bluuebunny/crossref_metadata_2025 huggingface dataset:
Day and night in the subterranean: measuring daily activity patterns of subterranean rodents (Ctenomys aff. knighti) using bio-logging
Authors: Jannetti Milene G , Buck C Loren , Valentinuzzi Veronica S , Oda Gisele A
Published: June 2019

While most studies of the impacts of climate change have investigated shifts in the spatial distribution of organisms, temporal shifts in the time of activity is another important adjustment made by animals in a changing world. Due to the importance of light and temperature cycles in shaping activity patterns, studies of activity patterns of organisms that inhabit extreme environments with respect to the 24-hour cyclicity of Earth have the potential to provide important insights into the interrelationships among abiotic variables, behaviour and physiology. Our previous laboratory studies with Argentinean tuco-tucos from the Monte desert (Ctenomys aff. knighti) show that these subterranean rodents display circadian activity/rest rhythms that can be synchronized by artificial light/dark cycles. Direct observations indicate that tuco-tucos emerge mainly for foraging and for removal of soil from their burrows. Here we used bio-logging devices for individual, long-term recording of daily activity/rest (accelerometry) and time on surface (light-loggers) of six tuco-tucos maintained in outdoor semi-natural enclosures. Environmental variables were measured simultaneously. Activity bouts were detected both during day and night but 77% of the highest values happened during the daytime and 47% of them coincided with time on surface. Statistical analyses indicate time of day and temperature as the main environmental factors modulating time on surface. In this context, the total duration that these subterranean animals spent on surface was high during the winter, averaging 3 h per day and time on surface occurred when underground temperature was lowest. Finally, transport of these animals to the indoor laboratory and subsequent assessment of their activity rhythms under constant darkness revealed a switch in the timing of activity. Plasticity of activity timing is not uncommon among desert rodents and may be adaptive in changing environments, such as the desert where this species lives.
Perioperative prehabilitation and rehabilitation in esophagogastric malignancies: a systematic review
Authors: Bolger Jarlath C , Loughney Lisa , Tully Roisin , Cunningham Melanie , Keogh Shane , McCaffrey Noel , Hickey Wendy , Robb William B
Published: June 2019

Cancers of the esophagus and stomach are challenging to treat. With the advent of neoadjuvant therapies, patients frequently have a preoperative window with potential to optimize their status before major resectional surgery. It is unclear as to whether a prehabilitation or optimization program can affect surgical outcomes. This systematic review appraises the current evidence for prehabilitation and rehabilitation in esophagogastric malignancy. A literature search was performed according to PRISMA guidelines using PubMed, EMBASE, Cochrane Library, Google Scholar, and Scopus. Studies including patients undergoing esophagectomy or gastrectomy were included. Studies reporting on at least one of aerobic capacity, muscle strength, quality of life, morbidity, and mortality were included. Twelve studies were identified for inclusion, comprising a total of 937 patients. There was significant heterogeneity between studies, with a variety of interventions, timelines, and outcome measures reported. Inspiratory muscle training (IMT) consistently showed improvements in functional status preoperatively, with three studies showing improvements in respiratory complications with IMT. Postoperative rehabilitation was associated with improved clinical outcomes. There may be a role for prehabilitation among patients undergoing major resectional surgery in esophagogastric malignancy. A large randomized controlled trial is warranted to investigate this further.
Multiple Stakeholders’ Perspectives on Respite Service Access for People With Dementia and Their Carers
Authors: O’Shea Emma , Timmons Suzanne , O’Shea Eamon , Irving Kate
Published: June 2019

Background and Objectives

People with dementia and carers do not always access respite services in a timely manner, or in some cases, at all. Although carers’ perspectives on respite access have been explored, other stakeholder perspectives, especially providers and people with dementia, are underrepresented in the existing literature. The aim of this study was to synthesize multiple stakeholders’ perspectives, including people with dementia, on accessing respite services in the context of dementia.

Research Design and Methods

Purposive maximum variation sampling was used. Semi-structured interviews were conducted with 35 key stakeholders, including people with dementia (n = 6), carers (n = 9), respite frontline staff (n = 4), respite managers (n = 8), primary care professionals (n = 3), and policy-makers/academics (n = 5). The process of consent is outlined. Data were interpreted inductively using thematic analysis. Reflexivity was considered throughout the research process.

Results

Three themes (“Service Acceptability,” “Navigational Knowledge and Skills,” “Constructing and Adjudicating Respite Need”) were identified that relate to how access to respite services is negotiated between service providers and dyads.

Discussion and Implications

A number of the findings support previous research; however, novel findings discussed relating to the access negotiation process include (a) the ambiguous legitimacy of respite needs, in a system configured to deliver a biomedical model of care and which considers nonmedical care as a family responsibility, and (b) the constraining effects of disparate conceptualizations of “respite” between carers and providers. Future research should interrogate the appropriate boundaries of public responsibility in relation to respite service planning/delivery for dementia, with particular reference to client preferences for community and in-home provision.
Next-generation AAV vectors—do not judge a virus (only) by its cover
Authors: Domenger Claire , Grimm Dirk
Published: June 2019

