Cancers

19 pages, 3894 KB

Open AccessArticle

Distinct Transcriptional and Migratory Programs Are Associated with Vasculogenic Mimicry Heterogeneity in Triple-Negative Breast Cancer

by Shilpa Madhavan-Kadali, Hyun-Mi Cho, Tal Sneh, Naamah Bloch, Joseph D. Rosenblatt, Abraham O. Samson and Hava Gil-Henn

Cancers 2026, 18(11), 1789; https://doi.org/10.3390/cancers18111789 - 29 May 2026

Abstract

Background: Vasculogenic mimicry (VM) is a tumor-driven vascularization strategy in which aggressive cancer cells form perfusable, endothelium-independent channels that support tumor growth, metastasis, and therapy resistance. VM is prevalent in triple-negative breast cancer (TNBC), but within this group of tumors, VM heterogeneity is [...] Read more.

Background: Vasculogenic mimicry (VM) is a tumor-driven vascularization strategy in which aggressive cancer cells form perfusable, endothelium-independent channels that support tumor growth, metastasis, and therapy resistance. VM is prevalent in triple-negative breast cancer (TNBC), but within this group of tumors, VM heterogeneity is underexplored. Likewise, VM competence and its relationship to classical endothelial angiogenesis (EA) remain incompletely understood. Methods: Here, as a proof of concept, we combine functional analysis of three molecularly distinct TNBC cell lines with a panel-wide DepMap transcriptomic survey to characterize VM heterogeneity. Results: Using an in vitro tube formation assay, we show that the VM-competent TNBC cell lines MDA-MB-231 and MDA-MB-231-4175 form robust 3D vessel-like networks in a matrigel matrix, whereas the VM-incompetent line MDA-MB-468 does not. As a control, we use an immortalized endothelial cell line, 3B-11, that forms classical EA vessel-like networks. Moreover, we visualize VM (Laminin-5⁺) and EA (CD31⁺) markers in vessel-like networks of VM-competent TNBC xenografts using immunohistochemical staining and show that while they are distinctly labeled, they can also coexist to form mosaic-like vessels. Then, we use DepMap-based transcription profiles and reveal that VM competence is associated with a distinct signature. Interestingly, VM and EA transcription profiles partially overlap, yet they also remain transcriptionally distinct, with inferred mechanistic divergence, with VM being more associated with cancer cell stemness (CSC), epithelial-to-mesenchymal transition (EMT), and extracellular matrix (ECM) remodeling programs and EA being more associated with vessel strength. In addition, VM-competent TNBC cells display migration patterns and transcriptomic features consistent with endothelial-like mechanosensitivity. Conclusions: Together, these findings indicate that VM is a distinct, heterogeneous, and therapy-relevant state in TNBC that complements classical angiogenesis. Finally, the mechanistic distinction between VM and EA programs made here will motivate future studies on dual-targeting strategies that inhibit both vascularization processes while also motivating future studies on VM for precision treatment in TNBC. Full article

(This article belongs to the Section Molecular Cancer Biology)

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14 pages, 710 KB

Open AccessArticle

Development and Internal Validation of a Side-Specific Nomogram Integrating mpMRI and Biopsy Features to Guide Nerve-Sparing Decision Making in Prostate Cancer with Capsular Contact

by Yusuf Ahmed, Kateryna Diahovets, Tician Schnitzler, Lea Seiler, Alexander Cornelius, Fiona Burkhard, Georg Müller, Rainer Grobholz, Marco Cattaneo, Manuel Walter, Livio Nowak, Pirmin Wolfsgruber, Stephen Wyler, Lukas Prause, Maciej Kwiatkowski and Luca Afferi

Cancers 2026, 18(11), 1788; https://doi.org/10.3390/cancers18111788 - 29 May 2026

Abstract

Background: Preoperative side-specific identification of extracapsular extension (ECE) is important for selecting an appropriate nerve-sparing strategy at radical prostatectomy. Patients with multiparametric magnetic resonance imaging (mpMRI)-defined capsular contact represent a clinically challenging subgroup because contact raises concern for ECE but does not [...] Read more.

Background: Preoperative side-specific identification of extracapsular extension (ECE) is important for selecting an appropriate nerve-sparing strategy at radical prostatectomy. Patients with multiparametric magnetic resonance imaging (mpMRI)-defined capsular contact represent a clinically challenging subgroup because contact raises concern for ECE but does not uniformly indicate extraprostatic disease. We aimed to develop a side-specific nomogram for individualized ECE prediction and perform preliminary internal validation in this selected population. Materials and Methods: We retrospectively analyzed 323 prostate lobes from 286 patients with biopsy-proven, non-metastatic prostate cancer and mpMRI-defined capsular contact who underwent robot-assisted radical prostatectomy between 2015 and 2021 at a single institution. The dataset was randomly split into training (70%) and testing (30%) cohorts. Three multivariable logistic-regression models were developed and compared. Discrimination was assessed using the area under the receiver operating characteristic curve (AUC-ROC), calibration by intercept and slope, and clinical utility by decision curve analysis. A nomogram was derived from the best-performing model in the internal split-sample comparison. Results: Side-specific ECE was present in 110/323 lobes (34.1%). Among the candidate models, the forward-selection model showed the most favorable apparent performance, with an AUC-ROC of 0.85 in training and 0.83 in testing, together with good test-set calibration (intercept 0.24; slope 0.97). The final model included a capsular contact length ≥10 mm, percentage tumor involvement in positive biopsy cores, number of positive biopsy cores, and index lesion size. At a 10% predicted risk threshold, 32% of lobes were classified as low risk, with an observed ECE rate of about 5%. Conclusions: We developed a side-specific nomogram tailored to patients with mpMRI-defined capsular contact and performed preliminary internal validation. The model may aid preoperative side-specific risk assessment relevant to nerve-sparing planning, but external validation and assessment of clinical impact are required before clinical adoption. Full article

(This article belongs to the Topic Prostate Cancer: Symptoms, Diagnosis & Treatment—3rd Edition)

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12 pages, 395 KB

Open AccessArticle

Prophylactic Anakinra to Prevent Neurotoxicity After CAR T-Cell Therapy in Aggressive B-Cell Lymphomas: A Single-Center Real-World Experience

by Tina Schmid, Inna Shaforostova, Ulrike Bacher, Katja Seipel, Marie-Noelle Kronig and Thomas Pabst

Cancers 2026, 18(11), 1787; https://doi.org/10.3390/cancers18111787 - 29 May 2026

Abstract

Background/Objectives: Chimeric antigen receptor T-cell (CAR T) therapy is an effective treatment for relapsed/refractory (r/r) aggressive B-cell lymphomas; however, acute toxicities, such as immune effector cell-associated neurotoxicity syndrome (ICANS), remain common. Interleukin-1 (IL-1) has been implicated in the pathogenesis of ICANS, suggesting [...] Read more.

