Cancers

10 pages, 611 KB

Open AccessArticle

The Impact of Lymph Node Ratio for Children with Wilms Tumors: A National Cancer Database Analysis

by Ioannis A. Ziogas, Andrii Khomiak, Kaitlin E. Olson, Dimitrios P. Moris, Alexandria J. Robbins, Jenny Stevens, Shannon N. Acker, Jonathan P. Roach, Kristine S. Corkum and Nicholas G. Cost

Cancers 2025, 17(19), 3276; https://doi.org/10.3390/cancers17193276 - 9 Oct 2025

Abstract

Background: Lymph node status is a prognostic factor in Wilms tumor, and adequate lymph node sampling is strongly recommended. This study investigates the impact of lymph node ratio (LNR) (number of positive to examined lymph nodes) on overall survival in children with resected [...] Read more.

Background: Lymph node status is a prognostic factor in Wilms tumor, and adequate lymph node sampling is strongly recommended. This study investigates the impact of lymph node ratio (LNR) (number of positive to examined lymph nodes) on overall survival in children with resected Wilms tumors. Methods: This retrospective National Cancer Database analysis included children (<18 years) who underwent resection with lymph node sampling for unilateral, non-metastatic Wilms tumor. Results: Among 2206 patients, the median age was three years, the median tumor size was 10.5 cm, and the median number of examined nodes was five. A total of 82.1% of patients had an LNR of 0, 5.4% had an LNR < 0.2, and 12.5% had an LNR ≥ 0.2. In multivariable Cox regression, LNR ≥ 0.2 was associated with worse survival (HR = 1.75, 95%CI: 1.03–2.97, p = 0.04), along with increasing age (HR = 1.11, 95%CI: 1.05–1.17, p < 0.001) and tumor size (HR = 1.03, 95%CI: 1.00–1.06, p = 0.03). Conclusions: LNR is an independent prognostic factor in Wilms tumor and may refine risk stratification and guide treatment decisions. Full article

(This article belongs to the Section Cancer Pathophysiology)

20 pages, 1465 KB

Open AccessReview

The Genomic Topography of Appendiceal Cancers: Our Current Understanding, Clinical Perspectives, and Future Directions

by Daniel J. Gironda, Richard A. Erali, Steven D. Forsythe, Ashok K. Pullikuth, Rui Zheng-Pywell, Kathleen A. Cummins, Shay Soker, Xianyong Gui, Edward A. Levine, Konstantinos I. Votanopoulos and Lance D. Miller

Cancers 2025, 17(19), 3275; https://doi.org/10.3390/cancers17193275 - 9 Oct 2025

Abstract

Background/Objectives: Appendiceal cancer (AC) is a rare and understudied malignancy with limited genomic data available to guide clinical interventions. Historically treated as a subtype of colorectal cancer, AC is now recognized as a distinct disease with unique histologic subtypes and molecular features. [...] Read more.

Background/Objectives: Appendiceal cancer (AC) is a rare and understudied malignancy with limited genomic data available to guide clinical interventions. Historically treated as a subtype of colorectal cancer, AC is now recognized as a distinct disease with unique histologic subtypes and molecular features. This review aims to consolidate current genomic data across AC subtypes and explore the clinical relevance of recurrent mutations. Methods: A systematic literature review was performed in accordance with general Preferred Reporting Items for Systemic Reviews and Meta-Analyses (PRISMA) guidelines. Using search engines such as PubMed and Web of Science, we selected studies based on relevance to AC genomics using search terms such as “appendix cancer”, “appendiceal cancer”, “pseudomyxoma peritonei”, “sequencing”, “mutation”, and “genotype”. Results: AC comprises five major histologic subtypes—appendiceal neuroendocrine neoplasms (ANENs), mucinous appendiceal neoplasms (MANs), goblet cell adenocarcinomas (GCAs), colonic-type adenocarcinomas (CTAs) and signet ring cell adenocarcinomas (SRCs)—each with unique clinical behaviors and mutational profiles. Low-grade tumors, such as ANENs and MANs, frequently harbor KRAS and GNAS mutations, while high-grade subtypes, such as CTAs and SRCs, are enriched for TP53, APC, and SMAD gene alterations. GCA tumors exhibit a distinct mutational spectrum involving chromatin remodeling genes such as ARID1A and KMT2D. Compared to colorectal cancer, AC demonstrates lower frequencies of APC and TP53 mutations and a higher prevalence of GNAS mutations, consistent with a pathological divergence from CRC. Conclusions: The genomic heterogeneity of AC is commensurate with its histological complexity and has important implications for diagnosis, prognosis and treatment. While certain actionable mutations are present in a subset of tumors, large-scale genomic characterization efforts and development of subtype-specific models will be essential for advancing precision medicine in AC. Full article

(This article belongs to the Special Issue Rare Cancers, Diagnostic Challenges and Personalized Therapeutic Approaches in the 21st Century (2nd Edition))

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17 pages, 649 KB

Open AccessArticle

Implementing a Geriatric Assessment-Guided Rehabilitation Care Model in Community Oncology Care: Feasibility and Impact on Patient-Reported and Performance-Based Outcomes

by Mackenzi Pergolotti, Kelley C. Wood, Mary Hidde, Tiffany D. Kendig, Deanna Meehan, Katie Hutzayluk, Alaina M. Newell, Jessica Bertram, Ashley Lightner, Stacye Mayo, Alina Hedaya, Smith Giri and Grant R. Williams

Cancers 2025, 17(19), 3274; https://doi.org/10.3390/cancers17193274 - 9 Oct 2025

Abstract

Background: Adults with cancer who are pre-frail or frail are at risk of poor outcomes. Geriatric assessment (GA) is recommended to assess and manage vulnerability and risk of frailty in older adults with cancer (≥65) and to inform referrals in supportive services, including [...] Read more.

