Cancers

20 pages, 2457 KB

Open AccessArticle

Comprehensive Assessment of Prognostic Factors for Immune-Related Adverse Events in Immune Checkpoint Inhibitor-Treated Melanoma

by Julian Kött, Myriam Merkle, Lina Bergmann, Noah Zimmermann, Tim Zell, Isabel Heidrich, Glenn Geidel, Klaus Pantel, Stefan W. Schneider, Christoffer Gebhardt and Daniel J. Smit

Cancers 2025, 17(17), 2806; https://doi.org/10.3390/cancers17172806 (registering DOI) - 27 Aug 2025

Abstract

Background: Immune checkpoint inhibition (ICI) is the standard treatment for advanced melanoma patients. Despite its high efficacy compared to previous treatment options, immune-related adverse events (irAEs) occur frequently. While most of the patients experience mild to moderate irAEs, some patients develop severe [...] Read more.

Background: Immune checkpoint inhibition (ICI) is the standard treatment for advanced melanoma patients. Despite its high efficacy compared to previous treatment options, immune-related adverse events (irAEs) occur frequently. While most of the patients experience mild to moderate irAEs, some patients develop severe to lethal irAEs under ICI treatment; hence, biomarkers are urgently required. Methods: In this retrospective single-center study, 157 advanced melanoma patients treated with ICI at the University Medical Center Hamburg–Eppendorf were included. IrAEs were correlated with clinico-pathological parameters, disease-related outcomes, and irAE-free survival. Results: In our cohort, 130 out of 157 patients receiving immunotherapy experienced irAE, of which more than half experienced irAE Grade ≥ 3. The most common irAE independent of its grade included cutaneous irAE, colitis, endocrine irAE, and hepatitis. Patients experiencing irAE had significantly longer progression-free survival (PFS) and overall survival (OS) compared to patients who did not experience irAE under ICI therapy. Stratification by irAE groups revealed that musculoskeletal irAEs are associated with the longest, whereas myocarditis is associated with the shortest OS and PFS. IrAE was a significant beneficial prognosticator for PFS in univariate, but not in multivariate Cox regression analysis. With respect to OS, the occurrence of irAE was an independent prognostic factor among ECOG status ≥ 2 and uveal melanoma. ROC analysis demonstrated that D-dimers have moderate predictive capability for irAE occurrence. Cox regression analysis demonstrated that elevated D-dimers and PD-1 monotherapy vs. CTLA-4 and PD-1 combination regimen are the only independent prospective prognostic markers for irAE-free survival. Conclusions: Our study demonstrates that different irAE across the irAE spectrum have a different impact on the PFS and OS of advanced melanoma patients. D-dimers may be used as a blood-based biomarker for irAE prediction, warranting future validation in multi-center studies. Full article

(This article belongs to the Section Cancer Immunology and Immunotherapy)

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39 pages, 912 KB

Open AccessReview

Comparative Mechanistic Insights and Therapeutic Potential of Pembrolizumab, Durvalumab, and Ipilimumab as Immune Checkpoint Inhibitors in the Targeted Management of Oral and Head and Neck Squamous Cell Carcinoma

by Piotr Kawczak, Igor Jarosław Feszak and Tomasz Bączek

Cancers 2025, 17(17), 2805; https://doi.org/10.3390/cancers17172805 - 27 Aug 2025

Abstract

Immune checkpoint inhibitors (ICIs) have transformed the landscape of cancer therapy by reactivating immune surveillance mechanisms against tumor cells. In the context of oral squamous cell carcinoma (OSCC) and broader head and neck squamous cell carcinoma (HNSCC), agents such as pembrolizumab, durvalumab, and [...] Read more.

Immune checkpoint inhibitors (ICIs) have transformed the landscape of cancer therapy by reactivating immune surveillance mechanisms against tumor cells. In the context of oral squamous cell carcinoma (OSCC) and broader head and neck squamous cell carcinoma (HNSCC), agents such as pembrolizumab, durvalumab, and ipilimumab target PD-1, PD-L1, and CTLA-4, respectively. This review comprehensively examines their clinical efficacy, safety profiles, mechanisms of action, and therapeutic potential in OSCC management, with an emphasis on strategies to overcome therapeutic resistance. A systematic analysis of the literature was conducted, focusing on clinical outcomes, ongoing trials, and emerging combination therapies. Pembrolizumab has demonstrated significant improvements in overall survival (OS) and progression-free survival (PFS) in OSCC patients. Durvalumab, mainly utilized in locally advanced or recurrent disease, has shown survival benefit, particularly in combination or maintenance settings. Ipilimumab exhibits durable responses in advanced OSCC, with enhanced efficacy observed when used alongside nivolumab in dual checkpoint blockade regimens. Although both pembrolizumab and nivolumab target PD-1, they differ in clinical indications and regulatory approvals. Notably, ICIs are associated with immune-related adverse events (irAEs), requiring careful monitoring. Collectively, these agents represent promising therapeutic options in oral cancer, though future studies must prioritize the identification of predictive biomarkers and the development of optimized combination strategies to maximize therapeutic benefit while minimizing toxicity. Full article

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

26 pages, 1346 KB

Open AccessReview

Anti-EGFR Therapy in Metastatic Colorectal Cancer: Identifying, Tracking, and Overcoming Resistance

by Luís Felipe Leite, Mariana Macambira Noronha, Junior Samuel Alonso de Menezes, Lucas Diniz da Conceição, Luiz F. Costa Almeida, Anelise Poluboiarinov Cappellaro, Marcos Belotto, Tiago Biachi de Castria, Renata D’Alpino Peixoto and Thais Baccili Cury Megid

Cancers 2025, 17(17), 2804; https://doi.org/10.3390/cancers17172804 - 27 Aug 2025

Abstract

Epidermal growth factor receptor (EGFR) inhibitors remain a cornerstone in the treatment of metastatic colorectal cancer with RAS and BRAF wild-type cancer. Yet, primary and acquired resistance limit their benefit for many patients. A growing body of evidence reveals that resistance is not [...] Read more.

