tbuckley/cabot-search huggingface dataset:
AB0509 SUSPENSIVE EFFICACY OF TOCILIZUMAB IN TREATMENT-NAÏVE PATIENTS WITH TAKAYASU ARTERITIS: TOCITAKA FRENCH PROSPECTIVE MULTICENTER OPEN-LABELLED TRIAL.
Authors: A. Mekinian, D. Saadoun, J. C. N. F. Jerome.Connault@chu-Nantes.Fr, I. Q. M. F. I-Quere@chu-Montpellier.Fr, P. Jégo, N. L. F. Nicolas.Limal@aphp.Fr, W. Wxv, J. E. Gottenberg, M. Vautier, L. S. F. Lea.Savey@aphp.Fr, P. Cacoub, O. Fain
Journal: Annals of the Rheumatic Diseases (2020)

Objectives: To assess long term efficacy of tocilizumab in treatment-naive patients with Takayasu arteritis (TAK). Methods: In this multicenter, prospective, open-labelled trial, we aim to evaluate the benefit of adding tocilizumab to steroids in treatment-naïve patients with TAK, on discontinuation of steroids after 6 months of tocilizumab treatment, and to assess relapse-free survival following tocilizumab discontinuation. Results: Thirteen patients with TAK were included, with a median age of 32 years [19-45] and 12 (92%) females. Six (54%) patients met the primary end-point. Among 11 (85%) patients which achieved remission at 6 months, 6 (54%) have reached primary endpoint.. Among the 5 remaining patients which continued steroids, 3 had a prednisone-equivalent dosage &lt; 5mg/day. A significant decrease of disease activity was observed after 6 months of tocilizumab therapy: decrease of median NIH scale (3 [3-4] at baseline, versus 1 [0-2] after 6 months; p &lt;0.001), ITAS-2010 score (5 [2-7] versus 3 [0-8]; p = 0.002), and ITAS-A score (7 [4-10] versus 4 [1-15]; p = 0.0001)]. All patients discontinued tocilizumab after 7 infusions, and no other immunosuppressive drugs was introduced, except for 1 patient which received methotrexate. After 9 and 12 months, respectively 7 (54%) and 6 (50%) patients achieved remission with less than 7.5 mg/day of prednisone, and 9 (69%) and 9 (75%) with doses &lt;10 mg/day. During the 12 months follow-up after tocilizumab discontinuation, a relapse occurred among 5 patients (45%) out of 11 in which achieved remission after 6 months of tocilizumab. No severe AEs were considered related to study treatment and none required tocilizumab interruption or dose reduction. No deaths have occurred during the study period. Conclusion: Tocilizumab seems an effective steroid sparing therapy in TAK but its effect appears to be suspensive. Disclosure of Interests: Arsene Mekinian: None declared, david Saadoun: None declared, jerome.connault@chu-nantes.fr jerome.connault@chu-nantes.fr: None declared, i-quere@chu-montpellier.fr i-quere@chu-montpellier.fr: None declared, Patrick Jégo: None declared, nicolas.limal@aphp.fr nicolas.limal@aphp.fr: None declared, wxv wxv: None declared, Jacques-Eric Gottenberg Grant/research support from: BMS, Pfizer, Consultant of: BMS, Sanofi-Genzyme, UCB, Speakers bureau: Abbvie, Eli Lilly and Co., Roche, Sanofi-Genzyme, UCB, Mathieu Vautier: None declared, lea.savey@aphp.fr&gt;; lea.savey@aphp.fr&gt;;: None declared, Patrice cacoub: None declared, olivier fain: None declared
IMbrave150: Updated overall survival (OS) data from a global, randomized, open-label phase III study of atezolizumab (atezo) + bevacizumab (bev) versus sorafenib (sor) in patients (pts) with unresectable hepatocellular carcinoma (HCC).
Authors: Richard S. Finn, Shukui Qin, Masafumi Ikeda, Peter R. Galle, Michel Ducreux, Tae-You Kim, Ho Yeong Lim, Masatoshi Kudo, Valeriy Vladimirovich Breder, Philippe Merle, Ahmed Omar Kaseb, Daneng Li, Wendy Verret, Hui Shao, Juan Liu, Lindong Li, Andrew X. Zhu, Ann-Lii Cheng
Journal: Journal of Clinical Oncology (2021)

