Synthetic cationic helical polypeptides for the stimulation of antitumour innate immune pathways in antigen-presenting cells.

Intracellular DNA sensors regulate innate immunity and can provide a bridge to adaptive immunogenicity. However, the activation of the sensors in antigen-presenting cells (APCs) by natural agonists such as double-stranded DNAs or cyclic nucleotides is impeded by poor intracellular delivery, serum stability, enzymatic degradation and rapid systemic clearance. Here we show that the hydrophobicity, electrostatic charge and secondary conformation of helical polypeptides can be optimized to stimulate innate immune pathways via endoplasmic reticulum stress in APCs. One of the three polypeptides that we engineered activated two major intracellular DNA-sensing pathways (cGAS-STING (for cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes) and Toll-like receptor 9) preferentially in APCs by promoting the release of mitochondrial DNA, which led to the efficient priming of effector T cells. In syngeneic mouse models of locally advanced and metastatic breast cancers, the polypeptides led to potent DNA-sensor-mediated antitumour responses when intravenously given as monotherapy or with immune checkpoint inhibitors. The activation of multiple innate immune pathways via engineered cationic polypeptides may offer therapeutic advantages in the generation of antitumour immune responses.

Ventriculoperitoneal shunting with an on-off valve for patients with leptomeningeal metastases and intracranial hypertension.

Background: We report our experience with using a ventriculoperitoneal shunt (VPS) with an on-off valve and in-line Ommaya reservoir for the treatment of hydrocephalus or intracranial hypertension in patients with leptomeningeal disease (LMD). Our goal was to determine whether control of intracranial pressure elevation combined with intrathecal (IT) chemotherapy would extend patient survival. Methods: In this IRB-approved retrospective study, we reviewed 58 cases of adult patients with LMD from solid cancers who received a VPS with a reservoir and an on-off valve at M D Anderson Cancer Center from November 1996 through December 2021. Primary tumors were most often melanoma (n = 19) or breast carcinoma (n = 20). Hydrocephalus was diagnosed by clinical symptoms and findings on magnetic resonance imaging (MRI), and LMD by MRI or cerebrospinal fluid analysis. Differences in overall survival (OS) were assessed with standard statistical techniques. Results: Patients who received a VPS and more than 3 IT chemotherapy sessions survived longer (n = 26; OS time from implantation 11.7 ± 3.6 months) than those who received an occludable shunt but no IT chemotherapy (n = 24; OS time from implantation 2.8 ± 0.7 months, P < .018). Peritoneal seeding appeared after shunt insertion in only two patients (3%). Conclusions: This is the largest series reported to date of patients with LMD who had had shunts with on-off valves placed to relieve symptoms of intracranial hypertension. Use of IT chemotherapy and control of hydrocephalus via such shunts was associated with improved survival.

Utilization of Locum Tenens in Neurosurgery.

INTRODUCTION: Despite its rising popularity, little has been described about locum tenens employment (locums) in neurosurgery. This study provides the first nationwide overview of the locums neurosurgery experience. METHODS: An anonymous online survey examined practice characteristics of respondents, extent of and satisfaction with locums, motivations for pursuing locums, case volumes, agencies used, compensation, and positive/negative aspects of experiences. Responses were collected between November 2020 and February 2021. RESULTS: Response rate for the 1852 neurosurgeons who opened the survey request was 4.9%; 36 of 91 respondents had previously worked locums and were commonly motivated by compensation or transitioning to new jobs or retirement. In our response group, 92% of locums respondents had taken more than one position and 47% had taken more than 10. Neurosurgeons performing <200 cases/year were significantly more likely to have also worked locums than those performing >200 cases/year (41.6% locums, 12.7% non-locums, P = 0.001). Responses showed that 69% of locums respondents earned $2000-$2999/day and 16% earned >$3500/day. Nearly 78% of locums respondents were satisfied with their experience(s) and 86% would take another future locums position. Being in practice for >15 years was significantly associated with satisfaction with locums (P = 0.03). Reported flaws included unfamiliarity with hospitals, limited continuity of care, credentialing burdens, and inadequate travel compensation. CONCLUSIONS: Locums is utilized by neurosurgeons across multiple practice types and may serve to complement workloads or "fill in gaps" between longer-term employment. Overall, locums neurosurgeons are well compensated, and the majority are satisfied with their experience(s). Inevitably, flaws still exist with locums employment, which may be the focus of organized efforts aiming to improve the experience.

