Cancers

13 pages, 1488 KiB

Open AccessArticle

Validation of a Quantitative Ultrasound Texture Analysis Model for Early Prediction of Neoadjuvant Chemotherapy Response in Breast Cancer: A Prospective Serial Imaging Study

by Daniel Moore-Palhares, Lakshmanan Sannachi, Adrian Wai Chan, Archya Dasgupta, Daniel DiCenzo, Sonal Gandhi, Rossanna Pezo, Andrea Eisen, Ellen Warner, Frances Wright, Nicole Look Hong, Ali Sadeghi-Naini, Mia Skarpathiotakis, Belinda Curpen, Carrie Betel, Michael C. Kolios, Maureen Trudeau and Gregory J. Czarnota

Cancers 2025, 17(15), 2594; https://doi.org/10.3390/cancers17152594 - 7 Aug 2025

Abstract

Background/Objectives: Patients with breast cancer who do not achieve a complete response to neoadjuvant chemotherapy (NAC) may benefit from intensified adjuvant systemic therapy. However, such treatment escalation is typically delayed until after tumour resection, which occurs several months into the treatment course. Quantitative [...] Read more.

Background/Objectives: Patients with breast cancer who do not achieve a complete response to neoadjuvant chemotherapy (NAC) may benefit from intensified adjuvant systemic therapy. However, such treatment escalation is typically delayed until after tumour resection, which occurs several months into the treatment course. Quantitative ultrasound (QUS) can detect early microstructural changes in tumours and may enable timely identification of non-responders during NAC, allowing for earlier treatment intensification. In our previous prospective observational study, 100 breast cancer patients underwent QUS imaging before and four times during NAC. Machine learning algorithms based on QUS texture features acquired in the first week of treatment were developed and achieved 78% accuracy in predicting treatment response. In the current study, we aimed to validate these algorithms in an independent prospective cohort to assess reproducibility and confirm their clinical utility. Methods: We included breast cancer patients eligible for NAC per standard of care, with tumours larger than 1.5 cm. QUS imaging was acquired at baseline and during the first week of treatment. Tumour response was defined as a ≥30% reduction in target lesion size on the resection specimen compared to baseline imaging. Results: A total of 51 patients treated between 2018 and 2021 were included (median age 49 years; median tumour size 3.6 cm). Most were estrogen receptor–positive (65%) or HER2-positive (33%), and the majority received dose-dense AC-T (n = 34, 67%) or FEC-D (n = 15, 29%) chemotherapy, with or without trastuzumab. The support vector machine algorithm achieved an area under the curve of 0.71, with 86% accuracy, 91% specificity, 50% sensitivity, 93% negative predictive value, and 43% positive predictive value for predicting treatment response. Misclassifications were primarily associated with poorly defined tumours and difficulties in accurately identifying the region of interest. Conclusions: Our findings validate QUS-based machine learning models for early prediction of chemotherapy response and support their potential as non-invasive tools for treatment personalization and clinical trial development focused on early treatment intensification. Full article

(This article belongs to the Special Issue Clinical Applications of Ultrasound in Cancer Imaging and Treatment)

► Show Figures

Figure 1

28 pages, 1748 KiB

Open AccessReview

Neutrophil Dynamics in Response to Cancer Therapies

by Huazhen Xu, Xiaojun Chen, Yuqing Lu, Nihao Sun, Karis E. Weisgerber, Manzhu Xu and Ren-Yuan Bai

Cancers 2025, 17(15), 2593; https://doi.org/10.3390/cancers17152593 - 7 Aug 2025

Abstract

Neutrophils are increasingly recognized as key players in the tumor microenvironment (TME), displaying functional plasticity that enables them to either promote or inhibit cancer progression. Depending on environmental cues, tumor-associated neutrophils (TANs) may polarize toward antitumor “N1” or protumor “N2” phenotypes, exerting diverse [...] Read more.

Neutrophils are increasingly recognized as key players in the tumor microenvironment (TME), displaying functional plasticity that enables them to either promote or inhibit cancer progression. Depending on environmental cues, tumor-associated neutrophils (TANs) may polarize toward antitumor “N1” or protumor “N2” phenotypes, exerting diverse effects on tumor growth, metastasis, immune modulation, and treatment response. While previous studies have focused on the pathological roles of TANs in cancer, less attention has been given to how cancer therapies themselves influence the behavior of TANs. This review provides a comprehensive synthesis of current knowledge regarding the dynamics of TANs in response to major cancer treatment modalities, including chemotherapy, radiotherapy, cell-based immunotherapies, and oncolytic viral and bacterial therapies. We discuss how these therapies influence TAN recruitment, polarization, and effector functions within the TME, and highlight key molecular regulators involved. By consolidating mechanistic and translational insights, this review emphasizes the potential to therapeutically reprogram TANs to enhance treatment efficacy. A deeper understanding of context-dependent TAN roles will be essential for developing more effective, neutrophil-informed cancer therapies. Full article

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

► Show Figures

Figure 1

17 pages, 1852 KiB

Open AccessArticle

Overall Survival Associated with Real-World Treatment Sequences in Patients with CLL/SLL in the United States

by Joanna M. Rhodes, Naleen Raj Bhandari, Manoj Khanal, Dan He, Sarang Abhyankar, John M. Pagel, Lisa M. Hess and Alan Z. Skarbnik

Cancers 2025, 17(15), 2592; https://doi.org/10.3390/cancers17152592 - 7 Aug 2025

Abstract

Background/Objectives: This study compared overall survival (OS) associated with common real-world treatment sequences in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) in the United States. Methods: Utilizing the nationwide Flatiron Health electronic health record-derived de-identified database, adult CLL/SLL patients who initiated [...] Read more.

