bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase III randomized, double-blind, placebo-controlled trial of donepezil in irradiated brain tumor survivors.
Authors: Rapp Stephen R. , Case Doug , Peiffer Ann , Naughton Michelle Joy , Stieber Volker W. , Bayer Gerald K. , Bilodeau Paul A. , Moore Dennis Frederic , Falchuk Steven Charles , Needles Burton M. , Piephoff James , Edenfield William j , Giguere Jeffrey K. , Erickson Nicholette , Loghin Monica Elena , Shaw Edward G.
Published: March 2020

2006

Background: This RCT assessed the effect of 24 weeks of 5-10 mg per day of donepezil, an acetyl cholinesterase inhibitor, on cognitive functioning (primary endpoint) and fatigue, mood and QOL in long-term brain tumor survivors following partial or whole-brain irradiation. Cognitive results are reported herein. Methods: From 2/08-12/11,198 adult primary and metastatic brain tumor survivors > 6 months post radiation treatment (>30 Gray) recruited at 24 sites affiliated with the Wake Forest Community Clinical Oncology Program Research Base, 3 CTSU sites and M.D. Anderson Cancer Center were randomly assigned to receive donepezil (n=99) or placebo (n=99). Cognitive function was assessed at baseline, 12 and 24 weeks with Hopkins Verbal Learning Test-Revised, Rey-Osterreith Complex Figure, Trail Making Test, Digit Span, Controlled Oral Word Association, and Grooved Pegboard. A Cognitive Composite (CC) score was the primary outcome. Results: The sample was 91% White, 54% female, and median age was 55 yrs. 66% had primary tumors, 27% brain metastases and 8% PCI. Median time since diagnosis: 38 mos. 95% had 0-1 ECOG performance status scores. 74% completed the study. CC score improved significantly by 24 weeks in both arms (p < .01); however, there was not a statistically significant difference between groups (p = .57). Donepezil group performed better than placebo on HVLT Recognition (p = .03) and Discrimination (p = .01) and GP-Dominant Hand (p = 0.02). Significant interactions were found between treatment arm and baseline cognitive scores for: CC (p = .01), HVLT Immed. Recall (p = .03), HVLT %Savings (p < .01), Digit Span Forward (p = .01), ROCF Copy (p = .03), TMT-B (p = .05) and GP-Dominant (p < .01). In all cases, the benefit of donepezil, relative to placebo, was greater for those with worse baseline scores. Conclusions: Long-term brain tumor survivors treated with brain irradiation who have cognitive impairment can benefit from 5-10mg of donepezil for 24 weeks. Improvements in verbal memory, working memory, visuo- and psychomotor performance and executive functioning were observed in this group. (Study supported by NIH/NINR grant 5R01NR009675-04, NIH/NCI grant 2 U10 CA 81851-09-13 and Eisai, Inc.) Clinical trial information: NCT00369785.
Interim analysis of a phase I/II study of panobinostat in combination with bevacizumab for recurrent glioblastoma.
Authors: Lee Eudocia Quant , Reardon David A. , Schiff David , Drappatz Jan , Muzikansky Alona , Hammond Samantha , Grimm Sean Aaron , Norden Andrew David , Beroukhim Rameen , McCluskey Christine Sceppa , Chi Andrew S. , Batchelor Tracy , Smith Katrina H. , Gaffey Sarah C. , Gerard Mary , Snodgrass Susan M. , Raizer Jeffrey J. , Wen Patrick Y.
Published: March 2020

2013

Background: Bevacizumab is frequently used to treat recurrent GBM, but responses are generally not durable. Panobinostat is a histone deacetylase inhibitor with anti-neoplastic and anti-angiogenic effects in GBM and may work synergistically with bevacizumab. We conducted a multicenter phase I/II trial of panobinostat in combination with bevacizumab in patients with recurrent GBM. Methods: In the phase II trial, patients with recurrent GBM were treated with oral panobinostat 30 mg three times per week, every other week, in combination with bevacizumab 10 mg/kg every other week. The primary endpoint was 6-month progression-free survival (PFS6) and the study was powered to discriminate between a 35% and 55% PFS6 rate (85% power at an alpha level of 0.07). A planned interim analysis specified suspension of accrual and careful data review if 12 or more of the first 21 patients accrued to the study progress within 6 months of initiating treatment. Patients with recurrent GBM enrolled in the phase I study at the maximum tolerated dose (which is the phase II dose) were eligible for inclusion in the interim analysis. Results: Thirteen of the first 21 patients accrued to the GBM arm of the study had progressed within 6 months of initiating study treatment. The study was closed to further accrual and a planned interim analysis was performed. Median age was 53 (range 22-66) and median KPS was 80% (60%-100%). PFS6 rate was 33.9% [95% CI 12.8, 56.5), median was PFS 5 months [95% CI 3 months, NR], and median OS was 342 days [95% CI 203 days, NR]. Five patients (23.8%) achieved partial responses. Conclusions: Although reasonably well-tolerated, this phase I/II study of panobinostat and bevacizumab in recurrent GBM did not meet criteria for continued accrual and the study was closed. Updated outcome and safety data will be presented at the meeting. Study Supported by: Novartis and Genentech Clinical trial information: NCT00859222.
A large prospective Italian population study (Project of Emilia-Romagna Region in Neuro-Oncology; PERNO) in newly diagnosed GBM patients (pts): Outcome analysis and correlations with MGMT methylation status in the elderly population.
Authors: Franceschi Enrico , Tosoni Alicia , Morandi Luca , Cerasoli Serenella , Lanza Giovanni , Depenni Roberta , Gamboni Alessandro , Dazzi Claudio , Marucci Gianluca , Gardini Giorgio , Pozzati Eugenio , Urbini Benedetta , Dascola Isabella , Bartolini Stefania , Biasini Claudia , Carpeggiani Paolo , Zunarelli Elena , Silini Enrico Maria , Ermani Mario , Brandes Alba Ariela
Published: March 2020

