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Angerstein AO, Young LEA, Thanasupawat T, Vriend J, Grimsley G, Lun X, Senger DL, Sinha N, Beiko J, Pitz M, Hombach-Klonisch S, Drake RR, Klonisch T. Distinct spatial N-glycan profiles reveal glioblastoma-specific signatures. J Pathol 2025; 265:486-501. [PMID: 39967571 DOI: 10.1002/path.6401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 11/21/2024] [Accepted: 12/24/2024] [Indexed: 02/20/2025]
Abstract
This study explored the complex interactions between glycosylation patterns, tumour biology, and therapeutic responses to temozolomide (TMZ) in human malignant glioma, specifically CNS WHO grade 3 oligodendroglioma (ODG) and glioblastoma (GB). Using spatial imaging of N-glycans in formalin-fixed paraffin-embedded (FFPE) tissue sections via MALDI-MSI, we analysed the N-glycome in primary and recurrent GB tissues and orthotopic xenografts of patient-derived brain tumour-initiating cells (BTIC) sensitive or resistant to TMZ. We identified unique N-glycosylation profiles, with nontumor brain (NTB) and ODG showing higher levels of bisecting and tri-antennary structures, while GB exhibited more tetra-antennary and sialylated N-glycans. Distinctive sialylation patterns were observed, with specific α2,6 and α2,3 isomeric linkages significantly altered in GB. Moreover, comparative analysis of primary and recurrent GB tissues revealed elevated high mannose N-glycans in primary GB and fucosylated bi- and tri-antennary N-glycans in recurrent GB tissues. Next, in the orthotopic xenografts of TMZ-sensitive and TMZ-resistant patient brain tumour initiating cells (BTIC), we identified potential N-glycan markers for TMZ treatment response and resistance. Finally, we found significantly altered expression of genes involved in N-glycan biosynthesis in malignant glioma, highlighting the crucial role of N-glycans in glioma and therapy resistance. This study lays the foundation for developing glycosylation-based diagnostic biomarkers and targeted therapies, potentially improving clinical outcomes for GB patients. © 2025 The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Aaron O Angerstein
- Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, USA
| | - Lyndsay E A Young
- Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, USA
| | - Thatchawan Thanasupawat
- Department of Human Anatomy and Cell Science, University of Manitoba, Rady Faculty of Health Sciences, Max Rady College of Medicine, Winnipeg, MB, Canada
| | - Jerry Vriend
- Department of Human Anatomy and Cell Science, University of Manitoba, Rady Faculty of Health Sciences, Max Rady College of Medicine, Winnipeg, MB, Canada
| | - Grace Grimsley
- Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, USA
| | - Xueqing Lun
- Cumming School of Medicine, Arnie Charbonneau Cancer Institute, Calgary, AB, Canada
| | - Donna L Senger
- Cumming School of Medicine, Arnie Charbonneau Cancer Institute, Calgary, AB, Canada
- Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- Gerald Bronfman Department of Oncology, McGill University, Montreal, QC, Canada
- Lady Davis Institute for Medical Research, Montreal, QC, Canada
| | - Namita Sinha
- Department of Pathology, University of Manitoba, Rady Faculty of Health Sciences, Max Rady College of Medicine, Winnipeg, MB, Canada
| | - Jason Beiko
- Department of Surgery, University of Manitoba, Rady Faculty of Health Sciences, Max Rady College of Medicine, Winnipeg, MB, Canada
| | - Marshall Pitz
- Department of Internal Medicine, University of Manitoba, Rady Faculty of Health Sciences, Max Rady College of Medicine, Winnipeg, MB, Canada
- Paul Albrechtsen Research Institute CancerCare Manitoba, Winnipeg, MB, Canada
| | - Sabine Hombach-Klonisch
- Department of Human Anatomy and Cell Science, University of Manitoba, Rady Faculty of Health Sciences, Max Rady College of Medicine, Winnipeg, MB, Canada
- Department of Pathology, University of Manitoba, Rady Faculty of Health Sciences, Max Rady College of Medicine, Winnipeg, MB, Canada
| | - Richard R Drake
- Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, USA
| | - Thomas Klonisch
- Department of Human Anatomy and Cell Science, University of Manitoba, Rady Faculty of Health Sciences, Max Rady College of Medicine, Winnipeg, MB, Canada
- Department of Pathology, University of Manitoba, Rady Faculty of Health Sciences, Max Rady College of Medicine, Winnipeg, MB, Canada
- Paul Albrechtsen Research Institute CancerCare Manitoba, Winnipeg, MB, Canada
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Jiang J, Xu J, Ji S, Yu X, Chen J. Unraveling the mysteries of MGMT: Implications for neuroendocrine tumors. Biochim Biophys Acta Rev Cancer 2024; 1879:189184. [PMID: 39303858 DOI: 10.1016/j.bbcan.2024.189184] [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: 01/28/2024] [Revised: 07/15/2024] [Accepted: 09/16/2024] [Indexed: 09/22/2024]
Abstract
Neuroendocrine tumors (NETs) are a diverse group of tumors that arise from neuroendocrine cells and are commonly found in various organs. A considerable proportion of NET patients were diagnosed at an advanced or metastatic stage. Alkylating agents are the primary treatment for NET, and O6-methylguanine methyltransferase (MGMT) remains the first-line of defense against DNA damage caused by these agents. Clinical trials have indicated that MGMT promoter methylation or its low/lacked expression can predict a favorable outcome with Temozolomide in NETs. Its status could help select NET patients who can benefit from alkylating agents. Therefore, MGMT status serves as a biomarker to guide decisions on the efficacy of Temozolomide as a personalized treatment option. Additionally, delving into the regulatory mechanisms of MGMT status can lead to the development of MGMT-targeted therapies, benefiting individuals with high levels of MGMT expression. This review aims to explore the polymorphism of MGMT regulation and summarize its clinical implications in NETs, which would help establish the role of MGMT as a biomarker and its potential as a therapeutic target in NETs. Additionally, we explore the benefits of combining Temozolomide and immunotherapy in MGMT hypermethylated subgroups. Future studies can focus on optimizing Temozolomide administration to induce specific immunomodulatory changes.
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Affiliation(s)
- Jianyun Jiang
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
| | - Junfeng Xu
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China.
| | - Shunrong Ji
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China.
| | - Xianjun Yu
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China.
| | - Jie Chen
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
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Andrini E, Ricco G, Zappi A, Aloi S, Giordano M, Altimari A, Gruppioni E, Maloberti T, de Biase D, Campana D, Lamberti G. Challenges and future perspectives for the use of temozolomide in the treatment of SCLC. Cancer Treat Rev 2024; 129:102798. [PMID: 38970838 DOI: 10.1016/j.ctrv.2024.102798] [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: 04/14/2024] [Revised: 06/09/2024] [Accepted: 07/02/2024] [Indexed: 07/08/2024]
Abstract
Small-cell lung cancer (SCLC), accounting for 10-20 % of all lung tumors, represents the most aggressive high-grade neuroendocrine carcinoma. Most patients are diagnosed with extensive-stage SCLC (ES-SCLC), with brian metastases identified in ∼ 80 % of cases during the disease cours, and the prognosis is dismal, with a 5-year survival rate of less than 5 %. Current available treatments in the second-line setting are limited, and topotecan has long been the only FDA-approved drug in relapsed or refractory ES-SCLC, until the recent approval of lurbinectedin, a selective inhibitor of RNA polymerase II. Temozolomide (TMZ) is an oral alkylating agent, which showed single-agent activity in SCLC, particularly among patients with O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation. Several studies have revealed the synergistic activity of temozolomide with poly-ADP-ribose polymerase (PARP) inhibitors, that prevent repair of TMZ-induced DNA damage. This review focuses on the rationale for the use of TMZ in ES-SCLC and provides an overview of the main trials that have evaluated and are currently investigating its role, both as a single-agent and in combinations, in relapse or refractory disease.
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Affiliation(s)
- Elisa Andrini
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum, University of Bologna, 40126 Bologna, Italy.
| | - Gianluca Ricco
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy.
| | - Arianna Zappi
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy.
| | - Serena Aloi
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy.
| | - Mirela Giordano
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy.
| | - Annalisa Altimari
- Solid Tumor Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
| | - Elisa Gruppioni
- Solid Tumor Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
| | - Thais Maloberti
- Solid Tumor Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
| | - Dario de Biase
- Solid Tumor Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; Department of Pharmacy and Biotechnology (FaBit), University of Bologna, Bologna, Italy.
| | - Davide Campana
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum, University of Bologna, 40126 Bologna, Italy.
| | - Giuseppe Lamberti
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum, University of Bologna, 40126 Bologna, Italy.
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Malik JR, Podany AT, Khan P, Shaffer CL, Siddiqui JA, Baranowska‐Kortylewicz J, Le J, Fletcher CV, Ether SA, Avedissian SN. Chemotherapy in pediatric brain tumor and the challenge of the blood-brain barrier. Cancer Med 2023; 12:21075-21096. [PMID: 37997517 PMCID: PMC10726873 DOI: 10.1002/cam4.6647] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 09/18/2023] [Accepted: 10/12/2023] [Indexed: 11/25/2023] Open
Abstract
BACKGROUND Pediatric brain tumors (PBT) stand as the leading cause of cancer-related deaths in children. Chemoradiation protocols have improved survival rates, even for non-resectable tumors. Nonetheless, radiation therapy carries the risk of numerous adverse effects that can have long-lasting, detrimental effects on the quality of life for survivors. The pursuit of chemotherapeutics that could obviate the need for radiotherapy remains ongoing. Several anti-tumor agents, including sunitinib, valproic acid, carboplatin, and panobinostat, have shown effectiveness in various malignancies but have not proven effective in treating PBT. The presence of the blood-brain barrier (BBB) plays a pivotal role in maintaining suboptimal concentrations of anti-cancer drugs in the central nervous system (CNS). Ongoing research aims to modulate the integrity of the BBB to attain clinically effective drug concentrations in the CNS. However, current findings on the interaction of exogenous chemical agents with the BBB remain limited and do not provide a comprehensive explanation for the ineffectiveness of established anti-cancer drugs in PBT. METHODS We conducted our search for chemotherapeutic agents associated with the blood-brain barrier (BBB) using the following keywords: Chemotherapy in Cancer, Chemotherapy in Brain Cancer, Chemotherapy in PBT, BBB Inhibition of Drugs into CNS, Suboptimal Concentration of CNS Drugs, PBT Drugs and BBB, and Potential PBT Drugs. We reviewed each relevant article before compiling the information in our manuscript. For the generation of figures, we utilized BioRender software. FOCUS We focused our article search on chemical agents for PBT and subsequently investigated the role of the BBB in this context. Our search criteria included clinical trials, both randomized and non-randomized studies, preclinical research, review articles, and research papers. FINDING Our research suggests that, despite the availability of potent chemotherapeutic agents for several types of cancer, the effectiveness of these chemical agents in treating PBT has not been comprehensively explored. Additionally, there is a scarcity of studies examining the role of the BBB in the suboptimal outcomes of PBT treatment, despite the effectiveness of these drugs for other types of tumors.
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Affiliation(s)
- Johid Reza Malik
- Antiviral Pharmacology LaboratoryCollege of Pharmacy, University of Nebraska Medical CenterOmahaNebraskaUSA
| | - Anthony T. Podany
- Antiviral Pharmacology LaboratoryCollege of Pharmacy, University of Nebraska Medical CenterOmahaNebraskaUSA
- Pediatric Clinical Pharmacology ProgramChild Health Research Institute, University of Nebraska Medical CenterOmahaNebraskaUSA
| | - Parvez Khan
- Department of Biochemistry and Molecular BiologyUniversity of Nebraska Medical CenterOmahaNebraskaUSA
| | - Christopher L. Shaffer
- Pediatric Clinical Pharmacology ProgramChild Health Research Institute, University of Nebraska Medical CenterOmahaNebraskaUSA
| | - Jawed A. Siddiqui
- Department of Biochemistry and Molecular BiologyUniversity of Nebraska Medical CenterOmahaNebraskaUSA
| | | | - Jennifer Le
- University of California San Diego Skaggs School of Pharmacy and Pharmaceutical SciencesSan DiegoCaliforniaUSA
| | - Courtney V. Fletcher
- Antiviral Pharmacology LaboratoryCollege of Pharmacy, University of Nebraska Medical CenterOmahaNebraskaUSA
| | - Sadia Afruz Ether
- Antiviral Pharmacology LaboratoryCollege of Pharmacy, University of Nebraska Medical CenterOmahaNebraskaUSA
| | - Sean N. Avedissian
- Antiviral Pharmacology LaboratoryCollege of Pharmacy, University of Nebraska Medical CenterOmahaNebraskaUSA
- Pediatric Clinical Pharmacology ProgramChild Health Research Institute, University of Nebraska Medical CenterOmahaNebraskaUSA
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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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6
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Wu L, Wang L, Zou W, Yang J, Jia W, Xu Y. Primary spinal anaplastic ependymoma: A single-institute retrospective cohort and systematic review. Front Oncol 2023; 13:1083085. [PMID: 36824145 PMCID: PMC9941548 DOI: 10.3389/fonc.2023.1083085] [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: 10/28/2022] [Accepted: 01/25/2023] [Indexed: 02/10/2023] Open
Abstract
Objective Primary spinal anaplastic ependymoma (PSAE) is an extremely rare disease. We aim to report the largest PSAE cohort, evaluate the treatments, and investigate the prognostic factors for progression-free survival (PFS). Methods Clinical data collected from the authors' institute and literature articles were pooled and described. Survival analysis and multivariable Cox regression analysis were performed to evaluate therapies and investigate prognostic factors for PFS. Results Our cohort included 22 females and 16 males, with a median age of 33 years. PSAE developed mostly on cervical and cervicothoracic levels. The median length measured 3 segments. Half of PSAE were intramedullary. Pain was the most common symptom. The median duration of symptoms was 6 months. Neurological statuses were improved in 76% following treatments, whereas clinical tumor progression occurred in 41.7%. The estimated median progression-free survival was 132 months, and the estimated median survival was 192 months. The median Ki-67 index was 15%. Patients aged less than or equal to 25 experienced worse neurological statuses and more repeated progression. Age less than or equal to 25 (HR 10.312, 95%CI 1.535-69.260, p=0.016), gross total resection (HR 0.116, 95%CI 0.020-0.688, p=0.018), and radiotherapy (HR 0.084, 95%CI 0.009-0.804, p=0.032) are three prognostic factors for tumor progression. Conclusion Tumor progression remains a big concern in the clinical course of PSAE. Being aged above 25, undergoing GTR, and accepting adjuvant radiotherapy put patients at lower risk for tumor progression. Younger patients might have worse neurological statuses compared with those aged over 25.
