Brain Metastases In Patients Research Articles

Single-cell sequencing reveals the immune landscape of breast cancer patients with brain metastasis.

Breast cancer has the highest incidence rate of cancer worldwide, and brain metastases (BrM) are among the most malignant cases. While some patients have benefited from immune checkpoint inhibitors (ICIs), the complex anatomical structure of the brain and the heterogeneity of metastatic tumors have made it difficult to characterize the tumor immune microenvironment (TME) of metastatic tumors. To address this, we used single-cell RNA sequencing (scRNA-seq) to analyze immune cells in the cerebrospinal fluid (CSF) of BrM patients with breast cancer, thereby providing a comprehensive view of the immune microenvironment landscape of BrM. Based on canonical marker genes, we identified nine cell types, and further identified their subtypes through differential expression gene (DEG) analysis. We compared the changes in cells and functions in the immune microenvironment of patients with different prognoses. Our analysis revealed a series of genes that promote tumor immune function (CCR5, LYZ, IGKC, MS4A1, etc.) and inhibit tumor immune function (SCGB2A2, CD24, etc.). The scRNA-seq in CSF provides a noninvasive method to describe the TME of breast cancer patients and guide immunotherapy.

Abstract A081: Real-world treatment patterns and clinical outcomes in patients with HER2+ metastatic breast cancer receiving systemic therapy in Ontario, Canada

Abstract Background: Real-world data on treatment patterns and prevalence of brain metastases in patients with HER2+ metastatic breast cancer (mBC) are limited. This study described treatment patterns and clinical outcomes among patients with HER2+ mBC in Canada. Methods: This was a retrospective chart review of adult patients diagnosed with de-novo or recurrent HER2+ mBC between Jan 1, 2014 and Mar 1, 2021 (prior to wide availability of new treatments) at Sunnybrook Research Institute and Sinai Health, two large BC treatment centres in Canada. Data on patient characteristics and treatment regimens were extracted. Treatment patterns, time to next treatment (TTNT; as a proxy for progression-free survival), and presence of brain metastases were assessed in the first-line (1L), second-line (2L), and third-line (3L) settings. TTNT analyses used Kaplan-Meier methodology to account for censoring. Results: Of 121 patients with HER2+ mBC, the median (IQR) age was 54.0 (17.0) years. 38.0% of patients had de-novo disease and 62.0% had recurrent mBC; 12 (9.9%) had brain metastases at the time of mBC diagnosis. Systemic therapies generally aligned with Canadian funded regimens for 1L (101 of 121 patients [83.5%] received trastuzumab + pertuzumab ± chemotherapy ± subsequent endocrine therapy; 8/121 [6.6%] received endocrine therapy only) and 2L (50/68 [73.5%] received T-DM1 ± endocrine therapy; 9/68 [13.2%] received endocrine therapy only). However, treatment patterns were heterogeneous in the 3L setting (14/46 [30.4%] received anti-HER2 TKI + chemotherapy ± trastuzumab; 10/46 [21.7%] received endocrine therapy only; 10/46 [21.7%] received chemotherapy). Median (95% CI) TTNT in months was 21.4 (16.1, 27.2) in 1L, 11.0 (8.5, 16.5) in 2L, and 8.7 (5.4, 15.6) in 3L. Median (IQR) follow-up was 29.9 (25.2) months. In total, 57 patients (47.1%) were diagnosed with brain metastases during the study period (17 pre-1L, 24 post-1L/pre-2L, 6 post-2L/pre-3L) and of these, 73.7% received radiation therapy. Conclusions: In patients with HER2+ mBC in Canada, 3L treatment patterns are heterogeneous, median TTNT is <1 year, and almost half develop brain metastases. These data from two large treating centres in Ontario suggest a high unmet need for more effective treatment regimens in later lines of therapy, particularly 3L, for patients with HER2+ mBC. Citation Format: Katarzyna J Jerzak, Ruth Moulson, Ling-I Hsu, Chris Lenhu, Dhivo Krishnathasan, Jessica Weiss, Christine Brezden-Masley. Real-world treatment patterns and clinical outcomes in patients with HER2+ metastatic breast cancer receiving systemic therapy in Ontario, Canada [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A081.

Lung adenocarcinoma with brain metastasis detected dual fusion of LOC399815-ALK and ALK-EML4 in combined treatment of Alectinib and CyberKnife: A case report.

