Cancers

17 pages, 9739 KB

Open AccessArticle

TCN1 Drives Malignant Progression of Pancreatic Cancer Through STAT4-Mediated Transcriptional Activation of the DUOX2/ROS Signaling Axis

by Zonglin Liu, Dongxue Ju, Ze Yu, Binru Zhang, Dongbo Xue and Yongwei Wang

Cancers 2025, 17(20), 3300; https://doi.org/10.3390/cancers17203300 (registering DOI) - 12 Oct 2025

Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by its aggressive clinical behavior and intricate microenvironment regulation, leading to dismal prognosis. Elucidating the molecular mechanisms underlying PDAC pathogenesis is crucial for developing improved therapeutic approaches. The functional significance and molecular basis of transcobalamin 1 [...] Read more.

Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by its aggressive clinical behavior and intricate microenvironment regulation, leading to dismal prognosis. Elucidating the molecular mechanisms underlying PDAC pathogenesis is crucial for developing improved therapeutic approaches. The functional significance and molecular basis of transcobalamin 1 (TCN1) in PDAC remain largely unexplored. Methods and Results: Through integrated analysis of TCGA and GTEx datasets combined with 80 clinical specimens, we identified significant TCN1 overexpression in PDAC, showing a positive association with tumor stage and negative associations with histological differentiation and overall survival. Functional investigations showed that TCN1 enhanced pancreatic cancer cell proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT) in both in vitro and in vivo models. Mechanistically, TCN1 physically interacts with signal transducer and activator of transcription 4 (STAT4) to enhance its transcriptional activity. Chromatin immunoprecipitation (ChIP) assays showed that STAT4-mediated transcriptional activation of dual oxidase 2 (DUOX2) occurs through direct promoter binding. As a pivotal reactive oxygen species (ROS)-generating enzyme, DUOX2 overexpression elevates intracellular ROS levels, thereby promoting EMT progression and activating proliferation-related signaling cascades. Antioxidant treatment effectively abrogated TCN1-driven oncogenic phenotypes, establishing ROS as the critical downstream mediator. Conclusions: Collectively, our findings reveal a novel TCN1/STAT4/DUOX2 regulatory axis that exacerbates PDAC progression by remodeling redox homeostasis. This signaling cascade may serve as a prognostic biomarker and a potential therapeutic target for ROS-directed precision therapy in PDAC. Full article

(This article belongs to the Special Issue Cell Biology of Cancer Invasion: 2nd Edition)

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Graphical abstract

19 pages, 591 KB

Open AccessArticle

Pulmonary Metastasectomy: A Multicenter Comparison of Wedge Resection Versus Anatomic Resection for Single Metastases of Colorectal Cancer

by Stefan Welter, Isabelle Moneke, Ramzi Wara, Antonia Uyen-Thao Le, Ahmad Shalabi, Thomas Graeter, Till Ploenes and Daniel Baum

Cancers 2025, 17(20), 3299; https://doi.org/10.3390/cancers17203299 (registering DOI) - 11 Oct 2025

Abstract

Background/Objectives: Patients with single metastases from colorectal cancer constitute a subgroup with an excellent 5-year OS of 55–70% and with a real chance for cure. In this situation, local margin recurrence in the lung may impair the prognosis and thus is the main [...] Read more.

Background/Objectives: Patients with single metastases from colorectal cancer constitute a subgroup with an excellent 5-year OS of 55–70% and with a real chance for cure. In this situation, local margin recurrence in the lung may impair the prognosis and thus is the main outcome target of surgery. Methods: A retrospective multicenter analysis of patients with single metastases from colorectal cancers was performed. Four German Thoracic Surgery units contributed data from their prospective metastasectomy databases. Statistical analysis was focused on tumor recurrence and risk factors for local margin recurrence. Results: 166 patients from four centers could be further analyzed. For later comparison, 93 (56%) anatomic resections and 73 (44%) non-anatomic resections were pooled. Tumor recurrence was detected: at any site 87/161 (54%), within the lung 62/161 (38.5%) at intrapulmonary margins 25/145 (17.2%) and in intrathoracic lymph nodes 14/138 (10.1%). Intrapulmonary local margin recurrence was more often found in non-anatomic (25.4%) versus anatomic (11.6%) resections (p = 0.052). After propensity score matching (PSM), local margin recurrence was significantly more frequent after non-anatomic resection of intermediate and peripherally located metastases (p = 0.042). Furthermore, local margin recurrence was associated with small safety margins (p < 0.001), small number of lymph nodes removed (p < 0.001) and with intrathoracic lymph node recurrence (p = 0.001). The 5- and 10-year OS of the whole group was 70% and 47% with a median survival of 9.0 years. The 5- and 10-year RFS of the whole group was 59% and 43% with a median of 7.3 years. Conclusions: This study demonstrates that anatomical resection of single CRC lung metastases is superior to non-anatomic resection with respect to local radicality and local intrapulmonary margin recurrence, but there was no difference in OS and RFS. Full article

(This article belongs to the Section Cancer Metastasis)

16 pages, 5469 KB

Open AccessArticle

Effectiveness of Atezolizumab in Addition to Chemotherapy in ES-SCLC: A Retrospective Real-World Monocentric Study

by Raffaella Pagliaro, Fabiana Vitiello, Marina Gilli, Antonio d’Orologio, Luca Borgese, Susan F. Campbell, Paola Maria Medusa, Giuseppe Signoriello, Fabio Perrotta, Danilo Rocco and Andrea Bianco

Cancers 2025, 17(20), 3298; https://doi.org/10.3390/cancers17203298 (registering DOI) - 11 Oct 2025

Abstract

Background: Small cell lung cancer (SCLC) is a malignant carcinoma characterized by high proliferative rate and early metastatization with limited treatment options and poor prognosis. The approval of ICIs has established a new standard of care for extensive-stage (ES)-SCLC (5). Atezolizumab, an [...] Read more.

