Cancers doi: 10.3390/cancers18101589

Authors: Monireh Sadat Seyyedsalehi William Anthony Powley Paolo Boffetta

Introduction: Talc, commonly used in products like baby powder and cosmetics, has been studied for a possible link to female genital cancers, especially ovarian cancer. However, evidence is inconclusive. We conducted a systematic review and meta-analysis to assess the association between talc exposure and the incidence and mortality of ovarian, cervical, and endometrial cancers, including ovarian cancer subtypes. Method: We searched MEDLINE (PubMed) and SCOPUS databases up to January 2026 for cohort and case–control studies. Studies were assessed for quality using a modified Newcastle–Ottawa Scale. Due to the nature of available data, meta-analysis was performed only on case–control studies on ovarian cancer, using a random-effects model. Publication bias was assessed through funnel plots and Egger’s test, and a leave-one-out sensitivity analysis was performed. Stratified analyses were conducted based on geographic location, year of publication, exposure source, and tumor characteristics. Additionally, a two-stage dose–response meta-analysis was performed for ovarian cancer regarding frequency and duration of talc use. Results: Our review identified 37 studies related to ovarian cancer, one to cervical cancer, and six to endometrial cancer. Twenty-five case–control studies were included in the meta-analysis. Results showed a positive association between talc use and ovarian cancer risk (RR 1.32; 95% CI: 1.25–1.39), with stronger associations observed for women who applied talc directly to the genital area (RR 1.38) and those who used talc after bathing (RR 1.30). The risk was also higher for specific ovarian cancer subtypes, such as serous (RR 1.36) and endometrioid tumors (RR 1.35). No evidence of publication bias was found. Results of the pooled analysis of four cohort studies showed no association (RR for ever-use 1.08; 95% CI: 0.99–1.17, no trend according to duration or frequency of use). For cervical and endometrial cancers, no significant associations with talc exposure were observed. Conclusions: Case–control studies suggest a modest link between genital talc use and ovarian cancer risk, especially serous and endometrioid types. Cohort studies show no association, and no links were found for cervical or endometrial cancers. Accordingly, the results should be interpreted with caution, and the current evidence does not conclusively establish a causal relationship.

Cancers doi: 10.3390/cancers18101588

Authors: Panuch Eiamprapaporn Cindy Venegas Mata Raj Nandani Thiti Susiriwatananont Keith L. Knutson Saranya Chumsri

Triple-negative breast cancer (TNBC) represents a biologically aggressive subtype with limited therapeutic targets; however, tumor-infiltrating lymphocytes (TILs) have emerged as the most robust immune biomarker with compelling prognostic and predictive significance. This comprehensive review synthesizes current evidence on TIL assessment methodology; the immunobiological landscape of TNBC, including regulatory T cell populations and PD-L1 correlations; gene expression underpinnings of the tumor immune microenvironment; and systematic evidence from meta-analyses and clinical trials. Meta-analytic estimates demonstrate that high TIL levels are associated with improved overall survival (HR 0.58, 95% CI 0.48–0.71) and disease-free survival (HR 0.66, 95% CI 0.57–0.76), with each 10% TIL increment conferring incremental benefit. High TILs predict superior pathologic complete response to neoadjuvant chemotherapy (OR 2.14, 95% CI 1.43–3.19), with lymphocyte-predominant breast cancer achieving pCR rates exceeding 80% with pembrolizumab-based chemoimmunotherapy. Future directions include prospective TIL-guided treatment trials, artificial intelligence-enabled standardization, and emerging adoptive TIL cellular therapies for metastatic disease.

Cancers doi: 10.3390/cancers18101587

Authors: Shirsa Udgata Alexa E. Schmitz Amani A. Gillette Alexandra G. Sorenson Jeremiah M. Riendeau Rian Engeldinger Jordan N. Stoecker Alyssa K. Steimle Katherine A. Johnson Devan Kittelson Alexandra Isaak Jeremy D. Kratz Evie Carchman Randall Kimple Cheri A. Pasch Melissa C. Skala Dustin A. Deming

Background: Therapies for metastatic colorectal cancer (CRC) are largely chosen without considering inter-patient heterogeneity, leading to unnecessary side effects without clinical benefit for some patients. Patient-derived cancer organoids (PDCOs) faithfully recapitulate the morphology and molecular profiles of the primary tumors from which they are derived, making them attractive preclinical models for predicting response to standard therapies, and thus, for use in drug development assays. Methods: Here, we investigate the hidden subclonal driver mutations in CRC PDCOs and the importance of individual PDCO-level heterogeneity when addressing PDCO treatment responses using changes in diameter and optical redox imaging. PDCO response is then compared to clinical response across a cohort of subjects with CRC receiving chemotherapy and/or chemoradiation. Results: Change in diameter and optical redox imaging are more sensitive to detecting therapeutic response than endpoint and well-level measurements. These measurements accurately reflect clinical responses to chemotherapy and chemoradiation. Conclusions: Overall, these studies demonstrate the importance of PDCO-level methods of PDCO assessment and further establish PDCOs as powerful tools for drug response assessment and developmental therapeutic studies.

Cancers doi: 10.3390/cancers18101585

Authors: Takuma Aoki Makoto Ohno Go Horiguchi Shunsuke Yanagisawa Daisuke Kawauchi Takaki Omura Genta Fujii Koji Saito Naoya Hashimoto Yoshitaka Narita

Background/Objectives: Glioblastoma (GBM) comprises a contrast-enhancing (CE) mass and peritumoral hyperintensity on fluid-attenuated inversion recovery (FLAIR) on magnetic resonance imaging (MRI). Although a smaller residual FLAIR lesion volume (FLV) after gross total resection (GTR) is associated with longer survival, the clinical observation of rapid FLV reduction within the first postoperative month remains unknown. We evaluated the independent prognostic contributions of early and late FLV reduction in patients with newly diagnosed GBM, isocitrate dehydrogenase (IDH)-wildtype, who underwent GTR. Methods: In a retrospective cohort of 51 adults with GBM, IDH-wildtype, who underwent GTR and standard chemoradiotherapy, semi-automated FLV was measured on MRI preoperatively, immediately postoperatively (FLV0), at 1 month (FLV1), and at 3 months (FLV3). FLV changes were expressed as percentage changes relative to the preceding timepoint (ΔFLV0-1, ΔFLV1-3). Using a 3-month landmark analysis, multivariable Cox models for overall survival (OS) were fitted, adjusted for age, O6-methylguanine-DNA-methyltransferase promoter (pMGMT) methylation, and postoperative Karnofsky Performance Status (KPS). Results: In the multivariable 3-month landmark analysis, each 10-percentage-point early FLV reduction (∆FLV0-1[10-pp]) was associated with lower mortality risk (hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.82–0.99, p = 0.037) whereas a late FLV reduction (∆FLV1-3[10-pp]) showed a smaller association with OS (HR 0.99, 95% CI 0.98–1.00, p = 0.043). In an exploratory dichotomized analysis at a 20% reduction threshold, early responders (∆FLV0-1 ≥ 20%) had markedly better OS (HR 0.33, p = 0.010). Conclusions: In selected patients with GBM, IDH-wildtype, who achieved radiographic GTR and received standard chemoradiotherapy, early postoperative FLV reduction at 1 month independently predicted longer OS, with a substantially larger effect than late reduction. Prospective multi-center validation is required before clinical implementation.

Cancers doi: 10.3390/cancers18101586

Authors: Nils Ludwig Carolin Feldmann Silvia Spoerl Saigopalakrishna S. Yerneni

Rationale: Oral squamous cell carcinoma (OSCC) carries a poor prognosis despite advances in multimodal therapy. Nanomedicine represents a compelling strategy to enhance targeted drug delivery and improve therapeutic outcomes. Here, we investigated sEV-mediated delivery of curcumin as a novel therapeutic approach for OSCC. Methods: Small extracellular vesicles (sEVs) were isolated from Jurkat cells by size-exclusion chromatography and loaded with curcumin via sonication to generate JCsEV. Functional effects were assessed in vitro using wound healing, transwell invasion, and metabolic activity assays across multiple cancer cell lines. Therapeutic efficacy in vivo was evaluated in the 4-nitroquinoline 1-oxide (4-NQO) immunocompetent murine model of oral carcinogenesis. Female C57BL/6J mice received intraperitoneal treatment for four weeks with PBS, free curcumin, unloaded JsEV, or JCsEV. Tumor number, tumor burden, and body weight changes were assessed at the experimental endpoint. Results: In vitro, JCsEV significantly inhibited tumor cell migration, invasion, and metabolic activity compared with controls (p < 0.05). In vivo, treatment with JCsEV significantly reduced tumor number and tumor burden in the 4-NQO model (p < 0.01). In addition, body weight loss was reduced in JCsEV-treated mice compared with controls. Conclusion: sEV-mediated delivery of curcumin effectively suppresses tumor progression in experimental OSCC. These findings establish proof-of-concept for sEV-based nanomedicine as a therapeutic strategy for OSCC and provide a compelling rationale for further translational investigation of sEVs as drug delivery platforms.

Cancers doi: 10.3390/cancers18101584

Authors: Laurens Hermie Charlotte Harth Kathia De Man Alexander Decruyenaere Celine Jacobs Karen Geboes

Background/Objectives: Image-guided percutaneous thermal ablation is an established local treatment for selected patients with liver metastases, provided that accurate tumor targeting and adequate ablation margins can be achieved. However, lesion detection, target delineation, and intraprocedural margin verification remain challenging in post-chemotherapy or previously treated lesions that may become morphologically inconspicuous or radiologically occult. Catheter-assisted C-arm (cone-beam) CT hepatic arteriography (CBCT-HA) improves intraprocedural visualization of tumor vascularity and supports streamlined workflows within the angiography suite, yet it may underestimate tumor extent in lesions with limited or absent angiographic conspicuity. This pictorial essay illustrates the feasibility and added value of integrating preprocedural PET/CT with intraprocedural CBCT-HA for liver tumor ablation. Methods: Representative clinical cases of percutaneous liver tumor ablation guided by PET–CBCT-HA fusion are presented. Preprocedural PET/CT datasets were rigidly registered and fused with intraprocedural CBCT-HA to support tumor detection, target delineation, ablation planning, and real-time intraprocedural margin assessment. The complementary roles of metabolic and angiographic imaging were evaluated qualitatively across different clinical scenarios. Results: PET–CBCT-HA fusion improved detection and delineation of viable tumor components that were occult or insufficiently defined on CBCT-HA alone, particularly in post-chemotherapy or previously treated lesions. Conversely, CBCT-HA identified angiographically evident lesions not apparent on PET/CT. The combined approach enabled confident target definition, biologically informed ablation planning, and immediate post-ablation verification of metabolic and angiographic coverage, supporting margin-oriented intraprocedural decision-making. Conclusions: By integrating complementary metabolic and vascular information into a single-session workflow, PET–CBCT-HA fusion represents a multimodal guidance strategy that enhances lesion visualization and intraprocedural margin assessment. This approach may improve local tumor control in complex post-treatment and oligometastatic liver disease.

Cancers doi: 10.3390/cancers18101583

Authors: Anastasiya S. Volkova Timur T. Valiev Mikhail V. Kiselevskiy Irina Zh. Shubina Kirill I. Kirgizov Svetlana R. Varfolomeeva Ivan S. Stilidi

Background: Anaplastic large cell lymphoma (ALCL) accounts for up to 15% of all pediatric and adolescent non-Hodgkin lymphomas and is characterized by significant clinical, morphological, and immunohistochemical heterogeneity. Expression of T-cell markers on tumor cells is considered as one of the factors in an unfavorable prognosis in ALCL. However, no treatment protocols based on ALCL immunological heterogeneity have been used, yet. Objective: To compare the effectiveness of immunophenotype-oriented chemotherapy in children with ALCL treated according to the ALCL NII DOiG 2003 protocol versus the standard NHL-BFM 95 protocol. Methods: A retrospective–prospective analysis of 100 newly diagnosed ALCL patients, who were treated between 2000 and 2023, was performed across five pediatric oncology and hematology centers in Russia. Patients were divided into two groups: those treated with the NHL-BFM 95 protocol (n = 52) and those treated with the ALCL NII DOiG 2003 protocol (n = 48). Comparative analysis used Kaplan–Meier survival curves constructed for each group, and statistical analysis was performed with IBM SPSS Statistics 21.0. Results: The 10-year overall survival was significantly higher in the ALCL NII DOiG 2003 group (95.3 ± 3.3%) compared to that of the NHL-BFM 95 group (82.0 ± 5.4%, p = 0.037). Event-free survival was also improved (95.3 ± 3.3% vs. 68.6 ± 6.5%, p = 0.001), as well as the relapse-free survival (97.3 ± 2.7% vs. 74.4 ± 6.4%, p = 0.003). Conclusions: The immunophenotype-oriented approach of the ALCL NII DOiG 2003 protocol provides significantly improved long-term outcomes compared to the common NHL-BFM 95. These findings support the benefit of personalized immunologically targeted therapy in pediatric ALCL treatment.

Cancers doi: 10.3390/cancers18101582

Authors: Bibo Gao Junjian Dai Xiao Yu Shilong Cao Congcong Wu Changsen Zhu Bingchan Li Anquan Shang Ning Wang Jianguo Meng

Background: Prolonged hospitalization after endoscopic endonasal transsphenoidal surgery for non-functioning pituitary adenomas increases costs and complications. Early identification of high-risk patients is crucial for optimizing perioperative management. Methods: In this dual-center retrospective study of 368 patients, a predictive model was developed using a training cohort (n = 268). Prolonged length of stay was defined as ≥75th percentile (≥16 days). LASSO regression selected features from clinical, radiological, and perioperative variables. Independent predictors from multivariable logistic regression were dichotomized via ROC analysis and integrated into a nomogram. Model performance was assessed internally and validated externally (n = 100). Results: Six independent predictors were identified: age > 50 years, vertical tumor diameter > 17.8 mm, anteroposterior diameter > 20.5 mm, transverse diameter > 17.8 mm, anesthesia duration > 194 min, and systolic blood pressure > 119 mmHg. The nomogram showed moderate but reproducible discrimination (AUC = 0.762 in training; 0.750 in validation). Calibration and decision curve analysis confirmed good fit and clinical utility. Conclusion: We developed and validated a practical nomogram predicting prolonged hospitalization risk using readily available perioperative variables. This tool may assist individualized risk stratification and perioperative planning in comparable clinical settings, with potential implications for patient flow and resource utilization.

Cancers doi: 10.3390/cancers18101581

Authors: Tianhao Zeng Yilin He Teng Zhang Caiyue Ren Jun Xu Jingyi Cheng Wenlong Ming

Objectives: To exploratorily evaluate the potential of baseline dedicated breast PET (D-PET) for noninvasive prediction of pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) in HER2-positive (HER2+) breast cancer, and to investigate a fusion strategy integrating conventional radiomics and deep learning features. Methods: We developed a multi-representation framework with radiomics based on data-driven high-/low-uptake metabolic subregions and deep learning trained on standardized 3D tumor volumes, and intratumoral heterogeneity (ITH) was quantified on the largest slice as an additional comparator. The outputs of these pathways were subsequently integrated through feature-level and decision-level fusion. Model performance was evaluated using the area under the receiver operating characteristic curve (AUC), and interpretability analyses were applied to identify image regions and features contributing to predictions. Results: In a HER2-positive breast cancer cohort (n = 147) with baseline D-PET, deep learning (3D ResNet, AUC = 0.79) and radiomics (logistic regression, AUC = 0.78) achieved comparable performance on the primary test set, whereas the ITH model showed limited value (AUC = 0.61). Fusion further improved discrimination on test set 1, with an AUC of 0.83 for decision-level fusion and 0.84 for feature-level fusion. On test set 2, decision-level fusion achieved the highest AUC (0.84), and feature-level fusion maintained stable performance (AUC = 0.80). Conclusions: In this exploratory study, baseline D-PET showed promising performance for noninvasive prediction of NAC response in HER2+ breast cancer. The fusion of deep learning and radiomics yielded improvements over single-representation models, highlighting the potential role of D-PET models as decision-support tools.

Cancers doi: 10.3390/cancers18101580

Authors: Soo Jin Seung Jane Bayani Lena Nguyen Ning Liu Jodi Gatley Anisia Wong Emilie Richard Sarah L. Barker Anna Ying-Wah Lee John M. S. Bartlett David Berman Andrew Loblaw Craig C. Earle Nicole Mittmann

Background: This study was conducted to evaluate the population-level healthcare resource utilization (HCRU) and costs for men diagnosed with low-risk prostate cancer (PCa) either on active surveillance (AS) or not on AS, in which AS was defined as receiving no treatment within 1 year of diagnosis and two biopsies. Methods: AS men aged 40 to 105 years, diagnosed with stage I or II PCa, had a prostate-specific antigen (PSA) level < 20 ng/mL, a Gleason score between 5 and 7, and were matched (1:1) with men not receiving AS. The index date is defined as the date 1 year after PCa diagnosis. HCRU and costs were assessed using a macro-based costing methodology and costs standardized to 2023 CAD. Means (SD) and medians (interquartile ranges) per person-year values were reported annually. Results: During the year leading up to the index date, the mean number of HCRU per patient-year (PPY) was significantly lower for the AS cases versus non-AS in terms of cancer clinic visits (1.7 vs. 26.7), hospital outpatient clinic visits (3.6 vs. 4.9), all physician visits (16.3 vs. 17.5), and specialist visits (10.7 vs. 11.6). The mean overall cost PPY was $6100 ± $12,400 for AS cases and $10,400 ± $17,800 for non-AS men (median overall cost PPY= $3500 [IQR: $2100–$5700] vs. $3700 [IQR: $2100–$7200] (p = 0.0001, respectively). Conclusions: HCRU and costs calculated for AS and non-AS low-risk PCa men indicate the cost savings potential for AS.

Cancers doi: 10.3390/cancers18101579

Authors: Louise N. Blaha Nicole M. Derosia Jeffrey D. Neighbors Raymond J. Hohl

Background: Merkel cell carcinoma (MCC) is a rare malignancy of the skin caused by Merkel cell polyomavirus (80% of cases) or by ultraviolet (UV) sun exposure (20% of cases). The isoprenoid biosynthesis pathway (IBP) is an essential metabolic pathway shown to be upregulated in tumorigenesis, causing aberrant activation of Ras and Rho GTPases and resulting in unregulated cellular proliferation and survival. Methods: Through the use of pharmacological inhibitors of the IBP, we assessed the role of the IBP and its downstream targets in viral-positive and viral-negative MCC cell lines. To identify the most critical IBP intermediates, cellular metabolic activity, cell death and cell cycle distribution were measured after IBP perturbation. Results: Across all cell lines, treatment with IBP inhibitors, especially fluvastatin, decreased metabolic activity; however, perturbation of different intermediates resulted in variable responses between viral-positive and viral-negative cell lines. Conclusions: Our findings demonstrate varying dependence on the IBP between viral-positive and viral-negative MCC and highlight the importance of cellular dynamics when determining a treatment regimen for patients with MCC.

Cancers doi: 10.3390/cancers18101578

Authors: Inês Leitão Joaquim Soares do Brito Miguel Esperança-Martins Cecília Melo-Alvim Raquel Lopes-Brás Daniel Jordão André Abrunhosa-Branquinho Filomena Pina Dolores Lopez-Presa Luís Vicente Saraiva Arielle Turpin José Portela

Appendicular soft tissue sarcoma (aSTS) is a group of highly heterogeneous tumors of mesenchymal origin for which standard care usually includes surgical resection with or without radiation therapy. The main goal of surgical treatment in aSTS is to achieve wide tumor resection with negative margins while promoting the best function possible for the affected limb. Orthoplastic surgery represents the concept of a multidisciplinary approach comprising a synergistic collaboration between orthopedic and plastic surgeons. The development of this philosophy allows us to push forward the concept of limb salvage surgery for sarcomas, even when dealing with extremely complex cases. Reconstruction techniques integrated with orthoplastic principles range from simple to highly complex surgeries. Vascularized auto- or allo-graft tissue transfers illustrate how far reconstruction options can go, allowing for repair of large soft tissue defects or even restoration of muscle function in key anatomic segments after oncological resection. The reported experience with orthoplastic philosophy in aSTS suggests that it is a feasible and reproducible strategy that can achieve limb salvage rates above 90%, optimal oncologic local control characterized by more than 95% of wide margin resection, and improved functional and esthetic results. Most patients with aSTS treated under orthoplastic principles present good-to-excellent postoperative Musculoskeletal Oncology Society (MSTS) scores, confirming the advantages of this comprehensive approach. While there is significant experience with the orthoplastic approach for trauma cases, the road still needs to be paved for musculoskeletal oncologic reconstruction. Nonetheless, the results are promising and could inspire a wider adoption of structured orthoplastic protocols for sarcoma patient care. Herein, the authors explore the current practice regarding the application of collaborative orthoplastic approaches for the management of appendicular soft tissue sarcomas, reporting on outcomes and elaborating on future trends.

Cancers doi: 10.3390/cancers18101577

Authors: Gianluca Giannarini Alessandro Crestani Giuliana Lista Paolo Corsi Gioacchino De Giorgi Davide Minardi Luca Di Gianfrancesco Davide De Marchi Antonio Amodeo Angelo Porreca

Background/Objectives: Surgical refinements in robot-assisted partial nephrectomy (RAPN) aim to reduce morbidity and optimize renal function preservation, particularly in patients with high-complexity renal tumours. This study describes the no-touch adaptive technique for RAPN and compares its perioperative outcomes, postoperative complications, and resulting early renal function with those of the conventional approach. Methods: A cohort of 72 consecutive patients with high-complexity renal tumours undergoing RAPN was evaluated. The study group included 38 patients treated with the no-touch adaptive technique, while 34 patients underwent the conventional approach. The no-touch adaptive technique consisted of sutureless, off-clamp, simple tumour enucleation with incremental haemostasis and the option to shift to arterial clamping, tumour enucleoresection, or renorrhaphy as needed. The conventional technique involved on-clamp minimal enucleoresection with double-layer renorrhaphy. Outcomes assessed included completion of a fully no-touch procedure, perioperative metrics, 90-day postoperative complications, and 3-month renal function change from baseline. Results: Baseline characteristics were comparable between groups. A fully no-touch RAPN was achieved in 30/38 (79%) patients. Adaptations were required in eight cases: shift to main arterial clamping (n = 2), renorrhaphy (n = 5), or both (n = 1), with one conversion to total nephrectomy due to intractable bleeding. Estimated blood loss was similar between groups (study: 150 mL [IQR 75–250] vs. control: 180 mL [IQR 100–400]). Length of stay was significantly shorter in the study group (3 days [IQR 3–4]) compared with controls (5 days [IQR 6–8]). Any-grade 90-day complications were significantly lower with the no-touch technique (21% vs. 56%, p < 0.01). Clinically significant 3-month eGFR decline occurred in 14% of controls versus 0% of study patients (p = 0.02). Conclusions: The no-touch adaptive RAPN technique is feasible in high-complexity renal tumours and provides reduced morbidity and superior early renal function preservation compared with the conventional approach.

