - 24 Jan 2025

Cited by 7 | Viewed by 5374

Abstract

Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, is rising in global incidence and mortality. Metabolic dysfunction-associated steatotic liver disease (MASLD), one of the leading causes of chronic liver disease, is strongly linked to metabolic conditions that can progress to [...] Read more.

Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, is rising in global incidence and mortality. Metabolic dysfunction-associated steatotic liver disease (MASLD), one of the leading causes of chronic liver disease, is strongly linked to metabolic conditions that can progress to liver cirrhosis and HCC. Iron overload (IO), whether inherited or acquired, results in abnormal iron hepatic deposition, significantly impacting MASLD development and progression to HCC. While the pathophysiological connections between hepatic IO, MASLD, and HCC are not fully understood, dysregulation of glucose and lipid metabolism and IO-induced oxidative stress are being investigated as the primary drivers. Genomic analyses of inherited IO conditions reveal inconsistencies in the association of certain mutations with liver malignancies. Moreover, hepatic IO is also associated with hepcidin dysregulation and activation of ferroptosis, representing promising targets for HCC risk assessment and therapeutic intervention. Understanding the relationship between hepatic IO, MASLD, and HCC is essential for advancing clinical strategies against liver disease progression, particularly with recent IO-targeted therapies showing potential at improving liver biochemistry and insulin sensitivity. In this review, we summarize the current evidence on the pathophysiological association between hepatic IO and the progression of MASLD to HCC, underscoring the importance of early diagnosis, risk stratification, and targeted treatment for these interconnected conditions. Full article

(This article belongs to the Special Issue Advanced Research in Oncology in 2024)

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15 pages, 1392 KB

Open AccessEditor’s ChoiceReview

Unraveling the Role of Fusobacterium nucleatum in Colorectal Cancer: Molecular Mechanisms and Pathogenic Insights

by Linda Galasso, Fabrizio Termite, Irene Mignini, Giorgio Esposto, Raffaele Borriello, Federica Vitale, Alberto Nicoletti, Mattia Paratore, Maria Elena Ainora, Antonio Gasbarrini and Maria Assunta Zocco

Cancers 2025, 17(3), 368; https://doi.org/10.3390/cancers17030368 - 23 Jan 2025

Cited by 34 | Viewed by 10090

Abstract

Fusobacterium nucleatum, a gram-negative anaerobic bacterium, has emerged as a significant player in colorectal cancer (CRC) pathogenesis. The bacterium causes a persistent inflammatory reaction in the colorectal mucosa by stimulating the release of pro-inflammatory cytokines like IL-1β, IL-6, and TNF-α, creating an [...] Read more.

Fusobacterium nucleatum, a gram-negative anaerobic bacterium, has emerged as a significant player in colorectal cancer (CRC) pathogenesis. The bacterium causes a persistent inflammatory reaction in the colorectal mucosa by stimulating the release of pro-inflammatory cytokines like IL-1β, IL-6, and TNF-α, creating an environment conducive to cancer progression. F. nucleatum binds to and penetrates epithelial cells through adhesins such as FadA, impairing cell junctions and encouraging epithelial-to-mesenchymal transition (EMT), which is associated with cancer advancement. Additionally, the bacterium modulates the host immune system, suppressing immune cell activity and creating conditions favorable for tumor growth. Its interactions with the gut microbiome contribute to dysbiosis, further influencing carcinogenic pathways. Evidence indicates that F. nucleatum can inflict DNA damage either directly via reactive oxygen species or indirectly by creating a pro-inflammatory environment. Additionally, it triggers oncogenic pathways, especially the Wnt/β-catenin signaling pathway, which promotes tumor cell growth and longevity. Moreover, F. nucleatum alters the tumor microenvironment, impacting cancer cell behavior, metastasis, and therapeutic responses. The purpose of this review is to elucidate the molecular mechanisms by which F. nucleatum contributes to CRC. Understanding these mechanisms is crucial for the development of targeted therapies and diagnostic strategies for CRC associated with F. nucleatum. Full article

(This article belongs to the Special Issue Novel Approaches and Advances in Interventional Oncology)

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12 pages, 1306 KB

Open AccessEditor’s ChoiceArticle

Comprehensive Molecular Profiling of Metastatic Pancreatic Adenocarcinomas

by Vijay Antony, Tong Sun, Darin Dolezal and Guoping Cai

Cancers 2025, 17(3), 335; https://doi.org/10.3390/cancers17030335 - 21 Jan 2025

Cited by 1 | Viewed by 2487

Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed late, with an extremely poor prognosis. Treatment options like surgery, radiation, and chemotherapy are rarely curative. Tumor progression from primary to metastatic PDAC remains poorly understood at the molecular level. Methods: In the current study, [...] Read more.

