bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy and safety of radiotherapy (RT) plus temozolomide (TMZ) in elderly patients (EP) with glioblastoma (GBM).
Authors: Lombardi Giuseppe , Bellu Luisa , Berti Franco , Farina Patrizia , Galuppo Sara , Zustovich Fable , Della Puppa Alessandro , Carollo Carla , Bertorelle Roberta , D'Avella Domenico , Zagonel Vittorina 
Published: March 2020

2043 Background: the optimal management of EP with GBM remains controversial. The role of RT with TMZ for EP is unclear, and EP are often treated with RT alone, TMZ alone or palliative approaches. We describe our experience of combining RT with concurrent TMZ for treatment of EP with GBM Methods: medical records of patients ≥65 years old with newly GBM, histologically confirmed at Veneto Institute of Oncology – Padua, and treated with RT plus TMZ, were reviewed. Concomitant TMZ was 75mg/m2/die. The adjuvant treatment consisted of TMZ 150-200mg/m2/die for six cycles. Median progression-free survival(PFS) and overall survival(OS) were estimated with Kaplan-Meier method. Toxicity was scored according to CTCAE 4.0 Results: we analyzed 60 patients(PTS), 34 males and 26 females; the average age was 70 (range 65-82); ECOG PS was 0-1 in 35 PTS and 2 in 25 PTS; complete surgery was performed in 35 PTS, partial surgery in 25 PTS. 40 and 20 PTS received RT within 6 or more weeks (range 7-9) from surgery. MGMT and IDH1 were analyzed in 43 PTS: MGMT methylated in 20 PTS (46%), all PTS had wild-type IDH1. 34 PTS were treated with RT 40Gy in 15 fractions, 26 PTS with RT 60Gy in 30 fractions with no significant difference in ECOG PS, MGMT and type of surgery between the two subgroups. For all PTS, PFS and OS were 9.5 and 12.7 ms, respectively. OS was 13.7 and 12.4 ms (p=0.9) in PTS receiving RT within 6 or more weeks from surgery, respectively. 13% of PTS showed grade 3-4 haematological toxicity, 12% grade 3-4 asthenia, 3% nausea/vomiting. MGMT methylated and complete surgery was associated with a longer survival. PFS was 9 vs 10 months (p=0.4) and OS was 11.7 vs 13.7 ms (p=0.1), for PTS treated with 40Gy and 60Gy, respectively. Regarding toxicity: grade 3-4 haematological toxicity was 9% vs 23%, severe asthenia was 9% vs 15%, nausea/vomiting was 3% vs 4% of PTS receiving RT 40Gy and 60Gy, respectively. Conclusions: RT plus TMZ is effective and safe in EP with GBM and good ECOG PS. PFS and OS was not statistically different between PTS receiving RT 40Gy or 60Gy, although we showed a trend for longer OS with RT 60Gy; in contrast, severe toxicity was higher in PTS with RT 60Gy. OS was similar between PTS receiving RT within 6 or more weeks (7-9ws) from surgery.
Quality of life (QOL) and cognitive status among irradiated brain tumor survivors treated with donepezil or placebo.
Authors: Case Doug , 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 Jeffery , Giguere Jeffrey K. , Erickson Nicholette , Loghin Monica Elena , Shaw Edward G. , Rapp Stephen R. 
Published: March 2020