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Affiliation(s)
- Liang Wu
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Li’ao Wang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Wanjing Zou
- Department of Pathology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Jun Yang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Wenqing Jia
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Yulun Xu
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China,*Correspondence: Yulun Xu,
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7
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Chen J, Wang T, Liu W, Qiu H, Zhang N, Chen X, Ding X, Zhang L. Extended adjuvant temozolomide in newly diagnosed glioblastoma: A single-center retrospective study. Front Oncol 2022; 12:1000501. [PMID: 36483042 PMCID: PMC9723160 DOI: 10.3389/fonc.2022.1000501] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Accepted: 11/02/2022] [Indexed: 12/23/2022] Open
Abstract
OBJECTIVE To investigate whether extending adjuvant temozolomide (TMZ) improved the prognosis of newly diagnosed glioblastoma (GBM) patients with different mutation statuses of O6-methylguanine DNA methyltransferase (MGMT), isocitrate dehydrogenase 1 (IDH1), p53 and different expression level of Ki67. METHODS This study was a retrospective cohort study that postoperative patients with newly diagnosed GBM who did not progress after receiving radiotherapy with concomitant and 6 cycles of adjuvant TMZ were enrolled in control group, and those received more than 6 cycles of adjuvant TMZ were incorporated in extended group. Patients were stratified by MGMT expression, IDH1 mutation, p53 mutation and expression level of Ki67. The primary endpoints were overall survival (OS) and progression-free survival (PFS). RESULT A total of 93 postoperative patients with newly diagnosed GBM were included in this study, 40 and 53 cases were included in control group and extended group, respectively. On the whole, extended adjuvant TMZ chemotherapy significantly prolonged OS and PFS of patients with newly diagnosed GBM [median OS (mOS): 29.00 months vs. 16.70 months, P < 0.001; median PFS (mPFS): 13.80 months vs. 9.60 months, P = 0.002]. The results of subgroup analysis showed that patients with methylated MGMT in extended group had significantly longer OS and PFS than those in control group; patients with IDH1 mutation benefited more from extended adjuvant TMZ chemotherapy than those with wild-type IDH1; there was no significant difference in the effect of extended TMZ chemotherapy on OS between GBM patients with wild-type p53 and those with mutant p53; compared with GBM patients with lower expression of Ki67, extended adjuvant TMZ treatment dramatically improved the OS and PFS of those with higher expression of Ki67. CONCLUSION The therapeutic schedule of extended adjuvant TMZ significantly prolonged OS and PFS of patients with newly diagnosed GBM regardless of p53 mutation status, and patients with different MGMT methylation, IDH1 mutation and Ki67 expression level benefited differently from extended adjuvant TMZ chemotherapy.
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Affiliation(s)
- Jie Chen
- Department of Radiation Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China,Cancer Center, Xuzhou Medical University, Xuzhou, China
| | - Tingting Wang
- First Clinical College, Xuzhou Medical University, Xuzhou, China
| | - Wanming Liu
- First Clinical College, Xuzhou Medical University, Xuzhou, China
| | - Hui Qiu
- Cancer Center, Xuzhou Medical University, Xuzhou, China
| | - Nie Zhang
- First Clinical College, Xuzhou Medical University, Xuzhou, China
| | - Xueting Chen
- First Clinical College, Xuzhou Medical University, Xuzhou, China
| | - Xin Ding
- Department of Radiation Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China,*Correspondence: Longzhen Zhang, ; Xin Ding,
| | - Longzhen Zhang
- Department of Radiation Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China,Cancer Center, Xuzhou Medical University, Xuzhou, China,*Correspondence: Longzhen Zhang, ; Xin Ding,
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Abstract
Glioblastoma is the most aggressive primary brain tumor with a poor prognosis. The 2021 WHO CNS5 classification has further stressed the importance of molecular signatures in diagnosis although therapeutic breakthroughs are still lacking. In this review article, updates on the current and novel therapies in IDH-wildtype GBM will be discussed.
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Affiliation(s)
- Jawad M Melhem
- Division of Neurology, Department of Medicine, Faculty of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Canada
| | - Jay Detsky
- Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Canada
| | - Mary Jane Lim-Fat
- Division of Neurology, Department of Medicine, Faculty of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Canada
| | - James R Perry
- Division of Neurology, Department of Medicine, Faculty of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Canada.
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9
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Alpuim Costa D, Sampaio-Alves M, Netto E, Fernandez G, Oliveira E, Teixeira A, Daniel PM, Bernardo GS, Amaro C. Hyperbaric Oxygen Therapy as a Complementary Treatment in Glioblastoma-A Scoping Review. Front Neurol 2022; 13:886603. [PMID: 35847231 PMCID: PMC9283648 DOI: 10.3389/fneur.2022.886603] [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: 02/28/2022] [Accepted: 05/24/2022] [Indexed: 11/13/2022] Open
Abstract
Glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults. The mainstay of management for GBM is surgical resection, radiation (RT), and chemotherapy (CT). Even with optimized multimodal treatment, GBM has a high recurrence and poor survival rates ranging from 12 to 24 months in most patients. Recently, relevant advances in understanding GBM pathophysiology have opened new avenues for therapies for recurrent and newly diagnosed diseases. GBM's hypoxic microenvironment has been shown to be highly associated with aggressive biology and resistance to RT and CT. Hyperbaric oxygen therapy (HBOT) may increase anticancer therapy sensitivity by increasing oxygen tension within the hypoxic regions of the neoplastic tissue. Previous data have investigated HBOT in combination with cytostatic compounds, with an improvement of neoplastic tissue oxygenation, inhibition of HIF-1α activity, and a significant reduction in the proliferation of GBM cells. The biological effect of ionizing radiation has been reported to be higher when it is delivered under well-oxygenated rather than anoxic conditions. Several hypoxia-targeting strategies reported that HBOT showed the most significant effect that could potentially improve RT outcomes, with higher response rates and survival and no serious adverse events. However, further prospective and randomized studies are necessary to validate HBOT's effectiveness in the 'real world' GBM clinical practice.
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Affiliation(s)
- Diogo Alpuim Costa
- Haematology and Oncology Department, CUF Oncologia, Lisbon, Portugal
- NOVA Medical School (NMS), Faculdade de Ciências Médicas (FCM), Lisbon, Portugal
- Faculty of Medicine, University of Lisbon, Lisbon, Portugal
- Centro de Medicina Subaquática e Hiperbárica, Azinhaga dos Ulmeiros, Lisbon, Portugal
- Centro Hiperbárico de Cascais, Cascais, Portugal
| | - Mafalda Sampaio-Alves
- Faculty of Medicine, University of Porto, Oporto, Portugal
- PTSurg – Portuguese Surgical Research Collaborative, Lisbon, Portugal
| | - Eduardo Netto
- Radioncology Department, Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), E.P.E., Lisbon, Portugal
| | | | - Edson Oliveira
- Faculty of Medicine, University of Lisbon, Lisbon, Portugal
- Neurosurgery Department, Cluster CUF Descobertas, Lisbon, Portugal
| | - Andreia Teixeira
- Faculty of Medicine, University of Lisbon, Lisbon, Portugal
- Centro de Medicina Subaquática e Hiperbárica, Azinhaga dos Ulmeiros, Lisbon, Portugal
| | - Pedro Modas Daniel
- Centro de Medicina Subaquática e Hiperbárica, Azinhaga dos Ulmeiros, Lisbon, Portugal
| | - Guilherme Silva Bernardo
- Faculty of Medicine, University of Lisbon, Lisbon, Portugal
- Centro de Medicina Subaquática e Hiperbárica, Azinhaga dos Ulmeiros, Lisbon, Portugal
- Urology Department, Hospital Professor Doutor Fernando Fonseca, Amadora, Portugal
| | - Carla Amaro
- Centro de Medicina Subaquática e Hiperbárica, Azinhaga dos Ulmeiros, Lisbon, Portugal
- Otorhinolaryngology Department, CUF Descobertas, Lisbon, Portugal
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Svec RL, McKee SA, Berry MR, Kelly AM, Fan TM, Hergenrother PJ. Novel Imidazotetrazine Evades Known Resistance Mechanisms and Is Effective against Temozolomide-Resistant Brain Cancer in Cell Culture. ACS Chem Biol 2022; 17:299-313. [PMID: 35119837 DOI: 10.1021/acschembio.2c00022] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Glioblastoma (GBM) is the most lethal primary brain tumor. Currently, frontline treatment for primary GBM includes the DNA-methylating drug temozolomide (TMZ, of the imidazotetrazine class), while the optimal treatment for recurrent GBM remains under investigation. Despite its widespread use, a majority of GBM patients do not respond to TMZ therapy; expression of the O6-methylguanine DNA methyltransferase (MGMT) enzyme and loss of mismatch repair (MMR) function as the principal clinical modes of resistance to TMZ. Here, we describe a novel imidazotetrazine designed to evade resistance by MGMT while retaining suitable hydrolytic stability, allowing for effective prodrug activation and biodistribution. This dual-substituted compound, called CPZ, exhibits activity against cancer cells irrespective of MGMT expression and MMR status. CPZ has greater blood-brain barrier penetrance and comparable hematological toxicity relative to TMZ, while also matching its maximum tolerated dose in mice when dosed once-per-day over five days. The activity of CPZ is independent of the two principal mechanisms suppressing the effectiveness of TMZ, making it a promising new candidate for the treatment of GBM, especially those that are TMZ-resistant.
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Affiliation(s)
- Riley L. Svec
- Department of Chemistry and Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States
| | - Sydney A. McKee
- Department of Chemistry and Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States
| | - Matthew R. Berry
- Department of Veterinary Clinical Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States
| | - Aya M. Kelly
- Department of Chemistry and Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States
| | - Timothy M. Fan
- Department of Veterinary Clinical Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States
- Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States
| | - Paul J. Hergenrother
- Department of Chemistry and Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States
- Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States
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11
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Liu D, Yang T, Ma W, Wang Y. Clinical strategies to manage adult glioblastoma patients without MGMT hypermethylation. J Cancer 2022; 13:354-363. [PMID: 34976195 PMCID: PMC8692679 DOI: 10.7150/jca.63595] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Accepted: 11/21/2021] [Indexed: 01/11/2023] Open
Abstract
Glioblastoma (GBM) is a highly malignant brain tumor with a dismal prognosis. Standard therapy for GBM comprises surgical resection, followed by radiotherapy plus concomitant and adjuvant temozolomide (TMZ) therapy. The methylation status of the O6-methylguanine DNA methyltransferase (MGMT) promoter is one of the most essential predictive biomarkers for patients with GBM treated with TMZ. Patients with an unmethylated MGMT promoter (umMGMT), who comprise 60% of patients with GBM, present an even worse prognosis because of TMZ resistance. Radiotherapy with various fractionation, chemotherapy compensating for TMZ, targeted therapy against diverse oncogenic pathways, immunotherapy of vaccine or immune checkpoint inhibitor, and tumor treating fields have been studied in umMGMT GBM patients. However, most efforts have yielded negative results or merely minimal improvements. Therefore, effective patient subgroup selection concerning precision medicine has become the focus. By assigning different treatments to the corresponding patient subgroups, a better curative effect and subsequently prolonged survival can be achieved. In this review, we re-evaluate the value of standard TMZ therapy and summarize the new clinical strategies and attempts to treat patients with umMGMT, which yielded positive and negative results, to provide alternative treatment options and discuss future directions of umMGMT GBM treatment.
