bluuebunny/crossref_metadata_2025 huggingface dataset:
Association Between Plasma Diacetylspermine and Tumor Spermine Synthase With Outcome in Triple-Negative Breast Cancer
Authors: Fahrmann Johannes F , Vykoukal Jody , Fleury Alia , Tripathi Satyendra , Dennison Jennifer B , Murage Eunice , Wang Peng , Yu Chuan-Yih , Capello Michela , Creighton Chad J , Do Kim-Anh , Long James P , Irajizad Ehsan , Peterson Christine , Katayama Hiroyuki , Disis Mary L , Arun Banu , Hanash Samir
Published: September 2019

Background

MYC is an oncogenic driver of development and progression in triple-negative breast cancer (TNBC). Ornithine decarboxylase, the rate-limiting enzyme in polyamine metabolism, is a transcriptional target of MYC. We therefore hypothesized that a plasma polyamine signature may be predictive of TNBC development and progression.

Methods

Using liquid chromatography mass spectrometry, polyamine levels were determined in plasma samples from newly diagnosed patients with TNBC (n = 87) and cancer-free controls (n = 115). Findings were validated in plasma samples from an independent prospective cohort of 54 TNBC, 55 estrogen receptor negative (ER−) and progesterone receptor negative (PR−) and HER2 positive (HER2+), and 73 ER+ case patients, and 30 cancer-free control subjects. Gene expression data and clinical data for 921 and 2359 breast cancer tumors were obtained from The Cancer Genome Atlas repository and the Oncomine database, respectively. Relationships between plasma diacetylspermine (DAS) and tumor spermine synthase (SMS) mRNA expression with metastasis-free survival and overall survival were determined using Cox proportional hazard models; Fisher exact tests were used to assess risk of distant metastasis in relation to tumor SMS mRNA expression.

Results

An increase in plasma DAS, a catabolic product of spermine mediated through SMS, was observed in the TNBC subtype of breast cancer. Plasma levels of DAS in TNBC associated with increased risk of metastasis (plasma DAS value ≥ 1.16, hazard ratio = 3.06, 95% confidence interval [CI] = 1.15 to 8.13, two-sided P = .03). SMS mRNA expression in TNBC tumor tissue was also found to be predictive of poor overall survival (top 25th percentile hazard ratio = 2.06, 95% CI = 1.04 to 4.08, one-sided P = .04) and increased risk of distant metastasis in TNBC (comparison of lowest SMS quartile [reference] to highest SMS quartile relative risk = 1.90, 95% CI = 0.97 to 4.06, one-sided Fisher exact test P=.03).

Conclusions

Metabolomic profiling identified plasma DAS as a predictive marker for TNBC progression and metastasis.
A mutation in the catalytic domain of cellulose synthase 6 halts its transport to the Golgi apparatus
Authors: Park Sungjin , Song Bo , Shen Wei , Ding Shi-You
Published: September 2019

D395N in the catalytic domain of CESA6 interrupts its normal transport to the Golgi, which hampers its function in cellulose synthesis.
Spectral variations of Lyman $\alpha$ emission within strongly lensed sources observed with MUSE
Authors: Claeyssens A , Richard J , Blaizot J , Garel T , Leclercq F , Patrício V , Verhamme A , Wisotzki L , Bacon R , Carton D , Clément B , Herenz E C , Marino R A , Muzahid S , Saust R , Schaye J
Published: September 2019

We present an analysis of ${\rm H\,\rm{\small {I}}}$ Lyman $\alpha$ emission in deep VLT/MUSE observations of two highly magnified and extended galaxies at $z=3.5$ and 4.03, including a newly discovered, almost complete Einstein ring. While these Lyman $\alpha$ haloes are intrinsically similar to the ones typically seen in other MUSE deep fields, the benefits of gravitational lensing allow us to construct exceptionally detailed maps of Lyman $\alpha$ line properties at sub-kpc scales. By combining all multiple images, we are able to observe complex structures in the Lyman $\alpha$ emission and uncover small ($\sim120$ km s−1 in Lyman $\alpha$ peak shift), but significant at $ \gt $4 $\sigma$, systematic variations in the shape of the Lyman $\alpha$ line profile within each halo. Indeed, we observe a global trend for the line peak shift to become redder at large radii, together with a strong correlation between the peak wavelength and line width. This systematic intrahalo variation is markedly similar to the object-to-object variations obtained from the integrated properties of recent large samples. Regions of high surface brightness correspond to relatively small line shifts, which could indicate that Lyman $\alpha$ emission escapes preferentially from regions where the line profile has been less severely affected by scattering of Lyman $\alpha$ photons.
From the outside looking in: what can Milky Way analogues tell us about the star formation rate of our own galaxy?
Authors: Fraser-McKelvie Amelia , Merrifield Michael , Aragón-Salamanca Alfonso
Published: September 2019

The Milky Way has been described as an anaemic spiral, but is its star formation rate (SFR) unusually low when compared to its peers? To answer this question, we define a sample of Milky Way analogues (MWAs) based on stringent cuts on the best literature estimates of non-transient structural features for the Milky Way. This selection yields only 176 galaxies from the whole of the SDSS DR7 spectroscopic sample which have morphological classifications in Galaxy Zoo 2, from which we infer SFRs from two separate indicators. The mean SFRs found are $\log (\rm {SFR}_{SED}/\rm {M}_{\odot }~\rm {yr}^{-1})=0.53$ with a standard deviation of 0.23 dex from SED fits, and $\log (\rm {SFR}_{W4}/\rm {M}_{\odot }~\rm {yr}^{-1})=0.68$ with a standard deviation of 0.41 dex from a mid-infrared calibration. The most recent estimate for the Milky Way’s SFR of $\log (\rm {SFR}_{MW}/\rm {M}_{\odot }~\rm {yr}^{-1})=0.22$ fits well within 2$\sigma$ of these values, where $\sigma$ is the standard deviation of each of the SFR indicator distributions. We infer that the Milky Way, while being a galaxy with a somewhat low SFR, is not unusual when compared to similar galaxies.
Star formation histories of dwarf galaxies in the FIRE simulations: dependence on mass and Local Group environment
Authors: Garrison-Kimmel Shea , Wetzel Andrew , Hopkins Philip F , Sanderson Robyn , El-Badry Kareem , Graus Andrew , Chan T K , Feldmann Robert , Boylan-Kolchin Michael , Hayward Christopher C , Bullock James S , Fitts Alex , Samuel Jenna , Wheeler Coral , Kereš Dušan , Faucher-Giguère Claude-André
Published: September 2019