Cancers doi: 10.3390/cancers18101576

Authors: Ömer Akgüller Mehmet Ali Balcı Gabriela Cioca

Background: Clinically actionable biomarkers that reliably distinguish glioblastoma (GBM) from lower-grade glioma (LGG) across expression platforms remain an unmet need. Existing transcriptomic signatures are frequently confounded by batch effects, platform heterogeneity, and the inability to translate to single-patient clinical workflows. Methods: We developed a topology-aware biomarker discovery framework in which analysis-of-variance ranking defines a candidate gene pool, hypergraph co-expression analysis at correlation threshold τ=0.75 identifies densely connected hubs within this pool, rough set reduct optimisation selects a minimal sufficient subset of these hubs, and a Random Forest classifier with stratified cross-validation performs the final discrimination. The pipeline was trained exclusively on GSE16011, a single-platform single-institution Affymetrix microarray cohort free from batch-class confound, and validated on two independent RNA-sequencing cohorts (CGGA-325 and CGGA-693). Robustness was further assessed through bootstrap optimism correction, DeLong cross-cohort equivalence testing, leave-one-gene-out analysis, and a sensitivity analysis under WHO CNS5 (2021) class definitions. Results: The pipeline identified a ten-gene biomarker panel (CSMD3, CHI3L1, PLP2, FRY, FCHSD2, ADM, MCUB, ANXA1, DUSP26, and HK2), achieving a fivefold cross-validation AUROC of 0.906±0.029 and a held-out AUROC of 0.831. External validation yielded AUROC =0.838 in CGGA-325 and AUROC =0.836 in CGGA-693. The biomarker-derived risk score demonstrated independent prognostic value in CGGA-693 (multivariate Cox hazard ratio =9.195; p<0.001) after adjustment for WHO histological grade, with Kaplan–Meier analysis confirming highly significant survival separation (log-rank p=4.60×10−37). Class definitions in the present work follow the histology-based pre-2021 WHO classification used in the source datasets and do not directly incorporate WHO CNS5 (2021) molecular criteria, such as IDH mutation status, that distinguish IDH-wild-type glioblastoma from IDH-mutant grade-IV astrocytoma. After excluding IDH-mutant grade-IV cases from the CGGA cohorts, the classification AUROCs increased to 0.906 in CGGA-325 and 0.872 in CGGA-693, with a Cox risk-score hazard ratio of 8.57 (p=1.4×10−13) and log-rank p=1.4×10−32 retained on the CNS5-aligned cohort. Conclusions: The methodological contributions introduced in this study, namely, the topology-aware hypergraph candidate pool construction, the rough set combinatorial reduct selection, the fixed-reference single-sample normalisation protocol, and the nested validation regime combining bootstrap optimism correction with cross-platform DeLong testing, are platform agnostic and directly applicable to future CNS5-aligned cohorts as such resources become publicly available, supporting the prospective re-derivation of molecularly defined glioma signatures within the integrated histopathological and molecular frameworks of contemporary neuro-oncology.

Cancers doi: 10.3390/cancers18101575

Authors: Mattia Russel Pantalone Giuseppe Stragliotto Nerea Martin-Almazan Inti Peredo-Harvey Jorge L. Jimenez-Macias Afsar Rahbar Sean Lawler Jiri Bartek Cecilia Söderberg-Naucler

Background: Emerging evidence suggests that antiviral treatment targeting human cytomegalovirus (HCMV) may improve outcomes in patients with glioblastoma (GBM). In this study, we analyzed serological data from the placebo-controlled VIGAS1 trial (Eudra number 2006-002022-29), which assessed the effect of valganciclovir (VGCV) on GBM progression in 42 patients, for impact of VGCV in preventing HCMV reactivation. Methods: VIGAS1 patients had undergone radical surgery and were randomized to receive either VGCV (n = 22) or placebo (n = 20) alongside standard radiochemotherapy. Blood was prospectively collected at baseline and 3-, 12- and 24-week follow-up visits. GBM cell lines and a cytomegalovirus-infected murine brain cancer model were used to validate the clinical findings. Results: Over the 24-week study period, we found that HCMV reactivation, as inferred from IgM seropositivity, occurred in 58.3% of patients in the placebo group, whereas this was completely prevented in the VGCV-treated group except for one patient with no treatment compliance (p = 0.0005). HCMV reactivation was linked to early recurrence. IgG-positive patients treated with VGCV showed a significantly longer time to progression (TTP) than those receiving placebo (6.7 vs. 3.7 months, p = 0.0408). We found a significant association between higher steroid doses and enhanced reactivation in the placebo group. In vitro and murine studies confirmed that corticosteroids, combined with radiation therapy, enhanced cytomegalovirus reactivation, which was mitigated by antiviral treatment. Conclusions: These findings suggest that preventing HCMV reactivation with antiviral therapy may improve patient outcomes, especially in HCMV-seropositive GBM patients, and further support the hypothesis that HCMV is a tumor-promoting virus.

Cancers doi: 10.3390/cancers18101573

Authors: Nhan (Justin) Vu Albert Du Daniel E. Hyer Alonso N. Gutierrez Andrew Wroe Ryan T. Flynn Kaustubh Patwardhan Eduardo Pons Kevin Erhart Karsten Wake Wesley S. Culberson Patrick M. Hill Blake R. Smith

Background and objectives: Previous dynamic collimator system (DCS) developments included: (1) hardware construction and commissioning, (2) an accurate dose calculation algorithm, (3) a quality assurance approach, and (4) development of optimization tools for treatment planning. Clinical DCS implementation necessitates efficient treatment plan delivery and fully integrated tools. In this work, a novel algorithm for minimizing treatment time was developed with the goal of reducing the DCS time increase, relative to conventional pencil beam scanning, to one minute or less per beam. In this extensive end-to-end evaluation, treatment plans generated with a modified U.S. Food and Drug Administration (FDA)-cleared treatment planning system were delivered on an Ion Beam Applications (IBA) Proteus Plus proton therapy system, with and without a DCS, to evaluate delivery times and dosimetric accuracy for a relatively large patient dataset, providing evidence of the clinical potential of the approach. Methods: Ten previously treated brain patients were replanned, consisting of both deep-seated central and superficial targets, the latter of which required an external 4 cm polyethylene range shifter. DCS treatments were optimized using a maximum conformity planning technique exploiting per-spot collimator capabilities. An optimization algorithm was incorporated to minimize treatment delivery time by determining the optimal sequencing of spot positions and collimator settings. Plan quality was quantified using conformity and dose-volume histogram (DVH)-based metrics while delivery accuracy was validated through measurements using both patient-specific quality assurance (PSQA) and log file analysis at the Miami Cancer Institute (MCI). Results: The DCS reduced the dose gradient index on average by 26.4% (17.7–37.1%) and the mean dose to the adjacent healthy tissue (within 10 mm of the target) by 19.3% (16.3–26.2%). The average reduction to the mean and maximum dose to the involved optic nerves was 50% (25.7–80.7%) and 18.7%, respectively, and the mean and D2cc dose to the involved brainstem was reduced by 63.9% (31.5–96.4%) and 60.4% (10.8–99.8%), respectively. PSQA pass rates among DCS-collimated and baseline uncollimated treatments were 99.7% and 99.2%, respectively. DCS treatment fields were delivered within an average of 49 s (32–61 s) from their uncollimated intensity modulated proton therapy (IMPT) counterparts. Average spot position errors were −0.05 ± 0.2 mm and 0.04 ± 0.2 mm for the x- and y-position, respectively. The maximum error in magnitude for collimator positioning was 0.2 mm or less. Conclusions: DCS collimated IMPT treatments can provide significant dosimetric improvements over uncollimated treatments. These highly collimated treatments can be delivered with sufficient accuracy for clinical use while incurring an additional time penalty of around one minute or less per field compared to uncollimated treatments.

Cancers doi: 10.3390/cancers18101574

Authors: Enrico Battistella Luca Pomba Riccardo Toniato Andrea Piotto Ivana Cataldo Mariella Lo Schirico Antonio Toniato

Background: Primary thyroid lymphoma (PTL) is a rare malignancy, accounting for less than 5% of thyroid cancers and less than 2% of extranodal lymphomas. It predominantly affects older women and is strongly associated with autoimmune thyroiditis, particularly Hashimoto’s thyroiditis. Diagnosis is often challenging due to non-specific clinical, imaging, and cytological findings, and the role of surgery has progressively shifted from therapeutic to primarily diagnostic. Methods: We conducted a retrospective single-center case series including nine patients treated for PTL between 2015 and 2025 at a tertiary referral endocrine surgery center. An analysis was conducted on clinical presentation, pre-existing thyroid disease, diagnostic work-up, histopathological subtypes, treatment strategies and outcomes. All patients underwent preoperative ultrasound and fine-needle aspiration cytology (FNAC); surgical intervention was performed to confirm cytology results, when cytology was inconclusive or when compressive symptoms were present. Results: The cohort included six females and three males, with a median age of 65.2 years. Four patients had Hashimoto’s thyroiditis and three had multinodular goiter. FNAC was diagnostic or suggestive of lymphoma in three cases only, and surgical biopsy or thyroidectomy for a definitive diagnosis was performed in eight cases. One case started follow-up after cytology and flow cytometry. Histological subtypes were heterogeneous, including diffuse large B-cell lymphoma, Burkitt’s lymphoma, Hodgkin lymphoma, follicular lymphoma, high-grade B-cell lymphoma, and MALT lymphoma. Seven patients received combined chemoimmunotherapy. A complete response was obtained in eight patients, with a minimum follow-up of three years; one patient died of unrelated causes. Conclusions: PTL remains a rare and diagnostically challenging thyroid malignancy. FNAC alone is frequently insufficient, and surgical biopsy retains an important role in cases with high clinical suspicion or compressive symptoms. While surgery has limited therapeutic value, a multidisciplinary approach and timely, tailored treatment are crucial to achieving favorable outcomes.

Cancers doi: 10.3390/cancers18101569

Authors: Huan Liu Meilan Chen Xiaozhe Li Lifen Kuang Jingxia Li Yanjuan Li Juan Li

Background/Objectives: The optimal duration of maintaining minimal residual disease (MRD) negative status remains unclear in transplant-eligible newly diagnosed multiple myeloma (TE-NDMM). This single-center retrospective study aimed to explore the minimum duration of sustained MRD negativity with prognostic value. Methods: This research included 223 TE-NDMM patients who achieved at least two consecutive MRD-negative assessments after initial treatment. We analyzed the influence of sustained MRD negativity on survival in different risk stratifications. Results: There was no difference in progression-free survival (PFS) between high-risk (HR) patients with an MRD negativity duration of ≥2 years and patients in the standard-risk (SR) group (70.77 vs. 67.38 months, p = 0.529). In SR patients, PFS showed no significant difference between patients maintaining MRD negativity for 2–3 years and those maintaining MRD negativity for more than 3 years (72.25 months vs. 107.50 months, p = 0.103). In contrast, in the HR group, there was no difference between a duration of 4–5 years and ≥5 years (NR vs. 84.53 months, p = 0.136). A duration over 2 years was associated with superior overall survival (OS) for all patients. Conclusions: Long-term maintenance of MRD-negative status was associated with good prognosis. Sustained MRD negativity for ≥2 years was associated with reducing the adverse influence of high-risk cytogenetics, and a duration over 4 years may be correlated with longer PFS in high-risk multiple myeloma patients in an exploratory analysis based on limited cases.

Cancers doi: 10.3390/cancers18101571

Authors: Liang Zhao Raghothama Chaerkady Naseruddin Höti Eric Zhao Anirudh Kashyap Morgan Fair Qing Wang Xiaonan Kang

Background: Prostate cancer remains a significant global health burden, yet current diagnostic reliance on PSA screening is heavily hampered by limited specificity and high rates of overdiagnosis. Methods: To address this clinical bottleneck, we utilized a highly sensitive Complete360®-MyMeta targeted-metabolomics platform to perform high-resolution profiling of 43 metabolites across the carnitine, polyamine, and methylation networks in plasma from a discovery cohort of all-stage (I–IV) PCa patients and healthy controls. Results: Our analysis identified 28 significantly altered metabolites (p < 0.05), revealing profound systemic metabolic reprogramming characterized by the depletion of circulating TML and putrescine, alongside the elevation of L-acetylcarnitine and sarcosine. These systemic shifts are consistent with a localized tumoral “metabolic sink”, wherein upregulated mitochondrial TML import via the SLC25A45 transporter actively fuels fatty acid oxidation, while parallel androgen signaling drives massive polyamine synthesis. Translating these mechanistic insights into a clinical tool, we developed a multivariable diagnostic signature utilizing mathematically stable bipartite metabolic ratios. An optimized, cross-validated model combining L-acetylcarnitine/TML and sarcosine/putrescine effectively mitigated physiological noise to achieve robust diagnostic separation, yielding an area under the curve (AUC) of 0.99. Conclusions: Ultimately, this study provides a discovery-phase proof-of-concept for the SLC25A45-TML axis as a mechanistically grounded, stage-independent liquid biopsy, offering a rational, non-invasive framework to significantly improve PCa detection.

Cancers doi: 10.3390/cancers18101572

Authors: Yoshito Nishimura Mariko Fujii Nanami Sako Quynh Thi Vu Ko Harada Hideharu Hagiya Urshila Durani Stephen M. Ansell James R. Cerhan Toshihiro Koyama

Background/Objectives: Racial/ethnic and regional disparities in neoplasm-related mortality remain a significant public health challenge. In this study, we aimed to evaluate long-term trends in county-level neoplasm-related mortality rates by race/ethnicity in the United States and examine associations with social determinants of health. Methods: We conducted a cross-sectional ecological study using population-based data from the Global Burden of Disease Study, including individuals residing in 50 states of the United States and the District of Columbia from 2000 to 2019. We analyzed age-standardized neoplasm-related mortality rates by ethnicity/race. Joinpoint regression analysis was used to identify significant changes in mortality trends, summarized as average annual percentage change. County-level correlations between mortality and key social determinants of health were also assessed. Results: Neoplasm-related mortality rates declined across all racial/ethnic groups from 2000 to 2019; however, disparities persisted. The age-standardized neoplasm-related mortality rates per 100,000 population decreased in all racial/ethnic subgroups. The average annual percentage change ranged from −0.94% (Hispanic and non-Hispanic American Indian or Alaska Native) to −1.90% (Black). Sex-specific analyses revealed similar trends. Southeastern states experienced slower declines than Northeastern states did. County-level smoking and poverty rates were positively correlated, whereas the primary care physician-to-population ratio, excessive alcohol consumption rate, mammography screening rate, and median household income were inversely correlated with neoplasm-related mortality rate, varying by race/ethnicity. Conclusions: Targeted, community-specific interventions are required to reduce inequities in cancer outcomes.

Cancers doi: 10.3390/cancers18101570

Authors: Öznur Aydın Onur Şahin Enis Akca Derya Deniz Kürekci Sude Hatun Aktimur Engin Kelkitli Mehmet Turgut

Background and Objectives: The hemoglobin, albumin, lymphocyte, and platelet (HALP) score is an immunonutritional biomarker reflecting systemic inflammation, nutritional status, and immune competence. Its dynamic behavior and prognostic relevance in multiple myeloma (MM) following autologous stem cell transplantation (ASCT) remain insufficiently characterized. Materials and Methods: In this retrospective cohort study, 95 MM patients undergoing ASCT were analyzed. HALP scores were calculated at diagnosis and at post-transplant day +100, and dynamic changes (ΔHALP) were assessed. Associations with overall survival (OS) and progression-free survival (PFS) were evaluated using Kaplan–Meier and multivariable Cox regression analyses, with maintenance therapy incorporated as a covariate. Results: During a median follow-up of 50 months (range: 11.0–144.0), 36.8% of patients progressed or relapsed, and 23.2% died. Baseline HALP was associated with both OS and PFS in unadjusted analyses; however, the inverse association at diagnosis was substantially attenuated after adjustment for maintenance therapy (HR: 0.71, 95% CI: 0.28–1.80; p = 0.466). HALP at day +100 showed a robust association with PFS that strengthened after adjustment (HR: 3.27, 95% CI: 1.45–7.38; p = 0.004). The discriminative performance for treatment response was limited, with 95% CIs encompassing AUC = 0.50. Conclusions: Post-transplant HALP at day +100 emerged as the most robust HALP-based prognostic indicator for PFS. Given the small sample size, limited OS events (n = 22), use of outcome-driven cut-offs, and absence of cytogenetic and minimal residual disease data, dynamic HALP assessment may provide exploratory prognostic information warranting validation in larger, prospective, multi-center cohorts.

Cancers doi: 10.3390/cancers18101568

Authors: Yin M. Myat Kyaw Z. Thein Myat M. Han Manmeet Ahluwalia Sarbajit Mukherjee Kyaw L. Aung

Tumor-agnostic therapies represent an evolving approach in oncology, shifting from conventional histology-based treatment models to strategies guided by molecular alterations. Regulatory approvals of therapies targeting tumors harboring genomic alterations such as NTRK and RET fusions, BRAF V600E mutation, and those with deficient mismatch repair (dMMR) and a high tumor mutational burden (TMB-H) have demonstrated clinical activity across multiple cancer types. However, responses to these therapies are not uniform across all tumors. This review examines the variability of clinical outcomes across different cancer histologies and the challenges associated with this tumor-agnostic treatment paradigm. Despite sharing the same molecular alterations, some malignancies, including pancreatic and colorectal cancers, demonstrate lower response rates due to tissue-specific resistance mechanisms such as bypass signaling pathways and co-occurring genomic alterations. We discuss how these biological differences influence treatment response and their implications for future drug development and clinical trial design. Addressing these biological and clinical complexities will be essential to optimize the use of tumor-agnostic therapies across diverse cancer types.

Cancers doi: 10.3390/cancers18101567

Authors: Trevor Silva Tomoko Yamazaki John M. Creasy Jon M. Gerry Binbin Zheng-Lin Amar J. Srivastava Kristina H. Young

Background/Objectives: The selection of neoadjuvant therapy for patients with non-metastatic pancreatic adenocarcinoma remains challenging. Methods: We performed a single-institution, retrospective analysis of 79 patients who underwent resection of their pancreatic adenocarcinoma after receiving neoadjuvant therapy. Clinical and pathologic data were collected. Tumor fibrosis was quantified using Masson’s trichrome staining, tumor-infiltrating lymphocytes (TIL) were evaluated by an AI-based analysis of whole-slide H&E images, and immune cell populations were quantified by multiplex immunohistochemistry. Correlation analyses were performed between neoadjuvant treatment regimen, tumor regression, immune phenotypes, and survival. Results: All patients received chemotherapy, 77% FOLFIRINOX and 23% Gemcitabine/nab-paclitaxel (Abraxane). Eighteen percent of patients went on to receive radiation. Tumor regression grade (TRG) correlated with the neoadjuvant regimen. A reduction in tumor markers and the baseline neutrophil-to-lymphocyte ratio (NLR) correlated with overall survival. Among patients with an NLR > 3.3, FOLFIRINOX conferred a survival benefit over Gemcitabine/nab-paclitaxel, and radiation trended towards improved survival. Radiation was associated with increased fibrosis and reduced infiltration of CD8+ and regulatory T cells (Tregs). Increased Tregs and PDL1+ stromal cells were associated with poor response to neoadjuvant therapy, and NLR > 3.3 correlated with increased Treg infiltration. Conclusions: Our data suggest that patients with a high baseline NLR may benefit from intensified neoadjuvant therapy with FOLFIRINOX and radiation. Combination immunotherapy targeting Tregs and the PD1/PDL1 axis may further improve outcomes.

Cancers doi: 10.3390/cancers18101566

Authors: Chintan Patel Austin J. Terlecky Melissa Baker Tara Lozy Kelly K. Yen Navjot Kaur Lauren Machere Alaa Ali Christina Cho Michele L. Donato Pashna N. Munshi Barry N. Kreiswirth Scott D. Rowley

Background: Fluoroquinolone prophylaxis during autologous stem cell transplantation (aSCT) reduces the risk of fever but raises the risk of bloodstream infection (BSI) with fluoroquinolone-resistant Enterobacterales (FRE). We performed a prospective cohort study to detect the presence and potential gain or loss of colonic FRE colonization using serial sampling before and after aSCT in a uniform population of patients with a diagnosis of multiple myeloma. Methods: Eligible subjects underwent aSCT after conditioning with dose-intense melphalan, 200 mg/m2. Peri-anal swabs were obtained before aSCT, upon hospital discharge, and 12–16 weeks after transplantation. Samples were cultured in tryptic soy broth supplemented with either ciprofloxacin or ceftriaxone with subsequent plating onto selective chromogenic agar designed to facilitate recovery and differentiation of Enterobacterales. Results: FRE colonization on pre-transplant sampling was detected for 23 of 117 subjects (19.7%) and 29 of 98 (29.6%) subjects at hospital discharge after a course of fluoroquinolone (116/117 subjects) prophylaxis (p < 0.001) and 28 of 92 (30.4%) subjects at 12–16 weeks. Including all three sampling time points, 48 of 117 subjects (41.0%) tested positive for FRE colonization. In total, 58 of the 90 FRE isolates (64.4%) from 48 subjects expressed extended-spectrum beta-lactamase (ESBL). Three FRE-colonized subjects developed FRE BSI. Bloodstream isolates for two subjects were identical to the organisms identified on pre-transplant sampling. Conclusions: We hypothesize that fluoroquinolone prophylaxis of subjects with undetected low levels of FRE colonization allows the expansion of the FRE population, placing subjects at risk of BSI with fluoroquinolone-resistant (and ESBL-expressing) Enterobacterales. Pre-transplant testing for FRE colonization permits patient-specific design of prophylactic and empiric antibiotic regimens.

Cancers doi: 10.3390/cancers18101565

Authors: Julia N. C. Parlow Nicolas Salcedo-Porras Fatma AlBulushi Stephen Yip Eric McGinnis Tara Spence

Background/Objectives: Genomic alterations play a central role in diagnosis, prognostication, and therapeutic planning for hematolymphoid malignancies. At our tertiary care center, frontline genomic testing relies on optical genome mapping, karyotyping, and fluorescence in situ hybridization, with targeted next-generation sequencing (NGS) performed externally. To provide more comprehensive genomic profiling, we evaluated two large-panel NGS platforms and subsequently performed a clinical validation of the selected assay. Methods: The Illumina PanHeme DNA panel and the SOPHiA Genetics Community Myeloid Solution were compared using 24 bone marrow aspirate specimens with previously characterized alterations, including single nucleotide variants (SNVs), insertions/deletions (indels), and copy number variants (CNVs). The selected panel underwent full analytical validation using 60 specimens. Results: Both panels demonstrated excellent concordance for SNVs and indels, with comparable analytical performance and workflow. CNV calling with SOPHiA was notably strong. Platform selection was influenced by practical considerations, including panel content and cost, leading to a preference for further evaluation of the Illumina assay. Clinical validation of the Illumina PanHeme DNA panel, along with a complementary RNA Exome panel, was subsequently performed. Sequence variant detection showed 100% concordance with orthogonal testing, while CNV detection was variable, reflecting known limitations of targeted NGS. The RNA panel detected all expected fusion transcripts. Conclusions: These findings demonstrate robust analytical performance of both evaluated DNA panels. Clinical validation of the Illumina PanHeme DNA and RNA Exome assays supports their use for comprehensive molecular profiling of hematologic malignancies.

