Cancers

24 pages, 1614 KB

Open AccessArticle

Leveraging Ensemble Machine Learning Models for the Detection of Primary Myelofibrosis in Electronic Health Records

by Arkadiusz Sycz, Michal J. Dabrowski, Kinga Marciniak, Aleksandra Jurczuk, Anna Meryn, Michał Konopelko, Marek Dudziński, Mirosław Markiewicz, Wojciech Homenda, Marta Sobas, Łukasz Szukalski, Karolina Kaczorowska-Bilska, Agnieszka Gala-Błądzińska, Szymon Fornagiel, Jarosław Piszcz, Grzegorz Helbig, Patryk Węglarz, Sylwia Kot, Paweł Turczyn, Brygida Kwiatkowska, Marcin Rymko, Artur Przelaskowski, Grzegorz W. Basak and Karol Lis Show full author list Hide full author list

Cancers 2026, 18(10), 1618; https://doi.org/10.3390/cancers18101618 (registering DOI) - 16 May 2026

Abstract

Background and Objectives: Primary myelofibrosis (PMF) is a rare hematologic malignancy with non-specific symptoms, causing diagnostic delays and missed diagnoses. Automated screening in heterogeneous electronic health records (EHRs) is challenging due to class imbalance, data sparsity, and incomplete labeling. We investigated two [...] Read more.

Background and Objectives: Primary myelofibrosis (PMF) is a rare hematologic malignancy with non-specific symptoms, causing diagnostic delays and missed diagnoses. Automated screening in heterogeneous electronic health records (EHRs) is challenging due to class imbalance, data sparsity, and incomplete labeling. We investigated two complementary objectives: (1) developing a screening algorithm using routine EHR data to identify PMF-risk patients for hematology consultation, and (2) assessing the applicability of positive-unlabeled (PU) learning. Methods: Using EHR data from 10 Polish hospitals, we evaluated several ensemble models and found that LightGBM achieved the best performance. Results: LightGBM achieved AP 20.83% (95% CI: 19.18–24.35%), sensitivity 45.52% (95% CI: 39.48–52.72%), and precision 14.72% (95% CI: 13.80–17.01%)—substantially exceeding expected prevalence (over 340-fold enrichment). The model captured interactions among RDW and PLT parameters revealing high-risk unlabeled patients with confirmed diagnoses (n = 5) or clinical profiles resembling PMF cases (n = 31), confirming PU problem. Conclusions: Although PU methods enhanced sensitivity, they reduced precision to levels exceeding real-world healthcare capacity. Ensemble learning enables disease identification in clinical settings. Full article

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

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17 pages, 1804 KB

Open AccessArticle

Twenty Years of Cytoreductive Surgery for Advanced Endometrial Carcinoma: A Single-Center Retrospective Cohort Study

by Britt Kilkens, Eva Maria Roes, Ingrid Boere, Jan-Willem Mens and Heleen van Beekhuizen

Cancers 2026, 18(10), 1617; https://doi.org/10.3390/cancers18101617 (registering DOI) - 16 May 2026

Abstract

Objectives: Endometrial carcinoma (EC), the most common gynecological malignancy, is associated with unfavorable survival in advanced stages. Treatment strategies now include cytoreductive surgery (CRS) and (neo)adjuvant chemotherapy, but survival rates remain limited. This study evaluates overall survival (OS) and surgical outcomes, including outcomes [...] Read more.

Objectives: Endometrial carcinoma (EC), the most common gynecological malignancy, is associated with unfavorable survival in advanced stages. Treatment strategies now include cytoreductive surgery (CRS) and (neo)adjuvant chemotherapy, but survival rates remain limited. This study evaluates overall survival (OS) and surgical outcomes, including outcomes of CRS and surgical complications, over a 20-year period at the Erasmus MC. Methods: This retrospective cohort study includes women diagnosed with FIGO stage III or IV EC between 2000 and 2020 who received treatment at the Erasmus MC. Data were collected from the Netherlands Comprehensive Cancer Organization and supplemented by medical record reviews. Statistical analyses were conducted to evaluate differences in OS based on FIGO stage, histological type, molecular characteristics, CRS outcome, and type of CRS. Results: A total of 188 patients were included, with a median age of 66 years. Most patients received surgery and additional chemotherapy and radiotherapy. A total of 64 patients (59.3%) underwent primary CRS, and 44 patients (40.7%) underwent interval CRS. Patients with complete CRS had a significant survival advantage over patients with optimal and incomplete CRS (HR 0.56; 95% CI 0.33–0.96, p = 0.036). Comparison between primary and interval CRS revealed no significant difference in OS (HR 1.42; 95% CI 0.82–2.44, p = 0.207). Surgical complications occurred in 33.1% of patients, with infections most common. Two patients died from severe complications. Conclusions: This study highlights the predominant role of surgery in the management of advanced EC. Complete CRS is often achievable and offers significant survival advantage. However, approximately one-third of patients experience surgical complications. Full article

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

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13 pages, 387 KB

Open AccessArticle

Single-Nucleotide Polymorphism (SNP) c.73G>A in the UBC9 (E2) SUMO Gene and Breast Cancer Risk in Polish Women

by Hanna Romanowicz, Grzegorz Sychowski, Szymon Kalinowski, Szymon Sypniewski, Oleksandr Zakharin, Marek Zadrożny, Honorata Łukasiewicz, Dariusz Samulak and Beata Smolarz

Cancers 2026, 18(10), 1616; https://doi.org/10.3390/cancers18101616 (registering DOI) - 16 May 2026

Abstract

Introduction: Breast cancer is one of the major killers among malignant conditions worldwide, affecting one out of 10 women in industrialized countries and being the leading cause of cancer-related morbidity and mortality in women. The relationships between risk factors and breast cancer [...] Read more.

Introduction: Breast cancer is one of the major killers among malignant conditions worldwide, affecting one out of 10 women in industrialized countries and being the leading cause of cancer-related morbidity and mortality in women. The relationships between risk factors and breast cancer development are not exactly known. The selection of the UBC9 gene and its c.73G>A polymorphism (rs11553473) in breast cancer studies is justified by the gene’s critical role in sumoylation, its impact on DNA repair, and its association with aggressive tumor characteristics. UBC9 (SUMO-conjugating enzyme) is frequently overexpressed in breast cancer, often 5–8-fold higher than in normal tissues, where it promotes tumor proliferation, invasion, and metastasis, often in a sumoylation-independent manner. Aim: In the present work, the association of polymorphism in the UBC9 genes c.73G>A with breast cancer risk was investigated. Materials and Methods: In the reported study, paraffin-embedded tumor tissue was collected from women with lymph node-negative (n = 59) and lymph node-positive (n = 41) ductal breast carcinoma. Samples from age-matched, cancer-free women (n = 100) served as controls. The genotypes of the UBC9 c.73G>A polymorphism were determined by ASO-PCR methods. Results: In the present work, a significant positive association between the UBC9 c.73G>A G/A genotype and breast cancer is demonstrated. The variant A allele of UBC9 increased breast cancer risk. Some correlation was observed between the genotypes of UBC9 polymorphism and breast cancer invasiveness. A statistically significant increase was observed regarding G/A heterozygote frequency in stage II patients, according to Bloom–Richardson classification. There were no significant differences in genotype distribution among subgroups defined by TNM stage, histological grade, hormone receptor status, or HER-2 expression. Conclusions: In conclusion, the reported study indicates that the polymorphisms of the UBC9 gene may be positively associated with the incidence of breast cancer. However, further research is needed on larger study populations. Full article