Epidermal growth factor receptor (EGFR) inhibitors remain a cornerstone in the treatment of metastatic colorectal cancer with RAS and BRAF wild-type cancer. Yet, primary and acquired resistance limit their benefit for many patients. A growing body of evidence reveals that resistance is not random but rather driven by a complex network of molecular alterations that sustain tumor growth independent of EGFR signaling. These include amplification of ERBB2 (HER2) and MET, activation of the PI3K and AKT pathways, EGFR extracellular domain mutations, and rare kinase fusions. The concept of negative hyperselection has emerged as a powerful strategy to refine patient selection by excluding tumors with these resistance drivers. Multiple clinical trials have consistently shown that patients who are hyperselected based on comprehensive molecular profiling achieve significantly higher response rates and improved survival compared to those selected by RAS and BRAF status alone. Liquid biopsy through circulating tumor DNA has further transformed this landscape, offering a noninvasive tool to capture tumor heterogeneity, monitor clonal evolution in real time, and guide rechallenge strategies after resistance emerges. Together, negative hyperselection, ctDNA-guided monitoring, and emerging therapeutics define a precision-oncology framework for identifying, tracking, and overcoming resistance to anti-EGFR therapy in mCRC, moving the field toward more effective and individualized care. Looking ahead, the development of innovative therapeutics such as bispecific antibodies, antibody drug conjugates, and RNA-based therapies promises to further expand in this challenging clinical scenario. These advances move precision oncology in colorectal cancer from concept to clinical reality, reshaping the standard of care through molecular insights. Full article

(This article belongs to the Special Issue The Advance of Biomarker-Driven Targeted Therapies in Cancer)

25 pages, 765 KB

Open AccessReview

KRAS G12C Inhibition in Solid Tumors: Biological Breakthroughs, Clinical Evidence, and Open Challenges

by Pietro Paolo Vitiello, Anna Amela Valsecchi, Eleonora Duregon, Paola Francia Di Celle, Paola Cassoni, Mauro Papotti, Alberto Bardelli and Massimo Di Maio

Cancers 2025, 17(17), 2803; https://doi.org/10.3390/cancers17172803 (registering DOI) - 27 Aug 2025

Abstract

KRAS is the most frequently mutated oncogene in cancer. Its activating mutations are associated with aggressive tumor behavior and resistance to certain therapies, including anti-EGFR treatments in colorectal cancer. In particular, the KRAS G12C mutation, which accounts for approximately 3–4% of colorectal cancers [...] Read more.

KRAS is the most frequently mutated oncogene in cancer. Its activating mutations are associated with aggressive tumor behavior and resistance to certain therapies, including anti-EGFR treatments in colorectal cancer. In particular, the KRAS G12C mutation, which accounts for approximately 3–4% of colorectal cancers (CRCs) and 12–14% of non-small cell lung cancers (NSCLCs), involves a cysteine substitution at codon 12. This has provided the opportunity to develop selective covalent inhibitors that trap the mutant protein in its inactive state. The first targeted therapies for KRAS G12C-mutant cancers comprise sotorasib and adagrasib, both of which have been authorized for use in patients with previously treated NSCLC and CRC. Nevertheless, despite the evidence of clinical activity for this class of agents, primary and acquired resistance, dose optimization, and toxicity management remain significant open challenges. In this review, we summarize recent advances in KRASG12C tumor biology and pharmacological targeting. We also provide additional insights to guide future efforts to overcome the limitations of the current approaches and implement the treatment of KRASG12C-mutant cancers. Full article

(This article belongs to the Section Cancer Therapy)

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11 pages, 838 KB

Open AccessArticle

Evaluating Clinical Factors Including HPV Clearance on Survival Outcomes in HPV+ Oropharyngeal Carcinoma

by Amanda Reyes, Sean Maroongroge, Michelle Afkhami, Victoria Villaflor, Arya Amini, Sagus Sampath, Ellie Maghami, Thomas Gernon, Krupal Patel, Xiaochen Li and Aditya Shreenivas

Cancers 2025, 17(17), 2802; https://doi.org/10.3390/cancers17172802 - 27 Aug 2025

Abstract

Background: The relationship between detectable circulating tumor DNA levels and clinical outcome following definitive therapy in patients with human papillomavirus (HPV)-mediated oropharyngeal squamous cell carcinoma has not been well established. Methods: In this retrospective analysis of patients with HPV-positive oropharyngeal squamous cell carcinoma [...] Read more.

Background: The relationship between detectable circulating tumor DNA levels and clinical outcome following definitive therapy in patients with human papillomavirus (HPV)-mediated oropharyngeal squamous cell carcinoma has not been well established. Methods: In this retrospective analysis of patients with HPV-positive oropharyngeal squamous cell carcinoma seen from 2016 to 2024 at a single institution, 88 patients met inclusion criteria with baseline-positive tumor tissue-modified viral HPV DNA (TTMV-HPV DNA) testing and post-treatment testing performed. Results: Of the 88 patients included in the survival analysis, 77 had undetectable tumor tissue-modified viral human papillomavirus DNA after treatment, while 11 had positive (detectable) tumor tissue-modified viral human papillomavirus DNA. TTMV-HPV DNA positivity after treatment was associated with worse 1-year and 2-year overall survival outcomes, at 63.5% (37.7–100, p = 0.022) and 50.8% (25.7–100, p = 0.017) compared to 100% and 96.4% (91.6–100, p = 0.017) in patients with undetectable TTMV-HPV DNA. Inability to clear TTMV-HPV DNA after treatment was associated with worse progression-free survival, at 45.0% (95% CI 21.8–92.7, p = 0.009) at 1 year and 11.3% (95% CI 1.8–71.2, p = <0.001) at 2 years compared to 93% (95% CI 87.3–99.1) and 84.7% (95% CI, 76.3–94.0) in patients with cleared TTMV-HPV DNA after treatment. Conclusion: Tumor tissue-modified viral human papillomavirus DNA positivity after definitive treatment was associated with worse survival and disease recurrence outcomes compared to that in patients with undetectable post-treatment TTMV-HPV DNA. Prospective studies are warranted to further establish the clinical utility of TTMV-HPV DNA testing and its use in surveillance, treatment intensification, or de-intensification. Full article

