bluuebunny/crossref_metadata_2025 huggingface dataset:
Spectral modification of magnetar flares by resonant cyclotron scattering
Authors: Yamasaki Shotaro , Lyubarsky Yuri , Granot Jonathan , Göğüș Ersin
Published: August 2020

Spectral modification of energetic magnetar flares by resonant cyclotron scattering (RCS) is considered. During energetic flares, photons emitted from the magnetically trapped fireball near the stellar surface should resonantly interact with magnetospheric electrons or positrons. We show by a simple thought experiment that such scattering particles are expected to move at mildly relativistic speeds along closed magnetic field lines, which would slightly shift the incident photon energy due to the Doppler effect. We develop a toy model for the spectral distortion by a single RCS that incorporates both a realistic seed photon spectrum from the trapped fireball and the velocity field of particles, which is unique to the flaring magnetosphere. We show that our spectral model can be effectively characterized by a single parameter: the effective temperature of the fireball, which enables us to fit observed spectra with low computational cost. We demonstrate that our single-scattering model is in remarkable agreement with Swift/BAT data of intermediate flares from SGR 1900+14, corresponding to effective fireball temperatures of Teff = 6–7 keV, whereas BeppoSAX/GRBM data of giant flares from the same source may need more elaborate models including the effect of multiple scatterings. Nevertheless, since there is no standard physically motivated model for magnetar flare spectra, our model could be a useful tool to study magnetar bursts, shedding light on the hidden properties of the flaring magnetosphere.
Confirming new white dwarf-ultracool dwarf binary candidates
Authors: Hogg M A , Casewell S L , Wynn G A , Longstaff E S , Braker I P , Burleigh M R , Tilbrook R H , Geier S , Koester D , Debes J H , Lodieu N
Published: August 2020

We present the results of a study to discover prospective new white dwarf-L dwarf binaries as identified by their near-infrared excesses in the UKIDSS catalogue. We obtained optical spectra to validate the white dwarf nature for 22 of the candidate primary stars, confirming ten as white dwarfs and determining their effective temperatures and gravities. For all 10 white dwarfs, we determined that the near-infrared excess was indeed indicative of a cool companion. Six of these are suggestive of late M dwarf companions, and three are candidate L dwarf companions, with one straddling the M−L boundary. We also present near-infrared spectra of eight additional candidate white dwarf-ultracool dwarf binaries, where the white dwarf primary had been previously confirmed. These spectra indicate one candidate at the M−L boundary, three potential L dwarf companions, and one suspected M dwarf, which showed photometric variability on a ∼6 h period, suggesting the system may be close. Radial velocity follow-up is required to confirm whether these systems are close, or widely separated.
The hydroxyl satellite-line ‘flip’ as a tracer of expanding H ii regions
Authors: Hafner Anita , Dawson J R , Wardle Mark
Published: August 2020

Observations of the four 2Π3/2,  J = 3/2 ground state transitions of the hydroxyl radical (OH) have emerged as an informative tracer of molecular gas in the Galactic interstellar medium (ISM). We discuss an OH spectral feature known as the ‘flip’, in which the satellite lines at 1612 and 1720 MHz flip – one from emission to absorption and the other the reverse – across a closely blended double feature. We highlight 30 examples of the flip from the literature, 27 of which exhibit the same orientation with respect to velocity: the 1720-MHz line is seen in emission at more negative velocities. These same examples are also observed towards bright background continuum, many (perhaps all) show stimulated emission, and 23 of these are coincident in on-sky position and velocity with H ii radio recombination lines. To explain these remarkable correlations, we propose that the 1720-MHz stimulated emission originates in heated and compressed post-shock gas expanding away from a central H ii region, which collides with cooler and more diffuse gas hosting the 1612-MHz stimulated emission. The foreground gas dominates the spectrum due to the bright central continuum; hence, the expanding post-shock gas is blue-shifted relative to the stationary pre-shock gas. We employ non-local thermodynamic equilibrium (LTE) excitation modelling to examine this scenario and find that indeed FIR emission from warm dust adjacent to the H ii region radiatively pumps the 1612-MHz line in the diffuse, cool gas ahead of the expanding shock front, while collisional pumping in the warm, dense shocked gas inverts the 1720-MHz line.
Fast radio bursts to be detected with the Square Kilometre Array
Authors: Hashimoto Tetsuya , Goto Tomotsugu , On Alvina Y L , Lu Ting-Yi , Santos Daryl Joe D , Ho Simon C-C , Wang Ting-Wen , Kim Seong Jin , Hsiao Tiger Y-Y
Published: August 2020

Fast radio bursts (FRBs) are mysterious extragalactic radio signals. Revealing their origin is one of the central foci in modern astronomy. Previous studies suggest that occurrence rates of non-repeating and repeating FRBs could be controlled by the cosmic stellar-mass density (CSMD) and cosmic star formation-rate density (CSFRD), respectively. The Square Kilometre Array (SKA) is one of the best future instruments to address this subject due to its high sensitivity and high-angular resolution. Here, we predict the number of FRBs to be detected with the SKA. In contrast to previous predictions, we estimate the detections of non-repeating and repeating FRBs separately, based on latest observational constraints on their physical properties including the spectral indices, FRB luminosity functions, and their redshift evolutions. We consider two cases of redshift evolution of FRB luminosity functions following either the CSMD or CSFRD. At $z$ ≳ 2, $z$ ≳ 6, and $z$ ≳ 10, non-repeating FRBs will be detected with the SKA at a rate of ∼104, ∼102, and ∼10 (sky−1 d−1), respectively, if their luminosity function follows the CSMD evolution. At $z$ ≳ 1, $z$ ≳ 2, and $z$ ≳ 4, sources of repeating FRBs will be detected at a rate of ∼103, ∼102, and ≲10 (sky−1 d−1), respectively, assuming that the redshift evolution of their luminosity function is scaled with the CSFRD. These numbers could change by about one order of magnitude depending on the assumptions on the CSMD and CSFRD. In all cases, abundant FRBs will be detected by the SKA, which will further constrain the luminosity functions and number density evolutions.
Towards a non-Gaussian model of redshift space distortions
Authors: Cuesta-Lazaro Carolina , Li Baojiu , Eggemeier Alexander , Zarrouk Pauline , Baugh Carlton M , Nishimichi Takahiro , Takada Masahiro
Published: August 2020

