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.

Cancers doi: 10.3390/cancers18152516

Authors: Luca Ruotolo Alessandro Ferrero Andrea Ruzzenente Felice Giuliante Vincenzo Mazzaferro Umberto Cillo Salvatore Gruttadauria Fabrizio Di Benedetto Giorgio Ercolani Matteo Ravaioli Giuseppe Maria Ettorre Andrea Belli Giovanni Vennarecci Raffaele Dalla Valle Elio Jovine Francesca Ratti on behalf of the I Go MILS Collaborative Group on behalf of the I Go MILS Collaborative Group

Background: The adoption of robotic surgery in minimally invasive liver surgery has accelerated globally in the last decade, yet its impact on clinical outcomes and the associated benefits remain to be explored. Methods: The study analyzed 8928 minimally invasive liver resections recorded in the I Go MILS registry between 2015 and 2025. Temporal trends in surgical approach, Pringle maneuver utilization, conversion to open surgery, and postoperative morbidity were assessed using Cochran–Armitage and Spearman tests. Case-mix evolution was quantified by the Kawaguchi–Gayet difficulty score. Results: Robotic utilization increased monotonically from 10.4% to 42.2%, while fully laparoscopic procedures declined from 89.6% to 57.8%. Despite this transition, aggregate conversion and morbidity showed no significant temporal trends. Stratified analysis demonstrated lower observed conversion rates in the robotic group and a progressively narrowing difference in morbidity. Overall case-mix complexity increased significantly, driven exclusively by the laparoscopic arm, while the robotic case mix remained structurally stable. Conclusions: Aggregate outcome stability during the robotic transition suggests progressive case-mix complexification rather than technological stagnation. The robotic platform seems to be associated with an apparent conversion advantage; its higher observed morbidity may be attributable to structural differences in operative difficulty. Robotics act not as a substitute for laparoscopy but as a complementary approach applied to more complex resections.

Cancers doi: 10.3390/cancers18152515

Authors: Marko Novak Andraž Perhavec Barbka Novak Supe Olga Blatnik Marija Skoblar Vidmar Mojca Unk Sonja Kramer Saša Marušič Manuel Ramanović

Background/Objectives: The aim of this study was to determine the oncologic outcomes for adult patients with primary extremity soft tissue sarcoma (ESTS) treated at the sarcoma referral center in the Republic of Slovenia. Methods: Patients from a prospectively maintained institutional database treated between January 2009 and December 2023 were retrospectively analyzed. The cohort was stratified into a high-risk group (HRG) and a low-risk group (LRG). Survival analyses focused on the HRG. Multivariable Cox models were constructed for local recurrence-free survival (LRFS) and distant metastasis-free survival (DMFS), and predictors of major wound complications were evaluated using multivariable logistic regression. Results: Among 315 included patients, 242 (76.8%) were in the HRG. In this group the median age was 61.5 years, 82.6% of tumors were in the lower extremity, and median tumor size was 9.0 cm. The most common histological subtype was undifferentiated pleomorphic sarcoma (28.5%). Clear margins were achieved in 86.8%, major postoperative complications occurred in 19.0%, and 60.7% of patients underwent radiotherapy. Local recurrence developed in 11.2%, regional recurrence in 5.0%, and distant metastasis in 32.6%. The corresponding 5-year overall survival, disease-specific survival, LRFS, and DMFS were 69.8%, 73.7%, 87.9%, and 66.8% in the HRG, respectively. In the LRG, only one local recurrence occurred and the 5-year LRFS was 100.0%. Preoperative radiotherapy showed a borderline association with major wound complications in the HRG (OR 2.70, 95% CI 1.00–7.28, p = 0.050). Tumor grade and size remained independent predictors of distant metastases, whereas margin status was not significantly associated with LRFS or DMFS. The primary amputation rate in the whole series was 2.9%. Conclusions: Treatment of primary ESTS patients in a specialized national referral cancer center achieved good overall survival (69.8%), a high limb-salvage rate (97.1%), and good local control, affirming that routine primary amputation is rarely needed. Outcomes in high-risk histologies remained driven mainly by distant metastases and showed clear histology-specific differences, whereas low-risk histologies had excellent outcomes with surgery alone. Preoperative radiotherapy was associated with a higher risk of major wound complications.

Cancers doi: 10.3390/cancers18152514

Authors: David Mourath Nour Susaeg Romdhani Viveka Bergman Jonathan Siikanen Thuy A. Tran Ali Alhuseinalkhudhur Anna Kistner Renske Altena

Background: Antibody-drug conjugates (ADCs) are gaining rapidly expanding clinical utility, with a growing number of approved indications across compounds that differ in target antigen, payload mechanism, and linker design. However, treatment response remains heterogeneous, and predictive biomarkers to identify patients most likely to benefit are limited. Given that ADC efficacy depends on sufficient target antigen expression and distribution across tumor lesions, positron emission tomography (PET) imaging offers a unique opportunity to non-invasively assess whole-body target availability. We therefore conducted a systematic literature review to evaluate the relationship between PET-measured tumor antigen expression and the therapeutic response to ADCs targeting the same antigen. Method: A systematic comprehensive search of PubMed, EMBASE and Web of Science databases was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, using terms related to targeted PET, ADC treatment and response assessment. Article screening, eligibility assessment, and data extraction were performed independently using predefined criteria by two reviewers. Disagreements were resolved by consensus. Results: A total of 5628 records were identified. After removing duplicates, 4323 records were screened by title and abstract. Fifty-eight underwent full-text review and seven were included in the final review. Four trials investigated human epidermal growth factor receptor 2 (HER2)-targeted therapy, one Nectin-4, one mesothelin and one STEAP1. In all HER2- and Nectin-4-related trials, patients with a higher uptake on targeted PET had a higher probability of responding to targeted treatment. Included trials were generally small and had a moderate risk of bias. Conclusion: Targeted PET imaging showed potential to predict treatment response in trials evaluating clinically active agents. Additional clinical trials across a broader range of targets, along with standardized acquisition protocols and harmonized study designs, are needed to enable the integration of this technique into clinical practice and ultimately translate its benefits to patients.

Cancers doi: 10.3390/cancers18152513

Authors: Massimo Martino Violetta Marafioti Martina Pitea Gaetana Porto Giorgia Policastro Filippo Antonio Canale Virginia Naso Caterina Alati

Background: The treatment paradigm for relapsed/refractory (R/R) large B-cell lymphoma (LBCL) has undergone significant change with the advent of CD19-directed chimeric antigen receptor T-cell (CAR-T) therapies and CD20 × CD3 bispecific antibodies (BsAbs). Although both approaches have shown high response rates in single-arm studies, the absence of prospective randomized head-to-head comparisons has resulted in true clinical equipoise. Methods: A narrative synthesis was conducted, incorporating pivotal and updated phase 2 and 3 trial data, real-world evidence, and published meta-analyses. Results: In the second-line setting, CAR-T therapy demonstrates superior event-free survival, progression-free survival, and overall survival compared to standard-of-care chemo-transplant regimens. In the third-line setting, a pooled meta-analysis indicates significantly higher complete response rates for CAR-T compared with BsAbs, as well as superior 12-month progression-free survival. BsAbs provide immediate availability, greater accessibility, more favorable neurotoxicity profiles, and are feasible for frail or elderly patients. Real-world data show that BsAb complete response rates are consistently lower than those observed in clinical trials, whereas CAR-T real-world effectiveness closely aligns with pivotal trial outcomes. Emerging phase 3 data on fixed-duration and monotherapy bispecific regimens suggest that a genuine, if less mature, curative fraction may also be achievable among BsAb-treated complete responders. Conclusions: CAR-T therapy remains the standard of care for fit, eligible patients with R/R LBCL in second- and third-line settings with curative intent, providing superior depth and durability of response and a growing potential for long-term cure. BsAbs constitute a critical therapeutic alternative for patients ineligible for CAR-T, those with rapidly progressive disease, frail or elderly individuals, and as bridging strategies. A patient-centered, scenario-specific clinical decision framework is recommended.

Cancers doi: 10.3390/cancers18152512

Authors: Aydin Talat Baydar Muhammed Bayindir Aysenur Coskun Baydar Baran Taskala

Background/Objectives: Surgery for extradural spinal metastases must balance neurologic and mechanical goals against limited survival. We evaluated whether a predefined three-tier surgical-intensity classification aligned with established measures of operative burden and whether intensity was associated with 90-day mortality or overall survival. Methods: This retrospective cohort included 141 adults with extradural spinal metastases operated on between June 2020 and December 2025. Surgical intensity was classified as low, moderate, or high. SMII was calculated for all patients as a secondary convergent construct measure. Firth penalized logistic regression and Cox regression adjusted for performance status, albumin, and tumor biology. Results: There were 37 low-, 39 moderate-, and 65 high-intensity procedures. Median SMII increased from 6 [5–11] to 14 [11.5–18.5] and 23 [18–28] across the three groups (p < 0.001; Spearman ρ = 0.711). High-intensity surgery was concentrated among unstable SINS lesions and was associated with longer operative time, transfusion, and hospitalization. Ninety-day mortality was 24.3%, 12.8%, and 23.1% for low-, moderate-, and high-intensity procedures, respectively. High intensity was not statistically associated with 90-day mortality (adjusted OR 0.81, 95% CI 0.28–2.36) or overall survival (adjusted HR 1.08, 95% CI 0.65–1.80). ECOG ≥ 3 and aggressive solid/unknown tumor biology were associated with worse outcomes. Conclusions: The intensity classification showed strong convergent validity with SMII and perioperative burden. Within this surgically selected cohort, intensity was not independently associated with early mortality or overall survival, although clinically meaningful differences cannot be excluded. Operative magnitude should be interpreted alongside mechanical need, systemic reserve, and tumor biology.

Cancers doi: 10.3390/cancers18152511

Authors: Alayna. N. Hay Lauren Ruger Elliana R. Vickers Sheryl Coutermarsh-Ott Eli Vlaisavljevich Joanne Tuohy

Background: Osteosarcoma (OS) is a devasting bone cancer that occurs primarily in pediatric patients, and pet dogs, and treatment options have not advanced in decades. There is a profound need for advancement of treatment options to improve patient prognosis given the grim 70% 5-year survival rate for human patients, and 10–12-month median survival for canine patients. A major hurdle in advancing treatment options is overcoming the immunosuppressive tumor microenvironment to mitigate metastatic disease progression—the leading cause of mortality in OS patients. Methods: We investigated the ability of a mechanical focused ultrasound ablation modality, histotripsy, to induce acute immunomodulation in canine patients with spontaneously occurring OS. Results: Immunomodulation was evident locally and systemically. Tumor gene signatures indicated upregulation of pro-inflammatory signaling pathways and T-cell receptor signaling, and B-cell activation, and systemically, increased monocyte activation was observed within 5 days post-histotripsy ablation. A subset of patients who received histotripsy prior to definitive standard-of-care exceeded the reported expected median survival time of 10–12 months for canine OS patients that received definitive standard-of-care only. Conclusions: Our results demonstrate the promising potential of histotripsy to overcome the immunosuppressive tumor microenvironment.

Cancers doi: 10.3390/cancers18152510

Authors: Wenqiao Zhou Xingchen Liu Junying Hu Yu Chen Feng Liu Bing Zhong

Olfactory neuroblastoma (ONB), also known as esthesioneuroblastoma, is a rare malignant tumor arising from the olfactory epithelium of the sinonasal tract. Surgery combined with radiotherapy remains the standard treatment for localized disease, whereas chemotherapy is mainly used in advanced or recurrent cases. However, recurrent and metastatic ONB continues to present major therapeutic challenges, and traditional staging and histological grading systems cannot fully explain the marked differences in clinical behavior among patients. The primary objective of this review is to summarize recent advances in the molecular pathology, tumor microenvironment (TME), and emerging targeted therapeutic strategies in ONB. Emerging genomic and transcriptomic studies suggest that ONB comprises biologically heterogeneous tumors with distinct molecular and transcriptional programs associated with proliferation, neuroendocrine differentiation, angiogenesis, and stromal remodeling. Furthermore, we explore the increasing attention directed toward the TME, including immune-cell infiltration, angiogenic signaling, and immune checkpoint expression, which may influence therapeutic response. These molecular findings have generated interest in several potential targeted treatment strategies, including peptide receptor radionuclide therapy (PRRT), anti-angiogenic therapy, epigenetic-targeted therapy, immunotherapy, and DNA-damage-response-targeted approaches. Ultimately, although the current evidence remains limited because of the rarity of the disease, novel therapeutic strategies for ONB are emerging. In addition to summarizing the current landscape, this review discusses the translational challenges and future directions for precision oncology and biomarker-driven therapy, aiming to provide insights for improving individualized patient management.

Cancers doi: 10.3390/cancers18152509

Authors: Kristina Fünfer Marco Mozaffari Hanna Illium Sophia Schlingmann Oliver Mayer Maximillian Deußing Elke Sattler Julia Welzel Sandra Schuh

Background/Objectives: Rapid optical assessment of freshly excised basal cell carcinoma (BCC) specimens may shorten the interval between excision and margin evaluation. This prospective pilot study estimated the diagnostic performance of ex vivo line-field confocal optical coherence tomography (LC-OCT) for detecting residual BCC at lateral surgical margins, using histopathology as the reference standard. Methods: Fifty-five clinically suspicious lesions from 48 patients were examined at two centers. Results were analyzed for the complete cohort and for a post-training inclusion phase comprising 32 lesions from 31 patients. Overall lesion-level consensus classifications were recorded separately from classifications of the four clock-face quadrants. Lesions with a negative overall LC-OCT assessment and at least one non-evaluable quadrant were classified as indeterminate and excluded from the primary lesion-level analysis. Thirteen lesions also underwent exploratory ex vivo fusion confocal microscopy (evFCM). Results: In the inclusion phase, 125 of 128 quadrants were evaluable. Thirteen true-positive, 106 true-negative, 2 false-negative, and 4 false-positive quadrant results yielded 86.7% sensitivity, 96.4% specificity, and 95.2% accuracy. At the lesion level, 2 of 32 results were indeterminate. Among the remaining 30 lesions, LC-OCT yielded 5 true-positive, 22 true-negative, 2 false-negative, and 1 false-positive results, corresponding to 71.4% sensitivity, 95.7% specificity, and 90.0% accuracy. The evFCM analysis was descriptive because the subset was small and nonconsecutive. Conclusions: Ex vivo LC-OCT showed promising specificity and overall accuracy for assessing lateral BCC margins after training. The limited number of margin-positive lesions, indeterminate results, clustered quadrant data, and absence of systematic deep-margin imaging require cautious interpretation. LC-OCT should not replace histopathological margin assessment on the basis of the present data.

Cancers doi: 10.3390/cancers18152508

Authors: Theo F. Hanson Margaret Hua Jorge Zarate Rodriguez Lauren H. Yaeger Shreya Rao Chilukuri Nikolaos A. Trikalinos Chet W. Hammill

In 2010, the World Health Organization (WHO) standardized neuroendocrine neoplasm terminology, dividing these tumors by differentiation into well-differentiated neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas. Registries such as the Surveillance, Epidemiology, and End Results (SEER) program and the National Cancer Database (NCDB) store legacy codes predating this framework, raising concern that registry-based research carries nomenclature errors into the clinical literature. We performed a scoping review of research published in 2012–2022 that used SEER and/or the NCDB to study gastroenteropancreatic neuroendocrine tumors, charting 170 articles (from 1079 citations) against the 2010 classification, with forward citation analysis (OpenAlex, Semantic Scholar) measuring downstream citation exposure. Of 141 assessable studies, 88% (n = 124) applied the nomenclature inaccurately: 82.3% included poorly or undifferentiated neoplasms within neuroendocrine tumor cohorts (mean 18.7% of the cohort) and 9.9% conflated database differentiation grade with WHO proliferation grade; appropriate usage did not improve over time. These discordant studies accumulated 7323 citations across 5145 works, with 87.9% cited by at least one review (1075 distinct reviews) and six cited by major guidelines (NCCN, ESMO, ENETS). Across research published from 2012 to 2022, nomenclature discordance was widespread, persistent throughout the study period, and present in studies frequently cited by the secondary and guideline literature. Because these cohorts incorporate more aggressive and poorly or undifferentiated neoplasms, their aggregate outcome estimates are likely biased toward a poorer prognosis, potentially overstating the aggressiveness of well-differentiated neuroendocrine tumors, particularly for prognostic estimates; this review characterized cohort composition rather than quantifying the effect on any individual study’s outcomes, and whether this bias has, in turn, affected clinical decision-making was not assessed here and remains a hypothesis for future work. Journals and guideline panels should require explicit alignment with current WHO definitions for registry-based studies.