Background: Adults with cancer who are pre-frail or frail are at risk of poor outcomes. Geriatric assessment (GA) is recommended to assess and manage vulnerability and risk of frailty in older adults with cancer (≥65) and to inform referrals in supportive services, including rehabilitation. Yet, adoption of the GA in community oncology practice lags, and frailty among adults younger than 65 often goes undetected and/or unaddressed. We evaluated the feasibility of a GA-guided rehabilitation care model and assessed changes in patient-reported and performance-based outcomes after rehabilitation. Methods: Adults (≥18 years) starting systemic therapy at a community oncology practice enrolled in the study. The GA was administered online and monthly for one year. Frailty/pre-frailty was identified using a previously validated 44-item index. The oncology team was notified of frail/pre-frail patients and then made referrals to outpatient rehabilitation. Feasibility outcomes (recruitment, retention, fidelity) and participant acceptability [7 items, 0–5 Likert scale] were analyzed descriptively. Patient-reported and performance-based outcomes were examined using the paired t-test. Results: 48% of eligible patients enrolled (N = 141), and 83% completed at least one GA. Frailty/pre-frailty was identified in 40% of the GAs, resulting in 282 referrals to rehabilitation (99% fidelity). Acceptability scores ranged from 3.5 ± 1.7 to 4.7 ± 0.6. Participants who attended rehabilitation (52%) improved significantly in outcomes measuring health-related quality of life, mobility, aerobic capacity, and strength (all p < 0.05). Conclusion: Implementing a GA-guided rehabilitation care model was feasible and acceptable to patients receiving systemic treatment. Those who attended rehabilitation experienced significant improvement in patient-reported and performance-based outcomes. Full article

(This article belongs to the Special Issue Treatment Outcomes in Older Adults with Cancer)

19 pages, 938 KB

Open AccessArticle

The Prognostic Role of Geriatric Nutritional Risk Index in Periampullary Cancer Patients Undergoing Pancreaticoduodenectomy: A Propensity Score-Matched Survival Study

by Chih-Ying Li, Wei-Feng Li, Yueh-Wei Liu, Yu-Yin Liu, Cheng-Hsi Yeh, Yu-Hung Lin, Jen-Yu Cheng and Shih-Min Yin

Cancers 2025, 17(19), 3273; https://doi.org/10.3390/cancers17193273 - 9 Oct 2025

Abstract

Background: The Geriatric Nutritional Risk Index (GNRI) is a simple tool for nutritional assessment, but its long-term prognostic value in patients undergoing pancreaticoduodenectomy (PD) remains unclear. Methods: This retrospective study included adult patients who underwent PD between January 2014 and December 2023 [...] Read more.

Background: The Geriatric Nutritional Risk Index (GNRI) is a simple tool for nutritional assessment, but its long-term prognostic value in patients undergoing pancreaticoduodenectomy (PD) remains unclear. Methods: This retrospective study included adult patients who underwent PD between January 2014 and December 2023 at Chang Gung Memorial Hospital. Patients were grouped by GNRI: inferior (<82), moderate (82–98), and superior (≥98). Propensity score matching was performed based on age, sex, cancer type, surgical approach, and ASA status. Primary outcomes were overall survival (OS) and recurrence-free survival (RFS). Results: Among 371 patients, inferior GNRI was associated with worse median survival time (18.64 vs. 34.62 months, HR = 2.953, p < 0.001). This association was observed in both pancreatic cancer and other periampullary malignancies. Inferior GNRI also correlated with higher short-term mortality and adverse perioperative outcomes, including longer ICU stay, and greater need for ventilator support, reintubation, reoperation and total parenteral nutrition (TPN). Conclusions: Preoperative GNRI is a strong predictor of survival and short-term outcomes in PD patients. Early nutritional assessment may aid risk stratification and intervention. Full article

(This article belongs to the Section Methods and Technologies Development)

23 pages, 974 KB

Open AccessReview

Immune Checkpoint Inhibitors in Merkel Cell Carcinoma of the Skin: A 2025 Comprehensive Review

by Patricia Tai, Omar Alqaisi, Suhair Al-Ghabeesh, Lorent Sijarina, Edward Yu, Aoife Jones Thachuthara, Avi Assouline, Osama Souied, Kimberly Hagel and Kurian Joseph

Cancers 2025, 17(19), 3272; https://doi.org/10.3390/cancers17193272 - 9 Oct 2025

Abstract

Objective: Merkel cell carcinoma (MCC) is a rare and aggressive form of skin cancer. Although immunotherapy has transformed MCC management, published data remain limited. This comprehensive review evaluates current evidence on immune checkpoint inhibitors (ICIs) in MCC, in relation to other treatment modalities [...] Read more.

Objective: Merkel cell carcinoma (MCC) is a rare and aggressive form of skin cancer. Although immunotherapy has transformed MCC management, published data remain limited. This comprehensive review evaluates current evidence on immune checkpoint inhibitors (ICIs) in MCC, in relation to other treatment modalities such as surgery and radiotherapy. Methods: Peer-reviewed articles published between January 2000 and August 2025 were searched manually in four databases: Scopus, ScienceDirect, PubMed and MEDLINE, using the keywords “Merkel cell carcinoma” AND “immunotherapy” AND “immune checkpoint inhibitors”. The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) methodology was employed. Results: ICIs can be given in different settings: (A) Neoadjuvant: The CheckMate 358 trial reported a 54.5% response rate among 33 radiologically evaluable patients treated with nivolumab, each showing over 30% tumor reduction. (B) Adjuvant: (1) The ADMEC-O phase II trial demonstrated improved disease-free survival with adjuvant nivolumab. (2) The ADAM phase III trial evaluates adjuvant avelumab in node-positive patients post-surgery/radiation, with common side effects including nausea, fatigue, and itching. (3) STAMP, a phase III trial, investigates pembrolizumab in stage I–III MCC. Both ADAM and STAMP have completed accrual and results are pending. (C) Primary therapy: KEYNOTE-017 and JAVELIN trials reported a 60% overall response rate and ~40% 3-year progression-free survival with first-line pembrolizumab or avelumab. Both agents also show promise as salvage therapies. Conclusions: ICIs demonstrate encouraging outcomes in MCC across various treatment stages. Continued research is essential to optimize treatment timing and integrate multimodal therapies. Full article

(This article belongs to the Special Issue Combination Immunotherapy for Cancer Treatment)

17 pages, 1534 KB

Open AccessArticle

RNF135 Expression Marks Chemokine (C-C Motif) Ligand-Enriched Macrophage–Tumor Interactions in the Glioblastoma Microenvironment

by Jianan Chen, Qiong Wu, Anders E. Berglund, Robert J. Macaulay, James J. Mulé and Arnold B. Etame

Cancers 2025, 17(19), 3271; https://doi.org/10.3390/cancers17193271 - 9 Oct 2025

Abstract

Background: Tumor-associated macrophages (TAMs) are essential regulators of the glioblastoma (GBM) microenvironment; their functional heterogeneity and interaction networks are not fully elucidated. We identify RNF135 as a novel TAM-enriched gene associated with immune activation and adverse prognosis in GBM. Methods: To evaluate RNF135 [...] Read more.

