Cancers

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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Graphical abstract

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)

24 pages, 1776 KB

Open AccessSystematic Review

Non-Cisplatin Concurrent Systemic Therapy with Radiotherapy for Locally Advanced Head and Neck Squamous Cell Carcinoma: A Network Meta-Analysis of Randomized Clinical Trials

by Katharina Sophie Schöbel, Anne-Josephin Schoele, Georg Wurschi, Klaus Pietschmann and Maximilian Römer

Cancers 2026, 18(10), 1599; https://doi.org/10.3390/cancers18101599 - 14 May 2026

Abstract

Background: Head and neck squamous cell carcinoma (HNSCC) is among the top 10 most common cancer entities worldwide. For patients with locally advanced, non-metastatic HNSCC, the standard of care treatment often includes concomitant chemoradiotherapy with cisplatin. However, a considerable number of these [...] Read more.

Background: Head and neck squamous cell carcinoma (HNSCC) is among the top 10 most common cancer entities worldwide. For patients with locally advanced, non-metastatic HNSCC, the standard of care treatment often includes concomitant chemoradiotherapy with cisplatin. However, a considerable number of these patients are cisplatin-ineligible. To inform treatment selection for cisplatin-unfit patients undergoing radiotherapy (RT) for HNSCC, a network meta-analysis was performed. Method: In November 2023 a systematic search was conducted and updated in January 2026 searching four electronic databases (Medline, Web of Science, Cochrane Library, and Scopus) to identify randomized controlled trials (RCTs) analyzing overall survival (OS), progression-free survival (PFS), locoregional control (LC) and adverse events (AE) of RT combined with chemo-/immunotherapy with relevance to treatment selection in cisplatin-ineligible patients with HNSCC. Results: From all (15,551) search results, 52 publications concerning 28 RCTs reporting on approximately 7000 patients were included. The therapeutic concepts in the experimental group included all combinations of RT with concurrent systemic therapy, excluding cisplatin-based regimens, and were compared with any control treatment. All studies had sufficient quality for inclusion. None of the systemic agents showed a significant improvement in OS, PFS, or LC compared to cisplatin. Carboplatin + 5-FU and mitomycin C + 5-FU improved LC compared to hyperfractionated accelerated radiotherapy (HART). Compared to cisplatin, durvalumab and cetuximab were associated with less dysphagia, cetuximab with less renal impairment, and panitumumab and cetuximab with less weight loss. Conclusions: Carboplatin + 5-FU and Mitomycin C + 5-FU achieve superior LC compared to HART. Targeted therapy and immunotherapy were associated with less severe AEs. Full article

(This article belongs to the Special Issue Targeted Therapy in Head and Neck Cancer)

22 pages, 6804 KB

Open AccessArticle

Diagnostic Value of Serum CFL1 and TAGLN2 for Non-Metastatic Gastric Cancer: A Retrospective and Prospective Real-World Study

by Kewei Du, Shan Gao, Haichen Wang, Wenfei Hu, Caiyan Gao, Xiaoling Zheng, Xiaoqing Meng, Tuanjie Che and Shangdi Zhang

Cancers 2026, 18(10), 1598; https://doi.org/10.3390/cancers18101598 - 14 May 2026

Abstract

Background: Timely screening and diagnosis are critical for improving prognosis and survival in gastric cancer. Building on prior serum proteomics findings, this study evaluated two novel early-stage diagnostic biomarkers, CFL1 and TAGLN2, using retrospective and prospective cohorts. Methods: Retrospective analysis included [...] Read more.

Background: Timely screening and diagnosis are critical for improving prognosis and survival in gastric cancer. Building on prior serum proteomics findings, this study evaluated two novel early-stage diagnostic biomarkers, CFL1 and TAGLN2, using retrospective and prospective cohorts. Methods: Retrospective analysis included 176 non-metastatic gastric cancer patients, 88 healthy controls, and patients with non-gastric non-metastatic cancers/malignancies (n = 143). A prospective study enrolled 88 gastroenterology patients with unknown cancer status before sampling; conventional markers, including CEA, AFP, CA199, and CA125, were measured for comparison. Results: Retrospectively, CFL1 and TAGLN2 achieved approximately 80% sensitivity and >70% accuracy in distinguishing gastric cancer from controls. Prospectively, both markers reached 87.5% sensitivity and 100% specificity, with high NPV and low negative likelihood ratio, supporting their potential for early screening. CFL1 showed higher disease specificity and pre-analytical stability than TAGLN2 across multiple non-gastric cancers and special-condition samples. Conclusions: A combined panel with routine markers improved calibration and decision-curve benefit, suggesting that multi-marker testing can enhance risk stratification and screening efficiency. Full article

