scholarly journals CBMT-24. CHARACTERIZATION OF PRIMARY CILIUM IN RECURRENT GLIOBLASTOMA: IMPLICATIONS FOR NEW THERAPEUTIC TARGETS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi38-vi38
Author(s):  
Vittorio Stumpo ◽  
Aruljothi Marappian ◽  
Quintino Giorgio D’Alessandris ◽  
Simone Pacioni ◽  
Rina Di Bonaventura ◽  
...  
Keyword(s):  
Primary Cilium ◽  
Intracellular Signaling ◽  
Treatment Resistance ◽  
Recurrent Glioblastoma ◽  
Newly Diagnosed ◽  
Ciliated Cells ◽  
Differentiation Markers ◽  
Compensatory Response ◽  
Who Grade ◽  
Recurrent Gbm

Abstract INTRODUCTION Primary cilium is a highly conserved, dynamic cellular organelle which plays several roles in embryonic development, intracellular signaling, and cell cycle. Structural alterations of primary cilium have been described in human gliomas including glioblastoma (GBM), however, its actual role in pathogenesis and treatment resistance of these tumors is largely unknown. METHODS We investigated cilium morphology and expression of cilium-related genes in human glioma of various WHO grade and in couples of patient-derived glioma stem-like cells (GSCs) that were established from the very same GBM at first diagnosis and at recurrence. Immunohistochemistry with anti-Arl13b antibody was used to assess cilium morphology. The expression levels of genes involved in ciliary disassembly complex (CDC) were analyzed by quantitative real-time PCR, using neural progenitor cells (NPCs) as control. Lastly, we assessed 3 GSC cultures that were treated with a drug inhibiting cilia disassembly (CCB-Cil). RESULTS Anaplastic oligodendroglioma and proneural GBM showed the highest percentage of ciliated cells. In GBM, we found the highest percentage of fragmented cilia. GSCs derived from newly diagnosed GBMs displayed lower percentages of ciliated cells than those derived from recurrent GBMs (20% vs 70%). Morphological analysis indicated that GSCs from recurrent GBM show cilia with extremely various morphology compared with GSCs from newly diagnosed GBM and NPCs. Gene analysis showed reduced expression of CDC-related genes in GSCs from newly diagnosed GBM with respect to those from recurrent GBMs. CCB-Cil treatment determined a global reduction of CDC-related genes, increased expression of differentiation markers (GFAP), and reduction of stemness markers (SOX2). CONCLUSIONS The increased percentage of ciliated cells in GSCs from recurrent GBM may be related to a compensatory response of CDC and to an accelerated ciliary turnover. Blocking cilia disassembly reduces stemness features and induces differentiation in GSCs, suggesting that this approach could represent a promising strategy for targeting GBM.

GBM AGILE: A global, phase 2/3 adaptive platform trial to evaluate multiple regimens in newly diagnosed and recurrent glioblastoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS2074-TPS2074
Author(s):  
Patrick Y. Wen ◽  
Ingo K. Mellinghoff ◽  
Meredith Becker Buxton ◽  
Webster K. Cavenee ◽  
Howard Colman ◽  
...  
Keyword(s):  
Active Sites ◽  
Drug Application ◽  
Recurrent Glioblastoma ◽  
Pharmacokinetic Data ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Adaptive Randomization ◽  
New Drug ◽  
Multiple Drugs ◽  
Recurrent Gbm