We study star formation histories (SFHs) of 500 dwarf galaxies (stellar mass $M_\ast =10^5\!-\!10^9\, \rm {M}_\odot$) from FIRE-2 cosmological zoom-in simulations. We compare dwarfs around individual Milky Way (MW)-mass galaxies, dwarfs in Local Group (LG)-like environments, and true field (i.e. isolated) dwarf galaxies. We reproduce observed trends wherein higher mass dwarfs quench later (if at all), regardless of environment. We also identify differences between the environments, both in terms of ‘satellite versus central’ and ‘LG versus individual MW versus isolated dwarf central.’ Around the individual MW-mass hosts, we recover the result expected from environmental quenching: central galaxies in the ‘near field’ have more extended SFHs than their satellite counterparts, with the former more closely resemble isolated (true field) dwarfs (though near-field centrals are still somewhat earlier forming). However, this difference is muted in the LG-like environments, where both near-field centrals and satellites have similar SFHs, which resemble satellites of single MW-mass hosts. This distinction is strongest for M* = 106–$10^7\, \rm {M}_\odot$ but exists at other masses. Our results suggest that the paired halo nature of the LG may regulate star formation in dwarf galaxies even beyond the virial radii of the MW and Andromeda. Caution is needed when comparing zoom-in simulations targeting isolated dwarf galaxies against observed dwarf galaxies in the LG.
HELP: a catalogue of 170 million objects, selected at 0.36–4.5 μm, from 1270 deg2 of prime extragalactic fields
Authors: Shirley Raphael , Roehlly Yannick , Hurley Peter D , Buat Veronique , Campos Varillas María del Carmen , Duivenvoorden Steven , Duncan Kenneth J , Efstathiou Andreas , Farrah Duncan , González Solares Eduardo , Malek Katarzyna , Marchetti Lucia , McCheyne Ian , Papadopoulos Andreas , Pons Estelle , Scipioni Roberto , Vaccari Mattia , Oliver Seb
Published: September 2019

We present an optical to near-infrared (NIR) selected astronomical catalogue covering 1270 deg2. This is the first attempt to systematically combine data from 23 of the premier extragalactic survey fields – the product of a vast investment of telescope time. The fields are those imaged by the Herschel Space Observatory that form the Herschel Extragalactic Legacy Project (HELP). Our catalogue of 170 million objects is constructed by a positional cross-match of 51 public surveys. This high-resolution optical, NIR, and mid-infrared catalogue is designed for photometric redshift estimation, extraction of fluxes in lower resolution far-infrared maps, and spectral energy distribution modelling. It collates, standardizes, and provides value added derived quantities including corrected aperture magnitudes and astrometry correction over the Herschel extragalactic wide fields for the first time. $grizy$ fluxes are available on all fields with g-band data reaching $5\sigma$ point-source depths in a 2 arcsec aperture of 23.5, 24.4, and 24.6 (AB) mag at the 25th, 50th, and 75th percentiles, by area covered, across all HELP fields. It has K or $K_s$ coverage over 1146 deg2 with depth percentiles of 20.2, 20.4, and 21.0 mag, respectively. The IRAC Ch 1 band is available over 273 deg2 with depth percentiles of 17.7, 21.4, and 22.2 mag, respectively. This paper defines the ‘masterlist’ objects for the first data release (DR1) of HELP. This large sample of standardized total and corrected aperture fluxes, uniform quality flags, and completeness measures provides large well-understood statistical samples over the full Herschel extragalactic sky.
Slow decline and rise of the broad [O iii] emission line in globular cluster black hole candidate RZ2109
Authors: Dage Kristen C , Zepf Stephen E , Bahramian Arash , Strader Jay , Maccarone Thomas J , Peacock Mark B , Kundu Arunav , Steele Matthew M , Britt Christopher T
Published: September 2019

RZ2109 is the first of several extragalactic globular clusters shown to host an ultraluminous X-ray source. RZ2109 is particularly notable because optical spectroscopy shows it has broad, luminous [O iii] λλ4959,5007 emission, while also having no detectable hydrogen emission. The X-ray and optical characteristics of the source in RZ2109 make it a good candidate for being a stellar mass black hole accreting from a white dwarf donor (i.e. an ultracompact black hole X-ray binary). In this paper we present optical spectroscopic monitoring of the [O iii]5007 emission line from 2007 to 2018. We find that the flux of the emission line is significantly lower in recent observations from 2016 to 2018 than it was in earlier observations in 2007–2011. We also explore the behaviour of the emission line shape over time. Both the core and the wings of the emission line decline over time, with some evidence that the core declines more rapidly than the wings. However, the most recent observations (in 2019) unexpectedly show the emission line core rebrightening
Studying the Solar system dynamics using pulsar timing arrays and the LINIMOSS dynamical model
Authors: Guo Y J , Li G Y , Lee K J , Caballero R N
Published: September 2019