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Affiliation(s)
- Delin Liu
- Department of Neurosurgery, Peking Union Medical College Hospital, Beijing, China
| | - Tianrui Yang
- Department of Neurosurgery, Peking Union Medical College Hospital, Beijing, China
| | - Wenbin Ma
- Department of Neurosurgery, Peking Union Medical College Hospital, Beijing, China
| | - Yu Wang
- Department of Neurosurgery, Peking Union Medical College Hospital, Beijing, China
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12
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Effect of long-term adjuvant temozolomide chemotherapy on primary glioblastoma patient survival. BMC Neurol 2021; 21:424. [PMID: 34724914 PMCID: PMC8561964 DOI: 10.1186/s12883-021-02461-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Accepted: 10/22/2021] [Indexed: 12/21/2022] Open
Abstract
Objective Glioblastoma multiforme (GBM) is the most common primary malignant central nervous system (CNS) tumor. The Stupp regimen is the standard treatment, although the optimal number of temozolomide (TMZ) treatment cycles remains controversial. We compared the effects of standard 6 cycles versus > 6 cycles of TMZ chemotherapy post-surgery with concurrent chemoradiotherapy on primary GBM patient survival. Patients and methods We performed a single center retrospective study of GBM patients that underwent total resection, concurrent chemoradiotherapy, and at least 6 cycles of adjuvant TMZ chemotherapy from June 2011 to August 2018. Patients were divided into 2 groups based on adjuvant TMZ treatment plan: Group A(n = 27): standard 6-cycle adjuvant TMZ therapy and Group B(n = 26): > 6 cycles of adjuvant TMZ therapy. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Continuous variables were analyzed by ANOVA, and the Kaplan-Meier method was used to evaluate PFS and OS. Univariate and multivariate COX analyses determined correlation between survival rates and covariates. We used The Mini Mental State Examination (MMSE) and Karnofsky Performance Status (KPS) to assess patients’ neurocognitive function and quality of life. Results After follow-up, median PFS was 15 months in in Group A (95%CI 9.5–20.5) and 20.1 months in Group B (95%CI 15.9–24.4). Group A median OS was 19.4 months (95%CI 15.5–23.2), compared to 25.6 months in Group B (95%CI 20.4–30.8). The 2-year survival rate of Groups A and B was 36% was 66%, respectively (P = 0.02). and 5-year survival was 7% in both. Multivariate COX regression analysis showed association between patient PFS and long-period adjuvant chemotherapy, but not OS. There were no significant difference in disability or quality of life during treatment with Stupp protocol, but differences in MMSE and KPS were in favour of the Groups B after year 1 of the treatment (P < 0.05). Conclusions Long-term adjuvant TMZ chemotherapy was beneficial for PFS and 2-year survival rate in GBM patients, and improved their quality of life contemporarily. But OS was not significantly improved.
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13
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Weathers SP, Rood-Breithaupt J, de Groot J, Thomas G, Manfrini M, Penas-Prado M, Puduvalli VK, Zwingelstein C, Yung WKA. Results of a phase I trial to assess the safety of macitentan in combination with temozolomide for the treatment of recurrent glioblastoma. Neurooncol Adv 2021; 3:vdab141. [PMID: 34693288 PMCID: PMC8528265 DOI: 10.1093/noajnl/vdab141] [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] [Indexed: 11/23/2022] Open
Abstract
Background There is an urgent need for additional therapies to treat recurrent glioblastoma (GBM). Preclinical studies suggest that high dose macitentan, an oral dual endothelin receptor antagonist, enhances the cytotoxic effects of temozolomide (TMZ) in GBM, improving survival. This phase I trial investigated the maximum tolerated dose of macitentan combined with TMZ in patients with recurrent GBM and assessed the safety and tolerability of high dose macitentan in these patients (NCT01499251). Methods Adults with recurrent GBM received ascending doses of macitentan from 30 mg once daily concomitantly with TMZ. Safety and tolerability were assessed in addition to exploratory efficacy and pharmacokinetic endpoints. An ancillary study examined biomarker expression following macitentan treatment prior to surgical resection of recurrent GBM. Results Thirty-eight patients with recurrent GBM were administered macitentan doses up to 300 mg once daily; no dose-limiting toxicities were observed, and a maximum tolerated dose was not determined. All patients experienced at least one treatment-emergent adverse event (TEAE), the majority associated with GBM or TMZ treatment. TEAEs related to macitentan and TMZ were reported for 16 (42.1%) and 26 (68.4%) patients, respectively, with no serious macitentan-related TEAEs. Macitentan concentrations increased with dose, with no plateau in exposure. Substantial heterogeneity was observed in the expression of efficacy biomarkers within tumors. The Kaplan-Meier estimate of median overall survival across all dose groups was 9.4 (95% CI 8.5, 13.4) months. Conclusion High-dose macitentan was well tolerated in recurrent GBM patients concomitantly receiving TMZ. TEAEs were consistent with those seen in patients receiving either drug individually.
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Affiliation(s)
| | | | - John de Groot
- University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Gail Thomas
- Actelion Pharmaceuticals Ltd, Allschwil, Switzerland
| | | | | | - Vinay K Puduvalli
- The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA
| | | | - W K Alfred Yung
- University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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14
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Franzese O, Torino F, Giannetti E, Cioccoloni G, Aquino A, Faraoni I, Fuggetta MP, De Vecchis L, Giuliani A, Kaina B, Bonmassar E. Abscopal Effect and Drug-Induced Xenogenization: A Strategic Alliance in Cancer Treatment? Int J Mol Sci 2021; 22:ijms221910672. [PMID: 34639014 PMCID: PMC8509363 DOI: 10.3390/ijms221910672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 09/23/2021] [Accepted: 09/28/2021] [Indexed: 11/16/2022] Open
Abstract
The current state of cancer treatment is still far from being satisfactory considering the strong impairment of patients' quality of life and the high lethality of malignant diseases. Therefore, it is critical for innovative approaches to be tested in the near future. In view of the crucial role that is played by tumor immunity, the present review provides essential information on the immune-mediated effects potentially generated by the interplay between ionizing radiation and cytotoxic antitumor agents when interacting with target malignant cells. Therefore, the radiation-dependent abscopal effect (i.e., a biological effect of ionizing radiation that occurs outside the irradiated field), the influence of cancer chemotherapy on the antigenic pattern of target neoplastic cells, and the immunogenic cell death (ICD) caused by anticancer agents are the main topics of this presentation. It is widely accepted that tumor immunity plays a fundamental role in generating an abscopal effect and that anticancer drugs can profoundly influence not only the host immune responses, but also the immunogenic pattern of malignant cells. Remarkably, several anticancer drugs impact both the abscopal effect and ICD. In addition, certain classes of anticancer agents are able to amplify already expressed tumor-associated antigens (TAA). More importantly, other drugs, especially triazenes, induce the appearance of new tumor neoantigens (TNA), a phenomenon that we termed drug-induced xenogenization (DIX). The adoption of the abscopal effect is proposed as a potential therapeutic modality when properly applied concomitantly with drug-induced increase in tumor cell immunogenicity and ICD. Although little to no preclinical or clinical studies are presently available on this subject, we discuss this issue in terms of potential mechanisms and therapeutic benefits. Upcoming investigations are aimed at evaluating how chemical anticancer drugs, radiation, and immunotherapies are interacting and cooperate in evoking the abscopal effect, tumor xenogenization and ICD, paving the way for new and possibly successful approaches in cancer therapy.
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Affiliation(s)
- Ornella Franzese
- School of Medicine, Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy; (O.F.); (G.C.); (A.A.); (I.F.); (L.D.V.)
| | - Francesco Torino
- Department of Systems Medicine, Medical Oncology, University of Rome Tor Vergata, 00133 Rome, Italy; (F.T.); (E.G.)
| | - Elisa Giannetti
- Department of Systems Medicine, Medical Oncology, University of Rome Tor Vergata, 00133 Rome, Italy; (F.T.); (E.G.)
| | - Giorgia Cioccoloni
- School of Medicine, Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy; (O.F.); (G.C.); (A.A.); (I.F.); (L.D.V.)
- School of Food Science and Nutrition, University of Leeds, Leeds LS29JT, UK
| | - Angelo Aquino
- School of Medicine, Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy; (O.F.); (G.C.); (A.A.); (I.F.); (L.D.V.)
| | - Isabella Faraoni
- School of Medicine, Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy; (O.F.); (G.C.); (A.A.); (I.F.); (L.D.V.)
| | - Maria Pia Fuggetta
- Institute of Translational Pharmacology, Consiglio Nazionale delle Ricerche (CNR), Via Fosso del Cavaliere, 00133 Rome, Italy; (M.P.F.); (A.G.)
| | - Liana De Vecchis
- School of Medicine, Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy; (O.F.); (G.C.); (A.A.); (I.F.); (L.D.V.)
| | - Anna Giuliani
- Institute of Translational Pharmacology, Consiglio Nazionale delle Ricerche (CNR), Via Fosso del Cavaliere, 00133 Rome, Italy; (M.P.F.); (A.G.)
| | - Bernd Kaina
- Institute of Toxicology, University Medical Center, D-55131 Mainz, Germany
- Correspondence: (B.K.); (E.B.)
| | - Enzo Bonmassar
- School of Medicine, Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy; (O.F.); (G.C.); (A.A.); (I.F.); (L.D.V.)
- Institute of Translational Pharmacology, Consiglio Nazionale delle Ricerche (CNR), Via Fosso del Cavaliere, 00133 Rome, Italy; (M.P.F.); (A.G.)
- Correspondence: (B.K.); (E.B.)
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15
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Xue T, Ding JS, Li B, Cao DM, Chen G. A narrative review of adjuvant therapy for glioma: hyperbaric oxygen therapy. Med Gas Res 2021; 11:155-157. [PMID: 34213498 PMCID: PMC8374463 DOI: 10.4103/2045-9912.318861] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 05/23/2020] [Accepted: 06/18/2020] [Indexed: 12/14/2022] Open
Abstract
Glioma is a kind of common malignant tumor in neurosurgery and has a high mortality and morbidity rate, which poses a serious threat to the health of people all over the world. Surgery is the preferred treatment for patients with glioma, radiotherapy or chemotherapy can be used after surgery. Although there are clear therapeutic protocols, the efficacy and safety of these protocols are clinically proven, a large number of patients are still dissatisfied with the treatment and the health of the patient remains unsatisfactory. Therefore, it is crucial to look for other treatments or complementary treatments. In the modern medical treatment, hyperbaric oxygen (HBO) therapy is widely used in various kinds of pathological state of adjuvant therapy, and existing studies confirm the efficacy of HBO therapy in combination with surgery, radiotherapy, chemotherapy, and photodynamic therapy. Studies have shown that HBO can inhibit the growth of tumor tissue as an adjunctive therapy. This provides novel insights into the clinical treatment of glioma patients. Although HBO is not licensed for use in cancer treatment, as a kind of adjuvant therapy, the treatment effect of HBO can be accepted by the patients and its cost lower, which could be regarded as an ideal safe treatment.
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Affiliation(s)
- Tao Xue
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Jia-Sheng Ding
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Bing Li
- Department of Neurosurgery, Yancheng City No. 1 People’s Hospital, The Fourth Affiliated Hospital of Nantong University, Yancheng, Jiangsu Province, China
| | - De-Mao Cao
- Department of Neurosurgery, The Affiliated Hospital of Yangzhou University, Yangzhou, Jiangsu Province, China
| | - Gang Chen
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
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16
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Tsakatikas S, Papageorgiou G, Fioretzaki R, Kosmas C. An overview of current results with the vincristine-irinotecan-temozolomide combination with or without bevacizumab in pediatric, adolescence and adult solid tumors. Crit Rev Oncol Hematol 2021; 166:103457. [PMID: 34428555 DOI: 10.1016/j.critrevonc.2021.103457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Revised: 01/02/2021] [Accepted: 08/19/2021] [Indexed: 11/29/2022] Open
Abstract
Malignant tumors in young patients present a significant therapeutic challenge for physicians, partially due to their rarity and a relative lack of data, at least compared to adult tumors. As a result, there is an urgent need to explore new possible therapeutic regimens, either by introducing novel agents or by exploring combinations of existing agents. Vincristine, Temozolomide and Irinotecan are chemotherapeutic drugs which have emerged over the last six decades as monotherapy or as part of therapeutic regimens in various solid tumors. Combining these agents can yield strong synergistic effects, as suggested by preclinical data and results from clinical trials. Furthermore, adding novel molecules, such as anti-VEGF factor Bevacizumab to the aforementioned regimens, has shown efficacy in a limited number of trials, which are thoroughly analyzed throughout this review. Data presented throughout this paper suggest that VIT(b) regimen should be further explored in solid tumors in pediatric and adolescent patients.
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Affiliation(s)
- Sergios Tsakatikas
- Department of Medical Oncology & Hematopoietic Cell Transplant Unit, "Metaxa" Memorial Cancer Hospital, 18537, Piraeus, Greece.
| | - George Papageorgiou
- Department of Medical Oncology & Hematopoietic Cell Transplant Unit, "Metaxa" Memorial Cancer Hospital, 18537, Piraeus, Greece.
| | - Rodanthi Fioretzaki
- Department of Medical Oncology & Hematopoietic Cell Transplant Unit, "Metaxa" Memorial Cancer Hospital, 18537, Piraeus, Greece.
| | - Christos Kosmas
- Department of Medical Oncology & Hematopoietic Cell Transplant Unit, "Metaxa" Memorial Cancer Hospital, 18537, Piraeus, Greece.
