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Cancers, Volume 17, Issue 14 (July-2 2025) – 125 articles

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16 pages, 2015 KiB  
Systematic Review
Immunotherapy and Advanced Vulvar Cancer: A Systematic Review and Meta-Analysis of Survival and Safety Outcomes
by Mauro Francesco Pio Maiorano, Vera Loizzi, Gennaro Cormio and Brigida Anna Maiorano
Cancers 2025, 17(14), 2392; https://doi.org/10.3390/cancers17142392 (registering DOI) - 19 Jul 2025
Abstract
Background: Advanced and recurrent vulvar squamous cell carcinoma (VSCC) presents a major therapeutic challenge with limited treatment options and poor outcomes. Immune checkpoint inhibitors (ICIs) have shown efficacy in other HPV-associated malignancies, but their role in VSCC remains poorly defined due to [...] Read more.
Background: Advanced and recurrent vulvar squamous cell carcinoma (VSCC) presents a major therapeutic challenge with limited treatment options and poor outcomes. Immune checkpoint inhibitors (ICIs) have shown efficacy in other HPV-associated malignancies, but their role in VSCC remains poorly defined due to the rarity of the disease and limited clinical trial data. Methods: We conducted a systematic review and meta-analysis following PRISMA guidelines and registered in PROSPERO (CRD420251067565). A comprehensive literature search identified prospective clinical trials evaluating ICIs in patients with advanced, unresectable, recurrent, or metastatic VSCC. The primary outcomes included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Risk of bias was assessed using the MINORS tool. Meta-analyses were performed using random-effects models, with subgroup analyses based on PD-L1 status and treatment regimens (monotherapy vs. combination therapy). Results: Six non-randomized single-arm trials involving 181 patients were included. The pooled ORR was 21%, with higher response rates observed in combination therapy (46%) compared to monotherapy (11%), though not statistically significant. Median PFS and OS were 2.2 months and 6.4 months, respectively. ORRs were similar between PD-L1-positive and PD-L1-negative subgroups. A safety analysis showed treatment-related adverse events (AEs) in 73% of patients and grade ≥ 3 AEs in 23%. The incidence of treatment-related death was 3%. Conclusions: ICIs demonstrate modest but durable efficacy and an acceptable safety profile in advanced VSCC. The current evidence supports their use in selected patients. However, response variability and the lack of reliable predictive biomarkers, such as PD-L1 or HPV status, underscore the need for biomarker-driven clinical trials and improved patient selection strategies. Full article
(This article belongs to the Topic New Advancements in Innate Immunity and Cancer Immunotherapy)
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25 pages, 828 KiB  
Review
Platelets in Hepatocellular Carcinoma—From Pathogenesis to Targeted Therapy
by Natalia Kluz, Hanna Grabowska, Paulina Chmiel, Kornelia Rynkiewicz, Alicja Skrobucha, Ewa Wysokińska, Łukasz Szymański, Piotr Tomasz Wysocki, Aleksandra Semeniuk-Wojtaś and Leszek Kraj
Cancers 2025, 17(14), 2391; https://doi.org/10.3390/cancers17142391 - 18 Jul 2025
Abstract
Hepatocellular carcinoma (HCC) is a malignancy with a complex pathogenesis, course, and prognosis with increasing incidence. The most significant contributing factor to the development of HCC is the chronic process of inflammation and remodeling of the cirrhotic liver, in which the interaction between [...] Read more.