Radiation Synergizes with IL2/IL15 Stimulation to Enhance Innate Immune Activation and Antitumor Immunity.

Ionizing radiation is known to possess immune modulatory properties. However, how radiotherapy (RT) may complement with different types of immunotherapies to boost antitumor responses is unclear. In mice implanted with EO771 syngeneic tumors, NL-201 a stable, highly potent CD25-independent agonist to IL2 and IL15 receptors with enhanced affinity for IL2Rßγ was given with or without RT. Flow analysis and Western blot analysis was performed to determine the mechanisms involved. STING (-/-) and CD11c+ knockout mice were implanted with EO771 tumors to confirm the essential signaling and cell types required to mediate the effects seen. Combination of RT and NL-201 to enhance systemic immunotherapy with an anti-PD-1 checkpoint inhibitor was utilized to determine tumor growth inhibition and survival, along characterization of tumor microenvironment as compared with all other treatment groups. Here, we showed that RT, synergizing with NL-201 produced enhanced antitumor immune responses in murine breast cancer models. When given together, RT and NL-201 enhanced activation of the cytosolic DNA sensor cyclic GMP-AMP synthase-stimulator of IFN genes (cGAS-STING) pathway, resulting in increased type I IFN production in dendritic cells (DC), and consequently greater tumor infiltration and more efficient priming of antigen-specific T cells. The immune stimulatory mechanisms triggered by NL-201 and RT resulted in superior tumor growth inhibition and survival benefit in both localized and metastatic cancers. Our results support further preclinical and clinical investigation of this novel synergism regimen in locally advanced and metastatic settings.

Age-associated disparity in phagocytic clearance affects the efficacy of cancer nanotherapeutics.

Nanomedicines have been approved to treat multiple human diseases. However, clinical adoption of nanoformulated agents is often hindered by concerns about hepatic uptake and clearance, a process that is not fully understood. Here we show that the antitumour efficacy of cancer nanomedicine exhibits an age-associated disparity. Tumour delivery and treatment outcomes are superior in old versus young mice, probably due to an age-related decline in the ability of hepatic phagocytes to take up and remove nanoparticles. Transcriptomic- and protein-level analysis at the single-cell and bulk levels reveals an age-associated decrease in the numbers of hepatic macrophages that express the scavenger receptor MARCO in mice, non-human primates and humans. Therapeutic blockade of MARCO is shown to decrease the phagocytic uptake of nanoparticles and improve the antitumour effect of clinically approved cancer nanotherapeutics in young but not aged mice. Together, these results reveal an age-associated disparity in the phagocytic clearance of nanotherapeutics that affects their antitumour response, thus providing a strong rationale for an age-appropriate approach to cancer nanomedicine.

Malignant primary tumors of scalp with cranial extension: multidisciplinary surgical strategies and outcomes.