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17
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Kumar N, Elangovan A, Madan R, Dracham C, Khosla D, Tripathi M, Gupta K, Kapoor R. Impact of Immunohistochemical profiling of Glioblastoma multiforme on clinical outcomes: Real-world scenario in resource limited setting. Clin Neurol Neurosurg 2021; 207:106726. [PMID: 34116459 DOI: 10.1016/j.clineuro.2021.106726] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 05/30/2021] [Accepted: 06/01/2021] [Indexed: 02/09/2023]
Abstract
OBJECTIVE Intuition into the molecular pathways of glioblastoma multiforme (GBM) has changed the diagnostic, prognostic, and therapeutic approaches. We investigated the influence of various clinical and molecular prognostic factors on survival outcomes in radically treated GBM patients. METHODS Medical records of 160 GBM patients treated between January-2012 and December-2018 with surgery followed by post-operative external beam radiotherapy (EBRT) with/without temozolomide (TMZ) were reviewed. Immunohistochemical (IHC) assays were performed for IDH1mutation, ATRX loss, TP53 overexpression and Ki-67% index. Apart from disease and treatment-related factors' influence on clinical outcomes, the impact of IHC markers in prognostication was analyzed using appropriate statistical tests. RESULTS The median overall survival (OS) was 14 months. EBRT with concurrent TMZ was given to 60% of patients and 42.5% completed the standard Stupp-protocol. Significant improvements in OS was observed in patients aged ≤ 50years (2-year OS: 22.1% vs. 12.5%, p = 0.001), those who underwent gross total resection (2-year OS: 21.8% vs. 12.8%, p = 0.002), received concurrent TMZ (21.9% vs. 12.5%, p = 0.005), completed the entire Stupp-protocol (2-year OS: 23.4% vs. 6.5%, p = 0.000), and with Ki-67 index <20% (2-year OS: 23.3% vs. 11.6%, p = 0.015). On multivariate analysis, IDH1 mutation, ATRX loss, TP53 expression, and Ki-67 ≤ 20% were significant prognosticators of outcomes. CONCLUSION GBM patients treated with concurrent chemoradiation and those who completed the full Stupp-protocol experienced better survival outcomes. Molecular biology significantly impacts clinical outcomes and plays a key deterministic role in newer management strategies.
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Affiliation(s)
- Narendra Kumar
- Department of Radiotherapy& Oncology, PGIMER, Chandigarh, India.
| | - Arun Elangovan
- Department of Radiotherapy& Oncology, PGIMER, Chandigarh, India.
| | - Renu Madan
- Department of Radiotherapy& Oncology, PGIMER, Chandigarh, India.
| | | | - Divya Khosla
- Department of Radiotherapy& Oncology, PGIMER, Chandigarh, India.
| | | | - Kirti Gupta
- Department of Pathology, PGIMER, Chandigarh, India.
| | - Rakesh Kapoor
- Department of Radiotherapy& Oncology, PGIMER, Chandigarh, India.
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18
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Adjuvant Temozolomide for the Treatment of Glioblastoma: A Meta-analysis of Randomized Controlled Studies. Clin Neuropharmacol 2021; 44:132-137. [PMID: 34039842 DOI: 10.1097/wnf.0000000000000458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
INTRODUCTION The efficacy of adjuvant temozolomide to radiotherapy for glioblastoma remained elusive. This meta-analysis aimed to explore the influence of radiotherapy plus adjuvant temozolomide on the efficacy and safety for glioblastoma. METHODS We have searched several databases including PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases through November 2020 and included randomized controlled trials assessing the efficacy and safety of adjuvant temozolomide to radiotherapy for glioblastoma. RESULTS Seven randomized controlled trials and 1900 patients were included in the meta-analysis. Overall, compared with radiotherapy for glioblastoma, adjuvant temozolomide was associated with significantly increased survival rate [odds ratio (OR), 4.04; 95% confidence interval (CI), 2.61-6.24; P < 0.00001], median progression-free survival (mean difference, 0.55; 95% CI, 0.03-1.07; P = 0.04), and hematological complications (OR, 4.12; 95% CI, 1.43-11.88; P = 0.009), but revealed no remarkable influence on adverse events (OR, 0.87; 95% CI, 0.36-2.09; P = 0.75) or serious adverse events (OR, 2.20; 95% CI, 0.55-8.70; P = 0.26). CONCLUSIONS Adjuvant temozolomide in combination with radiotherapy may improve the treatment efficacy for glioblastoma.
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19
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Nguyen VT, Tran TTN, Van TK, Tran T. DNA-Templated Silver Nanoclusters Used as a Label-Free Fluorescent Probe for the Detection of O6-Methyltransferase Activity. JOURNAL OF ANALYTICAL CHEMISTRY 2021. [DOI: 10.1134/s1061934821050130] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
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20
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Gilbert MR, Yuan Y, Wu J, Mendoza T, Vera E, Omuro A, Lieberman F, Robins HI, Gerstner ER, Wu J, Wen PY, Mikkelsen T, Aldape K, Armstrong TS. A phase II study of dose-dense temozolomide and lapatinib for recurrent low-grade and anaplastic supratentorial, infratentorial, and spinal cord ependymoma. Neuro Oncol 2021; 23:468-477. [PMID: 33085768 DOI: 10.1093/neuonc/noaa240] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND No standard medical treatment exists for adult patients with recurrent ependymoma, and prospective clinical trials in this population have not succeeded because of its rarity and challenges in accruing patients. The Collaborative Ependymoma Research Network conducted a prospective phase II clinical trial of dose-dense temozolomide (TMZ) and lapatinib, targeting the unmethylated O6-methylguanine-DNA methyltransferase (MGMT) promoter status and increased expression of ErbB2 (human epidermal growth factor receptor 2) and ErbB1 (epidermal growth factor receptor) in ependymomas. METHODS Patients age 18 or older with histologically proven and progressive ependymoma or anaplastic ependymoma were eligible and received dose-dense TMZ and daily lapatinib. The primary outcome measure was median progression-free survival (PFS). Landmark 6- and 12-month PFS and objective response were measured. Serial assessments of symptom burden using the MD Anderson Symptom Inventory Brain Tumor (MDASI-BT)/MDASI-Spine Tumor modules were collected. RESULTS The 50 patients enrolled had a median age of 43.5 years, median Karnofsky performance status of 90, and a median of 2 prior relapses. Twenty patients had grade III, 16 grade II, and 8 grade I ependymoma. Half had spinal cord tumors; 15 had a supratentorial tumor, 8 infratentorial, and 2 had disseminated disease. Treatment was well tolerated. The median PFS was 7.8 months (95% CI: 5.5,12.2); the 6- and 12-month PFS rates were 55% and 38%, with 2 complete and 6 partial responses. Measures of symptom burden showed reduction in moderate-severe pain and other disease-related symptoms in most patients. CONCLUSIONS This treatment, with demonstrated clinical activity with objective responses and prolonged disease control associated with disease-related symptom improvements, is an option as a salvage regimen for adult patients with recurrent ependymoma.
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Affiliation(s)
- Mark R Gilbert
- Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Ying Yuan
- The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jimin Wu
- The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Tito Mendoza
- The University of Texas MD Anderson Cancer Center, Houston, Texas
- Henry Ford Hospital, Detroit, Michigan
| | - Elizabeth Vera
- Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | | | | | - H Ian Robins
- University of Wisconsin-Madison, Madison, Wisconsin
| | | | - Jing Wu
- Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | | | | | - Kenneth Aldape
- Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Terri S Armstrong
- Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
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21
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Papageorgiou GI, Tsakatikas SA, Fioretzaki RG, Kosmas C. Notable response of a young adult with recurrent glioblastoma multiforme to vincristine-irinotecan-temozolomide and bevacizumab. Anticancer Drugs 2021; 32:330-336. [PMID: 33229903 DOI: 10.1097/cad.0000000000001021] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Glioblastoma multiforme is a malignant central nervous system (CNS) disease with dismal prognosis. Current treatment modalities only offer modest activity and usually of short duration, so there is an urgent need for the conduct of clinical trials exploring new treatment options and modalities. The vincristine-irinotecan-temozolomide and bevacizumab (VITb) regimen is an option of special interest, as it has produced encouraging results in young patients with various relapsed/refractory childhood and adolescence solid tumors, with an acceptable toxicity profile. With the current report, we present the case of a young male patient who was treated for GBM in second relapse at out institution, after previous surgical attempts and two radiotherapy sessions in conjunction with temozolomide and experienced a major and long-lasting response, weaned off steroids, to the VITb regimen followed by bevacizumab maintenance. The above case is discussed in the context of the existing literature regarding available evidence of synergy between the drugs used and the activity of certain components of the combination (i.e. combination of temozolomide-irinotecan ± vincristine, or bevacizumab-irinotecan in GBM) or the complete VITb regimen in other pediatric/adolescence solid tumors and the few cases reported with GBM.
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Affiliation(s)
- Georgios I Papageorgiou
- Division of Medical Oncology & Hematopoietic Cell Transplant Unit, Department of Medicine, Metaxa Cancer Hospital, Piraeus, Greece
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22
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Choi HJ, Choi SH, You SH, Yoo RE, Kang KM, Yun TJ, Kim JH, Sohn CH, Park CK, Park SH. MGMT Promoter Methylation Status in Initial and Recurrent Glioblastoma: Correlation Study with DWI and DSC PWI Features. AJNR Am J Neuroradiol 2021; 42:853-860. [PMID: 33632732 DOI: 10.3174/ajnr.a7004] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 11/16/2020] [Indexed: 11/07/2022]
Abstract
BACKGROUND AND PURPOSE O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status in primary and recurrent glioblastoma may change during treatment. The purpose of this study was to correlate MGMT promoter methylation status changes with DWI and DSC PWI features in patients with recurrent glioblastoma after standard treatment. MATERIALS AND METHODS Between January 2008 and November 2016, forty patients with histologically confirmed recurrent glioblastoma were enrolled. Patients were divided into 3 groups according to the MGMT promoter methylation status for the initial and recurrent tumors: 2 groups whose MGMT promoter methylation status remained, group methylated (n = 13) or group unmethylated (n = 18), and 1 group whose MGMT promoter methylation status changed from methylated to unmethylated (n = 9). Normalized ADC and normalized relative CBV values were obtained from both the enhancing and nonenhancing regions, from which histogram parameters were calculated. The ANOVA and the Kruskal-Wallis test followed by post hoc tests were performed to compare histogram parameters among the 3 groups. The t test and Mann-Whitney U test were used to compare parameters between group methylated and group methylated to unmethylated. Receiver operating characteristic curve analysis was used to measure the predictive performance of the normalized relative CBV values between the 2 groups. RESULTS Group methylated to unmethylated showed significantly higher means and 90th and 95th percentiles of the cumulative normalized relative CBV values of the nonenhancing region of the initial tumor than group methylated and group unmethylated (all P < .05). The mean normalized relative CBV value of the nonenhancing region of the initial tumor was the best predictor of methylation status change (P < .001), with a sensitivity of 77.78% and specificity of 92.31% at a cutoff value of 2.594. CONCLUSIONS MGMT promoter methylation status might change in recurrent glioblastoma after standard treatment. The normalized relative CBV values of the nonenhancing region at the first preoperative MR imaging were higher in the MGMT promoter methylation change group from methylation to unmethylation in recurrent glioblastoma.
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Affiliation(s)
- H J Choi
- From the Department of Radiology (H.J.C.), Cha Bundang Medical Center, Cha University, Seongnam, Korea
| | - S H Choi
- Department of Radiology (S.H.C., R.-E.Y., K.M.K., T.J.Y., J.-h.K., C.-H.S.), Seoul National University Hospital, Seoul, Korea
| | - S-H You
- Department of Radiology (S.-H.Y.), Korea University Hospital, Seoul, Korea
| | - R-E Yoo
- Department of Radiology (S.H.C., R.-E.Y., K.M.K., T.J.Y., J.-h.K., C.-H.S.), Seoul National University Hospital, Seoul, Korea
| | - K M Kang
- Department of Radiology (S.H.C., R.-E.Y., K.M.K., T.J.Y., J.-h.K., C.-H.S.), Seoul National University Hospital, Seoul, Korea
| | - T J Yun
- Department of Radiology (S.H.C., R.-E.Y., K.M.K., T.J.Y., J.-h.K., C.-H.S.), Seoul National University Hospital, Seoul, Korea
| | - J-H Kim
- Department of Radiology (S.H.C., R.-E.Y., K.M.K., T.J.Y., J.-h.K., C.-H.S.), Seoul National University Hospital, Seoul, Korea
| | - C-H Sohn
- Department of Radiology (S.H.C., R.-E.Y., K.M.K., T.J.Y., J.-h.K., C.-H.S.), Seoul National University Hospital, Seoul, Korea
| | - C-K Park
- Department of Neurosurgery (C.-K.P.), Seoul National University Hospital, Seoul, Korea
| | - S-H Park
- Department of Pathology (S.-H.P.), Seoul National University Hospital, Seoul, Korea
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Wang X, Li S, Liu X, Wu X, Ye N, Yang X, Li Z. Boosting Nanomedicine Efficacy with Hyperbaric Oxygen Therapy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1295:77-95. [PMID: 33543456 DOI: 10.1007/978-3-030-58174-9_4] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Nanomedicine has been a hot topic in the field of tumor therapy in the past few decades. Because of the enhanced permeability and retention effect (EPR effect), nanomedicine can passively yet selectively accumulate at tumor tissues. As a result, it can improve drug concentration in tumor tissues and reduce drug distribution in normal tissues, thereby contributing to enhanced antitumor effect and reduced adverse effects. However, the therapeutic efficacy of anticancer nanomedicine is not satisfactory in clinical settings. Therefore, how to improve the clinical therapeutic effect of nanomedicine has become an urgent problem. The grand challenges of nanomedicine lie in how to overcome various pathophysiological barriers and simultaneously kill cancer cells effectively in hypoxic tumor microenvironment (TME). To this end, the development of novel stimuli-responsive nanomedicine has become a new research hotspot. While a great deal of progress has been made in this direction and preclinical results report many different kinds of promising multifunctional smart nanomedicine, the design of these intelligent nanomedicines is often too complicated, the requirements for the preparation processes are strict, the cost is high, and the clinical translation is difficult. Thus, it is more practical to find solutions to promote the therapeutic efficacy of commercialized nanomedicines, for example, Doxil®, Oncaspar®, DaunoXome®, Abraxane®, to name a few. Increasing attention has been paid to the combination of modern advanced medical technology and nanomedicine for the treatment of various malignancies. Recently, we found that hyperbaric oxygen (HBO) therapy could enhance Doxil® antitumor efficacy. Inspired by this study, we further carried out researches on the combination of HBO therapy with other nanomedicines for various cancer therapies, and revealed that HBO therapy could significantly boost antitumor efficacy of nanomedicine-mediated photodynamic therapy and photothermal therapy in different kinds of tumors, including hepatocellular carcinoma, breast cancer, and gliomas. Our results implicate that HBO therapy might be a universal strategy to boost therapeutic efficacy of nanomedicine against hypoxic solid malignancies.
