Cancers

35 pages, 1601 KB

Open AccessSystematic Review

From Diagnosis to Therapy in Primary Cutaneous Extramammary Paget’s Disease: A Systematic Review of Non-Invasive and Non-Surgical Approaches

by Francesco D’Oria, Francesco Piscazzi, Matteo Liberi, Giulio Foggi, Luigi Lorini, Katia Maria Calcara, Emi Dika, Mario Valenti, Salvador González and Marco Ardigò

Cancers 2025, 17(21), 3594; https://doi.org/10.3390/cancers17213594 - 6 Nov 2025

Viewed by 579

Abstract

Background/Objectives: Extramammary Paget’s disease (EMPD) is a rare cutaneous malignancy arising in areas rich in apocrine glands that poses diagnostic and therapeutic difficulties. Although surgery remains the standard of care, achieving clear margins is challenging and recurrence rates are high. This review [...] Read more.

Background/Objectives: Extramammary Paget’s disease (EMPD) is a rare cutaneous malignancy arising in areas rich in apocrine glands that poses diagnostic and therapeutic difficulties. Although surgery remains the standard of care, achieving clear margins is challenging and recurrence rates are high. This review explores the contribution of non-invasive imaging for diagnosis and monitoring, and evaluates conservative, non-surgical therapies as alternatives to radical surgery. Methods: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), a systematic review was conducted: eligible studies included interventional and observational research, as well as case series and reports, assessing non-invasive diagnostic methods or non-surgical treatments for EMPD. Data extraction and risk-of-bias evaluation were performed independently by multiple reviewers, and a narrative synthesis summarized therapeutic outcomes and diagnostic performance. Results: Of 808 identified records, 82 met the inclusion criteria: 66 focused on non-surgical therapies, 15 on diagnostic techniques, and one on both. Reflectance confocal microscopy (RCM) and photodynamic diagnosis (PDD) showed high concordance with histopathology, aiding both diagnosis and margin delineation. Among therapies, topical imiquimod and photodynamic therapy (PDT) demonstrated encouraging response rates, while radiotherapy, laser ablation, and systemic chemotherapy were less consistently reported. Evidence quality was limited by small cohorts, heterogeneous regimens, and variable follow-up. Conclusions: Non-invasive imaging enhances diagnostic accuracy and surgical planning, while non-surgical treatments—particularly imiquimod and PDT—offer viable alternatives in selected cases. Larger prospective studies are needed to establish standardized protocols and clarify long-term outcomes. Full article

(This article belongs to the Special Issue Exploring Skin Cancer: Insights into New Diagnostic, Prognostic, and Therapeutic Strategies)

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13 pages, 962 KB

Open AccessArticle

SARIFA Is Associated with Lymph Node Metastases in PT3 and PT4 Gastric Cancers

by Krešimir Mustapić, Petar Đolonga, Tomislav Ivanović, Ana Paparella Karaman, Luka Minarik, Katarina Vukojević and Merica Glavina Durdov

Cancers 2025, 17(21), 3593; https://doi.org/10.3390/cancers17213593 - 6 Nov 2025

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Abstract

Background/Objectives: Advanced gastric cancer usually has an unfavorable prognosis. Stroma AReactive Invasion Front Area (SARIFA) is a newly recognized biomarker of aggressiveness, easily recognized as five tumor cells in direct contact with adipocytes in perigastric, submucosal, and perivascular adipose tissue. We investigated [...] Read more.

Background/Objectives: Advanced gastric cancer usually has an unfavorable prognosis. Stroma AReactive Invasion Front Area (SARIFA) is a newly recognized biomarker of aggressiveness, easily recognized as five tumor cells in direct contact with adipocytes in perigastric, submucosal, and perivascular adipose tissue. We investigated this phenomenon and correlated it with other pathohistological variables. Material and Methods: The sample includes 102 Croatian patients with locally advanced gastric cancer, who underwent total gastrectomy/lymphadenectomy between 2012–2018 and in 2023 at University Hospital Split, Croatia, and had pathological stage pT3 or pT4. Representative histological specimens were analyzed for SARIFA, and results were compared with other variables and overall survival. External validation and gene expression analysis of CD36 and FABP4 were performed using the TCGA-STAD cohort. Results: SARIFA was significantly associated with positive pN status (p = 0.009) and perineural invasion (p = 0.043). Patients with SARIFA had a more than fivefold increased risk of nodal involvement (OR = 6.35; 95% CI: 1.35–29.84; p = 0.019). Lymphovascular invasion (LVI) was associated with nodal disease (OR = 4.39; 95% CI: 1.194–16.143; p = 0.026), and SARIFA was marginally associated (OR = 4.886; 95% CI: 0.985–24.241; p = 0.052). Patients who had both LVI and SARIFA had a higher proportion of affected lymph nodes (p = 0.009). SARIFA status did not significantly affect overall survival. Gene expression analysis showed a significant increase in CD36 expression, while FABP4 expression was elevated but not statistically significant, in SARIFA-positive cases. Conclusions: SARIFA could be used as a marker for invasiveness and further investigated due to its predictive potential. Full article

(This article belongs to the Section Cancer Biomarkers)

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20 pages, 4807 KB

Open AccessArticle

Divergent Prognostic Value of Primary Tumor Segmentation Metrics on Baseline FDG PET/CT in Colorectal Cancer

by Ken Kudura, Nando Ritz, Yves Schaulin, Arkadiusz Miszczyszyn, Tim Kutzker, Rebecca Engel, Marco von Strauss und Torney, Wolfgang Harms and Robert Foerster

Cancers 2025, 17(21), 3592; https://doi.org/10.3390/cancers17213592 - 6 Nov 2025

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Abstract

Background: Colorectal cancer (CRC) remains a major global health concern, with increasing incidence and mortality projected over the coming decades. Despite the central role of staging systems, substantial heterogeneity in clinical outcomes persists among patients within the same stage, highlighting the need for [...] Read more.

Background: Colorectal cancer (CRC) remains a major global health concern, with increasing incidence and mortality projected over the coming decades. Despite the central role of staging systems, substantial heterogeneity in clinical outcomes persists among patients within the same stage, highlighting the need for additional prognostic biomarkers. This study aimed to evaluate whether segmentation-derived morphological and metabolic features of the primary tumor could serve as prognostic biomarkers associated with subsequent tumor evolution in CRC. Methods: In this retrospective, single-center study, 91 patients with histologically confirmed CRC who underwent baseline FDG PET/CT prior to treatment were analyzed. Morphological (tumor shape, cranio-caudal extension, volume) and metabolic (SUVmean, SUVmax, MTV, TLG) parameters of the primary tumor were extracted using 3D segmentation. Clinical benefit (CB) was defined according to RECIST criteria at six months. Logistic regression and Cox proportional hazards models were applied to identify predictors of short- and long-term outcomes, with performance assessed using ROC curves and Kaplan–Meier survival analyses. Results: Cranio-caudal extension was the strongest prognostic biomarker of short-term clinical benefit (AUC = 0.89), with a threshold of 6.2 cm discriminating favorable from unfavorable outcomes. In multivariate analysis, early UICC stage and lower cranio-caudal extension were independently associated with CB. For long-term outcomes, MTV emerged as a consistent prognostic factor: higher MTV predicted shorter progression-free survival (HR = 1.03, p < 0.01) and overall survival (HR = 1.03, p < 0.01). In addition, UICC stage IV significantly increased the risk of progression (HR = 9.65, p < 0.01). Conclusions: Segmentation of the primary tumor on baseline FDG PET/CT provides valuable prognostic information in CRC. While cranio-caudal extension was the strongest prognostic biomarker of short-term treatment response, MTV was independently associated with long-term outcomes, particularly progression-free survival. These findings highlight the complementary prognostic roles of morphological and metabolic tumor features and support the integration of PET/CT-based biomarkers into personalized treatment strategies for colorectal cancer. Full article

(This article belongs to the Special Issue Advanced Segmentation in Multimodal Nuclear Imaging of Solid Tumors and Lymphomas: Tools, Challenges, and Clinical Integration)

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13 pages, 948 KB

Open AccessArticle

The Real-World Impact of PARP Inhibitor Maintenance Therapy in High Grade Serous Tubo-Ovarian and Peritoneal Cancers

by Maryam Al-Ani, Bahaaeldin Baraka, Navin Mathiyalagan, Muhammad Adeel Sarwar, Avinash Segaran, Wafaa Abuzahra, Alayna Radford, Kersty Buxton, Lalith Seneviratne, Santhanam Sundar, Anjana Anand, David Nunns, Karin Williamson, Ben Wormald, Ketankumar Gajjar and Srinivasan Madhusudan

Cancers 2025, 17(21), 3591; https://doi.org/10.3390/cancers17213591 - 6 Nov 2025

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Abstract

Background: Pivotal clinical trials have led to the routine clinical use of PARP inhibitor (PARPi) (olaparib, niraparib, or rucaparib) maintenance therapy in high-grade serous tubo-ovarian and peritoneal cancers. Whether various PARPis have comparable clinical impact in the real-world is an area of ongoing [...] Read more.

