bluuebunny/crossref_metadata_2025_split huggingface dataset:
A first-in-human study of neural stem cells (NSCs) expressing cytosine deaminase (CD) in combination with 5-fluorocytosine (5-FC) in patients with recurrent high-grade glioma.
Authors: Portnow Jana , Badie Behnam , Synold Timothy W. , Annala Alexander , Chen Bihong , Frank Joseph , Moats Rex A. , Wood John , D'Apuzzo Massimo , Bedell Victoria , Frankel Paul Henry , Aboody Karen S. 
Published: March 2020

2018 Background: Human NSCs are inherently tumor-tropic, making them attractive drug delivery vehicles. This pilot-feasibility study assessed the safety of using genetically-modified NSCs for tumor selective enzyme/prodrug therapy. An immortalized, clonal NSC line was retrovirally-transduced to stably express CD, which converts the prodrug 5-FC to 5-fluorouracil (5-FU), producing chemotherapy locally at sites of tumor in the brain. Methods: Patients 18 years or older with recurrent high-grade glioma underwent intracranial administration of NSCs during tumor resection or biopsy. Four days later, 5-FC was administered orally every 6 hours for 7 days. Study treatment was given only once. A standard 3+3 dose escalation schema was used to increase doses of NSCs from 1 x 107 to 5 x 107 and 5-FC from 75 to 150 mg/kg/day. Intracerebral microdialysis was performed to measure brain levels of 5-FC and 5-FU; serial blood samples were obtained to assess systemic drug concentrations. Three patients received iron-labeled NSCs for MRI tracking. Brain autopsies were done on 2 patients. Results: Fifteen patients received study treatment. Three were inevaluable for toxicity and replaced. All patients tolerated the NSCs well. There was 1 dose-limiting toxicity (grade 3 transaminitis) possibly related to 5-FC. At the highest dose level of NSCs, the average steady-state concentration of 5-FU in the brain was 63.9±7.9 nM. The average maximum 5-FU level in brain was 104±88 nM compared to 24±36 nM in plasma, indicating local production of 5-FU in the brain by the NSCs. MR imaging of iron-labeled NSCs showed preliminary evidence of NSC migration. Autopsy data documented (by IHC, FISH, and PCR) NSCs at distant sites of tumor in the brain and no development of secondary tumors. Conclusions: This first-in-human study has demonstrated safety and proof-of-concept regarding NSC-mediated conversion of 5-FC to 5-FU and NSC tumor-tropism. NSCs have the potential to overcome obstacles of drug delivery that limit current gene therapy strategies. Results of this pilot study will serve as the foundation for future NSC studies. (Supported by NCI 1R21 CA137639-01A1, CIRM DR-01421). Clinical trial information: NCT01172964.
Biomarker (BM) evaluations in the phase III AVAglio study of bevacizumab (Bv) plus standard radiotherapy (RT) and temozolomide (T) for newly diagnosed glioblastoma (GBM).
Authors: Nishikawa Ryo , Saran Frank , Mason Warren , Wick Wolfgang , Cloughesy Timothy Francis , Henriksson Roger , Hilton Magalie , Garcia Josep , Vogt Tobias , Pallaud Celine , Chinot Oliver L. 
Published: March 2020

2023^ Background: Bv plus 1st-line standard of care (SoC; T+RT) achieved a PFS benefit in the AVAglio phase III, randomized, double-blind, placebo [P]-controlled trial in patients (pts) with newly diagnosed GBM. AVAglio includes BM evaluation to identify pts benefiting most from Bv. Analysis of plasma VEGF-A and VEGFR-2 was prioritized based on encouraging findings in Bv trials in several tumor types. Methods: AVAglio includes an optional, exploratory correlative BM analysis; participating pts provided informed consent for BMs. Baseline (BL) plasma samples were analyzed using the Roche IMPACT platform, based on multiplex ELISA technology. Pts were dichotomized according to BM levels using either Q1, median or Q3 cut-offs. Potential interactions between BL BM levels and PFS were tested using Cox regression analyses. Results: Of 921 patients enrolled, 571 (62%) were evaluable in the BM study. Baseline characteristics and PFS outcome were comparable in the ITT and BM-evaluable populations. Median BL VEGF-A and VEGFR-2 levels were 77.0 pg/mL and 12.6 ng/mL, respectively. No significant interaction for PFS was seen at α=0.025. Conclusions: The potential predictive (VEGF-A, VEGFR-2) and prognostic (VEGF-A) value seen in breast, pancreatic and gastric cancers was not apparent in BL BM samples from AVAglio using a median, Q1 or Q3 cut-off. Additional plasma and tumor BM analyses are ongoing. Clinical trial information: NCT00943826. [Table: see text]
Impact of adjuvant temozolomide and IDH mutation status among patients with anaplastic astrocytoma.