OBJECTIVE: Malignant cancers arising in the scalp may exhibit calvarial invasion, dural extension, and rarely cerebral involvement. Typically, such lesions require a multidisciplinary approach involving both neurosurgery and plastic surgery for optimal resection and reconstruction. The authors present a retrospective analysis of patients with scalp malignancies who underwent resection and reconstruction. METHODS: Patients presenting with scalp malignancies (1993-2021, n = 84) who required neurosurgical assistance for tumor resection were prospectively entered into a database. These data were retrospectively reviewed for this case series. The extent of neurosurgical resection was classified into four levels of involvement: scalp (level I), calvarial (level II), dural (level III), or intraparenchymal (level IV). Complications and evidence of local, locoregional, or regional recurrence were documented. RESULTS: Patients underwent level I (n = 2), level II (n = 61), level III (n = 13), and level IV (n = 8) resections. Pathologies consisted of primarily squamous cell carcinoma (n = 50, 59.5%), basal cell carcinoma (n = 11, 13.1%), and melanoma (n = 9, 10.7%), with infrequent lesions including sarcoma, atypical fibroxanthoma, and malignant fibrous histiocytoma. For cases requiring a cranioplasty, 92.2% were done using titanium mesh and 7.8% with methylmethacrylate. At a mean follow-up of 35.5 ± 45.9 months, the overall survival was 48.8% (n = 41) and recurrence-free survival was 31.0% (n = 43). Scalp-based reconstruction involving plastic surgery was performed in 75 (89.3%) patients. The most commonly used free flap was a latissimus dorsi muscle flap (n = 46, 61.3%). One or more postoperative complications occurred in 21.4% of all patients, the most common being wound dehiscence or delayed wound healing in 13% (n = 11). CONCLUSIONS: A multidisciplinary approach with aggressive neurosurgical resection is associated with good outcomes in patients with primary malignant scalp tumors, despite invasive disease on presentation. This analysis suggests that aggressive resection (level II and higher) is effective at reducing locoregional recurrence and is not associated with a higher risk of complications relative to resection without craniectomy. As most patients require scalp reconstruction to close the postresection defect, usually with vascularized free tissue transfer, involving a plastic surgeon in the surgical planning and execution is essential.

Differential Time-To-Promotion Trajectories Among Female and Male Neurosurgeons Contribute to Gender Disparities in Academic Rank Achievement.

OBJECTIVE: Despite the increasing representation of females in neurosurgical training, the fraction of female to male neurosurgeons decreases dramatically as faculty rank (Assistant, Associate, or Full Professor) increases. To assess this discrepancy, we quantified self-reported time-to-promotion trajectories for female and male neurosurgeons holding academic appointments. METHODS: In this cross-sectional institutional review board (IRB)-approved study, 147 female and 84 male neurosurgeons currently holding faculty positions in the US were contacted via email and invited to complete an anonymous, standardized survey. Respondents provided the calendar year of postgraduate training completion, promotion to different faculty ranks, geographic region of current practice (Western, Midwest, Southern, Northeast), and practice subspecialty. RESULTS: The response rate was 44.2% for females and 59.5% for males, with 114 participants included (65 female, 49 male). On average, female neurosurgeons required 25% longer to become an Associate Professor (P = 0.017), 34% longer to become a Full Professor (P = 0.004), 37% longer for promotion from Assistant to Associate Professor (P < 0.001), and 32% longer from Assistant to Full Professor (P = 0.012). Promotion timelines did not vary by region or specialty among male and female cohorts. Linear regressions revealed that female neurosurgeons with more recent training completion experienced shorter time-to-promotion to Associate and Full Professor compared to females of earlier generations (P = 0.005 and 0.001, respectively), while male timelines remained stable. CONCLUSIONS: This study identifies a significant delay in time-to-promotion for female neurosurgeons compared to their male counterparts. Investigation and standardization of promotion timelines are necessary to ensure meaningful representation gains from the increased number of women entering neurosurgical training.

Efficacy and Safety of Endoscopic Transsphenoidal Resection for Prolactinoma: A Retrospective Multicenter Case-series.

