Van Gool Research Articles

IMMU-11. CLINICAL EXPERIENCE WITH THE CONCEPT OF MULTIPHASE COMBINED TREATMENT FOR ADULTS WITH GBM

Abstract BACKGROUND We published survival data of 50 adults with GBM treated with individualized multimodal immunotherapy (IMI) as part of a multiphase combined treatment (Van Gool et al, https://doi:org/10.1016/bs.mcb.2023.06.001). Analysis was repeated with new observation data. METHODS Patient definition for retrospective analysis: start IMI between 27/05/2015 and 31/10/2023, >18y, newly diagnosed, IDH1 wild-type, MGMT promoter-methylation status documented, survival known, no second malignancy. RESULTS Forty (14 female, 26 male) GBM patients were MGMT-promoter-unmethylated (unmeth), while 31 (15 female, 16 male) were MGMT-promoter-methylated (meth). Comparing the molecular subgroups, both respective median age; 48 years (range 18-65) and 54 years (range 26-72), and respective Karnofsky performance index; 70 (range 50-100) and 80 (range 60-100), were equal. Patient distribution (< complete resection, complete resection, not documented) was equal: 17/15/8 (unmeth) versus 17/11/3 (meth). Both groups were treated similarly: in median 37 (range 0-147) sessions of modulated electrohyperthermia, in median 37 (range 5-147) bolus injections of Newcastle Disease Virus, in median 2 (range 0-6) IO-Vac® vaccines with a median total number of 30.7x10e6 DCs (range 0-158x10e6). The median overall survival (mOS) for the total group was 27 months. The 2-year overall survival (OS) was 57.9 % and the 3-year OS 37.1 %. The mOS for unmeth patients was 22.1 month, with a 2-year OS of 42.7%. The mOS for meth patients was 37.7 months, with a 2-year OS of 75.5%. Sampling five control arms of contemporary RCTs as external control arm (Liau et al, JAMA Oncol 2023) showed for unmeth and meth patients a mOS of 14.6 resp. 21.3 months with a 2-year OS of 21% resp. 42%, which reflects the current prognosis for these patients. CONCLUSIONS Our analysis confirms that the integration of IMI during and after standard of care improves the OS. Similar multiphase combined treatment strategy, including IMI, should be considered to treat childhood GBM.

Multi-channel and multi-featured extended orb with gabor filter and non-maximum suppression

This research paper presents an enhanced approach to feature extraction using the Oriented FAST and Rotated BRIEF (ORB) algorithm (Rublee et al., 2014). The proposed method leverages the power of Gabor filters (Mehrotra et al., 1992) in combination with Non-Maximum Suppression (Neuback and Van Gool, 2006) to improve the robustness and efficiency of feature detection in computer vision applications. The process begins with the acquisition of an RGB image, which is then transformed into seven single-channel images representing different color and intensity aspects: red, green, blue, hue, saturation, value, and grayscale. Each single-channel image is independently subjected to Gabor filtering, resulting in seven Gabor-filtered images. These images capture distinct texture and frequency information, enhancing the discriminative power of subsequent feature extraction. Subsequently, the Oriented FAST and Rotated BRIEF (ORB) algorithm is applied to each of the seven Gabor-filtered images to extract key points and descriptors. This step yields a comprehensive set of keypoints (Mallick et al., 2015) and descriptors, capturing rich local feature information across multiple image channels. To further refine the extracted features and eliminate redundant keypoints, Non-Maximum Suppression is employed independently on each single-channel image. This process effectively filters out overlapped and false keypoints, ensuring the selection of only the most salient features for downstream tasks. Experimental results demonstrate the efficacy of the proposed approach in improving feature detection performance compared to traditional methods. The combination of Gabor filtering and Non-Maximum Suppression enhances feature discriminability, robustness to noise, and resistance to image transformations, making it well-suited for various computer vision applications, including object recognition, image matching, and scene understanding.

Unblinding in the lecanemab trial in Alzheimer's disease.

