bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Mechanism-Based Forensic Investigation into the Postmortem Redistribution of Morphine
Authors: Gleba Jessica , Kim Jonghan 
Published: November 2019

AbstractThe interpretation of postmortem drug levels is complicated by the change in drug blood levels during the postmortem period, a phenomenon known as postmortem drug redistribution. We investigated the postmortem redistribution (PMR) of morphine, morphine-3-glucuronide and normorphine in the rat. Morphine (10 mg/kg) was intravenously injected into rats, followed by euthanasia 1 h post-injection. The carcasses were placed in a supine position at room temperature, and tissues including heart blood, femoral blood, liver, lung and brain were collected at different time points: 0, 8, 16 or 24 h postmortem. The samples were analyzed with a validated (following modified Scientific Working Group for Forensic Toxicology (SWGTOX) (20) guidelines) liquid chromatography–tandem mass spectrometry method. The use of a mechanism-based approach (involving the used set doses of drug with the study performed in controlled environment) to assess PMR using systematic and statistical analyses provides important information that has not previously been presented in PMR literature. While previous human studies focus on central to peripheral ratios as well as peripheral to tissue ratio, this work focused on the change in morphine and metabolite concentrations over the course of the postmortem interval in relation to each other in addition to the comparison to additional matrices at each postmortem interval. Postmortem redistribution was identified in several tissues across the postmortem interval; however, there was minimal statistical difference observed among each matrix at a given postmortem interval with the exception of normorphine and morphine-3-glucuronide. Combined, our study provides a valuable resource and reference information that can aide toxicologists, medical examiners or coroners when assessing postmortem drug concentrations of morphine and metabolites when they are making determinations of cause of death.
Radiative lifetimes, branching fractions, and oscillator strengths of high-lying levels in Re I
Authors: Li Yongfan , Gamrath Sébastien , Palmeri Patrick , Quinet Pascal , Li Qiu , Yu Qi , Zhang Meiqi , Zhou Lina , Dai Zhenwen 
Published: November 2019

Abstract
Radiative lifetimes of 19 levels in Re I were measured using the time-resolved laser-induced fluorescence method. As far as we know, 15 results are reported for the first time. By combining the experimental lifetimes determined from the present work with theoretical branching fractions obtained by a pseudo-relativistic Hartree–Fock model including core-polarization contributions, a new set of semi-empirical transition probabilities and oscillator strengths for 47 Re I lines from 18 newly measured levels were derived.
Structure of an RNA aptamer in complex with the fluorophore tetramethylrhodamine
Authors: Duchardt-Ferner Elke , Juen Michael , Bourgeois Benjamin , Madl Tobias , Kreutz Christoph , Ohlenschläger Oliver , Wöhnert Jens 
Published: November 2019

Abstract
RNA aptamers—artificially created RNAs with high affinity and selectivity for their target ligand generated from random sequence pools—are versatile tools in the fields of biotechnology and medicine. On a more fundamental level, they also further our general understanding of RNA-ligand interactions e. g. in regard to the relationship between structural complexity and ligand affinity and specificity, RNA structure and RNA folding. Detailed structural knowledge on a wide range of aptamer–ligand complexes is required to further our understanding of RNA–ligand interactions. Here, we present the atomic resolution structure of an RNA–aptamer binding to the fluorescent xanthene dye tetramethylrhodamine. The high resolution structure, solved by NMR-spectroscopy in solution, reveals binding features both common and different from the binding mode of other aptamers with affinity for ligands carrying planar aromatic ring systems such as the malachite green aptamer which binds to the tetramethylrhodamine related dye malachite green or the flavin mononucleotide aptamer.
ATIM-21. THE CURRENT STATUS OF AD-SGE-REIC GENE THERAPY FOR MALIGNANT GLIOMA
Authors: Kurozumi Kazuhiko , Fujii Kentaro , Oka Tetsuo , Shimazu Yosuke , Hattori Yasuhiko , Tomita Yusuke , Uneda Atsuhito , Matsumoto Yuji , Tsuboi Nobushige , Kaneda Keisuke , Makino Keigo , Michiue Hiroyuki , Kumorn Hiromi , Date Isao 
Published: November 2019

