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.

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 HGG-36. HIF-2: A NEW DRUG TARGET IN PEDIATRIC HIGH-GRADE GLIOMA WITH PROMISING PRECLINICAL RESULTS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii350-iii350
Author(s):  
Quentin Fuchs ◽  
Marina Pierrevelcin ◽  
Christophe Papin ◽  
Monique Dontenwill ◽  
Natacha Entz-Werlé
Keyword(s):  
Drug Testing ◽  
Treatment Resistance ◽  
High Grade Glioma ◽  
Clinical Work ◽  
Driver Mutations ◽  
High Grade ◽  
Innovative Strategy ◽  
Dismal Prognosis ◽  
Cell Arrest ◽  
And Migration

Abstract Pediatric high-grade gliomas (pHGGs) have a very dismal prognosis and need new innovative strategy for treatment. Despite the past discovery of histone H3 driver mutations, we are not able for instance to stop this induced epigenetic remodulation. Therefore, proactive translational studies wish to go further discovering new targetable proteins in pHGG. In our past clinical work, we were able to link significantly HIF-2alpha to a worse pHGG outcome and to their treatment resistance. We designed this new work to determine in several patient-derived cell lines (6 PDCLs) with or without H3.3 mutation the variation of HIF-2alpha, its role, its induction in normoxic and hypoxic microenvironment and its transcriptional targets using RNAseq, metabolomics and ChipSeq analyses. Complementary functional analyses were performed using siRNA strategy during cultures and migration assays. Finally, preclinical drug testing involving commercialized and non-commercialized HIF-2alpha specific inhibitors in the same PDCLs were evaluating their antiproliferative and pro-apoptotic effect. Our results confirmed the central role of HIF-2alpha in cell resistance to treatment, in pHGG stemness features and its direct link with metabolism adaptation and histone interaction. After the confirmation of its frequent presence in multiple PDCLs initiated from thalamic pHGGs and DIPG, we were using inhibitors in a single and combinatorial strategy targeting HIF-2alpha plus another hypoxia biomarker (mTor). This preclinical targeting was highly effective to favor cell arrest, apoptosis and to stop cell migration. In conclusion, HIF-2alpha seem to be a major biomarker in pHGGs that might be targeted giving a useful new opportunity for pHGG treatments.

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 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.

scholarly journals H3K27M and TERT Promoter Mutations Are Poor Prognostic Factors in Surgical Cases of Adult Thalamic High-Grade Glioma

2021 ◽  
Author(s):  
Yoshinari Osada ◽  
Ryuta Saito ◽  
Ichiyo Shibahara ◽  
Keisuke Sasaki ◽  
Takuhiro Shoji ◽  
...  
Keyword(s):  
Prognostic Significance ◽  
Progression Free Survival ◽  
High Grade Glioma ◽  
Molecular Characteristics ◽  
High Grade ◽  
Wild Type ◽  
Target Sequencing ◽  
Dismal Prognosis ◽  
Tert Promoter Mutations ◽  
Promoter Mutations

Abstract Background Thalamic high-grade gliomas (HGGs) are rare tumors with a dismal prognosis. H3K27M and telomerase reverse transcriptase promoter (TERTp) mutations reportedly contribute to poor prognoses in HGG cases. We investigated the outcomes of surgically treated adult thalamic HGGs to evaluate the prognostic significance of H3K27M and TERTp mutations. Methods We retrospectively analyzed 25 adult patients with thalamic HGG who underwent maximum surgical resection from January 1997 to March 2020. The histological and molecular characteristics, progression-free survival (PFS), and overall survival (OS) of the patients were compared. For molecular characteristics, target sequencing was used to determine the H3F3A, HIST1H3B, and TERTp mutations. Results H3K27M mutations were detected in 12/25 (48.0%) patients. TERTp mutations were not detected in H3K27M-mutant gliomas but were detected in 8/13 (61.5%) of H3 wild-type gliomas. Although it was not significant, H3K27M-mutant gliomas tended to have a shorter PFS (6.7 vs. 13.1 months; P = 0.2928) and OS (22.8 vs. 24.4 months; P = 0.2875) than H3 wild-type gliomas. Moreover, the prognosis of TERTp-mutant gliomas was as poor as that of H3K27M-mutant gliomas. Contrary, five gliomas harboring both H3 and TERTp wild-type showed a better median PFS (59.2 vs. 6.4 months; P = 0.0456) and OS (71.8 vs. 24.4 months; P = 0.1168) than those harboring H3K27M or TERTp mutations. Conclusions TERTp-mutant gliomas included in the H3 wild-type glioma group limited patient survival as they exhibited an aggressive course similar to H3K27M-mutant gliomas. Comprehensive molecular work-up for the H3 wild-type cases may further confirm this finding.

