Cancers

13 pages, 247 KB

Open AccessEditor’s ChoiceReview

Nodal Upstaging and Oncologic Outcomes After Segmentectomy Versus Lobectomy for Early-Stage Non-Small Cell Lung Cancer

by Alecsandra Tudor, Ye Tian, Edoardo Zanfrini, Etienne Abdelnour-Berchtold, Jean Yannis Perentes, Thorsten Krueger and Michel Gonzalez

Cancers 2026, 18(6), 1039; https://doi.org/10.3390/cancers18061039 - 23 Mar 2026

Cited by 3 | Viewed by 726

Abstract

Background: Segmentectomy is increasingly used and is emerging as a key treatment option for early-stage non-small cell lung cancer (NSCLC). However, questions remain regarding the adequacy of lymph node evaluation, particularly differences in N1 versus N2 dissection, and the implications for staging accuracy [...] Read more.

Background: Segmentectomy is increasingly used and is emerging as a key treatment option for early-stage non-small cell lung cancer (NSCLC). However, questions remain regarding the adequacy of lymph node evaluation, particularly differences in N1 versus N2 dissection, and the implications for staging accuracy and adjuvant therapy. Methods: This narrative review synthesizes evidence from studies published between 2019 and 2025 comparing nodal upstaging, survival outcomes, and the role of completion lobectomy following segmentectomy versus lobectomy. Results: Twelve studies, including more than 175,000 patients, were analyzed. Lobectomy was associated with a significantly higher overall nodal upstaging rate (14.5% vs. 6.6%, p < 0.001), driven primarily by increased detection of N1 disease (13.3% vs. 3.7%, p < 0.001), while N2 upstaging rates were similar between procedures (5.5% vs. 3.2%, p = 0.07). Despite lower N1 detection, adjusted analyses reported comparable survival outcomes among patients with occult pathologic N1 (pN1) or N2 (pN2) disease who received adjuvant therapy. Segmentectomy provided outcomes comparable to lobectomy, whereas wedge resection was associated with inferior survival (HR 1.23, p = 0.042). Completion lobectomy has not demonstrated a consistent survival benefit and was associated with substantial morbidity in limited retrospective series, including high rates of thoracotomy conversion and major complications. Conclusions: When performed with systematic nodal dissection, adequate surgical margins, and appropriate adjuvant therapy, segmentectomy appears to provide survival outcomes comparable to lobectomy in selected patients with early-stage NSCLC. Completion lobectomy may not be routinely required and should be considered on a case-by-case basis within a multidisciplinary context. These findings support the use of segmentectomy in carefully selected patients when high-quality surgical staging and integrated oncologic care are ensured, while highlighting the need for prospective studies addressing occult nodal disease in the modern treatment era. Full article

(This article belongs to the Special Issue Current Issues, Innovations, and Emerging Therapies in Thoracic Surgical Oncology)

23 pages, 753 KB

Open AccessEditor’s ChoiceReview

Circulating MicroRNA in Breast Cancer

by Alexander Sturzu, Ruixia Ma and Yaguang Xi

Cancers 2026, 18(6), 900; https://doi.org/10.3390/cancers18060900 - 11 Mar 2026

Cited by 2 | Viewed by 1680

Abstract

Background/Objectives: Despite recent advances in breast cancer diagnostics, therapies and personalized medicine through genetic profiling, effective treatment of aggressive subtypes, particularly triple-negative breast cancer (TNBC), remains a considerable clinical challenge. MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression that influence tumor progression and [...] Read more.

Background/Objectives: Despite recent advances in breast cancer diagnostics, therapies and personalized medicine through genetic profiling, effective treatment of aggressive subtypes, particularly triple-negative breast cancer (TNBC), remains a considerable clinical challenge. MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression that influence tumor progression and are detectable extracellularly in biofluids, where they are typically protected within extracellular vesicles (e.g., exosomes) or associated with RNA-binding proteins and lipoprotein complexes. This review integrates current evidence on oncogenic and tumor-suppressive extracellular miRNAs in breast cancer, with emphasis on subtype-specific functions and potential clinical relevance as liquid-biopsy biomarkers and therapeutic targets. Methods: A PubMed-based literature review (January 2000–February 2026) was conducted using search terms combining “breast cancer” with “miRNA/microRNA” and “circulating/plasma/serum/exosomal/extracellular vesicle.” Studies were prioritized if they provided validated targets/mechanisms and/or human clinical evidence for diagnostic, prognostic, or predictive utility; discrepant findings were evaluated in a subtype-aware framework. Findings were organized into functional categories (e.g., EMT/metastasis, cell-cycle/DNA damage, immune modulation, and hormone/growth factor signaling). Clinical and translational studies evaluating circulating miRNAs for diagnosis, prognosis, treatment response, and toxicity prediction were synthesized, together with key pre-analytical and analytical variables that affect reproducibility. Results: Across mechanistic and clinical studies, miR-21 and miR-155 recur as prominent oncogenic miRNAs, whereas miR-205 is frequently reported as a tumor-suppressive miRNA that is reduced in breast cancer and in circulation in several cohorts. Panels combining these miRNAs show promise for sensitive and specific breast cancer diagnostics. Additionally, several miRNAs show context- or subtype-dependent effects, with opposing activities reported between TNBC and estrogen receptor (ER)-positive disease (e.g., miR-17-92, miR-425, miR-181 family members, miR-31, and miR-24). Conclusions: Circulating miRNAs represent a promising class of minimally invasive biomarkers and potential therapeutic targets; however, translation is constrained by biological context dependence and by pre-analytical and analytical variability. Standardized protocols and rigorously validated, subtype-aware biomarker panels will be essential for clinical implementation and for enabling miRNA-informed precision oncology in breast cancer. Full article

(This article belongs to the Section Cancer Biomarkers)

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23 pages, 1041 KB

Open AccessEditor’s ChoiceReview

Beyond Gastric Specificity: V-Set and Immunoglobulin Domain-Containing 1 (VSIG1) in Digestive Tract Tumors

by Catalin-Bogdan Satala, Gabriela Patrichi, Alina-Mihaela Gurau, Andreea Onofrei (Popa) and Daniela Mihalache

Cancers 2026, 18(5), 867; https://doi.org/10.3390/cancers18050867 - 8 Mar 2026

Cited by 3 | Viewed by 827

Abstract

V-set and immunoglobulin domain-containing 1 (VSIG1) is a member of the immunoglobulin superfamily that has attracted increasing attention as a differentiation-associated protein in gastrointestinal neoplasia. Although initially described as a gastric-specific marker, accumulating evidence indicates that VSIG1 more accurately reflects gastric-enriched epithelial differentiation [...] Read more.

V-set and immunoglobulin domain-containing 1 (VSIG1) is a member of the immunoglobulin superfamily that has attracted increasing attention as a differentiation-associated protein in gastrointestinal neoplasia. Although initially described as a gastric-specific marker, accumulating evidence indicates that VSIG1 more accurately reflects gastric-enriched epithelial differentiation rather than strict anatomical origin. This conceptual shift has implications for phenotype-oriented tumor classification and diagnostic interpretation in the context of lineage plasticity. A structured and transparently reported literature search was conducted in PubMed/MEDLINE, Web of Science, and Scopus, covering studies published between 2000 and 2024. Eligible studies included original research and relevant reviews evaluating VSIG1 expression in normal tissues and digestive tract tumors, with emphasis on immunohistochemical patterns and clinicopathological correlations. In gastric cancer, VSIG1 expression consistently correlates with preserved glandular architecture and epithelial differentiation, whereas reduced or absent expression accompanies dedifferentiation and architectural disorganization. Outside the stomach, VSIG1 positivity is uncommon but reproducible in tumors exhibiting gastric-type or mixed differentiation, including settings of hepato-gastric phenotypic overlap. These patterns support interpretation of VSIG1 as a context-dependent indicator of lineage engagement and differentiation state rather than tumor origin or aggressiveness. Current data on independent prognostic value are limited and partially conflicting, and predictive roles remain unsupported, while functional data remain limited. Full article

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

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14 pages, 1402 KB

Open AccessEditor’s ChoiceReview

Drug-Tolerant Persister Cells and Tumor Dormancy in NSCLC: A New Frontier in Overcoming Therapeutic Resistance

by Mumtu Lalla, Akshay Ratnani, Jihua Yang, Meng Wang and Haiying Cheng

Cancers 2026, 18(5), 779; https://doi.org/10.3390/cancers18050779 - 28 Feb 2026

Cited by 3 | Viewed by 1314

Abstract

Targeted therapies and chemoimmunotherapy have transformed outcomes for non–small cell lung cancer (NSCLC), yet relapse remains common. Resistance is increasingly recognized to include an early, largely reversible phase in which a minor subpopulation survives lethal therapy through non-genetic adaptation. These drug-tolerant persister (DTP) [...] Read more.

Targeted therapies and chemoimmunotherapy have transformed outcomes for non–small cell lung cancer (NSCLC), yet relapse remains common. Resistance is increasingly recognized to include an early, largely reversible phase in which a minor subpopulation survives lethal therapy through non-genetic adaptation. These drug-tolerant persister (DTP) cells may be quiescent or cycling, and provide a reservoir from which stable, genetically resistant clones can later emerge. In parallel, late recurrence may reflect tumor dormancy, in which disseminated or residual cells persist for prolonged periods under microenvironmental constraint and/or immune surveillance. This review integrates DTP and dormancy frameworks in NSCLC, summarizes mechanisms that sustain persistence (chromatin and transcriptional plasticity, stress signaling, metabolic rewiring, and stromal/immune protection), and highlights experimental models and translational readouts, including circulating tumor DNA (ctDNA)–based minimal residual disease (MRD) monitoring. We also discuss potential therapeutic concepts to prevent DTP formation, exploit persister liabilities, or enforce dormancy in minimal-disease settings. A mechanistically grounded understanding of these survival programs is essential for rational combinations and biomarker-guided trials aimed at durable remission. Full article

(This article belongs to the Special Issue Molecular Advances in Lung Cancer: From Pathogenesis to Precision Therapy)

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15 pages, 473 KB

Open AccessEditor’s ChoiceReview

Liquid Biopsy in Non-Metastatic Prostate Cancer: Clinical Evidence and Future Directions

by Maria Chiara Sighinolfi, Giuseppe Pallotta, Marzia Del Re, Koosha Moosavi, Or Schubert, Francesco Rossi, Filippo Gavi, Simone Assumma, Enrico Panio, Angelo Totaro, Filippo Turri, Mauro Ragonese, Nazario Foschi, Pierluigi Russo, Ela Patel, Carlo Gandi, Giuseppe Palermo, Eros Scarciglia, Francesco Pinto, Simona Presutti, Marcio Covas Moschovas, Angelo Minucci, Roberto Iacovelli, Chiara Ciccarese, Luca Tagliaferri, Francesco Pierconti, Camilla Nero, Gian Franco Zannoni and Bernardo Rocco Show full author list Hide full author list

Cancers 2026, 18(5), 800; https://doi.org/10.3390/cancers18050800 - 28 Feb 2026

Cited by 3 | Viewed by 1116

Abstract

Background and Objective: Liquid biopsy has transformed the management of advanced prostate cancer, yet its clinical role in non-metastatic disease remains uncertain. Conventional biomarkers such as PSA, imaging, and pathology have limited ability to capture minimal residual disease and biological aggressiveness. The objective [...] Read more.

Background and Objective: Liquid biopsy has transformed the management of advanced prostate cancer, yet its clinical role in non-metastatic disease remains uncertain. Conventional biomarkers such as PSA, imaging, and pathology have limited ability to capture minimal residual disease and biological aggressiveness. The objective of this review was to critically evaluate the current evidence on circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) in non-metastatic prostate cancer, focusing on feasibility, prognostic value, and potential clinical applications. Methods: A narrative review of PubMed-indexed original studies evaluating liquid biopsy in clinically localized or non-metastatic prostate cancer was performed. Eligible studies included patients treated with curative-intent local therapy or experiencing biochemical recurrence without radiologic metastases. Study designs were predominantly prospective or retrospective observational cohorts. Liquid biopsy analytes included CTCs and ctDNA assessed from peripheral blood plasma using EpCAM-based enrichment, targeted next-generation sequencing, whole-genome sequencing, or ultra-sensitive tumor-informed assays. Primary outcomes included detection rates, associations with clinicopathologic features, biochemical recurrence, metastasis-free survival, and overall survival. Key Findings and Limitations: Across 11 studies, CTC detection using EpCAM-based platforms was infrequent in localized disease and biochemical recurrence and showed limited prognostic value (10–11% in preoperative settings). In contrast, ctDNA was detectable in a minority of patients but consistently identified biologically aggressive disease and a higher risk of recurrence when present, particularly using tumor-informed ultra-sensitive assays. Limitations include low detection rates, heterogeneous methodologies, small sample sizes, and predominantly exploratory study designs. Conclusions and Clinical Implications: Currently, its most promising application is not broad screening, but as a selective, biology-driven tool for detecting minimal residual disease and refining risk assessment. CtDNA acts as a biological risk modifier, potentially guiding the escalation or de-escalation of adjuvant therapy. However, prospective biomarker-driven trials are required to validate these strategies before routine clinical implementation. Full article

(This article belongs to the Special Issue Advances in the Management of Pelvic Tumors: 2nd Edition)

23 pages, 1348 KB

Open AccessEditor’s ChoiceReview

Menin Inhibition in Acute Myeloid MLL Rearranged Leukemias: A New Target for Precision Care

by Caterina Alati, Matteo Molica, Martina Pitea, Violetta Marafioti, Gaetana Porto, Giorgia Policastro, Erica Bilardi, Giovanna Utano, Laura Giordano, Annalisa Sgarlata, Ilaria Maria Delfino, Aurora Idato, Giulia Santoro, Marco Rossi and Massimo Martino

Cancers 2026, 18(4), 637; https://doi.org/10.3390/cancers18040637 - 15 Feb 2026

Cited by 2 | Viewed by 1877

Abstract

Menin inhibitors are the first targeted therapies for KMT2A-rearranged and NPM1-mutated acute leukemias, addressing a significant unmet need in these high-risk subtypes. Revumenib received approval in 2024–2025 for relapsed or refractory KMT2A-rearranged acute leukemia and NPM1-mutated AML. The AUG-MENT-101 trial reported a 23% [...] Read more.