267 Background: Atezo + bev has been approved globally for pts with unresectable HCC who have not received prior systemic therapy, based on results from IMbrave150 (NCT03434379). At a median of 8.6 mo follow-up, both coprimary endpoints were met, with statistically significant and clinically meaningful improvements observed with atezo + bev vs sor for OS (HR, 0.58 [95% CI, 0.42, 0.79]; P&lt;0.001) and independently-assessed progression-free survival (PFS; per RECIST 1.1; HR, 0.59 [95% CI, 0.47, 0.76]; P&lt;0.001) (Finn, et al. N Engl J Med 2020). Here, we report an updated OS analysis for IMbrave150. Methods: The global, multicenter, randomized, open-label, Phase III study IMbrave150 enrolled 501 systemic treatment–naive pts with unresectable HCC, ≥1 measurable untreated lesion (RECIST 1.1), Child-Pugh class A liver function and ECOG PS 0/1. Pts were randomized 2:1 to receive either atezo 1200 mg IV q3w + bev 15 mg/kg IV q3w or sor 400 mg bid until unacceptable toxicity or loss of clinical benefit per investigator. This post hoc, descriptive OS analysis was conducted with 12 mo of additional follow up from the primary analysis. Results: 501 pts were enrolled, including 336 to atezo + bev and 165 to sor. At the clinical cut-off date of Aug 31, 2020, median follow-up was 15.6 mo and 280 OS events were observed. Median OS was 19.2 mo with atezo + bev vs 13.4 mo with sor (HR, 0.66 [95% CI, 0.52, 0.85]; P=0.0009). Survival at 18 mo was 52% with atezo + bev and 40% with sor. Survival benefit with atezo + bev over sor was generally consistent across subgroups and with the primary analysis. The updated objective response rate (ORR; 29.8% per RECIST 1.1) with atezo + bev was in line with the primary analysis, with more pts achieving complete response (CR; 7.7%) than previously reported. Additional response data are in Table. Safety was aligned with the primary analysis, with no new signals identified. Conclusions: IMbrave150 showed consistent clinically meaningful treatment benefit and safety with 12 mo of additional follow-up. The combination provides the longest survival seen in a front-line Phase III study in advanced HCC, confirming atezo + bev as a standard of care for previously untreated, unresectable HCC. Clinical trial information: NCT03434379. [Table: see text]
Drugging the “Undruggable” MYCN Oncogenic Transcription Factor: Overcoming Previous Obstacles to Impact Childhood Cancers
Authors: Adam J. Wolpaw, Richard Bayliss, Gabriele Büchel, Chi V. Dang, Martin Eilers, W. Clay Gustafson, Gwenn H. Hansen, Natalia Jura, Stefan Knapp, Mark A. Lemmon, David Levens, John M. Maris, Ronen Marmorstein, Steven J. Metallo, Julie R. Park, Linda Z. Penn, Michael Rape, Martine F. Roussel, Kevan M. Shokat, William P. Tansey, Kliment A. Verba, Seychelle M. Vos, William A. Weiss, Elmar Wolf, Yaël P. Mossé
Journal: Cancer Research (2021)