Hepatocellular carcinoma (HCC) is a malignancy with a complex pathogenesis, course, and prognosis with increasing incidence. The most significant contributing factor to the development of HCC is the chronic process of inflammation and remodeling of the cirrhotic liver, in which the interaction between the tumor microenvironment (TME) and cancer cells plays a pivotal role. In recent years, increasing focus has been directed toward the role of platelets (PLTs) in mediating interactions between tumor cells and the TME and in the progression and spread of HCC, as well as other cancers. Due to their abundance in the bloodstream and intracellular granules rich in mediators facilitating their ability to modulate the immune system, PLTs play a significant role in carcinogenesis. In the context of HCC, the role of PLTs in the healing and regeneration processes of the liver has been recognized for some time. In recent years, there has been an increasing utilization of PLTs in prognostic models for patients with HCC. Given their role and the availability of clinical options that block PLTs’ action, clinical trials of platelet blockers in the adjunctive treatment of HCC are becoming increasingly common. However, further research, both preclinical and clinical, is necessary to fully elucidate the role of PLTs in HCC and their potential use as a therapeutic target. In this literature review, we summarize the current knowledge on PLTs in HCC and focus on their potential use in everyday clinical practice. Full article
(This article belongs to the Special Issue Treatment Response Biomarkers in Hepatocellular Carcinoma: From Basic Science to Clinical Validation)
19 pages, 1536 KiB  
Article
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  
Article
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  
Review
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  
Editorial
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  
Article
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  
Article
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  
Article
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  
Article
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  
Article
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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9 pages, 941 KiB  
Article
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  
Article
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  
Article
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  
Article
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 HRadj ≤ 0.29, Bonferroni-adjusted Pint ≤ 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  
Correction
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  
Article
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  
Article
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  
Article
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  
Review
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  
Article
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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13 pages, 505 KiB  
Systematic Review
Microsurgical Reconstruction with Free Tissue Transfer in Skin Cancer Patients: A Systematic Review
by Tito Brambullo, Stefano L’Erario, Francesco Marena, Roberta Carpenito, Alfio Luca Costa, Vincenzo Vindigni and Franco Bassetto
Cancers 2025, 17(14), 2371; https://doi.org/10.3390/cancers17142371 - 17 Jul 2025
Abstract
Background/Objectives: The gold standard of treatment for both melanoma and non-melanoma skin cancers is wide surgical resection to obtain oncological radicality, which occasionally results in functional or aesthetic impairment, potentially affecting quality of life. Despite the increased complexity of the technique, extended duration [...] Read more.
Background/Objectives: The gold standard of treatment for both melanoma and non-melanoma skin cancers is wide surgical resection to obtain oncological radicality, which occasionally results in functional or aesthetic impairment, potentially affecting quality of life. Despite the increased complexity of the technique, extended duration of hospitalization, and prolonged surgical operative times, microsurgery can facilitate the reconstruction of locally invasive skin cancers following ablative surgery and may yield superior functional and aesthetic outcomes. Consequently, microsurgical reconstruction is more likely to be necessary if a large skin tumor requires excision. However, the impact of this extensive and complex procedure on patients with skin cancer has not yet been fully elucidated. The objective of this research was to critically analyze the utilization of free flap reconstruction subsequent to skin cancer therapy. Through a comprehensive examination of published data, this study aimed to assess the potential benefits and drawbacks associated with this reconstructive approach. Methods: A systematic review of studies that were published from January 2004 to May 2024 was conducted using the MEDLINE online database search. To present an evidence summary and provide a systematic approach and quality assessment, the GRADE® rating was applied to the results. Results: This review summarizes the oncological and clinical data, including previous interventions, adjuvant and neoadjuvant therapies, nodal status, distant metastasis, and follow-up time. Surgical outcome parameters such as healing time, flap survival, revision rate success, and minor and major complications were documented. Along with the findings, a quality assessment of the studies was also provided. Conclusions: This systematic review underscores the extensive use and efficacy of microsurgery for reconstruction after skin cancer excision; however, the literature remains limited by inconsistent reporting of oncological outcomes and the lack of a standardized approach to evaluate the impact of free flap reconstruction on both immediate and long-term cancer-specific results. Full article
(This article belongs to the Special Issue New Concepts and Recent Advances in the Management of Skin Cancer)
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12 pages, 818 KiB  
Article
Risk Factors for Arterial Thromboembolic Events in Male Germ Cell Tumors Treated with Chemotherapy
by Daniele Frisone, Melinda Charrier, Grégoire Berthod, Sara Manzocchi-Besson, Daniel Danzer, Sandro Anchisi and Petros Tsantoulis
Cancers 2025, 17(14), 2370; https://doi.org/10.3390/cancers17142370 - 17 Jul 2025
Abstract
Background/Objectives: Germ cell tumors are the most common neoplasia in males < 50 y. In two case series, thromboembolic events (TEs) were reported in 8% and 13% of patients undergoing chemotherapy, whereas arterial thromboembolic events (ATEs) in other types of cancer treated with [...] Read more.