Pulsar timing arrays (PTAs) can be used to study the Solar system ephemeris (SSE), the errors of which can lead to correlated timing residuals and significantly contribute to the PTA noise budget. Most Solar system studies with PTAs assume the dominance of the term from the shift of the Solar system barycentre (SSB). However, it is unclear to which extent this approximation can be valid, since the perturbations on the planetary orbits may become important as data precision keeps increasing. To better understand the effects of SSE uncertainties on pulsar timing, we develop the linimoss dynamical model of the Solar system, based on the SSE of Guangyu Li. Using the same input parameters as DE435, the calculated planetary positions by linimoss are compatible with DE435 at centimetre level over a 20 yr timespan, which is sufficiently precise for pulsar-timing applications. We utilize linimoss to investigate the effects of SSE errors on pulsar timing in a fully dynamical way, by perturbing one SSE parameter per trial and examining the induced timing residuals. For the outer planets, the timing residuals are dominated by the SSB shift, as assumed in previous work. For the inner planets, the variations in the orbit of the Earth are more prominent, making previously adopted assumptions insufficient. The power spectra of the timing residuals have complex structures, which may introduce false signals in the search of gravitational waves. We also study how to infer the SSE parameters using PTAs, and calculate the accuracy of parameter estimation.
Galactic habitability re-examined: indications of bimodality
Authors: Stojković N , Vukotić B , Martinović N , Ćirković M M , Micic M
Published: September 2019

The problem of the extent of habitable zones in different kinds of galaxies is one of the outstanding challenges for contemporary astrobiology. In the present study, we investigate habitability in a large sample of simulated galaxies from the illustris Project in order to at least roughly quantify the hospitality to life of different galactic types. The pioneering study of Dayal et al. is critically examined and some of its results are amended. In particular, we find a tentative evidence for a second mode of galactic habitability comprising metal-rich dwarfs similar to IC 225, LMC, or M32. The role of the galactic environment and the observation-selection effects is briefly discussed and prospects for further research on the topic outlined.
Long-term multiwavelength view of the blazar 1ES 1218+304
Authors: Singh K K , Bisschoff B , van Soelen B , Tolamatti A , Marais J P , Meintjes P J
Published: September 2019

In this work, we present a multiwavelength study of the blazar 1ES 1218+304 using near simultaneous observations over 10 yr during the period 2008 September 1 to 2018 August 31 (MJD 54710–58361). We have analysed data from Swift-UVOT, Swift-XRT, and Fermi-LAT to study the long term behaviour of 1ES 1218+304 in different energy bands over the last decade. We have also used the archival data from OVRO, MAXI, and Swift-BAT available during the above period. The near simultaneous data on 1ES 1218+304 suggest that the long term multiwavelength emission from the source is steady and does not show any significant change in the source activity. The optical/UV fluxes are found to be dominated by the host galaxy emission and can be modelled using the pegase code. However, the time averaged X-ray and γ-ray emissions from the source are reproduced using a single zone leptonic model with log-parabolic distribution for the radiating particles. The intrinsic very high energy γ-ray emission during a low activity state of the source is broadly consistent with the predictions of the leptonic model for blazars. We have investigated the physical properties of the jet and the mass of the supermassive black hole at the centre of the host galaxy using long term X-ray observations from the Swift-XRT which is in agreement with the value derived using blackbody approximation of the host galaxy. We also discuss the extreme nature of the source on the basis of X-ray and γ-ray observations.
X-ray light curves from realistic polar cap models: inclined pulsar magnetospheres and multipole fields
Authors: Lockhart Will , Gralla Samuel E , Özel Feryal , Psaltis Dimitrios
Published: September 2019

Thermal X-ray emission from rotation-powered pulsars is believed to originate from localized ‘hotspots’ on the stellar surface occurring where large-scale currents from the magnetosphere return to heat the atmosphere. Light-curve modelling has primarily been limited to simple models, such as circular antipodal emitting regions with constant temperature. We calculate more realistic temperature distributions within the polar caps, taking advantage of recent advances in magnetospheric theory, and we consider their effect on the predicted light curves. The emitting regions are non-circular even for a pure dipole magnetic field, and the inclusion of an aligned magnetic quadrupole moment introduces a north–south asymmetry. As the quadrupole moment is increased, one hotspot grows in size before becoming a thin ring surrounding the star. For the pure dipole case, moving to the more realistic model changes the light curves by $5\!-\!10{{\, \rm per\, cent}}$ for millisecond pulsars, helping to quantify the systematic uncertainty present in current dipolar models. Including the quadrupole gives considerable freedom in generating more complex light curves. We explore whether these simple dipole+quadrupole models can account for the qualitative features of the light curve of PSR J0437−4715.
Gephebase, a database of genotype–phenotype relationships for natural and domesticated variation in Eukaryotes
Authors: Courtier-Orgogozo Virginie , Arnoult Laurent , Prigent Stéphane R , Wiltgen Séverine , Martin Arnaud
Published: September 2019

Gephebase is a manually-curated database compiling our accumulated knowledge of the genes and mutations that underlie natural, domesticated and experimental phenotypic variation in all Eukaryotes—mostly animals, plants and yeasts. Gephebase aims to compile studies where the genotype–phenotype association (based on linkage mapping, association mapping or a candidate gene approach) is relatively well supported. Human clinical traits and aberrant mutant phenotypes in laboratory organisms are not included and can be found in other databases (e.g. OMIM, OMIA, Monarch Initiative). Gephebase contains more than 1700 entries. Each entry corresponds to an allelic difference at a given gene and its associated phenotypic change(s) between two species or two individuals of the same species, and is enriched with molecular details, taxonomic information, and bibliographic information. Users can easily browse entries and perform searches at various levels using boolean operators (e.g. transposable elements, snakes, carotenoid content, Doebley). Data is exportable in spreadsheet format. This database allows to perform meta-analyses to extract global trends about the living world and the research fields. Gephebase should also help breeders, conservationists and others to identify promising target genes for crop improvement, parasite/pest control, bioconservation and genetic diagnostic. It is freely available at www.gephebase.org.
Sodium thiosulphate and progression of vascular calcification in end-stage renal disease patients: a double-blind, randomized, placebo-controlled study
Authors: Djuric Petar , Dimkovic Nada , Schlieper Georg , Djuric Zivka , Pantelic Milan , Mitrovic Milica , Jankovic Aleksandar , Milanov Marko , Kuzmanovic Pficer Jovana , Floege Jürgen
Published: September 2019

