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1
Connelly, Jennifer, Kathleen Schmainda, Mona Al-Gizawiy, Fernando Santos-Pinhero, and Christopher Chitambar. "TIPS-03 A PHASE 1 STUDY OF GALLIUM MALTOLATE (GAM) IN PATIENTS WITH RECURRENT GLIOBLASTOMA (GBM)." Neuro-Oncology Advances 5, Supplement_3 (August 1, 2023): iii34. http://dx.doi.org/10.1093/noajnl/vdad070.134.
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Abstract Glioblastoma remains the most aggressive malignant brain tumor with universally poor prognosis. New treatments are needed which target novelpathways. GBM cells have significantly greater requirements for iron and display markedly higher levels of transferrin receptors for iron uptake and ferritin for iron storage than surrounding normal astrocytes. The increased intracellular iron pool drives GBM activity. Previously, we showed that since gallium shares certain chemical properties with iron, it can inhibit malignant cell growth by disrupting tumor iron homeostasis. Recently, we reported that GaM is cytotoxic to GBM cell lines and stem cells but not to microvascular endothelial cells. In rodent orthotopically implanted human GBM xenografts, orally administered GaM reduced tumor volume and prolonged animal survival. These preclinical studies form the basis for our Phase 1 study which evaluates GaM in patients with recurrent GBM. The trial will follow a 3 + 3 phase 1 dose escalation design. Three to six patients at each dose level will receive GaM 500 mg/d, 1000 mg/d, or 1500 mg/day for a minimum of two 28-day cycles. Patients age >= 18 years with histologically confirmed GBM or molecular GBM with recurrent measurable disease are eligible. In the absence of measurable disease, pathologic confirmation of recurrence is required. Primary objectives are to determine a maximum-tolerated dose and recommended Phase 2 dose. Safety/tolerability will be assessed. Secondary objectives include disease assessments and evaluation of PFS and OS. Correlative studies planned are sequential blood levels of gallium, iron, Tf, ferritin, and hepcidin. Available tumor tissues will be examined for the expression iron biomarkers by immunochemistry. The study is currently enrolling. Patients will receive study drug until disease progression, unacceptable adverse events, patient withdrawal, or death. To date, 5 patients received GaM 500 mg/d without DLT and 4 patients started GaM 1000 mg/d.
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Wu, Mengwan, Ying Shi, Luyi Zhu, Luoyi Chen, Xinchen Zhao, and Chuan Xu. "Macrophages in Glioblastoma Development and Therapy: A Double-Edged Sword." Life 12, no. 8 (August 12, 2022): 1225. http://dx.doi.org/10.3390/life12081225.
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Glioblastoma (GBM) is one of the leading lethal tumors, featuring aggressive malignancy and poor outcome to current standard temozolomide (TMZ) or radio-based therapy. Developing immunotherapies, especially immune checkpoint inhibitors, have improved patient outcomes in other solid tumors but remain fatigued in GBM patients. Emerging evidence has shown that GBM-associated macrophages (GAMs), comprising brain-resident microglia and bone marrow-derived macrophages, act critically in boosting tumor progression, altering drug resistance, and establishing an immunosuppressive environment. Based on its crucial role, evaluations of the safety and efficacy of GAM-targeted therapy are ongoing, with promising (pre)clinical evidence updated. In this review, we summarized updated literature related to GAM nature, the interplay between GAMs and GBM cells, and GAM-targeted therapeutic strategies.
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Bergallo, Massimiliano, Cristina Costa, Stefano Gambarino, Alessandra Tornicelli, Sara Astegiano, Maria Elena Terlizzi, Paolo Solidoro, and Rossana Cavallo. "Human cytomegalovirus glycoprotein B genotyping from bronchoalveolar lavage specimens." Canadian Journal of Microbiology 57, no. 4 (April 2011): 273–77. http://dx.doi.org/10.1139/w11-014.
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The genes encoding glycoprotein complexes of human cytomegalovirus are often polymorphic; in particular, glycoprotein B (gB), which is essential for both in vivo and in vitro replication, is encoded by the highly polymorphic gene UL55. In this study, the distribution of gB genotypes was investigated in 44 bronchoalveolar lavage specimens from adult patients positive for human cytomegalovirus DNA by a multiplex nested fast PCR able to amplify 5 gB genotypes (gB1–gB5). The distribution of gB genotypes was as follows: 12 (27.3%) gB1, 11 (25%) gB2, 9 (20.4%) gB3, 4 (9.1%) gB4, 0 gB5, and 8 (18.2%) mixed genotypes. No difference in prevalence was found in relation to clinical features, including immunological status, non-transplant or transplant condition, and type of transplanted organ, or in follow-up specimens; while gB4 and gB3 were shown to be significantly more prevalent in patients with respiratory insufficiency, and gB4 and gB2 in those with pneumonia. The prevalence of gB genotypes in the lower respiratory tract was similar to that previously reported using other specimen types and patients, with gB1 found to be the most prevalent. The association of gB genotypes with specific clinical features should be further investigated.
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Nelson, James S. "Alzheimer Pathology in Elderly Patients With Glioblastoma Multiforme." Archives of Pathology & Laboratory Medicine 126, no. 12 (December 1, 2002): 1515–17. http://dx.doi.org/10.5858/2002-126-1515-apiepw.
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Abstract Context.—Alzheimer disease (AD) and glioblastoma multiforme (GBM) have similar peak, age-specific incidence rates; however, to my knowledge, only 1 case of GBM associated with AD has been reported to date. The frequency of AD pathology, including neuritic plaques, diffuse plaques, neurofibrillary tangles, and cerebral amyloid angiopathy in patients with GBM is unknown. Studies of cancer occurrence in patients with AD are contradictory, with frequencies reported as equal to and as less than that in the general population. The GBM/AD nonconcordance may reflect underreporting of AD pathology or other factors. Objective.—To compare the frequency and extent of neocortical AD pathology in autopsy cases involving patients aged 60 to 82 years, both with and without GBM. Design.—Case-control study. Setting.—Pathology department of a university hospital. Patients.—Thirty-six autopsy cases of GBM patients aged 60 to 82 years; 54 cases of patients in the same age group without GBM or other primary brain tumors. Methods.—Examination of tumor sections for GBM and of neocortical sections for AD pathology according to Consortium to Establish a Registry for Alzheimer Disease (CERAD) guidelines. Results.—Glioblastoma multiforme was confirmed in all tumor cases. Alzheimer disease pathology was present in 42% of cases with GBM and in 48% of cases without GBM; 28% of GBM cases had CERAD age-related plaque scores indicative or suggestive of AD; 43% of cases without GBM had CERAD age-related plaque scores indicative or suggestive of AD. Conclusions.—Alzheimer disease pathology was underreported in both GBM and non-GBM patients. The influence of neurodegenerative processes on GBM symptoms and therapy in elderly patients requires further study.
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Botturi, M., L. Fariselli, I. Milanesi, D. Asnaghi, S. Bracelli, G. Broggi, and D. Zanni. "GBM: A review of 118 patients." European Journal of Cancer 29 (January 1993): S193. http://dx.doi.org/10.1016/0959-8049(93)91700-u.
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Nakamura, Masaya, Osahiko Tsuji, Kanehiro Fujiyoshi, Kota Watanabe, Takashi Tsuji, Ken Ishii, Morio Matsumoto, Yoshiaki Toyama, and Kazuhiro Chiba. "Cordotomy for patients with thoracic malignant astrocytoma." Journal of Neurosurgery: Spine 13, no. 4 (October 2010): 418–23. http://dx.doi.org/10.3171/2010.4.spine09901.
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Object The optimal management of malignant astrocytomas remains controversial, and the prognosis of these lesions has been dismal regardless of the administered treatment. In this study the authors investigated the surgical outcomes of cordotomy in patients with thoracic malignant astrocytomas to determine the effectiveness of this procedure. Methods Cordotomy was performed in 5 patients with glioblastoma multiforme (GBM) and 2 with anaplastic astrocytoma (AA). A Kaplan-Meier survival analysis was performed, and the associations of the resection level with survival and postoperative complications were retrospectively examined. Results Cordotomy was performed in a single stage in 2 patients with GBM and in 2 stages in 3 patients with GBM and 2 patients with AA. In the 2 patients with GBM, cordotomy was performed 2 and 3 weeks after a partial tumor resection. In the 2 patients with AA, the initial treatment consisted of partial tumor resection and subtotal resection combined with radiotherapy, and rostral tumor growth and progressive paralysis necessitated cordotomy 2 and 28 months later. One patient with a secondary GBM underwent cordotomy; the GBM developed 1 year after subtotal resection and radiotherapy for a WHO Grade II astrocytoma. Four patients died 4, 5, 24, and 42 months after the initial operation due to CSF dissemination, and 3 patients (2 with GBM and 1 with AA) remain alive (16, 39, and 71 months). No metastasis to any other organs was noted. Conclusions One-stage cordotomy should be indicated for patients with thoracic GBM or AA presenting with complete paraplegia preoperatively. In patients with thoracic GBM, even if paralysis is incomplete, cordotomy should be performed before the tumor disseminates through the CSF. Radical resection should be attempted in patients with AA and incomplete paralysis. If the tumor persists, radiotherapy and chemotherapy are indicated, and cordotomy should be reserved for lesions growing progressively after such second-line treatments.
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Larionova, T. D., T. F. Kovalenko, M. I. Shakhparonov, and M. S. Pavlyukov. "The Prognostic Significance of Spliceosomal Proteins for Patients with Glioblastoma." Doklady Biochemistry and Biophysics 503, no. 1 (April 2022): 71–75. http://dx.doi.org/10.1134/s1607672922020090.
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Abstract Glioblastoma (GBM) is considered one of the most aggressive human cancers. Earlier, our group have demonstrated that alternative RNA splicing plays an important role in the regulation of the GBM phenotype. To continue this study, we analyzed the type of RNA splicing and the expression levels of the spliceosomal genes in a large number of tumor tissue samples and patient-derived GBM sphere lines. We demonstrated that the expression level of splicing factors allows dividing GBM patients into groups with different survival prognosis and also reflects the phenotype of the tumor. In addition, we identified the alternative splicing events that may regulate the GBM phenotype. Finally, we for the first time compared the expression profiles of the spliceosomal genes in different regions of the same tumor and identified splicing factors whose expression most significantly correlates with GBM patients’ survival. Aforementioned data emphasize the important role of pre-mRNA splicing in GBM progression.
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Takeuchi, Yasuo, Emiko Takeuchi, and Kouju Kamata. "A Possible Clue for the Production of Anti-Glomerular Basement Membrane Antibody Associated with Ureteral Obstruction and Hydronephrosis." Case Reports in Nephrology and Dialysis 5, no. 1 (March 31, 2015): 87–95. http://dx.doi.org/10.1159/000381396.
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Background: Anti-glomerular basement membrane (anti-GBM) antibody-mediated glomerulonephritis (anti-GBM GN) is an autoimmune disease with rapidly progressive glomerulonephritis. Based on a case report of anti-GBM GN following hydronephrosis, we hypothesized that hydronephrosis may act as a trigger for the development of anti-GBM antibodies. Patients and Methods: We evaluated 11 patients who were diagnosed with hydronephrosis. It was measured with serum anti-GBM antibody. These patients' medical histories as well as risk factors for the development of anti-GBM antibodies and causes of hydronephrosis were reviewed. Renal function and hematuria were also considered. The serum anti-GBM antibody was measured with enzyme-linked immunosorbent assays (ELISA) or chemiluminescent enzyme immunoassays (CLEIA). Histopathological findings of renal biopsy specimens were also evaluated. Results: No patient had a medical history of renal disease. Five patients had a history of smoking. Ten of the 11 patients had renal dysfunction as evidenced by serum creatinine levels of 0.85-13.8 mg/dl, while 8 patients had RBCs in their urinary sediment at the time of diagnosis for hydronephrosis. Two of the patients assessed by ELISA and CLEIA were positive for anti-GBM antibodies. In 1 of these 3 patients, anti-GBM antibodies and renal dysfunction improved upon treatment for hydronephrosis. Another of the 3 patients developed anti-GBM GN, but anti-GBM antibodies and renal dysfunction improved dramatically upon treatment. In the 3rd patient without improved hydronephrosis, anti-GBM antibodies and renal dysfunction remained unchanged. Conclusion: Our results provide insights into the development of anti-GBM antibodies in patients with ureteral obstruction and hydronephrosis.