Cancers doi: 10.3390/cancers18152507

Authors: Zuzanna Rogacz Wiktoria Weronika Pacuła Wiktor Janas Magda Markiewka Paulina Wala Marcel Madej Barbara Strzałka-Mrozik

Colorectal cancer (CRC) remains one of the leading causes of cancer-related morbidity and mortality worldwide despite substantial advances in surgery, chemotherapy, targeted therapies, and immunotherapy. The limited efficacy of current treatment strategies in advanced disease and the emergence of therapeutic resistance highlight the urgent need for novel adjunctive therapeutic approaches. Increasing evidence indicates that chronic stress and sustained activation of β-adrenergic signaling promote colorectal tumor initiation, progression, angiogenesis, metastatic dissemination, and immune evasion, thereby identifying this pathway as a potential therapeutic target. Drug repurposing has emerged as an attractive strategy for accelerating the development of new anticancer therapies by identifying novel applications for clinically approved drugs with well-established safety profiles. Among these, β-blockers have gained considerable attention because of their ability to inhibit β-adrenergic signaling and modulate multiple oncogenic pathways implicated in CRC progression. Although accumulating preclinical and observational clinical evidence suggests that β-blockers may possess anticancer potential, the underlying molecular mechanisms and their translational relevance have not yet been comprehensively integrated. This review provides a critical overview of the current evidence regarding the therapeutic potential of β-blockers in CRC by integrating findings from preclinical and clinical studies. Particular emphasis is placed on the regulation of key signaling pathways, including cAMP/PKA/CREB, PI3K/AKT/mTOR, and RAS/RAF/MEK/ERK, as well as on the effects of β-blockers on tumor cell proliferation, apoptosis, angiogenesis, epithelial–mesenchymal transition, metastasis, and modulation of the tumor microenvironment and antitumor immune responses. However, significant barriers limit the translation of these findings into routine clinical practice, including the limited representativeness of preclinical models, potential hemodynamic adverse effects, and the inherent limitations of observational studies. Importantly, owing to the lack of prospective randomized clinical trials, the current evidence remains insufficient to establish the clinical efficacy of β-blockers in colorectal cancer. Although β-blockers possess several characteristics that make them attractive candidates for drug repurposing, including a well-established safety profile, widespread availability, and low cost, further mechanistic studies, prospective randomized clinical trials, and biomarker-based patient stratification are essential to determine their clinical efficacy and define their role in personalized CRC therapy.

Cancers doi: 10.3390/cancers18152506

Authors: Hazuki Nitta Masashi Mizumoto Kazushi Maruo Yoshiko Oshiro Yinuo Li Kenji Kagawa Takashi Saito Haruko Numajiri Kei Nakai Tetsuo Nonaka Hideyuki Sakurai

Background/Objectives: The optimal radiotherapy modality for World Health Organization (WHO) Grade 1 meningioma remains uncertain. Proton therapy offers dosimetric advantages through reduced radiation exposure to normal brain tissue, but comparative clinical data across contemporary radiotherapy modalities are limited. We performed a systematic review and meta-analysis comparing local control (LC) outcomes among conventionally fractionated proton therapy (CF-PT), conventionally fractionated photon radiotherapy (CF-Photon RT), Linac-based stereotactic radiosurgery/radiotherapy (Linac-based SRS/SRT), and Gamma Knife radiosurgery (GKRS). Methods: A systematic literature search of PubMed (2000–2024) was conducted to identify studies reporting LC for WHO Grade 1 meningioma treated with CF-PT, CF-Photon RT, Linac-based SRS/SRT, or GKRS. Random-effects meta-analyses were performed to estimate pooled 1- to 5-year LC rates. Random-effects meta-regression analyses were conducted using modality, age, sex, and gross tumor volume (GTV) as covariates. Results: Twenty-four studies comprising 4673 patients were included in the meta-analysis. Median GTVs were larger in the CF-PT and CF-Photon RT cohorts than in the Linac-based SRS/SRT and GKRS cohorts. All modalities achieved excellent LC: 5-year LC rates were 95.9% for CF-PT, 93.0% for CF-Photon RT, 95.3% for Linac-based SRS/SRT, and 89.8% for GKRS. Meta-regression showed no significant association between modality or GTV and LC. In the CF-PT cohort, 5-year overall survival was 93.1%. Conclusions: Major radiotherapy modalities achieved excellent and comparable LC. Notably, CF-PT and CF-Photon RT maintained favorable LC despite being used for larger tumors than stereotactic approaches. Future studies are needed to evaluate long-term tumor control and treatment-related toxicity to define optimal treatment strategies.

Cancers doi: 10.3390/cancers18152505

Authors: Blackberrie Eddins Ting-Chun Kuo Hyungju Kwon Homan Kang Maged Henary Satoshi Kashiwagi Robert M. Hoffman Michael Bouvet

Background/Objectives: The majority of thyroid cancer patients are diagnosed with papillary thyroid cancer. A complete R0 resection significantly lowers cancer recurrence risk for high-risk papillary thyroid cancer but can be difficult to achieve because tumor margins are not easily visualized. The purpose of the present narrative review is to describe current work and future directions in fluorescence-guided thyroid cancer surgery. Methods: PubMed and Google Scholar were used to identify 45 articles that focused on fluorescence labeling and imaging of thyroid cancer published through February 2026 using the search terms “thyroid cancer” AND (“fluorescence imaging,” OR “NIR imaging” OR “optical imaging”) OR “fluorescence guided thyroidectomy”. Standalone abstracts and publications not available in English were excluded. Results: 17 fluorescent probes were shown to visualize tumor margins and micrometastases, 3 probes were able to visualize nerves, and 2 probes targeted lymph nodes. Most studies were done using animal models. Two probes (EMI-137, which targets tumors, and bevonescein, which targets nerves) were tested in clinical trials with good safety profiles. Conclusions: Several tumor-targeted fluorophores and optical imaging strategies have shown promise for thyroid cancer localization, margin assessment, lymph node evaluation, and nerve visualization; however, most remain preclinical, and clinical utility will require standardized dosing, imaging thresholds, safety assessment, and outcome-based validation with multicenter clinical trials.

Cancers doi: 10.3390/cancers18152504

Authors: Derya Koyun Seher Yüksel Sinem Civriz Bozdağ Timur Tuncalı Işınsu Kuzu Muhit Özcan

Background: Post-treatment erythrocytosis (PT-E+)—an increase in red blood cell counts after therapy—is an uncommon but reproducible finding in a subset of Hodgkin lymphoma (HL) survivors, and its biological basis remains undefined. Methods: A targeted DNA sequencing panel of 33 genes was used at diagnosis and during follow-up in PT-E+ patients and HL controls who did not develop erythrocytosis (E−; those without increased red blood cells). Germline (inherited) and somatic (acquired) genetic variants were compared, and changes in variant frequency over time were assessed. Results: PT-E+ patients had a unique molecular profile. They showed inherited variants in genes that regulate oxygen sensing and red blood cell production (EPAS1, EGLN3, HIF3A, PKLR, SH2B3, and RAB4B-EGLN2). Rare, acquired mutations affecting hypoxia, HIF, and EPO pathways (EGLN1/2/3, EPAS1, HIF1A/3A, VHL, EPO, and PKLR) were also found. These changes did not appear in E− controls, who instead had common clonal hematopoiesis mutations (DNMT3A, TET2, ASXL1, and JAK3). Most somatic variants in the hypoxia pathway in PT-E+ patients decreased or disappeared after treatment, which suggests these changes are temporary and influenced by the surrounding environment. Conclusions: PT-E+ is biologically different from polycythemia vera and from idiopathic or JAK2-unmutated erythrocytosis. Both inherited risk and HL-related hypoxic or inflammatory stress are present. This supports a two-hit model, in which genetically primed red blood cell pathways respond strongly to disease-related triggers. These results suggest a new way to understand erythrocytosis after HL treatment.

Cancers doi: 10.3390/cancers18152503

Authors: Martin Furlepa Isabella Watts Aisling S. Carr

In the published publication [...]

Cancers doi: 10.3390/cancers18152502

Authors: Theresa Walz Freerk T. Baumann Katharina Leuchte Damir Zubac Philomena Wawer Matos Reimer Konrad R. Koch Michael Mendes Wefelnberg

Background/Objectives: The aim of the present study was to assess the influence of physical activity on retinal microvascularization in patients with uveal melanoma (UM) and nevus. In addition, vascular differences between tumor and nevus patients as well as the interaction effect of physical activity (PA) and group on retinal microvascular density (MVD) were analyzed. Methods: This cross-sectional, observational clinical study was conducted at the outpatient ophthalmic oncology department at the Center for Integrated Oncology of the University Hospital Cologne (between April 2024 and July 2025). Patients with confirmed uveal melanoma or choroidal nevus were enrolled. Physical activity and retinal MVD via optical coherence tomography angiography were assessed. In addition, regression analyses were performed. Results: A total of 42 participants were enrolled with a mean age of 56.14 (±13.48) years (nevus) and 63.45 (±13.76) years (UM). UM eyes (N = 20) demonstrated significantly reduced MVD in both the superficial and deep layer compared to Nevus (N = 22, all p < 0.001, η2 = 0.155–0.190), while UM eyes showed greater mean vessel length (B = 5.54, p = 0.009, η2 = 0.104). Physical activity was positively associated with MVD in the superficial layer, including vessel area density (B = 1.07, p = 0.022, η2 = 0.133) and vessel length density (B = 0.28, p = 0.028, η2 = 0.119), independent of group. No significant associations were found in the deep layer and no interaction effects between group and PA were detected. Conclusions: Our findings suggest that habitual PA is positively associated with retinal MVD in the superficial layer, independent of diagnostic group, and may partially counteract tumor-induced as well as treatment-related microvascular disruption. As a low-risk and accessible intervention, PA holds promise as a supportive strategy in the oncological management of UM.

Cancers doi: 10.3390/cancers18152501

Authors: Cesare Mazzaro Riccardo Bomben Laura Gragnani Marcella Visentini Paolo Agostinis Silvia Marri Anna Linda Zignego Valter Gattei

Hepatitis C virus (HCV) infection is a major cause of chronic hepatitis, affecting approximately 50 million people worldwide. An estimated 15–30% of individuals with chronic HCV infection progress to cirrhosis, which may subsequently develop into hepatocellular carcinoma. Beyond liver disease, HCV is associated with a broad spectrum of extrahepatic manifestations, particularly mixed cryoglobulinemia (MC) and B-cell non-Hodgkin lymphoma (B-NHL). Persistent viral infection induces chronic antigenic stimulation of B lymphocytes, a key pathogenic mechanism underlying the progression from MC to overt B-NHL. These observations have important therapeutic implications and support the use of antiviral therapy as a cornerstone of treatment. The efficacy of direct-acting antivirals (DAAs) has been well established in patients with HCV-related MC and cryoglobulinemic vasculitis. Several studies have shown that DAAs achieve sustained virologic response rates exceeding 90%, often approaching 100% in contemporary cohorts. Viral eradication is frequently associated with clinical and immunological improvement, as well as regression of cryoglobulinemia. Encouraging outcomes have also been reported in patients with HCV-associated indolent B-NHL, particularly marginal zone lymphoma, although confirmation in larger studies with longer follow-up is needed. In patients with HCV-positive aggressive lymphomas, DAAs have been safely administered in combination with immunochemotherapy, yielding promising results. This review summarizes the current evidence on HCV-associated MC and B-NHL and discusses the impact of DAA therapy on the clinical course and management of these disorders.

Cancers doi: 10.3390/cancers18152500

Authors: Shen Yang Guangsheng Zhu Zixuan Hu Mingbiao Li Jianfang Wang Zhanrui Zhang Jun Chen Renwang Liu

Background: Neutrophil extracellular traps (NETs) promote tumor progression and immune evasion across multiple cancers. However, the mechanisms governing NET formation (NETosis) within the tumor immune microenvironment remain incompletely understood. Low P2RY13 expression is associated with the pro-tumor activity of neutrophils in lung adenocarcinoma. Methods: Pan-cancer bioinformatics analyses were performed, including differential gene expression, prognostic, tumor-infiltrating immune cell, and NET scoring analyses. Single-cell profiling was conducted using the Tumor Immune Single-cell Hub 2 database. Immunohistochemical (IHC) and multiplex immunofluorescence (mIF) staining of tissue microarrays (TMAs) was performed to validate findings in lung adenocarcinoma (LUAD), liver hepatocellular carcinoma (LIHC), and colorectal cancer (CRC). In vitro validation was conducted using gene modulation, tumor-cell-conditioned medium (CM) education, tumor-associated macrophage (TAM)-like macrophage CM transfer, immunofluorescence staining, and ELISA. Results: Bioinformatics analyses suggested that P2RY13 is frequently dysregulated in multiple cancers and that low P2RY13 expression is associated with poor prognosis and reduced immunotherapy responsiveness. Single-cell analyses revealed that P2RY13 is predominantly expressed in TAMs rather than tumor cells. Macrophages without detectable P2RY13 transcripts were markedly enriched in tumor tissues compared with paired normal tissues, and their high infiltration appeared to be associated with elevated NET scores. Tissue microarray-based IHC and mIF analyses further validated this infiltration pattern in LUAD, LIHC, and CRC. In vitro, CM from P2RY13-silenced, tumor-educated TAM-like macrophages enhanced neutrophil NETosis, whereas P2RY13 re-expression attenuated this effect. Furthermore, TMA staining indicated a positive correlation between P2RY13−CD68+ TAM infiltration and NET expression in the three malignancies. Conclusions: We identified a potentially conserved NETosis-regulating pattern in multiple cancers in which P2RY13-negative TAMs promote NET formation and are associated with adverse clinical outcomes. These findings suggest a previously unrecognized tumor-promoting mechanism and highlight potential therapeutic targets for cancer treatment.

Cancers doi: 10.3390/cancers18152499

Authors: Fjolla Rexhepi Sara Ali Akbari Mohammad Moradzad Saeed Khodayari Akhil Shukla Elodie Demontier Jean-François Lucier Anny Armas Cayarga Hugues Allard-Chamard Subburaj Ilangumaran Sheela Ramanathan

Background: IL-15 is a promising cytokine for cancer immunotherapy. IL-15 promotes differentiation and homeostasis of innate and adaptive immune cells, and their cytolytic effector functions. The IL-15 receptor is composed of IL-15Rα, IL-15Rβ and the common γc chains. IL-15 is also trans-presented as IL-15Rα:IL-15 complex to IL-15Rβ:γc on neighboring cells. IL-15Rα is dispensable for early immune response to infections and in autoimmune diabetes. The role of IL-15Rα in antitumor immune responses remains unclear. Methods: In WT, Il15−/− and Il15ra−/− mice, we studied the growth of syngeneic tumor cell lines and tumor immune surveillance against endogenous fibrosarcoma induced by methylcholanthrene (MCA). Immune gene signature and total proteome analysis were performed on MCA-induced tumors. Results: Lack of IL-15 or IL-15Rα did not enhance the growth of implanted tumor cell lines, despite reduced immune cell infiltration. MCA-induced tumor incidence was reduced in mice lacking IL-15Rα but not IL-15, although both are required for efficient tumor immunoediting. Il15−/− and Il15ra−/− tumors showed reduced Ifng expression but displayed differential modulation of Ifng-responsive genes. Proteome profiles of Il15−/− tumors, but not tumor-derived cell lines, showed significant reduction in antigen presentation pathways. B16-F10 melanoma cells expressing NLRC5, the IFNγ-induced transcriptional activator of tumor antigen presentation, still required IL-15 but not IL-15Rα for efficient tumor control. Conclusions: Our findings show that IL-15 plays a negligible role in immunosurveillance against spontaneous tumor development, whereas IL-15Rα restrains immunosurveillance. Neither IL-15 nor IL-15Rα have a significant impact on implanted tumor models, although IL-15 facilitates efficient control of highly immunogenic tumors for which IL-15Rα is dispensable.

