Cancers

19 pages, 1482 KiB

Open AccessSystematic Review

Brain Metastases from Primary Cardiac Tumors: A Systematic Review of Diagnosis, Treatment, and Prognosis

by Salvatore Marrone, Ignazio Alessio Gueli, Roberta Lo Coco, Lorenzo Scalia, Salvatore Rizzica, Giuliana Baiamonte, Roberta Costanzo, Antonino Salvatore Rubino, Gianluca Ferini, Giuseppe Emmanuele Umana and Gianluca Scalia

Cancers 2025, 17(10), 1621; https://doi.org/10.3390/cancers17101621 (registering DOI) - 10 May 2025

Abstract

Background: Primary cardiac tumors (PCTs) are rare entities, with only a minority being malignant and capable of distant dissemination. Among the rarest and most challenging metastatic events are brain metastases originating from cardiac tumors. Due to the heart’s direct access to systemic circulation, [...] Read more.

Background: Primary cardiac tumors (PCTs) are rare entities, with only a minority being malignant and capable of distant dissemination. Among the rarest and most challenging metastatic events are brain metastases originating from cardiac tumors. Due to the heart’s direct access to systemic circulation, even benign tumors such as atrial myxomas may cause cerebral embolic phenomena. Understanding the distinct biological behavior, diagnostic pathways, therapeutic strategies, and prognostic implications of these cases remains limited by the scarcity of the available literature. Methods: A systematic review was conducted following PRISMA guidelines. PubMed, Scopus, Embase, and other major databases were systematically searched using specific MeSH terms and keywords related to cardiac tumors and brain metastases. After applying strict inclusion and exclusion criteria, nineteen studies were included, comprising sixteen single-patient case reports and three multi-patient series. Extracted data included tumor histology, cardiac and brain imaging findings, neurological presentation, treatment approaches, and patient outcomes. Results: A total of 320 patients were analyzed. Atrial myxomas represented the predominant benign tumors causing embolic cerebral events, while angiosarcomas and other cardiac sarcomas were responsible for true hematogenous brain metastases. Brain involvement was frequently hemorrhagic and manifested with seizures, focal deficits, or signs of intracranial hypertension. Cardiac echocardiography and cardiac magnetic resonance imaging (CMR) were essential for tumor detection, while brain MRI, including SWI and DWI sequences, and CT scanning were critical for cerebral lesion characterization. Treatment strategies varied according to tumor type and included surgery, radiotherapy, and systemic therapies. Malignant cardiac tumors correlated with a poor prognosis, with median survival post-CNS involvement ranging from 12 to 14 months. Conclusions: Brain metastases from PCTs, though rare, represent a distinct and serious clinical phenomenon. Benign tumors like myxomas mainly cause embolic cerebral events, whereas malignant tumors, particularly sarcomas, lead to true metastatic brain lesions. Recognizing this biological distinction is crucial for diagnosis, prognostication, and therapeutic planning. An integrated multidisciplinary approach combining advanced cardiac and neuroimaging techniques is vital for early detection and appropriate management. Despite multimodal treatment, survival remains limited, underscoring the urgent need for novel targeted therapies and improved surveillance strategies. Full article

(This article belongs to the Special Issue Cancer Cells Fostered Microenvironment in Metastasis)

14 pages, 2079 KiB

Open AccessArticle

The Association Between Heatmap Position and the Diagnostic Accuracy of Artificial Intelligence for Colorectal Polyp Diagnosis

by Ayla Thijssen, Nikoo Dehghani, Ruud W. M. Schrauwen, Eric T. P. Keulen, Eveline J. A. Rondagh, Mark H. P. van Avesaat, Khalida Soufidi, Ankie Reumkens, Paul H. A. Bours, Quirine E. W. van der Zander, Peter H. N. de With, Bjorn Winkens, Fons van der Sommen and Erik J. Schoon

Cancers 2025, 17(10), 1620; https://doi.org/10.3390/cancers17101620 (registering DOI) - 10 May 2025

Abstract

Background/Objectives: Artificial intelligence (AI) algorithms for diagnosing colorectal polyps are emerging but not yet widely used. Trust in AI is lacking and could be improved by visually explainable AI, such as heatmaps. This study aims to investigate the association between heatmap position and [...] Read more.

Background/Objectives: Artificial intelligence (AI) algorithms for diagnosing colorectal polyps are emerging but not yet widely used. Trust in AI is lacking and could be improved by visually explainable AI, such as heatmaps. This study aims to investigate the association between heatmap position and AI accuracy for the endoscopic characterization of colorectal polyps. Methods: Four AI algorithms diagnosed 2133 prospectively collected images of 376 colorectal polyps from two hospitals, using histopathology as the gold standard. Heatmap position was compared to the human-annotated polyp position. Generalized estimating equations were used to assess the association between heatmap position and a correct AI diagnosis. Results: Higher percentages of heatmap covering the colorectal polyp were associated with correct diagnoses in all four algorithms (OR 1.013 [95% CI 1.006–1.019], OR 1.025 [95% CI 1.011–1.039], OR 1.038 [95% CI 1.024–1.053], and OR 1.039 [95% CI 1.020–1.058]—all p < 0.001). A higher percentage of polyp not covered by heatmap was associated with a correct diagnosis of Algorithm 1 (OR 1.006 [95% CI 1.003–1.010], p < 0.001), while in Algorithm 2, a lower percentage was associated with a correct diagnosis (OR 0.992 [95% CI 0.985–1.000], p 0.044). Algorithms 3 and 4 showed negative, but not statistically significant, associations. Conclusions: Higher percentages of heatmap covering the polyp were associated with correct diagnoses of four AI algorithms. This indicates that it is clinically relevant to strive for AI predictions with heatmaps covering as much colorectal polyp tissue as possible. Knowing how to interpret heatmaps could increase trust in AI and, with that, benefit the implementation of AI in clinical practice. Full article

(This article belongs to the Special Issue Advanced Diagnostics and Optical Imaging Technologies in Cancer Research)

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18 pages, 2130 KiB

Open AccessArticle

Personalizing Neoadjuvant Chemotherapy: The Impact of BRCA Variants on Pathologic Complete Response in Luminal B Breast Cancer

by Alba Di Leone, Antonio Franco, Virginia Castagnetta, Marta Silenzi, Cristina Accetta, Beatrice Carnassale, Sabatino D’Archi, Flavia De Lauretis, Enrico Di Guglielmo, Federica Gagliardi, Stefano Magno, Francesca Moschella, Maria Natale, Alejandro Martin Sanchez, Lorenzo Scardina, Riccardo Masetti and Gianluca Franceschini

Cancers 2025, 17(10), 1619; https://doi.org/10.3390/cancers17101619 (registering DOI) - 10 May 2025

Abstract

Background: Neoadjuvant chemotherapy (NACT) is effective in downstaging locally advanced breast cancer, improving surgical and oncological outcomes. However, luminal B breast cancer typically exhibits a poorer response to NACT, with only 10–15% of patients achieving a pathologic complete response (pCR). This study [...] Read more.