Abstract

INTRODUCTION
Expression of the gene encoding reduced expression in immortalized cells/Dickkopf-3 (REIC/Dkk-3) was reported to be reduced in a variety of human cancer cells. We previously examined the antitumor effect of an adenoviral vector carrying REIC/Dkk-3 gene (Ad-CAG-REIC). Recently, a novel adenoviral vector expressing REIC/Dkk-3 has also been developed based on the cytomegalovirus promoter-driven super gene expression system (Ad-SGE-REIC). We evaluated the anti-glioma effect of the Ad-SGE-REIC and planned a clinical trial of Ad-SGE-REIC for malignant glioma.

MATERIALS AND METHODS
We evaluated a cytotoxicity assay to treatments with Ad-SGE-REIC, Ad-CAG-REIC, or Ad-LacZ (control) using malignant glioma cells. The survival of mice in each group was analyzed by the Kaplan–Meier method. We also performed Good Laboratory Practice (GLP) toxicology tests and prepared a protocol for this clinical trial.

RESULTS
In the cytotoxicity assay, after treatment with Ad-SGE-REIC, the number of malignant glioma cells attached to the bottom of culture wells was significantly reduced in a time-dependent manner. Mice treated with Ad-SGE-REIC survived significantly longer than those treated with other vectors. We also performed GLP toxicology tests using intracranial injection of higher doses of Ad-SGE-REIC in rats at Shin Nippon Biomedical Laboratories (SNBL Japan) to determine the injection dose of Ad-SGE-REIC for this clinical trial. After finishing the consultation with Pharmaceuticals and Medical Devices Agency (PMDA), we prepared a protocol for a phase I/IIa clinical trial of Ad-SGE-REIC for the treatment of recurrent malignant glioma supported by Japan Agency for Medical Research and Development (AMED). This protocol was reviewed by institution review board (IRB) in March 2019. We submitted a notification of this trial in April 2019.

CONCLUSIONS
We demonstrated the anti-glioma effect of Ad-SGE-REIC. We will start a phase I/IIa clinical trial of Ad-SGE-REIC for the treatment of recurrent malignant glioma.
ATIM-23. PRELIMINARY FINDINGS OF A PHASE I SAFETY AND BIOIMAGING TRIAL OF KB004 (IFABOTUZUMAB) IN PATIENTS WITH GLIOBLASTOMA
Authors: Gan Hui , Cher Lawrence , Inglis Po , Lwin Zarnie , Lau Eddie , Ackermann Uwe , Coombs Nicole , Remen Kirsten , Guo Nancy , Ting Lee Sze , Gong Sylvia , Palmer Jodie , Pathmaraj Kunthi , O’Keefe Graeme , Scott Fiona , Day Bryan , Boyd Andrew , Thomas Paul , Durrant Cameron , Scott Andrew 
Published: November 2019

