BIOM-22. RELEVANCE OF TUMOR MUTATION BURDEN (TMB) IN HIGH-GRADE GLIOMAS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi15-vi15
Author(s):  
Hagai Ligumsky ◽  
Deborah Blumenthal ◽  
Felix Bokstein
Keyword(s):  
Medical Center ◽  
High Grade Glioma ◽  
Complete Response ◽  
Recurrent Glioblastoma ◽  
High Grade ◽  
Glial Tumors ◽  
Mmr Genes ◽  
Mutation Burden ◽  
History Of ◽  
Primary Glioma

Abstract BACKGROUND Efforts have been directed toward searching for molecular biomarkers predicting response to immunotherapy in glial tumors. Recently, FDA granted accelerated approval of pembrolizumab for treatment patients with solid tumors with high mutational burden (TMB-H; ≥ 10 mut/Mb). There are conflicting results regarding the use of this parameter in glial tumors. OBJECTIVE to review NGS examinations of patients with glial tumors and high TMB and to analyze their response to immunotherapy. METHODS we retrospectively reviewed NGS examinations from patients with glial tumors treated in Tel-Aviv Medical Center from 2016-2021. Cases with TMB-H were retrieved and analyzed. RESULTS We identified nine high-grade glioma patients with TMB-H. The median age was 38 (19-65). There were 4 patients with glioblastoma; three with anaplastic oligodendroglioma; and two with anaplastic astrocytoma. All but one received radiation prior to the biopsy used for NGS examination, and all were treated with temozolomide. The median TMB was 54 (19-252). Only one glioblastoma patient with a family history of Lynch syndrome had microsatellite instability (MSI)-high; all other patients were MSI stable (MSS). Nevertheless, in all cases, mutated mismatch repair (MMR) genes were detected (MSH6 in 3 patients, MSH2 in one patient, MLH1 in one patient, PMS 2 in one patient, and both MSH2 and 6 in one patient). Six patients received immunotherapy. Only one patient with recurrent glioblastoma and the highest TMB in the group (252) demonstrated a near complete response to pembrolizumab and remains on treatment more than three years. All other patients did not respond to immunotherapy. CONCLUSION TMB-H in primary glioma is associated with mutations of MMR genes. It is typically associated with MSS in these patients (MSI-high was seen in only one syndromic patient). In contrast to systemic neoplasms with TMB-H, the majority of our patients did not respond to immunotherapy.

scholarly journals A Pilot Study of Vaccine Therapy with Multiple Glioma Oncoantigen/Glioma Angiogenesis-Associated Antigen Peptides for Patients with Recurrent/Progressive High-Grade Glioma

2019 ◽  
Vol 8 (2) ◽  
pp. 263 ◽  
Author(s):  
Ryogo Kikuchi ◽  
Ryo Ueda ◽  
Katsuya Saito ◽  
Shunsuke Shibao ◽  
Hideaki Nagashima ◽  
...  
Keyword(s):  
T Lymphocyte ◽  
High Grade Glioma ◽  
Complete Response ◽  
Recurrent Glioblastoma ◽  
Vaccine Therapy ◽  
High Grade ◽  
Peptide Epitopes ◽  
Dismal Prognosis ◽  
Multiple Glioma ◽  
Lymphocyte Responses

High-grade gliomas (HGGs) carry a dismal prognosis despite current treatments. We previously confirmed the safety and immunogenicity of a vaccine treatment targeting tumor angiogenesis with synthetic peptides, for vascular endothelial growth factor receptor (VEGFR) epitopes in recurrent HGG patients. In this study, we evaluated a novel vaccine therapy targeting not only tumor vasculature but also tumor cells, using multiple glioma oncoantigen (GOA)/glioma angiogenesis-associated antigen (GAAA) peptides in HLA-A2402+ recurrent/progressive HGG patients. The vaccine included peptide epitopes from four GOAs (LY6K, DEPDC1, KIF20A, and FOXM1) and two GAAAs (VEGFR1 and VEGFR2). Ten patients received subcutaneous vaccinations. The primary endpoint was the safety of the treatment. T-lymphocyte responses against GOA/GAAA epitopes and treatment response were evaluated secondarily. The treatment was well tolerated without any severe systemic adverse events. The vaccinations induced immunoreactivity to at least three vaccine-targeted GOA/GAAA in all six evaluable patients. The median overall survival time in all patients was 9.2 months. Five achieved progression-free status lasting at least six months. Two recurrent glioblastoma patients demonstrated stable disease. One patient with anaplastic oligoastrocytoma achieved complete response nine months after the vaccination. Taken together, this regimen was well tolerated and induced robust GOA/GAAA-specific T-lymphocyte responses in recurrent/progressive HGG patients.