Authors: Kizilbash Sani Haider , Giannini Caterina , Voss Jesse S , Decker Paul A. , Jenkins Robert B. , Laack Nadia N. , Parney Ian F , Uhm Joon H. , Buckner Jan C. 
Published: March 2020

2025 Background: Although adjuvant radiation has demonstrated a clear survival benefit in anaplastic astrocytomas (AA), the role of concurrent temozolomide (TMZ) remains controversial. Methods: All adult patients diagnosed with AA from 2001 to 2011 and treated with standard doses of adjuvant radiation were identified retrospectively using the neuro-oncology database at the Mayo Clinic (Rochester, MN). Clinical data was extracted from the electronic medical record. IDH mutation status was also determined by obtaining either IDH1R132H immunostain on existing unstained slides or paraffin block sections, or by sequencing. Cumulative survival probabilities were estimated using the Kaplan-Meier method. Univariable and multivariable Cox proportional hazards regression models were fit to compare patients who did/did not receive TMZ. Results: 218 patients were identified that met inclusion criteria. 34 patients were excluded due to missing data on adjuvant chemotherapy. 146 patients had received adjuvant TMZ while 38 had not. Of these, IDH mutation status was determined on 124 patients who received TMZ and 33 of those who had not. The median duration of follow up was 36.4 months. On univariable analysis, adjuvant TMZ demonstrated a trend towards improved median survival from 35.2 to 53.1 months (p=0.06). As an independent variable, patients with IDH mutations had longer median survivals (111.7 months) when compared to IDH wild-type patients (23.3 months) (p<0.001). On multivariable analysis, five-year-survival was significantly impacted by receipt of adjuvant TMZ (HR = 0.56, p=0.03) and IDH mutation status remained a significant prognostic factor (HR = 0.19, p < 0.001) (see Table). Conclusions: IDH mutation strongly predicts a favorable outcome in patients with AA. Secondarily, concurrent TMZ is also associated with improved survival in patients with AA who are receiving adjuvant radiotherapy. [Table: see text]
Association of PIK3CA-activating mutations with more disseminated disease at presentation and earlier recurrence in glioblastoma.
Authors: Tanaka Shota , Batchelor Tracy , Iafrate Anthony John , Dias-Santagata Dora , Borger Darrell R. , Ellisen Leif William , Yang Daniel , Louis David N. , Cahill Daniel P. , Chi Andrew S. 
Published: March 2020

2029 Background: The PI3K signaling pathway is a potent pro-survival pathway and associated with increased grade of malignancy in glioma. Activating mutations in PIK3CA are observed in 6% to 15% of glioblastomas, although their clinical significance is unknown. Our objective was to examine whether PIK3CA activating mutation is associated with a specific phenotype in newly diagnosed glioblastoma patients. Methods: We molecularly profiled 183 consecutive adult glioblastomas from December 2009 to June 2012. We included in our analysis all newly diagnosed primary glioblastoma patients with a KPS score of 60 or greater who were treated with standard chemoradiation. Molecular profiling consisted of SNaPshot genotyping, FISH for gene amplification (EGFR, MET, PDGFRA), and methylation-specific PCR for MGMT promoter methylation. Results: 158 patients were included in the study (median age: 58 years (range, 23-85), 90 males, median KPS: 90). With a median follow-up of 13.8 months, median progression-free survival (PFS) and overall survival (OS) were 11.6 and 26.2 months, respectively. Established molecular prognostic factors such as IDH1 mutation and MGMT promoter methylation were associated with longer PFS and OS (IDH1: PFS p=0.001, OS p=0.02; MGMT: PFS p=0.0005, OS p=0.0002). 12 patients (7.6%) harbored PIK3CA activating mutation by SNaPshot assay (4 at R88, 4 at hotspots 542-546, 4 at H1047). PIK3CA mutation was associated with younger age (p=0.02) and shorter PFS (6.8 vs. 11.8 months, p=0.0004). Shorter PFS for PIK3CA mutation remained significant after adjusting for age, KPS, gross total resection, IDH1 mutation, and MGMT promoter methylation (p=0.01). There was a significant association between PIK3CA mutation and more disseminated disease at diagnosis, as defined by gliomatosis, multicentric lesions, or distant leptomeningeal lesions. Eight of 12 (66.7%) PIK3CA mutant GBMs were disseminated versus 15.1% of PIK3CA wild-type tumors (p=0.0002). Conclusions: PIK3CA activating mutations are associated with younger age and early recurrence in primary glioblastoma. The aggressive behavior of these tumors may be related to their propensity to present with widespread disease.
