University Medical Center Utrecht

Machine learning methods have shown large potential for the automatic early diagnosis of Alzheimer’s Disease (AD). However, some machine learning methods based on imaging data have poor interpretability because it is usually unclear how they make their decisions. Explainable Boosting Machines (EBMs) are interpretable machine learning models based on the statistical framework of generalized additive modeling, but have so far only been used for tabular data. Therefore, we propose a framework that combines the strength of EBM with high-dimensional imaging data using deep learning-based feature extraction. The proposed framework is interpretable because it provides the importance of each feature. We validated the proposed framework on the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset, achieving accuracy of 0.883 and area-under-the-curve (AUC) of 0.970 on AD and control classification. Furthermore, we validated the proposed framework on an external testing set, achieving accuracy of 0.778 and AUC of 0.887 on AD and subjective cognitive decline (SCD) classification. The proposed framework significantly outperformed an EBM model using volume biomarkers instead of deep learning-based features, as well as an end-to-end convolutional neural network (CNN) with optimized architecture.

Background Studies on the efficacy of rituximab in Primary CNS Lymphoma (PCNSL) reported conflicting results. Our international randomized phase III study showed that the addition of rituximab to high-dose methotrexate, BCNU, teniposide and prednisolone (MBVP) in PCNSL was not efficacious on the short-term. Here we present long-term results after a median follow-up of 82.3 months. Methods 199 eligible newly-diagnosed, non-immunocompromised patients with PCNSL aged 18-70 years with WHO performance status 0-3 were randomized between treatment with MBVP chemotherapy with or without rituximab, followed by high-dose cytarabine consolidation in responding patients, and reduced-dose WBRT in patients aged ≤60 years. Event-free survival was the primary endpoint. Overall survival rate, neurocognitive functioning (NCF), and health-related quality of life (HRQoL) were additionally assessed, with the IPCG test battery, EORTC QLQ-C30 and QLQ-BN20 questionnaires, respectively. Results For event-free survival, the hazard ratio was 0.85, 95% confidence interval 0.61-1.18, p=0.33. Overall survival rate at 5 years for MBVP and R-MBVP was 49% (39-59) and 53% (43-63) respectively. In total, 64 patients died in the MBVP arm and 55 in the R-MBVP arm, of which 69% due to PCNSL. At group level, all domains of NCF and HRQoL improved to a clinically relevant extent after treatment initiation, and remained stable thereafter up to 60 months of follow-up, except for motor speed which deteriorated between 24 and 60 months. Although fatigue improved initially, high levels persisted in the long-term. Conclusion Long-term follow-up confirms lack of added value of rituximab in addition to MBVP and HD-cytarabine for PCNSL.

Surgical resection combined with systemic chemotherapy is the cornerstone of treatment for patients with localized pancreatic cancer. Upfront surgery is considered suboptimal in cases with extensive vascular involvement, which can be classified as either borderline resectable pancreatic cancer or locally advanced pancreatic cancer. In these patients, FOLFIRINOX or gemcitabine plus nab-paclitaxel chemotherapy is currently used as preoperative chemotherapy and is eventually combined with radiotherapy. Thus, more patients might reach 5-year overall survival. Patient selection for chemotherapy, radiotherapy and subsequent surgery is based on anatomical, biological and conditional parameters. Current guidelines and clinical practices vary considerably regarding preoperative chemotherapy and radiotherapy, response evaluation, and indications for surgery. In this Review, we provide an overview of the clinical evidence regarding disease staging, preoperative therapy, response evaluation and surgery in patients with borderline resectable pancreatic cancer or locally advanced pancreatic cancer. In addition, a clinical work-up is proposed based on the available evidence and guidelines. We identify knowledge gaps and outline a proposed research agenda.