scholarly journals Hypofractionated Stereotactic Re-Irradiation with Pembrolizumab and Bevacizumab in Patients with Recurrent High Grade Gliomas: Results from a Phase 1 Study

2020 ◽  
Author(s):  
Solmaz Sahebjam ◽  
Peter A Forsyth ◽  
Nam D Tran ◽  
John A Arrington ◽  
Robert Macaulay ◽  
...  
Keyword(s):  
Phase 1 ◽  
Progression Free Survival ◽  
Complete Response ◽  
Recurrent Glioblastoma ◽  
High Grade ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
High Grade Gliomas ◽  
Grade 3 ◽  
Recommended Phase Ii Dose

Abstract Background Radiotherapy may synergize with programmed death 1 (PD-1)/PD-1 ligand (PD-L1) blockade. The purpose of this study was to determine the recommended Phase II dose, safety/tolerability, and preliminary efficacy of combining pembrolizumab, an anti-PD-1 monoclonal antibody, with hypofractionated stereotactic irradiation (HFSRT) and bevacizumab in patients with recurrent high grade gliomas (HGGs). Methods Eligible subjects with recurrent glioblastoma or anaplastic astrocytoma were treated with pembrolizumab (100 or 200 mg based on dose level Q3W) concurrently with HFSRT (30 Gy in 5 fractions) and bevacizumab 10 mg/kg Q2W. Results Thirty two patients were enrolled (bevacizumab naïve, n = 24; bevacizumab resistant, n = 8). The most common treatment-related adverse events (TRAEs) were proteinuria (40.6%), fatigue (25%), increased alanine aminotransferase (25%), and hypertension (25%). TRAEs leading to discontinuation occurred in 1 patient who experienced a grade 3 elevation of aspartate aminotransferase. In the bevacizumab naïve cohort, twenty patients (83%) had a complete response (CR) or partial response (PR). The median overall survival (OS) and progression-free survival (PFS) were 13.45 months (95% CI: 9.46-18.46) and 7.92 months (95% CI: 6.31-12.45), respectively. In the bevacizumab resistant cohort, PR was achieved in 5 patients (62%). Median OS was 9.3 months (95% CI: 8.97-18.86) with a median PFS of 6.54 months (95% CI: 5.95-18.86). The majority of patients (20/26 pts; 77%) had tumor-cell/tumor-microenvironment PD-L1 expression <1%. Conclusions The combination of HFSRT with pembrolizumab and bevacizumab in patients with recurrent HGG is generally safe and well tolerated. These findings merit further investigation of HFSRT with immunotherapy in HGGs.

Current Concepts in Brain Tumor Imaging

2012 ◽  
pp. 119-124
Author(s):  
Andrew D. Norden ◽  
Whitney B. Pope ◽  
Susan M. Chang
Keyword(s):  
Standard Treatment ◽  
Tumor Imaging ◽  
High Grade Glioma ◽  
Response Assessment ◽  
Recurrent Glioblastoma ◽  
High Grade ◽  
Resonance Imaging ◽  
Imaging Tool ◽  
Magnetic Resonance Imaging Mri ◽  
New Criteria

Overview: Magnetic resonance imaging (MRI) is the most useful imaging tool in the evaluation of patients with brain tumors. Most information is supplied by standard anatomic images that were developed in the 1980s and 1990s. More recently, functional imaging including diffusion and perfusion MRI has been investigated as a way to generate predictive and prognostic biomarkers for high-grade glioma evaluation, but additional research is needed to establish the added benefits of these indices to standard MRI. Response critieria for high-grade gliomas have recently been updated by the Response Assessment in Neuro-Oncology (RANO) working group. The new criteria account for nonenhancing tumor in addition to the contrast-enhancing abnormalities on which older criteria relied. This issue has recently come to the fore with the introduction of the antiangiogenic agent bevacizumab into standard treatment for recurrent glioblastoma. Because of its potent antipermeability effect, contrast enhancement is markedly reduced in patients who receive bevacizumab. The RANO criteria also address the phenomenon of pseudoprogression, in which there may be transient MRI worsening of a glioblastoma following concurrent radiotherapy and temozolomide.

scholarly journals Management of Locally Advanced Esthesioneuroblastoma in a Pregnant Woman