2021

Background: The role of temozolomide concurrent with and adjuvant to radiotherapy (RT/TMZ) in elderly pts with GBM remains unclear. We therefore evaluated the efficacy of this approach in pts >70 years in the context of the Project of Emilia-Romagna Region in Neuro-Oncology (PERNO), the first Italian prospective observational population-based study in neuro-oncology. Methods: The criteria for selecting pts enrolled in the PERNO study were: age >70 years; PS 0-3; histologically confirmed GBM; postoperative radiotherapy after surgery; residence in the Emilia Romagna region. Data were collected prospectively. Results: Pts accrual, started on January 1 2009, was closed, as planned, on December 31 2010. In the pts enrolled (n=53), median overall survival (mOS) was 11.1 months (95% CI: 8.8 - 13.5); survival rates at 1-, 2- and 3-years were 41.5% (95% CI: 28.2 – 54.8%), 15.2% (95% CI: 4.8 – 25.6%) and 6.1% (95%CI: 0 – 15.9%), respectively. Twenty-eight pts received RT/TMZ, and 25 pts RT alone. mOS was 11.6 months (95% CI: 8.6 – 14.6) following RT/TMZ and 9.3 months (95% CI: 8.1 – 10.6) following RT alone. mOS for pts with MGMT methylated status (n = 17) was 13.5 months (95% CI: 7.7 – 19.2), being 17.2 months (95% CI: 11.5 - 22.9) in those treated with RT/TMZ (n = 6) and 8.8 months (95% CI: 2 – 15.6) in those treated with RT alone (n = 11, p = 0.09). Elderly pts with MGMT unmethylated status (n = 25) had a mOS of 8.5 months (95% CI: 6 – 11, p = 0.014), being 8.5 months (95% CI: 2.3 – 14.7) in pts treated with RT/TMZ (n =10), and 8 months (95% CI: 3 – 12.9) in those treated with RT (n = 15, p = 0.55). Conclusions: RT/TMZ appears to be more effective in prolonging the mOS of elderly pts in those with MGMT methylation status (17.2 vs 8.5 months), and seem to perform better than TMZ alone, for which mOS was 9.7 months in the Nordic phase III trial. These findings underline the value of the ongoing randomized EORTC 26062-22061/NCIC CE.6 phase III comparing RT/TMZ with short course RT alone.
Preirradiation chemotherapy with methotrexate, rituximab, and temozolomide and post-irradiation temozolomide for primary central nervous system lymphoma: RTOG 0227 phase II study results.
Authors: Glass Jon , Won Minhee , Schultz Christopher J. , Brat Daniel , Bartlett Nancy , Suh John H. , Fisher Barbara Jean , Liepman Marcia K. , Mehta Minesh P.
Published: March 2020

2033

Background: This prospective phase II study tested a methotrexate (MTX), temozolomide (TMZ) and rituximab (RTX) pre-irradiation regimen with hyperfractionated whole brain radiation therapy (hWBRT) followed by post-irradiation TMZ for patients with primary CNS lymphoma (PCNSL). The primary phase II endpoint was the 2-year overall survival (OS) rate compared with the 2-year OS from RTOG 93-10 (MTX, procarbazine, vincristine, whole brain radiation therapy, cytarabine). Secondary endpoints were pre-irradiation chemotherapy tumor response rates (compared to RTOG 93-10), progression free survival (PFS), acute and late neurologic toxicities, and quality of life. Methods: 53 patients (28 women, 25 men), median age 57.5 years, median Zubrod 1 were treated with RTX 375 mg/m2 3 days prior to first cycle of MTX; 5 cycles of intravenous MTX 3.5 g/m2 with leucovorin rescue on weeks 1, 3, 5, 7, 9; TMZ 100 mg/m2 daily for 5 days weeks 4 and 8; hWBRT 1.2 Gy twice daily fractions 5 days/week on weeks 11, 12, 13 for a total of 36 Gy and TMZ 200 mg/m2 daily for 5 days on weeks 14, 18, 22, 26, 30, 34, 38, 42, 46, 50. Results: Dosing of pre-irradiation temozolomide at 100 mg/m2 was determined in the phase I portion of the study. With a median follow-up of 3.6 years, 2-year OS and PFS rates were 80.8% and 63.6%, respectively. Compared with historical controls from RTOG 93-10, 2-year OS and PFS were significantly improved (p = 0.006 and 0.03). The overall response rate to the pre-irradiation chemotherapy was 37.7% (complete response 11.3%, partial response 26.4%). 38% experienced grade 3 and 25% experienced grade 4 toxicities before the start of hWBRT. 33% experienced grade 3 and 21% experienced grade 4 toxicities attributable to post-hWBRT chemotherapy. Conclusions: The combination of MTX, TMZ, RTX followed by hWBRT and TMZ for PCNSL is safe with demonstrated improved 2 year OS and PFS compared with RTOG 93-10. Further investigations regarding the role of hWBRT and post-hWBRT TMZ are indicated. This project was supported by RTOG grant U10 CA21661 and CCOP grant U10 CA37422 from the National Cancer Institute (NCI) and Schering-Plough. Clinical trial information: NCT00068250.
RTOG 0913: A phase I study of daily everolimus (RAD001) in combination with radiation therapy and temozolomide in patients with newly diagnosed glioblastoma.
Authors: Chinnaiyan Prakash , Won Minhee , Wen Patrick Y. , Rojiani Amyn , Wendland Merideth M , DiPetrillo Thomas A. , Corn Benjamin W. , Mehta Minesh P.
Published: March 2020