Background: Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed late, with an extremely poor prognosis. Treatment options like surgery, radiation, and chemotherapy are rarely curative. Tumor progression from primary to metastatic PDAC remains poorly understood at the molecular level. Methods: In the current study, we analyzed the molecular profiles of metastatic PDAC obtained via the Oncomine Comprehensive Assay in comparison to primary PDAC. Results: The current study cohort consisted of 115 metastatic PDAC cases, of which 71 (62%) cases succeeded in molecular testing while the remaining 44 (38%) cases contained insufficient tumor cells. Molecular profiling of 71 cases revealed a total of 239 molecular alterations, 3.4 alterations per case on average, predominantly in the form of gene mutations. The most common gene mutations included KRAS (86%) and TP53 (83%) mutations. Gene copy number alterations were also detected in 19 (27%) cases involving genes such as CCNE1 and ERBB2. Compared to the molecular profiles of primary PDAC reported in our prior study and TCGA database, there seemed to be increased rates of TP53, ARID1A, BRAF, and PIK3CA mutations in the metastatic diseases. Conclusions: These findings suggest that metastatic PDAC possesses unique genetic characteristics, offering potential therapeutic targets in advanced-stage pancreatic cancer. Full article

(This article belongs to the Special Issue Histology and Pathology of Pancreatic Cancer)

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37 pages, 2321 KB

Open AccessEditor’s ChoiceReview

Triple-Negative Breast Cancer Progression and Drug Resistance in the Context of Epithelial–Mesenchymal Transition

by Ewa Błaszczak, Paulina Miziak, Adrian Odrzywolski, Marzena Baran, Ewelina Gumbarewicz and Andrzej Stepulak

Cancers 2025, 17(2), 228; https://doi.org/10.3390/cancers17020228 - 12 Jan 2025

Cited by 21 | Viewed by 10010

Abstract

Triple-negative breast cancer (TNBC) is one of the most difficult subtypes of breast cancer to treat due to its distinct clinical and molecular characteristics. Patients with TNBC face a high recurrence rate, an increased risk of metastasis, and lower overall survival compared to [...] Read more.

Triple-negative breast cancer (TNBC) is one of the most difficult subtypes of breast cancer to treat due to its distinct clinical and molecular characteristics. Patients with TNBC face a high recurrence rate, an increased risk of metastasis, and lower overall survival compared to other breast cancer subtypes. Despite advancements in targeted therapies, traditional chemotherapy (primarily using platinum compounds and taxanes) continues to be the standard treatment for TNBC, often with limited long-term efficacy. TNBC tumors are heterogeneous, displaying a diverse mutation profile and considerable chromosomal instability, which complicates therapeutic interventions. The development of chemoresistance in TNBC is frequently associated with the process of epithelial–mesenchymal transition (EMT), during which epithelial tumor cells acquire a mesenchymal-like phenotype. This shift enhances metastatic potential, while simultaneously reducing the effectiveness of standard chemotherapeutics. It has also been suggested that EMT plays a central role in the development of cancer stem cells. Hence, there is growing interest in exploring small-molecule inhibitors that target the EMT process as a future strategy for overcoming resistance and improving outcomes for patients with TNBC. This review focuses on the progression and drug resistance of TNBC with an emphasis on the role of EMT in these processes. We present TNBC-specific and EMT-related molecular features, key EMT protein markers, and various signaling pathways involved. We also discuss other important mechanisms and factors related to chemoresistance in TNBC within the context of EMT, highlighting treatment advancements to improve patients’ outcomes. Full article

(This article belongs to the Special Issue Triple Negative Breast Cancer Therapy Resistance and Metastasis)

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29 pages, 1367 KB

Open AccessEditor’s ChoiceReview

Current Paradigm and Future Directions in the Management of Nodal Disease in Locally Advanced Cervical Cancer

by Elki Sze-Nga Cheung and Philip Yuguang Wu

Cancers 2025, 17(2), 202; https://doi.org/10.3390/cancers17020202 - 9 Jan 2025

Cited by 3 | Viewed by 3215

Abstract

Approximately 36% of patients with cervical cancer present with regional nodal metastasis at diagnosis, which is associated with adverse survival outcomes after definitive treatment. In the modern era of chemoradiotherapy (CRT) and image-guided adaptive brachytherapy (IGABT), where excellent local control is achieved for [...] Read more.