Whole brain radiation therapy (WBRT) with or without oral topotecan (TPT) in patients (pts) with non-small cell lung cancer (NSCLC) with brain metastases: Final analysis of an open-label phase III study.
Authors: Ramlau Rodryg , Jassem Jacek , Papai-Szekely Zsolt , Chabot Pierre , Legenne Philippe , Levin Jeremey , Sherlock Jadwiga , Lane Stephen R. , Brennan John J , Sessa Tracey , Wissel Paul Stephen , Bonomi Philip 
Published: March 2020

2031 Background: Brain metastases from NSCLC occur in ~ 20% of pts and if untreated are associated with a 1 to 2 month overall survival (OS). Pre-clinical studies show that TPT added to radiation results in a radiotherapy enhancement ratio of 1.4 to 1.6. This trial was designed to test the effect of TPT co-administered with WBRT on OS. Methods: Pts with NSCLC and at least one measurable brain lesion were eligible. 472 pts were randomized to WBRT (3 Gy/day x 10 days) or WBRT and TPT 1.1 mg/m2/day for 10 days. Stratification factors: number of brain metastases and recursive partitioning analysis (RPA) class. Two weeks following WBRT, systemic anti-cancer therapy could be restarted at the treating physician’s discretion. Results: 468 pts were in the modified ITT population; 235 pts (WBRT + TPT) and 233 pts (WBRT+ best supportive care [BSC]). Of the 235 pts administered WBRT + TPT, 91 also received TPT after WBRT. The treatment arms were balanced for gender, age and smoking history. Median daily TPT dose was 2.25 mg. The median OS in the TPT arm was not better than in the BSC alone arm; 4.0 months (95%CI 3.4,4.8) vs.3.6 months (95%CI 3.0, 4.0), respectively; HR 0.88 (0.73, 1.07), P=0.1862. In the ITT population analysis by stratification variables, RPA class (I vs. II/III) was significantly different (HR 0.59) whereas baseline brain lesions (1 vs >1) were not (HR 0.97). Complete response and overall response rates in the WBRT+ TPT were 10% and 27%, and with BSC 5% and 26%, respectively. There were no differences in time to response or neurologic signs and symptoms. All adverse events (AEs) were more frequent in the TPT arm (87% vs. 64%) as were AEs related to study treatment (57% vs. 21%), serious AEs (41% vs. 18%) and fatal AEs (5% vs. 0%). The AEs more frequently seen in the TPT arm were typical for TPT (hematologic toxicity, febrile neutropenia and diarrhea). Conclusions: The study did not achieve its primary objective. There was no difference in OS achieved by the addition of TPT to WBRT. AEs were more common in the TPT arm. Clinical trial information: NCT00390806.
Multicenter randomized phase II trial of methotrexate (MTX) and temozolomide (TMZ) versus MTX, procarbazine, vincristine, and cytarabine for primary CNS lymphoma (PCNSL) in the elderly: An Anocef and Goelams Intergroup study.
