Brain Metastases Research Articles

We have investigated the involvement of K+channels in generating the membrane current in MDA-MB-436 cells, a model of triple-negative breast cancer (TNBC). The membrane current is strongly influenced by the opening of voltage-dependent channels insensitive to the nonspecific K+ channel inhibitor 4-aminopyridine (4-AP). Using the cell patch clamp technique, we observed a significant decrease in membrane current after exposure to the generic K+channel inhibitor tetraethylammonium chloride (TEA-Cl), indicating that K+ions contribute to the overall membrane current through K+channels that are insensitive to 4-AP but TEA-Cl-sensitive. RNA-sequencing analysis identified the Big Potassium (BK or Maxi-K or KCa1.1, encoded by KCNMA1) and the Kv2.1 (encoded by KCNB1) channels as putative candidates, both of which are involved in cancer cell proliferation and migration. Iberiotoxin, a specific inhibitor of BK channels, did not affect the total membrane current, just as CdCl₂ did, a potent inhibitor of Ca2⁺ channels involved in BK activation. Using selective inhibitors, stromatoxin and drofenine, we demonstrated that the Kv2.1 channel contributes to the membrane current in MDA-MB-436 cells. Furthermore, drofenine inhibited cell migration as measured by the xCELLigence Real-Time Cell Analyzer System and induced apoptosis. Single-cell analysis revealed that the Kv2.1 channel is expressed in both normal and cancerous tissues, with significant upregulation in brain metastases. This raises the possibility that Kv2.1 could be explored as a potential therapeutic target for controlling advanced stages of the neoplasia.

Primary mediastinal embryonal carcinoma is an exceptionally rare and aggressive extragonadal germ cell tumor, comprising less than 2% of mediastinal germ cell neoplasms. Cardiovascular complications, including pericardial effusion and tamponade physiology, are even more infrequent, with only isolated cases reported. We present the case of a 35-year-old male with no significant medical history who presented with progressive dyspnea, pleuritic chest pain, and right shoulder discomfort. Imaging revealed a massive anterior mediastinal mass (21.2 × 14.3 × 20.3 cm) compressing the left lung and shifting mediastinal structures rightward, with direct extension into the left atrium and pulmonary veins (Image 1 and 2). Echocardiography demonstrated a moderate-to-large pericardial effusion with right atrial inversion and respiratory variation in mitral inflow, suggestive of early tamponade (Image 3). However, due to stable hemodynamics and significant distortion of normal anatomy from the tumor mass, pericardiocentesis was deferred as high-risk. Multidisciplinary teams opted for conservative management, and the patient was initiated on systemic chemotherapy with ifosfamide, etoposide, and cisplatin. Serial imaging demonstrated stabilization of the pericardial effusion and early signs of tumor response. Pathology confirmed embryonal carcinoma with elevated tumor markers (AFP 514 ng/mL, β-hCG 158 mIU/mL, LDH 3,078 U/L). Neurological evaluation for multifocal infarcts revealed a brain metastasis and suspected embolic phenomena; vascular imaging showed a left popliteal artery thrombus. The case illustrates a rare instance where both malignant pericardial effusion and external tumor compression contributed to tamponade physiology without overt clinical collapse. It highlights the complexity of managing cardiac involvement in malignancy, where anatomy, mass effect, and clinical stability guide intervention. This case reinforces the need for individualized cardiovascular decision-making and interdisciplinary coordination in rare oncologic presentations involving pericardial pathology.

The role of brachytherapy in neuro-oncology has evolved through periods of enthusiasm and skepticism. We examined the historical landscape of brachytherapy, tracing influential studies, clinical adoption patterns, technological advancements, and ongoing trials that reflect its resurgence in neuro-oncology. We conducted a scoping literature review of brachytherapy. Because of their favorable safety profiles, cesium-131brachytherapy and low-kV intra-operative radiation therapy (IORT) have emerged as a preferred platform for intracranial brachytherapy. In glioblastoma and brain metastasis (BM) patients, published literature indicates that cesium-131 brachytherapy and low-kV IORT do not increase the risk of surgical morbidity or procedural complications. Radiation necrosis remains rare in most glioblastoma and brain metastasis cases. Consistent across the available literature, cesium-131 brachytherapy and low-kV IORT are associated with excellent local control, including large lesions with a maximal diameter of > 3.5 cm. Ongoing clinical trials aim to compare the effectiveness of these adjunctive radiation platforms to the current standard of care, while also exploring their potential for integration into multimodal treatment strategies. As prospective clinical trials mature, cesium-131 brachytherapy and IORT are poised to redefine the therapeutic landscape for glioblastoma and brain metastasis management.