Cancers doi: 10.3390/cancers18101564

Authors: Dia Kakkar Saloni Saxena Utkarshita Dhawan Naman Dosi Charvi Khanna Souren Paul

Autophagy and apoptosis are two evolutionarily conserved catabolic processes that play important roles in maintaining cellular homeostasis and in determining cell fate when cells are exposed to various stresses in vivo. The interaction between autophagy and apoptosis has been studied extensively in cancer research, and it has been shown to affect cancer initiation and tumor formation, disease progression, therapeutic resistance, and overall survival. Autophagy typically functions as a cytoprotective mechanism in cancer cells subjected to metabolic, hypoxic, or therapeutic stress, whereas apoptosis primarily functions as an intrinsic programmed cell death pathway. While apoptosis and autophagy function as distinct pathways, there is significant molecular crosstalk, allowing cells to modulate their behavior from survival to death depending on the severity and duration of exposure to a given stressor and the cellular environment. This review examines the molecular landscape of the autophagy–apoptosis interplay in cancers, with special attention paid to the major signaling pathways involved and their biological outcomes in oncology. We examine the molecular mechanisms and signal transduction pathways involved in the crosstalk between autophagy and apoptosis in cancer. In particular, we focus on several key proteins that regulate this crosstalk, including kinases, caspases, heat shock proteins and transcription factors. Furthermore, we describe the major signal transduction pathways that regulate this crosstalk, including the PI3K/Akt/mTOR, MAPK, unfolded protein response, oxidative stress, and calcium signaling pathways. Additionally, we discussed how dysregulation of these pathways contributes to cancer progression and treatment resistance. Finally, we summarized the use of currently available therapeutic agents targeting the crosstalk between autophagy and apoptosis, including FDA-approved drugs and natural products, with the potential to enhance the effectiveness of anticancer treatments. A better understanding of this complex process will allow the development of new, precision-based, combination cancer therapies.

Cancers doi: 10.3390/cancers18101563

Authors: Tiffany Jan Miranda Chen Fan-Ying Chan Nicole Kuderer Alexandre Chan

Background/Objectives: Using real-world data, this study evaluates the use of ADCs over a decade across six University of California (UC) medical centers, focusing on the incidence of neutropenia-related adverse effects and associated clinical outcomes. Methods: A real-world retrospective study utilizing UC Health Data Warehouse records of patients receiving at least one dose of the ten most-used ADCs at one of the 6 UC hospitals between 2012 and 2024. The outcomes evaluated in this study were grade 3+ neutropenia and febrile neutropenia (FN) during any treatment cycle, and healthcare utilization outcomes including G-CSF prophylaxis, hospital and ICU admission, and mortality. Multivariate logistic regression was conducted to identify predictors for neutropenia-related events after the first dose of ADC. Results: Data from 3511 patients (mean ± SD age: 56.7 ± 17.6 years) were analyzed. The most commonly observed cancer types were breast cancer (43.4%), lymphoid, hematopoietic (41.8%), and urinary tract cancer (13.4%). The top three most commonly prescribed ADCs were fam-trastuzumab deruxtecan (22.6%), ado-trastuzumab emtansine (19.4%), and brentuximab vedotin (18.1%). Their respective all-cycle rates of FN were 5.4%, 1.2%, and 10.4%, while grade 3+ neutropenia rates were 16.4%, 5.1%, and 40.1%. Gemtuzumab ozogamicin and inotuzumab ozogamicin were associated with the highest rates of FN (both 18.1%), and inotuzumab ozogamicin was associated with the highest rates of hospital admissions (27.1%), ICU admissions (3.8%), and deaths (5.2%). Anemia and immunodeficiency disorders were identified as predictors for first-dose FN among patients receiving ADCs. Conclusions: Real-world data from this large multi-center cohort showed substantial variation in neutropenia-related events across ADCs. As ADC use continues to grow, these findings highlight the need for vigilant monitoring and proactive supportive care.

Cancers doi: 10.3390/cancers18101562

Authors: Dana Bunevich Monika Wojarska Klaudia Kokot Stanisław Antoniak Amelia Barszczewska Marcel Barbucha Natalia Miszkin Bogdan Jabłoński Jerzy Jankau

Background/Objectives: Keratinocyte carcinomas (KCs), including squamous cell carcinomas (SCCs) and basal cell carcinomas (BCCs), are the most common malignancies worldwide. Accurate delineation of surgical margins is essential to ensure oncological control while preserving favourable aesthetic outcomes. Optical coherence tomography (OCT) is a non-invasive, real-time, high-resolution technique that may facilitate preoperative and intraoperative margin assessment. This systematic review aims to analyse existing evidence on the use of in vivo OCT in the assessment of surgical margins in KC. Methods: This systematic review was conducted in accordance with the PRISMA guidelines. The articles included were retrieved from the PubMed, Web of Science, Scopus and EBSCO databases. The search was limited to studies published between 2010 and November 2025. The inclusion criteria were the application of in vivo OCT as an adjunctive method in the surgical excision of KC. A total of 11 studies involving 303 patients met the inclusion criteria. OCT was used preoperatively, intraoperatively, combined pre- and intraoperatively and both pre-, intra- and postoperatively, with most studies focused on margin delineation by itself. Results: Agreement between OCT and histopathology ranges from 84% to 95.5%. Surgical benefits were observed in both conventional surgery and Mohs micrographic surgery, including reduction in MMS stages (1.89 to 1.23), fewer stages required, and narrower excision margins. Conclusions: Based on data analysis, it may be assumed that in vivo OCT may have potential in non-invasive margin assessment in the surgical treatment of KC. The available evidence is limited by the heterogeneity of protocols and devices and variability between lesion types, as well as the small sample sizes and limited comparability. Further research should focus on randomised multicentre trials involving large cohorts, cost–benefit analysis and evaluation of operator-dependent variability.

Cancers doi: 10.3390/cancers18101561

Authors: Luigi Schiavone Iliana Bednarova Marcella Buono Chiara Dal Bosco Domenico Ruggieri Lucia Pilati Massimo Ferrucci Roberto Grassi Francesca Caumo

Background: Preoperative contrast-enhanced breast imaging, particularly magnetic resonance imaging (MRI) and contrast-enhanced mammography (CEM), has become increasingly integrated into the surgical management of breast cancer. Although these techniques improve detection of multifocal, multicentric, and contralateral disease, their clinical value cannot be defined by sensitivity alone. Methods: This article was conceived as a critical narrative review supported by a targeted literature search primarily conducted in PubMed/MEDLINE, with additional cross-checking in Scopus and reference lists. English-language studies addressing preoperative MRI or CEM in relation to surgical planning, re-excision, mastectomy, additional disease detection, and oncologic outcomes were prioritized. Overall, 38 clinically relevant studies were included in the qualitative narrative synthesis. Results: A decision-oriented reading of the literature suggests that preoperative contrast-enhanced imaging does not produce a uniform clinical effect, but rather reshapes management through recurring patterns. Three main patterns can be identified: (1) refinement of surgical extent through improved disease mapping, most clearly in invasive lobular carcinoma, where MRI may reduce repeat surgery without consistently increasing mastectomy rates; (2) pre-emptive escalation aimed at avoiding reoperation, particularly in ductal carcinoma in situ, where lower re-excision rates are often accompanied by higher initial mastectomy rates; and (3) decision amplification driven by the detection of additional or indeterminate disease, frequently resulting in additional biopsies and treatment escalation without consistent evidence of long-term oncologic benefit. Across large observational cohorts, routine preoperative MRI has not been consistently associated with improvements in overall survival, disease-free survival, or locoregional control in unselected populations. These patterns should be understood as interpretive categories derived from recurring trends in a heterogeneous literature, rather than as formally validated decision classifications. Conclusions: The value of preoperative contrast-enhanced breast imaging depends less on sensitivity itself than on how imaging findings are translated into surgical action. Selective, question-driven use appears most valuable in settings such as invasive lobular carcinoma and assessment of nipple–areola complex involvement, whereas routine use in unselected populations often appears to increase surgical intensity more clearly than it improves long-term oncologic outcomes. Contrast-enhanced imaging should therefore be regarded as a decision-shaping tool whose clinical usefulness depends on explicit interpretive and multidisciplinary thresholds.

Cancers doi: 10.3390/cancers18101560

Authors: Jackson T. Bowers Jasmine Zain

Primary cutaneous anaplastic large cell lymphoma (pcALCL) is a type of cutaneous T-cell lymphoma (CTCL) classified as a CD30+ lymphoproliferative disorder along with lymphomatoid papulosis. Although it is the second most common subtype of CTCL after mycosis fungoides/Sézary syndrome, it remains rare, with an incidence of fewer than 0.5 cases per million person-years. Despite its histologic similarity to systemic anaplastic large cell lymphoma, pcALCL follows a largely indolent course with excellent outcomes, with disease-specific survival rates of 86–95% in contemporary series. This narrative review summarizes the clinical presentation, diagnostic evaluation, and management of pcALCL based on a semi-structured literature search, with emphasis on prospective studies and clinically relevant retrospective data. Diagnosis remains challenging due to overlap with other CD30-positive lymphoproliferative disorders and reactive conditions, requiring careful clinicopathologic correlation and exclusion of systemic disease. While regional lymph node involvement may be present, available evidence suggests it does not significantly impact prognosis, highlighting the importance of avoiding overtreatment. Management strategies are guided by disease extent, with strong evidence supporting skin-directed therapies, particularly radiation, for localized disease. For multifocal or relapsed disease, brentuximab vedotin demonstrates the most robust prospective data and has reshaped the treatment landscape; however, alternative systemic therapies, including methotrexate and retinoids, remain relevant in selected patients. Overall, current management is supported largely by non-randomized data, and key gaps remain in risk stratification, optimal sequencing of therapies, and management of uncommon aggressive variants.

Cancers doi: 10.3390/cancers18101559

Authors: Oussema Khamessi Rihab Mahjoub Ghada Mahjoub Kais Ghedira

Background/Objectives: The rapid expansion of targeted therapies has reshaped oncology by exploiting ligand-receptor interactions (LRI) to improve treatment specificity and patient outcomes. However, the data describing these ligands remain fragmented across multiple sources, limiting accessibility for researchers and clinicians. To address this gap, we developed the OncoSolidDB, the first curated and oncology-focused bioinformatics database dedicated to ligands associated with solid malignancies. Methods: OncoSolidDB integrates and harmonizes data from reliable repositories, including ChEMBL, DrugBank and the Anti-Cancer Fund, consolidating curated structural, chemical, pharmacological, and clinical annotations along with standardized identifiers. Results: The database currently encompasses 243 ligands across 15 major solid tumor types including breast, lung, colorectal, melanoma, prostate, gastric, ovarian, cervical, bladder, esophageal, head and neck, thyroid, pancreatic, renal and liver cancer (Hepatocellular Carcinoma, HCC). Each entry is annotated by standardized identifiers (DrugBank, ChEMBL), approval year, chemical structures (SMILES strings, 2D images), and downloadable protein structure files (PDB format). Temporal coverage spans 1953–2025, enabling exploration of historical trends in oncology drug approvals. The database content is suitable for bioinformatics analysis, molecular docking, virtual screening, ligand-based modeling, and drug repurposing studies. Outputs are available through a freely accessible web interface that supports search browsing by cancer type. Conclusions: By consolidating oncology-specific ligand data into a single, structured platform, OncoSolidDB offers a valuable resource for advancing drug discovery, repurposing strategies, and the rational design of next-generation targeted therapies for solid tumors. OncoSolidDB is accessible via our Bioinformatics Research PortalEinstein.

Cancers doi: 10.3390/cancers18101557

Authors: Antonio Giuseppe Amico Sonia Sapignoli Samuele Cavinato Badr El Khouzai Marco Andrea Rossato Marta Paiusco Chiara Paronetto Alessandro Scaggion Matteo Sepulcri Andrea Bettinelli

Background/Objectives: Online adaptive radiotherapy (oART) generates plans at each fraction by exploiting AI-assisted optimization engines without explicit user control over modulation. This process challenges quality assurance since measurement-based Patient Specific Quality Assurance (PSQA) cannot be performed daily. This study aimed: (i) to characterize plan complexity in IOE-generated plans for prostate cancer using a reproducible set of PCMs, including the decomposition of inter-patient and intra-patient variability sources; (ii) to evaluate the association between PCMs and delivery accuracy within a cohort-informed SPC framework validated through leave-one-patient-out cross-validation; (iii) to investigate whether inter-fraction anatomical variations explain the observed plan complexity patterns, or whether complexity is predominantly an intrinsic signature of the AI-assisted optimizer. Methods: Twenty-one prostate cancer patients treated on a CBCT-based oART platform were retrospectively analyzed across three anatomical targets: prostatic bed (PrB), prostate (Pr), and prostate with seminal vesicles (PrSV). Six PCMs, namely MU/cGy, Modulation Complexity Score (MCS), Aperture Area Variability (AAV), Leaf Sequence Variability (LSV), Average Leaf Gap (ALG) and Plan Irregularity, were extracted. Additionally, five anatomical metrics (AMs) were computed from daily contours. Linear mixed-effects models (LMEMs) compared reference/online plans, decomposed variance via intraclass correlation coefficients (ICCs), and assessed PCM–gamma passing rate (GPR) associations. Leave-one-patient-out cross-validation (LOPO-CV) evaluated SPC threshold stability. The relationships between PCMs and AMs were investigated using LMEMs. Results: The AI-assisted optimization engine generated plans characterized by elevated monitor unit demand (average MU/cGy ≥ 6.8 ± 0.9) and narrow MLC apertures (ALG ≤ 17.7 mm ± 1.9 mm). No complexity differences emerged between offline and online-adapted plans, nor between anatomical targets. All PCMs showed significant associations with global GPR (p ≤ 0.027), though marginal R² remained low (≤ 0.122). Notably, GPR dispersion increased systematically at higher complexity values, indicating that highly modulated plans exhibit reduced delivery predictability. LOPO-CV demonstrated stable tolerance/action limits. Anatomical variations explained less than 35% of the total variance in PCMs. Conclusions: Plan complexity in oART reflects the optimization paradigm and patient-specific anatomy rather than daily adaptation. PCMs can serve as surveillance indicators flagging high-risk fractions to support SPC-based monitoring.

Cancers doi: 10.3390/cancers18101558

Authors: Yangyang Xia Yihao Zhao Changdong Yue Jing Qi Shaojian Zhang Wenqiang Qi Junxian Li Chaobin Zhao Yang Zheng Benkang Shi Xuewen Jiang

Background: Pathological upstaging (PU) of clear cell renal cell carcinoma (ccRCC) from clinical cT1 to pT3 stage often requires conversion from partial to radical nephrectomy. Preoperative PU prediction lacks objective, precise methods, hindering surgical decision−making. Methods: We developed and validated a computed tomography−based radiomics ensemble learning model (CRIPEM) integrating intratumoral and peritumoral features to predict PU in cT1 ccRCC. We enrolled a multicenter cohort of 309 cT1 ccRCC patients from three institutions, divided into training (n = 170), internal validation (n = 73), and external validation (n = 66) cohorts. Bioinformatics analysis confirmed that peritumoral regions harbor critical predictive value for PU. Results: A total of 7336 radiomic features were extracted from intratumoral and peritumoral (1, 2, 3 mm) regions on preoperative CT images, with 50 robust features retained via a rigorous five−step selection process. CRIPEM, fusing optimal base learners (IT−MLP for intratumoral features, PT1−RF for 1−mm peritumoral features), achieved area under the curve values of 0.872, 0.807, and 0.826 in the training, internal, and external validation cohorts, respectively. Subgroup, calibration, and decision curve analyses confirmed its stability, superiority over single base learners, and significant clinical net benefits, with individualized cases verifying clinical applicability. Conclusions: CRIPEM is an objective, accurate, and robust tool for preoperative PU prediction in cT1 ccRCC, which can optimize surgical strategy selection and improve patient clinical management.

Cancers doi: 10.3390/cancers18101555

Authors: Tanner Carcione Bradley Callas Jack Thiara Walter N. Jungbauer Jonathan Jeger Edward Reece

Background/Objectives: Primary spinal sarcomas, encompassing both bone and soft tissue histotypes, demand individualized reconstruction due to heterogeneous tumor biology, anatomic complexity, and host environments compromised by radiation, systemic therapy, or prior surgery. This narrative review reframes post-resection spinal reconstruction through a precision-medicine lens. Methods: A structured literature review was performed using PubMed and Scopus, targeting articles published between 2000 and 2026. Searches encompassed spinal sarcoma reconstruction, radiation and fusion, biologic reconstruction, and emerging technologies. Results: Tumor grade, radiation exposure, and systemic therapy timing emerge as multiplicative determinants of reconstructive environment quality, with drug-class-specific perioperative effects warranting stratified management. Vascularized bone grafts achieve reliable fusion in compromised hosts where avascular constructs fail. A precision-oriented reconstructive ladder is proposed as a conceptual, hypothesis-generating framework to guide strategy selection. Hybrid PSI-VBG constructs may further expand reconstructive possibilities. The evidence base remains largely composed of small, retrospective series. Conclusions: Individualized strategies anchored in tumor biology and host environment are the cornerstone of durable spinal sarcoma reconstructions. The proposed framework requires prospective, multi-institutional validation. Standardized outcome definitions, prospective registries, and histotype-stratified analyses are needed to advance the field.

Cancers doi: 10.3390/cancers18101556

Authors: Jakub Stępień Julita Stępniak-Bielecka Anna Ciołek Jędrzej Piotrowski Aleksandra Kryca Grzegorz Piotrowski

Background/Objectives: Bradyarrhythmias are an under-recognized component of cancer therapy-related cardiovascular toxicity. As survivorship improves and exposure to targeted and immune therapies increases, clinicians increasingly face clinically relevant sinus node dysfunction and atrioventricular (AV) conduction disease that may interrupt otherwise effective oncologic treatment. We aimed to synthesize evidence on the incidence, phenotype, mechanisms, and management of bradyarrhythmias across major anticancer drug classes. Methods: We performed a narrative review of PubMed and major clinical guidelines, prioritizing prospective trials and large observational cohorts for incidence estimates, and case reports/series for phenotype and management details. Regulatory prescribing information and pharmacovigilance datasets were consulted to complement trial data. Evidence was organized by drug class and prototypical agents. Results: Bradyarrhythmias ranged from transient sinus bradycardia to high-grade atrioventricular block requiring pacing. The most severe phenotype was associated with immune checkpoint inhibitor-related myocarditis, whereas ALK inhibitors, thalidomide, antimetabolites—particularly 5-fluorouracil—and taxanes showed more reproducible signals for sinus bradycardia. Bradyarrhythmic events were also described with proteasome inhibitors, BTK (Bruton tyrosine kinase) inhibitors, anthracyclines, platinum compounds, high-dose cyclophosphamide, corticosteroids, and other agents, but the strength of evidence varied from regulatory or cohort-based data to isolated case reports. Conclusions: Bradyarrhythmias during cancer therapy are heterogeneous but clinically consequential. Recognition of class-specific patterns, proactive ECG/electrolyte monitoring, and context-specific management (e.g., drug interruption/dose modification, pacing when indicated, risk-factor control) can minimize therapy interruption while maintaining oncologic efficacy.

Cancers doi: 10.3390/cancers18101554

Authors: Diana Elena Parteni Mihaela Camelia Tîrnovanu Elena Țarcă Alina Belu Alina Jehac Ludmila Lozneanu Simona Eliza Giusca Carmen Ungureanu Eugenia Morosan Elena Cojocaru

Background/Objectives: Gonadal germ cell tumors (GCTs) arise in the testis and ovary from primordial germ cells. Despite shared origins, they display distinct molecular and genetic features. Understanding these differences is essential for clarifying tumor pathogenesis and improving diagnostic and therapeutic strategies. This review aims to compare these features and to better define the biological differences between testicular and ovarian GCTs. Methods: We reviewed cytogenetic alterations, epigenetic modifications, and somatic mutations reported in testicular and ovarian GCTs. Comparative analysis was performed to identify common and site-specific mechanisms. Results: Isochromosome 12p is a hallmark of testicular GCTs, while ovarian GCTs show diverse chromosomal changes. DNA methylation and other epigenetic marks differ by tumor subtype and gonadal origin. Somatic mutations affect pathways regulating cell cycle, pluripotency, and differentiation, with overlapping and unique patterns between testicular and ovarian tumors. Collectively, these findings define a molecular framework that explains both shared biology and gonadal-specific divergence in GCTs. Conclusions: Understanding molecular similarities and differences across gonadal GCTs can refine classification, guide biomarker discovery, and inform translational research. This comparative perspective highlights core pathogenetic mechanisms and gonadal-specific features relevant to clinical and experimental oncology.

Cancers doi: 10.3390/cancers18101553

Authors: Faiqa Mudassar Kristina M. Cook Zachary N. Warnken Neha Bal Joey Lai Brian Gloss Holly P. McEwen Ryan J. Duchatel Geraldine M. O’Neill Harriet Gee Han Shen Eric Hau

Diffuse intrinsic pontine glioma (DIPG) is a lethal childhood brain tumor. Radiotherapy remains the standard of care, but tumors recur due to radioresistance. Tumor hypoxia contributes to radioresistance, and evidence of oxidative metabolism and hypoxia-associated transcriptomic programs suggests that hypoxia may be relevant in DIPG. We therefore investigated the FDA-approved mitochondrial inhibitor atovaquone as a strategy to target oxidative metabolism and enhance radiation response in DIPG. Methods: Patient-derived DIPG cell lines were used to evaluate atovaquone by extracellular flux analysis, hypoxia and reactive oxygen species assays, clonogenic survival assays, metabolomics, and RNA sequencing. To improve brain exposure, an amorphous solid dispersion (ASD) atovaquone formulation was evaluated and tested in an orthotopic DIPG model. Results: In patient-derived DIPG cultures, atovaquone suppressed mitochondrial respiration, reduced hypoxia-associated readouts, decreased HIF-1α expression in 3D models, and enhanced radiation response. At higher concentrations, atovaquone also increased oxidative stress and enhanced the radiosensitivity of DIPG monolayers. Transcriptomics analysis revealed disruption of cell-cycle and mitotic pathways, supporting additional treatment-associated effects beyond hypoxia reduction alone. Commercial and ASD formulations showed comparable in vitro activity. In vivo, ASD atovaquone combined with radiation prolonged survival in an orthotopic DIPG model. Conclusions: Targeting mitochondrial metabolism enhances radiosensitivity in DIPG and supports mitochondrial metabolism as a potential therapeutic weakness in this disease. Its effects are associated with reduced hypoxia-related signaling and broader metabolic and transcriptional changes.

