Treatment Of Brain Metastases Research Articles

Treatment of brain metastases from non-small cell lung cancer: preclinical, clinical, and translational research

Lung cancer is the second most common type of cancer and is the leading cause of cancer-related deaths in the United States. Approximately 10-40% of patients with solid tumors develop brain metastases, with non-small cell lung cancer accounting for approximately 50% of all cases of patients with brain metastases. Many management options are available which can include surgery, radiation, and systemic therapy. A variety of factors go into the selection of management of brain metastases. In this review, we will focus on the treatment strategies and optimizing the management of brain metastases in patients with non-small cell lung cancer.

Adaptive stereotactic radiosurgery for cerebral metastases of non-small cell lung cancer: a retrospective study

INTRODUCTION: Non-small cell lung cancer (NSCLC) is a common cause of brain metastases (BM). Adaptive stereotactic radiosurgery (ASRS) may be a useful option in the treatment of patients with large unresectable brain metastases (BM), but to date there are only a limited number of studies evaluating the effectiveness of this method.OBJECTIVE: To analyze the effectiveness of ASRS in patients with large BM NSCLC not subject to surgical resection.MATERIAL AND METHODS: We retrospectively analyzed data from 37 patients suffering from NSCLC with 45 large (>2 cm in diameter, volume >4 cm3) unresectable BM treated with the Gamma Knife Perfexion model using two- and three-fraction ASRS. Of these, 14 foci (31.1%) were metastases of squamous cell lung cancer, 31 (68.9%) were metastases of adenocarcinoma. The median volume of lesions treated with ASRS was 9.8 (range 4.6–30.6 cm3). The dynamics of volume changes between fractions and the cumulative incidence of local relapses (CILR) were studied, and ROC analysis was performed for the tumor volume parameter. Intracranial progression-free survival (iPFS) and overall survival (OS) were assessed. Statistics: To establish statistical significance of differences for related variables, the Wilcoxon test for pairwise comparisons and the Friedman test for three or more groups were used. The Kaplan-Meier method was used to calculate local control, PFS, and OS rates. The log-rank test was used to compare survival data in two groups.RESULTS: The median follow-up period was 19.4 months. With two-fraction ASRS, the median volume of metastasis decreased by 28.6% by the second session, with three-fraction — by 40.0% by the third session. The 1-year and 2-year CILR rates were 8.6±6.1%, respectively; 26.1±12.3%. In ROC analysis, the area under the curve (AUC) for tumor volume was 0.80 (95% CI 0.6– 1.0) with an optimal cutoff of 18.5 cm3. The differences in CILR between the groups with metastasis volume <18.5 cm3 and ≥18.5 cm3 were statistically significant (p<0.001). Median iPFS was 8.3 (95% CI 5.9–10.7) months, 1-year iPFS was 33.5±8.1%;2-year — 7.8±5.2%. Median OS was 13.2 (95% CI 9.0–17.4) months; 1-year OS — 52.9±8.7%, 2-year — 22.4±8.8%.DISCUSSION: Using two- and three-fraction ASRS, we delivered doses to large BM sufficient for a high level of local control with an acceptable risk of neurotoxicity: 1-year local control was 91.4%; 2-year — 73.9%; the incidence of radionecrosis is 8.5%. A statistically significant effect of lesion volume ≥18.5 cm3 on the risk of local recurrence was found. The iPFS and OS indicators after ASRS can be considered satisfactory for this group of patients.CONCLUSION: ASRS is an effective and perhaps optimal strategy for the treatment of large unresectable BM in patients with NSCLC, but comparison with other modern radiotherapy modalities such as stereotactic hypofractionated radiotherapy and WBRT with simultaneous integrated boost is needed.

EP.13B.15 Radiotherapy Combined with Immunotherapy in the Treatment of Brain Metastases from Small Cell Lung Cancer

EP.13B.15 Radiotherapy Combined with Immunotherapy in the Treatment of Brain Metastases from Small Cell Lung Cancer

Adding immune checkpoint inhibitors to chemotherapy confers modest survival benefit in patients with small cell lung cancer and brain metastases: a retrospective analysis.