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Affiliation(s)
- Xiaoxian Wang
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Si Li
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Xin Liu
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Xian Wu
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Ningbing Ye
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Xiangliang Yang
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medical, Huazhong University of Science and Technology, Wuhan, China
| | - Zifu Li
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
- Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
- Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medical, Huazhong University of Science and Technology, Wuhan, China.
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24
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Tanaka S, Akimoto J, Narita Y. Determination of the cutoff point of the absolute value of MGMTmRNA for predicting the therapeutic resistance to temozolomide in glioblastoma. J Neurosurg Sci 2020; 64:434-439. [PMID: 33236861 DOI: 10.23736/s0390-5616.17.04209-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
BACKGROUND We previously reported that the absolute value of O<sup>6</sup>-methylguanine-DNA methyltransferase (MGMT) messenger RNA (mRNA) obtained using real-time reverse transcription polymerase chain reaction (RT-PCR) might be useful for predicting both the prognosis and the results of therapy for glioblastoma (GB) treated by temozolomide (TMZ). METHODS MGMT mRNA was measured in 55 newly diagnosed cases of GB less than 75 and had a Karnofsky performance status (KPS) of at least 60 by real-time reverse transcription polymerase chain reaction (RT-PCR) using the TaqMan probe. A receiver operating characteristic analysis was performed to determine the cutoff points for progression free survival (PFS) and overall survival (OS). RESULTS In 55 patients with GB, 1200 and 3600 for PFS, 1200, 2100 and 2900 copies/μgRNA for OS were the candidate cutoff points. Significantly longer PFS and OS were observed in patients who did not exceed 1200 copies/μg RNA. CONCLUSIONS One thousand and two hundred copies/μg RNA appeared to be the most reasonable cutoff point of MGMTmRNA in GB for deciding to use other anti-tumor drugs such as Bevacizumab together with TMZ.
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Affiliation(s)
- Satoshi Tanaka
- Department of Neuro-Oncology and Neurosurgery, Tokyo Nishi Tokushukai Hospital, Akishima, Japan -
| | - Jiro Akimoto
- Department of Neurosurgery, Tokyo Medical University Hospital, Tokyo, Japan
| | - Yoshitaka Narita
- Division of Neurosurgery, National Cancer Center Hospital, Tokyo, Japan
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Lafita-Navarro MC, Venkateswaran N, Kilgore JA, Kanji S, Han J, Barnes S, Williams NS, Buszczak M, Burma S, Conacci-Sorrell M. Inhibition of the de novo pyrimidine biosynthesis pathway limits ribosomal RNA transcription causing nucleolar stress in glioblastoma cells. PLoS Genet 2020; 16:e1009117. [PMID: 33201894 PMCID: PMC7707548 DOI: 10.1371/journal.pgen.1009117] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 12/01/2020] [Accepted: 09/14/2020] [Indexed: 12/15/2022] Open
Abstract
Glioblastoma is the most common and aggressive type of cancer in the brain; its poor prognosis is often marked by reoccurrence due to resistance to the chemotherapeutic agent temozolomide, which is triggered by an increase in the expression of DNA repair enzymes such as MGMT. The poor prognosis and limited therapeutic options led to studies targeted at understanding specific vulnerabilities of glioblastoma cells. Metabolic adaptations leading to increased synthesis of nucleotides by de novo biosynthesis pathways are emerging as key alterations driving glioblastoma growth. In this study, we show that enzymes necessary for the de novo biosynthesis of pyrimidines, DHODH and UMPS, are elevated in high grade gliomas and in glioblastoma cell lines. We demonstrate that DHODH's activity is necessary to maintain ribosomal DNA transcription (rDNA). Pharmacological inhibition of DHODH with the specific inhibitors brequinar or ML390 effectively depleted the pool of pyrimidines in glioblastoma cells grown in vitro and in vivo and impaired rDNA transcription, leading to nucleolar stress. Nucleolar stress was visualized by the aberrant redistribution of the transcription factor UBF and the nucleolar organizer nucleophosmin 1 (NPM1), as well as the stabilization of the transcription factor p53. Moreover, DHODH inhibition decreased the proliferation of glioblastoma cells, including temozolomide-resistant cells. Importantly, the addition of exogenous uridine, which reconstitutes the cellular pool of pyrimidine by the salvage pathway, to the culture media recovered the impaired rDNA transcription, nucleolar morphology, p53 levels, and proliferation of glioblastoma cells caused by the DHODH inhibitors. Our in vivo data indicate that while inhibition of DHODH caused a dramatic reduction in pyrimidines in tumor cells, it did not affect the overall pyrimidine levels in normal brain and liver tissues, suggesting that pyrimidine production by the salvage pathway may play an important role in maintaining these nucleotides in normal cells. Our study demonstrates that glioblastoma cells heavily rely on the de novo pyrimidine biosynthesis pathway to generate ribosomal RNA (rRNA) and thus, we identified an approach to inhibit ribosome production and consequently the proliferation of glioblastoma cells through the specific inhibition of the de novo pyrimidine biosynthesis pathway.
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Affiliation(s)
- M. Carmen Lafita-Navarro
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
| | - Niranjan Venkateswaran
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
| | - Jessica A. Kilgore
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
| | - Suman Kanji
- Department of Neurosurgery, University of Texas Health Science Center, San Antonio, Texas, United States of America
| | - Jungsoo Han
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
| | - Spencer Barnes
- Bioinformatics Core Facility, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
| | - Noelle S. Williams
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
| | - Michael Buszczak
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
| | - Sandeep Burma
- Department of Neurosurgery, University of Texas Health Science Center, San Antonio, Texas, United States of America
- Department of Biochemistry and Structural Biology, University of Texas Health Science Center, San Antonio, Texas, United States of America
| | - Maralice Conacci-Sorrell
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
- Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States of America
- Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
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26
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Ho KG, Uhlmann EN, Wong ET, Uhlmann EJ. Leukopenia is a biomarker for effective temozolomide dosing and predicts overall survival of patients with glioblastoma. Mol Clin Oncol 2020; 13:80. [PMID: 33062270 PMCID: PMC7549395 DOI: 10.3892/mco.2020.2150] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Accepted: 09/17/2020] [Indexed: 11/21/2022] Open
Abstract
The median survival time of patients with glioblastoma is 14-16 months with a 5-year overall survival rate of 9.8%. Standard of care treatment includes radiation with concomitant temozolomide followed by cyclic temozolomide. If the patient develops myelosuppression (thrombocytopenia, leukopenia or anemia), the dose of temozolomide is reduced or stopped to avoid bleeding or infections. Recent studies have demonstrated that mild leukopenia is associated with increased overall survival in patients with glioblastoma. To confirm prior results showing that leukopenia is associated with increased overall survival as a primary outcome in patients with glioblastoma, the present study retrospectively collected complete blood counts from 141 patients with glioblastoma treated at the Beth Israel Deaconess Medical Center (Boston, USA) between January 2012 and December 2017. According to Kaplan-Meier analysis with a log-rank test, the presence of leukopenia was associated with increased overall survival (P=0.008). Furthermore, patients with grade 2 leukopenia (Common Terminology Criteria for Adverse Events version 5.0) survived longer than those without myelosuppression (P=0.024). There was no difference in overall survival between patients with grade 1, 3 or 4 leukopenia and those without myelosuppression. Leukopenia was associated with longer survival independent of age or extent of surgery in Cox proportional hazards regression modeling (P=0.00205). A possible interpretation is that grade 2 leukopenia is a biomarker of adequate temozolomide dosing in a population with diverse DNA repair function, which may be the consequence of variable O6-methylguanine-DNA methyltransferase activity. A prospective dose escalation trial is necessary to determine if treatment-induced leukopenia is beneficial for all patients receiving temozolomide.
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Affiliation(s)
- K Grace Ho
- Department of Neurology, Beth Israel Deaconess Hospital and Harvard Medical School, Boston, MA 02215, USA
| | - Erik N Uhlmann
- Khoury College of Computer Sciences, Northeastern University, Boston, MA 02115, USA
| | - Eric T Wong
- Department of Neurology, Beth Israel Deaconess Hospital and Harvard Medical School, Boston, MA 02215, USA
| | - Erik J Uhlmann
- Department of Neurology, Beth Israel Deaconess Hospital and Harvard Medical School, Boston, MA 02215, USA
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27
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Wang Y, Feng Y. The efficacy and safety of radiotherapy with adjuvant temozolomide for glioblastoma: A meta-analysis of randomized controlled studies. Clin Neurol Neurosurg 2020; 196:105890. [DOI: 10.1016/j.clineuro.2020.105890] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2019] [Revised: 02/27/2020] [Accepted: 05/01/2020] [Indexed: 12/19/2022]
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28
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Herbener VJ, Burster T, Goreth A, Pruss M, von Bandemer H, Baisch T, Fitzel R, Siegelin MD, Karpel-Massler G, Debatin KM, Westhoff MA, Strobel H. Considering the Experimental use of Temozolomide in Glioblastoma Research. Biomedicines 2020; 8:E151. [PMID: 32512726 PMCID: PMC7344626 DOI: 10.3390/biomedicines8060151] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 05/30/2020] [Accepted: 05/31/2020] [Indexed: 12/17/2022] Open
Abstract
Temozolomide (TMZ) currently remains the only chemotherapeutic component in the approved treatment scheme for Glioblastoma (GB), the most common primary brain tumour with a dismal patient's survival prognosis of only ~15 months. While frequently described as an alkylating agent that causes DNA damage and thus-ultimately-cell death, a recent debate has been initiated to re-evaluate the therapeutic role of TMZ in GB. Here, we discuss the experimental use of TMZ and highlight how it differs from its clinical role. Four areas could be identified in which the experimental data is particularly limited in its translational potential: 1. transferring clinical dosing and scheduling to an experimental system and vice versa; 2. the different use of (non-inert) solvent in clinic and laboratory; 3. the limitations of established GB cell lines which only poorly mimic GB tumours; and 4. the limitations of animal models lacking an immune response. Discussing these limitations in a broader biomedical context, we offer suggestions as to how to improve transferability of data. Finally, we highlight an underexplored function of TMZ in modulating the immune system, as an example of where the aforementioned limitations impede the progression of our knowledge.
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Affiliation(s)
- Verena J. Herbener
- Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, D-89075 Ulm, Germany; (V.J.H.); (A.G.); (H.v.B.); (T.B.); (R.F.); (K.-M.D.); (H.S.)
| | - Timo Burster
- Department of Biology, School of Sciences and Humanities, Nazarbayev University, Nur-Sultan 010000, Kazakhstan;
| | - Alicia Goreth
- Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, D-89075 Ulm, Germany; (V.J.H.); (A.G.); (H.v.B.); (T.B.); (R.F.); (K.-M.D.); (H.S.)
| | - Maximilian Pruss
- Department of Gynecology and Obstetrics, Medical Faculty, University Hospital of the Heinrich-Heine-University Duesseldorf, D-40225 Duesseldorf, Germany;
- Department of Neurosurgery, University Medical Center Ulm, D-89081 Ulm, Germany;
| | - Hélène von Bandemer
- Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, D-89075 Ulm, Germany; (V.J.H.); (A.G.); (H.v.B.); (T.B.); (R.F.); (K.-M.D.); (H.S.)
| | - Tim Baisch
- Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, D-89075 Ulm, Germany; (V.J.H.); (A.G.); (H.v.B.); (T.B.); (R.F.); (K.-M.D.); (H.S.)
| | - Rahel Fitzel
- Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, D-89075 Ulm, Germany; (V.J.H.); (A.G.); (H.v.B.); (T.B.); (R.F.); (K.-M.D.); (H.S.)
| | - Markus D. Siegelin
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA;
| | - Georg Karpel-Massler
- Department of Neurosurgery, University Medical Center Ulm, D-89081 Ulm, Germany;
| | - Klaus-Michael Debatin
- Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, D-89075 Ulm, Germany; (V.J.H.); (A.G.); (H.v.B.); (T.B.); (R.F.); (K.-M.D.); (H.S.)
| | - Mike-Andrew Westhoff
- Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, D-89075 Ulm, Germany; (V.J.H.); (A.G.); (H.v.B.); (T.B.); (R.F.); (K.-M.D.); (H.S.)
| | - Hannah Strobel
- Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, D-89075 Ulm, Germany; (V.J.H.); (A.G.); (H.v.B.); (T.B.); (R.F.); (K.-M.D.); (H.S.)