To understand the nature of the accelerated expansion of the Universe, we need to combine constraints on the expansion rate and growth of structure. The growth rate is usually extracted from 3D galaxy maps by exploiting the effects of peculiar motions on galaxy clustering. However, theoretical models of the probability distribution function (PDF) of galaxy pairwise peculiar velocities are not accurate enough on small scales to reduce the error on theoretical predictions to the level required to match the precision expected for measurements from future surveys. Here, we improve the modelling of the pairwise velocity distribution by using the Skew-T PDF, which has non-zero skewness and kurtosis. Our model accurately reproduces the redshift space multipoles (monopole, quadrupole, and hexadecapole) predicted by N-body simulations, above scales of about $10\, h^{-1}{\rm Mpc}$. We illustrate how a Taylor expansion of the streaming model can reveal the contributions of the different moments to the clustering multipoles, which are independent of the shape of the velocity PDF. The Taylor expansion explains why the Gaussian streaming model works well in predicting the first two redshift space multipoles, although the velocity PDF is non-Gaussian even on large scales. Indeed, any PDF with the correct first two moments would produce precise results for the monopole down to scales of about $10\, h^{-1}{\rm Mpc}$, and for the quadrupole down to about $30\, h^{-1}{\rm Mpc}$. An accurate model for the hexadecapole needs to include higher order moments.
The highly variable time evolution of star-forming cores identified with dendrograms
Authors: Smullen Rachel A , Kratter Kaitlin M , Offner Stella S R , Lee Aaron T , Chen Hope How-Huan
Published: August 2020

We investigate the time evolution of dense cores identified in molecular cloud simulations using dendrograms, which are a common tool to identify hierarchical structure in simulations and observations of star formation. We develop an algorithm to link dendrogram structures through time using the three-dimensional density field from magnetohydrodynamical simulations, thus creating histories for all dense cores in the domain. We find that the population-wide distributions of core properties are relatively invariant in time, and quantities like the core mass function match with observations. Despite this consistency, an individual core may undergo large (>40 per cent), stochastic variations due to the redefinition of the dendrogram structure between time-steps. This variation occurs independent of environment and stellar content. We identify a population of short-lived (<200 kyr) overdensities masquerading as dense cores that may comprise $\sim\!20$ per cent of any time snapshot. Finally, we note the importance of considering the full history of cores when interpreting the origin of the initial mass function; we find that, especially for systems containing multiple stars, the core mass defined by a dendrogram leaf in a snapshot is typically less than the final system stellar mass. This work reinforces that there is no time-stable density contour that defines a star-forming core. The dendrogram itself can induce significant structure variation between time-steps due to small changes in the density field. Thus, one must use caution when comparing dendrograms of regions with different ages or environment properties because differences in dendrogram structure may not come solely from the physical evolution of dense cores.
Self-consistent method to extract non-linearities from pulsating star light curves – I. Combination frequencies
Authors: Lares-Martiz M , Garrido R , Pascual-Granado J
Published: August 2020

Stellar pulsation is a common phenomenon and is sustained because of coherent driving mechanisms. When pulsations are driven by heat or convective mechanisms, it is usual to observe combination frequencies in the power spectra of the stellar light-curves. These combination frequencies are not solutions of the perturbed stellar structure equations. In dense power spectra from a light-curve of a given multiperiodic pulsating star, they can compromise the mode identification in asteroseismic analyses, and hence they must be treated as spurious frequencies and removed. In this paper, a method based on fitting the set of frequencies that best describes a general non-linear model, like the Volterra series, is presented. The method allows these frequencies to be extracted from the power spectrum, thereby improving the frequency analysis and enabling hidden frequencies to emerge from what was initially considered as noise. Moreover, the method yields frequencies with uncertainties several orders of magnitude smaller than the Rayleigh dispersion, which is sometimes used as if it were an error when identifying combination frequencies. Furthermore, it is compatible with the classical counting cycles method, the so-called O-C method, which is valid only for mono-periodic stars. The method creates the possibility of characterizing the non-linear behaviour of a given pulsating star by studying in detail the complex generalized transfer functions on which the model is based.
A broad-band X-ray spectral study of the Seyfert 1 galaxy ESO 141–G055 with XMM–Newton and NuSTAR
Authors: Ghosh Ritesh , Laha Sibasish
Published: August 2020

We have extensively studied the broad--band X-ray spectra of the source ESO 141–G055 using all available XMM–Newton and NuSTAR observations. We detect a prominent soft excess below $2\rm \, \, {\rm keV}$, a narrow Fe line, and a Compton hump ($\gt 10\rm \, \, {\rm keV}$). The origin of the soft excess is still debated. We used two models to describe the soft excess: the blurred reflection from the ionized accretion disc and the intrinsic thermal Comptonization model. We find that both of these models explain the soft excess equally well. We confirm that we do not detect any broad Fe line in the X-ray spectra of this source, although both the physical models prefer a maximally spinning black hole scenario (a > 0.96). This may mean that either the broad Fe line is absent or blurred beyond detection. The Eddington rate of the source is estimated to be $\lambda _{\rm \, Edd}\sim 0.31$. In the reflection model, the Compton hump has a contribution from both ionized and neutral reflection components. The neutral reflector which simultaneously describes the narrow Fe K α and the Compton hump has a column density of $N_{\rm H} \ge 7\times 10^{24} \, \rm cm^{-2}$. In addition, we detect a partially covering ionized absorption with ionization parameter $\log \xi /\rm \, erg\, cm\, s^{-1}$  = $0.1^{+0.1}_{-0.1}$ and column density $N_{\rm H} =20.6^{+1.0}_{-1.0}\times 10^{22} \, \rm cm^{-2}$ with a covering factor of $0.21^{+0.01}_{-0.01}$.
Validation of emission-line galaxies target selection algorithms for the Dark Energy Spectroscopic Instrument using the MMT Binospec
Authors: Karim Tanveer , Lee Jae H , Eisenstein Daniel J , Burtin Etienne , Moustakas John , Raichoor Anand , Yèche Christophe
Published: August 2020

