Cancers

11 pages, 244 KB

Open AccessArticle

From Sample to Sequencing: The Importance of Pre-Analytical Sample Treatment in NGS Analysis of Patients with Chronic Lymphocytic Leukemia

by Mirjana Suver Stević, Hrvoje Holik, Vlatka Periša, Saška Marczi, Nikolina Kolobarić and Marina Samardžija

Cancers 2025, 17(22), 3668; https://doi.org/10.3390/cancers17223668 (registering DOI) - 15 Nov 2025

Abstract

Background/Objectives: Chronic lymphocytic leukemia (CLL) is a hematologic malignancy characterized by uncontrolled accumulation of B lymphocytes. A key feature of CLL is the presence of genetic aberrations, particularly alterations of chromosome 17, such as deletion of 17q and/or mutations in the TP53 gene. [...] Read more.

Background/Objectives: Chronic lymphocytic leukemia (CLL) is a hematologic malignancy characterized by uncontrolled accumulation of B lymphocytes. A key feature of CLL is the presence of genetic aberrations, particularly alterations of chromosome 17, such as deletion of 17q and/or mutations in the TP53 gene. Since these abnormalities are highly relevant for therapeutic decision-making, assessment of TP53 mutational status is strongly recommended in routine diagnostics. This study aimed to evaluate the reliability of TP53 sequencing results depending on the type of DNA sample analyzed. Methods: DNA was isolated from two different sample types of the same patient: mononuclear cells (CLL1) and purified CD19+ cells (CLL2). The entire coding region of TP53 (exons 2–11), including splice sites (+/− 10 bp), was analyzed using capture-based next-generation sequencing (NGS). Reads were aligned to the GRCh37/hg19 reference genome, and variants were interpreted using DRAGEN Enrichment (Illumina) and Franklin (QIAGEN). Results: In sample CLL1, the NM_000546.6:c.626_627del mutation (Tier I) was identified with a variant allele frequency (VAF) of 57.06%. The same mutation was confirmed in CLL2, but with a higher VAF of 94.78%. Importantly, an additional Tier I mutation (NM_000546.6:c.825_826del) was detected exclusively in CLL2 at a VAF of 1.59%. Both findings met the required sequencing depth as well as coverage per sample, confirming their validity. Conclusions: The study demonstrates that inadequate starting material for DNA isolation may mask low-frequency TP53 mutations, resulting in false-negative results. Accurate detection requires ensuring sufficient CD19+ cell content, which is critical for reliable diagnostics and supports personalized treatment approaches in CLL. Full article

(This article belongs to the Special Issue Chronic Lymphocytic Leukemia: From Genetics to Therapy)

19 pages, 7499 KB

Open AccessArticle

Caught in the Act: Tumor-Immune Interactions in Circulation of Patients with Immune Marker Positive Circulating Tumor Cells

by Amin Naghdloo, Mohamed Kamal, Dean Tessone, Valerie Hennes, James Hicks and Peter Kuhn

Cancers 2025, 17(22), 3667; https://doi.org/10.3390/cancers17223667 (registering DOI) - 15 Nov 2025

Abstract

Background/Objectives: Circulating tumor cells (CTCs) and large extracellular vesicles (LEVs) are key components of the liquid biopsy that provide minimally invasive access to tumor biology. A clinically relevant subset of CTCs coexpressing epithelial and immune markers (im.CTCs) has been described, yet the origin [...] Read more.

Background/Objectives: Circulating tumor cells (CTCs) and large extracellular vesicles (LEVs) are key components of the liquid biopsy that provide minimally invasive access to tumor biology. A clinically relevant subset of CTCs coexpressing epithelial and immune markers (im.CTCs) has been described, yet the origin of this phenotype remains unclear. In this study, we investigated the cellular and molecular context underlying the emergence of immune marker expression on CTCs and LEVs. Methods: Using high-resolution immunofluorescence microscopy of patient-derived blood samples, we identified direct physical interactions between white blood cells (WBCs) and both im.CTCs and im.LEVs, exclusively in patients harboring im.CTCs. Results: In several cases, WBCs partially encapsulated CTCs and LEVs, and quantitative analysis revealed localized enrichment of immune membrane markers at the contact interface, distinguishing these events from random proximity. Proteomic profiling further identified CD4+ T cells as the predominant interacting immune cell type and confirmed the presence of CD45, CD3, and CD4 on the interacting CTCs and LEVs, matching their WBC counterparts. Conclusion: These findings support membrane transfer as a potential mechanism for the acquisition of immune markers by CTCs and LEVs and provide in vivo evidence of contact-dependent tumor-immune interactions in circulation with implications for immune modulation and clinical interpretation of the im.CTC phenotype. Full article

(This article belongs to the Special Issue Recent Advances in Liquid Biopsy Biomarkers of Cancer)

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21 pages, 7923 KB

Open AccessArticle

Epigenetic Regulation of NKT-Cell-Related Gene Signatures and Prognostic Implications in Oropharyngeal Squamous Cell Carcinoma

by Luka Minarik, Rita Khoueiry, Mirela Leskur, Vincent Cahais, Zdenko Herceg, Merica Glavina Durdov and Benjamin Benzon

Cancers 2025, 17(22), 3666; https://doi.org/10.3390/cancers17223666 (registering DOI) - 15 Nov 2025

Abstract

Background: Oropharyngeal squamous cell carcinoma (OPSCC) is a major subtype of head and neck cancer, with prognosis increasingly influenced by the tumour immune microenvironment. Although immune checkpoint inhibitors have improved outcomes for some patients, reliable predictive biomarkers remain limited. Methods: This study aimed [...] Read more.