The anaplastic lymphoma kinase (ALK) gene fusion occurs in approximately 3% to 7% of nonsmall cell lung cancer (NSCLC), in which occurs approximately 23% to 31% of brain metastasis patients in poor prognosis. ALK tyrosine kinase inhibitors have shown efficacy in treating ALK-positive (ALK+) NSCLC. More than 90 distinct subtypes of ALK fusions have been identified through sequencing technique and would lead to significant differences in clinical efficacy, it is necessary to guide clinical treatment effectively by gene detection. A 56-year-old nonsmoking female admitted to hospital due to cough, expectoration, and chest pain. Chest computed tomography revealed a space-occupying lesion in the upper left lobe (5.0 cm × 2.4 cm × 2.9 cm), multiple enlarged lymph nodes in mediastinum 3A and 5 (largest size 1.5 cm × 1.4 cm), and evidence of thoracic vertebral metastasis, brain magnetic resonance imaging also showed brain metastasis. Lung adenocarcinoma with brain metastasis. The patient initially received conventional first-line chemotherapy, which led to a deteriorated condition. Blood-base liquid biopsy by next-generation sequencing resulted in double ALK fusions, in which with a neo-partner of lncRNA (LOC399815-ALK). Following subsequent treatment with Alectinib and stereotactic radiotherapy (CyberKnife) was subsequently employed to manage the brain metastatic lesions, resulting in a substantial decreased in both the number and size of tumor lesions. The patient's response to therapy efficacy resulted in a substantial decreased in both the number and size of tumor lesions that assessed comprehensively evaluated through computed tomography imaging and ctDNA sequencing. Patient's condition has been under control for over 29 months. Liquid biopsy may reveal the rare fusion forms of ALK, precisely guiding personalized treatment, and providing a reference method for longitudinal monitoring and efficacy evaluation of ALK-tyrosine kinase inhibitors in NSCLC patients.

Enhancing outcomes: neurosurgical resection in brain metastasis patients with poor Karnofsky performance score - a comprehensive survival analysis.

A reduced Karnofsky performance score (KPS) often leads to the discontinuation of surgical and adjuvant therapy, owing to a lack of evidence of survival and quality of life benefits. This study aimed to examine the clinical and treatment outcomes of patients with KPS < 70 after neurosurgical resection and identify prognostic factors associated with better survival. Patients with a preoperative KPS < 70 who underwent surgical resection for newly diagnosed brain metastases (BM) between 2007 and 2020 were retrospectively analyzed. The KPS, age, sex, tumor localization, cumulative tumor volume, number of lesions, extent of resection, prognostic assessment scores, adjuvant radiotherapy and systemic therapy, and presence of disease progression were analyzed. Univariate and multivariate logistic regression analyses were performed to determine the factors associated with better survival. Survival > 3 months was considered favorable and ≤ 3 months as poor. A total of 140 patients were identified. Median overall survival was 5.6 months (range 0-58). There was no difference in the preoperative KPS between the groups of > 3 and ≤ 3 months (50; range, 20-60 vs. 50; range, 10-60, p = 0.077). There was a significant improvement in KPS after surgery in patients with a preoperative KPS of 20% (20 vs 40 ± 20, p = 0.048). In the other groups, no significant changes in KPS were observed. Adjuvant radiotherapy was associated with better survival (44 [84.6%] vs. 32 [36.4%]; hazard ratio [HR], 0.0363; confidence interval [CI], 0.197-0.670, p = 0.00199). Adjuvant chemotherapy and immunotherapy resulted in prolonged survival (24 [46.2%] vs. 12 [13.6%]; HR 0.474, CI 0.263-0.854, p = 0.013]. Systemic disease progression was associated with poor survival (36 [50%] vs. 71 [80.7%]; HR 5.975, CI 2.610-13.677, p < 0.001]. Neurosurgical resection is an appropriate treatment modality for patients with low KPS. Surgery may improve functional status and facilitate further tumor-specific treatment. Combined treatment with adjuvant radiotherapy and systemic therapy was associated with improved survival in this cohort of patients. Systemic tumor progression has been identified as an independent factor for a poor prognosis. There is almost no information regarding surgical and adjuvant treatment in patients with low KPS. Our paper provides novel data on clinical outcome and survival analysis of patients with BM who underwent surgical treatment.

Dosimetric and radiobiological comparison of IMRT, VMAT, and helical tomotherapy planning techniques in hippocampal sparing whole brain radiotherapy with simultaneous integrated boost for multiple brain metastases.

To compare treatment planning and dosimetric outcomes for hippocampal sparing whole brain radiotherapy (WBRT) with the simultaneous integrated boost (SIB) in brain metastasis (BM) patients using tumour control probability (TCP) and normal tissue complication probability (NTCP) formalism between IMRT, VMAT, and HT techniques. In this retrospective study, the treatment data of 20 BM patients who typically received whole brain radiation with SIB treatment were used. Prescription doses of 30Gy and 36Gy was delivered in 10 fractions for WBRT and SIB, respectively. Niemierko and LKB models were applied for calculating TCP and NTCP. All the plans were evaluated for the RTOG 0933 protocol criteria and found acceptable. Additionally, the homogeneity of the PTV boost is 0.07 ± 0.01, 0.1 ± 0.04, and 0.08 ± 0.02 for IMRT, VMAT, and HT, respectively (P < 0.05). The percentage of TCP for the PTV boost was 99.99 ± 0.003, 99.98 ± 0.004, and 99.99 ± 0.002 of IMRT, VMAT, and HT, respectively, (P < 0.005). The NTCP value of the lenses was higher with the VMAT plan as compared to IMRT and HT Plans. The hippocampal NTCP values are equal in all three planning proficiencies. The techniques like IMRT, VMAT, and HT can reduce the dose received by hippocampus to the dosimetric threshold during the delivery of WBRT with hippocampal sparing and can simultaneously boost multiple metastases. Overall, the high-quality dose distribution, TCP, and NTCP comparison between all three planning techniques show that the HT technique has better results when compared to the VMAT and IMRT techniques.

