tbuckley/cabot-search huggingface dataset:
Recent advances of bispecific antibodies in solid tumors
Authors: Shengnan Yu, Anping Li, Qian Liu, Xun Yuan, Hanxiao Xu, Dechao Jiao, Richard G. Pestell, Xinwei Han, Kongming Wu
Journal: Journal of Hematology & Oncology (2017)

Cancer immunotherapy is the most exciting advancement in cancer therapy. Similar to immune checkpoint blockade and chimeric antigen receptor T cell (CAR-T), bispecific antibody (BsAb) is attracting more and more attention as a novel strategy of antitumor immunotherapy. BsAb not only offers an effective linkage between therapeutics (e.g., immune effector cells, radionuclides) and targets (e.g., tumor cells) but also simultaneously blocks two different oncogenic mediators. In recent decades, a variety of BsAb formats have been generated. According to the structure of Fc domain, BsAb can be classified into two types: IgG-like format and Fc-free format. Among these formats, bispecific T cell engagers (BiTEs) and triomabs are commonly investigated. BsAb has achieved an exciting breakthrough in hematological malignancies and promising outcome in solid tumor as showed in various clinical trials. In this review, we focus on the preclinical experiments and clinical studies of epithelial cell adhesion molecule (EpCAM), human epidermal growth factor receptor (HER) family, carcinoembryonic antigen (CEA), and prostate-specific membrane antigen (PSMA) related BsAbs in solid tumors, as well as discuss the challenges and corresponding approaches in clinical application.
SAT0314 A novel highly selective 5-hydroxytryptamine 2B (5-HT2B) receptor antagonist ameliorating fibrosis in preclinical models of systemic sclerosis
Authors: C Wenglén, L Pettersson, H Arozenius, G Ekström
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Microvascular injury is one of the first pathological events in systemic sclerosis, and precedes the fibrosis. A consequence of vascular damage is the exposure of subendothelial connective tissue that causes activation of platelets and local serotonin (5-hydroxytryptamine, 5-HT) release. Binding of 5-HT to 5-HT<sub>2B</sub> receptors on <i>e.g.</i> fibroblasts results in increased myofibroblast differentiation and release of excessive amounts of matrix proteins subsequently leading to fibrosis. Thus, pharmacologic inhibition of 5-HT<sub>2B</sub> receptor signalling may represent a new treatment opportunity for systemic sclerosis. <h3>Objectives</h3> The objective of the present study was to evaluate a novel highly selective 5-HT<sub>2B</sub> receptor antagonist for its ability to reduce the production of matrix proteins in human dermal fibroblasts and to ameliorate fibrosis in the tight-skin-1 model of systemic sclerosis. <h3>Methods</h3> Dermal fibroblasts isolated from patients with systemic sclerosis were cultured with different concentrations of the 5-HT<sub>2B</sub> receptor antagonist AM1125 with or without 1 μM 5-HT. Anti-fibrotic effects were evaluated by measuring matrix production, myofibroblast differentiation and TGF-β production. The tight-skin-1 model was used to evaluate anti-fibrotic effects <i>in vivo</i> using a therapeutic treatment approach. AM1125 was administered at 10 and 50 mg/kg orally, b.i.d. from week 5 to week 10. Hypodermal thickening, myofibroblast counts and collagen production (hydroxyproline) were evaluated at the end of the treatment period. <h3>Results</h3> <i>In vitro</i> the 5-HT<sub>2B</sub> receptor antagonist AM1125 dose-dependently reduced TGF-β, PAI, nuclear SMAD2/3 and collagens in human dermal fibroblasts. In addition, stress fiber formation and α-SMA mRNA were reduced indicating decreased myofibroblast differentiation. Therapeutic treatment with AM1125 at 50 mg/kg reduced hypodermal thickness (p&lt;0.001), myofibroblast counts (p&lt;0.05) and hydroxyproline content (p&lt;0.01) in the tight-skin-1 model. In addition, the lower dose (10 mg/kg) reduced hypodermal thickness (p&lt;0.001). <h3>Conclusions</h3> The results demonstrate that the 5-HT<sub>2B</sub> receptor antagonist AM1125 prevents pro-fibrotic events in human dermal fibroblasts and attenuates dermal fibrosis using a therapeutic treatment approach in the tight-skin-1 model. Thus, 5-HT<sub>2B</sub> receptor antagonists, exemplified by the novel compound AM1125, could represent a new treatment opportunity for systemic sclerosis. <h3>Disclosure of Interest</h3> C. Wenglén Employee of: AnaMar, L. Pettersson Employee of: AnaMar, H. Arozenius Employee of: AnaMar, G. Ekström Employee of: AnaMar