Brain metastases (BM) are highly prevalent and associated with a poor prognosis in patients with small cell lung cancer (SCLC). However, the evidence regarding the efficacy of immune checkpoint inhibitors (ICIs) in combination with chemotherapy for patients with SCLC and BM remains limited. Therefore, the objective of this study is to evaluate whether the addition of ICIs confers survival benefits for patients with SCLC and BM. This retrospective study enrolled patients with SCLC and BM at the Sun Yat-sen University Cancer Center between January 2018 and December 2022. Clinical characteristics were extracted from medical records. Depending on whether ICIs were added to the first-line treatment, the patients were categorized into the chemotherapy group and the chemoimmunotherapy group. The efficacy of these two treatment approaches was analyzed and compared. A total of 165 patients were enrolled, with 85 in the chemotherapy group and 80 in the chemoimmunotherapy group. The chemoimmunotherapy group showed a tendency towards prolonged intracranial [6.6 vs. 5.9 months, hazard ratio (HR) =0.77; P=0.14] and extracranial (6.9 vs. 6.5 months, HR =0.73; P=0.12) progression-free survival (PFS) and overall survival (OS) (15.6 vs. 14.5 months, HR =0.98; P=0.93) compared to the chemotherapy group. Cox regression analysis identified liver metastases and local treatment for BM as independent prognostic factors for OS in patients. Furthermore, the chemotherapy group and the chemoimmunotherapy group demonstrated similar patterns of initial disease progression. Adding ICIs to chemotherapy confers modest survival benefits in patients with SCLC and BM.

Blood-brain barrier and blood-brain tumor barrier penetrating peptide-drug conjugate as targeted therapy for the treatment of lung cancer brain metastasis

Lung cancer is the leading cause of cancer deaths worldwide. Brain metastasis of lung cancer, which counts for nearly 50% of late-stage lung cancer patients, is a sign of a really poor prognosis. However, the presence of blood–brain barrier (BBB) and blood–brain tumor barrier (BBTB) limits the penetration of drugs from the blood into the brain and thus restricts their accumulation in brain tumors. Systematic delivery of drugs into brain and brain tumor lesion using BBB and BBTB penetrating vehicles represents a promising strategy to overcome the BBB and BBTB limitations. Hence, we validated one of our previously identified BBB/BBTB penetrating peptide and its drug conjugate form for the treatment of lung cancer brain metastasis. With in vitro experiment, we first validated that the receptor LRP1, which mediated the peptide penetration of the BBB, was expressed on lung cancer cells and thus can be targeted by the peptide to overcome BBTB. With this delivery peptide, we constructed peptide-paclitaxel conjugate (the PDC) and in vitro validation showed that the PDC can across the BBB and efficiently kill lung cancer cells. We therefore constructed mouse lung cancer brain metastasis xenograft. In vivo anti-tumor validations showed that the PDC efficiently inhibited the proliferation of the brain resident lung cancer cells and significantly expanded the survival of the mouse xenograft, with no visible damages to the organs. Overall, our study provided potential therapeutic drugs for the treatment of lung cancer brain metastasis that may be clinically effective in the near future.

Brain Metastases from Ovarian Cancer: A Comprehensive Review

Ovarian Cancer Ovarian cancer (OC) is the current leading cause of gynecological cancer deaths. Despite its fatal outcome, only 20% of ovarian cancers are detected in the early stage. The reason involves a combination of factors — there is no reliable screening for ovarian cancer, and any symptoms of ovarian cancer tend to be vague and easily ignored. Consequently, OC is given the advantage of metastasizing due to ignorance. However, recently, overall survival from ovarian carcinoma has been reported to increase after improvements in treatment (Siegel et al., 2020). Brain Metastases from OC Central nervous system (CNS) metastasis from epithelial ovarian carcinoma (EOC) is uncommon, with an incidence of brain metastases ranging from 1–3% (Zumrut et al., 2020). Moreover, the treatment of brain metastases from ovarian carcinoma is currently ill-defined because of its rarity and the small affected population. The median survival after diagnosis of brain metastases was six months, meaning BMs mainly occurred while the patient was in stages III or VI of OC. Nevertheless, the median interval between diagnosis of ovarian carcinoma and consequent brain metastases is also quite long, approximately 2 years (Piura et al., 2011). However, neuro-cognition and quality of life across therapies are increasingly recognized as essential endpoints for patients as survival continues to increase. This paper is a comprehensive review of brain metastases from ovarian cancer, investigating tumour proliferation, metastatic mechanisms, the role of BRCA 1/2, and several therapy options, such as PARP inhibitors.