Background: Neoadjuvant chemotherapy (NACT) is effective in downstaging locally advanced breast cancer, improving surgical and oncological outcomes. However, luminal B breast cancer typically exhibits a poorer response to NACT, with only 10–15% of patients achieving a pathologic complete response (pCR). This study investigates whether BRCA pathogenic variants (BRCA PVs) influence pCR rates in luminal B breast cancer patients, aiming to identify potential predictors for personalized treatment strategies. Materials and Methods: This retrospective study included luminal B breast cancer patients who underwent NACT at the Fondazione Policlinico Universitario Agostino Gemelli IRCCS between January 2014 and June 2023. Patients were stratified according to BRCA status: BRCA PVs and BRCA wild-type (WT). Primary endpoint was to evaluate pCR rates, while secondary endpoints included locoregional disease-free survival (LR-DFS), distant disease-free survival (DDFS), and overall survival (OS). Results: In total, 495 patients were enrolled, of whom 442 (89.3%) carried BRCA WT and 53 (10.7%) BRCA PVs. The pCR rate was significantly higher in the BRCA PVs group (20.8% PVs vs. 10.9% WT; p = 0.044). Specifically, the breast pCR rate was 28.3% in BRCA PVs versus 15.4% in BRCA WT (p = 0.030). BRCA WT patients had better 5-year LR-DFS (91.1% WT vs. 79.5% PVs; p = 0.003), while no significant differences were observed in 5-year DDFS or OS. Conclusions: BRCA PVs are associated with a higher pCR rate in luminal B breast cancer patients receiving NACT, suggesting a potential predictive role in tailoring treatment strategies. Full article

(This article belongs to the Special Issue Predictive and Prognostic Biomarkers for Response to Neoadjuvant Chemotherapy for Breast Cancer)

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13 pages, 1043 KiB

Open AccessReview

Current and Future Developments in Radiation Oncology Approach for Rhabdomyosarcoma

by Raquel Dávila Fajardo, Henriette Magelssen, Alison L. Cameron, Tom Boterberg and Henry C. Mandeville

Cancers 2025, 17(10), 1618; https://doi.org/10.3390/cancers17101618 (registering DOI) - 10 May 2025

Abstract

Radiotherapy is an indispensable treatment modality in the management of rhabdomyosarcoma. Numerous efforts have been made to improve outcomes. The current thinking and future developments in the radiation oncology field about how to raise cure rates, especially in the highest-risk patients, are presented. [...] Read more.

Radiotherapy is an indispensable treatment modality in the management of rhabdomyosarcoma. Numerous efforts have been made to improve outcomes. The current thinking and future developments in the radiation oncology field about how to raise cure rates, especially in the highest-risk patients, are presented. Full article

(This article belongs to the Special Issue Improving Treatment for Rhabdomyosarcoma: A Collaborative Approach through the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG))

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16 pages, 2323 KiB

Open AccessArticle

Real-Time Intraoperative Decision-Making in Head and Neck Tumor Surgery: A Histopathologically Grounded Hyperspectral Imaging and Deep Learning Approach

by Ayman Bali, Saskia Wolter, Daniela Pelzel, Ulrike Weyer, Tiago Azevedo, Pietro Lio, Mussab Kouka, Katharina Geißler, Thomas Bitter, Günther Ernst, Anna Xylander, Nadja Ziller, Anna Mühlig, Ferdinand von Eggeling, Orlando Guntinas-Lichius and David Pertzborn

Cancers 2025, 17(10), 1617; https://doi.org/10.3390/cancers17101617 (registering DOI) - 10 May 2025

Abstract

Background: Accurate and rapid intraoperative tumor margin assessment remains a major challenge in surgical oncology. Current gold-standard methods, such as frozen section histology, are time-consuming, operator-dependent, and prone to misclassification, which limits their clinical utility. Objective: To develop and evaluate a novel hyperspectral [...] Read more.

Background: Accurate and rapid intraoperative tumor margin assessment remains a major challenge in surgical oncology. Current gold-standard methods, such as frozen section histology, are time-consuming, operator-dependent, and prone to misclassification, which limits their clinical utility. Objective: To develop and evaluate a novel hyperspectral imaging (HSI) workflow that integrates deep learning with three-dimensional (3D) tumor modeling for real-time, label-free tumor margin delineation in head and neck squamous cell carcinoma (HNSCC). Methods: Freshly resected HNSCC samples were snap-frozen and imaged ex vivo from multiple perspectives using a standardized HSI protocol, resulting in a 3D model derived from HSI. Each sample was serially sectioned, stained, and annotated by pathologists to create high-resolution 3D histological reconstructions. The volumetric histological models were co-registered with the HSI data (n = 712 Datacubes), enabling voxel-wise projection of tumor segmentation maps from the HSI-derived 3D model onto the corresponding histological ground truth. Three deep learning models were trained and validated on these datasets to differentiate tumor from non-tumor regions with high spatial precision. Results: This work demonstrates strong potential for the proposed HSI system, with an overall classification accuracy of 0.98 and a tumor sensitivity of 0.93, underscoring the system’s ability to reliably detect tumor regions and showing high concordance with histopathological findings. Conclusion: The integration of HSI with deep learning and 3D tumor modeling offers a promising approach for precise, real-time intraoperative tumor margin assessment in HNSCC. This novel workflow has the potential to improve surgical precision and patient outcomes by providing rapid, label-free tissue differentiation. Full article

(This article belongs to the Special Issue Technical and Technological Innovations in Head and Neck Cancer Surgery)

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15 pages, 2373 KiB

Open AccessArticle

Real-World Data on the Associations of Tricyclic Antidepressants and Selective Serotonin Reuptake Inhibitors with Gynecologic Cancer Risk

by Ching-Huan Wang, Chih-Wei Huang, Nhi Thi Hong Nguyen, Ming-Chin Lin, Phung-Anh Nguyen, Md. Mohaimenul Islam, Shuo-Chen Chien and Hsuan-Chia Yang

Cancers 2025, 17(10), 1616; https://doi.org/10.3390/cancers17101616 (registering DOI) - 10 May 2025

Abstract

Background: While the potential anti-cancer effects of antidepressants have been investigated, limited research has been conducted incorporating age-specific analyses for individual tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs). This study aims to elucidate the associations between TCAs and SSRIs with [...] Read more.

Background: While the potential anti-cancer effects of antidepressants have been investigated, limited research has been conducted incorporating age-specific analyses for individual tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs). This study aims to elucidate the associations between TCAs and SSRIs with gynecologic cancers and to identify specific age groups and cancer types that may benefit from the chemopreventive effects of these medications. Methods: A case-control study comprised 97,736 female patients diagnosed with gynecologic cancers between 2002 and 2016. Each newly diagnosed case of cervical, ovarian, or uterine cancer was matched with four controls. Both cases and controls were then stratified by age to perform subgroup analyses. Associations between antidepressant use and cancer risk were evaluated using multivariable conditional logistic regression models. Results: The TCA class was significantly associated with reduced risks of cervical, ovarian, and uterine cancers, displaying adjusted odds ratios (aORs) of 0.799, 0.775, and 0.813, respectively. The SSRI class also indicated reduced risks, with aORs of 0.736, 0.638, and 0.567 for the same cancer types. Particularly noteworthy were females aged 40–64, who demonstrated the most significant associations between gynecologic cancers and using TCAs or SSRIs. Conclusions: TCAs and SSRIs are associated with reduced risks of developing cervical, ovarian, and uterine cancers. The middle-aged population may have the most significant potential for future research on drug repurposing against gynecologic cancers, and both cervical and uterine cancers are potential targets for drug repurposing involving TCAs or SSRIs. Full article

(This article belongs to the Special Issue Gynecologic Cancer: Risk Factors, Interception and Prevention)

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14 pages, 721 KiB

Open AccessReview

Role of Artificial Intelligence in Musculoskeletal Interventions

by Anuja Dubey, Hasaam Uldin, Zeeshan Khan, Hiten Panchal, Karthikeyan P. Iyengar and Rajesh Botchu

Cancers 2025, 17(10), 1615; https://doi.org/10.3390/cancers17101615 (registering DOI) - 10 May 2025

Abstract

Artificial intelligence (AI) has rapidly emerged as a transformative force in musculoskeletal imaging and interventional radiology. This article explores how AI-based methods—including machine learning (ML) and deep learning (DL)—streamline diagnostic processes, guide interventions, and improve patient outcomes. Key applications discussed include ultrasound-guided procedures [...] Read more.

