1,720,998 research outputs found
Dinutuximab beta versus naxitamab in the treatment of re-lapsed/refractory neuroblastoma in patients with stable disease, minor response or partial response and disease in bone or bone marrow: systematic review and matching-adjusted indirect comparison
No full textObjective: Dinutuximab beta (DB) and naxitamab (NAXI) with GM-CSF are used for maintenance treatment of relapsed/refractory neuroblastoma. The objective of this study was to systematically assess comparative efficacy of the two therapies within their designated indications in accordance with established clinical guidelines. Methods: Relevant evidence was identified in systematic literature review. Individual patient data (IPD) from prospective clinical trials of DB were assessed and data on patients with disease in bone or bone marrow, as assessed in MRI, CT, mIBG or biopsy, with incomplete response to previous therapy were included. Patients with complete response, progressive disease and/or soft tissue disease were excluded. DB population was adjusted for sex, MYCN amplification, disease type (relapsed, refractory), and disease site (bone marrow and/or bone) to balance aggregated characteristics of NAXI population. More characteristics were included in sensitivity analyses, including DB treatment without interleukin-2, as currently recommended. Overall response rate (ORR) was assessed as best response. Results: Aggregated data for NAXI from Study 201 (n = 52) and Study 230 (n = 38) and IPD from DB studies (APN311-202, APN311-304, c = 77) met the inclusion criteria. Compared to NAXI, DB significantly extended progression-free survival (PFS): hazard ratio, DB vs. NAXI of 0.47 (95% CI: 0.26 to 0.87, p = 0.015). ORR was 60.1% (95% CI: 48.5% to 71.6%) for DB vs. 43.3% (33.1% to 53.6%) for NAXI (ORR odds ratio, DB vs. NAXI was 1.97, 95% CI: 1.02 to 3.80, p = 0.044). Sensitivity analyses and unadjusted comparisons supported the results. Conclusion: In the indirect comparison, dinutuximab beta significantly extended PFS and increased ORR compared to naxitamab.</p
Fcγ receptor polymorphism in relapsed/refractory high-risk neuroblastoma patients correlates with outcomes in the SIOPEN dinutuximab beta long-term infusion trial
No full textPurpose: to identify a tolerable dinutuximab beta long-term infusion (LTI) schedule with immunomodulatory activity for relapsed/refractory high-risk neuroblastoma. Patients and methods: in this Phase I/II trial, dinutuximab beta LTI (five 35-day cycles) with subcutaneous interleukin-2 was evaluated in high-risk neuroblastoma cohorts (1x exploratory, 2x confirmatory). The composite primary endpoint was >80% patients free of intravenous morphine by day 5/cycle 1 plus ≥100 natural killer cells/μL and ≥1 μg/mL dinutuximab beta concentration by day 15/cycle 1. Secondary endpoints included objective response rate, event-free survival, overall survival, Fc-gamma receptor polymorphisms, and natural killer cells. Results: overall, 122 patients were treated. At 10 mg/m2/day dinutuximab beta LTI, 95% patients (22/24 exploratory cohort; 20/20 confirmatory cohort 1) achieved the composite primary endpoint, with ≥80% patients intravenous morphine-free by day 5/cycle 1. End-of-treatment objective response rate was 45% in 78 evaluable patients. Two-year event-free survival and overall survival were 56% (±4%) and 73% (±4%) overall; and 45% (±5%) and 65% (±5%) in relapsed/refractory disease, respectively. Two-year survival rates were greater in patients with high-affinity Fc-gamma receptor polymorphisms and high-level natural killer cells versus patients with low-affinity Fc-gamma receptor polymorphisms and low-level natural killer cells (event-free survival, 79% [±9%] vs 35% [±11%], p=0.009; overall survival, 84% [±8%] vs 70% [±10%]; p=0.083). Multivariate analysis identified age >5 years, low-affinity Fc-gamma receptor polymorphisms, and relapse/refractory disease as independent risk factors.Conclusion: dinutuximab beta LTI was well tolerated and clinically active in patients with relapsed/refractory high-risk neuroblastoma, with Fc-gamma receptor polymorphisms and natural killer cells identified as prognostic biomarkers
Development of immunomonitoring of antibody-dependent cellular cytotoxicity against neuroblastoma cells using whole blood