Cancers doi: 10.3390/cancers18152498

Authors: Jianhua Wen Hualin Cao Jiayin Yu Jun Huang Hao Chen Xinyu Tan Zhuo Gong Feng Guo Zelin Cui Pengfei Luo

Background: Clear cell renal cell carcinoma (ccRCC) is characterized by marked molecular heterogeneity, aggressive clinical behavior, and prominent angiogenesis, highlighting the need to better understand the functional regulators underlying tumor progression and vascular remodeling. OTOF has previously been reported as a prognostically relevant gene in ccRCC; however, its biological function and potential involvement in tumor angiogenesis remain unclear. Methods: In the present study, we investigated the biological and pro-angiogenic roles of OTOF and explored the signaling pathways potentially involved. Results: Analysis of the TCGA-KIRC cohort confirmed that elevated OTOF expression was associated with unfavorable clinical outcomes. Functional experiments demonstrated that OTOF knockdown suppressed ccRCC cell proliferation, migration, and invasion and inhibited xenograft tumor growth. OTOF depletion also reduced intratumoral vascularization and impaired the ability of ccRCC cell-conditioned medium to promote HUVEC tube formation. Mechanistically, OTOF knockdown decreased VEGFA levels and was accompanied by reduced AKT phosphorylation and suppression of downstream HIF/VEGFA signaling. Pharmacological modulation of AKT signaling and VEGFA add-back experiments further supported the functional involvement of the AKT/HIF/VEGFA pathway in OTOF-associated angiogenesis. Conclusions: These findings extend previous observations regarding the prognostic relevance of OTOF by providing functional and mechanistic evidence that OTOF contributes to ccRCC progression and angiogenesis, at least in part, through AKT-dependent HIF/VEGFA signaling.

Cancers doi: 10.3390/cancers18152497

Authors: Christos Drosos Athina Kapsi Anthi Nikolaidou Antonis Giakountis

Non-coding RNAs (ncRNAs) are increasingly recognized as important regulators of cancer biology. Long non-coding RNAs (lncRNAs), defined as transcripts longer than 200 nucleotides, gain particular attention due to their cancer-specific expression patterns and functional roles in tumor progression, metastasis and therapeutic resistance. Although lncRNAs have been extensively studied as diagnostic, prognostic and predictive biomarkers, growing evidence indicates that they can also act as active mediators of therapeutic resistance, supporting their potential as therapeutic candidates. Here, we summarize how lncRNAs contribute to resistance against radiotherapy, chemotherapy, immunotherapy and targeted therapy, highlighting their molecular mechanisms. Next, we discuss RNA-based therapeutics as a strategy to target disease-relevant transcripts, focusing on antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), microRNA (miRNA) mimics and antimiRs, as well as approved RNA therapeutic agents, oncology-focused candidates in clinical development and emerging preclinical approaches directed against lncRNAs or lncRNA-controlled regulatory axes. Finally, we examine delivery platforms, including lipid-based nanovectors, extracellular vesicles, polymeric systems and other approaches designed to overcome key translational barriers, such as RNA instability, off-target effects, immune activation, renal clearance and inefficient tumor-specific delivery. By connecting lncRNA-mediated resistance mechanisms with RNA therapeutic strategies and delivery technologies, this review highlights lncRNA-directed RNA therapeutics as a promising yet developing approach in oncology.

Cancers doi: 10.3390/cancers18152496

Authors: Yunlong Jia Jiaxin Si Zhendong Zhang Tianxu Liu Shuman Zhen Yan Zhao Yu Wang Xuexiao Wang Jiali Wang Lihua Liu

Background: Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy with a poor prognosis, highlighting the urgent need to elucidate its molecular mechanisms to develop targeted therapies. Long non-coding RNAs (lncRNAs) play a critical role in cancer progression. However, the majority of lncRNAs involved in ESCC progression remain to be elucidated. Methods: We integrated bioinformatic analyses of the TCGA and GEO datasets to identify differentially expressed lncRNAs in ESCC, and the biological functions of the candidate lncRNA LINC01446 were investigated using loss-of-function assays in ESCC cell lines, including colony formation, wound healing, Transwell invasion, C11-BODIPY staining, malondialdehyde (MDA) quantification, and glutathione (GSH) evaluation. A nude mouse xenograft model was established for in vivo validation, and the underlying molecular mechanism was explored through RNA sequencing, fluorescence in situ hybridization (FISH), dual-luciferase reporter assays, AGO2-RIP, and rescue experiments. Results: LINC01446 was significantly upregulated in ESCC tissues and cell lines. Based on univariate analysis, high expression of LINC01446 was associated with poorer overall survival (OS). Functional studies showed that LINC01446 knockdown suppressed ESCC cell proliferation, migration, and invasion, promoted ferroptosis-related changes in vitro and was associated with increased lipid peroxidation and possible ferroptosis-related changes in vivo. Mechanistic analyses supported a regulatory relationship in which LINC01446 may function as a competing endogenous RNA (ceRNA) for miR-338-3p, thereby contributing to the upregulation of its downstream target, apurinic/apyrimidinic endodeoxyribonuclease 1 (APEX1), in ESCC cells. Moreover, APEX1 was found to be overexpressed in ESCC and associated with poor OS. Conclusions: This study suggests that the LINC01446/miR-338-3p/APEX1 regulatory axis may contribute to ESCC progression and ferroptosis-related regulation. Additionally, LINC01446 and APEX1 represent promising prognostic biomarkers and therapeutic targets for ESCC.

Cancers doi: 10.3390/cancers18152495

Authors: Francisco Call-Orellana Kishore Balasubramanian Hanyu Qiu Alexander Houpt Tushar Kanti Bhadra Georgios Toumbas Beste Gülsuna Jeffrey Zuccato Panayiotis Pelargos Abdul Basit Khan Hakeem J. Shakir

Background: Skull base plasmacytomas are rare plasma cell neoplasms arising from the clivus, sphenoid bone, and petrous apex, presenting with cranial neuropathies and bearing a high risk of progression to multiple myeloma. Optimal management remains poorly defined due to their rarity. Objective: The objectives of this study are to comprehensively characterize the clinical presentation, management strategies, and outcomes of skull base plasmacytomas and identify evolving trends in the literature. Methods: A systematic search of PubMed, EMBASE, Web of Science, and Cochrane databases was conducted, yielding 92 studies (18 case series and 74 case reports) encompassing 118 patients. Data on the demographics, symptoms, imaging, histopathology, treatment, and outcomes were extracted and analyzed. Results: The median patient age was 56 years; visual disturbances (66.1%) and headache (54.2%) were the most common presenting symptoms. The middle and posterior cranial fossae were most frequently involved, and cranial nerve VI was most affected (65.7%). Surgical resection was performed in 63.6% of cases with a gross total resection in 36%. At a median follow-up of 12 months (calculated across the entire cohort of 118 patients, including the 29 who presented with a prior diagnosis of multiple myeloma), 81.4% were alive, with symptom resolution at 38.1% or improvement at 26.2%. Recurrence occurred in 19.4% of patients, and multiple myeloma developed in 25.8% of patients without a prior diagnosis. Multiple myeloma status was the only independent predictor of survival on multivariate analysis (OR = 10.14, 95% CI: 1.63–63.04, p = 0.013). Conclusions: Skull base plasmacytomas show consistent clinical patterns but variable management strategies. Surgery is increasingly utilized; yet, its survival benefit remains unclear. Prospective multicenter studies with standardized outcome reporting and molecular profiling are needed to optimize individualized care.

Cancers doi: 10.3390/cancers18152494

Authors: Arezoo Darbandi Vittoria Raimondi Francesco Ciccarese Donna M. D’Agostino Vincenzo Ciminale

Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of an aggressive malignancy of mature T-cells termed adult T-cell leukemia/lymphoma (ATLL), as well as a spectrum of chronic inflammatory diseases. A defining feature of HTLV-1 infection is a profound dysregulation of apoptotic pathways, which is a key determinant of long-term viral persistence and favors malignant transformation. This review describes the mechanisms through which HTLV-1 gene products, including Tax and HBZ, reprogram host-cell signaling controlling the “apoptotic rheostat”, an integrated network connecting redox metabolism, and response to apoptotic cues and immune pressure. We also highlight emerging therapeutic strategies to restore sensitivity to apoptosis, including BH3-mimetic drugs and rational combination approaches. Deciphering how HTLV-1 reconfigures the apoptotic network provides a conceptual and therapeutic framework for targeting death pathway vulnerabilities in ATLL and potentially other hematological neoplasms.

Cancers doi: 10.3390/cancers18152493

Authors: Zheng Zeng Yining Chen Xiangyin Meng Yuliang Sun Junfang Yan Ke Hu Fuquan Zhang

Background/Objectives: Moderately hypofractionated radiotherapy (MHRT) may shorten treatment duration for cervical cancer but raises concerns regarding toxicity due to substantial interfractional pelvic organ motion. This prospective study evaluated the feasibility, workflow efficiency, dosimetric benefits, and acute toxicities of daily online adaptive radiotherapy (oART)-guided MHRT. Methods: Thirty patients with FIGO 2018 stage IB1–IIB or IIIC1 cervical squamous cell carcinoma receiving definitive chemoradiotherapy were prospectively included between September 2023 and April 2024 (NCT05994300). All patients underwent daily oART, receiving 43.35 Gy in 17 fractions to the pelvic target volume, with a simultaneous integrated boost to 54.40 Gy in 17 fractions for involved lymph nodes. The adaptive workflow consisted of iterative cone-beam computed tomography acquisition, artificial intelligence-assisted contouring, physician review, plan adaptation, and treatment verification. Workflow efficiency, plan selection, target coverage, organ-at-risk (OAR) sparing, treatment completion, early tumor response and acute toxicity were prospectively assessed. Results: A total of 510 adaptive fractions were delivered. The first-attempt adaptation success rate was 99.0%, and adapted plans were selected in 99.4% of fractions. The mean adaptive workflow and total treatment times were 17.3 and 23.3 min per fraction, respectively. Compared with scheduled plans, adapted plans significantly improved target coverage, with V100% increasing by 7.26% for the planning target volume of the uterus and 8.79% for planning target volume of the cervix (both p < 0.001), while significantly reducing doses to the bladder, rectum, small bowel, bone marrow, and femoral heads. All patients achieved complete clinical response at 3 months. Acute toxicity was generally manageable; Grade ≥ 3 gastrointestinal, genitourinary, and hematologic toxicities occurred in 10%, 0%, and 40% of patients, respectively, including one Grade 4 neutropenia event, and no treatment interruptions. Conclusions: Daily oART-guided MHRT was feasible and efficient, providing improved target coverage and reduced OAR doses compared with scheduled plans. Acute toxicity was acceptable. These findings provide early prospective evidence supporting the feasibility of this treatment strategy and warrant further validation in larger prospective studies with longer follow-up.

Cancers doi: 10.3390/cancers18152492

Authors: Eric K. Rowinsky Ghassan K. Abou-Alfa Junji Furuse Makoto Ueno Masafumi Ikeda Hiroko Tabuchi Kazuo Sekiguchi Michael Szarek

Background/Objectives: This exploratory post hoc analysis evaluated clinical and biomarker-defined treatment effects and accumulated nanvuranlat exposure in advanced biliary tract cancer (BTC). Methods: BICR-assessed progression-free survival (PFS) and overall survival (OS) were analyzed in the randomized Phase 2 full analysis set of 104 patients (nanvuranlat, n = 69; placebo, n = 35). Formal treatment-by-subgroup interaction tests assessed prior primary tumor resection status, LAT1 expression, and anatomical BTC subtype, evaluated both as a four-category variable and as pooled IHC/EHC/GBC versus AVC. Accumulated-exposure analyses pooled Phase 1 and Phase 2 data and were descriptive. Results: Median PFS was 46 versus 43 days (HR, 0.557; 95% CI, 0.344–0.903), and median OS was 155 versus 144 days (HR, 0.875; 95% CI, 0.551–1.390). Interaction tests were nominally significant for resection status with OS (p = 0.028) and for the four-category BTC-subtype variable with PFS (global p = 0.035), but not for LAT1 expression (PFS, p = 0.157; OS, p = 0.586) or pooled IHC/EHC/GBC versus AVC (PFS, p = 0.511; OS, p = 0.208). The binary and four-category subtype analyses addressed different hypotheses and were not considered contradictory. Higher accumulated-exposure quartiles showed numerically longer survival, but these analyses were susceptible to immortal-time bias, reverse causation, and time-dependent confounding. Conclusions: Nanvuranlat was associated with a lower hazard of progression or death than placebo, whereas the OS estimate was less conclusive. The subgroup and exposure findings remain exploratory but support prospective evaluation of resection status, anatomical subtype, and LAT1 expression.

Cancers doi: 10.3390/cancers18152491

Authors: Loraine Gresseau Marie-Eve Roy Stéphanie Duhamel Borhane Annabi

In the original publication [...]

Cancers doi: 10.3390/cancers18152490

Authors: Myriam Jerbaka Radwa Hablase Alexander Shushkevich Martin Koskas Christopher El Hadi Nadine El Kassis Wissam Arab David Atallah Jayanta Chatterjee

Background/Objectives: The prognostic and predictive values of biomarkers in fertility-sparing management of atypical hyperplasia (AH) and endometrial cancer (EC) remain ill-defined. We aimed to identify the impact of tumour profiles on oncologic and reproductive outcomes to inform clinical decision-making. Methods: We conducted a systematic review and meta-analysis by searching MEDLINE, PubMed, Embase, Cochrane Library, Scopus, Google Scholar, and ClinicalTrials.gov, up to July 2026. We intended to include comparative studies or clinical trials, in English or French, assessing outcomes according to molecular or hormonal profiles in reproductive-aged women diagnosed with AH or EC. The primary outcome was the best overall complete remission (CR). Pooled odds ratios (ORs) were calculated using a random-effects model with logit transformation and restricted maximum likelihood estimation. Risk of bias was assessed using the Newcastle–Ottawa scale (NOS). The study protocol was registered in PROSPERO (CRD42025632885). Results: Eighteen retrospective studies comprising 965 patients were included. No specific molecular profile (NSMP) tumours demonstrated significantly higher odds of CR (OR 2.04, 95% CI 1.33–3.11). p53-abnormal (p53abn) and deficient mismatch repair (dMMR) tumours were significantly less likely to achieve CR compared to NSMP (OR 3.87, 95% CI 1.80–8.29 and OR 2.48, 95% CI 1.44–4.29, respectively). POLE-mutated (POLEmut) tumours showed CR comparable to NSMP (OR 1.39, 95% CI 0.60–3.24). Progesterone receptor (PR) positivity was strongly associated with CR (OR 7.73, 95% CI 2.77–21.63). Conclusions: NSMP and PR-positivity represented a favourable prognosis and potential prediction of CR. POLEmut tumours demonstrated CR rates comparable to NSMP, whereas p53abn and dMMR demonstrated unfavourable outcomes. These findings support a biologically tailored approach to patient selection for fertility-sparing management.

Cancers doi: 10.3390/cancers18152487

Authors: U Sin Wong Dajiang Guo

Late-stage cutaneous melanoma management has already evolved into systemic therapy thanks to the fast development of novel targeted inhibitors and immune checkpoint blockers. Therefore, a reliable prediction of systemic therapy response became crucial for making a personalised management plan for melanoma patients. Although there are multiple biomarkers already available, the overall predictive confidence remains low due to heterogeneous responses among patients. Therefore, novel solid predictive biomarkers are still greatly needed. With the development of new technologies and artificial intelligence, new predictive models are being proposed and generated. In this review, we thoroughly evaluated the established biomarkers that are already in use for clinical practice. In addition, we proposed the emerging new markers with great potential by critically reviewing the literature. Furthermore, we proposed a future framework for making a tailored clinical management plan for melanoma patients.