Menin inhibitors are the first targeted therapies for KMT2A-rearranged and NPM1-mutated acute leukemias, addressing a significant unmet need in these high-risk subtypes. Revumenib received approval in 2024–2025 for relapsed or refractory KMT2A-rearranged acute leukemia and NPM1-mutated AML. The AUG-MENT-101 trial reported a 23% composite complete remission rate in heavily pretreated patients, with 61% of responders achieving MRD negativity. Several menin inhibitors, including ziftomenib, bleximenib, and enzomenib, are in clinical development. They demonstrate similar efficacy, but their safety profiles differ, especially regarding QTc prolongation and coverage of resistance mutations. Combination therapies with azacitidine and venetoclax or intensive chemotherapy have achieved high response rates in newly diagnosed patients, supporting their potential use in frontline treatment. Acquired resistance, often due to MEN1 mutations at the drug-binding interface, occurs in about 40% of cases. Distinct resistance patterns among menin inhibitors suggest the possibility of sequential therapy. Approximately 30–40% of responders in relapsed or refractory trials proceeded to allogeneic transplantation, which remains a key pathway to potential cure. This review examines the molecular mechanisms of the menin-KMT2A interaction, and summarizes clinical trial data on the efficacy and safety of menin inhibitors as monotherapy and in combination. Full article

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

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29 pages, 546 KB

Open AccessEditor’s ChoiceReview

Advances in the Therapeutic Landscape of Hepatocellular Carcinoma: Current Strategies and Future Perspectives

by Asahiro Morishita, Kyoko Oura, Hiroki Tai, Rie Yano, Mai Nakahara, Tomoko Tadokoro, Koji Fujita, Shima Mimura, Joji Tani, Miwa Tatsuta, Takashi Himoto and Hideki Kobara

Cancers 2026, 18(4), 609; https://doi.org/10.3390/cancers18040609 - 12 Feb 2026

Cited by 4 | Viewed by 2498

Abstract

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and a major cause of cancer mortality worldwide. Because HCC usually arises in cirrhotic livers, prognosis is shaped by the dual threats of tumor progression and hepatic decompensation, requiring treatment decisions that balance [...] Read more.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and a major cause of cancer mortality worldwide. Because HCC usually arises in cirrhotic livers, prognosis is shaped by the dual threats of tumor progression and hepatic decompensation, requiring treatment decisions that balance anticancer efficacy with preservation of liver function, portal hypertension control, and quality of life. In recent years, management has shifted from a predominantly locoregional approach to an integrated continuum that spans curative resection, ablation, and transplantation; refined transarterial and radiotherapy techniques; and modern systemic therapy dominated by immunotherapy-based combinations. These advances have improved response rates, enabled downstaging and conversion in selected patients, and expanded opportunities for sequential and multimodal treatment. However, challenges persist, including therapeutic decision-making in patients with Child–Pugh B liver function, lack of robust predictive biomarkers, and resistance after initial response. Emerging tools—liquid biopsy, radiomics, AI-assisted imaging, and microbiome modulation—may support future precision strategies and optimized treatment allocation. In this review, we summarize current evidence guiding staging and therapy selection, outline practical considerations across curative, locoregional, and systemic modalities, and discuss evolving biomarkers and next-generation immunotherapy as key steps toward more personalized, durable, and equitable global HCC care. Full article

(This article belongs to the Collection Advances in the Management of Hepatocellular Carcinoma)

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43 pages, 7304 KB

Open AccessEditor’s ChoiceArticle

miRNA-Based Breast Cancer Subtyping Using AHALA Multi-Stage Classification Approach

by Mohammed Qaraad, Eric P. Rahrmann and David Guinovart

Cancers 2026, 18(4), 586; https://doi.org/10.3390/cancers18040586 - 10 Feb 2026

Cited by 2 | Viewed by 1985

Abstract

Background: Breast cancers are heterogeneous in nature, including many molecular subtypes, each displaying varying characteristics in clinical outcomes as well as in responses to treatments. Subtyping requires absolute precision for the application of precision medicine; however, this is not an easy task, given [...] Read more.

Background: Breast cancers are heterogeneous in nature, including many molecular subtypes, each displaying varying characteristics in clinical outcomes as well as in responses to treatments. Subtyping requires absolute precision for the application of precision medicine; however, this is not an easy task, given the dimensionality as well as noise in miRNA expression profiles. Even though miRNAs display potential as a biological marker for subtyping breast cancers, feature selection and optimizing learning algorithms would help harness their potential as a diagnostic tool. Methods: We propose the Adaptive Hill Climbing Artificial Lemming Algorithm (AHALA), a hybrid optimization framework that integrates the global search capability of the Artificial Lemming Algorithm with an adaptive hill-climbing local search strategy. Low-variance filtering and differential gene expression analysis were first applied to reduce dimensionality and enhance biological relevance. AHALA was then used to optimize deep neural network hyperparameters for miRNA-based multi-class breast cancer subtype classification. The method was validated using TCGA breast cancer miRNA expression data and benchmarked against state-of-the-art optimization algorithms using the CEC2021 test suite. Results: AHALA had a high classification performance measure for each type of breast cancer with a mean accuracy of 95.74%, precision of 95.98%, recall of 95.74%, F1 measure of 95.74%, and AUC value of 0.9682. The new algorithm had superior convergence and significance compared with other optimization algorithms. Feature selection revealed miRNAs that belong to each subtype, such as hsa-miR-190b, hsa-miR-429, hsa-miR-505-3p, hsa-miR-3614-5p, and hsa-miR-935. Conclusions: The AHALA framework offers a potent and efficient method of performing miRNA-based subtyping of breast cancer that integrates global exploration and local search to its advantage. Its high level of classification, stability, and ability to identify biologically important biomarkers mark this method as promising. Full article

(This article belongs to the Section Cancer Pathophysiology)

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19 pages, 864 KB

Open AccessEditor’s ChoiceReview

FGFR2-Rearranged Biliary Tract Cancer: Biology, Resistance Mechanisms, and Emerging Therapeutic Strategies

by Xin Xin and Ruoyu Miao

Cancers 2026, 18(3), 531; https://doi.org/10.3390/cancers18030531 - 6 Feb 2026

Cited by 3 | Viewed by 1610

Abstract

Fibroblast growth factor receptor 2 (FGFR2) rearrangements represent one of the most actionable molecular alterations in biliary tract cancer, particularly in intrahepatic cholangiocarcinoma (iCCA). Approximately 10–16% of iCCA cases harbor FGFR2 fusions or rearrangements, defining a distinct molecular subtype characterized by sensitivity to [...] Read more.

Fibroblast growth factor receptor 2 (FGFR2) rearrangements represent one of the most actionable molecular alterations in biliary tract cancer, particularly in intrahepatic cholangiocarcinoma (iCCA). Approximately 10–16% of iCCA cases harbor FGFR2 fusions or rearrangements, defining a distinct molecular subtype characterized by sensitivity to FGFR-targeted therapies. Selective FGFR tyrosine kinase inhibitors, including the reversible inhibitor pemigatinib and the irreversible inhibitor futibatinib, have demonstrated clinically meaningful response rates and durable disease control in patients with previously treated FGFR2-altered iCCA, leading to regulatory approvals and the incorporation of FGFR inhibition into contemporary treatment paradigms. However, the development of acquired resistance—most commonly driven by secondary kinase-domain mutations and activation of bypass signaling pathways—remains a major limitation to sustained therapeutic benefit. This review summarizes the biological basis of FGFR2 alterations, highlights current clinical evidence supporting FGFR inhibition, and discusses the evolving landscape of resistance mechanisms. We further examine emerging therapeutic strategies aimed at overcoming resistance, including next-generation FGFR inhibitors and rational combination approaches. In addition, we highlight the growing role of circulating tumor DNA as a noninvasive tool for longitudinal molecular monitoring and treatment guidance. Together, these insights underscore the central role of FGFR2-directed therapy in precision oncology for biliary tract cancer and provide a framework for optimizing and extending targeted treatment in this molecularly defined disease subset. Full article

(This article belongs to the Special Issue Proteomic and Oncogenic Biomarkers in Gastrointestinal Cancer)

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30 pages, 1988 KB

Open AccessEditor’s ChoiceSystematic Review

MRI-Based Radiomics for Non-Invasive Prediction of Molecular Biomarkers in Gliomas

by Edoardo Agosti, Karen Mapelli, Gianluca Grimod, Amedeo Piazza, Marco Maria Fontanella and Pier Paolo Panciani

Cancers 2026, 18(3), 491; https://doi.org/10.3390/cancers18030491 - 2 Feb 2026

Cited by 6 | Viewed by 1549

Abstract

Background: Radiomics has emerged as a promising approach to non-invasively characterize the molecular landscape of gliomas, providing quantitative, high-dimensional data derived from routine MRI. Given the recent shift toward molecularly driven classification, radiomics may support precision oncology by predicting key genomic, epigenetic, and [...] Read more.

Background: Radiomics has emerged as a promising approach to non-invasively characterize the molecular landscape of gliomas, providing quantitative, high-dimensional data derived from routine MRI. Given the recent shift toward molecularly driven classification, radiomics may support precision oncology by predicting key genomic, epigenetic, and phenotypic alterations without the need for invasive tissue sampling. This systematic review aimed to synthesize current radiomics applications for the non-invasive prediction of molecular biomarkers in gliomas, evaluating methodological trends, performance metrics, and translational readiness. Methods: This review followed the PRISMA 2020 guidelines. A systematic search was conducted in PubMed, Ovid MEDLINE, and Scopus on 10 January 2025, and updated on 1 February 2025, using predefined MeSH terms and keywords related to glioma, radiomics, machine learning, deep learning, and molecular biomarkers. Eligible studies included original research using MRI-based radiomics to predict molecular alterations in human gliomas, with reported performance metrics. Data extraction covered study design, cohort size, MRI sequences, segmentation approaches, feature extraction software, computational methods, biomarkers assessed, and diagnostic performance. Methodological quality was evaluated using the Radiomics Quality Score (RQS), Image Biomarker Standardization Initiative (IBSI) criteria, and Newcastle–Ottawa Scale (NOS). Due to heterogeneity, no meta-analysis was performed. Results: Of 744 screened records, 70 studies met the inclusion criteria. A total of 10,324 patients were included across all studies (mean 140 patients/study, range 23–628). The most frequently employed MRI sequences were T2-weighted (59 studies, 84.3%), contrast-enhanced T1WI (53 studies, 75.7%), T1WI (50 studies, 71.4%), and FLAIR (48 studies, 68.6%); diffusion-weighted imaging was used in only 7 studies (12.8%). Manual segmentation predominated (52 studies, 74.3%), whereas automated approaches were used in 13 studies (18.6%). Common feature extraction platforms included 3D Slicer (20 studies, 28.6%) and MATLAB-based tools (17 studies, 24.3%). Machine learning methods were applied in 47 studies (67.1%), with support vector machines used in 29 studies (41.4%); deep learning models were implemented in 27 studies (38.6%), primarily convolutional neural networks (20 studies, 28.6%). IDH mutation was the most frequently predicted biomarker (49 studies, 70%), followed by ATRX (27 studies, 38.6%), MGMT methylation (8 studies, 11,4%), and 1p/19q codeletion (7 studies, 10%). Reported AUC values ranged from 0.80 to 0.99 for IDH, approximately 0.71–0.953 for 1p/19q, 0.72–0.93 for MGMT, and 0.76–0.97 for ATRX, with deep learning or hybrid pipelines generally achieving the highest performance. RQS values highlighted substantial methodological variability, and IBSI adherence was inconsistent. NOS scores indicated high-quality methodology in a limited subset of studies. Conclusions: Radiomics demonstrates strong potential for the non-invasive prediction of key glioma molecular biomarkers, achieving high diagnostic performance across diverse computational approaches. However, widespread clinical translation remains hindered by heterogeneous imaging protocols, limited standardization, insufficient external validation, and variable methodological rigor. Full article

(This article belongs to the Special Issue Radiomics and Molecular Biology in Glioma: A Synergistic Approach)

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25 pages, 2553 KB

Open AccessEditor’s ChoiceReview

Epigenetic Regulation of Higher-Order Chromatin Structure (HOCS) and Its Implication in Human Diseases

by Luisa Ladel, Bethsebie Sailo, Paromita Das, Ethan Samuel Lin, Wan Ying Tan, Ankit Chhoda, Haoyu Tang, Olivia Ang-Olson, Linda He, Nithyla John, Jeremy D. Kratz, Anup Sharma and Nita Ahuja

Cancers 2026, 18(3), 483; https://doi.org/10.3390/cancers18030483 - 31 Jan 2026

Cited by 3 | Viewed by 1828

Abstract

Higher-order chromatin structures (HOCS) are fundamental to genome organization, gene regulation, and cellular homeostasis. This review examines the epigenetic mechanisms shaping HOCS, including DNA methylation, histone modifications, chromatin remodeling, and RNA-based regulatory processes. We also discuss the role of architectural proteins in maintaining [...] Read more.

