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BACKGROUND: Adverse radiation effect (ARE) following stereotactic radiosurgery (SRS) for brain metastases is challenging to distinguish from tumor progression. This study characterizes the clinical implications of radiologic uncertainty (RU). METHODS: Cases reviewed retrospectively at a single-institutional, multi-disciplinary SRS Tumor Board between 2015-2022 for RU following SRS were identified. Treatment history, diagnostic or therapeutic interventions performed upon RU resolution, and development of neurologic deficits surrounding intervention were obtained from the medical record. Differences in lesion volume and maximum diameter at RU onset versus resolution were compared with paired t-tests. Median time from RU onset to resolution was estimated using the Kaplan-Meier method. Univariate and multivariate associations between clinical characteristics and time to RU resolution were assessed with Cox proportional-hazards regression. RESULTS: Among 128 lesions with RU, 23.5% had undergone ≥ 2 courses of radiation. Median maximum diameter (20 vs. 16 mm, p  6 and > 12 months in 25% and 7% of cases, respectively. Higher total EQD2 prior to RU onset (HR = 0.45, p = 0.03) and use of MR perfusion (HR = 0.56, p = 0.001) correlated with shorter time to resolution; larger volume (HR = 1.05, p = 0.006) portended longer time to resolution. Most lesions (57%) were diagnosed as ARE. Most patients (58%) underwent an intervention upon RU resolution; of these, 38% developed a neurologic deficit surrounding intervention. CONCLUSIONS: RU resolution took > 6 months in > 25% of cases. RU may lead to suboptimal outcomes and symptom burden. Improved characterization of post-SRS RU is needed.

Brain metastases present a formidable challenge in cancer management due to the infiltration of malignant cells from distant sites into the brain. Precise segmentation of brain metastases (BM) in medical imaging is vital for treatment planning and assessment. Leveraging deep learning techniques has shown promise in automating BM identification, facilitating faster and more accurate detection. This paper aims to develop an innovative novel deep learning model tailored for BM segmentation, addressing current approach limitations. Utilizing a comprehensive dataset of annotated magnetic resonance imaging (MRI) from Stanford University, the proposed model will undergo thorough evaluation using standard performance metrics. Comparative analysis with existing segmentation methods will highlight the superior performance and efficacy of our model. The anticipated outcome of this research is a highly accurate and efficient deep learning model for brain metastasis segmentation. Such a model holds potential to enhance treatment planning, monitoring, and ultimately improve patient care and clinical outcomes in managing brain metastases. [ABSTRACT FROM AUTHOR]

To improve immunotherapy for brain tumors, it is important to determine the principal intracranial site of T cell recruitment from the bloodstream and their intracranial route to brain tumors. Using intravital microscopy in mouse models of intracranial melanoma, we discovered that circulating T cells preferably adhered and extravasated at a distinct type of venous blood vessel in the tumor vicinity, peritumoral venous vessels (PVVs). Other vascular structures were excluded as alternative T cell routes to intracranial melanomas. Anti-PD-1/CTLA-4 immune checkpoint inhibitors increased intracranial T cell motility, facilitating migration from PVVs to the tumor and subsequently inhibiting intracranial tumor growth. The endothelial adhesion molecule ICAM-1 was particularly expressed on PVVs, and, in samples of human brain metastases, ICAM-1 positivity of PVV-like vessels correlated with intratumoral T cell infiltration. These findings uncover a distinct mechanism by which the immune system can access and control brain tumors and potentially influence other brain pathologies. [Display omitted] • PVVs are key structures for T cell recruitment to melanoma brain tumors • Anti-PD-1/CTLA-4 inhibitors boost T cell recruitment through PVVs • T cell recruitment and antitumor immunity is dependent on ICAM-1 expression on PVVs • ICAM-1 on PVVs correlates with T cell infiltration in human melanoma brain metastases How T cells are recruited to brain tumors from the blood remains unclear. Messmer et al. identify peritumoral venous vessels (PVVs) as key structures for T cell recruitment to melanoma brain tumors. PVVs are the sites of T cell extravasation and facilitated rapid T cell migration under immune checkpoint inhibition. T cell recruitment and antitumor immunity were dependent on ICAM-1. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Breast cancer remains a leading cause of brain metastases (BM), which carry a poor prognosis. The current approach to managing BMs in breast cancer patients involves a combination of local therapies (surgery, radiotherapy) and systemic treatments. Developing newer antibody–drug conjugates (ADCs) has sparked a revolution in metastatic breast cancer (MBC) care. ADCs such as ado-trastuzumab emtansine, trastuzumab deruxtecan, and sacituzumab govitecan have demonstrated significant improvement in patient outcomes and are standard of care in the treatment of MBC. Most of the ADC registration studies included patients with stable BMs but excluded individuals with active BM, making intracranial (IC) response assessment a challenge. Promising data has recently emerged, suggesting relevant IC activity for certain ADCs and ongoing studies in patients with active BM that will expand our knowledge. This review aims to summarize the effectiveness of approved ADCs as well as promising new ADCs in development for breast cancer with BM. [ABSTRACT FROM AUTHOR]

Background: Combining epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) with chemotherapy (ETC) offers more advantages for patients with EGFR-positive non-small cell lung cancer (NSCLC) than using EGFR TKIs alone (ET). However, whether this conclusion applies to patients with brain metastases (BM) remains controversial. This meta-analysis was performed to evaluate the benefits and risks of the two groups. Methods: Six databases were systematically searched for relevant literatures comparing ETC versus ET in treating EGFR-positive NSCLC patients with BM. The primary outcome assessed was overall survival (OS), while secondary outcomes included progression-free survival (PFS), and central nervous system (CNS)-PFS, responses, progression status and safety. Results: Seven studies based on five randomized clinical trials with 550 patients were included. The ETC group exhibited better OS (hazard ratio [HR]: 0.64 [0.48, 0.87]), PFS (HR: 0.42 [0.34, 0.52]), and CNS-PFS (HR: 0.42 [0.31, 0.57]). The benefits in survival for OS, PFS, and CNS-PFS were validated in nearly all subgroups. Meanwhile, the overall objective response rate (ORR) (risk ratio [RR]: 1.25 [1.02, 1.52]) and CNS-ORR (RR: 1.19 [0.93, 1.51]) also tended to favor the ETC group. However, the addition of chemotherapy also brought about more grade 3-5/serious adverse events (AEs). The top five grade 3-5 AEs in the ETC group were alanine aminotransferase increase (11.25%), neutropenia (7.5%), nausea (7.5%), anorexia (5%), and diarrhea (5%). Conclusions: ETC appears to be better than ET in treating EGFR-positive NSCLC patients with BM, with better OS, PFS, CNS-PFS, and responses. However, its poorer safety profile also needs to be taken into consideration. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024551073. [ABSTRACT FROM AUTHOR]

Surgically 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. Nine 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 BED 10Gy (BED 10Gy 95% and BED 10Gy 90%) and to RC + 0 to + 5 mm expansion margins, and parameters associated with radiation necrosis risk (V8 3Gy , V10 3Gy , V12 3Gy and V24 3Gy) to the normal brain were evaluated by a Wilcoxon-signed rank test. For RC + 0 mm, median BED 10Gy 90% for STaRT (90.1 Gy 10 , range: 64.1–140.9 Gy 10) was significantly higher than CK (74.3 Gy 10 , range:59.3–80.4 Gy 10 , p = 0.04), GK (69.4 Gy 10 , range: 59.8–77.1 Gy 10 , p = 0.005), and IMPT (49.3 Gy 10 , range: 49.0–49.7 Gy 10 , p = 0.003), respectively. However, for the RC + 5 mm, the median BED 10Gy 90% for STaRT (34.1 Gy 10 , range: 22.2–59.7 Gy 10) was significantly lower than CK (44.3 Gy 10 , range: 37.8–52.4 Gy 10), and IMPT (46.6 Gy 10 , range: 45.1–48.5 Gy 10), respectively, but not significantly different from GK (34.1 Gy 10 , range: 22.8–47.0 Gy 10). The median V24 3Gy 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). This comparative analysis suggests a 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. [ABSTRACT FROM AUTHOR]

Traditionally, postoperative whole-brain radiation therapy (WBRT) has been used for resected brain metastases, reducing local and intracerebral relapses. However, WBRT is associated with cognitive deterioration. Postoperative stereotactic radiotherapy (SRT) has emerged due to its neurocognitive preservation benefits. Despite its advantages, postoperative SRT has several drawbacks, including difficulties in target volume delineation, increased risk of radionecrosis (RN) and leptomeningeal disease (LMD), and prolonged treatment duration. Preoperative SRT has been proposed as a potential alternative, offering promising results in retrospective studies. Retrospective studies have suggested that preoperative SRT could achieve high local control rates with fewer LMD and RN rates compared to postoperative SRT. However, preoperative SRT is primarily based on retrospective data, and no phase 2/3 trials have been published to date. Ongoing clinical trials are expected to provide further insights into the efficacy and safety of preoperative SRT, addressing key questions regarding fractionation, dose, and timing relative to surgery. [ABSTRACT FROM AUTHOR]