Recombinant adeno-associated viruses (AAV) are under intensive investigation in numerous clinical trials after they have emerged as a highly promising vector for human gene therapy. Best exemplifying their power and potential is the authorization of three gene therapy products based on wild-type AAV serotypes, comprising Glybera (AAV1), Luxturna (AAV2) and, most recently, Zolgensma (AAV9). Nonetheless, it has also become evident that the current AAV vector generation will require improvements in transduction potency, antibody evasion and cell/tissue specificity to allow the use of lower and safer vector doses. To this end, others and we devoted substantial previous research to the implementation and application of key technologies for engineering of next-generation viral capsids in a high-throughput ‘top-down’ or (semi-)rational ‘bottom-up’ approach. Here, we describe a set of recent complementary strategies to enhance features of AAV vectors that act on the level of the recombinant cargo. As examples that illustrate the innovative and synergistic concepts that have been reported lately, we highlight (i) novel synthetic enhancers/promoters that provide an unprecedented degree of AAV tissue specificity, (ii) pioneering genetic circuit designs that harness biological (microRNAs) or physical (light) triggers as regulators of AAV gene expression and (iii) new insights into the role of AAV DNA structures on vector genome stability, integrity and functionality. Combined with ongoing capsid engineering and selection efforts, these and other state-of-the-art innovations and investigations promise to accelerate the arrival of the next generation of AAV vectors and to solidify the unique role of this exciting virus in human gene therapy.
On the exact modelling of linear systems
Authors: Pechlivanidou Georgia G , Karampetakis Nicholas P
Published: June 2019

It is well known that given the continuous-time AutoRegressive representation $A\left ( \rho \right ) \beta \left ( t\right ) =0,$ where $\rho $ denotes the differential operator and $A\left ( \rho \right ) $ a regular polynomial matrix, we can always construct the smooth behaviour of this system, by using the finite zero structure of $A\left ( \rho \right ) $. The main theme of this work is to study the following inverse problem: given a specific smooth behaviour, find a family of regular polynomial matrices $A\left ( \rho \right ) $, such that the system $A\left ( \rho \right ) \beta \left ( t\right ) =0$ has exactly the prescribed behaviour. Following an idea coming from Antoulas & Willems (1993) and Willems (1986, 1991) we present an algorithm which solve this problem and can be easily implemented either in a computer programming language like C++ or in a computer algebra system like Mathematica.
The Risks of Election Observation: International Condemnation and Post-Election Violence
Authors: von Borzyskowski Inken
Published: June 2019

Research on international election observation shows that observation reduces fraud, encourages participation, and boosts confidence in the election. However, this conventional account misses the negative, violence-inducing potential of observer criticism. This is the first study examining how observer criticism influences post-election violence. Democracy depends on the loser’s consent, and the willingness of election losers to be governed by the winners can be influenced by observer criticism. When reputable observers criticize the credibility of an election, they can encourage losers to challenge the result. Observer criticism strengthens the electoral loser by legitimizing a challenge and serving as a focal point for mobilization. Using data on post-election violence in thirty-eight countries in sub-Saharan Africa since 1990, I show that internationally condemned elections are more likely to turn violent than not-condemned elections. These results are robust to various control variables (including observer presence and election fraud) and accounting for potential selection, spuriousness, endogeneity, and omitted variables.
Investigating “Missing” Women: Gender, Ghosts, and the Bosnian Peace Process
Authors: McLeod Laura
Published: June 2019

Women usually play a limited role in peace processes, at times because of deliberate efforts to marginalize them. As a result, academic and practitioner knowledge has focused on the absence of female bodies from peace processes. I argue that we can generate knowledge about women and peace processes by exploring both the ways that women are omitted and the enduring effects of their exclusion. I use the 1991–1995 Bosnian peace process, which culminated with the November 1995 Dayton Peace Agreement, to explore how we can find something meaningful at the site of “missing.” Avery Gordon's language of ghosts and haunting allows us to notice how women are made missing from stories of the Bosnian peace process. Ghosts also linger, allowing us to notice how the past of exclusion continues to shape contemporary activism in Bosnia-Herzegovina. Thus, by paying attention to the effects of being (made) missing we can understand how scholars and practitioners produce knowledge about women and gender. Following ghosts highlights that when we find something missing, it matters how it is missing. It is insufficient just to note the absence of women, whether from peace processes or from other political phenomena. Rather, we need to examine the consequences of their absence.
Diagnostics of timing noise in middle-aged pulsars
Authors: Namkham Nakornping , Jaroenjittichai Phrudth , Johnston Simon
Published: June 2019

Radio pulsars are often used as clocks in a wide variety of experiments. Imperfections in the clock, known as timing noise, have the potential to reduce the significance of, or even thwart e.g. the attempt to find a stochastic gravitational wave (GW) background. We measure the timing noise in a group of 129 mostly middle-aged pulsars (i.e. characteristic ages near 1 Myr) observed with the Parkes radio telescope on a monthly basis since 2014. We examine four different metrics for timing noise, but it remains unclear which, if any, provides the best determination. In spite of this, it is evident that these pulsars have significantly less timing noise than their younger counterparts, but significantly more than the (much older) millisecond pulsars (MSPs). As with previous authors, we find a strong correlation between timing noise and the pulsar spin-down rate, $\dot{\nu}$. However, for a given $\dot{\nu}$ there is a spread of about a factor of 30 in the strength of the timing noise likely indicating that nuclear conditions in the interior of the stars differ between objects. We briefly comment on the implications for GW detection through pulsar timing arrays as the level of timing noise in MSPs may be less than predicted.
Probing cosmic dawn with emission lines: predicting infrared and nebular line emission for ALMA and JWST
Authors: Katz Harley , Galligan Thomas P , Kimm Taysun , Rosdahl Joakim , Haehnelt Martin G , Blaizot Jeremy , Devriendt Julien , Slyz Adrianne , Laporte Nicolas , Ellis Richard
Published: June 2019

