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Chernov AN, Skliar SS, Yatskou MM, Skakun VV, Pyurveev SS, Batotsyrenova EG, Zheregelya SN, Liu G, Kashuro VA, Ivanov DO, Ivanov SD. Glioblastoma and Blood Microenvironment Predictive Model for Life Expectancy of Patients. Biomedicines 2025; 13:1040. [PMID: 40426873 PMCID: PMC12108703 DOI: 10.3390/biomedicines13051040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2025] [Revised: 04/19/2025] [Accepted: 04/22/2025] [Indexed: 05/29/2025] Open
Abstract
Background: Glioblastoma multiforme (GBM) is a very malignant brain tumor. GBM exhibits cellular and molecular heterogeneity that can be exploited to improve patient outcomes by individually tailoring chemotherapy regimens. Objective: Our objective was to develop a predictive model of the life expectancy of GBM patients using data on tumor cells' sensitivity to chemotherapy drugs, as well as the levels of blood cells and proteins forming the tumor microenvironment. Methods: The investigation included 31 GBM patients from the Almazov Medical Research Centre (Saint Petersburg, Russia). The cytotoxic effects of chemotherapy drugs on GBM cells were studied by an MTT test using a 50% inhibitory concentration (IC50). We analyzed the data with life expectancy by a one-way ANOVA, principal component analysis (PCA), ROC, and Kaplan-Meier survival tests using GraphPad Prism and Statistica 10 software. Results: We determined in vitro the IC50 of six chemotherapy drugs for GBM and 32 clinical and biochemical blood indicators for these patients. This model includes an assessment of only three parameters: IC50 of tumor cells to carboplatin (CARB) higher than 4.115 μg/mL, as well as levels of band neutrophils (NEUT-B) below 2.5% and total protein (TP) above 64.5 g/L in the blood analysis, which allows predicting with 83.3% probability (sensitivity) the life expectancy of patients for 15 months or more. In opposite, a change in these parameters-CARB above 4115 μg/mL, NEUT-B below 2.5%, and TP above 64.5 g/L-predict with 83.3% probability (specificity) no survival rate of GBM patients for more than 15 months. The relative risk for CARB was 6.41 (95 CI: 4.37-8.47, p = 0.01); for NEUT-B, the RR was 0.40 (95 CI: 0.26-0.87, p = 0.09); and for TP, it was 2.88 (95 CI: 1.57-4.19, p = 0.09). Overall, the model predicted the risk of developing a positive event (an outcome with a life expectancy more than 10 months) eight times (95 CI 6.34-9.66, p < 0.01). Cross k-means validation on three clusters (n = 10) of the model showed that its average accuracy (sensitivity and specificity) for cluster 1 was 74.98%; for cluster 2, it was 66.7%; and for cluster 3, it was 60.0%. At the same time, the differences between clusters 1, 2, and 3 were not significant. The results of the Sobel test show that there are no interactions between the components of the model, and each component is an independent factor influencing the event (life expectancy, survival) of GBM patients. Conclusions: A simple predictive model for GBM patients' life expectancy has been developed using statistical analysis methods.
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Affiliation(s)
- Alexander N. Chernov
- Biological Chemistry Department, Federal State Budgetary Educational Institution of Higher Education Saint Petersburg State Pediatric Medical University of the Ministry of Health of Russia, 194100 Saint Petersburg, Russia; (S.S.P.); (E.G.B.); (S.N.Z.); (V.A.K.); (D.O.I.)
- Department of General Pathology and Pathophysiology, Federal State Budgetary Institution of Science “Institute of Experimental Medicine”, 197022 Saint Petersburg, Russia
| | - Sofia S. Skliar
- Laboratory of Neurooncology of Polenov Neurosurgical Institute, Almazov National Medical Research Centre, 197341 Saint Petersburg, Russia;
| | - Mikalai M. Yatskou
- Department of System Analysis and Computer Modeling, Belarussian State University, 220030 Minsk, Belarus; (M.M.Y.); (V.V.S.)
| | - Victor V. Skakun
- Department of System Analysis and Computer Modeling, Belarussian State University, 220030 Minsk, Belarus; (M.M.Y.); (V.V.S.)
| | - Sarng S. Pyurveev
- Biological Chemistry Department, Federal State Budgetary Educational Institution of Higher Education Saint Petersburg State Pediatric Medical University of the Ministry of Health of Russia, 194100 Saint Petersburg, Russia; (S.S.P.); (E.G.B.); (S.N.Z.); (V.A.K.); (D.O.I.)
- Department of General Pathology and Pathophysiology, Federal State Budgetary Institution of Science “Institute of Experimental Medicine”, 197022 Saint Petersburg, Russia
| | - Ekaterina G. Batotsyrenova
- Biological Chemistry Department, Federal State Budgetary Educational Institution of Higher Education Saint Petersburg State Pediatric Medical University of the Ministry of Health of Russia, 194100 Saint Petersburg, Russia; (S.S.P.); (E.G.B.); (S.N.Z.); (V.A.K.); (D.O.I.)
| | - Sergey N. Zheregelya
- Biological Chemistry Department, Federal State Budgetary Educational Institution of Higher Education Saint Petersburg State Pediatric Medical University of the Ministry of Health of Russia, 194100 Saint Petersburg, Russia; (S.S.P.); (E.G.B.); (S.N.Z.); (V.A.K.); (D.O.I.)
| | - Guodong Liu
- Department of Neurosurgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China;
| | - Vadim A. Kashuro
- Biological Chemistry Department, Federal State Budgetary Educational Institution of Higher Education Saint Petersburg State Pediatric Medical University of the Ministry of Health of Russia, 194100 Saint Petersburg, Russia; (S.S.P.); (E.G.B.); (S.N.Z.); (V.A.K.); (D.O.I.)
- Department of Maxillofacial Surgery and Surgical Dentistry, Medical Institute of Saint Petersburg State University, 199034 Saint Petersburg, Russia
- Department of Anatomy and Physiology of Humans and Animals, Herzen State Pedagogical University of Russia, 191186 Saint Petersburg, Russia
| | - Dmitry O. Ivanov
- Biological Chemistry Department, Federal State Budgetary Educational Institution of Higher Education Saint Petersburg State Pediatric Medical University of the Ministry of Health of Russia, 194100 Saint Petersburg, Russia; (S.S.P.); (E.G.B.); (S.N.Z.); (V.A.K.); (D.O.I.)
| | - Sergey D. Ivanov
- Federal State Budgetary Institution “National Medical Research Center of Oncology named after N.N. Petrov” of the Ministry of Health of the Russian Federation, 197758 Saint Petersburg, Russia;
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Shahlaei M, Asl SM, Derakhshani A, Kurek L, Karges J, Macgregor R, Saeidifar M, Kostova I, Saboury AA. Platinum-based drugs in cancer treatment: Expanding horizons and overcoming resistance. J Mol Struct 2024; 1301:137366. [DOI: 10.1016/j.molstruc.2023.137366] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Kreatsoulas D, Damante M, Cua S, Lonser RR. Adjuvant convection-enhanced delivery for the treatment of brain tumors. J Neurooncol 2024; 166:243-255. [PMID: 38261143 PMCID: PMC10834622 DOI: 10.1007/s11060-023-04552-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Accepted: 12/22/2023] [Indexed: 01/24/2024]
Abstract
BACKGROUND Malignant gliomas are a therapeutic challenge and remain nearly uniformly fatal. While new targeted chemotherapeutic agentsagainst malignant glioma have been developed in vitro, these putative therapeutics have not been translated into successful clinical treatments. The lack of clinical effectiveness can be the result of ineffective biologic strategies, heterogeneous tumor targets and/or the result of poortherapeutic distribution to malignant glioma cells using conventional nervous system delivery modalities (intravascular, cerebrospinal fluid and/orpolymer implantation), and/or ineffective biologic strategies. METHODS The authors performed a review of the literature for the terms "convection enhanced delivery", "glioblastoma", and "glioma". Selectclinical trials were summarized based on their various biological mechanisms and technological innovation, focusing on more recently publisheddata when possible. RESULTS We describe the properties, features and landmark clinical trials associated with convection-enhanced delivery for malignant gliomas.We also discuss future trends that will be vital to CED innovation and improvement. CONCLUSION Efficacy of CED for malignant glioma to date has been mixed, but improvements in technology and therapeutic agents arepromising.