Background/Objectives: Chimeric antigen receptor T-cell (CAR T) therapy is an effective treatment for relapsed/refractory (r/r) aggressive B-cell lymphomas; however, acute toxicities, such as immune effector cell-associated neurotoxicity syndrome (ICANS), remain common. Interleukin-1 (IL-1) has been implicated in the pathogenesis of ICANS, suggesting that prophylactic anakinra, an IL-1 receptor antagonist, might reduce its incidence or severity. Methods: We retrospectively analyzed 80 patients with B-cell lymphomas who received CD19-directed CAR T-cell therapy (tisagenlecleucel, axicabtagene ciloleucel, or lisocabtagene maraleucel) at the Bern University Hospital between April 2019 and June 2022. One cohort received prophylactic anakinra (100 mg subcutaneously on days 0 to +6 post-infusion), while the comparison cohort did not. Results: The incidence of ICANS was similar between groups (14 patients, 35%) with anakinra vs. 10 (25%) in the standard cohort (p = 0.464). Rates of grade 3 ICANS were also comparable (eight (20%) vs. seven (18%), p > 0.999). Among patients who developed ICANS, median hospitalization was numerically shorter with anakinra (27 vs. 40 days, p = 0.077). Anakinra did not impair CAR T-cell expansion and was well tolerated, with no treatment-related adverse events. Survival outcomes, including overall survival (OS) and progression-free survival (PFS), were similar between cohorts. Conclusions: In summary, prophylactic anakinra did not reduce the incidence or severity of ICANS in our analysis; however, it may be associated with shorter hospitalization in affected patients. Whether this reflects a direct therapeutic effect or improved overall toxicity management remains uncertain. Larger prospective studies are warranted to further clarify the role of anakinra for prophylactic treatment of ICANS following CAR T-cell therapy. Full article

(This article belongs to the Section Cancer Therapy)

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24 pages, 2587 KB

Open AccessReview

Mitochondrial Metabolic Reprogramming in Colorectal Cancer-Associated Fibroblasts: An Up-to-Date Review

by Ying Li, Dipanjan Chanda, Seong-Woo Jeon, Jae-Han Jeon and Min-Ji Kim

Cancers 2026, 18(11), 1786; https://doi.org/10.3390/cancers18111786 - 29 May 2026

Abstract

Colorectal cancer (CRC) progression stems from dynamic metabolic crosstalk between malignant cells and the tumor microenvironment (TME). Among stromal components, cancer-associated fibroblasts (CAFs) have emerged as pivotal metabolic drivers rather than mere structural elements. Specifically, evidence indicates that mitochondrial reprogramming in CAFs significantly [...] Read more.

Colorectal cancer (CRC) progression stems from dynamic metabolic crosstalk between malignant cells and the tumor microenvironment (TME). Among stromal components, cancer-associated fibroblasts (CAFs) have emerged as pivotal metabolic drivers rather than mere structural elements. Specifically, evidence indicates that mitochondrial reprogramming in CAFs significantly orchestrates tumor growth, therapeutic resistance, and immune evasion in CRC. This review synthesizes recent insights into how CAF mitochondrial dynamics and metabolic reprogramming dictate CRC biology. We first examine the functional diversity of CAF subpopulations and their distinct mitochondrial requirements. We then contrast mitochondrial dynamics—including fission–fusion balance and mitophagy—between CRC cells and CAFs, highlighting how tumor-derived signals modulate stromal mitochondrial function. We systematically evaluate key regulatory pathways of CAF mitochondrial reprogramming, including TGF-β/HIF-1α, ROS-NF-κB, PI3K–AKT–mTOR, AMPK–PGC-1α, YAP/TAZ mechanotransduction, and mtDNA-mediated cGAS–STING signaling. Furthermore, we discuss how remodeled CAF mitochondria foster metabolic symbiosis via lactate, ketone, and glutamine shuttling; maintain redox homeostasis through the NADPH–glutathione axis and UCP2; and establish immunosuppressive niches via mitochondrial stress signaling. Collectively, these mechanisms drive resistance to chemotherapy, targeted agents, radiotherapy, and immunotherapy. By integrating mitochondrial metabolism, stromal signaling, and clinical responses, this review identifies CAF mitochondria as an actionable target within the CRC TME. Targeting these CAF-specific pathways offers a novel strategy to disrupt tumor–stroma metabolic cooperation and overcome treatment resistance in colorectal cancer. Full article

(This article belongs to the Section Tumor Microenvironment)

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4 pages, 158 KB

Open AccessCorrection

Correction: Salakphet et al. Molecular Classification and Clinical Outcomes in Endometrial Cancer: Real-World Evidence from a Tertiary Care Center. Cancers 2026, 18, 181

by Tanadon Salakphet, Prapaporn Suprasert, Tip Pongsuvareeyakul, Chinachote Teerapakpinyo and Surapan Khunamornpong

Cancers 2026, 18(11), 1785; https://doi.org/10.3390/cancers18111785 - 29 May 2026

Abstract

Error in Table [...] Full article

16 pages, 276 KB

Open AccessArticle

Risk of Malignancy with Immunosuppressive Drugs Used in Organ Transplants Compared to Those Used for Non-Transplant Indications

by Connor Haines, Zachary Walton, Ian Curnutt, George Golovko, Yong-Fang Kuo, Cristiana Rastellini and Luca Cicalese

Cancers 2026, 18(11), 1784; https://doi.org/10.3390/cancers18111784 - 29 May 2026

Abstract

Background: Immunosuppressive drugs (ISDs) are essential for preventing organ rejection but have been reported to increase cancer risk with prolonged use. This study compares cancer risk between ISDs used for long-term maintenance after transplantation (T-ISDs) and those prescribed for non-transplant chronic conditions including [...] Read more.