Cancers doi: 10.3390/cancers18152489

Authors: Kuba Sękowski Mateusz Jankowski Stanisław Surma Agata Olearczyk Wojciech S. Zgliczyński Justyna Grudziąż-Sękowska

Background/Objectives: Cancer remains a major public health challenge, and public awareness of warning signs, risk factors, and prevention methods is essential for early detection and primary prevention. This study aimed to assess cancer knowledge among adults in Poland and identify sociodemographic factors associated with self-reported awareness. Methods: A nationwide cross-sectional survey was conducted in January 2026 among 1087 adults in Poland using computer-assisted web interviewing (CAWI). Non-probability quota sampling was applied based on sex, age, and place of residence. Results: Only 12.7% of respondents reported rather high or very high cancer knowledge. The most frequently recognized warning sign was a lump, mass, or thickening (66.9%). Tobacco use (64.9%) and genetic or familial predisposition (61.8%) were the most commonly identified risk factors, whereas 41.9% recognized overweight or obesity as a cancer risk factor. Smoking cessation and participation in cancer screening programs were each identified as preventive measures by 57.5%. However, 20.8% incorrectly believed that dietary supplements protect against cancer, and 16.2% endorsed “detox” beverages as cancer-preventive. In multivariable analysis, higher education (aOR: 1.67; 95% CI: 1.13–2.46), occupational activity (aOR: 1.56; 95% CI: 1.02–2.37), personal history of cancer (aOR: 4.27; 95% CI: 2.75–6.64), and family history of cancer (aOR: 1.85; 95% CI: 1.25–2.73) were independently associated with higher self-reported cancer knowledge. Conclusions: The findings indicate insufficient cancer awareness among the surveyed sample of Polish adults, particularly among men, younger adults, and individuals with lower educational attainment. Targeted educational initiatives may help improve knowledge of cancer symptoms, risk factors, and prevention strategies.

Cancers doi: 10.3390/cancers18152488

Authors: Piotr Jan Wysocki Łukasz Kwinta Ewa Wysocka

Background: Metronomic chemotherapy (MCT), understood as continuous, low-dose cytotoxic administration without prolonged drug-free intervals, has become an established strategy in several solid tumors, acting primarily through antiangiogenic, immunomodulatory, and direct cytostatic mechanisms rather than replication-dependent cytotoxicity. Despite an expanding evidence base, including positive randomized trials, validated predictive biomarkers of response remain unavailable. Methods: We searched PubMed/MEDLINE, Embase, and ClinicalTrials.gov (January 2000 to July 2026) for phase II/III randomized trials, prospective cohorts, and selected retrospective analyses of MCT in breast cancer, head and neck squamous cell carcinoma, NSCLC, and mCRC, and extracted biomarker data from embedded translational substudies of eligible trials. Results: In breast cancer, phase III SYSUCC-001 (adjuvant metronomic capecitabine, improved DFS in TNBC) and MECCA (metronomic capecitabine plus aromatase inhibitor in HR+/HER2− disease) provide the strongest evidence, supported by randomized phase II data for the VEX regimen (METEORA-II) and MCT-anti-PD-1 combinations. TEMPO LUNG established metronomic vinorelbine as effective in platinum-unfit NSCLC, while CAIRO3 confirmed metronomic capecitabine–bevacizumab as an effective mCRC maintenance therapy. Most recently, the phase III TMC-I trial extended positive randomized evidence to head and neck cancer. Candidate biomarkers span angiogenic, immune, tumor proliferative, molecular, pharmacodynamic cytokine, on-treatment clinical (adverse-event-based), and gut–microbiome domains, with FOXC1, circulating endothelial cell kinetics, VEGF pathway markers, and regulatory T-cell dynamics among the most promising; however, none has been prospectively validated in a dedicated confirmatory trial. Conclusions: MCT has moved from empirical use to an evidence-based strategy across multiple tumor types, but the lack of validated predictive biomarkers limits informed patient selection. Future trials should incorporate biomarker-driven designs, particularly FOXC1, endothelial cell kinetics, and immune profiling as co-primary objectives. Defining an MCT-sensitive biological phenotype remains the key translational challenge for the field.

Cancers doi: 10.3390/cancers18152486

Authors: Chiara Luongo Roberta Di Santillo Alessia Cadavere Franca Oglio Laura Pisapia Alessia Gaeta Chiara Scocco Juan Luis López-Cánovas Marco Michelini Monia De Aloe Anna Lintura Saranya Chumsri Roberto Berni Canani

Breast cancer is the most common cancer in women, causing more than 600,000 deaths every year. The human microbiome is increasingly recognized as a key regulator of cancer initiation, progression, and therapeutic response. Postbiotics—defined as non-viable microbial cells and/or their structural components and metabolites that confer health benefits—are emerging as promising and safer alternatives to live probiotics in oncology. This review provides a comprehensive mechanistic overview of the potential role of postbiotics against cancer, with a specific focus on breast cancer. Preclinical evidence demonstrates that selected postbiotics exert dose- and time-dependent anticancer effects against multiple breast cancer subtypes by modulating key oncogenic pathways (such as PI3K/AKT and NF-κB) and inducing epigenetic regulation through histone deacetylase inhibition. Beyond direct effects on tumor cell proliferation and apoptosis, postbiotics influence the breast cancer microenvironment by reshaping cytokine networks, suppressing pro-metastatic inflammation, and enhancing antitumor immune responses through the activation of NK cells and T cells. We also provide emerging links between microbiome composition, estrobolome activity, and breast cancer subtype-specific biology. Despite these encouraging findings, the clinical translation of postbiotics in oncology remains limited. Currently, only one registered clinical trial investigates postbiotics in the oncology setting (melanoma), and no clinical trials have specifically evaluated postbiotics in breast cancer patients. This highlights a substantial translational gap between preclinical evidence and clinical application. Accordingly, well-designed, tumor-specific clinical trials are urgently needed to validate the safety, efficacy, and therapeutic potential of postbiotics as novel strategies in personalized breast cancer management.

Cancers doi: 10.3390/cancers18152485

Authors: Chang Ik Yoon Hye Sun Lee Soyoung Jeon Jin Ah Lee Dooreh Kim Jong Min Lee

We thank Jin [...]

Cancers doi: 10.3390/cancers18152484

Authors: Jingliang Zhao Qirui Bai Qile Qiu Jiaying Song Siyu Kong Kun Zhu Yifan Zhang Shengtao Li Yanping Ma Lin Zhang Xiaoqi Qin

Background: Extramedullary disease (EMD) in multiple myeloma (MM) is associated with poor prognosis, yet the clinical distinctions between bone-related EMD (bEMD) and soft tissue-associated EMD (sEMD) remain incompletely characterized. This study aimed to compare the clinical features and outcomes of bEMD versus sEMD and to develop a simple pre-treatment risk stratification tool using baseline clinical parameters. Methods: We retrospectively analyzed 118 patients with MM and EMD treated at a single center from 2011 to 2025, including 72 bEMD and 46 sEMD cases. Baseline characteristics, laboratory parameters, cytogenetic abnormalities, and survival outcomes were compared. Results: Patients with sEMD had significantly higher serum β2-microglobulin (β2-MG) levels (6.4 mg/L vs. 4.5 mg/L, p = 0.007) and a higher proportion of relapsed/refractory disease (41.3% vs. 15.3%, p = 0.002) compared to bEMD. Median progression-free survival (PFS) and overall survival (OS) were markedly shorter in patients with sEMD than in those with bEMD (PFS: 12.0 vs. 29.0 months, p < 0.001; OS: 25.0 vs. 67.0 months, p = 0.009). Multivariate analysis identified thrombocytopenia (PLT < 100 × 109/L), elevated β2-MG, multisite extramedullary involvement, and TP53 deletion as independent adverse prognostic factors. A risk scoring system incorporating β2-MG (0–2 points), thrombocytopenia (1 point), and multisite involvement (1 point) stratified patients into low-risk (0–2 points) and high-risk (3–4 points) groups with significantly different PFS (27.0 vs. 10.0 months, p < 0.001) and OS (54.0 vs. 22.0 months, p = 0.008). Conclusions: sEMD represents a more aggressive subtype of MM with inferior outcomes. The proposed risk score, based on routinely available clinical parameters, effectively identifies high-risk patients at initial diagnosis and may guide individualized treatment strategies.

Cancers doi: 10.3390/cancers18152483

Authors: Jun Kinoshita Kenta Doden Kengo Hayashi Ryota Matsui Hiroto Saito Megumi Watanabe Toshikatsu Tsuji Daisuke Yamamoto Noriyuki Inaki

Background/Objectives: First-line therapy for advanced gastric cancer (AGC) has evolved from cytotoxic chemotherapy to HER2-targeted and immune checkpoint inhibitor (ICI)-based regimens, yet conversion surgery (CS) outcomes across these strategies remain poorly characterized. We describe CS outcomes and prognostic factors by first-line strategy at a single center. Methods: We retrospectively reviewed 187 patients with AGC who began first-line therapy from 2011, grouped as cytotoxic (CTX, n = 127), HER2-targeted (trastuzumab, n = 21), or ICI (n = 39). CS was defined as resection after response, including an extended oligometastatic definition (n = 74). Overall survival (OS) was measured from chemotherapy initiation, and prognostic factors were assessed by Cox regression. Results: Median OS was 14.8, 18.9, and 20.9 months for CTX, trastuzumab, and ICI, respectively (p = 0.048). CS rates were comparable (41%, 33%, and 38%; p = 0.794). Pathological response was more pronounced after trastuzumab/ICI (grade 3 and ypStage 0/1; both p < 0.001). Among CS cases, R0 resection (hazard ratio [HR] 0.31) and trastuzumab/ICI therapy (HR 0.37) were independent favorable factors, whereas high inflammatory–nutritional indices (NLR, CAR) were independent poor prognostic factors. OS was comparable between oligometastatic and conventional CS (p = 0.324). Conclusions: In this hypothesis-generating study, response depth tracked tumor biology, whereas survival was determined by R0 resection, targeted/ICI therapy, and host inflammatory–nutritional status—two largely dissociable axes informing biology- and host-based selection of CS candidates for prospective testing.

Cancers doi: 10.3390/cancers18152482

Authors: Yuting Tao Shuzhen Liao Tao Liu Ruyi Lai Chao Feng Qiuyan Wang

Objective: Vasculogenic mimicry (VM), characterized by the de novo formation of microvascular-like channels derived from aggressive tumor cells without involving traditional endothelial cells, is a pivotal pathological hallmark driving extreme invasiveness and dismal prognosis in hepatocellular carcinoma (HCC). This study aimed to establish a VM-based molecular subtyping system and systematically characterize its associated biological features, thereby providing a potential framework for individualized prognostic assessment and treatment decision-making in HCC. Methods: We integrated curated VM-associated gene sets with single-cell RNA sequencing data to identify malignant epithelial cell-enriched VM-associated candidate genes. Subsequently, univariate Cox regression, LASSO-Cox regression, and multivariate Cox regression were sequentially performed to identify six prognostic VM-related genes: HSPA9, TGFA, MAD2L1, PROM1, AGXT, and GCGR. HCC patients were stratified into VM, Mixed-VM, and Non-VM subtypes according to VM scores. Kaplan–Meier survival analysis, time-dependent ROC analysis, and Cox regression were used to assess prognostic performance. The biological features of the classification system were evaluated using bulk transcriptomic cohorts, spatial transcriptomics, Cytometry by Time-of-Flight (CyTOF), metabolomics, lipidomics, somatic mutation and copy number alteration analyses, and treatment-related HCC cohorts. Results: The VM score-based classification stratified HCC patients into three molecular subtypes with distinct prognostic and biological characteristics. Patients classified as the VM subtype had significantly poorer overall survival than those classified as Mixed-VM or Non-VM subtypes, and this prognostic pattern was validated across independent cohorts. Multi-omics analyses showed that the VM subtype was associated with YAP-TAZ-TEAD-related transcriptional programs, stemness/proliferation-related features, immunoregulatory and exhaustion-like tumor microenvironmental characteristics, and distinct metabolic and lipidomic alterations involving modified nucleosides, keto acid-related metabolites, cholesteryl esters, and sphingolipid-related species. Spatial transcriptomics revealed focal enrichment of VM-score-high regions and their association with YAP-TAZ-TEAD and immune checkpoint-related signatures. In orthotopic HCC mouse models, YAP1 overexpression increased PAS+/CD34− VM-like structures, whereas verteporfin treatment reduced these structures. In two treatment-related cohorts, the Non-VM subtype showed higher response rates to sorafenib and transarterial chemoembolization (TACE) than the VM subtype. Connectivity Map (CMap)-based computational drug prioritization and molecular docking analysis prioritized ivermectin as a candidate compound; however, its antitumor activity requires further experimental validation. Conclusions: This study establishes a VM score-based molecular classification framework for HCC and identifies VM-subtype-associated prognostic, spatial, immune, metabolic, genomic, and therapeutic features. These findings provide a candidate framework for molecular risk stratification and subtype-guided therapeutic exploration in HCC.

Cancers doi: 10.3390/cancers18152481

Authors: Elisa Danese Alessandro Esposito Matteo De Pastena Fabio Del Ben Gabriella Lionetto Alessia Scirpoli Mariateresa Rizza Roberto Salvia Giuseppe Lippi

Background: Circulating bile acid (BA) profiles are increasingly explored in pancreatic cancer, although their interpretation is often complicated by biliary obstruction and its clinical management. In this study, we characterized plasma BA profiles in pancreatic ductal adenocarcinoma (PDAC) and assessed the relative contributions of tumor localization, histological subtype, cholestasis, and cholestasis-related interventions. Methods: Plasma BAs were quantified by LC-MS/MS in patients with PDAC of the pancreatic head (hPDAC, n = 132), PDAC of the body-tail (tPDAC, n = 42), and non-PDAC tumors of the pancreatic head (hnonPDAC, n = 34). BA concentrations and derived ratios were log-transformed and standardized, and their associations with bilirubin were examined using multivariable linear models, LOESS, and multivariate longitudinal analyses. Results: UDCA therapy was associated with markedly increased circulating UDCA, higher total BA concentrations, and enrichment of secondary BA species. Direct bilirubin explained more variability in BA composition than binary jaundice classification and showed a non-linear association with BA remodeling, with a distinct metabolic profile emerging only at high bilirubin levels. Longitudinally, BA profiles changed substantially over time in hPDAC, largely in parallel with bilirubin, whereas they remained comparatively stable in tPDAC. After adjustment for bilirubin, tumor-related differences were modest and context-dependent. Conclusions: Overall, circulating BA profiles in pancreatic cancer appear to be driven predominantly by cholestasis and its management rather than by tumor-related features alone.

Cancers doi: 10.3390/cancers18152480

Authors: S. Jennifer Wang Carolyn Haynes Laura Graham Akhila Kunuthuru Gina Tuzzolo Anaya Surve Madison Isbell Jian He Rebecca K. Martin Harry Bear

Background: Immune-checkpoint blockade (ICB) is a recent addition to the treatment options for breast cancer, especially the triple-negative (TNBC) subset. Inhibiting immunosuppressive factors in the tumor microenvironment (TME) and preventing or reversing T cell exhaustion may increase the likelihood of a response to ICB. We have shown that decitabine and guadecitabine, DNA methyltransferase inhibitors (DNMTi), prevent the systemic and TME accumulation of myeloid-derived suppressor cells (MDSCs), which are immunosuppressive. Results: Here, we show that adding DNMTi to the neoadjuvant + adjuvant ICB-based treatment of ICB-resistant 4T1 and E0771 murine tumors in Balb/C and C57Bl/6 mice, respectively, effectively reduced the tumor burden, with 52% of 4T1 tumors completely regressing across several studies. DNMTi-based therapy overcame ICB resistance (ICBR) in a selected subline of E0771, and treated tumors showed a reduction in MDSCs. We also show that, in E0771, DNMTi can overcome ICBR to multiple checkpoint inhibitors, and in 4T1, it can modulate anti-tumor immunity by enhancing central memory T cell (Tcm) formation and reducing T cell exhaustion. Conclusion: These pre-clinical findings support the further investigation of incorporating DNMTi as a new immunotherapy modality for TNBC.

