Is serum-derived exosomal hTERT transcript a marker of oncogenic activity in primary brain tumors? An exploratory study.

BACKGROUND: In order to proliferate indefinitely, all tumors require a telomere maintenance mechanism. The expression of human telomerase reverse transcriptase (hTERT) enables telomere maintenance and provides cancer cells with limitless replicative potential. As such, it may serve as an attractive biomarker for oncogenic activity. This study explored whether a liquid biopsy that analyses blood derived exosomal hTERT transcript (e-hTERT-trans) may serve as such a biomarker in gliomas and meningiomas when compared to healthy controls. METHODS: Exosomes were isolated from the pre-operative sera of patients' samples stored in the biobank of both Rabin and Sheba Medical Centers. The levels of e-hTERT-trans were measured in 81 healthy controls, 117 meningiomas, 17 low-grade gliomas, and 61 glioblastomas. Clinical parameters of the patients were collected retrospectively and compared to the levels of the e-hTERT-trans. RESULTS: The upper normal limit of controls e-hTERT-trans was 1.85 relative quantitation (RQ). The rate of detection increased with rising tumor grade and correlated with tumor recurrence in meningiomas: mean RQ without recurrence (2.17 ± 11.7) versus with recurrence (3.59 ± 4.42; p = 0.002). In glioblastomas, preoperative measurements correlated with tumor volume and with the disease course on serial sampling. CONCLUSIONS: We demonstrated for the first time that the expression of e-hTERT-trans transcript can be measured in the serum of primary brain tumors. This exosomal marker carries the potential to serve as a biomarker once used in conjunction with other clinical and radiological parameters. Future studies are required to investigate whether the sensitivity could be augmented and whether it can be implemented into routine patients care.

Significant Systemic Insulin Resistance is Associated With Unique Glioblastoma Multiforme Phenotype.

Background: Some glioblastoma multiforme (GBM) are characterized by the presence of gemistocytes (GCs), a unique phenotype of reactive astrocytes. Certain GCs can be identified as neoplastic cells but these cells were also found to be associated with diabetes in non-neoplastic lesions of the central nervous system. Our aim was to find a correlation between insulin - resistance metabolic features and the presence of GCs in patients with newly diagnosed GBM. Methods: Medical records from histologically confirmed GBM patients were retrospectively extracted for different systemic metabolic variables. A statistic-based comparison was made between GBM, diabetic patients with and without GC. Patients with poorly controlled diabetes (ie, hemoglobin A1C ⩾ 8.0) were also compared between the 2 groups. Results: A total of 220 newly diagnosed GBM patients were included in our study. 58 (26.3%) patients had a history of diabetes mellitus type 2 (DM2) at the time of admission. The rate of poorly-controlled DM2 was nearly as twice in the GC-GBM group than in the non-GC GBM group (18.75% vs 9.5%; P = .130). In the DM2 cohort, the subgroup of GC-GBM was significantly associated with demographic and metabolic features related to insulin resistance such as male gender predominance (89% vs 50%, P = .073) and morbid obesity (weight ⩾85 kg: OR 6.16; P = .0019 and mean BMI: 34.1 ± 11.42 vs 28.7 ± 5.44; P = .034 for group with and without GCs, respectively). In the poorly-controlled DM2 group, none of the GC-GBM patients were using insulin prior to diagnosis, compared to 61.1% in the non-GC GBM patients (OR = 0.04, P = .045). Conclusion: Systemic metabolic factors related to marked insulin resistance (DM2, morbid obesity, male gender) are associated with a unique histologic phenotype of GBM, characterized by the presence of GCs. This feature is prominent in poorly-controlled DM2 GBM patients who are not using synthetic insulin. This novel finding may add to the growing data on the relevance of glucose metabolism in astrocytes and in astrocytes associated with high-grade gliomas. In GBM patients, a correlation between patients' metabolic status, tumor's histologic phenotype, tumor's molecular changes, use of anti-diabetic drugs and the respective impact of these factor on survival warrants further investigation.

[THERAPEUTIC OPTIONS FOR BRAIN OLIGOMETASTASES: COMPARISON BETWEEN SURGICAL RESECTION, STEREOTACTIC RADIOSURGERY, WHOLE BRAIN RADIATION THERAPY AND COMBINED MODULES IN RELATION TO SURVIVAL, FUNCTION AND OTHER CONSIDERATIONS].