Background/Objectives: Germ cell tumors are the most common neoplasia in males < 50 y. In two case series, thromboembolic events (TEs) were reported in 8% and 13% of patients undergoing chemotherapy, whereas arterial thromboembolic events (ATEs) in other types of cancer treated with cisplatin had a frequency of 2% in a retrospective series and 0.67% in a meta-analysis. Recent data found a frequency of 2.4% for ATE in a large cohort of testicular cancer patients. Risk factors are not clearly identified, and given the severity of these events, further exploration is needed to determine appropriate preventive measures. Methods: We performed a retrospective cohort study of 171 patients undergoing chemotherapy for germ cell tumors in two centers in Switzerland and recorded the occurrence of ATE or venous thromboembolic events (VTEs) during chemotherapy or in the 3 months after its completion. Results: of 171 patients, 33.3% underwent adjuvant chemotherapy for stage I disease. Overall, 32 patients had a TE (18.7%, 95% CI 13.3–25.5%), 26 (15.2%, 95% CI 10.3–21.7%) had VTEs, and 11 (6.4%, 95% CI 3.4–11.5%) had ATEs. Five patients had both a VTE and ATE. VTEs were associated with disease stage (II, III, or relapse, with OR 15.6, p = 0.0002), retroperitoneal lymph nodes ≥ 3.5 cm (OR 3.2, p = 0.012), LDH > 500 UI/L (OR 5.3, p = 0.0025), and age > 35 y (OR 3.4, p = 0.005). The Khorana Score (KS) varied between 1 and 2 in 96% of the patients. ATEs were associated with active smoking (OR 6.5 p = 0.010), KS of ≥2 (OR 6.4 p = 0.004), and age > 35 y (OR 6.3, p = 0.01). Conclusions: Our findings show that ATEs are more frequent in our cohort than previous reports. We found a strong association between smoking and ATEs, which should be further assessed. Platinum-induced endothelial damage may be amplified by smoking in young patients in the absence of other risk factors and preventive medication. Full article
(This article belongs to the Special Issue Quality of Life and Side Effects Management in Cancer Treatment (3rd Edition))
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14 pages, 1413 KiB  
Article
NRG Oncology Liver Proton SBRT and Hypofractionated Radiation Therapy: Current Treatment Technical Assessment and Practice Patterns
by Minglei Kang, Paige A. Taylor, Jiajian Shen, Jun Zhou, Jatinder Saini, Theodore S. Hong, Kristin Higgins, Wei Liu, Ying Xiao, Charles B. Simone II and Liyong Lin
Cancers 2025, 17(14), 2369; https://doi.org/10.3390/cancers17142369 - 17 Jul 2025
Abstract
Background/Objectives: Proton therapy delivers highly conformal doses to the target area without producing an exit dose, minimizing cumulative doses to healthy liver tissue. This study aims to evaluate current practices, challenges, and variations in the implementation of proton stereotactic body radiation therapy (SBRT) [...] Read more.
Background/Objectives: Proton therapy delivers highly conformal doses to the target area without producing an exit dose, minimizing cumulative doses to healthy liver tissue. This study aims to evaluate current practices, challenges, and variations in the implementation of proton stereotactic body radiation therapy (SBRT) and hypofractionated therapy for liver malignancies, with the goal of providing a technical assessment to promote broader adoption and support future clinical trials. Methods and Materials: An extensive survey was conducted by NRG Oncology across North American proton treatment centers to assess the current practices of proton liver SBRT and hypofractionated therapy. The survey focused on key aspects, including patient selection, prescription and normal tissue constraints, simulation and motion management, treatment planning, quality assurance (QA), treatment delivery, and the use of image-guided radiation therapy (IGRT). Results: This survey captures the current practice patterns and status of proton SBRT and hypofractionated therapy in liver cancer treatment.  Proton therapy is increasingly preferred for treating inoperable liver malignancies due to its ability to minimize healthy tissue exposure. However, the precision required for proton therapy presents challenges, particularly in managing uncertainties and target motion during high-dose fractions and short treatment courses. Survey findings revealed significant variability in clinical practices across centers, highlighting differences in motion management, dose fractionation schedules, and QA protocols. Conclusion: Proton SBRT and hypofractionated therapy offer significant potential for treating liver malignancies. A comprehensive approach involving precise patient selection, treatment planning, and QA is essential for ensuring safety and effectiveness. This survey provides valuable insights into current practices and challenges, offering a foundation for technical recommendations to optimize the use of proton therapy and guide future clinical trials. Full article
(This article belongs to the Special Issue Proton Therapy of Cancer Treatment)
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11 pages, 484 KiB  
Article
Breast Edema After Breast-Conserving Surgery and Radiotherapy: Introduction of a Clinically Meaningful Classification and Evaluation of the Incidence After Normo- and Hypofractionated Treatments
by Melsa Rojin Oyur, Robert Maximilian Blach, Hans Christiansen, Roland Merten, Jan-Niklas Becker, Anne Caroline Knöchelmann, Mirko Nitsche, Robert Michael Hermann and Mathias Alexander Sonnhoff
Cancers 2025, 17(14), 2368; https://doi.org/10.3390/cancers17142368 - 16 Jul 2025
Viewed by 102
Abstract
BE following RT after breast-conserving surgery is a common concern, impacting patients’ quality of life. This study introduces a clinically meaningful classification system for BE and retrospectively evaluates its incidence among patients treated with normofractionated (nfRT) and hypofractionated (hfRT) regimens. Data from 1156 [...] Read more.
