Cancers

11 pages, 543 KiB

Open AccessArticle

Prognostic Value of Preoperative Hemoglobin in Patients Undergoing Radical Prostatectomy for Localized Prostate Cancer

by Dominik Enderlin, Lea Hertelendy, Josias Bastian Grogg, Franz von Stauffenberg, Daniel Eberli and Cédric Poyet

Cancers 2025, 17(16), 2633; https://doi.org/10.3390/cancers17162633 - 12 Aug 2025

Abstract

Background: Hemoglobin (Hb) has been identified to be an independent prognostic marker for oncological outcomes in several malignancies. However, the impact of Hb levels before radical prostatectomy (RP) in localized prostate cancer remains unclear. Methods: Preoperative Hb levels were retrospectively collected [...] Read more.

Background: Hemoglobin (Hb) has been identified to be an independent prognostic marker for oncological outcomes in several malignancies. However, the impact of Hb levels before radical prostatectomy (RP) in localized prostate cancer remains unclear. Methods: Preoperative Hb levels were retrospectively collected from patients, who underwent RP from 2016 to 2022. Hb levels were analyzed as continuous and binary variables. For binary analysis, the cohort was divided into high-Hb (≥150 g/L) and low-Hb (<150 g/L) groups using the median as a cutoff. We used Spearman rank correlation to assess possible associations between Hb and continuous variables and logistic regression for Hb and binary variables. To assess the impact of preoperative Hb on recurrence-free survival (RFS), adjuvant treatment free survival (TFS), and metastasis-free survival (MFS), univariate and multivariate Cox regression analyses were performed. Results: A total of 567 patients were included in the analysis. Higher Hb levels, both when analyzed as a continuous variable and when divided in high and low groups, were inversely correlated with age (p < 0.001) and the International Society of Urological Pathology (ISUP) grade (p = 0.005 or p = 0.028, respectively). Patients in the high-Hb group showed a decreased risk of extraprostatic disease (≥pT3) (odds ratio [OR] 0.71, 95%-CI: 0.50–0.99, p = 0.047). In univariate cox regression analysis, high-Hb patients had a significantly longer RFS compared to the low-Hb group (hazard ratio [HR] 0.64, 95%-CI: 0.44–0.92, p = 0.015). When adjusting for age, ISUP grade, positive surgical margin, prostate specific antigen, nodal status, and ≥pT3, this effect was no longer statistically significant (HR 0.76, 95%-CI 0.56–1.22, p = 0.178). Hb was not a significant prognostic factor for TFS or MFS. Conclusions: In this large cohort, lower preoperative Hb values were associated with a more aggressive tumor grading and shorter RFS. However, we were unable to identify Hb as an independent predictor of oncological survival outcomes. Full article

(This article belongs to the Special Issue Clinical Studies and Outcomes in Urologic Cancer)

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40 pages, 480 KiB

Open AccessReview

The Role of Epigenetic Biomarkers as Diagnostic, Predictive and Prognostic Factors in Colorectal Cancer

by Zuzanna Chilimoniuk, Konrad Gładysz, Natalia Moniczewska, Katarzyna Chawrylak, Zuzanna Pelc and Radosław Mlak

Cancers 2025, 17(16), 2632; https://doi.org/10.3390/cancers17162632 - 12 Aug 2025

Abstract

Colorectal cancer (CRC) remains one of the leading causes of cancer-related morbidity and mortality worldwide. Despite significant advances in screening and treatment, the prognosis for advanced-stage disease continues to be poor. One thriving area of research focuses on the use of epigenetic alterations [...] Read more.

Colorectal cancer (CRC) remains one of the leading causes of cancer-related morbidity and mortality worldwide. Despite significant advances in screening and treatment, the prognosis for advanced-stage disease continues to be poor. One thriving area of research focuses on the use of epigenetic alterations for the diagnosis, prediction of treatment response, and prognosis of CRC. In this study, we evaluated original studies and meta-analyses published within the past five years to identify the most clinically relevant epigenetic biomarkers. DNA methylation-based assays, particularly those targeting SDC2 and SEPT9 in stool and plasma, exhibit superior diagnostic accuracy compared to other epigenetic modalities. Circulating microRNAs (miRNAs), including miR-211, miR-197, and miR-21, as well as specific long non-coding RNAs (lncRNAs) such as SNHG14, LINC01485, and ASB16-AS1, also show promising diagnostic potential. Furthermore, panels combining multiple epigenetic markers, especially those incorporating DNA methylation targets, have demonstrated improved sensitivity and specificity for early-stage CRC detection. In the context of therapeutic prediction, microRNAs such as miR-140, miR-21, and miR-4442 have been associated with chemotherapy resistance and recurrence risk. DNA methylation markers like LINE-1, mSEPT9 and ERCC1 have also shown predictive value, while lncRNAs including MALAT1 and GAS6-AS1 remain less validated. Regarding prognosis, miRNAs appear to be the most promising biomarkers, with miR-675-5p and miR-150 being associated with poor survival, while miR-767-5p and miR-215 predict favorable outcomes. Methylation of NKX6.1, IGFBP3, and LMX1A has been identified as an independent negative prognostic factor, while SFRP2 hypermethylation is linked to better prognosis. Selected lncRNAs, including THOR and LINC01094, have also demonstrated significant prognostic value. Despite these advances, challenges persist, including inconsistent reporting, limited external validation, and a lack of replication by independent research groups. Full article

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

28 pages, 3132 KiB

Open AccessArticle

Neutrophils in Cancer: Phenotypic Heterogeneity Across Tumor Models and Significant Alteration of Splenic Neutrophil Phenotype in Lymphosarcoma RLS₄₀ Model Following DNase I Treatment

by Khetam Sounbuli, Ludmila A. Alekseeva, Aleksandra V. Sen’kova, Oleg V. Markov, Innokenty A. Savin, Marina A. Zenkova and Nadezhda L. Mironova

Cancers 2025, 17(16), 2631; https://doi.org/10.3390/cancers17162631 - 12 Aug 2025

Abstract

Background/Objectives: Neutrophils have recently gained significant attention due to their heterogeneity in tumor settings. Recent data showed neutrophil pro- and anti-tumor profiles during tumor progression. However, the concessive causes of neutrophil skewing toward one or another profile are not fully understood. Methods [...] Read more.

