bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.