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  • 1
    In: Journal for ImmunoTherapy of Cancer, BMJ, Vol. 12, No. 1 ( 2024-01), p. e007829-
    Abstract: Relapse and graft-versus-host disease (GVHD) are the main causes of death after allogeneic hematopoietic cell transplantation (HCT). Preclinical murine models and clinical data suggest that invariant natural killer T (iNKT) cells prevent acute and chronic GVHD. In addition, iNKT cells are crucial for efficient immune responses against malignancies and contribute to reduced relapse rates after transplantation. Chimeric antigen receptors (CAR) redirect effector cells to cell surface antigens and enhance killing of target cells. With this study, we aimed to combine enhanced cytotoxicity of CD19-CAR-iNKT cells against lymphoma cells with their tolerogenic properties. Methods iNKT cells were isolated from peripheral blood mononuclear cells and transduced with an anti-CD19-CAR retrovirus. After in vitro expansion, the functionality of CD19-CAR-iNKT cells was assessed by flow cytometry, image stream analysis and multiplex analysis in single-stimulation or repeated-stimulation assays. Moreover, the immunoregulatory properties of CD19-CAR-iNKT cells were analyzed in apoptosis assays and in mixed lymphocyte reactions. The effect of checkpoint inhibition through nivolumab was analyzed in these settings. Results In this study, we could show that the cytotoxicity of CD19-CAR-iNKT cells was mediated either through engagement of their CAR or their invariant T-cell receptor, which may circumvent loss of response through antigen escape. However, encounter of CD19-CAR-iNKT cells with their target induced a phenotype of exhaustion. Consequently, checkpoint inhibition increased cytokine release, cytotoxicity and survival of CD19-CAR-iNKT cells. Additionally, they showed robust suppression of alloreactive immune responses. Conclusion In this work, we demonstrate that CAR-iNKT cells are a powerful cytotherapeutic option to prevent or treat relapse while potentially reducing the risk of GVHD after allogeneic HCT.
    Type of Medium: Online Resource
    ISSN: 2051-1426
    Language: English
    Publisher: BMJ
    Publication Date: 2024
    detail.hit.zdb_id: 2719863-7
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  • 2
    In: Gut, BMJ, Vol. 66, No. 10 ( 2017-10), p. 1734-1738
    Type of Medium: Online Resource
    ISSN: 0017-5749 , 1468-3288
    RVK:
    Language: English
    Publisher: BMJ
    Publication Date: 2017
    detail.hit.zdb_id: 80128-8
    detail.hit.zdb_id: 1492637-4
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  • 3
    In: Journal of NeuroInterventional Surgery, BMJ, Vol. 14, No. 8 ( 2022-08), p. 832-836
    Abstract: Onyx is frequently used for endovascular embolization of intracranial arteriovenous malformations (AVMs) and dural arteriovenous fistulas (dAVFs). One drawback of using Onyx is the generation of artifacts in cone-beam CT (CBCT). These artifacts can represent an obstacle for the detection of periprocedural hemorrhage or planning of subsequent radiosurgery. This study investigates the effect of artifact reduction by the syngo DynaCT SMART Metal Artifact Reduction (MAR) software. Methods A standardized in vitro tube model (n=10) was filled with Onyx 18 and CBCT image acquisition was conducted in a brain imaging phantom. Furthermore, post-interventional CBCT images of 20 patients with AVM (n=13) or dAVF (n=7), each treated with Onyx, were investigated. The MAR software was applied for artifact reduction. Artifacts of the original and the post-processed images were analyzed quantitatively (standard deviation in a region of interest on the layer providing the most artifacts) and qualitatively. For the patient images, the effect of the MAR software on brain parenchyma on artifact-free images was further investigated. Results Quantitative and qualitative analyses of both datasets demonstrated a lower degree of artifacts in the post-processed images (eg, patient images: 38.30±22.03 density units (no MAR; mean SD±SD) vs 19.83±12.31 density units (with MAR; p 〈 0.001). The MAR software had no influence on the brain parenchyma in artifact-free images. Conclusion The MAR software significantly reduced the artifacts evoked by Onyx in CBCT without affecting the visualization of brain parenchyma on artifact-free images. Applying this software could thus improve the quality of periprocedural CBCT images after embolization with Onyx.
