bluuebunny/crossref_metadata_2025 huggingface dataset:
Inception of a first quasar at cosmic dawn
Authors: Latif Muhammad A , Khochfar Sadegh
Published: August 2020

Earliest quasars at the cosmic dawn are powered by mass accretion on to supermassive black holes of a billion solar masses. Massive black hole (MBH) seeds forming through the direct collapse mechanism are considered the most promising candidates but how do they grow and coevolve with their host galaxies at early cosmic times remains unknown. We here present results from a cosmological radiation hydrodynamical simulation including self-consistent modelling of both Population III (Pop III) and Population II (Pop II) star formation, their radiative and supernova feedback in the host galaxy along with X-ray feedback from an accreting MBH of $\rm 10^5 \, M_{\odot }$ in a halo of $\rm 2 \times 10^9 \, M_{\odot }$ from z = 26 down to z = 16. Our results show that energy deposition from X-rays in the proximity of MBH suppresses Pop III star formation for about 12 Myr while at the same time these X-rays catalyse $\rm H_2$ formation that leads to the formation of a Pop III star cluster of 500 $\rm M_{\odot }$ in the close vicinity of the MBH. We find that mode of star formation for Pop III is episodic and bursty due to the clumpy accretion, while for Pop II it is continuous. The stellar mass of the host galaxy at z ∼ 16 is $\rm 2 \times 10^7 \, M_{\odot }$ with a star formation rate of ${\sim} 0.1\!-\!1 \, \mathrm{ M}_{\odot }\, \mathrm{ yr}^{-1}$. In total, the MBH accretes $\rm 1.5 \times 10^6\, M_{\odot }$ during 120 Myr with the mean accretion rate of ${\sim} 0.01\, \mathrm{ M}_{\odot }\, \mathrm{ yr}^{-1}$ corresponding to an average Eddington fraction of 50 per cent.
Infrared spectra of pyroxenes (crystalline chain silicates) at room temperature
Authors: Bowey J E , Hofmeister A M , Keppel E
Published: August 2020

Crystals of pyroxene are common in meteorites but few compositions have been recognized in astronomical environments due to the limited chemistries included in laboratory studies. We present quantitative room-temperature spectra of 17 Mg-, Fe-, and Ca-bearing ortho- and clinopyroxenes, and a Ca-pyroxenoid in order to discern trends indicative of crystal structure and a wide range of composition. Data are produced using a diamond anvil cell: our band strengths are up to six times higher than those measured in KBr or polyethylene dispersions, which include variations in path length (from grain size) and surface reflections that are not addressed in data processing. Pyroxenes have varied spectra: only two bands, at 10.22  and 15.34 μm in enstatite (En99), are common to all. Peak wavelengths generally increase as Mg is replaced by Ca or Fe. However, two bands in MgFe-pyroxenes shift to shorter wavelengths as the Fe component increases from 0 to 60 per cent. A high-intensity band shifts from 11.6 to 11.2 μm and remains at 11.2 μm as Fe increases to 100 per cent; it resembles an astronomical feature normally identified with olivine or forsterite. The distinctive pyroxene bands between 13  and 16 μm show promise for their identification in Mid-Infrared-Instrumentspectra obtained with the James Webb Space Telescope. The many pyroxene bands between 40 and 80 μm could be diagnositic of silicate mineralogy if data were obtained with the proposed Space Infrared Telescope for Cosmology and Astrophysics. Our data indicate that comparison between room-temperature laboratory bands for enstatite and cold ∼10 − K astronomical dust features at wavelengths $\gtrsim 28~\mu$m can result in the identification of (Mg,Fe)- pyroxenes that contain 7–15 per cent less Fe– than their true values because some temperature shifts mimic some compositional shifts. Therefore some astronomical silicates may contain more Fe, and less Mg, than previously thought.
Dynamical evolution of two-planet systems and its connection with white dwarf atmospheric pollution
Authors: Maldonado R F , Villaver E , Mustill A J , Chavez M , Bertone E
Published: August 2020

Asteroid material is detected in white dwarfs (WDs) as atmospheric pollution by metals, in the form of gas/dust discs, or in photometric transits. Within the current paradigm, minor bodies need to be scattered, most likely by planets, into highly eccentric orbits where the material gets disrupted by tidal forces and then accreted on to the star. This can occur through a planet–planet scattering process triggered by the stellar mass-loss during the post main-sequence (MS) evolution of planetary systems. So far, studies of the N-body dynamics of this process have used artificial planetary system architectures built ad hoc. In this work, we attempt to go a step further and study the dynamical instability provided by more restrictive systems that, at the same time, allow us an exploration of a wider parameter space: the hundreds of multiple planetary systems found around MS stars. We find that most of our simulated systems remain stable during the MS, Red, and Asymptotic Giant Branch and for several Gyr into the WD phases of the host star. Overall, only ≈2.3 ${{\ \rm per\ cent}}$ of the simulated systems lose a planet on the WD as a result of dynamical instability. If the instabilities take place during the WD phase most of them result in planet ejections with just five planetary configurations ending as a collision of a planet with the WD. Finally 3.2 ${{\ \rm per\ cent}}$ of the simulated systems experience some form of orbital scattering or orbit crossing that could contribute to the pollution at a sustained rate if planetesimals are present in the same system.
The BAHAMAS project: effects of dynamical dark energy on large-scale structure
Authors: Pfeifer Simon , McCarthy Ian G , Stafford Sam G , Brown Shaun T , Font Andreea S , Kwan Juliana , Salcido Jaime , Schaye Joop
Published: August 2020