Infrared and nebular lines provide some of our best probes of the physics regulating the properties of the interstellar medium (ISM) at high redshift. However, interpreting the physical conditions of high-redshift galaxies directly from emission lines remains complicated due to inhomogeneities in temperature, density, metallicity, ionization parameter, and spectral hardness. We present a new suite of cosmological, radiation-hydrodynamics simulations, each centred on a massive Lyman-break galaxy that resolves such properties in an inhomogeneous ISM. Many of the simulated systems exhibit transient but well-defined gaseous discs that appear as velocity gradients in [C ii] 157.6 $\mu$m emission. Spatial and spectral offsets between [C ii] 157.6 $\mu$m and [O iii] 88.33 $\mu$m are common, but not ubiquitous, as each line probes a different phase of the ISM. These systems fall on the local [C ii]–SFR relation, consistent with newer observations that question previously observed [C ii] 157.6 $\mu$m deficits. Our galaxies are consistent with the nebular line properties of observed z ∼ 2–3 galaxies and reproduce offsets on the BPT and mass-excitation diagrams compared to local galaxies due to higher star formation rate (SFR), excitation, and specific-SFR, as well as harder spectra from young, metal-poor binaries. We predict that local calibrations between H α and [O ii] 3727$\, \mathring{\rm A}$ luminosity and galaxy SFR apply up to z > 10, as do the local relations between certain strong line diagnostics (R23 and [O iii] 5007$\, \mathring{\rm A}$/H β) and galaxy metallicity. Our new simulations are well suited to interpret the observations of line emission from current (ALMA and HST) and upcoming facilities (JWST and ngVLA).
Inferring the jet parameters of active galactic nuclei using Bayesian analysis of VLBI data with a non-uniform jet model
Authors: Pashchenko Ilya N , Plavin Alexander V
Published: June 2019

The physical parameters of the jets of active galactic nuclei observed with Very Long Baseline Interferometry (VLBI) are usually inferred from core-shift measurements or from the flux and size measured at the peak frequency of the synchrotron spectrum. Both methods are preceded by modelling the observed VLBI jet structure with simple Gaussian templates. Here we infer the jet parameters using an inhomogeneous jet model directly, bypassing the modelling of the source structure with a Gaussian template or image deconvolution. We apply Bayesian analysis to multifrequency VLBA observations of radio galaxy NGC 315 and find that its parsec-scale jet is well described by an inhomogeneous conical model. Our results favour an electron–positron jet. We also detect a component as a part of a counter jet. Its position implies the presence of an external absorber with a steep density gradient close (r = 0.1 pc) to the central engine.
Statistical analysis of roAp, He-weak, and He-rich stars
Authors: Ghazaryan S , Alecian G , Hakobyan A A
Published: June 2019

To enlarge our data base of chemically peculiar stars, we compiled published data concerning the He-weak and He-rich stars observed by high-resolution spectroscopy techniques during last decades. Twenty He-weak and 28 He-rich stars have been added to the data base. We have also distinguished roAp stars from stars previously identified as Ap stars. To deepen our knowledge on statistical overview of the abundance anomalies versus the physical parameters of stars, we compared our data with previous compilations. We applied statistical tests on our data and found interesting correlations for effective temperature and surface gravity for all type of stars and a few correlations for projected rotation velocity only for He-rich stars. Because of the lack of the data, we could not check whether being a member of binary system is affecting on chemical peculiarities of those stars.
The ASAS-SN catalogue of variable stars – IV. Periodic variables in the APOGEE survey
Authors: Pawlak Michał , Pejcha O , Jakubčík P , Jayasinghe T , Kochanek C S , Stanek K Z , Shappee B J , Holoien T W-S , Thompson Todd A , Prieto J L , Dong S , Shields J V , Pojmanski G , Britt C A , Will D
Published: June 2019

We explore the synergy between photometric and spectroscopic surveys by searching for periodic variable stars among the targets observed by the Apache Point Observatory Galactic Evolution Experiment (APOGEE) using photometry from the All-Sky Automated Survey for Supernovae (ASAS-SN). We identified 1924 periodic variables among more than $258\, 000$ APOGEE targets; 465 are new discoveries. We homogeneously classified 430 eclipsing and ellipsoidal binaries, 139 classical pulsators (Cepheids, RR Lyrae, and δ Scuti), 719 long-period variables (pulsating red giants), and 636 rotational variables. The search was performed using both visual inspection and machine learning techniques. The light curves were also modelled with the damped random walk stochastic process. We find that the median [Fe/H] of variable objects is lower by 0.3 dex than that of the overall APOGEE sample. Eclipsing binaries and ellipsoidal variables are shifted to a lower median [Fe/H] by 0.2 dex. Eclipsing binaries and rotational variables exhibit significantly broader spectral lines than the rest of the sample. We make ASAS-SN light curves for all the APOGEE stars publicly available and provide parameters for the variable objects.
Redshift-space distortions of the H i 21-cm intensity mapping signal due to the internal motions within galaxies
Authors: Sarkar Debanjan , Bharadwaj Somnath
Published: June 2019

The H i 21-cm intensity mapping signal experiences redshift-space distortions due to the motion of the galaxies which contain the H i as well as the motions of the H i gas within the galaxies. A detailed modelling is essential if this signal is to be used for precision cosmology. Considering dark-matter-only simulations where the H i is assumed to reside in galaxies which are associated with haloes, in this work we introduce a technique to incorporate the H i motions within the galaxies. This is achieved through a line profile which accounts for both the rotational and random (thermal and turbulent) motions of the H i within galaxies. The functional form of the double-horned line profiles used here is motivated by observations of z = 0 spiral galaxies. Analyzing the simulated 21-cm power spectrum over the redshift range 1 ≤ z ≤ 6 we find that the H i motions within galaxies make a significant contribution that is manifested as an enhancement in the Finger of God (FoG) effect which can be modelled reasonably well through a Lorentzian damping profile with a single free parameter σp. The value of σp is significantly enhanced if motions within the galaxies are included. This is particularly important at z > 3 where σp is dominated by the internal motions and a measurement of the FoG effect here could provide a handle on the line profiles of high-redshift galaxies.
Incentives and Competition in the Airline Industry
Authors: Aggarwal Rajesh K , Schenone Carola
Published: June 2019

