julilili42/papers huggingface dataset:
439 Primary symptoms in women with different histopathological subtypes of gynaecological sarcoma – results of a prospective intergroup registry for gynaecological sarcoma (REGSA – NOGGO RU1)
2020-11-01

<h3>Introduction</h3> Gynaecological sarcomas are rare and there is very limited evidence about symptoms at primary diagnosis. Most knowledge is based on retrospective analysis. <h3>Methods</h3> We present data of 410 patients (pts) in the primary situation. Overall, 87.91% of pts had documented symptom data, which were analysed descriptively. A distinction was made between pre- (prem., ≤52 yrs) and postmenopausal (postm., &gt;52 yrs.). <h3>Results</h3> The average age of pts was 56 yrs (range 15–88 yrs). Leiomyosarcoma (LMS) was diagnosed in 44.7%, endometrial stromal sarcoma (ESS) in 26.6% (62.6% low grade (LG-ESS) and 37.4% high grade (HG-ESS)). Undifferentiated sarcoma (US) and adenosarcoma (AS) were observed in 5.7% and 8.7% respectively. In prem. and postm. pts with LMS, the leading symptom (LS) was abdominal pain (ap) in 34.4%. and 39.5% respectively. In prem. HG-ESS the LS were ap and bleeding disorders (bd) in both 33.3%. In postm. HG-ESS and prem. LG-ESS the LS was vaginal bleeding (vb) in 29% and 33.3% respectively. In prem. AS the LS was ap in 27.3%, whereas in postm. AS it was postmenopausal bleeding (pb) in 29.2%. In prem. US the LS were bd and vb both at 66.7%. In postm. US the LS was ap in 47.4%. <h3>Conclusions</h3> We analyzed the LS of different histopathological subtypes in primary gynaecological sarcoma for the first time. Bleeding disorders and abdominal pain are the main symptoms in all subtypes. Symptoms are heterogeneous and about every 5th woman reported unspecific symptoms. This underlines the importance of awareness for gynaecological sarcoma.
454 Study in progress: international retrospective study on lymphadenectomy in endometrioid ovarian carcinoma patients with early stage disease (LEOPARD)
2020-11-01

<h3>Introduction</h3> The benefit of systematic lymphadenectomy (LNE) in low-stage, low-grade ovarian carcinoma is unknown. However, most guidelines still recommend LNE in these patients. Prior studies examining the benefit of this invasive procedure have been hampered small numbers, and large-scale studies that consider modern classification are needed. <h3>Methods</h3> A cohort of 666 pathology-reviewed and immunohistochemistry-validated endometrioid ovarian carcinomas has recently been evaluated using endometrial carcinoma-inspired molecular subtyping. This molecularly characterized series is now being used to assess the value of LNE. Contributing centers are performing detailed chart reviews, so that surgical procedures and lymph node status can be correlated with molecular subtype and outcomes. <h3>Results</h3> 349 stage I, 181 stage II, 85 stage III, and 22 stage IV cases with a median OS follow-up of 6.11 years (RevKM) were collected from 17 centres across Canada and Europe. Analysis of the first 70/666 cases revealed positive nodes in only a single presumed low stage patient after systematic pelvic and paraaortic LNE (n=1/44). LNE was not performed in 3/44 and restricted to pelvic nodes in 6/44 low-stage cases, all of which were pN0. Tumor spread beyond the Uterus and/or Adnexa was associated with positive nodes in 33%. <h3>Conclusion</h3> Preliminary results indicate that abandonment of LNE in low-stage, low-grade endometrioid ovarian carcinoma may reduce morbidity without worsening prognosis for these patients. Completion and expansion of our international team initiative stands to provide a powerful statement on the value of LNE, and influence of molecular subtype on disease spread, possibly improving precision care for ovarian carcinoma patients.
344 Phase 3 trial of pembrolizumab and enzalutamide versus enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) (KEYNOTE-641)
2020-11-01

