Cancers

24 pages, 808 KB

Open AccessReview

Cervical Cancer Treatment and Fertility: What We Know and What We Do

by Nassir Habib, Salwa Idoubba, Francoise Futcher, Emilio Pieri, Giorgia Schettini, Matteo Giorgi, Ramon Rovira Negre and Centini Gabriele

Cancers 2025, 17(18), 3057; https://doi.org/10.3390/cancers17183057 (registering DOI) - 18 Sep 2025

Abstract

Cervical cancer is a major health issue worldwide, with approximately 660,000 new cases a year, particularly in women of reproductive age (47.4 ± 12.8 years at diagnosis). Current advances in screening and immunization have shifted cervical cancer diagnoses to earlier stages; as a [...] Read more.

Cervical cancer is a major health issue worldwide, with approximately 660,000 new cases a year, particularly in women of reproductive age (47.4 ± 12.8 years at diagnosis). Current advances in screening and immunization have shifted cervical cancer diagnoses to earlier stages; as a result, fertility preservation is an essential component of building a treatment plan. Objectives: This systematic review aims to synthesize the existing techniques for fertility preservation with a focus on early-stage cervical cancer (cancer stage IA1-IB1). We will describe the different surgical and medical approaches for the treatment of cervical cancer, followed by an analysis of their oncologic safety and the associated reproductive risks and outcomes. Methods: A descriptive synthesis of the strategies for surgical management, including conization, radical trachelectomy, neoadjuvant chemotherapy (NACT), and radiotherapy, was completed. Fertility and successful pregnancy rely on patient selection, prognostic variables, and obstetric outcomes. The use of transposition of the ovaries and cryopreservation in the context of gonadotoxic treatment plans also requires investigation. Results: For patients meeting conservative eligibility criteria, conservative surgery for tumors up to 2 cm has been considered a safe oncological management strategy, although evidence remains limited. Pregnancy rate after conization ranged from 36 to 55% and 10 to 38% after radical trachelectomy. Ovarian function can be successfully preserved in >60% of laparoscopic transposition cases but resulted in a less than 15% chance of natural conception; the need for assistive reproductive techniques was often required. Conclusions: Fertility-preserving management of cervical cancer is safe and feasible in carefully selected patients, with oncologic outcomes comparable to more radical management. Continued innovation and randomized control trials in treatment paths and oncologic and fertility outcomes will benefit the field. Full article

(This article belongs to the Section Cancer Therapy)

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19 pages, 4929 KB

Open AccessArticle

A Preliminary Study on Deep Learning-Based Plan Quality Prediction in Gamma Knife Radiosurgery for Brain Metastases

by Runyu Jiang, Yuan Shao, Yingzi Liu, Chih-Wei Chang, Aubrey Zhang, Malvern Madondo, Mohammadamin Moradi, Aranee Sivananthan, Mark C Korpics, Xiaofeng Yang and Zhen Tian

Cancers 2025, 17(18), 3056; https://doi.org/10.3390/cancers17183056 - 18 Sep 2025

Abstract

Background/Objectives: GK plan quality is strongly affected by lesion size and shape, and the same evaluation metrics may not be directly comparable across patients with different anatomies. This study proposes a deep learning-based method to predict achievable, clinically acceptable plan quality from patient-specific [...] Read more.

Background/Objectives: GK plan quality is strongly affected by lesion size and shape, and the same evaluation metrics may not be directly comparable across patients with different anatomies. This study proposes a deep learning-based method to predict achievable, clinically acceptable plan quality from patient-specific geometry. Methods: A hierarchically densely connected U-Net (HD-U-Net) was trained at the lesion level to predict 3D dose distributions for the estimation of plan quality metrics, including coverage, selectivity, gradient index (GI), and conformity index at a 50% prescription dose (CI50). To improve the prediction accuracy of plan quality metrics, Dice similarity coefficient losses for the 100% and 50% isodose lines were incorporated with conventional mean squared error (MSE) loss. Results: Ten-fold cross-validation on 463 brain metastases (BMs) from 175 patients showed that our method achieved smaller mean absolute errors across all four metrics than the HD-U-Net baseline trained with MSE loss. Improvements were pronounced in all metrics for small metastases, and were observed primarily in GI and CI50 for medium and large lesions. Paired Wilcoxon signed-rank tests confirmed the statistical significance of these improvements (p < 0.05). Conclusions: The proposed method outperformed the baseline model in capturing overall trends, improving per-lesion accuracy, and enhancing robustness to dataset variability. It can serve as a pre-planning tool to guide planners in constraint setting and priority tuning, a post-planning quality control tool to identify subpar plans that could be substantially improved, and as a foundation for developing deep reinforcement learning-based automated planning of GK treatments for brain metastases. Full article

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

32 pages, 1169 KB

Open AccessReview

Actinium-225/Bismuth-213 as Potential Leaders for Targeted Alpha Therapy: Current Supply, Application Barriers, and Future Prospects

by Mohamed F. Nawar, Adli A. Selim, Basma M. Essa, Alaa F. El-Daoushy, Mohamed M. Swidan, Claudia G. Chambers, Mohammed H. Al Qahtani, Charles J. Smith and Tamer M. Sakr

Cancers 2025, 17(18), 3055; https://doi.org/10.3390/cancers17183055 - 18 Sep 2025

Abstract

Alpha therapy (TAT) relies on combining alpha-emitting radionuclides with specific cell-targeting vectors to deliver a high payload of cytotoxic radiation capable of destroying tumor tissues. TAT efficacy comes from the tissue selectivity of the targeting vector, the high linear energy transfer (LET) of [...] Read more.