Background: Oropharyngeal squamous cell carcinoma (OPSCC) is a major subtype of head and neck cancer, with prognosis increasingly influenced by the tumour immune microenvironment. Although immune checkpoint inhibitors have improved outcomes for some patients, reliable predictive biomarkers remain limited. Methods: This study aimed to investigate the prognostic relevance and epigenetic regulation of natural killer T (NKT)-cell-related gene signatures in OPSCC. Clinicopathological and transcriptomic data from 81 OPSCC patients were analysed using single-sample gene set enrichment analysis (ssGSEA) to evaluate immune-related gene set enrichment scores. Associations with overall survival and clinical features were assessed, and candidate prognostic genes were further explored through expression, methylation, and network analyses. Results: High NKT cell differentiation enrichment scores were significantly associated with improved survival and favourable clinical features. Gene-level analyses identified ITK, ZNF683, and ATF2 as key prognostic markers linked to T-cell signalling and epigenetic regulation. Methylation profiling revealed hypermethylation of ITK and hypomethylation of ZNF683 in tumour tissues, suggesting an epigenetic basis for altered gene expression. Conclusions: These findings highlight NKT cell differentiation as a strong prognostic indicator in OPSCC and support further exploration of epigenetic–immunologic interactions as potential therapeutic targets. Full article

(This article belongs to the Special Issue Cancer Genetics and Epigenetics: Their Roles and Clinical Implications (2nd Edition))

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12 pages, 1677 KB

Open AccessArticle

MRI Reflects Meningioma Biology and Molecular Risk

by Julian Canisius, Julia Schuler, Maria Goldberg, Olivia Kertels, Marie-Christin Metz, Chiara Negwer, Igor Yakushev, Bernhard Meyer, Stephanie E. Combs, Jan S. Kirschke, Denise Bernhardt, Benedikt Wiestler and Claire Delbridge

Cancers 2025, 17(22), 3665; https://doi.org/10.3390/cancers17223665 (registering DOI) - 15 Nov 2025

Abstract

Background/Objectives: Large-scale (epi)genomic studies have substantially advanced our understanding of the molecular landscape of meningiomas, most recently embedded in the cIMPACT-NOW update 8. As a result, molecular data are increasingly integrated into risk-adapted treatment algorithms. However, it remains uncertain to what extent [...] Read more.

Background/Objectives: Large-scale (epi)genomic studies have substantially advanced our understanding of the molecular landscape of meningiomas, most recently embedded in the cIMPACT-NOW update 8. As a result, molecular data are increasingly integrated into risk-adapted treatment algorithms. However, it remains uncertain to what extent non-invasive MRI can capture underlying molecular variation and risk. Methods: We assembled a large, single-institution cohort of 225 newly diagnosed meningiomas (WHO grades 1–3) with available preoperative MRI, as well as comprehensive epigenome-wide methylation and copy-number profiling. Tumors were segmented into core and edema regions using a state-of-the-art automated pipeline from the BraTS challenge. Radiomic features were extracted and used to train Random Forest classifiers to predict WHO grade, molecular risk, and specific alterations such as 1p loss in a hold-out test set. Results: Our models achieved accuracy above 91% for integrated molecular risk classification, 87.5% for 1p chromosomal status, and 76.8% for WHO grade prediction, with corresponding AUCs of 0.91, 0.90, and 0.89, underscoring the robustness of radiomic features in capturing histopathological and, especially, molecular characteristics. Conclusions: Preoperative MRI effectively captures the underlying molecular biology of meningiomas and may enable rapid molecular assessment to inform decision-making and prioritization of confirmatory testing. However, it is not yet ready for clinical use, showing lower accuracy for current WHO grade classification. Full article

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

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11 pages, 651 KB

Open AccessArticle

Geographic Disparities in Survival After Surgery for Metastatic Bone Disease: A Retrospective Analysis from a German Sarcoma Centre

by Wolfram Weschenfelder, Paula Maria Nickl, Friederike Weschenfelder, Christian Spiegel, Karin Gabriela Schrenk, Thomas Ernst and Mark Lenz

Cancers 2025, 17(22), 3664; https://doi.org/10.3390/cancers17223664 (registering DOI) - 15 Nov 2025

Abstract

Background/Objectives: Metastatic bone disease (MBD) poses an increasing challenge in orthopaedic oncology due to prolonged survival. While clinical prognostic factors are well established, the role of socio-economic determinants remains unclear, particularly within universal healthcare systems. Methods: We retrospectively analysed 243 patients who underwent [...] Read more.