Effects of Liraglutide on Weight Loss, Fat Distribution, and β-Cell Function in Obese Subjects With Prediabetes or Early Type 2 Diabetes
Authors: Francesca Santilli, Paola G. Simeone, Maria T. Guagnano, Marika Leo, Marica T. Maccarone, Augusto Di Castelnuovo, Cristina Sborgia, Riccardo C. Bonadonna, Ermanno Angelucci, Virginia Federico, Stefano Cianfarani, Lamberto Manzoli, Giovanni Davì, Armando Tartaro, Agostino Consoli
Journal: Diabetes Care (2017)

OBJECTIVE Obesity is associated with an increased risk of type 2 diabetes and cardiovascular complications. The risk depends significantly on adipose tissue distribution. Liraglutide, a glucagon-like peptide 1 analog, is associated with weight loss, improved glycemic control, and reduced cardiovascular risk. We determined whether an equal degree of weight loss by liraglutide or lifestyle changes has a different impact on subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) in obese subjects with prediabetes or early type 2 diabetes. RESEARCH DESIGN AND METHODS Sixty-two metformin-treated obese subjects with prediabetes or newly diagnosed type 2 diabetes, were randomized to liraglutide (1.8 mg/day) or lifestyle counseling. Changes in SAT and VAT levels (determined by abdominal MRI), insulin sensitivity (according to the Matsuda index), and β-cell function (β-index) were assessed during a multiple-sampling oral glucose tolerance test; and circulating levels of IGF-I and IGF-II were assessed before and after a comparable weight loss (7% of initial body weight). RESULTS After comparable weight loss, achieved by 20 patients per arm, and superimposable glycemic control, as reflected by HbA1c level (P = 0.60), reduction in VAT was significantly higher in the liraglutide arm than in the lifestyle arm (P = 0.028), in parallel with a greater improvement in β-index (P = 0.021). No differences were observed in SAT reduction (P = 0.64). IGF-II serum levels were significantly increased (P = 0.024) only with liraglutide administration, and the increase in IGF-II levels correlated with both a decrease in VAT (ρ = −0.435, P = 0.056) and an increase in the β-index (ρ = 0.55, P = 0.012). CONCLUSIONS Liraglutide effects on visceral obesity and β-cell function might provide a rationale for using this molecule in obese subjects in an early phase of glucose metabolism dysregulation natural history.
AB0717 Conduction disturbances in a group of patients with axial spondyloarthropathy
Authors: HS Park, A Laiz, C Alonso, A Garcia-Guillén, M Millán, B Magallares, P Moya, I Castellví, C Díaz-Torné, JM De Llobet
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Cardiac conductance disturbances are known to be one of the many extra-articular manifestations of Ankylosing Spondilitis but not as well related to axial spondyloarthropathies. <h3>Objectives</h3> Description of conduction disturbances found in a group of patients with Axial Spondyloarthropathy (AxSpa) that met ASAS criteria. <h3>Methods</h3> Clinical and demographic variables of 78 patients with AxSpa were registered. It included cardiovascular risk factors as well as cardiacvascular adverse events. All of them had a routine electrocardiogram done which were analized by a cardiologist. <h3>Results</h3> 48 of the 78 patients were men, with a mean age of 61 with standard deviation (SD) of 14. The mean time of evolution of the disease was 23 years (SD ±16). HLA-B27 was prevalent in 54 (69.2%). The sacroileitis was found in radiologic examination of 72 (92.2%), and 6 (7.7%) of them presented edema in magnetic resonance imaging. Other clinical traits were: 43 (55.1%) peripheric arthritis 43, 8 (10.3%) dactilitis, 33 (42.3%) enthesitis, 16 uveitis (20.5%), 2 (2.6%) inflammatory bowel disease and psoriasis 34 (43.3%). The following cardiovascular risk factors were registered: 25 (32%) smokers, 42 (53%) hypertension, 32 (41%) dislipemia, 9 (12%) diabetes, 9 (12%) hyperuricemia and 20 (20%) obesity. 14 patients had structural cardiopathy (11 ischemic cardiopathy and 3 aortic valvulopathy). The electrocardiographic register showed conductance disorders in 20 patients (25.6%). The details of these findings are specified in table 1. <h3>Conclusions</h3> A quarter of our series of presented conduction disturbances in electrocardiography. The relation with disease evolution, as in Ankylosing Spondilitis remains yet to be analized. <h3>Disclosure of Interest</h3> None declared
AB0367 The prophylactic effect of sulfasalazine against pneumocystis pneumonia: an analysis of incidence for pneumocystis pneumonia in patients with rheumatoid arthritis in japan
Authors: T Nunokawa, N Yokogawa, K Shimada, S Sugii