TPS2074 Background: GBM AGILE, Glioblastoma Adaptive, Global, Innovative Learning Environment, is an international, multi-arm, seamless phase 2/3 response adaptive randomization platform trial designed to evaluate multiple therapies in newly diagnosed (ND) and recurrent glioblastoma (GBM) with the goal of identifying effective therapies matching them accurately to different patient subtypes in an accelerated manner. It is a collaboration between academic investigators, patient organizations and industry to support new drug applications for newly diagnosed and recurrent GBM. Methods: The primary objective of GBM AGILE is to identify therapies that effectively improve overall survival in patients with ND or recurrent GBM. Bayesian response adaptive randomization is used within subtypes of the disease to assign participants to investigational arms based on their performance. Operating under a Master Protocol, GBM AGILE allows multiple drugs from different pharmaceutical companies to be evaluated simultaneously and/or over time against a common standard of care control. Based on performance, a drug may graduate and move to a rapid stage 2 (phase 3) within the trial, and the totality of the data can be used for a new drug application. An active pipeline is critical to the ongoing success of GBM AGILE. With the leadership of the trial’s Arm Selection Committee, uniform processes for including new drugs have been established to ensure a consistent review of drugs/drug combinations over the course of the trial. Factors considered include relevant pre-clinical data, preliminary evidence for antitumor activity. pharmacokinetic data to support proposed drug dosing and administration, and potential biomarkers helpful for the development of a drug. GBM AGILE provides an efficient mechanism to screen and develop robust information regarding the efficacy of proposed novel therapeutics and associated biomarkers for GBM and to quickly move therapies and biomarkers into clinic. GBM AGILE received IND approval from the FDA in April 2019, screening its first patient in June 2019. Site activation is ongoing in the US, with over 35 active sites and over 425 patients screened (as of February 2021). Expansion to Canada, Europe and China are under progress. Clinical trial information: NCT03970447.

scholarly journals Very low mutation burden is a feature of inflamed recurrent glioblastomas responsive to cancer immunotherapy

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Matthias Gromeier ◽  
Michael C. Brown ◽  
Gao Zhang ◽  
Xiang Lin ◽  
Yeqing Chen ◽  
...  
Keyword(s):  
Genomic Analysis ◽  
Immune Checkpoint Blockade ◽  
Recurrent Glioblastoma ◽  
Newly Diagnosed ◽  
Who Grade ◽  
Term Survival ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Newly Diagnosed Glioblastoma

AbstractSeveral immunotherapy clinical trials in recurrent glioblastoma have reported long-term survival benefits in 10–20% of patients. Here we perform genomic analysis of tumor tissue from recurrent WHO grade IV glioblastoma patients acquired prior to immunotherapy intervention. We report that very low tumor mutation burden is associated with longer survival after recombinant polio virotherapy or after immune checkpoint blockade in recurrent glioblastoma patients. A relationship between tumor mutation burden and survival is not observed in cohorts of immunotherapy naïve newly diagnosed or recurrent glioblastoma patients. Transcriptomic analyses reveal an inverse relationship between tumor mutation burden and enrichment of inflammatory gene signatures in cohorts of recurrent, but not newly diagnosed glioblastoma tumors, implying that a relationship between tumor mutation burden and tumor-intrinsic inflammation evolves upon recurrence.

scholarly journals Laser interstitial thermal therapy for newly diagnosed and recurrent glioblastoma

2016 ◽  
Vol 41 (4) ◽  
pp. E12 ◽  
Author(s):  
Jonathan G. Thomas ◽  
Ganesh Rao ◽  
Yvonne Kew ◽  
Sujit S. Prabhu
Keyword(s):  
Median Survival ◽  
Progression Free Survival ◽  
Primary Brain Tumor ◽  
Recurrent Glioblastoma ◽  
Thermal Therapy ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Laser Interstitial Thermal Therapy ◽  
Median Progression Free Survival ◽  
Recurrent Gbm

OBJECTIVE Glioblastoma (GBM) is the most common and deadly malignant primary brain tumor. Better surgical therapies are needed for newly diagnosed GBMs that are difficult to resect and for GBMs that recur despite standard therapies. The authors reviewed their institutional experience of using laser interstitial thermal therapy (LITT) for the treatment of newly diagnosed or recurrent GBMs. METHODS This study reports on the pre-LITT characteristics and post-LITT outcomes of 8 patients with newly diagnosed GBMs and 13 patients with recurrent GBM who underwent LITT. RESULTS Compared with the group with recurrent GBMs, the patients with newly diagnosed GBMs who underwent LITT tended to be older (60.8 vs 48.9 years), harbored larger tumors (22.4 vs 14.6 cm3), and a greater proportion had IDH wild-type GBMs. In the newly diagnosed GBM group, the median progression-free survival and the median survival after the procedure were 2 months and 8 months, respectively, and no patient demonstrated radiographic shrinkage of the tumor on follow-up imaging. In the 13 patients with recurrent GBM, 5 demonstrated a response to LITT, with radiographic shrinkage of the tumor following ablation. The median progression-free survival was 5 months, and the median survival was greater than 7 months. CONCLUSIONS In carefully selected patients with recurrent GBM, LITT may be an effective alternative to surgery as a salvage treatment. Its role in the treatment of newly diagnosed unresectable GBMs is not established yet and requires further study.