Background: Tumor-associated macrophages (TAMs) are essential regulators of the glioblastoma (GBM) microenvironment; their functional heterogeneity and interaction networks are not fully elucidated. We identify RNF135 as a novel TAM-enriched gene associated with immune activation and adverse prognosis in GBM. Methods: To evaluate RNF135’s expression profile, prognostic significance, and functional pathways, extensive transcriptome analyses from TCGA and CGGA cohorts were conducted. The immunological landscape and cellular origin of RNF135 were outlined using single-cell RNA-seq analyses and bulk RNA-seq immune deconvolution (MCP-counter, xCell and ssGSEA). Cell–cell communication networks between tumor cells and RNF135-positive and -negative tumor-associated macrophage subsets were mapped using CellChat. Results: RNF135 predicted a poor overall survival and was markedly upregulated in GBM tissues. Functional enrichment analyses showed that increased cytokine signaling, interferon response, and innate immune activation were characteristics of RNF135-high samples. Immune infiltration profiling showed a strong correlation between the abundance of T cells and macrophages and RNF135 expression. According to the single-cell analyses, RNF135 was primarily expressed in TAMs, specifically in proliferation, phagocytic, and transitional subtypes. RNF135-positive TAMs demonstrated significantly improved intercellular communication with aggressive tumor subtypes in comparison to RNF135-negative TAMs. This was facilitated by upregulated signaling pathways such as MHC-II, CD39, ApoE, and most notably, the CCL signaling axis. The CCL3/CCL3L3–CCR1 ligand–receptor pair was identified as a major mechanistic driver of TAM–TAM crosstalk. High RNF135 expression was also linked to greater sensitivity to Selumetinib, a selective MEK1/2 inhibitor that targets the MAPK/ERK pathway, according to drug sensitivity analysis. Conclusions: RNF135 defines a TAM phenotype in GBM that is both immunologically active and immunosuppressive. This phenotype promotes inflammatory signaling and communication between cells in the tumor microenvironment. Targeting the CCL–CCR1 axis or combining RNF135-guided immunomodulation with certain inhibitors could be a promising therapeutic strategies for GBM. Full article

(This article belongs to the Special Issue Molecular Genomics in Brain Tumors)

22 pages, 703 KB

Open AccessSystematic Review

Current Perspectives on Non-Metastatic Male Breast Cancer: Genetics, Biology, and Treatment Advances: A Systematic Review

by Kathleen Melan, Pierre Loap and Youlia Kirova

Cancers 2025, 17(19), 3270; https://doi.org/10.3390/cancers17193270 - 9 Oct 2025

Abstract

Background/Objectives: Male breast cancer (MBC) is a rare malignancy representing less than 1% of all breast cancer cases, with rising incidence worldwide. Current treatment strategies largely rely on extrapolation from female breast cancer, despite clear biological and clinical distinctions. This review aims to [...] Read more.

Background/Objectives: Male breast cancer (MBC) is a rare malignancy representing less than 1% of all breast cancer cases, with rising incidence worldwide. Current treatment strategies largely rely on extrapolation from female breast cancer, despite clear biological and clinical distinctions. This review aims to summarize current knowledge on non-metastatic MBC, with a particular focus on genetic predisposition, tumor biology, and recent therapeutic advances. Methods: A systematic literature search was conducted using PubMed and PMC databases to identify clinical trials, observational studies and systematic reviews related to MBC published up to 1st June, 2025. Studies were selected for their relevance to genetic and molecular features, as well as treatment outcomes in non-metastatic disease. Results: Fifty-one studies were included in the review. Findings confirm the predominance of hormone receptor–positive tumors in MBC and underscore the central role of BRCA2 mutations. Germline mutations in BRCA2 and BRCA1 were reported in approximately 1 and 2% of male cases, respectively. Additional germline alterations were identified in PALB2, CHEK2, and other DNA repair genes. Comparative analyses of surgical approaches showed no significant difference in survival between breast-conserving surgery and mastectomy. Postmastectomy radiotherapy improved overall survival compared to surgery alone. Adjuvant tamoxifen therapy was independently associated with significant survival benefits, although adherence remains a challenge. Conclusions: MBC is a biologically distinct and molecularly heterogeneous disease. Breast-conserving surgery appears safe and effective in selected patients. Adjuvant radiotherapy and tamoxifen confer clear survival advantages. The lack of male-specific clinical trials remains a major limitation in optimizing evidence-based care for MBC. Full article

(This article belongs to the Section Cancer Therapy)

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19 pages, 1208 KB

Open AccessArticle

Local Recurrence After Nephron Surgery: What to Do? An Italian Multicentric Registry

by Angelo Porreca, Filippo Marino, Davide De Marchi, Marco Giampaoli, Daniele D’Agostino, Francesca Simonetti, Antonio Amodeo, Paolo Corsi, Francesco Claps, Alessandro Crestani, Riccardo Bertolo, Alessandro Antonelli, Fabrizio Di Maida, Andrea Minervini, Paolo Parma, Roberto Falabella, Stefano Zaramella, Francesco Greco, Maria Chiara Sighinolfi, Bernardo Rocco, Carmine Sciorio, Antonio Celia, Francesca Romana Prusciano, Pier Paolo Prontera, Gian Maria Busetto and Luca Di Gianfrancesco Show full author list Hide full author list

Cancers 2025, 17(19), 3269; https://doi.org/10.3390/cancers17193269 - 9 Oct 2025

Abstract

Introduction and Objectives: Local recurrence (LR) in patients treated with surgery for renal cell carcinoma (RCC) remains a significant clinical challenge that requires thorough investigation. Our study aimed to identify the relative risk factors and explore the optimal clinical management of LR. Materials [...] Read more.