Background/Objectives: Metastatic bone disease (MBD) poses an increasing challenge in orthopaedic oncology due to prolonged survival. While clinical prognostic factors are well established, the role of socio-economic determinants remains unclear, particularly within universal healthcare systems. Methods: We retrospectively analysed 243 patients who underwent surgery for MBD (excluding spine) between 2005 and 2024 at a German sarcoma centre. Socio-economic indicators were derived from national databases and linked to patients’ residential districts. Survival was analysed using Kaplan–Meier estimates and Cox regression, adjusting for clinical confounders. Results: Median postoperative survival was 22 months. Several socio-economic indicators—income, education, and employment—were associated with survival in univariate analysis. In multivariate models, only residential area size remained independently significant (p = 0.047). Patients from villages (<2000 inhabitants) and large cities (>100,000) had poorer survival than those from small or medium-sized towns. This effect persisted after adjustment for tumour type, pathological fractures, and year of surgery. Conclusions: Within a universal healthcare system, residential area size was associated with survival after surgery for MBD, suggesting that regional disparities may persist despite equal formal access to care. Further studies integrating individual-level socioeconomic data are needed to identify mechanisms and guide interventions to reduce geographic inequalities. Full article

(This article belongs to the Special Issue Health Disparities and Outcomes in Cancer Survivors)

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Graphical abstract

19 pages, 970 KB

Open AccessArticle

Genomic and Demographic Characteristics of Angiosarcoma as Described in the AACR Project GENIE Registry

by Eileen Leach, Amir Jafari, Elijah Torbenson, Beau Hsia and Abubakar Tauseef

Cancers 2025, 17(22), 3663; https://doi.org/10.3390/cancers17223663 - 14 Nov 2025

Abstract

Background: Despite the high mortality associated with angiosarcoma, its low prevalence has limited sample sizes in prior studies. To address these gaps, we analyzed the AACR Project GENIE registry, a large, multi-institutional database. Methods: 359 tumor samples from 346 patients with angiosarcoma were [...] Read more.

Background: Despite the high mortality associated with angiosarcoma, its low prevalence has limited sample sizes in prior studies. To address these gaps, we analyzed the AACR Project GENIE registry, a large, multi-institutional database. Methods: 359 tumor samples from 346 patients with angiosarcoma were identified from the AACR Project GENIE v18.0-public database using cBioPortal. Somatic mutations and copy number alterations were assessed. Statistical significance was assessed by t-test for continuous variables and a chi-squared test for categorical data, with significance set at p < 0.05. Results: Recurrent mutations included TP53 (20.6%), KDR (13.6%), and PIK3CA (10.6%). Copy number alterations occurred in MYC (27.3%), CRKL (10.4%), FLT4 (5.5%), and KDR (4.8%). Homozygous deletions occurred in CDKN2A (6.6%), CDKN2B (6.56%), and MTAP (3.81%). Significant co-occurrence included FAT1-NOTCH2, TP53-ATRX, and NOTCH1-ARID1A. Mutual exclusivity was seen with KDR-FLT4 and KDR-ATRX. Females exhibited enrichment in MYC and HRAS, while males exhibited enrichment in POT1, NTRK2, and FAT1. Compared with primary tumors, metastatic tumors more often displayed ZFHX4, FGFR1, MSI2, HIST1H1C, and TOP1 mutations, while MAPK7 mutations occurred only in primary tumors. Conclusions: In one of the largest genomic analyses of angiosarcoma to date, we identified recurrent alterations, suggesting potential future therapeutic targets. Full article

(This article belongs to the Section Cancer Informatics and Big Data)

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47 pages, 11615 KB

Open AccessReview

The Involvement of the Peptidergic Systems in Breast Cancer Development

by Manuel L. Sánchez, Prema Robinson, Zal Italia, Tan Hoang, Miguel Muñoz and Rafael Coveñas

Cancers 2025, 17(22), 3662; https://doi.org/10.3390/cancers17223662 - 14 Nov 2025

Abstract

The current known data on the involvement of the peptidergic systems in breast cancer progression is overwhelmingly vast. Peptidergic systems are useful tools for imaging, diagnosis, prognosis and treatment of breast cancer. These systems play a crucial role in both basic and clinical [...] Read more.

The current known data on the involvement of the peptidergic systems in breast cancer progression is overwhelmingly vast. Peptidergic systems are useful tools for imaging, diagnosis, prognosis and treatment of breast cancer. These systems play a crucial role in both basic and clinical breast cancer research by enabling the exploration of novel molecular mechanisms, signaling pathways, and the development of effective drug design strategies. Breast cancer cells overexpress peptide receptors; at the same time they are known to interact with peptides that (a) exert an oncogenic action (adrenomedullin 2, endothelin, gastrin-releasing peptide, neurokinin A, neuromedin, neuropeptide Y, neurotensin, substance P, vasoactive intestinal peptide), (b) exert an anticancer action (angiotensin (1–7), ghrelin, peptide YY) or (c) exert dual oncogenic and anticancer effects (adrenomedullin, angiotensin II, bradykinin, corticotropin-releasing factor, β-endorphin, glucagon-like peptide 1, gonadotropin-releasing hormone, kisspeptin, methionine-enkephalin, oxytocin). This indicates that peptides, as well as peptide receptor agonists and antagonists, may serve as antitumor agents due to their diverse actions against breast cancer development, including the inhibition of cell proliferation, migration and invasion, induction of apoptosis, and anti-angiogenesis. Multiple strategies have been developed to combat breast cancer, including peptide receptor silencing; antibodies conjugated to specific signaling proteins; antibodies targeting specific peptide receptors or oncogenic peptides; and the use of peptides or peptide receptor agonists/antagonists loaded with antitumor cargo. Future lines of research are suggested in breast cancer using promising anti-breast-cancer peptide receptor antagonists (HOE-140, exendin (9–39), bosentan, macitentan, PD168,368, CGP71,683A, SR48,692, aprepitant) or agonists (FR190,997, semaglutide, exendin 4, goserelin) mentioned in this review. Peptidergic systems have tremendous anti-breast-cancer clinical potential which must be exploited and developed. Taken together, the available data highlight the enormous promise of translational research into breast cancer and peptidergic systems for the development of effective treatments. A full understanding of the roles played by the peptidergic systems in breast cancer will serve to improve diagnosis and treatment. Full article

