Leiden University Medical Centre
Recent publications
Chimeric antigen receptor (CAR) T cell therapies have resulted in profound clinical responses in the treatment of CD19-positive hematological malignancies, but a significant proportion of patients do not respond or relapse eventually. As an alternative to CAR T cells, T cells can be engineered to express a tumor-targeting T cell receptor (TCR). Due to HLA restriction of TCRs, CARs have emerged as a preferred treatment moiety when targeting surface antigens, despite the fact that functional differences between engineered TCR (eTCR) T and CAR T cells remain ill-defined. Here, we compared the activity of CAR T cells versus engineered TCR T cells in targeting the B cell malignancy-associated antigen CD20 as a function of antigen exposure. We found CAR T cells to be more potent effector cells, producing higher levels of cytokines and killing more efficiently than eTCR T cells in a short time frame. However, we revealed that the increase of antigen exposure significantly impaired CAR T cell expansion, a phenotype defined by high expression of coinhibitory molecules and effector differentiation. In contrast, eTCR T cells expanded better than CAR T cells under high antigenic pressure, with lower expression of coinhibitory molecules and maintenance of an early differentiation phenotype, and comparable clearance of tumor cells.
While regulatory T cells (Tregs) and macrophages have been recognized as key orchestrators of cancer-associated immunosuppression, their cellular crosstalk within tumors has been poorly characterized. Here, using spontaneous models for breast cancer, we demonstrate that tumor-associated macrophages (TAMs) contribute to the intratumoral accumulation of Tregs by promoting the conversion of conventional CD4+ T cells (Tconvs) into Tregs. Mechanistically, two processes were identified that independently contribute to this process. While TAM-derived TGF-β directly promotes the conversion of CD4+ Tconvs into Tregs in vitro, we additionally show that TAMs enhance PD-1 expression on CD4+ T cells. This indirectly contributes to the intratumoral accumulation of Tregs, as loss of PD-1 on CD4+ Tconvs abrogates intratumoral conversion of adoptively transferred CD4+ Tconvs into Tregs. Combined, this study provides insights into the complex immune cell crosstalk between CD4+ T cells and TAMs in the tumor microenvironment of breast cancer, and further highlights that therapeutic exploitation of macrophages may be an attractive immune intervention to limit the accumulation of Tregs in breast tumors.
Issues related to controlled human infection studies using Schistosoma mansoni (CHI-S) were explored to ensure the ethical and voluntary participation of potential CHI-S volunteers in an endemic setting in Uganda. We invited volunteers from a fishing community and a tertiary education community to guide the development of informed consent procedures. Consultative group discussions were held to modify educational materials on schistosomiasis, vaccines and the CHI-S model and similar discussions were held with a test group. With both groups, a mock consent process was conducted. Fourteen in-depth key informant interviews and three group discussions were held to explore perceptions towards participating in a CHI-S. Most of the participants had not heard of the CHI-S. Willingness to take part depended on understanding the study procedures and the consenting process. Close social networks were key in deciding to take part. The worry of adverse effects was cited as a possible hindrance to taking part. Volunteer time compensation was unclear for a CHI-S. Potential volunteers in these communities are willing to take part in a CHI-S. Community engagement is needed to build trust and time must be taken to share study procedures and ensure understanding of key messages.
Background Destination left ventricular assist device placement is increasing as a result of donor shortages and changing patient attitudes. As organ shortages become critical, LVAD programs become fundamental even in more remote regions of the world including island states. Here, we provide a look into the current state and availability of LVAD programs in island states. Main body A narrative review was performed using the World Health Organization Global Index Medicus and PubMed/MEDLINE databases to identify articles describing the island states having reported LVAD placements and programs. Additionally, INTERMACS reports were used. Data were retrieved and a review is presented describing the current state of LVADs in island states. The Caribbean region as a whole has a heart failure (HF) prevalence of 814 per 100,000 and Oceania 667 per 100,000 people. We estimate that over 3000 people in these islands need either a heart transplant or an LVAD. Short conclusion For HF patients living in island regions, special attention should be paid to the inability of having access to specialized mainland medical care. The continuous quest for a solution to HF in island regions should include the establishing of high-quality LVAD programs in a transfer-network centralized/regionalized system to care for those patients not candidates for long-distance air-bridging.