We examine how performance changes at airlines in response to a change in executive incentives. Airlines with executive bonuses contingent on on-time arrival do improve on-time performance. We find evidence of strategic gaming of the incentive as some carriers increase scheduled flight times, making it easier for flights to arrive on time. This effect is more pronounced for competitive routes. Carriers also do not decrease the frequency of flights or the number of passengers to make it easier to be on time, but they do slightly decrease fares. Competitors on the same routes also improve their on-time performance, even when their executive bonuses are not contingent on on-time performance, consistent with competition in strategic complements. (JEL G30, G34, G32)

Received February 5, 2018; editorial decision April 3, 2019 by Editor Andrew Ellul.
Vida PURA: results from a pilot randomized trial of a culturally adapted screening and brief intervention to reduce unhealthy alcohol use among Latino day laborers
Authors: Ornelas India J , Doyle Suzanne R , Torres Vanessa N , Serrano Samantha E , Duran Bonnie , Donovan Dennis M
Published: June 2019

Among Latino day laborers at risk for unhealthy alcohol use, those who received a culturally adapted brief intervention did not reduce their alcohol use more than those not receiving the brief intervention.
Hydrogen Sulfide Promotes Nodulation and Nitrogen Fixation in Soybean–Rhizobia Symbiotic System
Authors: Zou Hang , Zhang Ni-Na , Pan Qing , Zhang Jian-Hua , Chen Juan , Wei Ge-Hong
Published: June 2019

The rhizobium–legume symbiotic system is crucial for nitrogen cycle balance in agriculture. Hydrogen sulfide (H2S), a gaseous signaling molecule, may regulate various physiological processes in plants. However, whether H2S has regulatory effect in this symbiotic system remains unknown. Herein, we investigated the possible role of H2S in the symbiosis between soybean (Glycine max) and rhizobium (Sinorhizobium fredii). Our results demonstrated that an exogenous H2S donor (sodium hydrosulfide [NaHS]) treatment promoted soybean growth, nodulation, and nitrogenase (Nase) activity. Western blotting analysis revealed that the abundance of Nase component nifH was increased by NaHS treatment in nodules. Quantitative real-time polymerase chain reaction data showed that NaHS treatment upregulated the expressions of symbiosis-related genes nodA, nodC, and nodD of S. fredii. In addition, expression of soybean nodulation marker genes, including early nodulin 40 (GmENOD40), ERF required for nodulation (GmERN), nodulation signaling pathway 2b (GmNSP2b), and nodulation inception genes (GmNIN1a, GmNIN2a, and GmNIN2b), were upregulated. Moreover, the expressions of glutamate synthase (GmGOGAT), asparagine synthase (GmAS), nitrite reductase (GmNiR), ammonia transporter (GmSAT1), leghemoglobin (GmLb), and nifH involved in nitrogen metabolism were upregulated in NaHS-treated soybean roots and nodules. Together, our results suggested that H2S may act as a positive signaling molecule in the soybean–rhizobia symbiotic system and enhance the system’s nitrogen fixation ability.
S115 IMPACT OF MESURABLE RESIDUAL DISEASE POSITIVITY ON OUTCOMES FOLLOWING UNMBILICAL CORD BLOOD TRANSPLANTATION: A STUDY FROM THE ACUTE LEUKEMIA WORKING PARTY OF THE EBMT AND EUROCORD
Authors: Baron F. , Labopin M. , Ruggeri A. , Sierra J. , Robinson S. , Labussière‐Wallet H. , Potter M. , Ribera Santasusana J. M. , Deconinck E. , Rambaldi A. , Rohrlich P.‐S. , de Revel T. , Gluckman E. , Nagler A. , Mohty M.
Published: June 2019

Background:

Cord blood transplantation (CBT) has been associated with good transplantation outcomes in acute leukemia patients with mesurable residual disease (MRD) at transplantation (Milano et al., N Engl J Med 375 :944–953, 2016).

Aims:

In the current retrospective analysis we assessed the impact of MRD positivity on CBT outcomes.

Methods:

Inclusion criteria were adult patients with acute myeloid (AML) or lymphoblastic (ALL) leukemia, undergoing CBT as first allogeneic hematopoietic cell transplantation from 2002–2017, first or second complete remission (CR) at transplantation, and available MRD status at the time of transplantation.

Results:

Data from 506 patients were included in the survey. Among them, 317 patients had AML and 189 ALL (including 102 patients with Phi‐pos ALL). Patients received either a single unit (n = 227) or a double CBT (n = 279). MRD positivity was reported in 169 patients (33%) while the remaining 337 patients were MRD negative at CBT. MRD was more frequently detected in ALL than in AML patients (P = 0.02), in patients given single CBT than in those receiving double CBT (P = 0.02), and in those given in vivo T‐cell depletion of the graft (P = 0.006). At 2 years, relapse incidence was 18% in patients with MRD negativity versus 33% in those with MRD positivity at transplantation (P < 0.001). Two‐year leukemia‐free survival (LFS) and overall survival (OS) were 57% and 60%, respectively, in MRD negative patients, versus 38% (P < 0.001) and 48% (P = 0.004), respectively, in those with MRD positivity. There was no statistical interaction between the impact of MRD positivity and disease type (AML versus ALL) nor disease status at transplantation (first versus second CR). In multivariate analyses, MRD positivity was associated with a higher risk of relapse (HR = 1.8, P = 0.003), comparable non‐relapse mortality (P = 0.44), worse LFS (HR = 1.4, P = 0.008) and a trend for worse OS (HR = 1.3, P = 0.065). Other factors associated with relapse incidence included reduced‐intensity conditionng (RIC) (HR = 1.8, P = 0.01) and in vivo T cell depletion (HR = 2.2, P < 0.001). Other factors associated with worse LFS included CR2 at transplantation (HR = 1.3, P = 0.04) as well as in vivo T cell depletion (HR = 1.9, P < 0.001)