Background: Pivotal clinical trials have led to the routine clinical use of PARP inhibitor (PARPi) (olaparib, niraparib, or rucaparib) maintenance therapy in high-grade serous tubo-ovarian and peritoneal cancers. Whether various PARPis have comparable clinical impact in the real-world is an area of ongoing investigation. Methods: We conducted a retrospective study of all patients who received PARPi maintenance therapy at Nottingham Cancer Centre from October 2017 to April 2025. Clinical data were extracted from multidisciplinary team electronic health records, including age, BRCA mutation status, HRD status, treatment history, type of PARP inhibitor received, progression-free survival (PFS), and overall survival (OS). Results: A total of 177 patients had received PARPi therapy with a mean age of 63 years at diagnosis. In all, 94/177 (53.1%) had received PARPi as primary maintenance, while 83/177 (46.9%) were treated in the recurrent setting. All together, 25/177 (14.1%) had BRCA1 germline mutation and 21/177 (11.9%) had BRCA2 germline mutation. In the primary olaparib setting, PFS was significantly better in BRCA2 germline-mutated patients compared to BRCA1 germline-mutated patients [median PFS was not reached vs. 29.0 months, respectively, p = 0.002]. In BRCA, wild-type patients receiving primary niraparib, median PFS was 11 months. Median PFS for patients with upfront surgery was 37 months compared to 19 months in the interval debulking group but not significant (p = 0.49). In the recurrent setting, there was no significant difference in median PFS between niraparib and rucaparib [10 months vs. 9 months, p = 0.594]. Conclusions: BRCA2 germline-mutated patients obtained significantly greater benefit from olaparib compared to BRCA1-mutated patients. PFS benefit from niraparib (primary or recurrent setting) is comparable to clinical trials. There was no difference in benefit between niraparib and rucaparib in the recurrent setting. Full article

(This article belongs to the Special Issue Advances in Ovarian Cancer Treatment: Past, Present and Future)

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16 pages, 387 KB

Open AccessArticle

Qualitative Outcomes of Colorectal Cancer Screening Outreach Using Patient Navigation to Follow-Up Colonoscopy in Rural Primary Care Practices

by Emily Myers, Jennifer Coury, Maryan Carbuccia-Abbott, Amanda F Petrik, Robert Durr, Jamie H Thompson, Erin S Kenzie, Gloria D Coronado and Melinda M Davis

Cancers 2025, 17(21), 3590; https://doi.org/10.3390/cancers17213590 - 6 Nov 2025

Viewed by 667

Abstract

Background/Objectives: Despite its effectiveness, colorectal cancer (CRC) screening rates are suboptimal in the United States. Navigating patients towards complete CRC screening can be effective in addressing barriers. However, to date, much research on patient navigation has occurred in urban settings or large health [...] Read more.

Background/Objectives: Despite its effectiveness, colorectal cancer (CRC) screening rates are suboptimal in the United States. Navigating patients towards complete CRC screening can be effective in addressing barriers. However, to date, much research on patient navigation has occurred in urban settings or large health systems, thereby missing some populations that could benefit the most. Methods: We report on a patient navigation program delivered by clinic staff during a large pragmatic study to improve CRC screening in rural Medicaid populations. We use qualitative and implementation data from interviews, contract logs, and tracking systems to explore the context, barriers, and facilitators of patient navigation, as well as feasibility and acceptability for rural primary care clinic partners. Results: A total of 35 patients were eligible for navigation following an abnormal FIT (n = 26, 74%) or due to higher CRC risk (n = 9, 24%); only 8 of the 14 intervention clinics (57%) had any eligible patients. Of the 26 patients who needed navigation following an abnormal FIT, 13 patients (50%) received navigation, and 3 (23%) completed a colonoscopy; all 9 of the higher-risk patients received navigation, but none completed colonoscopy. Several barriers impacted adherence to the navigation protocol, such as staffing disruptions, limited colonoscopy availability, patient mistrust, and data tracking limitations. Our findings also highlight implementation facilitators, including protocol adaptations and cross-team collaborations for low-volume settings. Conclusions: Future models to increase patient navigation in rural settings could include more centralized system-level interventions that build on relationships between clinics and colonoscopy providers or payers and leverage quality improvement best practices. Full article

(This article belongs to the Special Issue Cancer Screening and Primary Care)

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20 pages, 1123 KB

Open AccessReview

The Epitranscriptomic Landscape of Gastric Cancer Stem Cells: The Emerging Role of m⁶A RNA Modifications

by Diana Pádua, Patrícia Mesquita and Raquel Almeida

Cancers 2025, 17(21), 3589; https://doi.org/10.3390/cancers17213589 - 6 Nov 2025

Viewed by 721

Abstract

Cancer stem cells (CSCs) represent a small but critical subpopulation of tumor cells that drive therapy resistance, relapse and metastasis. Gastric cancer stem cells (GCSCs) have been identified through surface markers and transcriptional signatures, revealing their central role in tumor progression. Recently, N [...] Read more.

Cancer stem cells (CSCs) represent a small but critical subpopulation of tumor cells that drive therapy resistance, relapse and metastasis. Gastric cancer stem cells (GCSCs) have been identified through surface markers and transcriptional signatures, revealing their central role in tumor progression. Recently, N⁶-methyladenosine (m⁶A) RNA modification has emerged as a crucial epitranscriptomic regulator of CSC biology. The m⁶A machinery, including “writers” (METTL3, METTL14, WTAP, VIRMA), “erasers” (FTO, ALKBH5) and “readers” (YTHDFs/ YTHDCs, IGF2BPs, hnRNPA2B1), orchestrates RNA stability, splicing, translation and decay, thereby influencing self-renewal and oncogenic signaling. In GCSCs, m⁶A controls pluripotency factors, oncogenic transcripts and non-coding RNAs, collectively reinforcing stemness and malignant potential. Mounting evidence implicates dysregulated m⁶A effectors as not only key drivers of GCSC biology but also as promising biomarkers for patient stratification and therapeutic targets capable of selectively eliminating CSCs. Harnessing this knowledge could enable earlier diagnosis, more accurate patient stratification and more precise treatments. However, challenges remain regarding the resolution of m⁶A profiling, therapeutic selectivity to avoid unwanted toxicity and biomarker validation for clinical use. This review summarizes the discovery and features of CSCs, highlights the functional role of m⁶A in GCSCs, and explores diagnostic and therapeutic opportunities while outlining key difficulties for clinical translation. Full article

(This article belongs to the Special Issue Advances in Molecular Mechanisms of Gastrointestinal Tumors (2nd Edition))

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20 pages, 6289 KB

Open AccessArticle

The Role of FGFR3 in the Progression of Bladder Cancer

by Sahoko Ninomiya, Yukari Ishiguro, Hisashi Hasumi, Ryosuke Jikuya, Akihito Hashizume, Masanobu Yamazaki, Jun-ichi Teranishi, Kazuhide Makiyama, Hiroji Uemura, Hiroshi Miyamoto and Takashi Kawahara

Cancers 2025, 17(21), 3588; https://doi.org/10.3390/cancers17213588 - 6 Nov 2025

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Abstract

Introduction: Bladder cancer is associated with a high recurrence rate, and outcomes for muscle-invasive and metastatic disease remain poor. New targeted therapies, such as the FGFR inhibitor erdafitinib, have been introduced, but the progression from non-muscle-invasive to muscle-invasive disease remains a major clinical [...] Read more.

Introduction: Bladder cancer is associated with a high recurrence rate, and outcomes for muscle-invasive and metastatic disease remain poor. New targeted therapies, such as the FGFR inhibitor erdafitinib, have been introduced, but the progression from non-muscle-invasive to muscle-invasive disease remains a major clinical challenge. Methods: In this study, we performed immunohistochemical staining for FGFR1-FGFR4 on surgical specimens from 192 cases of urothelial carcinoma. We also conducted various functional assays on human bladder cancer cell lines to assess protein/gene expression, cell proliferation, migration, invasion, and colony formation. Results: FGFR2 and FGFR3 expressions were found to be significantly down-regulated in high-grade (0.014) and muscle-invasive (0.002) tumors, respectively. Functionally, the FGFR inhibitor erdafitinib suppressed cell proliferation and migration, and FGFR3 silencing also markedly reduced proliferation, migration, invasion, and colony formation in cancer cell lines. Conclusions: The down-regulation of FGFR3 in muscle-invasive bladder cancer, coupled with the inhibitory effect of its inactivation on cell growth, suggests a significant role for FGFR3 in bladder cancer progression. Full article

(This article belongs to the Special Issue New Insights into General, Functional and Oncologic Urology)

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12 pages, 864 KB

Open AccessArticle

High Implementation Adherence to Lenalidomide in Multiple Myeloma

by Irina Amitai, Hila Magen, Avi Leader, Antoine Pironet, Eric Tousset, Alon Rozental, Sabina De Geest, Iuliana Vaxman, Pia Raanani and Arnon Nagler

Cancers 2025, 17(21), 3587; https://doi.org/10.3390/cancers17213587 - 6 Nov 2025

Viewed by 399

Abstract

Background and Purpose: Adherence to oral anticancer therapy correlates with outcome. Lenalidomide (LEN) is an oral mainstay treatment for multiple myeloma (MM), administered in 21-day/7-day (on/off) cycles. Data on LEN adherence is limited. Electronic monitoring (EM) represents the most reliable adherence assessment method. [...] Read more.