Rate of pachymeningeal failure following adjuvant WBRT vs SRS in patients with brain metastases

BackgroundStereotactic radiosurgery (SRS) has supplanted whole brain radiotherapy (WBRT) as standard-of-care adjuvant treatment following surgery for brain metastasis (BrM). Concomitant with the adoption of adjuvant SRS, a new pattern of failure termed “Pachymeningeal failure” (PMF) has emerged. MethodsWe reviewed a prospective registry of 264 BrM patients; 145 and 119 were treated adjuvantly with WBRT and SRS, respectively. The Cox proportional hazards model was used to identify variables correlating to outcomes. Outcomes were calculated using the cumulative incidence (CI) method. Univariate (UVA) and multivariate analyses (MVA) were done to identify factors associated with PMF. ResultsCI of PMF was 2 % and 18 % at 12 months, and 2 % and 23 % at 24 months for WRBT and SRS, respectively (p < 0.001). The CI of classic leptomeningeal disease (LMD) was 3 % and 4 % at 12 months, and 6 % and 6 % at 24 months for WBRT and SRS, respectively (P = 0.67). On UVA, adjuvant SRS [HR 9.75 (3.43–27.68) (P < 0.001)]; preoperative dural contact (PDC) [HR 6.78 (1.64–28.10) (P = 0.008)]; GPA score [HR 1.64 (1.11–2.42) (P = 0.012)]; and lung EGFR/ALK status [HR 3.11 (1.02–9.45) (P = 0.045)]; were associated with PMF risk. On MVA, adjuvant SRS [HR 8.15 (2.69–24.7) (P < 0.001)]; and PDC [HR 6.28 (1.51–26.1) (P = 0.012)] remained associated with PMF. ConclusionsPreoperative dural contact and adjuvant SRS instead of adjuvant WBRT were associated with an increased risk of PMF. Strategies to improve pachymeningeal radiation coverage to sterilize at risk pachymeninges should be investigated.

Stereotactic radiotherapy for brain metastases in patients with non-small cell lung cancer: CyberKnife-M6 experience

Stereotactic radiotherapy for brain metastases in patients with non-small cell lung cancer: CyberKnife-M6 experience

Enhancing outcomes: Neurosurgical resection in brain metastasis patients with poor Karnofsky performance score - A comprehensive survival analysis

Enhancing outcomes: Neurosurgical resection in brain metastasis patients with poor Karnofsky performance score - A comprehensive survival analysis

Assessment of different head tilt angles in volumetric modulated arc therapy for hippocampus-avoidance whole-brain radiotherapy.

In the field of radiation therapy for brain metastases, whole-brain hippocampus-avoidance treatment is commonly employed. this study aims to examine the impact of different head tilt angles on the dose distribution in the whole-brain target area and organs at risk. It also aims to determine the head tilt angle to achieve optimal radiation therapy outcomes. CT images were collected from 8 brain metastases patients at 5 different groups of head tilt angle. The treatment plans were designed using the volumetric modulated arc therapy (VMAT) technique. The 5 groups of tilt angle were as follows: [0°,10°), [10°,20°), [20°,30°), [30°,40°), and [40°,45°]. The analysis involved assessing parameters such as the uniformity index, conformity index, average dose delivered to the target, dose coverage of the target, hot spots within the target area, maximum dose, and average dose received by organs at risk. Additionally, the study evaluated the correlation between hippocampal dose and other factors, and established linear regression models. Significant differences in dosimetric results were observed between the [40°,45°] and [0°,10°) head tilt angles. The [40°,45°] angle showed significant differences compared to the [0°,10°) angle in the average dose in the target area (31.49 ± 0.29 Gy vs. 31.99 ± 0.29 Gy, p=0.016), dose uniformity (1.20 ± 0.03 vs. 1.24 ± 0.03, p=0.016), hotspots in the target area (33.64 ± 0.35 Gy vs. 34.42 ± 0.49 Gy, p=0.016), maximum hippocampal dose (10.73 ± 0.36 Gy vs. 11.66 ± 0.59 Gy, p=0.008), maximum dose in the lens (2.82 ± 1.10 Gy vs. 4.99 ± 0.16 Gy, p=0.016), and average dose in the lens (1.93 ± 0.29 Gy vs. 4.22 ± 0.26 Gy, p=0.008). There is a moderate correlation between the maximum dose in the hippocampi and the PTV length (r=0.49, p=0.001). Likewise, the mean dose in the hippocampi is significantly correlated with the hippocampi length (r=0.34, p=0.04). The VMAT plan with a head tilt angle of [40°,45°] met all dose constraints and demonstrated improved uniformity of the target area while reducing the dose to organs at risk. Furthermore, the linear regression models suggest that increasing the head tilt angle within the current range of [0°,45°] is likely to lead to a decrease in the average hippocampal dose.