Artificial intelligence (AI) has rapidly emerged as a transformative force in musculoskeletal imaging and interventional radiology. This article explores how AI-based methods—including machine learning (ML) and deep learning (DL)—streamline diagnostic processes, guide interventions, and improve patient outcomes. Key applications discussed include ultrasound-guided procedures for joints, nerves, and tumor-targeted interventions, along with CT-guided biopsies and ablations, and fluoroscopy-guided facet joint and nerve block injections. AI-powered segmentation algorithms, real-time feedback systems, and dose-optimization protocols collectively enable greater precision, operator consistency, and patient safety. In rehabilitation, AI-driven wearables and predictive models facilitate personalized exercise programs that can accelerate recovery and enhance long-term function. While challenges persist—such as data standardization, regulatory hurdles, and clinical adoption—ongoing interdisciplinary collaboration, federated learning models, and the integration of genomic and environmental data hold promise for expanding AI’s capabilities. As personalized medicine continues to advance, AI is poised to refine risk stratification, reduce radiation exposure, and support minimally invasive, patient-specific interventions, ultimately reshaping musculoskeletal care from early detection and diagnosis to individualized treatment and rehabilitation. Full article

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

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17 pages, 2739 KiB

Open AccessArticle

TP53 Mutation-Specific Dysregulation of Store-Operated Calcium Entry and Apoptotic Sensitivity in Triple-Negative Breast Cancer

by Kaneez E. Rabab, Paul J. Buchanan, Grace Colley, Anita White, Aisling Murphy, Chloe McCormack and Alex J. Eustace

Cancers 2025, 17(10), 1614; https://doi.org/10.3390/cancers17101614 (registering DOI) - 10 May 2025

Abstract

Background: Triple-negative breast cancer (TNBC) is an aggressive subtype lacking estrogen, progesterone, and HER2 receptors, and is associated with poor prognosis and limited targeted therapeutic options. TP53 mutations occur in the majority of TNBC cases, disrupting p53’s role in DNA repair and apoptosis. [...] Read more.

Background: Triple-negative breast cancer (TNBC) is an aggressive subtype lacking estrogen, progesterone, and HER2 receptors, and is associated with poor prognosis and limited targeted therapeutic options. TP53 mutations occur in the majority of TNBC cases, disrupting p53’s role in DNA repair and apoptosis. Beyond gene regulation, p53 also influences calcium signalling through store-operated calcium entry (SOCE), a critical pathway for cell survival and death. However, the impact of different TP53 mutation types on calcium signalling remains unclear. Methods: Calcium channel gene expression was analysed using publicly available TNBC datasets. Calcium channel expression and SOCE activity were assessed in TNBC cell lines with different TP53 mutations using quantitative PCR and calcium imaging (Fura-2AM). Cell proliferation was measured using acid phosphatase assays, while apoptosis was evaluated through caspase 3/7 activation using the Incucyte live-cell fluorescent imager. The p53 reactivator COTI-2 was tested for its ability to restore TP53 function and modulate calcium signalling. Results: Analysis revealed significant downregulation of CACNA1D in TP53-mutant TNBCs. TNBC cell lines harbouring frameshift and stop TP53 mutations exhibited reduced SOCE, lower CACNA1D expression, and resistance to thapsigargin-induced apoptosis compared to wild-type cells. In contrast, cells with the TP53 R273H missense mutation demonstrated similar calcium signalling and proliferation to TP53 wild-type cels. COTI-2 treatment restored CACNA1D expression and SOCE in frameshift and stop mutant cells, enhancing apoptotic sensitivity. Combined treatment with COTI-2 and thapsigargin resulted in a synergistic increase in apoptosis. Conclusions: This study identifies a novel link between TP53 mutation type and calcium signalling in TNBC. Reactivating mutant p53 with COTI-2 restores calcium-mediated apoptosis, supporting combination strategies targeting both TP53 dysfunction and calcium signalling. Full article

(This article belongs to the Special Issue Calcium Signaling in Cancer Cell Progression)

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28 pages, 2508 KiB

Open AccessReview

Molecular Mechanisms of Drug Resistance in Clear Cell Renal Cell Carcinoma

by Nicoletta Bianchi, Pietro Ancona and Gianluca Aguiari

Cancers 2025, 17(10), 1613; https://doi.org/10.3390/cancers17101613 (registering DOI) - 10 May 2025

Abstract

Renal cell carcinoma (RCC) accounts for about 3% of all human tumors. Alterations of oxygen, lipids, iron, and energy metabolism are involved in carcinogenesis, development, and expansion. Thirty percent of patients affected by clear cell renal cell carcinoma (ccRCC) will develop relapses or [...] Read more.

Renal cell carcinoma (RCC) accounts for about 3% of all human tumors. Alterations of oxygen, lipids, iron, and energy metabolism are involved in carcinogenesis, development, and expansion. Thirty percent of patients affected by clear cell renal cell carcinoma (ccRCC) will develop relapses or distance metastases (mRCC), dramatically reducing their life expectancy. Current first-line therapies for mRCC patients are based on treatment with immune checkpoint inhibitors (ICIs) alone and in combination with each other or with tyrosine kinase inhibitors (TKIs). However, only 20% of patients show a mild response because of innate or acquired drug resistance during long-term treatment; therefore, resistant patients need alternative first-line or second-line therapies. Pharmacological resistance represents a big problem that counteracts the efficacy of treatment by reducing overall survival (OS) in mRCC patients. Investigating the molecular mechanisms underlying drug resistance is crucial to overcoming drug insensitivity and enhancing therapeutic outcomes. In this review, we emphasize the latest and most significant studies on the molecular mechanisms that drive drug resistance in ccRCC carcinoma. Particular attention is given to the key signaling pathways involved in resistance, including those mediated by HIF, p53, Akt-mTOR, MEK–ERK cascades, Wnt signaling, autophagy, membrane transporters, ferroptosis, and non-coding RNAs. Understanding these resistance mechanisms is essential for developing new therapeutic strategies aimed to enhancing overall OS and improving the quality of life for mRCC patients. This review also discusses recent clinical trial findings on the use of specific inhibitors able to circumvent drug resistance. The data presented here could be valuable for clinicians in understanding the mechanisms of drug resistance, ultimately aiding in the management of ccRCC patients. Full article

(This article belongs to the Section Cancer Therapy)

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10 pages, 423 KiB

Open AccessArticle

MoLEP vs. HoLEP for BPH: A 3-Year Greek Single-Center Retrospective Comparative Cohort Study on 1368 Cases

by Panayiotis Veveloyiannis, Nikolaos Bafaloukas and Dimitra S. Mouliou

Cancers 2025, 17(10), 1608; https://doi.org/10.3390/cancers17101608 (registering DOI) - 10 May 2025

Abstract

Background: Holmium Laser Enucleation of the Prostate (HoLEP) is an established treatment for benign prostatic hyperplasia (BPH). Pulse-modulated lasers, like MOSES technology (MoLEP), may enhance the procedure’s efficiency and safety. Methods: A 3-year single-center retrospective comparative study was conducted on 1368 patients treated [...] Read more.

