bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II study of bevacizumab and nitrosourea in patients with recurrent malignant glioma: A multicenter Italian study
Authors: Soffietti R. , Rudà R. , Trevisan E. , Picco E. , Guarneri D. , Caroli M. , Fabrini M. , Scotti V. 
Published: August 2020

2012 Background: Bevacizumab (BV) has shown a promising activity in recurrent malignant gliomas (MG) in combination with irinotecan. Few data are available on the combination of bevacizumab and nitrosoureas, that represent the standard cytotoxic option at recurrence. Methods: In this ongoing phase II study patients with MG recurrent after surgery, radiation therapy, and temozolomide are eligible. The treatment consists of an induction phase with BV at 10 mg/kg intravenously on day 1 and 15 and fotemustine (FTM) (a nitrosourea with elevated lipophilic properties) at 75 mg/m2 intravenously on day 1 and 8, followed after a 3-week interval by a maintenance phase with BV at 10 mg/kg i.v. and FTM 75 mg/m2 i.v. every 3 weeks until tumor progression or unacceptable toxicity. Patients undergo clinical and MRI assessment 1 month after the start of treatment and thereafter every 2 months. Monitoring of CBV with perfusion MRI is performed in selected centers. The co-primary endpoints are objective response rate (ORR), based on Mc Donald's criteria (CR + PR) and progression-free survival at 6 months (PFS6), with secondary endpoints of safety time to tumor progression (TTP) and overall survival. Results: From April 2008 to December 2008, 34 patients were enrolled and 31 (22 glioblastomas and 9 anaplastic gliomas) are evaluable for response. Overall response rate (2 CR and 9 PR) was 35% (glioblastomas 33%, anaplastic gliomas 41.5%). Median time to maximal response was 1 month. Steroids were reduced in 50% of patients. Sixteen of 31 patients progressed with a TTP of 2.6 months (1–8.5). Patterns of progression were local in 10/16, local + leptomeningeal spread in 3/16 and gliomatosis in 3/16. Fifteen patients are free of tumor progression (from 2 to 8 months). Toxicities included grade III-IV neutropenia in three patients, grade III-IV piastrinopenia in five, and grade III thrombosis in two. Seventeen patients developed mild to moderate fatigue, six arterial hypertension, and three grade I intratumoral haemorrhage. Conclusions: Combination of bevacizumab and fotemustine in recurrent malignant gliomas is safe and promising. Updated results, monitoring of CBV with perfusion MRI, and correlations between MGMT promoter methylation and response/outcome will be presented. No significant financial relationships to disclose.
Targeting brain tumor stem cells using a bispecific antibody directed against CD133+ and EGFRvIII+
Authors: Wong A. , Mitra S. , Gupta P. 
Published: August 2020

2022 Background: Using the marker CD133, cancer stem cells (CSCs) have been demonstrated for glioblastomas (GBMs) and medulloblastomas. However, CD133 is also present on normal neural stem cells. EGFRvIII is a tumor specific EGF receptor. We hypothesized that a recombinant bispecific antibody directed against CD133 and EGFRvIII would be a highly specific reagent. Methods: Single chain antibodies (scFv) were cloned for anti-EGFRvIII and anti-CD133 using existing hybridomas and published sequences. scFv were cloned into a bicistronic vector containing a human CH3 constant domain. The bispecific antibody (BsAb) contains the anti-CD133 (AC133) and anti-EGFRvIII single chain Fv; monospecific but bivalent reagents for anti-CD133 and anti-EGFRvIII were also constructed. Results: U87 cells were co-transfected with increasing amounts of CD133 and decreasing amounts of EGFRvIII cDNAs. The BsAb showed the highest binding for cells expressing both epitopes, whereas Di-EGFRvIII and Di-AC133 had the highest affinity for cells expressing high levels of individual antigens. When cells expressing both antigens were mixed with cells expressing high levels of either antigen alone, the BsAb only recognized CD133+/EGFRvIII+ cells. We then explored the efficiency of tumor cell killing. Using human CD16-expressing NK cells as the effectors at an effector:target ratio of 10:1 and an 83 nM antibody concentration, the BsAb induced 86% lysis of U87-EGFRvIII/CD133 cells, 42.5% in U87-vIII but only 27.3% in U87-CD133 cells. Di-EGFRvIII efficiently induced cytotoxicity in U87-EGFRvIII/CD133 and U87vIII cells but not in U87-CD133 cells. Di-CD133 was the least effective at inducing ADCC. Finally, we studied the ability of the BsAb to induce ADCC on tumor spheres and normal neurospheres. The BsAb showed at least 4X greater lysis on tumor spheres that were CD133+/EGFRvIII+ over normal neurospheres expressing CD133 alone at an E:T of 10:1. This was seen at concentrations as low as 0.83 nM. Conclusions: A recombinant bispecific antibody directed against CD133 and EGFRvIII is highly specific for cells that are positive for both antigens, but poorly targets cells expressing CD133 alone. It can potentially be used as a therapeutic agent for specifically targeting CD133+/EGFRvIII+ cancer stem cells. No significant financial relationships to disclose.
Angiotensin-(1–7), a small molecule inhibitor of glioblastoma growth
Authors: Lesser G. J. , Carver K. A. , Newton S. J. , Tallant E. A. , Gallagher P. E. 
Published: August 2020