Background: Immunosuppressive drugs (ISDs) are essential for preventing organ rejection but have been reported to increase cancer risk with prolonged use. This study compares cancer risk between ISDs used for long-term maintenance after transplantation (T-ISDs) and those prescribed for non-transplant chronic conditions including cell-mediated (C-ISDs) and receptor-mediated (R-ISDs) ISDs. We hypothesized that cancer risk would differ between T-ISDs and both C-ISD and R-ISD groups. Methods: Using the TriNetX database, solid organ transplant recipients treated with tacrolimus (TAC), cyclosporine (CY), rapamycin (RAPA), or mycophenolate (MMF) were compared to propensity-matched R-ISDs (adalimumab, infliximab, etc.) or C-ISDs (methotrexate, azathioprine, etc.) for at least 24 encounters to determine risk of malignancy. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to assess the three-year cancer risk. Results: After matching, T-ISDs were associated with higher malignancy risk compared to both R-ISDs (n = 29,748; HR 2.616, 95% CI 2.427–2.820) and C-ISDs (n = 31,704; HR 1.271, 95% CI 1.195–1.351). Each individual immunosuppressant in the T-ISD cohort was associated with increased cancer risk compared to R-ISDs, while only TAC and CY showed higher risk than C-ISDs (TAC: n = 9846, HR 1.354, 95% CI 1.228–1.492; CY: n = 1801, HR 1.234, 95% CI 1.007–1.512). Organ-specific analyses showed consistent patterns across systems. Conclusions: Overall, T-ISDs are associated with increased malignancy risk compared to R-ISDs and modestly compared to C-ISDs. TAC and CY confer the greatest risk, while MMF demonstrates relatively lower relative risk. These findings underscore the need to individualize ISD regimens to minimize long-term cancer risk. Full article

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

18 pages, 3691 KB

Open AccessArticle

Enoxaparin, Tinzaparin, and Apixaban Modulate Cancer Cell Procoagulant Activity and Viability: Comparison with Quercetin

by Mohammed A. Baghdadi, Pedro Henrique Fernandes do Carmo Las Casas, Elisabeth Mbemba, Aurélie Rousseau, Prakasha Kempaiah, Andrey A. Svistunov, Victoria Bitsadze, Michèle Sabbah, Jawed Fareed, Patrick Van Dreden, Varvara Trachana, Eleftheria Lefkou and Grigoris Gerotziafas

Cancers 2026, 18(11), 1783; https://doi.org/10.3390/cancers18111783 - 29 May 2026

Abstract

Background/Objectives: Tissue factor (TF)-expressing cancer cells and their extracellular vesicles (CaCe-dEVs) are key drivers of cancer-associated hypercoagulability and vascular dysfunction. While low-molecular-weight heparins (LMWHs) and direct FXa inhibitors are standard therapies for cancer-associated thrombosis, their direct effects on cancer cell procoagulant potential [...] Read more.

Background/Objectives: Tissue factor (TF)-expressing cancer cells and their extracellular vesicles (CaCe-dEVs) are key drivers of cancer-associated hypercoagulability and vascular dysfunction. While low-molecular-weight heparins (LMWHs) and direct FXa inhibitors are standard therapies for cancer-associated thrombosis, their direct effects on cancer cell procoagulant potential and endothelial responses remain incompletely defined. This study compared the impact of LMWHs (enoxaparin, tinzaparin), apixaban, and quercetin on cancer cell viability, thrombin generation, and CaCe-dEVs-induced endothelial injury. Methods: Pancreatic (BXPC3) and breast (MCF7) cancer cells and their vesicles were analyzed for TF expression and thrombin generation. Human umbilical vein endothelial cells (HUVECs) were pretreated with each agent prior to vesicle exposure. Cell viability, thrombin generation, and endothelial morphology were assessed using standard assays and microscopy. Results: Tinzaparin and quercetin significantly reduced cancer cell viability, whereas enoxaparin and apixaban showed no cytotoxicity. None of the agents affected HUVEC viability. All suppressed TF-mediated thrombin generation induced by cancer cells, with tinzaparin being most effective in BXPC3 cells. Quercetin exhibited a partial and limited protective effect on endothelial cells against CaCe-dEVs-induced dysfunction, while LMWHs and apixaban did not prevent endothelial damage. Conclusions: These findings suggest that LMWHs, apixaban, and quercetin modulate cancer-cell-driven hypercoagulability beyond anticoagulation, with quercetin and tinzaparin showing additional cytotoxic potential. Such dual effects may reduce thrombosis risk while impacting tumor progression, meriting further investigation. Full article

(This article belongs to the Special Issue Cancer-Associated Thrombosis, Arterial and Venous Thromboembolism)

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23 pages, 1038 KB

Open AccessArticle

Long-Term Consequences of Anticancer Therapy—Treatment Complexity and Quality of Life as Determinants of Affective Disorder Phenotypes in Adolescent Cancer Survivors

by Piotr Pawłowski, Maria Banasik, Mateusz Barłóg, Zuzanna Kwissa-Gajewska, Mikołaj Jeżak, Aneta Kościołek, Emilia Samardakiewicz-Kirol, Małgorzata Mitura-Lesiuk and Marzena Samardakiewicz

Cancers 2026, 18(11), 1782; https://doi.org/10.3390/cancers18111782 - 29 May 2026

Abstract

Introduction: Advances in pediatric oncology have transformed cancer into a condition with chronic and long-term developmental consequences. While survival rates have improved significantly, the literature on psychosocial outcomes remains fragmented and inconsistent, with a notable lack of person-centered analyses that account for the [...] Read more.