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

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21 pages, 4157 KB

Open AccessArticle

Optimizing Sequential Targeted Therapies in Advanced Renal Cell Carcinoma Using Patient-Derived Orthotopic Xenograft Mouse Avatars

by Amita Bhattarai, Ravan Moret, Xin Zhang, Grace Maresh, Henry Yip, Carl Haupt, Rachel Graham, Maria Latsis, Marc Matrana, Kyle Rose, Stephen Bardot and Li Li

Cancers 2026, 18(10), 1615; https://doi.org/10.3390/cancers18101615 (registering DOI) - 16 May 2026

Abstract

Background/Objectives: Advanced renal cell carcinoma (aRCC) remains incurable, with no established optimal sequence of targeted therapies due to interpatient heterogeneity and acquired resistance. We developed a luciferase-enabled patient-derived orthotopic xenograft (PDOX) avatar platform to evaluate sequential targeted therapies in individualized aRCC models that [...] Read more.

Background/Objectives: Advanced renal cell carcinoma (aRCC) remains incurable, with no established optimal sequence of targeted therapies due to interpatient heterogeneity and acquired resistance. We developed a luciferase-enabled patient-derived orthotopic xenograft (PDOX) avatar platform to evaluate sequential targeted therapies in individualized aRCC models that recapitulate tumor architecture, proliferation, angiogenesis, metastasis, and PD-L1 expression. Methods: Tumor specimens from two renal cell carcinoma (RCC) patients were expanded subcutaneously in NOD/SCID mice, transduced with luciferase/red fluorescent protein (Luc/RFP), and orthotopically implanted into mouse kidneys (KiCa-Pt58: sarcomatoid RCC, pT3aN1M1, Fuhrman grade 4; KiCa-Pt118: clear cell RCC with sarcomatoid component, pT3aNxM0, Fuhrman grade 4, respectively). Tumor growth and metastasis were monitored weekly by bioluminescence imaging (BLI). Mice were randomized into vehicle control or four sequential treatment groups (Everolimus→Sunitinib [E→S], Sunitinib→Everolimus [S→E], Pazopanib→Sunitinib [P→S], Pazopanib→Everolimus [P→E]). Drugs were administered orally three times weekly until resistance (>200% BLI increase), with one switch. At necropsy, tumor burden, ex vivo BLI metastasis, weights, H&E histology, and immunohistochemistry (Ki67, CD44, CD31, PD-L1) were assessed. Results: Two independent experiments were performed. In dosing optimization, PDOX tumors recapitulated parental histology and proliferative indices, mirroring patient trajectories. KiCa-Pt58 (metastatic sarcomatoid RCC; deceased 1-month post-nephrectomy) showed aggressive features: rapid engraftment at low doses, early growth (week 2), and lung metastases in 78% of mice (sacrifice day 34), reflecting a fulminant course. KiCa-Pt118 (non-metastatic; patient recurrence-free >8 years post nephrectomy) exhibited indolent behavior: delayed engraftment requiring higher doses plus lymph node stromal (HK) support, slower growth (week 4), no metastases, and later sacrifice (day 78), consistent with remission. In sequential therapy evaluation, for KiCa-Pt58, P→E yielded greatest reductions in tumor weight (p < 0.01), lung metastases (p < 0.01), Ki67+ proliferation, CD31+ angiogenesis, and PD-L1 expression versus control; E→S and S→E were also effective. For KiCa-Pt118, S→E and P→E reduced tumor burden (p < 0.01) and Ki67⁺ proliferation; S→E lowered CD31 and PD-L1. Conclusions: This RCC PDOX platform faithfully preserves patient-specific biology—including metastatic propensity, engraftment efficiency, growth kinetics, and stromal dependency—while enabling real-time evaluation of sequential targeted therapies. Given the limited number of models tested, these findings provide proof-of-concept for individualized treatment exploration in advanced RCC and support future investigation of rational combinations with immune checkpoint blockade in humanized or immunocompetent systems. Full article

(This article belongs to the Section Cancer Therapy)

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14 pages, 836 KB

Open AccessArticle

Centralized Homologous Recombination Repair Testing in Metastatic Castration-Resistant Prostate Cancer: Real-World Data from a Multicenter Spanish Precision Oncology Program

by Belén Caramelo, Pilar García-Berbel, Sofia del Carmen, Adriana Calapaqui, Luiz Corrêa, Lucia Martinez-Villaseñor, Marta Sotelo, Federico Rojo, Javier Gómez-Román, Ignacio Duran and Javier Freire

Cancers 2026, 18(10), 1614; https://doi.org/10.3390/cancers18101614 (registering DOI) - 16 May 2026

Abstract

Background/Objectives: Determining homologous recombination repair (HRR) status in metastatic castration-resistant prostate cancer (mCRPC) is essential to ensure access to targeted therapies, particularly PARP inhibitors. Yet, variability in testing access and analysis performance exists. This study evaluated feasibility and outcomes of a centralized HRR [...] Read more.

Background/Objectives: Determining homologous recombination repair (HRR) status in metastatic castration-resistant prostate cancer (mCRPC) is essential to ensure access to targeted therapies, particularly PARP inhibitors. Yet, variability in testing access and analysis performance exists. This study evaluated feasibility and outcomes of a centralized HRR testing strategy in Spain for prostate cancer patients. Methods: A total of 1412 formalin-fixed paraffin-embedded (FFPE) tumor samples from mCRPC patients from 89 Spanish institutions within a centralized multicenter molecular testing program were analyzed using a standardized 38-gene-based next-generation sequencing (NGS) assay in a central laboratory (HRR OncoKit, Health in Code, Valencia, Spain), which included five clinically relevant HRR genes: BRCA1, BRCA2, CHEK2, ATM, and CDK12. Results: HRR gene pathogenic or likely pathogenic alterations were identified in 18% (CI 95% = 16–20) of the patients, with BRCA2 being the most frequently altered gene (6%), followed by ATM (5%), CDK12 (4%), BRCA1 (2%), and CHEK2 (1%). Eleven percent had variants of uncertain significance. Only 13% of the samples were rejected due to poor DNA quality, low tumor content or sample age exceeding 5 years, and 2% of the samples analyzed failed since the minimum library technical quality score was not achieved. The average turnaround time for results was 18 ± 3 days. Conclusions: Centralized HRR testing in mCRPC patients in Spain was feasible, efficient and reliable, identifying pathogenic alterations in 18% of the cases, similarly to the prevalence described in the literature. This testing approach facilitates precision medicine by improving the detection of actionable HRR alterations. Full article