Background and Purpose: Adherence to oral anticancer therapy correlates with outcome. Lenalidomide (LEN) is an oral mainstay treatment for multiple myeloma (MM), administered in 21-day/7-day (on/off) cycles. Data on LEN adherence is limited. Electronic monitoring (EM) represents the most reliable adherence assessment method. Experimental Approach: We conducted a prospective observational study using electronic medication event monitoring (MEMS^®) in lenalidomide-naïve multiple myeloma patients to quantify adherence during on/off cycles and identify patterns of non-adherence in real-world practice. On and off cycles were determined semi-automatically. Implementation adherence was calculated as the proportion of prescribed drug taken, during each on cycle and across all on cycles. Daily adherence predictors were analyzed using logistic regression with generalized estimating equations. Key Results: Eighty-five patients were included. Median age was 68 years, 66% received LEN as a second-line treatment, 75% of patients perfectly adhered to the recommended 21/7-day on/off cycle. Median implementation adherence was 100%. Only 4% of patients had a proportion of doses taken below 90%. All doses were taken by 51% of patients, while 9% missed ≥4 doses. Among the 13 predictors investigated, only age under 80 and participation in a support group were statistically significant. Conclusions: this novel assessment of LEN adherence in MM patients demonstrated high implementation adherence and cycle duration compliance. Full article

(This article belongs to the Section Cancer Therapy)

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Graphical abstract

11 pages, 590 KB

Open AccessArticle

Mutational Landscape and Clinical Impact of SPEN Mutations in Patients with Chronic Lymphocytic Leukemia

by Priyatharsini Nirmalanantham, Andrés E. Quesada, Anindita Ghosh, Pei Lin, Chi Y. Ok, Richard K. Yang, Hong Fang, Sofia Garces, Rashmi Kanagal-Shamanna, Sanam Loghavi, Mark J. Routbort, Cameron Cheng Yin, Wang Wei, Sarah Pasyar, Roland Bassett, Siba El Hussein, Nitin Jain, Jan Burger, William G. Wierda, Sa Wang, Carlos Bueso-Ramos, Keyur P. Patel, Leonard Jeffrey Medeiros and Fatima Zahra Jelloul Show full author list Hide full author list

Cancers 2025, 17(21), 3586; https://doi.org/10.3390/cancers17213586 - 6 Nov 2025

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Abstract

Background/Objectives: NOTCH1 is frequently mutated in chronic lymphocytic leukemia (CLL) and is a marker of poor prognosis. In addition to NOTCH1, mutations in the NOTCH1 regulatory pathway including SPEN have been described in a limited number of CLL cases and others have [...] Read more.

Background/Objectives: NOTCH1 is frequently mutated in chronic lymphocytic leukemia (CLL) and is a marker of poor prognosis. In addition to NOTCH1, mutations in the NOTCH1 regulatory pathway including SPEN have been described in a limited number of CLL cases and others have suggested that these mutations are also associated with adverse patient outcomes Methods: In this study, 1617 CLL cases were assessed using targeted sequencing and a 29-gene panel and the results were correlated with prognosis. Results: SPEN mutations were detected in 48 (2.9%) CLL patients: 92.4% were deleterious (frameshift or truncating nonsense mutations) and the remaining (7.6%) were missense. Compared with SPEN wild type CLL patients, SPEN mutated patients had a statistically higher frequency of IGHV unmutated status (79.5% vs. 57.8%, p = 0.004), CD38 positivity (73.3% vs. 52.4%, p = 0.01), ZAP70 positivity (77.3% vs. 58.3%, p = 0.01) and trisomy 12 (43.5% vs. 13.7%, p < 0.001). The most common gene mutations co-occurring with SPEN mutations were as follows: NOTCH1 (43.7%), TP53 (22.9%), BIRC3 (12.5%), SF3B1 (10.4%), XPO1 (8.3%), MUC2 (6.2%), ATM (4.2%), FBXW7 (4.2%), and BTK (4.2%). Patients with SPEN mutated CLL had a significantly shorter time-to-first treatment compared to CLL patients with wild type SPEN (2.5 vs. 4.07 years, p = 0.01). The finding of shorter time-to-first treatment in SPEN mutated CLL patients was not maintained in a multivariable analysis. IGHV unmutated status, TP53 disruption, and trisomy 12 remained independently predictive of a shorter time-to-first treatment in a multivariable analysis. Conclusions: These data show that SPEN mutations in CLL are associated with adverse prognostic impact and should be included in sequencing assays performed for the prognostic workup of CLL patients. Full article

(This article belongs to the Special Issue Advances in Pathology of Lymphoma and Leukemia)

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21 pages, 1066 KB

Open AccessSystematic Review

A Systematic Review of the Cost-Effectiveness of Screening Modalities for Breast Cancer in European Countries

by Zacharoula Sidiropoulou and Vasco Fonseca

Cancers 2025, 17(21), 3585; https://doi.org/10.3390/cancers17213585 - 6 Nov 2025

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Abstract

Background: Breast cancer remains the most diagnosed cancer in European countries, with diverse screening modalities requiring economic evaluation for optimal resource allocation. This systematic review evaluated the cost-effectiveness of breast cancer screening strategies across European healthcare contexts. Methods: We conducted a comprehensive search [...] Read more.

Background: Breast cancer remains the most diagnosed cancer in European countries, with diverse screening modalities requiring economic evaluation for optimal resource allocation. This systematic review evaluated the cost-effectiveness of breast cancer screening strategies across European healthcare contexts. Methods: We conducted a comprehensive search across PubMed, ScienceDirect, Cochrane Library, Scopus, and Google Scholar following PRISMA guidelines (1990–2024). Studies were evaluated using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. Economic standardization employed healthcare-specific inflation indices and purchasing power parity adjustments, with costs converted to 2020 EUR. Results: From 1449 studies, 23 met inclusion criteria, with significant geographic imbalance (74% from North-Western/Central Europe, 4% from South-Eastern Europe). Mammography screening for women aged 50–69 years demonstrated consistent cost-effectiveness (EUR 3000–8000 per quality-adjusted life year (QALY)) with high confidence. For women under 50, screening showed substantially higher costs (EUR 105,000 per year of life saved). Magnetic resonance imaging (MRI) screening showed cost-effectiveness for high-risk populations (EUR 18,201–33,534 per QALY) with moderate confidence. Conclusions: Biennial mammography screening for women aged 50–69 demonstrates consistent cost-effectiveness across European contexts. Findings have highest applicability to North-Western and Central European healthcare systems, with limited generalizability to Southern and Eastern Europe due to evidence gaps. Full article

(This article belongs to the Special Issue Health Economic and Policy Issues Regarding Cancer)

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12 pages, 1185 KB

Open AccessArticle

Multiple Primaries: Differences in Survival of Patients with Glioma with or Without Second Malignancies

by Matthias Demetz, Aleksandrs Krigers, Alexander Miller-Michlits, Adelheid Wöhrer, Claudius Thomé, Christian F. Freyschlag and Johannes Kerschbaumer

Cancers 2025, 17(21), 3584; https://doi.org/10.3390/cancers17213584 - 6 Nov 2025

Viewed by 406

Abstract

Background and Objectives: The biological behavior of gliomas is influenced by various factors including molecular features and treatment response. This study investigates the prognostic implications of a second tumor in patients with glioma at time of diagnosis. Given the increasing number of patients [...] Read more.