Background/Objectives: This study compared overall survival (OS) associated with common real-world treatment sequences in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) in the United States. Methods: Utilizing the nationwide Flatiron Health electronic health record-derived de-identified database, adult CLL/SLL patients who initiated systemic therapy (JAN2016-NOV2023) and received at least two lines of therapy (LoTs) were analyzed. Treatment regimens were categorized based on drug class, and most frequent (n ≥ 50) sequences (first LoT followed by [→] second LoT) were compared. OS from initiation of the first LoT was compared using multivariable Cox proportional hazard models, and adjusted hazard ratios with 95% CIs were reported. Results: Among 2354 eligible patients, n = 1711 (73%) received the 16 most frequent treatment sequences. Sequencing chemoimmunotherapy (CIT) → CIT (HR: 2.29 [1.23–4.28]), anti-CD20 monoclonal antibody (anti-CD20mab) monotherapy → CIT (1.95 [1.03–3.69]), and covalent Bruton tyrosine kinase inhibitor (cBTKi) monotherapy → anti-CD20mab monotherapy (2.00 [1.07–3.74]) were associated with worse OS compared to patients treated with cBTKi monotherapy → B-cell lymphoma 2 inhibitors (BCL2i) + anti-CD20mab (reference). Conclusions: OS associated with other sequences were not significantly different from the reference sequence in adjusted analyses, suggesting a lack of evidence for the optimal standard of care for sequencing the first two LoTs in real-world settings. Future research should reassess sequencing outcomes as novel treatments become adopted into clinical practice. Full article

(This article belongs to the Section Cancer Therapy)

► Show Figures

Figure 1

17 pages, 2539 KiB

Open AccessArticle

Auxiliary Value of [¹⁸F]F-Fluorocholine PET/CT in Evaluating Post-Stereotactic Radiosurgery Recurrence of Lung Cancer Brain Metastases: A Comparative Analysis with Contrast-Enhanced MRI

by Yafei Zhang, Mimi Xu, Shuye Yang, Lili Lin, Huatao Wang, Kui Zhao, Hong Yang and Xinhui Su

Cancers 2025, 17(15), 2591; https://doi.org/10.3390/cancers17152591 - 7 Aug 2025

Abstract

Background/Objectives: This study aims to evaluate the additional value of [¹⁸F]F-fluorocholine ([¹⁸F]F-FCH) PET/CT over contrast-enhanced magnetic resonance imaging (CE-MRI) in detecting the recurrence of brain metastases (BMs) after stereotactic radiosurgery (SRS) in patients with lung cancer brain metastases (LCBMs). [...] Read more.

Background/Objectives: This study aims to evaluate the additional value of [¹⁸F]F-fluorocholine ([¹⁸F]F-FCH) PET/CT over contrast-enhanced magnetic resonance imaging (CE-MRI) in detecting the recurrence of brain metastases (BMs) after stereotactic radiosurgery (SRS) in patients with lung cancer brain metastases (LCBMs). Methods: Thirty-one patients with suspected recurrence of BM in LCBM after SRS were enrolled in this retrospective study. They underwent both [¹⁸F]F-FCH PET/CT and CE-MRI within 2 weeks. The tumor imaging parameters and clinical features were analyzed. The results of histopathology or radiographic follow-up served as the reference standard for the final diagnosis. Results: In these 31 patients, there were 54 lesions, of which 27 lesions were proven to be BM recurrence, while 27 lesions were non-recurrence. [¹⁸F]F-FCH PET/CT showed high radiotracer uptake in recurrent lesions of BM and identified 24 positive lesions (88.89% of sensitivity), while CE-MRI indicated 23 positive lesions (85.19% of sensitivity). [¹⁸F]F-FCH PET/CT indicated higher specificity (81.48%) and accuracy (85.19%) in detecting recurrence of BM than CE-MRI (40.74% and 62.96%, both p < 0.05), particularly in frontal lobes and cerebella. For lesion sizes, the accuracy of [¹⁸F]F-FCH PET/CT in detecting recurrent lesions was higher than that of CE-MRI for lesions over 1.0 cm but below 2.0 cm (p = 0.016). The detective performance of [¹⁸F]F-FCH PET/CT combined with CE-MRI was higher than [¹⁸F]F-FCH PET/CT or CE-MRI alone (all p < 0.05). Interestingly, TLC (≥4.11) was significantly correlated with poor intracranial PFS (iPFS), meaning it was a significant prognostic factor for iPFS. Conclusions: This study identified that compared with CE-MRI, [¹⁸F]F-FCH PET/CT demonstrated higher specificity and accuracy in diagnosing recurrence of BM in LCBM after SRS. Combining [¹⁸F]F-FCH PET/CT with CE-MRI has the potential to improve diagnostic performance for recurrence of BM and management of patient treatment. TLC was an independent risk factor for iPFS. Full article

(This article belongs to the Section Cancer Metastasis)

► Show Figures

Figure 1

21 pages, 1727 KiB

Open AccessReview

Immune Evasion in Head and Neck Squamous Cell Carcinoma: Roles of Cancer-Associated Fibroblasts, Immune Checkpoints, and TP53 Mutations in the Tumor Microenvironment

by Chung-Che Tsai, Yi-Chiung Hsu, Tin-Yi Chu, Po-Chih Hsu and Chan-Yen Kuo

Cancers 2025, 17(15), 2590; https://doi.org/10.3390/cancers17152590 - 7 Aug 2025

Abstract

Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive malignancy characterized by complex interactions within the tumor microenvironment (TME) that facilitate immune evasion and tumor progression. The TME consists of diverse cellular components, including cancer-associated fibroblasts, immune and endothelial cells, and [...] Read more.

Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive malignancy characterized by complex interactions within the tumor microenvironment (TME) that facilitate immune evasion and tumor progression. The TME consists of diverse cellular components, including cancer-associated fibroblasts, immune and endothelial cells, and extracellular matrix elements, that collectively modulate tumor growth, metastasis, and resistance to therapy. Immune evasion in HNSCC is orchestrated through multiple mechanisms, including the suppression of cytotoxic T lymphocytes, recruitment of immunosuppressive cells, such as regulatory T and myeloid-derived suppressor cells, and upregulation of immune checkpoint molecules (e.g., PD-1/PD-L1 and CTLA-4). Natural killer (NK) cells, which play a crucial role in anti-tumor immunity, are often dysfunctional within the HNSCC TME due to inhibitory signaling and metabolic constraints. Additionally, endothelial cells contribute to tumor angiogenesis and immune suppression, further exacerbating disease progression. Recent advancements in immunotherapy, particularly immune checkpoint inhibitors and NK cell-based strategies, have shown promise in restoring anti-tumor immunity. Moreover, TP53 mutations, frequently observed in HNSCC, influence tumor behavior and therapeutic responses, highlighting the need for personalized treatment approaches. This review provides a comprehensive analysis of the molecular and cellular mechanisms governing immune evasion in HNSCC with a focus on novel therapeutic strategies aimed at improving patient outcomes. Full article

(This article belongs to the Special Issue Oral Cancer: Prevention and Early Detection (2nd Edition))

► Show Figures

Figure 1

28 pages, 845 KiB

Open AccessReview

Circulating Tumor DNA in Prostate Cancer: A Dual Perspective on Early Detection and Advanced Disease Management

by Stepan A. Kopytov, Guzel R. Sagitova, Dmitry Y. Guschin, Vera S. Egorova, Andrei V. Zvyagin and Alexey S. Rzhevskiy

Cancers 2025, 17(15), 2589; https://doi.org/10.3390/cancers17152589 - 6 Aug 2025

Abstract

Prostate cancer (PC) remains a leading cause of malignancy in men worldwide, with current diagnostic methods such as prostate-specific antigen (PSA) testing and tissue biopsies facing limitations in specificity, invasiveness, and ability to capture tumor heterogeneity. Liquid biopsy, especially analysis of circulating tumor [...] Read more.

Prostate cancer (PC) remains a leading cause of malignancy in men worldwide, with current diagnostic methods such as prostate-specific antigen (PSA) testing and tissue biopsies facing limitations in specificity, invasiveness, and ability to capture tumor heterogeneity. Liquid biopsy, especially analysis of circulating tumor DNA (ctDNA), has emerged as a transformative tool for non-invasive detection, real-time monitoring, and treatment selection for PC. This review examines the role of ctDNA in both localized and metastatic PCs, focusing on its utility in early detection, risk stratification, therapy selection, and post-treatment monitoring. In localized PC, ctDNA-based biomarkers, including ctDNA fraction, methylation patterns, fragmentation profiles, and mutations, demonstrate promise in improving diagnostic accuracy and predicting disease recurrence. For metastatic PC, ctDNA analysis provides insights into tumor burden, genomic alterations, and resistance mechanisms, enabling immediate assessment of treatment response and guiding therapeutic decisions. Despite challenges such as the low ctDNA abundance in early-stage disease and the need for standardized protocols, advances in sequencing technologies and multimodal approaches enhance the clinical applicability of ctDNA. Integrating ctDNA with imaging and traditional biomarkers offers a pathway to precision oncology, ultimately improving outcomes. This review underscores the potential of ctDNA to redefine PC management while addressing current limitations and future directions for research and clinical implementation. Full article

(This article belongs to the Special Issue Cell-Free DNA as Prognostic and Predictive Biomarker in Solid Cancers (2nd Edition))

► Show Figures

Graphical abstract

17 pages, 1865 KiB

Open AccessArticle

Biomarkers in Renal Cell Carcinoma: A Systematic Review and Immunohistochemical Validation Study

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

Cancers 2025, 17(15), 2588; https://doi.org/10.3390/cancers17152588 - 6 Aug 2025

Abstract

Background and Objectives: The worldwide incidence of renal cell carcinoma (RCC) rose by 22% between 2012 and 2022. In Australia, RCC accounted for 2.8% of all cancer diagnoses and contributing to 1.8% of cancer-related deaths. Identification of RCC biomarkers may aid in [...] Read more.

Background and Objectives: The worldwide incidence of renal cell carcinoma (RCC) rose by 22% between 2012 and 2022. In Australia, RCC accounted for 2.8% of all cancer diagnoses and contributing to 1.8% of cancer-related deaths. Identification of RCC biomarkers may aid in diagnosis and management. Methods: A systematic review of immunohistochemical markers of RCC studies published between 1990 and 2019 was undertaken to select candidate biomarkers of RCC. Immunohistochemical staining of 73 clear cell RCC tumors and paired normal tissue was undertaken using selected markers. Semi-quantitative and quantitative analysis of staining intensity between paired samples was undertaken to evaluate utility as potential biomarkers, using Chi-square tests and paired t-tests for analysis. As an exploratory analysis, staining intensity was also compared on clinical/demographic variables using linear and logistic regression. Results: There were 123 candidate biomarkers identified in 91 studies. Four candidate markers were selected for further investigation: aminopeptidase A (APA)/cluster of differentiation (CD)249, aminopeptidase N (APN)/CD13, gamma-glutamyl transferase (GGT), and neuron-specific enolase (NSE). APA, GGT, and APN all demonstrated reduced staining intensity in the tumor compared with normal tissue (p < 0.001 for all). NSE demonstrated a statistically significant increase in expression in tumor compared with normal tissue (p < 0.001), and this was more pronounced in patients aged >60 years (p = 0.038). Conclusions: The utility of APA, APN, and GGT as diagnostic biomarkers in clear cell RCC is limited. NSE may have some role as a biomarker for clear cell RCC, particularly among older patients; however, further investigation is required. Full article

(This article belongs to the Special Issue Optimizing Surgical Procedures and Outcomes in Renal Cancer)

► Show Figures

Figure 1

14 pages, 340 KiB

Open AccessArticle

FLOT Versus CROSS—What Is the Optimal Therapeutic Approach for Locally Advanced Adenocarcinoma of the Esophagus and the Esophagogastric Junction?

by Martin Leu, Hannes Mahler, Johanna Reinecke, Ute Margarethe König, Leif Hendrik Dröge, Manuel Guhlich, Benjamin Steuber, Marian Grade, Michael Ghadimi, Volker Ellenrieder, Stefan Rieken and Alexander Otto König

Cancers 2025, 17(15), 2587; https://doi.org/10.3390/cancers17152587 - 6 Aug 2025

Abstract

Background/Objectives: Neoadjuvant radiochemotherapy and perioperative chemotherapy are both well-established treatment strategies for locally advanced adenocarcinoma of the esophagus (EAC) and the esophagogastric junction (AEGJ). However, recent knowledge controversially discusses whether neoadjuvant radiotherapy or perioperative chemotherapy represents superior therapeutic options to prolong survival or [...] Read more.