Alpha therapy (TAT) relies on combining alpha-emitting radionuclides with specific cell-targeting vectors to deliver a high payload of cytotoxic radiation capable of destroying tumor tissues. TAT efficacy comes from the tissue selectivity of the targeting vector, the high linear energy transfer (LET) of the radionuclide, and the short range of alpha particles in tissues. Recent research studies have been directed to evaluate TAT on a preclinical and clinical scale, including evaluating damage to tumor tissues with minimal toxic radiation effects on surrounding healthy tissues. This review highlights the use of Actinium-225/Bismuth-213 radionuclides as promising candidates for TAT. Herein, we begin with a discussion on the production and supply of [²²⁵Ac]Ac/[²¹³Bi]Bi followed by the formulation of [²²⁵Ac]Ac/[²¹³Bi]Bi-radiopharmaceuticals using different radiolabeling techniques. Finally, we have summarized the preclinical and clinical evaluation of these potential radiotheranostic agents. Full article

(This article belongs to the Section Cancer Therapy)

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15 pages, 446 KB

Open AccessArticle

Prevalence and Clinical Significance of Potential Drug–Drug Interactions in Hospitalized Pediatric Oncology Patients: A Prospective Pharmacoepidemiologic Study

by Omid Reza Zekavat, Narjes Zarsanj, Adel Sadeghdoust, Alekhya Lavu, Mohammadreza Bordbar, Sherif Eltonsy and Payam Peymani

Cancers 2025, 17(18), 3054; https://doi.org/10.3390/cancers17183054 - 18 Sep 2025

Abstract

Background: Drug–drug interactions (DDIs) are frequent and potentially harmful in pediatric cancer patients due to polypharmacy and complex chemotherapy regimens. However, data on DDIs in hospitalized pediatric oncology patients remain limited, particularly in Middle Eastern settings. Methods: In this prospective study, we analyzed [...] Read more.

Background: Drug–drug interactions (DDIs) are frequent and potentially harmful in pediatric cancer patients due to polypharmacy and complex chemotherapy regimens. However, data on DDIs in hospitalized pediatric oncology patients remain limited, particularly in Middle Eastern settings. Methods: In this prospective study, we analyzed prescriptions for hospitalized pediatric oncology patients in Iran to assess the prevalence, severity, and nature of potential DDIs (PDDIs). Chemotherapy and supportive medications were analyzed using two validated databases (Lexi-Interact™ and Drugs.com™) between November 2019 and June 2020. Results: Of 80 patients (median age 8.9 years), 21.2% had at least one documented PDDI. We identified 197 total PDDIs involving 42 unique drug pairs. The most common DDIs included acetaminophen and granisetron (severity rating: moderate). Methotrexate and vincristine were the most frequent antineoplastic DDI pair. Methotrexate alone accounted for 156 interactions. Conclusions: This is the first prospective study from Iran—and the largest in the region—investigating PDDIs in pediatric oncology. The dual-database screening approach improved PDDI detection. Clinical teams should routinely evaluate medication profiles in pediatric cancer patients to minimize avoidable harms from DDIs. Full article

(This article belongs to the Special Issue Evolution of Cancer Therapies: Access of Developing Countries to Modern Oncology)

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19 pages, 4883 KB

Open AccessReview

Latest Advancements and Future Directions in Prostate Cancer Surgery: Reducing Invasiveness and Expanding Indications

by Valerio Santarelli, Roberta Corvino, Giulio Bevilacqua, Stefano Salciccia, Giovanni Di Lascio, Francesco Del Giudice, Giovanni Battista Di Pierro, Giorgio Franco, Simone Crivellaro and Alessandro Sciarra

Cancers 2025, 17(18), 3053; https://doi.org/10.3390/cancers17183053 - 18 Sep 2025

Abstract

For more than 20 years, after the introduction of the first robotic system, research on prostate cancer (PCa) surgery has mainly focused on evaluating outcomes of Robotic-Assisted Radical Prostatectomy (RARP). In the last few years, however, a new generation of innovative techniques, surgical [...] Read more.

For more than 20 years, after the introduction of the first robotic system, research on prostate cancer (PCa) surgery has mainly focused on evaluating outcomes of Robotic-Assisted Radical Prostatectomy (RARP). In the last few years, however, a new generation of innovative techniques, surgical approaches, and expanded indications have emerged. The Single Port (SP) robotic system was the first real hardware innovation in robotic surgery, and has already demonstrated advantages in terms of shorter length of stay, better cosmetic results and reduced postoperative pain. Artificial Intelligence (AI)-powered algorithms are being proposed as reliable tools for surgical assistance, aiding in standardization and mass implementation of robotic training. New surgical indications are emerging on the basis of patient and tumor characteristics. The extensive adoption of PCa screening and the precision of diagnostic tools have increased the rate of PCa diagnoses in a localized stage. Partial prostatectomy, despite needing further validation, has emerged as a safe and minimally invasive treatment option for confined tumors, able to minimize the side effects of prostate surgery. For locally advanced PCa, radioguided surgery has not only enhanced the oncological effectiveness of lymphadenectomy by enabling the precise identification and extraction of pathological lymph nodes, but has also contributed to minimizing the side effects associated with unnecessarily extensive dissections. Finally, in light of the increased efficacy of modern systemic therapies and the longer life expectancy, RP is currently being evaluated for primary tumor management in the metastatic phase. Despite the novelty of the aforementioned treatment options, they are already set to shape the future evolution of PCa management and international guidelines. Full article

(This article belongs to the Section Cancer Therapy)

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28 pages, 646 KB

Open AccessReview

Chronic Liver Disease Associated Cholangiocarcinoma: Genomic Insights and Precision Therapeutic Strategies

by Kyoko Oura, Asahiro Morishita, Mai Nakahara, Tomoko Tadokoro, Koji Fujita, Joji Tani, Tsutomu Masaki and Hideki Kobara

Cancers 2025, 17(18), 3052; https://doi.org/10.3390/cancers17183052 - 18 Sep 2025

Abstract

Background: Cholangiocarcinoma (CCA) is a highly heterogeneous malignancy arising from the biliary epithelium, with an increasing incidence and poor prognosis worldwide. Recent advances in next-generation sequencing have revealed a variety of genomic alterations―such as FGFR2 fusions, IDH1 mutations, and ERBB2 amplification―that may [...] Read more.