The forthcoming Dark Energy Spectroscopic Instrument (DESI) experiment plans to measure the effects of dark energy on the expansion of the Universe and create a 3D map of the Universe using galaxies up to z ∼ 1.6 and QSOs up to z ∼ 3.5. In order to create this map, DESI will obtain spectroscopic redshifts of over 30 million objects; among them, a majority are [O ii] emitting star-forming galaxies known as emission-line galaxies (ELGs). These ELG targets will be pre-selected by drawing a selection region on the g − r versus r − z colour–colour plot, where high-redshift ELGs form a separate locus from the lower redshift ELGs and interlopers. In this paper, we study the efficiency of three ELG target selection algorithms – the Final Design Report (FDR) cut based on the DEEP2 photometry, Number Density Modelling (NDM) and Random Forest – to determine how the combination of these three algorithms can be best used to yield a simple selection boundary that will be best suited to meet DESI’s science goals. To do this, we selected 17 small patches in the DESI footprint where we run the three target selection algorithms to pre-select ELGs based on their photometry. We observed the pre-selected ELGs using the MMT Binospec, which is similar in functionality to the DESI instrument, to obtain their spectroscopic redshifts and fluxes of 1054 ELGs. By analysing the redshift and fluxing distribution of these galaxies, we find that although NDM performed the best, simple changes in the FDR definition would also yield sufficient performance.
Ground-based transmission spectroscopy with FORS2: A featureless optical transmission spectrum and detection of H2O for the ultra-hot Jupiter WASP-103b
Authors: Wilson Jamie , Gibson Neale P , Nikolov Nikolay , Constantinou Savvas , Madhusudhan Nikku , Goyal Jayesh , Barstow Joanna K , Carter Aarynn L , de Mooij Ernst J W , Drummond Benjamin , Mikal-Evans Thomas , Helling Christiane , Mayne Nathan J , Sing David K
Published: August 2020

We report ground-based transmission spectroscopy of the highly irradiated and ultra-short period hot-Jupiter WASP-103b covering the wavelength range ≈400–600 nm using the FORS2 instrument on the Very Large Telescope. The light curves show significant time-correlated noise which is mainly invariant in wavelength and which we model using a Gaussian process. The precision of our transmission spectrum is improved by applying a common-mode correction derived from the white light curve, reaching typical uncertainties in transit depth of ≈2 × 10−4 in wavelength bins of 15 nm. After correction for flux contamination from a blended companion star, our observations reveal a featureless spectrum across the full range of the FORS2 observations and we are unable to confirm the Na absorption previously inferred using Gemini/GMOS or the strong Rayleigh scattering observed using broad-band light curves. We performed a Bayesian atmospheric retrieval on the full optical-infrared transmission spectrum using the additional data from Gemini/GMOS, HST/WFC3, and Spitzer observations and recover evidence for H2O absorption at the 4.0 σ level. However, our observations are not able to completely rule out the presence of Na, which is found at 2.0 σ in our retrievals. This may in part be explained by patchy/inhomogeneous clouds or hazes damping any absorption features in our FORS2 spectrum, but an inherently small scale height also makes this feature challenging to probe from the ground. Our results none the less demonstrate the continuing potential of ground-based observations for investigating exoplanet atmospheres and emphasize the need for the application of consistent and robust statistical techniques to low-resolution spectra in the presence of instrumental systematics.
Mismatch repair and DNA polymerase δ proofreading prevent catastrophic accumulation of leading strand errors in cells expressing a cancer-associated DNA polymerase ϵ variant
Authors: Bulock Chelsea R , Xing Xuanxuan , Shcherbakova Polina V
Published: August 2020

Substitutions in the exonuclease domain of DNA polymerase ϵ cause ultramutated human tumors. Yeast and mouse mimics of the most common variant, P286R, produce mutator effects far exceeding the effect of Polϵ exonuclease deficiency. Yeast Polϵ-P301R has increased DNA polymerase activity, which could underlie its high mutagenicity. We aimed to understand the impact of this increased activity on the strand-specific role of Polϵ in DNA replication and the action of extrinsic correction systems that remove Polϵ errors. Using mutagenesis reporters spanning a well-defined replicon, we show that both exonuclease-deficient Polϵ (Polϵ-exo−) and Polϵ-P301R generate mutations in a strictly strand-specific manner, yet Polϵ-P301R is at least ten times more mutagenic than Polϵ-exo− at each location analyzed. Thus, the cancer variant remains a dedicated leading-strand polymerase with markedly low accuracy. We further show that P301R substitution is lethal in strains lacking Polδ proofreading or mismatch repair (MMR). Heterozygosity for pol2-P301R is compatible with either defect but causes strong synergistic increases in the mutation rate, indicating that Polϵ-P301R errors are corrected by Polδ proofreading and MMR. These data reveal the unexpected ease with which polymerase exchange occurs in vivo, allowing Polδ exonuclease to prevent catastrophic accumulation of Polϵ-P301R-generated errors on the leading strand.
Identification and characterization of hippuristanol-resistant mutants reveals eIF4A1 dependencies within mRNA 5′ leader regions
Authors: Steinberger Jutta , Shen Leo , J. Kiniry Stephen , Naineni Sai Kiran , Cencic Regina , Amiri Mehdi , Aboushawareb Sarah A E , Chu Jennifer , Maïga Rayelle Itoua , Yachnin Brahm J , Robert Francis , Sonenberg Nahum , Baranov Pavel V , Pelletier Jerry
Published: August 2020