2051 Background: Cognitive problems after cancer therapy can decrease QOL. This phase III randomized trial tested the effect of donepezil (5-10 mg daily for 24 weeks) on cognition and QOL in brain cancer patients. Methods: Between 2/2008-12/2011, 198 (99 placebo; 99 donepezil) adult primary and metastatic brain tumor survivors > 6 months post radiation (> 30 Gy) were recruited at 24 sites affiliated with the Wake Forest CCOP Research Base, 3 CTSU sites, and M.D. Anderson. Outcomes were assessed at baseline, 12 and 24 weeks. Regression analyses examined the association of demographics, fatigue (FACIT-Fatigue), and a cognitive performance composite score (CC) (comprised of the Controlled Oral Word Association Test, Hopkins Verbal Learning Test-Revised, Digit Span Test, Trail Making Test A&B, Rey-Osterreith Complex Figure-modified, Grooved Pegboard) on QOL, measured by the FACT-Brain (FACT-Br) total score. Results: Participants had a median age of 55, were predominantly female (54%) and non-Hispanic White (91%), with a median time from diagnosis of 38 months. Study completion was 74%. At 12 and 24 weeks, treatment had no significant effect on QOL, unadjusted and adjusted for race/ethnicity, age, sex, fatigue, baseline FACT-Br, and baseline CC. However, for those below the median on the baseline FACT-Br subscale (i.e., greater cognitive symptoms), donepezil was associated with higher (better) post-tx FACT-Br total scores (p =0.004), unadjusted for covariates. After adjustment for covariates, donepezil was borderline significantly associated with higher post-tx QOL (p=0.052). Improvement in QOL was associated with being female (p=0.017) and less baseline fatigue (p=0.005). For participants with baseline FACT-Br subscale scores above the median, only lower baseline FACT-Br total scores (p=0.015) were significantly related to greater improvements in FACT-Br. Donepezil treatment was not significant (p=0.48). Conclusions: The impact of donepezil on QOL was greater in survivors with more cognitive symptoms at baseline, although the results were borderline significant. Fatigue continued to be a major factor in lower QOL. Other interventions to better manage survivors’ symptoms are needed. Clinical trial information: NCT00369785.
Patterns of relapse after concurrent temozolomide and dose-escalated intensity-modulated radiation therapy (IMRT) in newly diagnosed glioblastoma (GBM).
Authors: Speers Corey , Junck Larry , Heth Jason , Cao Yue , Lawrence Theodore Steven , Tsien Christina 
Published: March 2020

2052 Background: We hypothesized that IMRT would permit us to safely escalate the dose of radiation with concurrent temozolomide substantially above the current standard of 60 Gy and that this increased dose would more adequately control local disease leading to an alteration in the patterns of relapse in patients with GBM. Methods: Between 2003 and 2012 a total of 69 patients were treated with dose-escalated IMRT with concurrent temozolomide. 39 patients were initially treated in a combined phase I/II trial with IMRT doses of 66 to 81 Gy over 6 weeks with concurrent daily temozolomide (75 mg/m2) followed by adjuvant cyclic temozolomide (200 mg/m2 d1-5 q28d for 6 or more cycles). Subsequently, 30 additional patients were treated to 66-72 Gy based on the reported efficacy and safety of the initial phase I/II study. Results: All 69 patients were assessed to evaluate the effect of dose escalation on late toxicity and patterns of progression. Median RT dose was 72 Gy and median overall survival was 19.0 months. Late CNS grade III toxicity was observed at 78 (2 of 7 patients) and 81 Gy (1 of 9 patients). 0 of 53 patients receiving 75 or less Gy developed necrosis. 64% (44/69) of patients had progression of their disease after dose-escalated chemoradiotherapy. The patterns of progression differ, however, from previous studies which identify in-field relapse of 72-80% with standard dose radiation (Brandes AA, Tosoni A, Franceschi E, et al: J Clin Oncol. 27:1275-9, 2009). In this cohort, 41% (18/44) of patients developed marginal or distant relapse compared to 59% (26/44) who developed local, in-field relapse. Conclusions: Patients with GBM can safely receive standard temozolomide with up to 75 Gy in 30 fractions, delivered using IMRT. Dose-escalated chemoradiotherapy improves local control and leads to an increased percentage of patients progressing distally, highlighting the need for improved tumor targeting with newer imaging modalities to identify the initial extent of tumor involvement as well as the need for more effective systemic treatment. I/II study.
Phase I adult brain tumor consortium (ABTC) trial of ABT-888 (veliparib), temozolomide (TMZ), and radiotherapy (RT) for newly diagnosed glioblastoma multiforme (GBM) including pharmacokinetic (PK) data.
Authors: Kleinberg Lawrence , Supko Jeffrey G. , Mikkelsen Tom , Blakeley Jaishri O'Neill , Stevens Glen , Ye Xiaobu , Desideri Serena , Ryu Samuel , Desai Bhardwaj , Giranda Vincent L. , Grossman Stuart A. 
Published: March 2020

