Incidence and imaging characteristics of difficult to detect retrospectively identified brain metastases in patients receiving repeat courses of stereotactic radiosurgery.

PURPOSE: During stereotactic radiosurgery (SRS) planning for brain metastases (BM), brain MRIs are reviewed to select appropriate targets based on radiographic characteristics. Some BM are difficult to detect and/or definitively identify and may go untreated initially, only to become apparent on future imaging. We hypothesized that in patients receiving multiple courses of SRS, reviewing the initial planning MRI would reveal early evidence of lesions that developed into metastases requiring SRS. METHODS: Patients undergoing two or more courses of SRS to BM within 6 months between 2016 and 2018 were included in this single-institution, retrospective study. Brain MRIs from the initial course were reviewed for lesions at the same location as subsequently treated metastases; if present, this lesion was classified as a "retrospectively identified metastasis" or RIM. RIMs were subcategorized as meeting or not meeting diagnostic imaging criteria for BM (+ DC or -DC, respectively). RESULTS: Among 683 patients undergoing 923 SRS courses, 98 patients met inclusion criteria. There were 115 repeat courses of SRS, with 345 treated metastases in the subsequent course, 128 of which were associated with RIMs found in a prior MRI. 58% of RIMs were + DC. 17 (15%) of subsequent courses consisted solely of metastases associated with + DC RIMs. CONCLUSION: Radiographic evidence of brain metastases requiring future treatment was occasionally present on brain MRIs from prior SRS treatments. Most RIMs were + DC, and some subsequent SRS courses treated only + DC RIMs. These findings suggest enhanced BM detection might enable earlier treatment and reduce the need for additional SRS.

Brain metastasis as the first and only metastatic relapse site portends worse survival in patients with advanced HER2 + breast cancer.

PURPOSE: Current systemic therapy guidelines for patients with HER2 + breast cancer brain metastases (BCBrM) diverge based on the status of extracranial disease (ECD). An in-depth understanding of the impact of ECD on outcomes in HER2 + BCBrM has never been performed. Our study explores the implications of ECD status on intracranial progression-free survival (iPFS) and overall survival (OS) after first incidence of HER2 + BCBrM and radiation. METHODS: A retrospective analysis was performed of 151 patients diagnosed with initial HER2 + BCBrM who received radiation therapy to the central nervous system (CNS) at Duke between 2008 and 2021. The primary endpoint was iPFS defined as the time from first CNS radiation treatment to intracranial progression or death. OS was defined as the time from first CNS radiation or first metastatic disease to death. Systemic staging scans within 30 days of initial BCBrM defined ECD status as progressive, stable/responding or none (isolated brain relapse). RESULTS: In this cohort, > 70% of patients had controlled ECD with either isolated brain relapse (27%) or stable/responding ECD (44%). OS from initial metastatic disease to death was markedly worse for patients with isolated intracranial relapse (median = 28.4 m) compared to those with progressive or stable/responding ECD (48.8 m and 71.5 m, respectively, p = 0.0028). OS from first CNS radiation to death was significantly worse for patients with progressive ECD (16.9 m) versus stable/responding (36.6 m) or isolated intracranial relapse (28.4 m, p = 0.007). iPFS did not differ statistically based on ECD status. Receipt of systemic therapy after first BCBrM significantly improved iPFS (HR 0.45, 95% CI: 0.25-0.81, p = 0.008) and OS (HR: 0.43 (95% CI: 0.23-0.81); p = 0.001). CONCLUSION: OS in patients with HER2 + isolated BCBrM was inferior to those with concurrent progressive or stable/responding ECD. Studies investigating initiation of brain-penetrable HER2-targeted therapies earlier in the disease course of isolated HER2 + intracranial relapse patients are warranted.

Current multidisciplinary management of brain metastases.

Brain metastasis (BM), the most common adult brain tumor, develops in 20% to 40% of patients with late-stage cancer and traditionally are associated with a poor prognosis. The management of patients with BM has become increasingly complex because of new and emerging systemic therapies and advancements in radiation oncology and neurosurgery. Current therapies include stereotactic radiosurgery, whole-brain radiation therapy, surgical resection, laser-interstitial thermal therapy, systemic cytotoxic chemotherapy, targeted agents, and immune-checkpoint inhibitors. Determining the optimal treatment for a specific patient has become increasingly individualized, emphasizing the need for multidisciplinary discussions of patients with BM. Recognizing and addressing the sequelae of BMs and their treatment while maintaining quality of life and neurocognition is especially important because survival for patients with BMs has improved. The authors present current and emerging treatment options for patients with BM and suggest approaches for managing sequelae and disease recurrence.

bcSeq: an R package for fast sequence mapping in high-throughput shRNA and CRISPR screens.

