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Volume 17
Issue 12
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Cancers, Volume 17, Issue 12 (June-2 2025) – 162 articles

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16 pages, 3131 KiB  
Article
Mesothelin-Associated Anti-Senescence Through P53 in Pancreatic Ductal Adenocarcinoma
by Dongliang Liu, Jianming Lu, Changyi Chen and Qizhi Yao
Cancers 2025, 17(12), 2058; https://doi.org/10.3390/cancers17122058 - 19 Jun 2025
Viewed by 324
Abstract
Objectives: Mesothelin (MSLN) is overexpressed in pancreatic ductal adenocarcinoma (PDAC), promoting cell proliferation, migration, and inhibiting apoptosis. While its oncogenic properties have been documented, the role of MSLN in regulating cellular senescence—a tumor-suppressive mechanism—has remained unexplored. This study is the first to [...] Read more.
Objectives: Mesothelin (MSLN) is overexpressed in pancreatic ductal adenocarcinoma (PDAC), promoting cell proliferation, migration, and inhibiting apoptosis. While its oncogenic properties have been documented, the role of MSLN in regulating cellular senescence—a tumor-suppressive mechanism—has remained unexplored. This study is the first to identify and characterize a novel mesothelin-associated anti-senescence (MAAS) effect in PDAC. Methods: A proteogenomic analysis of PDAC tissue samples from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) was performed to evaluate MSLN-associated senescence pathways using WebGestalt. Human and murine PDAC cell lines with modified MSLN expression were analyzed for senescence phenotypes via SA-β-gal staining, Western blotting of key regulators (P53, P21waf1, and P16ink4a), γH2AX immunoblotting, and IL-8 quantification using ELISA. Results: The CPTAC analysis revealed an inverse correlation between MSLN expression and DNA damage/repair pathways. MSLN-deficient cells exhibited classic senescence features—growth arrest, an enlarged morphology, and elevated SA-β-gal activity. The expression of P53, P21waf1, and P16ink4a was upregulated, alongside increased γH2AX levels, indicating the activation of the DNA damage response. IL-8 secretion was significantly higher in the MSLN knockdown cells and reduced in the MSLN-overexpressing cells, consistent with the modulation of the SASP. Notably, MSLN deficiency impaired cell viability without inducing overt cytotoxicity, supporting a shift toward senescence. Conclusions: Our findings uncover a previously unrecognized mechanism through which MSLN promotes tumor progression by suppressing senescence via P53-associated pathways. Targeting the MAAS pathway may offer a novel therapeutic strategy to restore tumor-suppressive senescence and enhance treatment efficacy in PDAC. Full article
(This article belongs to the Special Issue Unravelling Cancer Mechanism and Developing Novel Therapeutics: An Urgent Need to Treat Cancer (2nd Edition))
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12 pages, 233 KiB  
Article
Prognostic Biopsy of Choroidal Melanoma Before and After Ruthenium-106 Plaque Brachytherapy: Impact on Success of Cytogenetic Analysis
by Keri McLean, Helen Kalirai, Muhammad H. Amer, Bertil Damato, Sarah E. Coupland, Heinrich Heimann and Rumana N. Hussain
Cancers 2025, 17(12), 2057; https://doi.org/10.3390/cancers17122057 - 19 Jun 2025
Viewed by 191
Abstract
Background/Objectives: To determine if the results of cytogenetic analyses of choroidal melanoma biopsies after ruthenium-106 plaque brachytherapy (RPB) are affected by this procedure. Methods: A retrospective study was conducted on 368 patients with choroidal melanoma treated with RPB who underwent cytogenetic testing [...] Read more.
Background/Objectives: To determine if the results of cytogenetic analyses of choroidal melanoma biopsies after ruthenium-106 plaque brachytherapy (RPB) are affected by this procedure. Methods: A retrospective study was conducted on 368 patients with choroidal melanoma treated with RPB who underwent cytogenetic testing at the Liverpool Ocular Oncology Centre (LOOC) between May 2012 and November 2024. Data on demographics, tumor characteristics, treatment date, biopsy timing (pre- or post-RPB), and cytogenetic results were extracted from the LOOC database. Statistical analysis included descriptive statistics, binary, and multinomial logistic regression to assess associations between biopsy timing and biopsy success rates. Results: Biopsies were performed before RPB in 58.7% (216/368) cases, and post-PBR in 41.3%. Cytomorphological identification and molecular genetic testing were successful in 96.4% and 85.1% cases, respectively. Timing of biopsy, patient demographics, and tumor characteristics did not significantly influence cytogenetic test outcomes. Molecular testing could not be performed on 6.8% (25/368) cases as the DNA was insufficient in these samples. Genetic testing success slightly declined beyond three months post-RPB, though a few cases had delayed biopsy (n = 8). Pre-RPB biopsies more frequently demonstrated monosomy 3, whereas post-RPB biopsies had higher rates of disomy 3 (χ2, p < 0.05). Conclusions: Prognostic biopsies post-RPB provide reliable cytomorphological and molecular genetic results using MLPA or MSA. Test failure is not significantly influenced by biopsy timing, patient or tumor characteristics, biopsy modality, or genetic technique. Insufficient DNA yield remains a key limitation, emphasizing the importance of obtaining adequate tissue samples. Biopsies within three months are preferable to optimize success in molecular testing. Full article
(This article belongs to the Special Issue Treatments of Uveal Melanoma)
14 pages, 1040 KiB  
Article
High-Risk Early-Stage Endometrial Cancer: Role of Adjuvant Therapy and Prognostic Factors Affecting Survival
by Ji Hyun Hong, Jun Kang, Sung Jong Lee, Keun Ho Lee, Soo Young Hur and Yeon-Sil Kim
Cancers 2025, 17(12), 2056; https://doi.org/10.3390/cancers17122056 - 19 Jun 2025
Viewed by 179
Abstract
Background/Objectives: High-grade endometrial cancer, including non-endometrioid and grade 3 endometrioid histologies, is associated with poor prognosis despite early-stage diagnosis. This study assessed the prognosis of early-stage high-grade endometrial cancer, identified prognostic factors, and evaluated the optimal candidates for adjuvant therapy. Methods: We retrospectively [...] Read more.
Background/Objectives: High-grade endometrial cancer, including non-endometrioid and grade 3 endometrioid histologies, is associated with poor prognosis despite early-stage diagnosis. This study assessed the prognosis of early-stage high-grade endometrial cancer, identified prognostic factors, and evaluated the optimal candidates for adjuvant therapy. Methods: We retrospectively analyzed 106 patients with 2018 FIGO stage I–II high-grade endometrial cancer who underwent hysterectomies between 2008 and 2022. Adjuvant therapy was determined by a multidisciplinary team. Survival outcomes were evaluated using the Kaplan–Meier method and Cox regression model. Results: Of 106 patients, 60 had non-endometrioid, and 46 had grade 3 endometrioid carcinoma; 69 (65.1%) received adjuvant therapy. After a median follow-up of 48.8 months, 37 patients experienced disease progression, and 21 died. Non-endometrioid histology was significantly associated with worse overall survival (p = 0.002). Lack of lymph node dissection, deeper invasion, and the omission of adjuvant therapy were additional adverse prognostic factors. Adjuvant therapy improved the overall survival (p = 0.009), disease-free survival (p = 0.021), and locoregional recurrence-free survival (p = 0.034) in patients with one or two risk factors. Conclusions: Non-endometrioid histology, deep invasion, and the lack of lymph node dissection are associated with worse survival in early-stage high-grade endometrial cancer. Adjuvant therapy should be considered in patients with these risk factors. Full article
(This article belongs to the Special Issue What’s behind the Scenes? New Insights in Endometrial Cancer Management and Risk Stratification)
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23 pages, 7031 KiB  
Review
Current Perspectives on Mesenchymal Dendritic Cell Neoplasms of Lymphoid Tissue: Insights into Ontogeny, Updates on Classification, and Clinicopathologic Characteristics
by Neha Seth, Jithma P. Abeykoon, Gaurav Goyal, Ronald S. Go, Steven Tessier, Rebecca L. King and Aishwarya Ravindran
Cancers 2025, 17(12), 2055; https://doi.org/10.3390/cancers17122055 - 19 Jun 2025
Viewed by 293
Abstract
Mesenchymal dendritic cell neoplasms represent a distinct category of hematologic malignancies that challenge traditional classifications of histiocytic and classical dendritic/Langerhans cell neoplasms. Historically grouped under the broader umbrella of dendritic cell neoplasms, these entities differ significantly in their ontogeny, histopathologic features, molecular alterations, [...] Read more.
