Cancers

12 pages, 1769 KB

Open AccessCommunication

Evaluation of Mithramycin in Combination with Chemotherapeutic Agents Against Ewing Sarcoma Cell Lines

by Christoffer Briggs Lambring, Lina Albeer, Aneth Ochoa Negrete, Kayla Fure and Riyaz Basha

Cancers 2025, 17(18), 2977; https://doi.org/10.3390/cancers17182977 - 11 Sep 2025

Ewing Sarcoma (ES) is a rare, malignant bone neoplasm that is primarily diagnosed in childhood and adolescence. The aggressive nature of this neoplasm requires the use of surgery, radiation and a rigorous chemotherapy regimen. Metastatic ES carries a poor prognosis, which necessitates the [...] Read more.

Ewing Sarcoma (ES) is a rare, malignant bone neoplasm that is primarily diagnosed in childhood and adolescence. The aggressive nature of this neoplasm requires the use of surgery, radiation and a rigorous chemotherapy regimen. Metastatic ES carries a poor prognosis, which necessitates the development of new therapeutic agents. Mithramycin was tested in targeted therapy due to its specific inhibitory effects on the EWS-FLI1 fusion protein which is present in >85% of ES tumors. We tested the combination of Mithramycin with chemotherapeutic agents vincristine (VCR) and Etoposide (Eto) for inducing higher cytotoxicity against ES cells, CHLA10 and TC205. Cardiomyocyte cell line, H9C2 was used to test the effect on non-malignant cells. Cell viability was measured using the CellTiter-Glo kit, and the combination index was evaluated to determine the type of combination response (antagonistic, additive, or synergistic). Apoptotic cells were measured post-treatment with vehicle (DMSO, control), monotherapy (mithramycin or etoposide), or combination therapy (mithramycin + etoposide) using BD LSRII flow cytometer and analyzed utilizing FlowJo software V8.0. The apoptotic protein marker c-PARP in both treatment and control groups was analyzed using Western blot analysis. The results showed higher cytotoxicity for combination treatment when compared to individual agents, and the combination index confirmed the response as synergistic. H9C2 cells did not demonstrate significant decreases in cell viability when treated with combination therapy, highlighting the specificity of the treatment toward its target tissue. Flow cytometry confirmed the underlying mechanism as upregulation of apoptosis which is further supported by an increase in effector caspases 3/7 and elevated expression of c-PARP. These in vitro assays using ES cells provide preliminary evidence for the benefit of chemotherapy and mithramycin combination. Full article

(This article belongs to the Special Issue Research on Targeted Drugs in Cancer)

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12 pages, 1743 KB

Open AccessArticle

18-Hour Planar Scintigraphy Versus SPECT/CT for Sentinel Lymph Node Detection in Early-Stage Endometrial Cancer

by Wiktor Szatkowski, Karolina Pniewska, Paweł Blecharz, Małgorzata Nowak-Jastrząb, Janusz Ryś, Tomasz Banaś, Renata Pacholczak-Madej, Emilia Krzywonos, Kamila Rawojć and Kamil Kisielewicz

Cancers 2025, 17(18), 2976; https://doi.org/10.3390/cancers17182976 - 11 Sep 2025

Abstract

Background/Objectives: The preoperative detection of sentinel lymph nodes (SLN) using technetium-99m (Tc-99m) is crucial for surgical staging in early-stage endometrial cancer (EC). The optimal imaging timing and modality remain debated. This study compares early planar scintigraphy (30 min), SPECT/CT (1 h), and 18-h [...] Read more.

Background/Objectives: The preoperative detection of sentinel lymph nodes (SLN) using technetium-99m (Tc-99m) is crucial for surgical staging in early-stage endometrial cancer (EC). The optimal imaging timing and modality remain debated. This study compares early planar scintigraphy (30 min), SPECT/CT (1 h), and 18-h planar scintigraphy after a single Tc-99m injection. Methods: A total of 125 patients with early-stage EC underwent SLN mapping with Tc-99m (120 MBq). Imaging included 30-min planar scintigraphy, SPECT/CT (1 h), and 18-h planar scintigraphy on the day of surgery. Detection sensitivity, the bilateral mapping rate, and image quality (signal-to-noise ratio (SNR), contrast factor (C-factor)) were evaluated, with intraoperative gamma probe detection and histopathology as references. Results: The 18-h planar scintigraphy achieved the highest SLN detection sensitivity (94.4%, 118/125), compared with SPECT/CT (87.2%, OR = 2.48, 95% CI: 0.98–6.27, p = 0.051) and 30-min scintigraphy (72.0%). Only the 18-h protocol underwent intraoperative and histopathological verification; results for 30-min planar and 1-h SPECT/CT were based on imaging alone, which limits direct comparability. Bilateral detection was higher at 18 h (80.80%) than SPECT/CT (73.60%). All SLNs detected at 18 h were confirmed intraoperatively and histologically, yielding 100% PPV (95% CI: 96.9–100.0%) and NPV (95% CI: 59.0–100.0%). The 18-h protocol showed superior imaging contrast (C-factor: 10.30 ± 1.22) despite lower residual activity. The method remained effective in patients with BMI ≥ 30 (94.00%). Only 1.60% of patients required hysterectomy before mapping due to background interference. Conclusions: The 18-h planar scintigraphy is a highly effective, low-cost, and accessible method for SLN detection in early-stage EC, potentially reducing the need for SPECT/CT, radiation exposure, and costs. Full article

(This article belongs to the Special Issue Advanced Research on Radioresistant Tumors)

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13 pages, 2042 KB

Open AccessArticle

CDCA8 and TROAP as Prognostic Biomarkers of Postoperative Metastatic Progression in Clear Cell Renal Cell Carcinoma

by Mingyu Kim, Geehyun Song, Jaeyoung Joung, Hokyung Seo, Hyungho Lee and Jinsoo Chung

Cancers 2025, 17(18), 2975; https://doi.org/10.3390/cancers17182975 - 11 Sep 2025

Abstract

Objectives: Clear cell renal cell carcinoma (ccRCC) may later metastasize despite curative surgery. This study asked whether transcriptomic alterations detectable at nephrectomy are associated with subsequent metastatic progression, and whether such signals retain prognostic relevance in overt metastatic disease. Methods: Bulk RNA sequencing [...] Read more.

Objectives: Clear cell renal cell carcinoma (ccRCC) may later metastasize despite curative surgery. This study asked whether transcriptomic alterations detectable at nephrectomy are associated with subsequent metastatic progression, and whether such signals retain prognostic relevance in overt metastatic disease. Methods: Bulk RNA sequencing was performed in 30 ccRCC patients without metastasis at surgery; 4 developed distant metastasis during follow-up. Differential expression, enrichment, and network analyses identified hub genes, which were screened by ROC analysis with bootstrap optimism correction. External validation used TCGA-KIRC focusing on patients metastatic at baseline (M1) to evaluate overall and disease-specific survival with multivariable Cox models (per-SD expression, adjusted for age, sex, and stage); Kaplan–Meier curves were shown for visualization only. Results: Fifty-nine DEGs distinguished patients who later metastasized from those who remained metastasis-free, with enrichment in mitotic and chromosomal-segregation pathways. Five hub genes (BASP1, CDCA8, KIF2C, LMNB1, TROAP) showed high discrimination in the discovery set (optimism-corrected AUC ~0.92–0.93). In TCGA-M1, CDCA8, and TROAP were consistently associated with worse survival and remained significant in multivariable models. Conclusions: Dysregulation of mitotic control may underlie latent metastatic competence in ccRCC. CDCA8 and TROAP emerge as candidate prognostic biomarkers, linking postoperative metastatic progression in an initially M0 cohort with survival in metastatic disease. These hypothesis-generating findings warrant validation in larger, prospective cohorts. Full article

(This article belongs to the Special Issue Genitourinary Malignancies)

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14 pages, 916 KB

Open AccessReview

Pirtobrutinib in Chronic Lymphocytic Leukemia: Navigating Resistance and the Personalisation of BTK-Targeted Therapy

by Stefano Molica and David Allsup

Cancers 2025, 17(18), 2974; https://doi.org/10.3390/cancers17182974 - 11 Sep 2025

Abstract

Background/Objectives: Covalent Bruton’s tyrosine kinase (BTK) inhibitors (ibrutinib, acalabrutinib, zanubrutinib) improve outcomes in advanced chronic lymphocytic leukemia (CLL) but resistance, largely driven by BTK C481 mutations, and adverse events limit long-term benefit. Noncovalent BTK inhibitors (e.g., pirtobrutinib) reversibly inhibit the BTK ATP-binding pocket [...] Read more.