Background: Cholangiocarcinoma (CCA) is a highly heterogeneous malignancy arising from the biliary epithelium, with an increasing incidence and poor prognosis worldwide. Recent advances in next-generation sequencing have revealed a variety of genomic alterations―such as FGFR2 fusions, IDH1 mutations, and ERBB2 amplification―that may serve as therapeutic targets. However, the influence of underlying etiologic factors, including chronic liver and biliary diseases, on the molecular landscape of CCA remains unclear. Objective: This review aimed to synthesize the current knowledge on the genomic and molecular alterations of CCA in the context of diverse etiologic factors, including hepatitis B virus, hepatitis C virus, primary sclerosing cholangitis (PSC), primary biliary cholangitis, metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-related liver disease (ALD), and liver fluke infection. Main findings: Certain backgrounds, such as PSC and liver fluke infection, are associated with distinct molecular signatures (e.g., TP53, SMAD4, KRAS, and ERBB2 alterations), whereas others, such as MASLD or ALD, show limited and inconsistent genomic data. Targetable alterations―including FGFR2 fusions, IDH1 mutations, and ERBB2 amplification―are heterogeneously distributed across etiologies and anatomical subtypes. Molecular targeted therapies such as FGFR and IDH1 inhibitors have shown clinical benefits in selected patients. Conclusions: A better understanding of how chronic liver and biliary diseases shape the genomic landscape of CCA will inform the development of personalized treatments, surveillance strategies, and preventive approaches. Large-scale etiology-stratified genomic studies integrating multiomics and real-world clinical data are urgently needed to advance precision oncology in CCA. Full article

(This article belongs to the Special Issue Liver Inflammation and Hepato-Pancreatic Biliary Cancers (HPBCs))

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14 pages, 1327 KB

Open AccessArticle

Long-Term Survival After Thyroidectomy for Thyroid Cancer: A Propensity-Matched TriNetX Study with Specialty-Stratified Analyses

by Ci-Wen Luo, Meng-Hao Chang, Lan Lin, Frank Cheau-Feng Lin, Shih-Wei Chen, Yu-Hsiang Kuan, Pei-Chi Tsai, Ji-Kuen Yu and Stella Chin-Shaw Tsai

Cancers 2025, 17(18), 3051; https://doi.org/10.3390/cancers17183051 - 18 Sep 2025

Abstract

Background/Objectives: Whether thyroidectomy confers a long-term survival advantage over non-surgical management in real-world practice remains uncertain. We primarily evaluated the association between surgery and all-cause mortality in thyroid cancer; specialty-stratified outcomes were prespecified as secondary, exploratory analyses. Methods: Using the TriNetX US Collaborative [...] Read more.

Background/Objectives: Whether thyroidectomy confers a long-term survival advantage over non-surgical management in real-world practice remains uncertain. We primarily evaluated the association between surgery and all-cause mortality in thyroid cancer; specialty-stratified outcomes were prespecified as secondary, exploratory analyses. Methods: Using the TriNetX US Collaborative Network (2008–2024), we identified adults with thyroid cancer and created 1:1 propensity score-matched cohorts of patients who did or did not undergo thyroidectomy, balancing demographics, comorbidities, medications, and laboratory variables. Overall survival was assessed with Kaplan–Meier curves and Cox proportional hazard models. Among the surgical patients, we performed exploratory analyses stratified by operating specialty (otolaryngology–head and neck surgery (reference) vs. general/endocrine surgery and other/unknown, reported descriptively). Results: After matching, 49,219 patients were included per cohort. Thyroidectomy was associated with lower long-term mortality versus non-surgical care (adjusted HR 0.685, 95% CI 0.652–0.721). Among the surgical patients, secondary, exploratory specialty-stratified analyses suggested differences: compared with otolaryngology–head and neck surgery (ENT–HNS; reference), general/endocrine surgery (GS/ES) had a lower adjusted hazard of death (aHR 0.561, 95% CI 0.481–0.654), whereas other/unknown specialties had a higher adjusted hazard (aHR 1.583, 95% CI 1.302–1.924). These patterns are hypothesis-generating and may reflect residual confounding, including the tumor stage and histology, referral pathways, and surgeon or center experience. Conclusions: In a large, propensity-matched real-world cohort, surgery was linked to improved long-term survival regarding thyroid cancer. Observed specialty-related variation should be interpreted cautiously, and prospective studies incorporating tumor-level variables and provider/center characteristics are needed. Emphasis should remain on timely surgery within multidisciplinary care pathways. Full article

(This article belongs to the Special Issue Classification, Risk Assessment and Clinical Management of Malignant Thyroid Nodules: 2nd Edition)

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Graphical abstract

12 pages, 1845 KB

Open AccessArticle

Clinicopathological Features and Outcomes of Endoscopic Submucosal Dissection for Early Gastric Lymphoepithelioma-like Carcinoma

by Young Eun Oh, Tae-Se Kim, Yo Han Jeon, Soomin Ahn, Kyoung-Mee Kim, Yang Won Min, Hyuk Lee, Byung-Hoon Min, Jun Haeng Lee, Poong-Lyul Rhee and Jae J. Kim

Cancers 2025, 17(18), 3050; https://doi.org/10.3390/cancers17183050 - 18 Sep 2025

Abstract

Background/Objectives: The curability of endoscopic submucosal dissection (ESD) for early gastric lymphoepithelioma-like carcinoma (LELC) remains unclear, as this rare histological subtype is not well represented in current guidelines. We aimed to evaluate the clinicopathological features and outcomes of early gastric LELC following ESD. [...] Read more.