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Cases with <i>Pneumocystis</i> pneumonia (PCP) have been reported in patients with rheumatoid arthritis, mainly treated with biologics. An experimental study in the mouse revealed that sulfasalazine enhances the clearance of the <i>Pneumocystis</i> organism from the lung (1). Furthermore, a case-control study with small sample size indicated possible preventive effect of sulfasalazine against PCP (2). <h3>Objectives</h3> The aim of this study is to clarify the prophylactic effect of sulfasalazine against PCP in patients with rheumatoid arthritis with a large sample size. <h3>Methods</h3> This retrospective study focused on all patients with rheumatoid arthritis seen between April, 2011 and October, 2016. at department of rheumatology, Tokyo Metropolitan Tama Medical Center. We investigated their demographics and medication, including corticosteroids, disease-modifying antirheumatic drugs and prophylactic drugs against PCP. The person-time at risk was calculated from prescription records. We compared the incidence during the period of follow-up in which the patients received sulfasalazine with that in which they did not received sulfasalazine. The incidents were assumed to follow a Poisson distribution and statistical analysis was performed using z-test. <h3>Results</h3> In the study period, 2,394 patients with rheumatoid arthritis were treated at our hospital. Among them, 24 patients received the treatment for PCP because the infection was diagnosed or was strongly suspected. All the cases developed the condition while they were not taking sulfasalazine. The incidence rate of PCP was significantly lower in the treatment period with sulfasalazine than that without sulfasalazine (p&lt;0.001). <h3>Conclusions</h3> Our study confirmed that sulfasalazine has a preventive effect against PCP in patients with rheumatoid arthritis. <h3>References</h3> Wang J, Gigliotti F, Bhagwat SP, George TC, Wright TW. Immune modulation with sulfasalazine attenuates immunopathogenesis but enhances macrophage- mediated fungal clearance during pneumocystis pneumonia. PLoS Pathog. 2010;6(8):59–60. Mizushina K, Hirata A, Hayashi N, et al. Possible preventive effect of salazosulfapyridine against development of Pneumocystis pneumonia in methotrexate-receiving patients with rheumatoid arthritis. Mod Rheumatol. 2015;7595(November):1–8. <h3>Disclosure of Interest</h3> None declared
Early Detection of Molecular Residual Disease in Localized Lung Cancer by Circulating Tumor DNA Profiling
Authors: Aadel A. Chaudhuri, Jacob J. Chabon, Alexander F. Lovejoy, Aaron M. Newman, Henning Stehr, Tej D. Azad, Michael S. Khodadoust, Mohammad Shahrokh Esfahani, Chih Long Liu, Li Zhou, Florian Scherer, David M. Kurtz, Carmen Say, Justin N. Carter, David J. Merriott, Jonathan C. Dudley, Michael S. Binkley, Leslie Modlin, Sukhmani K. Padda, Michael F. Gensheimer, Robert B. West, Joseph B. Shrager, Joel W. Neal, Heather A. Wakelee, Billy W. Loo, Ash A. Alizadeh, Maximilian Diehn
Journal: Cancer Discovery (2017)

Identifying molecular residual disease (MRD) after treatment of localized lung cancer could facilitate early intervention and personalization of adjuvant therapies. Here, we apply cancer personalized profiling by deep sequencing (CAPP-seq) circulating tumor DNA (ctDNA) analysis to 255 samples from 40 patients treated with curative intent for stage I-III lung cancer and 54 healthy adults. In 94% of evaluable patients experiencing recurrence, ctDNA was detectable in the first posttreatment blood sample, indicating reliable identification of MRD. Posttreatment ctDNA detection preceded radiographic progression in 72% of patients by a median of 5.2 months, and 53% of patients harbored ctDNA mutation profiles associated with favorable responses to tyrosine kinase inhibitors or immune checkpoint blockade. Collectively, these results indicate that ctDNA MRD in patients with lung cancer can be accurately detected using CAPP-seq and may allow personalized adjuvant treatment while disease burden is lowest.Significance: This study shows that ctDNA analysis can robustly identify posttreatment MRD in patients with localized lung cancer, identifying residual/recurrent disease earlier than standard-of-care radiologic imaging, and thus could facilitate personalized adjuvant treatment at early time points when disease burden is lowest. Cancer Discov; 7(12); 1394-403. ©2017 AACR.See related commentary by Comino-Mendez and Turner, p. 1368This article is highlighted in the In This Issue feature, p. 1355.