2047

Background: To determine the safety of the mTOR inhibitor everolimus (RAD001) administered daily with concurrent radiation and temozolomide in newly diagnosed glioblastoma patients. Methods: Everolimus was administered daily with concurrent radiation (60 Gy in 30 fractions) and temozolomide (TMZ) (75 mg/m2/day). Everolimus was escalated from 2.5 (Dose Level 1), to 5 (Dose Level 2), to 10 mg/day (Dose Level 3). Maintenance TMZ was delivered at 150-200 mg/m2 on days 1 to 5 every 28 days for up to 12 cycles with concurrent everolimus at the previously established daily dose of 10 mg/day. Dose escalation continued if a dose level produced DLTs in ≤ 2 of the first 6 evaluable patients. Results: Between October 28, 2010 and July 2, 2012, the Radiation Therapy Oncology Group (RTOG) 0913 protocol initially registered a total of 35 patients, with 25 patients successfully meeting enrollment criteria, receiving drug and evaluable for toxicity. Everolimus was successfully escalated to the predetermined MTD of 10 mg/day. Two of the first 6 eligible patients experienced a DLT at each dose level. DLTs included: gait disturbance, febrile neutropenia, rash, fatigue, thrombocytopenia, hypoxia, ear pain, headache, and mucositis. Other common toxicities were Grade 1/2 hypercholesterolemia and hypertriglyceridemia. At the time of analysis, there was one death reported, which was attributed to tumor progression. Conclusions: Daily oral everolimus (10 mg) combined with both concurrent radiation therapy and TMZ followed by maintenance TMZ, is well tolerated, with an acceptable toxicity profile. A phase II randomized clinical trial with mandatory correlative biomarker analysis is currently underway, designed to both determine the efficacy of this regimen and identify molecular determinants of response. Supported by RTOG U10 CA21661 and CCOP U10 CA37422 grants from NCI and Novartis. Clinical trial information: NCT01062399.
89zr-GC1008 PET imaging and GC1008 treatment of recurrent glioma patients.
Authors: den Hollander Martha W. , Bensch Frederike , Glaudemans Andor W. J. M. , Enting Roelien H. , Bunskoek Sophie , Oude Munnink Thijs H. , Lub-de Hooge Marjolijn N. , Pearlberg Joseph , Gietema Jourik A. , de Vries Elisabeth G. E. , Walenkamp Annemiek M.E.
Published: March 2020

2050

Background: Transforming growth factor-β (TGF-β) signaling is involved in glioma development. GC1008 is a monoclonal antibody that has demonstrated significant neutralization of all mammalian isoforms of TGF-β in preclinical models (Lonning, Curr Pharm Biotechnol 2011). The aim of this study was to investigate whether GC1008 uptake in brain tumors can be visualized using the 89Zirkonium (Zr)-GC1008 PET scan and to assess treatment outcome in patients with recurrent glioma treated with GC1008 (NCT01472731). Methods: Patients with WHO II-IV glioma who presented with recurrent disease were eligible. After iv administration of 37 MBq (5 mg) 89Zr-GC1008, 89Zr-GC1008 PET scans were performed on day 2 and day 4 post injection. Thereafter, patients were treated with 5 mg/kg GC1008 iv every 3 weeks. MRI scans were made for response evaluation after 3 courses or as clinically indicated. Results: Twelve patients with 1st-8th recurrent disease were included (10 glioblastoma, 1 anaplastic oligodendroglioma, 1 anaplastic astrocytoma), all underwent an 89Zr-GC1008 PET scan on day 4, 4 patients also underwent a PET scan on day 2 after tracer injection. Median SUVmax on day 4 was in tumor lesions 4.6 (range 1.5-13.9) and median SUVmean in normal brain tissue 0.3 (range 0.2-0.5). In 3 out of 4 patients who underwent a day 2 and day 4 whole body scan uptake decreased in most normal organs but not in tumor lesions, supporting tumor specific 89Zr-GC1008 uptake. No major toxicity of GC1008 treatment was observed, but all patients showed clinical and/or radiological progressive disease after 1-3 cycles. Median progression free survival was 61 days (range 25-80) and median overall survival 106 days (range 37-287+). Conclusions: 89Zr-GC1008 showed excellent uptake by recurrent gliomas. Clinical benefit of GC1008 treatment was not observed in this limited study population. Clinical trial information: 01472731.
Survival benefit from bevacizumab in newly diagnosed glioblastoma (GBM) according to transcriptional subclasses.
Authors: Huse Jason T. , Beal Kathryn , Zhang Jianan , Kastenhuber Edward R. , Kaley Thomas Joseph , Abrey Lauren E. , Gutin Philip H. , Brennan Cameron W , Omuro Antonio Marcilio Padula
Published: March 2020

2057

Background: Genome-wide transcriptional studies (TCGA and others) have identified distinct GBM molecular subtypes, but to date this has not translated into prognostic or therapeutic implications. Bevacizumab has emerged as a new treatment option for GBMs, although a survival benefit has yet to be demonstrated in unselected patients (pts). We analyzed outcomes from a prospective phase II trial in newly diagnosed GBM treated with hypofractionated stereotactic radiotherapy (HFSRT) combined with temozolomide and bevacizumab, and correlated with GBM transcriptional subclasses. Methods: Pts with newly diagnosed GBM with tumor volume < 60cc were eligible. Treatment consisted of HFSRT (6x6 Gy to contrast-enhancing tumor and 6x4 Gy to FLAIR hypersignal with dose painting), concomitant with bevacizumab (10 mg/kg Q2 weeks) and temozolomide (75mg/m2 daily), followed by standard adjuvant bevacizumab/ temozolomide. Primary endpoint was 1-y overall survival (OS). To establish TCGA transcriptional subclasses, mRNA from formalin-fixed paraffin-embedded tissue blocks was analyzed with a validated, 151-probe Nanostring gene expression assay. Results: A total of 40 evaluable pts were accrued, achieving a 1-y OS of 90% (95% CI 76-96), 2-y OS of 32% (95%CI 19-47) and median OS of 17.4m. The molecular subclass could be defined in 31 pts, as follows: Mesenchymal: 14 (45%) pts, pro-neural: 8 (26%), classical: 7 (23%), neural: 2 (6%). The pro-neural phenotype was associated with reduced overall survival: median OS of 13.5m vs 21.2m for non pro-neural tumors (univariate: p = 0.015; multivariate: p = 0.003). MGMT promoter methylation did not predict survival (p = 0.13). Conclusions: We provide proof-of-principle that GBM transcriptional classification is biologically and therapeutically relevant, identifying non pro-neural GBMs as the best candidates for bevacizumab treatment. Our findings imply that angiogenesis and tumor invasion mechanisms in proneural tumors may be distinct from other subtypes, and we suggest such pts should not be offered bevacizumab treatment upfront. Future randomized trials focusing on non-proneural tumors may finally demonstrate a survival advantage for bevacizumab in GBM. Clinical trial information: NCT01392209.
Clinical and prognostic features of adult patients with gangliogliomas.
Authors: Yust-Katz Shlomit , Anderson Mark Daniel , Liu Diane , Yuan Ying , Fuller Greg , De Groot John Frederick
Published: March 2020