Introduction and Objectives: Local recurrence (LR) in patients treated with surgery for renal cell carcinoma (RCC) remains a significant clinical challenge that requires thorough investigation. Our study aimed to identify the relative risk factors and explore the optimal clinical management of LR. Materials and Methods: We conducted a non-randomized, observational, retrospective multicentric registry involving multiple Italian urological centers. We included patients treated with surgery (either nephron-sparing or radical nephrectomy) who later developed LR, defined as recurrence in the ipsilateral kidney or renal fossa. Patients with hereditary syndromes or metastatic disease at the time of LR diagnosis were excluded. Results: We reported 135 cases of LR with the following characteristics: most primary lesions were monofocal (85.7%), with a median size of 42 mm (23–53), the median R.E.N.A.L. score was 7 (6–8), and the median Padua score was 7 (6–9). Patients were treated with robot-assisted techniques in 59% of cases, laparoscopic surgery in 32.4%, and open surgery in 8.6%. Nephron-sparing surgery was performed in 75.2% of cases. Ischemia occurred in 61% of the cases, with a median ischemia time of 21 min (15.5–24). Intraoperative complications occurred in 3.8% of cases, while postoperative complications were reported in 13.8%, all of which were grade ≤3 according to the Clavien–Dindo classification. The primary tumors were pT1a in 43.5% of cases, pT1b in 26.3%, pT2 in 14.7% and pT3 in 15.5%. Histologically, 84% of cases were clear cell, 11.3% papillary type 1 or 2, and 3.7% chromophobe. Sarcomatoid/rhabdoid variants were present in 10.5% of cases. The median rate of LR was 1.3% (range 0.2–3.6), while the median time to LR was 18 months (12–39). LR occurred in the ipsilateral kidney in 70.5% of cases and in the ipsilateral renal fossa in 29.5%. The median rate of PSM in LR cases at initial surgery was 2.4% (range 0–4.3), while the median rate of negative surgical margin (NSM) in LR cases at initial surgery was 0.1 (0–0.3). Following LR diagnosis, most patients (49.2%) underwent surgery, 29.1% received cryoablation or radiotherapy, 17.1% received systemic treatment alone, and 4.6% followed a watchful waiting/active surveillance approach. At a median follow-up of 62 months, the highest oncological control in terms of 5-year cancer-specific survival and overall survival rates was achieved in surgically treated patients. The PSM, the histological variant, and their combination were found to be independent variables correlated with the occurrence of LR, with relative risks of 3.62, 2.71, and 8.12, respectively. Conclusions: LR after nephron-sparing or radical nephrectomy represents a significant clinical dilemma. Known risk factors are not always sufficient to predict recurrence, emphasizing the necessity of consistent radiological follow-up per guideline recommendations. Early detection of recurrence and a multidisciplinary approach involving expert centers are crucial for optimizing patient outcomes. Full article

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

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18 pages, 392 KB

Open AccessReview

Advanced Biliary Tract Cancer: Exploration of Third-Line and Other Therapeutic Areas After Failure of Chemotherapy Alone

by Li Ma and Cheng Yi

Cancers 2025, 17(19), 3268; https://doi.org/10.3390/cancers17193268 - 9 Oct 2025

Abstract

Biliary tract cancer (BTC) is a highly aggressive malignancy with an extremely poor prognosis and a gradually increasing incidence, warranting increased clinical attention. The majority of BTC patients are diagnosed at an unresectable stage, making systemic therapy—including first-line and subsequent treatments—critical for outcomes. [...] Read more.

Biliary tract cancer (BTC) is a highly aggressive malignancy with an extremely poor prognosis and a gradually increasing incidence, warranting increased clinical attention. The majority of BTC patients are diagnosed at an unresectable stage, making systemic therapy—including first-line and subsequent treatments—critical for outcomes. However, due to disparities in medical resources and limited understanding of the disease, outcomes following first- and second-line therapies remain suboptimal. In this context, third-line treatment offers a potential opportunity to further extend patient survival, although challenges such as poor treatment tolerance and significant drug-related toxicities remain. A rational integration of chemotherapy, targeted therapy, immunotherapy, and novel radiotherapy techniques may constitute a standardized third-line therapeutic strategy for BTC. This review aims to discuss potential therapeutic adaptations and options in the setting where conventional chemotherapy has failed. Full article

(This article belongs to the Special Issue Recent Advances in Hepatobiliary Cancers: From Diagnosis to Treatment (2nd Edition))

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22 pages, 21528 KB

Open AccessArticle

Prognostic Significance of CK5/6 and GATA3 Expression in Recurrent Urothelial Carcinoma

by Marzena Lenda-Petrykowska, Violetta Sulżyc-Bielicka, Wojciech Dobrzycki, Krzysztof Safranow, Jerzy Świtała, Dorota Kostrzewa-Nowak and Paweł Bielicki

Cancers 2025, 17(19), 3267; https://doi.org/10.3390/cancers17193267 - 9 Oct 2025

Abstract

Background/Objectives: The study aimed to determine whether the expression of CK5/6 and GATA3 is altered in UCa recurrences and to evaluate disease-free survival (DFS) and overall survival (OS) according to CK5/6 and GATA3 expression. Methods: A retrospective study was performed in 77 patients [...] Read more.

