Potential Molecular Targets in the Treatment of Patients with CNS Tumors.

The challenges in identifying effective therapies for CNS tumors continue to be daunting [...].

Post-Traumatic Gliomas in Adults: Review of the Case Reports and Studies.

Traumatic brain injury (TBI) was first proposed as a potential risk factor for developing a glioma in the 1800s, and conditions for establishing a causal relationship between brain injury and gliomas have since been proposed. Given the medical and legal ramifications, the current literature was reviewed to better understand this possible association. Articles that examined the relationship between TBI and glioma formation in adults and were published in English between 1978 and 2022 were reviewed. There were 19 case reports of 25 patients and 16 observational studies. The case reports describe glioma formation at the precise site of prior brain injury in continuity with traumatic scar; the observational studies report conflicting findings, but they largely demonstrate no association. Most of the observational studies are limited by their retrospective nature, but we identified one prospective cohort study which found a positive association. Altogether, we suggest that glioma formation after TBI is a rare occurrence that warrants further study.

An International Perspective on Preceding Infections in Guillain-Barré Syndrome: The IGOS-1000 Cohort.

BACKGROUND AND OBJECTIVES: Infections play a key role in the development of Guillain-Barré syndrome (GBS) and have been associated with specific clinical features and disease severity. The clinical variation of GBS across geographical regions has been suggested to be related to differences in the distribution of preceding infections, but this has not been studied on a large scale. METHODS: We analyzed the first 1,000 patients included in the International GBS Outcome Study with available biosamples (n = 768) for the presence of a recent infection with Campylobacter jejuni, hepatitis E virus, Mycoplasma pneumoniae, cytomegalovirus, and Epstein-Barr virus. RESULTS: Serologic evidence of a recent infection with C. jejuni was found in 228 (30%), M. pneumoniae in 77 (10%), hepatitis E virus in 23 (3%), cytomegalovirus in 30 (4%), and Epstein-Barr virus in 7 (1%) patients. Evidence of more than 1 recent infection was found in 49 (6%) of these patients. Symptoms of antecedent infections were reported in 556 patients (72%), and this proportion did not significantly differ between those testing positive or negative for a recent infection. The proportions of infections were similar across continents. The sensorimotor variant and the demyelinating electrophysiologic subtype were most frequent across all infection groups, although proportions were significantly higher in patients with a cytomegalovirus and significantly lower in those with a C. jejuni infection. C. jejuni-positive patients were more severely affected, indicated by a lower Medical Research Council sum score at nadir (p = 0.004) and a longer time to regain the ability to walk independently (p = 0.005). The pure motor variant and axonal electrophysiologic subtype were more frequent in Asian compared with American or European C. jejuni-positive patients (p < 0.001, resp. p = 0.001). Time to nadir was longer in the cytomegalovirus-positive patients (p = 0.004). DISCUSSION: Across geographical regions, the distribution of infections was similar, but the association between infection and clinical phenotype differed. A mismatch between symptom reporting and serologic results and the high frequency of coinfections demonstrate the importance of broad serologic testing in identifying the most likely infectious trigger. The association between infections and outcome indicates their value for future prognostic models.

EGFR ligand shifts the role of EGFR from oncogene to tumour suppressor in EGFR-amplified glioblastoma by suppressing invasion through BIN3 upregulation.

The epidermal growth factor receptor (EGFR) is a prime oncogene that is frequently amplified in glioblastomas. Here we demonstrate a new tumour-suppressive function of EGFR in EGFR-amplified glioblastomas regulated by EGFR ligands. Constitutive EGFR signalling promotes invasion via activation of a TAB1-TAK1-NF-κB-EMP1 pathway, resulting in large tumours and decreased survival in orthotopic models. Ligand-activated EGFR promotes proliferation and surprisingly suppresses invasion by upregulating BIN3, which inhibits a DOCK7-regulated Rho GTPase pathway, resulting in small hyperproliferating non-invasive tumours and improved survival. Data from The Cancer Genome Atlas reveal that in EGFR-amplified glioblastomas, a low level of EGFR ligands confers a worse prognosis, whereas a high level of EGFR ligands confers an improved prognosis. Thus, increased EGFR ligand levels shift the role of EGFR from oncogene to tumour suppressor in EGFR-amplified glioblastomas by suppressing invasion. The tumour-suppressive function of EGFR can be activated therapeutically using tofacitinib, which suppresses invasion by increasing EGFR ligand levels and upregulating BIN3.