Background and Objectives: The biological behavior of gliomas is influenced by various factors including molecular features and treatment response. This study investigates the prognostic implications of a second tumor in patients with glioma at time of diagnosis. Given the increasing number of patients presenting with multiple primary malignancies due to improved cancer survival and diagnostic accuracy, understanding the influence of double tumor burden on glioma outcomes is of growing clinical relevance. Methods: We retrospectively analyzed adult patients with intracranial gliomas (WHO grade 2–4), who were surgically treated between 2015 and 2022 at our institution. Patients were categorized into two groups: glioma only and glioma plus additional solid malignancy. We compared progression-free survival (PFS) and overall survival (OS) using Kaplan–Meier and Cox regression analyses. Results: Among 426 glioma patients, 75 (17.6%) harbored a second non-brain tumor. Patients with multiple primaries showed significantly poorer OS (median 6 vs. 14 months, p = 0.002). No significant difference in PFS or OS was observed for patients in case the systemic tumor was in complete remission as compared to those with sole glioma. However, patients with progressive or stable systemic tumor had significantly worse outcomes regarding OS (p < 0.05). Conclusions: Our findings suggest that the presence of a second systemic malignancy is an independent prognostic factor for worse outcome. Further studies are mandated to elucidate genetic situations and refine therapeutic strategies for these patients. Full article

(This article belongs to the Special Issue Outcomes in Glioblastoma Patients: From Diagnosis to Palliation: 2nd Edition)

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14 pages, 550 KB

Open AccessArticle

A Novel Cell-Free DNA Fragmentomic Assay and Its Application for Monitoring Disease Progression in Real Time for Stage IV Cancer Patients

by Sudhir K. Sinha, Hiromi Brown, Kevin Knopf, Patrick Hall, William D. Shannon and William Haack

Cancers 2025, 17(21), 3583; https://doi.org/10.3390/cancers17213583 - 6 Nov 2025

Viewed by 824

Abstract

Background/Objectives: Conventional imaging assesses therapy response in stage IV solid-tumor patients in 8- to 12-week intervals, delaying detection of non-responders. We evaluated a quantitative PCR (qPCR) assay that interrogates size-distributed cell-free DNA (cfDNA) fragments to provide earlier insights into treatment efficacy. Methods [...] Read more.

Background/Objectives: Conventional imaging assesses therapy response in stage IV solid-tumor patients in 8- to 12-week intervals, delaying detection of non-responders. We evaluated a quantitative PCR (qPCR) assay that interrogates size-distributed cell-free DNA (cfDNA) fragments to provide earlier insights into treatment efficacy. Methods: In this prospective study, 128 patients with metastatic lung, breast, or colorectal cancer provided plasma 12–21 days after the first dose of a new systemic regimen. The qPCR targets multi-copy retrotransposon element fragments of greater than 80 bp, greater than 105 bp, and greater than 265 bp, as well as an internal control. A model integrates these quantities into a Progression Score (PS) ranging from 0 to 100; higher values indicate probable disease progression. Results: The PS model yielded an area under (AUC) the receiver-operating-characteristic (ROC) curve of 0.93 for predicting radiographic progression at first imaging. Scores were strongly bimodal: 92% of patients with PS > 90 progressed, whereas 95% with PS < 10 did not. Intermediate scores (10–90) comprised a mixed cohort. Assay performance was unaffected by tumor genomic profile. Conclusions: This cfDNA-based Progression Score (PS) assay enables tumor- and therapy-agnostic, non-invasive monitoring of treatment response as early as two weeks after initiation. By flagging ineffective regimens well before standard imaging, the test can accelerate clinical decision-making, reduce exposure to futile therapy, and potentially improve outcomes in stage IV cancer. Early treatment plan changes may also avoid the high costs of ineffective treatments, prevent downstream toxicity-related hospitalizations, and free up limited imaging and infusion-suite capacity—yielding savings for patients, payers, and healthcare systems. Full article

(This article belongs to the Section Molecular Cancer Biology)

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34 pages, 3741 KB

Open AccessReview

Enhancing Cancer Therapy with TLR7/8 Agonists: Applications in Vaccines and Combination Treatments

by Jagannath Mondal, Swayam Prabha, Thomas S. Griffith, David Ferguson and Jayanth Panyam

Cancers 2025, 17(21), 3582; https://doi.org/10.3390/cancers17213582 - 6 Nov 2025

Viewed by 1192

Abstract

Targeting Toll-like receptors 7 and 8 (TLR7/8) has emerged as a promising strategy in cancer immunotherapy. TLR7/8 agonists activate robust Th1-type immune responses and bridge innate and adaptive immunity. Further, TLR7/8 agonists can serve as valuable adjuncts to conventional therapies, such as chemotherapy [...] Read more.

Targeting Toll-like receptors 7 and 8 (TLR7/8) has emerged as a promising strategy in cancer immunotherapy. TLR7/8 agonists activate robust Th1-type immune responses and bridge innate and adaptive immunity. Further, TLR7/8 agonists can serve as valuable adjuncts to conventional therapies, such as chemotherapy and radiotherapy, enhancing efficacy while reducing adverse effects. Their integration into combination regimens for cancer offers a dual advantage: amplifying antitumor immunity and reducing tumor burden. Notably, the incorporation of TLR7/8 agonists into cancer vaccine platforms has yielded encouraging results in preclinical models and is advancing toward clinical application. This review highlights the mechanisms of action, therapeutic potential, and recent progress in the development of TLR7/8 agonist-based strategies for cancer treatment. We also discuss ongoing clinical evaluations and the rationale for combining these agents with existing modalities to enable more effective, personalized, and accessible cancer therapies. Full article

(This article belongs to the Special Issue Insights from the Editorial Board Member)

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15 pages, 932 KB

Open AccessSystematic Review

Androgenetic Alopecia and Risks of Overall and Aggressive Prostate Cancer: An Updated Systematic Review and Meta-Analysis

by David G. Hanelin, Sapir Amar and Ilir Agalliu

Cancers 2025, 17(21), 3581; https://doi.org/10.3390/cancers17213581 - 6 Nov 2025

Viewed by 1367

Abstract

Background: Androgenetic alopecia, also known as male pattern baldness (MPB), is a common hair loss disorder among middle-aged men. MPB shares similar risk factors with prostate cancer (PrCa), including advancing age, family history, and sex hormones. Several studies have examined the associations between [...] Read more.

Background: Androgenetic alopecia, also known as male pattern baldness (MPB), is a common hair loss disorder among middle-aged men. MPB shares similar risk factors with prostate cancer (PrCa), including advancing age, family history, and sex hormones. Several studies have examined the associations between MPB and PrCa; however, the evidence remains unclear. We carried out an updated meta-analysis of epidemiological studies that examined the relationship between age at onset and patterns of MPB (either frontal, vertex, or both) and their associations with risks of total and aggressive PrCa. Methods: A literature search was performed using PubMed and Web of Science databases for epidemiological studies published between 1 January 2000 and 31 December 2024 that examined the associations between MPB and PrCa. From each eligible study, relevant data were extracted on study design and population, sample size, prevalence of MPB at various ages, and their association with PrCa. Pooled relative risks (RR) and corresponding 95% confidence intervals (CI) were calculated using the Der-Simonian and Laird random-effects models. Heterogeneity across studies was assessed by I² statistics, while the quality of studies was evaluated using the Newcastle–Ottawa Scale. Results: A total of 19 observational studies, including 17,810 cases and 146,806 controls/non-cases, were analyzed. The prevalence of MPB increased from 5% to 65% with aging and varied across the studies. Both frontal and vertex MPB were associated with a pooled RR of 1.08 (95% CI 1.02–1.14) for total PrCa, but there was no association with frontal-only MPB. Younger-onset MPB (<40 years old) was also associated with an RR = 1.13 (95% CI 0.96–1.31) for PrCa, although results were not statistically significant. Vertex-only MPB was associated with more aggressive PrCa (pooled RR = 1.14; 95% CI 1.02–1.25); however, there was substantial heterogeneity in the definition of aggressive PrCa across the studies. Conclusions: Men with both frontal and vertex MPB have a modestly elevated risk of PrCa. However, most studies were conducted in Caucasian men and they did not evaluate effect modifications by genetic variations in androgen metabolism pathway genes or changes in serum levels of androgens with aging. Large prospective cohort studies with more accurate longitudinal assessment of hair loss patterns are needed to better understand the complex relationship between genetic susceptibility, endogenous hormones, MPB, and subsequent risk of PrCa. Full article

(This article belongs to the Special Issue Urological Cancer: Epidemiology and Genetics)

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14 pages, 637 KB

Open AccessArticle

The Strange Case of Functional High-Risk Multiple Myeloma Patients: Is It Possible to Identify Them in Clinical Practice?

by Sonia Morè, Massimo Offidani, Laura Corvatta, Tommaso Za, Francesca Fazio, Martina Gherardini, Velia Bongarzoni, Barbara Anaclerico, Luca Franceschini, Silvia Ferraro, Luca Cupelli, Carmine Liberatore, Laura De Padua, Angela Rago, Silvia Gentili, Roberto Latagliata, Mariagrazia Garzia, Iole Cordone, Valeria Mezzanotte, Elena Rossi, Francesca Di Landro, Maria Zaira Limongi, Erika Morsia, Antonella Poloni and Maria Teresa Petrucci Show full author list Hide full author list

Cancers 2025, 17(21), 3580; https://doi.org/10.3390/cancers17213580 - 6 Nov 2025

Viewed by 488

Abstract

Background: Early relapse in multiple myeloma (MM) is a major predictor of poor prognosis, regardless of cytogenetic risk or treatment intensity. Methods: Here we analyzed 1026 MM patients treated across 12 Italian hematology centers. FHR was defined as progression-free survival (PFS) ≤18 months [...] Read more.