No full textNeuroblastoma, a childhood tumour of neuroectodermal origin, accounts for 15 % of paediatric cancer deaths, which is often metastatic at diagnosis and despite aggressive therapies, it has poor long-term prognosis with high risk of recurrence. Monoclonal antibody (mAb) therapy targeting GD2, a disialoganglioside expressed on neuroblastoma, has shown promise in recent trials with natural killer cell (NK)-mediated antibody-dependent cellular cytotoxicity (ADCC) thought to be central to efficacy, although other immune effectors may be important. To further enhance therapy, immunomonitoring of patients is essential to elucidate the in vivo mechanisms of action and provides surrogate end points of efficacy for future clinical trials. Our aim was to establish a ‘real-time’ ex vivo whole-blood (WB) immunomonitoring strategy to perform within the logistical constraints such as limited sample volumes, anticoagulant effects, sample stability and shipping time. A fluorescent dye release assay measuring target cell lysis was coupled with flow cytometry to monitor specific effector response. Significant target cell lysis with anti-GD2 antibody (p < 0.05) was abrogated following NK depletion. NK up-regulation of CD107a and CD69 positively correlated with target cell lysis (r > 0.6). The ADCC activity of WB correlated with peripheral blood mononuclear cells (r > 0.95), although WB showed overall greater target cell lysis attributed to the combination of NK-mediated ADCC, CD16+ granulocyte degranulation and complement-dependent cytotoxicity. Response was maintained in heparinised samples stored for 24 h at room temperature, but not 4 °C. Critically, the assay showed good reproducibility (mean % CV < 6.4) and was successfully applied to primary neuroblastoma samples. As such, WB provides a resourceful analysis of multiple mechanisms for efficient end point monitoring to correlate immune modulation with clinical outcome
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
DNA-Vakzinierung mit Tyrosinhydroxylase-Impfstoffen zur aktiven Immuntherapie des Neuroblastoms
Full text linkDas Neuroblastom ist der am weitesten verbreitete solide, extrakranielle Tumor im Kindesalter. Trotz intensiver Forschung sind die Überlebensraten von Patienten mit fortgeschrittenem Tumorwachstum nach wie vor schlecht. Die Idee, eine zelluläre, langanhaltende Immunantwort im Körper zu induzieren, vermittelt durch zytotoxische CD8+T-Zellen, die sich gegen den Tumor richten, scheint dabei besonders attraktiv. Als tumorassoziiertes Antigen (TAA) wurde zu diesem Zweck für diese Arbeit die murine Tyrosinhydroxylase (mTH), das Schrittmacherenzym der Katecholaminbiosynthese, gewählt, da sie in der Mehrzahl der Neuroblastome stark überexprimiert ist. Für die Impfexperimente wurden sog. DNA-Minigen-Vakzine, die für Peptide aus der mTH-Sequenz kodieren, konstruiert. Die Auswahl Minigen-Peptide erfolgte mit dem MHC-Klasse-I-Liganden-Vorhersageprogramm syfpeithi, welches drei vorhergesagte starke H2-Kk-Liganden lieferte (mTH3k). Außerdem wurden zwei weitere Vakzine hergestellt: als Negativkontrolle das Vakzin mTHlowest, dessen mTH-Peptide laut syfpeithi schlechte MHC-Klasse-I-Liganden darstellen und das Vakzin Ersatzepis, dessen Peptide auf der Oberfläche von murinen NXS2-Neuroblastomzellen aus MHC-Klasse-I-Komplexen isoliert werden konnten. Sowohl in prophylaktischen als auch therapeutischen Impfversuchen in Mäusen konnte das Tumorwachstum und die spontane Metastasierung in sekundäre Organe wie die Leber signifikant verhindert werden. Außerdem konnte gezeigt werden, daß der Antitumoreffekt auf der Induktion mTH-spezifischer, zytotoxischer CD8+T Zellen (CTLs) beruht. Zusätzlich und insbesondere interessant für eine eventuelle klinische Anwendung eines auf der TH basierenden DNA-Vakzins verursachte das mTH-Minigen-Vakzin zumindest in Mäusen keine Aktivierung selbst-reaktiver CD8+T-Zellen. Alles in allem lassen die in dieser Arbeit erhaltenen Ergebnisse den Schluß zu, daß sich die Tyrosinhydroxylase als TAA in Form eines DNA-Vakzins zur adjuvanten Therapie des Neuroblastoms eignet.Therapeutic vaccination against tumor antigens without induction of autoimmunity remains a major challenge in cancer immunotherapy. Here, we demonstrate for the first time effective therapeutic vaccination followed by eradication of established spontaneous neuroblastoma metastases using a tyrosine hydroxylase (TH) DNA minigene vaccine. We identified three novel mouse TH (mTH3) derived peptides with high predicted binding affinity to MHC class I H2-Kk according to prediction program syfpeithi and computer modeling of epitopes into MHC class I binding groove. Subsequently, a DNA minigene vaccine based on pCMV-F3Ub encoding for mutated ubiquitin (G76 to A76) and mTH3 was generated. Prophylactic and therapeutic efficacy of this vaccine was established following oral delivery using attenuated Salmonella typhimurium SL7207. Only mice immunized with mTH3 were free of spontaneous liver metastases. This effect was clearly dependant on ubiquitin and high affinity of the mTH epitopes to MHC class I. Specifically, we demonstrated a crucial role for minigene expression as a stable ubiquitin-Ala76 fusion peptide for vaccine efficacy. Interestingly, the unstable wild type ubiquitin-Gly76 vaccine was completely ineffective. The immune response following mTH3 DNA minigene vaccination was mediated by CD8+ T-cells as indicated by infiltration of primary tumors and TH specific cytolytic activity in vitro. Importantly, no infiltration was detectable in TH expressing adrenal medulla, indicating the absence of auto immunity. In summary, we demonstrate effective therapeutic vaccination against neuroblastoma with a novel rationally designed tyrosine hydroxylase minigene vaccine without induction of autoimmunity providing an important base line for clinical application of this strategy