Background

Sodium thiosulphate (NaTS) is mostly used in haemodialysis (HD) patients with calcific uraemic arteriolopathy. This double-blind, randomized, placebo-controlled study assessed the effect of NaTS on progression of cardiovascular calcifications in HD patients.

Methods

From 65 screened patients, we recruited 60 patients with an abdominal aorta Agatston calcification score ≥100. Thirty patients were randomized to receive NaTS 25 g/1.73 m2 and 30 patients to receive 100 mL of 0.9% sodium chloride intravenously during the last 15 min of HD over a period of 6 months. The primary endpoint was the absolute change of the abdominal aortic calcification score.

Results

The abdominal aortic calcification score and calcification volume of the abdominal aorta increased similarly in both treatment groups during the trial. As compared with the saline group, patients receiving NaTS exhibited a reduction of their iliac artery calcification score (−137 ± 641 versus 245  ± 755; P = 0.049), reduced pulse wave velocity (9.6  ± 2.7 versus 11.4 ± 3.6; P = 0.000) and a lower carotid intima-media thickness (0.77  ± 0.1 versus 0.83  ±  00.17; P = 0.033) and had better preservation of echocardiographic parameters of left ventricular hypertrophy. No patient of the NaTS group developed new cardiac valve calcifications during the trial as compared with 8 of 29 patients in the saline group. By univariate analysis, NaTS therapy was the only predictor of not developing new valvular calcifications. No adverse events possibly related to NaTS infusion were noted.

Conclusions

While NaTS failed to retard abdominal aortic calcification progress, it positively affected calcification progress in iliac arteries and heart valves as well as several other cardiovascular functional parameters.
PL2.2 Pembrolizumab (PEM) in recurrent high-grade glioma (HGG)patients with mismatch repair deficiency (dMMR): an observational study
Authors: Caccese M , Simonelli M , Fassan M , Padovan M , Persico P , Bellu L , Dipasquale A , Gardiman M , Indraccolo S , Zagonel V , Lombardi G
Published: September 2019

BACKGROUND

Pem, an immune checkpoint inhibitor, demonstrated to be activein various neoplasms with MMRd. No data exists about its efficacy in MMRdglioma patients.

MATERIAL AND METHODS

MMRd HGG relapsed after receiving RT and CT weretreated with Pem. MMR status was analyzed by immunohistochemistry,including the MLH1, MSH2, MSH6, and PMS2 markers. MMR deficiency wasdefined as presence of a weak (wMMRd) or absent (aMMRd) signal atimmunohistochemistry for at least one MMR protein. Other inclusion criteriawere: ECOG PS 0–2, histologically confirmed gliomas, dexamethasone ≤4 mg.Pem was administrated at 200 mg every 3 weeks until progression disease orunacceptable toxicity. Tumor response was evaluated by brain MRI every 10 weeksaccording to the RANO criteria. OS and PFS were evaluated by Kaplan-Meiercurves. CTCAE v4.0 was used for toxicity.

RESULTS

among 167 glioma patients, we found 22 MMRd gliomas. 12 PTS were treated with Pem: 8 wMMRd and 4 aMMRd. According to Bethesda criteria, allPTS had microsatellite stability. Tumor histologies included 5 anaplasticastrocytoma, 1 anaplastic oligodendroglioma, 6 glioblastoma (GBM). MSH2deficiency was found in 6 cases, MSH6 deficiency in 9 cases, PMS2 and MLH1deficiency in 2 cases. Median number of prior line of chemotherapy was 1 (range 1–5). Stable disease (SD) was reported in 4 PTS (33%); 8 PTS showedprogressive disease (PD). PTS with anaplastic gliomas showed a statisticallysignificant association with SD (p=0.03, OR=3); all GBM PTS reported PD; status of MMRd (weak/absent), IDH (mutated/wild-type), MSH2 and MLH6(deficient/proficient) were not associated with SD. Median follow up was 14.7 ms. OS was 5.6 ms (95% CI 0.1–13.8), PFS 2.4 ms (95% CI 1.8–2.9). OS was 2.8 ms and 5.6 ms (p=0.9), PFS was 1.8 ms and 3.1 ms (p=0.5) in PTS with wMMRd and aMMRd. PTS reporting SD and PD had PFS of 7.4 ms (95% CI 4.6–10.2) and 1.8 ms (95% CI 0.2–3.4), p=0.002; OS was “not reached” and 2.8 ms in PTS having SD vs PD (p=0.04). Grade ≥3 adverse eventswere reported in 8% of PTS.

