University Medical Center Utrecht

Objectives: To determine the presence and prognostic value of PD-L1 and PD-L2 expression, and tumor-infiltrating lymphocytes (TILs) in oral squamous cell carcinoma (OSCC) of non-smokers and non-drinkers (NSND). Materials and methods: Clinical characteristics and tumor tissue of 86 NSND with OSCC were retrospectively collected and analyzed for protein expression on tissue microarrays. Immunohistochemistry was performed for expression of PD-L1 CPS, PD-L2 TPS, and PD-1, CD45, CD8, CD4, CD3, and FoxP3-positive TILs/mm2. Slides were digitally evaluated using QuPath. Differences in 5-year DFS and OS were determined by log rank analysis. Predictors for survival were determined by multivariable cox regression analysis. Results: Eighty-eight percent (76/86) of OSCC showed PD-L1 expression (CPS ≥1). Patients with high numbers of CD4-positive TILs showed a better DFS and OS than patients with low numbers of CD4-positive TILs. In the best multivariable model, CD4-positive TILs were an independent predictor for DFS (p = 0.010) and OS (p = 0.002) too. Additionally, patients with high numbers of CD45-positive TILs and a high CD8/FoxP3 ratio showed a better OS, of which the CD8/FoxP3 ratio was a near significant independent predictor (p = 0.050). Over 40 % of OSCC were PD-L1+/TIL+. Conclusion: A large number of OSCC in NSND show PD-L1 expression (CPS ≥1). CD4 was a significant predictor for DFS and OS, in addition to the CD8/FoxP3 ratio being a near significant predictor for OS. The combination of frequent high CD8-positive TIL infiltrates in PD-L1-positive tumors makes NSND with OSCC in theory interesting candidates for treatment with immune checkpoint inhibitors.

Titanium-based lattice structures have gained significant attention in biomedical engineering due to their potential to mimic bone-like behavior and improve implant performance. This study evaluates the performance of bio-inspired Ti64 TPMS Gyroyd and Stochastic lattice structures fabricated via Powder Bed Fusion-Laser Beam (PBF-LB), focusing on their in-vivo and ex-vivo mechanical and biological responses for biomedical applications. Utilizing an SLM 280 HL printer, samples exhibited notable geometric accuracy essential for mechanical integrity. The study highlights significant mechanical properties and geometric precision improvements achieved through chemical etching. Mechanical characterization revealed that the as-built Gyroid lattice had the highest elastic modulus (3.64 GPa) and yield strength (200.65 MPa), which improved post-etching (3.62 GPa and 219.35 MPa, respectively). The Stochastic lattice demonstrated lower yield strength values post-etching (169.81 MPa). In-vivo analyses in horse models, both structures demonstrated excellent biocompatibility and osseointegration with no adverse inflammatory responses. Ex-vivo push-out tests showed that the chemically etched Gyroid structure achieved the highest resistance to push-out force (1645.407 N) and most significant displacement (2.754 mm), indicating superior energy absorption (4920.425 mJ). These findings underscore the critical influence of microstructural design and surface treatments on implant functionality, offering novel insights into improving biomedical implant performance through lattice architecture and post-processing.

Background It is well established that patients with severe mental illness and those treated with atypical antipsychotics (AAPs) are at an increased risk of cardiovascular disease. However, primary care currently lacks adequate monitoring of AAP usage, its effects, and the associated cardiovascular risk. We have developed TACTIC, a transmural collaborative care model for patients using AAPs prescribed by the general practitioner (GP) to address the issues of potential overtreatment with AAPs and undertreatment for cardiovascular risk. TACTIC comprises three steps: an informative video for patients, a multidisciplinary meeting, and a shared decision-making consultation with the GP. Objectives To evaluate TACTIC's effectiveness on cardiovascular risk and mental health and its cost-effectiveness. Methods We will conduct an incomplete stepped wedge cluster randomized trial in the Netherlands. 40 GP-nurse clusters are randomized into four waves. Each cluster recruits adult patients (25–85 years), without prior diagnoses of dementia, delirium, or cardiovascular disease, for whom the GP prescribes AAPs. Every five months, a new wave starts with TACTIC. Measurements are taken before the intervention starts and every 5 months until the study concludes. Primary outcomes are cardiovascular risk and mental health as measured with the QRISK3 score and MHI5, respectively. The economic evaluation consists of two cost-utility analyses, one on the data collected alongside the trial and one based on a model extrapolating the trial data to a 10-year horizon. We will also evaluate the process of delivering TACTIC. Conclusion This study will assess TACTIC's (cost)effectiveness and provide insights for successful delivery in general practice. Clinical trials registration clinicaltrials.gov NCT05647980.