<h3>Background</h3> Antitumor activity with pembrolizumab + enzalutamide was observed in cohort C of the phase 1b/2 KEYNOTE-365 (NCT02861573) study of abiraterone acetate–pretreated patients with mCRPC and in a phase 2 study (NCT02312557) of patients with mCRPC who experienced progression with enzalutamide alone. In KEYNOTE-365 cohort C, prostate-specific antigen (PSA) response rate was 22%, objective response rate (ORR) was 20%, and 12-month PFS and OS rates were 24.6% and 72.8%, respectively. Safety and tolerability of the combination was consistent with individual profiles of each agent. In the phase 2 study of enzalutamide-pretreated patients, 5 of 28 patients (18%) had a PSA decline of ≥50%, and 3 of 12 patients (25%) with measurable disease achieved objective response. KEYNOTE-641 (NCT03834493) is a randomized, phase 3 trial to assess efficacy and safety of pembrolizumab + enzalutamide versus placebo + enzalutamide in patients with mCRPC. <h3>Methods</h3> Enrolled patients have biochemical or radiographic progression with androgen deprivation therapy/after bilateral orchiectomy within 6 months of screening, ECOG PS 0/1, ongoing androgen deprivation with serum testosterone &lt;50 ng/dL, and tumor tissue availability for biomarker analysis. The study continues to enroll those who previously had abiraterone acetate therapy; the abiraterone-naive cohort is filled. Exclusion criteria are prior chemotherapy for mCRPC, checkpoint inhibition, or any treatment with a second-generation androgen receptor inhibitor. Treatment stratification factors are prior abiraterone acetate treatment (yes or no), metastases location (bone only or liver or other), and prior docetaxel treatment for metastatic hormone-sensitive prostate cancer (yes or no). Response and progression will be determined by imaging (CT/MRI/bone) per PCWG3–modified RECIST v1.1 on visits Q9W during the first year and Q12W thereafter. Approximately 1200 adults will be randomly assigned 1:1 in a double-blind fashion to receive enzalutamide 160 mg orally once daily + pembrolizumab 200 mg IV Q3W or enzalutamide 160 mg orally once daily + placebo for a maximum of 35 cycles or until disease progression, unacceptable toxicity, or consent withdrawal. Coprimary end points are radiographic PFS per PCWG3-modified RECIST v1.1, as assessed by blinded independent central review, and OS. The key secondary end point is time to subsequent anticancer therapy or death. Other secondary end points are ORR, DOR, PSA response rate, PSA undetectable rate, time to PSA progression, time to pain progression, time to symptomatic skeletal-related event, time to soft tissue progression, and safety. KEYNOTE-641 is ongoing or planned in 21 countries across Asia, Australia, Europe, and North and South America. <h3>Results</h3> N/A <h3>Conclusions</h3> N/A <h3>Trial Registration</h3> ClinicalTrials. gov, NCT03834493 <h3>Ethics Approval</h3> The study and the protocol were approved by the Institutional Review Board or ethics committee at each site.
779 Immune checkpoint blockade impacts the suppressive phenotype and function of regulatory T cells in an endogenous mouse lymphoma model
2020-11-01

<h3>Background</h3> Antibodies against programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) have become established part of anti-cancer therapy. However, the mechanisms contributing to the therapeutic success have not been entirely uncovered by now. Here we focus on the impact of PD-1/CTLA-4-blocking antibodies on regulatory T cells (Tregs), which are known to be involved in tumor immune evasion in many cancer types. <h3>Methods</h3> To evaluate how Tregs are affected by anti-PD-1/CTLA-4 therapy, we used a MYC-transgenic mouse model of spontaneously arising B-cell lymphoma, which can be effectively treated by immune checkpoint inhibition. Data were acquired by flow cytometry. <h3>Results</h3> As earlier shown, Tregs were involved in immune escape of MYC tumors. The Treg to effector T cell (Teff) ratio was elevated within the CD4-positive cell compartment. Tumor-infiltrating Tregs were predominantly thymic Tregs, which recognized overexpressed tumor-derived self-peptides in an MHC class II-restricted manner and showed upregulated expression of activation markers, Foxp3, CD25 and IL-10. To examine whether these phenotypic alterations correlated with the immunosuppressive capability of Tregs, an in vitro suppression assay was established. In this setting, MYC Tregs turned out to suppress proliferation and IFN-γ release of Teff cells more effectively than wildtype Tregs. The suppression observed in vitro was mediated by cell contacts and IL-10. Further suppressive mechanisms are likely to play a role, such as competition for MHC-II ligands and a consumption of IL-2. To investigate if immune checkpoint blockade interferes with these Treg-dependent immunosuppressive pathways, MYC mice were treated with a combination of anti-PD-1 and anti-CTLA-4 antibodies. Tregs from treated MYC mice showed decreased expression of CD69, CD137, Foxp3, CD25 and IL-10 as compared to Tregs from untreated MYC mice. This correlated with a lower suppressive capacity of Tregs from treated animals in the in vitro suppression assay. <h3>Conclusions</h3> Taken together, the data show that immune checkpoint blockade impairs the development of the suppressive phenotype of intratumoral Tregs. Thus, apart from the initially described Teff reactivation, other mechanisms are also relevant for unfolding the therapeutic effect of immune checkpoint inhibitors. <h3>Ethics Approval</h3> All animal experiments were approved by Regierung von Oberbayern, approval number 55.2-1-54.
267 Histopathologic ultrastaging of sentinel lymph nodes in endometrial carcinoma: A retrospective analysis of the tuebingen women’s hospital 2006-2016 patient cohort
2020-11-01