Background: Small cell lung cancer (SCLC) is a malignant carcinoma characterized by high proliferative rate and early metastatization with limited treatment options and poor prognosis. The approval of ICIs has established a new standard of care for extensive-stage (ES)-SCLC (5). Atezolizumab, an anti PD-L1 monoclonal antibody, has been the first immune checkpoint inhibitor (ICI) to be approved for SCLC patients. This study aims to retrospectively evaluate the real-world effectiveness and safety of atezolizumab in a cohort of patients with ES-SCLC. Methods: We conducted a monocentric retrospective analysis of SCLC patients who received atezolizumab in addition to chemotherapy, between January 2020 and December 2023. Study design endpoints included progression-free survival (PFS), overall survival (OS), and adverse events. Results: A total of 134 patients were included in this study. Out of 134 patients who began the CEA protocol, 100 continued maintenance. Currently, 25 are alive, 17 still on atezolizumab, 5 on second-line therapy, and 3 receiving best supportive care. The median age was 65 years. Patients received a median of four cycles of CEA (range 1–6 cycles), while the median number of atezolizumab maintenance cycles was eight (range 0–75). The overall median survival was 15 months, with patients who received more than 30 cycles of atezolizumab showing OS of 46.7% at 48 months. Common adverse events included skin disorders, pneumonitis, colitis, alanine, and aspartate deaminase increment, dysthyroidism, and blood disorders with only 3% of patients experiencing grade 3 or higher toxicities. Conclusions: In this real-world cohort, atezolizumab demonstrated comparable effectiveness to clinical trial results, with a manageable safety profile. These findings support the use of atezolizumab as a viable treatment option for ES-SCLC in routine clinical practice. Full article

(This article belongs to the Section Cancer Therapy)

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18 pages, 972 KB

Open AccessArticle

Survival Outcomes and Prognostic Factors in Metastatic Unresectable Appendiceal Adenocarcinoma Treated with Palliative Systemic Chemotherapy: A 10-Year Retrospective Analysis from Australia

by Jirapat Wonglhow, Hui-Li Wong, Michael Michael, Alexander Heriot, Glen Guerra, Catherine Mitchell and Jeanne Tie

Cancers 2025, 17(20), 3297; https://doi.org/10.3390/cancers17203297 (registering DOI) - 11 Oct 2025

Abstract

Background: Appendiceal adenocarcinoma is a rare malignancy, and data guiding its systemic treatment in metastatic settings are limited. This study aimed to determine the clinical outcomes, treatment efficacy, biomarkers, and prognostic factors in patients with metastatic or unresectable appendiceal adenocarcinoma receiving palliative chemotherapy. [...] Read more.

Background: Appendiceal adenocarcinoma is a rare malignancy, and data guiding its systemic treatment in metastatic settings are limited. This study aimed to determine the clinical outcomes, treatment efficacy, biomarkers, and prognostic factors in patients with metastatic or unresectable appendiceal adenocarcinoma receiving palliative chemotherapy. Methods: We retrospectively reviewed patients with metastatic appendiceal adenocarcinoma who received first-line palliative systemic chemotherapy at the Peter MacCallum Cancer Centre between January 2015 and December 2024. Results: Of the 40 patients included, fluoropyrimidine-based doublet regimens were most commonly used (82.5%) in first-line setting, achieving an objective response rate of 39.4%. Median overall survival (OS) was 21.6 months, and median first-line progression-free survival (PFS) was 8.9 months. 22 patients (55.0%) received second-line treatment. Median OS and PFS were 21.6 and 8.9 months, respectively, among patients treated with oxaliplatin-based doublet regimens, and 66.4 and 10.8 months, respectively, among those treated with irinotecan-based doublet regimens. Molecular biomarker testing was performed in 35 patients (87.5%). KRAS and NRAS mutations were identified in 68.6% and 2.9% of tested patients, respectively. Factors associated with poorer OS included male sex, elevated carcinoembryonic antigen levels, and overweight status. Bevacizumab use was not clearly associated with survival. Conclusions: Palliative systemic chemotherapy, particularly fluoropyrimidine-based doublet regimens, appears to be a reasonable and effective treatment option for patients with advanced appendiceal adenocarcinoma. Although this study was underpowered for formal comparison, the numerically longer OS and PFS of irinotecan-based regimens are hypothesis-generating and support further prospective evaluation. Molecular profiling emphasizes the need for personalized targeted therapeutic strategies. The identified prognostic factors may help guide risk stratification and patient counseling for treatment planning. Full article

(This article belongs to the Special Issue Clinical Efficacy of Drug Therapy in Gastrointestinal Cancers)

15 pages, 1110 KB

Open AccessArticle

Physical Therapy Utilization and Morbidity Outcomes After Breast Cancer Surgery: A Longitudinal Analysis of Three Combined Cohorts

by Ifat Klein, Danit R. Shahar, Michael Friger, Irena Rosenberg, Daphna Barsuk, Merav A. Ben-David and Sergio Susmallian

Cancers 2025, 17(20), 3296; https://doi.org/10.3390/cancers17203296 (registering DOI) - 11 Oct 2025

Abstract

Background: Upper-extremity morbidity after breast cancer surgery—including pain, lymphedema, and restricted shoulder range of motion—often develops gradually, emerging months after treatment and limiting daily activities. We aimed to characterize morbidity trajectories, physical therapy utilization, and predictors of physical therapy use. Methods: A retrospective [...] Read more.