Objective. The small bowel is one of the most radiosensitive organs-at-risk during radiotherapy in the pelvis. This is further complicated due to anatomical and physiological motion. Thus, its accurate tracking becomes of particular importance during therapy delivery, to obtain better dose-toxicity relations and/or to perform safe adaptive treatments. The aim of this work is to simultaneously optimize the MR imaging sequence and motion estimation solution towards improved small bowel tracking precision during radiotherapy delivery. Approach. An MRI sequence was optimized, to adhere to the respiratory and peristaltic motion frequencies, by assesing the performance of an image registration algorithm on data acquired on volunteers and patients. In terms of tracking, three registration algorithms, previously-employed in the scope of image-guided radiotherapy, were investigated and optimized. The optimized scan was acquired for 7.5 min, in 18 patients and for 15 min, in 10 volunteers at a 1.5 T MRL (Unity, Elekta AB). The tracking precision was evaluated and validated by means of three different quality assurance criteria: Structural Similarity Index Measure (SSIM), Inverse Consistency (IC) and Absolute Intensity Difference. Main results. The optimal sequence was a balanced Fast Field Echo, which acquired a 3D volume of the abdomen, with a dynamic scan time of 1.8 s. An optical flow algorithm performed best and which was able to resolve most of the motion. This was shown by mean IC values of <1 mm and a mean SSIM >0.9 for the majority of the cases. A strong positive correlation (p <0.001) between the registration performance and visceral fat percentage was found, where a higher visceral fat percentage gave a better registration due to the better image contrast. Significance. A method for simultaneous optimization of imaging and tracking was presented, which derived an imaging and registration procedure for accurate small bowel tracking on the MR-Linac.

Background In the Netherlands a centralised approach to respiratory care for patients with Amyotrophic Lateral Sclerosis is used based on national guidelines. Patients with Amyotrophic Lateral Sclerosis are referred to one of 4 centres for Home Mechanical Ventilation. Objective Our aim was to evaluate the respiratory care according to the Dutch guideline by evaluation of reasons for starting non-invasive ventilation, timing of initiating and survival in patients with Amyotrophic Lateral Sclerosis using non-invasive ventilation. Method A retrospective chart-review was performed of 323 patients, who had been referred to centres for Home Mechanical Ventilation in 2016–2018. Data collected included symptoms of hypoventilation, forced vital capacity, blood gasses, criteria for (not) initiating non-invasive ventilation, and survival. Kaplan-Meyer curves and Multivariate Cox proportional hazard regression were used in the analysis. Results The main criteria used for initiating non-invasive ventilation were hypercapnia (77%) and the presence of orthopnea and/or dyspnoea (25%). Median survival after starting non-invasive ventilation was 11 months, and was shorter for patients with bulbar disease onset and older age. The proportion of the total disease duration that was spent on non-invasive ventilation was not significantly affected by age, sex or site of disease. Seventy nine percent of the patients who didn’t start non-invasive ventilation had reached a joint decision with their caregivers and/or physicians. Conclusion Key outcomes of the Dutch centralised respiratory care approach have shown that most patients were initiated on non-invasive ventilation due to presence of hypercapnia and/or dyspnoea/orthopnea, which is according to the Dutch guidelines. Half of patients spent at least 33% of their disease duration on non-invasive ventilation. To help find the optimal criteria and timing for non-invasive ventilation it would be useful for other countries to share their key outcomes as well.

