Sex Difference in Disease-Related Adverse Events Post-Diagnosis of Lung Cancer Brain Metastases in Medicare Individuals ≥ 66 Years of Age.

Sex differences are evident in adverse events (AEs) related to brain tumors, yet sex differences in AEs specific to brain metastases (BrMs) are underexplored. Lung cancer BrMs dominate among BrM, comprising over half of cases. This study examined sex differences in AEs associated with lung cancer BrMs in individuals aged 66 or older using the SEER-Medicare dataset. Multivariable logistic regression, adjusted for demographic factors and comorbidities, stratified by histological subtype, treatment, age, and year of diagnosis were used to analyze AEs among those with BrMs from primary lung tumors. Year of diagnosis was grouped into prior/post-2013, to account for shifts in treatment paradigms. The results showed nuanced sex-specific AEs. Females diagnosed post-2013 with small-cell, squamous-cell, or other non-small-cell carcinoma BrMs had a higher headache likelihood than males. Males with adenocarcinoma post-2013 were more likely to experience brain herniation. Females aged 76 and older with small-cell BrM exhibited increased vision difficulty risk compared to males of the same age, with no significant difference in other age groups. Males treated for adenocarcinoma faced heightened hemorrhagic stroke risk. This study reveals sex-specific disparities in AEs among older individuals with lung cancer BrMs, varying by histological subtype, age, diagnosis year, and treatment.

Predicting peritumoral glioblastoma infiltration and subsequent recurrence using deep-learning-based analysis of multi-parametric magnetic resonance imaging.

Purpose: Glioblastoma (GBM) is the most common and aggressive primary adult brain tumor. The standard treatment approach is surgical resection to target the enhancing tumor mass, followed by adjuvant chemoradiotherapy. However, malignant cells often extend beyond the enhancing tumor boundaries and infiltrate the peritumoral edema. Traditional supervised machine learning techniques hold potential in predicting tumor infiltration extent but are hindered by the extensive resources needed to generate expertly delineated regions of interest (ROIs) for training models on tissue most and least likely to be infiltrated. Approach: We developed a method combining expert knowledge and training-based data augmentation to automatically generate numerous training examples, enhancing the accuracy of our model for predicting tumor infiltration through predictive maps. Such maps can be used for targeted supra-total surgical resection and other therapies that might benefit from intensive yet well-targeted treatment of infiltrated tissue. We apply our method to preoperative multi-parametric magnetic resonance imaging (mpMRI) scans from a subset of 229 patients of a multi-institutional consortium (Radiomics Signatures for Precision Diagnostics) and test the model on subsequent scans with pathology-proven recurrence. Results: Leave-one-site-out cross-validation was used to train and evaluate the tumor infiltration prediction model using initial pre-surgical scans, comparing the generated prediction maps with follow-up mpMRI scans confirming recurrence through post-resection tissue analysis. Performance was measured by voxel-wised odds ratios (ORs) across six institutions: University of Pennsylvania (OR: 9.97), Ohio State University (OR: 14.03), Case Western Reserve University (OR: 8.13), New York University (OR: 16.43), Thomas Jefferson University (OR: 8.22), and Rio Hortega (OR: 19.48). Conclusions: The proposed model demonstrates that mpMRI analysis using deep learning can predict infiltration in the peri-tumoral brain region for GBM patients without needing to train a model using expert ROI drawings. Results for each institution demonstrate the model's generalizability and reproducibility.

Molecular classification to refine surgical and radiotherapeutic decision-making in meningioma.

Treatment of the tumor and dural margin with surgery and sometimes radiation are cornerstones of therapy for meningioma. Molecular classifications have provided insights into the biology of disease; however, response to treatment remains heterogeneous. In this study, we used retrospective data on 2,824 meningiomas, including molecular data on 1,686 tumors and 100 prospective meningiomas, from the RTOG-0539 phase 2 trial to define molecular biomarkers of treatment response. Using propensity score matching, we found that gross tumor resection was associated with longer progression-free survival (PFS) across all molecular groups and longer overall survival in proliferative meningiomas. Dural margin treatment (Simpson grade 1/2) prolonged PFS compared to no treatment (Simpson grade 3). Molecular group classification predicted response to radiotherapy, including in the RTOG-0539 cohort. We subsequently developed a molecular model to predict response to radiotherapy that discriminates outcome better than standard-of-care classification. This study highlights the potential for molecular profiling to refine surgical and radiotherapy decision-making.

