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De Martino M, Daviaud C, Lira MC, Hernandez-Zirofsky K, Vanpouille-Box C. Dual blockade of PD-1 and CTLA-4 generates long-lasting immunity against irradiated glioblastoma. Cancer Lett 2025; 628:217856. [PMID: 40482909 DOI: 10.1016/j.canlet.2025.217856] [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: 09/13/2024] [Revised: 05/13/2025] [Accepted: 06/04/2025] [Indexed: 06/16/2025]
Abstract
Radiation therapy (RT) can release pro-inflammatory signals to jumpstart an anti-tumor immune response. However, glioblastoma (GBM) often recurs, suggesting that RT might not act as an immune adjuvant in this disease. A possible explanation for the lack of immune stimulation is the use of irradiation regimens that do not effectively stimulate anti-tumor immunity against GBM. Here, we tested the ability of various RT schedules to elicit type I interferon (IFN-I) response and explored its synergy with immunotherapy (IT) to trigger anti-tumor immunity against GBM. Using three murine GBM models, we show in vitro that single dose radiation ranging from 0Gy to 20Gy and fractionated radiation schedules (i.e. 3 daily fractions of 8Gy; 3 × 8Gy and 5 daily fractions of 6Gy; 5 × 6Gy) accumulates double stranded DNA and release IFN-I related cytokines in a dose-dependent fashion; with fractionated schedules being superior in triggering cancer-cell intrinsic IFN-I responses. Side-by-side comparison of various radiation regimen in vivo revealed that 5 × 6Gy better control GBM across the three GBM models tested. However, the addition of anti-PD1 or anti-CTLA4 to an immunogenic radiation schedule (i.e. 5 × 6Gy) did not prolong survival of irradiated mice. Surprisingly, only the dual blockade of PD-1 and CTLA4 promoted the expansion of proliferative T cells and conveyed immunological memory against irradiated GBM. Overall, this study demonstrates that an immunogenic radiation regimen is not sufficient to mount an anti-tumor immune response when combine with IT as monotherapy and highlights the need to combine an immunogenic irradiation with multiple IT to overcome immunosuppression of GBM.
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Affiliation(s)
- Mara De Martino
- Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA
| | - Camille Daviaud
- Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA
| | - María Cecilia Lira
- Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA
| | | | - Claire Vanpouille-Box
- Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA; Sandra and Edward Meyer Cancer Center, 10065, New York, NY, USA.
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2
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Qiu Y, Li Y, Jiang C, Wu X, Liu W, Fan C, Ye X, He L, Xiao S, Zhao Q, Wu W, Chen K, Tan C, Li Y, Wang H, Liu F. Toxicity and Efficacy of Different Target Volume Delineations of Radiation Therapy Based on the Updated Radiation Therapy Oncology Group/National Research Group and European Organization for Research and Treatment of Cancer Guidelines in Patients With Grade 3-4 Glioma: A Randomized Controlled Clinical Trial. Int J Radiat Oncol Biol Phys 2025; 121:1168-1181. [PMID: 39615657 DOI: 10.1016/j.ijrobp.2024.11.094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 11/12/2024] [Accepted: 11/15/2024] [Indexed: 12/22/2024]
Abstract
PURPOSE Our study aimed to evaluate the safety and efficacy of radiation therapy (RT) in the treatment of grade 3-4 glioma by comparing the updated Radiation Therapy Oncology Group (RTOG)/National Research Group (NRG) with European Organization for Research and Treatment of Cancer (EORTC) guidelines for target volume delineation. METHODS AND MATERIALS A total of 245 patients with newly diagnosed World Health Organization grade 3-4 glioma were enrolled and randomly assigned (1:1 ratio) to undergo postoperative RT with concurrent and maintenance temozolomide. The radiation target volume delineation was determined by using either the updated RTOG/NRG (n = 122) or EORTC guidelines (n = 123). The primary endpoint was the toxicity associated with treatment. Progression-free survival (PFS) and overall survival (OS) were considered secondary endpoints. RESULTS No differences in low- or high-grade toxicities between the 2 groups, and neither group exhibited grade 5 toxicities. No significant differences in neurologic toxicities were observed between the RTOG/NRG and EORTC groups. The median PFS in the RTOG/NRG group and the EORTC group was 11.0 months (95% confidence interval [CI], 7.1-14.9 months) and 10.0 months (95% CI, 3.8-16.2 months), respectively (P = .73). The median OS in the RTOG/NRG group and the EORTC group was 19.5 months (95% CI, 14.2-24.8 months) and 18.5 months (95% CI, 12.8-24.2 months), respectively (P = .80). In patients with isocitrate dehydrogenase wild-type glioblastoma, there were no significant differences between the RTOG/NRG group and the EORTC group in median PFS (8.0 months [95% CI, 6.8-9.2 months] vs. 8.0 months [95% CI, 7.0-9.0 months], P = .38) and median OS (12.0 months [95% CI, 7.2-16.8 months] vs. 11.0 months [95% CI, 9.7-12.3 months], P = .10). CONCLUSIONS Compared with EORTC principles, postoperative RT according to RTOG/NRG principles did not increase treatment-related toxicities and was equally effective for patients with grade 3-4 glioma, including the subgroup of patients with isocitrate dehydrogenase wild-type glioblastoma.
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Affiliation(s)
- Yanfang Qiu
- Department of Radiation Oncology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Hunan, China
| | - Yanxian Li
- Department of Radiation Oncology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Hunan, China
| | - Cuihong Jiang
- Department of Radiation Oncology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Hunan, China
| | - Xiangwei Wu
- Department of Radiation Oncology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Hunan, China
| | - Wen Liu
- Department of Radiation Oncology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Hunan, China
| | - Changgen Fan
- Department of Radiation Oncology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Hunan, China
| | - Xu Ye
- Department of Radiation Oncology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Hunan, China
| | - Lili He
- Department of Radiation Oncology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Hunan, China
| | - Shuai Xiao
- Department of Radiation Oncology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Hunan, China
| | - Qi Zhao
- Department of Radiation Oncology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Hunan, China
| | - Wenqiong Wu
- Department of Radiation Oncology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Hunan, China
| | - Kailin Chen
- Department of Radiation Oncology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Hunan, China
| | - Chao Tan
- Department of Radiation Oncology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Hunan, China
| | - Yuyi Li
- Department of Radiation Oncology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Hunan, China
| | - Hui Wang
- Department of Radiation Oncology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Hunan, China; Key Laboratory of Translational Radiation Oncology, Hunan Province, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Changsha, Hunan, China.
| | - Feng Liu
- Department of Radiation Oncology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Hunan, China.
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Vollmuth P, Karschnia P, Sahm F, Park YW, Ahn SS, Jain R. A Radiologist's Guide to IDH-Wildtype Glioblastoma for Efficient Communication With Clinicians: Part II-Essential Information on Post-Treatment Imaging. Korean J Radiol 2025; 26:368-389. [PMID: 40015559 PMCID: PMC11955384 DOI: 10.3348/kjr.2024.0983] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 11/08/2024] [Accepted: 11/30/2024] [Indexed: 03/01/2025] Open
Abstract
Owing to recent advancements in various postoperative treatment modalities, such as radiation, chemotherapy, antiangiogenic treatment, and immunotherapy, the radiological and clinical assessment of patients with isocitrate dehydrogenase-wildtype glioblastoma using post-treatment imaging has become increasingly challenging. This review highlights the challenges in differentiating treatment-related changes such as pseudoprogression, radiation necrosis, and pseudoresponse from true tumor progression and aims to serve as a guideline for efficient communication with clinicians for optimal management of patients with post-treatment imaging.
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Affiliation(s)
- Philipp Vollmuth
- Division for Computational Radiology & Clinical AI (CCIBonn.ai), Clinic for Neuroradiology, University Hospital Bonn, Bonn, Germany
- Medical Faculty Bonn, University of Bonn, Bonn, Germany
- Division of Medical Image Computing, German Cancer Research Center, Heidelberg, Germany
| | - Philipp Karschnia
- Department of Neurosurgery, Ludwig-Maximilians-University, Munich, Germany
- Department of Neurosurgery, Friedrich-Alexander-University University, Erlangen-Nuremberg, Germany
| | - Felix Sahm
- Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany
- Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Yae Won Park
- Department of Radiology and Research Institute of Radiological Science and Center for Clinical Imaging Data Science, Yonsei University College of Medicine, Seoul, Republic of Korea.
| | - Sung Soo Ahn
- Department of Radiology and Research Institute of Radiological Science and Center for Clinical Imaging Data Science, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Rajan Jain
- Department of Radiology, New York University Grossman School of Medicine, New York, USA
- Department of Neurosurgery, New York University Grossman School of Medicine, New York, USA
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Choi KS, Hwang I, Park CK, Park SH, Choi SH. New Subependymal Enhancement After Radiation Therapy in High-Grade Glioma: Utilizing Morphological Features and DSC Perfusion MRI in Differentiate Progression and Post-Radiation Changes. J Magn Reson Imaging 2025; 61:1751-1760. [PMID: 39238277 DOI: 10.1002/jmri.29586] [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: 05/15/2024] [Revised: 08/08/2024] [Accepted: 08/09/2024] [Indexed: 09/07/2024] Open
Abstract
BACKGROUND The specific patterns of subependymal enhancement (SE) that frequently occur as radiation-induced changes in high-grade gliomas following radiotherapy are often overlooked. Perfusion MRI may offer a diagnostic clue. PURPOSE To distinguish between radiation-induced SE and progression in adult high-grade diffuse gliomas after standard treatment. STUDY TYPE Retrospective. POPULATION Ninety-four consecutive high-grade diffuse glioma patients (mean age, 55 ± 14 years; 54 [57.4%] males) with new SE identified in follow-up MRI after completion of surgery plus chemoradiation: progression (N = 74) vs. regression (N = 20). FIELD STRENGTH/SEQUENCE 3 T, gradient-echo dynamic susceptibility contrast-enhanced MRI, 3D gradient-echo contrast-enhanced T1-weighted imaging. ASSESSMENT To differentiate between radiation changes and progression in SE evaluation, multivariable logistic regression was performed using significant variables among SE appearance interval, IDH mutation, morphological features, and rCBV. Cox regression was performed to predict the tumor progression. For the added value of the rCBV, a log-rank test was conducted between the multivariable logistic regression models with and without the rCBV. STATISTICAL TESTS Logistic regression, Cox regression, receiver operating characteristic analysis, log-rank test. RESULTS 38.3% (36/94) patients had first specific SE (9.2 ± 9.5 months after surgery), which disappeared in 21.3% (20/94) after 5.8 ± 5.8 months after initial appearance on post-radiation MRI. IDH mutation, elongated, small lesions with lower rCBV tended to regress: IDH mutation, elongation, diameter, and rCBV_p95; odds ratio, 0.32, 1.92, 1.70, and 2.47, respectively. Qualitative evaluation of shape revealed that thin and curvilinear-shaped SE tended to regress, indicating a significant correlation with quantitative shape features (r = 0.31). In Cox regression, rCBV and lesion shape were significant (hazard ratio = 1.09 and 0.54, respectively). For sub-centimeter lesions, the rCBV showed added value in predicting outcomes (area under the curve, 0.873 vs. 0.836; log-rank test). DATA CONCLUSION Smaller, elongated lesions with lower rCBV and IDH mutation are associated with regression when differentiating radiation changes from progression in high-grade glioma with post-radiotherapy SE. EVIDENCE LEVEL 3 TECHNICAL EFFICACY: Stage 2.
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Affiliation(s)
- Kyu Sung Choi
- Department of Radiology, Seoul National University Hospital, Seoul, Republic of Korea
| | - Inpyeong Hwang
- Department of Radiology, Seoul National University Hospital, Seoul, Republic of Korea
| | - Chul Kee Park
- Department of Neurosurgery, Seoul National University Hospital, Seoul, Republic of Korea
| | - Sung Hye Park
- Department of Pathology, Seoul National University Hospital, Seoul, Republic of Korea
| | - Seung Hong Choi
- Department of Radiology, Seoul National University Hospital, Seoul, Republic of Korea
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Renan A, Bruand M, Jolnerovski M, Diallo A, Demogeot N. Local control and recurrence patterns after stereotactic irradiation delivered in more than 4 fractions for hepatocellular carcinomas and liver metastases: a retrospective study. Radiat Oncol 2025; 20:19. [PMID: 39915761 PMCID: PMC11804025 DOI: 10.1186/s13014-025-02595-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Accepted: 01/31/2025] [Indexed: 02/09/2025] Open
Abstract
BACKGROUND Stereotactic Body Radiation Therapy (SBRT) is a safe and effective treatment for liver metastases or hepatocellular carcinoma (HCC) with a dose-response relationship for local control (LC). Proximity to organs at risk (OAR) often requires dose de-escalation. This study evaluated LC and recurrence patterns in patients administered hepatic SBRT in more than 4 fractions due to dosimetric constraints. METHODS This retrospective study included 33 patients treated with SBRT (Cyberknife®) in more than 4 fractions for HCC or liver metastases, between January 2011 and December 2019. Patients were ineligible for treatment in 3 or 4 fractions due to OAR proximity. Recurrence patterns were analysed according to the volume shared between recurrence and initial target or treatment isodose volumes. RESULTS The primary dose ranged from 35 to 50 Gy delivered in 5 to 7 fractions for the treatment of HCC (39%) or liver metastases (61%) mainly secondary to colorectal cancer (40%). LC rate was 64%, with 12 patients showing recurrence volume overlap with the initial target volume or treatment isodose. In-field recurrence occurred in only 12.5% of patients with most relapses being out-of-field. No grade ≥ 3 events were reported. CONCLUSION Despite dose reductions to spare OAR, SBRT showed satisfactory LC with low toxicity. Out-of-field recurrence remains the most common pattern identified and likely related to underlying disease. Prospective data are necessary to determine whether preserving dose while reducing planning target volume (PTV) coverage could enhance LC. Trial registration All patients were retrospectively registered, and this study is registered at the Health Data Hub site (number HDH414).
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Affiliation(s)
- Alizée Renan
- Academic Department of Radiation Therapy and Brachytherapy, Lorraine Institute of Cancerology-Alexis-Vautrin, 6 avenue de Bourgogne-CS, 30 519, 54 511, Vandoeuvre-Lès-Nancy Cedex, France.
- Faculté de Médecine de Nancy, Université de Lorraine, Vandoeuvre-Lès-Nancy, France.
| | - Marie Bruand
- Academic Department of Radiation Therapy and Brachytherapy, Lorraine Institute of Cancerology-Alexis-Vautrin, 6 avenue de Bourgogne-CS, 30 519, 54 511, Vandoeuvre-Lès-Nancy Cedex, France
- Faculté de Médecine de Nancy, Université de Lorraine, Vandoeuvre-Lès-Nancy, France
| | - Maria Jolnerovski
- Academic Department of Radiation Therapy and Brachytherapy, Lorraine Institute of Cancerology-Alexis-Vautrin, 6 avenue de Bourgogne-CS, 30 519, 54 511, Vandoeuvre-Lès-Nancy Cedex, France
| | - Aboubacar Diallo
- Methodology Biostatistics Unit, Institut de Cancérologie de Lorraine, Vandoeuvre-Les-Nancy, France
| | - Nicolas Demogeot
- Academic Department of Radiation Therapy and Brachytherapy, Lorraine Institute of Cancerology-Alexis-Vautrin, 6 avenue de Bourgogne-CS, 30 519, 54 511, Vandoeuvre-Lès-Nancy Cedex, France
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Jo H, Dalvi A, Yang W, Morozova E, Munoz S, Glasgow SM. A fetal oncogene NUAK2 is an emerging therapeutic target in glioblastoma. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2024.12.31.630965. [PMID: 39803558 PMCID: PMC11722409 DOI: 10.1101/2024.12.31.630965] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 01/16/2025]
Abstract
Glioblastoma Multiforme (GBM) is the most prevalent and highly malignant form of adult brain cancer characterized by poor overall survival rates. Effective therapeutic modalities remain limited, necessitating the search for novel treatments. Neurodevelopmental pathways have been implicated in glioma formation, with key neurodevelopmental regulators being re-expressed or co-opted during glioma tumorigenesis. Here we identified a serine/threonine kinase, NUAK family kinase 2 (NUAK2), as a fetal oncogene in mouse and human brains. We found robust expression of NUAK2 in the embryonic brain that decreases throughout postnatal stages and then is re-expressed in malignant gliomas. However, the role of NUAK2 in GBM tumorigenesis remains unclear. We demonstrate that CRIPSR-Cas9 mediated NUAK2 deletion in GBM cells results in suppression of proliferation, while overexpression leads to enhanced cell growth in both in vitro and in vivo models. Further investigation of the downstream biological processes dysregulated in the absence of NUAK2 reveals that NUAK2 modulates extracellular matrix (ECM) components to facilitate migratory behavior. Lastly, we determined that pharmaceutical inhibition of NUAK2 is sufficient to impede the proliferation and migration of malignant glioma cells. Our results suggest that NUAK2 is an actionable therapeutic target for GBM treatment.
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Affiliation(s)
- Hanhee Jo
- Neurobiology Department, School of Biological Sciences, University of California San Diego, La Jolla, 92093 CA, USA
- Neurosciences Graduate Program, University of California San Diego, La Jolla, 92093 CA, USA
| | - Aneesh Dalvi
- Neurobiology Department, School of Biological Sciences, University of California San Diego, La Jolla, 92093 CA, USA
| | - Wenqi Yang
- Neurobiology Department, School of Biological Sciences, University of California San Diego, La Jolla, 92093 CA, USA
| | - Elizabeth Morozova
- Neurobiology Department, School of Biological Sciences, University of California San Diego, La Jolla, 92093 CA, USA
| | - Sarah Munoz
- Neurobiology Department, School of Biological Sciences, University of California San Diego, La Jolla, 92093 CA, USA
| | - Stacey M. Glasgow
- Neurobiology Department, School of Biological Sciences, University of California San Diego, La Jolla, 92093 CA, USA
- Neurosciences Graduate Program, University of California San Diego, La Jolla, 92093 CA, USA
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7
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Spring BQ, Watanabe K, Ichikawa M, Mallidi S, Matsudaira T, Timerman D, Swain JWR, Mai Z, Wakimoto H, Hasan T. Red light-activated depletion of drug-refractory glioblastoma stem cells and chemosensitization of an acquired-resistant mesenchymal phenotype. Photochem Photobiol 2025; 101:215-229. [PMID: 38922889 PMCID: PMC11664018 DOI: 10.1111/php.13985] [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: 05/08/2024] [Accepted: 06/09/2024] [Indexed: 06/28/2024]
Abstract
Glioblastoma stem cells (GSCs) are potent tumor initiators resistant to radiochemotherapy, and this subpopulation is hypothesized to re-populate the tumor milieu due to selection following conventional therapies. Here, we show that 5-aminolevulinic acid (ALA) treatment-a pro-fluorophore used for fluorescence-guided cancer surgery-leads to elevated levels of fluorophore conversion in patient-derived GSC cultures, and subsequent red light-activation induces apoptosis in both intrinsically temozolomide chemotherapy-sensitive and -resistant GSC phenotypes. Red light irradiation of ALA-treated cultures also exhibits the ability to target mesenchymal GSCs (Mes-GSCs) with induced temozolomide resistance. Furthermore, sub-lethal light doses restore Mes-GSC sensitivity to temozolomide, abrogating GSC-acquired chemoresistance. These results suggest that ALA is not only useful for fluorescence-guided glioblastoma tumor resection, but that it also facilitates a GSC drug-resistance agnostic, red light-activated modality to mop up the surgical margins and prime subsequent chemotherapy.