Journal Article Accepted manuscript Unblinding in the lecanemab trial in Alzheimer's disease Get access Willem A Van Gool Willem A Van Gool Department of Public and Occupational Health, Amsterdam University Medical Centre, Amsterdam, The Netherlands Correspondence to: Willem A. Van Gool, Amsterdam UMC Locatie AMC - Public and Occupational Health, Meibergdreef 9 Amsterdam 1105 AZ, The Netherlands, E-mail: w.a.vangool@amsterdamumc.nl Search for other works by this author on: Oxford Academic PubMed Google Scholar Brain, awad171, https://doi.org/10.1093/brain/awad171 Published: 18 May 2023 Article history Received: 24 April 2023 Accepted: 13 May 2023 Published: 18 May 2023

Barr-exact categories and soft sheaf representations

It has long been known that a key ingredient for a sheaf representation of a universal algebra A consists in a distributive lattice of commuting congruences on A. The sheaf representations of universal algebras (over stably compact spaces) that arise in this manner have been recently characterised by Gehrke and van Gool (J. Pure Appl. Algebra, 2018), who identified the central role of the notion of softness.In this paper, we extend the scope of this theory by replacing varieties of algebras with Barr-exact categories, thus encompassing a number of “non-algebraic” examples. Our approach is based on the notion of K-sheaf: intuitively, whereas sheaves are defined on open subsets, K-sheaves are defined on compact ones. Throughout, we consider sheaves on complete lattices rather than spaces; this allows us to obtain point-free versions of sheaf representations whereby spaces are replaced with frames.These results are used to construct sheaf representations for the dual of the category of compact ordered spaces, and to recover Banaschewski and Vermeulen's point-free sheaf representation of commutative Gelfand rings (Quaest. Math., 2011).

Lattice-free and point-free: Vickers duality for subbases of stably locally compact spaces

Inspired by classic work of Wallman and more recent work of Jung-Kegelmann-Moshier and Vickers, we show how to encode general subbases of stably locally compact spaces via certain entailment relations. We further build this up to a categorical duality encompassing the classic Priestley-Stone duality and its various extensions to stably locally compact spaces by Shirota, De Vries, Hofmann-Lawson (in the stable case), Jung-Sünderhauf, Hansoul-Poussart, Bezhanishvili-Jansana, van Gool and Bice-Starling.

U-SPDNet: An SPD manifold learning-based neural network for visual classification

With the development of neural networking techniques, several architectures for symmetric positive definite (SPD) matrix learning have recently been put forward in the computer vision and pattern recognition (CV&PR) community for mining fine-grained geometric features. However, the degradation of structural information during multi-stage feature transformation limits their capacity. To cope with this issue, this paper develops a U-shaped neural network on the SPD manifolds (U-SPDNet) for visual classification. The designed U-SPDNet contains two subsystems, one of which is a shrinking path (encoder) making up of a prevailing SPD manifold neural network (SPDNet (Huang and Van Gool, 2017)) for capturing compact representations from the input data. Another is a constructed symmetric expanding path (decoder) to upsample the encoded features, trained by a reconstruction error term. With this design, the degradation problem will be gradually alleviated during training. To enhance the representational capacity of U-SPDNet, we also append skip connections from encoder to decoder, realized by manifold-valued geometric operations, namely Riemannian barycenter and Riemannian optimization. On the MDSD, Virus, FPHA, and UAV-Human datasets, the accuracy achieved by our method is respectively 6.92%, 8.67%, 1.57%, and 1.08% higher than SPDNet, certifying its effectiveness.

Mapping single-cell transcriptomes in the intra-tumoral and associated territories of kidney cancer.