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Chabot, Peter, Dominique Fontaine, Carmen del Genio, Yujia Shentu, and Arti Gaur. "BIOM-14. SYSTEMIC BIOMARKERS OF TUMOR BURDEN IN GLIOBLASTOMA PATIENTS." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii7. http://dx.doi.org/10.1093/neuonc/noac209.024.
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Abstract Glioblastomas (GBM) are Grade IV gliomas that are highly aggressive, lethal primary brain tumors. They are extremely heterogenous tumors both at a cellular and molecular level, harboring diverse oncogenes and mutated tumor suppressor genes with both inter- and intra-tumor variability in expression patterns. Currently, the presence of GBM cannot be predicted and they are diagnosed post-surgical resection by histologic evaluation of tumor tissue. There is an urgent, unmet need for the discovery of GBM-specific biomarkers that could precisely predict and monitor the presence of tumors in GBM patients. Over the last seven years we have carried out a prospective, multi-center, clinical study to longitudinally analyze tumor and plasma samples from GBM patients. We have characterized expression levels of microRNAs, mRNAs and proteins isolated from plasma samples collected from GBM patients throughout their treatment and compared these data to clinical and pathological reports for each patient. Our research has identified a set of systemic microRNAs and their targets that can be correlated to tumor burden in GBM patients. Data will be presented to demonstrate how specific sets of molecular markers and secreted proteins can track disease in GBM patients. This study provides insights into how systemically expressed biomarkers in GBM patients can be used in the development of methods for the precise assessment of disease progression and treatment efficacy while being minimally invasive and cost-effective. Combining clinicopathological findings and biomarker profiling will predict treatment outcomes and provide oncologists precise readouts for tumor burden and response to treatment. Furthermore, this research will also provide critically needed criteria for rigorous monitoring of efficacy of all new therapeutic trials for GBM.
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Bacha, Jeffrey A., Anne Steino, Richard Stephen Schwartz, John Langlands, Sarath Kanekal, Lorena Lopez, Barbara Jane O'Brien, Zhongping Chen, Marta Penas-Prado, and Dennis Brown. "Clinical trials of VAL-083 in patients with chemo-resistant glioblastoma." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): TPS2082. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.tps2082.
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TPS2082 Background: Glioblastoma (GBM) is the most common and aggressive primary brain cancer. Current standard of care includes surgery, radiation and treatment with temozolomide (TMZ), however nearly all tumors recur and the prognosis for recurrent GBM is dismal. Most GBM tumors have unmethylated promoter status for O6-methylguanine-DNA-methyltransferase (MGMT); a validated biomarker for TMZ-resistance. Second-line treatment with anti-angiogenic agent bevacizumab has not improved overall survival (OS) and 5-year survival is less than 3%. Dianhydrogalactitol (VAL-083) is a bi-functional alkylating agent targeting N7-Guanine and inducing interstrand DNA cross-links, double-strand breaks and cell death in GBM cell lines and GBM cancer stem cells, independent of MGMT status in vitro. VAL-083 readily crosses the blood-brain barrier and accumulates in brain tumor tissue. Our recent phase I/II clinical trial in recurrent GBM patients failing both TMZ and bevacizumab, suggested that VAL-083 offers clinically meaningful survival benefits for patients with recurrent GBM and pinpointed a new dosing regimen (40 mg/m2/d on days 1,2,3 of a 21-day cycle) which was well-tolerated and was selected for study in subsequent GBM trials. Methods: These trials include i) an ongoing single-arm, biomarker driven, Phase 2 study to determine if VAL-083 treatment of MGMT-unmethylated adult GBM patients at first recurrence/progression, prior to bevacizumab improves overall survival at 9 months, compared to historical control with lomustine (clinicaltrials.gov identifier: NCT02717962). ii) A pivotal Phase 3 study in recurrent GBM after failing both TMZ and bevacizumab. The control arm will consist of a limited number of salvage chemotherapies currently used in bevacizumab-failed GBM. If successful, this study will serve as the basis for a New Drug Application (NDA) submission for VAL-083. iii) A single arm, biomarker driven, Phase 2 study to confirm the tolerability and efficacy of VAL-083 in combination with radiotherapy in newly diagnosed MGMT-unmethylated GBM patients whose tumors are known to express high MGMT levels. The results of these studies may support a new treatment paradigm in chemotherapeutic regimens for the treatment of GBM. Clinical trial information: NCT02717962.
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Horta, Erika, Tobias Walbert, and James Snyder. "EPID-11. OCCURRENCE OF SYSTEMIC CANCER IN PATIENTS WITH GLIOBLASTOMA: POPULATION CHARACTERIZATION AND COMPLICATIONS." Neuro-Oncology 21, Supplement_6 (November 2019): vi76. http://dx.doi.org/10.1093/neuonc/noz175.311.
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Abstract It is unclear how the diagnosis of a second cancer influences the treatment and complications of patients with glioblastoma (GBM). A chart review of adults with primary or secondary GBM and another systemic cancer seen in the last five years was performed. Demographic data, thromboembolic events, cytopenia and deviations from the standardized GBM treatment protocol (EBRT with 60 Gy plus concurrent temozolomide followed by adjuvant temozolomide) were analyzed. Exclusion criteria was the diagnosis of genetic syndromes that predispose to tumorigenesis. A total of 56 GBM patients with 61 systemic cancers were identified. The most common systemic cancers were breast and prostate each representing 27 %. Men were 55% of patients (p=0.3) but older (69+11 years, p=0.003) than when compared to CBTRUS data. Systemic cancer was diagnosed before GBM in 82% of the cases. Age at the diagnosis of systemic cancer was 64 +11 years. Patients with systemic cancer diagnosed prior to GBM, had shorter survival (1.15+1.08 years versus 4.4+ 3.4 years, p < 0.001), but survival was not shorter than expected when compared to historical survival of GBM. Thromboembolism was seen in 27% of patients, only once it was seen before the diagnosis of GBM. Although all patients with hematological malignancies had low platelets, thrombocytopenia was not associated to prior chemotherapy. Deviation of GBM treatment was seen in 15% of the cases, a delay in the systemic cancer once. This is the largest documented series of patients with GBM and systemic cancer. We conclude that although this population is older than expected, thromboembolism rates and survival are similar to the literature for patients with GBM. In the light of all those considerations, patients with GBM and the diagnosis of a systemic cancer should be treated according to guideline.
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Lynch, David, Branka Powter, Joseph William Po, Adam Cooper, Celine Garrett, Eng-Siew Koh, Mark Sheridan, et al. "Isolation of Circulating Tumor Cells from Glioblastoma Patients by Direct Immunomagnetic Targeting." Applied Sciences 10, no. 9 (May 11, 2020): 3338. http://dx.doi.org/10.3390/app10093338.
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Glioblastoma (GBM) is the most common form of primary brain cancer in adults and tissue biopsies for diagnostic purposes are often inaccessible. The postulated idea that brain cancer cells cannot pass the blood–brain barrier to form circulating tumor cells (CTCs) has recently been overthrown and CTCs have been detected in the blood of GBM patients albeit in low numbers. Given the potential of CTCs to be analyzed for GBM biomarkers that may guide therapy decisions it is important to define methods to better isolate these cells. Here, we determined markers for immunomagnetic targeting and isolation of GBM-CTCs and confirmed their utility for CTC isolation from GBM patient blood samples. Further, we identified a new marker to distinguish isolated GBM-CTCs from residual lymphocytes.
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Shi, Zhong-Fang, Guan-Zhang Li, You Zhai, Chang-Qing Pan, Di Wang, Ming-Chen Yu, Chi Liu, Wei Zhang, and Xiao-Guang Yu. "EGFRvIII Promotes the Proneural–Mesenchymal Transition of Glioblastoma Multiforme and Reduces Its Sensitivity to Temozolomide by Regulating the NF-κB/ALDH1A3 Axis." Genes 14, no. 3 (March 4, 2023): 651. http://dx.doi.org/10.3390/genes14030651.
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(1) Background: Glioblastoma multiforme (GBM) is the most common and malignant intracranial tumor in adults. At present, temozolomide (TMZ) is recognized as the preferred chemotherapeutic drug for GBM, but some patients have low sensitivity to TMZ or chemotherapy resistance to TMZ. Our previous study found that GBM patients with EGFRvIII (+) have low sensitivity to TMZ. However, the reasons and possible mechanisms of the chemoradiotherapy resistance in GBM patients with EGFRvIII (+) are not clear. (2) Methods: In this study, tissue samples of patients with GBM, GBM cell lines, glioma stem cell lines, and NSG mice were used to explore the causes and possible mechanisms of low sensitivity to TMZ in patients with EGFRvIII (+)-GBM. (3) Results: The study found that EGFRvIII promoted the proneural–mesenchymal transition of GBM and reduced its sensitivity to TMZ, and EGFRvIII regulated of the expression of ALDH1A3. (4) Conclusions: EGFRvIII activated the NF-κB pathway and further regulated the expression of ALDH1A3 to promote the proneural–mesenchymal transition of GBM and reduce its sensitivity to TMZ, which will provide an experimental basis for the selection of clinical drugs for GBM patients with EGFRvIII (+).
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Munoz, Yamhilette Licon, Rachel B. Sidebottom, Frank J. Martinez, Samantha Varela, Christian A. Bowers, and Sara G. M. Piccirillo. "Abstract 5802: The impact of tumor-treating fields on cancer stem-like cells isolated from the sub-ventricular zone of glioblastoma patients." Cancer Research 83, no. 7_Supplement (April 4, 2023): 5802. http://dx.doi.org/10.1158/1538-7445.am2023-5802.
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Abstract Treatment of glioblastoma (GBM) is challenging due to its heterogeneous nature, invasive potential and poor response to standard of care treatments. As a result, GBM inevitably recurs and only approximately 9% of patients survive 5 years post-diagnosis. Areas of residual disease represent the source of the recurrent tumor that is fatal for GBM patients. However, targeting the residual disease is not offered as part of the standard of care because these areas are difficult to identify and, to date, they have not been characterized during disease progression. Our laboratory was the first to identify and characterize residual disease in the sub-ventricular zone (SVZ) of the lateral ventricles of GBM patients. Specifically, we found that in the majority of GBM patients the SVZ is a reservoir of tumor cells that promote therapeutic resistance and seed the recurrent tumor. Specifically, our work revealed that in 65% of the cases the SVZ contains treatment-resistant cancer stem-like cells (CSCs), thus investigating residual disease in this area may hold the key to developing a valid therapeutic target for many patients. In this study, we are examining the impact of Tumor-Treating Fields (TTFields) on treatment-resistant CSCs isolated from the SVZ of GBM patients using molecular techniques, such as single-cell transcriptomics and functional phenotyping analysis. To date, we have isolated and characterized 12 CSCs. These cells are maintained in conditions that preserve the molecular profile of the original patient tumor, thus representing bona fide models to study the impact of TTFields on GBM residual disease. We observed that: (i) CSCs show heterogeneous patterns of response to the alkylating agent Temozolomide (100 µM) and radiation (10 Gy), that mimic the standard of care for GBM patients, (ii) their treatment response is independent of the MGMT promoter methylation status and (iii) the proliferation of CSCs resistant to Temozolomide and radiation is significantly inhibited by TTFields when cells are exposed for 48 hours to the optimized frequency for GBM (200 kHz). Altogether, these findings point to the effectiveness of TTFields following Temozolomide and radiation and set the foundation for the single-cell transcriptomic and functional analysis to elucidate the mechanisms whereby TTFields impact the proliferation of CSCs in the SVZ of GBM patients. In the long run, the results of this work will allow the identification of SVZ-specific targets for the development of novel and more effective treatments for GBM patients. Citation Format: Yamhilette Licon Munoz, Rachel B. Sidebottom, Frank J. Martinez, Samantha Varela, Christian A. Bowers, Sara G.M. Piccirillo. The impact of tumor-treating fields on cancer stem-like cells isolated from the sub-ventricular zone of glioblastoma patients. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5802.