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

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51 pages, 1043 KB

Open AccessSystematic Review

Metastatic Carcinomas at the Episiotomy Site: A Systematic Literature Review

by Andrea Palicelli, Gabriele Tonni, Federica Torricelli, Beatrice Melli, Vincenza Ylenia Cusenza, Sandra Martinelli, Eleonora Zanetti, Alessandra Bisagni, Magda Zanelli, Maria Paola Bonasoni, Teresa Rossi, Lucia Mangone, Venus Damaris Medina-Illueca, Maurizio Zizzo, Andrea Morini, Giuseppe Broggi, Rosario Caltabiano, Serena Salzano, Francesca Sanguedolce, Nektarios I. Koufopoulos, Ioannis Boutas, Aleksandra Asaturova, Chiara Casartelli, Sara Rubagotti, Matteo Crotti, Lorenzo Aguzzoli and Vincenzo Dario Mandato Show full author list Hide full author list

Cancers 2025, 17(17), 2801; https://doi.org/10.3390/cancers17172801 - 27 Aug 2025

Abstract

Background/Objectives: Rarely, primary (PriCs) or metastatic (metECs) carcinomas occur in the episiotomy site. Methods: A systematic literature review of metECs was carried out. We reviewed the PRISMA guidelines and the Scopus, Pubmed, and Web of Science databases. Results: We found [...] Read more.

Background/Objectives: Rarely, primary (PriCs) or metastatic (metECs) carcinomas occur in the episiotomy site. Methods: A systematic literature review of metECs was carried out. We reviewed the PRISMA guidelines and the Scopus, Pubmed, and Web of Science databases. Results: We found 21 carcinomas; all of them were cervical carcinomas (11 squamous, SCC; 6 adenocarcinomas; 3 adenosquamous; 1 SCC or adenocarcinoma) diagnosed during pregnancy (38%) or 0.25–8 months postpartum (57%). SCCs were larger (mean size: 4.8 cm). At presentation, only two cases were pN+, and no distant metastases were found, excluding four episiotomy metastases (one anticipating the cervical cancer diagnosis); the remaining episiotomy metastases (mean size: 3 cm; one multifocal) were found at follow-up (these were first metastases in 86% of cases). The time range from the episiotomy/last delivery to first episiotomy metastasis was 1–66 (mean, 12.3) months. Treatment was variable: hysterectomy (71%) ± lymphadenectomy (67%) and/or adjuvant treatment (19%); chemoradiation/radiotherapy alone (24%). A total of 90% of cases recurred after 18 days to 66 months (mean, 12 months). At last follow-up, ten patients (48%) were disease-free after 12–120 (mean, 63.5) months, two patients (10%) were alive with disease, and nine (42%) patients died of disease after 6–36 (mean, 12.5) months (including two never-cleared/progressing cases). Conclusions: PriCs and metECs are rare. Iatrogenic/obstetric implantation or vascular dissemination of cervical cancer at the site of episiotomy may occur. For episiotomy lesions, accurate gynecological/perineal examination is required, and biopsy can be considered. Larger studies are required in order to determine treatment guidelines. Compared to PriCs, metECs occurred in younger (premenopausal) patients, were not associated with endometriosis, and demonstrated slightly smaller size and shorter mean time from episiotomy to episiotomy metastases, with a higher likelihood of a less favorable prognosis. Full article

(This article belongs to the Special Issue Advancements in Surgical Approaches for Gynecological Cancers)

28 pages, 2367 KB

Open AccessArticle

A Polyomavirus-Positive Merkel Cell Carcinoma Mouse Model Supports a Unified Origin for Somatic and Germ Cell Cancers

by Wendy Yang, Sara Contente and Sarah Rahman

Cancers 2025, 17(17), 2800; https://doi.org/10.3390/cancers17172800 - 27 Aug 2025

Abstract

Background/Objectives: The Germ Cell Theory of cancer posits that human primordial germ cells (hPGCs) are the cells of origin for malignancies. While this theory is well established for germ cell cancers, a germ cell origin for somatic cancers has been largely overlooked despite [...] Read more.