2024 Background: Recent studies suggest that anti-angiogenic therapies may be effective in patients with glioblastoma multiforme (GBM), a highly vascular tumor. We have previously demonstrated that angiotensin-(1–7) [Ang-(1–7)], an endogenous heptapeptide with anti-angiogenic properties, significantly reduced the serum-stimulated growth of three human glioblastoma cell lines which contained mRNA for the AT(1–7) receptor mas. We now provide the first evidence that Ang-(1–7) markedly decreases the proliferation and growth of human glioblastomas in vivo using a xenograft model. Methods: Athymic mice with tumors resulting from injection of human U87 glioblastoma cells were treated for 18 days with saline or 1000 μg/kg Ang-(1–7), delivered by subcutaneous injection every 12 h. Results: The average volume of the tumors from mice treated with the heptapeptide was approximately 3-fold less than the size of the tumors from control animals (586.1 ± 94.5 mm3 vs 1845.5 ± 238.1 mm3; n = 6, p < 0.05). Further, the tumors from mice injected with Ang-(1–7) weighed almost 50% less than the tumors from mice treated with saline (1.31 ± 0.12 g vs. 2.45 ± 0.23 g; n = 6, p < 0.05). The Ang-(1–7)-mediated reduction in tumor growth was associated with a significant decrease in immunoreactive Ki67, a proliferation marker. In addition, a marked down-regulation of cyclooxygenase 2 (COX-2), prostaglandin E synthase (PGES-1) and vascular endothelial growth factor (VEGF) was observed in tumors from Ang-(1–7)-injected mice compared to saline-treated controls (COX-2: 1.00 ± 0.06 vs 0.55 ± 0.07 relative gene expression; PGES-1: 1.03 ± 0.08 vs. 0.40 ± 0.06; VEGF: 1.05 ± 0.07 vs. 0.59 ± 0.09; n = 6, p < 0.05) with no effect on COX-1 or PGI synthase mRNA. Conclusions: These results suggest that Ang-(1–7) may reduce the concentration and ratio of proliferative and anti-proliferative prostaglandins to decrease glioblastoma growth as well as attenuate angiogenesis through a reduction in VEGF. Thus, Ang-(1–7) may be a new, first-in-class small molecule inhibitor for the treatment of glioblastoma, providing combination therapy as a selective COX-2/PGES-1 and angiogenic inhibitor, targeting a specific AT(1–7) receptor mas. No significant financial relationships to disclose.
Post-therapeutic changes in the molecular profile of glioblastomas
Authors: Horbinski C. , Mintz A. , Engh J. , Lieberman F. , Hamilton R. L. , Park D. M. 
Published: August 2020

2026 Background: Glioblastoma multiforme is the most common and malignant primary brain tumor in adults. Despite aggressive surgery, radiation, and chemotherapy, average survival time after diagnosis is about 1 year. This may be partly due to development of resistance to adjuvant therapies. While the molecular alterations in pretreated glioblastomas have been the subject of much research in recent years, changes in their genetic profile after adjuvant therapy are largely unknown. Methods: Herein we describe a cohort of over 40 glioblastomas with characterization of key genetic loci (EGFR, p53, 1p, 19q, 9p, 10q, 17p) using fluorescence in situ hybridization, PCR-based loss of heterozygosity (LOH) analysis, and immunohistochemistry on formalin-fixed, paraffin-embedded tissues. Analyses were performed on tumor tissue obtained at initial diagnosis and at first recurrence. Treatment regimen during the interval consisted of external beam radiation therapy and temozolomide, an alkylating chemotherapeutic agent. Results: About 50% showed large increases or decreases in hyperploidy of chromosomes 1, 7, 9, and/or 19 after therapy. Over 70% showed changes in LOH patterns on 1p, 19q, 9p, 10q, and/or 17p. 24% of previously non-EGFR-amplified tumors acquired low-grade amplification (less than 10 copies/chromosome 7 CEP signal) after treatment, and 16% of EGFR-amplified tumors lost amplification after treatment. Conclusions: Our results suggest that the molecular profile of these tumors is dynamic and that certain key alterations, including acquisition of low-level EGFR amplification in previously EGFR-negative tumors, occurs in a subset of cases. Such alterations may contribute to therapy resistance as the glioma evolves in a changing microenvironment. No significant financial relationships to disclose.
Change in MGMT methylation status between first and second surgery for recurrence: Clinical implications
Authors: Brandes A. A. , Franceschi E. , Tosoni A. , Fioravanti A. , Agati R. , Andreoli A. , Mazzocchi V. , Morandi L. , Bartolini S. , Ermani M. 
Published: August 2020