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Damestani, Yasaman, Minesh P. Mehta, Howard Colman, Kevin A. Camphausen, Michael Weller, Evanthia Galanis, Martin J. Van Den Bent, et al. "Digital measurement of functional status of patients with glioblastoma." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 2016. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.2016.
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2016 Background: Among the primary aims of new therapies for glioblastoma (GBM) are the reduction of morbidity and restoration or preservation of quality of life (QoL). Selinexor (SEL) is a first-in class, oral, selective inhibitor of nuclear export which blocks exportin 1 (XPO1), forcing the nuclear retention and reactivation of tumor suppressor proteins, ultimately causing cell death in cancer cells. SEL is approved for the treatment of previously treated multiple myeloma and DLBCL. XPORT-GBM-029 (NCT04421378) is a phase 1 dose finding study followed by an open-label randomized phase 2, 3-arm trial to evaluate SEL in combination with standard therapies for newly diagnosed and recurrent GBM: Arm A (ndGBM, uMGMT) – radiation +/- SEL; Arm B (ndGBM, mMGMT) – radiation and temozolomide +/- SEL; Arm C (rGBM) – lomustine +/- SEL at first relapse. We look to identify sensitive, reliable, and clinically meaningful digital assessments of the functional status of ndGBM and rGBM patients via a patient-centric approach. Methods: XPORT-GBM-029 incorporates standard clinical and imaging evaluations of GBM progression with novel digital tools that objectively measure motor and cognitive function. The study is conducted at 50 sites globally with the aim of enrolling 350 patients with newly diagnosed and recurrent GBM. Following discussions with KOLs and patient advocacy partners at EndbrainCancer, we surveyed GBM patients and their caregivers to identify disease manifestations critical to patients’ QoL. The survey revealed four key areas impacting patients’ QoL that can be affected by GBM therapies and can be objectively monitored: cognitive function, lateralization, fatigue, and sleep. In this trial we use objective measurements to evaluate SEL’s effects on GBM patients’ QoL. Patients wear inertial sensors to measure their activity and sleep and complete a cognitive battery at baseline and before each MRI. Results: Associations between objective digital measures of activity, gait, fatigue, sleep, and cognition will be examined with respect to clinical assessments including physical examinations, modified Response Assessment in Neuro-Oncology (mRANO), Neurologic Assessment in Neuro-Oncology (NANO), Karnofsky Performance Score (KPS) and Patient Reported Outcome (PRO) QoL questionnaires. Descriptive summary statistics and plots are employed in exploratory data analysis, and other advanced data mining methods may also be considered. Conclusions: XPORT-GBM-029 trial is probably the first large, prospective, longitudinal study in GBM patients employing digital markers and may provide useful information regarding the utility of wearable and mobile devices for measuring functional outcomes in clinical trials. Clinical trial information: NCT04421378.
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Alijani, Babak, Hamid Saeidi Saedi, Hadi Hajizadeh Fallah, Ehsan Kazemnejad Leili, Adel Kiumarsi, and Sasan Andalib. "Evaluation of effect of epidermal growth factor receptor and vascular endothelial growth factor overexpression in survival of patients with glioblastoma multiforme." Romanian Journal of Neurology 20, no. 1 (March 31, 2021): 66–71. http://dx.doi.org/10.37897/rjn.2021.1.9.
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Background. In the central nervous system, glioblastoma multiforme (GBM) is one of the most important neoplasms in adults. Amplification of EGFR and VEGF genes is common in GBM. However, the role of overexpression of EGFR and VEGF in survival of patients with GBM has been a contentious issue. Therefore, we performed the present study to assess the survival rate of patients with EGFR and VEGF overexpression. Materials and methods. Resected samples of GBM patients were evaluated by immunohistochemistry for overexpression of VEGF and EGFR. The patients were followed up for a year. Results. The mean±sd of age of patients was 56.2±13.1 years. The majority of the patients were male (65.9%). Most of the patients had primary GBM (67%), notwithstanding 33% of the patients with secondary GBM. Moreover, 19.2% and 49.5% of the samples were VEGF-positive and EGFR-positive, respectively. Overall 6, 12-, and 18-month survival rates were shown to be 61.5±5.1%, 17.6±4%, and 4.4±2.1%, respectively. There was a significant difference between the mean±se survival rate in VEGF-negative patients (12±1.9 months) VEGF-positive patients (7.8±0.5 months) (P=0.045). Conclusions. We found an association between VEGF and EGFR over-expression and the survival rate of GBM patients. The VEGF overexpression was significantly associated with the overall survival rate of the GBM patients, but failed to have a prognostic value for their mortality rate. However, EGFR was a predictor of overall survival rate and mortality of GBM patients. Moreover, VEGF overexertion has a stronger association with survival rate in GBM, compared to EGFR overexpression.
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Gmurczyk, Aleksandra, Shubhada N. Ahya, Robert Goldschmidt, George Kim, L. Tammy Ho, and Kevin Nash. "A Case of Simultaneous, Biopsy-Proven, Classic, ANCA-Positive Wegener's Granulomatosis and Anti-GBM Disease, but without Detectible Circulating Anti-GBM Antibodies." Scientific World JOURNAL 10 (2010): 1078–83. http://dx.doi.org/10.1100/tsw.2010.107.
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Wegener's granulomatosis (WG) is a systemic, necrotizing, granulomatous vasculitis of unknown etiology. Approximately 75% of cases present as classic WG with both pulmonary and renal involvement, while the remaining 25% of patients present with a limited form with either predominantly upper or lower respiratory tract symptoms. Ninety percent of WG patients have circulating anti–neutrophil cytoplasmic antibodies (ANCA), and approximately 10% have both circulating ANCA antibodies and concomitant anti–glomerular basement membrane (anti-GBM) disease on renal biopsy. Virtually all of these patients also have circulating anti-GBM antibodies. While it has been reported that some patients with ANCA vasculitis have circulating anti-GBM antibodies, and patients with anti-GBM disease may have positive ANCA, review of the literature does not demonstrate other cases of biopsy-proven, simultaneous, ANCA-associated vasculitis and anti-GBM disease. We report a case of simultaneous, biopsy-proven, classic, ANCA-positive WG and anti-GBM disease, but without detectible circulating anti-GBM antibodies. We present findings characteristic of both WG and linear IgG deposition along the GBM suggesting concurrent anti-GBM disease, in the absence of detectable circulating anti-GBM antibodies. Possible theories to explain the absence of these antibodies are discussed.
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Sloan, Anthony, Theresa Elder, Ansh Desai, Anna Wu, Serah Choi, and Andrew Sloan. "NCMP-06. VENOUS THROMBOEMBOLISM INCIDENCE AND THE IMPACT OF PRE-DISEASED ANTICOAGULATION THERAPY IN GLIOBLASTOMA PATIENTS." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii192. http://dx.doi.org/10.1093/neuonc/noac209.734.
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Abstract Glioblastoma (GBM) patients have a 24-30% risk of developing venous thromboembolism (VTE), including deep vein thrombosis or pulmonary embolism, over the course of their diagnosis. However, very little data exists regarding the impact of VTE on survival in GBM patients, with or without anticoagulation. This study aimed to investigate 1) the demographic factors associated with VTE incidence in GBM patients, 2) any correlation between VTE incidence and length of survival and, and 3) the impact of pre-diagnosis antiplatelet/anticoagulation therapy on VTE development and survival. A total of 150 GBM patients treated at University Hospital Seidman Cancer Center were included and retrospectively analyzed. Information was collected regarding history of aspirin, clopidogrel, DOAC, heparin, and/or warfarin use. The diagnosis of VTE both prior to GBM diagnosis and at various time points following diagnosis was determined followed by calculating overall survival and progression free survival (PFS). Of the 150 GBM patients, 53 (35.3%) developed a VTE overall. VTE incidence correlated with a lower KPS at presentation (r = -.225, p =.027) and a decrease in overall survival among GBM patients (r = -.191, p =.041). Antiplatelet/anticoagulation therapy prior to GBM diagnosis correlated with decreased VTE formation overall, as well as longer PFS among non-VTE patients (r =.261, p = .026) but not among patients who later developed VTE (r = .165, p = .302). Our findings demonstrate that patients with lower KPS are at a higher risk for developing VTE. Among GBM patients who did not develop VTEs, those on antiplatelet/anticoagulation therapy prior to diagnosis had longer PFS compared to those who were not on anticoagulants. These preliminary studies highlight the need for better VTE prophylaxis and therapy among GBM patients. These results further suggest the potential benefit of anticoagulation therapy in GBM patients irrespective of VTE formation.
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Troike, Katie M., Arlet M. Acanda de la Rocha, Tyler J. Alban, Matthew M. Grabowski, Balint Otvos, Gino Cioffi, Kristin A. Waite, et al. "The Translocator Protein (TSPO) Genetic Polymorphism A147T Is Associated with Worse Survival in Male Glioblastoma Patients." Cancers 13, no. 18 (September 8, 2021): 4525. http://dx.doi.org/10.3390/cancers13184525.
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Glioblastoma (GBM) is the most common primary brain tumor in adults, with few available therapies and a five-year survival rate of 7.2%. Hence, strategies for improving GBM prognosis are urgently needed. The translocator protein 18kDa (TSPO) plays crucial roles in essential mitochondria-based physiological processes and is a validated biomarker of neuroinflammation, which is implicated in GBM progression. The TSPO gene has a germline single nucleotide polymorphism, rs6971, which is the most common SNP in the Caucasian population. High TSPO gene expression is associated with reduced survival in GBM patients; however, the relation between the most frequent TSPO genetic variant and GBM pathogenesis is not known. The present study retrospectively analyzed the correlation of the TSPO polymorphic variant rs6971 with overall and progression-free survival in GBM patients using three independent cohorts. TSPO rs6971 polymorphism was significantly associated with shorter overall survival and progression-free survival in male GBM patients but not in females in one large cohort of 441 patients. We observed similar trends in two other independent cohorts. These observations suggest that the TSPO rs6971 polymorphism could be a significant predictor of poor prognosis in GBM, with a potential for use as a prognosis biomarker in GBM patients. These results reveal for the first time a biological sex-specific relation between rs6971 TSPO polymorphism and GBM.
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Giamas, Georgios, Chiara Cilibrasi, Thomas Simon, Nicolas Stewart, Giles Critchley, and Murat Eravci. "BIOM-06. IDENTIFICATION OF AN INFLAMMATORY BIOMARKER SIGNATURE IN PLASMA-DERIVED EXTRACELLULAR VESICLES OF GLIOBLASTOMA PATIENTS." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii5. http://dx.doi.org/10.1093/neuonc/noac209.016.
