Occurrence Of Brain Metastases Research Articles

Prophylactic cranial irradiation for limited-stage small-cell lung cancer in the modern magnetic resonance imaging era may be omitted: a propensity score-matched analysis.

We aimed to clarify whether prophylactic cranial irradiation (PCI) is associated with improved outcomes in limited-stage small-cell lung cancer (LS-SCLC) in the current era of magnetic resonance imaging (MRI). Data from patients with LS-SCLC who achieved a complete response to definitive chemoradiotherapy (CRT) at two medical centers were retrospectively reviewed. Propensity score-matching was performed in a 2:1 ratio to balance the baseline characteristics of the no-PCI and PCI groups. The endpoints were the incidence of brain metastasis (BM), neurological causes of death and overall survival (OS). Overall, 80% patients underwent head MRI during the initial staging and 75 patients (no-PCI, n = 50; PCI, n = 25) were matched. Their baseline characteristics were generally well-balanced except for age; patients in the no-PCI group tended to be older. The median follow-up period was 29months. Although the incidence of BMs tended to be higher in the no-PCI group (1-year BM occurrence: 26% vs 17%, P = 0.22), the incidence of multiple BMs (defined as >4 metastases) was similar between groups (1-year multiple BMs occurrence: 8% vs 9%, P = 0.65). The 2-year neurological causes of death and OS rate did not significantly differ between the groups (6% and 9%; P = 0.85; and 70% and 79%; P = 0.36, respectively). The 1-year occurrence of multiple BMs did not increase, even without PCI, when modern imaging modalities were integrated into the initial diagnosis, suggesting that PCI could be omitted after CRT, if MRI was incorporated into the initial diagnosis and follow-up.

Clinical characteristics and prognosis of brain metastasis in locally advanced rectal cancer

Objective: To investigate the clinical characteristics of brain metastases after radical surgery for locally advanced rectal cancer (LARC). Methods: The clinical characteristics of LARC with brain metastases treated in the Department of General Surgery, Peking Union Medical College Hospital from 2013 to 2023 were retrospectively analyzed. The inclusion criteria were rectal adenocarcinoma within 15 cm of the anal verge and having undergone radical surgery, and the exclusion criterion was primary malignant tumor of the brain. The main outcomes were overall survival (OS), disease-free survival (DFS), and disease-specific overall survival (determined as the interval between occurrence of brain metastasis to death from any causes). The Kaplan-Meier method was used for survival analysis. Results: We identified 4500 patients with LARC, 20 (0.4%) of whom had brain metastases. The mean age of patients with brain metastases was 63.8±9.3 years. They comprised five women and 15 men. The brain was the first site of metastasis in four patients (20%) whereas 18 patients had heterochronous extracranial metastases before brain metastasis. Two patients also had multi-organ metastases. The most common manifestations of brain metastases were dizziness and headache (five patients, 25%), sudden onset of limb weakness (four, 20%), sudden speech impairment (two, 10%), and polyopia (two, 10%). The metastases were diagnosed during follow-up in three patients (15%). Four of the patients were asymptomatic (20%). Treatment approaches included surgical resection (six patients, 30%), chemoradiotherapy (nine, 45%), and palliative (five, 25%). The median follow-up time was 45.5 (4-112) months until October 2023. 1y-OS, 3y-OS, and 5y-OS were 95.0%, 62.9%, and 43.3%, respectively. 1y-DFS, 3y-DFS, and 5y-DFS were 55.0%, 25.0%, and 5.0%, respectively. With brain metastasis as the starting point, the median duration of survival was 16 (10.2-21.8) months. Conclusion: The incidence of brain metastasis is relatively low in patients with LARC, who often have multiple synchronous extracranial metastases. Brain metastases lack specific manifestations and more often occur in male patients. Surgical intervention or combined radiotherapy and chemotherapy may improve disease-specific survival to a certain extent. However, the overall prognosis remains poor.

