Cancers

19 pages, 1536 KiB

Open AccessArticle

Enhancing Hepatocellular Carcinoma Surveillance: Comparative Evaluation of AFP, AFP-L3, DCP and Composite Models in a Biobank-Based Case-Control Study

by Coskun O. Demirtas, Sehnaz Akin, Demet Yilmaz Karadag, Tuba Yilmaz, Ugur Ciftci, Javid Huseynov, Tugba Tolu Bulte, Yasemin Armutcuoglu Kaldirim, Feyza Dilber, Osman Cavit Ozdogan and Fatih Eren

Cancers 2025, 17(14), 2390; https://doi.org/10.3390/cancers17142390 - 18 Jul 2025

Abstract

Background/Objectives: Biomarkers such as lens agglutinin-reactive alpha-fetoprotein and des-gamma-carboxy prothrombin, as well as biomarker- and/or clinical-parameter-derived composite models (GALAD, GAAP, ASAP, aMAP, Doylestown), may improve detection in addition to alpha-fetoprotein, yet comparative data across diverse populations remain limited. Methods: In this [...] Read more.

Background/Objectives: Biomarkers such as lens agglutinin-reactive alpha-fetoprotein and des-gamma-carboxy prothrombin, as well as biomarker- and/or clinical-parameter-derived composite models (GALAD, GAAP, ASAP, aMAP, Doylestown), may improve detection in addition to alpha-fetoprotein, yet comparative data across diverse populations remain limited. Methods: In this biobank-based case–control study, we evaluated 562 adults (120 healthy controls, 277 chronic liver disease, 165 hepatocellular carcinoma) from January 2019 to 2024. Diagnostic performance for any-stage and early-stage hepatocellular carcinoma was assessed across three thresholds: Youden-index-derived optimal cut-offs, research-established cut-offs, and cut-offs ensuring 90% specificity. Receiver operating characteristic analysis was performed. Subgroup analyses were stratified by etiology and alpha-fetoprotein status. Results: At optimal cut-offs, GALAD showed the highest sensitivity for any-stage (90.3%) and early-stage (89.1%) hepatocellular carcinoma, with 70–80% specificity. Using established cut-offs, GALAD retained the highest sensitivity for any-stage (75.8%) and early-stage (57.8%) hepatocellular carcinoma, with 93.5% specificity. GALAD demonstrated the best performance in non-viral hepatocellular carcinomas (area under the curve 0.872), whereas GAAP and ASAP showed similarly high area under the curve values in viral etiology (area under the curve 0.955–0.960). Conclusions: Our results demonstrate the consistent performance of the GALAD score across diverse populations and underscore its superiority over individual biomarkers and other composite models. Notably, the GAAP and ASAP scores—which use one less biomarker (AFP-L3)—exhibited comparable performance, particularly in viral etiology. These findings support the integration of the composite biomarker models into tailored hepatocellular carcinoma surveillance strategies. Full article

(This article belongs to the Special Issue Recent Advances in Hepatobiliary Cancers: From Diagnosis to Treatment (2nd Edition))

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14 pages, 830 KiB

Open AccessArticle

Metastatic Patterns of Apical Lymph Node and Prognostic Analysis in Rectal and Sigmoid Colon Cancer—A Multicenter Retrospective Cohort Study of 2809 Cases

by Mingguang Zhang, Fuqiang Zhao, Aiwen Wu, Xiaohui Du, Lei Zhou, Shiwen Mei, Fangze Wei, Shidong Hu, Xinzhi Liu, Hua Yang, Lai Xu, Yi Xiao, Xishan Wang, Qian Liu and on behalf of the Chinese Apical Lymph Node Study Consortium

Cancers 2025, 17(14), 2389; https://doi.org/10.3390/cancers17142389 - 18 Jul 2025

Abstract

Background/Objectives: The metastatic patterns of apical lymph node (ALN) in rectal and sigmoid colon cancer are currently unclear, and there is no consensus on the indications for dissection of ALN. This study aimed to analyze the impact of ALN metastasis on prognosis, [...] Read more.

Background/Objectives: The metastatic patterns of apical lymph node (ALN) in rectal and sigmoid colon cancer are currently unclear, and there is no consensus on the indications for dissection of ALN. This study aimed to analyze the impact of ALN metastasis on prognosis, determine the metastatic patterns of ALN and provide evidence for indications of ALN dissection in rectal and sigmoid colon cancer. Methods: In this multicenter, retrospective cohort study, patients from five centers with stage I-III rectal or sigmoid colon cancer who underwent laparoscopic radical surgery with ALN dissection without neoadjuvant treatment from January 2015 to December 2019 were enrolled. Results: Among 2809 patients, the positive rate of ALN was 1.9%. The 5-year overall survival and cancer-specific survival rate for patients with metastatic ALN were 37.5% and 41.0%, respectively. ALN metastasis was the independent risk factor for poor prognosis. Tumor size ≥5 cm (OR = 2.32, 95% CI: 1.30–4.13, p = 0.004), signet ring cell cancer/mucinous adenocarcinoma (vs. poor differentiated adenocarcinoma, OR = 0.19, 95% CI: 0.08–0.45, p < 0.001; vs. moderate to well differentiated adenocarcinoma, OR = 0.22, 95% CI: 0.11–0.42, p < 0.001), T4 stage (OR = 1.93, 95% CI: 1.05–3.55, p = 0.034), N2 stage (OR = 8.86, 95% CI: 4.45–17.65, p < 0.001) and radiologic evidence of extramural venous invasion (OR = 1.88, 95% CI: 1.03–3.42, p = 0.040) were independent risk factors for ALN metastasis. The nomogram model developed by these factors achieved a good predictive performance. Conclusions: This research offered insights into the incidence, risk factors, and prognostic significance of apical lymph node metastasis in cases of rectal and sigmoid colon cancer. Additionally, the study furnished empirical support for the criteria guiding ALN dissection. Furthermore, a pragmatic risk assessment model was developed to predict ALN metastasis. Full article