Abstract Effective treatment of pediatric solid tumors has been hampered by the predominance of currently “undruggable” driver transcription factors. Improving outcomes while decreasing the toxicity of treatment necessitates the development of novel agents that can directly inhibit or degrade these elusive targets. MYCN in pediatric neural-derived tumors, including neuroblastoma and medulloblastoma, is a paradigmatic example of this problem. Attempts to directly and specifically target MYCN have failed due to its similarity to MYC, the unstructured nature of MYC family proteins in their monomeric form, the lack of an understanding of MYCN-interacting proteins and ability to test their relevance in vivo, the inability to obtain structural information on MYCN protein complexes, and the challenges of using traditional small molecules to inhibit protein–protein or protein–DNA interactions. However, there is now promise for directly targeting MYCN based on scientific and technological advances on all of these fronts. Here, we discuss prior challenges and the reasons for renewed optimism in directly targeting this “undruggable” transcription factor, which we hope will lead to improved outcomes for patients with pediatric cancer and create a framework for targeting driver oncoproteins regulating gene transcription.
SP0065 Fibromyalgia: pain management strategies
Authors: C Cedraschi, J Desmeules, TL Vischer
Journal: Annals of the Rheumatic Diseases (2001)

<h3></h3> At present, there is no specific treatment for FM, partly because of the lack of understanding of its aetiology and pathogenesis. Self-management based programs have been proposed to help the patients cope with their symptoms and improve their quality of life. These programs mainly use information, physical conditioning, and cognitive-behavioural techniques. Information in chronic pain patients has been emphasised as an important component as a well-informed patient is an essential member of a successful chronic illness management team. Acknowledging FM patients’ pain and suffering is also a key point in these programs. FM patients have been shown to have functional impairment which include their ability to perform daily activities. They have decreased muscle strength and endurance, and low levels of physical fitness. Exercise programs are various and may include range-of-motion exercises, cycling, walking, swimming, specific muscular reinforcement, etc. Pool exercises have been used in various programs, as part of the training schedule or as a warming-down/relaxation procedure after an exercise session. Along with walking, warm water activities are best tolerated, but there are no contra-indications to endurance activities. Compliance has been described as one of the major problems in exercise programs for FM patients. An inactive lifestyle is associated with poor physical fitness, and pain may further discourage participation in physical activities. If exercises are started in the deconditioned body, the unaccustomed physical activity may lead to more complaints and to further avoidance of physical activity. A vicious circle leading to less and less activity may ensue. This vicious circle is probably one of the reasons of low rates of volunteering, poor compliance with the program and/or program follow-up prescriptions, or drop-outs. Self-management based programs will be illustrated with examples drawn from the literature and from our experience in Geneva.
Primary Pulmonary Hypertension
Authors: C. A. WAGENVOORT, NOEKE WAGENVOORT
Journal: Circulation (1970)

Morphologic and morphometric studies were carried out on pulmonary vessels in lung tissue from 156 patients, for whom a diagnosis of primary pulmonary hypertension had been made. This material was collected from 51 medical centers. Chronic pulmonary thromboembolism can be recognized by organizing thrombi, patchy intimal fibrosis, and intra-arterial septa. The media is only slightly thicker than normal; in 31 of the 156 cases the vascular lesions corresponded to this pattern. Other conditions such as chronic pulmonary venous hypertension, pulmonary veno-occlusive disease, sarcoidosis, chronic bronchitis, and pulmonary schistosomiasis could also be classified from the morphologic criteria. The largest group comprised 110 cases showing medial hypertrophy, laminar intimal fibrosis, and often fibrinoid necrosis, arteritis, and plexiform lesions. These alterations suggest that they were initiated by vasoconstriction. In children the sex ratio is equal; in adults there are almost four females to one male. In these patients with vasoconstrictive primary pulmonary hypertension, various stimuli are likely to bring about vasoconstriction in the presence of a pronounced pulmonary vascular hyperreactivity. A review of 602 cases from the literature is given.
Impact of the lockdown in an externalized HCV linkage-to-care model focusing on PWID patients with ongoing high risk practices
Authors: S. Lens, A. Miralpeix, M. Gálvez, E. Martró, N. González, S. Rodríguez-Tajes, Z. Mariño, V. Saludes, J. Reyes-Urueña, X. Majó, J. Colom, X. Forns
Journal: Hepatology (2020)