In this work, we consider the impact of spatially uniform but time-varying dark energy (or ‘dynamical dark energy’, DDE) on large-scale structure in a spatially flat universe, using large cosmological hydrodynamical simulations that form part of the BAHAMAS project. As DDE changes the expansion history of the universe, it impacts the growth of structure. We explore variations in DDE that are constrained to be consistent with the cosmic microwave background. We find that DDE can affect the clustering of matter and haloes at the $\sim 10{{\ \rm per\ cent}}$ level (suppressing it for so-called freezing models, while enhancing it for thawing models), which should be distinguishable with upcoming large-scale structure surveys. DDE cosmologies can also enhance or suppress the halo mass function (with respect to Lambda cold dark matter) over a wide range of halo masses. The internal properties of haloes are minimally affected by changes in DDE, however. Finally, we show that the impact of baryons and associated feedback processes is largely independent of the change in cosmology and that these processes can be modelled separately to typically better than a few per cent accuracy.
Discovery of optical outflows and inflows in the black hole candidate GRS 1716−249
Authors: Cúneo V A , Muñoz-Darias T , Sánchez-Sierras J , Jiménez-Ibarra F , Armas Padilla M , Buckley D A H , Casares J , Charles P , Corral-Santana J M , Fender R , Fernández-Ontiveros J A , Mata Sánchez D , Panizo-Espinar G , Ponti G , Torres M A P
Published: August 2020

We present optical spectroscopy obtained with the GTC, VLT, and SALT telescopes during the decline of the 2016–2017 outburst of the black hole candidate GRS 1716−249 (Nova Oph 1993). Our 18-epoch data set spans 6 months and reveals that the observational properties of the main emission lines are very variable, even on time-scales of a few hours. Several epochs are characterized by P-Cyg (as well as flat-top and asymmetric) profiles in the  Hα,  Hβ, and He  ii (λ4686) emission lines, implying the presence of an accretion disc wind, which is likely hot and dense. The wind’s terminal velocity (∼2000 km s−1) is similar to that observed in other black hole X-ray transients. These lines also show transient and sharp red-shifted absorptions, taking the form of inverted P-Cyg profiles. We argue that these profiles can be explained by the presence of infalling material at ∼1300 km s−1. We propose a failed wind scenario to explain this inflow and discuss other alternatives, such as obscuration produced by an accretion-related structure (e.g. the gas stream) in a high inclination system.
How do different spiral arm models impact the ISM and GMC population?
Authors: Pettitt Alex R , Dobbs Clare L , Baba Junichi , Colombo Dario , Duarte-Cabral Ana , Egusa Fumi , Habe Asao
Published: August 2020

The nature of galactic spiral arms in disc galaxies remains elusive. Regardless of the spiral model, arms are expected to play a role in sculpting the star-forming interstellar medium (ISM). As such, different arm models may result in differences in the structure of the ISM and molecular cloud properties. In this study, we present simulations of galactic discs subject to spiral arm perturbations of different natures. We find very little difference in how the cloud population or gas kinematics vary between the different grand design spirals, indicating that the ISM on cloud scales cares little about where spiral arms come from. We do, however, see a difference in the interarm/arm mass spectra, and minor differences in tails of the distributions of cloud properties (as well as radial variations in the stellar/gaseous velocity dispersions). These features can be attributed to differences in the radial dependence of the pattern speeds between the different spiral models, and could act as a metric of the nature of spiral structure in observational studies.
K2: Background Survey – the search for undiscovered transients in Kepler/K2 data
Authors: Ridden-Harper R , Tucker B E , Gully-Santiago M , Barentsen G , Rest A , Garnavich P , Shaya E
Published: August 2020

The K2 mission of the Kepler Space Telescope offers a unique possibility to examine sources of both Galactic and extragalactic origin with high-cadence photometry. Alongside the multitude of supernovae and quasars detected within targeted galaxies, it is likely that Kepler has serendipitously observed many transients throughout K2. Such events will likely have occurred in background pixels, coincidentally surrounding science targets. Analysing the background pixels presents the possibility to conduct a high-cadence survey with areas of a few square degrees per campaign. We demonstrate the capacity to independently recover key K2 transients such as KSN 2015K and SN 2018oh. With this survey, we expect to detect numerous transients and determine the first comprehensive rates for transients with lifetimes of ≤1 d.
Galactic inflow and wind recycling rates in the eagle simulations
Authors: Mitchell Peter D , Schaye Joop , Bower Richard G
Published: August 2020

The role of galactic wind recycling represents one of the largest unknowns in galaxy evolution, as any contribution of recycling to galaxy growth is largely degenerate with the inflow rates of first-time infalling material, and the rates with which outflowing gas and metals are driven from galaxies. We present measurements of the efficiency of wind recycling from the eagle cosmological simulation project, leveraging the statistical power of large-volume simulations that reproduce a realistic galaxy population. We study wind recycling at the halo scale, i.e. gas that has been ejected beyond the halo virial radius, and at the galaxy scale, i.e. gas that has been ejected from the interstellar medium to at least $\approx 10 \, {{\ \rm per\ cent}}$ of the virial radius. Galaxy-scale wind recycling is generally inefficient, with a characteristic return time-scale that is comparable to or longer than a Hubble time, and with an efficiency that clearly peaks at the characteristic halo mass of $M_{200} = 10^{12} \, \mathrm{M_\odot }$. Correspondingly, the majority of gas being accreted on to galaxies in eagle is infalling for the first time. Recycling is more efficient at the halo scale, with values that differ by orders of magnitude from those assumed by semi-analytical galaxy formation models. Differences in the efficiency of wind recycling with other hydrodynamical simulations are currently difficult to assess, but are likely smaller. We find that cumulative first-time gas accretion rates at the virial radius are reduced relative to the expectation from dark matter accretion for haloes with mass $M_{200} \lt 10^{12} \, \mathrm{M_\odot }$, indicating efficient preventative feedback on halo scales.
Magnetic field fluctuations in anisotropic, supersonic turbulence
Authors: Beattie James R , Federrath Christoph , Seta Amit
Published: August 2020