(This article belongs to the Special Issue Diagnostic Biomarkers in Cancers Study)

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17 pages, 1739 KB

Open AccessArticle

Total Neoadjuvant Approach for Borderline Resectable and Locally Advanced Pancreatic Adenocarcinoma—UK Tertiary Cancer Centre Experience

by Kai Tai Derek Yeung, Simon Gomberg, William Hodgson, Petula Jefferies, David Cunningham, Sheela Rao, Ian Chau, Naureen Starling, Charlotte Fribbens, Avani Athauda, Diana Tait, Irene Chong, Arabella Hunt, Magnus T. Dillon, Sacheen Kumar, Long R. Jiao, Ricky H. Bhogal and Katharine Aitken

Cancers 2026, 18(10), 1597; https://doi.org/10.3390/cancers18101597 - 14 May 2026

Abstract

Introduction: Pancreatic ductal adenocarcinoma (PDAC) remains a leading cause of cancer-related mortality. Radiological distinctions between borderline resectable (BR) and locally advanced disease (LA) are increasingly recognised as imperfect when considered without dynamic assessment. Neoadjuvant therapy (NAT) improves outcomes through tumour downstaging and early [...] Read more.

Introduction: Pancreatic ductal adenocarcinoma (PDAC) remains a leading cause of cancer-related mortality. Radiological distinctions between borderline resectable (BR) and locally advanced disease (LA) are increasingly recognised as imperfect when considered without dynamic assessment. Neoadjuvant therapy (NAT) improves outcomes through tumour downstaging and early treatment of occult metastatic disease, but the optimal NAT strategy, particularly in BR disease, remains uncertain. Published data evaluating combined systemic anti-cancer therapies (SACT) with or without chemoradiation (CRT) are limited and heterogeneous. Methods: This is a single-centre retrospective analysis of 44 patients with BR PDAC and a comparator cohort of 121 patients with LA PDAC treated with a total neoadjuvant approach of SACT with or without CRT and surgical resection between June 2017 and September 2022. Results: Median overall survival (OS) did not differ significantly between BR and LA disease (18 vs. 16 months, p = 0.14). Following NAT, 47.7% of BR and 18.1% of LA patients were anatomically suitable for surgical resection. Among unresected BR and LA patients, those treated with CRT in addition to SACT had a median OS of 18 and 21 months respectively. In the resected subgroup, resection margin status was the primary factor associated with survival; with R0 resection conferring a substantial OS advantage over R1, irrespective of initial BR/LA classification as diagnosis (47 vs. 22 months, p < 0.001). Conclusions: Despite anatomical differences at diagnosis, BR and LA PDAC demonstrated comparable survival outcomes when treated with total neoadjuvant strategies in this cohort. These findings challenge traditional radiological staging-based treatment paradigms and confirm that a margin-negative surgical resection offered the greatest opportunity for long-term survival for BR/LA PDAC patients. Full article

(This article belongs to the Special Issue Feature Papers in the Section “Cancer Therapy” in 2025-2026)

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23 pages, 1140 KB

Open AccessReview

Breast Cancer Milieu Maneuvers Cancer-Associated Macrophages to Synergize Neoplastic Repertoires

by Huey-Jen Lin, Yingguang Liu, Brooke Langevin and Jiayuh Lin

Cancers 2026, 18(10), 1596; https://doi.org/10.3390/cancers18101596 - 14 May 2026

Abstract

Breast cancer is one of the most devastating malignancies in women worldwide. A growing body of evidence has linked neoplastic growth, invasion, metastasis, immune escape, and therapeutic resistance to infiltrating tumor-associated macrophages. In a breast cancer mass, macrophages are largely polarized to two [...] Read more.

Breast cancer is one of the most devastating malignancies in women worldwide. A growing body of evidence has linked neoplastic growth, invasion, metastasis, immune escape, and therapeutic resistance to infiltrating tumor-associated macrophages. In a breast cancer mass, macrophages are largely polarized to two main subtypes, M1 and M2, albeit with continuum intermediates, based on their immunological behaviors, gene signatures, and functional roles. While the former portrays proinflammatory and anti-cancer effects, the latter elicits the opposite impacts. M2 macrophages have gained rising attention as they are largely involved in fostering an immune-suppressive, cancer-promoting landscape and are imperative for malignant features across breast cancer subtypes. Through a positive feedback paracrine loop, M2 macrophages can be enriched by a plethora of dysregulated oncogenic signaling mediators, exemplified by CSF1/CSF1R, STAT3, IL-6, YAP, PI3K, PDK1, and AKT. These modulators could be released from or activated by surrounding malignant cells, fibroblasts, secreted extracellular vesicles, cell fragments generated after chemotherapies, hypoxia, dysregulated immune checkpoint pathways or oncometabolites. This review aims to discern the molecular cues fortifying M2 subpopulations. Moreover, recent advances in single-cell sequencing, spatial, and computational approaches have refined the understanding of TAM heterogeneity, while clinical translation remains limited by low therapeutic specificity, compensatory signaling, and differences between murine and human macrophage biology. Future therapeutic regimens should include strategies aimed at correcting aberrations that favor M2 polarization and are justified with divergences between humans and mice. Full article