Background: Early relapse in multiple myeloma (MM) is a major predictor of poor prognosis, regardless of cytogenetic risk or treatment intensity. Methods: Here we analyzed 1026 MM patients treated across 12 Italian hematology centers. FHR was defined as progression-free survival (PFS) ≤18 months in transplant-eligible (TE) and ≤12 months in non-transplant-eligible (NTE) patients. Logistic regression and ROC analysis were used to identify significant predictors of FHR and build a risk score. Results: FHR status was identified in 175 patients (17%). These patients had significantly shorter PFS (7 vs. 57.5 months) and overall survival (19 months vs. not reached; p < 0.001). FHR status was associated with higher median LDH, lower Hb level, higher creatinine level and lower platelets count. Modified EASIX formula was built by these significant continuous variables, to be tested in a logistic analysis: [(LDH × creatinine)/(Hb × PLT) × 100]. A significantly higher rate of FHR was found with a score > 2.0 (89% vs. 11%, p < 0.001). Multivariate logistic analysis selected the above formula, ECOG PS ≥ 2 and ISS III as factors associated with FHR. Scoring these variables according to OR, three groups of patients were segregated with a rate of FHR patients of 7%, 29.5%, and 63.5%, respectively. Treatment with anti-CD38 monoclonal antibodies was associated with lower FHR frequency. Conclusions: This study proposes a simple, clinically applicable model to identify FHR MM patients early in their disease course. However, very in-depth biological tools, not available in clinical practice, are needed to identify singularly risk of becoming FHR. Full article

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

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14 pages, 915 KB

Open AccessArticle

Effects of Metformin on Cancer Survival Among Men Diagnosed with Advanced Prostate Cancer Treated with Androgen-Deprivation Therapy: Emulating a Target Trial

by David S. Lopez, Efstathia Polychronopoulou, Omer Abdelgadir, Raymond Greenberg, Lindsay G. Cowell, Sarah E. Messiah and Yong-Fang Kuo

Cancers 2025, 17(21), 3579; https://doi.org/10.3390/cancers17213579 - 6 Nov 2025

Viewed by 1063

Abstract

Background/Objectives: Metformin is one of the most frequently used concomitant medications among prostate cancer (PCa) patients. However, the effects of metformin on all-cause and PCa-specific mortality among men diagnosed with advanced/metastatic PCa treated with androgen-deprivation therapy (ADT) remain poorly understood, but they may [...] Read more.

Background/Objectives: Metformin is one of the most frequently used concomitant medications among prostate cancer (PCa) patients. However, the effects of metformin on all-cause and PCa-specific mortality among men diagnosed with advanced/metastatic PCa treated with androgen-deprivation therapy (ADT) remain poorly understood, but they may be specifically explained by emulating a target trial. Methods: We emulated a target trial of metformin therapy and survival using observational data on 7361 patients diagnosed with advanced PCa, who were treated with ADT, from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database (2008–2019), with completed follow-up until 2020. We included patients with diabetes, and participants were assigned as either “initiator of metformin within 6 months after advanced PCa diagnosis” or “non-initiator of metformin.” We estimated mortality risks using Cox proportional hazards models with adjustment for risk factors via inverse probability weighting using both intention-to-treat and per-protocol analyses. Results: Over 13 years of follow-up, with a maximum 3 years of follow-up after PCa diagnosis, all-cause mortality occurred in 52 metformin initiators (47.7%) versus 3052 non-initiators (42.1%), while PCa-specific mortality occurred in 36 initiators (33.0%) versus 1919 non-initiators (26.5%). In the intention-to-treat analysis, metformin initiation was not associated with all-cause mortality (Hazard Ratio [HR] = 1.38, 95% CI: 0.98–1.95) or PCa-specific mortality (HR = 0.99, 95% CI: 0.63–1.55). Similarly, in per-protocol analysis, there was no evidence of risk reduction with all-cause (HR = 1.20, 95% CI = 0.80–1.81) or PCa-specific mortality (HR = 1.45, 95% CI = 0.88–2.38) after adjusting for time-varying covariates and allowing a 30-day gap for metformin discontinuation, adjusted for via inverse probability weighting. Conclusions: Our findings align with prior randomized trials showing no survival benefit of metformin in advanced PCa patients receiving ADT. Timing of metformin discontinuation also showed no significant effect. However, the small size of the metformin initiator group precluded subgroup analyses for hormone-sensitive (HSPC) and castrate-resistant prostate cancer (CRPC), limiting our ability to explore potential differential effects. Full article

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

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23 pages, 1663 KB

Open AccessReview

Management of Musculoskeletal Oligometastatic Disease in Breast Cancer

by Kelly Kon-Liao, Josue Layme, Andrea Otero López-Lavalle, Marcos R. Gonzalez and Juan Pretell-Mazzini

Cancers 2025, 17(21), 3578; https://doi.org/10.3390/cancers17213578 - 6 Nov 2025

Viewed by 920

Abstract

Oligometastatic breast cancer represents an intermediate state between localized and disseminated disease with reasonable potential for clinical cure. Advancements in surgery, radiotherapy, and systemic therapy have improved prognosis. Due to the high prevalence of bone metastases, an increasing number of studies are evaluating [...] Read more.

Oligometastatic breast cancer represents an intermediate state between localized and disseminated disease with reasonable potential for clinical cure. Advancements in surgery, radiotherapy, and systemic therapy have improved prognosis. Due to the high prevalence of bone metastases, an increasing number of studies are evaluating new treatment strategies for oligometastatic bone disease. The decision to perform skeletal surgery is complex and depends on optimal patient selection. Major criteria include impending or pathologic long bone fractures, severe neurologic compromise, and an expected survival of over 3 months. Factors associated with improved survival include solitary bone metastases, preserved performance status, adequate surgical margins, absence of pathologic fracture, metachronous metastases, and ER-positivity status. Radiotherapy, especially SBRT, offers effective local control and palliation. Interventional radiology techniques such as percutaneous thermal ablation have also been described as potential treatment alternatives, particularly for fragile patients. Systemic treatment varies according to the tumor subtype. For HR+ and HER2 subtypes, a combination of endocrine therapy with CDK4/6 inhibitors may be considered. HER2+ patients are often treated with HER2-targeted therapies combined with chemotherapy. For triple-negative breast cancer, chemotherapy is the primary treatment. Bone-modifying agents are also recommended to maintain bone strength, prevent skeletal-related events, and reduce the need for additional interventions. Skeletal muscle metastases in breast cancer patients are rare and typically indicate advanced disease with poor prognosis. Treatment options include chemotherapy, radiotherapy, and surgical excision, but should be tailored to the patient’s clinical condition and prognosis. Full article

(This article belongs to the Section Cancer Metastasis)

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13 pages, 1991 KB

Open AccessArticle

Revisiting p53 Immunohistochemical Staining and Its Prognostic Implications in Advanced EGFR-Mutated Lung Adenocarcinoma

by Feng-Che Kuan, Shun-Fu Chang, Yao-Ren Yang, Yu-Ying Wu, Fen-Fen Chen, Kam-Fai Lee, Chen-Lin Chi, Meng-Hung Lin and Chung-Sheng Shi

Cancers 2025, 17(21), 3577; https://doi.org/10.3390/cancers17213577 - 5 Nov 2025

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Abstract

Background/Objectives: TP53 mutations in advanced epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer could worsen prognosis. Therefore, we aimed to investigate the clinical significance of TP53 mutations and p53 expression in these patients. Methods: Patients with advanced/metastatic EGFR-mutated lung adenocarcinoma treated with [...] Read more.

Background/Objectives: TP53 mutations in advanced epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer could worsen prognosis. Therefore, we aimed to investigate the clinical significance of TP53 mutations and p53 expression in these patients. Methods: Patients with advanced/metastatic EGFR-mutated lung adenocarcinoma treated with first-line tyrosine kinase inhibitors were retrospectively enrolled. Sanger sequencing was performed to detect TP53 mutations and immunohistochemical staining was used to verify p53 protein expression levels. Kaplan-Meier and Cox proportional hazards analyses were used to estimate survival and hazard ratio (HR) with 95% confidence interval (CI). Results: The study involved 83 patients with adequate tumor samples for TP53/p53 analysis. Patients with tumor p53 immunostaining ≥50% showed significantly better overall survival (OS) (HR: 0.49 [95% CI: 0.30–0.81], p < 0.001), but TP53 mutations were not associated with inferior progression-free survival (PFS) or OS (missense vs. wild-type [PFS, HR: 0.68 (95% CI: 0.40–1.15), p = 0.151; OS, HR: 0.88 (95% CI: 0.56–1.42), p = 0.599]). Areas under the receiver operating characteristic curves of TP53 mutations with different cut-off values for p53 positivity were 0.51–0.56. The Kaplan-Meier survival analysis revealed significant survival benefits in patients with EGFR L858R substitution and tumor p53 immunostaining ≥50% (median PFS: 8.0 vs. 5.3; median OS: 20.4 vs. 15.3 months; log-rank p = 0.025 and 0.049, respectively). Conclusions: Tumor p53 immunostaining (≥50%) was associated with better OS, especially in patients with TP53 mutations or L858R. Prospective clinical trials are required to explore the prognostic significance of p53 expression in the genomic era of TP53 mutations. Full article

(This article belongs to the Section Cancer Biomarkers)

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17 pages, 4150 KB

Open AccessArticle

An International Inter-Consortium Validation of Knowledge-Based Plan Prediction Modeling for Whole Breast Radiotherapy Treatment

by Lorenzo Placidi, Peter Griffin, Roberta Castriconi, Alessia Tudda, Giovanna Benecchi, Mark Burns, Elisabetta Cagni, Cathy Markham, Valeria Landoni, Eugenia Moretti, Caterina Oliviero, Giulia Rambaldi Guidasci, Guenda Meffe, Tiziana Rancati, Alessandro Scaggion, Karen McGoldrick, Vanessa Panettieri and Claudio Fiorino

Cancers 2025, 17(21), 3576; https://doi.org/10.3390/cancers17213576 - 5 Nov 2025

Viewed by 382

Abstract

Background: Knowledge-based (KB) planning is a promising approach to model prior planning experience and optimize radiotherapy. To enable the sharing of models across institutions, their transferability must be evaluated. This study aimed to validate KB prediction models developed by a national consortium using [...] Read more.

