2026-04-02
Begoña Pineda, Juan Jose Martinez-Pretel, Paloma Sanchez- Serrano, Stergios Boussios, Maria Rodrigo-Faus, Martín Pérez-Leal, Elena Obrador, Javier Perea, J. Alejandro Perez-Fidalgo
BackgroundHigh-grade serous ovarian cancer (HGSOC) and triple-negative breast cancer (TNBC) frequently exhibit mutations in DNA damage response (DDR) genes, as BRCA1, BRCA2 and TP53, which are associated with chemotherapy sensitivity. Olaparib, a PARP inhibitor, provides the greatest clinical benefit as maintenance therapy in HGSOC—particularly in tumors with BRCA1/2 mutations or broader homologous recombination deficiency (HRD)—whereas benefit in HRD−negative disease is limited. Eprenetapopt (APR-246) restores wild-type p53 function in tumor cells with TP53 mutations. This study investigates the potential of combining eprenetapopt with carboplatin to overcome resistance to the PARP inhibitor (PARPi) olaparib in HGSOC and TNBC cell lines.MethodsAs preclinical models, human ovarian cancer cell lines (HGSOC) (PEO1, Kuramochi) and a triple-negative breast cancer cell line (MDA-MB-231) were utilized as parental lines to generate their respective olaparib-resistant cell lines (PEO1R, Kuramochi-R, MDA-MB-231-R) by exposing the cells to increasing doses of olaparib. Cell viability, apoptosis and cell cycle progression, were assessed using MTT assays and Annexin V assay and propidium iodide staining, respectively. The Chou-Talalay method was used to calculate the combination index (CI) for drug synergism.ResultsOlaparib-resistance was confirmed in both HGSOC and TNBC cell lines, as they exhibited significantly higher IC50 values compared to their respective parental lines. Moreover, the olaparib-resistant cells exhibited cross-resistance to carboplatin. Remarkably, the combination of eprenetapopt with carboplatin showed a synergistic effect in both parental and resistant cell lines, reducing tumor cell viability and demonstrating synergistic interaction compared with single agents. Combinatorial treatment also significantly increased apoptotic cell population in parental HGSOC and TNBC cell lines as well as in MDA-MB-231-R olaparib-resistant cells. Cell cycle analysis revealed that carboplatin mainly induced a significant increase in S or G2/M phase accumulation and a reduction in G1-phase cells, with eprenetapopt having a minimal additional impact.ConclusionsCombining eprenetapopt with carboplatin shows promising preclinical efficacy by enhancing cytotoxicity in olaparib−resistant models and demonstrating synergistic interaction; these data support the combination as a potential strategy to mitigate PARPi resistance and carboplatin cross−resistance in TP53 mutant HGSOC and TNBC cell lines. Although further studies are needed to elucidate the molecular mechanisms underlying the synergistic effect, here we point out the combination of eprenetapopt and carboplatin as a potential therapeutic strategy to address olaparib resistance in HGSOC and TNBC patients.
DOI: 10.3389/fonc.2026.17548732026-04-02
Detao Wu, Ranliang Hua, Ze Mao, Yujing Hu, Jingjie Zhang, Congna Tian, Lu Zheng, Xinchao Zhang, Yanzhu Bian
Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is an indolent B-cell lymphoma for which current imaging modalities offer limited diagnostic value. This article reports a comparison of the imaging features of 18F-FDG and 68Ga-pentixafor in this disease and reviews the relevant literature. A 60-year-old woman presented with a 6-month history of fever and scattered systemic lymphadenopathy. The patient underwent both 18F-FDG and 68Ga-pentixafor PET/CT imaging within a 2-day period. 68Ga-pentixafor PET/CT identified significantly increased metabolic activity in enlarged lymph nodes, the spleen, and bone marrow. Immunohistochemical staining demonstrated a phenotypic profile positive for CD5, CD20, and CD23; showed focal positivity for cyclin D1; and was negative for CD10, BCL-6, and SOX11, findings consistent with the diagnosis of CLL/SLL. Compared with 18F-FDG, 68Ga-pentixafor PET/CT detected more lesions with significantly higher tracer uptake. This case suggests that, for patients with CLL/SLL, 68Ga-pentixafor PET/CT demonstrates significantly superior performance in evaluating the tumor burden and delineating the disease extent compared with 18F-FDG PET/CT.