Authors: Omuro Antonio Marcilio Padula , Chinot Oliver L. , Taillandier Luc , Ghesquieres Herve , Soussain Carole , Delwail Vincent , Lamy Thierry , Gressin Remy , Choquet Sylvain , Soubeyran Pierre-Louis , Maire Jean Philippe , Benouaich Amiel Alexandra , Lebouvier-Sadot Sophie , Gyan Emmanuel , Barrie Maryline , Sierra del Rio Monica , Gonzalez Alberto , Houillier Caroline , Tanguy Marie-Laure , Hoang-Xuan Khê 
Published: March 2020

2032 Background: There is no standard chemotherapy defined in PCNSL. Elderly patients (pts) are not candidates for whole brain radiotherapy and therefore establishing an optimal MTX-based regimen is crucial. This prospective multicenter study conducted in 13 French institutions tested two promising MTX-based chemotherapy regimens in elderly pts with newly diagnosed PCNSL. Methods: Pts with histologically confirmed newly diagnosed PCNSL with age ≥60 and KPS ≥40 were stratified by institution and KPS, then randomized to receive three 28-day cycles of MTX (3.5 g/m2 D1 and D15) and TMZ (100-150mg/m2 D1-5 and 15-19) [MT arm] or 3 cycles of MTX (3.5 g/m2 D1 and D15), procarbazine 100mg/m2 (D1-7), vincristine (1.4mg/m2 D1 and 15), followed by cytarabine consolidation (3g/m2/d X2d) [MPV-A arm]. Neither arm included radiotherapy; prophylactic G-CSF and standardized corticosteroids (methylprednisolone 60mg/d D1-5) were given to both arms. The primary endpoint was PFS (one-stage Fleming design; α= 5%; β=10%). Evaluations included neuropsychological testing and quality of life. Results: Accrual has been completed (7/2007- 3/2010), with 98 pts randomized and 95 analyzed (MT: 48 pts; MPV-A: 47). Pre-treatment characteristics were well balanced between the two arms (all pts: median age=72- range 60-85; median KPS= 70; range 40-100). In the MPV-A arm, the CR rate = 62% (vs 45% in MT arm [p=0.11]), objective response rate= 82% (vs 71%; p=0.23), median PFS= 9.5m (vs 6.1m; HR= 1.14- 95% CI [0.72 ; 1.81]; p=0.6) and median OS= 31m (vs 13.8m; HR= 1.4 - 95% CI [0.84 ; 2.34]; p=0.2). The incidence of grades 3-4 toxicities was 72% in the MPV-A vs 71% in the MT arm. Abnormal liver function test was the most common toxicity (MPV-A: 18 pts; MT: 21). Baseline cognitive impairment (MMSE >24 vs ≤24) predicted OS (p=0.04). Conclusions: This is the first randomized PCNSL study testing two different MTX-based combination regimens. In this elderly population, toxicities were frequent but similar in both arms, and all efficacy endpoints tended to favor the MPV-A arm. The MPV-A regimen is recommended for further development in PCNSL. Clinical trial information: NCT00503594.
Imaging biomarkers of ramucirumab and olaratumab in patients with recurrent glioblastoma.
Authors: Blakeley Jaishri O'Neill , Fisher Joy D. , Lieberman Frank S. , Lupo Janine , Nabors Louis B. , Crane Jason , Wen Patrick Y. , Cote Andre , Peereboom David M. , Wen Qiuting , Cloughesy Timothy Francis , Robins H. Ian , Desideri Serena , Grossman Stuart A. , Ye Xiaobu , Nelson Sarah ,   The Adult Brain Tumor Consortium
Published: March 2020

2044 Background: VEGF and PDGF receptors are overexpressed in glioblastoma (GBM). Both receptor families may be important therapeutic targets. We explored early biologic markers of VEGFR-2 or PDGFRa inhibition with functional MRI. Methods: A subset of patients (pts) from a multicenter phase II study of monoclonal antibodies to VEGFR-2 (ramucirumab 8mg/kg IV q2wks) or PDGFRa (olaratumab 20mg/kg IV q2wks) in adult patients with recurrent GBM underwent a standardized MRI brain protocol with dynamic contrast enhanced (CE); diffusion tensor; perfusion weighted and routine sequences at -1d, +1d, +28d and every +56d from treatment initiation. ACRIN performed site qualification and imaging QA. Regions of CE and T2w hyperintensity were manually defined; percent change in volumes and change in normalized image intensities was calculated. Results: 28 patients were evaluable. Pts receiving ramucirumab (n=11; 7 male) had a median age of 54 (43-67), KPS 90 (70-100) and Dex dose 2mg (0-8). Pts receiving olaratumab (n=17; 14male) had a median age of 58 (24-72), KPS 80 (70-100) and Dex dose 2mg (0-4mg). KPS and Dex were stable over time. Conclusions: Preliminary results show that within 1 day of ramucirumab, CE volume, relative CE intensity and blood volume decreased and by 28 days, T2 volume and ADC decreased suggesting a potent antiangiogeneic effect. PDGFRa inhibition had no effect on lesion volume, but reduced relative CE intensity and blood volume at 28 days. Clinical efficacy results are anticipated in mid-2013. Clinical trial information: NCT00895180. [Table: see text]
Final results from a large prospective Italian population study on glioblastoma and correlations with MGMT status: The Project of Emilia-Romagna Region in Neuro-oncology (PERNO).