(This article belongs to the Section Cancer Metastasis)

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19 pages, 577 KiB

Open AccessReview

Co-Occurring Genomic Alterations in NSCLC: Making Order into a Crowded List

by Ilaria Attili, Federico Pio Fabrizio and Filippo de Marinis

Cancers 2025, 17(14), 2388; https://doi.org/10.3390/cancers17142388 - 18 Jul 2025

Abstract

Worldwide, lung cancer is one of the most common cancers, with non-small cell lung cancer (NSCLC) including up to 80–85% of all lung cancer diagnoses. The landscape of NSCLC is characterized by a heterogeneous spectrum of gene alterations, with tyrosine kinase inhibitors (TKIs) [...] Read more.

Worldwide, lung cancer is one of the most common cancers, with non-small cell lung cancer (NSCLC) including up to 80–85% of all lung cancer diagnoses. The landscape of NSCLC is characterized by a heterogeneous spectrum of gene alterations, with tyrosine kinase inhibitors (TKIs) and targeted treatments that significantly improve survival outcomes for patients with oncogene-addicted NSCLC, offering superior efficacy, and often favorable safety and tolerability profiles compared to chemotherapy-based treatments. However, the complexity of NSCLC extends to co-occurring genomic alterations or amplifications in tumor suppressors and other oncogenes, such as TP53, STK11, KEAP1, PIK3CA, RB1, and others, that significantly influence disease progression, therapeutic resistance, and clinical outcomes. These co-mutations often contribute to the development of primary and acquired resistance to targeted therapies, complicating decision-making strategies. This review provides a timely and comprehensive synthesis of current insights into co-mutations in NSCLC, with a particular focus on their clinical implications, and offers a novel perspective by integrating recent molecular insights with therapeutic challenges, addressing existing knowledge gaps through a more integrative and clinically oriented analysis of co-mutations. Advances in next-generation sequencing (NGS) and molecular profiling have enabled the identification of these co-alterations, paving the way for more personalized therapeutic approaches. However, challenges remain in interpreting the functional interplay of co-mutations and translating these insights into effective clinical interventions. This review also highlights the significance of co-mutations in shaping NSCLC biology, and discusses their impact on current therapeutic paradigms, emphasizing the need for integrative biomarker-driven approaches to improve outcomes in NSCLC. Full article

(This article belongs to the Special Issue Current Status and Clinical Developments in Lung Cancer: What to Expect from Emerging Drugs? (2nd Edition))

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9 pages, 258 KiB

Open AccessEditorial

Acute Myeloid Leukemia: Updates on Diagnosis, Treatment and Management

by Francesco Lanza, Michela Rondoni and Giovanni Marconi

Cancers 2025, 17(14), 2387; https://doi.org/10.3390/cancers17142387 - 18 Jul 2025

Abstract

This Special Issue of Cancers, entitled “Acute Myeloid Leukemia (AML): Updates on Diagnosis, Treatment and Management”, will be a forum for stimulating discussions and thought-provoking debates, featuring cutting-edge scientific manuscripts on the most relevant topics related to the diagnosis and therapeutic advances [...] Read more.

This Special Issue of Cancers, entitled “Acute Myeloid Leukemia (AML): Updates on Diagnosis, Treatment and Management”, will be a forum for stimulating discussions and thought-provoking debates, featuring cutting-edge scientific manuscripts on the most relevant topics related to the diagnosis and therapeutic advances for the management of AML [...] Full article

(This article belongs to the Special Issue Acute Myeloid Leukemia: Updates on Diagnosis, Treatment and Management)

15 pages, 2610 KiB

Open AccessArticle

CT-Based Radiomics for a priori Predicting Response to Chemoradiation in Locally Advanced Lung Adenocarcinoma

by Erika Z. Chung, Laurentius O. Osapoetra, Patrick Cheung, Ian Poon, Alexander V. Louie, May Tsao, Yee Ung, Mateus T. Cunha, Ines B. Menjak and Gregory J. Czarnota

Cancers 2025, 17(14), 2386; https://doi.org/10.3390/cancers17142386 - 18 Jul 2025

Abstract

The standard treatment for patients with locally advanced non-small cell lung cancer (NSCLC) is concurrent chemoradiation. However, clinical responses are heterogeneous and generally not known until after the completion of therapy. Multiple studies have investigated imaging predictors (radiomics) for different cancer histologies, but [...] Read more.

The standard treatment for patients with locally advanced non-small cell lung cancer (NSCLC) is concurrent chemoradiation. However, clinical responses are heterogeneous and generally not known until after the completion of therapy. Multiple studies have investigated imaging predictors (radiomics) for different cancer histologies, but little exists for NSCLC. The objective of this study was to develop a multivariate CT-based radiomics model to a priori predict responses to definitive chemoradiation in patients with lung adenocarcinoma. Methods: Patients diagnosed with locally advanced unresectable lung adenocarcinoma who had undergone chemoradiotherapy followed by at least one dose of maintenance durvalumab were included. The PyRadiomics Python library was used to determine statistical, morphological, and textural features from normalized patient pre-treatment CT images and their wavelet-filtered versions. A nested leave-one-out cross-validation was used for model building and evaluation. Results: Fifty-seven patients formed the study cohort. The clinical stage was IIIA-C in 98% of patients. All but one received 6000–6600 cGy of radiation in 30–33 fractions. All received concurrent platinum-based chemotherapy. Based on RECIST 1.1, 20 (35%) patients were classified as responders (R) to chemoradiation and 37 (65%) patients as non-responders (NR). A three-feature model based on a KNN k = 1 machine learning classifier was found to have the best performance, achieving a recall, specificity, accuracy, balanced accuracy, precision, negative predictive value, F1-score, and area under the curve of 84%, 70%, 80%, 77%, 84%, 70%, 84%, and 0.77, respectively. Conclusions: Our results suggest that a CT-based radiomics model may be able to predict chemoradiation response for lung adenocarcinoma patients with estimated accuracies of 77–84%. Full article

