tbuckley/cabot-search huggingface dataset:
PF645 EXPOSURE‐RESPONSE ANALYSIS &amp; DISEASE MODELING FOR SELECTION OF OPTIMAL DOSING REGIMEN OF ISATUXIMAB AS SINGLE AGENT IN PATIENTS WITH MULTIPLE MYELOMA
Authors: H.‐T. Thai, L. Liu, K. Koiwai, C. Brillac, H. Van de Velde, L. Nguyen, C. Veyrat‐Follet, D. Semiond
Journal: HemaSphere (2019)

Background: Isatuximab is an anti‐CD38 monoclonal antibody with multiple modes of action for killing tumor cells through direct tumor targeting and immune cell engagement [1]. Aims: Exposure‐Response (E‐R) analysis and disease modelling of tumor burden were performed to evaluate the relationship between isatuximab exposure and efficacy outcome and to support dosing regimen selection for isatuximab as a single agent in relapsed/refractory multiple myeloma (RRMM) patients. Methods: The E‐R analyses were conducted in 194 RRMM patients evaluable for pharmacokinetics (PK) from two monotherapy trials, a phase 1/2 trial (NCT01084252)[2] and a phase 1 trial (NCT02514668). Isatuximab was administered intravenously at doses from 1 to 20 mg/kg once a week or every 2 weeks. Several isatuximab exposure parameters were tested and their association with the probability of achieving an objective response (CR, VGPR or PR) was examined by logistic regression modeling. Baseline covariates were also considered in the model to reduce their potential confounding effects. Disease progression was captured in a subset of 122 evaluable patients with the dynamics of the serum M‐protein and accounted for dropout using a joint model. Trial simulations were then performed to evaluate different dosing regimens of interest using both models. Results: The E‐R relationship was best described by Emax model, in which Ctrough at 4 weeks and percent of bone marrow plasma cells were significant predictors of overall response rate (ORR). Patients with bone marrow plasma cells lower than 50% were more likely to respond. For a given bone marrow plasma cell value, higher probability of response to treatment was obtained with higher Ctrough at 4 weeks. Longitudinal data of M‐protein was adequately described by a tumor growth inhibition model [3,4] and provided more insights into the response of patients over time. Therefore, a high loading dose of 20 mg/kg weekly over 4 weeks was chosen for maximizing the tumor response and a maintenance dose of 20 mg/kg every 2 weeks appeared sufficient to sustain efficacy. Clinical trial simulation demonstrated that this dosing regimen presented a probability of success of 76% to reach 30% ORR (5,000 trials with 100 patients) and would allow 52% reduction of serum M‐protein from baseline at 2 months of treatment. In addition, isatuximab appeared to be well tolerated at this dose level. Summary/Conclusion: Model‐based drug development has been successfully applied to support phase II isatuximab monotherapy dosing regimen selection in RRMM patients. This approach increases both the robustness of dose selection decision making and the chances of success for future clinical trials.
