bluuebunny/crossref_metadata_2025_split huggingface dataset:
Recurrent genetic alterations in primary central nervous system lymphoma of immunocompetent patients.
Authors: Gonzalez Alberto , Idbaih Ahmed , Boisselier Blandine , Jouvet Anne , Polivka Marc , Adam Clovis , Figarella-Branger Dominique , Miquel Catherine , Vital Anne , Ghesquieres Herve , Gressin Remy , Delwail Vincent , Taillandier Luc , Chinot Oliver L. , Soubeyran Pierre-Louis , Gyan Emmanuel , Choquet Sylvain , Soussain Carole , Mokhtari Karima , Hoang-Xuan Khê ,   LOC National Network
Published: March 2020

2023 Background: Little is known about the molecular pathogenesis of primary central nervous system lymphoma (PCNSL) in immunocompetent patients. Our objective was to identify the genetic changes involved in PCNSL oncogenesis and evaluate their clinical relevance. Methods: Twenty nine and four newly diagnosed, HIV-negative PCNSL patients were investigated using high-resolution single nucleotide polymorphism (SNPa) arrays (Infinium Illumina Human 610-Quad SNP array-Illumina; validated by real-time quantitative polymerase chain reaction) and whole-exome sequencing respectively. Molecular results were correlated with prognosis. Results: All PCNSLs were diffuse large B-cell lymphomas, and the patients received high-dose methotrexate-based polychemotherapy without radiotherapy as an initial treatment.SNPa analysis revealed recurrent large and focal chromosome imbalances that target candidate genes in PCNSL oncogenesis. The most frequent genomic changes were (i) 6p21.32 loss (79%), corresponding to the HLA locus; (ii) 6q loss (27-37%); (iii) CDKN2A homozygous deletions (45%); (iv) 12q12-q22 (27%); (v) chromosome 7q21 and 7q31 gains (20%). Sequencing of matched tumor and blood DNA samples identified novel somatic mutations in MYD88 (L265P hot spot mutation) and TBL1XR1 in 38% and 14% of the cases, respectively. The correlation of genetic abnormalities with clinical outcomes using multivariate analysis showed that 6q22 loss (p=0.006 and p=0.01), and CDKN2A homozygous deletion (p=0.02 and p=0.01) were significantly associated with shorter progression free survival and overall survival. Conclusions: Our study identified novel genetic alterations in PCNSL, such as MYD88 and TBL1XR1 somatic mutations, which would both contribute to the constitutive activation of the NFkB signaling pathway and represent potential promising targets for future therapeutic strategies.
The oral transforming growth factor-beta (TGF-ß) receptor I kinase inhibitor LY2157299 plus lomustine in patients with treatment-refractory malignant glioma: The first human dose study.
Authors: Azaro Analia , Baselga José , Sepúlveda Juan Manuel , Seoane Joan , Rodon Ahnert Jordi , Brana Irene , Gueorguieva Ivelina , Cleverly Ann , Lahn Michael M. F. , Pillay Sada , Paz-Ares Luis , Holdhoff Matthias , Blakeley Jaishri O'Neill , Carducci Michael Anthony 
Published: March 2020

2042 Background: Activated TGF-b signaling has been associated with poor survival in several tumors, including glioma. TGF-b inhibitors are expected to improve outcome. Part B of this Phase I trial assessed safety, pharmacokinetics, pharmacodynamics, and antitumor activity of the intermittent treatment with LY2157299 in combination with lomustine. Methods: After evaluating safety of LY2157299 monotherapy in part A of the study, 2 cohorts of patients were treated with LY2157299 at 160 or 300 mg/day with intermittent dosing (each cycle=14 days on followed by 14 days off) in combination with lomustine at standard dose (100 to 130 mg/m2 every 6 weeks) for ≥2 cycles. Toxicity was assessed using the Common Terminology Criteria for Adverse Events, version 3. Results: Twenty-six patients with glioma (18 WHO Grade IV; 5 Grade III; 3 unspecified grade) were treated with LY2157299 and lomustine (160 mg/day, n=15; 300 mg/day, n=11). There were