(This article belongs to the Section Cancer Therapy)

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20 pages, 12298 KiB

Open AccessArticle

Impact of Metastatic Microenvironment on Physiology and Metabolism of Small Cell Neuroendocrine Prostate Cancer Patient-Derived Xenografts

by Shubhangi Agarwal, Deepti Upadhyay, Jinny Sun, Emilie Decavel-Bueff, Robert A. Bok, Romelyn Delos Santos, Said Al Muzhahimi, Rosalie Nolley, Jason Crane, John Kurhanewicz, Donna M. Peehl and Renuka Sriram

Cancers 2025, 17(14), 2385; https://doi.org/10.3390/cancers17142385 - 18 Jul 2025

Abstract

Background: Potent androgen receptor pathway inhibitors induce small cell neuroendocrine prostate cancer (SCNC), a highly aggressive subtype of metastatic androgen deprivation-resistant prostate cancer (ARPC) with limited treatment options and poor survival rates. Patients with metastases in the liver have a poor prognosis relative [...] Read more.

Background: Potent androgen receptor pathway inhibitors induce small cell neuroendocrine prostate cancer (SCNC), a highly aggressive subtype of metastatic androgen deprivation-resistant prostate cancer (ARPC) with limited treatment options and poor survival rates. Patients with metastases in the liver have a poor prognosis relative to those with bone metastases alone. The mechanisms that underlie the different behavior of ARPC in bone vs. liver may involve factors intrinsic to the tumor cell, tumor microenvironment, and/or systemic factors, and identifying these factors is critical to improved diagnosis and treatment of SCNC. Metabolic reprogramming is a fundamental strategy of tumor cells to colonize and proliferate in microenvironments distinct from the primary site. Understanding the metabolic plasticity of cancer cells may reveal novel approaches to imaging and treating metastases more effectively. Methods: Using magnetic resonance (MR) imaging and spectroscopy, we interrogated the physiological and metabolic characteristics of SCNC patient-derived xenografts (PDXs) propagated in the bone and liver, and used correlative biochemical, immunohistochemical, and transcriptomic measures to understand the biological underpinnings of the observed imaging metrics. Results: We found that the influence of the microenvironment on physiologic measures using MRI was variable among PDXs. However, the MR measure of glycolytic capacity in the liver using hyperpolarized ¹³C pyruvic acid recapitulated the enzyme activity (lactate dehydrogenase), cofactor (nicotinamide adenine dinucleotide), and stable isotope measures of fractional enrichment of lactate. While in the bone, the congruence of the glycolytic components was lost and potentially weighted by the interaction of cancer cells with osteoclasts/osteoblasts. Conclusion: While there was little impact of microenvironmental factors on metabolism, the physiological measures (cellularity and perfusion) are highly variable and necessitate the use of combined hyperpolarized ¹³C MRI and multiparametric (anatomic, diffusion-, and perfusion- weighted) ¹H MRI to better characterize pre-treatment tumor characteristics, which will be crucial to evaluate treatment response. Full article

(This article belongs to the Special Issue Magnetic Resonance in Cancer Research)

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14 pages, 1865 KiB

Open AccessArticle

Plasma WFDC2 (HE4) as a Predictive Biomarker for Clinical Outcomes in Cancer Patients Receiving Anti-PD-1 Therapy: A Pilot Study

by Makoto Watanabe, Katsuaki Ieguchi, Takashi Shimizu, Ryotaro Ohkuma, Risako Suzuki, Emiko Mura, Nana Iriguchi, Tomoyuki Ishiguro, Yuya Hirasawa, Go Ikeda, Masahiro Shimokawa, Hirotsugu Ariizumi, Kiyoshi Yoshimura, Atsushi Horiike, Takuya Tsunoda, Mayumi Tsuji, Shinichi Kobayashi, Tatsunori Oguchi, Yuji Kiuchi and Satoshi Wada

Cancers 2025, 17(14), 2384; https://doi.org/10.3390/cancers17142384 - 18 Jul 2025

Abstract

Background/Objectives: Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy; however, reliable biomarkers of therapeutic efficacy remain limited. We investigated the clinical utility of plasma WFDC2 levels in patients receiving anti-PD-1 antibody treatment. Methods: Twenty-one patients with non-small cell lung, gastric, or [...] Read more.