BE following RT after breast-conserving surgery is a common concern, impacting patients’ quality of life. This study introduces a clinically meaningful classification system for BE and retrospectively evaluates its incidence among patients treated with normofractionated (nfRT) and hypofractionated (hfRT) regimens. Data from 1156 patients treated between 2011 and 2021 were analyzed. BE was graded according to the CTC and a so-called “WST classification” (grade 1: lymphatic drainage performed by the patient; grade 2: professional lymphatic drainage; grade 3: surgery). A total of 33%/17% developed BE according to the WST classification/CTC. Grade III BE was not reported. About 70% experienced a remission of BE during follow-up. Risk factors for the development of BE included RT of lymphatic drainage, complete axillary dissection compared to sentinel node dissection, and CTX. CTX was not confirmed in multivariate analysis. The incidence of BE did not differ significantly between the nfRT and hfRT groups, affirming the safety and comparability of hfRT regarding BE risk (HR: 0.833, p = 0.1219). This study emphasizes the importance of precise and standardized BE classification for improved treatment outcomes. Given its comparable risk profile and potential for enhanced therapy adherence, the findings support hfRT as a preferred regimen aligned with the current guidelines. Full article
(This article belongs to the Section Cancer Therapy)
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28 pages, 2365 KiB  
Systematic Review
The Roles of Tripartite Motif Proteins in Urological Cancers: A Systematic Review
by Yuta Yamada, Naoki Kimura, Kazuki Maki, Yuji Hakozaki, Fumihiko Urabe, Shoji Kimura, Tetsuya Fujimura, Satoshi Inoue and Haruki Kume
Cancers 2025, 17(14), 2367; https://doi.org/10.3390/cancers17142367 - 16 Jul 2025
Viewed by 39
Abstract
We aimed to investigate the roles of tripartite motif (TRIM) proteins in urological cancers. Methods: A systematic review was conducted to investigate the oncological role of tripartite motif proteins in urological cancers. Results: A total of 84 articles were identified for [...] Read more.
We aimed to investigate the roles of tripartite motif (TRIM) proteins in urological cancers. Methods: A systematic review was conducted to investigate the oncological role of tripartite motif proteins in urological cancers. Results: A total of 84 articles were identified for the final analysis (26 articles on kidney cancers, 19 on bladder cancers, 37 on prostate cancers, and 1 on testicular cancers). In total, 27 TRIM family proteins were involved in kidney cancer, of which 9 were associated with tumor-promoting findings (TRIM24, TRIM27, TRIM37, TRIM44, TRIM46, TRIM47, TRIM59, TRIM63, and TRIM65) and of which 9 TRIM proteins were tumor-suppressive (TRIM2, TRIM7, TRIM8, TRIM13, TRIM21, TRIM26, TRIM28, TRIM33, and TRIM58). Fourteen TRIM family proteins were associated with bladder cancer (tumor-promoting: TRIM9, TRIM25, TRIM26, TRIM28, TRIM29, TRIM59, TRIM65, and TRIM66; tumor-suppressive: TRIM19 and TRIM38). Ten TRIM family proteins were associated with prostate cancer (tumor-promoting: TRIM11, TRIM24, TRIM28, TRIM33, TRIM44, TRIM59, TRIM63, TRIM66, and TRIM68; tumor-suppressive: TRIM32 and TRIM36). Twenty-eight TRIM family proteins were identified to be associated with prostate cancer (tumor-promoting: TRIM11, TRIM24, TRIM28, TRIM33, TRIM44, TRIM59, TRIM63, TRIM66, and TRIM68; tumor-suppressive: TRIM32 and TRIM36). TRIM proteins regulate urological cancers by ubiquitination or modulation of oncologic pathways. Conclusions: This review identifies TRIM proteins that are involved in urological cancers. Some of these proteins have the potential to be the therapeutic target. Full article
(This article belongs to the Section Systematic Review or Meta-Analysis in Cancer Research)
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21 pages, 2238 KiB  
Review
Cell-Free DNA as a Prognostic Biomarker in Oral Carcinogenesis and Oral Squamous Cell Carcinoma: A Translational Perspective
by Pietro Rigotti, Alessandro Polizzi, Vincenzo Quinzi, Andrea Blasi, Teresa Lombardi, Eleonora Lo Muzio and Gaetano Isola
Cancers 2025, 17(14), 2366; https://doi.org/10.3390/cancers17142366 - 16 Jul 2025
Viewed by 109
Abstract
Oral squamous cell carcinoma (OSCC) remains one of the most common malignancies in the head and neck region, often preceded by a spectrum of oral potentially malignant disorders (OPMDs). Despite advances in diagnostic methods, reliable and non-invasive biomarkers for early detection and prognostic [...] Read more.