2027 Background: MGMT promoter methylation status is known to be a potent prognostic factor in newly diagnosed glioblastoma (GBM) patients (pts). However, it is not yet clear whether and, if so, how MGMT methylation status may change; nor is it known whether the prognostic role of this epigenetic feature is retained during the disease course. Methods: A retrospective analysis was made using a database of 614 GBM pts treated prospectively from January 2000 to August 2008. We evaluated only patients who met the following inclusion criteria: age ≥18; PS 0–2; two distinct surgical procedures; histological diagnosis of GBM both at first and at second surgery for recurrence; postoperative treatment consisting of: a) radiotherapy (RT) followed by temozolomide (TMZ) until 2005, and b) TMZ concurrent with and adjuvant to RT after 2005; a time interval ≥3 month between first and second surgery. The study aim was to evaluate changes of MGMT status during the course of GBM. The log-rank test was employed to evaluate the significance of the prognostic variables. The percentages of MGMT methylated cases at first and second surgery were compared using the McNemar test. Results: MGMT status, evaluated at first and second surgery in all 44 pts (M:F 32:12, median age: 49 years, range: 27–67), was assessable in 38 (86.4%) cases: MGMT promoter was methylated in 13 (34.2%) pts at first surgery. MGMT methylation status, unchanged in 63.2% of second surgery samples, changed more frequently in methylated than in unmethylated pts (61.5% vs 24%, p = 0.03). The median survival was 24.3 months (95% CI: 20.8–27.7), being 35.2 months (95% CI: 10.1–60.2) and 21.9 months (95% CI: 17.3–26.5) for pts with methylated and unmethylated MGMT assessed at first surgery, respectively (p = 0.04). However, MGMT status at second surgery was no longer prognostic for survival (p = 0.1). Conclusions: Significant changes in MGMT methylation status during the course of GBM occur more frequently in MGMT methylated than unmethylated cases. Moreover, while MGMT methylation status is prognostic at first surgery, it appears to be of no prognostic utility at the time of second surgery. No significant financial relationships to disclose.
A phase I evaluation of intravenous TM601 in recurrent glioblastoma: Use of perfusion MRI to monitor antiangiogenic effects
Authors: Akella N. S. , Nabors L. B. , Rosenfeld S. S. , Chamberlain M. C. , Mrugala M. M. , Jacoby D. B. , O'Neill A. M. 
Published: August 2020

2041 Background: TM601, a synthetic chlorotoxin, is a peptide derived from scorpion venom. In vitro data demonstrate binding to vascular endothelial cells, and blockage of endothelial cell invasion. In vivo, intravenous infusion of TM601 decreases neovascularization. Based on this work and previous clinical trials demonstrating tumor-specific uptake of 131I-TM601 in malignant glioma after IV delivery, a phase I trial was initiated with intravenous unlabeled TM-601. Methods: Six patients with recurrent glioblastoma have been enrolled. All patients received a test dose of 10 mCi 131I-TM601 to demonstrate tumor-specific uptake prior to TM601 treatment at doses of 0.04 mg/kg IV weekly for 3 weeks in a 4 week cycle. Treatment continued until tumor progression. Patients were evaluated at week 4 of each cycle with conventional and dynamic susceptibility contrast MRI (DSC-MRI) to assess perfusion. Anatomic and perfusion MRI evaluations were performed at baseline, 1 day after the initiation of TM601 therapy, and 21 days after initiation of each treatment cycle. MRI data were post-processed to yield an arterial input function and parametric hemodynamic maps. Results: With respect to safety, there has been one intratumoral hemorrhage that was considered to be possibly related to therapy. Three other serious adverse events considered to be unrelated to therapy included disease progression on therapy, a hip fracture and renal calculi in a patient with a history of renal calculi. Two of six patients in the first dosing cohort have demonstrated a greater than 25% reduction in relative cerebral blood flow (rCBF) and/or relative cerebral blood volume (rCBV) compared to baseline. Both patients with improvement in perfusion MRI had extended response to intravenous TM601. Conclusions: Intravenous unlabeled TM601 at the initial dose schedule produces measurable changes in perfusion MRI parameters which correlate with clinical response. Perfusion MRI parameters appear to correlate with clinical response to TM601 and are consistent with angiogenic inhibition. [Table: see text]
Treatment of recurrent malignant glioma with G207, a genetically engineered herpes simplex virus-1, followed by irradiation: Phase I study results
Authors: Karrasch M. , Gillespie G. Y. , Braz E. , Liechty P. G. , Nabors L. B. , Lakeman A. D. , Palmer C. A. , Parker J. N. , Whitley R. J. , Markert J. M. 
Published: August 2020