The rich structure that we observe in molecular clouds is due to the interplay between strong magnetic fields and supersonic (turbulent) velocity fluctuations. The velocity fluctuations interact with the magnetic field, causing it too to fluctuate. Using numerical simulations, we explore the nature of such magnetic field fluctuations, $\delta \mathrm{{\boldsymbol {\mathit {B}}}}$, over a wide range of turbulent Mach numbers, $\operatorname{\mathcal {M}}= 2\!-\!20$ (i.e. from weak to strong compressibility), and Alfvén Mach numbers, $\operatorname{\mathcal {M}_{\text{A0}}}= 0.1\!-\!100$ (i.e. from strong to weak magnetic mean fields, B0). We derive a compressible quasi-static fluctuation model from the magnetohydrodynamical (MHD) equations and show that velocity gradients parallel to the mean magnetic field give rise to compressible modes in sub-Alfvénic flows, which prevents the flow from becoming two dimensional, as is the case in incompressible MHD turbulence. We then generalize an analytical model for the magnitude of the magnetic fluctuations to include $\operatorname{\mathcal {M}}$, and find $|\delta \mathrm{{\boldsymbol {\mathit {B}}}}| = \delta B = c_{\rm s}\sqrt{\pi \rho _0}\operatorname{\mathcal {M}}\operatorname{\mathcal {M}_{\text{A0}}}$, where cs is the sound speed and ρ0 is the mean density of gas. This new relation fits well in the strong B-field regime. We go on to study the anisotropy between the perpendicular (B⊥) and parallel (B∥) fluctuations and the mean-normalized fluctuations, which we find follow universal scaling relations, invariant of $\operatorname{\mathcal {M}}$. We provide a detailed analysis of the morphology for the δB⊥ and δB∥ probability density functions and find that eddies aligned with B0 cause parallel fluctuations that reduce B∥ in the most anisotropic simulations. We discuss broadly the implications of our fluctuation models for magnetized gases in the interstellar medium.
The Genomic Selfing Syndrome Accompanies the Evolutionary Breakdown of Heterostyly
Authors: Wang Xin-Jia , Barrett Spencer C H , Zhong Li , Wu Zhi-Kun , Li De-Zhu , Wang Hong , Zhou Wei
Published: August 2020

The evolutionary transition from outcrossing to selfing can have important genomic consequences. Decreased effective population size and the reduced efficacy of selection are predicted to play an important role in the molecular evolution of the genomes of selfing species. We investigated evidence for molecular signatures of the genomic selfing syndrome using 66 species of Primula including distylous (outcrossing) and derived homostylous (selfing) taxa. We complemented our comparative analysis with a microevolutionary study of P. chungensis, which is polymorphic for mating system and consists of both distylous and homostylous populations. We generated chloroplast and nuclear genomic data sets for distylous, homostylous, and distylous–homostylous species and identified patterns of nonsynonymous to synonymous divergence (dN/dS) and polymorphism (πN/πS) in species or lineages with contrasting mating systems. Our analysis of coding sequence divergence and polymorphism detected strongly reduced genetic diversity and heterozygosity, decreased efficacy of purifying selection, purging of large-effect deleterious mutations, and lower rates of adaptive evolution in samples from homostylous compared with distylous populations, consistent with theoretical expectations of the genomic selfing syndrome. Our results demonstrate that self-fertilization is a major driver of molecular evolutionary processes with genomic signatures of selfing evident in both old and relatively young homostylous populations.
Single molecule mass photometry of nucleic acids
Authors: Li Yiwen , Struwe Weston B , Kukura Philipp
Published: August 2020

Mass photometry is a recently developed methodology capable of measuring the mass of individual proteins under solution conditions. Here, we show that this approach is equally applicable to nucleic acids, enabling their facile, rapid and accurate detection and quantification using sub-picomoles of sample. The ability to count individual molecules directly measures relative concentrations in complex mixtures without need for separation. Using a dsDNA ladder, we find a linear relationship between the number of bases per molecule and the associated imaging contrast for up to 1200 bp, enabling us to quantify dsDNA length with up to 2 bp accuracy. These results introduce mass photometry as an accurate, rapid and label-free single molecule method complementary to existing DNA characterization techniques.
The oncofetal RNA-binding protein IGF2BP1 is a druggable, post-transcriptional super-enhancer of E2F-driven gene expression in cancer
Authors: Müller Simon , Bley Nadine , Busch Bianca , Glaß Markus , Lederer Marcell , Misiak Claudia , Fuchs Tommy , Wedler Alice , Haase Jacob , Bertoldo Jean Borges , Michl Patrick , Hüttelmaier Stefan
Published: August 2020

The IGF2 mRNA-binding protein 1 (IGF2BP1) is a non-catalytic post-transcriptional enhancer of tumor growth upregulated and associated with adverse prognosis in solid cancers. However, conserved effector pathway(s) and the feasibility of targeting IGF2BP1 in cancer remained elusive. We reveal that IGF2BP1 is a post-transcriptional enhancer of the E2F-driven hallmark in solid cancers. IGF2BP1 promotes G1/S cell cycle transition by stabilizing mRNAs encoding positive regulators of this checkpoint like E2F1. This IGF2BP1-driven shortening of the G1 cell cycle phase relies on 3′UTR-, miRNA- and m6A-dependent regulation and suggests enhancement of cell cycle progression by m6A-modifications across cancers. In addition to E2F transcription factors, IGF2BP1 also stabilizes E2F-driven transcripts directly indicating post-transcriptional ‘super’-enhancer role of the protein in E2F-driven gene expression in cancer. The small molecule BTYNB disrupts this enhancer function by impairing IGF2BP1-RNA association. Consistently, BTYNB interferes with E2F-driven gene expression and tumor growth in experimental mouse tumor models.
The Sac10b homolog from Sulfolobus islandicus is an RNA chaperone
Authors: Zhang Ningning , Guo Li , Huang Li
Published: August 2020