Background/Objectives: Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy; however, reliable biomarkers of therapeutic efficacy remain limited. We investigated the clinical utility of plasma WFDC2 levels in patients receiving anti-PD-1 antibody treatment. Methods: Twenty-one patients with non-small cell lung, gastric, or bladder cancer received nivolumab or pembrolizumab. Plasma WFDC2 concentrations were measured by ELISA before ICI treatment (pre-ICI) and after two and four treatment cycles. Associations between WFDC2 expression changes and overall survival (OS), progression-free survival (PFS), and tumor progression were assessed. ROC curve analyses compared the predictive performance of WFDC2, soluble PD-L1 (sPD-L1), soluble PD-1 (sPD-1), and their combinations, with the area under the curve (AUC) evaluating predictive accuracy. Results: Levels of WFDC2 pre-ICI and those after two cycles were significantly higher than levels in healthy donors. However, no significant differences in WFDC2 levels were found between the time points during treatment. Greater increases in WFDC2 levels were significantly correlated with shorter OS (p = 0.002), shorter PFS (p = 0.037), and tumor progression (p = 0.003). ROC analysis revealed that WFDC2 achieved a higher AUC (0.700) than sPD-L1 (0.538) or sPD-1 (0.650). Combining biomarkers improved the predictive accuracy, with sPD-L1 plus WFDC2 showing the highest AUC (0.825). Conclusions: Serial increases in plasma WFDC2 are associated with poor clinical outcomes, highlighting its potential as a biomarker. Baseline plasma WFDC2 outperformed sPD-L1 and sPD-1 diagnostically. These findings should be interpreted as exploratory and hypothesis-generating, requiring confirmation in larger, tumor-specific cohorts with multivariate adjustment. WFDC2 represents a promising minimally invasive biomarker for the early identification of patients unlikely to benefit from ICI therapy. Full article

(This article belongs to the Special Issue Cancer Immunotherapy: Focus on Immune Checkpoint Inhibitors and Immune Modulators)

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15 pages, 2992 KiB

Open AccessArticle

Radiotherapy Upregulates the Expression of Membrane-Bound Negative Complement Regulator Proteins on Tumor Cells and Limits Complement-Mediated Tumor Cell Lysis

by Yingying Liang, Lixin Mai, Jonathan M. Schneeweiss, Ramon Lopez Perez, Michael Kirschfink and Peter E. Huber

Cancers 2025, 17(14), 2383; https://doi.org/10.3390/cancers17142383 - 18 Jul 2025

Abstract

Background/Objectives: Radiotherapy (RT) is a mainstay of clinical cancer therapy that causes broad immune responses. The complement system is a pivotal effector mechanism in the innate immune response, but the impact of RT is less well understood. This study investigates the interaction [...] Read more.

Background/Objectives: Radiotherapy (RT) is a mainstay of clinical cancer therapy that causes broad immune responses. The complement system is a pivotal effector mechanism in the innate immune response, but the impact of RT is less well understood. This study investigates the interaction between RT and the complement system as a possible approach to improve immune responses in cancer treatment. Methods: Human solid cancer (lung, prostate, liver, breast cancer), lymphoma, and leukemia cells were irradiated using X-rays and treated with polyclonal antibodies or anti-CD20 monoclonal antibodies, respectively. Chromium release assay was applied to measure cell lysis after radiation with or without complement-activating antibody treatment. The expression of membrane-bound complement regulatory proteins (mCRPs; CD46, CD55, CD59), which confer resistance against complement activation, CD20 expression, apoptosis, and radiation-induced DNA double-strand breaks (γH2AX), was measured by flow cytometry. The radiosensitivity of tumor cells was assessed by colony-forming assay. Results: We demonstrate that RT profoundly impacts complement function by upregulating the expression of membrane-bound complement regulatory proteins (mCRPs) on tumor cells in a dose- and time-dependent manner. Impaired complement-mediated tumor cell lysis could thus potentially contribute to radiotherapeutic resistance. We also observed RT-induced upregulation of CD20 expression on lymphoma and leukemic cells. Notably, complement activation prior to RT proved more effective in inducing RT-dependent early apoptosis compared to post-irradiation treatment. While complement modulation does not significantly alter RT-induced DNA-damage repair mechanisms or intrinsic radiosensitivity in cancer cells, our results suggest that combining RT with complement-based anti-cancer therapy may enhance complement-dependent cytotoxicity (CDC) and apoptosis in tumor cells. Conclusions: This study sheds light on the complex interplay between RT and the complement system, offering insights into potential novel combinatorial therapeutic strategies and a potential sequential structure for certain tumor types. Full article

(This article belongs to the Special Issue Combination Immunotherapy for Cancer Treatment)

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20 pages, 3053 KiB

Open AccessArticle

ERRα and HIF-1α Cooperate to Enhance Breast Cancer Aggressiveness and Chemoresistance Under Hypoxic Conditions

by Dimas Carolina Belisario, Anna Sapino, Ilaria Roato, Amalia Bosia, Sophie Doublier and Serena Marchiò

Cancers 2025, 17(14), 2382; https://doi.org/10.3390/cancers17142382 - 18 Jul 2025

Abstract

Background/Objectives: HIF-1α and ERRα are both implicated in breast cancer progression, yet their functional interplay remains poorly understood. This study investigates their molecular crosstalk in the context of hypoxia-induced drug resistance. Methods: MCF-7 (estrogen receptor, ER-positive) spheroids and CoCl₂-treated [...] Read more.

Background/Objectives: HIF-1α and ERRα are both implicated in breast cancer progression, yet their functional interplay remains poorly understood. This study investigates their molecular crosstalk in the context of hypoxia-induced drug resistance. Methods: MCF-7 (estrogen receptor, ER-positive) spheroids and CoCl₂-treated SK-BR-3 (ER-negative) cells were used to model tumor hypoxia. Protein expression, coimmunoprecipitation, chromatin immunoprecipitation (ChIP), pharmacological inhibition, and siRNA-mediated gene silencing were employed to assess physical and functional interactions. Immunohistochemistry (IHC) on a tissue microarray (TMA) of 168 invasive breast carcinomas was performed to evaluate clinical relevance. Results: ERRα levels remained unchanged under hypoxia, while its coactivator, Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1 α (PGC-1α), was upregulated. ERRα physically interacted with HIF-1α and was required for HIF-1 transcriptional activity under hypoxic conditions. ChIP assays showed that ERRα-driven overexpression of Permeability glycoprotein 1 (P-gp) and Vascular Endothelial Growth Factor (VEGF) was mediated by HIF-1α binding to the MDR1 and VEGF promoters. Inhibition or silencing of ERRα reversed P-gp overexpression and restored intracellular doxorubicin. TMA analysis confirmed the clinical correlation between ERRα, HIF-1α, and P-gp expression, highlighting the role of ERRα in hypoxia-induced drug resistance. ERRα expression was independent of ER status, suggesting an estrogen-independent function. Conclusions: This study identifies a novel physical and functional interaction between ERRα and HIF-1α that promotes chemoresistance in hypoxic breast tumors. Targeting ERRα may represent a promising therapeutic strategy to overcome drug resistance in aggressive, ER-independent breast cancer subtypes. Full article