INTRODUCTION: Brain metastases (BM) are a leading cause of morbidity and mortality in patients with systemic cancer. In the last two decades, an enormous improvement in controlling extra-cranial disease has been achieved, positively affecting the overall survival of patients. However, this has led to an increased number of patients who live long enough to develop BM. In addition, technological improvements in neurosurgery and radiotherapy caused both surgical resection and stereotactic radiosurgery (SRS) to become an integral part of the armamentarium when treating a patient with 1-4 BM. These increased therapeutic possibilities and combination of therapeutic options such as surgical resection, SRS, whole brain radiation therapy (WBRT) and lately targeted molecular therapy, have led to an enormous amount of, yet sometimes confusing, published data.

Reciprocal interactions between innate immune cells and astrocytes facilitate neuroinflammation and brain metastasis via lipocalin-2.

Brain metastasis still encompass very grim prognosis and therefore understanding the underlying mechanisms is an urgent need toward developing better therapeutic strategies. We uncover the intricate interactions between recruited innate immune cells and resident astrocytes in the brain metastatic niche that facilitate metastasis of melanoma and breast cancer. We show that granulocyte-derived lipocalin-2 (LCN2) induces inflammatory activation of astrocytes, leading to myeloid cell recruitment to the brain. LCN2 is central to inducing neuroinflammation as its genetic targeting or bone-marrow transplantation from LCN2-/- mice was sufficient to attenuate neuroinflammation and inhibit brain metastasis. Moreover, high LCN2 levels in patient blood and brain metastases in multiple cancer types were strongly associated with disease progression and poor survival. Our findings uncover a previously unknown mechanism, establishing a central role for the reciprocal interactions between granulocytes and astrocytes in promoting brain metastasis and implicate LCN2 as a prognostic marker and potential therapeutic target.

Detection of gene mutations and gene-gene fusions in circulating cell-free DNA of glioblastoma patients: an avenue for clinically relevant diagnostic analysis.

Glioblastoma (GBM) is the most common type of glioma and is uniformly fatal. Currently, tumour heterogeneity and mutation acquisition are major impedances for tailoring personalized therapy. We collected blood and tumour tissue samples from 25 GBM patients and 25 blood samples from healthy controls. Cell-free DNA (cfDNA) was extracted from the plasma of GBM patients and from healthy controls. Tumour DNA was extracted from fresh tumour samples. Extracted DNA was sequenced using a whole-genome sequencing procedure. We also collected 180 tumour DNA datasets from GBM patients publicly available at the TCGA/PANCANCER project. These data were analysed for mutations and gene-gene fusions that could be potential druggable targets. We found that plasma cfDNA concentrations in GBM patients were significantly elevated (22.6 ± 5 ng·mL-1 ), as compared to healthy controls (1.4 ± 0.4 ng·mL-1 ) of the same average age. We identified unique mutations in the cfDNA and tumour DNA of each GBM patient, including some of the most frequently mutated genes in GBM according to the COSMIC database (TP53, 18.75%; EGFR, 37.5%; NF1, 12.5%; LRP1B, 25%; IRS4, 25%). Using our gene-gene fusion database, ChiTaRS 5.0, we identified gene-gene fusions in cfDNA and tumour DNA, such as KDR-PDGFRA and NCDN-PDGFRA, which correspond to previously reported alterations of PDGFRA in GBM (44% of all samples). Interestingly, the PDGFRA protein fusions can be targeted by tyrosine kinase inhibitors such as imatinib, sunitinib, and sorafenib. Moreover, we identified BCR-ABL1 (in 8% of patients), COL1A1-PDGFB (8%), NIN-PDGFRB (8%), and FGFR1-BCR (4%) in cfDNA of patients, which can be targeted by analogues of imatinib. ROS1 fusions (CEP85L-ROS1 and GOPC-ROS1), identified in 8% of patient cfDNA, might be targeted by crizotinib, entrectinib, or larotrectinib. Thus, our study suggests that integrated analysis of cfDNA plasma concentration, gene mutations, and gene-gene fusions can serve as a diagnostic modality for distinguishing GBM patients who may benefit from targeted therapy. These results open new avenues for precision medicine in GBM, using noninvasive liquid biopsy diagnostics to assess personalized patient profiles. Moreover, repeated detection of druggable targets over the course of the disease may provide real-time information on the evolving molecular landscape of the tumour.