DOI: 10.3389/fonc.2026.16995682026-04-02
Yacheng Wang, Heng Zhang, Zibo Tang, Dehua Kang, Weihao Xie, Xiaoshi Zhang, Lixia Lu
Background and purposeMelanoma brain metastasis (MBM) is associated with a poor prognosis and a high risk of intracranial hemorrhage (ICH), which may complicate the use of stereotactic radiosurgery (SRS). This study evaluated the efficacy and safety of hypofractionated radiotherapy (HFRT) for MBM, with a specific focus on metastases with hemorrhagic components.Patients and methodsIn this single-center retrospective study, 26 patients with MBMs received HRT regimens of 30 Gy/5 fractions, 36 Gy/6 fractions, or 42 Gy/7 fractions. The primary endpoint was the local control (LC) rate assessed on the first MRI evaluation after radiotherapy completion (1–3 months after radiotherapy completion). Secondary endpoints included intracranial progression-free survival (IPFS), overall survival (OS), and treatment-related adverse events (AEs).ResultsThe disease control rate was 96% at the 3-month assessment (2 complete responses, 16 partial responses, 7 stable disease). The median OS was 10.5 months and the median IPFS was 4.5 months. No grade ≥3 AEs or symptomatic radiation necrosis occurred during the follow-up period (median 7.5 months). Notably, no radiotherapy-related ICH or exacerbation of pre-existing hemorrhage was observed, and hemorrhage reduction was achieved in all 11 patients with baseline ICH (100%).ConclusionHFRT demonstrated promising local control and a favorable safety profile in this cohort of MBM patients, It shows particular potential for treating hemorrhagic metastases and may offer a valuable alternative to SRS in selected high-risk scenarios, meriting further investigation in larger studies.
DOI: 10.3389/fonc.2026.17821022026-04-02
Yuxin Li, Ruiyun Qiao, Xuan Zhang, Yahong Li
Primary vitreoretinal lymphoma (PVRL) is a rare intraocular malignancy for which the optimal therapeutic strategy remains controversial, largely due to the disease’s rarity and considerable heterogeneity in treatment approaches across medical centers. While some studies suggest that combined systemic chemotherapy may prevent central nervous system progression in PVRL, others have failed to confirm such benefits, particularly given the severe treatment-related toxicities associated with intensive regimens. Although agents such as lenalidomide and Bruton’s tyrosine kinase(BTK) inhibitors have demonstrated efficacy in relapsed/refractory (R/R)PVRL, their role in treatment-naïve patients remains unclear. Herein, we retrospectively report the efficacy and safety of Orelabrutinib and rituximab combined with intravitreal methotrexate(MTX) in a patient with PVRL. The patient received this regimen as first-line treatment, which led to rapid improvement in visual acuity and intraocular tumor control in all affected eyes. Interleukin-10, a well-established biomarker for vitreoretinal lymphoma, decreased to normal levels after five months of therapy. The treatment was well-tolerated, with no reported adverse events. In conclusion, the combination of Orelabrutinib, rituximab, and intravitreal MTX is a feasible therapeutic strategy for PVRL. Our findings may contribute to a potential paradigm shift in the management of this rare disease.
DOI: 10.3389/fonc.2026.18005292026-04-01
Zeqi Tang, Xiaoming Zhang, Zhanqi Sun, Shiyan Zhang, Xiaoling Feng, Yixia Chen, Haiqi Xu
BackgroundThe efficacy of combining programmed cell death protein-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors with multi-targeted anti-angiogenic tyrosine kinase inhibitors (TKIs) in advanced or metastatic non-small cell lung cancer (NSCLC) remains controversial. This study therefore aimed to systematically evaluate the efficacy of this combination regimen in patients with advanced or metastatic NSCLC.MethodsWe systematically searched PubMed, EMBASE, Web of Science, ClinicalTrials.gov, and the Cochrane Library databases for relevant randomized controlled trials (RCTs) up to July 2025. The primary outcomes were progression-free survival (PFS) and overall survival (OS), analyzed using the hazard ratio (HR) and 95% confidence interval (95%CI).ResultsA total of six RCTs were included, involving 2,787 participants. Results demonstrated that the intervention group receiving PD-1/PD-L1 inhibitors combined with anti-angiogenic TKIs showed improved PFS compared with the control group (HR = 0.82, 95%CI: 0.69-0.97, p=0.021). However, no statistically significant difference was observed between the two groups in OS (HR = 0.97, 95%CI: 0.88-1.07, p=0.554). Subgroup analyses indicated that the PFS benefit was more pronounced in patients aged 0.05).ConclusionThe combination of PD-1/PD-L1 inhibitors and anti-angiogenic TKIs significantly improved PFS in patients with advanced or metastatic NSCLC but did not translate into an OS benefit.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD420251126527.