(This article belongs to the Section Cancer Drug Development)

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Graphical abstract

9 pages, 941 KiB

Open AccessArticle

Transperineal Free-Hand Prostate Fusion Biopsy with AI-Driven Auto-Contouring: First Results of a Prospective Study

by Marco Oderda, Giorgio Calleris, Alessandro Dematteis, Alessandro Greco, Alessandro Marquis, Giancarlo Marra, Umberto Merani, Alberto Sasia, Alessio Venturi, Andrea Zitella and Paolo Gontero

Cancers 2025, 17(14), 2381; https://doi.org/10.3390/cancers17142381 - 18 Jul 2025

Abstract

Background: prostate fusion biopsies are key in the diagnosis of prostate cancer (PCa); however, the fusion imaging system is not always user-friendly or reliable. The aim of this study was to assess the feasibility, accuracy, and effectiveness of transperineal fusion biopsies performed [...] Read more.

Background: prostate fusion biopsies are key in the diagnosis of prostate cancer (PCa); however, the fusion imaging system is not always user-friendly or reliable. The aim of this study was to assess the feasibility, accuracy, and effectiveness of transperineal fusion biopsies performed with a novel fusion imaging device equipped with AI-driven auto-contouring. Methods: data from 148 patients who underwent MRI-targeted and systematic prostate fusion biopsy with UroFusion (Esaote) were prospectively collected. All biopsies were performed in-office, under local anaesthesia. Results: cancer detection rate was 64% overall and 56% for clinically significant PCa (csPCa, ISUP ≥ 2). PCa was detected in 35%, 65% and 84% of lesions scored as PI-RADS 3, 4 and 5, respectively. Outfield positive systematic cores were found in the contralateral lobe in one third of cases. Median device-time to obtain fusion imaging was 5 min and median biopsy duration was 15 min. Median difference in volume estimation between ultrasound and MRI auto-contouring was only 1 cc. Detection rate did not differ between experienced and novice, supervised users. Conclusions: in this initial prospective experience, fusion biopsies performed with UroFusion AI-driven auto-contouring system appeared time-efficient, accurate, well tolerated, and user-friendly, with comparable outcomes between experienced and novice users. Systematic biopsies remain highly recommended given the non-negligible rates of positive outfield cores. Full article

(This article belongs to the Special Issue Advances in Oncological Imaging (2nd Edition))

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27 pages, 3379 KiB

Open AccessArticle

Cutaneous T-Cell Lymphoma: Yin-Yang Effects of Transcription Factors HLF and NFIL3 in Regulation of Malignant T-Cell Markers in the Context of HDAC Inhibitor Romidepsin Treatment

by Andrew V. Kossenkov, Noor Dawany, Sonali Majumdar, Celia Chang, Calen Nichols, Maria Wysocka, Richard Piekarz, Michael K. Showe, Susan E. Bates, Alain H. Rook, Ellen J. Kim and Louise C. Showe

Cancers 2025, 17(14), 2380; https://doi.org/10.3390/cancers17142380 - 17 Jul 2025

Abstract

Background/Objectives: We examined the in vivo effects of successive treatments with the histone deacetylase (HDAC) inhibitor romidepsin in patients with cutaneous T-cell lymphoma (CTCL), using changes in gene expression in peripheral blood mononuclear cells (PBMCs). Methods: Exploiting data from a highly responsive CTCL [...] Read more.

Background/Objectives: We examined the in vivo effects of successive treatments with the histone deacetylase (HDAC) inhibitor romidepsin in patients with cutaneous T-cell lymphoma (CTCL), using changes in gene expression in peripheral blood mononuclear cells (PBMCs). Methods: Exploiting data from a highly responsive CTCL patient through 12 months of treatment, we identified a malignant cell predictor (MCP), a gene signature associated with the diminishing numbers of circulating malignant cells. Results: The MCP was successfully validated in the patient’s relapse sample 9 months after treatment was terminated and via an independent set of CTCL patient samples. Conclusions: The MCP set of genes contained novel CTCL markers, including membrane-associated proteins not normally expressed in lymphocytes. A subclass of those markers was also detectable in residual malignant cells undetected by flow cytometry in remission samples from a patient who relapsed 10 months later. We identified a subset of transcriptional regulators, miRNAs and methylation patterns associated with the effect of progressive treatments revealing potential mechanisms of transcriptional dysregulation and functional effects in the malignant cells. We demonstrate a role for transcriptional activator HLF, over-expressed in malignant cells, and downregulated transcriptional-suppressor and immune-modulator NFIL3, as regulators of CTCL-specific genes. Full article

(This article belongs to the Special Issue Cutaneous Lymphomas: From Pathology to Treatment)

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13 pages, 3490 KiB

Open AccessArticle

The Prognostic Role of Tertiary Lymphoid Structures and Immune Microenvironment Signatures in Early-Stage EGFR-Mutant Lung Adenocarcinoma

by Wei-Hsun Hsu, Chia-Chi Hsu, Min-Shu Hsieh and James Chih-Hsin Yang

Cancers 2025, 17(14), 2379; https://doi.org/10.3390/cancers17142379 - 17 Jul 2025

Abstract

Background/Objectives: The role of tertiary lymphoid structures (TLSs) in cancer prognosis is well established, yet their significance in early-stage EGFR-mutant lung adenocarcinoma remains unclear. While outcomes for early-stage lung cancer are generally better than those of late-stage disease, recurrence remains a significant [...] Read more.