Gemistocytes in newly diagnosed glioblastoma multiforme: Clinical significance and practical implications in the modern era.

BACKGROUND: Gemistocytes (GCs) in low grade gliomas are associated with rapid growth and worse prognosis. However, their clinical significance in glioblastomas (GBM) is a matter of debate. AIM OF STUDY: To investigate the clinical significance of the presence of GCs in newly-diagnosed GBM patients in the modern era. METHODS: Computerized medical records from newly diagnosed GBM patients were retrospectively reviewed and extracted for demographic, clinical, radiological and pathological variables. Patients with at least 5% GCs of neoplastic cells were considered GC-GBM (group 1). All other cases were considered non-GC GBM (group 2). Group 1 was further divided into two subgroups: Low percentage GCs (group 1a, ≤ 20% GCs) and high percentage GC (group 1b, >20% GCs). RESULTS: A total of 220 patients with newly diagnosed GBM were included. 14.5% were defined as GC-GBM (group I, n = 32) and 85.5% were defined as non-GC GBM (group 2, n = 188). 8.5% had ≤ 20% GCs (group 1a, n = 19) and 5.9% had > 20% GCs (group 1b, n = 13). Groups were similar for most epidemiological and clinical variables. There was a trend toward worse prognosis in group 1b. Several distinguished radiological and molecular features were observed in group 1. CONCLUSION: GCs are found in minority of naïve, newly diagnosed, GBM cases in adults. They seem to carry minimal implications on daily clinical practice. Higher percentage of GCs is associated with distinct radiological features such as multifocality that might be correlated with decreased OS. High-percentage GC-GBMs are also associated with increased prevalence of isocitrate dehydrogenase (IDH) mutations.

Height in adolescence as a risk factor for glioma subtypes: a nationwide retrospective cohort study of 2.2 million subjects.

BACKGROUND: Gliomas manifest in a variety of histological phenotypes with varying aggressiveness. The etiology of glioma remains largely unknown. Taller stature in adulthood has been linked with glioma risk. The aim of this study was to discern whether this association can be detected in adolescence. METHODS: The cohort included 2 223 168 adolescents between the ages of 16 and 19 years. Anthropometric measurements were collected at baseline. Incident cases of glioma were extracted from the Israel National Cancer Registry over a follow-up period spanning 47 635 745 person-years. Cox proportional hazard models were used to estimate the hazard ratio (HR) for glioma and glioma subtypes according to height, body mass index (BMI), and sex. RESULTS: A total of 1195 patients were diagnosed with glioma during the study period. Mean (SD) age at diagnosis was 38.1 (11.7) years. Taller adolescent height (per 10-cm increase) was positively associated with the risk for glioma of any type (HR: 1.15; P = .002). The association was retained in subgroup analyses for low-grade glioma (HR: 1.17; P = .031), high-grade glioma (HR: 1.15; P = .025), oligodendroglioma (HR: 1.31; P = .015), astrocytoma (HR: 1.12; P = .049), and a category of presumed IDH-mutated glioma (HR: 1.17; P = .013). There was a trend toward a positive association between height and glioblastoma, however this had borderline statistical significance (HR: 1.15; P = .07). After stratification of the cohort by sex, height remained a risk factor for men but not for women. CONCLUSIONS: The previously established association between taller stature in adulthood and glioma risk can be traced back to adolescence. The magnitude of association differs by glioma subtype.

Multicentric non-enhancing lesions in glioblastoma: A retrospective study.