Nucleic acid-binding proteins of the Sac10b family, also known as Alba, are widely distributed in Archaea. However, the physiological roles of these proteins have yet to be clarified. Here, we show that Sis10b, a member of the Sac10b family from the hyperthermophilic archaeon Sulfolobus islandicus, was active in RNA strand exchange, duplex RNA unwinding in vitro and RNA unfolding in a heterologous host cell. This protein exhibited temperature-dependent binding preference for ssRNA over dsRNA and was more efficient in RNA unwinding and RNA unfolding at elevated temperatures. Notably, alanine substitution of a highly conserved basic residue (K) at position 17 in Sis10b drastically reduced the ability of this protein to catalyse RNA strand exchange and RNA unwinding. Additionally, the preferential binding of Sis10b to ssRNA also depended on the presence of K17 or R17. Furthermore, normal growth was restored to a slow-growing Sis10b knockdown mutant by overproducing wild-type Sis10b but not by overproducing K17A in this mutant strain. Our results indicate that Sis10b is an RNA chaperone that likely functions most efficiently at temperatures optimal for the growth of S. islandicus, and K17 is essential for the chaperone activity of the protein.
The nucleic acid chaperone activity of the HIV-1 Gag polyprotein is boosted by its cellular partner RPL7: a kinetic study
Authors: Karnib Hassan , Nadeem Muhammad F , Humbert Nicolas , Sharma Kamal K , Grytsyk Natalia , Tisné Carine , Boutant Emmanuel , Lequeu Thiebault , Réal Eleonore , Boudier Christian , de Rocquigny Hugues , Mély Yves
Published: August 2020

The HIV-1 Gag protein playing a key role in HIV-1 viral assembly has recently been shown to interact through its nucleocapsid domain with the ribosomal protein L7 (RPL7) that acts as a cellular co-factor promoting Gag's nucleic acid (NA) chaperone activity. To further understand how the two proteins act together, we examined their mechanism individually and in concert to promote the annealing between dTAR, the DNA version of the viral transactivation element and its complementary cTAR sequence, taken as model HIV-1 sequences. Gag alone or complexed with RPL7 was found to act as a NA chaperone that destabilizes cTAR stem-loop and promotes its annealing with dTAR through the stem ends via a two-step pathway. In contrast, RPL7 alone acts as a NA annealer that through its NA aggregating properties promotes cTAR/dTAR annealing via two parallel pathways. Remarkably, in contrast to the isolated proteins, their complex promoted efficiently the annealing of cTAR with highly stable dTAR mutants. This was confirmed by the RPL7-promoted boost of the physiologically relevant Gag-chaperoned annealing of (+)PBS RNA to the highly stable tRNALys3 primer, favoring the notion that Gag recruits RPL7 to overcome major roadblocks in viral assembly.
Location specific annealing of miR-122 and other small RNAs defines an Hepatitis C Virus 5′ UTR regulatory element with distinct impacts on virus translation and genome stability
Authors: Kunden Rasika D , Ghezelbash Sarah , Khan Juveriya Q , Wilson Joyce A
Published: August 2020

Hepatitis C virus (HCV) replication requires annealing of a liver specific small-RNA, miR-122 to 2 sites on 5′ untranslated region (UTR). Annealing has been reported to (a) stabilize the genome, (b) stimulate translation and (c) promote the formation of translationally active Internal Ribosome Entry Site (IRES) RNA structure. In this report, we map the RNA element to which small RNA annealing promotes HCV to nucleotides 1–44 and identify the relative impact of small RNA annealing on virus translation promotion and genome stabilization. We mapped the optimal region on the HCV genome to which small RNA annealing promotes virus replication to nucleotides 19–37 and found the efficiency of viral RNA accumulation decreased as annealing moved away from this region. Then, by using a panel of small RNAs that promote replication with varying efficiencies we link the efficiency of lifecycle promotion with translation stimulation. By contrast small RNA annealing stabilized the viral genome even if they did not promote virus replication. Thus, we propose that miR-122 annealing promotes HCV replication by annealing to an RNA element that activates the HCV IRES and stimulates translation, and that miR-122 induced HCV genome stabilization is insufficient alone but enhances virus replication.
Aberrant mucosal immunoreaction to tonsillar microbiota in immunoglobulin A nephropathy
Authors: Yamaguchi Hiroki , Goto Shin , Takahashi Nao , Tsuchida Masafumi , Watanabe Hirofumi , Yamamoto Suguru , Kaneko Yoshikatsu , Higashi Koichi , Mori Hiroshi , Nakamura Yukio , Horii Arata , Kurokawa Ken , Narita Ichiei
Published: August 2020

Background

Immunoglobulin A nephropathy (IgAN) is the most common glomerulonephritis worldwide, characterized by mesangial polymeric IgA1 deposition. IgAN is believed to develop owing to aberrant mucosal immunoreaction against commensals in the tonsils. However, the exact interrelation between pathogenic IgA and mucosal microbiota in IgAN patients is unclear.

