bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hyperbolic Orbits in the Solar System: Interstellar Origin or Perturbed Oort Cloud Comets?
Authors: Higuchi Arika , Kokubo Eiichiro 
Published: November 2019

Abstract
We study the dynamical properties of objects in hyperbolic orbits passing through the inner Solar system in the context of two different potential sources: interstellar space and the Oort cloud. We analytically derive the probability distributions of eccentricity, e, and perihelion distance, q, for each source and estimate the numbers of objects produced per unit of time as a function of these quantities. By comparing the numbers from the two sources, we assess which origin is more likely for a hyperbolic object having a given eccentricity and perihelion distance. We find that the likelihood that a given hyperbolic object is of interstellar origin increases with decreasing eccentricity and perihelion. Conversely, the likelihood that a hyperbolic object has been scattered from the Oort cloud by a passing star increases with decreasing eccentricity and increasing perihelion. By carefully considering their orbital elements, we conclude that both 1I/2017 U1 ’Oumuamua (e ≃ 1.2 and q ≃ 0.26 au) and 2I/2019 Q4 Borisov (e ≃ 3.3 and q ≃ 2 au) are most likely of interstellar origin, not scattered from the Oort cloud. However, we also find that Oort cloud objects can be scattered into hyperbolic orbits like those of the two known examples, by sub-stellar and even sub-Jovian mass perturbers. This highlights the need for better characterization of the low mass end of the free-floating brown dwarf and planet population.
corrfunc – a suite of blazing fast correlation functions on the CPU
Authors: Sinha Manodeep , Garrison Lehman H 
Published: November 2019

ABSTRACT
The two-point correlation function (2PCF) is the most widely used tool for quantifying the spatial distribution of galaxies. Since the distribution of galaxies is determined by galaxy formation physics as well as the underlying cosmology, fitting an observed correlation function yields valuable insights into both. The calculation for a 2PCF involves computing pair-wise separations and consequently, the computing time-scales quadratically with the number of galaxies. The next-generation galaxy surveys are slated to observe many millions of galaxies, and computing the 2PCF for such surveys would be prohibitively time-consuming. Additionally, modern modelling techniques require the 2PCF to be calculated thousands of times on simulated galaxy catalogues of at least equal size to the data and would be completely unfeasible for the next-generation surveys. Thus, calculating the 2PCF forms a substantial bottleneck in improving our understanding of the fundamental physics of the Universe, and we need high-performance software to compute the correlation function. In this paper, we present corrfunc – a suite of highly optimized, openmp parallel clustering codes. The improved performance of corrfunc arises from both efficient algorithms as well as software design that suits the underlying hardware of modern CPUs. corrfunc can compute a wide range of 2D and 3D correlation functions in either simulation (Cartesian) space or on-sky coordinates. corrfunc runs efficiently in both single- and multithreaded modes and can compute a typical two-point projected correlation function [wp(rp)] for ∼1 million galaxies within a few seconds on a single thread. corrfunc is designed to be both user-friendly and fast and is publicly available at https://github.com/manodeep/Corrfunc.
ATIM-03. ANTI-TGFß2 RNA THERAPEUTIC OT-101 INDUCES DURABLE OBJECTIVE RESPONSES IN PATIENTS WITH RECURRENT/REFRACTORY (R/R) GLIOBLASTOMA MULTIFORME (GBM, WHO GRADE 4) OR ANAPLASTIC ASTROCYTOMA (AA, WHO GRADE 3)
Authors: Uckun Fatih , Qazi Sanjive , Hwang Larn , Nam David , Trieu Vuong 
Published: November 2019

Abstract

BACKGROUND
High-grade gliomas (HGG) are characterized by a T-cell exhaustion signature and pronounced T-cell hyporesponsiveness of their tumor microenvironment (TME). Transforming growth factor beta 2 (TGF-ß2) has been implicated as a key contributor to the immunosuppressive landscape of the TME in HGG. OT-101 is a first-in-class RNA therapeutic designed to abrogate the immunosuppressive actions of TGF-ß2. Here we report the single-agent activity of OT-101 in adult patients with R/R HGG.

METHODS
In this phase 2 clinical trial (NCT00431561), OT-101 was administered with an intratumoral catheter using a convection enhanced delivery (CED) system. 77 patients received 4–11 cycles of OT-101 via continuous infusion over 7d. Response determinations were based on central review of MRI scans by an independent review committee according to standard and modified McDonald criteria. Standard statistical methods were applied for the analysis of data.