Background/Objectives: Covalent Bruton’s tyrosine kinase (BTK) inhibitors (ibrutinib, acalabrutinib, zanubrutinib) improve outcomes in advanced chronic lymphocytic leukemia (CLL) but resistance, largely driven by BTK C481 mutations, and adverse events limit long-term benefit. Noncovalent BTK inhibitors (e.g., pirtobrutinib) reversibly inhibit the BTK ATP-binding pocket independent of C481, potentially overcoming resistance and reducing toxicity. This review summarizes clinical evidence for pirtobrutinib in CLL. Methods: A PubMed search of articles through July 2025 was conducted, focusing on clinical trials of pirtobrutinib. We extracted efficacy, safety, and resistance data, emphasizing the BRUIN CLL-321 phase 3 trial and related studies. Results: Pirtobrutinib demonstrates activity against BTK resistance mutations with a favorable safety profile, partly due to high kinase selectivity. In BRUIN CLL-321, pirtobrutinib achieved an overall response rate (ORR) of 62% and a median progression-free survival (PFS) of 20 months in heavily pretreated patients, including those with resistance mutations. Yet, resistance mechanisms—such as alternative pathway activation and additional BTK mutations—emerge in a subset. Baseline genetic features, including BTK mutation status and cytogenetics, influence response durability and outcomes. Ongoing phase 3 trials comparing pirtobrutinib with covalent BTK inhibitors will clarify its potential as a first-line option and its integration into treatment algorithms. In relapsed/refractory CLL, noncovalent BTK inhibitors may be incorporated into personalized pathways, including bridging to CAR-T therapy, to optimize long-term disease control. Conclusions: Pirtobrutinib offers a promising strategy to address resistance and potentially improve durable disease control in CLL. Definitive trials will define its role relative to covalent BTK inhibitors and its utility across treatment lines within personalized, multimodal regimens. Full article

(This article belongs to the Special Issue Advances in Blood Cancers: How We Define Success)

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33 pages, 16798 KB

Open AccessArticle

Wavelia Microwave Breast Imaging Phase#2 Clinical Investigation: Methodological Evolutions and Multidimensional Radiomics Analysis Towards Controlled Specificity

by Angie Fasoula, Giannis Papatrechas, Petros Arvanitis, Luc Duchesne, Julio Daniel Gil Cano, John O’Donnell, Sami Abd Elwahab and Michael Kerin

Cancers 2025, 17(18), 2973; https://doi.org/10.3390/cancers17182973 - 11 Sep 2025

Abstract

Background/Objectives: The Wavelia Microwave Breast Imaging (MWBI) technology aims to increase sensitivity in dense breasts, where X-ray mammography is of limited value. Its potential contribution to the reduction in the false positives in breast cancer diagnosis, by developing MWBI image descriptors supporting malignant-to-benign [...] Read more.

Background/Objectives: The Wavelia Microwave Breast Imaging (MWBI) technology aims to increase sensitivity in dense breasts, where X-ray mammography is of limited value. Its potential contribution to the reduction in the false positives in breast cancer diagnosis, by developing MWBI image descriptors supporting malignant-to-benign lesion discrimination, is also being investigated. After a First-In-Human (FiH) study with interesting findings on a small dataset of 24 symptomatic breast lesions, an upgraded 2nd prototype of Wavelia was manufactured and tested on a larger and more diverse dataset, including 62 patients and a balanced distribution of malignant and benign symptomatic breast lesions. Methods: A set of technological and methodological evolutions, outlined in this article, was implemented in Wavelia#2 to handle the diversity in larger patient datasets. Multi-modal MWBI imaging is employed to parameterize the interaction mechanisms between the microwaves and the imaged breast at varying geometrical and tissue consistency conditions. MWBI Region-Of-Interest (ROI) extraction and characterization based on multidimensional radiomic feature vectors is implemented to expand the malignant-to-benign lesion diagnostics potential of MWBI compared to the limited scope of the FiH study with Wavelia#1, which employed three specific preselected features. Results: This study demonstrates significant diagnostic accuracy of multiple texture-based and intensity-based features to discriminate between malignant and benign breast lesions with Wavelia#2 MWBI. A phenomenological qualitative assessment of the false positive rate on healthy breasts is also presented for the MWBI technology for the first time. Conclusions: The analysis contributes to the rationalization of the MWBI imaging and image analysis outputs towards standardization, objective interpretability, and ultimate clinical acceptance. Full article

(This article belongs to the Special Issue Imaging in Breast Cancer Diagnosis and Treatment)

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10 pages, 610 KB

Open AccessArticle

Impact of Obesity on Sentinel Lymph Node Mapping in Patients with Endometrial Intraepithelial Neoplasia Undergoing Robotic Surgery: A Retrospective Cohort Study

by Tomer Bar-Noy, Yossi Tzur, Yoav Brezinov, Emad Matanes, Rebecca Lozano-Franco, Shannon Salvador, Melica Nourmoussavi Brodeur, Walter Gotlieb and Susie Lau

Cancers 2025, 17(18), 2972; https://doi.org/10.3390/cancers17182972 - 11 Sep 2025

Abstract

Background/Objectives: Lymph node (LN) assessment for cases of endometrial intraepithelial neoplasia (EIN), a known precursor to endometrial cancer (EC), is a topic of debate. Some experts believe this practice could avoid re-staging of disease and influence the decision to administer adjuvant treatment. [...] Read more.

Background/Objectives: Lymph node (LN) assessment for cases of endometrial intraepithelial neoplasia (EIN), a known precursor to endometrial cancer (EC), is a topic of debate. Some experts believe this practice could avoid re-staging of disease and influence the decision to administer adjuvant treatment. However, it is known that obtaining sentinel lymph node (SLN) biopsies in patients with an elevated body mass index (BMI) can be more challenging. We thus sought to evaluate the effect of BMI on the SLN detection rate (DR) during robotic hysterectomy in EIN cases. Methods: We conducted a retrospective chart review for patients with a pre-operative diagnosis of EIN who underwent robotic hysterectomy with SLN sampling. Five BMI categories were determined according to the literature. Distribution normality was assessed with the Kolmogorov–Smirnov test. Continuous variables, non-parametric continuous variables and categorical variables were assessed with the appropriate statistical tests (two-tailed Student’s t-tests, Mann–Whitney U-tests, and chi-squared tests, respectively). Results: 115 patients were included (average BMI of 34.75 ± 9.38 SD). The bilateral SLN DR was not significantly different between BMI groups (p = 0.606). The difference in unilateral SLN DR between BMI groups was also non-significant (p = 0.269). When examining high BMI subgroups (BMI > 30 and BMI > 40), no significant difference was found in bilateral nor unilateral SLN DR. A logistic regression model showed that for every unit of BMI, the likelihood of SLN DR did not change significantly. Conclusions: We found no connection between obesity (BMI > 30) or morbid obesity (BMI > 40) and reduced SLN DR in EIN cases, nor a significant variation in the DR when comparing all the different BMI subgroups. Full article

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

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17 pages, 2154 KB

Open AccessArticle

Impact of Serum Albumin Levels on Prognosis and Recurrence in Patients with Hepatocellular Carcinoma

by Naoko Hayata, Atsushi Hosui, Tomohide Kurahashi, Shigeki Suemura, Akane Namiki, Akino Okamoto, Takafumi Tanimoto, Hiroki Murai, Kohsaku Ohnishi, Motohiro Hirao, Takuya Yamada and Naoki Hiramatsu

Cancers 2025, 17(18), 2971; https://doi.org/10.3390/cancers17182971 - 11 Sep 2025

Abstract

Background: Liver function is a critical factor, both in the selection of treatment and in the prediction of prognosis in patients with hepatocellular carcinoma (HCC). The ALBI grade, introduced as a more objective method of assessing liver function, utilizes serum albumin (Alb) [...] Read more.

Background: Liver function is a critical factor, both in the selection of treatment and in the prediction of prognosis in patients with hepatocellular carcinoma (HCC). The ALBI grade, introduced as a more objective method of assessing liver function, utilizes serum albumin (Alb) and total bilirubin (Bil) levels. Although albumin is widely recognized for its role in maintaining colloid osmotic pressure and regulating plasma volume, recent studies have implicated it in tumor progression, invasion, and metastasis. The purpose of this study is to determine the impact of serum albumin levels on overall survival (OS) and tumor invasion/metastasis in HCC patients with the same liver function (ALBI grade) at the time of diagnosis. Methods: In this study, 285 patients diagnosed with primary HCC at our institution from 2015 to 2019 were classified by ALBI grade and analyzed. Among them, 78 patients with ALBI grade 2 status were selected to evaluate the impact of albumin level. To further isolate the effect of albumin rather than bilirubin, patients in the ALBI grade 2 cohort were divided into two groups based on mean values of Alb (3.5 g/dL) and Bil (1.0 mg/dL). Alb normal group (Group A): Alb ≥ 3.5 g/dL, Bil ≥ 1.0 mg/dL (n = 42). Bil normal group (Group T): Alb < 3.5 g/dL, Bil < 1.0 mg/dL (n = 36). Liver function was almost the same in these two groups based on the ALBI grade. OS, progression-free survival (PFS), types of recurrence, and pathological findings were compared between the two groups. OS was analyzed by the log-rank test, and comparisons between the two groups were performed by the t-test and chi-square test, with p < 0.05 indicating statistical significance. Results: OS was significantly worse in Group T than in Group A before and after propensity score matching based on age, performance status, and HCC stage (p < 0.001 and p = 0.011). Among the 44 patients who received curative treatment (surgery or radiofrequency ablation), OS was also significantly worse in Group T (p < 0.001). An analysis of the recurrence patterns of 44 curatively treated patients revealed that Group T had significantly shorter PFS (p < 0.001), and all recurrence patterns were multiple (p = 0.002). Pathological analysis in 28 surgical patients showed that serosal invasion was present in significantly more patients in Group T (p = 0.003). Conclusions: Low serum albumin levels in patients with HCC indicate both liver dysfunction and increased tumor invasion and metastasis. Nutritional support and albumin supplementation may help reduce intrahepatic metastases and improve prognosis. Further studies are needed to explore the underlying mechanisms and therapeutic potential. Full article

(This article belongs to the Special Issue New Approaches in the Treatment of Hepatocellular Carcinoma and Liver Tumor)

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16 pages, 2426 KB

Open AccessArticle

Mortality Trends in Pediatric Hepatoblastoma: A Brazilian and Global Perspective

by Raquel Francine Liermann Garcia, Camila Barbosa, José Guilherme Pickler, Francis Rosseti Pedack, Christian Evangelista Garcia, Hercilio Fronza Junior, Bruna Louise Silva, Paulo Henrique Condeixa de França, Bárbara Sarni Sanches, Marcelo Gerardin Poirot Land, Rafael Roesler and Karina Munhoz de Paula Alves Coelho

Cancers 2025, 17(18), 2970; https://doi.org/10.3390/cancers17182970 - 11 Sep 2025

Abstract

Background: Hepatoblastoma is a rare malignant liver tumor that accounts for 1–2% of pediatric cancers. Despite its low incidence, it is a significant cause of cancer-related mortality in early childhood. Methods: This ecological study analyzed hepatoblastoma mortality in Brazilian children and adolescents (2008–2023) [...] Read more.