Dosimetric Comparison of Hippocampal Sparing Whole Brain Radiotherapy by Volumetric Modulated Arc Therapy, Linac-based Intensity-modulated Radiation Therapy and 3-D Conformal Radiation Therapy: A Cross-sectional Study

Introduction: Brain metastases are treated with Whole-Brain Radiotherapy (WBRT) using the 3-D Conformal Radiation Therapy (3DCRT) technique. Attempts have been made to perform dosimetric analysis of WBRT with hippocampal sparing using 3DCRT, Volumetric Modulated Arc Therapy (VMAT), and Linac-based Intensity Modulated Radiation Therapy (linac-based IMRT), anticipating technical challenges during contouring and treatment planning. Aim: To perform a dosimetric analysis and comparison ofhippocampal sparing cranial irradiation by 3DCRT, VMAT, and IMRT treatment plans in brain metastases patients. Materials and Methods: The analytical cross-sectional dosimetric study was conducted from November 2022 to September 2023 at Government Medical College, Kottayam, Kerala, India. Ten patients treated for brain metastases with WBRT using 3DCRT were considered for dosimetric analysis. The Planning Target Volume (PTV) dosimetry and hippocampal dosimetry were studied for all ten patients. The important dosimetric parameters included volume receiving 100% dose, Target Coverage (TC), Homogeneity Index (HI) in PTV dosimetry, the mean hippocampal dose, and maximal hippocampal dose in hippocampal dosimetry. The hippocampus and hippocampal avoidance volume were contoured. Treatment plans for 3DCRT, VMAT, and Linac-based IMRT were generated for each patient’s prescription dose of 30 Gy in 10 fractions. The non-parametric Kruskal-Wallis test was used for data analysis. Results: The mean whole brain Planned Target Volume (PTV) was 1190 cm3 . The mean hippocampal avoidance volume was 30 cm3 , which occupied 2.5% of the whole brain PTV. The average median dose received by the hippocampus was 30.05 Gy, 17.1 Gy, and 17.5 Gy for 3DCRT, Linac-based IMRT, and VMAT, respectively. The mean dose for the hippocampus was 31.03 Gy, 17.7 Gy, and 17.5 Gy for 3DCRT, Linac-based IMRT, and VMAT, respectively (p&lt;0.001). VMAT offered better hippocampal sparing compared to IMRT and 3DCRT. On average, VMAT offered a 2% improvement, and 3DCRT offered a 5% improvement in TC compared to IMRT. The HI of 3DCRT was 0.09, IMRT 0.199, and VMAT 0.150. Conclusion: VMAT and LINAC-based IMRT permit hippocampal-sparing WBRT with adequate target volume coverage and acceptable homogeneity when compared to 3DCRT plans. Thus, the dosimetric study suggests that modern radiotherapy techniques should be advocated for hippocampal-sparing WBRT.

Outcomes of Operated Cases of Central Nervous System Metastases at a Tertiary Cancer Hospital – An Analysis

Abstract Background: Recent advances in the treatment have increased the survival of patients with common cancers. As a result, the incidence of symptomatic central nervous system (CNS) metastases has increased over time. Although systemic therapies remain the mainstay of metastatic cancers, surgical treatment is often required for progressive neurological deficits and to buy time for other modalities to be effective. The present retrospective study aimed to analyze various demographic, neurological, and short-term survival outcomes among operated cases of symptomatic CNS metastases. Materials and Methods: All surgically treated symptomatic brain and spine metastasis patients between August 2018 and March 2022 were included in the study. Patients who underwent procedures for primary tumors of the brain and spine were excluded. The details of demographic and clinical profile, neurological data, surgical treatment, and short-term survival data were retrieved from hospital medical records and analyzed. Patients with motor deficits (power grade 3/5 or less) were analyzed to look for improvement in motor deficits after surgery. Results: The first 100 operated cases of symptomatic CNS metastases were reviewed. The mean age of presentation was 46.42 years (females – 44.28, males – 49.13). Breast malignancy was the most common source of primary overall (29%) and lung malignancy (15%) was second most common. A total of 53 brain surgeries and 47 spine surgeries were performed. Preoperative motor deficits were seen more commonly among spine metastases (30/47) than brain metastases (17/53) patients. Around 64% of patients who presented with neurological deficits (motor deficits) had improvement postsurgery. Such improvement from deficits was observed more in patients with spine metastases (23/30; 76.7%) than brain metastases (7/17; 41.2%). Conclusion: Neurosurgery has an important role in the management of CNS metastases, and timely surgical intervention in a selected group of symptomatic CNS metastases can improve the quality of life of the patients.