<h3>Introduction</h3> Lymph node metastases are considered a major risk factor in endometrial carcinoma patient management and nodal assessment is an integral part of staging. While still under investigation sentinel node biopsy has been established in many centers. It has been shown that histopathologic ultrastaging leads to an increased detection of isolated tumor cells (ITC) and micrometastases (MIC). However, the clinical impact of ITC and MIC is not yet clearly defined. The aim of this study was to retrospectively perform histopathologic ultrastaging in a large series of endometrial carcinoma patients all of which have been treated at the Tuebingen University Women's Hospital. <h3>Method</h3> Patients with sentinel node biopsy during endometrial carcinoma surgery were identified. All cases with negative sentinel nodes, were submitted to retrospective histopathologic ultrastaging (5 × 100μm intervals followed by 500μm sections and immunohistochemical pancytokeratine staining of the entire lymphnode). <h3>Results</h3> A total of n=159 cases was available, of which in 5/159 (3.0%) case positive nodes were detected during initial routine pathology workup (pT1a,G3: n=1; pT1b,G1: n=1; pT1b,G3: n=2; pT2,G2: n=1). After retrospective ultrastaging additional micrometastases were identified in n=3 cases (pT1a,G1; pT1a,G2; pT1a,G3), isolated tumor cells in n=2 cases (pT1a,G3; pT1b,G3), a macrometastasis was revealed in one case (pT1b,G3). Overall 11/159 cases (6,7%) were finally reported positive. <h3>Conclusion</h3> In our cohort histopathologic ultrastaging of endometrial carcinoma sentinel nodes led to a substantially increased detection rate of nodes with isolated tumor cells, micro- and macrometastases. We suggest that histopathologic ultrastaging should be mandatory in endometrial carcinoma sentinel lymph node workup.
Mechanisms of angina in patients with biopsy-proven viral myocarditis: insights from intracoronary acetylcholine testing
2020-11-01

Abstract Background Patients with myocarditis often present with angina pectoris despite unobstructed coronary arteries. The underlying pathophysiological mechanism of angina in these patients remains to be elucidated. Coronary artery spasm is a well-known cause of angina in patients with unobstructed coronary arteries. In this study, we sought to assess the frequency of coronary vasomotor disorders in patients with biopsy-proven viral myocarditis. Methods In total, 700 consecutive patients who underwent endomyocardial biopsy for suspected myocarditis between 2008 and 2018 were retrospectively screened. Of these patients, viral myocarditis was confirmed in 303 patients defined as histological/immunohistological evidence of myocardial inflammation and presence of viral genome confirmed by PCR. Of these patients, 34 patients had angina despite unobstructed coronary arteries and underwent intracoronary acetylcholine (ACh) provocation testing in search of coronary spasm. Epicardial spasm was defined as acetylcholine-induced reproduction of the patient's symptoms associated with ischemic ECG changes and &amp;gt;90% epicardial vasoconstriction. Microvascular spasm was defined as symptom reproduction and ECG changes in the absence of significant epicardial vasoconstriction. Results Patients were 49±16 years old, 62% were male and left ventricular ejection fraction was 54±16%. Most frequent viruses were parvovirus B19 (PVB19, 59%) and human herpes virus 6 (HHV6, 26%), 2 patients had combined PVB19/HHV6 infection and 3 patients other herpesviruses (CMV, EBV, VZV). Epicardial spasm was observed in 10 patients (29%) during ACh testing and microvascular spasm was found in 11 patients (32%). The rate of coronary spasm (epicardial and microvascular) was higher in the PVB19 subgroup compared to HHV6 (80% vs. 33%, p=0.031). In particular, there was a higher prevalence of microvascular spasm in PVB19 compared to HHV6 (45% vs. 0%, p=0.018). Conclusion We observed a high prevalence of microvascular and epicardial spasm in patients with biopsy-proven viral myocarditis suggesting coronary spasm as a potential underlying mechanism for angina in these patients. Microvascular spasm was most often observed in patients with PVB19-associated myocarditis. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Robert-Bosch-Stiftung; Berthold-Leibinger-Stiftung
Impact of left atrial diameter on outcome in patients undergoing edge-to-edge mitral valve repair: results from the German TRAnscatheter Mitral valve Interventions registry (TRAMI)
2020-11-01