Summary: CRISPR-Cas9 and shRNA high-throughput sequencing screens have abundant applications for basic and translational research. Methods and tools for the analysis of these screens must properly account for sequencing error, resolve ambiguous mappings among similar sequences in the barcode library in a statistically principled manner, and be computationally efficient. Herein we present bcSeq, an open source R package that implements a fast and parallelized algorithm for mapping high-throughput sequencing reads to a barcode library while tolerating sequencing error. The algorithm uses a Trie data structure for speed and resolves ambiguous mappings by using a statistical sequencing error model based on Phred scores for each read. Availability and implementation: The package source code and an accompanying tutorial are available at http://bioconductor.org/packages/bcSeq/. Supplementary information: Supplementary data are available at Bioinformatics online.

The bromodomain protein Brd4 insulates chromatin from DNA damage signalling.

DNA damage activates a signalling network that blocks cell-cycle progression, recruits DNA repair factors and/or triggers senescence or programmed cell death. Alterations in chromatin structure are implicated in the initiation and propagation of the DNA damage response. Here we further investigate the role of chromatin structure in the DNA damage response by monitoring ionizing-radiation-induced signalling and response events with a high-content multiplex RNA-mediated interference screen of chromatin-modifying and -interacting genes. We discover that an isoform of Brd4, a bromodomain and extra-terminal (BET) family member, functions as an endogenous inhibitor of DNA damage response signalling by recruiting the condensin II chromatin remodelling complex to acetylated histones through bromodomain interactions. Loss of this isoform results in relaxed chromatin structure, rapid cell-cycle checkpoint recovery and enhanced survival after irradiation, whereas functional gain of this isoform compacted chromatin, attenuated DNA damage response signalling and enhanced radiation-induced lethality. These data implicate Brd4, previously known for its role in transcriptional control, as an insulator of chromatin that can modulate the signalling response to DNA damage.

Coenzyme A protects against ferroptosis via CoAlation of thioredoxin reductase 2.

The Cystine-xCT transporter-Glutathione (GSH)-GPX4 axis is the canonical pathway to protect against ferroptosis. While not required for ferroptosis-inducing compounds (FINs) targeting GPX4, FINs targeting the xCT transporter require mitochondria and its lipid peroxidation to trigger ferroptosis. However, the mechanism underlying the difference between these FINs is still unknown. Given that cysteine is also required for coenzyme A (CoA) biosynthesis, here we show that CoA supplementation specifically prevents ferroptosis induced by xCT inhibitors but not GPX4 inhibitors. We find that, auranofin, a thioredoxin reductase inhibitor, abolishes the protective effect of CoA. We also find that CoA availability determines the enzymatic activity of thioredoxin reductase, but not thioredoxin. Importantly, the mitochondrial thioredoxin system, but not the cytosolic thioredoxin system, determines CoA-mediated ferroptosis inhibition. Our data show that the CoA regulates the in vitro enzymatic activity of mitochondrial thioredoxin reductase (TXNRD2) by covalently modifying the thiol group of cysteine (CoAlation) on Cys-483. Replacing Cys-483 with alanine on TXNRD2 abolishes its in vitro enzymatic activity and ability to protect cells from ferroptosis. Targeting xCT to limit cysteine import and, therefore, CoA biosynthesis reduced CoAlation on TXNRD2, an effect that was rescued by CoA supplementation. Furthermore, the fibroblasts from patients with disrupted CoA metabolism demonstrate increased mitochondrial lipid peroxidation. In organotypic brain slice cultures, inhibition of CoA biosynthesis leads to an oxidized thioredoxin system, mitochondrial lipid peroxidation, and loss in cell viability, which were all rescued by ferrostatin-1. These findings identify CoA-mediated post-translation modification to regulate the thioredoxin system as an alternative ferroptosis protection pathway with potential clinical relevance for patients with disrupted CoA metabolism.

Determinants of Symptomatic Intracranial Progression After an Initial Stereotactic Radiosurgery Course.