Background/Objectives: Neutrophils have recently gained significant attention due to their heterogeneity in tumor settings. Recent data showed neutrophil pro- and anti-tumor profiles during tumor progression. However, the concessive causes of neutrophil skewing toward one or another profile are not fully understood. Methods: In this study, using RT-qPCR, flowcytometry, and confocal microscopy, we investigated the phenotype of splenic neutrophils of mice bearing Lewis lung carcinoma LLC, RLS₄₀ lymphosarcoma, and B16 melanoma. Results: Our data showed an immunosuppressive phenotype in the case of the LLC model with PD-L1 and IL10 expression. In the B16 model, minimal changes in the neutrophil phenotype were observed, regardless of tumor size. In the RLS₄₀ model, the neutrophil phenotype was associated with the tumor growth rate, where, in aggressively progressed tumors (RLS₄₀^High), CCL17 was expressed, while, in mice with controlled tumor growth (RLS₄₀^Low), anti-tumor markers were expressed (FAS, ICAM-1, PD-L1). DNase I treatment significantly reduced tumor growth and metastasis in the RLS₄₀ model but not in B16, enhanced the anti-tumor profile in RLS₄₀ neutrophils, and tended to reduce NET formation induced by A23187. Conclusions: The phenotype of neutrophils from tumor-bearing mice is influenced by the tumor type and progression stage. DNase I had anti-tumor, antimetastatic, and immunostimulatory effects and significantly modified the neutrophil profile in the immunogenic model RLS₄₀. Full article

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

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21 pages, 903 KiB

Open AccessSystematic Review

Targeting of Mutant Isocitrate Dehydrogenase in Glioma: A Systematic Review

by Tyler A. Lanman and L. Nicolas Gonzalez Castro

Cancers 2025, 17(16), 2630; https://doi.org/10.3390/cancers17162630 - 12 Aug 2025

Abstract

Background/Objectives: Mutant isocitrate dehydrogenase (IDH) inhibitors represent a major advance in precision oncology. The recent Food and Drug Administration approval of vorasidenib for IDH-mutant glioma highlights its therapeutic potential in this setting. As this and other mutant IDH inhibitors enter the clinical [...] Read more.

Background/Objectives: Mutant isocitrate dehydrogenase (IDH) inhibitors represent a major advance in precision oncology. The recent Food and Drug Administration approval of vorasidenib for IDH-mutant glioma highlights its therapeutic potential in this setting. As this and other mutant IDH inhibitors enter the clinical setting, providers are tasked with staying informed of the evolving therapeutic landscape as more is learned about this unique class of medications. We aimed to summarize insights from preclinical studies and clinical trials exploring their use in IDH-mutant glioma. Methods: We reviewed notable preclinical studies establishing the rationale for targeting mutant IDH. We performed a systematic review of clincaltrials.gov to identify both completed and ongoing interventional IDH-directed trials in patients with IDH-mutant glioma. Results: We identified 8 published and 15 ongoing clinical trials evaluating IDH-directed therapies. IDH inhibitors have been shown to slow and, in some cases, reverse glioma tumor growth, with activity that may extend beyond their currently approved indications. The presence of contrast enhancement is consistently a negative predictor of response for ivosidenib and vorasidenib, although safusidenib and olutasidenib preliminarily may retain efficacy in these cases. Novel approaches such as IDH-directed vaccines and combination therapy using mutant IDH inhibitors with immunotherapy are currently under active investigation. Conclusions: Mutant IDH inhibition is a promising, well-tolerated, and evolving approach for many patients with IDH-mutant glioma. Ongoing research will clarify its optimal clinical utility and potentially expand its indication. Full article

(This article belongs to the Special Issue Interrogating Molecular Regulators and Chemical Agents in Brain Tumor Progression)

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13 pages, 2448 KiB

Open AccessArticle

Pelvic Floor Functionality and Outcomes in Oncologic Patients Treated with Pelvic Bone Resection

by Edoardo Ipponi, Pier Luigi Ipponi, Fabrizia Gentili, Elena Bechini, Vittoria Bettarini, Paolo Domenico Parchi and Lorenzo Andreani

Cancers 2025, 17(16), 2629; https://doi.org/10.3390/cancers17162629 - 12 Aug 2025

Abstract

Background: Pelvic resections represent some of the most challenging procedures in orthopedic oncology, often necessitating the sacrifice of large bone segments and, subsequently, the loss of nearby soft tissues. Our study aims to evaluate the impact of surgical resections of pelvic bone tumors [...] Read more.

Background: Pelvic resections represent some of the most challenging procedures in orthopedic oncology, often necessitating the sacrifice of large bone segments and, subsequently, the loss of nearby soft tissues. Our study aims to evaluate the impact of surgical resections of pelvic bone tumors on the performance of the pelvic floor and digestive, urinary, and genital systems. Methods: We evaluated all malignant or locally aggressive pelvic bone tumors treated with bone resection in our institution between January 2017 and January 2024. The reconstructive approaches were recorded. Pre- and post-operative MRI and CT scans were used to evaluate the grade of pelvic prolapse. The prolapse of the pelvic floor was assessed with the M-line, the H-line, and the anorectal angle. Hydronephrosis was also evaluated. Urinary and fecal incontinence were evaluated with the Pelvic Floor Impact Questionnaire (PFIQ7). Results: Thirty cases were included in our study. Nine cases were treated with custom-made prostheses, five had ice-cone prostheses, two massive allografts, and one composite allograft-prosthesis. The others had no bone reconstruction. Meshes were used to reconstruct the pelvic floor in 9 cases. Patients with discontinuity of the pelvic ring had a significantly higher grade of pelvic prolapse (M-line) and worse PFIQ7 scores. Conclusions: The resection of pelvic bone tumors represents one of the main challenges in orthopedic oncology. While planning surgical demolition and performing the subsequent reconstruction, surgeons should also consider the impact of the surgical treatment on the pelvic floor and surrounding organs. Intra-operative reconstructions and post-operative rehabilitation are advisable. Full article