THU0552 Compliance to colchicine treatment in familial meditterranean fever related amyloidosis
Authors: B Yurttas, S Ugurlu, H Ozdogan
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Objectives</h3> To assess the colchicine compliance in patients diagnosed with Familial Mediterrenean Fever (FMF) related amyloidosis in our center. <h3>Methods</h3> Fourty one patients (18 male/23 female) were questioned with regards to colchicine compliance by using retrospective scanning of patient data. <h3>Results</h3> The mean age at the symptomatic onset of FMF was 7.13±5.24 years. The mean age at the time of the FMF diagnosis was 21.21±14.85 years. The mean age at the initiation of colchicine treatment was 21.42±14.75 years and the mean age at time of the diagnosis of amyloidosis was found 29.57±12.14 years. Mean duration of the disease was 31.702±11.84 years and the duration of delayed diagnosis was 14.35±13.84 years. Maximum dose of colchicine was 2,103±0,673 mg/day. Compliance of colchicine treatment was poor in FMF related amyloidosis during their follow-up (11/25, %44), rates of skipped doses were also high (17/25, %68). Compliance rates were high in patients in whom FMF and amyloidosis were diagnosed simultaneously (12/13, %93), rates of skipped doses were also low (2/13, %14). One of the patients diagnosed with FMF after the diagnosis of amyloidosis was compliant, two of them were non-compliant; with regards to skipping doses, two patients were found to be compliant and therefore never skipped doses while one was skipping doses. The compliance to colchicine was high in all FMF patients once amyloidosis was evident (31/41, %75), and rates of skipped doses were also low (12/41, %30). In five FMF patients, amyloidosis was observed despite their compliance to treatment. <h3>Conclusions</h3> The overall delay of diagnosis in FMF patients with amyloidosis was found to be high. Particularly the FMF patients who were diagnosed with amyloidosis during their follow up were found to have lower rates of compliance. There were also a group of patients who were diagnosed with amyloidosis despite adequate and convenient colchicine treatment. It was emphasized that not only the early diagnosis and adequate treatment, but also the close follow up is important in managing FMF patients. <h3>Disclosure of Interest</h3> None declared
OP0039 A population-based study on mortality and the influence of medication use in 4356 patients with systemic lupus erythematosus and 21845 matched controls from the united kingdom
Authors: IE Bultink, A Lalmohamed, F de Vries
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Systemic lupus erythematosus (SLE) has been associated with an increased mortality rate. However, population-based data on all-cause, age-specific and sex-specific mortality risk are limited and data on the influence of medication exposure on mortality risk in SLE are scarce. <h3>Objectives</h3> To estimate the magnitude of the risk from all-cause, age-specific, and sex-specific mortality in patients with SLE and relative risks compared with matched controls, and to evaluate the influence of medication exposure on mortality risk in SLE. <h3>Methods</h3> We conducted a population-based cohort study using the Clinical Practice Research Datalink (from 1987 to 2012). Each SLE patient (n=4356) was matched with up to 6 controls (n=21845) by age and sex. Multivariate Cox regression analysis estimated adjusted relative rates (RR) of mortality, and time interaction terms to evaluate mortality timing patterns. Time-dependent Cox models were used to evaluate the association of glucocorticoid use and hydroxychloroquine use on mortality and were adjusted for age, sex, lifestyle parameters, comorbidities and comedication. <h3>Results</h3> A total of 442 out of 4356 SLE patients died during the study period. Patients with SLE had an increased mortality rate for all-cause mortality compared with age- and sex-matched subjects, after adjustment for confounders (adjusted RR 1.80, 95% CI 1.57–2.08). Glucocorticoid use in the previous six months raised the mortality rate while the adjusted RR was 45% decreased with low dose hydroxychloroquine use. The RR was highest in patients aged 18–39 years (adjusted RR 4.87, 95% CI 1.93–12.3) and slightly higher in females (adjusted RR 1.82, 95% CI 1.56–2.13) compared to male patients (adjusted RR 1.68, 95% CI 1.19–2.39). The mortality rate was significantly increased for patients with a history of dementia, seizures, diabetes, cancer, and renal disease (Table 1). <h3>Conclusions</h3> Patients with SLE have a 1.8-fold increased mortality rate compared with the general population. Glucococorticoid use, female sex and young age are associated with an increased mortality risk while low dose hydroxychloroquine use significantly reduces the mortality rate. In addition, special attention should be paid to lupus patients with neuropsychiatric complications, diabetes, malignancy or renal disease since these subgroups of patients are at high risk of death. <h3>Disclosure of Interest</h3> I. Bultink Grant/research support from: Lilly Netherlands, MSD, Amgen, UCB, A. Lalmohamed: None declared, F. de Vries: None declared