CONCLUSION

a subgroup of recurrent MMRd HGG might benefit from Pem,especially anaplastic gliomas. There was a trend for a longer PFS and OS in PTS with aMMRd. Analyses for identifying additional molecular predictive factors is ongoing.
PL3.1 A phase 1, open-label, perioperative study of ivosidenib (AG-120) and vorasidenib (AG-881) in recurrent, IDH1-mutant, low-grade glioma: results from cohort 1
Authors: Mellinghoff I K , Wen P Y , Taylor J W , Maher E A , Arrillaga-Romany I , Peters K B , Le K , Tai F , Steelman L , Cloughesy T F
Published: September 2019

BACKGROUND

Mutant isocitrate dehydrogenase (mIDH) enzymes produce the oncometabolite D-2-hydroxyglutarate (2-HG). Ivosidenib (IVO; AG-120) is a first-in-class oral inhibitor of mIDH1 being evaluated in 66 glioma patients (pts) in an ongoing phase 1 study (NCT02073994). Vorasidenib (VOR; AG-881) is an oral, potent, brain-penetrant inhibitor of mIDH1/2 being evaluated in 52 glioma pts in an ongoing phase 1 study (NCT02481154). In an orthotopic glioma model, IVO and VOR reduced 2-HG levels by 85% and 98%, respectively, despite different brain:plasma ratios (<0.04 vs 1.33).

MATERIAL AND METHODS

This is a phase 1, multicenter, open-label, perioperative study (NCT03343197). Pts with recurrent, nonenhancing WHO 2016 Grade (Gr) 2 or 3 mIDH1-R132H oligodendroglioma or astrocytoma undergoing craniotomy were randomized 2:2:1 to IVO 500 mg QD, VOR 50 mg QD, or no treatment (control) for 4 wk preoperatively in Cohort 1. Postoperatively, pts continued to receive IVO or VOR, and control pts were randomized 1:1 to IVO or VOR. Tumors were assessed for mIDH1 status, cellularity, 2-HG, and drug concentration. Treated samples were compared with control pts and mIDH1 and wild type (WT) banked reference (ref) samples. Plasma and CSF 2-HG were assessed. Primary endpoint: brain tumor 2-HG concentration with IVO or VOR treatment. Pts with nonevaluable tissue were replaced.

RESULTS

As of 29 Nov 2018, 26 pts (17 men, 9 women; 25 Gr 2, 1 Gr 3) were randomized preoperatively (IVO 10, VOR 11, control 5) and 25 received drug (IVO 12, VOR 13). At the data cut, 19 tumors were analyzed, with 16 evaluable. Treatment-emergent adverse events in >10% of patients (all Gr 1 or 2) were diarrhea (36%); hypocalcemia and constipation (each 20%); anemia, hyperglycemia, pruritus, headache, and nausea (each 16%); and hypokalemia and fatigue (each 12%). Mean brain:plasma ratio was 0.16 for IVO and 2.4 for VOR. Geometric mean (range) tumor 2-HG levels (μg/mL) were: IVO (n=6), 10 (2.2-104); VOR (n=6), 6.8 (3.9-10); control mIDH1 (n=65 [4 pts, 61 ref]), 141 (4.8-909); and WT ref (n=15), 2.7 (0.46-12). Mean changes (95% CI) in 2-HG level vs control were IVO -93% (74%, 98%) and VOR -95% (82%, 99%). Updated data from Cohort 1 will be presented.

CONCLUSION

In Cohort 1 of this phase 1 perioperative study, IVO and VOR were CNS penetrant and lowered tumor 2-HG levels compared with untreated samples. Cohort 2 is open and will evaluate IVO 250 mg BID and VOR 10 mg QD.

FUNDING

Agios Pharmaceuticals, Inc.
JS1.1 Specific genetic alterations of breast tumors lead to Yo paraneoplastic cerebellar syndromes
Authors: Desestret V , Pissaloux D , Treilleux I , Small M , Robert M , Rogemond V , Picard G , Psimaras D , Alentorn A , Honnorat J
Published: September 2019

BACKGROUND

Paraneoplastic cerebellar degenerations with anti-Yo antibodies (Yo-PCD) are rare syndromes associated with ovarian or breast cancers and caused by an auto-immune response against neuronal antigens expressed by tumor cells. We previously demonstrated in Yo-PCD ovarian cancers an association between massive infiltration of ovarian tumors by activated immune effector cells and recurrent gains and/or mutations of onconeural Yo genes (CDR2L and CDR2), suggesting that such genetic alterations in ovarian tumor cells may trigger immune tolerance breakdown and initiation of the auto-immune reaction against Purkinje cells.

MATERIAL AND METHODS

We pursued the characterization of Yo-PCD tumors and specifically studied breast cancer by IHC, FISH, CGH array and RNA sequencing analysis of 17 breast Yo-PCD tumors and by comparing their genetic characteristics with 10 sporadic breast tumors and public databases.

RESULTS

We confirmed that specific genetic alterations were also present in breast cancers associated with Yo-PCD. Moreover, this study provides additional evidence for a role of tumor cell specificities in PCD immunopathology by revealing peculiarities in Yo-PCD breast tumors compared to Yo-PCD ovarian cancer. Indeed, not only the CDR2L Yo gene was amplified in 8/9 breast Yo-PCD cancers but also the Erb2/Her2 gene in 15/16 (both genes are on chromosome 17q). In addition to this original Her2 and Yo antigen amplification confirmed by FISH, we observed an overexpression of these proteins by IHC analysis. These Yo-PCD breast cancers are also all negative for hormone receptors (HR). Thus, Yo-PCD breast tumors seem to belong to the molecularly and clinically distinct class of HR-negative and Her2-enriched breast cancers, which represents less than 10 % of breast cancers in the general population. Transcriptomic analysis confirmed that breast Yo-PCD tumors differ by their expression programs from classical breast cancers molecular subtypes.