Methods

Biopsy-proven IgAN or recurrent tonsillitis (RT) patients who had undergone tonsillectomy were enrolled. We used 16S ribosomal RNA gene amplicon sequencing with a flow cytometry-based bacterial cell sorting technique) and immunoglobulin repertoire sequencing of the IgA heavy chain to characterize IgA-coated bacteria of the tonsillar microbiota (IgA-SEQ) and their corresponding IgA repertoire. Furthermore, we fractionated patient serum using gel-filtration chromatography and performed flow cytometry-based analysis of IgA binding to bacteria cultured from incised tonsils.

Results

Tonsillar proliferation-inducing ligand and B-cell activating factor levels were significantly higher in IgAN than in RT patients. IgA-SEQ for tonsillar microbiota revealed the preferential binding ability of IgA to Bacteroidetes in IgAN tonsils compared with those from RT patients. Expression of immunoglobulin heavy (IGH) constant alpha 1 with IGH variable 3–30 was significantly higher in IgAN than that in RT, and positively correlated with the IgA-coated enrichment score of Bacteroidetes. Serum polymeric IgA, comprising high levels of GdIgA1, exhibited considerable binding to Bacteroidetes strains cultured from the tonsils of IgAN patients.

Conclusions

These findings provide evidence that aberrant mucosal immune responses to tonsillar anaerobic microbiota, primarily consisting of members of the phylum Bacteroidetes, are involved in IgAN pathophysiology.
Neuropathology of Surgically Managed Epilepsy Specimens
Authors: Thomas Diana L , Pierson Christopher R
Published: August 2020

Epilepsy is characterized as recurrent seizures, and it is one of the most prevalent disorders of the human nervous system. A large and diverse profile of different syndromes and conditions can cause perturbations in neural networks that are associated with epilepsy. Advances in neuroimaging and electrophysiological monitoring have enhanced our ability to localize the neuropathological lesions that alter the neural networks giving rise to epilepsy, whereas advances in surgical management have resulted in excellent seizure control in many patients following resections. Histopathologic study using a variety of special stains, molecular analysis, and functional studies of these resected tissues has facilitated the neuropathological characterization of these lesions. Here, we review the neuropathology of common structural lesions that cause epilepsy and are amenable to neurosurgical resection, such as hippocampal sclerosis, focal cortical dysplasia, and its associated principal lesions, including long-term epilepsy-associated tumors, as well as other malformations of cortical development and Rasmussen encephalitis.
07. RETROSPECTIVE ANALYSIS OF SALVAGE SURGERY FOR LOCAL PROGRESSION OF BRAIN METASTASIS PREVIOUSLY TREATED WITH STEREOTACTIC IRRADIATION: DIAGNOSTIC CONTRIBUTION, FUNCTIONAL OUTCOME, AND PROGNOSTIC FACTORS
Authors: Mitsuya Koichi , Deguchi Shoichi , Hayashi Nakamasa , Harada Hideyuki , Nakasu Yoko
Published: August 2020

BACKGROUND

Stereotactic irradiation (STI) is a primary treatment for patients with newly diagnosed brain metastases. Some of these patients experience local progression, which is difficult to differentiate from radiation necrosis, and difficult to treat. Just a few studies have clarified the prognosis and effectiveness of salvage surgery after STI. We evaluated the diagnostic value and improvement of functional outcomes after salvage surgery.

METHODS

We evaluated patients with brain metastases treated with salvage surgery for local progression from October 2002 to July 2019. These patients had undergone salvage surgery based on magnetic resonance imaging findings and/or clinical evidence of post-STI local progression and stable systemic disease. We employed two prospective strategies according to the eloquency of the lesions. Lesions in non-eloquent areas had been resected completely with a safety margin, utilizing a fence-post method; while lesions in eloquent areas had been treated with minimal resection and postoperative STI. Prognostic factors for survival were analyzed.

RESULTS

Fifty-four salvage surgeries had been performed on 48 patients. The median age of patients was 64 years. The median diameter of the enhanced lesions was 35 mm (range 19–58 mm). The median overall survival was 20.2 months from salvage surgery and 37.5 months from initial STI. Primary cancers were lung 31, breast 9, and others 8. Local recurrence developed in 13 of 54 lesions (24%). Leptomeningeal dissemination occurred after surgery in 3 patients (5.6%). Primary breast cancer (breast vs. lung: HR: 0.17), (breast vs. others: HR: 0.08) and RPA class 1–2 (RPA 1 vs. 3, HR: 0.13), (RPA 2 vs 3, HR: 0.4) were identified as good prognostic factors for overall survival (OS) in multivariate analyses.

CONCLUSION

We insist that salvage surgery leads to rapid improvement of neurological function and clarity of histological diagnosis. Salvage surgery is recommended for large lesions especially with surrounding edema either in eloquent or non-eloquent areas.
13. MANAGEMENT OF BRAIN METASTASES FROM SMALL CELL LUNG CANCER USING SRS
Authors: Koffler Daniel , Viswanatha Sirisha , Fekrmandi Fatemeh , Rana Zaker , Schulder Michael , Goenka Anuj
Published: August 2020

PURPOSE/OBJECTIVE(S)

The management of brain metastases in patients with SCLC has become controversial in the MRI era. We examine our institutional experience treating patients with SCLC with stereotactic radiosurgery. We hypothesize that an SRS strategy in well-selected patients with close MRI surveillance will result in acceptable tumor control, and without disproportionate future neurological symptoms associated with intracranial disease.