2063

Background: Gangliogliomas (GG) represent less than 1% of primary brain tumors in adults. Little is known regarding prognostic features, clinical characteristics or the impact of treatment on patient (pt) outcomes. Methods: In this IRB approved retrospective study, our neuro-oncology longitudinal database was screened for pts with GG from 1992-2012. 67 adult pts (age>18) were identified. Results: 60 pts presented with low grade GG and 7 with anaplastic GG. The median age at diagnosis was 27 years (18-59). 22 pts developed recurrent disease (18 low grade and 4 high grade) with a median time to recurrence of 87 weeks from surgery. 7 of the pts with low grade GG had malignant transformation to a malignant tumor (anaplastic GG or GBM). 22 pts received radiation therapy, 16 at diagnosis. 14 pts received chemotherapy at recurrence. Pts with incomplete resections or higher grade tumors were more likely to receive chemotherapy or radiation. The median overall survival (OS) time for these pts was not reached with a median follow-up time of 4.6 years. The 2-, 5- and 10-year OS were 98%, 87%, and 76%. Factors on univariate analysis that were significantly associated with OS were KPS at presentation (HR 10.1; 95% CI 2.6, 39.1; p = 0.0008), extent of resection (EOR) (biopsy vs gross total; HR 12.1; 95% CI 2.3, 63.6; p = 0.003), histologic grade (Grade 1-2 vs Grade 3-4; HR 0.06; 95% CI 0.01, 0.3; p = 0.0002), and seizure control following surgery (Engel I vs Engel 2-3; HR 0.1; 95% CI 0.01, 0.9; p = 0.02). Factors on univariate analysis that were significantly associated with progression free survival (PFS) were EOR (biopsy vs gross total; HR 4.0; 95% CI 1.4, 11.9; p = 0.01) and histologic grade (Grade 1-2 vs .Grade 3-4; HR 0.3; 95% CI 0.08, 0.8; p = 0.02). On multivariate analysis, EOR is most significant for PFS (p = 0.01), while tumor grade is most significant for OS (p = 0.004). Conclusions: While GG have an excellent prognosis, malignant histological grade, diagnosis with a biopsy only, poor initial KPS, and presence of seizures following surgery could indicate a worse prognosis. The role of chemotherapy and radiation therapy for incompletely resected or inaccessible low grade GG is unclear.
Alteration of the p53 and Rb tumor suppressor pathways by p16/INK4a and p14/ARF promoter methylation and loss of protein expression in recurrent and nonrecurrent meningiomas.
Authors: Martinez Juan Carlos , Ropero Santiago , Mateos Concepcion , Toledo Maria DEL VAL , Samaniego Rafael , Sacristan Silvia , Esteller Manel
Published: March 2020

2064

Background: Promoter methylation inactivates tumor suppressor genes (TSG). The INK4a/ARF locus encodes p16INKa and p14ARF cell cycle regulatory proteins, which control Rb and p53 TSG pathways. Most meningiomas are slow growing tumors, but in spite of complete surgical removal, the recurrence rate at 5 years is 5%, rising to 19% in long-term follow-up. However, there are no markers predictive of this evolution. Epigenetic changes in low-grade meningiomas have not been previously addressed. To get insights into the possible role of p16INK4a and p14ARF TSG alterations in grade 1 meningiomas, we study the methylation status and protein expression of these genes in 140 specimens of meningiomas: 29 nonrecurrent and 57 recurrent in one, two or three times. Methods: Methylation specific PCR and bisulfate modification followed by bisulfate genomic sequencing of CpG islands and staining with p16INKa and p14ARF antibodies (Ab’s). Results: Our data show p16INK4a and p14ARF methylation in 43.4% and14.2% meningiomas respectively. Methylation of p16INK4a is found in a similar proportion in non-recurrent meningiomas (37.9%) and the first biopsy of recurrent cases (38.8%) and increases to a 52.3% in successive biopsies of recurrent cases. Methylation of p14ARF occurs in 13.8% of nonrecurrent vs. 9.6% recurrent meningiomas (first biopsy) and 19.6% of successive recurrent meningiomas. Loss of p16INK4a and p14ARF protein expression was shown in 52.7% and 18.6% of meningiomas respectively. p16INK4a and p14ARF methylation was associated with loss of protein expression in 54.7% and 18.8% of meningiomas. Loss of p16INK4a and p14ARF expression was associated with unmethylated promoters in 52.9% and 17.6% of cases respectively. Conclusions: Epigenetic changes of p16INK4a and p14ARF genes and loss of protein expression leading to Rb and p53 TSG pathways alterations, may have a pathogenic role in human meningiomas. Loss of p16INK4a and p14ARF protein expression associated with unmethylated promoters, could be due to loss of heterozigosity or gen mutation. Increase of p16INK4a and p14ARF methylation along the following biopsies of recurrent cases suggests a possible role of methylation in tumor progression.
Induction of atypical anoikis in glioma cells through inhibition of integrin functions.
Authors: Roth Patrick , Silginer Manuela , Weller Michael
Published: March 2020