(This article belongs to the Section Cancer Biomarkers)

28 pages, 10544 KB

Open AccessArticle

Non-Temperature-Induced Antitumor Effects of Amplitude-Modulated Radiofrequency: Molecular and Functional Synergies with Radiotherapy

by Paraskevi Danai Veltsista, Wolfgang Walther, Sebastian Torke, Andranik Ivanov, Anna Dieper, Dieter Beule, Daniel Zips, Ulrike Stein and Pirus Ghadjar

Cancers 2026, 18(10), 1613; https://doi.org/10.3390/cancers18101613 (registering DOI) - 16 May 2026

Abstract

Background/Objectives: Amplitude-modulated radiofrequency (AMRF) fields have emerged as promising non-temperature-induced strategies in oncology. While conventional hyperthermia (HT) relies on thermal stress, the biological impact of AMRF, particularly in combination with radiotherapy (RT), remains insufficiently characterized. Methods: We assessed RF and AMRF, alone or [...] Read more.

Background/Objectives: Amplitude-modulated radiofrequency (AMRF) fields have emerged as promising non-temperature-induced strategies in oncology. While conventional hyperthermia (HT) relies on thermal stress, the biological impact of AMRF, particularly in combination with radiotherapy (RT), remains insufficiently characterized. Methods: We assessed RF and AMRF, alone or with RT, using phenotypic analyses of proliferation, apoptosis, and necrosis across four cancer cell lines (HT29, SW620, U343, U138). Transcriptomic profiling with Kyoto Encyclopedia of Genes and Genomes (KEGG), GO:BP, and Reactome enrichment was performed in SW620 and U138 cells, selected for their strong phenotypic responses. Results: Across the panel, AMRF was associated with broader cytotoxic responses than RF or HT in most but not all cell lines. AMRF+RT produced the strongest necrotic responses, with cell-line-specific exceptions identified explicitly in the Results (the absence of a significant AMRF+RT apoptotic effect in SW620 and the absence of a significant AMRF+RT necrotic response in U343). In SW620 cells, AMRF was associated with extensive transcriptional reprogramming involving immune modulation, extracellular matrix remodeling, and cell cycle regulation, whereas RF alone showed narrower and delayed effects. In contrast, U138 cells showed elevated apoptosis and necrosis but limited transcriptional changes—a phenotype–transcriptome divergence that points to mechanisms operating downstream of transcription and warrants functional investigation in dedicated follow-up studies. Conclusions: AMRF and AMRF+RT emerge as promising non-temperature-induced anticancer modalities in the cell-line models profiled here, with the pattern of response varying between cell lines. These findings expand the biological impact of RF-based treatments and set the grounds for further investigation in mechanistic and translational studies. Full article

(This article belongs to the Special Issue Feature Papers in Section “Methods and Technologies Development” in 2026)

15 pages, 1074 KB

Open AccessArticle

Risk Factors and Nonlinear Risk Patterns of Prolonged Air Leak After Robot-Assisted Lung Resection for Lung Cancer: A Retrospective Cohort Study

by Hao Xu, Han Zhang and Linyou Zhang

Cancers 2026, 18(10), 1612; https://doi.org/10.3390/cancers18101612 - 15 May 2026

Abstract

Background/Objectives: Prolonged air leak (PAL) remains a common complication after lung resection and may delay postoperative recovery and subsequent treatment. This study aimed to identify clinical factors associated with PAL after robot-assisted thoracic surgery (RATS) and to explore potential nonlinear relationships using restricted [...] Read more.

Background/Objectives: Prolonged air leak (PAL) remains a common complication after lung resection and may delay postoperative recovery and subsequent treatment. This study aimed to identify clinical factors associated with PAL after robot-assisted thoracic surgery (RATS) and to explore potential nonlinear relationships using restricted cubic spline (RCS) modeling. Methods: A retrospective cohort of 1185 patients who underwent RATS for primary lung cancer was analyzed. Multivariable Firth logistic regression was used to identify independent predictors of PAL (≥5 days). A nomogram was constructed based on the final model and internally validated using 1000 bootstrap resamples; its clinical utility was assessed using decision curve analysis. RCS analysis was performed to evaluate potential nonlinear associations. Results: A total of 98 patients (8.3%) developed PAL. Male sex was independently associated with increased PAL risk (OR 3.29, p < 0.001), whereas higher FEV1 was associated with reduced risk (OR 0.50 per 1-L increase, p < 0.001). BMI showed a modest protective effect (OR 0.91, p = 0.01). Age was not significant in the linear model (p = 0.86), but RCS analysis demonstrated a significant nonlinear association, with increased risk at older ages. The nomogram demonstrated moderate discrimination (apparent C-statistic 0.670, optimism-corrected 0.644) and good calibration, with decision curve analysis confirming net clinical benefit over treat-all and treat-none strategies. Conclusions: Male sex and impaired pulmonary function are key predictors of PAL after RATS. Nonlinear modeling revealed complex age-related risk patterns not captured by conventional approaches. The proposed nomogram may assist in preoperative risk stratification and perioperative decision-making. Full article

(This article belongs to the Special Issue Advances in Minimally Invasive Surgery in Thoracic Oncology)

23 pages, 1730 KB

Open AccessReview

Mitochondrial Hijacking and MicroRNA Crosstalk: Cancer Stem Cell-Mediated Immune Evasion and Metabolic Plasticity in the Tumor Microenvironment

by Maziar Ashrafian Bonab, Shahrzad Salehi, Amirreza Aghababaie, Ali Amini, Hoda Alizadeh and Babak Behnam

Cancers 2026, 18(10), 1611; https://doi.org/10.3390/cancers18101611 - 15 May 2026

Abstract

The tumor microenvironment (TME) is a highly adaptive and heterogeneous niche in which cancer stem cells (CSCs) promote immune evasion, metastatic dissemination, and therapy resistance. Among the mechanisms that support this phenotype, mitochondrial hijacking has emerged as a central strategy through which CSCs [...] Read more.