Approximately 36% of patients with cervical cancer present with regional nodal metastasis at diagnosis, which is associated with adverse survival outcomes after definitive treatment. In the modern era of chemoradiotherapy (CRT) and image-guided adaptive brachytherapy (IGABT), where excellent local control is achieved for patients with locally advanced cervical cancer (LACC), nodal failure remains a major challenge to cure. To optimize treatment outcomes for node-positive LACC and reduce the incidence of nodal failure, various treatment approaches have been explored, including methods of surgical nodal staging or dissection, RT dose escalation strategies, such as intensity-modulated radiotherapy (IMRT) with simultaneous integrated boost (SIB) to involved nodes, and elective treatment of subclinical para-aortic (PAO) disease. Additionally, there is growing interest in emerging precision RT techniques, such as magnetic resonance-guided radiotherapy (MRgRT) and proton therapy, which may allow for further improvement in the therapeutic ratio. This review outlines the various methods of detection of nodal metastasis, treatment options for node-positive LACC, techniques of nodal radiotherapy and their clinical evidence in efficacy and toxicity profiles. Furthermore, recent advances in systemic therapy and promising novel therapeutic directions that may shape the management of node-positive LACC are discussed. Full article

(This article belongs to the Special Issue Advanced Research in Oncology in 2024)

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24 pages, 13647 KB

Open AccessEditor’s ChoiceArticle

Blockade of LIF and PD-L1 Enhances Chemotherapy in Preclinical PDAC Models

by Jian Ye, Shuyang S. Qin, Angela L. Hughson, Gary Hannon, Tara G. Vrooman, Maggie L. Lesch, Sarah L. Eckl, Lauren Benoodt, Bradley N. Mills, Edith M. Lord, Brian A. Belt, David C. Linehan, Nadia Luheshi, Jim Eyles and Scott A. Gerber

Cancers 2025, 17(2), 204; https://doi.org/10.3390/cancers17020204 - 9 Jan 2025

Cited by 2 | Viewed by 2617

Abstract

Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC), expecting to be the second leading cause of cancer deaths by 2030, resists immune checkpoint therapies due to its immunosuppressive tumor microenvironment (TME). Leukemia inhibitory factor (LIF) is a key target in PDAC, promoting stemness, epithelial–mesenchymal transition [...] Read more.

Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC), expecting to be the second leading cause of cancer deaths by 2030, resists immune checkpoint therapies due to its immunosuppressive tumor microenvironment (TME). Leukemia inhibitory factor (LIF) is a key target in PDAC, promoting stemness, epithelial–mesenchymal transition (EMT), and therapy resistance. Phase 1 clinical trials showed anti-LIF therapy is safe but with limited efficacy, suggesting better outcomes when combined with chemotherapy, radiotherapy, or immunotherapy. Methods: We assessed the combination of chemotherapy (gemcitabine/nab-paclitaxel) and dual blockade of LIF and PD-L1 on tumor growth and survival in orthotopic and spontaneous PDAC models. Flow cytometry and scRNA-seq were utilized to monitor the antitumor immune response. The role of key immune cells was further confirmed by depleting these immune cells, including CD4, CD8, or inflammatory monocytes. Results: Sequential treatment with chemotherapy (gemcitabine/nab-paclitaxel) and dual blockade of LIF and PD-L1 significantly improved antitumor efficacy compared to monotherapy or dual combinations of these therapies. This chemo/anti-LIF/anti-PD-L1 approach reduced EMT in tumor cells and enhanced the antitumor immune response, primarily through CD8 T cells, as depleting CD8 cells largely abrogated the effect of treatment. This combination therapy also shifted macrophages and dendritic cells towards an antitumor phenotype. Conclusions: The combination of chemotherapy, anti-LIF, and anti-PD-L1 not only targeted tumor cells but also augmented the anti-tumor immune response. These findings strongly support advancing chemo/anti-LIF/anti-PD-L1 combination therapy to clinical trials in PDAC. Full article