(This article belongs to the Topic Recent Advances in Anticancer Strategies, 2nd Edition)

15 pages, 6444 KB

Open AccessReview

Radiomics in Soft Tissue Sarcoma: Toward Precision Imaging in Oncology

by Anuj Shah, Francesco Alessandrino, Emanuela Palmerini, Domenika Ortiz Requena, Brooke Crawford and Ty K. Subhawong

Cancers 2025, 17(22), 3661; https://doi.org/10.3390/cancers17223661 - 14 Nov 2025

Abstract

Radiomics entails a data-driven approach to imaging with a wide array of potential uses in characterizing soft tissue sarcomas, enabling extraction of quantitative features from routine clinical CT and MRI examinations. These features—encompassing descriptors of size, shape, and internal heterogeneity—can improve diagnostic accuracy, [...] Read more.

Radiomics entails a data-driven approach to imaging with a wide array of potential uses in characterizing soft tissue sarcomas, enabling extraction of quantitative features from routine clinical CT and MRI examinations. These features—encompassing descriptors of size, shape, and internal heterogeneity—can improve diagnostic accuracy, tumor grading, and treatment response assessment. Radiomics has shown promise in distinguishing benign from malignant lesions, subtyping sarcomas, and predicting metastatic potential. In particular, models integrating radiomic data with clinical variables have demonstrated performance comparable to expert radiologists in challenging diagnostic scenarios. Machine learning enhances radiomics by automating feature selection and improving predictive modeling. Despite its potential, challenges remain in standardizing imaging protocols, ensuring reproducibility, and integrating radiomics into clinical workflows. Multi-institutional collaboration is essential for broader model validation and clinical integration. By leveraging specific radiomics features as novel quantitative imaging biomarkers, radiomics can drive precision oncology in sarcoma, supporting tailored therapies and improving prognostic accuracy. Full article

(This article belongs to the Special Issue Innovative Strategies and Techniques in Diagnosing, Treating and Surveying Soft Tissue Sarcomas)

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14 pages, 2895 KB

Open AccessArticle

Interpretable and Performant Multimodal Nasopharyngeal Carcinoma GTV Segmentation with Clinical Priors Guided 3D-Gaussian-Prompted Diffusion Model (3DGS-PDM)

by Jiarui Zhu, Zongrui Ma, Ge Ren and Jing Cai

Cancers 2025, 17(22), 3660; https://doi.org/10.3390/cancers17223660 - 14 Nov 2025

Abstract

Background: Gross tumor volume (GTV) segmentation of Nasopharyngeal Carcinoma (NPC) crucially determines the precision of image-guided radiation therapy (IGRT) for NPC. Compared to other cancers, the clinical delineation of NPC is especially challenging due to its capricious infiltration of the adjacent rich tissues [...] Read more.

Background: Gross tumor volume (GTV) segmentation of Nasopharyngeal Carcinoma (NPC) crucially determines the precision of image-guided radiation therapy (IGRT) for NPC. Compared to other cancers, the clinical delineation of NPC is especially challenging due to its capricious infiltration of the adjacent rich tissues and bones, and it routinely requires multimodal information from CT and MRI series to identify its ambiguous tumor boundary. However, the conventional deep learning-based multimodal segmentation method suffers from limited prediction accuracy and frequently performs as well as or worse than single-modality segmentation models. The limited multimodal prediction performance indicates defective information extraction and integration from the input channels. This study aims to develop a 3D Gaussian-prompted Diffusion Model (3DG-PDM) for more clinically targeted information extraction and effective multimodal information integration, thereby facilitating more accurate and clinically interpretable GTV segmentation for NPC. Methods: We propose a 3D-Gaussian-Prompted Diffusion Model (3DGS-PDM) that operates NPC tumor contouring in multimodal clinical priors through a guided stepwise process. The proposed model contains two modules: a Gaussian Initialization Module that utilizes a 3D-Gaussian-Splatting technique to distill 3D-Gaussian representations based on clinical priors from CT, MRI-t2 and MRI-t1-contract-enhanced-fat-suppression (MRI-t1-cefs), respectively, and a Diffusion Segmentation Module that generates tumor segmentation step-by-step from the fused 3D-Gaussians prompts. We retrospectively collected data on 600 NPC patients from four hospitals through paired CT, MRI series and clinical GTV annotations, and divided that dataset into 480 training volumes and 120 testing volumes. Results: Our proposed method can achieve a mean dice similarity cofficient (DSC) of 84.29 ± 7.33, a mean average symmetric surface distance (ASSD) of 1.31 ± 0.63, and a 95th percentile of Hausdorff (HD₉₅) of 4.76 ± 1.98 on primary NPC tumor (GTVp) segmentation, and a DSC of 79.25 ± 10.01, an ASSD of 1.19 ± 0.72 and an HD₉₅ of 4.76 ± 1.71 on metastasis NPC tumor (GTVnd) segmentation. Comparative experiments further demonstrate that our method can significantly improve the multimodal segmentation performance on NPC tumors, with superior advantages over five other state-of-the-art comparative methods. Visual evaluation on the segmentation prediction process and a three-step ablation study on input channels further demonstrate the interpretability of our proposed method. Conclusions: This study proposes a performant and interpretable multimodal segmentation method for GTV of NPC, contributing greatly to precision improvement for NPC therapy treatment. Full article