2065 Background: ABTC conducted a dose finding trial of ABT-888, an orally administered Poly(ADP-ribose) polymerase [PARP] inhibitor, during daily TMZ with post-operative RT for GBM. PARP is important in repair pathways for RT induced DNA injury and TMZ induced alkylation at N7-methylguanine and N3-methyldenine. Methods: An initial safety group (no concurrent RT), received ABT-888 10 mg BID po during 42 days of daily TMZ 75 mg/m2. After this, the planned dosing steps included ABT-888 BID concurrent with standard RT and TMZ, with planned ABT-888 dose escalation or de-escalation based on observed toxicity. Dose limiting toxicity (DLT) is ≥ grade 3 non-hematologic or neurologic not responding to steroids, and hematologic ANC<500/mm3 and platelets (PLT) < 25K/mm3. The pharmacokinetics (PK) of ABT-888 were characterized for dose 1 and at steady-state. Results: Without concurrent RT, DLT (thrombocytopenia) occurred in 1/6 patients. With concurrent RT/TMZ and ABT-888 10 mg BID, 4/12 patients had DLT (thrombocytopenia). As per the planned dose de-escalation, ABT-888 10 mg BID was then given every other week during TMZ/RT. This resulted in 3/6 patients with DLT (2 thrombocytopenia, 1 neutropenia). The hematologic toxicity with this regimen was judged high enough that accrual was discontinued. In the setting of continuous dosing for 6 weeks, the total body clearance of ABT-888 for the first dose (27.5±9.5 L/h, n = 15) and at steady-state after BID dosing (23.5±10.4 L/h, n = 18) were similar. Accumulation for BID dosing was 56±33%. Steady-state peak and trough concentrations of the drug in plasma were 66±29 ng/mL and 18±10 ng/mL, respectively. Additional PK data will be presented. Conclusions: Administering ABT-888 BID po in combination with standard RT/TMZ was not tolerable in GBM patients as a result of hematologic toxicity. ABT-888 PK in GBM patients were very similar to findings reported for solid tumor patients. There is strong scientific rationale for continued development of an appropriate dosing regimen for this agent in the initial therapy of GBM. Clinical trial information: NCT00770471.
Retrospective multicentric study on adult intramedullary spinal cord gliomas from a cohort of 319 patients.
Authors: Campello Chantal , Parker fABRICE , Slimani Sonia , Le Floch Anne , Aghakhani Nozar 
Published: March 2020

2068 Background: Intramedullary spinal cord tumors (IMST) are among the rarest types of tumors, account for 2 to 4% of all central nervous system tumors. This study was conducted to describe clinical features, radiological imaging, anatomopathological characteristics, management and outcome of neuroepithelial IMST. Methods: in this retrospective review, a total of 319 patients were included from 7 French neurosurgical University Hospital Centers, between 1984 and 2011. The patient’s pre and postoperative neurological state were classified according to the Mac Cormick scale. Only patients with a preoperative MRI and confirmed histological were included. Results: Mean age at diagnostic was 42.4 for ependymomas, 39.6 for astrocytomas, (included 20 patients older than 65 years old). The male/female ratio was 1.6 for ependymomas, and 1.1 for astrocytomas. Ependymomas were associated with neurofibromatosis in four patients. Pain was the most common presenting symptom (74%), followed by motor (72%), and sensory (66%) complaints. Pre and post operative neurological states were more severe in astrocytomas than ependymomas. The most frequently involved localization was the cervical region for ependymomas, and the thoracic region for astrocytomas. Partial and total resection was achieved in 80% of ependymomas, and 20% of astrocytomas, (diagnostic of other tumors was performed by biopsy). Histological types, according to WHO classification were ependymomas in 72% patients, (94% were low grades), astrocytomas in 24% patiens, (29% were high grades), oligoastrocytomas in 2.4% , and oligodendrogliomas in 1.7%. Postoperative radiotherapy was used especially in high-grade tumors, (67% of ependymomas, 71% of astrocytomas), in absence of severe toxicity. 18% of low-grade astrocytomas received radiotherapy. Chemotherapy was used only in 33% of ependymomas and 24% of astrocytomas. The five-year overall survival rate was 76.8% for astrocytomas, and 94.5% for ependymomas. Conclusions: Histology, preoperative functional score, and grades tumors are confirmed as prognostic factors in this study. Questions about adjuvant therapy for astrocytomas, like intracranial tumors, are answered.
An EGFRvIII-specific IHC IUO test for patient selection in AMG 595 phase I trial.
Authors: Damore Michael A. , Coberly Suzanne K. , Wakamiya Karen , Webster Scott , Tanna Vaishali , Xu Xiaolei , Klement Ivan , Welcher Rosanne , Kiaei Panteha , Liu Yi , Samayoa Kimberly , Wong Susan , Shamon-Taylor Lisa , Friberg Gregory R. , Hill John S. , Patterson Scott D. 
Published: March 2020

