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1.
The utilization of fluorescein in brain tumor surgery: a systematic review.
Cavallo, C, De Laurentis, C, Vetrano, IG, Falco, J, Broggi, M, Schiariti, M, Ferroli, P, Acerbi, F
Journal of neurosurgical sciences. 2018;(6):690-703
Abstract
INTRODUCTION Sodium fluorescein (SF) is a green, water-soluble dye with the capacity to accumulate in cerebral areas as a result of damaged blood-brain barrier (BBB); this property allows SF to concentrate specifically at the tumor site of various types of brain neoplasms, making the tumor tissue more clearly visible. EVIDENCE ACQUISITION A literature search (1947-2018) was conducted with the keywords "fluorescein neurosurgery," "YELLOW neurosurgery," "fluorescein brain tumor," "YELLOW brain tumor." We included clinical studies, clinical trials, observational studies, only conducted on humans and concerning surgery; in addition, we have included 3 articles derived from the analysis of the references of other papers. Ultimately, 57 articles were included for further analysis. EVIDENCE SYNTHESIS Fluorescein as a fluorescent tracer in neuro-oncology is gaining a wider acceptance in the neurosurgical literature: until February 1st, 2018, at least 1099 neuro-oncological patients have been operated through fluorescein-assistance, mostly only after 2012. The most important application remains the aim to improve tumor visualization and extent of resection for high-grade gliomas (HGG), but the nonspecific mechanism of action is the theoretical base for its use also for tumors different from HGG. Nevertheless, no homogenous protocol of fluorescein utilization in neurosurgical oncology can be found in literature. CONCLUSIONS Fluorescein-guided surgery is a safe and effective technique to improve visualization and resection of different CNS tumors and conditions, based on BBB alteration, with a growing evidence-based background.
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2.
The social trajectory of brain tumor: a qualitative metasynthesis.
Cubis, L, Ownsworth, T, Pinkham, MB, Chambers, S
Disability and rehabilitation. 2018;(16):1857-1869
Abstract
PURPOSE Research indicates that strong social ties can buffer the adverse effects of chronic illness on psychological well-being. Brain tumor typically leads to serious functional impairments that affect relationships and reduce social participation. This metasynthesis aimed to identify, appraise and integrate the findings of qualitative studies that reveal the impact of brain tumor on social networks. METHODS Four major databases (PubMed, CINAHL, Cochrane Library and PsycINFO) were systematically searched from inception to September 2016 for qualitative studies that reported findings on the impact of primary brain tumor on social networks during adulthood. Twenty-one eligible studies were identified and appraised according to the Consolidated Criteria for Reporting Qualitative Research. Key findings of these studies were integrated to form superordinate themes. RESULTS The metasynthesis revealed the core themes of: 1) Life disrupted; 2) Navigating the new reality of life; and 3) Social survivorship versus separation. CONCLUSIONS Multiple changes typically occur across the social trajectory of brain tumor, including a loss of pre-illness networks and the emergence of new ones. Understanding the barriers and facilitators for maintaining social connection may guide interventions for strengthening social networks and enhancing well-being in the context of brain tumor. Implications for rehabilitation Social networks and roles are disrupted throughout the entire trajectory of living with brain tumor Physical, cognitive and psychological factors represent barriers to social integration Barriers to social integration may be addressed by supportive care interventions Compensatory strategies, adjusting goals and expectations, educating friends and family and accepting support from others facilitate social reintegration throughout the trajectory of living with brain tumor.
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3.
Brachytherapy of Intracranial Gliomas.