Background/Objectives: The role of tertiary lymphoid structures (TLSs) in cancer prognosis is well established, yet their significance in early-stage EGFR-mutant lung adenocarcinoma remains unclear. While outcomes for early-stage lung cancer are generally better than those of late-stage disease, recurrence remains a significant challenge. This study investigates the prognostic value of TLSs and their molecular characteristics in early-stage EGFR-mutant lung adenocarcinoma. Methods: TLSs were identified in tumor samples using multiplex immunohistochemistry (IHC), and their density was quantified. The PD-L1 tumor proportion score (TPS) and TLS density were analyzed for associations with disease-free survival (DFS). Gene expression profiling was performed to compare tumor microenvironment signatures between high- and low-TLS-density groups. Results: High TLS density correlated with significantly longer DFS (43 vs. 20.5 months, p = 0.0082). No relationship was found between TLS density and PD-L1 TPS or EGFR mutation subtype. Transcriptomic analysis revealed upregulated immune response genes in the high-TLS-density group, including those involved in T and B cell activation. Low-TLS-density tumors exhibited gene signatures promoting tumor growth, such as cell cycle and WNT pathway activation. Conclusions: In summary, TLS density is a potential prognostic biomarker for DFS in early-stage EGFR-mutant lung adenocarcinoma, independent of PD-L1 TPS or EGFR mutation subtype. Enhanced immune activation in high-TLS-density tumors highlights TLSs as a potential target for improving outcomes in these patients. Full article

(This article belongs to the Section Molecular Cancer Biology)

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23 pages, 2349 KiB

Open AccessArticle

Prognostic Differences of Adjuvant Radiotherapy in Breast Cancer Cohorts Based on PRLR Genotypes, Expression, and Transcriptional Network Regulation

by Floor Munnik, Kelin Gonçalves de Oliveira, Christopher Godina, Karolin Isaksson and Helena Jernström

Cancers 2025, 17(14), 2378; https://doi.org/10.3390/cancers17142378 - 17 Jul 2025

Abstract

Background: Prolactin receptor (PRLR) signaling affects breastfeeding and potentially breast cancer treatment response. Methods: The prognostic impact of 20 PRLR single nucleotide polymorphisms (SNPs) in relation to adjuvant treatment groups in patients with primary breast cancer (n = 1701, 2002–2016, Sweden) was [...] Read more.

Background: Prolactin receptor (PRLR) signaling affects breastfeeding and potentially breast cancer treatment response. Methods: The prognostic impact of 20 PRLR single nucleotide polymorphisms (SNPs) in relation to adjuvant treatment groups in patients with primary breast cancer (n = 1701, 2002–2016, Sweden) was evaluated. Genomic DNA was genotyped on Illumina OncoArray, and survival analyses with up to 15-year follow-up were performed. Interaction models, adjusted for potential confounders, were created with different adjuvant treatment modalities: chemotherapy, radiotherapy, tamoxifen, and aromatase inhibitors. Results: Five SNPs (rs7734558, rs6860397, rs2962101, rs7732013, and rs4703503) showed interactions with radiotherapy and were utilized to create seven combined genotypes: six unique and one ‘rare’. Patients carrying combined genotype AG/GG/TT/CC/TC or ‘rare’ combinations derived greater benefits from radiotherapy than other patient groups (both HR_adj ≤ 0.29, Bonferroni-adjusted P_int ≤ 0.039). Expression Quantitative Trait Loci (eQTL) analysis revealed that three PRLR SNPs were associated with decreased PRLR expression. To explore potential SNP-associated effects, gene expression and transcriptional networks were analyzed in the METABRIC cohort and indicated that PRLR-low tumors were associated with reduced DNA repair signaling and enhanced anti-tumoral immunity. Conclusions: PRLR merits further evaluation as a putative pharmacogenomic biomarker in relation to radiotherapy for breast cancer patients. Full article

(This article belongs to the Special Issue Transcription Factors in Breast Cancer)

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4 pages, 779 KiB

Open AccessCorrection

Correction: Hung et al. Cul4A Modulates Invasion and Metastasis of Lung Cancer through Regulation of ANXA10. Cancers 2019, 11, 618

by Ming-Szu Hung, Yi-Chuan Chen, Paul-Yann Lin, Ya-Chin Li, Chia-Chen Hsu, Jr-Hau Lung, Liang You, Zhidong Xu, Jian-Hua Mao, David M. Jablons and Cheng-Ta Yang

Cancers 2025, 17(14), 2377; https://doi.org/10.3390/cancers17142377 - 17 Jul 2025

Abstract

In the original publication [...] Full article

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16 pages, 2108 KiB

Open AccessArticle

Decoding the JAK-STAT Axis in Colorectal Cancer with AI-HOPE-JAK-STAT: A Conversational Artificial Intelligence Approach to Clinical–Genomic Integration

by Ei-Wen Yang, Brigette Waldrup and Enrique Velazquez-Villarreal

Cancers 2025, 17(14), 2376; https://doi.org/10.3390/cancers17142376 - 17 Jul 2025

Abstract

Background/Objectives: The Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway is a critical mediator of immune regulation, inflammation, and cancer progression. Although implicated in colorectal cancer (CRC) pathogenesis, its molecular heterogeneity and clinical significance remain insufficiently characterized—particularly within early-onset CRC [...] Read more.