Cancers doi: 10.3390/cancers18101552

Authors: Elnaz Rahbarlayegh Natsuko Nomura Tiffany M. Juarez Pranav R. Kesari Santosh Kesari

Background: Immunotherapy has transformed cancer treatment by enhancing cytotoxic T-cell activity and interferon-γ (IFN-γ)-mediated tumor clearance. However, glioblastoma (GBM) remains largely refractory to these approaches, reflecting a profoundly immunosuppressive and myeloid-dominant tumor microenvironment. IFN-γ is central to antitumor immunity, yet chronic exposure can paradoxically promote adaptive resistance. How GBM cells respond to sustained IFN-γ signaling, and whether these responses differ across tumor states, remains poorly understood. Methods: To address this, we modeled chronic IFN-γ exposure in mesenchymal-like (U87) and proneural-like (U251) GBM cells over 28 days and performed integrated analyses of transcriptional, proteomic, and secretory responses. Results: While IFN-γ initially suppressed growth in both models, their long-term adaptations diverged. U87 cells developed a persistence-prone state characterized by progressive activation of PI3K–AKT signaling, whereas U251 cells exhibited sustained interferon signaling with persistent interferon-related DNA damage resistance signature (IRDS) expression and suppressed AKT activity. These transcriptional and signaling programs were incompletely reversible after cytokine withdrawal, indicating stable interferon conditioning. Analysis of TCGA glioblastoma datasets demonstrated that interferon-associated transcriptional programs are present across human tumors and are positively associated with PI3K–AKT pathway activity across molecular subtypes. Conclusions: Together, these findings reveal that chronic IFN-γ exposure drives distinct, lineage-dependent adaptive states in GBM, linking interferon signaling to divergent survival and immune-modulatory programs. While IFN-γ enhances immune activation, prolonged signaling may also promote tumor persistence. These results support therapeutic strategies that combine IFN-based approaches with interventions targeting adaptive survival pathways and immune reprogramming.

Cancers doi: 10.3390/cancers18101551

Authors: Matteo Garibotto Debora Soncini Roberto Massimo Lemoli Antonia Cagnetta Michele Cea

Despite transformative therapeutic advances, multiple myeloma (MM) remains an incurable malignancy characterized by sequential relapses and progressive treatment resistance. Patients with heavily pretreated relapsed or refractory MM continue to face limited therapeutic options and poor outcomes. Melflufen (melphalan flufenamide) is a peptide–drug conjugate that enhances intracellular delivery of alkylating agents via aminopeptidase-mediated activation. Early clinical studies demonstrated encouraging activity in advanced MM, leading to accelerated approval by the U.S. Food and Drug Administration in 2021. However, results from the phase III OCEAN trial raised concerns regarding overall survival, ultimately resulting in withdrawal of the drug from the U.S. market. In this review, we examine the biological rationale, clinical development, and regulatory trajectory of melflufen, and critically reassess its role within the evolving therapeutic landscape of MM. While the negative survival findings observed in the phase III OCEAN trial substantially limited the clinical development of melflufen, the biological principles underlying enzyme-targeted intracellular drug delivery may still provide relevant insights for biomarker-driven therapeutic strategies and future peptide–drug conjugate development in MM.

Cancers doi: 10.3390/cancers18101550

Authors: Silvio Caringi Antonella Delvecchio Annachiara Casella Valentina Ferraro Matteo Stasi Nunzio Tralli Tommaso Maria Manzia Michele Tedeschi Riccardo Memeo

Parenchyma-sparing pancreatic surgery (PSPS) is a patient-centered alternative to traditional radical resections for benign and low-grade pancreatic lesions. Unlike pancreaticoduodenectomy and distal pancreatectomy, which tend to cause long-term exocrine and endocrine deficiency, PSPS aims to preserve functional tissue with a guarantee of oncologic safety. Techniques such as enucleation, central pancreatectomy, duodenum-preserving head resection, and uncinectomy are illustrative of this equipoise, with less risk of new-onset diabetes and malabsorption but more short-term morbidity in the form of postoperative pancreatic fistula. Advances in imaging technology, minimally invasive procedures, and robotics technology have extended PSPS indications beyond conventional candidates to thoughtfully selected neuroendocrine tumors, cystic neoplasms, and solid pseudopapillary neoplasms. Results are strongly dependent on patient selection, surgeon experience, and institutional volume, highlighting the importance of centralization and subspecialist training. While oncologic proficiency remains essential in aggressive tumors, evidence is in favor of PSPS being a curative and function-preserving option for properly screened patients with low-grade or benign conditions. Priorities for the future include multicenter prospective trials, optimization of perioperative techniques, and inclusion of patient-reported outcomes. PSPS represents a paradigm shift in pancreatic surgery, where technical innovation is balanced with quality of life in the long term and evolving principles of modern, individualized surgical practice.

Cancers doi: 10.3390/cancers18101549

Authors: Brett Berezowski Robert Boothe Billy Chaplin Sharon J. Del Vecchio Zakariya Fares Tyrone L. R. Humphries Keng Lim Ng Taylor Noonan Hemamali Samaratunga Aaron Urquhart David A. Vesey Simon T. Wood Glenda C. Gobe Robert J. Ellis

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Cancers doi: 10.3390/cancers18101548

Authors: Beatrice Jung Isabel Sperrhake Saskia Sachsenmaier Tilmann Busse Eren Demir Maria Christina Stefanescu Constantin Doetsch Sophie Zorn Frank Traub

Background: Although survival rates for patients with malignant bone tumors have improved significantly, complications following tumor resection and limb-sparing reconstruction remain a major clinical challenge, particularly in young individuals. Intercalary resection often results in large bone defects, necessitating complex reconstructions. Fibula grafts offer biological advantages; however, their long-term outcomes, especially regarding mechanical complications and comprehensive patient-reported well-being, require further detailed exploration, particularly in cohorts utilizing non-vascularized grafts. Objective: This retrospective study evaluated the complication rates, bone hypertrophy, limb function, and quality of life following non-vascularized fibular graft reconstruction for malignant bone tumors in a single-center cohort. This study offers insights into long-term success and patient well-being, with a particular focus on correlations with systemic therapy and defect size, factors that remain insufficiently explored in the current literature. Methods: In this single-center retrospective study, twenty-four non-vascularized fibular grafts were used to reconstruct intercalary bone defects following malignant tumor resection. Complications were categorized using the Clavien–Dindo classification. Graft hypertrophy was evaluated according to the method described by Weiland and de Boer. Functional outcomes were assessed using the MSTSs and TESSs, while quality of life was measured using the SF-36 questionnaire. Notably, the cohort analyzed represents a relatively large single-center series focusing exclusively on the outcomes of non-vascularized fibular grafts. Results: Our findings revealed significant rates of mechanical complications, with osteosynthesis material failure occurring in 50.0% of cases, pseudarthrosis in 47.6%, and fractures of the fibular grafts in 38.1% of cases. Importantly, there were significant correlations between mechanical complications and systemic therapy (p = 0.017), as well as between defect size and fractures (p = 0.013), identifying critical risk factors. Despite these considerable complication rates, patients achieved satisfactory limb function (MSTS: 74 ± 17; TESS: 83 ± 15) and quality of life scores comparable to national norms, with notably higher mental health indices, highlighting their psychological resilience. Conclusions: Non-vascularized fibular graft reconstruction, despite high mechanical complication rates, significantly facilitates long-term functional recovery and psychological well-being. These findings emphasize the necessity of risk-adapted surgical strategies and long-term follow-up protocols to mitigate complications, optimize long-term function, and ultimately advance patient-centered care.

Cancers doi: 10.3390/cancers18101546

Authors: Farideh Bagherzadeh-Khiabani Kevin R. Krull Shizue Izumi Sedigheh Mirzaei Tiange Zheng Jose Miguel Martinez Martinez Kirsten K. Ness Gregory T. Armstrong Melissa M. Hudson Leslie L. Robison Yutaka Yasui I-Chan Huang

Background: Adult survivors of childhood cancer face a significant risk for treatment-related late effects that may impair health-related quality of life (HRQoL). Incorporating longitudinal changes in patient-reported symptoms beyond treatment-based risk factors may enhance the prediction of HRQoL. Methods: Survivors (N = 576) dually enrolled in the St. Jude Lifetime Cohort Study and Childhood Cancer Survivor Study reported 37 symptoms across 10 domains at three time points over 20 years to ascertain longitudinal symptom change patterns. HRQoL was subsequently assessed using SF-36 scores. Prediction models were developed using Bayesian Information Criterion Elastic Net (BIEN), first including demographic, diagnosis, and treatment variables, then adding symptom change patterns. Prediction of suboptimal HRQoL (score < 40) was evaluated using 10-fold cross-validated area under the receiver operating characteristic curve values (AUC). Results: Participants (median baseline age 26.7 years, 52% female, 90% non-Hispanic white, 41% leukemia, and 30% Hodgkin/non-Hodgkin lymphoma survivors) most frequently reported symptom domains of sensory, pain, and anxiety (50–60% at any time point), followed by depression and memory (40–50%). Consistent absence throughout follow-up was the most common pattern (41.7–98.1%), while patterns requiring symptom presence at ≥1 time point were less common (0.0–16.7%), and persistent presence throughout follow-up was rare (0.0–6.8%). Across 10 SF36-HRQoL scores, symptom-enhanced models improved prediction over non-symptom models (AUCs 0.75–0.85 vs. 0.56–0.66; p-values < 0.001). Conclusions: Longitudinal symptom change patterns substantially improved future HRQoL prediction, achieving prediction accuracy that may be of clinical effectiveness. This supports regular symptom assessment and further research towards symptom-informed risk stratification in survivorship care.

Cancers doi: 10.3390/cancers18101547

Authors: Michele Brancaccio Armando Galdieri Andrea Cosenza Francesco Barletta Pietro Scilipoti Leonardo Quarta Paolo Zaurito Alfonso Santangelo Alessandro Viti Angelo Occhi Maria Elena Porzi Alessia Colistro Giulia Roca Simone Scuderi Vito Cucchiara Armando Stabile Francesco Montorsi Alberto Briganti Giorgio Gandaglia

Prostate cancer (PCa) screening has long relied on PSA testing, a strategy that has shaped diagnostic pathways for decades but remains limited by substantial overdiagnosis and downstream overtreatment. As screening practices evolve, the relevance of historical evidence must be reconsidered in the context of contemporary diagnostic workflows that now incorporate imaging, refined biopsy techniques, and risk-adapted management. This narrative review examines the transition from PSA-only screening toward modern, risk-adapted early detection strategies. We synthesize evidence supporting the integration of mpMRI, refined biopsy techniques, and active surveillance (AS) as key components of contemporary screening pathways aimed at improving the detection of clinically significant disease while minimizing unnecessary interventions. Particular emphasis is placed on second-line MRI-based approaches, which consistently reduce the number of avoidable biopsies and enhance the diagnostic precision. In addition, we review the role of blood-based and genomic biomarkers in pre-biopsy risk stratification, discussing established tools within a unified framework of individualized screening. The review also contextualizes very recent regulatory developments, including the FDA approval of a novel structure-based PSA assay, as part of the ongoing evolution of biomarker-supported screening rather than a paradigm shift. Overall, this article provides a timely synthesis of mature randomized evidence and emerging diagnostic innovations, offering a clinically grounded perspective on how PCa screening is being reshaped toward more personalized and harm-aware strategies.

Cancers doi: 10.3390/cancers18101543

Authors: Sai Kiran Kuchana Uday Kumar Repalle Nikhilesh V. Alahari Manpreet Kondamuri Sai Kiran Manduva Raghu Vamsi Vanguru Sri Anjali Gorle Suresh K. Alahari

Background: Artificial intelligence (AI) is reshaping oncology at every stage of the cancer care pathway, from population-level screening through molecular diagnosis, treatment planning, and post-treatment surveillance. Despite an exponential growth in AI oncology publications exceeding 5000 peer-reviewed studies annually, a critical and persistent gap separates demonstrated algorithmic performance from genuine patient benefit. Most published evidence derives from retrospective, single-institution studies conducted in curated dataset environments that systematically differ from real-world clinical deployment conditions. This comprehensive review examines the translational maturity of AI applications across 18 major malignancies, providing an evidence-stratified, cross-cancer assessment of where AI has fulfilled, approaches, or remains far from fulfilling its transformative potential in oncological care. Methods: A structured narrative review was conducted across PubMed/MEDLINE, Embase, IEEE Xplore, and the Cochrane Library, supplemented by regulatory grey literature including FDA 510(k) decision summaries, CE Technical Files, and ClinicalTrials.gov. Search terms combined cancer site-specific terminology with AI methodology terms and translational outcome descriptors. Studies were only included if they applied an AI or machine learning methodology to a defined clinical oncological task, reported a clearly specified performance evaluation, and involved human subjects or human-derived clinical data. Evidence quality was assessed using QUADAS-2, PROBAST, and Cochrane RoB 2. A five-tier translational readiness framework, grounded in the NIH T0–T4 translational spectrum and CONSORT-AI/SPIRIT-AI guidelines, was applied a priori to enable cross-cancer comparison. A rigorous distinction was maintained between diagnostic accuracy and clinical utility, defined as demonstrated impact on clinical decision-making or patient-centered outcomes. Results: Across all 18 malignancies, AI development varied profoundly by cancer type. Breast cancer and prostate cancer (Tier 1) represent the most mature AI ecosystems, with multiple FDA-cleared tools for mammographic screening and digital pathology achieving prospective multi-institutional validation; however, randomized evidence demonstrating reduced cancer-specific mortality remains absent. Lung, hepatocellular, and melanoma AI (Tier 2) have achieved regulatory milestones but face documented performance disparities across demographic subgroups, including DermaSensor’s 20.7% specificity in primary care settings and HCC model failures in non-viral disease etiologies. Colorectal, glioma, pancreatic, and ovarian cancers (Tier 3) exhibit technical maturity without clinical clarity: colorectal CADe systems increase adenoma detection but meta-analyses of 18,232 patients across 21 RCTs fail to demonstrate improvement in advanced neoplasia detection or cancer incidence reduction. A full study-level presentation of pooled estimates, confidence intervals, and heterogeneity statistics for each cited randomized evidence base across all cancer types would extend beyond the intended scope and format of this cross-cancer narrative review. Gastric, esophageal, cervical, bladder, head and neck, and endometrial cancers (Tier 4) demonstrate promising single-institutional or geographically restricted results without multi-institutional external validation, particularly notable for cervical cancer AI’s transformative potential in low- and middle-income countries constrained by absent regulatory frameworks. Hematologic malignancies, sarcoma, and pediatric solid tumors (Tier 5) face structural barriers, workflow incompatibility in hematopathology, extreme rarity in sarcoma (>70 subtypes, <15,000 US cases annually), and irreducible ethical constraints in pediatric data governance, that cannot be resolved through algorithmic refinement alone. Conclusions: Oncological AI has not yet fulfilled its clinical promise. Across all five translational tiers, a single finding is consistent: diagnostic accuracy is not a surrogate for patient benefit. AI tools with high sensitivity and specificity have repeatedly failed to demonstrate equivalent reductions in cancer-specific mortality, overdiagnosis, or procedural harm under real-world outcome scrutiny. Simultaneously, documented performance disparities across races, ethnicity, disease etiology, and geographic setting reveal that current AI systems risk amplifying the very health inequities they are positioned to resolve. Bridging this translational gap requires three coordinated systemic shifts: regulatory frameworks mandating post-market outcome surveillance as a condition of clinical clearance; prospective trial designs measuring patient-centered endpoints rather than diagnostic concordance alone; and sustained infrastructure investment in federated data governance, demographically inclusive training datasets, and LMIC-accessible regulatory pathways. AI holds genuine potential to reduce cancer mortality on a global scale—but only if held to the evidentiary and equity standards that the stakes of oncological care demand.

Cancers doi: 10.3390/cancers18101545

Authors: Eiji Ito Masasuke Ohno Mao Yokota Shunichiro Kuramitsu Toru Nagasaka Toshiaki Inomo Tadashi Watanabe Mitsugu Fujita

Background/Objectives: WHO grade II meningiomas show highly variable growth rates that are difficult to predict using conventional histology. We investigated relationships between immune components within the tumor immune microenvironment (TIME) and explored their association with tumor growth kinetics. Methods: We retrospectively evaluated a small, preselected cohort of 15 patients with WHO grade II meningiomas who underwent initial “watch-and-wait” observation with serial preoperative MRI. Notably, this cohort represents a specific clinical subset—tumors deemed initially observable—and may not be representative of all WHO grade II meningiomas. Densities of Iba1-positive macrophages (TAMs) and B7-H3-positive tumor cells were quantified by digital pathology. The relative growth rate (RGR) was calculated from serial MRI. Results: A strong inverse correlation was observed between TAM density and B7-H3-positive tumor cell density (Spearman’s R = −0.921, p < 0.001). Individual immune components did not show significant linear correlations with RGR; on median-split stratification, high B7-H3-positive tumor cell density was associated with a nominally significant difference in RGR (p = 0.0428, unadjusted). Low TAM density showed a non-significant trend in the same direction. Conclusions: Our findings generate the hypothesis that WHO grade II meningiomas exhibit an inverse relationship between TAMs and B7-H3 and that macrophage-poor/B7-H3-high and macrophage-rich/B7-H3-low patterns may differ in preoperative growth behavior. These observations are derived from a small, preselected cohort of tumors managed with an initial “watch-and-wait” strategy and require validation in broader populations.

Cancers doi: 10.3390/cancers18101544

Authors: Joana Ferreira André Albergaria Fernando Schmitt

Background/Objectives: Metastatic breast cancer (MBC) remains a daunting clinical challenge, accounting for approximately 90% of all breast cancer-related deaths. The management of MBC has shifted from traditional chemotherapy to a sophisticated, biomarker-driven model of precision oncology. This evolution is predicated on the ability of biomarkers to provide prognostic and predictive information. The objective of this review is to provide a comprehensive synthesis of the current landscape of biomarker testing in MBC, detailing which biomarkers to test and the clinical rationale for doing so. Methods: This is a comprehensive review based on current international clinical practice guidelines, peer-reviewed literature, and evidence regarding clinically actionable and emerging biomarkers in metastatic breast cancer. Results: Key biomarkers currently in routine use include the established estrogen receptor (ER), progesterone receptor (PR), and HER2, alongside newer, clinically actionable alterations such as mutations in PIK3CA and ESR1, germline/somatic BRCA1/2, and PD-L1 expression. Furthermore, liquid biopsy, particularly the analysis of circulating tumor DNA (ctDNA), is rapidly gaining prominence as a non-invasive tool for real-time disease monitoring and resistance detection, highlighting the critical need for re-testing at metastasis due to tumor heterogeneity. Conclusions: The future of personalized oncology in MBC will be defined by the seamless integration of dynamic biomarkers and cutting-edge technologies. The integration of AI and spatial transcriptomics will move the field of pathology beyond a static diagnosis to a more dynamic and predictive model, reinforcing the pathologist’s role as the “molecular gatekeeper” for adaptive and personalized cancer care.

Cancers doi: 10.3390/cancers18101542

Authors: Carolina Mendez-Guerra Jose Chacon Irvin E. Altamirano W. Rodrigo Calmet Rocca Juan Pretell-Mazzini

Soft tissue sarcomas (STS) comprise a rare and highly heterogeneous group of mesenchymal-derived malignancies, accounting for less than 1% of all cancers and characterized by diverse histologic and molecular subtypes. Despite their low incidence, STS account for a disproportionate burden of cancer-related morbidity and mortality, largely driven by their risk of metastatic dissemination. Early detection of metastatic spread is a cornerstone of preoperative staging, treatment planning, and postoperative monitoring in patients with STS. Although conventional imaging modalities remain fundamental for surveillance of metastatic disease, they may fail to accurately detect metastatic sites and provide limited insight into tumor biology. Advances in precision medicine have positioned liquid biopsy as a minimally invasive approach for the analysis of tumor-derived material, facilitating characterization of tumor biology and identification of prognostic biomarkers. Circulating tumor cells (CTCs) represent intact and viable tumor cells that provide unique genomic and phenotypic traits that could not be assessed using acellular tumor-derived material. They have emerged as promising biomarkers for monitoring disease progression, assessing treatment response, and stratifying prognosis. Particularly, their clinical value as prognostic biomarkers has been established in epithelial-derived malignancies. Despite these advances, the role of CTCs in STS remains largely investigational, mainly due to STS heterogeneity and the lack of standardized protocols for detection across platforms. Therefore, this narrative review summarizes the biomolecular mechanisms underlying CTCs in STS, including the role of phenotypic plasticity in tumor intravasation, anoikis resistance and its interaction with the tumor microenvironment, and stem cell-like phenotypes in tumor initiation at distant sites. Furthermore, we discuss current methodologies for CTC detection, highlighting emerging approaches developed to address the limitations of conventional methods. Finally, we provide a critical overview of subtype-specific detection strategies, as well as their clinical implications in treatment response monitoring and prognostic assessment.

Cancers doi: 10.3390/cancers18101541

Authors: Eirini Papadopoulou Georgios N. Tsaousis Romina Alevizou Dimitrios Alexandrou Theodoros Argyriou Anna Giannopoulou Markos Thanos Sofia Kakoulaki Christos Kalyvopoulos Maria Kanara Christos Kanistras Nikolaos Katsiakis Anastasios Katsourakis Dimitrios Kokkonis Theodoros Kontoulis Ioanna Konstantiadou Dimitrios Tryfonopoulos Sofia Karageorgopoulou Anna Koumarianou Dimitrios Ziogas Stavros Bikos Effrosyni Bompou Georgios Boutsikos Varvara Pantelidou Aikaterini Savvidou Vasileios Sakellariou Maria Matiatou Panagiotis Karathanasis Maroulio Stathoulopoulou Vassileios Venizelos

Background: Breast cancer and gynecological malignancies, including cervical, ovarian, and endometrial cancers, remain leading causes of cancer incidence and mortality among women worldwide. This study investigated hereditary predisposition rates in women diagnosed with breast or gynecological cancer, focusing on the effect of age on germline pathogenic/likely pathogenic (P/LP) variant detection. We sought to determine whether younger age at diagnosis should be used as a criterion for patient selection for genetic testing. Methods: A total of 9084 consecutive females with breast cancer or gynecological tumors underwent germline NGS-based genetic testing (52 cancer-relevant genes) at Genekor laboratory from 2020–2026. Multivariable logistic regression evaluated factors associated with P/LP variant detection, adjusting for tumor type and family history. Results: Overall P/LP prevalence was approximately 20% (one in five patients), with tumor-specific rates of 19.24% in breast cancer, 27.59% in ovarian cancer, and 26.67% in endometrial cancer. P/LP prevalence declined significantly with age from 24.37% in patients <40 years to 15.90% in those ≥70 years, while Variants of Uncertain Significance (VUS) remained stable (40–43%). P/LP patients had earlier diagnosis (median 45 vs. 46 years, p < 0.001), driven predominantly by high-risk genes (13.87% in <40 y vs. 7.11% in ≥70 y). BRCA1 showed stronger age enrichment than BRCA2 (8.14% vs. 3.16% in <40 y; median diagnosis 43 vs. 45 years). Age remained independently associated with P/LP detection in multivariable analysis, with an 18% reduction in odds per 10-year increase for any P/LP (OR 0.82, 95% CI 0.78–0.86) and a stronger 28% reduction for high-risk variants (OR 0.72, 95% CI 0.67–0.78). Family history also independently predicted P/LP detection (OR 1.40, 95% CI 1.19–1.66). Conclusions: Although derived from a referral-based (and thus selected) population, these findings show that while younger patients have a higher prevalence of high-risk P/LP variants, clinically actionable findings are present across all age groups, including those ≥70 years. These results suggest that reliance on age alone to determine eligibility for genetic testing may be insufficient. Broadening access to testing beyond strict age-based criteria could improve the identification of hereditary cancer risk and inform patient management, although further evaluation in less selected populations is warranted.