Mesenchymal dendritic cell neoplasms represent a distinct category of hematologic malignancies that challenge traditional classifications of histiocytic and classical dendritic/Langerhans cell neoplasms. Historically grouped under the broader umbrella of dendritic cell neoplasms, these entities differ significantly in their ontogeny, histopathologic features, molecular alterations, and clinical behavior. They are categorized into three main subtypes including follicular dendritic cell sarcoma, fibroblastic reticular cell tumor, and EBV-positive inflammatory follicular dendritic cell sarcoma/fibroblastic reticular cell tumor. They originate from mesenchymal stromal cells, and genetic alterations activating the NF- κβ pathway are frequent in follicular dendritic cell sarcomas. Immunophenotypic characterization is critical to distinguish these from other hematologic malignancies including histiocytic and classical dendritic/Langerhans cell neoplasms and other solid (non-hematopoietic) cancers. This review recapitulates current knowledge on existing classifications, details their diverse ontogeny from classical dendritic cell neoplasms, and provides insights into their clinicopathologic characteristics to improve diagnostic accuracy. We detail two case studies that demonstrate the challenges involved in the histopathologic diagnosis of these rare tumors, necessitating a comprehensive workup. Integrating developmental biology into practical diagnostic algorithms is essential to improve recognition and classification of these underdiagnosed neoplasms, ultimately guiding timely management. Full article
(This article belongs to the Special Issue Advanced Research in Oncology in 2025)
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10 pages, 839 KiB  
Article
Atrial Fibrillation Risk in Relation to the Clinical Staging of Gastric Cancer: A Nationwide Population-Based Cohort Study
by Mi Jin Oh, Yoon Jin Choi, Jin-Hyung Jung, Seunghan Lee, Kyungdo Han and Soo-Jeong Cho
Cancers 2025, 17(12), 2054; https://doi.org/10.3390/cancers17122054 - 19 Jun 2025
Viewed by 150
Abstract
Background/Objectives: Patients with gastric cancer (GC) have an elevated risk of atrial fibrillation (AF) and cardiovascular mortality, compared with the general population. However, the effect of the cancer stage on the development of AF remains unclear. This study aimed to evaluate the relationship [...] Read more.
Background/Objectives: Patients with gastric cancer (GC) have an elevated risk of atrial fibrillation (AF) and cardiovascular mortality, compared with the general population. However, the effect of the cancer stage on the development of AF remains unclear. This study aimed to evaluate the relationship between the risk of AF and GC stage based on the Surveillance, Epidemiology, and End Results (SEER) stage classifications. Methods: This retrospective population-based cohort study enrolled patients diagnosed with GC between 2012 and 2019, using anonymized data from the Cancer Public Library Database of South Korea. Patients were followed up until 2020. The risk of AF was assessed in relation to the SEER stage of GC (localized, regional, distant) using adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs). Subgroup analyses were performed according to age, sex, year of diagnosis, and comorbidities. Results: Of the 211,500 patients enrolled in this study, 7266 were diagnosed with AF during follow-up. The risk of AF increased progressively with cancer stage, with aHRs of 2.00 (95% CI 1.81–2.22) for the distant stage and 1.32 (95% 1.25–1.41) for the regional stage, compared with the localized stage. Subgroup analyses showed a consistent association between advanced cancer stage and a higher AF risk; the association was stronger in the younger, female, and non-hypertensive subgroups. Conclusions: The risk of AF in patients with GC is associated with the initial stage, highlighting the need for the closer monitoring and management of AF to improve the survival of patients with advanced-stage GC. Full article
(This article belongs to the Special Issue Medical Complications and Supportive Care in Patients with Cancer (2nd Edition))
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23 pages, 1321 KiB  
Article
Impact of Chemotherapy on Implant-Based Breast Reconstruction in Breast Cancer Patients: A Nationwide, Retrospective, Cohort Study
by Jin Ah Lee, Hye Sun Lee, Soyoung Jeon, Dooreh Kim, Young Joo Lee, Soo Youn Bae, Woo-Chan Park, Chang Ik Yoon and Jangyoun Choi
Cancers 2025, 17(12), 2053; https://doi.org/10.3390/cancers17122053 - 19 Jun 2025
Viewed by 164
Abstract
Background: Implant-based breast reconstruction (IBBR) is a widely adopted technique following mastectomy in breast cancer patients. However, the impact of chemotherapy type and duration on the development of capsular contracture remains unclear. Methods: This nationwide, retrospective, cohort study used Health Insurance Review and [...] Read more.
Background: Implant-based breast reconstruction (IBBR) is a widely adopted technique following mastectomy in breast cancer patients. However, the impact of chemotherapy type and duration on the development of capsular contracture remains unclear. Methods: This nationwide, retrospective, cohort study used Health Insurance Review and Assessment Service data to identify breast cancer patients who received chemotherapy and underwent immediate IBBR between January 2015 and December 2018. Follow-up continued until January 2024, with a median follow-up of 5.2 years. A total of 4303 patients (direct-to-implant [DTI], n = 2083; tissue expander insertion [TEI], n = 2220) were included. Results: Chemotherapy type and duration were not significantly associated with capsular contracture risk in either the DTI or TEI groups. In the DTI cohort, no significant difference in contracture incidence was found between neoadjuvant and adjuvant chemotherapy before or after matching (p = 0.056 and p = 0.121, respectively). In the TEI cohort, an initially significant difference (p = 0.019) was no longer observed after matching (p = 0.213). Similarly, chemotherapy duration (≤12 weeks vs. >12 weeks) did not impact contracture risk in either cohort. Multivariate analysis identified age, radiotherapy, lymphedema, and axillary lymph node dissection (ALND) as independent risk factors for contracture (p < 0.005). Comorbidities, such as diabetes and autoimmune diseases, also showed no significant association with contracture risk. Conclusions: These findings suggest that chemotherapy decisions should not be guided by contracture concerns. Instead, optimizing reconstruction outcomes should focus on modifiable factors, such as radiotherapy, lymphedema, and ALND. Full article
(This article belongs to the Section Methods and Technologies Development)
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26 pages, 926 KiB  
Article
Prospective Evaluation of the Influence of Chemoradiotherapy and Stoma on Functional and Symptomatic Outcomes in Rectal Cancer Patients
by Michael Schenker, Luiza Cristiana Bițînă, Ramona Adriana Schenker, Ana-Maria Ciurea, Alina Maria Mehedințeanu, Tradian Ciprian Berisha, Lucian Dragoș Bratu, Monica Laura Cara, Andrei Mircea Dicianu and Puiu Olivian Stovicek
Cancers 2025, 17(12), 2052; https://doi.org/10.3390/cancers17122052 - 19 Jun 2025
Viewed by 244
Abstract
Background and Objectives: Rectal cancer is a major cause of morbidity and mortality worldwide, and although current therapeutic protocols have improved survival, treatment-related toxicities may significantly affect patients’ daily functioning and emotional well-being. This study aimed to prospectively assess the impact of radiotherapy [...] Read more.
Background and Objectives: Rectal cancer is a major cause of morbidity and mortality worldwide, and although current therapeutic protocols have improved survival, treatment-related toxicities may significantly affect patients’ daily functioning and emotional well-being. This study aimed to prospectively assess the impact of radiotherapy with concurrent capecitabine on functional and symptomatic outcomes in patients with rectal cancer, with a particular focus on the presence of a stoma and treatment strategy. Materials and Methods: From 165 patients initially assessed, 64 were included in this study after applying eligibility criteria. All received pelvic radiotherapy (50.4 Gy in 28 fractions); 62.5% also received CAPOX chemotherapy. The quality of life was assessed using EORTC QLQ-C30 and QLQ-CR29 questionnaires administered at three time points: before treatment, mid-treatment (day 15), and post-treatment. Results: A statistically significant deterioration was observed in physical, emotional, social, and role functioning over the course of treatment, along with an increase in symptom scores for fatigue, pain, gastrointestinal, and urinary complaints. The presence of a stoma was significantly associated with worse gastrointestinal symptoms and emotional functioning. No significant differences were noted between patients with or without chemotherapy. Despite symptom worsening, global quality-of-life scores remained relatively stable. Conclusions: These findings highlight the complex interplay between treatment toxicity and patient adaptation. The presence of a stoma and other clinical or demographic factors significantly influence patients’ experience during therapy. Integrating routine assessment of functional and symptomatic burden into clinical practice could support individualized interventions aimed at maintaining daily functioning and psychological resilience during treatment. Full article
(This article belongs to the Special Issue Emerging Trends in Global Cancer Epidemiology: 2nd Edition)
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15 pages, 1153 KiB  
Article
Counties with Low Employment and Education Status Are Associated with Higher Age-Adjusted Cancer Mortality
by Minu Ponnamma Mohan, Joel B. Epstein, Kapil S. Meleveedu, Roberto Pili and Poolakkad S. Satheeshkumar
Cancers 2025, 17(12), 2051; https://doi.org/10.3390/cancers17122051 - 19 Jun 2025
Viewed by 202
Abstract
Background: This study aims to evaluate the potential relationship between county-level social determinants of health (SDOH)—specifically education and job status—and cancer mortality. Methods: We utilized Social Determinants of Health (SDOH) data from the Agency for Healthcare Quality (AHRQ) 2015 county database for [...] Read more.