CONCLUSION

Understanding the tumor genetic features leading to the immune breakdown and anti-tumor immune response as well as nervous tissue attack remains challenging and seems to be specific according to the tumor subtypes. Herein, our results suggest that, despite sharing common genetic alterations (copy number variations and mutations affecting Yo genes), the Yo-PCD immunopathogenesis of breast and ovarian cancers differ by involving different tumor-specific molecular pathways.
JS1.4 Neurological follow-up of neurotoxicity after CAR T cell therapy in lymphoma patients: A French neurological multi-center survey
Authors: Belin C , Simard C , Dos Santos A , Ayrignac X , Berger C , Cartron G , Le Gouill S , Sesques P , Thieblemont C , Carpentier A F
Published: September 2019

BACKGROUND

Chimeric antigen receptor-modified T (CAR T) cell therapy is a highly promising treatment for haematological malignancies but is frequently associated with cytokine-release syndrome (CRS) and neurotoxicity. The physiopathological mechanisms of neurological complications and their links with CRS remain largely unknown. The aims of this study are: a) to follow-up longitudinally patients treated with CAR-T cell therapy; b) to exhaustively identify neurological signs and symptoms and; c) to describe their occurrence over time.

MATERIAL AND METHODS

Since September 2018, all patients treated with CD19-targeted CAR T cell therapy for relapsing lymphoma were systematically followed-up and monitored for signs of neurotoxicity by a neurologist. Five different centres (Paris-Saint-Louis, Nantes, Lyon, Montpellier, and Rennes) participated in this study.

RESULTS

As of April 1st 2019, 57 patients, mean age 49 years (range from 22 to 72 years, median age 50 years), 22 females / 35 males, all treated for lymphoma, were included in this study Neurotoxicity, defined as the presence of at least one neurological sign or symptoms appearing after treatment infusion, was present in 33 % of patients. The median time to onset was 7.5 days after infusion with a median duration of symptoms of 5 days. Neurological symptoms were: Encephalopathy (52%), cerebellar syndrome (26%), aphasia (15%), agraphia (15%), executive syndrome (10%), myoclonus (10%), dysarthria (10%), meningismus (5%), transverse myelitis (5%), seizure (5%), neuralgia (5%), and dysesthesia (5%). The severity grade of neurotoxicity was grade 4: 2 patients, Grade 3: 7 patients, grade 2: 5 patients and grade 1: 5 patients (CTCAE grading). CRS was observed in 75% of patients. All patients who developed neurological disorders also had CRS (grade 1: 68%, grade 2: 10%, grade 3: 15%, grade 4: 5%) that preceded neurotoxicity. As the study is still ongoing, updated results will be presented at the EANO meeting.

CONCLUSION

Neurotoxicity associated with CAR-T therapies occurs in one third of patients. This high frequency underlines the need: 1 - to neurologically assess all patients before and repeatedly after therapy infusions; 2 - to provide guidelines for neurological assessment and relevant investigations to improve early recognition of neurotoxicity and its management
OS2.3 Relevance of Neurofibromatosistype 1 and schwannomotosis in extramedullary spine tumors
Authors: Eoli M E , Bianchessi D , Moscatelli M , Chiapparini L , Ibba C , Finocchiaro G , Bruzzone M
Published: September 2019

BACKGROUND

Extramedullary spine tumors represent two-thirds of all primary spine neoplasms. Approximately half of these are peripheral nerve sheath tumors, mainly neurofibromas and schwannomas and neurofibromatosis or schwannomatosis can be suspected. Given the rarity of this condition the clinical genetic and radiological features remains to be better define. The aim of this study was to characterize the clinical, radiologic presentation of patients with widespread spinal disease and to identify gene mutation.

MATERIAL AND METHODS

We selected patient with a at least: intradural extramedullary, or extradural intraspinal (tumor within the spinal canal), or extradural paraspinal (tumor at the neural foramenor extending outward into adjacent tissues) neoplasms and no other tumors such as meningiomas in the spine at spine MRI. Patients’ DNA were analyzed by Targeted NGS by means a custom gene panel including NF1, NF2, LZTR1, SMARCB1 genes.

RESULTS

63 patients were identified31 had few isolated tumors, involving spinal roots (Multiple Neurofibromas Few Spinal Root, MNFSR), 18 had bilateral neurofibromas involving all spinal roots. 14 had a single lesion; 10 cases were familiar and 53 sporadic. Genetic analysis showed NF1 gene mutations (in prevalence splicing or missense) in 49 cases LZTR1 mutations in 3 and in the others 11 no mutation or deletion was detected. Pain was the hallmark symptom in patients with LZTR1 mutations, while all familial cases all had NF1 diagnosis. About 50% of them had few cutaneous manifestations.

CONCLUSION

In patients with extramedullary spine tumors is important to look for signs of neurofibromatosis or schawannomatosis and if there are present genetic testing should be performed.
OS4.4 Hypofractionated stereotactic radiotherapy and anti-PDL1 Durvalumab combination in recurrent glioblastoma: Results of the phase I part of the phase I/II STERIMGLI trial
Authors: Pouessel D , Mervoyer A , Larrieu-Ciron D , Cabarrou B , Robert M , Frenel J , Olivier P , Mounier M , Cohen-Jonathan Moyal E
Published: September 2019

BACKGROUND

Glioblastoma (GBM) remains a lethal disease with inevitable local relapse and no standard treatment. Re-irradiation by hypofractionated stereotactic radiotherapy (hFSRT) is an option of treatment with tolerable safety, but needs improvement in term of efficacy. Radiotherapy (RT) causes immunogenic tumor cell death but also induces PDL1 and PD1 expression on tumors and immune cells, potentially evoking resistance to RT. Pre-clinical studies combining hFSRT with an anti-PD-1 antibody in GBM have shown increased efficacy of the combination. Clinical studies also show encouraging results when checkpoint inhibitors have been combined with high dose RT. We hypothesized that combining the anti PD-L1 Durvalumab (Durva) with hFSRT will be an effective regimen for patients with recurrent GBM. We designed a phase I/II clinical trial studying the combination of hFSRT with Durva for recurrent GBM≤35 mm diameter. Results of the phase I are presented.

