Cancers doi: 10.3390/cancers18162617

Authors: Marionna Cathomas Franco Fortunato Eli Zamir Marisa Isabell Keller Toohina Gobin Laila Jötten Elias Gauer Max Heckler Bo Kong Rogier Aäron Gaiser Ingmar F. Rompen Jonathan M. Harnoss Sabine Schmidt Michael Kuhn Eran Elinav Peer Bork Christoph W. Michalski Thomas Hank

Background: Recent evidence suggests that gut microbiome plays a role in the development of pancreatic ductal adenocarcinoma (PDAC) and influences treatment response. However, the association of tumor location and preoperative biliary stenting (PBS) with gut microbial composition and diversity remains poorly understood. Methods: Preoperative stool specimens were prospectively collected from patients with PDAC undergoing surgery between March 2020 and July 2021 at the Department of Surgery, Heidelberg University Hospital, Germany. Whole-genome shotgun metagenomic sequencing was performed. Microbial diversity was assessed using the Shannon index and Bray–Curtis dissimilarity with principal coordinates analysis. Results: A total of 63 preoperative stool samples were analyzed from 40 patients with pancreatic head (63.5%) and 23 with body/tail tumors (36.5%). Baseline characteristics were comparable between groups. Microbial community composition differed significantly between tumor locations (Bray–Curtis, p = 0.005), with enrichment of Ruminococcus bromii in body/tail tumors. Among patients with pancreatic head tumors, PBS was associated with reduced alpha diversity (Shannon index, p = 0.04) and depletion of taxa including Eubacteriales and Clostridiales taxa, and members of the genera Raoultella and Prevotella. PBS was associated with a higher rate of major complications > 3a according to the Clavien–Dindo classification (28.6% vs. 3.8%; p = 0.04). Conclusions: PBS was associated with reduced microbial diversity and distinct taxonomic alterations of the gut microbiome. These findings suggest that biliary stenting is associated with microbiome alterations that may be relevant for perioperative risk stratification and warrant further investigation.

Cancers doi: 10.3390/cancers18162615

Authors: Tradian Ciprian Berisha Florin Burada Mihai Gabriel Cucu Ana-Maria Ciurea Alina Maria Mehedinteanu Puiu Olivian Stovicek Ramona Adriana Schenker Michael Schenker Monica-Laura Cara

Background/Objectives: Colorectal cancer (CRC) remains a major contributor to the global oncological burden, with marked disparities in mortality and survival between Western and Eastern European countries. Romania continues to report unfavorable CRC outcomes, driven by delayed diagnosis, limited screening uptake, and heterogeneous care pathways. This study aimed to assess the 15-year institutional description of colorectal cancer case-mix in South-West Oltenia, Romania, using real-world data from a high-volume oncology referral center. Methods: We conducted a retrospective observational study including 3497 patients with newly diagnosed CRC registered between 2011 and 2025. Sociodemographic characteristics, tumor localization, stage at diagnosis, and histopathological grade were analyzed. Temporal patterns were assessed across three five-year intervals. Results: The institutional CRC case volume increased, with 434 cases recorded in 2011–2015, 1015 in 2016–2020, and 2048 in 2021–2025. Male patients accounted for 60.5% and urban residents for 60.3% of cases. Early-onset CRC was identified in 12.0% of patients, with no significant temporal trend. Rectosigmoid junction/rectal cancers represented the largest anatomical group, followed by left-sided cancers, with stable distribution across periods. Advanced stage disease was frequent, with 77.1% of patients diagnosed in stage III–IV, increasing from 67.7% to 82.0% across study intervals (p < 0.001). Histopathological grade changed significantly (p < 0.001), due to a progressive increase in unspecified grade, from 16.1% to 45.5%. Conclusions: Colorectal cancer represents a substantial institutional workload at this regional referral center, emphasizing the need for strengthened early detection strategies, optimized referral system, improved diagnostic access, and standardized pathological reporting practices.

Cancers doi: 10.3390/cancers18162614

Authors: Qijie Li Anello Marcello Poma Donghao Tang Paola Vignali Rossella Bruno Elisabetta Macerola Beatrice Fuochi Clara Ugolini

In colorectal cancer (CRC), tumor progression is influenced by immunosuppressive tumor microenvironment (TME), in which innate immunity and adaptive immunity play an important role. CD47 is one of the key molecules in the process. It sends a “don’t eat me” signal to macrophages by binding to signal regulatory protein alpha (SIRPα), thus helping tumor cells escape immune clearance. Forkhead box P3 (FOXP3)+ regulatory immune cells further suppress antitumor T-cell responses. Here, based on a review of the literature and publicly available transcriptomic data, we propose that CD47 expression and FOXP3+ regulatory T cells in CRC are interconnected components of a broader myeloid–regulatory immunosuppressive phenotype, rather than a simple linear CD47–FOXP3 pathway. Evidence from cancer studies and exploratory GEPIA3/TIMER3.0 analyses supports a weak and method-dependent association between CD47 expression, FOXP3 transcripts, and estimated Treg infiltration. Hippo/Yes-associated protein/transcriptional coactivator with PDZ-binding motif (YAP/TAZ) signaling serves as a potential upstream program contributing to this immune context.

Cancers doi: 10.3390/cancers18162613

Authors: Filippo Caudana Mattia Ronca Francesco Ditonno Greta Pettenuzzo Celeste Manfredi Alessandro Veccia Riccardo Giuseppe Bertolo Gaëlle Margue Riccardo Autorino Jean-Christophe Bernhard Alessandro Antonelli

Background/Objectives: To compare perioperative, pathological, functional, and oncological outcomes of robot-assisted radical nephrectomy with inferior vena cava tumor thrombectomy (RARN-TT) versus open (ORN-TT) and laparoscopic (LRN-TT) approaches. Methods: PubMed, Scopus, and Web of Science were searched for studies of adults with renal cell carcinoma and Mayo/Neves level I–IV inferior vena cava tumor thrombus undergoing RARN-TT versus ORN-TT and/or LRN-TT. Risk ratios and mean differences with 95% confidence intervals were calculated using random effects models with restricted maximum-likelihood estimation. Results: Eight retrospective studies including 1781 patients were included: 221 underwent robotic surgery, 1411 open surgery, and 149 laparoscopic surgery. Compared with ORN-TT, RARN-TT was associated with lower estimated blood loss (mean difference −900.5 mL, 95% confidence interval −1234.0 to −566.9; p = 0.001), lower transfusion probability (risk ratio 0.395, 95% confidence interval 0.159–0.979; p = 0.046), and shorter hospital stay (mean difference −3.79 days, 95% confidence interval −4.83 to −2.76; p < 0.001). No significant differences were observed in operative time, intensive care unit stay, postoperative complications, perioperative mortality, pathological outcomes, or overall survival. Evidence for cancer-specific and progression-free survival was limited. Comparisons with LRN-TT were exploratory. Conclusions: RARN-TT may reduce blood loss, transfusion requirements, and hospital stay compared with ORN-TT, without evidence of worse perioperative, pathological, or survival outcomes. However, all studies were retrospective and affected by selection bias and heterogeneity. RARN-TT may be considered for selected patients at experienced centers, particularly for lower-level thrombi. Prospective multicenter studies stratified by thrombus level are needed.

Cancers doi: 10.3390/cancers18162611

Authors: Ömer Tarık Çiçek Muharrem Okan Çakır Begüm Kurt Betül Karademir Yılmaz G. Hossein Ashrafi Mustafa Özdoğan

Background/Objectives: Immune exclusion in head and neck squamous cell carcinoma (HNSCC) limits immunotherapy efficacy, yet the molecular determinants of stromal-immune organization remain incompletely characterized. The desmosomal cadherin DSG2 is highly expressed in squamous epithelium; its role in shaping the tumor microenvironment (TME) is unknown. Methods: We integrated bulk RNA-seq from 836 HNSCC patients (TCGA-HNSC n = 566, GSE65858 n = 270), single-cell RNA-seq (GSE139324, n = 26 patients, 133,308 cells), spatial transcriptomics (GSE208253, n = 12), proteomics (CPTAC-HNSCC, n = 108), and external validation cohorts (GSE41613, n = 97). CellChat ligand-receptor analysis, mediation analysis, Mendelian randomization (MR), LASSO-penalized Cox regression, HPV-stratified sensitivity analysis, and transcription factor (TF) correlation analysis were employed. Results: DSG2 exhibited epithelial-specific expression and showed consistent positive correlation with CXCL8 (IL-8; TCGA ρ = 0.228, p = 4.4 × 10−8) and myCAF activation across independent cohorts. Single-cell analysis revealed that 99.5% of CXCL8-producing cells have zero DSG2 expression, establishing the bulk correlation as compositional rather than cell-intrinsic. CellChat identified CXCL8-CXCR2 as the strongest tumor-stroma interaction in DSG2-high regions (probability = 0.821, 1.80-fold enrichment). Mediation analysis demonstrated 43.6% (95% CI [34.3–53.6%]) of DSG2’s tissue-level association with myCAF activation is mediated through CXCL8 (compositional mediation). Multi-instrument MR (IVW: Beta = −0.028, p = 0.028; I2 = 0.0%) corroborated the compositional model. Protein-level validation in CPTAC-HNSCC confirmed DSG2-CD8A inverse correlation (Spearman ρ = −0.35, p = 2.2 × 10−4). Pan-squamous meta-analysis confirmed negative DSG2-cytolytic activity correlations (pooled ρ = −0.213, 95% CI [−0.296, −0.128], I2 = 58.6%, 4 cohorts). DSG2 correlated with TIDE score (ρ = 0.176) and TGF-β exclusion subscore (ρ = 0.428). DepMap analysis identified CXCR2 inhibitor collateral sensitivity (ρ = −0.408, p < 0.0001). An eight-gene co-expression module was validated in two independent cohorts (GSE41613: HR = 3.09, p = 0.003; GSE65858: HR = 1.57, p = 0.032). Conclusions: DSG2 marks a stromal-immune organizational state characterized by CXCL8-CXCR2 paracrine signaling, myCAF activation, and immune exclusion, conserved across squamous malignancies. DSG2-high/PD-L1-high tumors (30.4% prevalence) exhibit the worst predicted ICI response and represent a candidate population for biomarker-selected CXCR2 inhibitor trials in combination with anti-PD-1 therapy.

Cancers doi: 10.3390/cancers18162612

Authors: Diana Luísa Almeida-Nunes Ana Mendes-Frias Mariana Nunes Verónica Ferreira Cláudia Lobo Paula Monteiro Miguel Henriques Abreu Carla Bartosch Claudia Nobrega Ricardo Jorge Dinis-Oliveira Ricardo Silvestre Sara Ricardo

Background/Objectives: High-grade serous carcinoma (HGSC) represents the most frequent subtype of epithelial ovarian cancer (OC) and is associated with malignant ascitic fluid (MAF), which fosters a pro-inflammatory microenvironment that supports tumor progression. Given its rich cellular and soluble content, MAF offers a valuable window into tumor–host interactions and disease dynamics. This study examines the immune landscape of MAF samples from 22 newly diagnosed treatment-naïve HGSC patients. Methods: Immune cell phenotypes and cytokine profiles were analyzed via flow cytometry. Patients were stratified according to time to death or recurrence (TDR), using a six-month interval from diagnosis to either documented recurrence or disease-specific death as the cutoff: TDR < 6 months defined as the worse prognosis group, whereas TDR ≥ 6 months defined the better prognosis group. The expression of immune checkpoint molecules on T cells and the effects of PD-1 blockade with Pembrolizumab were also assessed. Results: Patients with worst prognosis exhibited a marked pro-inflammatory cytokine milieu, with elevated levels of TNFα, IL-1β, IL-23, and IFNγ. Concurrently, their CD4+ and CD8+ T cells displayed evidence of a functional exhaustion-associated phenotype, marked by heightened expression of the inhibitory receptors TIM-3, PD-1, and LAG-3. Notably, treatment with Pembrolizumab (a PD-1 checkpoint inhibitor) significantly enhance T cell effector function. Conclusions: These results underscore a potential immunotherapeutic approach in anti-tumor immunity among selected HGSC patients, presenting a compelling direction for advancing OC treatment.

Cancers doi: 10.3390/cancers18162610

Authors: Dongli Guo Jing Jin Xin Su Wanyu Yang Bin Guo Wenpeng Jiao Yutong He

Esophageal cancer is a common malignancy of the upper gastrointestinal tract that is associated with high incidence and mortality rates. Radiotherapy constitutes a cornerstone therapeutic modality for esophageal cancer. In radiotherapy, ionizing radiation is used to eliminate tumor cells through direct DNA damage and indirect reactive oxygen species (ROS)-mediated effects. However, clinical outcomes are frequently limited by interpatient heterogeneity and intrinsic tumor radioresistance. This review systematically describes the determinants of radiosensitivity in esophageal cancer within the established radiobiological framework of the “6Rs”: DNA damage repair (Repair), which is mediated by γ-H2AX phosphorylation, PARP family enzymes, and nonhomologous end joining (NHEJ) and homologous recombination (HR) pathways; cell cycle redistribution (Redistribution), which is regulated by G1/S and G2/M checkpoint dynamics; tumor repopulation (Repopulation), which is driven by cancer stem cell activity during fractionated treatment; reoxygenation (Reoxygenation), which is modulated through HIF-1α signaling and ROS homeostasis; intrinsic radiosensitivity (Radiosensitivity), which reflects interindividual and histopathological variability; and reactivation of antitumor immune responses (Reactivation), which enhances efficacy by remodeling the tumor immune microenvironment. Furthermore, regulated cell death mechanisms, including ferroptosis, autophagy, and apoptosis, significantly modulate radiotherapeutic responses. Elucidating these interconnected mechanisms provides a robust theoretical foundation for developing targeted interventions, identifying predictive biomarkers, and advancing precision radiotherapy strategies to optimize clinical outcomes for patients with esophageal cancer.

Cancers doi: 10.3390/cancers18162609

Authors: Nathalie F. van Rhee Celine M. L. H. Wilmes Hidde K. Krijnen Mischa Hofman Jonathan Woodburn Rosanne C. Schoonbeek Inge Wegner Henri A. M. Marres Michel R. M. San Giorgi Gyorgy B. Halmos Guido B. van den Broek Boudewijn E. C. Plaat David J. Wellenstein

Background/Objectives: Supraglottic and hypopharyngeal carcinomas are aggressive malignancies that are often diagnosed at advanced stages. Timely recognition of these malignancies is influenced by many factors, such as endoscope quality and experience. This study evaluated the potential of artificial intelligence (AI) to support real-time detection and classification of such lesions during flexible endoscopy in the outpatient clinic. Methods: A previously developed deep learning (DL) algorithm was extended from a glottic lesion model to the unified localization and classification of glottic, supraglottic, and hypopharyngeal lesions during flexible endoscopy. Lesion frames were extracted from endoscopy videos obtained at two head and neck oncology centers and one secondary referral center between 2012 and 2024. These frames were annotated and labeled based on histopathological or clinically confirmed reference diagnoses. The primary outcome was the unified model’s performance in detection of lesions per frame. After training (70% of data), the positive predictive value (precision) and sensitivity (recall) of this model were calculated on an independent test set (30% of data), stratified by subsite and tumor (T-) classification. Secondly, the model’s binary classification performance (benign or malignant) was evaluated. Results: From 490 supraglottic and hypopharyngeal endoscopy videos, 40,059 frames with a benign or malignant lesion were extracted and added to the 56,036 glottic lesion frames in the database, comprising 1336 lesion videos and 123 healthy control videos (total n = 1459). On the test set, the model achieved a detection precision of 92.1% (95% CI: 90.9–93.2) and a recall of 73.3% (95% CI: 69.8–76.6). Detection performance increased with higher T-stage. Among correctly detected lesion instances in a malignancy-dominated test set (65.3% of lesion instances), sensitivity for malignancy detection was 94.3% (95% CI: 91.8–96.5). Combined end-to-end performance for correct malignant lesion detection and classification was estimated at 69.1% (object-level recall 73.3% × classification sensitivity 94.3%). Evaluation of 33 lesion-free videos demonstrated a mean frame-level specificity of 46.6% and a median of 19 false positive detections per video. Conclusions: This is the first study to report a DL model for real-time endoscopic detection and classification of benign and malignant laryngeal and pharyngeal lesions. The developed model showed promising lesion detection and cancer classification performance in the evaluated test set. T1 tumor detection remains an important limitation, particularly because early-stage detection is a primary aim of AI-assisted endoscopy. Further model testing is required in real-world lesion prevalence settings, where external validation and clinical usability should be investigated.

Cancers doi: 10.3390/cancers18162608

Authors: Ali Awad Joe Khodeir Qusai AlQudah Nur Saleh Mariam Chalhoub M. Chadi Alraies

Background: Immune checkpoint inhibitors (ICIs) have transformed the treatment of advanced melanoma, but the comparative cardiac safety of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)-containing regimens versus programmed cell death protein 1 (PD-1)-only regimens in real-world populations remains poorly characterized. We compared cardiac outcomes between melanoma patients exposed to CTLA-4 blockade (ipilimumab) and those treated with anti-PD-1 therapy alone (nivolumab or pembrolizumab) using a large multicenter electronic health record database. Methods: This retrospective cohort study used de-identified data from the TriNetX Research Network (111 US healthcare organizations). Adults with melanoma (ICD-10-CM C43) who received ipilimumab (CTLA-4 exposed) were compared with those who received nivolumab or pembrolizumab without ipilimumab (anti–PD-1 only); both groups were therefore treated with immune checkpoint inhibitors, isolating the effect of CTLA-4 exposure. Propensity score matching (1:1) balanced demographics, cardiovascular comorbidities, and baseline antiarrhythmic use. The primary outcome was a cardiac conduction disorder composite; outcomes were assessed at 1 and 3 years. Results: Of 7313 CTLA-4-exposed and 11,481 anti-PD-1-only patients, 6841 matched pairs were analyzed (all standardized mean differences <0.03). CTLA-4 exposure was associated with a significantly higher incidence of cardiac conduction disorders that was already present at 1 year (3.8% vs. 2.1%; RR 1.82; 95% CI 1.48–2.24; p < 0.001) and persisted at 3 years (5.1% vs. 3.7%; RR 1.36; 95% CI 1.16–1.60; p < 0.001). Atrioventricular block was higher at both 1 year (RR 2.10; 95% CI 1.59–2.78) and 3 years (RR 1.49; 95% CI 1.20–1.85), and complete heart block was markedly increased at 3 years (0.5% vs. 0.2%; RR 3.28; 95% CI 1.67–6.43; p < 0.001). Heart failure was modestly higher with CTLA-4 exposure at both timepoints (1-year RR 1.35; 3-year RR 1.17). Conclusions: Among melanoma patients treated with immune checkpoint inhibitors, CTLA-4-containing therapy is associated with a higher burden of cardiac conduction disorders, including a roughly three-fold excess of complete heart block, that is evident within the first year and sustained thereafter. Because the CTLA-4-exposed cohort comprised both ipilimumab monotherapy and nivolumab plus ipilimumab and the subgroup analyses localized the excess risk to the combination regimen, this association reflects CTLA-4-containing (predominantly combination) therapy rather than ipilimumab monotherapy in isolation. These findings support electrocardiographic surveillance beginning during, not only after, treatment for patients receiving CTLA-4-containing immunotherapy.

Cancers doi: 10.3390/cancers18162607

Authors: Xin Feng Wenwen Zhang Fukui Huan Yuxiang Liu Deqi Chen Huan Chen Ningyu Wang Qian Liu Huijuan Peng Guodong Jin Jianrong Dai Yueping Liu Kuo Men

Background/Objectives: Adaptive radiotherapy (ART) is essential yet expensive in prostate cancer treatment. This study aims to preliminarily validate the feasibility of an integrated AI workflow for CBCT-guided adaptive radiotherapy in prostate cancer, and to provide a technical foundation for subsequent clinical translation. Methods: Planning CT and CBCT images from 120 patients were used for training and validation, while 21 patients were reserved for testing. A CycleGAN-ResNet generated synthetic CT (sCT) from CBCT, and an nnU-Net model performed auto-segmentation on the sCT. Image quality and segmentation accuracy were quantitatively assessed. The original plan was recalculated on sCT to evaluate actual dose delivery; if clinical constraints were unmet, adaptive re-optimization was performed, and plans were compared. Results: The total time per fraction in this study was approximately 19 ± 6 min, falling within the reported feasibility range for online ART. sCT image quality was significantly improved, making them suitable for subsequent auto-segmentation and treatment planning. The auto-segmentation technique substantially enhanced contouring efficiency, with the automatically generated contours requiring only minor modifications to meet clinical standards. In dosimetric analysis, the adaptive plans provided superior target coverage, CI, and HI. Compared with the actual dose delivered by the original plan, the adaptive plans yielded lower bladder V40 and lower rectal mean dose/V30/V40/V50. Conclusions: This study preliminarily validated the feasibility of an integrated AI workflow that concatenates CycleGAN-based sCT generation, nnU-Net-based auto-segmentation, and sCT-based adaptive plan re-optimization. Compared with conventional segmented studies, this integrated exploration facilitates a more comprehensive assessment of the potential value of AI technologies in CBCT-guided prostate cancer ART, offering a preliminary solution for promoting a cost-effective adaptive radiotherapy approach.

Cancers doi: 10.3390/cancers18162606

Authors: Ahmad Nanaa Jeremy Kao Martin Davis Mary Pasquinelli Margaret Wright Geise Li Liu Ryan Huu-Tuan Nguyen Frank Weinberg

Background: Lung cancer remains the leading cause of cancer-related mortality in the United States, characterized by poor overall survival rates (OS), particularly for advanced-stage disease. While smoking is a primary risk factor, other contributors include environmental exposures, genetics, comorbidities, and socioeconomic factors. Methods: We included 232 patients with lung cancer (96% NSCLC). Patients were categorized into DNA damage response (DDR)-mutant (DDRmt, n = 67, 29%) and DDR-wild-type (DDRwt, n = 165, 71%) groups. We evaluated the correlations between individual and socioeconomic factors between DDRmt and DDRwt lung cancer patients. Results:Nineteen DDR genes were identified, with ARID1A(31.3%), CHEK2 (19.4%), ATM (14.9%), BRCA2 (14.9%), ATRX (11.9%), MUTYH (11.9%), ATR (8.9%), and MSH6 (5.9%) being the most common. The DDRmt group had a significantly higher median tumor mutational burden (TMB) (12 vs. 9; p = 0.006) and a higher prevalence of adenocarcinoma (85.1% vs. 64.8%, p = 0.003). Logistic regression identified adenocarcinoma histology (OR = 10.03, p = 0.002) and lower area deprivation index (OR = 0.98, p = 0.04) as predictors of DDR mutation status. Having advanced stage at diagnosis was associated with, age (p = 0.03), lack of lung cancer screening (p < 0.001), and adenocarcinoma histology (p < 0.001). While median OS was 61 months for the DDRmt group vs. 44 months for the DDRwt group (p = 0.654), patients with ATR mutations had significantly shorter survival (13 vs. 67 months; p = 0.0008). Population-level factors, including food insecurity (HR = 2.33, p = 0.002), lack of insurance (HR = 2.39, p = 0.008), and proximity to potential chemical accidents (HR = 1.73, p = 0.037), were significant predictors of OS. Conclusions: These findings suggest that DDRmt lung cancers represent a biologically distinct subgroup characterized by higher tumor mutational burden and enrichment for adenocarcinoma histology; however, DDR mutation status alone was not associated with overall survival. Instead, outcomes appeared to vary by individual DDR gene, with ATR alterations identifying a subgroup with particularly poor survival. In parallel, food insecurity, lack of insurance, and proximity to potential environmental hazards were associated with outcomes, highlighting the need to integrate genomic biomarkers with social and environmental determinants of health. These data suggest the need for future prospective studies incorporating treatment-response data, longitudinal social determinants of health (SDOH) assessment, and environmental exposure measures to define how DDR alterations can guide precision oncology strategies while addressing modifiable barriers to equitable cancer care.