Higher-order chromatin structures (HOCS) are fundamental to genome organization, gene regulation, and cellular homeostasis. This review examines the epigenetic mechanisms shaping HOCS, including DNA methylation, histone modifications, chromatin remodeling, and RNA-based regulatory processes. We also discuss the role of architectural proteins in maintaining chromatin topology while allowing dynamic changes to chromatin structure, thereby influencing gene expression. Growing evidence indicates that disruptions in HOCS contribute to a diverse array of human diseases, including cancer, aging-related disorders, and congenital abnormalities, primarily through aberrant gene regulation. We further discuss the concept of distinct genomic areas, in which specific chromatin regions orchestrate three-dimensional (3D) genome dynamics, positioning them as potential biomarkers and therapeutic targets. By emphasizing chromatin architecture on a global scale rather than at the level of individual genes, this review underscores its emerging relevance to precision medicine. Finally, we synthesize current technical advances, outline future directions for leveraging chromatin topology in disease diagnosis and treatment, and highlight key biological insights to reshape our understanding of genome function. Full article

(This article belongs to the Special Issue Epigenetics in Cancer and Drug Therapeutics)

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24 pages, 380 KB

Open AccessEditor’s ChoiceReview

Immune Checkpoint Blockade in Hematological Malignancies: Current Status and Future Directions

by Hiu-Ching Lau and Yok-Lam Kwong

Cancers 2026, 18(3), 485; https://doi.org/10.3390/cancers18030485 - 31 Jan 2026

Cited by 3 | Viewed by 1355

Abstract

Immune checkpoint proteins including PD-1, CTLA-4, LAG-3, TIM-3, and TIGIT regulate T-cell functions, which are essential for anti-tumor immunity. Over-expression of these immune checkpoint proteins leads to T-cell exhaustion and a significant impairment of anti-tumor immunity. Rejuvenation of effector T-cell function with immune [...] Read more.

Immune checkpoint proteins including PD-1, CTLA-4, LAG-3, TIM-3, and TIGIT regulate T-cell functions, which are essential for anti-tumor immunity. Over-expression of these immune checkpoint proteins leads to T-cell exhaustion and a significant impairment of anti-tumor immunity. Rejuvenation of effector T-cell function with immune checkpoint inhibitors (ICI) restores anti-tumor immunity, which translates into clinical efficacy in the frontline and salvage treatment of various hematological malignancies. Efficacy of ICIs is highest in classical Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, and NK/T-cell lymphomas, and modest in immune-privileged-site lymphomas and cutaneous T-cell lymphoma. However, in myeloid malignancies and multiple myeloma, the efficacy of ICIs remains doubtful. In addition to being used as single agents, ICIs have also been combined with other ICIs; as well as chemotherapy, antibody drug conjugates, and epigenetic agents (histone deacetylase inhibitors and hypomethylating agents). More innovative strategies include the use of ICIs in the context of allogeneic haematopoietic stem cell transplantation and chimeric antigen receptor T-cell therapy. This review synthesizes current evidence for the use of ICI in different haematological malignancies, and highlights future directions toward biomarker-driven, rationally designed therapeutic combinations. Full article

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

14 pages, 541 KB

Open AccessEditor’s ChoiceArticle

Discrepancies Between MDT Recommendations and AI-Generated Decisions in Gynecologic Oncology: A Retrospective Comparative Cohort Study

by Vasilios Pergialiotis, Nikolaos Thomakos, Vasilios Lygizos, Maria Fanaki, Antonia Varthaliti, Dimitrios Efthymios Vlachos and Dimitrios Haidopoulos

Cancers 2026, 18(3), 452; https://doi.org/10.3390/cancers18030452 - 30 Jan 2026

Cited by 3 | Viewed by 1129

Abstract

Background: Multidisciplinary tumor boards (MDTs) remain the foundation of gynecologic cancer management, yet increasing diagnostic complexity and rapidly evolving molecular classifications have intensified interest in artificial intelligence (AI) as a potential decision-support tool. This study aimed to evaluate the concordance between MDT-derived recommendations [...] Read more.

Background: Multidisciplinary tumor boards (MDTs) remain the foundation of gynecologic cancer management, yet increasing diagnostic complexity and rapidly evolving molecular classifications have intensified interest in artificial intelligence (AI) as a potential decision-support tool. This study aimed to evaluate the concordance between MDT-derived recommendations and those generated by ChatGPT 5.0 across a large, real-world cohort of gynecologic oncology cases. Methods: This single-center retrospective analysis included 599 consecutive patients with cervical, endometrial, ovarian, or vulvar cancer evaluated during MDT meetings over a 2-month period. Standardized anonymized case summaries were entered into ChatGPT 5.0, which was instructed to follow current ESGO guidelines. AI-generated staging and treatment recommendations were compared with MDT decisions. Discrepancies were independently assessed by two reviewers and stratified by malignancy type, disease stage, and treatment domain. Results: Overall concordance for FIGO staging was 77.0%, while treatment-related decisions demonstrated lower discordance, particularly in chemotherapy (8.2%) and targeted therapy (6.8%). The highest staging disagreement occurred in early-stage endometrial cancer (32.6%), reflecting the complexity of newly revised molecular classifications. In recurrent ovarian and cervical cancer, discrepancies were more pronounced in surgical and systemic therapy recommendations, suggesting limited AI capacity to integrate multimodal imaging, prior treatments, and individualized considerations. Vulvar cancer cases showed the highest overall agreement. Conclusions: ChatGPT 5.0 aligns with MDT decisions in many straightforward scenarios but falls short in complex or nuanced cases requiring contextual, multimodal, and patient-specific reasoning. These findings underscore the need for prospective, real-time evaluation, multimodal data integration, external validation, and explainable AI frameworks before LLMs can be safely incorporated into routine gynecologic oncology decision-making. Full article

(This article belongs to the Special Issue Advances in Ovarian Cancer Treatment: Past, Present and Future)

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20 pages, 644 KB

Open AccessEditor’s ChoiceReview

Risks, Benefits, and Molecular Targets of Fenugreek Administration in the Treatment of Hepatocellular Carcinoma

by Maanya Vittal, Bruna Menegassi and Manlio Vinciguerra

Cancers 2026, 18(3), 458; https://doi.org/10.3390/cancers18030458 - 30 Jan 2026

Cited by 2 | Viewed by 2498

Abstract

Fenugreek (Trigonella foenum-graecum) has attracted growing interest as a complementary agent in the management of hepatocellular carcinoma (HCC), a leading cause of cancer-related mortality worldwide. Its rich botanical and phytochemical profile, including key bioactive compounds such as diosgenin, trigonelline, saponins, and [...] Read more.

Fenugreek (Trigonella foenum-graecum) has attracted growing interest as a complementary agent in the management of hepatocellular carcinoma (HCC), a leading cause of cancer-related mortality worldwide. Its rich botanical and phytochemical profile, including key bioactive compounds such as diosgenin, trigonelline, saponins, and flavonoids, underpins a spectrum of biological activities relevant to liver cancer therapy. This review critically examines the risks, benefits, and molecular targets of fenugreek administration in HCC, synthesising current evidence on extraction methods, standardisation, pharmacokinetics, and mechanisms of action. Preclinical studies highlight fenugreek’s antitumor efficacy, mediated by apoptosis induction, cell cycle regulation, and modulation of oxidative stress and inflammatory pathways, while its hepatoprotective effects are supported by robust antioxidant and anti-inflammatory properties. However, the safety profile is nuanced, with potential risks including reproductive toxicity, rare hypersensitivity reactions, and herb–drug interactions, particularly in patients with compromised hepatic function or polypharmacy. The review identifies critical gaps in clinical evidence, especially regarding long-term safety and synergistic effects with conventional therapies and underscores the need for rigorous standardisation and patient monitoring. We describe the potential integration of fenugreek into multimodal HCC treatment strategies, if safety concerns are addressed. Future research should elucidate precise molecular targets, optimise formulations, and conduct well-controlled clinical trials to fully realise fenugreek’s therapeutic potential in HCC management. Full article

(This article belongs to the Special Issue Tumor Suppressor and Targeted Therapy in Hepatocellular Carcinoma: From Diagnosis to Treatment (2nd Edition))

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16 pages, 3175 KB

Open AccessEditor’s ChoiceArticle

Laboratory Evaluation of Peripheral Blood Involvement in Mycosis Fungoides and Sézary Syndrome: Evolution of Flow Cytometry and Morphology Quantification and Interpretation

by Lucy Fu, Payton Trimark, Yijie Liu, Hamza Tariq, Qing Chen, Yi-Hua Chen, Juehua Gao, Barina Aqil, Joan Guitart and Kristy Wolniak

Cancers 2026, 18(3), 434; https://doi.org/10.3390/cancers18030434 - 29 Jan 2026

Cited by 2 | Viewed by 1119

Abstract

Background/Objectives: Mycosis fungoides (MF) and Sézary syndrome (SS) are cutaneous T-cell lymphomas (CTCLs) with variable clinical outcomes. Peripheral blood (PB) involvement in MF/SS is an independent predictor of prognosis. Accurate laboratory determination of PB involvement by MF/SS cells, however, is an ongoing [...] Read more.

Background/Objectives: Mycosis fungoides (MF) and Sézary syndrome (SS) are cutaneous T-cell lymphomas (CTCLs) with variable clinical outcomes. Peripheral blood (PB) involvement in MF/SS is an independent predictor of prognosis. Accurate laboratory determination of PB involvement by MF/SS cells, however, is an ongoing challenge. Both flow cytometry (FC) and morphology-based quantification are limited by the overlap of CTCL cells and reactive T-cells. This study looks at the optimization over time of CTCL blood burden evaluation. Methods: This retrospective study reviews CTCL blood assessment at Northwestern Memorial Hospital from 2012 to 2021. Test ordering and reporting practices for morphology-based Sézary cell counts and FC were evaluated. For each assay, quantitative and qualitative results were analyzed and compared including percentages and absolute counts of abnormal T-cell populations and pathologist interpretations. Results: A total of 514 patients were evaluated, with increasing numbers of both tests ordered over time. FC quantitative metrics showed a moderate to high correlation with morphology metrics, especially for absolute CD4+/CD7− counts (correlation coefficient = 0.901, p-value < 0.001). Qualitative pathologist interpretations had moderate agreement between methods (kappa = 0.58). The recent addition of TRBC1 clonality assessment to our FC assay further optimizes the evaluation for CTCL blood burden. Conclusions: Flow cytometry offers a reliable approach for blood staging in MF/SS, and morphologic assessment may be redundant. This study provides a foundation for designing a new FC approach with TRBC1. This comprehensive review of the evolution of our laboratory practices may serve as a guide for other institutions with similar clinical needs. Full article

(This article belongs to the Special Issue The Role of Flow Cytometry in Hematologic Malignancies)

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27 pages, 932 KB

Open AccessEditor’s ChoiceReview

Cancer Prevention Clinical Trials: Advances and Challenges

by Elizabeth R. Francis, Farzeen Z. Syed, Arun Rajan and Eva Szabo

Cancers 2026, 18(3), 390; https://doi.org/10.3390/cancers18030390 - 27 Jan 2026

Cited by 2 | Viewed by 1606

Abstract

Prevention of cancer is an appealing strategy to reduce the burden of illness associated with cancer, but despite the rapidly advancing understanding of the early phases of carcinogenesis, translation of biologic insights into actionable public health strategies has been challenging. Phase III clinical [...] Read more.

Prevention of cancer is an appealing strategy to reduce the burden of illness associated with cancer, but despite the rapidly advancing understanding of the early phases of carcinogenesis, translation of biologic insights into actionable public health strategies has been challenging. Phase III clinical trials have historically required large numbers of participants and lengthy durations to show effects in the minority of participants who develop cancer during the finite span of each trial. Early-phase trials help to refine intervention strategies and provide preliminary human safety and efficacy data to justify phase III trials. Recent advances in trial methodology and developments in immunopreventive strategies have energized the field of cancer prevention and provide potential paths for prevention of multiple cancer types. In this review we discuss the history and current state of cancer prevention trials, with a focus on overcoming inherent biologic and methodologic barriers to preventive agent development. Full article

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

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78 pages, 5907 KB

Open AccessEditor’s ChoiceReview

Immune-Centered Cross-Talk Between Cancer Cells and the Tumor Microenvironment—Implications for Therapy

by Eliza Turlej, Aleksandra Domaradzka, Rostyslav Koksharov and Agnieszka Gizak

Cancers 2026, 18(3), 344; https://doi.org/10.3390/cancers18030344 - 23 Jan 2026

Cited by 2 | Viewed by 5095

Abstract

The tumor microenvironment (TME), composed of various immune and non-immune cells, as well as cancer stem cells, plays a critical role not only in promoting cancer cell proliferation and metastasis but also in modulating therapeutic response. A wide range of therapeutic strategies targeting [...] Read more.

The tumor microenvironment (TME), composed of various immune and non-immune cells, as well as cancer stem cells, plays a critical role not only in promoting cancer cell proliferation and metastasis but also in modulating therapeutic response. A wide range of therapeutic strategies targeting the TME are currently employed in cancer treatment, including standard chemotherapy, radiotherapy, immunotherapy, anti-angiogenic therapies, agents targeting cancer-associated fibroblasts (CAFs), oncolytic viruses (OVs), cold atmospheric plasma therapy, and nanovaccines. This review provides a comprehensive overview of the influence of the TME on cancer sensitivity to these therapies across all types of solid tumors. Full article

(This article belongs to the Section Tumor Microenvironment)

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20 pages, 5169 KB

Open AccessEditor’s ChoiceArticle

Clinical Behavior of Aggressive Variants of Papillary Thyroid Carcinoma: A Retrospective Case–Control Study

by Jovan Ilic, Nikola Slijepcevic, Katarina Tausanovic, Bozidar Odalovic, Goran Zoric, Marija Milinkovic, Branislav Rovcanin, Milan Jovanovic, Matija Buzejic, Duska Vucen, Boban Stepanovic, Sara Ivanis, Milan Parezanovic, Milan Marinkovic and Vladan Zivaljevic

Cancers 2026, 18(2), 345; https://doi.org/10.3390/cancers18020345 - 22 Jan 2026

Cited by 2 | Viewed by 913

Abstract

Background/Objectives: Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy. The classic variant (cPTC) is characterized by indolent behavior and excellent prognosis. However, rare subtypes of PTC most often exhibit adverse clinical behavior. The aim of the study was to assess the [...] Read more.