2079

Background: Integrins regulate cellular adhesion and transmit signals important for cell survival, proliferation, differentiation and motility. Both αvβ3 and αvβ5 integrins are upregulated in glioma cells, and therefore, integrin inhibition may represent a promising therapeutic strategy in glioblastoma. Methods: SMA-560 and GL-261 mouse glioma cells were cultured as adherent monolayers in serum-containing medium or as sphere cultures in neurobasal medium. Integrin function was inhibited using RNA interference, blocking antibodies or pharmacological inhibitors. Cell death after integrin inhibition was examined by flow cytometry. Immunoblot was used to assess apoptosis and autophagy. Results: GL-261 and SMA-560 glioma cells grown under standard conditions uniformly detached and formed large cell clusters after integrin gene silencing or pharmacological inhibition using EMD-121974 (cilengitide), a synthetic Arg-Gly-Asp-motif peptide, or GLPG0187, a non-peptidic integrin inhibitor. After 120 h, the clusters induced by integrin inhibition disintegrated and cells died. In contrast, no morphological effects were observed when cell lines were grown as stem-like sphere cultures. Since Poly-HEMA-mediated detachment had similar effects on cell viability as integrin inhibition, we postulated that cell death may result from detachment alone which was confirmed using various permissive and non-permissive substrates. No signs of apoptosis or autophagy were found using Annexin V/PI staining, DEVD-amc cleaving assay or caspase-3 and LC3A/B immunoblot. Recently, we demonstrated that integrin inhibition results in an inhibition of the TGF-β pathway in human glioma cells. Addition of recombinant TGF-β2 indeed partially rescued integrin inhibition-induced cell death, whereas exposure to the TGF-β receptor inhibitor SD-208 increased the number of dead cells. Conclusions: Cell death following integrin inhibition is essentially necrotic and may involve the TGF-β pathway.
Effect of silencing thymosin beta 4 gene expression on stemness and invasiveness in glioblastoma.
Authors: Tabatabai Ghazaleh , Krishnan Shanmugarajan , Florea Ana-Maria , Frei Karl , Hasenbach Kathy , Reifenberger Guido , Krayenbuehl Niklaus , Weller Michael , Wirsching Hans-Georg
Published: March 2020

2081

Background: Thymosin β4 (TB4) is a pleiotropic actin-sequestering polypeptide that is involved in wound healing and developmental processes. TB4 gene silencing promotes differentiation of neural progenitor cells whereas TB4 overexpression initiates cortical folding of developing brain hemispheres. However, a role of TB4 in malignant gliomas has not yet been investigated. Methods: We first analyzed TB4 expression on tissue microarrays and performed REMBRANDT and TCGA database interrogations. We analyzed TB4 expression in a panel of 8 long-term glioma cell lines and 7 glioma-initiating cell lines. Using lentiviral transduction, we modulated TB4 expression in LNT-229, U87MG and the glioma-initiating cell line GS-2. We studied clonogenic survival, migration, invasion, self-renewal, differentiation capacity of TB4-depleted or TB4-overexpressing glioma cells in vitro and tumorigenicity upon orthotopic implantation in vivo. Finally, we performed an Affymetrix gene chip analysis to unravel the molecular network of TB4 signaling effects. Results: TB4 expression increased with the grade of malignancy in gliomas and correlated with patient survival. In vitro, TB4 gene silencing by lentiviral transduction decreased migration, invasion, growth and self-renewal, and promoted differentiation and the susceptibility to undergo apoptotic cell death upon nutrient depletion in LNT-229, U87MG and the glioma stem-cell line GS2, respectively. In vivo, survival of nude mice bearing tumors derived from TB4-depleted glioma cells was improved and the tumorigenicity of the GS2 glioma stem-cell line was decreased. The gene expression pattern was shifted from the mesenchymal towards the pro-neural gene signature upon TB4 gene silencing. The clustering of differentially regulated genes involved TGF-β and p53 signaling networks. Conclusions: TB4 may be a key regulator of malignancy in glioblastoma and therefore a novel candidate molecular target for anti-glioma therapies.
Association of human neurotropic JC virus with pediatric gangliogliomas.
Authors: Mullinax Jennifer Rose , Parker Struckhoff Amanda , Trillo-Tinoco Jimena , Ripple Michael , Craver Randall , Del Valle Luis
Published: March 2020

2085

Background: JC virus (JCV), a member of the Polyomaviridaefamily, is a widespread ubiquitous human pathogen found in greater than 80% of the adult population, where it persists in a latent state, most likely in the kidneys and bone marrow. JCV is tumorogenic in animals and is associated with a variety of human malignancies, including brain tumors where it infects glial cells. JCV exerts its oncogenic effects through the oncoprotein T-Antigen, which binds and inactivates tumor suppressor proteins p53 and Rb. In addition, T-Antigen can translocate IRS-1 to the nucleus, where it impedes faithful DNA repair. In this study, we will investigate the presence of JC virus and the oncoprotein T-Antigen and explore their role in pediatric gangliogliomas. Methods: Formalin-fixed paraffin-embedded tissue samples of pediatric gangliogliomas were obtained from the archives of the Pathology Department at Children’s Hospital in New Orleans. PCR amplification was performed with specific primers for the T-Antigen coding region of JCV. Immunohistochemistry for T-Antigen, p53, Rb, and IRS-1, the docking molecule of the IGF-1 pathway, was also performed. Results: Our study included 15 samples of pediatric gangliogliomas. JCV genomic sequences were amplified in 12 of the 15 samples (80%). T-Antigen expression was found in the nuclei of tumor cells in 7 of the 15 samples (47%) by immunohistochemistry. T-Antigen was present in both the glial and neuronal components of the tumors. Of the seven samples positive for T-Antigen, five were positive for both p53 and Rb, one was positive for p53, and one was negative for both p53 and Rb, but positive for nuclear IRS-1. Conclusions: The presence of JCV genomic sequences in pediatric tumors suggests that primary infection occurs early in life. The expression of T-Antigen in both the glial and neuronal components of gangliogliomas suggests that these mixed tumors most likely originate in a common primitive cell, which then differentiates into two different phenotypes. The co-localization of T-Antigen with p53 and Rb suggests that cell cycle deregulation is one oncogenic pathway in gangliogliomas. Nuclear IRS-1 suggests alterations on faithful DNA repair mechanisms. These findings warrant further investigation.
C-met, a new prognostic biomarker in glioblastoma multiforme.
Authors: Dahlrot Rikke Hedegaard , Petterson Stine Asferg , Hermansen Simon Kjaer , Kristensen Bjarne Winther , Hansen Steinbjorn
Published: March 2020