NRG-BN002: Phase I study of ipilimumab, nivolumab, and the combination in patients with newly diagnosed glioblastoma.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have efficacy in several solid tumors but limited efficacy in glioblastoma (GBM). This study evaluated the safety of anti-CTLA-4 and anti-PD-1 ICIs alone or in combination in newly diagnosed GBM after completion of standard radiochemotherapy with the subsequent intent to test combinatorial ICIs in this setting. METHODS: The primary endpoint was dose-limiting toxicity (DLT) for adults with unifocal, supratentorial newly diagnosed GBM after resection and chemoradiation. Ipilimumab and nivolumab were tested separately and in combination with a planned expansion cohort dependent upon DLT results. RESULTS: Thirty-two patients were enrolled at 9 institutions: 6 to each DLT assessment cohort and 14 to the expansion cohort. Median age: 55 years, 67.7% male, 83.9% White. Treatment was well tolerated with 16% Grade 4 events; the combination did not have unexpectedly increased toxicity, with no Grade 5 events. One DLT was seen in each single-agent treatment; none were observed in the combination, leading to expanded accrual of the combined treatment. The median follow-up was 19.6 months. For all patients receiving combination treatment, median overall survival (OS) and progression-free survival (PFS) were 20.7 and 16.1 months, respectively. CONCLUSIONS: IPI and NIVO are safe and tolerable with toxicities similar to those noted with other cancers when given in combination with adjuvant temozolomide for newly diagnosed GBM. Combination IPI + NIVO is not substantially more toxic than single agents. These results support a subsequent efficacy trial to test the combination of ICIs in Phase II/III for patients with newly diagnosed GBM. CLINICALTRIALS.GOV REGISTRATION: NCT02311920.

Outcomes of initial therapy for synchronous brain metastases from small cell lung cancer: a single-institution retrospective analysis.

Small cell lung cancer (SCLC) has a propensity for brain metastases, which is associated with poor prognosis. We sought to determine predictors of overall survival (OS) and brain progression-free survival (bPFS) in SCLC patients with synchronous brain metastases at the time of initial SCLC diagnosis. A total of 107 SCLC patients with synchronous brain metastases treated at a single institution were included in this retrospective analysis. These patients had brain lesions present on initial staging imaging. Survival was estimated using the Kaplan-Meier method with log-rank test. Factors predictive of OS and bPFS were analyzed using Cox proportional hazards regression model. Median OS for the entire cohort was 9 months (interquartile range, 4.2-13.8 months) and median bPFS was 7.3 months (interquartile range, 3.5-11.1 months). OS was 30.3% at 1 year and 14.4% at 2 years, while bPFS was 22.0% at 1 year and 6.9% at 2 years. The median number of brain lesions at diagnosis was 3 (interquartile range, 2-8), and the median size of the largest metastasis was 2.0 cm (interquartile range, 1.0-3.3 cm). Increased number of brain lesions was significantly associated with decreased OS. Patients who received both chemotherapy and whole brain radiation therapy (WBRT) had improved OS (P=0.02) and bPFS (P=0.005) compared to those who had either chemotherapy or WBRT alone. There was no significant difference in OS or bPFS depending on the sequence of therapy or the dose of WBRT. Thirteen patients underwent upfront brain metastasis resection, which was associated with improved OS (P=0.02) but not bPFS (P=0.09) compared to those who did not have surgery. The combination of chemotherapy and WBRT was associated with improved OS and bPFS compared to either modality alone. Upfront brain metastasis resection was associated with improved OS but not bPFS compared to those who did not have surgery.

Evaluating the Base Excision Repair Inhibitor TRC102 and Temozolomide for Patients with Recurrent Glioblastoma in the Phase 2 Adult Brain Tumor Consortium Trial BERT.

