tbuckley/cabot-search huggingface dataset:
AB1224 IS THERE A NEED TO OPTIMIZE REFERRAL DIAGNOSIS TO A RHEUMATOLOGY DEPARTMENT?:
Authors: Tobias Hoffmann, Peter Oelzner, Gunter Wolf, Alexander Pfeil
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> The initial visitation of patient suffering from rheumatic disease related symptoms often occurs in absence of a rheumatologist. <h3>Objectives:</h3> This study evaluated the following questions: I. Which medical specialists referral patients to a rheumatology department? II. To quantify the accordance of the presumptive diagnosis and the finial diagnosis of a rheumatologist. <h3>Methods:</h3> 1151 patients (355 men and 796 women) were admitted to a hospital for rheumatological diagnostic. The referral medical specialists were identified. Kappa-Analysis was performed to evaluate the presumptive diagnosis and the finial diagnosis by the rheumatologists. <h3>Results:</h3> 73.0% of the referrals were performed by general practitioner. The other referrals were: 7.7% rheumatologist, 4.8% specialist in internal medicine (excluding rheumatology), 4.3% orthopaedic surgeon, 1.0% orhter surgeon and 9.2% other specialists. The highest accordance of the presumptive diagnosis and the finial diagnosis was κ=0,534 for rheumatologists and κ=0,400 for specialist in internal medicine (excluding rheumatology). Lower kappa values were evaluated for general practitioner (κ=0,345), orthopaedic surgeon (κ=0,310) and other specialists (κ=0,252). <h3>Conclusion:</h3> The referrals were frequently realized by general practitioners. In this context the presumptive diagnosis of a general practitioner presents a low accordance with the finial diagnosis. In this context, general practitioners should achieve a detailed education in the assessment of rheumatic-related symptoms to optimize the dedicated referral to rheumatological departments. <h3>Disclosure of Interests::</h3> Tobias Hoffmann: None declared, Peter Oelzner: None declared, Gunter Wolf: None declared, Alexander Pfeil Grant/research support from: This study is a part of the Investigator Initiated Study "The quantification of inflammatory related periarticular bone loss in certolizumab pegol treated patients with rheumatoid arthritis" which is funded and supported by UCB Pharma GmbH, Monheim, Germany (number: IIS-2014-101458).
Development of an assay based on SOMAmer affinity reagents that detects drug-unbound serum EGFR in the presence of cetuximab and panitumumab.
Authors: Noh Jin Park, Xiuqiang Wang, Dana Root, Angelica Diaz, Weimin Sun, Robert j Morrone, Frederic Waldman, Charles m Strom
Journal: Journal of Clinical Oncology (2012)

2587 Background: EGFR is an oncogene product whose extracellular domain (ECD) can be either up-regulated or down-regulated in serum of patients with various cancers. In colon cancer patients with positive tissue EGFR expression, 2 EGFR ECD-targeting monoclonal antibody drugs, cetuximab (Erbitux) and panitumumab (Vectibix), are widely used chemotherapeutic agents. Patient responses to these drugs vary, and the mechanism of this variability remains unelucidated. Methods: A Slow Off-Rate Modified Aptamer (SOMAmer) targeting the EGFR ECD was selected via Systematic Evolution of Ligands by Exponential Enrichment (SELEX). Using this SOMAmer as a capturing reagent and based on published studies ( Gold et al. PLoS ONE; Dec 7, 2010:10.1371/journal.pone.0015004), we developed a quantitative serum EGFR assay to reliably quantify EGFR in serum. Results: Recovery tests using various amounts of purified EGFR spiked into serum demonstrated a full level of EGFR. Intra and inter assay variability were tested and showed minimum variability. The detection range is 0.95 ng/ml to 600 ng/ml. Interestingly, when serum samples from patients taking cetuximab or panitumumab at the time of blood collection were tested, we observed markedly lower levels of EGFR-captured SOMAmer. ELISA assays from 2 different vendors showed normal to high levels of EGFR in these samples. We further showed that pretreatment of normal serum with either cetuximab or panitumumab can dose-dependently reduce the EGFR SOMAmer signal. The data suggest that our EGFR SOMAmer assay detects serum EGFR molecules that are unbound by cetuximab or panitumumab. Some treated patient samples had more drastic reductions in circulating serum EGFR than others. Conclusions: Various assay development parameters such as accuracy, detection range, and intra and inter assay variability showed that a SOMAmer-based assay detecting serum EGFR can be used in a clinical setting. Our data suggest that this assay can accurately measure drug-unbound EGFR in patients, which may serve as a surrogate drug efficacy indicator, and this may help physicians to adjust the drug dosage. Further studies will be necessary to investigate this possibility.