Cancers doi: 10.3390/cancers18101540

Authors: Pavel A. Solopov Alayna Enos Mantas Silkunas Giedre Silkuniene Eleni Zivla Andrei G. Pakhomov Olga N. Pakhomova

Background/Objectives: Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy with poor prognosis and limited treatment options, highlighting the need for reliable preclinical models for translational research. Although xenograft models are widely used in cancer biology, systematic characterization of subcutaneous ESCC models under defined implantation conditions remains limited. The objective of this study was to systematically compare implantation conditions and define histopathological and growth-related parameters that enable reproducible tumor establishment while maintaining a practical experimental window for therapeutic studies. Methods: We established and characterized a subcutaneous ESCC xenograft model using human ESCC cell line KYSE-30 implanted into immunodeficient J:NU mice. Tumor growth dynamics were compared under three implantation conditions: cells suspended in phosphate-buffered saline (PBS), Matrigel (Corning, basement membrane matrix), or Matrigel diluted with PBS. Results: Tumors generated from Matrigel-embedded cells exhibited rapid growth, reaching substantial size within approximately one week after implantation, which limited their utility for controlled therapeutic studies. In contrast, tumors generated from cells suspended in Matrigel + PBS demonstrated slower but consistent expansion, providing a more suitable and reproducible experimental window for therapeutic intervention. Cells injected in PBS alone showed inefficient tumor establishment. Histopathologic and immunohistochemical analyses revealed matrix-dependent differences in necrosis, stromal organization, and proliferative activity, while confirming epithelial tumor identity and baseline vascularization. Conclusions: Collectively, these findings define a reproducible KYSE-30 subcutaneous xenograft model and identify Matrigel dilution with PBS as an optimal implantation strategy that balances reliable tumor engraftment with controlled tumor growth suitable for therapeutic studies.

Cancers doi: 10.3390/cancers18101539

Authors: Kyoko Asai Takahiro Hasebe Masahiro Ohara Masataka Hirasaki Kazuo Matsuura Hiroshi Ishiguro Akihiko Osaki Toshiaki Saeki

Background/Objectives: CD138 (syndecan-1) is a cell-surface heparan sulfate proteoglycan involved in cell–matrix interactions and growth factor signaling, and it has been implicated in tumor progression. However, the clinical significance of compartment-specific CD138 expression in breast cancer remains unclear. In this study, we investigated the prognostic and transcriptomic features of compartment-specific CD138 expression in invasive breast cancer. Methods: We performed an integrated analysis of immunohistochemistry and RNA sequencing of 111 invasive ductal carcinoma specimens. Tumors were classified into four groups according to CD138 expression in the tumor and stromal compartments. Clinicopathological data and survival outcomes were obtained from medical records, and transcriptomic profiles were analyzed using RNA sequencing. Results: The tumor-positive/stroma-negative phenotype (Group 1) was associated with poorer recurrence-free survival than the other phenotypes. According to multivariable Cox regression analysis, Group 1 remained an independent prognostic factor after adjustment for age, lymph node status, and Ki-67 index (hazard ratio, 5.493; p = 0.0028). Group 1 was also associated with lymph node metastasis and HER2 expression. All brain metastases occurred in Group 1, although the number of events was low. Transcriptomic profiling identified the upregulation of small nucleolar RNAs in Group 1 tumors, with the enrichment of pathways related to ribosome biogenesis, RNA processing, and translational regulation. Conclusions: Compartment-specific CD138 expression identifies an aggressive breast cancer phenotype with distinct transcriptomic features. This phenotype may have prognostic value and warrants validation using larger, independent cohorts.

Cancers doi: 10.3390/cancers18101536

Authors: Weng Ian Che James N. Jarvis International Lymphoma Epidemiology Consortium (InterLymph) IMACS Genetics Group (MYOGEN) Ingrid E. Lundberg Karin E. Smedby Janine A. Lamb Marie Holmqvist

Objectives: The genetic architecture of B-cell lymphomas is not fully characterized. We aimed to identify novel candidate variants associated with four common B-cell lymphoma subtypes—diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), and marginal zone lymphoma (MZL)—through cross-trait analyses with correlated idiopathic inflammatory myopathies subtypes, dermatomyositis (DM) and polymyositis (PM). Methods: Leveraging shared genetic susceptibility with DM and PM, we applied a pleiotropy-informed conditional false discovery rate (condFDR) method to recompute nominal single nucleotide polymorphism association p-values for each B-cell lymphoma subtype. Associations were considered significant at condFDR <0.01. Functional annotation was performed using FUMA (Functional Mapping and Annotation of Genome-Wide Association Studies), followed by Gene Ontology (GO) enrichment analysis via clusterProfiler, with similar GO terms clustered for interpretation and visualization. Results: We identified 4, 2, 13, and 6 novel candidate loci for DLBCL, FL, CLL, and MZL, respectively. Most loci exhibited regulatory effects on genes involved in adaptive immune responses and cell death pathways. Notably, for DLBCL locus 1q23.3 affects SLAMF genes implicated in natural killer and lymphocyte activation. A trans-eQTL at 2q13 for FL was associated with BCL11A, a multifunctional oncogene. For CLL, a novel locus at 16q24.1 regulates IRF8, a known CLL risk gene. Functional mapping of previously reported CLL risk loci revealed RIPK1 (6p25.2), linked to necroptosis. No enriched biological pathways were detected for MZL risk-associated genes. Conclusions: These findings advance our understanding of the genetic architecture of four B-cell lymphoma subtypes and aim to inform future genetic and functional studies.

Cancers doi: 10.3390/cancers18101538

Authors: José del Corral-Morales Carlos Ayala-de Miguel Laura Quintana-Cortés Santiago González-Santiago José Fuentes-Pradera Pablo Ayala-de Miguel

Background/Objectives: Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape of non-small cell lung cancer (NSCLC), introducing a distinct spectrum of immune-related toxicities (irAEs). However, the real-world impact of irAEs and corticosteroid use on treatment outcomes remains uncertain. Methods: We conducted a multicenter, retrospective study including patients with advanced NSCLC treated with ICIs alone or in combination with chemotherapy between April 2017 and December 2023. Clinical records were reviewed to collect data on irAEs and corticosteroid administration. Efficacy and safety outcomes were compared according to irAE occurrence, grade, and corticosteroid use. Categorical variables were analyzed using chi-square tests, while PFS and OS were estimated using the Kaplan–Meier method and compared with the log-rank test. Cox proportional hazards models were used to estimate HRs and 95% CIs. Results: Among 452 patients, 151 (33.4%) experienced irAEs of any grade, and 37 (8.2%) developed grade ≥3 events. The most common irAEs were dermatologic (11.1%), endocrine disorders (9.1%), and arthritis (5.5%). Corticosteroids were administered for irAE management in 60 patients (13.3%). Patients who developed irAEs achieved significantly improved progression-free survival (median PFS: 23.2 vs. 4.2 months; HR = 0.29; p < 0.001) and overall survival (median OS: 31.2 vs. 7.6 months; HR = 0.35; p < 0.001), including those with grade ≥3 events. The survival benefit associated with irAEs was not compromised by corticosteroid (CS) use for irAE management (median PFS 46.3 in irAE vs. 5.5 months in non-irAE/no use; HR = 0.28; p < 0.001). Temporary ICI discontinuation due to irAEs was associated with longer median PFS (39.1 vs. 5.6 months; HR = 0.29; p < 0.001), as was permanent ICI discontinuation due to irAEs (median not reached vs. 7.4 months; HR = 0.20; p < 0.001). Conclusions: In this retrospective cohort, the occurrence of irAEs—and their management with CS—was associated with enhanced ICI efficacy in metastatic NSCLC, including among patients who developed high-grade toxicities and those who discontinued treatment due to toxicity.

Cancers doi: 10.3390/cancers18101535

Authors: Mateusz Czajkowski Michał Falis Jan Mandrysz Magdalena Sternau Marcin Matuszewski Oliver W. Hakenberg

Background/Objectives: Optimal surgical margin management in penile squamous cell carcinoma remains debated because organ-preserving surgery must balance oncological control with functional preservation. Historically, wide excision margins have been recommended; however, subsequent evidence has challenged this threshold, shifting practice towards narrower margins without a demonstrated increase in local recurrence. We evaluated whether invasive positive surgical margins and minimal negative margin widths were associated with local recurrence and survival after surgery for penile squamous cell carcinoma. Methods: We retrospectively analysed 157 consecutive men who underwent surgical treatment at a single centre between 2011 and 2024. Time-to-event analyses were performed in 131 patients with invasive non-metastatic disease after excluding those with penile intraepithelial neoplasia (PeIN)-only lesions (n = 23) and distant metastases (n = 3) at diagnosis. The margins were classified as either invasive-negative or invasive-positive. Among histologically negative-margin cases, minimal margin width was grouped a priori as <2 mm, 2–5 mm, and >5 mm. Results: The median follow-up was 25 months (interquartile range [IQR], 10–52). In the invasive (M0) cohort, 101/131 patients had invasive-negative margins and 30/131 had invasive-positive margins; local recurrence occurred in 42/131 patients. Margin status was not independently associated with recurrence-free, overall, or cancer-specific survival rates. Non-sparing surgery was associated with a lower hazard of local recurrence, whereas grade 3 (G3) histology independently predicted worse recurrence-free, overall, and cancer-specific survival. Advanced stage according to the Tumour, Node, Metastasis (TNM) classification independently predicted worse cancer-specific survival. Conclusions: Among patients with histologically negative margins, outcomes did not differ significantly across the predefined margin-width categories. These findings support tissue-preserving surgery aimed at histologically negative margins within a structured surveillance framework.

Cancers doi: 10.3390/cancers18101537

Authors: Cory B. Fines Sorcha Kelly Helen O. McCarthy Niamh E. Buckley

Breast cancer is the second leading cause of cancer death in women. Among its various subtypes, triple-negative breast cancer (TNBC) is an aggressive form characterised by the absence of hormone receptor expression and lack of HER2 amplification, which severely limits treatment options. While some targeted therapies exist, chemotherapy remains the primary treatment for TNBC. Interestingly, despite TNBC patients showing the highest initial response rates to chemotherapy, they also experience the lowest overall survival. This phenomenon is often referred to as the “TNBC paradox,” which makes achieving curative outcomes incredibly challenging due to the unpredictable nature of the disease. This highlights a significant unmet clinical need to develop tailored medicine approaches to maximise patient response. Unlike other breast cancer subtypes, TNBC is considered “immune hot,” meaning it has a higher presence of immune cells within the tumour microenvironment. This characteristic has made the development of immunotherapies a major focus of research. PD-1/PD-L1 checkpoint inhibitors have already become the standard of care for high-risk early stage TNBC patients, and other immunomodulatory therapies, such as therapeutic vaccines, are currently under investigation. Given that chemotherapy is still the cornerstone of TNBC treatment, understanding its impact on systemic and tumour immune cells is crucial for improving the effectiveness of combination therapies. This review will delve into the specific roles of TNBC chemotherapies on key immune cells during both tumour progression and regression.

Cancers doi: 10.3390/cancers18101532

Authors: Harsh Goel Avanish Kumar Pandey Anshul Arya Rahul Kumar Rakesh Kumar Harshita Makkar Ravi Kumar Majhi Sujata Bhattacharya Jay Singh Mohit Kumar Divakar Payal Vasudeva Saran Kumar Anita Chopra Amar Ranjan Jagdish Prasad Meena Aditya Kumar Gupta Ganesh Kumar Viswanathan Atul Batra Goura Kishor Rath Showket Hussain Garima Jain Aroonima Misra Ekta Rahul Sameer Bakhshi Pranay Tanwar

Background/Objectives: Acute myeloid leukemia (AML) is a hematologic malignancy of substantial genetic heterogeneity that exhibits clonal growth and blocked differentiation of myeloid progenitor cells in the bone marrow (BM). Genetic alterations play a vital role in the progression, initiation, and recurrence of AML. The aim of this study was to identify the somatic mutational landscape, pathway perturbations, mutational signatures, and druggability of baseline (at diagnosis) and relapsed AML to determine possible treatment options. Methods: Between 2020 and 2026, 120 diagnostic BM or PB samples were prospectively collected from baseline (at diagnosis) AML patients at AIIMS, New Delhi. WES was conducted of 10 BM samples from five baseline (at diagnosis) and five relapsed patients with AML. Somatic variations were identified by GATK-Mutect2 and annotated by ANNOVAR. Driver genes and pathways were analyzed using Maftools, OncodriveCLUST, and clusterProfiler. Extraction of mutational signatures was performed with the help of SigProfilerExtractor, and evaluation of drug–gene interactions was carried out with the help of DGIdb. In addition, RT-PCR was performed to estimate the expression level of TET1. The recurrent TET1 variation was validated using Sanger sequencing and PCR amplification. Results: Missense mutations were the most common variant type in the cohort, and C > T transitions were the predominant nucleotide substitution pattern. There were recurrent mutations in core AML driver genes, including TET1, FLT3, and TP53, and relapsed samples demonstrated increased involvement and complexity of the signaling system. Pathway analysis revealed widespread dysregulation of carcinogenic networks, including RTK-RAS, WNT, TP53, and PI3K signaling. Mutational signature analysis identified COSMIC SBS5, SBS8, and SBS40, which are associated with mechanisms involving oxidative damage. A large number of actionable targets were identified through druggability screening, particularly involving epigenetic regulators and kinase-associated pathways. RT-PCR analysis also supported altered TET1 expression in AML samples. The TET1 A256V variant was detected and experimentally validated. Conclusions: This study highlights the somatic mutational landscape of baseline (at diagnosis) and relapsed AML and identifies recurrent driver genes, altered signaling pathways, mutational signatures, and actionable targets with possible therapeutic relevance. The integration of mutational and expression analyses further supports a potential role for TET1 in AML biology, although the functional significance of specific variants such as A256V remains uncertain.

Cancers doi: 10.3390/cancers18101534

Authors: Sung Hak Lee Kwangil Yim Hyun-Jong Jang

Background: Accurate prognostic stratification in hepatocellular carcinoma (HCC) remains challenging due to substantial tumor heterogeneity. Deep learning (DL)-based approaches, particularly convolutional neural networks (CNNs), have been widely applied for prognostic prediction using histopathological images. Recently, pathology foundation models combined with multiple-instance learning (MIL) have emerged as a promising alternative. In this study, we aimed to provide a comparative evaluation of conventional CNN-based and foundation model-based approaches for HCC prognosis prediction, with a focus on tissue selection strategies and cross-dataset generalizability. Methods: We compared a patch-level CNN approach with a foundation model-based MIL approach for overall survival (OS) prediction from hematoxylin and eosin-stained whole-slide images. A total of 256 patients from Seoul St. Mary’s Hospital (SSMH) and 334 patients from the TCGA dataset were included. Models were trained using either all tissue regions or tumor-only regions under five-fold cross-validation. Model performance was evaluated using the concordance index (C-index), Kaplan–Meier analysis, and time-dependent receiver operating characteristic analysis. Cross-dataset validation and combined-dataset training assessed generalizability. Results: In the SSMH dataset, the CNN model performed better with tumor-only regions (C-index 0.8308) than with all tissue regions (0.7498). In contrast, the foundation model-based MIL approach showed stable performance regardless of input regions (C-indices: 0.8701 and 0.8752). Similar stability was observed in the TCGA dataset (0.7744 and 0.7722). Cross-dataset validation showed reduced performance, indicating limited generalizability. Combining datasets did not lead to performance improvement. Subgroup analyses showed prognostic information beyond histologic grade, and feature visualization revealed relevant histopathologic patterns. Conclusions: A foundation model-based MIL approach provides robust and interpretable prognostic modeling in HCC. DL-based prediction offers complementary information beyond conventional clinicopathological variables. Future efforts integrating multimodal data and improving generalizability will be essential for clinical translation.

Cancers doi: 10.3390/cancers18101530

Authors: Aina Xiao Yu’E Liu Wenjia Guo

Background/Objectives: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, with limited effective therapies. Dihydroartemisinin (DHA), a derivative of artemisinin, exhibits potent antitumor activity, but its molecular mechanisms in HCC are unclear. Here, we identified kinesin family member 11 (KIF11) as a critical effector of DHA. Methods: Bioinformatic analyses revealed that KIF11 is significantly upregulated in HCC and associated with poor prognosis, and gene expression profiling suggested its oncogenic role via the PI3K/Akt pathway. Functional studies demonstrated that DHA inhibits HCC cell proliferation, migration, invasion, and colony formation, while inducing apoptosis. Xenograft models of nude mice were established for validation. Results: DHA downregulated KIF11 and epithelial–mesenchymal transition markers, whereas KIF11 overexpression attenuated DHA’s inhibitory effects; the inhibition of PI3K restored DHA sensitivity in KIF11-overexpressing cells. In vivo, DHA markedly suppressed tumor growth and malignancy in xenograft models, consistent with modulation of KIF11 and EMT-related proteins. Conclusions: DHA exerts antitumor effects in HCC by acting via KIF11 and PI3K/Akt modulation, providing a potential therapeutic strategy.

Cancers doi: 10.3390/cancers18101533

Authors: Yilin Cai Ying Zeng Qihang Li Guihua Yi Donghong Yang Tongyuan Deng Xiangyong Li Haiqing Luo

Objectives: This study compared the efficacy and safety of a single oral dose of a fixed-dose combination of netupitant and palonosetron (NEPA) with an intravenous regimen of fosaprepitant (FosAPR, 150 mg) plus palonosetron (PALO, 0.25 mg) in patients with locally advanced nasopharyngeal carcinoma (LA-NPC). Methods: This single-center retrospective cohort study included patients with stage III–IVa NPC who received cisplatin-based induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CCRT) from January 2020 to October 2025. Propensity score matching (PSM) generated 214 patients per group. All patients also received olanzapine and dexamethasone. Complete response (CR, defined as no emesis and no rescue medication), nausea control, adverse events, and nutritional status changes were assessed across the acute, delayed, overall, and extended (0–168 h) phases. Results: After PSM, 214 patients were included in each group. During the first IC cycle, the oral NEPA group achieved a higher CR rate in the extended overall phase (0–168 h) than the FosAPR + PALO group (80.0% vs. 70.1%, p = 0.019). A similar difference was seen in the first CCRT cycle (74.8% vs. 64.5%, p = 0.021). The advantage persisted across subsequent cycles, with no between-group difference in the acute phase. Nausea control also favored oral NEPA: rates of no significant nausea (visual analog scale < 25 mm) during the extended overall phase were 77.1% versus 65.9% in the first IC cycle (p= 0.010) and 72.9% versus 60.3% in the first CCRT cycle (p = 0.006). Fewer patients in the NEPA group required rescue antiemetics (14.5% vs. 22.0% in the first IC cycle, p = 0.045), and the median time to first rescue was longer (58.3 vs. 51.3 h, p < 0.001). Adverse event profiles were similar between groups, with constipation being the most common. Nutritional outcomes, including weight loss ≥ 5% and severe malnutrition, did not differ significantly. Conclusions: For patients with LA-NPC receiving highly emetogenic chemotherapy (HEC), oral NEPA appears to offer superior and sustained chemotherapy-induced nausea and vomiting (CINV) prophylaxi with a simplified administration schedule compared with the intravenous FosAPR plus PALO regimen. These findings warrant confirmation in prospective studies.

Cancers doi: 10.3390/cancers18101531

Authors: Constantin N. Baxevanis Ourania E. Tsitsilonis Angelos D. Gritzapis

Cancer has traditionally been described as a disease driven by uncontrolled cell growth caused by the gradual accumulation of genetic alterations [...]

Cancers doi: 10.3390/cancers18101529

Authors: Tatsuro Jo Takahiro Sakai Kazuhiro Noguchi Kaori Yamaguchi Kaho Umemoto Masatoshi Matsuo Yasushi Sawayama Jun Taguchi Ritsuko Kubota-Koketsu Kuniko Abe Kazuto Shigematsu

Background/Objectives: Follicular helper T-cell (TFH)-type lymphomas, including angioimmunoblastic T-cell lymphoma (AITL) and TFH lymphoma, not otherwise specified (TFH-NOS), are characterized by marked immune dysregulation in the tumor microenvironment. We investigated whether TFH-type lymphomas are enriched in immunosuppressive cells and explored immunologic changes associated with denileukin diftitox (DD) treatment. Methods: FOXP3-positive mononuclear cells were quantified by immunohistochemistry in lymph node specimens from 10 patients with TFH-type lymphoma and six with non-TFH-type T-cell lymphoma. Paired skin biopsy specimens obtained before and after DD treatment from two patients with AITL were evaluated for CD4, CD8, CD68, CD163, and FOXP3 expression. Longitudinal flow cytometric T-cell receptor Vβ repertoire analysis of CD8-positive T-cell subsets was performed in three patients with AITL treated with DD. Clinical responses were retrospectively assessed in seven patients with relapsed or refractory TFH-type lymphoma treated with DD. Results: TFH-type lymphomas showed significantly higher intra-tumoral FOXP3-positive cell densities than non-TFH-type lymphomas (p = 0.0024). In paired skin biopsies, DD treatment was associated with reductions in CD68- and CD163-positive macrophage-rich infiltrates and a suggested decrease in FOXP3-positive cells. Among seven patients treated with DD, the overall response rate was 86%, including one complete response and five partial responses. Responders showed selective Vβ over-representation patterns in effector and/or memory CD8-positive T-cell subsets, whereas such findings were not convincing in the non-responder. Conclusions: TFH-type lymphomas were associated with higher FOXP3-positive cell density than selected non-TFH-type comparators. DD treatment may be associated with changes in tissue immune infiltrates and peripheral CD8/TCR Vβ skewing in responding cases, although these findings remain exploratory and do not establish causality.