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Abstract Diagnosis of Glioblastoma (GBM) remains a clinical challenge, currently relying on symptomatic presentation of the tumour, brain imaging and invasive biopsy. Description of effective biomarkers in biofluids could prove invaluable in GBM diagnosis. Extracellular vesicles (EVs) are essential to intercellular crosstalk in the tumour bulk and circulating EVs have been described as a potential reservoir of GBM biomarkers. Our work focuses on the: (i) isolation of EVs from blood liquid biopsies of GBM patients. (ii) Characterisation of their transcriptomic and proteomic cargoes to identify/validate novel candidate GBM biomarkers that could improve GBM diagnosis/prognosis. (iii) For cases where the original GBM tumour tissues are available, we will examine the expression of the identified biomarker signatures (derived from blood-EVs) to see if the content of EVs mirrors the transcriptomic/proteomic profile of the original tissue. Similar comparisons will be performed in GBM cohorts available in TCGA. Ultimately, in future studies, transcriptomic/proteomic analyses will be assessed during patients’ follow-ups to correlate the observed biomarker profiles with MRI data,treatment,recurrence, including molecular and clinical features.Our preliminary data comparing the proteomic cargoes of EVs derived from GBM patients (n=15) and those from healthy volunteers (n=10) indicated the presence of a GBM inflammatory biomarker signature comprising members of the complement and regulators of inflammation and coagulation. Bioinformatic analysis highlighted that all potential markers exclusively identified in patient samples have been linked with either GBM diagnosis,prognosis or associated signalling, suggesting that sEVs protein cargo could mirror the landscape of the original tumour and that selective circulating sEV-derived proteins might be used as hallmarks for GBM patients.Overall, this study is a step forward in the development of a non-invasive liquid biopsy approach for the identification of valuable biomarkers that could significantly improve GBM diagnosis and, consequently, patients’ prognosis and quality of life.
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Curtin, Lee, Paula Whitmire, Cassandra Rickertsen, Peter D. Canoll, Maciej Mrugala, Kristin Swanson, and Leland Hu. "RARE-09. CYSTIC GLIOBLASTOMA PRESENTATION AS A BENEFICIAL PROGNOSTIC INDICATOR FOR OVERALL SURVIVAL." Neuro-Oncology 21, Supplement_6 (November 2019): vi223. http://dx.doi.org/10.1093/neuonc/noz175.932.
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Abstract Glioblastoma (GBM) is the most aggressive primary brain tumor with a median overall survival of 15 months with standard-of-care treatment. GBM patients sometimes present with a cystic component, which can be identified through magnetic resonance imaging (MRI). Previous studies suggest that cysts occur in 7–22% of GBM patients and have reported mixed results regarding whether cystic GBM have a survival benefit compared to noncystic GBM. Using our large retrospective cohort of 493 first-diagnosis GBM patients, we aim to elucidate this link between cystic GBM and survival. Within this cohort, 88 patients had a significant cystic component at presentation as identified on MRI. Compared to noncystic GBM (n=405), cystic GBM patients had significantly better overall survival (15 vs 22 months median, log-rank, p=0.001) and were significantly younger at the time of presentation (t-test, p=0.002). However, within patients that received current standard-of-care treatment (n=184), cystic GBM (n=40) was not as beneficial for outcome (22 vs 25 months, log-rank, p=0.3). We also did not observe a significant survival benefit when comparing this standard-of-care cystic cohort to cystic GBM patients diagnosed before the standard was established (n=19, 25 vs 23 months, log-rank, p=0.3), but the analogous result for noncystic GBM patients gives a sizeable benefit, as expected (n=144, n=111, respectively, 22 vs 12 months, log-rank p < 0.0001). Together, these results on current standard-of-care may explain later studies that note no significant survival benefit for cystic GBM patients receiving current standard-of-care. We also report differences in the absolute and relative sizes of imaging abnormalities on MRI and in prognostic impact of cysts based on sex. We discuss current hypotheses for these observed differences, including the possibility that the presence of a cyst could be indicative of a less aggressive tumor.
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Gareev, I. F., O. A. Beylerli, Sh Zhao, G. Yang, J. Sun, A. T. Beilerli, and Sh M. Safin. "Extraction of Exosomes from Glioblastoma Multiforme Patients’ Blood Plasma." Creative surgery and oncology 9, no. 3 (November 20, 2019): 234–38. http://dx.doi.org/10.24060/2076-3093-2019-9-3-234-238.
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Introduction. Glioblastoma multiforme (GBM) is the most common and aggressive form of primary malignant brain tumour in adults associated with a poor prognosis. Exosomes have been shown to be useful non-invasive biomarkers for the diagnosis and prognosis of tumours, GBM included. Exosomes play a role of biological carriers which can perform various tasks through various signalling pathways of carcinogenesis, such as PI3K/AKT, SOX2, PTEN, ERK and STAT3.Materials and methods. Exosomes were isolated from blood plasma taken from patients diagnosed with GBM prior to surgical resection.Results and discussion. Plasma exosomes from patients with GBM had spherical shape and varied in size from 40 to 100 nm matching the exosomes’ morphological characteristics. The combination of ultrafiltration and double ultracentrifugation makes it possible to extract exosome examples from plasma without the presence of contaminating particles over 100 nm in size; the shape and size of these vesicles match the characteristics of exosomes isolated from other biological fluids.Conclusion. The experimental protocol for the extraction of exosomes from GBM patients’ plasma described here proves effective as a method used to ensure the purity of exosomes. Applying this method offers further opportunities for research into the role of exosomes in GBM pathogenesis. Equally this method can be used in research involving other human pathologies.
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Wu, Zhe Bao, Chao Qiu, An Li Zhang, Lin Cai, Shao Jian Lin, Yu Yao, Qi Sheng Tang, et al. "Glioma-Associated Antigen HEATR1 Induces Functional Cytotoxic T Lymphocytes in Patients with Glioma." Journal of Immunology Research 2014 (2014): 1–12. http://dx.doi.org/10.1155/2014/131494.
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A2B5+ glioblastoma (GBM) cells have glioma stem-like cell (GSC) properties that are crucial to chemotherapy resistance and GBM relapse. T-cell-based antigens derived from A2B5+ GBM cells provide important information for immunotherapy. Here, we show that HEAT repeat containing 1 (HEATR1) expression in GBM tissues was significantly higher than that in control brain tissues. Furthermore, HEATR1 expression in A2B5+ U87 cells was higher than that in A2B5−U87 cells (P=0.016). Six peptides of HEATR1 presented by HLA-A*02 were selected for testing of their ability to induce T-cell responses in patients with GBM. When peripheral blood mononuclear cells from healthy donors (n=6) and patients with glioma (n=33) were stimulated with the peptide mixture, eight patients with malignant gliomas had positive reactivity with a significantly increased number of responding T-cells. The peptides HEATR1682–690, HEATR11126–1134, and HEATR1757–765had high affinity for binding to HLA-A*02:01 and a strong capacity to induce CTL response. CTLs against HEATR1 peptides were capable of recognizing and lysing GBM cells and GSCs. These data are the first to demonstrate that HEATR1 could induce specific CTL responses targeting both GBM cells and GSCs, implicating that HEATR1 peptide-based immunotherapy could be a novel promising strategy for treating patients with GBM.
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Saadeh, Fadi S., Rami Z. Morsi, Abdallah El-Kurdi, Georges Nemer, Rami Mahfouz, Maya Charafeddine, Jessica Khoury, Marwan W. Najjar, Pierre Khoueiry, and Hazem I. Assi. "Correlation of genetic alterations by whole-exome sequencing with clinical outcomes of glioblastoma patients from the Lebanese population." PLOS ONE 15, no. 11 (November 25, 2020): e0242793. http://dx.doi.org/10.1371/journal.pone.0242793.
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Introduction Glioblastoma (GBM) is an aggressive brain tumor associated with high degree of resistance to treatment. Given its heterogeneity, it is important to understand the molecular landscape of this tumor for the development of more effective therapies. Because of the different genetic profiles of patients with GBM, we sought to identify genetic variants in Lebanese patients with GBM (LEB-GBM) and compare our findings to those in the Cancer Genome Atlas (TCGA). Methods We performed whole exome sequencing (WES) to identify somatic variants in a cohort of 60 patient-derived GBM samples. We focused our analysis on 50 commonly mutated GBM candidate genes and compared mutation signatures between our population and publicly available GBM data from TCGA. We also cross-tabulated biological covariates to assess for associations with overall survival, time to recurrence and follow-up duration. Results We included 60 patient-derived GBM samples from 37 males and 23 females, with age ranging from 3 to 80 years (mean and median age at diagnosis were 51 and 56, respectively). Recurrent tumor formation was present in 94.8% of patients (n = 55/58). After filtering, we identified 360 somatic variants from 60 GBM patient samples. After filtering, we identified 360 somatic variants from 60 GBM patient samples. Most frequently mutated genes in our samples included ATRX, PCDHX11, PTEN, TP53, NF1, EGFR, PIK3CA, and SCN9A. Mutations in NLRP5 were associated with decreased overall survival among the Lebanese GBM cohort (p = 0.002). Mutations in NLRP5 were associated with decreased overall survival among the Lebanese GBM cohort (p = 0.002). EGFR and NF1 mutations were associated with the frontal lobe and temporal lobe in our LEB-GBM cohort, respectively. Conclusions Our WES analysis confirmed the similarity in mutation signature of the LEB-GBM population with TCGA cohorts. It showed that 1 out of the 50 commonly GBM candidate gene mutations is associated with decreased overall survival among the Lebanese cohort. This study also highlights the need for studies with larger sample sizes to inform clinicians for better prognostication and management of Lebanese patients with GBM.
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Vauleon, Elodie, Tony Avril, Brigitte Collet, Jean Mosser, and Véronique Quillien. "Overview of Cellular Immunotherapy for Patients with Glioblastoma." Clinical and Developmental Immunology 2010 (2010): 1–18. http://dx.doi.org/10.1155/2010/689171.
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High grade gliomas (HGG) including glioblastomas (GBM) are the most common and devastating primary brain tumours. Despite important progresses in GBM treatment that currently includes surgery combined to radio- and chemotherapy, GBM patients' prognosis remains very poor. Immunotherapy is one of the new promising therapeutic approaches that can specifically target tumour cells. Such an approach could also maintain long term antitumour responses without inducing neurologic defects. Since the past 25 years, adoptive and active immunotherapies using lymphokine-activated killer cells, cytotoxic T cells, tumour-infiltrating lymphocytes, autologous tumour cells, and dendritic cells have been tested in phase I/II clinical trials with HGG patients. This paper inventories these cellular immunotherapeutic strategies and discusses their efficacy, limits, and future perspectives for optimizing the treatment to achieve clinical benefits for GBM patients.
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Shah, Farah, and Zhi Sheng. "Using PIK3CB and connexin-43 inhibition to sensitize pediatric glioblastoma cells to temozolomide." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e13572-e13572. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e13572.