Background/Objectives: The curability of endoscopic submucosal dissection (ESD) for early gastric lymphoepithelioma-like carcinoma (LELC) remains unclear, as this rare histological subtype is not well represented in current guidelines. We aimed to evaluate the clinicopathological features and outcomes of early gastric LELC following ESD. Methods: We retrospectively compared 51 patients with early gastric LELC and 8243 patients with well- or moderately differentiated (WD or MD) tubular adenocarcinoma who underwent ESD. Results: LELC was more frequently located in the proximal stomach than WD/MD adenocarcinoma (52.9% vs. 10.3%). The deep submucosal invasion rate was significantly higher in LELC (77.3% vs. 9.5%), whereas the lymphatic invasion rate was comparable between the two groups (5.7% vs. 9.2%). No LELC cases were diagnosed preoperatively using forceps biopsy. Despite the comparable en bloc with R0 and complete resection rates, the curative resection rate of LELC was significantly lower than that of WD/MD adenocarcinoma, primarily due to deep submucosal invasion. Post-ESD bleeding was more frequent in LELC (11.3% vs. 2.7%). During a mean follow-up of 38.1 months, no extra-gastric recurrence was observed in patients who did not undergo additional surgery, and no lymph node metastasis was detected among the 23 patients who underwent gastrectomy. No gastric cancer-specific deaths occurred in the study population during follow-up. Conclusions: Considering these favorable long-term outcomes despite a low curative resection rate, early gastric LELC fulfilling the conventional curative criteria of current guidelines can be regarded as having been curatively treated by ESD, particularly in patients with high surgical morbidity. Full article

(This article belongs to the Section Clinical Research of Cancer)

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16 pages, 1081 KB

Open AccessSystematic Review

Defining Standard Data Reporting in Pelvic Exenterations for Non-Rectal Cancers: A Systematic Review of Current Data Reporting

by PelvEx Collaborative

Cancers 2025, 17(18), 3049; https://doi.org/10.3390/cancers17183049 - 18 Sep 2025

Abstract

Introduction: Pelvic exenteration (PEx) was first described in the 1940s as a palliative procedure in managing cervical cancer. Since then, advancements in perioperative care have transformed the options available to patients. This highly morbid procedure now offers a “cure” in a select cohort [...] Read more.

Introduction: Pelvic exenteration (PEx) was first described in the 1940s as a palliative procedure in managing cervical cancer. Since then, advancements in perioperative care have transformed the options available to patients. This highly morbid procedure now offers a “cure” in a select cohort of patients with locally advanced and recurrent pelvic cancers. The large volume of literature in this field has resulted in a heterogeneity of data reporting, making comparative analysis extremely difficult. As such, we set out to examine the current literature and identify currently reported outcomes to guide development of a core information set (CIS) for data reporting for PEx in non-rectal cancers. Methods: A systematic review was carried out. Studies reporting on outcomes following PEx for advanced and recurrent gynecological, urological, and other non-rectal malignancies were included. Standardized outcomes were extracted and mapped to pre-determined domains. Results: Forty-four studies were found to meet our inclusion criteria. A total of 1735 data elements (DEs) were extracted verbatim, and these were assimilated into 111 standard DEs across nine domains. A wide range of reporting frequencies was observed, with the pathological domain containing the highest overall frequencies of DE reporting. Conversely, patient-reported and functional outcomes were noted to be the domain with the lowest frequency. Conclusions: This review highlights recent trends of increased reporting in the field of PEx and how this had invariably resulted in heterogeneous data reporting. We aim to guide the development of a CIS for reporting in non-rectal pelvic malignancies to help standardize future reporting. Full article

(This article belongs to the Section Systematic Review or Meta-Analysis in Cancer Research)

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14 pages, 1623 KB

Open AccessArticle

Evolution of Potentially Actionable Genomic Alterations in Advanced Prostate Cancer: A Real-World Analysis of Serial Circulating Tumor DNA Testing

by Miguel Muniz, L. Jill Tsai, Jacob J. Orme, Leslie A. Bucheit, Spyridon P. Basourakos, Nancy Wei, Regina M. Koch, Zachary Scharf, Sounak Gupta, Adam M. Kase, Rodrigo Rodrigues Pessoa, Irbaz B. Riaz, Eugene D. Kwon, Jack R. Andrews and Daniel S. Childs

Cancers 2025, 17(18), 3048; https://doi.org/10.3390/cancers17183048 - 18 Sep 2025

Abstract

Background: Longitudinal genomic profiling through serial circulating tumor DNA (ctDNA) testing offers a noninvasive method to monitor clonal evolution in advanced prostate cancer. This study evaluated the frequency and nature of newly emergent and potentially actionable genomic alterations detected through serial testing in [...] Read more.

Background: Longitudinal genomic profiling through serial circulating tumor DNA (ctDNA) testing offers a noninvasive method to monitor clonal evolution in advanced prostate cancer. This study evaluated the frequency and nature of newly emergent and potentially actionable genomic alterations detected through serial testing in a real-world setting. Methods: We conducted a retrospective analysis of advanced prostate cancer patients who underwent multiple Guardant360 ctDNA tests between October 2020 and March 2023. The study focused on identifying new genomic alterations absent in the initial test, with particular attention to alterations relevant for on-label therapies, therapies approved in other oncologic indications (i.e., off-label), or a clinical trial. Results: Among 479 patients with at least two ctDNA tests, the median interval between the first and second evaluable tests was 207 days. New and potentially actionable alterations emerged in 57.8% of patients, including potential targets for on-label therapies (16.7%), off-label therapies (16.5%), and clinical trials (55.7%). Tumor mutational burden (TMB) increased from “low” to “high” in 11% of patients, although none had microsatellite instability or mismatch repair deficiency. In a Mayo Clinic subset, ten patients received olaparib based on treatment-emergent alterations, but none achieved a prostate-specific antigen (PSA) response. Two patients who transitioned from low to high TMB received pembrolizumab, both with progressive disease as best response. Conclusions: In a large real-world cohort, serial ctDNA testing frequently identified new alterations that were not detected at baseline and are potentially actionable therapeutic targets, highlighting the value of serial genomic profiling for capturing clonal dynamics. Additional research is needed to better establish a framework for retesting and to clarify how these results should influence subsequent treatment decisions. Full article