MATERIALS/METHODS

Patients with a diagnosis of high grade neuroendocrine lung cancer who had undergone SRS between 2013 and 2019 were identified and divided into two groups: SRS-primary and SRS-salvage. SRS-primary was defined as patients who, at time of SRS, had not received previous PCI or WBRT. SRS-salvage was defined as patients who had received previous PCI or WBRT. Primary outcome was intracranial progression free survival. Secondary outcomes included overall survival and neurologic symptom free survival (N-SFS), defined as time to development of neurologic symptoms attributed disease.

RESULTS

Twenty patients were identified with median follow-up of 14.1 months. 11 patients were identified as SRS-primary, 9 as SRS-salvage. Among SRS-primary, median PFS and OS were 6.1 months (range 0.9 – 14.5 months) and 15.6 months (4.1–43.5) respectively. N-SFS was 11.2 months (range 3.6–40.0). 3 of 11 patients developed neurological symptoms attributable to disease. 3 underwent salvage SRS and 2 salvage WBRT. None died from intracranial disease. Among SRS-salvage, median PFS following PCI/WBRT was 9.8 months (range 1.8 – 23.6 months) and OS following salvage SRS 5.5 months (range 1.1 – 27.8 months). 3 of 9 patients developed further brain metastases post-SRS. 1 patient died from intracranial disease.

CONCLUSION

Among well-selected patients followed with MRI surveillance, our data suggest SRS as primary management of brain metastases from SCLC may be reasonable. Symptomatic intracranial disease was uncommon after SRS, and no patients undergoing upfront SRS died from intracranial disease. Prospective data are required to validate these results.
14. DELAYED MRI RESPONSE TO LITT IN PATIENTS UNDERGOING IMMUNOTHERAPY
Authors: Hong Christopher , Chiang Veronica
Published: August 2020

Laser interstitial thermal therapy (LITT) is an effective treatment for regrowing lesions after previous radiosurgery to brain metastases, typically resulting in decreased perilesional edema within weeks followed by delayed reduction in lesion size. We have anecdotally observed that patients on immunotherapy (IT) at time of LITT may exhibit a delayed edema resolution response to laser ablation. Post-operative imaging for cases of LITT, performed by the senior author from June 2012-July 2019, for regrowing lesions after prior radiosurgery for brain metastases were retrospectively reviewed. The IT group was defined as any patient receiving IT treatment within 3 months of LITT. Post-operative MRIs obtained at serial time points after surgery (2 weeks, 6 weeks, 3 months, 6 months, and 12 months) were reviewed for treatment response to LITT, defined as change in surrounding edema on T2 FLAIR and change of lesion size on T1-weighted post-contrast images. Out of 60 ablated lesions, 22 were in the IT and 38 were in the non-IT groups. There were no differences in distribution of original cancer pathology (IT: 9 melanoma, 8 lung, 5 other, non-IT: 6 melanoma, 20 lung, 12 other; p>0.05). Time to lesion size response on T1-weighted post-contrast MRI neared but did not reach statistical significance between the IT and non-IT groups: median 3.0 versus 2.25 months (HR 1.5, 0.8–2.5, 95% CI, p=0.08), respectively. However, time to reduction of perilesional edema on T2-weighted MRI was significantly longer in the IT group, compared to the non-IT group: median 2.25 versus 1.5 months (HR 1.5, 0.9–2.5, 95% CI, p=0.04), respectively. These data suggest that IT around the time of LITT may lead to delayed edema reduction on MRI after LITT. We hypothesize IT may enhance normal immune-mediated mechanisms thus increasing perilesional inflammation after LITT. Further studies are needed to corroborate our observations and explore the underlying pathophysiology.
16. GAMMA KNIFE CLINICAL DOSE PROFILE FOR EXTENSIVE BRAIN METASTASES
Authors: Bowden Greg , Kim Jong , Faramand Andrew , Fallon Kevin , Flickinger John , Lunsford L Dade
Published: August 2020

BACKGROUND

The use of Gamma Knife stereotactic radiosurgery (GKSRS) for the treatment of extensive intracranial metastases has been expanding due to its superior dosimetry and efficacy. However, there remains a dearth of data regarding the dose parameters in actual clinical scenarios. We endeavored to calculate the radiation dose to the brain when treating >15 brain metastases with GKSRS.

METHODS

This retrospective analysis reviewed dosage characteristics for patients requiring single session GKSRS for the treatment of 315 brain metastases. Forty-two patients met the inclusion criteria between 2008 and 2017. The median number of tumors at the initial GKSRS procedure was 20 (15–39) which accounted for 865 tumors in this study. The median aggregate tumor volume was 3.1cm3(0.13–13.26) and the median marginal dose was 16Gy (14-19Gy).

RESULTS

The median of the mean brain dose was 2.58Gy (range 0.95–3.67Gy) and 79% of patients had a dose <3Gy. The 12Gy dose volume was a median of 12.45cm3, which was equivalent to 0.9% of the brain volume. The median percentage of brain receiving 5Gy and 3Gy was 6.7% and 20.4%, respectively. There was no correlation between the number of metastases and the mean dose to the brain (p=0.8). A higher tumor volume was significantly associated with an increased mean brain dose (p<0.001). The median of the mean dose to the bilateral hippocampi was 2.3Gy. Sixteen patients had supplementary GKSRS, resulting in an additional mean dose of 1.4Gy (0.2–3.8Gy) to the brain.

