Cancers

21 pages, 7357 KiB

Open AccessReview

Advances in Endoscopic Management of Distal Biliary Stricture: Integrating Clinical Evidence into Patient-Specific Decision-Making

by Reiko Yamada, Tetsuro Miwata, Yoshifumi Nakamura, Kenji Nose, Takamitsu Tanaka, Hirono Owa, Minako Urata, Yasuaki Shimada and Hayato Nakagawa

Cancers 2025, 17(16), 2644; https://doi.org/10.3390/cancers17162644 (registering DOI) - 13 Aug 2025

Abstract

The majority (70–85%) of biliary strictures—a narrowing of the bile ducts—are associated with malignancy, particularly pancreatic adenocarcinoma and cholangiocarcinoma, and are unresectable at presentation. Management options for distal biliary obstruction depend on several clinical factors, including the underlying cause and the location and [...] Read more.

The majority (70–85%) of biliary strictures—a narrowing of the bile ducts—are associated with malignancy, particularly pancreatic adenocarcinoma and cholangiocarcinoma, and are unresectable at presentation. Management options for distal biliary obstruction depend on several clinical factors, including the underlying cause and the location and complexity of the stricture. Endoscopic stent placement has lower morbidity and mortality rates compared with more invasive surgical options and is usually the first-line treatment to clear the blockage or allow the bile duct to drain internally. There are several stenting techniques to treat stenosis, but the current quality of evidence regarding the approach for different etiologies mostly ranges from moderate to low, and there is a lack of patient-specific guidelines regarding treatment decisions and for optimizing clinical outcomes. This review describes recent developments in stent technology and distal biliary stricture management, particularly endoscopic ultrasonography-guided drainage, and synthesizes findings from clinical trials and emerging research to highlight the role of patient-specific factors, such as anatomy and comorbidities, in tailoring treatment strategies. The integration of trial evidence into clinical practice paves the way for more effective and personalized care while addressing current knowledge gaps. Future research directions are identified to advance the development of innovative stent designs, enhance the quality of life, and improve long-term outcomes for patients with biliary strictures. Full article

(This article belongs to the Special Issue Clinical Trials for Hepatobiliary and Pancreatic Cancer Diagnosis and Treatment)

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19 pages, 8542 KiB

Open AccessArticle

Lower Respiratory Tract Microbiome Signatures of Health and Lung Cancer Across Different Smoking Statuses

by Vladimir G. Druzhinin, Elizaveta D. Baranova, Pavel S. Demenkov, Liudmila V. Matskova, Alexey V. Larionov and Arseniy E. Yuzhalin

Cancers 2025, 17(16), 2643; https://doi.org/10.3390/cancers17162643 (registering DOI) - 13 Aug 2025

Abstract

Background: The respiratory microbiota is pivotal in maintaining pulmonary health and modulating disease; however, the intricate interplay between smoking, lung cancer, and microbiome composition remains incompletely understood. Here, we characterized the lower respiratory tract microbiome in a Russian cohort of 297 individuals, comprising [...] Read more.

Background: The respiratory microbiota is pivotal in maintaining pulmonary health and modulating disease; however, the intricate interplay between smoking, lung cancer, and microbiome composition remains incompletely understood. Here, we characterized the lower respiratory tract microbiome in a Russian cohort of 297 individuals, comprising healthy subjects and lung cancer patients of different smoking statuses (current smokers, former smokers, and nonsmokers). Methods: Using next-generation sequencing of the 16S rRNA gene from unstimulated sputum samples, we identify distinct microbiota signatures linked to smoking and lung cancer. A PERMANOVA (Adonis) test and linear discriminant analysis effect size were used for statistical analysis of data. Results: In healthy individuals, smoking did not affect microbiome diversity but markedly altered its composition, characterized by an increase in Streptococcus and a reduction in Neisseria as well as other genera such as Fusobacterium, Alloprevotella, Capnocytophaga, and Zhouea. Healthy former smokers’ microbiota profiles closely resembled those of healthy nonsmokers. In lung cancer patients, microbiome diversity and composition were minimally impacted by smoking, possibly due to the dominant influence of tumor-microenvironment-related factors. Nevertheless, Neisseria abundance remained significantly lower in smokers across advanced-stage lung cancer. Lung cancer patients exhibited distinctive microbiota signatures, including enrichment of Flavobacteriia, Bacillales, and Pasteurellales and depletion of Alphaproteobacteria, Coriobacteriaceae, and Microbacteriaceae, irrespective of smoking status. Conclusions: Our findings emphasize the profound impact of smoking on healthy respiratory microbiota which may be masked by lung-cancer-related factors. These insights highlight the necessity of considering smoking status in microbiome studies to enhance the understanding of respiratory health and disease. Full article

(This article belongs to the Special Issue Predictive Biomarkers for Lung Cancer)

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12 pages, 796 KiB

Open AccessArticle

Angiogenetic Factors in Hepatocellular Carcinoma During Transarterial Chemoembolization: A Pilot Study

by Joško Osredkar, Špela Koršič, Uršula Prosenc Zmrzljak, Hana Trček and Peter Popović

Cancers 2025, 17(16), 2642; https://doi.org/10.3390/cancers17162642 - 13 Aug 2025

Abstract

Background: Hepatocellular carcinoma (HCC) is the most common primary liver cancer and remains a significant global health challenge. Transarterial chemoembolization (TACE) is the treatment of choice for intermediate-stage HCC patients. While TACE induces localized cytotoxic and ischemic tumor necrosis, the resultant hypoxia [...] Read more.