Abstract Background Left atrium (LA) dimension is a marker of disease severity and outcome in primary and secondary mitral regurgitation. In transcatheter mitral valve repair LA enlargement might additionally impact on device handling and technical success through an altered anatomy and atrial annular dilatation. Methods Data from the multicenter German transcatheter mitral valve intervention registry “TRAMI” were used to analyse the association of baseline LA diameter by tertiles and efficacy, safety and long-term clinical outcome in patients undergoing edge-to-edge repair with the MitraClip. Results In 520 of 843 patients prospectively enrolled in TRAMI baseline LA diameter were reported (median [interquartile range] LA diameter in tertiles: 44 [40–46] mm, 51 [48–53] mm and 60 [55–66] mm). Larger LA diameters were significantly associated with secondary etiology of mitral regurgitation, lower ejection fraction, larger left ventricle, male sex and atrial fibrillation (all p&amp;lt;0.05). Technical success was not different across tertiles (96%, 95.4%, 98.4% respectively, p=0.43) as were major in-hospital cardiovascular and cerebral adverse events (mortality, myocardial infarction or stroke) (1.8%, 1.2% and 4.4%, p=0.11 across tertiles). However, 4-year mortality significantly increased with larger LA diameter (32.9%, 46.4% and 51.7% respectively, p&amp;lt;0.01), as did hospitalization in survivors (60%, 67.6% and 78.9% respectively, p&amp;lt;0.05). The association between LA diameter and all-cause mortality remained significant after multivariable adjustment including baseline left ventricular end-diastolic diameter. Conclusion LA enlargement is a strong and independent predictor of adverse long-term outcome in mitral regurgitation suggesting that timely transcatheter mitral valve repair may have the potential to modify outcome. Funding Acknowledgement Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): The TRAMI registry has been supported by proprietary means of IHF. Additional funding is provided by “Deutsche Herzstiftung” and a grant from Abbott Vascular.
Autoantibody-Mediated Changes in Platelets Sialic Pattern: Potential Impact on Platelet Functionality and Lifespan in Immune Thrombocytopenia
2020-11-01

Introduction Immune thrombocytopenia (ITP) is a bleeding disorder mediated by autoantibodies (AAbs) that are targeting different glycoproteins (GPs) on the platelet (PLT) surface. Desialylation, the loss of sialic acid from PLT GPs, has been reported to contribute to the increased PLT destruction in ITP. In this work, we investigated the impact of AAb-mediated desialylation on the function as well as apoptotic status of human platelets.
BIOM-59. TERT PROMOTER MUTATION AND MGMT PROMOTER METHYLATION-MEDIATED SENSITIVITY TO TEMOZOLOMIDE IN IDH-WILDTYPE GLIOBLASTOMA: IS THERE A LINK?
2020-11-01

Abstract BACKGROUND Benefit from temozolomide (TMZ) chemotherapy in the treatment of isocitrate dehydrogenase (IDH)-wildtype glioblastoma is essentially limited to patients with O6-methylguanine DNA methyltransferase (MGMT) promoter-methylated tumors. Recent studies suggest that the impact of the MGMT status on chemosensitivity may be modulated by telomerase reverse transcriptase (TERT) promoter hotspot mutations. METHODS MGMT promoter methylation and TERT promoter mutation status were assessed in an exploratory prospective cohort of IDH-wildtype glioblastoma patients of the German Glioma Network (GGN) (n=298) and validated in a retrospective cohort from Düsseldorf, Germany, and Zurich, Switzerland (n=302). RESULTS In the prospective GGN discovery cohort of patients with MGMT promoter-unmethylated tumors, TERT promoter mutation showed inferior outcome (p=0.044). In contrast, TERT promoter mutations were not associated with improved outcome in patients with MGMT promoter-methylated tumors. Different TERT promoter hotspot mutations were not associated with distinct outcomes. The association of TERT promoter mutation in MGMT promoter-unmethylated tumors was not confirmed in the retrospective validation cohort. CONCLUSIONS Analysis of two independent cohorts of glioblastoma patients, including the prospective GGN cohort, did not confirm previous data suggesting that TERT promoter mutations confer an enhanced benefit from TMZ in patients with MGMT promoter-methylated glioblastoma. Thus, diagnostic testing for TERT promoter mutations may not be required for prediction of TMZ sensitivity in IDH-wildtype glioblastoma patients.
Apoptosis Inhibition: A Promising Approach for Cold Storage of Apheresis Platelet Concentrates
2020-11-01