Purpose: Clinical and imaging surveillance of patients with brain metastases is important after stereotactic radiosurgery (SRS) because many will experience intracranial progression (ITCP) requiring multidisciplinary management. The prognostic significance of neurologic symptoms at the time of ITCP is poorly understood. Methods and Materials: This was a multi-institutional, retrospective cohort study from 2015 to 2020, including all patients with brain metastases completing an initial course of SRS. The primary outcome was overall survival (OS) by presence of neurologic symptoms at ITCP. OS, freedom from ITCP (FF-ITCP), and freedom from symptomatic ITCP (FF-SITCP) were assessed via Kaplan-Meier method. Cox proportional hazard models tested parameters impacting FF-ITCP and FF-SITCP. Results: Among 1383 patients, median age was 63.4 years, 55% were female, and common primaries were non-small cell lung (49%), breast (15%), and melanoma (9%). At a median follow-up of 8.72 months, asymptomatic and symptomatic ITCP were observed in 504 (36%) and 194 (14%) patients, respectively. The majority of ITCP were distant ITCP (79.5%). OS was worse with SITCP (median, 10.2 vs 17.9 months, P < .001). SITCP was associated with clinical factors including total treatment volume (P = .012), melanoma histology (P = .001), prior whole brain radiation therapy (P = .003), number of brain metastases (P < .001), interval of 1 to 2 years from primary and brain metastasis diagnosis (P = .012), controlled extracranial disease (P = .042), and receipt of pre-SRS chemotherapy (P = .015). Patients who were younger and received post-SRS chemotherapy (P = .001), immunotherapy (P < .001), and targeted or small-molecule inhibitor therapy (P < .026) had better FF-SITCP. Conclusions: In this cohort study of patients with brain metastases completing SRS, neurologic symptoms at ITCP is prognostic for OS. This data informs post-SRS surveillance in clinical practice as well as future prospective studies needed in the modern management of brain metastases.

Dose-Incorporated Deep Ensemble Learning for Improving Brain Metastasis Stereotactic Radiosurgery Outcome Prediction.

PURPOSE: To develop a novel deep ensemble learning model for accurate prediction of brain metastasis (BM) local control outcomes after stereotactic radiosurgery (SRS). METHODS AND MATERIALS: A total of 114 brain metastases (BMs) from 82 patients were evaluated, including 26 BMs that developed biopsy-confirmed local failure post-SRS. The SRS spatial dose distribution (Dmap) of each BM was registered to the planning contrast-enhanced T1 (T1-CE) magnetic resonance imaging (MRI). Axial slices of the Dmap, T1-CE, and planning target volume (PTV) segmentation (PTVseg) intersecting the BM center were extracted within a fixed field of view determined by the 60% isodose volume in Dmap. A spherical projection was implemented to transform planar image content onto a spherical surface using multiple projection centers, and the resultant T1-CE/Dmap/PTVseg projections were stacked as a 3-channel variable. Four Visual Geometry Group (VGG-19) deep encoders were used in an ensemble design, with each submodel using a different spherical projection formula as input for BM outcome prediction. In each submodel, clinical features after positional encoding were fused with VGG-19 deep features to generate logit results. The ensemble's outcome was synthesized from the 4 submodel results via logistic regression. In total, 10 model versions with random validation sample assignments were trained to study model robustness. Performance was compared with (1) a single VGG-19 encoder, (2) an ensemble with a T1-CE MRI as the sole image input after projections, and (3) an ensemble with the same image input design without clinical feature inclusion. RESULTS: The ensemble model achieved an excellent area under the receiver operating characteristic curve (AUCROC: 0.89 ± 0.02) with high sensitivity (0.82 ± 0.05), specificity (0.84 ± 0.11), and accuracy (0.84 ± 0.08) results. This outperformed the MRI-only VGG-19 encoder (sensitivity: 0.35 ± 0.01, AUCROC: 0.64 ± 0.08), the MRI-only deep ensemble (sensitivity: 0.60 ± 0.09, AUCROC: 0.68 ± 0.06), and the 3-channel ensemble without clinical feature fusion (sensitivity: 0.78 ± 0.08, AUCROC: 0.84 ± 0.03). CONCLUSIONS: Facilitated by the spherical image projection method, a deep ensemble model incorporating Dmap and clinical variables demonstrated excellent performance in predicting BM post-SRS local failure. Our novel approach could improve other radiation therapy outcome models and warrants further evaluation.

Effects of Ataxia-Telangiectasia Mutated Variants on Radionecrosis and Local Control After Stereotactic Radiation Surgery for Non-Small Cell Lung Cancer Brain Metastases.