Background/Objectives: The Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway is a critical mediator of immune regulation, inflammation, and cancer progression. Although implicated in colorectal cancer (CRC) pathogenesis, its molecular heterogeneity and clinical significance remain insufficiently characterized—particularly within early-onset CRC (EOCRC) and across diverse treatment and demographic contexts. We present AI-HOPE-JAK-STAT, a novel conversational artificial intelligence platform built to enable the real-time, natural language-driven exploration of JAK/STAT pathway alterations in CRC. The platform integrates clinical, genomic, and treatment data to support dynamic, hypothesis-generating analyses for precision oncology. Methods: AI-HOPE-JAK-STAT combines large language models (LLMs), a natural language-to-code engine, and harmonized public CRC datasets from cBioPortal. Users define analytical queries in plain English, which are translated into executable code for cohort selection, survival analysis, odds ratio testing, and mutation profiling. To validate the platform, we replicated known associations involving JAK1, JAK3, and STAT3 mutations. Additional exploratory analyses examined age, treatment exposure, tumor stage, and anatomical site. Results: The platform recapitulated established trends, including improved survival among EOCRC patients with JAK/STAT pathway alterations. In FOLFOX-treated CRC cohorts, JAK/STAT-altered tumors were associated with significantly enhanced overall survival (p < 0.0001). Stratification by age revealed survival advantages in younger (age < 50) patients with JAK/STAT mutations (p = 0.0379). STAT5B mutations were enriched in colon adenocarcinoma and correlated with significantly more favorable trends (p = 0.0000). Conversely, JAK1 mutations in microsatellite-stable tumors did not affect survival, emphasizing the value of molecular context. Finally, JAK3-mutated tumors diagnosed at Stage I–III showed superior survival compared to Stage IV cases (p = 0.00001), reinforcing stage as a dominant clinical determinant. Conclusions: AI-HOPE-JAK-STAT establishes a new standard for pathway-level interrogation in CRC by empowering users to generate and test clinically meaningful hypotheses without coding expertise. This system enhances access to precision oncology analyses and supports the scalable, real-time discovery of survival trends, mutational associations, and treatment-response patterns across stratified patient cohorts. Full article

(This article belongs to the Special Issue AI-Based Applications in Cancers)

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13 pages, 1000 KiB

Open AccessArticle

The Emerging Role of Left Atrial Strain in Cardiovascular Risk Stratification for Multiple Myeloma Patients Undergoing Carfilzomib Therapy

by Anna Colomba, Lorenzo Airale, Alice Lasagno, Giulia Mingrone, Anna Astarita, Fabrizio Vallelonga, Dario Leone, Martina Sanapo, Arianna Paladino, Francesca Novello, Sara Bringhen, Francesca Gay, Franco Veglio and Alberto Milan

Cancers 2025, 17(14), 2375; https://doi.org/10.3390/cancers17142375 - 17 Jul 2025

Abstract

Background: Carfilzomib (CFZ) is a proteasome inhibitor with known cardiotoxic effects used in multiple myeloma (MM) treatment. Cardio-oncology guidelines recommend cardiovascular risk assessment via echocardiography. Left atrial strain (LAS) is not yet included as a marker of cardiotoxicity, but it is emerging as [...] Read more.

Background: Carfilzomib (CFZ) is a proteasome inhibitor with known cardiotoxic effects used in multiple myeloma (MM) treatment. Cardio-oncology guidelines recommend cardiovascular risk assessment via echocardiography. Left atrial strain (LAS) is not yet included as a marker of cardiotoxicity, but it is emerging as a potential indicator of cardiac dysfunction. Objective: This study evaluates LAS as a predictor of CFZ-related hypertensive cardiovascular adverse events (CVAEs) in MM patients, with or without prior hypertension. Methods: A total of 125 MM patients treated with CFZ at the Hypertension Center, “Città della Salute e della Scienza” in Turin, were enrolled. Baseline assessments included transthoracic echocardiography for LAS analysis via Philips QLAB software. Results: During CFZ therapy, 52% of patients experienced hypertensive events. LAS conduit was significantly impaired in those who experienced CVAEs (−16.20 [−20.75; −12.65] vs. −20.80 [−26.30; −15.40], p = 0.006) and LAS conduit > −22 acted as a predictor of hypertensive adverse events in the normotensive population (OR 2.37 [1.02; 5.50]). Conclusion: These findings indicate that alterations in LAS conduit are linked to an increased risk of hypertensive adverse events during CFZ treatment. Incorporating LAS measurement into cardiovascular risk assessments may improve personalized risk stratification for MM patients, especially those without pre-existing hypertension. Full article

(This article belongs to the Special Issue Cardio-Oncology: An Emerging Paradigm in Modern Medicine: 2nd Edition)

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23 pages, 860 KiB

Open AccessArticle

Trends in Cancer Incidence and Associated Risk Factors in People Living with and Without HIV in Botswana: A Population-Based Cancer Registry Data Analysis from 1990 to 2021

by Anikie Mathoma, Gontse Tshisimogo, Benn Sartorius and Saajida Mahomed

Cancers 2025, 17(14), 2374; https://doi.org/10.3390/cancers17142374 - 17 Jul 2025

Abstract

Background: With a high human immunodeficiency virus (HIV) adult prevalence, people living with HIV (PLHIV) in Botswana continue to experience a high burden of comorbid HIV and cancer. We sought to investigate the trends of acquired immunodeficiency syndrome (AIDS) defining cancers (ADCs), [...] Read more.