The tumor microenvironment (TME) is a highly adaptive and heterogeneous niche in which cancer stem cells (CSCs) promote immune evasion, metastatic dissemination, and therapy resistance. Among the mechanisms that support this phenotype, mitochondrial hijacking has emerged as a central strategy through which CSCs reprogram immune and stromal cells to favor tumor progression. This review synthesizes current evidence on how CSCs exploit mitochondrial transfer, particularly via tunneling nanotubes (TNTs) and extracellular vesicles (EVs), to impair antitumor immunity and remodel the metastatic niche. CSCs display marked metabolic plasticity, shifting between glycolysis and oxidative phosphorylation (OXPHOS) in response to environmental stress. They exploit this adaptability by transferring mitochondria and mitochondrial components to recipient cells, including tumor-associated macrophages (TAMs) and cytotoxic T cells, thereby disrupting ATP production, increasing oxidative stress, and skewing immune polarization. This mitochondrial hijacking contributes to an immunosuppressive milieu, stabilizes HIF-1α, and enhances PD-L1 expression, ultimately weakening T-cell activity and reinforcing CSC survival. EVs add another layer of regulation by transporting bioactive cargo, including oncogenic microRNAs (miRNAs) and mitomiRs such as miR-21, miR-210, and miR-34a. These molecules modulate mitochondrial gene expression, reshape immune signaling, and reinforce CSC phenotypes through autocrine and paracrine loops. Single-cell and spatial transcriptomic approaches have further revealed metabolic heterogeneity within CSC–immune synapses, identifying “metabolic hotspots” associated with profound immune dysfunction. Therapeutic strategies targeting OXPHOS, EV biogenesis, and miRNA activity are therefore being explored. In parallel, mitochondria-associated proteins such as TSGA10 may also contribute to CSC-driven immunometabolism regulation and deserve further investigation. Targeting downstream heterogeneity is like cutting the branches of a weed. Targeting the upstream mechanisms of mitochondrial hijacking and miRNA crosstalk aims to destroy the root (CSC plasticity) that generates the heterogeneity and drives therapy resistance in the first place. This review highlights mitochondrial hijacking and miRNA-mediated reprogramming as central determinants of CSC-driven immune escape and proposes a framework for precision interventions targeting CSC–immune interactions in metastatic cancer. Full article

(This article belongs to the Special Issue Advances in Cellular Heterogeneity and Plasticity in the Tumor Microenvironment)

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47 pages, 3333 KB

Open AccessReview

miRNA–lncRNA Cross-Regulation Landscape in Cancer: From Molecular Mechanisms to Therapeutic and Diagnostic Applications

by Giuseppe Scafuro, Myriam Karam, Ayesha Khan, Chiara Tammaro, Takehiro Nagatsuka, Anna Grimaldi, Alessia Maria Cossu, Silvia Zappavigna, Michele Caraglia, Gabriella Misso and Michela Falco

Cancers 2026, 18(10), 1610; https://doi.org/10.3390/cancers18101610 - 15 May 2026

Abstract

Background/Objectives: Over the past two decades, non-coding RNAs (ncRNAs) have emerged as key regulators of gene expression, reshaping the classical view of the genome as predominantly protein-coding. Among them, microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) play central roles in controlling gene expression [...] Read more.

Background/Objectives: Over the past two decades, non-coding RNAs (ncRNAs) have emerged as key regulators of gene expression, reshaping the classical view of the genome as predominantly protein-coding. Among them, microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) play central roles in controlling gene expression at multiple levels. Rather than acting independently, these molecules form complex and interconnected regulatory networks, and their interplay appears particularly relevant in cancer. This review aims to examine the mechanisms underlying miRNA-lncRNA cross-regulation and to explore their functional and clinical implications in tumor biology. Methods: We performed a comprehensive analysis of the current literature focusing on studies investigating miRNA-lncRNA interactions in cancer. Particular attention was given to mechanistic insights, including the competing endogenous RNA (ceRNA) hypothesis, as well as alternative regulatory models involving direct RNA interactions and chromatin-associated processes. Results: miRNA-lncRNA interactions have been associated with cancer progression and therapeutic response across different tumor types, although their mechanisms are highly context-dependent. While the ceRNA hypothesis, based on competition for shared microRNA response elements (MREs), provides a useful framework, it does not fully explain all observed phenomena. Evidence shows that miRNAs can directly regulate lncRNA stability, whereas lncRNAs can influence miRNA biogenesis. Additionally, chromatin-related mechanisms suggest that these interactions extend beyond post-transcriptional regulation. These RNA networks intersect with major oncogenic pathways, including PI3K/AKT/mTOR signaling, hypoxia responses, and epigenetic regulators such as EZH2, thereby affecting key cancer processes such as proliferation, epithelial–mesenchymal transition (EMT), and metabolic reprogramming. From a clinical perspective, the stability of ncRNAs in biological fluids highlights their potential as biomarkers. Combined miRNA-lncRNA signatures may improve diagnostic and prognostic accuracy compared to single markers, although further validation is required. Therapeutic strategies targeting ncRNA networks, such as miRNA mimics, antagomiRs, and lncRNA-directed approaches, are under investigation; however, challenges related to delivery, specificity, and toxicity remain. Conclusions: miRNA-lncRNA cross-regulation represents a complex and multifaceted layer of gene regulation in cancer. A deeper understanding of these interactions could support the development of more accurate diagnostic tools and more effective RNA-based therapeutic strategies, although significant technical and biological challenges still need to be addressed. Full article

(This article belongs to the Special Issue Targeting RNA to Improve Cancer Precision Medicine)

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17 pages, 2811 KB

Open AccessArticle

Efficacy of Spectral-Aided Visual Enhancer in Classification of Esophageal Cancer

by Kok-Yean Koh, Arvind Mukundan, Riya Karmakar, Chaudhary Tirth Atulbhai, Tsung-Hsien Chen, Wei-Chun Weng and Hsiang-Chen Wang

Cancers 2026, 18(10), 1609; https://doi.org/10.3390/cancers18101609 - 15 May 2026

Abstract

Background/Objectives: Esophageal cancer is one of the major global causes of cancer mortality, and the 5-year survival rate remains below 20% because many cases are detected late. In this study, a Spectral-Aided Vision Enhancer (SAVE) algorithm was utilized to convert conventional white-light endoscopic [...] Read more.

Background/Objectives: Esophageal cancer is one of the major global causes of cancer mortality, and the 5-year survival rate remains below 20% because many cases are detected late. In this study, a Spectral-Aided Vision Enhancer (SAVE) algorithm was utilized to convert conventional white-light endoscopic images (WLI) into hyperspectral-like narrow-band imaging (NBI) images for machine-learning classification of Dysplasia, Normal, and Squamous Cell Carcinoma (SCC). Methods: A total of 762 WLI images obtained from Kaohsiung Medical University were augmented to 1074 using the Al bumentations library, employing vertical flipping, horizontal flipping, and rotations. The SAVE conversion pipeline employs a 24-patch Macbeth color checker for calibration, γ-correction, CIE XYZ transformation, and multivariate regression to interpolate spectral bands, yielding an average color difference of 2.79 (CIEDE2000) from true NBI. The training outcomes and performance metrics illustrate the versatility of the machine learning/deep learning models—Random Forest (RF), Support Vector Machine (SVM), and Convolutional Neural Network (CNN)—which were trained and evaluated on both the original WLI and SAVE datasets. Performance metrics were analyzed based on precision, recall, accuracy, and F1-score. Results: The CNN sample achieved an accuracy of 100 percent on SAVE data, compared to 93 percent for WLI. The accuracy of RF improved, with WLI at 91% and SAVE at 96%, while SVM increased from 79% to 84%. These improvements indicate the diagnostically valuable spectral variations that can be amplified with SAVE, resulting in significant enhancements in pre-cancer/SCC sensitivity. Conclusions: The proposed SAVE method demonstrates significant potential for enhancing endoscopic imaging and advancing computer-aided diagnosis in esophageal cancer screening, with applicability in other gastrointestinal imaging scenarios as well. Full article

