Yang Gao

Objectives: To evaluate clinical outcomes and identify prognostic determinants in patients with lung cancer leptomeningeal metastasis (LCLM) treated with Ommaya reservoir-based intrathecal (IT) chemotherapy. Method: We retrospectively reviewed 154 LCLM patients treated at Fudan University Shanghai Cancer Center (2022-2025). All patients underwent Ommaya reservoir implantation, or combined with VP shunt. IT pemetrexed (30 mg/week) was delivered for 4–6 consecutive weeks. Clinical characteristics, cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI) features were collected. Survival outcomes were assessed using Kaplan–Meier and Cox regression analyses. Results: The cohort had a median age of 59 years (IQR, 53-65) with predominance of female sex (59.1%), lung adenocarcinoma (98.1%), and EGFR mutations (76.7%). Median overall survival (OS) for the entire cohort was 331 days (IQR, 266–446). To provide guidance on clinical decision making, we established an exploratory four-tier prognostic system integrating KPS and intracranial pressure (ICP), categorizing patients into distinct prognostic quartiles. Our analysis revealed that among patients with Karnofsky Performance Status (KPS) ≥70, a normal ICP was associated with superior survival. Conversely, in patients with KPS ≤ 50, a decrease in intracranial pressure indicates a poorer prognosis for the patients. Multivariate Cox regression identified KPS, extracranial metastasis, MRI morphology, and CSF glucose/protein as independent prognostic factors. A nomogram developed from these variables showed excellent discrimination (AUC = 0.894) and robust calibration. Conclusions: This study establishes a practical risk stratification system and a prognostic nomogram to assist individualized clinical decision-making for LCLM patients.

Malignant brain tumors have high morbidity and poor prognosis. Prostate-specific membrane antigen (PSMA) has emerged as a promising vascular biomarker in this setting, particularly in gliomas and brain metastases. This review synthesizes current evidence on PSMA expression patterns, regulatory mechanisms, imaging applications, and translational potential in malignant brain tumors. Across studies, PSMA expression in gliomas is predominantly localized to tumor-associated neovasculature and closely associated with angiogenic signaling. In brain metastases, PSMA expression appears more heterogeneous and more strongly influenced by metastatic origin and the brain microenvironment. These biological features provide a rationale for PSMA-targeted positron emission tomography, which offers high lesion-to-background contrast. Clinically, PSMA-targeted imaging shows promise for glioma grading, selected post-treatment assessment, and detection of brain metastases across multiple primary tumors. However, therapeutic translation remains limited because compartment-specific target distribution, inconsistent target retention, delivery barriers, and uncertain dosimetry continue to constrain the efficacy of PSMA-targeted treatment strategies in malignant brain tumors. Current evidence supports PSMA as a promising complementary imaging biomarker rather than as a validated therapeutic target in malignant brain tumors. Future progress will require standardized detection methods, stronger mechanistic validation, and dosimetry-guided clinical development.

Metastasis and immunosuppression remain major barriers to effective treatment of lung adenocarcinoma (LUAD), yet the metabolic mechanisms governing the pro-tumor functions of tumor-associated macrophages are incompletely understood. In this study, we identified Uridine Phosphorylase 1 (UPP1) as a macrophage-enriched metabolic regulator associated with LUAD progression. By integrating single-cell RNA sequencing with clinical cohort analyses, we found that UPP1 was preferentially expressed in tumor-associated macrophages and was associated with adverse clinical outcomes. Functional and mechanistic studies demonstrated that dysregulated UPP1 disrupted nucleotide homeostasis, leading to mitochondrial reactive oxygen species accumulation and mitochondrial DNA leakage. These mitochondrial stress signals activated the cGAS-STING pathway, which preferentially engaged NLRP3 inflammasome signaling rather than canonical antiviral responses. Consequently, macrophages underwent pyroptosis and released elevated levels of interleukin-1β (IL-1β). Through paracrine signaling, macrophage-derived IL-1β promoted epithelial-mesenchymal transition in LUAD cells and enhanced their invasive capacity in vitro. Consistent with these findings, co-injection of UPP1-overexpressing macrophages significantly increased spontaneous lung metastasis in vivo. Clinically, elevated UPP1 expression served as an independent predictor of poor survival. Furthermore, pharmacological blockade of this signaling cascade or neutralization of IL-1β attenuated macrophage-induced malignant phenotypes in tumor cells, highlighting the therapeutic relevance of this pathway. Collectively, our findings identify a macrophage-specific immunometabolic circuit in which UPP1-driven mitochondrial stress activates the mtROS–cGAS–NLRP3 axis, promoting IL-1β-dependent macrophage–tumor crosstalk and metastatic progression. These results suggest that UPP1 may serve as both a prognostic biomarker and a potential therapeutic target in LUAD.