CONCLUSION

GKSRS is a viable means of managing extensive brain metastases. This procedure provides a relatively low dose of radiation to the brain, especially when compared to traditional whole brain radiation protocols.
22. COMPARATIVE EFFICACY OF ALK-INHIBITORS IN ALK INHIBITOR-NAIVE ALK+ LUNG CANCER BRAIN METASTASES: A NETWORK META-ANALYSIS
Authors: Haddad Philip , Hammoud Dalia , Gallagher Kevin
Published: August 2020

BACKGROUND

Lung cancer has been the leading cause of cancer death for both men and women worldwide. Non-small-cell lung cancer (NSCLC) displays an array of molecular abnormalities most commonly involving ALK and EGFR pathways. NSCLC with ALK rearrangements comprises around 5% of cases. Over the years, several ALK inhibitors (ALKI) have been approved with notable activity in brain metastases. However, there have been limited comparative studies exploring their relative efficacies. This analysis was conducted to compare the relative efficacy of ALKIs against ALKI-naïve ALK+ lung cancer brain metastases.

METHODOLOGY

A review of the medical literature was conducted using online databases. Inclusion criteria consisted of English language; diagnosis of ALKI-naïve ALK+ lung cancer trials with brain metastases; treatment with Crizotinib (CRZ), Alectinib (ALC), Brigatinib (BRG), and Ceritinib (CER); and comparative studies reporting brain metastases specific responses/events. A Bayesian and a frequentists network meta-analysis were conducted using netmeta package and the random-effects model.

RESULTS

Eight studies comprising a total of 665 participants with ALKI-naive ALK+ lung cancer brain metastases were included. When compared pair-wise to CRZ, ALC (RR=0.49;95%CI:0.36–0.66), BRG (RR=0.39;95%CI:0.24–0.64), and CER (RR=0.36;95%CI:0.19–0.68) demonstrated significantly superior response rates in patients with untreated or previously treated lung cancer brain metastases. When the efficacy of each ALKI was compared to each other, BRG and CER were ranked the highest followed by ALC then CRZ in decreasing order.

CONCLUSIONS

This network meta-analysis is the first to compare and rank ALKIs used in treating metastatic ALK+ lung cancer. It indicates that BRG, CER, and ALC are better therapeutic options for patients with ALK-naive ALK+ lung cancer brain metastases when compared to CRZ.
29. ROLE OF AGE AND CNS MYELOID CELLS ON BREAST CANCER BRAIN METASTASIS
Authors: Lai Wu Alex Man , Gossa Selamawit , Samala Ramakrishna , Chung Monika , Gril Brunilde , Yang Howard , Thorsheim Helen , Tran Andy , Wei Debbie , Isanogle Kristine , Yang Yuan , Dolan Emma , Robinson Christina , Difilippantonio Simone , Lee Maxwell , Smith Quentin , McGavern Dorian , Wakefield Lalage , Steeg Patricia
Published: August 2020

Women diagnosed with breast cancer at a younger age (typically defined as < 40 years old) often have a poorer prognosis and an increased risk of brain metastasis compared to their older counterparts. Multivariate analyses accounting for differences in tumor characteristics have shown that age is an independent predictor of worse outcome. We therefore hypothesized that rather than intrinsic tumor properties, extrinsic microenvironmental factors contribute to age-related differences in aggressiveness. The effect of age was examined by injecting brain-selected breast cancer cells into young (2 – 6 months) and older (>12 months) mice. In four brain metastasis models examined, young mice developed 2- to 16-fold (p < 0.05) more brain metastases compared to older mice. The effect of age was not observed in mouse breast cancer models that metastasize to liver and lungs, suggesting that this is an organ-specific phenomenon. Flow cytometry-based immune-profiling of mouse brains showed that T-cells (CD4+, CD8+, and FOXP3+CD25+ regulatory T-cells), monocytes and neutrophils were elevated in brains with metastases, but the abundance of these populations did not vary dramatically with age. Furthermore, antibody-based depletion of T-cells, monocytes and neutrophils did not significantly alter brain metastasis development. Microglia, which are resident CNS myeloid cells, were 1.5-fold more abundant in young brains compared to older brains. Depletion of CNS myeloid cells using the colony stimulating factor-1-receptor inhibitor PLX3397 reduced brain metastatic tumor burden in young mice by 2.1-fold (p < 0.001). Importantly, loss of CNS myeloid cells/microglia, which are normally more activated in aged mice and thus may protect the older brain against metastasis, did not augment brain metastasis formation in older mice. These results suggest that the younger brain is more permissive for breast cancer metastasis and that targeting resident CNS myeloid cells may be an effective strategy to prevent brain metastasis development in younger patients.
31. RADIATION NECROSIS IN STEREOTACTIC RADIOSURGERY AND CHECKPOINTS INHIBITORS FOR BRAIN METASTASES FROM LUNG ADENOCARCINOMA
Authors: Jurica James , Dalwadi Shraddha , Baskin David , Bernicker Eric , Butler Brian , Rostomily Robert , Teh Bin , Tremont-Lukats Ivo , Farach Andrew
Published: August 2020

PURPOSE

Treatment with stereotactic radiosurgery (SRS) and immune checkpoint inhibitors (ICI) is increasingly common for brain metastases (BM) from lung adenocarcinoma. Rates of radiation necrosis (RN) with SRS in the setting of ICIs is an ongoing area of research. We investigated rates of RN in patients with BM from lung adenocarcinoma treated with SRS with or without concurrent ICIs.

METHODS

We identified 39 patients at a single institution who underwent SRS treatment for BM from lung adenocarcinoma. Of these, 19 (49%) received SRS without ICIs and 20 (51%) patients received ICIs within a month of SRS. The rate of RN, defined by MRI features and histology when available, was compared between each group using multivariate analysis. Kaplan Meier survival estimates were calculated based on overall survival and compared to median survival predicted by the graded prognostic assessment.