Distinct tumor architectures and microenvironments for the initiation of breast cancer metastasis in the brain

Brain metastasis, a serious complication of cancer, hinges on the initial survival, microenvironment adaptation, and outgrowth of disseminated cancer cells. To understand the early stages of brain colonization, we investigated two prevalent sources of cerebral relapse, triple-negative (TNBC) and HER2+ (HER2BC) breast cancers. Using mouse models and human tissue samples, we found that these tumor types colonize the brain, with a preference for distinctive tumor architectures, stromal interfaces, and autocrine programs. TNBC models tend to form perivascular sheaths with diffusive contact with astrocytes and microglia. In contrast, HER2BC models tend to form compact spheroids driven by autonomous tenascin C production, segregating stromal cells to the periphery. Single-cell transcriptomics of the tumor microenvironment revealed that these architectures evoke differential Alzheimer's disease-associated microglia (DAM) responses and engagement of the GAS6 receptor AXL. The spatial features of the two modes of brain colonization have relevance for leveraging the stroma to treat brain metastasis.

Multimodal radiomics-based methods using deep learning for prediction of brain metastasis in non-small cell lung cancer with 18F-FDG PET/CT images

Objective. Approximately 57% of non-small cell lung cancer (NSCLC) patients face a 20% risk of brain metastases (BMs). The delivery of drugs to the central nervous system is challenging because of the blood–brain barrier, leading to a relatively poor prognosis for patients with BMs. Therefore, early detection and treatment of BMs are highly important for improving patient prognosis. This study aimed to investigate the feasibility of a multimodal radiomics-based method using 3D neural networks trained on 18F-FDG PET/CT images to predict BMs in NSCLC patients. Approach. We included 226 NSCLC patients who underwent 18F-FDG PET/CT scans of areas, including the lung and brain, prior to EGFR-TKI therapy. Moreover, clinical data (age, sex, stage, etc) were collected and analyzed. Shallow lung features and deep lung-brain features were extracted using PyRadiomics and 3D neural networks, respectively. A support vector machine (SVM) was used to predict BMs. The receiver operating characteristic (ROC) curve and F1 score were used to assess BM prediction performance. Main result. The combination of shallow lung and shallow-deep lung-brain features demonstrated superior predictive performance (AUC = 0.96 ± 0.01). Shallow-deep lung-brain features exhibited strong significance (P < 0.001) and potential predictive performance (coefficient > 0.8). Moreover, BM prediction by age was significant (P < 0.05). Significance. Our approach enables the quantitative assessment of medical images and a deeper understanding of both superficial and deep tumor characteristics. This noninvasive method has the potential to identify BM-related features with statistical significance, thereby aiding in the development of targeted treatment plans for NSCLC patients.

Survival Analysis, Clinical Characteristics, and Predictors of Cerebral Metastases in Patients with Colorectal Cancer.

Colorectal cancer (CRC) is the third most common cancer globally and a leading cause of cancer-related deaths. While liver metastasis is common, brain metastasis (BM) is rare, occurring in 0.1% to 14% of cases. Risk factors for BM include lung metastasis at diagnosis, rectal cancer, and mutations in RAS and KRAS genes. Due to its rarity, guidelines for BM screening and treatment are limited. The aim of this study is to identify the clinical characteristics and predictors of BM at the time of the initial diagnosis of CRC. We evaluated patients ≥18 years old with metastatic colorectal cancer and brain metastases at diagnosis from the SEER database (2010-2021). A retrospective cohort study was conducted to analyze overall survival and predictive factors for brain metastasis, utilizing multivariate logistic regression, Kaplan-Meier survival analysis, and the Cox proportional hazards models, with p-values < 0.05 considered significant. Out of 24,703 patients with metastatic colorectal cancer (mCRC), 228 (0.92%) had brain metastasis (BM) at diagnosis. BM was more prevalent in average-onset mCRC (≥50 years) compared to early-onset (<50 years) (1% vs. 0.55%, p = 0.004). Certain factors, such as older age and adenocarcinoma subtype, were associated with BM. Additionally, Asians/Pacific-Islanders (HR 1.83 CI: 1.01-3-33, p = 0.045) and American Indians/Alaska Natives (HR 4.79 CI 1.15-19.97, p = 0.032) had higher mortality rates, while surgical treatment and chemotherapy were linked to decreased mortality. Patients with BM had significantly worse overall survival (6 months vs. 21 months, p < 0.001). BM in mCRC is uncommon, but it is associated with significantly worse outcomes, including markedly reduced overall survival. Our study highlights several critical factors associated with the presence of BM, such as older age and specific racial/ethnic groups, which may inform risk stratification and early-detection strategies. Our findings emphasize the need for heightened awareness and screening for BM in high-risk mCRC patients, as well as the inclusion of these patients in clinical trials to explore tailored therapeutic approaches aimed at improving survival and quality of life.