(This article belongs to the Special Issue Image-Guided Adaptive Radiation Therapy (IGART): Advancing Precision Oncology)

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23 pages, 1024 KB

Open AccessArticle

Exploring Novel Applications: Repositioning Clinically Approved Therapies for Medulloblastoma Treatment

by Arthur Karaulic, Clémence Fournier and Gilles Pagès

Cancers 2025, 17(22), 3659; https://doi.org/10.3390/cancers17223659 - 14 Nov 2025

Abstract

Background/Objectives: The advent of tyrosine kinase inhibitors (TKI), therapeutic antibodies and inducers of apoptosis has revolutionized cancer treatment, yet their application in pediatric tumors, particularly medulloblastoma, remains understudied. Understanding the expression of these targets in specific genetic subgroups could unveil potential repositioning opportunities [...] Read more.

Background/Objectives: The advent of tyrosine kinase inhibitors (TKI), therapeutic antibodies and inducers of apoptosis has revolutionized cancer treatment, yet their application in pediatric tumors, particularly medulloblastoma, remains understudied. Understanding the expression of these targets in specific genetic subgroups could unveil potential repositioning opportunities for already approved drugs. Methods: We analyzed RNA-sequencing data from the R2 Genomics Analysis and Visualization Platform (N = 763 patients, multiple cohorts) and the TCGA database (six individual cohorts 828 patients) to assess the expression of 73 potential targets of TKIs and antibodies targeting immune checkpoint inhibitors (ICI) or membrane receptors and inducers of apoptosis. These treatments, FDA-approved or in phase II clinical trials for solid or hematologic cancers, and their targets were evaluated in both non-metastatic and metastatic patients when data was available. Additionally, we examined treatments tailored to mutated targets crucial for tumorigenesis or resistance to conventional therapies. Results: Overexpression of certain targets beyond predefined cutoff values in Kaplan–Meier analyses correlated with either prolonged or shortened overall survival. Targets associated with shorter survival suggested potentially relevant treatments, thereby highlighting the importance of defining specific treatments for distinct genetic subgroups. Notably, certain immune checkpoint inhibitors showed relevance for specific subgroups but detriment for others. As a positive control, our analysis confirmed the use of axitinib, an anti-angiogenic treatment, as demonstrated by our recent publication. Surprisingly, a treatment developed for hematological tumors, venetoclax, demonstrated potential efficacy in medulloblastoma. Conclusions: Medulloblastoma displays subtype-specific expressions of FDA-approved TKI, ICI and pro-apoptotic drug targets, impacting overall survival. Clinical trials investigating these approved treatments in medulloblastoma are therefore warranted. Full article

(This article belongs to the Section Molecular Cancer Biology)

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15 pages, 2091 KB

Open AccessArticle

Using Machine Learning to Revise the AJCC Staging System for Neuroendocrine Tumors of the Pancreas

by Jacob Hillman, Quinn Clark, Liam Rehm, Anwar E. Ahmed and Dechang Chen

Cancers 2025, 17(22), 3658; https://doi.org/10.3390/cancers17223658 - 14 Nov 2025

Abstract

Background: Staging systems are essential for guiding treatment and predicting outcomes in cancer patients. For pancreatic neuroendocrine tumors, the American Joint Committee on Cancer (AJCC) Tumor, Lymph Node, and Metastasis (TNM) system is the current standard. However, its predictive accuracy is limited, [...] Read more.

Background: Staging systems are essential for guiding treatment and predicting outcomes in cancer patients. For pancreatic neuroendocrine tumors, the American Joint Committee on Cancer (AJCC) Tumor, Lymph Node, and Metastasis (TNM) system is the current standard. However, its predictive accuracy is limited, as survival curves often overlap, particularly between Stage I and Stage II. Improved methods of patient stratification are therefore needed. Methods: We applied the Ensemble Algorithm for Clustering Cancer Data (EACCD) that involves calculating dissimilarities, ensemble learning, and hierarchical clustering. Data were obtained from the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute. Models were developed with AJCC TNM variables (T, N, M) and expanded by including patient age. Results: The AJCC TNM system achieved a C-index of 0.6656 (95% CI: 0.6473–0.6839), with survival curves showing poor separation. In contrast, the EACCD model using TNM variables produced four prognostic groups with refined and clear separation, yielding a comparable C-index of 0.6685 (95% CI: 0.6518–0.6852). When age was added, EACCD identified five groups with even stronger stratification and a higher C-index of 0.7015 (95% CI: 0.6852–0.7178). Conclusions: EACCD provides a refined prognostic framework for pancreatic neuroendocrine tumors, outperforming the AJCC TNM system by offering clearer survival stratification, comparable or higher C-index values, and integration of additional clinical factors. Full article