scholarly journals IMT-03 CLINICAL TRIAL FOR NEWLY DIAGNOSED MALIGNANT GLIOMA WITH WT1-W10 VACCINATION

2019 ◽  
Vol 1 (Supplement_2) ◽  
pp. ii17-ii17
Author(s):  
Yu Kawanishi ◽  
Keiko Udaka ◽  
Toshio Yawata ◽  
Eiichi Nakai ◽  
Hitoshi Fukuda ◽  
...  
Keyword(s):  
Malignant Glioma ◽  
Wilms Tumor ◽  
Malignant Gliomas ◽  
Group Analysis ◽  
Treatment Resistance ◽  
Cell Vaccine ◽  
Newly Diagnosed ◽  
Serious Adverse Events ◽  
Who Grade ◽  
Vaccination Therapy

Abstract OBJECT Wilms’ tumor 1 (WT1) peptide vaccination is considered a potentially effective therapy against malignant glioma. We conducted a Phase I/II study to investigate the safety and feasibility of novel WT1 peptide (W10) vaccination therapy for patients with newly diagnosed malignant glioma. METHODS WT1 vaccination therapy was performed for patients with malignant glioma who have undergone concurrent radiotherapy and temozolomide therapy. A mixture of WT1 peptide with inactivated pertussis whole cell vaccine was injected intradermally once a week for at least 12 weeks. RESULTS Twenty-seven patients (12 men, 15 women; median 65 years) with the following tumors were enrolled: WHO grade IV (15), WHO grade III (12). PFS and OS of glioblastoma cases were 12.7 months 21.9 months, respectively. PFS of the MGMT unmethylated group was shorter than the methylated group. Interestingly enough, overall survival in the MGMT unmethylated group was not significantly different from the methylated group. Analysis of recurrent cases after immunotherapy showed decreased expression of WT1 antigen and increased Treg. They were suggested as a cause of treatment resistance. No serious adverse events were observed except for Grade 1 erythema at the injection sites. CONCLUSIONS This study of a novel WT1 vaccination therapy demonstrated safety and feasibility in the management of newly diagnosed malignant gliomas.

scholarly journals Multiplex-inhibitor bead mass spectrometry reveals differential kinome signatures in newly diagnosed and recurrent glioblastoma

2020 ◽  
Author(s):  
Anna Jermakowicz ◽  
Alison M. Kurimchak ◽  
Jann Sarkaria ◽  
Ricardo Komotar ◽  
Michael E. Ivan ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Clinical Trials ◽  
Signaling Pathways ◽  
Surgical Resection ◽  
Kinase Inhibitors ◽  
Resistance Mechanisms ◽  
Recurrent Glioblastoma ◽  
Adult Brain ◽  
Newly Diagnosed ◽  
Recurrent Gbm

ABSTRACTGlioblastoma (GBM) is the most common and aggressive adult brain tumor. Despite years of research, clinical trials have not improved the outcome for GBM. Standard of care for newly diagnosed GBM includes surgical resection, followed by radiation and chemotherapy. Tumor recurrence is inevitable and since most patients are not candidates for a second surgical resection, there is an urgent need to identify resistance mechanisms that arise in recurrent GBM. We postulated that examining the differences of activated kinases between newly diagnosed and recurrent GBM may provide insight to resistance mechanisms.To map the kinome landscape of newly diagnosed (nGBM) and recurrent GBM (rGBM) patient derived xenograft tumors, we used Multiplexed Inhibitor Beads and Mass Spectrometry (MIB-MS). We performed pathway analysis of kinases that differed in MIB-binding between nGBM and rGBM to identify kinase-driven signaling pathways. We also analyzed transcriptional profiles to determine the overlap in signaling pathways seen using proteomics or transcriptomics.Using MIB-MS kinome profiling, we found key differences in kinase-driven signaling pathways that may account for the increase in aggressive behavior seen in recurrent GBM. This included a shift in pathways driving cell invasion and proliferation, as well as upregulation of signaling pathways that drive GBM stem-cell like cell differentiation. Analysis of RNA-sequencing showed no statistically significant differences between enriched gene ontologies in nGBM and rGBM, demonstrating the importance of MIB-MS kinome profiling. Collectively, these studies suggest that kinome profiling may inform future clinical trials for kinase inhibitors in GBM.