Purpose: Genetic variants affecting the radiation response protein ataxia-telangiectasia mutated (ATM) have been associated with increased adverse effects of radiation but also with improved local control after conventional radiation therapy. However, it is unknown whether ATM variants affect rates of radionecrosis (RN) and local intracranial progression (LIP) after stereotactic radiosurgery (SRS) for brain metastases. Methods and Materials: Patients undergoing an initial course of SRS for non-small cell lung cancer (NSCLC) brain metastases at a single institution were retrospectively identified. Kaplan-Meier estimates were calculated and Cox proportional hazards testing was performed based on ATM variant status. Results: A total of 541 patients completed SRS for brain metastasis secondary to NSCLC, of whom 260 completed molecular profiling. Variants of ATM were identified in 36 cases (13.8%). Among patients who completed molecular profiling, RN incidence was 4.9% (95% CI, 1.6%-8.2%) at 6 months and 9.9% (95% CI, 4.8%-15.0%) at 12 months. Incidence of RN was not significantly increased among patients with ATM variants, with an RN incidence of 5.3% (95% CI, 0.0%-15.3%) at both 6 and 12 months (P = .46). For all patients who completed genomic profiling, LIP was 5.4% (95% CI, 2.4%-8.4%) at 6 months and 9.8% (5.5%-14.1%) at 12 months. A significant improvement in LIP was not detected among patients with ATM variants, with an LIP incidence of 3.1% (0.0%-9.1%) at both 6 and 12 months (P = .26). Although differences according to ATM variant type (pathologic variant or variant of unknown significance) did not reach significance, no patients with ATM pathologic variants experienced LIP. Conclusions: We did not detect significant associations between ATM variant status and RN or LIP after SRS for NSCLC brain metastases. The current data set allows estimation of patient cohort sizes needed to power future investigations to identify genetic variants that associate with significant differences in outcomes after SRS.

Long-Term Intracranial Outcomes With Combination Dual Immune-Checkpoint Blockade and Stereotactic Radiosurgery in Patients With Melanoma and Non-Small Cell Lung Cancer Brain Metastases.

PURPOSE: The intracranial benefit of offering dual immune-checkpoint inhibition (D-ICPI) with ipilimumab and nivolumab to patients with melanoma or non-small cell lung cancer (NSCLC) receiving stereotactic radiosurgery (SRS) for brain metastases (BMs) is unknown. We hypothesized that D-ICPI improves local control compared with SRS alone. METHODS AND MATERIALS: Patients with melanoma or NSCLC treated with SRS from 2014 to 2022 were evaluated. Patients were stratified by treatment with D-ICPI, single ICPI (S-ICPI), or SRS alone. Local recurrence, intracranial progression (IP), and overall survival were estimated using competing risk and Kaplan-Meier analyses. IP included both local and distant intracranial recurrence. RESULTS: Two hundred eighty-eight patients (44% melanoma, 56% NSCLC) with 1,704 BMs were included. Fifty-three percent of patients had symptomatic BMs. The median follow-up was 58.8 months. Twelve-month local control rates with D-ICPI, S-ICPI, and SRS alone were 94.73% (95% CI, 91.11%-96.90%), 91.74% (95% CI, 89.30%-93.64%), and 88.26% (95% CI, 84.07%-91.41%). On Kaplan-Meier analysis, only D-ICPI was significantly associated with reduced local recurrence (P = .0032). On multivariate Cox regression, D-ICPI (hazard ratio [HR], 0.4003; 95% CI, 0.1781-0.8728; P = .0239) and planning target volume (HR, 1.022; 95% CI, 1.004-1.035; P = .0059) correlated with local control. One hundred seventy-three (60%) patients developed IP. The 12-month cumulative incidence of IP was 41.27% (95% CI, 30.27%-51.92%), 51.86% (95% CI, 42.78%-60.19%), and 57.15% (95% CI, 44.98%-67.59%) after D-ICPI, S-ICPI, and SRS alone. On competing risk analysis, only D-ICPI was significantly associated with reduced IP (P = .0408). On multivariate Cox regression, D-ICPI (HR, 0.595; 95% CI, 0.373-0.951; P = .0300) and presentation with >10 BMs (HR, 2.492; 95% CI, 1.668-3.725; P < .0001) remained significantly correlated with IP. The median overall survival after D-ICPI, S-ICPI, and SRS alone was 26.1 (95% CI, 15.5-40.7), 21.5 (16.5-29.6), and 17.5 (11.3-23.8) months. S-ICPI, fractionation, and histology were not associated with clinical outcomes. There was no difference in hospitalizations or neurologic adverse events between cohorts. CONCLUSIONS: The addition of D-ICPI for patients with melanoma and NSCLC undergoing SRS is associated with improved local and intracranial control. This appears to be an effective strategy, including for patients with symptomatic or multiple BMs.