RESULTS
The median progression-free survival (PFS) and overall survival (OS) were 86d and 432d, respectively. 26 patients (33.8%) had marked reductions of their tumor volume after receiving OT-101: 19 achieved durable objective responses (CR: 3, PR: 16). The median time for 90% reduction of the baseline tumor volume was 11.7 months (Range: 4.9–57.7 months). The mean log reduction of the tumor volume was 2.2 ± 0.4 (Median = 1.4: Range: 0.4–4.5) logs. 7 had stable disease (SD) lasting > 6 months. The median PFS (1109d [95% CI: 992 - > 1423] vs. 37d [95% CI: 35 – 59] (Log-rank Chi Square = 69.9, P-value < 0.0001) and OS (1280d [95% CI: 1116- > 1743] vs. 240d [95% CI: 169 – 361] (Log-rank Chi Square = 47.0, P-value < 0.0001) of these 26 patients was significantly better than the PFS or OS of the remaining 51 patients.

CONCLUSION
Anti-TGFß2 RNA therapeutic OT-101 exhibits clinically meaningful single-agent activity and induces durable CR/PR/SD in R/R HGG patients.
ATIM-40. CIRCULATING MYELOID-DERIVED SUPPRESSOR CELLS PREDICT FAVORABLE RESPONSE TO IMMUNE CHECKPOINT THERAPY IN A RANDOMIZED TRIAL OF NIVOLUMAB AND BEVACIZUMAB IN RECURRENT GBM
Authors: Ahluwalia Manmeet , Grabowski Matthew , Alban Tyler , Otvos Balint , Bayik Defne , Saeed Bamashmos Anas , Rayman Patricia , Diaz-Montero Marcela , Reardon David , Wen Patrick , Peereboom David , Lathia Justin 
Published: November 2019

Abstract
Glioblastoma (GBM) creates an immunosuppressive environment that presents a challenge to efficacy of immunotherapeutic approaches. Results from the CheckMate-143 trial demonstrated responses in 8% of patients with nivolumab, underscoring the need for further insight into the mechanisms and markers of immune suppression and response. Given a limited set of biomarkers predictive of immunotherapy response in GBM, we explored the changes in immune cell populations in nivolumab and bevacizumab-treated GBM patients pre and post-treatment in order to help predict response. In these studies, we utilized traditional and newly developed approaches, including mass cytometry time-of-flight (CyTOF), single-cell RNA sequencing, and 10X Genomics simultaneous cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq). We analyzed patients’ samples in a randomized, phase 2 study of nivolumab and bevacizumab at GBM first recurrence (NCT03452579). Nine patients were identified as responders or non-responders at 8 weeks after therapy initiation. Utilizing peripheral blood samples, we observed a 6.4-fold decrease in immunosuppressive myeloid-derived suppressor cells (MDSCs) between baseline and first imaging follow-up in responders compared to non-responders, with a 4.9-fold decrease in the granulocytic MDSC (G-MDSC) subtype in responders over non-responders. While no significant changes in overall T-cell numbers were noted, expression of PD-1 on CD4+ T cells was significantly elevated at baseline and follow-up in responders as compared to non-responders – signatures which were confirmed by CyTOF. Given these immunophenotypic changes, preliminary results of a detailed investigation of this cohort by CITE-seq indicate that responders had increased IL7R-positive T cells post-treatment, which was not observed in non-responders. These results are currently being validated in an additional 40 patients that have been enrolled. Altogether, differences in immunophenotypes that were specific to responders and non-responders were observed, and characterization of these immune populations may be helpful in identifying GBM patients likely to benefit from immunotherapy.
ACTR-05. PROCARBAZINE AND CCNU CHEMOTHERAPY FOR RECURRENT GLIOBLASTOMA WITH MGMT PROMOTER METHYLATION
Authors: Kil Hong Yong , Ho Yang Seung 
Published: November 2019

Abstract

BACKGROUND
While procarbazine, CCNU (lomustine), and vincristine (PCV) has been an alternative chemotherapy option for malignant gliomas, it is worth investigating whether the combination of only procarbazine and CCNU is comparable because vincristine adds toxicity with uncertain benefit. The purpose of this study was to evaluate the feasibility of procarbazine and CCNU chemotherapy for recurrent glioblastoma multiforme (GBM) with O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation.

METHODS
Eight patients with recurrent GBM following concurrent chemoradiotherapy and temozolomide (TMZ) adjuvant therapy were enrolled in this trial; they received no other chemotherapeutic agents or target therapy. They received CCNU (75 mg/m2) on day 1 and procarbazine (60 mg/m2) through days 11 and 24 every 4 weeks. The median cycle of CCNU and procarbazine was 3.5 (range: 2–6).