(This article belongs to the Special Issue Prostate Cancer Epidemiology and Genetics: 2nd Edition)

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16 pages, 606 KB

Open AccessArticle

Alterations in ¹³C and ¹⁵N Isotope Abundance as Potential Biomarkers for Tumor Biology and Risk Factors for Cervical Lymph Node Metastases in Oral Squamous Cell Carcinoma

by Katarzyna Bogusiak, Piotr Paneth, Józef Kobos and Marcin Kozakiewicz

Cancers 2025, 17(18), 3047; https://doi.org/10.3390/cancers17183047 - 18 Sep 2025

Abstract

Background: Cervical lymph node metastases are a major prognostic factor in patients with oral squamous cell carcinoma (OSCC). Despite advances in imaging, accurate preoperative prediction of nodal involvement remains a challenge. This study evaluated the utility of Isotope Ratio Mass Spectrometry (IRMS) in [...] Read more.

Background: Cervical lymph node metastases are a major prognostic factor in patients with oral squamous cell carcinoma (OSCC). Despite advances in imaging, accurate preoperative prediction of nodal involvement remains a challenge. This study evaluated the utility of Isotope Ratio Mass Spectrometry (IRMS) in assessing the risk of lymph node metastases in patients with OSCC. We hypothesize that alterations in the abundance of ¹³C and ¹⁵N stable isotopes in OSCC tumor tissues reflect metabolic reprogramming associated with tumor progression and may correlate with cervical lymph node metastases. Methods: A prospective cohort of 61 patients with primary OSCC undergoing surgical treatment was analyzed. Tumor tissue samples were evaluated for the relative abundance of nitrogen-15 (¹⁵N) and carbon-13 (¹³C) isotopes using IRMS. Correlations between isotopic values and nodal metastases, as well as established clinicopathological risk factors, were assessed. Results: IRMS measurements of ¹³C and ¹⁵N abundance did not directly correlate with the presence of lymph node metastases but were associated with advanced tumor stages and negative prognostic features, such as angioinvasion/neuroinvasion. The median of the average nitrogen ¹⁵N content was higher in patients with more advanced clinical stages (11.89% in stage IV vs. 11.12% in stages I–III; p = 0.04‰), and the median δ¹³C was lower in stage IV compared to stages I–III (−22.40‰ vs. −22.88‰; p < 0.05). Patients with angioinvasion/neuroinvasion also had a lower median δ¹³C (−22.26‰ vs. −22.75‰; p < 0.05). These findings suggest that IRMS reflects metabolic changes in tumor biology rather than specifically predicting nodal metastases. Multivariate logistic regression identified age, gender, and clinical tumor stage as independent predictors of nodal involvement. Conclusion: IRMS-based isotopic profiling may reflect key metabolic alterations associated with OSCC progression. Although IRMS parameters of carbon ¹³C and nitrogen ¹⁵N were not independently predictive of lymph node status, they were associated with key adverse prognostic features, indicating their potential as adjunctive biomarkers that may complement traditional histopathological evaluation. Full article

(This article belongs to the Section Cancer Biomarkers)

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Graphical abstract

15 pages, 617 KB

Open AccessReview

Head and Neck Cancer in Fanconi Anemia: Clinical Challenges and Molecular Insights into a DNA Repair Disorder

by Juhye Choi and Moonjung Jung

Cancers 2025, 17(18), 3046; https://doi.org/10.3390/cancers17183046 - 18 Sep 2025

Abstract

Fanconi anemia (FA) is a genetic disorder characterized by congenital anomalies, bone marrow failure, and cancer predisposition. Among other solid cancers, head and neck squamous cell carcinoma (FA HNSCC) is the most common cancer type in individuals with FA. The FA pathway is [...] Read more.

Fanconi anemia (FA) is a genetic disorder characterized by congenital anomalies, bone marrow failure, and cancer predisposition. Among other solid cancers, head and neck squamous cell carcinoma (FA HNSCC) is the most common cancer type in individuals with FA. The FA pathway is required for the complete repair of DNA interstrand crosslinks (ICLs), and unresolved ICLs result in cell cycle arrest, apoptosis, or complex chromosomal rearrangements due to chromosome breaks, ultimately leading to tumorigenesis. FA HNSCCs present earlier (median age of onset in the 30s) and exhibit a more aggressive course with frequent recurrence and second primaries, and entail a poorer survival rate compared to sporadic HNSCC. FA HNSCCs are mostly human papillomavirus (HPV)-negative and frequently carry somatic copy number variations (CNVs), which amplify oncogenes implicated in sporadic HNSCC, but single-nucleotide variants or small insertions and deletions are less frequent than in HPV-negative sporadic HNSCC. A subset of sporadic HNSCC carries pathogenic mutations or promoter methylation in FA genes, which also harbor characteristic somatic CNVs, suggesting shared molecular underpinnings with FA HNSCC. Heightened inflammation from genomic instability and transcriptional activation of retrotransposons contribute to tumorigenesis and increased invasiveness by the epithelial-to-mesenchymal transition. Due to heightened sensitivity to DNA crosslinking agents in patients with FA, platinum-based chemotherapy is generally avoided, which presents a significant hurdle for treatment and thereby leaves limited therapeutic options. Surgical management is the mainstay of therapy if possible, and targeted therapy has been increasingly studied in HNSCC in FA. Full article

(This article belongs to the Special Issue Targeting Pathogenic Variants in Hereditary Cancer Diagnosis and Screening)

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21 pages, 3552 KB

Open AccessArticle

Computational Drug Repurposing Across the Multiple Myeloma Spectrum: From MGUS to MM

by Kyriaki Savva, Marilena M. Bourdakou, Dimitris Stellas, Jerome Zoidakis and George M. Spyrou

Cancers 2025, 17(18), 3045; https://doi.org/10.3390/cancers17183045 - 18 Sep 2025

Abstract

Background/Objectives: Multiple myeloma (MM) is a challenging, B cell malignancy characterised by the uncontrolled proliferation of plasma cells within the bone marrow. Despite significant advances in treatment options nowadays, MM remains an incurable malignancy, with the majority of patients succumbing to the disease. [...] Read more.