Cancers doi: 10.3390/cancers18162605

Authors: David Homewood Brendan Yanada Clancy Mullholland Benjamin Lyttwin Prabhpreet Mangat Tanita Botha Niranjan Sathianathen George N. Thalmann Niall M. Corcoran Marc A. Furrer

Background and Objectives: The outcomes for patients with localised prostate cancer are variable, even within defined tumour grades or clinical risk groups. Identifying features associated with disease aggression is imperative in contemporary PCa research. ISUP 2 PCa is particularly important in this regard as it exhibits a wide range of oncologic behaviour. The aim of this study was to evaluate the relationship between the tumour volume at radical prostatectomy (RP) and metastasis-free survival (MFS) in patients with ISUP 2 PCa. Methods: In this longitudinal multicentre cohort study, we reviewed the data of 809 consecutive patients with ISUP 2 PCa who underwent RP between 1996 and 2021. The tumour volume was estimated by summing the visual percentage involvement and multiplying it by specimen weight. Kaplan–Meier and Cox regression models were used to assess MFS. Linear regression was used to identify the preoperative predictors of the tumour volume (TV), with the appropriate assumption checks. Key Findings: The median TV was 2.9 cc (IQR: 1.4–7.0 cc). The TV categories were <2 cc (37%), 2–20 cc (53%), and >20 cc (11%). The median PSA follow-up was 42 months; 11% experienced biochemical recurrence (BCR). The BCR rates differed significantly across volume categories (p < 0.01). At 120 months, MFS was highest in the <2 cc group (97%) and lowest in the >20 cc group (87%) (p < 0.01). Conclusions and Clinical Implications: Prostate-TV in ISUP-grade group 2 disease is independently associated with MFS. Tumours > 20 cc warrant closer monitoring and may benefit from adjuvant therapy. The improved pre-operative prediction of TV could support more tailored treatment strategies, including suitability for surveillance. What does the study add? We demonstrate for first time that tumour volume at prostatectomy is correlated with metastasis-free survival in ISUP 2 PCa. At 120 months, MFS was highest in the <2 cc group (97%) and lowest in the >20 cc group (87%) (p < 0.01). This has implications for post-operative surveillance.

Cancers doi: 10.3390/cancers18162604

Authors: Sarah M. Parks Werner J. Geldenhuys Scott A. Weed

References Errors [...]

Cancers doi: 10.3390/cancers18162603

Authors: Stelios Lamprou Styliana Georgiou Triantafyllos Stylianopoulos Chrysovalantis Voutouri

Background/Objectives: Histological biomarkers of therapy response remain incompletely defined in preclinical breast cancer models. We evaluated whether quantitative immunofluorescence imaging and multimodal machine learning (ML) could identify image-derived tissue biomarkers associated with response in a 4T1 murine breast cancer therapy-response setting. Methods: We analysed 1696 immunofluorescence images across nine immunofluorescence staining panels: aPDL1, alpha-smooth muscle actin-CD31, alpha-smooth muscle actin-Ki67, CD3-CD31, CD8-Ki67, collagen–hyaluronic acid (HA), granzyme B-CD8, HMGB1, and pimonidazole/hypoxia. A Python image-analysis algorithm extracted 117 RGB-channel, intensity, morphometric, and cross-channel spatial features per image. The modelling framework included image-only deep learning (DL), tabular ML on extracted histological features, and image-plus-tabular gated fusion. Models were evaluated using stratified cross-validation, train-fold-only class balancing, bootstrap confidence intervals, permutation testing, nested feature-selection sensitivity analysis, and grouped leakage controls. Results: Histological staining panels classified treatment-response status across the nine-panel benchmark. Collagen–HA was the strongest staining (AUC 0.954), followed by alpha-smooth muscle actin-Ki67 (AUC 0.851) and hypoxia (AUC 0.837). DL achieved the best performance in eight of nine stainings. In 346 collagen–HA images, combined collagen and HA features achieved AUC 0.848, collagen-only features AUC 0.833, and hyaluronic-acid-only features AUC 0.805. In 104 animals with matched hypoxia and collagen–hyaluronic-acid images, extracellular-matrix features achieved AUC 0.985, hypoxia-only features achieved AUC 0.929, and adding hypoxia did not improve extracellular-matrix-only prediction. Conclusions: Quantitative extracellular-matrix imaging provides a strong preclinical signal for therapy-response stratification in 4T1 breast cancer. The findings are hypothesis-generating and require independent preclinical and human validation before clinical translation.

Cancers doi: 10.3390/cancers18162602

Authors: Matilde Callegarin Valentina Angerilli Jessica Gasparello Francesca Bergamo Rodrigo Humberto Giron Cuestas Paola Parente Sara Lonardi Matteo Fassan

Squamous cell carcinoma of the anal canal (SCAC) is a rare malignancy whose incidence has been steadily increasing worldwide. Persistent infection with high-risk human papillomavirus (HPV), particularly HPV16 and HPV18 genotypes, is the main etiological factor and plays a central role in tumor development. While combined chemoradiotherapy remains the standard treatment for localized disease and achieves high rates of tumor control, a considerable proportion of patients experience recurrence or present with advanced disease. For the latter, therapeutic options remain limited. Over the last decade, advances in genomic profiling have significantly expanded our understanding of SCAC biology. Recurrent alterations affecting the PI3K/AKT/mTOR pathway, especially PIK3CA mutations, have emerged as the most common molecular events, particularly in HPV-positive tumors. Additional alterations involve receptor tyrosine kinase signaling, chromatin remodeling genes, DNA damage response pathways, and components of the MAPK cascade. Moreover, HPV-positive and HPV-negative tumors display distinct molecular features with important prognostic implications. Immunotherapy has recently become an important component of treatment for advanced SCAC, although reliable predictive biomarkers are still lacking. This review summarizes the current evidence on the molecular landscape of SCAC, discusses emerging prognostic and predictive biomarkers, and highlights potential opportunities for the development of more personalized therapeutic strategies.

Cancers doi: 10.3390/cancers18162601

Authors: Songming Chen Wei Zhang Luohuan Dai Yubin Kuang Haodi Yang Jia Gu Kang Peng Nian Jiang Hongwei Liu Xuejun Li

Gliomas, and glioblastoma in particular, remain difficult to model because molecular heterogeneity, diffuse invasion, blood–brain and blood–tumour barrier effects, immune suppression and repeated therapeutic escape converge in the same disease. Two-dimensional cultures, glioma stem cell (GSC) systems, acute tumour slices and animal models remain indispensable for mechanistic research, pharmacology and in vivo validation. Glioma organoids are complementary research platforms, not components of routine diagnostic or treatment procedures. This review links model construction, microenvironmental validation, treatment perturbation and evidence-graded interpretation. We compare patient-derived glioma organoids, GSC-derived organoids, brain organoid–glioma co-cultures, genetically engineered brain tumour organoids, and vascular-associated, immune-cell-containing and chip-based platforms. We distinguish phenotypic resemblance from physiological fidelity, tumour-intrinsic drug sensitivity from delivery competence, and proof-of-concept activity from demonstrated clinical utility. We also examine temozolomide resistance, radiotherapy, targeted and combination therapy, antiangiogenic treatment, tumour-treating fields, immune-cell therapy, oncolytic viruses, multi-omic quality control and prospective validation. Organoids should not substitute for animal models or clinical trials. Their most defensible role is to provide a patient-derived functional layer between mechanism, regimen ranking and molecular tumour-board interpretation, with claims limited by assay reproducibility, clinically achievable exposure and outcome linkage.

Cancers doi: 10.3390/cancers18162600

Authors: Timo Ylikomi Matthias Nees

Ketogenic metabolic therapy (KMT), typically implemented as a ketogenic diet (KD), has re-emerged as a potential adjuvant strategy in oncology. Its rationale is grounded in the metabolic reprogramming of cancer cells, including their reliance on glucose and lipid substrates and the signaling functions of ketone bodies. Despite extensive preclinical evidence of anti-proliferative and immunomodulatory effects, clinical translation in cancer therapy has been slow and inconsistent. This review critically examines the mechanistic basis, experimental and clinical evidence, and translational challenges of KMT across epithelial cancers. We emphasize that “ketogenic interventions” comprise mechanistically distinct modalities, including classical KD, fasting, fasting-mimicking diets, and exogenous ketone supplementation, which are frequently conflated yet differ substantially in their endocrine and metabolic contexts. Across clinical studies, KMT is generally feasible and associated with improvements in quality of life and metabolic parameters; however, robust evidence for the survival benefit of KMT remains limited and heterogeneous. Mechanistically, ketone bodies exert both metabolic and signaling functions, including inhibition of histone deacetylases, lysine β-hydroxybutyrylation, and receptor-mediated effects. Tumor responses are highly context-dependent: ketolytic capacity, governed by enzymes such as OXCT1, can render ketones either a metabolic vulnerability or an alternative fuel for cancer cells. KMT can modify the complex tumor microenvironment, exerting potentially opposing effects on cancer cells, immune cell populations, fibroblasts, and adipocytes. We argue that the central limitation of the field is not a lack of biological activity, but of insufficient integration of tumor-intrinsic metabolism, host physiology, and microenvironmental context. KD/KMT should therefore be regarded not as a universal anticancer therapy, but as a stratified metabolic intervention, whose progress will depend on biomarker-guided patient selection, improved experimental models, and rational combination strategies within a “press-pulse” therapeutic framework.

Cancers doi: 10.3390/cancers18162599

Authors: Francesca Bressan Riccardo Ghermandi Cristiana Griffoni Andrea Giacovazzo Riccardo Rosa Valerio Pipola Chiara Cini Bruna Maccaferri Lisa Berti Alberto Leardini Alessandro Gasbarrini

Objectives: Spinal tumors often require complex surgical treatments, in particular en bloc vertebrectomy, and a pre-operative kinematics and functional assessment of the spine could be advised to improve surgical outcomes and patients’ quality of life. However, established protocols for stereophotogrammetry-based gait analysis are not available. This study aims at evaluating the feasibility of an experimental protocol for multi-segment trunk and spine kinematics in patients scheduled for en bloc vertebrectomy. Methods: Ten patients and ten age- and sex-matched healthy controls underwent full-body gait analysis using an established marker-set able to track the lower limbs, pelvis, thorax, shoulders, and five spine line segments. The participants completed static double leg standing, barefoot level walking, and elementary trunk movements. A preliminary within-session repeatability assessment in two individuals (one representative patient and one healthy participant) was performed (root mean square error smaller than 10% of ROM; intra-class correlation coefficients > 0.8). Results: Compared with controls, patients affected by spinal tumors showed slower gait, shorter stride length, smaller ROM at the pelvis and thorax, and reduced frontal-plane mobility between spine line segments, but physiological lower-limb joint kinematics. During elementary movements, patients exhibited reduced trunk ROM in the anatomical plane of motion, particularly at a central spine segment, and smaller pelvic mobility in axial rotations. Conclusions: The results of this study support the feasibility of the proposed protocol for gait analysis in the rare clinical population of patients affected by spinal tumors and provide descriptive functional information that may complement conventional pre-operative clinical and imaging assessments.

Cancers doi: 10.3390/cancers18162598

Authors: Behzad Amoozgar Ayrton Bangolo Danielle C. Thor Shibhani Rajanna Shareif Abdelwahab Ahmed S. Mohamed Charlene Mansour Syed Usman Ehsanullah

Hematologic malignancies, including acute myeloid leukemia, myelodysplastic syndromes, lymphoma, and multiple myeloma, are characterized by profound biological heterogeneity and highly dynamic treatment trajectories that conventional, static prognostic systems incompletely capture. Cellular therapies, such as chimeric antigen receptor T-cell therapy and hematopoietic stem cell transplantation, offer potentially curative options for relapsed or refractory disease, yet outcomes remain highly variable, and management decisions regarding conditioning intensity, lymphodepletion, immunosuppression, and toxicity surveillance continue to be largely protocol-driven rather than individually adapted. Artificial intelligence (AI) and machine learning (ML) have demonstrated substantial promise in diagnostic support, prognostic stratification, and multimodal data integration across hematologic malignancies, but existing models remain predominantly static and related to pre-treatment in orientation, limiting their utility for real-time clinical guidance. This review summarizes current AI applications in hematologic oncology; critically compares the strengths, limitations, and clinical applicability of major AI model classes, including traditional machine learning, deep learning, multimodal integrative frameworks, reinforcement learning, digital twins, and emerging foundation models and large language models; and proposes an adaptive, multimodal paradigm. We examine key enabling technologies and address the clinical, regulatory, ethical, and implementation challenges that must be resolved before these systems can be deployed at the bedside. We argue that the central challenge facing the field is no longer whether AI can predict outcomes, but whether it can actively guide real-time therapeutic decisions, and that achieving this transition will require interdisciplinary collaboration, prospective validation, and governance frameworks capable of ensuring interpretability, equity, and clinical trustworthiness.

Cancers doi: 10.3390/cancers18162597

Authors: Alexandre Tavartkiladze Levan Tavartkiladze Russel J. Reiter Michel Burnier Engin Ulukaya Revaz Turmanidze Pati Revazishvili

Background/objectives: Melatonin has circadian, antioxidant, mitochondrial, and immunomodulatory functions, but human data linking relative melatonergic status to coordinated systemic biomarker burden remain limited. We examined this association and tested its internal robustness to alternative score construction, outlier handling, and missing-data assumptions. Methods: We performed an adult-only cross-sectional secondary analysis of a deidentified biomarker dataset. Of 322 source records, six participants younger than 18 years and two records without age were excluded, yielding 314 adults. Plasma melatonin and 24 h urinary aMT6s were converted to within-cohort rank percentiles and averaged to form a relative melatonergic-axis score. Equal-weight z-score composites represented inflammation, oxidative damage, antioxidant deficit, and biological aging/biological injury; their mean was the integrated systemic biomarker-burden score. Analyses included Kruskal–Wallis tests; Spearman correlations with bootstrap confidence intervals; standardized regression adjusted for age, sex, and BMI; robust covariance estimates; principal component analysis (PCA), winsorization, leave-one-domain/marker-out analyses, and missing-BMI sensitivity models. Results: The lower, intermediate, and higher relative melatonergic tertiles included 105, 104, and 105 adults, respectively. The melatonergic-axis score correlated inversely with integrated systemic burden (Spearman ρ = −0.944; 5000-resample bootstrap 95% CI, −0.953 to −0.931; p < 0.001). In age-, sex-, and BMI-adjusted complete-case models (N = 250), each 1 SD higher axis score was associated with a 0.95 SD lower integrated burden (β = −0.949; HC3 95% CI, −0.983 to −0.915; p < 0.001). Results were similar for separate plasma melatonin and aMT6s models, winsorized composites, a PCA-derived score (PC1 explained 75.5% of marker variance; ρ = −0.947), leave-one-domain/marker-out analyses, and missing-BMI sensitivity models. Conclusions: Lower relative melatonergic status was associated with a highly coordinated adverse systemic biomarker pattern. The exceptional magnitude of the association requires audit of primary assay provenance and independent external replication. Because cancer, microbiome, and liquid biopsy endpoints were not measured, oncology implications remain untested prospective hypotheses.

Cancers doi: 10.3390/cancers18162596

Authors: Chihiro Kosugi Kiyohiko Shuto Mikito Mori Daisuke Suzuki Akihiro Usui Yoshito Oka Hiroaki Shimizu

Background: Surgical site infection (SSI) is a common complication after colorectal cancer (CRC) surgery. We evaluated routinely available perioperative biomarkers for early prediction of superficial SSI after curative CRC surgery. Methods: This retrospective study included 488 patients undergoing elective curative CRC resection. Preoperative and postoperative day (POD) 1 laboratory parameters were evaluated using receiver operating characteristic curve analysis and multivariable logistic regression. Results: Superficial SSI developed in 66 patients (13.5%). In the perioperative multivariable association model, preoperative serum albumin ≤ 3.70 g/dL (odds ratio [OR], 1.918; 95% confidence interval [CI], 1.066–3.449; p = 0.030) and WBC count ≥ 6.30 × 103/µL (OR, 1.970; 95% CI, 1.123–3.458; p = 0.018) were independently associated with superficial SSI. On POD1, serum albumin ≤ 2.80 g/dL (OR, 3.447; 95% CI, 1.993–5.963; p < 0.001) and WBC count ≥ 10.50 × 103/µL (OR, 2.822; 95% CI, 1.600–4.976; p < 0.001) remained independently associated with SSI. Although lower POD1 lymphocyte-to-monocyte ratio was associated with SSI in univariable analysis, it was not significant after adjustment. A combined model incorporating dichotomized preoperative and POD1 albumin and WBC counts showed modest discrimination (AUC, 0.731; 95% CI, 0.663–0.800), with 47.0% sensitivity and 89.3% specificity. Conclusions: Perioperative albumin and WBC counts were independently associated with superficial SSI. POD1 assessment may aid early risk stratification; however, the modest performance indicates that these biomarkers should complement rather than replace clinical surveillance. Prospective external validation is required.

Cancers doi: 10.3390/cancers18162595

Authors: Lucas I. Becker Nicolas Noel Neidert Roberto Doria-Medina Manou Overstijns Maryam Wendeberg Urs Würtemberger Horst Urbach

Background: Glioblastoma (GBM) carries a median survival of 15 months. Approximately 16–27% of patients die within six months despite standard therapy. Radiomic MRI features have been proposed as prognostic biomarkers, yet many published studies employ standard cross-validation (CV) with feature selection on the full dataset, introducing data leakage. Methods: Sixty patients with IDH-wildtype GBM from the publicly available UCSF-PDGM dataset (single-center, GE Discovery MR750, 3 T; 2015–2021) with BraTS 2021 segmentation masks were analyzed. One thousand two hundred eighty-four (1284) IBSI-compliant radiomic features (7 feature classes × 4 MRI sequences × 3 tumor subregions) were extracted using PyRadiomics. After preprocessing (variance filter, correlation filter |r| > 0.95), approximately 120 features remained per fold. Feature selection was performed strictly within each training fold of a nested 5-fold cross-validation framework (5-fold × 3 repeats = 15 outer folds). Results: For 1-year mortality, radiomics AUC dropped from 0.816 (standard CV) to 0.593 (nested CV; ΔAUC = −0.223, 27% inflation), while clinical models remained stable (0.708 vs. 0.705). For early mortality (≤180 days, n = 16 events), standard CV inflated radiomics AUC to 0.888, whereas nested CV yielded 0.815 (ΔAUC = −0.073, 8% inflation). In feature stability analysis, whole-tumor surface area (13/15 folds) and mesh volume (10/15 folds) showed the highest cross-endpoint stability; nine of 13 exploratory OS-associated features were never selected for early mortality classification. Extent of resection (HR = 0.44, p = 0.009) and age (HR = 1.03, p = 0.038) were independently associated with overall survival; tumor surface area remained independently associated with survival (HR = 1.38, p = 0.021). Conclusions: Nested cross-validation revealed substantial performance inflation in standard radiomics pipelines. These descriptive inflation estimates are specific to this dataset and pipeline configuration and should not be generalized as universal parameters for radiomics.

Cancers doi: 10.3390/cancers18162594

Authors: Chuanfei Zhan Yuanyuan Zhai Tianming Chen Xiaokang Shen Zi Wang Shuliang Ma Shilin Chen

Background: Incomplete microwave ablation (iMWA) of lung cancer often leads to rapid recurrence and metastasis, yet the underlying mechanisms remain unclear. This study explored whether iMWA promotes tumor progression by activating the cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS–STING) signaling pathway and its downstream effector ZEB1 in tumor cells. Materials and Methods: An in vivo iMWA model was established in nude mice bearing H1650 lung tumors, and an in vitro sublethal heat treatment model was used to mimic incomplete ablation. Transcriptomic profiling, molecular assays and functional analyses assessed cellular behavior and signaling activity changes post-iMWA; genetic and pharmacologic interventions modulated STING signaling and autophagy. Results: Post-iMWA residual cells exhibited enhanced proliferation and invasion. Thermal injury induced necrosis and inhibited mitophagy, causing cytosolic mtDNA accumulation that activated the intrinsic cGAS–STING pathway. This upregulation of ZEB1 drove epithelial–mesenchymal transition and dissemination. Notably, silencing STING or ZEB1, or pharmacologically restoring autophagy, significantly suppressed tumor growth and metastasis. Conclusions: iMWA drives malignant progression of lung cancer through an mtDNA–cGAS–STING–ZEB1 signaling axis. Targeting this pathway—by inhibiting STING or enhancing autophagy—may represent a promising therapeutic strategy to mitigate recurrence and metastasis following microwave ablation.

Cancers doi: 10.3390/cancers18162593

Authors: Mariam Ismail Zaid Alabed Khaled Alhallaq Ebtesam Al-Najjar Nour Mustafa Yacoub Aldroubi Yazan Hamdaneh Abdullah Esmail

Immune checkpoint inhibitors (ICIs) have significantly changed the treatment landscape of several gastrointestinal (GI) malignancies, particularly microsatellite instability-high (MSI-H) and mismatch repair-deficient (dMMR) tumors. However, most GI cancers remain resistant to current PD-1/PD-L1-based immunotherapy because of complex and highly suppressive tumor microenvironments characterized by immune stromal exclusion, myeloid-driven immune suppression, defective antigen presentation, and adaptive immune resistance mechanisms. Emerging evidence suggests that alternative inhibitory pathways, including lymphocyte activation gene-3 (LAG-3), T-cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), and V-domain Ig suppressor of T-cell activation (VISTA), contribute substantially to persistent T-cell dysfunction and resistance to checkpoint blockade. This review summarizes the immune landscape of GI malignancies and discusses the biological mechanisms underlying resistance to current ICIs. We highlight the evolving role of next-generation immune checkpoints, ongoing clinical development of novel inhibitors, and emerging combination strategies involving chemotherapy, anti-angiogenic therapy, radiation, bispecific antibodies, and tumor microenvironment modulation. In addition, we discuss current limitations in biomarker development and the growing role of circulating tumor DNA, spatial immune profiling, and multi-omics approaches in patient selection. Finally, we explore future directions aimed at improving precision immunotherapy and expanding durable responses across GI cancers.

Cancers doi: 10.3390/cancers18162592

Authors: Fatima Zahra Kamal Radu Lefter Vasile Burlui Alin Stelian Ciobîcă Gabrielle Dăscălescu Said Rammali Andrei Luca Ancuța Andreea Miler Hina Alim Otilia Novac Bouchaib Bencharki Bogdan Novac

Cancer therapy is increasingly focused on manipulating the tumor microenvironment rather than directly eradicating malignant cells. Vascular-targeting strategies are emerging, and calcium-mediated vascular disruption is an exciting approach through which rapid and irreversible blood flow shutdown can be achieved. Here, we overview the molecular and physiological basis of calcium signaling in vascular homeostasis and outline how unregulated calcium dysfunctions in endothelial cells compromise their functionality and represent therapeutic opportunities. Elevation of intracellular calcium concentrations in endothelial cells promotes their dysfunction, coagulation, mitochondrial collapse, oxidative stress, and ultimately apoptosis, resulting in catastrophic vascular depletion and secondary necrosis that follows such collapse. A promising area of calcium-mediated attack is the emergence of exciting nanotechnologies that result in the development of calcium phosphate, calcium carbonate, and calcium peroxide nanoparticles, exploiting the enhanced permeability and retention effect of nanoparticle therapeutics to achieve selective tumor accumulation and controlled calcium release. Indeed, hybrid therapeutic platforms that couple calcium dysregulation with chemotherapy, photodynamic therapy, sonodynamic therapy, immunotherapy, or thermal ablation can exhibit pronounced antitumor effects through synergistic means. There is good preclinical evidence for the feasibility of vascular collapse mediated via calcium dysregulation. The transition of calcium to the clinic faces hurdles in relation to biosafety, how to achieve precise delivery, pharmacokinetics, and regulatory harmonization. Compared to traditional vascular disrupting agents and anti-angiogenic therapies, calcium modalities can provide rapid occlusion of vessels, are less prone to resistance development, and potentially have less systemic toxicity. Overall, calcium-mediated vascular collapse is thus an exciting next-generation technology for the vascular-targeted treatment of cancer, and likely to play an important role in precision oncology therapeutics.