(This article belongs to the Special Issue Machine Learning and Artificial Intelligence in Cancer Diagnostic and Monitoring)

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17 pages, 2981 KB

Open AccessArticle

CD44v9 Expression in Pretreatment Biopsies as a Predictor of Chemotherapy Resistance in Gastric Cancer

by Katsuji Sawai, Kenji Koneri, Masato Tamaki, Yasuo Hirono and Takanori Goi

Cancers 2025, 17(22), 3657; https://doi.org/10.3390/cancers17223657 - 14 Nov 2025

Abstract

Background: Gastric cancer is a major global health burden. Although neoadjuvant chemotherapy and conversion surgery can improve survival, treatment responses vary owing to chemotherapy resistance. Cancer stem cells (CSCs), characterized by self-renewal and drug resistance, are closely linked to treatment efficacy and prognosis. [...] Read more.

Background: Gastric cancer is a major global health burden. Although neoadjuvant chemotherapy and conversion surgery can improve survival, treatment responses vary owing to chemotherapy resistance. Cancer stem cells (CSCs), characterized by self-renewal and drug resistance, are closely linked to treatment efficacy and prognosis. Among these, CD44 variant 9 (CD44v9) plays an important role in redox regulation and chemoresistance. Although its expression in resected gastric cancer specimens has been associated with poor prognosis, little is known about its expression in pretreatment biopsies and its relationship with therapeutic responses. This study aimed to clarify the predictive value of CD44v9 expression in gastric cancer biopsy specimens. Methods: Pretreatment biopsy specimens from 84 patients with gastric cancer who underwent neoadjuvant chemotherapy or conversion surgery at our institution were analyzed. Associations between CD44v9 expression, histological response, and prognosis were evaluated. Results: High CD44v9 expression was observed in 25% of patients and was significantly associated with a poor histological response (p = 0.046). Although CD44v9 expression was not directly linked to prognosis, a poor histological response correlated with worse survival (p = 0.045). In the multivariate analysis, conversion surgery (p = 0.018) and poor histological response (p = 0.011) were identified as independent predictors of poor outcomes. Conclusions: Evaluation of CD44v9 expression in pretreatment biopsies may help predict chemotherapy resistance in patients with gastric cancer. This biomarker assessment could guide individualized treatment strategies and improve patient management outcomes. Full article

(This article belongs to the Section Cancer Therapy)

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13 pages, 428 KB

Open AccessReview

Photon-Counting Computed Tomography in Thoracic Surgery: A Narrative Review of Current and Future Applications

by Giuseppe Mangiameli, Debora Brascia, Filippo Lococo and Giuseppe Marulli

Cancers 2025, 17(22), 3656; https://doi.org/10.3390/cancers17223656 - 14 Nov 2025

Abstract

Photon-counting computed tomography (PCCT) introduces a new era in thoracic imaging by offering ultra-high spatial resolution, reduced noise, spectral imaging capabilities, and lower radiation dose compared to conventional CT. These features are particularly relevant in thoracic surgery, where precise anatomical and functional assessment [...] Read more.

Photon-counting computed tomography (PCCT) introduces a new era in thoracic imaging by offering ultra-high spatial resolution, reduced noise, spectral imaging capabilities, and lower radiation dose compared to conventional CT. These features are particularly relevant in thoracic surgery, where precise anatomical and functional assessment is essential throughout the perioperative period. This narrative review outlines the clinical potential of PCCT in surgical planning, intra- and postoperative evaluation, and follow-up of both oncologic and non-oncologic thoracic conditions. PCCT enables accurate bronchovascular mapping and iodine-based perfusion imaging, supporting sublobar resection planning and risk stratification in patients with complex anatomy or reduced lung function. Postoperatively, it enhances detection of subtle complications—such as air leaks or hematomas—and improves image quality near metallic implants through advanced artifact reduction techniques. The ability to combine high-resolution imaging with functional data allows for comprehensive evaluation in a single scan and may aid in differentiating fibrosis from local recurrence. Despite its promises, PCCT adoption is currently limited by high cost, restricted availability, and the need for training and system integration. Furthermore, prospective clinical studies are still needed to determine its impact on surgical outcomes. As technological and infrastructural challenges are addressed, PCCT may become a valuable component of image-guided thoracic surgery, contributing to safer, more personalized care. Full article

(This article belongs to the Special Issue Emerging Technologies in Thoracic Surgery)

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11 pages, 228 KB

Open AccessArticle

Documentation of Advance Care Planning in Early Phase Cancer Clinical Trials: An Australian Single-Centre Experience

by Nancy Huang, Joseph Descallar, Samuel Vo, Su Saint Lee, Kate Wilkinson, Aflah Roohullah, Adam Cooper, Victoria Bray, Wei Chua, Danielle Ní Chróinín and Abhijit Pal

Cancers 2025, 17(22), 3655; https://doi.org/10.3390/cancers17223655 - 14 Nov 2025

Abstract

Background/Objectives: Patients with incurable cancers enrolled in early phase clinical trials often face uncertainty about prognosis, yet advance care planning (ACP) is frequently delayed. The objective of this study was to assess the documentation of ACP discussions among patients enrolled in early phase [...] Read more.