(This article belongs to the Special Issue Sarcoma Management in Orthopaedic Oncology)

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40 pages, 2934 KiB

Open AccessReview

Nanoparticle-Based Delivery Strategies for Combating Drug Resistance in Cancer Therapeutics

by Seohyun Park, Guo-Liang Lu, Yi-Chao Zheng, Emma K. Davison and Yan Li

Cancers 2025, 17(16), 2628; https://doi.org/10.3390/cancers17162628 - 11 Aug 2025

Abstract

Multidrug resistance (MDR) remains a formidable barrier to successful cancer treatment, driven by mechanisms such as efflux pump overexpression, enhanced DNA repair, evasion of apoptosis and the protective characteristics of the tumour microenvironment. Nanoparticle-based delivery systems have emerged as promising platforms capable of [...] Read more.

Multidrug resistance (MDR) remains a formidable barrier to successful cancer treatment, driven by mechanisms such as efflux pump overexpression, enhanced DNA repair, evasion of apoptosis and the protective characteristics of the tumour microenvironment. Nanoparticle-based delivery systems have emerged as promising platforms capable of addressing these challenges by enhancing intracellular drug accumulation, enabling targeted delivery and facilitating stimuli-responsive and controlled release. This review provides a comprehensive overview of the molecular and cellular mechanisms underlying MDR and critically examines recent advances in nanoparticle strategies developed to overcome it. Various nanoparticle designs are analysed in terms of their structural and functional features, including surface modifications, active targeting ligands and responsiveness to tumour-specific cues. Particular emphasis is placed on the co-delivery of chemotherapeutic agents with gene regulators, such as siRNA, and the use of nanoparticles to deliver CRISPR/Cas9 gene editing tools as a means of re-sensitising resistant cancer cells. While significant progress has been made in preclinical settings, challenges such as tumour heterogeneity, limited clinical translation and immune clearance remain. Future directions include the integration of precision nanomedicine, scalable manufacturing and non-viral genome editing platforms. Collectively, nanoparticle-based drug delivery systems offer a multifaceted approach to combat MDR and hold great promise for improving therapeutic outcomes in resistant cancers. Full article

(This article belongs to the Special Issue Integrating Precision Medicine with Nanotechnology to Overcome Drug Resistance in Cancer)

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14 pages, 2557 KiB

Open AccessArticle

An In Silico Feasibility Study of Dose-Escalated Hypofractionated Proton Therapy for Rectal Cancer

by Erik Almhagen, Ali Alkhiat, Bruno Sorcini, Freja Alpsten, Camilla J. S. Kronborg, Heidi S. Rønde, Marianne G. Guren, Sara Pilskog and Alexander Valdman

Cancers 2025, 17(16), 2627; https://doi.org/10.3390/cancers17162627 - 11 Aug 2025

Abstract

Background/Objectives: The current standard treatment for locally advanced rectal cancer (LARC) is neoadjuvant chemoradiotherapy, or total neoadjuvant therapy (TNT), followed by total mesorectal excision (TME). If the neoadjuvant treatment results in a clinical complete response (cCR), non-operative management of LARC might be [...] Read more.

Background/Objectives: The current standard treatment for locally advanced rectal cancer (LARC) is neoadjuvant chemoradiotherapy, or total neoadjuvant therapy (TNT), followed by total mesorectal excision (TME). If the neoadjuvant treatment results in a clinical complete response (cCR), non-operative management of LARC might be possible. It is hypothesized that cCR rates will increase with increasing radiotherapy doses. By using proton therapy, doses to organs at risk (OAR) may be decreased. In preparation for a clinical trial on dose-escalated proton therapy for LARC, the purpose of this study is to establish the feasibility of proton therapy for dose-escalated hypofractionated radiotherapy of LARC. Methods: Ten patients, having previously received short course radiotherapy (SCRT) for LARC, were included in this planning study. Two photon plans and two proton plans were created for each patient: one with a standard 5 × 5 Gy fractionation and one dose-escalated up to 5 × 7 Gy. Proton plans were robustly optimized. For all plans the integral dose (ID) was computed, and for the proton plans relative biological effectiveness (RBE) distributions were calculated. Feasibility was assessed in terms of target coverage and OAR doses. Results: All treatment plans satisfied target coverage criteria. Three of the photon and two of the proton dose-escalated plans exceeded recommended OAR objectives. Proton IDs were on average lower by a factor of 1.97 compared to photon IDs. Mean doses to OAR were, in general, lower for protons. All proton RBE values in the escalated target volumes were between 1.09 and 1.16. Conclusions: The proposed dose escalation was found to be feasible. Protons can reduce the integral dose and mean doses to OARs compared to photons in both the dose-escalated and non-escalated cases. Differences in RBE between escalated and standard fractionation were small. Full article

(This article belongs to the Special Issue The Advance of Pencil Beam Scanning Proton Beam Therapy in Cancers)

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12 pages, 330 KiB

Open AccessArticle

Real Life Evolution of Surgical Approaches in the Management of Endometrial Cancer in Poland

by Agnieszka Rychlik, Tomasz Kluz, Grzegorz Szewczyk, Pluvio J. Coronado, Tomasz Łatkiewicz, Rafał Tarkowski, Anna Woińska-Przekwas, Krzysztof Nowosielski, Kaja Skowronek, Rafał Stojko, Michał Skuza, Marcin Misiek, Krzysztof Jabłoński, Paweł Sadłecki, Marta Ciosek, Katarzyna Pasicz, Anna Bogaczyk and Mariusz Bidziński

Cancers 2025, 17(16), 2626; https://doi.org/10.3390/cancers17162626 - 11 Aug 2025

Abstract

Objective: The primary objective of this study was to evaluate the evolution of surgical approaches in the management of endometrial cancer in Polish tertiary referral hospitals, comparing the use of minimally invasive surgery (MIS) and laparotomy in 2023 versus 2013. Methods: This retrospective [...] Read more.

