Glucose-driven histone lactylation promotes the immunosuppressive activity of monocyte-derived macrophages in glioblastoma.

Immunosuppressive macrophages restrict anti-cancer immunity in glioblastoma (GBM). Here, we studied the contribution of microglia (MGs) and monocyte-derived macrophages (MDMs) to immunosuppression and mechanisms underlying their regulatory function. MDMs outnumbered MGs at late tumor stages and suppressed T cell activity. Molecular and functional analysis identified a population of glycolytic MDM expressing GLUT1 with potent immunosuppressive activity. GBM-derived factors promoted high glycolysis, lactate, and interleukin-10 (IL-10) production in MDMs. Inhibition of glycolysis or lactate production in MDMs impaired IL-10 expression and T cell suppression. Mechanistically, intracellular lactate-driven histone lactylation promoted IL-10 expression, which was required to suppress T cell activity. GLUT1 expression on MDMs was induced downstream of tumor-derived factors that activated the PERK-ATF4 axis. PERK deletion in MDM abrogated histone lactylation, led to the accumulation of intratumoral T cells and tumor growth delay, and, in combination with immunotherapy, blocked GBM progression. Thus, PERK-driven glucose metabolism promotes MDM immunosuppressive activity via histone lactylation.

Profiling the molecular and clinical landscape of glioblastoma utilizing the Oncology Research Information Exchange Network brain cancer database.

Background: Glioblastoma exhibits aggressive growth and poor outcomes despite treatment, and its marked variability renders therapeutic design and prognostication challenging. The Oncology Research Information Exchange Network (ORIEN) database contains complementary clinical, genomic, and transcriptomic profiling of 206 glioblastoma patients, providing opportunities to identify novel associations between molecular features and clinical outcomes. Methods: Survival analyses were performed using the Logrank test, and clinical features were evaluated using Wilcoxon and chi-squared tests with q-values derived via Benjamini-Hochberg correction. Mutational analyses utilized sample-level enrichments from whole exome sequencing data, and statistical tests were performed using the one-sided Fisher Exact test with Benjamini-Hochberg correction. Transcriptomic analyses utilized a student's t-test with Benjamini-Hochberg correction. Expression fold changes were processed with Ingenuity Pathway Analysis to determine pathway-level alterations between groups. Results: Key findings include an association of MUC17, SYNE1, and TENM1 mutations with prolonged overall survival (OS); decreased OS associated with higher epithelial growth factor receptor (EGFR) mRNA expression, but not with EGFR amplification or mutation; a 14-transcript signature associated with OS > 2 years; and 2 transcripts associated with OS < 1 year. Conclusions: Herein, we report the first clinical, genomic, and transcriptomic analysis of ORIEN glioblastoma cases, incorporating sample reclassification under updated 2021 diagnostic criteria. These findings create multiple avenues for further investigation and reinforce the value of multi-institutional consortia such as ORIEN in deepening our knowledge of intractable diseases such as glioblastoma.

Clinical outcomes of melanoma brain metastases treated with nivolumab and ipilimumab alone versus nivolumab and ipilimumab with stereotactic radiosurgery.

PURPOSE: Upfront dual checkpoint blockade with immune checkpoint inhibitors (ICI) has demonstrated efficacy for treating melanoma brain metastases (MBM) in asymptomatic patients. Whether the combination of stereotactic radiosurgery (SRS) with dual checkpoint blockade improves outcomes over dual-checkpoint blockade alone is unknown. We evaluated clinical outcomes of patients with MBM receiving ICI with nivolumab and ipilimumab, with and without SRS. METHODS: 49 patients with 158 MBM receiving nivolumab and ipilimumab for untreated MBM between 2015 and 2022 were identified at our institution. Patient and tumor characteristics including age, Karnofsky Performance Status (KPS), presence of symptoms, cancer history, MBM burden, and therapy course were recorded. Outcomes measured from initiation of MBM-directed therapy included overall survival (OS), local control (LC), and distant intracranial control (DIC). Time-to-event analysis was conducted with the Kaplan-Meier method. RESULTS: 25 patients with 74 MBM received ICI alone, and 24 patients with 84 MBM received concurrent SRS. Median follow-up was 24 months. No differences in age (p = 0.96), KPS (p = 0.85), presence of symptoms (p = 0.79), prior MBM (p = 0.68), prior MBM-directed surgery (p = 0.96) or SRS (p = 0.68), MBM size (p = 0.67), or MBM number (p = 0.94) were seen. There was a higher rate of nivolumab and ipilimumab course completion in the SRS group (54% vs. 24%; p = 0.029). The SRS group received prior immunotherapy more often than the ICI alone group (54% vs. 8.0%; p < 0.001). There was no significant difference in 1-year OS (72% vs. 71%, p = 0.20) and DIC (63% v 51%, p = 0.26) between groups. The SRS group had higher 1-year LC (92% vs. 64%; p = 0.002). On multivariate analysis, LC was improved with combination therapy (AHR 0.38, p = 0.01). CONCLUSION: In our analysis, patients who received SRS with nivolumab and ipilimumab had superior LC without increased risk of toxicity or compromised immunotherapy treatment completion despite the SRS cohort having higher rates of prior immunotherapy. Further prospective study of combination nivolumab and ipilimumab with SRS is warranted.