Introduction: Advances in pediatric oncology have transformed cancer into a condition with chronic and long-term developmental consequences. While survival rates have improved significantly, the literature on psychosocial outcomes remains fragmented and inconsistent, with a notable lack of person-centered analyses that account for the heterogeneity of adaptive trajectories. Current evidence fails to explain why survivors with similar clinical profiles exhibit divergent psychological phenotypes, particularly regarding the late effects of multimodal treatments. The aim of this study was to identify heterogeneous psychosocial profiles among adolescent cancer survivors and to examine their associations with treatment complexity and quality of life. Materials and Methods: This cross-sectional study included 165 adolescents aged 12–18 years (mean age: 14.64 years) who were in clinical remission following oncological treatment. Standardized assessment tools were used: the Children’s Depression Inventory 2 (CDI-2™) to measure depressive symptoms, the KIDSCREEN-10 index to assess health-related quality of life (HRQoL), and a scale evaluating satisfaction across 14 life domains. Adaptive profiles were identified using a Two-Stage Cluster Procedure, and risk factors were examined using multinomial logistic regression. Results: Four clusters were identified in the study population: a depressive–dysphoric profile, an anhedonic-withdrawn profile, a highly adaptive profile, and a mixed (struggling) profile. Treatment complexity was identified as a significant independent predictor of membership in the high-distress (depressive) cluster. While each additional therapeutic modality beyond standard chemotherapy was associated with a markedly increased risk (OR = 8.91; p < 0.001), the relatively wide confidence interval (95% CI: 3.27–24.31) suggests that the exact magnitude of this effect should be interpreted with caution. The high lower bound of the interval (3.27), however, strongly supports the directional association of cumulative iatrogenic burden with psychological adaptation. Subjective quality of life functioned as a protective factor against depressive symptoms (OR = 0.57); however, paradoxically, higher self-reported quality of life increased the likelihood of classification into the anhedonic group (OR = 1.81). This divergence between high self-reported HRQoL and social withdrawal potentially suggests a ‘well-being paradox’. It is hypothesized that standard HRQoL instruments may primarily capture physical remission and relief from acute somatic symptoms, potentially masking underlying social–emotional deficits. This suggests that HRQoL scores in survivors should be interpreted with caution and complemented by specific affective screenings. Conclusions: The absence of a uniform pattern of psychological response to cancer among adolescent survivors supports the validity of a patient-centered approach. The burden associated with intensive multimodal treatment significantly increases the likelihood of full-syndrome depression during adolescence. Moreover, the identification of a cluster suggestive of anhedonic and socially withdrawn features highlights the limitations of standard screening tools focused solely on the detection of overt sadness. This heterogeneity underscores the need for personalized psycho-oncological care and the implementation of intensified monitoring for patients at high medical risk. Full article

(This article belongs to the Special Issue Long-Term Cancer Survivors: Rehabilitation and Quality of Life)

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14 pages, 584 KB

Open AccessReview

Review of Management of Clinical Stage I Small Cell Lung Cancer: The Rising Role of Surgical Resection

by Gabriella R. Rasmussen, Eric Klipsch and Kathryn E. Engelhardt

Cancers 2026, 18(11), 1781; https://doi.org/10.3390/cancers18111781 - 29 May 2026

Abstract

Background: Small cell lung cancer (SCLC) is an aggressive malignancy that has traditionally been treated as a systemic disease, with surgery largely excluded from standard management. A small subset of patients, however, present with clinical Stage I disease (T1–2N0M0). With improvements in imaging, [...] Read more.

Background: Small cell lung cancer (SCLC) is an aggressive malignancy that has traditionally been treated as a systemic disease, with surgery largely excluded from standard management. A small subset of patients, however, present with clinical Stage I disease (T1–2N0M0). With improvements in imaging, staging, and systemic therapy, local therapy warrants consideration. Methods: We performed a narrative review of the literature focused on clinical Stage I SCLC, prioritizing studies addressing epidemiology, tumor biology, diagnostic workup, staging, treatment approaches, and surveillance. Emphasis was placed on current guideline recommendations and contemporary retrospective data relevant to surgical and non-surgical local therapies. Results: Clinical Stage I SCLC is rare and is frequently upstaged with complete diagnostic evaluation, highlighting the need for thorough staging and pathologic confirmation of node-negative disease when surgery is considered. Even in presumed local disease, distant metastases are many times evident with a proper staging workup. Retrospective analyses suggest potential for long-term control of disease in carefully selected Stage I patients treated with surgical resection, particularly lobectomy, as part of multimodality therapy that includes adjuvant systemic therapy. For patients who are not surgical candidates, stereotactic body radiation therapy combined with systemic therapy is a reasonable alternative. The role of prophylactic cranial irradiation and optimal surveillance strategies in Stage I disease remain areas of uncertainty. Conclusions: Clinical Stage I SCLC affects a small and unique group of patients where traditional treatment strategies may need to be reconsidered. Taken together, retrospective evidence suggests a survival benefit for surgery in carefully selected patients, although prospective validation is lacking. Surgery warrants consideration in appropriately staged, operable patients, while recognizing the limitations of existing data and the need for further study in this rare population. Full article

(This article belongs to the Special Issue State-of-the-Art Surgical Treatment for Lung Cancers)

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13 pages, 2428 KB

Open AccessArticle

Usefulness and Prognostic Impact of Preoperative Dynamic CT in the Diagnosis of Extrapancreatic Extension in Resectable Pancreatic Adenocarcinoma

by Kazuma Horiguchi, Hiroyuki Kato, Takahiro Tashiro, Daisuke Koike, Hidetoshi Nagata, Yuka Kondo, Hironobu Yasuoka, Takashi Imanaka, Hiroki Tani, Yoshiki Kunimura, Masahiro Ito, Yutaro Kato, Tsunekazu Hanai, Zenichi Morise, Shuji Isaji, Ryota Hanaoka and Akihiko Horiguchi

Cancers 2026, 18(11), 1780; https://doi.org/10.3390/cancers18111780 - 29 May 2026

Abstract

Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal gastrointestinal cancers, and reliable preoperative predictors of aggressive tumor biology are essential for optimizing treatment strategies, particularly in resectable PDAC (RPDAC). This retrospective study evaluated the diagnostic accuracy of dynamic computed tomography [...] Read more.

Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal gastrointestinal cancers, and reliable preoperative predictors of aggressive tumor biology are essential for optimizing treatment strategies, particularly in resectable PDAC (RPDAC). This retrospective study evaluated the diagnostic accuracy of dynamic computed tomography (CT) for detecting extrapancreatic extension, peripancreatic plexus (PL), serosal (S), and retroperitoneal (RP) invasion, and assessed its prognostic significance. Methods: Ninety-four patients who underwent curative-intent upfront surgery for resectable PDAC between 2007 and 2020 were included. Dynamic CT was reviewed using standardized window settings (WL 35/WW 350) to identify soft-tissue projections extending beyond the pancreatic contour. Results: Pathological S, RP, and PL invasion occurred in 29.8%, 56.3%, and 17.0% of patients, respectively. Dynamic CT demonstrated accuracies of 73.4%, 76.6%, and 87.2% for S, RP, and PL invasion, respectively. Notably, patients with PL-positive CT findings had significantly poorer disease-specific survival (DSS) than those with PL-negative, with 3- and 5-year DSS rates of 37% and 0% versus 61% and 53% (p < 0.001). Multivariate analysis confirmed preoperative PL invasion as the only independent predictor of poor prognosis. Conclusions: Dynamic CT provides reasonable diagnostic performance for assessing extrapancreatic invasion. In addition, CT-identified PL invasion reflects aggressive tumor behavior and may justify consideration of neoadjuvant therapy, even in anatomically resectable disease. Full article

(This article belongs to the Special Issue Neoadjuvant Therapy in Hepatopancreatobiliary Malignancies: Current Trends and Future Directions)

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21 pages, 3760 KB

Open AccessReview

Advances in Brain Tumor Biomarkers: From Molecular Profiling to Liquid Biopsy and AI-Driven Detection

by Trang T. T. Nguyen, Lan N. Ðoàn, Evgenii Boriushkin and Christian E. Badr

Cancers 2026, 18(11), 1779; https://doi.org/10.3390/cancers18111779 - 29 May 2026

Abstract

Brain tumors in older adults are difficult to diagnose and manage due to nonspecific symptoms, overlapping with neurodegenerative diseases such as dementia, and significant tumor heterogeneity. Although molecular markers such as IDH1/2 mutations, MGMT promoter methylation, TERT alterations, and 1p/19q co-deletion have improved [...] Read more.

Brain tumors in older adults are difficult to diagnose and manage due to nonspecific symptoms, overlapping with neurodegenerative diseases such as dementia, and significant tumor heterogeneity. Although molecular markers such as IDH1/2 mutations, MGMT promoter methylation, TERT alterations, and 1p/19q co-deletion have improved glioma classification and prognostic assessment, current care still relies on invasive tissue biopsies, which limit longitudinal monitoring and may not fully capture tumor complexity because of sampling bias, assay variability, and limited accessibility. Liquid biopsy offers a promising alternative that enables the detection of tumor-derived DNA, RNA, proteins, and extracellular vesicles, supporting earlier diagnosis and real-time monitoring of disease progression and treatment response. However, liquid biopsy for brain tumors is not yet clinically definitive due to low biomarker abundance, lack of standardization, and limited validation, and therefore, it cannot replace tissue diagnosis. Ongoing research focuses on multi-analyte biomarker panels, improved assay standardization, and integration with imaging and tissue-based data. In parallel, artificial intelligence and machine learning are advancing the field by integrating multi-omics and radiomic data to enhance detection, classify tumors, and predict key molecular alterations, supporting the emerging framework of radiogenomics. Together, these developments are driving a shift toward more precise and dynamic approaches to brain tumor diagnosis and management, with relevance for improving outcomes in older adults with brain cancer. Full article

(This article belongs to the Special Issue Advancements in Brain Cancer Research: From Molecular Mechanisms to Translational Therapeutic Strategies)

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2 pages, 173 KB

Open AccessReply

Reply to Borewad et al. Comment on “Rao et al. The Oncological Outcome of Postoperative Radiotherapy in Patients with Node-Negative Early-Stage (T1/T2/N0) Oral Squamous Cell Carcinoma and Perineural Invasion: A Meta-Analysis. Cancers 2025, 17, 862”

by Karthik N. Rao, Sreeram M. P., Remco de Bree, William M. Mendenhall, Primož Strojan, Göran Stenman, Antti Mäkitie, Alfons Nadal, Juan P. Rodrigo, Sweet Ping Ng, June Corry, Alessandra Rinaldo, Avraham Eisbruch and Alfio Ferlito

Cancers 2026, 18(11), 1778; https://doi.org/10.3390/cancers18111778 - 29 May 2026

Abstract

We sincerely thank Borewad et al [...] Full article

(This article belongs to the Special Issue New Approaches in Radiotherapy for Cancer)

12 pages, 1694 KB

Open AccessArticle

Comparison of Growth Inhibition and Clonogenic Assays for Assessing Radiotherapy Responses in Breast Cancer Cell Lines

by MacKenzie R. Coon-Haworth, P. Finley Durham and Matthew L. Scarpelli

Cancers 2026, 18(11), 1777; https://doi.org/10.3390/cancers18111777 - 29 May 2026

Abstract

Background: In vitro assays are widely used to optimize emerging radiotherapy strategies before undertaking more resource-intensive in vivo or clinical studies. However, multiple assay types are currently employed, and it remains unclear whether they yield comparable or complementary measures of radiosensitivity, complicating [...] Read more.