Background: Hepatocellular carcinoma (HCC) is the most common primary liver cancer and remains a significant global health challenge. Transarterial chemoembolization (TACE) is the treatment of choice for intermediate-stage HCC patients. While TACE induces localized cytotoxic and ischemic tumor necrosis, the resultant hypoxia paradoxically activates pro-angiogenic signaling pathways, which may promote tumor revascularization and recurrence. This study aimed to evaluate the plasma levels of angiogenetic factors pre- and post-TACE to assess their dynamic changes and potential clinical implications. Methods: Twenty-five intermediate-stage HCC patients were included in this monocentric prospective study. Peripheral blood samples were collected at baseline (pre-TACE), 24 h, 3 days, and 1 month post-TACE. Angiogenic factor levels were analyzed using a multiplex bead-based assay. Results: Angiopoietin-2 levels were significantly elevated three days post-TACE, followed by a gradual decline after one month. A similar pattern was observed for hepatocyte growth factor, with a marked increase at 24 h post-TACE and subsequent normalization. Endothelin-1 also exhibited a temporary increase, although it was only detected in four patients. Fibroblast growth factors (1 and 2) and vascular endothelial growth factor A were detected in a limited number of patients, which may indicate low systemic release or the need for a more sensitive detection method. Conclusions: These findings suggest that TACE induces a transient increase in angiogenic factors, likely due to tumor ischemia, tissue injury, or microenvironmental responses. Future studies should explore more sensitive detection methods and evaluate whether these factors could serve as prognostic biomarkers or therapeutic targets in HCC treatment. Full article

(This article belongs to the Special Issue Clinical Efficacy of Drug Therapy in Gastrointestinal Cancers)

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12 pages, 9574 KiB

Open AccessArticle

Metabolic Imaging in Electrochemotherapy: Insights from FDG-PET Analysis in Metastatic Melanoma—A Pilot Study

by Sophie C. Siegmund, Maximilian Deußing, Rudolf A. Werner, Daniela Hartmann and Christian Kunte

Cancers 2025, 17(16), 2641; https://doi.org/10.3390/cancers17162641 - 13 Aug 2025

Abstract

Background/Objectives: Electrochemotherapy (ECT) has emerged as a promising locoregional treatment modality for patients with cutaneous and subcutaneous melanoma metastases. While systemic therapies have improved overall disease control, effective local tumor management remains crucial, particularly in oligometastatic or symptomatic disease. This pilot study [...] Read more.

Background/Objectives: Electrochemotherapy (ECT) has emerged as a promising locoregional treatment modality for patients with cutaneous and subcutaneous melanoma metastases. While systemic therapies have improved overall disease control, effective local tumor management remains crucial, particularly in oligometastatic or symptomatic disease. This pilot study investigates the role of metabolic imaging with [¹⁸F]FDG PET/CT to assess tumor metabolism in melanoma patients undergoing ECT, building on prior evidence that PET offers valuable functional information beyond anatomical changes detected by conventional imaging. Methods: This retrospective study included 11 patients with histologically confirmed melanoma and cutaneous or subcutaneous metastases treated with ECT. [¹⁸F]FDG PET/CT scans were performed either before ECT, after ECT, or both. Metabolic response was assessed by measuring the tracer uptake (SUV_max) of the ten hottest lesions. Morphological changes were evaluated using CT. Local progression-free survival was determined. Results: A total of 66 lesions were analyzed. Patients with PET/CT only after ECT showed significantly higher SUV_max and lesion size compared to those imaged before treatment (mean SUV_max: 9.9 ± 11.2 vs. 10.3 ± 5.5; p = 0.034). Progression-free survival differed significantly based on pre-ECT SUV_max values (χ² = 3.90; p = 0.048). Among two patients with follow-up imaging, one showed new lesions on CT with only mild FDG uptake, while the other developed newly FDG-avid metastases after ECT. Conclusions: FDG PET/CT provides valuable information on tumor viability and treatment response in melanoma patients undergoing ECT, demonstrated by significant differences in metabolic activity between lesions imaged before and after treatment. The lack of longitudinal intra-individual imaging limits definitive conclusions about the direct metabolic effects of ECT. Full article

(This article belongs to the Special Issue Novel Research on the Diagnosis and Treatment of Melanoma)

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13 pages, 1195 KiB

Open AccessArticle

Urinary microRNAs as Prognostic Biomarkers for Predicting the Efficacy of Immune Checkpoint Inhibitors in Patients with Urothelial Carcinoma

by Yosuke Hirasawa, Atsushi Satomura, Mitsuo Okada, Mieko Utsugi, Hiroki Ogura, Tsuyoshi Yanagi, Yuta Nakamori, Masayuki Takehara, Kokichi Murakami, Go Nagao, Takeshi Kashima, Naoya Satake, Yoriko Ando, Motoki Mikami, Mika Mizunuma, Yuki Ichikawa and Yoshio Ohno

Cancers 2025, 17(16), 2640; https://doi.org/10.3390/cancers17162640 - 13 Aug 2025

Abstract

Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of urothelial carcinoma (UC); however, their efficacy varies among patients. Identifying reliable biomarkers to predict response to ICIs remains challenging. We aimed to explore urinary microRNAs (miRNAs) as potential biomarkers for predicting ICI [...] Read more.

Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of urothelial carcinoma (UC); however, their efficacy varies among patients. Identifying reliable biomarkers to predict response to ICIs remains challenging. We aimed to explore urinary microRNAs (miRNAs) as potential biomarkers for predicting ICI efficacy in patients with UC. Methods: We prospectively collected urinary samples from patients with UC before ICI initiation and investigated the predictive value of urinary miRNAs in patients with UC receiving ICIs. The expression levels of these miRNAs in pretreated urine samples were analyzed using next-generation sequencing. The patients were categorized as responders (those with stable disease or better for >6 months) or nonresponders (those who experienced disease progression within 6 months of treatment initiation). Urinary miRNA levels were compared between the groups to assess their potential as predictive biomarkers. Results: Elevated expression of miR-185-5p and miR-425-5p in the responder group was significantly associated with improved overall and progression-free survival in patients with bladder cancer treated with ICIs (p < 0.05). Conversely, higher levels of miR-30a-5p and miR-542-3p in the nonresponder group were correlated with a poorer response to ICIs, suggesting a potential role in immune resistance. Conclusions: miR-185-5p and miR-425-5p can serve as predictive biomarkers of favorable ICI efficacy in bladder cancer, whereas miR-30a-5p and miR-542-3p could be associated with resistance mechanisms. These findings highlight the potential of miRNA-based biomarkers, particularly those found in urine samples, to guide personalized immunotherapeutic strategies for UC treatment. Full article

(This article belongs to the Special Issue Advancements in “Cancer Biomarkers” for 2025–2026)

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19 pages, 965 KiB

Open AccessReview

Immune Biomarkers for Checkpoint Blockade in Solid Tumors: Transitioning from Tissue to Peripheral Blood Monitoring and Future Integrated Strategies

by Ioannis P. Trontzas and Konstantinos N. Syrigos

Cancers 2025, 17(16), 2639; https://doi.org/10.3390/cancers17162639 - 13 Aug 2025

Abstract

Immunotherapy with immune checkpoint inhibitors has changed the treatment landscape in many solid tumors. Despite the unprecedent success, many patients will develop primary or secondary resistance to treatment or will hold up therapy due to the emerging immune-related toxicity. Traditionally, tissue-based immune biomarkers, [...] Read more.

Immunotherapy with immune checkpoint inhibitors has changed the treatment landscape in many solid tumors. Despite the unprecedent success, many patients will develop primary or secondary resistance to treatment or will hold up therapy due to the emerging immune-related toxicity. Traditionally, tissue-based immune biomarkers, such as PD-L1 expression, have been used to select patients who will benefit most from immunotherapy. However, these markers demonstrate major limitations, such as tumor heterogeneity and sample constraints. In addition, they do not reflect the dynamic interplay of tumor and hosts immune response during treatment. Peripheral blood immunomarkers offer a minimally invasive, real-time assessment of the immune system and its interaction with the tumor. Integration of traditional tissue-based and peripheral blood markers coupled with the recent developments in computational platforms, artificial intelligence, and machine learning models may provide more successful biomarkers for prognosis, prediction of immunotherapy-related outcomes, the early evaluation of forthcoming disease progression, and the prediction of the emerging immune-related adverse events. Despite the promising developments in the field of immune biomarkers, several issues including assay standardization, clinical validation, and biological variability should be addressed to improve personalized immunotherapy approaches. In this comprehensive review we provide an update on immune biomarker evolution, and we discuss the current limitations and future directions. Full article

(This article belongs to the Special Issue Immune Biomarkers in Solid Tumors: From Peripheral Blood Parameters to Tissue-Based Indicators for Prognosis and Therapy Response)

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20 pages, 1930 KiB

Open AccessArticle

Ki67 and TNFRII as Potential Clinical Markers for Effective Clinical Staging of Advanced Prostate Cancer

by Edyta Idalia Wolny-Rokicka and Marta Grabowska

Cancers 2025, 17(16), 2638; https://doi.org/10.3390/cancers17162638 - 13 Aug 2025

Abstract

Background: Currently, it is a priority to develop prognostic biomarkers that would allow the identification of patients with progressing prostate diseases with a low risk of progression, so that unnecessary treatment and patient burden can be avoided. Objectives: This study aimed [...] Read more.

Background: Currently, it is a priority to develop prognostic biomarkers that would allow the identification of patients with progressing prostate diseases with a low risk of progression, so that unnecessary treatment and patient burden can be avoided. Objectives: This study aimed to assess the clinical features and concentrations of selected mediators of apoptosis, markers of inflammation, and immunoexpression of Ki67 and selected mediators of inflammation in patients with PCa after prostatectomy procedures and who underwent palliative radiotherapy for bone metastases, as well as patients with benign prostatic hyperplasia (BPH). Methods: A total of 88 patients, including 54 cases with PCa and 34 with BPH, were included. Stage and tumor grades were determined according to Gleason’s grading system. Immunoenzymatic methods were used to determine apoptotic and inflammatory mediators in serum, as well as deoxynucleotidyl transferase-mediated dUTP Nick End Labeling (TUNEL) reaction, and immunohistochemistry to determine selected markers of inflammation and Ki67 expression. Results: Strong differentiating indicators were revealed, such as Ki67, and tumor necrosis factor receptor 2. Ki-67 expression was significantly associated with the Gleason score. In turn, the tumor necrosis factor receptor 2 (TNFRII) showed the highest expression in the inflammatory environment of cancer in the metastatic stage. Conclusions: Ki67 and TNFRII can be classified as high-value clinical markers. These factors may be treated as markers regarding future information about the implementation or withdrawal of more aggressive treatment to possibly avoid toxic complications associated with both increased doses in radiotherapy and prolonged hormonal therapy. Full article

(This article belongs to the Collection Biomarkers for Detection and Prognosis of Prostate Cancer)

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24 pages, 3941 KiB

Open AccessReview

PET/CT and Paraneoplastic Syndromes: A Comprehensive Review

by Motaz Daraghma, Yashant Aswani, Sanchay Jain, Riccardo Laudicella, Ali Gholamrezanezhad, Yusuf Menda and Ahmad Shariftabrizi

Cancers 2025, 17(16), 2637; https://doi.org/10.3390/cancers17162637 - 13 Aug 2025

Abstract

Paraneoplastic syndromes (PNSs) are pathologic conditions produced by neoplasms not attributable to tumor invasion or metastasis. The clinical manifestations of PNSs can precede the diagnosis; these symptoms may serve as early indicators of underlying malignancy. Standard imaging modalities, such as computed tomography (CT) [...] Read more.