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Affiliation(s)
- Daniel Kreatsoulas
- Department of Neurological Surgery, The Ohio State University Wexner Medical Center, The Ohio State University, N1019 Doan Hall, 410 W 10Th Avenue, Columbus, OH, 43210, USA.
| | - Mark Damante
- Department of Neurological Surgery, The Ohio State University Wexner Medical Center, The Ohio State University, N1019 Doan Hall, 410 W 10Th Avenue, Columbus, OH, 43210, USA
| | - Santino Cua
- Department of Neurological Surgery, The Ohio State University Wexner Medical Center, The Ohio State University, N1019 Doan Hall, 410 W 10Th Avenue, Columbus, OH, 43210, USA
| | - Russell R Lonser
- Department of Neurological Surgery, The Ohio State University Wexner Medical Center, The Ohio State University, N1019 Doan Hall, 410 W 10Th Avenue, Columbus, OH, 43210, USA
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Mekala JR, Adusumilli K, Chamarthy S, Angirekula HSR. Novel sights on therapeutic, prognostic, and diagnostics aspects of non-coding RNAs in glioblastoma multiforme. Metab Brain Dis 2023; 38:1801-1829. [PMID: 37249862 PMCID: PMC10227410 DOI: 10.1007/s11011-023-01234-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Accepted: 05/09/2023] [Indexed: 05/31/2023]
Abstract
Glioblastoma Multiforme (GBM) is the primary brain tumor and accounts for 200,000 deaths each year worldwide. The standard therapy includes surgical resection followed by temozolomide (TMZ)-based chemotherapy and radiotherapy. The survival period of GBM patients is only 12-15 months. Therefore, novel treatment modalities for GBM treatment are urgently needed. Mounting evidence reveals that non-coding RNAs (ncRNAs) were involved in regulating gene expression, the pathophysiology of GBM, and enhancing therapeutic outcomes. The combinatory use of ncRNAs, chemotherapeutic drugs, and tumor suppressor gene expression induction might provide an innovative, alternative therapeutic approach for managing GBM. Studies have highlighted the role of Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) in prognosis and diagnosis. Dysregulation of ncRNAs is observed in virtually all tumor types, including GBMs. Studies have also indicated the blood-brain barrier (BBB) as a crucial factor that hinders chemotherapy. Although several nanoparticle-mediated drug deliveries were degrading effectively against GBM in vitro conditions. However, the potential to cross the BBB and optimum delivery of oligonucleotide RNA into GBM cells in the brain is currently under intense clinical trials. Despite several advances in molecular pathogenesis, GBM remains resistant to chemo and radiotherapy. Targeted therapies have less clinical benefit due to high genetic heterogeneity and activation of alternative pathways. Thus, identifying GBM-specific prognostic pathways, essential genes, and genomic aberrations provide several potential benefits as subtypes of GBM. Also, these approaches will provide insights into new strategies to overcome the heterogenous nature of GBM, which will eventually lead to successful therapeutic interventions toward precision medicine and precision oncology.
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Affiliation(s)
- Janaki Ramaiah Mekala
- Department of Bio-Technology, Koneru Lakshmaiah Education Foundation (KLEF), Vaddeswaram, Guntur, 522302, Andhra Pradesh, India.
| | - Kowsalya Adusumilli
- Department of Bio-Technology, Koneru Lakshmaiah Education Foundation (KLEF), Vaddeswaram, Guntur, 522302, Andhra Pradesh, India
| | - Sahiti Chamarthy
- Department of Bio-Technology, Koneru Lakshmaiah Education Foundation (KLEF), Vaddeswaram, Guntur, 522302, Andhra Pradesh, India
| | - Hari Sai Ram Angirekula
- Department of Bio-Technology, Koneru Lakshmaiah Education Foundation (KLEF), Vaddeswaram, Guntur, 522302, Andhra Pradesh, India
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Rocha Pinheiro SL, Lemos FFB, Marques HS, Silva Luz M, de Oliveira Silva LG, Faria Souza Mendes dos Santos C, da Costa Evangelista K, Calmon MS, Sande Loureiro M, Freire de Melo F. Immunotherapy in glioblastoma treatment: Current state and future prospects. World J Clin Oncol 2023; 14:138-159. [PMID: 37124134 PMCID: PMC10134201 DOI: 10.5306/wjco.v14.i4.138] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 02/06/2023] [Accepted: 04/12/2023] [Indexed: 04/21/2023] Open
Abstract
Glioblastoma remains as the most common and aggressive malignant brain tumor, standing with a poor prognosis and treatment prospective. Despite the aggressive standard care, such as surgical resection and chemoradiation, median survival rates are low. In this regard, immunotherapeutic strategies aim to become more attractive for glioblastoma, considering its recent advances and approaches. In this review, we provide an overview of the current status and progress in immunotherapy for glioblastoma, going through the fundamental knowledge on immune targeting to promising strategies, such as Chimeric antigen receptor T-Cell therapy, immune checkpoint inhibitors, cytokine-based treatment, oncolytic virus and vaccine-based techniques. At last, it is discussed innovative methods to overcome diverse challenges, and future perspectives in this area.
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Affiliation(s)
- Samuel Luca Rocha Pinheiro
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabian Fellipe Bueno Lemos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Hanna Santos Marques
- Campus Vitória da Conquista, Universidade Estadual do Sudoeste da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Marcel Silva Luz
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | | | | | | | - Mariana Santos Calmon
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Matheus Sande Loureiro
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabrício Freire de Melo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
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Trifănescu OG, Trifănescu RA, Mitrică R, Mitrea D, Ciornei A, Georgescu M, Butnariu I, Galeș LN, Șerbănescu L, Anghel RM, Păun MA. Upstaging and Downstaging in Gliomas-Clinical Implications for the Fifth Edition of the World Health Organization Classification of Tumors of the Central Nervous System. Diagnostics (Basel) 2023; 13:diagnostics13020197. [PMID: 36673007 PMCID: PMC9858599 DOI: 10.3390/diagnostics13020197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Revised: 12/28/2022] [Accepted: 01/01/2023] [Indexed: 01/06/2023] Open
Abstract
In 2021, the 5th edition of the WHO Classification of Tumors of the Central Nervous System (WHO-CNS5) was published as the sixth volume of the international standard for brain and spinal cord tumor classification. The most remarkable practical change in the current classification involves grading gliomas according to molecular characterization. IDH mutant (10%) and IDH wild-type tumors (90%) are two different entities that possess unique biological features and various clinical outcomes regarding treatment response and overall survival. This article presents two comparative cases that highlight the clinical importance of these new classification standards. The first clinical case aimed to provide a comprehensive argument for determining the IDH status in tumors initially appearing as low-grade astrocytoma upon histologic examination, thus underlining the importance of the WHO-CNS5. The second case showed the implications of the histologic overdiagnosis of glioblastoma using the previous classification system with a treatment span of 7 years that proceeded through full-dose re-irradiation up to metronomic therapy. The new WHO-CNS5 classification significantly impacted complex neurooncological cases, thus changing the initial approach to a more precise therapeutic management.
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Affiliation(s)
- Oana Gabriela Trifănescu
- Department of Oncology, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Radiotherapy II, “Prof. Dr. Al. Trestioreanu” Institute of Oncology, 022328 Bucharest, Romania
| | - Raluca Alexandra Trifănescu
- Department of Endocrinology, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania
- “C. I. Parhon” Bucharest Institute of Endocrinology, 011863 Bucharest, Romania
| | - Radu Mitrică
- Department of Oncology, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Radiotherapy II, “Prof. Dr. Al. Trestioreanu” Institute of Oncology, 022328 Bucharest, Romania
- Correspondence: (R.M.); (D.M.); Tel.: +40-741964311 (R.M.); +40-723226233 (D.M.)
| | - Dan Mitrea
- Radiotherapy II, “Prof. Dr. Al. Trestioreanu” Institute of Oncology, 022328 Bucharest, Romania
- Neuroaxis Neurology Clinic, 011302 Bucharest, Romania
- Correspondence: (R.M.); (D.M.); Tel.: +40-741964311 (R.M.); +40-723226233 (D.M.)