Glioblastoma (GBM) typically presents as a single lesion. Multicentric GBM are defined as well separated lesions on MRI (enhancing and non-enhancing). Multicentric GBM with non-enhancing lesions (MNE-GBM) are rarely described in literature. We aimed at describing the radiologic characteristics, treatment, and clinical course of those patients. The institutional neuropathological database was searched for GBM patients diagnosed between 1/1/2015 and 31/05/2018. All pre-operative MRI brain scans were reviewed to identify patients with MNE-GBM. Electronic medical records and follow-up MRI scans were reviewed to assess progression-free survival (PFS) and overall survival (OS). Out of 149 adult patients with newly diagnosed GBM, 12 met the inclusion criteria of MNE-GBM, all of them presented at least one enhancing lesion. Median follow-up for the MNE-GBM patients was 16.1 months. At last follow-up, all patients had recurrence (median PFS 7.6 months) and eleven patients had deceased. Median OS was 16.2 months (95% CI, 4.1-27.5). Eleven patients received radiotherapy concomitant with temozolomide as initial treatment. Radiation field included all the disease foci (enhancing and non-enhancing lesions) in 8 patients, five of them progressed within the non-enhancing lesion. Three patients did not receive radiation for the entire non-enhancing lesions, and two of them progressed within the non-irradiated areas. In conclusion, MNE-GBM is not rare, and has high risk of aggressive progression within the separate non-enhancing lesion.

Height as a risk factor in meningioma: a study of 2 million Israeli adolescents.

BACKGROUND: Meningiomas are the most common primary central nervous system tumors. Potential risk factors include obesity, height, history of allergy/atopy, and autoimmune diseases, but findings are conflicting. This study sought to assess the role of the different risk factors in the development of meningioma in adolescents/young adults. METHODS: The cohort included 2,035,915 Jewish men and women who had undergone compulsory physical examination between 1967 and 2011, at age 16 to 19 years, prior to and independent of actual military enlistment. To determine the incidence of meningioma, the military database was matched with the Israel National Cancer Registry. Cox proportional hazard models were used to estimate the hazard ratios for meningioma according to sex, body mass index (BMI), height, and history of allergic or autoimmune disease. RESULTS: A total of 480 subjects (328 females) were diagnosed with meningioma during a follow-up of 40,304,078 person-years. Median age at diagnosis was 42.1 ± 9.4 years (range 17.4-62.6). On univariate analysis, female sex (p < 0.01) and height (p < 0.01) were associated with risk of meningioma. When the data were stratified by sex, height remained a significant factor only in men. Spline analysis of the male subjects showed that a height of 1.62 m was associated with a minimum disease risk and a height of 1.85+ meters, with a significant risk. CONCLUSIONS: This large population study showed that sex and adolescent height in males (> 1.85 m) were associated with an increased risk of meningioma in adulthood.

The Utility of Early Postoperative Neuroimaging in Elective/Semielective Craniotomy Patients: A Single-Arm Prospective Trial.

BACKGROUND: The necessity and timing of early postoperative imaging (POI) are debated in many studies. Despite the consensus that early POI does not change patient management, these examinations are routinely performed. This is the first prospective study related to POI. Our aims were to assess the necessity of early POI in asymptomatic patients and to verify accuracy of the presented algorithm. METHODS: This was an algorithm-based prospective single-center study. The algorithm addressed preoperative, perioperative, and postoperative considerations, including estimated pathology type, device placement, and postoperative neurologic change. Early computed tomography scans were obtained in all patients, but if postoperative algorithm indications did not recommend a scan, the treating team was blinded to them, and patient management was conducted based on clinical examinations alone. A neuroradiologist and study-independent neurosurgeon reviewed all the scans. RESULTS: Of 103 enrolled patients, 88 remained asymptomatic, and 15 experienced symptoms postoperatively. Pathology was present on POI in 1% of the asymptomatic patients and 53% of the symptomatic patients (P < 0.001). In the asymptomatic group, no treatment modifications were made postoperatively. Blinding of the surgical team was not removed, and 20% of the symptomatic patients returned to the operating room because of imaging and neurologic findings. The goal of <5% algorithm failure was reached with statistical significance. CONCLUSIONS: In asymptomatic postoperative patients in whom early imaging is not performed for oncologic indications, device placement verification, or similar reasons, POI is unnecessary and does not change the management of these patients.

Echoes from the past- changing associations between brain tumors and ethnicity.