RESULTS
One patient achieved stable disease. The median progression-free survival (PFS) with procarbazine and CCNU chemotherapy was eight weeks (range: 5–73), and the PFS rates were 25% and 12.5% at 16 and 30 weeks, respectively. The median overall survival (OS) from the initial diagnosis to death was 40 months, and the median OS from the administration of procarbazine and CCNU chemotherapy to death was 9.7 months (95% confidence interval: 6.7–12.7). Serious adverse events were found at six visits, and two cases were considered to be grade 3 toxicities.

CONCLUSION
The efficacy of procarbazine and CCNU chemotherapy is not satisfactory. This study suggests the need to develop other treatment strategies for recurrent and TMZ-refractory GBM
ACTR-10. PHASE 0 TRIAL OF CERITINIB IN BRAIN METASTASES AND RECURRENT GLIOBLASTOMA
Authors: Fiorelli Roberto , Li Jing , Bao Xun , DeRogatis Alanna , Pennington-Krygier Chelsea , Kim Seongho , Mehta Shwetal , Sanai Nader 
Published: November 2019

Abstract

BACKGROUND
Ceritinib is an orally bioavailable, small molecule inhibitor for ALK/IGFR1/FAK, which are highly expressed in glioblastoma and brain metastases. Preclinical and clinical reports suggest ceritinib activity in central nervous system (CNS) malignancies, yet there is no direct evidence in patients. This study assessed the pharmacokinetics (PK) and pharmacodynamics (PD) of ceritinib in brain metastases and recurrent glioblastoma patients.

METHODS
Ten patients with brain metastases (n=3) or glioblastoma (n=7) exhibiting high expression of pSTAT5b/pFAK/pIGFR1 were treated with 10 days of oral ceritinib (750 mg daily) prior to tumor resection. Plasma, tumor, and cerebrospinal fluid (CSF) samples were collected at ~ 4 and 24 h following the last dose. Total and unbound drug concentrations were determined using LC-MS/MS. PD response was assessed by immunohistochemical analysis of pALK, pFAK, pIGFR1, and pIRS1 staining in treated tumor and matched archival tissues.

RESULTS
Ceritinib was highly bound to human plasma protein (median fraction unbound (Fu), 1.4%) and to brain tumor tissue (median Fu, 0.073% and 0.14% in enhancing and non-enhancing regions respectively). There was a large interindividual variability in drug CNS penetration, with the median unbound concentrations in enhancing, non-enhancing, and CSF of 0.040, 0.006, and 0.012 µM, respectively. The median unbound tumor-to-plasma ratio was 2.44 and 0.33 in enhancing and non-enhancing areas, respectively. In one brain metastasis patient, drug binding to enhancing tumor was significantly lower (Fu, 1.62%), resulting in a higher unbound drug tumor and CSF concentration as compared to all other patients. In all patients, no pharmacodynamic response was detected in sampled tumor tissue.

CONCLUSION
Ceritinib is highly bound to plasma proteins and tumor tissues. Unbound drug concentrations in brain metastasis and glioblastoma appear insufficient for target modulation. Despite recent reports of clinical response, our findings suggest no role for ceritinib in treating glioblastoma and an unfavorable profile for brain metastases.
ACTR-12. PHASE 2 STUDY OF DIANHYDROGALACTITOL (VAL-083) IN PATIENTS WITH MGMT-UNMETHYLATED, BEVACIZUMAB-NAÏVE GLIOBLASTOMA IN THE RECURRENT AND ADJUVANT SETTING
Authors: O’Brien Barbara , Penas-Prado Marta , Kamiya Carolos , Pei Weathers Shiao- , Yung Alfred , Loghin Monica , Harrison Rebecca , Bacha Jeffrey , Brown Dennis , Johnson Gregory , Langlands John , Schwartz Richard , Kanekal Sarath , Lopez Lorena , deGroot John 
Published: November 2019