Background: This study aims to evaluate the potential relationship between county-level social determinants of health (SDOH)—specifically education and job status—and cancer mortality. Methods: We utilized Social Determinants of Health (SDOH) data from the Agency for Healthcare Quality (AHRQ) 2015 county database for a cross-sectional study investigating the primary independent variables—low education and low employment status—and the outcome of cancer mortality. Results: Out of 3134 counties, 906 exhibited poor employment levels, while 467 showed low educational attainment. The age-adjusted cancer death rate for non-low-education counties was 172.90 [157.00, 188.40], but for low-education counties it was 186.20 [161.72, 209.33], p < 0.001. Conversely, this was 169.15 [154.00, 183.50], compared to 189.80 [171.90, 207.10], p < 0.001, for counties with low employment. The adjusted analysis indicated that counties with low education levels were correlated with elevated age-adjusted cancer mortality (7.68, 95% CI: 5.06–10.31), and similarly, counties with low employment rates were linked to increased age-adjusted cancer mortality (4.69, 95% CI: 2.58–6.79). Conclusions: Our findings indicate that counties characterized by low educational attainment and poor employment levels are associated with elevated age-adjusted cancer death rates. Full article
(This article belongs to the Special Issue Health Disparities and Outcomes in Cancer Survivors)
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31 pages, 2104 KiB  
Review
Balancing Regeneration and Resistance: Targeting DCLK1 to Mitigate Gastrointestinal Radiation Injury and Oncogenesis
by Landon L. Moore, Jerry Jaboin, Milton L. Brown and Courtney W. Houchen
Cancers 2025, 17(12), 2050; https://doi.org/10.3390/cancers17122050 - 19 Jun 2025
Viewed by 294
Abstract
Ionizing radiation (IR) poses a dual challenge in medicine; while essential for cancer therapy, it inflicts collateral damage to normal tissues, particularly the gastrointestinal (GI) tract. High-dose IR triggers acute radiation syndrome (ARS), characterized by crypt stem cell depletion, mucosal barrier disruption, inflammation, [...] Read more.
Ionizing radiation (IR) poses a dual challenge in medicine; while essential for cancer therapy, it inflicts collateral damage to normal tissues, particularly the gastrointestinal (GI) tract. High-dose IR triggers acute radiation syndrome (ARS), characterized by crypt stem cell depletion, mucosal barrier disruption, inflammation, and potential progression to fibrosis and secondary malignancy. Emerging evidence identifies the epithelial kinase doublecortin-like kinase 1 (DCLK1)—highly expressed in GI tuft cells and cancer stem-like cells—as a master regulator of post-IR responses. DCLK1 integrates DNA repair (via p53/ATM), and survival signaling (via NF-κB, TGF-β, and MAPK) to promote epithelial regeneration, yet these same mechanisms contribute to therapy resistance and oncogenesis. DCLK1 further modulates the immune microenvironment by skewing macrophages toward an immunosuppressive M2 phenotype, enhancing tissue remodeling, angiogenesis, and immune evasion. Preclinical studies demonstrate that DCLK1 inhibition sensitizes tumors to radiotherapy while preserving mucosal repair. Therapeutic strategies targeting DCLK1, alongside radioprotective agents, immunomodulators, and senolytics, may enhance regeneration, limit fibrosis, and eradicate therapy-resistant cancer stem cells. This review highlights DCLK1’s dual role in regeneration and tumorigenesis and evaluates its potential as a therapeutic target and biomarker in IR-induced GI damage. Full article
(This article belongs to the Section Cancer Biomarkers)
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22 pages, 3052 KiB  
Article
Evaluation of Spectral Imaging for Early Esophageal Cancer Detection
by Li-Jen Chang, Chu-Kuang Chou, Arvind Mukundan, Riya Karmakar, Tsung-Hsien Chen, Syna Syna, Chou-Yuan Ko and Hsiang-Chen Wang
Cancers 2025, 17(12), 2049; https://doi.org/10.3390/cancers17122049 - 19 Jun 2025
Viewed by 203
Abstract
Objective: Esophageal carcinoma (EC) is the eighth most prevalent cancer and the sixth leading cause of cancer-related mortality worldwide. Early detection is vital for improving prognosis, particularly for dysplasia and squamous cell carcinoma (SCC). Methods: This study evaluates a hyperspectral imaging conversion method, [...] Read more.
Objective: Esophageal carcinoma (EC) is the eighth most prevalent cancer and the sixth leading cause of cancer-related mortality worldwide. Early detection is vital for improving prognosis, particularly for dysplasia and squamous cell carcinoma (SCC). Methods: This study evaluates a hyperspectral imaging conversion method, the Spectrum-Aided Vision Enhancer (SAVE), for its efficacy in enhancing esophageal cancer detection compared to conventional white-light imaging (WLI). Five deep learning models (YOLOv9, YOLOv10, YOLO-NAS, RT-DETR, and Roboflow 3.0) were trained and evaluated on a dataset comprising labeled endoscopic images, including normal, dysplasia, and SCC classes. Results: Across all five evaluated deep learning models, the SAVE consistently outperformed conventional WLI in detecting esophageal cancer lesions. For SCC, the F1 score improved from 84.3% to 90.4% in regard to the YOLOv9 model and from 87.3% to 90.3% in regard to the Roboflow 3.0 model when using the SAVE. Dysplasia detection also improved, with the precision increasing from 72.4% (WLI) to 76.5% (SAVE) in regard to the YOLOv9 model. Roboflow 3.0 achieved the highest F1 score for dysplasia of 64.7%. YOLO-NAS exhibited balanced performance across all lesion types, with the dysplasia precision rising from 75.1% to 79.8%. Roboflow 3.0 also recorded the highest SCC sensitivity of 85.7%. In regard to SCC detection with YOLOv9, the WLI F1 score was 84.3% (95% CI: 71.7–96.9%) compared to 90.4% (95% CI: 80.2–100%) with the SAVE (p = 0.03). For dysplasia detection, the F1 score increased from 60.3% (95% CI: 51.5–69.1%) using WLI to 65.5% (95% CI: 57.0–73.8%) with SAVE (p = 0.04). These findings demonstrate that the SAVE enhances lesion detectability and diagnostic performance across different deep learning models. Conclusions: The amalgamation of the SAVE with deep learning algorithms markedly enhances the detection of esophageal cancer lesions, especially squamous cell carcinoma and dysplasia, in contrast to traditional white-light imaging. This underscores the SAVE’s potential as an essential clinical instrument for the early detection and diagnosis of cancer. Full article
(This article belongs to the Special Issue Role of Cancer Biomarkers for Diagnosis, Prognosis and Targeted Therapy in Gastrointestinal Cancers)
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12 pages, 1127 KiB  
Article
Automated Clinical Dosimetry Planning of Dense Lattice Radiation Therapy
by David Macias-Verde, Javier Burgos-Burgos and Pedro C. Lara
Cancers 2025, 17(12), 2048; https://doi.org/10.3390/cancers17122048 - 19 Jun 2025
Viewed by 275
Abstract
Background: Patients bearing large-volume, bulky primary or relapsed tumors, are usually referred to palliative low-dose radiotherapy with very poor results. Lattice Radiation Therapy (LRT) is able to produce a high number of high-dose foci or vortexes (multiple SBRT treatments), separated by low-dose zones [...] Read more.
Background: Patients bearing large-volume, bulky primary or relapsed tumors, are usually referred to palliative low-dose radiotherapy with very poor results. Lattice Radiation Therapy (LRT) is able to produce a high number of high-dose foci or vortexes (multiple SBRT treatments), separated by low-dose zones (valleys). Treatment planning on vortex placing, valley definition, and dose administered depends on individual decisions of the treating team. The aim of our study is to assess for the first time the possibility of a dense fractionated LRT within the target volume. Methods: A total of 22 treatments in 20 patients were performed in the frame of a prospective observational study of fractionated LRT ongoing in our institution. According to our aim of achieving dense LRT, no GTV contraction was considered to create the LRTV (GTV is equal to LRTV). The vortexes were segmented as 1 cm diameter at a 1.5 cm vortex-to-vortex distance. Dose prescription to the vortexes per fraction was 12 Gy. Results: The vortex/LRTV ratio was 7.38 ± 2.13% (3.4–10.40%, median 7.60%). Mean dose to the vortex volume was 11.90 ± 0.09 Gy (11.70–12.10 Gy, median 11.90 Gy). Mean dose administered to the valley volume was 8.29 ± 0.70 (7.05–9.51 Gy, median 8.29 Gy). Valley/vortex (peak) dose ratio (VPDR) was 69.40 ± 6.02% (59.00–79.80%, median 69.70%). The mean peripheral tumor dose was 5.11 ± 0.8710 Gy (3.16–6.78 Gy, median 5.18 Gy). Conclusions: Our dense LRT schedule fulfilled most of the recommended guidelines for LRT, increasing the high dose points without risking the dose to the surrounding tissues. Further analysis of feasibility and safety are needed to secure the clinical relevance of our proposed protocol. Full article
(This article belongs to the Special Issue New Approaches in Radiotherapy for Cancer)
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14 pages, 8962 KiB  
Article
Diverse Landscape of Group 1 Innate Lymphoid Cells Predicts the Prognosis in Patients with Head and Neck Squamous Cell Carcinoma
by Hideyuki Takahashi, Toshiyuki Matsuyama, Hiroe Tada, Hiroyuki Hagiwara, Miho Uchida and Kazuaki Chikamatsu
Cancers 2025, 17(12), 2047; https://doi.org/10.3390/cancers17122047 - 19 Jun 2025
Viewed by 368
Abstract
Objectives: Innate lymphoid cells (ILCs) and natural killer (NK) cells represent a diverse group of innate immune populations that modulate immune responses and tissue equilibrium across various diseases, including cancer. In the present study, we analyzed single-cell RNA sequencing (scRNA-seq) data to explore [...] Read more.