Hippuristanol (Hipp) is a natural product that selectively inhibits protein synthesis by targeting eukaryotic initiation factor (eIF) 4A, a DEAD-box RNA helicase required for ribosome recruitment to mRNA templates. Hipp binds to the carboxyl-terminal domain of eIF4A, locks it in a closed conformation, and inhibits its RNA binding. The dependencies of mRNAs for eIF4A during initiation is contingent on the degree of secondary structure within their 5′ leader region. Interest in targeting eIF4A therapeutically in cancer and viral-infected settings stems from the dependencies that certain cellular (e.g. pro-oncogenic, pro-survival) and viral mRNAs show towards eIF4A. Using a CRISPR/Cas9-based variomics screen, we identify functional EIF4A1 Hipp-resistant alleles, which in turn allowed us to link the translation-inhibitory and cytotoxic properties of Hipp to eIF4A1 target engagement. Genome-wide translational profiling in the absence or presence of Hipp were undertaken and our validation studies provided insight into the structure-activity relationships of eIF4A-dependent mRNAs. We find that mRNA 5′ leader length, overall secondary structure and cytosine content are defining features of Hipp-dependent mRNAs.
Rational design of minimal synthetic promoters for plants
Authors: Cai Yao-Min , Kallam Kalyani , Tidd Henry , Gendarini Giovanni , Salzman Amanda , Patron Nicola J
Published: August 2020

Promoters serve a critical role in establishing baseline transcriptional capacity through the recruitment of proteins, including transcription factors. Previously, a paucity of data for cis-regulatory elements in plants meant that it was challenging to determine which sequence elements in plant promoter sequences contributed to transcriptional function. In this study, we have identified functional elements in the promoters of plant genes and plant pathogens that utilize plant transcriptional machinery for gene expression. We have established a quantitative experimental system to investigate transcriptional function, investigating how identity, density and position contribute to regulatory function. We then identified permissive architectures for minimal synthetic plant promoters enabling the computational design of a suite of synthetic promoters of different strengths. These have been used to regulate the relative expression of output genes in simple genetic devices.
Altered Motor Excitability in Patients With Diffuse Gliomas Involving Motor Eloquent Areas: The Impact of Tumor Grading
Authors: Lavrador José Pedro , Gioti Ifigeneia , Hoppe Szymon , Jung Josephine , Patel Sabina , Gullan Richard , Ashkan Keyoumars , Bhangoo Ranjeev , Vergani Francesco
Published: August 2020

BACKGROUND

Diffuse gliomas have an increased biological aggressiveness across the World Health Organization (WHO) grading system. The implications of glioma grading on the primary motor cortex (M1)-corticospinal tract (CST) excitability is unknown.

OBJECTIVE

To assess the excitability of the motor pathway with navigated transcranial magnetic stimulation (nTMS).

METHODS

Retrospective cohort study of patients admitted for surgery with diffuse gliomas within motor eloquent areas. Demographic, clinical, and nTMS-related variables were collected. The Cortical Excitability Score (CES 0 to 2 according to the number of abnormal interhemispheric resting motor threshold (RMT) ratios) was calculated for patients where bilateral upper and lower limb mapping was performed.

RESULTS

A total of 45 patients were included: 9 patients had a low-grade glioma and 36 patients had a high-grade glioma. The unadjusted analysis revealed an increase in the latency of the motor evoked potential of the lower limb with an increase of the WHO grade (P = .038). The adjusted analysis confirmed this finding (P = .013) and showed a relation between the increase in the WHO and a decreased RMT (P = .037) of the motor evoked responses in the lower limb. When CES was calculated, an increase in the score was related with an increase in the WHO grade (unadjusted analysis—P = .0001; adjusted analysis—P = .001) and in isocitrate dehydrogenase (IDH) wild-type tumors (unadjusted analysis—P = .020).

CONCLUSION

An increase in the WHO grading system and IDH wild-type tumors are associated with an abnormal excitability of the motor eloquent areas in patients with diffuse gliomas.
12. OUTCOMES AFTER SURGICAL RESECTION OF MELANOMA BRAIN METASTASES IN THE AGE OF CHECKPOINT INHIBITOR TREATMENT
Authors: Morshed Ramin , Chung Jason , Sudhakar Vivek , Cummins Daniel , Young Jacob , Daras Mariza , Aghi Manish
Published: August 2020

BACKGROUND

Metastasis of melanoma to the brain is associated with poor outcomes. Recent trials demonstrate improved survival after treatment with immune checkpoint inhibitors.

OBJECTIVE

To examine the impact that checkpoint inhibitor treatment has on overall survival (OS) and central nervous system (CNS) progression in a cohort of patients undergoing surgical resection of melanoma brain metastases.

METHODS

This retrospective, single-center study included patients undergoing first-time surgical resection of melanoma brain metastases. A multivariate Cox proportional model was used to estimate the association of patient and treatment factors with OS and CNS progression.