INNV-07. TTFIELDS TREATMENT OF GLIOSARCOMA AND RECURRENT ANAPLASTIC OLIGODENDROGLIOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi106-vi106
Author(s):  
Nicholas Blondin ◽  
Robert Fulbright ◽  
Anita Huttner ◽  
Jennifer Moliterno-Gunel
Keyword(s):  
Stable Disease ◽  
Case Series ◽  
Standard Of Care ◽  
Recurrent Glioblastoma ◽  
Anaplastic Oligodendroglioma ◽  
Newly Diagnosed ◽  
Who Grade ◽  
Radiographic Findings ◽  
Tumor Treating Fields ◽  
Grade 3

Abstract INTRODUCTION The Optune device delivers tumor treating fields (TTFields) and is considered as a standard of care for newly diagnosed and recurrent glioblastoma patients. The efficacy of Optune in other glioma subtypes, such as gliosarcoma and anaplastic oligodendroglioma, is still unclear. In this small case series, we present the clinical, pathologic and radiographic findings of two patients who utilized Optune and had improved outcomes compared to historical controls. CASE 1 A 49 year old woman underwent resection of a right temporal lobe gliosarcoma in November 2017. She received conventional radiation therapy with concurrent temozolomide, which was complicated by significant thrombocytopenia and leukopenia. She initiated Optune as monotherapy six weeks after completing radiation, and used the device for 24 months. She still has not had a recurrence, now 3.5 years since her initial diagnosis. CASE 2 A 46 year old woman underwent resection of a right frontal lobe oligodendroglioma, WHO Grade 2, in September 2011. She received one cycle of temozolomide in April 2014, complicated by thrombocytopenia, and no further chemotherapy was administered. In November 2017, she underwent resection of a new focus of enhancement at the margin of the resection cavity, which was confirmed to have transformed to WHO Grade 3. In August 2019, a radiographic progression of an enhancing nodule was observed. She initiated Optune as monotherapy in September 2019, and since that time, has had stable disease for 18 months. Optune treatment is still ongoing. CONCLUSIONS In a case of newly diagnosed gliosarcoma, Optune monotherapy has contributed to progression-free and overall survival of 3.5 years to date. In a case of recurrent anaplastic oligodendroglioma, Optune monotherapy has achieved stable disease for at least 18 months. These cases demonstrate that Optune can be safely utilized in these glioma subtypes and contributed to improved survival outcomes in these two patients.

Use of immunotherapy in recurrent glioblastoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e13523-e13523
Author(s):  
Ashley Love Sumrall ◽  
David Lowell Jennings ◽  
Daniel Ernest Haggstrom ◽  
James Thomas Symanowski
Keyword(s):  
Checkpoint Inhibitors ◽  
Staining Intensity ◽  
Recurrent Glioblastoma ◽  
Recurrent Tumor ◽  
Newly Diagnosed ◽  
Checkpoint Inhibition ◽  
Tumor Patients ◽  
Initial Tumor ◽  
Tumor Profiling ◽  
Recurrent Gbm