Background/Objectives: The Germ Cell Theory of cancer posits that human primordial germ cells (hPGCs) are the cells of origin for malignancies. While this theory is well established for germ cell cancers, a germ cell origin for somatic cancers has been largely overlooked despite clinical observations of malignant somatic transformation (MST), wherein germ cell cancers give rise to diverse somatic cancer phenotypes, often without additional mutations. Methods: To test the Germ Cell Theory experimentally in somatic cancer, we established a virus-driven MST model linking hPGC-like cells (hPGCLCs) to Merkel cell polyomavirus (MCPyV)-positive Merkel cell carcinoma (MCC), a highly aggressive somatic cancer with a germ cell cancer-like, low-mutation epigenetic profile. The MCPyV genome was transduced into human induced pluripotent stem cells (hiPSCs) or hPGC-like cells by lentiviral transfection, followed by xenotransplantation. Results: Virus-positive MCC (VP-MCC)-like tumors were consistently induced without additional oncogenic mutations. These tumors recapitulated VP-MCC’s high-grade neuroendocrine carcinoma histology and molecular profiles. DNA methylation analysis revealed near-complete global hypomethylation in VP-MCC-like tumors, matching the unique epigenetic state of late-stage hPGCs. Notably, pluripotent intermediates were neither necessary nor sufficient for MST; transformation required acquisition of a late-hPGC-like epigenetic state. Conclusions: This is the first MST model of a somatic cancer arising through an aberrant germline-to-soma transition. Our findings unify VP-MCC and germ cell cancer biology, challenge mutation- and soma-centric paradigms, and provide a tractable platform to investigate developmental and epigenetic mechanisms of oncogenesis. This MST model supports a unifying germ cell origin for both germ cell and non-germ cell somatic malignancies. Full article

(This article belongs to the Special Issue Stem Cell Origin of Cancers: Biological and Clinical Implications of a Unified Theory of Cancer (2nd Edition))

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22 pages, 1989 KB

Open AccessReview

Machine Learning Models for Predicting Gynecological Cancers: Advances, Challenges, and Future Directions

by Pankaj Garg, Madhu Krishna, Prakash Kulkarni, David Horne, Ravi Salgia and Sharad S. Singhal

Cancers 2025, 17(17), 2799; https://doi.org/10.3390/cancers17172799 - 27 Aug 2025

Abstract

Gynecological cancer, especially breast, cervical, and ovarian cancer, are significant health issues affecting women worldwide. When screened they are mostly detected at later stages because of non-specific signs and symptoms as well as the unavailability of reliable screening methods. The improvement of early [...] Read more.

Gynecological cancer, especially breast, cervical, and ovarian cancer, are significant health issues affecting women worldwide. When screened they are mostly detected at later stages because of non-specific signs and symptoms as well as the unavailability of reliable screening methods. The improvement of early oncologic prediction methods is therefore needed to work out the survival rates, guide individualized treatment, and relieve healthcare pressures. Outcome forecasting and clinical detection are rapidly changing with the use of machine learning (ML), one of the promising technologies used to analyze complex biomedical data. Artificial intelligence (AI)-based ML models are capable of determining low-level trends and making accurate predictions of disease risk and outcomes, because they can combine different datasets (clinical records, genomics, proteomics, medical imaging) and learn to identify subtle patterns. Standard algorithms, including support vector machines, random forests, and deep learning (DL) models, such as convolutional neural networks, have demonstrated high potential in identifying the type of cancer, monitoring disease progression, and designing treatment patterns. This manuscript reviews the recent developments in the use of ML models to advance oncologic prediction tasks in gynecologic oncology. It reports on critical domains, like screening, risk classification, and survival modeling, as well as comments on difficulties, like data inconsistency, inability of interpretation of models, and issues of clinical interpretation. New developments, such as explainable AI, federated learning (FL), and multi-omics fusion, are discussed to develop these models and to make them applicable in practice because of their reliability. Conclusively, this article emphasizes the transformative role of ML in precision oncology to deliver improved, patient-centered outcomes to women who are victims of gynecological cancers. Full article

(This article belongs to the Special Issue Advancements in Preclinical Models for Solid Cancers)

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43 pages, 2086 KB

Open AccessReview

The Targeted Inhibition of Histone Lysine Demethylases as a Novel Promising Anti-Cancer Therapeutic Strategy—An Update on Recent Evidence

by Jarosław Paluszczak and Robert Kleszcz

Cancers 2025, 17(17), 2798; https://doi.org/10.3390/cancers17172798 - 27 Aug 2025

Abstract

A growing body of evidence confirms that non-mutational epigenetic reprogramming constitutes an important hallmark of cancer, contributing to the heterogeneity and phenotypic plasticity observed in cancers. Among the many epigenetic modulators, histone lysine demethylases (KDMs) have emerged as promising targets for pharmacological inhibition [...] Read more.

A growing body of evidence confirms that non-mutational epigenetic reprogramming constitutes an important hallmark of cancer, contributing to the heterogeneity and phenotypic plasticity observed in cancers. Among the many epigenetic modulators, histone lysine demethylases (KDMs) have emerged as promising targets for pharmacological inhibition in cancer treatment. KDMs were found to be frequently overexpressed and/or hyperactivated in cancer cells, and their inhibition was shown to result in the inhibition of cancer cell growth both in vitro and in vivo. The inhibition of Lysine-specific histone demethylase 1A (LSD1), KDM3, KDM4, KDM5, and KDM6 may affect cell survival, proliferation, motility, and apoptosis induction. Importantly, KDM inhibitors can be used as modulators of anti-cancer immune response and sensitivity to radiation and chemotherapy. This narrative review aims to present the most recent evidence documenting the anti-cancer potential of KDM inhibitors. Full article

(This article belongs to the Special Issue Feature Review for Cancer Therapy: 2nd Edition)

12 pages, 1340 KB

Open AccessArticle

Oligometastatic Mesothelioma Treated with Ablative Radiotherapy (OMAR): A Multicenter Study

by Davide Franceschini, Paolo Ghirardelli, Patricia Frrokaj, Nicolaus H. Andratschke, Luca Nicosia, Elisabetta Parisi, Gaia Piperno, Matteo Sepulcri, Emanuele Alì, Antonio Marco Marzo, Stefano Bendoni, Ruggero Spoto, Marco Krengli, Patrizia Ciammella, Barbara A. Jereczek-Fossa, Antonino Romeo, Rosario Mazzola, Filippo Alongi, Matthias Guckenberger, Giovanni Luca Ceresoli, Mauro Loi, Paolo Borghetti and Marta Scorsetti Show full author list Hide full author list

Cancers 2025, 17(17), 2797; https://doi.org/10.3390/cancers17172797 - 27 Aug 2025

Abstract

Background/Objectives: This multicenter retrospective study aims to evaluate the role of Ablative Radiotherapy (RT) in patients with unresectable pleural mesothelioma (PM) who experienced radiological progression after at least one line of chemotherapy, with a maximum involvement of three pleural or extrapleural sites. Methods: [...] Read more.