Abstract
Glioblastoma (GBM) is the most frequent and lethal primary brain neoplasm. EphA3 is a tumor restricted antigen expressed in 38–40% of GBM and 100% of the tumor vasculature. Ifabotuzumab is a non-fucosylated IgG1κ antibody targeting EphA3 receptor. A Phase 1 study of ifabotuzumab in haematological malignancies was well tolerated and clinically active. Here we report on a Phase I dose escalation and biodistribution study of ifabotuzumab in recurrent glioblastoma. DESIGN The primary objective is to determine the toxicity and recommended phase II dose of Ifabotuzumab in GBM patients (pts). Secondary objectives are to determine the biodistribution and pharmacokinetics (PK) of 89Zr-Ifabotuzumab, the frequency of EphA3 positive GBM and response rates. Eligible pts received a trace (5mg) dose of zirconium-89 labelled ifabotuzumab (89Zr-ifab) on day 1 followed by sequential PET imaging over 1 week to determine its biodistribution, frequency of in situ EphA3 expression and tumor uptake. Safety and PK assessments were undertaken. On Day 8, pts commenced weekly ifabotuzumab infusions until PD. Three cohorts are planned (3.5mg/kg, 5.25 mg/kg, 7.9 mg/kg). On day 36, pts received both 89Zr-ifab and Ifabotuzumab, to assess receptor occupancy. Response rate (RANO) and survival data were collected. RESULTS: To date, 7 of 12 pts have enrolled (6 at 3.5 mg/kg,1 at 5.25 mg/kg; Mean age: 55 years (±12.6), 4 are male). Treatment emergent AEs included infusion reactions, seizures, cerebral oedema, rash, pruritis, headaches, eye disorder. Most were considered related to study drug, seizures and infusion reactions were readily managed with increased premedications after the first occurrence. Best response in cohort 1 is SD for 23 weeks. 89Zr-ifab PET/CT scans showed rapid, specific targeting at all known tumor sites and in all pts, but no normal tissue uptake. MRI scans showed predominant T2/FLAIR changes, occasionally marked, which were consistent with treatment effect on tumor vasculature.
ATIM-26. INTERIM RESULTS OF THE EXTENSION PHASE OF A PHASE I/IIA TRIAL OF A THERAPEUTIC CMV VACCINE AGAINST RECURRENT GLIOBLASTOMA (GBM)
Authors: Wen Patrick , Reardon David , Lee Eudocia , Iwamoto Fabio , Anderson David , Diaz-Mitoma Francisco , Lassman Andrew 
Published: November 2019

Abstract
Cytomegalovirus (CMV) antigens have been reported in over 90% of GBM tumors. CD4+and CD8+T cells are most frequently directed against the gB and pp65 antigens, respectively, and are immunogenic targets in a CMV-based GBM vaccine. We have initiated a phase I/IIa clinical trial for patients with recurrent GBM using gB/pp65 enveloped virus-like particles (eVLPs) formulated with GM-CSF and administered intradermally. In phase I, eligible patients were age 18–70 with Karnofsky Performance Status at least 70, normal end-organ function, on stable or decreasing corticosteroids of at most 4mg dexamethasone (or equivalent), with recurrent GBM following any standard initial therapy and any number of recurrences of any size. Patients were vaccinated monthly until tumor progression, with immune-monitoring performed 2 weeks after each vaccination and MRI exams every 6 weeks. The primary endpoint was safety/tolerability and secondarily to assess immunogenicity. Three vaccine doses (0.4µg, 2µg, and 10µg pp65) were evaluated with 6 patients in each cohort, and the DSMB identified no DLTs or safety concerns with any of the doses. The highest 10µg dose was chosen for the Phase IIa extension phase of the trial based on stable disease (3 months or longer) observed in 3/6 patients, which correlated with vaccine-induced IFN-γ-secreting T cell responses against CMV. Enrollment in phase IIa of the trial, which is designed to explore initial potential efficacy signals in an additional 10 patients that receive the optimal 10µg dose of vaccine, is expected in June 2019 and includes the additional requirements of unifocal, measurable enhancing tumor 1–3 cm across at first recurrence and no prior immunotherapy. Patients will be vaccinated monthly until clinical progression. Tumor responses and associated immunological biomarkers will be presented, and are expected to include initial data for all 10 patients.
ATIM-31. SAFETY OF TUMOR-SPECIFIC PEPTIDE VACCINE TARGETING ISOCITRATE DEHYDROGENASE 1 MUTATION IN RECURRENT RESECTABLE LOW GRADE GLIOMA PATIENTS
Authors: Peters Katherine , Congdon Kendra , Archer Gary , Woodring Sarah , Jaggers Denise , Lipp Eric , Healy Patrick , Herndon James , Soher Brian , Vlahovic Gordana , Johnson Margaret , Randazzo Dina , Desjardins Annick , Friedman Henry , Friedman Allan , Ashley David , Yan Hai , Sampson John 
Published: November 2019

Abstract

BACKGROUND
Low grade gliomas (LGGs) represent 10–15% of glial tumors in adults and while LGG patients have a better prognosis over high-grade gliomas, these cancers ultimately recur and transform to more aggressive tumors. Isocitrate dehydrogenase 1 (IDH1) is commonly mutated in LGG, and when mutated, it is the oncogenic driver by leading to the production of oncometabolite 2-hydroxyglutarate (2-HG). We developed a phase 1 study for recurrent resectable IDH1 mutant LGG utilizing a tumor-specific peptide vaccine targeting IDH1 mutant protein that spans the mutated region of IDHR132H (PEPIDH1M vaccine).