Plaque Permeability Assessed With DCE-MRI Associates With USPIO Uptake in Patients With Peripheral Artery Disease
Authors: Kang H. Zheng, Jasper Schoormans, Lotte C.A. Stiekema, Claudia Calcagno, Iwona Cicha, Christoph Alexiou, Gustav J. Strijkers, Aart J. Nederveen, Erik S.G. Stroes, Bram F. Coolen
Journal: JACC. Cardiovascular imaging (2019)
TLR4 signaling induces hepatocellular carcinomas by synergistic interactions between alcohol and hepatitis C virus
Authors: Keigo Machida, Hidekazu Tsukamoto, Hasmik Mkrtchyan, Alla Dynnyk, Helene Liu, Jiaohong Wang, Ranjit Ray, Ratna Ray, Alexandra Levine, Michael Lai
Journal: Cancer Research (2008)

4923   [Background] Alcohol exacerbates hepatitis C virus (HCV)-induced liver disease as exemplified by their synergistic effects on the incidence of hepatocellular carcinoma (HCC). Inflammation plays an important role in HCC oncogenesis. HCV NS5A protein induces expression of TLR4, which mediates inflammation in response to endotoxin. It is yet to be tested whether TLR4 induction plays a role in the alcohol-HCV synergism for oncogenic potential. [Objectives] We aimed to determine whether chronic alcohol intake causes synergistic induction of HCC by HCV NS5A in mice. [Methods] HCV NS5A transgenic (Tg) and wild type (wt) mice were fed with Lieber-DeCarlie alcohol diet for 12 months or infused with alcohol diet for 4 week by intragastric infusion model. [Results] HCCs in NS5A Tg mice were induced by 12-month-chronic alcohol feeding (0% vs. 25%). Further, 4-week-ethanol-infused NS5A Tg mice displayed sub-massive necrosis and inflammation in the midzone accompanied by accentuated elevation of plasma ALT levels as compared to alcohol-fed wt mice (95±18 vs. 181±21). This pathology resembled necrosis commonly observed in chronically ethanol-fed rodents given acute lipopolysaccharide (LPS) and is consistent with TLR4-mediated injury in NS5A Tg mice. Further, weekly enteral administration of LPS to ethanol-fed NS5A Tg mice resulted in an additional increment in ALT levels and pathology. LPS injection in NS5A Tg mice increased mortality, liver damage, and TNF-α production through TGF-β-activated kinase 1 (TAK1) and TNFR-associated factor 6 (TRAF6) complexes and phosphorylation of JNK in liver. TAK1-TRAF6 complex formation was induced in HCCs in NS5A Tg mice fed with alcohol. These results demonstrate that alcohol feeding induces HCCs in the liver of NS5A Tg mice through induction of TLR4. The TLR4 signaling molecules, involving TAK1, TRAF6, and JNK, are involved in alcohol-induced oncogenesis in NS5A Tg mice. We conclude that there is a synergistic interaction between HCV proteins and alcohol because of the enhanced endotoxin-induced inflammation through TLR4.