A biomarker exploration in small-cell lung cancer for brain metastases risk and prophylactic cranial irradiation therapy efficacy

BackgroundSmall-cell lung cancer (SCLC) is an aggressive malignancy with a poor prognosis. Limited-stage (LS)-SCLC comprises only one-third of SCLC cases, resulting in limited molecularly targeted therapies and treatment options. Despite advances in thoracic and cranial irradiation leading to improved outcomes, a notable proportion of patients develop brain metastasis (BM), highlighting the importance of identifying high-risk patients for tailored screening and treatment strategies. Materials and MethodsWe analyzed baseline tumor biopsies from 180 LS-SCLC patients who received frontline definitive chemoradiotherapy (dCRT) using a 474-gene pan-cancer panel. The cumulative incidence of BM was calculated with death scored as a competing risk. Independent prognostic factors for BM risk were identified using the Fine-Gray model. ResultsAlterations in the cell cycle pathway, particularly RB1 mutations, were more common in patients with BM, while FLT4 mutations were more frequent in those without BM (P=0.002 and P=0.021, respectively). Significant risk factors for BM include smoking (subdistribution hazard ratio [SHR]: 1.73; 95 % confidence interval [CI]: 1.11–2.70; P=0.016), RB1 mutations (SHR: 2.19; 95 % CI: 1.27–3.81; P=0.005), and BCL3 amplification (SHR: 2.27; 95 % CI: 1.09–4.71; P=0.028). Conversely, prophylactic cranial irradiation (PCI) (SHR: 0.39; 95 % CI: 0.25–1.60; P<0.001), FLT4 mutations (SHR: 0.26; 95 % CI: 0.07–0.98; P=0.047), and NOTCH pathway alterations (SHR: 0.65; 95 % CI: 0.43–1.00; P=0.049) were associated with a lower incidence of BM in LS-SCLC. Notably, consolidation PCI therapy did not reduce the BM risk in patients with baseline RB1 mutations, with BM occurrence probabilities of 34.7 % at 20 months and 62.6 % at 40 months. ConclusionOur study yields valuable insights into the genetic characteristics of LS-SCLC patients with and without BM, aiding the development of personalized treatment strategies. Identifying risk factors associated with the incidence and timing of BM, within the standard regimen of dCRT followed by PCI, may help optimize clinical decision-making for LS-SCLC.

ITGB4 is a prognostic biomarker and correlated with lung adenocarcinoma brain metastasis.

The aim of this study is to explore the prognostic value and immune signature of ITGB4 expression in lung adenocarcinoma (LUAD) brain metastasis. We comprehensively screened genes associated with LUAD brain metastasis by integrating datasets from the GEO database and TMT-based quantitative proteomics profiles. Univariable survival and Multivariate Cox analysis was used to compare several clinical characteristics with survival, and a risk model was constructed. The biological functions were explored via GO and KEGG analysis. Gene set enrichment analysis (GSEA) was performed using the TCGA dataset. In addition, we use TIMER to explore the collection of ITGB4 Expression and Immune Infiltration Level in LUAD. The ability of ITGB4 to regulate tumor metastasis was further assessed by migration, invasion assay and Western-blot in H1975-BrM4 cells. We found that ITGB4 was the only gene with high clinical diagnostic and prognostic value in LUAD. Enrichment analysis indicated that ITGB4 is associated with brain metastasis, infiltration of immune cells, and the response to immunotherapy. ITGB4 expression can effectively predict the outcomes of patients with LUAD who are receiving anti-PD-1 therapy. ITGB4 knockdown inhibited the invasion, migration of H1975-BrM4 brain metastasis cells, as well as epithelial-mesenchymal transition (EMT) abilities. The heightened expression of ITGB4 protein was shown to promote EMT and enhance the metastatic potential. ITGB4 promotes the progression in H1975-BrM4 cells via MEK/ERK signaling pathway. Our findings indicate that the expression of ITGB4 is linked to the occurrence of brain metastasis and infiltration of immune cells, suggesting that ITGB4 might be a clinical treatment target for LUAD.

Abstract PO5-03-03: Nomogram for predicting brain metastasis in early-stage breast cancer patients