Oral squamous cell carcinoma (OSCC) remains one of the most common malignancies in the head and neck region, often preceded by a spectrum of oral potentially malignant disorders (OPMDs). Despite advances in diagnostic methods, reliable and non-invasive biomarkers for early detection and prognostic stratification are still lacking. In recent years, circulating cell-free DNA (cfDNA) has emerged as a promising liquid biopsy tool in several solid tumors, offering insights into tumor burden, heterogeneity, and molecular dynamics. However, its application in oral oncology remains underexplored. This study aims to review and discuss the current evidence on cfDNA quantification and mutation analysis (including TP53, NOTCH1, and EGFR) in patients with OPMDs and OSCC. Particular attention is given to cfDNA fragmentation patterns, methylation signatures, and tumor-specific mutations as prognostic and predictive biomarkers. Moreover, we highlight the challenges in standardizing pre-analytical and analytical workflows in oral cancer patients and explore the potential role of cfDNA in monitoring oral carcinogenesis. Understanding cfDNA dynamics in the oral cavity might offer a novel, minimally invasive strategy to improve early diagnosis, risk assessment, and treatment decision-making in oral oncology. Full article
(This article belongs to the Special Issue Cell-Free DNA as Prognostic and Predictive Biomarker in Solid Cancers (2nd Edition))
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23 pages, 3053 KiB  
Article
MICA+ Tumor Cells Modulate Macrophage Phenotype and Function via PPAR/EHHADH-Mediated Fatty Acid Metabolism in Hepatocellular Carcinoma (HCC)
by Jingquan Huang, Yumeng Teng, Peng Yan, Yan Yang, Shixun Lin, Qiulin Wu, Qiang Du, Xicai Li, Ming Yao, Jianjun Li, Yubin Huang, Xiaoyong Cai, David A. Geller and Yihe Yan
Cancers 2025, 17(14), 2365; https://doi.org/10.3390/cancers17142365 - 16 Jul 2025
Viewed by 110
Abstract
Background: Tumor-associated macrophages (TAMs) play a crucial role in the tumor microenvironment (TME), and the metabolic activities of both tumor cells and TAMs have an impact on the TME. Moreover, the expression of MICA in tumor cells is closely associated with immune cells [...] Read more.