Background/Objectives: Neoadjuvant radiochemotherapy and perioperative chemotherapy are both well-established treatment strategies for locally advanced adenocarcinoma of the esophagus (EAC) and the esophagogastric junction (AEGJ). However, recent knowledge controversially discusses whether neoadjuvant radiotherapy or perioperative chemotherapy represents superior therapeutic options to prolong survival or cause less toxicity. Methods: We retrospectively analyzed 76 patients with locally advanced EAC or AEGJ treated at our tertiary cancer center between January 2015 and March 2023. Patients received either perioperative FLOT chemotherapy (n = 36) or neoadjuvant radiochemotherapy following the CROSS protocol (n = 40), followed by surgical resection and standardized follow-up. We compared survival outcomes, toxicity profiles, treatment compliance, and surgical results between the two groups. Results: There were no statistically significant differences between FLOT and CROSS treatments in five-year loco-regional controls (LRC: 61.5% vs. 68.6%; p = 0.81), progression-free survival (PFS: 33.9% vs. 42.8%; p = 0.82), overall survival (OS: 60.2% vs. 63.4%; p = 0.91), or distant controls (DC: 42.1% vs. 56.5%; p = 0.39). High-grade hematologic toxicities did not significantly differ between groups (p > 0.05). Treatment compliance was lower in the FLOT group, with 50% (18/36) not completing all the planned chemotherapy cycles, compared to 17.5% (7/40) in the CROSS group. All the patients in the CROSS group received the full radiotherapy dose. Surgical outcomes and post-surgical tumor status were comparable between the groups. Conclusions: Although perioperative chemotherapy with FLOT has recently become a standard of care for locally advanced EAC and AEGJ, neoadjuvant radiochemotherapy per the CROSS protocol remains a well-tolerated alternative. In appropriately selected patients, both approaches yield comparable oncological outcomes. Full article

(This article belongs to the Special Issue Current Treatments of Esophageal and Esophagogastric Junction Cancers)

► Show Figures

Figure 1

22 pages, 885 KiB

Open AccessArticle

MRI-Based Radiomics for Outcome Stratification in Pediatric Osteosarcoma

by Esther Ngan, Dolores Mullikin, Ashok J. Theruvath, Ananth V. Annapragada, Ketan B. Ghaghada, Andras A. Heczey and Zbigniew A. Starosolski

Cancers 2025, 17(15), 2586; https://doi.org/10.3390/cancers17152586 - 6 Aug 2025

Abstract

Background/Objectives: Osteosarcoma (OS) is the most common malignant bone tumor in children and adolescents; the survival rate is as low as 24%. Accurate prediction of clinical outcomes remains a challenge due to tumor heterogeneity and the complexity of pediatric cases. This study [...] Read more.

Background/Objectives: Osteosarcoma (OS) is the most common malignant bone tumor in children and adolescents; the survival rate is as low as 24%. Accurate prediction of clinical outcomes remains a challenge due to tumor heterogeneity and the complexity of pediatric cases. This study aims to improve predictions of progressive disease, therapy response, relapse, and survival in pediatric OS using MRI-based radiomics and machine learning methods. Methods: Pre-treatment contrast-enhanced coronal T1-weighted MR scans were collected from 63 pediatric OS patients, with an additional nine external cases used for validation. Three strategies were considered for target region segmentation (whole-tumor, tumor sampling, and bone/soft tissue) and used for MRI-based radiomics. These were then combined with clinical features to predict OS clinical outcomes. Results: The mean age of OS patients was 11.8 ± 3.5 years. Most tumors were located in the femur (65%). Osteoblastic subtype was the most common histological classification (79%). The majority of OS patients (79%) did not have evidence of metastasis at diagnosis. Progressive disease occurred in 27% of patients, 59% of patients showed adequate therapy response, 25% experienced relapse after therapy, and 30% died from OS. Classification models based on bone/soft tissue segmentation generally performed the best, with certain clinical features improving performance, especially for therapy response and mortality. The top performing classifier in each outcome achieved 0.94–1.0 validation ROC AUC and 0.63–1.0 testing ROC AUC, while those without radiomic features (RFs) generally performed suboptimally. Conclusions: This study demonstrates the strong predictive capabilities of MRI-based radiomics and multi-region segmentations for predicting clinical outcomes in pediatric OS. Full article

(This article belongs to the Special Issue The Roles of Deep Learning in Cancer Radiotherapy)

► Show Figures

Figure 1

14 pages, 1870 KiB

Open AccessArticle

Analysis of Risk Factors for High-Risk Lymph Node Metastasis in Papillary Thyroid Microcarcinoma

by Yi-Hsiang Chiu, Shu-Ting Wu, Yung-Nien Chen, Wen-Chieh Chen, Lay-San Lim, Yvonne Ee Wern Chiew, Ping-Chen Kuo, Ya-Chen Yang, Shun-Yu Chi and Chen-Kai Chou

Cancers 2025, 17(15), 2585; https://doi.org/10.3390/cancers17152585 - 6 Aug 2025

Abstract

Background: Papillary thyroid microcarcinoma (PTMC) is associated with certain features that carry an increased risk of local recurrence, underscoring the importance of preoperative risk assessment. This study investigated the clinicopathological factors associated with high-risk lymph node metastasis (HRLNM) and patient outcomes. HRLNM is [...] Read more.