Abstract Nomogram for predicting brain metastasis in early-stage breast cancer patients Background: Brain metastasis is a significant concern for patients with early-stage breast cancer, as it can have a detrimental impact on survival and quality of life. Clinical and pathological characteristics of the primary tumor may be modeled into a nomogram that can predict the risk of brain metastasis. The goal is to create a nomogram and clinical calculator to assist in selection of patients with high risk of brain metastasis to enrich patient population for accrual on clinical trials for the purpose of preventing or delaying emergence of brain metastasis, at an early stage of their disease. Methods: We reviewed all early-stage breast cancer patients (stages I to III) N=40290 from the University of Texas MD Anderson Cancer Center, Houston, TX, from 1/1/1997 to 5/8/2020. We utilized multiple predictive statistical models to identify the most relevant variables and optimal predictive criteria. Variables for the model included patient age, tumor characteristics (such as grade,hormone receptor and HER2 status) and medical treatment (such as chemotherapy and endocrine therapy). The Receiver Operating Characteristic (ROC), and its AUC (area under the curve) was used to demonstrate the performance of the multivariate model to predict the occurrence of brain metastasis at different time points (1 year, 2 years, and 5 years), distinguishing between patients who develop brain metastasis in a time-dependent manner and those who do not. Results: The results showed the following clinical variables to be statistically significant in predicting brain metastasis: younger age, high estrogen and progesterone receptor percentage, higher tumor size; use of aromatase inhibitor therapy, and use of selective estrogen receptor modulator therapy were associated with a decreased risk of brain metastasis. Higher grade, Ki-67 levels, HER2-positive status, lymphovascular invasion and the use of chemotherapy was associated with an increased risk. The AUC values for the prediction of brain metastasis at different time points are as follows: 0.85 at 1 year, 0.83 at 2 years, and 0.82 at 5 years. These values indicate that the multivariate model has good discriminative ability, with higher values indicating a better predictive performance. An AUC of 0.85 suggests that the model has a high probability of correctly distinguishing between patients who will develop brain metastasis and those who will not at 1 year. Conclusions: Our predictive tool holds promise in assisting clinicians when making informed, personalized care decisions for patients at risk of developing brain metastasis. The model will be validated using independent patient cohorts from Institut Jules Bordet, Brussel, Belgium, to assess their accuracy and reproducibility. Continued research and validation will further refine these models, increasing their reliability and their clinical/clinical research applicability. Citation Format: Akshara Singareeka Raghavendra, Nuria Kotecki, Kristofer Jennings, Ottavia Amato, Debu Tripathy, Ahmad Awada, Nuhad Ibrahim. Nomogram for predicting brain metastasis in early-stage breast cancer patients [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-03-03.

Machine learning-driven prediction of brain metastasis in lung adenocarcinoma using miRNA profile and target gene pathway analysis of an mRNA dataset.

Brain metastasis (BM) is common in lung adenocarcinoma (LUAD) and has a poor prognosis, necessitating predictive biomarkers. MicroRNAs (MiRNAs) promote cancer cell growth, infiltration, and metastasis. However, the relationship between the miRNA expression profiles and BM occurrence in patients with LUAD remains unclear. We conducted an analysis to identify miRNAs in tissue samples that exhibited different expression levels between patients with and without BM. Using a machine learning approach, we confirmed whether the miRNA profile could be a predictive tool for BM. We performed pathway analysis of miRNA target genes using a matched mRNA dataset. We selected 25 miRNAs that consistently exhibited differential expression between the two groups of 32 samples. The 25-miRNA profile demonstrated a strong predictive potential for BM in both Group 1 and Group 2 and the entire dataset (area under the curve [AUC] = 0.918, accuracy = 0.875 in Group 1; AUC = 0.867, accuracy = 0.781 in Group 2; and AUC = 0.908, accuracy = 0.875 in the entire group). Patients predicted to have BM, based on the 25-miRNA profile, had lower survival rates. Target gene analysis of miRNAs suggested that BM could be induced through the ErbB signaling pathway, proteoglycans in cancer, and the focal adhesion pathway. Furthermore, patients predicted to have BM based on the 25-miRNA profile exhibited higher expression of the epithelial-mesenchymal transition signature, TWIST, and vimentin than those not predicted to have BM. Specifically, there was a correlation between EGFR mRNA levels and BM. This 25-miRNA profile may serve as a biomarker for predicting BM in patients with LUAD.

Plasma THBS1 as a predictive biomarker for poor prognosis and brain metastasis in patients with HER2-enriched breast cancer.

Thrombospondin-1 (THBS1) is a secretory adhesive glycoprotein involved in the progression of multiple malignancies, including breast cancer. However, the clinical significance and prognostic role of plasma THBS1 in breast cancer have yet to be clarified. Plasma THBS1 levels in 627 breast cancer patients were analyzed by enzyme-linked immunosorbent assay. Bone marrow blood was drawn from the anterior/posterior superior iliac spine to detect the presence of disseminated tumor cells (DTCs). The effects of plasma THBS1 on the clinicopathological characteristics and survival prediction of breast cancer patients were explored. Plasma THBS1 did not correlate with overall survival, breast cancer-specific survival (BCSS), and distant disease-free survival (DDFS) in the entire breast cancer cohort. Notably, HER2-enriched patients with high-plasma THBS1 levels had significantly shorter BCSS (P = 0.027) and DDFS (P = 0.011) than those with low levels. Multivariate analyses revealed that plasma THBS1 was an independent prognostic marker of BCSS (P = 0.026) and DDFS (P = 0.007) in HER2-enriched patients. THBS1 levels were 24% higher in positive DTC patients than in negative DTC patients (P = 0.031), and high levels were significantly associated with poor BCSS in positive DTC patients (HR 2.08, 95% CI 1.17-3.71; P = 0.019). Moreover, high-plasma THBS1 levels were specifically associated with an increased occurrence of brain metastasis in HER2-enriched patients (P = 0.041). These findings suggest that plasma THBS1 may be serving as an unfavorable prognosis predictor for HER2-enriched breast cancer and justifies the need for further research.