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

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32 pages, 382 KB

Open AccessEditor’s ChoiceReview

Management of Patients with Vulvar Cancers: A Systematic Comparison of International Guidelines (NCCN–ASCO–ESGO–BGCS–IGCS–FIGO–French Guidelines–RCOG)

by Stefano Restaino, Giulia Pellecchia, Martina Arcieri, Giorgio Bogani, Cristina Taliento, Pantaleo Greco, Lorenza Driul, Vito Chiantera, Rosa Pasqualina De Vincenzo, Giorgia Garganese, Francesco Sopracordevole, Violante Di Donato, Andrea Ciavattini, Paolo Scollo, Giovanni Scambia, Giuseppe Vizzielli and Gynecologic Oncology Group

Cancers 2025, 17(2), 186; https://doi.org/10.3390/cancers17020186 - 8 Jan 2025

Cited by 16 | Viewed by 10807

Abstract

Background: Vulvar carcinoma is an uncommon gynecological tumor primarily affecting older women. Its treatment significantly impacts the quality of life and, not least, aesthetics because of the mutilating surgery it requires. Objectives: The management requires a multidisciplinary team of specialists who know how [...] Read more.

Background: Vulvar carcinoma is an uncommon gynecological tumor primarily affecting older women. Its treatment significantly impacts the quality of life and, not least, aesthetics because of the mutilating surgery it requires. Objectives: The management requires a multidisciplinary team of specialists who know how to care for the patient in her entirety, not neglecting psychological aspects and reconstructive surgery. How do the guidelines address multidisciplinarity, team surgical management, passing through preoperative diagnosis, and follow-up in such a challenging rare tumor to treat? Methods: To answer these questions, we compared the main scientific recommendations to identify similarities and differences in diagnostic and therapeutic management to provide an overview of the gaps that there are currently in European and American international recommendations in providing management guidance in a cancer that is both among the rarest and most difficult to manage. In this way, we aim to encourage an update in practices based on the latest scientific evidence. Results: A review of various international guidelines, some dating back to 2014, shows significant variation in approaches, ranging from initial diagnostic procedures to managing relapses. The most recent guidelines also lacked references to the latest literature, indicating that more robust scientific evidence is needed before new treatments, such as electrochemotherapy for palliation and reconstructive surgery post exenteration, can be widely adopted. Conclusions: From the systematic comparison of the main international guidelines, a strong heterogeneity emerged in the diagnostic and therapeutic recommendations as well as for the multidisciplinary approach that today is essential. Our work certainly stimulated an update of the main guidelines. Full article

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

19 pages, 792 KB

Open AccessEditor’s ChoiceReview

Recurrent and Metastatic Head and Neck Cancer: Mechanisms of Treatment Failure, Treatment Paradigms, and New Horizons

by William T. Barham, Marshall Patrick Stagg, Rula Mualla, Michael DiLeo and Sagar Kansara

Cancers 2025, 17(1), 144; https://doi.org/10.3390/cancers17010144 - 5 Jan 2025

Cited by 4 | Viewed by 4351

Abstract

Background: Head and neck cancer is a deadly disease with over 500,000 cases annually worldwide. Metastatic head and neck cancer accounts for a large proportion of the mortality associated with this disease. Many advances have been made in our understanding of the mechanisms [...] Read more.

Background: Head and neck cancer is a deadly disease with over 500,000 cases annually worldwide. Metastatic head and neck cancer accounts for a large proportion of the mortality associated with this disease. Many advances have been made in our understanding of the mechanisms of metastasis. The application of immunotherapy to locally recurrent or metastatic head and neck cancer has not only improved oncologic outcomes but has also provided valuable insights into the mechanisms of immune evasion and ultimately treatment failure. Objectives: This review paper will review our current understanding of biological mechanisms of treatment failure and metastasis. Published and ongoing clinical trials in the management of metastatic head and neck cancer will also be summarized. Methods: A narrative review was conducted to address the current understanding of the mechanisms of treatment failure and current treatment paradigms in recurrent and metastatic head and neck carcinoma. Conclusions: Our understanding of treatment failure in this disease is rapidly evolving. Immunotherapy represents a valuable new tool in the fight against recurrent and metastatic head and neck squamous cell carcinoma. Integrating patient and tumor specific data via artificial intelligence and deep learning will allow for a precision oncology approach, thereby achieving better prognostication and management of patients with this deadly disease. Full article