AB1115 OBESITY AND FLAT VERTEBRAE
Authors: Maria Del Pilar Ahijado Guzman, Raul Maria Veiga Cabello, Miguel Cantalejo Moreira, Justo Ruiz Ruiz, Antonio Zapatero Gaviria
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Spine is a mechanical structure, in a young and healthy individual, under a radiological focus, disposes their vertebral bodies in harmony with their stature, and progressively increasing in magnitude from the cervical to the lumbar spine, in a range of vertical growth that it can exceed the horizontal (1). It is postulated that the important obesity in the early stages of life, could modify the vertebral parameters by skeletal overloads, but the problem is that the current vertebral indexes do not measure a relation of the person height with his vertebra (2). <h3>Objectives</h3> Thus, to check whether the childhood obesity could modify the vertebral parameters, or it is accepted that it entails a loss of equivalent stature, and in this case would be necessary a study comparative of average height, or whether the harmony of the individual is accepted, it would be necessary to create an index that combine these variables to objectify if its value is a constant, and thus, eliminate the ambiguity of the observer. <h3>Methods</h3> We selected a population of obese (BMI≥35), both sex, between 20 and 55 years old, in bariatric surgery protocol, with a significant obesity in their development. Was excluded any cause that could produce vertebral flattening. As a control group, was included any patient that went to outpatient visit of rheumatology, and which met the inclusion and exclusion criteria above, except obesity. As variables, sex, age, body mass index (BMI), and with a chest lateral plate, not rotated, and in the eighth dorsal vertebra, we calculate his length (LVD8) and his height (HVD8), measured in mm. Figure 1. Finally, we applied a comparative study of average of height and vertebral index (VI) results: VI = 10 x LVD8/(HVD8 x stature) <h3>Results</h3> 90 patients were analyzed. 20 patients in the study group (22.2%): 48.1% female, 48.6 years old, 38.2 BMI, and VI 11.6 Meters-1 And 70 patients in the control group (77.8%): 51.1% females 45.15 yers old, 26.2 BMI, and VI 11.2 Meters-1 The comparative analysis of averages does not show any significant differences in the index or in the stature of these patients. <h3>Conclusion</h3> It is a small study, and according to height or the created index, it does not seem that obesity in development modifies the overall height or the vertebral parameters. In addition, the index gives a stable value regarding the sex of both populations in the eighth dorsal vertebra. <h3>References</h3> [1] White AA, Panjabi MM. Clinical Biomechanics of the Spine. 2nd ed, Lippincott Williams &amp; Wilkins, 1990. [2] Gooding CA, Neuhause EBD (1965) Growth and developedment of the vertebral body in the presence and absence of normal stress. AJR 93:388. [3] Veiga C RM. Vértebra plana. Revisión de concepto y aproximación diagnóstica. Semin Fund Esp Reumatol. 2009;10(2):56-63. <h3>Disclosure of Interests</h3> None declared
Neuraminidase inhibition contributes to influenza A virus neutralization by anti-hemagglutinin stem antibodies
Authors: Ivan Kosik, Davide Angeletti, James S. Gibbs, Matthew Angel, Kazuyo Takeda, Martina Kosikova, Vinod Nair, Heather D. Hickman, Hang Xie, Christopher B. Brooke, Jonathan W. Yewdell
Journal: The Journal of Experimental Medicine (2019)

Broadly neutralizing antibodies (Abs) that bind the influenza virus hemagglutinin (HA) stem may enable universal influenza vaccination. Here, we show that anti-stem Abs sterically inhibit viral neuraminidase (NA) activity against large substrates, with activity inversely proportional to the length of the fibrous NA stalk that supports the enzymatic domain. By modulating NA stalk length in recombinant IAVs, we show that anti-stem Abs inhibit virus release from infected cells by blocking NA, accounting for their in vitro neutralization activity. NA inhibition contributes to anti-stem Ab protection in influenza-infected mice, likely due at least in part to NA-mediated inhibition of FcγR-dependent activation of innate immune cells by Ab bound to virions. Food and Drug Administration-approved NA inhibitors enhance anti-stem-based Fc-dependent immune cell activation, raising the possibility of therapeutic synergy between NA inhibitors and anti-stem mAb treatment in humans.