Nachbichler, SB, Kreth, FW
Progress in neurological surgery. 2018;:72-86
Abstract
Interstitial implantation of radioactive materials (brachytherapy [BT]) has been designed to protractedly deliver a high radiation dose to a well-defined target volume, while minimizing irradiation of the adjacent normal tissues. Even though promising results have been reported over time, the role of this treatment modality in the management of brain tumors is still poorly defined, and only a few centers worldwide apply it in clinical practice. Nevertheless, temporary or permanent interstitial implantation of low activity (<20 mCi) and low dose rate (≤10 cGy/h) iodine-125 (125I) seeds as possible therapy of intracranial gliomas is currently undergoing a definite revival, and several indications for its use have been identified. Generally, 125I-BT may be considered a reasonable option in cases of unresectable, well-circumscribed, either newly diagnosed or recurrent tumors with a diameter of ≤4 cm, virtually in any location within the brain. Importantly, this treatment does not narrow down the spectrum of the possible subsequent salvage therapeutic options, since neither repeated interstitial nor additional external beam irradiation at the time of tumor progression after BT is associated with a significantly increased risk of radiogenic complications. Using correct patient selection criteria, appropriate surgical technique, and established treatment parameters, would make BT a truly minimally invasive procedure with a low risk of complications and reasonable efficacy.
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4.
Akt and mTORC1 signaling as predictive biomarkers for the EGFR antibody nimotuzumab in glioblastoma.
Ronellenfitsch, MW, Zeiner, PS, Mittelbronn, M, Urban, H, Pietsch, T, Reuter, D, Senft, C, Steinbach, JP, Westphal, M, Harter, PN
Acta neuropathologica communications. 2018;(1):81
Abstract
Glioblastoma (GB) is the most frequent primary brain tumor in adults with a dismal prognosis despite aggressive treatment including surgical resection, radiotherapy and chemotherapy with the alkylating agent temozolomide. Thus far, the successful implementation of the concept of targeted therapy where a drug targets a selective alteration in cancer cells was mainly limited to model diseases with identified genetic drivers. One of the most commonly altered oncogenic drivers of GB and therefore plausible therapeutic target is the epidermal growth factor receptor (EGFR). Trials targeting this signaling cascade, however, have been negative, including the phase III OSAG 101-BSA-05 trial. This highlights the need for further patient selection to identify subgroups of GB with true EGFR-dependency. In this retrospective analysis of treatment-naïve samples of the OSAG 101-BSA-05 trial cohort, we identify the EGFR signaling activity markers phosphorylated PRAS40 and phosphorylated ribosomal protein S6 as predictive markers for treatment efficacy of the EGFR-blocking antibody nimotuzumab in MGMT promoter unmethylated GBs. Considering the total trial population irrespective of MGMT status, a clear trend towards a survival benefit from nimotuzumab was already detectable when tumors had above median levels of phosphorylated ribosomal protein S6. These results could constitute a basis for further investigations of nimotuzumab or other EGFR- and downstream signaling inhibitors in selected patient cohorts using the reported criteria as candidate predictive biomarkers.
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5.
Diagnostic Accuracy of Amino Acid and FDG-PET in Differentiating Brain Metastasis Recurrence from Radionecrosis after Radiotherapy: A Systematic Review and Meta-Analysis.
Li, H, Deng, L, Bai, HX, Sun, J, Cao, Y, Tao, Y, States, LJ, Farwell, MD, Zhang, P, Xiao, B, et al
AJNR. American journal of neuroradiology. 2018;(2):280-288
Abstract
BACKGROUND Current studies that analyze the usefulness of amino acid and FDG-PET in distinguishing brain metastasis recurrence and radionecrosis after radiation therapy are limited by small cohort size. PURPOSE Our aim was to assess the diagnostic accuracy of amino acid and FDG-PET in differentiating brain metastasis recurrence from radionecrosis after radiation therapy. DATA SOURCES Studies were retrieved from PubMed, Embase, and the Cochrane Library. STUDY SELECTION Fifteen studies were included from the literature. Each study used PET to differentiate radiation necrosis from tumor recurrence in contrast-enhancing lesions on follow-up brain MR imaging after treating brain metastasis with radiation therapy. DATA ANALYSIS Data were analyzed with a bivariate random-effects model. Sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio were pooled, and a summary receiver operating characteristic curve was fit to the data. DATA SYNTHESIS The overall pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio of PET were 0.85, 0.88, 7.0, 0.17, and 40, respectively. The area under the receiver operating characteristic curve was 0.93. On subgroup analysis of different tracers, amino acid and FDG-PET had similar diagnostic accuracy. Meta-regression analysis demonstrated that the method of quantification based on patient, lesion, or PET scan (based on lesion versus not, P = .07) contributed to the heterogeneity. LIMITATIONS Our study was limited by small sample size, and 60% of the included studies were of retrospective design. CONCLUSIONS Amino acid and FDG-PET had good diagnostic accuracy in differentiating brain metastasis recurrence from radionecrosis after radiation therapy.