Leptomeningeal melanoma metastases (LMM) are associated with poor survival. Diagnosis is based on clinical presentation, brain MRI and cerebrospinal fluid (CSF) analysis. Inconclusive findings at initial presentation can delay treatment. In this single‐center case series, detection of BRAFV600‐ and NRASQ61‐mutant cell‐free tumor DNA (cfDNA) in CSF was evaluated as a complementary diagnostic biomarker. In 12 patients with clinical suspicion of LMM, a retrospective analysis of MRI, CSF cytology and cfDNA analysis on 1 mL of CSF using the Idylla® platform was carried out. Nine patients displayed MRI abnormalities suggesting LMM. CSF analysis identified malignant cells in three patients (including one without MRI abnormalities). BRAFV600‐ or NRASQ61‐mutant cfDNA was detected in CSF of nine patients (eight with and one without MRI abnormalities; all patients with positive CSF cytology). Subsequent follow‐up confirmed LMM in all patients with positive and in one patient with a negative CSF cfDNA analysis (sensitivity 81.8%; specificity 100%). Our findings suggest that analyzing BRAFV600‐ and NRASQ61‐mutant cfDNA in CSF using the Idylla® platform holds promise as a sensitive and specific complementary diagnostic biomarker for LMM, particularly in case of inconsistency between imaging and CSF cytology. The 110‐min analysis can facilitate urgent treatment decisions. [ABSTRACT FROM AUTHOR]

Leptomeningeal disease (LMD) is a devastating complication of melanoma with a dismal prognosis. We present the case of a young man with stage IV BRAF V600E mutant melanoma with lung, lymph node, and brain metastases initially treated with ipilimumab and nivolumab, who subsequently developed LMD. Upon change to BRAF/MEK targeted therapy with nivolumab, a durable complete response was achieved and remains ongoing, off treatment, 7 years from diagnosis. Management of symptomatic LMD remains a critical unmet clinical challenge, with limited clinical trial data. This exceptional case is instructive, as the first published case of the use of the triplet, and the first durable response with therapy discontinuation, in melanoma LMD. The triple‐drug regimen may be considered a viable option in fit patients. This case highlights the potential for long‐term disease control and the critical and urgent need to develop clinical trials inclusive of patients with LMD to define the best treatment strategies. [ABSTRACT FROM AUTHOR]

Treatment options for human epidermal growth factor receptor 2 (HER2)-positive breast cancer brain metastases (BCBMs) remain limited. We previously reported central nervous system (CNS) activity for neratinib and neratinib–capecitabine. Preclinical data suggest that neratinib may overcome resistance to ado-trastuzumab emtansine (T-DM1) when given in combination. In Translational Breast Cancer Research Consortium (TBCRC) 022's cohort 4, we examined the efficacy of neratinib plus T-DM1 in patients with HER2-positive BCBM. In this multicenter, phase II study, patients with measurable HER2-positive BCBM received neratinib 160 mg daily plus T-DM1 3.6 mg/kg intravenously every 21 days in three parallel-enrolling cohorts [cohort 4A—previously untreated BCBM, cohorts 4B and 4C—BCBM progressing after local CNS-directed therapy without (4B) and with (4C) prior exposure to T-DM1]. Cycle 1 diarrheal prophylaxis was required. The primary endpoint was the Response Assessment in Neuro-Oncology-Brain Metastases (RANO-BM) by cohort. The overall survival (OS) and toxicity were also assessed. Between 2018 and 2021, 6, 17, and 21 patients enrolled in cohorts 4A, 4B, and 4C. Enrollment was stopped prematurely for slow accrual. The CNS objective response rate in cohorts 4A, 4B, and 4C was 33.3% [95% confidence interval (CI) 4.3% to 77.7%], 35.3% (95% CI 14.2% to 61.7%), and 28.6% (95% CI 11.3% to 52.2%), respectively; 38.1%-50% experienced stable disease for ≥6 months or response. Diarrhea was the most common grade 3 toxicity (22.7%). The median OS was 30.2 [cohort 4A; 95% CI 21.9-not reached (NR)], 23.3 (cohort 4B; 95% CI 17.6-NR), and 20.9 (cohort 4C; 95% CI 14.9-NR) months. We observed intracranial activity for neratinib plus T-DM1, including those with prior T-DM1 exposure, suggesting synergistic effects with neratinib. Our data provide additional evidence for neratinib-based combinations in patients with HER2-positive BCBM, even those who are heavily pretreated. • T-DM1–neratinib is active for HER2+ BCBMs (radiation-naive, heavily pretreated, and T-DM1 exposed). • Approximately one-third of participants experienced a CNS partial response. • 38.1%-50.0% across study cohorts experienced stable disease for ≥6 months or response. • Our data provide further evidence for neratinib-based combinations for HER2+ BCBMs. • We believe this is the first trial to examine the activity of a T-DM1-inclusive combination after progression on T-DM1. [ABSTRACT FROM AUTHOR]

Many chemotherapeutic and molecular targeted drugs have been used to treat brain metastases, e.g. , anti-angiogenic vandetanib. However, the blood-brain barrier and brain-specific resistance mechanisms make these systemic therapeutic approaches inefficacious. Brain metastatic cancer cells could mimic neurons to upregulate multiple serpins and secrete them into the extracellular environment to reduce local plasmin production to promote L1CAM-mediated vessel co-option and resist anti-angiogenesis therapy. Here, we developed brain-tumor-seeking and serpin-inhibiting outer membrane vesicles (DE@OMVs) to traverse across the blood-brain barrier, bypass neurons, and specially enter metastatic cancer cells via targeting GRP94 and vimentin. Through specific delivery of dexamethasone and embelin, reduced serpin secretion, restored plasmin production, significant L1CAM inactivation and tumor cell apoptosis were specially found in intracranial metastatic regions, leading to delayed tumor growth and prolonged survival in mice with brain metastases. By combining the brain-tumor-seeking properties with the regulation of the serpin/plasminogen activator/plasmin/L1CAM axis, this study provides a potent and highly-selective systemic therapeutic option for brain metastases. [Display omitted] • Serpin secretion reduces brain interstitial plasmin to promote brain metastases. • L1CAM expression mediates tumor vessel co-option to resist anti-angiogenic therapy. • OMV-inspired nanocarriers cross the BBB and specially enter brain metastases. • Nanocarriers reduce serpin secretion to promote local plasmin production. • Restored plasmin degrades L1CAM and induces paracrine tumor apoptosis for therapy. [ABSTRACT FROM AUTHOR]

Purpose: To study survival outcomes and prognostic factors in patients undergoing whole brain radiation therapy (WBRT) for brain metastases in the contemporary setting. Methods: Patients undergoing WBRT from 2013–2021 were retrospectively included in an ethics-approved institutional database. Patient and treatment characteristics were assessed, including patient age, primary tumor histology, Karnofsky Performance Status (KPS), extracranial disease, as well as WBRT dose. Overall survival (OS) was calculated from onset of WBRT using the Kaplan-Meier method. Results: A total of 328 patients (median age 63 years) were included. Most patients (52%) had ≥ 10 brain metastases, and 17% had leptomeningeal disease. WBRT was delivered with 10 × 3 Gy (64%), 5 × 4 Gy (25%), or other regimens (11%). Median follow-up was 4.4 months (range, 0.1–154.3), and median OS was 4.7 months (95%CI, 3.8–6.0). OS differed between histologies (p = 0.01), with the longest survival seen in breast cancer (median 7.7 months). Patients with KPS of 90–100 survived for a median of 8.3 months, compared to 4.1 months with KPS 70–80, and 1.7 months with KPS < 70 (p < 0.01). Multivariate analyses revealed that KPS had the largest impact on survival. Patients who received a WBRT dose of ≥ 30 Gy also had a reduced risk of death (HR 0.45; p < 0.001). Survival differed between subgroups reclassified according to the Rades scoring system (p < 0.01). Conclusion: Survival outcomes of patients undergoing WBRT in the contemporary era appear comparable to historical cohorts, although individual patient factors need to be considered. Patients with otherwise favorable prognostic factors may benefit from longer-course WBRT. [ABSTRACT FROM AUTHOR]

Background: Local recurrent brain metastases are defined as lesions that recur in the brain at the same site after a previous local therapy. In patients already submitted to surgery, a second operation may be potentially challenging due to scar formation, infiltration of cerebral vessels or eloquent brain areas and local effect of previous radiotherapy. The aim of this study is to retrospectively review the results and complications of a second surgical treatment in a series of local recurrent lesions and to review the literature on this topic. Methods: 37 patients submitted to surgery for a local, histologically confirmed, recurrent brain metastases between 2000 and 2022 were retrospectively analyzed with respect to the following parameters: age, histology, anatomic location, time to recurrence, previous radiotherapy, size of recurrent tumors, preoperative and postoperative Karnofsky Performance Status (KPS) score, recursive partitioning analysis (RPA) class and graded prognostic assessment (GPA) score, surgery-related complications and the presence of further cerebral metastases. Overall survival (OS) was calculated using the Kaplan-Meier method. A multivariate Cox proportional hazard model was developed using stepwise regression (forwards selection) with predictive variables that were significant in the univariate analyses. Results: A significant improvement of post-operative KPS status was obtained after second surgery. At multivariate analysis better results in terms of OS were achieved in patients with a pre-operative KPS ≥ 70 and in patients who had received radiotherapy after the initial surgery. No significant postoperative complications related to previous treatments were observed. Conclusions: Surgical resection of local recurrent brain metastases may improve patients ́ neurologic conditions allowing more time for systemic therapies to act with a low incidence of surgery-related morbidity and mortality. However, careful patient selection with a fair pre-operative clinical status seems mandatory to achieve the best post-operative results, since uniform treatment-paradigms cannot be established yet, due to the highly heterogeneous patient cohort. [ABSTRACT FROM AUTHOR]