Abstract
Current standard-of-care for glioblastoma (GBM) includes surgery followed by concurrent therapy with radiation and temozolomide (TMZ) followed by adjuvant TMZ (days 1–5 every 28 days. Almost all GBM patients experience recurrent/progressive disease, with a median survival after recurrence of 3–9 months. Second-line treatment for recurrent GBM with bevacizumab (BEV) has not improved survival, and effective therapies for GBM are lacking. Unmethylated promoter for O6-methylguanine-DNA-methyltransferase (MGMT) is a validated biomarker for TMZ-resistance and is correlated with poor patient prognosis. VAL-083 is a bi-functional DNA-targeting agent which rapidly induces interstrand DNA cross-links at N7-guanine, induces double-strand breaks and acts independent of MGMT DNA repair. The current ongoing trial is a biomarker-driven Phase 2 study in MGMT-unmethylated BEV-naïve adult GBM. The primary objective of this study is to determine the effect of VAL-083 on median overall survival (mOS) for MGMT-unmethylated GBM patients compared to historical control. Secondary efficacy endpoints include progression-free survival (PFS), overall response rate (ORR), duration of response (DOR), and quality-of-life. Thirty-five (35) subjects with recurrent GBM have received 40 mg/m2/day VAL-083 on days 1, 2, 3 of a 21-day cycle as the starting dose. Myelosuppression is the most common adverse event and a higher potential for this toxicity correlated with those patients who received a higher number of cycles of prior TMZ maintenance therapy, (>5 cycles vs. ≤5 cycles, p< 0.05). To minimize the potential for hematological toxicity in rGBM, subsequent subjects initiated treatment at 30 mg/m2/d VAL-083 x 3 consecutive days every 21 days. In addition, since TMZ is of limited value in the MGMT-unmethylated setting, a second arm in newly diagnosed GBM has been included to explore whether substituting TMZ with VAL-083 offers clinical benefit and extends the time to recurrence. Enrollment, safety data and study updates will be presented at the meeting. Clinicaltrials.gov identifier: NCT02717962.
ACTR-24. A RANDOMIZED PHASE II TRIAL OF VELIPARIB (V), RADIOTHERAPY (RT) AND TEMOZOLOMIDE (TMZ) IN PATIENTS (PTS) WITH UNMETHYLATED MGMT (uMGMT) GLIOBLASTOMA (GBM): THE VERTU STUDY
Authors: Khasraw Mustafa , Leanne McDonald Kerrie , Rosenthal Mark , Lwin Zarnie , Ashley David , Wheeler Helen , Barnes Elizabeth , Foote Matthew , Koh Eng-Siew , Sulman Erik , Back Michael , Buckland Michael , Sim Hao-Wen , Fisher Lauren , Leonard Robyn , Hall Merryn , Yip Sonia , Simes John 
Published: November 2019

Abstract

BACKGROUND
TMZ offers minimal benefit in pts with de novo uMGMT GBM. V is synergistic with RT and TMZ in uMGMT preclinical GBM models, safe when combined with either RT or TMZ clinically, but the triplet (V+RT+TMZ) is poorly tolerated. VERTU tested V in pts with uMGMT GBM.

METHODS
VERTU is a randomized Phase 2 trial comparing Standard Arm (Arm A), RT (60Gy/30 fractions) + TMZ (75mg/m2 daily) followed by TMZ (150–200mg/m2D 1–5) every 28 days for 6 cycles vs Experimental Arm (Arm B), RT (60Gy/30 fractions) + V (200mg PO BID) followed by TMZ (150–200mg/m2D 1–5) + V (40mg bid, D 1–7) every 28 days for 6 cycles in pts with de novo uMGMT GBM according to centralised testing.

RESULTS
125 pts were randomized 1:2 (41:84). The 2 groups were matched for age, sex, performance status and extent of resection. Median follow-up was 25.8 months and 91 pts had died. The 6-month Progression-Free Survival (6mPFS) for Arms A and B were 34% (95% CI 20–48) and 46% (95% CI 36–57) respectively. The median PFS for Arms A and B were 4.2m (95% CI 2.5–6.0) and 5.7m (95% CI 4.1–6.6) respectively (HR = 0.80, 95%CI 0.55–1.18). 55% of pts in both arms experienced Grade 3/4 adverse events (AEs) with no significant differences in frequency or severity between the arms. Most common Grade 3/4 AEs were thrombocytopenia, seizures, hyperglycaemia and diarrhoea.

CONCLUSION
VERTU demonstrated that a novel treatment strategy for patients with de novo uMGMT GBM was feasible and tolerable. The observed 6mPFS and PFS were similar in both arms. Overall survival and other endpoints will be presented. Central MRI review, biomarker analyses, including DNA repair and methylation signature analyses are ongoing.
(ANZCTR#ACTRN12615000407594).
ACTR-28. A CALL FOR INCREASED ROLE OF NEUROSURGEONS IN SURGICAL TRIALS FOR NON-GLIOMATOUS PRIMARY CNS TUMORS: A SYSTEMATIC REVIEW OF THE CLINICALTRIALS.GOV DATABASE
Authors: Mansouri Alireza , Beyn Michelle , Chow Clement , Pancholi Aditya , Boutet Alexandre , Elias Gavin , Germann Jurgen , Zadeh Gelareh 
Published: November 2019

Abstract

BACKGROUND
Surgery continues to be part of the mainstay of therapy for most primary CNS tumors. However, neurosurgical innovations advancing treatment options have stagnated. An understanding of past and current investigational trends is necessary to catalyze innovation in surgical trials.