| | - Ana Ciornei
- Radiotherapy II, “Prof. Dr. Al. Trestioreanu” Institute of Oncology, 022328 Bucharest, Romania
| | - Mihai Georgescu
- Department of Oncology, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Radiotherapy II, “Prof. Dr. Al. Trestioreanu” Institute of Oncology, 022328 Bucharest, Romania
| | - Ioana Butnariu
- Department of Neurology, National Institute of Neurology and Neurovascular Diseases, 041914 Bucharest, Romania
| | - Laurenția Nicoleta Galeș
- Department of Oncology, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Medical Oncology II, “Prof. Dr. Al. Trestioreanu” Institute of Oncology, 022328 Bucharest, Romania
| | - Luiza Șerbănescu
- Department of Oncology, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Radiotherapy II, “Prof. Dr. Al. Trestioreanu” Institute of Oncology, 022328 Bucharest, Romania
| | - Rodica Maricela Anghel
- Department of Oncology, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Radiotherapy II, “Prof. Dr. Al. Trestioreanu” Institute of Oncology, 022328 Bucharest, Romania
| | - Mihai-Andrei Păun
- Radiotherapy II, “Prof. Dr. Al. Trestioreanu” Institute of Oncology, 022328 Bucharest, Romania
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Winograd E, Germano I, Wen P, Olson JJ, Ormond DR. Congress of Neurological Surgeons systematic review and evidence-based guidelines update on the role of targeted therapies and immunotherapies in the management of progressive glioblastoma. J Neurooncol 2022; 158:265-321. [PMID: 34694567 PMCID: PMC8543777 DOI: 10.1007/s11060-021-03876-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 10/11/2021] [Indexed: 11/20/2022]
Abstract
The following questions and recommendations are pertinent to the following: TARGET POPULATION: These recommendations apply to adults with progressive GBM who have undergone standard primary treatment with surgery and/or chemoradiation. QUESTION 1: In adults with progressive glioblastoma is the use of bevacizumab as monotherapy superior to standard salvage cytotoxic chemotherapy as measured by progression free survival and overall survival? RECOMMENDATION Level III: Treatment with bevacizumab is suggested in the treatment of progressive GBM, as it provides improved disease control compared to historical controls as measured by best imaging response and progression free survival at 6 months, while not providing evidence for improvement in overall survival. QUESTION 2: In adults with progressive glioblastoma is the use of bevacizumab as combination therapy with cytotoxic agents superior to standard salvage cytotoxic chemotherapy as measured by progression free survival and overall survival? RECOMMENDATION Level III: There is insufficient evidence to show benefit or harm of bevacizumab in combination with cytotoxic therapies in progressive glioblastoma due to a lack of evidence supporting a clearly defined benefit without significant toxicity. QUESTION 3: In adults with progressive glioblastoma is the use of bevacizumab as a combination therapy with targeted agents superior to standard salvage cytotoxic chemotherapy as measured by progression free survival and overall survival? RECOMMENDATION There is insufficient evidence to support a recommendation regarding this question. QUESTION 4: In adults with progressive glioblastoma is the use of targeted agents as monotherapy superior to standard salvage cytotoxic chemotherapy as measured by progression free survival and overall survival? RECOMMENDATION There is insufficient evidence to support a recommendation regarding this question. QUESTION 5: In adults with progressive glioblastoma is the use of targeted agents in combination with cytotoxic therapies superior to standard salvage cytotoxic chemotherapy as measured by progression free survival and overall survival? RECOMMENDATION There is insufficient evidence to support a recommendation regarding this question. QUESTION 6: In adults with progressive glioblastoma is the use of immunotherapy monotherapy superior to standard salvage cytotoxic chemotherapy as measured by progression free survival and overall survival? RECOMMENDATION There is insufficient evidence to support a recommendation regarding this question. QUESTION 7: In adults with progressive glioblastoma is the use of immunotherapy in combination with targeted agents superior to standard salvage cytotoxic chemotherapy as measured by progression free survival and overall survival? RECOMMENDATION There is insufficient evidence to support a recommendation regarding this question. QUESTION 8: In adults with progressive glioblastoma is the use of immunotherapy in combination with bevacizumab superior to standard salvage cytotoxic chemotherapy as measured by progression free survival and overall survival? RECOMMENDATION There is insufficient evidence to support a recommendation regarding this question.
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Affiliation(s)
- Evan Winograd
- Department of Neurosurgery, University of Colorado School of Medicine, Aurora, CO, USA
| | - Isabelle Germano
- Department of Neurosurgery, The Mount Sinai Hospital, New York, NY, USA
| | - Patrick Wen
- Center for Neuro-Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Jeffrey J Olson
- Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA, USA
| | - D Ryan Ormond
- Department of Neurosurgery, University of Colorado School of Medicine, Aurora, CO, USA.
- Department of Neurosurgery, University of Colorado Anschutz Medical Campus, 12631 E. 17th Ave., Mail Stop C307, Aurora, CO, 80045, USA.
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Boonmee A, Benjaskulluecha S, Kueanjinda P, Wongprom B, Pattarakankul T, Palaga T. The chemotherapeutic drug carboplatin affects macrophage responses to LPS and LPS tolerance via epigenetic modifications. Sci Rep 2021; 11:21574. [PMID: 34732786 PMCID: PMC8566489 DOI: 10.1038/s41598-021-00955-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 10/18/2021] [Indexed: 12/22/2022] Open
Abstract
Following re-exposure to lipopolysaccharide (LPS), macrophages exhibit an immunosuppressive state known as LPS tolerance, which is characterized by repressed proinflammatory cytokine production. LPS-induced tolerance in macrophages is mediated in part by epigenetic changes. Carboplatin, an anticancer chemotherapeutic drug, exerts its effect by inhibiting DNA replication and transcription, as well as through epigenetic modifications. Through an unbiased screen, we found that carboplatin rescued TNF-α and IL-6 production in LPS-tolerant macrophages. Transcriptomic analysis and gene set enrichment analyses revealed that p53 was one of the most significantly upregulated hallmarks in both LPS-primed and LPS-tolerant macrophages in the presence of carboplatin, while E2F and G2/M were the most negatively regulated hallmarks. Heterochromatin protein 1 (HP1-α), which is associated with gene silencing, was significantly reduced in carboplatin-treated LPS-tolerant macrophages at the mRNA and protein levels. Dynamic changes in the mRNA level of genes encoding H3K9me3 methyltransferases, setdb2, kdm4d, and suv39h1 were induced in the presence of carboplatin in LPS-tolerant macrophages. Taken together, we provide evidence that carboplatin treatment interferes with proinflammatory cytokine production during the acute LPS response and LPS tolerance in macrophages, possibly via H3K9me3 modification.
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Affiliation(s)
- Atsadang Boonmee
- Department of Microbiology, Faculty of Science, Chulalongkorn University, Bangkok, Thailand
- Center of Excellence in Immunology and Immune-Mediated Diseases, Chulalongkorn University, Bangkok, Thailand
| | - Salisa Benjaskulluecha
- Center of Excellence in Immunology and Immune-Mediated Diseases, Chulalongkorn University, Bangkok, Thailand
- Inter-Disciplinary Graduate Program in Medical Microbiology, Graduate School, Chulalongkorn University, Bangkok, Thailand
| | - Patipark Kueanjinda
- Center of Excellence in Immunology and Immune-Mediated Diseases, Chulalongkorn University, Bangkok, Thailand
- Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Benjawan Wongprom
- Department of Microbiology, Faculty of Science, Chulalongkorn University, Bangkok, Thailand
- Center of Excellence in Immunology and Immune-Mediated Diseases, Chulalongkorn University, Bangkok, Thailand
| | - Thitiporn Pattarakankul
- Department of Microbiology, Faculty of Science, Chulalongkorn University, Bangkok, Thailand
- Center of Excellence in Immunology and Immune-Mediated Diseases, Chulalongkorn University, Bangkok, Thailand
| | - Tanapat Palaga
- Department of Microbiology, Faculty of Science, Chulalongkorn University, Bangkok, Thailand.
- Center of Excellence in Immunology and Immune-Mediated Diseases, Chulalongkorn University, Bangkok, Thailand.
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Transmembrane protein DCBLD2 is correlated with poor prognosis and affects phenotype by regulating epithelial-mesenchymal transition in human glioblastoma cells. Neuroreport 2021; 32:507-517. [PMID: 33788813 DOI: 10.1097/wnr.0000000000001611] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE We attempt to investigate the biological function of the discoidin, complement C1r/C1s,Uegf, and Bmp1 and Limulus factor C, Coch, and Lgl domain-containing 2 (DCBLD2) in glioblastoma, as well as its effect on the epithelial-mesenchymal transition (EMT) process. METHODS The public expression data of glioblastoma samples and normal brain samples from The Cancer Genome Atlas database, Genotype-Tissue Expression database and Chinese Glioma Genome Atlas database were used to analyze the expression of DCBLD2 and its relationship with the survival of patients with glioblastoma. Quantitative real-time PCR and western blot were used to evaluate mRNA and protein levels of DCBLD2. Cell viabilities were tested using Cell Counting Kit-8 and clone formation assays. Cell invasive and migratory abilities were measured by transwell assays. RESULTS DCBLD2 expression was upregulated in glioblastoma and has a significantly positive correlation with the WHO classification. In addition, high expression of DCBLD2 was closely correlated with poor prognosis in primary and recurrent patients with glioblastoma. What is more, we found that knockdown of DCBLD2 notably reduced the cell proliferative, invasive and migratory capacities by elevating the expression of E-cadherin and inhibiting the expression of vimentin, snail, slug and twist. However, overexpression of DCBLD2 presented the opposite results. CONCLUSION The current study reveals that high expression of DCBLD2 is closely related to poor prognosis in glioblastoma and can significantly enhance the tumor cell viability and metastasis by activating the EMT process, suggesting that DCBLD2 may be a possible biomarker for glioblastoma treatment.