In the last few decades, atherosclerotic cardiovascular disease (ASCVD) risk has decreased dramatically among individuals affected by familial hypercholesterolaemia (FH) as a result of the early initiation of statin treatment in childhood. Contemporaneously important improvements in care for people with diabetes have also been made, such as the prevention of mortality from acute diabetic complications. However, individuals with type 1 diabetes still have a two to eight times higher risk of death than the general population. In the last 20 years, a few landmark studies on excess mortality in people with type 1 diabetes, in particular young adults, have been published. Although these studies were carried out in different populations, all reached the same conclusion: individuals with type 1 diabetes have a pronounced increased risk of ASCVD. In this review, we address the role of lipid abnormalities in the development of ASCVD in type 1 diabetes and FH. Although type 1 diabetes and FH are different diseases, lessons could be learned from the early initiation of statins in children with FH, which may provide a rationale for more stringent control of dyslipidaemia in children with type 1 diabetes. Graphical Abstract

Diffusion‐weighted magnetic resonance imaging (DW‐MRI) aims to disentangle multiple biological signal sources in each imaging voxel, enabling the computation of innovative maps of tissue microstructure. DW‐MRI model development has been dominated by brain applications. More recently, advanced methods with high fidelity to histology are gaining momentum in other contexts, for example, in oncological applications of body imaging, where new biomarkers are urgently needed. The objective of this article is to review the state‐of‐the‐art of DW‐MRI in body imaging (ie, not including the nervous system) in oncology, and to analyze its value as compared to reference colocalized histology measurements, given that demonstrating the histological validity of any new DW‐MRI method is essential. In this article, we review the current landscape of DW‐MRI techniques that extend standard apparent diffusion coefficient (ADC), describing their acquisition protocols, signal models, fitting settings, microstructural parameters, and relationship with histology. Preclinical, clinical, and in/ex vivo studies were included. The most used techniques were intravoxel incoherent motion (IVIM; 36.3% of used techniques), diffusion kurtosis imaging (DKI; 16.7%), vascular, extracellular, and restricted diffusion for cytometry in tumors (VERDICT; 13.3%), and imaging microstructural parameters using limited spectrally edited diffusion (IMPULSED; 11.7%). Another notable category of techniques relates to innovative b ‐tensor diffusion encoding or joint diffusion‐relaxometry. The reviewed approaches provide histologically meaningful indices of cancer microstructure (eg, vascularization/cellularity) which, while not necessarily accurate numerically, may still provide useful sensitivity to microscopic pathological processes. Future work of the community should focus on improving the inter‐/intra‐scanner robustness, and on assessing histological validity in broader contexts. Level of Evidence NA Technical Efficacy Stage 2

The urogenital tract is a target for many congenital and acquired diseases, both benign and oncogenic. In males, the urethra that transports urine and semen can be obstructed by a fibrotic disease called urethral stricture disease (USD). In severe USD, the whole organ including the vascular embedding, the corpus spongiosum (CS), is affected. Recurrent or severe USD is treated by reconstructive surgery. Tissue engineering may improve the outcome of urethral reconstruction in patients with complicated USD. Currently in urethral reconstruction only the epithelial layer is replaced, no substitution for the CS is provided, while the CS is important for mechanical support and vascularization. To develop a tissue engineering strategy for the CS, it is necessary to know the protein composition of the CS. As the extracellular matrix (ECM) plays an important role in the formation of fibrosis, we analyzed the distribution and localization of ECM components in human healthy and fibrotic CS tissue using immunohistology. The morphology of components of the elastic network were affected in USD. After decellularization a clear enrichment of proteins belonging to the ECM was found. In the proteomic analysis collagens COL15A1 and COL4A2 as well as inter-alpha-trypsin inhibitor ITIH4 were upregulated in fibrotic samples. The glycoproteins Periostin (POSTN), Microfibrillar-associated protein 5 (MFAP5) and EMILIN2 are downregulated in fibrotic tissue. To our knowledge this is the first proteomic study of ECM proteins of the CS in healthy and in USD. With these results a regenerating approach for tissue engineered CS can be developed, including relevant ECM proteins that reduce fibrosis and promote healthy healing in urethral reconstructive surgery.