Background/Objectives: The study aimed to determine whether the expression of CK5/6 and GATA3 is altered in UCa recurrences and to evaluate disease-free survival (DFS) and overall survival (OS) according to CK5/6 and GATA3 expression. Methods: A retrospective study was performed in 77 patients with UCa. Surgery was performed in 35 patients. UCa recurrence was observed in 75% of patients. An immunohistochemical assessment of CK5/6 and GATA3 was performed in the primary and recurrent UCa groups. Results: CK5/6(+) in primary UCa was associated with a 73% probability of CK5/6(+) recurrence (p = 0.000005) and incidence at a younger age. CK5/6(−) in primary UCa was associated with an 84% probability of CK5/6(−) recurrence (p = 0.000005) and incidence at older age. A higher probability of UCa GATA3(+) recurrence was a significant independent factor associated with longer OS (p = 0.015). A greater probability of UCa CK5/6(+) recurrence was a significant independent factor associated with shorter OS (p = 0.044). Patients with CK5/6(+)-only UCa recurrences had significantly worse OS compared to UCa patients with at least one CK5/6(−) recurrence. Conclusions: 1. CK5/6 and GATA3 in UCa recurrences may differ from CK5/6 and GATA3 expression in primary UCa. Intensified oncological surveillance is suggested for patients with recurrent CK5/6(+) 2. Patients with at least one UCa CK5/6(−) recurrence have better prognosis compared to patients with only CK5/6(+) recurrences. Full article

(This article belongs to the Section Molecular Cancer Biology)

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Graphical abstract

18 pages, 617 KB

Open AccessSystematic Review

Movement-Based Interventions in Patients Affected by Bone Metastases: Impact on Physical Function and Functional Autonomy—A Systematic Review

by Giorgia Petrucci, Agnese Broccolo, Anna Marchetti, Chiara Monterosso, Giuseppe Casale, Chiara Timarco, Tea Zeppola, Silvia Dsoke, Elena Sandri, Michela Piredda, Giuseppe Francesco Papalia and Maria Grazia De Marinis

Cancers 2025, 17(19), 3266; https://doi.org/10.3390/cancers17193266 - 9 Oct 2025

Abstract

Background: Bone metastases are a common complication in patients with advanced cancer. These patients often experience a decline in physical function and autonomy, particularly in the ability to perform Activities of Daily Living, and structured movement-based interventions may represent an important supportive strategy. [...] Read more.

Background: Bone metastases are a common complication in patients with advanced cancer. These patients often experience a decline in physical function and autonomy, particularly in the ability to perform Activities of Daily Living, and structured movement-based interventions may represent an important supportive strategy. The aim of this study is to describe the available evidence regarding the impact of physical activity and exercise interventions on functional status and ADL performance in patients with bone metastases. Methods: A systematic literature review was conducted in PubMed, Scopus, Embase, Web of Science, and CINAHL database up to March 2025 and reported according to PRISMA guidelines. Eligible studies included adults (≥18 years) with confirmed bone metastases who underwent physical activity interventions designed to enhance functional status and ADLs. Studies’ methodological quality was assessed using the Joanna Briggs Institute critical appraisal tools, selected according to study design. Results: Eleven studies were included: four randomized controlled trials, four quasi-experimental studies, one randomized feasibility trial, one cross-sectional observational study, and one case report. Despite heterogeneity in intervention type, duration, and outcome measures, most studies reported improvements in physical function, including mobility, muscle strength, walking capacity, and endurance, as well as enhanced performance in ADLs and reductions in fatigue. No serious adverse events were reported. Conclusions: Structured physical activity appears safe and may improve function and independence in patients with bone metastases. These findings support the integration of individualized exercise programs into multidisciplinary supportive care. Full article

(This article belongs to the Special Issue Nursing and Supportive Care for Cancer Survivors)

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13 pages, 1016 KB

Open AccessArticle

Clinical Predictors and Prognostic Significance of Pathologic Disease Upstaging at Radical Cystectomy in Patients with Muscle-Invasive Bladder Cancer

by Salvador Jaime-Casas, Wesley Yip, Daniel J. Lama, Vitor Goes, Miguel Zugman, Koral Shah, Regina Barragan-Carrillo, Hedyeh Ebrahimi, Daniela V. Castro, Yu Jun Li, Benjamin Mercier, JoAnn Hsu, Xiaochen Li, Clayton S. Lau, Kevin G. Chan, Bertram E. Yuh, Alexander Chehrazi-Raffle, Sumanta K. Pal and Abhishek Tripathi

Cancers 2025, 17(19), 3265; https://doi.org/10.3390/cancers17193265 - 9 Oct 2025

Abstract

Introduction: Staging inaccuracies in muscle-invasive bladder cancer (MIBC) can lead to undertreatment or overtreatment. We evaluated clinical and pathological predictors of pathologic upstaging (pUS) stratifying by neoadjuvant chemotherapy (NAC) receipt among patients undergoing robot-assisted radical cystectomy (RARC). Methods: We included patients with MIBC [...] Read more.

Introduction: Staging inaccuracies in muscle-invasive bladder cancer (MIBC) can lead to undertreatment or overtreatment. We evaluated clinical and pathological predictors of pathologic upstaging (pUS) stratifying by neoadjuvant chemotherapy (NAC) receipt among patients undergoing robot-assisted radical cystectomy (RARC). Methods: We included patients with MIBC (≥cT2N0M0) who underwent RARC from February 2004 through October 2020. Patients were grouped as (1) pUS with NAC, (2) pUS without NAC, and (3) no pUS (reference). Baseline characteristics were summarized using descriptive statistics. Logistic regression assessed the association between baseline characteristics and odds for upstaging. Kaplan–Meier method estimated overall survival (OS) and recurrence-free survival (RFS), and log-rank test compared the survival distribution between groups. Univariable and multivariable Cox regression models identified variables associated with OS and RFS. Results: Among 277 patients, 38.6% (n = 107) were upstaged with NAC (n = 37) or without NAC (n = 70). Most were male (79%), white (72%), and had cT2 stage (85%). Median age at surgery was 72 yrs. Preoperative hydronephrosis showed higher odds of upstaging [OR 2.24 (95% CI, 1.31–3.81), p = 0.003]. pUS with NAC [HR 1.99 (95% CI, 1.23–3.22), p = 0.005] and without NAC [HR 3.18 (95% CI, 2.21–4.55), p < 0.001] predicted worse OS (33.5 vs. 18.8 mos) compared to patients without pUS (135.3 mos). pUS with NAC [HR 2.49 (95% CI, 1.58–3.94) p < 0.001] and without NAC [HR 3.02 (95% CI 2.11–4.31), p < 0.001] predicted worse RFS. Conclusions: Preoperative hydronephrosis was the strongest predictor for pUS, independent of other baseline covariates. This highlights the need for better pre-operative risk stratification strategies for patients with MIBC undergoing RARC. Full article

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

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15 pages, 3047 KB

Open AccessArticle

From CT to Microscopy: Radiological–Histopathological Correlation for Understanding Abdominal Lymphomas

by Ante Luetić, Martina Luetić, Benjamin Benzon and Danijela Budimir Mršić

Cancers 2025, 17(19), 3264; https://doi.org/10.3390/cancers17193264 - 9 Oct 2025

Abstract

Background: Non-Hodgkin lymphomas (NHLs) are a heterogeneous group of indolent or aggressive lymphoproliferative neoplasms arising from lymph nodes or in extranodal locations. Computed tomography (CT) is the imaging modality of choice, while the definitive diagnosis is confirmed by analyzing tissue samples. The aim [...] Read more.