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e13572 Background: Glioblastoma (GBM) is one of the most common high grade gliomas in pediatric patients, accounting for 2.8% of central nervous system tumors. Standard of care for glioblastoma includes surgical resection, radiation, and temozolomide chemotherapy. However, many pediatric patients are not suitable candidates for surgery, and their tumors inevitably develop temozolomide resistance. Despite aggressive treatment, temozolomide (TMZ) resistance leads to tumor recurrence in 90% of patients. Thus, outcome for children with pediatric GBM remains poor with a 2-year survival rate ranging from 10-30%, highlighting the need for new therapeutic approaches. Connexin-43 (Cx43) and PIK3CB are proteins involved in conferring temozolomide resistance in glioblastoma. Combined inhibition of these proteins could improve temozolomide sensitivity and help develop a selective therapy that significantly improves quality of life and prognosis in pediatric glioblastoma patients. Methods: Primary GBM cells were plated in a 96-well plate and treated with vehicle (DMSO), TMZ (50 μmol/L), TGX-221 (20 μmol/L), αCT1 (30 μmol/L), or a combination of the latter three drugs. Cell viability was measured using the MTS assay. Primary pediatric GBM cell lines SJ-GBM2 and CHLA-200 were tested. These drug combinations were also tested in normal human astrocytes to make sure there were no off-target effects. Results: We found that targeting PIK3CB and Cx43 in primary pediatric GBM increases their sensitivity to TMZ. The triple combination of TMZ, TGX-221, and αCT1 significantly decreased cell viability than each drug alone while sparing normal human astrocytes. Conclusions: Our findings suggest that inhibiting PIK3CB and Cx43 enhances therapeutic response to TMZ and limits off-target effects in pediatric GBM. These findings closely mirror our results using the triple combination in adult glioblastoma as well, thus laying the groundwork for a novel combination therapeutic that can be used across age groups.
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Montemurro, Nicola, Paolo Perrini, and Biagio Rapone. "Clinical Risk and Overall Survival in Patients with Diabetes Mellitus, Hyperglycemia and Glioblastoma Multiforme. A Review of the Current Literature." International Journal of Environmental Research and Public Health 17, no. 22 (November 17, 2020): 8501. http://dx.doi.org/10.3390/ijerph17228501.
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The relationship between type 2 diabetes mellitus (DM2) and hyperglycemia with cancer patients remains controversial also in the setting of patients with glioblastoma multiforme (GBM), the most common and aggressive form of astrocytoma with a short overall survival (OS) and poor prognosis. A systematic search of two databases was performed for studies published up to 19 August 2020, reporting the OS of patients with DM2 or high blood sugar level and GBM and the clinical risk of diabetic patients for development of GBM. According to PRISMA guidelines, we included a total of 20 papers reporting clinical data of patients with GBM and diabetes and/or hyperglycemia. The aim of this review was to investigate the effect of DM2, hyperglycemia and metformin on OS of patients with GBM. In addition, we evaluated the effect of these factors on the risk of development of GBM. This review supports accumulating evidence that hyperglycemia, rather than DM2, and elevated BMI are independent risk factors for poor outcome and shorter OS in patients with GBM. GBM patients with normal weight compared to obese, and diabetic patients on metformin compared to other therapies, seems to have a longer OS. Further studies are needed to understand better these associations.
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Richard, Seidu A. "Explicating the Pivotal Pathogenic, Diagnostic, and Therapeutic Biomarker Potentials of Myeloid-Derived Suppressor Cells in Glioblastoma." Disease Markers 2020 (November 4, 2020): 1–13. http://dx.doi.org/10.1155/2020/8844313.
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Glioblastoma (GBM) is a malignant and aggressive central nervous tumor that originates from astrocytes. These pathogenic astrocytes divide rapidly and are sustained by enormous network of blood vessels via which they receive requisite nutrients. It well proven that GBM microenvironment is extremely infiltrated by myeloid-derived suppressor cells (MDSCs). MDSCs are a heterogeneous cluster of immature myeloid progenitors. They are key mediates in immune suppression as well as sustenance glioma growth, invasion, vascularization, and upsurge of regulatory T cells via different molecules. MDSCs are often elevated in the peripheral blood of patients with GBM. MDSCs in the peripheral blood as well as those infiltrating the GBM microenvironment correlated with poor prognosis. Also, an upsurge in circulating MDSCs in the peripheral blood of patients with GBM was observed compared to benign and grade I/II glioma patients. GBM patients with good prognosis presented with reduced MDSCs as well as augmented dendritic cells. Almost all chemotherapeutic medication for GBM has shown no obvious improvement in overall survival in patients. Nevertheless, low-dose chemotherapies were capable of suppressing the levels of MDSCs in GBM as well as multiple tumor models with metastatic to the brain. Thus, MDSCs are potential diagnostic as well as therapeutic biomarkers for GBM patients.
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Zhou, Chengmao, Ying Wang, Mu-Huo Ji, Jianhua Tong, Jian-Jun Yang, and Hongping Xia. "Predicting Peritoneal Metastasis of Gastric Cancer Patients Based on Machine Learning." Cancer Control 27, no. 1 (January 1, 2020): 107327482096890. http://dx.doi.org/10.1177/1073274820968900.
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Objective: The aim is to explore the prediction effect of 5 machine learning algorithms on peritoneal metastasis of gastric cancer. Methods: 1080 patients with postoperative gastric cancer were divided into a training group and test group according to the ratio of 7:3. The model of peritoneal metastasis was established by using 5 machine learning (gbm(Light Gradient Boosting Machine), GradientBoosting, forest, Logistic and DecisionTree). Python pair was used to analyze the machine learning algorithm. Gbm algorithm is used to show the weight proportion of each variable to the result. Result: Correlation analysis showed that tumor size and depth of invasion were positively correlated with the recurrence of patients after gastric cancer surgery. The results of the gbm algorithm showed that the top 5 important factors were albumin, platelet count, depth of infiltration, preoperative hemoglobin and weight, respectively. In training group: Among the 5 algorithm models, the accuracy of GradientBoosting and gbm was the highest (0.909); the AUC values of the 5 algorithms are gbm (0.938), GradientBoosting (0.861), forest (0.796), Logistic(0.741) and DecisionTree(0.712) from high to low. In the test group: among the 5 algorithm models, the accuracy of forest, DecisionTree and gbm was the highest (0.907); AUC values ranged from high to low to gbm (0.745), GradientBoosting (0.725), forest (0.696), Logistic (0.680) and DecisionTree (0.657). Conclusion: Machine learning can predict the peritoneal metastasis in patients with gastric cancer.
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Li, Zhiyong, Yinghui Jin, Qingping Zou, Xiaofeng Shi, Kaishu Li, Qun He, Zhiying Lin, et al. "Integrated genomic and transcriptomic analysis identified KRT18 mutation and MTAP loss as key genetic alterations related to the prognosis of astrocytoma and glioblastoma." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e14039-e14039. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e14039.
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e14039 Background: Astrocytoma and glioblastoma (GBM) are two main subtypes of glioma classified by WHO guide of center nervous system (CNS) tumors to different grades. GBM is the most malignant among all CNS tumors with a 5-year survival rate of less than 5%. Although the prognosis of patients with astrocytoma is better than that of GBM in general, astrocytoma patients with IDH wild-type have a similar prognosis as GBM. Exploring the molecular driving force behind the malignant phenotype of astrocytoma and GBM will help explain the diversity of glioma and discover new drug targets. Methods: We enrolled 12 patients with astrocytoma and 12 patients with GBM and performed whole-exome sequencing (WES) and RNA-seq analysis on tumor samples from the patients. Comparative analysis of somatic mutation, copy number variation, cytoband alteration and differently expressed genes were performed between astrocytoma and GBM. Immune cells infiltration was analyzed by CIBERSORT Algorithm with LM22 immune subsets. Results: This study includes 14 male patients and 10 female patients, and the median age was 45.5 (range, 18-68) years old. Seven patients had IDH1 mutation, including 6 patients with astrocytoma and 1 patient with GBM. Somatic mutation of KRT18, which is associated with cell apoptosis and adhesion by interacting with TRADD and Pinin , was significantly enriched in astrocytoma, but rare in GBM. Copy number loss of MTAP, which is a potential drug target and closely related to a poor prognosis of glioma, was found significantly enriched in GBM. Pathway enrichment analysis found that GBM was mainly enriched in tumor-related pathways, such as cell adhesion, cell division, and angiogenesis, but astrocytoma was mainly enriched in pathways with ion transport, cell-cell signaling and neurogenesis. Immune cells infiltration analysis showed that macrophages M0 was significantly enriched in GBM, and activated mast cells, monocytes and plasma cells were significantly enriched in astrocytoma. Conclusions: This study revealed the distinct characteristics of astrocytoma and GBM at the DNA and RNA levels. Somatic mutation of KRT18, which was first reported in glioma, may be closely related to the malignant phenotype of astrocytoma. Copy number loss of MTAP, which was associated with the susceptibility to purine starvation and specific chemotherapy, was a key genetic alterative gene in GBM and had the potential to become the therapeutic target of GBM.
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Cilibrasi, Chiara, Thomas Simon, Marian Vintu, Christos Tolias, Mark Samuels, Nektarios Mazarakis, Murat Eravci, Nicholas Stewart, Giles Critchley, and Giorgios Giamas. "Identification of an Inflammatory Biomarker Signature in Plasma-Derived Extracellular Vesicles of Glioblastoma Patients." Neuro-Oncology 24, Supplement_4 (October 1, 2022): iv6—iv7. http://dx.doi.org/10.1093/neuonc/noac200.027.
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Abstract AIMS Description of effective biomarkers present in biofluids could prove invaluable in GBM diagnosis. Extracellular vesicles (EVs) are essential to intercellular crosstalk in the tumour bulk and circulating EVs have been described as a potential reservoir of GBM biomarkers. Therefore, EV-based liquid biopsies have been suggested as a promising tool for GBM METHOD Ethical approval was obtained for a prospective study of healthy donors and consenting GBM patients at the University Hospitals Sussex (Brighton). To identify GBM specific proteins, small EVs (sEVs) were isolated from plasma samples using differential ultracentrifugation and validated through Nanoparticles tracking analysis, transmission electron microscopy and detection of known sEVs markers such as CD9, CD63, CD81 and HSP70. sEVs content was characterised through mass spectrometry and bioinformatic tools. RESULTS Our data indicate the presence of a GBM inflammatory biomarker signature comprising members of the complement and regulators of inflammation and coagulation including VWF, FCGBP, C3, PROS1, and SERPINA1. Bioinformatic analysis highlighted that all potential markers exclusively identified in patient samples had already been linked with either GBM diagnosis, prognosis or associated signalling, suggesting that sEVs protein cargo could mirror the landscape of the original tumour and that selective circulating sEV-derived proteins might be used as hallmarks for GBM patients. CONCLUSION this study is a step forward in the development of a non-invasive liquid biopsy approach for the identification of valuable biomarkers that could significantly improve GBM diagnosis and, consequently, patients’ prognosis and quality of life.
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Santoni, Giorgio, Federica Maggi, Consuelo Amantini, Antonietta Arcella, Oliviero Marinelli, Massimo Nabissi, Matteo Santoni, and Maria Beatrice Morelli. "Coexpression of TRPML1 and TRPML2 Mucolipin Channels Affects the Survival of Glioblastoma Patients." International Journal of Molecular Sciences 23, no. 14 (July 13, 2022): 7741. http://dx.doi.org/10.3390/ijms23147741.
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Among brain cancers, glioblastoma (GBM) is the most malignant glioma with an extremely poor prognosis. It is characterized by high cell heterogeneity, which can be linked to its high malignancy. We have previously demonstrated that TRPML1 channels affect the OS of GBM patients. Herein, by RT-PCR, FACS and Western blot, we demonstrated that TRPML1 and TRPML2 channels are differently expressed in GBM patients and cell lines. Moreover, these channels partially colocalized in ER and lysosomal compartments in GBM cell lines, as evaluated by confocal analysis. Interestingly, the silencing of TRPML1 or TRPML2 by RNA interference results in the decrease in the other receptor at protein level. Moreover, the double knockdown of TRPML1 and TRPML2 leads to increased GBM cell survival with respect to single-channel-silenced cells, and improves migration and invasion ability of U251 cells. Finally, the Kaplan–Meier survival analysis demonstrated that patients with high TRPML2 expression in absence of TRPML1 expression strongly correlates with short OS, whereas high TRPML1 associated with low TRPML2 mRNA expression correlates with longer OS in GBM patients. The worst OS in GBM patients is associated with the loss of both TRPML1 and TRPML2 channels.