Background: Holmium Laser Enucleation of the Prostate (HoLEP) is an established treatment for benign prostatic hyperplasia (BPH). Pulse-modulated lasers, like MOSES technology (MoLEP), may enhance the procedure’s efficiency and safety. Methods: A 3-year single-center retrospective comparative study was conducted on 1368 patients treated with HoLEP/MoLEP at MITERA Hospital. Results: A total of 688 patients were treated with HoLEP and 680 with MoLEP. Compared to HoLEP, MoLEP demonstrated shorter surgical (50.5 min [IQR 33–60] vs. 58 min [IQR 46–69], p < 0.01) and enucleation times (34 min [IQR 23–43] vs. 43 min [IQR 34–51], p < 0.001) and shorter hospital stay (8 h [IQR 6–19] vs. 12 h [IQR 9–24], p = 0.027), catheterization time (19 h [IQR 12–48] vs. 24 h [IQR 24–48], p < 0.001), and irrigation duration (5 h [IQR 2–8] vs. 7 h [IQR 3–10], p < 0.001), with similar morcellated tissue weight and morcellation time. At 1 month, MoLEP showed higher Qmax (27.3 mL/s [IQR 23.9–30.3] vs. 20 mL/s [IQR 17–23.6], p < 0.001), lower PVR (11.4 mL [IQR 7.7–15] vs. 12.5 mL [IQR 7–18], p = 0.005), better IPSS (4 [IQR 3–6] vs. 7 [IQR 5–11], p < 0.005), QoL (1 [IQR 1–2] vs. 2 [IQR 1–2], p < 0.001), lower PSA (1.8 ng/mL [IQR 1.1–2.6] vs. 2.4 ng/mL [IQR 1.3–3.5], p < 0.001), which were maintained at 6 months, and fewer Clavien-Dindo I (2.5% vs. 7.5%, p < 0.001) and II (16% vs. 25.7%, p < 0.001) complications. Conclusions: MoLEP offered significant advantages over HoLEP in this study. Full article

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

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13 pages, 378 KiB

Open AccessReview

Whispers in the Lungs: Small Extracellular Vesicles in Lung Cancer and COPD Crosstalk

by Yetemwork Aleka, Fantahun Biadglegne and Ulrich Sack

Cancers 2025, 17(10), 1612; https://doi.org/10.3390/cancers17101612 (registering DOI) - 9 May 2025

Abstract

Lung cancer is one of the deadliest forms of cancer. Its prognosis becomes even worse when it co-occurs with other diseases, such as chronic obstructive pulmonary disease (COPD). Both illnesses have numerous shared risk factors, including the use of tobacco smoke, and have [...] Read more.

Lung cancer is one of the deadliest forms of cancer. Its prognosis becomes even worse when it co-occurs with other diseases, such as chronic obstructive pulmonary disease (COPD). Both illnesses have numerous shared risk factors, including the use of tobacco smoke, and have similar underlying mechanisms like long-term inflammation. There are some other less studied but equally important molecules, like small extracellular vesicles (sEVs), that have been shown to mediate effective communication at the cellular level and may affect the progression of a disease or cause resistance to therapies. In sEVs from lung cancer tumors, there are onco-proteins (e.g., tumor initiator EGFR mutations, onco-miR, miR-21), while in sEVs from patients with COPD, there are pro-inflammatory cytokines like IL-6 and TNF-α that enhance airway inflammation. These potential biomarkers of sEVs from chronic lung disease have great value in defense against emerging health problems; however, limitations in sample extraction and analysis are obstacles that hinder clinical enhanced applicability. This review focuses on sEV-derived biomarkers in lung cancer and COPD for diagnostic, prognostic, and therapeutic monitoring purposes. To make these molecules more useful in real-life therapy and determine their signature’s role, further investigation with a high-scale study is necessary. Full article

(This article belongs to the Special Issue Advancements in “Cancer Biomarkers” for 2025–2026)

16 pages, 528 KiB

Open AccessArticle

Ectopic Cushing’s Syndrome in Advanced Small-Cell Lung Cancer (SCLC): Clinical Challenges and Therapeutic Insights

by Aleksandra Gamrat-Żmuda, Mari Minasyan, Piotr J. Wysocki, Alicja Hubalewska-Dydejczyk and Aleksandra Gilis-Januszewska

Cancers 2025, 17(10), 1611; https://doi.org/10.3390/cancers17101611 - 9 May 2025

Abstract

Background/Objectives: Ectopic Cushing’s syndrome (ECS) is a rare, life-threatening condition caused by uncontrolled ACTH secretion from tumors, most commonly small-cell lung cancer (SCLC). ECS is traditionally reported in 1–6% of SCLC cases; however, recent data suggest it may be much higher. This study [...] Read more.

Background/Objectives: Ectopic Cushing’s syndrome (ECS) is a rare, life-threatening condition caused by uncontrolled ACTH secretion from tumors, most commonly small-cell lung cancer (SCLC). ECS is traditionally reported in 1–6% of SCLC cases; however, recent data suggest it may be much higher. This study compares the clinical presentation of SCLC-related ECS (ECS-SCLC) with other ECS etiologies and analyzes the diagnosis, treatment, and outcomes of ECS-SCLC. Methods: We retrospectively analyzed the records of 39 ECS patients diagnosed between 2000 and 2024 at a tertiary endocrinology center. Seven cases (18%) were due to SCLC. Diagnosis was based on clinical signs, biochemical testing, imaging, and histopathology. Results: ECS-SCLC patients (five men, two women; median age 61), compared to other ECS etiologies, had a shorter time to diagnosis (median 1 vs. 2 months; p = 0.03), worse general condition (ECOG 4 vs. 3; p = 0.01), greater muscle weakness (Lovett scale median 2[IQR 1–2] vs. 2[IQR 2–3]; p = 0.04), more severe hypokalemia (2.12 vs. 2.7 mmol/L; p = 0.03), and required higher potassium supplementation (200 vs. 120 mEq/day; p = 0.001). All ECS-SCLC patients experienced weight loss (median 5 kg). Cortisol-lowering therapy (metyrapone or osilodrostat) was initiated in six patients (mean initiation time 3.7 days), leading to clinical improvement. Oncological treatment (chemotherapy or radiotherapy) was administered in five patients after stabilization. The median follow-up time was 3 months. Conclusions: Early recognition of ECS-SCLC and a multidisciplinary approach are critical. Severe hypokalemia and muscle weakness should prompt timely evaluation for hypercortisolism. Cortisol-lowering therapy may improve clinical status and facilitate oncological treatment. Full article

(This article belongs to the Special Issue Neuroendocrine Tumors: From Diagnosis to Therapy)

22 pages, 886 KiB

Open AccessReview

PI3Kδ as a Novel Therapeutic Target for Aggressive Prostate Cancer

by Bi-Dar Wang, Alyssa Lucero, Siyoung Ha and Reyhaneh Yarmohammadi

Cancers 2025, 17(10), 1610; https://doi.org/10.3390/cancers17101610 - 9 May 2025

Abstract

Phosphoinositide 3-kinases (PI3Ks) signaling represents an important pathway regulating cell proliferation, survival, invasion, migration, and metabolism. Notably, PI3K/AKT/mTOR signaling is frequently dysregulated in the majority of malignancies. Among the class IA PI3Ks (PI3Kα/β/δ), emerging evidence has implicated that PI3Kδ is not only overexpressed [...] Read more.