Background: Upper-extremity morbidity after breast cancer surgery—including pain, lymphedema, and restricted shoulder range of motion—often develops gradually, emerging months after treatment and limiting daily activities. We aimed to characterize morbidity trajectories, physical therapy utilization, and predictors of physical therapy use. Methods: A retrospective multicenter cohort included 1602 women treated with breast surgery 0–36 months earlier. Patient-reported outcomes included Quick Disabilities of the Arm, Shoulder and Hand (QuickDASH), pain, range of motion limitation, axillary web syndrome, and lymphedema. Clinical variables included surgery type and nodal procedure. Outcomes were summarized across four postoperative windows (0–6, 7–12, 13–24, 25–36 months). Logistic and multinomial regression identified predictors of physical therapy uptake and timing (early, ≤3 months vs. late, >3 months; No physical therapy). Results: Anxiety declined across postoperative windows (p < 0.001), and axillary web syndrome decreased from early to later periods (p < 0.001). In contrast, range of motion restriction and decreased function remained common without significant differences between windows (p = 0.145 and p = 0.273). Pain was generally low-to-moderate by median [interquartile range], with a modest rise at 7–12 months (p < 0.001). In adjusted multinomial models (reference: Early physical therapy ≤ 3 months), higher pain was associated with No physical therapy and Late physical therapy (both p < 0.05); lymphedema with No PT and Late physical therapy (both p < 0.05); and axillary web syndrome with Late physical therapy (p = 0.001). Other symptoms (range of motion, function level, anxiety and physical activity) were not independently associated with physical therapy timing. Conclusions: Long-term postoperative morbidity is common. Early assessment and structured follow-up can mitigate its impact and should be embedded as core elements of survivorship health-promotion policy. Full article

(This article belongs to the Special Issue Epidemiology of Cancer and Risk Factors: Pushing Boundaries in Public Health Research and Policy)

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18 pages, 1007 KB

Open AccessReview

From Carcinogenesis to Drug Resistance: The Multifaceted Role of Oxidative Stress in Head and Neck Cancer

by Enas Bani-Ahmad, Joshua Dass and Crispin R Dass

Cancers 2025, 17(20), 3295; https://doi.org/10.3390/cancers17203295 (registering DOI) - 11 Oct 2025

Abstract

Objectives: This review examines the role of oxidative stress in the survival, apoptosis, and therapy resistance of head and neck squamous cell carcinoma (HNSCC) cells, with a focus on how redox imbalance influences tumour progression and treatment outcomes. Methods: A literature search was [...] Read more.

Objectives: This review examines the role of oxidative stress in the survival, apoptosis, and therapy resistance of head and neck squamous cell carcinoma (HNSCC) cells, with a focus on how redox imbalance influences tumour progression and treatment outcomes. Methods: A literature search was conducted in Scopus using the keywords head and neck squamous cell carcinoma, oxidative stress, reactive oxygen species (ROS), and antioxidant systems. Articles published in English were included, without restrictions on publication year. Reviews, clinical studies, and experimental research addressing oxidative stress mechanisms in HNSCC were considered, while non-English papers and studies unrelated to HNSCC were excluded. Key Findings: ROS exhibit dual effects in HNSCC, promoting tumour growth and DNA damage while also inducing apoptosis through molecular interactions. Elevated ROS contribute to drug resistance by inhibiting apoptosis, altering autophagy, and enhancing proliferation. Cancer cells counteract this via adaptive antioxidant responses involving transcriptional regulation and upregulation of enzymatic defences. Major risk factors for HNSCC—alcohol, tobacco, and high-risk HPV infection—disrupt redox homeostasis, underscoring the central role of oxidative stress in both carcinogenesis and therapy response. Conclusions: Oxidative stress plays a context-dependent role in HNSCC progression and treatment resistance. Targeting redox-regulatory pathways may provide therapeutic benefit. This review synthesizes recent insights on ROS-mediated mechanisms, highlighting potential strategies for improving HNSCC management beyond existing literature. Full article

(This article belongs to the Section Cancer Drug Development)

13 pages, 554 KB

Open AccessArticle

Disparities in Radiation Therapy Utilization for Solitary Plasmacytoma of Bone: A Surveillance, Epidemiology, and End Results Database Analysis

by Kate Woods, Mitchell Taylor, Omar Hamadi, Aditya Sharma, Xudong Li and Peter Silberstein

Cancers 2025, 17(20), 3294; https://doi.org/10.3390/cancers17203294 (registering DOI) - 11 Oct 2025

Abstract

Background/Objectives: Solitary plasmacytoma of bone (SPB) results from abnormal proliferation of plasma cells and accounts for 2–5% of all plasmacytic malignancies. Radiation therapy is the standard of care in treating SPB due to its efficacy in controlling disease progression and optimizing patient [...] Read more.

Background/Objectives: Solitary plasmacytoma of bone (SPB) results from abnormal proliferation of plasma cells and accounts for 2–5% of all plasmacytic malignancies. Radiation therapy is the standard of care in treating SPB due to its efficacy in controlling disease progression and optimizing patient survival. However, prior studies have highlighted disparities in radiation therapy receipt among various cancer types. In this study, we aim to investigate whether similar sociodemographic and clinical disparities exist in the treatment of SPB through use of the Surveillance, Epidemiology, and End Results (SEER) database. Methods: The SEER database was queried for biopsy-confirmed cases of SPB between 2000 and 2021 using the ICD-O-3 histology code 9731/3 and primary site codes C40.0–41.9. Chi-square tests, Fisher’s exact tests, and multivariable logistic regression were completed using SPSS v29.0.2, with significance set to p < 0.05. Results: A total of 4139 patients were identified, of which 75.3% received treatment with radiation therapy. Multivariable analysis revealed that low-income patients making less than $74,999 annually (aOR 0.80, 95% CI 0.67–0.97), as well as those from non-Hispanic Asian/Pacific Islander (aOR 0.49, 95% CI 0.33–0.73) and Hispanic (aOR 0.77, 95% CI 0.60–0.98) racial and ethnic groups, were significantly less likely to receive radiation therapy. Conclusions: These findings reveal notable disparities in radiation therapy utilization for SPB patients based on income and race and ethnicity, emphasizing the need for interventions to address systemic inequities, improve access to care, and ensure that all patients receive high-quality cancer care to optimize long-term outcomes. Full article