Cancers doi: 10.3390/cancers18152479

Authors: Takumi Inaba Narushi Sugii Hidehiro Kohzuki Shunichiro Miki Takao Tsurubuchi Masahide Matsuda Eiichi Ishikawa

Background/Objective: Intraoperative local photodynamic therapy (PDT) using talaporfin sodium (TS) and photodynamic diagnosis (PDD) with 5-aminolevulinic acid (5-ALA) are valuable adjuncts in the treatment of malignant brain tumors. Although their concomitant use was previously contraindicated due to photosensitivity concerns, a 2022 regulatory revision permitted their combined application. Transient postoperative hyperintensity on diffusion-weighted imaging (DWI) at the irradiation site serves as a biomarker for PDT effects, but the radiological and clinical impact of combining 5-ALA and TS remains unclarified. To compare and evaluate postoperative DWI findings and clinical outcomes in patients undergoing TS-PDT with or without concomitant 5-ALA-guided PDD. Methods: This retrospective study analyzed 34 patients with recurrent primary malignant brain tumors who underwent TS-PDT between January 2019 and November 2025. Patients were divided into a TS alone group (n = 19) and a TS + 5-ALA group (n = 15). Postoperative DWI hyperintensity thickness and minimum apparent diffusion coefficient (ADC) values at the laser irradiation site were measured. Adverse events including photosensitivity were also compared. Results: No significant differences were observed between the TS alone and TS + 5-ALA groups in DWI hyperintensity thickness (3.71 mm vs. 3.90 mm; p = 0.703 or median ADC values (601.0 × 10−6 mm2/s vs. 527.0 × 10−6 mm2/s; p = 0.205). Furthermore, there were no significant differences in the incidence of photosensitivity and liver enzyme elevation. Conclusions: Concomitant use of 5-ALA-PDD and TS-PDT can be used without worsening DWI findings at the PD laser irradiation site.

Cancers doi: 10.3390/cancers18152478

Authors: Edwin Aguirre-Milachay Mario J. Valladares-Garrido Nallely V. Chapoñan-Agip Nelson Luis Cahuapaza-Gutierrez Betzy C. Torres-Zegarra Milagros Diaz-Torres Darwin A. León-Figueroa Fernando M. Runzer-Colmenares

Background: Older adults with cancer are at increased risk of severe treatment-related toxicity. CARG, CRASH, and CARG-BC were developed as toxicity-risk prediction models, whereas G8 was developed as a geriatric screening instrument but has also been evaluated as a predictor of treatment-related toxicity. This study aimed to assess, separately for each instrument, the accuracy with which these tools identify older adults who develop severe chemotherapy-related toxicity. Methods: A systematic review and meta-analysis were conducted in accordance with PRISMA 2020 guidelines. Seven databases were searched through May 2026 for observational studies evaluating the predictive accuracy of the CARG, CRASH, CARG-BC and G8 tools in patients aged ≥65 years initiating chemotherapy. Pooled sensitivity and specificity with 95% confidence intervals (CIs) were calculated, and ROC curves were constructed. Risk of bias was assessed using QUADAS-2 and certainty of evidence was evaluated using GRADE. Results: Twenty-one studies were included, with an overall toxicity prevalence of 52.6%. CARG demonstrated a pooled sensitivity of 79.7% and specificity of 38.3% (AUC = 0.632). CRASH showed sensitivity of 86.9% and specificity of 68.2% (AUC = 0.866), but estimates were based on only four studies. CRASH hematological toxicity showed sensitivity of 75.9% and specificity of 53.1% (AUC = 0.694), with substantial heterogeneity. G8 yielded sensitivity of 69.5% and specificity of 41.5% (AUC = 0.666). CARG-BC showed sensitivity of 83.3% and specificity of 54.4% (AUC = 0.763), based on two breast cancer studies. Certainty of evidence ranged from low to very low. Conclusions: The instruments have distinct purposes and were not pooled against one another. CARG and G8 may be useful for initial risk screening, whereas CRASH showed a more balanced profile but remains supported by limited evidence. None should be used as a stand-alone basis to withhold or modify treatment.

Cancers doi: 10.3390/cancers18152477

Authors: Nives Kolesarić Ivan Pezelj Igor Tomašković Goran Štimac Monika Ulamec Božo Krušlin

Background/Objectives: Prostate needle biopsy often underestimates tumor aggressiveness due to limited tissue sampling, leading to Gleason score upgrading after radical prostatectomy (RP). Phosphatase and Tensin Homolog (PTEN) loss is an established tissue-based marker of adverse prostate cancer biology. This study evaluated whether reduced or absent PTEN immunoreactivity in diagnostic biopsies is associated with subsequent Gleason score and International Society of Urological Pathology (ISUP) Grade Group upgrading in RP specimens. Methods: This retrospective study included 85 prostate cancer patients who underwent multiparametric magnetic resonance imaging (mpMRI)-guided biopsy and subsequent RP. PTEN expression on biopsy samples was assessed via immunohistochemistry. Patients were stratified into PTEN-preserved (PTEN+, n = 75) and PTEN-deficient (PTEN−, n = 10) groups. Results: Upgrading occurred in 70% (7/10) of PTEN-deficient cases compared with 20% (15/75) of PTEN-preserved cases. This difference was statistically significant (two-sided Fisher’s exact p = 0.0024), with PTEN-deficient patients showing a 3.50-fold higher relative risk of upgrading (RR = 3.50, 95% CI: 1.91–6.43). Preoperative PSA levels (p = 0.91) and Prostate Imaging Reporting and Data System (PI-RADS) scores (p = 0.73) did not differ significantly between the groups. Conclusions: Reduced PTEN protein expression, as assessed by immunohistochemistry in prostate needle biopsies, was significantly associated with Gleason score/ISUP Grade Group upgrading at radical prostatectomy. PTEN immunohistochemistry warrants further evaluation as a potentially complementary tissue-based marker of biopsy undergrading. However, the observed unadjusted association does not establish PTEN immunoreactivity as an independent predictor of upgrading.

Cancers doi: 10.3390/cancers18152476

Authors: Kazuaki Tanabe Ruxin Lei Yoshihiro Saeki Emi Chikuie Hideki Ohdan

Proximal gastrectomy preserves gastric function; however, reconstruction choice influences reflux control and quality of life (QOL), and the comparative efficacy of available techniques remains unclear. A PRISMA-guided search of PubMed and Web of Science Core Collection (January 2000–April 2025) identified studies reporting reflux or QOL outcomes after proximal gastrectomy. Eligible studies included adult gastric cancer cohorts with original clinical data. Two reviewers independently screened articles, extracted predefined variables, and performed a narrative synthesis. The protocol was archived on the OSF. Thirty-two studies (2958 patients) met inclusion criteria. Simple esophagogastrostomy (EG) consistently demonstrated the poorest reflux control and widest range of stricture rates. Double-tract reconstruction (DTR) showed a generally favorable balance among reflux control, low leakage rates, and acceptable stricture rates, suggesting that it may represent a practical and broadly applicable reconstruction option. Jejunal interposition and pouch variants were reported in small, heterogeneous series, limiting their generalizability. Among valve-forming methods, the double-flap technique was associated with very low rates of endoscopic reflux in two Los Angeles–graded cohorts, though a 4–6% stricture rate remained a concern. Evidence for the side overlap with fundoplication by Yamashita, both original and modified, was sparse and inconsistent. Global QOL, assessed using PGSAS-45/37 and EORTC instruments, did not differ consistently between reconstruction types, although specific domains—such as appetite loss, nausea, and weight maintenance—varied sporadically. Available evidence suggests that DTR may be considered a practical and broadly applicable reconstruction option following proximal gastrectomy, whereas the double-flap technique appears to provide strong reflux control but may be associated with a risk of anastomotic stricture. Simple EG may was associated with higher reflux rates across studies and may be less favorable for reflux control. Larger multicenter studies using standardized, nutrition-sensitive QOL measures and physiological reflux testing are needed to optimize reconstruction choice. However, substantial heterogeneity and the limited quality of the available evidence preclude definitive conclusions regarding the superiority of any single reconstruction method.

Cancers doi: 10.3390/cancers18152475

Authors: Samir Atiya Jiayou Liang Kwaku Ofori-Atta Michelle Peng Huili Wang Yifei Zhou Ankush Patel Mary Edgertion Junhan Zhao Utku Pamuksuz

Background/Objectives: Breast cancer biomarker detection through immunohistochemistry (IHC) is essential for treatment planning but faces challenges including turnaround time, variability, and laboratory resource constraints. Large open-source vision-language foundation models offer a potential avenue for inferring biomarker status directly from hematoxylin-and-eosin (H&E)-stained whole-slide images (WSIs). Methods: We evaluated two open-source pathology foundation models—TITAN (Transformer-based Pathology Image and Text Alignment Network, approximately 48.5 M parameters) and CHIEF (Clinical Histopathology Imaging Evaluation Foundation Model, approximately 1.2 M parameters)—for predicting estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status from H&E-stained breast cancer WSIs. WSI data were obtained from The Cancer Genome Atlas Breast Invasive Carcinoma collection (TCGA-BRCA) via the NCI Imaging Data Commons, with biomarker labels from the NCI Genomic Data Commons. In total, 937 cases (995 WSIs; 78.3% ER-positive) were evaluated for ER, 934 cases (992 WSIs; 68.4% PR-positive) for PR, and 646 cases (691 WSIs; 21.1% HER2-positive) for HER2. All evaluation was performed under a strict patient-level 50/25/25 split with 10 independent random partitions; metrics are reported as the mean across partitions with percentile-based 95% confidence intervals. Performance was assessed using area under the receiver operating characteristic curve (AUROC), area under the precision-recall curve (AUPRC), sensitivity, specificity, and positive predictive value (PPV). Results: TITAN and CHIEF achieved comparable performance for ER (TITAN AUROC: 0.885 [95% CI: 0.848, 0.921], AUPRC: 0.954 [0.940, 0.964]; CHIEF AUROC: 0.877 [0.831, 0.914], AUPRC: 0.955 [0.938, 0.969]) and PR (TITAN AUROC: 0.799, AUPRC: 0.868; CHIEF AUROC: 0.791, AUPRC: 0.864). At the default 0.5 operating point, ER PPV was 0.90 and PR PPV was 0.79–0.81. For HER2, both models achieved AUROC values of 0.71–0.74 and AUPRC values of 0.41–0.45—well above the prevalence-based random baseline (approximately 0.211)—but default-threshold sensitivity was very low (approximately 0.07–0.08), reflecting class imbalance and the use of an uncalibrated default threshold rather than a categorical absence of morphologic signal. Conclusions: Under retrospective evaluation, both models demonstrate strong discriminative performance for ER and moderate performance for PR; HER2 prediction at the default operating point is limited and motivates threshold-calibration and multimodal extensions before any clinical use. AUPRC summarizes precision−recall behavior across thresholds and is distinct from threshold-specific precision (PPV); the two should be reported together for clinical-utility assessment in pathology AI. The findings are hypothesis-generating and motivate prospective external validation across independent institutional cohorts before any clinical deployment is considered.

Cancers doi: 10.3390/cancers18152474

Authors: Shafiya Imtiaz Rafiqi Juan Carlos Jaume

The advent of cancer immunotherapy opened a transformative era in oncology, shifting the focus from targeting mutated genes through precision oncology to harnessing the body’s immune system via agnostic therapies. This paradigm has demonstrated that a deeper understanding of the tumor immune microenvironment (TIME) can transcend the challenges posed by cancer’s genetic diversity and evolutionary dynamics. In the case of thyroid cancer, progress in immunotherapy has been comparatively slow. Much of the current research still centers on the genetic landscape of thyroid tumors rather than on comprehensive exploration of their TIME. The TIME, composed of immune cells such as macrophages, lymphocytes, natural killer cells, and mast cells, along with a network of signaling molecules, evolves alongside tumor growth and metastasis. It both influences and is influenced by genetic alterations, metabolic conditions, and therapeutic interventions. This dynamic crosstalk defines the clinical and biological heterogeneity of thyroid cancers; from the aggressive anaplastic thyroid carcinoma (ATC) to the more indolent papillary thyroid carcinoma (PTC). Mapping the spatial and temporal changes within the TIME offers the opportunity to design therapies that counter immune evasion and enhance treatment response. As understanding of the tumor microenvironment deepens, thyroid cancer therapy is undergoing a major shift; from strategies aimed merely at genetic mutations to integrated, combinational approaches incorporating personalized immunotherapy. Building on recent findings, which detail immune cell composition and therapeutic implications in thyroid malignancies, this review expands on the molecular and cellular mechanisms shaping the microenvironment. We highlight how oncogenic signaling, stromal remodeling, and metabolic reprogramming coordinate to influence tumor immunity, and we explore emerging strategies that aim to reengineer the tumor microenvironment for improved therapeutic outcomes.

Cancers doi: 10.3390/cancers18152473

Authors: Rulon Mayer Yuan Yuan Jayaram Udupa Baris Turkbey Charles B. Simone

Background/Objectives: Deciding between active surveillance and treatment for prostate cancer patients often requires accurate risk assessment of prostate tumors detected with multi-parametric MRI. Conventionally, radiologists visually inspect MRI and use scoring procedures such as PI-RADS to help assess the scans. More recently, artificial intelligence (AI) applied to MRI has allowed for supplementation and is complementary to clinical assessment. However, AI is computationally expensive and severely saps scarce energy and water resources and requires special processing components, requiring alternate approaches that require less computation and fewer resources. The novel, simpler spectral/statistics approach that mimics color vision was previously successfully applied in a number of retrospective pilot studies of bi-parametric MRI of prostate cancer. The novel approach needs far fewer resources, is less computationally intensive, and is simpler than artificial intelligence to evaluate prostate tumors. However, these earlier spectral/statistics pilot studies required intervention by an analyst and too much time for implementation in future large patient studies that are needed to validate the novel approach. This retrospective pilot study further developed, applied, and tested new automation tools to expedite simpler spectral statistical techniques that need fewer resources to evaluate prostate tumors on multi-parametric MRI. Methods: Automated spatial registration, automated prostate organ segmentation, automated blob generation and selection for spectral signatures derived from the apparent diffusion coefficient, high-B-value DWI, and T2 MRI were performed on 76 consecutive patients in the PI-CAI cohort in this retrospective pilot study. The signal-to-clutter ratio (SCR) was computed using target signatures and the processed statistical metrics of the registered prostate bi-parametric MRI. The processed SCR, spectral/spatial features of blobs and clinical metrics predict clinically significant prostate cancer using multivariate logistic regression. The proposed method was assessed using the area under the curve (AUC) from the receiver operating characteristic curve. Results: AUC values of >0.90 were achieved by combining the SCR with blob and clinical metrics. Increasing the number of non-congruent, independent variables resulted in higher AUC scores. Restricting analysis to blob volumes > 0.1 cm3 achieved higher AUC values. The additional total savings in time by applying the new automation tools reduced the processing time by 80 to 170 min for 10 patients. Implementing the new automation tools resulted in an overall processing time of 40 to 80 min per 10 patients. Conclusions: Automating the spectral/statistics approach resulted in AUCs not inferior to those obtained from AI. The automation achieved sufficiently high AUCs and also reduced processing times, warranting future assessments in large patient cohorts.

Cancers doi: 10.3390/cancers18152472

Authors: Velizar Shivarov

Immune checkpoint inhibitors have transformed the treatment of multiple malignancies by restoring antitumor T-cell activity. Their clinical identity is therefore that of immune-enhancing therapies. However, the biology of the PD-1/PD-L1 axis is more complex than simple immune inhibition. Human inborn errors of PD-1 or PD-L1 signaling indicate that this pathway contributes to immune homeostasis, tolerance, protection against selected infections, and the development of memory B cells and antibody responses. These observations raise an important translational question: Can prolonged pharmacologic blockade of PD-1 or PD-L1 can, in selected clinical contexts, induce or reveal acquired humoral immune dysfunction? This review synthesizes evidence linking PD-1/PD-L1 disruption to altered class-switched memory B-cell biology, antibody responses, vaccine immunogenicity, infection susceptibility, and secondary antibody deficiency. It also incorporates emerging evidence that checkpoint blockade may expand age-associated B cells, a population associated with impaired neutralizing antibody responses after vaccination, and counterbalances evidence that vaccination during ICI therapy may enhance antitumor immunity and survival. Current clinical evidence does not establish the incidence, prevalence, reversibility, dose dependence, or causality of an ICI-induced antibody-deficiency syndrome. Instead, the available data support a hypothesis-generating model of heterogeneous humoral remodeling, ranging from preserved or enhanced vaccine-associated immune activation to qualitative antibody failure and secondary antibody deficiency in susceptible patients. Future studies should incorporate baseline and longitudinal measurements of immunoglobulins, vaccine-specific and neutralizing antibodies, class-switched memory B cells, age-associated B cells, plasmablasts, infection burden, and exposure to immunosuppressive treatment.