Primary versus acquired epidermal growth factor receptor Thr790Met mutant non-small cell lung cancer: clinical features and prognoses.

This study aimed to identify the impact of epidermal growth factor receptor (EGFR) T790M mutations on clinical characteristics and prognosis. Retrospective analyses were conducted on the differences on clinicopathological features and prognosis between primary and acquired T790M mutations. Subgroup analyses were performed for primary T790M coexisting with othermutations. Patients with primary T790M mutations showed a 60.53% (23/38) incidence of concurrent L858R mutations, 18.42% (7/38) for 19del mutations and a 21.05% (8/38) occurrence of brain metastases. Conversely, those with acquired T790M mutations demonstrated respective frequencies of 36.53% (61/167), 58.68% (98/167) and 44.31% (74/167), with all comparisons yielding p < 0.05. The median overall survival differed significantly between the two groups, with a duration of 33months for patients with primary T790M mutations as compared to 48months for those with acquired mutations (p = 0.030). Notably, among patients with L858R co-mutations, when treated with third-generation EGFR-TKIs, those with acquired T790M mutations experienced a significantly prolonged median time to treatment failure compared to those with primary mutations (17months vs. 9months, p = 0.009). Patients with primary T790M have unique molecular features and had worse prognosis compared with acquired T790M. Resistance to third-generation EGFR-TKIs seems to be associated with the presence of EGFR co-mutations.

Epithelial ovarian cancer and brain metastases: might the BRCA status, PARP inhibitor administration, and surgical treatment impact the survival?

ObjectiveTo evaluate disease characteristics and survival according to BRCA status, administration of poly-(ADP-ribose) polymerase inhibitors (PARPi), and surgery in patients with ovarian cancer and brain metastases.MethodsThis is a monocentric retrospective...

Prognostic Value of Baseline 18F-FDG PET/CT to Predict Brain Metastasis Development in Melanoma Patients.

To investigate the value of 18F-FDG-PET/CT in predicting the occurrence of brain metastases in melanoma patients, in this retrospective study 201 consecutive patients with pathology-proven melanoma, between 2008 and 2021, were reviewed. Those who underwent 18F-FDG-PET/CT for initial staging were considered eligible. Baseline assessment included histopathology, 18F-FDG-PET/CT, and brain MRI. Also, all patients had serial follow-ups for diagnosing brain metastasis development. Baseline 18F-FDG-PET/CT parameters were analysed using competing risk regression models to analyze their correlation with the occurrence of brain metastases. Overall, 159 patients entered the study. The median follow-up was six years. Among clinical variables, the initial M-stage and TNM-stage were significantly correlated with brain metastasis. Regarding 18F-FDG-PET/CT parameters, regional metastatic lymph node uptake values, as well as prominent SULmax (pSULmax) and prominent SUVmean (pSUVmean), were significantly correlated with the outcome. Cumulative incidences were 10% (6.3-16%), 31% (24.4-38.9%), and 35.2% (28.5-43.5%) after 1, 5, and 10 years. There were significant correlations between pSULmax (p-value < 0.001) and pSULpeak (p-value < 0.001) and the occurrence of brain metastases. The higher these values, the sooner the patient developed brain metastases. Thus, baseline 18F-FDG-PET/CT may have the potential to predict brain metastasis in melanoma patients. Those with high total metabolic activity should undergo follow-up/complementary evaluations, such as brain MRI.