2019 ◽  
Vol 2019 ◽  
pp. 1-5
Author(s):  
Inês Maria Guerreiro ◽  
Cláudia Vieira ◽  
André Soares ◽  
António Braga ◽  
Manuel Jácome ◽  
...  
Keyword(s):  
Pregnant Woman ◽  
Nasal Obstruction ◽  
Standard Treatment ◽  
Combined Treatment ◽  
Locally Advanced ◽  
Cervical Lymphadenopathy ◽  
Complete Response ◽  
High Grade ◽  
History Of ◽  
Worse Prognosis

Esthesioneuroblastoma (ENB) is a rare malignant tumor that commonly develops in the upper nasal cavity. Standard treatment is not established, especially in locally advanced disease which portends the worse prognosis. Hereby, we report a case of a 27-year-old, 23-week pregnant woman, with a 2-month history of progressively growing right cervical lymphadenopathy, nasal obstruction, anosmia, frequent episodes of epistaxis, and right frontal headache. Imagiological evaluation revealed a lesion with 7×5,2×3,2 cm in the nasal fossae with extension to the ethmoidal complex and right olfactive fend and invasion of the endocranial compartment associated with lymphadenopathy. The biopsy revealed a high-grade EBN. Neoadjuvant chemotherapy with cisplatin and etoposide was administrated during pregnancy and continued after delivery up to 6 cycles of treatment with partial response. Radiotherapy followed, with complete response. This case report is intended to highlight that a high grade of suspicion should be kept in the presence of nonspecific symptoms of nasal obstruction, anosmia, facial pain, and/or headache and focus that chemotherapy is an important component of a combined-treatment modality for locally advanced ENB that can be used during pregnancy in a lifesaving situation.

scholarly journals Bevacizumab in recurrent high-grade glioma: a single institution retrospective analysis on 92 patients

2021 ◽  
Author(s):  
Beatrice Detti ◽  
Silvia Scoccianti ◽  
Maria Ausilia Teriaca ◽  
Virginia Maragna ◽  
Victoria Lorenzetti ◽  
...  
Keyword(s):  
Recurrent Disease ◽  
Performance Status ◽  
High Grade Glioma ◽  
Recurrent Glioblastoma ◽  
High Grade ◽  
Two Phase ◽  
Primary Tumors ◽  
Entire Cohort ◽  
Bevacizumab Treatment ◽  
High Grade Gliomas

Abstract Background High-grade gliomas are among the most aggressive central nervous system primary tumors, with a high risk of recurrence and a poor prognosis. Re-operation, re-irradiation, chemotherapy are options in this setting. No-best therapy has been established. Bevacizumab was approved on the basis of two Phase 2 trials that evaluated its efficacy in patients with recurrent glioblastoma. Materials and methods We have retrospectively review data of patients with high-grade glioma treated at our institution that undergone radiological or histological progression after at least one systemic treatment for recurrent disease. Bevacizumab was administered alone or in combination with chemotherapy until disease progression or unacceptable toxicity. Bevacizumab regimen was analyzed to assess PFS and OS. Histological, molecular and clinical features of the entire cohort were collected. Results We reviewed data from 92 patients, treated from April 2009 to November 2019, with histologically confirmed diagnosis of high-grade gliomas and recurrent disease. A PFS of 55.2%, 22.9% and 9.6% was observed at 6, 12 and 24 months, respectively. Performance status, age at diagnosis (< 65 or > 65 ys.) and use of corticosteroids during bevacizumab therapy were strongly associated with PFS. The OS was 74.9% at 6 months, 31.7% at 12 months, 10.1% at 24 months. In our cohort, 51.1% were long-term responders (PFS > 6 months). Globally, bevacizumab treatment was well tolerated. Conclusion Our analysis confirms the efficacy of bevacizumab in recurrent high-grade glioma patients with an acceptable toxicity profile, in keeping with its known safety in the literature.

Correlation of PD-L1 with VEGF and KI-67 index in patients with primary glioma.