FRI0531 THE ARTICULAR PROTECTION EFFECT OF ISORHAMNETIN IN THE RATS OF MONOSODIUM IODOACETATE-INDUCED OSTEOARTHRITIS
Authors: Deng-Ho Yang, Hsiang-Cheng Chen
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Osteoarthritis (OA) is a degenerative joint disease with damage to the articular cartilage. Active production of inflammatory cytokine/chemokine and matrix metalloproteinases may be found during the progression of OA. Isorhamnetin had the effects of anti-inflammatory, antioxidant, anti-ischemia, anti-atherosclerotic hepatoprotective and anticancer activities. <h3>Objectives</h3> Our study was focused on the effects of isorhamnetin treatment in OA. <h3>Methods</h3> We used monosodium iodoacetate (MIA)-induced OA rats to evaluate the effects of isorhamnetin related anti-inflammatory process. The rats in all groups were sacrificed on four weeks post-MIA injection. The measurements of knee joint swelling, histological analysis, serum inflammatory biomarkers and Western blot were evaluated. <h3>Results</h3> We found that isorhamnetin may reduce MIA-induced knee swelling by significantly reduction of articular cartilage damage in rats. The severity of OA lesion was graded using the modified Mankin scoring system, and we found that the overall modified Mankin's scores were significantly decreased after isorhamnetin treatment compared with a MIA-treated group. The production of IL-1β, IL-6, and TNF-α decreased in isorhamnetin treatment group compared with MIA alone group. Isorhamnetin inhibited the production of NO and PGE2, and the expression of iNOS and COX-2. The production of COMP and CTX-II were also inhibited in MIA-induced OA rats. <h3>Conclusion</h3> Isorhamnetin may modulate the inflammatory progression of OA in MIA-induced OA rats. The prevention of cartilage damage was found in OA after adequate isorhamnetin treatment. Isorhamnetin may serve as a potential agent for the management of OA. <h3>References</h3> [1] Sellam J, Berenbaum F. The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis. Nat Rev Rheumatol2010; 6: 625-635. [2] Manu KA, Shanmugam MK, Ramachandran L, et al. Isorhamnetin augments the anti-tumor effect of capeciatbine through the negative regulation of NF-kappaB signaling cascade in gastric cancer. Cancer Lett2015; 363: 28-36. [3] Chen TL, Zhu GL, Wang JA, et al. Protective effects of isorhamnetin on apoptosis and inflammation in TNF-alpha-induced HUVECs injury. Int J Clin Exp Pathol2015; 8: 2311-2320. <h3>Disclosure of Interests</h3> None declared
PS1405 USE OF POMALIDOMIDE-BASED REGIMENS IN RELAPSED/REFRACTORY MULTIPLE MYELOMA IN FOUR EUROPEAN COUNTRIES – FINDINGS FROM PREAMBLE
Authors: H. Goldschmidt, G. Cook, P. Moreau, C. Chen, C. Davis
Journal: HemaSphere (2019)

Background: Approval of new standards of treatment in cancer is preceded by phase III clinical trials that provide information on safety and efficacy. Nevertheless, excessive rigidity eligibility criteria may compromise extrapolation of results to the target population (external validity). Klausen et al (Leukemia 18), report that over 60% of patients diagnosed of multiple myeloma (MM) would not fulfill eligibility criteria for clinical trials. So, safety and efficacy data may differ from clinical trials to real life. Aims: The aim of our study is to assess the correlation between patient comorbidities by Cumulative Illness rating score (CIRS) score and eligibility in clinical trials. Methods: Eligibility criteria of 3 commercial (VISTA, FIRST, ALCIONE) and 2 academic clinical trials (GEM05MAS65 and GEM10MAS65) were verified for all patients with newly diagnosed transplant-ineligible multiple myeloma (TIMM) at Hospital Universitario de Araba (Spain). CIRS score was calculated for all de patients. Results: From February 2010 to December 2017, 143 MM patients were diagnosed. Of them, 92 patients (64%) were transplant-ineligible