Background/Objectives: Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy. The classic variant (cPTC) is characterized by indolent behavior and excellent prognosis. However, rare subtypes of PTC most often exhibit adverse clinical behavior. The aim of the study was to assess the aggressiveness of rare variants of PTC by analyzing clinicopathological characteristics (CPCs) and survival outcomes. Methods: We analyzed 80 patients with rare PTC variants treated between 2009 and 2019 who were compared with cPTC and matched with a control group for age and tumor size. The variants were categorized into high-risk (HRV: tall cell, diffuse sclerosing, columnar cell, and hobnail variants), intermediate-risk (IRV: solid variant (SV)), and low-risk (LRV: oncocytic (OV) and Warthin-like (WLV)) variants. Different CPCs (capsule and blood vessel invasion, lymphonodal metastases, microscopic and macroscopic extrathyroid extension, multifocal and bilateral presentation) and survival outcomes—overall (OS), disease-specific (DSS), and disease-free survival (DFS) were compared. Results: HRVs exhibited significantly more aggressive CPCs and worse OS, DSS, and DFS compared to cPTC (p < 0.001). IRVs showed no significant difference in CPCs or survival outcomes compared to cPTC. LRVs showed excellent survival but were associated with several unfavorable CPCs. Multivariate analysis identified classification in HRVs as the only independent predictor of recurrence (p = 0.014). Conclusions: Tumors in the HRV group should retain their status as aggressive PTC variants due to unfavorable behavior and poorer prognosis. SVs, despite earlier assumptions, do not exhibit aggressive characteristics. Although the OV and WLV have similar survival to cPTC, their potential for adverse CPCs requires caution. Full article

(This article belongs to the Special Issue Thyroid Cancer Recurrence: Integrating Surgical, Clinical, and Translational Research)

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17 pages, 1351 KB

Open AccessEditor’s ChoiceReview

Integrated and Comprehensive Diagnostics: An Emerging Paradigm in Precision Oncology

by Kakoli Das, Jens Samol, Irfan Sagir Khan, Bernard Ho and Khoon Leong Chuah

Cancers 2026, 18(2), 327; https://doi.org/10.3390/cancers18020327 - 21 Jan 2026

Cited by 2 | Viewed by 1265

Abstract

Recent advances in molecular pathology, driven by integrated and comprehensive diagnostic approaches, have significantly advanced precision oncology. By leveraging multiomics technologies, molecular pathology enables the simultaneous assessment of genomic alterations, transcriptomic profiles, proteomic activity, and metabolic states integrated with conventional pathological evaluation to [...] Read more.

Recent advances in molecular pathology, driven by integrated and comprehensive diagnostic approaches, have significantly advanced precision oncology. By leveraging multiomics technologies, molecular pathology enables the simultaneous assessment of genomic alterations, transcriptomic profiles, proteomic activity, and metabolic states integrated with conventional pathological evaluation to better explain tumour biology and behaviour. Large-scale international consortia, including The Cancer Genome Atlas (TCGA) and the Clinical Proteomic Tumour Analysis Consortium (CPTAC) have systematically demonstrated the value of harmonised multiomics analyses in defining tumour subtypes, uncovering functional dependencies, and generating clinically actionable insights. Evidence from coordinated precision oncology initiatives, such as the National Cancer Institute—Molecular Analysis for Therapy Choice (NCI-MATCH) trial further indicates that treatment strategies guided by molecular pathology profiling are associated with improved clinical outcomes, including progression-free survival in molecularly selected patient populations. Consequently, molecularly stratified treatment approaches are increasingly required in routine clinical practice to enable targeted therapies for selected tumour entities. Integration of molecular data with functional and clinical outcomes has further facilitated the detection of emerging mechanisms of therapeutic resistance and heterogeneous treatment responses. Importantly, studies have shown that reliance on genomic analysis alone is insufficient to achieve optimal targeted therapy, underscoring the need for multi-layered molecular interrogation. This review highlights the biological and clinical relevance of multiomics integration, emphasising its critical role in comprehensive morpho-molecular tumour assessment and functional analyses while providing clinicians with a practical framework for interpreting integrated molecular diagnostics and addressing the methodological and translational challenges that must be overcome to enable broader implementation of precision oncology in routine practice. Full article

(This article belongs to the Special Issue Molecular Pathology and Human Cancers)

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38 pages, 10428 KB

Open AccessEditor’s ChoiceArticle

Conversational AI-Enabled Precision Oncology Reveals Context-Dependent MAPK Pathway Alterations in Hispanic/Latino and Non-Hispanic White Colorectal Cancer Stratified by Age and FOLFOX Exposure

by Fernando C. Diaz, Brigette Waldrup, Francisco G. Carranza, Sophia Manjarrez and Enrique Velazquez-Villarreal

Cancers 2026, 18(2), 293; https://doi.org/10.3390/cancers18020293 - 17 Jan 2026

Cited by 2 | Viewed by 863

Abstract

Background: Colorectal cancer (CRC) demonstrates substantial clinical and biological diversity across age groups, ancestral backgrounds, and treatment settings, alongside a rising incidence of early-onset disease (EOCRC). The mitogen-activated protein kinase (MAPK) pathway is a major driver of CRC development and therapy response; however, [...] Read more.

Background: Colorectal cancer (CRC) demonstrates substantial clinical and biological diversity across age groups, ancestral backgrounds, and treatment settings, alongside a rising incidence of early-onset disease (EOCRC). The mitogen-activated protein kinase (MAPK) pathway is a major driver of CRC development and therapy response; however, the distribution and prognostic value of MAPK alterations across distinct patient subgroups remain unclear. Methods: We analyzed 2515 CRC tumors with harmonized demographic, clinical, genomic, and treatment metadata. Patients were stratified by ancestry (Hispanic/Latino [H/L] vs. non-Hispanic White [NHW]), age at diagnosis (early-onset [EO] vs. late-onset [LO]), and FOLFOX chemotherapy exposure. MAPK pathway alterations were identified using a curated gene set encompassing canonical EGFR-RAS-RAF-MEK-ERK signaling components and regulatory nodes. Conversational artificial intelligence (AI-HOPE and AI-HOPE-MAPK) enabled natural language-driven cohort construction and exploratory analytics; findings were validated using Fisher’s exact testing, chi-square analyses, and Kaplan–Meier survival estimates. Results: MAPK pathway disruption demonstrated marked heterogeneity across ancestry and treatment contexts. Among EO H/L patients, FGFR3, NF1, and RPS6KA6 mutations were significantly enriched in tumors not receiving FOLFOX, whereas PDGFRB alterations were more frequent in FOLFOX-treated EO H/L tumors relative to EO NHW counterparts. In late-onset H/L disease, NTRK2 and PDGFRB mutations were more common in non-FOLFOX tumors. Distinct MAPK-associated alterations were also observed among NHW patients, particularly in non-FOLFOX settings, including AKT3, FGF4, RRAS2, CRKL, DUSP4, JUN, MAPK1, RRAS, and SOS1. Survival analyses provided borderline evidence that MAPK alterations may be linked to improved overall survival in treated EO NHW patients. Conversational AI markedly accelerated analytic throughput and multi-parameter discovery. Conclusions: Although MAPK alterations are pervasive in CRC, their distribution varies meaningfully by ancestry, age, and treatment exposure. These findings highlight NF1, MAPK3, RPS6KA4, and PDGFRB as potential biomarkers in EOCRC and H/L patients, supporting the need for ancestry-aware precision oncology approaches. Full article

(This article belongs to the Special Issue Innovations in Addressing Disparities in Cancer)

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17 pages, 568 KB

Open AccessEditor’s ChoiceArticle

Liquid Biopsy in Clear Cell Renal Cell Carcinoma: Diagnostic Potential of Urinary miRNAs

by Giacomo Vannuccini, Alessio Paladini, Matteo Mearini, Francesca Cocci, Giuseppe Giardino, Paolo Mangione, Vincenza Maulà, Daniele Mirra, Ettore Mearini and Giovanni Cochetti

Cancers 2026, 18(2), 285; https://doi.org/10.3390/cancers18020285 - 16 Jan 2026

Cited by 3 | Viewed by 1065

Abstract

Background: Clear cell renal cell carcinoma (ccRCC) is the most prevalent kidney cancer subtype and, in most cases, it is incidentally diagnosed, as early-stage disease is often asymptomatic. Therefore, the identification of stable, noninvasive biomarkers is a major unmet clinical need. Urinary microRNAs [...] Read more.

Background: Clear cell renal cell carcinoma (ccRCC) is the most prevalent kidney cancer subtype and, in most cases, it is incidentally diagnosed, as early-stage disease is often asymptomatic. Therefore, the identification of stable, noninvasive biomarkers is a major unmet clinical need. Urinary microRNAs (miRNAs) have emerged as promising candidates since they are extraordinarily stable in urine and show a close relationship with tumour biology. Methods: In this study, urinary expression levels of five miRNAs (miR-15a, miR-15b, miR-16, miR-210, and miR-let-7b) were analysed in RCC patients before surgery, 5 days after, and one month after surgery, and compared to healthy controls. Results: Non-parametric analyses revealed significant postoperative decreases for miR-15a (p = 0.002), miR-16 (p = 0.025), miR-210 (p = 0.030), and in the overall miRNA Sum (p = 0.002), suggesting that these miRNAs are directly linked to tumour presence. In the comparison between preoperative and one-month postoperative samples, miR-let-7b (p = 0.049) and the global miRNA Sum (p = 0.037) remained significantly reduced after intervention, indicating a partial normalisation of urinary miRNA profiles. Correlation analyses demonstrated positive associations between specific miRNAs and clinical parameters such as age, ischemia time, and surgical time, reinforcing their potential relevance to tumour biology and treatment response. Conclusions: These findings support urinary miRNAs as promising, minimally invasive biomarkers for ccRCC diagnosis and postoperative monitoring. Full article

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

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16 pages, 289 KB

Open AccessEditor’s ChoiceReview

Artificial Intelligence in Oncologic Thoracic Surgery: Clinical Decision Support and Emerging Applications

by Francesco Petrella and Stefania Rizzo

Cancers 2026, 18(2), 246; https://doi.org/10.3390/cancers18020246 - 13 Jan 2026

Cited by 4 | Viewed by 1971

Abstract

Artificial intelligence (AI) is rapidly reshaping thoracic surgery, advancing from decision support to the threshold of autonomous intervention. AI-driven technologies—including machine learning (ML), deep learning (DL), and computer vision—have demonstrated significant improvements in diagnostic accuracy, surgical planning, intraoperative navigation, and postoperative outcome prediction. [...] Read more.

Artificial intelligence (AI) is rapidly reshaping thoracic surgery, advancing from decision support to the threshold of autonomous intervention. AI-driven technologies—including machine learning (ML), deep learning (DL), and computer vision—have demonstrated significant improvements in diagnostic accuracy, surgical planning, intraoperative navigation, and postoperative outcome prediction. In lung cancer and thoracic oncology, AI enhances imaging analysis, histopathological classification, and risk stratification, supporting multidisciplinary decision-making and personalized therapy. Robotic-assisted and AI-guided systems are optimizing surgical precision and workflow efficiency, while real-time decision-support tools and augmented reality are improving intraoperative safety. Despite these advances, widespread adoption is limited by challenges in algorithmic bias, data integration, regulatory approval, and ethical transparency. The literature emphasizes the need for multicenter validation, explainable AI, and robust governance frameworks to ensure safe and effective clinical integration. Future research should focus on digital twin technology, federated learning, and transparent AI outputs to further enhance reliability and accessibility. AI is poised to transform thoracic surgery, but responsible implementation and ongoing evaluation are essential for realizing its full potential. The aim of this review is to evaluate and synthesize the current landscape of artificial intelligence (AI) applications across the thoracic surgical pathway, from preoperative decision-support to intraoperative guidance and emerging autonomous interventions. Full article

(This article belongs to the Special Issue Thoracic Neuroendocrine Tumors and the Role of Emerging Therapies)

14 pages, 436 KB

Open AccessEditor’s ChoiceArticle

Real-World Clinical Experience of First-Line Ribociclib Combined with an Aromatase Inhibitor in Metastatic Breast Cancer

by Ana S. Cvetanović, Kristina B. Jankovic, Ana S. Stojković, Nikola D. Živković, Miloš S. Kostić and Lazar S. Popović

Cancers 2026, 18(2), 242; https://doi.org/10.3390/cancers18020242 - 13 Jan 2026

Cited by 2 | Viewed by 1702

Abstract

Background/Objectives: Despite initial sensitivity to ET, most patients with HR+/HER2− breast cancer develop resistance. A key molecular mechanism of endocrine resistance in HR+ breast cancer involves dysregulation of the cyclin D–CDK4/6–Rb signaling axis, which controls the transition from the G1 to S phase [...] Read more.