Micrometer-scale structure in shark vertebral centra.

The vertebral centra of sharks consist of cartilage, and many species' centra contain a bioapatite related to that in bone. Centra microarchitectures at the 0.5-50 µm scale do not appear to have been described previously. This study examines centrum microarchitecture in lamniform and carcharhiniform sharks with synchrotron microComputed Tomography (microCT), scanning electron microscopy and spectroscopy and light microscopy. The analysis centers on the blue shark (carcharhiniform) and shortfin mako (lamniform), species studied with all three modalities. Synchrotron microCT results from seven other species complete the report. The main centrum structures, the corpus calcareum and intermedialia, consist of fine, closely-spaced, mineralized trabeculae whose mean thicknesses and spacings range from 4.5 to 11.2 µm and 4.5 to 15.6 µm, respectively. A significant (p = 0.00001) positive linear relationship between and exists for multiple positions within one mako centrum. Carcharhiniform species' and exhibit an inverse linear relationship (p = 0.005) while in lamniforms these variables tend toward a positive relationship which does not reach statistical significance (p = 0.099). In all species, the trabeculae form an uninterrupted, interconnected network, and the unmineralized volumes are similarly interconnected. Small differences in mineralization level are observed in trabeculae. Centrum growth band pairs are found to consist of locally higher /lower mineral volume fraction. Within the intermedialia, radial canals and radial microrods were characterized, and compacted trabeculae are prominent in the mako intermedialia. The centra's mineralized central zones were non-trabecular and are also described. STATEMENT OF SIGNIFICANCE: This study's novel result is the demonstration that the mineralized cartilage of sharks' vertebral bodies (centra) consists of a fine 3D array of interconnected plates (trabeculae) and an interpenetrating network of unmineralized tissue. This microstructure is radically different from that in tesserae or in teeth, the other main mineralized shark tissues. Using volumetric synchrotron microComputed Tomography, numerical values of mean trabecular thickness and spacing and their relationship were measured for nine species. Scanning electron microscopy added a higher resolution view of the microstructures, and histology provided complementary information on cartilage and cells. The present results suggest centra microstructure helps accommodate the very large in vivo strains and may prevent damage accumulation during millions of cycles of swimming-induced loading.

Development of a "Geo-Tagged" tumor sample registry: intra-operative linkage of sample location to imaging.

PURPOSE: There is a growing body of literature documenting glioma heterogeneity in terms of radiographic, histologic, molecular, and genetic characteristics. Incomplete spatial specification of intraoperative tumor samples may contribute to variability in the results of pathological and biological investigations. We have developed a system, termed geo-tagging, for routine intraoperative linkage of each tumor sample to its location via neuronavigation. METHODS: This is a single-institution, IRB approved, prospective database of undergoing clinically indicated surgery. We evaluated relevant factors affecting data collection by this registry, including tumor and surgical factors (e.g. tumor volume, location, grade and surgeon). RESULTS: Over a 2-year period, 487 patients underwent craniotomy for an intra-axial tumor. Of those, 214 underwent surgery for a newly diagnosed or recurrent glioma. There was significant variation in the average number of samples collected per registered case, with a range of samples from 2.53 to 4.75 per tumor type. Histology and grade impacted on sampling with a range of 2.0 samples per tumor in Grade four, IDH-WT gliomas to 4.5 samples in grade four, IDH-mutant gliomas. The range of cases with sampling per surgeon was 6 to 99 with a mean of 47.6 cases and there was a statistically significant differences between surgeons. Tumor grade did not have a statistically significant impact on number of samples per case. No significant correlation was found between the number of samples collected and enhancing tumor volume, EOR, or volume of tumor resected. CONCLUSION: We are using the results of this analysis to develop a prospective sample collection protocol.