(This article belongs to the Special Issue Advances in Endoscopic Management of Esophageal Cancer)

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22 pages, 6875 KB

Open AccessArticle

Integrative Multi-Omics Analysis Identifies IL18R1 as a Circulating Prognostic Biomarker for Risk Stratification in Extensive-Stage Small Cell Lung Cancer

by Shengjuan Hu, Sicong Li, Yiyuan Cui, Ying Wang, Luyao Chen, Xiyuan Zhang, Li Hou and Li Feng

Cancers 2026, 18(10), 1608; https://doi.org/10.3390/cancers18101608 - 15 May 2026

Abstract

Background: Small cell lung cancer (SCLC) carries a dismal prognosis with limited biomarkers for risk stratification. This study aimed to identify circulating prognostic biomarkers. Methods: We prioritized SCLC risk-associated genes using Summary-data-based Mendelian Randomization of pQTL/eQTL, differential expression, and weighted gene [...] Read more.

Background: Small cell lung cancer (SCLC) carries a dismal prognosis with limited biomarkers for risk stratification. This study aimed to identify circulating prognostic biomarkers. Methods: We prioritized SCLC risk-associated genes using Summary-data-based Mendelian Randomization of pQTL/eQTL, differential expression, and weighted gene co-expression network analysis. Five machine learning approaches were compared to develop a diagnostic model based on ACE, AGER, and IL18R1, trained on GSE149507 and validated in GSE60052. We conducted single-cell transcriptomic analysis using public datasets (GSE150766 and GSE279570) and peripheral blood mononuclear cells (PBMCs) from our extensive-stage cohort. Finally, prioritizing the lead candidate IL18R1, we enrolled a prospective clinical cohort to assess its prognostic utility. A LASSO–Cox prognostic model incorporating plasma IL18R1 and clinical variables was internally validated (7:3 split) for progression-free survival (PFS) prediction. Results: Integrative multi-omics identified ACE, AGER, and IL18R1 as SCLC-protective genes. Elastic Net machine learning identified a two-gene predictive signature (AGER and IL18R1) with robust diagnostic accuracy. Single-cell RNA sequencing revealed the predominant downregulation of ACE, AGER, and IL18R1 in T cells and alveolar type II cells from SCLC patients. PBMC analysis further supported IL18R1 downregulation in CD8⁺ T cells, NK cells, and dendritic cells. In an independent prospective cohort (n = 300), lower plasma IL18R1 levels were independently associated with shorter PFS (HR = 0.997 per unit increase; 95% CI: 0.995–0.999; and p = 0.003), with time-dependent AUCs of 0.77–0.86. Performance in limited-stage disease was inconsistent and requires further validation. A prognostic model incorporating plasma IL18R1 and 11 clinical parameters stratified patients into distinct risk groups (HR = 5.19), showing a strong discriminative ability in extensive-stage SCLC. Conclusions: We identified ACE, AGER, and IL18R1 as protective factors against SCLC progression. Integration of plasma IL18R1 with clinical parameters provides a prognostic tool for extensive-stage SCLC. Full article

(This article belongs to the Topic Biomarkers of Disease: Discovery and Clinical Applications)

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23 pages, 4124 KB

Open AccessArticle

Tumor Implantation Site of Syngeneic Oral Cancer Models Differentially Induces Site-Dependent Local and Systemic Immunosuppression

by Andrea H. Molina, Gemalene M. Sunga, Shawn Nguyen, Neeraja Dharmaraj, Ratna Veeramachaneni, Roberto Rangel, Jeffrey N. Meyers, Jeffrey D. Hartgerink, Andrew G. Sikora and Simon Young

Cancers 2026, 18(10), 1607; https://doi.org/10.3390/cancers18101607 - 15 May 2026

Abstract

Background/Objectives: Preclinical studies of head and neck squamous cell carcinoma (HNSCC) commonly use subcutaneous heterotopic (flank) tumor models for simplicity; however, orthotopic models may better reflect the native tumor environment. Direct comparisons of the tumor immune microenvironments (TIME) and tumor-draining lymph nodes (tdLNs) [...] Read more.

Background/Objectives: Preclinical studies of head and neck squamous cell carcinoma (HNSCC) commonly use subcutaneous heterotopic (flank) tumor models for simplicity; however, orthotopic models may better reflect the native tumor environment. Direct comparisons of the tumor immune microenvironments (TIME) and tumor-draining lymph nodes (tdLNs) between these models remain limited. Better understanding of site-specific immune differences could improve model selection and interpretation of translational HNSCC studies. Methods: ROC1 tumors were established in murine heterotopic and orthotopic sites, followed by assessment of tumor growth kinetics, survival, and the tumor microenvironment. Immune composition of tumors, blood, tdLNs, and spleen was evaluated at three tumor progression timepoints using multiparameter spectral flow cytometry. Results: Heterotopic and orthotopic tumor models showed similar growth kinetics and survival. Immune profiling revealed increased infiltration of CD3⁺ T-cells, natural killer (NK) cells, and myeloid populations in both models. Heterotopic tumors were enriched in dendritic cells (DCs), plasmacytoid DCs, and monocytic myeloid-derived suppressor cells (M-MDSCs), whereas orthotopic tumors showed increased macrophages, granulocytic MDSCs, and M-MDSCs. Despite temporal variation, both TIMEs were dominated by macrophages, DCs, and CD3⁺ T-cells. Late-stage heterotopic tumors contained more CD4⁺ T-cells. Reduced T-cell cytotoxicity (PD-1, CD107a) and increased immune checkpoint expression across myeloid cells indicated an immunosuppressive TIME. Systemically, effector cells were preserved despite suppressive cell trafficking, and tdLNs in both models exhibited immunosuppressive PD-L1 expression. Conclusions: Heterotopic and orthotopic ROC1 tumors share key immune features, but site-specific differences in the TIME and tdLNs reveal tissue-dependent regulation. These local effects align with systemic changes, supporting global tumor-associated immunosuppression. Full article

(This article belongs to the Special Issue Decoding and Remodeling the Suppressive Tumor Immune Microenvironment in Head and Neck Cancer)

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21 pages, 3412 KB

Open AccessArticle

EZH2-Associated Hypermethylated Gene Signature Predicts Immunotherapy Response and Implicates DUSP5 in Tumor-Immune Regulation in Triple-Negative Breast Cancer

by Mingzhan Xue, Sujitha Jeya, Reem Elasad, Sarra Mestiri, Fares Al Ejeh and Mariam Al-Muftah

Cancers 2026, 18(10), 1606; https://doi.org/10.3390/cancers18101606 - 15 May 2026

Abstract

Background/Objectives: Triple-negative breast cancer (TNBC) is a candidate for immune checkpoint blockade; however, current biomarkers remain insufficient to predict therapeutic response or capture tumor-intrinsic mechanisms. Enhancer of Zeste Homolog 2 (EZH2)-mediated epigenetic repression has been implicated in immune evasion, yet the contribution of [...] Read more.