Background: Hepatoblastoma is a rare malignant liver tumor that accounts for 1–2% of pediatric cancers. Despite its low incidence, it is a significant cause of cancer-related mortality in early childhood. Methods: This ecological study analyzed hepatoblastoma mortality in Brazilian children and adolescents (2008–2023) using data from the Mortality Information System (SIM/DATASUS). Mortality rates were calculated using official population estimates. Temporal trends were assessed using Prais-Winsten regression. Age and sex differences were analyzed using the chi-square test. Global mortality estimates (2008–2021) were obtained from the Global Burden of Disease Study for descriptive comparison. Results: A total of 267 deaths were recorded, most (66.7%) in children aged 0–4 years. Males accounted for 61.4% of cases. Although no significant mortality trends were observed for younger age groups, a significant annual decline was found among adolescents aged 15–19 years (Annual Percent Change (APC) = −38.4%, p = 0.016). Regional disparities were evident, with the Southeast presenting the highest number of deaths. Globally, the estimated number of deaths and age-specific mortality rate (ASMR) decreased over time, particularly among children under five. Conclusions: Hepatoblastoma remains a significant cause of mortality in early childhood. While Brazilian mortality rates remained stable in younger groups, mortality in adolescents showed a marked reduction. Global estimates suggest a progressive reduction in mortality. Full article

(This article belongs to the Special Issue Study on Epidemiology of Childhood Cancer)

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22 pages, 7134 KB

Open AccessArticle

Hemopexin Suppresses Hepatocellular Carcinoma via TNF-α-Mediated Mitochondrial Apoptosis

by Liying Ren, Yuxin Man, Xue Zhang, Qian Guo, Shaoping She, Yao Yang, Ran Fei, Xu Cong, Dongbo Chen, Wen Wei and Hongsong Chen

Cancers 2025, 17(18), 2969; https://doi.org/10.3390/cancers17182969 - 11 Sep 2025

Abstract

Fibrinolysis plays a crucial role in maintaining coagulation homeostasis, but its functions in hepatocellular carcinoma (HCC) remain poorly understood. This study aimed to develop a fibrinolysis-based molecular classification and prognostic signature for HCC and to identify a key regulatory gene. Using non-negative matrix [...] Read more.

Fibrinolysis plays a crucial role in maintaining coagulation homeostasis, but its functions in hepatocellular carcinoma (HCC) remain poorly understood. This study aimed to develop a fibrinolysis-based molecular classification and prognostic signature for HCC and to identify a key regulatory gene. Using non-negative matrix factorization (NMF), we identified distinct fibrinolysis-related HCC subtypes with specific clinical outcomes and tumor microenvironment characteristics. A six-gene prognostic signature comprising ACAT1, GRHPR, HPX, PCK2, IYD, and PON1 was established through weighted gene co-expression network analysis (WGCNA) and LASSO-Cox regression, which effectively stratified patients into different risk groups across multiple cohorts. Hemopexin (HPX) was identified as the top candidate and functionally validated: HPX overexpression suppressed clonogenicity and migration, promoted apoptosis, and inhibited xenograft tumor growth. RNA sequencing analysis suggested associations between HPX and apoptosis as well as TNF-α signaling pathways, which were confirmed through flow cytometry apoptosis assays, mitochondrial membrane potential measurements, and TUNEL staining. Western blot and immunohistochemical analyses further demonstrated that HPX upregulates the Bax/Bcl-2 ratio via the TNF-α signaling pathway. This study defines novel molecular subtypes of HCC and reveals that HPX exerts anti-tumor effects through TNF-α-mediated mitochondrial apoptosis, characterized by an increased Bax/Bcl-2 ratio. Full article

(This article belongs to the Special Issue Tumor Microenvironment Dynamics in Hepatocellular Carcinoma)

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18 pages, 1458 KB

Open AccessArticle

First-in-Human Study of MDG1011, a TCR-T Therapy Directed Against HLA-A*02:01-Restricted PRAME Antigen for High-Risk Myeloid and Lymphoid Neoplasms

by Simone Thomas, Martin Wermke, Vladan Vučinić, Eva Wagner-Drouet, Andreas Mackensen, Robert Zeiser, Gesine Bug, Michael Schmitt, Wolfgang Herr, Petra U. Prinz, Maja Bürdek, Silke Raffegerst, Anna Tafuri, Christiane Geiger, Kirsty Crame, René Goedkoop, Kai Pinkernell and Dolores J. Schendel

Cancers 2025, 17(18), 2968; https://doi.org/10.3390/cancers17182968 - 11 Sep 2025

Abstract

Background/objectives: MDG1011 is a Preferentially Expressed Antigen in Melanoma (PRAME)-specific autologous T cell receptor (TCR) T cell therapy for HLA-A*02:01-positive patients. Data from the first-in-human (FIH) clinical trial, CD-TCR-001, are reported here regarding treatment feasibility, safety, tolerability, and clinical activity of MDG1011 in [...] Read more.

Background/objectives: MDG1011 is a Preferentially Expressed Antigen in Melanoma (PRAME)-specific autologous T cell receptor (TCR) T cell therapy for HLA-A*02:01-positive patients. Data from the first-in-human (FIH) clinical trial, CD-TCR-001, are reported here regarding treatment feasibility, safety, tolerability, and clinical activity of MDG1011 in patients with relapsed/refractory (r/r) acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and multiple myeloma (MM). Methods: Nine of thirteen enrolled patients received MDG1011 at dose levels ranging from 0.1 to 5 × 10⁶ TCR-T cells per kg body weight. In addition to clinical assessments, immune monitoring of cytokines associated with cytokine release syndrome (CRS), presence and persistence of MDG1011, and changes in levels of PRAME mRNA were used to assess safety and potential biological activity at defined time points. Results: The treatment was well tolerated. No dose-limiting toxicities (DLTs) were observed, and the most common serious adverse events were associated with lymphodepleting chemotherapy and/or disease progression. Various parameters, such as measurable clinical responses in two patients, the occurrence of CRS in two additional patients, and reductions in PRAME mRNA levels in bone marrow (BM) or peripheral blood (PB) in seven patients, served as signs of the clinical and biological activity of MDG1011 TCR-T therapy. Conclusions: Patients enrolled in the phase 1 part of CD-TCR-001 displayed signs of potential clinical and biological activity of MDG1011 among the small number of patients studied. Advanced disease stage and rapid progression in the r/r AML patients limited clinical impact. The acceptable safety profile of MDG1011 merits further investigation of this TCR-T therapy, potentially in patients at an earlier stage of their disease and with lower tumor burden. Full article

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

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18 pages, 1093 KB

Open AccessArticle

Salvage Surgery: A Concrete Opportunity in Unresectable Non-Small Cell Lung Cancer Following Definitive Chemo-Immunotherapy

by Maria Giovanna Mastromarino, Elena Guerrini, Lisa Maria Caciagli, Andrea La Rosa, Diana Bacchin, Vittorio Aprile, Stylianos Korasidis, Alessandra Lenzini, Alessandra Celi, Greta Alì, Marcello Carlo Ambrogi and Marco Lucchi

Cancers 2025, 17(18), 2967; https://doi.org/10.3390/cancers17182967 - 10 Sep 2025

Abstract

Background: The advent of immunotherapy has significantly improved survival outcomes in advanced non-small cell lung cancer (NSCLC). In this evolving context, salvage surgery has emerged as a potential curative strategy, despite the risk of serious complications. This study aimed to evaluate the safety [...] Read more.