Cancers doi: 10.3390/cancers18162590

Authors: Mathilde F. Køtter Maya E. R. Schambye Simon Espensen Ninna Aggerholm-Pedersen Daniel T. H. Dybdal Jesper S. Brok Lisa L. Hjalgrim

Background/Objectives: Survival in children, adolescents and young adults (CAYA) with bone sarcoma remains inferior to that of many other early-life cancers. Early recognition and treatment initiation may reduce the risk of presenting with advanced disease. We aimed to synthesize evidence on five predefined diagnostic intervals, separately synthesize pathway-specific intervals, and identify factors associated with diagnostic interval duration. Methods: A systematic review was conducted according to PRISMA guidelines. We included studies reporting the duration of a diagnostic interval in at least five patients aged 0–39 years with primary bone sarcomas, including osteosarcoma, Ewing sarcoma, and less common histological subtypes. MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, and Scopus were searched for studies published between 2000 and 2025. Risk of bias was assessed using a custom domain-based tool. Results: Twenty-nine studies including 9271 patients from high-income countries met the inclusion criteria. Substantial heterogeneity in study design, populations, and interval reporting precluded meta-analysis. Reported median intervals were patient intervals of 13–84 days, diagnostic intervals of 15–123 days, total diagnostic intervals of 28–150 days, treatment intervals of 7–24 days, and total intervals of 66–88 days. Older age within the CAYA population and axial tumor location were the factors most consistently associated with longer diagnostic intervals. No consistent association between diagnostic interval duration and survival was identified. Pathway-specific intervals provided additional insight into different components of the diagnostic pathway, particularly after initial healthcare contact, although evidence remained limited. Conclusions: Diagnostic interval durations varied substantially across studies, reflecting methodological heterogeneity and differences in diagnostic pathways. Standardized prospective studies are needed to strengthen the evidence base.

Cancers doi: 10.3390/cancers18162591

Authors: Imran Shair Mohammad Anup Kumar Patel Steven T. Rosen Marcin Kortylewski Jonathan Kessler Julie Ressler Chandana Lall Catalina Guerra Jason Chiang F. Edward Boas

Purpose: Systemic immunotherapy is less effective in patients with liver metastases. Immunoembolization could potentially overcome the immunosuppressive tumor microenvironment, but the optimal immunotherapy agent, embolic, and release kinetics are unknown. Methods: A wide range of immunotherapy agents (cytokines, small molecules, and oligonucleotides) were loaded onto various embolics (stabilized lipiodol emulsions, microspheres-in-lipiodol, LC beads, and PLGA microspheres). Drug loading and release kinetics were evaluated in vitro. A pilot study of transarterial immunoembolization was performed in a pig liver tumor model, using extended release lipiodol/CpG-STAT3ASO formulations. CpG-STAT3ASO is a first-in-class dual-function immunotherapy agent that both stimulates the anti-tumor immune response, and counters immunosuppression in immunologically cold tumors. Safety, pharmacokinetics and efficacy were evaluated in pigs. Results: Immunotherapy-loaded embolics released drug with a half-life ranging from days to weeks in vitro, and up to four days in pig liver tumors (depending on the formulation). A stabilized lipiodol emulsion demonstrated 100% burst release (within five minutes after immunoembolization), compared to <1% burst release with microspheres-in-lipiodol. Immunoembolization using lipiodol/CpG-STAT3ASO resulted in decreased size of pig liver tumors, compared to bland embolization. No adverse events were seen, based on clinical, laboratory, and radiographic evaluation, but peritoneal adhesions were observed in association with immunoembolization using microspheres-in-lipiodol. Conclusions: Extended-release immunotherapy-loaded embolics generate sustained intratumoral delivery of immune stimulants. A pilot study of immunoembolization of pig liver tumors showed decreased tumor size, compared to bland embolization, with no autoimmune adverse events.

Cancers doi: 10.3390/cancers18162589

Authors: Tania Raya-Bahena Rene M. Rivera-Escobar Elisabeth Hernández-Gallegos Javier E. Jiménez-Salazar Pablo Damián-Matsumura Janice García-Quiroz Javier Camacho

Background/Objectives: Cervical cancer (CC) is the most clinically significant HPV-associated malignancy. Platinum-based chemotherapies produce drug resistance and serious adverse effects. Drug repurposing and combinations are promising approaches to improve the antitumor response. Here, we evaluated the antineoplastic potential of loratadine and simvastatin alone and in combination with cisplatin and gefitinib in HPV-positive CC cells. Methods: HeLa and SiHa CC cells were treated with loratadine, simvastatin, cisplatin, gefitinib, or their combinations. Metabolic activity was assessed using the MTT assay to determine drug inhibitory concentrations (IC20, IC50) from concentration–response curves. Apoptosis was assessed by Annexin V-FITC/PI flow cytometry. Clonogenic survival and migratory capacity were evaluated using colony formation and wound-healing assays, respectively. Tumor formation was evaluated in vivo using the chick chorioallantoic membrane model. Results: Metabolic activity decreased in a concentration-dependent manner following drug treatment in both cell lines. Several combination regimens at IC20 significantly improved reductions in metabolic activity and increases in apoptosis compared with monotherapies or two-drug combinations. Notably, some three-drug combinations, with or without cisplatin, had similar effects to the quadruple regimen. Combination treatments also reduced clonogenic survival and migratory capacity, as well as tumor formation and cancer cell dissemination in vivo. Conclusions: Drug combinations at relatively low concentrations (IC20) significantly enhanced the anticancer effects on CC cells in in vitro and in vivo settings. These findings support the potential of drug repurposing and combination strategies as promising approaches to decrease adverse side effects while improving therapeutic efficacy for the benefit of CC patients.

Cancers doi: 10.3390/cancers18162588

Authors: Aditi Yellu Aidan S. Weitzner Craig Cronin Joon Kyung Kim Soum D. Lokeshwar

Objective: To evaluate current and emerging perioperative optimization strategies in genitourinary surgery and assess their potential to improve surgical outcomes, particularly in patients with modifiable risk factors. Methods: A literature review was conducted using PubMed databases examining perioperative interventions relevant to patients undergoing surgery for genitourinary cancers. Areas of focus included enhanced recovery after surgery protocols, nutritional optimization, exercise prehabilitation, smoking cessation, glucagon-like peptide-1 receptor agonists, and gut microbiome modulation. Evidence from clinical trials, observational studies, systematic reviews, and current clinical guidelines was reviewed and synthesized. Results: Current evidence supports the use of enhanced recovery after surgery protocols to reduce acute complications, shorten length of stay and decrease recovery time. Nutritional optimization and exercise prehabilitation demonstrated improved functional and metabolic capacity. Smoking cessation improved wound healing and decreased pulmonary and infectious complications. Emerging evidence suggests GLP-1 RAs offer metabolic benefits, and microbiome-targeted interventions may improve postoperative recovery through gut microbiome diversity preservation, although clinical data remains limited. Conclusions: Perioperative strategies demonstrate promising potential to improve outcomes in patients undergoing genitourinary surgeries by addressing modifiable risk factors. Further prospective studies are needed to guide clinical implementation.

Cancers doi: 10.3390/cancers18162587

Authors: Azusa Miyashita Satoshi Fukushima

Background: Extramammary Paget disease (EMPD) is a rare epithelial malignancy that arises in the apocrine gland-bearing skin. Although localized intraepidermal EMPD generally follows an indolent clinical course, invasive EMPD is associated with lymph node metastasis, distant dissemination, and poor survival. Owing to its rarity, high-level evidence is limited and treatment strategies remain incompletely standardized, particularly for advanced disease. Recent advances in molecular profiling have revealed actionable therapeutic targets and created new opportunities for precision medicine. Methods: A narrative review was conducted using the PubMed database through May 2026. Relevant literature regarding the epidemiology, prognostic factors, surgical and non-surgical management, lymph node management, radiotherapy, systemic therapies, molecularly targeted therapies, and future therapeutic directions for EMPD is reviewed and summarized. Results: Surgical excision remains the standard treatment for resectable localized EMPD. Margin-controlled approaches, including Mohs micrographic surgery, complete circumferential peripheral and deep margin assessments, and mapping biopsy-guided excision, have contributed to improved local disease control. Radiotherapy, topical imiquimod, and photodynamic therapy provide alternative treatment options for patients who are unsuitable candidates for surgery; however, recurrence remains a major challenge. The management of regional lymph node metastases includes sentinel lymph node biopsy, lymph node dissection, and adjuvant radiotherapy in selected patients. For metastatic disease, conventional chemotherapy based on taxanes and fluoropyrimidine/platinum combinations has demonstrated moderate antitumor activity but limited durability. Molecular characterization of EMPD has identified several promising therapeutic targets. HER2 overexpression or amplification, observed in approximately 30–40% of cases, has emerged as the most clinically validated biomarker, with trastuzumab-based therapies demonstrating substantial efficacy. Immune checkpoint inhibitors have shown activity in selected patients, particularly those with a high tumor mutational burden, although predictive biomarkers remain inadequately defined. Additional emerging targets include androgen receptor signaling, TROP2, NECTIN4, FOXM1, and PIK3CA-associated pathways. Conclusions: In addition to conventional surgery- and chemotherapy-based approaches, biomarker-driven precision oncology is gaining attention as a treatment strategy for EMPD. HER2-targeted therapies, antibody–drug conjugates, and rationally selected immunotherapeutic strategies are expected to play increasingly important roles in the treatment of advanced disease. Continued translational research, international collaboration, and prospective clinical trials are essential to establish evidence-based treatment algorithms and improve outcomes in patients with this rare but potentially aggressive malignancy.

Cancers doi: 10.3390/cancers18162586

Authors: Giorgia Silvestrini Serena Travaglini Luca Guarnera Nicole Lelli Mariadomenica Divona Elisa Casciani Sara Ceccolini Giulia Falconi Tiziana Ottone Maria Teresa Voso

Fms-related receptor tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations occur in approximately 20–25% of patients with acute myeloid leukemia (AML) and are associated with increased relapse risk and inferior survival outcomes. Although measurable residual disease (MRD) has become a key prognostic tool for guiding post-remission treatment decisions, FLT3-ITD was historically considered a suboptimal MRD marker because of its subclonal nature, structural heterogeneity and dynamic behavior during disease evolution. In addition, FLT3-ITD has not yet been fully integrated into routine MRD monitoring due to methodological limitations and a lack of standardized workflows. The latest European LeukemiaNet (ELN)-DAVID 2025 recommendations stressed the use of ultra-high sensitivity (UHS) next-generation sequencing (NGS) technologies to detect FLT3-ITD MRD with improved precision, enabling reliable longitudinal tracking of patient-specific clones at very low variant allele frequencies (VAF). Indeed, despite prospective evidence supporting this approach remaining limited, FLT3-ITD-based MRD monitoring is emerging as a clinically relevant prognostic indicator, contributing to the identification of patients at increased risk of relapse and refining risk stratification, while also informing therapeutic decision-making, particularly in the peri-transplant setting. The present review summarizes the biological underpinnings of FLT3-ITD mutated (FLT3-ITDmut) AML, discusses the methodological challenges of MRD detection, and critically evaluates the evolving role of MRD in refining relapse prediction, supporting post-remission therapy tailoring, and contributing to a harmonized framework for FLT3-ITDmut AML management.

Cancers doi: 10.3390/cancers18162585

Authors: Andrew P. Leynes Jonathan Andreas Saenger Anna Weber Thomas Frauenfelder Andreas Boss

Purpose: Breast cancer screening relies primarily on two-dimensional (2D) digital mammography, which is limited by tissue superposition and compression-related patient discomfort. Dedicated spiral breast computed tomography (BCT) overcomes these limitations by providing isotropic, fully three-dimensional (3D) volumetric images without compression. However, translating artificial intelligence (AI) advancements to 3D BCT lesion detection is hindered by the scarcity of large-scale annotated 3D datasets and substantial computational constraints. The purpose of this study is to evaluate the feasibility of repurposing a pre-trained 2D mammography AI model for 3D BCT malignancy detection without dedicated model retraining. Methods: In this exploratory proof-of-concept study, the dataset comprised BCT examinations of female patients with malignant lesions. We developed a slab projection framework that systematically rotates the BCT volume and extracts overlapping tissue slabs to simulate mammography-like 2D images compatible with the input requirements of the pre-existing 2D mammography model. The 2D inferences were subsequently back-projected to their original 3D spatial coordinates and aggregated via a consensus voting scheme. Optimization and performance evaluation were performed on the same dataset to establish an internal baseline. Object-level detection performance was assessed using the F1 score, and segmentation quality was evaluated using the Dice coefficient. Results: Application of the proposed framework enabled 3D lesion localization in BCT volumes without requiring domain-specific training. An optimal configuration was found with a sparser angular sampling combined with medium slab thickness (45° angular spacing, 50-voxel thickness), which achieved an F1 score of 0.346, with 48.3% precision and 26.9% recall. Evaluation of segmentation quality corroborated these findings, yielding a maximum mean Dice coefficient of 0.336 for the 45°/30-voxel configuration. Conclusions: This exploratory proof-of-concept demonstrates the technical feasibility of adapting a pre-trained 2D mammography AI model to volumetric BCT without architectural modifications or retraining. The reported performance represents an internal same-dataset baseline under substantial domain shift and should not be interpreted as generalizable or clinically deployable performance. These findings provide a foundation for future domain-adapted models and independent external validation of AI-based tumour detection in breast CT.

Cancers doi: 10.3390/cancers18162584

Authors: Beth Chasty Agata Rembielak Richard Berman Eva Oldenburger

The management of oligometastatic disease has undergone a significant paradigm shift over the past two decades. Once considered uniformly incurable, selected patients with metastatic disease can now achieve prolonged progression-free survival, durable disease control, and, in carefully selected cases, long-term remission or cure through metastasis-directed therapies. Advances in stereotactic ablative radiotherapy (SABR), surgery, systemic therapies, and the emerging concept of Curative Oligometastatic Radiotherapy (CORT) have challenged the traditional distinction between curative and palliative treatment. Concurrent developments in imaging, including PET/CT, prostate-specific membrane antigen (PSMA) PET, whole-body MRI, and MR-guided adaptive radiotherapy (MR-linac), together with evolving biomarker research, are improving disease characterisation, refining patient selection, and treatment personalisation. As survival improves, an increasing number of patients are living with durably controlled metastatic cancer and experience long-term physical, psychological, cognitive, functional, and financial consequences of treatment. Despite these challenges, evidence-based survivorship pathways for patients with oligometastatic disease remain poorly defined. Supportive oncology is becoming an essential component of modern radiation oncology rather than an adjunct to cancer treatment. This emerging discipline focuses on optimising symptom control, minimising toxicity, and delivering structured survivorship care. Rather than being limited to end-of-life care, supportive oncology is embedded throughout the patient journey; from diagnosis and treatment selection to prehabilitation, rehabilitation, patient-reported outcome (PRO) monitoring, surveillance for late effects, multidisciplinary follow-up, and long-term survivorship. This review discusses how advances in precision radiotherapy, molecular imaging, biomarkers, and emerging treatment technologies are reshaping the management of oligometastatic disease while simultaneously creating a growing population of long-term survivors with increasingly complex supportive care needs. It highlights the expanding role of supportive oncology in the care of patients with oligometastatic disease, encompassing multidisciplinary symptom management and argues that improvements in disease control must now be matched by the development of evidence-based multidisciplinary survivorship pathways that integrate supportive oncology to optimise quality of life (QoL), functional independence, and patient-centred outcomes. Finally, this review highlights current evidence gaps and proposes future research priorities for developing evidence-based survivorship models for this rapidly expanding patient population.

Cancers doi: 10.3390/cancers18162583

Authors: Michał Kapałka Estera Pazek Michał Krawiec Michał Sikorski Grzegorz Hirnle Tomasz Hrapkowicz

Background: Primary pericardial mesothelioma (PPM) is a rare and aggressive tumor. We aimed to analyze diagnostic pathways and factors influencing survival. Methods: A systematic review was conducted in accordance with PRISMA 2020 guidelines and registered in PROSPERO (CRD420261277326). MEDLINE, Web of Science, and EMBASE were searched up to March 2025. Case reports and case series published from 2010 onwards de- scribing histologically confirmed PPM were included. Data were extracted independently by multiple reviewers. Risk of bias was assessed using Joanna Briggs Institute tools. Individual patient data were pooled. Survival was analyzed using Kaplan-Meier and log-rank tests, and factors associated with survival ≥12 months were evaluated using univariable logistic regression. Results: A total of 120 patients were included (108 case reports, 4 case series). Diffuse pericardial involvement predominated (74.2%), while localized tumors occurred in 30.8%. Constrictive pericarditis was present in 31.7%. Median overall survival from diagnosis was 7.4 months (IQR 1.75–13.5). Use of CT and PET in the diagnostic process was associated with longer survival (CT: 9.1 vs. 1.5 months, p = 0.02; PET: 14 vs. 6 months, p = 0.04). Chemotherapy was associated with improved survival (OR 3.3; 95% CI 1.3–8.4; p = 0.01). Greater pericardial effusion volume was also associated with longer survival (OR 1.56; 95% CI 1.05–2.32; p = 0.028). Worse outcomes were observed in patients with constrictive pericarditis (p = 0.01) and diffuse disease (p = 0.04). Conclusions: PPM carries a poor prognosis. Chemotherapy and advanced imaging are associated with longer survival, whereas constrictive pericarditis and diffuse involvement indicate worse outcomes. Early recognition may reduce diagnostic delay. Findings should be interpreted with caution due to limitations of case-based data.

Cancers doi: 10.3390/cancers18162582

Authors: Dou-Dou Li Jie-Yun Zhang Yi-Yang Zhang Yu-Feng Yang Jun-Xi Chen Xi-Yuan Chen Xi Chen Zhi-Huang Hu Hai-Xia Wu Chen-Chen Wang

Immune checkpoint inhibitors targeting the PD-1 pathway have improved outcomes in advanced gastric cancer; however, substantial heterogeneity in treatment response remains. Current prediction strategies mainly rely on pretreatment biomarkers, which provide static assessments and may not capture the evolving interactions between tumor progression and host immunity. This study aimed to develop a dynamic prediction framework integrating longitudinal clinical trajectories and immune remodeling for continuous risk assessment during PD-1 inhibitor therapy. Methods: This retrospective study included 171 patients with gastric cancer receiving PD-1 inhibitor-based treatment. A landmark analysis framework was established using sequential 28-day follow-up windows to predict subsequent progressive disease (PD) or recurrence based on available clinical and immune information. Three nested models were developed: a baseline model (M0), a dynamic clinical model (M1), and an immune-integrated model (M2) incorporating longitudinal lymphocyte subset features. Model performance was evaluated using discrimination, calibration, and internal validation with patient-level resampling strategies. Results: Predictive performance improved progressively with incorporation of longitudinal information. The ROC AUC increased from 0.559 (95% CI, 0.429–0.690) in M0 to 0.737 (95% CI, 0.613–0.852) in M1 and 0.786 (95% CI, 0.681–0.883) in M2. Dynamic clinical information significantly improved discrimination compared with baseline prediction (ΔAUC = 0.178, p = 0.025), while additional immune features further enhanced risk stratification (ΔAUC = 0.049, p = 0.040). Interpretation analysis identified tumor burden evolution, neutrophil-to-lymphocyte ratio trajectories, and immune functional axes involving T-cell, innate cytotoxicity, and humoral immunity as major contributors to risk estimation. Landmark analyses demonstrated the feasibility of continuously updating PD/recurrence risk during treatment. Conclusions: This study establishes a dynamic landmark prediction framework integrating longitudinal clinical trajectories and immune remodeling for continuous risk assessment during PD-1 inhibitor therapy. Dynamic clinical and immune features provided complementary predictive information beyond baseline characteristics, supporting an adaptive approach for precision immunotherapy monitoring in gastric cancer.

Cancers doi: 10.3390/cancers18162581

Authors: Mohammed Rafea Kanaan Pouriya Faraj Tabrizi Jessica Schmitz Jan H. Bräsen Markus A. Kuczyk Hossein Tezval

Background/Objectives: Antibody–drug conjugates (ADCs) targeting Nectin-4 (enfortumab vedotin) and TROP-2 (sacituzumab govitecan) have transformed the management of advanced urothelial carcinoma (UC), but evidence on their molecular targets in rare non-urothelial bladder carcinomas (N-UC) is scarce. We evaluated the immunohistochemical expression of TROP-2 and Nectin-4 in muscle-invasive UC and N-UC and assessed their association with tumour stage, nodal status and overall survival. Methods: In this retrospective single-centre study, 111 consecutive patients with primary muscle-invasive bladder carcinoma (73 UC, 38 N-UC including squamous, adenocarcinoma, neuroendocrine and sarcomatoid variants) were analysed. TROP-2 and Nectin-4 expression was quantified using the H-score; positivity was defined as ≥15. Marker expression was correlated with clinicopathological characteristics and overall survival (OS) using chi-squared, linear-by-linear, log-rank, and Cox regression analyses. Results: TROP-2 positivity was observed in 46.6% of UC and 36.8% of N-UC (p = 0.925); Nectin-4 positivity in 17.8% and 28.9%, respectively (p = 0.275). Among positive cases, TROP-2 H-scores were higher in N-UC than in UC (mean 109 vs. 70; Mann–Whitney p = 0.045; Cliff’s delta 0.37, 95% CI 0.05–0.66); as no adjustment for multiple testing was applied, this difference is regarded as nominally significant and exploratory. Nectin-4 H-scores were numerically higher in UC (mean 82 vs. 53) but did not reach statistical significance (p = 0.84). Across the cohort, TROP-2 expression increased with advancing T stage (linear-by-linear p = 0.026) and was associated with nodal involvement (p = 0.043). Nectin-4 showed no significant stage association. Sarcomatoid carcinomas were negative for both markers. Median OS was 41 months in UC versus 19 months in N-UC (p = 0.668). Neither marker independently predicted OS, whereas advanced T stage (p = 0.003) and nodal involvement (p = 0.021) were significantly associated with poorer survival; T stage remained independently prognostic in multivariable analysis. Conclusions: TROP-2 and Nectin-4 are expressed at comparable rates in muscle-invasive UC and rare N-UC, except in sarcomatoid variants. TROP-2 expression increased with advancing tumour stage, suggesting stage-dependent regulation in muscle-invasive disease. Therefore, both markers should be interpreted as potential therapeutic targets whose expression can be demonstrated in these tumours, rather than as prognostic biomarkers or as validated predictive biomarkers of ADC response; because no patient received an ADC, the present study cannot determine whether expression predicts clinical benefit, and this distinction requires prospective, treatment-linked evaluation that includes patients with N-UC.

Cancers doi: 10.3390/cancers18162580

Authors: Carmen Blanco Abad Diego Casas Deza Fátima Mocha Campillo Natalia Pascual de la Fuente Sofía Elena Ruffini Egea Luis Gallart Caballero Cristina Serrano Delgado Carlos Alfonso Rivas Molina María Dolores Miramar Gallart María José Agustín Ferrández Paula Gomila Pons Sara Elena Campos Ramírez Marta Gascón Ruiz Eduardo Polo Marques Roberto Antonio Pazo Cid

Background and Aim: Germline testing (GT) is increasingly relevant in pancreatic ductal adenocarcinoma (PDAC) because of therapeutic and familial implications. We evaluated real-world GT uptake, the diagnostic yield of pathogenic/likely pathogenic germline variants (P/LP), and their clinical implications. Methods: We retrospectively evaluated 674 consecutive patients with PDAC. GT was performed using targeted single-gene testing or multigene panels. Survival analyses among patients receiving platinum-based chemotherapy according to P/LP germline variant status in HRR-associated genes were exploratory. Results: Overall, 28.9% of patients underwent GT, increasing to 45.9% in 2021–2025 (p < 0.001). Results were available for 194 patients; 28 (14.4%) harbored P/LP variants, most commonly BRCA2 (4.6%) and ATM (3.1%). P/LP variants were identified in 6.8% of patients who did not meet classical referral criteria. Among the 28 carriers, 12 (42.9%) harbored BRCA1/2 or PALB2, variants with established therapeutic relevance, while eight (28.6%) carried ATM, FANCA, or FANCM, variants with potential therapeutic relevance. Of these 20 patients, 11 (55.0%) received matched therapy, and treatment was modified because of the germline result in six (30.0%). In exploratory analyses, among platinum-treated patients, carriers of P/LP germline variants in HRR-associated genes had longer PFS than non-carriers (23.9 vs. 4.8 months; log-rank p = 0.017), although only six HRR-associated variant carriers were included in this platinum-treated survival analysis. Conclusions: GT remained underused despite increasing implementation. Early systematic GT may identify clinically relevant variants missed by selective referral strategies and inform treatment, genetic counseling, and cascade testing. Survival findings require prospective validation.