RESULTS

85 patients underwent first-time resection of 97 melanoma brain metastases with a median follow-up of 9.5 months. Checkpoint inhibitors (Pembrolizumab, Ipilimumab, and/or Nivolumab) were used in 55.1% of cases (19 pre-op; 47 post-op; median 9 cycles). Patients treated with checkpoint inhibitors had similar peri-op systemic disease status and KPS but had been treated with more systemic agents and had more instances of CNS progression prior to surgery. Median OS and time to CNS progression for the cohort were 1 year and 237 days, respectively. In a multivariate Cox regression model, age (HR 1.03 by decade; p=0.02), treatment with a checkpoint inhibitor (HR 0.27; p<0.0001), prior radiotherapy (HR 2.44; p=0.007), and number of brain metastases at the time of surgery (HR 1.05 per metastasis; p=0.04) were significant predictors of OS. Checkpoint inhibitor treatment was associated with longer OS from surgery (median 3 vs 0.5 yrs, log-rank p=0.004). However, patients who underwent craniotomy after prior checkpoint inhibitor treatment had poor OS (median 0.56 yrs). Prior radiotherapy was also associated with poor OS (median 0.53 yrs).

CONCLUSIONS

While checkpoint inhibitor treatment was associated with improved survival in this surgical cohort of melanoma brain metastases, patients who require surgical resection after checkpoint inhibitor treatment or radiotherapy are poor surgical candidates.
23. RETROSPECTIVE REVIEW OF ADULT PATIENTS WITH LEPTOMENINGEAL DISEASE SECONDARY TO MELANOMA AT MOFFITT CANCER CENTER: DIAGNOSIS, TREATMENT AND OUTCOMES
Authors: Pina Yolanda , Evernden Brittany , Smalley Keiran , Forsyth Peter
Published: August 2020

BACKGROUND

Nearly 5–8% of solid cancers present with leptomeningeal disease (LMD). Patients with LMD have a dismal prognosis with survival measured in weeks-to-months. The pathophysiology of this devastating disease remains unknown.

METHODS

A retrospective chart review was performed of twenty-five adult patients with LMD due to melanoma who were enrolled in the MCC 50172 clinical trial between 05/26/2015 and 07/17/2018.

RESULTS

Patients had a median age 63 years (31–80) at diagnosis with LMD. Sixteen had confirmed LMD and five did not meet criteria for LMD, but had positive cerebrospinal fluid (CSF)-circulating tumor cells (CTC’s). Those with LMD had a median KPS of 70 (30–90) at presentation, and symptoms most commonly included altered mentation n=6 (37%), headaches n=4 (25%), focal weakness n=3 (19%), and paresthesia n=2 (12%). Eleven patients were diagnosed by MRI. Ten patients (62%) had positive CSF cytology on first attempt and fourteen (87%) on first-two attempts. Lumbar puncture mean OP was 29.4 cmH2O (18–65), with CSF WBC 21.8/cumm (SD 25.6), RBC 2942.5/cumm (SD 9056.1), and protein 187.6 mg/dL (SD 166.1). CSF-CTC’s CellSearch analysis had a sensitivity of 0.75 (12[12 + 4]) and specificity of 0.44 (4[4 + 5]); PPV 0.71 and NPV 0.50. Twelve patients with LMD had positive CSF-CTC’s. Prior to LMD diagnosis, patients were treated with immune checkpoint inhibitors (ICI’s) n=9 (56%), BRAF+/-MEK inhibitors n=5 (31%), and/or RT n=5 (31%). Patients with LMD were treated with Ommaya n=13 +VPS n=3, WBRT n=7, ICI’s n=5, BRAF+MEK inhibitors n=4, and IT topotecan. LMD patients had a median survival 3.27 months after diagnosis (0.30–39). Two patients outlived their counterparts by 21.1 and 39.0 months. The 2 long-term survivors were treated with WBRT and either ICI, pembrolizumab or ipilimumab+nivolumab.

CONCLUSION

Clinical studies in LMD can provide critical insights and help to develop improved guidelines and current therapies.
30. RADIOSURGERY FOLLOWED BY TUMOR TREATING FIELDS FOR BRAIN METASTASES (1–10) FROM NSCLC IN THE PHASE 3 METIS TRIAL
Authors: Mehta Minesh P , Gondi Vinai , Brown Paul , Ahluwalia Manmeet
Published: August 2020

BACKGROUND

Tumor Treating Fields (TTFields) are non-invasive, loco-regional, anti-mitotic treatment modality comprising alternating electric fields. TTFields have demonstrated efficacy in preclinical non-small cell lung cancer (NSCLC) models. TTFields treatment to the brain was safe and extended overall survival in newly-diagnosed glioblastoma. The objective of the METIS study [NCT02831959] is evaluation of the efficacy and safety of TTFields in NSCLC patients with brain metastases.

METHODS

NSCLC patients (N=270) with 1–10 brain metastases were randomized 1:1 to stereotactic radio surgery (SRS) followed by continuous TTFields ((150 kHz, > 18 hours/day) within 7 days of SRS or supportive care. The portable device delivered TTFields to the brain using 4 transducer arrays, while patients received the best standard-of-care for systemic disease. Patients were followed every two months until second intracranial progression. Key inclusion criteria: KPS ≥70, new diagnosis of 1 inoperable or 2–10 supra- and/or infratentorial brain metastases from NSCLC amenable to SRS; and optimal therapy for extracranial disease. Prior WBRT, surgical resection of metastases, or recurrent brain metastases were exclusionary. Primary endpoint was time to 1st intracranial progression. Secondary endpoints included time to neurocognitive failure (HVLT, COWAT and TMT), overall survival, radiological response rate (RANO-BM and RECIST V1.1); quality-of-life; adverse events; time to first/second intracranial progression for patients with 1–4 and 5–10 brain metastases; bi-monthly intracranial progression rate from 2–12 months; and time to second intracranial and distant progression. The sample size (N=270) was calculated using a log-rank test (Lakatos 1988 and 2002) with 80% power at two sided alpha of 0.05 to detect a hazard ratio of 0.57. On September, 2019, an independent Data Monitoring Committee (DMC) reviewed METIS trial data collected to that point. The DMC concluded that no unexpected safety issues had emerged and recommended continuation of the METIS study as planned.
41. PROGNOSTIC VALIDATION OF THE EANO ESMO CLASSIFICATION OF LEPTOMENINGEAL METASTASIS
Authors: Le Rhun Emilie , Devos Patrick , Weller Johannes , Seystahl Katharina , Mo Francesca , Compter Annette , Sophie Berghoff Anna , Jongen Joost , Wolpert Fabian , Rudà Roberta , Brandsma Dieta , van den Bent Martin , Preusse Matthias , Herrlinger Ulrich , Weller Michael
Published: August 2020