(This article belongs to the Section Cancer Epidemiology and Prevention)

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18 pages, 362 KB

Open AccessArticle

Inflammatory Bowel Disease Patients with a History of Cancer: Safety of Immunomodulators in a Multicenter Study

by Roberto Mancone, Benedetto Neri, Clara De Francesco, Livio Bonacci, Mariasofia Fiorillo, Sara Concetta Schiavone, Anna Galbusera, Alba Sparacino, Anna Testa, Ambrogio Orlando, Emma Calabrese, Irene Marafini, Stefano Festa, Fabiana Castiglione, Walter Fries, Giovanni Monteleone and Livia Biancone

Cancers 2025, 17(20), 3293; https://doi.org/10.3390/cancers17203293 (registering DOI) - 11 Oct 2025

Abstract

Introduction: The risk of new or recurrent cancer in inflammatory bowel disease (IBD) patients with a history of cancer treated with immunomodulators (IMMs), including conventional immunosuppressors (ISSs), biologics or small molecules is undefined. The primary aim was to assess the frequency of [...] Read more.

Introduction: The risk of new or recurrent cancer in inflammatory bowel disease (IBD) patients with a history of cancer treated with immunomodulators (IMMs), including conventional immunosuppressors (ISSs), biologics or small molecules is undefined. The primary aim was to assess the frequency of new or recurrent cancer in IBD patients treated with IMMs after first cancer. The secondary aim was to evaluate risk factors for new/recurrent cancer in the same IBD population. Methods: In a retrospective multicenter study, all IBD patients using any IMM after first (index) cancer were enrolled. Inclusion criteria: Crohn’s disease (CD) or ulcerative colitis (UC), history of any cancer, detailed clinical history, and follow-up after cancer of ≥6 months. Exclusion criteria: IMM use for ≤3 months. Results: In total, 122 IBD patients (84 CD, 38 UC) treated with IMMs after first cancer were enrolled (age 59.5 [26–89] years). Index cancer included (n = [%]) genitourinary tract cancer (18 [14.8]), non-melanotic skin cancer (NMSC) (17 [13.9]), breast cancer (15 [12.3]), thyroid cancer (13 [10.7]), melanoma (14 [11.4]), colorectal cancer (CRC) (11 [9.0]), hematopoietic cancer (9 [7.4]), prostatic cancer (8 [6.6]), neuroendocrine cancer (4 [3.3]), head and neck cancer (3 [2.5]), liver cancer (3 [2.5]), endometrium cancer (2 [1.6]), lung cancer (1 [0.8]) and others (3 [2.5]). ISSs after cancer included (n = [%]) thiopurines (10 [37]), methotrexate (MTX) (14 [51.9]) and others (3 [11.1]) Biologics included (n = [%]) TNF-inhibitors (36 [32.4]), vedolizumab (60 [53.6]), ustekinumab (45 [40.2]), small molecules (9 [7.3]) and others (6 [5.4]). In a median follow-up of 8 [1–45] years after index cancer, 12/122 (9.8%) patients using IMMs after cancer developed new or recurrent cancer. No risk factors for new/recurrent cancer (i.e., age at diagnosis of cancer, smoke, gender, IBD type, IMM use, duration before or after cancer) were identified. Conclusions: In a multicenter study, ISSs or biologics after cancer were not identified as risk factors for new or recurrent cancer in IBD. However, IMMs were used after a long-term interval from index cancer. Full article

(This article belongs to the Special Issue Chronic Intestinal Inflammation and Cancers (2nd Edition))

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15 pages, 606 KB

Open AccessSystematic Review

Artificial Intelligence for Risk–Benefit Assessment in Hepatopancreatobiliary Oncologic Surgery: A Systematic Review of Current Applications and Future Directions on Behalf of TROGSS—The Robotic Global Surgical Society

by Aman Goyal, Michail Koutentakis, Jason Park, Christian A. Macias, Isaac Ballard, Shen Hong Law, Abhirami Babu, Ehlena Chien Ai Lau, Mathew Mendoza, Susana V. J. Acosta, Adel Abou-Mrad, Luigi Marano and Rodolfo J. Oviedo

Cancers 2025, 17(20), 3292; https://doi.org/10.3390/cancers17203292 (registering DOI) - 11 Oct 2025

Abstract

Background: Hepatopancreatobiliary (HPB) surgery is among the most complex domains in oncologic care, where decisions entail significant risk–benefit considerations. Artificial intelligence (AI) has emerged as a promising tool for improving individualized decision-making through enhanced risk stratification, complication prediction, and survival modeling. However, its [...] Read more.

Background: Hepatopancreatobiliary (HPB) surgery is among the most complex domains in oncologic care, where decisions entail significant risk–benefit considerations. Artificial intelligence (AI) has emerged as a promising tool for improving individualized decision-making through enhanced risk stratification, complication prediction, and survival modeling. However, its role in HPB oncologic surgery has not been comprehensively assessed. Methods: This systematic review was conducted in accordance with PRISMA guidelines and registered with PROSPERO ID: CRD420251114173. A comprehensive search across six databases was performed through 30 May 2025. Eligible studies evaluated AI applications in risk–benefit assessment in HPB cancer surgery. Inclusion criteria encompassed peer-reviewed, English-language studies involving human s ubjects. Two independent reviewers conducted study selection, data extraction, and quality appraisal. Results: Thirteen studies published between 2020 and 2024 met the inclusion criteria. Most studies employed retrospective designs with sample sizes ranging from small institutional cohorts to large national databases. AI models were developed for cancer risk prediction (n = 9), postoperative complication modeling (n = 4), and survival prediction (n = 3). Common algorithms included Random Forest, XGBoost, Decision Trees, Artificial Neural Networks, and Transformer-based models. While internal performance metrics were generally favorable, external validation was reported in only five studies, and calibration metrics were often lacking. Integration into clinical workflows was described in just two studies. No study addressed cost-effectiveness or patient perspectives. Overall risk of bias was moderate to high, primarily due to retrospective designs and incomplete reporting. Conclusions: AI demonstrates early promise in augmenting risk–benefit assessment for HPB oncologic surgery, particularly in predictive modeling. However, its clinical utility remains limited by methodological weaknesses and a lack of real-world integration. Future research should focus on prospective, multicenter validation, standardized reporting, clinical implementation, cost-effectiveness analysis, and the incorporation of patient-centered outcomes. Full article