Cancers doi: 10.3390/cancers18162579

Authors: Agnieszka Genowska Jerzy Jaroszewicz Dorota Zarębska-Michaluk Katarzyna Lewtak Krystyna Dobrowolska Krzysztof Kanecki Anna Parfieniuk-Kowerda Aneta Nitsch-Osuch Piotr Rzymski Robert Flisiak

Background/Objectives: Primary liver and intrahepatic bile duct cancers remain important causes of cancer morbidity and mortality worldwide, yet contemporary nationwide data on affected populations in Poland are limited. This study evaluated sociodemographic patterns of first-time hospitalizations due to malignant neoplasms of the liver and intrahepatic bile ducts in Poland during 2012–2023. Methods: Data were obtained from the Nationwide General Hospital Morbidity Study and included 30,898 first-time hospitalizations identified using the ICD-10 category C22. First-time hospitalization rates were assessed according to sex, age, place of residence, disease subtype, length of stay, and comorbidities. Results: Men accounted for 57.7% of urban and 58.4% of rural cases and had significantly higher first-time hospitalization rates than women. These rates were higher among urban than rural residents (men: 9.5 vs. 6.0 per 100,000; women: 6.3 vs. 4.2 per 100,000). Liver cell carcinoma was the most frequent subtype (36.3%), followed by intrahepatic bile duct carcinoma (12.6%). Hospitalizations were uncommon before the age of 40 years and peaked in the 65–69-year age group. Mean age increased over time among men and urban women. In 2020, the number of first-time hospitalizations decreased from 2754 to 2060, corresponding to 694 fewer hospitalizations and a 25.2% decline compared with 2019. This decrease occurred against the background of nationwide reductions of 22.1% in patients treated in general-hospital wards and 8.1% in oncology-ward patients, suggesting that pandemic-related healthcare disruption may have contributed to the observed decline. Hospitalization rates subsequently increased. Rates for liver cell carcinoma remained relatively stable in most population groups, whereas those for intrahepatic bile duct carcinoma were significantly higher in 2020–2023 than in 2012–2019 across all sex and place-of-residence groups. Length-of-stay patterns were broadly similar across the analyzed groups, and diseases of the digestive system were the most common comorbidity category (23.1%). Conclusions: The findings demonstrate important sociodemographic differences and temporal changes in first-time hospitalizations due to malignant neoplasms of the liver and intrahepatic bile ducts in Poland. These findings suggest evolving epidemiological patterns and underscore the need for continued prevention, surveillance, and early detection efforts.

Cancers doi: 10.3390/cancers18162578

Authors: David Farkas József Baracs Zsombor Ritter David Sipos

Background/Objectives: Colorectal carcinoma (CRC) remains a leading cause of cancer-related morbidity and mortality worldwide, with increasing incidence in younger populations. Despite advances in imaging, conventional approaches remain limited by subjective interpretation and insufficient characterization of tumor heterogeneity. Radiomics, particularly in a multiparametric framework integrating computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET), has emerged as a promising tool to enhance diagnostic and prognostic performance. This review aims to critically evaluate methodological strategies for optimizing multiparametric radiomics in CRC. Methods: A narrative review was conducted based on a literature search of PubMed/MEDLINE, Scopus, and Web of Science up to March 2026. Studies focusing on CT-, MRI-, and PET-based radiomics in CRC were included. Key methodological aspects analyzed included imaging acquisition and standardization, tumor segmentation techniques, radiomic feature extraction, feature selection methods (e.g., LASSO and PCA), and model validation approaches. Results: Multiparametric radiomics models integrating CT, MRI, and PET consistently demonstrated superior diagnostic accuracy compared to single-modality approaches, particularly in T-staging and lymph node involvement prediction. PET-derived metabolic features further enhanced characterization of tumor biology and improved prognostic stratification, including prediction of progression-free survival (PFS) and overall survival (OS). However, methodological heterogeneity, small sample sizes, and variability in imaging protocols and segmentation practices remain significant limitations affecting reproducibility and generalizability. Conclusions: Multiparametric radiomics represents a powerful advancement in precision oncology for CRC, enabling improved tumor characterization, risk stratification, and personalized treatment planning. Standardization, multicentric validation, and integration with artificial intelligence are essential for successful clinical translation.

Cancers doi: 10.3390/cancers18162577

Authors: Hendrik Dapper Felix Aigner Christoph Stephan Claudia Rudroff Daniel Martin Franz Rödel Bruce Minsky Ethan B. Ludmir Craig Messick Caleah Kitchens Paul B. Romesser Julio Garcia-Aguilar J. Joshua Smith Claus Rödel Ulrike Wieland Luisa Bopp Emmanouil Fokas

Background/Objectives: People living with HIV (PLWH) are at substantially increased risk of anal high-grade squamous intraepithelial lesions (HSIL), a recognized precursor of anal cancer. Although the ANCHOR trial demonstrated that treatment reduces progression to invasive disease, important uncertainties remain regarding durability of response, recurrence patterns, and treatment-related toxicity across available therapeutic strategies. Methods: We conducted a systematic review of studies evaluating treatment outcomes for anal HSIL published between 2000 and 2026. PubMed, Embase, and the Cochrane Library were searched according to PRISMA guidelines, with a particular focus on studies involving PLWH. Results: A total of 45 studies comprising 6093 patients, including five randomized controlled trials, met the inclusion criteria. Definitions of treatment response, recurrence, and adverse events varied considerably across studies, together with differences in assessment methods and follow-up, limiting direct comparisons between treatment modalities. Ablative, topical, and surgical approaches achieved variable short-term clearance; however, no modality demonstrated consistent durable disease control. Recurrence rates were high, frequently exceeding 50% in PLWH, consistent with the chronic and relapsing nature of HPV-driven disease in this population. Serious adverse events were uncommon, although treatment-related morbidity was frequent and varied across modalities. Conclusions: Randomized evidence supports treatment of biopsy-confirmed anal HSIL in PLWH for prevention of squamous cell carcinoma of the anus. However, comparative evidence remains limited by few randomized trials, heterogeneous study designs, and inconsistent outcome reporting. High recurrence rates and limited durability of response support the need for improved therapeutic strategies, biomarker-driven risk stratification, and longitudinal management approaches.

Cancers doi: 10.3390/cancers18162576

Authors: Carlo Liverani Veronica Boero Ermelinda Monti Carlotta Caia Leonardo Natalini Paolo Vercellini Michele Vignali Andrea Ciavattini

Human papillomavirus (HPV) infection is a necessary but insufficient cause of cervical cancer (CC) and reflects a long-standing host–virus equilibrium shaped by immune control, viral persistence, and latency. The transition from cytology-based screening to primary high-risk HPV testing has substantially improved early detection of cervical precancerous lesions but has also introduced new clinical challenges related to fluctuating test results, overdiagnosis, overtreatment, and patient anxiety, whose magnitude may vary across countries depending on screening organization and access to prevention services. This narrative review provides a clinically oriented overview of HPV-based CC screening in the context of evolving knowledge on HPV natural history, persistence, and immune interaction, and discusses the implications for the interpretation of test results and risk stratification. New emerging screening and triage approaches, including molecular biomarkers, exosome-based biomarkers, and artificial-intelligence-supported risk assessment, are reshaping CC prevention strategies by enabling more precise identification of women at risk for clinically significant disease. These tools may be particularly relevant in self-sampling-based screening pathways, where molecular triage strategies can reduce the need for additional clinician-collected samples and improve management of HPV-positive women. At the same time, improved understanding of viral latency and host-related determinants of progression supports a shift from binary test interpretation toward longitudinal and individualized risk assessment. Integrating biological insight with technological innovation may facilitate personalized screening strategies that maintain high sensitivity while reducing unnecessary interventions. An evolutionary-informed and risk-adapted approach to HPV-related disease management is essential to optimize prevention outcomes and preserve the benefits of population-based screening programs.

Cancers doi: 10.3390/cancers18162575

Authors: Csongor Kárpáti Richárd Tóth Barbara Sebők Pál Sebok Attila Keszthelyi Petra Merkely Balázs Lintner Lotti Lőczi Nándor Ács Márton Keszthelyi Balázs Vida

Background: Prognosis in vulvar squamous cell carcinoma (VSCC) is strongly influenced by lymph node involvement and adverse clinicopathological features. Systemic inflammatory indices derived from blood counts may reflect tumor–host interactions associated with adverse pathological phenotypes. Objective: To assess associations of preoperative neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR) with nodal metastasis, lymphovascular space invasion (LVSI), and tumor size. Methods: This retrospective single-center study included 93 surgically treated patients between March 2017 and February 2026. Results: NLR was associated with nodal metastasis (unadjusted p = 0.015; false discovery rate [FDR]-adjusted q = 0.047) and LVSI (unadjusted p < 0.001; FDR-adjusted q = 0.006). NLR showed modest discrimination for nodal metastasis (area under the receiver operating characteristic curve [AUC] = 0.647). For LVSI, NLR had the highest AUC among the evaluated markers (AUC = 0.789; 95% confidence interval [CI]: 0.683–0.894), but 16 cases were positive and the positive predictive value (PPV) was low (0.378). Nominal MLR findings for LVSI and large tumor size did not remain significant after FDR correction (both q = 0.308), while PLR showed no consistent associations. Elevated NLR was associated with nodal metastasis in univariable analysis (odds ratio [OR] = 3.291; p = 0.012) but not in multivariable models including LVSI (adjusted OR = 1.296; p = 0.654) or excluding LVSI (adjusted OR = 1.823; p = 0.261). Conclusions: NLR was associated with adverse pathological features but was not independently associated with nodal metastasis and should not be used as a standalone predictive or clinical decision-making tool.

Cancers doi: 10.3390/cancers18162574

Authors: Jennifer Den Kamil Khanipov Vicki Suzanne Klimberg Raj Vaghjiani

Background/Objectives: Axillary management in breast cancer continues to de-escalate, with trials showing similar outcomes between sentinel lymph node biopsy (SLNB) and axillary lymph node dissection (ALND) in clinically node-negative patients. However, equivalence has not been demonstrated in estrogen receptor-positive (ER+), clinically node-positive (cN1) patients. We hypothesize that SLNB would not be associated with inferior outcomes compared to ALND among this population. Methods: Using the TriNetX Network, we identified women aged ≥18 years with cN1, ER+ breast cancer who underwent axillary surgery, inclusive of both upfront surgery and neoadjuvant-treated patients. Stage IV disease was excluded. The index event was the first axillary surgery (SLNB or ALND). Propensity score matching (1:1) was performed, balancing for age, receptor status, tumor characteristics, treatment, surgical procedure, and comorbidities. Outcomes included overall survival (OS) and local recurrence (LR). Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using Cox models. Results: A total of 1162 women were identified (SLNB 641, ALND 521). After matching, 435 patients remained in each cohort. At up to 10 years, OS was similar between groups (77% vs. 76%, HR 0.9, 95% CI 0.66–1.27). Breast recurrence occurred in 5% versus 7% (HR 0.82, 95% CI 0.47–1.42). Axillary recurrence occurred in 21% versus 24% (HR 0.9, 95% CI 0.69–1.21). None of these differences reached statistical significance. Conclusions: In ER+, cN1 node-positive breast cancer, SLNB was not associated with worse survival or recurrence compared with ALND. These real-world findings are hypothesis-generating but support the continued investigation and refinement of axillary de-escalation guidelines for clinically node-positive disease.

Cancers doi: 10.3390/cancers18162573

Authors: Nowreen Islam Chowdhury Hebatollah Ewida Mahmoud Salama Ahmed Heidi Villalba

Glioblastoma (GBM) is one of the most aggressive and treatment-resistant cancers, shaped by a tumor microenvironment (TME) that is both metabolically demanding and strongly immunosuppressive. GBM relies heavily on fatty acid (FA) metabolism to sustain growth of rapidly dividing tumor cells and survive metabolic stress. GBM cells enhance lipid uptake, activate sterol regulatory element-binding protein 1 (SREBP-1)-driven lipogenesis, store excess lipids in droplets to prevent toxicity, and depend on fatty acid oxidation (FAO) to generate adenosine triphosphate (ATP) and maintain redox balance, particularly under nutrient-limited conditions. GBM TME is also consistently enriched with regulatory T cells (Tregs), which maintain suppressive activity despite the nutrient restrictions that impair effector T cells (Teffs). In hypoxia and nutrient limitation within the TME, Tregs can adapt by using FAO, lactate oxidation, and OXPHOS, supported by forkhead box P3 (Foxp3)-dependent metabolic programming, cluster of differentiation 36 (CD36)-mediated FA uptake, and hypoxia-related signals. At the same time, programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) signaling reduces glycolytic activity in Teffs and contributes to metabolic dysfunction, while also supporting the stability of oxidative metabolism in Tregs. Evidence from pre-clinical and clinical studies suggests a possible association between Treg enrichment in GBM and reduced responsiveness to immune checkpoint inhibitors (ICIs), although this relationship is not yet fully defined. Overall, current findings point to FA metabolism as a shared metabolic axis that supports both tumor progression and Treg-mediated immune resistance. Targeting lipid-driven pathways may offer an opportunity to disrupt these advantages and improve the effectiveness of existing immunotherapies for GBM.

Cancers doi: 10.3390/cancers18162572

Authors: Michele Cavo Melissa Bersanelli Alessandro Corso Carlotta Galeone Silvia Mangiacavalli Roberto Mina Renato Zambello Elisabetta Antonioli Angelo Belotti Cirino Botta Gabriele Buda Francesco Di Raimondo Monica Galli Francesca Gay Massimo Offidani Maria Teresa Petrucci Alessandra Romano Elena Zamagni Antonella Semeraro Barbara Veggia Paolo Mariani

Background/Objectives: The treatment landscape of relapsed/refractory multiple myeloma (RRMM) has significantly evolved with the introduction of novel classes of agents and, more recently, of T-cell-redirecting therapies, including bispecific antibodies (BsAbs). It is essential to enhance and harmonize the therapeutic management of BsAbs within clinical practice. Methods: We performed a modified Delphi expert consensus study on the use of BsAbs targeting the B-Cell Maturation Antigen (BCMA) in patients with triple-class-exposed (TCE) RRMM. The study was conducted in April–November 2025 following established guidelines and best practices for defining consensus. The key phases in the use of anti-BCMA BsAbs were identified and explored. Results: Fifteen Italian hematologists with expertise in the care of TCE RRMM completed two Delphi rounds. Agreement (defined as ≥67% of panelists) was achieved on most of the topics evaluated. In particular, all panelists considered the step-up dosing phase feasible in an outpatient setting, under specific circumstances, and dosing de-escalation in responding patients to reduce the risk of adverse events. For most of them, anti-BCMA BsAb treatment is also feasible in several challenging subgroups, including frail patients (93% agreement) and those with high-risk cytogenetics (93%), extramedullary disease (93%), end-stage renal disease (86%), active plasma cell leukemia (79%), and central nervous system involvement (67%). In addition, agreement (93%) was reached on the possible sequential use of BCMA-targeting therapies, preferentially BsAbs following CAR-T, though a switch in the target antigen should primarily be considered. Conclusions: In this article, we address the main challenges related to the real-world use of anti-BCMA BsAbs in patients with TCE RRMM, offering expert recommendations to complement existing guidelines and support clinical practice.

Cancers doi: 10.3390/cancers18162571

Authors: Funa Yang Tao Zhang Wei Wei Xiaocan Jia Lanwei Guo Fengjuan Liu Peinan Chen Haibo Sun Hongying Shi Wei Cui

Background: Postoperative pneumonia (POP) is a critical complication after minimally invasive esophagectomy (MIE) for esophageal squamous cell carcinoma (ESCC). However, the comparative odds of POP among different neoadjuvant treatment strategies remain controversial. This study aimed to compare the associations between different treatment strategies and POP in this population. Methods: A retrospective cohort of ESCC patients undergoing MIE between March 2021 and July 2025 was analyzed. Patients were divided into four groups: the surgery alone (S-alone) group (n = 282), the neoadjuvant chemotherapy (NCT) group (n = 127), the neoadjuvant chemoradiotherapy (NCRT) group (n = 60), and the neoadjuvant chemoimmunotherapy (NCIT) group (n = 71). To address baseline confounding, generalized overlap weighting (GOW) was used for the four-group comparison, and overlap weighting (OW) was used for the pairwise comparisons of NCRT versus NCT and NCIT versus NCT. Logistic regression models were used to evaluate the associations between treatment strategies and the odds of POP. Sensitivity analyses of the pairwise comparisons were performed using stabilized inverse probability of treatment weighting (S-IPTW). Results: In the four-group comparison, neither NCT nor NCRT was associated with significantly higher odds of POP than S-alone, whereas NCIT was associated with higher odds (weighted odds ratio [OR], 1.95; 95% confidence interval [CI], 1.02–3.70). In pairwise analyses, the weighted ORs were 0.45 (95% CI, 0.20–1.01) for NCRT versus NCT and 2.32 (95% CI, 1.14–4.71) for NCIT versus NCT. Sensitivity analyses were directionally consistent. Conclusions: In this single-center observational cohort, NCRT was not associated with higher odds of POP than S-alone or NCT, whereas NCIT was associated with higher odds of POP. These findings support careful perioperative respiratory management in patients receiving neoadjuvant immunotherapy.

Cancers doi: 10.3390/cancers18162570

Authors: Jostein Dahle Sebastian Patzke

Background: Identification of tumor-specific cell surface targets is a critical step in the development of precision oncology therapeutics, including radioligand- and antibody-based approaches. However, existing strategies often rely on single-layer analyses and lack systematic integration of proteomic, genomic, and clinical metadata. Methods: We developed a multi-layered proteogenomic filtering framework integrating quantitative proteomics from colorectal cancer (CRC) cohorts with curated metadata on protein localization, normal tissue expression, and druggability. Eleven complementary filtering strategies were applied, followed by manual curation for extracellular accessibility and composite scoring based on protein rank, localization, and clinical relevance. Results: Application of the pipeline to metastatic CRC (mCRC) identified multiple high-confidence candidate targets, including GPRC5A, SLC2A1, CD47, DPEP1 and IFITM1. The average pairwise overlap between filtering strategies was low (0.11), indicating limited redundancy and complementary target identification across approaches. Importantly, candidates detected by multiple strategies were significantly enriched for established biomarkers (FAP, CEACAM5, ITGAV, ITGB4), which were exclusively found among multi-strategy candidates (10.3% vs. 0%; Fisher’s exact test, p = 0.0064), supporting overlap-based prioritization as a marker of biological and translational relevance. Composite scoring further prioritized GPRC5A as a leading candidate. Additional validation layers supported tumor-enriched expression, plasma membrane localization, and relevance across multiple cancer indications. Conclusions: This study presents a scalable framework for prioritization of cell surface therapeutic targets, using mCRC as proof-of-concept indication. By integrating multiple data layers and incorporating translational criteria early in the discovery process, this approach may facilitate more efficient identification of targets for downstream development, including antibody- and radioligand-based therapies.

Cancers doi: 10.3390/cancers18162569

Authors: Dami Aiyejuto Ananya Luthria Thompson Hui Anitha Kota Shenoy

Colorectal cancer (CRC) remains a major cause of cancer-related mortality, with recurrence and treatment resistance as persistent challenges. Increasing evidence supports the cancer stem cell (CSC) model in CRC, in which a subpopulation of self-renewing colorectal cancer stem cells (CCSCs) sustains tumor growth, metastasis, and therapy resistance. CCSCs are increasingly recognized as key drivers of tumor progression, therapeutic resistance, and relapse, and are increasingly being investigated not only as therapeutic targets but also as biomarkers with diagnostic and prognostic relevance in CRC. Multiple signaling pathways regulate CCSC maintenance and aggressive behavior, including Wnt/β-catenin, Notch, Hedgehog, PI3K/AKT, MAPK/ERK, NF-κB, and TGF-β signaling. These pathways form the basis of therapeutic strategies aimed at modulating stemness-associated pathways, with several CSC-focused agents and pathway inhibitors currently under translational and clinical investigation. In parallel, CCSC surface markers and molecular signatures are being explored as putative tools for early detection, minimal residual disease monitoring, and outcome prediction. However, successful translation of CSC-directed approaches into effective and safe clinical applications remains difficult. Tumor heterogeneity, CSC plasticity, compensatory signaling mechanisms, and the shared regulatory networks between malignant and normal intestinal stem cells pose substantial barriers. In this review, we summarize the molecular mechanisms underlying CCSC biology, discuss their diagnostic and prognostic implications. We also focus on clinical trials that apply CCSC-directed therapeutic, biomarker, and prevention strategies in CRC., Finally, we emphasize the lessons learned and the translational challenges, including the need for rigorously validated, CCSC-specific biomarkers, that continue to shape the development of these therapeutic and biomarker strategies.

Cancers doi: 10.3390/cancers18162568

Authors: Morena d’Avenia Laila Sara Arroyo Mühr Marcella Mastromauro Federica Spadaccino Elisabetta Razzuoli Michela Iacobellis Filippo Dell’Anno

Background/Objectives: Human papillomavirus (HPV) testing is widely used in cervical cancer screening because of its high sensitivity, although its limited specificity requires effective triage strategies. This study aimed to evaluate the association between relative viral load (RVL) and cervical lesion severity, focusing on HPV-positive women with non-high-grade cytology. Methods: The study included 997 women with histological outcomes from a cohort of 2765 HPV-positive individuals identified among 37,030 women screened in the Bari metropolitan area (Italy) using a real-time HPV-DNA test. Associations between RVL, estimated using the ΔCt method, and lesion severity were assessed using histological and cytological classifications. Logistic regression models evaluated the independent effect of RVL, adjusting for age and HPV detection channel. Results: Lower ΔCt values (indicating higher RVL) were significantly associated with high-grade lesions (CIN2+) (OR = 0.91, 95% CI: 0.89–0.94, p < 0.001). The association was observed for HPV16 and the pooled 12-high-risk HPV detection channel, while no significant association was observed for HPV18. A similar association was observed when cytological classification was used as the outcome. Age showed a modest effect, with reduced odds of high-grade lesions observed in women aged ≥50 years. Among women with non-high-grade cytology who subsequently underwent histological assessment, 17.6% had underlying CIN2+, and RVL remained significantly associated with lesion severity in this subgroup. However, ΔCt showed only modest discrimination for high-grade lesions [AUC = 0.643 (95% CI: 0.605–0.681)]. Conclusions: Higher HPV RVL is associated with increased lesion severity, particularly for HPV16 and the pooled 12-high-risk detection channel, but not for HPV18. Given its modest standalone discriminatory performance and the selected nature of the histologically verified cohort, ΔCt should be considered an exploratory marker rather than a validated triage tool. Prospective validation is required to determine whether it provides incremental clinical value.