Paraneoplastic syndromes (PNSs) are pathologic conditions produced by neoplasms not attributable to tumor invasion or metastasis. The clinical manifestations of PNSs can precede the diagnosis; these symptoms may serve as early indicators of underlying malignancy. Standard imaging modalities, such as computed tomography (CT) and magnetic resonance imaging (MRI), have limited sensitivity in detecting small or early-stage PNS-associated tumors. FDG PET/CT identifies hypermetabolic lesions suggestive of malignancy and, therefore, facilitates early diagnosis, refined treatment planning, and potentially prolonged patient survival. This review evaluates the diagnostic accuracy, clinical utility, and emerging role of FDG PET/CT in detecting occult malignancies. Syndrome-targeted applications discussed include limbic encephalitis, cerebellar degeneration, Lambert-Eaton myasthenic syndrome, Cushing’s syndrome, hypercalcemia of malignancy, dermatomyositis, and tumor-induced osteomalacia. In addition, the limitations of FDG PET/CT, including false-positive or false-negative findings, are reviewed, while newer PET tracers, like ⁶⁸Ga-DOTATATE, are also highlighted. Ultimately, FDG PET/CT has transformed clinical decision-making, enabling more timely interventions and improved patient management in the context of PNSs. Future directions in imaging, including PET/MRI and ongoing refinements in tracer design, promise to further enhance diagnostic precision, and therapeutic outcomes are also discussed. Full article

(This article belongs to the Special Issue Advances in PET/CT for Predicting Cancer Outcomes)

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19 pages, 2189 KiB

Open AccessReview

IGSF11-Mediated Immune Modulation: Unlocking a Novel Pathway in Emerging Cancer Immunotherapies

by Sapna Srivastava, Apriliana E. R. Kartikasari, Srinivasa Reddy Telukutla, Magdalena Plebanski and Dibyendu Banerjee

Cancers 2025, 17(16), 2636; https://doi.org/10.3390/cancers17162636 - 13 Aug 2025

Abstract

Immunoglobulin superfamily member 11 (IGSF11) has recently emerged as a critical immune checkpoint ligand that interacts with the V-domain immunoglobulin suppressor of T-cell activation (VISTA) receptor to inhibit T-cell activation and promote immune escape. Preclinical studies have demonstrated that targeting the IGSF11-VISTA axis [...] Read more.

Immunoglobulin superfamily member 11 (IGSF11) has recently emerged as a critical immune checkpoint ligand that interacts with the V-domain immunoglobulin suppressor of T-cell activation (VISTA) receptor to inhibit T-cell activation and promote immune escape. Preclinical studies have demonstrated that targeting the IGSF11-VISTA axis effectively reverses immunosuppression by enhancing T-cell effector functions and increasing the secretion of prostimulatory cytokines such as IFN-γ. This immune modulation shifts the tumor microenvironment from an immune “cold” state, characterized by low immune infiltration and activity, to a more immunoreactive “hot” state that is more susceptible to immune-mediated destruction. Moreover, combining IGSF11 inhibition with established therapies such as anti-PD-1/PD-L1 improves treatment efficacy in various cancer models. In this review, we focus on the immunomodulatory functions of IGSF11, its role in combination immunotherapies, and preclinical evidence supporting its potential as a novel therapeutic target to overcome resistance and improve cancer immunotherapy outcomes. Full article

(This article belongs to the Section Cancer Causes, Screening and Diagnosis)

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20 pages, 4084 KiB

Open AccessArticle

CT-Based Pericardial Composition Change as an Imaging Biomarker for Radiation-Induced Cardiotoxicity

by Arezoo Modiri, Ivan R. Vogelius, Cynthia Terrones Campos, Denis Kutnar, Jean Jeudy, Mette Pohl, Timm-Michael L. Dickfeld, Soren M. Bentzen, Amit Sawant and Jens Petersen

Cancers 2025, 17(16), 2635; https://doi.org/10.3390/cancers17162635 - 13 Aug 2025

Abstract

Background/Objectives: No reliable noninvasive biomarkers are available to predict RT-induced cardiotoxicity. Because the pericardial sac is a fast responder to cardiac injury, we investigated whether RT-induced radiographic pericardial changes might serve as early imaging biomarkers for late cardiotoxicity. Methods: We performed a retrospective [...] Read more.

Background/Objectives: No reliable noninvasive biomarkers are available to predict RT-induced cardiotoxicity. Because the pericardial sac is a fast responder to cardiac injury, we investigated whether RT-induced radiographic pericardial changes might serve as early imaging biomarkers for late cardiotoxicity. Methods: We performed a retrospective study of 476 patients (210 males, 266 females; median age, 69 years; median follow-up, 26.7 months) treated with chemo-RT for small cell and non-small cell lung cancers at one single institution from 2009 to 2020. The heart and its 4 mm outmost layer (representing the pericardial sac) were contoured on standard-of-care baseline CTs. Six-month post-RT follow-up CTs were deformably registered on the baseline CTs. Data were harmonized for the effect of contrast. We labeled voxels as Fat, Fluid, Heme, Fibrous, and Calcification using Hounsfield units (HUs). We studied pericardial HU-change histograms as well as volume change and voxel-based mass change in each tissue composition. Results: Pericardial HU-change histograms had skewed distributions with a mean that was significantly correlated with mean pericardial dose. Voxels within Fluid, Heme, and Fibrous had mass changes consistent with the dose. In Kaplan–Meier curves, Fibrous and Heme volume changes (translating into thickening and effusion), Fat mass change, mean doses to heart and pericardium, history of cardiac disease, and being male were significantly associated with shorter survival, whereas thickening and effusion were significantly associated with shorter time to a post-RT cardiovascular disease diagnosis. Conclusions: Pericardium composition distribution has dose-dependent changes detectable on standard-of-care CTs at around 6 months post-RT and may serve as surrogate markers for clinically relevant cardiotoxicity. The findings should be validated with additional research. Full article