Leptomeningeal metastasis (LM) is a lethal complication of advanced malignancy with limited therapeutic options and poor survival. Intrathecal chemotherapy represents a standard treatment for LM and can be administered via repeated lumbar puncture (LP) or an intraventricular Ommaya reservoir. However, the comparative efficacy and safety of these two administration routes remain unclear. This study aims to compare the clinical outcomes of intrathecal chemotherapy delivered by Ommaya reservoir versus LP in patients with LM, and to provide further evidence for clarifying the advantages of the Ommaya reservoir in clinical practice. We systematically searched PubMed, Embase and Web of Science for relevant studies published between 1986 and 2026. Studies directly comparing intrathecal chemotherapy delivered via Ommaya reservoir and LP were included in the meta-analysis. Disease control rate (DCR) was pooled as odds ratios (OR) using a random-effects Mantel–Haenszel model to account for between-study heterogeneity, and overall survival (OS) was pooled as hazard ratios (HR) using the inverse-variance method. Because adverse events (AEs) were incompletely reported in comparative studies, an additional safety analysis including single-arm cohorts was conducted using a binomial generalized linear mixed model (GLMM) with a logit link. Risk of bias was assessed using the ROBINS-I tool. A total of four comparative studies with a moderate overall risk of bias were included in our meta-analysis. Three studies contributed data on DCR, and three studies contributed data on OS. The pooled analysis showed no significant difference in DCR between the Ommaya and LP groups (OR 2.03; 95% CI 0.53–7.78, p = 0.30), with moderate heterogeneity (I² = 66%). In contrast, Ommaya-based intraventricular delivery was associated with significantly improved OS compared with LP (HR 0.39; 95% CI, 0.25–0.61, p < 0.0001), with no significant heterogeneity (I² = 0%). In the exploratory safety analysis of six single-arm cohorts, the estimated probability of overall AEs was numerically lower in the Ommaya group (OR 0.43; 95% CI, 0.21–0.87, p = 0.0191). While this finding is derived from non-comparative data and should be treated cautiously, it offers valuable insight into safety profile. Ommaya reservoir–based intraventricular administration of intrathecal chemotherapy may provide a survival advantage over LP in patients with LM, while demonstrating a generally acceptable and manageable safety profile. Further comparative studies with standardized response criteria and rigorous safety reporting are warranted. The online version contains supplementary material available at 10.1007/s11060-026-05652-x.

Background Leptomeningeal metastasis (LM) is a lethal complication of advanced malignancy with limited therapeutic options and poor survival. Intrathecal chemotherapy represents a standard treatment for LM and can be administered via repeated lumbar puncture (LP) or an intraventricular Ommaya reservoir. However, the comparative efficacy and safety of these two administration routes remain unclear. This study aimed to compare clinical outcomes of intrathecal chemotherapy delivered by Ommaya reservoir versus LP in patients with LM, and to provide further evidence for clarifying the advantages of Ommaya reservoir in clinical practice. Methods We systematically searched MEDLINE, PubMed, and Web of Science for relevant studies published between 1986 and 2026. Studies directly comparing intrathecal chemotherapy delivered via Ommaya reservoir and LP were included in the meta-analysis. Disease control rate (DCR) was pooled as odds ratios (OR) using the Mantel–Haenszel method, and overall survival (OS) was pooled as hazard ratios (HR) using the inverse-variance method. Because adverse events (AEs) were incompletely reported in comparative studies, an additional safety analysis including single-arm cohorts was conducted using a binomial generalized linear mixed model (GLMM) with a logit link. Results A total of four comparative studies were enrolled in our meta-analysis. Three studies contributed data on DCR, and three studies contributed data on OS. The pooled analysis showed no significant difference in DCR between the Ommaya and LP groups (OR 1.43; 95% CI 0.76–2.68, p = 0.27), with moderate heterogeneity (I² = 66%). In contrast, Ommaya-based intraventricular delivery was associated with significantly improved OS compared with LP (HR 0.39; 95% CI, 0.25–0.61, p < 0.0001), with no significant heterogeneity (I² = 0%). In the additional safety analysis of six single-arm cohorts, Ommaya delivery was associated with lower estimated risks of overall AEs than LP(OR 0.43; 95% CI, 0.21–0.87, p = 0.0191). Conclusion Ommaya reservoir–based intraventricular administration of intrathecal chemotherapy may provide a survival advantage and lower risk of AEs over LP in patients with LM.