Background/Objectives: This multicenter retrospective study aims to evaluate the role of Ablative Radiotherapy (RT) in patients with unresectable pleural mesothelioma (PM) who experienced radiological progression after at least one line of chemotherapy, with a maximum involvement of three pleural or extrapleural sites. Methods: Adult patients (≥18 years) with PM treated with stereotactic radiotherapy between 2011 and 2022, limited to a maximum of three pleural or extrapleural sites, were included in the analysis. Ablative RT was required to be administered with radical intent. Endpoints were time to further systemic therapy (TFST), local control (LC), progression-free survival (PFS), overall survival (OS), and acute and late radiotherapy-related toxicity. Results: A total of 56 patients were identified from six Italian and one Swiss radiotherapy center. Treatment was generally well tolerated. Ten patients experienced grade 1 or 2 acute toxicity, while four patients reported persistent chest pain, with one case reaching grade 3 as late toxicity. The median TFST was 18.6 months, with TFST rates of 61.7% and 46.4% at 12 and 24 months, respectively. The median OS was 37.63 months, with 1- and 2-year OS rates of 85.2% and 65.6%. Local control was favorable (79% at 1 year), but most patients experienced disease recurrence outside the SABR treatment volume. The median disease progression-free survival (DPFS) was 8.17 months, with 1- and 2-year DPFS rates of 36% and 19%, respectively. Smoking history correlated with OS and DPFS in univariate analysis, while statistical significance for OS was maintained in multivariate analysis. Additionally, nodal status and PTV volume were associated with OS. Conclusion: SABR is a safe and effective approach for the treatment of oligorecurrent/oligoprogressive PM. The time to further systemic therapy was extended up to 18 months. At two years, 10% of patients remained disease-free, and more than half were alive at three years, suggesting a potentially indolent biological behavior in oligometastatic PM. Full article

(This article belongs to the Special Issue New Perspectives in the Treatment of Thoracic Cancers)

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14 pages, 746 KB

Open AccessArticle

CD19 CAR-T Outcomes in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma: A Retrospective Cohort Study from the Calabria Referral Center in Southern Italy

by Daniele Caracciolo, Filippo Antonio Canale, Virginia Naso, Caterina Alati, Violetta Marafioti, Gaetana Porto, Ludovica Tedesco, Giulia Pensabene, Enrica Antonia Martino, Alessandro Allegra, Demetrio Gabriele Gerace, Michele Cimminiello, Massimo Gentile, Pierosandro Tagliaferri, Pierfrancesco Tassone and Massimo Martino

Cancers 2025, 17(17), 2796; https://doi.org/10.3390/cancers17172796 - 27 Aug 2025

Abstract

Background: Chimeric antigen receptor (CAR) T-cell therapy has transformed the therapeutic landscape for relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Our study aims to describe the clinical outcomes of CAR T-cell therapy in patients with R/R DLBCL treated at a single [...] Read more.

Background: Chimeric antigen receptor (CAR) T-cell therapy has transformed the therapeutic landscape for relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Our study aims to describe the clinical outcomes of CAR T-cell therapy in patients with R/R DLBCL treated at a single regional center in Italy, with the goal of comparing these outcomes to those reported by high-volume academic centers. Methods: Data were retrospectively collected from a cohort of consecutive 41 patients who underwent to CD19 CAR-T infusion from June 2020 until September 2024 at CAR-T center of Reggio Calabria (Italy). Results: The median age was 66 years, 60.9% were refractory to their most recent regimen, and 24.4% had previously failed autologous stem cell transplant. Bridging therapy was administered in 82.9% of cases. A total of 27 patients (65.8%) received Axi-cel, and 14 (34.2%) received Tisa-cel. At median follow-up of 6.9 months, the best ORR and CR rate were 63.4% and 51.2%, respectively. Median PFS was 3 months, and median OS was 8.4 months. A total of 81.4% of patients developed a CRS, grade 1 in most cases (78.4%); 26.8% developed ICANS: two (5.4%) and three (8.1%) had grade 2 and 3, respectively. In univariate analyses, early response predicted longer survival, whereas high tumor burden and more than one extranodal site were associated with worse outcomes. Conclusions: Our retrospective cohort study reports similar data in terms of clinical response as compared to pivotal trials and other reports, confirming that CAR-T may offer more durable response rates and longer progression-free intervals in R/R DLBCL in our real-world context. Full article

(This article belongs to the Special Issue Innovative Immunotherapies: CAR-T Cell Therapy for Cancers: 2nd Edition)

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24 pages, 1039 KB

Open AccessReview

The Gut Microbiome’s Impact on the Pathogenesis and Treatment of Gastric Cancer—An Updated Literature Review

by Ahmed S. Mohamed, Ruchi Bhuju, Emelyn Martinez, Marina Basta, Ashrakat Deyab, Charlene Mansour, Daniel Tejada, Vishal Deshpande, Sameh Elias and Vignesh Krishnan Nagesh

Cancers 2025, 17(17), 2795; https://doi.org/10.3390/cancers17172795 - 27 Aug 2025

Abstract

The gut microbiota plays a critical role in maintaining gastrointestinal homeostasis, immune regulation, and metabolic processes. Recent evidence has highlighted its significant influence on gastric carcinogenesis. Helicobacter pylori, a well-established class I carcinogen, remains the most prominent microbial risk factor for gastric [...] Read more.