A Correlative Study on EGFR Gene Mutation Status of Primary Lung Tumor and Brain Metastases in NSCLC

Objective: This study aims to explore the predictive role of EGFR gene mutation in the primary lung tumor on brain metastases in Non-Small Cell Lung Cancer (NSCLC). Methods: Morphological differences between EGFR gene 19 exon deletion mutant HCC827 and wild-type EGFR gene A549 human lung adenocarcinoma cells were observed under a microscope. The MTT method was employed to detect the proliferation differences between HCC827 and A549 cells. The Transwell in vitro cell invasion experiment was used to compare the invasion capabilities of the two cell lines. Furthermore, the Χ2 test was applied to analyze the relationship between the EGFR mutation in the primary lung tumor and the occurrence of brain metastases in 253 NSCLC patients. Results: A549 cells were smaller in size, resembling paving stones, whereas HCC827 cells were larger and polygonal. MTT analysis revealed that wild-type EGFR A549 human lung adenocarcinoma cells proliferated faster than EGFR mutant HCC827 cells, with a significant difference (P&lt;0.05). The Transwell in vitro cell invasion experiment indicated that HCC827 cells were significantly stronger than A549 cells (P&lt;0.05). The incidence of brain metastases in 253 NSCLC patients was 12.3% (31/253), among which eight cases had EGFR gene mutations in primary lung tumor, with a mutation rate of only 25.81% (8/31). No significant correlation was found between the occurrence of brain metastases and the mutation in primary lung tumor. Conclusion: EGFR gene mutation in NSCLC cells can significantly enhance their invasive activity. However, the correlation between EGFR gene mutation in primary lung tumor and the occurrence of brain metastases warrants further study.

Frequency of metastases within the hypothalamic–pituitary area and the associated high-risk factors in patients with brain metastases

ObjectiveBrain radiotherapy often results in impairment of hypothalamic–pituitary (HT-P) function, which in turn causes secretory dysfunction of related hormones. In this paper, the frequency of metastasis in the HT-P area and its high-risk factors in patients with brain metastasis were retrospectively analyzed, and thus provide experimental evidence for protecting HT-P area during whole brain radiotherapy (WBRT).MethodsA retrospective analysis was performed on the data of patients with brain metastasis diagnosed by cranial magnetic resonance imaging (MRI) at the First Hospital of Lanzhou University from 2017 to 2020. The anatomical positions of the hypothalamus and pituitary were delineated, followed by their expansion by 5 mm outwards, respectively, in the three-dimensional direction, and the hypothalamus +5 mm and pituitary +5 mm were obtained as the avoidance area, in which the frequency of brain metastasis was evaluated. Univariate and multivariate logistic regression models were used to analyze the high risk factors of brain metastasis in HT-P area.ResultsA total of 3,375 brain metastatic lesions from 411 patients were included in the analysis. The rates of brain metastasis in the hypothalamus +5 mm and pituitary +5 mm in the whole group of cases were 2.9% (12/411) and 1.5% (6/411) respectively; the frequency of lesions was 0.4% (13/3375) and 0.2% (6/3375) respectively. Univariate and multivariate analyses showed that the number of brain metastases (OR = 14.946; 95% CI = 4.071–54.880; p &amp;lt; 0.001), and the occurrence of brain metastasis in the pituitary (OR = 13.331; 95% CI = 1.511–117.620; p = 0.020) were related to brain metastasis in the hypothalamus, and that the only relevant factor for brain metastasis in the pituitary was the occurrence of that in the hypothalamus (OR = 0.069; 95% CI = 0.010–0.461; p = 0.006). There was no correlation between tumor pathological types, the maximum diameter, the total volume of brain metastatic lesions and the risk of brain metastasis in hypothalamus and pituitary.ConclusionThe frequency of brain metastasis in the HT-P area is extremely low. The risk of brain metastases in the hypothalamus is correlated with their number. The larger the number of metastatic lesions, the higher the frequency of brain metastasis. Protection of the HT-P area during WBRT may be unlikely to compromise the tumor recurrence rate for patients with a relatively small number of brain metastases.

The Impact of Time Interval on Prognosis in Patients with Non-Small Cell Lung Cancer Brain Metastases After Metastases Surgery