Enhancing outcomes in extensive-stage small cell lung cancer brain metastases: a retrospective study on the synergistic effects of immune checkpoint inhibitor, brain radiotherapy, and chemotherapy.

Brain metastasis is a frequent complication in small cell lung cancer (SCLC), and there is an urgent need for new treatment modalities, given the limited success of traditional approaches. This study evaluates the combined efficacy and safety of brain radiotherapy (BRT), chemotherapy, and immune checkpoint inhibitors (ICIs) in the treatment of brain metastases in patients with extensive-stage SCLC (ES-SCLC). Additionally, it seeks to identify prognostic factors in these cases. A retrospective analysis was performed on 187 patients with ES-SCLC and brain metastases treated at Zhejiang Cancer Hospital from January 2017 to October 2023. Patients were divided into three groups based on their initial treatment: BRT alone, ICI alone, and a combined ICI + BRT approach, with chemotherapy included in all regimens. Variables such as age, number of brain metastases, symptoms, comorbidities, Karnofsky Performance Status (KPS) scores, smoking history, Graded Prognostic Assessment (GPA) scores, survival time, and treatment-related adverse events (TRAEs), including hematologic and hepatic toxicities were evaluated. Prognostic factors were assessed using univariate and multivariate analyses via Cox's proportional hazards model. The study also compared outcomes and TRAEs between patients undergoing synchronous treatment (ICI and BRT within four weeks) versus those with asynchronous therapy (more than four weeks apart). Median overall survival (OS) times differed significantly across the groups: 11.6 months for BRT, 11.6 months for ICI, and 20.9 months for ICI + BRT (P<0.001). The ICI + BRT group also exhibited notably better progression-free survival (PFS) and intracranial PFS (iPFS), with medians of 12.6 and 14.9 months, respectively (P<0.001). This group demonstrated significantly improved systemic and intracranial objective response rates (ORR) and disease control rates (DCR). No significant differences in acute radiation injury rates were observed between the BRT and ICI + BRT groups. Multivariate analysis identified several factors influencing OS, including treatment regimen, number of chemotherapy and ICI cycles, presence of bone and multiple brain metastases, and antiangiogenesis therapies and extracranial radiotherapy. Both atezolizumab and serplulimab ICIs, in combination with various radiotherapy regimens [whole BRT (WBRT), WBRT with boost], were effective. Notably, asynchronous ICI and BRT treatment demonstrated advantages in PFS and iPFS over concurrent therapy, with no significant differences in other therapeutic indices or TRAE incidence rates. For ES-SCLC patients with synchronous brain metastases, combined ICI and BRT, alongside chemotherapy, surpasses the efficacy of either treatment alone with manageable TRAEs. Importantly, asynchronous ICI and BRT therapy showed superior outcomes compared to synchronous treatment modalities.

Role of Neurotropic Viruses in Brain Metastasis of Breast Cancer: Mechanisms and Therapeutic Implications.