BACKGROUND: Endoscopic transsphenoidal surgery (ETSS) for prolactinoma is reserved for dopamine agonist (DA) resistance, intolerance, or apoplexy. High remission (overall 67%, microprolactinoma up to 90%), low recurrence (5-20%) rates highlighted that surgery might be first-line treatment. AIMS: To report on outcomes of ETSS in a cohort of prolactinomas. METHODS: Multicenter retrospective cohort of 137 prolactinoma patients (age 38.2 ± 13.7 years; 61.3% female, median follow-up 28.0 [15.0-55.5] months) operated between 2010-2019 with histopathological confirmation. RESULTS: Median preoperative prolactin levels were 166 (98-837 µg/L; males 996 [159-2145 µg/L] vs. females 129 [84-223 µg/L], p <0.001). 56 (40.9%) microprolactinomas, 69 (50.4%) macroprolactinomas, and 7 (5.1%) giant prolactinomas were included, whereas no adenoma was detected in 5 (3.6%) patients. Males had larger tumors (macroprolactinomas: 38, 71.7%) vs. 31 (36.9%), p <0.001; giant prolactinomas: 7 (13.2%) vs. 0 (0.0%), (p <0.001). Prolactinomas were graded as KNOSP-3 in 15 (11.5%), and KNOSP-4 in 20 (15.3%) patients. Primary indication was DA intolerance (59, 43.1%); males 14 (26.4%) vs. females 45 (53.6%), p = 0.006. Long-term remission (i.e., DA-free prolactin level <1xULN) was achieved in 87 (63.5%) patients, being higher in intended complete resection (69/92 [75.0%]), and lower in males (25 [47.2%] vs. 62 females [73.8%], p = 0.002). Transient DI (n = 29, 21.2%) was the most frequent complication. CONCLUSIONS: Despite high proportions of macroprolactinoma and KNOSP 3-4, long-term remission rates were 63.5% overall, and 83.3% in microprolactinoma patients. Males had less favorable remission rate compared to females. These findings highlight that ETSS may be a safe and efficacious treatment to manage prolactinoma.

Engineering a tunable micropattern-array assay to sort single extracellular vesicles and particles to detect RNA and protein in situ.

The molecular heterogeneity of extracellular vesicles (EVs) and the co-isolation of physically similar particles, such as lipoproteins (LPs), confounds and limits the sensitivity of EV bulk biomarker characterization. Herein, we present a single-EV and particle (siEVP) protein and RNA assay (siEVP PRA) to simultaneously detect mRNAs, miRNAs, and proteins in subpopulations of EVs and LPs. The siEVP PRA immobilizes and sorts particles via positive immunoselection onto micropatterns and focuses biomolecular signals in situ. By detecting EVPs at a single-particle resolution, the siEVP PRA outperformed the sensitivities of bulk-analysis benchmark assays for RNA and protein. To assess the specificity of RNA detection in complex biofluids, EVs from various glioma cell lines were processed with small RNA sequencing, whereby two mRNAs and two miRNAs associated with glioblastoma multiforme (GBM) were chosen for cross-validation. Despite the presence of single-EV-LP co-isolates in serum, the siEVP PRA detected GBM-associated vesicular RNA profiles in GBM patient siEVPs. The siEVP PRA effectively examines intravesicular, intervesicular, and interparticle heterogeneity with diagnostic promise.

Adaptive design of mRNA-loaded extracellular vesicles for targeted immunotherapy of cancer.

The recent success of mRNA therapeutics against pathogenic infections has increased interest in their use for other human diseases including cancer. However, the precise delivery of the genetic cargo to cells and tissues of interest remains challenging. Here, we show an adaptive strategy that enables the docking of different targeting ligands onto the surface of mRNA-loaded small extracellular vesicles (sEVs). This is achieved by using a microfluidic electroporation approach in which a combination of nano- and milli-second pulses produces large amounts of IFN-γ mRNA-loaded sEVs with CD64 overexpressed on their surface. The CD64 molecule serves as an adaptor to dock targeting ligands, such as anti-CD71 and anti-programmed cell death-ligand 1 (PD-L1) antibodies. The resulting immunogenic sEVs (imsEV) preferentially target glioblastoma cells and generate potent antitumour activities in vivo, including against tumours intrinsically resistant to immunotherapy. Together, these results provide an adaptive approach to engineering mRNA-loaded sEVs with targeting functionality and pave the way for their adoption in cancer immunotherapy applications.

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

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

Effect of Dexmedetomidine on Perception of Paresthesia during Subthalamic Nucleus Deep Brain Stimulation Surgery for Parkinson's Disease.