Primary central nervous system lymphoma: a real-world comparison of therapy access and outcomes by hospital setting.

Background: This study analyzes sociodemographic barriers for primary CNS lymphoma (PCNSL) treatment and outcomes at a public safety-net hospital versus a private tertiary academic institution. We hypothesized that these barriers would lead to access disparities and poorer outcomes in the safety-net population. Methods: We reviewed records of PCNSL patients from 2007-2020 (n = 95) at a public safety-net hospital (n = 33) and a private academic center (n = 62) staffed by the same university. Demographics, treatment patterns, and outcomes were analyzed. Results: Patients at the safety-net hospital were significantly younger, more commonly Black or Hispanic, and had a higher prevalence of HIV/AIDS. They were significantly less likely to receive induction chemotherapy (67% vs 86%, P = .003) or consolidation autologous stem cell transplantation (0% vs. 47%, P = .001), but received more whole-brain radiation therapy (35% vs 16%, P = .001). Younger age and receiving any consolidation therapy were associated with improved progression-free (PFS, P = .001) and overall survival (OS, P = .001). Hospital location had no statistical impact on PFS (P = .725) or OS (P = .226) on an age-adjusted analysis. Conclusions: Our study shows significant differences in treatment patterns for PCNSL between a public safety-net hospital and an academic cancer center. A significant survival difference was not demonstrated, which is likely multifactorial, but likely was positively impacted by the shared multidisciplinary care delivery between the institutions. As personalized therapies for PCNSL are being developed, equitable access including clinical trials should be advocated for resource-limited settings.

Primary central nervous system sarcomas in adults: A systematic review.

BACKGROUND: Primary central nervous system (CNS) sarcomas represent a heterogeneous group of rare neoplasms with unclear etiology. Available data on clinical characteristics, treatment strategies, and survival are scarce. We comprehensively reviewed management strategies and outcomes of primary CNS sarcomas in adults. METHODS: PubMed, Scopus, and Cochrane were search following the PRISMA guidelines to include studies on primary CNS sarcomas in adults. Clinical features, management strategies, and survival were analyzed. RESULTS: We included 9 studies comprising 78 patients. Primary CNS sarcomas were mostly intracranial (87.2%), frequently located in the parietal (17.9%), frontal (14.1%), and temporal (14.1%) lobes. Spinal CNS sarcomas were found in 10 patients (12.8%). The most common tumor histology were fibrosarcoma (16.7%), intracranial synovial sarcoma (12.8%), extraosseous mesenchymal chondrosarcoma (11.5%), perivascular sarcoma (11.5%), reticulum cell sarcoma (11.5%), and myeloid sarcoma (9%). Partial resection (57.7%) was preferred over complete resection (42.3%), and 43 patients (55.1%) received adjuvant treatments: radiotherapy (51.3%) and/or systemic chemotherapy (20.5%). 21 patients experienced CNS sarcomas recurrences, with a median progression-free survival of 9 months (range, 4-48). At last follow-up, 60 patients (76.9%) were dead, with a median overall survival of 9 months (0.1-396). Overall survival was significantly longer in patients with fibrosarcoma (p = 0.001). CONCLUSION: Surgical resection coupled with adjuvant chemotherapy or radiation has historically been the cornerstone treatment for CNS sarcoma but showed poor local control and dismal survival. A better understanding of the CNS sarcoma microenvironment may favor the development of tailored strategies aimed at improving survival.

Evaluating the Efficacy of an Online Learning Tool for EEG Teaching: A Prospective Cohort Study.