Background: Among several treatment options for BRAF-mutant metastatic melanoma, a combination of BRAF inhibitor, MEK inhibitor, and anti-PDL1 antibody seems to be a new emergent approach recently registered in the Russian Federation. It is still not clear which patient population benefits more from this simultaneous use of three drugs instead of its sequencing. Aim: This study aimed to evaluate patients' characteristics treated in real practice in 14 Russian regions by triple combination and to analyze their outcomes depending on biomarkers (PD-L1 expression). Methods: This was a part (cohort A1) of a prospective non-interventional study of clinical outcomes and biomarkers in patients with skin melanoma. Patients were included in cohort A1 if combination treatment with vemurafenib (vem) + cobimetinib (cobi) + atezolizumab (atezo) was initiated no earlier than 12 weeks (84 days) prior to written informed consent to participate in this study. The index event was the initiation of therapy with all three drugs vem + cobi + atezo (i.e., triple combination). The primary efficacy endpoint of the study was the 24-month overall survival (OS), defined as the time from the index date to the date of death from any cause. If the patient did not experience an event, the OS will be censored at the date of the last contact. Objective response rate (ORR), duration of response (DoR), and progression-free survival (PFS) in the Intention to treat (ITT) population, in biomarker positive population, and in population with brain metastases were also evaluated. Quality of life questionnaires were pre-planned by protocol if it was a part of routine practice. Adverse events were also collected. Results: Between March 2021 and May 2023, 59 patients were enrolled in 19 centers from 14 regions of Russia. Thirty-one of 59 (52.4%) patients had central nervous system metastases, and 18 of 31 (58.4%) were symptomatic. Forty of 59 patients (68%) received the triple combination as the first-line treatment. The median follow-up period was 16.83 [95% confidence interval (CI) 13.8-19.8] months. The mean duration of therapy with this regimen was 9.95 months (95% CI 7.48-13.8). ORR was 55.1%; progression as the best outcome was seen in 16.3%. The median DoR was 12.95 months (95% CI 11.0-14.8 months), with a median of 20.3 months (95% CI 9.1-31.5 months) when triple therapy was administered in the first-line treatment. In patients with brain metastases (N = 31), ORR was 45.1%; the median DoR was 12.95 (95% CI 11.0-14.8 months). The median PFS in the entire population was 13.6 months (95% CI 8.6-18.6); the 24-month PFS was 22%. The estimated median OS in the entire population was 15.8 months (95% CI NA); 24-month OS was 45% (95% CI 0.32-0.64). In multivariate Cox regression model, biomarkers of interest [lactate dehydrogenase, Programmed cell death ligand-1 (PD-L1)] did not have statistically significant impact on PFS, OS, or DoR probably due to high data missing rate. No unexpected adverse events were reported. Grades 3-4 AEs were seen in 23 of 59 patients (38%) with most common were skin and liver toxicity. Conclusion: Triple combination of atezolizumab, vemurafenib, and cobimetinib had proven its efficacy and tolerability in real settings. No impact of potential predictive biomarkers was seen (NCT05402059). [ABSTRACT FROM AUTHOR]

Background: The anti-angiogenic agent anlotinib offers a new treatment option for triple-negative breast cancer (TNBC) patients with brain metastases. This study aimed to evaluate the efficacy and safety of anlotinib in the treatment of TNBC patients with brain metastases. Methods: Between October 2019 and April 2024, 29 TNBC patients with brain metastases who had failed prior therapy and were treated with anlotinib were retrospectively analyzed. The primary endpoint was central nervous system (CNS) progression-free survival (PFS), and secondary endpoints included overall survival (OS), intracranial disease control rate (iDCR), intracranial objective response rate (iORR), and safety. Results: The median CNS PFS of 29 patients was 7.2 months (95% confidence interval [CI], 3.5-10.9 months), and the median OS was 10.2 months (95% CI, 5.6-14.8 months). The iORR and iDCR were 31.0% and 86.2%, respectively. Five patients (17.2%) experienced grade 3-4 adverse events (AEs), with bone marrow suppression (2/29, 6.9%) being the most common. Most AEs were clinically manageable, and no treatment-related death was observed. Conclusion: Anlotinib demonstrated encouraging efficacy and manageable toxicity in the treatment of TNBC patients with brain metastases who had failed standard treatment. [ABSTRACT FROM AUTHOR]

Objective: This study aims to evaluate the effectiveness of a nomogram model constructed using Diffusion Kurtosis Imaging (DKI) and 3D Arterial Spin Labeling (3D-ASL) functional imaging techniques in distinguishing between cerebral alveolar echinococcosis (CAE) and brain metastases (BM). Methods: Prospectively collected were 24 cases (86 lesions) of patients diagnosed with CAE and 16 cases (69 lesions) of patients diagnosed with BM at the affiliated hospital of Qinghai University from 2018 to 2023, confirmed either pathologically or through comprehensive diagnosis. Both patient groups underwent DKI and 3D-ASL scanning. DKI parameters (Kmean, Dmean, FA, ADC) and cerebral blood flow (CBF) were analyzed for the parenchymal area, edema area, and symmetrical normal brain tissue area in both groups. There were 155 lesions in total in the two groups of patients. We used SPSS to randomly select 70% as the training set (108 lesions) and the remaining 30% as the test set (47 lesions) and performed a difference analysis between the two groups. The independent factors distinguishing CAE from BM were identified using univariate and multivariate logistic regression analyses. Based on these factors, a diagnostic model was constructed and expressed as a nomogram. Result: Univariate and multivariate logistic regression analyses identified nDmean1 and nCBF1 in the lesion parenchyma area, as well as nKmean2 and nDmean2 in the edema area, as independent factors for distinguishing CAE from BM. The model's performance, measured by the area under the ROC curve (AUC), had values of 0.942 and 0.989 for the training and test sets, respectively. Calibration curves demonstrated that the predicted probabilities were highly consistent with the actual values, and DCA confirmed the model's high clinical utility. Conclusion: The nomogram model, which incorporates DKI and 3D-ASL functional imaging, effectively distinguishes CAE from BM. It offers an intuitive, accurate, and non-invasive method for differentiation, thus providing valuable guidance for subsequent clinical decisions. [ABSTRACT FROM AUTHOR]

Simple Summary: Incidence of brain metastases from genito-urinary cancers has increased over the last years due to improved imaging techniques and better survival outcomes for patients even at an advanced metastatic stage thanks to therapeutic advances. However, no clear consensus exists on their management, and every case ought to be discussed in a multidisciplinary panel. We perform a single-centre retrospective study to report on incidence, patient demographics, clinicopathological characteristics, and treatment modalities. We also manage to identify predictive factors of outcome. Background: Incidence of brain metastases is precisely unknown and there is no clear consensus on their management. We aimed to determine the incidence of brain metastases among patients with genito-urinary primaries, present patients' characteristics and identify prognostic factors. Method: We identified 51 patients treated in Geneva University Hospitals between January 1992 and December 2019. We retrospectively correlated their overall survival with 23 variables. We repeated a multivariate analysis with significant variables. Results: Overall incidence of Brain Metastases (BMs) among Genito-Urinary (GU) patients is estimated to be 1.76% (range per primary GU tumour type: 0.00–6.65%). BMs originate from germ cell tumours in two cases (3.92%), from urothelial cell carcinoma in 15 cases (29.41%), from prostate cancer in 13 cases (25.49%), and from renal cell carcinoma in 21 cases (41.18%); there are no BMs from penile cancer in our cohort. The median age at BM diagnosis is 67 years old (range: 25–92). Most patients (54%) have a stage IV disease at initial diagnosis and 11 patients (22%) have BM at initial diagnosis. Only six patients (12%) are asymptomatic at BM diagnosis. The median Overall Survival (OS) from BM diagnosis is 3 months (range: 0–127). Five patients (10%) are long survivors (OS > 24 months). OS is significantly influenced by patient performance status and administration of systemic treatment. In the absence of meningeal carcinomatosis, OS is influenced by systemic treatment and stereotactic radiosurgery. We also apply the Graded Prognostic Assessment (GPA) score to our cohort and note significant differences between groups. Conclusion: Brain metastases from solid tumours is not a uniform disease, with a prognosis varying a lot among patients. The optimal management for patients with genito-urinary malignancies with brain metastases remain unclear and further research is needed. [ABSTRACT FROM AUTHOR]