Background: Knowledge-based (KB) planning is a promising approach to model prior planning experience and optimize radiotherapy. To enable the sharing of models across institutions, their transferability must be evaluated. This study aimed to validate KB prediction models developed by a national consortium using data from another multi-institutional consortium in a different country. Methods: Ten right whole breast tangential field (RWB-TF) models were built within the national consortium. A cohort of 20 patients from the external consortium was used for testing. Transferability was defined when the ipsilateral (IPSI) lung first principal component (PC1) was within the 10th–90th percentile of the training set. Predicted dose–volume parameters were compared with clinical dose–volume histograms (cDVHs). Results: Planning target volume (PTV) coverage strategies were comparable between the two consortia, even though significant volume differences were observed for the PTV and contralateral breast (p = 0.002 and p = 0.02, respectively). For the IPSI lung, the standard deviation of predicted mean dose/V20 Gy was 1.13 Gy/2.9% in the external consortium versus 0.55 Gy/1.6% in the training consortium. Differences between the cDVH and the predicted IPSI lung mean dose and the volume receiving more than 20 Gy (V20 Gy) were <2 Gy and <5% in 88.7% and 92.3% of cases, respectively. PC1 values fell within the 10th–90th percentile for ≥90% of patients in 6/10 models and 65–85% for the remaining 4. Conclusions: This study demonstrates the feasibility of applying RWB-TF KB models beyond the consortium in which they were developed, supporting broader clinical implementation. This retrospective study was supported by AIRC (Associazione Italiana per la Ricerca sul Cancro) and registered on ClinicalTrials.gov (NCT06317948, 12 March 2024). Full article

(This article belongs to the Special Issue AI-Enhanced Radiotherapy in Oncology: Optimization from Planning to Clinical Impact)

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14 pages, 697 KB

Open AccessReview

The Evolving Interplay Between Targeted Therapy and Surgery for Resectable Lung Cancer

by Victoria Yin and Mara B. Antonoff

Cancers 2025, 17(21), 3575; https://doi.org/10.3390/cancers17213575 - 5 Nov 2025

Viewed by 825

Abstract

Background: Recent landmark clinical trials have introduced the role of targeted therapy with surgery for resectable non-small cell lung cancers (NSCLCs). Methods: This narrative review summarizes data from recent clinical trials and retrospective studies to highlight the evolving interplay between targeted [...] Read more.

Background: Recent landmark clinical trials have introduced the role of targeted therapy with surgery for resectable non-small cell lung cancers (NSCLCs). Methods: This narrative review summarizes data from recent clinical trials and retrospective studies to highlight the evolving interplay between targeted therapy and resectable NSCLC. Results: For patients with epidermal growth factor receptor (EGFR) mutations, the ADAURA trial demonstrated significant improvements in disease-free and overall survival with adjuvant osimertinib after complete resection. The NeoADAURA trial expanded the role of osimertinib to neoadjuvant treatment as it showed benefit in major pathologic response rates when compared to chemotherapy alone. Neoadjuvant osimertinib may facilitate surgical resection, especially for patients with lymph node involvement. Furthermore, the ALINA trial established the role of adjuvant alectinib, another targeted therapy, for patients with anaplastic lymphoma kinase (ALK) positive resectable NSCLC. Given the evidence for use of these novel targeted therapies in patients with resectable lung cancer, early molecular profiling is critical for patients with NSCLC to help guide pre- and postoperative treatment. The use of targeted therapies may even expand to stage IV NSCLC as clinical trials are ongoing and could possibly redefine the role of surgery in advanced disease. Conclusions: While there are ongoing trials to clarify the optimal timing of targeted therapies and surgical resection, current data supports the use of targeted therapies as part of multimodality care in surgically resectable NSCLC. Full article

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

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15 pages, 477 KB

Open AccessArticle

The Impact of Different Hepatitis B Virus Serological Statuses on the Safety of Different Chemotherapy Regimens in Female Breast Cancer Patients: A Within-Subject Longitudinal Study

by Zhao-Xing Li, Dong-Li Liu, Lei Hu, Bai-Qing Peng, Xiu-Quan Qu, Li-Yuan Mu, Xiao-Chun Cheng, Pu Qiu, Yu-Xuan Huang, Xi-Rui Li and Ling-Quan Kong

Cancers 2025, 17(21), 3574; https://doi.org/10.3390/cancers17213574 - 5 Nov 2025

Viewed by 495

Abstract

Background: Breast cancer patients with hepatitis B virus (HBV) infection or past HBV infection face heightened risks of chemotherapy-induced hepatotoxicity and HBV reactivation (HBVr). This study aims to evaluate the impact of different HBV serological statuses on the safety of chemotherapy regimens based [...] Read more.

Background: Breast cancer patients with hepatitis B virus (HBV) infection or past HBV infection face heightened risks of chemotherapy-induced hepatotoxicity and HBV reactivation (HBVr). This study aims to evaluate the impact of different HBV serological statuses on the safety of chemotherapy regimens based on paclitaxel throughout the treatment cycle. Methods: This retrospective cohort study analyzed 4562 female breast cancer patients, categorized into three groups: 366 with HBV infection (HBsAg+), 2529 with past HBV infection (HBsAg−/HBcAb+), and 1667 without HBV infection (control group). The Primary events included liver injury, HBVr, treatment interruption, and laboratory indicator evaluation. Demographic characteristics and periodic laboratory parameters were recorded for within-subject longitudinal analysis. Results: Before chemotherapy, the incidence of liver injury was highest in the HBV-infected group (18.2%), intermediate in the past-infection group (13.2%), and lowest in the control group (12.0%). Throughout chemotherapy, the cumulative incidence of liver injury remained highest in the HBV-infected group (83.2%), compared to the past-infection (71.2%) and control (70.9%) groups. Chemotherapy interruption rates followed a similar gradient: 12.4% in the HBV-infected group, 6.9% in the past-infection group, and 5.5% in the control group. HBV-infected patients had a significantly higher risk of hepatotoxicity than controls during cycle 4 (relative risk 1.56, 95% CI 1.06 to 2.29) and cycle 5 (1.28, 1.09 to 1.75). HBVr occurred in 13 patients with HBV-infected. Conclusions: HBV serological status significantly impacts chemotherapy safety and treatment interruption. Prophylactic antiviral therapy and intensified monitoring during high-risk cycles (cycle 4 and cycle 5) are critical. These findings underscore the necessity of stratified management for HBV-affected breast cancer patients during chemotherapy. Full article

(This article belongs to the Special Issue New Perspectives in the Management of Breast Cancer)

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16 pages, 1882 KB

Open AccessArticle

Evaluation of the Ability to Predict Subsequent Metastasis of Early Oral Squamous Cell Carcinoma Using PET Radiomics Machine Learning Models

by Yutaka Nikkuni, Hideyoshi Nishiyama, Masaki Takamura, Taichi Kobayashi, Marie Soga, Makiko Ike, Kouji Katsura and Takafumi Hayashi

Cancers 2025, 17(21), 3573; https://doi.org/10.3390/cancers17213573 - 5 Nov 2025

Viewed by 500

Abstract

Background/Objectives: Oral squamous cell carcinoma (OSCC) carries a risk of late metastasis not only in advanced stages but also in early stages. In this study, we built and tested radiomics-based machine learning (ML) models for predicting the risk of metastasis from early [...] Read more.