Background/Objectives: Patients with incurable cancers enrolled in early phase clinical trials often face uncertainty about prognosis, yet advance care planning (ACP) is frequently delayed. The objective of this study was to assess the documentation of ACP discussions among patients enrolled in early phase oncology trials. Methods: We conducted a retrospective review of electronic medical records for all adults enrolled in early phase clinical trials at a single Australian institution (2012–2021). Data included time from metastatic diagnosis to first ACP discussion, clinical and sociodemographic factors, triggers for discussion, and clinician specialty. Results: Among 170 patients (58% male; median age 65 years), ACP documentation was identified in 109 (64%). ACP was most often initiated within the final year of life (73.8%), with a median interval of 23.5 months from metastatic diagnosis to first documentation. Common triggers were disease progression (39.6%) and hospital admission (37.8%). Discussions were typically led by the treating oncologist or trials specialist (43%) and palliative care physician (37.8%). The most frequently documented topic was the limitations of invasive care such as intubation (60%). Conclusions: ACP documentation was present in two-thirds of patients enrolled in early phase clinical trials, typically late in the disease trajectory. Integrating structured, earlier ACP discussions into oncology pathways would improve alignment of care with patient goals and enhance end-of-life care. Full article

(This article belongs to the Special Issue Medical Complications and Supportive Care in Patients with Cancer (2nd Edition))

14 pages, 551 KB

Open AccessArticle

RapidPlan Knowledge-Based Radiotherapy Planning Compared to Manual Planning in Locally Advanced Non-Small-Cell Lung Cancer

by Tal Falick Michaeli, Tamar Abu Said, Stanislav Raskin, Antoni Skripai, Yakir Rottenberg, Jonathan Arnon and Philip Blumenfeld

Cancers 2025, 17(22), 3654; https://doi.org/10.3390/cancers17223654 - 14 Nov 2025

Abstract

Background/Objectives: Treatment planning for stage III non–small cell lung cancer (NSCLC) presents dosimetric challenges due to the proximity of critical structures. RapidPlan (RP), a knowledge-based planning (KBP) system, offers the potential for improved plan consistency and organ-at-risk (OAR) sparing. The objective of this [...] Read more.

Background/Objectives: Treatment planning for stage III non–small cell lung cancer (NSCLC) presents dosimetric challenges due to the proximity of critical structures. RapidPlan (RP), a knowledge-based planning (KBP) system, offers the potential for improved plan consistency and organ-at-risk (OAR) sparing. The objective of this study was to compare dosimetric and clinical outcomes of RP-generated plans versus manually optimized plans in patients with stage III NSCLC undergoing IMRT or VMAT. Methods: In this retrospective analysis, 50 patients treated with concurrent chemoradiation for stage III NSCLC at Hadassah Medical Center (2015–2021) were analyzed. RP plans were generated using a lung-specific model in the Eclipse treatment planning system and compared with the original clinical manual plans. Dosimetric parameters for target volumes and OARs were evaluated, and subgroup analyses were performed by technique (IMRT vs. VMAT). Toxicity and survival outcomes were analyzed, and Normal Tissue Complication Probability (NTCP) modeling was conducted. Results: RP significantly reduced mean heart dose (Δ = −2.54 Gy, p < 0.001), spinal cord maximum dose (Δ = −4.08 Gy, p < 0.001), and esophageal mean dose (Δ = −3.89 Gy, p < 0.001) compared with manual plans. Lung doses were slightly higher in RP plans (V20 Δ = +2.12%, p < 0.001). VMAT-RP plans demonstrated greater cardiac and esophageal sparing than VMAT-manual plans. RP yielded significant NTCP reductions for the heart (0.34% → 0.20%) and esophagus (16.6% → 11.5%), but no improvement for lung or spinal cord. Lung toxicity ≥ grade 2 was associated with reduced overall survival (16.2 vs. 51.8 months, p < 0.001). Conclusions: RapidPlan-based knowledge-based planning enhances OAR sparing while maintaining target coverage in locally advanced NSCLC. Slight increases in lung dose highlight the need for ongoing model refinement. An association between lung toxicity and reduced survival was observed, underscoring the impact of treatment-related morbidity on outcomes. Full article

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

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15 pages, 2333 KB

Open AccessArticle

Integrating PET and MRI Radiomics for Staging and Prognostic Stratification in Anal Canal Cancer

by Vanessa Murad, Andres Kohan, Lisa Avery, Claudia Ortega, Aruz Mesci, Patrick Veit-Haibach and Ur Metser

Cancers 2025, 17(22), 3653; https://doi.org/10.3390/cancers17223653 - 14 Nov 2025

Abstract

Anal canal cancer accounts for approximately 0 [...] Full article

(This article belongs to the Special Issue Oncology: State-of-the-Art Research in Canada)