Objective: The primary objective of this study was to evaluate the evolution of surgical approaches in the management of endometrial cancer in Polish tertiary referral hospitals, comparing the use of minimally invasive surgery (MIS) and laparotomy in 2023 versus 2013. Methods: This retrospective observational study analyzed data from tertiary referral centers in Poland. All surgeries performed for apparently early-stage endometrial cancer in 2013 and 2023 were included. Results: A total of 1062 patients were analyzed, with 417 undergoing operations in 2013 and 640 in 2023. In 2013, 92.6% (386/417) of patients underwent laparotomy. By 2023, 80.1% (513/640) of patients were treated using minimally invasive approaches, including laparoscopy (56.2%, 362/640), robotic-assisted laparoscopy (21.7%, 139/640), and vaginal surgery (1.9%, 12/640). No conversions to laparotomy were recorded in 2013. In 2023, 22 conversions occurred—21 in the laparoscopy group (5.8%, 21/362) and one in the vaginal surgery group (8.3%, 1/12). No conversions were reported in the robotic-assisted group. Intraoperative complications were observed in 2.2% (8/362) of laparoscopic cases, and postoperative complications in 4.4% (16/362). In the robotic-assisted group, one intraoperative complication (0.7%) was reported, with no postoperative complications. Conclusions: Over the past decade, there has been a significant shift in the surgical management of endometrial cancer in Poland, with a growing preference for minimally invasive surgery (MIS). The rate of conversion from MIS to laparotomy remains below 6%. Robotic-assisted laparoscopic surgery may offer additional benefits, particularly for obese patients. Full article

(This article belongs to the Special Issue Advances in Surgical Treatment of Gynecological Cancers)

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23 pages, 508 KiB

Open AccessSystematic Review

AI-Driven Innovations in Neuroradiology and Neurosurgery: Scoping Review of Current Evidence and Future Directions

by Bartosz Szmyd, Małgorzata Podstawka, Karol Wiśniewski, Karol Zaczkowski, Tomasz Puzio, Arkadiusz Tomczyk, Adam Wojciechowski, Dariusz J. Jaskólski and Ernest J. Bobeff

Cancers 2025, 17(16), 2625; https://doi.org/10.3390/cancers17162625 - 11 Aug 2025

Abstract

Background/Objectives: The rapid development of artificial intelligence is transforming the face of medicine. Due to the large number of imaging studies (pre-, intra-, and postoperative) combined with histopathological and molecular findings, its impact may be particularly significant in neurosurgery. We aimed to [...] Read more.

Background/Objectives: The rapid development of artificial intelligence is transforming the face of medicine. Due to the large number of imaging studies (pre-, intra-, and postoperative) combined with histopathological and molecular findings, its impact may be particularly significant in neurosurgery. We aimed to perform a scoping review of recent applications of deep learning in MRI-based diagnostics of brain tumors relevant to neurosurgical practice. Methods: We conducted a systematic search of scientific articles available in the PubMed database. The search was performed on 22 April 2024, using the following query: ((MRI) AND (brain tumor)) AND (deep learning). We included original studies that applied deep-learning methods to brain tumor diagnostics using MRI, with potential relevance to neuroradiology or neurosurgery. A total of 893 records were retrieved, and after title/abstract screening and full-text assessment by two independent reviewers, 229 studies met the inclusion criteria. The study was not registered and received no external funding. Results: Most included articles were published after 1 January 2022. The studies primarily focused on developing models to differentiate between specific CNS tumors. With improved radiological analysis, deep-learning technologies can support surgical planning through enhanced visualization of cerebral vessels, white matter tracts, and functional brain areas. Over half of the papers (52%) focused on gliomas, particularly their detection, grading, and molecular characterization. Conclusions: Recent advancements in artificial intelligence methods have enabled differentiation between normal and abnormal CNS imaging, identification of various pathological entities, and, in some cases, precise tumor classification and molecular profiling. These tools show promise in supporting both diagnosis and treatment planning in neurosurgery. Full article

(This article belongs to the Special Issue Applications of Imaging Techniques in Neurosurgery)

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19 pages, 1655 KiB

Open AccessArticle

Gene Expression in Muscle-Invasive and Non-Muscle-Invasive Bladder Cancer Cells Exposed to Hypoxia

by Rekaya Shabbir, Conrado G. Quiles, Brian Lane, Leo Zeef, Peter J. Hoskin, Ananya Choudhury, Catharine M. L. West and Tim A. D. Smith

Cancers 2025, 17(16), 2624; https://doi.org/10.3390/cancers17162624 - 11 Aug 2025

Abstract

Introduction: Hypoxic cancers are radioresistant, but biomarkers based on expression of multiple genes can identify patients who will benefit from hypoxia modification. Most studies identifying relevant genes exposed cells in culture to 1% oxygen, which activates hypoxia-inducible factor (HIF). However, oxygen concentrations in [...] Read more.