A multi-institutional meningioma MRI dataset for automated multi-sequence image segmentation.

Meningiomas are the most common primary intracranial tumors and can be associated with significant morbidity and mortality. Radiologists, neurosurgeons, neuro-oncologists, and radiation oncologists rely on brain MRI for diagnosis, treatment planning, and longitudinal treatment monitoring. However, automated, objective, and quantitative tools for non-invasive assessment of meningiomas on multi-sequence MR images are not available. Here we present the BraTS Pre-operative Meningioma Dataset, as the largest multi-institutional expert annotated multilabel meningioma multi-sequence MR image dataset to date. This dataset includes 1,141 multi-sequence MR images from six sites, each with four structural MRI sequences (T2-, T2/FLAIR-, pre-contrast T1-, and post-contrast T1-weighted) accompanied by expert manually refined segmentations of three distinct meningioma sub-compartments: enhancing tumor, non-enhancing tumor, and surrounding non-enhancing T2/FLAIR hyperintensity. Basic demographic data are provided including age at time of initial imaging, sex, and CNS WHO grade. The goal of releasing this dataset is to facilitate the development of automated computational methods for meningioma segmentation and expedite their incorporation into clinical practice, ultimately targeting improvement in the care of meningioma patients.

A neural ordinary differential equation model for visualizing deep neural network behaviors in multi-parametric MRI-based glioma segmentation.

PURPOSE: To develop a neural ordinary differential equation (ODE) model for visualizing deep neural network behavior during multi-parametric MRI-based glioma segmentation as a method to enhance deep learning explainability. METHODS: By hypothesizing that deep feature extraction can be modeled as a spatiotemporally continuous process, we implemented a novel deep learning model, Neural ODE, in which deep feature extraction was governed by an ODE parameterized by a neural network. The dynamics of (1) MR images after interactions with the deep neural network and (2) segmentation formation can thus be visualized after solving the ODE. An accumulative contribution curve (ACC) was designed to quantitatively evaluate each MR image's utilization by the deep neural network toward the final segmentation results. The proposed Neural ODE model was demonstrated using 369 glioma patients with a 4-modality multi-parametric MRI protocol: T1, contrast-enhanced T1 (T1-Ce), T2, and FLAIR. Three Neural ODE models were trained to segment enhancing tumor (ET), tumor core (TC), and whole tumor (WT), respectively. The key MRI modalities with significant utilization by deep neural networks were identified based on ACC analysis. Segmentation results by deep neural networks using only the key MRI modalities were compared to those using all four MRI modalities in terms of Dice coefficient, accuracy, sensitivity, and specificity. RESULTS: All Neural ODE models successfully illustrated image dynamics as expected. ACC analysis identified T1-Ce as the only key modality in ET and TC segmentations, while both FLAIR and T2 were key modalities in WT segmentation. Compared to the U-Net results using all four MRI modalities, the Dice coefficient of ET (0.784→0.775), TC (0.760→0.758), and WT (0.841→0.837) using the key modalities only had minimal differences without significance. Accuracy, sensitivity, and specificity results demonstrated the same patterns. CONCLUSION: The Neural ODE model offers a new tool for optimizing the deep learning model inputs with enhanced explainability. The presented methodology can be generalized to other medical image-related deep-learning applications.

A Deep Learning-Based Computer Aided Detection (CAD) System for Difficult-to-Detect Brain Metastases.

PURPOSE: We sought to develop a computer-aided detection (CAD) system that optimally augments human performance, excelling especially at identifying small inconspicuous brain metastases (BMs), by training a convolutional neural network on a unique magnetic resonance imaging (MRI) data set containing subtle BMs that were not detected prospectively during routine clinical care. METHODS AND MATERIALS: Patients receiving stereotactic radiosurgery (SRS) for BMs at our institution from 2016 to 2018 without prior brain-directed therapy or small cell histology were eligible. For patients who underwent 2 consecutive courses of SRS, treatment planning MRIs from their initial course were reviewed for radiographic evidence of an emerging metastasis at the same location as metastases treated in their second SRS course. If present, these previously unidentified lesions were contoured and categorized as retrospectively identified metastases (RIMs). RIMs were further subcategorized according to whether they did (+DC) or did not (-DC) meet diagnostic imaging-based criteria to definitively classify them as metastases based upon their appearance in the initial MRI alone. Prospectively identified metastases (PIMs) from these patients, and from patients who only underwent a single course of SRS, were also included. An open-source convolutional neural network architecture was adapted and trained to detect both RIMs and PIMs on thin-slice, contrast-enhanced, spoiled gradient echo MRIs. Patients were randomized into 5 groups: 4 for training/cross-validation and 1 for testing. RESULTS: One hundred thirty-five patients with 563 metastases, including 72 RIMS, met criteria. For the test group, CAD sensitivity was 94% for PIMs, 80% for +DC RIMs, and 79% for PIMs and +DC RIMs with diameter <3 mm, with a median of 2 false positives per patient and a Dice coefficient of 0.79. CONCLUSIONS: Our CAD model, trained on a novel data set and using a single common MR sequence, demonstrated high sensitivity and specificity overall, outperforming published CAD results for small metastases and RIMs - the lesion types most in need of human performance augmentation.