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Affiliation(s)
- Bryan Q. Spring
- Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
- Department of Physics, Northeastern University, Boston, MA 02115, USA
| | - Kohei Watanabe
- Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
- Healthcare Optics Research Laboratory, Canon USA, Inc., Cambridge MA 02139, USA
| | - Megumi Ichikawa
- Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Srivalleesha Mallidi
- Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
- Department of Biomedical Engineering, Tufts University, Medford, MA 02155, USA
| | - Tatsuyuki Matsudaira
- Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Dmitriy Timerman
- Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Joseph W. R. Swain
- Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Zhiming Mai
- Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Hiroaki Wakimoto
- Brain Tumor Research Center and Molecular Neurosurgery Laboratory, Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Tayyaba Hasan
- Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
- Division of Health Sciences and Technology, Harvard University and Massachusetts Institute of Technology, Cambridge, MA 02139, USA
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Wang X, Sun Q, Liu T, Lu H, Lin X, Wang W, Liu Y, Huang Y, Huang G, Sun H, Chen Q, Wang J, Tian D, Yuan F, Liu L, Wang B, Gu Y, Liu B, Chen L. Single-cell multi-omics sequencing uncovers region-specific plasticity of glioblastoma for complementary therapeutic targeting. SCIENCE ADVANCES 2024; 10:eadn4306. [PMID: 39576855 PMCID: PMC11584018 DOI: 10.1126/sciadv.adn4306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/09/2023] [Accepted: 10/23/2024] [Indexed: 11/24/2024]
Abstract
Glioblastoma (GBM) cells are highly heterogeneous and invasive, leading to treatment resistance and relapse. However, the molecular regulation in and distal to tumors remains elusive. Here, we collected paired tissues from the tumor core (TC) and peritumoral brain (PTB) for integrated snRNA-seq and snATAC-seq analyses. Tumor cells infiltrating PTB from TC behave more like oligodendrocyte progenitor cells than astrocytes at the transcriptome level. Dual-omics analyses further suggest that the distal regulatory regions in the tumor genome and specific transcription factors are potential determinants of regional heterogeneity. Notably, while activator protein 1 (AP-1) is active in all GBM states, its activity declines from TC to PTB, with another transcription factor, BACH1, showing the opposite trend. Combined inhibition of AP-1 and BACH1 more efficiently attenuates the tumor progression in mice and prolongs survival than either single-target treatment. Together, our work reveals marked molecular alterations of infiltrated GBM cells and a synergy of combination therapy targeting intratumor heterogeneity in and distal to GBM.
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Affiliation(s)
- Xin Wang
- RNA Institute, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan University, Wuhan 430072, China
- BGI Research, Hangzhou 310030, China
| | - Qian Sun
- RNA Institute, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan University, Wuhan 430072, China
| | | | - Haoran Lu
- RNA Institute, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan University, Wuhan 430072, China
| | - Xuyi Lin
- BGI Research, Hangzhou 310030, China
| | - Weiwen Wang
- China National GeneBank, BGI Research, Shenzhen 518120, China
| | - Yang Liu
- BGI Research, Hangzhou 310030, China
| | - Yunting Huang
- China National GeneBank, BGI Research, Shenzhen 518120, China
| | | | - Haixi Sun
- BGI Research, Shenzhen 518083, China
- BGI Research, Beijing 102601, China
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Qianxue Chen
- RNA Institute, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan University, Wuhan 430072, China
| | - Junmin Wang
- RNA Institute, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan University, Wuhan 430072, China
| | - Daofeng Tian
- RNA Institute, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan University, Wuhan 430072, China
| | - Fan'en Yuan
- RNA Institute, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan University, Wuhan 430072, China
| | | | - Bo Wang
- China National GeneBank, BGI Research, Shenzhen 518120, China
- BGI Research, Shenzhen 518083, China
| | - Ying Gu
- BGI Research, Hangzhou 310030, China
- BGI Research, Shenzhen 518083, China
- BGI Research, Beijing 102601, China
- Guangdong Provincial Key Laboratory of Genome Read and Write, BGI Research, Shenzhen 518083, China
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Baohui Liu
- RNA Institute, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan University, Wuhan 430072, China
| | - Liang Chen
- RNA Institute, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan University, Wuhan 430072, China
- BGI Research, Hangzhou 310030, China
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Kass L, Thang M, Zhang Y, DeVane C, Logan J, Tessema A, Perry J, Hingtgen S. Development of a biocompatible 3D hydrogel scaffold using continuous liquid interface production for the delivery of cell therapies to treat recurrent glioblastoma. Bioeng Transl Med 2024; 9:e10676. [PMID: 39545092 PMCID: PMC11558199 DOI: 10.1002/btm2.10676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 03/21/2024] [Accepted: 04/18/2024] [Indexed: 11/17/2024] Open
Abstract
Glioblastoma (GBM) is the most common primary malignant brain tumor diagnosed in adults, carrying with it an extremely poor prognosis and limited options for effective treatment. Various cell therapies have emerged as promising candidates for GBM treatment but fail in the clinic due to poor tumor trafficking, poor transplantation efficiency, and high systemic toxicity. In this study, we design, characterize, and test a 3D-printed cell delivery platform that can enhance the survival of therapeutic cells implanted in the GBM resection cavity. Using continuous liquid interface production (CLIP) to generate a biocompatible 3D hydrogel, we demonstrate that we can effectively seed neural stem cells (NSCs) onto the surface of the hydrogel, and that the cells can proliferate to high densities when cultured for 14 days in vitro. We show that NSCs seeded on CLIP scaffolds persist longer than freely injected cells in vivo, proliferating to 20% higher than their original density in 6 days after implantation. Finally, we demonstrate that therapeutic fibroblasts seeded on CLIP more effectively suppress tumor growth and extend survival in a mouse model of LN229 GBM resection compared to the scaffold or therapeutic cells alone. These promising results demonstrate the potential to leverage CLIP to design hydrogels with various features to control the delivery of different types of cell therapies. Future work will include a more thorough evaluation of the immunological response to the material and improvement of the printing resolution for biocompatible aqueous resins.
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Affiliation(s)
- Lauren Kass
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of PharmacyThe University of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
| | - Morrent Thang
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of PharmacyThe University of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
| | - Yu Zhang
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of PharmacyThe University of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
| | - Cathleen DeVane
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of PharmacyThe University of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
| | - Julia Logan
- Department of Chemistry, UNC College of Arts and SciencesThe University of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
| | - Addis Tessema
- Department of Chemistry, UNC College of Arts and SciencesThe University of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
| | - Jillian Perry
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of PharmacyThe University of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
- Center for Nanotechnology in Drug Delivery, Eshelman School of PharmacyThe University of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
| | - Shawn Hingtgen
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of PharmacyThe University of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
- Lineberger Comprehensive Cancer CenterThe University of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
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10
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Senyurek S, Aygun MS, Kilic Durankus N, Akdemir EY, Sezen D, Topkan E, Bolukbasi Y, Selek U. The Systemic Inflammation Response Index Efficiently Discriminates between the Failure Patterns of Patients with Isocitrate Dehydrogenase Wild-Type Glioblastoma Following Radiochemotherapy with FLAIR-Based Gross Tumor Volume Delineation. Brain Sci 2024; 14:922. [PMID: 39335417 PMCID: PMC11430255 DOI: 10.3390/brainsci14090922] [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: 08/11/2024] [Revised: 09/12/2024] [Accepted: 09/13/2024] [Indexed: 09/30/2024] Open
Abstract
BACKGROUND/OBJECTIVES The objective of this study was to assess the connection between the systemic inflammation response index (SIRI) values and failure patterns of patients with IDH wild-type glioblastoma (GB) who underwent radiotherapy (RT) with FLAIR-based gross tumor volume (GTV) delineation. METHODS Seventy-one patients who received RT at a dose of 60 Gy to the GTV and 50 Gy to the clinical target volume (CTV) and had documented recurrence were retrospectively analyzed. Each patient's maximum distance of recurrence (MDR) from the GTV was documented in whichever plane it extended the farthest. The failure patterns were described as intra-GTV, in-CTV/out-GTV, distant, and intra-GTV and distant. For analytical purposes, the failure pattern was categorized into two groups, namely Group 1, intra-GTV or in-CTV/out-GTV, and Group 2, distant or intra-GTV and distant. The SIRI was calculated before surgery and corticosteroid administration. A receiver operating characteristic (ROC) curve analysis was used to determine the optimal SIRI cut-off that distinguishes between the different failure patterns. RESULTS Failure occurred as follows: intra-GTV in 40 (56.3%), in-CTV/out-GTV in 4 (5.6%), distant in 18 (25.4%), and intra-GTV + distant in 9 (12.7%) patients. The mean MDR was 13.5 mm, and recurrent lesions extended beyond 15 mm in only seven patients. Patients with an SIRI score ≥ 3 demonstrated a significantly higher incidence of Group 1 failure patterns than their counterparts with an SIRI score < 3 (74.3% vs. 50.0%; p = 0.035). CONCLUSIONS The present results show that using the SIRI with a cut-off value of ≥3 significantly predicts failure patterns. Additionally, the margin for the GTV can be safely reduced to 15 mm when using FLAIR-based target delineation in patients with GB.
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Affiliation(s)
- Sukran Senyurek
- Department of Radiation Oncology, School of Medicine, Koc University, 03457 Istanbul, Turkey; (S.S.); (N.K.D.); (E.Y.A.); (D.S.); (Y.B.)
| | - Murat Serhat Aygun
- Department of Radiology, Altunizade Acibadem Hospital, 03457 Istanbul, Turkey;
| | - Nulifer Kilic Durankus
- Department of Radiation Oncology, School of Medicine, Koc University, 03457 Istanbul, Turkey; (S.S.); (N.K.D.); (E.Y.A.); (D.S.); (Y.B.)
| | - Eyub Yasar Akdemir
- Department of Radiation Oncology, School of Medicine, Koc University, 03457 Istanbul, Turkey; (S.S.); (N.K.D.); (E.Y.A.); (D.S.); (Y.B.)
| | - Duygu Sezen
- Department of Radiation Oncology, School of Medicine, Koc University, 03457 Istanbul, Turkey; (S.S.); (N.K.D.); (E.Y.A.); (D.S.); (Y.B.)
| | - Erkan Topkan
- Department of Radiation Oncology, Faculty of Medicine, Baskent University, 01120 Adana, Turkey;
| | - Yasemin Bolukbasi
- Department of Radiation Oncology, School of Medicine, Koc University, 03457 Istanbul, Turkey; (S.S.); (N.K.D.); (E.Y.A.); (D.S.); (Y.B.)
| | - Ugur Selek
- Department of Radiation Oncology, School of Medicine, Koc University, 03457 Istanbul, Turkey; (S.S.); (N.K.D.); (E.Y.A.); (D.S.); (Y.B.)
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11
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Tsuchiya T, Kawauchi D, Ohno M, Miyakita Y, Takahashi M, Yanagisawa S, Osawa S, Fujita S, Omura T, Narita Y. Risk Factors of Distant Recurrence and Dissemination of IDH Wild-Type Glioblastoma: A Single-Center Study and Meta-Analysis. Cancers (Basel) 2024; 16:2873. [PMID: 39199644 PMCID: PMC11352485 DOI: 10.3390/cancers16162873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2024] [Revised: 08/16/2024] [Accepted: 08/17/2024] [Indexed: 09/01/2024] Open
Abstract
Isocitrate dehydrogenase (IDH) wild-type glioblastoma (GBM) is a highly aggressive brain tumor with a high recurrence rate despite adjuvant treatment. This study aimed to evaluate the risk factors for non-local recurrence of GBM. In the present study, we analyzed 104 GBMs with a single lesion (non-multifocal or multicentric). Univariate analysis revealed that subventricular zone (SVZ) involvement was significantly associated with non-local recurrence (hazard ratio [HR]: 2.09 [1.08-4.05]). Tumors in contact with the trigone of the lateral ventricle tended to develop subependymal dissemination (p = 0.008). Ventricular opening via surgery did not increase the risk of non-local recurrence in patients with SVZ involvement (p = 0.190). A systematic review was performed to investigate the risk of non-local recurrence, and 21 studies were identified. A meta-analysis of previous studies confirmed SVZ involvement (odds ratio [OR]: 1.30 [1.01-1.67]) and O-6-methylguanine DNA methyltransferase promoter methylation (OR: 1.55 [1.09-2.20]) as significant risk factors for local recurrence. A time-dependent meta-analysis revealed a significant association between SVZ involvement and dissemination (HR: 1.69 [1.09-2.63]), while no significant association was found for distant recurrence (HR: 1.29 [0.74-2.27]). Understanding SVZ involvement and specific tumor locations associated with non-local recurrence provides critical insights for the management of GBM.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Yoshitaka Narita
- Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Tokyo 104-0045, Japan; (T.T.); (D.K.); (M.O.); (Y.M.); (M.T.); (S.Y.); (S.O.); (S.F.); (T.O.)
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12
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Mubeen S, Raza I, Ujjan B, Wasim B, Khan L, Naeem N, Enam SA, Hanif F. Iloperidone and Temozolomide Synergistically Inhibit Growth, Migration and Enhance Apoptosis in Glioblastoma Cells. Biomedicines 2024; 12:1134. [PMID: 38927341 PMCID: PMC11200733 DOI: 10.3390/biomedicines12061134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 05/06/2024] [Accepted: 05/14/2024] [Indexed: 06/28/2024] Open
Abstract
Glioblastoma (GBM) is a fatal astrocytic glioma with poor prognosis and treatment resistance. Repurposing potential FDA-approved drugs like anti-psychotics can address the concerns in a timely and cost-effective manner. Epidemiological studies have shown that patients with schizophrenic using anti-psychotics have a low incidence of GBM. Therefore, we aimed to investigate the therapeutic potential of atypical anti-psychotic Iloperidone (ILO) alone and in combination with Temozolomide (TMZ) against GBM. The study assessed the growth inhibitory effect of ILO, TMZ, and their combination (ILO + TMZ) on U-87MG and T-98G cell lines using an MTT assay. The drug interaction coefficient (CDI) was determined, and doses with synergistic effects were used for subsequent experiments, including migratory, invasion, and TUNEL assays. The expressions of DRD2, β-catenin, Dvl2, Twist, and Slug were assessed by RTq-PCR, whereas the β-catenin protein expression was also determined by immunocytochemistry. ILO (p < 0.05) and TMZ (p < 0.01) significantly inhibited the growth of U-87MG cells at all tested doses. The combination of 60 µM of both drugs showed synergistic activity with CDI < 1. The inhibition of migration and apoptosis was more pronounced in the case of combination treatment (p < 0.001). Inhibition of the invading cells was also found to be significant in ILO- and combination-treated groups (p < 0.001). ILO and combination treatment also significantly downregulated the expression of DRD2, while TMZ upregulated the expression (p < 0.001). The expressions of β-catenin (p < 0.001), Dvl2 (p < 0.001), Twist (p < 0.001), and Slug (p < 0.001) were also significantly downregulated in all treatment groups as compared to the vehicle control. The data suggest that ILO possesses strong growth inhibitory activity, possibly due to its effect on DRD2 and β-catenin expression and has the potential to be repurposed against GBM.
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Affiliation(s)
- Sahar Mubeen
- Department of Anatomy, Dow International Medical College, Dow University of Health Sciences, Karachi 75330, Pakistan;
| | - Iffat Raza
- Department of Anatomy, Karachi Institute of Medical Sciences, Karachi 75080, Pakistan;
| | - Badaruddin Ujjan
- Department of Neurosurgery, Dow University Hospital, Dow University of Health Sciences, Karachi 74200, Pakistan;
| | - Bushra Wasim
- Department of Anatomy, Ziauddin University Hospital, Karachi 75600, Pakistan;
| | - Lubna Khan
- Department of Biochemistry, Dow International Medical College, Dow University of Health Sciences, Karachi 75330, Pakistan;
| | - Nadia Naeem
- Dow Research Institute of Biotechnology & Biomedical Sciences, Karachi 75330, Pakistan;
| | - Syed Ather Enam
- Center of Oncological Research in Surgery, Aga Khan University Hospital, Karachi 74800, Pakistan;
| | - Farina Hanif
- Department of Biochemistry, Dow International Medical College, Dow University of Health Sciences, Karachi 75330, Pakistan;
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13
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Tseng CL, Zeng KL, Mellon EA, Soltys SG, Ruschin M, Lau AZ, Lutsik NS, Chan RW, Detsky J, Stewart J, Maralani PJ, Sahgal A. Evolving concepts in margin strategies and adaptive radiotherapy for glioblastoma: A new future is on the horizon. Neuro Oncol 2024; 26:S3-S16. [PMID: 38437669 PMCID: PMC10911794 DOI: 10.1093/neuonc/noad258] [Citation(s) in RCA: 19] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/06/2024] Open
Abstract
Chemoradiotherapy is the standard treatment after maximal safe resection for glioblastoma (GBM). Despite advances in molecular profiling, surgical techniques, and neuro-imaging, there have been no major breakthroughs in radiotherapy (RT) volumes in decades. Although the majority of recurrences occur within the original gross tumor volume (GTV), treatment of a clinical target volume (CTV) ranging from 1.5 to 3.0 cm beyond the GTV remains the standard of care. Over the past 15 years, the incorporation of standard and functional MRI sequences into the treatment workflow has become a routine practice with increasing adoption of MR simulators, and new integrated MR-Linac technologies allowing for daily pre-, intra- and post-treatment MR imaging. There is now unprecedented ability to understand the tumor dynamics and biology of GBM during RT, and safe CTV margin reduction is being investigated with the goal of improving the therapeutic ratio. The purpose of this review is to discuss margin strategies and the potential for adaptive RT for GBM, with a focus on the challenges and opportunities associated with both online and offline adaptive workflows. Lastly, opportunities to biologically guide adaptive RT using non-invasive imaging biomarkers and the potential to define appropriate volumes for dose modification will be discussed.
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Affiliation(s)
- Chia-Lin Tseng
- Department of Radiation Oncology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada
| | - K Liang Zeng
- Department of Radiation Oncology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada
- Department of Radiation Oncology, Simcoe Muskoka Regional Cancer Program, Royal Victoria Regional Health Centre, University of Toronto, Toronto, Ontario, Canada
| | - Eric A Mellon
- Department of Radiation Oncology, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida, USA
| | - Scott G Soltys
- Department of Radiation Oncology, Stanford University, Stanford, California, USA
| | - Mark Ruschin
- Department of Radiation Oncology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada
| | - Angus Z Lau
- Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario, Canada
- Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Natalia S Lutsik
- Department of Radiation Oncology, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida, USA
| | - Rachel W Chan
- Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario, Canada
| | - Jay Detsky
- Department of Radiation Oncology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada
| | - James Stewart
- Department of Radiation Oncology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada
| | - Pejman J Maralani
- Department of Medical Imaging, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada
| | - Arjun Sahgal
- Department of Radiation Oncology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada
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14
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Luzzi S, Agosti A. Radiomics Multifactorial in Silico Model for Spatial Prediction of Glioblastoma Progression and Recurrence: A Proof-of-Concept. World Neurosurg 2024; 183:e677-e686. [PMID: 38184226 DOI: 10.1016/j.wneu.2024.01.002] [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: 10/02/2023] [Revised: 12/30/2023] [Accepted: 01/01/2024] [Indexed: 01/08/2024]
Abstract
BACKGROUND Radiomics-based prediction of glioblastoma spatial progression and recurrence may improve personalized strategies. However, most prototypes are based on limited monofactorial Gompertzian models of tumor growth. The present study consists of a proof of concept on the accuracy of a radiomics multifactorial in silico model in predicting short-term spatial growth and recurrence of glioblastoma. METHODS A radiomics-based biomathematical multifactorial in silico model was developed using magnetic resonance imaging (MRI) data from a 53-year-old patient with newly diagnosed glioblastoma of the right supramarginal gyrus. Raw and optimized models were derived from the MRI at diagnosis and matched to the preoperative MRI obtained 28 days after diagnosis to test the accuracy in predicting the short-term spatial growth of the tumor. An additional optimized model was derived from the early postoperative MRI and matched to the MRI documenting tumor recurrence to test spatial accuracy in predicting the location of recurrence. The spatial prediction accuracy of the model was reported as an average Jaccard index. RESULTS Optimized models yielded an average Jaccard index of 0.69 and 0.26 for short-term tumor growth and long-term recurrence site, respectively. CONCLUSIONS The present radiomics-based multifactorial in silico model was feasible, reliable, and accurate for short-term spatial prediction of glioblastoma progression. The predictive value for the spatial location of recurrence was still low, and refinements in the description of tissue reorganization in the peritumoral and resected areas may be critical to optimize accuracy further.