Cancers doi: 10.3390/cancers18101527

Authors: Nisrina Ekayani Nasrun Akihiko Tanimura Koki Yoshida Osamu Uehara Yuki Kunisada Kiyofumi Takabatake Akihiro Hosoya Hiroaki Takebe Hitoshi Nagatsuka Yoshihiro Abiko Muhammad Ruslin Tsuyoshi Shimo

Background: Oral squamous cell carcinoma (OSCC) remains a clinically challenging malignancy characterized by aggressive behavior and limited therapeutic options. Bitter taste receptors (TAS2Rs), expressed across multiple tissues and cancer types, have recently emerged as regulators of tumor biology and immune responses; however, their functional significance in OSCC remains poorly understood. Methods: Immunohistochemical analysis was performed using surgically resected human tongue OSCC specimens and a tissue microarray (TMA) cohort. In parallel, four TAS2R agonists were evaluated in SCC7 cells to assess intracellular calcium responses. RNA sequencing was conducted to analyze transcriptional changes following diphenidol treatment, and functional assays, including proliferation, migration, and apoptosis analyses, were performed in vitro. Antitumor effects were further evaluated in a syngeneic SCC7 mouse model, followed by TUNEL staining and flow cytometry to assess apoptosis and immune cell infiltration. Results: TAS2R38 expression was markedly upregulated in dysplastic and invasive OSCC lesions with predominant nuclear localization and was associated with histological grade and clinical stage, indicating an early and sustained alteration during tumor progression. Among the agonists tested, diphenidol most strongly induced IP3-dependent intracellular Ca2+ elevation. RNA sequencing revealed upregulation of Il1rl1 and Lzts2. Functionally, diphenidol significantly suppressed SCC7 cell proliferation and migration and induced apoptosis in vitro. In vivo, diphenidol reduced tumor volume and weight and increased apoptotic activity. Flow cytometry demonstrated a marked reduction in tumor-infiltrating CD4+CD25+Foxp3+ regulatory T cells, indicating modulation of the tumor immune microenvironment. Conclusions: TAS2R activation by diphenidol suppresses tumor growth through both tumor-intrinsic mechanisms and modulation of the tumor immune microenvironment in OSCC. These findings define TAS2R-mediated calcium signaling as a novel axis linking tumor progression and immunoregulation. Given that diphenidol is a clinically approved drug with an established safety profile, our results provide a strong rationale for TAS2R-targeted drug repurposing strategies in cancer therapy.

Cancers doi: 10.3390/cancers18101528

Authors: Ashleigh Witt Nicole M. Rankin Hanson Siu Nicholas Wilsmore Shaun Yo Christopher Lyne Kexin Sun Kanishka Rangamuwa Tracy Leong Ashleigh Hocking Shankar Siva Daniel P. Steinfort

Introduction: Accurate mediastinal staging with endobronchial ultrasound (EBUS) is essential in determining prognosis and management of patients with non-small cell lung carcinoma (NSCLC). Procedural documentation is often variable and incomplete due to reliance on free-text reporting. Synoptic reporting, which is a structured, standardised approach, improves documentation quality in other specialties, but has not been evaluated in EBUS. This study aimed to evaluate the impact of synoptic reporting on quality metrics in systematic staging EBUS. Methods: This multicentre ambispective study was conducted across five Australian tertiary hospitals. Synoptic reporting was implemented for EBUS procedures where systematic staging is recommended. Outcomes from three months of pre-intervention data were compared with three months post-intervention. The primary outcome was completeness of systematic mediastinal staging. Secondary outcomes included number of lymph nodes sampled per procedure, number of radiologically normal nodes sampled, detection of positron emission tomography (PET)-occult lymph node metastases, and report completeness. Results: Ninety-six procedures were included pre-intervention, and 77 post-intervention. Complete mediastinal staging increased from 17/96 (17.7%) to 67/77 (87%) (OR 3.2; p < 0.001). The mean number of lymph nodes sampled per procedure increased from 1.75 to 2.45 (p < 0.001), and sampling of radiologically normal nodes increased from 37/96 (38.5%) to 55/77 (71.4%) (OR 3.95; p < 0.001). Detection of PET-occult nodal metastases increased from 3/96 (3.1%) to 9/77 (11.7%) (OR 4.07; p = 0.036). Report completeness improved across most mandated domains. Conclusions: Synoptic procedural improves the quality and performance of systematic staging EBUS and represents a scalable quality improvement intervention.

Cancers doi: 10.3390/cancers18101526

Authors: Marzieh Nejabat Lucian Beer Theresa Servus Ahmed Ba-Ssalamah Peter Mazal Lukas Nics Marcus Hacker Georgios Karanikas Sazan Rasul

Background: Dual-tracer positron emission tomography/magnetic resonance imaging (PET/MRI) using [18F]-fluorodeoxyglucose (18F-FDG) and [18F]-fluoroethylcholine (18F-FEC) may reveal complementary aspects of hepatocellular carcinoma (HCC) biology. This retrospective study evaluates whether PET parameters obtained from 18F-FDG and 18F-FEC correlate with MRI enhancement parameters, tumor histological grade, and survival in patients with HCC. Methods: We retrospectively evaluated 25 patients who underwent integrated PET/MRI. Lesions were analyzed on pre-contrast MRI and at early (3–5 min) and late (20–30 min) post-contrast phases. For 18F-FDG and 18F-FEC, standardized uptake values (SUV maximum, mean, and peak) and metabolic tumor volume were measured, along with lesion size, MRI enhancement ratios, AFP levels, and survival. For patient-level imaging analyses, the largest lesion per patient was defined as the index lesion. Correlation analysis using Spearman’s rank correlation coefficient, Kaplan–Meier analysis, log-rank testing, and exploratory Cox proportional hazards models were performed. Results:18F-FDG SUVmean (index lesion) showed the strongest inverse association with survival (r = −0.61, p = 0.003), followed by SUVpeak (r = −0.50, p = 0.012). 18F-FDG SUVmean differed across tumor grades (G1–G3; p = 0.040), without a consistent trend. In Cox regression, 18F-FDG SUVpeak was significantly associated with shorter overall survival (HR 1.22, 95% CI 1.05–1.42, p = 0.01), whereas SUVmean showed only a borderline association (p = 0.07). When split at the median, SUVmean was also significantly associated with shorter survival (p < 0.001; HR 10.39, 95% CI 2.75–39.3). 18F-FEC parameters were not associated with survival but showed a moderate correlation with AFP levels (r = 0.41, p = 0.01). Dynamic MRI early and delayed enhancement of the index lesion were strongly correlated (r = 0.70, p < 0.001) but not associated with survival. Conclusions: In HCC, 18F-FDG uptake provides prognostic information beyond MRI enhancement and histology, reflecting tumor aggressiveness and independently predicting survival. While 18F-FEC-PET complements lesion characterization and correlates with AFP, it does not show meaningful prognostic value. MRI enhancement parameters were not associated with survival in this cohort. 18F-FDG-based metabolic imaging may improve pre-treatment risk stratification, whereas dual-tracer PET/MRI should be considered a selective, exploratory approach rather than routine imaging.

Cancers doi: 10.3390/cancers18101522

Authors: James Birch-Ford Ben Crosby Grace Langford Alexandra Johnson Helen Wong Shobha Silva Amy Jackson Roopa Kurup Joachim Chan Alia Alchawaf Tom Crosby

Background: Chemoimmunotherapy has improved survival compared with chemotherapy alone in phase III trials of advanced oesophago-gastric (OG) cancers; however, real-world UK data under National Institute for Health and Care Excellence (NICE) eligibility criteria remain limited. This study evaluated the effectiveness and safety of first-line pembrolizumab- or nivolumab-based chemoimmunotherapy in routine clinical practice. Methods: We conducted a retrospective, multi-centre cohort study of patients with unresectable or metastatic oesophageal, gastro-oesophageal junction, or gastric cancers treated with first-line chemoimmunotherapy at two UK tertiary centres between April 2021 and July 2024. Clinical, laboratory, radiological, and toxicity data were collected. Radiological outcomes were based on retrospective review of reports issued by consultant radiologists during routine clinical care. Overall survival (OS) and progression-free survival (PFS) were analysed using the Kaplan–Meier method, with exploratory analyses of prognostic factors. Results: Seventy-six patients were included (59.2% ≥ 65 years; 81.6% adenocarcinoma; 71.1% metastatic). At a median follow-up of 11 months, 46 deaths had occurred. Median OS was 16.0 months (95% CI: 11.0–20.9), and median PFS was 8.0 months (95% CI: 6.8–9.2). Disease control occurred in 80.3% of patients and was associated with improved OS compared with progressive disease (17.0 vs. 4.0 months; p < 0.001). Survival outcomes did not differ significantly by tumour site, histology, or immunotherapy agent. Immunotherapy-related adverse events occurred in 31 patients (40.8%), with grade ≥ 3 toxicities in 13.2% and two treatment-related deaths. Exploratory analyses suggested potential associations between survival and baseline lymphocyte count and neutrophil–lymphocyte ratio, although these did not reach statistical significance. Conclusions: In this real-world UK multi-centre cohort, first-line chemoimmunotherapy demonstrated survival outcomes comparable to pivotal clinical trials, with manageable toxicity. These findings support the use of chemoimmunotherapy in routine practice. Prospective collaborative studies incorporating robust biomarker evaluation are warranted to optimise patient selection and better define predictors of response and toxicity.

Cancers doi: 10.3390/cancers18101525

Authors: Laura Valerio Alfonso Sagnella Fabio Maino Elisa Mattii Alessandra Cartocci Maria Grazia Castagna

Background: The clinical impact of familial history on the prognosis of non-medullary thyroid cancer (NMTC) remains controversial. This study aimed to investigate whether familial NMTC (fNMTC) is associated with different patterns of response-to-therapy evolution over time compared to sporadic NMTC (sNMTC), using a dynamic risk stratification (DRS) approach. Methods: We analyzed 665 sNMTC cases and 130 fNMTC cases. Response to therapy was assessed at the first follow-up (6–12 months after initial therapy) and at the last outcome. Univariate and multivariate analyses were used to assess the role of family history as a modifier of response reclassification, independently of established prognostic factors. Results: A significant difference in the dynamic pattern of response evolution was observed between fNMTC and sNMTC (p = 0.003), with familial cases showing higher response variability. Among patients with an initial excellent response (n = 558), familial status remained the only independent predictor of losing excellent response (OR 3.3, 95% CI 1.54–7.12; p = 0.002). The worsening in fNMTC was primarily driven by transitions to indeterminate or biochemical incomplete responses (12.3% vs. 4.2%, p = 0.006), while structural progression remained rare and similar between groups (2.5% vs. 1.3%, p = 0.33). Regarding recovery, 50.2% of patients with an initial non-excellent response achieved an excellent response, with no significant difference between familial and sporadic cases (61.2% vs. 47.3%, p = 0.1). An intermediate-to-high ATA risk class was independently associated with a lower probability of achieving an excellent response (OR 0.45, 95% CI 0.25–0.91; p = 0.01). Conclusions: These findings suggest that “Excellent Response” is more fragile in a familial context. Familial NMTC might require prolonged and vigilant biochemical surveillance, even when cases appear to be in full remission.

Cancers doi: 10.3390/cancers18101524

Authors: Huishan Zhang Mengru Quan Zhongqiao Lin Zequn Sun Yu Chen Jing Lin

Objective: The prognosis of patients with advanced melanoma remains poor, particularly in those with brain metastases. To date, no standardized later-line treatment regimen has been established for this patient population. This study aimed to explore prognostic factors in patients with advanced melanoma and brain metastases, with a specific focus on the prognostic significance of baseline lactate dehydrogenase (LDH) levels and cranial radiotherapy. Materials and Methods: This retrospective cohort study consecutively enrolled 145 patients diagnosed with melanoma brain metastases (MBM) between 1 December 2015 and 31 August 2024. Baseline LDH data were available for 139 patients (95.9%), while the remaining six cases were excluded from LDH-stratified analyses. Patients were divided into an elevated LDH group (>250 U/L) and a normal LDH group (≤250 U/L). Collected clinical variables included brain intensity-modulated radiotherapy (IMRT), systemic treatment strategies (immunotherapy, targeted therapy, and chemotherapy), the number of prior treatment lines, and neurological symptoms at diagnosis. The completeness of all other clinical variables reached 100%. Univariate and multivariate Cox regression analyses were performed to identify independent prognostic factors for overall survival (OS) and progression-free survival (PFS). All statistical analyses were conducted using SPSS 21.0. Results: The median OS of the entire cohort was 6.7 months (range: 0.4–101.0 months). Multivariate Cox regression identified three independent protective factors for superior OS and PFS: brain IMRT administration (OS: HR = 0.565, 95% CI: 0.365–0.874, p = 0.010; PFS: HR = 0.623, 95% CI: 0.420–0.924, p = 0.019), normal baseline LDH (OS: HR = 2.091, 95% CI: 1.425–3.069, p < 0.001; PFS: HR = 1.456, 95% CI: 1.023–2.071, p = 0.037), and ≤3 prior lines of systemic therapy before MBM diagnosis (OS: HR = 0.853, p = 0.004; PFS: HR = 1.679, p = 0.015). Moreover, the absence of neurological symptoms at baseline was an independent favorable prognostic factor for OS (HR = 1.919, p = 0.001) but not for PFS. Patients with normal LDH combined with brain IMRT exhibited the best OS and PFS outcomes (p < 0.001). Conclusions: Baseline LDH level and cranial radiotherapy are robust independent prognostic indicators for survival in MBM patients. More prior treatment lines and the presence of neurological symptoms correlate with inferior clinical outcomes. These findings provide evidence for clinical risk stratification and individualized treatment decision-making for this high-risk and challenging population.

Cancers doi: 10.3390/cancers18101523

Authors: Luca Orecchia Simone Steffani Andrea Micillo Roberto Miano Eric Walser Guglielmo Manenti

Background: The management of localized prostate cancer (PCa) suffers from the dilemma between the overtreatment associated with radical surgery and the uncertainty of active surveillance, highlighting a significant therapeutic gap specifically for intermediate-risk patients and selected low-risk patients. Focal therapy (FT) emerges as an advanced technological solution to balance rigorous oncological control with anatomical and functional preservation. Methods: A narrative review of the literature was conducted to analyze the physical principles underlying various ablative energies (thermal, cryogenic, and non-thermal) as well as radiation-based focal approaches. The review examines the oncological rationale of targeted ablation, recent innovations in imaging, and the expanding clinical scenarios for FT application. Results: Evidence supports the oncological rationale of “Index Lesion” ablation as a targeted curative strategy for clinically significant disease, rather than merely a palliative one. The review highlights the emerging concept of “pushing the disease” and demonstrates the valuable role of salvage focal therapy in the setting of radio-recurrent carcinoma. Furthermore, recent innovations in multiparametric magnetic resonance imaging (mpMRI) and fusion systems have significantly refined patient selection, rendering this minimally invasive approach highly targeted. Conclusions: The current barrier to the universal adoption of focal therapy is the lack of a standardized consensus on the definitions of therapeutic failure and the inadequacy of traditional PSA-based criteria. However, evidence suggests that FT represents a promising, organ-sparing alternative for carefully selected patients with localized PCa, though long-term comparative data are still required.

Cancers doi: 10.3390/cancers18101521

Authors: Skylar L. Nahi Amanda M. Dann

Desmoid tumors (DTs) are rare, fibroblastic neoplasms characterized by locally aggressive behavior, unpredictable clinical trajectories, and a substantial impact on patient quality of life despite minimal metastatic potential. Although the underlying biology of DTs remains incompletely defined, associations with prior trauma, hormonal exposure, and aberrant Wnt/β-catenin signaling—including somatic CTNNB1 mutations and germline APC alterations seen in Familial Adenomatous Polyposis—have informed both historical and contemporary therapeutic approaches. Management strategies have evolved from surgery-dominant paradigms toward individualized, multimodal treatment algorithms emphasizing systemic medical therapy, as reflected in current NCCN and Desmoid Tumor Working Group recommendations. This review focuses on the medical management of DTs, tracing the evolution from earlier noncytotoxic therapies, including antiestrogen agents such as tamoxifen, to modern systemic options supported by prospective and randomized data. We summarize available evidence for four principal classes of medical therapy: nonsteroidal anti-inflammatory drugs, cytotoxic chemotherapy (with particular emphasis on anthracycline-based regimens), tyrosine kinase inhibitors—most notably sorafenib—and the emerging class of γ-secretase inhibitors. Recent phase III data supporting the efficacy of nirogacestat highlight a shift toward mechanism-based, targeted treatment with demonstrable benefits in progression-free survival, symptom control, and patient-reported outcomes. Collectively, these advances underscore a maturing therapeutic landscape in which systemic therapy plays a central role in disease control, symptom palliation, and preservation of function for patients with advanced desmoid tumors.

Cancers doi: 10.3390/cancers18101520

Authors: Ganesh Datta Borewad Bhavya Kanakarajulu Zayba Noor Arun Krishna Shalini Thakur Anand Subash Vishal U. S. Rao

We read with great interest the recent meta-analysis by Rao et al. [...]

Cancers doi: 10.3390/cancers18101519

Authors: Ting-Kang Chang Shiu-Ling Li Anne-Cécile Brunac Jia-Jun Huang Yen-Hsiu Yeh Pierre Brousset Jean-Marc Egly Tsai-Kun Li

Background: Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), increase colorectal cancer (CRC) risk. Methods: Mouse IBD and CRC models with a combination of pharmacological, knockout and knock-in approaches was employed to analyze the involvement of TOP2s and NOS2 in CRC tumorigenesis. Key pathologies, such as inflammatory and neoplastic scores, were examined by immunohistochemical assays. Results: In colon tissues from acute, chronic colitis and CRC mouse models and from CD patients, the biomarkers γH2AX and 53BP1pS25/S29 of DNA breaks (mainly representing DSBs) accumulated, alongside increases in topoisomerase II (TOP2) and nitric oxide synthase 2 (NOS2). Genetic ablation of NOS2 (Nos2-/-) or TOP2β (Top2βf/f) as well as pharmacological inhibition with ICRF-193 (a TOP2 inhibitor) or PTIO (a NO scavenger) reduced DSB formation and disease severity. Consistently, Nos2-/-, or ICRF-treated, mice exhibited decreased tumor burden. DSBs and tumor accumulation were pronounced in the distal colon, mirroring human CRC distribution. While ICRF-193 suppressed tumor growth, Top2βf/f deficiency (with a compensatory TOP2α upregulation) enhanced tumor development, indicating potential roles for TOP2 isozymes in tumor formation and progression. Conclusion: Collectively, these findings identify the cooperative action of TOP2 and NOS2 in driving DSBs, highlighting a potential therapeutic target in inflammation-associated CRC.

Cancers doi: 10.3390/cancers18101518

Authors: Somayah Alsolami Jennifer Ji Lynn Hoang

Vulvar squamous cell carcinoma (VSCC) and its precursor lesions are relatively rare malignancies of the gynecologic tract. In recent years, international organizations and pathologic reporting guidelines endorse the subdivision of VSCC into human papillomavirus (HPV)-associated and HPV-independent types. There is also growing evidence for the further separation of HPV-independent into p53 abnormal and p53 wild-type cancers. Although the diagnosis and subclassification of VSCC is often straightforward, using immunohistochemical markers such as p16 and p53 as surrogate markers for high-risk HPV infection and TP53 mutation respectively, rare and unusual scenarios exist that can complicate VSCC classification. Herein we discuss these challenging scenarios in VSCC classification, as well as emerging VSCC prognostic biomarkers such as cyclin D1. In addition, the pathologic diagnosis of VSCC precursor lesions, particularly those of HPV-independent type, are frequently challenging to distinguish from benign conditions of the vulva. We discuss the recent literature describing the added diagnostic value of immunohistochemical biomarkers p53, CK17, CK13, SOX2, GATA3, GLUT1 and others, which may be particularly helpful when morphology is inconclusive. It is anticipated that with improved VSCC classification and precursor recognition, avenues for more tailored therapeutic strategies and earlier therapeutic intervention can be achieved.

Cancers doi: 10.3390/cancers18101517

Authors: Nadja Grübel Anne-Kathrin Uerschels Karsten Wrede Nora F. Dengler Benjamin Mayer Christian Rainer Wirtz Maria Teresa Pedro

Background/Objectives: This prospective study used a standardized preoperative assessment to characterize the full spectrum of pain in patients with peripheral nerve tumors, addressing the lack of structured pain phenotyping in this population. Methods: Between June 2024 and October 2025, preoperative pain symptoms were assessed in 91 patients, representing 16% of the Peripheral Nerve Tumor Registry (PNTR) cohort, using the PainDETECT questionnaire (0–38) at two centers: University Hospital Ulm, Günzburg (n = 72), and University Hospital Essen (n = 19). Results: Ninety-one patients (61.5% male; mean age, 49 years) were included. Most tumors were located in the lower extremity (54.9%). PainDETECT scores were ≤12 in 51.6%, 13–18 in 24.1%, and ≥19 in 21.9% of patients. Malignant tumors (6.5%) had the highest mean score (17), but benign tumors also showed a relevant pain burden (mean 11.9). Hybrid peripheral nerve sheath tumors and neurofibromas had numerically higher mean scores than schwannomas, although the difference was not statistically significant. Pain severity was not associated with tumor size, depth, or affected nerve. The most common sensory features were electric-shock-like and pressure-related pain, as reflected by a positive Tinel sign in 86.8% of patients. The most frequent pain pattern was intermittent attacks with pain-free intervals (46%). Conclusions: These interim results indicate that pain is common even in benign peripheral nerve tumors, challenging the assumption that these lesions are often asymptomatic. Malignant tumors showed the highest pain scores. The heterogeneous pain phenotypes highlight the need for individualized assessment and management. Expansion to a multicenter evaluation within the framework of the PNTR is planned.

Cancers doi: 10.3390/cancers18101516

Authors: Kristjana Sigurðardóttir Nanna Friðriksdóttir Nanna Margrét Kristinsdóttir Lára Kristjánsdóttir Hjalti Gunnlaugur Skúlason Álfheiður Haraldsdóttir Sigríður Ása Alfonsdóttir Anna Kristín B. Jóhannesdóttir Helgi Birgisson Helga Tryggvadóttir Freyja Birgisdóttir Heiðdís Valdimarsdóttir Thor Aspelund Lonneke van de Poll-Franse Sigríður Gunnarsdóttir

Background: Population-based studies using patient-reported outcomes provide important insights into health-related quality of life (HRQoL) and the long-term impact of cancer and its treatment. Declining response rates and potential non-response bias have presented methodological challenges, particularly in registry-based surveys including both cancer survivors and population controls. The SURV-ICE study was established to assess HRQoL and health literacy among cancer survivors in Iceland while evaluating recruitment processes and participation patterns in a nationwide mixed-mode survey. Methods: SURV-ICE is a nationwide, population-based cross-sectional survey conducted in Iceland in 2025. Adults diagnosed with invasive cancer between 2014 and 2024 were identified through the Icelandic Cancer Registry and invited alongside an age- and gender-matched control group sampled from national registers. Participants completed validated EORTC instruments. Recruitment used a mixed-mode strategy including postal invitations, web-based and paper questionnaires, electronic reminders via the national health portal, and targeted telephone follow-up. Results: Among 10,005 cancer survivors 5489 (54.9%) responded to the questionnaires and among 5663 controls 2297 (40.6%) responded to the questionnaires. In both groups participation peaked among individuals aged 60–79 years and was lowest among the youngest and oldest groups. Cancer survivors had higher odds of participation than controls (OR 1.84; 95% CI 1.72–1.97). Most responses followed the initial postal invitation and first electronic reminder. Data completeness was high (≥80% item completion in 95.7% of instruments). Conclusions: Nationwide registry-based recruitment for large-scale PRO research is feasible in Iceland and can achieve competitive response rates without incentives. SURV-ICE provides an infrastructure for future research on cancer survivorship, HRQoL, and health literacy.