Glioblastoma Stem Cell Targeting Peptide Isolated Through Phage Display Binds Cadherin 2.

Glioblastoma stem cells (GSCs) have unique properties of self-renewal and tumor initiation that make them potential therapeutic targets. Development of effective therapeutic strategies against GSCs requires both specificity of targeting and intracranial penetration through the blood-brain barrier. We have previously demonstrated the use of in vitro and in vivo phage display biopanning strategies to isolate glioblastoma targeting peptides. Here we selected a 7-amino acid peptide, AWEFYFP, which was independently isolated in both the in vitro and in vivo screens and demonstrated that it was able to target GSCs over differentiated glioma cells and non-neoplastic brain cells. When conjugated to Cyanine 5.5 and intravenously injected into mice with intracranially xenografted glioblastoma, the peptide localized to the site of the tumor, demonstrating intracranial tumor targeting specificity. Immunoprecipitation of the peptide with GSC proteins revealed Cadherin 2 as the glioblastoma cell surface receptor targeted by the peptides. Peptide targeting of Cadherin 2 on GSCs was confirmed through ELISA and in vitro binding analysis. Interrogation of glioblastoma databases demonstrated that Cadherin 2 expression correlated with tumor grade and survival. These results confirm that phage display can be used to isolate unique tumor-targeting peptides specific for glioblastoma. Furthermore, analysis of these cell specific peptides can lead to the discovery of cell specific receptor targets that may serve as the focus of future theragnostic tumor-homing modalities for the development of precision strategies for the treatment and diagnosis of glioblastomas.

Canagliflozin Attenuates PromarkerD Diabetic Kidney Disease Risk Prediction Scores.

PromarkerD is a biomarker-based blood test that predicts kidney function decline in people with type 2 diabetes (T2D) who may otherwise be missed by current standard of care tests. This study examined the association between canagliflozin and change in PromarkerD score (Δ score) over a three-year period in T2D participants in the CANagliflozin cardioVascular Assessment Study (CANVAS). PromarkerD scores were measured at baseline and Year 3 in 2008 participants with preserved kidney function (baseline eGFR ≥60 mL/min/1.73 m2). Generalized estimating equations were used to assess the effect of canagliflozin versus placebo on PromarkerD scores. At baseline, the participants (mean age 62 years, 32% females) had a median PromarkerD score of 3.9%, with 67% of participants categorized as low risk, 14% as moderate risk, and 19% as high risk for kidney function decline. After accounting for the known acute drop in eGFR following canagliflozin initiation, there was a significant treatment-by-time interaction (p < 0.001), whereby participants on canagliflozin had decreased mean PromarkerD scores from baseline to Year 3 (Δ score: -1.0% [95% CI: -1.9%, -0.1%]; p = 0.039), while the scores of those on placebo increased over the three-year period (Δ score: 6.4% [4.9%, 7.8%]; p < 0.001). When stratified into PromarkerD risk categories, participants with high risk scores at baseline who were randomized to canagliflozin had significantly lower scores at Year 3 (Δ score: -5.6% [-8.6%, -2.5%]; p < 0.001), while those on placebo retained high scores (Δ score: 4.5% [0.3%, 8.8%]; p = 0.035). This post hoc analysis of data from CANVAS showed that canagliflozin significantly lowered PromarkerD risk scores, with the effect greatest in those T2D participants who were classified at study entry as at high risk of a subsequent decline in kidney function.

Use of phage display biopanning as a tool to design CAR-T cells against glioma stem cells.