2088

Background: C-met is a tyrosine kinase receptor involved in growth, invasiveness and malignant progression in glioblastoma multiforme (GBM). Activation of the C-met pathway increases resistance towards DNA damage in glioma cell lines and it has been shown that an orally administrated C-met kinase inhibitor inhibits intracranial glioma growth in immunodeficient mice, suggesting that C-met is a potential target in glioma treatment. The purpose of the present study was to investigate the prognostic value of C-met in GBMs and subsequently correlate the prognostic value to known clinical variables, identified in a population-based cohort. Methods: Tissue samples from 186 GBM patients were analyzed using immunohistochemical staining and advanced quantitative image analysis. This provided continuous measurements based on staining intensity. Results: Median intensity was 70.8 (range 15.5-200.1). When divided at the median C-met was not prognostic. Further exploration showed that dichotomizing at an intensity of 75 (60% vs. 40%), high levels of C-met were associated with poor survival. However; C-met is a time-dependent factor and no prognostic effect was observed within the first 8.5 months after diagnosis (HR 0.97, 95% CI 0.62-1.51, p = 0.892). After 8.5 months, patients with high levels of C-met had a significantly poorer survival as compared to patients with low levels (HR 2.06, 95% CI 1.33-3.18, p = 0.001). This was significant in multivariate analysis adjusted for clinical variables; C-met (HR 1.89, 95% CI 1.22-2.93, p = 0.004), age (HR 1.02, 95% CI 1.00-1.03, p = 0.037), performance status (HR1.55, 95% CI 1.38-1.74, p = 0.004), and tumor crossing midline (HR 1.72, 955 CI 0.75-3.92, p = 0.201). Interestingly; C-met was only prognostic in patients who received post-surgical treatment, whereas no effect was observed in the 31 patients who underwent surgery only (HR 0.54, 95% CI 0.26-1.15, p = 0.113). Conclusions: Using advanced quantitative image analysis, we found that C-met was an independent prognostic factor of poor survival in GBMs. The effect did not appear within the first 8.5 months after the diagnosis and it was only seen in patients who received post-surgical treatment.
Effect of metformin and statins in high-grade brain tumors.
Authors: Lee Guek Eng , Tan Iain B. , Tham Chee Kian
Published: March 2020

2091

Background: Metformin and statins are thought to have anti-cancer properties. Metformin induces AMPK activation and may be implicated in potentiating the therapeutic outcome of temazolamide. Statins at low dose are thought to have anti-cancer properties by inhibiting pro-angiogenic factors with resultant inhibition of tumor growth, but statins at high dose are thought to have counter-productive effects. Hyperglycaemia was shown to be associated with a poorer outcome in patients with newly diagnosed glioblastoma. Hence we investigate the effect of metformin and statins in high grade brain tumours. Methods: Among 249 patients with brain tumour, we identified 142 patients with high grade gliomas. 116 patients did not receive metformin or statins and 26 patients received metformin or statins. Patients’ demographics, clinical and histopathological characteristics were recorded. Overall survival was evaluated. Results: Among 142 patients with high grade gliomas, there were 86 patients with glioblastoma multiforme, and 56 patients with anaplastic astrocytoma or anaplastic oligodendroma. Median age was 60 years old. The average value of HbA1c value for patients on metformin was 7.2%. The average dose of simvastatin used was 20 mg and average total cholesterol was 5.1mmol/l. For patients who did not receive metformin or statins, the median survival was 72.9 months (95% confidence interval, 47.8 – 98.1); patients who received metformin or statins, the median survival was 39.1 months (95% confidence interval, 21.7 – 56.4) p = 0.24. Conclusions: There is a trend towards shorter overall survival of patients who received metformin and statins. Despite the anti-cancer properties of metformin and statins, patients with diabetes mellitus and hyperlipidaemia still fare worse. The effect of diabetes mellitus, hyperlipidaemia, as well as sugar and cholesterol control deserves a larger cohort study in patients with high grade brain tumours.
Phase I/II study of dianhydrogalactitol in patients with recurrent malignant glioma or progressive secondary brain tumor.
Authors: Peyton James D. , Burris Howard A. , Bacha Jeffrey A. , Brown Dennis , Garner William J. , Schwartz Richard Stephen , Shih Kent C.
Published: March 2020

2093

Background: Recurrent glial tumors of the brain continue to be one of the most challenging malignancies to treat, and median survival for patients with recurrent disease is approximately 6 months for glioblastoma multiforme (GBM). The front-line therapy for GBM - temozolomide (TMZ) - is subject to resistance by DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT), leading to poor prognoses for patients with recurrent GBM. Dianhydrogalactitol (VAL-083)is a first-in-class bi-functional N7 DNA alkylating agent shown to cross the blood-brain barrier, accumulate in brain tissue, and have activity against GBM. Studies suggest that VAL-083 overcomes MGMT-driven drug resistance in vitro and targets cancer stem cells. The purpose of this study is to determine the maximal tolerated dose (MTD) of VAL-083 in patients with recurrent GBM or progressive secondary brain tumor, and explore the safety, pharmacokinetics and tumor responses to treatment. Methods: Open-label phase I/II dose-escalation study of VAL-083 in patients with histologically confirmed primary WHO grade 4 malignant GBM, now recurrent, previously treated for GBM with surgery and/or radiation, if appropriate, and have failed both bevacizumab and temozolomide; or progressive secondary brain tumor, has failed standard brain radiotherapy, and has brain tumor progression after at least one line of systemic therapy. The study uses a 3 + 3 dose escalation design, until reaching the MTD or maximum specified dose. Patients receive IV VAL-083 on days 1, 2, and 3 of each 21-day treatment cycle. In phase II, additional patients are treated at the MTD (or selected optimum dose) to measure tumor responses. Results: Cohort 1 (3 patients) and cohort 2 (4 patients) were completed without any DLT’s. Adverse events (AEs) have all been grade 1/2, with only 1 grade 3 AE, unrelated to treatment. Cohort 3 currently has 4 patient enrolled, without reaching the MTD. 1/7 (14.3%) patients in cohorts 1and 2 has prolonged stable disease (15+ cycles) on VAL-083 treatment. Conclusions: VAL-083 up to the 2nd dose level was well tolerated without any safety signals. Dose escalation is continuing. Clinical trial information: NCT01478178.
Phase I trial of temsirolimus (TEM) and perifosine (PER) for recurrent or progressive malignant glioma (MG).
Authors: Kaley Thomas Joseph , Pentsova Elena , Omuro Antonio Marcilio Padula , Mellinghoff Ingo K. , Nolan Craig , Gavrilovic Igor T. , DeAngelis Lisa Marie , Lacouture Mario E. , Holland Eric C. , Lassman Andrew B.
Published: March 2020