Non-small cell lung cancer (NSCLC) is a prominent malignancy often linked to the development of brain metastases (BM), which commonly appear at diverse time intervals (TI) following the lung cancer diagnosis. This study endeavors to determine the prognostic significance of the time interval in patients with NSCLC who undergo BM surgery. Through this investigation, we aim to improve our understanding of the factors impacting the prognosis of BM cases originating from NSCLC. We analyzed data from 74 patients (2011-2021) who underwent BM surgery at our institution. The relationship between various clinical, radiological, and histopathological factors, as well as TI and overall survival (OS), was examined. The median TI from initial NSCLC diagnosis to BM surgery was 19months (range: 9-36months). Notably, a shorter TI of less than 23months was found to be independently associated with postoperative survival (adjusted odds ratio [aOR] 2.87, 95% confidence interval [CI] 1.03-8.02, P= 0.045). Additionally, a shorter TI was independently correlated with the absence of adjuvant chemotherapy for NSCLC (aOR 0.25, 95% CI 0.07-0.83, P= 0.023) and lack of targeted therapy (aOR 0.02, 95% CI 0.00-0.16, P<0.001). Late-onset BM (TI≥36months) was observed in 15 cases (20.3%), in this subgroup, patients aged 60years or older at the time of lung cancer diagnosis exhibited a significant independent correlation with late-onset BM (aOR 7.24, 95% CI 1.59-32.95, P= 0.011). NSCLC patients who underwent adjuvant chemotherapy displayed a notable correlation with late-onset BM (aOR 6.46, 95% CI 1.52-27.43, P= 0.011), while those who received targeted therapy also exhibited an independent association (aOR 2.27, 95% CI 1.70-3.03, P < 0.001). Multiple factors contribute to the variability in the onset interval of BM subsequent to NSCLC diagnosis. The occurrence of BM within TI<23months following the initial diagnosis of NSCLC was demonstrated as an independent factor associated with an unfavorable prognosis following BM surgery. Furthermore, patients with NSCLC who did not receive adjuvant chemotherapy and lacked targeted therapy were shown to have an elevated likelihood of developing BM after a long progression-free survival.

Association between systemic treatment with immune checkpoint inhibitor therapy in renal cell carcinoma and reduced risk of brain metastasis development.

Immune checkpoint inhibitor (ICI) efficacy in the treatment of metastatic renal cell carcinoma (RCC) without brain metastases (BMs) is well established in several clinical trials; however, patients with BMs were typically excluded from these trials. Therefore, the efficacy of ICI in the treatment or prevention of BM remains unclear. The primary aim of the study was to address the efficacy of ICI in treatment of patients with RCC BMs compared with patients receiving targeted therapies. A secondary aim was to evaluate the risk of RCC BM development among patients who received ICI versus targeted therapies early in their treatment course. A retrospective single-center review between 2011 and 2018 identified 425 patients treated for metastatic RCC. The study group included patients who received ICI and/or targeted therapies during their disease. Data analyzed included demographic information, systemic treatments, overall survival from RCC diagnosis (OSRCC) and from BM diagnosis (OSBM), and BM development. Fisher's exact test was used to evaluate the frequency of BM occurrence. Survival was assessed using Kaplan-Meier curves and log-rank tests. Of the 425 patients, 125 received ICI and 300 were treated with molecular targeted agents only during their clinical course. BMs occurred in 113 (9.5%) of the 425 patients. Among patients with BMs, OSRCC was improved with the use of ICI (77.2 vs 25.2 months, p < 0.001), with 1-, 2-, and 5-year survival rates of 93.9%, 81.8%, and 62.6%, respectively. The use of ICI was associated with increased OSBM (21.7 vs 8.9 months, p = 0.001). The rate of BM development was lower when patients were treated with ICI (8/100 [8.0%]) compared with targeted therapy (47/267 [17.6%]) (OR 0.41, 95% CI 0.18-0.89; p = 0.021). ICI was associated with improved OSRCC and OSBM in patients with BMs and decreased the probability of BM development in patients with metastatic RCC. Prospective trials are needed to further evaluate optimal use of ICI in treatment of RCC BMs.

An Italian multicenter retrospective real-life analysis of patients with brain metastases from renal cell carcinoma: the BMRCC study

The treatment of patients with brain-spread renal cell carcinoma (RCC) is an unmet clinical need, although more recent therapeutic strategies have significantly improved RCC patients' life expectancy. Our multicenter, retrospective, observational study investigated a real-world cohort of patients with brain metastases (BM) from RCC (BMRCC). A total of 226 patients with histological diagnosis of RCC and radiological evidence of BM from 22 Italian institutions were enrolled. Univariate and multivariate models were performed to investigate the impact of clinicopathological features and multimodal treatments on both overall survival (OS) from the BM diagnosis and intracranial progression-free survival (iPFS). The median OS from the BM diagnosis was 18.8 months (interquartile range: 6.2-43 months). Multivariate analysis confirmed the following as positive independent prognostic factors: a Karnofsky Performance Status >70% [hazard ratio (HR)= 0.49, 95% confidence interval (CI) 0.26-0.92, P= 0.0026] and a single BM (HR= 0.51, 95% CI 0.31-0.86, P= 0. 0310); in contrast, the following were confirmed as worse prognosis factors: progressive extracranial disease (HR= 1.66, 95% CI 1.003-2.74, P= 0.00181) and only one line of systemic therapy after the BM occurrence (HR= 2.98, 95% CI 1.62-5.49, P= 0.029). Subgroup analyses showed no difference in iPFS according to the type of the first systemic treatment [immunotherapy (IT) or targeted therapy (TT)] carried out after the BM diagnosis (HR= 1.033, 95% CI 0.565-1.889, P= 0.16), and revealed that external radiation therapy (eRT) significantly prolonged iPFS when combined with IT (10.7 months, 95% CI 4.9-48 months, P= 0.0321) and not when combined with TT (9.01 months, 95% CI 2.7-21.2 months, P= 0.59). Our results suggest a potential additive effect in terms of iPFS for eRT combined with IT and encourage a more intensive multimodal therapeutic strategy in a multidisciplinary context to improve the survival of BMRCC patients.

