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      A Meta-Analysis of Survival Outcomes Following Reoperation in Recurrent Glioblastoma: Time to Consider the Timing of Reoperation

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          Abstract

          Background: Glioblastoma multiforme (GBM) inevitably recurs, but no standard regimen has been established for recurrent patients. Reoperation at recurrence alleviates mass effects, and the survival benefit has been reported in many studies. However, in most studies, the effect of reoperation timing on survival benefit was ignored. The aim of this meta-analysis was to investigate whether reoperation provided similar survival benefits in recurrent GBM patients when it was analyzed as a fixed or time-dependent covariate.

          Methods: A systematic literature search of PubMed, EMBASE, and Cochrane databases was performed to identify original articles that evaluated the associations between reoperation and prognosis in recurrent GBM patients.

          Results: Twenty-one articles involving 8,630 patients were included. When reoperation was considered as a fixed covariate, it was associated with better overall survival (OS) and post-progression survival (PPS) (OS: HR = 0.66, 95% CI 0.61-0.71, p < 0.001, I 2 = 0%; PPS: HR = 0.70, 95% CI 0.57–0.88, p < 0.01, I 2 = 70.2%). However, such a survival benefit was not observed when reoperation was considered as a time-dependent covariate (OS: HR = 2.19, 95% CI 1.47–3.27, p < 0.001; PPS: HR = 0.95, 95% CI 0.82–1.10, p = 0.51, I 2 = 0%). The estimate bias caused by ignoring the time-dependent nature of reoperation was further demonstrated by the re-analysis of survival data in three included studies.

          Conclusions: The timing of reoperation may have an impact on the survival outcome in recurrent GBM patients, and survival benefits of reoperation in recurrent GBM may be overestimated when analyzed as fixed covariates. Proper analysis methodology should be used in future work to confirm the clinical benefits of reoperation.

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          Most cited references37

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          Independent association of extent of resection with survival in patients with malignant brain astrocytoma.

          With recent advances in the adjuvant treatment of malignant brain astrocytomas, it is increasingly debated whether extent of resection affects survival. In this study, the authors investigate this issue after primary and revision resection of these lesions. The authors retrospectively reviewed the cases of 1215 patients who underwent surgery for malignant brain astrocytomas (World Health Organization [WHO] Grade III or IV) at a single institution from 1996 to 2006. Patients with deep-seated or unresectable lesions were excluded. Based on MR imaging results obtained < 48 hours after surgery, gross-total resection (GTR) was defined as no residual enhancement, near-total resection (NTR) as having thin rim enhancement of the resection cavity only, and subtotal resection (STR) as having residual nodular enhancement. The independent association of extent of resection and subsequent survival was assessed via a multivariate proportional hazards regression analysis. Magnetic resonance imaging studies were available for review in 949 cases. The mean age and mean Karnofsky Performance Scale (KPS) score at time of surgery were 51 +/- 16 years and 80 +/- 10, respectively. Surgery consisted of primary resection in 549 patients (58%) and revision resection for tumor recurrence in 400 patients (42%). The lesion was WHO Grade IV in 700 patients (74%) and Grade III in 249 (26%); there were 167 astrocytomas and 82 mixed oligoastrocytoma. Among patients who underwent resection, GTR, NTR, and STR were achieved in 330 (35%), 388 (41%), and 231 cases (24%), respectively. Adjusting for factors associated with survival (for example, age, KPS score, Gliadel and/or temozolomide use, and subsequent resection), GTR versus NTR (p < 0.05) and NTR versus STR (p < 0.05) were independently associated with improved survival after both primary and revision resection of glioblastoma multiforme (GBM). For primary GBM resection, the median survival after GTR, NTR, and STR was 13, 11, and 8 months, respectively. After revision resection, the median survival after GTR, NTR, and STR was 11, 9, and 5 months, respectively. Adjusting for factors associated with survival for WHO Grade III astrocytoma (age, KPS score, and revision resection), GTR versus STR (p < 0.05) was associated with improved survival. Gross-total resection versus NTR was not associated with an independent survival benefit in patients with WHO Grade III astrocytomas. The median survival after primary resection of WHO Grade III (mixed oligoastrocytomas excluded) for GTR, NTR, and STR was 58, 46, and 34 months, respectively. In the authors' experience with both primary and secondary resection of malignant brain astrocytomas, increasing extent of resection was associated with improved survival independent of age, degree of disability, WHO grade, or subsequent treatment modalities used. The maximum extent of resection should be safely attempted while minimizing the risk of surgically induced neurological injury.
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            Time-dependent prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes.