PURPOSE: Patients with glioblastoma (GBM) have a dismal prognosis. Although the DNA alkylating agent temozolomide (TMZ) is the mainstay of chemotherapy, therapeutic resistance rapidly develops in patients. Base excision repair inhibitor TRC102 (methoxyamine) reverses TMZ resistance in preclinical glioma models. We aimed to investigate the efficacy and safety of oral TRC102+TMZ in recurrent GBM (rGBM). PATIENTS AND METHODS: A preregistered (NCT02395692), nonrandomized, multicenter, phase 2 clinical trial (BERT) was planned and conducted through the Adult Brain Tumor Consortium (ABTC-1402). Arm 1 included patients with bevacizumab-naïve GBM at the first recurrence, with the primary endpoint of response rates. If sufficient activity was identified, a second arm was planned for the bevacizumab-refractory patients. The secondary endpoints were overall survival (OS), progression-free survival (PFS), PFS at 6 months (PFS6), and toxicity. RESULTS: Arm 1 enrolled 19 patients with a median of two treatment cycles. Objective responses were not observed; hence, arm 2 did not open. The median OS was 11.1 months [95% confidence interval (CI), 8.2-17.9]. The median PFS was 1.9 months (95% CI, 1.8-3.7). The PFS6 was 10.5% (95% CI, 1.3%-33.1%). Most toxicities were grades 1 and 2, with two grade 3 lymphopenias and one grade 4 thrombocytopenia. Two patients with PFS ≥ 17 months and OS > 32 months were deemed "extended survivors." RNA sequencing of tumor tissue, obtained at diagnosis, demonstrated significantly enriched signatures of DNA damage response (DDR), chromosomal instability (CIN70, CIN25), and cellular proliferation (PCNA25) in "extended survivors." CONCLUSIONS: These findings confirm the safety and feasibility of TRC102+TMZ in patients with rGBM. They also warrant further evaluation of combination therapy in biomarker-enriched trials enrolling GBM patients with baseline hyperactivated DDR pathways.

Sex differences in adverse events in Medicare individuals ≥ 66 years of age post glioblastoma treatment.

PURPOSE: Glioblastoma (GB) is the most common primary malignant brain tumor with the highest incidence occurring in older adults with a median age at diagnosis of 64 years old. While treatment often improves survival it brings toxicities and adverse events (AE). Here we identify sex differences in treatment patterns and AE in individuals ≥ 66 years at diagnosis with GB. METHODS: Using the SEER-Medicare dataset sex differences in adverse events were assessed using multivariable logistic regression performed to calculate the male/female odds ratio (M/F OR) and 95% confidence intervals [95% CI] of experiencing an AE adjusted for demographic variables and Elixhauser comorbidity score. RESULTS: Males with GB were more likely to receive standard of care (SOC; Surgery with concurrent radio-chemotherapy) [20%] compared to females [17%], whereas females were more likely to receive no treatment [26%] compared to males [21%]. Females with GB receiving SOC were more likely to develop gastrointestinal disorders (M/F OR = 0.76; 95% CI,0.64-0.91, p = 0.002) or blood and lymphatic system disorders (M/F OR = 0.79; 95% CI,0.66-0.95, p = 0.012). Males with GB receiving SOC were more likely to develop cardiac disorders (M/F OR = 1.21; 95% CI,1.02-1.44, p = 0.029) and renal disorders (M/F OR = 1.65; 95% CI,1.37-2.01, p < 0.001). CONCLUSIONS: Sex differences for individuals, 66 years and older, diagnosed with GB exist in treatment received and adverse events developed across different treatment modalities.

Lymphatic endothelial-like cells promote glioblastoma stem cell growth through cytokine-driven cholesterol metabolism.

Glioblastoma is the most lethal primary brain tumor with glioblastoma stem cells (GSCs) atop a cellular hierarchy. GSCs often reside in a perivascular niche, where they receive maintenance cues from endothelial cells, but the role of heterogeneous endothelial cell populations remains unresolved. Here, we show that lymphatic endothelial-like cells (LECs), while previously unrecognized in brain parenchyma, are present in glioblastomas and promote growth of CCR7-positive GSCs through CCL21 secretion. Disruption of CCL21-CCR7 paracrine communication between LECs and GSCs inhibited GSC proliferation and growth. LEC-derived CCL21 induced KAT5-mediated acetylation of HMGCS1 on K273 in GSCs to enhance HMGCS1 protein stability. HMGCS1 promoted cholesterol synthesis in GSCs, favorable for tumor growth. Expression of the CCL21-CCR7 axis correlated with KAT5 expression and HMGCS1K273 acetylation in glioblastoma specimens, informing patient outcome. Collectively, glioblastomas contain previously unrecognized LECs that promote the molecular crosstalk between endothelial and tumor cells, offering potentially alternative therapeutic strategies.