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Fisher JP, Adamson DC. Current FDA-Approved Therapies for High-Grade Malignant Gliomas. Biomedicines 2021; 9:biomedicines9030324. [PMID: 33810154 PMCID: PMC8004675 DOI: 10.3390/biomedicines9030324] [Citation(s) in RCA: 178] [Impact Index Per Article: 44.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 03/16/2021] [Accepted: 03/17/2021] [Indexed: 12/26/2022] Open
Abstract
The standard of care (SOC) for high-grade gliomas (HGG) is maximally safe surgical resection, followed by concurrent radiation therapy (RT) and temozolomide (TMZ) for 6 weeks, then adjuvant TMZ for 6 months. Before this SOC was established, glioblastoma (GBM) patients typically lived for less than one year after diagnosis, and no adjuvant chemotherapy had demonstrated significant survival benefits compared with radiation alone. In 2005, the Stupp et al. randomized controlled trial (RCT) on newly diagnosed GBM patients concluded that RT plus TMZ compared to RT alone significantly improved overall survival (OS) (14.6 vs. 12.1 months) and progression-free survival (PFS) at 6 months (PFS6) (53.9% vs. 36.4%). Outside of TMZ, there are four drugs and one device FDA-approved for the treatment of HGGs: lomustine, intravenous carmustine, carmustine wafer implants, bevacizumab (BVZ), and tumor treatment fields (TTFields). These treatments are now mainly used to treat recurrent HGGs and symptoms. TTFields is the only treatment that has been shown to improve OS (20.5 vs. 15.6 months) and PFS6 (56% vs. 37%) in comparison to the current SOC. TTFields is the newest addition to this list of FDA-approved treatments, but has not been universally accepted yet as part of SOC.
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Affiliation(s)
- Jacob P. Fisher
- Division of Biochemistry, Southern Virginia University, Buena Vista, VA 24416, USA
- Correspondence:
| | - David C. Adamson
- Department of Neurosurgery, School of Medicine, Emory University, Atlanta, GA 30322, USA;
- Atlanta VA Healthcare System, Decatur, GA 30033, USA
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11
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Impact of adverse events of bevacizumab on survival outcomes of patients with recurrent glioblastoma. J Clin Neurosci 2020; 74:36-40. [PMID: 31982279 DOI: 10.1016/j.jocn.2020.01.066] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2019] [Accepted: 01/12/2020] [Indexed: 10/25/2022]
Abstract
BACKGROUND Bevacizumab is widely used for treatment of recurrent glioblastoma (rGB). It is well known that adverse events (AEs) due to bevacizumab can cause early discontinuation of treatment. However, the association between AEs and survival outcomes is not well defined. METHODS We retrospectively identified patients with rGB, who were treated with single-agent bevacizumab or bevacizumab-based combination regimens from 07/2005 through 07/2014, and who discontinued bevacizumab due to either AEs or physician's decision. Those who discontinued bevacizumab because of tumor progression were excluded. Demographic, treatment, and survival data were collected from the database. RESULTS Of 298 adults with rGB treated with bevacizumab in our database, 65 patients discontinued bevacizumab due to AEs (n = 39, 60%) or physician's decision (n = 26, 40%). There were no statistically significant differences in regards to age, performance status, extent of resection, number of lesions, the time between diagnosis and first recurrence, time between diagnosis and initiation of bevacizumab, number of recurrences before bevacizumab initiation, and duration of bevacizumab treatment between the two groups. Interestingly, patients who discontinued bevacizumab because of AEs progressed earlier after bevacizumab discontinuation (3.9 months vs 5.7 months; p = 0.02), had significantly shorter progression-free survival (PFS) (10.4 months vs 14.2 months; p = 0.01) and shorter overall survival (OS) from bevacizumab initiation (13.9 months vs 32.5 months; p = 0.01) as well as shorter OS from tumor diagnosis (20 months vs 49.3 months; p = 0.007) when compared to patients who discontinued bevacizumab due to a physician's decision. CONCLUSIONS Our results indicate that the development of AEs to bevacizumab or bevacizumab-containing regimens is associated with unfavorable glioma-related survival outcomes in patients with rGB.
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12
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Phase II study of weekly carboplatin in pretreated adult malignant gliomas. J Neurooncol 2019; 144:211-216. [PMID: 31273578 DOI: 10.1007/s11060-019-03223-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Accepted: 06/16/2019] [Indexed: 01/08/2023]
Abstract
PURPOSE Patients with relapse of recurrent glioma have a poor outcome and limited treatment options. The aim of this study is to investigate the clinical benefit and tolerability of weekly intravenous administration of carboplatin-based monotherapy in adult glioma patients who had progressed from previous chemotherapy lines based on temozolomide and nitrosoureas. METHODS This was a single-arm, phase II study. Eligibility criteria included progressive or recurrent glioma after radiotherapy and chemotherapy-based treatments and Karnofsky performance status (KPS) > 60. RESULTS Thirty-two patients (median age 43.5 years) were enrolled to receive weekly carboplatin monotherapy in an intravenous method of administration. The median duration of response was 7.3 months with an overall disease control rate of 31.3%. Median progression-free survival was 2.3 months while overall survival was 5.5 months. Pre-treatment with corticosteroids (i.e. dexamethasone) was associated to clinical benefit in 43.8% of patients. Patients achieving clinical benefit exhibited a longer progression-free survival (4.6 vs. 1.5 months; p > 0.001) and overall survival (7.9 vs. 3.2 months; p = 0.041) compared with those not achieving clinical benefit. CONCLUSIONS Our findings show that single agent, weekly, intravenous administration of carboplatin may have a role in patients with recurrent glioma and suggest that pre-treatment with corticosteroids may confer survival benefit.
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Cardona AF, Rojas L, Wills B, Ruiz-Patiño A, Abril L, Hakim F, Jiménez E, Useche N, Bermúdez S, Mejía JA, Ramón JF, Carranza H, Vargas C, Otero J, Archila P, Rodríguez J, Rodríguez J, Behaine J, González D, Jacobo J, Cifuentes H, Feo O, Penagos P, Pineda D, Ricaurte L, Pino LE, Vargas C, Marquez JC, Mantilla MI, Ortiz LD, Balaña C, Rosell R, Zatarain-Barrón ZL, Arrieta O. A comprehensive analysis of factors related to carmustine/bevacizumab response in recurrent glioblastoma. Clin Transl Oncol 2019; 21:1364-1373. [DOI: 10.1007/s12094-019-02066-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Accepted: 02/15/2019] [Indexed: 11/30/2022]
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14
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Hanna RM, Lopez EA, Hasnain H, Selamet U, Wilson J, Youssef PN, Akladeous N, Bunnapradist S, Gorin MB. Three patients with injection of intravitreal vascular endothelial growth factor inhibitors and subsequent exacerbation of chronic proteinuria and hypertension. Clin Kidney J 2018; 12:92-100. [PMID: 30746134 PMCID: PMC6366143 DOI: 10.1093/ckj/sfy060] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Accepted: 05/28/2018] [Indexed: 12/31/2022] Open
Abstract
Vascular endothelial growth factor (VEGF) receptor inhibition is a commonly used tool to prevent vascular proliferation in tumors and retinal diseases. The antiangiogenic effects of these drugs have made them potent adjunct therapies when given systemically for malignancies. They are also useful tools to ameliorate diminishing eyesight in retinopathy. Hypertension and proteinuria have been observed in systemic VEGF inhibitor therapy, with rarer presentations involving nephrotic-range proteinuria due to glomerulopathies. Pharmacokinetic studies have shown detectable blood levels of anti-VEGF inhibitors up to 30 days postintravitreal injection. Animal studies have also demonstrated binding of VEGF inhibitors in simian glomeruli 1 week after a single intravitreal injection. We report three patients who received intravitreal bevacizumab and/or aflibercept with worsening hypertension, proteinuria and renal injury. Data regarding emerging evidence of VEGF inhibitor nephrotoxicity after intravitreal injections are also presented. The clinical data and the existing literature are reviewed to support the hypothesis that intravitreal anti-VEGF agents may be unrecognized nephrotoxins. These agents are given to vulnerable patients with diabetes, hypertension and preexisting nephropathy and proteinuria. This case series is reported to spur further study of the systemic effects of intravitreal VEGF inhibitors.
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Affiliation(s)
- Ramy M Hanna
- Division of Nephrology, Department of Medicine, UCLA David Geffen School of Medicine, Los Angeles, CA, USA
| | - Eduardo A Lopez
- Division of Nephrology, Department of Medicine, Kaiser Permanente Panorama City, Panorama City, CA, USA
| | - Huma Hasnain
- Division of Nephrology, Department of Medicine, UCLA David Geffen School of Medicine, Los Angeles, CA, USA
| | - Umut Selamet
- Division of Nephrology, Department of Medicine, UCLA David Geffen School of Medicine, Los Angeles, CA, USA
| | - James Wilson
- Division of Nephrology, Department of Medicine, UCLA David Geffen School of Medicine, Los Angeles, CA, USA
| | - Peter N Youssef
- Division of Transplant Nephrology, Department of Medicine, UCLA David Geffen School of Medicine, Los Angeles, CA, USA
| | - Nermeen Akladeous
- Department of Preventative Medicine, Loma Linda University School of Medicine, Los Angeles, CA, USA
| | - Suphamai Bunnapradist
- Division of Ophthalmology, Department of Surgery, Kaiser Permanente La Palma, La Palma, CA, USA
| | - Michael B Gorin
- Retinal Disorders and Ophthalmic Genetics, Department of Ophthalmology, UCLA David Geffen School of Medicine, Los Angeles, CA, USA
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15
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Tipping M, Eickhoff J, Ian Robins H. Clinical outcomes in recurrent glioblastoma with bevacizumab therapy: An analysis of the literature. J Clin Neurosci 2017; 44:101-106. [PMID: 28711289 DOI: 10.1016/j.jocn.2017.06.070] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2017] [Accepted: 06/22/2017] [Indexed: 12/31/2022]
Abstract
Bevacizumab (BEV) is a common treatment for recurrent glioblastoma (GBM). After progression on BEV, there is no consensus on subsequent therapy, as multiple chemotherapy trials have failed to demonstrate discernible activity for salvage. A previous review (995 patients) estimated a progression free survival (PFS) on BEV of 4.2months (SD±2.1) with an overall survival (OS) after progression on BEV at 3.8months (SD±1). We endeavored to establish a more rigorous historical control, both as a benchmark for efficacy, and a prognostic tool for clinical practice. A comprehensive literature review was performed utilizing PubMed and societal presentation abstracts. A total 2388 patients from 53 arms of 42 studies were analyzed in three groups: 1) thirty-two studies in which survival post-BEV was determined by subtracting PFS from OS (2045 patients): PFS on BEV=4.38months (95% CI 4.09-4.68); OS post-BEV=3.36months (95% CI 3.12-3.66); 2) two studies (94 patients) in which OS post-BEV is reported: OS=3.26 (95% CI 2.39-4.42); 3) eight studies of salvage therapy after progression on BEV (249 patients): of OS post-BEV=4.46months (95% CI 3.68-5.54). These estimates provide a firm historical control for PFS on BEV, as well as OS after disease progression on BEV therapy.