Brain metastases are an exceptionally rare and diagnostically challenging manifestation of differentiated thyroid carcinoma (DTC) in pediatric and young adult patients. The authors present the case of a 21-year-old woman with a history of follicular variant papillary thyroid carcinoma who developed multiple intracranial lesions concerning for metastases. The patient had previously undergone total thyroidectomy and radioactive iodine ablation, with normal serum thyroglobulin and no known systemic spread. Brain biopsy was deferred given the location of the lesions and the risk associated with biopsy. Despite the rarity of brain metastases in pediatric and young adult populations with DTC, especially in the absence of concurrent extracranial disease, this case highlights the importance of thorough neurological evaluation and consideration of CSF thyroglobulin as a potential marker. This case emphasizes the need for vigilance in surveillance and an alternative to brain biopsy when intracranial metastasis is suspected. https://thejns.org/doi/10.3171/CASE25386.

Brain metastases (BM) pose a significant challenge due to limited treatment options and poor prognosis. Combining PD-1/PD-L1 inhibitors with stereotactic radiosurgery (SRS) may enhance tumor control through synergistic effects. This study assessed the efficacy and safety of this combined approach for BM. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we systematically searched PubMed, Embase, Web of Science, and Scopus up to 27 June 2024. Studies involving PD-1/PD-L1 inhibitors and SRS for BM were included. Outcomes included local control (LC), progression-free survival (PFS), overall survival (OS), radiological response, and adverse events. Data were analyzed using STATA V.17 with a random-effects model. Sixteen studies with 1529 patients were included. Pooled 6- and 12-month LC rates were 85% (95% CI 75-95%) and 84% (95% CI 75-93%), respectively. One- and three-year PFS rates were both 51% (95% CI 39-64% and 41-62%), while one- and two-year OS rates were 67% (95% CI 57-78%) and 30% (95% CI 16-45%). Overall response rate was 61% (95% CI 44-78%), with a complete response rate of 39% (95% CI 25-53%). Adverse radiation effects occurred in 31% (95% CI 3-58%), with radiation necrosis in 12% (95% CI 2-23%). Subgroup analyses showed no significant impact of drug type, primary tumor site, prior treatment, or SRS fractionation on outcomes. Combining PD-1/PD-L1 inhibitors with SRS for BM yields robust local control and improved one-year survival compared to historical data, with manageable toxicities. However, variability in outcomes and lack of comparator groups highlight the need for standardized protocols and prospective trials to optimize treatment strategies and identify predictive biomarkers.

Objective: Non-small cell lung cancer (NSCLC) is a common and deadly cancer, and predicting survival can be useful for guiding treatment. This study aimed to investigate the impact of metabolic status-specifically resting energy expenditure (REE)-and clinicopathological characteristics on survival outcomes in patients with metastatic NSCLC receiving nivolumab as second-line therapy following platinum-based chemotherapy. Methods: This prospective, non-interventional, observational, single-center study included 148 adult patients with metastatic NSCLC receiving nivolumab as second-line treatment. Demographic data, cancer diagnosis-related characteristics, laboratory parameters, measured REE (mREE), and predicted REE (pREE) were recorded just before nivolumab treatment was initiated. Results: The mean ages of non-hypermetabolic and hypermetabolic patients were 63 ± 8 and 64 ± 9, respectively. Weight, height, BMI, and pREE were significantly higher in the non-hypermetabolic group. In the hypermetabolic group, the incidence of brain metastasis and the mREE were significantly higher. The median progression-free survival (PFS) and overall survival (OS) were 5.3 and 15.8 months, respectively. Multivariate analysis identified several predictors of survival. Poor ECOG performance status (PS) (p < 0.001), liver metastases (p = 0.018), and mREE/pREE ratio > 120% (p = 0.005) were significantly associated with shorter PFS. Similarly, poor ECOG PS (p = 0.037), liver metastases (p = 0.041), and mREE/pREE ratio > 120% (p = 0.009) were also linked to reduced OS. Conclusions: In patients with NSCLC treated with nivolumab, poor ECOG PS, the presence of liver metastases, and an mREE/pREE ratio > 120% were associated with poorer survival outcomes. Further prospective multicenter studies are required to validate these findings.

Peripheral neural crest tumor brain metastases management: a single-institution retrospective study.

Patritumab deruxtecan (HER3-DXd) in patients with active brain metastases of non-small-cell lung cancer (TUXEDO-3): a multicentre, single-arm, phase 2 trial.

Real-world efficacy and safety of amivantamab in EGFR exon-20-mutant non-small cell lung cancer in a French early-access program: Amexon 20 GFPC study.