Background: Deep brain stimulation (DBS) has become a well-established treatment for the management of Parkinson's disease (PD). The most common method of lead targeting utilizes microelectrode recording (MER) and intraoperative macrostimulation to confirm accurate placement of the lead. This has been significantly aided by the use of dexmedetomidine (DEX) sedation during the procedure. Despite the frequent use of DEX, it has been theorized that DEX may have some effects on the MER during intraoperative testing. The effect on the perception of sensory thresholds during macrostimulation in the form of paresthesia is still unreported. Objectives: To investigate the effect of the sedative DEX on sensory perception thresholds observed in the intraoperative versus postoperative settings for patients undergoing subthalamic nucleus (STN) DBS surgery for PD. Materials and Methods: Adult patients (n = 8) with a diagnosis of PD underwent placement of DBS leads (n = 14) in the STN. Patients were subjected to intraoperative macrostimulation for capsular and sensory thresholds prior to placement of each DBS lead. These were compared to sensory thresholds observed in the postoperative setting during outpatient programming at three depths on each lead (n = 42). Results: In most contacts (22/42) (P = 0.19), sensory thresholds for paresthesia perception were either perceived at a higher voltage or absent during intraoperative testing in comparison to those observed in the postoperative setting. Conclusions: DEX appears to have measurable (though not statistically significant) effect on the perception of paresthesia observed during intraoperative testing.

Targeting phagocytosis to enhance antitumor immunity.

Many patients with metastatic or treatment-resistant cancer have experienced improved outcomes after immunotherapy that targets adaptive immune checkpoints. However, innate immune checkpoints, which can hinder the detection and clearance of malignant cells, are also crucial in tumor-mediated immune escape and may also serve as targets in cancer immunotherapy. In this review, we discuss the current understanding of immune evasion by cancer cells via disruption of phagocytic clearance, and the potential effects of blocking phagocytosis checkpoints on the activation of antitumor immune responses. We propose that a more effective combination immunotherapy strategy could be to exploit tumor-intrinsic processes that inhibit key innate immune surveillance processes, such as phagocytosis, and incorporate both innate and adaptive immune responses for treating patients with cancer.

Frequency of seizures in patients with metastatic brain tumors.

INTRODUCTION: We sought to determine the influence of primary tumor histology and metastatic tumor location on the frequency of seizures among patients with brain metastases. A secondary aim was to determine if surgery reduced the occurrence and frequency of seizures. METHODS: We retrospectively reviewed patients with cerebral metastasis at a single institution from 2006 to 2016. RESULTS: Among 1949 patients identified as having had cerebral metastasis, 168 (8.6%) had documentation of one or more seizures. The incidence of seizures was highest among patients with metastases from melanoma (19.8%), followed by those with colon cancer (9.7%), renal cell carcinoma (RCC; 8.3%), and lung cancer (7.0%). Among 1581 patients with melanoma, colon cancer, RCC, non-small cell lung cancer, or breast cancer, having metastases in the frontal lobe seemed to confer the greatest risk of seizures (n = 100), followed by foci in the temporal lobe (n = 20) and elsewhere (n = 16). CONCLUSION: Patients with cerebral metastasis are at increased risk for seizures. Seizure rates seem to be higher for certain primary tumors, such as melanoma, colon cancer, and RCC, and for lesions located in the frontal lobe.

Waking immune-resistant tumors with neddylation.

The CD47/signal regulatory protein α (SIRPα) axis, which functions as an inhibitory phagocytosis checkpoint, also serves as a key mediator in cancer immune evasion. Many cancers, including colorectal cancer (CRC), exploit the expression of CD47 to escape phagocytic clearance and activate the innate immune system. Previous work has indicated that distinct paradigms of posttranslational modifications mediate the regulatory mechanisms of the CD47/SIRPα axis. In this issue of the JCI, Li et al. show that neddylation, a ubiquitin-like modification, inactivates Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2), a downstream target of this pathway. They further show that inhibition of SHP2 sensitizes CRC cells to immunotherapies to which they were previously resistant. Collectively, the results underscore the need for cotargeting SHP2 and immune checkpoints (e.g., programmed death 1 [PD1]) in CRC and possibly other immunotherapy-resistant tumors.