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Affiliation(s)
- Matthew Tipping
- Department of Medicine University of Wisconsin, 600 Highland Avenue, Madison, WI 53792, United States
| | - Jens Eickhoff
- Department of Biostatistics and Medical Informatics, University of Wisconsin, 600 Highland Avenue, Madison, WI 53792, United States; University of Wisconsin Carbone Cancer Center, UWSMPH, United States
| | - H Ian Robins
- University of Wisconsin Carbone Cancer Center, UWSMPH, United States; Departments of Medicine, Human Oncology and Neurology, K4/534 Clinical Science Center, University of Wisconsin, 600 Highland Avenue, Madison, WI 53792, United States.
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16
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Wehbe M, Malhotra A, Anantha M, Roosendaal J, Leung AWY, Plackett D, Edwards K, Gilabert-Oriol R, Bally MB. A simple passive equilibration method for loading carboplatin into pre-formed liposomes incubated with ethanol as a temperature dependent permeability enhancer. J Control Release 2017; 252:50-61. [PMID: 28286316 DOI: 10.1016/j.jconrel.2017.03.010] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Revised: 02/17/2017] [Accepted: 03/04/2017] [Indexed: 02/01/2023]
Abstract
A passive equilibration method which relies on addition of candidate drugs to pre-formed liposomes is described as an alternative method for preparing liposome encapsulated drugs. The method is simple, rapid and applicable to liposomes prepared with high (45mol%) or low (<20mol%) levels of cholesterol. Passive equilibration is performed in 4-steps: (i) formation of liposomes, (ii) addition of the candidate drug to the liposomes in combination with a permeability enhancing agent, (iii) incubation at a temperature that facilitates diffusion of the added compound across the lipid bilayer, and (iv) quenching the enhanced membrane permeability by reduction in temperature and/or removal of the permeabilization enhancer. The method is fully exemplified here using ethanol as the permeabilization enhancer and carboplatin (CBDCA) as the drug candidate. It is demonstrated that ethanol can be added to liposomes prepared with 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and Cholesterol (Chol) (55:45mol ratio) in amounts up to 30% (v/v) with no change in liposome size, even when incubated at temperatures>60°C. Super-saturated solutions of CBDCA (40mg/mL) can be prepared at 70°C and these are stable in the presence of ethanol even when the temperature is reduced to <30°C. maximum CBDCA encapsulation is achieved within 1h after the CBDCA solution is added to pre-formed DSPC/Chol liposomes in the presence of 30% (v/v) ethanol at 60°C. When the pre-formed liposomes are mixed with ethanol (30% v/v) at or below 40°C, the encapsulation efficiency is reduced by an order of magnitude. The method was also applied to liposomes prepared from other compositions include a cholesterol free formulations (containing 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[carboxy(polyethylene glycol)-2000] (DSPE-PEG2000)) and a low Chol (<20mol%) formulations prepared with the distearoyl-sn-glycero-3-phospho-(1'-rac-glycerol) DSPG)). The cytotoxic activity of CBDCA was unaffected when prepared in this manner and two of the resultant formulations exhibited good stability in vitro and in vivo. The cytotoxic activity of CBDCA was unaffected when prepared in this manner and the resultant formulations exhibited good stability in vitro and in vivo. Pharmacokinetics studies in CD-1 mice indicated that the resulting formulations increased the circulation half life of the associated CBDCA significantly (AUC0-24h of CBDCA=0.016μg·hr/mL; AUC0-24h of the DSPC/Chol CBDCA formulation=1014.0μg·hr/mL and AUC0-24h of the DSPC/DSPG/Chol CBDCA formulation=583.96μg·hr/mL). Preliminary efficacy studies in Rag-2M mice with established subcutaneous H1975 and U-251 tumors suggest that the therapeutic activity of CBDCA is improved when administered in liposomal formulations. The encapsulation method described here has not been disclosed previously and will have broad applications to drugs that would normally be encapsulated during liposome manufacturing.
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Affiliation(s)
- Moe Wehbe
- Experimental Therapeutics, British Columbia Cancer Agency, 675 West 10th Avenue, Vancouver, BC V5Z 1L3, Canada.; Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, Vancouver, BC V6T 1Z3, Canada..
| | - Armaan Malhotra
- Experimental Therapeutics, British Columbia Cancer Agency, 675 West 10th Avenue, Vancouver, BC V5Z 1L3, Canada
| | - Malathi Anantha
- Experimental Therapeutics, British Columbia Cancer Agency, 675 West 10th Avenue, Vancouver, BC V5Z 1L3, Canada
| | - Jeroen Roosendaal
- Experimental Therapeutics, British Columbia Cancer Agency, 675 West 10th Avenue, Vancouver, BC V5Z 1L3, Canada.; Department of Pharmaceutics, Section of Biopharmacy and Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Utrecht University, PO Box 80082, 3508 TB Utrecht, The Netherlands
| | - Ada W Y Leung
- Experimental Therapeutics, British Columbia Cancer Agency, 675 West 10th Avenue, Vancouver, BC V5Z 1L3, Canada.; Department of Pathology and Laboratory Medicine, University of British Columbia, 2211 Wesbrook Mall, Vancouver, BC V6T 2B5, Canada
| | - David Plackett
- Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, Vancouver, BC V6T 1Z3, Canada
| | - Katarina Edwards
- Department of Chemistry, University of Uppsala, 3 Husargatan (B7), Uppsala, Sweden
| | - Roger Gilabert-Oriol
- Experimental Therapeutics, British Columbia Cancer Agency, 675 West 10th Avenue, Vancouver, BC V5Z 1L3, Canada
| | - Marcel B Bally
- Experimental Therapeutics, British Columbia Cancer Agency, 675 West 10th Avenue, Vancouver, BC V5Z 1L3, Canada.; Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, Vancouver, BC V6T 1Z3, Canada.; Department of Pathology and Laboratory Medicine, University of British Columbia, 2211 Wesbrook Mall, Vancouver, BC V6T 2B5, Canada.; Center for Drug Research and Development, Vancouver, BC V6T 1Z4, Canada
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17
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Hanna RM, Lopez E, Wilson J, Barathan S, Cohen AH. Minimal change disease onset observed after bevacizumab administration. Clin Kidney J 2015; 9:239-44. [PMID: 26985375 PMCID: PMC4792614 DOI: 10.1093/ckj/sfv139] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2015] [Accepted: 11/17/2015] [Indexed: 01/24/2023] Open
Abstract
This is a report of a patient with minimal change disease (MCD) onset after bevacizumab administration. A 72-year-old man with inoperable Grade 3 astrocytoma was treated with a combination of temozolomide and the vascular endothelial growth factor monoclonal antibody bevacizumab. After two biweekly treatments, he developed nephrotic syndrome. Despite cessation of bevacizumab, his renal function deteriorated and a renal biopsy disclosed MCD. Thereafter, he was started on high-dose oral prednisone and renal function immediately improved. Within weeks, the nephrotic syndrome resolved. Although rare, biologic agents can cause various glomerulopathies that can have important therapeutic implications. MCD should be considered in patients who develop nephrotic syndrome while exposed to antiangiogenic agents.