The gut microbiota plays a critical role in maintaining gastrointestinal homeostasis, immune regulation, and metabolic processes. Recent evidence has highlighted its significant influence on gastric carcinogenesis. Helicobacter pylori, a well-established class I carcinogen, remains the most prominent microbial risk factor for gastric cancer. However, emerging studies indicate that alterations in the broader gastric and intestinal microbial communities, referred to as dysbiosis, may also contribute to tumor initiation, progression, and immune evasion. These microbial shifts can lead to chronic inflammation, genotoxic metabolite production, and modulation of signaling pathways such as NF-κB and Wnt/β-catenin. This review explores the current understanding of the gut microbiome’s contribution to gastric cancer pathogenesis, including microbial signatures associated with precancerous lesions and the tumor microenvironment. Furthermore, the potential of microbiota-based biomarkers and therapeutic interventions, including probiotics, prebiotics, and fecal microbiota transplantation, is discussed as part of emerging precision medicine strategies. Full article

(This article belongs to the Special Issue New Challenges for Gastric Cancer—Gut Microbiota, Post-eradication and Chemotherapy)

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24 pages, 1951 KB

Open AccessReview

Targeting the Tumor Immune Microenvironment in Triple-Negative Breast Cancer: The Promise of Polyphenols

by Aaron L. Hilliard, Tanya D. Russell, Patricia Mendonca and Karam F. A. Soliman

Cancers 2025, 17(17), 2794; https://doi.org/10.3390/cancers17172794 - 27 Aug 2025

Abstract

Breast cancer remains a formidable global health challenge, with triple-negative breast cancer (TNBC) posing unique clinical complexities. Characterized by its aggressive nature and limited number of specific therapeutic targets, this breast cancer subtype disproportionately affects African American women, highlighting critical disparities in care. [...] Read more.

Breast cancer remains a formidable global health challenge, with triple-negative breast cancer (TNBC) posing unique clinical complexities. Characterized by its aggressive nature and limited number of specific therapeutic targets, this breast cancer subtype disproportionately affects African American women, highlighting critical disparities in care. The tumor immune microenvironment (TIME) plays a critical role in breast cancer development and response to immunotherapy, and it is essential in fostering an immunosuppressive and pro-inflammatory niche. Inflammation, primarily mediated by the NF-κB signaling pathway and chemokine signaling, particularly involving CCL2, plays a pivotal role in TNBC progression and therapy resistance. This review describes some of the molecular mechanisms of polyphenols, which are naturally occurring compounds abundant in various dietary sources, and their potential use as therapeutic agents in the management of TNBC. Polyphenolic compounds have been described as modulating the TIME through the inhibition of tumor progression, immune evasion, and therapy resistance, due to their diverse bioactivities, including anti-inflammatory, antioxidant, and anticancer properties, making them attractive candidates for combating the aggressiveness of TNBC and addressing treatment disparities. Polyphenols, such as curcumin, gossypol, butein, epigallocatechin gallate, cardamonin, and resveratrol, have demonstrated efficacy in modulating several signaling pathways within the TIME, which are implicated in the progression of TNBC. This review highlights the potential effects of polyphenols on inflammatory cytokine release, programmed cell death ligand 1 (PD-L1) expression, which is associated with immune evasion by the host cell, and various intracellular signaling cascades, demonstrating their potential use in personalized therapeutic interventions for TNBC. This study also describes differential responses of TNBC cell lines to polyphenol treatment, highlighting the importance of considering genetic variability in therapeutic strategies, as well as the importance of the interaction of polyphenols with the gut microbiome, which may establish the bioavailability and effectiveness of these compounds toward therapeutic outcomes. Further preclinical and clinical studies are warranted to fully elucidate the therapeutic potential of polyphenols and translate these findings into clinical practice, thereby improving outcomes for patients with TNBC worldwide. Full article

(This article belongs to the Section Tumor Microenvironment)

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14 pages, 1301 KB

Open AccessArticle

Early Continence and Erectile Function Recovery Following Transvesical Single-Port Robot-Assisted Radical Prostatectomy: Initial Single Institution Experience

by Brandon L. Ward, Anthony Y. Zhang, Michael S. Leapman, Jaime A. Cavallo and Isaac Y. Kim

Cancers 2025, 17(17), 2793; https://doi.org/10.3390/cancers17172793 - 27 Aug 2025

Abstract

Background/Objectives: Early recovery of urinary continence and sexual function remains a key focus following radical prostatectomy. The transvesical single-port robot-assisted radical prostatectomy (SP-TV-RARP) approach is a novel technique with very limited evidence that has been suggested to preserve the Retzius space and [...] Read more.

Background/Objectives: Early recovery of urinary continence and sexual function remains a key focus following radical prostatectomy. The transvesical single-port robot-assisted radical prostatectomy (SP-TV-RARP) approach is a novel technique with very limited evidence that has been suggested to preserve the Retzius space and allow extraperitoneal access through the bladder. We aimed to evaluate early functional and oncologic outcomes following SP-TV-RARP at a single academic institution. Methods: We retrospectively reviewed 21 patients who underwent SP-TV-RARP by a single surgeon between September 2024 and May 2025. Continence is defined as being pad-free, and return of erectile function is defined as having erections sufficient for penetration. Functional and oncologic outcomes were assessed using clinical follow-up documentation and analyzed with Kaplan–Meier analysis. Results: The median patient age was 65 years, and 52.4% had pT3 disease. Positive surgical margins were observed in 62% overall and 30% in men with organ-confined disease. No intraoperative or 30-day postoperative complications occurred. Approximately 43% of patients achieved continence within one day of urethral catheter removal, with 75% of patients being pad-free at 3 months. Median SHIM and AUA-SS scores did not significantly decline at 3 months compared to baseline. The median time to recovery of erectile function was 69 days, and 67% recovered at the last follow-up. Biochemical recurrence occurred in 2 patients (15.4%) within 6 months. Conclusions: SP-TV-RARP appears safe and may facilitate early return of urinary continence and erectile function. Although inferior oncologic outcome is a potential concern during early adoption, functional outcomes were favorable. Further prospective evaluation is warranted to confirm long-term oncologic efficacy. Full article