METHODS
We performed a phase 1, single-center, clinical trial in recurrent resectable IDH1 mutant WHO grade II glioma patients. Subjects received three PEPIDH1M vaccine q2wks and then proceeded to surgical resection. If subject’s tumor retained grade II status, then the subject proceeded with 12 cycles of daily TMZ (50 mg/m2 X 28 days) and PEPIDH1M vaccine (12 injections q4wks). If subject’s tumor transformed to grade III, then subject proceeded to radiation therapy (RT) with concurrent TMZ followed by 12 cycles of daily TMZ (50 mg/m2 X 28 days) and PEPIDH1M vaccine (12 injections q4wks). Primary endpoint was safety of PEPIDH1M vaccine in combination with adjuvant TMZ and/or XRT/TMZ and evaluable subjects needed to receive ≥6 PEPIDH1M vaccines. We assessed safety using CTCAE 4.03.

RESULTS
We enrolled 24 recurrent LGG subjects with mean age of 43.8 yrs (sd=11.4 yrs). Twenty subjects completed ≥6 PEPIDH1M vaccines. Most common related toxicity was grade 1 injection site reaction (N=20) and skin induration (n=17) with no grade 3–4 related toxicities.

CONCLUSIONS
PEPIDH1M vaccine in combination with surgical resection, daily TMZ and/or RT + TMZ with daily TMZ was safe and well tolerated in recurrent IDH1 mutant LGG. We are currently exploring secondary/correlative endpoints including immunogenicity of PEPIDH1M vaccine and magnetic resonance spectroscopy for 2-HG.
ATIM-47. NIVOLUMAB VS BEVACIZUMAB IN PATIENTS WITH RECURRENT GLIOBLASTOMA: EXPLORATORY ANALYSIS OF MGMT METHYLATION STATUS AND BASELINE CORTICOSTEROID USE
Authors: Weller Michael , Reardon David , Brandes Alba , Sampson John , Mulholland Paul , Wick Antje , Baehring Joachim , Ahluwalia Manmeet , Roth Patrick , Bähr Oliver , Phuphanich Surasak , Sepulveda Juan , de Souza Paul , Sahebjam Solmaz , Potter Von , Tatsuoka Kay , Taitt Corina , Zwirtes Ricardo , Omuro Antonio , Lim Michael 
Published: November 2019

Abstract

BACKGROUND
Current therapies for recurrent glioblastoma provide limited survival benefit. In the open-label, phase 3 CheckMate 143 study (NCT02017717), although the primary endpoint was not met, the median overall survival (mOS) was comparable between nivolumab (anti–PD-1) and bevacizumab in the overall population of patients with glioblastoma at first recurrence after temozolomide chemoradiotherapy (Reardon et al, WFNOS 2017). Exploratory subgroup analyses were conducted to evaluate the association of O-6-methylguanine DNA methyltransferase (MGMT) promoter methylation status and corticosteroid use at baseline with mOS.

METHODS
Prespecified patient subgroups included MGMT promoter status (methylated vs unmethylated) and baseline corticosteroid use (yes [within 5 days of first dose] vs no). FINDINGS: Methylation status was available for 102/184 (55%) nivolumab-treated and 109/185 (59%) bevacizumab-treated patients. Using a multivariable Cox proportional hazards model analysis, no baseline corticosteroid use (HR, 0.59 [95% CI, 0.36–0.95]) and methylated MGMT status (HR, 0.47 [95% CI, 0.29–0.78]) were each associated with longer mOS among nivolumab-treated patients. Among patients with methylated MGMT and no baseline corticosteroid use, mOS was 17.0 months with nivolumab (n=31) and 10.1 months with bevacizumab (n=22; HR, 0.58 [95% CI, 0.30–1.11]). In patients with methylated tumors and baseline corticosteroids, mOS was 7.7 months with nivolumab (n=12) and 13.5 months with bevacizumab (n=17). Among patients with unmethylated tumors and no baseline corticosteroids, mOS was 8.3 months with nivolumab (n=30) and 10.3 months with bevacizumab (n=29). In patients with unmethylated tumors and baseline corticosteroids, mOS was 5.6 months with nivolumab (n=28) and 8.3 months with bevacizumab (n=28).