Background: Non-Hodgkin lymphomas (NHLs) are a heterogeneous group of indolent or aggressive lymphoproliferative neoplasms arising from lymph nodes or in extranodal locations. Computed tomography (CT) is the imaging modality of choice, while the definitive diagnosis is confirmed by analyzing tissue samples. The aim of this study was to determine the correlation between CT characteristics and histopathological types of abdominal lymphomas. Methods: A retrospective cross-sectional study included 119 patients with histopathologically confirmed abdominal lymphomas who underwent CT of the abdomen and pelvis prior to treatment. The following CT parameters were extracted: morphological presentation (enlarged lymph nodes/conglomerates, solid mass/masses, gastrointestinal wall thickening, abdominal organ involvement, intra- and extraperitoneal infiltrates), location, two-dimensional size, propagation if present, and postcontrast enhancement. Results: Enlarged lymph nodes were a slightly more common CT morphological appearance in the indolent B NHL group, while gastrointestinal (GI) wall thickening, solid masses, and infiltrates were more frequent in the aggressive B NHL group (p = 0.0256). Aggressive B-cell lymphomas had larger size at time of diagnosis compared to other types (p = 0.0436). CT postcontrast enhancement showed lymphomas originating from the gastrointestinal tract, which presented as wall thickening, had the highest enhancement (p = 0.0065 and p = 0.0485). Conclusions: Observed differences in abdominal lymphomas’ histopathological and imaging characteristics including location/origin, CT morphological appearance, and postcontrast enhancement revealed that extranodal lymphomas were more often of the aggressive B-cell type, aggressive B-cell types were larger, and GI tract lymphomas showed the most prominent enhancement. These findings can help in the diagnostic process and enable better management of lymphomas. Full article

(This article belongs to the Section Cancer Pathophysiology)

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12 pages, 517 KB

Open AccessArticle

Understanding the Will Rogers Phenomenon in Cholangiocarcinoma Research and Beyond

by Ruslan Akhmedullin, Zhandos Burkitbayev, Tair Koishibayev, Zhanat Spatayev, Abylaikhan Sharmenov, Oxana Shatkovskaya, Dinara Zharlyganova, Almira Manatova, Zhuldyz Kuanysh, Sanzhar Shalekenov and Abduzhappar Gaipov

Cancers 2025, 17(19), 3263; https://doi.org/10.3390/cancers17193263 - 8 Oct 2025

Abstract

Background. The existing literature highlights a lack of comparative studies between subtypes of cholangiocarcinoma (CC) and the impact of misclassification on the epidemiological parameters. Methods. A retrospective study was conducted to evaluate the surgical outcomes. The authors used Poisson regression with modified errors [...] Read more.

Background. The existing literature highlights a lack of comparative studies between subtypes of cholangiocarcinoma (CC) and the impact of misclassification on the epidemiological parameters. Methods. A retrospective study was conducted to evaluate the surgical outcomes. The authors used Poisson regression with modified errors to calculate the risk ratios (RR) and reported post-estimation marginal effects. Coefficient estimates, variance inflation factors, and Pearson’s goodness-of-fit test statistics were used to check for multicollinearity and model fit, respectively. We also performed a reclassification analysis by modeling Klatskin tumors (PCC) as extrahepatic (ECC), reclassifying them as intrahepatic (ICC), and comparing the corresponding changes in estimates. Results. Regression analysis revealed an increased risk of death in patients with ICC (RR = 2.05, 95% CI 1.11–3.78) and PCC (RR = 2.03, 95% CI 0.97–4.24) compared to those with DCC. When PCC was analyzed as an ECC, the ICC revealed an RR of 1.52 (95% CI 0.84–2.73). Further reclassification of PCC showed an RR of 2.04 for ICC (95% CI: 1.53–3.53). The adjusted marginal effects saw a reduction in the death probability for both ICC and ECC. However, post hoc analyses revealed insufficient evidence for differences between the reclassified models. Conclusions. Patients with DCC had slightly better prognosis compared to ICC and PCC. We found no differences in survival between ICC and ECC (combining DCC and PCC). The decrease in mortality risk due to reclassification in both groups was not confirmed statistically. Future studies should focus on statistical evidence when referring to the Will Rogers phenomenon, instead of inferring from raw comparisons. Full article

(This article belongs to the Section Methods and Technologies Development)

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26 pages, 1116 KB

Open AccessReview

Optimizing Anti-PD1 Immunotherapy: An Overview of Pharmacokinetics, Biomarkers, and Therapeutic Drug Monitoring

by Joaquim Faria Monteiro, Alexandrina Fernandes, Diogo Gavina Tato, Elias Moreira, Ricardo Ribeiro, Henrique Reguengo, Jorge Gonçalves and Paula Fresco

Cancers 2025, 17(19), 3262; https://doi.org/10.3390/cancers17193262 - 8 Oct 2025

Abstract

Anti-PD-1 therapies have transformed cancer treatment by restoring antitumor T cell activity. Despite their broad clinical use, variability in treatment response and immune-related adverse events underscore the need for therapeutic optimization. This article provides an integrative overview of the pharmacokinetics (PKs) of anti-PD-1 [...] Read more.