Association of partial T2-FLAIR mismatch sign and isocitrate dehydrogenase mutation in WHO grade 4 gliomas: results from the ReSPOND consortium.

PURPOSE: While the T2-FLAIR mismatch sign is highly specific for isocitrate dehydrogenase (IDH)-mutant, 1p/19q-noncodeleted astrocytomas among lower-grade gliomas, its utility in WHO grade 4 gliomas is not well-studied. We derived the partial T2-FLAIR mismatch sign as an imaging biomarker for IDH mutation in WHO grade 4 gliomas. METHODS: Preoperative MRI scans of adult WHO grade 4 glioma patients (n = 2165) from the multi-institutional ReSPOND (Radiomics Signatures for PrecisiON Diagnostics) consortium were analyzed. Diagnostic performance of the partial T2-FLAIR mismatch sign was evaluated. Subset analyses were performed to assess associations of imaging markers with overall survival (OS). RESULTS: One hundred twenty-one (5.6%) of 2165 grade 4 gliomas were IDH-mutant. Partial T2-FLAIR mismatch was present in 40 (1.8%) cases, 32 of which were IDH-mutant, yielding 26.4% sensitivity, 99.6% specificity, 80.0% positive predictive value, and 95.8% negative predictive value. Multivariate logistic regression demonstrated IDH mutation was significantly associated with partial T2-FLAIR mismatch (odds ratio [OR] 5.715, 95% CI [1.896, 17.221], p = 0.002), younger age (OR 0.911 [0.895, 0.927], p < 0.001), tumor centered in frontal lobe (OR 3.842, [2.361, 6.251], p < 0.001), absence of multicentricity (OR 0.173, [0.049, 0.612], p = 0.007), and presence of cystic (OR 6.596, [3.023, 14.391], p < 0.001) or non-enhancing solid components (OR 6.069, [3.371, 10.928], p < 0.001). Multivariate Cox analysis demonstrated cystic components (p = 0.024) and non-enhancing solid components (p = 0.003) were associated with longer OS, while older age (p < 0.001), frontal lobe center (p = 0.008), multifocality (p < 0.001), and multicentricity (p < 0.001) were associated with shorter OS. CONCLUSION: Partial T2-FLAIR mismatch sign is highly specific for IDH mutation in WHO grade 4 gliomas.

Multiple plasma membrane reporters discern LHFPL5 region that blocks trafficking to the plasma membrane.

The mechano-electrical transduction (MET) channel of the inner ear receptor cells, termed hair cells, is a protein complex that enables our senses of hearing and balance. Hair cell MET requires an elaborate interplay of multiple proteins that form the MET channel. One of the MET complex components is the transmembrane protein LHFPL5, which is required for hair cell MET and hearing. LHFPL5 is thought to form a multi-protein complex with other MET channel proteins, such as PCDH15, TMIE, and TMC1. Despite localizing to the plasma membrane of stereocilia, the mechanosensing organelles of hair cells, LHFPL5 requires its binding partner within the MET complex, PCDH15, to localize to the stereocilia tips in hair cells and to the plasma membrane in heterologous cells. Using the Aquaporin 3-tGFP reporter (AGR) for plasma membrane localization, we found that a region within extracellular loop 1, which interacts with PCDH15, precludes the trafficking of AGR reporter to the plasma membrane in heterologous cell lines. Our results suggest that the presence of protein partners may mask endoplasmic reticulum retention regions or enable the proper folding and trafficking of the MET complex components, to facilitate expression of the MET complex at the stereocilia membrane.

Comparison of Near-Infrared Imaging Agents Targeting the PTPmu Tumor Biomarker.

