scholarly journals ACT-18 SHOULD THE DOSE OF TEMOZOLOMIDE BE DECREASED FOR PATIENTS WITH HIGH-GRADE GLIOMAS WHO ARE ON HEMODIALYSIS?

2019 ◽  
Vol 1 (Supplement_2) ◽  
pp. ii15-ii15
Author(s):  
Jun Muto ◽  
Tomoo Matsutani ◽  
Ryosuke Matsuda ◽  
Masashi Kinoshita ◽  
Mitsuteru Oikawa ◽  
...  
Keyword(s):  
Adverse Events ◽  
High Grade Glioma ◽  
Similar Rate ◽  
Hemodialysis Patients ◽  
The Body ◽  
Study Patient ◽  
Treatment Schedule ◽  
High Grade ◽  
Concomitant Radiochemotherapy ◽  
High Grade Gliomas

Abstract BACKGROUND The pharmacokinetics of temozolomide in patients with severe renal impairments (creatinine clearance less than 36 mL/min/m2) or in hemodialysis patients has not been investigated. Temozolomide and its metabolic products are mainly excreted in urine, as retention of these in the body may result in increased adverse events in hemodialysis patients harboring a high-grade glioma. METHODS Eight hemodialysis patients with high-grade gliomas from seven institutions were included in the study. Patient characteristics, treatment schedule, clinical course, pathological/molecular findings, and adverse events were evaluated. RESULTS The histopathological diagnoses were Isocitrate dehydrogenase (IDH) wild-type glioblastoma in four cases, Not other specified (NOS) glioblastoma in two cases and IDH-mutant anaplastic astrocytoma in one case. Five of the seven patients completed radiotherapy (48–60 Gy) with concomitant temozolomide (75 mg/m2) followed by adjuvant 5-day temozolomide (150 mg/m2) every 28 days. During the entire course of treatment with temozolomide, severe (Common Terminology Criteria for Adverse Events (CTCAE) more than grade 3) lymphocytopenia occurred in 57%(41.7–61%: non hemodialysis patients data, the same as below), neutropenia in 0%(1–15.4%) and thrombocytopenia in 14%(0–16.7%) of the patients. Generally, the frequency and degree of myelosuppression do not increase in hemodialysis patients with high-grade gliomas. Two of the seven (28.5%) patients died of infectious disease despite having no direct correlation to myelosuppression that is similar rate of 21.9% of the death results from infection in hemodialysis patients in Japan. CONCLUSIONS The high-grade glioma patients under study on hemodialysis did not require decreasing doses of Temozolomide during concomitant radiochemotherapy and maintenance therapy. However, careful clinical and hematological observation is required to avoid critical hematotoxicity and infection.

scholarly journals Temozolomide radiochemotherapy for high-grade glioma patients with hemodialysis: a case series of 7 patients

2019 ◽  
Vol 7 (1) ◽  
pp. 111-117 ◽  
Author(s):  
Jun Muto ◽  
Tomoo Matsutani ◽  
Ryosuke Matsuda ◽  
Masashi Kinoshita ◽  
Mitsuteru Oikawa ◽  
...  
Keyword(s):  
Adverse Events ◽  
Case Series ◽  
High Grade Glioma ◽  
Patient Characteristics ◽  
The Body ◽  
Study Patient ◽  
Treatment Schedule ◽  
High Grade ◽  
Concomitant Radiochemotherapy ◽  
High Grade Gliomas