OBJECTIVE: To determine the effectiveness of a 6-month, interactive, multimodal, Web-based EEG teaching program (EEGonline) in improving EEG analysis and interpretation skills for neurologists, neurology residents, and technologists, particularly in resource-limited settings. METHODS: Between June 2017 and November 2018, 179 learners originating from 20 African countries, Europe, and the United States were registered on the EEGonline course. Of these, 128 learners (91% African) participated in the study. Pre- and postcourse multiple choice question (MCQ) test results and EEGonline user logs were analyzed. Differences in pre- and posttest performance were correlated with quantified exposure to various EEGonline learning modalities. Participants' impressions of EEGonline efficacy and usefulness were assessed through pre- and postcourse satisfaction surveys. RESULTS: Ninety-one participants attempted both pre- and postcourse tests (71% response rate). Mean scores improved from 46.7% ± 17.6% to 64.1% ± 18%, respectively (p < 0.001, Cohen d 0.974). The largest improvement was in correct identification of normal features (43.2%-59.1%; p < 0.001, Cohen d 0.664) and artifacts (43.3%-61.6%; p < 0.001, Cohen d 0.836). Improvement in knowledge was associated with improved subjective confidence in EEG analysis. Overall confidence among postcourse survey respondents improved significantly from 35.9% to 81.9% (p < 0.001). Lecture notes, self-assessment quizzes, and discussion forums were the most utilized learning modalities. The majority of survey respondents (97.2%) concluded that EEGonline was a useful learning tool and 93% recommended that similar courses should be included in EEG training curricula. CONCLUSIONS: This study demonstrated that a multimodal, online EEG teaching tool was effective in improving EEG analysis and interpretation skills and may be useful in resource-poor settings.

Anterior temporal lobectomy: A cross-sectional observational study of potential surgical candidates at a single institute.

BACKGROUND: Epilepsy is a common neurological disorder, associated with serious cognitive, physical, and psychosocial burdens. Mesial temporal lobe epilepsy (mTLE) is the commonest form of focal epilepsy. The aim of this study was to establish the incidence of patients with electroencephalographic epileptiform discharges consistent with mTLE attending a tertiary hospital in South Africa, and determine whether these patients may be candidates for anterior temporal lobectomy. METHODS: This was a cross-sectional observational study of all patients receiving scalp electroencephalograms (EEG) performed at the Groote Schuur Hospital Neurophysiology laboratory during the period January 1, 2017-December 31, 2019. Where magnetic resonance imaging (MRI) brain scans had been performed, these were assessed for corroborative evidence of mTLE. RESULTS: Over the 3-year period, 4 342 EEGs were assessed. A total of 411 (11%) showed epileptiform discharges consistent with all epilepsy types. Of these, 327 (69%) were of focal onset and 108 (33% of all focal onset epilepsies) were consistent with mTLE. Of the patients with electroencephalographic features of mTLE, only 27 (25%) had had MRI brain scans performed according to an epilepsy surgery protocol. None of these patients had been considered for surgery. CONCLUSION: Surgery, especially anterior temporal lobectomy, is widely acknowledged to be an efficacious and cost-effective intervention in patients with drug-resistant mTLE. The findings of our study suggest that patients with mTLE in our setting are under-investigated for potential surgery; and that it is under-utilized. These findings are in line with similar studies in both well-resourced and resource-constrained countries. Our study also highlights the utility of EEG as a practical screening tool to identify potential surgical candidates, as well as the establishment of an EEG and MRI database to assist in recognizing these patients.

A Modified Nucleoside 6-Thio-2'-Deoxyguanosine Exhibits Antitumor Activity in Gliomas.

PURPOSE: To investigate the therapeutic role of a novel telomere-directed inhibitor, 6-thio-2'-deoxyguanosine (THIO) in gliomas both in vitro and in vivo. EXPERIMENTAL DESIGN: A panel of human and mouse glioma cell lines was used to test therapeutic efficacy of THIO using cell viability assays, flow cytometric analyses, and immunofluorescence. Integrated analyses of RNA sequencing and reverse-phase protein array data revealed the potential antitumor mechanisms of THIO. Four patient-derived xenografts (PDX), two patient-derived organoids (PDO), and two xenografts of human glioma cell lines were used to further investigate the therapeutic efficacy of THIO. RESULTS: THIO was effective in the majority of human and mouse glioma cell lines with no obvious toxicity against normal astrocytes. THIO as a monotherapy demonstrated efficacy in three glioma cell lines that had acquired resistance to temozolomide. In addition, THIO showed efficacy in four human glioma cell lines grown as neurospheres by inducing apoptotic cell death. Mechanistically, THIO induced telomeric DNA damage not only in glioma cell lines but also in PDX tumor specimens. Integrated computational analyses of transcriptomic and proteomic data indicated that THIO significantly inhibited cell invasion, stem cell, and proliferation pathways while triggering DNA damage and apoptosis. Importantly, THIO significantly decreased tumor proliferation in two PDO models and reduced the tumor size of a glioblastoma xenograft and a PDX model. CONCLUSIONS: The current study established the therapeutic role of THIO in primary and recurrent gliomas and revealed the acute induction of telomeric DNA damage as a primary antitumor mechanism of THIO in gliomas.