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6.
Sodium fluorescein guided resection of malignant glioma.
Waqas, M, Shamim, MS
JPMA. The Journal of the Pakistan Medical Association. 2018;(6):968-970
Abstract
The average rate of gross total resection (GTR) for malignant gliomas (MGs) is reported to be around 36%. One of the major challenges to GTR is the recognition of tumour margins. Sodium fluorescein is a freely available fluorophore used to recognize the boundaries of MGs. It accumulates in tumour areas with disrupted blood brain barrier that can then be visualized under a microscope with dedicated filters. No randomized controlled trial or meta-analysis is available that reports the impact of fluorescein use on the extent of tumour resection. Several prospective studies and a phase II trial prove it to be safe and helpful in achieving GTR rates of 68.42-100%. At higher doses i.e., 15-20 mg/Kg, sodium fluorescein can even be used under white illumination. The dye is safe even at high doses and has helped achieve GTR rates of 80-84.4.
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7.
Final results of a phase I dose-escalation, dose-expansion study of adding disulfiram with or without copper to adjuvant temozolomide for newly diagnosed glioblastoma.
Huang, J, Campian, JL, Gujar, AD, Tsien, C, Ansstas, G, Tran, DD, DeWees, TA, Lockhart, AC, Kim, AH
Journal of neuro-oncology. 2018;(1):105-111
Abstract
Disulfiram has shown promising activity including proteasome inhibitory properties and synergy with temozolomide in preclinical glioblastoma (GBM) models. In a phase I study for newly diagnosed GBM after chemoradiotherapy, we have previously reported our initial dose-escalation results combining disulfiram with adjuvant temozolomide and established the maximum tolerated dose (MTD) as 500 mg per day. Here we report the final results of the phase I study including an additional dose-expansion cohort of disulfiram with concurrent copper. The phase I study consisted of an initial dose-escalation phase of disulfiram 500-1000 mg daily during adjuvant temozolomide, followed by a dose-expansion phase of disulfiram 500 mg daily with copper 2 mg three times daily. Proteasome inhibition was assessed using fluorometric 20S proteasome assay on peripheral blood cell. A total of 18 patients were enrolled: 7 patients received 500 mg disulfiram, 5 patients received 1000 mg disulfiram, and 6 patients received 500 mg disulfiram with copper. Two dose-limiting toxicities occurred with 1000 mg disulfiram. At disulfiram 500 mg with or without copper, only 1 patient (7%) required dose-reduction during the first month of therapy. Addition of copper to disulfiram did not increase toxicity nor proteasome inhibition. The median progression-free survival was 4.5 months (95% CI 0.8-8.2). The median overall survival (OS) was 14.0 months (95% CI 8.3-19.6), and the 2-year OS was 24%. The MTD of disulfiram at 500 mg daily in combination with adjuvant temozolomide was well tolerated by GBM patients, but 1000 mg daily was not. Toxicity and pharmacodynamic effect of disulfiram were similar with or without concurrent copper. The clinical efficacy appeared to be comparable to historical data. Additional clinical trials to combine disulfiram and copper with chemoradiotherapy or to resensitize recurrent GBM to temozolomide are ongoing.
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8.
Update on amino acid PET of brain tumours.