no dose-limiting toxicities. No clinically meaningful cardiotoxicities were observed. Twenty-one SAEs occurred in 10 patients, all considered to be related to lomustine and none to LY2157299. Of the 26 patients, 7 had thrombocytopenia (27%), and recovery around weeks 4 to 6 was not impacted by the second cycle of LY2157299. Two patients taking 160 mg/day were treated for >6 cycles, with 1 of the 2 patients showing an unconfirmed partial response. At the 300 mg/day dose, no responses were observed; 2 patients were treated for >6 cycles. Co-administration of lomustine did not alter LY2157299 exposure. Observed exposure of LY2157299 increased with dose escalation between the 2 cohorts. On Day 7, the variability estimates (coefficients of variation) of exposure and maximum concentration were slightly higher in presence of lomustine (58%) when compared with LY2157299 alone (47%) and then again reduced on Day 14 (53%). Pharmacodynamic results will be reported at a later date. Conclusions: The 14 days on/14 days off treatment with LY2157299 did not increase the known lomustine toxicity. Given the overall safety profile and antitumor effect, LY2157299 is being investigated in Phase II studies.
Expression of CXCR7, CXCR4, CXCR3 and their chemokine ligands in glioblastoma.
Authors: Berahovich Robert D. , Walters Matthew J. , Sullivan Timothy J. , Kohrt Holbrook Edwin , Karamchandani Jason , Jaen Juan C. , Schall Thomas J. 
Published: March 2020

2043 Background: The chemokine receptors CXCR4 and CXCR7, and their shared ligand CXCL12/SDF-1, have been implicated in multiple aspects of tumorigenesis, including tumor cell proliferation, angiogenesis, vasculogenesis, and metastasis. Recently, a role for CXCR4 and CXCR7 has been postulated in the control of glioblastoma growth and vasculogenesis. We set out to define the expression patterns of these proteins on primary glioblastoma tumors and associated vasculature. Methods: First, a tumor microarray containing grades 1, 3, and 4 glioma samples were analyzed by immunohistochemical techniques for the expression of CXCR7. Second, two glioblastoma microarrays were analyzed by the same technique for CXCR7, CXCR4, and their shared chemokine ligand CXCL12. The same microarrays were also probed for the expression of the additional CXCR7 ligand, CXCL11/ITAC, as well as the chemokine receptor CXCR3, which is also a receptor for CXCL11. Tissues were scored in a blinded fashion by a certified neuropathologist for both the intensity of signal and location of signal for all proteins tested. Results: CXCR7 expression was largely dependent on tumor grade, as the receptor was usually absent on most grade 1 gliomas but was moderately-to-highly expressed in the majority of anaplastic astrocytomas and glioblastomas. CXCR7 expression on tumor-associated vasculature was seen in all samples and its expression level also increased with glioma grade. In contrast to CXCR7, CXCR4 expression in glioblastoma was usually limited to the glioma cells, with only infrequent expression on the vasculature. Conversely, CXCL12 expression in glioblastoma was usually limited to the vasculature. CXCR3 was detected in a subset of glioblastomas, and only on the glioma cells. The CXCR7 and CXCR3 ligand CXCL11 was, like CXCR7, expressed on both the glioma cells and vasculature. Conclusions: These results, in light of prior evidence for CXCR7 in tumor growth, suggest a positive role for CXCR7 in the development of glioblastoma. Because CXCR7 colocalizes with its ligands, CXCL12 and CXCL11, as well as their other receptors, CXCR4 and CXCR3, the function of CXCR7 in glioblastoma may lie in the regulation of both the CXCR4/CXCL12 and CXCR3/CXCL11 axes.
Impaired expression of ketone metabolizing enzymes in malignant gliomas: Implication for ketogenic diet therapy.
Authors: Chang Howard T. , Olson Lawrence Karl , Schwartz Kenneth A. 