Introduction: Hypoxic cancers are radioresistant, but biomarkers based on expression of multiple genes can identify patients who will benefit from hypoxia modification. Most studies identifying relevant genes exposed cells in culture to 1% oxygen, which activates hypoxia-inducible factor (HIF). However, oxygen concentrations in hypoxic tumours are heterogeneous ranging from <0.1%. As lower oxygen levels would likely affect transcriptional responses, we aimed to investigate how gene selection at different oxygen levels affects the genes identified and their prognostic capability. Methods: Four MIBC (J82, T24, UMUC3, HT1376) and two non-MIBC (RT4, RT112) bladder cancer cell lines were exposed to varying oxygen levels (20%, 1%, 0.2% and 0.1% O₂) for 24 h and were then harvested and frozen. RNA was extracted and transcriptomes analysed using Clariom S microarrays. Differences in gene expression were investigated. Prognostic and predictive significance of a published 24-gene signature was compared with one generated from genes identified at lower oxygen levels. Results: The number of upregulated genes increased with decreasing O₂ level. The number of biological pathways involved also increased. Differences between cell lines dominated those due to hypoxia. Some genes were commonly upregulated in MIBC and NMIBC cells and others increased exclusively in either MIBC or NMIBC cells. The median expression of a published 24-gene bladder cancer hypoxia-associated signature increased with decreasing oxygen levels. Seventy-seven genes were upregulated in at least three cell lines by exposure to 0.1% O₂. The median expression of the 77 genes was of borderline prognostic significance in the bladder cancer cohort in the TCGA (The Cancer Genome Atlas). Five of the seventy-seven genes upregulated by hypoxia were present in the twenty-four-gene bladder hypoxia signature. The median expression of the 5 genes demonstrated identical prognostication to the 24-gene signature but failed to predict benefit from hypoxia modification. Conclusions: The number of genes upregulated by exposure of bladder cancer cells to hypoxia increases as O₂ level is decreased from 1% to 0.2% to 0.1%. Differential upregulation of gene expression by MIBC and NMIBC cells and the associated biological pathways may be useful in understanding the genetics of bladder cancer invasiveness. Based on a search of the literature, this is the first study that assessed the expression of genes in bladder cancer using three hypoxic concentration levels to identify biomarkers for disease progression and prognosis among differentially expressed bladder cancer genes. Full article

(This article belongs to the Special Issue Application of Large-Scale Genome Data in Identifying Clinically Actionable Targets in Cancer)

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15 pages, 3609 KiB

Open AccessArticle

Activation of G Protein-Coupled Estrogen Receptor Induces p53 and ADAMTS1 to Inhibit Tumor Growth and Suppress Liver Cancer Metastasis

by Hee Jung Kwon, Ga Seul Lee, Jeong Hee Moon and Joohee Jung

Cancers 2025, 17(16), 2623; https://doi.org/10.3390/cancers17162623 - 11 Aug 2025

Abstract

Background/Objectives: Liver cancer is a common cause of cancer-related deaths among men and women globally. A disintegrin and metalloproteinase with thrombospondin motif 1 (ADAMST1) has been associated with various cancers, including prostate, esophageal, renal, and breast cancers. However, its role in liver [...] Read more.

Background/Objectives: Liver cancer is a common cause of cancer-related deaths among men and women globally. A disintegrin and metalloproteinase with thrombospondin motif 1 (ADAMST1) has been associated with various cancers, including prostate, esophageal, renal, and breast cancers. However, its role in liver cancer remains unclear. The aim of this study was to investigate the relationship between G protein-coupled estrogen (GPER) activation via its agonist, G1, and ADAMTS1 in suppressing liver cancer metastasis. Methods: Following preliminary assessment of Hep3B, Huh7, and SK-Hep-1 cells, SK-Hep-1 cells were selected owing to their elevated GPER expression and reduced cell viability. Cells were subjected to flow cytometry, RNA sequencing, and proteomics analyses. We established an SK-Hep-1 xenograft model for in vivo analysis. Results: We observed G1-induced G2-M phase cell cycle arrest, increased p53 and p21, and decreased cell cycle-related factors. In vivo, G1 significantly inhibited tumor growth and increased p53 protein expression. ADAMTS1, a metastasis regulator, was significantly upregulated by G1. G1 reduced the proliferating cell nuclear antigen and increased E-cadherin expression in SK-Hep-1 cells and in vivo. Tumor invasion was reduced with G1 and ADAMTS1 expression. In vivo, G1 reduced liver metastasis, increased E-cadherin, and decreased vimentin and proliferating cell nuclear antigen in primary tumor tissues and increased ADAMTS1 at the tumor edge. Conclusions: GPER agonists, such as G1, show potential for suppressing liver cancer progression and metastasis. Full article

(This article belongs to the Special Issue Liver Cancer: Improving Standard Diagnosis and Therapy: 2nd Edition)

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17 pages, 1285 KiB

Open AccessFeature PaperArticle

Preliminary Outcomes of a Digital Remote Care Solution for Colorectal Cancer Patients

by Marta Chaparro-Mirete, Cristina González Callejas, María de los Ángeles García-Martínez, Jorge Ramos-Sanfiel, Maria Sol Zurita-Saavedra, Paola De Castro-Monedero, Javier Gómez-Sánchez, Ángela Argote-Camacho, Alfredo Ubiña-Martínez, Cristina González-Puga, Carlos Garde-Lecumberri, Teresa Nestares and Benito Mirón-Pozo

Cancers 2025, 17(16), 2622; https://doi.org/10.3390/cancers17162622 - 11 Aug 2025

Abstract

Background/Objectives: Colorectal cancer (CRC) ranks third in the Western world in cancer incidence and second as the cause of cancer-related deaths. Despite advances in perioperative care, minimizing postoperative morbidity is crucial in clinical practice. Digitalization of the healthcare process plays a key [...] Read more.

Background/Objectives: Colorectal cancer (CRC) ranks third in the Western world in cancer incidence and second as the cause of cancer-related deaths. Despite advances in perioperative care, minimizing postoperative morbidity is crucial in clinical practice. Digitalization of the healthcare process plays a key role in genuinely and effectively engaging patients. Our aim was to evaluate a digital solution for remote monitoring of patients with CRC, from surgery indication to postoperative discharge. Methods: We developed a digital solution using Value Stream Mapping (VSM) to identify patient care flow and Lean Sigma for optimization and efficiency. We incorporated the Enhanced Recovery After Surgery (ERAS)/RICA pentamodal recommendations to create a program with an individualized schedule for each patient, who received tailored educational, medical, and practical information at every stage of the process. Results: A total of 193 patients used the digital solution, with >75% adhering to ERAS recommendations. The median length of hospital stay was 5 days, with low adherence leading to 3.4 (p = 0.628) or 3.27 (p = 0.642) extra days in the hospital compared to patients with intermediate and high adherence, respectively. The mean comprehensive complication index (CCI) was 9.1/100, which was higher in patients with low adherence (15) versus intermediate (8.17; p = 0.027) and high (7.42; p = 0.011) adherence. An increase in self-perception of quality of life by 9.2% was identified at the end of the process compared to the outcome at the beginning (p = 0.09), and 80% rated their overall satisfaction with the care process as 8 or higher out of 10. Conclusions: The digital solution facilitates the monitoring of CRC care and implementation and adherence to ERAS recommendations, improving patient engagement and satisfaction. Full article