and were treated with a bortezomib-melphalan-prednisone scheme. For TIMM patients median age was 77 years old, higher than published trials (median age VISTA: 71, FIRST: 73, ALCIONE: 71, GEM05: 73, GEM10: 75). CIRS score identify different prognostic groups in overall survival: CIRS <4: 52.3 months; CIRS 4 to 8: 57 months and CIRS> 8: 13.5 months (p: 0.017) (figure 1). Applying eligibility criteria, clinical trials result in high exclusion rates: VISTA: 75% FIRST: 70%; ALCIONE 75%; GEM05: 75%; GEM10: 77%. Considering only external validity criteria, exclusion rate was slightly lower: VISTA: 59%; FIRST: 46%; ALCIONE 59%; GEM05: 58%; GEM10: 62%. Regarding comorbidities, no correlation among CIRS score and possibility to be included in clinical trials was observed, although high exclusion was observed for patients with CIRS score >8 vs ≤8 (VISTA 77% vs. 54%; FIRST: 50% vs. 44%; ALCIONE 67% vs. 56%; GEM05: 72% vs. 54%; GEM10: 83% vs. 57%, respectively) (table 1). The presence of grade 3 or 4 comorbidities was not associated with higher exclusion rates.Summary/Conclusion: Eligibility criteria in multiple myeloma clinical trials are excessively restrictive, and do not reflect comorbidities of the patients. Safety and efficacy of recently approved drugs and combinations schemes for treatment of newly diagnosed TIMM in real life may differ from those reported on clinical trials. Selection criteria of clinical trials must be updated and adapted to reality.
Significant overall survival improvement in proliferative subtype ovarian cancer patients receiving bevacizumab.
Authors: Stefan Kommoss, Florian Heitz, Boris J. N. Winterhoff, Chen Wang, Jalid Sehouli, Constantin Aliferis, Rainer Kimmig, Jinhua Wang, Sisi Ma, Nikolaus de Gregorio, Sven Mahner, Andreas Du Bois, Roshan Tourani, Tjoung-Won Park-Simon, Klaus Baumann, Florin Andrei Taran, Friedrich Kommoss, Willibald Schroeder, Sean Christopher Dowdy, Jacobus Pfisterer
Journal: Journal of Clinical Oncology (2018)

5520 Background: We previously demonstrated that bevacizumab may differentially improve ovarian cancer progression-free survival (PFS) depending on TCGA molecular subtypes. Despite recent progress in the molecular biology of epithelial ovarian cancer, results have not yet translated into individualized treatment options or improved disease outcome. In the current study we correlated mature overall survival data with TCGA molecular subtypes in ovarian cancer patients from the AGO-OVAR11 (ICON7) trial. Methods: Whole genome DASL gene expression arrays were performed on FFPE tissues from the AGO OVAR11 (ICON7) trial. Patients were stratified into four TCGA molecular subtypes. Correlation between molecular subtype and the efficacy of randomly assigned therapy with bevacizumab was assessed. Results: Among all four TCGA suptypes, only patients with tumors of the proliferative subtype had a statistically significant benefit from the addition of bevacizumab to standard chemotherapy. Median PFS and OS of proliferative subtype patients was 22.17 and 52.43 months respectively if bevacizumab was added to standard chemotherapy but only 12.0 and 35.27 months in the control arm group of patients. Thus anti-angiogenic therapy resulted in a median improvement of PFS of 10.2 months (HR 0.48 [95%CI 0.3-0.76], p = 0.002) and in a median improvement of overall survival (OS) of 17.2 months (HR 0.54 [95%CI 0.3-0.9], p = 0.021) among TCGA proliferative subtype patients. The remaining three non-proliferative subtypes showed no statistically significant improvement of PFS or OS after addition of bevacizumab. Conclusions: We demonstrate for the first time significant OS benefit in patients with TCGA proliferative molecular subtype. Our findings may help to develop molecularly stratified treatment strategies and hold potential to ultimately improve outcome in patients with ovarian cancer.