Background/Objectives: Despite initial sensitivity to ET, most patients with HR+/HER2− breast cancer develop resistance. A key molecular mechanism of endocrine resistance in HR+ breast cancer involves dysregulation of the cyclin D–CDK4/6–Rb signaling axis, which controls the transition from the G1 to S phase of the cell cycle. Introducing cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) has changed therapeutic paradigms in HR+/HER2− breast cancer, as their synergistic use with endocrine therapy significantly prolongs progression-free survival (PFS) and effectively mitigates clinically relevant endocrine resistance in this patient population compared to ET alone. The aim of our study was to evaluate patients’ clinical characteristics, the clinical effectiveness of treatment, measured by progression-free survival (PFS), and the safety profile of combined ribociclib (CDK4/6i) and standard endocrine therapy (aromatase inhibitor) as a first-line treatment for patients with HR+/HER2− advanced or metastatic breast cancer at the Clinic of Oncology, University Clinical Centre Nis, Serbia. Methods: In this study, we present a retrospective prospective analysis of all patients with metastatic HR+/HER2− breast cancer treated with a combination of ribociclib and aromatase inhibitors in the first-line treatment of metastatic HR+/HER2− BC between June 2022 and January 2025, with a follow-up completed in October 2025. A total of 132 patients who met the criteria were included. Results: The median progression-free survival (PFS) in the entire group was 30 months, while the 12-, 24-, and 36-month PFS were 82.15%, 72.24%, and 28.75%, respectively. The overall response rate (ORR) was 41.7%, while the clinical benefit rate (CBR) was 89.3%. There was no statistically significant difference in PFS with respect to tumor grade (p = 0.54), Ki 67 level (<20% vs. >20%, p = 0.83), or the type of adjuvant endocrine therapy used (tamoxifen vs. AI) It is important to emphasize that female patients who had not previously received chemotherapy had a better response to ribociclib compared to those who had (33 m vs. 28 m, p = 0.05). Although a numerical difference in PFS was found in patients with bone-only metastases compared to those with metastases in other organs, the difference was not statistically significant (PFS 33 m vs. 30 m, p = 0.27;), and efficacy was consistent across menopausal status groups. The most common adverse effect was neutropenia, occurring in 89.4% of patients, 47.7% of whom presented with grade 3 or 4. As for hepatotoxicity, transaminase increase occurred in 25 patients (18.8%), 5 of whom (3.8%) were grade 3–4, and QTc interval prolongation occurred in 5.3% of patients. Conclusions: The results in terms of PFS and AEs are consistent with those of pivotal studies and real clinical practice data, but a direct comparison is not possible due to differences in patient populations. Ribociclib once again demonstrated efficacy in all patient subgroups and remains the gold standard, alongside ET, for first-line HR+/HER2-negative mBC. Full article

(This article belongs to the Special Issue Breast Cancer and Hormone-Related Therapy: 2nd Edition)

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19 pages, 2708 KB

Open AccessEditor’s ChoiceReview

A Comprehensive Review of Immunotherapeutic Modalities in Glioblastoma: Mechanisms, Efficacy, and Safety Considerations ^†

by Savi Agarwal, Simon Han, Aadi Lal, Viranshi Vira, Anubhav Chandla, Pasha Mehranpour, Isaac Yang and Madhuri Wadehra

Cancers 2026, 18(2), 212; https://doi.org/10.3390/cancers18020212 - 9 Jan 2026

Cited by 3 | Viewed by 1833

Abstract

Background: Glioblastoma multiforme (GBM), the most aggressive primary brain malignancy in adults, is associated with poor prognosis and recurrence despite standard of care and newer immunotherapies. This warrants exploration of synergistic approaches such as combination immunotherapy for improved tumor control. Methods: We initiated [...] Read more.

Background: Glioblastoma multiforme (GBM), the most aggressive primary brain malignancy in adults, is associated with poor prognosis and recurrence despite standard of care and newer immunotherapies. This warrants exploration of synergistic approaches such as combination immunotherapy for improved tumor control. Methods: We initiated a systematic review of articles from 2015–2025 in PubMed, Embase, Scopus, Cochrane, and Web of Science if they assessed immunotherapy for GBM. Results: We included 49 studies (n = 3002 patients) with no significant demographic differences across publications. Combination immunotherapy regimens demonstrated higher pooled ORRs in limited comparative analyses, though findings were driven by a small number of studies. Single-arm analysis for overall survival (OS), progression-free survival (PFS), treatment-related adverse events (TRAEs), and ORR showed no significant differences among the groups. However, treatment–control arm analysis showed pooled ORs of 9.51 for combination immunotherapies and 0.44 in the control group. Conclusions: Combining immunotherapeutics across mechanisms may potentiate immune response effectiveness against GBM. Full article

(This article belongs to the Section Cancer Therapy)

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15 pages, 1216 KB

Open AccessEditor’s ChoiceReview

Autophagy Modulates Immunogenic Cell Death in Cancer

by Maiko Matsushita and Miyu Moriwaki

Cancers 2026, 18(2), 205; https://doi.org/10.3390/cancers18020205 - 8 Jan 2026

Cited by 3 | Viewed by 1870

Abstract

Immunogenic cell death (ICD) is a subtype of regulated cell death characterized by the spatiotemporally coordinated emission of damage-associated molecular patterns (DAMPs), such as calreticulin (CALR), ATP, and high-mobility group box-1 (HMGB1), which collectively prime tumor-specific T-cell responses. Autophagy, a lysosome-dependent catabolic process, [...] Read more.

Immunogenic cell death (ICD) is a subtype of regulated cell death characterized by the spatiotemporally coordinated emission of damage-associated molecular patterns (DAMPs), such as calreticulin (CALR), ATP, and high-mobility group box-1 (HMGB1), which collectively prime tumor-specific T-cell responses. Autophagy, a lysosome-dependent catabolic process, is increasingly recognized as a key modifier of antitumor immunity and the tumor microenvironment (TME). In preclinical models, autophagy can not only promote ICD by sustaining endoplasmic reticulum (ER) stress, eukaryotic translation initiation factor-2α (eIF2α) phosphorylation, and secretory pathways, but it can also limit ICD by degrading DAMPs, antigenic cargo, and major histocompatibility complex (MHC) molecules. The net outcome is highly context-dependent and determined by the tumor type, the nature and intensity of the stress, and the level at which autophagy is modulated. Herein, we summarize how autophagy affects the three canonical ICD-associated DAMPs, highlight solid-tumor models in which autophagy supports ICD, and contrast them with systems wherein autophagy inhibition is required for immunogenicity. We then focus on hematological malignancies, especially multiple myeloma, where recent reports implicate the autophagy-related protein GABARAP in bortezomib-induced ICD. Finally, we discuss the translational implications, including rational combinations of autophagy modulators with ICD-inducing chemotherapies, targeted drugs, and cellular immunotherapies, and outline the remaining challenges for safely harnessing the autophagy–ICD axis in the clinical setting. Full article

(This article belongs to the Special Issue Autophagy and Apoptosis in Cancer Progression)

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19 pages, 340 KB

Open AccessEditor’s ChoiceReview

Risk Scores for Stratifying Hepatocellular Carcinoma and Optimizing Surveillance Strategies

by Yu-Ping Chang, Yun-Chu Chen and Chen-Hua Liu

Cancers 2026, 18(1), 158; https://doi.org/10.3390/cancers18010158 - 2 Jan 2026

Cited by 2 | Viewed by 1095

Abstract

Background: Hepatocellular carcinoma (HCC) is a major global health burden, with poor outcomes largely due to diagnosis at an advanced stage and the limited performance of current surveillance tools. Ultrasound with alpha fetoprotein (AFP) provides insufficient sensitivity for early-stage detection, highlighting the [...] Read more.

Background: Hepatocellular carcinoma (HCC) is a major global health burden, with poor outcomes largely due to diagnosis at an advanced stage and the limited performance of current surveillance tools. Ultrasound with alpha fetoprotein (AFP) provides insufficient sensitivity for early-stage detection, highlighting the need to better identify the at-risk population. Focus of the review: Many HCC risk scores have been proposed; however, some depend on specialized laboratory data that are not widely available. This review summarizes risk scores that show reliable discrimination and rely on demographic, clinical, or molecular information that can be readily obtained in routine care. Conclusions: Advances in HCC risk scores support the move toward surveillance approaches based on individual risk. These tools can improve risk stratification, increase the likelihood of early detection, and potentially support better outcomes for people who belong to the at-risk population for HCC. Full article

(This article belongs to the Special Issue Prevention, Early Detection, and Surgical Oncology in Hepatocellular Carcinoma, Pancreatic Cancer, and Gastrointestinal Cancer)

15 pages, 462 KB

Open AccessEditor’s ChoiceReview

Advances in Neoantigen-Based Cancer Vaccines

by An-Chih Wu, Yusuke Nakamura and Kazuma Kiyotani

Cancers 2026, 18(1), 144; https://doi.org/10.3390/cancers18010144 - 31 Dec 2025

Cited by 5 | Viewed by 3101

Abstract

Neoantigen-based immunotherapies harness somatic mutations as tumor-specific targets and represent a major advance in personalized cancer treatment. Since neoantigens are presented exclusively on cancer cells, they enable highly selective T-cell recognition with minimal off-tumor toxicity. Neoantigen vaccines are rapidly emerging as a versatile [...] Read more.

Neoantigen-based immunotherapies harness somatic mutations as tumor-specific targets and represent a major advance in personalized cancer treatment. Since neoantigens are presented exclusively on cancer cells, they enable highly selective T-cell recognition with minimal off-tumor toxicity. Neoantigen vaccines are rapidly emerging as a versatile class of personalized cancer immunotherapies designed to prime tumor-specific T cells by targeting somatic mutations unique to each patient’s tumor. Multiple types of neoantigen vaccines, using peptide, mRNA, and DNA, have shown feasibility, safety, and immunogenicity across diverse solid tumors. Emerging comparative data indicate that the vaccines using peptide-pulsed dendritic cells (DCs) elicit higher per-epitope CD8⁺ T cell responses than mRNA-based vaccines, likely due to more efficient class I presentation of synthetic peptides and ex vivo-loaded DCs. In contrast, mRNAs, despite their capacity of targeting multiple neoantigen peptides simultaneously, often induce CD4⁺-dominant responses due to immunodominance patterns during antigen processing. Recent clinical trials in melanoma, glioblastoma, pancreatic cancer, and other types of cancer have demonstrated not only robust immune activation but also encouraging relapse-free outcomes when administered in adjuvant settings. Treatment timing strongly influenced immune responsiveness; patients with early-stage disease or those vaccinated after surgical resection generally exhibit more preserved systemic immunity and greater vaccine-induced T cell expansion compared to those with advanced disease. Future progress will rely on improved neoantigen prediction, including incorporation of post-translationally modified antigenic targets and acceleration of manufacturing pipelines to ensure timely, personalized vaccine delivery. Collectively, neoantigen vaccines offer substantial promise for integration into next-generation cancer treatment strategies. Full article

(This article belongs to the Special Issue Neoantigen Vaccines for Cancer Therapy)

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28 pages, 3140 KB

Open AccessEditor’s ChoiceReview

The Impact of Senescence-Associated Secretory Phenotype (SASP) on Head and Neck Cancers: From Biology to Therapy

by Md Tanjim Alam, Mishfak A. M. Mansoor, Sarah A. Ashiqueali, Pawel Golusinski, Ewelina Golusinska-Kardach, Joanna K. Strzelczyk, Blazej Rubis, Wojciech Golusinski and Michal M. Masternak

Cancers 2025, 17(24), 4024; https://doi.org/10.3390/cancers17244024 - 17 Dec 2025

Cited by 6 | Viewed by 3634

Abstract

Cellular senescence is defined as a state of permanent cell cycle arrest, providing a natural barrier against cancer. However, senescent cells are very metabolically active and secrete a complex mixture of bioactive molecules collectively known as the senescence-associated secretory phenotype (SASP), which play [...] Read more.

Cellular senescence is defined as a state of permanent cell cycle arrest, providing a natural barrier against cancer. However, senescent cells are very metabolically active and secrete a complex mixture of bioactive molecules collectively known as the senescence-associated secretory phenotype (SASP), which play a dual role in cancer biology. While the SASP can suppress tumors by facilitating immunosurveillance, it can also promote tumor progression by fostering a pro-inflammatory milieu, stimulating angiogenesis, enhancing invasiveness, and enabling immune evasion. In Head and Neck Cancers (HNCs), a highly heterogeneous group of malignancies, SASP has emerged as a critical player in disease progression and treatment resistance. Persistent DNA damage response (DDR) signaling drives SASP and thereby contributes to the progression of head and neck cancer by modulating the tumour microenvironment. It influences the tumor microenvironment (TME) by facilitating epithelial-to-mesenchymal transition (EMT), promoting cancer stem cell-like properties, and impairing the efficacy of radiotherapy, chemotherapy, and immune checkpoint inhibitors. These effects underscore the need for targeted interventions to regulate SASP activity. This review presents a comprehensive overview of the molecular mechanisms underlying SASP generation and its effects on HNCs. We discuss the dual roles of SASP in tumor suppression and progression, its contribution to therapy resistance, and emerging therapeutic strategies, including novel senolytic and senomorphic drugs. Finally, we highlight key challenges and future directions for translating SASP-targeted therapies into clinical practice, emphasizing the need for biomarker discovery, and a deeper understanding of SASP heterogeneity. By targeting the SASP, there is potential to enhance therapeutic outcomes and improve the management of HNCs. Full article

(This article belongs to the Special Issue Targeting Tumor Microenvironment in Cancer: An Impact on Therapeutic Efficacy)

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26 pages, 703 KB

Open AccessEditor’s ChoiceReview

HER2-Low and HER2-Ultralow Metastatic Breast Cancer and Trastuzumab Deruxtecan: Common Clinical Questions and Answers

by Nusayba A. Bagegni, Karthik V. Giridhar and Daphne Stewart

Cancers 2025, 17(24), 4021; https://doi.org/10.3390/cancers17244021 - 17 Dec 2025

Cited by 5 | Viewed by 5005

Abstract

Approximately 80% of invasive breast cancers are classified as human epidermal growth factor receptor 2 (HER2)-negative; however, many of these tumors have detectable levels of HER2 surface expression. Trastuzumab deruxtecan (T-DXd) is a HER2-directed antibody-drug conjugate with a membrane-permeable payload that is cytotoxic [...] Read more.

Approximately 80% of invasive breast cancers are classified as human epidermal growth factor receptor 2 (HER2)-negative; however, many of these tumors have detectable levels of HER2 surface expression. Trastuzumab deruxtecan (T-DXd) is a HER2-directed antibody-drug conjugate with a membrane-permeable payload that is cytotoxic to both HER2-expressing tumor cells and neighboring cells via the bystander antitumor effect. T-DXd has shown significant antitumor activity in clinical trials for patients with HER2-positive (immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization [ISH]+) breast cancer. In addition, the results of the DESTINY-Breast04 trial demonstrated the clinical benefit of T-DXd in patients with HER2-low (IHC 1+ or IHC 2+/ISH−) breast cancer after receiving prior chemotherapy. DESTINY-Breast06 demonstrated the clinical benefit of T-DXd in patients with hormone receptor (HR)-positive, HER2-low (IHC 1+ or IHC 2+/ISH−), and HER2-ultralow (IHC 0 with membrane staining) metastatic breast cancer who had not received prior chemotherapy in the advanced setting. These results validate the need for a standard-of-care diagnostic test to identify HER2-low and HER2-ultralow expression levels in patients with metastatic breast cancer to guide therapeutic decision-making. Furthermore, effective treatment sequencing strategies and adverse event management are essential for maximizing patient benefit. This review presents the identification of HER2-low and HER2-ultralow breast cancer, sequencing of T-DXd with other treatments, and management of common or clinically significant adverse events reported with T-DXd. Full article

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

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30 pages, 2692 KB

Open AccessEditor’s ChoiceReview

Therapeutic Applications of Fibroblast Activation Protein (FAP)-Binding Radiopharmaceuticals: Review of Opportunities and Challenges

by Justine Maes, Bernard Pôlet, Janke Kleynhans, Filip Van Herpe, Karolien Goffin, Jeroen Dekervel, Philippe Nafteux, Baki Topal, Frederik Cleeren and Christophe M. Deroose

Cancers 2025, 17(24), 4019; https://doi.org/10.3390/cancers17244019 - 17 Dec 2025

Cited by 7 | Viewed by 2779

Abstract

Fibroblast activation protein (FAP)-binding radiopharmaceuticals have emerged as promising candidates for both diagnostic and therapeutic applications in oncology due to their selective targeting of cancer-associated fibroblasts (CAFs). This review evaluates the current literature on the therapeutic use of FAP-targeted radiopharmaceuticals in human studies, [...] Read more.