Brain metastases (BMs) are the most frequent tumors of the central nervous system. Diffusion tensor imaging (DTI) is a magnetic resonance imaging technique that provides insights into brain microstructural alterations and tensor metrics and generates tractography to visualize white matter fiber tracts based on diffusion directionality. This systematic review assessed evidence from DTI biomarker alterations in BMs and comparable tumors such as glioblastoma. PubMed, Scopus, and Web of Science were searched, and published between January 2000 and August 2023. The key inclusion criteria were studies reporting DTI metrics in BMs and comparisons with other tumors. Data on study characteristics, tumor types, sample details, and main DTI findings were extracted. Fifty-seven studies with 1592 BM patients and 1578 comparable brain tumors were included. Peritumoral fractional anisotropy (FA) consistently differentiates BMs from primary brain tumors, whereas intratumoral FA shows limited discriminatory power. Mean diffusivity increased in BMs versus comparators. Intratumoral metrics were less consistent but revealed differences in BM origin. Axial and radial diffusivity have provided insights into the effects of radiation, tumor origin, and infiltration. Axial diffusivity/radial diffusivity differentiated tumor infiltration from vasogenic edema. Tractography revealed anatomical relationships between white matter tracts and BMs. In addition, tractography-guided BM surgery and radiotherapy planning are required. Machine learning models incorporating DTI biomarkers/metrics accurately classified BMs versus comparators and improved diagnostic classification. DTI metrics provide noninvasive biomarkers for distinguishing BMs from other tumors and predicting outcomes. Key metrics included peritumoral FA and mean diffusivity. [ABSTRACT FROM AUTHOR]

Simple Summary: Each patient responds uniquely to treatment, which makes personalized ultra-fractionated stereotactic adaptive radiotherapy (PULSAR) a promising strategy that delivers high-dose radiation at extended intervals for tailored adaptation. Currently, treatment modifications mainly rely on physicians' assessments of tumor size changes. Our study aims to develop a more objective multiomics-based approach for predicting treatment outcomes in PULSAR, including radiomics, dosiomics, and delta features. By leveraging multiomics analysis and machine learning, we intend to transition the adaptation and decision-making process from empirical judgments to a more data-informed strategy, allowing clinicians to swiftly respond to changes in tumor behavior and provide more personalized treatment for each patient. Objectives: This retrospective study aims to develop a multiomics approach that integrates radiomics, dosiomics, and delta features to predict treatment responses in brain metastasis (BM) patients undergoing PULSAR. Methods: A retrospective study encompassing 39 BM patients with 69 lesions treated with PULSAR was undertaken. Radiomics, dosiomics, and delta features were extracted from both pre-treatment and intra-treatment MRI scans alongside dose distributions. Six individual models, alongside an ensemble feature selection (EFS) model, were evaluated. The classification task focused on distinguishing between two lesion groups based on whether they exhibited a volume reduction of more than 20% at follow-up. Performance metrics, including sensitivity, specificity, accuracy, precision, F1 score, and the area under the receiver operating characteristic (ROC) curve (AUC), were assessed. Results: The EFS model integrated the features from pre-treatment radiomics, pre-treatment dosiomics, intra-treatment radiomics, and delta radiomics. It outperformed six individual models, achieving an AUC of 0.979, accuracy of 0.917, and F1 score of 0.821. Among the top nine features of the EFS model, six features came from post-wavelet transformation and three from original images. Conclusions: The study demonstrated the feasibility of employing a data-driven multiomics approach to predict treatment outcomes in BM patients receiving PULSAR treatment. Integrating multiomics with intra-treatment decision support in PULSAR shows promise for optimizing patient management and reducing the risks of under- or over-treatment. [ABSTRACT FROM AUTHOR]

Background: Brain metastases (BM) are the most common intracranial neoplasms in adults and are a significant cause of morbidity and mortality. The brain is an unusual site for distant metastases of thyroid cancer; indeed, the most common sites are lungs and bones. In this narrative review, we discuss about the clinical characteristics, diagnosis, and treatment options for patients with BM from differentiated thyroid cancer (DTC). Summary: BM can be discovered before initial therapy due to symptoms, but in most patients, BM is diagnosed during follow-up because of imaging performed before starting tyrosine kinase inhibitors (TKI) or due to the onset of neurological symptoms. Older male patients with follicular thyroid cancer (FTC), poorly differentiated thyroid cancer (PDTC), and distant metastases may have an increased risk of developing BM. The gold standard for detection of BM is magnetic resonance imaging with contrast agent administration, which is superior to contrast-enhanced computed tomography. The treatment strategies for patients with BM from DTC remain controversial. Patients with poor performance status are candidates for palliative and supportive care. Neurosurgery is usually reserved for cases where symptoms persist despite medical treatment, especially in patients with favorable prognostic factors and larger lesions. It should also be considered for patients with a single BM in a surgically accessible location, particularly if the primary disease is controlled without other systemic metastases. Additionally, stereotactic radiosurgery (SRS) may be the preferred option for treating small lesions, especially those in inaccessible areas of the brain or when surgery is not advisable. Whole brain radiotherapy is less frequently used in treating these patients due to its potential side effects and the debated effectiveness. Therefore, it is typically reserved for cases involving multiple BM that are too large for SRS. TKIs are effective in patients with progressive radioiodine-refractory thyroid cancer and multiple metastases. Conclusions: Although routine screening for BM is not recommended, older male patients with FTC or PDTC and distant metastases may be at higher risk and should be carefully evaluated for BM. According to current data, patients who are suitable for neurosurgery seem to have the highest survival benefit, while SRS may be appropriate for selected patient. [ABSTRACT FROM AUTHOR]

This systematic review and network meta-analysis evaluates first-line treatment options for patients with EGFR-mutant non-small cell lung cancer (NSCLC) and brain metastases. We analyzed 24 randomized controlled trials (RCTs) involving 2,682 patients, comparing various EGFR tyrosine kinase inhibitors (TKIs) and combination therapies. Direct comparisons showed that the addition of bevacizumab or chemotherapy to first-generation (1G) EGFR-TKIs improved overall survival (OS) compared to 1G TKIs alone, with HRs of 0.704 (95% CI: 0.433–0.973) and 0.682 (95% CI: 0.464–0.899), respectively. However, third-generation (3G) TKI monotherapy did not significantly improve OS compared with 1G TKIs, with an HR of 0.855 (95% CI: 0.511–1.198). Indirect comparisons suggested that the combination of 3G TKIs with chemotherapy provided the most significant improvements in OS and progression-free survival (PFS), significantly outperforming 3G TKIs, with HRs of OS 1.69 (95% CI: 1.14–3.4) and PFS 2.13 (95% CI: 1.28–3.54). Intracranial PFS was best with 1G TKIs plus bevacizumab. Our findings suggest that 3G EGFR-TKIs in combination with chemotherapy may be the most effective strategy for patients with EGFR-mutant NSCLC and brain metastases, though further head-to-head trials are needed for validation. [ABSTRACT FROM AUTHOR]

Background Stereotactic radiosurgery (SRS) following surgical resection is the standard of care for patients with symptomatic oligo brain metastasis (BM), however, it is associated with 10–15% local failure. Targeting a resection cavity is imprecise, thus preoperative radiosurgery where the target is well-defined may be superior, however, the efficacy of preoperative SRS has not yet been tested in a clinical trial. Methods We conducted a phase 2, single-arm trial of preoperative SRS followed by surgical resection in patients with 1–4 symptomatic oligo BMs (NCT03398694) with the primary objective of measuring 6-month local control (LC). SRS was delivered to all patients utilizing a gamma knife or linear accelerator as per RTOG-9005 dosing criteria [Shaw E, Scott C, Souhami L, et al. Single dose radiosurgical treatment of recurrent previously irradiated primary brain tumors and brain metastases: final report of RTOG protocol 90-05. Int J Radiat Oncol Biol Phys. 2000;47(2):291–298] based on tumor diameter with the exception that the largest lesion diameter treated was 5 cm with 15 Gy with all SRS treatment given in single fraction dosing. Results The trial screened 50 patients, 48 patients were treated under the protocol and 32 patients completed the entire follow-up period. Of all the patients who completed the follow-up period, the primary endpoint of 6-month LC was 100% (95% CI: 0.891–1.000; P  = .005). Secondary endpoints, presented as medians, were overall survival (17.6 months), progression-free survival (5.3 months), distant in-brain failure (40.8% at 1 year), leptomeningeal failure (4.8% at 1 year), and radiation necrosis (7.7% at 1 year). Conclusions Our data confirms superior local control in patients who received preoperative SRS when compared to historical controls. Further study with a larger randomized cohort of patients is warranted to fully understand the benefits of preoperative SRS. [ABSTRACT FROM AUTHOR]