2095

Background: PI3K/AKT/mTOR signaling is important in MG biology, and therefore a potential therapeutic target. The mTOR inhibitor TEM and the AKT inhibitor PER are well tolerated as single agents but have limited activity. Preclinical data demonstrate synergistic anti-tumor effects during combined therapy including extensive tumor apoptosis, cell-cycle arrest among surviving cells, and inhibition of both AKT and mTOR. Therefore, we initiated a phase I trial of combined therapy in recurrent MGs. Methods: Adults with recurrent MG, KPS≥60, and not taking enzyme inducing AEDs were enrolled. There was no limitation on prior therapies except prior RT and temozolomide were mandatory. The dose of TEM was escalated in each cohort using standard 3 + 3 design from 15 mg to 170 mg administered once weekly. The dose of PER was fixed as a 600 mg load on day 1 followed by 100 mg nightly (the single dose MTD) until dose level 7 when the load increased to 900mg. Results: Thirty-four patients (24 men) with median age 52 (range, 21-71) and median KPS 80 (range, 60-100) participated. Diagnoses included GBM (18), AA (7), AO (7) or transformed LGG (2). Twenty-one received bevacizumab previously. There were a total of 5 DLTs: 1 at dose level 3 (50mg TEM), then 2 at dose level 7 expansion (170mg TEM), and then 2 at dose level 6 expansion (170mg TEM). DLTs included thrombocytopenia (n=3), intracerebral hemorrhage (n=1) and lung infection (n=1). Two uPR were seen at 170mg TEM. Grade 3 non-dose limiting toxicities per patient included lymphopenia (7), hyperglycemia (4), anemia (2), neutropenia (1), transaminitis (3), hypophosphatemia (3), hypercholesterolemia (3), thrombocytopenia (2), and mucositis (2). The MTD is defined as 115mg TEM (dose level 5). Conclusions: Combination therapy with TEM 115 mg weekly and PER 100 mg daily (following 600 mg load) is tolerable in heavily pre-treated adults with recurrent MGs. Clinical trial information: NCT01051557.
Graded prognostic assessment index for breast cancer patients with brain metastases (BCBM).
Authors: Alva Venur Vyshak , Dahiya Saurabh , Du Lingling , Garje Rohan , Osei-Boateng Kwabena , Elson Paul , Suh John H. , Chao Samuel T. , Ahluwalia Manmeet Singh
Published: March 2020

2096

Background: The Graded Prognostic Assessment (GPA) is a commonly used prognostic index based on RTOG protocols in patients with brain metastases (BM). The purpose of this study was to evaluate prognostic factors to predict for overall survival (OS) in breast cancer BM (BCBM) treated at a single tertiary care center. Methods: After obtaining IRB approval, the Cleveland Clinic Brain Tumor and Neuro-Oncology Center’s database was used to identify BCBM who were treated in the recent years (2000-12). A proportional hazards model was used to assess OS, which was measured from the date of diagnosis of brain metastases to death or last follow-up. Results: 161 BCBM (160 females) median age 52 years (range 27-84) were included for analysis. 48% of patients were ER positive, 31% were PR positive, 50% were HER2 positive while 31% of patients were triple negative. The median number of BM was 2 (range, 1-15). Karnofsky Performance Scale (KPS) of the patient was 90-100 in 50%, 70-80 in 47%) and <70 in 43%. Extracranial Metastases was present in 85% of patients. Overall 85% of patients had died at the time of analysis; median OS was 19.0 months (95% C.I. 15.7-23.2). Breast GPA that includes age, KPS and subtype was 0-1.0 in 5%, 1.5-2 in 31%, 2.5-3 in 35% and 3.5-4 in 29% of patients. Although GPA was statistically significant (p=0.002), some but not all of the factors used to derive it were significant (KPS [p=0.05],subtype [p=0.003] age [p=0.50]). Factors noted to be independently prognostic for OS (multivariable Cox proportional hazards model) included location of BM, number of extracranial metastases and uncontrolled primary tumor (Table). Conclusions: New GPA based on a set of independent prognostic factors is proposed. [Table: see text]
Post-bevacizumab treatment and clinical outcomes in recurrent malignant glioma.
Authors: Cha Yongjun , Kim Yu Jung , Kim Tae Min , Choi Seung Hong , Lee Se-Hoon , Kim Dong-Wan , Park Chul-Kee , Kim Il Han , Kim Jee Hyun , Kim Eunhee , Choi Byung Se , Kim Chae-yong , Kim In Ah , Heo Dae Seog
Published: March 2020

