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Background Neurological failure contributes to 15–50% of deaths in patients with brain metastases, yet the underlying mechanisms remain poorly understood. Clinical causes range from local compression to meningeal metastasis. In this context, a link between infiltrative histopathological growth patterns (HGPs) and meningeal metastasis was recently described and prompted this reverse translation study. Methods We conducted a retrospective postmortem histological assessment and a prospective MRI-based proof-of-concept study to explore neurological decline mechanisms in two experimental brain metastasis models with different HGPs: (i) the non-infiltrative TUBO model, characterized by well-defined tumor borders and a multilayered astrocytic capsule; and (ii) the infiltrative E0771-LG model, exhibiting diffuse infiltration and widespread astrogliosis. Results In the TUBO model, neurological death resulted from local metastatic expansion compressing vital structures, while the E0771-LG model caused mortality mainly through widespread secondary dissemination. We provide the first direct evidence of contralateral recolonization by secondary metastasis-initiating cells (secMICs), and highlight the high efficiency of secondary spread. Additionally, we show that secMICs exploit distinct anatomical structures to reach distant brain regions, bypassing classical vascular dissemination routes. Notably, the HGP and its associated features are intrinsic to tumor cells and are established early during metastatic colonization. Conclusions This study identifies the HGP as a potential surrogate for predicting the underlying cause of organ failure in brain metastases. Additionally, it highlights the significant role of secondary dissemination and recolonization in brain metastasis, processes that have been largely overlooked in clinical practice. These findings address a critical knowledge gap and may inform future treatment strategies.

The multidisciplinary management of patients with brain metastases (BM) consists of surgical resection, different radiation treatment modalities, cytotoxic chemotherapy, and targeted molecular treatment. This review presents the current state of neurosurgical technology applied to achieve maximal resection with minimal morbidity as a treatment paradigm in patients with BM. In addition, we discuss the contribution of neurosurgical resection on functional outcome, advanced systemic treatment strategies, and enhanced understanding of the tumor biology.

Treatment of glioblastoma (GBM) consists of microsurgical resection followed by concomitant radiochemotherapy and adjuvant chemotherapy. The best outcome regarding progression free (PFS) and overall survival (OS) is achieved by maximal resection. The foundation of a specialized neuro-oncology care center (NOC) has enabled the implementation of a large technical portfolio including functional imaging, awake craniotomy, PET scanning, fluorescence-guided resection, and integrated postsurgical therapy. This study analyzed whether the technically improved neurosurgical treatment structure yields a higher rate of complete resection, thus ultimately improving patient outcome. Patients and methods: The study included 149 patients treated surgically for newly diagnosed GBM. The neurological performance score (NPS) and the Karnofsky performance score (KPS) were measured before and after resection. The extent of resection (EOR) was volumetrically quantified. Patients were stratified into two subcohorts: treated before (A) and after (B) the foundation of the Regensburg NOC. The EOR and the PFS and OS were evaluated. Results: Prognostic factors for PFS and OS were age, preoperative KPS, O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation status, isocitrate dehydrogenase 1 (IDH1) mutation status and EOR. Patients with volumetrically defined complete resection had significantly better PFS (9.4 vs. 7.8 months; p = 0.042) and OS (18.4 vs. 14.5 months; p = 0.005) than patients with incomplete resection. The frequency of transient or permanent postoperative neurological deficits was not higher after complete resection in both subcohorts. The frequency of complete resection was significantly higher in subcohort B than in subcohort A (68.2% vs. 34.8%; p = 0.007). Accordingly, subcohort B showed significantly longer PFS (8.6 vs. 7.5 months; p = 0.010) and OS (18.7 vs. 12.4 months; p = 0.001). Multivariate Cox regression analysis showed complete resection, age, preoperative KPS, and MGMT promoter status as independent prognostic factors for PFS and OS. Our data show a higher frequency of complete resection in patients with GBM after the establishment of a series of technical developments that resulted in significantly better PFS and OS without increasing surgery-related morbidity.

Brain metastases (BM) develop in about 30% of all cancer patients. Surgery plays an important role in confirming neuropathological diagnosis, relieving mass effects and improving the neurological status. To select patients with the highest benefit from surgical resection, prognostic indices (RPA, GPA) have been formulated which are solely focused on survival without considering neurological improvement. In this study we analyzed the impact of surgical resection on the neurological status in addition to overall survival in 206 BM patients. Surgical mortality and morbidity was 0.0% and 10.3% respectively. New neurologic deficits occurred in 6.3% of all patients. The median overall survival was 6.3 months. Poor RPA class and short time interval between diagnosis of cancer and the occurrence of BM were independent factors predictive for poor survival. Improvement of neurological performance was achieved in 56.8% of all patients, with the highest improvement rate seen in patients presenting with increased intracranial pressure and hemiparesis. Notably, the neurological benefits were independent from RPA class. In conclusion, surgical resection leads to significant neurological improvement despite poor RPA class and short overall survival. Considering the low mortality and morbidity rates, resection should be considered as a valid option to increase neurological function and quality of life for patients with BM.