(This article belongs to the Special Issue The Development and Application of Imaging Biomarkers in Cancer)

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13 pages, 1252 KiB

Open AccessArticle

Prognostic Impact of Gastrointestinal Immune-Related Adverse Events Depends on Nutritional Status in Cancer Patients Treated with Immune Checkpoint Inhibitors

by Shoichiro Hirata, Yoshiyasu Kono, Emi Tanaka, Masahiko Sue, Yasuto Takeuchi, Tomoki Yoshikawa, Yoshie Maki, Tomohiro Kamio, Daisuke Kametaka, Katsunori Matsueda, Chihiro Sakaguchi, Kenta Hamada, Masaya Iwamuro, Seiji Kawano, Yoshiro Kawahara and Motoyuki Otsuka

Cancers 2025, 17(16), 2634; https://doi.org/10.3390/cancers17162634 - 12 Aug 2025

Abstract

Background: Gastrointestinal immune-related adverse events (GI-irAEs) are recognized complications of immune checkpoint inhibitors (ICIs), but their prognostic relevance and associated risk factors remain unclear. This study aimed to assess whether baseline nutritional status, measured using the prognostic nutritional index (PNI), modifies the prognostic [...] Read more.

Background: Gastrointestinal immune-related adverse events (GI-irAEs) are recognized complications of immune checkpoint inhibitors (ICIs), but their prognostic relevance and associated risk factors remain unclear. This study aimed to assess whether baseline nutritional status, measured using the prognostic nutritional index (PNI), modifies the prognostic impact of GI-irAEs, and to identify clinical factors associated with their occurrence. Methods: We retrospectively analyzed 1104 cancer patients treated with ICIs at a single institution. GI-irAEs were defined as gastrointestinal symptoms requiring clinical intervention. Patients were stratified by irAE type and PNI (≥40 vs. <40), and differences in survival and treatment response were evaluated. Potential risk factors for developing GI-irAEs were also examined. Results: GI-irAEs occurred in 2.7% of patients and were associated with prolonged overall survival (median: 28.7 vs. 14.0 months) among those with PNI ≥ 40. This survival advantage was not observed in patients with PNI < 40. The PNI-dependent prognostic pattern was specific to GI-irAEs and not observed for non-GI irAEs. Similar trends were confirmed in 4- and 8-week landmark analyses. Differences in objective response rate and disease control rate by PNI status were most pronounced in patients with GI-irAEs. The use of anti-CTLA-4 antibodies was significantly associated with GI-irAE development (odds ratio 4.24; 95% confidence interval 1.73–10.39). Conclusions: GI-irAEs appear to confer a survival benefit primarily in patients with preserved nutritional status. PNI may serve as a useful tool to contextualize the clinical relevance of GI-irAEs and help identify patients most likely to benefit from immune activation during ICI therapy. Full article

(This article belongs to the Special Issue Advances in the Treatment of Gastrointestinal (GI) Cancers)

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11 pages, 543 KiB

Open AccessArticle

Prognostic Value of Preoperative Hemoglobin in Patients Undergoing Radical Prostatectomy for Localized Prostate Cancer

by Dominik Enderlin, Lea Hertelendy, Josias Bastian Grogg, Franz von Stauffenberg, Daniel Eberli and Cédric Poyet

Cancers 2025, 17(16), 2633; https://doi.org/10.3390/cancers17162633 - 12 Aug 2025

Abstract

Background: Hemoglobin (Hb) has been identified to be an independent prognostic marker for oncological outcomes in several malignancies. However, the impact of Hb levels before radical prostatectomy (RP) in localized prostate cancer remains unclear. Methods: Preoperative Hb levels were retrospectively collected [...] Read more.

Background: Hemoglobin (Hb) has been identified to be an independent prognostic marker for oncological outcomes in several malignancies. However, the impact of Hb levels before radical prostatectomy (RP) in localized prostate cancer remains unclear. Methods: Preoperative Hb levels were retrospectively collected from patients, who underwent RP from 2016 to 2022. Hb levels were analyzed as continuous and binary variables. For binary analysis, the cohort was divided into high-Hb (≥150 g/L) and low-Hb (<150 g/L) groups using the median as a cutoff. We used Spearman rank correlation to assess possible associations between Hb and continuous variables and logistic regression for Hb and binary variables. To assess the impact of preoperative Hb on recurrence-free survival (RFS), adjuvant treatment free survival (TFS), and metastasis-free survival (MFS), univariate and multivariate Cox regression analyses were performed. Results: A total of 567 patients were included in the analysis. Higher Hb levels, both when analyzed as a continuous variable and when divided in high and low groups, were inversely correlated with age (p < 0.001) and the International Society of Urological Pathology (ISUP) grade (p = 0.005 or p = 0.028, respectively). Patients in the high-Hb group showed a decreased risk of extraprostatic disease (≥pT3) (odds ratio [OR] 0.71, 95%-CI: 0.50–0.99, p = 0.047). In univariate cox regression analysis, high-Hb patients had a significantly longer RFS compared to the low-Hb group (hazard ratio [HR] 0.64, 95%-CI: 0.44–0.92, p = 0.015). When adjusting for age, ISUP grade, positive surgical margin, prostate specific antigen, nodal status, and ≥pT3, this effect was no longer statistically significant (HR 0.76, 95%-CI 0.56–1.22, p = 0.178). Hb was not a significant prognostic factor for TFS or MFS. Conclusions: In this large cohort, lower preoperative Hb values were associated with a more aggressive tumor grading and shorter RFS. However, we were unable to identify Hb as an independent predictor of oncological survival outcomes. Full article

(This article belongs to the Special Issue Clinical Studies and Outcomes in Urologic Cancer)

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40 pages, 480 KiB

Open AccessReview

The Role of Epigenetic Biomarkers as Diagnostic, Predictive and Prognostic Factors in Colorectal Cancer

by Zuzanna Chilimoniuk, Konrad Gładysz, Natalia Moniczewska, Katarzyna Chawrylak, Zuzanna Pelc and Radosław Mlak

Cancers 2025, 17(16), 2632; https://doi.org/10.3390/cancers17162632 - 12 Aug 2025

Abstract

Colorectal cancer (CRC) remains one of the leading causes of cancer-related morbidity and mortality worldwide. Despite significant advances in screening and treatment, the prognosis for advanced-stage disease continues to be poor. One thriving area of research focuses on the use of epigenetic alterations [...] Read more.