Reversibly Modulating the Blood-Brain Barrier by Laser Stimulation of Molecular-Targeted Nanoparticles.

The blood-brain barrier (BBB) is highly selective and acts as the interface between the central nervous system and circulation. While the BBB is critical for maintaining brain homeostasis, it represents a formidable challenge for drug delivery. Here we synthesized gold nanoparticles (AuNPs) for targeting the tight junction specifically and demonstrated that transcranial picosecond laser stimulation of these AuNPs post intravenous injection increases the BBB permeability. The BBB permeability change can be graded by laser intensity, is entirely reversible, and involves increased paracellular diffusion. BBB modulation does not lead to significant disruption in the spontaneous vasomotion or the structure of the neurovascular unit. This strategy allows the entry of immunoglobulins and viral gene therapy vectors, as well as cargo-laden liposomes. We anticipate this nanotechnology to be useful for tissue regions that are accessible to light or fiberoptic application and to open new avenues for drug screening and therapeutic interventions in the central nervous system.

Recurrent Hodgkin's Disease Presenting as a Clinically Isolated Cavernous Sinus Syndrome.

BACKGROUND: Hodgkin's disease involving the central nervous system is uncommon and is usually seen in patients with uncontrolled systemic disease or those who have had multiple episodes of recurrent disease. Common symptoms of intracranial Hodgkin's disease are motor and/or sensory deficits, headache, papilloedema, coma, and seizures. The rarity of Hodgkin's disease presenting with intracranial involvement is marked, but patients presenting with cavernous sinus syndrome is even rarer. Despite its rarity, the presence of a cavernous sinus syndrome in a patient with a known history of Hodgkin's disease warrants full utilization of modern diagnostic techniques in terms of investigation. Case Presentation. A 34-year-old woman, known with previous Hodgkin's lymphoma and now in remission for the past 7 years, presented with signs and symptoms suggestive of a left cavernous sinus syndrome. She was otherwise systemically well with no other complaints. Extensive investigations revealed no obvious cause for the cavernous sinus syndrome. A CT chest revealed subclinical axillary lymphadenopathy, which on excisional biopsy confirmed recurrent Hodgkin's disease. The patient's sole clinical presentation of her recurrent disease was the cavernous sinus syndrome, with no other clinically obvious systemic signs or symptoms to suggest a relapse. This was treated with steroids, and clinical improvement was noted; she was referred to oncology for extensive chemotherapy. CONCLUSIONS: Whilst there is a paucity of literature around this topic, it must be remembered by the clinician that cavernous sinus syndrome may be the sole clinical presentation of recurrent Hodgkin's disease. Even though it is reported that lymphomatous involvement in the brain usually occurs late in the disease process, this case is evidence that cavernous sinus syndrome may precede other systemic signs and symptoms. Recognising this possibility will ensure a rigorous search for Hodgkin's disease, an early and effective diagnosis, and a better prognosis in affected patients.

Spectral fitting strategy to overcome the overlap between 2-hydroxyglutarate and lipid resonances at 2.25 ppm.