Phosphoinositide 3-kinases (PI3Ks) signaling represents an important pathway regulating cell proliferation, survival, invasion, migration, and metabolism. Notably, PI3K/AKT/mTOR signaling is frequently dysregulated in the majority of malignancies. Among the class IA PI3Ks (PI3Kα/β/δ), emerging evidence has implicated that PI3Kδ is not only overexpressed in leukocytes but also in solid tumors, including prostate cancer. The critical role of PI3Kδ in tumorigenesis and in the creation of a suppressive tumor microenvironment, along with the recent finding of PI3Kδ splice isoforms in promoting tumor aggressiveness and resistance, further demonstrates the potential of developing novel PI3Kδ-targeted cancer therapies. In this review, we comprehensively describe the functional mechanisms underlying the PI3Kδ-driven tumor progression and immune regulation in prostate cancer diseases. Furthermore, the recent preclinical and clinical studies on the development of PI3Kδ-/PI3K-targeted inhibitors as single agents and in combination therapies (with chemotherapy, radiation, hormone therapy, or immunotherapy) are summarized. Finally, we discuss the potential novel therapies for improving the treatment efficacies, as well as the current limitations and challenges of PI3Kδ-based therapies for prostate cancer. Full article

(This article belongs to the Special Issue New Insights into Urologic Oncology)

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15 pages, 1289 KiB

Open AccessSystematic Review

Continuing Cyclin-Dependent Kinase 4/6 Inhibitors Beyond Progression in Advanced Breast Cancer: A Meta-Analysis

by Neha Pathak, Sudhir Kumar, Diego Malon Gimenez, Massimo Di Iorio, Jacqueline Savill, Yael Berner-Wygoda, Meredith Li, Consolacion Molto Valiente, Danielle Cuthbert, Aarushi Gupta, Diana P. Arteaga, Atul Batra, Eitan Amir and Abhenil Mittal

Cancers 2025, 17(10), 1609; https://doi.org/10.3390/cancers17101609 - 9 May 2025

Abstract

Background: The use of cyclin-dependent kinase 4/6 inhibitors (CDK 4/6i) with endocrine therapy (ET) is a first-line standard treatment for hormone receptor-positive (ER+) Human Epidermal Growth factor Receptor-2-negative (HER2-) advanced breast cancer. The data supporting incorporation of CDK 4/6i + ET beyond progression [...] Read more.

Background: The use of cyclin-dependent kinase 4/6 inhibitors (CDK 4/6i) with endocrine therapy (ET) is a first-line standard treatment for hormone receptor-positive (ER+) Human Epidermal Growth factor Receptor-2-negative (HER2-) advanced breast cancer. The data supporting incorporation of CDK 4/6i + ET beyond progression are variable. Here, we report a pooled analysis of this strategy. Methods: A systematic review identified reports of both observational and clinical studies, which evaluated the continuation of CDK4/6i beyond progression. The mean overall response rate (ORR) and progression-free survival (PFS) weighted by the study sample size were calculated. Meta-regression comprising linear regression weighted by the sample size (mixed effects) was performed to explore the association between disease and treatment-related factors and the benefit from continuing CDK4/6i. Quantitative significance was assessed using the Burnand criteria. Results: Thirteen studies comprising 1530 patients were included. The median age was 58 years, 50.8% had visceral metastases, and 48% had ESR1 mutations; the median lines of prior therapies were 1 (range 1–5), and 96.3% received palbociclib as the initial CDK4/6i. Eight studies tested a CDK4/6i switch as the intervention. The median PFS was 5.3 months, and the ORR was 14%. In randomized studies, statistically significant differences were observed between CDK4/6i continuation and control, although it is uncertain whether the magnitude of the effect is clinically meaningful. Increasing age, lack of prior chemotherapy, no visceral metastasis or ESR1 mutations, and a switch to a non-palbociclib CDK4/6i were associated with better outcomes. Conclusion: Continuing a CDK 4/6i + ET beyond progression yields modest benefits. Switching CDK4/6i likely results in improved ORR and PFS. Continuing palbociclib beyond progression is likely ineffectual. Full article

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

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23 pages, 2431 KiB

Open AccessReview

Unraveling the Burden of Pancreatic Cancer in the 21st Century: Trends in Incidence, Mortality, Survival, and Key Contributing Factors

by Jakob Zottl, Christian Günther Sebesta, Elena Tomosel, Marie-Christine Sebesta and Christian Sebesta

Cancers 2025, 17(10), 1607; https://doi.org/10.3390/cancers17101607 - 9 May 2025

Abstract

Background: PC has become a significant global health challenge, with incidence and mortality rates rising over the past three decades. While traditionally associated with aging, recent data indicate an increasing burden among younger populations. This study aims to analyze global trends in PC [...] Read more.

Background: PC has become a significant global health challenge, with incidence and mortality rates rising over the past three decades. While traditionally associated with aging, recent data indicate an increasing burden among younger populations. This study aims to analyze global trends in PC incidence and mortality and to identify key contributing factors, particularly modifiable risk factors such as obesity, diabetes, and smoking. Methods: Using data from the Global Burden of Disease Study (GBD) 2021, population-based cancer registries globally and nationally, systematic reviews and analysis trends in PC incidence, mortality and survival were analyzed. To assess epidemiological shifts, we utilized previously published annual percentage change (AAPC) values stratified by region, age group, and sex, as reported in the cited literature. Additionally, the influence of modifiable risk factors was evaluated to determine their contribution to rising incidence rates. Results: Between 1990 and 2021, the global incidence of PC increased by 8.9%, from 5.47 to 5.96 per 100,000, with the highest rates observed in high-Sociodemographic-Index (SDI) regions (10.00 per 100,000) and the lowest in low-SDI regions (1.59 per 100,000). Significant increases in incidence were noted in several countries, particularly among men in Iceland (AAPC 8.85) and women in Malta (AAPC 6.04). Early-onset PC is becoming more prevalent, especially among younger women. Modifiable risk factors, including obesity, diabetes, and smoking, play a critical role, with excess body weight contributing to 17.9% of PC cases and smoking to 13.9% in the United States (U.S.). Conclusions: The rising burden of PC, particularly among younger populations, highlights the need for targeted prevention strategies, early detection efforts, and further research into the underlying mechanisms driving these trends. Addressing modifiable risk factors could be key to mitigating the increasing incidence of this highly lethal cancer. Full article

(This article belongs to the Special Issue Diagnosis, Treatment and Prevention of Gastrointestinal Cancer (2nd Edition))

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11 pages, 448 KiB

Open AccessArticle

Sentinel Node Biopsy Using Two Concurrent Labeling Techniques (Radioactive Tracer With/Without Blue Dye vs. Indocyanin Green-ICG) in Early-Stage Endometrial Cancer Patients (TESLA–1): A Prospective Observational Study CEEGOG EX-02

by Maja Pakiz, David Cibula, Dariusz Grzegorz Wydra, Jaroslav Klat, Michal Zikan, Olga Matylevich, Renata Poncova, Anna Abacjew-Chmylko, Andrej Cokan, Martina Romanova, Filip Frühauf, Sambor Sawicki, Leyla Al Mahdawi, Roman Kocian, Zuzanna Mascianica, Jure Knez, Lukas Dostalek, Paulina Zygowska, Jiri Slama, Marek Murawski, Daniela Fischerova, Radoslaw Owczuk and Andraz Dovnik Show full author list Hide full author list

Cancers 2025, 17(10), 1606; https://doi.org/10.3390/cancers17101606 - 9 May 2025

Abstract

Background: While sentinel lymph node (SLN) biopsy has been integrated into international guidelines for endometrial cancer, a standardized technique is still lacking. This study addresses whether the concurrent use of two tracers, technetium-99 (Tc) and indocyanine green (ICG), administered intracervically through distinct techniques, [...] Read more.