Background/Objectives: Multiple myeloma (MM) is a challenging, B cell malignancy characterised by the uncontrolled proliferation of plasma cells within the bone marrow. Despite significant advances in treatment options nowadays, MM remains an incurable malignancy, with the majority of patients succumbing to the disease. MM develops from a pre-malignant state known as monoclonal gammopathy of unknown significance (MGUS), which then has the potential to evolve either into smouldering (asymptomatic) multiple myeloma (SMM) or into MM. Since novel drug discovery takes years to reach the clinic, drug repurposing, which concerns the detection of existing drugs for a novel disease, can be applied. Methods: To address this critical and still unmet medical need, we present a comprehensive signature-based drug-repurposing approach using all the publicly available bulk transcriptomics datasets on mGUS, sMM, and MM. Results: Our study included an in-house scoring scheme approach enabling further filtering and prioritisation, resulting in 25 candidate repurposed drugs for mGUS, 23 for sMM, and 66 for MM. The corresponding gene targets and the related functional terms have been analysed, providing extra information for stage-specific underlying mechanisms in myeloma. Lastly, enabled by a specific computational workflow, we propose drug combinations between our top candidate repurposed drugs and FDA-approved drugs for MM. Conclusions: Together, these results deliver a stage-specific, transparent resource for MM drug repurposing and combination design, intended to accelerate translation toward earlier disease intervention and improved patient outcomes. Full article

(This article belongs to the Section Cancer Drug Development)

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10 pages, 544 KB

Open AccessArticle

Prediction of Occult Cervical Lymph Node Metastasis in Bone-Invasive pT4a cN0 Oral Squamous Cell Carcinoma in Relation to Tumor Size: A Retrospective Observational Cohort Study

by Friedrich Mrosk, Victoria Vertic, Maximilian Richter, Erin Sprünken, Lukas Mödl, Jan Oliver Voss, Anna Sofroniou, Carsten Rendenbach, Max Heiland and Steffen Koerdt

Cancers 2025, 17(18), 3044; https://doi.org/10.3390/cancers17183044 - 18 Sep 2025

Abstract

Objective: The T classification of oral squamous cell carcinoma (OSCC) is linear according to the tumor size, excluding T4a by its criteria of invasion into adjacent structures, such as cortical bone. This may lead to the upstaging of otherwise small tumors. The objective [...] Read more.

Objective: The T classification of oral squamous cell carcinoma (OSCC) is linear according to the tumor size, excluding T4a by its criteria of invasion into adjacent structures, such as cortical bone. This may lead to the upstaging of otherwise small tumors. The objective was to analyze patients with OSCC and negative nodal staging to assess the impact of T-staging with tumor size on the incidence of occult cervical lymph node metastasis (CLNM) and regional neck failure. Methods: This retrospective cohort study included patients with OSCC and clinically negative necks (cN0), treated surgically between 2010 and 2024. All T4a OSCC classified due to bone invasion were additionally reclassified into T1–T3 based on size and depth of invasion according to the current staging manual. The primary endpoint of this study was the association between OSCC stratified by T-stage and tumor size as well as the presence of occult CLNM. Results: A total of 642 patients were included, with an overall occult CLNM rate of 20.2%. Bone invasion in T1-sized tumors was significantly associated with occult CLNM (OR 6.38, 95% CI: 1.48–27.42), whereas no such association was observed in T2 or T3 tumors (OR 0.80, 95% CI: 0.37–1.73; and OR 0.77, 95% CI: 0.37–1.62, respectively). Additionally, in T1–T2 tumors, bone invasion did not correlate with worse survival outcomes. Conclusions: Bone invasion was not significantly associated with occult CLNM in T2-3 sized OSCC, suggesting that the prognostic relevance is size-dependent. These findings question the uniform upstaging to T4a and support a more differentiated approach, potentially enabling neck management de-escalation in selected early-stage cases. Full article

(This article belongs to the Special Issue Surgical Treatment of Oral Squamous Cell Carcinoma)

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15 pages, 2712 KB

Open AccessArticle

The Prognostic Value of a Nomogram Model Based on Tumor Immune Markers and Clinical Factors for Adult Primary Glioma

by Junpeng Wen, Ziling Zhang, Yan Zhao, Yingzi Liu, Jiangwei Yuan, Yuxiang Wang and Juan Li

Cancers 2025, 17(18), 3043; https://doi.org/10.3390/cancers17183043 - 18 Sep 2025

Abstract

Objective: This study aimed to identify the factors associated with overall survival (OS) in adult patients with primary gliomas, construct a nomogram prediction model, and evaluate its predictive performance. Methods: Clinical data were retrospectively collected from adult patients newly diagnosed with gliomas [...] Read more.