Exploration of radiotherapy strategy for brain metastasis patients with driver gene positivity in lung cancer.

Objective: To assess the disparities in effectiveness and identify outcome predictors in the treatment of a targeted-first and radiotherapy-first regimen with driver gene-positive lung cancer brain metastases. Materials and Methods: This retrospective study analyzed patients with driver gene-positive lung cancer brain metastases who received first-targeted and first-radiotherapy regimens, respectively, with SIB-WBRT (whole brain tissue 40 Gy/20 fractions, tumor tissue boosted to 56-60 Gy/20 fractions) and local irradiation (prescription dose range of 20-60 Gy/2-25 fractions, most commonly delivered as 30 Gy/5 fractions, with a BED range of 28-100.8 Gy) at Peking Union Medical College Hospital from September 2015 to December 2021. The primary endpoint was intracranial progression free survival (iPFS). Secondary endpoints included overall survival (OS), intracranial new lesions, and tumor control. The Kaplan-Meier method was utilized to depict and estimate iPFS, OS, intracranial new lesions and tumor control. The Cox regression analysis was conducted to assess the association between relevant factors and outcomes. Results: 88 patients were enrolled in targeted-first and radiotherapy-first regimen, totally. And no difference was found in the comparison of iPFS between the two groups (HR=1.180, 95%CI: 0.622-2.237, P=0.613). No difference was found in the comparison of OS between the two groups (HR=1.208, 95%CI: 0.679-2.150, P=0.520). No difference was found in the comparison of intracranial new lesions between the two groups (HR=1.184, 95%CI: 0.569-2.463, P=0.652). There was a difference in the local control time between the two groups, with radiotherapy-first regimen being superior (HR=2.397, 95% CI:1.453-3.954, P<0.001). Patient age (HR=1.054, 95%CI: 1.026- 1.082, P<0.001), radiotherapy modality (HR=0.128, 95%CI: 0.041-0.401, P<0.001), metastasis volume (HR=1.426, 95%CI: 1.209-1.682, P<0.001), number of metastases(HR=14.960, 95%CI: 1.990-112.444, P=0.009), extracranial disease status (HR=0.387, 95%CI: 0.170-0.880, P=0.023) and therapy sequence (HR=13.800, 95%CI: 4.455-42.751, P<0.001) were associated with local control. Conclusion: Targeted-first regimen was not found to improve patients' iPFS relative to radiotherapy-first regimen in patients with brain metastases. Radiotherapy-first regimen for brain metastases demonstrated superior local control compared to targeted-first regimen. Patient's age, radiotherapy modality, metastasis volume, number of metastases, extracranial disease status and therapy sequence may be related to local control of metastases.

Dissecting patterns and predictors of interhospital transfers for patients with brain metastasis.

Interhospital transfers in the acute setting may contribute to high cost, patient inconvenience, and delayed treatment. The authors sought to understand patterns and predictors in the transfer of brain metastasis patients after emergency department (ED) encounter. The authors analyzed 3037 patients with brain metastasis who presented to the ED in Massachusetts and were included in the Healthcare Cost and Utilization Project State Inpatient Database and State Emergency Department Database in 2018 and 2019. The authors found that 6.9% of brain metastasis patients who presented to the ED were transferred to another facility, either directly or indirectly after admission. The sending EDs were more likely to be nonteaching hospitals without neurosurgery and radiation oncology services (p < 0.01). Transferred patients were more likely to present with neurological symptoms compared to those admitted or discharged (p < 0.01). Among those transferred, approximately 30% did not undergo a significant procedure after transfer and approximately 10% were discharged within 3 days, in addition to not undergoing significant interventions. In total, 74% of transferred patients were sent to a facility significantly farther (> 3 miles) than the nearest facility with neurosurgery and radiation oncology services. Further distance transfers were not associated with improvements in 30-day readmission rate (OR [95% CI] 0.64 [0.30-1.34] for 15-30 miles; OR [95% CI] 0.73 [0.37-1.46] for > 30 miles), 90-day readmission rate (OR [95% CI] 0.50 [0.18-1.28] for 15-30 miles; OR [95% CI] 0.53 [0.18-1.51] for > 30 miles), and length of stay (OR [95% CI] 1.21 days [0.94-1.29] for both 15-30 miles and > 30 miles) compared to close-distance transfers. The authors identified a notable proportion of transfers without subsequent significant intervention or appreciable medical management. This may reflect ED physician discomfort with the neurological symptoms of brain metastasis. Many patients were also transferred to hospitals distant from their point of origin and demonstrated no differences in readmission rates and length of stay.

Branch Chain Amino Acid Metabolism Promotes Brain Metastasis of NSCLC through EMT Occurrence by Regulating ALKBH5 activity.