Background/Objectives: Triple-negative breast cancer (TNBC) is a candidate for immune checkpoint blockade; however, current biomarkers remain insufficient to predict therapeutic response or capture tumor-intrinsic mechanisms. Enhancer of Zeste Homolog 2 (EZH2)-mediated epigenetic repression has been implicated in immune evasion, yet the contribution of EZH2-repressed genes to anti-tumor immunity and clinical outcomes in TNBC remains unclear. We aimed to identify EZH2-associated epigenetically repressed genes in TNBC and evaluate their relevance as tumor-intrinsic regulators and potential predictors of immunotherapy outcome. Methods: We performed integrative in silico analyses of The Cancer Genome Atlas (TCGA) breast cancer cohorts to identify EZH2-associated hypermethylated genes in TNBC. A composite 30-gene signature (30GS) was defined based on transcriptional repression and promoter hypermethylation. Associations with clinical outcomes, tumor- and immune-related programs, and therapeutic response were evaluated, with validation in the I-SPY2 cohort and an independent TNBC patient cohort. Results: The 30GS was significantly reduced in TNBC and basal-like tumors and associated with improved clinical outcomes and enrichment of tumor- and immune-related signatures. In the I-SPY2 cohort, the 30GS predicted pathological complete response in patients receiving chemo-immunotherapy (AUC = 0.7377, p = 0.0007). Gene-level analysis identified Dual Specificity Phosphatase 5 (DUSP5) as the gene most consistently associated with immune-related parameters. In an independent TNBC cohort, DUSP5-high tumors demonstrated transcriptional programs enriched for inflammatory, immune-related, and signaling pathways within the NanoString Breast Cancer 360 panel. Conclusions: This study defines an EZH2-associated epigenetic program linked to tumor-intrinsic immune programs in TNBC and identifies DUSP5 as a candidate gene associated with immune-related transcriptional states. Full article

(This article belongs to the Section Cancer Biomarkers)

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11 pages, 1955 KB

Open AccessArticle

P16 DNA Methylation Coupled with Somatic Copy Number Variations in the Development of Gastric Carcinomas

by Ziqian Yang, Jing Zhou, Lewen Deng, Juanli Qiao, Liankun Gu and Dajun Deng

Cancers 2026, 18(10), 1605; https://doi.org/10.3390/cancers18101605 - 15 May 2026

Abstract

Background/Objectives: Tumor suppressor genes are often inactivated by genetic and epigenetic mechanisms. However, whether genetic alterations of these genes, including CDKN2A/P16, are coupled with epigenetic changes in cancer development and progression is unknown. Methods: Freshly frozen gastric carcinoma (GC) samples, [...] Read more.

Background/Objectives: Tumor suppressor genes are often inactivated by genetic and epigenetic mechanisms. However, whether genetic alterations of these genes, including CDKN2A/P16, are coupled with epigenetic changes in cancer development and progression is unknown. Methods: Freshly frozen gastric carcinoma (GC) samples, paired noncancer surgical margin (SM) samples, white blood cell (WBC) samples, and clinicopathological information were collected from 200 patients. The copy number (CN) of the CDKN2A/P16 gene in these samples was determined by a P16-Light assay and normalized to that in white blood cells (WBCs). The DNA methylation level of the P16 promoter in GC and SM samples was determined by a 115 bp P16-specific MethyLight assay. Results: Both the P16 copy number and the DNA methylation level were significantly lower in GC samples than in SM samples (median, 1.94 vs. 2.14, p < 0.001 for P16 CN; 0.0004 vs. 0.0013, p = 0.002 for P16 methylation) and were associated with GC metastasis. The normalized P16 copy number was significantly lower in GCs without vs. with P16 methylation (p = 0.007). Similarly, more P16 somatic copy number deletions (SCNdel) were detected in GCs without vs. with P16 methylation (38.6% vs. 24.1%, p = 0.027). Conclusions: Somatic P16 copy number variations are closely coupled with P16 promoter DNA methylation during GC development. SCNdel and promoter DNA methylation complementarily inactivate P16 in GC development and promote GC metastasis. Full article

(This article belongs to the Section Cancer Metastasis)

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15 pages, 672 KB

Open AccessReview

Intraoperative Peritoneal Lavage for Detection of Malignant Cells: Technique, Evidence, Clinical Relevance and Future Perspectives

by Resa Puffert, Anna Quarder, Fabian Kockelmann, Thomas Wirth, Tanja Reineke-Plaaß, Mieke Raap, Moritz Schmelzle, Linda Feldbrügge, Beate Rau and Franziska Köhler

Cancers 2026, 18(10), 1604; https://doi.org/10.3390/cancers18101604 - 14 May 2026

Abstract

Background/Objectives: Peritoneal metastases represent a common manifestation of advanced gastrointestinal malignancies and are associated with poor survival. Their early detection is essential for adequate tumor staging, prognosis, and treatment selection, especially to avoid unnecessary surgery. Intraoperative peritoneal lavage has been established as a [...] Read more.

Background/Objectives: Peritoneal metastases represent a common manifestation of advanced gastrointestinal malignancies and are associated with poor survival. Their early detection is essential for adequate tumor staging, prognosis, and treatment selection, especially to avoid unnecessary surgery. Intraoperative peritoneal lavage has been established as a diagnostic tool to detect occult peritoneal disease. However, reported techniques, analytical methods, and detection rates vary considerably. The objective of this review was to summarize current approaches to intraoperative peritoneal lavage, evaluate different detection methods, and assess their clinical relevance. Methods: A literature search was performed using the PubMed database for studies published between 2015 and 2025. The search terms “intraoperative peritoneal lavage” or “peritoneal fluid cytology” were used. Studies were included if they evaluated peritoneal lavage as a diagnostic method for detecting malignant cells, including all primary tumors and disease stages. Articles focusing on lavage as a therapeutic intervention or lacking methodological details were excluded. Results: Physiological saline solution was used for lavage in all included studies, with volumes ranging from 10 to 1000 mL. Sampling was predominantly performed immediately after abdominal access in various abdominal sites. Detection methods varied widely, with conventional cytology being most frequently used, while molecular techniques were used in a smaller number of studies. Positive detection rates showed broad variations and were higher in advanced tumor stages. Conventional cytology showed limited detection rates compared to molecular approaches. Conclusions: Intraoperative peritoneal lavage remains a valuable but methodologically heterogeneous diagnostic tool with limited detection rates when relying on conventional cytology alone. Molecular techniques seem to improve the detection rate of occult peritoneal disease but require further standardization and validation before routine clinical implementation. The technique of peritoneal lavage should be standardized by implementing an international consensus including lavage sites, volume of applied fluid, and detection method. Full article