Intradermally delivered mRNA-encapsulating extracellular vesicles for collagen-replacement therapy.

The success of messenger RNA therapeutics largely depends on the availability of delivery systems that enable the safe, effective and stable translation of genetic material into functional proteins. Here we show that extracellular vesicles (EVs) produced via cellular nanoporation from human dermal fibroblasts, and encapsulating mRNA encoding for extracellular-matrix α1 type-I collagen (COL1A1) induced the formation of collagen-protein grafts and reduced wrinkle formation in the collagen-depleted dermal tissue of mice with photoaged skin. We also show that the intradermal delivery of the mRNA-loaded EVs via a microneedle array led to the prolonged and more uniform synthesis and replacement of collagen in the dermis of the animals. The intradermal delivery of EV-based COL1A1 mRNA may make for an effective protein-replacement therapy for the treatment of photoaged skin.

Pretreatment findings on magnetic resonance imaging in primary central nervous system lymphoma may predict overall survival duration.

BACKGROUND: and purpose: Primary central nervous system lymphoma (PCNSL) lesions often show avid contrast enhancement on T1-weighted contrast-enhanced MRI sequences. However, several case reports and a clinical study have described PCNSL in patients with no contrast enhancement on MRI. We assessed whether overall survival (OS) time was related to any tumor characteristics (lesion location, volume, and number; contrast enhancement; necrosis; proximity to the subarachnoid space; and edema) on MRI in patients with PCNSL. MATERIALS AND METHODS: We retrospectively reviewed records (MRI features, pathology, and survival data) of all patients at our institution with PCNSL who had been seen from, 2007 through 2017, and had undergone pretreatment MRI. RESULTS: We identified 79 patients (42 men, 37 women) with a mean age at diagnosis of 61.7 ± 10.4 years. The mean OS duration was 44.6 ± 41.7 months. The most common pathological diagnosis (74 patients) was diffuse large B-cell lymphoma. No associations were found between OS time and lesion location, volume, and number; contrast enhancement; necrosis; proximity to the subarachnoid space; or edema. However, a sole patient with non-enhancing PCNSL on MRI was found to have low-grade disease, with prolonged survival (>83 months). Several other patients with leptomeningeal disease had a mean OS time of 80 months. Patients with hemorrhagic lesions had a mean OS of 25.5 months. CONCLUSIONS: The survival time for patients with PCNSL may be longer than previously thought, especially for patients with leptomeningeal seeding and lesions with hemorrhagic components Also, non-enhancing tumors may be less aggressive than enhancing tumors.

Association of circulating markers with cognitive decline after radiation therapy for brain metastasis.

BACKGROUND: A recent phase III trial (NCT01372774) comparing use of stereotactic radiosurgery [SRS] versus whole-brain radiation therapy [WBRT] after surgical resection of a single brain metastasis revealed that declines in cognitive function were more common with WBRT than with SRS. A secondary endpoint in that trial, and the primary objective in this secondary analysis, was to identify baseline biomarkers associated with cognitive impairment after either form of radiotherapy for brain metastasis. Here we report our findings on APOE genotype and serum levels of associated proteins and their association with radiation-induced neurocognitive decline. METHODS: In this retrospective analysis of prospectively collected samples from a completed randomized clinical trial, patients provided blood samples every 3 months that were tested by genotyping and enzyme-linked immunosorbent assay, and results were analyzed in association with cognitive impairment. RESULTS: The APOE genotype was not associated with neurocognitive impairment at 3 months. However, low serum levels of ApoJ, ApoE, or ApoA protein (all P < .01) and higher amyloid beta (Aß 1-42) levels (P = .048) at baseline indicated a greater likelihood of neurocognitive decline at 3 months after SRS, whereas lower ApoJ levels were associated with decline after WBRT (P = .014). CONCLUSIONS: Patients with these pretreatment serum markers should be counseled about radiation-related neurocognitive decline.