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Affiliation(s)
- Sabino Luzzi
- Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy; Neurosurgery Unit, Department of Surgical Sciences, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
| | - Abramo Agosti
- Department of Mathematics, University of Pavia, Pavia, Italy
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15
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Fukami S, Akimoto J, Nagai K, Saito Y, Kohno M. Photodynamic therapy using talaporfin sodium for non-totally resectable malignant glioma. Photodiagnosis Photodyn Ther 2024; 45:103869. [PMID: 38787766 DOI: 10.1016/j.pdpdt.2023.103869] [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: 08/05/2023] [Revised: 10/25/2023] [Accepted: 10/27/2023] [Indexed: 05/26/2024]
Abstract
BACKGROUND For malignant glioma, intraoperative photodynamic therapy (PDT) using talaporfin sodium is a powerful tool for local tumor control, when gross total removal is performed. However, the efficacy of PDT for non-totally resectable malignant glioma has not been clearly confirmed. Therefore, the purpose of this study was to clarify the usefulness of PDT using talaporfin sodium for non-totally resectable malignant glioma. METHODS Eighteen patients with malignant glioma (16 new onset, 2 recurrent) in whom gross total removal was judged to be difficult from the images obtained before surgery were evaluated. Fifteen patients had glioblastoma (14 newly diagnosed, 1 recurrent), and 3 patients had anaplastic oligodendroglioma (2 newly diagnosed, 1 recurrent). The whole resection cavity was subjected to PDT during the surgery. For newly diagnosed glioblastoma, postoperative therapy involved the combined use of radiation and temozolomide. Bevacizumab treatment was also started at an early stage after surgery. RESULTS In some patients, reduction of the residual tumor was observed at an early stage of chemoradiotherapy after the surgery, suggesting the positive effect of PDT. Recurrence occurred in 15 of the 18 patients during the course of treatment. Distant recurrence occurred in 8 of these 15 patients, despite good local tumor control. In the 14 patients with newly diagnosed glioblastoma, the median progression-free survival was almost 10.5 months, and the median overall survival was almost 16.9 months. CONCLUSIONS PDT for malignant glioma is expected to slightly improve local tumor control for non-totally resectable lesions.
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Affiliation(s)
- Shinjiro Fukami
- Department of Neurosurgery, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-023, Japan.
| | - Jiro Akimoto
- Department of Neurosurgery, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-023, Japan; Department of Neurosurgery, Kohsei Chuo General Hospital, Tokyo, Japan
| | - Kenta Nagai
- Department of Neurosurgery, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-023, Japan
| | - Yuki Saito
- Department of Neurosurgery, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-023, Japan
| | - Michihiro Kohno
- Department of Neurosurgery, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-023, Japan
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16
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Seaberg MH, Kazda T, Youland RS, Laack NN, Pafundi DH, Anderson SK, Sarkaria JN, Galanis E, Brown PD, Brinkmann DH. Dosimetric patterns of failure in the era of novel chemoradiotherapy in newly-diagnosed glioblastoma patients. Radiother Oncol 2023; 188:109768. [PMID: 37385378 DOI: 10.1016/j.radonc.2023.109768] [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: 11/18/2022] [Revised: 06/09/2023] [Accepted: 06/21/2023] [Indexed: 07/01/2023]
Abstract
BACKGROUND Patterns of failure (POF) may provide an alternative quantitative endpoint to overall survival for evaluation of novel chemoradiotherapy regimens with glioblastoma. MATERIALS AND METHODS POF of 109 newly-diagnosed glioblastoma patients per 2016 WHO classification who received conformal radiotherapy with concomitant and adjuvant temozolomide were reviewed. Seventy-five of those patients also received an investigational chemotherapy agent (everolimus, erlotinib, or vorinostat). Recurrence volumes were defined with MRI contrast enhancement. POF at protocol (POFp), initial (POFi), and RANO (POFRANO) progression timepoints were characterized by the percentage of recurrence volume within the 95% dose region. POFp, POFi, and POFRANO of each patient were categorized (central, non-central, or both). RESULTS POF of the temozolomide-only control cohort were unchanged (79% central, 12% non-central, and 9% both) across protocol, initial, and RANO progression timepoints. Unlike the temozolomide-only cohort, POF of the collective novel chemotherapy cohort appeared increasingly non-central when comparing POFi with POFp, with a non-central component increasing from 16% to 29% (p = 0.078). POF did not correlate with overall survival or time to progression. CONCLUSION POF of patients receiving a novel chemotherapy appeared to be influenced by the timepoint of analysis and were increasingly non-central at protocol progression as compared with initial recurrence, suggesting that recurrence originates from the central region. Addition of everolimus and vorinostat appeared to influence POF, despite similar survival outcomes with the temozolomide-only control group. In studies dealing with novel therapeutic agents, robust and properly-timed dosimetric POF analysis may be helpful to evaluate biologic aspects of novel agents.
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Affiliation(s)
- Maasa H Seaberg
- University of California San Francisco Medical Center, Department of Radiation Oncology, San Francisco, CA, USA
| | - Tomas Kazda
- Department of Radiation Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic
| | | | - Nadia N Laack
- Mayo Clinic, Department of Radiation Oncology, Rochester, MN, USA
| | - Deanna H Pafundi
- Mayo Clinic, Department of Radiation Oncology, Jacksonville, FL, USA
| | | | - Jann N Sarkaria
- Mayo Clinic, Department of Radiation Oncology, Rochester, MN, USA
| | | | - Paul D Brown
- Mayo Clinic, Department of Radiation Oncology, Rochester, MN, USA
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17
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Hu LS, D'Angelo F, Weiskittel TM, Caruso FP, Fortin Ensign SP, Blomquist MR, Flick MJ, Wang L, Sereduk CP, Meng-Lin K, De Leon G, Nespodzany A, Urcuyo JC, Gonzales AC, Curtin L, Lewis EM, Singleton KW, Dondlinger T, Anil A, Semmineh NB, Noviello T, Patel RA, Wang P, Wang J, Eschbacher JM, Hawkins-Daarud A, Jackson PR, Grunfeld IS, Elrod C, Mazza GL, McGee SC, Paulson L, Clark-Swanson K, Lassiter-Morris Y, Smith KA, Nakaji P, Bendok BR, Zimmerman RS, Krishna C, Patra DP, Patel NP, Lyons M, Neal M, Donev K, Mrugala MM, Porter AB, Beeman SC, Jensen TR, Schmainda KM, Zhou Y, Baxter LC, Plaisier CL, Li J, Li H, Lasorella A, Quarles CC, Swanson KR, Ceccarelli M, Iavarone A, Tran NL. Integrated molecular and multiparametric MRI mapping of high-grade glioma identifies regional biologic signatures. Nat Commun 2023; 14:6066. [PMID: 37770427 PMCID: PMC10539500 DOI: 10.1038/s41467-023-41559-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Accepted: 09/06/2023] [Indexed: 09/30/2023] Open
Abstract
Sampling restrictions have hindered the comprehensive study of invasive non-enhancing (NE) high-grade glioma (HGG) cell populations driving tumor progression. Here, we present an integrated multi-omic analysis of spatially matched molecular and multi-parametric magnetic resonance imaging (MRI) profiling across 313 multi-regional tumor biopsies, including 111 from the NE, across 68 HGG patients. Whole exome and RNA sequencing uncover unique genomic alterations to unresectable invasive NE tumor, including subclonal events, which inform genomic models predictive of geographic evolution. Infiltrative NE tumor is alternatively enriched with tumor cells exhibiting neuronal or glycolytic/plurimetabolic cellular states, two principal transcriptomic pathway-based glioma subtypes, which respectively demonstrate abundant private mutations or enrichment in immune cell signatures. These NE phenotypes are non-invasively identified through normalized K2 imaging signatures, which discern cell size heterogeneity on dynamic susceptibility contrast (DSC)-MRI. NE tumor populations predicted to display increased cellular proliferation by mean diffusivity (MD) MRI metrics are uniquely associated with EGFR amplification and CDKN2A homozygous deletion. The biophysical mapping of infiltrative HGG potentially enables the clinical recognition of tumor subpopulations with aggressive molecular signatures driving tumor progression, thereby informing precision medicine targeting.
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Affiliation(s)
- Leland S Hu
- Department of Radiology, Mayo Clinic Arizona, Phoenix, AZ, USA.
- Department of Cancer Biology, Mayo Clinic Arizona, Scottsdale, AZ, USA.
- Department of Neurological Surgery, Mayo Clinic Arizona, Scottsdale, AZ, USA.
| | - Fulvio D'Angelo
- Department of Neurological Surgery, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA.
| | - Taylor M Weiskittel
- Mayo Clinic Alix School of Medicine Minnesota, Rochester, MN, USA
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA
| | - Francesca P Caruso
- Department of Electrical Engineering and Information Technologies, University of Naples, "Federico II", I-80128, Naples, Italy
- BIOGEM Institute of Molecular Biology and Genetics, I-83031, Ariano Irpino, Italy
| | - Shannon P Fortin Ensign
- Department of Cancer Biology, Mayo Clinic Arizona, Scottsdale, AZ, USA
- Department of Hematology and Oncology, Mayo Clinic Arizona, Phoenix, AZ, USA
| | - Mylan R Blomquist
- Department of Cancer Biology, Mayo Clinic Arizona, Scottsdale, AZ, USA
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA
- Mayo Clinic Alix School of Medicine Arizona, Scottsdale, AZ, USA
| | - Matthew J Flick
- Department of Radiology, Mayo Clinic Arizona, Phoenix, AZ, USA
- Department of Cancer Biology, Mayo Clinic Arizona, Scottsdale, AZ, USA
- Mayo Clinic Alix School of Medicine Arizona, Scottsdale, AZ, USA
| | - Lujia Wang
- H. Milton Stewart School of Industrial and Systems Engineering, Georgia Institute of Technology, Atlanta, GA, USA
| | - Christopher P Sereduk
- Department of Cancer Biology, Mayo Clinic Arizona, Scottsdale, AZ, USA
- Department of Neurological Surgery, Mayo Clinic Arizona, Scottsdale, AZ, USA
| | - Kevin Meng-Lin
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA
| | - Gustavo De Leon
- Department of Neurological Surgery, Mayo Clinic Arizona, Scottsdale, AZ, USA
| | - Ashley Nespodzany
- Department of Neuroimaging Research, Barrow Neurological Institute, Dignity Health, Phoenix, AZ, USA
| | - Javier C Urcuyo
- Department of Neurological Surgery, Mayo Clinic Arizona, Scottsdale, AZ, USA
| | - Ashlyn C Gonzales
- Department of Neuroimaging Research, Barrow Neurological Institute, Dignity Health, Phoenix, AZ, USA
| | - Lee Curtin
- Department of Neurological Surgery, Mayo Clinic Arizona, Scottsdale, AZ, USA
| | - Erika M Lewis
- School of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ, USA
| | - Kyle W Singleton
- Department of Neurological Surgery, Mayo Clinic Arizona, Scottsdale, AZ, USA
| | | | - Aliya Anil
- Department of Neuroimaging Research, Barrow Neurological Institute, Dignity Health, Phoenix, AZ, USA
| | - Natenael B Semmineh
- Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Teresa Noviello
- Department of Electrical Engineering and Information Technologies, University of Naples, "Federico II", I-80128, Naples, Italy
- BIOGEM Institute of Molecular Biology and Genetics, I-83031, Ariano Irpino, Italy
| | - Reyna A Patel
- Department of Radiology, Mayo Clinic Arizona, Phoenix, AZ, USA
| | - Panwen Wang
- Quantitative Health Sciences, Mayo Clinic Arizona, Scottsdale, AZ, USA
| | - Junwen Wang
- Division of Applied Oral Sciences & Community Dental Care, The University of Hong Kong, Hong Kong SAR, China
| | - Jennifer M Eschbacher
- Department of Neuropathology, Barrow Neurological Institute, Dignity Health, Phoenix, AZ, USA
| | | | - Pamela R Jackson
- Department of Neurological Surgery, Mayo Clinic Arizona, Scottsdale, AZ, USA
| | - Itamar S Grunfeld
- Department of Psychology, Hunter College, The City University of New York, New York, NY, USA
- Department of Psychology, The Graduate Center, The City University of New York, New York, NY, USA
| | | | - Gina L Mazza
- Quantitative Health Sciences, Mayo Clinic Arizona, Scottsdale, AZ, USA
| | - Sam C McGee
- Department of Speech and Hearing Science, Arizona State University, Tempe, AZ, USA
| | - Lisa Paulson
- Department of Neurological Surgery, Mayo Clinic Arizona, Scottsdale, AZ, USA
| | | | | | - Kris A Smith
- Department of Neurosurgery, Barrow Neurological Institute, Dignity Health, Phoenix, AZ, USA
| | - Peter Nakaji
- Department of Neurosurgery, Banner University Medical Center, University of Arizona, Phoenix, AZ, USA
| | - Bernard R Bendok
- Department of Neurological Surgery, Mayo Clinic Arizona, Scottsdale, AZ, USA
| | - Richard S Zimmerman
- Department of Neurological Surgery, Mayo Clinic Arizona, Scottsdale, AZ, USA
| | - Chandan Krishna
- Department of Neurological Surgery, Mayo Clinic Arizona, Scottsdale, AZ, USA
| | - Devi P Patra
- Department of Neurological Surgery, Mayo Clinic Arizona, Scottsdale, AZ, USA
| | - Naresh P Patel
- Department of Neurological Surgery, Mayo Clinic Arizona, Scottsdale, AZ, USA
| | - Mark Lyons
- Department of Neurological Surgery, Mayo Clinic Arizona, Scottsdale, AZ, USA
| | - Matthew Neal
- Department of Neurological Surgery, Mayo Clinic Arizona, Scottsdale, AZ, USA
| | - Kliment Donev
- Department of Pathology, Mayo Clinic Arizona, Phoenix, AZ, USA
| | | | - Alyx B Porter
- Department of Neurology, Mayo Clinic Arizona, Phoenix, AZ, USA
| | - Scott C Beeman
- School of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ, USA
| | | | - Kathleen M Schmainda
- Departments of Biophysics and Radiology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Yuxiang Zhou
- Department of Radiology, Mayo Clinic Arizona, Phoenix, AZ, USA
| | - Leslie C Baxter
- Department of Radiology, Mayo Clinic Arizona, Phoenix, AZ, USA
- Departments of Psychiatry and Psychology, Mayo Clinic, AZ, USA
| | - Christopher L Plaisier
- School of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ, USA
| | - Jing Li
- H. Milton Stewart School of Industrial and Systems Engineering, Georgia Institute of Technology, Atlanta, GA, USA
| | - Hu Li
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA
| | - Anna Lasorella
- Department of Biochemistry and Molecular Biology, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - C Chad Quarles
- Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Kristin R Swanson
- Department of Cancer Biology, Mayo Clinic Arizona, Scottsdale, AZ, USA
- Department of Neurological Surgery, Mayo Clinic Arizona, Scottsdale, AZ, USA
| | - Michele Ceccarelli
- Department of Public Health Sciences, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA.
| | - Antonio Iavarone
- Department of Neurological Surgery, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA.
| | - Nhan L Tran
- Department of Cancer Biology, Mayo Clinic Arizona, Scottsdale, AZ, USA.
- Department of Neurological Surgery, Mayo Clinic Arizona, Scottsdale, AZ, USA.
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18
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Huang-Hobbs E, Cheng YT, Ko Y, Luna-Figueroa E, Lozzi B, Taylor KR, McDonald M, He P, Chen HC, Yang Y, Maleki E, Lee ZF, Murali S, Williamson MR, Choi D, Curry R, Bayley J, Woo J, Jalali A, Monje M, Noebels JL, Harmanci AS, Rao G, Deneen B. Remote neuronal activity drives glioma progression through SEMA4F. Nature 2023; 619:844-850. [PMID: 37380778 PMCID: PMC10840127 DOI: 10.1038/s41586-023-06267-2] [Citation(s) in RCA: 74] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 05/26/2023] [Indexed: 06/30/2023]
Abstract
The tumour microenvironment plays an essential role in malignancy, and neurons have emerged as a key component of the tumour microenvironment that promotes tumourigenesis across a host of cancers1,2. Recent studies on glioblastoma (GBM) highlight bidirectional signalling between tumours and neurons that propagates a vicious cycle of proliferation, synaptic integration and brain hyperactivity3-8; however, the identity of neuronal subtypes and tumour subpopulations driving this phenomenon is incompletely understood. Here we show that callosal projection neurons located in the hemisphere contralateral to primary GBM tumours promote progression and widespread infiltration. Using this platform to examine GBM infiltration, we identified an activity-dependent infiltrating population present at the leading edge of mouse and human tumours that is enriched for axon guidance genes. High-throughput, in vivo screening of these genes identified SEMA4F as a key regulator of tumourigenesis and activity-dependent progression. Furthermore, SEMA4F promotes the activity-dependent infiltrating population and propagates bidirectional signalling with neurons by remodelling tumour-adjacent synapses towards brain network hyperactivity. Collectively our studies demonstrate that subsets of neurons in locations remote to primary GBM promote malignant progression, and also show new mechanisms of glioma progression that are regulated by neuronal activity.
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Affiliation(s)
- Emmet Huang-Hobbs
- The Integrative Molecular and Biomedical Sciences Graduate Program, Baylor College of Medicine, Houston, TX, USA
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA
- Center for Cancer Neuroscience, Baylor College of Medicine, Houston, TX, USA
| | - Yi-Ting Cheng
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA
- Center for Cancer Neuroscience, Baylor College of Medicine, Houston, TX, USA
- Program in Developmental Biology, Baylor College of Medicine, Houston, TX, USA
| | - Yeunjung Ko
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA
- Center for Cancer Neuroscience, Baylor College of Medicine, Houston, TX, USA
- Program in Immunology and Microbiology, Baylor College of Medicine, Houston, TX, USA
- Department of Neurosurgery, Baylor College of Medicine, Houston, TX, USA
| | - Estefania Luna-Figueroa
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA
- Center for Cancer Neuroscience, Baylor College of Medicine, Houston, TX, USA
| | - Brittney Lozzi
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA
- Center for Cancer Neuroscience, Baylor College of Medicine, Houston, TX, USA
- Department of Neurosurgery, Baylor College of Medicine, Houston, TX, USA
- Program in Genetics and Genomics, Baylor College of Medicine, Houston, TX, USA
| | - Kathryn R Taylor
- Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA
| | - Malcolm McDonald
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA
- Center for Cancer Neuroscience, Baylor College of Medicine, Houston, TX, USA
- Program in Development, Disease, Models and Therapeutics, Baylor College of Medicine, Houston, TX, USA
| | - Peihao He
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA
- Center for Cancer Neuroscience, Baylor College of Medicine, Houston, TX, USA
- Program in Cancer Cell Biology, Baylor College of Medicine, Houston, TX, USA
| | - Hsiao-Chi Chen
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA
- Center for Cancer Neuroscience, Baylor College of Medicine, Houston, TX, USA
- Program in Cancer Cell Biology, Baylor College of Medicine, Houston, TX, USA
| | - Yuhui Yang
- Department of Neurosurgery, Baylor College of Medicine, Houston, TX, USA
| | - Ehson Maleki
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA
- Center for Cancer Neuroscience, Baylor College of Medicine, Houston, TX, USA
| | - Zhung-Fu Lee
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA
- Center for Cancer Neuroscience, Baylor College of Medicine, Houston, TX, USA
- Program in Development, Disease, Models and Therapeutics, Baylor College of Medicine, Houston, TX, USA
| | - Sanjana Murali
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA
- Center for Cancer Neuroscience, Baylor College of Medicine, Houston, TX, USA
- Program in Cancer Cell Biology, Baylor College of Medicine, Houston, TX, USA
| | - Michael R Williamson
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA
- Center for Cancer Neuroscience, Baylor College of Medicine, Houston, TX, USA
| | - Dongjoo Choi
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA
- Center for Cancer Neuroscience, Baylor College of Medicine, Houston, TX, USA
| | - Rachel Curry
- The Integrative Molecular and Biomedical Sciences Graduate Program, Baylor College of Medicine, Houston, TX, USA
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA
| | - James Bayley
- Department of Neurosurgery, Baylor College of Medicine, Houston, TX, USA
| | - Junsung Woo
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA
- Center for Cancer Neuroscience, Baylor College of Medicine, Houston, TX, USA
| | - Ali Jalali
- Center for Cancer Neuroscience, Baylor College of Medicine, Houston, TX, USA
- Department of Neurosurgery, Baylor College of Medicine, Houston, TX, USA
| | - Michelle Monje
- Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA
- Department of Neurosurgery, Stanford University, Stanford, CA, USA
- Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA
| | - Jeffrey L Noebels
- Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, TX, USA
- Department of Neurology, Baylor College of Medicine, Houston, TX, USA
| | - Akdes Serin Harmanci
- Center for Cancer Neuroscience, Baylor College of Medicine, Houston, TX, USA
- Department of Neurosurgery, Baylor College of Medicine, Houston, TX, USA
| | - Ganesh Rao
- Center for Cancer Neuroscience, Baylor College of Medicine, Houston, TX, USA
- Department of Neurosurgery, Baylor College of Medicine, Houston, TX, USA
| | - Benjamin Deneen
- The Integrative Molecular and Biomedical Sciences Graduate Program, Baylor College of Medicine, Houston, TX, USA.
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA.
- Center for Cancer Neuroscience, Baylor College of Medicine, Houston, TX, USA.
- Program in Developmental Biology, Baylor College of Medicine, Houston, TX, USA.
- Department of Neurosurgery, Baylor College of Medicine, Houston, TX, USA.
- Program in Development, Disease, Models and Therapeutics, Baylor College of Medicine, Houston, TX, USA.