(This article belongs to the Special Issue Surgical Innovations in Advanced Gastric Cancer)

15 pages, 3616 KB

Open AccessArticle

Validation of Synthetic Megavoltage Computed Tomography (MVCT) for Dose Calculation in Radiotherapy Treatment Planning

by Aurora Corso, Niki Martinel, Mubashara Rehman, Joseph Stancanello, Christian Micheloni, Cristian Deana, Cristina Cappelletto, Paola Chiovati, Riccardo Spizzo, Giuseppe Fanetti, Andrea Dassie and Michele Avanzo

Cancers 2026, 18(10), 1603; https://doi.org/10.3390/cancers18101603 - 14 May 2026

Abstract

Background/Objectives: Dental metallic implants cause severe streaking artifacts in kilovoltage CT (kVCT), compromising dose calculation in radiotherapy (RT) treatment planning. The purpose of this study is to assess the dosimetric agreement of synthetic MVCT (sMVCT) images generated from artifact-affected kVCT using a [...] Read more.

Background/Objectives: Dental metallic implants cause severe streaking artifacts in kilovoltage CT (kVCT), compromising dose calculation in radiotherapy (RT) treatment planning. The purpose of this study is to assess the dosimetric agreement of synthetic MVCT (sMVCT) images generated from artifact-affected kVCT using a deep learning network with respect to true MVCT (tMVCT) acquired at the treatment machine. Methods: Nineteen head and neck cancer patients with dental metallic implants treated with RT were included. Planning kVCT images were converted to sMVCT using Metal Artifact Reduction through Domain Transformation Network (MAR-DTN), a UNet-inspired deep learning network. The sMVCT images were rigidly registered to true MVCT (tMVCT) acquired on the Hi-Art II Tomotherapy system. Mean Hounsfield Unit (HU) values were compared across seven structures (thyroid, bilateral parotids, brainstem, spinal cord, GTV, PTV70) using pairwise Wilcoxon tests and Two One-Sided Tests (TOST) for statistical equivalence within a pre-specified margin of ±20 HU (corresponding to a 2% deviation in physical density). Dose distributions were recalculated on sMVCT using the AAA algorithm and compared to reference tMVCT-based plans via dose–volume histogram (DVH) metrics, evaluated for equivalence by TOST within a margin of ±2% of the prescribed dose (±142 cGy of 70.95 Gy), and via 3D gamma index, evaluated by one-sided non-inferiority test against the clinically accepted thresholds of 90% (2 mm/2%) and 95% (3 mm/3%). A pre-specified sensitivity analysis was performed by repeating all comparisons on the strictly independent sub-cohort (n = 16) excluding three patients drawn from the MAR-DTN training set. Results: All seven anatomical structures showed statistical equivalence between sMVCT and tMVCT under the ±20 HU margin (TOST p < 0.05; mean HU differences in the range −1.1 to +8.4 HU; all Wilcoxon p > 0.05). All nine DVH metrics achieved formal dosimetric equivalence within ±2% of the prescribed dose (TOST p < 0.05). Mean 3D gamma pass rates were 94.3% (95% CI: 89.3–97.1) for the 2 mm/2% criterion and 97.6% (95% CI: 94.8–99.0) for the 3 mm/3% criterion, both formally non-inferior to the respective clinical thresholds (p < 0.0001). Residual gamma failures were concentrated at the patient surface, consistent with inter-session repositioning uncertainty rather than errors in synthetic image generation. Sensitivity analysis on the n = 16 sub-cohort confirmed all conclusions, with mean HU and DVH differences smaller than in the full cohort for the structures showing the largest mean differences, and comparable for the remaining structures, with all TOST equivalence and gamma non-inferiority tests confirmed in both cohorts. Conclusions: sMVCT images generated via MAR-DTN show dosimetric agreement with physically acquired tMVCT in head and neck patients with dental implants, formally demonstrated by TOST equivalence within ±2% of prescribed dose for all DVH metrics. The combined HU and gamma index framework presented here represents a promising quality assurance approach for AI-based synthetic imaging tools in radiotherapy, pending validation in larger prospective multicentre cohorts. Full article

(This article belongs to the Special Issue AI-Enhanced Radiotherapy in Oncology: Optimization from Planning to Clinical Impact)

14 pages, 604 KB

Open AccessArticle

Analysis of the Frequency and Associated Factors of Skin Toxicity in Patients Receiving Ribociclib-Based Therapy for Metastatic Breast Cancer

by Esther Kim, Youra Lim, Ahrong Ham, Hyun Goo Kim, Jun Woo Lee, Jang Hee Lee, Joohyun Woo, Woosung Lim, Byung In Moon, Sei Hyun Ahn, Hye Ah Lee and Kyoung Eun Lee

Cancers 2026, 18(10), 1602; https://doi.org/10.3390/cancers18101602 - 14 May 2026

Abstract

Introduction: In the treatment of hormone receptor-positive (HR+), HER2-negative (HER2−) metastatic breast cancer (MBC), the current guidelines recommend endocrine therapy combined with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors as the preferred first-line treatment to preserve quality of life. Ribociclib is a CDK4/6 inhibitor that [...] Read more.

Introduction: In the treatment of hormone receptor-positive (HR+), HER2-negative (HER2−) metastatic breast cancer (MBC), the current guidelines recommend endocrine therapy combined with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors as the preferred first-line treatment to preserve quality of life. Ribociclib is a CDK4/6 inhibitor that has been used in combination with aromatase inhibitors or fulvestrant in patients with HR+, HER2− metastatic breast cancer. Various adverse drug reactions associated with ribociclib have been reported, including cutaneous reactions, hepatotoxicity, and hematologic toxicity. In this study, we aimed to evaluate the clinical manifestations and risk factors of dermatologic toxicities in patients with metastatic breast cancer treated with ribociclib. Methods: This retrospective study included patients with metastatic/recurrent breast cancer who were prescribed ribociclib from April 2021 to December 2024 at a single institution. We retrospectively reviewed the medical records of these patients to identify the frequency of cutaneous adverse events, the time of onset, and the clinical characteristics of skin reactions. Logistic regression analysis was performed on several clinical factors, including body surface area (BSA) and concomitant medications, to identify risk factors associated with the occurrence of cutaneous adverse events. Results: A total of 110 patients with MBC were enrolled during the study period. The median age was 53 years (range, 28–82); all 110 patients (100.0%) were female; the median BSA was 1.56 m² (range, 1.29–2.07); and 32 patients (29.1%) were premenopausal. Ribociclib plus letrozole was administered in 48 patients (43.6%) and ribociclib plus fulvestrant in 29 patients (26.4%). An additional 33 patients (30.0%) received ribociclib plus letrozole with a gonadotropin-releasing hormone (GnRH) agonist. Cutaneous adverse events occurred in 29 patients (26.4%), and the median time to onset was 84 days (range, 3–498). The cutaneous adverse event patterns included pruritus, erythematous macular rash, eczematous rash/contact dermatitis, vitiligo, urticarial reactions, polymorphous light eruption, toxic epidermal necrolysis (TEN), and desquamation. Grade 1 or 2 cutaneous adverse events occurred in 93.1% of patients; Grade 3 toxicity occurred in one patient; and Grade 4 toxicity, namely toxic epidermal necrolysis (TEN), was reported in one patient. Dose reduction was required in three patients (10.3%), and permanent discontinuation of ribociclib occurred in one patient. Clinical improvement was achieved in the majority of patients (86.2%) with cutaneous adverse events following supportive care. Logistic regression analysis revealed that age, Eastern Cooperative Oncology Group (ECOG) performance status, body surface area (BSA), treatment regimen, and use of cholesterol-lowering medications were not independently associated with the development of cutaneous adverse events. Conclusion: CDK4/6 inhibitors represent one of the most important treatment options for HR+/HER2− metastatic breast cancer. Regardless of their clinical efficacy, cutaneous adverse events remain a common source of patient discomfort. Therefore, careful clinical attention and appropriate supportive care are essential to improve patients' quality of life. Full article