Background: While sentinel lymph node (SLN) biopsy has been integrated into international guidelines for endometrial cancer, a standardized technique is still lacking. This study addresses whether the concurrent use of two tracers, technetium-99 (Tc) and indocyanine green (ICG), administered intracervically through distinct techniques, enhances the performance of SLN biopsies. As the blue dye is used routinely by some centers, it can be used alone; however, our analysis focused on only Tc and ICG (as is used in the majority of centers). Methods: A prospective multicentric observational study was designed to evaluate the unilateral detection rate, bilateral detection rates, sensitivity, and consistency of SLNs when using both tracers simultaneously in patients with early-stage endometrial cancer. Results: Our findings demonstrated that the simultaneous use of ICG and Tc significantly outperformed the use of either tracer alone. Unilateral detection rates were 69.2% for Tc, 84.9% for ICG, and 88.4% for both. Bilateral detection rates were 57.0% for Tc, 77.9% for ICG, and 83.6% for both. Additionally, the incidence of “empty pockets” was low with both tracers, at 2.7%. Notably, the concurrent application of both tracers identified instances where the Tc-labeled sentinel node differed from the ICG-labeled sentinel node. Conclusions: The combined use of Tc and ICG in SLN biopsy for early-stage endometrial cancer significantly enhances detection rates and reduces the occurrence of “empty pockets”, potentially decreasing the need for site-specific lymphadenectomy. Full article

(This article belongs to the Special Issue Clinicopathological Study of Gynecologic Cancer (2nd Edition))

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21 pages, 4595 KiB

Open AccessArticle

TIMP1 Overexpression in Ovarian Cancer Spheroids: Implications for Prognosis, Resistance, and Metastatic Potential

by Andrea Jemma, Alessandra Ardizzoia, Chiara Villa, Sara Bonomo, Mario Mauri, Carla Reale, Concetta Ambrosino, Massimiliano Cadamuro, Marialuisa Lavitrano and Donatella Conconi

Cancers 2025, 17(10), 1605; https://doi.org/10.3390/cancers17101605 - 9 May 2025

Abstract

Background: High dissemination potential and resistance to standard therapy significantly contribute to high mortality associated with ovarian cancer. Cancer stem cells (CSCs) drive tumor progression, metastasis, and recurrence after treatments’ failure. Here, we provide the first evidence of TIMP1 overexpression in ovarian CSCs, [...] Read more.

Background: High dissemination potential and resistance to standard therapy significantly contribute to high mortality associated with ovarian cancer. Cancer stem cells (CSCs) drive tumor progression, metastasis, and recurrence after treatments’ failure. Here, we provide the first evidence of TIMP1 overexpression in ovarian CSCs, suggesting its potential role as a prognostic biomarker. Methods: Different ovarian cancer cell models were used to explore the potential link between TIMP1 and stem-like phenotypes. Experiments included spheroid formation, drug treatments, gene expression, functional assays, and zebrafish xenograft models to assess cell behavior and molecular changes. Results: TIMP1 was overexpressed in CSCs, and its expression was also upregulated in chemoresistant and anoikis-resistant cells. Our database analysis revealed a correlation between TIMP1 expression levels and poor patient prognosis. Overexpression of TIMP1 in ovarian cancer cell lines was able to recapitulate several features of the ovarian cancer stem cell phenotype, including treatment resistance, expression of stem cell markers, and anoikis resistance. TIMP1-overexpressing cells also exhibited enhanced migration potential in vitro and increased metastatic potential in vivo. Moreover, TIMP1 overexpression significantly altered the transcriptome landscape of cells, highlighting its role in modulating critical pathways associated with cell migration and inflammation. Conclusions: This study identifies the pivotal role of TIMP1 in ovarian CSCs and its contribution to therapy resistance, recurrence, and metastasis. Full article

(This article belongs to the Special Issue Ovarian Cancer Biomarkers, Diagnostic, and Therapeutic Technologies 2nd Edition)

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21 pages, 4194 KiB

Open AccessReview

Deep Learning to Enhance Diagnosis and Management of Intrahepatic Cholangiocarcinoma

by Charalampos Theocharopoulos, Achilleas Theocharopoulos, Stavros P. Papadakos, Nikolaos Machairas and Timothy M. Pawlik

Cancers 2025, 17(10), 1604; https://doi.org/10.3390/cancers17101604 - 9 May 2025

Abstract

Intrahepatic cholangiocarcinoma (iCCA) is associated with a poor prognosis and necessitates a multimodal, multidisciplinary approach from diagnosis to treatment to achieve optimal outcomes. A noninvasive preoperative diagnosis using abdominal imaging techniques can represent a clinical challenge. Given the differential response of iCCA to [...] Read more.

Intrahepatic cholangiocarcinoma (iCCA) is associated with a poor prognosis and necessitates a multimodal, multidisciplinary approach from diagnosis to treatment to achieve optimal outcomes. A noninvasive preoperative diagnosis using abdominal imaging techniques can represent a clinical challenge. Given the differential response of iCCA to localized and systemic therapies compared with hepatocellular carcinoma and secondary hepatic malignancies, an accurate diagnosis is crucial. Deep learning (DL) models for image analysis have emerged as a promising adjunct for the abdominal radiologist, potentially enhancing the accurate detection and diagnosis of iCCA. Over the last five years, several reports have proposed robust DL models, which demonstrate a diagnostic accuracy that is either comparable to or surpasses that of radiologists with varying levels of experience. Recent studies have expanded DL applications into other aspects of iCCA management, including histopathologic diagnosis, the prediction of histopathological features, the preoperative prediction of survival, and the pretreatment prediction of responses to systemic therapy. We herein critically evaluate the expanding body of research on DL applications in the diagnosis and management of iCCA, providing insights into the current progress and future research directions. We comprehensively synthesize the performance and limitations of DL models in iCCA research, identifying key challenges that serve as a translational reference for clinicians. Full article

(This article belongs to the Section Cancer Therapy)

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15 pages, 1748 KiB

Open AccessArticle

Outcomes in Patients with Non-Small-Cell Lung Cancer with Brain Metastases: A Real-World Data Study from a Resource-Limited Country

by Nevena Randjelovic, Marina Petronijevic, Marina Calamac, Marija Peulic, Biljana Filipovic, Vladan Mutavdzic, Aleksandar Djuric, Teodora Rankovic, Milos Bugarcic, Ivana Canak, Jelena Mikov, Nebojsa Igrutinovic, Stela Novak, Marko Marjanovic, Jelena Perovic, Teodora Urosevic and Tanja Cufer

Cancers 2025, 17(10), 1603; https://doi.org/10.3390/cancers17101603 - 9 May 2025

Abstract

Background: Real-world data provide insights into populations underrepresented in clinical trials such as non-small-cell cancer (NSCLC) patients with brain metastases (BMs). Despite global survival improvement due to novel drug employment, their impact in resource-limited settings like Serbia remains underexplored. This study analyzes the [...] Read more.

Background: Real-world data provide insights into populations underrepresented in clinical trials such as non-small-cell cancer (NSCLC) patients with brain metastases (BMs). Despite global survival improvement due to novel drug employment, their impact in resource-limited settings like Serbia remains underexplored. This study analyzes the overall survival (OS) of NSCLC patients with BMs treated in routine clinical practice, considering patient-, disease- and treatment-related factors amid restricted access to novel drugs. Methods: We retrospectively analyzed 267 NSCLC patients diagnosed with BMs from 2018 to 2022 at a single Serbian clinical center. Inclusion required histologically confirmed NSCLC, radiologically verified BMs and complete clinical data. OS was defined as the time from BM verification to death or last follow-up. Kaplan–Meier curves and Cox regression were used for survival analysis. Results: Median OS (mOS) was 5.0 months. Univariate analysis linked age < 65 years, female gender, single BM, asymptomatic BMs, ECOG PS 0–1, BM verification at diagnosis and combined systemic and local therapy to better OS. Combined therapy offered the best survival rates (mOS: 9.0 months), while best supportive care and local-only therapy both resulted in a poor mOS of 2.0 months. Immunotherapy and targeted therapy were associated with the highest mOS, outperforming chemotherapy alone (13.0 vs. 7.0 months, p < 0.001). Multivariate analysis confirmed younger age, single BM, early BM verification and combined therapy as independent predictors of improved survival. Conclusions: limited access to novel therapies remains associated with poor patient survival, highlighting the need for better global availability. Full article

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

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27 pages, 707 KiB

Open AccessReview

Single-Agent and Associated Therapies with Monoclonal Antibodies: What About Follicular Lymphoma?

by Gabriella Cancemi, Chiara Campo, Santino Caserta, Iolanda Rizzotti and Donato Mannina

Cancers 2025, 17(10), 1602; https://doi.org/10.3390/cancers17101602 - 8 May 2025

Viewed by 191

Abstract

Monoclonal antibodies (mAbs) have become a cornerstone in the treatment of follicular lymphoma (FL), offering highly specific therapeutic targeting that enhances efficacy while minimizing systemic toxicity. Their mechanisms of action include antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and direct apoptotic signaling, effectively [...] Read more.