BACKGROUND

The EANO ESMO guidelines have proposed a classification of leptomeningeal metastases (LM) based on clinical (typical/atypical), cytological (positive/negative/equivocal) and MRI (A linear, B nodular, C linear and nodular, D normal or hydrocephalus only) presentation. Type I LM is defined by the presence of tumor cells in the cerebrospinal fluid (CSF) (confirmed LM) whereas type II LM is defined by typical clinical and MRI signs (probable or possible LM). Here we explored the clinical utility of these EANO ESMO LM subtypes.

PATIENTS AND METHODS

We retrospectively assembled data from 254 patients with newly diagnosed LM from different solid tumors, including as main primary tumors breast cancer (n=98, 45%), lung cancer (n=65, 25.5%) and melanoma (n=51, 13.5%). Survival curves were estimated using the Kaplan-Meier method and compared by Log-rank test.

RESULTS

Median age at LM diagnosis was 56.5 years (range 20–82 years). Typical clinical LM symptoms or signs were noted in 225 patients (88.5%); only 13 patients (5%) were clinically asymptomatic. The most common MRI subtype was A seen in 117 patients (46%). Types B (n=33, 13%), C (n=54, 21%) and D (n=50, 19.5%) were less common. Tumor cells were observed in the CSF in 186 patients (73%) whereas the CSF was equivocal in 24 (9.5%) and negative in 44 (17.5%) patients. Patients with confirmed LM had inferior outcome than patients with probable or possible LM (p=0.0063). Type I patients had inferior outcome than type II patients (p=0.0019). Nodular disease was a negative prognostic factor in type II LM, but not in type I LM (p=0.0138).

CONCLUSION

The presence of tumor cells in the CSF appears to have a greater prognostic role than the neuroimaging presentation. EANO ESMO LM subtypes are highly prognostic and should be considered in the design of clinical trials.
45. DELAY OR FAILURE TO ADMINISTER STEREOTACTIC RADIOSURGERY TO THE CAVITY AFTER SURGERY FOR BRAIN METASTASES. AN INTENTION-TO-TREAT ANALYSIS
Authors: O’Brien Diana Roth , Kaye Sydney , Poppas Phillip , Mahase Sean , An Anjile , Christos Paul , Liechty Benjamin , Pisapia David , Ramakrishna Rohan , Wernicke A Gabriella , Knisely Jonathan , Pannullo Susan , Schwartz Theodore
Published: August 2020

BACKGROUND

Data regarding the efficacy of adjuvant stereotactic radiosurgery (SRS) for resected brain metastases (BM) is often limited to patients completing SRS within a specified timeframe. We performed an intention-to-treat analysis to determine local recurrence (LR) for all BM patients referred for SRS.

METHODS

We retrospectively identified resected BM patients referred for SRS between 2012 and 2018. Patients were divided based on delay to SRS into four categories: 1) ≤4 weeks, 2) >4–8 weeks, 3) >8 weeks, and 4) never received. We investigated the relationship between delay to SRS and LR, local recurrence-free survival (LRFS), and overall survival, as well as the predictors of and reason for delays.

RESULTS

In our cohort of 159 patients, median age was 64.0 years, 56.5% patients were female, median tumor diameter was 2.9 cm, and gross total resection was achieved in 83.0%. On intention-to-treat analysis, LR was 22.6%. Delays to SRS correlated with LR: 2.3% with SRS ≤4 weeks postoperatively, 14.5% with SRS at >4–8 weeks (p=0.03), 48.5% with SRS at >8 weeks (p<0.001). No LR difference was observed with SRS delayed by >8 weeks, vs. never completed, 48.5% vs. 50.0% (p=0.91). 53 (33.3%) patients comprised these latter two categories. A similar relationship emerged between delay to SRS and LRFS (p<0.01). Non-small cell lung cancer pathology (p=0.04) and earlier year of treatment (p<0.01) were predictive of delays. Common reasons for delays included logistics, management of systemic disease, complications, or comorbidities.

CONCLUSION

A significant number of patients referred for SRS never receive it, or are treated with a delay >8 weeks, conferring equivalent LR risk. Accordingly, the actual efficacy of adjuvant SRS may need reassessment. Reasons for delays and mechanisms for reducing them are discussed. For patients likely to experience significant delays, other techniques, such as preoperative SRS or intraoperative brachytherapy, may be considered.
46. PAN-CANCER ANALYSIS OF ORTHOTOPIC PATIENT DERIVED XENOGRAFTS FROM BRAIN METASTASES
Authors: Zeng Yu , Pelton Kristine , Yerrum Smitha , Kao Pei-Lun , Sinai Claire , Tran Tony , Sinha Rileen , Shetty Aniket , Tolstorukov Michael Y , Jaber Aliya , Freitas Dylan E , Pisano William , Verselis Sigitas J , Herbert Zach T , Lin Nancy U , Zhao Jean J , Weinstock David M , Chukwueke Ugonma N , Aizer Ayal A , Chiocca E Antonio , Bi Wenya Linda , Wen Patrick Y , Lee Eudocia Q , Nayak Lakshmi , Meredith David M , Santagata Sandro , Chow Kin-Hoe , Ligon Keith L
Published: August 2020