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

20 pages, 807 KB

Open AccessArticle

Quality Without Compromise: A Propensity Score-Matched Analysis of Robotic Versus Laparoscopic Surgery for Locally Advanced Colorectal Cancer

by Marcin Kubiak, Wojciech Górski, Radosław Mlak, Zuzanna Dąbrowska, Jolanta Sado, Kinga Bielarska, Szymon Bielecki, Karol Rawicz-Pruszyński and Katarzyna Sędłak

Cancers 2026, 18(10), 1601; https://doi.org/10.3390/cancers18101601 - 14 May 2026

Abstract

Background: Minimally invasive surgery is the standard approach in colorectal cancer (CRC), yet the clinical value of robotic-assisted surgery (RAS) compared with laparoscopy remains under debate. This study aimed to compare surgical quality using textbook outcome (TO) and textbook oncological outcome (TOO) in [...] Read more.

Background: Minimally invasive surgery is the standard approach in colorectal cancer (CRC), yet the clinical value of robotic-assisted surgery (RAS) compared with laparoscopy remains under debate. This study aimed to compare surgical quality using textbook outcome (TO) and textbook oncological outcome (TOO) in patients undergoing minimally invasive resection for locally advanced CRC. Methods: A retrospective analysis of patients with locally advanced CRC (cT2-4N0-2M0) treated in a high-volume centre was performed. Patients undergoing laparoscopic or robotic surgery were included. Propensity score matching (PSM) was applied to balance baseline characteristics. TO was defined as an optimal perioperative course without complications, conversion, reintervention, prolonged length of stay, or mortality. TOO extended TO by including oncological parameters such as R0 resection and adequate lymph node yield. Results: A total of 123 patients were included (80 laparoscopic, 43 robotic), with 80 patients analyzed after PSM (40 per group). RAS was associated with significantly higher rates of intracorporeal (97% vs. 18.9%) and mechanical anastomoses (96.9% vs. 48.6%). No differences were observed in postoperative complications, reintervention rates, length of stay, or mortality. Although the comprehensive complication index was lower in the robotic group, this did not translate into improved TO or TOO rates. After matching, TO was achieved in 72.5% of RAS and 85.0% of laparoscopic cases (p = 0.1745), while TOO rates were also comparable between groups. No independent predictors of TO or TOO were identified in multivariable analysis. Conclusions: Robotic surgery for locally advanced CRC provides comparable perioperative safety and oncological quality to laparoscopy. The implementation of RAS in a high-volume centre does not compromise short-term outcomes, supporting its safe integration into clinical practice. Full article

(This article belongs to the Special Issue Laparoscopic and Robotic Surgery in Gastrointestinal Cancers)

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28 pages, 1928 KB

Open AccessReview

Deciphering the Heterogeneity of Cancer-Associated Fibroblasts in Prostate Cancer: From Stromal Biology to Clinical Translation

by Ho Trong Tan Truong, Whi-An Kwon, Hyeong Jung Woo, Minseok S. Kim, Nhu Quang Tran and Jae Young Joung

Cancers 2026, 18(10), 1600; https://doi.org/10.3390/cancers18101600 - 14 May 2026

Abstract

Prostate cancer (PCa) progression and treatment resistance are driven by tumor-intrinsic mechanisms and adaptive remodeling of the tumor microenvironment, in which cancer-associated fibroblasts (CAFs) play a crucial role. Although CAF biology is increasingly recognized, a major translational gap remains: CAFs are highly heterogeneous, [...] Read more.

Prostate cancer (PCa) progression and treatment resistance are driven by tumor-intrinsic mechanisms and adaptive remodeling of the tumor microenvironment, in which cancer-associated fibroblasts (CAFs) play a crucial role. Although CAF biology is increasingly recognized, a major translational gap remains: CAFs are highly heterogeneous, and comprise distinct functional states with divergent effects on disease progression, immune regulation, and therapeutic resistance. To bridge this gap, we synthesize evidence from single-cell and spatial transcriptomic studies, tissue-based pathology, liquid biopsy assays, and molecular imaging to construct an evidence-tiered, decision-oriented translational framework that connects stromal mechanisms, translational measurement strategies, and therapeutic interventions in PCa. Single-cell and spatial transcriptomic analyses have consistently identified multiple CAF programs, including matrix-remodeling, inflammatory, immunoregulatory, antigen-presenting, and therapy-imprinted states, each with distinct functional outputs and clinical correlates. Tissue-based readouts, including reactive stromal grade (RSG) and fibroblast activation protein (FAP) immunohistochemistry, provide practical proxies for stromal activation and correlate with disease-specific mortality and imaging phenotypes. Circulating CAFs (cCAFs) represent an emerging liquid biopsy modality for longitudinal stromal monitoring, although technical standardization is required before clinical implementation. FAP-targeted PET imaging and emerging dual prostate-specific membrane antigen (PSMA)/FAP-targeted theranostic strategies provide noninvasive tools for patient selection and response assessment, particularly in PSMA-discordant or tracer-heterogeneous disease. Androgen receptor (AR)-targeted therapy can reprogram stromal states toward resistance-promoting circuits, highlighting the dynamic and plastic nature of the CAF compartment. A state-based CAF framework organizes stromal biology into testable translational hypotheses rather than immediate clinical standards. RSG and FAP-based tissue or imaging readouts are practical markers of stromal activation, whereas spatial CAF-immune signatures and cCAF assays remain investigational and require assay harmonization and prospective validation. Future trials should pre-specify stromal biomarkers as enrichment or pharmacodynamic variables when matched to the intervention and should avoid treating CAFs as a uniform therapeutic target. Full article

(This article belongs to the Special Issue Advances in the Diagnosis and Treatment of Prostate Cancer: From Biomarkers to Precision Surgery)

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