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Welling, Leonardo, José Carlos Lynch, Celestino Pereira, Ricardo Andrade, Fabiana Polycarpo Hidalgo, Alessandra G. L. Pereira, and Claúdia Escoteguy. "Prognostic factors in glioblastoma multiforme." Arquivos Brasileiros de Neurocirurgia: Brazilian Neurosurgery 29, no. 04 (December 2010): 121–25. http://dx.doi.org/10.1055/s-0038-1625613.
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Abstract Objective: To study if the prognosis variables such as age, the Karnofsky Performance Status (KPS), extension of tumor removal by surgery, radiotherapy and tumor volume influenced the survival of patients with glioblastoma multiforme (GBM). Method: Retrospective analysis of GBM patients operated at Hospital dos Servidores do Estado between 1998 and 2008. Results: We could observe that age, the KPS and radiotherapy influenced the survival. The other variables did not have any prognosis implications. Conclusions: Despite many researches and many improvements regarding the diagnosis and the surgical techniques, the survival of patients with GBM has not changed in the last 30 years and is a therapeutic challenge. The surgical resection followed by radiotherapy is the standard treatment for patients with GBM. The importance of each variable in the patient's prognosis is still to be established in the multivariate analyzes.
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Xia, Xiangping, Fang Cao, Xiaolu Yuan, Qiang Zhang, Wei Chen, Yunhu Yu, Hua Xiao, Chong Han, and Shengtao Yao. "Low expression or hypermethylation of PLK2 might predict favorable prognosis for patients with glioblastoma multiforme." PeerJ 7 (November 19, 2019): e7974. http://dx.doi.org/10.7717/peerj.7974.
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Background As the most aggressive brain tumor, patients with glioblastoma multiforme (GBM) have a poor prognosis. Our purpose was to explore prognostic value of Polo-like kinase 2 (PLK2) in GBM, a member of the PLKs family. Methods The expression profile of PLK2 in GBM was obtained from The Cancer Genome Atlas database. The PLK2 expression in GBM was tested. Kaplan–Meier curves were generated to assess the association between PLK2 expression and overall survival (OS) in patients with GBM. Furthermore, to assess its prognostic significance in patients with primary GBM, we constructed univariate and multivariate Cox regression models. The association between PLK2 expression and its methylation was then performed. Differentially expressed genes correlated with PLK2 were identified by Pearson test and functional enrichment analysis was performed. Results Overall survival results showed that low PLK2 expression had a favorable prognosis of patients with GBM (P-value = 0.0022). Furthermore, PLK2 (HR = 0.449, 95% CI [0.243–0.830], P-value = 0.011) was positively associated with OS by multivariate Cox regression analysis. In cluster 5, DNA methylated PLK2 had the lowest expression, which implied that PLK2 expression might be affected by its DNA methylation status in GBM. PLK2 in CpG island methylation phenotype (G-CIMP) had lower expression than non G-CIMP group (P = 0.0077). Regression analysis showed that PLK2 expression was negatively correlated with its DNA methylation (P = 0.0062, Pearson r = −0.3855). Among all differentially expressed genes of GBM, CYGB (r = 0.5551; P < 0.0001), ISLR2 (r = 0.5126; P < 0.0001), RPP25 (r = 0.5333; P < 0.0001) and SOX2 (r = −0.4838; P < 0.0001) were strongly correlated with PLK2. Functional enrichment analysis results showed that these genes were enriched several biological processes or pathways that were associated with GBM. Conclusion Polo-like kinase 2 expression is regulated by DNA methylation in GBM, and its low expression or hypermethylation could be considered to predict a favorable prognosis for patients with GBM.
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Deng, Xinqing, Jian Ren, Zhongsheng Bi, and Zhenghao Fu. "Positive Expression of Retinol-Binding Protein 4 Is Related to the Malignant Clinical Features Leading to Poor Prognosis of Glioblastoma." Genetics Research 2022 (December 26, 2022): 1–10. http://dx.doi.org/10.1155/2022/5435523.
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Backgrounds. Retinol-binding protein 4 (RBP4) is a monomeric-binding protein belonging to the lipocalin protein family, which has been reported to be dysregulated in several malignancies such as breast cancer and lung cancer. However, the expression and function of RBP4 in glioblastoma (GBM) are completely unknown. Materials and Methods. TCGA datasets were used for analyzing the mRNA level of RBP4 in GBM and its clinical relevance. A retrospective GBM cohort (n = 73) was enrolled from our hospital to test the protein expression profile of RBP4 in GBM tissues as well as its correlation with patients’ prognoses. Two human GBM cell lines, LN229 and U251, were collected to conduct overexpression and knockdown experiments targeting RBP4. The tumor-related effects of RBP4 in GBM were finally evaluated by proliferation and invasion assays. Results. Both the higher mRNA level and protein level of RBP4 in GBM tissues were significantly correlated with poorer patients’ overall survival. Multivariate analysis identified RBP4 as a novel independent prognostic predictor in GBM patients. Overexpression of RBP4 resulted in enhanced GBM proliferation capacity, which was consistent with clinical findings on the positive correlation between RBP4 level and tumor size. Meanwhile, overexpressing RBP4 promoted GBM cell migration and invasion, while silencing RBP4 led to the opposite results. Conclusions. RBP4 overexpression in tumor tissues is correlated with poorer prognosis of GBM patients, which functions by promoting GBM proliferation and invasion, thus, may serve as an invaluable predictive biomarker and therapeutic target.
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Huang, Bin, Ju Yang, Kongcheng Wang, Weitao Chen, Hongbin Ni, and Jing Yan. "NF1 may serve as a novel genetic biomarker of response to treatment and prognosis in glioblastoma (GBM)." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e14539-e14539. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e14539.
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e14539 Background: The intrinsic capacity of glioblastoma (GBM) tumor cells to infiltrate normal brain predictably results in high rates of early recurrence. Little has changed over the last decade in the treatment available for GBM with survival remaining poor and a novel genetic biomarker is necessary found to predict response to treatment and prognosis in GBM. Methods: Biomarker discovery was performed by a genome-wide screen using DNA extracted from tissue and blood samples of GBM patients. The biomarker was then evaluated for its predictability in OS of GBM patients compared with the Chinese Glioma Genome Atlas (CGGA) and revealed the relationship with tumor-associated macrophages (TAMs). Results: Median OS for NF1-deleted/mutated GBM patients (n = 11) treated with surgery and Chemoradiotherapy was 9.1 mon vs 17.2 mon for NF1 wildtype ones(n = 47), HR (95% CI) 1.83 (0.8753,3.817), p = 0.1. In addition, NF1-deleted/mutated GBMs showed reduced tumor purity and more infiltration of tumor-associated macrophages through pathological stainings. Conclusions: These data suggest that NF1-deleted/mutated GBM patients have a poor prognosis and NF1 may play a role in organizing the tumor microenvironment. NF1 in GBM will be further evaluated in a planned randomized ph 2b study in newly diagnosed GBM patients.
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Bushara, Omar, Alexander Guzner, Kirsten Burdett, Patrick Murday, Matias Pollevick, Denise Scholtens, and Priya Kumthekar. "IMMU-44. PRE-DIAGNOSTIC EOSINOPHIL LEVEL AND GLIOBLASTOMA DEVELOPMENT IN PATIENTS WITH AND WITHOUT ATOPIC DISEASE." Neuro-Oncology 22, Supplement_2 (November 2020): ii114. http://dx.doi.org/10.1093/neuonc/noaa215.474.
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Abstract BACKGROUND Glioblastoma (GBM) is the most common primary malignant brain tumor and carries a very poor prognosis. Recent data report a negative association between the incidence of GBM and atopic disease. The underlying immunologic mechanisms of protection and the associated potential biomarkers are unclear. The aim of this retrospective study is to assess the relationship of eosinophil count to GBM risk by collecting eosinophil count in GBM patients with and without existing atopic disease. METHODS This is a retrospective study of 790 patients diagnosed with GBM from 2009–2019. Of those patients, 140 had laboratory values at least one year prior to diagnosis. Chart review was used to exclude patients with lymphoma, leukemia, other cancers, myelodysplastic syndromes, and unconfirmed drug, food, and adhesive reactions. 14 patients with chart-confirmed allergic rhinitis, asthma, or eczema and 47 controls were found. Wilcoxon rank sum test was used to compare the two groups. RESULTS The two groups did not differ in pre-diagnostic eosinophil counts (p=0.426). The two groups also did not differ in pre-diagnostic basophil, lymphocyte, neutrophil, or monocyte counts. Pre-diagnostic eosinophil to lymphocyte, monocyte to lymphocyte, and neutrophil to lymphocyte ratios also did not differ between the two groups. There were no other quantitative differences that would suggest a difference in immune cell profile. CONCLUSIONS In our study, the subset of GBM patients with atopic disease did not significantly differ in eosinophil count or other white blood cell subtypes when compared to GBM patients without atopic disease. Given that atopic disease is a known protective factor, and our atopic patients with GBM had normal eosinophil counts, we conclude that underlying immunologic factors such as eosinophilia may be protective from GBM as opposed to simply the presence of atopic disease. Prospective analysis to best understand eosinophil count as a surrogate for GBM risk is warranted.
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Sapirstein, E., Y. Laviv, A. Kanner, S. Berkowitch, S. Fichman, A. Benouaich -Amiel, S. Yust-Katz, and T. Siegal. "P12.01.B Systemic metabolic features associated with significant insulin resistance in diabetes mellitus type 2 patients are related to the presence of gemistocytes in glioblastoma." Neuro-Oncology 24, Supplement_2 (September 1, 2022): ii76—ii77. http://dx.doi.org/10.1093/neuonc/noac174.266.
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Abstract Background Gemistocytes (GCs) are unique phenotype of reactive astrocytes. In diffuse low-grade gliomas, they are associated with grim prognosis. Less is known regarding their pathogenesis and prognostic significance in glioblastoma (GBM). Previous data on-neoplastic central nervous system (CNS) lesions has linked the presence of GCs with states of uncontrolled hyperglycaemia in diabetes mellitus type 2 patients. study purpose is to find a correlation between systemic metabolic features and the presence of GCs in patients with GBM.Also, to try and correlate between the presence of GCs, molecular changes, and use of anti-diabetic drugs on overall survival of GBM patients. Methods Electronic medical records from newly diagnosed GBM patients were retrospectively reviewed and extracted for demographic, clinical, metabolic, radiological and pathological variables with emphasis on different metabolic - related features. A statistic-based comparison was made between GBM patients with and without GCs for the same variables. We compared DM2 GC-GBM patients to DM2 non-GC GBM patients in a cohort of poorly controlled DM2 (i.e., HBA1C ≥ 8.0). A possible influence of metformin administration on OS of DM2 GBM patients, with and without GCs, and with and without TP53 mutations was investigated. Results A total of 220 patients with newly diagnosed GBM were included in the study. 14.5% were defined as GC-GBM (group 1, n=32) and 85.5% were defined as non-GC GBM (group 2, n=188). The incidence of DM2 was 25% in both groups. The rate of poorly-controlled DM2 was nearly as twice in group 1 than in group 2 (18.75% vs. 9.5%; p=0.130). In the DM2 GBM group, significant differences were found between DM2 GC-GBM (group 1a, n=9) and DM2 non-GC GBM (group 2a, n=49) patients with male gender predominance (89% vs. 50%, p=0.073) and obesity. Patients in group 1a were more likely to have weight ≥85kg (OR 6.16; 95% CI 1.3336 to 28.5147, p=0.0019) and had higher BMI values (mean BMI of 34.1±11.42 vs. 28.7±5.44 for group 1a and 2a respectively; OR= 1.095, 95%CI 1.053-1.207;p=0.034). Similar significant findings were in the poorly-controlled DM2 subgroup. None of the poorly-controlled DM2 GC-GBM patients were using insulin prior to diagnosis (0% vs. 61.10%, p=0.016). Survival analyses have shown trends for differences in overall survival between subgroups in correlation with presence of GCs, p53 mutations and use of metformin. Conclusion GBM patients with systemic metabolic factors that are associated with marked insulin resistance and are not using insulin at time of diagnosis are significantly more likely to have GCs in their initial pathology. This is a novel finding that may add to data on glucose metabolism in astrocytes and in astrocytes-associated tumors. The presence of GCs, molecular changes in the tumor, and under the influence of anti-diabetic drugs such as metformin, may affect the prognosis of different GBM subgroups.