2071 Background: EGFRvIII is a mutant version of EGF receptor resulting from the genomic deletion of exons 2 through 7 and is expressed only in certain tumors. AMG 595 is an experimental therapeutic specifically targeting EGFRvIII and consists of an EGFRvIII-specific antibody conjugated to the maytansinoid antimicrotubule agent DM-1. Due to its specificity, mechanism of action, and pre-clinical activity, AMG 595 is expected to have clinical effect only in tumors expressing EGFRvIII. Since the reported prevalence of EGFRvIII in glioblastoma multiforme (GBM) is ~30%, prospective selection of patients with EGFRvIII positive tumors was desired for clinical development. An immunohistochemical (IHC) assay developed with Dako using a novel EGFRvIII antibody is currently being employed for patient selection for the AMG 595 phase I study in recurrent GBM (NCT01475006). Methods: An appropriate IHC reagent for human tissue was created using the variable region of a novel EGFRvIII-specific antibody developed using Xenomouse technology. Staining conditions were optimized using Dako pharmDx reagents, the Dako Link 48 Autostainer, and FFPE tissue sections. Confirmatory transcript analyses of adjacent sections were conducted using the NanoString platform. Results: Robust and reproducible staining for EGFRvIII was observed using archived GBM resections. Percentage of stained cells correlated with levels of EGFRvIII transcripts, and tumors without staining did not express EGFRvIII transcripts. Although some tumors exhibited homogenous staining, most were heterogeneous with varying distribution and percentages of stained tumor cells similar to literature reports of IHC analysis utilizing other EGFRvIII-specific antibodies. Tumor samples from patients entering into the AMG 595 Phase 1 study analyzed with this IHC test have displayed the predicted staining prevalence. Conclusions: The developed EGFRvIII IHC assay, approved under an Investigational Device Exemption, is currently being successfully employed to prospectively select patients in an ongoing phase I trial. Use of this well characterized IHC test will enable correlation of clinical outcome and staining characteristics to inform subsequent studies.
Genotypes of human glioma xenografts compared with glioma stem cell-derived tumors.
Authors: Chen Selby , Peterson Timothy , Anderson S. Keith , Eckel-Passow Jeanette , Decker Paul A. , Sarkaria Jann Nagina , Parney Ian F 
Published: March 2020

2072 Background: Human glioma stem cells and xenograft lines are common translational models in neuro-oncology but it has not been established if they are genetically and phenotypically comparable. This study aimed to determine if human glioma xenografts and stem cell-derived tumors had similar genotypes. Methods: Matched glioma stem cell cultures and subcutaneous xenograft lines were generated from four human glioblastoma specimens (BT114, BT116, BT120, BT132). Comparison was made between subcutaneous stem cell-derived tumors (flank) and xenografts established in nude mice. Copy number variation (CNV) and gene expression microarray studies were performed. Results: Various differences in copy number and gene expression were seen. Observed CNVs included regions within EGFR, myc, and p16 (INK). For example, EGFR copy number was two fold higher in xenografts vs. stem cell-derived tumor in one line (BT114). This difference was corroborated by western blot. Other differences included a heat shock protein homolog (DNAJA4), tetraspanin 13, and a p53 family target gene (ISG20L1). Two lines (BT114, BT116) had a greater than two fold increase in DNAJA4 expression in xenografts vs. stem cell-derived tumors (p = 0.04, 0.01). Two cell lines (BT116, BT120) had a two to eight fold increase in tetraspanin 13 expression in xenografts (p = 0.02, 0.05). However, neither copy number nor gene expression variations were consistent across all cell lines. Conclusions: Xenografts and glioma stem cell-derived tumors established from the same patient specimens have distinct genotypes. Further work is needed to establish if these differences are random or represent characteristic changes selected by different in vitro or in vivo pressures. However, these variations raise questions regarding which model is ideal for studying glioma biology, and which ones best replicate glioma characteristics in human patients.
Effect of RTVP-1 on the mesenchymal transformation of glioma stem cells (GSCs) and their self-renewal and migration.
Authors: Brodie Chaya , Giladi Nissim , Ziv-Av Amotz , Lee Hae Kyung , Finniss Susan , Cazacu Simona , Xiang Cunli , Poisson Laila , Slavin Shimon , Mikkelsen Tom 
Published: March 2020