2042 Background: G207 is a doubly mutated (deletion of both γ134.5 loci, insertional inactivation of UL39) herpes simplex virus (HSV)-1. Safety and efficacy of intracerebral inoculations of G207 to patients suffering from recurrent malignant gliomas have been demonstrated in previous clinical trials. Methods: In this phase I clinical trial, a total of 1 x 109 plaque forming units (pfu) G207 were administered by five stereotactic injections of 0.2 mL each into regions of recurrent malignant glioma defined by MRI, followed by focal radiation therapy 24 hours post injection. Included patients suffered from inoperable pathologically proven recurrent glioblastoma multiforme (GBM) or anaplastic astrocytoma (AA) which was progressive despite radiotherapy or chemotherapy and failed external beam radiotherapy > 5 Gray prior to study enrolment. Results: 9 patients were treated in this phase I study. 5 patients were suffering from relapsed GBM, 4 patients were suffering from relapsed AA. 1 month after treatment, 3 patients (3xGBM) showed SD, 2 patients (1xGBM, 1xAA) PR, and 4 patients (1xGBM, 3xAA) PD. The 2 patients with initial PR (1xGBM, 1xAA) were re-treated with G207/Irradiation at time point of tumor recurrence, showing PR one month after re-treatment again. Median overall survival time for all 9 patients was 229 days (7.6 months), with one patient still alive at time of abstract submission. In patients suffering from relapsed GBM, mOS was 7.4 months, in patients suffering from relapsed AA, mOS was 9.25 months. 20 serious adverse events occurred in this study, only 3 were possible/probable related to G207/irradiation. Within persistent areas of tumor, HSV staining was present by using a polyclonal antibody for HSV, indicating intratumoral G207 replication (proof of concept). Conclusions: In 9 patients suffering from relapsed GBM or AA, stereotactic intracerebral G207 inoculation followed by radiation therapy was feasible, safe, and induced clinically relevant responses. G207/Irradiation re-treatment was possible and induced anew clinical responses. Median overall survival is superior to published data in this patient population. Therefore, further clinical development of G207 in GBM is medically reasonable. [Table: see text]
MGMT methylation status as a prognostic factor in anaplastic astrocytomas
Authors: Tosoni A. , Franceschi E. , Ermani M. , Bacci A. , Volpin L. , Lombardo L. , Ravenna G. , Pinna G. , Poggi R. , Brandes A. A. 
Published: August 2020

2052 Background: MGMT methylation status has been found to be an important prognostic factor in glioblastoma patients (pts). However, further data on the epigenetic feature are needed before its role in rare diseases such as anaplastic astrocytomas (AA) can be established. Methods: A retrospective analysis was made on a database of 139 AA pts followed prospectively from January 1995 and August 2008. We evaluated only pts who met the following inclusion criteria: age >18 years; PS 0–2; histological diagnosis of AA; postoperative radiotherapy (RT) and chemotherapy (CT). MGMT status was determined with methylation specific PCR. The study aim was to evaluate the role of MGMT methylation status in AA. The log-rank test was employed to evaluate the significance of the prognostic variables. Results: 80 pts (m/f: 46/34, median age: 41 years, range: 18–71 years) were enrolled. MGMT was assessable in 71 of 80 pts (88.8%), being methylated in 30 (42.9%), and unmethylated in 41 (57.7%) pts. Median PFS was 48.6 months (95% CI: 33.7 - 63.5), being 96 months (95% CI: 29–163) and 38 months (95%CI: 18.9–57.2) in MGMT methylated and unmethylated pts, respectively (p = 0.09). At univariate analysis, complete resection (p = 0.02), age (p = 0.002), and KPS (p = 0.003) were significantly correlated with PFS. At multivariate analysis only age remains correlated with PFS (p = 0.01). Median survival (OS) was 93.7 months (95% CI: 63.5–123.8), being not reached and 77 months (95% CI: 20–134.2), in MGMT methylated and unmethylated pts, respectively (p = 0.03). MGMT methylation (p = 0.03), age (p = 0.0003), and KPS (p = 0.03) were significantly correlated with OS at univariate analysis. At multivariate analysis, age (p = 0.0002) and MGMT methylation (p = 0.01) were correlated with a better OS. Conclusions: MGMT methylation status is an independent prognostic factor together with age in AA. This datum should provide the background to improve the therapeutic index with temozolomide concurrent with and adjuvant to RT in AA. No significant financial relationships to disclose.
Neurocognitive function in patients with glioblastoma multiforme in first or second relapse treated with bevacizumab in the BRAIN study
Authors: Wefel J. S. , Cloughesy T. , Zazzali J. , Yi J. , Friedman H. S. 
Published: August 2020