Background Pediatric healthcare professionals facilitate children to enhance and maintain a physically active lifestyle. Activity monitors (AM) can help pediatric healthcare professionals assess physical activity in everyday life. However, validation research of activity monitors has often been conducted in laboratories and insight into physical activity of children in their own everyday environment is lacking. Our goal was to study the criterion validity of a prototype AM (AM-p) model in a natural setting. Methods Cross-sectional community-based study with ambulatory children (2-19 years) with and without developmental disability. Children wore the AM-p on the ankle and were filmed (gold standard) while performing an activity protocol in a natural setting. We labelled all videos per 5-second epoch with individual activity labels. Raw AM-p data were synchronized with activity labels. Using machine learning techniques, activity labels were subdivided in three pre-defined categories. Accuracy, recall, precision, and F1 score were calculated per category. Results We analyzed data of 93 children, of which 28 had a developmental disability. Mean age was 11 years (SD 4.5) with 55% girls. The AM-p model differentiated between ‘stationary’, ‘cycling’ and ‘locomotion’ activities with an accuracy of 82%, recall of 78%, precision of 75%, and F1 score of 75%, respectively. Children older than 13 years with typical development can be assessed more accurately than younger children (2-12 years) with and without developmental disabilities. Conclusion The single ankle-worn AM-p model can differentiate between three activity categories in children with and without developmental disabilities with good accuracy (82%). Because the AM-p can be used for a heterogenous group of ambulatory children with and without developmental disabilities, it may support the clinical assessment for pediatric healthcare professionals in the future.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) aims to cure patients without inducing severe graft-versus-host disease (GVHD) or relapse. In prospective studies of mostly pediatric patients with haploidentical donors, ex vivo αβTCR/CD19 depletion has shown to have low incidences of GVHD, but data for adults with matched related (MRD) or unrelated donors (MUD) remain limited. We analyzed the outcomes of recipients who received a myeloablative regimen plus ATG, followed by an αβTCR/CD19-depleted allograft (cohort D+ATG (n = 122)), and compared outcomes to T cell-replete cohorts (cohort R (N = 60)); without ATG; R+ATG = with ATG (N = 129) in a single-center retrospective analysis. In D+ATG, the incidence of aGVHD grade III–IV was 7%, compared to 13% in R and 16% in R+ATG (p = 0.09). Extensive cGVHD was reduced from 23% in R and 10% in R+ATG to 2% in D+ATG (p < 0.001). The reduced incidence of cGVHD led to a superior GVHD-relapse-free survival (GRFS) of 56.7% in D+ATG versus 36.7% in R and 42.8% in R+ATG (p = 0.03) at 2 years. In conclusion, the combination of myeloablative conditioning, ATG, and ex vivo αβTCR/CD19 depletion appears to be a promising approach to enhance GRFS in adult patients up to 75 years of age undergoing allo-HSCT.

An estimated 10% of coronavirus disease (COVID‐19) survivors suffer from persisting symptoms referred to as long COVID (LC), a condition for which approved treatment options are still lacking. This systematic review (PROSPERO: CRD42024499281) aimed to explore the pathophysiological mechanisms underlying LC and potential treatable traits across symptom‐based phenotypes. We included studies with primary data, written in English, focusing on omics analyses of human samples from LC patients with persistent symptoms of at least 3 months. Our search in PubMed and Embase, conducted on January 8, 2024, identified 642 studies, of which 29 met the inclusion criteria after full‐text assessment. The risk of bias was evaluated using the Joanna Briggs Institute appraisal tool. The synthesis of omics data, including genomics, transcriptomics, proteomics, metabolomics, and metagenomics, revealed common findings associated with fatigue, cardiovascular, pulmonary, neurological, and gastrointestinal phenotypes. Key findings included mitochondrial dysfunction, dysregulated microRNAs associated with pulmonary dysfunction, tissue impairment, blood–brain barrier disruption, coagulopathy, vascular dysfunction, microbiome disturbances, microbial‐derived metabolite production and persistent inflammation. Limitations include cross‐study heterogeneity and variability in sampling methods. Our review emphasizes the complexity of LC and the need for further longitudinal omics‐integrated studies to advance the development of biomarkers and targeted treatments.