Published: March 2020

2056 Background: Malignant glial cells may have altered expression of mitochondrial enzymes that are key for deriving energy from ketones. The novel strategy of treating malignant gliomas with a ketogenic diet has been tested in animal models with promising results. To evaluate the applicability of these findings to human patients we tested the hypothesis that high grade human gliomas may lack or have decreased expression of mitochondrial enzymes that are important for metabolizing ketones. Methods: We evaluated the expression of 2 key mitochondrial enzymes involved in ketone metabolism in 22 patients (17 males and 5 females, mean age 55,range 30-85) with either glioblastoma (GBM, WHO grade IV) or anaplastic glioma (WHO grade III) (Table). Immunohistochemistry reactions were performed on formalin-fixed paraffin-embedded sections from brain biopsies, using antibodies raised against succinyl CoA: 3-oxoacid CoA transferase (OXCT1) and 3-hydroxybutyrate dehydrogenase 1 (BDH1). Immunoreactivities were graded using a semi-quantitative scale based on the percentage of positive cells: negative (NEG) ≤ 5%; intermediate (INT) 5-20%; and positive (POS) more than 20%. Focal non-neoplastic “normal” brain tissue present within the specimens expressed both enzymes and served as an internal positive control. Results: Either absent or marked decreased expression of OXCT1 and BDH1 were observed in most GBM and anaplastic glioma. Concordance for absent or marked decrease expression of both OXCT1 and BDH1 was observed in 14 of the 17 (82%) GBM’s, and 1 of 5 (20%) anaplastic gliomas. Conclusions: These data support the rationale for a pilot clinical study investigating the therapeutic utility of a ketogenic diet in selected glioma patients. Malignant gliomas with diminished expression of key enzymes (e.g., OXCT1, BDH1) may benefit from the ketogenic diet therapy, whereas those with positive expression of these enzymes likely will not. [Table: see text]
Impact of duration of bevacizumab (Bev) treatment in the prognosis of adults with recurrent malignant gliomas.
Authors: Hamza Mohamed Ali , Conrad Charles A. , De Groot John Frederick , Gilbert Mark R. , Groves Morris D. , Yung W. K. Alfred , Puduvalli Vinay K. 
Published: March 2020

2064 Background: Bev is the standard treatment for patients with recurrent glioblastoma (GB) but is also used in treating recurrent anaplastic gliomas (AG). Differences in outcome between these groups and optimal duration of treatment with Bev in pts with recurrent malignant gliomas are not well defined. We examined the relationship between the duration of Bev treatment and the outcome in pts with GB and AG. Methods: In this retrospective chart and data review derived from our longitudinal database, we identified pts with recurrent AG and GB who were treated with Bev alone or Bev-containing regimens between 2005 and 2009; the data was analyzed to determine the overall survival (OS) and the progression free survival (PFS). Results: A total of 261 patients with recurrent malignant gliomas (196 with GB and 65 with AG) were identified. There was no significant difference between the median length of treatment between AG and GB (5.81±0.66 months vs. 6.77±0.52 months, p=0.32). PFS6 was 34.2% (95% CI, 27.8-41.3) for patients with GB and 44.2% (95% CI, 32.5-56.7) for patients with AG. Patients with GB who were treated ≥6 months had a significantly higher OS (29.13 months vs. 20.16 months, p= 0.001) compared to those treated <6 months, and a significantly higher PFS compared to those treated <6months (11.33 months vs. 3.7 months, p=0.0001). For patients with AG, although treatment ≥6 months had a significantly higher PFS (13.93 months vs. 3.53 months, p<0.0001), OS was not significantly different (months 38.6 vs. 52.5 months, p=0.6) compared with those treated <6 months. Conclusions: Length of treatment ≥6 mo with Bev or Bev-containing regimen was associated with improved PFS in both AG and GB but only the GB subgroup showed improved OS. These results suggest equivocal survival benefit in patients with AG with longer duration of bevacizumab treatment, which requires further study in prospective trials.