Background: Papillary thyroid microcarcinoma (PTMC) is associated with certain features that carry an increased risk of local recurrence, underscoring the importance of preoperative risk assessment. This study investigated the clinicopathological factors associated with high-risk lymph node metastasis (HRLNM) and patient outcomes. HRLNM is defined as ≥5 metastatic lymph nodes and/or lateral neck metastasis. Methods: We conducted a retrospective review of 985 patients with PTMC who underwent thyroidectomy at the Kaohsiung Chang Gung Memorial Hospital from 2013 to 2022. Results: Among the 985 patients, 100 (10.2%) had lymph node metastasis (LNM), and 27% of these were classified as having HRLNM. Male sex (OR 3.61, p = 0.04) and extranodal extension (OR 3.76, p = 0.043) were independent predictors of HRLNM. Patients with LNM exhibited lower rates of excellent treatment response (75% vs. 87%, p = 0.001), higher recurrence rates (9.0% vs. 0.6%, p = 0.001), and an increased risk of distant metastasis (2.0% vs. 0%). Recurrence-free survival (RFS) was significantly shorter in patients with LNM (120.9 vs. 198.6 months, p < 0.001). Although HRLNM showed a trend toward reduced RFS (113.5 vs. 124.6 months, p = 0.177), its impact on long-term survival remains uncertain. Conclusions: Male sex and extranodal extension were significant risk factors for HRLNM in patients with PTMC. These findings highlight the need for individualized risk stratification to guide treatment strategies and improve patient outcomes. Full article

(This article belongs to the Special Issue Clinical Applications of Precision Diagnosis for Thyroid Cancers and Its Clinical Use for Treatments Choice)

► Show Figures

Figure 1

21 pages, 1557 KiB

Open AccessReview

Neoadjuvant Therapy or Upfront Surgery for Pancreatic Cancer—To Whom, When, and How?

by Daria Kwaśniewska, Marta Fudalej, Anna Maria Badowska-Kozakiewicz, Aleksandra Czerw and Andrzej Deptała

Cancers 2025, 17(15), 2584; https://doi.org/10.3390/cancers17152584 - 6 Aug 2025

Abstract

The management of resectable pancreatic ductal adenocarcinoma (R-PDAC) and borderline resectable pancreatic ductal adenocarcinoma (BR-PDAC) remains a topic of active debate. Although neoadjuvant therapy (NAT) has shown clinical benefits in BR-PDAC, especially in increasing resectability and achieving higher rates of margin-negative (R0) resections, [...] Read more.

The management of resectable pancreatic ductal adenocarcinoma (R-PDAC) and borderline resectable pancreatic ductal adenocarcinoma (BR-PDAC) remains a topic of active debate. Although neoadjuvant therapy (NAT) has shown clinical benefits in BR-PDAC, especially in increasing resectability and achieving higher rates of margin-negative (R0) resections, its role in R-PDAC is less clearly defined. Additionally, the role of immunotherapy in PDAC is still being explored, with ongoing trials investigating new combinations to overcome the tumor’s immune-resistant microenvironment. This article provides a comprehensive narrative review of the current evidence comparing NAT with upfront surgery in pancreatic cancer management, focusing on randomized controlled trials and meta-analyses that assess outcomes in R-PDAC and BR-PDAC. The review aims to determine whether NAT offers a significant survival advantage over traditional post-operative strategies and to clarify which clinical scenarios may benefit most from NAT. The literature was identified through a systematic search of PubMed, Scopus, and Google Scholar databases up to March 2025. Article selection adhered to the PRISMA guidelines. Our review of existing evidence supports NAT as the standard of care for BR-PDAC. Meanwhile, management of R-PDAC should be tailored individually, guided by risk stratification that considers both clinical parameters and molecular features. Immunotherapy and targeted therapies are still in early research phases, and their further integration as NAT remains controversial. Full article

(This article belongs to the Special Issue Targeted Therapies in Pancreatic Cancer—Current Landscape and Future Directions)

► Show Figures

Figure 1

18 pages, 2164 KiB

Open AccessArticle

The Fanconi Anemia Pathway Inhibits mTOR Signaling and Prevents Accelerated Translation in Head and Neck Cancer Cells

by Bianca Ruffolo, Sara Vicente-Muñoz, Khyati Y. Mehta, Cosette M. Rivera-Cruz, Xueheng Zhao, Lindsey Romick, Kenneth D. R. Setchell, Adam Lane and Susanne I. Wells

Cancers 2025, 17(15), 2583; https://doi.org/10.3390/cancers17152583 - 6 Aug 2025

Abstract

Background/Objectives: The Fanconi anemia (FA) pathway is essential for the repair of DNA interstrand crosslinks and maintenance of genomic stability. Germline loss of FA pathway function in the inherited Fanconi anemia syndrome leads to increased DNA damage and a range of clinical phenotypes, [...] Read more.