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Affiliation(s)
- Ramy M Hanna
- Department of Medicine, Division of Nephrology, Cedars Sinai Medical Center-Office Towers, Los Angeles, CA, USA
| | - Eduardo Lopez
- Department of Nephrology, Kaiser Permanente, Panorama City, CA, USA
| | - James Wilson
- Surgical Consultative Nephrology, UCLA David Geffen School of Medicine, Director UCLA Stone Center, Los Angeles, CA, USA
| | - Shrinath Barathan
- Department of Medicine, Division of Nephrology, Cedars Sinai Medical Center-Office Towers, Los Angeles, CA, USA
| | - Arthur H Cohen
- Department of Pathology, Cedars Sinai Medical Center, Los Angeles, CA, USA
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Abstract
Glioblastoma, the most aggressive of the gliomas, has a high recurrence and mortality rate. The nature of this poor prognosis resides in the molecular heterogeneity and phenotypic features of this tumor. Despite research advances in understanding the molecular biology, it has been difficult to translate this knowledge into effective treatment. Nearly all will have tumor recurrence, yet to date very few therapies have established efficacy as salvage regimens. This challenge is further complicated by imaging confounders and to an even greater degree by the ever increasing molecular heterogeneity that is thought to be both sporadic and treatment-induced. The development of novel clinical trial designs to support the development and testing of novel treatment regimens and drug delivery strategies underscore the need for more precise techniques in imaging and better surrogate markers to help determine treatment response. This review summarizes recent approaches to treat patients with recurrent glioblastoma and considers future perspectives.
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Affiliation(s)
- Carlos Kamiya-Matsuoka
- Department of Neuro-Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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19
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Heiland DH, Masalha W, Franco P, Machein MR, Weyerbrock A. Progression-free and overall survival in patients with recurrent Glioblastoma multiforme treated with last-line bevacizumab versus bevacizumab/lomustine. J Neurooncol 2015; 126:567-75. [PMID: 26614518 DOI: 10.1007/s11060-015-2002-z] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2015] [Accepted: 11/19/2015] [Indexed: 10/22/2022]
Abstract
Bevacizumab (BEV) is widely used for treatment of patients with recurrent glioblastoma multiforme (GBM). 1-(2-Chlorethyl)-cyclohexyl-nitrosourea (CCNU, lomustine) monotherapy is an approved chemotherapeutical option for recurrent GBM. Recent evidence demonstrated a survival benefit of combined treatment with BEV and CCNU in patients with a first recurrence of GBM. We examined the outcome of recurrent GBM patients with BEV monotherapy versus BEV/CCNU therapy when used as last-line therapy. 35 patients with recurrent GBM treated between 2010 and 2014 were included in this retrospective study. Progression-free and overall survival was determined with reference to the beginning of BEV or BEV/CCNU therapy and initial diagnosis. 17 patients received BEV monotherapy, 18 patients received combined BEV and CCNU therapy. The impact of parameters such as IDH mutation, MGMT promoter methylation, tumor localization, histology and the number of surgeries were included in a multivariate ANOVA analysis. Furthermore, Karnofsky performance score (KPS), neurological function and toxicity were assessed. BEV/CCNU treatment led to an extension of PFS (6.11 months; 95% CL 3.41-12.98 months; log-rank p = 0.00241) and OS (6.59 months; 95% CL 5.51-16.3 months; log-rank p = 0.0238) of 2 months compared to BEV monotherapy. This survival advantage was independent of histology, IDH mutation status or the number of previous surgeries. Neurological function, KPS and toxicity were not significantly different between both treatment groups. Last-line therapy with BEV/CCNU results in a longer PFS and OS compared to BEV monotherapy and is well-tolerated. These findings confirm the role of these agents in the treatment of recurrent GBM and are in line with other studies.
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Affiliation(s)
- D H Heiland
- Department of Neurosurgery, Medical Center - University of Freiburg, BreisacherStrasse 64, 79106, Freiburg, Germany
| | - W Masalha
- Department of Neurosurgery, Medical Center - University of Freiburg, BreisacherStrasse 64, 79106, Freiburg, Germany
| | - P Franco
- Department of Neurosurgery, Medical Center - University of Freiburg, BreisacherStrasse 64, 79106, Freiburg, Germany
| | - M R Machein
- Department of Neurosurgery, Medical Center - University of Freiburg, BreisacherStrasse 64, 79106, Freiburg, Germany
| | - A Weyerbrock
- Department of Neurosurgery, Medical Center - University of Freiburg, BreisacherStrasse 64, 79106, Freiburg, Germany.
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20
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Field KM, Simes J, Nowak AK, Cher L, Wheeler H, Hovey EJ, Brown CSB, Barnes EH, Sawkins K, Livingstone A, Freilich R, Phal PM, Fitt G, Rosenthal MA. Randomized phase 2 study of carboplatin and bevacizumab in recurrent glioblastoma. Neuro Oncol 2015; 17:1504-13. [PMID: 26130744 DOI: 10.1093/neuonc/nov104] [Citation(s) in RCA: 112] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2015] [Accepted: 05/24/2015] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND The optimal use of bevacizumab in recurrent glioblastoma (GBM), including the choice of monotherapy or combination therapy, remains uncertain. The purpose of this study was to compare combination therapy with bevacizumab monotherapy. METHODS This was a 2-part randomized phase 2 study. Eligibility criteria included recurrent GBM after radiotherapy and temozolomide, no other chemotherapy for GBM, and Eastern Cooperative Oncology Group performance status 0-2. The primary objective (Part 1) was to determine the effect of bevacizumab plus carboplatin versus bevacizumab monotherapy on progression-free survival (PFS) using modified Response Assessment in Neuro-Oncology criteria. Bevacizumab was given every 2 weeks, 10 mg/kg; and carboplatin every 4 weeks, (AUC 5). On progression, patients able to continue were randomized to continue or cease bevacizumab (Part 2). Secondary endpoints included objective radiological response rate (ORR), quality of life, toxicity, and overall survival (OS). RESULTS One hundred twenty-two patients (median age, 55y) were enrolled to Part 1 from 18 Australian sites. Median follow-up was 32 months, and median on-treatment time was 3.3 months. Median PFS was 3.5 months for each arm (hazard ratio [HR]: 0.92, 95% CI: 0.64-1.33, P = .66). ORR was 14% (combination) versus 6% (monotherapy) (P = .18). Median OS was 6.9 (combination) versus 7.5 months (monotherapy) (HR: 1.18, 95% CI: 0.82-1.69, P = .38). The incidence of bevacizumab-related adverse events was similar to prior literature, with no new toxicity signals. Toxicities were higher in the combination arm. Part 2 data (n = 48) will be reported separately. CONCLUSIONS Adding carboplatin resulted in more toxicity without additional clinical benefit. Clinical outcomes in patients with recurrent GBM treated with bevacizumab were inferior to those in previously reported studies. CLINICAL TRIALS REGISTRATION NR ACTRN12610000915055.
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Affiliation(s)
- Kathryn M Field
- Royal Melbourne Hospital, Parkville, Australia (K.M.F, P.M.P, M.A.R.), National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia (J.S., C.S.B.B., E.H.B, K.S., A.L.); Sir Charles Gairdner Hospital, Nedlands, Australia (A.K.N); School of Medicine and Pharmacology, University of Western Australia, Crawley, Australia (A.K.N); Austin Health, Heidelberg, Australia (L.C., G.F.); Royal North Shore Hospital, St Leonards, Australia (H.W.); Prince of Wales Hospital, Randwick, Australia (E.J.H); University of New South Wales, Sydney, Australia (E.J.H); Monash Medical Centre, Clayton, Australia (R.F.); Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Australia (P.M.P., M.A.R., G.F.)
| | - John Simes
- Royal Melbourne Hospital, Parkville, Australia (K.M.F, P.M.P, M.A.R.), National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia (J.S., C.S.B.B., E.H.B, K.S., A.L.); Sir Charles Gairdner Hospital, Nedlands, Australia (A.K.N); School of Medicine and Pharmacology, University of Western Australia, Crawley, Australia (A.K.N); Austin Health, Heidelberg, Australia (L.C., G.F.); Royal North Shore Hospital, St Leonards, Australia (H.W.); Prince of Wales Hospital, Randwick, Australia (E.J.H); University of New South Wales, Sydney, Australia (E.J.H); Monash Medical Centre, Clayton, Australia (R.F.); Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Australia (P.M.P., M.A.R., G.F.)
| | - Anna K Nowak
- Royal Melbourne Hospital, Parkville, Australia (K.M.F, P.M.P, M.A.R.), National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia (J.S., C.S.B.B., E.H.B, K.S., A.L.); Sir Charles Gairdner Hospital, Nedlands, Australia (A.K.N); School of Medicine and Pharmacology, University of Western Australia, Crawley, Australia (A.K.N); Austin Health, Heidelberg, Australia (L.C., G.F.); Royal North Shore Hospital, St Leonards, Australia (H.W.); Prince of Wales Hospital, Randwick, Australia (E.J.H); University of New South Wales, Sydney, Australia (E.J.H); Monash Medical Centre, Clayton, Australia (R.F.); Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Australia (P.M.P., M.A.R., G.F.)
| | - Lawrence Cher
- Royal Melbourne Hospital, Parkville, Australia (K.M.F, P.M.P, M.A.R.), National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia (J.S., C.S.B.B., E.H.B, K.S., A.L.); Sir Charles Gairdner Hospital, Nedlands, Australia (A.K.N); School of Medicine and Pharmacology, University of Western Australia, Crawley, Australia (A.K.N); Austin Health, Heidelberg, Australia (L.C., G.F.); Royal North Shore Hospital, St Leonards, Australia (H.W.); Prince of Wales Hospital, Randwick, Australia (E.J.H); University of New South Wales, Sydney, Australia (E.J.H); Monash Medical Centre, Clayton, Australia (R.F.); Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Australia (P.M.P., M.A.R., G.F.)