Background: The advent of immunotherapy has significantly improved survival outcomes in advanced non-small cell lung cancer (NSCLC). In this evolving context, salvage surgery has emerged as a potential curative strategy, despite the risk of serious complications. This study aimed to evaluate the safety and efficacy of surgical resection following chemo-immunotherapy in patients with initially unresectable NSCLC. Methods: We retrospectively analyzed patients with stage III–IVB NSCLC who underwent salvage surgery at our institution between January 2019 and June 2024. All cases were initially deemed unresectable by a multidisciplinary tumor board. Perioperative complications, complete (R0) resection rate, major pathologic response (MPR), complete pathologic response (pCR), progression-free survival (PFS), and overall survival (OS) were analyzed. Results: Twenty-one patients (thirteen males, eight females; median age: 68 years [IQR: 9]) were included. Reasons for initial unresectability were metastatic disease (28.6%), N2 bulky disease (14.3%), local invasiveness (33.3%), or a combination of factors (23.7%). Chemo-immunotherapy was administered in 19 patients (90.5%), while 2 (9.5%) received immunotherapy alone, with a median of four treatment cycles (IQR: 1). Complete (R0) resection was achieved in all patients (100%). Anatomical resections were performed in 17 patients (81%), predominantly lobectomies (66.7%). There were no intraoperative or major postoperative complications, and 30-day mortality was zero. Median hospital stay was 7 days (IQR: 4). pCR and MPR were achieved in 33.3% and 14.3% of patients, respectively. After a median follow-up of 17 months (IQR: 19), the estimated 3-year PFS and OS were 50.9% and 66.3%, respectively. Recurrences included locoregional (4.8%), distant (14.3%), and combined (14.3%). Cox regression analysis identified stage III at diagnosis (OR: 0.292; 95% CI: 0.093–0.912; p = 0.034) and achieved pCR or MPR (OR: 0.113; 95% CI: 0.013–0.959; p = 0.046) as independent predictors of improved PFS. Conclusions: Salvage surgery after chemo-immunotherapy in initially unresectable NSCLC appears to be a safe and effective strategy in selected patients, offering favorable pathological responses and encouraging mid-term oncologic outcomes. Full article

(This article belongs to the Special Issue The EGFR-Tyrosine Kinase Inhibitors (EGFR-TKIs) and Immune Checkpoint Inhibitors (ICIs) for Non-Small Cell Lung Cancer)

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29 pages, 10950 KB

Open AccessSystematic Review

Cervical Cancer Screening in Refugee and Migrant Populations: Results of Systematic Review and Meta-Analysis in Cross-Sectional and Cohort Studies

by Vincenzo Restivo, Davide Graci, Angelo Immordino, Daniele Giacomo Mancuso, Fátima Morales, Chiara Pace, Alessandra Pirrello, Alessandra Casuccio and Palmira Immordino

Cancers 2025, 17(18), 2966; https://doi.org/10.3390/cancers17182966 - 10 Sep 2025

Abstract

Background/Objectives: Cervical cancer is currently the fourth leading cause of cancer in women. It is primarily caused by Human Papilloma Virus (HPV) infections. Primary prevention methods, such as vaccines, and secondary prevention strategies, such as screening, have significantly reduced the burden of these [...] Read more.

Background/Objectives: Cervical cancer is currently the fourth leading cause of cancer in women. It is primarily caused by Human Papilloma Virus (HPV) infections. Primary prevention methods, such as vaccines, and secondary prevention strategies, such as screening, have significantly reduced the burden of these diseases. The screening could be a crucial factor in the early diagnosis. This study aims to estimate the access of migrant and refugee populations to cervical cancer screening (CCS). Methods: A meta-analysis of scientific literature present in Pubmed and Scopus databases was conducted according to the PRISMA 2020 guidelines. Eighty-seven cross-sectional and five cohort unique studies were examined, to evaluate the participation of migrant and refugee populations to CCS programs in different world regions. Results: Statistical analysis was performed using STATA 14.2 software. Among cross-sectional studies, mean regular adherence to CCS for migrant and refugees resulted being 56% (95% CI 53–60), while participation at least once is 60% (95% CI 54–65). In cohort studies, regular adherence and participation at least once are, respectively, 55% (95% CI 50–59) and 56% (95% CI 52–61). Conclusions: The results of this review show how migrant and refugee populations have limited access to prevention interventions due to several socio-cultural factors. Our work calls for public health professionals’ efforts in order to promote more inclusive policies and prevention strategies towards those populations, aiming to reduce disparities and public health expenditures. Full article

(This article belongs to the Special Issue Cancer Disparities: Biological, Social, and Environmental Determinants)

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13 pages, 2846 KB

Open AccessArticle

Insight into the Wnt Pathway in Sporadic Small Bowel Adenocarcinoma

by Takayoshi Nishimoto, Atsushi Tatsuguchi, Takeshi Yamada, Sho Kuriyama, Aitoshi Hoshimoto, Jun Omori, Naohiko Akimoto, Katya Gudis, Keigo Mitsui, Shu Tanaka, Shunji Fujimori, Tsutomu Hatori, Akira Shimizu and Masanori Atsukawa

Cancers 2025, 17(18), 2965; https://doi.org/10.3390/cancers17182965 - 10 Sep 2025

Abstract

Background/Objectives: The Wnt signaling pathway is pivotal in the adenoma–carcinoma sequence; however, its role in small bowel adenocarcinoma (SBA) remains insufficiently characterized. We analyzed the clinicopathological significance of Wnt pathway-related gene mutations and the expression of downstream or associated proteins in SBA. Methods: [...] Read more.

Background/Objectives: The Wnt signaling pathway is pivotal in the adenoma–carcinoma sequence; however, its role in small bowel adenocarcinoma (SBA) remains insufficiently characterized. We analyzed the clinicopathological significance of Wnt pathway-related gene mutations and the expression of downstream or associated proteins in SBA. Methods: Immunohistochemical staining for β-catenin, cyclin D1, c-Myc, E-cadherin, and Wnt5a was performed in 75 primary SBA surgical specimens. Targeted next-generation sequencing was conducted in 48 of these cases. Results: The genomic alterations in the Wnt pathway were identified as APC (14.6%) and CTNNB1 (8.3%), with no overlap between the two mutations. Aberrant (reduced membranous and/or nuclear) expression of β-catenin was observed in 37% of cases. Cyclin D1 and c-Myc were expressed in 60% and 41% of cases, respectively. Aberrant expression of β-catenin and/or Wnt5a was present in 60% of cases and was correlated with cyclin D1 and c-Myc expression. Mutations in APC and CTNNB1 were found in intestinal- and gastrointestinal-type SBAs, but were absent in gastric-type SBA. In intestinal-type SBA, the mutation frequency of APC and CTNNB1 was 39%, closely aligning with the 45% aberrant expression of β-catenin. Aberrant expression of β-catenin and/or Wnt5a, a ligand of the noncanonical Wnt pathway, was detected in 60% of cases and showed a correlation with both cyclin D1 and c-Myc expression. Conclusions: These findings suggest that both canonical and noncanonical Wnt pathway-related proteins are involved in SBA carcinogenesis and progression. Notably, the canonical Wnt pathway appears to play a predominant role in intestinal-type SBA. Full article

(This article belongs to the Special Issue Molecular Pathways in Cancers (2nd Edition))

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11 pages, 1150 KB

Open AccessArticle

Characterizing Trends of Lymphedema After Axillary Lymph Node Dissection with and Without Immediate Lymphatic Reconstruction

by Kella L. Vangsness, Andre-Philippe Sam, Jeff Chang, Yash A. Mehta, Michael W. Chu, Mouchammed Agko and Antoine L. Carré

Cancers 2025, 17(18), 2964; https://doi.org/10.3390/cancers17182964 - 10 Sep 2025

Abstract

Background and Objectives: Breast cancer-related lymphedema (BCRL) is a complication of axillary lymph node dissection (ALND). Immediate lymphatic reconstruction (ILR) may help to decrease lymphedema after ALND by creating lymphatic bypasses. This retrospective single-institution study aimed to compare lymphedema in patients undergoing ALND [...] Read more.

Background and Objectives: Breast cancer-related lymphedema (BCRL) is a complication of axillary lymph node dissection (ALND). Immediate lymphatic reconstruction (ILR) may help to decrease lymphedema after ALND by creating lymphatic bypasses. This retrospective single-institution study aimed to compare lymphedema in patients undergoing ALND with and without ILR. Materials and Methods: Bioimpedance and limb measurements determined the presence of BCRL. The categorical data that were collected and analyzed included BMI, comorbidities, BCRL onset, and number of lymphatic bypasses. Pearson’s chi-square test and multivariable logistic regression were performed to identify factors associated with the onset of lymphedema. An odds ratio compared the incidence of BCRL with and without ILR. Results: In total, 186 patients underwent ALND, 44 (24%) with ILR and 142 (76%) without. The mean number of bypasses during ILRs created was 3.54. The odds of developing lymphedema with ILR were 64% lower than for ALND alone. ILR patients who developed BCRL had a mean onset of 543 days post-operatively versus 389 days in the control group. Age, ethnicity, BMI, and bypass amount had no significant influence on lymphedema development. Conclusions: ILR was associated with lower rates of BCRL after ALND. Patients who developed lymphedema despite undergoing ILR did so 8 months later than the controls. Full article

(This article belongs to the Special Issue Innovations in Microsurgical Techniques for Breast Cancer Reconstruction)

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13 pages, 2826 KB

Open AccessArticle

Tumor Mutational Burden in Cervical Cancer as Potential Marker for Immunotherapy Responders

by Magdalena Ewa Kowalkowska, Katarzyna Kamińska, Joanna Wojtysiak, Krzysztof Koper, Adrianna Makarewicz, Bronisława Pietrzak, Dorota Bomba-Opoń, Marzena Dębska, Mirosław Wielgoś, Marek Grabiec and Marzena Anna Lewandowska

Cancers 2025, 17(18), 2963; https://doi.org/10.3390/cancers17182963 - 10 Sep 2025

Abstract

Background/Objectives: Tumor mutational burden (TMB) has emerged as a potential biomarker of response to immunotherapy across multiple solid tumors. However, its role in cervical cancer remains insufficiently defined. This study aimed to evaluate the genomic landscape and TMB profile in a cohort [...] Read more.