Clinical Factors Associated With 30-Day Mortality Among Patients Undergoing Radiation Therapy for Brain Metastases.

Purpose: Existing brain metastasis prognostic models do not identify patients at risk of very poor survival after radiation therapy (RT). Identifying patient and disease risk factors for 30-day mortality (30-DM) after RT may help identify patients who would not benefit from RT. Methods and Materials: All patients who received stereotactic radiosurgery (SRS) or whole-brain RT (WBRT) for brain metastases from January 1, 2017, to September 30, 2020, at a single tertiary care center were included. Variables regarding demographics, systemic and intracranial disease characteristics, symptoms, RT, palliative care, and death were recorded. Thirty-day mortality was defined as death within 30 days of RT completion. The Kaplan-Meier method was used to estimate median overall survival. Univariate and multivariable logistic regression models were used to assess associations between demographic, tumor, and treatment factors and 30-DM. Results: A total of 636 patients with brain metastases were treated with either WBRT (n = 117) or SRS (n = 519). The most common primary disease types were non-small cell lung (46.7%) and breast (19.8%) cancer. Median survival time was 6 months (95% CI, 5-7 months). Of the 636 patients, 75 (11.7%) died within 30 days of RT. On multivariable analysis, progressive intrathoracic disease (hazard ratio [HR], 4.67; 95% CI, 2.06-10.60; P = .002), progressive liver and/or adrenal metastases (HR, 2.20; 95% CI, 1.16-3.68; P = .02), and inpatient status (HR, 4.51; 95% CI, 1.78-11.42; P = .002) were associated with dying within 30 days of RT. A higher Karnofsky Performance Status (KPS) score (HR, 0.95; 95% CI, 0.93-0.97; P < .001), synchronous brain metastases at time of initial diagnosis (HR, 0.45; 95% CI, 0.21-0.96; P = .04), and outpatient palliative care utilization (HR, 0.45; 95% CI, 0.20-1.00; P = .05) were associated with surviving more than 30 days after RT. Conclusions: Multiple factors including a lower KPS, progressive intrathoracic disease, progressive liver and/or adrenal metastases, and inpatient status were associated with 30-DM after RT. A higher KPS, brain metastases at initial diagnosis, and outpatient palliative care utilization were associated with survival beyond 30 days. These data may aid in identifying which patients may benefit from brain metastasis-directed RT.

Intracranial and Extracranial Progression and Their Correlation With Overall Survival After Stereotactic Radiosurgery in a Multi-institutional Cohort With Brain Metastases.