e13523 Background: With the recent explosion of interest in immunotherapy to treat cancer, it has moved into management of glioblastoma (GBM). Several trials are ongoing, investigating use of checkpoint inhibition for newly diagnosed and recurrent GBM. Methods: We reviewed the records of patients with recurrent glioblastoma (including gliosarcoma). Six of the eight patients demonstrated PD-1 positivity via immunohistochemical (IHC) staining. Two patients demonstrated PD-L1 positivity as 2+ staining intensity via IHC. Patients were managed with checkpoint inhibitors for at least four weeks. When feasible, patients had tumor profiling of initial tumor and recurrent tumor. Patients were followed for response, progression, and survival. Results: Eight patients were identified with recurrent GBM who received immunotherapy with checkpoint inhibitors. They ranged from first through fifth recurrence following radiation and temozolomide. Three patients received pembrolizumab. Of those, two were PD-L1 positive. Five patients received nivolumab, and all were PD-1 positive. There were no partial or complete responses. Five of the eight subjects died, and the median survival time among the 8 subjects was 3.6 months. Six of eight subjects progressed on treatment, and the median PFS was 2.2 months. Bevacizumab was given to two patients for suspected “tumor flare” while on nivolumab. Four of the eight patients had tumor profiling completed at initial diagnosis and recurrence. Treatment was well-tolerated with only minimal toxicity observed. Conclusions: Despite increasing interest in utilizing these medications for recurrent glioblastoma, overall survival in our cohort was consistent with historical control (3 to 5 months). Additionally, we did not witness any responses.

scholarly journals Comparison of Tumor Immune Environment Between Newly Diagnosed and Recurrent Glioblastoma in Matched Patients

2022 ◽  
Author(s):  
Fei Wang ◽  
Sahara J Cathcart ◽  
Dominick J DiMaio ◽  
Nan Zhao ◽  
Jie Chen ◽  
...  
Keyword(s):  
Tumor Infiltrating Lymphocytes ◽  
Distribution Patterns ◽  
Primary Brain Tumor ◽  
Primary Diagnosis ◽  
Recurrent Glioblastoma ◽  
Initial Diagnosis ◽  
Newly Diagnosed ◽  
Response To Chemotherapy ◽  
Tissue Specimens ◽  
Recurrent Gbm

Abstract Purpose: Glioblastoma (GBM) is the most lethal primary brain tumor in adult patients. The disease progression, response to chemotherapy and radiotherapy at initial diagnosis, and prognosis are profoundly associated with the tumor microenvironment (TME), especially the features of tumor-infiltrating immune cells (TII). Recurrent GBM is even more challenging to manage. Differences in the immune environment between newly diagnosed and recurrent GBM and an association with tumor prognosis are not well defined. Methods: To address this knowledge gap, we analyzed the clinical data and tissue specimens from 24 GBM patients (13 at initial diagnosis and 11 at recurrence). The expression levels of multiple immunobiological markers in patients’ GBM at initial diagnosis versus at recurrence were compared, including five patients with both specimens available (paired). The distribution patterns of TII were evaluated in both the intratumoral and perivascular regions. Results: We found that tumors from recurrent GBM have significantly more tumor-infiltrating lymphocytes (TILs) and macrophages and higher PD-L1 expression than tumors at primary diagnosis and benign brain specimens from epilepsy surgery. The pattern changes of the TILs and macrophages of the five paired specimens were consistent with the unpaired patients, while the CD8 to CD4 ratio remained constant from diagnosis to recurrence in the paired tissues. The levels of TILs and macrophages at initial diagnosis did not correlate with OS. TILs and macrophages were increased in recurrent tumors both in intratumoral and perivascular areas, with higher distribution levels in intratumoral than perivascular regions. Higher CD4 or CD8 infiltration at recurrence was associated with worse prognosis, respectively. Conclusion: Our study elucidated that TIL and TAM tend to accumulate in perivascular region and are more abundant in recurrent GBM than newly diagnosed GBM.

scholarly journals SURG-25. EFFECT OF VENTRICULAR ENTRY DURING GLIOBLASTOMA RESECTION ON PATIENT OUTCOMES

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii209-ii209
Author(s):  
Jacob Young ◽  
Andrew Gogos ◽  
Matheus Pereira ◽  
Ramin Morshed ◽  
Jing Li ◽  
...  
Keyword(s):  
Extent Of Resection ◽  
Tumor Location ◽  
Senior Author ◽  
Recurrent Glioblastoma ◽  
Leptomeningeal Disease ◽  
Newly Diagnosed ◽  
Ventriculoperitoneal Shunting ◽  
Two Factors ◽  
Postoperative Hydrocephalus