Cancers doi: 10.3390/cancers18101515

Authors: Meghana Maddula Jordan E. Cohen Dulitha Kumarasinghe Mandy L. Ballinger Jaqueline L. E. Tearle Kylie R. James Adnan Nagrial Megan Barnet Subotheni Thavaneswaran

Background: The incidence of early-onset colorectal cancer (EOCRC) is rising globally, yet its underlying risk factors remain incompletely understood, particularly in cases without recognised hereditary syndromes. Objectives: To update and synthesise the current body of evidence on modifiable and non-modifiable risk factors for sporadic early-onset colorectal cancer. Methods: A systematic review of peer-reviewed articles published in English reporting original observational research examining risk factors for sporadic early-onset colorectal cancer (<50 years old) was conducted. PubMed and EMBASE databases were searched from inception to March 2025. Across studies, effect measures varied; therefore, the synthesis focused on the consistency of associations rather than the direct comparison of effect sizes. Results: The initial search identified 2575 papers; 34 studies were included after screening. Several consistent associations were identified, with dietary and lifestyle factors along with metabolic conditions emerging as key risk factors. EOCRC risk was higher in males (adjusted odds ratio (aOR) 1.36–2.21 across studies), individuals of Caucasian ethnicity (aORs 1.48–2.56), and in individuals whose age was approaching 50 years (per year, aORs 1.05–1.11). Putatively sporadic EOCRC was associated with a family history of CRC or other cancers (aORs up to 8.61). Other key factors linked to higher risk included obesity (aORs 1.92–2.88; adjusted Hazard Ratios (aHRs) 1.04–1.82), metabolic syndrome (aORs 1.25–2.48; aHRs 1.2–1.26), diabetes (aORs 1.24–3.42), Western dietary patterns (aORs 1.84–2.99), and sedentary behaviours (adjusted relative risks (aRR) 1.69–2.44). Moderate-to-vigorous exercise appeared protective (aORs 0.34–0.58), as did higher vitamin D levels (aHRs 0.41–0.61). Evidence for smoking, alcohol, medications and early/in utero environmental exposures was inconsistent. Conclusions: Lifestyle and metabolic factors, including Western dietary patterns, obesity and sedentary behaviours, were associated with sporadic EOCRC. Family history also emerged as a significant contributor to putatively sporadic disease, suggesting heritable influences beyond recognised syndromes and interplay between environmental factors and genetic predisposition. Future research should focus on integrated tumour and germline profiling, including broader genomic analyses in well-characterised cohorts, to better understand potential pathogenic mechanisms and support the development of risk stratification approaches.

Cancers doi: 10.3390/cancers18101514

Authors: David Zahrieh Daniel Satele Hiboombe Haamankuli Xin Shelley Wang Jennifer G. Le-Rademacher Minji Lee Heshan Liu Julian Diaz-Cobo Shu-En Shen Selina Chow Maryam Lustberg Kathryn J. Ruddy Ellen M. Lavoie Smith

Background/Objectives. Decades of research have failed to uncover effective approaches to prevent chemotherapy-induced peripheral neuropathy (CIPN), a common side effect of neurotoxic chemotherapy. Increased interest in placebo response as a potentially under-recognized confounder in CIPN trials was recently sparked by the results of a multisite NCI-funded phase II-III CIPN prevention study of duloxetine, a promising serotonin–norepinephrine reuptake inhibitor that enhances pain-inhibitory mechanisms within the central nervous system. Study findings revealed high and nearly equivalent response rates in three randomized treatment groups—little to no CIPN was reported by 65.2%, 66.0%, and 68.0% of study participants who received duloxetine 30 mg, 60 mg, or placebo treatment, respectively. Methods. We performed a meta-analysis of placebo response rates from seven randomized, double-blinded, placebo-controlled trials conducted over the past 20 years and comprising 191 placebo participants that were specifically testing interventions for oxaliplatin- and paclitaxel-induced peripheral neuropathy and that serially collected patient responses on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Chemotherapy-Induced Neuropathy questionnaire. Additionally, we sought to identify trial- and patient-specific factors that predicted higher placebo response rates from a participant-level pooled analysis. Results. The placebo response rate was 10.0% [95% CI: 5.8%, 16.6%] when response was defined more conservatively as patients reporting no neuropathy at all. When the placebo response was defined more broadly based on patients reporting no or a little neuropathy, the placebo response rate was higher (39.6% [95% CI: 27.4%, 53.2%]). Male participants, receipt of oxaliplatin, and a 2:1 randomization ratio favoring the intervention arm were individually associated with a higher placebo response. Conclusions. High placebo response rates can threaten scientific progress toward identifying effective treatments for cancer treatment-associated side effects, like CIPN. Careful attention to study design factors, participant eligibility, and patient and research staff expectations may help to minimize placebo response rates in future CIPN intervention studies.

Cancers doi: 10.3390/cancers18101512

Authors: Arkadeep Dhali Dushyant Singh Dahiya Abdul Rafae Faisal Asad Zaman Fayaz Khan Jyotirmoy Biswas Hareesha Rishab Bharadwaj Saikat Mandal

Background: Gamma-glutamyl transferase (GGT) has been associated with increased risks of multiple cancers and mortality. Because GGT is also a marker of hepatobiliary injury, metabolic dysfunction, and alcohol exposure, this study evaluated associations between persistently elevated GGT and hepatobiliary and pancreatic outcomes. Materials and Methods: This retrospective cohort study used TriNetX data from the US Collaborative Network to compare adults aged 40 years or older with persistently elevated GGT against those with normal GGT using a 65 U/L threshold on two occasions 6–12 months apart. Outcomes were assessed from 180 to 1095 days after the index event. Following 1:1 propensity score matching, 14,590 patients per cohort were analyzed. Cox proportional hazards analysis estimated hazard ratios (HRs) with 95% confidence intervals (CIs). Results: Elevated GGT was associated with increased hazards of cholangiocarcinoma (HR 3.715, 95% CI 1.899–7.268), hepatocellular carcinoma (HR 2.260, 95% CI 1.677–3.045), acute pancreatitis (HR 3.359, 95% CI 2.284–4.941), chronic pancreatitis (HR 3.086, 95% CI 1.975–4.821), pancreatic cysts (HR 2.160, 95% CI 1.493–3.127), hospitalization (HR 1.363, 95% CI 1.236–1.503), and all-cause mortality (HR 2.250, 95% CI 2.051–2.467). No statistically significant association was observed with pancreatic cancer (HR 1.591, 95% CI 0.766–3.303; log-rank p = 0.209). Mean follow-up after matching was 799.722 ± 391.071 days in the elevated GGT cohort and 844.685 ± 374.676 days in controls. Conclusions: Persistent GGT elevation was associated with hepatobiliary malignancies, pancreatic inflammatory diseases, pancreatic cysts, hospitalization, and all-cause mortality, but not pancreatic cancer. These results suggest that persistent GGT elevation may be a non-specific clinical marker of underlying hepatobiliary and metabolic risk.

Cancers doi: 10.3390/cancers18101513

Authors: Koshiro Ishiyama Ryoko Nozaki Ryota Kakuta Shota Igaue Eigo Akimoto Daichi Utsunomiya Daisuke Kurita Yasuyuki Seto Hiroyuki Daiko

Background: Cervical esophagogastric anastomosis using a gastric conduit is commonly performed after esophagectomy for esophageal cancer, but anastomotic leakage remains a major postoperative complication. Totally mechanical Collard (TMC) anastomosis provides favorable stricture outcomes; however, leakage rates remain variable. The clinical benefit of staple-line oversewing in TMC anastomosis has not been fully clarified. Methods: This retrospective cohort study included consecutive patients who underwent esophagectomy with TMC cervical anastomosis between January 2017 and December 2024. Patients were divided into oversewing and non-oversewing groups according to whether staple-line oversewing was performed. The primary endpoint was anastomotic leakage. Secondary endpoints included leakage severity, timing of leakage onset, healing duration, anastomotic stricture, and postoperative complications. Multivariable logistic regression analysis was used to identify independent risk factors for leakage. Results: A total of 803 patients were included (oversewing: n = 313; non-oversewing: n = 490). Baseline characteristics were well balanced between the two groups. The incidence of anastomotic leakage was significantly lower in the oversewing group than in the non-oversewing group (4.4% vs. 8.1%, p = 0.043). Leakage severity was also reduced, with Grade I leakage occurring more frequently in the oversewing group (78.5% vs. 30%, p = 0.004). Leakage occurred later in the oversewing group (12.7 ± 7.6 vs. 8.9 ± 4.2 days, p = 0.01), whereas healing duration was comparable between groups. The incidence of anastomotic stricture did not differ significantly between the two groups (3.5% vs. 5.3%, p = 0.3). Multivariable analysis identified body mass index ≥25 kg/m2 (OR 2.37, 95% CI 1.08–4.93, p = 0.03) and the absence of staple-line oversewing (OR 2.15, 95% CI 1.03–4.82, p = 0.04) as independent risk factors for leakage. Conclusions: Staple-line oversewing of TMC cervical anastomosis was associated with a reduced incidence and milder severity of anastomotic leakage without increasing anastomotic stricture. This simple and reproducible technique may improve anastomotic stability after esophagectomy for esophageal cancer.

Cancers doi: 10.3390/cancers18101510

Authors: Faika Nur Erkol Nuray Alaca Nuran Beşe Cihan Uras

Background/Objectives: To evaluate the effectiveness of manual lymph drainage (MLD) in treating breast edema in patients who have undergone breast-conserving surgery and adjuvant radiotherapy. Methods: Twenty-five female participants who underwent breast-conserving surgery and received adjuvant radiotherapy were enrolled in the study. Twelve participants were assigned to the treatment group (education, compression, exercise therapy, and MLD), and 13 to the control group (education, compression, and exercise therapy). The participants were assessed after radiotherapy (baseline) and three months post-treatment. The following variables were evaluated: general body pain, fatigue, breast pain, breast edema (breast edema questionnaire and LENT-SOMA-breast criteria), anxiety, depression, and quality of life. Results: In both groups, within-group analyses showed improvements in general body pain, fatigue, breast pain, breast edema, anxiety, depression, and some quality of life subscales (p < 0.05). Between-group comparisons revealed additional improvements in breast pain, breast edema, and breast-related criteria in the treatment group compared with the control group (p < 0.05). Additionally, the treatment group showed greater improvements in some quality of life subscales (global health status, fatigue, pain, systemic treatment side effects, and breast and arm symptoms) compared with the control group (p < 0.05). Conclusions: The addition of MLD may provide additional benefits within complex decongestive therapy for breast edema following breast-conserving surgery and radiotherapy. However, these findings should be considered preliminary and interpreted with caution due to the small sample size, lack of objective outcome measures, absence of a no-treatment control group, and lack of blinding of participants and treating clinicians. As both groups received active treatment during a period of expected natural recovery, the independent effect of MLD cannot be fully isolated. Confirmation in future well-designed, blinded randomized controlled trials incorporating objective outcome measures is warranted.

Cancers doi: 10.3390/cancers18101511

Authors: Panayiotis Gavriil Pavlos Altsitzioglou Ioannis Trikoupis Efthalia Maleka Panagiotis Briassoulis Jendrik Hardes Panayiotis Papagelopoulos Vasileios Kontogeorgakos

Background/Objectives: Diagnosing periprosthetic joint infection (PJI) after megaprosthetic reconstruction may be difficult due to altered inflammatory responses, extensive prior surgery, and the limited performance of conventional criteria such as the 2018 ICM score. Synovial calprotectin is a rapid neutrophil-derived biomarker that may improve diagnostic accuracy in this challenging setting. The primary aim of this study was to evaluate the diagnostic performance of synovial calprotectin in detecting periprosthetic infection in patients treated with tumor megaprostheses; secondary aims included comparison with ICM classification, assessment in infection classification-inconclusive cases, and exploratory performance in patients with low CRP. Methods: This prospective study included 20 consecutive megaprosthesis patients evaluated for suspected PJI at ATTIKON University Hospital, Athens, with a minimum follow-up of 1 year after biomarker testing. Synovial calprotectin was measured using a lateral-flow assay (positive ≥ 50 mg/L) and compared with a predefined infection reference standard. ICM final status (0 = aseptic, 1 = inconclusive, 2 = infected) was recorded for all cases. Other synovial biomarkers (α-defensin, leukocyte esterase, synovial D-dimer) were not routinely available. The cohort had a mean age of 52.9 ± 22.5 years, 70% were male, and reconstructions involved the knee (80%), hip (15%), and humerus (5%). Preoperative cultures were positive in 40%, the median systemic WBC was 7100/μL, and the median time from last surgery to testing was 1.0 years (IQR 0.46–2.0). Among infected cases, the most common microorganisms were coagulase-negative staphylococci (61.5%) and Staphylococcus aureus (23.1%), with 30.8% demonstrating polymicrobial infection. Results: Thirteen of 20 patients (65%) were classified as infected. Using the ≥50 mg/L threshold, synovial calprotectin demonstrated high apparent diagnostic accuracy in this exploratory cohort, and no false positives, yielding a sensitivity of 92.3%, specificity of 100%, PPV of 100%, NPV of 87.5%, LR+ = ∞, and LR− = 0.08. The AUC for continuous values was 1.00. Agreement with the ICM final classification was substantial (κ = 0.76), with no directional discordance (McNemar p = 1.00). Among the three ICM-inconclusive cases, calprotectin correctly reclassified two (66.7%). In patients with low CRP (<10 mg/L), a clinically difficult subgroup, calprotectin maintained strong performance (sensitivity 75%, specificity 100%, NPV 85.7%). Conclusion: Synovial calprotectin demonstrated promising diagnostic performance for PJI in megaprosthesis patients, with high sensitivity and specificity, and substantial agreement with the 2018 ICM criteria. It successfully clarified most ICM-inconclusive cases and remained reliable even in patients with low CRP. These findings support calprotectin as a valuable adjunctive biomarker in the complex diagnostic environment of megaprosthetic reconstruction and justify further validation in larger cohorts.

Cancers doi: 10.3390/cancers18101509

Authors: Jonathan René García-Bernal Luis Javier Reséndiz-Castillo Marcela Guadalupe Martínez-Barajas Carlos Daniel Díaz-Palomera Adrián Ramírez-de-Arellano Alejandra Natali Vega-Magaña Lesly Jazmin Bueno-Urquiza Luis Reneé González-Lucano Marcela Peña-Rodríguez Julio César Villegas-Pineda Ana Laura Pereira-Suárez

Background: E2 is fundamental to the onset and progression of CC. CAFs are the most abundant stromal population in the tumor microenvironment. CAFs have been shown to promote protumoral effects in CC cell lines; however, the effects of E2-stimulated CAFs remain to be explored. Objectives: This study aimed to evaluate whether E2-stimulated CAFs modify the behavior of SiHa and HeLa tumor cells, including their metabolism, ROS production, migration, apoptosis, and gene expression. Methods: Characterization and estrogen receptor expression in primary CAF cultures were evaluated by immunofluorescence. Supernatants from non-stimulated and E2-stimulated CAFs were used to culture CC cells, and mitochondrial metabolism was measured by MTT, ROS production by H2DCFDA, migration using the wound-healing assay, apoptosis by Annexin V assay, and gene expression by next-generation RNA-seq. Results: Stimulation of CC cells with CAFs’ supernatants demonstrated that it influences tumor cells in different ways. In SiHa cells, the metabolic shift was supported by decreased mitochondrial metabolism, increased ROS production, and enhanced gene enrichment for glycolysis and hypoxia responses. On the other hand, in HeLa cells, CAFs enhanced migration and gene enrichment in KRAS signaling, epithelial-mesenchymal transition, and the proinflammatory response, via enrichment of the IL6/JAK/STAT3 signaling pathway, along with the overexpression of cytokines such as IFN-γ, IL-6, and IL-8. Conclusions: CAFs exert protumoral effects by promoting a metabolic shift in SiHa cells or enhancing migration and cytokine secretion in HeLa cells; these effects are independent of E2 stimulation in CAFs.

Cancers doi: 10.3390/cancers18101508

Authors: Ashley M. Mello Marina Pasca di Magliano Kyoung Eun Lee

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense stromal microenvironment and profound hypoxia, which contribute to therapeutic resistance. Using an in vitro system incorporating pancreatic cancer cells and cancer-associated fibroblasts (CAFs), we show that hypoxia suppresses CD8+ T cell accumulation and, in combination with cancer cell- and CAF-derived factors, further impairs T cell fitness by increasing cell death and reducing proliferation. Although the combination of hypoxia and cancer cell/CAF-derived factors enhances IFNγ and granzyme B expression in CD8+ T cells on a per-cell basis, the overall number of functional effector T cells is markedly reduced. Analysis of human PDAC single-cell RNA sequencing data corroborates these findings, revealing that CD8+ T cells enriched for hypoxia signatures exhibit elevated apoptosis and stress-response pathways. Furthermore, hypoxia is associated with downregulation of stemness-related genes and upregulation of terminal differentiation markers. Together, these data suggest that the integration of intrinsic hypoxic responses and extrinsic cues from tumor cells and CAFs impairs CD8+ T cell fitness and correlates with a terminally differentiated, dysfunctional T cell state.

Cancers doi: 10.3390/cancers18101507

Authors: Lin Li Qi Li Zhengrong Zou Zoufang Huang Yijian Chen

The journal retracts the article “TRIM10 is downregulated in acute myeloid leukemia and plays a tumor suppressive role via regulating NF-κB pathway” [...]

Cancers doi: 10.3390/cancers18101506

Authors: Utku Iltar Unal Atas Orhan Kemal Yucel Ozan Salim Levent Ündar

We read with great interest the comprehensive review by Bangolo et al [...]

Cancers doi: 10.3390/cancers18101505

Authors: Kirti Arora Lara Soueid Louis Williams Jahanvi Grover Diana Basali Jack Khouri Yuvraj Kaushal Sandra Mazzoni Rockey Dahiya Beth Faiman Jason Valent Faiz Anwer Shahzad Raza

Smoldering multiple myeloma (SMM) is an asymptomatic plasma cell disorder characterized by a heterogeneous risk of progression to overt multiple myeloma (MM). Historically managed with active surveillance, advances in risk stratification and the development of novel therapeutics have renewed debate regarding early intervention, particularly in patients with high-risk disease. We conducted a narrative review of clinical trials and observational studies evaluating early treatment versus observation in SMM. Outcomes assessed included progression-free survival (PFS), time to progression (TTP), overall survival (OS), treatment-related toxicity, and quality-of-life measures, alongside evolving diagnostic criteria and risk-stratification models that influence therapeutic decision-making. Early randomized trials using conventional cytotoxic therapy did not demonstrate a survival advantage and supported observation as the standard management approach. However, contemporary studies using novel agents have demonstrated improved disease control in selected high-risk populations. The QuiRedex and ECOG-E3A06 trials showed significant reductions in progression risk with lenalidomide-based therapy, and long-term follow-up suggests a potential overall survival benefit in Qui-Redex. The phase III AQUILA trial further demonstrated delayed progression with daratumumab in high-risk SMM using updated diagnostic criteria. Phase II studies evaluating combination regimens, including KRd-based and daratumumab-containing approaches, have reported high response rates and MRD negativity, although survival data remain immature. Importantly, many benefits reflect delayed biochemical or imaging-defined progression rather than prevention of symptomatic end-organ damage. Current evidence supports selective early intervention in carefully defined high-risk SMM populations; however, uncertainties remain regarding long-term survival benefit, optimal treatment duration, quality-of-life impact, and clonal evolution. Active surveillance with modern monitoring remains appropriate for many patients.

Cancers doi: 10.3390/cancers18101503

Authors: Duaa Mohammad Alawad Mark Fertel Chindo Hicks

Background: Despite remarkable progress in clinical management and screening, colorectal cancer (CRC) remains a major cause of cancer-related deaths worldwide. Sadly, both the number of CRC incidences and the mortality rate are trending upwards, particularly in younger individuals. There is an urgent need for the identification of reliable diagnostic biomarkers and therapeutic targets, and the development of accurate algorithms to guide therapeutic decision-making at the point of care. Here, we leverage multi-model integrative Machine Learning (ML) algorithms using RNA-Seq and somatic mutation data for the classification of tumor–normal samples and the discovery of potential biomarkers and therapeutic targets. Methods: We used RNA sequencing (RNA-Seq) and somatic mutation data from The Cancer Genome Atlas (TCGA) for the development of classification models and the discovery of biomarkers and therapeutic targets. The models were validated using two independent datasets. Results: ML algorithms accurately classified tumor samples and identified a signature for 58 genes, which could serve as potential diagnostic biomarkers. Functional analysis revealed the Wnt and GPCR signaling pathways enriched for somatic mutations. Conclusions: Multi-model integrative ML algorithms integrating gene expression with somatic mutation data represent a powerful approach to the classification of tumor samples and the discovery of biomarkers.

Cancers doi: 10.3390/cancers18101504

Authors: Zuoliang Liu Mia Yang Ang Chin Siang Kue

Colorectal cancer (CRC) is a biologically heterogeneous disease in which single-omics analyses incompletely capture the cross-layer mechanisms underlying tumor progression, immune evasion, and therapeutic resistance. This review critically examines how the integration of genomics, transcriptomics, proteomics, metabolomics, and microbiome profiling is redefining CRC biology and precision oncology. Landmark integrative efforts, including TCGA analyses of 276 colorectal cancer samples, CPTAC proteogenomic profiling of 95 tumors, and recent whole-genome sequencing studies of 2023 CRC cases, have refined molecular subtyping, expanded the driver landscape, and revealed clinically relevant discordance between mRNA abundance and protein activity. Integrative studies further show that oncogenic signaling may be driven by post-transcriptional and post-translational regulation, while spatially resolved profiling and microbiome–metabolite analyses are uncovering previously obscured tumor–microenvironment interactions. We also discuss how artificial intelligence-based approaches, including factor analysis, deep learning, graph-based models, and explainable AI, are improving subtype classification, biomarker discovery, and treatment-response prediction, with particular relevance to microsatellite instability-high and early-onset CRC. Finally, we critically evaluate the principal barriers to clinical translation, including batch effects, cross-platform variability, limited external validation, regulatory constraints, and cost, and outline priorities for building reproducible, clinically deployable multi-omics pipelines for CRC management.

Cancers doi: 10.3390/cancers18101502

Authors: Dimitrios Tsolakidis Dimitrios Zouzoulas

Ovarian carcinoma is the third most common gynecological malignancy and the leading cause of death among breast and genital track cancers in women [...]