Tumor behavior is intricately dependent on the oncogenic properties of cancer cells and their multi-cellular interactions. To understand these dependencies within the wider microenvironment, we studied over 270,000 single-cell transcriptomes and 100 microdissected whole exomes from 12 patients with kidney tumors, prior to validation using spatial transcriptomics. Tissues were sampled from multiple regions of the tumor core, the tumor-normal interface, normal surrounding tissues, and peripheral blood. We find that the tissue-type location of CD8+ Tcell clonotypes largely defines their exhaustion state with intra-tumoral spatial heterogeneity that is not well explained by somatic heterogeneity. De novo mutation calling from single-cell RNA-sequencing data allows us to broadly infer the clonality of stromal cells and lineage-trace myeloid cell development. We report six conserved meta-programs that distinguish tumor cell function, and find an epithelial-mesenchymal transition meta-program highly enriched at the tumor-normal interface that co-localizes with IL1B-expressing macrophages, offering a potential therapeutic target.

Prevention of Fetal Neural Tube Defect with Folic Acid Supplementation

Prevention of Fetal Neural Tube Defect with Folic Acid Supplementation

COVID-19 vasculitis and novel vasculitis mimics.

COVID-19 has been occasionally linked to histologically confirmed cutaneous vasculitis and a Kawasaki-like vasculitis, with these entities generally having minimal or no lung involvement and a good prognosis. Unlike these vasculitis types, patients with severe COVID-19 pneumonia can develop cutaneous vasculitis-like lesions and systemic arterial and venous thromboemboli, including cryptogenic strokes and other vasculopathy features. Proposed underlying mechanisms for these severe manifestations have encompassed immune dysregulation, including an anti-phospholipid syndrome-like state, complement activation, viral dissemination with direct systemic endothelial infection, viral RNAaemia with immunothrombosis, clotting pathway activation mediated by hypoxaemia, and immobility. In this Viewpoint, we highlight how imaging and post-mortem findings from patients with COVID-19 indicate a novel thrombosis in the pulmonary venous territory distal to the alveolar capillary bed, a territory that normally acts as a clot filtration system, which might represent an unappreciated nidus for systemic microembolism. Additionally, we suggest that this mechanism represents a novel vasculitis mimic related to COVID-19 that might lead to cryptogenic strokes across multivessel territories, acute kidney injury with haematuria, a skin vasculitis mimic, intestinal ischaemia, and other organ ischaemic manifestations. This finding is supported by pathological reports of extensive pulmonary venular thrombosis and peripheral organ thrombosis with pauci-immune cellular infiltrates. Therefore, severe COVID-19 pneumonia with extensive pulmonary intravascular coagulopathy might help to explain the numerous systemic complications of COVID-19, in which the demonstration of direct organ infection has not adequately explained the pathology.

Liver Segmentation on a Variety of Computed Tomography (CT) Images Based on Convolutional Neural Networks Combined with Connected Components

Liver Segmentation on a Variety of Computed Tomography (CT) Images Based on Convolutional Neural Networks Combined with Connected Components

From Guild to Society: The Foundation of Confrerie Pictura in The Hague Revisited

The foundation of the Confrerie Pictura (an artistic brotherhood) in The Hague has given rise to controversy on several occasions. In the eighteenth century, for example, Johan van Gool was annoyed by Houbraken, who believed that the artist painters of The Hague had founded their Confrerie in 1662, while it was abundantly clear to Van Gool that the correct date was 1656. Nowadays the question under discussion is the nature of the Confrerie as an organisation. Was it the first step towards an eighteenth-century society, as Hoogewerff suggested in his authoritative book on the Dutch St Luke’s guilds, or was the new organisation more like a guild, as later argued by Hoogewerff’s most important critic Hessel Miedema? Based on archival records, this article maps out the early history and establishment of the Confrerie in order to determine what kind of organisation it had been between 1656 and 1700. This article argues that all four authors are right: the Confrerie was both a guild and a society, and however paradoxical it may sound, it was founded in 1656 and again in 1662.