Objectives: Innate lymphoid cells (ILCs) and natural killer (NK) cells represent a diverse group of innate immune populations that modulate immune responses and tissue equilibrium across various diseases, including cancer. In the present study, we analyzed single-cell RNA sequencing (scRNA-seq) data to explore the landscape and functional status of ILC subsets in patients with head and neck squamous cell carcinoma (HNSCC). Methods: The GSE164690 dataset, which includes preprocessed scRNA-seq and clinical data, was acquired from the Gene Expression Omnibus database. The Cancer Genome Atlas database was used to develop the survival prediction model. Results: A total of 95,809 immune cells were clustered into 16 immune cell clusters, among which 7278 NK cells were further subdivided into 11 clusters. Among the 11 clusters, eight NK cell clusters, two intraepithelial ILC1 (ieILC1) clusters, and one ieILC1–NK-intermediate (ieILC1-NK-int) cluster were identified. Among the ieILC1/NK clusters, ieILC1-1 exhibited the highest immunological activity and was mainly derived from human papillomavirus-positive samples. Further, ieILC1s showed higher enrichment of pathways related to inflammation and effector functions—such as inflammatory response, interferon-gamma response, and interferon-alpha response—compared to the other clusters. Moreover, we developed prognostic prediction models based on differentially expressed genes in the ieILC1/NK clusters. Risk scores of the ieILC1-1, ieILC1-NK-int, and NK clusters were identified as independent prognostic factors for shorter overall survival (OS) and progression-free survival (PFS). Recursive partitioning revealed that combining ieILC1-1 and the NK clusters strongly predicted shorter OS and PFS. Conclusions: Our findings highlight the diverse landscape and prognostic significance of ieILC1/NK cells in patients with HNSCC. Full article
(This article belongs to the Special Issue Molecular Mechanisms in Head and Neck Cancer)
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14 pages, 472 KiB  
Article
Liver Transplantation for Colorectal Metastases: Impact of a Standardised Protocol for Patient Selection on Transplant Outcomes
by Alberto Stocco, Andrea Laurenzi, Matteo Serenari, Enrico Prosperi, Guido Fallani, Chiara Bonatti, Giorgia Radi, Margherita Prior, Federica Odaldi, Chiara Zanfi, Federica Mirici Cappa, Antonio Siniscalchi, Maria Cristina Morelli, Matteo Ravaioli and Matteo Cescon
Cancers 2025, 17(12), 2046; https://doi.org/10.3390/cancers17122046 - 19 Jun 2025
Viewed by 245
Abstract
Background: Colorectal liver metastases (CRLM) occur in up to 50% of colorectal cancer with a significant impact on patient survival, of whom only 20–30% will be considered suitable for surgical treatment. Despite the progress in systemic therapies, palliative chemotherapy alone results in a [...] Read more.
Background: Colorectal liver metastases (CRLM) occur in up to 50% of colorectal cancer with a significant impact on patient survival, of whom only 20–30% will be considered suitable for surgical treatment. Despite the progress in systemic therapies, palliative chemotherapy alone results in a 5-year overall survival (OS) < 10%. Recently, liver transplantation (LT) has been reconsidered as an option and demonstrates improved survival in highly selected patients. This study assessed the impact of implementing a standardised patient selection protocol (LITORALE) on post-transplant outcomes for unresectable CRLM (uCRLM) at a high-volume single centre. Methods: This is a prospective observational study including all consecutive patients transplanted for uCRLM at our institution between July 2015 and September 2024. This prospective observational study evaluated the impact of the LITORALE protocol on post-transplant outcomes in uCRLM patients at a single centre. Patients who underwent LT between July 2015 and September 2024 were grouped into pre-LITORALE (2015–2021) and LITORALE (post-2021) cohorts. Recipient profiles, transplant variables, and post-transplant outcomes were compared. Results: Twenty-one patients were included (eight pre-LITORALE, thirteen LITORALE). The LITORALE group had a lower median number of lesions (4 vs. 17.5, p = 0.004), a smaller major lesion size (3 cm vs. 5.5 cm, p = 0.082), and a significantly lower tumour burden score (6.32 vs. 18.02, p = 0.002). Similar to recent major clinical trials, one- and three-years OS were 100% and 83%, respectively, after protocol introduction; recurrence patterns were significantly different, with reduced multi-site recurrences (7.7% vs. 50%, p = 0.048) and a higher incidence of lung-only recurrences in the LITORALE group (50% vs. 0%, p = 0.033). Conclusions: The introduction of the LITORALE protocol significantly influenced patient selection and recurrence patterns in LT for uCRLM. Although the limited number of patients and the short study timespan highlight the need for future validation, these preliminary results support the adoption of structured, multidisciplinary criteria to optimise oncologic outcomes. Full article
(This article belongs to the Special Issue Insights from the Editorial Board Member)
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21 pages, 4441 KiB  
Review
An Update on Flow Cytometry Analysis of Hematological Malignancies: Focus on Standardization
by Eda Holl, Michael Kapinsky and Anis Larbi
Cancers 2025, 17(12), 2045; https://doi.org/10.3390/cancers17122045 - 19 Jun 2025
Viewed by 285
Abstract
Flow cytometry use has significantly increased in clinical laboratories and has significantly helped improve the diagnosis of leukemias, lymphomas, and follow-up of minimal residual disease. Mastering this technique enables the performance of multiparametric single-cell analysis and increases the odds of identifying abnormal populations. [...] Read more.
Flow cytometry use has significantly increased in clinical laboratories and has significantly helped improve the diagnosis of leukemias, lymphomas, and follow-up of minimal residual disease. Mastering this technique enables the performance of multiparametric single-cell analysis and increases the odds of identifying abnormal populations. As in many fields, there is a need to improve the quality of the data generated for accuracy, reproducibility, and trueness. The implementation of solutions reducing variability is achievable and needed, as the flow cytometry workflow involves many manual steps and items susceptible to operator bias and human error. Standardization of flow cytometry assays is sought and already implemented in many clinical hematology laboratories. However, the clinical community would highly benefit from further efforts in that direction to increase the comparability of findings across laboratories. This review covers the strengths and weaknesses of flow cytometry and focuses on the standardization approaches developed, including recent advances in the field. Full article
(This article belongs to the Section Methods and Technologies Development)
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23 pages, 3148 KiB  
Article
Reduction of NFX1-123 and HPV 16 E6 and E7 Decreased Telomerase and CENP-F in Cervical Cancer Cell Lines
by Sreenivasulu Chintala, Maura A. Dankoski, Titus K. Maina, Cliff I. Oduor, Kevin M. Quist, Jeffrey A. Bailey and Rachel A. Katzenellenbogen
Cancers 2025, 17(12), 2044; https://doi.org/10.3390/cancers17122044 - 19 Jun 2025
Viewed by 291
Abstract
Background: Telomerase activity is a cancer hallmark, and hTERT is the rate-limiting catalytic subunit of telomerase. In human papillomavirus type 16 E6 (16E6)-expressing epithelial cells, NFX1-123 augments and is required for full hTERT expression, leading to a growth advantage. However, no studies have [...] Read more.