Neurotropic viruses have been implicated in altering the central nervous system microenvironment and promoting brain metastasis of breast cancer through complex interactions involving viral entry mechanisms, modulation of the blood-brain barrier, immune evasion, and alteration of the tumour microenvironment. This narrative review explores the molecular mechanisms by which neurotropic viruses such as Herpes Simplex Virus, Human Immunodeficiency Virus, Japanese Encephalitis Virus, and Rabies Virus facilitate brain metastasis, focusing on their ability to disrupt blood-brain barrier integrity, modulate immune responses, and create a permissive environment for metastatic cell survival and growth within the central nervous system. Current therapeutic implications and challenges in targeting neurotropic viruses to prevent or treat brain metastasis are discussed, highlighting the need for innovative strategies and multidisciplinary approaches in virology, oncology, and immunology.

Successful pain control with add-on methadone for refractory neuropathic pain due to radiation necrosis in pontine metastatic lesion: a case report

BackgroundCentral pain, characterized by neuropathic pain, can manifest due to injury to the superior spinothalamic tract. The brainstem includes sensory and motor pathways as well as nuclei of the cranial nerves, and therefore cancer metastasis in the region requires early intervention. Although stereotactic radiosurgery (SRS) is commonly employed for the treatment of brain metastasis, it poses risks of late complications like radiation necrosis (RN). RN exacerbates the progression of brain lesions within the irradiated area, and in the brainstem, it can damage multiple nerves, including the superior spinothalamic tract. Central neuropathic pain is often intractable and empirically managed with a combination of conventional drugs, such as serotonin-norepinephrine reuptake inhibitors (SNRIs) and anticonvulsants. However, their efficacy is often limited, leading to a decline in performance status (PS) and quality of life (QOL).Case presentationWe present the case of a 53-year-old man diagnosed with stage IV lung cancer, referred to our palliative care team for managing severe central pain resulting from SRS-related RN in the pons. Despite administration of opioids, including oxycodone and hydromorphone, and adjuvant analgesics, the patient continued to require frequent use of immediate-release opioids. The addition of methadone alone proved successful in achieving optimal pain control.ConclusionsProvided that RN in the brainstem can lead to intractable neuropathic pain, it is advisable to avoid SRS for brainstem metastasis when possible. Add-on methadone should be considered as a viable pain management medication for patients experiencing unresolved central pain.

Gastric cancer and brain metastasis: A systematic review and meta‑analysis.

Gastric cancer (GC) constitutes one of the most wide-ranging cancers, with brain metastasis (BM) being a markedly uncommon and unfavorable outcome. The present meta-analysis evaluated the relationship between no-surgical treatment vs. additional surgical BM resection on the patient's quality of life and potential survival using electronic databases, including PubMed (1980-April 2024), Medline (1980-April 2024), Cochrane Library, and EMBASE (1980-April 2024). After a literature search, six articles were included in the final study pool. The number of patients with BM and conservative treatment was 289 (80.05%) compared with those that underwent an additional surgical resection 72 (19.95%). The mean age was 59.2 years, and the males were 195 (73.8%) of 264 available from five studies. The findings of the present meta-analysis revealed that the curative effect of BM tumor resection on patients with GC undergoing additional treatment with stereotactic radiosurgery, whole-brain radiotherapy or chemotherapy was favorable for their survival.

Comparative effectiveness of frame-based and mask-based Gamma Knife stereotactic radiosurgery in brain metastases: A 509 patient meta-analysis.

Stereotactic Radiosurgery (SRS) is the primary treatment for patients with limited numbers of small brain metastases. Head fixation is usually performed with framed-based (FB) fixation; however, mask-based (MB) fixation has emerged as a less invasive alternative. A comparative meta-analysis between both approaches has not been performed. Databases were searched until August 28th, 2023, to identify studies comparing MB and FB SRS in the treatment of brain metastases. Our outcomes of interest included local tumor control (LTC), radiation necrosis (RN), mortality, and treatment time (TT). Mean difference (MD), risk ratio (RR), and hazard ratio (HR) were used for statistical comparisons. From 295 articles initially identified, six studies (1 clinical trial) involving 509 patients were included. LTC revealed comparable RR at 6-months (RR = 0.95[95%CI = 0.89-1.01], p = 0.12) and a marginal benefit in FB SRS at 1-year (RR = 0.87[95%CI = 0.78-0.96], p = 0.005). However, in oligometastases exclusively treated with single-fraction SRS, LTC was similar among groups (RR = 0.92 [95%CI = 0.89-1.0], p = 0.30). Similarly, in patients with oligometastases treated with single-fraction SRS, RN (HR = 1.69; 95%CI = 0.72-3.97, p = 0.22), TT (MD = -29.64; 95%CI = -80.38-21.10, p = 0.25), and mortality were similar among groups (RR = 0.62; 95%CI = 0.22-1.76, p = 0.37). Our findings suggest that FB and MB SRS, particularly oligometastases treated with single-fraction, are comparable in terms of LTC, RN, TT, and mortality. Further research is essential to draw definitive conclusions.