Monoclonal antibodies (mAbs) have become a cornerstone in the treatment of follicular lymphoma (FL), offering highly specific therapeutic targeting that enhances efficacy while minimizing systemic toxicity. Their mechanisms of action include antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and direct apoptotic signaling, effectively mediating malignant B-cell depletion. Anti-CD20 mAbs, such as rituximab and obinutuzumab, have significantly improved progression-free survival (PFS) and overall survival (OS), establishing immunochemotherapy as the standard of care for FL. However, the emergence of treatment resistance, often characterized by CD20 antigen downregulation or immune escape, has prompted the development of next-generation mAbs with enhanced effector functions. Bispecific antibodies (BsAbs), which simultaneously engage CD20-expressing tumor cells and CD3-positive cytotoxic T cells, have emerged as a novel immunotherapeutic strategy, redirecting T-cell activity to eliminate malignant B cells independently of major histocompatibility complex (MHC) antigen presentation. Additionally, antibody–drug conjugates (ADCs) offer a targeted cytotoxic approach by delivering potent chemotherapeutic payloads directly to tumor cells while limiting off-target effects. The integration of mAbs with immune checkpoint inhibitors and immunomodulatory agents is further enhancing treatment outcomes by overcoming immunosuppressive mechanisms within the tumor microenvironment. Despite these advancements, challenges remain, including optimizing the treatment sequence, mitigating immune-related toxicities—particularly cytokine release syndrome (CRS)—and identifying predictive biomarkers to guide patient selection. As the role of monoclonal antibodies continues to expand, their integration into therapeutic regimens is transforming the management of FL, paving the way for chemotherapy-free treatment approaches and long-term disease control. This review provides an updated overview of mAbs therapies for FL, emphasizing the advances brought by BsAbs and ADCs toward more tailored and effective treatments. Full article

(This article belongs to the Special Issue Monoclonal Antibodies in Lymphoma)

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28 pages, 1911 KiB

Open AccessReview

Long Non-Coding RNAs and RNA-Binding Proteins in Pancreatic Cancer Development and Progression

by Pit Preckwinkel, Khursheed Ul Islam Mir, Florian W. Otto, Hend Elrewany, Andrea Sinz, Stefan Hüttelmaier, Nadine Bley and Tony Gutschner

Cancers 2025, 17(10), 1601; https://doi.org/10.3390/cancers17101601 - 8 May 2025

Viewed by 231

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and is responsible for about 467,000 cancer deaths annually. An oftentimes asymptomatic early phase of this disease results in a delayed diagnosis, and patients often present with advanced disease. Current treatment [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and is responsible for about 467,000 cancer deaths annually. An oftentimes asymptomatic early phase of this disease results in a delayed diagnosis, and patients often present with advanced disease. Current treatment options have limited survival benefits, and only a minor patient population carries actionable genomic alterations. Hence, innovative personalized treatment strategies that consider molecular, cellular and functional analyses are urgently needed for pancreatic cancer patients. However, the majority of the genetic alterations found in PDAC are currently undruggable, or patients’ response is not as expected. Therefore, non-genomic biomarkers and alternative molecular targets should be considered in order to advance the clinical management of PDAC patients. In line with this, recent gene expression and single-cell transcriptome analyses have identified molecular subtypes and transcriptional cell states that affect disease progression and drug efficiency. In this review, we will introduce long non-coding RNAs (lncRNAs) as well as RNA-binding proteins (RBPs) that are able to modulate the transcriptome of a cell through diverse mechanisms, thereby contributing to disease progression. We will provide a brief overview about the general functions of lncRNAs and RBPs, respectively. Subsequently, we will highlight selected lncRNAs and RBPs that have been shown to play a role in PDAC development, progression and drug response. Finally, we will present strategies aiming to interfere with the expression and function of lncRNAs and RBPs. Full article

(This article belongs to the Special Issue Management of Pancreatic Cancer)

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16 pages, 533 KiB

Open AccessArticle

Real-World Management of High-Risk Prostate Cancer Post-Radical Prostatectomy: Insights from a Regional Quality Collaborative

by Aaron R. Hochberg, Annie H. Ho, Rasheed A. M. Thompson, Matthew B. Buck, Costas D. Lallas, Christine Ibilibor, Jeffrey J. Tomaszewski, Serge Ginzburg, Andres Correa, Robert Uzzo, Marc C. Smaldone, John F. Danella, Thomas J. Guzzo, Daniel J. Lee, Laurence Belkoff, Jeffrey Walker, Jay D. Raman, Roderick K. Clark, Adam Reese, Bruce Jacobs, Thomas Jang, Keith J. Kowalczyk, Meghan Smith and Mihir S. Shah Show full author list Hide full author list

Cancers 2025, 17(10), 1600; https://doi.org/10.3390/cancers17101600 - 8 May 2025

Viewed by 137

Abstract

Prostate cancer (CaP) remains the most diagnosed malignancy in men, and the incidence of high-grade disease at diagnosis is increasing [...] Full article

(This article belongs to the Special Issue Robot-Assisted Radical Prostatectomy for Urologic Cancer: State of the Art)

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34 pages, 1202 KiB

Open AccessReview

The Role of the Tumor Microenvironment in Pancreatic Ductal Adenocarcinoma: Recent Advancements and Emerging Therapeutic Strategies

by Franciszek Glapiński, Weronika Zając, Marta Fudalej, Andrzej Deptała, Aleksandra Czerw, Katarzyna Sygit, Remigiusz Kozłowski and Anna Badowska-Kozakiewicz

Cancers 2025, 17(10), 1599; https://doi.org/10.3390/cancers17101599 - 8 May 2025

Viewed by 200

Abstract

Pancreatic cancer (PC), with pancreatic ductal adenocarcinoma (PDAC) comprising about 90% of all cases, is one of the most aggressive and lethal solid tumors. PDAC remains one of the most significant challenges of oncology to this day due to its inadequate response to [...] Read more.