Background/Objectives: Tumor mutational burden (TMB) has emerged as a potential biomarker of response to immunotherapy across multiple solid tumors. However, its role in cervical cancer remains insufficiently defined. This study aimed to evaluate the genomic landscape and TMB profile in a cohort of patients with cervical cancer treated at a tertiary gynecologic oncology center, with a focus on TMB’s associations with clinical features, HPV infection, and treatment modalities. Methods: A total of 61 patients diagnosed with cervical cancer (82.0% ca. planoepitheliale, 18.0% adenocarcinoma) were retrospectively analyzed. Tumor samples were collected during primary surgery, biopsy, or conization and subjected to targeted next-generation sequencing using the ONCOaccuPanel™ and BRCAaccuTest PLUS™ (NGeneBio). TMB was calculated as non-synonymous mutations per megabase and analyzed using NGeneAnalySys^® software. Variant classification followed ACMG guidelines. Comparative analyses were conducted between TMB-high (≥10 mut/Mb) and TMB-low subgroups, and correlations with clinical and molecular variables were assessed using univariable statistics. Results: High TMB was identified in 36 patients (59.0%), while microsatellite instability was found in only 2 cases (3.3%). No significant associations were observed between TMB status and FIGO stage, histologic subtype, or HPV 16/18 infection. However, higher TMB values were observed in patients with nodal involvement, diabetes, and HPV52 infection. A diverse spectrum of mutations was detected, with PIK3CA and ARID1A being most frequently altered. Several variants of uncertain significance were identified in genes not classically associated with cervical cancer. Conclusions: TMB-high status is relatively frequent in cervical cancer and appears to be independent of FIGO stage or histological subtype. While not predictive of clinical stage, TMB correlates with specific molecular and comorbidity profiles, suggesting its potential relevance for future patient stratification in immunotherapy trials. Full article

(This article belongs to the Special Issue Cervical Cancer: Study on Molecular Landscape and Protein Biomarkers. Current Diagnostic and Therapeutic Capabilities)

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16 pages, 546 KB

Open AccessArticle

Real-World Outcomes Between Perioperative Chemotherapy (FLOT) and Preoperative Concurrent Chemoradiotherapy (CROSS) in Localized Esophageal and Esophagogastric Junction Adenocarcinoma: A Retrospective Cohort Study

by Jirapat Wonglhow, Hui-Li Wong, Cuong Duong, John Spillane, David S. Liu, Trevor Leong, Julie Chu and Michael Michael

Cancers 2025, 17(18), 2962; https://doi.org/10.3390/cancers17182962 - 10 Sep 2025

Abstract

Background: The management of localized esophageal and esophagogastric junction (EGJ) adenocarcinomas remains challenging. Although perioperative chemotherapy with the fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) regimen or preoperative concurrent chemoradiotherapy with carboplatin and paclitaxel (CROSS) regimen followed by surgery are standard options, the optimal [...] Read more.

Background: The management of localized esophageal and esophagogastric junction (EGJ) adenocarcinomas remains challenging. Although perioperative chemotherapy with the fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) regimen or preoperative concurrent chemoradiotherapy with carboplatin and paclitaxel (CROSS) regimen followed by surgery are standard options, the optimal approach is still debated. This study evaluated real-world outcomes of perioperative FLOT versus preoperative CROSS in such patients. Methods: A retrospective cohort study was conducted at a tertiary cancer center in Australia, including patients treated with FLOT or CROSS between 2014 and 2024. Multivariate Cox regression models adjusted for baseline differences, including demographics, tumor stage, differentiation, location, and surgical resection. Results: Among 70 patients, 15 received FLOT and 55 received CROSS. Median overall survival (OS) was 30.3 months for FLOT and 37.5 months for CROSS (p = 0.75). Median event-free survival (EFS) was not reached in the FLOT group and was 14.8 months in the CROSS group (p = 0.49). After multivariate adjustment, differences in OS and EFS were not significant. Compared to FLOT, CROSS was associated with higher treatment completion and response rates. CROSS also led to greater pathological tumor and nodal downstaging, as well as higher rates of complete pathological response. Conclusions: Both FLOT and CROSS appear to be effective treatment options for localized esophageal and EGJ adenocarcinomas. CROSS may offer advantages in terms of treatment tolerability and tumor response, and may be particularly suitable for patients with bulky tumors or reduced performance status. Owing to the limited sample size and follow-up, these findings should be interpreted cautiously. Personalized treatment decisions should be guided by multidisciplinary discussions, considering tumor characteristics, patient condition, and access to adjuvant immunotherapy. Full article

(This article belongs to the Special Issue Neoadjuvant Chemoradiotherapy for Gastrointestinal Cancer)

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14 pages, 609 KB

Open AccessArticle

Real-World Adoption of Adjuvant Therapies for Resected Stage IB–III Non-Small-Cell Lung Cancer

by Arvind Kumar, Steven Tohmasi, Daniel B. Eaton, Jr., Nahom Seyoum, Whitney S. Brandt, Theodore S. Thomas, Martin W. Schoen, Nikki E. Rossetti, Su-Hsin Chang, Yan Yan, Mayank R. Patel, Sara Malone, Molly C. Tokaz, Bryan F. Meyers, Benjamin D. Kozower, Varun Puri and Brendan T. Heiden

Cancers 2025, 17(18), 2961; https://doi.org/10.3390/cancers17182961 - 10 Sep 2025

Abstract

Background: Recent clinical trials support adjuvant treatment with novel immunotherapy and targeted therapy agents for selected non-small-cell lung cancer (NSCLC) after resection. The “real-world” implementation of these treatments, however, remains unknown. This study evaluated trends in the uptake of adjuvant chemotherapy, immunotherapy, [...] Read more.

Background: Recent clinical trials support adjuvant treatment with novel immunotherapy and targeted therapy agents for selected non-small-cell lung cancer (NSCLC) after resection. The “real-world” implementation of these treatments, however, remains unknown. This study evaluated trends in the uptake of adjuvant chemotherapy, immunotherapy, and targeted therapy for patients with resected NSCLC. Methods: Patients with resected stage IB-III NSCLC within the Veterans Health Administration (2017−2023) were included. Use of adjuvant chemotherapy, immunotherapy, and/or targeted therapy was evaluated over the study period. Factors associated with adjuvant therapy use were identified using multivariable-adjusted logistic regression. Results: Of the 1980 patients included, 846 (42.7%) underwent adjuvant therapy. There was a modest but not statistically significant increase in adjuvant therapy use from 37.1% in 2017 to 45.9% in 2023. Use of adjuvant chemotherapy alone declined from 36.6% to 23.5%, while use of adjuvant immunotherapy (0.5% to 21.2%) and targeted therapy (0% to 1.2%) increased. Factors associated with adjuvant therapy use included younger age, fewer comorbidities, and higher tumor stage. Conclusions: Despite the increased use of adjuvant immunotherapy and targeted therapy for resected stage IB-III NSCLC, overall adjuvant therapy uptake remains low. Further efforts will be necessary to better incorporate these novel treatments into routine clinical practice. Full article

(This article belongs to the Special Issue Surgical Advances in Cancer Treatments: Exploring Innovative Approaches and Emerging Perspectives)

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14 pages, 796 KB

Open AccessArticle

Small Renal Mass Cryoablation: Trifecta Outcomes of a Single-Institution Experience with a 20-Year Follow-Up

by Mahdi Mottaghi, Alireza Ghoreifi, Sriram Deivasigamani, Sudharshanan Balaji, Eric S. Adams, Matvey Tsivian, Charles Y. Kim and Thomas J. Polascik

Cancers 2025, 17(18), 2960; https://doi.org/10.3390/cancers17182960 - 10 Sep 2025

Abstract

Background/Objectives: Cryoablation is a minimally invasive treatment option for patients with a small renal mass (SRM). We aimed to present the long-term functional and oncologic outcomes of cryoablation for SRMs. Methods: We retrospectively reviewed patients treated with percutaneous or laparoscopic cryoablation for an [...] Read more.