            The aims of this study were to identify the most significant prognostic factors in myelodysplastic syndromes (MDS) taking into account both their values at clinical onset and their changes in time and to develop a dynamic model for predicting survival and leukemic evolution that can be applied at any time during the course of the disease. We studied a learning cohort of 426 MDS patients diagnosed at the Department of Hematology, San Matteo Hospital, Pavia, Italy, between 1992 and 2004, and a validation cohort of 739 patients diagnosed at the Heinrich-Heine-University Hospital, Düsseldorf, Germany, between 1982 and 2003. All patients were reclassified according to WHO criteria. Univariable and multivariable analyses were performed using Cox models with time-dependent covariates. The most important variables for the prognostic model were WHO subgroups, karyotype, and transfusion requirement. We defined a WHO classification-based prognostic scoring system (WPSS) that was able to classify patients into five risk groups showing different survivals (median survival from 12 to 103 months) and probabilities of leukemic evolution (P < .001). WPSS was shown to predict survival and leukemia progression at any time during follow-up (P < .001), and its prognostic value was confirmed in the validation cohort. WPSS is a dynamic prognostic scoring system that provides an accurate prediction of survival and risk of leukemic evolution in MDS patients at any time during the course of their disease. This time-dependent system seems particularly useful in lower risk patients and may be used for implementing risk-adapted treatment strategies.
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              Surgical oncology for gliomas: the state of the art

              Surgical resection remains the mainstay of treatment for patients with glioma of any grade. Maximal resection of the tumour is central to achieving long-term disease control; however, the relationship between the extent of glioma resection and actual clinical benefit for the patient is predicated on the balance between cytoreduction and neurological morbidity. For the neurosurgical oncologist, the clinical rationale for undertaking increasingly extensive resections has gained traction. In parallel, novel surgical techniques and technologies have been developed that help improve patient outcomes. During the past decade, neurosurgeons have leveraged advanced intraoperative imaging methods, fluorescence-based tumour biomarkers, and real-time mutational analyses to maximize the extent of tumour resection. In addition, approaches to minimizing the risk of perioperative morbidity continue to be improved through the combined use of stimulation-mapping techniques, corticospinal tract imaging, and stereotactic thermal ablation. Taken together, these modern principles of neurosurgical oncology bear little resemblance to historical therapeutic strategies for patients with glioma and have dramatically altered the approach to the treatment of patients with these brain tumours. Herein, we outline the state of the art in surgical oncology for gliomas.
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                Author and article information

                Contributors
                Journal
                Front Neurol
                Front Neurol
                Front. Neurol.
                Frontiers in Neurology
                Frontiers Media S.A.
                1664-2295
                26 March 2019
                2019
                : 10
                : 286
                Affiliations
                [1] 1Department of Neurosurgery, Zhongnan Hospital, Wuhan University , Wuhan, China
                [2] 2Department of Physiology, School of Basic Medical Sciences, Wuhan University , Wuhan, China
                [3] 3Department of Neurosurgery, University Hospital Zurich , Zurich, Switzerland
                [4] 4Division of Neurosurgery, University Hospital La Princesa , Madrid, Spain
                [5] 5Department of Neurosurgery, Sainte-Anne Hospital , Paris, France
                [6] 6Paris Descartes University, Sorbonne Paris Cité , Paris, France
                Author notes

                Edited by: Sandro M. Krieg, Technische Universität München, Germany

                Reviewed by: Yoshua Esquenazi, University of Texas Health Science Center at Houston, United States; Seunggu Jude Han, Oregon Health & Science University, United States

                *Correspondence: Zhi-Qiang Li lizhiqiang@ 123456whu.edu.cn

                This article was submitted to Neuro-Oncology and Neurosurgical Oncology, a section of the journal Frontiers in Neurology

                †These authors have contributed equally to this work

                Article
                10.3389/fneur.2019.00286
                6448034
                30984099
                74af4337-15af-488c-a033-88e04f608ad7
                Copyright © 2019 Zhao, Wang, Pan, Péus, Delgado-Fernandez, Pallud and Li.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 21 December 2018
                : 05 March 2019
                Page count
                Figures: 6, Tables: 2, Equations: 0, References: 49, Pages: 10, Words: 5794
                Funding
                Funded by: National Natural Science Foundation of China 10.13039/501100001809
                Award ID: No. 81573459
                Categories
                Neurology
                Systematic Review

                Neurology
                glioblastoma,recurrence,reoperation,time-dependent covariate,survival
                Neurology
                glioblastoma, recurrence, reoperation, time-dependent covariate, survival

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