Anti-PD-1 therapies have transformed cancer treatment by restoring antitumor T cell activity. Despite their broad clinical use, variability in treatment response and immune-related adverse events underscore the need for therapeutic optimization. This article provides an integrative overview of the pharmacokinetics (PKs) of anti-PD-1 antibodies—such as nivolumab, pembrolizumab, and cemiplimab—and examines pharmacokinetic–pharmacodynamic (PK-PD) relationships, highlighting the impact of clearance variability on drug exposure, efficacy, and safety. Baseline clearance and its reduction during therapy, together with interindividual variability, emerge as important dynamic biomarkers with potential applicability across different cancer types for guiding individualized dosing strategies. The review also discusses established biomarkers for anti-PD-1 therapies, including tumor PD-L1 expression and immune cell signatures, and their relevance for patient stratification. The evidence supports a shift from traditional weight-based dosing toward adaptive dosing and therapeutic drug monitoring (TDM), especially in long-term responders and cost-containment contexts. Notably, the inclusion of clearance-based biomarkers—such as baseline clearance and its reduction—into therapeutic models represents a key step toward individualized, dynamic immunotherapy. In conclusion, optimizing anti-PD-1 therapy through PK-PD insights and biomarker integration holds promise for improving outcomes and reducing toxicity. Future research should focus on validating PK-based approaches and developing robust algorithms (machine learning models incorporating clearance, tumor burden, and other validated biomarkers) for tailored cancer treatment. Full article

(This article belongs to the Special Issue Therapeutic Optimization of Anti-Tumor Drugs Based on Pharmacokinetics)

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21 pages, 555 KB

Open AccessReview

Beyond Visualization: Advanced Imaging, Theragnostics and Biomarker Integration in Urothelial Bladder Cancer

by Eduardo Albers Acosta, Lira Pelari Mici, Carlos Márquez Güemez, Clara Velasco Balanza, Manuel Saavedra Centeno, Marta Pérez Pérez, Guillermo Celada Luis, Cristina Quicios Dorado, José Daniel Subiela, Rodrigo España Navarro, Patricia Toquero Diez, Nuria Romero Laorden and Luis San José Manso

Cancers 2025, 17(19), 3261; https://doi.org/10.3390/cancers17193261 - 8 Oct 2025

Abstract

Background/Objectives: Bladder cancer is characterized by high recurrence and progression rates, posing a challenge to current diagnostic and treatment strategies. This review aims to provide a comprehensive overview of emerging technologies, including novel PET tracers, AI-assisted cystoscopy, theragnostics, and molecular biomarkers. Methods: [...] Read more.

Background/Objectives: Bladder cancer is characterized by high recurrence and progression rates, posing a challenge to current diagnostic and treatment strategies. This review aims to provide a comprehensive overview of emerging technologies, including novel PET tracers, AI-assisted cystoscopy, theragnostics, and molecular biomarkers. Methods: We performed a narrative review of the recent literature focusing on innovations in imaging, AI, theragnostics, and biomarker research relevant to bladder cancer diagnosis and management. Results: Several novel PET tracers, such as 68Ga-PSMA and fibroblast activation protein inhibitor (FAPI), demonstrated potential in improving detection sensitivity. AI-enhanced cystoscopy has shown promise in real-time lesion detection, while theragnostic agents enable combined diagnostic and therapeutic applications. Advances in molecular biomarkers, including circulating Tumor DNA (ctDNA) and gene expression signatures, offer new avenues for patient stratification and monitoring. Conclusions: Integration of advanced imaging, AI, theragnostics, and biomarker analysis may transform bladder cancer management, supporting personalized and more effective care strategies. Full article

(This article belongs to the Special Issue The Emerging Role of Multiplexed Imaging for Cancer Diagnosis and Therapy (2nd Edition))

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19 pages, 1056 KB

Open AccessArticle

“Are You Just Looking to ‘Survive’?”: A Qualitative Study of Importance of Oncology Endpoints Beyond Overall Survival in Early-Stage Cancer

by Shelagh M. Szabo, Sarah Walker, Evelyn Griffin, Aya McMillan, Robert Bick, Frances Simbulan, Eon Ting and Stephanie Snow

Cancers 2025, 17(19), 3260; https://doi.org/10.3390/cancers17193260 - 8 Oct 2025

Abstract

Background/Objectives: In early-stage oncology clinical trials, the use of endpoints beyond overall survival (OS), including recurrence-free survival (RFS) or event-free survival (EFS), is becoming more common. To understand whether these outcomes are important to patients, this study explored the perceived value of non-OS [...] Read more.

Background/Objectives: In early-stage oncology clinical trials, the use of endpoints beyond overall survival (OS), including recurrence-free survival (RFS) or event-free survival (EFS), is becoming more common. To understand whether these outcomes are important to patients, this study explored the perceived value of non-OS endpoints among Canadians treated for early-stage cancer or with curative intent. Methods: Canadians treated for early-stage breast, lung, or gastrointestinal cancer participated in semi-structured interviews. Participants provided perspectives on OS, RFS, disease-free survival (DFS), EFS, and pathological complete response (pCR) endpoints. Reflexive thematic analysis was used to explore patterns in responses and alignment of trial endpoints with patient treatment goals, priorities and preferences. Results: The mean age of the 33 participants was 54.8 years, and 21 were female; 28 reported prior surgery, and 21 were also treated with chemotherapy (11 specified as neo-adjuvant; 9 specified adjuvant). All participants valued OS, and most viewed non-OS endpoints as reflective of their treatment priorities, including maintaining health-related quality of life and getting back to ‘normal’. They also valued timely and equitable treatment access and equated having access to new treatments with better options. While participants considered efficacy data from clinical trials provided by non-OS endpoints sufficient to want access to new treatments, the relative importance of being disease- or recurrence-free versus maximizing length of life differed according to recurrence status, prognosis, cancer type and life stage. Conclusions: These findings support the relevance and importance of non-OS endpoints to Canadians with early-stage cancer and highlight participants’ desire for rapid approval of treatments with demonstrated improvements in non-OS endpoints. Full article

(This article belongs to the Section Cancer Survivorship and Quality of Life)

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37 pages, 916 KB

Open AccessSystematic Review

Failure to Rescue After Surgery for Pancreatic Cancer: A Systematic Review and Narrative Synthesis of Risk Factors and Safety Strategies

by Masashi Uramatsu, Yoshikazu Fujisawa, Paul Barach, Hiroaki Osakabe, Moe Matsumoto and Yuichi Nagakawa

Cancers 2025, 17(19), 3259; https://doi.org/10.3390/cancers17193259 - 8 Oct 2025

Abstract

Background: Failure to rescue (FTR), defined as death after major postoperative complications, is a critical quality indicator in pancreatic cancer surgery. Despite advances in surgical techniques and perioperative care, FTR rates remain high and vary across institutions. Methods: This systematic review [...] Read more.