Background: With a high human immunodeficiency virus (HIV) adult prevalence, people living with HIV (PLHIV) in Botswana continue to experience a high burden of comorbid HIV and cancer. We sought to investigate the trends of acquired immunodeficiency syndrome (AIDS) defining cancers (ADCs), non-AIDS defining cancers (NADCs), and associated risk factors in PLHIV compared with those without HIV. Methods: We analyzed data from adults aged ≥18 years reported in Botswana National Cancer Registry and National Data Warehouse. The crude, age-standardized incidence rate (ASIR), standardized incidence ratios (SIRs) of cancers and time trends were computed. Risk factors were determined using the Cox-regression model. Results: Over a 30-year period, 27,726 cases of cancer were documented. Of these, 13,737 (49.5%) were PLHIV and 3505 (12.6%) were people without HIV and 10,484 (37.8%) had an unknown HIV status. Compared to the HIV-uninfected, the PLHIV had higher and increasing trends in the cancer incidence overall during the study period (from 44.2 to 1047.6 per 100,000; p-trend < 0.001) versus (from 1.4 to 27.2 per 100,000; p-trend < 0.001). The ASIRs also increased in PLHIV for overall ADCs, NADCs and other sub-types like cervical, lung, breast, and conjunctiva cancers (p-trend < 0.001). Further, PLHIV had elevated SIRs for cervical cancer, Kaposi sarcoma in males and some NADCs. The most common risk factors were HIV infection and female sex for ADCs incidence and advanced age and being HIV-uninfected for NADCs incidence. Conclusions: Increasing trends of ADCs and NADCs during ART expansion were observed among PLHIV compared to those without HIV highlighting a greater need for targeted effective prevention and screening strategies including the provision of access to timely HIV and cancer treatment. Full article

(This article belongs to the Section Cancer Epidemiology and Prevention)

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14 pages, 486 KiB

Open AccessReview

Bisphenol A Promotes the Progression of Hormone-Sensitive Breast Cancers Through Several Inflammatory Pathways

by Michael Thoene, Kamila Zglejc-Waszak, Marcin Jozwik and Joanna Wojtkiewicz

Cancers 2025, 17(14), 2373; https://doi.org/10.3390/cancers17142373 - 17 Jul 2025

Abstract

Background/Objectives: Bisphenol A (BPA) is found throughout the environment and exposure to it has been shown to cause several health problems, including cancer. The problem with BPA is that it is a xenoestrogen that is chemically very similar to 17β-estradiol. Chronic exposure [...] Read more.

Background/Objectives: Bisphenol A (BPA) is found throughout the environment and exposure to it has been shown to cause several health problems, including cancer. The problem with BPA is that it is a xenoestrogen that is chemically very similar to 17β-estradiol. Chronic exposure to BPA overstimulates the estrogen receptors and leads to inflammation that triggers several pathways leading to cancer progression. This is especially true in the case of hormone-sensitive breast cancers. This article reviewed the main pathways thought to be involved in the formation and/or progression of the most common forms of hormone-sensitive breast cancers due to BPA exposure. The main results were compiled and presented in tables along with a more detailed discussion of each pathway within the text. In most cases, chronic BPA exposure led to inflammation, which then triggered pathways leading to cancer stem cell formation and maintenance. In other cases, BPA exposure led to the formation of reactive oxygen species that damaged DNA and caused the formation of mutated p53 and tumorigenesis. Conclusions: The article summarizes the key pathways that are currently known, pertaining to how BPA leads to the progression and maintenance of breast cancer. The article then concludes by discussing how prenatal and perinatal BPA exposure may also predispose women to hormone-sensitive breast cancers later in life. Full article

(This article belongs to the Special Issue Epidemiology of Cancer and Risk Factors: Pushing Boundaries in Public Health Research and Policy)

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12 pages, 1044 KiB

Open AccessArticle

Therapeutic Efficacy of a Very Low/Low Dose of Lenvatinib in Advanced Radioiodine-Refractory Thyroid Cancer: A Real-World Series from a Single Center

by Vittorio Oteri, Fiorenza Gianì, Giulia Sapuppo, Stefania Panebianco, Ilenia Marturano, Giusi Blanco, Pasqualino Malandrino, Marco Russo, Francesco Frasca and Gabriella Pellegriti

Cancers 2025, 17(14), 2372; https://doi.org/10.3390/cancers17142372 - 17 Jul 2025

Abstract

Background: Lenvatinib is a receptor tyrosine kinase inhibitor indicated for advanced radioiodine-refractory thyroid cancer (RAI-RTC). It is recommended to start at 24 mg per day; however, in patients who are at risk of severe adverse events, it may be reasonable to start at [...] Read more.

Background: Lenvatinib is a receptor tyrosine kinase inhibitor indicated for advanced radioiodine-refractory thyroid cancer (RAI-RTC). It is recommended to start at 24 mg per day; however, in patients who are at risk of severe adverse events, it may be reasonable to start at lower doses. Patients and Methods: We included 15 patients with RAI-RTC who started lenvatinib at a very low/low dose and evaluated the efficacy and safety. Results: Eight patients (53.3%) did not show progression of the disease, and about half of the patients (53.3%) were alive at the last follow-up visit. Up to 26.6% of patients achieved a partial response to therapy, with a notable volume reduction in the local and metastatic lesions. However, 80% of patients experienced adverse events, mainly of a moderate grade. Conclusions: Although these findings are based on a small sample size and a single-center study, treatment with lenvatinib at very low/low doses in fragile patients seems to be a promising strategy for the management of RAI-RTC, balancing effective disease control with a favorable safety profile. Full article

(This article belongs to the Section Cancer Pathophysiology)

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