Metabolic reprogramming is one of the essential features of tumors that may dramatically contribute to cancer metastasis. Employing liquid chromatography-tandem mass spectrometry-based metabolomics, we analyzed the metabolic profile from 12 pairwise serum samples of NSCLC brain metastasis patients before and after CyberKnife Stereotactic Radiotherapy. We evaluated the histopathological architecture of 144 surgically resected NSCLC brain metastases. Differential metabolites were screened and conducted for functional clustering and annotation. Metabolomic profiling identified a pathway that was enriched in the metabolism of branched-chain amino acids (BCAAs). Pathologically, adenocarcinoma with a solid growth pattern has a higher propensity for brain metastasis. Patients with high BCAT1 protein levels in lung adenocarcinoma tissues were associated with a poor prognosis. We found that brain NSCLC cells had elevated catabolism of BCAAs, which led to a depletion of α-KG. This depletion, in turn, reduced the expression and activity of the m6A demethylase ALKBH5. Thus, ALKBH5 inhibition participated in maintaining the m6A methylation of mesenchymal genes and promoted the occurrence of epithelial-mesenchymal transition (EMT) in NSCLC cells and the proliferation of NSCLC cells in the brain. BCAA catabolism plays an essential role in the metastasis of NSCLC cells.

Mitigating radiation-induced cognitive toxicity in brain metastases: More questions than answers.

The emergence of advanced systemic therapies added to the use of cranial radiation techniques has significantly improved outcomes for cancer patients with multiple brain metastases (BM), leading to a considerable increase in long-term survivors. In this context, the rise of radiation-induced cognitive toxicity (RICT) has become increasingly relevant. In this critical narrative review, we address the controversies arising from clinical trials aimed at mitigating RICT. We thoroughly examine interventions such as memantine, hippocampal avoidance irradiation during BM treatment or ina prophylactic setting, and the assessment of cognitive safety in stereotactic radiosurgery (SRS). Our focus extends to recent neuroscience research findings, emphasizing the importance of preserving not only the hippocampal cortex but also other cortical regions involved in neural dynamic networks and their intricate role in encoding new memories. Despite treatment advancements, effectively managing patients with multiple BM and determining the optimal timing and integration of radiation and systemic treatments remain areas requiring further elucidation. Future trials are required to delineate optimal indications and ensure SRS safety. Additionally, the impact of new systemic therapies and the potential effects of delaying irradiation on cognitive functioning also need to be addressed. Inclusive trial designs, encompassing patients with multiple BM and accounting for diverse treatment scenarios, are essential for advancing effective strategies in managing RICT and the treatment of BM patients.

The Impact of Immune Checkpoint Inhibition on the Risk of Radiation Necrosis Following Stereotactic Radiotherapy for Metastatic Brain Cancer.

Purpose/objective Forty percentof cancer patients develop brain metastases (BM) and are often treated with stereotactic radiation (SRS/SRT). Checkpoint inhibitor (CI) use is suspected of increasing the risk of radiation necrosis (RN). Our aim is to determine whether treatment with CI is associated with an increased risk of RN in BM patients treated with SRS/SRT. Methods We retrospectively identified the medical records of BM patients treated with SRS/SRT between 1/2017 and 12/2021 using an institutional database.RN was defined by MRI imaging read by neuroradiologists and/or surgical pathology. V12GY of patients with and without RN was compared using the Mann-Whitney test. The chi-square test was used to see if RN was associated with CI use, histology, particular CI agent used, > 1 course SRS/SRT, SRS/SRT dose, chemotherapy, whole brain radiotherapy (WBRT), age, or sex. Results Two hundred and fifty-ninepatients treated with 455 courses of SRS/SRT were analyzed. The most common primary histologies were lung 56% (N=146), breast 14% (N= 37), melanoma 9% (N=24), and renal cancer 7% (N=18). A total of 53.8% (N = no. of patients) were treated with CI. The overall rate of any RN was 21.8% (N=27) in the CI group compared to 14.8% (N=141) in the non-CI group (p=0.174). Mean V12Gy was 15.525 cc and 9.419 cc in patients with and without RN (p=0.02768). Mean number of SRS/SRT courses was 2 and 1.53 for patients with and without RN, and >1 course of SRS/SRT was a predictor of RN (p <0.01). Other features analyzed were not significant. Conclusion RN was higher in the BM patients treated with SRS/SRT receiving CI compared to non-CI patients (21.8%, N=27, versus 14.6%, N= 16), but failed to reach statistical significance. V12Gy and > 1 course of SRS/SRT was associated with RN. Caution should be taken in treating patients with SRS/SRT and CI there might be an increased risk of RN.