Brain metastases (BM) are a leading cause of cancer death and prognosis remains poor despite treatment advances at other sites. Models are central to therapeutic development, but few orthotopic patient-derived xenograft (PDX) models of BM exist. To represent diversity across BM types, we established a program to create orthotopic PDX at scale from all BM patients. To date BM were received from 100 patients and PDX attempted by direct brain injection (PDX, n=89) or injection of low passage patient-derived cell lines (PDCLX, n=11). We created 65 successful BM PDX from 13 cancers: 17 lung (55% take), 15 breast (68%), 6 melanoma (75%), 5 CNS lymphoma (83%), 3 gastrointestinal (75%), 2 esophageal (40%), 2 ovarian (67%), 1 sarcoma (100%), 1 laryngeal (100%), 1 prostate (100%), 1 pancreatic (100%), 1 uterine adenosarcoma (100%), and 1 yolk sac tumor (100%). Take rate was similar for models derived from patients with prior chemotherapy-only versus immune/targeted therapy-only (63 vs 58%). Fifteen patients had live tumor and matching PBMCs archived for modeling in vitro immunotherapy responses. Mean time to moribund among different cancer types ranged from 27 days (yolk sac tumor) to 177.5 days (ovarian). BM PDX had a favorable timeline for preclinical study (90% moribund at 180 days). All PDX matched the patient driver SNVs and copy aberrations, even at >P4. No significant differences noted by immunodeficient strain (SCID versus NSG) or injection site (orthotopic versus heterotopic). Explants from BM PDX were able to generate long-term cell lines (60%) or short-term cultures with qualitative concordance of model-to-patient responses to targeted therapy (Osimertinib, EGFRi) and immunotherapy (Pembrolizumab, PD1i). Genomic and clinical data were used to create the DFCI BM PDX cBioPortal for public release and models distribution will be available through the DFCI Center for Patient Derived Models.
59. A RADIOMICS-BASED MACHINE LEARNING MODEL FOR DISTINGUISHING RADIATION NECROSIS FROM PROGRESSION OF BRAIN METASTASES TREATED WITH STEREOTACTIC RADIOSURGERY (SRS)
Authors: Chen Xuguang , Parekh Vishwa , Peng Luke , Chan Michael , Soike Michael , McTyre Emory , Jacobs Michael , Kleinberg Lawrence
Published: August 2020

PURPOSE

This study aims to test whether MRI radiomic signatures can distinguish radiation necrosis (RN) from tumor progression (TP) in a multi-institution dataset using machine learning.

METHODS

Brain metastases treated with SRS were followed by serial MRI, and those showing evidence of RN or TP underwent pathologic confirmation. Radiomic features were extracted from T1 post-contrast (T1c) and T2 fluid attenuated inversion recovery (T2 FLAIR) MRI. High dimensional radiomic feature space was visualized in a two-dimensional space using t-distributed stochastic neighbor embedding (t-SNE). Cases from 2 institutions were combined and randomly assigned to training (2/3) and testing (1/3) cohorts. Backward elimination was used for feature selection, followed by random forest algorithm for predictive modeling.

RESULTS

A total of 135 individual lesions (37 RN and 98 TP) were included. The majority (72.6%) received single-fraction SRS to a median dose of 18Gy. Clear clustering of cases around the institutional origin was observed on t-SNE analysis. 21 T1c and 4 FLAIR features were excluded from subsequent modeling due to significant correlation with the institutional origin. Backward elimination yielded 6 T1c and 6 FLAIR features used for model construction. A random forest model based on the 6 FLAIR features (cluster shade, neighborhood gray tone difference matrix (NGTDM) coarseness, NGTDM texture strength, run length nonuniformity, run percentage, and short run high gray-level emphasis) achieved sensitivity of 76% and specificity of 70% on the training cohort (AUC 0.74, 95% CI 0.60–0.88), and sensitivity of 67% and specificity of 83% on the testing cohort (AUC 0.75, 95% CI 0.59–0.93). Addition of the T1c features resulted in overfitting of the training cohort (AUC 1.00), but did not improve model performance on the testing cohort (AUC 0.69, 95% CI 0.51–0.87).

CONCLUSION

MRI radiomics based machine learning can distinguish RN from TP after brain SRS in a heterogeneous image dataset.
62. PRESENCE OF EXTRACRANIAL TUMORS INFLUENCES RESPONSE TO IMMUNE CHECKPOINT INHIBITORS IN A PRE-CLINICAL MODEL OF MELANOMA BRAIN METASTASIS
Authors: Nayyar Naema , Singh Mohini , Stocking Jackson , Brehm Michael , Brastianos Priscilla
Published: August 2020

Up to 75% of patients with melanoma develop brain metastases. While immune checkpoint inhibitors (ICI) targeting PD-1 and CTLA4 have revolutionized the treatment of metastatic melanoma, responses within the immune-specialized microenvironment of the brain are not well understood and there is a paucity of animal models to investigate the effect of ICI intracranially. We characterized responses to checkpoint inhibitors in a syngeneic mouse model of melanoma brain metastasis with concurrent intracranial and subcutaneous melanoma. D3UV3 cells (obtained from David Fisher’s laboratory) were derived using UVB irradiation from D4M.3A melanoma cell line and implanted into the striatum using stereotactic injection or subcutaneously injected into the flank of C57BL/6 mice. Mice were then treated with anti-PD-1 antibody, anti-CTLA4 antibody, a combination of anti-PD-1 and anti-CTLA4, or isotype controls. While mice with intracranial melanoma alone had no response to monotherapy with anti-PD-1 or anti-CTLA4 antibody (p=1 and 0.1, respectively), and only a slight response to combination therapy (p=0.049), mice with concurrent subcutaneous tumors had significantly improved responses to anti-PD-1, anti-CTLA4 and combination treatment (p=0.002, 0.01 and 0.01 respectively compared to mice with intracranial tumors alone with equivalent treatment). These results demonstrate that the presence of an extracranial tumor influences response to ICI in pre-clinical mouse models of melanoma brain metastasis. We have therefore established a pre-clinical model with concurrent intracranial and extracranial tumors to better recapitulate the clinically observed context of melanoma brain metastases and lead to a better understanding of the setting in which ICI are effective for patients with this devastating complication.
70. A PHASE 1–2 CLINICAL TRIAL OF EO1001, A NOVEL IRREVERSIBLE pan-ErbB INHIBITOR WITH PROMISING BRAIN PENETRATION
Authors: Wheeler Helen , Bacha Jeffrey , Kanekal Sarath , Pedersen Harry , Sankar Neil , Wang Shen , Nesbit Ian , Skoff Kathy , Brown Dennis
Published: August 2020