PURPOSE: 1 H MRS provides a noninvasive tool for identifying mutations in isocitrate dehydrogenase (IDH). Quantification of the prominent 2-hydroxyglutarate (2HG) resonance at 2.25 ppm is often confounded by the lipid resonance at the same frequency in tumors with elevated lipids. We propose a new spectral fitting approach to separate these overlapped signals, therefore, improving 2HG evaluation. METHODS: TE 97 ms PRESS was acquired at 3T from 42 glioma patients. New lipid basis sets were created, in which the small lipid 2.25-ppm signal strength was preset with reference to the lipid signal at 0.9 ppm, incorporating published fat relaxation data. LCModel fitting using the new lipid bases (Fitting method 2) was conducted along with fitting using the LCModel built-in lipid basis set (Fitting method 1), in which the lipid 2.25-ppm signal is assessed with reference to the lipid 1.3-ppm signal. In-house basis spectra of low-molecular-weight metabolites were used in both fitting methods. RESULTS: Fitting method 2 showed marked improvement in identifying IDH mutational status compared with Fitting method 1. 2HG estimates from Fitting method 2 were overall smaller than those from Fitting method 1, which was because of differential assignment of the signal at 2.25 ppm to lipids. In receiver operating characteristic analysis, Fitting method 2 provided a complete distinction between IDH mutation and wild-type whereas Fitting method 1 did not. CONCLUSION: The data suggest that 1 H MR spectral fitting using the new lipid basis set provides a robust fitting strategy that improves 2HG evaluation in brain tumors with elevated lipids.

Basis for Immunotherapy for Treatment of Meningiomas.

Meningiomas are common tumors that account for approximately one third of CNS tumors diagnosed every year. They are classified by the World Health Organization in grades I-III. Higher grades have an increased rate of growth, invasiveness, rate of recurrence, and worse outcomes than lower grades. Most meningiomas are grade I, while ~18% of meningiomas are grade II and III in hospital-based series. Meningiomas are typically "benign" tumors that are treated with surgery and radiation. However, when they recur or are unresectable, treatment options are very limited, especially since they are chemotherapy-resistant. Recent advances in the treatment of cancers with immunotherapy have focused on checkpoint blockade as well as other types of immunotherapy. There is emerging evidence supporting the use of immunotherapy as a potentially effective treatment strategy for meningioma patients. The immune microenvironment of meningiomas is a complex interplay of genetic alterations, immunomodulatory protein expression, and tumor-immune cell interactions. Meningiomas are known to be infiltrated by immune cells including microglia, macrophages, B-cells, and T-cells. Several mechanisms contribute to decreased an ti-tumor immune response, allowing tumor growth and evasion of the immune system. We discuss the most current knowledge on the immune micro-environment of meningiomas, preclinical findings of immunotherapy in meningiomas, meningioma immunotherapy clinical trials, and also offer insight into future prospects for immunotherapies in meningiomas.

Intrasession Reliability of Arterial Spin-Labeled MRI-Measured Noncontrast Perfusion in Glioblastoma at 3 T.

Arterial spin-labeled magnetic resonance imaging can provide quantitative perfusion measurements in the brain and can be potentially used to evaluate therapy response assessment in glioblastoma (GBM). The reliability and reproducibility of this method to measure noncontrast perfusion in GBM, however, are lacking. We evaluated the intrasession reliability of brain and tumor perfusion in both healthy volunteers and patients with GBM at 3 T using pseudocontinuous labeling (pCASL) and 3D turbo spin echo (TSE) using Cartesian acquisition with spiral profile reordering (CASPR). Two healthy volunteers at a single time point and 6 newly diagnosed patients with GBM at multiple time points (before, during, and after chemoradiation) underwent scanning (total, 14 sessions). Compared with 3D GraSE, 3D TSE-CASPR generated cerebral blood flow maps with better tumor-to-normal background tissue contrast and reduced image distortions. The intraclass correlation coefficient between the 2 runs of 3D pCASL with TSE-CASPR was consistently high (≥0.90) across all normal-appearing gray matter (NAGM) regions of interest (ROIs), and was particularly high in tumors (0.98 with 95% confidence interval [CI]: 0.97-0.99). The within-subject coefficients of variation were relatively low in all normal-appearing gray matter regions of interest (3.40%-7.12%), and in tumors (4.91%). Noncontrast perfusion measured using 3D pCASL with TSE-CASPR provided robust cerebral blood flow maps in both healthy volunteers and patients with GBM with high intrasession repeatability at 3 T. This approach can be an appropriate noncontrast and noninvasive quantitative perfusion imaging method for longitudinal assessment of therapy response and management of patients with GBM.