2056 Background: Patients with glioblastoma multiforme (GBM) suffer from neurocognitive decline due to both the disease and its treatment. We analyzed neurocognitive function of patients with recurrent GBM who participated in the BRAIN study, a phase II, multicenter, randomized, noncomparative clinical trial which assessed the efficacy and safety of bevacizumab alone or in combination with irinotecan. Methods: Eighty-five patients who participated in the bevacizumab-only group of the BRAIN study were assessed with the Hopkins Verbal Learning Test-Revised (HVLT-R), Trail Making Test parts A (TMTA) and B (TMTB), and the Controlled Oral Word Association (COWA) test. Assessments were conducted at baseline and then every 6 weeks while patients remained on study drug, up to 52 weeks. Change in neurocognitive function from baseline to Week 6 was categorized as improved, stable, or declined, using the reliable change index. Changes were confirmed at the next assessment, when available. Results were not adjusted for practice effects. Results: Between 93 and 98% of patients completed each test at baseline and 73–78% completed each test at both baseline and Week 6. The majority of patients demonstrated stable performance on each test at Week 6, relative to baseline. With the exception of the COWA test, 18–25% of patients demonstrated improved performance on one or more tests at Week 6. Conclusions: Preliminary results suggest that the majority of patients with recurrent GBM who were treated with bevacizumab alone in the BRAIN study demonstrated stable or improved neurocognitive function during the first 6 weeks of treatment. Changes across tasks and associations with measures of clinical efficacy, patient characteristics, and concomitant medications will be explored. [Table: see text] [Table: see text]
Correlation of serum urokinase plasminogen activator (uPA) to progression of recurrent malignant glioma during bevacizumab treatment: A marker of invasive phenotype and a candidate to monitor therapy
Authors: Chinot O. L. , Boudouresque F. , Bequet C. , Barrie M. , Thiebaut A. , Matta M. , Autran D. , Ouafik L. 
Published: August 2020

2059 Background: Identification of circulating markers that predict tumor response or reflect progression is of crucial importance when using antiangiogenic agents. However, to date, no such parameters have been identified particularly for bevacizumab, for which, recently, increasing data have supported a role in patient with recurrent malignant glioma. Methods: Serial serum levels of VEGF, VEGFR2, FGF, SDFα, urokinase plasminogen activator (uPA), plasminogen activator inhibitor type I (PAI-1), and metalloprotesase type 9 (MMP9) were determined in a cohort of 32 patients treated with bevacizumab and irinotecan for recurrent malignant glioma. Samples were collected at the start of treatment and then at 4 weeks intervals until progression. Serum levels were measured using an enzyme-linked immunosorbent assay. Progression was defined by MacDonald's criteria, modified by integrating increase of infiltration as measured on MRI by Flair sequence. All subjects were followed for PFS and OS. Cox model analysis is used for correlation between markers and clinical outcome. Results: This preliminary analysis is restricted to pre-treatment (D0; n = 32), day 30 (D30; n = 27), and at progression time (DP; n = 15). None of the pretreatment serum level (n = 32) significantly affect PFS or OS although uPA and MMP9 tend to influence OS. Decrease of median level of all serum markers except PAI1 and VEGFR2 is observed from D0 to D30 under bevacizumab therapy, but only uPA and FGF variations tend to impact clinical outcome. From D30 to DP, increase of uPA is correlated to PFS (p = 0.028) while the observed increased of FGF and SDFα fail to reach significant correlation to PFS and OS. Conclusions: Increase of uPA serum level appear to be correlated to disease progression for patients with recurrent malignant glioma treated with bevacizumab and may reflect the invasive phenotype of glioma progression. Serum uPA may help in assessing treatment response under bevacizumab and warrant further studies. No significant financial relationships to disclose.