Background: Glioblastoma (GBM) is both the most common and aggressive type of primary brain tumor, associated with high mortality rates and resistance to conventional therapy. Despite recent advancements in knowledge and molecular profiling, recurrence of GBM is nearly inevitable. This recurrence has been attributed to the presence of glioma stem cells (GSCs), a small fraction of cells resistant to standard-of-care treatments and capable of self-renewal and tumor initiation. Therefore, targeting these cancer stem cells will allow for the development of more effective therapeutic strategies against GBM. We have previously identified several 7-amino acid length peptides which specifically target GSCs through in vitro and in vivo phage display biopanning. Methods and results: We have combined two of these peptides to create a dual peptide construct (EV), and demonstrated its ability to bind GSCs in vitro and target intracranial GBM in mouse models. A peptide pull-down performed with peptide EV followed by mass spectrometry determined N-cadherin as the binding partner of the peptide, which was validated by enzyme-linked immunosorbent assay and surface plasmon resonance. To develop cytotoxic cellular products aimed at specifically targeting GSCs, chimeric antigen receptors (CARs) were engineered containing the peptide EV in place of the single-chain variable fragment (scFv) as the antigen-binding domain. EV CAR-transduced T cells demonstrated specific reactivity towards GSCs by production of interferon-gamma when exposed to GSCs, in addition to the induction of GSC-specific apoptosis as illustrated by Annexin-V staining. Conclusion: These results exemplify the use of phage display biopanning for the isolation of GSC-targeting peptides, and their potential application in the development of novel cytotoxic therapies for GBM.

Patient satisfaction and cost savings analysis of the telemedicine program within a neuro-oncology department.

PURPOSE: Unique challenges exist in the utilization of telemedicine for neurological and surgical specialties. We examined the differences in patient satisfaction for telemedicine versus in-person visits within a Neuro-Oncology Program to assess whether there was a difference between surgical and medical specialties. We also examined the potential cost savings benefits of utilizing telemedicine. METHODS: 1189 Press Ganey surveys in the Department of Neuro-Oncology (982 in-person and 207 telemedicine) by surgical and medical neuro-oncology patients between 04/01/2020 and 06/30/2021 were reviewed. Survey results were divided into 4 categories (Access, Provider, Technology (telemedicine only), and Overall Satisfaction). Results were analyzed for the impact of telemedicine versus in-person visits, and gender, age, insurance, and specialty. Cost savings were calculated based on potential travel distance and lost productivity. RESULTS: Survey results from telemedicine visits demonstrated that patients with private insurance returned higher scores in the Provider (p = 0.0089), Technology (p = 0.00187), and Overall (p = 0.00382) categories. Surgical patients returned higher scores for Access (p = 0.0015), Technology (p = 0.0002), and Overall (p = 0.0019). When comparing telemedicine to in-person scores, in-person scored higher in Provider (p = 0.0092) for all patients, while in-person scored higher in Access (p = 0.0252) amongst surgical patients. Cost analysis revealed that telemedicine allowed patients to save an average of 4.1 to 5.6 h per visit time and a potential cost savings of up to $223.3 ± 171.4. CONCLUSION: Telemedicine yields equivalent patient satisfaction when employed in surgical as compared to medical Neuro-Oncology patients with the potential to lessen the financial and time burden on neuro-oncology patients.

Three-dimensional mapping of mineral in intact shark centra with energy dispersive x-ray diffraction.

The centra of shark vertebrae consist of cartilage mineralized by a bioapatite similar to bone's carbonated hydroxyapatite, and, without a repair mechanism analogous to remodeling in bone, these structures still survive millions of cycles of high-strain loading. The main structures of the centrum are an hourglass-shaped double cone and the intermedialia which supports the cones. Little is known about the nanostructure of shark centra, specifically the relationship between bioapatite and cartilage fibers, and this study uses energy dispersive diffraction (EDD) with polychromatic synchrotron x-radiation to study the spatial organization of the mineral phase and its crystallographic texture. The unique energy-sensitive detector array at beamline 6-BM-B, the Advanced Photon Source, enables EDD to quantify the texture within each sampling volume with one exposure while constructing 3D maps via specimen translation across the sampling volume. This study maps a centrum from two shark orders, a carcharhiniform and a lamniform, with different intermedialia structures. In the blue shark (Prionace glauca, Carcharhiniformes), the bioapatite's c-axes are oriented laterally within the centrum's cone walls but axially within the wide wedges of the intermedialia; the former is interpreted to resist lateral deformation, the latter to support axial loads. In the shortfin mako (Isurus oxyrinchus, Lamniformes), there is some tendency for c-axis variation with position, but the situation is unclear because one dimension of the sampling volume is considerably larger than the thickness and spacing of the intermedialia's radially-oriented lamellae. Because elastic modulus in collagen plus bioapatite mineralized tissues varies significantly with both volume fraction of bioapatite and crystallographic texture, the present 3D EDD-derived maps should inform future 3D numerical models of shark centra under applied load.