Respiratory syncytial virus (RSV) infections are a major public health concern for pediatric populations and older adults. Viral kinetics, the dynamic processes of viral infection within an individual over time, vary across different populations. However, RSV transmission in different age groups is incompletely understood from the perspective of individual-level viral kinetics. Using a mathematical model and a hierarchical Bayesian framework, we analyzed viral kinetics in 53 individuals from different age groups to estimate infection parameters and linked within-host viral load to transmission probability through a probabilistic model. We found that children had higher peak viral loads and longer shedding periods compared to other age groups, suggesting a higher transmission probability over the infectious period. We validated our findings by comparing the estimated secondary attack rate across different age groups to empirical estimates from household transmission studies. Our work highlights the importance of age-specific considerations in understanding and managing RSV infections.

Background The Dutch acute health care system faces challenges with limited resources and increasing patient numbers. To reduce outpatient follow-up, direct discharge (DD) has been implemented in over 30 out of 80 Dutch hospitals. With DD, no routine follow-up appointments are scheduled after the emergency department (ED) visit for low-complex, isolated, and stable musculoskeletal injuries. This policy is supported by information leaflets, a smartphone app, and a telephone helpline with human support. Growing evidence shows that DD is satisfactory, safe, and effective in reducing secondary health care use, but thorough patient experiences are lacking. Objective The aim of this study was to explore the experiences of patients with DD to ensure durable adoption and to improve the treatment protocol. Methods A mixed method study was conducted parallel to the implementation of DD in 3 hospitals. Data were collected through a survey directly after the ED visit, a survey 3 months post injury, and semistructured interviews. Quantitative data were reported descriptively, and qualitative data used thematic analysis. Outcomes included the Bowen feasibility parameters: implementation, acceptance, preliminary efficacy, and demand. All patients who consented to the study face-to-face with one of the 12 low-complex musculoskeletal injuries were included in the study during the implementation period. Results Of the 429 patients who started the primary survey, 138 patients completed both surveys. A total of 18 semistructured interviews were conducted and analyzed. Patients reported a median treatment satisfaction score of 7.8 (IQR 6.6-8.8) on a 10-point scale of DD at the ED. Information quality was experienced as good (106/138, 77%), and most preferred DD over face-to-face follow-up (79/138, 59%). Patient information demands and app use varied among patients, with a median frequency of use of 4 times (ranging from 1 to 30). Conclusions This study shows that patients consider DD a feasible and safe alternative to traditional treatment, with a favorable perception of its acceptability, efficacy, applicability, and demand. Nevertheless, response rates were relatively low, and personal nuances and preferences must be considered when implementing DD. Clinicians and policy makers can use the insights to improve DD and work towards the integration of DD into clinical practice and future guidelines.

Home‐sampling for therapeutic drug monitoring (TDM) for oral targeted anticancer drugs offers a promising alternative to traditional hospital‐based sampling methods, though it presents challenges. This review aims to summarize the state‐of‐the‐art of home‐sampling methods for TDM and evaluates the analytical and clinical validation challenges. A comprehensive search was conducted across Embase, Medline, and Scopus. Eligible articles described analytical and/or clinical validation of home‐sampling methods for oral targeted anticancer drugs. ASReview was used to process unique references and to identify relevant studies. Of the 39 included articles, 32 detailed on analytical validation experiments, while 27 covered clinical validation experiments. Dried blood spot and volumetric absorptive microsampling were the primary sampling methods. Key challenges were ensuring robust sample collection, sample pretreatment, hematocrit effects, and sample stability, which were generally thoroughly investigated. Clinical validation yielded promising results for most analytes, although external validation remains crucial for confirming reliability. Home‐sampling methods for TDM of oral targeted anticancer drugs show promising results for clinical implementation. Methods for well‐studied drugs may be clinically implemented immediately, while others require further external validation. Future research should address device‐specific challenges and assess patient feasibility to facilitate the routine use of home‐sampling in clinical practice.