Colorectal cancer (CRC) remains one of the leading causes of cancer-related morbidity and mortality worldwide. Despite significant advances in screening and treatment, the prognosis for advanced-stage disease continues to be poor. One thriving area of research focuses on the use of epigenetic alterations for the diagnosis, prediction of treatment response, and prognosis of CRC. In this study, we evaluated original studies and meta-analyses published within the past five years to identify the most clinically relevant epigenetic biomarkers. DNA methylation-based assays, particularly those targeting SDC2 and SEPT9 in stool and plasma, exhibit superior diagnostic accuracy compared to other epigenetic modalities. Circulating microRNAs (miRNAs), including miR-211, miR-197, and miR-21, as well as specific long non-coding RNAs (lncRNAs) such as SNHG14, LINC01485, and ASB16-AS1, also show promising diagnostic potential. Furthermore, panels combining multiple epigenetic markers, especially those incorporating DNA methylation targets, have demonstrated improved sensitivity and specificity for early-stage CRC detection. In the context of therapeutic prediction, microRNAs such as miR-140, miR-21, and miR-4442 have been associated with chemotherapy resistance and recurrence risk. DNA methylation markers like LINE-1, mSEPT9 and ERCC1 have also shown predictive value, while lncRNAs including MALAT1 and GAS6-AS1 remain less validated. Regarding prognosis, miRNAs appear to be the most promising biomarkers, with miR-675-5p and miR-150 being associated with poor survival, while miR-767-5p and miR-215 predict favorable outcomes. Methylation of NKX6.1, IGFBP3, and LMX1A has been identified as an independent negative prognostic factor, while SFRP2 hypermethylation is linked to better prognosis. Selected lncRNAs, including THOR and LINC01094, have also demonstrated significant prognostic value. Despite these advances, challenges persist, including inconsistent reporting, limited external validation, and a lack of replication by independent research groups. Full article

(This article belongs to the Special Issue Role of Cancer Biomarkers for Diagnosis, Prognosis and Targeted Therapy in Gastrointestinal Cancers)

28 pages, 3132 KiB

Open AccessArticle

Neutrophils in Cancer: Phenotypic Heterogeneity Across Tumor Models and Significant Alteration of Splenic Neutrophil Phenotype in Lymphosarcoma RLS₄₀ Model Following DNase I Treatment

by Khetam Sounbuli, Ludmila A. Alekseeva, Aleksandra V. Sen’kova, Oleg V. Markov, Innokenty A. Savin, Marina A. Zenkova and Nadezhda L. Mironova

Cancers 2025, 17(16), 2631; https://doi.org/10.3390/cancers17162631 - 12 Aug 2025

Abstract

Background/Objectives: Neutrophils have recently gained significant attention due to their heterogeneity in tumor settings. Recent data showed neutrophil pro- and anti-tumor profiles during tumor progression. However, the concessive causes of neutrophil skewing toward one or another profile are not fully understood. Methods [...] Read more.

Background/Objectives: Neutrophils have recently gained significant attention due to their heterogeneity in tumor settings. Recent data showed neutrophil pro- and anti-tumor profiles during tumor progression. However, the concessive causes of neutrophil skewing toward one or another profile are not fully understood. Methods: In this study, using RT-qPCR, flowcytometry, and confocal microscopy, we investigated the phenotype of splenic neutrophils of mice bearing Lewis lung carcinoma LLC, RLS₄₀ lymphosarcoma, and B16 melanoma. Results: Our data showed an immunosuppressive phenotype in the case of the LLC model with PD-L1 and IL10 expression. In the B16 model, minimal changes in the neutrophil phenotype were observed, regardless of tumor size. In the RLS₄₀ model, the neutrophil phenotype was associated with the tumor growth rate, where, in aggressively progressed tumors (RLS₄₀^High), CCL17 was expressed, while, in mice with controlled tumor growth (RLS₄₀^Low), anti-tumor markers were expressed (FAS, ICAM-1, PD-L1). DNase I treatment significantly reduced tumor growth and metastasis in the RLS₄₀ model but not in B16, enhanced the anti-tumor profile in RLS₄₀ neutrophils, and tended to reduce NET formation induced by A23187. Conclusions: The phenotype of neutrophils from tumor-bearing mice is influenced by the tumor type and progression stage. DNase I had anti-tumor, antimetastatic, and immunostimulatory effects and significantly modified the neutrophil profile in the immunogenic model RLS₄₀. Full article

(This article belongs to the Special Issue The Role of Neutrophils in Tumor Progression and Metastasis)

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21 pages, 903 KiB

Open AccessSystematic Review

Targeting of Mutant Isocitrate Dehydrogenase in Glioma: A Systematic Review

by Tyler A. Lanman and L. Nicolas Gonzalez Castro

Cancers 2025, 17(16), 2630; https://doi.org/10.3390/cancers17162630 - 12 Aug 2025

Abstract

Background/Objectives: Mutant isocitrate dehydrogenase (IDH) inhibitors represent a major advance in precision oncology. The recent Food and Drug Administration approval of vorasidenib for IDH-mutant glioma highlights its therapeutic potential in this setting. As this and other mutant IDH inhibitors enter the clinical [...] Read more.