Simple Summary: Although some of the novel systemic treatments, especially the group of tyrosine kinase inhibitors, have shown a durable central nervous system response, ionizing radiation remains the mainstay in the management of brain metastases (BM). Recent technological advancements have enabled the replacement of whole-brain radiotherapy with localized stereotactic radiotherapy (SRT) for treating up to 10 BM, either as a primary or combined treatment, reducing neurotoxicity and improving local control (LC). The delivered target dose and patient selection play a crucial role in enhancing treatment efficacy. However, there is still limited evidence supporting which factors most affect LC and which patients derive the greatest benefit from SRT. This retrospective single-institutional study evaluated treatment outcomes in a heterogeneous patient population treated with Linac-based SRT, with the aim of identifying potential dosimetric and clinical prognostic factors to better inform the decision-making process. Background/Objectives: To report on predictive factors in Linac-based SRT for single and multiple BM. Methods: Consecutive patients receiving either one or three fractions of single-isocenter coplanar VMAT SRT were retrospectively included. The GTV-PTV margin was 1–2 mm. The delivered target dose was estimated by recalculating the original plans on roto-translated CT according to errors recorded by post-treatment CBCT. The Kaplan–Meier method estimated local progression-free survival (LPFS), intracranial progression-free survival (IPFS), and overall survival (OS). Log-rank and Wilcoxon–Mann–Whitney tests evaluated inter-group differences, whereas Cox regression analysis assessed prognostic factors. Results: Fifty females and fifty males, with a median age of 69 years, received 107 SRTs. A total of 213 BM (range, 1–10 per treatment) with a median volume of 0.22 cc were irradiated with a median minimum BED of 59.5 Gy. The median delivered GTV D95 reduction was −0.3%. The median follow-up was 11 months. Nineteen LP events and a 1-year LC rate of 90.1% were observed. The GTV coverage did not correlate with LC, while the GTV volume was a risk factor for LP, with the 1-year rate dropping to 73% for volumes ≥ 0.88 cc. The median LPFS, IPFS, and OS were 6, 5, and 7 months, respectively. Multivariate analysis showed that patients with melanoma histology and those receiving a second or subsequent systemic therapy line had the worst outcomes, whereas patients with adenocarcinoma histology and mutations showed better results. Conclusions: The accuracy and efficacy of the Linac-based SRT approach for BM were confirmed, but the dose distribution alone failed to predict the treatment response, suggesting that other factors must be considered to maximize SRT outcomes. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to compare the therapeutic effect of radiotherapy (RT) plus systemic therapy (ST) with RT alone in patients with simple brain metastasis (BM) after first-line treatment of limited-stage small cell lung cancer (LS-SCLC). Methods: The patients were treated at a single center from January 2011 to January 2022. BM only without metastases to other organs was defined as simple BM. The eligible patients were divided into RT alone (monotherapy arm) and RT plus ST (combined therapy arm). Univariate and multivariate Cox proportional hazards analyses were used to examine factors associated with increased risk of extracranial progression. After 1:1 propensity score matching analysis, two groups were compared for extracranial progression-free survival (ePFS), PFS, overall survival (OS), and intracranial PFS (iPFS). Results: 133 patients were identified and 100 were analyzed (monotherapy arm: n = 50, combined therapy arm: n = 50). The ePFS of the combined therapy was significantly longer than that of the monotherapy, with a median ePFS of 13.2 months (95% CI, 6.6–19.8) in combined therapy and 8.2 months (95% CI, 5.7–10.7) in monotherapy (P = 0.04). There were no statistically significant differences in PFS (P = 0.057), OS (P = 0.309), or iPFS (P = 0.448). Multifactorial analysis showed that combined therapy was independently associated with better ePFS compared with monotherapy (HR = 0.617, P = 0.034); more than 5 BMs were associated with worse ePFS compared with 1–5 BMs (HR = 1.808, P = 0.012). Conclusions: Compared with RT alone, combined therapy improves ePFS in patients with simple BM after first-line treatment of LS-SCLC. Combined therapy and 1–5 BMs reduce the risk of extracranial recurrence. [ABSTRACT FROM AUTHOR]

Purpose: Recent studies have investigated if the sodium fluorescein-guided (SFg) improves the extent of resection of BMs when compared to standard white light (sWL). Therefore, we aimed to assess the comparative efficacy and safety of SFg and sWL for resection of BMs. Methods: We searched Medline, Embase, and Cochrane Library databases following Cochrane and PRISMA guidelines for studies reporting comparative data of SFg and WL resection of BMs. We pooled odds ratios (OR) with 95% confidence intervals under random effects and applied I² statistics and leave-one-out sensitivity analysis to assess heterogeneity. I² > 40% was considered significant for heterogeneity. Results: Five studies involving 816 patients were included, of whom 390 underwent BMs resection with SFg and 426 with sWL, and ages ranging between 26 and 86.2 years old. Analysis revealed a statistically significant higher likelihood of complete resection in the SFg group when compared to the sWL group (OR = 2.15, 95%CI: 1.18–3.92, p = 0.01; I² = 47%). Sensitivity analysis revealed a consistent result in all five scenarios, with low heterogeneity in two of the five scenarios. Three studies reported significant improvement in OS in the SFg group, and the qualitative assessment of complications and procedure-related mortality did not provide sufficient information for conclusions. Conclusion: This systematic review and meta-analysis identified a higher likelihood of complete resection in the SFg group when compared to the standard sWL group. This study is the first to directly compare the impact of SFg and sWL on resection outcomes for BMs. [ABSTRACT FROM AUTHOR]

Purpose: Targeted treatment options for non-small cell lung cancer (NSCLC) brain metastases (BMs) may be combined with stereotactic radiosurgery (SRS) to optimize survival. We assessed patient outcomes after SRS for NSCLC BMs, identifying survival trajectories associated with targetable mutations. Methods: In this retrospective time-dependent analysis, we analyzed median overall survival of patients who received ≥ 1 SRS courses for BM from NSCLC from 2001 to 2021. We compared survival of patients with and without targetable mutations based on clinical variables and treatment. Results: Among the 213 patients included, 87 (40.8%) had targetable mutations—primarily EGFR (22.5%)—and 126 (59.2%) did not. Patients with targetable mutations were more often female (63.2%, p <.001) and nonsmokers (58.6%, p <.001); had higher initial lung-molGPA (2.0 vs. 1.5, p <.001) and lower cumulative tumor volume (3.7 vs. 10.6 cm3, p <.001); and received more concurrent (55.2% vs. 36.5%, p =.007) and total (median 3 vs. 2, p <.001) systemic therapies. These patients had lower mortality rates (74.7% vs. 91.3%, p <.001) and risk (HR 0.298 [95%CI 0.190-0.469], p <.001) and longer median overall survival (20.2 vs. 7.4 months, p <.001), including survival ≥ 3 years (p =.001). Survival was best predicted by SRS with tumor resection in patients with non-targetable mutations (HR 0.491 [95%CI 0.318–757], p =.001) and by systemic therapy with SRS for those with targetable mutations (HR 0.124 [95%CI 0.013-1.153], p =.067). Conclusion: The presence of targetable mutations enhances survival in patients receiving SRS for NSCLC BM, particularly when used with systemic therapies. Survival for patients without targetable mutations was longest with SRS and surgical resection. These results inform best practices for managing patients with NSCLC BM based on driver mutation status. [ABSTRACT FROM AUTHOR]

There is increasing awareness of radiotherapy's potential side effects, such as lymphopenia. Therefore, this study aimed to establish the association between WBRT and the development of lymphopenia in patients with brain metastases undergoing brain radiotherapy (RT), along with evaluating the corresponding clinical outcomes. Including 116 patients with brain metastases undergoing brain radiotherapy, the study collected the absolute lymphocyte counts (ALC) within 2 weeks before brain radiotherapy (pre-radiotherapy, pre-RT), as well as ones at 1 and 2 months after completing RT (post-RT). Univariate and multivariate analyses were performed to identify associations between radiation modality and post-RT ALC. The relationships between post-RT ALC and overall survival were evaluated with Kaplan–Meier analysis and a multivariate Cox regression model. The median ALC definitely decreased at 1 month post-RT, but at 2 months post-RT, gradually rose but not to the pre-RT ALC. The multivariate analysis identified WBRT and lower pre-RT ALC as independent risk factors associated with the decrease in post-RT ALC at 1 month. It also revealed more than 4 brain metastases, G3-4 lymphopenia at 1 month and lower post-RT ALC at 2 months exhibited significantly worse prognosis regardless of the radiation modality. However, there was indeed an independent correlation between radiation modality and the outcome of intracranial progression-free survival (PFS). To approach the feasibility and reasonableness of treatment, clinicians should carefully consider various factors to achieve long-term survival of patients. [ABSTRACT FROM AUTHOR]

Background: Early detection of T790M mutation in exon 20 of epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) patients with brain metastasis is crucial for optimizing treatment strategies. In this study, we developed radiomics models to distinguish NSCLC patients with T790M-positive mutations from those with T790M-negative mutations using multisequence MR images of brain metastasis despite an imbalanced dataset. Various resampling techniques and classifiers were employed to identify the most effective strategy. Methods: Radiomic analyses were conducted on a dataset comprising 125 patients, consisting of 18 with EGFR T790M-positive mutations and 107 with T790M-negative mutations. Seventeen first- and second-order statistical features were selected from CET1WI, T2WI, T2FLAIR, and DWI images. Four classifiers (logistic regression, support vector machine, random forest [RF], and extreme gradient boosting [XGBoost]) were evaluated under 13 different resampling conditions. Results: The area under the curve (AUC) value achieved was 0.89, using the SVM-SMOTE oversampling method in combination with the XGBoost classifier. This performance was measured against the AUC reported in the literature, serving as an upper-bound reference. Additionally, comparable results were observed with other oversampling methods paired with RF or XGBoost classifiers. Conclusions: Our study demonstrates that, even when dealing with an imbalanced EGFR T790M dataset, reasonable predictive outcomes can be achieved by employing an appropriate combination of resampling techniques and classifiers. This approach has significant potential for enhancing T790M mutation detection in NSCLC patients with brain metastasis. [ABSTRACT FROM AUTHOR]