PS1331 MYELOMONOCYTIC SKEWING IN CHRONIC MYELOMONOCYTIC LEUKEMIA: PHENOTYPIC, GENOTYPIC AND BIOLOGIC FEATURES AND IMPACT ON SURVIVAL
Authors: K. Geissler, E. Jäger, A. Barna, M. Gurbisz, R. Marschon, T. Graf, E. Graf, B. Borjan, R. Jilch, C. Geissler, G. Hörmann, H. Esterbauer, I. Schwarzinger, T. Nösslinger, M. Pfeilstöcker, H. Tüchler, R. Reisner, T. Sliwa, F. Keil, P. Bettelheim, S. Machherndl-Spandl, O. Zach, A. Weltermann, S. Heibl, J. Thaler, A. Zebisch, H. Sill, R. Stauder, G. Webersinke, A. Petzer, R. Kusec, E. Ulsperger, B. Schneeweiss, J. Berger, L. Öhler, U. Germing, W.R. Sperr, P. Knöbl, U. Jäger, P. Valent
Journal: HemaSphere (2019)

Background: The interstitial deletion of the long arm of chromosome 5—del(5q)—is the most common cytogenetic abnormality in MDS occurring either as a sole aberration or as a part of complex karyotypes (CK). MDS with isolated del(5q) are associated with a favorable outcome while MDS with CK relate to poor prognosis. Extent of deleted segment is highly variable. However, it remains unclear whether its size matters for the different MDS phenotypes. Aims: The aim was to compare the extent of deletion in 264 MDS patients [116 with isolated del(5q) and 148 with del(5q) involved in CK] and to assess the relationship of del(5q) extent and TP53 gene mutation. Methods: Extent of del(5q) was analyzed using I-FISH (Abbott, MetaSystems), mBAND (MetaSystems) and array CGH/SNP (CytoChip Cancer SNP 180K, Illumina or SurePrint G3 Cancer CGH+SNP 4x180K, Agilent). CK were analyzed with mFISH (MetaSystems). Sequence analysis of TP53 gene was performed in 84 cases using amplicon deep sequencing (exons 4–11) on a 454 GS Junior system (Roche) or with TruSight Myeloid Panel Kit on MiSeq sequencing instruments (Illumina). Results: In the group with isolated del(5q), the most frequently deleted segment ranged between the bands 5q14 and 5q33.3, with the smallest deletion encompassing the 5q31.1–5q31.3 region (18.527 Mb). The TP53 mutation was proved in 19.4% cases. The size of the deletion did not significantly differ in patients with and without TP53 mutation. In the group with CK, the deletion often involved entire long arm including the telomeric region. In some cases, a part of short arm was also deleted, but we never observed the loss of the entire chromosome 5. The commonly conserved region (CCR) was localized in bands 5p12 to 5p14.1. In this group, the mutation of TP53 and/or LOH17p was detected in 49% of patients. The commonly deleted regions (CDR) were in the band 5q31.1 (5.522 Mb) in cases with isolated del(5q) and between the bands 5q31.1 and 5q31.3 (18.527 Mb) in patients with CK. Summary/Conclusion: Patients with isolated del(5q) had a smaller size of the deleted segment. More extensive 5q deletion was associated with higher karyotype complexity, increased frequency of TP53 aberrations and worse prognosis. Accurate analysis of breakpoints and range of del(5q) points out to the correlation of deletion size with increasing genomic instability in MDS and contributes to a better understanding of the MDS pathogenesis. Supported by RVO-VFN64165, GACR P302/12/G157, ProgresQ28/LF1, MHCR 00023736.
Abstract 14897: Statins Reduce Periprocedural and Long-term Risks of Stroke and Death After Carotid Artery Revascularization
Authors: Mohamad A Hussain, Sneha Raju, Konrad Salata, Muhammad Mamdani, Jack V Tu, Gustavo Saposnik, Deepak L Bhatt, Subodh Verma, Mohammed Al-Omran
Journal: Circulation (2017)

Introduction: Preoperative statin therapy has been shown to reduce cardiovascular events after coronary interventions; however, the effect of statins on outcomes after carotid artery interventions ...