Cancers doi: 10.3390/cancers18152471

Authors: Marco Agostini Pietro Traldi Mahmoud Hamdan

Proteins and associated post-translational modifications are receiving deserved attention in the search for immune therapies to combat a long list of diseases, including a number of fatal forms of cancer. Such attention has been fueled by a number of clinical results generated by numerous clinical trials, together with datasets generated by academic research. The title of this review is based on a couple of considerations: most, if not all, researched immune checkpoints are proteins, each of which can experience one or more post-translational modifications (PTMs). It is also known that among the main functions of post-translational modifications is their direct impact on protein localization. Given that most activities of known checkpoints are performed on the surface of the host cells, post-translational modifications are bound to influence the role of these proteins, both as drivers of various diseases and as therapeutic targets. The second consideration concerns another class of proteins, which is responsible for a severe toxic reaction in the immune system following treatment with immune cell inhibitors, a reaction known as cytokine release syndrome (CRS). Cytokines are low-molecular-weight proteins, among which the key members are interleukin-1 (IL-1), interleukin-6 (IL-6), and interferon γ (IFN-γ). A number of clinical trials have shown that the symptoms of CRS toxicities are frequently accompanied by elevated levels of cytokines, including IL-6 and IFN-γ. The recent literature suggests that we still need to know more about the biology of these proteins and the type of modifications that these key members of cytokines can experience. Such additional knowledge may contribute to more effective and safer immune cell therapy. The contribution of mass-spectrometry-based proteomics to the investigation of PTMs associated with immune checkpoints and cytokines is discussed.

Cancers doi: 10.3390/cancers18152470

Authors: Ivan Lomangino Giacomo Grisorio Domenico Albano Luca Vecchiarelli Matteo Rota Matteo Baldi Letizia Perri Mauro Roberto Benvenuti Salvatore Grisanti Francesco Bertagna

Objectives: Precise lymph node staging remains a cornerstone in the management of early-stage and locally advanced non-small cell lung cancer (NSCLC), directly influencing surgical planning and multimodal therapy. Despite the widespread use of 2-[18F]FDG PET/CT, occult nodal metastases frequently lead to unexpected upstaging after surgery, potentially affecting prognosis and therapeutic strategies. This study aimed to investigate whether radiomic features derived from preoperative PET/CT scans can predict nodal involvement in patients with early-stage lung cancer. Methods: A retrospective analysis was conducted on 124 patients with cT1N0 NSCLC who underwent 2-[18F]FDG PET/CT scans as part of the preoperative workup, followed by anatomical lung resection and systematic mediastinal lymph node dissection. Radiomic features were extracted from PET predictive of pathological nodal upstaging. Results: During the study period, 67 patients who underwent anatomical lung resection for early-stage lung cancer demonstrated unexpected nodal metastasis; a continuous series of 57 patients with the same clinical TMN was enrolled as a control group. Several radiomic parameters were significantly associated with nodal upstaging. According to variable importance (VIMP) analysis, metabolic tumor volume (MTV), total lesion glycolysis (TLG), run-length non-uniformity (RLNU), and gray-level non-uniformity (GLNU) emerged as the strongest predictors of lymph node involvement. Conclusions: Although the clinical utility of these findings remains to be validated, radiomic analysis of 2-[18F]FDG PET/CT imaging offers non-invasive biomarkers that may enhance the preoperative prediction of nodal involvement in early-stage NSCLC. Integrating radiomics into clinical workflows could improve surgical decision-making, refine patient selection, and reduce the incidence of unforeseen nodal upstaging.

Cancers doi: 10.3390/cancers18152469

Authors: Cristina Terlizzi Ylenia Ferrara Annachiara Sarnella

Breast cancer is a highly heterogeneous disease characterized by distinct molecular subtypes, dynamic tumor–microenvironment interactions, and variable therapeutic responses. Despite the availability of multiple preclinical platforms, a major challenge remains the lack of a coherent multiscale framework capable of integrating biological complexity across experimental systems. This limitation reduces the predictive power of individual models and highlights the need for complementary strategies that reproduce disease progression across multiple biological scales. In this context, advanced imaging technologies have emerged as essential tools for linking preclinical platforms and enhancing their translational relevance. This review examines how multimodal imaging supports the integration of in vitro, ex vivo, and in vivo breast cancer models. We discuss how optical imaging, high-frequency ultrasound, magnetic resonance imaging, positron emission tomography/computed tomography, and intravital microscopy provide complementary molecular, functional, anatomical, and cellular information for the longitudinal assessment of tumor growth, metastatic dissemination, microenvironment remodeling, and therapeutic response. Particular attention is given to emerging translational workflows that combine patient-derived models with advanced imaging to investigate drug sensitivity, treatment resistance, and tumor progression within a precision oncology perspective. We also highlight the role of multimodal imaging in biomarker validation across platforms and in the development of clinically relevant preclinical pipelines. Overall, advanced imaging represents a critical translational bridge across breast cancer model systems, improving the predictive value of preclinical studies and supporting imaging-guided precision oncology from bench to bedside.

Cancers doi: 10.3390/cancers18152468

Authors: Elisa Mattavelli Valentina Da Prat Lorenzo Perrone Francesca De Simeis Laura Boldrini Salvatore Corallo Annarita Sabbatini Paolo Pedrazzoli Roberto Biffi Riccardo Caccialanza

Background/Objectives: Nutritional impairment is common across the cancer care continuum and may negatively affect treatment tolerance, functional status, quality of life, and caregiver burden. Digital tools may offer new opportunities to extend nutritional care beyond conventional clinical encounters, but their application in oncology remains heterogeneous and poorly defined. This narrative review aims to describe the current landscape of digital nutritional care in oncology, focusing on quality of life and patient perspectives while also considering the emerging role of caregivers. Methods: We conducted a narrative review of the available evidence on digital nutritional and lifestyle interventions in cancer care, including mobile applications, web-based platforms, teleconsultations, SMS- or email-based communication, remote monitoring systems, and hybrid models. Results: Digital nutritional and lifestyle interventions have been evaluated across active treatment, postoperative recovery, and survivorship. Available studies indicate that these interventions are generally feasible and may improve nutritional status, dietary behaviors, and physical activity levels. However, quality-of-life outcomes remain heterogeneous and have not been consistently assessed across studies. Some interventions combining digital tools with personalization, professional feedback, behavioral support, or clinically actionable monitoring reported favorable patient-centered outcomes. However, heterogeneity across studies limits the interpretation of these findings and the identification of specific intervention features associated with effectiveness. Patient and caregiver perspectives further highlight the importance of usability, trust, access to reliable information, communication with healthcare professionals, and practical support in the home setting. Conclusions: Digital nutritional care has the potential to extend and strengthen the delivery of nutritional care. Rather than replacing conventional interventions, it should be implemented through hybrid, supervised, equitable, and clinically integrated models. Future studies should consistently assess quality of life and other patient-reported outcomes while also addressing caregiver needs, digital burden, psychological safety, and inequalities in access.

Cancers doi: 10.3390/cancers18152467

Authors: Naifah Alshameri Francisco Marchi Xueyuan Cao Jeffrey E. Rubnitz Raul C. Ribeiro Soheil Meshinchi Stanley B. Pounds Jatinder K. Lamba

Background: Aberrant DNA methylation is a hallmark of acute myeloid leukemia (AML) and contributes to leukemogenesis, treatment response, and clinical heterogeneity. While genome-wide methylation studies have identified prognostic methylation signatures, the impact of DNA methylation within pharmacologic pathways and AML-relevant disease genes remains incompletely understood. We investigated the association of DNA methylation in genes of pharmacokinetic/pharmacodynamic (PK/PD) pathways of drugs used to treat AML and in myeloid leukemia-related genes with treatment outcomes in pediatric AML. Methods: DNA methylation profiles from 924 pediatric AML patients treated on Children’s Oncology Group trials (AAML1031, AAML0531, and AAML03P1—available publicly) were analyzed as a discovery cohort. A validation cohort included 159 patients treated on the AML02 trial. A total of 2296 variable CpG sites mapping to 65 PK/PD genes and 107 AML biology/leukemia stemness genes were evaluated. Associations between CpG methylation, gene expression, event-free survival (EFS), overall survival (OS), and measurable residual disease after induction I (MRD1) were assessed using Cox proportional hazards, logistic regression, and correlation analyses. Results: Twenty-three CpG sites in PK/PD genes and forty-two CpG sites in AML-related genes were significantly associated with at least one clinical endpoint after Bonferroni correction (p < 2.17 × 10−5). Hypermethylation of drug transporters ABCA3, ABCC1, and SLC22A1, as well as pharmacologically relevant genes MPO, NOS3, and CTPS1, was associated with inferior survival and/or increased MRD1 positivity. Among AML biology genes, methylation of ETV6, NOTCH1, RUNX1, KIT, MPL, DNMT3A, and DNMT3B demonstrated consistent associations with outcomes across discovery and validation cohorts. Several genes exhibited significant inverse correlations between DNA methylation and gene expression, including MPO, KIT, MPL, SPINK2, and DNMT3B, supporting functional epigenetic regulation. Notably, hypermethylation of ABCA3, MPO, and MPL was reproducibly associated with poor OS and EFS in both cohorts. Conclusions: DNA methylation of key pharmacologic and leukemia-related genes is associated with clinical outcomes in pediatric AML. These findings identify biologically and clinically relevant epigenetic biomarkers that may improve risk stratification and support the development of precision medicine approaches incorporating DNA methylation profiling and epigenetic therapies in pediatric AML.

Cancers doi: 10.3390/cancers18152466

Authors: Hyun Ho Kim Changhyeok An Kyu-na Lee Kyung-do Han Kang Woong Jun

Background/Objectives: Colorectal cancer (CRC) is among the most common cancers in Korea, and visceral adiposity is an established modifiable risk factor. The body roundness index (BRI), derived from waist circumference and height, estimates visceral adipose tissue more accurately than the body mass index (BMI) alone. We investigated the longitudinal association between the BRI and incident CRC in a large Korean national cohort. Methods: A nationwide cohort of 4,492,697 adults aged ≥20 years who participated in the 2012 Korean National Health Insurance Service health check-up was followed through December 2023 (mean 10.32 years). BRI values were categorized into quartiles (Q1–Q4). After applying a 1-year lag period, Cox proportional hazards regression estimated hazard ratios (HRs) and 95% confidence intervals (CIs), adjusting for age, sex, smoking, alcohol consumption, exercise, income, diabetes, hypertension, hypercholesterolemia, and chronic kidney disease. Subgroup and site-specific analyses were also performed. Results: During 46,382,686 person-years of follow-up, 57,644 incident CRCs were diagnosed. A higher BRI was independently and dose-dependently associated with CRC risk (Q4 vs. Q1: aHR 1.104, 95% CI 1.075–1.135; p for trend < 0.001). The association was significantly stronger in men (Q4 aHR 1.352, 95% CI 1.302–1.404) than in women (Q4 aHR 0.891, 95% CI 0.858–0.925; p for interaction < 0.001) and most pronounced in middle-aged adults (40–64 years). Site-specific analyses revealed a proximal-to-distal gradient: proximal colon (Q4 aHR 1.363), distal colon (Q4 aHR 1.244), and rectum (Q4 aHR 1.070). Conclusions: A higher BRI is independently and dose-dependently associated with increased CRC incidence in Korean adults, particularly in men and those with general obesity. The BRI may serve as a practical complement to the BMI for CRC risk stratification in populations with a high prevalence of metabolic obesity.

Cancers doi: 10.3390/cancers18152465

Authors: Cristina Cano Garcia Joseph Moryousef Jehonathan H. Pinthus Darryl P. Leong

In metastatic prostate cancer, there have been pronounced survival gains driven by the introduction of combination and intensification strategies. Consequently, many patients now experience prolonged survival with metastatic disease. While these advances represent a major therapeutic success, prolonged exposure to systemic therapies is associated with a broad spectrum of adverse effects. These side effects affect multiple domains, including bone health, cardiovascular risk, physical function, and psychological well-being. As a result, survivorship has emerged as a critical and increasingly relevant aspect of care in metastatic prostate cancer. In parallel, the importance of patient-reported outcomes in clinical trials, alongside traditional oncologic endpoints, is increasingly acknowledged. Overall, survivorship care in metastatic disease remains incompletely conceptualized as the long-term impact of cumulative treatment burden is often underrecognized. This narrative review examines key survivorship challenges in metastatic prostate cancer in an era of improving survival, with a focus on treatment-related toxicities, quality of life, and unmet needs in supportive care. We highlight current evidence, identify gaps in knowledge, and discuss future directions for integrating survivorship into routine clinical practice.

Cancers doi: 10.3390/cancers18152464

Authors: Ouafa Badre Sue-Ling Chang Belkacem Abdous Julie Lemieux Francine Durocher André Tchernof Caroline Diorio

Background/Objectives: Mammary adipose tissue functions as an active endocrine organ, potentially influencing breast carcinogenesis through metabolic and inflammatory mechanisms. This systematic review synthesized evidence on associations between mammary adipocyte size, obesity-related adipose tissue dysfunction, and breast cancer. Methods: A comprehensive literature search was conducted across MEDLINE, EMBASE, CENTRAL, CINAHL and Web of Science (January 2010–September 2025) for observational studies measuring mammary adipocyte size in human breast tissue. Two reviewers independently conducted screening following the Cochrane Review’s rigorous methodology, and bias assessment using the ROBINS-E (Risk Of Bias In Non-randomized Studies of Exposure) tool. Random-effects meta-analyses were performed for quantifiable outcomes, with heterogeneity assessed using the I2 statistic. Results: Twenty-one studies were included in the systematic review. Meta-analyses indicated that mammary adipocyte diameter was positively correlated with body mass index (8 studies; n = 720; correlation coefficient (r) = 0.44, 95% CI: 0.29–0.56), crown-like structure (CLS) density (5 studies; n = 383; r = 0.45, 95% confidence interval (CI): 0.36–0.54), aromatase expression (3 studies; n = 333; r = 0.36, 95% CI: 0.05–0.61), and three studies compared adipocyte diameter between CLS-positive and CLS-negative tissue (n = 297; mean difference = 9.69 μm, 95% CI: 4.94–14.44). Conclusions: This review summarizes moderate positive correlations of mammary adipocyte size with systemic adiposity, local breast inflammation, and aromatase expression, supporting a potential role for mammary adipose tissue in obesity-related metabolic dysfunction. Future prospective studies with standardized measurement protocols and improved control for confounding variables are needed to strengthen causal inference and clinical applications.

Cancers doi: 10.3390/cancers18152463

Authors: Vanessa L. Merker Shivani Ahlawat Robert A. Avery Diana Bradford Andrea M. Gross Jennifer Janusz Andrés J. Lessing Linda Manth Miranda L. McManus Beverly Oberlander Dominique C. Pichard William Riter Kavita Y. Sarin Steven Sheard Russell Taylor Sundby Karin S. Walsh Pamela L. Wolters Brigitte C. Widemann Scott R. Plotkin

Background: In decentralized clinical trials, some or all activities occur outside of traditional sites, which may reduce time away from school/work and decrease participation burden for patients and their parents/caregivers. This methodology may improve recruitment and retention in studies, which is important for rare diseases like neurofibromatosis type 1 (NF1) and schwannomatosis (SWN). Published guidance exists for the general conduct of decentralized trials, but specific considerations for clinical trial design and endpoints in NF1/SWN have not yet been explored. Methods: The Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) International Collaboration is a group of researchers, clinicians, and people affected by NF1 and SWN whose shared goal is to advance clinical trial methodology for NF1/SWN. In December 2023, REiNS members met to discuss the opportunities and challenges of conducting NF1/SWN decentralized trials. Results: Endpoints that are promising for use in NF1/SWN decentralized trials include visual acuity (as tested by the computerized amblyopia treatment study HOTV testing algorithm); electronic versions of REiNS-recommended patient reported outcome measures; digital health technologies for functional outcomes; radiography and computed tomography scans for imaging outcomes; remote photography to assess cutaneous neurofibromas; “e-centralized” evaluations of neurocognitive functioning; and remote biomarkers collected with analyte stabilizing tubes and self-collection devices. Conclusions: Further research is necessary to validate endpoints for decentralized trials for NF1/SWN and evaluate their feasibility. However, trial designs that incorporate decentralized elements hold considerable promise for rare diseases like NF1/SWN where patients encounter significant barriers to traditional clinical trial participation.