Background: Cerebral radiation necrosis (RN), a severe complication of stereotactic radiotherapy (SRT), has been shown to significantly decrease patient survival time and quality of life. The purpose of this study was to analyze whether bevacizumab can prevent or reduce the occurrence of SRT-induced cerebral RN in non-small cell lung cancer (NSCLC) patients with brain metastases. Materials and methods: We retrospectively reviewed the clinical records of NSCLC patients with brain metastases from March 2013 to June 2023 who were treated with SRT. Patients were divided into two groups: those in the bevacizumab group received SRT with four cycles of bevacizumab, and patients in the control group received SRT only. Inverse probability of treatment weighting (IPTW) was performed based on a multinomial propensity score model to balance the baseline characteristics. The chi-square test was used. A Cox model was used to evaluate overall survival (OS). Results: A total of 80 patients were enrolled, namely, 28 patients in the bevacizumab group and 52 patients in the control group. The possibility of developing cerebral RN and/or symptomatic edema (RN/SE) was significantly decreased in patients treated with bevacizumab compared to those who did not receive bevacizumab before IPTW (p=0.036) and after IPTW (p=0.015) according to chi-square analysis. The IPTW-adjusted median OS was 47.7 months (95% CI 27.4-80.8) for patients in the bevacizumab group and 44.1 months (95% CI 36.7-68.0) (p=0.364) for patients in the control group. Conclusion: The application of bevacizumab concurrent with SRT may prevent or reduce the occurrence of cerebral RN in NSCLC patients with brain metastases. [ABSTRACT FROM AUTHOR]

Brain metastases (BM) represent a common and severe complication of breast cancer (BC), emerging in approximately 10%-16% of all BC patients. The prevalent approach for treating BC patients with BM encompasses a multimodal strategy, combining surgery, whole brain radiation therapy, and stereotactic radiosurgery. Yet, a concrete guideline for localized treatment strategies remains elusive, while systemic treatments like small-moleculetargeted therapy and immunotherapy are still in the clinical trial phase. This case study presents a significant clinical response to anlotinib treatment in a patient with estrogen receptor-negative, progesterone receptor-positive, and human epidermal growth factor receptor 2 (HER2)-positive breast cancer, complicated by BM. After the standard first-line treatment including albuminbound paclitaxel, trastuzumab and pertuzumab, and a second-line treatment involving pyrotinib, capecitabine, and radiotherapy did not produce the desired results, the patient was then administered anlotinib in combination with pyrotinib and letrozole as a third-line treatment, which led to a partial response (PR). The findings suggest that anti-angiogenic therapy, specifically anlotinib, could be regarded as a promising therapeutic option for BC patients with BM. [ABSTRACT FROM AUTHOR]

Background: In radiotherapy, the delineation of the gross tumor volume (GTV) in brain metastases using computed tomography (CT) simulation localization is very important. However, despite the criticality of this process, a pronounced gap exists in the availability of tools tailored for the automatic segmentation of the GTV based on CT simulation localization images. Purpose: This study aims to fill this gap by devising an effective tool specifically for the automatic segmentation of the GTV using CT simulation localization images. Methods: A dual‐network generative adversarial network (GAN) architecture was developed, wherein the generator focused on refining CT images for more precise delineation, and the discriminator differentiated between real and augmented images. This architecture was coupled with the Mask R‐CNN model to achieve meticulous GTV segmentation. An end‐to‐end training process facilitated the integration between the GAN and Mask R‐CNN functionalities. Furthermore, a conditional random field (CRF) was incorporated to refine the initial masks generated by the Mask R‐CNN model to ensure optimal segmentation accuracy. The performance was assessed using key metrics, namely, the Dice coefficient (DSC), intersection over union (IoU), accuracy, specificity, and sensitivity. Results: The GAN+Mask R‐CNN+CRF integration method in this study performs well in GTV segmentation. In particular, the model has an overall average DSC of 0.819 ± 0.102 and an IoU of 0.712 ± 0.111 in the internal validation. The overall average DSC in the external validation data is 0.726 ± 0.128 and the IoU is 0.640 ± 0.136. It demonstrates favorable generalization ability. Conclusion: The integration of the GAN, Mask R‐CNN, and CRF optimization provides a pioneering tool for the sophisticated segmentation of the GTV in brain metastases using CT simulation localization images. The method proposed in this study can provide a robust automatic segmentation approach for brain metastases in the absence of MRI. [ABSTRACT FROM AUTHOR]

Simple Summary: Brain metastases from systemic cancer are the most common tumors of the central nervous system. For prostate metastases to the brain, the clinical progression is poorly understood. This retrospective study aims to elucidate clinical risk factors associated with overall survival (OS; months post-diagnosis) in prostate metastases to the brain, and then develop a nomogram to aid in clinical decision making for this vulnerable population. We identified several factors associated with survival, including race, tumor size, and the presence of additional metastases. This study should serve as a clinical framework for prognostication in metastatic prostate cancer to the brain. Brain metastases are an uncommon yet life-limiting manifestation of prostate cancer. However, there is limited insight into the natural progression, therapeutics, and patient outcomes for prostate cancer once metastasized to the brain. This is a retrospective study of 461 patients with metastatic prostate cancer to the brain with a primary outcome of median overall survival (OS). The Surveillance, Epidemiology, and End Results (SEER) database was examined using Cox regression univariate and multivariable analyses, and a corresponding nomogram was developed. The median overall survival was 15 months. In the multivariable analysis, Hispanic patients had significantly increased OS (median OS 17 months, p = 0.005). Patients with tumor sizes greater than three centimeters exhibited significantly reduced OS (median OS 19 months, p = 0.014). Patients with additional metastases to the liver exhibited significantly reduced OS (median OS 3.5 months, p < 0.001). Increased survival was demonstrated in patients treated with chemotherapy or systemic treatment (median OS 19 months, p = 0.039), in addition to radiation and chemotherapy (median OS 25 months, p = 0.002). The nomogram had a C-index of 0.641. For patients with prostate metastases to the brain, median OS is influenced by race, tumor size, presence of additional metastases, and treatment. The lack of an association between traditional prostate cancer prognosis metrics, including Gleason and ISUP grading, and mortality highlights the need for individualized, metastasis-specific prognosis metrics. This prognostic nomogram for prostate metastases to the brain can be used to guide the management of affected patients. [ABSTRACT FROM AUTHOR]

Simple Summary: It is known that there are sex differences in adverse events experienced following cancer treatment. However, little is known about sex differences in adverse events experienced in individuals with metastatic cancer. Here, using SEER-Medicare data, we investigate sex differences in adverse events in lung cancer individuals with brain metastasis who are 66 years old and older. Sex differences in adverse events were observed and were dependent on lung cancer histology, age at diagnosis, year of diagnosis and treatment as well as potential interplay between these variables. Sex differences are evident in adverse events (AEs) related to brain tumors, yet sex differences in AEs specific to brain metastases (BrMs) are underexplored. Lung cancer BrMs dominate among BrM, comprising over half of cases. This study examined sex differences in AEs associated with lung cancer BrMs in individuals aged 66 or older using the SEER-Medicare dataset. Multivariable logistic regression, adjusted for demographic factors and comorbidities, stratified by histological subtype, treatment, age, and year of diagnosis were used to analyze AEs among those with BrMs from primary lung tumors. Year of diagnosis was grouped into prior/post-2013, to account for shifts in treatment paradigms. The results showed nuanced sex-specific AEs. Females diagnosed post-2013 with small-cell, squamous-cell, or other non-small-cell carcinoma BrMs had a higher headache likelihood than males. Males with adenocarcinoma post-2013 were more likely to experience brain herniation. Females aged 76 and older with small-cell BrM exhibited increased vision difficulty risk compared to males of the same age, with no significant difference in other age groups. Males treated for adenocarcinoma faced heightened hemorrhagic stroke risk. This study reveals sex-specific disparities in AEs among older individuals with lung cancer BrMs, varying by histological subtype, age, diagnosis year, and treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Treating non-small cell lung cancer (NSCLC) patients with brain metastases (BM) is challenging, especially when brain involvement is the first sign of cancer. This study retrospectively analyzed 25 patients with newly diagnosed brain metastatic NSCLC without EGFR or ALK alterations. The findings suggest that patients with symptomatic BM at diagnosis may have better survival outcomes due to increased use of multimodal local treatments. Combining local approaches with first-line immune checkpoint inhibitors (ICI) and chemotherapy appears to improve survival in these patients. Additionally, a nonsystematic literature review was conducted to better understand the topic and explore the potential benefits of various immunotherapy-based combinations for brain metastatic NSCLC. This research aims to highlight the survival outcomes of this underrepresented population and provide insights into optimal treatment strategies. In the era of immune checkpoint inhibitors (ICI), managing non-oncogene driven non-small cell lung cancer (NSCLC) with brain metastases (BM) is challenging, especially when brain involvement is the initial sign. Patients with newly diagnosed brain metastatic NSCLC without epidermal growth factor receptor (EFGR) nor anaplastic lymphoma kinase (ALK) alterations were retrospectively included. Twenty-five patients were analyzed; 15 (60%) had symptomatic BM as the first sign (group 1), while 10 (40%) had BM discovered during complementary examinations (group 2). Fourteen patients (56%) had concomitant extracerebral metastases, primarily in group 2. Eight (32%) had oligometastatic disease, with seven in group 1. Over half received chemotherapy and pembrolizumab as first-line treatment. BM surgical resection occurred in twelve (80%) patients in group 1 and one in group 2. Median cerebral progression-free survival was 10 months: 12 in group 1 and 5 in group 2. Median overall survival was 25 months: not reached in group 1 and 6 months in group 2. This case series highlights survival outcomes for patients with inaugural BM, a demographic underrepresented in pivotal trials. Oligometastatic disease and symptomatic BM as initial signs seem associated with better prognosis due to increased use of multimodal local approaches. Combining local approaches with first-line ICI+/− chemotherapy appears to improve survival in brain metastatic NSCLC. A literature review was conducted to explore key questions regarding upfront ICI alone or in combination with systemic drugs or local approaches in brain metastatic NSCLC. [ABSTRACT FROM AUTHOR]