(This article belongs to the Special Issue Urologic Cancer: Endoscopic, Laparoscopic, and Robot-Assisted Surgery Management (2nd Edition))

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14 pages, 248 KB

Open AccessReview

A Narrative Review of Treatment Options for Patients with Node-Positive Disease After Radical Prostatectomy: Current Evidence and Controversies

by Paolo Zaurito, Andrea Cosenza, Leonardo Quarta, Pietro Scilipoti, Mattia Longoni, Alfonso Santangelo, Alessandro Viti, Abigail Gettman, Francesco Barletta, Simone Scuderi, Vito Cucchiara, Armando Stabile, Francesco Montorsi, Alberto Briganti and Giorgio Gandaglia

Cancers 2025, 17(17), 2792; https://doi.org/10.3390/cancers17172792 - 27 Aug 2025

Abstract

Purpose of Review: In approximately 10–15% of patients with prostate cancer (PCa), pathological lymph node metastases (pN1) are detected at radical prostatectomy (RP). The aim of this review is to describe the various treatment options for pN1 patients, with a focus on [...] Read more.

Purpose of Review: In approximately 10–15% of patients with prostate cancer (PCa), pathological lymph node metastases (pN1) are detected at radical prostatectomy (RP). The aim of this review is to describe the various treatment options for pN1 patients, with a focus on the most recent evidence reported in the literature. Evidence Synthesis: Due to the lack of prospective studies, several retrospective analyses were conducted according to different types of treatment. Most common strategies are represented by observation plus early salvage radiotherapy (RT) in case of PSA rising, adjuvant androgen deprivation therapy (ADT) alone, or adjuvant RT with or without ADT. Patients with pN1 disease and favorable disease characteristics (lower T stage and ISUP ≤ 2 at RP, <3 metastatic nodes at pathology) have a similar overall mortality risk if observed with PSA testing and eventual use of early salvage RT compared to patients directly treated with adjuvant RT with or without ADT. While conflicting results in terms of survival benefit were reported for the use of adjuvant ADT only, several studies showed an overall survival benefit in patients with pN1 disease treated with adjuvant RT when high-risk features (such as an increasing number of positive nodes, ISUP > 3) were detected at RP. Lastly, few studies analyzed the rate of adverse events following adjuvant ADT or RT, leaving the issue of treatment-related side effects still open. Summary: There is no clearly established standard of care for men with pN1 PCa, and disease characteristics should guide the choice of optimal post-operative management for these patients. Prospective data and clinical trials are clearly needed to define the most effective therapeutic strategy. Full article

(This article belongs to the Special Issue Updates on Urologic Oncology: From Diagnosis to Localized and Systemic Therapy Options (2nd Edition))

18 pages, 1890 KB

Open AccessReview

Cell Death, Molecular Targeted Therapies, and Metabolic Reprogramming in EGFR-Mutant Lung Cancer

by Himani Joshi and M. Saeed Sheikh

Cancers 2025, 17(17), 2791; https://doi.org/10.3390/cancers17172791 - 27 Aug 2025

Abstract

Lung cancer is responsible for high morbidity and mortality worldwide. In general, lung cancer can be divided into two major types, including small cell lung carcinoma (SCLC) and the more common non-small cell lung carcinoma (NSCLC). Molecular events underlying lung cancer development, growth, [...] Read more.

Lung cancer is responsible for high morbidity and mortality worldwide. In general, lung cancer can be divided into two major types, including small cell lung carcinoma (SCLC) and the more common non-small cell lung carcinoma (NSCLC). Molecular events underlying lung cancer development, growth, and progression remain complex. In addition to a variety of genetic aberrations, alterations in cellular metabolism have been implicated. Epidermal growth factor receptor (EGFR) is a cell surface protein that is frequently mutated in NSCLC. In this review, we discuss the effects of EGFR mutants on cell proliferative and survival signals, as well as metabolic reprogramming, in NSCLC. We also discuss the use and mechanisms of action of tyrosine kinase inhibitors (TKIs) that target EGFR-mutants and mediate their inhibitory effects by inducing cell death. Development of resistance to EGFR-TKIs is a problem in the clinic. We further discuss the approaches that are used to overcome this resistance, including the development of fourth-generation EGFR-TKIs. Immunotherapy is not very effective in EGFR-mutant NSCLC. We also discuss possible underlying mechanisms for the inadequate response of EGFR-mutant tumors to immunotherapeutics. Given that mutant EGFR transduces survival signals, and affects cellular metabolism, a better understanding of the crosstalk between mutant EGFR-mediated signals and metabolic reprogramming is expected to facilitate the development of newer personalized therapeutics to manage lung cancer. Full article

(This article belongs to the Special Issue Emerging Insights into Cell Death in Cancer)

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14 pages, 1049 KB

Open AccessArticle

The Peritoneal Cancer Index as a Predictor of Cytoreductive Surgery Outcomes and Heatmapping of Ovarian Cancer Distribution: A Retrospective Analysis

by Ayisha A. Ashmore, Joud Al-Majali, Samantha Kimi Chui, Susan Addley, Summi Abdul, Viren Asher, Anish Bali and Andrew Phillips

Cancers 2025, 17(17), 2790; https://doi.org/10.3390/cancers17172790 - 27 Aug 2025

Abstract

Objective: This study aimed to evaluate the association between the Peritoneal Cancer Index (PCI) and the completeness of cytoreductive surgery (CRS) in patients undergoing surgery for advanced ovarian cancer (AOC). Secondary objectives included identifying a PCI cut-off predictive of incomplete cytoreduction, assessing the [...] Read more.