Background: In vitro assays are widely used to optimize emerging radiotherapy strategies before undertaking more resource-intensive in vivo or clinical studies. However, multiple assay types are currently employed, and it remains unclear whether they yield comparable or complementary measures of radiosensitivity, complicating cross-study comparisons. Purpose: This study provides the first direct comparison of two of the most widely used radiosensitivity assays, clonogenic survival and growth inhibition, using commonly reported but non-identical protocols. The goals are to determine whether the assay measurements are correlated and assess their repeatability in breast cancer cell lines. Methods: Five cancer cell lines (4T1, SKBR3, BT474, MCF7, and MDA-MB-231) underwent clonogenic and growth inhibition assays following X-ray irradiation at 2, 4, 6, and 8 Gy. Correlations between assay measurements were assessed using Spearman correlations. The entire experiment was repeated twice for each assay to assess repeatability. Results: At a given radiation dose, no significant correlations were observed between the clonogenic assay measures and the growth inhibition measures. Across cell lines, the radiation dose resulting in 50% growth inhibition for the growth inhibition assay (mean = 3.2 Gy) was significantly higher than the dose resulting in 50% survival for the clonogenic assay (mean 1.3 Gy; p = 0.02). The coefficient of variation between repeat percent of control measurements for growth inhibition assay was trending lower than for clonogenic assay in every experimental condition and was statistically significant at 8 Gy (p = 0.02). However, the coefficient of variation values for D₅₀ measurements were not significantly different between the assays. Conclusions: This procedural comparison demonstrates that clonogenic survival and growth inhibition assays do not yield correlated measurements under the specific conditions tested and instead provide complementary information about cellular radiation response. These findings highlight important practical considerations for assay selection and suggest that the combined use of both assays may provide a more complete characterization of radiosensitivity. Full article

(This article belongs to the Special Issue New Insights into Cancer Radiotherapy)

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13 pages, 2057 KB

Open AccessArticle

Systemic Lenvatinib Therapy Combined with Locoregional Chemoembolisation and Hepatic Arterial Infusion Chemotherapy for Advanced Hepatocellular Carcinoma with Main Portal Vein Invasion: A Multicentre Retrospective Case—Control Study

by Dedi Wu, Ze Song, Jun Tang, Hongfei Miao, Min Tian, Wenzhe Fan, Jiahang Du, Zhiyong Lu, Hao Zhang and Yingqiang Zhang

Cancers 2026, 18(11), 1776; https://doi.org/10.3390/cancers18111776 - 29 May 2026

Abstract

Background/Objectives: Management of hepatocellular carcinoma (HCC) with main portal vein (MPV) invasion is challenging. We aimed to explore the efficacy and safety of systemic lenvatinib therapy combined with potent locoregional transarterial therapy (e.g., chemoembolisation plus infusion chemotherapy) for the treatment of HCC with [...] Read more.

Background/Objectives: Management of hepatocellular carcinoma (HCC) with main portal vein (MPV) invasion is challenging. We aimed to explore the efficacy and safety of systemic lenvatinib therapy combined with potent locoregional transarterial therapy (e.g., chemoembolisation plus infusion chemotherapy) for the treatment of HCC with MPV invasion. Methods: A direct comparison of different therapeutic regimens through a retrospective matched case—control study was conducted to evaluate the survival benefits of lenvatinib monotherapy versus lenvatinib combined with transarterial chemoembolisation (Len-TACE) versus Len-TACE plus hepatic arterial infusion chemotherapy (Len-TACE-HAIC) with oxaliplatin, fluorouracil, and leucovorin. Between January 2022 and December 2024, consecutive patients with HCC and MPV invasion who received lenvatinib, Len-TACE, or Len-TACE-HAIC from multiple centres in South China were enrolled for this analysis. Overall survival (OS), progression-free survival (PFS), and the objective response rate (ORR) were compared across the treatment groups. Adverse events (AEs) related to treatment were also recorded. Results: A total of 169 patients were included in the study: 48 patients received lenvatinib as systemic treatment, 56 received Len-TACE for locoregional and systemic therapy, and 65 received Len-TACE-HAIC for intensified locoregional and systemic treatment. Patients in the Len-TACE-HAIC group achieved a significantly greater ORR (53.8% vs. 28.6% vs. 6.3%, p < 0.001) than those in the Len-TACE group and the Len group did. Consistently, Len-TACE-HAIC resulted in markedly improved PFS (median, 7.0 vs. 5.0 vs. 2.0 months; p < 0.001) and OS (median, 15.0 vs. 10.0 vs. 7.0 months; p < 0.001). The incidence of grade 3-4 AEs was comparable across the three treatment groups. Conclusions: The results demonstrated that lenvatinib combined with potent locoregional therapy, i.e., the Len-TACE-HAIC regimen, provided superior survival benefits with an acceptable safety profile in patients with HCC and MPV invasion. Full article

(This article belongs to the Section Cancer Therapy)

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39 pages, 2696 KB

Open AccessArticle

Comprehensive Analysis of Genomic and Phenomic Data Reveals Context-Dependent Function of A20 (TNFAIP3) in Renal Cell Carcinoma

by Nour Abu Jayab, Burcu Yener, Reem Sami Alhamidi, Mansi Bhavsar, Alaa Muayad Altaie, Muna Abdalla Alhammadi, Vidya Bijosh Mohan, Marwa Khamis Almazrouei, Lina Sahnoon, Rola Abujabal, Basel Al-Ramadi, Riyad Bendardaf, Iman M. Talaat and Rifat Hamoudi

Cancers 2026, 18(11), 1775; https://doi.org/10.3390/cancers18111775 - 28 May 2026

Abstract

Background: A20, encoded by tumor necrosis factor alpha-induced protein 3 (TNFAIP3), is a key negative regulator of NF-κB signaling with context-dependent functions in cancer. Its role in renal cell carcinoma (RCC), particularly clear-cell RCC (ccRCC), remains incompletely defined. Methods: Public GEO transcriptomic data [...] Read more.