2098

Background: Bevacizumab (Bev) and irinotecan combination therapy is effective against recurrent malignant glioma. However, post-Bev treatment and its clinical outcomes are not well investigated. Methods: We identified 103 consecutive recurrent malignant glioma patients who received Bev plus irinotecan at our institutions.Clinical records and magnetic resonance images were reviewed. Response and progression were assessed by RANO criteria. Results: Bev and irinotecan treatment produced response rate of 37.9% (95% CI, 29.1-47.5%). At a median follow-up time of 41 weeks, the median progression-free survival (PFS) was 17.1 weeks (95% CI, 14.3-20.0), and 6-month PFS (6M-PFS) was 27.8% (95% CI, 18.4-37.2). The median overall survival (OS) was 33.4 weeks (95% CI, 27.8-39.1). Response predicted for superior PFS (25.0 weeks vs. 11.0 weeks, p < .001) and OS (45.9 weeks vs. 26.7 weeks, p < .001). A total of 93 patients discontinued Bev treatment and the reasons for discontinuation were: disease progression in 59 (63.4%), toxicities in 4 (4.3%), physician’s decision in 5 (5.4%), patient’s refusal to further treatment in 25 (26.9%). The median OS was 26.7 weeks in 59 patients who discontinued Bev due to disease progression, and 45.7 weeks in 34 patients who discontinued Bev for reasons other than disease progression (p < .001). Among 85 patients who progressed after Bev, 42 (49.4%) received further therapy: chemotherapy in 32 (37.6%), radiotherapy in 9 (10.6%), and surgery in 1 (1.2%). Further chemotherapy regimens included temozolomide (31.2%), ACNU/CDDP (25.0%), Bev reintroduction (18.8%), erlotinib (12.5%), PCV (9.4%), and intrathecal methotrexate (3.1%). The median survival time after Bev failure was 15.6 weeks (95% CI, 13.3-17.8). Patients who received further therapy showed longer median OS (18.6 weeks vs. 12.9 weeks, p < .001). In patients who received chemotherapy, the median PFS and OS was 6.6 weeks and 20.6 weeks, respectively. Conclusions: Prognosis after Bev failure was poor. Proper selection of patients who may benefit from further treatment is warranted.
Vorinostat as a radiosensitizer for CNS malignancies: Preclinical results and phase I trial in brain metastasis.
Authors: Shi Wenyin , Lawrence Yaacov Richard , Choy Hak , Wachsberger Phyllis R. , Andrews David W. , Werner-Wasik Maria , Dicker Adam
Published: March 2020

2100

Background: To evaluate the effect of vorinostat as radiosensitizer in human Glioblastoma cell lines in preclinical study, as well as a phase I study to evaluate the safety, and tolerability of vorinostat, an HDAC inhibitor, when combined with whole brain radiation treatment (WBRT) for patients with brain metastasis. Methods: Preclinical studies evaluated the effect of vorinostat on DNA repair enzyme expression, repair of radiation induced DNA damage, and cell survival to radiation treatment as a proof of concept. Further phase I clinical trial included patients with histological diagnosis of malignancy and radiographic evidence of brain metastasis. WBRT was 37.5 Gy in 2.5 Gy fractions delivered over 3 weeks. Vorinostat was administrated by mouth, once daily, Monday through Friday, concurrently with radiation treatment. The vorinostat dose was escalated from 200 mg to 400 mg daily using a 3+3 trial design. Results: Preclinical studies showed with increasing doses of vorinostat more profoundly decrease expression of key genes involved in DNA repair, inhibiting the repair of DNA damage induced by ionizing radiation and leading to decreased clonogenic survival. It enhanced the radiation effect in vitro. In the phase I trial, 17 patients were enrolled, 4 patients were excluded from the analysis due to either incorrect radiation dose (n=1), or early treatment termination due to disease progression (n = 3). There were no treatment related grade 3 or higher toxicities in the 200 mg and 300 mg dose levels. In the 400mg cohort there was a grade 3 pulmonary embolus and one death within 30 days of treatment. Although both events were most likely related to disease progression rather than treatment. However, to be more conservative, we defined the death as a dose limiting toxicity. Conclusions: Preclinical studies demonostrated that vorinostat profoundly decrease expression of key genes involved in DNA repair, inhibiting the repair of DNA damage induced by ionizing radiation and leading to decreased clonogenic survival. Vorinostat administered orally once daily with concurrent whole brain radiation treatment is well tolerated to the dose of 300 mg. This is the recommended dose for phase II study. Clinical trial information: NCT00838929.
Characterization of the exposure-response relationship leading to recommendations for dosing optimization in a new drug application review.
Authors: Yang Jun , Mehrotra Nitin , Zhao Hong , Giusti Ruthann Marie , Demko Suzanne , Keegan Patricia , Booth Brian , Rahman Nam Atiqur
Published: March 2020

2510

Background: On November 29 2012, the U. S. FDA approved cabozantinib (COMETRIQ) for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC). Drug-related toxicity was common at a dose of 140 mg once daily across Phase 1 to Phase 3 trials submitted in this NDA. During the review of this application, these safety findings raised the question whether the optimal cabozantinib dose was selected for the treatment of MTC. Exposure-response (E-R) analyses were performed to assess the appropriateness of the cabozantinib dose. Methods: The data were obtained from an international, multi-center, randomized (2:1), placebo-controlled trial enrolling 330 patients with metastatic MTC. To account for variable exposure levels due to dose modification and inter-individual pharmacokinetic variability, average exposure (Starting Dose*Dose intensity/individual CL/F) was used as the exposure metric in the E-R analyses. The relationships between cabozantinib exposure and progression free survival (PFS), and selected safety endpoints including diarrhea, palmar-plantar erythrodysesthesia (PPE) syndrome and time to dose modification (TTDM) were evaluated. Results: Kaplan-Meier analyses of PFS for each quartile of average cabozantinib exposure suggest that patients with lower exposure and those with higher exposure may have equivalent PFS, comparatively. The multivariate Cox proportional analysis identified individual patient’s clearance as a significant covariate for prediction of TTDM with a hazard ratio of 1.95 (95% CI [1.47-2.59]), suggesting that patients with higher exposures required dose modification earlier than patients with lower exposures. The results of the E-R analyses may be difficult to interpret due to the high rate of dose modification. Nevertheless, these results indicate that a lower dose may be as effective with improved tolerability. Conclusions: The E-R analyses along with the observed safety and efficacy data in the clinical trials led to an FDA requirement to conduct a post marketing clinical trial to evaluate the safety and efficacy of a lower cabozantinib dose.