Plasma levels of IL-8 and g-CSF in high-grade gliomas treated with bevacizumab.
Authors: Eoli Marica , Rabascio Cristina , Cuppini Lucia , Anghileri Elena , Pellegatta Serena , Calleri Angelica , Mancuso Patrizia , Porrati Paola , Bertolini Francesco , Finocchiaro Gaetano 
Published: March 2020

2083 Background: Bevacizumab, an anti-VEGF antibody, has shown significant activity in high grade gliomas (HGG). However, tumor recurrence inevitably occurs. Methods: We treated 63 recurrent HGG patients with poor prognostic factors with bevacizumab (10 mg/kg) and irinotecan (125 or 340 mg/m2) every 2 weeks, and investigated IL-12, IL-13, IL-17, FGF basic, G-CSF, MIP-1b, PDGF-beta, plasma levels before starting treatment and every 8 weeks by Bioplex. Ten age- and sex-matched healthy controls were used for comparison. Results: After a median follow-up of 27 weeks, median OS and PFS were 33 and 18 weeks, respectively. PFS at 6 and 12 months were 32% and 12%, respectively. OS at 6 months was 60%. Toxicity was mild. Baseline higher amounts of IL-13 (48±174 pg/ml vs 3.44±0.9 pg/ml, p=0.0001) and lower amounts of MIP-1b (35.3±20.9 pg/ml vs 67.2±18.8 pg/ml, p=0.0002), PDGF-beta (1585.5±1585 pg/ml vs 7098±1585 pg/ml, p=0.0001) and VEGF (27±39.8 pg/ml vs 54.5±32 pg/ml, p=0.001) were detected in patients than in healthy controls. In a cohort of 15 non-responders (patients who progressed 8 weeks after treatment onset), baseline IL-8 (15.7±10.8 pg/ml vs 10.9±9.4 pg/ml, p=0.03) and G-CSF (113.3±54 pg/ml vs 84.9±59.2 pg/ml, p=0.03) were significantly higher than in patients responding to treatment. In the same cohort no significant reduction of VEGF and other cytokines was observed after 8 weeks of treatment, while a decrease of plasma VEGF was observed in the remaining patients (26±32 pg/ml vs 13.3±28.5 pg/ml, p=0.001). Furthermore, in a cohort of 22 long-term responders (patients who progressed after more than 18 weeks of treatment), levels of VEGF decreased after 8 weeks of treatment when compared to baseline, whereas no difference was observed in baseline levels (23.9±22.6 pg/ml vs 9.8±9.4 pg/ml, p=0.001). Conclusions: Data suggest that high levels of IL-8 and G-CSF at baseline associated with a lack of VEGF decrease after 8 weeks of treatment identify patients who are resistant to bevacizumab. This hypothesis should be tested in a large number of patients.
Comparison of fractionated and single session radiosurgery for radiation resistant brain metastases.
Authors: Oermann Eric Karl , Wu Jing , Collins Brian Timothy , Morris David E. , Ewend Matthew G. 
Published: March 2020

2091 Background: Melanoma and renal cell carcinoma are commonly called radiation resistant tumors due to the decreased response rate to traditional radiation (1.8-2 Gy /Fraction). Large brain metastases from radioresistant primaries are clinical challenges. This study examines the impact of fractionation on the treatment of intracranial metastases from radiation resistant tumors. Methods: Patients with a primary diagnosis of melanoma or renal cell carcinoma and intracranial metastases who completed treatment at The University of North Carolina with frameless robotic radiosurgery between 2007-2011 were retrospectively analyzed. Patients were treated with either single or 3-5 fractions depending on volume. The study’s primary endpoints were overall survival (OS) and local control (LC), and its secondary endpoint was patient steroid requirements. Outcomes data and pre-treatment variables were analyzed for significance using appropriate non-parametric tests. Results: 25 patients were included in the single fraction arm and 13 patients in the multi-fraction arm, and both had equivalent pre-treatment characteristics with the exception of tumor volume which was larger in the multi-fraction arm (p=0.01). At a median follow-up of 4.7 months (range, 1.8-11.6), the median OS for all patients was 6.2 months. One year survival was 35.1% and 5 patients (13%) had local failures at a median time to local failure of 5.5 months. Patients in the multi-fraction arm failed at a higher rate (10.5%) than patients in the single fraction arm (2.6%) (p=0.04), but there was no difference in OS (p=0.34). There was no difference between pre-treatment and post-treatment steroid requirements between the two arms (p=0.351). Conclusions: Fractionation is intended to facilitate radiosurgery in large tumors by limiting high doses of radiation to a large portion of normal brain. In our study of radioresistant intracranial metastases, large tumors receiving multi-fraction radiosurgery had decreased local control with no difference in toxicity or OS. These results suggest a need for either dose escalation, or combination therapy designed to reduce tumor size (resection or aspiration) in order to facilitate single fraction treatment.