BACKGROUND: cranial X radiation therapy was the standard of care for treating dermatological conditions until the 1960s, when its association to cancer and particularly high rates of brain tumors was discovered. This study examines associations found between incidence of brain tumor and ethnicity. METHODS: This study analyzed two cohorts who underwent examination at age 17 and were followed by linkage to the national cancer registry. The first cohort included 376,336 participants born in 1948-1959 (when treatment with cranial X radiation was standard care for treating tinea capitis), and the second 474,923 participants born in 1960-1971. RESULTS: In the first cohort, ethnicity was strongly associated with the incidence of brain tumor (BT), with higher incidence observed among patients with origins in North Africa or the Middle East. This effect was ablated in the second cohort, and a significant decrease in the rate of meningiomas was noted. CONCLUSION: The association of brain tumor with ethnicity was present only during the period when treatment with cranial X radiation was the standard of care for TC in Israel, therefore it is most likely that radiation exposure was a confounding factor, and that ethnic susceptibility for brain cancer was not causative in these cohorts.

Neurocognitive evaluation of brain metastases patients treated with post-resection stereotactic radiosurgery: a prospective single arm clinical trial.

PURPOSE: Post-operative radiation therapy for brain metastases (BM) has become standard treatment. Concerns regarding the deleterious cognitive effects of Whole Brain Radiation Therapy spurred a trend to use focal therapies such as stereotactic radiosurgery (SRS). The purpose of this study was to prospectively evaluate the neuropsychological effects following post-resection SRS treatment since limited data exist in this context. METHODS: We conducted a prospective single arm cohort study of patients with 1-2 BM, who underwent resection of a single BM between May 2015 to December 2016. Patients were evaluated for cognitive functions (NeuroTrax computerized neuropsychological battery; Modiin, Israel) and quality of life (QOL; QLQ-30, QLQ-BN20) before and 3 months following post-resection SRS. RESULTS: Twelve out of 14 patients completed pre- and post-SRS neurocognitive assessments. Overall, we did not detect significant neurocognitive or QOL changes 3 months following SRS. In a subgroup analysis among patients younger than 60 years, median global cognitive score increased from a pre-treatment score of 88 (72-102) to 95 (79-108), 3 months following SRS treatment, p = 0.042; Wilcoxon paired non-parametric test. Immediate verbal memory and executive functions scores increased from 86 (72-98) to 98 (92-112) and 86 (60-101) to 100 (80-126), respectively, p = 0.043. No significant cognitive changes were discovered among patients at the age of 60 or older. CONCLUSIONS: Post-resection radiosurgery has a safe neuro-cognitive profile and is associated with preservation of nearly all quality of life parameters. Patients younger than 60 years benefit most and may even regain some cognitive functions within a few months after treatment.

Combined treatment approach to cerebral arteriovenous malformation in pediatric patients: stereotactic radiosurgery to partially Onyx-embolized AVM.

PURPOSE: Treatment of cerebral arteriovenous malformations (AVM)-the most common cause of stroke in the pediatric population-can be challenging due to the complexity of size, morphology, and location. There is a significant risk in comparison to AVM treatment among adults. Thus, AVM treatment in the pediatric population imposes unique challenges. Recent improvements include optimized catheter techniques and better embolization materials, such as Onyx, a non-adhesive liquid embolic agent used in the adult population. These improvements have increased the success rate of total and near-total obliteration of cerebral AVM. However, the use of Onyx causes significant distortion of the MR and CT images, which must be accounted for in any radiation treatment planning predicated on CT and MRI. These image distortions impact on the actual delivered dose to the nidus and behoove heterogeneity correction. Our group has previously shared a solution for heterogeneity correction in the adult population. The purpose of this study is to show our experience in this unique group of pediatric patients. METHODS: This is a retrospective review of pediatric patients, who were undergoing combined endovascular embolization followed by SRS. The cohort consists of 14 patients undergoing SRS treatment in our institute between November 2006 and December 2012 with a mean follow-up of 49.9 months. Within this cohort, we retrospectively reviewed 12 consecutive pediatric patients who underwent a combined endovascular and SRS approach with a mean follow-up of 52.1 months and two patients receiving SRS-only treatment were excluded. RESULTS: In our cohort of 14 patients, 7 (50%) were male, with a mean age of 17.3 years (12.0-22.9) at the time of radiosurgery treatment. Mean age of beginning the combined modality treatment was 15.3 years (8.4-20). The median time from diagnosis to SRS was 24.3 months (11.1-64.4 months) in the complete cohort and 25.6 months (11.1-64.4) in the multimodality group. The overall median follow-up period was 49.9 months (range 12.8-118.8 months) in the complete cohort and 52.1 months (range 12.8-118.8 months) in the multimodality group. Eleven (78.6%) patients had at least one episode of hemorrhage prior to treatment. Spezler-Martin grades at baseline ranged from 2 to 5 (mean 3.2). Fifty percent had grade IV and V. Patients underwent a median of 2 (range 1-5) embolization procedures. The radiosurgical treatment dose to the margin of the angiography-based nidus: median prescription dose of 21.49 Gy (14.39-27.51) with a median max dose of 27.77 Gy (18.93-32.52). The median treatment volume was 0.6 cm3 (0.1-7.3 cm3). The Onyx embolization reduced the nidus target volume by a median of 66.7% (12.0-92.7%). We confirmed 10/14 (71%) complete closures. In 2/14 (14.2%) additional patients, a significant flow reduction was noted. In 1/14 (7.1%) patients, no significant change was noted during the observation period and two (14.2%) patients were without follow-up information. In two patients, post-treatment edema was noted; however, none was clinically significant and resolved without additional intervention or treatment. CONCLUSIONS: This cohort comprises the largest combined Onyx-SRS pediatric experience in the literature. In conjunction with our adult group study, we show that the use of Onyx reduces the SRS treatment target volume significantly. Importantly, we implemented the heterogeneity correction to avoid increased radiation exposure to normal surrounding brain tissue. The combined approach appears to be safe provided that the above-mentioned corrections are implemented.