RESULTS

Overall survival for all patients from diagnosis of brain metastases was 16.6 months (range 3.6–45.9) and median survival predicted by the graded prognostic assessment was 13.7 months (range 6.9–26.5). In total 11 (28%) patients developed MRI and/or histologic evidence for RN during the follow-up period; 5 of 20 (25%) from the SRS with ICI group and 6 of 19 (31%) from the SRS without ICI group. In multivariate analysis, ICI treatment had no significant impact on rates of RN between groups (OR 0.72 [95% CI: 0.17–2.93]; p=0.65) while bevacizumab treatment was associated with a decreased RN risk (OR 0.88 [95% CI: 0.43–0.99]; p=0.02).

CONCLUSION

Retrospective analysis of patients with BM from lung adenocarcinoma treated with SRS suggested that administration of ICIs does not increase risk for development of RN. Further, concomitant treatment with bevacizumab may decrease risk of RN. These findings suggest that patients with BM from lung adenocarcinoma can be treated with combination therapy without increased risk of neurologic toxicity.
33. SYSTEMATIC REVIEW AND META-ANALYSIS OF BREAST CANCER BRAIN METASTASIS AND PRIMARY TUMOR RECEPTOR EXPRESSION DISCORDANCE
Authors: Kotecha Rupesh , Tonse Raees , Rubens Muni , McDermott Michael , Odia Yazmin , Appel Haley , Mehta Minesh
Published: August 2020

BACKGROUND

Discordance in hormone receptor (estrogen [ER] and progesterone [PR]) and human epidermal growth factor receptor2 (HER2) status between the primary tumor and brain metastases and its effect on tumor classification subtype switching has been described but remains understudied.

METHODS

Using the PRISMA guidelines, a systematic review was performed of series published prior to April 2020 of biopsied or resected breast cancer brain metastasis (BCBM) from the Medline database using the keywords “breast cancer” and “brain metastasis” combined with “estrogen receptor/ER,” “progesterone receptor/PR,” “HER2/neu,” and “receptor conversion/dis- or concordance.” Weighted random effects models were used to calculate pooled estimates.

RESULTS

Fifteen full-text articles met inclusion criteria and cumulatively reported on 1373 patients who underwent biopsy or resection of at least one BCBM to compare to their primary tumor. At initial diagnosis, receptor expression profiles were 45.0% ER+, 41.0% ER-, 31.0% PR+, 51.0% PR-, 35% HER2+, and 47.0% HER2-. Corresponding receptor expression profiles from the BCBM were 19.0% ER+, 31.0% ER-, 13.0% PR+, 40.0% PR-, 21.0% HER2+, and 26.0% HER2-. Intra-patient receptor discordance comparisons revealed that 540 patients (42.6%) exhibited discordance in any receptor with 17.0% (95% CI: 13.0%-23.0%) discordance for ER status, 23.0% (95% CI: 18.0%-30.0%) for PR status, and 12.0% (95% CI: 8.0%-16.0%) for HER2 status. The most common receptor discordance events found in BCBM compared to primary tumors were ER loss 11.0% (95% CI: 8.0%-16.0%), PR loss 15.0% (95% CI: 11.0%-21.0%), and HER2 gain 9.0% (95% CI: 7.0%-11.0%).

CONCLUSIONS

BCBM commonly exhibit receptor expression changes on comparison to primary tumors including a 10% HER2 gain rate, a potential actionable target. Classification patterns need to be updated to reflect changes in overall tumor subtype grouping and which factors predict for BCBM/primary tumor discordance. Overall, tumor subtype switching and its effect on clinical management remains underappreciated.
44. EFFECT OF STEREOTACTIC RADIOSURGERY ON NON-SMALL CELL LUNG CANCER BRAIN METASTASIS: CONTINUED CORRELATIVE RADIOBIOLOGIC ANALYSIS OF DNA AND RNA GENOMIC PROFILES FROM PHASE-II CLINICAL TRIAL NCT03398694
Authors: Henriquez Mario , Huff Wei , Shireman Jack , Monaco Gina , Agrawal Namita , Hong Park Choel , Saathoff Miranda , Watson Gordon , Ahmed Atique , Dey Mahua
Published: August 2020

BACKGROUND

Stereotactic radiosurgery (SRS) is an increasingly common modality used with or without surgery for the treatment of brain metastases (BM). However, the effects of SRS on tumors in vivo is unknown.

METHODS

Patients were treated with SRS prior to surgery as per clinical trial NCT03398694. Resected tumor was divided into two groups: ‘center’ and ‘periphery’ with respect to SRS treatment. Tissue were analyzed by DNA and RNA sequencing and compared between the two and to non-radiated tumor.

RESULTS

DNA analysis showed at the individual level, matched comparison of SRS samples from the center or periphery of the same tumor had mutational burden differences. RNA analysis revealed no differentially expressed genes between center and periphery, but there were 62 and 192 differentially expressed genes between the center or periphery and non-radiated control, respectively. At an individual level, matched center and periphery tumor had an average of 16641 differentially expressed genes. Comparing total number of up- and downregulated genes with SNP and Indel mutations of matched patient samples, in patients with higher mutational burdens in peripheral tumors as compared to center there was a higher number of upregulated genes. Reciprocally, when mutation burden was higher in center tumor, total number of genes that were either up- or downregulated were about the same. Pooled analysis revealed significant downregulation of oncogenes, such as TP63 and RECQL4, in the SRS group. DO enrichment analysis also revealed pathways related to NSCLC and lung carcinoma significantly altered in radiation cohort.

CONCLUSION

In summary, this study demonstrates that SRS alters the molecular and genomic profile of NSCLC BM. It results in downregulation of oncogenes and pathways related to lung cancer. Additionally, by sampling the tumor at the center and periphery, there are differential effects of the dose gradient on the cellular and molecular response to ionizing radiation.