THU0486 PREGABALIN EFFICACY IN THE TREATMENT OF CHRONIC PAIN IN PATIENTS WITH RHEUMATOID ARTHRITIS
Authors: Ekaterina Filatova, Shandor Erdes
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> <h3>Objectives</h3> To study the efficacy of Pregabalin in the treatment of chronic pain in patients with rheumatoid arthritis. <h3>Methods</h3> We enrolled 80 patients with rheumatoid arthritis. Screening with the DN4 neuropathic pain questionnaire showed that 31% of patients (n=25) had a neuropathic pain component (NPC+), DN4&gt;4 points. Mean age was 57,0 ±7,49 years, disease duration - 9.87 ± 9.5 years, DAS28 disease activity - 5.5 ± 1.3, VAS pain intensity - 73.1 ± 17.4. All patients were randomized into two groups: group I received pregabalin in combination with DMARDs; group II received DMARDs only. All patients underwent a clinical and neurological examination, disease activity was assessed with the DAS28 index, the effect of treatment on neuropathic pain was assessed with the DN4 and Pain DETECT questionnaires, pain intensity at rest – with the VAS scale. <h3>Results</h3> There were no significant differences between groups before the start of the study (Table 1) Positive dynamics of VAS pain intensity was observed in both groups [Fig. 1] (77.0 ± 13.5 vs 75.2 ± 14.7, at week 2 48.8 ± 14.2 vs 72.9 ± 16.9, at week 5 48.3 ± 34.2 vs 64.5 ± 20.2 p = 0.004). Neuropathic pain indices improved significantly according to the DN4 (5.2 ± 1.1 vs 5.0 ± 0.6, at week 5 2.3 ± 0.6 vs 4.5 ± 0.6) and Pain DETECT questionnaires (17.0 ± 3.2 vs 18.4 ± 2.2, at week 5 7.3 ± 3.06 vs 16.8 ± 3.8). However, disease activity did not differ significantly in either group (group I 5.6 ± 0.6 vs 4.8 ± 1.6 p = 0.4; group II 4.9 ± 0.3 vs 5.2 ± 1.2 p = 0.8). <h3>Conclusion</h3> This preliminary data shows greater effectiveness of Pregabalin in comparison with NSAID and DMARD treatment, both in terms of pain intensity and the neuropathic pain component, which is of practical importance. <h3><b>Disclosure of Interests:</b>&nbsp;</h3> Ekaterina Filatova: None declared, Shandor Erdes Consultant for: Development of studies concepts., Speakers bureau: Educational meetings organized or supported by companies.&nbsp;
Abstract 11640: Increased Fitness Modifies the Obesity Paradox by Body Composition Even in Individuals With Low Cardio-Respiratory Fitness
Authors: Sergey Kachur, Alban De Schutter, Carl Lavie, Homeyar Dinshaw, Eiman Jahangir, Richard Milani
Journal: Circulation (2016)

Introduction: An association of obesity and increased survival has been shown in stable coronary heart disease (CHD) patients, especially in individuals with low cardiorespiratory fitness (CRF). We aimed to examine the impact of fitness improvement on this paradoxical relationship. Hypothesis: Increasing fitness after cardiac rehabilitation will change the nature of the obesity paradox by body composition even in a population with low baseline cardiorespiratory fitness. Methods: 588 subjects with stable CHD referred for cardiac rehabilitation with CRF (&lt;17 cc/kg/min peak oxygen consumption [VO2]) where stratified based on their degree of improvement in CRF. Mortality from the cohort was analyzed with respect to body mass index (BMI), body fat (BF), and lean mass index (LMI). Results: In all subjects, higher BMI, BF, and LMI were associated with significant protective effects after adjusting for age, gender, left ventricular ejection fraction, and baseline VO2 (HR 0.5 p = 0.01; HR = 0.60 p = 0.006; HR 0.20 p &lt; 0.001, respectively). In a subgroup that comprised the top 50 th percentile of VO2 improvement, obesity by BMI and BF was no longer associated with improved survival (HR 0.75 p = 0.4 for BMI and HR 0.83 p = 0.6 for BF, Figure 1), but increased lean mass continued to be protective (HR 0.2 p &lt; 0.001). Conclusions: Persons with low baseline CRF who have significant improvement in absolute VO2 continue to have survival benefits from increased LMI but not from increased BF and BMI. The obesity paradox by BF may be limited to those individuals with low CRF that fail to improve after CR.