Fibroblast activation protein (FAP)-binding radiopharmaceuticals have emerged as promising candidates for both diagnostic and therapeutic applications in oncology due to their selective targeting of cancer-associated fibroblasts (CAFs). This review evaluates the current literature on the therapeutic use of FAP-targeted radiopharmaceuticals in human studies, with a focus on their safety, efficacy, and clinical applicability. Data on radionuclide type, clinical outcome, radiological and metabolic response and adverse events were extracted and summarized. The included studies demonstrated that lutetium-177,yttrium-90 and actinium-225 (in combination therapy) labeled FAP inhibitors exhibit high tumor uptake, with varying but mostly sufficient retention and a favorable safety profile. While mild adverse events such as fatigue, nausea and grade 1 or 2 hematotoxicity were observed, severe toxicities were rare. FAPI-based radionuclide therapies generally show high disease control rates, with promising results from tandem and combination strategies. The heterogeneity of tumor types and small sample sizes limited the generalizability of findings. FAP-targeted radioligand therapy appears to be a promising treatment option for patients with advanced cancer who have exhausted standard therapies. However, further large-scale, prospective clinical trials are necessary to determine optimal dosing strategies, long-term safety and efficacy across different tumor types. Emerging approaches, such as covalently binding FAP-targeted radiopharmaceuticals and the use of alpha-emitters such as actinium-225, lead-212 and bismuth-213, may further enhance treatment outcomes and warrant future investigation. Full article

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

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33 pages, 640 KB

Open AccessEditor’s ChoiceReview

Liquid Biopsy and Circulating Biomarkers in Head and Neck Cancer: Advancing Non-Invasive Detection and Tailored Management

by Ilaria Morelli, Chiara Ghirardini, Laura Faccani, Claudia Casanova, Ignacio Javier Fernandez and Stefano Tamberi

Cancers 2025, 17(24), 3974; https://doi.org/10.3390/cancers17243974 - 12 Dec 2025

Cited by 7 | Viewed by 2151

Abstract

The incidence of Head and Neck cancer is rapidly growing, now representing the sixth most common non-skin cancer worldwide [...] Full article

(This article belongs to the Special Issue Circulating Tumour DNA and Liquid Biopsy in Oncology)

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18 pages, 1132 KB

Open AccessEditor’s ChoiceArticle

Long-Term Oncological Outcomes of Laparoscopic Versus Open Radical Surgery in Early-Stage Cervical Cancer: A Propensity Score–Matched Analysis

by Rattiya Phianpiset, Chayanid Detwongya, Sunisa Phookiaw, Manatsawee Manopunya, Chailert Phongnarisorn and Kittipat Charoenkwan

Cancers 2025, 17(24), 3960; https://doi.org/10.3390/cancers17243960 - 11 Dec 2025

Cited by 2 | Viewed by 1453

Abstract

Objective: To assess the oncological outcomes of laparoscopic versus open radical hysterectomy (RH) in patients with early-stage cervical cancer using propensity score–matched analysis. Methods: We conducted a retrospective cohort study of 1244 patients who underwent RH with pelvic lymphadenectomy at Chiang [...] Read more.

Objective: To assess the oncological outcomes of laparoscopic versus open radical hysterectomy (RH) in patients with early-stage cervical cancer using propensity score–matched analysis. Methods: We conducted a retrospective cohort study of 1244 patients who underwent RH with pelvic lymphadenectomy at Chiang Mai University Hospital between 2003 and 2019. Of these, 82 patients received a laparoscopic approach (LAP) and 1162 underwent open radical hysterectomy. Propensity-score matching was performed in a 1:4 ratio using a caliper of 0.2 standard deviations to achieve balance between groups. Overall survival (OS) and progression-free survival (PFS) were analyzed with Kaplan–Meier curves and the log-rank test. Subgroup analysis was conducted based on tumor size (≤ 2 cm vs. > 2 cm). In addition, multivariable Cox proportional hazards models incorporating all relevant clinical and pathological variables were applied to the overall cohort to assess independent predictors of OS and PFS. Results: After matching, 72 LAP RH cases were compared with 279 open RH cases, showing well-balanced baseline features. At 5 years, OS was nearly the same between the LAP and the open groups (95.8% vs. 95.5%; p = 0.95), and PFS was also similar (92.3% vs. 93.8%; p = 0.85). Subgroup analyses demonstrated that LAP RH did not result in a survival disadvantage for tumors ≤ 2 cm or > 2 cm. In multivariable Cox analysis, surgical approach was not an independent predictor of (HR 0.83, 95% CI 0.40–1.71, p = 0.61) or PFS (HR 1.12, 95% CI 0.44–2.84, p = 0.82). Conclusions: In our single-center cohort analyzed using propensity score matching, LAP RH showed long-term oncological outcomes comparable to those of open RH. These results support LAP RH as a safe surgical option for selected patients with early-stage cervical cancer within our setting, where procedures were performed by experienced surgeons following standardized techniques. Further evaluation in diverse clinical contexts is still needed. Full article

(This article belongs to the Special Issue Cervical Cancer: Screening and Treatment in 2024-2025)

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25 pages, 684 KB

Open AccessEditor’s ChoiceReview

The Pathogenesis of the Neurofibroma-to-Sarcoma Transition in Neurofibromatosis Type I: From Molecular Profiles to Diagnostic Applications

by Sabrina Busciglio, Ilenia Rita Cannizzaro, Anita Luberto, Antonietta Taiani, Barbara Moschella, Enrico Ambrosini, Sofia Cesarini, Mirko Treccani, Cinzia Azzoni, Lorena Bottarelli, Domenico Corradi, Vera Uliana, Davide Martorana, Valeria Barili and Antonio Percesepe

Cancers 2025, 17(24), 3955; https://doi.org/10.3390/cancers17243955 - 11 Dec 2025

Cited by 3 | Viewed by 1596

Abstract

Neurofibromatosis type 1 (NF1) predisposes to a spectrum of peripheral nerve sheath tumors, ranging from benign plexiform neurofibromas (PN) to atypical neurofibromatous neoplasms of uncertain biological potential (ANNUBP) and malignant peripheral nerve sheath tumors (MPNST). Tumorigenesis follows a multistep molecular cascade initiated by [...] Read more.

Neurofibromatosis type 1 (NF1) predisposes to a spectrum of peripheral nerve sheath tumors, ranging from benign plexiform neurofibromas (PN) to atypical neurofibromatous neoplasms of uncertain biological potential (ANNUBP) and malignant peripheral nerve sheath tumors (MPNST). Tumorigenesis follows a multistep molecular cascade initiated by biallelic NF1 inactivation, followed by CDKN2A loss and disruption of the Polycomb Repressive Complex 2 (PRC2). These events guide chromatin remodeling, widespread epigenetic dysregulation, and activation of oncogenic pathways such as RAS/MAPK and PI3K/AKT. Here, we integrate genomic, transcriptomic, and epigenomic studies to delineate the molecular trajectories underlying tumor progression and to define promising biomarkers for the early detection of malignant transformation. Emerging liquid biopsy approaches, based on circulating tumor DNA (ctDNA) analyses, reveal distinctive copy number variations (CNVs) and methylation patterns that mirror tissue-derived profiles, enabling the detection of malignant transformation. Together, these findings support a model in which cumulative genetic and epigenetic alterations drive the PN–ANNUBP–MPNST continuum. They also underscore the value of multi-omics and liquid biopsy-based strategies to improve early diagnosis, patient risk stratification, and personalized management of NF1-associated tumors, thereby advancing precision medicine in this complex disease spectrum. Full article

(This article belongs to the Special Issue Neurofibromatosis)

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39 pages, 406 KB

Open AccessEditor’s ChoiceReview

Management of Patients with Epithelial Ovarian Cancer: A Systematic Comparison of International Guidelines from Scientific Societies (AIOM-BGCS-ESGO-ESMO-JGSO-NCCN-NICE)

by Martina Arcieri, Veronica Tius, Sara Filippin, Giovanni Aletti, Domenica Lorusso, Anna Fagotti, Jalid Sehouli, Ignacio Zapardiel, Pierandrea De Iaco, Paolo Scollo, Andrea Ciavattini, Marco Petrillo, Violante Di Donato, Federica Perelli, Giorgio Bogani, Stefano Restaino, Giuseppe Vizzielli and the Gynecologic Oncology Group

Cancers 2025, 17(24), 3915; https://doi.org/10.3390/cancers17243915 - 7 Dec 2025

Cited by 8 | Viewed by 5282

Abstract

Epithelial ovarian cancer (EOC) remains the most lethal gynecological malignancy worldwide, primarily due to late-stage diagnosis, limited early screening tools, and the aggressive nature of the disease. Increasing global efforts have been directed toward harmonizing clinical guidelines and ensuring equitable access to optimal [...] Read more.

Epithelial ovarian cancer (EOC) remains the most lethal gynecological malignancy worldwide, primarily due to late-stage diagnosis, limited early screening tools, and the aggressive nature of the disease. Increasing global efforts have been directed toward harmonizing clinical guidelines and ensuring equitable access to optimal care. This narrative review provides a comprehensive overview and critical comparison of the most recent international guidelines for ovarian cancer management, emphasizing similarities and discrepancies. Each section examines diagnostic, surgical, and therapeutic recommendations across all disease stages—from prevention to recurrence. Emerging advances that are reshaping the management of EOC such as preclinical models and the application of artificial intelligence are also discussed. This work provides an updated and practical synthesis to support clinicians, researchers, and policymakers in optimizing ovarian cancer management and guiding future research priorities in precision oncology. Full article

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

12 pages, 1160 KB

Open AccessEditor’s ChoiceArticle

The Prognostic Role of Different Blood Cell Count-to-Lymphocyte Ratios in Patients with Lung Cancer at Diagnosis

by Ourania Papaioannou, Oraianthi Fiste, Eva Theohari, Fotios Sampsonas, Foteinos-Ioannis Dimitrakopoulos, Angelos Koutras, Ioannis Gkiozos, Ioannis Vathiotis, Elias Kotteas and Argyrios Tzouvelekis

Cancers 2025, 17(23), 3879; https://doi.org/10.3390/cancers17233879 - 4 Dec 2025

Cited by 3 | Viewed by 1734

Abstract

Background: Lung cancer (LC) is a complex-to-treat disease and remains the leading cause of cancer-related mortality. Methods: Our aim was to investigate the prognostic role of neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and monocyte to lymphocyte ratio [...] Read more.

Background: Lung cancer (LC) is a complex-to-treat disease and remains the leading cause of cancer-related mortality. Methods: Our aim was to investigate the prognostic role of neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and monocyte to lymphocyte ratio (MLR) in patients with LC. In this retrospective study, examining the period between 1 June 2020 and 31 May 2024, we recorded consecutive patients who presented to the Department of Respiratory Medicine, University Hospital of Patras, Patras, Greece, and received a first diagnosis of LC. The primary outcome was mortality risk analysis based on NLR, PLR, and MLR at diagnosis. Secondary outcomes included associations of tumor, node, metastasis (TNM) staging, and smoking with NLR, PLR, and MLR at diagnosis. Results: We identified 353 patients with a first diagnosis of LC. The mean age ± SD at the time of diagnosis was 68.1 ± 9.1 years. Most patients were male (77.9%, n = 275) and current or ex-smokers (58.1%, n = 205, and 39.1%, n = 138, respectively). Histological diagnosis was non-small-cell lung cancer (NSCLC), small-cell lung cancer (SCLC), and not otherwise specified (NOS) in 67.1% (n = 237), 29.8% (n = 105), and 3.1% (n = 11) of patients, respectively. Adenocarcinoma NSCLC was more common (40.2%, n = 142) compared to squamous NSCLC (25.5%, n = 90). In 12.9% of patients, we identified EGFR, KRAS, ALK, or BRAF molecular driver mutations, while PD-L1 expression was positive in 20.7% of patients. The majority of enrolled patients presented with advanced stage IV LC at diagnosis (63.2%, n = 223). Kaplan–Meier curves showed that patients with higher than the median NLR and PLR at diagnosis were associated with significantly higher mortality risk compared to those with lower than the median [HR: 0.58, (95% CI: 0.42 to 0.81) p = 0.0009 and HR: 0.71, (95% CI: 0.53 to 0.95) p = 0.02, respectively], while no differences in mortality risk were observed between patients with higher versus lower than the median MLR [HR: 0.84, (95% CI: 0.63 to 1.12) p = 0.22]. With regard to secondary outcomes, no associations between higher versus lower than the median NLR, PLR, or MLR values and TNM staging [4.0 (95% CI: 4.0–4.0) vs. 4.0 (95% CI: 4.0–4.0), p = 0.95, 4.0 (95% CI: 4.0–4.0) vs. 4.0 (95% CI: 4.0–4.0), p = 0.09, 4.0 (95% CI: 4.0–4.0) vs. 4.0 (95% CI: 4.0–4.0), p = 0.4, respectively], as well as smoking status [70 (95% CI: 60–80) vs. 80 (95% CI: 60–80), p = 0.10, 70 (95% CI: 60–80) vs. 80 (95% CI: 60–80), p = 0.46, 80 (95% CI: 60–80) vs. 70 (95% CI: 60–80), p = 0.96, respectively] were reported. Conclusions: NLR and PLR could serve as reliable and clinician-friendly prognosticators of clinical outcomes in patients with LC. Further validation cohorts are sorely needed to prove this notion. Full article

(This article belongs to the Special Issue The Role of Neutrophils in Tumor Progression and Metastasis)

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15 pages, 1276 KB

Open AccessEditor’s ChoiceReview

Radiation-Induced Immune Responses from the Tumor Microenvironment to Systemic Immunity

by Shaun Png, Sirimuvva Tadepalli and Edward E. Graves

Cancers 2025, 17(23), 3849; https://doi.org/10.3390/cancers17233849 - 30 Nov 2025

Cited by 13 | Viewed by 2367

Abstract

Radiotherapy remains a central component of cancer therapy that induces DNA damage and cancer cell death. Beyond its cytotoxic effects, radiotherapy acts as a potent immunomodulator by releasing immunogenic molecules, inflammatory mediators, and neoantigens that shape anti-tumor immunity. Radiation-induced immune responses can have [...] Read more.