Cancers doi: 10.3390/cancers18162567

Authors: Rostyslav Marunych Dorota Bartusik-Aebisher Barbara Smolak Klaudia Dynarowicz David Aebisher

This review analyzes how Zinc(II) coordination alters the electronic configuration of porphyrin-based photosensitizers to optimize reactive oxygen species (ROS) generation and subcellular targeting in photodynamic therapy (PDT). By focusing on the structural design principles that govern excited-state behavior, the work moves beyond clinical descriptions to provide a mechanistic understanding of how engineered metalloporphyrins can achieve precise tumor destruction. When these engineered metal porphyrins are exposed to specific wavelengths of light, they transfer energy to create ROS, such as singlet oxygen, which directly damages and kills tumor tissue. The review evaluates structural modifications that drive selective accumulation within critical subcellular organelles, notably the mitochondria, to maximize cytotoxic efficiency. By analyzing the impact of the tumor microenvironment on hypoxia, the work outlines strategies for maintaining efficacy in oxygen-deprived zones and highlights how the biocompatible, redox-inactive nature of Zinc(II) minimizes systemic toxicity, providing a blueprint for the design of targeted, translation-ready photosensitizers.

Cancers doi: 10.3390/cancers18162566

Authors: Grzegorz Chmielewski Rafał Stando Hubert S. Gabryś Maksym Fritsak Stephanie Tanadini-Lang Matthias Guckenberger Stanisław Góźdź

Objectives: We evaluated the performance of mammography-based radiomics in prediction of clinical nodal status, clinical tumor stage, clinical disease stage, status of the PIK3CA mutation and concordance with the radiologist-assessed BI-RADS category. Mammography is often the first imaging modality performed in the screening or diagnostic workup of breast cancer. Materials and Methods: In this single-center retrospective study, we included 102 histopathologically confirmed cases of breast cancer from 100 patients. The tumor region and whole-breast parenchyma were contoured on 368 craniocaudal and mediolateral-oblique mammograms. Cases were temporally split into training and test sets by histopathological diagnosis date (training: 70%, held-out test: 30%). Six linear models were tuned by 5-fold x 3-repeat stratified cross-validation. The winning model per endpoint was applied once to the test set. We report AUCs with 95% confidence intervals, permutation p-values and Benjamini–Hochberg false discovery rate (BH-FDR) correction across five endpoints. Results: Three of the studied endpoints reached significance after BH-FDR correction: clinical nodal status (cN0 vs. cN-positive; AUC: 0.726 (95% CI: 0.501–0.886)), clinical tumor stage (cT1-2 vs. cT3-4; AUC: 0.792 (95% CI: 0.575–0.929)) and overall disease stage (I–II vs. III–IV; AUC: 0.778 (95% CI: 0.572–0.917)). Mammography-based radiomics failed to predict the presence of PIK3CA mutation and concordance with radiologist-assessed BI-RADS category. Conclusions: Mammography-based radiomics has shown a hypothesis-generating discriminative value for differentiation between cN-negative and cN-positive disease, early from advanced clinical tumor stage, and early from advanced overall disease stage in breast cancer. Mammography-based radiomics did not predict PIK3CA status and did not discriminate between radiologist-assessed BI-RADS 4 and 5 groups.

Cancers doi: 10.3390/cancers18162565

Authors: Nagi B. Kumar Matthew Schabath Mark Alexandrow Jhanelle Gray Tawee Tanventyanon Farah Khalil José Laborde Michael J. Schell Donald Klippenstein

Background: Former and current smokers in lung cancer screening remain at elevated risk for lung cancer despite smoking cessation. We and others have shown that curcumin (CUR) exhibits anti-inflammatory and antiproliferative effects but is limited by poor bioavailability. However, since CUR is lipophilic, co-administration with ω-3 FAs represents a mechanistically rational strategy to enhance delivery and target complementary pathways, including signal transducer and activator of transcription 3 (STAT3) and the transcription factor NF-κB (NF-κB) signaling for lung cancer chemoprevention. Methods: We conducted a randomized, single-blind, placebo-controlled Phase II pilot study evaluating CUR combined with ω-3 FAs in high-risk former and current smokers with CT-detected pulmonary nodules. Participants received intervention agents with active-dose groups (low dose = 3; high dose = 9) or a placebo (n = 7) for 6 months. Primary endpoints included radiologic changes in nodule size, number, and density. Secondary endpoints included safety, adherence to the study agent and exploratory biomarker analyses. Correlation analyses of imaging-derived metrics were performed to assess relationships among LDCT parameters. Results: Nineteen participants were enrolled (intervention, n = 12; placebo, n = 7). Eighteen (11 intervention, 7 placebo) subjects completed post-intervention imaging. One subject was unable to complete follow-up and study-related procedures. Data from the treatment arms were pooled for analysis and comparison with the placebo arm. No statistically significant between-group differences were observed in primary imaging endpoints. The intervention was well tolerated, with predominantly grade 1 adverse events. Exploratory analyses demonstrated consistent positive correlations among established imaging biomarkers, with clustering of size-based metrics (mean diameter, volume, sum of longest diameters) and density-based parameters. Multidimensional scaling supported this structure, indicating internal coherence among imaging-derived endpoints. Conclusions: Although no statistically significant treatment effect on the image biomarkers was observed, this pilot study demonstrates feasibility challenges and identifies coherent imaging biomarkers that may serve as intermediate endpoints in early-phase chemoprevention trials. These results support further investigation of strategies utilizing agent combinations with enhanced bioavailability and safety and refinement of trial design in high-risk lung cancer patient populations.

Cancers doi: 10.3390/cancers18162564

Authors: Martina Schiavello Elena Gazzano Loredana Bergandi Francesca Silvagno Roberta Libener Chiara Riganti Elisabetta Aldieri

The journal retracts the article titled “Identification of Redox-Sensitive Transcription Factors as Markers of Malignant Pleural Mesothelioma” [...]

Cancers doi: 10.3390/cancers18162563

Authors: Ryuk Jun Kwon Yohwan Lim

Background: Metabolic and alcohol-associated liver disease (MetALD) has been associated with an increased risk of cancer. However, it remains unclear whether combinations of favorable, intermediate, and adverse lifestyle behaviors differentiate cancer risk within MetALD. Methods: We analyzed 25,712 participants with MetALD using UK Biobank. Smoking, moderate-to-vigorous physical activity (MVPA), and diet were classified into favorable, intermediate, and adverse categories. Favorable and adverse behavior counts ranged from 0 to 3, and a unified lifestyle profile was constructed. Cox proportional hazards models were used to analyze adjusted hazard ratios (aHRs) and 95% confidence interval (CI) for incidence of all cancers. Results: During 296,965 person-years of follow-up, 4416 incident cancers occurred. Compared with no favorable behaviors, those having two favorable behaviors showed significance 0.92 (95% CI, 0.84–1.00). Compared with no adverse behaviors, the aHRs were 1.06 (95% CI, 1.00–1.13), 1.15 (95% CI, 1.04–1.27), and 1.11 (95% CI, 0.84–1.47) for one, two, and three adverse behaviors, respectively (p for trend = 0.003). The mixed/intermediate profile was associated with higher cancer risk than the favorable profile (aHR, 1.09; 95% CI, 1.02–1.16), whereas the adverse-profile estimate was not statistically significant. Among individual lifestyle behaviors, current smoking was associated with a higher cancer risk than never smoking (aHR, 1.20; 95% CI, 1.09–1.32; p < 0.001). Conclusions: Among participants with MetALD, favorable and adverse behavior counts showed opposite adjusted trends in cancer risk. Current smoking showed the strongest association with cancer risk among the individual behaviors.

Cancers doi: 10.3390/cancers18162562

Authors: Julia Michel Jens Hoeppner Michael Leitz Fabian Nimczewski Zsolt Madarasz

Background/Objectives: Robotic surgery offers an additional minimally invasive option for gastric gastrointestinal stromal tumor (GIST) resection, particularly in anatomically demanding locations. Evidence regarding its integration into routine surgical practice remains limited. This study evaluated the evolution of surgical approaches for primary localized gastric GIST following the introduction of an institutional robotic program. Methods: We retrospectively analyzed 44 consecutive patients who underwent curative-intent resection for primary localized gastric GIST at a tertiary referral center between July 2015 and June 2025. Surgical management and perioperative outcomes were described for an early era (2015–2021; n = 29) and a later era after the introduction of robotic surgery (2022–2025; n = 15). Results: Overall, 22 procedures were completed laparoscopically, six robotically, and 13 through a primary open approach; three laparoscopic procedures were converted to open surgery. In the later era, robotic surgery accounted for 40.0% of resections, and no conversions occurred. The proportion of completed minimally invasive resections was 62.1% in the early era and 66.7% in the later era. R0 resection was achieved in all patients, and no tumor rupture was documented. Median operative time was 73.5 min, median postoperative length of stay was 7.5 days, and major morbidity occurred in six patients (13.6%). One patient (2.3%) died from sepsis within 30 days after reoperation for a postoperative gastric suture-line leak. Conclusions: Following the introduction of robotic surgery, management of primary gastric GIST evolved toward a more diversified and individualized surgical strategy. Robotic surgery was incorporated as an additional minimally invasive option, while the overall proportion of completed minimally invasive resections remained stable. These findings represent an early institutional experience and do not establish equivalence or comparative superiority among surgical approaches.

Cancers doi: 10.3390/cancers18162561

Authors: Ido Haimi Ravi Rajaram

Locally advanced non-small cell lung cancer (NSCLC) is a biologically and clinically heterogeneous disease in which mediastinal lymph node involvement remains the principal prognostic and therapeutic discriminator. Accurate nodal staging guides selection among surgical resection, definitive chemoradiotherapy, immunotherapy, and targeted therapy. This narrative review synthesizes contemporary evidence on mediastinal staging modalities, nodal disease burden, and treatment selection in stage II-III NSCLC. Contemporary staging integrates CT and FDG-PET/CT with systematic tissue confirmation using EBUS-TBNA and EUS, with surgical mediastinal staging reserved for selected high-risk or discordant cases. The ninth edition TNM N2a/N2b distinction, increasing use of neoadjuvant and perioperative immunotherapy, and molecularly guided therapy have further amplified the clinical consequences of under- or over-staging. Nodal assessment should therefore be interpreted through a multidisciplinary framework that integrates anatomy, biology, treatment response, and patient operability.

Cancers doi: 10.3390/cancers18162560

Authors: Donald L. Helseth Nicholas Miller Mathew Yang Henry Wittich Qin Zhao Tom Werth Linda M. Sabatini Mir Alikhan Megan Parilla Amandeep Kaur Xiaoyan Yang Kathy A. Mangold Michael Bouma Henry M. Dunnenberger Dyson T. Wake Annette Sereika Gayathri Moorthy Peter J. Hulick Karen L. Kaul Janaradan D. Khandekar

Background/Objectives: We describe how our in-house bioinformatics platform, Flype, has evolved from being a variant repository to an enterprise role as an electronic medical record (EMR) content provider, powering molecular pathology reporting, pharmacogenomics reporting, sending discrete data to our EMR, aggregating internal and external molecular test results and powering our molecular tumor board (MTB). Methods: In response to critical pain points, we developed Docket, a sample tracking system in Flype, which manages multiple individual in-house molecular tests for NGS assays, pharmacogenomic (PGX) assays and additional molecular testing. To help with interpretation and integration of all internal and external assays, we developed a clinical outcomes view in Flype. To improve the efficiency of our molecular pathologists reporting results, we developed Convo 2.0, which integrates OncoKB interpretations and other information. Flype can also be used by our pathologists to submit patient molecular results to NCI’s ComboMATCH and retrieve clinical trial recommendations. Results: Flype was used during our Kellogg Cancer Genomic Initiative for reporting PGX integration, MTB review and integration of EMR prescription information with internal and external molecular test results. Integrating PGX results led to several recommendations against the use of drugs metabolized by, for example, CYP2D6 or TPMT, along with warnings about altered pain relief. Enhancements in report sign-out and the use of file transfer scripts have led to reduced turnaround time. Conclusions: Flype supports hundreds of users performing different roles in molecular diagnostics. We discuss lessons learned adapting our software to support continuously changing test requirements.

Cancers doi: 10.3390/cancers18162559

Authors: Sven Richter Benedikt Leinauer Alicia Thoma Ann-Kristin Schmälter Johanna Waidhauser Christoph Schmid Andreas Rank Phillip Löhr

Background/Objectives: Flow-cytometric readouts in acute myeloid leukemia (AML) may depend on specimen source and processing. We assessed whether sample source (peripheral blood [PB] vs. bone marrow [BM]) and cryopreservation influence immune-evasion-related markers on AML blasts. Methods: Paired PB and BM samples from 19 adults were analyzed fresh and after cryopreservation. Viable CD45dim singlets were assessed for ULBP1-6, MICA/B, CD34, CD44, CD70, CD80, and CD184 using median fluorescence intensity (MFI) and relative fluorescence index (RFI). Paired comparisons used two-sided Wilcoxon signed-rank tests with Benjamini–Hochberg correction across six markers within each endpoint and comparison. Discordance was also assessed using a predefined conventional 20% reference threshold. Results: After adjustment, RFI did not differ between fresh and cryopreserved samples within PB or BM, or between fresh PB and BM. In cryopreserved samples, PB and BM differed for CD70 (q = 0.042) and ULBP1-6 (q = 0.028). Cryopreservation increased MFI for CD184 and ULBP1-6 in PB and BM and for MICA/B in PB; no PB-BM MFI difference remained significant. Threshold-based classification was discordant for CD34, CD44, CD80, CD184, MICA/B, and ULBP1-6 in 5.3–38.9% of pairs, whereas CD70 showed none. Conclusions: Cohort-level differences were limited to specific markers and conditions, while patient-level threshold discordance persisted. Sample source and cryopreservation should therefore be considered when interpreting threshold-based classifications.

Cancers doi: 10.3390/cancers18162558

Authors: Paulina Piesch Maciej Krężel Hanna Adamska Inga Buława Maja Hrynczyszyn Michalina Świetlicka Marta Szepietowska Piotr K. Krajewski Grażyna Kamińska-Winciorek Marcin Ziętek Łukasz Matusiak Jacek C. Szepietowski

Introduction: Melanoma is a chronic disease that significantly affects patients’ daily functioning and emotional well-being. Beyond its somatic burden, it often leads to substantial changes in quality of life (QoL). This study aimed to assess illness acceptance among melanoma patients and examine its associations with selected clinical characteristics (disease stage, pruritus and time since diagnosis), psychological distress (depression and anxiety) and QoL. Materials and Methods: A cross-sectional study was conducted between June 2025 and February 2026 at two tertiary oncology centers in Poland. Initially, 191 consecutive melanoma patients were recruited, of whom 162 (58.6% men; mean age 59.8 ± 13.7 years) were included in the final analysis (response rate: 84.8%). Participants completed validated questionnaires assessing illness acceptance (Acceptance of Illness Scale (AIS)), depression (PHQ-9, HADS-D), anxiety (GAD-7, HADS-A), and QoL (DLQI). Statistical analyses were performed, with p < 0.05 considered statistically significant. Results: The mean AIS score was 13.28 ± 7.50 points, indicating a remarkably low level of illness acceptance. In the multivariable linear regression analysis, greater depressive symptoms (HADS-D: β = −1.16, 95% CI −1.79 to −0.54; p < 0.001) and more advanced melanoma stage (β = −1.52, 95% CI −2.92 to −0.12; p = 0.034) were independently associated with lower illness acceptance. In addition, illness acceptance showed significant correlations with depressive symptoms, anxiety symptoms, and dermatology-related QoL, whereas no significant associations were observed with most evaluated demographic and clinical variables. Conclusions: Patients with melanoma demonstrated remarkably low illness acceptance. Depressive symptoms and more advanced melanoma stage were independently associated with lower illness acceptance. These findings support the integration of psychological assessment into comprehensive melanoma care.

Cancers doi: 10.3390/cancers18162557

Authors: Tomasz Milecki Jan Stępka Joanna Wesoły Wojciech A. Cieślikowski

Background/Objectives: Evaluation of renal tumour masses relies on conventional imaging, which cannot reliably characterise the histopathological type, and no validated blood-based diagnostic marker is available for renal cell carcinoma. The cfDNA integrity index, the ratio of long to short circulating cell-free DNA (cfDNA) fragments, may reflect the necrotic origin of tumour-derived DNA and is a candidate qualitative marker of malignancy. This exploratory, single-centre case–control study assessed the preoperative plasma cfDNA integrity index in patients with clear cell renal cell carcinoma (ccRCC). Methods: Plasma concentrations of 90 bp and 222 bp cfDNA fragments were measured by quantitative real-time PCR (qPCR) in 46 patients with histopathologically confirmed ccRCC (before surgery) and 17 healthy volunteers; the two groups were a convenience sample, were not matched, and differed in age and body-mass index. The cfDNA integrity index was defined as the ratio of the 222 bp to the 90 bp fragment concentration. Results: The cfDNA integrity index was higher in patients with ccRCC than in controls (median 0.28 vs. 0.15; p < 0.001, Mann–Whitney test) and rose progressively across healthy, non-metastatic (M0) and metastatic (M1) groups (p < 0.001, Kruskal–Wallis test; M0 vs. M1 p = 0.004). In unadjusted ROC analysis, both the integrity index (AUC 0.83, 95% CI 0.72–0.94) and its long 222 bp fragment component (AUC 0.93) discriminated patients with ccRCC from healthy volunteers, and the index separated metastatic from non-metastatic disease with an AUC of 0.79 (95% CI 0.64–0.88). The index was higher in high-grade (Fuhrman G3 + G4) tumours (p = 0.04) and in tumours with lymphovascular invasion (p < 0.001), and correlated with primary-tumour diameter. Conclusions: In this exploratory cohort, the preoperative plasma cfDNA integrity index was higher in patients with ccRCC than in healthy volunteers and was associated with several adverse pathological features; these findings require confirmation in larger, matched studies that include benign renal masses before any diagnostic role can be claimed.

Cancers doi: 10.3390/cancers18162556

Authors: Diana Sawicka Alicja Roztocka Patryk Osiński Jakub Nowak Marta Pietruszyńska Halina Car

Imidazolium salt derivatives (IMSDs) represent a structurally diverse class of compounds that has attracted increasing interest as a source of novel anticancer agents due to their tunable chemical architecture and broad spectrum of biological activities. This review summarizes current advances in the development of organic imidazolium derivatives and metal–N-heterocyclic carbene (NHC) complexes, with particular emphasis on their structure–activity relationships (SARs), mechanisms of action, and therapeutic potential. Numerous IMSDs exhibit significant antiproliferative activity against a wide range of cancer cell lines through multiple mechanisms, including DNA damage, reactive oxygen species generation, mitochondrial dysfunction, thioredoxin reductase inhibition, cell-cycle arrest, and apoptosis induction. Among the reported compounds, Au(I)-, Pt(II)-, and Ag(I)-NHC complexes consistently demonstrate the highest cytotoxic potency, whereas hybrid derivatives incorporating pharmacologically active moieties, such as lithocholic acid, have been investigated as potential approaches to improving selectivity and multitarget activity. Current SAR analyses indicate that metal coordination, bulky aromatic substituents, molecular hybridization, and balanced lipophilicity are key determinants of enhanced biological activity. Despite these encouraging findings, most available evidence is limited to in vitro studies, while comprehensive in vivo evaluation, pharmacokinetic characterization, and systematic toxicological assessment remain insufficient. Consequently, the clinical relevance of these compounds has yet to be established. Future research should focus on rational structural optimization, standardized preclinical evaluation, combination therapies, and advanced drug delivery strategies, including nanomedicine, to facilitate the translation of IMSDs into clinically useful anticancer agents.

Cancers doi: 10.3390/cancers18162555

Authors: Mai Kitahara Kei Saito Yoko Oki Noriyuki Kuniyoshi Shuzo Nomura Mariko Fujisawa Hirofumi Kogure

Background: Based on the demonstrated survival benefits of gemcitabine plus cisplatin (GemCis) therapy in the TOPAZ-1 and KEYNOTE-966 trials, GemCis plus immune checkpoint inhibitor (ICI) therapy has become a standard first-line treatment for unresectable biliary tract cancer. However, its safety and efficacy in elderly patients and those requiring biliary drainage remain insufficiently evaluated in real-world practice. We aimed to evaluate the efficacy and safety of GemCis plus ICI therapy, with a focus on elderly patients and those requiring biliary drainage. Methods: We retrospectively analyzed the clinical characteristics of patients with unresectable biliary tract cancer treated with GemCis plus ICI at our institution between April 2022 and September 2025. Progression-free survival (PFS) was analyzed using the Kaplan–Meier method, and prognostic factors were examined using Cox proportional hazards models. PFS and immune-related adverse events (irAEs) were compared between durvalumab and pembrolizumab. Results: Of the 51 patients diagnosed with unresectable biliary tract cancer during the observation period, 26 (51.0%) received GemCis plus ICI therapy. The median age was 73 years (range, 46–83 years), and 15 (57.7%) patients were male. Distant metastases were present in 22 patients (84.6%), and biliary drainage was performed in 15 (57.7%). The primary tumor sites were intrahepatic cholangiocarcinoma (n = 8), perihilar cholangiocarcinoma (n = 6), gallbladder cancer (n = 11), and cancer of unknown primary origin (n = 1). The ICIs used were durvalumab in 18 patients and pembrolizumab in eight patients. The median follow-up period was 214 days (range, 30–1114). The response rate was 28.6%, the disease control rate was 90.5%, and the transition rate to ICI maintenance therapy was 29.2%. IrAEs occurred in six patients (23.1%), with a significantly higher frequency in the pembrolizumab group than in the durvalumab group (50.0% vs. 11.1%). The median PFS was 8.2 months in the durvalumab group and 8.9 months in the pembrolizumab group, with no significant difference (p = 0.88). Multivariate analysis incorporating age, performance status, metastatic burden, and liver function confirmed that age ≥ 75 years remained the only independent predictor of shorter PFS (HR 5.62; 95% CI, 1.35–23.4; p = 0.02), whereas ICI regimen and biliary drainage were not significant prognostic factors. Conclusions: In clinical practice, GemCis plus ICI therapy showed no statistically significant difference in efficacy between ICI regimens in this small cohort, although this comparison was not statistically powered. Given the exploratory nature of these findings, the lower incidence of immune-related adverse events (irAEs) observed in the durvalumab group should be interpreted with caution. Age ≥ 75 years was associated with shorter PFS. Careful patient selection is warranted when considering GemCis plus ICI therapy in elderly patients with biliary tract cancer.

Cancers doi: 10.3390/cancers18162554

Authors: Lubna Bakr Hanna Binti Mohd Azhari Muhammad Saad Asif Mandip Chaubey Adam Peryt Aman S. Coonar Giuseppe Aresu

Background/Objectives: Robotic-assisted thoracic surgery continues to spread internationally for anatomical lung resection, yet evidence on learning curve dynamics and conversion behaviour remains limited beyond the da Vinci system. The published clinical experience on the Versius CMR Surgical System does not yet match that of the da Vinci system. This study examines the learning curve and conversion pattern of a mature Versius programme using cumulative sum (CUSUM) analysis. Methods: Single-centre retrospective cohort study encompassing 206 consecutive anatomical lung resections (154 lobectomies, 52 segmentectomies) undertaken using the Versius CMR platform between April 2023 and February 2026. CUSUM analysis was applied at programme and individual surgeon level. Logistic regression was performed to identify independent predictors of conversion. Operative time and post-operative length of stay were examined, along with a comparative sub-analysis between converted and pure robotic cases, stratified by surgeon. Results: The programme-level CUSUM inflection point occurred at case 49 (7.3 months), with mean operative time falling from 250.9 ± 65.4 min in the early phase to 215.5 ± 46.8 min in the late phase (p = 0.001). Post-operative LOS improved from 5.8 to 4.7 days (p = 0.031). Forty-six cases (22.3%) required conversion, 87% of which were elective, with no significant change across programme phases (p = 1.00). A six-fold difference in conversion rate existed between the two main surgeons (35.4% vs. 6.1%). Surgeon-1’s conversions carried no operative time penalty (225.2 vs. 223.3 min, p = 0.96) or LOS penalty (3.9 vs. 5.0 days, p = 0.83), whereas Surgeon-2’s converted cases were significantly longer (333.3 vs. 216.9 min, p = 0.004) and associated with longer hospital stay (8.8 vs. 4.7 days, p = 0.004). On multivariable analysis, surgeon identity (aOR 5.39, 95% CI 2.25–12.92, p < 0.001), intra-operative adhesions (aOR 3.41, 95% CI 1.53–7.64, p = 0.003) and clinical stage II or higher (aOR 3.55, 95% CI 1.43–8.79, p = 0.006) were each independently associated with conversion. Conclusions: The Versius CMR system supports a definable and reproducible learning curve in anatomical lung resection. Conversion was determined both by operative difficulty and by individual surgeon decision-making philosophy, the latter accounting for the greater share of the programme’s conversion burden. Early elective conversion, when indicated, preserves operative efficiency and post-operative recovery, and should be viewed as wise surgical judgement, not a marker of programme immaturity.