| | - Helen Wheeler
- Royal Melbourne Hospital, Parkville, Australia (K.M.F, P.M.P, M.A.R.), National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia (J.S., C.S.B.B., E.H.B, K.S., A.L.); Sir Charles Gairdner Hospital, Nedlands, Australia (A.K.N); School of Medicine and Pharmacology, University of Western Australia, Crawley, Australia (A.K.N); Austin Health, Heidelberg, Australia (L.C., G.F.); Royal North Shore Hospital, St Leonards, Australia (H.W.); Prince of Wales Hospital, Randwick, Australia (E.J.H); University of New South Wales, Sydney, Australia (E.J.H); Monash Medical Centre, Clayton, Australia (R.F.); Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Australia (P.M.P., M.A.R., G.F.)
| | - Elizabeth J Hovey
- Royal Melbourne Hospital, Parkville, Australia (K.M.F, P.M.P, M.A.R.), National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia (J.S., C.S.B.B., E.H.B, K.S., A.L.); Sir Charles Gairdner Hospital, Nedlands, Australia (A.K.N); School of Medicine and Pharmacology, University of Western Australia, Crawley, Australia (A.K.N); Austin Health, Heidelberg, Australia (L.C., G.F.); Royal North Shore Hospital, St Leonards, Australia (H.W.); Prince of Wales Hospital, Randwick, Australia (E.J.H); University of New South Wales, Sydney, Australia (E.J.H); Monash Medical Centre, Clayton, Australia (R.F.); Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Australia (P.M.P., M.A.R., G.F.)
| | - Christopher S B Brown
- Royal Melbourne Hospital, Parkville, Australia (K.M.F, P.M.P, M.A.R.), National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia (J.S., C.S.B.B., E.H.B, K.S., A.L.); Sir Charles Gairdner Hospital, Nedlands, Australia (A.K.N); School of Medicine and Pharmacology, University of Western Australia, Crawley, Australia (A.K.N); Austin Health, Heidelberg, Australia (L.C., G.F.); Royal North Shore Hospital, St Leonards, Australia (H.W.); Prince of Wales Hospital, Randwick, Australia (E.J.H); University of New South Wales, Sydney, Australia (E.J.H); Monash Medical Centre, Clayton, Australia (R.F.); Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Australia (P.M.P., M.A.R., G.F.)
| | - Elizabeth H Barnes
- Royal Melbourne Hospital, Parkville, Australia (K.M.F, P.M.P, M.A.R.), National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia (J.S., C.S.B.B., E.H.B, K.S., A.L.); Sir Charles Gairdner Hospital, Nedlands, Australia (A.K.N); School of Medicine and Pharmacology, University of Western Australia, Crawley, Australia (A.K.N); Austin Health, Heidelberg, Australia (L.C., G.F.); Royal North Shore Hospital, St Leonards, Australia (H.W.); Prince of Wales Hospital, Randwick, Australia (E.J.H); University of New South Wales, Sydney, Australia (E.J.H); Monash Medical Centre, Clayton, Australia (R.F.); Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Australia (P.M.P., M.A.R., G.F.)
| | - Kate Sawkins
- Royal Melbourne Hospital, Parkville, Australia (K.M.F, P.M.P, M.A.R.), National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia (J.S., C.S.B.B., E.H.B, K.S., A.L.); Sir Charles Gairdner Hospital, Nedlands, Australia (A.K.N); School of Medicine and Pharmacology, University of Western Australia, Crawley, Australia (A.K.N); Austin Health, Heidelberg, Australia (L.C., G.F.); Royal North Shore Hospital, St Leonards, Australia (H.W.); Prince of Wales Hospital, Randwick, Australia (E.J.H); University of New South Wales, Sydney, Australia (E.J.H); Monash Medical Centre, Clayton, Australia (R.F.); Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Australia (P.M.P., M.A.R., G.F.)
| | - Ann Livingstone
- Royal Melbourne Hospital, Parkville, Australia (K.M.F, P.M.P, M.A.R.), National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia (J.S., C.S.B.B., E.H.B, K.S., A.L.); Sir Charles Gairdner Hospital, Nedlands, Australia (A.K.N); School of Medicine and Pharmacology, University of Western Australia, Crawley, Australia (A.K.N); Austin Health, Heidelberg, Australia (L.C., G.F.); Royal North Shore Hospital, St Leonards, Australia (H.W.); Prince of Wales Hospital, Randwick, Australia (E.J.H); University of New South Wales, Sydney, Australia (E.J.H); Monash Medical Centre, Clayton, Australia (R.F.); Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Australia (P.M.P., M.A.R., G.F.)
| | - Ron Freilich
- Royal Melbourne Hospital, Parkville, Australia (K.M.F, P.M.P, M.A.R.), National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia (J.S., C.S.B.B., E.H.B, K.S., A.L.); Sir Charles Gairdner Hospital, Nedlands, Australia (A.K.N); School of Medicine and Pharmacology, University of Western Australia, Crawley, Australia (A.K.N); Austin Health, Heidelberg, Australia (L.C., G.F.); Royal North Shore Hospital, St Leonards, Australia (H.W.); Prince of Wales Hospital, Randwick, Australia (E.J.H); University of New South Wales, Sydney, Australia (E.J.H); Monash Medical Centre, Clayton, Australia (R.F.); Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Australia (P.M.P., M.A.R., G.F.)
| | - Pramit M Phal
- Royal Melbourne Hospital, Parkville, Australia (K.M.F, P.M.P, M.A.R.), National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia (J.S., C.S.B.B., E.H.B, K.S., A.L.); Sir Charles Gairdner Hospital, Nedlands, Australia (A.K.N); School of Medicine and Pharmacology, University of Western Australia, Crawley, Australia (A.K.N); Austin Health, Heidelberg, Australia (L.C., G.F.); Royal North Shore Hospital, St Leonards, Australia (H.W.); Prince of Wales Hospital, Randwick, Australia (E.J.H); University of New South Wales, Sydney, Australia (E.J.H); Monash Medical Centre, Clayton, Australia (R.F.); Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Australia (P.M.P., M.A.R., G.F.)
| | - Greg Fitt
- Royal Melbourne Hospital, Parkville, Australia (K.M.F, P.M.P, M.A.R.), National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia (J.S., C.S.B.B., E.H.B, K.S., A.L.); Sir Charles Gairdner Hospital, Nedlands, Australia (A.K.N); School of Medicine and Pharmacology, University of Western Australia, Crawley, Australia (A.K.N); Austin Health, Heidelberg, Australia (L.C., G.F.); Royal North Shore Hospital, St Leonards, Australia (H.W.); Prince of Wales Hospital, Randwick, Australia (E.J.H); University of New South Wales, Sydney, Australia (E.J.H); Monash Medical Centre, Clayton, Australia (R.F.); Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Australia (P.M.P., M.A.R., G.F.)
| | | | - Mark A Rosenthal
- Royal Melbourne Hospital, Parkville, Australia (K.M.F, P.M.P, M.A.R.), National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia (J.S., C.S.B.B., E.H.B, K.S., A.L.); Sir Charles Gairdner Hospital, Nedlands, Australia (A.K.N); School of Medicine and Pharmacology, University of Western Australia, Crawley, Australia (A.K.N); Austin Health, Heidelberg, Australia (L.C., G.F.); Royal North Shore Hospital, St Leonards, Australia (H.W.); Prince of Wales Hospital, Randwick, Australia (E.J.H); University of New South Wales, Sydney, Australia (E.J.H); Monash Medical Centre, Clayton, Australia (R.F.); Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Australia (P.M.P., M.A.R., G.F.)
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Abstract
In almost all patients, malignant glioma recurs following initial treatment with maximal safe resection, conformal radiotherapy, and temozolomide. This review describes the many options for treatment of recurrent malignant gliomas, including reoperation, alternating electric field therapy, chemotherapy, stereotactic radiotherapy or radiosurgery, or some combination of these modalities, presenting the evidence for each approach. No standard of care has been established, though the antiangiogenic agent, bevacizumab; stereotactic radiotherapy or radiosurgery; and, perhaps, combined treatment with these 2 modalities appear to offer modest benefits over other approaches. Clearly, randomized trials of these options would be advantageous, and novel, more efficacious approaches are urgently needed.