Frameless stereotactic radiosurgery for brain metastasis: a systematic review and meta-analysis.

Stereotactic Radiosurgery (SRS) delivers a high dose of radiation to a specific brain area while limiting radiation to nearby healthy tissue. While most SRS has traditionally been performed with a stereotactic frame-based approach, this study aims to investigate the safety and efficacy of frameless radiosurgery in patients with brain metastases. Our study followed the recommended guidelines summarized in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist. The electronic databases of PubMed/Medline, Scopus, Embase, and Web of Science (WOS) were searched from inception to 10 October 2023. The pooled rate of outcomes was calculated using random effect model and Restricted maximum-likelihood (REML) method. All statistical analysis was performed by STATA V.17. A total of 499 studies were recruited from the electronic databases. After removing duplicates (n = 117), 382 studies were used for title/abstract, and 329 were removed from the study selection process. A total of 53 articles were used for full-text assessment, and 35 studies were included for data extraction. Our analysis revealed a significant increase across all pooled survival rates and local control rates by initiating the radiosurgery for patients, estimating the pooled 6-month OSR of 75% (95% CI: 68-81%), 1-year overall survival rate (OSR) of 60% (95% CI: 51-69%), 18-month OSR of 48% (95% CI: 10-85%), 2-year OSR of 39% (95% CI: 19-58%), 1-year progression-free survival rate (PFSR) of 68% (95% CI: 39-98%), 2-year PFSR of 75% (95% CI: 58-91%), 6-month local control rate (LCR) of 93% (95% CI: 90-96%), and 12-month LCR of 86% (95% CI: 82-90%). Our meta-analysis findings confirm the efficacy of frameless radiosurgery in treating brain metastases. Using data from several trials, we were able to demonstrate stereotactic radiosurgery's effectiveness as a therapy option for brain metastasis patients, demonstrating local control and reasonable overall survival.

Treatment Reproducibility in Brain Stereotactic Radiotherapy Using a Shim Mask Versus a Standard Mask.

Introduction This study aimed to evaluate the setup accuracy of the new shim mask with mouth bite compared to the standard full brain mask in stereotactic radiosurgery (SRS) and radiotherapy (SRT) treatments for brain metastases or tumors. Method A combined retrospective and prospective design was employed, involving 40 patients treated at our center. Patients previously treated using standard head masks formed the retrospective cohort, while those treated with the Shim mask and mouth bite formed the prospective cohort. Daily cone-beam computed tomography (CBCT) scans were obtained before each treatment session to ensure patient setup accuracy. Key metrics included absolute shifts in translational and rotational directions, the number of repeat CBCTs, and the time interval between CBCTs. Results The Shim mask significantly reduced the mean setup errors in the lateral translation (p=0.022) from 0.17 cm (SD=0.10) to 0.10 cm (SD=0.10), and in X-axis rotation (p=0.030) from 0.79° (SD=0.43) to 0.47° (SD=0.47). By considering cutoff points of 1 mm in translational and 1° in rotational directions, the Shim mask was significantly more accurate in the lateral direction (p=0.004). Moreover, while 70% of patients in the standard group required repeat CBCT scans, none in the Shim group did, resulting in an average time saving of 10.4 minutes per patient. Conclusion The Shim mask with mouth bite offers enhanced immobilization accuracy in SRT/SRS treatments, leading to time and potential cost savings by reducing the need for repeat CBCT scans. This underscores the importance of adopting innovative immobilization techniques to optimize patient outcomes.