Langen, KJ, Galldiks, N
Current opinion in neurology. 2018;(4):354-361
Abstract
PURPOSE OF REVIEW The aim of this study was to give an update on the emerging role of PET using radiolabelled amino acids in the diagnostic workup and management of patients with cerebral gliomas and brain metastases. RECENT FINDINGS Numerous studies have demonstrated the potential of PET using radiolabelled amino acids for differential diagnosis of brain tumours, delineation of tumour extent for treatment planning and biopsy guidance, differentiation between tumour progression and recurrence versus treatment-related changes, and for monitoring of therapy. The Response Assessment in Neuro-Oncology (RANO) working group - an international effort to develop new standardized response criteria for clinical trials in brain tumours - has recently recommended the use of amino acid PET imaging for brain tumour management in addition to MRI at every stage of disease. With the introduction of F-18 labelled amino acids, a broader clinical application has become possible, but is still hampered by the lack of regulatory approval and of reimbursement in many countries. SUMMARY PET using radiolabelled amino acids is a rapidly evolving method that can significantly enhance the diagnostic value of MRI in brain tumours. Current developments suggest that this imaging technique will become an indispensable tool in neuro-oncological centres in the near future.
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9.
Associations of anticoagulant use with outcome in newly diagnosed glioblastoma.
Le Rhun, E, Genbrugge, E, Stupp, R, Chinot, OL, Nabors, LB, Cloughesy, T, Reardon, DA, Wick, W, Gorlia, T, Weller, M
European journal of cancer (Oxford, England : 1990). 2018;:95-104
Abstract
BACKGROUND To test the hypothesis that despite bleeding risk, anticoagulants improve the outcome in glioblastoma because of reduced incidence of venous thromboembolic events and modulation of angiogenesis, infiltration and invasion. METHODS We assessed survival associations of anticoagulant use from baseline up to the start of temozolomide chemoradiotherapy (TMZ/RT) (period I) and from there to the start of maintenance TMZ chemotherapy (period II) by pooling data of three randomised clinical trials in newly diagnosed glioblastoma including 1273 patients. Progression-free survival (PFS) and overall survival (OS) were compared between patients with anticoagulant use versus no use; therapeutic versus prophylactic versus no use; different durations of anticoagulant use versus no use; anticoagulant use versus use of anti-platelet agents versus neither anticoagulant nor anti-platelet agent use. Cox regression models were stratified by trial and adjusted for baseline prognostic factors. RESULTS Anticoagulant use was documented in 75 patients (5.9%) in period I and in 104 patients (10.2%) in period II. Anticoagulant use during period II, but not period I, was associated with inferior OS than no use on multivariate analysis (p = 0.001, hazard ratio [HR] = 1.52, 95% confidence interval [CI]: 1.18-1.95). No decrease in OS became apparent when only patients with prophylactic anticoagulant use were considered. No survival association was established for anti-platelet agent use. CONCLUSIONS Anticoagulant use was not associated with improved OS. Anticoagulants may not exert relevant anti-tumour properties in glioblastoma.
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10.
Outcome of Bevacizumab Therapy in Patients with Recurrent Glioblastoma Treated with Angiotensin System Inhibitors.
Johansen, MD, Urup, T, Holst, CB, Christensen, IJ, Grunnet, K, Lassen, U, Friis, S, Poulsen, HS
Cancer investigation. 2018;(9-10):512-519
Abstract
PURPOSE Antihypertensive therapy may improve bevacizumab efficacy in cancer patients. We examined efficacy and toxicity of angiotensin system inhibitors (ASI) and other antihypertensive drugs in bevacizumab treated recurrent glioblastoma patients. METHODS We retrospectively combined a national prescription registry with a clinical database with recurrent glioblastoma patients (n = 243). RESULTS Patients who initiated ASI after bevacizumab (n = 26) showed a tendency towards improved progression-free survival and overall survival (OS) with hazard rate (HR) reductions (HR = 0.70 and HR = 0.79, respectively). Calcium antagonists during bevacizumab therapy significantly improved OS (HR = 0.57). CONCLUSIONS Overall the study supports a potential beneficial effect of antihypertensive treatment on prognosis of bevacizumab treated glioblastoma patients.