    Type of Medium: Online Resource
    ISSN: 1759-8478 , 1759-8486
    Language: English
    Publisher: BMJ
    Publication Date: 2022
    detail.hit.zdb_id: 2506028-4
    detail.hit.zdb_id: 2514982-9
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  • 4
    In: Journal of NeuroInterventional Surgery, BMJ, Vol. 16, No. 8 ( 2024-08), p. 830-837
    Abstract: Mechanical thrombectomy (MT) is the standard of care for patients with a stroke and large vessel occlusion. Clot composition is not routinely assessed in clinical practice as no specific diagnostic value is attributed to it, and MT is performed in a standardized ‘non-personalized’ approach. Whether different clot compositions are associated with intrinsic likelihoods of recanalization success or treatment outcome is unknown. Methods We performed a prospective, non-randomized, single-center study and analyzed the clot composition in 60 consecutive patients with ischemic stroke undergoing MT. Clots were assessed by ex vivo multiparametric MRI at 9.4 T (MR microscopy), cone beam CT, and histopathology. Clot imaging was correlated with preinterventional CT and clinical data. Results MR microscopy showed red blood cell (RBC)-rich (21.7%), platelet-rich (white,38.3%) or mixed clots (40.0%) as distinct morphological entities, and MR microscopy had high accuracy of 95.4% to differentiate clots. Clot composition could be further stratified on preinterventional non-contrast head CT by quantification of the hyperdense artery sign. During MT, white clots required more passes to achieve final recanalization and were not amenable to contact aspiration compared with mixed and RBC-rich clots (maneuvers: 4.7 vs 3.1 and 1.2 passes, P 〈 0.05 and P 〈 0.001, respectively), whereas RBC-rich clots showed higher probability of first pass recanalization (76.9%) compared with white clots (17.4%). White clots were associated with poorer clinical outcome at discharge and 90 days after MT. Conclusion Our study introduces MR microscopy to show that the hyperdense artery sign or MR relaxometry could guide interventional strategy. This could enable a personalized treatment approach to improve outcome of patients undergoing MT.
    Type of Medium: Online Resource
    ISSN: 1759-8478 , 1759-8486
    Language: English
    Publisher: BMJ
    Publication Date: 2024
    detail.hit.zdb_id: 2506028-4
    detail.hit.zdb_id: 2514982-9
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  • 5
    In: BMJ Open, BMJ, Vol. 10, No. 5 ( 2020-05), p. e034565-
    Abstract: Target-specific anticancer drugs are under rapid development. Little is known, however, about the risk of administering target-specific drugs to patients who have tumours with molecular alterations or other characteristics that can make the drug ineffective or even harmful. An increasing number of randomised clinical trials (RCTs) investigating target-specific anticancer drugs include subgroup analyses based on tumour characteristics. Such subgroup analyses have the potential to be more credible and influential than subgroup analyses based on traditional factors such as sex or tumour stage. In addition, they may more frequently lead to qualitative subgroup effects, that is, show benefit in one but harm in another subgroup of patients (eg, if the tumour characteristic makes the drug ineffective or even enhance tumour growth). If so, subgroup analyses based on tumour characteristics would be highly relevant for patient safety. The aim of this study is to systematically assess the frequency and characteristics of subgroup analyses based on tumour characteristics, the frequency of qualitative subgroup effects, their credibility, and the interpretations that investigators and guidelines developers report. Methods and analysis We will perform a systematic survey of 433 RCTs testing the effect of target-specific anticancer drugs. Teams of methodologically trained investigators and oncologists will identify eligible studies, extract relevant data and assess the credibility of putative subgroup effects using a recently developed formal instrument. We will systematically assess how trial investigators interpret apparent subgroup effects based on tumour characteristics and the extent to which they influence subsequent practice guidelines. Our results will provide empirical data characterising an increasingly used type of subgroup analysis in cancer trials and its potential impact on precision medicine to predict benefit or harm. Ethics and dissemination Formal ethical approval is not required for this study. We will disseminate the findings in a peer-reviewed and open-access journal publication.