Cancers doi: 10.3390/cancers18162553

Authors: Huixia Li Wing San Yiu Guo-Min Li Feng-Ming (Spring) Kong

Background: Immunotherapy has improved outcomes in non-small cell lung cancer (NSCLC), but reliable predictive biomarkers remain limited. DNA damage response (DDR) gene mutations may enhance tumor immunogenicity and response to immune checkpoint inhibitors (ICIs), yet clinical findings remain inconsistent. We aimed to systematically evaluate the association between DDR gene mutations and ICI outcomes in NSCLC. Methods: PubMed and Embase were searched for eligible studies. Data on objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were extracted and pooled using random-effects models. Subgroup analyses were performed by treatment regimen. Results: A total of 13 studies involving 5989 patients were included from 606 records. The pooled RR for ORR comparing DDR wild-type with DDR-mutated patients was 0.63 (95% CI: 0.49–0.82, p < 0.001), indicating higher ORR in the DDR-mutated group. DDR mutations were also associated with improved PFS (HR = 0.56, 95% CI: 0.43–0.74, p < 0.001) and OS (HR = 0.82, 95% CI: 0.68–0.98, p < 0.05). In subgroup analyses, benefits were more consistent with ICI monotherapy, including improved PFS (HR = 0.59, 95% CI: 0.44–0.79, p < 0.001) and ORR (RR = 0.60, 95% CI: 0.44–0.82, p = 0.001), while OS showed a nonsignificant trend. Evidence in the ICI-plus-chemotherapy subgroup remained inconclusive because of the limited number of available studies and substantial between-study heterogeneity. Conclusions: DDR gene mutations were associated with improved clinical outcomes in NSCLC patients treated with ICIs, particularly in the ICI monotherapy setting.

Cancers doi: 10.3390/cancers18162552

Authors: Meibao Feng Xuesong Wu Li Jiang Jinyan Huang Jing Zhang Pei Chen Chengdong Chang

Background: Colorectal cancers (CRCs) harboring the BRAFV600E (V600E) mutation exhibit aggressive clinical behavior and chemotherapy resistance, yet the underlying mechanisms remain poorly understood. Ferroptosis, which is driven by iron-dependent lipid peroxidation, has emerged as a potential therapeutic vulnerability. This study aimed to explore whether the NF-κB/Lipocalin 2 (LCN2) pathway modulates cisplatin sensitivity through Fenton-reaction-induced ferroptosis in BRAFV600E-overexpressing CRC cells. Methods: BRAF mutation status and the expression of LCN2, PTGS2, and cleaved caspase3 were examined in clinical CRC specimens by immunohistochemistry. The correlations between ferroptosis and apoptosis markers and 5-year survival rate were evaluated in TCGA datasets. CRC cells with LCN2 knockdown/knockout or BRAF/V600E/LCN2 overexpression were established to assess the proliferation, lipid metabolism, iron levels, and NF-κB/LCN2 signaling under cisplatin treatment. In vivo studies were employed with BALB/c xenograft models. Results: V600E-mutant clinical specimens exhibit significantly reduced expression of the ferroptosis marker PTGS2, and the iron metabolism regulators LCN2. Within a KRAS-mutant cellular model, V600E overexpression attenuated cisplatin-induced ferroptosis through suppression of the NF-κB/LCN2 signaling axis, leading to impairment of Fenton-reaction-mediated lipid peroxidation. Restoration of LCN2 expression re-sensitized V600E-overexpressing cells to cisplatin both in vitro and in vivo. Interestingly, inhibition of apoptosis contributes to the resistance of cisplatin induced ferroptosis in V600E overexpression cells, implying a crosstalk between ferroptosis and apoptosis within the therapeutic resistance. Conclusions: Our findings show that the NF-κB/LCN2 axis drives Fenton-reaction-induced ferroptosis to promote the vulnerability of V600E overexpression CRC cells within a KRAS-mutant background to cisplatin. LCN2 restoration partially overcomes V600E overexpression resistance both in vitro and in vivo, suggesting LCN2 as a promising therapeutic target. The crosstalk between ferroptosis and apoptosis may offer potential strategies to overcome chemotherapy resistance of this high-risk CRC subtype.

Cancers doi: 10.3390/cancers18162551

Authors: Ying Ye Zhichao Fu Xinpeng Wang Shilong Deng Lvjuan Cai Jing Feng Fengmei Wang

Objective: This study aims to investigate the expression of CAVIN3 in cervical cancer, its effect on radiotherapy outcomes, and its potential molecular mechanisms. Materials and Methods: The GEPIA2 database was used to screen genes that may affect cervical cancer prognosis. Then, we analyzed 133 cervical cancer patients from the TCGA database who received radiotherapy to evaluate CAVIN3 gene expression and function. Receiver operating characteristic (ROC) curves and Cox regression models were employed to assess the diagnostic value of CAVIN3 and its association with radiotherapy outcomes. GSEA, GO, and KEGG databases were used to perform pathway enrichment analysis of CAVIN3-related signaling pathways. We also collected pretreatment biopsy specimens from 66 patients who were subsequently treated with radiotherapy from our center to validate the findings from the database analysis. Results: In the TCGA database, CAVIN3 expression was significantly lower in cervical cancer tissues than in normal cervical tissues (p = 0.019), a finding that was independently corroborated in our own cohort (p = 0.002). Receiver operating characteristic analysis yielded area-under-the-curve values of 0.894 for the TCGA RNA-seq data and 0.947 for our center, underscoring the gene’s potential diagnostic utility. Next, we stratified cervical cancer patients who received radiotherapy by intratumoral CAVIN3 levels. Notably, the low-expression group consistently showed better treatment outcomes. In the TCGA cohort, high CAVIN3 expression was associated with significantly shorter median overall survival (mOS, 31.8 months versus not reached within follow-up; p = 0.043). This pattern was confirmed in our validation cohort, where high CAVIN3 expression predicted markedly inferior median progression-free survival (mPFS, 9.8 vs. 59.9 months; p < 0.05) and mOS (17.45 months vs. not reached; p < 0.05). Consistent with these survival differences, the objective response rate to radiotherapy was lower in the high-expression group than in the low-expression group (56.5% vs. 88.2%, p = 0.006), revealing better radiotherapy response among tumors with low CAVIN3 expression. Enrichment analysis revealed that the high CAVIN3 expression group was primarily enriched in pathways related to extracellular matrix formation and remodeling, extracellular matrix–cell membrane interactions, cell adhesion and migration, integrin β1 signaling, and the regulation of cell growth, differentiation, and apoptosis. Together, these functions indicate a more differentiated, matrix-attached phenotype that can promote radioresistance. Conversely, low CAVIN3 expression likely reflects a poorly differentiated state with diminished matrix interaction, which renders the tumor more vulnerable to radiation. Conclusions: CAVIN3 downregulation is a frequent event in cervical cancer and may contribute to tumor susceptibility. Paradoxically, within tumors, low expression of CAVIN3 is associated with an enhanced response to radiotherapy, likely stemming from the underlying phenotype characterized by poor differentiation and heightened radiosensitivity. Therefore, CAVIN3 expression levels are correlated with cervical cancer development and the radiotherapy response of cervical cancer patients.

Cancers doi: 10.3390/cancers18162550

Authors: Merve Tokocin Sevda Yener Selçuk Cin Nigar Erkoç Eda Cingoz Nihan Nizam Nizam Burçin Çakan Demirel Şahin Bedir Turan Pehlivan Atilla Çelik

Background: Radiotracer- and magnetic seed-based targeted axillary staging techniques are increasingly used after neoadjuvant chemotherapy (NAC) in patients with initially node-positive breast cancer who convert to clinical node-negative (ycN0) status. However, these technologies remain unavailable in many centres worldwide. We evaluated the effectiveness of radiotracer-free axillary staging using dual-tracer sentinel lymph node biopsy (SLNB) with indocyanine green (ICG) and methylene blue, with particular focus on the clinical implications of clipped node non-retrieval. Methods: This retrospective single-centre cohort study included 49 patients with biopsy-proven cN1 breast cancer who achieved ycN0 status following NAC and underwent dual-tracer SLNB using ICG and methylene blue between 2021 and 2024. Clipped node retrieval rates, tracer-specific detection patterns, recurrence outcomes, and disease-free survival (DFS) were analysed. Clinical outcomes, including recurrence and disease-free survival, were compared between patients with successful and unsuccessful clipped node retrieval. Results: Clipped node retrieval was achieved in 41 of 49 patients (83.7%). ICG outperformed methylene blue for clipped node identification (80.5% vs. 61.0%) and was the sole detecting tracer in 39.0% of cases. Using methylene blue alone would have reduced the retrieval rate to 51.0% (p = 0.001). ICG identified the clipped node in all six patients with axillary micrometastases (ypN1mi). Clipped node non-retrieval occurred in eight patients, all of whom had negative SLNB findings and did not undergo completion axillary lymph node dissection. Recurrence rates were similar between the retrieval and non-retrieval groups (17.1% vs. 12.5%, p = 1.000), and no isolated axillary recurrences were observed. Baseline tumour size was the only independent predictor of disease-free survival in multivariable analysis (HR 2.05, 95% CI 1.20–3.51; p = 0.008). Conclusions: Radiotracer-free axillary staging using ICG and methylene blue achieved a high clipped node retrieval rate in patients with ycN0 breast cancer after neoadjuvant chemotherapy. ICG significantly improved clipped node identification compared with methylene blue alone and identified the clipped node in all patients with residual nodal micrometastatic disease. Among patients with negative SLNB findings, clipped node non-retrieval was not associated with higher recurrence rates or worse disease-free survival during follow-up. However, given the small number of clipped node non-retrieval cases (n = 8) and recurrence events (n = 8), these findings should be interpreted with caution and require confirmation in larger prospective studies. These findings support the feasibility of a radiotracer-free dual-tracer approach in settings where radiotracer-based techniques are not available. Prospective multicentre studies are warranted to validate both the oncological performance of radiotracer-free axillary staging and the clinical implications of clipped node non-retrieval.

Cancers doi: 10.3390/cancers18162549

Authors: Silvia Negro Sara Lessio Daniele Passeri Andrea Baldo Marco Scarpa Angelo Paolo Dei Tos Ganmaria Pennelli Francesca Schiavi Claudia Pinato Matteo Fassan Quoc Riccardo Bao Francesca Bergamo Sara Lonardi Gaya Spolverato Emanuele Damiano Luca Urso

Background: Mismatch repair deficiency (MMRd) is a central molecular determinant of colorectal cancer (CRC) biology, prognosis, and treatment response, and Universal Tumour Screening (UTS) is advocated for Lynch syndrome (LS) detection; yet real-world performance across clinical subgroups remains limited. We evaluated MMRd distribution and UTS-based LS detection in a large consecutive surgical cohort. Methods: We retrospectively analyzed 1022 consecutive CRC patients undergoing surgical resection at the University Hospital of Padua (2015–2023). MMR status was assessed by immunohistochemistry; MMRd cases underwent reflex BRAF mutation testing and, when available, MLH1 promoter methylation analysis, followed by germline multigene panel testing for suspected LS. Clinicopathological features were compared by MMR status, age at onset, and tumour location. Results: MMR testing was performed in 875 patients (85.6%), rising from 67.0% (2015–2017) to 97.4% (2021–2023). MMRd was identified in 139 tumors (15.9%) and was independently associated with age ≥ 70 years, colonic location, and stage 0–II. Of 22 patients with confirmed LS, 13 (59.1%) were newly identified through UTS; family history showed no significant univariate association with LS status and was not independently associated with MMRd after multivariable adjustment. MMRd prevalence was numerically higher in early- than late-onset CRC (20.0% vs. 15.4%), approaching significance after multivariable adjustment (OR 1.90, 95% CI 0.99–3.64; p = 0.054); hereditary syndromes were also more frequent in early-onset disease. MMRd was markedly rarer in rectal than colonic cancer (4.1% vs. 22.5%; p < 0.0001), though MMRd rectal cancers arose in younger patients. Conclusions: UTS identified a substantial proportion of LS carriers missed by age- or family-history criteria. The relationship between age and MMRd prevalence proved more nuanced than a simple comparison would suggest, reinforcing the value of universal over selective testing across the age spectrum, while MMRd rectal cancer shows a distinct younger profile relevant to immunotherapy-based organ preservation.

Cancers doi: 10.3390/cancers18162548

Authors: Laurentius Oscar Osapoetra Lakshmanan Sannachi Schontal Halstead David Alberico Daniel Moore-Palhares Gregory J. Czarnota

Background/Objectives: We aimed to evaluate the generalizability of QUS spectral parametric imaging radiomics for breast tumor characterization in a large cohort through methodological optimization and rigorous validation, including comprehensive feature extraction and evaluation of multiple classifiers, addressing limitations of previous studies potentially affected by data leakage. Methods: This study included 277 participants (185 malignant cases (median age, 51 years [IQR: 44–63 years]) and 92 benign cases (median age, 46 years [IQR: 38–51 years]) with breast masses, acquired between September 2014 and October 2021. QUS spectroscopic analysis resulted in five maps, from which first-order statistical, various textural, and morphological features were extracted from both the tumor core and a surrounding 5 mm margin. The ground truth label was determined from histopathological analysis. Predictive models were developed to distinguish malignant from benign lesions. Their generalization performance was assessed using hold-out validation. Beyond assessing models’ performance, SHapley Additive exPlanations (SHAP) analysis identified the most influential features to the predictions. Results: 329 radiomics features demonstrated statistically significant differences (p-values < 0.00005). Averaged across 50 partitions, SVM-Linear models produced test performance of 82 ± 8% (CI: 59–97) recall, 79 ± 9% (CI: 50–100) specificity, and 0.87 ± 0.05 (CI: 0.71–0.98) area under the receiver operating characteristic curve (AUROC). The best single partition performance with an SVM-Linear model was 92% recall, 89% specificity, and 0.97 AUROC. Conclusions: This work establishes a performance benchmark for handcrafted radiomic features derived from QUS spectral parametric images in breast lesion characterization, demonstrating its strong generalization and servicing as a reference for future model development.

Cancers doi: 10.3390/cancers18162547

Authors: Supriya Peshin Ehab Takrori Mohammad Sajid Mithani Deepthi Devagudi Joseph H. Yazji Ayse Gul Korkmaz Adit Dharia Waleed Maher Mohammad Tayyem Shaas Ibrahim Qadoumi Sakshi Singal

Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine malignancy associated with rapid proliferation, early metastatic spread, and poor long-term survival. Despite high initial responsiveness to chemotherapy and radiotherapy, most patients experience relapse, and therapeutic progress historically remained limited. Recent years, however, have seen meaningful advances that are beginning to reshape the management of SCLC. In extensive-stage disease, the incorporation of PD-L1 inhibitors into platinum-etoposide chemotherapy has established chemoimmunotherapy as the first-line standard, while underscoring the continued need for more durable disease control. In limited-stage SCLC, consolidation durvalumab following concurrent chemoradiotherapy has emerged as a practice-changing strategy with significant survival benefit. In relapsed disease, DLL3-targeted therapy has opened a new therapeutic avenue, with tarlatamab demonstrating clinically relevant efficacy in previously treated extensive-stage SCLC and becoming the first approved bispecific T-cell engager in this setting. Alongside these milestones, ongoing investigation is focused on maintenance strategies, novel targeted agents, biomarker development, molecular subtyping, and more effective integration of systemic therapy with radiation-based approaches. Nevertheless, resistance, toxicity management, central nervous system involvement, and the absence of validated predictive biomarkers remain major barriers to sustained progress. This narrative review examines recent advances in the biology and clinical management of SCLC, with emphasis on practice-changing developments, emerging therapeutic platforms, and future strategies aimed at improving outcomes in this historically difficult-to-treat disease.

Cancers doi: 10.3390/cancers18162546

Authors: Carlos Rabaça Domingos Roda Guy Vieira Bruno Pereira Ricardo Godinho Mário Lourenço José Alberto Pereira Margarida Regencio Sofia Macedo Rui Caetano Oliveira Amilcar Sismeiro Anabela Mota Pinto

Background: Prostate cancer patients with intermediate disease risk [Gleason score (GS)7] can be divided into two groups: GS = 7(3 + 4) (ISUP 2) (favorable disease risk) and GS = 7(4 + 3) (ISUP 3) (unfavorable disease risk). Low-dose-rate brachytherapy (LDR-BT) is an effective treatment for low- and intermediate-disease-risk patients. Objectives: The main goal of this study was to evaluate the effectiveness of LDR-BT monotherapy in prostate cancer patients classified as ISUP 3 when compared with ISUP 2 patients. Methods: This was a retrospective study that evaluated prostate cancer patients classified as ISUP 2 and ISUP 3 followed up at the Center for the Treatment of Urological Diseases, Portugal, who underwent LDR-BT. Overall survival (OS), biochemical recurrence-free survival (BRFS), bone metastasis and complications post-LDR-BT treatment were evaluated. Results: A total of 602 patients classified with GS = 7 (481/602 ISUP 2 and 121/602 ISUP 3) treated with LDR-BT were recruited. High OS rates and a reduced frequency of complications were described in both groups of patients. ISUP 3 patients had a lower BRFS rate, a higher risk of biochemical recurrence, and developed more bone metastasis in a shorter period when compared with ISUP 2 patients. No significant differences were detected in prostate-cancer-specific mortality between groups. Conclusions: LDR-BT monotherapy is a safe and effective treatment for prostate cancer patients with favorable and unfavorable intermediate disease risk, with similar OS rates and reduced complications.

Cancers doi: 10.3390/cancers18162545

Authors: Dominik Pawlicki Marta Gamrot-Wrzoł Olga Karłowska-Bijak Tomasz Stącel Michał Napierała Maciej Misiołek Paweł Sowa

Background/Objectives: Indwelling tracheoesophageal prostheses have a limited lifespan and require repeated replacement. We examined the determinants of the replacement interval. Methods: This study conducted a retrospective single-center analysis of 147 consecutive Provox replacements in 82 laryngectomized patients (June 2024–February 2026), reported according to STROBE, using mixed-effects and gap-time recurrent-event models. Results: Median device survival was 141 days. Prior irradiation was associated with a shorter interval (−38.3 days; 95% CI −67.2 to −9.3; p = 0.010), with a gradient by treatment intensity: the median survival was 179, 136, and 84 days after primary surgery, radiotherapy alone, and chemoradiotherapy (log-rank p < 0.001; cluster-robust hazard ratios 2.19 and 5.13 against primary surgery). A higher cumulative replacement burden—in terms of lifetime exchanges per patient, with a median of eight and range of 1–28—was also associated with shorter intervals (β = −3.70 days per additional lifetime exchange; 95% CI −5.84 to −1.57), but it summarizes the same event process as the outcome and is reported as a phenotype marker. Intervals ending in elective exchange were longer (β = 35.47 days; 95% CI 15.80 to 55.14), but in the primary recurrent-event model, containing only covariates fixed at interval start and retaining censored intervals, elective placement showed no association with device lifetime (HR 0.574; 95% CI 0.309–1.066; p = 0.079); between-patient heterogeneity remained substantial (θ = 0.452; p = 0.002). Complications occurred in seven of 147 procedures (4.8%), which were all managed without life-threatening events. Conclusions: Prior oncological treatment, particularly chemoradiotherapy, is associated with materially shorter device survival and can be used to identify patients likely to require more frequent exchange. Outpatient exchange appears safe. The association between elective replacement and longer intervals reflects conditioning inherent in comparing scheduled with failure-driven exchange, not a benefit of scheduling.

Cancers doi: 10.3390/cancers18162544

Authors: Federica Mangili Donatella Treppiedi Erika Peverelli Giovanna Mantovani

Pituitary neuroendocrine tumors (PitNETs) represent one of the most common intracranial lesions. The pharmacological approach to PitNETs is mainly based on the use of somatostatin (SS) receptor ligands (SRLs) and dopamine agonists (DAs), although resistance or poor efficacy occurs in a percentage of patients. SS receptors (SSTs) and dopamine receptor type 2 (DRD2) represent the principal targets of SRLs and DAs, respectively, in PitNET therapy. Over the years, SSTs and DRD2-related activated pathways have been characterized. Different factors that might play a role in affecting intracellular signaling transduction have been studied, including splicing machinery and its related factors. A severe dysregulation of splicing machinery components in all PitNET subtypes compared to normal pituitary was observed, and possible alterations that might underlie pharmacological resistance or intracellular pathway alterations were investigated. The detection of these alterations presented the opportunity to investigate small molecules that regulate splicing components as an alternative approach for PitNETs treatment. A systematic literature search was conducted in the PubMed database and supplemented by screening the references of the identified articles. A narrative synthesis of the research findings was provided, including relevant studies from 2015 up to date. It aimed to summarize the emerging role of splicing machinery, focusing on different splicing factors shown to be altered in different PitNET subtypes that might affect responsiveness to pharmacological treatment. Different ways to target splicing machinery and its mechanism of action have been described, with the goal of developing novel therapies for PitNETs.

Cancers doi: 10.3390/cancers18162543

Authors: Maria Pimenta Macedo Isabel Dionísio Sousa Nuno Teixeira Tavares

Background/Objectives: Treatment with adjuvant abemaciclib plus endocrine therapy (ET) has been demonstrated to improve outcomes in patients with HR+/HER2- early breast cancer at high risk of recurrence. However, real-world data regarding abemaciclib tolerability and treatment maintenance remain limited. In this study we describe the occurrence of adverse events (AEs) and their management through dose adjustments—dose reductions and temporary treatment interruptions—reflecting strategies that maximize compliance. Methods: We conducted a retrospective cohort study at the Oncology Department of ULS São João, in Porto, Portugal. Inclusion criteria comprised patients with HR+/HER2- early breast cancer treated, for at least three months, with abemaciclib, between January 2022 and January 2026. Clinical data were collected from electronic medical records and were analyzed using descriptive statistics, with continuous variables reported as median (IQR) and categorical variables as frequencies and percentages. Results: Fifty-six patients were included in this cohort. With the median follow-up of 14.5 months, 98.2% of patients experienced at least one AE. Most common AEs were gastrointestinal and hematological and occurred within the first 3 months of treatment. Dose reductions occurred in 46.4% of patients and temporary treatment interruptions in 25% of patients. However, no permanent treatment discontinuations were reported. Conclusions: In this cohort, AEs associated with adjuvant abemaciclib were common but generally low-grade and manageable. Early recognition of AEs allows appropriate dose adjustments and supportive measures, which support treatment maintenance. These findings highlight the importance of close clinical monitoring and patient counseling to enhance treatment compliance.

Cancers doi: 10.3390/cancers18162542

Authors: Daniel Yi Michael Kahn

Somatic stem cells, as well as cancer stem cells, exist in two basic “states”, quiescent versus activated. The regulation of the balance between quiescence and activation is critical to tissue homeostasis and repair after injury. Additionally, after being activated, the decision to divide symmetrically or asymmetrically is critical. Aberrant regulation of stem cell quiescence and mode of mitotic division is associated with aging and diseases of aging including cancer, fibrosis, sarcopenia and neurodegeneration. Based on over 25 years of chemical genetic and genetic investigation, we discuss the differential roles of the two Kat3 coactivators (Kat3A/CREBBP/CBP and Kat3B/EP300/p300) in regulating stem cell quiescence and the mode of division of activated stem cells. The ability to pharmacologically regulate differential Kat3 coactivator usage has important implications to ameliorate the aging process as well as to eliminate quiescent cancer stem cells, which are the cause of disease relapse and metastasis.