Brain metastases (BMs) from colorectal cancer (CRC) are a small percentage of metastatic patients and surgery is considered the best choice to improve survival. While most research has focused on the risk of CRC spreading to the brain, no studies have examined the characteristics of BMs in relation to surgery and outcome. In this study, we evaluate the clinical and radiologic features of BMs from CRC patients who underwent surgery and analyze their outcomes. The study is a retrospective observational analysis that included a cohort of 31 patients affected by CRC surgically-treated for their related BMs. For all patients, clinical and surgical data (number, site, side, tumor and edema volume, and morphology) were recorded. Analysis found that synchronous diagnosis and lesion morphology, particularly cystic versus solid, had the most significant impact on survival (6 vs. 22 months, P = 0.04). To compare BMs with cystic morphology to those with solid morphology, a multivariate analysis was conducted. No significant differences were observed between the 2 groups in terms of age, sex, clinical onset, or performance status. The analysis revealed no significant differences in localization with regard to site, tumor and edema volume, biology, or complications rate. BMs derived from CRC have a significantly different prognosis depending on whether they present as a solid or cystic pattern. Although solid pattern is more common, cystic BMs in this tumor type are less frequent and are associated with a poorer prognosis, regardless of molecular expression, location, size, and adjuvant treatment. [ABSTRACT FROM AUTHOR]

This study aimed to pinpoint independent predictors influencing overall survival (OS) and cancer-specific survival (CSS) in elderly patients with small cell lung cancer (SCLC) brain metastasis (BM), and to create and validate nomograms for OS and CSS prediction. Data from elderly SCLC BM patients were extracted out of the Surveillance, Epidemiology, and End Results database, including 1200 patients identified from 2010 and 2015 who were randomly allocated into a training set and an internal validation set at a proportion of 7:3, and 666 patients diagnosed between 2018 and 2020 as a temporal external validation set. Independent predictors for OS and CSS were determined through univariate Cox analysis, least absolute shrinkage and selection operator analysis, and multivariate Cox analysis sequentially. Nomograms for OS and CSS were constructed, and validated by the internal and temporal external validation sets. Age, N stage, chemotherapy, and liver metastasis were determined as independent predictors of OS and CSS, while radiotherapy and surgery were not. Nomograms were constructed based on these independent predictors. The results of the receiver operator characteristic curves, the areas under the curve and calibration curve demonstrated that the nomograms exhibited commendable discriminative ability and calibration. Moreover, decision curve analysis, net reclassification improvement, and integrated discrimination improvement also suggested that the nomograms possessed superior clinical usefulness and predictive capability relative to the TNM system. Prognostic nomograms for elderly patients with SCLC BM have been developed, demonstrating good performance in terms of accuracy, reliability, and practicality. [ABSTRACT FROM AUTHOR]

Introduction: Brain metastases are the most common malignant lesions in the central nervous system. Brain metastases from pancreatic cancer are very rare, with poor prognosis. The present paper aims to describe a rare pathology and the work carried out for the patient's care. Case report: 49-year-old man with personality changes, depression, and apathy. Five days before admission, he presented dysarthria, added left hemiparesis, and disorientation that progressed to sudden neurological deterioration that required advanced airway management. A computed tomography study was seen with cerebral cystic lesions. A decompressive craniectomy and drainage of the larger lesion was performed, with subsequent resection. The study protocol with immunohistochemistry reports CK 19, compatible with pancreatic adenocarcinoma. Conclusions: A rare case of multiple brain metastases and suspected lung metastasis, both secondary to primary pancreatic adenocarcinoma was presented. The patient began with symptoms associated with brain lesions. The incidence of brain metastases with a primary pancreatic tumor is very low, and this is an exceptional case when presenting with neurological symptoms. Surgical resection of the brain lesion had a limited role in the clinical improvement of the patient since the progression of the disease was rapid. Still, it was useful to establish a diagnosis by immunohistochemistry. Since there are no screening tests for pancreatic tumors, it is difficult to identify them in early stages and without gastrointestinal symptoms. [ABSTRACT FROM AUTHOR]

Single-fraction stereotactic radiosurgery (SRS) or fractionated SRS (FSRS) are well established strategies for patients with limited brain metastases. A broad spectrum of modern dedicated platforms are currently available for delivering intracranial SRS/FSRS; however, SRS/FSRS delivered using traditional CT-based platforms relies on the need for diagnostic MR images to be coregistered to planning CT scans for target volume delineation. Additionally, the on-board image guidance on traditional platforms yields limited inter-fraction and intra-fraction real-time visualization of the tumor at the time of treatment delivery. MR Linacs are capable of obtaining treatment planning MR and on-table MR sequences to enable visualization of the targets and organs-at-risk and may subsequently help identify anatomical changes prior to treatment that may invoke the need for on table treatment adaptation. Recently, an MR-guided intracranial package (MRIdian A3i BrainTxTM) was released for intracranial treatment with the ability to perform high-resolution MR sequences using a dedicated brain coil and cranial immobilization system. The objective of this report is to provide, through the experience of our first patient treated, a comprehensive overview of the clinical application of our institutional program for FSRS adaptive delivery using MRIdian's A3i BrainTx system—highlights include reviewing the imaging sequence selection, workflow demonstration, and details in its delivery feasibility in clinical practice, and dosimetric outcomes. [ABSTRACT FROM AUTHOR]

Background: Liquid biopsy represents a major development in cancer research, with significant translational potential. Similarly, it is increasingly recognized that multi-omic molecular approaches are a powerful avenue through which to understand complex and heterogeneous disease biology. We hypothesize that merging these two promising frontiers of cancer research will improve the discriminatory capacity of current models and allow for improved clinical utility. Methods: We have compiled a cohort of patients with glioblastoma, brain metastasis, and primary central nervous system lymphoma. Cell-free methylated DNA immunoprecipitation (cfMeDIP) and shotgun proteomic profiling was obtained from the cerebrospinal fluid (CSF) of each patient and used to build tumour-specific classifiers. Results: We show that the DNA methylation and protein profiles of cerebrospinal fluid can be integrated to fully discriminate lymphoma from its diagnostic counterparts with perfect AUC of 1 (95% confidence interval 1–1) and 100% specificity, significantly outperforming single-platform classifiers. Conclusions: We present the most specific and accurate CNS lymphoma classifier to date and demonstrates the synergistic capability of multi-platform liquid biopsies. This has far-reaching translational utility for patients with newly diagnosed intra-axial brain tumours. [ABSTRACT FROM AUTHOR]

Introduction: 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. Methods: 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. Results: 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). Conclusion: 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. [ABSTRACT FROM AUTHOR]

Background and Objectives: The impact of surgery for recurrent brain metastases in elderly patients has been the object of debate due to limited information in the literature. We analyzed clinical outcome and survival of elderly patients with recurrent brain metastases in order to assess potentially beneficial role of surgery. Materials and methods: In total, 219 patients with recurrent brain metastases between 2007 and 2022 were identified, of which 95 underwent re-resection; 83 patients aged 65 and older were analyzed. A survival analysis was performed, and clinical outcomes were evaluated. Results: The median survival time after surgery for recurrent brain metastases was 6 months (95CI 4–10) in older patients and 8 (95CI 7–9) in younger patients (p = 0.619). Out of all the older patients, 33 who underwent surgical resection showed prolonged survival compared with patients who did not receive surgical resection (median: 14, 95CI 8–19 vs. 4, 95CI 4–7, p = 0.011). All patients had preoperative Karnofsky performance scores of >70, which did not deteriorate after surgery (87.02 ± 5.76 vs. 85 ± 6.85; p = 0.055). In the univariate analysis, complete cytoreduction was a favorable prognostic factor. The tumor volume, the number of metastases, extracranial disease progression, adjuvant radiation, and systemic therapy did not affect survival in this cohort. Conclusions: Patients aged 65 and older benefit from neurosurgical resections of recurrent brain metastases. Survival did not differ from that in younger patients, which can be explained by a better preoperative functional status. Moreover, independent of the extent of resection, older patients who underwent surgery showed better survival than patients who did not receive surgical treatment. Complete cytoreduction was a favorable prognostic marker. [ABSTRACT FROM AUTHOR]