- Program in Cancer Cell Biology, Baylor College of Medicine, Houston, TX, USA.
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19
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Cumba Garcia LM, Bouchal SM, Bauman MMJ, Parney IF. Advancements and Technical Considerations for Extracellular Vesicle Isolation and Biomarker Identification in Glioblastoma. Neurosurgery 2023; 93:33-42. [PMID: 36749103 DOI: 10.1227/neu.0000000000002393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Accepted: 12/06/2022] [Indexed: 02/08/2023] Open
Abstract
Extracellular vesicles (EVs) are membrane-bound particles released by all cells. Previous research has found that these microscopic vesicles contribute to intercellular signaling and communication. EVs carry a variety of cargo, including nucleic acids, proteins, metabolites, and lipids. The composition of EVs varies based on cell of origin. Therefore, EVs can serve as an important biomarker in the diagnosis and treatment of various cancers. EVs derived from glioblastoma (GBM) cells carry biomarkers, which could serve as the basis for a potential diagnostic strategy known as liquid biopsy. Multiple EV isolation techniques exist, including ultrafiltration, size exclusion chromatography, flow field-flow fractionation, sequential filtration, differential ultracentrifugation, and density-gradient ultracentrifugation. Recent and ongoing work aims to identify cellular markers to distinguish GBM-derived EVs from those released by noncancerous cells. Strategies include proteomic analysis of GBM EVs, identification of GBM-specific metabolites, and use of Food and Drug Administration-approved 5-aminolevulinic acid-an oral agent that causes fluorescence of GBM cells-to recognize GBM EVs in a patient's blood. In addition, accurately and precisely monitoring changes in EV cargo concentrations could help differentiate between pseudoprogression and GBM recurrence, thus preventing unnecessary surgical interventions.
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Affiliation(s)
- Luz M Cumba Garcia
- Department of Immunology, Mayo Clinic Graduate School of Biomedical Sciences, Rochester, Minnesota, USA
| | - Samantha M Bouchal
- Mayo Clinic Alix School of Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Megan M J Bauman
- Mayo Clinic Alix School of Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Ian F Parney
- Department of Neurological Surgery, Mayo Clinic, Rochester, Minnesota, USA
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20
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Guberina N, Padeberg F, Pöttgen C, Guberina M, Lazaridis L, Jabbarli R, Deuschl C, Herrmann K, Blau T, Wrede KH, Keyvani K, Scheffler B, Hense J, Layer JP, Glas M, Sure U, Stuschke M. Location of Recurrences after Trimodality Treatment for Glioblastoma with Respect to the Delivered Radiation Dose Distribution and Its Influence on Prognosis. Cancers (Basel) 2023; 15:cancers15112982. [PMID: 37296942 DOI: 10.3390/cancers15112982] [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: 03/24/2023] [Revised: 05/22/2023] [Accepted: 05/26/2023] [Indexed: 06/12/2023] Open
Abstract
BACKGROUND While prognosis of glioblastoma after trimodality treatment is well examined, recurrence pattern with respect to the delivered dose distribution is less well described. Therefore, here we examine the gain of additional margins around the resection cavity and gross-residual-tumor. METHODS All recurrent glioblastomas initially treated with radiochemotherapy after neurosurgery were included. The percentage overlap of the recurrence with the gross tumor volume (GTV) expanded by varying margins (10 mm to 20 mm) and with the 95% and 90% isodose was measured. Competing-risks analysis was performed in dependence on recurrence pattern. RESULTS Expanding the margins from 10 mm to 15 mm, to 20 mm, to the 95%- and 90% isodose of the delivered dose distribution with a median margin of 27 mm did moderately increase the proportion of relative in-field recurrence volume from 64% to 68%, 70%, 88% and 88% (p < 0.0001). Overall survival of patients with in-and out-field recurrence was similar (p = 0.7053). The only prognostic factor significantly associated with out-field recurrence was multifocality of recurrence (p = 0.0037). Cumulative incidences of in-field recurrences at 24 months were 60%, 22% and 11% for recurrences located within a 10 mm margin, outside a 10 mm margin but within the 95% isodose, or outside the 95% isodose (p < 0.0001). Survival from recurrence was improved after complete resection (p = 0.0069). Integrating these data into a concurrent-risk model shows that extending margins beyond 10 mm has only small effects on survival hardly detectable by clinical trials. CONCLUSIONS Two-thirds of recurrences were observed within a 10 mm margin around the GTV. Smaller margins reduce normal brain radiation exposure allowing for more extensive salvage radiation therapy options in case of recurrence. Prospective trials using margins smaller than 20 mm around the GTV are warranted.
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Affiliation(s)
- Nika Guberina
- Department of Radiation Therapy, West German Cancer Center, University of Duisburg-Essen, University Hospital Essen, 45147 Essen, Germany
| | - Florian Padeberg
- Department of Radiation Therapy, West German Cancer Center, University of Duisburg-Essen, University Hospital Essen, 45147 Essen, Germany
| | - Christoph Pöttgen
- Department of Radiation Therapy, West German Cancer Center, University of Duisburg-Essen, University Hospital Essen, 45147 Essen, Germany
| | - Maja Guberina
- Department of Radiation Therapy, West German Cancer Center, University of Duisburg-Essen, University Hospital Essen, 45147 Essen, Germany
| | - Lazaros Lazaridis
- Department of Neurology, University of Duisburg-Essen, University Hospital Essen, 45147 Essen, Germany
| | - Ramazan Jabbarli
- Department of Neurosurgery and Spine Surgery, West German Cancer Center, University of Duisburg-Essen, University Hospital Essen, 45147 Essen, Germany
| | - Cornelius Deuschl
- Institute of Diagnostic and Interventional Radiology and Neuroradiology, University of Duisburg-Essen, University Hospital Essen, 45147 Essen, Germany
| | - Ken Herrmann
- Department of Nuclear Medicine, University Duisburg-Essen, University Hospital Essen, 45147 Essen, Germany
| | - Tobias Blau
- Institute of Neuropathology, University of Duisburg-Essen, University Hospital Essen, 45147 Essen, Germany
| | - Karsten H Wrede
- Department of Neurosurgery and Spine Surgery, West German Cancer Center, University of Duisburg-Essen, University Hospital Essen, 45147 Essen, Germany
| | - Kathy Keyvani
- Institute of Neuropathology, University of Duisburg-Essen, University Hospital Essen, 45147 Essen, Germany
| | - Björn Scheffler
- German Cancer Consortium (DKTK), Partner Site University Hospital Essen, 45147 Essen, Germany
- DKFZ-Division Translational Neurooncology at the West German Cancer Center (WTZ), DKTK Partner Site, University Duisburg-Essen, University Hospital Essen, 45147 Essen, Germany
| | - Jörg Hense
- Department of Medical Oncology, West German Cancer Center, University of Duisburg-Essen, University Hospital Essen, 45147 Essen, Germany
| | - Julian P Layer
- Department of Radiation Oncology, University of Bonn, University Hospital Bonn, 53127 Bonn, Germany
- Institute of Experimental Oncology, University of Bonn, University Hospital Bonn, 53127 Bonn, Germany
| | - Martin Glas
- Department of Neurology, University of Duisburg-Essen, University Hospital Essen, 45147 Essen, Germany
| | - Ulrich Sure
- Department of Neurosurgery and Spine Surgery, West German Cancer Center, University of Duisburg-Essen, University Hospital Essen, 45147 Essen, Germany
| | - Martin Stuschke
- Department of Radiation Therapy, West German Cancer Center, University of Duisburg-Essen, University Hospital Essen, 45147 Essen, Germany
- German Cancer Consortium (DKTK), Partner Site University Hospital Essen, 45147 Essen, Germany
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21
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Datta D, Dasgupta A, Chatterjee A, Sahu A, Bhattacharya K, Meena L, Joshi K, Puranik A, Dev I, Moiyadi A, Shetty P, Singh V, Patil V, Menon N, Epari S, Sahay A, Gupta T. Imaging-Based Patterns of Failure following Re-Irradiation for Recurrent/Progressive High-Grade Glioma. J Pers Med 2023; 13:685. [PMID: 37109071 PMCID: PMC10144403 DOI: 10.3390/jpm13040685] [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: 01/13/2023] [Revised: 03/17/2023] [Accepted: 04/17/2023] [Indexed: 04/29/2023] Open
Abstract
BACKGROUND Re-irradiation (ReRT) is an effective treatment modality in appropriately selected patients with recurrent/progressive high-grade glioma (HGG). The literature is limited regarding recurrence patterns following ReRT, which was investigated in the current study. METHODS Patients with available radiation (RT) contours, dosimetry, and imaging-based evidence of recurrence were included in the retrospective study. All patients were treated with fractionated focal conformal RT. Recurrence was detected on imaging with magnetic resonance imaging (MRI) and/ or amino-acid positron emission tomography (PET), which was co-registered with the RT planning dataset. Failure patterns were classified as central, marginal, and distant if >80%, 20-80%, or <20% of the recurrence volumes were within 95% isodose lines, respectively. RESULTS Thirty-seven patients were included in the current analysis. A total of 92% of patients had undergone surgery before ReRT, and 84% received chemotherapy. The median time to recurrence was 9 months. Central, marginal, and distant failures were seen in 27 (73%), 4 (11%), and 6 (16%) patients, respectively. None of the patient-, disease-, or treatment-related factors were significantly different across different recurrence patterns. CONCLUSION Failures are seen predominantly within the high-dose region following ReRT in recurrent/ progressive HGG.
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Affiliation(s)
- Debanjali Datta
- Department of Radiation Oncology, Tata Memorial Centre, Mumbai 400012, India (A.D.)
- Homi Bhabha National Institute (HBNI), Mumbai 400012, India
| | - Archya Dasgupta
- Department of Radiation Oncology, Tata Memorial Centre, Mumbai 400012, India (A.D.)
- Homi Bhabha National Institute (HBNI), Mumbai 400012, India
| | - Abhishek Chatterjee
- Department of Radiation Oncology, Tata Memorial Centre, Mumbai 400012, India (A.D.)
- Homi Bhabha National Institute (HBNI), Mumbai 400012, India
| | - Arpita Sahu
- Homi Bhabha National Institute (HBNI), Mumbai 400012, India
- Department of Radio-Diagnosis, Tata Memorial Centre, Mumbai 400012, India
| | - Kajari Bhattacharya
- Homi Bhabha National Institute (HBNI), Mumbai 400012, India
- Department of Radio-Diagnosis, Tata Memorial Centre, Mumbai 400012, India
| | - Lilawati Meena
- Homi Bhabha National Institute (HBNI), Mumbai 400012, India
- Department of Medical Physics, Tata Memorial Centre, Mumbai 400012, India
| | - Kishore Joshi
- Homi Bhabha National Institute (HBNI), Mumbai 400012, India
- Department of Medical Physics, Tata Memorial Centre, Mumbai 400012, India
| | - Ameya Puranik
- Homi Bhabha National Institute (HBNI), Mumbai 400012, India
- Department of Nuclear Medicine, Tata Memorial Centre, Mumbai 400012, India
| | - Indraja Dev
- Homi Bhabha National Institute (HBNI), Mumbai 400012, India
- Department of Nuclear Medicine, Tata Memorial Centre, Mumbai 400012, India
| | - Aliasgar Moiyadi
- Homi Bhabha National Institute (HBNI), Mumbai 400012, India
- Department of Neurosurgery, Tata Memorial Centre, Mumbai 400012, India
| | - Prakash Shetty
- Homi Bhabha National Institute (HBNI), Mumbai 400012, India
- Department of Neurosurgery, Tata Memorial Centre, Mumbai 400012, India
| | - Vikas Singh
- Homi Bhabha National Institute (HBNI), Mumbai 400012, India
- Department of Neurosurgery, Tata Memorial Centre, Mumbai 400012, India
| | - Vijay Patil
- Homi Bhabha National Institute (HBNI), Mumbai 400012, India
- Department of Medical Oncology, Tata Memorial Centre, Mumbai 400012, India
| | - Nandini Menon
- Homi Bhabha National Institute (HBNI), Mumbai 400012, India
- Department of Medical Oncology, Tata Memorial Centre, Mumbai 400012, India
| | - Sridhar Epari
- Homi Bhabha National Institute (HBNI), Mumbai 400012, India
- Department of Pathology, Tata Memorial Centre, Mumbai 400012, India
| | - Ayushi Sahay
- Homi Bhabha National Institute (HBNI), Mumbai 400012, India
- Department of Pathology, Tata Memorial Centre, Mumbai 400012, India
| | - Tejpal Gupta
- Department of Radiation Oncology, Tata Memorial Centre, Mumbai 400012, India (A.D.)
- Homi Bhabha National Institute (HBNI), Mumbai 400012, India
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22
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Minniti G, Tini P, Giraffa M, Capone L, Raza G, Russo I, Cinelli E, Gentile P, Bozzao A, Paolini S, Esposito V. Feasibility of clinical target volume reduction for glioblastoma treated with standard chemoradiation based on patterns of failure analysis. Radiother Oncol 2023; 181:109435. [PMID: 36529439 DOI: 10.1016/j.radonc.2022.11.024] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 11/02/2022] [Accepted: 11/27/2022] [Indexed: 12/23/2022]
Abstract
PURPOSE To analyze recurrence patterns in patients with glioblastoma (GBM) after standard chemoradiation according to different target volume delineation strategies. METHODS AND MATERIALS Two hundred seven patients with GBM who recurred after standard chemoradiation were evaluated. According to ESTRO target volume delineation guideline, the CTV was generated by adding a 2-cm margin to the GTV, defined as the resection cavity plus residual tumor. Patterns of failure were analyzed using dose-volume histogram. Recurrent lesions were defined as in-field, marginal, or distant if > 80 %, 20-80 %, or < 20 % of the intersecting volume was included in the 95 % isodose line.For each patient, a theoretical plan consisting of reduced 1-cm GTV-to-CTV margin was created to compare patterns of failure and radiation doses to normal brain. RESULTS Median overall survival and progression-free survival times were 15.3 months and 7.8 months, respectively, from the date of surgery. Recurrences were in-field in 180, marginal in 5, and distant in 22 patients. According to MGMT promoter methylation, distant recurrences occurred in 18.6 % of methylated and 6 % of unmethylated tumors (p = 0.0046). Following replanning with 1-cm reduced margin, dosimetric analysis showed similar patterns of failure. Recurrences were in-field, marginal, and distant in 177, 3, and 27 plans, respectively, although radiation doses to the healthy brain and hippocampi were significantly lower compared with standard target delineation (p = 0.0001). CONCLUSION Current provide the rationale for evaluating GTV-to-CTV margin reduction in future clinical trials with the aim of limiting the cognitive sequelae of GBM irradiation while maintaining survival benefits of standard chemoradiation.
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Affiliation(s)
- Giuseppe Minniti
- Department of Medicine, Surgery and Neurosciences, University of Siena, Italy; IRCCS Neuromed, 86077 Pozzilli, IS, Italy.
| | - Paolo Tini
- Department of Medicine, Surgery and Neurosciences, University of Siena, Italy
| | - Martina Giraffa
- UPMC Hillman Cancer Center, San Pietro Hospital FBF, Rome, Italy
| | - Luca Capone
- UPMC Hillman Cancer Center, San Pietro Hospital FBF, Rome, Italy
| | - Giorgio Raza
- UPMC Hillman Cancer Center, San Pietro Hospital FBF, Rome, Italy
| | - Ivana Russo
- UPMC Hillman Cancer Center, Villa Maria, Mirabella Eclano, AV, Italy
| | - Elisa Cinelli
- Department of Medicine, Surgery and Neurosciences, University of Siena, Italy
| | | | - Alessandro Bozzao
- Neuroradiology Unit, NESMOS Department, Sant'Andrea Hospital, La Sapienza University, Rome, Italy
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23
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Huang-Hobbs E, Cheng YT, Ko Y, Luna-Figueroa E, Lozzi B, Taylor KR, McDonald M, He P, Chen HC, Yang Y, Maleki E, Lee ZF, Murali S, Williamson M, Choi D, Curry R, Bayley J, Woo J, Jalali A, Monje M, Noebels JL, Harmanci AS, Rao G, Deneen B. Remote neuronal activity drives glioma infiltration via Sema4f. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.03.15.532832. [PMID: 36993539 PMCID: PMC10055154 DOI: 10.1101/2023.03.15.532832] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 06/19/2023]
Abstract
The tumor microenvironment (TME) plays an essential role in malignancy and neurons have emerged as a key component of the TME that promotes tumorigenesis across a host of cancers. Recent studies on glioblastoma (GBM) highlight bi-directional signaling between tumors and neurons that propagates a vicious cycle of proliferation, synaptic integration, and brain hyperactivity; however, the identity of neuronal subtypes and tumor subpopulations driving this phenomenon are incompletely understood. Here we show that callosal projection neurons located in the hemisphere contralateral to primary GBM tumors promote progression and widespread infiltration. Using this platform to examine GBM infiltration, we identified an activity dependent infiltrating population present at the leading edge of mouse and human tumors that is enriched for axon guidance genes. High-throughput, in vivo screening of these genes identified Sema4F as a key regulator of tumorigenesis and activity-dependent infiltration. Furthermore, Sema4F promotes the activity-dependent infiltrating population and propagates bi-directional signaling with neurons by remodeling tumor adjacent synapses towards brain network hyperactivity. Collectively, our studies demonstrate that subsets of neurons in locations remote to primary GBM promote malignant progression, while revealing new mechanisms of tumor infiltration that are regulated by neuronal activity.
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Affiliation(s)
- Emmet Huang-Hobbs
- The Integrative Molecular and Biomedical Sciences Graduate Program (IMBS), Baylor College of Medicine, Houston TX 77030
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston TX 77030
- Center for Cancer Neuroscience, Baylor College of Medicine, Houston, TX 77030
| | - Yi-Ting Cheng
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston TX 77030
- Center for Cancer Neuroscience, Baylor College of Medicine, Houston, TX 77030
- Program in Developmental Biology, Baylor College of Medicine, Houston TX 77030
| | - Yeunjung Ko
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston TX 77030
- Center for Cancer Neuroscience, Baylor College of Medicine, Houston, TX 77030
- Program in Immunology and Microbiology, Baylor College of Medicine, Houston, TX 77030
- Department of Neurosurgery, Baylor College of Medicine, Houston TX 77030
| | - Estefania Luna-Figueroa
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston TX 77030
- Center for Cancer Neuroscience, Baylor College of Medicine, Houston, TX 77030
| | - Brittney Lozzi
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston TX 77030
- Center for Cancer Neuroscience, Baylor College of Medicine, Houston, TX 77030
- Department of Neurosurgery, Baylor College of Medicine, Houston TX 77030
- Program in Genetics and Genomics, Baylor College of Medicine, Houston TX 77030
| | - Kathryn R Taylor
- Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA
| | - Malcolm McDonald
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston TX 77030
- Center for Cancer Neuroscience, Baylor College of Medicine, Houston, TX 77030
- Program in Development, Disease, Models and Therapeutics, Baylor College of Medicine, Houston TX 77030
| | - Peihao He
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston TX 77030
- Center for Cancer Neuroscience, Baylor College of Medicine, Houston, TX 77030
- Program in Cancer Cell Biology, Baylor College of Medicine, Houston TX 77030
| | - Hsiao-Chi Chen
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston TX 77030
- Center for Cancer Neuroscience, Baylor College of Medicine, Houston, TX 77030
- Program in Cancer Cell Biology, Baylor College of Medicine, Houston TX 77030
| | - Yuhui Yang
- Department of Neurosurgery, Baylor College of Medicine, Houston TX 77030
| | - Ehson Maleki
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston TX 77030
- Center for Cancer Neuroscience, Baylor College of Medicine, Houston, TX 77030
| | - Zhung-Fu Lee
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston TX 77030
- Center for Cancer Neuroscience, Baylor College of Medicine, Houston, TX 77030
- Program in Development, Disease, Models and Therapeutics, Baylor College of Medicine, Houston TX 77030
| | - Sanjana Murali
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston TX 77030
- Center for Cancer Neuroscience, Baylor College of Medicine, Houston, TX 77030
- Program in Cancer Cell Biology, Baylor College of Medicine, Houston TX 77030
| | - Michael Williamson
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston TX 77030
- Center for Cancer Neuroscience, Baylor College of Medicine, Houston, TX 77030
| | - Dongjoo Choi
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston TX 77030
- Center for Cancer Neuroscience, Baylor College of Medicine, Houston, TX 77030
| | - Rachel Curry
- The Integrative Molecular and Biomedical Sciences Graduate Program (IMBS), Baylor College of Medicine, Houston TX 77030
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston TX 77030
| | - James Bayley
- Department of Neurosurgery, Baylor College of Medicine, Houston TX 77030
| | - Junsung Woo
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston TX 77030
- Center for Cancer Neuroscience, Baylor College of Medicine, Houston, TX 77030
| | - Ali Jalali
- Center for Cancer Neuroscience, Baylor College of Medicine, Houston, TX 77030
- Department of Neurosurgery, Baylor College of Medicine, Houston TX 77030
| | - Michelle Monje
- Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA
- Department of Neurosurgery, Stanford University, Stanford, CA, USA
- Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA
| | - Jeffrey L Noebels
- Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, TX, 77030
- Department of Neurology, Baylor College of Medicine, Houston, TX 77030
| | - Akdes Serin Harmanci
- Center for Cancer Neuroscience, Baylor College of Medicine, Houston, TX 77030
- Department of Neurosurgery, Baylor College of Medicine, Houston TX 77030
| | - Ganesh Rao
- Center for Cancer Neuroscience, Baylor College of Medicine, Houston, TX 77030
- Department of Neurosurgery, Baylor College of Medicine, Houston TX 77030
| | - Benjamin Deneen
- The Integrative Molecular and Biomedical Sciences Graduate Program (IMBS), Baylor College of Medicine, Houston TX 77030
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston TX 77030
- Center for Cancer Neuroscience, Baylor College of Medicine, Houston, TX 77030
- Program in Developmental Biology, Baylor College of Medicine, Houston TX 77030
- Department of Neurosurgery, Baylor College of Medicine, Houston TX 77030
- Program in Development, Disease, Models and Therapeutics, Baylor College of Medicine, Houston TX 77030
- Program in Cancer Cell Biology, Baylor College of Medicine, Houston TX 77030
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Jia Y, Xu S, Han G, Wang B, Wang Z, Lan C, Zhao P, Gao M, Zhang Y, Jiang W, Qiu B, Liu R, Hsu YC, Sun Y, Liu C, Liu Y, Bai R. Transmembrane water-efflux rate measured by magnetic resonance imaging as a biomarker of the expression of aquaporin-4 in gliomas. Nat Biomed Eng 2023; 7:236-252. [PMID: 36376487 DOI: 10.1038/s41551-022-00960-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 10/10/2022] [Indexed: 11/16/2022]
Abstract
The water-selective channel protein aquaporin-4 (AQP4) contributes to the migration and proliferation of gliomas, and to their resistance to therapy. Here we show, in glioma cell cultures, in subcutaneous and orthotopic gliomas in rats, and in glioma tumours in patients, that transmembrane water-efflux rate is a sensitive biomarker of AQP4 expression and can be measured via conventional dynamic-contrast-enhanced magnetic resonance imaging. Water-efflux rates correlated with stages of glioma proliferation as well as with changes in the heterogeneity of intra-tumoural and inter-tumoural AQP4 in rodent and human gliomas following treatment with temozolomide and with the AQP4 inhibitor TGN020. Regions with low water-efflux rates contained higher fractions of stem-like slow-cycling cells and therapy-resistant cells, suggesting that maps of water-efflux rates could be used to identify gliomas that are resistant to therapies.