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Westhoff MA, Baisch T, Herbener VJ, Karpel-Massler G, Debatin KM, Strobel H. Comment in Response to "Temozolomide in Glioblastoma Therapy: Role of Apoptosis, Senescence and Autophagy etc. by B. Kaina". Biomedicines 2020; 8:biomedicines8040093. [PMID: 32326020 PMCID: PMC7235879 DOI: 10.3390/biomedicines8040093] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Accepted: 04/17/2020] [Indexed: 12/17/2022] Open
Abstract
It is with great pleasure that we acknowledge the fact that our review on Temozolomide (TMZ) has initiated a discussion [1-3]. [...].
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Affiliation(s)
- Mike-Andrew Westhoff
- Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, D-89075 Ulm, Germany; (T.B.); (V.J.H.); (K.-M.D.); (H.S.)
- Correspondence:
| | - Tim Baisch
- Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, D-89075 Ulm, Germany; (T.B.); (V.J.H.); (K.-M.D.); (H.S.)
| | - Verena J. Herbener
- Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, D-89075 Ulm, Germany; (T.B.); (V.J.H.); (K.-M.D.); (H.S.)
| | - Georg Karpel-Massler
- Department of Neurosurgery, University Medical Center Ulm, D-89081 Ulm, Germany;
| | - Klaus-Michael Debatin
- Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, D-89075 Ulm, Germany; (T.B.); (V.J.H.); (K.-M.D.); (H.S.)
| | - Hannah Strobel
- Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, D-89075 Ulm, Germany; (T.B.); (V.J.H.); (K.-M.D.); (H.S.)
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Good tolerability of maintenance temozolomide in glioblastoma patients after severe hematological toxicity during concomitant radiotherapy and temozolomide treatment: report of two cases. Anticancer Drugs 2019; 29:924-928. [PMID: 30080691 DOI: 10.1097/cad.0000000000000678] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Glioblastoma is the most common and aggressive primitive brain tumor in adults. Temozolomide (TMZ) administered daily with radiation therapy, followed by adjuvant TMZ has become the standard treatment. Although TMZ treatment has been considered to have a low toxicity profile, studies have noted the development of a severe myelosuppression, especially during the concomitant treatment; this toxicity may in some cases be prolonged and consequently treatment must be definitively discontinued. We analyzed two cases treated at our oncological center who developed severe and prolonged hematological toxicity during concomitant chemoradiotherapy treatment with TMZ. Hypothesizing that radiation therapy and daily TMZ could be the major causes of severe hematological toxicity during the concomitant phase, we decided to treat both patients with maintenance TMZ at the time of recovery of hematological values. Patients showed good tolerability without important myelosuppression. In conclusion, we suggest that glioblastoma patients with severe myelotoxicity during daily TMZ and radiation therapy be treated with maintenance TMZ at the time of blood value recovery.
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31
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Simsek C, Esin E, Yalcin S. Metronomic Chemotherapy: A Systematic Review of the Literature and Clinical Experience. JOURNAL OF ONCOLOGY 2019; 2019:5483791. [PMID: 31015835 PMCID: PMC6446118 DOI: 10.1155/2019/5483791] [Citation(s) in RCA: 86] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Revised: 12/24/2018] [Accepted: 02/05/2019] [Indexed: 02/07/2023]
Abstract
Metronomic chemotherapy, continuous and dose-dense administration of chemotherapeutic drugs with lowered doses, is being evaluated for substituting, augmenting, or appending conventional maximum tolerated dose regimens, with preclinical and clinical studies for the past few decades. To date, the principle mechanisms of its action include impeding tumoral angiogenesis and modulation of hosts' immune system, affecting directly tumor cells, their progenitors, and neighboring stromal cells. Its better toxicity profile, lower cost, and easier use are main advantages over conventional therapies. The evidence of metronomic chemotherapy for personalized medicine is growing, starting with unfit elderly patients and also for palliative treatment. The literature reviewed in this article mainly demonstrates that metronomic chemotherapy is advantageous for selected patients and for certain types of malignancies, which make it a promising therapeutic approach for filling in the gaps. More clinical studies are needed to establish a solidified role for metronomic chemotherapy with other treatment models in modern cancer management.
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Affiliation(s)
- Cem Simsek
- Department of Internal Medicine, Hacettepe University, Ankara, Turkey
| | - Ece Esin
- Department of Medical Oncology, A.Y. Ankara Training Hospital, Ankara, Turkey
| | - Suayib Yalcin
- Department of Medical Oncology, Hacettepe University, Ankara, Turkey
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32
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Looking for A Place for Dose-Dense TMZ Regimens in GBM Patients: An Experience with MGMT Exploratory Evaluation. Bioengineering (Basel) 2019; 6:bioengineering6010011. [PMID: 30678211 PMCID: PMC6466220 DOI: 10.3390/bioengineering6010011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Revised: 01/19/2019] [Accepted: 01/21/2019] [Indexed: 12/23/2022] Open
Abstract
Prolonged exposure to temozolomide (TMZ) could improve clinical outcomes in recurrent glioblastoma multiforme (GBM) patients. We previously developed a dose-dense regimen of TMZ in a phase II study (180 mg/m2 from days 1 to 5 every two weeks). A retrospective analysis of patients with macroscopic residual GBM treated with “post-induction” dose-dense TMZ was conducted, adding an explorative subgroup analyses among patients with different O6-methylguanine DNA methyltransferase (MGMT) expressions (negative vs positive, < vs ≥ of 50 % of cells stained, < vs ≥ 70% of cells stained). Thirty-six patients were evaluated; after a median follow-up of 36 weeks, median Progression Free Survival (PFS) and median Overall Survival (OS) were 19 and 34 weeks, respectively. MGMT expression (70% cut-off) and sex were confirmed as independent predictors for disease control rate (DCR) at multivariate analysis. At univariate analysis ECOG-PS, Sex (female), extensive tumor resection was shown to be related to a longer PFS, while MGMT expression (cut-off 70%) to a shorter PFS. Multivariate analysis with Cox hazard regression confirmed only ECOG-PS as an independent predictor for PFS. ECOG-PS showed to be significant related to a longer OS. Our analysis showed that dose-dense TMZ regimens are still an option for patients with recurrent GBM, but should be used for re-challenge treatments. MGMT immunohistochemistry high expression might be used as a “surrogate” negative predictor for DCR for dd-TMZ treatments.
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Chemotherapy sensitization of glioblastoma by focused ultrasound-mediated delivery of therapeutic liposomes. J Control Release 2018; 295:130-139. [PMID: 30537486 DOI: 10.1016/j.jconrel.2018.12.009] [Citation(s) in RCA: 72] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Revised: 12/04/2018] [Accepted: 12/07/2018] [Indexed: 02/08/2023]
Abstract
In glioblastoma, the benefit from temozolomide chemotherapy is largely limited to a subgroup of patients (30-35%) with tumors exhibiting methylation of the promoter region of the O6-methylguanine-DNA methyltransferase (MGMT) gene. In order to allow more patients to benefit from this treatment, we explored magnetic resonance image-guided microbubble-enhanced low-intensity pulsed focused ultrasound (LIFU) to transiently open the blood-brain barrier and deliver a first-in-class liposome-loaded small molecule MGMT inactivator in mice bearing temozolomide-resistant gliomas. We demonstrate that a liposomal O6-(4-bromothenyl)guanine (O6BTG) derivative can efficiently target MGMT, thereby sensitizing murine and human glioma cells to temozolomide in vitro. Furthermore, we report that image-guided LIFU mediates the delivery of the stable liposomal MGMT inactivator in the tumor region resulting in potent MGMT depletion in vivo. Treatment with this new liposomal MGMT inactivator facilitated by LIFU-mediated blood-brain barrier opening reduced tumor growth and significantly prolonged survival of glioma-bearing mice, when combined with temozolomide chemotherapy. Exploring this novel combined approach in the clinic to treat glioblastoma patients with MGMT promoter-unmethylated tumors is warranted.
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Chammas M, Saadeh F, Maaliki M, Assi H. Therapeutic Interventions in Adult Low-Grade Gliomas. J Clin Neurol 2018; 15:1-8. [PMID: 30198226 PMCID: PMC6325362 DOI: 10.3988/jcn.2019.15.1.1] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Revised: 06/18/2018] [Accepted: 06/19/2018] [Indexed: 01/05/2023] Open
Abstract
Treating adult low-grade gliomas (LGGs) is particularly challenging due to the highly infiltrative nature of this type of brain cancer. Although surgery, radiotherapy, and chemotherapy are the mainstay treatment modalities for LGGs, the optimal combination management plan for a particular patient based on individual symptoms and the risk of treatment-induced toxicity remains unclear. This review highlights the competency and limitations of standard treatment options while providing an essential therapeutic update regarding current clinical trials aimed at implementing targeted therapies with morbidity rates lower than those for current LGG treatments and also augmenting the killing of cancerous cells while maintaining an improved quality of life.
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Affiliation(s)
- Majid Chammas
- American University of Beirut, Faculty of Medicine, Beirut, Lebanon
| | - Fadi Saadeh
- American University of Beirut, Faculty of Medicine, Beirut, Lebanon
| | - Maya Maaliki
- American University of Beirut, Faculty of Medicine, Beirut, Lebanon
| | - Hazem Assi
- Department of Internal Medicine, Naef K. Basile Cancer Institute, American University of Beirut Medical Center, Beirut, Lebanon.
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Dose-dense temozolomide for recurrent high-grade gliomas: a single-center retrospective study. Med Oncol 2018; 35:136. [PMID: 30155806 DOI: 10.1007/s12032-018-1198-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2018] [Accepted: 08/22/2018] [Indexed: 01/10/2023]
Abstract
There are limited treatment modalities after high-grade gliomas recurrence. MGMT depletion modulated by dose-dense temozolomide (ddTMZ) remains a debated therapy for initial TMZ responders. Patients were selected retrospectively from our practice with diagnosis of high-grade gliomas (WHO grade III or IV), and were followed since the start of ddTMZ until death or change of therapy. Twenty-one patients were reviewed, with a median age of 47 (25-61) years and a median of 5.8 (1.5-38.8) cycles of ddTMZ. The majority were males (71.4%). Sixty-six percent received 21 on/28 off ddTMZ schedule, 28.6% daily, and 1 patient received a 7 days on/7 days off schedule. IDH mutation status was available for 18 (85.7%) patients, with 7 (33.3%) IDH mutant and 11 (52.5%) IDH wild type. MGMT methylation was assessed in 6 (28.6%) of the patients, being MGMT methylated in 3 (14.3%) patients, and non-methylated in 3 (14.3%) patients. The majority of patients (57.1%) were receiving ddTMZ in addition to other forms of therapy, including either bevacizumab (38.1%) or tumor-treating fields (TTFields) (19.1%). Overall ddTMZ was well tolerated, with few adverse events reported. The estimated median overall survival after ddTMZ start was 11 months. Median progression-free survival (PFS) was 6 months. Outcomes did not vary between patients receiving ddTMZ alone or those using TTFields or bevacizumab as concomitant therapy, but there was a trend to longer survival with the use of concomitant TTFields. Our results demonstrate benefit of ddTMZ after previous treatment with standard TMZ dosing with no apparent increase in treatment-related toxicities. In summary, ddTMZ should be considered in TMZ responsive patients and warrants further investigation.
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Wang HC, Lin YT, Lin WC, Ho RW, Lin YJ, Tsai NW, Ho JT, Lu CH. Tumor Volume Changes During and After Temozolomide Treatment for Newly Diagnosed Higher-Grade Glioma (III and IV). World Neurosurg 2018; 114:e766-e774. [DOI: 10.1016/j.wneu.2018.03.078] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2017] [Accepted: 03/09/2018] [Indexed: 11/28/2022]
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Liu Y, Feng F, Ji P, Liu B, Ge S, Yang C, Lou M, Liu J, Li B, Gao G, Qu Y, Wang L. Improvement of health related quality of life in patients with recurrent glioma treated with bevacizumab plus daily temozolomide as the salvage therapy. Clin Neurol Neurosurg 2018; 169:64-70. [PMID: 29631109 DOI: 10.1016/j.clineuro.2018.03.026] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2018] [Revised: 03/22/2018] [Accepted: 03/26/2018] [Indexed: 11/17/2022]
Abstract
OBJECTIVES Bevacizumab (BEV) plus daily temozolomide (TMZ) as a salvage therapy have been recommended to recurrent glioma. The objective of this retrospective study was to evaluate the effect of the combined regimen on health related quality of life (HRQL) and treatment response in patients with recurrent glioma. PATIENTS AND METHODS Twenty patients with recurrent glioma were treated with BEV (5-10 mg/kg, i.v. every 2 weeks) plus daily TMZ (daily, 50 mg/m2). The treatment response was evaluated via the RANO criteria. HRQL were measured using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire core 30 (QLQ-C30) and Brain Module (QLQ-BN20). RESULTS Twenty patients received a total of 85 cycles of BEV with a median number of 4 cycles (range: 2-10). No patients showed complete response (CR) to treatment. Twelve patients had partial response (PR), stable disease (SD) in 5 patients with, and 3 patients showed progressive disease (PD). In the functioning domains of QLQ-C30, physical functioning, cognitive functioning and emotional functioning significantly improved after the second cycle of BEV compared to baseline, with the mean score of 45.0 vs. 64.0 (p = 0.020), 55.8 vs. 71.7 (p = 0.020) and 48.3 vs. 67.5 (p = 0.015), respectively. In the symptom scales, the scores of pain and nausea/vomiting significantly decreased compared to baseline from the mean score of 39.1 to 20.0 (p = 0.020) and 29.2 to 16.7 (p = 0.049), respectively. Score of global health status also increased from 47.5 to 63.3 (p = 0.001). As determined with the QLQ-BN20, motor dysfunction (43.3 vs. 25.0, p = 0.021), weakness of legs (36.7 vs. 18.3, p = 0.049), headache (38.3 vs. 20.0, p = 0.040), and drowsiness (50.0 vs. 30.0, p = 0.026) after the second cycle of BEV also significantly improved compared to baseline. CONCLUSION BEV plus daily TMZ as a salvage therapy improved HRQL in patients with recurrent glioma.