Background: Failure to rescue (FTR), defined as death after major postoperative complications, is a critical quality indicator in pancreatic cancer surgery. Despite advances in surgical techniques and perioperative care, FTR rates remain high and vary across institutions. Methods: This systematic review uses a narrative synthesis followed by PRISMA 2020. A PubMed search (1992–2025) identified 83 studies; after screening, 52 studies (2010–2025) were included. Eligible designs were registry-based, multicenter, single-center, or prospective audits. Given substantial heterogeneity in study designs, FTR definitions, and outcome measures, a narrative synthesis was performed; no formal risk-of-bias assessment or meta-analysis was conducted. Results: Definitions of FTR varied (in-hospital, 30-day, 90-day, severity-based, and complication-specific cases). Reported rates differed by definition: average reported rates were 13.2% for 90-day CD ≥ III (G1); 10.3% for in-hospital/30-day CD ≥ III (G3); and 7.4% for 30-day “serious/major” morbidity (G8). Absolute differences were +3.0 and +2.9 percentage points (exploratory, descriptive comparisons). Five domains were consistently associated with lower FTR: (i) centralization to high-volume centers; (ii) safe adoption/refinement of surgical techniques; (iii) optimized perioperative management including early imaging and structured escalation pathways; (iv) patient-level risk stratification and prehabilitation; and (v) non-technical skills (NTSs) such as decision-making, situational awareness, communication, teamwork, and leadership. Among NTS domains, stress and fatigue management were not addressed in any included study. Limitations: Evidence is predominantly observational with substantial heterogeneity in study designs and FTR definitions; the search was limited to PubMed; and no formal risk-of-bias, publication-bias assessment, or meta-analysis was performed. Consequently, estimates and associations are descriptive/associative with limited certainty and generalizability. Conclusions: NTSs were rarely used or measured across the included studies, with validated instruments; quantitative assessment was uncommon, and no study evaluated stress or fatigue management. Reducing the FTR after pancreatic surgery will require standardized, pancreas-specific definitions of FTR, process-level rescue metrics, and deliberate strengthening of NTS. We recommend a pancreas-specific operational definition with an explicit numerator/denominator: numerator = all-cause mortality within 90 days of surgery; denominator = patients who experience major complications (Clavien–Dindo grade III–V, often labeled “CD ≥ 3”). Addressing the gaps in stress and fatigue management and embedding behavioral metrics into quality improvement programs are critical next steps to reduce preventable mortality after complex pancreatic cancer procedures. Full article

(This article belongs to the Special Issue Novel Diagnosis and Treatment Approaches in Pancreatic Cancer)

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32 pages, 1122 KB

Open AccessReview

Bispecific Monoclonal Antibodies in Diffuse Large B-Cell Lymphoma: Dawn of a New Era in Targeted Therapy

by Mattia Schipani, Matteo Bellia, Carola Sella, Riccardo Dondolin, Mariangela Greco, Abdurraouf Mokhtar Mahmoud, Clara Deambrogi, Riccardo Moia, Gianluca Gaidano and Riccardo Bruna

Cancers 2025, 17(19), 3258; https://doi.org/10.3390/cancers17193258 - 8 Oct 2025

Abstract

Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive non-Hodgkin lymphoma (NHL) worldwide. Currently, approximately sixty percent of patients are cured with R-CHOP as frontline treatment, while the remaining patients experience primary refractory or relapsed (R/R) disease. Recently, the introduction of Pola-R-CHP [...] Read more.

Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive non-Hodgkin lymphoma (NHL) worldwide. Currently, approximately sixty percent of patients are cured with R-CHOP as frontline treatment, while the remaining patients experience primary refractory or relapsed (R/R) disease. Recently, the introduction of Pola-R-CHP as front-line therapy has represented a major advance in the management of DLBCL, resulting in improved outcomes. Prognosis of R/R DLBCL patients is poor, particularly for those eligible neither for chimeric antigen receptor (CAR) T-cell therapy nor autologous stem cell transplantation (ASCT), representing a significant unmet clinical need. The advent of bispecific monoclonal antibodies (BsAbs), such as bispecific T-cell engagers (BiTEs), dual affinity retargeting (DART) molecules and IgG-like bispecific antibodies, offers a novel promising therapeutic approach in the treatment of DLBCL, both as frontline treatment and in the R/R setting. BsAbs simultaneously engage two different antigens, a tumor-associated antigen and an immune cell antigen, redirecting T-cells against malignant cells and enhancing the immune response. Most BsAbs developed for the treatment of NHLs engage T-cells via CD3 and malignant B-cells via CD20, a surface antigen expressed on most lymphomatous cells. Engagement of malignant B-cells by BsAbs activates T-cells, leading to the release of multiple cytokines and potentially to two characteristic adverse events: cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The most extensively studied BsAbs, in both the frontline and relapsed/refractory (R/R) settings, include epcoritamab, glofitamab, mosunetuzumab, and odronextamab. Epcoritamab and glofitamab have received FDA and EMA approval for R/R DLBCL after two or more systemic line of therapies. EMA has also approved glofitamab in combination with gemcitabine and oxaliplatin (GemOx) for patients with R/R DLBCL ineligible for ASCT, whereas this indication has not been approved by FDA. Odronextamab is approved by EMA for R/R DLBCL and FL in patients who have received at least two prior lines of therapy, but it has not been approved by FDA. Mosunetuzumab is approved by both agencies—but only for R/R follicular lymphoma (FL). BsAbs represent a breakthrough therapy in the treatment of DLBCL, especially in R/R diseases. The purpose of this article is to review the landscape of BsAbs in DLBCL. Full article

(This article belongs to the Special Issue Monoclonal Antibodies in Lymphoma)

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