scholarly journals Successful Treatment of Severe Type B Lactic Acidosis in a Patient with HIV/AIDS-Associated High-Grade NHL

2018 ◽  
Vol 2018 ◽  
pp. 1-4 ◽  
Author(s):  
Marco Mejia ◽  
Ariel Perez ◽  
Harold Watson ◽  
Daniel Sanchez ◽  
Jorge Parellada ◽  
...  
Keyword(s):  
Lactic Acidosis ◽  
Abdominal Mass ◽  
B Cell Lymphoma ◽  
Complete Response ◽  
Hematologic Malignancies ◽  
High Grade ◽  
Type B ◽  
Tissue Mass ◽  
Dismal Prognosis ◽  
Metabolic Complication

Type B lactic acidosis is a rare metabolic complication sometimes associated with hematologic malignancies. When present, this type of lactic acidosis is most commonly seen in patients with high-grade lymphomas or leukemias and is usually indicative of a dismal prognosis. We report a case of a 27-year man with acquired immunodeficiency syndrome (AIDS) that presented with bilateral lower extremity swelling, an abdominal mass, and weight loss. His lab values showed elevated anion gap with lactic acidosis and computed tomography (CT) of the abdomen showed a large soft-tissue mass arising from the left hepatic lobe. Biopsy of the abdominal mass demonstrated a high-grade diffuse large B-cell lymphoma. The patient’s lactic acidosis resolved after starting chemotherapy, and a complete response was evident on PET-CT after a third cycle of rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (EPOC-RR). Care-givers should be aware of the implications of lactic acidosis associated with malignancy and the need for prompt diagnosis and treatment.

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.

scholarly journals P03.10 Analyzing the role of reoperation in high grade gliomas: a retrospective study

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii27-iii27
Author(s):  
V González ◽  
J Ibáñez ◽  
J Fuster ◽  
M Brell
Keyword(s):  
Clinical Condition ◽  
Progression Free Survival ◽  
High Grade Glioma ◽  
Primary Treatment ◽  
Recurrent Glioblastoma ◽  
High Grade ◽  
Free Survival ◽  
Second Surgery ◽  
Good Clinical Condition

Abstract BACKGROUND Primary treatment of high grade glioma consists in a standard therapeutic regimen that involves maximal surgical safe resection followed by chemoradiotherapy. Unfortunately, due to its aggressive behavior, relapse is the rule in all patients. When this situation arises, treatment strategy is less clear and reintervention in selected cases is controversial and still a reason for debate. MATERIAL AND METHODS We retrospectively analysed (n=393) patients affected with high grade glioma in our institution during a period of 14 years (from January 2005 to March 2019). Treatment modality at diagnosis and recurrence, overall and progression-free survival were reviewed. RESULTS There were 320 grade IV and 73 grade III gliomas. Regarding to the modality of treatment, more procedures with radical intention (n=227) than biopsies (n=166) were performed. At progression, glioblastoma patients were treated in (n=118) cases. We decided to reoperate (n=30) cases who also received second-line chemotherapies.The other group (n=88) received only systemic treatment. Median overall survival assessed from initial diagnosis was 23 months(95% CI 17–28.9) versus 17 months (95% CI 15.7–18.2) in patients with surgery at recurrence comparing to those who did not undergo second surgery, (p< 0.05). In addition, clinical condition of most patients did not worsen after the second surgery. CONCLUSION Second surgery for recurrent glioblastoma was associated with a survival advantage. Reoperation should be considered in patients with tumours located in low eloquence areas and good clinical condition.

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