CONCLUSION
A trend toward longer mOS with nivolumab was observed in a subgroup of patients with methylated MGMT and no baseline corticosteroid use. These findings suggest that MGMT methylation status and corticosteroid use at baseline could be used to identify patients who may benefit from nivolumab and thus warrant further study.
ACTR-13. FINAL RESULTS WITH CHEMORADIOTHERAPY FOR ANAPLASTIC OLIGODENDROGLIAL TUMORS FROM NRG ONCOLOGY/RTOG 9402
Authors: Lassman Andrew , Won Minhee , Gregory Cairncross J , Shaw Edward , Ashby Lynn , Souhami Luis , Laack Nadia , Fink Karen , Macdonald David , Bahary Jean-Paul , Hartford Alan , Whitton Anthony , Werner-Wasik Maria , Laperriere Normand , Suh John , Robinson Clifford , Mehta Minesh 
Published: November 2019

Abstract

BACKGROUND
Adding intensive-procarbazine, lomustine, and vincristine (iPCV) to radiotherapy (RT) prolonged progression-free (PFS) and overall survival (OS) for patients with 1p19q codeleted anaplastic oligodendroglial tumors (AOTs); some benefit was also observed for IDH-mutant non-codeleted cases (Cairncross et al 2013, 2014, 2016). Now, 25 years after study activation, we updated survival, further assessed IDH as a predictive biomarker, and are exploring the benefit from vincristine.

METHODS
Eligible adults (KPS ≥ 60, adequate end-organ function) were randomized to pre-RT iPCV (4 cycles x 6 weeks each) vs. RT alone, stratified by age (< or ≥ 50), KPS (60–70 or ≥ 80), and level of anaplasia. Histology (anaplastic oligodendroglioma/oligo-astrocytoma required) and biomarkers (IDH and 1p19q, post-hoc) were determined centrally. Survival was estimated by Kaplan-Meier and Hazard Ratios (HRs) by Cox-regression.

RESULTS
Overall (n=289), median follow-up was 16.4 years vs. 11.3 years at last report. In codeleted cases, 40% randomized to iPCV remained alive vs. 53% at last report; 5, 10, and 14 year-PFS and -OS rates were 62%, 50%, 41% and 70%, 57%, 46%, respectively; and iPCV unequivocally prolonged PFS (median 9.8 vs. 2.9 years, HR 0.46, 95% CI 0.3–0.7, p< 0.001) and OS (median 13.2 vs. 7.3 years, HR 0.61, 95% CI 0.40–0.94; p=0.02). With IDH mutation but without codeletion (n=66), iPCV prolonged PFS (median 2.8 vs. 1.9 years, HR 0.58, 95% CI 0.34–0.99, p=0.046); OS was longer with a trend for significance (median 5.5 vs. 3.3 years, HR 0.6, 95% CI 0.34–1.03, p=0.06) on this underpowered exploratory post-hoc analysis.

CONCLUSION
For codeleted AOTs, long-term analyses confirmed that pre-RT iPCV produced meaningful and significant prolongations of PFS and OS. With IDH mutation but without codeletion, iPCV significantly prolonged PFS and showed a trend for prolonged OS. The value of vincristine is being assessed. Supported by NCI grants U10CA180868, U10CA180822, U24CA196067, and UG1CA189867.
ACTR-19. REPORT ON THE COMBINATION OF AXITINIB AND TUMOR TREATING FIELDS (TTFIELDS) IN THREE PATIENTS WITH RECURRENT GLIOBLASTOMA
Authors: Schulz Ellina , Kessler Almuth F , Weiland Judith , Linsenmann Thomas , Ernestus Ralf-Ingo , Hagemann Carsten , Löhr Mario 
Published: November 2019

Abstract

OBJECTIVE
Tumor Treating Fields (TTFields) significantly improved survival of newly diagnosed glioblastoma (ndGBM) patients in the EF-14 trial. Axitinib is an orally available tyrosine kinase inhibitor which is approved for the treatment of metastatic renal cell carcinoma. It has a high affinity and specificity for vascular endothelial growth factor receptors. In phase 2 trials, Axitinib improved response rate and PFS in recurrent GBM (rGBM) patients with a manageable toxicity profile. Here, three rGBM patients treated with TTFields and Axitinib (AxiTTFields) are presented.