(This article belongs to the Special Issue The Tumor Microenvironment and Molecular Aberrations Convey Immune Evasion (Third Edition))

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51 pages, 996 KB

Open AccessSystematic Review

Neoadjuvant Treatment for Penile Cancer: A Systematic Review of Contemporary Evidence

by Jordan Santucci, Daniel Crisafi, Niranjan Sathianathen, Renu Eapen, Damien Bolton, Declan Murphy, Nathan Lawrentschuk and Marlon Perera

Cancers 2026, 18(10), 1595; https://doi.org/10.3390/cancers18101595 - 14 May 2026

Abstract

Background/Objectives: Penile squamous cell carcinoma (SCC) is a rare but aggressive malignancy in which survival declines sharply once regional lymph nodes are involved. Neoadjuvant therapy is recommended for clinically node-positive disease to improve resectability and address micro-metastatic spread; however, the supporting evidence [...] Read more.

Background/Objectives: Penile squamous cell carcinoma (SCC) is a rare but aggressive malignancy in which survival declines sharply once regional lymph nodes are involved. Neoadjuvant therapy is recommended for clinically node-positive disease to improve resectability and address micro-metastatic spread; however, the supporting evidence remains limited. We systematically reviewed contemporary data on neoadjuvant strategies for penile SCC, including cytotoxic chemotherapy, radiotherapy, immunotherapy, and molecularly targeted agents. Methods: A systematic search of MEDLINE, EMBASE, ClinicalTrials.gov, and CENTRAL was conducted from inception to January 2026 in accordance with MECIR guidance. Eligible studies included patients with histologically confirmed penile cancer treated with neoadjuvant intent prior to curative surgery. Primary outcomes were objective response rate (ORR), pathological complete response (pCR), progression-free survival (PFS), and overall survival (OS). Data were synthesised narratively by treatment modality. Results: Forty-two studies met the inclusion criteria (32 chemotherapy, five radiotherapy, five immunotherapy, three targeted therapy). The evidence base was dominated by retrospective cohorts with limited prospective phase II data and no completed randomised trials. Across chemotherapy studies, the median reported ORR was 50% (range 29–90%), with pCR/ypN0 rates ranging 10–25%. Median reported PFS and OS were approximately 11 and 18 months, respectively, with durable survival concentrated among responders undergoing complete surgical consolidation. Radiotherapy data were sparse and heterogeneous. Early-phase immunotherapy combinations reported higher short-term response and pCR signals than historical chemotherapy, though the results were based on small single-arm cohorts. Molecularly targeted systemic monotherapy demonstrated modest activity. Conclusions: Neoadjuvant taxane–platinum-based chemotherapy remains the guideline-supported standard for cN2-3 penile SCC, supported by phase II and retrospective data but limited by methodological heterogeneity and absence of randomised evidence. Emerging combination immunotherapy strategies show promising efficacy signals and warrant prospective validation within biomarker-informed trial frameworks. Full article

(This article belongs to the Special Issue Advances in the Treatment of Urological Cancer)

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11 pages, 349 KB

Open AccessArticle

Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis Following CAR T-Cell Therapy: Results of a Real-World Study

by Inna Shaforostova, Marie-Noelle Kronig, Katja Seipel, Alicia Rovo, Ulrike Bacher and Thomas Pabst

Cancers 2026, 18(10), 1594; https://doi.org/10.3390/cancers18101594 - 14 May 2026

Abstract

Background: Immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) is a rare, life-threatening complication following CAR T-cell therapy. Diagnosis is challenging due to overlap with severe CRS, sepsis and lack of standardized criteria. Clinical data remain limited. Methods: We retrospectively analyzed 301 [...] Read more.