MicroRNA-522-3p promotes brain metastasis in non-small cell lung cancer by targeting Tensin 1 and modulating blood-brain barrier permeability

Brain metastases account for more than 50 % of intracranial central nervous system tumors. The blood-brain barrier (BBB) is mainly composed of endothelial cells, which exhibit low endocytosis and high efflux pumps. Although they are connected by continuous tight junctions and serve as a protective insulation, the BBB does not prevent the development of brain metastases from non-small cell lung cancer (NSCLC). Improving understanding on the mechanisms underlying the development of brain metastasis and the differential molecular characteristics relative to the primary tumor are therefore key in the treatment of brain metastases. This study evaluated the differential expression of miR-522-3p in NSCLC and brain metastases using the Gene Expression Omnibus database. NSCLC brain metastasis model was constructed to screen for cell lines that demonstrated high potential for brain metastasis; We also observed differential expression of miRNA-522-3p in the paraffin-embedded specimens of non-small cell lung cancer and brain metastases from our hospital. The molecular biological functions of miRNA-522-3p were verified using 5-ethynyl-2′-deoxyuridine (EdU) proliferation assay and Transwell invasion assays. RNA-seq was employed to identify downstream target proteins, and the dual-luciferase reporter assay confirmed Tensin 1 (TNS1), a protein that links the actin cytoskeleton to the extracellular matrix, as the downstream regulatory target protein. In vitro blood-brain barrier models and co-culture models were constructed to further identify the role of miRNA-522-3p and TNS1; the expression of BBB-related proteins (ZO-1 and OLCN) was also identified. In vivo experiments were performed to verify the effects of miRNA-522-3p on the time and incidence of NSCLC brain metastasis. The results showed significantly high expression in GSE51666; consistent results were obtained in brain metastasis cells and paraffin samples. RNA-seq combined with miRNA target protein prediction demonstrated TNS1 to be directly downstream of miR-522-3p and to be associated with cell proliferation and invasion. By regulating ZO-1 and OCLN expression, mi-522-3p/TNS1 may increase tumor cell penetration through the BBB while decreasing its permeability. In vivo, miR-522-3p was further demonstrated to significantly promote the formation of brain metastases. miR-522-3p/TNS1 can affect BBB permeability and encourage the growth of brain metastases by modifying the BBB TJ proteins. This axis offers new therapeutic targets for the prevention of brain metastasis.

Surgically targeted radiation therapy versus stereotactic radiation therapy: A dosimetric comparison for brain metastasis resection cavities

BackgroundSurgically targeted radiation therapy (STaRT) with Cesium-131 seeds embedded in a collagen tile is a promising treatment for recurrent brain metastasis. In this study, the biological effective doses (BED) for normal and target tissues from STaRT plans were compared with those of external beam radiotherapy (EBRT) modalities. MethodsNine patients (n=9) with 12 resection cavities (RCs) who underwent STaRT (cumulative physical dose of 60 Gy to a depth of 5 mm from the RC edge) were replanned with CyberKnife® (CK), Gamma Knife® (GK), and intensity modulated proton therapy (IMPT) using an SRT approach (30 Gy in 5 fractions). Statistical significance comparing D95% and D90% in BED10Gy (BED10Gy95% and BED10Gy90%) and to RC + 0 to + 5 mm expansion margins, and parameters associated with radiation necrosis risk (V83Gy, V103Gy, V123Gy and V243Gy) to the normal brain were evaluated by a Wilcoxon-signed rank test. ResultsFor RC+0 mm, median BED10Gy90% for STaRT (90.1 Gy10, range: 64.1-140.9 Gy10) was significantly higher than CK (74.3 Gy10, range:59.3-80.4 Gy10, p=0.04), GK (69.4 Gy10, range: 59.8-77.1 Gy10, p=0.005), and IMPT (49.3 Gy10, range: 49.0-49.7 Gy10, p=0.003), respectively. However, for the RC+5 mm, the median BED10Gy90% for STaRT (34.1 Gy10, range: 22.2-59.7 Gy10) was significantly lower than CK (44.3 Gy10, range: 37.8-52.4 Gy10), and IMPT (46.6 Gy10, range: 45.1-48.5 Gy10), respectively but not significantly different from GK (34.1 Gy10, range: 22.8-47.0 Gy10). The median V243Gy was significantly higher in CK (11.7 cc, range: 4.7-20.1 cc), GK(6.2 cc, range: 2.3-11.9 cc) and IMPT (19.9 cc, range: 11.1-36.6 cc) compared to STaRT (1.1 cc, range: 0.0-7.8 cc) (p<0.01). ConclusionThis comparative analysis suggests the STaRT approach may treat recurrent brain tumors effectively via delivery of higher radiation doses with equivalent or greater BED up to at least 3 mm from the RC edge as compared to EBRT approaches.