Background/Objectives: Cryoablation is a minimally invasive treatment option for patients with a small renal mass (SRM). We aimed to present the long-term functional and oncologic outcomes of cryoablation for SRMs. Methods: We retrospectively reviewed patients treated with percutaneous or laparoscopic cryoablation for an SRM (≤4 cm in diameter) at our tertiary hospital between October 2001 and December 2011. Primary outcomes included technical failure (persistent CT enhancement post-ablation) and progression (local recurrence or metastasis). Trifecta is defined as the absence of severe complications (Clavien–Dindo > 2), no oncological progression, and ≤10% decline in eGFR. Results: A total of 129 patients with a median age of 67 (IQR 58–74) years were analyzed. The median (IQR) clinical and radiologic follow-ups across all patients were 136 (54–180) and 74 (23–147) months, respectively, with a median (IQR) tumor volume of 3.3 (1.6–6.6) cm³. Among those with available biopsy data (n = 86), 62 (72%) were diagnosed with Renal Cell Carcinoma (RCC), and 24 (28%) exhibited benign pathologies, including angiomyolipoma, oncocytic neoplasm, and non-diagnostic pathology. Of all patients, six experienced high-grade complications. Among non-solitary kidney patients with available creatinine values between 13 and 36 months post-treatment, 64% had ≤10% eGFR decline compared to baseline. Notably, 58% (26/48) of patients with RCC (non-solitary kidney) achieved our trifecta definition at 36 months. Metastasis-free, cancer-specific, and overall survival at 15-year follow-up were 85%, 96%, and 46%, respectively. Univariable regression identified tumor volume and solitary kidney status at ablation as significant predictors for oncological progression. Conclusions: Cryoablation for the SRM showed sustained oncological and functional efficacy over long-term follow-up. Full article

(This article belongs to the Special Issue Clinical Outcomes in Urologic Cancers)

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21 pages, 8915 KB

Open AccessSystematic Review

Radiotherapy for Locally Advanced Pancreatic Cancer in the Modern Era: A Systematic Review and Meta-Analysis

by Sun Hyun Bae, Won Il Jang, Jeong Il Yu, Hee Chul Park, Ji Eun Moon, Karin Haustermans, Marta Scorsetti, Morten Høyer and Mi Sook Kim

Cancers 2025, 17(18), 2959; https://doi.org/10.3390/cancers17182959 - 10 Sep 2025

Abstract

Background: The optimal treatment strategy for locally advanced unresectable pancreatic cancer (LAPC) is still investigated. Therefore, we evaluated the role of radiotherapy (RT) in the management of LAPC in the modern era. Methods: A systematic review was conducted following the Preferred Reporting Items [...] Read more.

Background: The optimal treatment strategy for locally advanced unresectable pancreatic cancer (LAPC) is still investigated. Therefore, we evaluated the role of radiotherapy (RT) in the management of LAPC in the modern era. Methods: A systematic review was conducted following the Preferred Reporting Items for Systemic Review and Meta-Analyses guidelines. Eligible studies were about for LAPC treated with curative-intent modern RT techniques including intensity-modulated radiotherapy (IMRT), stereotactic body radiotherapy (SBRT), and particle beam therapy (PBT) until September 2024. Results: In total, 53 observational studies, encompassing 2548 patients (993 treated with IMRT, 998 with SBRT, and 557 with PBT), met the inclusion criteria. Concurrent chemoradiotherapy (CCRT) was implemented in 28 studies, including only 3 studies in the SBRT group. Elective nodal irradiation (ENI) was adopted in 22%. The pooled 2-year overall survival (OS) rate was 29% (95% confidence interval [CI], 25–34%) for all patients, with no significant differences among RT techniques: 28% (95% CI, 22–34%) for IMRT, 26% (95% CI, 19–34%) for SBRT, and 43% (95% CI, 28–57%) for PBT (p = 0.1121). The pooled rate of acute hematologic toxicity (HT) ≥ grade 3 was 17% (95% CI, 9–26%), with significant differences among RT techniques: 23% (95% CI, 9–40%) for IMRT, 4% (95% CI, 0–11%) for SBRT, and 20% (95% CI, 6–37%) for PBT (p = 0.0181). In addition, CCRT (p = 0.0084) and ENI (p = 0.0145) significantly increased the risk of acute HT. Gastrointestinal toxicities rarely occurred. Conclusions: This systematic review and meta-analysis showed similar efficacy among modern RT techniques for LAPC management. Since almost all studies have single-arm design, and chemotherapy regimens have changed over time, conclusions must be drawn with caution. The use of modern RT techniques is individually selected according to clinical practice and resource availability. Full article

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

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16 pages, 34747 KB

Open AccessArticle

Evaluation of a Novel Pan-RAS Inhibitor in 3D Bioprinted Tumor Models

by Daniela D. De Nobrega, Logan C. Eiler, Parmanand Ahirwar, Sonika Nallapu, Urvi P. Rawal, Chelsea L. Crawford, Donald J. Buchsbaum, Adam B. Keeton, Yulia Y. Maxuitenko, Xi Chen, Gary A. Piazza, Allan Tsung and Karim I. Budhwani

Cancers 2025, 17(18), 2958; https://doi.org/10.3390/cancers17182958 - 10 Sep 2025

Abstract

Background: Colorectal cancer (CRC) remains a significant global health burden, with KRAS mutations driving ~40% of cases. The efficacy of recently approved, mutant-specific KRAS inhibitors is limited by mutational status as well as intrinsic and adaptive resistance mechanisms. Pan-RAS inhibitors, such as [...] Read more.

Background: Colorectal cancer (CRC) remains a significant global health burden, with KRAS mutations driving ~40% of cases. The efficacy of recently approved, mutant-specific KRAS inhibitors is limited by mutational status as well as intrinsic and adaptive resistance mechanisms. Pan-RAS inhibitors, such as ADT-007, offer broader therapeutic potential by targeting multiple RAS isoforms. Here, we evaluate ADT-007 in 3D bioprinted ex vivo slice tissue (BEST) generated from KRAS-mutant and RAS wild-type (WT) CRC cell lines. Methods: Potency and selectivity of ADT-007 were benchmarked against bortezomib (proteasome inhibitor) and YM155 (survivin inhibitor) using high-content imaging and ATP-based luminescence assays. Apoptosis induction was assessed with Annexin V/propidium iodide and flow cytometry. Results: ADT-007 exhibited high potency and selectivity in KRAS-mutant BEST, reducing tumor burdens >30% at nanomolar concentrations, and demonstrated superior selectivity with minimal cytotoxicity in WT RAS BEST. Annexin V staining confirmed selective induction of apoptosis in KRAS-mutant cells. Conclusions: The selective potency and specificity of ADT-007 warrant further investigation of pan-RAS inhibitors for treating RAS-driven cancers. This study also underscores the translational utility of 3D BEST models for preclinical drug response assessment. Further validation in patient-derived BEST is necessary to evaluate the potential of ADT-007 in clinical settings. Full article

(This article belongs to the Special Issue Cancer Drug Discovery and Development: 2nd Edition)

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5 pages, 171 KB

Open AccessEditorial

Introduction to the Special Issue on Advances in Pediatric and Adolescent Psychosocial Oncology

by Lori Wiener and Amanda Thompson

Cancers 2025, 17(18), 2957; https://doi.org/10.3390/cancers17182957 - 10 Sep 2025

Abstract

Psychosocial care is critical to supporting the adjustment, coping, and quality of life of children and families from the time of diagnosis throughout treatment and into survivorship or through end of life and bereavement [...] Full article

(This article belongs to the Special Issue Advances in Pediatric and Adolescent Psycho-Oncology)

15 pages, 493 KB

Open AccessReview

Evaluating the Evolving Treatment Landscape of Systemic Therapies in Penile Cancer

by Salvador Jaime-Casas, Regina Barragan-Carrillo, Federico Eskenazi, Juan P. Dugarte, Jad Chahoud, Philippe E. Spiess and Luis G. Medina

Cancers 2025, 17(18), 2956; https://doi.org/10.3390/cancers17182956 - 10 Sep 2025

Abstract

Penile squamous cell carcinoma (PSCC) represents a malignancy with low incidence. Despite advances in chemotherapy-based management, outcomes for patients with locally advanced and metastatic disease remain poor, with 5-year survival rates of 51% and 9%, respectively. Early diagnosis is crucial, yet psychosocial/structural barriers [...] Read more.

Penile squamous cell carcinoma (PSCC) represents a malignancy with low incidence. Despite advances in chemotherapy-based management, outcomes for patients with locally advanced and metastatic disease remain poor, with 5-year survival rates of 51% and 9%, respectively. Early diagnosis is crucial, yet psychosocial/structural barriers often delay it. Treatment strategies are stage-dependent, ranging from organ-sparing surgery and targeted radiotherapy for early-stage disease to cisplatin-based chemotherapy for locally advanced and metastatic cases. However, systemic therapies provide modest survival benefits and can expose the patient to unnecessary toxicities. Immunotherapy has emerged as a promising area, given the high expression of PD-L1 in PSCC and the significant proportion of HPV-driven tumors. Although initial results from immunotherapy-based trials are limited, preliminary trials such as HERCULES, ALPACA, PULSE, and PERICLES aim to define their role better. Similarly, combination regimens utilizing toripalimab in combination with nimotuzumab and taxane-based chemotherapy (TNT) followed by consolidative surgery are currently underway. Furthermore, the development of therapeutic HPV vaccines offers a novel strategy to enhance local antitumor immunity. Antibody–drug conjugates (ADCs) targeting HER-2, Trop-2, and Nectin-4 antigens represent another evolving therapeutic avenue that has shown preliminary promising results. As the landscape of penile cancer treatment continues to grow, incorporating these novel strategies could further improve survival outcomes and/or offer improved quality of life. This review provides a comprehensive overview of emerging systemic therapies in PSCC, underscoring ongoing research efforts to address unmet needs. Full article

(This article belongs to the Section Cancer Therapy)

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2 pages, 509 KB

Open AccessCorrection

Correction: Kandimalla et al. Targeted Oral Delivery of Paclitaxel Using Colostrum-Derived Exosomes. Cancers 2021, 13, 3700

by Raghuram Kandimalla, Farrukh Aqil, Sara S. Alhakeem, Jeyaprakash Jeyabalan, Neha Tyagi, Ashish Agrawal, Jun Yan, Wendy Spencer, Subbarao Bondada and Ramesh C. Gupta

Cancers 2025, 17(18), 2955; https://doi.org/10.3390/cancers17182955 - 10 Sep 2025

Abstract

In the original publication [...] Full article

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16 pages, 1931 KB

Open AccessArticle

Nationwide Trends and Projections of Early Onset Gastrointestinal Cancers in China

by Tianyu Li, Chen Lin and Weibin Wang

Cancers 2025, 17(18), 2954; https://doi.org/10.3390/cancers17182954 - 9 Sep 2025

Abstract

Early-onset (15–49 years) gastrointestinal cancers are an emerging public health concern in China, yet national trend analyses remain limited. Drawing on data from the Global Burden of Disease 2021 study, we evaluated nationwide trends in the incidence and mortality of early-onset gastrointestinal cancers [...] Read more.