DOI: 10.3389/fonc.2026.17991262026-04-01
Qingsheng Zheng, Shuai Peng, Xueying Wu
BackgroundGastric cancer (GC) is the fifth most commonly diagnosed malignancy and the fourth leading cause of cancer-related mortality worldwide. RNA-binding motif protein 3 (RBM3) has been associated as a prognostic marker in several cancers; however, its genetic contribution and functional role in gastric cancer remain unclear.MethodsGenome-wide association study (GWAS) data was integrated with experimental validation to investigate the role of RBM3 in GC. RBM3-associated expression quantitative trait loci (eQTLs) were identified from a GWAS of 3,301 individuals and evaluated for their association with GC risk using a large-scale GWAS comprising 456,348 individuals. Colocalization analysis was performed using stomach tissue eQTL data. RBM3 expression was assessed in 60 paired GC and adjacent normal tissues and in multiple GC cell lines. Functional effects of RBM3 modulation were examined through proliferation, colony formation, migration, invasion, and xenograft assays.ResultsSeveral independent variants within the RBM3 locus showed a consistent protective association with GC risk and were linked to RBM3 expression regulation. RBM3 expression was significantly reduced in GC tissues compared with adjacent normal tissues (P < 0.001). Low RBM3 expression correlated with advanced tumor stage (III–IV), lymph node and distant metastasis, and larger tumor size. Functionally, RBM3 overexpression inhibited GC cell proliferation, clonogenicity, migration, and invasion in vitro. In vivo, RBM3 overexpression suppressed xenograft tumor growth, reduced Ki67-positive proliferation, and enhanced apoptotic activity.ConclusionOur findings demonstrate that RBM3 acts as a genetically supported tumor suppressor in gastric cancer. RBM3-associated germline variants contribute to GC susceptibility, and RBM3 downregulation promotes aggressive tumor behavior. RBM3 therefore represents a promising biomarker and potential therapeutic target in gastric cancer.
DOI: 10.3389/fonc.2026.17901972026-04-01
Xiao-Dan Qian, Li-De Tao, Li-Hong Zhang, An-Lai Ji, Lei Wang, Muhammad Mudasar Iqbal, Yi Luo
Cellular senescence represents a state of stable, often irreversible cell cycle arrest. Unlike apoptosis, senescent cells (SCs) remain metabolically active and engage in robust secretory activity, most notably through the senescence-associated secretory phenotype (SASP). The SASP exerts profound and context-dependent effects on tumor initiation and progression. This review analyzes the dual role of senescent cells in tumor immunity. On one hand, they can exhibit anti-tumorigenic effects through SASP-mediated enhancement of immune surveillance and their inherent high immunogenicity. On the other hand, they can promote tumorigenesis by fostering an immunosuppressive microenvironment, polarizing immune cells via the SASP, and upregulating senescence-associated immune checkpoints (SAICs) to facilitate immune escape. These dual characteristics inform promising therapeutic strategies: first, inducing senescence in tumor cells, and second, selectively eliminating the resulting senescent populations. Notably, systemic senescence induction can cause off-target effects in healthy tissues, underscoring the need for targeted delivery systems. In conclusion, we highlight emerging senescence-targeted immunotherapies as a next-generation approach to strategically harness senescence for cancer control.
DOI: 10.3389/fonc.2026.17376522026-04-01
Qingbo Wang, Qingze Zeng, Kaicheng Li, Qiaojun Chen, Xiao Luo
Ependymomas are uncommon tumors arising from ependymal cells of the central nervous system, with lipomatous metaplasia representing an extremely rare pathological variant. We report a case of a 28-year-old male who presented with a 5-year history of an incidentally discovered intracranial mass and recent-onset dizziness. Magnetic resonance imaging (MRI) revealed a left frontotemporal lesion characterized by significant fat signal, progressive enhancement, and mass effect on adjacent structures. The patient underwent gross-total resection, and histopathology confirmed a World Health Organization (WHO) Grade II ependymoma with lipomatous metaplasia. Immunohistochemical analysis further supported the diagnosis, highlighting features of both ependymal differentiation and fatty metaplasia. We also provide a comprehensive literature review of previously reported cases, emphasizing the rarity, imaging characteristics, differential diagnosis, and surgical considerations for this unique pathological variant. This case underscores the importance of careful radiological and pathological evaluation to guide diagnosis and management, and aims to raise awareness of this rare subtype among clinicians and pathologists.