Histopathologically confirmed radiation-induced damage of the brain – an in-depth analysis of radiation parameters and spatio-temporal occurrence

BackgroundRadiation-induced damage (RID) after radiotherapy (RT) of primary brain tumors and metastases can be challenging to clinico-radiographically distinguish from tumor progression. RID includes pseudoprogression and radiation necrosis; the latter being irreversible and often associated with severe symptoms. While histopathology constitutes the diagnostic gold standard, biopsy-controlled clinical studies investigating RID remain limited. Whether certain brain areas are potentially more vulnerable to RID remains an area of active investigation. Here, we analyze histopathologically confirmed cases of RID in relation to the temporal and spatial dose distribution.MethodsHistopathologically confirmed cases of RID after photon-based RT for primary or secondary central nervous system malignancies were included. Demographic, clinical, and dosimetric data were collected from patient records and treatment planning systems. We calculated the equivalent dose in 2 Gy fractions (EQD22) and the biologically effective dose (BED2) for normal brain tissue (α/β ratio of 2 Gy) and analyzed the spatial and temporal distribution using frequency maps.ResultsThirty-three patients were identified. High-grade glioma patients (n = 18) mostly received one normofractionated RT series (median cumulative EQD22 60 Gy) to a large planning target volume (PTV) (median 203.9 ccm) before diagnosis of RID. Despite the low EQD22 and BED2, three patients with an accelerated hyperfractionated RT developed RID. In contrast, brain metastases patients (n = 15; 16 RID lesions) were often treated with two or more RT courses and with radiosurgery or fractionated stereotactic RT, resulting in a higher cumulative EQD22 (median 162.4 Gy), to a small PTV (median 6.7 ccm). All (n = 34) RID lesions occurred within the PTV of at least one of the preceding RT courses. RID in the high-grade glioma group showed a frontotemporal distribution pattern, whereas, in metastatic patients, RID was observed throughout the brain with highest density in the parietal lobe. The cumulative EQD22 was significantly lower in RID lesions that involved the subventricular zone (SVZ) than in lesions without SVZ involvement (median 60 Gy vs. 141 Gy, p = 0.01).ConclusionsAccelerated hyperfractionated RT can lead to RID despite computationally low EQD22 and BED2 in high-grade glioma patients. The anatomical location of RID corresponded to the general tumor distribution of gliomas and metastases. The SVZ might be a particularly vulnerable area.

Predictive value of metabolic parameters derived from preoperative 18F-FDG positron emission tomography/computed tomography for brain metastases in patients with surgically resected non-small cell lung cancer.

Brain metastases (BMs) are common complications in patients with non-small cell lung cancer (NSCLC). The purpose of this study was to investigate whether the metabolic parameters derived from preoperative 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) can predict BM development in patients with surgically resected NSCLC. We retrospectively reviewed 128 consecutive patients with stage I-IIIA NSCLC who underwent 18F-FDG PET/CT before curative surgery at The First Affiliated Hospital of Jinan University between November 2012 and October 2021. By drawing a volume of interest (VOI), the maximum standardized uptake values (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of the primary tumor as well as the mean SUV (SUVmean) of the liver and arterial blood were measured. The tumor-to-liver SUV ratio (TLR) and tumor-to-blood SUV ratio (TBR) were also calculated. Receiver operating characteristic curve analysis was used to determine the best cut-off values for positron emission tomography (PET) parameters to predict BM-free survival, and Cox proportional hazards regression analysis was used to assess the predictive value of clinical variables and PET parameters. The median follow-up duration for survival patients was 23.4 months, and 15 patients (11.7%) experienced BM as the initial relapse site. The cumulative rates of BM over the course of 1, 2, and 5 years were 4.5%, 10.5%, and 17.5%, respectively. The optimal cut-off values for the prediction of BM-free survival were 7.7, 4.9, and 4.5 for SUVmax, TLR, and TBR, and 5.5 mL and 16.1 for MTV and TLG, respectively. In the Cox proportional hazards model, the risk of BM was significantly associated with TLR [hazard ratio (HR) =10.712; 95% confidence interval (CI): 2.958-38.801; P<0.001] and MTV (HR =3.150; 95% CI: 0.964-10.293; P=0.020) after adjusting for tumor stage, clinicopathological factors, and other PET parameters. Preoperative TLR and MTV of the primary tumor may be helpful in predicting BM development in patients with surgically resected NSCLC. Tumor metabolic parameters may potentially be used to stratify the risk of BM and determine individualized surveillance strategies.