2017 ◽  
Vol 35 (7_suppl) ◽  
pp. 94-94
Author(s):  
Song Xue ◽  
Man Hu ◽  
Jinming Yu ◽  
Bingjie Fan ◽  
Ji Ma
Keyword(s):  
Immune Escape ◽  
Treatment Strategies ◽  
High Grade Glioma ◽  
Continuous Variable ◽  
Low Grade ◽  
High Grade ◽  
Grade Group ◽  
Ki 67 ◽  
Primary Glioma ◽  
The Mean

94 Background: The treatment strategies for glioma, especially glioblastoma multiforme, are not effective. The programmed death ligand 1 (PD-L1) immune escape and increased angiogenesis may be two of the underlying sources of treatment resistance. However, the relationship between these pathways in human glioma is still unknown. Methods: Data for 64 patients with primary glioma recorded from June 2007 to December 2013 in Shan Dong Cancer Hospital were immunohistochemically evaluated for the expressions of PD-L1, VEGF, MMP-9 and KI-67 index. Image ProPlus software was used to quantify the mean optical density (MOD) of the immunohistochemical image. Results: PD-L1 expression was observed in 65.22% of low-grade glioma and 90.24% of high-grade glioma, respectively. The whole expression rate of PD-L1 in glioma was 81.25%. The expression of PD-L1 is significantly related to pathological grade ( p <0.001), VEGF ( p= 0.017) and KI-67 index ( p= 0.009). The mean of PD-L1 MOD in High-grade group was 0.1144±0.02754, higher than that in low-grade group, 0.005129±0.001441 ( p= 0.004). In addition, Expression of VEGF, MMP-9 and KI-67 was significantly different between low-grade and high-grade gliomas ( p= 0.008, 0.04, 0.004 for VEGF, MMP-9 and KI-67, respectively). When analyzed as a continuous variable, the expressions of PD-L1 was positively correlated with VEGF (r = 0.392, p= 0.001) and KI-67 (r = 0.388, p= 0.001). Conclusions: These data suggest, for the first time, that PD-L1 play an important role in glioma angiogenesis and proliferation potential, providing the possibility for considering additional combinations of targeted VEGF therapies and anti-PD-L1 immunotherapy for the treatment of human brain glioma.

scholarly journals High-Grade Glioma of the Ventrolateral Medulla in an Adult: Case Presentation and Discussion of Surgical Considerations

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Angela Spurgeon ◽  
Viet Le ◽  
Sanjay Konakondla ◽  
Douglas C. Miller ◽  
Tamera Hopkins ◽  
...  
Keyword(s):  
Multimodality Treatment ◽  
High Grade Glioma ◽  
Lateral Approach ◽  
Ventrolateral Medulla ◽  
Illustrative Case ◽  
High Grade ◽  
Lower Extremity Weakness ◽  
Far Lateral Approach ◽  
History Of ◽  
Long Term Prognosis

Background. High-grade gliomas of the brainstem are rare in adults and are particularly rare in the anterolateral medulla. We describe an illustrative case and discuss the diagnostic and treatment issues associated with a tumor in this location, including differential diagnosis, anatomical considerations for options for surgical management, multimodality treatment, and prognosis.Case Description. A 69-year-old woman presented with a 3-week history of progressive right lower extremity weakness. She underwent an open biopsy via a far lateral approach with partial condylectomy, which revealed a glioblastoma. Concurrent temozolomide and radiation were completed; however, she elected to stop her chemotherapy after 5.5 weeks of treatment. She succumbed to her disease 11 months after diagnosis.Conclusions. Biopsy can be performed relatively safely to provide definitive diagnosis to guide treatment, but long-term prognosis is poor.

scholarly journals HGG-49. A PEDIATRIC THALAMIC HIGH-GRADE GLIOMA WITH H3F3A K27M AND BRAF V600E DOUBLE MUTATIONS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii352-iii352
Author(s):  
Keita Terashima ◽  
Masahiro Sugawa ◽  
Kenichi Sakamoto ◽  
Chikako Kiyotani ◽  
Tomoo Osumi ◽  
...  
Keyword(s):  
High Grade Glioma ◽  
Endoscopic Biopsy ◽  
Braf V600e ◽  
Small Cells ◽  
Molecular Testing ◽  
Histopathological Diagnosis ◽  
High Grade ◽  
Ki 67 ◽  
History Of ◽  
Mri Study

Abstract CASE A 18-month-old boy presented with approximately 2 months history of progressive left hemiparesis and left exotropia. MRI study showed a 3–4 cm T1-iso, T2-high tumor at right thalamus to midbrain with little contrast enhancement. The patient underwent endoscopic biopsy of the tumor, which showed relatively dense proliferation of small cells with round nuclei, mitosis of the tumor cell, but no necrosis. Immunohistochemical showed positive stain of GFAP and Olig2. Ki-67 was 34%. The histopathological diagnosis was compatible with high grade glioma. Chemotherapy with vincristine, cyclophosphamide, cisplatin and etoposide was initiated. Molecular testing of the tumor revealed H3F3A K27M and BRAF V600E double mutations in DNA from frozen tumor tissue. DISCUSSION The concurrent mutation of H3F3A K27M and BRAF V600E in pediatric glioma is very rare, but there are several cases previously reported in literature. Interestingly those cases are heterogenous in age, location, histopathological subtypes and clinical outcome.