Introduction Transfusion of platelet concentrates is routinely used to treat or prevent bleeding. Bacterial infection caused by storage at room temperature (RT) still remains a major drawback of this established therapeutic approach. Recently, we showed that cold-stored APCs are associated with better PLT functionality, such as adhesion and aggregation ability, but also with shorter survival in vivo (Haematologica 2018, PMID: 30115655). Cold-induced apoptosis was identified as a potential mechanism of the accelerated PLT clearance. In this study, we investigated the protective effect of apoptotic inhibitors during cold storage of APCs.
Flow Cytometric Assessment of AKT Signaling in Platelet Activation: An Alternative Diagnostic Tool for Small Volumes of Blood
2020-11-01

Introduction The diagnosis of platelet function disorder in children is challenging. Light transmission aggregometry is the gold standard for platelet function disorders. However, large blood volumes are required. By now, there are no existing tools for diagnosis of platelet function disorders in small blood volumes. AKT signaling plays a key role in platelet activation during hemostasis and can be visualized by flow cytometry in small volumes of blood.
Combined Acquired Alpha- and Delta-Storage Pool Disease in Endstage Renal
2020-11-01

Background Bleeding due to platelet dysfunction can result from congenital or acquired defects. The laboratory approach to identify the pathogeneses of acquired platelet dysfunctions is challenging, especially in pediatric patients. A combination of immunofluorescent microscopy (IFM), flow cytometry (FC), and lumino-aggregometry (LA) may help establishing the right diagnosis.
Communication-related vulnerability to disasters: A heuristic framework
2020-11-02

The concept of social vulnerability has been increasingly applied in disaster literature, but its communicative drivers have remained understudied. In this article, we put forward a heuristic framework for explaining how communication-related factors may adversely affect people's capacity to prepare for and respond to disasters. This will help researchers, policy makers, and practitioners in the field of disasters and crises to systematically identify individual, social-structural, and situational factors of vulnerability that shape how people access, understand, and act upon information about hazards. We integrate ideas from recent literature on information disorders – various forms and effects of false or harmful information that are characteristic to modern communication ecosystems – to improve our understanding of how the new media environments may transform the ways people learn about hazards and cope with disasters.
Improvement of islet transplantation by the fusion of islet cells with functional blood vessels
2020-11-02

Pancreatic islet transplantation still represents a promising therapeutic strategy for curative treatment of type 1 diabetes mellitus. However, a limited number of organ donors and insufficient vascularization with islet engraftment failure restrict the successful transfer of this approach into clinical practice. To overcome these problems, we herein introduce a novel strategy for the generation of prevascularized islet organoids by the fusion of pancreatic islet cells with functional native microvessels. These insulin-secreting organoids exhibit a significantly higher angiogenic activity compared to freshly isolated islets, cultured islets, and non-prevascularized islet organoids. This is caused by paracrine signaling between the β-cells and the microvessels, mediated by insulin binding to its corresponding receptor on endothelial cells. In vivo, the prevascularized islet organoids are rapidly blood-perfused after transplantation by the interconnection of their autochthonous microvasculature with surrounding blood vessels. As a consequence, a lower number of islet grafts are required to restore normoglycemia in diabetic mice. Thus, prevascularized islet organoids may be used to improve the success rates of clinical islet transplantation.
Modern models of trophic meta-communities
2020-11-02

Dispersal and foodweb dynamics have long been studied in separate models. However, over the past decades, it has become abundantly clear that there are intricate interactions between local dynamics and spatial patterns. Trophic meta-communities, i.e. meta-foodwebs, are very complex systems that exhibit complex and often counterintuitive dynamics. Over the past decade, a broad range of modelling approaches have been used to study these systems. In this paper, we review these approaches and the insights that they have revealed. We focus particularly on recent papers that study trophic interactions in spatially extensive settings and highlight the common themes that emerged in different models. There is overwhelming evidence that dispersal (and particularly intermediate levels of dispersal) benefits the maintenance of biodiversity in several different ways. Moreover, some insights have been gained into the effect of different habitat topologies, but these results also show that the exact relationships are much more complex than previously thought, highlighting the need for further research in this area. This article is part of the theme issue ‘Integrative research perspectives on marine conservation’.