(This article belongs to the Special Issue Rehabilitation Opportunities in Cancer Survivorship)

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14 pages, 1084 KiB

Open AccessPerspective

Stem Cell Origin of Cancer: Biological Principles and Clinical Strategies for Chemoprevention and Maintenance Therapy in Cancer Care

by Yusra Medik, Sehrish Sardar, Jaskirat S. Sethi, Marcelo P. Bigarella, Sunny R. K. Singh and Shi-Ming Tu

Cancers 2025, 17(16), 2621; https://doi.org/10.3390/cancers17162621 - 11 Aug 2025

Abstract

In this Perspective, we discuss a stem cell origin of cancer and consider the biological principles and clinical strategies for chemoprevention in cancer care. We examine the role of vitamin D, tumor microenvironment, and GLP-1R agonists in chemoprevention and maintenance therapy. If cancer [...] Read more.

In this Perspective, we discuss a stem cell origin of cancer and consider the biological principles and clinical strategies for chemoprevention in cancer care. We examine the role of vitamin D, tumor microenvironment, and GLP-1R agonists in chemoprevention and maintenance therapy. If cancer were a stem cell disease, then keeping stem cells pristine and healthy would be essential and keeping cancer stem cells (CSC) dormant and innocuous necessary. According to a stem cell (unified) theory of cancer, chemoprevention is effective when we refrain from disturbing CSCs and/or inciting non-CSCs with inflammatory factors and/or insulinemic habits. We postulate that many effective chemoprevention (and anti-cancer) treatments modulate stem-ness/stem-like cells and operate through anti-stem-ness/stem-like mechanisms. They affect progenitor stem cells versus progeny differentiated cells as well as their malignant counterparts and respective microenvironments. We propose that to fulfill the visions and missions of cancer prevention, it is imperative to first formulate a pertinent scientific theory and then adopt and adhere to the proper scientific method in our conduct of cancer research and provision of cancer care. Full article

(This article belongs to the Special Issue Stem Cell Origin of Cancers: Biological and Clinical Implications of a Unified Theory of Cancer (2nd Edition))

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13 pages, 1609 KiB

Open AccessArticle

A Decision-Making Method for Photon/Proton Selection for Nasopharyngeal Cancer Based on Dose Prediction and NTCP

by Guiyuan Li, Xinyuan Chen, Jialin Ding, Linyi Shen, Mengyang Li, Junlin Yi and Jianrong Dai

Cancers 2025, 17(16), 2620; https://doi.org/10.3390/cancers17162620 - 11 Aug 2025

Abstract

Introduction: Decision-making regarding radiotherapy techniques for patients with nasopharyngeal cancer requires a comparison of photon and proton plans generated using planning software, which requires time and expertise. We developed a fully automated decision tool to select patients for proton therapy that predicts [...] Read more.

Introduction: Decision-making regarding radiotherapy techniques for patients with nasopharyngeal cancer requires a comparison of photon and proton plans generated using planning software, which requires time and expertise. We developed a fully automated decision tool to select patients for proton therapy that predicts proton therapy (XT) and photon therapy (PT) dose distributions using only patient CT image data, predicts xerostomia and dysphagia probability using predicted critical organ mean doses, and makes decisions based on the Netherlands’ National Indication Protocol Proton therapy (NIPP) to select patients likely to benefit from proton therapy. Methods: This study used 48 nasopharyngeal patients treated at the Cancer Hospital of the Chinese Academy of Medical Sciences. We manually generated a photon plan and a proton plan for each patient. Based on this dose distribution, photon and proton dose prediction models were trained using deep learning (DL) models. We used the NIPP model to measure xerostomia levels 2 and 3, dysphagia levels 2 and 3, and decisions were made according to the thresholds given by this protocol. Results: The predicted doses for both photon and proton groups were comparable to those for manual plan (MP). The Mean Absolute Error (MAE) for each organ at risk in the photon and proton plans did not exceed 5% and showed a good performance of the dose prediction model. For proton, the normal tissue complication probability (NTCP) of xerostomia and dysphagia performed well, p > 0.05. There was no statistically significant difference. For photon, the NTCP of dysphagia performed well, p > 0.05. For xerostomia p < 0.05 but the absolute deviation was 0.85% and 0.75%, which would not have a great impact on the prediction result. Among the 48 patients’ decisions, 3 were wrong, and the correct rate was 93.8%. The area under curve (AUC) of operating characteristic curve (ROC) was 0.86, showing the good performance of the decision-making tool in this study. Conclusions: The decision tool based on DL and NTCP models can accurately select nasopharyngeal cancer patients who will benefit from proton therapy. The time spent generating comparison plans is reduced and the diagnostic efficiency of doctors is improved, and the tool can be shared with centers that do not have proton expertise. Trial registration: This study was a retrospective study, so it was exempt from registration. Full article

(This article belongs to the Special Issue Proton Therapy of Cancer Treatment)

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13 pages, 1334 KiB

Open AccessArticle

Machine Learning-Based Gene Expression Analysis to Identify Prognostic Biomarkers in Upper Tract Urothelial Carcinoma

by Bernat Padullés, Ruben López-Aladid, Mercedes Ingelmo-Torres, Fiorella L. Roldán, Carmen Martínez, Judith Juez, Laura Izquierdo, Lourdes Mengual and Antonio Alcaraz

Cancers 2025, 17(16), 2619; https://doi.org/10.3390/cancers17162619 - 11 Aug 2025

Abstract

Background: Upper tract urothelial carcinoma (UTUC) is a rare and aggressive malignancy with limited prognostic tools to predict disease progression. Due to its low incidence, the molecular pathogenesis of UTUC remains poorly understood, and few studies have explored transcriptomic profiling in this setting. [...] Read more.