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Affiliation(s)
- Yinhang Jia
- Department of Physical Medicine and Rehabilitation of the Affiliated Sir Run Run Shaw Hospital AND Interdisciplinary Institute of Neuroscience and Technology, Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Biomedical Engineering of Ministry of Education, College of Biomedical Engineering and Instrument Science, Zhejiang University, Hangzhou, China
- Department of Neurosurgery, Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Shangchen Xu
- Department of Neurosurgery, Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Guangxu Han
- Key Laboratory of Biomedical Engineering of Ministry of Education, College of Biomedical Engineering and Instrument Science, Zhejiang University, Hangzhou, China
| | - Bao Wang
- Department of Radiology, Qilu Hospital of Shandong University, Jinan, China
| | - Zejun Wang
- Key Laboratory of Biomedical Engineering of Ministry of Education, College of Biomedical Engineering and Instrument Science, Zhejiang University, Hangzhou, China
| | - Chuanjin Lan
- Department of Neurosurgery, Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Peng Zhao
- Department of Neurosurgery, Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Meng Gao
- Department of Neurosurgery, Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Yi Zhang
- Department of Radiology, Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Wenhong Jiang
- Zhejiang University School of Medicine, Hangzhou, China
| | - Biying Qiu
- Zhejiang University School of Medicine, Hangzhou, China
| | - Rui Liu
- Zhejiang University School of Medicine, Hangzhou, China
| | - Yi-Cheng Hsu
- MR Collaboration, Siemens Healthcare, Shanghai, China
| | - Yi Sun
- MR Collaboration, Siemens Healthcare, Shanghai, China
| | - Chong Liu
- MOE Frontier Science Center for Brain Science and Brain-machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, China
| | - Yingchao Liu
- Department of Neurosurgery, Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
- Shandong National Center for Applied Mathematics, Shandong University, Jinan, China.
| | - Ruiliang Bai
- Department of Physical Medicine and Rehabilitation of the Affiliated Sir Run Run Shaw Hospital AND Interdisciplinary Institute of Neuroscience and Technology, Zhejiang University School of Medicine, Hangzhou, China.
- Key Laboratory of Biomedical Engineering of Ministry of Education, College of Biomedical Engineering and Instrument Science, Zhejiang University, Hangzhou, China.
- MOE Frontier Science Center for Brain Science and Brain-machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, China.
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25
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Supratotal Resection of Glioblastoma: Better Survival Outcome than Gross Total Resection. J Pers Med 2023; 13:jpm13030383. [PMID: 36983564 PMCID: PMC10053695 DOI: 10.3390/jpm13030383] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 02/11/2023] [Accepted: 02/17/2023] [Indexed: 02/24/2023] Open
Abstract
Objective: Supratotal resection (SupTR) of glioblastoma allows for a superior long-term disease control and increases overall survival. On the other hand, aggressive conventional approaches, including gross total resections (GTR), are limited by the impairment risk of adjacent eloquent areas, which may cause severe postoperative functional morbidity. This study aimed to analyze institutional cases with respect to the potential survival benefits of additional resection, including lobectomy, as a paradigm for SupTR in patients of glioblastoma. Methods: Between 2014 and 2018, 15 patients with glioblastoma underwent SupTR (GTR and additional lobectomy) at the authors’ institution. The postoperative Karnofsky performance score (KPS), progression-free survival (PFS), and overall survival (OS) were analyzed for the patients. Results: Patients with SupTR showed significantly prolonged PFS and OS. The median PFS and OS values for the entire study group were 33.5 months (95% confidence intervals (CI): 18.5–57.3 months) and 49.1 months (95% CI: 24.7–86.6 months), respectively. Multivariate analysis revealed that the O6-DNA-methylguanine methyltransferase (MGMT) promoter methylation status was the only predictor for both superior PFS (p = 0.03, OR 5.7, 95% CI 1.0–49.8) and OS (p = 0.04, OR 6.5, 95% CI 1.1–40.2). There was no significant difference between the pre- and postoperative KPS scores. Conclusions: Our results suggest that SupTR with lobectomy allows for a superior PFS and OS without negatively affecting patient performance. However, due to the small number of patients, further studies that include more patients are needed.
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Liu H, Zhang L, Tan Y, Jiang Y, Lu H. Observation of the delineation of the target volume of radiotherapy in adult-type diffuse gliomas after temozolomide-based chemoradiotherapy: analysis of recurrence patterns and predictive factors. Radiat Oncol 2023; 18:16. [PMID: 36691100 PMCID: PMC9872393 DOI: 10.1186/s13014-023-02203-w] [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: 08/06/2022] [Accepted: 01/10/2023] [Indexed: 01/25/2023] Open
Abstract
BACKGROUND Radiation therapy is the cornerstone of treatment for adult-type diffuse gliomas, but recurrences are inevitable. Our study assessed the prognosis and recurrence pattern of different radiotherapy volumes after temozolomide-based chemoradiation in our institution. METHODS The treatment plans were classified into two groups, the plan 1 intentionally involved the entire edema area while plan 2 did not. Retrospectively investigate the differences in outcomes of 118 adult-type diffuse gliomas patients between these two treatment plans. Then, patients who underwent relapse were selected to analyze their recurrence patterns. Continuous dynamic magnetic resonance images (MRI) were collected to categorized the recurrence patterns into central, in-field, marginal, distant, and cerebrospinal fluid dissemination (CSF-d) recurrence. Finally, the clinical and molecular characteristics which influenced progression were analyzed. RESULTS Plan 1 (n = 63) showed a median progression-free survival (PFS) and overall survival (OS) of 9.5 and 26.4 months while plan 2 (n = 55) showed a median PFS and OS of 9.4 and 36.5 months (p = 0.418; p = 0.388). Treatment target volume had no effect on the outcome in patients with adult-type diffuse gliomas. And there was no difference in radiation toxicity (p = 0.388). Among the 90 relapsed patients, a total of 58 (64.4%) patients had central recurrence, 10 (11.1%) patients had in-field recurrence, 3 (3.3%) patients had marginal recurrence, 11 (12.2.%) patients had distant recurrence, and 8 (8.9%) patients had CSF-d recurrence. By treatment plans, the recurrence patterns were similar and there was no significant difference in survival. Reclassifying the progression pattern into local and non-local groups, we observed that oligodendroglioma (n = 10) all relapsed in local and no difference in PFS and OS between the two groups (p > 0.05). Multivariable analysis showed that subventricular zone (SVZ) involvement was the independent risk factor for non-local recurrence in patients with GBM (p < 0.05). CONCLUSION In our study, deliberately including or not the entire edema had no impact on prognosis and recurrence. Patients with varied recurrence patterns had diverse clinical and genetic features.
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Affiliation(s)
- Hongbo Liu
- grid.412521.10000 0004 1769 1119Department of Radiation Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Lu Zhang
- grid.412521.10000 0004 1769 1119Department of Radiation Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Ye Tan
- grid.412521.10000 0004 1769 1119Department of Radiation Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yanxia Jiang
- grid.412521.10000 0004 1769 1119Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Haijun Lu
- grid.412521.10000 0004 1769 1119Department of Radiation Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China
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Urso G, Boncu AG, Carrara N, Zaman DT, Malfassi L, Marcarini S, Minoli L, Pavesi S, Sala M, Scanziani E, Dolera M. Cranial Spinal Spreading of Canine Brain Gliomas after Hypofractionated Volumetric-Modulated Arc Radiotherapy and Concomitant Temozolomide Chemotherapy: A Four-Case Report. Vet Sci 2022; 9:541. [PMID: 36288154 PMCID: PMC9608067 DOI: 10.3390/vetsci9100541] [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: 08/08/2022] [Revised: 09/20/2022] [Accepted: 09/27/2022] [Indexed: 11/29/2022] Open
Abstract
Gliomas are the second-most-common primary brain tumors in dogs. Surgery and radiotherapy are established treatment approaches with similar median survival time, whereas conventional chemotherapy is burdened by severe adverse effects. Spinal and leptomeningeal spread of gliomas have been described following radiotherapy treatment alone. The purpose of this study was to evaluate the outcome for four dogs with primary high-grade gliomas in the forebrain without evidence, at diagnosis, of neoplastic invasion along the spinal cord, that were treated with concomitant chemotherapy (temozolomide) and hypofractionated volumetric-modulated arc radiotherapy (VMAT-RT). Temozolomide was selected for its radiosensitive properties, and radiotherapy dose protocols of 37 Gy in 7 fractions or 42 Gy in 10 fractions were used. After an initial complete or partial response, tumors recurred across the cranial-spinal pathway. Post-mortem macroscopic examinations confirmed swollen spinal cord and hyperemic meningeal sleeve, with nodular lesions on the meningeal surface. Microscopically, infiltration of the spinal cord and meninges by neoplastic cells (with features of oligodendrogliomas) were observed. This work seems to suggest that the entire central nervous system should be investigated in diagnostic examinations of canine gliomas. Dose-escalation trials and/or spinal cord prophylaxis treatment could also be evaluated to prevent tumor progression.
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Affiliation(s)
- Gaetano Urso
- Azienda Socio Sanitaria Territoriale di Lodi, 26900 Lodi, Italy
| | | | - Nancy Carrara
- La Cittadina Fondazione Studi e Ricerche Veterinarie, 26014 Romanengo, Italy
| | - Dragos-Teodor Zaman
- La Cittadina Fondazione Studi e Ricerche Veterinarie, 26014 Romanengo, Italy
| | - Luca Malfassi
- La Cittadina Fondazione Studi e Ricerche Veterinarie, 26014 Romanengo, Italy
| | - Silvia Marcarini
- La Cittadina Fondazione Studi e Ricerche Veterinarie, 26014 Romanengo, Italy
| | - Lucia Minoli
- Dipartimento di Scienze Veterinarie, Università degli Studi di Torino, 10095 Grugliasco, Italy
| | - Simone Pavesi
- La Cittadina Fondazione Studi e Ricerche Veterinarie, 26014 Romanengo, Italy
| | - Massimo Sala
- La Cittadina Fondazione Studi e Ricerche Veterinarie, 26014 Romanengo, Italy
| | - Eugenio Scanziani
- Dipartimento di Medicina Veterinaria e Scienze Animali, Università degli Studi di Milano, 20122 Milano, Italy
- Mouse and Animal Pathology Lab (MAPLab), Università degli Studi di Milano–La Statale–Fondazione UniMi, 20122 Milano, Italy
| | - Mario Dolera
- La Cittadina Fondazione Studi e Ricerche Veterinarie, 26014 Romanengo, Italy
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Kis D, Szivos L, Rekecki M, Shukir BS, Mate A, Hideghety K, Barzo P. Predicting the true extent of glioblastoma based on probabilistic tractography. Front Neurosci 2022; 16:886465. [PMID: 36213748 PMCID: PMC9533086 DOI: 10.3389/fnins.2022.886465] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 08/16/2022] [Indexed: 11/25/2022] Open
Abstract
Glioblastoma is the most frequent type of primary brain tumors. Despite the advanced therapy, most of the patients die within 2 years after the diagnosis. The tumor has a typical appearance on MRI: a central hypointensity surrounded by an inhomogeneous, ring-shaped contrast enhancement along its border. Too small to be recognized by MRI, detached individual tumor cells migrate along white matter fiber tracts several centimeters away from the edge of the tumor. Usually these cells are the source of tumor recurrence. If the infiltrated brain areas could be identified, longer survival time could be achieved through supratotal resection and individually planned radiation therapy. Probabilistic tractography is an advanced imaging method that can potentially be used to identify infiltrated pathways, thus the real extent of the glioblastoma. Our study consisted of twenty high grade glioma patients. Probabilistic tractography was started from the tumor. The location of tumor recurrence on follow-up MRI was considered as the primary infiltrated white matter tracts. The results of probabilistic tractography were evaluated at thirteen different thresholds. The overlap with the tumor recurrence of each threshold level was then defined to calculate the sensitivity and specificity. In the group level, sensitivity (81%) and specificity (90%) were the most reliable at 5% threshold level. There were two outliers in the study group, both with high specificity and very low sensitivity. According to our results, probabilistic tractography can help to define the true extent of the glioblastoma at the time of diagnosis with high sensitivity and specificity. Individually planned surgery and irradiation could provide a better chance of survival in these patients.
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Affiliation(s)
- David Kis
- Department of Neurosurgery, Faculty of Medicine, University of Szeged, Szeged, Hungary
- *Correspondence: David Kis,
| | - Laszlo Szivos
- Department of Neurosurgery, Faculty of Medicine, University of Szeged, Szeged, Hungary
| | - Mark Rekecki
- Department of Neurosurgery, Faculty of Medicine, University of Szeged, Szeged, Hungary
| | - Bayan Salam Shukir
- Department of Neurosurgery, Faculty of Medicine, University of Szeged, Szeged, Hungary
| | - Adrienn Mate
- Department of Neurosurgery, Faculty of Medicine, University of Szeged, Szeged, Hungary
| | - Katalin Hideghety
- Department of Oncology, Faculty of Medicine, University of Szeged, Szeged, Hungary
| | - Pal Barzo
- Department of Neurosurgery, Faculty of Medicine, University of Szeged, Szeged, Hungary
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Christie JD, Chiocca EA. Treat and repeat: oncolytic virus therapy for brain cancer. Nat Med 2022; 28:1540-1542. [PMID: 35864255 DOI: 10.1038/s41591-022-01901-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Affiliation(s)
- John D Christie
- Harvey Cushing Neuro-oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - E Antonio Chiocca
- Harvey Cushing Neuro-oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
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Duval T, Lotterie JA, Lemarie A, Delmas C, Tensaouti F, Moyal ECJ, Lubrano V. Glioblastoma Stem-like Cell Detection Using Perfusion and Diffusion MRI. Cancers (Basel) 2022; 14:cancers14112803. [PMID: 35681782 PMCID: PMC9179449 DOI: 10.3390/cancers14112803] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 05/21/2022] [Accepted: 05/25/2022] [Indexed: 01/25/2023] Open
Abstract
Simple Summary Glioblastoma stem-like cells (GSCs) are known to be aggressive and radio-resistant and proliferate heterogeneously in preferred environments. Additionally, quantitative diffusion and perfusion MRI biomarkers provide insight into the tissue micro-environment. This study assessed the sensitivity of these imaging biomarkers to GSCs in the hyperintensities-FLAIR region, where relapses may occur. A total of 16 patients underwent an MRI session and biopsies were extracted to study the GSCs. In vivo and in vitro biomarkers were compared and both Apparent Diffusion Coefficient (ADC) and relative Cerebral Blood Volume (rCBV) MRI metrics were found to be good predictors of GSCs presence and aggressiveness. Abstract Purpose: With current gold standard treatment, which associates maximum safe surgery and chemo-radiation, the large majority of glioblastoma patients relapse within a year in the peritumoral non contrast-enhanced region (NCE). A subpopulation of glioblastoma stem-like cells (GSC) are known to be particularly radio-resistant and aggressive, and are thus suspected to be the cause of these relapses. Previous studies have shown that their distribution is heterogeneous in the NCE compartment, but no study exists on the sensitivity of medical imaging for localizing these cells. In this work, we propose to study the magnetic resonance (MR) signature of these infiltrative cells. Methods: In the context of a clinical trial on 16 glioblastoma patients, relative Cerebral Blood Volume (rCBV) and Apparent Diffusion Coefficient (ADC) were measured in a preoperative diffusion and perfusion MRI examination. During surgery, two biopsies were extracted using image-guidance in the hyperintensities-FLAIR region. GSC subpopulation was quantified within the biopsies and then cultivated in selective conditions to determine their density and aggressiveness. Results: Low ADC was found to be a good predictor of the time to GSC neurospheres formation in vitro. In addition, GSCs were found in higher concentrations in areas with high rCBV. Conclusions: This study confirms that GSCs have a critical role for glioblastoma aggressiveness and supports the idea that peritumoral sites with low ADC or high rCBV should be preferably removed when possible during surgery and targeted by radiotherapy.
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Affiliation(s)
- Tanguy Duval
- ToNIC, Toulouse NeuroImaging Center, Université de Toulouse, Inserm, UPS, 31000 Toulouse, France; (J.-A.L.); (F.T.); (V.L.)
- Correspondence:
| | - Jean-Albert Lotterie
- ToNIC, Toulouse NeuroImaging Center, Université de Toulouse, Inserm, UPS, 31000 Toulouse, France; (J.-A.L.); (F.T.); (V.L.)
- Department of Nuclear Medicine, CHU Purpan, 31000 Toulouse, France
| | - Anthony Lemarie
- U1037 Toulouse Cancer Research Center CRCT, INSERM, 31000 Toulouse, France; (A.L.); (E.C.-J.M.)
- Université Paul Sabatier Toulouse III, 31000 Toulouse, France
| | - Caroline Delmas
- Institut Claudius Regaud, IUCT-Oncopole, 31000 Toulouse, France;
| | - Fatima Tensaouti
- ToNIC, Toulouse NeuroImaging Center, Université de Toulouse, Inserm, UPS, 31000 Toulouse, France; (J.-A.L.); (F.T.); (V.L.)
- Institut Claudius Regaud, IUCT-Oncopole, 31000 Toulouse, France;
| | - Elizabeth Cohen-Jonathan Moyal
- U1037 Toulouse Cancer Research Center CRCT, INSERM, 31000 Toulouse, France; (A.L.); (E.C.-J.M.)
- Université Paul Sabatier Toulouse III, 31000 Toulouse, France
- Institut Claudius Regaud, IUCT-Oncopole, 31000 Toulouse, France;
| | - Vincent Lubrano
- ToNIC, Toulouse NeuroImaging Center, Université de Toulouse, Inserm, UPS, 31000 Toulouse, France; (J.-A.L.); (F.T.); (V.L.)