Cancers doi: 10.3390/cancers18162541

Authors: Nahuel Paesano Violeta Catalá Juan Camean Tomás Eduardo Olmedo Joaquín Ignacio Gurovich Maximiliano Ringa Berta Miró Lucas Regis Olga Mendez Enrique Trilla Juan Morote

Background: External validation of predictive models is needed in new populations after their implementation. Objective: We aimed to validate and compare the performance of the BCN-MRI PM and ERSPC-MRI PM in an Ibero-American population. Methods: We conducted a retrospective analysis of 540 men with suspected PCa who underwent MRI and prostate biopsy in 2025. Individual csPCa risk estimates were calculated using the online calculators for the BCN-MRI PM and ERSPC-MRI PM. The reference standard outcome was the rate of avoided biopsies. Calibration, discrimination of csPCa, net benefit, and clinical utility were analyzed with R software. Results: All participants underwent MRI and prostate biopsy. The median age was 66 years (95% CI 61–71). The overall csPCa detection rate was 55.7%. The BCN-MRI PM demonstrated good calibration, with close agreement between predicted and observed csPCa probabilities, whereas the ERSPC-MRI PM underestimated risk in the intermediate-probability range. Discrimination for csPCa was significantly better with the BCN-MRI PM (AUC, 0.807; 95% CI 0.771–0.843) than with the ERSPC-MRI PM (AUC, 0.764; 95% CI 0.724–0.803; p < 0.001). Decision curve analysis showed a greater net benefit for the BCN-MRI PM than for the ERSPC-MRI PM and the strategy of biopsying all men. Clinical utility curves demonstrated a more favorable balance between avoided biopsies and missed csPCa cases across threshold probabilities. At a sensitivity of 95%, the BCN-MRI PM achieved a specificity of 38.9% (95% CI, 32.5–45.1%) compared with 30.1% (95% CI, 24.6–35.7%) for the ERSPC-MRI PM, avoiding 21.5% and 16.3% of biopsies, respectively (p = 0.043). The performance of both models was also evaluated according to PI-RADS category and participating center. Conclusions: In this Ibero-American cohort, the BCN-MRI PM demonstrated superior calibration and overall clinical performance compared with the ERSPC-MRI PM.

Cancers doi: 10.3390/cancers18162540

Authors: Onur C. Koyun Yongxin Guo Hao Lu Muhammet Fatih Demir Abbas Alili Nabil Rahoui Diana Cardona Metin N. Gurcan

Background/Objectives: Digital pathology models increasingly infer molecular phenotypes from hematoxylin and eosin whole-slide images (WSIs), but most assume that one slide adequately represents patient-level tumor biology. We quantified prediction instability caused by slide selection and evaluated multi-WSI aggregation. Methods: Six multiple-instance learning architectures were developed in task-specific subsets of TCGA-BRCA (source cohort: 1006 patients and 1065 WSIs) and independently evaluated in 122 patients (400 WSIs) from CPTAC-BRCA. The clinically realistic comparison was random one-slide-per-patient inference versus patient-level aggregation of all available WSIs. Label-conditioned best- and worst-slide analyses were used only as retrospective oracle bounds. The recurrence-risk endpoint was a research-derived 21-gene recurrence-score surrogate calculated from RNA sequencing rather than a clinically reported Oncotype DX result. Results: Random single-slide selection yielded AUCs of 0.77–0.86 for recurrence-risk prediction and 0.65–0.77 for HER2 status. Patient-level multi-WSI aggregation yielded AUCs of 0.81–0.89 and 0.71–0.80, respectively. The architecture-controlled AUC improvement from random selection to aggregation ranged from 0.026 to 0.041 for recurrence risk and from 0.036 to 0.073 for HER2. Aggregation also reduced Brier scores by 0.010–0.028 and 0.009–0.106, respectively. The label-conditioned oracle analyses demonstrated wider theoretical performance ranges of 0.46–0.97 and 0.40–0.92, respectively. Slide-selection sensitivity persisted after excluding tumor-evidence-negative and low-tumor-content WSIs. Conclusions: Slide selection is a material source of sampling-dependent prediction uncertainty. Patient-level multi-WSI aggregation mitigated selection-dependent degradation across architectures, although validation using routine institutional material and clinically reported molecular assays remains necessary.

Cancers doi: 10.3390/cancers18162539

Authors: Masahiko Kinoshita Shoji Kubo Kimika Kato Daisuke Inoue Takuto Yasuda Kosuke Hatta Atsushi Sugimoto Ryota Tanaka Jun Tauchi Sadaaki Nishimura Genki Watanabe Kohei Nishio Hiroji Shinkawa Takeaki Ishizawa Yasunori Sato

Background/Objectives: Intraductal papillary neoplasm of the bile duct (IPNB) is a premalignant lesion of cholangiocarcinoma. Currently, its tumor immune microenvironment (TIME) remains poorly characterized. Occupational cholangiocarcinoma provides a unique setting wherein multiple IPNBs arise in a background of chronic biliary injury caused by organic solvents. This study evaluated TIME alternations in IPNB lesions in occupational cholangiocarcinoma, focusing on histological subclassifications, phenotypes, invasive status, and tumor size. Methods: Thirteen IPNB lesions in six patients with occupational cholangiocarcinoma were immunohistochemically stained for CD8, CD163, programmed death protein 1 (PD-1), and programmed death ligand 1 (PD-L1). CD8-, CD163-, and PD-1-positive cells were counted in the most densely infiltrated areas. PD-L1 expression was assessed using the combined positive score (CPS), and associations with each status were analyzed. Results: Within the occupational IPNB cohort, type 2 IPNBs demonstrated significantly higher CD8, CD163, and PD-1 expression levels than type 1 IPNBs. Invasive lesions showed significantly higher CD8 expression and CPS than noninvasive lesions. Tumor size was positively correlated with CD163 expression (R = 0.504), CD8 expression (R = 0.627), and CPS (R = 0.569) in the TIME. When stratified by tumor size (<10 vs. ≥10 mm), lesions ≥ 10 mm in size demonstrated significantly higher CD163 expression and CPS. Notably, all lesions with CPS ≥1 were ≥10 mm in size. Conclusions: In IPNB arising from occupational cholangiocarcinoma, tumor enlargement is associated with progressive TIME alterations. Lesions ≥ 10 mm in size may represent a threshold at which immunoediting and invasive potential become more prominent.

Cancers doi: 10.3390/cancers18162538

Authors: Lidia Boldeanu Alice Elena Ghenea Alina Elena Ciobanu Plasiciuc Mihail Virgil Boldeanu Rodica Pădureanu Mohamed-Zakaria Assani Vlad Pădureanu Isabela Siloși Marius Bogdan Novac Ancuța-Ramona Boicea Camen

Background/Objectives: Microsatellite-stable colorectal cancer (MSS CRC) accounts for the vast majority of CRC cases and remains largely resistant to immune checkpoint inhibitors. Emerging evidence suggests that the gut microbiome is an important regulator of antitumor immunity and may contribute to immunotherapy resistance through multiple mechanisms involving the tumor microenvironment. This review aims to summarize current knowledge of the microbiome–immunity–therapy axis in MSS CRC and to explore microbiome-based strategies to enhance immunotherapy responsiveness. Methods: A narrative review of the recent literature was conducted, focusing on studies published within the last five years that investigated gut microbiota composition, microbial metabolites, tumor immune regulation, immunotherapy response, and microbiome-targeted therapeutic interventions in CRC. Evidence from mechanistic studies, translational research, clinical investigations, and multi-omics analyses was integrated. Results: Current evidence indicates that gut dysbiosis contributes to immune resistance in MSS CRC through immune exclusion, myeloid-driven immunosuppression, T-cell dysfunction, chronic inflammation, and altered microbial metabolite signaling. Specific microorganisms, including Fusobacterium nucleatum, enterotoxigenic Bacteroides fragilis, pks-positive Escherichia coli, and other CRC-associated pathobionts, have been implicated in tumor progression and modulation of antitumor immunity. Microbial metabolites such as short-chain fatty acids, tryptophan-derived compounds, bile acids, succinate, and inosine represent key functional mediators linking microbial communities to host immune responses. Emerging microbiome-targeted interventions, including fecal microbiota transplantation, next-generation probiotics, postbiotics, selective microbial depletion, and engineered bacterial therapeutics, have shown promising results in preclinical models and early translational or clinical studies, although robust clinical evidence remains limited. In parallel, advances in metagenomics, metabolomics, spatial transcriptomics, and artificial intelligence are facilitating the development of precision immuno-microbiome oncology approaches. Conclusions: The gut microbiome functions as a critical regulator of immune resistance in MSS CRC through coordinated effects on microbial composition, metabolite production, and tumor immune remodeling. Microbiome-targeted interventions, combined with multi-omics-based patient stratification, may provide new opportunities to overcome immunotherapy resistance and expand the clinical benefits of immune checkpoint blockade in this traditionally refractory disease.

Cancers doi: 10.3390/cancers18162537

Authors: Vesna Zeljković Slaviša Minić Marko Mladenović Dejan Milenković Zoran Marković Tanja V. Soldatović Vanja Kunkin Maja Karaman

Background: Metabolic reprogramming enables cancer cells to adapt to energetic stress and sustain proliferation. Simultaneous inhibition of glycolysis and mitochondrial respiration has emerged as a promising strategy to overcome metabolic plasticity. This study evaluated the antiproliferative effects of the glycolytic inhibitor 2-deoxy-D-glucose (2-DG) alone and in combination with metformin in human cancer cell lines. Methods: Human cervical carcinoma (HeLa), lung adenocarcinoma (A549), colorectal adenocarcinoma (HT-29), and normal lung fibroblasts (MRC-5) were treated with 2-DG or metformin individually, or with metformin in the presence of a fixed concentration of 2-DG (1 mM). Cell viability was assessed using the sulforhodamine B assay after 24 and 48 h. IC50 values were calculated by nonlinear regression, Dose Reduction Index (DRI) analysis evaluated sensitization to metformin, and molecular docking was performed to investigate interactions with selected metabolic targets. Results: Both 2-DG and metformin inhibited cell proliferation in a concentration- and time-dependent manner. HeLa cells were the most sensitive to glycolytic inhibition, while A549 and HT-29 cells showed moderate susceptibility. Co-treatment with 2-DG significantly enhanced metformin activity, reducing its IC50 in HeLa cells from 6.04 to 2.00 mM after 24 h and from 2.28 to 1.56 mM after 48 h. DRI analysis demonstrated increased sensitivity to metformin in all cancer cell lines, particularly HT-29 and A549, whereas normal MRC-5 fibroblasts remained comparatively less affected. Molecular docking revealed favorable binding of both 2-DG and metformin to proteins involved in cellular energy metabolism. Conclusions: Combined inhibition of glycolysis and mitochondrial respiration potentiates the antiproliferative effects of metformin, increases metabolic vulnerability in cancer cells, and is supported by molecular docking evidence of interactions with metabolic targets, while showing limited toxicity toward normal fibroblasts. These findings support dual metabolic targeting as a promising therapeutic strategy and warrant further mechanistic and in vivo studies.

Cancers doi: 10.3390/cancers18162536

Authors: Zsuzsa S. Kocsis Péter Ágoston Gyöngyi Farkas Gábor Székely Gyöngyvér Orsolya Sándor Kliton Jorgo László Gesztesi Tibor Major Csilla Pesznyák András Herein Gábor Stelczer Dalma Mihály Georgina Fröhlich Zoltán Takácsi-Nagy Csaba Polgár Zsolt Jurányi

Background: There are limited data comparing the effect of different radiotherapy techniques on healthy cells in the same patient group. Furthermore, assessing radiotherapy-induced T-lymphocyte damage may be important given the increasing use of immunotherapy. We aimed to measure and compare DNA damage in T-lymphocytes after four types of radiotherapy for low- and intermediate-risk prostate cancer and monitor their persistence for five years. Methods: A prospective comparison of patients receiving conventional LINAC (linear accelerator) (70–78 Gy), CyberKnife teletherapy (37.5–40 Gy), low-dose-rate brachytherapy (LDR; 145 Gy) and high-dose-rate brachytherapy (HDR; 19–21 Gy was performed using the chromosome aberration technique (at 3, 6, 9, 12, 24, 36, 48, and 60 months, 192 patients). Multivariate regression analyses were conducted to assess the predictive potential of chromosome aberrations for toxicities. Results: We found that teletherapy techniques (conventional LINAC and CyberKnife therapy) caused 1.6–3.6-fold more chromosomal aberrations than brachytherapy. At three months, 4.4–13.1% of T-lymphocytes were damaged. Five years after treatment, the total aberration values of conventional LINAC and LDR brachytherapy patients were still significantly higher than those before treatment (p < 0.001 for LINAC and p = 0.011 for LDR). Significant regression models suggested that total aberrations or aberrant cell frequency might predict toxicities in addition to the biologically effective dose (BED) and the irradiated volume (V100%) (p = 0.020 for the model including total aberrations, p = 0.010 for the model including aberrant cell frequency). Conclusions: We observed a lower chromosome aberration frequency and fewer toxicities in brachytherapy patients. We also demonstrated that long-term T-lymphocyte damage depends on the type of radiotherapy.

Cancers doi: 10.3390/cancers18162535

Authors: Shahed Azzam Ahmed Abdullah Richard Flavin

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of clinically aggressive mature T-cell and natural killer (NK)-cell neoplasms that account for approximately 10–15% of all non-Hodgkin lymphomas in Western countries . The most common subtypes include extranodal NK/T-cell lymphoma (ENKTL), nodal T-follicular helper cell lymphomas, peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), anaplastic large cell lymphoma (ALK-positive and ALK-negative), and T-cell lymphoblastic lymphoma. Non-coding RNAs (ncRNAs) constitute the majority of the human transcriptome and play critical roles in regulating gene expression, cellular proliferation, differentiation, migration, and apoptosis. Among these, long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) have emerged as key regulators of lymphomagenesis and disease progression in PTCLs. These molecules modulate diverse oncogenic pathways through chromatin remodeling, transcriptional regulation, competing endogenous RNA activity, and interactions with RNA-binding proteins, thereby influencing proliferation, immune evasion, treatment resistance, and clinical outcomes. Representative examples include the lncRNA TCLlnc1, which promotes PTCL progression through activation of transforming growth factor-β (TGF-β) signaling, and the circRNAs circKIF4A, circADARB1, and circ-LAMP1, which regulate miRNA-dependent signaling networks involving PDK1/BCL11A, STAT3, and DDR2, respectively. In this review, we summarize the current understanding of the biological and clinical roles of lncRNAs and circRNAs in PTCL and related T-cell and NK-cell neoplasms and highlight their potential as diagnostic and prognostic biomarkers as well as therapeutic targets. We also discuss recent advances and future directions for integrating ncRNA-based approaches into precision medicine for T-cell lymphoma.

Cancers doi: 10.3390/cancers18162534

Authors: Daniela Molena Tamar Nobel Marisa Sewell Amirthavarsini Manikandan Kay See Tan Matthew J. Bott Katherine D. Gray Hans Gerdes Pari Shah Makoto Nishimura Laura Tang Bernard J. Park Smita Sihag David R. Jones

Objective: To evaluate the feasibility of sentinel lymph node (SLN) identification in distal esophageal and esophagogastric junction (EGJ) adenocarcinoma and determine whether the SLN concept applies to this disease. Methods: Patients undergoing esophagectomy for clinical stage I-IVA esophageal and EGJ adenocarcinoma underwent SLN mapping by near-infrared detection of indocyanine green (ICG) injected via endoscopy before esophagectomy. Lymphatic drainage patterns were recorded, and the first identified nodes (SLNs) were harvested. Standard esophagectomy and lymphadenectomy were performed. SLN status was compared with overall nodal status. Results: Of 90 included patients, 77 received ICG; SLN mapping was successful in 64 (83%). Ten patients had two SLN stations identified; the remainder had one. The most common SLN location was along the left gastric artery (36/74 [48%]), followed by the paracardial (17/74 [23%]) and periesophageal (15/74 [20%]) stations. Seven patients had SLNs positive for metastasis (in one, the SLN was the only positive node; in the rest, metastatic nodes were identified in the same or other stations). Of the 57 patients with negative SLNs, 11 (19%) had ≥1 positive node in the same or different nodal station. The false-negative rate was 61.1%. Conclusions: SLN mapping with ICG is feasible in patients with distal esophageal and EGJ adenocarcinoma, with a high rate of successful node identification. Occult nodal metastasis in patients with negative SLNs limits the reliability of SLN assessment as a determinant for selective lymphadenectomy.

Cancers doi: 10.3390/cancers18162533

Authors: Ágnes Stier Anna Páldy

Background: Long-term mortality trends for melanoma and non-melanoma skin cancer (NMSC) in Hungary have not been comprehensively assessed. Methods: We conducted a retrospective nationwide study of deaths registered in Hungary between 1980 and 2020 among individuals aged 35 years or older, where melanoma (ICD-10 C43) or NMSC (ICD-10 C44) was recorded as the primary cause of death. Annual crude death rates (CDRs; overall and age-specific 35–64 and ≥65 years) and age-standardised death rates (ASDRs) per 100,000 population were calculated by sex. Trends were analysed using Joinpoint regression. Results: Overall, 18,857 skin cancer deaths, including 12,026 melanoma and 6831 NMSC deaths, were identified. Melanoma mortality was consistently higher in men. Among men, melanoma ASDR increased until 1994 and then stabilised, while crude mortality among older men continued to increase. Among women, the ASDR of melanoma increased until 1994 and subsequently declined. Crude mortality decreased after 2005 in women aged 35–64 years. Although NMSC mortality was lower than melanoma mortality, NMSC accounted for 36.2% of skin cancer deaths. In both sexes, NMSC mortality was concentrated in adults ≥ 65 years. In older women, crude NMSC mortality increased again after the mid-2000s, whereas ASDR remained broadly stable. Conclusions: Melanoma mortality trends in Hungary partially stabilised or improved after the mid-1990s, particularly in age-standardised analyses, but mortality remained high among older adults, especially among men. NMSC represented a substantial proportion of skin cancer deaths, with the burden concentrated in adults ≥ 65 years, supporting the inclusion of NMSC in routine mortality surveillance and disease burden assessments.

Cancers doi: 10.3390/cancers18162532

Authors: Jesús Baltasar González-Rubino Rocío Martín-Valero Francisco José Vera-Serrano Ismael García-Campanario Francisco Javier Martin-Vega Maria Jesus Vinolo-Gil

Background/Objectives: Breast cancer treatments, including adjuvant radiotherapy, significantly improve survival but are associated with cancer-related fatigue (CRF), a debilitating symptom that severely impacts quality of life. Previous studies often evaluate fatigue by combining radiotherapy with systemic therapies, confounding its independent association. This study aims to isolate the specific relation between exclusive radiotherapy and the longitudinal progression of fatigue in surgically treated breast cancer patients. Methods: A longitudinal study was conducted in a cohort of 70 women with breast cancer who underwent breast-conserving surgery and subsequent adjuvant radiotherapy. Cancer-related fatigue levels were evaluated across behavioral, affective, sensory, and cognitive dimensions using the Piper Fatigue Scale-Revised (PFS-R), while global health status and quality of life (QoL) were measured using the EORTC QLQ-C30 questionnaire, both before and after radiotherapy. Data were analyzed using generalized linear mixed-effects models. Results: Following radiotherapy, a marked and statistically significant increase was observed in total fatigue (1.61 ± 1.16 vs. 5.37 ± 2.76; p < 0.001) and across all specific domains (p < 0.001), accompanied by a decline in global health status (82.6 ± 20.2 to 60.1 ± 29.2). Assessment time (pre- vs. post-RT) was identified as the factor most strongly associated with an increase in fatigue. However, better baseline global health status significantly attenuated the increase in total, behavioral, affective, and sensory fatigue (time × QoL interaction, p < 0.001). Furthermore, higher physical activity levels were significantly associated with lower behavioral fatigue (p = 0.042) and showed a protective trend for sensory (p = 0.055) and total fatigue (p = 0.092). Conclusions: Radiotherapy is strongly associated with a significant increase in cancer-related fatigue scores across all dimensions. Better baseline quality of life acts as a protective factor that is associated with attenuated fatigue progression, while regular physical activity correlates with a mitigated impact, particularly within the behavioral domain, although it did not reach statistical significance across all fatigue dimensions. These findings highlight the critical need for routine clinical monitoring of fatigue and strongly support the implementation of structured, exercise-based interventions during adjuvant treatment.

Cancers doi: 10.3390/cancers18162531

Authors: Jacob Lindquist Josh Heyza Istri Ndoja Nasrin Movahhedin Chris Yunker Marina Cardo-Vila Seongho Kim Joann Sweasy Steve M. Patrick

Background/Objectives: With the advent of genome sequencing and its widespread use in the clinic, there is a great need to identify mutational biomarkers that predict therapeutic responses. DNA polymerase beta (Polβ) and the base excision repair (BER) pathway have been previously implicated as modulators of response to platinum-based chemotherapies and are mutated in as many as 30% of cancers. Methods: Here, we show in a triple-negative breast cancer (TNBC) model that two classes of mutations in Polβ, reduced catalytic activity (E295K and D256A mutations) and reduced fidelity (I260M), are sufficient to drive cisplatin and carboplatin-specific sensitivity. Cellular response to oxaliplatin in these Polβ mutant models is minimal relative to cisplatin and carboplatin. Results: We show that sensitivity is associated with reduced repair of both platinum-induced DNA intrastrand adducts and interstrand crosslinks (ICLs). Downregulation of the upstream BER factor uracil DNA glycosylase (UNG) reverses drug sensitivity, which is consistent with these Polβ mutations negatively impacting ICL DNA repair to drive drug sensitivity. In addition, the intrastrand adduct repair readout indicates that these lesions also play a role in the sensitivity observed in Polβ mutant models. In vivo studies demonstrate a significant effect on tumor growth delay with cisplatin treatment in tumor xenografts harboring Polβ mutations. Conclusions: These results support the potential for using Polβ mutations as predictive biomarkers for cisplatin and carboplatin therapies in the clinical setting.

Cancers doi: 10.3390/cancers18162530

Authors: Norihito Kamo Shu Soeda Tsuyoshi Honda Keiya Fujimori

Delayed relapse after curative-intent treatment remains difficult to explain and predict in human papillomavirus (HPV)-associated cervical cancer, including after periods of sustained remission with undetectable circulating tumor DNA (ctDNA) or circulating HPV DNA. This limitation of tumor-centered surveillance demands the evaluation of immune parameters alongside tumor-derived biomarkers. We propose “immune absence” as a hypothesis-generating, operational framework referring to the sustained reduction or non-persistence of pre-specified tumor-reactive T-cell receptor (TCR) clonotypes in serial peripheral blood samples, obtained during minimal residual disease states in which antigen exposure may be limited or intermittent. We hypothesize that this longitudinal pattern may precede molecular or clinical evidence of relapse in a subset of patients and coexist with established mechanisms, such as tumor evolution, immune escape, T-cell dysfunction, and therapeutic resistance. Integrating serial ctDNA or circulating HPV DNA measurements with tumor-reactive TCR clonotype dynamics may provide complementary information on residual tumor burden and the persistence of circulating tumor-reactive T-cell responses. Peripheral blood TCR non-detection does not establish complete loss of anti-tumor immunity and may reflect compartmentalized immunity, clonal replacement, antigenic evolution, or assay limitations. Prospective longitudinal studies are required to establish the prognostic value of this framework before clinical use.