Cell encapsulation within three‐dimensional hydrogels is a promising approach to mimic tissues. However, true biomimicry of the intricate microenvironment, biophysical and biochemical gradients, and the macroscale hierarchical spatial organisations of native tissues is an unmet challenge within tissue engineering. This review provides an overview of the macromolecular chemistries that have been applied towards the design of cell‐friendly hydrogels, as well as their application towards controlling biophysical and biochemical bulk and gradient properties of the microenvironment. Furthermore, biofabrication technologies provide the opportunity to simultaneously replicate macroscale features of native tissues. Biofabrication strategies are reviewed in detail with a particular focus on the compatibility of these strategies with the current macromolecular toolkit described for hydrogel design and the challenges associated with their clinical translation. This review identifies that the convergence of the ever‐expanding macromolecular toolkit and technological advancements within the field of biofabrication, along with an improved biological understanding, represents a promising strategy towards the successful tissue regeneration. This article is protected by copyright. All rights reserved

Background The key correlate of protection of respiratory syncytial virus (RSV) vaccines and monoclonal antibodies (mAb) is virus neutralization, measured using sera obtained through venipuncture. Dried blood obtained with a finger prick can simplify acquisition, processing, storage, and transport in trials, and thereby reduce costs. In this study we validate an assay to measure RSV neutralization in dried capillary blood. Methods Functional antibodies were compared between matched serum and dried blood samples from a phase I trial with RSM01, an investigational anti-RSV Prefusion F mAb. Hep-2 cells were infected with a serial dilution of sample-virus mixture using RSV-A2-mKate to determine half-maximal inhibitory concentration. Stability of dried blood was evaluated over time and during temperature stress. Results Functional antibodies in dried blood were highly correlated with serum (R2 = 0.98, p < 0.0001). The precision of the assay for dried blood was similar to serum. The function of mAb remained stable for 9 months at room temperature and frozen dried blood samples. Interpretation We demonstrated the feasibility of measuring RSV neutralization using dried blood as a patient-centered solution that may replace serology testing in trials against RSV or other viruses, such as influenza and SARS-CoV-2.

Multifocal disease in PTC is associated with an increased recurrence rate. Multifocal disease (MD) is underdiagnosed with the current gold standard of pre-operative ultrasound staging. Here, we evaluate the use of EMI-137 targeted molecular fluorescence-guided imaging (MFGI) and spectroscopy as a tool for the intra-operative detection of uni- and multifocal papillary thyroid cancer (PTC) aiming to improve disease staging and treatment selection. A phase-1 study (NCT03470259) with EMI-137 was conducted to evaluate the possibility of detecting PTC using MFGI and quantitative fiber-optic spectroscopy. Fourteen patients underwent hemi- or total thyroidectomy (TTX) after administration of 0.09 mg/kg (n = 1), 0.13 mg/kg (n = 8), or 0.18 mg/kg (n = 5) EMI-137. Both MFGI and spectroscopy could differentiate PTC from healthy thyroid tissue after administration of EMI-137, which binds selectively to MET in PTC. 0.13 mg/kg was the lowest dosage EMI-137 that allowed for differentiation between PTC and healthy thyroid tissue. The smallest PTC focus detected by MFGI was 1.4 mm. MFGI restaged 80% of patients from unifocal to multifocal PTC compared to ultrasound. EMI-137-guided MFGI and spectroscopy can be used to detect multifocal PTC. This may improve disease staging and treatment selection between hemi- and total thyroidectomy by better differentiation between unifocal and multifocal disease. NCT03470259

Purpose The shift from adjuvant to neoadjuvant treatment in colon cancer demands the radiological selection of patients for systemic therapy. The aim of this study was to evaluate the accuracy of the CT-based TNM stage and high-risk features, including extramural venous invasion (EMVI) and tumour deposits, in the identification of patients with histopathological advanced disease, currently considered for neoadjuvant treatment (T3-4 disease). Methods All consecutive patients surgically treated for non-metastatic colon cancer between January 2018 and January 2020 in a referral centre for colorectal cancer were identified retrospectively. All tumours were staged on CT according to the TNM classification system. Additionally, the presence of EMVI and tumour deposits on CT was evaluated. The histopathological TNM classification was used as reference standard. Results A total of 176 patients were included. Histopathological T3-4 colon cancer was present in 85.0% of the patients with CT-detected T3-4 disease. Histopathological T3-4 colon cancer was present in 96.4% of the patients with CT-detected T3-4 colon cancer in the presence of both CT-detected EMVI and CT-detected tumour deposits. Histopathological T0-2 colon cancer was present in 50.8% of the patients with CT-detected T0-2 disease, and in 32.4% of the patients without CT-detected EMVI and tumour deposits. Conclusion The diagnostic accuracy of CT-based staging was comparable with previous studies. The presence of high-risk features on CT increased the probability of histopathological T3-4 colon cancer. However, a substantial part of the patients without CT-detected EMVI and tumour deposits was diagnosed with histopathological T3-4 disease. Hence, more accurate selection criteria are required to correctly identify patients with locally advanced disease.