Background: A20, encoded by tumor necrosis factor alpha-induced protein 3 (TNFAIP3), is a key negative regulator of NF-κB signaling with context-dependent functions in cancer. Its role in renal cell carcinoma (RCC), particularly clear-cell RCC (ccRCC), remains incompletely defined. Methods: Public GEO transcriptomic data from 23 controls and 32 ccRCC samples were analyzed using gene set enrichment analysis (GSEA). A20-overexpressing HEK293 and 786-O cells were assessed by functional assays and transcriptomic profiling. Eight ccRCC FFPE samples were profiled to compare A20-associated transcriptional patterns with cell-line data. Targeted DNA sequencing was performed in 11 ccRCC and 8 papillary RCC samples, and whole-exome sequencing was conducted in A20-overexpressing 786-O cells. Key genes were further evaluated using Kaplan-Meier survival analysis in 530 ccRCC patients and TCGA-KIRC data comprising 533 primary tumors and 72 normal samples. Results: GEO analysis showed significant TNFAIP3/A20 upregulation in ccRCC (p = 3.96 × 10⁻⁵) and enrichment of NF-κB-related gene sets (p = 0.01). A20 overexpression produced distinct phenotypes in HEK293 and 786-O cells. In HEK293 cells, A20 increased BIK and ARHGAP6 expression and was associated with increased apoptosis and reduced wound closure. In 786-O cells, A20 suppressed ARHGAP6 and APAF1 and was associated with increased proliferation, enhanced wound closure, and reduced apoptosis relative to EV controls. A20-high ccRCC samples showed enrichment of NF-κB, TGF-β, DNA repair, mTOR/metabolic, hypoxia, and proteasome-related pathways. Genomic analyses identified alterations in NF-κB-related genes, including CARD10 and IRAK1. Conclusions: A20/TNFAIP3 may exert cell-context-dependent effects in RCC and is associated with tumor-relevant transcriptional and genomic alterations requiring further validation. Full article

(This article belongs to the Section Cancer Informatics and Big Data)

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19 pages, 646 KB

Open AccessReview

Is There Geographic Variation in Poland in the Distribution of Specific High-Risk HPV Genotypes in Normal Cervical Epithelium, Dysplastic Lesions, and Cervical Cancers?

by Beata Biesaga, Anna Mucha-Małecka, Anna Kruczak and Wiktor Szatkowski

Cancers 2026, 18(11), 1774; https://doi.org/10.3390/cancers18111774 - 28 May 2026

Abstract

Cervical cancer remains a major public health challenge worldwide and in Poland, where mortality rates are among the highest in the European Union. Persistent infection with high-risk human papillomavirus (hrHPV), particularly genotype HPV16, plays a central role in cervical carcinogenesis. This study aimed [...] Read more.

Cervical cancer remains a major public health challenge worldwide and in Poland, where mortality rates are among the highest in the European Union. Persistent infection with high-risk human papillomavirus (hrHPV), particularly genotype HPV16, plays a central role in cervical carcinogenesis. This study aimed to evaluate the regional variability of hrHPV prevalence and genotype distribution in Poland and to assess its potential implications for cervical cancer incidence and prevention strategies. A systematic literature review was conducted using PubMed, Scopus, and Google Scholar to identify studies published up to May 2025 reporting hrHPV prevalence and genotypes among Polish women. Eligible studies included population-based cohorts, women undergoing screening, and patients with cervical lesions or cancer. The analysis revealed substantial heterogeneity in hrHPV prevalence and genotype distribution across regions and study populations. Nationwide data indicate high overall HPV prevalence (up to 50.9%), with HPV16 consistently dominating, followed by HPV31, HPV51, HPV52, and HPV66. Regional differences were observed, including a higher prevalence of HPV51 in southern Poland and HPV56 and HPV45 in central regions. Studies in women with abnormal cytology or cervical cancer showed markedly higher hrHPV prevalence (often >90%), with HPV16 predominating in high-grade lesions and invasive cancer. These findings confirm the dominant oncogenic role of HPV16 while highlighting significant regional variability in other hrHPV genotypes. Such differences may influence the effectiveness of screening and vaccination programs. Strengthening standardized, regionally stratified HPV surveillance is essential to optimize cervical cancer prevention and tailor public health interventions in Poland. Full article

(This article belongs to the Special Issue Human Papillomavirus (HPV) and Related Cancer)

12 pages, 832 KB

Open AccessArticle

Concordance of Actionable Driver Alterations Between Primary Lung Adenocarcinoma and Paired Thoracic Metastases: A Prospective Next-Generation Sequencing Study

by Luca Bertolaccini, Mariano Lombardi, Matteo Chiari, Alessandra Rappa, Monica Casiraghi, Marianna D’Ercole, Antonio Mazzella, Giorgio Lo Iacono, Shehab Mohamed, Valeria Midolo De Luca, Nicola Fusco, Elena Guerini Rocco and Lorenzo Spaggiari

Cancers 2026, 18(11), 1773; https://doi.org/10.3390/cancers18111773 - 28 May 2026

Abstract

Background: The molecular concordance between primary lung adenocarcinoma and metastatic lesions remains incompletely characterized despite its direct implications for precision oncology and biopsy-driven therapeutic decision-making. This prospective monocentric paired-sample study evaluated genomic concordance between primary lung adenocarcinoma and synchronous thoracic metastatic lesions using [...] Read more.

Background: The molecular concordance between primary lung adenocarcinoma and metastatic lesions remains incompletely characterized despite its direct implications for precision oncology and biopsy-driven therapeutic decision-making. This prospective monocentric paired-sample study evaluated genomic concordance between primary lung adenocarcinoma and synchronous thoracic metastatic lesions using targeted next-generation sequencing (NGS). Methods: We identified 27 treatment-naïve patients with histologically confirmed lung adenocarcinoma who underwent paired molecular profiling of the primary tumor and a synchronous thoracic metastatic site (pleural or intrapulmonary). DNA and RNA were analyzed using validated institutional NGS platforms. Genomic alterations, including clinically actionable oncogenic drivers consistently covered by the sequencing panel used in each pair, were compared across matched samples. Concordance was assessed using exact binomial confidence intervals, Cohen’s κ statistics, McNemar tests, and paired Wilcoxon signed-rank tests. Results: Actionable driver alterations were identified in 17 of 27 patients (63.0%; 95% CI 42.4–80.6), including EGFR mutations (40.7%), KRAS alterations (18.5%), and one ALK gene rearrangement (3.7%). TP53 concurrent mutations were detected in 14 cases (51.9%). Across all 27 paired samples, driver-level concordance was 100% (95% CI 87.2–100), with perfect agreement for EGFR, KRAS, and ALK alterations (κ = 1.00). TP53 mutations showed high concordance (92.9%; κ = 0.85), while CNVs were concordant in 88.0% of evaluable pairs. Variant allele frequency (VAF) comparisons, adjusted for tumor cellularity, further supported the apparent clonal stability of driver alterations across paired samples. Conclusions: This study demonstrates very high molecular concordance between primary lung adenocarcinomas and their synchronous pleural or intrapulmonary metastases. The observed 100% concordance of actionable driver alterations across paired specimens supports the clinical reliability of thoracic metastatic biopsies for baseline molecular profiling in treatment-naïve disease. Although limited by sample size, these findings support the biological stability of actionable driver alterations during early thoracic metastatic dissemination. Full article