Brain metastasis in breast cancer remains difficult to treat and its incidence is increasing. Therefore, the development of new therapies is of utmost clinical relevance. Recently, toll-like receptor (TLR) 4 was correlated with IL6 expression and poor prognosis in 1 215 breast cancer primaries. In contrast, we demonstrated that TLR4 stimulation reduces microglia-assisted breast cancer cell invasion. However, the expression, prognostic value, or therapeutic potential of TLR signaling in breast cancer brain metastasis have not been investigated. We thus tested the prognostic value of various TLRs in two brain-metastasis gene sets. Furthermore, we investigated different TLR agonists, as well as MyD88 and TRIF-deficient microenvironments in organotypic brain-slice ex vivo co-cultures and in vivo colonization experiments. These experiments underline the ambiguous roles of TLR4, its adapter MyD88, and the target nitric oxide (NO) during brain colonization. Moreover, analysis of the gene expression datasets of breast cancer brain metastasis patients revealed associations of TLR1 and IL6 with poor overall survival. Finally, our finding that a single LPS application at the onset of colonization shapes the later microglia/macrophage reaction at the macro-metastasis brain-parenchyma interface (MMPI) and reduces metastatic infiltration into the brain parenchyma may prove useful in immunotherapeutic considerations.

High-grade glioma (HGG) is associated with a limited prognosis. Drug repurposing has become of increasing interest to improve standard therapy. Statins and NSAIDs inhibit glioma cell growth in vitro and in vivo, but data on statin and NSAID treatment in relation to survival of patients with HGG are sparse. We performed multivariable adjusted Cox-regression analyses among 1,093 patients with HGG from a regional cancer registry to obtain Hazard Ratios (HRs) with 95% Confidence Intervals (CIs) for overall survival (OS) and progression-free survival (PFS) according to treatment with statins or NSAIDs. Data on dose and duration of treatment was mostly lacking in our analysis, therefore we were not able to perform dose-response analyses. Use of statins was unrelated to OS or PFS of glioma patients. Use of aspirin was associated with prolonged OS and PFS in patients with WHO grade III, but not WHO grade IV glioma. Use of other NSAIDs (diclofenac, ibuprofen) or non-NSAID analgesics (paracetamol) was mostly unrelated to survival of glioma patients. Use of selective COX-2 inhibitors and metamizol was related to inferior patient survival in parts of the analyses. Use of statins or NSAIDS, including aspirin, was not associated with prolonged OS or PFS of patients with WHO grade IV glioma in our selected cohort. There was an indication for improved survival in patients with WHO grade III glioma using aspirin, but further studies are needed to confirm our first observation.

Microsurgical resection is the primary treatment of skull base meningiomas. Maximal resection provides the best tumor control rates but can be associated with high surgical morbidity. To understand the relation between extent of resection (EOR) and functional outcome we have analyzed the neurological improvement and recurrence rate in a large consecutive series of skull base meningioma patients. In addition, we defined anatomical and biological factors predictive for recurrence and overall outcome. We investigated 226 skull base meningioma patients receiving tumor resection in our institution. The most frequent location was the medial sphenoid ridge (29.6 %). EOR was rated according to the Simpson scale. Overall performance was measured by the Karnofsky performance score (KPS); neurological deficits were quantified using the Medical Research Council Neurological Severity Score (MRC-NPS). Complete resection was achieved in 62.8 % and the EOR was significantly correlated to tumor location. The morbidity and mortality rate was 32.1 and 2.7 % respectively, new permanent neurological deficits occurred in 3.5 % of all patients. From all patients with focal neurological deficits, 60.1 % experienced significant improvement. Both the MRC-NPS and the KPS significantly improved from the preoperative status to discharge, however the improvement rate was dependent on the tumor location. Recurrence rate was 15.5 %; tumor size, bone- and venous sinus infiltration, WHO grade, poor EOR but not MIB-1 labeling index were independent factors predictive for recurrence. Microsurgical resection of skull base meningiomas improves neurological impairment in the majority of patients. Specific risk factors for recurrence require consideration for postoperative management.