Abstract A148: The radiosensitizing effects of the novel brain penetrant and potent ATM inhibitor WSD0628 in glioblastoma and melanoma patient derived xenografts

Abstract Radiation therapy (RT) is an important non-surgical clinical treatment for glioblastoma (GBM) and brain metastases, but inherent radio-resistance can limit the efficacy in many patients. The Ataxia Telangiectasia Mutated (ATM) protein critically regulates radiotherapy-mediated DNA damage repair pathways, and defects in this kinase can lead to profound radiosensitivity. In this study, the efficacy of the highly potent ATM inhibitor WSD0628 was evaluated in GBM and melanoma brain metastasis patient derived xenografts (PDXs). In short term explant cultures of three PDXs, WSD0628 robustly suppressed RT-induced autophosphorylation of ATM at serine 1981 and ATM-mediated phosphorylation of Chk2 at threonine-68 and KAP1 at serine-824, with maximal inhibition at 100 nM. Similarly, RT-induced gH2AX foci were significantly reduced when combined with WSD0628 in the GBM43 cells. Consistent with the importance of ATM in the DNA damage response after radiation, WSD0628 significantly increased the radiosensitivity of U251 cells in clonogenic survival assays (0nM vs. 30nM at 5Gy, p&amp;lt;0.01). To evaluate the optimal duration of drug exposure, WSD0628 was removed from U251 cells at various intervals following irradiation with 5 Gy. Using clonogenic survival as a readout, a 10-fold increase in cytotoxicity was observed with an 8 hour drug exposure, with progressively increasing cytotoxicity gains with exposures up to 24 hours. In vivo efficacy of WSD0628 was evaluated in multiple intracranial PDX models. In an initial dose-ranging study, robust radiosensitization was observed in GBM43 treated with 2 Gy x 5 fractions combined with 5 mg/kg WSD0628 (20 day survival extension) or 10mg/kg WSD0628 (39 day with 10 mg/kg; p&amp;lt;0.01 for both dose levels). Moreover, a single dose of 12.5 Gy combined with 10 mg/kg WSD0628 had profound impact on treatment efficacy in the melanoma brain metastasis M12 PDX: at 180 days post-treatment, all mice in the combination group were electively euthanized, while median survival for sham or RT alone was 17d and 49d, respectively. Histologic analysis identified large intracranial tumors in all sham and RT-only treated mice, but only a small accumulation of melanotic cells without obvious tumor in the combination-treated mice. Immunohistochemical staining of NeuN and GFAP in the combination-treated mice showed preserved neuronal density at the 180-post treatment timepoint and minimal reactive gliosis within the ‘tumor scar’. An ongoing study is comparing this single-fraction 12.5 Gy regimen to a 2.4 Gy x 10 fraction regimen alone or in combination with WSD0628. Collectively, this study demonstrates the potential for profound radiosensitizing effects of WSD0628 in combination without obvious neuronal toxicity and has provided the scientific rational for the first-in-man study of this combination in recurrent GBM (NCT05917145) at Mayo Clinic. Citation Format: Zhiyi Xue, Ann C. Mladek, Sneha Rathi, Danielle M. Burgenske, Shiv K. Gupta, Brett L. Carlson, Zeng Hu, Lauren L Ott, Katrina K. Bakken, Rachael A. Vaubel, William F Elmquist, Wei Zhong, Jann N Sarkaria. The radiosensitizing effects of the novel brain penetrant and potent ATM inhibitor WSD0628 in glioblastoma and melanoma patient derived xenografts [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A148.

Brain metastasis, EGFR mutation subtype and generation of EGFR-TKI jointly influence the treatment outcome of patient with EGFR-mutant NSCLC

Non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation is brain metastasis (BM)-prone. We determined the impact of this hallmark, along with EGFR subtype and generation of tyrosine kinase inhibitor (TKI) treatment, on patients’ outcome. 553 metastatic EGFR-mutant NSCLC patients received front-line EGFR-TKI treatment. Progression-free survival (PFS), overall survival (OS) and secondary T790M rate were analysed. BM was observed in 211 (38.2%) patients. BM (HR 1.20 [95% CI 0.99–1.48]; p = 0.053), ECOG PS 0–1 (HR 0.71 [95% CI 0.54–0.93]; p = 0.014) and afatinib treatment (HR 0.81 [95% CI 0.66–0.99]; p = 0.045) were associated with PFS. Afatinib-treated patients without BM demonstrated a significantly longer PFS (16.3 months) compared to afatinib-treated patients with BM (13.7 months) and to gefitinib/erlotinib-treated patients with (11.1 months) or without BM (14.2 months; p < 0.001). CNS-only progression trended higher in afatinib-treated patients. ECOG PS 0–1 (HR 0.41 [95% CI 0.31–0.56]; p < 0.001) and EGFR L858R mutation (HR 1.46 [95% CI 1.13–1.88]; p = 0.003), but not BM, were the predictors for OS. BM (OR 2.02 [95% CI 1.02–4.08]; p = 0.040), afatinib treatment (OR 0.26 [95% CI 0.12–0.50]; p < 0.001) and EGFR L858R mutation (OR 0.55 [95% CI 0.28–1.05]; p = 0.070) were associated with secondary T790M rate. In BM patients, gefitinib/erlotinib-treated ones with 19 deletion mutation and afatinib-treated ones with L858R mutation had the highest and the lowest T790M rate (94.4% vs. 27.3%, p < 0.001), respectively. BM and generation of EGFR-TKI jointly impact PFS and secondary T790M rate in patients with EGFR-mutant NSCLC, whereas OS was mainly associated with EGFR subtype.