Patritumab deruxtecan (HER3-DXd) in patients with active brain metastases of breast cancer (TUXEDO-3): a multicentre, single-arm, phase 2 trial.

Amphiregulin reflects brain metastasis progression and leads to PD-L1 expression in non-small cell lung cancer cells.

Third-generation EGFR tyrosine kinase inhibitors (TKIs) have improved outcomes in EGFR-mutant non-small cell lung cancer (NSCLC), but resistance occurs, especially in patients with Brain metastases (BMs). Antiangiogenic therapy may enhance CNS drug delivery and EGFR-TKI efficacy​. We evaluated the efficacy of high-dose furmonertinib plus bevacizumab in patients with BMs after third-generation EGFR-TKI failure. We conducted a single-center retrospective study in EGFR-mutant NSCLC patients with BMs (leptomeningeal and/or parenchymal) who had progressed after ≥1 third-generation EGFR-TKI. Patients received furmonertinib 160 mg daily plus bevacizumab 7.5 mg/kg every 3 weeks until progression or unacceptable toxicity. Primary endpoints were intracranial and overall progression-free survival (iPFS, PFS); secondary endpoints were intracranial and systemic objective response rates (iORR, ORR) and safety. Among the 78 enrolled patients (median follow-up: 11.8 months), median iPFS and PFS were 7.2 months (95 % CI: 5.6-10.5) and 5.85 months (95 % CI: 4.6-7.4), respectively. The iORR was 37.1 %, and ORR was 28.6 %. OS data remain immature at the time of analysis. In patients with both parenchymal and leptomeningeal metastases (n = 47), median iPFS was 7.63 months (95 % CI: 5.0-10.8), and median PFS was 5.7 months (95 % CI: 4.5-10.0); iORR and ORR were 40.5 % and 34.2 %, respectively. In the parenchymal-only subgroup (n = 31), median iPFS and PFS were 7.20 months (95 % CI: 5.5-NR) and 6.4 months (95 % CI: 4.4-11.3), iORR and ORR were 32 % and 20 %. In multivariate analysis, EGFR exon 19 deletion was independently associated with prolonged iPFS (HR = 0.32, P = 0.011) and PFS (HR = 0.47, P = 0.047). CNS radiotherapy administered during treatment also emerged as an independent prognostic factor for both iPFS (HR = 0.34, P = 0.022) and PFS (HR = 0.40, P = 0.018). In this retrospective study, high-dose furmonertinib combined with bevacizumab demonstrated favorable intracranial and systemic activity with an acceptable safety profile in EGFR-mutant NSCLC patients with CNS metastases after resistance to third-generation EGFR-TKIs. These findings provide preliminary evidence supporting the potential clinical benefit of this chemotherapy-sparing strategy. Importantly, these findings warrant further validation in biomarker-stratified prospective trials to guide patient selection and optimize treatment outcomes.

Brain metastases following esophagectomy for cancer are rare but can greatly affect quality of life. To date, risk factors for, time to development of, and treatment strategies for brain metastasis are not well defined. Consecutive patients treated with esophagectomy for clinical stage I-IVA esophageal cancer from 2010 to 2021 across five centers were included. Logistic regression analyses were performed to identify risk factors for development of solitary brain metastases. Overall survival was assessed using Kaplan-Meier analysis. Of 3191 included patients, 91 (2.9%) developed solitary brain metastasis. Multivariable analysis identified increasing clinical nodal stage, adenocarcinoma (adjusted odds ratio [aOR] 4.00; 95% confidence interval [CI] 1.91-10), neoadjuvant chemoradiotherapy (aOR 2.18; 95% CI 1.19-4.28), and adjuvant therapy (OR 2.48; 95% CI 1.10-5.18) as risk factors for developing solitary brain metastases. Complete pathological responders were more likely to develop brain metastases than distant metastases (aOR 2.43; 95% CI 1.23-4.55). Patients with early solitary brain metastasis had the worst median overall survival (4.4 months, 95% CI 2.2-17) compared with classic (11 months, 95% CI 8.3-18) or late (7.4 months, 95% CI 2.1-not reached) (p = 0.20). Treatment involving surgery combined with radiation (adjusted hazard ratio [aHR] 0.10; 95% CI 0.05-0.20) resulted in better median overall survival (18 months, 95% CI 13-26) than did radiation (aHR 0.20; 95% CI 0.11-0.36) (10 months, 95% CI 6.1-14) or best supportive care (1.3 months, 95% CI 0.39-2.8) (p < 0.001). After esophagectomy for cancer, nodal involvement, adenocarcinoma, neoadjuvant and adjuvant therapy, and complete pathologic response appear to be risk factors for developing solitary brain metastases. Survival of selected patients with solitary brain metastasis is possible, especially if they are able to undergo surgery combined with radiation therapy.