Background/Objectives: Mutant isocitrate dehydrogenase (IDH) inhibitors represent a major advance in precision oncology. The recent Food and Drug Administration approval of vorasidenib for IDH-mutant glioma highlights its therapeutic potential in this setting. As this and other mutant IDH inhibitors enter the clinical setting, providers are tasked with staying informed of the evolving therapeutic landscape as more is learned about this unique class of medications. We aimed to summarize insights from preclinical studies and clinical trials exploring their use in IDH-mutant glioma. Methods: We reviewed notable preclinical studies establishing the rationale for targeting mutant IDH. We performed a systematic review of clincaltrials.gov to identify both completed and ongoing interventional IDH-directed trials in patients with IDH-mutant glioma. Results: We identified 8 published and 15 ongoing clinical trials evaluating IDH-directed therapies. IDH inhibitors have been shown to slow and, in some cases, reverse glioma tumor growth, with activity that may extend beyond their currently approved indications. The presence of contrast enhancement is consistently a negative predictor of response for ivosidenib and vorasidenib, although safusidenib and olutasidenib preliminarily may retain efficacy in these cases. Novel approaches such as IDH-directed vaccines and combination therapy using mutant IDH inhibitors with immunotherapy are currently under active investigation. Conclusions: Mutant IDH inhibition is a promising, well-tolerated, and evolving approach for many patients with IDH-mutant glioma. Ongoing research will clarify its optimal clinical utility and potentially expand its indication. Full article

(This article belongs to the Special Issue Interrogating Molecular Regulators and Chemical Agents in Brain Tumor Progression)

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13 pages, 2448 KiB

Open AccessArticle

Pelvic Floor Functionality and Outcomes in Oncologic Patients Treated with Pelvic Bone Resection

by Edoardo Ipponi, Pier Luigi Ipponi, Fabrizia Gentili, Elena Bechini, Vittoria Bettarini, Paolo Domenico Parchi and Lorenzo Andreani

Cancers 2025, 17(16), 2629; https://doi.org/10.3390/cancers17162629 - 12 Aug 2025

Abstract

Background: Pelvic resections represent some of the most challenging procedures in orthopedic oncology, often necessitating the sacrifice of large bone segments and, subsequently, the loss of nearby soft tissues. Our study aims to evaluate the impact of surgical resections of pelvic bone tumors [...] Read more.

Background: Pelvic resections represent some of the most challenging procedures in orthopedic oncology, often necessitating the sacrifice of large bone segments and, subsequently, the loss of nearby soft tissues. Our study aims to evaluate the impact of surgical resections of pelvic bone tumors on the performance of the pelvic floor and digestive, urinary, and genital systems. Methods: We evaluated all malignant or locally aggressive pelvic bone tumors treated with bone resection in our institution between January 2017 and January 2024. The reconstructive approaches were recorded. Pre- and post-operative MRI and CT scans were used to evaluate the grade of pelvic prolapse. The prolapse of the pelvic floor was assessed with the M-line, the H-line, and the anorectal angle. Hydronephrosis was also evaluated. Urinary and fecal incontinence were evaluated with the Pelvic Floor Impact Questionnaire (PFIQ7). Results: Thirty cases were included in our study. Nine cases were treated with custom-made prostheses, five had ice-cone prostheses, two massive allografts, and one composite allograft-prosthesis. The others had no bone reconstruction. Meshes were used to reconstruct the pelvic floor in 9 cases. Patients with discontinuity of the pelvic ring had a significantly higher grade of pelvic prolapse (M-line) and worse PFIQ7 scores. Conclusions: The resection of pelvic bone tumors represents one of the main challenges in orthopedic oncology. While planning surgical demolition and performing the subsequent reconstruction, surgeons should also consider the impact of the surgical treatment on the pelvic floor and surrounding organs. Intra-operative reconstructions and post-operative rehabilitation are advisable. Full article

(This article belongs to the Special Issue Sarcoma Management in Orthopaedic Oncology)

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40 pages, 2934 KiB

Open AccessReview

Nanoparticle-Based Delivery Strategies for Combating Drug Resistance in Cancer Therapeutics

by Seohyun Park, Guo-Liang Lu, Yi-Chao Zheng, Emma K. Davison and Yan Li

Cancers 2025, 17(16), 2628; https://doi.org/10.3390/cancers17162628 - 11 Aug 2025

Abstract

Multidrug resistance (MDR) remains a formidable barrier to successful cancer treatment, driven by mechanisms such as efflux pump overexpression, enhanced DNA repair, evasion of apoptosis and the protective characteristics of the tumour microenvironment. Nanoparticle-based delivery systems have emerged as promising platforms capable of [...] Read more.

Multidrug resistance (MDR) remains a formidable barrier to successful cancer treatment, driven by mechanisms such as efflux pump overexpression, enhanced DNA repair, evasion of apoptosis and the protective characteristics of the tumour microenvironment. Nanoparticle-based delivery systems have emerged as promising platforms capable of addressing these challenges by enhancing intracellular drug accumulation, enabling targeted delivery and facilitating stimuli-responsive and controlled release. This review provides a comprehensive overview of the molecular and cellular mechanisms underlying MDR and critically examines recent advances in nanoparticle strategies developed to overcome it. Various nanoparticle designs are analysed in terms of their structural and functional features, including surface modifications, active targeting ligands and responsiveness to tumour-specific cues. Particular emphasis is placed on the co-delivery of chemotherapeutic agents with gene regulators, such as siRNA, and the use of nanoparticles to deliver CRISPR/Cas9 gene editing tools as a means of re-sensitising resistant cancer cells. While significant progress has been made in preclinical settings, challenges such as tumour heterogeneity, limited clinical translation and immune clearance remain. Future directions include the integration of precision nanomedicine, scalable manufacturing and non-viral genome editing platforms. Collectively, nanoparticle-based drug delivery systems offer a multifaceted approach to combat MDR and hold great promise for improving therapeutic outcomes in resistant cancers. Full article