PC-FACS

PC-FACS

The effects of some exergetic indicators on the performance of thin layer drying process of long green pepper in a solar dryer

In this study, exergy analysis of the thin layer drying process of long green pepper was performed in solar dryer with forced convection. The effects of some exergetic indicators on the performance of a thin layer solar drying system by using the experimental data in the literature for long green pepper (Akpinar and Bicer in Energy Convers Manag 49: 1367–1375, 2008) were investigated. For this purpose, the exergetic indicators such as exergetic efficiency, waste exergy ratio, environmental impact factor, exergetic sustainability index and improvement potential, previously used in the literature, were taken into account (Zisopoulos et al. in Crit Rev Food Sci Nutr 57(1):197–211, 2017, Midilli and Kucuk in Int J Exergy 16(3): 278–292, 2015, Van Gool 1997). The exergetic efficiency and improvement potential of the solar drying system decreased with the increase of drying time. The waste exergy ratio increased with the increase of drying time. The exergetic sustainability index increased with increasing the exergetic efficiency, decreased with decreasing the exergetic efficiency. The environmental impact factor decreased with increasing the exergetic efficiency.

CRISPR/Cas9-Mediated Knockin Application in Cell Therapy: A Non-viral Procedure for Bystander Treatment of Glioma in Mice.

The use of non-viral procedures, together with CRISPR/Cas9 genome-editing technology, allows the insertion of single-copy therapeutic genes at pre-determined genomic sites, overcoming safety limitations resulting from random gene insertions of viral vectors with potential for genome damage. In this study, we demonstrate that combination of non-viral gene delivery and CRISPR/Cas9-mediated knockin via homology-directed repair can replace the use of viral vectors for the generation of genetically modified therapeutic cells. We custom-modified human adipose mesenchymal stem cells (hAMSCs), using electroporation as a transfection method and CRISPR/Cas9-mediated knockin for the introduction and stable expression of a 3 kb DNA fragment including the eGFP (selectable marker) and a variant of the herpes simplex virus 1 thymidine kinase genes (therapeutic gene), under the control of the human elongation factor 1 alpha promoter in exon 5 of the endogenous thymidine kinase 2 gene. Using a U87 glioma model in SCID mice, we show that the therapeutic capacity of the new CRISPR/Cas9-engineered hAMSCs is equivalent to that of therapeutic hAMSCs generated by introduction of the same therapeutic gene by transduction with a lentiviral vector previously published by our group. This strategy should be of general use to other applications requiring genetic modification of therapeutic cells.

Editorial: Matricellular Receptors As Potential Targets in Anti-Cancer Therapeutic Strategies

Editorial: Matricellular Receptors As Potential Targets in Anti-Cancer Therapeutic Strategies

Editorial: Immunogenic Cell Death in Cancer: From Benchside Research to Bedside Reality.