Background/Objectives: The Fanconi anemia (FA) pathway is essential for the repair of DNA interstrand crosslinks and maintenance of genomic stability. Germline loss of FA pathway function in the inherited Fanconi anemia syndrome leads to increased DNA damage and a range of clinical phenotypes, including a heightened risk of head and neck squamous cell carcinoma (HNSCC). Non-synonymous FA gene mutations are also observed in up to 20% of sporadic HNSCCs. The mechanistic target of rapamycin (mTOR) is known to stimulate cell growth, anabolic metabolism including protein synthesis, and survival following genotoxic stress. Methods/Results: Here, we demonstrate that FA− deficient (FA−) HNSCC cells exhibit elevated intracellular amino acid levels, increased total protein content, and an increase in protein synthesis indicative of enhanced translation. These changes are accompanied by hyperactivation of the mTOR effectors translation initiation factor 4E Binding Protein 1 (4E-BP1) and ribosomal protein S6. Treatment with the mTOR inhibitor rapamycin reduced the phosphorylation of these targets and blocked translation specifically in FA− cells but not in their isogenic FA− proficient (FA+) counterparts. Rapamycin-mediated mTOR inhibition sensitized FA− but not FA+ cells to rapamycin under nutrient stress, supporting a therapeutic metabolism-based vulnerability in FA− cancer cells. Conclusions: These findings uncover a novel role for the FA pathway in suppressing mTOR signaling and identify mTOR inhibition as a potential strategy for targeting FA− HNSCCs. Full article

(This article belongs to the Special Issue Targeted Therapy in Head and Neck Cancer)

► Show Figures

Figure 1

23 pages, 789 KiB

Open AccessPerspective

Therapeutic Cancer Vaccines in Colorectal Cancer: Platforms, Mechanisms, and Combinations

by Chiara Gallio, Luca Esposito and Alessandro Passardi

Cancers 2025, 17(15), 2582; https://doi.org/10.3390/cancers17152582 - 6 Aug 2025

Abstract

Colorectal cancer (CRC) remains one of the most lethal malignancies worldwide, with high recurrence rates and limited curative options in metastatic settings. Cancer vaccines represent an emerging immunotherapeutic approach that aims to stimulate robust, tumor-specific immune responses. This review summarizes the current state [...] Read more.

Colorectal cancer (CRC) remains one of the most lethal malignancies worldwide, with high recurrence rates and limited curative options in metastatic settings. Cancer vaccines represent an emerging immunotherapeutic approach that aims to stimulate robust, tumor-specific immune responses. This review summarizes the current state of CRC vaccine development, including tumor cell-based, dendritic cell-based, peptide-based, nucleic acid-based (DNA and mRNA), and virus-based platforms. We highlight findings from key clinical trials that demonstrate immunogenicity, safety, and preliminary efficacy, with particular attention to combinations with chemotherapy and immune checkpoint inhibitors. Furthermore, we explore critical challenges such as tumor heterogeneity, immunosuppressive tumor microenvironments, and the logistical complexity; in this context, we particularly focus on the current development of personalized cancer vaccines, exploring the newly identified encouraging epitopes and their safety and efficacy in recent trials. The integration of cancer vaccines with in silico modeling, advanced delivery systems such as nanoparticles or AI-guided designs, and microbiome modulation represents a promising avenue for enhancing their clinical utility. Overall, therapeutic and prophylactic cancer vaccines may soon contribute meaningfully to the comprehensive management of CRC, especially in settings of minimal residual disease or early recurrence. Full article

(This article belongs to the Special Issue Exploring Immunotherapy in Colorectal Cancer)

► Show Figures

Figure 1

12 pages, 616 KiB

Open AccessArticle

Surgical Margin Analysis in Osteosarcoma: Impact on Survival and Local Control

by Sebastian Breden, Simone Beischl, Florian Hinterwimmer, Sarah Consalvo, Carolin Knebel, Rüdiger von Eisenhart-Rothe, Rainer Burgkart and Ulrich Lenze

Cancers 2025, 17(15), 2581; https://doi.org/10.3390/cancers17152581 - 6 Aug 2025

Abstract

Background/Objectives: The quality of surgical margins has been shown to be a prognostic factor in many sarcoma entities, yet its role in osteosarcoma remains controversial. While previous studies have shown that the outcome was not related to the margin width in bone, the [...] Read more.

Background/Objectives: The quality of surgical margins has been shown to be a prognostic factor in many sarcoma entities, yet its role in osteosarcoma remains controversial. While previous studies have shown that the outcome was not related to the margin width in bone, the impact of the extraosseous margin width (margin at the soft tissue invasion)—which needs to be close sometimes due to neurovascular structures—needs to be assessed. This study aims to evaluate the influence of soft tissue surgical margins on local recurrence and overall survival in patients with high-grade osteosarcoma. Methods: We conducted a retrospective, single-center study including 75 patients treated for high-grade osteosarcoma. All patients underwent standardized neoadjuvant chemotherapy followed by complete surgical resection. Patients were stratified into three groups based on the histological margin width of the extraosseous parts: group 1 (<1 mm), group 2 (1–5 mm), and group 3 (≥5 mm). Primary endpoints were local recurrence and overall survival (OS), analyzed using Kaplan–Meier estimates, log-rank tests, and Cox regression. Results: Local recurrence occurred in seven patients (9%). Although the overall comparison between the three groups was not statistically significant (p = 0.074), a subgroup analysis revealed a significantly higher recurrence rate in patients with margins < 1 mm compared to those with wider margins (p = 0.024). No significant differences in overall survival (OS) were observed between the groups (p = 0.896). Tumor location, metastatic status, and UICC stage were significant predictors for both endpoints in univariate analysis. However, none of these association were confirmed in multivariate analyses. Conclusions: Very close surgical margins (<1 mm) may increase the risk of local recurrence in high-grade osteosarcoma; however, they do not appear to affect overall survival. Full article

(This article belongs to the Special Issue Clinical Treatment of Osteosarcoma)

► Show Figures

Figure 1

23 pages, 406 KiB

Open AccessSystematic Review

Advances in Bidirectional Therapy for Peritoneal Metastases: A Systematic Review of Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) Combined with Systemic Chemotherapy

by Manuela Robella, Marco Vitturini, Andrea Di Giorgio, Matteo Aulicino, Martin Hubner, Emanuele Koumantakis, Felice Borghi, Paolo Catania, Armando Cinquegrana and Paola Berchialla

Cancers 2025, 17(15), 2580; https://doi.org/10.3390/cancers17152580 - 6 Aug 2025

Abstract

Background: Peritoneal metastases (PM) represent a common and challenging manifestation of several gastrointestinal and gynecologic malignancies. Bidirectional treatment—combining Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) with systemic chemotherapy—has emerged as a strategy to enhance locoregional control while maintaining systemic coverage. Objective: This systematic [...] Read more.