Early-onset (15–49 years) gastrointestinal cancers are an emerging public health concern in China, yet national trend analyses remain limited. Drawing on data from the Global Burden of Disease 2021 study, we evaluated nationwide trends in the incidence and mortality of early-onset gastrointestinal cancers (esophagus, stomach, liver, colon and rectum, gallbladder and biliary tract, and pancreas) in China from 1990 to 2021 and projected future patterns through 2040 using Bayesian age–period–cohort models. Between 1990 and 2021, age-standardized rates for esophageal, stomach, and liver cancers declined markedly while those for colorectal and biliary tract cancers increased, and pancreatic cancer rates rose modestly. Mortality for upper-GI cancers fell substantially, whereas colorectal cancer deaths rose modestly, with the age-standardized mortality rate declining despite rising incidence. Projections suggest continued declines in upper-GI cancers, further increases in colorectal and biliary tract cancers, and a peak in the age-standardized incidence rate of pancreatic cancer around 2030. These divergent trends highlight an urgent need for targeted prevention and early-detection strategies focused on colorectal, biliary, and pancreatic cancers among patients aged 15–49 years in China. Full article

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

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29 pages, 3313 KB

Open AccessSystematic Review

Epigenetic Reprogramming by Decitabine in Triple-Negative Breast Cancer: Mechanisms, Immune Modulation, and Therapeutic Synergy

by Fathima Raahima Riyas Mohamed, Safiah Aldubaisi, Arshiya Akbar, Mohammad Imran Khan and Ahmed Yaqinuddin

Cancers 2025, 17(18), 2953; https://doi.org/10.3390/cancers17182953 - 9 Sep 2025

Abstract

Background/Objectives: Triple-negative breast cancer (TNBC) is an aggressive subtype lacking ER, PR, and HER2 expression, with limited targeted therapies and poor outcomes. Epigenetic dysregulation, particularly aberrant DNA methylation, is a key driver. Decitabine, a DNA methyltransferase inhibitor (DNMTi), shows promise by reactivating [...] Read more.

Background/Objectives: Triple-negative breast cancer (TNBC) is an aggressive subtype lacking ER, PR, and HER2 expression, with limited targeted therapies and poor outcomes. Epigenetic dysregulation, particularly aberrant DNA methylation, is a key driver. Decitabine, a DNA methyltransferase inhibitor (DNMTi), shows promise by reactivating silenced tumor suppressor genes and modulating immune responses. This systematic review evaluates preclinical and clinical evidence on decitabine’s efficacy, mechanisms, and translational potential in TNBC. Methods: A PRISMA-2020 compliant search of PubMed, EBSCO, Web of Science, and Semantic Scholar was conducted up to April 2025. Included studies assessed decitabine alone or in combination in TNBC preclinical or clinical settings. Risk of bias was assessed using QUIPS and RoB 2.0 tools. Results: Twenty-five studies were included. In vitro, decitabine-induced growth inhibition, apoptosis, and re-expression of silenced genes (such as BRCA1 and CDH1). In vivo, it reduced tumor burden and enhanced anti-tumor immunity through MHC-I, PD-L1, and STING pathway upregulation. Synergy was noted with anti-PD-1, HDAC inhibitors, and chemotherapy. Resistance mechanisms included persistent DNMT activity, low DCK, and miRNA-driven escape (miR-155–TSPAN5). Conclusions: Decitabine demonstrates strong preclinical and early clinical potential in TNBC via epigenetic reprogramming and immune activation. Future strategies should focus on biomarker-based selection and resistance mitigation. Full article

(This article belongs to the Special Issue Epigenetics in Cancer and Drug Therapeutics)

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15 pages, 1147 KB

Open AccessArticle

Survival Machine Learning Methods Improve Prediction of Histologic Transformation in Follicular and Marginal Zone Lymphomas

by Tong-Yoon Kim, Tae-Jung Kim, Eun Ji Han, Gi-June Min, Seok-Goo Cho, Seoree Kim, Jong Hyuk Lee, Byung-Su Kim, Joon Won Jeoung, Hye Sung Won and Youngwoo Jeon

Cancers 2025, 17(18), 2952; https://doi.org/10.3390/cancers17182952 - 9 Sep 2025

Abstract

Background/Objectives: Follicular lymphoma (FL) and marginal zone lymphoma (MZL) are low-grade B-cell lymphomas (LGBCLs) with indolent clinical courses but a lifelong risk of histologic transformation (HT) to aggressive lymphomas, particularly diffuse large B-cell lymphoma. Predicting HT can be challenging due to class imbalances [...] Read more.

Background/Objectives: Follicular lymphoma (FL) and marginal zone lymphoma (MZL) are low-grade B-cell lymphomas (LGBCLs) with indolent clinical courses but a lifelong risk of histologic transformation (HT) to aggressive lymphomas, particularly diffuse large B-cell lymphoma. Predicting HT can be challenging due to class imbalances and the inherent complexity of time-dependent events. While there are current prognostic indices for survival, they do not specifically address HT risk. This study aimed to develop and validate survival-based and traditional classification machine-learning models to predict HT in cohorts. Methods: Using a multicenter retrospective dataset (n = 1068), survival models (Cox proportional hazards, Lasso-Cox, Random Survival Forest, Gradient-boosted Cox [GBM-Cox], eXtreme Gradient Boosting [XGBoost]-Cox), and classification models (Logistic regression, Lasso logistic, Random Forest, Gradient Boosting, XGBoost) were compared. The best-performing survival models—XGBoost-Cox, Lasso-Cox, and GBM-Cox—were assessed on an independent test set (n = 92). Model sensitivity was maximized using optimal binary risk cutoff points based on Youden’s index. Results: Survival models showed superior predictive performance than classical classifiers, with XGBoost-Cox exhibiting the highest mean accuracy (85.3%), time-dependent area under the curve (0.795), sensitivity (98%), specificity (83.9%), and concordance index (0.836). Incorporating next-generation sequencing (NGS) data improved model accuracy and specificity, indicating that genetic factors improve HT prediction. Principal component analysis revealed distinct gene mutation patterns associated with HT risk, highlighting DNA-repair genes such as TP53, BLM, and RAD50. Conclusions: This study highlights the clinical value of survival-based machine-learning methods integrated with NGS data to personalize HT risk stratification for patients with FL and MZL. Full article

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

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15 pages, 794 KB

Open AccessSystematic Review

Rehabilitation Protocols and Functional Outcomes in Oncological Patients Treated with Modular Megaprosthesis: A Systematic Review

by Filip Fryderyk Brzeszczyński, Michał Karpiński, Marcel Aleksander Brzeszczyński, Oktawiusz Bończak and David F. Hamilton

Cancers 2025, 17(18), 2951; https://doi.org/10.3390/cancers17182951 - 9 Sep 2025

Abstract

Background/Objectives: Bone reconstruction using megaprostheses is increasingly performed following bone tumour resections, including sarcomas, to enhance patient outcomes and quality of life. However, this is a complex patient group, and there is little consensus as to postoperative rehabilitation and associated outcomes. Methods: A [...] Read more.