Influence of Treatment With Tumor-Treating Fields on Health-Related Quality of Life of Patients With Newly Diagnosed Glioblastoma: A Secondary Analysis of a Randomized Clinical Trial.

IMPORTANCE: Tumor-treating fields (TTFields) therapy improves both progression-free and overall survival in patients with glioblastoma. There is a need to assess the influence of TTFields on patients' health-related quality of life (HRQoL). OBJECTIVE: To examine the association of TTFields therapy with progression-free survival and HRQoL among patients with glioblastoma. DESIGN, SETTING, AND PARTICIPANTS: This secondary analysis of EF-14, a phase 3 randomized clinical trial, compares TTFields and temozolomide or temozolomide alone in 695 patients with glioblastoma after completion of radiochemotherapy. Patients with glioblastoma were randomized 2:1 to combined treatment with TTFields and temozolomide or temozolomide alone. The study was conducted from July 2009 until November 2014, and patients were followed up through December 2016. INTERVENTIONS: Temozolomide, 150 to 200 mg/m2/d, was given for 5 days during each 28-day cycle. TTFields were delivered continuously via 4 transducer arrays placed on the shaved scalp of patients and were connected to a portable medical device. MAIN OUTCOMES AND MEASURES: Primary study end point was progression-free survival; HRQoL was a predefined secondary end point, measured with questionnaires at baseline and every 3 months thereafter. Mean changes from baseline scores were evaluated, as well as scores over time. Deterioration-free survival and time to deterioration were assessed for each of 9 preselected scales and items. RESULTS: Of the 695 patients in the study, 639 (91.9%) completed the baseline HRQoL questionnaire. Of these patients, 437 (68.4%) were men; mean (SD) age, 54.8 (11.5) years. Health-related quality of life did not differ significantly between treatment arms except for itchy skin. Deterioration-free survival was significantly longer with TTFields for global health (4.8 vs 3.3 months; P < .01); physical (5.1 vs 3.7 months; P < .01) and emotional functioning (5.3 vs 3.9 months; P < .01); pain (5.6 vs 3.6 months; P < .01); and leg weakness (5.6 vs 3.9 months; P < .01), likely related to improved progression-free survival. Time to deterioration, reflecting the influence of treatment, did not differ significantly except for itchy skin (TTFields worse; 8.2 vs 14.4 months; P < .001) and pain (TTFields improved; 13.4 vs 12.1 months; P < .01). Role, social, and physical functioning were not affected by TTFields. CONCLUSIONS AND RELEVANCE: The addition of TTFields to standard treatment with temozolomide for patients with glioblastoma results in improved survival without a negative influence on HRQoL except for more itchy skin, an expected consequence from the transducer arrays. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00916409.