Cancers doi: 10.3390/cancers18101501

Authors: Nihal E. Mohamed Donna L. Berry Justin McReynolds Talia Korn Holden Kata Emma Benn Danielle Scharp John Sfakianos Reza Mehrazin Peter Wiklund William B. Lober

Background/Objectives: Radical cystectomy with urinary diversion is the standard treatment for patients with muscle-invasive bladder cancer, which represents a complex, preference-sensitive decision about the diversion options. To facilitate patient-clinician shared decision-making, we developed and evaluated the feasibility and acceptability of the Personal Patient Profile–Bladder Cancer (P3-BC), a web-based decision support system for patients considering urinary diversion options. Materials and Methods: We employed an iterative development approach following an established framework, including qualitative assessments of radical cystectomy patients’ (n = 30) needs to inform content development, followed by usability testing with 10 key stakeholders. We then conducted a feasibility study with patients newly diagnosed with bladder cancer undergoing cystectomy. Feasibility was assessed through P3-BC completion rates among patients randomized to the intervention and study retention rates. Acceptability was measured using a program-based 12-item questionnaire integrating the six-item Acceptability E-Scale. Secondary outcomes included decisional conflict, shared decision-making, psychological distress, and decisional regret. Results: Of 114 eligible patients, 24 provided consent (21% consent rate), and 15 were randomized to receive the P3-BC intervention (n = 10) or usual care (n = 5). Retention was 93% at 1 month and 73% at 3 months. Among intervention participants, P3-BC achieved high feasibility (100% accessed the program) and acceptability, with 86% reporting overall satisfaction and 86% reporting ease of use. No statistically significant between-group differences were observed in secondary outcomes. Although the study was not powered to examine group differences, numerical trends suggest improvements in decisional conflict and symptom burden over time, particularly in the intervention group. Conclusions: P3-BC demonstrated feasibility and acceptability as a web-based decision support intervention for patients with bladder cancer considering cystectomy and urinary diversion. Primary barriers to enrollment included treatment burden, limited diagnosis-treatment time, and technology concerns. Findings support progression to an adequately powered randomized controlled trial to evaluate clinical effectiveness.

Cancers doi: 10.3390/cancers18101500

Authors: Zivile Useckaite Ashleigh J. Hocking Lauren A. Mortimer John Salamon Simon Lee Yazad Irani Lucy Franzon Arya L. Arul Sarita Prabhakaran Sonja Klebe

Background: Pleural mesothelioma (PM) is characterised by often rapid therapeutic failure and chemotherapy resistance. While terminal resistance is well studied, the initial transition into a drug-tolerant phenotype remains poorly understood. Methods: We established patient-derived organoids (PDOs) from malignant pleural effusions to model this transition. Cisplatin-tolerant lines were generated via repeated incremental exposure to cisplatin and compared to time-matched treatment-naive controls using RNA sequencing and Seahorse XFe96 metabolic flux analysis. Results: Integrated profiling suggested that the route to tolerance may be influenced by the underlying mutational profile. In this cohort, all BAP1-retained models (including those with KRAS mutations or MTAP loss) adopted an elevated basal metabolic hybrid phenotype, significantly upregulating baseline oxidative phosphorylation and glycolysis to fuel survival mechanisms. Conversely, BAP1-deficient models entered a hypometabolic state of dormancy, characterised by baseline bioenergetic suppression and reduced Ki-67 proliferation. Transcriptomic analysis identified a vesicular transport signature (SYNGR3, VPS52, PROM2) in plastic models, suggesting altered membrane trafficking as a potential survival strategy. Conclusions: Our findings demonstrate that mesothelioma therapeutic escape is not a uniform process. Identifying these patient-specific metabolic and transcriptomic trajectories via 3D PDOs provides a hypothesis-generating framework to explore potential avenues for future personalised therapy.

Cancers doi: 10.3390/cancers18101499

Authors: Tuba Baydaş İlker Nihat Ökten Filiz Özen Süheyla Emre İbrahim Çil Metin Eser Adnan Gündoğdu Osman Cem Yılmaz Mahmut Gümüş

Background: The increasing use of multigene germline testing in breast cancer has expanded the detection of pathogenic/likely pathogenic (P/LP) variants and variants of uncertain significance (VUSs) across a broad range of breast cancer susceptibility genes. However, the extent to which pathogenic certainty and penetrance level are associated with distinct clinicopathological phenotypes and management patterns remains incompletely defined. Methods: In this multicenter retrospective study, we included 405 breast cancer patients with germline alterations in breast cancer susceptibility genes. Patients were classified into three groups: high-penetrance P/LP (n = 116), moderate/low-penetrance P/LP (n = 69), and VUS (n = 220). The primary endpoint was non-luminal invasive breast cancer phenotype, defined as HER2-positive or triple-negative disease versus luminal A/B disease. Multivariable logistic regression was performed to assess the association between genetic group and non-luminal phenotype, adjusted for age at diagnosis and family history. Secondary analyses evaluated management patterns across groups and examined a prespecified non-BRCA cohort. Results: Patients with high-penetrance P/LP variants were younger at diagnosis and had higher Ki-67 values than those in the other groups. Molecular subtype distribution differed significantly across groups, with triple-negative disease most frequent in the high-penetrance P/LP group (33.9%) compared with the moderate/low-penetrance P/LP (9.8%) and VUS (12.9%) groups. In multivariable analysis, high-penetrance P/LP status was independently associated with increased odds of non-luminal phenotype compared with VUS (OR 1.79, 95% CI 1.06–3.04; p = 0.029), whereas moderate/low-penetrance P/LP status was not (OR 0.96, 95% CI 0.48–1.91; p = 0.911). Management patterns also differed significantly. Initial mastectomy was performed in 65.4% of evaluable patients in the high-penetrance P/LP group, compared with 46.4% in the moderate/low-penetrance P/LP group and 45.5% in the VUS group. Final bilateral mastectomy was observed in 62.6%, 17.5%, and 9.9%, respectively (p < 0.001). In the prespecified non-BRCA analysis, non-BRCA P/LP status was not associated with non-luminal phenotype compared with non-BRCA VUS (OR 0.83, 95% CI 0.40–1.72; p = 0.609). Conclusions: Among breast cancer patients with germline alterations in breast cancer susceptibility genes, high-penetrance P/LP variants are associated with a distinct clinicopathological profile characterized by younger age at diagnosis, higher proliferative activity, and increased likelihood of non-luminal disease. In contrast, moderate/low-penetrance P/LP variants, especially VUSs, do not show the same degree of phenotype specificity. These findings support a framework in which pathogenic certainty and penetrance level remain central to the interpretation of multigene germline testing in breast cancer.

Cancers doi: 10.3390/cancers18101498

Authors: Takao Suzuki Hasan Jamil Aminu Kende Abubakar Tshewang Gyeltshen Hellen Wairimu Babu Phuong The Nguyen

Background: Japan’s national health promotion plan, Health Japan 21, aims to achieve 60% lung cancer screening coverage by 2028. This study projected screening uptake through 2028 and estimated the probability of achieving this target at the national and prefectural levels, stratified by gender. Methods: We analyzed lung cancer screening in Japan using the Comprehensive Survey of Living Conditions data (2013, 2016, 2019, 2022) for adults aged 40–69. Bayesian linear regressions estimated trends in logit-transformed screening coverage, with projections through 2028. We estimated annual changes, the probability of reaching 60% by 2028, and the first year in which the probability of target attainment exceeded 80%. Results: National screening coverage increased from 42.3% in 2013 to 49.7% in 2022, with an annual percentage-point change of 0.83 (95% CrI: −0.20 to 1.80). At this rate, the probability of reaching 60% by 2028 is 12.2%. Only 11 of 47 prefectures are projected to meet the target, while 4 (Kyoto, Kumamoto, Kagoshima, and Okinawa) are unlikely to reach it. Sex disparities were observed, with the probability of achievement at 25.4% for men versus 7.1% for women. The female annual change (0.99) exceeded the male annual change (0.65). Conclusions: Lung cancer screening participation varies significantly across regions and between genders, reflecting uneven progress toward the national goal. If current trends continue, achieving 60% coverage by 2028 will be challenging for most prefectures. Policy and system reforms could speed up uptake by focusing on prefectures and populations with the lowest participation rates.

Cancers doi: 10.3390/cancers18101497

Authors: Rami Babas Demitrios H. Vynios Aristotelis Kompothrekas Basilis Boutsinas Nikos Karamanos

Background/Objectives: Traditional breast cancer prognostic tools relying on clinical staging often miss molecular heterogeneity, leading to divergent patient outcomes. Extracellular matrix (ECM) remodeling, driven by the Matrix Metalloproteinase (MMP), ADAM, and ADAMTS enzyme families, is critical to tumor progression. This study evaluates whether integrating ECM protease transcript abundance with standard clinical variables improves survival prediction accuracy and personalized risk stratification. Methods: Clinical and transcriptomic data from The Cancer Genome Atlas (TCGA) breast cancer cohort were analyzed. We integrated the protein-coding transcripts per million (pTPM) of top-ranked protease genes with standard clinical covariates (age, ordinal stage). Cox Proportional Hazards (CoxPH), penalized Cox (CoxNet), Random Survival Forest (RSF), and Gradient Boosting Survival (GBS) models were evaluated under a stratified 70/30 train–test split, followed by five-fold cross-validation. The locked final RSF model was then externally tested in METABRIC without retraining or risk-cutoff optimization. Results: Univariate screening identified ADAM15, MMP15, and ADAMTSL1 as global risk factors, whereas ADAMTS8 and MMP7 were protective. Prognostic signals were subtype-dependent. Integrated multivariable models outperformed transcript-only approaches in internal testing. The integrative RSF achieved the highest held-out discrimination (C-index = 0.797), outperforming a clinical-only Cox baseline trained on age and stage alone (C-index = 0.742, 95% CI 0.636–0.826). In METABRIC, the external C-index was 0.581 (95% CI 0.562–0.598), with significant survival separation across training-defined risk groups (log-rank p < 0.0001). Conclusions: ECM protease transcript profiles provide complementary prognostic information in TCGA-BRCA and show partial transportability to METABRIC. However, the modest external C-index indicates limited individual-level discrimination across platforms, so these candidate markers should be interpreted as hypothesis-generating and require further validation before clinical implementation.

Cancers doi: 10.3390/cancers18101496

Authors: Onyekachi Anya Ogbonna Chikere Progress Asoluka Helen Oletu

Background: Prostate cancer remains a major cause of cancer morbidity and mortality among men in the United States. Differences in diagnosis and survival across racial and socioeconomic groups continue to raise concern in clinical and public health research. Population-based datasets provide an opportunity to examine patterns of advanced disease and survival outcomes across diverse demographic groups. Objective: This study evaluated racial and socioeconomic disparities in cancer-specific survival among patients with metastatic prostate cancer using a national population-based dataset. Methods: A retrospective population-based study was conducted using data from the Surveillance, Epidemiology, and End Results (SEER) program. Patients diagnosed with malignant prostate cancer between 2004 and 2020 with distant stage disease were included. The final analytic sample consisted of 54,062 patients. Variables included race and ethnicity, age group, metastatic sites at diagnosis, treatment variables, and median household income. Descriptive analyses compared characteristics by cancer-specific death using chi-square tests for categorical variables and t tests for continuous variables. Survival patterns were examined using Kaplan–Meier methods and log-rank tests. Multivariable Cox proportional hazards model was used to estimate adjusted hazard ratios for factors associated with cancer-specific mortality. Results: Cancer-specific mortality differed across racial and socioeconomic groups. Higher mortality was observed among non-Hispanic Black patients (aHR = 1.15, 95% CI: 1.00 to 1.31, p = 0.046) and non-Hispanic American Indian or Alaska Native patients (aHR = 1.15, 95% CI: 1.10 to 1.20, p < 0.001) compared with non-Hispanic White patients, while Hispanic and non-Hispanic Asian or Pacific Islander patients showed lower mortality risk. Older age groups demonstrated higher mortality. Liver, lung, and brain metastases were associated with increased risk of prostate cancer death. Patients in higher income groups showed lower mortality compared with patients in lower income groups (aHR = 0.83, 95% CI: 0.80 to 0.87, p < 0.001). Conclusions: This study highlights persistent racial and socioeconomic differences in cancer-specific survival among patients with advanced prostate cancer in the United States. These findings support continued efforts to address disparities in early detection, access to care, and treatment pathways. Future research should further explore clinical and structural factors that influence survival differences across population groups.

Cancers doi: 10.3390/cancers18091495

Authors: Katarzyna Nowogrodzka Maciej Tota Aleksandra Piotrowska Andrzej Bieniek Piotr Dzięgiel Alina Jankowska-Konsur

Background: Angiogenesis is critical for tumor progression. Microvessel density (MVD) is commonly assessed using CD31 and CD34, which detect both mature and newly formed vessels and therefore cannot distinguish active neoangiogenesis from stable, quiescent vasculature. Nestin, an intermediate filament protein expressed preferentially in proliferating endothelial cells, has been proposed as a complementary marker of active angiogenesis and has been investigated in several solid tumor types, including pancreatic, colorectal, and breast carcinomas. However, no studies have quantitatively compared nestin-positive MVD across AK, BCC, and SCC using standardized methods. Methods: Immunohistochemistry for nestin, CD31, and CD34 was performed on 118 patient samples collected in 2015–2019 and diagnosed with AK, BCC, or SCC. MVD was quantified by averaging vessel counts in three representative “hot spot” areas. Results: Nestin-positive MVD was significantly lower in patients with AK compared to patients with BCC and SCC (p < 0.001). The mean MVD of nestin-positive vessels was significantly lower in AK than in BCC and SCC (p < 0.0001). In all three groups, nestin-positive MVD demonstrated a strong, positive correlation with both CD34 and CD31. Conclusions: Nestin-positive MVD was significantly elevated in BCC and SCC compared to AK lesions and demonstrated strong correlations with standard angiogenic markers. These findings suggest that nestin may warrant further investigation as a complementary marker of angiogenesis in non-melanoma skin cancer. Whether nestin-positive MVD offers independent diagnostic or prognostic value in this context remains to be determined in larger, prospective, multicentre studies.

Cancers doi: 10.3390/cancers18091489

Authors: Xiaowei Zhang Na Zhang Yuqing Zhong Siqi Ou Guitao Wu Taohui Ouyang Kejun He

Background: Gliomas exhibit substantial intratumoral heterogeneity, which limits prognostic precision and therapeutic efficacy. Selenoproteins are key regulators of redox homeostasis, but their role in glioma progression remains insufficiently defined. This study aimed to characterize glioma cells with high selenoprotein activity and to determine their biological and clinical significance. Methods: We performed integrated multi-omic analyses combining bulk transcriptomic, single-cell transcriptomic, and spatial transcriptomic data to identify and characterize glioma cell states associated with elevated selenoprotein expression. Functional validation was conducted using SELENOS knockdown assays to evaluate effects on glioma proliferation, invasion, tumor growth, macrophage recruitment, CSF1 expression, and macrophage polarization. Results: We identified a malignant glioma cell state, termed SehighMali, characterized by elevated selenoprotein expression and distinct metabolic and immunological features. SehighMali cells showed enhanced oxidative phosphorylation, MYC-associated transcription, and DNA repair activity, and preferentially engaged in immunosuppressive crosstalk with myeloid cells through the CSF1–CSF1R axis. Spatial analyses demonstrated enrichment of SehighMali cells in tumor cores and close colocalization with immunosuppressive myeloid populations. Across bulk cohorts, higher SehighMali abundance was associated with aggressive molecular features, poor clinical outcomes, and a predicted temozolomide-resistant phenotype. SELENOS knockdown suppressed glioma proliferation, invasion, and tumor growth, reduced macrophage recruitment, decreased CSF1 expression, and promoted macrophage polarization toward a pro-inflammatory phenotype. Conclusions: These findings define a selenoprotein-driven malignant glioma state associated with immune evasion and therapeutic vulnerability. They further identify SELENOS as a potential therapeutic target and provide insight into how selenoprotein-related programs contribute to glioma progression.

Cancers doi: 10.3390/cancers18091494

Authors: Yuanjie Cao Chen Li Baozhong Zhang Jie Chen

Background and purpose: Organ-preservation strategies are increasingly being incorporated into rectal cancer management, but the role of HDR endorectal/endoluminal brachytherapy boost remains less well defined than that of broader non-operative treatment pathways. Existing literature is frequently mixed with contact X-ray brachytherapy series, neoadjuvant protocols with planned surgery, or heterogeneous watch-and-wait cohorts, limiting the interpretation of this specific strategy. Materials and methods: We performed a PROSPERO-registered systematic review and meta-analysis of studies evaluating definitive-intent external beam radiotherapy (EBRT), with or without chemotherapy, followed by HDR endorectal/endoluminal brachytherapy boost in histologically confirmed rectal adenocarcinoma managed without planned surgery. Pooled analyses were performed for clinical complete response (cCR) and late grade ≥3 gastrointestinal (GI) toxicity. Regrowth/local failure outcomes were synthesized descriptively because of heterogeneity in endpoint definitions, denominator selection, and follow-up structure. Results: Six studies were included in the quantitative evidence base, with one additional small feasibility report summarized narratively. The pooled cCR proportion was 69.2% (95% confidence interval [CI], 43.7–86.6). The pooled proportion of late grade ≥3 GI toxicity was 18.1% (95% CI, 10.9–28.6). Reported regrowth/local failure outcomes were not suitable for formal pooling because of inconsistent definitions, differing denominator structures, and non-uniform follow-up frameworks across studies. Conclusion: Current evidence suggests that EBRT plus HDR endorectal/endoluminal brachytherapy boost may represent a selective organ-preservation strategy for carefully chosen patients with rectal adenocarcinoma, particularly where surgery is not feasible or not desired. Its broader clinical use remains limited not only by the small size of the evidence base, but also by fragmented endpoint definitions, inconsistent denominator reporting, and insufficiently standardized durable local-control outcomes. These findings support cautious interpretation of the current evidence and highlight priorities for future prospective studies in rectal cancer management.

Cancers doi: 10.3390/cancers18091493

Authors: Lulu Kong Chunling Fu Lianggui Song Wenxiao Wang Mengchu Ji Fei Li Xiaofeng Shi Wei Chen

Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by clonal hematopoietic dysregulation, amplification of chronic inflammation, and progressive remodeling of the bone marrow fibrotic niche, clinically manifesting as bone marrow failure, splenomegaly, and systemic inflammatory symptoms. Although Janus kinase (JAK) inhibitors can alleviate symptom burden and reduce spleen size, they have limited capacity to eradicate malignant clones or reverse fibrosis. Allogeneic hematopoietic stem cell transplantation remains the only potentially curative option; however, its application is constrained by advanced age, comorbidities, unavailable donor, and transplant-related risks. Therefore, the development of disease-modifying therapeutic strategies has become a central focus in MF research. Chimeric antigen receptor T (CAR-T)-cell therapy has demonstrated robust efficacy across various hematologic malignancies. Its application in MF holds the potential not only to selectively eliminate malignant hematopoietic clones but also to modulate the immunosuppressive and profibrotic microenvironment through advanced cellular engineering, thereby enabling a dual therapeutic paradigm involving both clonal control and microenvironmental reprogramming. In this context, potential targets and pathways include CD123, myeloproliferative leukemia protein (MPL), fibroblast activation protein (FAP), the TGF-β signaling axis, the CXCR4–CXCL12 niche-regulatory axis, and molecules associated with myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). Future strategies may optimize both efficacy and safety through combinatorial approaches, including integration with JAK inhibitors, development of armored CAR-T constructs, and bridging to hematopoietic stem cell transplantation. Collectively, CAR-T-cell therapy offers a promising avenue for shifting MF management from symptomatic control toward true disease modification.

Cancers doi: 10.3390/cancers18091491

Authors: Ankita Chakrawal Aashruti Pathania Ruhi Dixit Manoj Pandey

Background: Head and neck cancer (HNC) presents unique challenges due to impairments in vital functions and appearance. This narrative synthesis of systematic review synthesizes evidence on the prevalence and predictors of distress in HNC and proposes a Multifactorial Cycle of Distress to explain how psychological burdens compromise clinical outcomes. Methods: A systematic search of PubMed and Scopus was conducted (up to June 2025). From 342 articles, 32 were included, covering HNC patients with quantitative or qualitative distress assessments related to quality of life (QoL) and survival. Results: Distress prevalence ranged from 23–47%, with 30% of survivors experiencing persistent symptoms long-term. Key predictors included advanced tumor stage, radiotherapy-induced side effects, and pre-treatment depression, which increased distress risk 2- to 3-fold. Notably, distress was associated with a 25% reduction in radiotherapy completion and a 55% increased risk of mortality. Additionally, 71% of patients experienced decision regret, further impacting outcomes. Psychosocial interventions, including cognitive-behavioral therapy and mindfulness, showed potential in reducing anxiety by 15–20%. Conclusions: Distress in HNC functions as a self-perpetuating cycle where physical morbidity triggers psychological barriers that directly impair treatment adherence and survival. Routine screening using tools like the Distress Thermometer or DIC-2 and integrated multidisciplinary care are essential to break this cycle and improve patient and caregiver well-being.

Cancers doi: 10.3390/cancers18091492

Authors: Saki Yoshida Yoriaki Komeda Masashi Kono Kohei Handa Tomoyuki Nagai Satoru Hagiwara Shunsuke Omoto Mamoru Takenaka Hiroshi Kashida George Tribonias Koji Daito Junichiro Kawamura Masatoshi Kudo

Background/Objectives: Ulcerative colitis (UC)-associated neoplasia (UCAN) often presents as flat lesions with indistinct margins, and biopsy sensitivity is limited. Therefore, we evaluated endoscopic criteria to distinguish UCAN from sporadic neoplasia, assessing the accuracy of endoscopic ultrasonography (EUS) for invasion depth and the role of endoscopic submucosal dissection (ESD) as a “total biopsy.” Methods: We reviewed 212 endoscopically treated neoplastic lesions in UC-affected mucosa (April 2016–January 2025). We compared preoperative diagnoses using macroscopic type, pit pattern, and the Japan Narrow-Band Imaging Expert Team classification with final histology. We compared depth estimates with pathology in 10 UCAN-suspected lesions undergoing EUS. Lesions < 2 cm underwent conventional endoscopic resection, whereas those ≥ 2 cm underwent ESD. Results: No UCAN was found in 189 lesions < 2 cm. Among 23 ESD lesions, 8 suspected sporadic lesions were non-UCAN. Of 15 UCAN-suspected lesions, 8 were UCAN, 6 sporadic, and 1 inflammatory. For positive T1b or deeper invasion, the sensitivity, specificity, positive and negative predictive values, and overall accuracy of EUS were 50.0%, 100%, 100%, 88.9%, and 90.0%, respectively. EUS depth assessment agreed with pathology in 9/10 cases; nine lesions were T1a or shallower, and one was T1b. Third-layer thickening occurred in two lesions—both UCAN—including the T1b cancer. In ESD cases, redness and a VI pit pattern were independent predictors of UCAN. Conclusions: EUS-based depth assessment is useful for determining optimal treatment strategies. Beyond therapy, ESD enables comprehensive histologic assessment of the entire lesion, functioning as a total biopsy to guide management while preserving bowel function.