Bioapatite in shark centra studied by wide-angle and by small-angle X-ray scattering.

Members of subclass Elasmobranchii possess cartilage skeletons; the centra of many species are mineralized with a bioapatite, but virtually nothing is known about the mineral's organization. This study employed high-energy, small-angle X-ray scattering (SAXS) and wide-angle X-ray scattering (WAXS, i.e. X-ray diffraction) to investigate the bioapatite crystallography within blocks cut from centra of four species (two carcharhiniform families, one lamniform family and 1-ID of the Advanced Photon Source). All species' crystallographic quantities closely matched and indicated a bioapatite closely related to that in bone. The centra's lattice parameters a and c were somewhat smaller and somewhat larger, respectively, than in bone. Nanocrystallite sizes (WAXS peak widths) in shark centra were larger than typical of bone, and little microstrain was observed. Compared with bone, shark centra exhibited SAXS D-period peaks with larger D magnitudes, and D-period arcs with narrower azimuthal widths. The shark mineral phase, therefore, is closely related to that in bone but does possess real differences which probably affect mechanical property and which are worth further study.

Molecular determinants of outcomes in meningiomas.

Meningiomas are the most common intracranial primary tumor in adults. Surgery is the predominant therapeutic modality for symptomatic meningiomas. Although the majority of meningiomas are benign, there exists a subset of meningiomas that are clinically aggressive. Recent advances in genetics and epigenetics have uncovered molecular alterations that drive tumor meningioma biology with prognostic and therapeutic implications. In this review, we will discuss the advances on molecular determinants of therapeutic response in meningiomas to date and discuss findings of targeted therapies in meningiomas.

Paramedian Wiltse Approach for Giant Paraspinal Lumbar Schwannoma: Technical Note and Alternative Approaches.

BACKGROUND: Paraspinal lumbar schwannomas are primarily located outside of the spinal canal with minimal extension into the neural foramen. Approaching these tumors through a traditional posterior approach can be challenging given their lateral location to the spine and is likely to require extensive bony removal and potential destabilization of the spine. Alternatives approaches have been identified that may circumvent the need for extensive bony removal. OBJECTIVE: To examine the use of the paramedian Wiltse approach for giant extraspinal tumors and compare the approach with other nonposterior approaches. METHODS: We present 2 cases in which the paramedian Wiltse approach is used to effectively approach large paraspinal schwannomas and achieve complete tumor resection without destabilization of the spine. RESULTS: The paramedian Wiltse approach along with expandable retractors systems were able to achieve complete resection of the giant paraspinal schwannomas. Neural preservation was able to be achieved in one case which was facilitated by the exposure achieved through the posterior paramedian corridor that allowed for visualization of the proximal and distal ends of the tumor. CONCLUSION: The paramedian Wiltse approach is an ideal approach to target large extraspinal schwannomas for complete resection and potential neural preservation without the need for destabilization of the spine.

Spontaneous Spinal Subdural Hematoma Secondary to Hemophilia A and Zanubrutinib.

Spontaneous spinal subdural hematomas (SSH) are rare occurrences that can occur most commonly secondary to vascular malformations or coagulopathies. Only a small fraction of spontaneous SSHs are caused by acquired coagulation disorders such as leukemia, hemophilia, and thrombocytopenia. This case report describes a patient with a history of Guillain-Barré syndrome (GBS), hemophilia A, and mantle cell lymphoma, on zanubrutinib therapy, a Bruton tyrosine kinase inhibitor associated with a risk of spontaneous hemorrhage. This patient developed a spontaneous spinal subdural hematoma, most likely due to the zanubrutinib therapy and exacerbated due to hemophilia. Treatment was delayed due to the patient's history of GBS that confounded the clinical diagnosis. This case is the first report of a spontaneous SSH in a patient on zanubrutinib, highlighting the need for a high index of suspicion for CNS hemorrhage in patients on Bruton's tyrosine kinase (BTK) inhibitor therapy.