Pancreatic cancer (PC), with pancreatic ductal adenocarcinoma (PDAC) comprising about 90% of all cases, is one of the most aggressive and lethal solid tumors. PDAC remains one of the most significant challenges of oncology to this day due to its inadequate response to conventional treatment, gradual rise in incidence since 2004, and poor five-year survival rates. As cancer cells are the primary adversary in this uneven fight, they remain the primary research target. Nevertheless, increasing attention is being paid to the tumor microenvironment (TME). The most crucial TME constellation components are immune cells, especially macrophages, stellate cells and lymphocytes, fibroblasts, bacterial and fungal microflora, and neuronal cells. Depending on the particular phenotype of these cells, the composition of the microenvironment, and the cell ratio, patients can experience different disease outcomes and varying vulnerability to treatment approaches. This study aims to present the current knowledge and review the most up-to-date scientific findings regarding the microenvironment of PC. It contains detailed information on the structure and cellular composition of the stroma, including its impact on disease development, metastasis, and response to treatment, as well as the therapeutic opportunities that arise from targeting this tissue. Full article

(This article belongs to the Special Issue Advances in Pancreatic Ductal Adenocarcinoma Diagnosis and Treatment 2nd Edition)

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20 pages, 5630 KiB

Open AccessArticle

Deep Learning for Automated Ventricle and Periventricular Space Segmentation on CT and T1CE MRI in Neuro-Oncology Patients

by Mart Wubbels, Marvin Ribeiro, Jelmer M. Wolterink, Wouter van Elmpt, Inge Compter, David Hofstede, Nikolina E. Birimac, Femke Vaassen, Kati Palmgren, Hendrik H. G. Hansen, Hiska L. van der Weide, Charlotte L. Brouwer, Miranda C. A. Kramer, Daniëlle B. P. Eekers and Catharina M. L. Zegers

Cancers 2025, 17(10), 1598; https://doi.org/10.3390/cancers17101598 - 8 May 2025

Viewed by 112

Abstract

Purpose: This study aims to create a deep learning (DL) model capable of accurately delineating the ventricles, and by extension, the periventricular space (PVS), following the 2021 EPTN Neuro-Oncology Atlas guidelines on T1-weighted contrast-enhanced MRI scans (T1CE). The performance of this DL model [...] Read more.

Purpose: This study aims to create a deep learning (DL) model capable of accurately delineating the ventricles, and by extension, the periventricular space (PVS), following the 2021 EPTN Neuro-Oncology Atlas guidelines on T1-weighted contrast-enhanced MRI scans (T1CE). The performance of this DL model was quantitatively and qualitatively compared with an off-the-shelf model. Materials and Methods: An nnU-Net was trained for ventricle segmentation using both CT and T1CE MRI images from 78 patients. Its performance was compared to that of a publicly available pretrained segmentation model, SynthSeg. The evaluation was conducted on both internal (N = 18) and external (n = 18) test sets, with each consisting of paired CT and T1CE MRI images and expert-delineated ground truths (GTs). Segmentation accuracy was assessed using the volumetric Dice Similarity Coefficient (DSC), 95th percentile Hausdorff distance (HD95), surface DSC, and added path length (APL). Additionally, a local evaluation of ventricle segmentations quantified differences between manual and automatic segmentations across both test sets. All segmentations were scored by radiotherapy technicians for clinical acceptability using a 4-point Likert scale. Results: The nnU-Net significantly outperformed the SynthSeg model on the internal test dataset in terms of median [range] DSC, 0.93 [0.86–0.95] vs. 0.85 [0.67–0.91], HD95, 0.9 [0.7–2.5] mm vs. 2.2 [1.7–4.8] mm, surface DSC, 0.97 [0.90–0.98] vs. 0.84 [0.70–0.89], and APL, 876 [407–1298] mm vs. 2809 [2311–3622] mm, all with p < 0.001. No significant differences in these metrics were found in the external test set. However clinical ratings favored nnU-Net segmentations on the internal and external test sets. In addition, the nnU-Net had higher clinical ratings than the GT delineation on the internal and external test set. Conclusions: The nnU-Net model outperformed the SynthSeg model on the internal dataset in both segmentation metrics and clinician ratings. While segmentation metrics showed no significant differences between the models on the external set, clinician ratings favored nnU-Net, suggesting enhanced clinical acceptability. This suggests that nnU-Net could contribute to more time-efficient and streamlined radiotherapy planning workflows. Full article

(This article belongs to the Special Issue Clinical and Experimental Application of Artificial Intelligence in Neuro-Oncology Imaging)

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12 pages, 3464 KiB

Open AccessCommentary

The Central Role of Ribosomal Proteins in p53 Regulation

by Mikael S. Lindström

Cancers 2025, 17(10), 1597; https://doi.org/10.3390/cancers17101597 - 8 May 2025

Viewed by 138

Abstract

The tumor suppressor protein p53 prevents the malignant transformation of cells by responding to DNA damage, oncogene activation, and abnormal growth signals including ribosome assembly defects. Under normal conditions, p53 activity is controlled by the regulatory proteins MDM2 and MDM4, which suppress its [...] Read more.

The tumor suppressor protein p53 prevents the malignant transformation of cells by responding to DNA damage, oncogene activation, and abnormal growth signals including ribosome assembly defects. Under normal conditions, p53 activity is controlled by the regulatory proteins MDM2 and MDM4, which suppress its function through ubiquitin-mediated degradation and transcriptional inhibition. A subset of ribosomal proteins initiates the p53 response to impaired ribosome biogenesis. The ability of some ribosomal proteins to control MDM2 and MDM4 activities, and thereby p53, underscores an intriguing aspect of cell biology: proteins primarily known for their roles in ribosome function can exert extra-ribosomal functions. One notable example is the cellular RNA-protein complex involving RPL5, RPL11, and 5S rRNA (5S RNP) which inhibits MDM2 and stabilizes p53. Another RP, RPL22, is frequently mutated in cancers with microsatellite instability and its paralog RPL22L1 is often amplified. Recent studies have revealed that RPL22 directly modulates the alternative splicing of MDM4 to promote p53 activation, suggesting that the ribosomal protein-p53 relationship is more complex than previously thought. Cellular responses to ribosome biogenesis inhibition extend beyond general alterations in transcription and translation to actively determine cancer cell fate by selectively engaging tumor-suppressor pathways. RPL22’s effect on MDM4 and other mRNA splicing events is a striking example. A better understanding of the mechanisms involved could guide the development of improved cancer treatments. Full article

(This article belongs to the Special Issue Insights from the Editorial Board Member)

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13 pages, 402 KiB

Open AccessArticle

Predictors of High-Burden Residual Axillary Disease After Neoadjuvant Therapy in Breast Cancer

by Damiano Gentile, Jacopo Canzian, Erika Barbieri, Andrea Sagona, Simone Di Maria Grimaldi and Corrado Tinterri

Cancers 2025, 17(10), 1596; https://doi.org/10.3390/cancers17101596 - 8 May 2025

Viewed by 146

Abstract

Background: Neoadjuvant therapy (NAT) plays a crucial role in breast cancer (BC) management by enabling tumor and nodal downstaging. While axillary lymph node dissection (ALND) remains the standard for patients with residual nodal disease after NAT, its prognostic benefit is debated. Identifying predictors [...] Read more.

Background: Neoadjuvant therapy (NAT) plays a crucial role in breast cancer (BC) management by enabling tumor and nodal downstaging. While axillary lymph node dissection (ALND) remains the standard for patients with residual nodal disease after NAT, its prognostic benefit is debated. Identifying predictors of high-burden residual axillary disease may guide treatment intensification and surgical de-escalation strategies. Methods: We retrospectively analyzed 262 BC patients treated with NAT followed by ALND between 2006 and 2023. Patients were stratified into low- (ypN0-mi-1) and high-burden (ypN2-3) residual axillary disease groups. Univariate and multivariate logistic regression analyses were performed to identify independent predictors of high-burden residual disease. Results: High-burden residual axillary disease was observed in 35.9% of patients. Baseline cN+ status (OR = 7.697, p = 0.013), HR+/HER2− subtype (OR = 3.945, p = 0.003), and larger post-NAT tumor size (OR = 1.043, p < 0.001) were independent predictors. Conclusions: Identifying patients at risk of high-burden residual axillary disease is essential to optimize neoadjuvant strategies. Increasing axillary pathological complete response may reduce the need for ALND, minimizing surgical morbidity without compromising oncological outcomes. Full article

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

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