Abstract Background The pharmacokinetics of temozolomide (TMZ) in patients with severe renal impairments (creatinine clearance, <36 mL/min/m2) or in hemodialysis (HD) patients has not been investigated. TMZ and its metabolic products are mainly excreted in urine, as retention of these in the body may result in increased adverse events in HD patients. Methods Seven HD patients with high-grade gliomas from 6 institutions were included in the study. Patient characteristics, treatment schedule, clinical course, pathological/molecular findings, and adverse events were evaluated. Results The histopathological diagnoses were isocitrate dehydrogenase (IDH) wild-type glioblastoma in 4 cases, not other specified (NOS) glioblastoma in 2 cases, and IDH-mutant anaplastic astrocytoma in 1 case. Five of the 7 patients completed radiotherapy (48-60 Gy) with concomitant TMZ (75 mg/m2) followed by adjuvant 5-day TMZ (150 mg/m2) every 28 days. During the entire course of treatment with TMZ, severe (Common Terminology Criteria for Adverse Events [CTCAE] ≥ Grade 3) lymphocytopenia occurred in 57%, neutropenia in 0%, and thrombocytopenia in 14% of the patients. Generally, the frequency and degree of myelosuppression do not increase in HD patients with high-grade gliomas. Two of the 7 (28.5%) patients died of infectious disease despite having no direct correlation to myelosuppression; that is similar to the death rate of 21.9% resulting from infection in HD patients in Japan. Conclusions Decreasing the dose of TMZ might not be required in HD patients with high-grade gliomas during concomitant radiochemotherapy and maintenance therapy. However, careful clinical and hematological observation is required to avoid critical hematotoxicity and infection.

scholarly journals Against the Resilience of High-Grade Gliomas: The Immunotherapeutic Approach (Part I)

2021 ◽  
Vol 11 (3) ◽  
pp. 386
Author(s):  
Alice Giotta Lucifero ◽  
Sabino Luzzi
Keyword(s):  
Monoclonal Antibodies ◽  
Natural Killer ◽  
Immune Escape ◽  
Meta Analysis ◽  
Treatment Options ◽  
High Grade Glioma ◽  
High Grade ◽  
Future Challenges ◽  
Genetic Landscape ◽  
High Grade Gliomas

The resilience of high-grade gliomas (HGGs) against conventional chemotherapies is due to their heterogeneous genetic landscape, adaptive phenotypic changes, and immune escape mechanisms. Innovative immunotherapies have been developed to counteract the immunosuppressive capability of gliomas. Nevertheless, further research is needed to assess the efficacy of the immuno-based approach. The aim of this study is to review the newest immunotherapeutic approaches for glioma, focusing on the drug types, mechanisms of action, clinical pieces of evidence, and future challenges. A PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis)-based literature search was performed on PubMed/Medline and ClinicalTrials.gov databases using the keywords “active/adoptive immunotherapy,” “monoclonal antibodies,” “vaccine,” and “engineered T cell.”, combined with “malignant brain tumor”, “high-grade glioma.” Only articles written in English published in the last 10 years were selected, filtered based on best relevance. Active immunotherapies include systemic temozolomide, monoclonal antibodies, and vaccines. In several preclinical and clinical trials, adoptive immunotherapies, including T, natural killer, and natural killer T engineered cells, have been shown to be potential treatment options for relapsing gliomas. Systemic temozolomide is considered the backbone for newly diagnosed HGGs. Bevacizumab and rindopepimut are promising second-line treatments. Adoptive immunotherapies have been proven for relapsing tumors, but further evidence is needed.

scholarly journals Convection Enhanced Delivery in the Setting of High-Grade Gliomas

Pharmaceutics ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 561
Author(s):  
Chibueze D. Nwagwu ◽  
Amanda V. Immidisetti ◽  
Michael Y. Jiang ◽  
Oluwasegun Adeagbo ◽  
David C. Adamson ◽  
...  
Keyword(s):  
Rapid Development ◽  
Systemic Exposure ◽  
Therapeutic Index ◽  
High Grade Glioma ◽  
High Grade ◽  
Clinical Experiences ◽  
Convection Enhanced Delivery ◽  
Drug Concentrations ◽  
Infiltrative Growth Pattern ◽  
High Grade Gliomas

Development of effective treatments for high-grade glioma (HGG) is hampered by (1) the blood–brain barrier (BBB), (2) an infiltrative growth pattern, (3) rapid development of therapeutic resistance, and, in many cases, (4) dose-limiting toxicity due to systemic exposure. Convection-enhanced delivery (CED) has the potential to significantly limit systemic toxicity and increase therapeutic index by directly delivering homogenous drug concentrations to the site of disease. In this review, we present clinical experiences and preclinical developments of CED in the setting of high-grade gliomas.