A preclinical model of patient-derived cerebrospinal fluid circulating tumor cells for experimental therapeutics in leptomeningeal disease from melanoma.

BACKGROUND: Leptomeningeal disease (LMD) occurs as a late complication of several human cancers and has no rationally designed treatment options. A major barrier to developing effective therapies for LMD is the lack of cell-based or preclinical models that recapitulate human disease. Here, we describe the development of in vitro and in vivo cultures of patient-derived cerebrospinal fluid circulating tumor cells (PD-CSF-CTCs) from patients with melanoma as a preclinical model to identify exploitable vulnerabilities in melanoma LMD. METHODS: CSF-CTCs were collected from melanoma patients with melanoma-derived LMD and cultured ex vivo using human meningeal cell-conditioned media. Using immunoassays and RNA-sequencing analyses of PD-CSF-CTCs, molecular signaling pathways were examined and new therapeutic targets were tested for efficacy in PD-CSF-CTCs preclinical models. RESULTS: PD-CSF-CTCs were successfully established both in vitro and in vivo. Global RNA analyses of PD-CSF-CTCs revealed several therapeutically tractable targets. These studies complimented our prior proteomic studies highlighting IGF1 signaling as a potential target in LMD. As a proof of concept, combining treatment of ceritinib and trametinib in vitro and in vivo demonstrated synergistic antitumor activity in PD-CSF-CTCs and BRAF inhibitor-resistant melanoma cells. CONCLUSIONS: This study demonstrates that CSF-CTCs can be grown in vitro and in vivo from some melanoma patients with LMD and used as preclinical models. These models retained melanoma expression patterns and had signaling pathways that are therapeutically targetable. These novel models/reagents may be useful in developing rationally designed treatments for LMD.

Surgical and anatomic factors predict development of leptomeningeal disease in patients with melanoma brain metastases.

BACKGROUND: Leptomeningeal disease (LMD) is a devastating complication of systemic malignancy, of which there is an unclear etiology. The aim of this study is to determine if surgical or anatomic factors can predict LMD in patients with metastatic melanoma. METHODS: A retrospective chart review was performed of 1162 patients treated at single institution for melanoma brain metastases (MBM). Patients with fewer than 3 months follow-up or lacking appropriate imaging were excluded. Demographic information, surgical, and anatomic data were collected. RESULTS: Eight hundred and twenty-seven patients were included in the final review. On multivariate analysis for the entire cohort, female gender, dural-based and intraventricular metastasis, and tumor bordering CSF spaces were associated with increased risk of LMD. Surgical resection was not significant for risk of LMD. On multivariate analysis of patients who have undergone surgical resection of a metastatic tumor, dural-based and intraventricular metastasis, ventricular entry during surgery, and metastasis in the infratentorial space were associated with increased risk of LMD. On multivariate analysis of patients who did not undergo surgery, chemotherapy after initial diagnosis and metastasis bordering CSF spaces were associated with increased risk of LMD. CONCLUSION: In a single-institution cohort of MBM, we found that surgical resection alone did not result in an increased risk of LMD. Anatomical factors such as dural-based and intraventricular metastasis were significant for developing LMD, as well as entry into a CSF space during surgical resection. These data suggest a strong correlation between anatomic location and tumor cell seeding in relation to the development of LMD.

Capecitabine and stereotactic radiation in the management of breast cancer brain metastases.

BACKGROUND: Little is known about the safety and efficacy of concurrent capecitabine and stereotactic radiotherapy in the setting of breast cancer brain metastases (BCBM). METHODS: Twenty-three patients with BCBM underwent 31 stereotactic sessions to 90 lesions from 2005 to 2019 with receipt of capecitabine. The Kaplan-Meier method was used to calculate overall survival (OS), local control (LC), and distant intracranial control (DIC) from the date of stereotactic radiation. Imaging was independently reviewed by a neuro-radiologist. RESULTS: Median follow-up from stereotactic radiation was 9.2 months. Receptor types of patients treated included triple negative (n = 7), hormone receptor (HR)+/HER2- (n = 7), HR+/HER2+ (n = 6), and HR-/HER2+ (n = 3). Fourteen patients had stage IV disease prior to BCBM diagnosis. The median number of brain metastases treated per patient was 3 (1 to 12). The median dose of stereotactic radiosurgery (SRS) was 21 Gy (range: 15-24 Gy) treated in a single fraction and for lesions treated with fractionated stereotactic radiation therapy (FSRT) 25 Gy (24-30 Gy) in a median of 5 fractions (range: 3-5). Of the 31 stereotactic sessions, 71% occurred within 1 month of capecitabine. No increased toxicity was noted in our series with no cases of radionecrosis. The 1-year OS, LC, and DIC were 46, 88, and 30%, respectively. CONCLUSIONS: In our single institution experience, we demonstrate stereotactic radiation and capecitabine to be a safe treatment for patients with BCBM with adequate LC. Further study is needed to determine the potential synergy between stereotactic radiation and capecitabine in the management of BCBM.