Purpose: The study aimed to investigate the optimal isodose line (IDL) in linear accelerator‐based stereotactic radiotherapy for single brain metastasis, using HyperArc. We compared the dosimetric parameters for target and normal brain tissue among six plans with different IDLs. Methods: This study included 30 patients with single brain metastasis. We retrospectively generated six plans for each tumor with different IDLs (80%, 70%, 60%, 50%, 40%, and 33%) using HyperArc. All treatment plans were normalized to the prescription dose of 35 Gy in five fractions which was covered by 95% of the planning target volume (PTV), defined by adding a 1.0 mm margin to the gross tumor volume (GTV). The dosimetric parameters were compared among the six plans. Results: For GTV > 0.1 cm3, the ratio of brain–GTV volumes receiving 25 Gy to PTV (V25Gy/PTV) was significantly lower at IDL 40%–70% than at IDL 80% and 33% (p < 0.01, retrospectively). For GTV < 0.1 cm3, V25Gy/PTV decreased continuously as IDL decreased. The values of D99% and D80% for GTV increased with decreasing IDL. An IDL of 50% or less was required to achieve D99% of greater than 43 Gy and D80% of greater than 50 Gy. The mean values of D99% and D80% for IDL 50% were 44.3 and 51.9 Gy. Conclusion: The optimal IDL is 40%–50% for GTV > 0.1 cm3. These lower IDLs could increase D99% and D80% of GTV while lowering V25Gy of normal brain tissue, which may help reduce the risk of radiation necrosis and improve local control. [ABSTRACT FROM AUTHOR]

Abstract Objective This study aims to evaluate the effectiveness of a nomogram model constructed using Diffusion Kurtosis Imaging (DKI) and 3D Arterial Spin Labeling (3D-ASL) functional imaging techniques in distinguishing between cerebral alveolar echinococcosis (CAE) and brain metastases (BM). Methods Prospectively collected were 24 cases (86 lesions) of patients diagnosed with CAE and 16 cases (69 lesions) of patients diagnosed with BM at the affiliated hospital of Qinghai University from 2018 to 2023, confirmed either pathologically or through comprehensive diagnosis. Both patient groups underwent DKI and 3D-ASL scanning. DKI parameters (Kmean, Dmean, FA, ADC) and cerebral blood flow (CBF) were analyzed for the parenchymal area, edema area, and symmetrical normal brain tissue area in both groups. There were 155 lesions in total in the two groups of patients. We used SPSS to randomly select 70% as the training set (108 lesions) and the remaining 30% as the test set (47 lesions) and performed a difference analysis between the two groups. The independent factors distinguishing CAE from BM were identified using univariate and multivariate logistic regression analyses. Based on these factors, a diagnostic model was constructed and expressed as a nomogram. Result Univariate and multivariate logistic regression analyses identified nDmean1 and nCBF1 in the lesion parenchyma area, as well as nKmean2 and nDmean2 in the edema area, as independent factors for distinguishing CAE from BM. The model's performance, measured by the area under the ROC curve (AUC), had values of 0.942 and 0.989 for the training and test sets, respectively. Calibration curves demonstrated that the predicted probabilities were highly consistent with the actual values, and DCA confirmed the model's high clinical utility. Conclusion The nomogram model, which incorporates DKI and 3D-ASL functional imaging, effectively distinguishes CAE from BM. It offers an intuitive, accurate, and non-invasive method for differentiation, thus providing valuable guidance for subsequent clinical decisions.

Abstract This systematic review and network meta-analysis evaluates first-line treatment options for patients with EGFR-mutant non-small cell lung cancer (NSCLC) and brain metastases. We analyzed 24 randomized controlled trials (RCTs) involving 2,682 patients, comparing various EGFR tyrosine kinase inhibitors (TKIs) and combination therapies. Direct comparisons showed that the addition of bevacizumab or chemotherapy to first-generation (1G) EGFR-TKIs improved overall survival (OS) compared to 1G TKIs alone, with HRs of 0.704 (95% CI: 0.433–0.973) and 0.682 (95% CI: 0.464–0.899), respectively. However, third-generation (3G) TKI monotherapy did not significantly improve OS compared with 1G TKIs, with an HR of 0.855 (95% CI: 0.511–1.198). Indirect comparisons suggested that the combination of 3G TKIs with chemotherapy provided the most significant improvements in OS and progression-free survival (PFS), significantly outperforming 3G TKIs, with HRs of OS 1.69 (95% CI: 1.14–3.4) and PFS 2.13 (95% CI: 1.28–3.54). Intracranial PFS was best with 1G TKIs plus bevacizumab. Our findings suggest that 3G EGFR-TKIs in combination with chemotherapy may be the most effective strategy for patients with EGFR-mutant NSCLC and brain metastases, though further head-to-head trials are needed for validation.

Abstract There is increasing awareness of radiotherapy’s potential side effects, such as lymphopenia. Therefore, this study aimed to establish the association between WBRT and the development of lymphopenia in patients with brain metastases undergoing brain radiotherapy (RT), along with evaluating the corresponding clinical outcomes. Including 116 patients with brain metastases undergoing brain radiotherapy, the study collected the absolute lymphocyte counts (ALC) within 2 weeks before brain radiotherapy (pre-radiotherapy, pre-RT), as well as ones at 1 and 2 months after completing RT (post-RT). Univariate and multivariate analyses were performed to identify associations between radiation modality and post-RT ALC. The relationships between post-RT ALC and overall survival were evaluated with Kaplan–Meier analysis and a multivariate Cox regression model. The median ALC definitely decreased at 1 month post-RT, but at 2 months post-RT, gradually rose but not to the pre-RT ALC. The multivariate analysis identified WBRT and lower pre-RT ALC as independent risk factors associated with the decrease in post-RT ALC at 1 month. It also revealed more than 4 brain metastases, G3-4 lymphopenia at 1 month and lower post-RT ALC at 2 months exhibited significantly worse prognosis regardless of the radiation modality. However, there was indeed an independent correlation between radiation modality and the outcome of intracranial progression-free survival (PFS). To approach the feasibility and reasonableness of treatment, clinicians should carefully consider various factors to achieve long-term survival of patients.

Brain metastases represent a formidable challenge in cancer management, impacting a significant number of patients and contributing significantly to cancer-related mortality. Conventional diagnostic methods frequently fall short, underscoring the imperative for non-invasive alternatives. Non-coding RNAs (ncRNAs), specifically microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), present promising avenues for exploration. These ncRNAs exert influence over the prognosis and treatment resistance of brain metastases, offering valuable insights into underlying mechanisms and potential therapeutic targets. Dysregulated ncRNAs have been identified in brain metastases originating from various primary cancers, unveiling opportunities for intervention and prevention. The analysis of ncRNA expression in bodily fluids, such as serum and cerebrospinal fluid, provides a noninvasive means to differentiate brain metastases from primary tumors. NcRNAs, particularly miRNAs, assume a pivotal role in orchestrating the immune response within the brain microenvironment. MiRNAs exhibit promise in diagnosing brain metastases, effectively distinguishing between normal and cancer cells, and pinpointing the tissue of origin for metastatic brain tumors. The manipulation of miRNAs holds substantial potential in cancer treatment, offering the prospect of reducing toxicity and enhancing efficacy. Given the limited treatment options and the formidable threat of brain metastases in cancer patients, non-coding RNAs, especially miRNAs, emerge as beacons of hope, serving as both diagnostic tools and therapeutic targets. Further clinical studies are imperative to validate the specificity and sensitivity of ncRNAs, potentially reshaping approaches to tackle this challenge and elevate treatment outcomes for affected patients.

In patients with non‐small cell lung cancer (NSCLC), oncogenic variants present in <5% of cases are considered rare, the predominant of which include human epidermal growth factor receptor 2 (HER2) mutations, mesenchymal–epithelial transition (MET) alterations, c‐ros oncogene 1 (ROS1) rearrangements, rearrangement during transfection (RET) fusions, v‐raf mouse sarcoma virus oncogene homolog B1 (BRAF) mutations, and neurotrophic troponin receptor kinase (NTRK) fusions. Brain metastases (BMs) occur in approximately 10%–50% of patients with NSCLC harboring rare genetic variants. The recent advent of small‐molecule tyrosine kinase inhibitors and macromolecular antibody–drug conjugates (ADCs) has conferred marked survival benefits to patients with NSCLC harboring rare driver alterations. Despite effective brain lesion control for most targeted agents and promising reports of intracranial remission associated with novel ADCs, BM continues to be a major therapeutic challenge. This review discusses the recent advances in the treatment of NSCLC with rare genetic variants and BM, with a particular focus on intracranial efficacy, and explores future perspectives on how best to treat these patients. [ABSTRACT FROM AUTHOR]