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Pająk, Beata. "Looking for the Holy Grail—Drug Candidates for Glioblastoma Multiforme Chemotherapy." Biomedicines 10, no. 5 (April 26, 2022): 1001. http://dx.doi.org/10.3390/biomedicines10051001.
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Glioblastoma multiforme (GBM) is the deadliest and the most heterogeneous brain cancer. The median survival time of GBM patients is approximately 8 to 15 months after initial diagnosis. GBM development is determined by numerous signaling pathways and is considered one of the most challenging and complicated-to-treat cancer types. Standard GBM therapy consist of surgery followed by radiotherapy or chemotherapy, and combined treatment. Current standard of care (SOC) does not offer a significant chance for GBM patients to combat cancer, and the selection of available drugs is limited. For almost 20 years, there has been only one drug, Temozolomide (TMZ), approved as a first-line GBM treatment. Due to the limited efficacy of TMZ and the high rate of resistant patients, the implementation of new chemotherapeutics is highly desired. However, due to the unique properties of GBM, many challenges still need to be overcome before reaching a ‘breakthrough’. This review article describes the most recent compounds introduced into clinical trials as drug candidates for GBM chemotherapy.
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Pająk, Beata. "Looking for the Holy Grail—Drug Candidates for Glioblastoma Multiforme Chemotherapy." Biomedicines 10, no. 5 (April 26, 2022): 1001. http://dx.doi.org/10.3390/biomedicines10051001.
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Glioblastoma multiforme (GBM) is the deadliest and the most heterogeneous brain cancer. The median survival time of GBM patients is approximately 8 to 15 months after initial diagnosis. GBM development is determined by numerous signaling pathways and is considered one of the most challenging and complicated-to-treat cancer types. Standard GBM therapy consist of surgery followed by radiotherapy or chemotherapy, and combined treatment. Current standard of care (SOC) does not offer a significant chance for GBM patients to combat cancer, and the selection of available drugs is limited. For almost 20 years, there has been only one drug, Temozolomide (TMZ), approved as a first-line GBM treatment. Due to the limited efficacy of TMZ and the high rate of resistant patients, the implementation of new chemotherapeutics is highly desired. However, due to the unique properties of GBM, many challenges still need to be overcome before reaching a ‘breakthrough’. This review article describes the most recent compounds introduced into clinical trials as drug candidates for GBM chemotherapy.
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Liang, Dandan, Shaoshan Liang, Feng Xu, Mingchao Zhang, Xiaomei Li, Yiyao Tu, Zhihong Liu, and Caihong Zeng. "Clinicopathological features and outcome of antibody-negative anti-glomerular basement membrane disease." Journal of Clinical Pathology 72, no. 1 (October 12, 2018): 31–37. http://dx.doi.org/10.1136/jclinpath-2018-205278.
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AimTo explore the clinicopathological characteristics of patients with anti-GBM antibody-negative anti-GBM disease.MethodsThe clinical and renal pathological findings were retrospectively studied in 19 patients. All patients met the following inclusion criteria: linear GBM IgG deposition on immunofluorescence(IF); and lack of serum anti-GBM antibodies by ELISA and indirect immunofluorescence assay.ResultsThere were 17 male and two female patients, with a median age of 36 years (range 15–61 years). Hypertension was present in 68% of cases, nephrotic-range proteinuria (> 3.5 g/24 hours) in 42%, nephrotic syndrome in 37%, microhaematuria in 95%, renal insufficiency in 63% and lung involvement in 16%. On biopsy all patients had linear GBM staining for polyclonal IgG by IF. The dominant IgG subtype was IgG4 or IgG1. By light microscopy, mesangial proliferative GN without crescents was seen in four patients; proliferative GN (mesangial proliferative GN in eight; endocapillary proliferative GN in two; and membranoproliferative GN in two) with crescents (focal in 11; diffuse in one) in 12 patients; and crescentic GN without mesangial or endocapillary proliferative or membranoproliferative changes in three patients. By electron microscopy, six patients showed scarce electron dense deposits in glomeruli and 11 patients had global podocyte effacement. Totally, 10 (53%) patients received immunosuppressive therapy. The median follow-up was 15 months and six (32%) patients progressed to end-stage renal disease.ConclusionsAnti-GBM antibody-negative anti-GBM disease was different from classic anti-GBM disease clinically and pathologically. The pathogenesis of the renal injury in these patients has not been elucidated until now and it should be studied and identified further.
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Chahal, Manik, Brian Thiessen, and Caroline Mariano. "Treatment of Older Adult Patients with Glioblastoma: Moving towards the Inclusion of a Comprehensive Geriatric Assessment for Guiding Management." Current Oncology 29, no. 1 (January 14, 2022): 360–76. http://dx.doi.org/10.3390/curroncol29010032.
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Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, and over half of patients with newly diagnosed GBM are over the age of 65. Management of glioblastoma in older patients includes maximal safe resection followed by either radiation, chemotherapy, or combined modality treatment. Despite recent advances in the treatment of older patients with GBM, survival is still only approximately 9 months compared to approximately 15 months for the general adult population, suggesting that further research is required to optimize management in the older population. The Comprehensive Geriatric Assessment (CGA) has been shown to have a prognostic and predictive role in the management of older patients with other cancers, and domains of the CGA have demonstrated an association with outcomes in GBM in retrospective studies. Furthermore, the CGA and other geriatric assessment tools are now starting to be prospectively investigated in older GBM populations. This review aims to outline current treatment strategies for older patients with GBM, explore the rationale for inclusion of geriatric assessment in GBM management, and highlight recent data investigating its implementation into practice.
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Pellerino, Alessia, Francesco Bruno, Edoardo Pronello, Francesca Mo, Federica Franchino, Roberta Rudà, and Riccardo Soffietti. "NCOG-19. PROGNOSTIC FACTORS IN ELDERLY PATIENTS WITH GLIOBLASTOMA: A RETROSPECTIVE INSTITUTIONAL SERIES OF 160 PATIENTS." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi156. http://dx.doi.org/10.1093/neuonc/noab196.610.
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Abstract INTRODUCTION Glioblastoma (GBM) prevails in elderly patients, who often suffer from other comorbidities that may affect the outcome. The aim of the study was to investigate clinical characteristics, comorbidities, and treatment-related complications that may impact the outcome of elderly patients with GBM. PATIENTS AND METHODS In this institutional retrospective study, we included GBM patients ≥ 65 years diagnosed with glioblastoma from 2015 to 2020. We retained information about comorbidities according to Charlson Comorbidity Index (CCI), Karnofsky prognostic score (KPS), MGMTp methylation, and clinical complications during treatment or follow-up. RESULTS We included 160 patients. Median age was 72 years (65-88). Median time of follow-up was 9.25 months. Median progression-free survival (mPFS) and overall survival (mOS) were 5.84 and 9.67 months. In a multivariate analysis, factors affecting survival were: KPS after surgery ≥ 70 (mPFS: HR 0.24, 0.13-0.44; mOS: HR 0.43, 0.24–0.76. 95% CI), partial vs gross total resection (mPFS: HR 2.15, 1.23–3.77; mOS: HR 2.61, 1.34–5.07. 95% CI), MGMTp methylation (mPFS: HR 0.35, 0.22–0.55; mOS: HR 0.37, 0.24–0.76. 95% CI), and complications after surgery (mPFS: HR 2.52, 1.39–4.55; mOS: HR 2.96, 1.63–5.40. 95% CI). Conversely, age and CCI were not significantly correlated with prognosis. CONCLUSIONS For elderly patients with GBM, CCI does not seem to predict the outcome. Other factors such as extent of surgery, MGMTp methylaton, postoperative KPS, and clinical complications after surgery retain a significant prognostic importance. Further studies are needed to standardize clinical prognostic scales specific for elderly GBM patients.
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Li, Qiao, Weijie Sun, Yi Lu, Didi Guo, Tiantian Han, Guanghua Lu, Xiaomin Li, Ran Ding, and Fanfeng Bu. "The analysis of EGFR variants in Chinese adult glioblastoma patients." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e14020-e14020. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e14020.
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e14020 Background: Glioblastoma multiforme (GBM) is the most common primary brain tumor with complex genetic alterations and genomic profiles. EGFR amplification occurs in approximately 40% of primary GBM，EGFR mutation is also a prevalent genetic abnormality in GBM. A series of potential therapies targeting EGFR variants are currently in development, such as tyrosine kinase inhibitors (TKIs), monoclonal antibodies, vaccines, etc. However, to date, EGFR-targeted therapy continues to face significant challenges. A deeper understanding of EGFR variant profiles and pathobiology of GBM will be required. Methods: Next-generation sequencing of 131-gene profiling was performed to analyze EGFR activating mutations from 891 Chinese glioma patients in 2019-2020. Somatic mutations and copy number variations were detected following the standard operating procedure (SOP). We screened out the EGFR activating mutation and calculated the mutation frequency and the tumor location. Results: 51 GBM patients had activating mutations. The average age was 49 years (range,25-73 years). Most of the tumors occurred in the cerebral hemisphere (56.9%), followed by ventricles (3.9%) and thalamus (3.9%), etc. 43/51 (84.3%) were accompanied by high-fold EGFR amplification. 9/12 (75%) were EGFR intracellular mutation occurs with EGFR amplification, 31/35 (88.6%) were EGFR extracellular mutation occurs with EGFR amplification. Moreover, 4 patients carried EGFR intracellular and extracellular mutation occurs with EGFR amplification. There was no significant difference between the ratio of intracellular mutations and extracellular mutations with EGFR amplification (P=0.3496). Conclusions: In our GBM patients, EGFR activating mutations were accompanied by high-fold EGFR amplification. As we know that, GBM benefit from EGFR-TKIs may be limited. Therefore, multi-targeted combination therapy research could be considered in the future.
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Frandsen, Simone, Helle Broholm, Vibeke A. Larsen, Kirsten Grunnet, Søren Møller, Hans Skovgaard Poulsen, and Signe Regner Michaelsen. "RARE-21. CLINICAL CHARACTERISTICS OF GLIOSARCOMA AND OUTCOME FROM STANDARDIZED TREATMENT RELATIVE TO CONVENTIONAL GLIOBLASTOMA." Neuro-Oncology 21, Supplement_6 (November 2019): vi225—vi226. http://dx.doi.org/10.1093/neuonc/noz175.944.