The Editorial on the Research Topic Immunogenic Cell Death in Cancer: From Benchside Research to Bedside Reality Immunogenic cell death (ICD) has emerged as a cornerstone of therapy-induced antitumor immunity (1–3). ICD is distinguished by spatiotemporally defined emission of danger signals or damage-associated molecular patterns (DAMPs) that elevate the immunogenic potential of dying cells [Garg et al.; (4)]. The important role played by DAMPs in immunity, tissue remodeling, and inflammation is discussed in details by Venereau et al. (Marco E. Bianchi lab). Most potent ICD inducers, characterized so far, elicit danger signaling through oxidative-endoplasmic reticulum stress (5). Several ICD inducers have been characterized, e.g., some chemotherapies, some physicochemical therapies (e.g., radiotherapy or photodynamic therapy/PDT), and oncolytic viruses (2, 6). Here, radiotherapy is among the first recognized immunogenic therapies [on account of “abscopal-effect” (7)]. The immunogenic potential of radiotherapy and possibilities for its combination with immune checkpoint blockers is discussed by Derer et al. (Udo S. Gaipl lab). It is noteworthy that ICD can also be achieved by various “smart” combinatorial strategies – an important point for clinically applied non-ICD inducers, discussed in details by Bezu et al. (Guido Kroemer lab). Several lines of experimental evidence have established the validity of ICD. However, the overreliance on usage of prophylactic vaccination in transplantable (heterotopic) tumor models has attracted some criticism (8). While these criticisms are valid, the field is already moving toward tumors produced orthotopically (curative/therapeutic) or in genetically engineered mouse models (GEMM) (at least for few ICD inducers, e.g., hypericin-PDT, Newcastle disease virotherapy and anthracyclines) (9–12). Moreover, the clinical existence of ICD has been proven through retrospective analysis involving cancer patient’s survival/therapy-responsiveness data (13–17). These observations have encouraged the increased usage of ICD-associated DAMPs as predictive/prognostic biomarkers – a point discussed in detail by Fucikova et al. (Radek Spisek lab). The promising results generated by systemically administered ICD inducers have also paved way for application of ICD-based dendritic cell (DC) vaccines (12). This important development has been discussed from the preclinical/clinical vantage points of various solid tumors by Vandenberk et al. (Stefaan W. van Gool lab) and lymphoma by Zappasodi et al. (Massimo Di Nicola lab). In the latter case, it is clear that the field is moving toward chimeric antigen receptor (CAR)-T cell’s application, and it will be interesting to see its combination with ICD in near future. Nevertheless, the insurmountable complexity of cancer makes it inevitable that in certain contexts, ICD may fail. This failure may stem from various factors, e.g., tumor heterogeneity (8), MHC-level heterogeneity (12), pre-established niches enriched in immunosuppressive factors or immune-checkpoints (1), stem cell-based immune-evasion (12), low mutational load, inactivating mutations/polymorphisms in certain immune-receptors (1), general ablation of danger signaling (14), and other genetic or even epigenetic causes. Several of these pro-cancerous immune-evasive mechanisms and immunotherapeutic strategies required for overcoming them are discussed in detail by Kersten et al. (Karin E. de Visser lab). The strategies for targeting epigenetic processes to improve immunotherapy are further discussed by Wachowska et al. (Jakub Golab lab). We believe that the valuable contributions of key researchers/clinicians toward this research topic/special edition have largely fulfilled its primary aim, i.e., to foster a critical discussion on experimental and clinical relevance of ICD. In fact, to further summarize and organize the fields of ICD and DAMPs, we have produced a multi-author consensus paper within this research topic that attempts to classify DAMPs and ICD inducers with an eye on translational potential of ICD (Garg et al.). This classification paper brings together >50 authors from the fields of ICD and DAMPs, and tries to reach a comprehensive accord on various terminologies related to DAMPs/ICD, the historical background of these concepts, ICD classification system (Type I vs. Type II inducers), and the relevant preclinical/clinical criteria crucial for the field(s) (Garg et al.). We hope that this consensus paper will be a useful literature resource for various researchers/clinicians. These contributions, while summarizing the status quo, have also exposed a set of major questions and challenges that still need to be addressed.

The hidden costs of drug and alcohol use in hospital emergency departments.

This study estimates the burden of drug and alcohol morbidity on hospitals in New South Wales (NSW) by observing a multi-site collective sample utilising survey information and data linkage. Specifically we aimed to determine the prevalence of alcohol and other drug (AOD) problems and to estimate patterns of utilisation of hospital services, costs of presentations, and admissions for patients with AOD problems. Patients were recruited from eight NSW public hospitals presenting to the hospital emergency department over a 10 day period. Participants completed a self-administered survey with demographic characteristics and questions about substance use. More than two-thirds (68%) of participants consented to provide access to their NSW Health medical data for a period spanning 2.5 years. One-third (35%) of the total sample were identified as having problematic AOD use with one in five of these patients requiring a high level of intervention. Those patients requiring a high level of intervention present more often and cost more per presentation. If admitted they were more likely to have longer stays and were also more likely to be admitted to a psychiatric ward and have a longer stay in the ward. This study demonstrates a need for AOD interventions in the emergency department setting, both because it represents an opportunity for intervention in a population in which problems with substance use is highly prevalent, and because there is evidence that AOD imposes additional costs on the health system. [Butler K, Reeve R, Arora S, Viney R, Goodall S, van Gool K, Burns L. The hidden costs of drug and alcohol use in hospital emergency departments. Drug Alcohol Rev 2016;35:359-366].