Objective: This study aimed to evaluate the association between the Peritoneal Cancer Index (PCI) and the completeness of cytoreductive surgery (CRS) in patients undergoing surgery for advanced ovarian cancer (AOC). Secondary objectives included identifying a PCI cut-off predictive of incomplete cytoreduction, assessing the relationship between PCI and surgical complexity via the Aletti Surgical Complexity Score (SCS), and exploring disease distribution to better understand ovarian cancer distribution. Methods: A retrospective review of 227 patients undergoing primary or interval debulking surgery for AOC from January 2017 to September 2024 at University Hospitals of Derby and Burton was conducted. PCI was recorded intra-operatively, and procedures were classified using the SCS. ROC analysis identified PCI thresholds for incomplete CRS, logistic regression predicted CRS outcomes, and heat mapping visualised disease distribution. Results: Complete CRS of visible disease (R0) was achieved in 90.75% of patients, while 9.25% had incomplete CRS. Median PCI was significantly higher in incomplete CRS cases (28, IQR 21–32) compared to complete CRS (15, IQR 8–23, p < 0.001). ROC analysis identified a PCI threshold of 25.5 with 71.4% sensitivity and 83.5% specificity for predicting incomplete CRS. PCI > 25.5 increased the odds of incomplete cytoreduction by 12.65 times (p < 0.001). Higher PCI scores correlated with increased surgical complexity, operative time, and blood loss, though complication rates were similar. Heat maps showed stepwise disease distribution from pelvis to upper abdomen. Conclusions: PCI is a reliable predictor of CRS completeness in AOC, with a threshold of >25.5 indicating a high risk of incomplete cytoreduction. The study underscores PCI’s role in surgical planning and calls for multi-centre studies to validate these findings and further examine disease distribution. Full article

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

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20 pages, 3100 KB

Open AccessArticle

Diminished Estrogen Induced Mitochondrial Protection and Immunosuppressive Microenvironment in Gastric Cancer with Depression

by Yixin Liu, Sheng Tian, Yujia Tan, Picheng Yan, Pan Liu, Huiying Zhu, Sachiyo Nomura, Tianhe Huang and Yongchang Wei

Cancers 2025, 17(17), 2789; https://doi.org/10.3390/cancers17172789 - 26 Aug 2025

Abstract

Background: It is established that depression significantly contributes to tumor development, yet its molecular link to gastric cancer progression remains unclear. Methods: In this study, we examined depression-related gene expression profiles in relation to clinical prognosis and identified estradiol and the NOTCH3 gene [...] Read more.

Background: It is established that depression significantly contributes to tumor development, yet its molecular link to gastric cancer progression remains unclear. Methods: In this study, we examined depression-related gene expression profiles in relation to clinical prognosis and identified estradiol and the NOTCH3 gene as critical factors involved in gastric cancer progression in the context of depression. Using a chronic unpredictable stress-induced tumor-bearing mouse model, we validated the impact of depression on tumor development. Additionally, the underlying molecular mechanisms were explored through a range of biological techniques, including Western blotting, immunofluorescence, flow cytometry and immunohistochemistry. Results: Depression significantly accelerated gastric cancer growth in our mouse model, characterized by decreased estradiol levels and increased NOTCH3 expression. Importantly, exogenous estradiol supplementation effectively counteracted depression-induced tumor growth. Consistently, in vitro studies showed that estradiol treatment suppressed NOTCH3 expression in HGC-27 and YTN3 cell lines. Furthermore, NOTCH3 was shown to modulate intracellular reactive oxygen species levels by regulating SOD2 activity, thereby influencing cell proliferation. Conclusions: This work identified the estrogen/NOTCH3 signaling as a key link between depression and gastric cancer development, offering promising therapeutic strategies to improve outcomes for patients suffering from psychological disorders. Full article

(This article belongs to the Special Issue Gastrointestinal Malignancy: Epidemiology and Risk Factors)

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30 pages, 418 KB

Open AccessReview

Efficacy and Predictability of Cyclin-Dependent Kinase 4/6 Inhibitors in HER2-Positive Breast Cancer

by Muhammad Shahmir Abbasi, Muhammad Zubair Afzal, Tayyaba Sarwar and Holly A. Gamlen-Steves

Cancers 2025, 17(17), 2788; https://doi.org/10.3390/cancers17172788 - 26 Aug 2025

Abstract

HER2-positive breast cancer represents a biologically aggressive subtype associate with poor prognosis, despite advances in targeted therapies. Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), initially approved for hormone-receptor-positive, HER2-negative disease, are now being explored in HER2-positive settings due to their mechanistic synergy with the HER2 [...] Read more.

HER2-positive breast cancer represents a biologically aggressive subtype associate with poor prognosis, despite advances in targeted therapies. Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), initially approved for hormone-receptor-positive, HER2-negative disease, are now being explored in HER2-positive settings due to their mechanistic synergy with the HER2 signaling pathway. This review synthesizes evolving clinical evidence from trials and highlights further research into biomarker discovery. CDK4/6i may redefine treatment paradigms in HER2-positive breast cancer, offering a potential, non-chemotherapy option with durable benefit in select patient populations. Full article

(This article belongs to the Collection The Molecular Predictive and Prognostic Biomarkers in Breast Cancer)

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