Background: Upper tract urothelial carcinoma (UTUC) is a rare and aggressive malignancy with limited prognostic tools to predict disease progression. Due to its low incidence, the molecular pathogenesis of UTUC remains poorly understood, and few studies have explored transcriptomic profiling in this setting. Identifying gene expression biomarkers associated with progression may help improve risk stratification and guide postoperative management. Methods: In this study, we applied a machine learning approach to gene expression data from radical nephroureterectomy (RNU) specimens of 17 consecutive patients with pT2 or pT3 UTUC treated at our institution. RNA was extracted from formalin-fixed paraffin-embedded tissues and sequenced using the Ion AmpliSeq™ Transcriptome Human Gene Expression Kit on an Illumina HiSeq 2500 platform. Differential gene expression was assessed using DESeq2, and results were visualized with volcano plots. Predictive power was evaluated through logistic regression and receiver operating characteristic (ROC) analysis. Gene Ontology enrichment analysis was used to explore biological pathways. Results: A total of 76 genes were differentially expressed between progressive and non-progressive patients. A random forest classifier identified ten key genes with prognostic potential. Validation with logistic regression yielded an area under the ROC curve (AUC) of 0.88, indicating high discriminative ability. These genes were associated with immune regulation, cell cycle control, and tumor progression. Conclusions: This pilot study demonstrates the potential of integrating machine learning with transcriptomic analysis to identify prognostic biomarkers in UTUC. Further validation in larger, independent cohorts is needed to confirm these findings and support their clinical application. Full article

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

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17 pages, 408 KiB

Open AccessArticle

Differential miRNA Expressions Linking Environmental Risk Factors to Triple-Negative Breast Cancer Stages at Diagnosis

by Amjila Bam, Yawen Hu, Xiaocheng Wu, Meng Luo, Nubaira Rizvi, Luis Del Valle, Arnold H. Zea, Fokhrul Hossain, Denise Moore Danos, Jovanny Zabaleta, Augusto Ochoa, Lucio Miele, Edward Trapido and Qingzhao Yu

Cancers 2025, 17(16), 2618; https://doi.org/10.3390/cancers17162618 - 11 Aug 2025

Abstract

Background/Objectives: Triple negative breast cancer (TNBC) is an aggressive, molecularly heterogeneous subtype of breast cancer, accounting for approximately 10–15% of all cases. While reproductive and metabolic factors contribute to breast cancer development, growing concerns about environmental exposures, alongside biological and socio-cultural influences, underscore [...] Read more.

Background/Objectives: Triple negative breast cancer (TNBC) is an aggressive, molecularly heterogeneous subtype of breast cancer, accounting for approximately 10–15% of all cases. While reproductive and metabolic factors contribute to breast cancer development, growing concerns about environmental exposures, alongside biological and socio-cultural influences, underscore the need for targeted prevention strategies across diverse populations. Despite increasing evidence linking biological, socioeconomic, and environmental factors to TNBC outcomes, the molecular mechanisms underlying these relationships remain poorly understood. Micro-RNAs (miRNAs), which regulate gene expression and play critical roles in cancer development, have emerged as potential mediators between environmental exposures and TNBC progression. The goal of this research is to identify environmental risk factors that directly relate to TNBC stages and enhance understanding of the mechanisms underlying how miRNAs link environmental exposures to TNBC stages. Methods: In this study, we analyzed 434 Formalin-Fixed, Paraffin-Embedded (FFPE) tumor samples from 434 women diagnosed with TNBC between 2009 and 2019, encompassing diverse cancer stages (184 cases from early stage and 250 cases from advanced stage), racial backgrounds, and socioeconomic statuses. The sequencing data were linked with the Louisiana Tumor Registry data and the Environmental Justice index. Results: A total of 348 unique miRNAs were identified as differentially expressed across environmental risk factors statistically associated with TNBC stage, adjusting for plate effects. An UpSet plot revealed 44 miRNAs commonly differentially expressed across TNBC stages and multiple environmental exposures. At least one differentially expressed (DE) miRNA was shared between the TNBC stage and each environmental factor, with many associated with receptor-negative and aggressive breast cancer subtypes. Conclusions: These findings highlight potential biological pathways through which exposures may drive the TNBC progression and contribute to disparities in outcomes. Full article

(This article belongs to the Special Issue New Perspectives in the Management of Breast Cancer)

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16 pages, 2511 KiB

Open AccessArticle

Brightly Visualizing Pancreatic Cancer Margins in Orthotopic Mouse Models with an Anti-CA19-9 Antibody Conjugated to a Near-Infrared Fluorophore

by Kristin E. Cox, Javier Bravo, Sunidhi Jaiswal, Siamak Amirfakhri, Thinzar M. Lwin, Abhijit Aithal, Sumbal Talib, Lily J. Jih, Aylin Din Parast Saleh, Keita Kobayashi, Kavita Mallya, Maneesh Jain, Robert M. Hoffman, Aaron M. Mohs, Surinder K. Batra and Michael Bouvet

Cancers 2025, 17(16), 2617; https://doi.org/10.3390/cancers17162617 - 10 Aug 2025

Abstract

Background/Purpose: The only potentially curative procedure for pancreatic cancer is R0 resection, which is difficult to achieve due to poorly defined tumor margins. In the present study, we used an anti-CA19-9 antibody conjugated to a near-infrared fluorophore in orthotopic mouse models to target [...] Read more.