Objective: This study aimed to identify the factors associated with overall survival (OS) in adult patients with primary gliomas, construct a nomogram prediction model, and evaluate its predictive performance. Methods: Clinical data were retrospectively collected from adult patients newly diagnosed with gliomas who underwent surgical treatment in the Department of Neurosurgery of the Fourth Hospital of Hebei Medical University, between January 2019 and December 2023. External validation was conducted using data from the China Glioma Genome Atlas (CGGA) database. Data analysis and visualization were performed using SPSS 26.0 and R software (Version 4.4.1). Results: A total of 257 adult patients were included in this study. Multivariate Cox regression analysis identified age, Karnofsky Performance Status (KPS) score, tumor diameter, WHO grade, and postoperative radiotherapy and chemotherapy, as well as the expression of ATRX, IDH1, and Ki-67, as independent prognostic factors. These factors were incorporated into a nomogram for predicting 1-year, 2-year, and 3-year survival rates. The model demonstrated excellent discrimination, calibration, and clinical utility in both internal and external validations. Conclusions: The nomogram model incorporating clinical factors (age, WHO grade), treatment (radiotherapy, chemotherapy), and tumor markers (ATRX, IDH1, Ki-67) has good predictive efficacy and may serve as a practical and effective alternative to molecular testing for prediction of survival in adult patients with primary glioma. Full article

(This article belongs to the Section Cancer Biomarkers)

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15 pages, 910 KB

Open AccessArticle

Clinicopathological Factors Affecting Prognosis in Patients with Advanced Cervical Cancer Undergoing Concurrent Chemoradiation Therapy

by Maitreyee Parulekar, Min Kyung Kim, Joseph J. Noh, Dong Hoon Suh, Kidong Kim, Yong Beom Kim and Jae Hong No

Cancers 2025, 17(18), 3042; https://doi.org/10.3390/cancers17183042 - 18 Sep 2025

Abstract

Background: Concurrent chemoradiation therapy (CCRT) is the standard treatment for patients with locally advanced cervical cancer (LACC), including those with parametrial or lymphatic metastasis. However, therapeutic outcomes vary, and prognostic factors remain inadequately defined. Methods: We conducted a retrospective study involving 128 patients [...] Read more.

Background: Concurrent chemoradiation therapy (CCRT) is the standard treatment for patients with locally advanced cervical cancer (LACC), including those with parametrial or lymphatic metastasis. However, therapeutic outcomes vary, and prognostic factors remain inadequately defined. Methods: We conducted a retrospective study involving 128 patients with cervical cancer who received definitive CCRT between 2003 and 2022 at Seoul National University Bundang Hospital. We evaluated clinicopathological variables, including age, height, body weight, histologic type, tumor size, human papillomavirus (HPV) type, squamous cell carcinoma (SCC) antigen levels, and involvement of the parametrium, lower vagina, and lymph nodes. Survival outcomes were analyzed using Kaplan–Meier curves and Cox proportional hazards models. Results: Stage IIIC1r, according to the 2018 FIGO staging system, was the most common disease stage among the study population. Para-aortic lymph node metastasis was significantly associated with increased recurrence risk (odds ratio [OR] = 5.892; 95% confidence interval [CI]: 2.030–17.097; p = 0.001) and was linked to poorer progression-free survival (PFS, p = 0.001), overall survival (OS, p = 0.014), and treatment-free interval (TFI, p = 0.001). Obesity (body mass index ≥ 25 kg/m²) was also associated with higher recurrence risk (OR = 2.737; 95% CI: 1.093–6.855; p = 0.032) and reduced PFS (p = 0.0089). Conclusions: Para-aortic lymph node metastasis and obesity are significant prognostic factors in patients undergoing definitive CCRT for LACC. These findings highlight the need for risk-adapted treatment strategies and potential incorporation of adjunctive therapies to improve clinical outcomes in high-risk patient subgroups. Full article

(This article belongs to the Special Issue Recent Updates on Imaging and Staging of Gynecologic Cancers)

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16 pages, 17489 KB

Open AccessReview

Immature Teratoma of the Ovary—A Narrative Review

by Giuseppe Marino, Serena Negri, Filippo Testa, Jasmine Corti, Daniela Giuliani, Daniele Lugotti, Tommaso Grassi, Marta Jaconi, Alessandra Casiraghi, Cristina Maria Bonazzi and Robert Fruscio

Cancers 2025, 17(18), 3041; https://doi.org/10.3390/cancers17183041 - 18 Sep 2025

Abstract

Immature teratoma of the ovary is a rare condition primarily affecting young women and constitutes a significant proportion of ovarian cancer cases in adolescents and young adults. It is commonly diagnosed at stage I, though advanced-stage disease is not infrequent. Accurate diagnosis and [...] Read more.

Immature teratoma of the ovary is a rare condition primarily affecting young women and constitutes a significant proportion of ovarian cancer cases in adolescents and young adults. It is commonly diagnosed at stage I, though advanced-stage disease is not infrequent. Accurate diagnosis and a fertility-sparing approach are central to the management of this condition, as many affected women retain, or have yet to develop, a desire for childbearing. However, due to the rarity of this disease, management is often guided by retrospective data derived from subanalyses of studies on malignant ovarian germ cell tumors, which can complicate the treatment of these patients once diagnosed. The aim of this review is to summarize the current evidence on immature teratoma of the ovary, considering it as a distinct clinical and pathological entity. Full article

(This article belongs to the Special Issue Primary and Recurrent Gynecological Cancer: Epidemiology, Management and New Therapies)

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18 pages, 4478 KB

Open AccessArticle

Tumour-Infiltrating Lymphocytes, Tumour Cell Density, and Response to Neoadjuvant Short-Course Radiotherapy in Rectal Cancer: A Translational Sub-Study from the MRC CR07 Clinical Trial

by Jonathan P. Callaghan, Ross Jarrett, Alice C. Westwood, Jon Laye, Philip Quirke, Derek R. Magee, Daniel Bottomley, David Sebag-Montefiore, Lindsay Thompson, Angela Meade, Heike I. Grabsch and Nicholas P. West

Cancers 2025, 17(18), 3040; https://doi.org/10.3390/cancers17183040 - 17 Sep 2025

Abstract

Background: Rectal cancer is common and frequently treated with neoadjuvant radiotherapy prior to surgery to reduce the risk of tumour recurrence. However, the therapeutic benefits and side effects of radiotherapy can vary between patients, and there are currently no validated biomarkers to [...] Read more.