Background: Peritoneal metastases (PM) represent a common and challenging manifestation of several gastrointestinal and gynecologic malignancies. Bidirectional treatment—combining Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) with systemic chemotherapy—has emerged as a strategy to enhance locoregional control while maintaining systemic coverage. Objective: This systematic review aimed to analyze the study design, characteristics, and timing of the treatments administered—including the type of systemic chemotherapy, intraperitoneal agents used in PIPAC, and interval between administrations—as well as the clinical outcomes, safety profile, and overall methodological quality of the available literature on bidirectional treatment for peritoneal metastases. Methods: A systematic literature search was conducted across the PubMed, Embase, and Cochrane Library databases up to April 2025. Studies were included if they reported clinical outcomes of patients undergoing bidirectional treatment. Data extraction focused on survival, response assessment (PRGS, PCI), adverse events, systemic and intraperitoneal regimens, treatment interval, and study methodology. Results: A total of 22 studies involving 1015 patients (742 treated with bidirectional therapy) were included. Median overall survival ranged from 2.8 to 19.6 months, with the most favorable outcomes observed in gastric and colorectal cancer cohorts. PRGS improvement after multiple PIPAC cycles was reported in >80% of evaluable cases. High-grade adverse events (CTCAE ≥ 3) occurred in up to 17% of patients in most studies, with only one study reporting treatment-related mortality. However, methodological quality was generally moderate, with considerable heterogeneity in treatment protocols, response criteria, systemic regimens, and toxicity attribution. Conclusions: Bidirectional therapy with PIPAC and systemic chemotherapy appears to be a feasible and potentially effective strategy for selected patients with peritoneal metastases. Despite encouraging outcomes, definitive conclusions are limited by the retrospective nature and heterogeneity of available studies. Prospective standardized trials are needed to confirm efficacy, clarify patient selection, and optimize treatment protocols. Full article

(This article belongs to the Section Cancer Therapy)

► Show Figures

Figure 1

22 pages, 688 KiB

Open AccessReview

The Evolving Treatment Landscape for the Elderly Multiple Myeloma Patient: From Quad Regimens to T-Cell Engagers and CAR-T

by Matthew James Rees and Hang Quach

Cancers 2025, 17(15), 2579; https://doi.org/10.3390/cancers17152579 - 5 Aug 2025

Abstract

Multiple myeloma (MM) is predominantly a disease of the elderly. In recent years, a surge of highly effective plasma cell therapies has revolutionized the care of elderly multiple myeloma (MM) patients, for whom frailty and age-related competing causes of mortality determine management. Traditionally, [...] Read more.

Multiple myeloma (MM) is predominantly a disease of the elderly. In recent years, a surge of highly effective plasma cell therapies has revolutionized the care of elderly multiple myeloma (MM) patients, for whom frailty and age-related competing causes of mortality determine management. Traditionally, the treatment of newly diagnosed elderly patients has centered on doublet or triplet combinations composed of immunomodulators (IMIDs), proteasome inhibitors (PIs), anti-CD38 monoclonal antibodies (mAbs), and corticosteroids producing median progression-free survival (PFS) rates between 34 and 62 months. However, recently, a series of large phase III clinical trials examining quadruplet regimens of PIs, IMIDs, corticosteroids, and anti-CD38 mAbs have shown exceptional outcomes, with median PFS exceeding 60 months, albeit with higher rates of peripheral neuropathy (≥Grade 2: 27% vs. 10%) when PIs and IMIDs are combined, and infections (≥Grade 3: 40% vs. 29–41%) with the addition of anti-CD38mAbs. The development of T-cell redirecting therapies including T-cell engagers (TCEs) and CAR-T cells has further expanded the therapeutic arsenal. TCEs have shown exceptional activity in relapsed disease and are being explored in the newly diagnosed setting with promising early results. However, concerns remain regarding the logistical challenges of step-up dosing, which often necessitates inpatient admission, the infectious risks, and the financial burden associated with TCEs in elderly patients. CAR-T, the most potent commercially available therapy for MM, offers the potential of a ‘one and done’ approach. However, its application to elderly patients has been tempered by significant concerns of cytokine release syndrome, early and delayed neurological toxicity, and its overall tolerability in frail patients. Robust data in frail patients are still needed. How CAR-T and TCEs will be sequenced among the growing therapeutic armamentarium for elderly MM patients remains to be determined. This review explores the safety, efficacy, cost, and logistical barriers associated with the above treatments in elderly MM patients. Full article

(This article belongs to the Special Issue The Elderly Multiple Myeloma Patient in the Era of Quad Therapy and CAR-T Cells)

► Show Figures

Figure 1

17 pages, 4105 KiB

Open AccessArticle

Evaluation of the Effect of X-Ray Therapy on Glioma Rat Model Using Chemical Exchange Saturation Transfer and Diffusion-Weighted Imaging

by Kazuki Onishi, Koji Itagaki, Sachie Kusaka, Tensei Nakano, Junpei Ueda and Shigeyoshi Saito

Cancers 2025, 17(15), 2578; https://doi.org/10.3390/cancers17152578 - 5 Aug 2025

Abstract

Background/Objectives: This study aimed to examine the changes in brain metabolites and water molecule diffusion using chemical exchange saturation transfer (CEST) imaging and diffusion-weighted imaging (DWI) after 15 Gy of X-ray irradiation in a rat model of glioma. Methods: The glioma-derived [...] Read more.