SAT0341 Pilot study: home management of iloprost in the micropump/24 hours, in patients suffering from scleroderma, followed for 12 months
Authors: G Pistone, R Daita, C Arcuri, N Catalano, S Liuzza, C Rinollo, G D'Aguanno, A Allotta, M Lo Monaco, R Mallaci Bocchio, G Natoli, S Corrao
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> evaluate the effectiveness on Raynaud9s phenomenon and on digital ulcers, safety and side effects, during intravenous infusion of iloprost therapy in patients with diffuse and limited scleroderma <h3>Objectives</h3> the effectiveness of the therapy was assessed at 0 and 12 months, on the basis of daily number of episodes of Raynaud9s phenomenon, evaluation of digital ulcers changes of the vascular nail bed to capillaroscopio, evaluation of pulmonary hypertension. Security according to the appearance of adverse events. <h3>Methods</h3> They were enrolled consecutively, for a period of 12 months, 12 patients, 9 women and 2 men, 9 suffering from diffuse scleroderma (positive Scl70) and 3 suffering from limited scleroderma (positive anticentromere), middle age 52,91 years, mean age of disease 7,8 years, 11 non-smoking. They were subjected to infusion of iloprost 1/2 vial diluted in 25 cc of saline solution to 0,6 ml/h, in micropump Infonde for 24 consecutive hours, for 4 days a month for 12 months, 10 patients with peripheral lines and 2 with central venous access. <h3>Results</h3> of 12 patients with the Raynaud9s phenomenon, there was a reduction in the daily number in 4 patients, unchanged in 8 patients. Digital ulcers disappeared in 6 patients, they were unchanged in 5 patients, improved although present in 1 patient. In 7 patients capillaroscopic framework remained unchanged, in 5 patients improved capillary density. 10 patients had no pulmonary hypertension, 2 patients had pulmonary hypertension, no change in the two groups at T0 and T 12. None of the patients experienced side effects during the infusion. <h3>Conclusions</h3> the cyclical infusion therapy iloprost prevented the onset of ulcers in patients at T0 not presented or the appearance of new ulcers; it has contributed to the reduction in the daily number of Raynaud9s phenomenon and also allowed to reach the same effective dose of a vial of iloprost to dilute in 50 cc of saline solution, allowing the patient to perform at home therapy with greater compliance. In terms of safety none of the patients experienced side effects or adverse effects <h3>Disclosure of Interest</h3> None declared
THU0304 Vasculitis patients admitted to intensive care unit: implications from a single-center retrospective study
Authors: A Watad, O Shovman, NL Bragazzi, Y Shoenfeld, H Amital, Y Haviv
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Vasculitides are a heterogeneous group of disorders that are characterized by the inflammation of the vasculature vessels. Vasculitides may present as a life-threatening condition and cause higher rates of morbidity and mortality. There are few studies assessing the outcome and prognosis of patients with vasculitides admitted to the intensive care (ICU). <h3>Objectives</h3> To assess the outcome of vasculitides patients required admission to ICU and to identify factors associated with mortality <h3>Methods</h3> A retrospective study was carried out, including all patients who were diagnosed with vasculitides and admitted to the ICU of the Sheba Medical Center, Tel-Hashomer, throughout the years 2000–2014. Continuous variables were computed as mean±standard deviation, whilst categorical variables were recorded as percentages, where appropriate. Student9s t-test and chi-squared analyses were performed for investigating the impact of the clinical variables on mortality. <h3>Results</h3> Twenty-five vasculitides patients admitted to the ICU were included in the present study (mean age 52±14y, sex ratio M/F: 12/13). The mortality rate among these patients was 48%. Leading causes for ICU admission were: infection (64%), vasculitides exacerbation (34%), and hemorrhage (16%). Variables significantly associated with mortality were: the use of Rituximab prior to admission ICU (p=0.039), involvement of the hemodynamic system (p=0.024), the SOFA score (p=0.041), blood infections during the first week at ICU (p=0.018) and persisting after the first week (p=0.007). <h3>Conclusions</h3> Our study confirms the high mortality rate among vasculitides patients and mainly among those requiring admission to ICU. SOFA score and pre-admission treatment with rituximab have been found to be predictive of mortality. <h3>Disclosure of Interest</h3> None declared