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Affiliation(s)
- John P Kirkpatrick
- Department of Radiation Oncology, Duke Cancer Institute, Durham, NC; Department of Surgery, Duke Cancer Institute, Durham, NC.
| | - John H Sampson
- Department of Radiation Oncology, Duke Cancer Institute, Durham, NC; Department of Surgery, Duke Cancer Institute, Durham, NC
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Field KM, Jordan JT, Wen PY, Rosenthal MA, Reardon DA. Bevacizumab and glioblastoma: Scientific review, newly reported updates, and ongoing controversies. Cancer 2015; 121:997-1007. [DOI: 10.1002/cncr.28935] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
Affiliation(s)
- Kathryn M. Field
- Department of Medical Oncology; Royal Melbourne Hospital; Melbourne Victoria Australia
| | - Justin T. Jordan
- Center for Neuro-Oncology; Dana-Farber Cancer Institute; Boston Massachusetts
| | - Patrick Y. Wen
- Center for Neuro-Oncology; Dana-Farber Cancer Institute; Boston Massachusetts
| | - Mark A. Rosenthal
- Department of Medical Oncology; Royal Melbourne Hospital; Melbourne Victoria Australia
| | - David A. Reardon
- Center for Neuro-Oncology; Dana-Farber Cancer Institute; Boston Massachusetts
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23
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Rhun EL, Taillibert S, Chamberlain MC. The future of high-grade glioma: Where we are and where are we going. Surg Neurol Int 2015; 6:S9-S44. [PMID: 25722939 PMCID: PMC4338495 DOI: 10.4103/2152-7806.151331] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2014] [Accepted: 10/15/2014] [Indexed: 01/12/2023] Open
Abstract
High-grade glioma (HGG) are optimally treated with maximum safe surgery, followed by radiotherapy (RT) and/or systemic chemotherapy (CT). Recently, the treatment of newly diagnosed anaplastic glioma (AG) has changed, particularly in patients with 1p19q codeleted tumors. Results of trials currenlty ongoing are likely to determine the best standard of care for patients with noncodeleted AG tumors. Trials in AG illustrate the importance of molecular characterization, which are germane to both prognosis and treatment. In contrast, efforts to improve the current standard of care of newly diagnosed glioblastoma (GB) with, for example, the addition of bevacizumab (BEV), have been largely disappointing and furthermore molecular characterization has not changed therapy except in elderly patients. Novel approaches, such as vaccine-based immunotherapy, for newly diagnosed GB are currently being pursued in multiple clinical trials. Recurrent disease, an event inevitable in nearly all patients with HGG, continues to be a challenge. Both recurrent GB and AG are managed in similar manner and when feasible re-resection is often suggested notwithstanding limited data to suggest benefit from repeat surgery. Occassional patients may be candidates for re-irradiation but again there is a paucity of data to commend this therapy and only a minority of selected patients are eligible for this approach. Consequently systemic therapy continues to be the most often utilized treatment in recurrent HGG. Choice of therapy, however, varies and revolves around re-challenge with temozolomide (TMZ), use of a nitrosourea (most often lomustine; CCNU) or BEV, the most frequently used angiogenic inhibitor. Nevertheless, no clear standard recommendation regarding the prefered agent or combination of agents is avaliable. Prognosis after progression of a HGG remains poor, with an unmet need to improve therapy.
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Affiliation(s)
- Emilie Le Rhun
- Department of Neuro-oncology, Roger Salengro Hospital, University Hospital, Lille, and Neurology, Department of Medical Oncology, Oscar Lambret Center, Lille, France, Inserm U-1192, Laboratoire de Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM), Lille 1 University, Villeneuve D’Ascq, France
| | - Sophie Taillibert
- Neurology, Mazarin and Radiation Oncology, Pitié Salpétrière Hospital, University Pierre et Marie Curie, Paris VI, Paris, France
| | - Marc C. Chamberlain
- Department of Neurology and Neurological Surgery, University of Washington, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
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The added value of bevacizumab concomitantly administered with carboplatin versus carboplatin alone in patients with recurrent glioblastomas. TUMORI JOURNAL 2015; 101:41-5. [PMID: 25702676 DOI: 10.5301/tj.5000210] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/28/2014] [Indexed: 11/20/2022]
Abstract
AIMS AND BACKGROUND Carboplatin (CBDCA) and bevacizumab (BEV) are active in glioblastoma (GBM) with different profiles of toxicity. To date, no study has compared the value of the addition of BEV to historical or traditional cytotoxic chemotherapy. We sought to determine the relative value of BEV in combination with CBDCA versus CBDCA alone in patients with recurrent GBM. METHODS AND STUDY DESIGN Eligible patients with progressive GBM following surgery, radiotherapy and temozolomide received CBDCA either alone (group 1, n = 25) or in combination with BEV (group 2, n = 23) at 5 mg/kg once every 3 weeks between June 2010 and December 2013. Baseline characteristics and outcomes after treatment were recorded. The primary end points of this retrospective analysis were progression-free survival (PFS) and objective response rate. Secondary end points included safety and overall survival (OS). RESULTS Forty-eight patients were enrolled. The median number of cycles was 4 in group 1 and 6 in group 2. No toxicities or intracerebral bleeding were observed. The objective response rate was higher in group 2 than group 1, 66% vs 24% (p = 0.003). The estimated median PFS and OS were 3.1 vs 6.7 months (p<0.0001) and 6.1 vs 8.6 months (p = 0.09) in group 1 vs group 2, respectively. CONCLUSIONS The combination of BEV and CBDCA is associated with improved response rates and survival compared with CBDCA alone. These results highlight the value of BEV in recurrent GBM. However, the clinical benefit of this interesting approach needs validation in a larger patient cohort.
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Arakawa Y, Mizowaki T, Murata D, Fujimoto K, Kikuchi T, Kunieda T, Takahashi JC, Takagi Y, Miyamoto S. Retrospective analysis of bevacizumab in combination with ifosfamide, carboplatin, and etoposide in patients with second recurrence of glioblastoma. Neurol Med Chir (Tokyo) 2013; 53:779-85. [PMID: 24140770 PMCID: PMC4508722 DOI: 10.2176/nmc.oa2013-0211] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Bevacizumab has been reported to be effective for recurrent glioblastoma. In our hospital, ifosfamide, carboplatin, etoposide (ICE) is the second-line chemotherapy for first recurrence of glioblastoma after temozolomide failure. In the present analysis, we retrospectively investigated the feasibility and effectiveness of bevacizumab combined with ICE in patients with glioblastoma at second relapse during ICE treatment. Between 2010 and 2012, tumor progressions were diagnosed in consecutive 8 patients who were treated with ICE for the first recurrence of glioblastoma. These patients were administered 3 cycles of 10 mg/kg bevacizumab every two weeks in combination with ICE treatment. The objective response rate of bevacizumab combination was 75% in Neuro-Oncology Working Group (RANO criteria), including complete response and partial response. Median progression free survival (PFS) and median overall survival (OS) after second relapse were 3.7 months (95% confidence interval [CI], 2.5–18.5 months) and 6.0 months (95% CI, 3.2–19.7 months), respectively. The 6-month PFS rates were 25% (95% CI, 0–55.0%). The median OS after initial diagnosis was 23.3 months (95% CI, 16.2–55.8 months). The grade 2 or 3 hematologic adverse events were identified in 7 of 8 patients, most of which might be due to ICE chemotherapy. The results of our retrospective analysis suggest that combination treatment with bevacizumab and ICE may be safe and beneficial in patients with recurrent glioblastoma.
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Affiliation(s)
- Yoshiki Arakawa
- Department of Neurosurgery, Kyoto University Graduate School of Medicine
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Andria B, Auriemma L, Attanasio C, Cozzolino S, Cristinziano A, Zeuli L, Mancini A. The impact of innovation for biotech drugs: an Italian analysis of products licensed in Europe between 2004 and 2011. Eur J Hosp Pharm 2013. [DOI: 10.1136/ejhpharm-2013-000293] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
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Rinne ML, Lee EQ, Nayak L, Norden AD, Beroukhim R, Wen PY, Reardon DA. Update on bevacizumab and other angiogenesis inhibitors for brain cancer. Expert Opin Emerg Drugs 2013; 18:137-53. [PMID: 23668489 DOI: 10.1517/14728214.2013.794784] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
INTRODUCTION Primary and metastatic brain tumors remain a major challenge. The most common primary adult malignant brain tumor, glioblastoma (GBM), confers a dismal prognosis as does the development of CNS metastases for most systemic malignancies. Anti-angiogenic therapy has been a major clinical research focus in neuro-oncology over the past 5 years. AREAS COVERED Culmination of this work includes US FDA accelerated approval of bevacizumab for recurrent GBM and the completion of two placebo-controlled Phase III studies of bevacizumab for newly diagnosed GBM. A multitude of anti-angiogenics are in evaluation for neuro-oncology patients but none has thus far surpassed the therapeutic benefit of bevacizumab. EXPERT OPINION These agents demonstrate adequate safety and the majority of GBM patients derive benefit. Furthermore, their anti-permeability effect can substantially decrease tumor-associated edema leading to stable or improved neurologic function and quality of life. In particular, anti-angiogenics significantly prolong progression-free survival - a noteworthy achievement in the context of infiltrative and destructive brain tumors like GBM; however, in a manner analogous to other cancers, their impact on overall survival for GBM patients is modest at best. Despite substantial clinical research efforts, many fundamental questions regarding anti-angiogenic agents in brain tumor patients remain unanswered.
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Affiliation(s)
- Mikael L Rinne
- Dana-Farber/Brigham and Women's Cancer Center, Center for Neuro-Oncology, Boston, MA, USA
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