PATIENT SECTION
A 53-year-old male patient (#1) presented with a progressing GBM after initial surgery, radiochemotherapy followed by 4 cycles of temozolomide (TMZ) and TTFields. In a 46-year-old male patient (#2), early progress occurred after surgery, radiochemotherapy and 3 cycles of TMZ combined with TTFields. In both patients Axitinib was added to the treatment regimen to meet the urgent need of an alternative treatment. In a 61-year-old male patient (#3) with rGBM after surgery, radiochemotherapy and 6 cycles of TMZ, TTFields therapy was initiated at recurrence and the treatment regimen was adapted to AxiTTFields.

RESULTS
No additional adverse events due to the combined therapy of AxiTTFields were observed. Patients #1 and #2 were on AxiTTFields therapy for more than 8 months, presenting an improved neurological status with a partial response in the MRI 3 months after initiating AxiTTFields. #3 declined in his neurological status without any change in the MRI monitoring and died 2.4 months after initiating AxiTTFields. With an average of 77%, the TTFields usage rate was above the independent prognostic threshold of 75%, underlining the feasibility of this approach.

CONCLUSION
AxiTTFields was feasible and safe in three rGBM patients. The addition of Axitinib to TTFields therapy is a promising approach and safety/feasibility will be further investigated in a pilot trial.
ACTR-27. EVOLUTION OF THE NEUROSURGEON’S ROLE IN CLINICAL TRIALS FOR GBM: A SYSTEMATIC OVERVIEW OF THE CLINICALTRIALS.GOV DATABASE
Authors: Mansouri Alireza , Beyn Michelle , Pancholi Aditya , Chow Clement , Boutet Alexandre , Elias Gavin , Germann Jurgen , Zadeh Gelareh 
Published: November 2019

Abstract

BACKGROUND
The therapeutic challenge of glioblastoma (GBM) has catalyzed the active pursuit of a high volume of clinical trials to evaluate novel interventions for this deadly disease. Our enhanced understanding of the biology of GBMs has translated into an evolution of the role of the neurosurgeon as well. In this study, we have evaluated the current landscape of surgical clinical trials in GBM to characterize this evolution, describe current trends, and identify potential gaps in methodological features.

METHODS
The ClinicalTrials.gov database was searched for surgical/procedural trials in individuals with GBM on May 14th, 2019 without date limitations. Demographics, specific intervention (e.g. technical, device use, or local drug delivery), phase, sample size, and main outcome measures were abstracted.

RESULTS
270 of 2140 trials (12.6%) were identified as procedural. The majority were based in the USA (189/270, 70%), single-center (188/270, 70%), and not randomized by design (215/270, 80%). Primary and recurrent GBMs were evenly addressed. Industry-funding supported 106/270 (39%) of studies. The leading test intervention was local delivery of therapeutics (44.8%), followed by use of novel devices (33%). Surgical technique/procedures comprised 20%. Early Phase designs predominated (177/270, 65.5%) but 67 (24.8%) did not report Phase. The greatest surge in new registrations over the last decade was seen in Phase I trials. The top primary outcome was safety/tolerability/ feasibility (107/270, 39%), followed by survival (62/270, 22%); 35 (12.6%) did not report a primary outcome. Approximately 15% of studies were terminated, withdrawn or suspended. Only 6 records were associated with reported results.

CONCLUSIONS
In GBMs, procedural interventions comprise a notable proportion of trials. Local delivery of therapeutics and novel device applications, predominantly through Phase I designs, represent the evolved role of the neurosurgeon in neuro-oncology. Improved documentation of design, outcomes, and reporting of results are needed to better inform the field and increase efficiency.