Predictors of prognosis of synchronous brain metastases in small-cell lung cancer patients.

Patients with small cell lung cancer (SCLC) are more likely to have synchronous brain metastasis (SBM) at the time of diagnosis than patients with any other extracranial primary malignancy. We sought to identify which factors predicted an increased risk of SBM in SCLC as well as which factors affected the prognosis of these patients. 38,956 Patients in the Surveillance, Epidemiology, and End Results (SEER) database with microscopically confirmed SCLC from 2010 to 2016 were identified. 6264 (16.1%) Patients with SCLC had SBM at the time of diagnosis. In the multivariable logistic regression, disease specific factors that were predictive of SBM were primary tumor size > 7 cm (adjusted OR = 1.14, 95% CI [1.02, 1.28], p = 0.02), synchronous lung metastases, and synchronous bone metastases. Demographic specific factors predictive of increased SBM risk in this model were younger age, male sex, and race (American Indian/Alaska Native and black patients). Patients insured through Medicaid were less likely to present with SBM. In the multivariate Cox proportional hazards model, lack of insurance was the strongest predictor of mortality (adjusted HR = 1.47, 95% CI [1.26, 1.73], p < 0.001). Other factors associated with an increased risk of mortality include male sex, older age, health insurance coverage through Medicaid, synchronous liver metastasis, synchronous lung metastasis, and primary tumor size > 7 cm. In contrast, Asian patients had a lower risk of mortality. This study identifies risk factors for SBM among patients with SCLC, as well as indicators of prognosis among this patient population.

Occurrence of Glioma in Pregnant Patients: An Institutional Case Series and Review of the Literature.

BACKGROUND/AIM: Gliomas present a uniquely challenging clinical situation in the context of pregnancy, with no standard recommendations. This case series aimed to describe the treatment regimen and outcomes of five pregnant patients with gliomas. PATIENTS AND METHODS: This is a retrospective study. A patient database from electronic medical records was evaluated to identify pregnant patients with gliomas treated at our institution between 2008-2018. RESULTS: Five study patients who were pregnant with gliomas were identified. Of these, 4 were diagnosed during pregnancy, while 1 was diagnosed prior to her pregnancy. One patient had grade 2 astrocytoma, 1 had grade 3 anaplastic astrocytoma, and 3 had grade 4 glioblastomas (GBM). All patients received surgery, and one patient received radiation therapy without concurrent chemotherapy during her pregnancy. All delivered healthy babies. Three of the 5 patients remain alive, and 2 of the 5 were progression-free at the last follow-up. CONCLUSION: Treatment plans must be specifically tailored to the individual patient based on the glioma grade, the mother's desire to continue the pregnancy, and the risks of delaying treatment until after pregnancy. Additional studies need to be performed to definitively establish uniform guidelines for the treatment of pregnant patients with glioma.

Prolonged Steroid Dependence in Adult Patients With Glioma.

BACKGROUND/AIM: Prolonged use of glucocorticoids (GC) in glioma treatment can lead to adrenal insufficiency (AI) and subsequent steroid dependence due to suppression of the hypothalamic-pituitary-adrenal (HPA) axis. This is challenging to diagnose due to its nonspecific clinical symptoms erroneously ascribed to treatment. This study aimed to evaluate the risk factors predisposing patients with gliomas to develop AI. PATIENTS AND METHODS: Charts in the neuro-oncology clinic from July 2018 to March 2019 were reviewed. Inclusion criteria included >18 y/o with WHO Grade II-IV gliomas, and secondary AI. Demographic profile, tumor characteristics, and treatment profile were compared. RESULTS: The majority of patients were started on high dose dexamethasone at >8 mg daily, and were on dexamethasone for 4-8 months. The minimum dose needed to prevent symptoms was 0.5 mg to 2 mg daily. The majority received standard radiation doses ranging from 54-60 Gy. Most patients had radiation exposure to the HPA axis within the prescription isodose levels. CONCLUSION: Prolonged steroid dependency can result from chronic GC use in patients with glioma. Dose and duration of GC are risk factors for its development. Radiation exposure to the HPA axis may also be a contributing factor.