    Type of Medium: Online Resource
    ISSN: 2044-6055 , 2044-6055
    Language: English
    Publisher: BMJ
    Publication Date: 2020
    detail.hit.zdb_id: 2599832-8
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  • 6
    In: Journal of NeuroInterventional Surgery, BMJ, Vol. 15, No. 6 ( 2023-06), p. 594-599
    Abstract: Endovascular embolization using liquid embolic agents (LEAs) is frequently applied for the treatment of intracranial vascular malformations. Appropriate visibility of LEAs during embolization is essential for visual control and to prevent complications. Since LEAs contain different radiopaque components of varying concentrations, our aim was the systematic assessment of the visibility of the most used LEAs in fluoroscopy. Methods A specifically designed in vitro model, resembling cerebral vessels, was embolized with Onyx 18, Squid 18, Squid 12, PHIL (precipitating hydrophobic injectable liquid) 25%, PHIL LV (low viscosity) and NBCA (n-butyl cyanoacrylate) mixed with iodized oil (n=3 for each LEA), as well as with contrast medium and saline, both serving as a reference. Fluoroscopic image acquisition was performed in accordance with clinical routine settings. Visibility was graded quantitatively (contrast to noise ratio, CNR) and qualitatively (five-point scale). Results Overall, all LEAs provided at least acceptable visibility in this in vitro model. Onyx and Squid as well as NBCA mixed with iodized oil were best visible at a comparable level and superior to the formulations of PHIL, which did not differ in quantitative and qualitative analyses (eg, Onyx 18 vs PHIL 25% along the 2.0 mm sector: mean CNR±SD: 3.02±0.42 vs 1.92±0.35; mean score±SD: 5.00±0.00 vs 3.75±0.45; p≤0.001, respectively). Conclusion In this systematic in vitro study, relevant differences in the fluoroscopic visibility of LEAs in neurointerventional embolization procedures were demonstrated, while all investigated LEAs provided acceptable visibility in our in vitro model.
    Type of Medium: Online Resource
    ISSN: 1759-8478 , 1759-8486
    Language: English
    Publisher: BMJ
    Publication Date: 2023
    detail.hit.zdb_id: 2506028-4
    detail.hit.zdb_id: 2514982-9
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  • 7
    In: Journal of NeuroInterventional Surgery, BMJ, Vol. 15, No. 7 ( 2023-07), p. 712-716
    Abstract: Transvenous embolization (TVE) is an emerging technique for the endovascular treatment of cerebral arteriovenous malformations (AVMs). The aim of this study was to investigate two in vivo AVM models and to assess TVE techniques using these models. Methods Blood flow in the porcine rete mirabile (RM) was modified by either creating a carotid–jugular fistula or by placing a balloon guide catheter in the carotid artery. The RM was embolized with precipitating hydrophobic injectable liquid (PHIL) 25% via transarterial embolization (TAE; control group) and compared with TVE applying the transvenous retrograde pressure cooker technique and TVE using a Woven EndoBridge (WEB) device for flow control (n=6, respectively). The embolization extent (penetration of the RM), the number of events of reflux or embolization distal to the RM and the procedure times were assessed. Results The modified RM could be successfully used for embolization in all cases. There were no significant differences regarding the outcome parameters between the two AVM models (fistula or balloon). TVE using the pressure cooker technique led to a higher extent of embolization (median 98.8% vs 63.5%; p=0.008), a lower number of reflux or distal embolization events (p 〈 0.001) and a shorter procedure time (p 〈 0.001) compared with conventional TAE. TVE using a WEB device for flow control was technically feasible and achieved a moderate extent of embolization (median 83.8%). Conclusion After surgical or endovascular modification, the porcine RM is a feasible in vivo AVM model for the investigation of TVE techniques. TVE using the pressure cooker technique is superior to conventional TAE in this experimental model.
    Type of Medium: Online Resource
    ISSN: 1759-8478 , 1759-8486
    Language: English
    Publisher: BMJ
    Publication Date: 2023
    detail.hit.zdb_id: 2506028-4
    detail.hit.zdb_id: 2514982-9
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