Abstract BACKGROUND Tumor proximity to the ventricle and ventricular entry (VE) during surgery have both been associated with poorer prognoses; however, the interaction between these two factors is poorly understood. METHODS The UCSF tumor registry was searched for patients with newly diagnosed and recurrent supratentorial glioblastoma who underwent surgical resection with the senior author between 2013 – 2018. Tumor location with respect to the subventricular zone (SVZ), size, VE, and extent of resection were assessed using pre and postoperative imaging. RESULTS In the 200-patient cohort of newly diagnosed and recurrent glioblastoma, 26.5% had VE. Comparing patients with VE to those without VE, there was no difference in postoperative hydrocephalus (1.9% vs. 4.8%, p = 0.36), ventriculoperitoneal shunting (0% vs. 3.4%, p = 0.17), pseudomeningoceles (7.5% vs. 5.4%, p = 0.58), or subdural hematomas (11.3% vs. 3.4%, p = 0.07). Importantly, rates of leptomeningeal disease (7.5% in VE vs. 10.2% w/o VE, p = 0.57) and distant parenchymal recurrence (17.9% in VE vs. 23.1% w/o VE, p = 0.35) were not different between the groups. There was no effect of VE on EOR when controlling for SVZ type. Newly diagnosed patients with tumors contacting the SVZ (Type 1 or 2) had worse survival than patients with tumors that did not contact the SVZ (Type 3 or 4) (1.27 vs 1.84 years, p = 0.014, HR 1.8, CI 1.08 – 3.03), but VE was not associated with worse survival in these patients with high risk SVZ Type 1 and 2 tumors (1.15 vs 1.68 years, p = 0.151, HR 0.59, CI 0.26 – 1.34). DISCUSSION VE was well tolerated with complications being rare events. There was no increase in leptomeningeal spread or distant parenchymal recurrence in patients with VE. Finally, VE did not change survival for patients with tumors contacting the ventricle.

scholarly journals Machine-Learning-Based Radiomics MRI Model for Survival Prediction of Recurrent Glioblastomas Treated with Bevacizumab

Diagnostics ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 1263
Author(s):  
Samy Ammari ◽  
Raoul Sallé de Chou ◽  
Tarek Assi ◽  
Mehdi Touat ◽  
Emilie Chouzenoux ◽  
...  
Keyword(s):  
Machine Learning ◽  
Therapeutic Option ◽  
Binary Classification ◽  
Progression Free Survival ◽  
Recurrent Glioblastoma ◽  
Machine Learning Algorithms ◽  
Survival Prediction ◽  
Classification Models ◽  
Angiogenic Therapy ◽  
Recurrent Gbm

Anti-angiogenic therapy with bevacizumab is a widely used therapeutic option for recurrent glioblastoma (GBM). Nevertheless, the therapeutic response remains highly heterogeneous among GBM patients with discordant outcomes. Recent data have shown that radiomics, an advanced recent imaging analysis method, can help to predict both prognosis and therapy in a multitude of solid tumours. The objective of this study was to identify novel biomarkers, extracted from MRI and clinical data, which could predict overall survival (OS) and progression-free survival (PFS) in GBM patients treated with bevacizumab using machine-learning algorithms. In a cohort of 194 recurrent GBM patients (age range 18–80), radiomics data from pre-treatment T2 FLAIR and gadolinium-injected MRI images along with clinical features were analysed. Binary classification models for OS at 9, 12, and 15 months were evaluated. Our classification models successfully stratified the OS. The AUCs were equal to 0.78, 0.85, and 0.76 on the test sets (0.79, 0.82, and 0.87 on the training sets) for the 9-, 12-, and 15-month endpoints, respectively. Regressions yielded a C-index of 0.64 (0.74) for OS and 0.57 (0.69) for PFS. These results suggest that radiomics could assist in the elaboration of a predictive model for treatment selection in recurrent GBM patients.

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