Authors: Brandes Alba Ariela , Ermani Mario , D'Alessandro Roberto , Albani Fiorenzo , Franceschi Enrico , Cavallo Michele , Valentini Antonella , Cremonini Anna Maria , Mucciarini Claudia , Faedi Marina , Crisi Girolamo , Fainardi Enrico , Marcello Norina , Pisanello Anna , Agati Raffaele , Michiara Maria , Pasini Giuseppe , Giombelli Ermanno , Servadei Franco , Baruzzi Agostino 
Published: March 2020

2048 Background: The impact on the general population of temozolomide concurrent with and adjuvant to radiotherapy (RT/TMZ) was assessed in the context of the Registry of the Project of the Emilia-Romagna Region in Neuro-Oncology (PERNO), the first Italian prospective observational population-based study in the field of neuro-oncology. Methods: Patients (pts) meeting the following inclusion criteria were evaluated: age ≥18 years; PS 0-3; histologically confirmed GBM, no previous or concomitant non-glial tumoral disease, residence in the Emilia Romagna region. The data were collected prospectively. Results: Study accrual, started on January 1 2009, was closed, as planned, on December 31 2010. Two hundred sixty-eight pts (F=111, M=157; median age, 63.5 [range 29-34] years) were studied. mOS was 10.7 months (95%CI: 9.2 – 12.3). MGMT status, assessed in 186 (89%) of 210 pts who had at least radiotherapy was evaluable in 174 pts (83%), being methylated in 76 (43.7%), and unmethylated in 98 (56.3%) pts. mOS for pts with MGMT methylated status was 18.5 months (95%CI: 14.4-22.6), and 12.4 months for those with MGMT unmethylated status (95%CI: 10.5 - 14.3, p<0.0001). 140 pts <70 years were treated with RT/TMZ; mOS in this group was 16.4 months (95% CI: 14.5 – 18.4). mOS was 20 months in the 59 pts (42%) harboring MGMT methylation (95% CI: 12.8 - 27.2), and 13.5 months in the 73 pts (52%) without MGMT methylation (95% CI: 10.8 – 16.2, p<0.0001). At multivariate analysis, a significant prognostic role was found for performance status (p=0.001), extent of surgery (p=0.009), age (p=0.004), postsurgical treatment (p=0.03), and MGMT status (methylated vs unmethylated, p=0.01). Conclusions: The data from the present large prospective population study are in line with those reported in the EORTC/NCIC randomized trial, confirming that this successful approach has been widely incorporated in daily practice.
Safety interim data from a three-arm phase II study evaluating safety and pharmacokinetics of the oral transforming growth factor-beta (TGF-ß) receptor I kinase inhibitor LY2157299 monohydrate in patients with glioblastoma at first progression.