Cancers doi: 10.3390/cancers18152462

Authors: Riccardo Serra Siddharth R. Shah Adarsha P. Malla Tina Wang Alexander Ksendzovsky Dirk Mayer Eli E. Bar Graeme F. Woodworth

Brain tumors exhibit extensive metabolic reprogramming that supports proliferation, invasion, therapeutic resistance, and adaptation to dynamic microenvironmental conditions. These alterations provide opportunities for metabolic imaging approaches that extend beyond conventional anatomical neuroimaging. Hyperpolarized magnetic resonance imaging (hpMRI) has emerged as a novel metabolic imaging platform capable of non-invasively visualizing real-time cellular metabolism through dynamic nuclear polarization of carbon-13-labeled substrates. By dramatically enhancing magnetic resonance signal intensity, hpMRI enables interrogation of enzyme-specific metabolic pathways and provides unique insight into tumor energetics, metabolic heterogeneity, and treatment response. The distinct contribution of this review is an updated, brain tumor-specific, clinically oriented framework that integrates recent human evidence with longitudinal metabolic phenotyping, emerging pathway-specific probes, acquisition standardization, multimodal validation, and the remaining barriers to clinical implementation. Particular emphasis is placed on hyperpolarized [1-13C]pyruvate, which has demonstrated feasibility and safety in patients with gliomas and has enabled assessment of glycolytic metabolism, oxidative phosphorylation, tumor recurrence, and longitudinal treatment response. Serial changes in lactate and bicarbonate flux may also reflect evolution toward more glycolytic, heterogeneous, and treatment-resistant tumor phenotypes, supporting the potential prognostic value of hpMRI before conventional radiographic progression becomes evident. We also review emerging applications involving α-ketoglutarate metabolism, redox biology, glutathione cycling, perfusion imaging, and molecular characterization of clinically relevant alterations including IDH1, TERT, and c-MYC-associated metabolic programs. In addition, we discuss recent advances in acquisition methods, image standardization, and multimodal integration with conventional MRI and positron emission tomography. Although several technical and logistical challenges remain, hpMRI is an investigational, radiation-free metabolic imaging modality with potential applications in diagnosis, molecular stratification, and treatment monitoring; however, substantial technical, regulatory, logistical, and economic barriers currently limit routine clinical use, molecular stratification, therapeutic monitoring, and precision medicine approaches in neuro-oncology. Continued clinical translation and development of novel metabolic probes may further expand its role in brain tumors and other neurological diseases.

Cancers doi: 10.3390/cancers18152461

Authors: Takafumi Morisaki Takashi Morisaki

The discovery of neoantigens and their application in cancer vaccines have brought about a paradigm shift in cancer immunotherapy, similar to the way in which immune checkpoint inhibitors redefined therapeutic strategies for cancer treatment. Early neoantigen vaccine approaches primarily focused on eliciting HLA class I-restricted CD8+ cytotoxic T lymphocyte (CTL) responses, whereas it has become clear that such strategies alone may be insufficient to establish durable and effective antitumor immunity. Increasing attention has therefore shifted toward HLA class II-restricted neoantigens (“helper neoantigens”) that activate tumor-specific CD4+ helper T cells. Recent studies have revealed that neoantigen-reactive CD4+ helper T cells play a central role in coordinating antitumor immune responses through dendritic cell licensing, thereby sustaining CD8+ CTL function, preventing T-cell exhaustion, and promoting the generation of long-lived memory T cells. These findings have highlighted the pivotal role of helper neoantigens in shaping vaccine efficacy. In this review, we discuss the mechanistic basis underlying the contribution of helper neoantigens to tumor immunity and highlight recent advances in the real-world application of helper neoantigen-based vaccine strategies.

Cancers doi: 10.3390/cancers18152460

Authors: Carley M. Elliott Tamalika Paul Michaela Hall Sofia Killar Eli Vlaisavljevich Irving C. Allen

Focused ultrasound (FUS) comprises a diverse group of non-invasive, non-ionizing acoustic technologies that have evolved from tools for localized tissue destruction into platforms capable of influencing complex biological processes. In oncology, growing evidence suggests that the effects of focused ultrasound extend beyond direct tumor treatment to include modulation of the tumor microenvironment and anti-tumor immunity. This review examines the major FUS modalities currently under investigation for cancer therapy, including high-intensity focused ultrasound (HIFU), intrinsic threshold histotripsy, boiling histotripsy, shock-scattering histotripsy, and low-intensity focused ultrasound (LIFU), with emphasis on the distinct physical mechanisms that underlie their biological effects. Although these modalities differ in how they interact with tissue, they share the capacity to alter tumor biology through changes in antigen availability, inflammatory signaling, and immune cell activity. These responses have been associated with enhanced immune recognition of tumors, remodeling of immunosuppressive microenvironments, and improved therapeutic responsiveness in preclinical and emerging clinical studies. As interest in focused ultrasound continues to expand, understanding the relationship between modality-specific bioeffects and downstream immune outcomes has become increasingly important. Collectively, the literature highlights focused ultrasound as a versatile therapeutic platform capable of linking precise local intervention with broader biological and immunological consequences, supporting its continued development as both a tumor-directed and immune-modulating strategy in cancer therapy.

Cancers doi: 10.3390/cancers18152459

Authors: Alireza Nathani Jack Inglis H. Erhan Dincer

This review examines the expanding role of the pulmonologist in the care of patients with lung cancer, including diagnosis, mediastinal staging, tissue stewardship, therapeutic bronchoscopy, and involvement in longitudinal pulmonary care. A multidisciplinary approach is essential in providing high-quality patient care. Emerging strategies include structured nodule programs, mobile health screening, and artificial intelligence to improve the timely diagnosis of lung cancer.

Cancers doi: 10.3390/cancers18152458

Authors: Parastou Tizro Eric Vail Manoj Sapkota Matthew G. Gayhart Celeste C. Eno

Background/Objectives: Myeloproliferative neoplasms (MPNs) are chronic myeloid malignancies characterized by substantial genetic heterogeneity. Although routine molecular evaluation focuses on canonical driver alterations (BCR::ABL1, JAK2, CALR, and MPL), additional somatic mutations have important diagnostic and prognostic implications. Methods: We retrospectively analyzed 1209 consecutive patients who underwent peripheral blood next-generation sequencing (NGS) for suspected or established MPNs using a comprehensive 75-gene DNA/RNA panel. Results: Canonical driver alterations were identified in 141 patients, while 1068 were driver-negative. Retrospective analysis demonstrated that 251 patients (21%) harbored at least one additional pathogenic or likely pathogenic mutation that was not routinely reported. Among driver-positive patients, 57 of 141 (40%) carried clinically relevant co-mutations, including high-molecular-risk genes such as ASXL1, TP53, SRSF2, SF3B1, RUNX1, U2AF1, and IDH2. Furthermore, 194 of 1068 (18%) driver-negative patients harbored additional pathogenic mutations, several of which supported clonal hematopoiesis or alternative myeloid neoplasms. Peripheral blood and bone marrow molecular findings demonstrated high concordance (R2 = 0.87). Conclusions: These findings indicate that comprehensive NGS performed at the time of initial evaluation provides clinically relevant genomic information beyond canonical driver mutations, improves disease classification and risk stratification, and may facilitate earlier diagnosis and personalized management of patients with suspected MPNs.

Cancers doi: 10.3390/cancers18152457

Authors: Sun Woong Kim Jun Sik Yoon Young Lee Heejoon Jang

Background/Objectives: The 2026 Barcelona Clinic Liver Cancer (BCLC) update recommends surgical resection for a single hepatocellular carcinoma larger than 2 cm with preserved liver function and states that age alone should not preclude surgery. How often eligible older patients undergo resection, and how they fare, remains unquantified. Methods: Using the Korean Primary Liver Cancer Registry (2008–2021), we identified 3374 patients meeting all registry-based eligibility criteria of the 2026 BCLC update. Survival was measured from the date of radiological diagnosis in every patient, with vital status and cause of death obtained by linkage to national death records. We compared use of resection and survival among patients younger than 75 years and those 75 years or older, and across resection, ablation, other treatment, and no treatment, using Cox regression, restricted mean survival time (RMST), and competing-risk models. Results: Resection was performed in 60.6% of patients younger than 75 years versus 28.9% of those 75 years or older (p < 0.001); among older patients not undergoing resection, 21.5% received none. Older age was independently associated with lower odds of resection (adjusted odds ratio 0.36, 95% CI 0.28–0.46; p < 0.001). In this age group, 5-year survival was 61.3%, 62.1%, 32.9%, and 6.5% across the four treatment categories; the adjusted hazard ratio for no treatment versus resection was 4.97 (95% CI 3.26–7.57; p < 0.001). In unadjusted analysis, mean survival within the first 5 years was 13.3 months longer after resection (RMST difference, 95% CI 9.7–16.9; p < 0.001). Findings were consistent in competing-risk, weighted, cirrhosis-adjusted, and multiply imputed analyses. Conclusions: Older patients meeting eligibility criteria underwent resection far less often than younger patients, and a substantial minority received none, a pattern associated with markedly shorter survival.

Cancers doi: 10.3390/cancers18152456

Authors: Federico Venturi Maria Luisa Orlando Barbara Corti Paola Valeria Marchese Francesca Comito Barbara Melotti Elisabetta Magnaterra Biagio Scotti Aurora Maria Alessandrini Leonardo Veneziano Elena Maria Cama Emi Dika

Background: Nevus-associated melanomas (NAM) are frequently diagnosed at an early stage, yet risk heterogeneity within thin tumors remains poorly characterized. Whether classical histopathologic features can refine risk stratification in this subgroup is unclear. Objective: To evaluate the prognostic significance of histopathologic features, particularly mitotic activity and tumor-infiltrating lymphocytes (TILs), in thin nevus-associated melanoma (pTis–pT1a) (<0.8 mm). Methods: Retrospective cohort study of 138 consecutive patients with histologically confirmed NAM diagnosed at a tertiary dermatologic oncology center (October 2006–December 2023). Staging was reassessed as per AJCC 8th edition. A predefined subgroup analysis of 100 patients with thin NAM (pTis–pT1a) evaluated adverse outcomes (distant metastasis or death) within 10 years. Associations were assessed using χ2 tests and logistic regression. Results: Median age was 53.5 years (IQR 44.0–63.8); 60.9% were male. Median Breslow thickness was 0.57 mm (IQR 0.4–0.8). Overall survival was 90.9% at 5 years and 86.0% at 10 years. Among thin NAM, eight patients (8%) experienced adverse outcomes. Mitotic activity ≥ 1/mm2 was associated with higher adverse event rates (10.9% vs. 2.8%; OR, 4.30; 95% CI, 0.51–36.43; p = 0.18). A gradient was observed across TIL categories: adverse events occurred in 13.8% with absent TILs, 7.3% with non-brisk, and 0% with brisk TILs (p = 0.24). Exploratory multivariable analysis showed consistent effect directions without reaching statistical significance. Conclusions: Thin nevus-associated melanomas are not uniformly low risk. Mitotic activity and absent TILs were associated with higher adverse event rates, suggesting that classical histopathologic features may refine risk stratification in early-stage NAM.

Cancers doi: 10.3390/cancers18152455

Authors: Judith Altmann Nadine Einsiedel Janna Pape Susanna Weidlinger Tanya Karrer Michael von Wolff Magdalena Balcerek

Introduction: Leukemia is the most common childhood malignancy. Treatment requires urgent polychemotherapy and may escalate to hematopoietic stem cell transplantation (HSCT) with or without total body irradiation (TBI). Due to the frequently young age at diagnosis, time limitations and unpredictable course, fertility preservation (FP) is especially challenging and may not be feasible prior to treatment, particularly in females. Methods: We conducted a systematic review and meta-analysis of fertility outcomes in leukemia survivors using MEDLINE, Embase, and Cochrane databases (search date: 13 June 2024). Results: Forty-two studies with 2048 patients were included. Overall infertility was 37% (95% CI 23–54%) with substantial heterogeneity. The highest infertility rates were observed after HSCT (68%) and after testicular irradiation (92%) or TBI ≥ 10–12 Gy (66%). Chemotherapy alone was associated with lower infertility (4%). Sex-specific differences were noted, with higher infertility in males following chemotherapy-only regimens (18% vs. 6% in females), while females were more affected after HSCT (70% vs. 59% in males). Subfertility affected about one-fifth of survivors. Conclusions: While standard chemotherapy is associated with relatively low gonadotoxicity, HSCT and irradiation confer substantial risk. These findings support individualized fertility counseling and long-term reproductive follow-up based on treatment exposure.

Cancers doi: 10.3390/cancers18152454

Authors: Robert Rottscholl Johanna Winkelmann Konstantin Fritz Verena Gassenmaier Isabell Goetting Annette Staebler Annika Simma Sascha Hoffmann Birgitt Schoenfisch Stefan Kommoss Sara Y. Brucker Andreas D. Hartkopf Christina B. Walter

Background/Objectives: Numerous innovations have changed diagnosis and treatment of endometrial cancer in recent years, with molecular classification being a major factor. Limited data exist on how molecular classification changes in recurrence or metastasis and what effect this may have on therapy. This retrospective study aimed to compare the molecular classification and other histopathological parameters of the primary tumor with those of recurrence or metastasis and to discuss their implications. Methods: A total of 43 patients with primary endometrial cancer and histologically confirmed recurrence treated at the Tuebingen University Women’s Hospital between January 2003 and January 2017 were identified within a cohort of 964 cases. Immunohistochemistry for mismatch-repair status, estrogen receptor, p53 and L1CAM, as well as next-generation sequencing of the POLE genes were performed. Further histopathological and clinical data were collected and statistical analyses were performed. Results: No POLE-mutated patients were found. A higher proportion of high-grade tumors was observed in the recurrence (30% vs. 46%). All p53-mutated patients remained p53-mutated, while a changed molecular profile of the NSMP and MMRd subtypes was observed in nine patients (21%). L1CAM remained stable in 70% of the patients. A change in molecular profile was not associated with altered prognosis. Conclusions: Our study underlines the importance of additional histopathological analysis in case of recurrence or metastasis for individualized therapy planning. Further studies with larger case numbers are necessary to validate our findings.

Cancers doi: 10.3390/cancers18152453

Authors: Maria Chiara Siciliano Cosimo Lori Margherita Vannucchi Teresa Amato Giorgio Bertolazzi Raffaella Guazzo Onyango Noel Timothy Onyuma Massimo Granai Roberto Boccacci Kiraka Grace Oyiro Peter Simon Onsongo Magoma Georgina Sakeah Patience Wedaga Kwawu Foster Hagembe Mildred Nyagol Joshua Anja Fischer Cristiana Bellan Reiner Siebert Lorenzo Leoncini Stefano Lazzi

Background/Objectives: B-cell receptor (BCR) signalling is implicated in Burkitt lymphoma (BL) lymphomagenesis, although its activation may differ across biological and epidemiological settings. While surface IgM is the predominant immunoglobulin isotype of BCR in BL, cases expressing IgA transcripts or lacking detectable surface immunoglobulin (sIg) expression have been reported, suggesting a more complex pattern of sIg expression than previously recognized. This study aimed to evaluate sIg heavy-chain expression by immunohistochemistry in a relatively large series of BL cases from endemic and sporadic settings and to investigate the mutational landscape of surface immunoglobulin-undetectable (sIg-UND) cases. Methods: sIg heavy-chain expression was assessed by immunohistochemistry in 55 formalin-fixed paraffin-embedded BL samples. Targeted next-generation sequencing was performed on four sIg-UND cases using an Illumina capture-based custom panel covering 74 lymphoma-related genes. KRAS and NRAS hotspot mutations were additionally assessed by real-time PCR. Results: Overall, 41/55 cases showed IgM expression, including 31 IgM-positive and 10 IgM+/UND cases, whereas 8/55 cases showed IgA expression (IgA+/UND). IgA-expressing cases were significantly enriched at mucosal sites, particularly the oral cavity and gastrointestinal tract, consistent with the relevance of these anatomical sites to mucosal IgA production. Six cases lacked detectable sIg expression, showing negativity for all tested immunoglobulin heavy chains in more than 90% of neoplastic cells. Four sIg-UND cases were available for sequencing. These cases harbored mutations affecting genes commonly altered in BL, together with alterations in genes less commonly represented in recurrent BL series, such as MEF2B, CREBBP, PRDM1, PIM1, ARID3A, HIST1H1B, and HIST1H1C. Conclusions: Our study provides a systematic immunohistochemical characterization of surface immunoglobulin heavy-chain expression in a relatively large series of endemic and sporadic BL. We identified a subset of IgA-expressing BL cases enriched at mucosal sites, whereas rarer cases lacked detectable surface immunoglobulin expression. The mutational profile of sIg-UND cases highlights alterations affecting genes involved in epigenetic regulation, chromatin organization, and B-cell differentiation, which may contribute to the biological heterogeneity of these cases. No KRAS or NRAS hotspot mutations were detected in the four sequenced sIg-UND cases, as assessed by targeted NGS and real-time PCR. Further functional studies are needed to clarify the biological and clinical significance of sIg-UND BL cases and to determine the functional relevance of the identified alterations.