Background: The lockdown during the COVID-19 pandemic had an strong impact on the management of patients with liver diseases in Spain We analyzed the impact of the lockdown period on PWID with ongoing high-risk practices attending an externalized hepatology outpatient clinic at the biggest harm reduction center (HRC) in Barcelona Methods: On site HCV point-of-care screening for HCV-IgG antibody and HCV-RNA (GenXpert®), liver stiffness measurement (LSM), antiviral therapy delivery and sustained virological response (SVR12) assessment were performed at the HRC Dried blood spot (DBS) was collected at baseline, SVR12 and every 6 months in order to differentiate relapse vs reinfection Adherence was assessed by daily or weekly visits The program included educative and harm-reduction interventions Results: Before the lockdown 845 individuals had been prospectively enrolled in the program Of these, 386 (46%) accepted HCV screening, of whom 212 (55%) were HCV-RNA positive Of the 149 (70%) individuals who already started treatment, median (P25-P75) age was 42 years (35-47), 86% were male, 45% foreigners, 33% homeless, 73% unemployed and 62% had been imprisoned before At enrolment, 72% injected daily (55% more than once a day) In regard to high risk practices, 30% reported either needle or paraphernalia sharing and 38% unprotected sexual relationships Baseline LSM values were 6 (4 9-7 6) kPa with 12% patients having advanced fibrosis (>9 5 kPa)  All patients received pan-genotypic antiviral therapy either 8 or 12 weeks During Spain's lockdown period the center's attendance was reduced from 300 users/day to 70 users/day and the program recruitment rate from 6 6 to 1 3 individuals/day No patient initiated antiviral therapy during this period Overall 34 (28%) missed their follow-up visits during this period, including 4/10 patients under ongoing antiviral therapy The overall reinfection rate was 16/100 patients/year, 4(23%) happened after lockdown Although there was an increase in the use of drugs on the street/at home, 50% reduced the injection frequency during the lockdown period Conclusion: This patient-centered circuit demonstrates that HCV treatment can be successfully delivered to active PWID with high-risk practices However, the lockdown had a negative impact on loses to follow-up and also altered drug consumption habits, supporting the role of specific interventions
Addressing Stroke Risk in a Patient with CREST Syndrome and Atrial Fibrillation with Left Atrial appendage Occluder Device (WATCHMAN)
Authors: Ali Alkhayru
Journal: Clinical Cardiology and Cardiovascular Interventions (2021)

CREST syndrome is rare autoimmune disease causing calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly and telangiectasias. We present a case of an eighty-two year old female with CREST syndrome who presented to our clinic with atrial fibrillation and prohibitive bleeding risk. Managing stroke risk in atrial fibrillation is essential to minimize the morbidity and mortality of the condition. Those with CREST syndrome presenting with recurrent gastrointestinal bleeding may require alternatives to anticoagulation. Recently, the left atrial appendage occluder device became widely used to manage patients at increased risk for bleeding. The device provides a safe and efficacious alternative in lowering atrial fibrillation associated stroke risk. Our patient underwent uncomplicated implantation of the left atrial appendage occluder device. She was closely monitored for one year where she remained stroke free and had one minor episode of gastrointestinal hemorrhage.
Psychotic illness in ethnic groups
Authors: N. Airey
Journal: BMJ (1995)

health care and its evaluation have led to the expectation that studies of use of health services will become prominent.It would be deplorable if unreasonable procedures regarding access to data were to hinder practical applications of health record linkage.Some people will undoubtedly argue that the consent of each subject should be obtained for any procedure that links records.We believe that governments, as custodians of health care data- bases, have a duty to allow scientific investigators access to them in view of the benefits that have resulted from previous studies based on these databases.A requirement for individual consent would lead to the extinction of useful research using health care databases.
Phase I Study of Elacestrant (RAD1901), a Novel Selective Estrogen Receptor Degrader, in ER-Positive, HER2-Negative Advanced Breast Cancer
Authors: Aditya Bardia, Virginia Kaklamani, Sharon Wilks, Amy Weise, Donald Richards, Wael Harb, Cynthia Osborne, Robert Wesolowski, Meghan Karuturi, Paul Conkling, Rebecca G. Bagley, Yamei Wang, Maureen G. Conlan, Peter Kabos
Journal: Journal of Clinical Oncology (2021)