Background Acute postoperative seizures (APOS) are common phenomena following resective epilepsy surgery and can be categorized as running-down (RDS) or running-up seizures (RUS). This differentiation is made retrospectively, considering their classification is based on seizure recurrence. However, early differentiation of RDS from RUS may prevent unnecessary escalation of anti-seizure medication or reoperation. This review provides an overview of the available literature on variables influencing the evolution to RDS/RUS in patients exhibiting acute or early postoperative seizures. Methods A database search was performed addressing studies related to the running-down phenomenon and postoperative seizures in PubMed and Embase. Eligibility required a clear definition of acute or early postoperative seizures. Studies concerning any type of epilepsy surgery or pathology were accepted, excluding those related to high-grade malignancies. Results The search yielded a total of n = 1,690 records. We included n = 21 studies with a total of n = 1,496 patients, which examined variables associated with long-term seizure outcome. Interictal epileptiform discharge presence/laterality, epileptogenic zone size, APOS frequency, and history of generalized tonic–clonic seizures, head trauma, or encephalitis were associated with seizure outcome. Ictal expression and timing of seizure recurrence appeared less relevant. However, these associations are uncertain due to conflicting results between studies, likely due to small sample sizes, a limited reporting of secondary variables, and heterogeneity in study population and methodology. Conclusions The variability in clinical outcome following APOS highlights the need for a refined classification of postoperative seizures. Future research should focus on constructing and validating a multifactorial model integrating EEG-derived variables, APOS frequency, and medical history to more accurately predict long-term seizure outcome following resective epilepsy surgery.

Objective To investigate cognitive impairments in amyotrophic lateral sclerosis (ALS), extending both within and beyond the established frontotemporal dementia (FTD) spectrum, using the Complementary Cognitive ALS Screen (C-CAS). Methods The C-CAS, designed to complement the Edinburgh cognitive and behavioural ALS screen (ECAS), explores cognitive (sub)domains not investigated by the ECAS. Normative data were collected, and models adjusted for age, sex, and education level were developed. Item scores below the 5th percentile in controls were considered abnormal. A sum score was constructed, and C-CAS impairments were compared between ALS patients and controls, and to ECAS impairments. Results Data from 314 controls and 184 ALS patients were analyzed. The C-CAS is feasible, well-tolerated, and takes 15–20 min to complete. ALS patients performed worse across all 12 items. Within the FTD spectrum, impairments in social cognition, inhibition, and cognitive flexibility were identified in up to 16%, 14%, and 12% of ALS patients, respectively, with minimal overlap with ECAS impairments. Beyond the FTD spectrum, impairments were found in visuoconstruction, incidental non-verbal memory and body orientation (13% each), with minimal overlap with ECAS memory or visuospatial impairments. Overall, 24% of the ALS patients obtained an abnormal C-CAS sum score. Compared to the ECAS, the C-CAS detected additional impairments in 15% of ALS patients. Item-specific and sum score results based on normative data can be accessed at (https://apps4mnd.com/ccas/). Interpretation We identified cognitive impairments in ALS within and beyond the FTD spectrum not captured by existing screening tools. The C-CAS complements the ECAS, improving personalized counseling and research stratification in ALS.

BACKGROUND: Studies in young patients with stroke identified coronary artery disease (CAD) as a main contributor to mortality. In the present NOR-­ SYS (Norwegian Stroke in the Young Study), we aimed to investigate the prevalence of CAD, and the impact on new vascular events and mortality. METHODS: A total of 385 patients with ischemic stroke, aged ≤60 years, were included. CAD was defined as a history of CAD or positive coronary imaging (computed tomography or coronary angiography). RESULTS: Mean age was 49.6 years, and 68.1% were men. The prevalence of CAD was 25.2% (n=97) (nonobstructive, 9.6% [n=37]; and obstructive, 15.6% [n=60]). In the subsample of patients without clinical CAD but with femoral plaque on ultrasound (n=58) who underwent cardiac computed tomography, 46% (n=27) had nonobstructive CAD and 28% (n=16) had obstructive CAD. During a median follow-­ up of 10.1 years, 36 patients (9.4%) died, 84 (21.8%) reached a composite end point of new stroke, myocardial infarction, or death, whereas 64 (16.6%) had a composite end point of new stroke or death. Event-­ free survival was significantly lower in patients with obstructive CAD versus no CAD or nonobstructive CAD (log-­ rank P<0.001). In the multivari- able Cox regression models, CAD was a strong and independent predictor of all-­ cause mortality (hazard ratio [HR], 2.20 [95% CI, 1.05–4.60]; P=0.037) and the composite end point of death or recurrent ischemic stroke (HR, 3.24 [95% CI, 1.46–7.20];P=0.004). CONCLUSIONS: In young and middle-­ aged ischemic stroke survivors, a quarter of patients had CAD. CAD was an independent predictor of recurrent stroke and mortality. In patients without previous CAD, but femoral plaque on ultrasound, nearly a half had nonobstructive and one-­ fourth had obstructive CAD. Systematic screening with cardiac computed tomography may identify high-­ risk patients after ischemic stroke.