Background: Telomerase activity is a cancer hallmark, and hTERT is the rate-limiting catalytic subunit of telomerase. In human papillomavirus type 16 E6 (16E6)-expressing epithelial cells, NFX1-123 augments and is required for full hTERT expression, leading to a growth advantage. However, no studies have investigated the role of NFX1-123 in telomerase activity regulation in HPV-associated cancers. Methods: We knocked out NFX1-123 in CaSki cells (CaSki KO) and performed single-cell RNA sequencing to determine mRNA alterations affected by reduced NFX1-123. Results: In CaSki KO cells, there were three cell clusters based on gene expression, each associated with different enriched biological processes. When pooled and compared with control cells, CaSki KO cells had 1661 decreased and 565 increased mRNAs involving RNA regulation, cell cycle and division, chromatin regulation, and carcinogenesis processes and pathways. CENP-F, a cell cycle and chromosome segregation gene increased in cervical cancers, was among 10 genes with the greatest decrease in mRNA expression in CaSki KO cells. CaSki and SiHa cells with either reduced NFX1-123 or knocked down HPV 16 E6 and E7, demonstrated reduced hTERT, CENP-F, and telomerase activity, and when both NFX1-123 and HPV 16 E6 and E7 were decreased, hTERT and telomerase activity fell further. Finally, hTERT and CENP-F were increased in cervical cancer primary tumors and in HPV-positive head and neck cancer primary tumors in the TCGA database. Conclusions: These findings highlight the shared role that NFX1-123 has with HPV 16 oncogenes in driving and maintaining RNA, cell cycle, and carcinogenesis pathways, and specifically regulating hTERT, telomerase, and CENP-F. Full article
(This article belongs to the Section Infectious Agents and Cancer)
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15 pages, 266 KiB  
Review
Challenges and Opportunities for Colorectal Cancer Prevention in Young Patients
by Hyung Kim, Anna Melio, Vlad Simianu and Gautam Mankaney
Cancers 2025, 17(12), 2043; https://doi.org/10.3390/cancers17122043 - 19 Jun 2025
Viewed by 244
Abstract
There has been a well-documented increase in the incidence of colorectal cancer in patients under 50 years of age. Additionally, these patients present with later-stage cancer at diagnosis compared to their over-50 counterparts. However, there is limited consensus on how the impact of [...] Read more.
There has been a well-documented increase in the incidence of colorectal cancer in patients under 50 years of age. Additionally, these patients present with later-stage cancer at diagnosis compared to their over-50 counterparts. However, there is limited consensus on how the impact of this evolving epidemiology should impact existing prevention and screening tools. Recently proposed strategies include increased genetic testing, improved young patient awareness through targeted media campaigns, and initiatives to increase clinical suspicion in primary care providers. Prevention is further complicated by nuances of treating colorectal cancer in the younger population, with underexplored concerns regarding fertility, sexual health, financial impact, and extended post-treatment surveillance. This review aims to summarize the changing epidemiology of colorectal cancer in young patients, overview existing screening guidelines, and discuss challenges and opportunities surrounding prevention of early-onset colon cancer. Full article
(This article belongs to the Section Cancer Therapy)
15 pages, 554 KiB  
Article
Long-Term Clinical Outcomes for Adolescent and Young-Adult Uveal Melanoma Patients Treated with Dedicated Particle-Beam Radiation
by Carly Zako, Arina Nisanova, Vivian Weinberg, Jessica Scholey, Carisa Swason, Armin R. Afshar, Jeanne Quivey, Inder K. Daftari, Tony Tsai, Susanna S. Park, Michael Seider, Robert N. Johnson, Devron H. Char and Kavita K. Mishra
Cancers 2025, 17(12), 2042; https://doi.org/10.3390/cancers17122042 - 19 Jun 2025
Viewed by 174
Abstract
Uveal melanoma (UM) is a rare tumor and a challenging diagnosis for adolescent and young-adult (AYA) patients, as it can threaten vision, quality of life, and life expectancy [...] Full article
(This article belongs to the Special Issue Advances in Uveal Melanoma)
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12 pages, 707 KiB  
Article
Adjuvant Chemoradiotherapy or Radiotherapy Alone for Early Squamous Cervical Cancer with a Single Surgical-Pathological High-Risk Factor
by Ester P. Olthof, Hans H. B. Wenzel, Jacobus van der Velden, Lukas J. A. Stalpers, Maaike A. van der Aa and Constantijne H. Mom
Cancers 2025, 17(12), 2041; https://doi.org/10.3390/cancers17122041 - 18 Jun 2025
Viewed by 167
Abstract
Objective: This study aims to explore the benefit of adjuvant chemoradiotherapy compared with radiotherapy alone following a radical hysterectomy with pelvic lymphadenectomy. The study focuses on patients with clinically early-stage squamous cervical cancer who have a single high-risk factor postoperatively. Methods: This retrospective [...] Read more.
Objective: This study aims to explore the benefit of adjuvant chemoradiotherapy compared with radiotherapy alone following a radical hysterectomy with pelvic lymphadenectomy. The study focuses on patients with clinically early-stage squamous cervical cancer who have a single high-risk factor postoperatively. Methods: This retrospective study included women diagnosed between 2001 and 2018, with: (1) clinical tumour (cT) stage 1A2–2A2, (2) cervical squamous carcinoma, (3) treated with radical hysterectomy and pelvic lymphadenectomy (4) followed by adjuvant (chemo)radiotherapy, and with (5) one high-risk factor (i.e., positive resection margins, parametrial involvement, or pelvic lymph node metastases). Recurrence-free and overall survival were estimated using Kaplan−Meier and Cox proportional hazards analyses. Inverse probability treatment weighting was used to adjust for confounding. Results: Of the 122 patients with squamous cell carcinoma and one high-risk factor, 76 (62%) received adjuvant chemoradiotherapy and 46 (38%) received adjuvant radiotherapy alone. Larger tumour size, tumour grade 3, and pathological parametrial invasion were more common in the radiotherapy group, while patients who received chemoradiotherapy were more likely to have multiple lymph node metastases. The unadjusted and for confounding adjusted 5-year survival rates were comparable between the adjuvant chemoradiotherapy and radiotherapy groups for both recurrence-free survival (85% versus 87%; p = 0.58, and 84% versus 91%; p = 0.49) and overall survival (84% versus 87%; p = 0.51, and 84% versus 91%; p = 0.49). Conclusions: Adding chemotherapy to radiotherapy may not improve survival of patients with early squamous cervical cancer treated with radical hysterectomy and pelvic lymphadenectomy, and with a single postoperative high-risk factor. Full article
(This article belongs to the Section Cancer Therapy)
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12 pages, 229 KiB  
Review
Surgical Management of Oligometastatic Non-Small Cell Lung Cancer
by Susana Fortich, Deniz Piyadeoglu, Nafiye Busra Celik and Mara Antonoff
Cancers 2025, 17(12), 2040; https://doi.org/10.3390/cancers17122040 - 18 Jun 2025
Viewed by 494
Abstract
Background: Oligometastatic non-small cell lung cancer (NSCLC) represents a biologically and clinically distinct state characterized by limited metastatic spread. Increasing evidence suggests that aggressive local therapies, including surgical resection, may confer a survival benefit in this population. The objective of this review is [...] Read more.
Background: Oligometastatic non-small cell lung cancer (NSCLC) represents a biologically and clinically distinct state characterized by limited metastatic spread. Increasing evidence suggests that aggressive local therapies, including surgical resection, may confer a survival benefit in this population. The objective of this review is to evaluate the current role of surgery in the management of oligometastatic NSCLC, with emphasis on patient selection, surgical strategy, integration with systemic therapy, and ongoing clinical investigations. Methods: This narrative review synthesizes retrospective and prospective clinical data, meta-analyses, major consensus guidelines, and ongoing trials since 2012. We highlight prognostic factors, staging strategies, and the evolving role of molecular and biomarker-based stratification. Results: Multiple retrospective studies and several randomized trials have demonstrated improved progression-free and overall survival with local consolidative therapy in oligometastatic NSCLC. Prognostic factors associated with favorable outcomes include a limited number of metastases (≤3), good performance status, absence of mediastinal nodal disease, metachronous presentation, and actionable molecular alterations. The integration of surgery with systemic therapies, including targeted agents and immunotherapy, has become increasingly common in selected patients. Ongoing trials such as LONESTAR, NORTHSTAR, and BRIGHTSTAR are expected to further define the role of surgery in this setting. Conclusions: Surgery is emerging as a key component of multimodal treatment for carefully selected patients with oligometastatic NSCLC. Future efforts should focus on refining patient selection through molecular stratification and expanding prospective trial data to guide personalized biology-driven treatment strategies. Full article
(This article belongs to the Special Issue The Current Status of Treatment for Oligometastatic Lung Cancer)
13 pages, 1106 KiB  
Systematic Review
Peptide Receptor Radionuclide Therapy in Patients with Advanced, Recurrent or Progressive Meningioma: An Updated Systematic Review and Meta-Analysis
by Barbara Muoio, Cesare Michele Iacovitti, Davide Giovanni Bosetti, Maddalena Sansovini, Marco Cuzzocrea, Gaetano Paone and Giorgio Treglia
Cancers 2025, 17(12), 2039; https://doi.org/10.3390/cancers17122039 - 18 Jun 2025
Viewed by 213
Abstract
Background: Peptide receptor radionuclide therapy (PRRT) could be a therapeutic option for patients with advanced, recurrent or progressing meningiomas overexpressing somatostatin receptors. The aim of this study is to perform an updated meta-analysis to establish the disease control rate of PRRT in these [...] Read more.