CTNI-41. INITIAL RESULTS OF A PHASE I WINDOW OF OPPORTUNITY TRIAL EVALUATING A FIRST-IN-CLASS CD29 INHIBITOR, OS2966, IN RECURRENT HIGH-GRADE GLIOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi69-vi69
Author(s):  
James Liu ◽  
Chibueze D Nwagwu ◽  
Amanda V Immidisetti ◽  
Gabriela Bukanowska ◽  
Anne-Marie Carbonell ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
Tumor Resection ◽  
High Grade Glioma ◽  
Underlying Disease ◽  
Tissue Level ◽  
High Grade ◽  
Convection Enhanced Delivery ◽  
Tumor Biopsy ◽  
Safety Issues

Abstract BACKGROUND OS2966 is a first-in-class, humanized and deimmunized monoclonal antibody which antagonizes CD29/β1integrin, a mechanosignaling receptor prominently upregulated in glioblastoma. Preclinical studies in mice and non-human primates have demonstrated safety and encouraging efficacy. A two-part, ascending concentration, phase I clinical trial was therefore initiated to evaluate the safety and feasibility of delivering OS2966 directly to the site of disease via convection-enhanced delivery (CED) in recurrent high-grade glioma patients. METHODS This study has a 2-part design: In part 1, patients undergo stereotactic tumor biopsy followed by placement of a multiport CED catheter for delivery of OS2966 to the bulk contrast enhancing tumor. Subsequently, patients undergo a clinically-indicated tumor resection followed by placement of two CED catheters and delivery of OS2966 to the surrounding tumor-infiltrated brain. A unique concentration-based accelerated titration design is utilized for dose escalation. Given availability of pre and post infusion samples, pharmacodynamic data will be analyzed to explore mechanism of action of OS2966. RESULTS Two subjects have been treated at two corresponding dose levels (0.2mg/mL and 0.4 mg/mL). No dose-limiting toxicity or unexpected safety issues have been identified. To date, reported adverse events were mild (i.e., grade 1) and consistent with underlying disease and surgical procedures. No adverse events were attributed to OS2966 or CED catheter placement. Further, no clinically significant changes from baseline neurological exam have been noted for either patient through initial follow-up. Maximal tumor coverage and concomitant gross total resection were achieved for both patients. Tumor volume measured 1.63 cm3 and 16 cm3 for Patient 1 and 2 respectively with an intratumoral Vd/Vi ratio of 1.3. and 0.94. Pharmacodynamic analysis via tissue-level biomarkers is ongoing and will be presented. CONCLUSION Initial data demonstrates the safety and feasibility of direct intracranial delivery of OS2966.

scholarly journals Impact of mass effect, tumor location, age, and surgery on the cognitive outcome of patients with high-grade gliomas: a longitudinal study

2017 ◽  
Vol 4 (4) ◽  
pp. 229-240 ◽  
Author(s):  
Monica Dallabona ◽  
Silvio Sarubbo ◽  
Stefano Merler ◽  
Francesco Corsini ◽  
Giuseppe Pulcrano ◽  
...  
Keyword(s):  
Tumor Volume ◽  
High Grade Glioma ◽  
Joint Effect ◽  
Cognitive Outcome ◽  
Tumor Localization ◽  
High Grade ◽  
Patient Age ◽  
Patient Âgé ◽  
High Grade Gliomas

Abstract Background High-grade gliomas are the most frequently occurring brain tumors and carry unfavorable prognosis. Literature is controversial regarding the effects of surgery on cognitive functions. Methods We analyzed a homogenous population of 30 patients with high-grade glioma who underwent complete resection. Patients underwent extensive neuropsychological analysis before surgery, 7 days after surgery, and approximately 40 days after surgery, before adjuvant treatments. Thirty-four neuropsychological tests were administered in the language, memory, attention, executive functions, and praxis domains. Results The preoperative percentage of patients with impairment in the considered tests ranged from 0% to 53.3% (mean 20.9%). Despite a general worsening at early follow-up, a significant recovery was observed at late follow-up. Preoperative performances in language and verbal memory tasks depended on the joint effect of tumor volume, volume of surrounding edema, and tumor localization, with major deficits in patients with left lateralized tumor, especially insular and temporal. Preoperative performances in attention and constructive abilities tasks depended on the joint effect of tumor volume, volume of surrounding edema, and patient age, with major deficits in patients ≥ 65 years old. Recovery at late follow-up depended on the volume of resected tumor, edema resorption, and patient age. Conclusions Longitudinal neuropsychological performance of patients affected by high-grade glioma depends, among other factors, on the complex interplay of tumor volume, volume of surrounding edema, tumor localization, and patient age. Reported results support the definition of criteria for surgical indication based on the above factors. They may be used to propose more customized surgical, oncological, and rehabilitative strategies.