Importance: Clinical trials for metastatic malignant neoplasms are increasingly being extended to patients with brain metastases. Despite the preeminence of progression-free survival (PFS) as a primary oncologic end point, the correlation of intracranial progression (ICP) and extracranial progression (ECP) events with overall survival (OS) is poorly understood for patients with brain metastases following stereotactic radiosurgery (SRS). Objective: To determine the correlation of ICP and ECP with OS among patients with brain metastases completing an initial SRS course. Design, Setting, and Participants: This multi-institutional retrospective cohort study was conducted from January 1, 2015, to December 31, 2020. We included patients who completed an initial course of SRS for brain metastases during the study period, including receipt of single and/or multifraction SRS, prior whole-brain radiotherapy, and brain metastasis resection. Data analysis was performed on November 15, 2022. Exposures: Non-OS end points included intracranial PFS, extracranial PFS, PFS, time to ICP, time to ECP, and any time to progression. Progression events were radiologically defined, incorporating multidisciplinary clinical consensus. Main Outcomes and Measures: The primary outcome was correlation of surrogate end points to OS. Clinical end points were estimated from time of SRS completion via the Kaplan-Meier method, while end-point correlation to OS was measured using normal scores rank correlation with the iterative multiple imputation approach. Results: This study included 1383 patients, with a mean age of 63.1 years (range, 20.9-92.8 years) and a median follow-up of 8.72 months (IQR, 3.25-19.68 months). The majority of participants were White (1032 [75%]), and more than half (758 [55%]) were women. Common primary tumor sites included the lung (757 [55%]), breast (203 [15%]), and skin (melanoma; 100 [7%]). Intracranial progression was observed in 698 patients (50%), preceding 492 of 1000 observed deaths (49%). Extracranial progression was observed in 800 patients (58%), preceding 627 of 1000 observed deaths (63%). Irrespective of deaths, 482 patients (35%) experienced both ICP and ECP, 534 (39%) experienced ICP (216 [16%]) or ECP (318 [23%]), and 367 (27%) experienced neither. The median OS was 9.93 months (95% CI, 9.08-11.05 months). Intracranial PFS had the highest correlation with OS (ρ = 0.84 [95% CI, 0.82-0.85]; median, 4.39 months [95% CI, 4.02-4.92 months]). Time to ICP had the lowest correlation with OS (ρ = 0.42 [95% CI, 0.34-0.50]) and the longest median time to event (median, 8.76 months [95% CI, 7.70-9.48 months]). Across specific primary tumor types, correlations of intracranial PFS and extracranial PFS with OS were consistently high despite corresponding differences in median outcome durations. Conclusions and Relevance: The results of this cohort study of patients with brain metastases completing SRS suggest that intracranial PFS, extracranial PFS, and PFS had the highest correlations with OS and time to ICP had the lowest correlation with OS. These data may inform future patient inclusion and end-point selection for clinical trials.

Novel Mechanisms and Future Opportunities for the Management of Radiation Necrosis in Patients Treated for Brain Metastases in the Era of Immunotherapy.

Radiation necrosis, also known as treatment-induced necrosis, has emerged as an important adverse effect following stereotactic radiotherapy (SRS) for brain metastases. The improved survival of patients with brain metastases and increased use of combined systemic therapy and SRS have contributed to a growing incidence of necrosis. The cyclic GMP-AMP (cGAMP) synthase (cGAS) and stimulator of interferon genes (STING) pathway (cGAS-STING) represents a key biological mechanism linking radiation-induced DNA damage to pro-inflammatory effects and innate immunity. By recognizing cytosolic double-stranded DNA, cGAS induces a signaling cascade that results in the upregulation of type 1 interferons and dendritic cell activation. This pathway could play a key role in the pathogenesis of necrosis and provides attractive targets for therapeutic development. Immunotherapy and other novel systemic agents may potentiate activation of cGAS-STING signaling following radiotherapy and increase necrosis risk. Advancements in dosimetric strategies, novel imaging modalities, artificial intelligence, and circulating biomarkers could improve the management of necrosis. This review provides new insights into the pathophysiology of necrosis and synthesizes our current understanding regarding the diagnosis, risk factors, and management options of necrosis while highlighting novel avenues for discovery.

Outcomes in Patients with Intact and Resected Brain Metastasis Treated with 5-Fraction Stereotactic Radiosurgery.

Purpose: Hypofractionated stereotactic radiosurgery (HF-SRS) with or without surgical resection is potentially a preferred treatment for larger or symptomatic brain metastases (BMs). Herein, we report clinical outcomes and predictive factors following HF-SRS. Methods and Materials: Patients undergoing HF-SRS for intact (iHF-SRS) or resected (rHF-SRS) BMs from 2008 to 2018 were retrospectively identified. Linear accelerator-based image-guided HF-SRS consisted of 5 fractions at 5, 5.5, or 6 Gy per fraction. Time to local progression (LP), time to distant brain progression (DBP), and overall survival (OS) were calculated. Cox models assessed effect of clinical factors on OS. Fine and Gray's cumulative incidence model for competing events examined effect of factors on LP and DBP. The occurrence of leptomeningeal disease (LMD) was determined. Logistic regression examined predictors of LMD. Results: Among 445 patients, median age was 63.5 years; 87% had Karnofsky performance status ≥70. Fifty-three % of patients underwent surgical resection, and 75% received 5 Gy per fraction. Patients with resected BMs had higher Karnofsky performance status (90-100, 41 vs 30%), less extracranial disease (absent, 25 vs 13%), and fewer BMs (multiple, 32 vs 67%). Median diameter of the dominant BM was 3.0 cm (interquartile range, 1.8-3.6 cm) for intact BMs and 4.6 cm (interquartile range, 3.9-5.5 cm) for resected BMs. Median OS was 5.1 months (95% confidence interval [CI], 4.3-6.0) following iHF-SRS and 12.8 months (95% CI, 10.8-16.2) following rHF-SRS (P < .01). Cumulative LP incidence was 14.5% at 18 months (95% CI, 11.4-18.0%), significantly associated with greater total GTV (hazard ratio, 1.12; 95% CI, 1.05-1.20) following iFR-SRS, and with recurrent versus newly diagnosed BMs across all patients (hazard ratio, 2.28; 95% CI, 1.01-5.15). Cumulative DBP incidence was significantly greater following rHF-SRS than iHF-SRS (P = .01), with respective 24-month rates of 50.0 (95% CI, 43.3-56.3) and 35.7% (95% CI, 29.2-42.2). LMD (57 events total; 33% nodular, 67% diffuse) was observed in 17.1% of rHF-SRS and 8.1% of iHF-SRS cases (odds ratio, 2.46; 95% CI, 1.34-4.53). Any radionecrosis and grade 2+ radionecrosis events were observed in 14 and 8% of cases, respectively. Conclusions: HF-SRS demonstrated favorable rates of LC and radionecrosis in postoperative and intact settings. Corresponding LMD and RN rates were comparable to those of other studies.