Summary/Conclusion:

In acute leukemia patients undergoing CBT achieving MRD negativity at time of transplantation is associated with a lower risk of relapse translated into better LFS. Novel strategies are in need for those leukemic patients with positive MRD pre‐CBT aiming at achieving MRD negativity and thus improving transplantation results.
PF192 CLINICAL PROFILE OF POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME IN HAEMATOLOGY PATIENTS AT A TERTIARY CARE CENTRE
Authors: Gupta G. , Seth T. , Mahapatra M. , Aggarwal M. , Dhawan R.
Published: June 2019

Background:

Posterior reversible encephalopathy syndrome (PRES) is a disorder of reversible subcortical vasogenic brain edema with acute neurological symptoms in patients of renal failure, hypertension and on cytotoxic drugs. Established diagnostic criteria have been lacking and diagnosis can be made on exclusion based on clinical criteria, serum markers, CSFand imaging. The treatment is symptomatic depending on underlying condition. The overall prognosis is favourable but some patients may have long‐term sequale.

Aims:

To study the clinico‐radiologic profile and outcomes of PRES in hematological disorders.

Methods:

We retrospectively reviewed clinical and neuroimaging findings of patients diagnosed with PRES from January 2016 ‐ October 2018. PRES was diagnosed based on clinical signs and MRI findings.

Results:

There were total of 16 patients diagnosed with PRES. There were 7 females and 9 males with age ranging from 2–25 years. Maximum (12/16) patients were ALL on induction chemotherapy (BFM protocol), rest were AML on consolidation high dose cytarabine (HiDAC), thalassemia post HSCT and aplastic anaemia. None of the patients had prior history of seizures, hypertension or evidence of CNS disease. Most patients had hypertension and generalised tonic clonic seizures (GTCS) as presenting complaints. CSF examination done in all was inconclusive. The most common MRI finding (12/16) was bilateral symmetrical subcortical white matter hyperintensity on T2 and FLAIR images in occipital and parietal lobes. Others had frontal lobe, temporal lobe, thalamus and cerebellar involvement. For management cytotoxic drugs were

stopped, antihypertensive (amlodipine, labetalol) and anti‐epileptics were started. Most patients experienced normalisation of blood pressure in an average of 8.6 days (range 4–15 days). Two patients expired during the course due to fungal pneumonia and intra‐cerebral haemorrhage respectively. Patients were continued on antiepileptics for 6–12 months after last seizure episode. Antihypertensives were used for period of one month and then tapered off successfully. Most patients (14/16) were discharged and are under our follow up with no active PRES related complications except one patient who has persistence of neurological deficit in the form of right sided hemiparesis.

Summary/Conclusion:

Amongst patients with hematological malignancy, PRES is especially seen in ALL where steroids are the backbone of induction chemotherapy. Close blood pressure monitoring in settings of induction chemotherapy and immunosuppressive drugs like calcineurin inhibitors should always be prescribed. Early recognition of PRES may facilitate appropriate treatment in a timely manner, conferring a better prognosis. Future studies should be done to address questions like duration of interruption of drug implicated in PRES, if the implicating drug has to be eliminated permanently, optimal duration of anti‐hypertensives and anti‐epileptics.

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PF251 GILTERITINIB PROLONGS SURVIVAL IN PATIENTS WITH FLT3‐MUTATED RELAPSED/REFRACTORY AML WHO HAVE COMMON AML CO‐MUTATIONS OR A HIGH FLT3‐ITD ALLELIC RATIO
Authors: Levis M. , Perl A. , Martinelli G. , Cortes J. , Neubauer A. , Berman E. , Montesinos P. , Baer M. , Larson R. , Chou W.‐C. , Yokoyama H. , Recher C. , Yoon S.‐S. , Hill J. , Rosales M. , Liu C. , Bahceci E.
Published: June 2019

Background:

Treatment with the FLT3 inhibitor, gilteritinib, resulted in superior response rates and overall survival compared with salvage chemotherapy in patients with FLT3‐mutated (FLT3
mut+) relapsed/refractory AML in the phase 3 ADMIRAL study.

Aims:

We analyzed the impact of baseline co‐mutations and baseline FLT3‐internal tandem duplication (ITD) allelic ratio on achievement of complete remission/complete remission with partial hematologic recovery (CR/CRh) and overall survival.

Methods:

A total of 37 recurrently mutated genes in AML (Archer Core Myeloid Panel) were analyzed by next‐generation sequencing; the cutoff for co‐mutation positivity (co‐mut+) was ≥0.027. Baseline FLT3‐ITD allelic ratio (FLT3‐ITD to FLT3 wild‐type DNA) was measured by the LeukoStrat® CDx FLT3 Mutation Assay. The median FLT3‐ITD allelic ratio value of 0.77 was used to define high (≥0.77) vs low (<0.77) FLT3‐ITD allelic ratio.