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14 pages, 1529 KB

Open AccessArticle

Evaluating the Role of Morphological Subtypes in the Classification of Periampullary Adenocarcinomas

by João Bernardo Sancio, Raul Valério Ponte, Henrique Araújo Lima, Augusto Henrique Marchiodi, Yuiti Pedro Henrique Yamashita, Leonardo do Prado Lima, Priscila Ferreira de Lima e Souza, Eduardo Paulino Junior, Marcelo Dias Sanches and Vivian Resende

Cancers 2025, 17(22), 3652; https://doi.org/10.3390/cancers17223652 - 14 Nov 2025

Abstract

Background: Morphological subclassification may refine prognosis after curative pancreaticoduodenectomy (PD) for periampullary cancers. Methods: We conducted a single-center retrospective cohort including 120 consecutive PDs performed between 2005 and 2022. Tumors were classified as intestinal (INT), pancreatobiliary (PB), or pancreatic ductal adenocarcinoma [...] Read more.

Background: Morphological subclassification may refine prognosis after curative pancreaticoduodenectomy (PD) for periampullary cancers. Methods: We conducted a single-center retrospective cohort including 120 consecutive PDs performed between 2005 and 2022. Tumors were classified as intestinal (INT), pancreatobiliary (PB), or pancreatic ductal adenocarcinoma (PAN). Clinicopathologic variables included T stage, margin status, lymphovascular and perineural invasion, and lymph node ratio (LNR; cutoff 0.154 determined by ROC/Youden). Overall survival (OS) was the primary endpoint and was analyzed using Kaplan–Meier with log-rank tests and multivariable Cox regression. Results: INT tumors were associated with earlier T stage, fewer adverse histologic features, and higher R0 resection rates compared with PB and PAN. In multivariable analysis, mortality risk was higher for PB (HR 4.41; 95% CI 1.25–15.53) and PAN (HR 13.96; 95% CI 3.99–48.75) relative to INT. LNR ≥ 0.154 independently predicted worse OS (HR 1.93; 95% CI 1.11–3.35). Mean OS was 108.8 months for INT, 62.0 months for PB, and 22.7 months for PAN (log-rank p < 0.001). Conclusions: Morphological subtype and LNR are independent prognostic factors after PD for periampullary malignancies. Integrating morphology and nodal burden into risk models may improve postoperative stratification and guide adjuvant therapy. Full article

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

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1 pages, 136 KB

Open AccessCorrection

Correction: Topchu et al. PIP4K2B Protein Regulation by NSD1 in HPV-Negative Head and Neck Squamous Cell Carcinoma. Cancers 2024, 16, 1180

by Iuliia Topchu, Igor Bychkov, Ekaterina Roshchina, Petr Makhov and Yanis Boumber

Cancers 2025, 17(22), 3650; https://doi.org/10.3390/cancers17223650 - 14 Nov 2025

Abstract

In the published publication [...] Full article

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

16 pages, 1601 KB

Open AccessArticle

Quality of Life and Clinical Outcomes in Patients with Skull Base Chordoma and Chondrosarcoma Treated with Pencil-Beam Scanning Proton Therapy

by Katarina Bryjova, Paul-Henry Mackeprang, Dominic Leiser and Damien C. Weber

Cancers 2025, 17(22), 3651; https://doi.org/10.3390/cancers17223651 - 13 Nov 2025

Abstract

Background: skull base chordoma (Ch) and chondrosarcoma (ChSa) are rare neoplasms prone to local relapse. Alongside surgery, proton therapy (PT) is a well-established treatment for them. Given the relatively long patient survival expectancy, post-treatment quality of life (QoL) is crucial. This study [...] Read more.

Background: skull base chordoma (Ch) and chondrosarcoma (ChSa) are rare neoplasms prone to local relapse. Alongside surgery, proton therapy (PT) is a well-established treatment for them. Given the relatively long patient survival expectancy, post-treatment quality of life (QoL) is crucial. This study prospectively assessed long-term QoL in this collective. Methods: seventy-seven adult patients (median age, 50 years; male n = 31; 40.3%) with skull base Ch/ChSa completed at least two EORTC-QLQ-C30 and BN20 questionnaires during and after PT. Oncological outcomes and therapy-related toxicities were recorded during follow-up. QoL was analyzed, with post-treatment scores compared to each patient’s baseline and correlated to oncological outcomes. Results: median follow-up was 51 months (range, 1–94), with 5-year overall survival (5yOS) and local control (5yLC) rates of 88.8% and 82.8%, respectively. The time to local or distant failure ranged from 8 to 58 (median, 22) months. QoL deteriorated directly at completion of PT and two to three years thereafter, especially in patients with local or distant failure. From the fifth year onward, QoL improved again. Complete resection before PT correlated to better QoL at all time points. Disease progression was associated with overall worse QoL, higher neurological symptoms already before PT, and higher symptom burden one year thereafter. Males reported better QoL before and one year after PT than females. Conclusions: PT achieves excellent OS and LC in patients with skull base Ch/ChSa. QoL declines directly after PT but remains close to reference population values. From the fifth year onward, QoL improves again. Gender, resection status, and disease progression significantly affect QoL in these patients. Full article

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

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