Background The potential of learning analytics dashboards in virtual reality simulation‐based training environments to influence occupational self‐efficacy via self‐reflection phase processes in the Chemical industry is still not fully understood. Learning analytics dashboards provide feedback on learner performance and offer points of comparison (i.e., comparison with one's own past performance or comparison with peer performance) to help learners make sense of their feedback. Objectives We present a theoretical framework for describing learning analytics reference frames and investigate the impact of feedback delivered through dashboards with different reference frames on occupational self‐efficacy, while controlling for workplace self‐reflection. Methods This experimental study engaged 42 chemical operator employees, aged between 18 and 55 years, each with at least one year of experience. We utilised a two‐group design to ask two research question each with three competing hypotheses related to changes in occupational self‐efficacy, employing Bayesian informative hypothesis evaluation. Results and Conclusions Results for the primary research question suggest that dashboards with progress reference frames do not elicit greater change to self‐efficacy than those with social reference frames, however, they may elicit equal change. Furthermore, dashboards with social reference frames may elicit greater change to self‐efficacy than those with progress reference frames. Exploratory results found that dashboards with progress reference frames may elicit greater positive directional change than those with social reference frames and that they may elicit equal directional change. These findings contribute to the understanding of self‐efficacy beliefs within the Chemical industry, with potential impacts on skill development. The research may inform the design of targeted interventions and training programs to influence self‐efficacy. From a practical perspective, this research suggests that careful consideration is needed when choosing reference frames in learning analytics dashboards due to their potential consequences on the formation of learner self‐efficacy.

Aim A first episode of psychosis (FEP) is a stressful, often life‐changing experience. Scarce information is available about personal preferences regarding their care needs during and after a FEP. Whereas a more thorough understanding of these preferences is essential to aid shared decision‐making during treatment and improve treatment satisfaction. Methods Face‐to‐face interviews with participants in remission of a FEP were set up, addressing personal preferences and needs for care during and after a FEP. The interviews were conducted by a female and a male researcher, the latter being an expert with lived experience. Results Twenty individuals in remission of a FEP were interviewed, of which 16 had been hospitalized. The distinguished themes based on personal preferences were tranquillity, peace and quietness, information, being understood, support from significant others, and practical guidance in rebuilding one's life. Our findings revealed that the need for information and the need to be heard were often not sufficiently met. For 16/20 participants, the tranquillity of inpatient treatment of the FEP was predominantly perceived as a welcome safe haven. The presence and support of family and close friends were mentioned as an important factor in the process of achieving remission. Conclusions The current exploratory study showed that patients were able to indicate their personal needs. Important findings are the need for information and the need to be heard. Interestingly, hospitalization was mostly seen as an opportunity to achieve tranquillity. More lived experience expertise is needed to elucidate the needs of individuals in the early phase of a FEP to aid people who are recovering from their first psychosis in rebuilding their lives again.