Abstract 19024: Identification of Candidate Long QT Syndrome Type 2 Patients Starting From Exome Sequences in a Biobank Cohort
Authors: Allison Hall, Don Burgess, Jennifer Smith, Pierre Fwelo, Corey Anderson, Craig January, Ann Stepanchick, Jonathan Z Luo, Dustin N Hartzel, Uyenlinh Mirshahi, Michael Murray, Tooraj Mirshahi, Brian P Delisle
Journal: Circulation (2017)

Introduction: Every year congenital long QT syndrome (LQTS) is thought to cause sudden cardiac death in hundreds of individuals in the US. Genetic screening potentially could identify LQTS patients...
Abstract 17981: Prognostic Value of Troponins in Chronic Stable Heart Failure: A Systematic Review
Authors: Vijaiganesh Nagarajan, Adrian V Hernandez, WH Wilson Tang
Journal: Circulation (2012)

Introduction: Cardiac troponins have become the ‘gold standard’ for diagnosing myocardial infarction, but the prognostic value of different types of troponin in chronic stable heart failure is not ...
Morphine withdrawal recruits lateral habenula cytokine signaling to reduce synaptic excitation and sociability
Authors: Kristina Valentinova, Anna Tchenio, Massimo Trusel, Joseph A. Clerke, Arnaud L. Lalive, Stamatina Tzanoulinou, Alessandro Matera, Imane Moutkine, Luc Maroteaux, Rosa C. Paolicelli, Andrea Volterra, Camilla Bellone, Manuel Mameli
Journal: Nature Neuroscience (2019)
Comparison of Services Available in 5-Star and Non–5-Star Patient Experience Hospitals
Authors: Zishan K. Siddiqui, Mohammed Abusamaan, Amanda Bertram, Lisa Allen, Albert W. Wu, Junya Zhu, Daniel J. Brotman
Journal: JAMA Internal Medicine (2019)

This survey study uses data from the Centers for Medicare and Medicaid Services, the American Hospital Association, and US News &amp; World Report to compare services available in hospitals with and without 5-star patient experience summary ratings.
Non-Random Inversion Landscapes in Prokaryotic Genomes Are Shaped by Heterogeneous Selection Pressures
Authors: Jelena Repar, Tobias Warnecke
Journal: Molecular Biology and Evolution (2017)

Inversions are a major contributor to structural genome evolution in prokaryotes. Here, using a novel alignment-based method, we systematically compare 1,651 bacterial and 98 archaeal genomes to show that inversion landscapes are frequently biased toward (symmetric) inversions around the origin-terminus axis. However, symmetric inversion bias is not a universal feature of prokaryotic genome evolution but varies considerably across clades. At the extremes, inversion landscapes in Bacillus-Clostridium and Actinobacteria are dominated by symmetric inversions, while there is little or no systematic bias favoring symmetric rearrangements in archaea with a single origin of replication. Within clades, we find strong but clade-specific relationships between symmetric inversion bias and different features of adaptive genome architecture, including the distance of essential genes to the origin of replication and the preferential localization of genes on the leading strand. We suggest that heterogeneous selection pressures have converged to produce similar patterns of structural genome evolution across prokaryotes.