(This article belongs to the Special Issue Application of Artificial Intelligence-Based Approaches in Cancer Diagnosis, Treatment and Prognosis)

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34 pages, 1837 KB

Open AccessArticle

Lead Exposure and Bladder Cancer: Molecular Insights from TCGA RNA-Seq and Toxicogenomic Integration

by Gözde Öztan, Halim İşsever, Tuğçe İşsever and Levent Şahin

Cancers 2025, 17(20), 3291; https://doi.org/10.3390/cancers17203291 - 10 Oct 2025

Abstract

Background/Objectives: Bladder cancer (BC) carries a substantial global burden. Although lead (Pb) exposure has been linked to cancer, its molecular impact on bladder tumors remains unclear. We asked whether Pb-responsive transcriptional programs are present and clinically relevant in BC by integrating toxicogenomic resources [...] Read more.

Background/Objectives: Bladder cancer (BC) carries a substantial global burden. Although lead (Pb) exposure has been linked to cancer, its molecular impact on bladder tumors remains unclear. We asked whether Pb-responsive transcriptional programs are present and clinically relevant in BC by integrating toxicogenomic resources with tumor transcriptomes and whether a composite lead-response score has prognostic value. Methods: Differential expression was performed on TCGA bladder urothelial carcinoma (BLCA) RNA-seq data (tumor vs. normal). Lead-associated genes were curated from the Comparative Toxicogenomics Database (CTD) and tested for over-representation among BLCA differentially expressed genes (DEGs) using a hypergeometric framework, with a stricter |log₂FC| ≥ 1 sensitivity. A tumor-level lead-response score was derived from the Pb–DEG overlap. Associations with overall survival (OS) were assessed using Cox models adjusted for age, sex, and pathological stage; secondary endpoints included PFI/DFI/DSS. Results: Lead-associated genes were significantly enriched among BLCA DEGs (background M = 20,530; K = 2618; n = 11,436; k = 1595; p = 4.21 × 10⁻⁹), and enrichment persisted under |log₂FC| ≥ 1 (n = 4275; k = 698; p = 9.86 × 10⁻¹⁵). Pathway over-representation highlighted synaptic/neuronal-like adhesion and transmission, MAPK-centered signaling, and cell-cycle control. Among top candidates, AQP12B was independently prognostic for OS (HR per 1 SD increase = 0.76; 95% CI 0.63–0.92; p = 0.0038; N = 404). The composite lead-response score showed a directionally protective but non-significant association in multivariable OS models (HR per 1 SD = 0.93; 95% CI 0.81–1.05; p = 0.244), while median-split Kaplan–Meier (KM) curves separated (p = 0.045). Conclusions: Lead-responsive transcriptional programs are detectable in BLCA and intersect adhesion, MAPK signaling, and cell-cycle pathways. AQP12B emerges as a plausible prognostic marker, and a composite lead-response score warrants external validation for risk stratification and clinical translation. Full article

(This article belongs to the Section Molecular Cancer Biology)

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19 pages, 5463 KB

Open AccessArticle

From TNM 8 to TNM 9: Stage Migration and Histology-Specific Patterns in Lung Cancer

by Amalia Constantinescu, Radu-Nicolae Căprariu, Emil-Robert Stoicescu, Roxana Iacob, Marius Mânzatu, Janet Camelia Drimus, Alessia-Stephania Roșian, Alexandre Ionescu, Cristian Oancea and Diana Manolescu

Cancers 2025, 17(20), 3290; https://doi.org/10.3390/cancers17203290 (registering DOI) - 10 Oct 2025

Abstract

Introduction: The 9th edition of the TNM classification for lung cancer implemented significant revisions, notably the subdivision of the N2 and M1c categories, to enhance anatomical precision and prognostic accuracy. Nonetheless, the actual effects of these modifications on stage distribution, histology-specific patterns, and [...] Read more.

Introduction: The 9th edition of the TNM classification for lung cancer implemented significant revisions, notably the subdivision of the N2 and M1c categories, to enhance anatomical precision and prognostic accuracy. Nonetheless, the actual effects of these modifications on stage distribution, histology-specific patterns, and clinical interpretation remain to be fully evaluated. Objectives: To compare lung cancer staging distributions between the 8th and 9th TNM editions, analyze patterns of stage migration, and evaluate histology-specific reclassification trends. Although TNM 9 applies the same descriptors across all histological subtypes, the magnitude of stage migration varies. In our cohort and in international datasets, adenocarcinoma demonstrated a higher likelihood of reclassification into advanced stages compared to other subtypes. Methods: A retrospective analysis was performed on a cohort of lung cancer patients staged according to the 8th and 9th editions of the TNM classification. Stage distribution alterations were analyzed by chi-squared tests, whereas McNemar’s test examined the directional shifts in upstaging and downstaging. Further investigations evaluated the correlation between histological subtype and stage reclassification. Results: A statistically significant redistribution of stages was noted (χ² = 1013.03, df = 64, p < 0.0001), with a notable prevalence of upstaging (p = 0.0019). The most significant proportional increase was observed in stage IIIA, mostly attributable to the N2 subdivision (N2a vs. N2b). Adenocarcinoma was the predominant histological subtype at all stages and showed a greater tendency for reclassification into advanced stages, specifically IIIA and IIIB. Squamous cell carcinoma was predominantly observed in stages IIB and IIIA, whereas small cell and large cell carcinomas were concentrated in advanced stages. These histology-specific patterns correspond with international findings, including research confirming the prognostic relevance of N2 subdivision. Conclusions: The 9th edition of the TNM classification results in significant stage migration, particularly in adenocarcinoma cases, indicating the improved sensitivity of the updated criteria in identifying advanced nodal disease. These modifications significantly impact prognostic evaluation and global comparability of clinical cohorts, supporting the implementation of TNM 9 as a more anatomically and biologically relevant staging system. Full article