Surgery for Recurrent High-Grade Glioma After Treatment with Bevacizumab.

BACKGROUND: Bevacizumab (BVZ) is an antiangiogenic agent approved by the Food and Drug Administration that is used for the treatment of recurrent glioblastoma. Complications related to impaired healing may adversely affect patients resected for recurrent high-grade glioma (HGG) after treatment with BVZ. OBJECTIVE: To examine the complication rate, outcome, and tumor vasculature in patients resected for recurrent HGG after treatment with BVZ. METHODS: Data were reviewed retrospectively from patients undergoing surgery for recurrent HGG after treatment with BVZ. Results were compared with a control group of recurrently operated BVZ-naïve HGG. Tumor samples and magnetic resonance imaging scans were analyzed. RESULTS: Fifteen patients underwent HGG resection after progression after BVZ. Forty-four BVZ-naïve patients who underwent surgeries for tumor recurrence were included as controls. Median time from BVZ treatment to surgery was 30 days (2-107). Median overall survival from time of tumor diagnosis was 21.0 months (12-83.0), and median survival from post-BVZ surgery was 5.0 months (2.0-19.0), compared with 8.1 months in BVZ-naïve controls measured from time of their last reoperation. Five of the 15 patients survived 6 or more months after post-BVZ surgery. Nine patients developed postsurgical complications requiring intervention. Complication rates for surgery after BVZ treatment were 66.7% compared with 38.6% in the control group (P = 0.077). We did not see overt changes in histopathology or immunohistochemistry staining; however, tumor vasculature in tumors resected after treatment with BVZ showed a significant decrease in mean vessel density. CONCLUSIONS: Surgery for recurrent HGG may be feasible in a select group of patients. Mean tumor vessel density may be decreased after treatment with BVZ.

Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs Maintenance Temozolomide Alone on Survival in Patients With Glioblastoma: A Randomized Clinical Trial.

Importance: Tumor-treating fields (TTFields) is an antimitotic treatment modality that interferes with glioblastoma cell division and organelle assembly by delivering low-intensity alternating electric fields to the tumor. Objective: To investigate whether TTFields improves progression-free and overall survival of patients with glioblastoma, a fatal disease that commonly recurs at the initial tumor site or in the central nervous system. Design, Setting, and Participants: In this randomized, open-label trial, 695 patients with glioblastoma whose tumor was resected or biopsied and had completed concomitant radiochemotherapy (median time from diagnosis to randomization, 3.8 months) were enrolled at 83 centers (July 2009-2014) and followed up through December 2016. A preliminary report from this trial was published in 2015; this report describes the final analysis. Interventions: Patients were randomized 2:1 to TTFields plus maintenance temozolomide chemotherapy (n = 466) or temozolomide alone (n = 229). The TTFields, consisting of low-intensity, 200 kHz frequency, alternating electric fields, was delivered (≥ 18 hours/d) via 4 transducer arrays on the shaved scalp and connected to a portable device. Temozolomide was administered to both groups (150-200 mg/m2) for 5 days per 28-day cycle (6-12 cycles). Main Outcomes and Measures: Progression-free survival (tested at α = .046). The secondary end point was overall survival (tested hierarchically at α = .048). Analyses were performed for the intent-to-treat population. Adverse events were compared by group. Results: Of the 695 randomized patients (median age, 56 years; IQR, 48-63; 473 men [68%]), 637 (92%) completed the trial. Median progression-free survival from randomization was 6.7 months in the TTFields-temozolomide group and 4.0 months in the temozolomide-alone group (HR, 0.63; 95% CI, 0.52-0.76; P < .001). Median overall survival was 20.9 months in the TTFields-temozolomide group vs 16.0 months in the temozolomide-alone group (HR, 0.63; 95% CI, 0.53-0.76; P < .001). Systemic adverse event frequency was 48% in the TTFields-temozolomide group and 44% in the temozolomide-alone group. Mild to moderate skin toxicity underneath the transducer arrays occurred in 52% of patients who received TTFields-temozolomide vs no patients who received temozolomide alone. Conclusions and Relevance: In the final analysis of this randomized clinical trial of patients with glioblastoma who had received standard radiochemotherapy, the addition of TTFields to maintenance temozolomide chemotherapy vs maintenance temozolomide alone, resulted in statistically significant improvement in progression-free survival and overall survival. These results are consistent with the previous interim analysis. Trial Registration: clinicaltrials.gov Identifier: NCT00916409.