(This article belongs to the Special Issue The Role of Anatomical Resections in Secondary Lung Cancer: Indications, Techniques, and Outcomes)

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16 pages, 859 KB

Open AccessArticle

CLDN-2 Expression Aligns with Invasion-Associated Epithelial Remodeling in Colorectal Cancer

by Adam R. Markowski, Anna J. Sadowska, Konstancja Mantiuk, Wiktoria Romańczyk, Anna Pryczynicz and Katarzyna Guzińska-Ustymowicz

Cancers 2026, 18(11), 1772; https://doi.org/10.3390/cancers18111772 - 28 May 2026

Abstract

Background: Remodeling of epithelial junctional architecture contributes to colorectal cancer (CRC) progression; however, the spatial organization linking tight-junction components to early dissemination remains incompletely characterized. Claudin-2 (CLDN-2) is frequently upregulated in CRC, yet whether it is associated with compartment-specific epithelial remodeling has not [...] Read more.

Background: Remodeling of epithelial junctional architecture contributes to colorectal cancer (CRC) progression; however, the spatial organization linking tight-junction components to early dissemination remains incompletely characterized. Claudin-2 (CLDN-2) is frequently upregulated in CRC, yet whether it is associated with compartment-specific epithelial remodeling has not been systematically examined. Methods: In a retrospective single-center cohort of 54 surgically resected CRCs, we integrated clinicopathological variables, quantitative tumor budding counts, compartment-specific membranous E-cadherin expression, lymphovascular invasion, lymphoid follicles, and immune-cell densities. Analyses focused on spatial structural relationships within the tumor. Results: Higher CLDN-2 expression was enriched among node-positive tumors and advanced TNM stages. CLDN-2–higher tumors exhibited increased tumor budding and spatially selective adhesion remodeling, characterized by reduced membranous E–cadherin at the invasive front and budding sites, with more preserved membranous epithelial organization within metastatic lymph-node deposits. Descriptive co-occurrence and correlation analyses demonstrated concordant spatial relationships among CLDN-2 expression, tumor budding, nodal involvement, lymphovascular invasion, and compartment-specific E-cadherin patterns. In contrast, immune-related parameters showed weaker differentiation across CLDN-2 strata. Conclusions: CLDN-2 expression is associated with spatial epithelial remodeling in colorectal cancer, characterized by compartment-specific adhesion changes and increased microinvasive activity. The findings support a model in which CLDN-2 expression aligns with an invasion-associated epithelial configuration linked to tumor budding and nodal dissemination. These observations warrant validation in independent cohorts with outcome data. Full article

(This article belongs to the Special Issue Cancer Metastasis in 2025–2026)

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20 pages, 1590 KB

Open AccessArticle

The Prognostic Potential of PD-L1, PD-1, CD3, CD4, and CD8 Expression in Patients with Head and Neck Cancers Depending on HPV16 Infection

by Anna Mucha-Małecka, Beata Biesaga, Natalia Amrogowicz, Aleksandra Grela-Wojewoda, Mirosława Püsküllüoğlu, Marcin Przewoźnik, Elżbieta Pluta, Anna Patla, Krzysztof Roszkowski and Krzysztof Małecki

Cancers 2026, 18(11), 1771; https://doi.org/10.3390/cancers18111771 - 28 May 2026

Abstract

Objective: The aim of this study was to evaluate the expression of PD-L1, PD-1, CD3, CD4, and CD8 in tumor tissues of patients with head and neck squamous cell carcinoma from southern Poland, and to assess their prognostic value in relation to disease-free [...] Read more.

Objective: The aim of this study was to evaluate the expression of PD-L1, PD-1, CD3, CD4, and CD8 in tumor tissues of patients with head and neck squamous cell carcinoma from southern Poland, and to assess their prognostic value in relation to disease-free survival (DFS), taking into account HPV16 status and other clinical, pathological, and demographic factors. Material/Methods: This study included 155 unselected patients with head and neck squamous cell carcinoma (HNSCC) from the southern Poland region, who underwent diagnostic evaluation and surgical treatment. Formalin-fixed, paraffin-embedded (FFPE) tissue blocks were obtained from these centers. The patients were treated at the Maria Skłodowska-Curie National Research Institute of Oncology, Kraków Branch, between 1991 and 2014, with treatment approaches including induction therapy (preoperative), adjuvant therapy (postoperative), or definitive chemoradiotherapy with cisplatin. Protein expression was assessed using immunohistochemistry and quantified (TPS, CPS, H-score). Relationships between expression levels and epidemiological, clinical, and histopathological features were analyzed. Results: The results show that PD-L1 overexpression was associated with worse DFS, whereas overexpression of PD-1, CD3, CD4, and CD8 correlated with improved DFS. These associations were statistically significant in the HPV16-negative subgroup, while no such correlations were found in HPV16-positive patients. In multivariate analysis, independent prognostic factors associated with improved DFS included HPV16 infection, absence of PD-L1 overexpression, overexpression of CD4 and CD8, and combined chemoradiotherapy with cisplatin. Conclusions: These findings confirm the prognostic relevance of PD-L1, PD-1, and T-cell markers in HNSCC, particularly in HPV16-negative patients, and support further research into the use of these biomarkers in personalized treatment strategies. Full article

(This article belongs to the Special Issue Human Papillomavirus (HPV) and Related Cancer)

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