Background/Objectives: Oral squamous cell carcinoma (OSCC) carries a risk of late metastasis not only in advanced stages but also in early stages. In this study, we built and tested radiomics-based machine learning (ML) models for predicting the risk of metastasis from early OSCC on ¹⁸F-FDG positron emission tomography (PET). Methods: Patients diagnosed with T1 or T2 squamous cell carcinoma who underwent a preoperative ¹⁸F-FDG PET-CT examination at a single institution between 2016 and December 2022 were included in this retrospective study. The presence or absence of late cervical lymph node metastasis was confirmed for all patients. Among the radiomics features extracted from the images, we selected those that were useful for predicting late metastasis and used them to create ML models. We then verified the prediction accuracy of the models. Results: A total of 109 subjects were included, of which 31 had late lymph node metastasis and 78 were without metastasis. The most accurate ML model created using radiomics features selected from the subject cases had an area under the curve of 0.977 and accuracy of 87.5%. Conclusions: We confirmed that ML models using radiomics features extracted from PET images can be useful for predicting late metastasis in patients with early-stage OSCC. Full article

(This article belongs to the Special Issue Machine Learning and Artificial Intelligence in Cancer Diagnostic and Monitoring)

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21 pages, 3645 KB

Open AccessArticle

Dual Role of Diallyl Disulfide (DADS) on Invasive Potential and β-Catenin Dynamics in HER2-Positive Breast Cancer Cells

by Marcello Dell’Aira, Silvia Grassilli, Marina Pierantoni, Valeria Bertagnolo and Federica Brugnoli

Cancers 2025, 17(21), 3572; https://doi.org/10.3390/cancers17213572 - 5 Nov 2025

Viewed by 467

Abstract

Background/Objectives: Natural compounds are being increasingly explored as potential adjuvants to conventional drugs in oncological treatments. Regarding breast tumors, several studies indicate that garlic (Allium sativum) may protect against onset, counteracts aggressiveness, and prevents malignant progression of cells from non-invasive tumors. [...] Read more.

Background/Objectives: Natural compounds are being increasingly explored as potential adjuvants to conventional drugs in oncological treatments. Regarding breast tumors, several studies indicate that garlic (Allium sativum) may protect against onset, counteracts aggressiveness, and prevents malignant progression of cells from non-invasive tumors. It has been widely demonstrated that garlic derivatives induce apoptosis and reduce invasive potential in ER-positive and triple-negative breast tumor cells. However, the current literature lacks studies investigating their effects on HER2-positive (HER2+) breast cancers. This study therefore aimed to explore the effects of a garlic extract and diallyl disulfide (DADS), one of its most bioactive organosulfur compounds, on HER2+ phenotype breast tumor cells. Methods: The effects of a garlic extract and diallyl disulfide (DADS) were investigated on MDA-MB-453 and SKBR3 breast tumor cell lines. Cell growth, invasive potential, and Akt-related signaling were assessed after 4–72 h of garlic derivatives administration. The intracellular localization of β-catenin was examined with immunofluorescent confocal microscopy. Results: A dual role of DADS, dependent on the duration of treatment, was revealed. Acute administration induced a significant decrease in invasive potential, while prolonged treatment promoted HER2+ cell invasiveness. These effects were directly correlated with the activation of Akt and the nuclear accumulation of β-catenin, known to induce expression of genes associated with tumor malignancy. Conclusions: Although further investigations are needed to establish the exact mechanism and to assess the in vivo reproducibility of these phenomena, our results highlight the heterogeneous response to natural compounds of complex diseases like cancer. Full article

(This article belongs to the Special Issue Cancer Cell Motility (2nd Edition))

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21 pages, 12238 KB

Open AccessArticle

CircATP2C1 Drives Prostate Cancer Progression Through miR-654-3p-Mediated SLC7A11 Upregulation and Ferroptosis Suppression

by Zhihai Deng, Qiang Shen, Nan Deng, Jun Wu, Xinghui Cheng, Jiaxing Wang, Hangyang Peng, Weijie Zeng, Ziyi Song, Dongmei Jiang, Daojun Lv and Xiangming Mao

Cancers 2025, 17(21), 3571; https://doi.org/10.3390/cancers17213571 - 5 Nov 2025

Viewed by 505

Abstract

Background: Prostate cancer, an epithelial malignancy occurring in the prostate, is the most common malignant tumor of the male genitourinary system and has a low survival rate in advanced prostate cancer after metastasis. It is urgent to explore novel therapeutic targets and [...] Read more.

Background: Prostate cancer, an epithelial malignancy occurring in the prostate, is the most common malignant tumor of the male genitourinary system and has a low survival rate in advanced prostate cancer after metastasis. It is urgent to explore novel therapeutic targets and strategies for treating prostate cancer. Circular RNA (circRNA) and ferroptosis both play critical roles in prostate cancer progression. However, the regulatory effect of circRNA on ferroptosis remains unclear. Methods: Here, circRNA expression profiles in prostate cancer were explored by bioinformatics analysis and human prostate cancer tissue microarray. Stable circRNA-knockdown or overexpressed prostate cancer cell lines were constructed by lentivirus. AGO2-RNA immunoprecipitation (AGO2-RIP) was utilized to identify circRNA-microRNA (miRNA) interaction. Results: Results of this study indicate that circATP2C1 is highly expressed in prostate cancer. In addition, circATP2C1 promotes prostate cancer cell proliferation, migration, and invasion by suppressing ferroptosis in vitro. Moreover, circATP2C1 facilitates the tumorigenicity of prostate cancer by inhibiting ferroptosis in vivo. Conclusions: Mechanistically, circATP2C1 hinders ferroptosis by increasing solute carrier family 7 member 11 (SLC7A11) expression via sponging miR-654-3p. In summary, our findings highlight the oncogenic role of circATP2C1 in prostate cancer and provide novel targets and strategies for treating prostate cancer. Full article

(This article belongs to the Section Molecular Cancer Biology)

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16 pages, 1894 KB

Open AccessArticle

Impact of Body Mass Index on Robotic Surgery Outcomes in Early-Stage Endometrial Cancer: A Retrospective Cohort Study

by Dimitrios Papageorgiou, Eleftherios Zachariou, Ioakeim Sapantzoglou, Elias Tsakos, Emmanouil M. Xydias, Dimitrios Dimitroulis and Nikolaos Plevris

Cancers 2025, 17(21), 3570; https://doi.org/10.3390/cancers17213570 - 5 Nov 2025

Viewed by 463

Abstract

Background/Objectives: Obesity is a well-established risk factor for endometrial cancer and presents challenges for surgical management. Robotic-assisted surgery offers a minimally invasive approach with potential benefits for obese patients. This study sought to assess the impact of body mass index (BMI) on [...] Read more.

Background/Objectives: Obesity is a well-established risk factor for endometrial cancer and presents challenges for surgical management. Robotic-assisted surgery offers a minimally invasive approach with potential benefits for obese patients. This study sought to assess the impact of body mass index (BMI) on surgical performance and short-term outcomes in patients undergoing robotic surgery for early-stage endometrial cancer, focusing on follow-up and perioperative treatment. Methods: A retrospective analysis was conducted on 54 patients with early-stage endometrial cancer who underwent a robotic total hysterectomy, bilateral salpingo-oophorectomy, and indocyanine green sentinel lymph node biopsy between January 2021 and December 2024 at two tertiary centers. Patients were stratified by body mass index. Surgical variables, sentinel lymph node detection rates, peri- and postoperative complications, length of hospital stay, and short-term oncologic outcomes were assessed. Statistical comparisons were performed using ANOVA, chi-square tests, and Pearson’s correlation analysis. Results: The mean patient age was 59.7 years, with a mean BMI of 31.1 kg/m². Bilateral sentinel lymph node detection was successful in 87% of cases, with no significant differences between BMI groups. Console time, hospital stay, and complication rates were comparable across BMI categories. Console time positively correlated with the number of lymph nodes removed (r = 0.302, p = 0.026), but not with BMI. At a mean follow-up of 24.4 months, no recurrences were observed. Conclusions: Robotic surgery for early-stage endometrial cancer is safe and effective regardless of BMI, including in patients with Class III obesity. BMI does not negatively impact surgical or short-term oncologic outcomes, supporting robotic surgery as an optimal approach in obese endometrial cancer patients. Full article

(This article belongs to the Special Issue Evolving Trends in the Surgical Therapy of Patients with Gynecological Cancer)

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12 pages, 752 KB

Open AccessCommunication

Teclistamab Dosing Strategies in Relapsed/Refractory Myeloma: A Real-World Comparison of Weekly and Biweekly Versus Fixed Intervals

by Jordan Snyder, Shebli Atrash, Barry Paul, Abdullah Mohammad Khan, Alma Habib, Hira Shaikh, Christopher Strouse, Omar Alkharabsheh, Anita Mazloom, Nausheen Ahmed, Zahra Mahmoudjafari, Muhammad Umair Mushtaq, Anas Zayad, Joseph McGuirk, Yun Kyoung Tiger, Mansi R. Shah and Al-Ola Abdallah

Cancers 2025, 17(21), 3569; https://doi.org/10.3390/cancers17213569 - 5 Nov 2025

Viewed by 1468

Abstract

Background/Objectives: Teclistamab is a bispecific antibody targeting BCMA and CD3, approved for relapsed/refractory multiple myeloma. It is administered continuously until progression or intolerance; however, prolonged use may increase infections and treatment burden. This study compares continuous versus fixed-duration teclistamab to determine whether treatment [...] Read more.