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

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20 pages, 3833 KB

Open AccessArticle

Targeting NFAT2 for Reversing the P-gp-Mediated Multidrug Resistance to Paclitaxel by Manidipine

by Jian Zhou, Nan Wang, Yu-Kang Lin, Qi-Lu Li, Rui-Ming Liu, Jia-Qin Hu, Hua Zhou, Hai Lan and Ying Xie

Cancers 2025, 17(20), 3289; https://doi.org/10.3390/cancers17203289 - 10 Oct 2025

Abstract

Background: Multidrug resistance (MDR), primarily driven by P-glycoprotein (P-gp)-mediated drug efflux, presents a significant challenge in cancer therapy, contributing to chemotherapy failure and poor patient outcomes. Objectives: In this study, we explored the potential of manidipine (MA), a clinically approved calcium channel blocker, [...] Read more.

Background: Multidrug resistance (MDR), primarily driven by P-glycoprotein (P-gp)-mediated drug efflux, presents a significant challenge in cancer therapy, contributing to chemotherapy failure and poor patient outcomes. Objectives: In this study, we explored the potential of manidipine (MA), a clinically approved calcium channel blocker, to reverse P-gp-mediated MDR through modulation of calcium signaling via nuclear factor of activated T cells 2 (NFAT2). Methods: Paclitaxel (PTX) resistance ABCB1-overexpressing cancer in vitro and in vivo were used for evualting the anti-MDR effects of MA, as well as the underlying mechanism with siRNA of NFAT2. Results: We found that MA at non-toxic concentrations (0.6–5.4 μM) significantly sensitize drug-resistant colorectal (HCT-8/T) and non-small cell lung (A549/T) cells to PTX, reducing its IC₅₀ by up to 1328-fold in vitro models. Mechanistically, MA inhibited P-gp efflux activity without altering its expression, as shown by an increased intracellular accumulation of doxorubicin and Flutax-2 (2.3- and 3.1-fold, respectively) and dose-dependent modulation of ATPase activity (EC₅₀ = 4.16 μM). Notably, MA reduced intracellular calcium levels (52% reduction, p < 0.001) and downregulated NFAT2, an oncogene overexpressed in resistant cells. In vivo, MA (3.5 mg/kg) synergizes with PTX to inhibit tumor growth by 68% (p < 0.001) in A549/T xenograft model, without an observable decrease in weight. Conclusions: In sum, all these results position MA as a novel NFAT2 inhibitor to overcome P-gp-mediated MDR via modulating calcium signaling, which points to further investigation for its clinical applications. Full article

(This article belongs to the Section Molecular Cancer Biology)

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17 pages, 467 KB

Open AccessReview

Optimizing Post-Neoadjuvant Treatment in Early Triple-Negative Breast Cancer

by Hervé Bischoff, Laura Somme and Thierry Petit

Cancers 2025, 17(20), 3288; https://doi.org/10.3390/cancers17203288 - 10 Oct 2025

Abstract

Neoadjuvant therapy has become the standard of care in early-stage triple-negative breast cancer (TNBC), providing both prognostic information and a platform for treatment individualization. The achievement of a pathological complete response (pCR) is strongly associated with excellent long-term outcomes, whereas the presence of [...] Read more.

Neoadjuvant therapy has become the standard of care in early-stage triple-negative breast cancer (TNBC), providing both prognostic information and a platform for treatment individualization. The achievement of a pathological complete response (pCR) is strongly associated with excellent long-term outcomes, whereas the presence of residual disease (RD) indicates a markedly increased risk of recurrence. This dual prognostic value has established post-neoadjuvant treatment as a critical arena for risk-adapted strategies. In patients achieving pCR, de-escalation of adjuvant therapy is under active investigation, with several randomized trials assessing whether surveillance may safely replace prolonged immunotherapy. Conversely, the management of patients with RD has become increasingly complex, as clinicians must navigate between established options such as capecitabine, olaparib, and pembrolizumab, while antibody-drug conjugates are likely to emerge as future therapeutic options in this high-risk setting. In parallel, locoregional approaches are evolving, with trials evaluating axillary de-escalation and even the omission of surgery in highly selected cases. Looking forward, the integration of biomarkers such as circulating tumor DNA and tumor-infiltrating lymphocytes may help refine these strategies, paving the way toward truly personalized post-neoadjuvant care in TNBC. Full article

(This article belongs to the Special Issue Post-Neoadjuvant Strategies in Breast Cancer (2nd Edition))

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15 pages, 1596 KB

Open AccessArticle

Impact of Neoadjuvant Chemotherapy with Gemcitabine Plus S-1 in Patients with Resectable Pancreatic Ductal Adenocarcinoma

by Kazuya Yasui, Kosei Takagi, Tomokazu Fuji, Takeyoshi Nishiyama, Yasuo Nagai, Kazuyuki Matsumoto, Shigeru Horiguchi, Yuki Fujii, Motoyuki Otsuka and Toshiyoshi Fujiwara

Cancers 2025, 17(20), 3287; https://doi.org/10.3390/cancers17203287 - 10 Oct 2025

Abstract

Background/Objectives: Although neoadjuvant chemotherapy (NAC) is not universally recommended for resectable pancreatic ductal adenocarcinoma (PDAC), NAC with gemcitabine plus S-1 (NAC-GS) has become a commonly used regimen for resectable PDAC in Japan. Furthermore, the impact of achieving textbook outcomes (TO) in patients [...] Read more.