PURPOSE: Maximal, safe resection of solid tumors is considered a critical first step in successful cancer treatment. The advent of fluorescence image-guided surgery (FIGS) using non-specific agents has improved patient outcomes, particularly in the case of glioblastoma. Molecularly targeted agents that recognize specific tumor biomarkers have the potential to augment these gains. Identification of the optimal combination of targeting moiety and fluorophore is needed prior to initiating clinical trials. PROCEDURES: A 20-amino acid peptide (SBK2) recognizing the receptor protein-tyrosine phosphatase mu (PTPmu)-derived tumor-specific biomarker, with or without a linker, was conjugated to three different near-infrared fluorophores: indocyanine green (ICG), IRDye® 800CW, and Tide Fluor™ 8WS. The in vivo specificity, time course, and biodistribution were evaluated for each using mice with heterotopic human glioma tumors that express the PTPmu biomarker to identify component combinations with optimal properties for FIGS. RESULTS: SBK2 conjugated to ICG demonstrated excellent specificity for gliomas in heterotopic tumors. SBK2-ICG showed significantly higher in vivo tumor labeling compared to the Scram-ICG control from 10 min to 24 h, p < 0.01 at all timepoints, following injection, as well as a significantly higher ex vivo tumor signal at 24 h, p < 0.001. Inserting a six-amino acid linker between the targeting peptide and ICG increased the clearance rate and resulted in significantly higher in vivo tumor signal relative to its linker-containing Scrambled control from 10 min to 8 h, p < 0.05 at all timepoints, after dosing. Agents made with the more hydrophilic IRDye® 800CW and Tide Fluor™ 8WS showed no specific tumor labeling relative to the controls. The IRDye 800CW-conjugated agents cleared within 1 h, while the non-specific fluorescent tumor signal generated by the Tide Fluor 8WS-conjugated agents persists beyond 24 h. CONCLUSIONS: The SBK2 PTPmu-targeting peptide conjugated to ICG specifically labels heterotopic human gliomas grown in mice between 10 min and 24 h following injection. Similar molecules constructed with more hydrophilic dyes demonstrated no specificity. These studies present a promising candidate for use in FIGS of PTPmu biomarker-expressing tumors.

Novel 3D magnetic resonance fingerprinting radiomics in adult brain tumors: a feasibility study.

OBJECTIVES: To test the feasibility of using 3D MRF maps with radiomics analysis and machine learning in the characterization of adult brain intra-axial neoplasms. METHODS: 3D MRF acquisition was performed on 78 patients with newly diagnosed brain tumors including 33 glioblastomas (grade IV), 6 grade III gliomas, 12 grade II gliomas, and 27 patients with brain metastases. Regions of enhancing tumor, non-enhancing tumor, and peritumoral edema were segmented and radiomics analysis with gray-level co-occurrence matrices and gray-level run-length matrices was performed. Statistical analysis was performed to identify features capable of differentiating tumors based on type, grade, and isocitrate dehydrogenase (IDH1) status. Receiver operating curve analysis was performed and the area under the curve (AUC) was calculated for tumor classification and grading. For gliomas, Kaplan-Meier analysis for overall survival was performed using MRF T1 features from enhancing tumor region. RESULTS: Multiple MRF T1 and T2 features from enhancing tumor region were capable of differentiating glioblastomas from brain metastases. Although no differences were identified between grade 2 and grade 3 gliomas, differentiation between grade 2 and grade 4 gliomas as well as between grade 3 and grade 4 gliomas was achieved. MRF radiomics features were also able to differentiate IDH1 mutant from the wild-type gliomas. Radiomics T1 features for enhancing tumor region in gliomas correlated to overall survival (p < 0.05). CONCLUSION: Radiomics analysis of 3D MRF maps allows differentiating glioblastomas from metastases and is capable of differentiating glioblastomas from metastases and characterizing gliomas based on grade, IDH1 status, and survival. KEY POINTS: • 3D MRF data analysis using radiomics offers novel tissue characterization of brain tumors. • 3D MRF with radiomics offers glioma characterization based on grade, IDH1 status, and overall patient survival.

ABTC-0904: targeting glioma stem cells in GBM: a phase 0/II study of hedgehog pathway inhibitor GDC-0449.