Background: Peptide receptor radionuclide therapy (PRRT) could be a therapeutic option for patients with advanced, recurrent or progressing meningiomas overexpressing somatostatin receptors. The aim of this study is to perform an updated meta-analysis to establish the disease control rate of PRRT in these patients. Methods: A comprehensive literature search of studies on PRRT in patients with advanced, recurrent or progressing meningioma was carried out. Four different databases (PubMed/MEDLINE, EMBASE, Cochrane library, Google Scholar) were screened until April 2025. Only original articles about PRRT in advanced, progressive or refractory meningiomas were selected. Case reports were excluded. Three review authors independently performed the literature search, the article selection and the data extraction. Main findings of eligible studies were summarized and a proportion meta-analysis on the disease control rate was carried out using a random-effects model. Results: In total, 18 studies (269 patients) published from 2006 to 2025 were included in the analysis. In most of the included studies, PRRT was performed using [177Lu]Lu-DOTATATE. The pooled disease control rate was 67.7% (95% confidence interval values: 59.6–75.7%). PRRT was well-tolerated in most patients with advanced, recurrent or progressive meningioma. Moderate statistical heterogeneity was found in the meta-analysis (I-square: 53%). Conclusions: PRRT is an effective and well-tolerated treatment in patients with advanced, progressive or recurrent meningiomas, showing a significant disease control rate (in about two-thirds of patients). Even if well-designed clinical trials are needed to corroborate these findings, evidence-based data seem to support the clinical use of PRRT for this indication. Full article
(This article belongs to the Special Issue Novel Targeted Therapies in Brain Tumors)
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18 pages, 847 KiB  
Article
Predictive Factors Aiding in the Estimation of Intraoperative Resources in Gastric Cancer Oncologic Surgery
by Alexandru Blidișel, Mihai-Cătălin Roșu, Andreea-Adriana Neamțu, Bogdan Dan Totolici, Răzvan-Ovidiu Pop-Moldovan, Andrei Ardelean, Valentin-Cristian Iovin, Ionuț Flaviu Faur, Cristina Adriana Dehelean, Sorin Adalbert Dema and Carmen Neamțu
Cancers 2025, 17(12), 2038; https://doi.org/10.3390/cancers17122038 - 18 Jun 2025
Viewed by 136
Abstract
Background/Objectives: Operating rooms represent valuable and pivotal units of any hospital. Therefore, their management affects healthcare service delivery through rescheduling, staff shortage/overtime, cost inefficiency, and patient dissatisfaction, among others. To optimize scheduling, we aim to assess preoperative evaluation criteria that influence the prediction [...] Read more.
Background/Objectives: Operating rooms represent valuable and pivotal units of any hospital. Therefore, their management affects healthcare service delivery through rescheduling, staff shortage/overtime, cost inefficiency, and patient dissatisfaction, among others. To optimize scheduling, we aim to assess preoperative evaluation criteria that influence the prediction of surgery duration for gastric cancer (GC) patients. In GC, radical surgery with curative intent is the ideal treatment. Nevertheless, the intervention sometimes must be palliative if the patient’s status and tumor staging prove too advanced. Methods: A 6-year retrospective cohort study was performed in a tertiary care hospital, including all cases diagnosed with GC (ICD-10 code C16), confirmed through histopathology, and undergoing surgical treatment (N = 108). Results: The results of our study confirm male predominance (63.89%) among GC surgery candidates while bringing new perspectives on patient evaluation criteria and choice of surgical intervention (curative—Group 1, palliative—Group 2). Surgery duration, including anesthesiology (175.19 [95% CI (157.60–192.77)] min), shows a direct correlation with the number of lymph nodes dissected (Surgical duration [min] = 10.67 × No. of lymph nodes removed − 32.25). Interestingly, the aggressiveness of the tumor based on histological grade (highly differentiated being generally less aggressive than poorly differentiated) shows differential correlation with surgery duration among curative and palliative surgery candidates. Similarly, TNM staging indicates the need for a longer surgical duration (pTNM stage IIA, IIB, and IIIA) for curative interventions in patients with less advanced stages, as opposed to shorter surgery duration for palliative interventions (pTNM stage IIIC and IV). Conclusions: The study quantitatively presents the resources needed for the optimal surgical treatment of different groups of GC patients, as the disease coding systems in use regard the treatment of each pathology as “standard” in terms of patient management. The results obtained are anchored in the global perspectives of surgical outcomes and aim to improve the management of operating room scheduling, staff, and resources. Full article
(This article belongs to the Special Issue State-of-the-Art Research on Gastric Cancer Surgery)
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20 pages, 2533 KiB  
Article
Redefining the Use of Regorafenib and Trifluridine/Tipiracil Without Bevacizumab in Refractory Metastatic Colorectal Cancer: Findings from the ReTrITA Study
by Carlo Signorelli, Maria Alessandra Calegari, Annunziato Anghelone, Alessandro Passardi, Chiara Gallio, Alessandro Bittoni, Jessica Lucchetti, Lorenzo Angotti, Emanuela Di Giacomo, Ina Valeria Zurlo, Cristina Morelli, Emanuela Dell’Aquila, Adele Artemi, Donatello Gemma, Alessandra Emiliani, Marta Ribelli, Domenico Cristiano Corsi, Giulia Arrivi, Federica Mazzuca, Federica Zoratto, Mario Giovanni Chilelli, Marta Schirripa, Francesco Schietroma, Maria Grazia Morandi, Fiorenza Santamaria, Manuela Dettori, Antonella Cosimati, Rosa Saltarelli, Alessandro Minelli, Emanuela Lucci-Cordisco and Michele Bassoadd Show full author list remove Hide full author list
Cancers 2025, 17(12), 2037; https://doi.org/10.3390/cancers17122037 - 18 Jun 2025
Viewed by 195
Abstract
Background: Regorafenib (R) and trifluridine/tipiracil (T) are approved treatments for metastatic colorectal cancer (mCRC) in refractory cases. However, the optimal sequencing of these agents is unknown. The ReTrITA study planned to assess the real-world efficacy of R and T, administered either sequentially or [...] Read more.
Background: Regorafenib (R) and trifluridine/tipiracil (T) are approved treatments for metastatic colorectal cancer (mCRC) in refractory cases. However, the optimal sequencing of these agents is unknown. The ReTrITA study planned to assess the real-world efficacy of R and T, administered either sequentially or as monotherapy, in a large Italian multicentre population. Methods: This retrospective observational analysis comprised 1156 mCRC patients treated between 2012 and 2023 at 17 Italian cancer centres. Patients were divided into four groups: sequential T/R (n = 261), sequential R/T (n = 155), R monotherapy (n = 313), and T monotherapy (n = 427). The primary objectives were overall survival (OS) and progression-free survival (PFS), with secondary goals being disease control rate, objective response rate, and treatment-related toxicity. Results: The monotherapy cohorts showed no significant difference in OS (R: 5.0 months; T: 5.9 months; p = 0.8371) or PFS (R: 3.2 months; T: 3.3 months; p = 0.6531). Compared to T/R, the sequential R/T group had significantly better outcomes: median OS was 16.6 vs. 12.6 months (HR = 0.67; p = 0.0004), and median PFS was 11.5 vs. 8.5 months (HR = 0.60; p < 0.0001). The survival advantage of R/T was consistent across clinical subgroups. The toxicity profiles were comparable with known safety data, with a lower prevalence of neutropenia reported in the R/T sequence. Conclusions: ReTrITA confirms the efficacy of R and T as monotherapies and provides compelling real-world evidence that the R/T sequence improves survival in refractory mCRC. These findings support a regorafenib-first approach in patients who are eligible, and they emphasise the need for future research into combination strategies and comparisons with newer drugs such as fruquintinib. Full article
(This article belongs to the Special Issue Real-World Evidence and Emerging Therapeutic Strategies in Refractory Metastatic Colorectal Cancer)
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17 pages, 4602 KiB  
Article
Dual-Plasma Discharge Tube for Synergistic Glioblastoma Treatment
by William Murphy, Alex Horkowitz, Vikas Soni, Camil Walkiewicz-Yvon and Michael Keidar
Cancers 2025, 17(12), 2036; https://doi.org/10.3390/cancers17122036 - 18 Jun 2025
Viewed by 217
Abstract
Background: Glioblastoma (GBM) resists current therapies due to its rapid proliferation, diffuse invasion, and heterogeneous cell populations. We previously showed that a single cold atmospheric plasma discharge tube (DT) reduces GBM viability via broad-spectrum electromagnetic (EM) emissions. Here, we tested whether two DTs [...] Read more.