MATERIAL AND METHODS

Patients were included from February 2017 to October 2017.

A standard 3 + 3 de-escalation design was used. Patients were treated by hFSRT 24 Gy, 8 Gy/fraction at 80% isodose, every other day, combined with Durva infusion 1500mg first dose (Level 1) or 750 mg (Level -1) delivered on the last hFSRT day followed by 1500 mg Durva infusion every four weeks until relapse. The schema was defined as safe if one patient or less among 6 presents a dose limiting toxicity (DLT). Brain MRI was performed before RT and then every 8 weeks until relapse. Tumor assessment was performed according to RANO criteria.

RESULTS

Among the 6 patients (3 methylated MGMT, 3 unmethylated MGMT; all wild type IDH) included at the level 1, all completed the hFSRT course, only one had a DLT which was an immune related grade 3 vestibular neuritis. At the time of analysis (24/01/19), all the patients had a local tumor progression, 4 were still alive. Local progression free interval (LPFI) ranges from 2.1 to 8.1 months. Interestingly the 2 patients who presented a pseudo-progression had a prolonged LPFI (5.7 and 8.1 months) compared to the other patients. All the patients except these 2 patients had a lymphopenia at inclusion. PDL-1 expression varied from 0 to 70% in the primary tumor.

CONCLUSION

Combining three 8 Gy fractions of hFSRT with 1500 mg Durvalumab on the 3rd fraction hFSRT and every 4 weeks for recurrent GBM is well tolerated justifying exploration of its efficacy in the phase II which is currently in interim analysis
OS5.1 Phase I clinical trial with oncolytic virus DNX-2401 for DIPGs
Authors: Alonso M M , Iñigo I , Gonzalez-Huarriz M , Dominguez P , Patiño A , Jones C , Gomez-Manzano C , Fueyo J , Díez-Valle R , Tejada S
Published: September 2019

BACKGROUND

Despite our increased understanding of the genetic make-up and new therapies for pediatric high grade glioma (pHGG) and Diffuse Intrinsic Pontine Glioma (DIPG) the outcome remains grim. Delta-24-RGD (DNX-2401 in the clinic) has been tested for adult glioblastoma presenting a safe profile and promising efficacy. Recently our group has showed that the virus is safe and effective in preclinical models of pHGG and DIPG. Moreover, we showed that the virus is able to trigger an antitumor immune response. These outstanding preclinical results allowed us to propel a phase I clinical trial for newly diagnosed DIPGs (NCT03178032) where the patients received an intratumoral viral injection followed by standard radiotherapy.

MATERIALS AND METHODS

A phase I clinical trial with DNX-2401 for patients with newly diagnosed DIPG to assess the MTD is taking place in our hospital (N=12). Tumor biopsy is performed through the cerebellar peduncle, followed by virus injection. The virus is injected using a cannula, MEMS cannula (Alcyone Lifesciences) that prevents the reflux. Virus will be injected starting with 1010 pv. The trial is uncontrolled, unicentric with a 3 + 3 design. The objective of this trial is to determine the safety, tolerability, and toxicity of DNX-2401 in subjects with DIPG and to collect tumor samples of this type of tumor. Secondary endpoints are overall survival at 12 months (OS12), percentage of responses and induced immune response against tumor. The follow up includes close monitoring of neurological status, blood tests and brain MRI. If this trial shows evidence of safety and efficacy will propel a multicenter clinical trial.

RESULTS

All the clinical data from the trial available until September 2019 will be presented during the congress, to date 8 patients have been treated within the trial. Three patients were treated with the D1=1x1010vp and because the lack of toxicity we escalated to the D2= 5x1010vp. The procedure was well tolerated and safe. Patients were home 3–4 days after the injection. All the patients displayed a reduced tumor volume after combined treatment. We performed molecular studies in 6 out of the 8 patients. We are currently assessing the immune responses to the virus.

CONCLUSIONS

Information acquired within this clinical study would aid to understand the response of DIPGs to viral therapies and therefore to better tailor this strategy to improve the survival and the quality of life of pediatric brain tumors.
OS5.3 Quantitative signaling pathway analysis of Diffuse Intrinsic Pontine Glioma identifies two subtypes, respectively high TGFβ/MAPK-AP1 and high PI3K/HH pathway activity, which are potentially clinically actionable
Authors: van de Stolpe A , Verhaegh W , Holtzer L
Published: September 2019

BACKGROUND

Diffuse Intrinsic Pontine Glioma (DIPG) is a pediatric brain tumor (glioma), resistant to chemotherapy, with only a temporary response to radiotherapy and an extremely bad prognosis. Genomic abnormalities have been found, indicating abnormal activation of certain growth factor signaling pathways, while expression analysis suggests involvement of developmental signaling pathways.10–15 signal transduction pathways can drive cancer growth and metastasis. We have developed, and biologically validated, a method which enables quantitative measurements of functional activity of signal transduction pathways in individual cell/tissue samples, based on Bayesian computational model inference of pathway activity from measurements of mRNA levels of target genes of the transcription factor associated with the respective signalling pathway. A major envisioned clinical utility is prediction of therapy response.

MATERIAL AND METHODS

For signaling pathway analysis, Affymetrix expression microarray data were available (GEO dataset GSE26576) from 2 normal brain stem samples and from 6 low grade glioma and 26 DIPG samples (post-mortem after therapy). Of one DIPG patient samples were available before and after therapy. Signaling pathway activity scores were calculated for estrogen and androgen receptor, PI3K-FOXO, MAPK-AP1, JAK-STAT, NFκB, Hedgehog (HH), TGFβ, NOTCH and Wnt pathways. PI3K pathway activity is the reverse of FOXO activity, in the absence of oxidative stress (measured by SOD2 expression). Pathway activity scores were compared between normal tissue and low grade glioma samples and DIPG, and k-means cluster analysis was performed on the DIPG pathway activity scores.