Background Evidence on the (long‐term) safety of systemic immunomodulating therapies in atopic dermatitis (AD) generated by real‐world data is sparse. Objectives To describe real‐world reported adverse drug reactions (AEs) related to systemic immunomodulating therapy in patients with AD and to compare the incidence rates of AEs with the Summaries of Product Characteristics (SmPCs). Methods We conducted an observational prospective multi‐centre cohort study, using the TREAT NL registry. All severe AEs, AEs of special interest and serious AEs in adult and paediatric patients on systemic immunomodulating treatment (ciclosporin, methotrexate, azathioprine, mycophenolic acid, dupilumab, tralokinumab, baricitinib and upadacitinib) were assessed. Incidences rates of all (potentially) drug‐related AEs were standardized in patient years and compared to the cumulative incidences in the associated SmPCs. Results We collected 422 patient years of safety data from 266 patients, of whom 129 (48.5%) reported a total of 224 (potentially) drug‐related AEs. Compared to dupilumab's SmPC, higher incidence rates were found for four AEs (reported ≥5 times): eosinophilia, blepharitis, dry eyes and head and neck erythema (i.e. dupilumab facial redness). A higher incidence rate of fatigue was found in patients on oral methotrexate in our cohort compared to the SmPC. Two new drug‐related AEs (reported ≥5 times) were found in patients on dupilumab, including non‐infectious conjunctivitis and meibomian gland dysfunction. Conclusions Real‐world reported AEs captured in AD patient registries can add information on the estimated incidence of AEs and benefit clinical decision aids. Future studies using data derived from the TREAT NL registry combined with data from other registries within the TREAT Registry Taskforce will provide more information on (rare) AEs associated with immunomodulating therapy in AD patients.

For elderly frail patients with diffuse large B‐cell lymphoma (DLBCL), an attenuated chemo‐immunotherapy strategy of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R‐miniCHOP) was introduced as a treatment option as from 2014 onward in the Netherlands. Although R‐miniCHOP is more tolerable, reduction of chemotherapy could negatively affect survival compared to R‐CHOP. The aim of this analysis was to assess survival of patients treated with R‐miniCHOP compared to R‐CHOP. DLBCL patients ≥65 years, newly diagnosed in 2014–2020, who received ≥1 cycle of R‐miniCHOP or R‐CHOP were identified in the Netherlands Cancer Registry, with survival follow‐up through 2022. Patients were propensity‐score‐matched for baseline characteristics. Main endpoints were progression‐free survival (PFS), overall survival (OS), and relative survival (RS). The use of R‐miniCHOP in DLBCL increased from 2% in 2014 to 15% in 2020. In total, 384 patients treated with R‐miniCHOP and 384 patients treated with R‐CHOP were included for comparison (median age; 81 years, stage 3–4; 68%). The median number of R‐(mini)CHOP cycles was 6 (range, 1–8). The 2‐year PFS, OS and RS were inferior for patients treated with R‐miniCHOP compared to R‐CHOP (PFS 51% vs. 68%, p < .01; OS 60% vs. 75%, p < .01; RS 69% vs. 86%, p < .01). In multivariable analysis, patients treated with R‐miniCHOP had higher risk of all‐cause mortality compared to patients treated with R‐CHOP (HR 1.73; 95%CI, 1.39–2.17). R‐miniCHOP is effective for most elderly patients. Although survival is inferior compared to R‐CHOP, the use of R‐miniCHOP as initial treatment is increasing. Therefore, fitness needs to be carefully weighed in treatment selection.

Purpose To identify barriers and facilitators for implementing the Survivorship Passport (SurPass) v2.0 in six long-term follow-up (LTFU) care centres in Europe. Methods Stakeholders including childhood cancer survivors (CCSs), healthcare providers (HCPs), managers, information and technology (IT) specialists, and others, participated in six online Open Space meetings. Topics related to Care, Ethical, Legal, Social, Economic, and Information & IT-related aspects of implementing SurPass were evaluated. Results The study identified 115 barriers and 159 facilitators. The main barriers included the lack of standardised LTFU care in centres and network cooperation, uncertainty about SurPass accessibility, and uncertainty about how to integrate SurPass into electronic health information systems. The main facilitators included standardised and coordinated LTFU care in centres, allowing CCSs to conceal sensitive information in SurPass and (semi)automatic data transfer and filing. Conclusions Key barriers to SurPass implementation were identified in the areas of care, ethical considerations, and information & IT. To address these barriers and facilitate the implementation on SurPass, we have formulated 27 recommendations. Key recommendations include using the internationally developed protocols and guidelines to implement LTFU care, making clear decisions about which parties have access to SurPass data in accordance with CCSs, and facilitating (semi)automated data transfer and filing using Health Level 7 (HL7) Fast Healthcare Interoperability Resources (FHIR). Implications for Cancer Survivors The findings of this study can help to implement SurPass and to ensure that cancer survivors receive high-quality LTFU care with access to the necessary information to manage their health effectively.