- Department of Nuclear Medicine, CHU Purpan, 31000 Toulouse, France
- Service de Neurochirurgie, Clinique de l’Union, 31240 Toulouse, France
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31
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Kuo CY, Liu WH, Chou YC, Li MH, Tsai JT, Huang DYC, Lin JC. To Optimize Radiotherapeutic Plans for Superior Tumor Coverage Predicts Malignant Glioma Prognosis and Normal Tissue Complication Probability. J Clin Med 2022; 11:jcm11092413. [PMID: 35566538 PMCID: PMC9099532 DOI: 10.3390/jcm11092413] [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: 03/05/2022] [Revised: 04/06/2022] [Accepted: 04/20/2022] [Indexed: 02/05/2023] Open
Abstract
Background: Radiotherapy (RT) provides a modern treatment to enhance the malignant glioma control rate. The purpose of our study was to determine the effect of tumor coverage on disease prognosis and to predict optimal RT plans to achieve a lower normal tissue complication probability (NTCP). Methods: Ten malignant-glioma patients with tumors adjacent to organs at risk (OARs) were collected. The patients were divided into two groups according to adequate coverage or not, and prognosis was analyzed. Then, using intensity-modulated radiation therapy (IMRT), volume-modulated arc therapy (VMAT), and helical tomotherapy (TOMO) to simulate new treatment plans for 10 patients, the advantages of these planning systems were revealed for subsequent prediction of NTCP. Results: The results of clinical analysis indicated that overall survival (p = 0.078) between the adequate and inadequate groups showed no differences, while the adequate group had better recurrence-free survival (p = 0.018) and progression-free survival (p = 0.009). TOMO had better CI (p < 0.001) and also predicted a lower total-irradiated dose to the normal brain (p = 0.001) and a lower NTCP (p = 0.027). Conclusions: The TOMO system provided optimal therapeutic planning, reducing NTCP and achieving better coverage. Combined with the clinical results, our findings suggest that TOMO can make malignant glioma patients close to OARs achieve better disease control.
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Affiliation(s)
- Chun-Yuan Kuo
- Department of Radiation Oncology, Shuang Ho Hospital, Taipei Medical University, Taipei 11031, Taiwan; (C.-Y.K.); (M.-H.L.); (J.-T.T.)
- School of Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei 11031, Taiwan
| | - Wei-Hsiu Liu
- Department of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, No.325, Sec. 2, Cheng-Kung Road, Taipei 11490, Taiwan;
- Department of Surgery, School of Medicine, National Defense Medical Center, Taipei 11490, Taiwan
| | - Yu-Ching Chou
- School of Public Health, National Defense Medical Center, Taipei 11490, Taiwan;
| | - Ming-Hsien Li
- Department of Radiation Oncology, Shuang Ho Hospital, Taipei Medical University, Taipei 11031, Taiwan; (C.-Y.K.); (M.-H.L.); (J.-T.T.)
| | - Jo-Ting Tsai
- Department of Radiation Oncology, Shuang Ho Hospital, Taipei Medical University, Taipei 11031, Taiwan; (C.-Y.K.); (M.-H.L.); (J.-T.T.)
- Department of Radiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - David YC Huang
- Department of Medical Physics, Duke University, Durham, NC 27708, USA;
| | - Jang-Chun Lin
- Department of Radiation Oncology, Shuang Ho Hospital, Taipei Medical University, Taipei 11031, Taiwan; (C.-Y.K.); (M.-H.L.); (J.-T.T.)
- Department of Radiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Correspondence: ; Tel.: +886-2-22490088; Fax: +886-2-22484822
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Gyriform infiltration as imaging biomarker for molecular glioblastomas. J Neurooncol 2022; 157:511-521. [PMID: 35364762 DOI: 10.1007/s11060-022-03995-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 03/23/2022] [Indexed: 10/18/2022]
Abstract
BACKGROUND Molecular glioblastomas (i.e. without the histological but with the molecular characteristics of IDH-wild-type glioblastoma) frequently lack contrast enhancement, which can wrongly lead to suspect a lower-grade glioma. Herein, we aimed to assess the diagnostic value of gyriform infiltration as an imaging marker for molecular glioblastomas. METHODS Two independent investigators reviewed the MRI scans from patients with newly diagnosed gliomas for the presence of a gyriform infiltration defined as an elective cortical hypersignal on MRI FLAIR sequence. Diagnostic test performance of this sign for the diagnosis of molecular glioblastoma were calculated. RESULTS A total of 426 patients were included, corresponding to 31 molecular glioblastoma, 294 IDH-wild-type glioblastoma, 50 IDH-mutant astrocytoma, and 51 IDH-mutant 1p19q-codeleted oligodendroglioma. A gyriform infiltration was observed in 16/31 (52%) molecular glioblastoma, 40/294 (14%) IDH-wild-type glioblastoma, and none of the IDH-mutant glioma. All the 56 gyriform-infiltration-positive tumors were IDH-wild-type and all but two had a TERT promoter mutation. The inter-rater agreement was good (κ = 0.69, p < 0.001). The sensitivity, specificity, positive predictive value and negative predictive value of the presence of a gyriform infiltration for the diagnosis of molecular glioblastoma were 52%, 90%, 29%, 96%, respectively. The median overall survival was better for gyriform-infiltration-negative patients compared to gyriform-infiltration-positive patients in the whole series and in patients with non-enhancing lesions (n = 95) (25.6 vs 16.9 months, p = 0.005 and 20.2 months vs not reached, p < 0.001). CONCLUSION Gyriform infiltration is a specific imaging marker of molecular glioblastomas that can help distinguishing these tumors from IDH-mutant lower-grade gliomas.
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Collet S, Guillamo JS, Berro DH, Chakhoyan A, Constans JM, Lechapt-Zalcman E, Derlon JM, Hatt M, Visvikis D, Guillouet S, Perrio C, Bernaudin M, Valable S. Simultaneous Mapping of Vasculature, Hypoxia, and Proliferation Using Dynamic Susceptibility Contrast MRI, 18F-FMISO PET, and 18F-FLT PET in Relation to Contrast Enhancement in Newly Diagnosed Glioblastoma. J Nucl Med 2021; 62:1349-1356. [PMID: 34016725 PMCID: PMC8724903 DOI: 10.2967/jnumed.120.249524] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Accepted: 01/14/2021] [Indexed: 11/16/2022] Open
Abstract
Conventional MRI plays a key role in the management of patients with high-grade glioma, but multiparametric MRI and PET tracers could provide further information to better characterize tumor metabolism and heterogeneity by identifying regions having a high risk of recurrence. In this study, we focused on proliferation, hypervascularization, and hypoxia, all factors considered indicative of poor prognosis. They were assessed by measuring uptake of 18F-3'-deoxy-3'-18F-fluorothymidine (18F-FLT), relative cerebral blood volume (rCBV) maps, and uptake of 18F-fluoromisonidazole (18F-FMISO), respectively. For each modality, the volumes and high-uptake subvolumes (hot spots) were semiautomatically segmented and compared with the contrast enhancement (CE) volume on T1-weighted gadolinium-enhanced (T1w-Gd) images, commonly used in the management of patients with glioblastoma. Methods: Dynamic susceptibility contrast-enhanced MRI (31 patients), 18F-FLT PET (20 patients), or 18F-FMISO PET (20 patients), for a total of 31 patients, was performed on preoperative glioblastoma patients. Volumes and hot spots were segmented on SUV maps for 18F-FLT PET (using the fuzzy locally adaptive bayesian algorithm) and 18F-FMISO PET (using a mean contralateral image + 3.3 SDs) and on rCBV maps (using a mean contralateral image + 1.96 SDs) for dynamic susceptibility contrast-enhanced MRI and overlaid on T1w-Gd images. For each modality, the percentages of the peripheral volumes and the peripheral hot spots outside the CE volume were calculated. Results: All tumors showed highly proliferated, hypervascularized, and hypoxic regions. The images also showed pronounced heterogeneity of both tracers regarding their uptake and rCBV maps, within each individual patient. Overlaid volumes on T1w-Gd images showed that some proliferative, hypervascularized, and hypoxic regions extended beyond the CE volume but with marked differences between patients. The ranges of peripheral volume outside the CE volume were 1.6%-155.5%, 1.5%-89.5%, and 3.1%-78.0% for 18F-FLT, rCBV, and 18F-FMISO, respectively. All patients had hyperproliferative hot spots outside the CE volume, whereas hypervascularized and hypoxic hot spots were detected mainly within the enhancing region. Conclusion: Spatial analysis of multiparametric maps with segmented volumes and hot spots provides valuable information to optimize the management and treatment of patients with glioblastoma.
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Affiliation(s)
- Solène Collet
- Normandie University, UNICAEN, CEA, CNRS, ISTCT/CERVOxy Group, GIP Cyceron, Caen, France
- Radiophysics Department, Centre François Baclesse, Caen, France
| | - Jean-Sébastien Guillamo
- Normandie University, UNICAEN, CEA, CNRS, ISTCT/CERVOxy Group, GIP Cyceron, Caen, France
- Department of Neurology, CHU de Caen, Caen, France
- Department of Neurology, CHU de Nimes, Nimes, France
| | - David Hassanein Berro
- Normandie University, UNICAEN, CEA, CNRS, ISTCT/CERVOxy Group, GIP Cyceron, Caen, France
- Department of Neurosurgery, CHU de Caen, Caen, France
| | - Ararat Chakhoyan
- Normandie University, UNICAEN, CEA, CNRS, ISTCT/CERVOxy Group, GIP Cyceron, Caen, France
| | - Jean-Marc Constans
- Normandie University, UNICAEN, CEA, CNRS, ISTCT/CERVOxy Group, GIP Cyceron, Caen, France
- Department of Neuroradiology, CHU de Caen, Caen, France
| | - Emmanuèle Lechapt-Zalcman
- Normandie University, UNICAEN, CEA, CNRS, ISTCT/CERVOxy Group, GIP Cyceron, Caen, France
- Department of Pathology, CHU de Caen, Caen, France
- Department of Neuropathology, GHU Paris Psychiatry and Neuroscience, Paris, France
| | - Jean-Michel Derlon
- Normandie University, UNICAEN, CEA, CNRS, ISTCT/CERVOxy Group, GIP Cyceron, Caen, France
| | - Mathieu Hatt
- LaTIM, INSERM, UMR 1101, University of Brest, Brest, France; and
| | | | - Stéphane Guillouet
- Normandie University, UNICAEN, CEA, CNRS, ISTCT/LDM-TEP Group, GIP Cyceron, Caen, France
| | - Cécile Perrio
- Normandie University, UNICAEN, CEA, CNRS, ISTCT/LDM-TEP Group, GIP Cyceron, Caen, France
| | - Myriam Bernaudin
- Normandie University, UNICAEN, CEA, CNRS, ISTCT/CERVOxy Group, GIP Cyceron, Caen, France
| | - Samuel Valable
- Normandie University, UNICAEN, CEA, CNRS, ISTCT/CERVOxy Group, GIP Cyceron, Caen, France;
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Harland A, Liu X, Ghirardello M, Galan MC, Perks CM, Kurian KM. Glioma Stem-Like Cells and Metabolism: Potential for Novel Therapeutic Strategies. Front Oncol 2021; 11:743814. [PMID: 34532295 PMCID: PMC8438230 DOI: 10.3389/fonc.2021.743814] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 08/09/2021] [Indexed: 12/21/2022] Open
Abstract
Glioma stem-like cells (GSCs) were first described as a population which may in part be resistant to traditional chemotherapeutic therapies and responsible for tumour regrowth. Knowledge of the underlying metabolic complexity governing GSC growth and function may point to potential differences between GSCs and the tumour bulk which could be harnessed clinically. There is an increasing interest in the direct/indirect targeting or reprogramming of GSC metabolism as a potential novel therapeutic approach in the adjuvant or recurrent setting to help overcome resistance which may be mediated by GSCs. In this review we will discuss stem-like models, interaction between metabolism and GSCs, and potential current and future strategies for overcoming GSC resistance.
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Affiliation(s)
- Abigail Harland
- Brain Tumour Research Centre, Bristol Medical School, University of Bristol, Bristol, United Kingdom
| | - Xia Liu
- Brain Tumour Research Centre, Bristol Medical School, University of Bristol, Bristol, United Kingdom
| | - Mattia Ghirardello
- Galan Research Group, School of Chemistry, University of Bristol, Bristol, United Kingdom
| | - M Carmen Galan
- Galan Research Group, School of Chemistry, University of Bristol, Bristol, United Kingdom
| | - Claire M Perks
- IGFs and Metabolic Endocrinology Group, Bristol Medical School, Translational Health Sciences, Southmead Hospital, University of Bristol, Bristol, United Kingdom
| | - Kathreena M Kurian
- Brain Tumour Research Centre, Bristol Medical School, University of Bristol, Bristol, United Kingdom
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Abou-Mrad Z, Bou Gharios J, Moubarak MM, Chalhoub A, Moussalem C, Bahmad HF, Abou-Kheir W. Central nervous system tumors and three-dimensional cell biology: Current and future perspectives in modeling. World J Stem Cells 2021; 13:1112-1126. [PMID: 34567429 PMCID: PMC8422930 DOI: 10.4252/wjsc.v13.i8.1112] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 05/02/2021] [Accepted: 07/07/2021] [Indexed: 02/06/2023] Open
Abstract
Central nervous system (CNS) tumors are a variety of distinct neoplasms that present multiple challenges in terms of treatment and prognosis. Glioblastoma, the most common primary tumor in adults, is associated with poor survival and remains one of the least treatable neoplasms. These tumors are highly heterogenous and complex in their nature. Due to this complexity, traditional cell culturing techniques and methods do not provide an ideal recapitulating model for the study of these tumors' behavior in vivo. Two-dimensional models lack the spatial arrangement, the heterogeneity in cell types, and the microenvironment that play a large role in tumor cell behavior and response to treatment. Recently, scientists have turned towards three-dimensional culturing methods, namely spheroids and organoids, as they have been shown to recapitulate tumors in a more faithful manner to their in vivo counterparts. Moreover, tumor-on-a-chip systems have lately been employed in CNS tumor modeling and have shown great potential in both studying the pathophysiology and therapeutic testing. In this review, we will discuss the current available literature on in vitro three-dimensional culturing models in CNS tumors, in addition to presenting their advantages and current limitations. We will also elaborate on the future implications of these models and their benefit in the clinical setting.
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Affiliation(s)
- Zaki Abou-Mrad
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Jolie Bou Gharios
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Maya M Moubarak
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Ahmad Chalhoub
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Charbel Moussalem
- Division of Neurosurgery, Department of Surgery, American University of Beirut Medical Center, Beirut 1107-2020, Lebanon
| | - Hisham F Bahmad
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Wassim Abou-Kheir
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107-2020, Lebanon.
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Shibahara I, Miyasaka K, Sekiguchi A, Ishiyama H, Inukai M, Yasui Y, Watanabe T, Sato S, Hide T, Kumabe T. Long-term follow-up after BCNU wafer implantation in patients with newly diagnosed glioblastoma. J Clin Neurosci 2021; 86:202-210. [PMID: 33775329 DOI: 10.1016/j.jocn.2021.01.037] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 01/17/2021] [Accepted: 01/23/2021] [Indexed: 12/12/2022]
Abstract
1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU, or Carmustine) wafers are intraoperatively implantable wafers used to achieve local tumor control. There is scarce data about the behavior of wafers in the long-term follow-up of implanted cases. We reviewed the data of 64 patients with newly diagnosed glioblastoma treated by surgery, BCNU wafers, radiation therapy, and temozolomide administration. This cohort included 55 patients who presented first recurrence, and 49 of them showed tumor progression to death. The MR imaging of each patient at the terminal stage and an autopsy case were used to elucidate the tumor progression pattern after the wafer implantation. We subdivided the first recurrence pattern into local, distant, and multifocal based on MR imaging or into infield, outfield, and marginal based on the radiation field. The first recurrence pattern was 33 patients (60%) with local, 13 (24%) with distant, and nine (16%) with multifocal recurrence, or 38 patients (69%) with infield, 13 (24%) with outfield, and four (7%) with marginal. The median and mean time intervals between MR imaging at the terminal stage and death were 2.0 and 2.3 months, respectively. Of note, 13 patients with first distant recurrence had no obvious radiological local tumor progression even at the terminal stage. Long-term follow-up after BCNU wafer implantation revealed that patients with first distant recurrence had long-lasting local tumor control until the terminal stage.
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Affiliation(s)
- Ichiyo Shibahara
- Departments of Neurosurgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
| | - Kazuhiro Miyasaka
- Departments of Neurosurgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Akane Sekiguchi
- Radiology and Radiation Oncology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Hiromichi Ishiyama
- Radiology and Radiation Oncology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Madoka Inukai
- Departments of Neurosurgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan; Pathology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Yoshie Yasui
- Departments of Neurosurgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Takashi Watanabe
- Department of General Internal Medicine, JCHO Sendai Hospital, Sendai, Miyagi, Japan
| | - Sumito Sato
- Departments of Neurosurgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Takuichiro Hide
- Departments of Neurosurgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Toshihiro Kumabe
- Departments of Neurosurgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
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Griffith JI, Rathi S, Zhang W, Zhang W, Drewes LR, Sarkaria JN, Elmquist WF. Addressing BBB Heterogeneity: A New Paradigm for Drug Delivery to Brain Tumors. Pharmaceutics 2020; 12:E1205. [PMID: 33322488 PMCID: PMC7763839 DOI: 10.3390/pharmaceutics12121205] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 12/08/2020] [Accepted: 12/10/2020] [Indexed: 12/11/2022] Open
Abstract
Effective treatments for brain tumors remain one of the most urgent and unmet needs in modern oncology. This is due not only to the presence of the neurovascular unit/blood-brain barrier (NVU/BBB) but also to the heterogeneity of barrier alteration in the case of brain tumors, which results in what is referred to as the blood-tumor barrier (BTB). Herein, we discuss this heterogeneity, how it contributes to the failure of novel pharmaceutical treatment strategies, and why a "whole brain" approach to the treatment of brain tumors might be beneficial. We discuss various methods by which these obstacles might be overcome and assess how these strategies are progressing in the clinic. We believe that by approaching brain tumor treatment from this perspective, a new paradigm for drug delivery to brain tumors might be established.
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Affiliation(s)
- Jessica I. Griffith
- Department of Pharmaceutics, University of Minnesota, Minneapolis, MN 55455, USA; (S.R.); (W.Z.); (W.Z.)
| | - Sneha Rathi
- Department of Pharmaceutics, University of Minnesota, Minneapolis, MN 55455, USA; (S.R.); (W.Z.); (W.Z.)
| | - Wenqiu Zhang
- Department of Pharmaceutics, University of Minnesota, Minneapolis, MN 55455, USA; (S.R.); (W.Z.); (W.Z.)
| | - Wenjuan Zhang
- Department of Pharmaceutics, University of Minnesota, Minneapolis, MN 55455, USA; (S.R.); (W.Z.); (W.Z.)
| | - Lester R. Drewes
- Department of Biomedical Sciences, University of Minnesota Medical School—Duluth, Duluth, MN 55812, USA;
| | - Jann N. Sarkaria
- Department of Radiation Oncology, Mayo Clinic, Rochester, MN 55902, USA;
| | - William F. Elmquist
- Department of Pharmaceutics, University of Minnesota, Minneapolis, MN 55455, USA; (S.R.); (W.Z.); (W.Z.)
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Tallman MM, Zalenski AA, Deighen AM, Schrock MS, Mortach S, Grubb TM, Kastury PS, Huntoon K, Summers MK, Venere M. The small molecule drug CBL0137 increases the level of DNA damage and the efficacy of radiotherapy for glioblastoma. Cancer Lett 2020; 499:232-242. [PMID: 33253788 DOI: 10.1016/j.canlet.2020.11.027] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 11/05/2020] [Accepted: 11/23/2020] [Indexed: 11/17/2022]
Abstract
Glioblastoma (GBM) is an incurable brain tumor with inevitable recurrence. This is in part due to a highly malignant cancer stem cell (CSC) subpopulation of tumor cells that is particularly resistant to conventional treatments, including radiotherapy. Here we show that CBL0137, a small molecule anti-cancer agent, sensitizes GBM CSCs to radiotherapy. CBL0137 sequesters the FACT (facilitates chromatin transcription) complex to chromatin, resulting in cytotoxicity preferentially within tumor cells. We show that when combined with radiotherapy, CBL0137 inhibited GBM CSC growth and resulted in more DNA damage in the CSCs compared to irradiation or drug alone. Using an in vivo subcutaneous model, we showed that the frequency of GBM CSCs was reduced when tumors were pretreated with CBL0137 and then exposed to irradiation. Survival studies with orthotopic GBM models resulted in significantly extended survival for mice treated with combinatorial therapy. As GBM CSCs contribute to the inevitable recurrence in patients, targeting them is imperative. This work establishes a new treatment paradigm for GBM that sensitizes CSCs to irradiation and may ultimately reduce tumor recurrence.