Safety and efficacy of the addition of bevacizumab to temozolomide and radiation therapy followed by bevacizumab, temozolomide, and irinotecan for newly diagnosed glioblastoma multiforme.
Authors: Vredenburgh James J , Desjardins Annick , Peters Katherine B. , Reardon David A. , Herndon James Emmett , Coan April D. , Kirkpatrick John , Bailey Leighann , Threatt Stevie , Sampson John Howard , Friedman Allan H. , Friedman Henry S. 
Published: March 2020

2094^ Background: Glioblastoma (GBM) has a very poor prognosis, and the majority of patients die within 2 years of diagnosis. GBMs have high concentrations of vascular endothelial growth factor (VEGF), and the more VEGF, the worse the prognosis. Bevacizumab is a humanized antibody to VEGF and is active in recurrent GBMs. The study aims to improve the survival of newly diagnosed GBM patients by incorporating an anti-angiogenic agent with radiation and temozolomide, and adding a topoisomerase I inhibitor, and an anti-angiogenic agent to temozolomide post-radiation therapy. Methods: Patients received standard radiation and temozolomide at 75 mg/m2/day, with bevacizumab at 10 mg/kg every 14 days beginning a minimum of 28 days post-operatively. Following the completion of radiation therapy, patients received 6-12 cycles of bevacizumab, temozolomide and irinotecan. Each cycle was 28 days. Bevacizumab was given at a dose of 10 mg/kg days 1 and 15, temozolomide 200 mg/m2 days 1-5 and irinotecan on days 1 and 15 at 125 mg/m2 for patients not on an enzyme inducing anti-epileptic (EIAED) and 340 mg/m2 for patients on an EIAED. The statistical design was a goal of 60% overall survival at 16 months. Results: 125 patients were enrolled between 8/07 and 3/09. All the patients have completed therapy. Nine patients had thromboembolic complications (DVT or PE). Two patients had wound dehiscence, one bowel perforation, one secondary AML and two pneumocystis carinii pneumonias (PCP). Seventeen had grade 4 hematologic toxicity requiring dose decrements. There were 4 toxic deaths, one each with a myocardial infarction PCP, PE and sepsis. At a median follow-up of 40 mos, the median overall survival was 20.9 mos, the median progression-free survival was 13.8 mos and the 2-year overall survival was 42.4%. Conclusions: Adding bevacizumab to temozolomide and radiation therapy followed by bevacizumab, temozolomide with irinotecan is tolerable and efficacious.
Effects of lazaroid U-74389G liposomes in a glioblastoma mouse model.