(This article belongs to the Collection Advances in Diagnostics and Treatment of Head and Neck Cancer)

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32 pages, 3337 KB

Open AccessEditor’s ChoiceReview

Exploring the Metabolic Impact of FLASH Radiotherapy

by Febe Geirnaert, Lisa Kerkhove, Pierre Montay-Gruel, Thierry Gevaert, Inès Dufait and Mark De Ridder

Cancers 2025, 17(1), 133; https://doi.org/10.3390/cancers17010133 - 3 Jan 2025

Cited by 12 | Viewed by 4838

Abstract

FLASH radiotherapy (FLASH RT) is an innovative modality in cancer treatment that delivers ultrahigh dose rates (UHDRs), distinguishing it from conventional radiotherapy (CRT). FLASH RT has demonstrated the potential to enhance the therapeutic window by reducing radiation-induced damage to normal tissues while maintaining [...] Read more.

FLASH radiotherapy (FLASH RT) is an innovative modality in cancer treatment that delivers ultrahigh dose rates (UHDRs), distinguishing it from conventional radiotherapy (CRT). FLASH RT has demonstrated the potential to enhance the therapeutic window by reducing radiation-induced damage to normal tissues while maintaining tumor control, a phenomenon termed the FLASH effect. Despite promising outcomes, the precise mechanisms underlying the FLASH effect remain elusive and are a focal point of current research. This review explores the metabolic and cellular responses to FLASH RT compared to CRT, with particular focus on the differential impacts on normal and tumor tissues. Key findings suggest that FLASH RT may mitigate damage in healthy tissues via altered reactive oxygen species (ROS) dynamics, which attenuate downstream oxidative damage. Studies indicate the FLASH RT influences iron metabolism and lipid peroxidation pathways differently than CRT. Additionally, various studies indicate that FLASH RT promotes the preservation of mitochondrial integrity and function, which helps maintain apoptotic pathways in normal tissues, attenuating damage. Current knowledge of the metabolic influences following FLASH RT highlights its potential to minimize toxicity in normal tissues, while also emphasizing the need for further studies in biologically relevant, complex systems to better understand its clinical potential. By targeting distinct metabolic pathways, FLASH RT could represent a transformative advance in RT, ultimately improving the therapeutic window for cancer treatment. Full article

(This article belongs to the Special Issue Feature Paper in Section “Cancer Therapy” in 2024)

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13 pages, 432 KB

Open AccessEditor’s ChoiceReview

Advancing Thoracic Surgical Oncology in the Era of Precision Medicine

by Giacomo Argento, Erino Angelo Rendina and Giulio Maurizi

Cancers 2025, 17(1), 115; https://doi.org/10.3390/cancers17010115 - 2 Jan 2025

Cited by 2 | Viewed by 1799

Abstract

The landscape of surgical oncology is rapidly evolving with the advent of precision medicine, driven by breakthroughs in genomics and proteomics. This article explores how integrating molecular data is transforming surgical decision-making and enabling personalized treatment strategies. We examine emerging technologies such as [...] Read more.

The landscape of surgical oncology is rapidly evolving with the advent of precision medicine, driven by breakthroughs in genomics and proteomics. This article explores how integrating molecular data is transforming surgical decision-making and enabling personalized treatment strategies. We examine emerging technologies such as next-generation sequencing, proteomic analysis, and molecular imaging, which provide critical insights into tumor biology and guide surgical interventions. The article also highlights the application of genomic and proteomic data in preoperative planning and the development of personalized resection strategies. Additionally, we will address the current challenges and future opportunities in this rapidly evolving field, emphasizing the need for continuous education, interdisciplinary collaboration, and ongoing research to fully realize the potential of precision medicine in thoracic surgical oncology, paving the way for more effective and individualized cancer treatments. Full article

(This article belongs to the Special Issue Oncogenomic and Multi-Omic Data Science and Data Engineering)

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