Authors: Carpentier Antoine F , Brandes Alba Ariela , Kesari Santosh , Sepúlveda Juan Manuel , Wheeler Helen , Chinot Oliver L. , Cher Lawrence , Steinbach Joachim Peter , Specenier Pol M. , Cleverly Ann , Tomlin Irene , Desaiah Durisala , Lahn Michael M. F. , Wick Wolfgang 
Published: March 2020

2061 Background: Based on preclinical data suggesting an additive antitumor effect of a TGF-ß inhibitor and lomustine, a phase II study was initiated to evaluate the activity of this combination in patients with glioblastoma after first progression. We here report are the safety and PK interim data. Methods: Lomustine was given every 6 weeks as approved, starting on day 7 of cycle 1. LY2157299 (300 mg/day) was administered as intermittent dosing (each cycle = 14 days on followed by 14 days off). Patients received lomustine with either LY2157299 or placebo thereby blinding for LY2157299, while patients receiving LY2157299 alone were unblinded (randomization 2:1:1). Toxicity was assessed using CTCAE, version 4.0. Results: After 31 patients had completed at least 1 cycle (28 days, 3 weeks of lomustine), 50 patients had received at least 1 dose of study drug (LY2157299 or lomustine). Aggregate safety data of the 31 patients are provided: 1 patient died on treatment due to multi-organ failure, not considered related to study treatment. At least 3 patients had the following TEAEs with severity, of grade 3 or 4, and drug relatedness (DR, specific drug not indicated): vomiting (n = 5, 4 DR), fatigue (n = 5, 3 DR,1gr 3), dysphasia (n = 4,1 gr 3), other nervous system disorder (n = 4, 3 gr 3), constipation (n = 3), nausea (n = 3, 3 DR), confusion (n = 3, 1 gr 3). Other grade 3/4 TEAEs observed were: abdominal pain, allergic reaction (DR), fall, syncope, pain, lymphocytes, ANC and thrombocytopenia (all DR) and alanine aminotransferase – in 1patient each. No difference in the LY2157299 concentrations between LY2157299 monotherapy and combination arms was observed. Conclusions: The combination of lomustine with LY2157299 or placebo is consistent with the known profile of lomustine with no unexpected clusters of adverse events and similar to a previous phase I study (Azaro et al. abstract 2042, J Clin Oncol. 30, 2012). The phase II study continues after the first interim assessment on safety. Clinical trial information: NCT01582269.
Heterogeneity in the geographic distribution of diffuse grade II and III gliomas in France.
Authors: Bauchet Luc , Darlix Amelie , Zouaoui Sonia , Virion Jean Marc , Rigau Valerie , Mathieu Daude Helene , Blonski Marie , Reyes-Botero German , Bessaoud Faiza , Tretarre Brigitte , Bauchet Fabienne , Capelle Laurent , Fabbro Michel , Kerr Christine , Figarella-Branger Dominique , Duffau Hugues , Taillandier Luc ,   Societe Francaise de Neurochirurgie, Societe Francaise de Neuropathologie, and ANOCEF
Published: March 2020

2067 Background: Diffuse WHO grade II and III gliomas (DGII/IIIG) are rare tumors (incidence ≤ 2/105person-years). Specific epidemiological studies are very rare. The main objective of this work is to study the geographical distribution of all newly diagnosed and histologically confirmed DGII/IIIG in metropolitan France. Methods: The methodology is based on a multidisciplinary national network already established by the French Brain Tumor DataBase. Personal addresses at the moment of the surgical procedure for all DGII/IIIG cases were collected for the years 2006-2009. For each area, the incidence of DGII/IIIG was analyzed and standardized on age and sex distribution of the French population (pop). Results: The total number of patients with newly diagnosed and histologically confirmed DGII/IIIG was 4790 (1220, 1190, 1228, and 1152 for years 2006-2009). The Table shows the number of tumors by histology, sex and median age at diagnosis. The overall crude rate was 19.4/106. To enable international comparisons, standardized rates were calculated as follows: 19.8/106 (reference pop, Europe), 18.8/106 (reference pop, US 2000), and 16.0/106 (reference pop, world). The geographic distribution by regions in France showed significant differences. For example, the standardized rates (for 106person-years, 95% confidence intervals, reference pop: France) for Auvergne, Champagne-Ardenne, and Basse-Normandie, were 30.9 (26.4-35.5), 28.5 (24.0-33.0), and 13.9 (10.9-17.0), respectively. Conclusions: To our knowledge, this work is the first to study the geographical distribution of DGII/IIIG across one entire country, and it shows significant heterogeneity. These results will enable to look for different environmental and genetic factors in these different regions. [Table: see text]