Background: Tumor-associated macrophages (TAMs) play a crucial role in the tumor microenvironment (TME), and the metabolic activities of both tumor cells and TAMs have an impact on the TME. Moreover, the expression of MICA in tumor cells is closely associated with immune cells in hepatocellular carcinoma (HCC). However, it remains unclear whether MICA expression correlates with TAMs and influences the switch in macrophage phenotype by mediating metabolic alterations. Methods: Various biostatistical tools, qPCR, and IHC staining experiments were utilized to analyze data from The Cancer Genome Atlas (TCGA) and collected HCC tumor tissues. Single-cell RNA sequencing (scRNA-seq) analyses and a co-culture model of HCC cells with macrophages were performed to validate the findings from the biostatistical analyses. Results: Through the intersection of differentially expressed genes (DEGs), metabolism-related genes (MRGs), and co-expression genes (CEGs) with MICA in HCC, the EHHADH gene was identified. Gene set enrichment analyses were conducted to further confirm the role of EHHADH. EHHADH expression is decreased in HCC tumors and can serve as a prognostic biomarker for HCC. Expressions of MICA and EHHADH exhibited significant correlations with various phenotypic macrophages and exerted opposing effects on M1-like and M2-like macrophages infiltrating HCC. The underlying metabolic and molecular mechanisms revealed that MICA in tumor cells induced M2-like polarization through the PPAR/EHHADH pathway, which regulates the fatty acid oxidation (FAO) in macrophages. Conclusions: The metabolic gene EHHADH, which is associated with MICA, led to alterations in M2-like macrophages by promoting heightened fatty acid uptake and augmenting levels of FAO within macrophages. Full article
(This article belongs to the Section Tumor Microenvironment)
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20 pages, 1063 KiB  
Review
ANGPTL4: A Comprehensive Review of 25 Years of Research
by Pedro Ramos, Qiongyu Shi, Jeremy Kleberg, Chandra K. Maharjan, Weizhou Zhang and Ryan Kolb
Cancers 2025, 17(14), 2364; https://doi.org/10.3390/cancers17142364 - 16 Jul 2025
Viewed by 191
Abstract
Angiopoietin-like 4 (ANGPTL4) is a secreted glycoprotein that was discovered in 2000 by three independent laboratories. In the ensuing two and a half decades, extensive work has been conducted to determine its physiological and pathological functions. ANGPTL4 has been shown to be involved [...] Read more.
Angiopoietin-like 4 (ANGPTL4) is a secreted glycoprotein that was discovered in 2000 by three independent laboratories. In the ensuing two and a half decades, extensive work has been conducted to determine its physiological and pathological functions. ANGPTL4 has been shown to be involved in many biological processes, including glucose and lipid metabolism, angiogenesis, and wound healing, with implications in diseases such as type 2 diabetes, cardiovascular (e.g., atherosclerosis) and renal diseases, and cancer. For instance, ANGPTL4 is upregulated in several cancers, including renal cell carcinoma, breast cancer, and colorectal cancer. Interestingly, ANGPTL4 has been shown to exhibit both pro-tumor—promoting tumor growth, cell survival, angiogenesis and metastasis—as well as anti-tumor activities, underscoring its complex roles in cancer biology. This review examines the comprehensive biological functions of ANGPTL4 and its contributions to disease mechanisms with a specific emphasis on cancer, as well as its potential as a therapeutic target across different types of human cancers. Full article
(This article belongs to the Section Molecular Cancer Biology)
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23 pages, 2406 KiB  
Article
Ex Vivo Drug Sensitivity of Pleural Effusion-Derived Cells from Lung Cancer and Pleural Mesothelioma Patients Is Linked to Clinical Response
by Rita Hutyra-Gram Ötvös, Hanna Krynska, Greta Gudoityte, Marcus Skribek, Anca Oniscu, Olena Berkovska, Katharina Strauß, Jenny Zipprick, David Tamborero, Andrey Alexeyenko, Annica Karin Britt Gad, Brinton Seashore-Ludlow and Katalin Dobra
Cancers 2025, 17(14), 2363; https://doi.org/10.3390/cancers17142363 - 16 Jul 2025
Viewed by 123
Abstract
Background: Tumors of the pleura, such as metastatic lung cancer and mesothelioma, are amongst the most lethal and therapy-resistant tumors. The first manifestation of the disease is often pleural effusion, the first available material for diagnosis. The five-year survival rate is exceptionally low, [...] Read more.
Background: Tumors of the pleura, such as metastatic lung cancer and mesothelioma, are amongst the most lethal and therapy-resistant tumors. The first manifestation of the disease is often pleural effusion, the first available material for diagnosis. The five-year survival rate is exceptionally low, around 10–20%, and only a small proportion of patients harbor mutations that allow targeted treatments. Almost all patients develop resistance to treatment, which is often palliative. There is therefore an urgent need to refine the selection of drugs and patients for personalized treatment. Methods: We isolated and cultured cells from pleural effusions in 3D cell aggregates and compared their drug sensitivity ex vivo to the clinical response to the same chemotherapeutic agents, combined with targeted sequencing and network analysis. Results: The ex vivo drug response showed a positive correlation with the treatment response and survival of patients in the clinic, with a stronger link to overall survival than to progression-free survival. Cryopreserved cells showed a similar response to freshly collected cells from the clinic. Conclusions: The findings advance the field of ex vivo screening and present an opportunity to combine strategies for functional precision medicine with comprehensive characterization of disease for improved treatment and future management of lung cancer. Full article
(This article belongs to the Special Issue Pre-Clinical Studies of Personalized Medicine for Cancer Research)
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