PURPOSE: Gliomagenesis and resistance of glioblastoma (GBM) are believed to be mediated by glioma stem cells (GSC). Evidence suggests that SHH signaling promotes GSC proliferation and self-renewal. METHODS: ABTC-0904 was a two-arm, multicenter phase 0/II study of GDC-0449, an oral inhibitor of Smoothened (SMO) in patients undergoing resection for recurrent GBM. All patients (Arms I and II) had surgery and received drug post-operatively. Only patients in Arm I received drug prior to surgery. The primary objective was to determine 6-month progression free survival (PFS-6). Secondary endpoints include median PFS (mPFS) and overall survival (mOS), response rate, and toxicity. Correlative studies included bioanalysis of GDC-0449, and inhibition of SHH signaling, GSC proliferation and self-renewal. RESULTS: Forty-one patients were enrolled. Pharmacokinetics of GDC-0449 in plasma demonstrated levels within expected therapeutic range in 75% of patients. The proportion of tumorcells producing CD133+ neurospheres, neurosphere proliferation, self-renewal, and expression of the SHh downstream signaling was significantly decreased in Arm I following GDC-0449 treatment (p < 0.005; p < 0.001 respectively) compared to Arm II (no drug pre-op). Treatment was well tolerated. There were no objective responders in either arm. Overall PFS-6 was 2.4% (95% CI 0.9-11.1%). Median PFS was 2.3 months (95% CI 1.9-2.6) and mOS was 7.8 months (95% CI 5.4-10.1). CONCLUSIONS: GDC-0449 was well tolerated, reached tumor, and inhibited CD133+ neurosphere formation, but had little clinical efficacy as a single agent in rGBM. This suggests growth and maintenance of rGBM is not solely dependent on the SHH pathway thus targeting SMO may require combined approaches.

Glioma stem cells activate platelets by plasma-independent thrombin production to promote glioblastoma tumorigenesis.

Background: The interaction between platelets and cancer cells has been underexplored in solid tumor models that do not metastasize, for example, glioblastoma (GBM) where metastasis is rare. Histologically, it is known that glioma stem cells (GSCs) are found in perivascular and pseudsopalisading regions of GBM, which are also areas of platelet localization. High platelet counts have been associated with poor clinical outcomes in many cancers. While platelets are known to promote the progression of other tumors, mechanisms by which platelets influence GBM oncogenesis are unknown. Here, we aimed to understand how the bidirectional interaction between platelets and GSCs drives GBM oncogenesis. Methods: Male and female NSG mice were transplanted with GSC lines and treated with antiplatelet and anti-thrombin inhibitors. Immunofluorescence, qPCR, and Western blots were used to determine expression of coagulation mechanism in GBM tissue and subsequent GSC lines. Results: We show that GSCs activate platelets by endogenous production of all the factors of the intrinsic and extrinsic coagulation cascades in a plasma-independent manner. Therefore, GSCs produce thrombin resulting in platelet activation. We further demonstrate that the endogenous coagulation cascades of these cancer stem cells are tumorigenic: they activate platelets to promote stemness and proliferation in vitro and pharmacological inhibition delays tumor growth in vivo. Conclusions: Our findings uncover a specific preferential relationship between platelets and GSCs that drive GBM malignancies and identify a therapeutically targetable novel interaction.

Stereotactic radiosurgery and resection for treatment of multiple brain metastases: a systematic review and analysis.