Cancers doi: 10.3390/cancers18152451

Authors: Xinmei Chen Zhixiang Wang

The epidermal growth factor receptor (EGFR) was the first receptor tyrosine kinase identified soon after v-Src was recognized as a tyrosine kinase. EGFR signaling begins when EGF binds to EGFR at the cell surface, inducing receptor dimerization, activation, and autophosphorylation. The resulting phosphotyrosine sites recruit downstream effectors that activate signaling cascades such as the RAS-RAF-MEK-ERK and PI3K-Akt pathways, thereby regulating cell growth, proliferation, and survival. EGF binding also promotes EGFR endocytosis, which can direct the receptor to lysosomal degradation. Aberrant EGFR activity is associated with many cancers, and the receptor has been therapeutically targeted using small-molecule tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs). Furthermore, EGFR endocytosis has been exploited for the targeted delivery of anticancer agents into EGFR-expressing cancer cells through antibody–drug conjugates (ADCs) and antibody–nanoparticle conjugates (ANCs). Although ADCs and ANCs both utilize mAbs as homing mechanisms to recognize cancer-associated antigens, they further harness EGFR endocytosis to deliver therapeutic payloads directly into target cells. In this review, we briefly discuss EGFR structure, activation, signaling, and endocytosis, as well as the mechanisms underlying EGFR function in cancer development. We then focus on current advances and future perspectives in using EGFR endocytosis pathways to improve targeted cancer drug delivery and therapy, particularly in the context of ANCs.

Cancers doi: 10.3390/cancers18152452

Authors: Carla S. Dos Santos Ana C. Magalhães Veronica Fernandes António Pombinho Lurdes Torres Margarida André Adelaide Sousa Pedro Sequeira Daniel Pinto Cláudia Pereira Paulo M. Costa Lúcio Lara Santos Luisa Pereira

Background/Objectives: Prostate cancer (PC) exhibits marked disparities in incidence and mortality across ethnicities, with men of Sub-Saharan African (SSA) ancestry experiencing 1.7 and 2.0 times higher values, respectively, than European men (EUR). However, SSA preclinical models remain scarce (just one commercial cell line). In this study, we established and characterized a novel panel of PC cell lines derived from SSA patients using conditional reprogramming (CR), a method that enables efficient propagation of primary cells while maintaining their genotypic and phenotypic features. Methods: CR was applied to five SSA-PC samples, and successfully propagated samples were authenticated by STR and ~1 million SNP profiling, and extensively characterized for proliferative capacity, migratory behaviour, karyotyping and epithelial and prostate tumour lineage markers. To explore drug response profiles, a high-throughput screen (HTS) of 1280 clinically annotated compounds was conducted. Results: Three SSA-PC cell lines were successfully established and authenticated, and five potential drug hits were validated. A new finding was the reduced sensitivity of SSA-derived models (9.0 times difference compared to commercial EUR PC cell lines) to camptothecin, a TOP1 inhibitor, while being equally sensitive to epirubicin hydrochloride, a TOP2 inhibitor. The cardiac glycoside digoxin, anthelmintic pyrvinium pamoate and antirheumatic agent auranofin were also efficient drugs in the in vitro testing. Conclusions: These results support the relevance of SSA-derived PC models for preclinical drug screening and highlight the value of including ancestry-diverse models in oncobiology research.

Cancers doi: 10.3390/cancers18152450

Authors: Malwina Lisek Julia Tomczak Natalia Bochenska Julia Duraj Tomasz Boczek

Calcium signaling is a fundamental regulator of cell physiology, controlling proliferation, differentiation, migration, metabolism, gene expression, and cell death. In cancer, these signaling pathways are extensively remodeled to generate spatially and temporally restricted Ca2+ signals that support malignant progression while avoiding calcium-induced cytotoxicity. PMCAs traditionally regarded as high-affinity calcium extrusion pumps, have recently emerged as multifunctional regulators of compartmentalized calcium signaling. In addition to maintaining low cytosolic Ca2+ concentrations, PMCA isoforms organize specialized signaling microdomains by interacting with receptors, ion channels, scaffold proteins, and downstream signaling molecules, thereby selectively modulating calcium-dependent pathways involved in tumor growth and metastasis. Accumulating evidence demonstrates that PMCA isoforms exert distinct, context-dependent functions in cancer. PMCA1 primarily contributes to basal calcium homeostasis but has also been implicated in tumor progression, angiogenesis, and regulation of the tumor immune microenvironment. PMCA2 promotes survival and oncogenic signaling in HER2-positive breast cancer through stabilization of receptor signaling complexes. PMCA3 has been linked mainly to endocrine tumors and selected malignancies, although mechanistic evidence remains limited. PMCA4 exhibits the greatest functional diversity, acting either as a tumor suppressor or a promoter depending on the cancer type by regulating localized calcium signaling, cell migration, invasion, differentiation, and interactions with oncogenic signaling networks. This review summarizes current advances in the structural biology, regulation, and signaling functions of PMCA isoforms, with particular emphasis on their emerging roles in cancer biology. We also discuss the potential of PMCAs as prognostic biomarkers and therapeutic targets, highlighting the importance of isoform-specific strategies for targeting calcium signaling in cancer.

Cancers doi: 10.3390/cancers18152449

Authors: Huiwen Liu Jiazi Zhou Hong Liu Depei Wu

Background: Multiple myeloma (MM) is a malignant plasma cell disorder associated with substantial mortality and long-term disability. With rapid population aging in China, its disease burden may be increasing, yet comprehensive long-term assessments remain limited. Methods: Using data from the Global Burden of Disease Study 2023, we evaluated trends in prevalence, incidence, deaths, and disability-adjusted life years (DALYs) of MM in China from 1990 to 2023. Age-standardized rates were analyzed using Joinpoint regression to estimate temporal trends. Results: Between 1990 and 2023, prevalence, incidence, deaths, and DALYs of MM increased markedly in China, with consistent upward trends in age-standardized rates. The burden was concentrated among older adults and was higher in males than females. Decomposition analysis showed that epidemiological changes were the primary driver of increased DALYs and deaths. Forecasting analyses suggest that although age-standardized mortality and DALY rates may gradually decline, the absolute number of deaths is expected to continue rising. Conclusions: The burden of MM in China has increased substantially over the past three decades and is projected to remain high. Strengthening early detection, risk-oriented prevention, and long-term management strategies is essential to mitigate future disease burden.

Cancers doi: 10.3390/cancers18152447

Authors: Bobban Subhadra Ryan Green Prakasha Kempaiah Niya Bobban Lary A. Robinson Subhra Mohapatra

Background: Lung cancer (LC) remains a leading cause of cancer-related mortality, often compounded by suboptimal chemotherapy efficacy and systemic toxicity. Emerging evidence implicates the gut microbiota in modulating tumor progression, immune function, and treatment outcomes. Methods: We evaluated Zowell, a novel live bacterial therapeutic (LBT) developed via LiveBiom® co-fermentation, as an adjunct to cisplatin in a murine LC model harboring humanized microbiota. Mice were assigned to treatment groups: Zowell alone, cisplatin alone, their combination, and fecal microbiota transplantation (FMT) as a benchmark. Results: Zowell monotherapy significantly reduced tumor burden, and its combination with cisplatin produced synergistic anti-tumor effects. 16S rRNA sequencing revealed enrichment of beneficial taxa (Bifidobacterium, Lactobacillus, and Allobaculum) and suppression of contextual genera (Clostridium and Akkermansia). Treatment rebalanced gut ecology, evidenced by a lowered Firmicutes/Bacteroidetes ratio and increased alpha diversity. Zowell outperformed FMT in reducing tumor volume and inflammatory indices. Lipidomic profiling of tumor tissues identified elevated levels of immunomodulatory lipid mediators, including resolvins and prostanoids, suggesting remodeling of the tumor microenvironment toward inflammation resolution and immune activation. Conclusions: These findings support Zowell as a precision microbiome therapeutic that potentiates chemotherapy through gut microbial reprogramming and tumor lipid signaling modulation, offering translational promise for enhancing immunotherapeutic response and mitigating chemotherapy-induced toxicity.

Cancers doi: 10.3390/cancers18152448

Authors: Maria Chiara Sighinolfi Vincenzo Cavarra Giuseppe Pallotta Francesco Rossi Nicoletta Testori Simone Assumma Enrico Panio Filippo Turri Carlo Gandi Giuseppe Palermo Mauro Ragonese Pierluigi Russo Nazario Foschi Filippo Gavi Giuseppe Colloca Luca Tagliaferri Chiara Ciccarese Roberto Iacovelli Angelo Totaro Marco Racioppi Bernardo Rocco

Background: Elderly and frail patients undergoing surgery for urological cancer have increased vulnerability to postoperative complications, delayed recovery, and functional decline. The da Vinci Single-Port (SP) platform may reduce surgical stress by enabling regionalized extraperitoneal, retroperitoneal, or transvesical access through a single incision. Objective: The objective was to provide a narrative review of the comparative evidence on da Vinci SP versus conventional multi-port (MP) robotic surgery in elderly or frail urological cancer patients. Methods: A structured search was performed to identify comparative studies reporting outcomes in patients defined as elderly by chronological age (≥65 years) or as frail by a validated frailty index. Findings are reported separately according to the vulnerability construct that was actually measured. Because of procedural and methodological heterogeneity, a narrative synthesis was performed, and the risk of bias was appraised qualitatively along the domains of the ROBINS-I tool. Results: Only three retrospective comparative studies are currently available: two on robot-assisted radical prostatectomy (one in patients aged ≥65 years and one in patients stratified by the 5-item modified frailty index) and one on robot-assisted partial nephrectomy in patients aged ≥65 years. Across these studies, SP surgery was associated with fewer early postoperative complications, shorter length of stay, and more favourable recovery-related endpoints, and in the frailty-stratified study the apparent protective effect increased with frailty burden. All estimates are those published by the original authors, are reported descriptively, and were not pooled. Importantly, in none of the three studies was the SP platform compared with MP surgery performed through the same access route: SP procedures were predominantly extraperitoneal or retroperitoneal and MP procedures were predominantly transperitoneal, so the effect of the platform cannot be separated from that of the access route. Conclusions: The available data are compatible with a reduction in early perioperative morbidity after SP robotic surgery in selected elderly or frail urological cancer patients, particularly when the platform enables extraperitoneal or retroperitoneal access. Because this evidence rests on three retrospective studies at serious risk of bias, the findings are preliminary and hypothesis-generating rather than confirmatory. Prospective studies incorporating geriatric screening, validated frailty metrics, patient-reported recovery, cost-effectiveness, and long-term oncological outcomes are needed.

Cancers doi: 10.3390/cancers18152446

Authors: Haonan Jin

The study by Yoon et al [...]

Cancers doi: 10.3390/cancers18152445

Authors: Xinliang Liu Cheng Zhou Wenlong Qiu Zongqi Li Fangze Wei Tixian Xiao Shiwen Mei Fei Huang Fuqiang Zhao Qian Liu

Purpose: This study aimed to determine the optimal temporal threshold for distinguishing “early” from “late” liver metastasis in patients who developed liver metastasis after colorectal cancer (CRC) surgery, and to evaluate whether KRAS and BRAFV600E mutations, along with other clinicopathological factors, are associated with the timing of liver metastasis. Methods: This retrospective study utilized clinical and pathological data from patients who developed liver metastasis after radical CRC surgery at two centers from 2019 to 2023. X-tile software was used to identify the optimal temporal threshold. Logistic regression analysis was applied to determine if KRAS/BRAFV600E mutations and other potential factors are independently associated with the time to onset of liver metastasis. Results: X-tile analysis identified 11 months post-surgery as the optimal cutoff for distinguishing early metachronous liver metastasis (EMLM) from late metachronous liver metastasis (LMLM), classifying 114 cases into the EMLM group and 72 into the LMLM group. Comparative analysis indicated statistically significant differences between the two groups in lymphovascular tumor emboli, perineural invasion, and postoperative adjuvant therapy (p < 0.05). Logistic regression analysis revealed that neither KRAS mutation (OR, 1.185; 95% CI: 0.641–2.190; p = 0.587) nor BRAFV600E mutation (OR, 2.836; 95% CI: 0.302–26.642; p = 0.363) was independently associated with the timing of liver metastasis. In contrast, postoperative adjuvant therapy showed a statistical association with a likelihood of LMLM (OR, 0.253; 95% CI: 0.105–0.611; p = 0.002). Conclusions: This study identified 11 months post-CRC surgery as the optimal cutoff for differentiating EMLM versus LMLM. In this cohort, no statistically significant association was observed between KRAS/BRAFV600E mutations and the timing of liver metastasis, whereas postoperative adjuvant therapy was statistically correlated with the likelihood of LMLM. This stratification may guide personalized surveillance strategies and provide valuable insights for future mechanistic investigations into the temporal heterogeneity of post-surgical liver metastasis. However, the interpretation and generalization of the findings require external validation in prospective cohorts.

Cancers doi: 10.3390/cancers18152443

Authors: Indiana Neumann Eva Bezak Shahraam Afshar Vahid Edward Simpson Scott Penfold

Background/Objectives: Particle arc therapy (PArc) is an emerging radiotherapy technique with the potential to improve dose conformity and organ-at-risk (OAR) sparing, while also enhancing biological effectiveness through favourable dose-averaged linear energy transfer (LETd) distributions. This scoping review aimed to evaluate the current evidence on PArc, including dosimetric, biological, and delivery-related outcomes, and to identify key limitations and future research directions. Methods: Following the PRISMA-ScR 2018 guidelines, a systematic search was conducted across MEDLINE, Scopus, and Google Scholar in December 2025, identifying 74 relevant studies. Eligible studies included peer-reviewed articles reporting treatment planning, dosimetric, biological, or delivery outcomes, with comparisons to conventional particle therapy techniques. Data were extracted and synthesised qualitatively due to heterogeneity in study designs, reported metrics, and outcome definitions. Results: Relative to conventional particle therapy techniques, PArc generally demonstrated maintained target coverage, enhanced conformity (median relative improvement in conformity index: 6.3%), and more variable dose homogeneity. Improved OAR sparing and reduced integral dose (median relative reduction in integral dose: 10.5%) were commonly observed, although these benefits were sometimes accompanied by an increased low-dose bath, reflecting a trade-off between low-dose and intermediate–high-dose regions. Reductions in intermediate-to-high dose volumes were often associated with improved modelled biological outcomes, including reduced predicted normal tissue complication probabilities and secondary cancer risk. Enhanced LETd distributions were reported, with redistribution of high LETd from surrounding healthy tissue to the tumour volume, particularly in studies of carbon-ion arc therapy and radioresistant tumours. Robustness findings were mixed, with trade-offs among conformity, homogeneity, delivery efficiency, and LETd enhancement, and strong dependence on tumour site, delivery strategy, and evaluation method. Delivery efficiency was also variable, depending on machine capabilities and optimisation strategies. Conclusions: PArc shows significant potential to improve radiotherapy outcomes; however, the current evidence is largely limited to in silico studies. Further research is required to establish standardised methodologies and evaluation frameworks, integrate biological optimisation, and validate findings through prospective clinical studies before routine clinical implementation can be achieved.