DOI: 10.3389/fonc.2026.16745472026-04-01
Qinshan Li, Mingli Zeng, Danmei Liang, Xuemei Zheng, Xiaoxia Zhang, Ruben Martin-Payo
BackgroundMachine learning (ML) has emerged as a transformative approach for developing high-performance clinical prediction models (CPMs). By leveraging multidimensional patient data, ML enables more accurate disease risk stratification, prognostic assessment, and clinical decision-making. In recent years, research on CPMs has expanded rapidly, with nearly 250,000 publications indexed as of 2024. Despite this remarkable growth, a comprehensive bibliometric analysis of the field is currently lacking.ObjectiveThis study aimed to analyze the global research status, evolutionary trends, and thematic hotspots of machine learning-based clinical prediction models (ML-CPMs) through bibliometric and visualization techniques.MethodsPublications related to ML-CPMs were retrieved from the Web of Science Core Collection and the Scopus database (up to May 9, 2025). Bibliometric analyses were performed using various tools, including R, VOSviewer, and CiteSpace, to generate annual publication trends, collaboration networks, and journal distributions, as well as co-citation, clustering, and keyword analyses.ResultsA total of 8,619 publications (8,000 original articles and 619 reviews) from 118 countries were identified. Since 2015, annual publications have grown exponentially (R² = 0.9919). While China led in total publication volume, the United States maintained the highest academic influence (H-index = 105; Total Citations = 66,788). Harvard University and BMC Medical Informatics and Decision Making emerged as the most productive institution and journal, respectively. Tian J from the Chinese Academy of Sciences led in publication count, while Wynants L from KU Leuven in Belgium recorded the highest citation frequency. Key research hotspots include algorithm optimization, multimodal data integration, and model interpretability, with clinical applications primarily focused on oncology, cardiovascular diseases, and critical care medicine.ConclusionResearch on ML-CPMs has experienced rapid global growth over the past decade, forming extensive international collaboration networks. However, challenges such as limited interpretability, data heterogeneity, and privacy concerns persist. Future studies should prioritize external validation, clinical applicability, and the integration of human-AI collaborative decision-making to ensure robust implementation in real-world clinical settings.
DOI: 10.3389/fonc.2026.17861762026-04-01
Hala Majeed, Nathan Shelman, Jitesh A. Patel, Janeesh S. Veedu, Insija I. Selene, Ashlyn Whitesell, Zin W. Myint
This case report describes an exceptionally rare manifestation of prostate adenocarcinoma presenting with peritoneal carcinomatosis, rectal obstruction, and markedly elevated carcinoembryonic antigen (CEA), closely mimicking colorectal cancer. A 65-year-old man with localized high-grade prostate adenocarcinoma (Gleason 4 + 4) underwent robotic prostatectomy in November 2020, followed by salvage radiation and stereotactic body radiation therapy for early biochemical recurrence. He achieved an excellent response to androgen deprivation therapy (ADT) combined with abiraterone and prednisone, maintaining an undetectable prostate-specific antigen (PSA) level for over 2 years. In late 2024, the patient developed hematochezia, narrow stools, and abdominal pain. Imaging revealed a rectal mass, diffuse peritoneal carcinomatosis, and new hepatic lesions. Despite an undetectable PSA, his serum CEA exceeded 7,000 ng/mL, strongly suggesting a colorectal primary. Multiple biopsies and immunohistochemical stains were inconclusive, showing poorly differentiated adenocarcinoma without definitive prostate or colorectal markers. Given the clinical presentation, FOLFOX chemotherapy was initiated empirically for presumed colorectal carcinoma. Next-generation sequencing (NGS) of rectal tissue ultimately identified a TMPRSS2::ERG fusion identical to that in the original prostatectomy specimen, strongly supporting a diagnosis of metastatic prostate adenocarcinoma origin. A subsequent liver biopsy corroborated the findings. The patient transitioned to docetaxel plus ADT, resulting in symptomatic improvement and partial radiologic response. Despite temporary stabilization, progressive bowel dysfunction required a palliative colostomy. Omental biopsies again confirmed metastatic prostate adenocarcinoma. This report underscores several key clinical lessons. First, peritoneal metastasis from prostate cancer is exceedingly uncommon and can masquerade as gastrointestinal malignancy, particularly when accompanied by high CEA levels and rectal involvement. Second, standard markers such as PSA and immunohistochemistry may be misleading in atypical presentations. Finally, the case highlights the decisive role of molecular diagnostics, specifically NGS, in identifying tumor origin and preventing misdiagnosis.
DOI: 10.3389/fonc.2026.1736081