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Affiliation(s)
- Miranda M Tallman
- Department of Radiation Oncology, James Cancer Hospital and Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH, USA; Biomedical Graduate Program, The Ohio State University, Columbus, OH, USA
| | - Abigail A Zalenski
- Department of Radiation Oncology, James Cancer Hospital and Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH, USA; Neuroscience Graduate Program, The Ohio State University, Columbus, OH, USA
| | - Amanda M Deighen
- Department of Radiation Oncology, James Cancer Hospital and Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH, USA
| | - Morgan S Schrock
- Department of Radiation Oncology, James Cancer Hospital and Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH, USA
| | - Sherry Mortach
- Department of Radiation Oncology, James Cancer Hospital and Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH, USA
| | - Treg M Grubb
- Department of Radiation Oncology, James Cancer Hospital and Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH, USA
| | - Preetham S Kastury
- Department of Radiation Oncology, James Cancer Hospital and Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH, USA
| | - Kristin Huntoon
- Department of Neurological Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Matthew K Summers
- Department of Radiation Oncology, James Cancer Hospital and Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH, USA
| | - Monica Venere
- Department of Radiation Oncology, James Cancer Hospital and Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH, USA.
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Teyateeti A, Geno CS, Stafford SS, Mahajan A, Yan ES, Merrell KW, Laack NN, Parney IF, Brown PD, Jethwa KR. Does the dural resection bed need to be irradiated? Patterns of recurrence and implications for postoperative radiotherapy for temporal lobe gliomas. Neurooncol Pract 2020; 8:190-198. [PMID: 33898052 DOI: 10.1093/nop/npaa073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Background Patterns of recurrence and survival with different surgical and radiotherapy (RT) techniques were evaluated to guide RT target volumes for patients with temporal lobe glioma. Methods and Materials This retrospective cohort study included patients with World Health Organization grades II to IV temporal lobe glioma treated with either partial (PTL) or complete temporal lobectomy (CTL) followed by RT covering both the parenchymal and dural resection bed (whole-cavity radiotherapy [WCRT]) or the parenchymal resection bed only (partial-cavity radiotherapy [PCRT]). Patterns of recurrence, progression-free survival (PFS) and overall survival (OS) were evaluated. Results Fifty-one patients were included and 84.3% of patients had high-grade glioma (HGG). CTL and PTL were performed for 11 (21.6%) and 40 (78.4%) patients, respectively. Median RT dose was 60 Gy (range, 40-76 Gy). There were 82.4% and 17.6% of patients who received WCRT and PCRT, respectively. Median follow-up time was 18.4 months (range, 4-161 months). Forty-six patients (90.2%) experienced disease recurrence, most commonly at the parenchymal resection bed (76.5%). No patients experienced an isolated dural recurrence. The median PFS and OS for the PCRT and WCRT cohorts were 8.6 vs 10.8 months (P = .979) and 19.9 vs 18.6 months (P = .859), respectively. PCRT was associated with a lower RT dose to the brainstem, optic, and ocular structures, hippocampus, and pituitary. Conclusion We identified no isolated dural recurrence and similar PFS and OS regardless of postoperative RT volume, whereas PCRT was associated with dose reduction to critical structures. Omission of dural RT may be considered a reasonable alternative approach. Further validation with larger comparative studies is warranted.
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Affiliation(s)
- Achiraya Teyateeti
- Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, US.,Division of Radiation Oncology, Department of Radiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Connie S Geno
- Department of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota, US
| | - Scott S Stafford
- Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, US
| | - Anita Mahajan
- Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, US
| | - Elizabeth S Yan
- Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, US
| | - Kenneth W Merrell
- Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, US
| | - Nadia N Laack
- Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, US
| | - Ian F Parney
- Department of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota, US
| | - Paul D Brown
- Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, US
| | - Krishan R Jethwa
- Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, US.,Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut, US
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Jiang H, Yu K, Li M, Cui Y, Ren X, Yang C, Zhao X, Lin S. Classification of Progression Patterns in Glioblastoma: Analysis of Predictive Factors and Clinical Implications. Front Oncol 2020; 10:590648. [PMID: 33251147 PMCID: PMC7673412 DOI: 10.3389/fonc.2020.590648] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Accepted: 10/12/2020] [Indexed: 12/16/2022] Open
Abstract
Background This study was designed to explore the progression patterns of IDH-wildtype glioblastoma (GBM) at first recurrence after chemoradiotherapy. Methods Records from 247 patients who underwent progression after diagnosis of IDH-wildtype GBM was retrospectively reviewed. Progression patterns were classified as either local, distant, subependymal or leptomeningeal dissemination based on the preoperative and serial postoperative radiographic images. The clinical and molecular characteristics of different progression patterns were analyzed. Results A total of 186 (75.3%) patients had local progression, 15 (6.1%) patients had distant progression, 33 (13.3%) patients had subependymal dissemination, and 13 (5.3%) patients had leptomeningeal dissemination. The most favorable survival occurred in patients with local progression, while no significant difference of survival was found among patients with distant progression, subependymal or leptomeningeal dissemination who were thereby reclassified into non-local group. Multivariable analysis showed that chemotherapy was a protective factor for non-local progression, while gender of male, subventricular zone (SVZ) involvement and O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation were confirmed as risk factors for non-local progression (P < 0.05). Based on the factors screened by multivariable analysis, a nomogram was constructed which conferred high accuracy in predicting non-local progression. Patients in non-local group could be divided into long- and short-term survivors who differed in the rates of SVZ involvement, MGMT promoter methylation and reirradiation (P < 0.05), and a nomogram integrating these factors showed high accuracy in predicting long-term survivors. Conclusion Patients harboring different progression patterns conferred distinct clinical and molecular characteristics. Our nomograms could provide theoretical references for physicians to make more personalized and precise treatment decisions.
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Affiliation(s)
- Haihui Jiang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.,National Clinical Research Center for Neurological Diseases, Center of Brain Tumor, Beijing Institute for Brain Disorders and Beijing Key Laboratory of Brain Tumor, Beijing, China
| | - Kefu Yu
- Department of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Mingxiao Li
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.,National Clinical Research Center for Neurological Diseases, Center of Brain Tumor, Beijing Institute for Brain Disorders and Beijing Key Laboratory of Brain Tumor, Beijing, China
| | - Yong Cui
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.,National Clinical Research Center for Neurological Diseases, Center of Brain Tumor, Beijing Institute for Brain Disorders and Beijing Key Laboratory of Brain Tumor, Beijing, China
| | - Xiaohui Ren
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.,National Clinical Research Center for Neurological Diseases, Center of Brain Tumor, Beijing Institute for Brain Disorders and Beijing Key Laboratory of Brain Tumor, Beijing, China
| | - Chuanwei Yang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.,National Clinical Research Center for Neurological Diseases, Center of Brain Tumor, Beijing Institute for Brain Disorders and Beijing Key Laboratory of Brain Tumor, Beijing, China
| | - Xuzhe Zhao
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.,National Clinical Research Center for Neurological Diseases, Center of Brain Tumor, Beijing Institute for Brain Disorders and Beijing Key Laboratory of Brain Tumor, Beijing, China
| | - Song Lin
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.,National Clinical Research Center for Neurological Diseases, Center of Brain Tumor, Beijing Institute for Brain Disorders and Beijing Key Laboratory of Brain Tumor, Beijing, China
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The Utility of Diffusion and Perfusion Magnetic Resonance Imaging in Target Delineation of High-Grade Gliomas. BIOMED RESEARCH INTERNATIONAL 2020; 2020:8718097. [PMID: 32851090 PMCID: PMC7439164 DOI: 10.1155/2020/8718097] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 03/22/2020] [Accepted: 07/21/2020] [Indexed: 02/01/2023]
Abstract
Background The tumor volume of high-grade glioma (HGG) after surgery is usually determined by contrast-enhanced MRI (CE-MRI), but the clinical target volume remains controversial. Functional magnetic resonance imaging (multimodality MRI) techniques such as magnetic resonance perfusion-weighted imaging (PWI) and diffusion-tensor imaging (DTI) can make up for CE-MRI. This study explored the survival outcomes and failure patterns of patients with HGG by comparing the combination of multimodality MRI and CE-MRI imaging with CE-MRI alone. Methods 102 patients with postoperative HGG between 2012 and 2016 were included. 50 were delineated based on multimodality MRI (PWI, DTI) and CE-MRI (enhanced T1), and the other 52 were delineated based on CE-MRI as control. Results The median survival benefit was 6 months. The 2-year overall survival, progression-free survival, and local-regional control rates were 48% vs. 25%, 42% vs. 13.46%, and 40% vs. 13.46% for the multimodality MRI and CE-MRI cohorts, respectively. The two cohorts had similar rates of disease progression and recurrence but different proportions of failure patterns. The univariate analysis shows that characteristics of patients such as combined with epilepsy, the dose of radiotherapy, the selection of MRI were significant influence factors for 2-year overall survival. However, in multivariate analyses, only the selection of MRI was an independent significant predictor of overall survival. Conclusions This study was the first to explore the clinical value of multimodality MRI in the delineation of radiotherapy target volume for HGG. The conclusions of the study have positive reference significance to the combination of multimodality MRI and CE-MRI in guiding the delineation of the radiotherapy target area for HGG patients.
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42
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Shieh LT, Guo HR, Ho CH, Lin LC, Chang CH, Ho SY. Survival of glioblastoma treated with a moderately escalated radiation dose-Results of a retrospective analysis. PLoS One 2020; 15:e0233188. [PMID: 32413077 PMCID: PMC7228055 DOI: 10.1371/journal.pone.0233188] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Accepted: 04/29/2020] [Indexed: 11/18/2022] Open
Abstract
Glioblastoma (GBM) has the highest fatality rate among primary malignant brain tumors and typically tends to recur locally just adjacent to the original tumor site following surgical resection and adjuvant radiotherapy. We conducted a study to evaluate the survival outcomes between a standard dose (≤ 60 Gy) and moderate radiation dose escalation (>60 Gy), and to identify prognostic factors for GBM. We retrospectively reviewed the medical records of primary GBM patients diagnosed between 2005 and 2016 in two referral hospitals in Taiwan. They were identified from the cancer registry database and followed up from the date of diagnosis to October 2018. The progression-free survival (PFS) and overall survival (OS) were compared between the two dose groups, and independent factors for survival were analyzed through Cox proportional hazard model. We also affirmed the results using Cox regression with least absolute shrinkage and selection operator (LASSO) approach. From our cancer registry database, 142 GBM patients were identified, and 84 of them fit the inclusion criteria. Of the 84 patients, 52 (62%) were males. The radiation dose ranged from 50.0 Gy to 66.6 Gy, but their treatment volumes were similar to the others. Fifteen (18%) patients received an escalated dose boost >60.0 Gy. The escalated group had a longer median PFS (15.4 vs. 7.9 months, p = 0.01 for log-rank test), and a longer median OS was also longer in the escalation group (33.8 vs. 12.5 months, p <0.001) than the reference group. Following a multivariate analysis, the escalated dose was identified as a significant predictor for good prognosis (PFS: hazard ratio [HR] = 0.48, 95% confidence interval [95%CI]: 0.23-0.98; OS: HR = 0.40, 95%CI: 0.21-0.78). Using the LASSO approach, we found age > 70 (HR = 1.55), diagnosis after 2010 (HR = 1.42), and a larger radiation volume (≥ 250ml; HR = 0.81) were predictors of PFS. The escalated dose (HR = 0.47) and a larger radiation volume (HR = 0.76) were identified as predictors for better OS. Following detailed statistical analysis, a moderate radiation dose escalation (> 60 Gy) was found as an independent factor affecting OS in GBM patients. In conclusion, a moderate radiation dose escalation (> 60 Gy) was an independent predictor for longer OS in GBM patients. However, prospective studies including more patients with more information, such as molecular markers and completeness of resection, are needed to confirm our findings.
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Affiliation(s)
- Li-Tsun Shieh
- Department of Radiation Oncology, Chi Mei Medical Center, Liouying, Tainan, Taiwan, Republic of china
| | - How-Ran Guo
- Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of china
- Department of Occupational and Environmental Medicine, National Cheng Kung University Hospital, Tainan, Taiwan, Republic of china
| | - Chung-Han Ho
- Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan, Republic of china
- Department of Hospital and Health Care Administration, Chia Nan University of Pharmacy and Science, Tainan, Taiwan, Republic of china
| | - Li-Ching Lin
- Department of Radiation Oncology, Chi Mei Medical Center, Tainan, Taiwan, Republic of china
| | - Chin-Hong Chang
- Department of Neurosurgery, Chi Mei Medical Center, Tainan, Taiwan, Republic of china
| | - Sheng-Yow Ho
- Department of Radiation Oncology, Chi Mei Medical Center, Liouying, Tainan, Taiwan, Republic of china
- Department of Radiation Oncology, Chi Mei Medical Center, Tainan, Taiwan, Republic of china
- Graduate Institute of Medical Science, Chang Jung Christian University, Tainan, Taiwan, Republic of china
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43
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Roh TH, Kang SG, Moon JH, Sung KS, Park HH, Kim SH, Kim EH, Hong CK, Suh CO, Chang JH. Survival benefit of lobectomy over gross-total resection without lobectomy in cases of glioblastoma in the noneloquent area: a retrospective study. J Neurosurg 2020; 132:895-901. [PMID: 30835701 DOI: 10.3171/2018.12.jns182558] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Accepted: 12/03/2018] [Indexed: 11/06/2022]
Abstract
OBJECTIVE Following resection of glioblastoma (GBM), microscopic remnants of the GBM tumor remaining in nearby tissue cause tumor recurrence more often than for other types of tumors, even after gross-total resection (GTR). Although surgical oncologists traditionally resect some of the surrounding normal tissue, whether further removal of nearby tissue may improve survival in GBM patients is unknown. In this single-center retrospective study, the authors assessed whether lobectomy confers a survival benefit over GTR without lobectomy when treating GBMs in the noneloquent area. METHODS The authors selected 40 patients who had undergone GTR of a histopathologically diagnosed isocitrate dehydrogenase (IDH)-wild type GBM in the right frontal or temporal lobe and divided the patients into 2 groups according to whether GTR of the tumor involved lobectomy, defined as a supratotal resection (SupTR group, n = 20) or did not (GTR group, n = 20). Progression-free survival (PFS), overall survival (OS), and Karnofsky Performance Status (KPS) scores were compared between groups (p ≤ 0.05 for statistically significant differences). RESULTS The median postoperative PFS times for each group were as follows: GTR group, 11.5 months (95% CI 8.8-14.2) and SupTR group, 30.7 months (95% CI 4.3-57.1; p = 0.007). The median postoperative OS times for each group were as follows: GTR group, 18.7 months (95% CI 14.3-23.1) and SupTR group, 44.1 months (95% CI 25.1-63.1; p = 0.040). The mean postoperative KPS scores (GTR, 76.5; SupTR, 77.5; p = 0.904) were not significantly different. In multivariate analysis, survival for the SupTR group was significantly longer than that for the GTR group in terms of both PFS (HR 0.230; 95% CI 0.090-0.583; p = 0.002) and OS (HR 0.247; 95% CI 0.086-0.704; p = 0.009). CONCLUSIONS In cases of completely resectable, noneloquent-area GBMs, SupTR provides superior PFS and OS without negatively impacting patient performance.
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Affiliation(s)
- Tae Hoon Roh
- 1Yonsei University Graduate School, Seoul
- 2Department of Neurosurgery, Brain Tumor Center, Ajou University Hospital, Ajou University School of Medicine, Suwon
| | - Seok-Gu Kang
- 3Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University Health System, Seoul
| | - Ju Hyung Moon
- 3Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University Health System, Seoul
| | - Kyoung Su Sung
- 4Department of Neurosurgery, Dong-A University Hospital, Dong-A University College of Medicine, Busan
| | - Hun Ho Park
- 5Department of Neurosurgery, Gangnam Severance Hospital, Yonsei University Health System, Seoul
| | - Se Hoon Kim
- 6Department of Pathology, Brain Tumor Center, Severance Hospital, Yonsei University Health System, Seoul; and
| | - Eui Hyun Kim
- 3Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University Health System, Seoul
| | - Chang-Ki Hong
- 5Department of Neurosurgery, Gangnam Severance Hospital, Yonsei University Health System, Seoul
| | - Chang-Ok Suh
- 7Department of Radiation Oncology, Brain Tumor Center, Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea
| | - Jong Hee Chang
- 3Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University Health System, Seoul
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Kumar N, Kumar R, Sharma SC, Mukherjee A, Khandelwal N, Tripathi M, Miriyala R, Oinam AS, Madan R, Yadav BS, Khosla D, Kapoor R. Impact of volume of irradiation on survival and quality of life in glioblastoma: a prospective, phase 2, randomized comparison of RTOG and MDACC protocols. Neurooncol Pract 2020; 7:86-93. [PMID: 32257287 PMCID: PMC7104885 DOI: 10.1093/nop/npz024] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Though conformal partial-brain irradiation is the standard adjuvant treatment for glioblastoma, there is no consensus regarding the optimal volume that needs to be irradiated. European Organisation for Research and Treatment of Cancer (EORTC) and The University of Texas MD Anderson Cancer Center (MDACC) guidelines differ from the Radiation Therapy Oncology Group (RTOG) in their approach toward peritumoral edema, whereas RTOG and MDACC guidelines differ from EORTC in the concept of boost phase. A scarcity of randomized comparisons has resulted in remarkable variance in practice among institutions. METHODS Fifty glioblastoma patients were randomized to receive adjuvant radiotherapy using RTOG or MDACC protocols. Apart from dosimetric and volumetric analysis, acute toxicities, recurrence patterns, progression-free survival (PFS), overall survival (OS), and quality of life (QoL) were compared using appropriate statistical tests. RESULTS Both groups were comparable with respect to demographic characteristics. Dosimetric analysis revealed significantly lower boost-phase planning treatment volumes and V60 Gy in the MDACC arm (chi-squared, P = .001 and .013, respectively). No significant differences were observed in doses with respect to organs at risk, acute toxicity, or recurrence patterns (chi-squared, P > .05). On the log-rank test, median PFS (8.8 months vs 6.1 months, P = .043) and OS (17 months vs 12 months, P = .015) were statistically superior in the MDACC group.Age, extent of resection, and proportion of whole brain receiving prescription dose were associated with improved PFS and OS on regression analysis. QoL of patients was significantly better in the MDACC group in all domains except cognitive, as assessed with the EORTC Quality of Life Questionnaire (QLQ-C30) and Brain Cancer Module (QLQ-BN20) (general linear model, P < .05). CONCLUSIONS Use of limited-margin MDACC protocol can potentially improve survival outcomes apart from QoL of glioblastoma patients, as compared with the RTOG protocol.