OBJECTIVE: Stereotactic radiosurgery (SRS) has recently emerged as a minimally invasive alternative to resection for treating multiple brain metastases. Given the lack of consensus regarding the application of SRS versus resection for multiple brain metastases, the authors aimed to conduct a systematic literature review of all published work on the topic. METHODS: The PubMed, OVID, Cochrane, Web of Science, and Scopus databases were used to identify studies that examined clinical outcomes after resection or SRS was performed in patients with multiple brain metastases. Radiological studies, case series with fewer than 3 patients, pediatric studies, or national database studies were excluded. Data extracted included patient demographics and mean overall survival (OS). Weighted t-tests and ANOVA were performed. RESULTS: A total of 1300 abstracts were screened, 450 articles underwent full-text review, and 129 studies met inclusion criteria, encompassing 20,177 patients (18,852 treated with SRS and 1325 who underwent resection). The OS for the SRS group was 10.2 ± 6 months, and for the resection group it was 6.5 ± 3.8 months. A weighted ANOVA test comparing OS with covariates of age, sex, and publication year revealed that the treatment group (p = 0.045), age (p = 0.034), and publication year (0.0078) were all independently associated with OS (with SRS, younger age, and later publication year being associated with longer survival), whereas sex (p = 0.95) was not. CONCLUSIONS: For patients with multiple brain metastases, SRS and resection are effective treatments to prolong OS, with published data suggesting that SRS may have a trend toward lengthened survival outcomes. The authors encourage additional work examining outcomes of treatments for multiple brain metastases.

Multidisciplinary approaches to gliosarcoma: A case report and review of the literature.

A 58-year-old right-handed man presented to our tertiary care center with gliosarcoma (GS) infiltration through the dura, skull, and soft tissue. Patient had a previous history of right temporal GS, with four intracranial surgeries prior to presentation. A multidisciplinary approach was used to treat the lesion and perform reconstruction.

Detection of tumor-specific DNA methylation markers in the blood of patients with pituitary neuroendocrine tumors.

BACKGROUND: DNA methylation abnormalities are pervasive in pituitary neuroendocrine tumors (PitNETs). The feasibility to detect methylome alterations in circulating cell-free DNA (cfDNA) has been reported for several central nervous system (CNS) tumors but not across PitNETs. The aim of the study was to use the liquid biopsy (LB) approach to detect PitNET-specific methylation signatures to differentiate these tumors from other sellar diseases. METHODS: We profiled the cfDNA methylome (EPIC array) of 59 serum and 41 plasma LB specimens from patients with PitNETs and other CNS diseases (sellar tumors and other pituitary non-neoplastic diseases, lower-grade gliomas, and skull-base meningiomas) or nontumor conditions, grouped as non-PitNET. RESULTS: Our results indicated that despite quantitative and qualitative differences between serum and plasma cfDNA composition, both sources of LB showed that patients with PitNETs presented a distinct methylome landscape compared to non-PitNETs. In addition, LB methylomes captured epigenetic features reported in PitNET tissue and provided information about cell-type composition. Using LB-derived PitNETs-specific signatures as input to develop machine-learning predictive models, we generated scores that distinguished PitNETs from non-PitNETs conditions, including sellar tumor and non-neoplastic pituitary diseases, with accuracies above ~93% in independent cohort sets. CONCLUSIONS: Our results underpin the potential application of methylation-based LB profiling as a noninvasive approach to identify clinically relevant epigenetic markers to diagnose and potentially impact the prognostication and management of patients with PitNETs.

Healthy myeloid-derived suppressor cells express the surface ectoenzyme Vanin-2 (VNN2).

Study of human monocytic Myeloid-Derived Suppressor cells Mo-MDSC (CD14+ HLA-DRneg/low) has been hampered by the lack of positive cell-surface markers. In order to identify positive markers for Mo-MDSC, we performed microarray analysis comparing Mo-MDSC cells from healthy subjects versus CD14+ HLA-DRhigh monocytes. We have identified the surface ectoenzyme Vanin-2(VNN2) protein as a novel biomarker highly-enriched in healthy subjects Mo-MDSC. Indeed, healthy subjects Mo-MDSC cells expressed 68 % VNN2, whereas only 9% VNN2 expression was observed on CD14+ HLA-DRhigh cells (n = 4 p < 0.01). The top 10 percent positive VNN2 monocytes expressed CD33 and CD11b while being negative for HLA-DR, CD3, CD15, CD19 and CD56, consistent with a Mo-MDSC phenotype. CD14+VNN2high monocytes were able to inhibit CD8 T cell proliferation comparably to traditional Mo-MDSC at 51 % and 48 % respectively. However, VNN2 expression on CD14+ monocytes from glioma patients was inversely correlated to their grade. CD14+VNN2high monocytes thus appear to mark a monocytic population similar to Mo-MDSC only in healthy subjects, which may be useful for tumor diagnoses.