An Analysis of the SURF Method

The SURF method (Speeded Up Robust Features) is a fast and robust algorithm for local, similarity invariant representation and comparison of images. Similarly to many other local descriptor-based approaches, interest points of a given image are defined as salient features from a scale-invariant representation. Such a multiple-scale analysis is provided by the convolution of the initial image with discrete kernels at several scales (box filters). The second step consists in building orientation invariant descriptors, by using local gradient statistics (intensity and orientation). The main interest of the SURF approach lies in its fast computation of operators using box filters, thus enabling real-time applications such as tracking and object recognition. The SURF framework described in this paper is based on the PhD thesis of H. Bay [ETH Zurich, 2009], and more specifically on the paper co-written by H. Bay, A. Ess, T. Tuytelaars and L. Van Gool [Computer Vision and Image Understanding, 110 (2008), pp. 346–359]. An implementation is proposed and used to illustrate the approach for image matching. A short comparison with a state-of-the-art approach is also presented, the SIFT algorithm of D. Lowe [International Journal of Computer Vision, 60 (2004), pp. 91–110], with which SURF shares a lot in common.

Testing Van Gool’s Hypothesis: A Method to Predict Side Effects of Cholinesterase Inhibitors in Patients with Cellular Degenerative and Vascular Dementia

This study investigates a method to predict medical outcome of cholinesterase inhibitors in patients with Alzheimer’s disease (AD) and vascular dementia (VaD). Van Gool predicts that patients with cholinergic deficit symptoms will benefit from treatment whereas patients without will experience side effects because of overstimulation of the cholinergic system. We predicted that AD and VaD patients with a longer RT experience fewer side effects than patients with a faster response and that VaD patients have a longer RT than AD patients. A number of 71 patients with AD or VaD diagnosis were included. A sustained attention task was administered, as well as the MMSE and a questionnaire about side effects. Results indicated that VaD patients with a longer RT reported fewer side effects. Furthermore, patients with VaD had a longer RT than patients with AD. MMSE was negatively correlated with RT in the VaD group. Thus, the performance on the attention task seems associated with suffering from side effects and thus tends to predict medical outcome in VaD, but not in AD. Perhaps this attention task was not sensitive enough to measure cholinergic deficit symptoms in AD patients. Furthermore, different doses of medication might confound the effect for the AD group.

P02.05 * CLINICAL STUDY PHASE II WITH DENDRITIC CELL VACCINATION AND TUMOUR LYSATE AS ADD-ON THERAPY IN HIGH GRADE GLIOMA

AIM: To improve treatment of high-grade glioma (HGG) with immune therapy based on vaccination with autologous dendritic cells (DC) loaded with tumour-derived lysate (DCm-HGG-L). BACKGROUND: Immune therapy of CNS tumours is an emerging modality that potentially can enhance the current multimodal treatment approaches being used. This autologous vaccine is both tumour-specific and well tolerated, given intradermally, a technique which has been developed by van Gool et al in Leuven, Belgium. METHODS: Adult patients underwent leukaferesis after radical surgery. The DC were extracted by CD14+ enrichement with the CliniMacs platform. Blood samples for immunologic stimulation analysis (CD4, CD8) were collected prior to therapy and before each intradermal vaccination. RESULTS: Since December 2009, DCm-HGG-L has been produced at the Karolinska University Hospital for HGG patients, according to a GMP protocol required by the Medical Product Agency. Twelve patients have been treated, 6 with de novo glioblastoma, 4 with recurrent high grade glioma, one with recurrent PNET, and one with recurrent rhabdoid tumor. Age 2 and 20-50 yr, KPS 70-100. All underwent radical surgery followed by radiochemotherapy. Median PFS 2 yrs. The CD4 and CD8 blasts increased and remained at high level after the 3 rd vaccine. CONCLUSION: The immunological therapy for High Grade Glioma is safe. Further evaluation is under way to implement this strategy, especially in the adult population.