Cancers doi: 10.3390/cancers18152529

Authors: Caroline Norup Bistrup Morten Kranker Larsen Peter Junker Vibe Skov Lasse Kjær Trine Alma Knudsen Morten Karsdal Nicholas Willumsen Hans Carl Hasselbalch

Background and objectives: Myeloproliferative neoplasms (MPNs) are blood cancers characterized by elevated blood cell counts, bone marrow fibrosis (BMF), and chronic inflammation, which drives disease progression. BMF results from disrupted collagen turnover in the bone marrow extracellular matrix (ECM), making its reduction or stabilization a key therapeutic goal. Non-invasive biomarkers reflecting collagen turnover could potentially improve early detection of BMF and monitor disease activity. Methods: We evaluated serum biomarkers of collagen turnover in 130 MPN patients (MPN subtypes: ET = 49, PV = 60, pre-PMF = 8, PMF = 13) included in the DALIAH trial (ClinicalTrials.gov identifier: #NCT01387763). Type I and type III collagen formation (PRO-C1 and PRO-C3) and MMP-degraded type I, III, and IV collagens (C1M, C3M, and C4M) were measured by ELISA in serum. Biomarker levels were compared to age- and sex-matched healthy individuals and were assessed according to disease subtypes, somatic driver mutations, JAK2V617F VAF, and fibrosis grade. Furthermore, we studied correlations between the biomarker levels and conventional hematological markers for disease activity, such as hemoglobin, white blood cell count (WBCs), platelet counts, and lactate dehydrogenase (LDH). Results: Baseline PRO-C3 (p = 0.0005) and C1M (p = 0.0102) were elevated in MPN patients compared to healthy individuals, whereas C3M was decreased (p < 0.0001). Patients with primary myelofibrosis (PMF) had higher levels of PRO-C3 compared to patients with ET (p = 0.0041) and PV (p = 0.0172), correlated with higher JAK2V617F VAF (≥50%) (p = 0.0069) and advanced fibrosis grade (p = 0.0002). In addition, PRO-C3 was positively correlated to LDH, which is a biomarker of disease activity in MPNs (r = 0.5754, p < 0.0001). Conclusions: Taken together, these findings emphasize the role of ECM remodeling in MPN pathophysiology and the potential of soluble ECM neoepitopes as biologically plausible disease markers.

Cancers doi: 10.3390/cancers18152528

Authors: Michael Schwartz Kieran Sweeney Steven C. Smith Kartik Angara Celia Reynolds Alberto S. Pappo Andrew Elliott Matthew J. Oberley Mark G. Evans Armita Bahrami

Background: NTRK gene fusions are established oncogenic drivers in a diverse spectrum of mesenchymal neoplasms. Although classically described in pediatric entities, NTRK-rearranged sarcomas also occur in adults, where their clinicopathologic features, genomic context, and response to TRK inhibition are less well characterized. Methods: We retrospectively queried a national referral genomics database to identify sarcomas in patients >18 years harboring pathogenic NTRK1, NTRK2, or NTRK3 fusions. Gastrointestinal stromal tumors, duplicate specimens, and cases lacking digitized hematoxylin and eosin slides were excluded. Fusions were identified by whole-transcriptome sequencing, co-occurring genomic alterations by exome-based sequencing, and real-world survival and time on TRK inhibitor therapy were derived from linked insurance claims data; fusion-negative sarcomas and NTRK-rearranged non-sarcoma tumors from the same database served as comparison cohorts. Results: Among 13,040 profiled sarcomas, 19 adult tumors with pathogenic NTRK fusions were identified (median age, 43 years; range, 21–77), most of which were high grade (68%) and advanced stage (63% stage IV). Histology was heterogeneous, including spindle cell sarcoma (53%), pleomorphic sarcoma (21%), and tumors corresponding to defined entities such as NF1-associated malignant peripheral nerve sheath tumor and MDM2-amplified dedifferentiated liposarcoma (11% each). NTRK1 and NTRK3 fusions were equally frequent (9 cases each); fusion partners were diverse, with TPM3 (n = 5), EML4 (n = 2), and TFG (n = 2) recurrent and other partners non-recurrent. Additional genomic alterations were common and heterogeneous (72%), including high genome-wide loss of heterozygosity and infrequent but recurrent alterations involving the TERT promoter, NF1, and RB1. All evaluable tumors showed transcriptional activation of the NTRK fusion and increased MAPK pathway activity compared with fusion-negative sarcomas. Nine patients received TRK inhibitors; median time on larotrectinib was 12.5 months, similar to that observed in NTRK-rearranged non-sarcoma tumors, but treatment duration was variable. Conclusions: Adult sarcomas harboring NTRK fusions are rare, morphologically heterogeneous, and biologically diverse. NTRK fusion status alone may not fully capture oncogenic dependence and should be interpreted within the broader clinicopathologic and genomic context.

Cancers doi: 10.3390/cancers18152527

Authors: Yu-Hsiang Chang Chao-Hsiang Chang Chi-Ping Huang Wen-Jeng Wu Ching-Chia Li Marcelo Chen Wun-Rong Lin Chih-Chin Yu Vincent F. S. Tsai Yao-Chou Tsai

Background/Objectives: Radical nephroureterectomy (RNU) is the standard of care for high-risk upper tract urothelial carcinoma (UTUC) but causes permanent renal decline, often disqualifying patients from essential cisplatin-based adjuvant chemotherapy. Segmental ureteral resection (SUR) preserves renal function, but its safety in high-risk patients remains fiercely debated due to historical treatment selection biases and a lack of competing risk adjustments. We aimed to compare long-term oncological outcomes and postoperative renal function preservation between SUR and RNU for high-risk UTUC strictly localized to the ureter. Methods: Retrospective data from 859 patients (783 RNU, 76 SUR) with high-risk ureteral UTUC (high-grade or pathologic T2–T4) were analyzed from a 21-hospital nationwide database. Propensity score overlap weighting was implemented to achieve covariate balance. Overall survival (OS) was assessed via Cox proportional hazards regression, whereas cancer-specific survival (CSS), metastasis-free survival (MFS), and local recurrence-free survival (LRFS) were evaluated using multivariable Fine–Gray subdistribution hazard models to robustly account for the competing risk of non-cancer mortality. Results: Overlap weighting achieved excellent baseline comparability with an effective sample size of 429.5 patients per cohort. Weighted analyses demonstrated comparable long-term trajectories between SUR and RNU for OS (p = 0.62), CSS (hazard ratio [HR]: 0.94, p = 0.835), and MFS (HR: 0.88, p = 0.664). The Fine–Gray model confirmed that the surgical approach was not a significant independent predictor of local recurrence (HR: 0.74, p = 0.351). Crucially, the SUR group demonstrated a significantly lower renal function decline both at 1 month (−0.11 vs. −10.58 mL/min/1.73 m2, p < 0.001) and through final clinical follow-up (−5.33 vs. −12.49 mL/min/1.73 m2, p = 0.001). Conclusions: For meticulously selected patients with high-risk ureteral UTUC, SUR provides equivalent oncological control and survival outcomes to standard RNU. Crucially, this kidney-sparing approach significantly preserves postoperative renal function, safeguarding the physiological reserve required for patients to maintain eligibility for optimal subsequent systemic adjuvant therapies.

Cancers doi: 10.3390/cancers18152526

Authors: Cristina Maria Macrea Tiberia Ilias Alexandra Costea Paula Trif Viorela-Romina Murvai Ovidiu C. Fratila

Colorectal cancer (CRC) remains one of the leading causes of cancer-related morbidity and mortality worldwide despite substantial advances in screening, surgical techniques, systemic therapies, and multidisciplinary care. The increasing implementation of precision oncology has fundamentally transformed CRC management by enabling molecularly guided therapeutic strategies based on tumor-specific genetic alterations. In recent years, the molecular landscape of CRC has expanded considerably beyond traditional histopathological classification, incorporating a growing number of clinically actionable biomarkers with prognostic, predictive, and therapeutic significance. This review provides a comprehensive and up-to-date overview of the genetic landscape of CRC, focusing on established biomarkers currently integrated into clinical practice, including microsatellite instability/mismatch repair deficiency (MSI/dMMR), KRAS, NRAS, BRAF, HER2, and NTRK alterations. In addition, emerging biomarkers such as tumor mutational burden (TMB), POLE/POLD1 mutations, circulating tumor DNA (ctDNA), DNA damage repair (DDR) alterations, transcriptomic signatures, and artificial intelligence-based molecular prediction models are critically discussed. Particular emphasis is placed on their biological significance, diagnostic methodologies, prognostic and predictive value, and potential role in treatment selection. A structured, database-informed narrative review identified 140 relevant publications, primarily published between January 2020 and June 2026, supplemented by earlier seminal studies and major clinical guidelines. Based on the available evidence, we propose a Clinical Actionability Framework for CRC, categorizing biomarkers into three hierarchical tiers according to their level of clinical validation and therapeutic relevance: established standard-of-care biomarkers, emerging clinical biomarkers, and future precision oncology biomarkers. Collectively, current evidence supports a progressive transition from single-gene testing toward integrated multi-omics precision medicine. Advances in comprehensive genomic profiling, liquid biopsy technologies, transcriptomics, radiogenomics, and artificial intelligence are expected to further refine patient stratification, optimize therapeutic decision-making, and facilitate the development of adaptive precision oncology models. Understanding the evolving genetic landscape of CRC is therefore essential for maximizing treatment efficacy and improving patient outcomes in the era of personalized cancer care.

Cancers doi: 10.3390/cancers18152525

Authors: Morgiane Bridou Léonore Robieux

Background/Objectives: Patients facing cancer’s challenges develop various coping strategies. This systematic review identifies the psychological resources that influence their mental health and quality of life. Methods: Following PRISMA guidelines, we searched Medline, PsycINFO, PubMed, Science Direct, Springerlink, and Wiley for empirical studies published between 2010 and 2025 for articles containing the term “cancer” and one or more terms relating to psychological resources. Including studies focused on peer-reviewed articles evaluating at least one psychological resource and one mental health outcome in adult cancer patients. A total of 95 studies (N = 21,683) were included after a formal screening process. Results: Risk of Bias in Non-randomized Studies—of Exposures (ROBINS-E) assessments of the risk of bias showed the overall quality of the included studies, with 89% of studies having a low or moderate risk of bias. The review identified 16 psychological resources. We described each resource’s impact based on the strength of current empirical evidence. Optimism, resilience, hope, and self-compassion emerged as the most prominent predictors of reduced psychological distress. By analyzing study designs, these resources were organized into a functional hierarchy reflecting their specific roles within the coping process. Conclusions: Based on this categorization, we propose a conceptual model illustrating the interplay between these resources. This framework suggests a theoretical basis for future empirical validation and provides directions for designing targeted psychological interventions.

Cancers doi: 10.3390/cancers18152524

Authors: Joshua Mijares Eric Gan Neil K. Jairath Judy Hamad Ahmed Alomari Vignesh Ramachandran Syril Keena T. Que

Background: Histopathologic grading is an essential step in guiding treatment recommendations and follow-up for cutaneous lesions. However, inter-observer variability in determining differentiation of cutaneous squamous cell carcinoma (cSCC) and dysplasia of melanocytic nevi remain a challenge. Retrieval-augmented generation (RAG)-assisted artificial intelligence may offer educational and diagnostic support in this process. Methods: Two isolated RAG pathways using Claude 4.5 Opus, each grounded via ChromaDB vector retrieval of task-specific literature, graded 60 cSCC cases by differentiation and 67 melanocytic nevus cases by dysplasia. Each case was analyzed three times, with the majority result used as the final grade. Concordance with reference dermatopathologist grading was calculated with 95% Wilson score confidence intervals; inter-rater reliability was assessed using Cohen’s kappa. Results: For cSCC, the LLM achieved 90.0% concordance (95% CI, 79.9–95.3%) with excellent agreement (κ = 0.85, 95% CI, 0.74–0.96). For nevi, concordance was 44.8% (95% CI, 33.5–56.6%) with agreement not statistically distinguishable from chance (κ = 0.072, 95% CI, −0.10–0.24). Discordant nevus classifications skewed toward the moderately dysplastic category (65.7% of LLM classifications vs. 41.8% of reference classifications), and no severely dysplastic case was concordantly classified (0/6). Conclusions: Despite an identical RAG architecture, concordance with reference dermatopathologist grading was markedly task-dependent: high for cSCC differentiation, low for nevus dysplasia grading. This pattern parallels reported human inter-rater reliability for these tasks, suggesting that task-specific validation is needed before clinical or educational use.

Cancers doi: 10.3390/cancers18152521

Authors: Kang Hu Qichen Ye Rongrong Zhao Chao Ma Xiao Zhang Tianhao Xie Chenye Shao Cheng Ding Jun Zhao Hao Ding

Background: Mesothelioma is a rare but highly aggressive malignancy strongly associated with asbestos exposure. Owing to its long latency and poor prognosis, its burden requires systematic evaluation. Methods: Data on prevalence, incidence, deaths, disability-adjusted life years (DALYs), and age-standardized rates were extracted from the Global Burden of Disease Study 2023. The estimated annual percentage change, Joinpoint regression, Das Gupta decomposition, and Nordpred forecasting were used to assess temporal trends, identify turning points, quantify demographic and epidemiological contributions, and project future burden through 2045. Results: From 1990 to 2023, the absolute burden of mesothelioma in China increased substantially. Prevalent cases rose by 189%, incident cases by 150%, DALYs by 98%, and deaths by 142%. Males consistently showed a higher burden than females, and the burden was concentrated mainly among middle-aged and older adults. The age-standardized prevalence rate and age-standardized incidence rate increased, whereas the age-standardized DALY rate and age-standardized mortality rate remained stable or declined slightly. Decomposition analysis indicated that population growth and aging were the principal drivers of increased DALYs and deaths, while epidemiological change contributed negatively. Projections suggested that deaths may continue to increase through 2045, despite declining age-standardized fatal burden. Conclusions: This is the first update of the burden of mesothelioma in China over the past thirty-four years. The absolute burden of mesothelioma in China, as estimated by the GBD study, increased markedly, largely driven by demographic changes. Strengthening asbestos exposure surveillance, diagnostic standardization, and cancer registration systems would enable burden estimates to be derived from directly observed and certified data rather than relying primarily on model-based assumptions, while potentially identifying previously unrecognized sources of asbestos exposure.

Cancers doi: 10.3390/cancers18152523

Authors: Jiro Kimura Kosei Takagi Tomokazu Fuji Kazuya Yasui Takeyoshi Nishiyama Toshiyoshi Fujiwara

Background/Objectives: Lung metastasis (LM) is the most common type of extrahepatic metastasis after hepatectomy for hepatocellular carcinoma. However, the predictive factors for LM after hepatectomy for hepatocellular carcinoma remain incompletely characterized. This study aimed to examine the predictive factors for LM after hepatectomy for hepatocellular carcinoma and clarify the association between preoperative biomarkers and LM. Methods: We analyzed data of 644 consecutive patients with hepatocellular carcinoma who underwent primary hepatectomy between July 2003 and December 2023. Patients were divided into two groups: LM (+) and LM (−). Additionally, the association between perioperative factors and LM was investigated. Subsequently, a risk model was developed to predict LM. Results: Of the 644 patients, 43 (6.7%) experienced LM. Regarding biochemical scores, only the proportion of high Controlling Nutritional Status (CONUT) score (≥3) was significantly different (43.9% in the LM (−) group vs. 60.5% in the LM (+) group, p = 0.04). In multivariable analysis, a high CONUT score, tumor size, and microvascular invasion were identified as independent predictive factors for LM. The risk model exhibited accuracy with an area under the curve of 0.93, 0.85, and 0.83 in the 1-, 3-, and 5-year LM, respectively. Conclusions: The present study demonstrated an association between CONUT score and LM after primary hepatectomy for hepatocellular carcinoma and found that a high CONUT score is a complementary predictive factor for LM.

Cancers doi: 10.3390/cancers18152522

Authors: Massimiliano Domenico Rizzaro Claudia Fanizzi Giorgio Fiore Luigi Gianmaria Remore Guido Del Vecchio Elena Scagliotti Giovanni Pratelli Stefano Borsa Stefania Elena Navone Ilaria Bertorelli Luca Enrico Sironi Gabriella Roda Giovanni Marfia Manuela Caroli Marco Locatelli

Background/Objectives: Recurrent glioblastoma has a poor prognosis and no universally accepted standard of care. Regorafenib has been investigated in this setting, but its use may be limited by treatment-related toxicity. This study evaluated the feasibility, safety, and clinical outcomes of reduced-dose regorafenib in patients with recurrent IDH-wildtype glioblastoma. Methods: We retrospectively analyzed 21 patients with recurrent IDH-wildtype glioblastoma (WHO 2021) treated at a single center after progression according to the Stupp protocol. Regorafenib was started at 80 mg/day on the standard 3-weeks-on/1-week-off schedule. We assessed overall survival from diagnosis (OS1) and from first progression (OS2), progression-free survival from diagnosis (PFS1) and from first progression (PFS2), treatment exposure, dose modifications, and treatment-related adverse events (CTCAE v5.0). Results: Median PFS2 was 5 months (95% CI, 3–8), median OS2 was 6 months (95% CI, 5–10), and median OS1 was 21 months (95% CI, 15–27). No grade ≥ 3 adverse events occurred, and no patient discontinued treatment permanently because of toxicity. Conclusions: In this retrospective single-center cohort, reduced-dose regorafenib was feasible and well tolerated in selected patients. These descriptive, hypothesis-generating findings warrant prospective studies to define the role of individualized regorafenib dosing in recurrent glioblastoma.

Cancers doi: 10.3390/cancers18152520

Authors: Sandra López Gordo Humberto M. Pontillo Zile Lidia Blay Aulina Marta Eguía Larrea Anna Garcia-Monferrer Raquel Arranz Jimenez Isabel Prieto Nieto Cristina Serra-Serra Elisa York Pineda

Axillary lymph node staging remains a cornerstone of the surgical management of breast cancer. Conventional axillary lymph node dissection (ALND) has historically been the standard procedure for evaluating nodal involvement; however, it is associated with significant morbidity, including lymphedema, sensory disturbances, and reduced shoulder mobility. Over the past few decades, minimally invasive surgery has demonstrated clear benefits in multiple surgical fields, particularly in reducing postoperative morbidity, improving recovery, and enhancing cosmetic outcomes. In breast surgery, these principles have been progressively incorporated into clinical practice. Endoscopic techniques were first introduced in the late 1990s as a minimally invasive alternative to axillary lymph node dissection. Early studies have demonstrated the technical feasibility of endoscopic axillary lymphadenectomy (EALND), reporting adequate lymph node retrieval and acceptable perioperative outcomes. Although the widespread adoption of sentinel lymph node biopsy and the progressive de-escalation of axillary surgery have limited the diffusion of this approach, the potential advantages of minimally invasive techniques appear to be applicable to axillary surgery. In recent years, minimally invasive approaches, including endoscopic and robot-assisted procedures, have been expanded in breast surgery and are now being explored for axillary management. Advances in instrumentation, optics, and imaging technologies, such as fluorescence, have improved surgical visualization and may facilitate safer and more precise dissection of axillary structures. This review summarizes the historical development, technical evolution, and current evidence regarding endoscopic axillary lymphadenectomy for breast cancer. Furthermore, we discuss the potential role of this approach in the modern era of axillary de-escalation and highlight the emerging technologies that may contribute to the future development of minimally invasive axillary surgery.

Cancers doi: 10.3390/cancers18152519

Authors: Erica C. Garcia Ian J. LaRue Nathan D. Griggs Juliet V. Spencer

Background: Hormone receptor-positive breast cancer depends on estrogen and progesterone signaling, yet factors that modulate hormone receptor expression within tumors remain incompletely understood. Human cytomegalovirus (HCMV), a widespread herpesvirus detected in breast tumors, has been associated with reduced expression of estrogen receptor-α (ERα) and progesterone receptor (PR), but a direct causal relationship has not been established. Methods: ER+/PR+ breast cancer cell lines MCF-7 and T47D were infected with HCMV in vitro. ERα and PR protein levels were assessed by immunoblotting, and transcript levels of ESR1 and PGR were quantified by qPCR. To determine whether virus replication was required, parallel experiments used UV-inactivated HCMV. Results: HCMV infection resulted in a marked reduction in ERα and PR protein levels in both cell lines, accompanied by decreased ESR1 and PGR transcript levels by 48 h post-infection. Notably, UV-inactivated HCMV produced a comparable suppression of hormone receptor expression, indicating that viral gene expression and productive replication are not required for this effect. Conclusions: These findings indicate that HCMV exposure suppresses ERα and PR expression in breast cancer cells through a replication-independent mechanism. This effect suggests that viral components or host responses to infection may alter hormone receptor signaling within tumors, with potential implications for hormone receptor signaling and endocrine therapy responsiveness that warrant further investigation. Together, these results identify HCMV as a previously underrecognized modulator of hormone receptor pathways in breast cancer.

Cancers doi: 10.3390/cancers18152518

Authors: Leif Håkansson Pontus Dunér Annika Håkansson

Cancer progression is driven by early dysregulation of the immune system and tumor-intrinsic mechanisms. Hypoxia, lactate accumulation and IL-6 signaling induce highly overlapping tumor-promoting effects, including angiogenesis, epithelial–mesenchymal transition, metastasis, immune evasion and treatment resistance, suggesting that these pathways interact and amplify one another. This parallel activation complicates therapeutic targeting, as inhibition of one pathway may be compensated for by another. Increased proteolytic activity emerges early during tumor development and profoundly alters immune regulation. We recently identified a protease-generated albumin fragment, the IL-6-inducing factor (IL-6IF), which triggers pathological IL-6 production. IL-6 in turn enhances both HIF-1α expression and nuclear translocation, promotes glycolysis and lactate production, and forms positive feedback loops with STAT3 and multiple signaling pathways. Together, these mechanisms integrate into a self-sustaining IL-6/HIF-1α/STAT3 axis that drives tumor progression and suppresses anti-tumor immunity. The strong overlap among IL-6, its enhancing loops and hypoxia-driven mechanisms highlights IL-6 as a central regulator of metabolic and immunological reprogramming in cancer. However, a broad IL-6 blockade can impair physiological immune function. Selective inhibition of IL-6IF offers a novel strategy to prevent pathological IL-6 production while preserving physiological IL-6-dependent immune function required for effective tumor control. Reducing pathologically enhanced IL-6 synthesis by targeting IL-6IF, therefore, might represent a potential therapeutic approach to disrupt multiple tumor-promoting pathways simultaneously and may thereby improve responsiveness to cancer immunotherapy.

Cancers doi: 10.3390/cancers18152517

Authors: Jia Qi Ming Cai Xiaowen Wang Peng Zhang Jiani Wang Jiezhong Wu Weiling Huang Wenxuan Wu Kunpeng Hu Xiaoyuan Liang

Triple-negative breast cancer (TNBC) is an aggressive subtype lacking effective targeted therapies. The molecular drivers of its progression and metabolic reprogramming remain unclear. Here, we identify cell division cycle-associated 4 (CDCA4) as a novel oncogenic driver in TNBC. Analysis of the TCGA-BRCA dataset, including 1085 breast cancer tissues and 112 normal tissues, showed that CDCA4 expression was significantly upregulated in breast cancer tissues. Subgroup analysis of TCGA-BRCA samples further showed higher CDCA4 expression (fold change = 1.707) in TNBC than in non-TNBC samples [TNBC, n = 116; non-TNBC, n = 984]. Survival analysis demonstrated that high CDCA4 expression was associated with poorer overall survival, with a hazard ratio of 1.54 (log-rank p = 0.0053). Functional assays demonstrated that CDCA4 knockdown suppresses proliferation, migration, invasion, and tumor growth in vitro and in vivo, whereas overexpression exerts opposite effects. RNA-sequencing revealed that CDCA4-regulated genes are enriched in lipid metabolism and mTOR signaling pathways. Mechanistically, CDCA4 depletion reduces intracellular lipids and the expression of lipogenic enzymes (FASN, ACC1). We show that CDCA4 activates mTOR and increases the nuclear active form of SREBP1, enhancing its promoter occupancy. Pharmacological mTOR inhibition reverses CDCA4-induced malignancy and metabolic alterations. Furthermore, Our findings suggest that SESN2 may contribute to CDCA4-mediated activation of mTOR signalling. SESN2 knockdown attenuates mTOR signaling and negates the pro-tumorigenic effects of CDCA4 overexpression. Collectively, these findings demonstrate that CDCA4 drives TNBC progression and lipid reprogramming via the SESN2/mTOR/SREBP1 axis, positioning CDCA4 as a potential prognostic biomarker and therapeutic target.