PurposeWe compared failure patterns in patients with inoperable stage III non-small cell lung cancer (NSCLC) treated with chemoradiotherapy (CRT) alone versus CRT combined with sequential and/or concurrent immune checkpoint inhibitors (CRT-IO).MethodsRetrospective real-world data from 221 patients across two German tertiary cancer centers were analyzed. Of these, 74 received CRT-IO, including sequential durvalumab (85%) and concurrent/sequential nivolumab (15%), while 148 received CRT alone. First failure site and time to failure were compared.ResultsBetween 2012 and 2022, all patients received thoracic radiotherapy (≥ 60 Gy) and at least two cycles of platinum-based chemotherapy. Induction chemotherapy was administered in 36%, and induction chemo-immunotherapy in 2%. Median follow-up was 51.7 months (95% CI 47.0–56.4). Median overall survival (OS) for the entire cohort was 37.1 months (95% CI 26.0–48.2), with OS in the CRT-IO group not reached vs. 27.1 months (95% CI 18.5–25.7) in the CRT group (p < 0.001). Median progression-free survival (PFS) was 22.8 months (95% CI 6.4–39.1) for CRT-IO versus. 9.9 months (95% CI 7.0–12.8) for CRT (p = 0.001, see Fig. 1).Failure patterns differed significantly. CRT-IO patients had lower loco-regional progression (LRP) rates (9.5% vs. 21.8%, p = 0.023) and were more frequently alive without progression (45.9% vs. 16.3%, p < 0.001). Brain metastasis (BM) as the first failure, multifocal progression (MFP) and isolated extracranial distant metastasis (ecDM) rates were comparable between the CRT and CRT-IO subgroup. Women had a higher risk of isolated BM (17.3% vs. 6.8%, p = 0.016), whereas squamous cell carcinoma (SCC) patients had higher LRP rates (25.3% vs. 13.0%, p = 0.016). Median post-progression survival (PPS) was 19.4 months (95% CI 16.8–22.0) for CRT-IO and 9.5 months (95% CI 5.8–13.1) for CRT (p = 0.207). PPS was longer after BM (19.9 months) vs. LRP (8.5 months, p = 0.076) and significantly better in women (20.7 vs. 8.9 months, p = 0.012) and adenocarcinoma/non-otherwise-specified-carcinoma (AC/NOS) vs. SCC (p < 0.001).ConclusionCRT-IO significantly improves OS, PFS, and LRP control compared to CRT alone. Failure patterns and survival disparities by histology and gender suggest tailored surveillance and treatment strategies are needed. Further studies should optimize management of LRP and long-term outcomes in CRT-IO-treated patients.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00432-025-06355-y.

Multilevel factors associated with timeliness of care along the lung cancer care continuum - A systematic review.

Enhanced 5-methylcytosine methylation of PSD4 facilitates vasculogenic mimicry in breast cancer brain metastases through ferroptotic resistance.

Comparative efficacy of osimertinib with and without radiation therapy in EGFR-mutated non-small cell lung cancer with brain metastases.

The treatment landscape for advanced non-small cell lung cancer (NSCLC) with common EGFR mutations has evolved significantly, with osimertinib established as the first-line standard. Two recent phase III trials, FLAURA2 and MARIPOSA, demonstrated that first-line intensification-through osimertinib plus chemotherapy or amivantamab-lazertinib-significantly prolongs overall survival compared to osimertinib alone. The aim of this review was to critically assess whether treatment intensification should be adopted as a new standard and, if so, in which patients. We identified high-risk subgroups more likely to benefit from upfront combination strategies, such as those with brain or liver metastases, L858R mutations, TP53 co-mutations, or detectable ctDNA. However, the improved efficacy comes with increased rates of grade ≥ 3 adverse events and treatment discontinuation, raising concerns about tolerability and quality of life (QoL), particularly in real-world settings with frailer patients. Post-progression strategies are also evolving and may impact the long-term value of upfront intensification. Emerging approaches, including targeted and untargeted therapies, and novel antibody-drug conjugates (ADCs), offer promising alternatives that may change future treatment options. Careful patient selection, improved toxicity management, and integration of QoL measures will be critical to ensure that the survival advantage demonstrated in trials can translate into true benefit in routine clinical practice. Future research should focus on identifying robust clinical and molecular markers to guide personalized treatment decisions.

Baseline and Time-Dependent Predictors of Cognitive Decline for Brain Metastasis Patients Treated with Radiotherapy– A Secondary Analysis of the ATHENA Trial

Development of a machine learning-based prognostic model for survival prediction in patients with lung cancer brain metastases using multicenter clinical data.