Radiotherapy remains a central component of cancer therapy that induces DNA damage and cancer cell death. Beyond its cytotoxic effects, radiotherapy acts as a potent immunomodulator by releasing immunogenic molecules, inflammatory mediators, and neoantigens that shape anti-tumor immunity. Radiation-induced immune responses can have opposing effects, including immune activation or immunosuppression that dictate local tumor responses. Increasing evidence suggests these immunologic effects are not confined to the site of irradiation, as radiation exposure to surrounding normal tissue can trigger systemic immune signaling that affects local tumor progression as well as metastatic spread. This review examines radiotherapy-induced immune responses across three interconnected contexts: (i) tumor-intrinsic signaling during radiation; (ii) tumor microenvironmental changes where innate and adaptive immune responses alter local outcomes; and (iii) systemic and off-target effects contributing to broader immune remodeling. A comprehensive understanding of radiotherapy-induced immune responses will guide therapeutic strategies to enhance its immunological potential while minimizing unintended immune and off-target effects. Full article

(This article belongs to the Special Issue Radiation Exposure, Inflammation and Cancers)

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23 pages, 864 KB

Open AccessEditor’s ChoiceReview

Modulating Prostate Cancer Therapy Through the Gut Microbiome: A Comprehensive Review

by Mohammed A. Magashi Ali and Sarki A. Abdulkadir

Cancers 2025, 17(23), 3842; https://doi.org/10.3390/cancers17233842 - 29 Nov 2025

Cited by 6 | Viewed by 2855

Abstract

Background/Objectives: There is growing interest in the gut microbiome’s role in cancer, particularly its influence on prostate cancer therapy. This review explores how the gut microbiota modulates treatment outcomes and how prostate cancer therapies affect microbial composition. Methods: A semi-systematic PubMed [...] Read more.

Background/Objectives: There is growing interest in the gut microbiome’s role in cancer, particularly its influence on prostate cancer therapy. This review explores how the gut microbiota modulates treatment outcomes and how prostate cancer therapies affect microbial composition. Methods: A semi-systematic PubMed search was performed for English-language articles published between 2010 and 2025 using relevant keywords related to prostate cancer therapy and the gut microbiome. Both original research and reviews were included, with additional studies identified through citation tracking. Results: The literature reveals a dynamic, bidirectional relationship between the gut microbiome and prostate cancer therapies. Gut microbes can modulate treatment efficacy and toxicity through immune regulation, metabolic activity, and the production of bioactive compounds such as short-chain fatty acids and tryptophan derivatives. These interactions influence responses to androgen deprivation therapy, chemotherapy, radiotherapy, and immunotherapy. In parallel, prostate cancer treatments induce notable shifts in gut microbial composition, reducing diversity, increasing intestinal permeability, and promoting dysbiosis. These changes may impair therapeutic outcomes. Specific microbial taxa, including Akkermansia muciniphila, Faecalibacterium, and Bacteroides, have been linked to both therapeutic response and microbiome alterations. Conclusions: The reciprocal influence between gut microbes and prostate cancer therapies presents a compelling avenue for therapeutic innovation. However, current knowledge is largely derived from preclinical or cross-cancer studies, highlighting a major evidence gap in prostate-specific research. Bridging this gap through well-designed translational studies could inform clinical strategies that harness microbiome modulation to enhance treatment efficacy, reduce toxicity, and personalize prostate cancer therapy. Full article

(This article belongs to the Section Cancer Therapy)

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24 pages, 1325 KB

Open AccessEditor’s ChoiceReview

Bridging Discovery and Treatment: Cancer Biomarker

by Hengrui Liu, Ilayda Karsidag, Rebecca Golin and Guangzhen Wu

Cancers 2025, 17(22), 3720; https://doi.org/10.3390/cancers17223720 - 20 Nov 2025

Cited by 9 | Viewed by 4657

Abstract

Biomarkers have transformed cancer care by linking molecular insights to personalized treatment strategies. This review first surveys the spectrum of detection modalities, including tissue genomics and histopathology; liquid biopsies such as circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and extracellular vesicles; imaging [...] Read more.

Biomarkers have transformed cancer care by linking molecular insights to personalized treatment strategies. This review first surveys the spectrum of detection modalities, including tissue genomics and histopathology; liquid biopsies such as circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and extracellular vesicles; imaging and radiomics; and multi-omic approaches spanning epigenomics, transcriptomics, proteomics, metabolomics, and microbiomics. We then critically appraise the translational challenges that hinder clinical implementation, assay standardization, data integration, analytical and clinical validation, regulatory pathways, and cost-effectiveness. Finally, we explore emerging solutions, including artificial intelligence (AI)-driven multi-modal phenotyping, adaptive trial designs, and point-of-care assays, and outline future directions for expanding access and equitable adoption. By emphasizing the central role of biomarkers in guiding targeted and immune-based therapies, we underscore their potential to overcome tumor heterogeneity, preempt resistance, and ultimately improve patient outcomes. Full article

(This article belongs to the Special Issue Diagnostic Biomarkers in Cancers Study)

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19 pages, 824 KB

Open AccessEditor’s ChoiceReview

From Slide to Insight: The Emerging Alliance of Digital Pathology and AI in Melanoma Diagnostics

by Federico Venturi, Giulia Veronesi, Alberto Gualandi, Elisabetta Magnaterra, Biagio Scotti, Ina Sotiri, Carlotta Baraldi, Aurora Maria Alessandrini, Leonardo Veneziano, Sabina Vaccari, Elena Maria Cama, Daniela Tassone, Barbara Corti and Emi Dika

Cancers 2025, 17(22), 3696; https://doi.org/10.3390/cancers17223696 - 18 Nov 2025

Cited by 7 | Viewed by 2370

Abstract

Background: Cutaneous melanoma (CM) poses significant diagnostic challenges due to its biological heterogeneity and the subjective interpretation of histopathologic criteria. While early and accurate diagnosis remains critical for patient outcomes, conventional pathology is limited by interobserver variability and diagnostic ambiguity, especially in borderline [...] Read more.

Background: Cutaneous melanoma (CM) poses significant diagnostic challenges due to its biological heterogeneity and the subjective interpretation of histopathologic criteria. While early and accurate diagnosis remains critical for patient outcomes, conventional pathology is limited by interobserver variability and diagnostic ambiguity, especially in borderline lesions. Objective: This narrative review explores the integration of digital pathology (DP) and artificial intelligence (AI)—including deep learning (DL), machine learning (ML), and interpretable models—into the histopathologic workflow for CM diagnosis. Methods: We systematically searched PubMed, Scopus, and Web of Science (2013–2025) for studies using whole slide imaging (WSI) and AI to assist melanoma diagnosis. We categorized findings across five domains: WSI-based classification models, feature extraction (e.g., mitoses, ulceration), spatial modeling and TIL analysis, molecular prediction (e.g., BRAF mutation), and interpretable pipelines based on nuclei morphology. Results: We included 87 studies with diverse AI methodologies. Convolutional neural networks (CNNs) achieved diagnostic accuracy comparable to expert dermatopathologists. U-Net and Mask R-CNN models enabled robust detection of critical histologic features, while nuclei-level analyses offered explainable classification strategies. Spatial and morphometric modeling allowed quantification of tumor–immune interactions, and select models inferred molecular alterations directly from H&E slides. However, generalizability remains limited due to small, homogeneous datasets and lack of external validation. Conclusions: AI-enhanced digital pathology holds transformative potential in CM diagnosis, offering accuracy, reproducibility, and interpretability. Yet, clinical integration requires multicentric validation, standardized protocols, and attention to workflow, ethical, and medico-legal challenges. Future developments, including multimodal AI and integration into molecular tumor boards, may redefine diagnostic precision in melanoma. Full article

(This article belongs to the Special Issue Novel Research on the Diagnosis and Treatment of Melanoma)

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36 pages, 5976 KB

Open AccessEditor’s ChoiceReview

The Unfolded Protein Response—Novel Mechanisms, Challenges, and Key Considerations for Therapeutic Intervention

by P. M. Quan Mai, Tam-Anh Truong, Sai Kumar Samala, Bhoomika Muruvekere Lakshmisha, Prapannajeet Biswal, Khadijeh Koushki, Prudhvi Chand Mallepaddi, Geraldine Vijay and Sunil Krishnan

Cancers 2025, 17(22), 3639; https://doi.org/10.3390/cancers17223639 - 13 Nov 2025

Cited by 7 | Viewed by 4594

Abstract

Background: The unfolded protein response (UPR) is an evolutionarily conserved, synchronized, and orchestrated process triggered by eukaryotic cells in response to endoplasmic reticulum (ER) stress. UPR restores the ER’s capacity to handle large protein loads within it, and still fold and process these [...] Read more.

Background: The unfolded protein response (UPR) is an evolutionarily conserved, synchronized, and orchestrated process triggered by eukaryotic cells in response to endoplasmic reticulum (ER) stress. UPR restores the ER’s capacity to handle large protein loads within it, and still fold and process these proteins accurately. Many recent studies have documented the non-canonical roles of the UPR, outside of protein quality control, in the context of lipid metabolism and the immune system in cancer. Cancer cells have been known to hijack the UPR to promote survival and evade immune surveillance. However, the underlying mechanisms remain poorly understood. Objectives: Here, we critically summarize canonical and non-canonical UPR mechanisms in the contexts of tumor immune microenvironment and lipid metabolism, dissect their crosstalk with other cell fate signaling pathways within cancer, and propose therapeutic strategies to exploit this relationship. We also discuss the fundamental challenges of solely targeting UPR and emphasize the importance of patient stratification, biomarker development, and rational combination therapies to maximize the potential for therapeutic gain. We provide a deconvoluted mechanistic understanding of the UPR process in an attempt to spark prospective clinically relevant therapeutics research. Full article

(This article belongs to the Section Molecular Cancer Biology)

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26 pages, 1096 KB

Open AccessEditor’s ChoiceReview

Emerging Diagnostics and Therapies in Neuroendocrine Neoplasms: A Critical Review

by Jorge H. Hernandez-Felix, Monica Isabel Meneses-Medina, Rachel Riechelmann, Jonathan Strosberg, Rocio Garcia-Carbonero and Jaydira del Rivero

Cancers 2025, 17(22), 3632; https://doi.org/10.3390/cancers17223632 - 12 Nov 2025

Cited by 3 | Viewed by 4634

Abstract

Neuroendocrine neoplasms (NENs) are biologically diverse tumors. This article is a critical review of recent evidence focusing on systemic therapies (through mid-2025). We summarize what is most practice-relevant and where gaps remain. In diagnosis, somatostatin-receptor PET/CT has largely replaced older scintigraphy, and adding [...] Read more.

Neuroendocrine neoplasms (NENs) are biologically diverse tumors. This article is a critical review of recent evidence focusing on systemic therapies (through mid-2025). We summarize what is most practice-relevant and where gaps remain. In diagnosis, somatostatin-receptor PET/CT has largely replaced older scintigraphy, and adding FDG PET can flag more aggressive disease. Blood-based tests and selected tissue markers (e.g., MGMT, DAXX/ATRX/ALT) show promise but require cautious interpretation in routine care. In treatment, radioligand therapy (PRRT) is used earlier in appropriate receptor-positive disease; cabozantinib improves progression-free survival after prior therapy; and belzutifan offers a biomarker-guided option for malignant pheochromocytoma/paraganglioma. Immunotherapy remains limited to defined subsets, including high-grade neoplasms. We appraise strengths and limitations of key trials, note issues of access and toxicity, and highlight active areas in development (SSTR antagonists, alpha emitters, and dose-guided PRRT). Our goal is to provide a concise, evidence-based map of the field to support informed clinical judgment and future research priorities. Full article

(This article belongs to the Collection Neuroendocrine Tumors: Treatment and Management)

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22 pages, 862 KB

Open AccessEditor’s ChoiceReview

When and for Whom Does Intensive Care Unit Admission Change the Prognosis in Oncology?—A Scoping Review

by Ioana Roxana Codru and Liliana Vecerzan

Cancers 2025, 17(22), 3636; https://doi.org/10.3390/cancers17223636 - 12 Nov 2025

Cited by 4 | Viewed by 2702

Abstract

Background: The intersection between oncology and intensive care has shifted from predominantly end-of-life care to a therapeutic bridge that can preserve anticancer trajectories in carefully selected patients. Yet, criteria separating benefit from futility remain fragmented. Objective: This paper seeks to map contemporary evidence [...] Read more.