A novel risk signature for predicting brain metastasis in patients with lung adenocarcinoma.

Brain metastasis (BM) are a devastating consequence of lung cancer. This study was aimed to screen risk factors for predicting BM. Using an in vivo BM preclinical model, we established a series of lung adenocarcinoma (LUAD) cell subpopulations with different metastatic ability. Quantitative proteomics analysis was used to screen and identify the differential protein expressing map among subpopulation cells. Q-PCR and Western-blot were used to validate the differential proteins in vitro. The candidate proteins were measured in LUAD tissue samples (n = 81) and validated in an independent TMA cohort (n = 64). A nomogram establishment was undertaken by performing multivariate logistic regression analysis. The quantitative proteomics analysis, qPCR and Western blot assay implied a five-gene signature that might be key proteins associated with BM. In multivariate analysis, the occurrence of BM was associated with age ≤ 65 years, high expressions of NES and ALDH6A1. The nomogram showed an area under the receiver operating characteristic curve (AUC) of 0.934 (95% CI, 0.881-0.988) in the training set. The validation set showed a good discrimination with an AUC of 0.719 (95% CI, 0.595-0.843). We have established a tool that is able to predict occurrence of BM in LUAD patients. Our model based on both clinical information and protein biomarkers will help to screen patient in high-risk population of BM, so as to facilitate preventive intervention in this part of the population.

Risk of brain metastases in metastatic non-small cell lung cancer without baseline brain metastasis: Pooled analysis of individualized patient data from three randomized clinical trials involving first-line atezolizumab treatment.

2032 Background: Data on the efficacy of immune checkpoint inhibitors on delaying or preventing the occurrence of brain metastases (BMs) in metastatic NSCLC without initial BMs is limited. We explored the benefit of first-line atezolizumab versus chemotherapy in the occurrence of BMs in patients without baseline BMs. Methods: Individual patient data from IMpower1301, IMpower131, and IMpower150 were pooled. All patients in the intention to treat population were analyzed. Primary endpoints included BM free survival (BMFS) and the cumulative incidence of BM. Patients without baseline BMs were categorized into two groups: patients who received treatment including atezolizumab (atezolizumab group) and patients who received comparator chemotherapies (chemotherapy group). Results: In 2543 patients without baseline BMs, 87 (3.4%) developed BM, including 58 (3.4%) and 29 (3.4%) in the atezolizumab group and the chemotherapy group, respectively. The median BMFS was 8.31 months (95% CI 7.79-8.67). The cumulative incidence of BM at 6 months, 12 months, and 24 months was 1.9%, 3.1%, and 3.8%, respectively. Compared to the chemotherapy group, BMFS was significantly improved in the atezolizumab group (8.6 months versus 7.3 months, p &lt; 0.001). After taking the competing risk events into account, no significant difference of the cumulative incidence of BM was observed between the two groups ( p = 0.671), suggesting that the significantly better BMFS in the atezolizumab group analyzed by Kaplan-Meier method should be due to the lower incidence of extracranial progression or death. Baseline bone metastasis and non-squamous NSCLC were identified as two risk factors for BM. Conclusions: In patients with NSCLC without baseline BMs, first-line atezolizumab improved BMFS but not the cumulative incidence of BM compared to chemotherapy, indicating that atezolizumab could not reduce the intrinsic risk of intracranial tumor spreading. [Table: see text]

Brain metastases in adult patients with melanoma of unknown primary in the Netherlands (2011–2020)