Background/Objectives: This study aimed to examine the changes in brain metabolites and water molecule diffusion using chemical exchange saturation transfer (CEST) imaging and diffusion-weighted imaging (DWI) after 15 Gy of X-ray irradiation in a rat model of glioma. Methods: The glioma-derived cell line, C6, was implanted into the striatum of the right brain of 7-week-old male Wistar rats. CEST imaging and DWI were performed on days 8, 10, and 17 after implantation using a 7T-magnetic resonance imaging. X-ray irradiation (15 Gy) was performed on day 9. Magnetization transfer ratio (MTR) and apparent diffusion coefficient (ADC) values were calculated for CEST and DWI, respectively. Results: On day 17, the MTR values at 1.2 ppm, 1.5 ppm, 1.8 ppm, 2.1 ppm, and 2.4 ppm in the irradiated group decreased significantly compared with those of the control group. The standard deviation for the ADC values on a pixel-by-pixel basis increased from day 8 to day 17 (0.6 ± 0.06 → 0.8 ± 0.17 (×10⁻³ mm²/s)) in the control group, whereas it remained nearly unchanged (0.6 ± 0.06 → 0.8 ± 0.11 (×10⁻³ mm²/s)) in the irradiated group. Conclusions: This study revealed the effects of 15 Gy X-ray irradiation in a rat model of glioma using CEST imaging and DWI. Full article

(This article belongs to the Special Issue Intraoperative Visualization Techniques and Advanced Imaging in Brain Tumors)

► Show Figures

Figure 1

23 pages, 1642 KiB

Open AccessReview

The Multifaceted Role of Autophagy in Nasopharyngeal Carcinoma: Translational Perspectives on Pathogenesis, Biomarkers, Treatment Resistance, and Emerging Therapies

by Abdul L. Shakerdi, Emma Finnegan, Yin-Yin Sheng and Graham P. Pidgeon

Cancers 2025, 17(15), 2577; https://doi.org/10.3390/cancers17152577 - 5 Aug 2025

Abstract

Background: Nasopharyngeal carcinoma (NPC) is an epithelial malignancy arising from the nasopharyngeal mucosa. Despite treatment advances such as the use of intensity-modulated radiotherapy and immune checkpoint inhibitors, resistance remains a significant clinical challenge. Many tumours are also diagnosed at an advanced stage associated [...] Read more.

Background: Nasopharyngeal carcinoma (NPC) is an epithelial malignancy arising from the nasopharyngeal mucosa. Despite treatment advances such as the use of intensity-modulated radiotherapy and immune checkpoint inhibitors, resistance remains a significant clinical challenge. Many tumours are also diagnosed at an advanced stage associated with poor prognosis. Objective: This review aims to explore the biological roles of autophagy in NPC, primarily highlighting its involvement in disease pathogenesis and treatment resistance. Methods: We performed a review of the recent literature examining the role of autophagy-related pathways in NPC pathogenesis, biomarker discovery, and therapeutic targeting. Results: Autophagy plays a dual role in NPC as it contributes to both tumour suppression and progression. It is involved in tumour initiation, metastasis, immune modulation, and treatment resistance. Autophagy-related genes such as SQSTM1, Beclin-1, and AURKA may serve as prognostic and therapeutic biomarkers. Various strategies are being investigated for their role to modulate autophagy using pharmacologic inhibitors, RNA interventions, and natural compounds. Conclusions: Further research into autophagy’s context-dependent roles in NPC may inform the development of personalised therapies and allow progress in translational and precision oncology. Full article

(This article belongs to the Special Issue From Molecular Insights to Cancer Treatments: Progress in Translational Science)

► Show Figures

Figure 1

16 pages, 4092 KiB

Open AccessArticle

Ribosome Biogenesis Underpins Tumor Progression: A Comprehensive Signature for Survival and Immunotherapy Response Prediction

by Amr R. Elhamamsy, Salma M. Aly, Rajeev S. Samant and Lalita A. Shevde

Cancers 2025, 17(15), 2576; https://doi.org/10.3390/cancers17152576 - 5 Aug 2025

Abstract

Background: RiBi is integral to cell proliferation, and its dysregulation is increasingly recognized as a hallmark of aggressive cancers. We sought to develop and validate a composite “PanRibo-515 score” reflecting RiBi activity across multiple tumor types, assess its prognostic significance, and explore [...] Read more.

Background: RiBi is integral to cell proliferation, and its dysregulation is increasingly recognized as a hallmark of aggressive cancers. We sought to develop and validate a composite “PanRibo-515 score” reflecting RiBi activity across multiple tumor types, assess its prognostic significance, and explore its relationship with immune checkpoint therapy outcomes. Methods: We curated 515 RiBi–associated genes (PanRibo-515) and used a LASSO regression-based strategy on a training dataset (GSE202203) to select the prognostically most relevant subset of 68 genes (OncoRibo-68). Directionality (positive or negative impact on survival) was assigned based on the sign of the LASSO coefficients. We integrated a forward selection approach to identify a refined subset of genes for computing the OncoRibo-68 score. For validation, patients in The Cancer Genome Atlas (TCGA) were stratified into high or low OncoRibo-68 score groups for survival analyses. Additional validation for immunotherapy response was conducted using bioinformatic platforms used for immunotherapy response analysis. Results: A higher OncoRibo-68 score consistently correlated with poorer overall and progression-free survival across multiple cancers. Elevated OncoRibo-68 score was linked to an immunosuppressive tumor microenvironment, but interestingly to increased response to checkpoint inhibitors. Conclusions: Our findings highlight RiBi as an important determinant of tumor aggressiveness and identify the OncoRibo-68 score as a promising biomarker for risk stratification and therapy selection. Future research may evaluate whether targeting RiBi pathways could enhance treatment efficacy, particularly in combination with immunotherapy. Full article

(This article belongs to the Special Issue Alterations in Ribosome Structure, Integrity and Function in Cancer and in Response to Cancer Treatments)

► Show Figures

Figure 1

Journal Description

Cancers

Latest Articles

Journal Menu

Journal Browser

Highly Accessed Articles

Latest Books

E-Mail Alert

News

Topics

Conferences

Special Issues

Topical Collections

Further Information

Guidelines

MDPI Initiatives

Follow MDPI