Mechlorethamine, vincristine, and procarbazine chemotherapy for recurrent high-grade glioma in adults: a phase II study.

1990 ◽  
Vol 8 (12) ◽  
pp. 2014-2018 ◽  
Author(s):  
T Coyle ◽  
J Baptista ◽  
J Winfield ◽  
K Clark ◽  
B Poiesz ◽  
...  
Keyword(s):  
Phase Ii ◽  
Response Rate ◽  
Phase Ii Study ◽  
Performance Status ◽  
Pneumocystis Carinii ◽  
High Grade Glioma ◽  
Complete Response ◽  
High Grade ◽  
Computed Tomographic ◽  
Improved Performance

We undertook a phase II study of combination chemotherapy with mechlorethamine (nitrogen mustard) 6 mg/m2 intravenously day 1 and day 8, vincristine 2 mg intravenously day 1 and day 8, and procarbazine 100 mg/m2 orally days 1 through 14 (MOP) in adults with recurrent high-grade glioma. There were 31 patients entered and 27 patients assessable for response. The median age was 49 years old. All patients had prior maximal radiotherapy, and eight had previous chemotherapy. Responses were determined based on clinical and computed tomographic (CT) scan/magnetic resonance imaging (MRI) criteria. The response rate (partial response [PR] plus objective qualitative response [OQR] plus complete response [CR]) was 52% with one CR. The response rate was higher in patients with anaplastic astrocytoma as compared with glioblastoma multiforme (P less than .05). The median duration of response was 42 weeks. Median survival for all assessable patients was 30 weeks, and for responders, it was 60 weeks. Response was correlated with ability to decrease dexamethasone doses and improved performance status. Toxicity was mainly hematologic with leukopenia being common. There was one treatment-related death from listeria meningitis, and two patients developed Pneumocystis carinii pneumonia. There were three episodes of neutropenic fever. We conclude that MOP is active and merits further investigation in adult high-grade glioma.

scholarly journals Bevacizumab in high-grade glioma patients following intraparenchymal hemorrhage

2016 ◽  
Vol 4 (1) ◽  
pp. 24-28 ◽  
Author(s):  
Xuling Lin ◽  
Mariza Daras ◽  
Elena Pentsova ◽  
Craig P. Nolan ◽  
Igor T. Gavrilovic ◽  
...  
Keyword(s):  
Risk Factors ◽  
Therapeutic Option ◽  
Treatment Options ◽  
High Grade Glioma ◽  
Recurrent Glioblastoma ◽  
Anaplastic Oligodendroglioma ◽  
High Grade ◽  
Intraparenchymal Hemorrhage ◽  
Grade 3 ◽  
Poor Functional Status

AbstractBackgroundIntraparenchymal hemorrhage (IPH) is a relative contraindication to bevacizumab therapy, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody approved for the treatment of recurrent glioblastoma. However, in patients with symptomatic enhancing tumors and poor functional status, bevacizumab may be the only beneficial therapeutic option.MethodsWe retrospectively reviewed all patients with high-grade glioma who were treated between January 1, 2005 and December 31, 2014 with bevacizumab despite prior IPH.ResultsEighteen patients met our study criteria. There were 12 women and 6 men with a median age of 56 years. Tumor types were glioblastoma (n = 15), anaplastic astrocytoma (n = 2), and anaplastic oligodendroglioma (n = 1). Seventeen patients had prior spontaneous intratumoral bleed (13 grade 1–2; 4 grade 3–4); the 1 remaining patient had a grade 3 bleed due to cerebral venous thrombosis. Among them, identifiable risk factors for hemorrhage were anti-VEGF therapy, anticoagulation use, thrombocytopenia, and hypertension; seven had no identifiable risk factors. The median duration from IPH to (re-)initiation of bevacizumab was 113 days (range 13–1367). Brain imaging performed prior to bevacizumab treatment showed persistent or evolving hemorrhage in 8 patients and complete resolution in 10 patients. With a median follow-up duration of 137 days after bevacizumab re-initiation, only 1 (6%) of the 18 patients re-bled; this patient had an anaplastic oligodendroglioma and developed a grade 2 intratumoral bleed after 3 doses of bevacizumab.ConclusionsThe incidence of re-bleed is rare. Bevacizumab use was safe in patients with recurrent high-grade glioma following IPH for whom no other meaningful treatment options existed.

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