This phase I study (RAD1901-005; NCT02338349) evaluated elacestrant, an investigational oral selective estrogen receptor degrader (SERD), in heavily pretreated women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer, including those with estrogen receptor gene alpha (
Antibody-mediated depletion of viral reservoirs is limited in SIV-infected macaques treated early with antiretroviral therapy
Authors: Adrienne E. Swanstrom, Taina T. Immonen, Kelli Oswald, Cathi Pyle, James A. Thomas, William J. Bosche, Lorna Silipino, Michael Hull, Laura Newman, Vicky Coalter, Adam Wiles, Rodney Wiles, Jacob Kiser, David R. Morcock, Rebecca Shoemaker, Randy Fast, Matthew W. Breed, Joshua Kramer, Duncan Donohue, Tyler Malys, Christine M. Fennessey, Charles M. Trubey, Claire Deleage, Jacob D. Estes, Jeffrey D. Lifson, Brandon F. Keele, Gregory Q. Del Prete
Journal: Journal of Clinical Investigation (2021)

The effectiveness of virus-specific strategies, including administered HIV-specific mAbs, to target cells that persistently harbor latent, rebound-competent HIV genomes during combination antiretroviral therapy (cART) has been limited by inefficient induction of viral protein expression. To examine antibody-mediated viral reservoir targeting without a need for viral induction, we used an anti-CD4 mAb to deplete both infected and uninfected CD4+ T cells. Ten rhesus macaques infected with barcoded SIVmac239M received cART for 93 weeks starting 4 days after infection. During cART, 5 animals received 5 to 6 anti-CD4 antibody administrations and CD4+ T cell populations were then allowed 1 year on cART to recover. Despite profound CD4+ T cell depletion in blood and lymph nodes, time to viral rebound following cART cessation was not significantly delayed in anti-CD4-treated animals compared with controls. Viral reactivation rates, determined based on rebounding SIVmac239M clonotype proportions, also were not significantly different in CD4-depleted animals. Notably, antibody-mediated depletion was limited in rectal tissue and negligible in lymphoid follicles. These results suggest that, even if robust viral reactivation can be achieved, antibody-mediated viral reservoir depletion may be limited in key tissue sites.
17β-estradiol and estrogen receptor α protect right ventricular function in pulmonary hypertension via BMPR2 and apelin
Authors: Andrea L. Frump, Marjorie Albrecht, Bakhtiyor Yakubov, Sandra Breuils-Bonnet, Valérie Nadeau, Eve Tremblay, Francois Potus, Junichi Omura, Todd Cook, Amanda Fisher, Brooke Rodriguez, R. Dale Brown, Kurt R. Stenmark, C. Dustin Rubinstein, Kathy Krentz, Diana M. Tabima, Rongbo Li, Xin Sun, Naomi C. Chesler, Steeve Provencher, Sebastien Bonnet, Tim Lahm
Journal: Journal of Clinical Investigation (2021)