Results:

An analysis of 361 FLT3
mut+ patients identified four major co‐mutation cohorts, each with ≥10% of the patients: NPM1 (n = 173; 47.9%), DNMT3A (n = 115; 31.9%), DNMT3A/NPM1 (n = 86; 23.8%), and WT1 (n = 65; 18.0%). In addition, seven patients (1.9%) had all three co‐mutations (ie, NPM1, DNMT3A, and WT1). The gilteritinib arm had superior CR/CRh rates and overall survival across all four major co‐mutation cohorts, with the greatest survival benefit in patients with DNMT3A/NPM1 co‐mut+ (Table). In FLT3‐ITD allelic ratio analyses (n = 335), gilteritinib conferred longer overall survival than salvage chemotherapy in patients with a high or low FLT3‐ITD allelic ratio (gilteritinib: high FLT3‐ITD allelic ratio, 7.1 months vs low FLT3‐ITD allelic ratio, 10.6 months; salvage chemotherapy: high FLT3‐ITD allelic ratio, 4.3 months vs low FLT3‐ITD allelic ratio, 6.9 months). In both arms, overall survival was longer in the low FLT3‐ITD allelic ratio cohort than in the high FLT3‐ITD allelic ratio cohort, but the difference in the gilteritinib arm was not statistically significant (gilteritinib: hazard ratio = 1.341, P = 0.0712; salvage chemotherapy: hazard ratio = 2.01, P = 0.0021).

Summary/Conclusion:

The ADMIRAL trial shows that the clinical benefit of gilteritinib in FLT3
mut+ relapsed/refractory AML is maintained regardless of NPM1, DNMT3A, DNMT3A/NPM1, or WT1 co‐mut+ or high FLT3‐ITD allelic ratio.

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PF254 RESULTS FROM THE FIRST‐IN‐HUMAN STUDY OF MIVEBRESIB (ABBV‐075), A PAN‐INHIBITOR OF BROMODOMAIN AND EXTRA TERMINAL PROTEINS, IN PATIENTS WITH RELAPSED/REFRACTORY ACUTE MYELOID LEUKEMIA
Authors: Borthakur G. , Odenike O. , Wolff J.E. , Aldoss I. , Rizzieri D. , Prebet T. , Hu B. , Dinh M.H. , Chen X. , Modi D.A. , Freise K.J. , Jonas B.A.
Published: June 2019

Background:

Bromodomain and extra‐terminal (BET) proteins bind to acetyllysines and upregulate oncogenic target genes. Mivebresib (ABBV‐075) is a pan‐BET inhibitor with antitumor activity in vitro and xenograft models of AML. This 2‐part phase 1 study evaluates the safety and pharmacokinetics of mivebresib at monotherapy or combination dosing schedules in patients with solid tumors (part 1) and acute myeloid leukemia (AML; part 2) (NCT02391480).

Aims:

Here, we report preliminary data from part 2 in patients with relapsed/refractory (RR) AML.

Methods:

Mivebresib monotherapy (MIV‐mono), or combined with venetoclax (MIV‐VEN), were administered daily to adult patients with AML. The dose‐limiting toxicity (DLT) period was 28 d.

Results:

As of Dec 2018, 41 patients (median age: 69 y [range, 29–84]; 19 patients had >2 prior therapies) were enrolled: 19 in MIV‐mono (5 of whom switched to MIV‐combo) and 22 who began treatment in MIV‐VEN cohorts. 23 patients had high cytogenetic risk. Median time on treatment was 28 d (range, 8–562). There were no DLTs. All patients experienced a treatment‐emergent adverse event (AE), most commonly (≥40% patient incidence), fatigue (56%), dysgeusia (46%), decreased appetite (44%), diarrhoea (42%), nausea (42%), vomiting (42%). 40 patients had grade ≥3 AEs (febrile neutropenia (37%), anemia (34%) and thrombocytopenia (32%). 33 patients had serious AEs, most commonly febrile neutropenia (19%). 25 deaths were reported; 15 patients died of causes unrelated to mivebresib and 10 patients due to AML progression. The median best % bone marrow blast change for 26 evaluable patients was −20% (range, −98% to +300%). Gene expression analysis in pre‐ and post‐treatment peripheral blood samples showed that HEXIM1, DCXR and CD93 genes were reliable PD biomarkers of ABBV‐075 which were consistently modulated in a dose‐dependent manner. At the cutoff date, median overall survival for all patients was 2.6 m.

Summary/Conclusion:

Mivebresib was well tolerated and showed antileukemic effects in patients with RR AML.
PF258 REAL‐WORLD DATA ON DOSE‐RELATED EFFECT OF ARSENIC TRIOXIDE IN THE RELAPSE OF ACUTE PROMYELOCYTIC LEUKEMIA
Authors: Wang H. , Gong S. , Zhang H. , Zhang X.
Published: June 2019

Background:

Acute promyelocytic leukemia (APL) has evolved from a highly fatal to a highly curable disease because of all‐trans retinoic acid (ATRA) based regimens. Although the cure rate has been improved with the addition of arsenic trioxide (ATO), the relapse rate is still 1–10%. It is not known whether ATO dosage is related to the relapse rate in real‐world.

Aims:

This study was designed to elucidate the relationship between the dosage of ATO in post‐remission therapy and relapse rate in APL, and to explore the optimum dosage of ATO.

Methods:

According to 2019 NCCN guideline, the recommended ATO dosage in post‐remission therapy is 12 mg/kg in low‐risk and 7.95–12 mg/kg in high‐risk APL. 112 patients with newly diagnosed APL, receiving the combination of ATRA and anthracycline‐based chemotherapy and different dose of ATO for variable cycles, were divided into the high‐dose group (ATO dosage ≥12 mg/kg) and low‐dose group (ATO dosage <12 mg/kg). The 4‐year cumulative relapse‐free survival(RFS) was compared. Receiver operating characteristic (ROC) curve was used to determine the cutoff value.