5-Aminolevulinic acid for enhanced surgical visualization of high-grade gliomas: a prospective, multicenter study

2021 ◽  
pp. 1-10
Author(s):  
Alexander J. Schupper ◽  
Rebecca B. Baron ◽  
William Cheung ◽  
Jessica Rodriguez ◽  
Steven N. Kalkanis ◽  
...  
Keyword(s):  
Adverse Events ◽  
Diagnostic Accuracy ◽  
Tumor Volume ◽  
Aminolevulinic Acid ◽  
Intraoperative Imaging ◽  
The United States ◽  
Histopathological Analysis ◽  
High Grade ◽  
Neurological Morbidity ◽  
High Grade Gliomas

OBJECTIVE Greater extent of resection (EOR) is associated with longer overall survival in patients with high-grade gliomas (HGGs). 5-Aminolevulinic acid (5-ALA) can increase EOR by improving intraoperative visualization of contrast-enhancing tumor during fluorescence-guided surgery (FGS). When administered orally, 5-ALA is converted by glioma cells into protoporphyrin IX (PPIX), which fluoresces under blue 400-nm light. 5-ALA has been available for use in Europe since 2010, but only recently gained FDA approval as an intraoperative imaging agent for HGG tissue. In this first-ever, to the authors’ knowledge, multicenter 5-ALA FGS study conducted in the United States, the primary objectives were the following: 1) assess the diagnostic accuracy of 5-ALA–induced PPIX fluorescence for HGG histopathology across diverse centers and surgeons; and 2) assess the safety profile of 5-ALA FGS, with particular attention to neurological morbidity. METHODS This single-arm, multicenter, prospective study included adults aged 18–80 years with Karnofsky Performance Status (KPS) score > 60 and an MRI diagnosis of suspected new or recurrent resectable HGG. Intraoperatively, 3–5 samples per tumor were taken and their fluorescence status was recorded by the surgeon. Specimens were submitted for histopathological analysis. Patients were followed for 6 weeks postoperatively for adverse events, changes in the neurological exam, and KPS score. Multivariate analyses were performed of the outcomes of KPS decline, EOR, and residual enhancing tumor volume to identify predictive patient and intraoperative variables. RESULTS Sixty-nine patients underwent 5-ALA FGS, providing 275 tumor samples for analysis. PPIX fluorescence had a sensitivity of 96.5%, specificity of 29.4%, positive predictive value (PPV) for HGG histopathology of 95.4%, and diagnostic accuracy of 92.4%. Drug-related adverse events occurred at a rate of 22%. Serious adverse events due to intraoperative neurological injury, which may have resulted from FGS, occurred at a rate of 4.3%. There were 2 deaths unrelated to FGS. Compared to preoperative KPS scores, postoperative KPS scores were significantly lower at 48 hours and 2 weeks but were not different at 6 weeks postoperatively. Complete resection of enhancing tumor occurred in 51.9% of patients. Smaller preoperative tumor volume and use of intraoperative MRI predicted lower residual tumor volume. CONCLUSIONS PPIX fluorescence, as judged by the surgeon, has a high sensitivity and PPV for HGG. 5-ALA was well tolerated in terms of drug-related adverse events, and its application by trained surgeons in FGS for HGGs was not associated with any excess neurological morbidity.

scholarly journals Elimination of Cancer Stem–Like Side Population in Human Glioblastoma Cells Accompanied With Stemness Gene Suppression by Korean Herbal Recipe MSC500