Damoctocog Alfa Pegol: A Review in Haemophilia A
Authors: Julia Paik, Emma D. Deeks
Journal: Drugs (2019)

Damoctocog alfa pegol (Jivi®) is approved in the USA, EU, Japan and Canada for the treatment and prophylaxis of previously treated patients aged ≥ 12 years with haemophilia A. Formulated with a 60 kDa polyethylene glycol (PEG) moiety, damoctocog alfa pegol is an intravenously (IV) administered recombinant factor VIII (rFVIII) product with a longer terminal half-life than non-PEGylated FVIII and rFVIII products. In the multinational phase II/III PROTECT VIII trial, prophylaxis with damoctocog alfa pegol reduced the likelihood of bleeding in previously treated patients aged ≥ 12 years with severe haemophilia A, with dosing schedules ranging from twice weekly to once every 7 days. Interim data from the ongoing extension phase indicated that the reduced annualized bleeding rates (ABRs) were maintained for up to 5.2 years of prophylaxis with damoctocog alfa pegol. Damoctocog alfa pegol was also effective in treating bleeding episodes and in providing haemostatic control during surgery. Damoctocog alfa pegol was generally well tolerated in adult and adolescent patients with severe haemophilia A, with most adverse events considered to be unrelated to treatment. There were no new or confirmed cases of FVIII inhibitor development and anti-PEG antibodies, observed in some patients, were of low titre and transient. Damoctocog alfa pegol extends the available treatment options in previously treated adults and adolescents with haemophilia A, offering the possibility of up to once-weekly administration for suitable patients.
PS1195 TIME TO HEALTH‐RELATED QUALITY OF LIFE IMPROVEMENT IN THE PHASE 3 BFORE TRIAL: FIRST‐LINE BOSUTINIB VS IMATINIB IN CHRONIC PHASE CHRONIC MYELOID LEUKEMIA
Authors: T.H. Brümmendorf, A.G. Bushmakin, J.C. Cappelleri, A. Reisman, A. Viqueira, C. Mamolo, S. Isfort
Journal: HemaSphere (2019)

Background: Bosutinib showed improved efficacy vs imatinib for newly diagnosed chronic phase chronic myeloid leukemia (CP CML) in the ongoing BFORE trial (NCT02130557). Gastrointestinal events and transaminase increases were more frequent with bosutinib; musculoskeletal events and edema were more common with imatinib. Improvement or preservation of health‐related quality of life (HRQoL) was seen in both treatment arms after 12 months. Aims: In post hoc analyses, we examined time to improvement of HRQoL with bosutinib or imatinib. Methods: HRQoL was assessed at study visits with the patient‐reported Functional Assessment of Cancer Therapy–Leukemia (FACT‐Leu) questionnaire. Nonparametric models (with SAS Proc Lifetest) were used to estimate median times to transient improvement (any increase in a FACT‐Leu domain score from baseline) and sustained improvement (any increase for 2 consecutive visits) of HRQoL. Results: Median times to transient improvement of FACT‐Leu scores were similar with bosutinib and imatinib (Table). Median time to sustained improvement was numerically shorter with bosutinib for FACT‐Leu total, FACT‐General (FACT‐G) total, emotional well‐being and leukemia subscale scores. Differences between treatment arms for both models (transient or sustained events) were not statistically significant ( P &gt;0.05). Summary/Conclusion: Median time to HRQoL improvement was comparable with bosutinib and imatinib, suggesting differences in rates of specific side effects of individual tyrosine kinase inhibitors for CP CML do not necessarily translate into measurable differences in patient‐reported HRQoL. image
Abstract 12053: Incidence, Characteristics and Predictors of In-Hospital Mortality in Patients With Heart Failure With Preserved Ejection Fraction and Heart Failure With Reduced Ejection Fraction: A National Population Based Cohort Study
Authors: Chayakrit Krittanawong, Anirudh Kumar, Mario Rodriguez, Hafeez Ul Hassan Virk, Bing Yue, Xin Wei, Joseph A Puma, Eyal Herzog, Usman Baber, W. H. Wilson Tang
Journal: Circulation (2018)

Introduction: Half of patients with heart failure (HF) have a preserved left ventricular ejection fraction (HFpEF) and the remainder exhibit reduced ejection fraction (HFrEF). However, there is pau...