The treatment landscape for metastatic colorectal cancer (mCRC) has evolved into a continuum of care with an essential role for biomarkers and molecular subgroups. Treatment guidelines are primarily based on trial results; however, populations and outcomes differ from clinical practice. To support the interpretation of trial results and to assist in tailored patient counseling, we evaluated real‐world treatment patterns and outcomes according to RAS/BRAF status. We included all patients diagnosed with BRAFV600E‐mutated mCRC in 2015–2020, participating in the Prospective Dutch Colorectal Cancer cohort study, plus a 1:2 random selection of patients with RAS‐mutated and double wild‐type mCRC. We evaluated differences in administered lines of treatment (LOTs), local treatment, attrition rates, treatment duration, progression‐free survival (PFS) and overall survival (OS). 178 BRAFV600E‐mutated, 221 RAS‐mutated, and 174 double wild‐type patients were included. Of BRAFV600E‐mutated patients, 26% received ≥3 LOTs, compared to 42% and 47% of the RAS‐mutated and double wild‐type patients, respectively (p = .002). Local treatment was performed in 25% of BRAFV600E‐mutated, 43% of RAS‐mutated, and 49% of double wild‐type patients (p < .001). Median OS from diagnosis was 15.4, 24.1, and 32.6 months, respectively (p < .001) and loss of prognostic value of RAS/BRAF was observed from the 3rd LOT onwards (p = .17 and p = .54). This paper provides a comprehensive overview of the treatment landscape of mCRC per RAS/BRAF status in daily clinical practice. The observed substantial treatment heterogeneity within and between molecular subgroups underlines the importance of collecting real‐world data to address post‐trial knowledge gaps and to optimize individualized counseling for all mCRC patients.

Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) constitute a promising therapy for myocardial infarction (MI). The lack of an effective immunosuppressive regimen, combined with single-cell transplantations, results in suboptimal outcomes, such as poor engraftment and compromised therapeutic efficacy. This study aimed to confirm the increased retention of hiPSC-CMs microtissues (CMTs) over single-cell grafts. To ensure the long-term survival of CMTs for potential cardiac applications, CMTs were transplanted in a porcine model of MI using a triple immunosuppression protocol designed to limit immune cell infiltration. Acute evaluation of spherical hiPSC-CMs aggregates and dissociated aggregates followed by the development of a triple immunosuppression protocol were performed in healthy animals. Long-term survival of CMTs was later examined in pigs that underwent a transient coronary occlusion. Two weeks post-MI, the immunosuppression treatment was initiated and on day 28 the animals were transplanted with CMTs and followed for four more weeks. Acutely, CMTs showed superior retention compared to their dissociated counterparts. The immunosuppression regimen led to no organ damage and stable levels of circulating drugs once optimal dose was achieved. Two weeks post-xenotransplantation in healthy pigs, histology revealed that immunosuppressed animals displayed a significant decrease in total cellular infiltrates, particularly in CD3⁺ T cells. Pigs that underwent coronary occlusion, which later were immunosuppressed and treated with CMTs (5 × 10⁷ cells), showed cell engraftment onto the native myocardium four weeks post-transplantation. This study supports the use of a triple immunosuppression cocktail to ensure long-term survival of CMTs for the treatment of MI. Graphical Abstract In vivo evaluation of CMT transplantation as a regenerative therapy for myocardial infarction. Cardiac microtissues are potential therapies that, when administered in immunosuppressed pigs, have the potential to survive long-term and remuscularize the infarcted myocardium. Figure created with https://BioRender.com.