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Affiliation(s)
- Narendra Kumar
- Department of Radiotherapy, PGIMER (Post-Graduate Institute of Medical Education and Research), Chandigarh, India
| | - Ridu Kumar
- Department of Radiotherapy, PGIMER (Post-Graduate Institute of Medical Education and Research), Chandigarh, India
| | - Suresh C Sharma
- Department of Radiotherapy, PGIMER (Post-Graduate Institute of Medical Education and Research), Chandigarh, India
| | - Anindya Mukherjee
- Department of Radiotherapy, PGIMER (Post-Graduate Institute of Medical Education and Research), Chandigarh, India
| | | | | | - Raviteja Miriyala
- Department of Radiotherapy, PGIMER (Post-Graduate Institute of Medical Education and Research), Chandigarh, India
| | - Arun S Oinam
- Department of Radiotherapy, PGIMER (Post-Graduate Institute of Medical Education and Research), Chandigarh, India
| | - Renu Madan
- Department of Radiotherapy, PGIMER (Post-Graduate Institute of Medical Education and Research), Chandigarh, India
- Department of Radiotherapy, PGIMER, Chandigarh, India
| | - Budhi S Yadav
- Department of Radiotherapy, PGIMER (Post-Graduate Institute of Medical Education and Research), Chandigarh, India
| | - Divya Khosla
- Department of Radiotherapy, PGIMER (Post-Graduate Institute of Medical Education and Research), Chandigarh, India
| | - Rakesh Kapoor
- Department of Radiotherapy, PGIMER (Post-Graduate Institute of Medical Education and Research), Chandigarh, India
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Thompson G, Lawrie TA, Kernohan A, Jenkinson MD, Cochrane Gynaecological, Neuro‐oncology and Orphan Cancer Group. Interval brain imaging for adults with cerebral glioma. Cochrane Database Syst Rev 2019; 12:CD013137. [PMID: 31873964 PMCID: PMC6953319 DOI: 10.1002/14651858.cd013137.pub2] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
BACKGROUND Clinical practice guidelines suggest that magnetic resonance imaging (MRI) of the brain should be performed at certain time points or intervals distant from diagnosis (interval or surveillance imaging) of cerebral glioma, to monitor or follow up the disease; it is not known, however, whether these imaging strategies lead to better outcomes among patients than triggered imaging in response to new or worsening symptoms. OBJECTIVES To determine the effect of different imaging strategies (in particular, pre-specified interval or surveillance imaging, and symptomatic or triggered imaging) on health and economic outcomes for adults with glioma (grades 2 to 4) in the brain. SEARCH METHODS The Cochrane Gynaecological, Neuro-oncology and Orphan Cancers (CGNOC) Group Information Specialist searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and Embase up to 18 June 2019 and the NHS Economic Evaluation Database (EED) up to December 2014 (database closure). SELECTION CRITERIA We included randomised controlled trials, non-randomised controlled trials, and controlled before-after studies with concurrent comparison groups comparing the effect of different imaging strategies on survival and other health outcomes in adults with cerebral glioma; and full economic evaluations (cost-effectiveness analyses, cost-utility analyses and cost-benefit analyses) conducted alongside any study design, and any model-based economic evaluations on pre- and post-treatment imaging in adults with cerebral glioma. DATA COLLECTION AND ANALYSIS We used standard Cochrane review methodology with two authors independently performing study selection and data collection, and resolving disagreements through discussion. We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS We included one retrospective, single-institution study that compared post-operative imaging within 48 hours (early post-operative imaging) with no early post-operative imaging among 125 people who had surgery for glioblastoma (GBM: World Health Organization (WHO) grade 4 glioma). Most patients in the study underwent maximal surgical resection followed by combined radiotherapy and temozolomide treatment. Although patient characteristics in the study arms were comparable, the study was at high risk of bias overall. Evidence from this study suggested little or no difference between early and no early post-operative imaging with respect to overall survival (deaths) at one year after diagnosis of GBM (risk ratio (RR) 0.86, 95% confidence interval (CI) 0.61 to 1.21; 48% vs 55% died, respectively; very low certainty evidence) and little or no difference in overall survival (deaths) at two years after diagnosis of GBM (RR 1.06, 95% CI 0.91 to 1.25; 86% vs 81% died, respectively; very low certainty evidence). No other review outcomes were reported. We found no evidence on the effectiveness of other imaging schedules. In addition, we identified no relevant economic evaluations assessing the efficiency of the different imaging strategies. AUTHORS' CONCLUSIONS The effect of different imaging strategies on survival and other health outcomes remains largely unknown. Existing imaging schedules in glioma seem to be pragmatic rather than evidence-based. The limited evidence suggesting that early post-operative brain imaging among GBM patients who will receive combined chemoradiation treatment may make little or no difference to survival needs to be further researched, particularly as early post-operative imaging also serves as a quality control measure that may lead to early re-operation if residual tumour is identified. Mathematical modelling of a large glioma patient database could help to distinguish the optimal timing of surveillance imaging for different types of glioma, with stratification of patients facilitated by assessment of individual tumour growth rates, molecular biomarkers and other prognostic factors. In addition, paediatric glioma study designs could be used to inform future research of imaging strategies among adults with glioma.
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Affiliation(s)
- Gerard Thompson
- University of EdinburghCentre for Clinical Brain SciencesChancellor’s Building FU201a49 Little France CrescentEdinburghScotlandUKEH16 4SB
| | - Theresa A Lawrie
- The Evidence‐Based Medicine Consultancy Ltd3rd Floor Northgate HouseUpper Borough WallsBathUKBA1 1RG
| | - Ashleigh Kernohan
- Newcastle UniversityInstitute of Health & SocietyBaddiley‐Clark Building, Richardson RoadNewcastle upon TyneUKNE2 4AA
| | - Michael D Jenkinson
- Institute of Translational MedicineUniversity of Liverpool & Department of NeurosurgeryThe Walton Centre NHS Foundation TrustLiverpoolMerseysideUK
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Thomas RP, Nagpal S, Iv M, Soltys SG, Bertrand S, Pelpola JS, Ball R, Yang J, Sundaram V, Lavezo J, Born D, Vogel H, Brown JM, Recht LD. Macrophage Exclusion after Radiation Therapy (MERT): A First in Human Phase I/II Trial using a CXCR4 Inhibitor in Glioblastoma. Clin Cancer Res 2019; 25:6948-6957. [PMID: 31537527 PMCID: PMC6891194 DOI: 10.1158/1078-0432.ccr-19-1421] [Citation(s) in RCA: 74] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 07/17/2019] [Accepted: 09/11/2019] [Indexed: 01/18/2023]
Abstract
PURPOSE Preclinical studies have demonstrated that postirradiation tumor revascularization is dependent on a stromal cell-derived factor-1 (SDF-1)/C-X-C chemokine receptor type 4 (CXCR4)-driven process in which myeloid cells are recruited from bone marrow. Blocking this axis results in survival improvement in preclinical models of solid tumors, including glioblastoma (GBM). We conducted a phase I/II study to determine the safety and efficacy of Macrophage Exclusion after Radiation Therapy (MERT) using the reversible CXCR4 inhibitor plerixafor in patients with newly diagnosed glioblastoma. PATIENTS AND METHODS We enrolled nine patients in the phase I study and an additional 20 patients in phase II using a modified toxicity probability interval (mTPI) design. Plerixafor was continuously infused intravenously via a peripherally inserted central catheter (PICC) line for 4 consecutive weeks beginning at day 35 of conventional treatment with concurrent chemoradiation. Blood serum samples were obtained for pharmacokinetic analysis. Additional studies included relative cerebral blood volume (rCBV) analysis using MRI and histopathology analysis of recurrent tumors. RESULTS Plerixafor was well tolerated with no drug-attributable grade 3 toxicities observed. At the maximum dose of 400 μg/kg/day, biomarker analysis found suprathreshold plerixafor serum levels and an increase in plasma SDF-1 levels. Median overall survival was 21.3 months [95% confidence interval (CI), 15.9-NA] with a progression-free survival of 14.5 months (95% CI, 11.9-NA). MRI and histopathology support the mechanism of action to inhibit postirradiation tumor revascularization. CONCLUSIONS Infusion of the CXCR4 inhibitor plerixafor was well tolerated as an adjunct to standard chemoirradiation in patients with newly diagnosed GBM and improves local control of tumor recurrences.
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Affiliation(s)
- Reena P Thomas
- Department of Neurology, Division of Neuro Oncology, Stanford, California.
| | - Seema Nagpal
- Department of Neurology, Division of Neuro Oncology, Stanford, California
| | - Michael Iv
- Department of Radiology, Division of Neuro Radiology, Stanford, California
| | | | - Sophie Bertrand
- Department of Neurology, Division of Neuro Oncology, Stanford, California
| | - Judith S Pelpola
- Department of Neurology, Division of Neuro Oncology, Stanford, California
| | - Robyn Ball
- Department of Medicine, Quantitative Sciences Unit, Stanford, California
| | - Jaden Yang
- Department of Medicine, Quantitative Sciences Unit, Stanford, California
| | - Vandana Sundaram
- Department of Medicine, Quantitative Sciences Unit, Stanford, California
| | - Jonathan Lavezo
- Department of Pathology, Division of Neuro Pathology, Stanford University, Stanford, California
| | - Donald Born
- Department of Pathology, Division of Neuro Pathology, Stanford University, Stanford, California
| | - Hannes Vogel
- Department of Pathology, Division of Neuro Pathology, Stanford University, Stanford, California
| | - J Martin Brown
- Department of Neurology, Division of Neuro Oncology, Stanford, California
| | - Lawrence D Recht
- Department of Neurology, Division of Neuro Oncology, Stanford, California
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Wright CH, Wright J, Onyewadume L, Raghavan A, Lapite I, Casco-Zuleta A, Lagman C, Sajatovic M, Hodges TR. Diagnosis, treatment, and survival in spinal dissemination of primary intracranial glioblastoma: systematic literature review. J Neurosurg Spine 2019; 31:723-732. [PMID: 31374545 DOI: 10.3171/2019.5.spine19164] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Accepted: 05/15/2019] [Indexed: 11/06/2022]
Abstract
OBJECTIVE Spinal metastases from primary intracranial glioblastoma (GBM) are infrequently reported, and the disease has yet to be well characterized. A more accurate description of its clinical presentation and patient survival may improve understanding of this pathology, guide patient care, and advocate for increased inclusion in GBM research. The authors sought to describe the clinical presentation, treatment patterns, and survival in patients with drop metastases secondary to primary intracranial GBM. METHODS A systematic review was performed using the PRISMA guidelines. PubMed/MEDLINE, Scopus, Web of Science, and Cochrane databases were queried for abstracts that included patients with primary intracranial GBM and metastases to the spinal axis. Descriptive statistics were used to evaluate characteristics of the primary brain lesion, timing of spinal metastases, clinical symptoms, anatomical location of the metastases, and survival and treatment parameters. Kaplan-Meier analysis and log-rank analysis of the survival curves were performed for selected subgroups. RESULTS Of 1225 abstracts that resulted from the search, 51 articles were selected, yielding 86 subjects. The patients' mean age was 46.78 years and 59.74% were male. The most common symptom was lumbago or cervicalgia (90.24%), and this was followed by paraparesis (86.00%). The actuarial median survival after the detection of spinal metastases was 2.8 months and the mean survival was 2.72 months (95% CI 2.59-4.85), with a 1-year cumulative survival probability of 2.7% (95% CI 0.51%-8.33%). A diagnosis of leptomeningeal disease, present in 53.54% of the patients, was correlated, and significantly worse survival was on log-rank analysis in patients with leptomeningeal disease (p = 0.0046; median survival 2.5 months [95% CI 2-3] vs 4.0 months [95% CI 2-6]). CONCLUSIONS This study established baseline characteristics of GBMs metastatic to the spinal axis. The prognosis is poor, though these results will provide patients and clinicians with more accurate survival estimates. The quality of studies reporting on this disease pathology is still limited. There is significant need for improved reporting methods for spinal metastases, either through enrollment of these patients in clinical trials or through increased granularity of coding for metastatic central nervous system diseases in cancer databases.
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Affiliation(s)
- Christina Huang Wright
- 1Department of Neurological Surgery, University Hospitals Cleveland Medical Center
- 2Case Western Reserve University School of Medicine; and
| | - James Wright
- 1Department of Neurological Surgery, University Hospitals Cleveland Medical Center
- 2Case Western Reserve University School of Medicine; and
| | | | | | - Isaac Lapite
- 2Case Western Reserve University School of Medicine; and
| | | | - Carlito Lagman
- 1Department of Neurological Surgery, University Hospitals Cleveland Medical Center
- 2Case Western Reserve University School of Medicine; and
| | - Martha Sajatovic
- 3Neurological and Behavioral Outcomes Research Center and
- 4Departments of Neurology and Psychiatry, University Hospitals Cleveland Medical Center, Cleveland, Ohio
| | - Tiffany R Hodges
- 1Department of Neurological Surgery, University Hospitals Cleveland Medical Center
- 2Case Western Reserve University School of Medicine; and
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Sarria GR, Sperk E, Han X, Sarria GJ, Wenz F, Brehmer S, Fu B, Min S, Zhang H, Qin S, Qiu X, Hänggi D, Abo-Madyan Y, Martinez D, Cabrera C, Giordano FA. Intraoperative radiotherapy for glioblastoma: an international pooled analysis. Radiother Oncol 2019; 142:162-167. [PMID: 31629553 DOI: 10.1016/j.radonc.2019.09.023] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Revised: 08/27/2019] [Accepted: 09/24/2019] [Indexed: 10/25/2022]
Abstract
PURPOSE To report the results of the first international pooled analysis of patients with glioblastoma treated with intraoperative radiotherapy (IORT) in addition to standard of care therapy. METHODS Data from 51 patients treated at five centers in Germany, China and Peru were analyzed. All patients underwent tumor resection followed by a single application of IORT (10-40 Gy, prescribed to the applicator surface) with low-energy X-rays. Thereafter, standard adjuvant radiochemotherapy and maintenance chemotherapy were applied. Factors of interest were overall survival (OS), progression-free survival (PFS), local PFS (L-PFS; defined as appearance of new lesions ≤1 cm to the cavity border) and distant PFS (D-PFS; lesions >1 cm). The same endpoints were estimated at 1-, 2- and 3-years using the Kaplan-Meier method. Additionally, rates and severity (as per Common Terminology Criteria for Adverse Events Version 5.0) of radionecrosis (RN) were analyzed. RESULTS The median age was 55 years (range: 16-75) and the median Karnofsky Performance Status was 80 (20-100). At a median follow-up of 18.0 months (2-42.4), the median OS, PFS, L-PFS and D-PFS were 18.0 months (95% CI: 14.7-21.3), 11.4 months (95%CI: 7.58-15.22), 16 months (95%CI: 10.21-21.8) and 30.0 months (95%CI: 18.59 - 41.41), respectively. The estimated 1-, 2- and 3-year OS, PFS, L-PFS and D-PFS were 79.5%, 38.7% and 25.6%; 46.2%, 29.4%, and 5.9%; 60.9, 37.9%, and 12.6%; and 76.7%, 65.0%, and 39.0% respectively. First progression occurred locally in only 35.3% of cases. Grade 1 RN was detected in 7.8% and grade 3 in 17.6% of the patients. No grade 4 toxicity was reported and no treatment-related deaths occurred. CONCLUSION Compared to historical data, this pooled analysis suggests improved efficacy and safety of IORT with low-energy X-rays for newly diagnosed glioblastoma. Prospective data is warranted to confirm these findings.
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Affiliation(s)
- Gustavo R Sarria
- Department of Radiation Oncology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Elena Sperk
- Department of Radiation Oncology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
| | - Xiaodi Han
- Department of Neurosurgery Beijing Tiantan Hospital, Capital Medical University, Beijing, China; Department of Neurosurgery, Beijing Tiantan Puhua Hospital, China; China National Clinical Research Center for Neurological Diseases, Beijing, China
| | - Gustavo J Sarria
- Department of Radiotherapy, Oncosalud - AUNA, Lima, Peru; Department of Radiotherapy, Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru
| | - Frederik Wenz
- Department of Radiation Oncology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; University Medical Center Freiburg, Freiburg, Germany
| | - Stefanie Brehmer
- Department of Neurosurgery, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Bing Fu
- Department of Neurosurgery, Beijing Tiantan Puhua Hospital, China
| | - Siming Min
- Department of Neurosurgery, Beijing Tiantan Puhua Hospital, China
| | - Hongjun Zhang
- Department of Neurosurgery, Beijing Tiantan Puhua Hospital, China
| | - Shusen Qin
- Department of Neurosurgery, Beijing Tiantan Puhua Hospital, China
| | - Xiaoguang Qiu
- Department of Radiotherapy, Beijing Tiantan Puhua Hospital, Capital Medical University, Beijing, China
| | - Daniel Hänggi
- Department of Neurosurgery, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Yasser Abo-Madyan
- Department of Radiation Oncology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - David Martinez
- Department of Radiotherapy, Oncosalud - AUNA, Lima, Peru
| | - Carla Cabrera
- Department of Radiotherapy, Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru
| | - Frank A Giordano
- Department of Radiation Oncology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
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Mistry AM, Kelly PD, Thompson RC, Chambless LB. Cancer Dissemination, Hydrocephalus, and Survival After Cerebral Ventricular Entry During High-Grade Glioma Surgery: A Meta-Analysis. Neurosurgery 2019; 83:1119-1127. [PMID: 29790976 DOI: 10.1093/neuros/nyy202] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Accepted: 04/16/2018] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND The consequences of ventricular entry during resection of high-grade gliomas (HGG) are uncertain and often not detectable clinically. OBJECTIVE To reveal odds of tumor dissemination, hydrocephalus, and mortality in adult patients who had ventricular entry during surgical resection of HGG. METHODS Titles and abstracts of published journals in the NCBI/NLM PubMed and OVID EMBASE databases were searched without language restriction and systematically screened. Outcomes extracted included the odds of leptomeningeal dissemination and hydrocephalus in patients with ventricular entry during HGG resection compared to without. They were analyzed using a random-effects model to calculate summary odds ratios (sORs). Overall survival data were also compared between patients with and without ventricular entry. RESULTS Twenty final studies with 2251 total patients were included from the 6910 retrieved. Patients with ventricular entry during HGG resection demonstrated higher odds of leptomeningeal dissemination (sOR: 3.91 [95% confidence interval (CI): 1.89-8.10]; P = .0002; 86/410 vs 57/847 patients in 9 studies) and hydrocephalus (sOR: 7.78 [95% CI: 3.77-16.05]; P < .00001; 58/431 vs 11/565 patients in 11 studies). They also had decreased survival (median survival: 16.8 vs 19.1 mo; 413 vs 322 patients in 10 studies; hazard ratio: 1.25 [95% CI: 1.05-1.48], P = .01). CONCLUSION The association between ventricular entry during HGG resection and tumor dissemination, hydrocephalus, and decreased survival invites investigations to understand this link. Neurosurgeons and neuro-oncologists must be aware of the consequences of ventricular entry during surgery for HGG.
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Affiliation(s)
- Akshitkumar M Mistry
- Department of Neurosurgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Patrick D Kelly
- Department of Neurosurgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Reid C Thompson
- Department of Neurosurgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Lola B Chambless
- Department of Neurosurgery, Vanderbilt University Medical Center, Nashville, Tennessee
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50
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Zhong L, Chen L, Lv S, Li Q, Chen G, Luo W, Zhou P, Li G. Efficacy of moderately hypofractionated simultaneous integrated boost intensity-modulated radiotherapy combined with temozolomide for the postoperative treatment of glioblastoma multiforme: a single-institution experience. Radiat Oncol 2019; 14:104. [PMID: 31196126 PMCID: PMC6567425 DOI: 10.1186/s13014-019-1305-1] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Accepted: 05/24/2019] [Indexed: 11/10/2022] Open
Abstract
PURPOSE Despite recent advances in multimodal treatments, the prognosis of patients with glioblastoma multiforme (GBM) remains poor. The aim of this study was to evaluate the efficacy of moderately hypofractionated simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) combined with temozolomide (TMZ) for the postoperative treatment of GBM. MATERIALS AND METHODS From February 2012 to February 2018, 80 patients with newly diagnosed and histologically confirmed GBM in our institute were reviewed retrospectively. All patients underwent complete resection or partial resection surgery and then received hypofractionated SIB-IMRT with concomitant TMZ followed by adjuvant TMZ. A total dose of 64 Gy over 27 fractions was delivered to the gross tumor volume (GTV), clinical target volume 1 (CTV1) received 60 Gy over 27 fractions, and CTV2 received 54 Gy over 27 fractions. The progression-free survival (PFS) and overall survival (OS) rates and the toxicities were evaluated. Prognostic factors were analyzed using univariate and multivariate Cox models. RESULTS The median follow-up was 16 months (range, 5~72 months). The median PFS was 15 months, and the 1-, 2-, and 3-year PFS rates were 56.0, 27.6, and 19.5%, respectively. The median OS was 21 months, and the 1-, 2-, 3-, and 5-year OS rates were 77.6, 41.6, 32.8, and 13.4%, respectively. The toxicities were mild and acceptable. Age, KPS scores and the total number of TMZ cycles were significant factors influencing patient survival. CONCLUSION Moderately hypofractionated SIB-IMRT combined with TMZ is a feasible and safe treatment option with mild toxicity and good PFS and OS.
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Affiliation(s)
- Liangzhi Zhong
- Cancer Research Institute of the Chinese People's Liberation Army, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
| | - Lu Chen
- Cancer Research Institute of the Chinese People's Liberation Army, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
| | - Shengqing Lv
- Department of neurosurgery, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
| | - Qingrui Li
- Biobank, Southwest Hospital, Army Medical University, Chongqing, 400038, China
| | - Guangpeng Chen
- Cancer Research Institute of the Chinese People's Liberation Army, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
| | - Wen Luo
- Cancer Research Institute of the Chinese People's Liberation Army, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
| | - Pu Zhou
- Cancer Research Institute of the Chinese People's Liberation Army, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
| | - Guanghui Li
- Cancer Research Institute of the Chinese People's Liberation Army, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China.
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