Impact of Onyx Embolization on Radiosurgical Management of Cerebral Arteriovenous Malformations: Treatment and Outcome.

BACKGROUND: Stereotactic radiosurgery (SRS) is a well-established treatment modality for cerebral arteriovenous malformations (AVMs). The main limiting factor in the radiosurgical treatment of AVMs is the volume of the nidus, with high-grade lesions often requiring combined treatment to reduce the SRS target volume. To overcome this limitation, we have been using a combined treatment approach consisting of endovascular embolization with Onyx followed by SRS. OBJECTIVE: To evaluate our clinical experience for safety and feasibility of this multimodality treatment approach. METHODS: This is a retrospective review of all adult patients with cerebral AVMs who received SRS treatment to their AVM after endovascular embolization with Onyx between June 2007 and June 2014. RESULTS: Thirty-five consecutive patients were identified. The mean follow-up period was 52.4 ± 22.6 months (range 18-97 months). We confirmed 18 (51.4%) complete nidus closures at a median time of 49.5 months (range 6.5-81 months) from SRS. High-resolution Magnetic resonance imaging/magnetic resonance angiography was performed routinely in all patients until closure of the nidus. Digital subtraction angiography was performed to confirm complete obliteration in 5 of the patients (28%); 13 patients are either planned for digital subtraction angiography or have refused it. In 6 patients (17%) a significant flow reduction was noted after a mean of 32 ± 16 months. No significant improvement was observed in 9 patients (26%) during the follow-up period. Two patients were lost to follow-up. CONCLUSIONS: The multimodality treatment of cerebral AVMs using embolization with Onyx followed by SRS is feasible and safe. The use of Onyx significantly reduced the SRS treatment target volume.

Health-related quality of life, cognitive screening, and functional status in a randomized phase III trial (EF-14) of tumor treating fields with temozolomide compared to temozolomide alone in newly diagnosed glioblastoma.

We characterized health-related quality of life (HRQoL), cognitive, and functional status in newly diagnosed glioblastoma (GBM) patients receiving Tumor treating fields (TTFields) with temozolomide (TMZ) versus TMZ alone in a planned interim analysis of a randomized phase III trial [NCT00916409], which showed significant improvement in progression-free and overall survival with TTFields/TMZ. After radiotherapy with concomitant TMZ, newly diagnosed GBM patients were randomized (2:1) to TTFields/TMZ (n = 210) or TMZ (n = 105). Interim analysis was performed in 315 patients with ≥18 months of follow-up. HRQoL, a secondary endpoint, was evaluated in per-protocol patient population and expressed as change from baseline (CFB) at 3, 6, and 9 months for each subscale in the EORTC QLQ-C30/BN20. Karnofsky performance scores (KPS) and Mini-Mental State Examination scores (MMSE) were assessed. CFB in HRQoL was balanced in treatment groups at the 12-month time point. Initially, HRQoL improved in patients treated with TTFields/TMZ (CFB3: 24% and CFB6: 13%) versus TMZ (CFB3: -7% and CFB6: -17%), though this difference was no longer evident at the 9-month point. General scales, including physical and social functioning, showed no difference at 9 and 12 months. TTFields/TMZ group reported higher concerns of "itchy skin". KPS over 12 months was just below 90 in both groups. Cognitive status (MMSE) was stable over time. HRQoL, KPS, and MMSE were balanced in both groups over time. There was no preliminary evidence that HRQoL, cognitive, and functional status is adversely affected by the continuous use of TTFields.

Regression of intracranial meningioma following treatment with nivolumab: Case report and review of the literature.

The treatment of refractory meningiomas remains a challenge for both neurosurgeons and neuro-oncologists. There have been no clinical reports of the use or effects of anti-PD-1 therapy in patients with meningioma. We describe a patient whose intracranial meningioma decreased significantly in size after treatment with nivolumab, a monoclonal antibody targeting PD-1, for a concomitant advanced lung cancer. This is the first clinical report suggesting that antibodies targeting PD-1 are effective in treating meningioma. It should encourage further research into the use of checkpoint inhibitors in meningioma.