2073 Background: Glioblastoma (GBM), the most aggressive primary brain tumors, exhibit increased invasiveness and resistance to anti-tumor treatments. GBM are categorized into proneural, neural, classical and mesenchymal subgroups, the latter being characterized by increased invasion and poor prognosis. We recently reported that RTVP-1 is highly expressed in GBM and its expression is correlated with astrocytic tumor grade. Methods: We employed promoter and Chip analyses, analysis of tumor specimens submitted to TCGA , GSC self-renewal and migration assays, mesenchymal and neural differentiation, gene array analysis and pull-down assay followed by FRET. Results: The RTVP-1 promoter binds STAT3 and C/EBPb, the transcription factors that regulate mesenchymal transformation of GBM. The expression of RTVP-1 is higher in mesenchymal GBM and is inversely correlated with patient survival in the proneural group. We examined the expression and functions of RTVP-1 in GSCs, a small population of cancer stem cells that are implicated in the increased migration, radio- and chemo-resistance of GSCs and tumor recurrence. RTVP-1 was expressed in the different GSCs but not in the normal human neural stem cells (NSCs). Overexpression of RTVP-1 in NSCs induced their mesenchymal transformation, whereas silencing of RTVP-1 in GSCs decreased their mesenchymal and increased their neural phenotypes. Moreover, RTVP-1 promoted the self-renewal and migration of GSCs. Using gene array analysis of RTVP-1 silenced cells we identified IL-6 and CXCR4 as major mediators of RTVP-1 effects on the mesenchymal transformation and self-renewal of GSCs. In addition, using a pull down assay with His-tagged RTVP-1 we identified N-WASP and hnRNPK as novel interacting proteins of RTVP-1 that mediate its effects on glioma cell migration. Conclusions: RTVP-1 expression is associated with mesenchymal transformation of GSCs. RTVP-1 promotes self-renewal and migration of GSCs and these effects are mediated by the increased expression of IL-6 and CXCR4 and via interaction with N-WASP and hnRNPK. Collectively, these results suggest that RTVP-1 may represent a novel diagnostic marker and a therapeutic target in GBM.
Final results of a single-arm phase II study of bevacizumab and temozolomide following radiochemotherapy in newly dignosed adult glioblastoma patients.
Authors: Nicholas Martin Kelly , Lukas Rimas Vincas , Amidei Christine , Vick Nicholas , Paleologos Nina , Malkin Mark Gordon , Krouwer Hendrikus , Junck Larry , Arzbaecher Jean , Lai Albert , Merrell Ryan 
Published: March 2020

2076 Background: This study evaluated efficacy and safety of bevacizumab (BEV) added to the post-radiation treatment phase for patients with newly diagnosed glioblastoma (GBM). Methods: Sixty-two participants with newly diagnosed GBM were enrolled between May 2007 and June 2010. Participants received standard radiation therapy (RT) within 6 weeks of surgery, and concomitant administration of temozolomide (TMZ). Four weeks after radiation, treatment with TMZ (Days 1-5 of a 28 day cycle) with BEV, (days 1 and 15 of a 28 day cycle) was started, and continued until disease progressed or adverse effects indicated need to stop treatment. Analyses were completed for all participants by intention to treat (ITT), with progression-free survival (PFS) and overall survival (OS) serving as primary and secondary endpoints respectively. Results: Subbjects completed a mean of 7.7 (range 0-29) cycles of post-RT with BEV and TMZ. Twenty participants (32%) were unable to proceed to the post-RT phase. The forty-two participants who did proceed to the post-RT phase completed a mean of 11.5 cycles of treatment. Thirty-eight participants (61%) stopped the study due to disease progression; 6 participants (14%) voluntarily discontinued treatment after 24 cycles with at least stable disease. At a median follow-up time of 24 months, median progression-free survival (PFS) for all participants was 8.8 months while median overall survival (OS) was 16.5 months for all participants. Ly with These results also compare favorably with recently reported results from the AVAglio study (PFS = 10.6 mo.). The toxicity profile was consistent with that reported in similar studies. MGMT promoter methtion.ylation status is under investiga Conclusions: Participants in this study demonstrated a median 1.9 month PFS benefit as compared to the 6.9 median OS reported by Stupp, et al. (2005) and a median 1.9 month OS benefit as compared to the 14.6 month median OS reported by Stupp, et al. (2005). Results suggest that the addition of bevacizumab to the post-RT phase of treatment improves both PFS and OS for persons with GBM despite the high percentage of participants being unable to progress to post-radiation treatment. Clinical trial information: NCT005906.