Long-term outcomes with reduced-dose whole-brain radiotherapy and a stereotactic radiosurgery boost for primary central nervous system lymphoma.

Background: Primary central nervous system lymphoma (PCNSL) is an aggressive diffuse large B-cell lymphoma. Treatment approaches are historically associated with neurotoxicity, particularly with high-dose whole-brain radiotherapy (WBRT). We hypothesized that reduced dose-WBRT (rd-WBRT) followed by a stereotactic radiosurgery (SRS) boost could provide durable disease control without significant adverse effects. Methods: We retrospectively reviewed PCNSL patients treated with rd-WBRT plus an SRS boost at Duke University between 2008 and 2021. Progression-free survival and overall survival (OS) were estimated using competing risk and Kaplan-Meier methods. Results: We identified 23 patients with pathologically confirmed PCNSL. Median age at diagnosis was 69 years (Q1Q3: 52-74) and median Karnofsky Performance Scale (KPS) was 80 (Q1Q3: 70-80). Median follow-up was 21 months. Median doses for rd-WBRT and SRS were 23.4 Gy (Q1Q3: 23.4-23.4) and 12 Gy (Q1Q3: 12-12.5), respectively. The cumulative incidence of intracranial progression at 2 years was 23% (95% CI: 8-42). Six patients (26%) developed distant radiographic progression while 2 patients (9%) developed both distant and local progression. Ten patients (44%) were alive without progression at last follow-up. By Kaplan-Meier estimate, the 2-year OS was 69% (95% CI: 46-84). There were no reported grade 3 + radiation-induced toxicities. Conclusions: The combination of rd-WBRT with an SRS boost appears well-tolerated with durable intracranial control. This approach may represent a treatment option for select patients, such as those with progressive or refractory disease. Further prospective studies are needed to validate these findings and determine whether this approach could be incorporated into consolidation strategies.

MAPKAP Kinase-2 phosphorylation of PABPC1 controls its interaction with 14-3-3 proteins after DNA damage: A combined kinase and protein array approach.

14-3-3 proteins play critical roles in controlling multiple aspects of the cellular response to stress and DNA damage including regulation of metabolism, cell cycle progression, cell migration, and apoptotic cell death by binding to protein substrates of basophilic protein kinases following their phosphorylation on specific serine/threonine residues. Although over 200 mammalian proteins that bind to 14-3-3 have been identified, largely through proteomic studies, in many cases the relevant protein kinase responsible for conferring 14-3-3-binding to these proteins is not known. To facilitate the identification of kinase-specific 14-3-3 clients, we developed a biochemical approach using high-density protein filter arrays and identified the translational regulatory molecule PABPC1 as a substrate for Chk1 and MAPKAP Kinase-2 (MK2) in vitro, and for MK2 in vivo, whose phosphorylation results in 14-3-3-binding. We identify Ser-470 on PABPC1 within the linker region connecting the RRM domains to the PABC domain as the critical 14-3-3-binding site, and demonstrate that loss of PABPC1 binding to 14-3-3 results in increased cell proliferation and decreased cell death in response to UV-induced DNA damage.

Erratum to "E.C. Lerner, E.S. Srinivasan, G. Broadwater, et al. Factors Associated With New-Onset Seizures Following Stereotactic Radiosurgery for Newly Diagnosed Brain Metastases. Adv Radiat Oncol. 2022;7:101054."

[This corrects the article DOI: 10.1016/j.adro.2022.101054.].