Results:

Based on the total ATO dosage in post‐remission therapy, 72 (64.3%) patients were in the low‐dose group, whereas 40 (35.7%) patients were in the high‐dose group. There was no significant difference in the baseline characteristics between the two groups. After a median follow‐up time of 53 months, the 4‐year cumulative relapse‐free survival was 83% in the low‐dose group and 100% in the high‐dose group respectively (p = 0.008). ROC analysis indicated if the dose of ATO in post‐remission reached 5.49 mg/kg, the relapse rate had no significant difference with the dose of ATO more than 12 mg/kg (p < 0.001). In the binary logistic regression analysis, an increased ATO dosage has an independent protective factor in terms of probability of relapse (odds ratio = 0.67, 95%CI, 0.51–0.88, p = 0.004). Age, WBC count, and the occurrence of differentiation syndrome had no relationship with relapse rate (p > 0.05).

Summary/Conclusion:

The results indicate that the relapse rate of APL is significantly associated with the dosage of ATO in post‐remission therapy. Regardless of low or high‐risk APL, the ATO dosage should be 12 mg/kg or at least more than 5.49 mg/kg.

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PF262 COMPREHENSIVE DIAGNOSTICS OF ACUTE MYELOID LEUKEMIA BY WHOLE TRANSCRIPTOME RNA SEQUENCING
Authors: Griffioen M. , Arindrarto W. , Borràs D.M. , Locher I.J. , van Diessen S.A. , van der Holst R. , van der Meijden E.D. , Honders M.W. , de Leeuw R.H. , Jedema I. , Kroes W.G. , Knijnenburg J. , Vermaat J.S. , Valk P.J. , Janssen B. , de Knijff P. , van Bergen C.A. , van den Akker E.B. , ’t Hoen P.A. , Kiełbasa S.M. , Laros J.F. , Veelken H.
Published: June 2019

Background:

Acute myeloid leukemia (AML) is characterized by uncontrolled proliferation of malignant myeloid precursor cells in the bone marrow. Genetic aberrations play an important role in pathogenesis as well as in classification of AML, which is relevant for accurate diagnosis, risk assessment and personalized treatment of AML. Genetic aberrations in AML are structurally diverse and currently measured by different diagnostic tests.

Aims:

The aim of the study is to establish whole transcriptome messenger RNA sequencing (RNAseq) as single and flexible diagnostic platform for AML classification, prognostication, and choice of targeted agents.

Methods:

Whole transcriptome RNA sequencing was performed on 100 AML cases and the bioinformatics pipeline HAMLET (Human AML Expedited Transcriptomics) was developed for simultaneous detection of fusion genes, small variants, long tandem duplications and gene expression. HAMLET results were validated by reference assays and targeted resequencing.

Results:

HAMLET accurately detected all fusion genes and overexpression of EVI1 irrespective of 3q26 aberrations. In addition, small variants in 13 genes that are often mutated in AML were called with 99.2% sensitivity and 100% specificity, and internal tandem duplications in FLT3 (FLT3‐ITD) and partial tandem duplications in KMT2A (KMT2A‐PTD) were detected by a novel algorithm based on soft clipped reads with 100% sensitivity and 97.1% specificity.

Summary/Conclusion:

HAMLET accurately provides comprehensive diagnostic information relevant for AML classification, risk assessment and personalized therapy on a single technology platform. Instead of current AML diagnostics based on various assays that target selected aberrations, RNAseq‐HAMLET represents a new diagnostic paradigm according to a “measure all – analyse relevant” approach, which can be adapted to advances in sequencing technology and novel insights in AML pathogenesis, and allows individual retrospective reassessment.
PF275 NAT10 UPREGULATION INDICATES A POOR PROGNOSIS IN ACUTE MYELOID LEUKEMIA
Authors: Liang P. , Hu R. , Liu Z. , Miao M. , Jiang H. , Li C.
Published: June 2019

Background:

Acute myeloid leukemia (AML) is a series of hematologic malignancies with high morbidity and mortality. It is characterized by impaired differentiation, excessive proliferation, and apoptosis escape. N‐acetyltransferase 10 (NAT10) is a transcriptional activator of telomerase reverse transcriptase (hTERT)[1]. It has acyltransferase domain and participates in microtubule acetylation, rRNA modification, DNA damage response, and cytokinesis[2–5]. NAT10 was upregulated in various kinds of tumors such as hepatocellular carcinoma, colorectal cancer, ovarian cancer and melanoma[6–9]. NAT10 upregulation is associated with poor prognosis. This study investigated NAT10 expression in AML patients and its correlation with clinical characteristics, chemotherapy response and prognosis.

Aims:

N‐acetyltransferase 10 (NAT10) is considered as an oncogene in many tumors. This study investigated the NAT10 expression in Chinese acute myeloid leukemia patients and evaluated the predictive significance of NAT10 with a single‐center retrospective study.

Methods:

We collected bone marrow samples of 48 newly diagnosed acute myeloid leukemia patients and 20 benign controls in our center. NAT10 mRNA expression levels were detected by Real‐time qPCR. Clinical data was obtained from inpatient medical records.

Results:

AML patients had higher NAT10 expression level than the normal controls (P < 0.01). NPM1‐mutant patients had higher NAT10 expression level than NPM1‐wt patients. NAT10 expression level was higher in non‐remission group than that of overall remission group (P < 0.05). High NAT10 expression indicated a poor progress free survival and overall survival.

Summary/Conclusion:

The results support NAT10 as a potential prognostic and therapeutic biomarker for acute myeloid leukemia.