Background/Objectives: Bone reconstruction using megaprostheses is increasingly performed following bone tumour resections, including sarcomas, to enhance patient outcomes and quality of life. However, this is a complex patient group, and there is little consensus as to postoperative rehabilitation and associated outcomes. Methods: A systematic search was conducted in MEDLINE and EMBASE databases according to the Implementing Prisma in Exercise, Rehabilitation, Sport medicine and SporTs science (PERSiST) guidelines. Studies describing rehabilitation protocols and functional outcomes following bone tumour resection and modular oncologic megaprosthesis reconstruction were included. All papers were individually assessed for methodological quality using the Joanna Briggs Institute (JBI) critical appraisal tool. Results: The search generated 105 records, 28 underwent full-text review, and 13 studies were included. Available data reflect 371 patients with a mean age of 49.17 (S.D. 21.40) years and a mean postoperative follow-up of 41.88 (S.D. 32.88) months. Surgical indications were documented as sarcomas in 9 studies, and tumour metastasis to the bone in 10 studies. Rehabilitation protocols were reported in 5 studies following proximal humerus resection with a mean dislocation rate of 14.5% (S.D. 5.26). All protocols advised brace immobilisation for a period ranging between 10 days and 6 months. Superior Constant-Murley shoulder score was reported in patients with early active isometric exercises at 6 weeks. Six studies reported proximal femur prosthesis rehabilitation and functional outcomes, with a mean dislocation rate of 10% (S.D. 9.82). Enhanced outcomes were reported in studies employing early mobilisation. Two studies assessed distal femur prosthesis; both studies reported similar protocols with full weight bearing 3 weeks following surgery. The methodological quality of the studies varied, but was overall modest, with 10/13 studies meeting at least 50% of JBI reporting criteria. Conclusions: The existing literature on rehabilitation and outcomes in orthopaedic oncology patients following arthroplasty with megaprosthesis is limited, with rehabilitative protocols variably described. However, it seems that early active mobilisation does not increase the risk of joint dislocations or infections. Full article

(This article belongs to the Special Issue Sarcoma Management in Orthopaedic Oncology)

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16 pages, 3357 KB

Open AccessArticle

Cabozantinib Sensitizes NSCLC Cells to Radiation by Inducing Ferroptosis via STAT3/MCL1/BECN1/SLC7A11 Axis Suppression

by Cheng-Yi Wang, Chao-Yuan Huang, Li-Ju Chen, Grace Chen and Shiao-Ya Hong

Cancers 2025, 17(18), 2950; https://doi.org/10.3390/cancers17182950 - 9 Sep 2025

Abstract

Background/Objectives: Intrinsic radioresistance in non-small-cell lung cancer (NSCLC) is partially driven by adaptive redox mechanisms that prevent oxidative cell death. Ferroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation, has emerged as a potential therapeutic vulnerability in tumors with elevated [...] Read more.

Background/Objectives: Intrinsic radioresistance in non-small-cell lung cancer (NSCLC) is partially driven by adaptive redox mechanisms that prevent oxidative cell death. Ferroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation, has emerged as a potential therapeutic vulnerability in tumors with elevated antioxidant capacity. However, its mechanistic integration with radiotherapy remains incompletely understood. Methods: We compared the effects of three clinically approved VEGFR-targeting tyrosine kinase inhibitors (TKIs), cabozantinib, lenvatinib, and ripretinib, on NSCLC cell viability with and without radiation. Subsequent mechanistic studies focused on cabozantinib and included ferroptosis rescue assays (ferrostatin-1, deferoxamine), lipid ROS quantification, glutathione assays, clonogenic survival, co-immunoprecipitation of BECN1–SLC7A11 complexes, and BECN1 knockdown by siRNA and shRNA. Results: All three TKIs were evaluated for cytotoxicity, but only cabozantinib significantly reduced NSCLC cell viability in combination with radiation in a ferroptosis-dependent manner. Cabozantinib inhibited STAT3 phosphorylation and downregulated MCL1, resulting in the release of BECN1. This allowed BECN1 to bind and suppress SLC7A11, disrupting system Xc⁻ function, depleting glutathione, and promoting lipid ROS accumulation. Genetic silencing of BECN1 reversed these effects and restored redox balance and clonogenic capacity. Lenvatinib and ripretinib failed to elicit similar responses, indicating that the inhibition of non-VEGFR targets (e.g., MET, AXL) may be essential for ferroptosis induction by cabozantinib. Conclusions: Cabozantinib enhances the radiosensitization of NSCLC cells through ferroptosis induction mediated by the suppression of the STAT3/MCL1/BECN1/SLC7A11 axis. These findings uncover a novel mechanism linking kinase inhibition to redox imbalance and suggest that the pharmacologic modulation of ferroptosis using multi-target TKIs may represent a rational approach to overcome radioresistance in NSCLC. Full article

(This article belongs to the Special Issue Advances in Lung Cancer Treatment Strategies)

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21 pages, 7246 KB

Open AccessArticle

Heterogeneity of Tertiary Lymphoid Structures and Plasma Cells in PDAC with and Without Lymph Node Metastasis

by Mengfei Wang, Lizhi Zhang and Hailong Chen

Cancers 2025, 17(18), 2949; https://doi.org/10.3390/cancers17182949 - 9 Sep 2025

Abstract

Background/Objectives: TLSs are favorable PDAC prognostic biomarkers. However, the mechanisms underlying TLSs formation and their contribution to the humoral antitumor immune response remain poorly understood. Methods: We used mIF staining combined with AI-based pathological image analysis software to assess the heterogeneity [...] Read more.

Background/Objectives: TLSs are favorable PDAC prognostic biomarkers. However, the mechanisms underlying TLSs formation and their contribution to the humoral antitumor immune response remain poorly understood. Methods: We used mIF staining combined with AI-based pathological image analysis software to assess the heterogeneity in the distribution of TLSs, B cells, plasma cells, and tumor cells between N0 and N1/2 PDAC. Three scRNA-seq datasets and the TCGA-PAAD database were utilized to investigate the functional heterogeneity in B cells and plasma cells. Results: The TLS area and maturity in N0 PDAC were higher than those in N1/2 PDAC. The densities of memory B cells and germinal-center B cells in intratumoral mTLSs, as well as plasma cells in stromal imTLSs, were associated with the density of intratumoral plasma cells. Moreover, plasma cells in N0 PDAC exhibited stronger IgG antibody production than those in N1/2 PDAC. IgG⁺ tumor cells congregated within 40 μm of IgG⁺ plasma cells, forming an IgG⁺ plasma cell-related immune hotspot in N0 PDAC, which was not observed in N1/2 PDAC. The distance between IgG⁺ plasma cells and the nearest IgG⁺ tumor cells was a new prognosis biomarker. Conclusions: The TLS formation and development in N0 PDAC were better than those in N1/2 PDAC, and there is an IgG⁺ plasma cell-related immune hotspot in N0 PDAC. The TLS area and maturity and the distance between IgG⁺ plasma cells and the nearest IgG⁺ tumor cells could be PDAC prognostic biomarkers. Full article

(This article belongs to the Section Tumor Microenvironment)

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19 pages, 1376 KB

Open AccessArticle

Dendritic Cells of Leukemic Origin (DC_leu) Modulate the Expression of Inhibitory Checkpoint Molecules and Their Ligands on T Cells and Blasts in AML Relapse After Allogeneic Stem Cell Transplantation

by Xiaojia Feng, Giuliano Filippini Velázquez, Sophia Bohlscheid, Marianne Unterfrauner, Philipp Anand, Hazal Aslan Rejeski, Anne Hartz, Tobias Baudrexler, Christoph Schmid and Helga Maria Schmetzer

Cancers 2025, 17(18), 2948; https://doi.org/10.3390/cancers17182948 - 9 Sep 2025

Abstract

Background: Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a potentially curative treatment for high-risk acute myeloid leukemia and myelodysplastic neoplasms (AML/MDS). However, AML/MDS relapse post-transplant is driven by immune escape mechanisms, limiting treatment options and contributing to poor prognosis. Granulocyte–Macrophage Colony-Stimulating Factor (GM-CSF) [...] Read more.

Background: Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a potentially curative treatment for high-risk acute myeloid leukemia and myelodysplastic neoplasms (AML/MDS). However, AML/MDS relapse post-transplant is driven by immune escape mechanisms, limiting treatment options and contributing to poor prognosis. Granulocyte–Macrophage Colony-Stimulating Factor (GM-CSF) and Prostaglandin-E1 (PGE-1) (termed “Kit M”) induce dendritic cells of leukemic origin (DC_leu) that have been shown to induce antileukemic immune responses. Methods: Using flow cytometry, we analyzed ICM/ICML-expressing uncultured T-cells/blasts in whole blood (WB) samples from patients with AML/MDS relapse post-allo-HCT who had received salvage treatment. Using Kit M, DC_leu were generated ex vivo. T-cell-enriched mixed-lymphocyte cultures (MLC) were performed for functional assessment of DC/DC_leu to stimulate (leukemia specifically) patients’ immune cells. After MLC, ICM/ICML-expressing cells and immune activation were assessed. The experimental results were correlated with patients’ clinical responses to salvage treatment. Results: WB samples from 15 patients were analyzed. On average, high frequencies of ICM (CTLA4/PD1)-co-expressing blasts and high frequencies of ICM (CTLA4/PD1/TIGIT/TIM3/2B4)-co-expressing T-cells were found in uncultured WB, compared to the frequencies of healthy ICM-expressing T-cells. Treatment with Kit M induced DC/DC_leu, which, after MLC, downregulated ICM-expressing T-cells and enhanced activated and memory T-cells. High frequencies of ICM-co-expressing uncultured T-cells/blasts correlated negatively with the blast lysis capacity and patients’ clinical response to relapse treatment. However, post-MLC, Kit-mediated modulation of ICM-expressing T cells did not correlate with blast lysis, nor with patients’ clinical response to treatment. Conclusions: We conclude that Kit M contributes to overcoming impaired antileukemic reactions, independent of the presence of ICM-expressing T-cells in relapsed AML patients after allo-HCT ex vivo. Full article

(This article belongs to the Special Issue The New Challenge of Curing AML: Analysis of Mechanisms of Resistance of Target Drugs and Future Perspectives)

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Cancers, Volume 17, Issue 18 (September-2 2025) – 37 articles

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