Newer 3D culturing approaches are a promising way to better mimic the tumor microenvironment and to study the interactions between the heterogeneous cell populations of glioblastoma multiforme. Like many other tumors, glioblastoma uses extracellular vesicles as an intercellular communication system to prepare surrounding tissue for invasive tumor growth. However, little is known about the effects of 3D culture on extracellular vesicles. The aim of this study was to comprehensively characterize extracellular vesicles in 3D organoid models and compare them to conventional 2D cell culture systems. Primary glioblastoma cells were cultured as 2D and 3D organoid models. Extracellular vesicles were obtained by precipitation and immunoaffinity, with the latter allowing targeted isolation of the CD9/CD63/CD81 vesicle subpopulation. Comprehensive vesicle characterization was performed and miRNA expression profiles were generated by smallRNA-sequencing. analysis of differentially regulated miRNAs was performed to identify mRNA targets and corresponding signaling pathways. The tumor cell media and extracellular vesicle proteome were analyzed by high-resolution mass spectrometry. We observed an increased concentration of extracellular vesicles in 3D organoid cultures. Differential gene expression analysis further revealed the regulation of twelve miRNAs in 3D tumor organoid cultures (with nine miRNAs down and three miRNAs upregulated). MiR-23a-3p, known to be involved in glioblastoma invasion, was significantly increased in 3D. MiR-7-5p, which counteracts glioblastoma malignancy, was significantly decreased. Moreover, we identified four miRNAs (miR-323a-3p, miR-382-5p, miR-370-3p, miR-134-5p) located within the DLK1-DIO3 domain, a cancer-associated genomic region, suggesting a possible importance of this region in glioblastoma progression. Overrepresentation analysis identified alterations of extracellular vesicle cargo in 3D organoids, including representation of several miRNA targets and proteins primarily implicated in the immune response. Our results show that 3D glioblastoma organoid models secrete extracellular vesicles with an altered cargo compared to corresponding conventional 2D cultures. Extracellular vesicles from 3D cultures were found to contain signaling molecules associated with the immune regulatory signaling pathways and as such could potentially change the surrounding microenvironment towards tumor progression and immunosuppressive conditions. These findings suggest the use of 3D glioblastoma models for further clinical biomarker studies as well as investigation of new therapeutic options.

An important phenomenon observed in glioma metabolism is increased aerobic glycolysis in tumor cells, which is generally referred to as the Warburg effect. Transforming growth factor (TGF)-beta2, which we previously showed to be induced by lactic acid, is a key pathophysiological factor in glioblastoma, leading to increased invasion and severe local immunosuppression after proteolytic cleavage from its latency associated peptide. In this study we tested the hypothesis, that lactate regulates TGF-beta2 expression and glioma cell migration via induction of Thrombospondin-1 (THBS-1), a TGF-beta activating protein. Lactate levels were reduced by knockdown of LDH-A using specific small interfering RNA (siRNA) and competitive inhibition of LDH-A by sodium oxamate. Knockdown of THBS-1 was performed using specific siRNA. Western Blot, qRT-PCR, and ELISA were used to investigate expression levels of LDH-A, LDH-B, TGF-beta2 and THBS-1. Migration of cells was examined by Spheroid, Scratch and Boyden Chamber assays. Knockdown of LDH-A with subsequent decrease of lactate concentration leads to reduced levels of THBS-1 and TGF-beta2 in glioma cells. Lactate addition increases THBS-1 protein, leading to increased activation of TGF-beta2. Inhibition of THBS-1 reduces TGF-beta2 protein and migration of glioma cells. Addition of synthetic THBS-1 can rescue reduced TGF-beta2 protein levels and glioma cell migration in siLDH-A treated cells. We define a regulatory cascade between lactate, THBS-1 and TGF-beta2, leading to enhanced migration of glioma cells. Our results demonstrate a specific interaction between tumor metabolism and migration and provide a better understanding of the mechanisms underlying glioma cell invasion.

Background Patients with glioblastoma (GB) not only suffer from a life-threatening oncological disease but also present with severe neurological symptoms and high psychosocial distress. The unfavorable prognosis and the early decline in neurological functions and activities of daily living, such as mobility, lead to a significant deterioration in quality of life aspects. The need for palliative care (PC) therefore arises at an early stage and increases as the disease progresses but is often inadequately assessed and treated. Methods In this single-center, retrospective study, we investigated prognostic factors, survival outcomes and neuro-oncologically focused primary palliative care (nPPC) as well as specialized palliative care (SPC) interventions. Pearson’s Chi-square test and an univariable and multivariable binary logistic regression analysis were used to test the independence between categorical variables and the correlation between SPC and tumor-specific therapy prior to death. The Kaplan-Meier method and a multivariable Cox regression analysis were performed to estimate the impact of SPC on survival. Results A cohort of 274 patients with GB was investigated, of whom 251 (91.6%) received nPPC and 210 (76.6%) SPC. Patients with SPC ( p  < 0.001; OR: 0.302; 95% CI: 0.157–0.584) and patients with methylation of the MGMT promoter region ( p  = 0.005; OR: 0.375; 95% CI: 0.190–0.739) were less likely to receive a tumor-specific therapy in the 30 days prior to death. Median overall survival was 16.9 months (95% CI: 14.5–19.3 months) for patients with SPC ( n  = 210) vs. 12.9 months (95% CI: 10.8–15.1 months) for patients without ( n  = 64) ( p  = 0.100; not significant). The Cox proportional hazards model demonstrated that SPC significantly correlates with longer overall survival ( p  = 0.017; HR: 0.707; 95% CI: 0.532–0.939). Conclusion This study revealed a broad availability of PC interventions for patients with GB. After adjustment of known prognostic factors, an association between SPC supply and prolonged OS was observed. Utmost efforts should be made to incorporate PC into the care of every patient within a standardized framework. Data on PC in patients with GB is still rare; therefore, further research should be made to improve PC in this highly burdened patient group.