Background/Objectives: Although neoadjuvant chemotherapy (NAC) is not universally recommended for resectable pancreatic ductal adenocarcinoma (PDAC), NAC with gemcitabine plus S-1 (NAC-GS) has become a commonly used regimen for resectable PDAC in Japan. Furthermore, the impact of achieving textbook outcomes (TO) in patients receiving NAC-GS remains unclear. Methods: This retrospective study included 265 patients who were diagnosed with resectable PDAC at our institution between January 2009 and December 2023. Patients were categorized into two groups: the NAC-GS group (n = 81; 2019–2023) and the upfront surgery (UFS) group (n = 164; 2009–2018). After comparing the clinical outcomes between groups, multivariate analyses for survival were performed. Additionally, outcomes stratified by the achievement of the modified TO were analyzed in the NAC-GS group. Results: The completion rate of NAC-GS was 90.1%. Patients in the NAC-GS group exhibited significantly longer survival than those in the UFS group (2-year recurrence-free survival: 61.4% vs. 37.9%, p < 0.01; 2-year overall survival: 83.2% vs. 61.2%, p < 0.01). Multivariate analyses identified lymph node metastasis, NAC-GS induction, and completion of adjuvant chemotherapy as factors significantly associated with improved survival. Moreover, among patients who received NAC-GS, those who achieved modified TO demonstrated significantly longer survival than those who did not. Conclusions: This study demonstrated the clinical efficacy of NAC-GS in patients with resectable PDAC. Induction of NAC-GS was significantly associated with improved long-term outcomes. In multidisciplinary treatment strategies for PDAC, achieving a modified TO may lead to improved survival of patients undergoing NAC-GS. Full article

(This article belongs to the Section Cancer Therapy)

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13 pages, 2192 KB

Open AccessArticle

Robot-Assisted Radical Prostatectomy for Locally Advanced Prostate Cancer: Oncological Potential and Limitations as the Primary Treatment

by Noriyoshi Miura, Masaki Shimbo, Kensuke Shishido, Shota Nobumori, Naoya Sugihara, Takatora Sawada, Shunsuke Haga, Haruna Arai, Keigo Nishida, Osuke Arai, Tomoya Onishi, Ryuta Watanabe, Kenichi Nishimura, Tetsuya Fukumoto, Yuki Miyauchi, Tadahiko Kikugawa, Takato Nishino, Fumiyasu Endo, Kazunori Hattori and Takashi Saika

Cancers 2025, 17(20), 3286; https://doi.org/10.3390/cancers17203286 - 10 Oct 2025

Abstract

Background: Locally advanced prostate cancer (PCa) is commonly treated with multimodal therapy; however, long-term outcomes of surgery alone are poorly defined. We investigated the potential and limitations of robot-assisted radical prostatectomy (RARP) as primary treatment without perioperative systemic therapy in patients with locally [...] Read more.

Background: Locally advanced prostate cancer (PCa) is commonly treated with multimodal therapy; however, long-term outcomes of surgery alone are poorly defined. We investigated the potential and limitations of robot-assisted radical prostatectomy (RARP) as primary treatment without perioperative systemic therapy in patients with locally advanced PCa. Methods: We retrospectively analyzed 258 patients who underwent RARP with extended pelvic lymph node dissection between 2012 and 2022 with locally advanced PCa, defined as present if at least one of the following was met: clinical stage cT3b–T4; primary Gleason pattern 5; >4 biopsy cores with Grade Group 4 or 5; or more than one NCCN high-risk characteristic. Patients who received neoadjuvant or adjuvant therapy were excluded. Endpoints included biochemical recurrence-free survival, metastasis-free survival, cancer-specific survival, and predictors of persistent PSA. Results: Median follow-up was 60.6 months. Pathological stage ≥ pT3a occurred in 63.6% and nodal involvement (pN1) in 27.1%. Five-year BRFS, MFS, and CSS were 36.6%, 88.9%, and 98.3%, respectively. Persistent PSA occurred in 21.3%. Preoperative predictors included PSA > 40 ng/mL, clinical stage ≥ cT3a, and >4 biopsy cores with a Gleason score of 8–10; patients with ≥2 features had significantly poorer BRFS and MFS. Postoperative predictors of recurrence were pathological stage, lymphovascular invasion, and nodal involvement. Conclusions: RARP alone provided durable long-term cancer control in selected men with locally advanced PCa, whereas patients with multiple adverse features were unlikely to be cured with surgery alone. Careful risk stratification may identify candidates for surgical monotherapy and help avoid overtreatment, while others may benefit from multimodal therapy. Full article

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

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27 pages, 428 KB

Open AccessReview

Allogeneic Hematopoietic Stem Cell Transplantation as a Platform to Treat Chemorefractory Acute Myeloid Leukemia in Adult Patients

by Daniel Alzetta, Irene M. Cavattoni and Federico Mosna

Cancers 2025, 17(20), 3285; https://doi.org/10.3390/cancers17203285 - 10 Oct 2025

Abstract

Adult patients affected by acute myeloid leukemia who fail to achieve remission after two cycles of intensive chemotherapy based on a combination of anthracyclines and cytarabine are considered chemorefractory and are unlikely to benefit from further induction attempts. Characterized by a poor prognosis, [...] Read more.