FRI0271 USE OF CONTRAST ENHANCED ULTRASOUND SONOGRAPHY (CEUS) IN LARGE VESSEL VASCULITIS (LVV)
Authors: Raoul Bergner, Jan Splitthoff, Daniel Wadsack
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are important parameters in the monitoring of LVV. Since Tocilizumab is approved for treatment of LVV these cheap and easy repeatable parameters are worthless because of their normalisation by Tocilizumab. MRI and PET-CT as an alternative are not only much more expensive, they are also not arbitrarily repeatable and available. Thus, monitoring of LVV-Patients undergoing a Tocilizumab therapy remains unclear – especially upon showing a persisting thickened vessel wall. <h3>Objectives</h3> CEUS can increase the visibility of tissue perfusion, particularly if there is a very slow bloodflow, which cannot be detected by (power)-doppler sonography. <h3>Methods</h3> In this proof of concept study we investigated patients with active and inactive LVV (aLVV/iLVV) with CEUS. After injection of ultrasound contrast agent we measured the contrasted area of large vessels in a transverse section first if the lumen was completely contrasted and once again 4-8 seconds later. If the vessel wall incorporated the contrast agent the contrasted area increased (Fig 1). The increase of the contrasted area (CA) was correlated with CRP and ESR. Patients were only included if they were not treated with Tocilizumab and therefore ESR and CRP were usable to evaluate the disease activity. <h3>Results</h3> Investigated were 16 patients (13 female, 3 male), 8 with aLVV and 8 with iLVV, respectively. The mean CRP was 85±69 (aLVV) vs. 4±2 mg/l (iLVV) (p&lt;0.0001), the ESR 80±28 (aLVV) vs. 7±4 (iLVV) mm/h (p&lt; 0.0001). The mean age was 74.6±8.4 y (range 56-82). The increase of the CA was 66.6±44.6 (aLVV) vs. 2.4±6.6% (iLVV) (p&lt;0.0001). The increase correlated significantly with the CRP r=0.87, p&lt;0.0001. An increase of CA of ≥20% has a sensitivity of 92,3% and a specificity of 90% for active LVV. <h3>Conclusion</h3> The results of our proof of concept study demonstrate, that CEUS can detect aLVV with a good sensitivity and specificity. Including CEUS in clinical routine will be much easier repeatable, save, quicker and by far more cost-effective then MRI or PET-CT. CEUS might be a good method for monitoring disease activity in LVV treated with Tocilizumab. The limitation of our study is the small number of patients, the missing blinding of the investigator and the method intrinsic fact, that you can't investigate all involved vessels by ultrasound/CEUS. <h3>References</h3> None <h3>Disclosure of Interests</h3> Raoul Bergner Speakers bureau: Abbvie, Roche, Novartis, Bristol Myers Squibb, Jan Splitthoff: None declared, Daniel Wadsack Speakers bureau: Bristol Myers Squibb
Severe influenza pneumonitis in children with inherited TLR3 deficiency
Authors: Hye Kyung Lim, Sarah X.L. Huang, Jie Chen, Gaspard Kerner, Olivier Gilliaux, Paul Bastard, Kerry Dobbs, Nicholas Hernandez, Nicolas Goudin, Mary L. Hasek, Eduardo Javier García Reino, Fabien G. Lafaille, Lazaro Lorenzo, Priya Luthra, Tatiana Kochetkov, Benedetta Bigio, Soraya Boucherit, Flore Rozenberg, Catherine Vedrinne, Michael D. Keller, Yuval Itan, Adolfo García-Sastre, Marie Celard, Jordan S. Orange, Michael J. Ciancanelli, Isabelle Meyts, Qian Zhang, Laurent Abel, Luigi D. Notarangelo, Hans-Willem Snoeck, Jean-Laurent Casanova, Shen-Ying Zhang
Journal: The Journal of Experimental Medicine (2019)

Autosomal recessive IRF7 and IRF9 deficiencies impair type I and III IFN immunity and underlie severe influenza pneumonitis. We report three unrelated children with influenza A virus (IAV) infection manifesting as acute respiratory distress syndrome (IAV-ARDS), heterozygous for rare TLR3 variants (P554S in two patients and P680L in the third) causing autosomal dominant (AD) TLR3 deficiency. AD TLR3 deficiency can underlie herpes simplex virus-1 (HSV-1) encephalitis (HSE) by impairing cortical neuron-intrinsic type I IFN immunity to HSV-1. TLR3-mutated leukocytes produce normal levels of IFNs in response to IAV. In contrast, TLR3-mutated fibroblasts produce lower levels of IFN-β and -λ, and display enhanced viral susceptibility, upon IAV infection. Moreover, the patients’ iPSC-derived pulmonary epithelial cells (PECs) are susceptible to IAV. Treatment with IFN-α2b or IFN-λ1 rescues this phenotype. AD TLR3 deficiency may thus underlie IAV-ARDS by impairing TLR3-dependent, type I and/or III IFN–mediated, PEC-intrinsic immunity. Its clinical penetrance is incomplete for both IAV-ARDS and HSE, consistent with their typically sporadic nature.