Background/Objectives: Teclistamab is a bispecific antibody targeting BCMA and CD3, approved for relapsed/refractory multiple myeloma. It is administered continuously until progression or intolerance; however, prolonged use may increase infections and treatment burden. This study compares continuous versus fixed-duration teclistamab to determine whether treatment discontinuation after response is feasible without compromising outcomes. Methods: A multicenter retrospective study was conducted on adults with relapsed/refractory multiple myeloma treated with teclistamab between August 2022 and May 2024. Patients received step-up dosing followed by weekly administration. Those who achieved ≥VGPR and discontinued therapy due to deep response, toxicity, or preference were assigned to the fixed-duration group. Outcomes included response rates, progression-free survival (PFS), overall survival (OS), and adverse events. Results: Eighty-eight patients were included (continuous: n = 72; fixed: n = 16). The fixed group had higher complete response rates (69% vs. 44%) and shorter median time to best response (1 vs. 2 months). Median PFS was 16 months for continuous dosing versus 13 months for fixed-duration. Twelve-month PFS was similar (65% vs. 66%). Twelve-month OS was 83% vs. 81% in the continuous and fixed groups, respectively. Cytokine release syndrome and neurotoxicity rates were similar. Infections were more frequent and severe in the fixed cohort (75% any grade; 69% grade ≥ 3). Conclusions: Fixed-duration teclistamab after deep response appears feasible in appropriately selected patients, with comparable early survival outcomes to continuous treatment. Prospective studies are needed to define selection criteria, immune recovery markers, and optimal discontinuation timing. Full article

(This article belongs to the Section Cancer Drug Development)

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15 pages, 1323 KB

Open AccessArticle

Mitomycin-C for HPV-Positive and HPV-Negative Platinum-Refractory, Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: A Phase 2 Trial

by Peter Oppelt, Jessica Ley, Christine Auberle, Brendan Knapp, Jesse Zaretsky, Fei Wan and Douglas Adkins

Cancers 2025, 17(21), 3568; https://doi.org/10.3390/cancers17213568 - 4 Nov 2025

Viewed by 636

Abstract

Background/Objectives: Functional p53 is critical for anti-tumor activity of mitomycin-C. In wild-type TP53 human papillomavirus (HPV)-positive squamous cell carcinoma (SCC) cell lines, mitomycin-C repressed E6 oncoprotein expression and induced p53, p21, and Bax, resulting in apoptosis. In mutant TP53 HPV-negative SCC cell lines, [...] Read more.

Background/Objectives: Functional p53 is critical for anti-tumor activity of mitomycin-C. In wild-type TP53 human papillomavirus (HPV)-positive squamous cell carcinoma (SCC) cell lines, mitomycin-C repressed E6 oncoprotein expression and induced p53, p21, and Bax, resulting in apoptosis. In mutant TP53 HPV-negative SCC cell lines, mitomycin-C was inactive. The primary aim of this trial was to determine the objective response rate (ORR) with mitomycin-C among patients with HPV-positive (cohort A) and HPV-negative (cohort B) platinum-refractory, recurrent or metastatic head and neck SCC (RM-HNSCC). Methods: Patients with platinum-refractory RM-HNSCC received mitomycin-C (10 mg/m² on day one every five weeks) until discontinuation criteria were met. Tumor response was assessed by RECIST1.1. We hypothesized an ORR of ≥30% (H₁) with mitomycin-C (vs. H₀ ORR of ≤10%). Using a two-stage Simon phase 2 design for each cohort, 2 or more responses among 12 evaluable patients were required to enroll 23 additional patients. H₁ was accepted if 6 or more responses occurred among 35 evaluable patients (power 0.90; one-sided α = 0.10). Results: Forty-seven patients were treated with mitomycin-C: 34 in cohort A and 13 in cohort B. Tumor response occurred in 3 of 33 evaluable patients in cohort A (ORR 9.1%, 95%CI: 0–19.4) and in 0 of 12 evaluable patients in cohort B. The duration of tumor responses in cohort A was 2.3, 2.5, and 4.5 months. The most common treatment-related AEs of any grade were anemia (96%), fatigue (62%), and thrombocytopenia (40%). No treatment-related deaths occurred. Conclusions: Mitomycin-C had limited activity in HPV-positive, and no activity in HPV-negative, platinum-refractory RM-HNSCC. Full article

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

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1 pages, 144 KB

Open AccessRetraction

RETRACTED: Sarfstein et al. Identification of Insulin-Like Growth Factor-I Receptor (IGF-IR) Gene Promoter-Binding Proteins in Estrogen Receptor (ER)-Positive and ER-Depleted Breast Cancer Cells. Cancers 2010, 2, 233–261

by Rive Sarfstein, Antonino Belfiore and Haim Werner

Cancers 2025, 17(21), 3567; https://doi.org/10.3390/cancers17213567 - 4 Nov 2025

Viewed by 323

Abstract

The journal retracts the article “Identification of Insulin-Like Growth Factor-I Receptor (IGF-IR) Gene Promoter-Binding Proteins in Estrogen Receptor (ER)-Positive and ER-Depleted Breast Cancer Cells” [...] Full article

10 pages, 215 KB

Open AccessReview

Best Practices and Communication Strategies for Informing Oncology Patients About Treatment Discontinuation and Transition to Palliative Care—A Practical Guide for Oncologists

by Aleksandra Piórek, Adam Płużański, Dariusz M. Kowalski and Maciej Krzakowski

Cancers 2025, 17(21), 3566; https://doi.org/10.3390/cancers17213566 - 3 Nov 2025

Viewed by 698

Abstract

Discontinuing active oncological treatment and initiating palliative care is a critical moment in cancer care, requiring oncologists to address complex clinical, ethical, and emotional challenges. This narrative review aims to provide clinicians with practical guidance for conducting conversations about treatment discontinuation and transitioning [...] Read more.

Discontinuing active oncological treatment and initiating palliative care is a critical moment in cancer care, requiring oncologists to address complex clinical, ethical, and emotional challenges. This narrative review aims to provide clinicians with practical guidance for conducting conversations about treatment discontinuation and transitioning patients to palliative or hospice care. Drawing from current clinical guidelines, empirical research, and expert perspectives, the article reviews evidence-based communication strategies and frameworks, including the SPIKES protocol, Ask–Tell–Ask, the WHO model, and the disclosure model. The article also explores the clinical, functional, psychosocial, and ethical criteria relevant to treatment withdrawal decisions, as well as the timing and structure of end-of-life discussions. A practical algorithm is proposed, synthesizing key principles into a step-by-step guide for use in daily oncology practice. The algorithm supports clinicians in balancing medical indications with patient values and preferences, fostering shared decision-making and maintaining therapeutic relationships even in the most difficult circumstances. The review concludes that structured yet flexible communication enhances patient understanding, reduces unnecessary interventions, and improves the quality of end-of-life care. By promoting patient-centered care and timely palliative integration, this article offers oncologists a clear and adaptable approach to one of the most sensitive aspects of cancer care. Full article

(This article belongs to the Special Issue Integrating Palliative Care in Oncology)

16 pages, 9541 KB

Open AccessArticle

Integrated Multi-Omics Analysis Uncovers Immune–Metabolic Interplay in Hepatocellular Carcinoma Tumor Microenvironment

by Jong-Heon Park, Dae Won Sim, Sook-Young Kim, Joon Young Choi, Seung Hyup Hyun and Je-Gun Joung

Cancers 2025, 17(21), 3565; https://doi.org/10.3390/cancers17213565 - 3 Nov 2025

Viewed by 609

Abstract

Background: Hepatocellular carcinoma (HCC) is one of the most common malignant liver tumors worldwide and is associated with a high mortality rate. Methods: In this study, we performed an integrated multi-omics analysis to characterize the immune and metabolic features of the [...] Read more.

Background: Hepatocellular carcinoma (HCC) is one of the most common malignant liver tumors worldwide and is associated with a high mortality rate. Methods: In this study, we performed an integrated multi-omics analysis to characterize the immune and metabolic features of the tumor microenvironment (TME) in HCC. Tumor samples from 60 HCC patients were stratified into two groups based on immune activity score, and differentially expressed genes as well as differentially methylated regions were identified between these groups. Results: Our analysis identified key markers including AGXT2 and DPYS (metabolism-related genes) and TNFSF8 (an immune-related gene). Their increased expression, driven by promoter hypomethylation, was linked to distinct TME profiles. Furthermore, single-cell RNA sequencing revealed cell type-specific expression patterns of these genes, and their higher expression levels were correlated with favorable patient prognosis. Conclusions: These findings demonstrate that the interplay between metabolic pathways and epigenetic regulation of immune genes strongly influences the HCC microenvironment and clinical outcomes. The identified genes could serve as promising therapeutic targets, emphasizing the importance of multi-omics approaches in dissecting tumor heterogeneity. Full article

(This article belongs to the Section Tumor Microenvironment)

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Cancers, Volume 17, Issue 21 (November-1 2025) – 199 articles

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