Adult patients affected by acute myeloid leukemia who fail to achieve remission after two cycles of intensive chemotherapy based on a combination of anthracyclines and cytarabine are considered chemorefractory and are unlikely to benefit from further induction attempts. Characterized by a poor prognosis, they may still benefit from allogeneic hematopoietic stem cell transplantation, even if long-term survival rarely exceeds 20–30%. Still, the use of sequential high-dose chemotherapy followed by reduced-intensity conditioning, with transplantation performed during aplasia, and the optimization of the alloreactivity of donor leukocytes against leukemia (i.e., the graft-versus-leukemia effect) may ameliorate these results. Optimization of alloreactivity against leukemic cells can be achieved by proper donor selection, by the early withdrawal of immunosuppressive therapy, by post-transplant administration of donor lymphocyte infusions as prophylaxis of leukemia relapse, and by several other maintenance and preemptive therapies. Far from being the final stage of consolidation therapy, allogeneic hematopoietic stem cell transplantation is now considered as the moment when a unique immunological platform can be established in these patients, to be used for additional post-transplant measures. In this study we will critically review the different pre- and post-transplant strategies used in clinical trials to improve long-term survival in adult patients transplanted with chemorefractory leukemia. Full article

(This article belongs to the Special Issue New Challenges in Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia)

12 pages, 346 KB

Open AccessReview

Role of Radiomics in Parotid Malignant Disease: A Scoping Review

by Andrea Migliorelli, Marianna Manuelli, Andrea Ciorba, Francesco Stomeo, Stefano Pelucchi and Chiara Bianchini

Cancers 2025, 17(20), 3284; https://doi.org/10.3390/cancers17203284 - 10 Oct 2025

Abstract

Malignant tumors of the salivary glands are rare, accounting for approximately 1–7% of all head and neck tumors. The parotid gland is the most commonly affected gland. An accurate preoperative diagnosis distinguishing between malignant and benign tumors is necessary for the appropriate management [...] Read more.

Malignant tumors of the salivary glands are rare, accounting for approximately 1–7% of all head and neck tumors. The parotid gland is the most commonly affected gland. An accurate preoperative diagnosis distinguishing between malignant and benign tumors is necessary for the appropriate management of patients. The aim of this review is to analyze the results of the most recent literature studying the use of radiomics in malignant tumors of the parotid gland. A comprehensive literature review was performed using the PubMed/MEDLINE, EMBASE and Cochrane Library databases, in accordance with the PRISMA review criteria (from 2020 to July 2025). The final analysis comprised a total of six articles and 560 patients. Four studies evaluated the role of Magnetic Resonance Imaging (MRI), one of Computed Tomography (CT) and one of Positron Emission Tomography/Computed Tomography (PET/CT). Radiomics models achieved good overall diagnostic performance, with AUC values ranging from 0.769 to 0.952 across studies, although methodological heterogeneity prevented data pooling. The results of this review indicate that radiomics has the potential to play an important role in the management of malignant tumors of the parotid gland. Nevertheless, the absence of clear and standardized protocols does not allow the comparison of results. Further studies are necessary to confirm these findings. Full article

(This article belongs to the Special Issue Radiomics and Imaging in Cancer Analysis)

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13 pages, 1162 KB

Open AccessArticle

Prognostic Impact of Infectious Agents After Definitive Treatment in Non-Small Cell Lung Cancer

by Özlem Koca, Umur Kağan Kahya, Meltem Beydilli Şahiner, Rahmi Atıl Aksoy, Timur Koca and Aylin Fidan Korcum

Cancers 2025, 17(20), 3283; https://doi.org/10.3390/cancers17203283 - 10 Oct 2025

Abstract

Background: Infections are common complications in patients with non-small cell lung cancer (NSCLC) and may adversely influence clinical outcomes. Their prognostic impact after definitive treatment is not well established. This study aimed to investigate the incidence, microbiological profile, and prognostic significance of infections [...] Read more.

Background: Infections are common complications in patients with non-small cell lung cancer (NSCLC) and may adversely influence clinical outcomes. Their prognostic impact after definitive treatment is not well established. This study aimed to investigate the incidence, microbiological profile, and prognostic significance of infections occurring within one year after definitive treatment in patients with NSCLC. Methods: We retrospectively analyzed patients with NSCLC who completed definitive treatment between 1 January 2016, and 31 December 2023. Microbiological culture results obtained within one-year post-treatment and inflammatory markers measured one month after treatment were evaluated. Pathogens were classified as healthcare-associated infection (HAI) or non-HAI agents. Overall survival (OS) was estimated using the Kaplan–Meier method, and prognostic factors were assessed using Cox regression analysis. Results: Among 214 eligible patients, 45 had positive microbiological cultures. Gram-negative bacteria predominated (n = 24), with Pseudomonas aeruginosa (n = 8) and Acinetobacter baumannii (n = 6) being the most frequently isolated species. Among all isolates, 20 Gram-negative and 6 Gram-positive microorganisms were identified as HAI pathogens. In multivariate analysis, culture positivity (HR: 2.75, p < 0.001) remained an independent prognostic factor for worse OS. Conclusion: Infections within the first year after definitive treatment, particularly those caused by HAI-related Gram-negative pathogens, are associated with reduced OS in NSCLC. Early microbiological diagnosis, targeted antimicrobial therapy, and strict infection prevention strategies may help improve outcomes in this high-risk population. Full article

(This article belongs to the Special Issue Lung Cancer: Updates on Therapy and Prognostic Prediction)

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21 pages, 1736 KB

Open AccessArticle

Molecular Characterization of Oral Squamous Cell Carcinoma in Mexican Patients: A Genomic and Epidemiological Overview

by Javier Lopez-Gomez, Dennis Cerrato-Izaguirre, Ericka Marel Quezada-Maldonado, L. A. Gaitan-Cepeda, Mauricio Salcedo, Marco Antonio Hernandez-Castillo, Martín Granados-García, Yesennia Sánchez-Pérez and Claudia M. García-Cuellar

Cancers 2025, 17(20), 3282; https://doi.org/10.3390/cancers17203282 - 10 Oct 2025

Abstract

Oral squamous cell carcinoma (OSCC) is one of the most common malignancies affecting the head and neck and account for over 90% of all oral cancers (1) [...] Full article

(This article belongs to the Special Issue Molecular Mechanisms in Head and Neck Cancer)

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