Women with pulmonary arterial hypertension (PAH) exhibit better right ventricular (RV) function and survival than men; however, the underlying mechanisms are unknown. We hypothesized that 17β-estradiol (E2), through estrogen receptor α (ER-α), attenuates PAH-induced RV failure (RVF) by upregulating the procontractile and prosurvival peptide apelin via a BMPR2-dependent mechanism. We found that ER-α and apelin expression were decreased in RV homogenates from patients with RVF and from rats with maladaptive (but not adaptive) RV remodeling. RV cardiomyocyte apelin abundance increased in vivo or in vitro after treatment with E2 or ER-α agonist. Studies employing ER-α-null or ER-β-null mice, ER-α loss-of-function mutant rats, or siRNA demonstrated that ER-α is necessary for E2 to upregulate RV apelin. E2 and ER-α increased BMPR2 in pulmonary hypertension RVs and in isolated RV cardiomyocytes, associated with ER-α binding to the Bmpr2 promoter. BMPR2 is required for E2-mediated increases in apelin abundance, and both BMPR2 and apelin are necessary for E2 to exert RV-protective effects. E2 or ER-α agonist rescued monocrotaline pulmonary hypertension and restored RV apelin and BMPR2. We identified what we believe to be a novel cardioprotective E2/ER-α/BMPR2/apelin axis in the RV. Harnessing this axis may lead to novel RV-targeted therapies for PAH patients of either sex.
FRI0167 Clinicopathologic evaluation of nodular lesions of behÇet’s disease
Authors: C Demirkesen, N Tüzüner, C Mat, M Senocak, N Büyükbabani, Y Tüzün, H Yazici
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Among the cutaneous manifestations, nodular lesions are rather common in Behçet’s disease (BD). <h3>Objectives</h3> The histologic nature of these lesions has been a matter of controversy. <h3>Methods</h3> In order to establish their distinguishing features, biopsies taken from nodular lesions of 24 patients with BD, 25 with nodular vasculitis (NV), and 20 with erythema nodosum (EN) were compared. <h3>Results</h3> Statistical analysis revealed that there was insignificant difference between BD and NV. However, neutrophil predominating infiltrate in the subcutis was more common in BD, while necrosis and granuloma formation were encountered more frequently in NV. On the other hand, there was a statistically significant difference between BD and EN. Septal panniculitis, lymphocyte predominating infiltrate, absence of many vascular changes as well as vasculitis, and necrosis were features in favour of EN. <h3>Conclusion</h3> EN-like lesions of BD are mainly neutrophilic vascular reactions with accompanying changes in subcutis. Their histology are more similar to NV than EN. Thus suggests that these nodular lesions of BD may, indeed be due to vasculitis. On the other hand, the histologic feature of these nodular lesions has enough specificity to differentiate them from EN due to other causes. ?Copyright © 2001 by the American Society of Clinical Pathologists. Reprinted by Permission?
SP0042 Endothelial activation in inflammation and atherosclerosis
Authors: D Haskard, Dorian O Haskard
Journal: Annals of the Rheumatic Diseases (2001)

<h3></h3> Endothelial activation is an integral component of inflammatory rheumatic diseases, and also of atherosclerosis. Leukocytes emigrate from the blood into inflamed tissues through a series of adhesion events ("the adhesion cascade"), each of which is dependent upon the state of endothelial cell activation. Initial rolling of neutrophils on vascular endothelium is mediated by transient interactions between selectins (L-selectin on leukocytes, E-selectin on cytokine-activated endothelial cells (EC) and P-selectin on both activated EC and activated platelets) and carbohydrate-bearing counter-structures on the opposing cell. Whilst rolling, leukocytes become exposed to activating signals (such as chemokines), resulting in an upregulation of the capacity of b2 integrins (eg LFA-1, Mac-1) to bind ligands (eg ICAM-1, -2) on EC. This integrin-mediated secondary adhesion results in leukocyte arrest and is followed by their transmigration into the tissues. In the case of mononuclear cells, adhesion of a4 integrins to EC ligands (eg VCAM-1) may contribute to both the rolling and firm adhesion stages of their interaction with EC. The talk will focus on comparisons between inflammatory rheumatic diseases and atherosclerosis, and will discuss recent technical advances that have allowed an improved understanding of the patterns of endothelial activation and adhesion molecule expression that occur in acute and chronic inflammatory settings.