On using machine learning algorithms to define clinically meaningful patient subgroups
Authors: Iago Pinal-Fernandez, Andrew Lee Mammen
Journal: Annals of the Rheumatic Diseases (2019)

authors subsequently proposed a new myositis classification criteria based on the number of patient subgroups defined by their algorithm. 4Correspondence Figure 1 Machine learning algorithms define clusters in data sets that do not contain meaningful clusters.A data set with a multivariate normal distribution with 1000 observations and four variables was generated.The Ward agglomerative hierarchical clustering algorithm was applied to this data set and three clusters were defined (coloured in green, red and black).Panel A shows the hierarchical clustering, panel B the hierarchical clustering projected on the factor map, panel C the uncolored factor map and panel D the coloured factor map.
Abstract 81: Absence of Macrophage microRNA-155 Affects Cardiac Metabolic and Inflammatory Remodeling Following Diabesotension and Protects Against Development of Heart Failure
Authors: Monika Rech, Kristiaan Wouters, Julie Lecomte, Nicole Bitsch, Stephane Heymans, Marc van Bilsen, Blanche Schroen
Journal: Circulation Research (2016)

The co-existence of diabetes, obesity, hypertension - diabesotension - is a major burden in western societies and often culminates into heart failure (HF). Diabesotension is associated with a chronic status of low-grade inflammation, involving macrophage infiltration into adipose and cardiac tissues, local activation of inflammatory pathways and concomitant insulin-resistance. We showed that the microRNA miR-155 is a powerful modulator of hypertension-induced cardiac inflammation and HF. Here we hypothesize that absence of miR-155 in macrophages protects against adipose tissue and cardiac inflammation during diabesotension and thereby prevents insulin resistance and cardiac dysfunction. Male C57Bl/6J mice received a bone marrow transplantation of miR-155 WT (n=30) or miR-155 KO (n=30) donors with same genetic background. High fat (HFD; n=22/gr) or chow diet (n=8/gr) was given for 20 weeks. An HFD subgroup was subjected to pressure overload by angiotensin II (1.5mg/kg/d) for 4 weeks (HFD+PO; n=12/gr). Glycaemia, glucose tolerance test, cardiac MRI were performed after 16 and/or 20 weeks. Organs were stored for histology, RNA and FACS analysis. After 16 weeks of HFD, body weight (+11% WT; +14% KO; p&lt;0.05) and glycaemia (+16% WT; +18% KO; p&lt;0.05) increased compared to chow diet animals in both genotypes, confirming the status of obesity and pre-diabetes. Absence of macrophage miR-155 protected HFD-mice from glucose intolerance (at T15: WT 25.08; KO 18.15 mmol/L; p&lt;0.05), suggesting that adipose tissue macrophages might contribute to insulin resistance. In addition, HFD+PO caused mild systolic dysfunction in WT but not in miR-155 KO animals compared to control (ejection fraction: -19% WT, p&lt;0.05; -7% KO, n.s.). While cardiac interstitial fibrosis was not affected by absence of macrophage miR-155, cardiac CD45-positive leukocyte infiltration upon HFD+PO was abrogated. HFD+PO-induced cardiac expression of two PPAR-dependent metabolic genes, angiopoietin-like 4 and uncoupling protein 3, is repressed in the absence of macrophage miR-155. Our data suggest that macrophage miR-155 plays a role in the development of insulin resistance and cardiac dysfunction, possibly by affecting local immune cell function and metabolic programming.