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Affiliation(s)
- Yong Liu
- Glioma Research and Therapy Center, Department of neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an City 710038, PR China
| | - Fuqiang Feng
- Glioma Research and Therapy Center, Department of neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an City 710038, PR China; Department of neurosurgery, Shanxi Medical University Second Hospital, Taiyuan City 030001, PR China
| | - Peigang Ji
- Glioma Research and Therapy Center, Department of neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an City 710038, PR China
| | - Bolin Liu
- Glioma Research and Therapy Center, Department of neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an City 710038, PR China
| | - Shunnan Ge
- Glioma Research and Therapy Center, Department of neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an City 710038, PR China
| | - Chen Yang
- Glioma Research and Therapy Center, Department of neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an City 710038, PR China
| | - Miao Lou
- Glioma Research and Therapy Center, Department of neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an City 710038, PR China
| | - Jinghui Liu
- Glioma Research and Therapy Center, Department of neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an City 710038, PR China
| | - Baofu Li
- Glioma Research and Therapy Center, Department of neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an City 710038, PR China
| | - Guodong Gao
- Glioma Research and Therapy Center, Department of neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an City 710038, PR China
| | - Yan Qu
- Glioma Research and Therapy Center, Department of neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an City 710038, PR China
| | - Liang Wang
- Glioma Research and Therapy Center, Department of neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an City 710038, PR China.
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Tena I, Gupta G, Tajahuerce M, Benavent M, Cifrián M, Falcon A, Fonfria M, Del Olmo M, Reboll R, Conde A, Moreno F, Balaguer J, Cañete A, Palasí R, Bello P, Marco A, Ponce JL, Merino JF, Llombart A, Sanchez A, Pacak K. Successful Second-Line Metronomic Temozolomide in Metastatic Paraganglioma: Case Reports and Review of the Literature. CLINICAL MEDICINE INSIGHTS-ONCOLOGY 2018; 12:1179554918763367. [PMID: 29720885 PMCID: PMC5922490 DOI: 10.1177/1179554918763367] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Accepted: 02/04/2018] [Indexed: 12/25/2022]
Abstract
Metastatic pheochromocytoma and paraganglioma (mPHEO/PGL) are frequently associated with succinate dehydrogenase B (SDHB) mutations. Cyclophosphamide-dacarbazine-vincristine (CVD) regimen is recommended as standard chemotherapy for advanced mPHEO/PGL. There is limited evidence to support the role of metronomic schemes (MS) of chemotherapy in mPHEO/PGL treatment. We report 2 patients with SDHB-related mPGL who received a regimen consisting of MS temozolomide (TMZ) and high-dose lanreotide after progression on both CVD chemotherapy and high-dose lanreotide. Molecular profiling of the tumor tissue from both patients revealed hypermethylation of the O6-methylguanine-DNA-methyltransferase (MGMT) promoter. In one patient, progression-free survival was 13 months and the second patient remained under treatment after 27 months of stabilization of metabolic response of his disease. Treatment was well tolerated, and adverse effects were virtually absent. A modification in the scheme of TMZ from standard schemes to MS is safe and feasible and can be considered in patients with progressive mPHEO/PGL refractory to dacarbazine in standard doses.
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Affiliation(s)
- Isabel Tena
- Department of Medical Oncology, Castellon Provincial Hospital, Castellón, Spain.,Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Garima Gupta
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Marcos Tajahuerce
- Department of Medical Oncology, Castellon Provincial Hospital, Castellón, Spain
| | - Marta Benavent
- Medical Oncology Department, Virgen del Rocío University Hospital, Seville, Spain
| | | | - Alejandro Falcon
- Medical Oncology Department, Virgen del Rocío University Hospital, Seville, Spain
| | - María Fonfria
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | | | - Rosa Reboll
- Department of Medical Oncology, Arnau de Vilanova Hospital, Valencia, Spain
| | - Antonio Conde
- Department of Medical Oncology, Castellon Provincial Hospital, Castellón, Spain
| | | | | | | | | | | | | | | | | | - Antonio Llombart
- Department of Medical Oncology, Arnau de Vilanova Hospital, Valencia, Spain
| | - Alfredo Sanchez
- Department of Medical Oncology, Castellon Provincial Hospital, Castellón, Spain
| | - Karel Pacak
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
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Hombach-Klonisch S, Mehrpour M, Shojaei S, Harlos C, Pitz M, Hamai A, Siemianowicz K, Likus W, Wiechec E, Toyota BD, Hoshyar R, Seyfoori A, Sepehri Z, Ande SR, Khadem F, Akbari M, Gorman AM, Samali A, Klonisch T, Ghavami S. Glioblastoma and chemoresistance to alkylating agents: Involvement of apoptosis, autophagy, and unfolded protein response. Pharmacol Ther 2018; 184:13-41. [DOI: 10.1016/j.pharmthera.2017.10.017] [Citation(s) in RCA: 206] [Impact Index Per Article: 29.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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40
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Zhu P, Du XL, Lu G, Zhu JJ. Survival benefit of glioblastoma patients after FDA approval of temozolomide concomitant with radiation and bevacizumab: A population-based study. Oncotarget 2018; 8:44015-44031. [PMID: 28467795 PMCID: PMC5546458 DOI: 10.18632/oncotarget.17054] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2016] [Accepted: 03/20/2017] [Indexed: 11/25/2022] Open
Abstract
Few population-based analyses have investigated survival change in glioblastoma multiforme (GBM) patients treated with concomitant radiotherapy-temozolomide (RT-TMZ) and adjuvant temozolomide (TMZ) and then bevacizumab (BEV) after Food and Drug Administration (FDA) approval, respectively. We aimed to explore the effects on survival with RT-TMZ, adjuvant TMZ and BEV in general GBM population based on the Surveillance, Epidemiology, and End Results (SEER) and Texas Cancer Registry (TCR) databases. A total of 28933 GBM patients from SEER (N = 24578) and TCR (N = 4355) between January 2000 and December 2013 were included. Patients were grouped into three calendar periods based on date of diagnosis: pre-RT-TMZ and pre-BEV (1/2000-2/2005, P1), post-RT-TMZ and pre-BEV (3/2005-4/2009, P2), and post-RT-TMZ and post-BEV (5/2009-12/2013, P3). The association between calendar period of diagnosis and survival was analyzed in SEER and TCR, separately, by the Kaplan-Meier method and Cox proportional hazards model. We found a significant increase in median overall survival (OS) across the three periods in both populations. In multivariate models, the risk of death was significantly reduced during P2 and further decreased in P3, which remained unchanged after stratification. Comparison and validation analysis were performed in the combined dataset, and consistent results were observed. We conclude that the OS of GBM patients in a "real-world" setting has been steadily improved from January 2000 to December 2013, which likely resulted from the administrations of TMZ concomitant with RT and adjuvant TMZ for newly diagnosed GBM and then BEV for recurrent GBM after respective FDA approval.
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Affiliation(s)
- Ping Zhu
- Department of Epidemiology, Human Genetics, and Environmental Sciences, The University of Texas Health Science Center at Houston (UTHealth), School of Public Health, Houston, TX 77030, USA.,The Vivian L. Smith Department of Neurosurgery, The University of Texas Health Science Center at Houston (UTHealth), McGovern Medical School, and Memorial Hermann at Texas Medical Center, Houston, TX 77030, USA
| | - Xianglin L Du
- Department of Epidemiology, Human Genetics, and Environmental Sciences, The University of Texas Health Science Center at Houston (UTHealth), School of Public Health, Houston, TX 77030, USA
| | - Guangrong Lu
- The Vivian L. Smith Department of Neurosurgery, The University of Texas Health Science Center at Houston (UTHealth), McGovern Medical School, and Memorial Hermann at Texas Medical Center, Houston, TX 77030, USA
| | - Jay-Jiguang Zhu
- The Vivian L. Smith Department of Neurosurgery, The University of Texas Health Science Center at Houston (UTHealth), McGovern Medical School, and Memorial Hermann at Texas Medical Center, Houston, TX 77030, USA
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Xie Y, Zeng X, Wu X, Hu J, Zhu Y, Yang X. Hyperbaric oxygen as an adjuvant to temozolomide nanoparticle inhibits glioma growth by inducing G2/M phase arrest. Nanomedicine (Lond) 2018; 13:887-898. [PMID: 29473458 DOI: 10.2217/nnm-2017-0395] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
AIM To study the effects of combinational treatment of hyperbaric oxygen (HBO) and nanotemozolomide in glioma. MATERIALS & METHODS Temozolomide (TMZ)-loaded porous silicon nanoparticles (TMZ/PSi NPs) were prepared. In vitro and in vivo evaluations were performed. RESULTS The cell uptake of TMZ/PSi NPs could be tracked by autofluorescence of porous silicon. The concentration of oxygen in tumor was improved and the antitumor rate was increased to 84.2% in the TMZ/PSi NPs combined with HBO group. The viability of hypoxia-induced glioma C6 cells was decreased and cell cycle was arrested at G2/M phase in response to TMZ/PSi NPs treatment with HBO compared with continuous treatment with hypoxia. CONCLUSION The combinational treatment of TMZ/PSi NPs and HBO could be a promising therapeutic strategy for glioma.
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Affiliation(s)
- Yuanyuan Xie
- College of Life Science & Technology, National Engineering Research Center for Nanomedicine, Huazhong University of Science & Technology, Wuhan, 430074, PR China
| | - Xiaofan Zeng
- College of Life Science & Technology, National Engineering Research Center for Nanomedicine, Huazhong University of Science & Technology, Wuhan, 430074, PR China
| | - Xian Wu
- College of Life Science & Technology, National Engineering Research Center for Nanomedicine, Huazhong University of Science & Technology, Wuhan, 430074, PR China
| | - Jun Hu
- College of Life Science & Technology, National Engineering Research Center for Nanomedicine, Huazhong University of Science & Technology, Wuhan, 430074, PR China
| | - Yanhong Zhu
- College of Life Science & Technology, National Engineering Research Center for Nanomedicine, Huazhong University of Science & Technology, Wuhan, 430074, PR China
| | - Xiangliang Yang
- College of Life Science & Technology, National Engineering Research Center for Nanomedicine, Huazhong University of Science & Technology, Wuhan, 430074, PR China
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Erpolat OP, Akmansu M, Goksel F, Bora H, Yaman E, Büyükberber S. Outcome of Newly Diagnosed Glioblastoma Patients Treated by Radiotherapy plus Concomitant and Adjuvant Temozolomide: A Long-Term Analysis. TUMORI JOURNAL 2018; 95:191-7. [DOI: 10.1177/030089160909500210] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Aims and background Glioblastoma is the most common primary brain tumor in adults. The standard treatment is surgery and radiotherapy. In this study, the results of radiotherapy plus concomitant and adjuvant temozolomide are reported. In addition, the efficiency of adjuvant temozolomide is evaluated. Methods and study design Forty-one patients were analyzed. All patients received radiotherapy (2 Gy daily fractionation dose, median 60 Gy total doses) and concomitant temozolomide (at a daily dose of 75 mg/m2/day, 7 days per week) after surgery. Thirty-one patients received an average of 6 cycles (range, 1–8 cycles) of adjuvant temozolomide after radiotherapy, every 28 days for 5 days at a dose of 200 mg/m2/day. The primary end point was overall survival. Results The median overall survival was 16.7 months. The overall survival significantly increased in the adjuvant temozolomide group compared to the group with no adjuvant therapy (18.9 vs 9.8 months). The difference in overall survival between adjuvant temozolomide cycles of ≤ and >3 was significant (8.7 vs 20 months). On multivariate analyses, the important prognostic factors were type of surgery and application of adjuvant temozolomide for at least 4 cycles. Grade III/IV toxicity was seen in 4% and 6.5% of patients during concomitant and adjuvant therapy, respectively. Conclusions The study confirmed the effectiveness of radiotherapy plus temozolomide in newly diagnosed glioblastoma. It was established that the application of adjuvant temozolomide for at least 4 cycles is required to obtain a benefit from adjuvant therapy. However, further studies are needed to confirm these data.