Background: Glioblastoma (GBM) resists current therapies due to its rapid proliferation, diffuse invasion, and heterogeneous cell populations. We previously showed that a single cold atmospheric plasma discharge tube (DT) reduces GBM viability via broad-spectrum electromagnetic (EM) emissions. Here, we tested whether two DTs arranged in a helmet configuration could generate overlapping EM fields to amplify the anti-tumor effects without thermal injury. Methods: The physical outputs of the single- and dual-DT setups were characterized by infrared thermography, broadband EM field probes, and oscilloscope analysis. Human U87-MG cells were exposed under the single or dual configurations. The viability was quantified with WST-8 assays mapped across 96-well plates; the intracellular reactive oxygen species (ROS), membrane integrity, apoptosis, and mitochondrial potential were assessed by multiparametric flow cytometry. Our additivity models compared the predicted versus observed dual-DT cytotoxicity. Results: The dual-DT operation produced constructive EM interference, elevating electric and magnetic field amplitudes over a broader area than either tube alone, while temperatures remained <39 °C. The single-DT exposure lowered the cell viability by ~40%; the dual-DT treatment reduced the viability by ~60%, exceeding the additive predictions. The regions of greatest cytotoxicity co-localized with the zones of highest EM field overlap. The dual-DT exposure doubled the intracellular ROS compared with single-DT and Annexin V positivity, confirming oxidative stress-driven cell death. The out-of-phase operation of the discharge tubes enabled the localized control of the treatment regions, which can guide future treatment planning. Conclusions: Two synchronously operated plasma discharge tubes synergistically enhanced GBM cell killing through non-thermal mechanisms that coupled intensified overlapping EM fields with elevated oxidative stress. This positions modular multi-DT arrays as a potential non-invasive adjunct or alternative to existing electric-field-based therapies for glioblastoma. Full article
(This article belongs to the Special Issue Plasma and Cancer Treatment)
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19 pages, 1827 KiB  
Article
ISUP Grade Prediction of Prostate Nodules on T2WI Acquisitions Using Clinical Features, Textural Parameters and Machine Learning-Based Algorithms
by Teodora Telecan, Alexandra Chiorean, Roxana Sipos-Lascu, Cosmin Caraiani, Bianca Boca, Raluca Maria Hendea, Teodor Buliga, Iulia Andras, Nicolae Crisan and Monica Lupsor-Platon
Cancers 2025, 17(12), 2035; https://doi.org/10.3390/cancers17122035 - 18 Jun 2025
Viewed by 191
Abstract
Background: Prostate cancer (PCa) represents a matter at the forefront of healthcare, being divided into clinically significant (csPCa) and indolent PCa based on prognostic and treatment options. Although multi-parametric magnetic resonance imaging (mpMRI) has enabled significant advances, it cannot differentiate between the aforementioned [...] Read more.
Background: Prostate cancer (PCa) represents a matter at the forefront of healthcare, being divided into clinically significant (csPCa) and indolent PCa based on prognostic and treatment options. Although multi-parametric magnetic resonance imaging (mpMRI) has enabled significant advances, it cannot differentiate between the aforementioned categories; therefore, in order to render the initial diagnosis, invasive procedures such as transrectal prostate biopsy are still necessary. In response to these challenges, artificial intelligence (AI)-based algorithms combined with radiomics features offer the possibility of creating a textural pixel pattern-based surrogate, which has the potential of correlating the medical imagery with the pathological report in a one-to-one manner. Objective: The aim of the present study was to develop a machine learning model that can differentiate indolent from csPCa lesions, as well as individually classifying each nodule into corresponding ISUP grades prior to prostate biopsy, using textural features derived from mpMRI T2WI acquisitions. Materials and Methods: The study was conducted in 154 patients and 201 individual prostatic lesions. All cases were scanned using the same 1.5 Tesla mpMRI machine, employing a standard protocol. Each nodule was manually delineated using the 3D Slicer platform (version 5.2.2) and textural parameters were derived using the PyRadiomics database (version 3.1.0). We compared three machine learning classification models (Random Forest, Support Vector Machine, and Logistic Regression) in full, partial and no correlation settings, in order to differentiate between indolent and csPCa, as well as between ISUP 2 and ISUP 3 lesions. Results: The median age was 65 years (IQR: 61–69), the mean PSA value was 10.27 ng/mL, and 76.61% of the segmented lesions had a PI-RADS score of 4 or higher. Overall, the highest performance was registered for the Random Forest model in the partial correlation setting, differentiating between indolent and csPCa and between ISUP 2 versus ISUP 3 lesions, with accuracies of 88.13% and 82.5%, respectively. When the models were trained on combined clinical data and radiomic signatures, these accuracies increased to 91.11% and 91.39%, respectively. Conclusions: We developed a machine learning decision support tool that accurately predicts the ISUP grade prior to prostate biopsy, based on the textural features extracted from T2 MRI acquisitions. Full article
(This article belongs to the Section Cancer Causes, Screening and Diagnosis)
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13 pages, 1648 KiB  
Article
KAT/3BP: A Metabolism-Targeting Agent with Single and Combination Activity in Aggressive B-Cell Lymphomas
by Chiara Tarantelli, Filippo Spriano, Elisa Civanelli, Luca Aresu, Giorgia Risi, Eleonora Cannas, Omar Kayali, Luciano Cascione, Alberto J. Arribas, Anastasios Stathis, Young H. Ko and Francesco Bertoni
Cancers 2025, 17(12), 2034; https://doi.org/10.3390/cancers17122034 - 18 Jun 2025
Viewed by 215
Abstract
Background/Objectives: Reprogramming of the cellular metabolism is a hallmark of cancer, offering therapeutic opportunities to target cancer cell vulnerabilities for therapeutic purposes. 3-Bromopyruvate (3BP) is a small alkylating agent that functions as an anti-metabolite, targeting key substrates in cancer metabolism and demonstrating antitumor [...] Read more.
Background/Objectives: Reprogramming of the cellular metabolism is a hallmark of cancer, offering therapeutic opportunities to target cancer cell vulnerabilities for therapeutic purposes. 3-Bromopyruvate (3BP) is a small alkylating agent that functions as an anti-metabolite, targeting key substrates in cancer metabolism and demonstrating antitumor activity across multiple cancer types. However, unformulated 3BP is associated with significant toxicity. This study investigates the efficacy of KAT/3BP, a clinical derivative of 3BP currently in phase 1 trials for hepatocellular carcinoma, in preclinical lymphoma models. Results: In vitro, KAT/3BP exhibited cytotoxic activity across 12 lymphoma cell lines—including diffuse large B-cell lymphoma and mantle cell lymphoma—with a median IC50 of 3.7 μM. It also remained effective against lymphoma cell lines with acquired resistance to FDA-approved therapies. In vivo, treatment with KAT/3BP led to reduced tumor size in a syngeneic mouse model, with the combination of oral and intratumoral administration showing the greatest efficacy. Furthermore, KAT/3BP demonstrated synergistic activity when combined with standard lymphoma therapies such as bendamustine and R-CHOP. Conclusions: Our findings highlight the potential of KAT/3BP as a novel therapeutic option, either as a single agent or in combination regimens, for treating lymphomas. Full article
(This article belongs to the Special Issue Combination Therapy in Lymphoma)
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15 pages, 1256 KiB  
Article
A Pragmatic Grouping Model for Bone-Only De Novo Metastatic Breast Cancer (MetS Protocol MF22-03)
by Berk Goktepe, Berkay Demirors, Kazim Senol, Serdar Ozbas, Efe Sezgin, Anthony Lucci and Atilla Soran
Cancers 2025, 17(12), 2033; https://doi.org/10.3390/cancers17122033 - 18 Jun 2025
Viewed by 343
Abstract
De novo metastatic breast cancer (dnMBC) accounts for 3–10% of newly diagnosed cases, with 20–40% presenting as a bone-only metastatic disease, which can achieve survival outcomes exceeding 10 years with multimodal therapy. However, the role of multimodal therapy remains controversial in the guidelines. [...] Read more.