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Abstract INTRODUCTION Gliosarcoma (GS) is a rare histopathologic variant of glioblastoma (GBM) characterized by a biphasic growth pattern consisting of both glial and sarcomatous components. Reports regarding its relative prognosis compared to conventional GBM are conflicting and although GS is treated as conventional GBM, supporting evidence is lacking. The aim of this study was to characterize demographic trends, clinical outcomes and prognostic variables of GS patients receiving standardized therapy and compare these to conventional GBM. METHODS 680 GBM patients, treated with maximal safe resection followed by Stupp’s regimen (radiotherapy with concomitant and adjuvant temozolomide) at a single institution, were retrospective reevaluated by reviewing histopathological records and tumor tissue for identification of GS patients. Clinicohistopathological characteristics obtained via assessment of medical records and imaging analysis were compared between the GS and GBM cohorts. Kaplan-Meier survival estimates were compared with log-rank testing, while cox-regression modeling tested for prognostic factors in GS patients. RESULTS The cohort revealed 26 primary gliosarcoma (PGS) patients (3.8 %) and 7 secondary gliosarcoma (SGS) patients (1.0 %). Compared to conventional GBM tumors, PGS tumors were significantly more often located in the temporal lobe (53.8 %, p = 0.006) and MGMT-unmethylated (73.9 %, p = 0.009). No significant differences were found between PGS and conventional GBM in progression-free-survival (6.8 and 7.6 months respectively, p = 0.105) and in overall survival (13.4 and 15.7 months respectively, p = 0.201). Also, survival from recurrence was not significant different between PGS, SGS and GBM (5.8, 8.6 and 7.4 months respectively, p = 0.694). MGMT status was the only factor prognostic for PGS survival (p = 0.022). CONCLUSION Despite tumor difference between GS and GBM, the patients present similar survival outcome from standardized treatment. This support continues practice of radiation and temozolomide for GS patients.
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Otvos, Balint, Matthew Grabowski, Tyler Alban, Joshua Golubovsky, Chase Neumann, Anja Rabjlenovic, Defne Bayik, et al. "GENE-26. HOST GENETIC VARIATIONS IN MACROPHAGE MIGRATION INHIBITOR FACTOR CONFER WORSE PROGNOSIS IN GLIOBLASTOMA." Neuro-Oncology 21, Supplement_6 (November 2019): vi103. http://dx.doi.org/10.1093/neuonc/noz175.428.
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Abstract Genetic and systemic prognostic factors have been identified in glioblastoma (GBM) that correlate with survival, but patient-specific genomic risk factors that impact prognosis or response to immunotherapies have not been elucidated. GBM promotes an immune suppressive microenvironment via many mechanisms including the production of macrophage migration inhibitory factor (MIF) by GBM cancer stem cells, which activates myeloid derived suppressor cells (MDSCs). Increased circulating and intracranial MDSCs as well as intratumoral MIF expression in GBM patients portend a worse overall prognosis. Endogenous MIF expression is dependent on two genetic microsatellite loci: single nucleotide polymorphisms (SNPs) and CATT repeats within the promoter. To determine whether these genetic variations were linked to GBM development and/or prognosis, we assessed peripheral nucleated blood from 520 GBM patients for the MIF SNPs and CATT repeats. MIF microsatellite frequencies were similar between the normal population and GBM patients indicating loci variability was not a risk factor for GBM development. However, newly diagnosed IDH wild-type GBM patients with a minor allele SNP who received standard of care therapy had a 3.1 month shorter progression free survival (PFS), and a 4.3 month shorter overall survival (OS) when compared to patients with two major allele SNPs. This association was seen also with the CATT-repeat analyses. Furthermore, in a multivariate analysis for PFS that included age, sex, Karnofsky performance status, MGMT methylation status, 1p/19q co-deletion, and SNP status as covariates, only age and SNP status were independently associated with shorter PFS. Taken together, patients with variant MIF microsatellite loci experienced shorter PFS and decreased OS compared to those with the most common loci. These results are currently being validated in a separate 1700 patient cohort with the intent of understanding how MIF expression influences myeloid populations within the GBM microenvironment and then developing novel peripheral GBM screening markers for aggressiveness.
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Kim, Jung-Young, Jennifer G. Jackman, Sarah Woodring, Frances McSherry, James E. Herndon, Annick Desjardins, Henry S. Friedman, and Katherine B. Peters. "Second primary cancers in long-term survivors of glioblastoma." Neuro-Oncology Practice 6, no. 5 (February 4, 2019): 386–91. http://dx.doi.org/10.1093/nop/npz001.
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Abstract Background Overall survival (OS) in glioblastoma (GBM) is poor at an average of 14 to 18 months, and long-term survivors (LTS) of GBM are rare. LTS of GBM, defined as surviving >5 years postdiagnosis, represent only 2% to 10% of all GBM patients. LTS of cancer are at high risk of developing second primary neoplasms. This study looks at occurrences of second primary neoplasms in LTS of GBM. Methods Records from adult patients newly diagnosed with GBM between January 1, 1998 and February 8, 2010, were retrospectively reviewed to identify LTS, defined as patients who survived ≥5 years. We focused on the identification of a new diagnosis of cancer occurring at least 2 years after the initial GBM diagnosis. Results We identified 155 LTS of GBM, with a median OS of 11.0 years (95% CI: 9.0 to 13.1 years) and a median follow-up of 9.6 years (95% CI: 8.7 to 10.7 years). In this cohort of patients, 13 (8.4%) LTS of GBM developed 17 secondary cancers. Eight could potentially be attributed to previous radiation and chemotherapy (skin cancer in radiation field [n = 4], leukemia [n = 2], low-grade glioma [n = 1], and sarcoma of the scalp [n = 1]). The other 9 cases included melanoma (n = 2), prostate cancer (n = 2), bladder cancer (n = 1), endometrioid adenocarcinoma (n = 1), basal cell carcinoma (n = 1), and renal cell carcinoma (n = 1). Conclusions Although second primary cancers are rare in GBM LTS, providers should continue close monitoring with appropriate oncologic care. Moreover, this highlights the need for survivorship care of patients with GBM.
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Zhai, Lijie, April Bell, Jun Qian, Erik Ladomersky, Kristen Lauing, and Derek Wainwright. "IMMU-22. TARGETING NON-CANONICAL FUNCTION OF IDO1 IN GLIOBLASTOMA IMMUNOTHERAPY." Neuro-Oncology 21, Supplement_6 (November 2019): vi123. http://dx.doi.org/10.1093/neuonc/noz175.515.
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Abstract Recent failure of immune checkpoint blockade, anti-PD-1 therapy in patients suffering recurrent glioblastoma (GBM) indicates that development of novel immunosuppressive mediator-targeted therapeutic strategy is critical for more effective immunotherapies against GBM. Indoleamine 2, 3-dioxygenase 1 (IDO1) has been shown to mediate tumor-induced immunosuppression through its tryptophan catabolic activity. Surprisingly, pharmacological IDO1 enzyme inhibitors have not demonstrated any survival benefit in cancer patients either mono-therapeutically or in combination with other therapies. Previously we confirmed that tumor IDO1 mRNA expression is significantly upregulated in GBM patients compared to those from patients with lower grades gliomas. Furthermore, knockdown of IDO1 in mouse GBM cells significantly increased mouse survival and decreased tumor infiltrating Tregs, but did not affect tumor local tryptophan catabolism. Consistently, inhibition of IDO1 enzymatic activity on GBM-bearing mice did not yield any survival benefit. These findings indicate that IDO1 may suppress immune response through a non-enzymatic pathway. To test this hypothesis, IDO1-deficient mouse GBM cells were created and modified to stably express either wild-type (WT) or enzyme-null IDO1. Syngeneic mice intracranially engrafted with both WT and enzyme-null IDO1 overexpressing GBM cells showed significantly increase of tumor infiltrating Tregs and decreased survival in comparison to mice engrafted with IDO1-deficient GBM cells. In contrast, no difference was observed between WT-IDO1 GBM and enzyme-null IDO1 GBM groups. Additionally, when co-cultured with splenic monocytes, both WT and enzyme-null IDO1 overexpressing GBM cells induced more mature macrophages than IDO1-deficient GBM cells. Taken together, our data strongly imply an enzyme independent pathway associated with IDO1-driven immunosuppression in mouse GBM. Validation of this novel mechanism on human GBM cells is ongoing. A soluble molecule has been identified as a potential mediator for the non-enzymatic function of IDO1. Results from this study will provide innovative strategies for IDO1-based immunotherapy against GBM.
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Loussouarn, Delphine, Lisa Oliver, Celine Salaud, Edouard Samarut, Raphaël Bourgade, Christophe Béroud, Emilie Morenton, Dominique Heymann, and Francois M. Vallette. "Spatial Distribution of Immune Cells in Primary and Recurrent Glioblastoma: A Small Case Study." Cancers 15, no. 12 (June 20, 2023): 3256. http://dx.doi.org/10.3390/cancers15123256.
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Only a minority of patients with glioblastoma (GBM) respond to immunotherapy, and always only partially. There is a lack of knowledge on immune distribution in GBM and in its tumor microenvironment (TME). To address the question, we used paired primary and recurrent tumors from GBM patients to study the composition and the evolution of the immune landscape upon treatment. We studied the expression of a handful of immune markers (CD3, CD8, CD68, PD-L1 and PD-1) in GBM tissues in 15 paired primary and recurrent GBM. In five selected patients, we used Nanostring Digital Spatial Profiling (DSP) to obtain simultaneous assessments of multiple biomarkers both within the tumor and the microenvironment in paired primary and recurrent GBM. Our results suggest that the evolution of the immune landscape between paired primary and recurrent GBM tumors is highly heterogeneous. However, our study identifies B3-H7 and HLA-DR as potential targets in primary and recurrent GBM. Spatial profiling of immune markers from matched primary and recurrent GBM shows a nonlinear complex evolution during the progression of cancer. Nonetheless, our study demonstrated a global increase in macrophages, and revealed differential localization of some markers, such as B7-H3 and HLA-DR, between GBM and its TME.
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O'Brien, B. J., J. A. Bacha, D. M. Brown, A. Steino, R. Schwartz, S. Kanekal, L. M. Lopez, and M. Penas-Prado. "PC3 - 155 Phase II Study of Dianhydrogalactitol in Patients with MGMT-Unmethylated, Bevacizumab-Naïve Recurrent Glioblastoma." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 43, S4 (October 2016): S18. http://dx.doi.org/10.1017/cjn.2016.382.
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Glioblastoma (GBM) is the most common brain cancer. Most GBM tumors have unmethylated promoter status for O6-methylguanine-DNA-methyltransferase (MGMT); a validated biomarker for MGMT protein-expression and ensuing temozolomide-resistance. Second-line treatment with bevacizumab has not improved overall survival (OS). Dianhydrogalactitol (VAL-083) is a bi-functional alkylating agent targeting N7-Guanine, thus MGMT-independently inducing interstrand cross-links, DNA double-strand breaks and cell-death in GBM cell-lines and cancer stem cells. VAL-083 is currently in Phase I/II clinical trial for recurrent GBM, post-TMZ and post-bevacizumab. In this Phase II clinical trial, the main goal is to assess the 9-month OS in MGMT-unmethylated, recurrent, bevacizumab-naive GBM. RATIONALE: The vast majority of GBM patients experience recurrent/progressive disease within a year from initial diagnosis and median survival after recurrence is 3-9 months. Chemotherapy regimens for these patients are lacking and there is a significant unmet medical need. Given VAL-083’s novel alkylating mechanism, promising clinical benefit, and favorable safety profile, a trial studying VAL-083 in MGMT-unmethylated recurrent GBM is warranted. METHOD: Randomized, non-comparative biomarker-driven Phase II clinical trial in MGMT-unmethylated GBM patients at first recurrence/progression, prior to bevacizumab. 48 patients will be randomized to receive VAL-083 or “standard-of-care” salvage drug lomustine. 32 patients will receive VAL-083 40mg/m2/day on days 1,2,3 of a 21-day cycle. 16 patients will receive lomustine 90 mg/m2/day on day 1 of a 42-day cycle. Patients will be followed until death or for at least 9 months from enrollment, whichever occurs earlier. Survival will be compared to the BELOB trial for recurrent MGMT-unmethylated GBM patients treated with lomustine.