Background: The intersection between oncology and intensive care has shifted from predominantly end-of-life care to a therapeutic bridge that can preserve anticancer trajectories in carefully selected patients. Yet, criteria separating benefit from futility remain fragmented. Objective: This paper seeks to map contemporary evidence (2015–2025) on outcomes after Intensive Care Unit (ICU) admission in adults with cancer and to identify clinical constellations in which ICU-level care still changes prognosis. Methods: PRISMA-ScR scoping review (PCC framework). PubMed search (2015–2025), dual screening, standardized extraction; narrative/thematic synthesis across six clusters (hematologic, solid tumors, sepsis/non-COVID-19 infection, COVID-19/viral pneumonia, novel/targeted-therapy toxicities, end-of-life/aggressive ICU) were used. No meta-analysis given heterogeneity. Results: Seventy-three studies (>170,000 ICU admissions) were included, mostly cohort designs across 27 countries. ICU mortality ranged 8–72% (weighted mean ≈ 41%); hospital ≈ 38%; 90-day ≈ 46%; 1-year ≈ 62%. About one third of ICU survivors resumed systemic therapy. Benefit concentrated in early admissions, single-organ failure, controlled/remission disease, postoperative/elective monitoring, and reversible treatment-related toxicities (e.g., ICI pneumonitis, CAR-T CRS/ICANS). Futility clustered around ≥3 organ supports, RRT > 7 days, refractory/progressive disease, and ECOG ≥ 3. Sepsis outcomes averaged 45–55% ICU mortality but improved with rapid recognition and source control; COVID-19 mortality was particularly high in hematologic malignancies early in the pandemic, with subsequent declines post-vaccination. Conclusions: In modern oncologic practice, ICU care changes prognosis when the acute physiological insult is reversible and cancer control remains plausible; conversely, high organ-support burden and refractory disease define practical futility thresholds. These signals support time-limited ICU trials, earlier ICU involvement for sepsis/irAEs, and embedded palliative care to align intensity with goals. Full article

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

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31 pages, 1214 KB

Open AccessEditor’s ChoiceReview

Gene Therapy Strategies for Hepatocellular Carcinoma (HCC): Current Landscape and Future Directions

by Ali Gawi Ermi, Rabha M. Younis, Kayla Rodriguez and Devanand Sarkar

Cancers 2025, 17(22), 3608; https://doi.org/10.3390/cancers17223608 - 8 Nov 2025

Cited by 6 | Viewed by 4181

Abstract

The liver is the primary metabolic organ in the body, metabolizing nutrients and drugs. Advanced liver diseases result in compromised metabolic function of the liver. These diseases are often difficult to treat with drugs because of inability of the liver to generate effective [...] Read more.

The liver is the primary metabolic organ in the body, metabolizing nutrients and drugs. Advanced liver diseases result in compromised metabolic function of the liver. These diseases are often difficult to treat with drugs because of inability of the liver to generate effective drug metabolites and/or to properly inactivate the drugs resulting in high drug-induced toxicity with subsequent reduced patient compliance. Hepatocellular carcinoma (HCC) is a disease that develops on a fibrotic/cirrhotic liver and is mostly diagnosed at an advanced stage. Current protocol for treating advanced HCC includes a combination of immunotherapy or tyrosine kinase inhibitors (TKIs), which provides a survival benefit of only ~2 years. In addition, immunotherapy is effective in only 27% of HCC patients and patients treated with TKIs invariably develop drug resistance within 6 months. In this scenario gene therapy serves as an alternative approach that might bring significant benefits to HCC patients. Although gene therapy approaches for HCC or other liver diseases have yet to obtain approval from the Food and Drug Administration (FDA), a significant advancement has been made over the years in this field. In this review article, we highlight very recent literature showing the promise of gene therapy in managing HCC patients, extending survival benefits and providing improved quality of life. Full article

(This article belongs to the Special Issue New Approaches in the Treatment of Hepatocellular Carcinoma and Liver Tumor)

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16 pages, 1894 KB

Open AccessEditor’s ChoiceArticle

Impact of Body Mass Index on Robotic Surgery Outcomes in Early-Stage Endometrial Cancer: A Retrospective Cohort Study

by Dimitrios Papageorgiou, Eleftherios Zachariou, Ioakeim Sapantzoglou, Elias Tsakos, Emmanouil M. Xydias, Dimitrios Dimitroulis and Nikolaos Plevris

Cancers 2025, 17(21), 3570; https://doi.org/10.3390/cancers17213570 - 5 Nov 2025

Cited by 4 | Viewed by 1210

Abstract

Background/Objectives: Obesity is a well-established risk factor for endometrial cancer and presents challenges for surgical management. Robotic-assisted surgery offers a minimally invasive approach with potential benefits for obese patients. This study sought to assess the impact of body mass index (BMI) on [...] Read more.

Background/Objectives: Obesity is a well-established risk factor for endometrial cancer and presents challenges for surgical management. Robotic-assisted surgery offers a minimally invasive approach with potential benefits for obese patients. This study sought to assess the impact of body mass index (BMI) on surgical performance and short-term outcomes in patients undergoing robotic surgery for early-stage endometrial cancer, focusing on follow-up and perioperative treatment. Methods: A retrospective analysis was conducted on 54 patients with early-stage endometrial cancer who underwent a robotic total hysterectomy, bilateral salpingo-oophorectomy, and indocyanine green sentinel lymph node biopsy between January 2021 and December 2024 at two tertiary centers. Patients were stratified by body mass index. Surgical variables, sentinel lymph node detection rates, peri- and postoperative complications, length of hospital stay, and short-term oncologic outcomes were assessed. Statistical comparisons were performed using ANOVA, chi-square tests, and Pearson’s correlation analysis. Results: The mean patient age was 59.7 years, with a mean BMI of 31.1 kg/m². Bilateral sentinel lymph node detection was successful in 87% of cases, with no significant differences between BMI groups. Console time, hospital stay, and complication rates were comparable across BMI categories. Console time positively correlated with the number of lymph nodes removed (r = 0.302, p = 0.026), but not with BMI. At a mean follow-up of 24.4 months, no recurrences were observed. Conclusions: Robotic surgery for early-stage endometrial cancer is safe and effective regardless of BMI, including in patients with Class III obesity. BMI does not negatively impact surgical or short-term oncologic outcomes, supporting robotic surgery as an optimal approach in obese endometrial cancer patients. Full article

(This article belongs to the Special Issue Evolving Trends in the Surgical Therapy of Patients with Gynecological Cancer)

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14 pages, 1038 KB

Open AccessEditor’s ChoiceArticle

Comparative Analysis of Targeted RNA-Seq and Optical Genome Mapping for Detecting Gene Rearrangements in Acute Leukemia

by Chi Young Ok, Guilin Tang, Sanam Loghavi, Shimin Hu, Qing Wei, Andres E. Quesada, Mark J. Routbort, Rashmi Kanagal-Shamanna, C. Cameron Yin, Iman Sarami, Sofia Garces, Nitin K. Agarwal, Raja Luthra, Hong Fang, Fatima Zahra Jelloul, Julian Bryan, L. Jeffrey Medeiros, Keyur P. Patel and Gokce A. Toruner

Cancers 2025, 17(21), 3458; https://doi.org/10.3390/cancers17213458 - 28 Oct 2025

Cited by 4 | Viewed by 2062

Abstract

Background/Objectives: Gene rearrangements involving oncogenes are major drivers in acute leukemia, influencing disease classification, prognosis, and therapeutic decision-making. Targeted RNA sequencing (RNA-Seq) panels capable of detecting intergenic and intragenic fusions across multiple genes are increasingly used in diagnostic settings. However, comparative evaluation with [...] Read more.

Background/Objectives: Gene rearrangements involving oncogenes are major drivers in acute leukemia, influencing disease classification, prognosis, and therapeutic decision-making. Targeted RNA sequencing (RNA-Seq) panels capable of detecting intergenic and intragenic fusions across multiple genes are increasingly used in diagnostic settings. However, comparative evaluation with orthogonal technologies remains limited. Material and Methods: We compared the performance of a 108-gene anchored multiplex PCR (AMP)-based RNA-Seq panel with that of Optical Genome Mapping (OGM) in 467 acute leukemia cases. The cohort included 360 cases of acute myeloid leukemia (AML), 89 B-lymphoblastic leukemia (B-ALL), 12 T-lymphoblastic leukemia (T-ALL), and 6 cases of mixed phenotype acute leukemia (MPAL). Results: Results of both methods were concordant in 175 (74.7%) of 234 detected gene/rearrangement fusions. The concordance rate varied significantly across different leukemia types, ranging from 80.2% in B-ALL to 41.7% in T-ALL (p < 0.001) OGM uniquely detected 37 of 234 (15.8%) clinically relevant rearrangements, whereas RNA-Seq exclusively identified 22 of 234 (9.4%). Enhancer-hijacking lesions, including MECOM and BCL11B rearrangements, CDK6::MNX1, and IGH rearrangements, had a markedly lower concordance (20.6%) compared with all other aberrations (93.1%) (p < 0.001). Conversely, some gene fusions arising from intrachromosomal deletions were interpreted by OGM as simple deletions rather than rearrangements or fusions. Conclusions: Targeted RNA-Seq was effective for detecting chimeric fusion transcripts and showed slightly better performance in identifying fusions resulting from deletions. However, OGM was effective for detecting enhancer-hijacking events that do not generate fusion transcripts. Both methods are complementary for the workup of acute leukemia cases. Full article

(This article belongs to the Special Issue Diagnostic Biomarkers in Cancers Study)

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23 pages, 1424 KB

Open AccessEditor’s ChoiceReview

Overcoming Immune Evasion in the Prostate Tumor Microenvironment: Novel Targeted Strategies to Improve Treatment Outcomes

by Jing Huang, Ademola Ojo, Serena Tsao, Amir Horowitz, Natasha Kyprianou and Che-Kai Tsao

Cancers 2025, 17(21), 3441; https://doi.org/10.3390/cancers17213441 - 27 Oct 2025

Cited by 10 | Viewed by 3216

Abstract

Despite advances in diagnostic and therapeutic technology, prostate cancer remains a leading cause of morbidity and mortality among men. While androgen deprivation therapy and next-generation androgen receptor pathway inhibitors offer durable responses, the emergence of the lethal phenotype, metastatic castration-resistant prostate cancer (mCRPC) [...] Read more.

Despite advances in diagnostic and therapeutic technology, prostate cancer remains a leading cause of morbidity and mortality among men. While androgen deprivation therapy and next-generation androgen receptor pathway inhibitors offer durable responses, the emergence of the lethal phenotype, metastatic castration-resistant prostate cancer (mCRPC) eventually develops for most. A growing body of evidence points to the tumor microenvironment (TME) as a key driver of immune evasion and therapeutic failure. This review focuses on the current knowledge of immune suppression in the prostate TME, including cancer-associated fibroblasts, myeloid-derived suppressor cells, tumor-associated macrophages, immune checkpoint pathways, and several associated key metabolic alterations. These cellular and molecular networks contribute to therapeutic resistance and disease progression and may be used as therapeutic targets. We will also examine emerging treatment strategies aimed at reprogramming the TME, as well as combination approaches incorporating immunotherapies with other signaling inhibitors. Future success in clinical therapeutic development for mCRPC will depend on rational combinations that address both tumor-intrinsic resistance and extrinsic immune suppression, with emphasis on biomarker-driven patient and treatment selection. Full article

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

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14 pages, 518 KB

Open AccessEditor’s ChoiceReview

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

by Zhenyun Yang, Fengyu Song and Jin Zhong

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

Cited by 13 | Viewed by 5202

Abstract

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

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

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

20 pages, 554 KB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 5 | Viewed by 5105

Abstract

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

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

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

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25 pages, 800 KB

Open AccessEditor’s ChoiceReview

Radioligand Therapy in Cancer Management: A Global Perspective

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

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

Cited by 15 | Viewed by 7390

Abstract

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

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

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

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20 pages, 2387 KB

Open AccessEditor’s ChoiceArticle

Prognostic Value of Dynamic Changes in Immune-Inflammatory and Tumor Biomarkers Following Chemoradiotherapy in Locally Advanced Rectal Cancer

by Mahmoud Al-Masri, Yasmin Safi, Mohammad Almasri, Ramiz Kardan, Daliana Mustafa, Osama Alayyan, Bilal Kahalah and Rama AlMasri

Cancers 2025, 17(20), 3383; https://doi.org/10.3390/cancers17203383 - 20 Oct 2025

Cited by 6 | Viewed by 1649

Abstract

Background: The prognostic utility of inflammatory and tumor biomarkers, including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and carcinoembryonic antigen (CEA), in rectal cancer has been increasingly studied, but results remain inconsistent. This study evaluates the prognostic significance of pre- and post-chemoradiotherapy (CRT) levels [...] Read more.

Background: The prognostic utility of inflammatory and tumor biomarkers, including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and carcinoembryonic antigen (CEA), in rectal cancer has been increasingly studied, but results remain inconsistent. This study evaluates the prognostic significance of pre- and post-chemoradiotherapy (CRT) levels and dynamic changes in NLR, PLR, and CEA for predicting overall survival (OS) and disease-free survival (DFS) in locally advanced rectal cancer (LARC). Methods: This retrospective study included 261 LARC patients treated with neoadjuvant CRT followed by curative surgery. Pre- and post-CRT NLR, PLR, and CEA were collected. Survival analyses were performed using Kaplan–Meier curves and Cox proportional hazards models. ROC curves assessed predictive performance, and patients were stratified by cut-offs and biomarker changes (delta values). Results: The cohort had a mean age of 55.5 years; 55.9% were male, and 93.5% had clinical stage III disease. Post-CRT NLR (HR: 1.05, p = 0.007) and CEA (HR: 1.00, p < 0.001) were independently associated with OS, while post-CRT CEA and AJCC stage III were predictors of DFS (HR: 4.12, p = 0.009). ROC analysis showed improved accuracy when combining NLR (AUC = 0.66) and CEA (AUC = 0.70), yielding a combined AUC of 0.84 for OS. Patients with decreases in both NLR and CEA had the most favorable outcomes, whereas increases in both markers indicated poor prognosis (OS p < 0.0001; DFS p = 0.00019). Conclusions: Post-CRT levels and dynamic changes in NLR and CEA are independent prognostic markers in rectal cancer. Their combined assessment enhances survival prediction and may guide personalized postoperative surveillance and treatment strategies. Full article

(This article belongs to the Special Issue Biomarkers for Therapy Response in Gastrointestinal Malignancies: Predicting Outcomes and Personalizing Care)

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