2014 ◽  
Vol 13 (6) ◽  
pp. 541-554 ◽  
Author(s):  
Chih-Jung Yao ◽  
Tae-Young Han ◽  
Ping-Hsiao Shih ◽  
Tsu-Yi Yi ◽  
I-Chun Lai ◽  
...  
Keyword(s):  
Glioblastoma Multiforme ◽  
Molecular Mechanisms ◽  
Side Population ◽  
High Grade Glioma ◽  
Therapeutic Effects ◽  
Mrna Levels ◽  
High Grade ◽  
Human Glioblastoma ◽  
High Grade Gliomas ◽  
E Cadherin

Background: High-grade gliomas are the most common and invasive malignant brain tumors in adults, and they are almost universally fatal because of drug resistance and recurrence. In spite of the progress in adjuvant therapy (like temozolomide) and irradiation after surgery, no effective salvage therapy is currently available for relapsed patients. A Korean herbal recipe MSC500 has been reported to have beneficial therapeutic effects in patients with high-grade gliomas who are relapsed or refractory to conventional treatments. But the underlying molecular mechanisms remain unclear. Methods: As Cancer stem cell (CSC) plays a pivotal role in the resistance to conventional cancer therapy, we explored the effects of MSC500 on the CSC-like side population (SP) in GBM8401 human glioblastoma multiforme cells. Results: Compared with the parental cells, the SP cells were more resistant to temozolomide but sensitive to MSC500. The mRNA levels of stemness genes such as Nanog, CD133, and ABCG2 were much higher in the SP cells, and so was E-cadherin, which was reported to correlate with the aggressiveness of glioblastoma multiforme. Treatment with MSC500 decreased the proportion of SP cells and high ALDH activity cells from 1.6% to 0.3% and from 0.9% to 0.1%, respectively, accompanied with suppression of the aforementioned stemness genes and E-cadherin, as well as other CSC markers such as ABCB5, Oct-4, Sox-2, β-catenin, Gli-1, and Notch-1. Conclusion: Our results suggest the potential role of MSC500 as an integrative and complementary therapeutic for advanced or refractory high-grade glioma patients.

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 CREB3L1 and PTN expressions correlate with prognosis of brain glioma patients

2018 ◽  
Vol 38 (3) ◽  
Author(s):  
Li-qiang Liu ◽  
Li-fei Feng ◽  
Cheng-rui Nan ◽  
Zong-mao Zhao
Keyword(s):  
Mrna Expression ◽  
Survival Time ◽  
Population Distribution ◽  
High Grade Glioma ◽  
Low Grade ◽  
High Grade ◽  
Brain Glioma ◽  
Expression Levels ◽  
Cell Counts ◽  
High Grade Gliomas

The present study was conducted to investigate the clinical significance of cAMP responsive element binding protein 3 like 1 (CREB3L1) and pleiotrophin (PTN) expression in prognosis of patients with brain gliomas. Human brain tissue samples were collected from normal glial tissues (control), low- and high-grade glioma tissues. CREB3L1 and PTN expression levels in cells were assessed by immunohistochemistry (IHC), and population distribution of the CREB3L1- and PTN-presenting patients was examined. The CREB3L1 and PTN mRNA expression levels in three types of the brain cells was determined by RT-PCR. Survival rates for population of the CREB3L1- and PTN-presenting patients were examined. CREB3L1+ cell counts were decreased with increased PTN+ cells in the low-grade and high-grade glioma tissues as compared with the control. Population proportion of the CREB3L1+-presenting patients decreased from the control to the high-grade glioma and the population of the PTN+-presenting patients increased in low- and high-grade gliomas as compared with the control (both P<0.05). The decrease in the CREB3L1 mRNA expression was associated with the increase in the PTN mRNA expression in the low- and high-grade gliomas (P<0.05). Survival time for patients with CREB3L1− and PTN+ gliomas was shorter than patients with CREB3L1+ and PTN− gliomas in the investigated cohorts (both P<0.05). There was a relationship between the expression levels of both proteins and survival time. CREB3L1 and PTN expression levels serve as biomarkers with utility in grading gliomas. Absence of CREB3L1 and presence of PTN in brain glioma cells correlate with survival time of the glioma patients.

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