Background: Rectal cancer is common and frequently treated with neoadjuvant radiotherapy prior to surgery to reduce the risk of tumour recurrence. However, the therapeutic benefits and side effects of radiotherapy can vary between patients, and there are currently no validated biomarkers to predict treatment response. Tumour cell density (TCD) and tumour-infiltrating lymphocyte (TIL) density are proven prognostic biomarkers in colorectal cancer; however, their utility in predicting radiotherapy response remains unclear. We assessed the prognostic and predictive value of TCD and TIL density in rectal cancer patients treated with radiotherapy. Methods: TCD was quantified using a manual point-counting method in 253 pre-treatment biopsies and across the entire tumour area of 569 resection specimens from the MRC CR07 clinical trial, which randomised patients to either neoadjuvant short-course radiotherapy (SCRT) or straight to surgery (control). TIL density was measured in 102 biopsies and matched resection specimens (73 SCRT, 29 control) across different tumour areas using deep learning-based cell detection in MIM (HeteroGenius Ltd., Leeds, UK). Cutoffs for low/high-TCD and TIL density were both pre-defined and derived from survival data using the survminer R package. Survival analyses were performed to evaluate the predictive and prognostic value of TCD/TIL in relation to overall and cancer-specific survival. Results: TCD in the resection specimens was lower in the SCRT group (19.9%, IQR 12.9–26.7%) than the control group (34.3%, IQR 27.7–40.5%, p < 0.001). In control resections, low-TCD was associated with a higher risk of all-cause mortality (HR 2.20, 95% CI 1.41–3.44, p < 0.001) and cancer-related death (HR 2.69, 95% CI 1.41–5.13, p = 0.0026). In contrast, after SCRT, low resection TCD was associated with a reduced risk of death (HR 0.63, 95% CI 0.40–0.98, p = 0.04). In the SCRT group, low biopsy TCD prior to radiotherapy was associated with a reduced risk of cancer-related death (HR 0.34, 95% CI 0.13–0.89, p = 0.028). Across both trial arms, TIL density was higher in pre-treatment biopsies than resections (2492 vs. 1304/mm², p < 0.001). Low biopsy TIL density was associated with an increased risk of all-cause mortality (HR 2.43, 95% CI 1.24–4.76, p = 0.01). The SCRT group had lower TIL density in the resection compared with controls (1210 vs. 1615/mm², p < 0.001), and low resection TIL density across the whole tumour area was associated with a higher risk of death (HR 2.55, 95% CI 1.11–5.87, p = 0.027). Conclusions: Our findings support the role of TCD and TIL density as quantitative biomarkers in rectal cancer patients. TCD can be used to assess the degree of response to radiotherapy, and contrasting survival associations are observed between straight-to-surgery and SCRT-treated patients. This study raises the possibility of using TCD as both a prognostic and predictive biomarker. TIL density failed to show predictive value but demonstrated expected prognostic associations. Full article

(This article belongs to the Special Issue The Survival of Colon and Rectal Cancer (2nd Edition))

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16 pages, 1338 KB

Open AccessArticle

Carbon-Ion Radiotherapy for Prostate Cancer in Patients with a History of Surgery for Benign Prostatic Hyperplasia

by Atsushi Okato, Kosei Miura, Tomoki Yamaguchi, Mio Nakajima, Hirokazu Makishima, Takanobu Utsumi, Koichiro Akakura, Hiroyoshi Suzuki, Masaru Wakatsuki, Hiroshi Tsuji, Tomohiko Ichikawa and Hitoshi Ishikawa

Cancers 2025, 17(18), 3039; https://doi.org/10.3390/cancers17183039 - 17 Sep 2025

Abstract

Background/Objectives: Carbon-ion radiotherapy (CIRT) offers precise dose distribution and enhanced biological effectiveness in localized prostate cancer. However, the safety of CIRT in patients with a history of surgery for benign prostatic hyperplasia (BPH), such as transurethral resection of the prostate (TURP), remains [...] Read more.

Background/Objectives: Carbon-ion radiotherapy (CIRT) offers precise dose distribution and enhanced biological effectiveness in localized prostate cancer. However, the safety of CIRT in patients with a history of surgery for benign prostatic hyperplasia (BPH), such as transurethral resection of the prostate (TURP), remains unclear. This study aimed to evaluate the long-term safety and oncological outcomes of CIRT in this population. Methods: A retrospective analysis was conducted in 74 of 3848 patients with prostate cancer and a history of surgery for BPH who underwent CIRT combined with risk-adapted androgen deprivation therapy between 2007 and 2023. Adverse events were assessed using CTCAE v5.0. Biochemical recurrence-free survival was estimated using the Kaplan–Meier method and risk factors for hematuria with multivariate logistic regression and receiver operation characteristic (ROC) analysis. Results: CIRT was generally well-tolerated. Early Grade 2 genitourinary (GU) adverse events occurred in 5.4% of patients, and late-Grade 2 or higher GU events occurred in 8.1%. The cumulative incidence of Grade 2 ≥ GU events remained 10% at 36 months. Compared to holmium laser enucleation of the prostate, a shorter interval between BPH surgery and CIRT initiation and a history of TURP were independently associated with an increased risk of hematuria. Notably, 5-year bRFS was 100% in low- and intermediate-risk groups and 88.6% in the high-risk group. Conclusions: CIRT demonstrates acceptable oncological outcomes and urinary complication rates in patients with prostate cancer and a history of BPH surgery. These findings suggest that CIRT can be a feasible treatment option in this surgically altered population, but careful patient selection, individualized treatment planning, and long-term follow-up are essential. Given the absence of a non-BPH control group, oncological efficacy should be interpreted with caution. Full article

(This article belongs to the Special Issue Prostate Cancer Therapy: Supporting Strategies and Management Options)

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