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Affiliation(s)
- Ozge Petek Erpolat
- Kutahya Evliya Celebi Governement Hospital, Department of Radiation Oncology, Kutahya, Turkey
| | - Muge Akmansu
- Gazi University Medical School, Department of Radiation Oncology, Ankara, Turkey
| | - Fatih Goksel
- Erzurum Numune Hospital, Department of Radiation Oncology, Erzurum, Turkey
| | - Huseyin Bora
- Gazi University Medical School, Department of Radiation Oncology, Ankara, Turkey
| | - Emel Yaman
- Gazi University Medical School, Department of Medical Oncology, Ankara, Turkey
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Pietrantonio F, de Braud F, Milione M, Maggi C, Iacovelli R, Dotti KF, Perrone F, Tamborini E, Caporale M, Berenato R, Leone G, Pellegrinelli A, Bossi I, Festinese F, Federici S, Di Bartolomeo M. Dose-Dense Temozolomide in Patients with MGMT-Silenced Chemorefractory Colorectal Cancer. Target Oncol 2017; 11:337-43. [PMID: 26538496 DOI: 10.1007/s11523-015-0397-2] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
BACKGROUND In a phase II study, we showed that temozolomide (TMZ) was tolerable and active in heavily pre-treated patients with advanced colorectal cancer (CRC) and MGMT methylation. A schedule of dose-dense TMZ may have enhanced activity due to the higher cumulative dose and induction of MGMT depletion, even in resistant tumors. METHODS Thirty-two patients with chemorefractory MGMT-methylated CRC were treated with TMZ at a daily dose of 75 mg/m(2) for 21 consecutive days every 4 weeks, for up to six cycles or until the occurrence of progressive disease/unacceptable toxicity. The primary endpoint was treatment activity in terms of objective response rate (ORR). MGMT protein expression was tested by immunohistochemistry (IHC) on two pooled cohorts: patients from the previous study of standard-dose TMZ and those from the current investigation. RESULTS From November 2013 to December 2014, 32 patients were treated at Fondazione IRCCS Istituto Nazionale dei Tumori. We observed only three episodes of grade 3 asthenia and no significant myelotoxicity. The ORR was 16 % (all partial responses occurring in RAS-BRAF-mutated tumors). Median progression-free survival (PFS) and overall survival (OS) were 2.3 and 6.7 months, respectively. Patients with MGMT-low expression by IHC had a significantly higher ORR (p < 0.0001) and PFS (p = 0.001) compared to those with MGMT-high expression, while no difference was observed in OS. CONCLUSIONS Our data confirm the encouraging activity of TMZ in chemorefractory CRC patients selected for MGMT silencing, even in the RAS-BRAF-mutated population. The role of MGMT IHC as a biomarker for improving patient selection warrants further prospective confirmation.
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Affiliation(s)
- Filippo Pietrantonio
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1 - 20133, Milan, Italy.
| | - Filippo de Braud
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1 - 20133, Milan, Italy
| | - Massimo Milione
- Pathology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Claudia Maggi
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1 - 20133, Milan, Italy
| | - Roberto Iacovelli
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1 - 20133, Milan, Italy
| | - Katia Fiorella Dotti
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1 - 20133, Milan, Italy
| | - Federica Perrone
- Pathology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Elena Tamborini
- Pathology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Marta Caporale
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1 - 20133, Milan, Italy
| | - Rosa Berenato
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1 - 20133, Milan, Italy
| | - Giorgia Leone
- Pathology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | | | - Ilaria Bossi
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1 - 20133, Milan, Italy
| | - Fabrizio Festinese
- Pharmacy Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Stefano Federici
- Pharmacy Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Maria Di Bartolomeo
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1 - 20133, Milan, Italy
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44
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Badruddoja MA, Pazzi M, Sanan A, Schroeder K, Kuzma K, Norton T, Scully T, Mahadevan D, Ahmadi MM. Phase II study of bi-weekly temozolomide plus bevacizumab for adult patients with recurrent glioblastoma. Cancer Chemother Pharmacol 2017; 80:715-721. [DOI: 10.1007/s00280-017-3405-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Accepted: 06/16/2017] [Indexed: 10/19/2022]
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45
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Khan BA, Khan S, White B, Eranki A. Severe pneumocystis jiroveci pneumonia in a patient on temozolomide therapy: A case report and review of literature. Respir Med Case Rep 2017; 22:179-182. [PMID: 28861334 PMCID: PMC5568882 DOI: 10.1016/j.rmcr.2017.08.012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Revised: 07/31/2017] [Accepted: 08/11/2017] [Indexed: 11/17/2022] Open
Abstract
A 66 year old man was diagnosed with CNS diffuse large B-cell lymphoma, and underwent treatment with Temozolomide, Dexamethasone, Rituximab, and radiation therapy, and prolonged steroid taper with Dexamethasone. Approximately one month after this, he presented with severe acute hypoxemic respiratory failure, and was admitted to the Medical Intensive Care Unit. Imaging showed diffuse ground glass opacities. Patient underwent diagnostic bronchoalveolar lavage which was positive for Pneumocystis jiroveci. He did not respond well to appropriate therapy and was transitioned to comfort care per his family's wishes, and expired. Pneumocystis jiroveci should always be included in the differential diagnosis of pneumonia in patients treated with Temozolomide, especially when this agent is used in combination with long term, high dose corticosteroids and radiation therapy.
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Zhou Z, Howard TA, Villano JL. Long-term daily temozolomide with dose-dependent efficacy in MGMT promotor methylation negative recurrent high-grade astrocytoma. Cancer Chemother Pharmacol 2017; 80:1043-1046. [PMID: 28791452 DOI: 10.1007/s00280-017-3415-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Accepted: 08/03/2017] [Indexed: 10/19/2022]
Abstract
Temozolomide (TMZ) for malignant gliomas is traditionally dosed in 5 out of a 28-day cycle, however alternative regimens exist, including dose-dense. Continuous daily dosing is available, but the acceptable dose and duration of therapy is unknown. We document a 40-year-old male with recurrent anaplastic astrocytoma, IDH mutant and MGMT promotor methylation negative, who has well-tolerated continuous daily TMZ for 20 months at 100 mg per day for nearly the length of this period. A trial at 80 mg per day demonstrated disease progression with response upon return to 100 mg per day. Prior to the daily TMZ, the patient underwent three surgical resections, radiation therapy with concurrent TMZ according to the EORTC-NCIC protocol, and subsequently bevacizumab in combination with use of the Optune device. Long-term survival of patients with recurrent malignant gliomas is uncommon, and currently no standard treatment strategies exist for these patients. We present this case to demonstrate the tolerability and dose dependency of prolonged daily TMZ dosing as a therapeutic option for recurrent anaplastic astrocytomas.
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Affiliation(s)
- Zhengqiu Zhou
- Markey Cancer Center, University of Kentucky, Lexington, KY, USA
| | - Tracy A Howard
- Markey Cancer Center, University of Kentucky, Lexington, KY, USA
| | - John L Villano
- Markey Cancer Center, University of Kentucky, Lexington, KY, USA. .,Departments of Medicine, Neurosurgery, and Neurology, University of Kentucky, 800 Rose St., CC446, Lexington, KY, 40536-0093, USA.
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Anjum K, Shagufta BI, Abbas SQ, Patel S, Khan I, Shah SAA, Akhter N, Hassan SSU. Current status and future therapeutic perspectives of glioblastoma multiforme (GBM) therapy: A review. Biomed Pharmacother 2017; 92:681-689. [PMID: 28582760 DOI: 10.1016/j.biopha.2017.05.125] [Citation(s) in RCA: 171] [Impact Index Per Article: 21.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Revised: 05/19/2017] [Accepted: 05/25/2017] [Indexed: 12/16/2022] Open
Abstract
Glioblastoma multiforme (GBM) is the deadliest form of heterogeneous brain cancer. It affects an enormous number of patients every year and the survival is approximately 8 to 15 months. GBM has driven by complex signaling pathways and considered as a most challenging to treat. Standard treatment of GBM includes surgery, radiation therapy, chemotherapy and also the combined treatment. This review article described inter and intra- tumor heterogeneity of GMB. In addition, recent chemotherapeutic agents, with their mechanism of action have been defined. FDA-approved drugs also been focused over here and most importantly highlighting some natural and synthetic and novel anti- glioma agents, that are the main focus of researchers nowadays.
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Affiliation(s)
- Komal Anjum
- Ocean College, Zhejiang University, Hangzhou, 310058, China
| | - Bibi Ibtesam Shagufta
- Department of Zoology, Kohat University of Science and Technology (KUST), K.P.K 26000, Pakistan
| | - Syed Qamar Abbas
- Faculty of Pharmacy, Gomal University D.I.Khan, K.P.K 29050, Pakistan
| | - Seema Patel
- Bioinformatics and Medical Informatics Research Center, San Diego State University, San Diego-92182, USA
| | - Ishrat Khan
- Ocean College, Zhejiang University, Hangzhou, 310058, China
| | | | - Najeeb Akhter
- Ocean College, Zhejiang University, Hangzhou, 310058, China
| | - Syed Shams Ul Hassan
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
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Chakroun RW, Zhang P, Lin R, Schiapparelli P, Quinones-Hinojosa A, Cui H. Nanotherapeutic systems for local treatment of brain tumors. WILEY INTERDISCIPLINARY REVIEWS-NANOMEDICINE AND NANOBIOTECHNOLOGY 2017; 10. [PMID: 28544801 DOI: 10.1002/wnan.1479] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Revised: 04/14/2017] [Accepted: 04/18/2017] [Indexed: 12/31/2022]
Abstract
Malignant brain tumor, including the most common type glioblastoma, are histologically heterogeneous and invasive tumors known as the most devastating neoplasms with high morbidity and mortality. Despite multimodal treatment including surgery, radiotherapy, chemotherapy, and immunotherapy, the disease inevitably recurs and is fatal. This lack of curative options has motivated researchers to explore new treatment strategies and to develop new drug delivery systems (DDSs); however, the unique anatomical, physiological, and pathological features of brain tumors greatly limit the effectiveness of conventional chemotherapy. In this context, we review the recent progress in the development of nanoparticle-based DDSs aiming to address the key challenges in transporting sufficient amount of therapeutic agents into the brain tumor areas while minimizing the potential side effects. We first provide an overview of the standard treatments currently used in the clinic for the management of brain cancers, discussing the effectiveness and limitations of each therapy. We then provide an in-depth review of nanotherapeutic systems that are intended to bypass the blood-brain barrier, overcome multidrug resistance, infiltrate larger tumorous tissue areas, and/or release therapeutic agents in a controlled manner. WIREs Nanomed Nanobiotechnol 2018, 10:e1479. doi: 10.1002/wnan.1479 This article is categorized under: Implantable Materials and Surgical Technologies > Nanomaterials and Implants Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.
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Affiliation(s)
- Rami Walid Chakroun
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA
| | - Pengcheng Zhang
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA
| | - Ran Lin
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA
| | | | | | - Honggang Cui
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA
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Urbschat S, Sippl C, Engelhardt J, Kammers K, Oertel J, Ketter R. Importance of biomarkers in glioblastomas patients receiving local BCNU wafer chemotherapy. Mol Cytogenet 2017; 10:16. [PMID: 28484518 PMCID: PMC5418867 DOI: 10.1186/s13039-017-0317-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Accepted: 04/24/2017] [Indexed: 12/18/2022] Open
Abstract
Background To assess the influence of molecular markers with potential prognostic value to groups of patients with newly diagnosed glioblastoma patients were examined: group A with 36 patients (surgical resection plus standard combined chemoradiotherapy) and group B with 36 patients (surgical resection, standard combined chemoradiotherapy plus carmustine wafer implantation). Our aim was to determine chromosomal alterations, methylation status of MGMT, p15, and p16 (CDKN2A) in order to analyse the influence on patient survival time as well as radio- and chemotherapy responses. Promoter hypermethylation of MGMT, p16, and p15 genes were determined by MS-PCR. Comparative genomic hybridisation (CGH) analyses were performed with isolated, labelled DNA of each tumor to detect genetic alterations. Results Age of onset of the disease showed a significant effect on overall survival (OS) (p < 0.0001). Additional treatment with carmustine wafer (group B) compared to the control group (group A) did not result in improved OS (p = 0.562). Patients with a methylated MGMT promotor showed a significant longer OS compared to those patients with unmethylated MGMT promotor (p = 0.041). Subgroup analyses revealed that patients with methylated p15 showed a significant shorter OS when administered to group B rather than in group A (p = 0.0332). In patients additionally treated with carmustine wafer an amplification of 4q12 showed a significant impact on a reduced OS (p = 0.00835). In group B, a loss of 13q was significantly associated with a longer OS (p = 0.0364). If a loss of chromosome 10 occurred, patients in group B showed a significantly longer OS (p = 0.0123). Conclusion A clinical benefit for the widespread use of additional carmustine wafer implantation could not be found. However, carmustine wafer implantation shows a significantly improved overall survival if parts of chromosome 10 or chromosome 13 are deleted. In cases of 4q12 amplification and in cases of a methylated p15 promotor, the use of carmustine wafers is especially not recommended. The MGMT promoter methylation is a strong prognostic Biomarker for benefit from temozolomide and BCNU chemotherapy.
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Affiliation(s)
- Steffi Urbschat
- Department of Neurosurgery, Saarland University, 66421 Homburg/Saar, Germany
| | - Christoph Sippl
- Department of Neurosurgery, Saarland University, 66421 Homburg/Saar, Germany
| | - Jana Engelhardt
- Department of Neurosurgery, Saarland University, 66421 Homburg/Saar, Germany
| | - Kai Kammers
- Division of Biostatistics and Bioinformatics, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD USA
| | - Joachim Oertel
- Department of Neurosurgery, Saarland University, 66421 Homburg/Saar, Germany
| | - Ralf Ketter
- Department of Neurosurgery, Saarland University, 66421 Homburg/Saar, Germany
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O 6 -Methylguanine-DNA methyltransferase (MGMT): A drugable target in lung cancer? Lung Cancer 2017; 107:91-99. [DOI: 10.1016/j.lungcan.2016.07.014] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2016] [Revised: 07/07/2016] [Accepted: 07/17/2016] [Indexed: 01/01/2023]
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