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Mechanism and efficacy of a GD2-specific immunotherapy using NK cells
Full text linkDas Neuroblastom (NB) ist ein solider, extrakranieller Tumor neuroektodermalen Ursprungs, der sich im Kleinkindalter manifestiert. Ein etabliertes Zielantigen für die passive Immuntherapie beim NB ist das Disialogangliosid GD2. Aufgrund der geringen oder fehlenden Expression von MHC Klasse I Molekülen sowie der Tatsache, dass die Lyse von NB-Zellen durch verschiedene Mechanismen der natürlichen Zytotoxizität von NK-Zellen vermittelt werden kann, stellt eine auf NK-Zellen basierende Therapie einen vielversprechenden Ansatz zur Behandlung dieser Erkrankung dar. Auf dieser Grundlage wurde eine NK-Zelllinie generiert, die einen GD2-spezifischen chimären Antigenrezeptor (CAR) exprimiert (NK-92-scFv(ch14.18)-zeta). Die Hauptbestandteile dieses CARs sind ein Einzelkettenantikörper, welcher die variablen Regionen des GD2-spezifischen Antikörpers ch14.18 enthält, und die CD3ζ-Kette als signaltransduzierende Komponente. Im Rahmen dieser Arbeit konnte gezeigt werden, dass NK-92-scFv(ch14.18)-zeta in der Lage sind, auch Chemotherapie-resistente GD2-positive NB-Zelllinien effektiv abzutöten und dass dabei die Interaktion des CARs mit GD2 den Hauptmechanismus darstellt. Die anti-tumorale Wirkung von NK-92-scFv(ch14.18)-zeta in vivo wurde in einem Chemotherapie-resistenten GD2-positiven Xenograft-Mausmodell gezeigt. Die wiederholte Applikation von NK-92-scFv(ch14.18)-zeta in Kombination mit IL-2 resultierte in einem signifikant verlangsamten Tumorwachstum und einem verbesserten Überleben. Die Ergebnisse dieser Arbeit belegen, dass GD2-spezifische NK-92 das Potential für eine zukünftige klinische Anwendung besitzen. Demnach stellt der Einsatz einer solchen GD2-spezifischen NK-Zelllinie, die unter GMP-Bedingungen expandiert werden kann und zu jeder Zeit in einer standardisierten Qualität verfügbar wäre, eine vielversprechende Alternative zur Behandlung von Hochrisikopatienten dar, deren Erkrankung nicht mehr auf die Standardtherapie anspricht.Neuroblastoma (NB) is a solid extracranial childhood malignancy of neuroectodermal origin. The Disialoganglioside GD2 is an established antigen for passive immunotherapy of NB. Cellular therapy of NB with natural killer (NK) cells is especially appealing because MHC class I expression is absent or low in most NB, rendering this tumor sensitive to NK cell recognition. Additionally, natural cytotoxicity of NK cells, mediated by interaction of activating NK cell receptors and their respective ligands on tumor cells, has been shown to play a role in lysis of NB cells. It is therefore tempting to assume that a combination of passive immunotherapy with GD2-specific antibodies and adoptive transfer of NK effector cells would result in an improved NB therapy. To achieve this goal an NK cell line expressing a GD2-specific chimeric antigen receptor (CAR) was engineered: NK-92-scFv(ch14.18)-zeta. This CAR consists of a GD2-specific scFv-fragment, which was generated from ch14.18, and the CD3ζ-chain as intracellular signal-transducing domain. Within this thesis, GD2-specificity of NK-92-scFv(ch14.18)-zeta as well as efficacy towards GD2-expressing NB cell lines, including relapse cell lines that exhibit partial or multidrug resistance were demonstrated. Blocking the interaction between the CAR and GD2 resulted in almost complete abrogation of NK-92-scFv(ch14.18)-zeta-mediated lysis of GD2-positive NB cell lines in vitro, indicating that this interaction is the main mechanism of activation of NK-92-scFv(ch14.18)-zeta. Importantly, repeated application of NK-92-scFv(ch14.18)-zeta in combination with IL-2 significantly decreased tumor growth and prolonged survival of mice in an aggressively growing drug-resistant xenograft NB mouse model. These findings suggest that GD2-specific NK-92 has potential for a future clinical application as NB-specific effector cells that would be ready on demand in a standardized quality
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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