Dosimetric comparison of ZAP-X, Gamma Knife, and CyberKnife stereotactic radiosurgery for single brain metastasis

PurposeTo evaluate the dosimetric characteristics of ZAP-X stereotactic radiosurgery (SRS) for single brain metastasis by comparing with two mature SRS platforms.MethodsThirteen patients with single brain metastasis treated with CyberKnife (CK) G4 were selected retrospectively. The prescription dose for the planning target volume (PTV) was 18–24 Gy for 1–3 fractions. The PTV volume ranged from 0.44 to 11.52 cc.Treatment plans of thirteen patients were replanned using the ZAP-X plan system and the Gamma Knife (GK) ICON plan system with the same prescription dose and organs at risk (OARs) constraints. The prescription dose of PTV was normalized to 70% for both ZAP-X and CK, while it was 50% for GK. The dosimetric parameters of three groups included the plan characteristics (CI, GI, GSI, beams, MUs, treatment time), PTV (D2, D95, D98, Dmin, Dmean, Coverage), brain tissue (volume of 100%-10% prescription dose irradiation V100%-V10%, Dmean) and other OARs (Dmax, Dmean),all of these were compared and evaluated. All data were read and analyzed with MIM Maestro. One-way ANOVA or a multisample Friedman rank sum test was performed, where p < 0.05 indicated significant differences.ResultsThe CI of GK was significantly lower than that of ZAP-X and CK. Regarding the mean value, ZAP-X had a lower GI and higher GSI, but there was no significant difference among the three groups. The MUs of ZAP-X were significantly lower than those of CK, and the mean value of the treatment time of ZAP-X was significantly shorter than that of CK. For PTV, the D95, D98, and target coverage of CK were higher, while the mean of Dmin of GK was significantly lower than that of CK and ZAP-X. For brain tissue, ZAP-X showed a smaller volume from V100% to V20%; the statistical results of V60% and V50% showed a difference between ZAP-X and GK, while the V40% and V30% showed a significant difference between ZAP-X and the other two groups; V10% and Dmean indicated that GK was better. Excluding the Dmax of the brainstem, right optic nerve and optic chiasm, the mean value of all other OARs was less than 1 Gy. For the brainstem, GK and ZAP-X had better protection, especially at the maximum dose.ConclusionFor the SRS treating single brain metastasis, all three treatment devices, ZAP-X system, CyberKnife G4 system, and GammaKnife system, could meet clinical treatment requirements. The newly platform ZAP-X could provide a high-quality plan equivalent to or even better than CyberKnife and Gamma Knife, with ZAP-X presenting a certain dose advantage, especially with a more conformal dose distribution and better protection for brain tissue. As the ZAP-X systems get continuous improvements and upgrades, they may become a new SRS platform for the treatment of brain metastasis.

Brachytherapy in Brain Metastasis Treatment: A Scoping Review of Advances in Techniques and Clinical Outcomes.

Brain metastases pose a significant therapeutic challenge in the field of oncology, necessitating treatments that effectively control disease progression while preserving neurological and cognitive functions. Among various interventions, brachytherapy, which involves the direct placement of radioactive sources into or near tumors or into the resected cavity, can play an important role in treatment. Current literature describes brachytherapy's capacity to deliver targeted, high-dose radiation while minimizing damage to adjacent healthy tissues-a crucial consideration in the choice of treatment modality. Furthermore, advancements in implantation techniques as well as in the development of different isotopes have expanded its efficacy and safety profile. This review delineates the contemporary applications of brachytherapy in managing brain metastases, examining its advantages, constraints, and associated clinical outcomes, and provides a comprehensive understanding of advances in the use of brachytherapy for brain metastasis treatment, with implications for improved patient outcomes and enhanced quality of life.