Authors: Ibrahim Fady , New Pamela Z. , Cui Kemi , Zhao Hong , Wang Lulu , Chow Diana , Wong Stephen 
Published: March 2020

2098 Background: Lazaroid U-74389G (LAZ) is a 21-aminosteroid that has radioprotective effects against radiation-induced lipid peroxidation. Also in vitro antiproliferative effects have been reported against glioblastoma cell lines. The aim of this study was to use a liposomal formulation to evaluate LAZ radioprotective and antiproliferative effects in a glioblastoma mouse model. Methods: LAZ PEGylated liposomes (Lipo G) were developed at the University of Houston, College of Pharmacy. Glioblastoma cell line U87-expressing firefly luciferase reporter gene (100,000 cells in 2 μL) was injected intracranially in each male SCID hairless outbred mouse. There were 4 treatment groups (n=8-9, each): brain model (M) without treatment (control), radiation 2Gy weekly (M+R), Lipo G at 5 mg/kg dose IP twice per week (M+L) and radiation with Lipo G (M+R+L). Treatment lasted three weeks. Tumor size was monitored using non-invasive bioluminescence imaging (BLI), in each mouse. Mice were sacrificed after 3 weeks. Brain was harvested for immunohistochemistry examinations. Lipid peroxidation of brain tissues was quantified by measuring malondialdehyde (MDA) as a surrogate biomarker. Survival was evaluated using Kaplan Meier analysis at P= 0.05. Results: The relative BLI intensity was 4002.03±1737.67, 2034±737.72, 1387.36±684.53 and 2498.89±2521.32 % for M, M+R, M+L and M+R+L, respectively. The tumor size of the M+L group was reduced by 65% compared to control . For the radiation treated groups (M+R and M+R+L), there was no significant difference in tumor size compared to control group. MDA brain concentration in M+L and M+R+L groups was significantly less than in M+R group (8.27±0.78 and 10.37±3.30 µM/gm vs. 23.09± 3.79 µM/gm). The survival mean was 22.67, 25.33, 25.22 and 27.13 days for M, M+R, M+R+L and M+L groups, respectively. Mean survival of LAZ treated groups (M+L and M+R+L) was significantly longer than that of the control group Conclusions: LAZ liposomal formulations administered at 5 mg/kg dose reduced tumor growth by 65%. LAZ also protected brain tissue from radiation-induced lipid peroxidation by reducing MDA concentration by 50%. These provocative data warrant further investigation of LAZ as a radiation protectant and chemotherapeutic agent.
Ascending dose trials of the safety and tolerability of Toca 511, a retroviral replicating vector encoding cytosine deaminase, in patients with recurrent high-grade glioma.
Authors: Pertschuk Daniel , Cloughesy Timothy Francis , Chang Susan Marina , Aghi Manish K. , Vogelbaum Michael A. , Liau Linda M. , Shafa Bob B. , Yong William H. , Chen Clark , Kesari Santosh , Ibanez Carlos E. , Perez Omar D. , Robbins Joan M. , Jolly Douglas J. , Gruber Harry E. 
Published: March 2020

2101 Background: Patients with the most common and aggressive form of brain cancer, glioblastoma multiforme (GBM), have a poor prognosis and current treatments are only palliative. Gene therapy approaches using replication-deficient viral vectors have been investigated previously for GBM with limited efficacy, likely due to poor gene delivery throughout the tumor. Methods: Toca 511 is a novel retroviral replicating vector (RRV) that is engineered to deliver a modified cytosine deaminase prodrug activator gene (CD) selectively to cancer cells. In those cancer cells expressing the CD gene, the antifungal prodrug 5-FC is converted to 5-FU. We are currently evaluating the safety and tolerability of a single dose of Toca 511 administered by direct intratumoral injection to subjects with recurrent high grade glioma (rHGG). After a period of time during which the vector is allowed to spread through the tumor, the patient begins oral 5-FC which is repeated cyclically. Results: Three subjects have been enrolled in each of the first two dose groups. No dose limiting toxicities (DLTs) have been identified in these groups and the treatment was well tolerated. There have been no grade 3 or 4 AEs considered related to either Toca 511 or 5-FC. A further 9 subjects were then enrolled at the 3rd dose level and are being followed. A second study has been initiated in which Toca 511 is injected into the walls of the resection cavity at the time of surgery for rHGG and followed by cyclic treatment with oral 5-FC. Conclusions: These clinical studies are the first to investigate a RRV to deliver genes to human brain tumors and further dose escalation is anticipated.