CNS metastasis has become a prominent driver of morbidity and mortality in recent years as new targeted therapies have improved systemic outcomes. Mutations in the ErbB family of kinases are known oncodrivers in many of these cancers. ErbB family member “crosstalk” is associated with rapid development acquired resistance to ErbB TKIs. The development of agents targeting multiple ErbB receptors has shown promise but has been limited by toxicity and poor brain penetration. EO1001 is a first-in-class, oral, brain penetrating, irreversible pan-ErbB inhibitor with superior CNS penetration targeting ErbB1, ErbB2 and ErbB4. Preclinical data suggests a favorable pharmacokinetic and safety profile and promising activity against ErbB-driven cancers in patient-derived xenograft models. Male or female adult participants with confirmed ErbB-positive cancer, including patients with CNS involvement, who have progressed after standard of care therapy, with adequate bone marrow, renal and liver function are eligible. An accelerated dose-escalation design is employed. One subject per dose cohort will be recruited until drug related toxicity (≥G2) is observed in the first dosing cycle, after which dose escalation will revert to a 3 + 3 design to determine the maximum tolerated dose (MTD). Dose Escalation: Cycle 1: Patients will receive a single dose EO1001 on day 1 and single dose pharmacokinetics will be performed. Beginning on day 8, EO1001 will be administered once daily for 21 days; multi-dose pharmacokinetics will be performed. Cycles 2–6: Oral EO1001 will be administered once daily in continuous 28-day cycles for up to 20 weeks. MTD Expansion: Oral EO1001 will be administered once daily at the MTD in continuous 28-day cycles for up to 6 cycles (24 weeks). Toxicity is assessed based on NCI CCTCAEv5 and tumor response will be assessed by RECIST 1.1 or RANO for CNS disease. CNS exposure is evaluated in patients via CSF collection with confirmed CNS disease involvement.
72. THE COMBINED USE OF STEROIDS AND IMMUNE CHECKPOINT INHIBITORS IN BRAIN METASTASES PATIENTS: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Jessurun Charissa , Hulsbergen Alexander , de Wit Anouk , Tewarie Ishaan Ramlochan , Broekman Marike
Published: August 2020

INTRODUCTION

Immune checkpoint inhibitors (ICI) are increasingly being administered to cancer patients, including those with brain metastases (BMs). However, little is known about the interaction between ICI and steroids such as dexamethasone. The aim of this study was to perform a systematic literature review and meta-analysis on the association between steroid use and overall survival (OS) in BM patients receiving ICI.

METHODS

A systematic literature search was performed in PubMed, Embase, Web of Science, Cochrane, Academic Search Premier, and PsycINFO. Pooled effect estimates were calculated using random-effects models; analysis was performed across all included studies and stratified by tumor type.

RESULTS

After screening 978 abstracts, thirteen studies were included for systematic review. Ten studies reported sufficient data for meta-analysis, comprising 838 BM patients of which 335 (40%) had received steroids. In the steroid group, median OS ranged from 2.9 months to 10.2 months across studies. In the non-steroid group, median OS ranged from 4.9 to 25.1 months. Pooling results demonstrated significantly worse survival in the steroid group (HR 1.97; 95% CI 1.65–2.36); no significant heterogeneity (I2 = 0%) or publication bias (Egger’s p = 0.29) was identified. Stratified analysis showed a consistent effect across melanoma (HR 1.71, 95% CI 1.34–2.18) and non-small cell lung cancer (HR 2.26, 95% CI 1.49–3.43) subgroups.

CONCLUSION

Administration of steroids is associated with a significantly worse OS in BM patients receiving ICI. Further investigation on dose, timing and duration of steroids in this population is needed to elucidate the cause of this association and optimize outcomes in BM patients receiving ICI.
Analytic Philosophy of Photography
Authors: Walden Scott
Published: August 2020

The literature on the analytic philosophy of photography is related to, but distinct from, the literatures on film theory and photography theory. All three revolve around the question of whether images can be importantly divided into the categories of photographic and manugraphic on the basis of their differing etiologies. The first, however, tends to focus on how this question intersects with core areas of philosophical research, while the second and third tend, instead, to look for intersections with larger cultural issues. As well, the first is burdened with methodological considerations, a self-awareness that reflects larger methodological contests that have roiled analytic philosophy over the past century. This article focuses on the first. Arguably the photographic formative process excludes the mentation of photographers in ways that the manugraphic formative process does not exclude the mentation of painters or sketchers. The alleged implications of such photographic objectivity include skepticism about the possibility of photographs functioning as artworks, assertions regarding various epistemic advantages associated with the medium, claims regarding a special phenomenology associated with viewing photographs, concerns that photographic images cannot function as representations, and, finally, special ethical considerations that emerge with photographic subjects that are persons. Methodological considerations divide contributors on the basis of whether they proceed in a traditional philosophical fashion by taking as their starting point ordinary linguistic usage of key terms, such as “art,” “photography,” and “representation,” and then exploring inconsistencies between these, one the one hand, or whether, on the other, they proceed in a naturalistic fashion by taking as their starting point various phenomena associated with viewing photographs and then postulating whatever natural kinds are required in order to explain them.