Background/Purpose: The only potentially curative procedure for pancreatic cancer is R0 resection, which is difficult to achieve due to poorly defined tumor margins. In the present study, we used an anti-CA19-9 antibody conjugated to a near-infrared fluorophore in orthotopic mouse models to target and visualize pancreatic cancer. Methods: Orthotopic models of the human pancreatic cancer cell lines SW1990 and BxPC3 were established by implanting tumor fragments into the pancreas of athymic nude mice. Anti-CA19-9 and control IgG were conjugated with IRDye800CW. Mice received 50 µg of CA19-9–IRDye800CW or IgG-IRDye800CW via tail-vein injection and were imaged after 72 h. MIA PaCa-2, a CA19-9-negative cell line, was used in subcutaneous models to assess targeting specificity. Results: Using the LI-COR Pearl imaging system in the SW1990 model, the tumor-to-pancreas ratio (TPR) was 4.51 (±0.74), and the tumor to the liver ratio (TLR) was 3.05 (±0.60) with CA19-9-IRDye800CW, while the TPR was 1.67 (±0.16) and the TLR was 0.95 (±0.05) for the non-specific control IgG–IRDye800CW. Using a clinically available fluorescence laparoscope, CA19-9-1RDye800CW demonstrated a TPR of 2.34 (±0.44) and a TLR of 2.23 (±0.49), compared to 1.11 (±0.13) and 0.69 (±0.07), respectively, for IgG-IRDye800CW in the SW1990 orthotopic model. In the BxPC3 models, the TPR was 3.82 (±0.55) and the TLR was 4.13 (±0.77) for CA19-9-IRDye800CW compared to 2.40 (±0.31) and 1.49 (±0.23), respectively, for IgG-IRDye800CW. Conclusions: CA19-9-IRDye800CW provided specific in vivo targeting of two human pancreatic cancer cell lines in orthotopic nude mouse models with superior TPRs and TLRs compared to IgG-IRDye800CW. This tumor-specific fluorescent CA19-9 antibody is a promising clinical tool for improved visualization of pancreatic cancer. Full article

(This article belongs to the Special Issue Research on Fluorescence-Guided Surgery in Cancer Treatment)

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16 pages, 3993 KiB

Open AccessArticle

Risk Stratification of Thyroid Nodules Using Ultrasound Cine-Loop Video Sequences

by Tabea Nikola Schmidt, Martin Freesmeyer, Christian Kühnel, Falk Gühne, Larissa Rosenbaum, Robert Drescher and Philipp Seifert

Cancers 2025, 17(16), 2616; https://doi.org/10.3390/cancers17162616 - 9 Aug 2025

Abstract

Background/Objectives: Static image captures (SICs) are the prevailing methodology for documenting thyroid nodules (TNs) on ultrasound examinations. Ultrasound cine-loop (CL) video sequences of the thyroid enable the storage and review of the entire organ in PACS, analogous to sectional imaging modalities such as [...] Read more.

Background/Objectives: Static image captures (SICs) are the prevailing methodology for documenting thyroid nodules (TNs) on ultrasound examinations. Ultrasound cine-loop (CL) video sequences of the thyroid enable the storage and review of the entire organ in PACS, analogous to sectional imaging modalities such as CT or MRI. Expanding on SIC, the collection of more extensive datasets is possible, with the potential to enhance diagnostic performance. However, there is an absence of reliable data concerning this process. Methods: This retrospective, tertiary care, single-center study included all patients with cytologically and histopathologically diagnosed TNs from 01/16 to 12/23. A standardized CL protocol was routinely acquired in addition to conventional SIC. The diagnostic performance of ACR and Kwak TIRADS was examined for both CL and SIC in a PACS. Advantages, challenges, and limitations of CL were analyzed. Conclusions: In total, 189 patients with 329 TNs (78% females, aged 54 ± 15 years; 76% diagnosed via surgery; 14% malignant) were included. On SIC, 58 TNs (18%) were not identified (all benign). When comparing CL with SIC, a strong correlation was observed for nearly all ultrasound features (echogenicity, composition, margin, and foci; each p < 0.001) and both TIRADSs (each p < 0.001). The diagnostic accuracy of CL was slightly superior, with maximum values of 85% for ACR and 87% for Kwak TIRADS, respectively. Rating confidence and image quality exhibited superiority on SIC (each p < 0.001). The occurrence of image artifacts was more prevalent in CL (p < 0.001). The integration of cine loops into thyroid ultrasound was found to be a seamless process, thereby enhancing the risk stratification of nodules. Image quality impairments manifested more frequently in cine loops, while static image captures demonstrated higher levels of assessment confidence. Full article

(This article belongs to the Special Issue Thyroid Cancer: Diagnosis, Prognosis and Treatment (2nd Edition))

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18 pages, 2492 KiB

Open AccessArticle

Cohesin Loading Factor NIPBL Is Essential for MYCN Expression and MYCN-Driven Oncogenic Transcription in Neuroblastoma

by Jee-Youn Kang, Kaitlyn A. Tremble, Philip Homan and Carol J. Thiele

Cancers 2025, 17(16), 2615; https://doi.org/10.3390/cancers17162615 - 9 Aug 2025

Abstract

High-risk neuroblastoma remains a major clinical challenge, with a five-year survival rate below 50% despite intensive multimodal therapies. MYCN amplification, a hallmark of high-risk disease, drives an aggressive transcriptional program that maintains undifferentiated and proliferative states in neuroblastoma cells. Given its central role [...] Read more.

High-risk neuroblastoma remains a major clinical challenge, with a five-year survival rate below 50% despite intensive multimodal therapies. MYCN amplification, a hallmark of high-risk disease, drives an aggressive transcriptional program that maintains undifferentiated and proliferative states in neuroblastoma cells. Given its central role in oncogenic transcription, MYCN represents an attractive therapeutic target; however, its undruggable nature has prompted efforts to identify upstream regulators or cofactors that sustain MYCN expression and oncogenic function. In this study, we investigate the role of the cohesin loading factor NIPBL in supporting the MYCN-driven transcriptional program. We demonstrate that elevated NIPBL expression is associated with undifferentiated, proliferative neuroblastoma cell states and poor clinical outcomes in neuroblastoma patients. Functionally, NIPBL depletion reduces MYCN mRNA and protein levels and induces widespread transcriptional reprogramming consistent with neuronal differentiation. These transcriptional changes are accompanied by decreased neuroblastoma cell proliferation and increased neuronal differentiation, reflecting impaired regulation of MYCN target genes upon NIPBL loss. Collectively, we have established a mechanistic link between NIPBL and the MYCN-driven transcriptome, highlighting NIPBL as a potential therapeutic vulnerability to promote differentiation in high-risk neuroblastoma. Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series: Treatment of Pediatric Solid Tumors)

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