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PF282 THE EFFECT OF MODERN THERAPEUTICS IN ADULT ACUTE MYELOID LEUKEMIA (AML): POPULATION‐BASED ANALYSIS OF LONG‐TERM OUTCOMES FROM THE MANITOBA CANCER REGISTRY
Authors: Tapley L. , Bucher O. , Galloway K. , Paulson K. , Seftel M.
Published: June 2019

Background:

While the prognosis for adults with acute myeloid leukemia (AML) is historically poor, advances in supportive care and new therapeutics such as blood and marrow transplant (BMT) and hypomethylating agents may have improved overall outcomes. In the Canadian province of Manitoba, all patients with AML are managed at a single cancer centre with support from a community cancer program. Clinical and demographic data are collected in a provincial cancer registry. This registry captures all cases of AML, increasing the reliability of population‐based data as case ascertainment and follow‐up follow a uniform approach.

Aims:

We sought to describe the clinical characteristics, incidende and relative survival for patients with AML in the province of Manitoba, with attention to temporal trends and outcomes in rural patients, where access to care may be challenging.

Methods:

We collected data on consecutively diagnosed adult cases of AML that were reported to the Manitoba Cancer Registry (MCR) from 1990 ‐ 2014. Life tables from Statistics Canada were used as a reference for expected survival in the general population. Patient demographics were stratified by age, time period and residence at diagnosis. Two‐year age‐standardized relative survival estimates of patients in Manitoba with AML were estimated using the cohort method within various subcategories, including time period of diagnosis (in 5 year increments), sex and urban (Winnipeg) versus non‐Winnipeg location.

Results:

A total of 910 patients from the ages of 15 to 99 were diagnosed from 1990 ‐ 2014 with available survival data to 2016. Of the 910 patients, 517 were men and 393 were women and 511 (56%) were residents of Winnipeg at diagnosis. Two‐year crude relative survival estimates by time period and age group demonstrated improving relative survival for each age quintile category within each 5‐year time period, with the most notable increase over time in patients aged 15–44 and 45–54. Total two‐year age‐standardized relative survival for all patients was 20.37% (CI 95% 17.81–23.05%). Two‐year age‐standardized relative survival in males was 19.22% (CI 95% 15.95–22.73%) and 21.93% (CI 95% 17.88–26.25%) in females. Two‐year age‐standardized relative survival by residence at diagnosis was 20.32% (CI 95%. 16.92–23.94%) for urban (Winnipeg) residents, and 20.54% (CI 95% 16.74–24.62%) for those outside of Winnipeg.

Summary/Conclusion:

We demonstrate improved relative survival in adult AML over time, most notably in adults aged 15–54, where BMT has played an increasingly important therapeutic role. Advanced supportive care and hypomethylating agents may also have contributed to improved outcomes, especially in older patients. Similar relative survival for urban and rural patients supports the benefits of a centralized and coordinated leukemia centre with its closely linked community cancer program.
PF313 NEW TREATMENT FOR DOUBLE/TRIPLE HIT LYMPHOMA WITH DOSE INTENSE PROTOCOL: RITUXIMAB,DOXORUBICIN,ETOPOSIDE,PREDNISOLONE/GEMCITABINE+OXALIPLATIN SHAWING BETTER SURVIVAL RATE
Authors: Salamoon M. , balti M. , kenj M.
Published: June 2019

Background:

unclassifiable B‐cell lymphoma with features between diffuse large B‐cell and Burkitt, Burkitt‐like with a complex karyotype involving MYC and BCL‐2 genes (double hit) and BCL‐6 gene (triple hit). This kind of lymphoma shows high mitotic rates and an aggressive course for which no definitive treatment have been established so far.

Aims:

the study is aiming at evaluating a new dose intense chemotherapy in patients with double/triple hit lymphoma with end points including progression free and overall survival at 5 years.

Methods:

this is a multicenter study with Al Bairouni university cancer center in Damascus, Syria as the main investigator performed between 2014 and 2018 where we recruited 66 patients with ages between 18 and 65 years having double/triple hit lymphoma confirmed by immuno‐histochemistry as well as FISH technique. Patients received a dose intense protocol as follows: (Rituximab 375 mg/m2 with Doxorubicin 75 mg/m2, Cyclophosphamide 1200 mg/m2, Etopdside 300 mg/m2 and Prednisolone 1 mg/kg for 5 days) repeated every 21 days for 6 cycles with 5 days G‐csf support. Then partial and complete responders were given (Gemcitabine 1gr/m2+ Oxaliplatin 85 mg/m2) for 6 cycles repeated every 14 days. End‐points were progression free survival and overall survival at 5 years.

Results:

overall response rate (ORR) was documented in 58 patients (87.8%) (42 complete responders and 16 partial responders). 12 patients progressed at different stages of follow up with a progression free survival (PFS) of 82% (95% CI 77–88). However, 51 patients were found to still alive at 5 years with an overall survival (OS) rate of 77.2(95% CI 71–82). Survival was shorter in those presented with synchronous central nervous system and abdominal localizations (P value 0.02). The most frequent toxicities were, neutropenia and thromcytopenia of different grades, tumorlysis syndrome in few patients and different degrees of mucositis and peripheral neuropathy, however, no documented death was attributed to toxicity profile.

Summary/Conclusion:

double/triple hit lymphoma is a new subtype of lymphoma involving a 2–3 genes abnormalities which increase the aggressiveness course of disease with most patients resisting the old standards. Recently, patients were responding to the classical R‐CHOP as well as to R‐EPOCH in both young and elderly patients, however, survival rates were not exceeding 65% at 5 years. That is why we have developed this protocol with high dose chemotherapy in order to overcome resistance and consolidate the primary response. Compared with studies published in the literature, our protocol confers better progression free and overall survival rates, however, bigger trials should be performed to validate our results