Although patients with melanoma of unknown primary (MUP) have a better prognosis than similar-staged melanoma patients with known primary, the occurrence of brain metastases (BM) entails a serious complication. This study provides an overview of the incidence, treatment patterns, and overall survival (OS) of adult patients with BM-MUP in the Netherlands. BM-MUP cases were retrieved fromthe Netherlands Cancer Registry. Patient, disease and treatment-related characteristics were summarised using descriptive statistics. Overall survival (OS) was calculated by the Kaplan-Meier method, and the impact of prognostic factors on OS was assessed using Cox proportional hazard regression analyses. Among 1779 MUP patients, 450 were identified as BM-MUP (25.3%). Of these patients, 381 (84.7%) presented with BM along with other metastases, while 69 (15.3%) had BM only. BM-MUP patients were predominantly male (68.2%), and had a median age of 64years at diagnosis (interquartile range 54-71years). Over time, the proportion of BM along other metastatic sites increased, and the occurrence of BM decreased (p = 0.01). 1-Year OS improved for the total population, from 30.0% (95% confidence interval (CI): 19.8-40.9%) in 2011-2012 to 43.6% (95%CI: 34.5-52.3%) in 2019-2020, and median OS more than doubled from 4.2months (95%CI: 3.3-6.2months) to 9.8months (95%CI: 7.0-13.2months). Patient's age, localisation of BM, presence of synchronous liver metastasis and treatment were identified as independent predictors of OS. Notwithstanding the progress made in OS for patients with BM-MUP in the past decade, their overall prognosis remains poor, and further efforts are needed to improve outcomes.

Extracellular vesicle-derived LINC00482 induces microglial M2 polarization to facilitate brain metastasis of NSCLC

Considering the crucial role of long non-coding RNAs (lncRNAs) in non-small cell lung cancer (NSCLC), we tried to analyze the role of extracellular vesicle (EV)-derived LINC00482 in the occurrence of brain metastasis in NSCLC. LINC00482 expression was quantified in EVs isolated from serum samples of NSCLC patients (serum-EVs). Ectopic expression and depletion assays were conducted in the microglial cell line HMC3 co-cultured with serum-EVs and in xenograft mouse models of NSCLC to explore the roles of EV-carried LINC00482. LINC00482 was enriched in serum-EVs and induced M2 polarization of microglial cells HMC3 in vitro. LINC00482 competitively bound to miR-142-3p and upregulated the expression of miR-142-3p target gene TGF-β1 in HMC3 cells, thus promoting microglial M2 polarization. EV-derived LINC00482-induced M2 microglia promoted the malignant properties of NSCLC cells. In vivo data demonstrated that EVs transmitted LINC00482 to regulate the miR-142-3p/TGF-β1 axis, induce microglial M2 polarization and affect the pre-metastatic niche, thus enhancing brain metastasis of NSCLC. Overall, suppression of the expression of tumor-derived LINC00482 or LINC00482-containing EVs, may serve as an effective target for contributing to the reduction of brain metastasis of NSCLC.

Survival after resection of brain metastasis: impact of synchronous versus metachronous metastatic disease

PurposePatients with brain metastasis (BM) from solid tumors are in an advanced stage of cancer. BM may occur during a known oncological disease (metachronous BM) or be the primary manifestation of previously unknown cancer (synchronous BM). The time of diagnosis might decisively impact patient prognosis and further treatment stratification. In the present study, we analyzed the prognostic impact of synchronous versus (vs.) metachronous BM occurrence following resection of BM.MethodsBetween 2013 and 2018, 353 patients had undergone surgical therapy for BM at the authors’ neuro-oncological center. Survival stratification calculated from the day of neurosurgical resection was performed for synchronous vs. metachronous BM diagnosis.ResultsNon-small-cell lung carcinoma (NSCLC) was the most common tumor entity of primary site (43%) followed by gastrointestinal cancer (14%) and breast cancer (13%). Synchronous BM occurrence was present in 116 of 353 patients (33%), metachronous BM occurrence was present in 237 of 353 patients (67%). NSCLC was significantly more often diagnosed via resection of the BM (56% synchronous vs. 44% metachronous situation, p = 0.0001). The median overall survival for patients with synchronous BM diagnosis was 12 months (95% confidence interval (CI) 7.5–16.5) compared to 13 months (95% CI 9.6–16.4) for patients with metachronous BM diagnosis (p = 0.97).ConclusionsThe present study indicates that time of BM diagnosis (synchronous vs. metachronous) does not significantly impact patient survival following surgical therapy of BM. These results suggest that the indication for neurosurgical BM resection should be made regardless of a synchronous or a metachronous time of BM occurrence.