De novo metastatic breast cancer (dnMBC) accounts for 3–10% of newly diagnosed cases, with 20–40% presenting as a bone-only metastatic disease, which can achieve survival outcomes exceeding 10 years with multimodal therapy. However, the role of multimodal therapy remains controversial in the guidelines. Objective: This study aims to identify dnBOMBC subgroups to develop a pragmatic staging system for guiding locoregional therapy decisions. Materials and Methods: Data from the MF07-01 phase III randomized trial (2021, median follow-up time (mFT): 40 months (range 1–131)) and the BOMET prospective multi-institutional registry trial (2021, mFT: 34 months (range 25–45)) were combined for analysis, including only patients who presented with bone-only metastases. Exclusion criteria were patients under 18 and those with a history of prior cancer or cancer metastases. Patients with missing data and positive surgical margins were excluded. Out of 770 patients, 589 were included. Survival analyses were first conducted according to molecular subgroups, after which patients were further stratified by hormone receptor status, human epidermal human epidermal growth factor receptor 2 (HER2) status, tumor grade, and clinical T (cT) stage. Group A (GrA) included hormone receptor (HR)-positive, low- or intermediate-grade tumors at any cT; HR-positive, high-grade tumors with cT0–3; or any HER2-positive tumors. Group B (GrB) included HR-positive, high-grade tumors with cT4 disease or any triple-negative (TN) tumors. Results: The hazard of death (HoD) was 43% lower in GrA than in GrB. Median OS was 65 months (39–104) for GrA patients and 44 months (28–72) for GrB patients (HR 0.57, 95% CI 0.41–0.78, p = 0.0003). Primary tumor surgery (PTS) significantly improved OS in GrA patients, regardless of the number of metastases (solitary: HR, 0.375, 95% CI 0.259–0.543, p < 0.001; multiple: HR 0.435, 95% CI 0.334–0.615, p < 0.001). Conversely, GrB patients did not experience a significant benefit from PTS. Conclusions: This study demonstrates that GrA patients have better OS than GrB patients, and PTS reduces the HoD in GrA patients compared to systemic therapy alone. These findings support using a modified staging system in dnBOBMC to identify patients who may benefit from multimodal therapy including PTS. Full article
(This article belongs to the Section Cancer Metastasis)
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2 pages, 149 KiB  
Retraction
RETRACTED: Kalicińska et al. Pneumonia in Patients with Chronic Lymphocytic Leukemia Treated with Venetoclax-Based Regimens: A Real-World Analysis of the Polish Adult Leukemia Group (PALG). Cancers 2024, 16, 4168
by Elżbieta Kalicińska, Paula Jabłonowska-Babij, Marta Morawska, Elżbieta Iskierka-Jażdżewska, Joanna Drozd-Sokołowska, Ewa Paszkiewicz-Kozik, Łukasz Szukalski, Judyta Strzała, Urszula Gosik, Jakub Dębski, Iga Andrasiak, Anna Skotny, Krzysztof Jamroziak and Tomasz Wróbel
Cancers 2025, 17(12), 2032; https://doi.org/10.3390/cancers17122032 - 18 Jun 2025
Viewed by 145
Abstract
The Cancers journal retracts the article titled “Pneumonia in Patients with Chronic Lymphocytic Leukemia Treated with Venetoclax-Based Regimens: A Real-World Analysis of the Polish Adult Leukemia Group (PALG)” [...] Full article
12 pages, 1481 KiB  
Article
Mucin4 (MUC4) Antibody Labeled with an NIR Dye Brightly Targets Pancreatic Cancer Liver Metastases and Peritoneal Carcinomatosis
by Sunidhi Jaiswal, Siamak Amirfakhri, Javier Bravo, Keita Kobayashi, Abhijit Aithal, Sumbal Talib, Kavita Mallya, Maneesh Jain, Aaron M. Mohs, Robert M. Hoffman, Surinder K. Batra and Michael Bouvet
Cancers 2025, 17(12), 2031; https://doi.org/10.3390/cancers17122031 - 18 Jun 2025
Viewed by 225
Abstract
Background/Objectives: Pancreatic cancer is the fourth leading cause of deaths related to cancer. It is a highly aggressive malignancy and often metastasizes quickly to other parts of the body and organs. The most effective cure is surgical resection, which also is limited by [...] Read more.
Background/Objectives: Pancreatic cancer is the fourth leading cause of deaths related to cancer. It is a highly aggressive malignancy and often metastasizes quickly to other parts of the body and organs. The most effective cure is surgical resection, which also is limited by tumor identification and clear tumor margin visualization. Previously, we used MUC4 antibodies labeled with IRDye800CW (anti-MUC4-IR800) to target primary human pancreatic cancer in orthotopic cell line mouse models. Methods: In the present study, we established a pancreatic cancer liver metastasis mouse model by implanting a tumor fragment in the liver and a peritoneal carcinomatosis mouse model by injecting pancreatic cancer cells interperitoneally. Once the tumors were established, anti-MUC4-IR800 was administered to the mice by tail vein injection. Laparotomy was performed and tumors were imaged under white-light and near-infrared (NIR) fluorescence with the Pearl Small Animal Imaging System. Results: NIR imaging after 72 h shows the bright targeting of pancreatic cancer metastasis in both mouse models with high tumor-to-background ratios. Conclusions: Anti-MUC4-IR800 was able to successfully target and brightly label metastatic pancreatic cancer as small as 1 mm. Future clinical applications of the results of the present study are discussed. Full article
(This article belongs to the Special Issue Enhancing Cancer Treatments through Fluorescence-Guided Surgery)
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21 pages, 12176 KiB  
Article
Lymph Node Reporting and Data System (LN-RADS)—Retrospective Evaluation for Ultrasound Classification of Superficial Lymph Nodes
by Cezary Chudobiński, Katarzyna Pasicz, Małgorzata Hanke, Adam Kaczmarek, Mateusz Pajdziński, Agnieszka Kołacińska-Wow, Leszek Gottwald, Wojciech Kuncman, Michał Podgórski and Andrzej Cieszanowski
Cancers 2025, 17(12), 2030; https://doi.org/10.3390/cancers17122030 - 18 Jun 2025
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Abstract
Introduction: The evaluation of lymph nodes (LNs) in patients with suspected oncological disease is a crucial factor influencing further diagnostics and management. However, there is a lack of a dedicated system for the precise and comprehensive assessment of LNs. To address this gap, [...] Read more.
Introduction: The evaluation of lymph nodes (LNs) in patients with suspected oncological disease is a crucial factor influencing further diagnostics and management. However, there is a lack of a dedicated system for the precise and comprehensive assessment of LNs. To address this gap, we developed the Lymph Node Reporting and Data System (LN-RADS). Methods: This retrospective multiparametric analysis included the assessment of 719 LNs in 489 patients. The images were evaluated by three radiologists using the LN-RADS scale, assigning each case to one of six group: 1 (normal), 2 (steatotic), 3 (reactive), 4a (low suspicion of malignancy) vs. 4b (high suspicion of malignancy), and 5 (definitely malignant) and were then correlated with histopathological results. The diagnostic performance of LN-RADS was validated. The analysis of 12 morphological features of LNs was performed to identify predictors of malignancy. Results: Histopathological analysis confirmed 389 malignant and 330 benign LNs. LN-RADS achieved 89% sensitivity, 85% specificity, and 87% accuracy in the diagnosis of malignant LN. The observed risk of malignancy by group was 0% for LN-RADS 1, 0% for LN-RADS 2, 2% for LN-RADS 3, 31% for LN-RADS 4a, 77% for LN-RADS 4b, and 97% for LN-RADS 5. Cohen’s kappa statistic indicated substantial inter-reader agreement. Among the evaluated features, the strongest predictor of malignancy was the cortex thickness diameter, with a threshold value of ≥6 mm (82% accuracy; AUC = 0.894). Conclusions: This study demonstrated the high efficacy of the LN-RADS system in distinguishing between benign and malignant lymph nodes and in stratifying malignancy risk. It also showed substantial inter-rater agreement. Full article
(This article belongs to the Special Issue Prevention, Screening and Early Detection of Cancer)
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17 pages, 1378 KiB  
Article
Papillary Thyroid Microcarcinoma in Thyroid Surgical Practice: Incidental vs. Non-Incidental: A Ten-Year Comparative Study
by Amani A. Bashir, Mohamed M. El-Zaheri, Ahmad A. Bashir, Luma Fayyad, Aiman H. Obed, Dima Alkam and Abdalla Y. Bashir
Cancers 2025, 17(12), 2029; https://doi.org/10.3390/cancers17122029 - 18 Jun 2025
Viewed by 342
Abstract
Background/Objectives: With evolving guidelines favoring de-escalation in the management of papillary thyroid microcarcinoma (PTMC), options such as active surveillance and minimally invasive procedures are now considered for patients with low-risk disease. However, a subset of PTMCs—particularly non-incidental cases—may exhibit aggressive behavior. This study [...] Read more.
Background/Objectives: With evolving guidelines favoring de-escalation in the management of papillary thyroid microcarcinoma (PTMC), options such as active surveillance and minimally invasive procedures are now considered for patients with low-risk disease. However, a subset of PTMCs—particularly non-incidental cases—may exhibit aggressive behavior. This study compares disease characteristics and outcomes between incidental and non-incidental PTMCs over a 10-year period. Methods: This is a single-center retrospective comparative analysis utilizing a prospectively collected database of patients referred for thyroid surgery. Results: Papillary thyroid carcinoma accounted for 86.7% of thyroid malignancies, with PTMC comprising 36.2% (137 patients). Incidental PTMC represented 109 out of 1012 patients undergoing surgery for benign thyroid disease (10.8%). Non-incidental PTMC (NIPTMC), diagnosed preoperatively and presenting clinically without coexisting thyroid disease, was identified in 28 patients (20.4%). NIPTMCs were more frequently associated with high-risk features (75% vs. 10.1%, p = 0.004), including extrathyroidal extension (21.43% vs. 7.3% p = 0.0015), positive central lymph nodes (21.43% vs. 2.8%, p = 0.0291), positive lateral lymph nodes (28.6% vs. 0% p = 0.012), and lymphovascular invasion (3.6% vs. 0%). Multifocal PTMC was seen in 37 patients (27%), of which 27 had bilobar disease. Multifocal tumors had a higher likelihood of high-risk features (48.6% vs. 14%, p = 0.007). NIPTMC was a significant predictor of multifocality (p = 0.0098). All patients underwent surgery, none opted for active surveillance. Conclusions: NIPTMC is more often associated with high-risk features and multifocality, necessitating more extensive surgery. These findings emphasize the need for careful preoperative risk stratification to guide individualized management. Full article
(This article belongs to the Section Cancer Metastasis)
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