Background: Immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) is a rare, life-threatening complication following CAR T-cell therapy. Diagnosis is challenging due to overlap with severe CRS, sepsis and lack of standardized criteria. Clinical data remain limited. Methods: We retrospectively analyzed 301 patients treated with CD19- or BCMA-directed CAR T-cells for hematologic malignancies at a single center from January 2019 to January 2026. IEC-HS was defined according to American Society for Transplantation and Cellular Therapy criteria. Results: Median follow-up was 31 months. IEC-HS was diagnosed in 14 patients (4.7%), median age 67 years. Underlying diseases included diffuse large B-cell lymphoma (n = 4), multiple myeloma (n = 7), mantle cell lymphoma, Burkitt lymphoma and B-lymphoblastic leukemia (n = 1 each). All patients had hyperferritinemia and cytopenias at baseline; most had high tumor burden (9/14) and elevated LDH (10/14). CRS occurred in all patients and ICANS in 6/14. IEC-HS occurred at median 10 days and was characterized by hyperferritinemia (median 15,321 µg/L), neutropenia, thrombocytopenia, hepatic dysfunction and high CAR-T-cell expansion in peripheral blood. Treatment included corticosteroids and anakinra (12/14). Refractory patients received IVIG (5/14), tocilizumab (3/14), siltuximab, ruxolitinib, emapalumab or etoposide (each n = 1). Infections occurred in 11/14; 4/14 had mixed infections. IEC-HS resolved in 7/14 (median 7 days). Mortality was 79% (11/14), mainly due to IEC-HS (7/14). Three patients were alive at last follow-up. One-year OS was lower vs. the whole cohort (31% vs. 69%, p < 0.0001). Conclusions: IEC-HS was associated with severe cytopenias, hyperferritinemia, hepatic dysfunction and high infection risk. Despite intensive immunosuppressive therapy, outcomes remain poor. Early biomarker-driven identification and multicenter studies are needed. Full article

(This article belongs to the Section Cancer Immunology and Immunotherapy)

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17 pages, 1164 KB

Open AccessArticle

Limited Incremental Diagnostic Value of Perilesional and Systematic Biopsies in PI-RADS 4–5 Lesions: A Retrospective Single-Center Study

by Emiliano Scarrone, Vittorio Canale, Luca Antonelli, Jordi Stira, Carmen Gravina, Giovanni Zarrelli and Alessandro Sciarra

Cancers 2026, 18(10), 1593; https://doi.org/10.3390/cancers18101593 - 14 May 2026

Abstract

Objective: This study aims to evaluate the additional diagnostic value of systematic (SBx) and perilesional biopsies (PBx) compared with targeted biopsy (TBx) in patients with mpMRI-detected PI-RADS 3-4–5 lesions. Methods: We performed a retrospective analysis of 208 men with PI-RADS ≥ 3 lesions [...] Read more.

Objective: This study aims to evaluate the additional diagnostic value of systematic (SBx) and perilesional biopsies (PBx) compared with targeted biopsy (TBx) in patients with mpMRI-detected PI-RADS 3-4–5 lesions. Methods: We performed a retrospective analysis of 208 men with PI-RADS ≥ 3 lesions who underwent mpMRI–ultrasound fusion biopsy at a single institution. Clinically significant prostate cancer (csPCa; ISUP ≥ 2) was identified in 155 patients (74.5%), who constituted the study cohort. All patients underwent a standardized biopsy protocol consisting of 3–5 TBx cores, 3 PBx cores sampled within a 10 mm radius of the index lesion, and 10 SBx cores using the KOELIS Trinity^® system. Detection rates of csPCa and ISUP grade upgrading were analyzed and stratified by PI-RADS category. Results: TBx csPCa detection rates increased progressively with PI-RADS score: 39% for PI-RADS 3, 50% for PI-RADS 4, and 60% for PI-RADS 5 lesions. PBx showed a 42.5% detection rate of csPCa in PI-RADS 3 and 58% and 85.3% of csPCa in PI-RADS 4 and 5 respectively, whereas SBx detected 34.5% of csPCa in PI-RADS 3, 46% of csPCa in PI-RADS 4, and 60.5% of csPCa in PI-RADS 5. Despite these detection rates, PBx and SBx rarely provided clinically meaningful upgrading over TBx findings. ISUP grade upgrading occurred in only 7.3% of PBx cases and 1.8% of SBx cases in PI-RADS 5 lesions, with similarly low upgrading rates observed in PI-RADS 3–4 lesions. Conclusions: In patients with high-grade lesions like PI-RADS 4–5, TBx alone identifies the vast majority of csPCa, while SBx and PBx contribute minimal additional diagnostic or grading benefit. These findings support biopsy de-escalation strategies in high-risk mpMRI settings to reduce unnecessary sampling and procedure-related morbidity. On the other hand, in the PI-RADS 3 subgroup, omitting non-targeted sampling (SBx and/or PBx) may lead to underdiagnosis of higher-grade tumors not captured by TBx alone, potentially resulting in substantial changes in therapeutic strategy and, consequently, patient prognosis. Full article

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

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