(This article belongs to the Special Issue Integrating Precision Medicine with Nanotechnology to Overcome Drug Resistance in Cancer)

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14 pages, 2557 KiB

Open AccessArticle

An In Silico Feasibility Study of Dose-Escalated Hypofractionated Proton Therapy for Rectal Cancer

by Erik Almhagen, Ali Alkhiat, Bruno Sorcini, Freja Alpsten, Camilla J. S. Kronborg, Heidi S. Rønde, Marianne G. Guren, Sara Pilskog and Alexander Valdman

Cancers 2025, 17(16), 2627; https://doi.org/10.3390/cancers17162627 - 11 Aug 2025

Abstract

Background/Objectives: The current standard treatment for locally advanced rectal cancer (LARC) is neoadjuvant chemoradiotherapy, or total neoadjuvant therapy (TNT), followed by total mesorectal excision (TME). If the neoadjuvant treatment results in a clinical complete response (cCR), non-operative management of LARC might be [...] Read more.

Background/Objectives: The current standard treatment for locally advanced rectal cancer (LARC) is neoadjuvant chemoradiotherapy, or total neoadjuvant therapy (TNT), followed by total mesorectal excision (TME). If the neoadjuvant treatment results in a clinical complete response (cCR), non-operative management of LARC might be possible. It is hypothesized that cCR rates will increase with increasing radiotherapy doses. By using proton therapy, doses to organs at risk (OAR) may be decreased. In preparation for a clinical trial on dose-escalated proton therapy for LARC, the purpose of this study is to establish the feasibility of proton therapy for dose-escalated hypofractionated radiotherapy of LARC. Methods: Ten patients, having previously received short course radiotherapy (SCRT) for LARC, were included in this planning study. Two photon plans and two proton plans were created for each patient: one with a standard 5 × 5 Gy fractionation and one dose-escalated up to 5 × 7 Gy. Proton plans were robustly optimized. For all plans the integral dose (ID) was computed, and for the proton plans relative biological effectiveness (RBE) distributions were calculated. Feasibility was assessed in terms of target coverage and OAR doses. Results: All treatment plans satisfied target coverage criteria. Three of the photon and two of the proton dose-escalated plans exceeded recommended OAR objectives. Proton IDs were on average lower by a factor of 1.97 compared to photon IDs. Mean doses to OAR were, in general, lower for protons. All proton RBE values in the escalated target volumes were between 1.09 and 1.16. Conclusions: The proposed dose escalation was found to be feasible. Protons can reduce the integral dose and mean doses to OARs compared to photons in both the dose-escalated and non-escalated cases. Differences in RBE between escalated and standard fractionation were small. Full article

(This article belongs to the Special Issue The Advance of Pencil Beam Scanning Proton Beam Therapy in Cancers)

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12 pages, 330 KiB

Open AccessArticle

Real Life Evolution of Surgical Approaches in the Management of Endometrial Cancer in Poland

by Agnieszka Rychlik, Tomasz Kluz, Grzegorz Szewczyk, Pluvio J. Coronado, Tomasz Łatkiewicz, Rafał Tarkowski, Anna Woińska-Przekwas, Krzysztof Nowosielski, Kaja Skowronek, Rafał Stojko, Michał Skuza, Marcin Misiek, Krzysztof Jabłoński, Paweł Sadłecki, Marta Ciosek, Katarzyna Pasicz, Anna Bogaczyk and Mariusz Bidziński

Cancers 2025, 17(16), 2626; https://doi.org/10.3390/cancers17162626 - 11 Aug 2025

Abstract

Objective: The primary objective of this study was to evaluate the evolution of surgical approaches in the management of endometrial cancer in Polish tertiary referral hospitals, comparing the use of minimally invasive surgery (MIS) and laparotomy in 2023 versus 2013. Methods: This retrospective [...] Read more.

Objective: The primary objective of this study was to evaluate the evolution of surgical approaches in the management of endometrial cancer in Polish tertiary referral hospitals, comparing the use of minimally invasive surgery (MIS) and laparotomy in 2023 versus 2013. Methods: This retrospective observational study analyzed data from tertiary referral centers in Poland. All surgeries performed for apparently early-stage endometrial cancer in 2013 and 2023 were included. Results: A total of 1062 patients were analyzed, with 417 undergoing operations in 2013 and 640 in 2023. In 2013, 92.6% (386/417) of patients underwent laparotomy. By 2023, 80.1% (513/640) of patients were treated using minimally invasive approaches, including laparoscopy (56.2%, 362/640), robotic-assisted laparoscopy (21.7%, 139/640), and vaginal surgery (1.9%, 12/640). No conversions to laparotomy were recorded in 2013. In 2023, 22 conversions occurred—21 in the laparoscopy group (5.8%, 21/362) and one in the vaginal surgery group (8.3%, 1/12). No conversions were reported in the robotic-assisted group. Intraoperative complications were observed in 2.2% (8/362) of laparoscopic cases, and postoperative complications in 4.4% (16/362). In the robotic-assisted group, one intraoperative complication (0.7%) was reported, with no postoperative complications. Conclusions: Over the past decade, there has been a significant shift in the surgical management of endometrial cancer in Poland, with a growing preference for minimally invasive surgery (MIS). The rate of conversion from MIS to laparotomy remains below 6%. Robotic-assisted laparoscopic surgery may offer additional benefits, particularly for obese patients. Full article

(This article belongs to the Special Issue Advances in Surgical Treatment of Gynecological Cancers)

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