Phage display targeting identifies EYA1 as a regulator of glioblastoma stem cell maintenance and proliferation.

Glioblastoma (GBM) ranks among the most lethal of human malignancies with GBM stem cells (GSCs) that contribute to tumor growth and therapeutic resistance. Identification and isolation of GSCs continue to be a challenge, as definitive methods to purify these cells for study or targeting are lacking. Here, we leveraged orthogonal in vitro and in vivo phage display biopanning strategies to isolate a single peptide with GSC-specific binding properties. In silico analysis of this peptide led to the isolation of EYA1 (Eyes Absent 1), a tyrosine phosphatase and transcriptional coactivator. Validating the phage discovery methods, EYA1 was preferentially expressed in GSCs compared to differentiated tumor progeny. MYC is a central mediator of GSC maintenance but has been resistant to direct targeting strategies. Based on correlation and colocalization of EYA1 and MYC, we interrogated a possible interaction, revealing binding of EYA1 to MYC and loss of MYC expression upon targeting EYA1. Supporting a functional role for EYA1, targeting EYA1 expression decreased GSC proliferation, migration, and self-renewal in vitro and tumor growth in vivo. Collectively, our results suggest that phage display can identify novel therapeutic targets in stem-like tumor cells and that an EYA1-MYC axis represents a potential therapeutic paradigm for GBM.

Initial Approach to Patients with a Newly Diagnosed Solitary Brain Metastasis.

Solitary brain metastasis is defined by a single metastatic brain lesion as the only site of metastasis. The initial approach to this condition consists of radiographical evaluation to establish diagnosis, followed by assessment of functional and prognostic status. Neurologic symptom management consists of using dexamethasone and antiepileptic medications. Treatment consists of a combination of surgical and radiation therapy. Surgical treatment is indicated where there is a need for tissue diagnosis or immediate alleviation of neurologic symptoms and mass effect. Stereotactic radiosurgery has become an effective treatment modality. Whole-brain radiation therapy may have a role as an adjunctive therapy.

Adult Intracranial Myxoid Mesenchymal Tumor with EWSR1-ATF1 Gene Fusion.

BACKGROUND: Intracranial myxoid mesenchymal tumors (IMMTs) carrying an EWSR1-CREB gene family fusion are extremely rare and have only been identified in 10 previous reports. All but one has been found in children or young adults. Although there appear to be similarities to a myxoid variant of angiomatoid fibrous histiocytoma (AFH), clear histologic differences exist that appear to distinguish IMMTs as a distinct and novel entity. Previous reports have lacked detailed long-term follow-up and recommendations regarding treatment approach. CASE DESCRIPTION: This case describes a 48-year-old woman who presented with a left intraventricular mass that was identified on histology as an IMMT with an EWSR1-ATF1 gene fusion. After initial resection, the tumor demonstrated local recurrence. Repeat resection was performed followed by immediate demonstration of local and distant tumor recurrence. Histologic analysis of the tumor demonstrated a myxoid mesenchymal tumor distinct from AFH. Fractionated stereotactic radiation therapy was administered after the second resection, and tumor control was achieved at 1 year. CONCLUSIONS: Intracranial myxoid mesenchymal tumor is a novel and rare entity that has been previously identified in only 10 cases. This case is particularly remarkable because it is only the second IMMT case to occur in a middle-aged adult and shares striking similarities in clinical presentation to the previously reported case. Given the aggressive recurrence seen with the presented case, we recommend the treatment plan to be surgical resection followed by adjuvant radiation therapy.