Objectives: Brain metastasis (BM) represents one of the most severe complications of lung adenocarcinoma (LUAD), associated with poor prognosis and survival. We aimed to establish a reproducible and stable animal model of lung cancer brain metastasis, and to preliminarily explore the mechanism of lung cancer brain metastasis using this model. Methods: Construct a brain metastasis model by intracardiac injection of H2030 cells (2 × 10 ⁵ cells), record the weight of the mice every week, and record the neurological symptoms and time of occurrence in the mice. Identify the formation of brain metastases through magnetic resonance imaging, in vivo imaging, and HE staining, and record the time of brain metastasis formation. Evaluate the function of cells with high brain metastasis tendency through migration and invasion time assessment. Results: In this study, a total of 72 animal models were established (generations 1–5). Among these, 19 cases showed positive intracranial imaging at 4–5 weeks, and 17 cases were histologically confirmed as LUADBM via immuno-histochemistry following dissection. The BM rates for the fourth (H2030-BM3) and fifth generations (H2030-BM4) were 58.3 % and 50 %, respectively, both significantly higher than that of the first generation (H2030). Compared to H2030, brain metastatic cells exhibiting a high propensity for BM demonstrated enhanced migratory and invasive capabilities, as well as increased tumor-forming capacity in the brain. Furthermore, molecular analysis revealed that, relative to H2030, the expression of Jun oncogene (JUN), Cellular Communication Network Factor 2 (CCN2), and C-X-C motif chemokine ligand 8 (CXCL8) was significantly downregulated in H2030-BM5 cells with high BM tendency, while Neural Cell Adhesion Molecule 1 (NCAM1) and SRY-box containing gene 2 (SOX2) were markedly upregulated. The WB analysis revealed upregulation of NCAM1 and SOX2 in brain-metastatic LUAD cells. These results support bioinformatic predictions, suggesting downregulated genes may suppress metastasis while upregulated genes promote brain tropism. Conclusions: The animal model of BM in LUAD has been successfully established through the injection of LUAD cells into the left ventricle. Notably, the reprogramming of gene expression following the metastasis of LUAD cells to the brain underscores the specific evolution of the brain microenvironment during this metastatic process.

Background: Breast cancer continues to pose a significant global health burden, accounting for a substantial proportion of cancer-related mortality in women worldwide. Despite advancements in therapeutic strategies, overall survival rates remain suboptimal, underscoring the critical need for innovative prognostic tools to improve patient outcomes. Methods: In this study, we introduced a novel tumor mitochondria transfer (TMT) scoring system based on 17 core genes to assess mitochondrial dynamics and their potential impact on the tumor microenvironment. Utilizing comprehensive datasets from TCGA-BRCA and GEO databases, we investigated the association between TMT scores and immune-metabolic features at both multi-cell and single-cell resolutions. Single-cell RNA sequencing (scRNA-seq) profiles were used to delineate the biological consequences of mitochondrial transfer. Additionally, co-culture experiments were conducted to validate our findings. Results: Our analysis revealed that elevated TMT scores are strongly associated with adverse clinical outcomes in patients with breast cancer. Tumors with high TMT scores exhibited pronounced hypoxia, immune suppression, and metabolic reprogramming. Specifically, these tumors demonstrated impaired T-cell functionality and enhanced mitochondrial transfer to tumor cells, suggesting a pivotal role for mitochondrial dynamics in promoting immune evasion and metabolic adaptations that drive tumor progression. Conclusions: The TMT score may represent a novel prognostic biomarker in breast cancer, highlighting the intricate relationship between mitochondrial transfer and tumor pathophysiology. Our findings suggested that targeting mitochondrial dynamics could be a potential therapeutic avenue for exploration, which might enhance breast cancer management strategies. Further exploration of the mitochondrial mechanisms in cancer biology may pave the way for more precise and effective therapeutic interventions

Tertiary lymphoid structures (TLSs) are ectopic lymphoid formations that develop in chronically inflamed tissues, including various solid tumours. In the context of gliomas, the presence of TLSs has recently attracted considerable attention because of their potential implications in tumour immunology and therapy. The tumour immune microenvironment (TIME) plays a crucial role in cancer progression, and tumour-infiltrating immune cells (TILs) are key players in this environment. These immune cell aggregates, known as TLSs, display distinct characteristics across different solid tumours. However, central nervous system (CNS) tumours are highly heterogeneous, and the immune environment within these tumours is often more deficient than that of peripheral tissue tumours. This leads to differences in the formation and function of TLSs in CNS tumours. These variations are particularly relevant in the context of glioma immunotherapy and could have important implications for treatment strategies. This review focuses on the composition and function of TLSs, examines the complexity of the glioblastoma (GBM) immune microenvironment, and highlights the unique characteristics of TLSs in GBM, providing new theoretical insights and practical foundations for targeting TLSs in glioma immunotherapy.