NRG/RTOG 1122: A phase 2, double-blinded, placebo-controlled study of bevacizumab with and without trebananib in patients with recurrent glioblastoma or gliosarcoma.

BACKGROUND: Targeting vascular endothelial growth factor (VEGF) alone does not improve overall survival (OS) in recurrent glioblastoma (rGBM). The angiopoiein (Ang)-TIE2 system may play a role in tumor survival under VEGF inhibition. We conducted a phase 2, double-blinded, placebo-controlled trial of bevacizumab plus trebananib (a novel Fc fusion protein that sequesters Ang1/Ang2) over bevacizumab alone in rGBM. METHODS: Patients ≥18 years of age with a Karnofsky performance status ≥70 and GBM or variants in first or second relapse were randomized to bevacizumab 10 mg/kg every 2 weeks plus trebananib 15 mg/kg every week or bevacizumab plus placebo. The primary endpoint was 6-month progression-free survival (PFS). RESULTS: After an initial 6-patient lead-in cohort confirmed the safety of combining bevacizumab and trebananib, 115 eligible patients were randomized to the control (n = 58) or experimental treatment (n = 57). In the control arm, 6-month PFS was 41.1%, median survival time was 11.5 months (95% CI, 8.4-14.2 months), median PFS was 4.8 months (95% CI, 3.8-7.1 months), and radiographic response (RR) was 5.9%. In the experimental arm, 6-month PFS was 22.6%, median survival time was 7.5 months (95% CI, 6.8-10.1 months), median PFS was 4.2 months (95% CI, 3.7-5.6 months), and RR was 4.2%. The rate of severe toxicities was not significantly different between arms. CONCLUSION: The combination of bevacizumab and trebananib was well tolerated but did not significantly improve 6-month PFS rate, PFS, or OS for patients with rGBM over bevacizumab alone. The shorter PFS in the experimental arm with a hazard ratio of 1.51 (P = .04) suggests that the addition of trebananib to bevacizumab is detrimental.

Glycine by MR spectroscopy is an imaging biomarker of glioma aggressiveness.

BACKGROUND: High-grade gliomas likely remodel the metabolic machinery to meet the increased demands for amino acids and nucleotides during rapid cell proliferation. Glycine, a non-essential amino acid and intermediate of nucleotide biosynthesis, may increase with proliferation. Non-invasive measurement of glycine by magnetic resonance spectroscopy (MRS) was evaluated as an imaging biomarker for assessment of tumor aggressiveness. METHODS: We measured glycine, 2-hydroxyglutarate (2HG), and other tumor-related metabolites in 35 glioma patients using an MRS sequence tailored for co-detection of glycine and 2HG in gadolinium-enhancing and non-enhancing tumor regions on 3T MRI. Glycine and 2HG concentrations as measured by MRS were correlated with tumor cell proliferation (MIB-1 labeling index), expression of mitochondrial serine hydroxymethyltransferase (SHMT2), and glycine decarboxylase (GLDC) enzymes, and patient overall survival. RESULTS: Elevated glycine was strongly associated with presence of gadolinium enhancement, indicating more rapidly proliferative disease. Glycine concentration was positively correlated with MIB-1, and levels higher than 2.5 mM showed significant association with shorter patient survival, irrespective of isocitrate dehydrogenase status. Concentration of 2HG did not correlate with MIB-1 index. A high glycine/2HG concentration ratio, >2.5, was strongly associated with shorter survival (P < 0.0001). GLDC and SHMT2 expression were detectable in all tumors with glycine concentration, demonstrating an inverse correlation with GLDC. CONCLUSIONS: The data suggest that aggressive gliomas reprogram glycine-mediated one-carbon metabolism to meet the biosynthetic demands for rapid cell proliferation. MRS evaluation of glycine provides a non-invasive metabolic imaging biomarker that is predictive of tumor progression and clinical outcome. KEY POINTS: 1. Glycine and 2-hydroxyglutarate in glioma patients are precisely co-detected using MRS at 3T.2. Tumors with elevated glycine proliferate and progress rapidly.3. A high glycine/2HG ratio is predictive of shortened patient survival.