RESULTS

After treatment, HH pathway activity was increased in DIPG compared to low grade glioma (p=0.0003), PI3K pathway activity scores showed large variations in activity in the DIPG group. Tumors with cell cycle (CDK4/6, CCND1-3) or Receptor Tyrosine Kinase-related gene amplifications had higher PI3K and HH pathway activity compared to tumors without identified amplifications (p<0.05) which, in contrast, had higher MAPK-AP1 pathway activity (p<0.002). Pathway-based clustering analysis revealed two DIPG clusters, C1: high TGFβ/MAPK-AP1 and low PI3K/HH pathway activity; C2: low TGFβ/MAPK-AP1, high PI3K/HH pathway activity. C1 best resembled low grade glioma. In the patient with pre/post treatment samples, a C1 pathway profile switched to a C2 profile after treatment.

CONCLUSION

Using our quantitative analysis of signaling pathway activity in post-treatment DIPG, two pathway activity subtypes were identified, of which the HH/PI3K high, TGFβ low activity subtype was associated with defined gene amplifications, and may have been induced by chemoradiation therapy. Clusters are supported by a clear biological rationale. Identified signaling pathways are potentially drug targetable.
OS8.1 A phase 0/2 clinical trial of a CDK4/6 inhibitor in aggressive meningioma patients
Authors: Tien A , Li J , Bao X , DeRogatis A , Fujita Y , Pennington-Krygier C , Kim S , Mehta S , Sanai N
Published: September 2019

BACKGROUND

New approaches are urgently needed for aggressive meningiomas, which remain largely incurable. Forkhead Box M1 (FOXM1) has been identified as a master transcription factor in aggressive meningiomas and Cyclin D-dependent Kinases (CDK) are positive regulators of cell-cycle entry, promoting tumorigenesis through FOXM1 activation. We evaluated the tumor pharmacokinetics (PK), tumor pharmacodynamics (PD), and preliminary clinical response of ribociclib, a selective CDK4/6-inhibitor, in aggressive meningioma patients.

MATERIAL AND METHODS

Eight aggressive WHO Grade II/III meningioma patients with intact RB expression were enrolled and administered oral ribociclib daily (900mg) for 5 days prior to tumor resection. Plasma, tumor, and cerebrospinal fluid (CSF) samples were collected at 2, 8, or 24 h after the last dose. Total and unbound drug concentrations were determined using a validated LC-MS/MS method. PD effects, including RB and FoxM1 phosphorylation, were compared to matched archival tissue. Patients with PK and PD responses in tumor tissue, defined as unbound ribociclib concentration > 5-fold in vitro IC50 (0.04µM) and >20% decrease in pRB levels, respectively, were enrolled into an exploratory Phase 2 cohort.

RESULTS

The median CSF concentration of ribociclib was 0.25 µM. In tumor tissue, the median unbound ribociclib concentration was 1.36 µM and the median unbound tumor-to-plasma ratio was 5.34. Suppression of G1-to-S phase was inferred in tumors with declining FoxM1 phosphorylation (50%), RB phosphorylation (38%), and cellular proliferation (75%). Four patients demonstrated concurrent PK and PD responses and were graduated to continuous ribociclib therapy. At one year, two of these patients (one Grade II and one Grade III) demonstrate partial responses per RANO criteria.

CONCLUSION

Ribociclib achieves pharmacologically-active concentrations in aggressive meningioma tissue. Target modulation was demonstrated by a decrease in FOXM1-mediated tumor proliferation. Further investigation of ribociclib as a therapeutic strategy for aggressive meningiomas is warranted.
OS9.1 Clinical significance of hypermutation in gliomas
Authors: Touat M , Li Y , Boynton A , Spurr L , Iorglescu B , Geduldig J , Birzu C , Lim Fat M , Santagata S , Coulet F , Beuvon F , Mokhtari K , Giry M , Block S , Guillerm E , Carpentier A , Huang R , Delattre J , Hoang-Xuan K , Sanson M , Duval A , Cherniack A , Reardon D , Wen P , Idbaih A , Marabelle A , Bandopadhayay P , Beroukhim R , Bielle F , Ligon K
Published: September 2019

BACKGROUND

Among patients with glioma, little is known about the clinical significance of hypermutation. We sought to define the determinants of hypermutation in gliomas, and to assess the value of this biomarker for predicting response to standard of care and immune checkpoint blockade.

MATERIAL AND METHODS

We performed comprehensive molecular characterization of 2420 pediatric and adult gliomas with clinical annotation. We determined the clinical and molecular characteristics associated with hypermutation, and assessed the relationship between hypermutation and clinical response to cancer therapies.

RESULTS

Overall, 114 hypermutated gliomas were identified. Hypermutation occurred predominantly in therapy-responsive subtypes characterized by methylated MGMT promoter, IDH1/2mutation or 1p/19q co-deletion. Hypermutation was almost always associated with prior treatment with temozolomide and molecular defects in DNA mismatch repair (MMR), which were identified in one-third of IDH1/2-mutated recurrent gliomas and was associated with shorter survival in multivariate analyses (hazard ratio 2.11 [95% CI 1.24–3.6], P=0.006). The molecular mechanisms whereby gliomas undergo hypermutation during therapy with alkylating agents were dissected using patient-derived glioma models in vitro and in vivo. Outcomes of hypermutated gliomas treated with immune checkpoint blockade or with standard of care agents will be presented at the conference.

CONCLUSION

This study establishes that mutation burden and mutation signatures are clinically and biologically significant biomarkers that can be used to predict therapy response and guide treatment decisions in gliomas.