OBJECTIVE
To evaluate the landscape of surgical clinical trials for non-diffusely infiltrating primary CNS tumors.

METHODS
ClinicalTrials.gov was searched on May 14th, 2019 for surgical/procedural trials based on non-diffusely infiltrating primary CNS tumors, with a focus on meningiomas, ependymomas, medulloblastomas, pituitary adenomas, vestibular scwhannomas, and chordomas. Key trial design parameters were extracted. Purely surgical interventions were classified as “technical” while fluorescence-guided and other intraoperative imaging modalities were classified as image-guided surgery. Any invasive mode of drug delivery (e.g. intra-arterial or intra-ventricular, local chemotherapy wafers, and oncolytic virus injection) was considered.

RESULTS
Among 944 total trial records (257 medulloblastomas, 254 ependymomas, 179 meningiomas, 156 pituitary adenomas, 56 vestibular schwannomas, and 48 chordomas) only 54 (5.7%) were procedural in nature. Ependymomas had the highest absolute number (18/254, 7%) while vestibular schwannomas had the highest percentage (6/56, 10.7%) of surgical trials. The majority of records were not randomized (41/54, 75.9%), not industry-funded (45/54, 83.3%), and were early Phase (30/54, 55.6%); there were only three Phase III trials. The relative number of new surgical trial registrations has not changed significantly over time (1990s: 5, 2000s: 19, and 2010s: 30). Approaches integrated with other disciplines, such as image-guided surgery (16/54, 29.6%) and local drug delivery (16/24, 29.6%), were among the leading categories of trials.

CONCLUSIONS
Despite the clinical role of surgery in management of non-diffusely infiltrating primary CNS tumors, a paucity of innovative surgical trials has been put forth. Multi-disciplinary approaches appear to be necessary for pushing the therapeutic envelope for individuals affected by these tumors, with imaging and drug development at the forefront.
ACTR-45. FATTY ACID SYNTHASE INHIBITOR TVB-2640 INCREASES PROGRESSION FREE SURVIVAL IN RECURRENT GBM
Authors: Konkel Brandon , Michalek Joel , Diaz Duque Enrique , Liu Qiangia , Caflisch Laura , Madhu Vinu , Brenner Andrew 
Published: November 2019

Abstract

BACKGROUND
Standard of care for glioblastoma (GBM) is surgical resection followed by temozolamide, with bevacizumab (bev) given at relapse. Responses to bev remain brief; resistance may involve overexpression of Fatty Acid Synthase (FASN).

METHODS
This is a prospective phase 2 study of bev with TVB-2640 in patients with rGBM at first relapse. Primary end point is progression free survival (PFS). Inclusion criteria are: age ≥ 18, ECOG 0 to 2, GBM progression following standard combined modality treatment. An exploratory phase randomization into 2 separate arms of single agent bev or in combination with TVB-2640 with MR-Spectroscopy (MRS) and serum sampling for exosome analysis obtained on all patients at day 1 and 28 of first cycle. Starting on cycle 2 day 1, all patients converged to a single arm and continue to receive bev in combination with TVB-2640. A total sample size of 24 patients will provide 90% power to detect a 4 month difference in PFS (3–4 months for Bev alone (historic controls) (i.e., a hazard ratio of 0.43) using a one-sided log-rank test with alpha=0.1.

RESULTS
Enrollment is complete with 28 patients to date. 3 failed screening. 21 came off study and 4 are active. No grade 4 or higher treatment-related AEs have occurred, with Grade 3 events included 3 cases of palmar-plantar erythrodysesthesia; 1 each of hypertension, stomatitis, optic neuritis, DVT, and wound infection. 95.2% of patients have achieved at least stable disease by RANO Criteria, with a 66.7% overall response rate (ORR). Median time to progression was 5.9, which is statistically superior to historical controls. Overall survival as well as biomarker analysis (exosome, MRS), is pending.

CONCLUSIONS
The combination of TVB2640 with bev appears well tolerated and with PFS6 significantly improved over historical controls. Final data analysis as well as exploratory biomarker analysis will be presented.