Background: Four-dimensional (4D) flow cardiovascular magnetic resonance (CMR) allows quantification of biventricular blood flow by flow components and kinetic energy (KE) analyses. However, it remains unclear whether 4D flow parameters can predict cardiopulmonary exercise testing (CPET) as a clinical outcome in repaired tetralogy of Fallot (rTOF). Current study aimed to (1) compare 4D flow CMR parameters in rTOF with age- and gender-matched healthy controls, (2) investigate associations of 4D flow parameters with functional and volumetric right ventricular (RV) remodelling markers, and CPET outcome. Methods: Sixty-three rTOF patients (14 paediatric, 49 adult; 30 ± 15 years; 29 M) and 63 age- and gender-matched healthy controls (14 paediatric, 49 adult; 31 ± 15 years) were prospectively recruited at four centers. All underwent cine and 4D flow CMR, and all adults performed standardized CPET same day or within one week of CMR. RV remodelling index was calculated as the ratio of RV to left ventricular (LV) end-diastolic volumes. Four flow components were analyzed: direct flow, retained inflow, delayed ejection flow and residual volume. Additionally, three phasic KE parameters normalized to end-diastolic volume (KEiEDV), were analyzed for both LV and RV: peak systolic, average systolic and peak E-wave. Results: In comparisons of rTOF vs. healthy controls, median LV retained inflow (18% vs. 16%, P = 0.005) and median peak E-wave KEiEDV (34.9 µJ/ml vs. 29.2 µJ/ml, P = 0.006) were higher in rTOF; median RV direct flow was lower in rTOF (25% vs. 35%, P < 0.001); median RV delayed ejection flow (21% vs. 17%, P < 0.001) and residual volume (39% vs. 31%, P < 0.001) were both greater in rTOF. RV KEiEDV parameters were all higher in rTOF than healthy controls (all P < 0.001). On multivariate analysis, RV direct flow was an independent predictor of RV function and CPET outcome. RV direct flow and RV peak E-wave KEiEDV were independent predictors of RV remodelling index. Conclusions: In this multi-scanner multicenter 4D flow CMR study, reduced RV direct flow was independently associated with RV dysfunction, remodelling and, to a lesser extent, exercise intolerance in rTOF patients. This supports its utility as an imaging parameter for monitoring disease progression and therapeutic response in rTOF. Clinical Trial Registration https://www.clinicaltrials.gov . Unique identifier: NCT03217240.
Background Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. Methods Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes. Results Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions. Conclusion This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.
Purpose Dynamic radiostereometric analysis (dRSA) enables precise non-invasive three-dimensional motion-tracking of bones for assessment of joint kinematics. Hereby, the biomechanical effects of arthroscopic osteochondroplasty of the hip (ACH) can be evaluated in patients with femoroacetabular impingement (FAI). The aim was to investigate the pre- and postoperative range of motion (ROM) and the CT bone volume removed (BV) after ACH. We hypothesize increase in ROM 1 year after surgery. Methods Thirteen patients (6 female) with symptomatic FAI were included prospectively. The patient’s hips were CT-scanned and CT-bone models were created. Preoperative dRSA recordings were acquired during passive flexion to 90°, adduction, and internal rotation (FADIR). ACH was performed, CT and dRSA were repeated 3 months and 1 year postoperatively. Hip joint kinematics before, and 3 months and 1 year after ACH were compared pairwise. The bone volume removal was quantified and compared to change in ROM. Results Mean hip internal rotation, adduction and flexion were all unchanged after ACH at 1-year follow-up ( p > 0.84). HAGOS scores revealed improvement of quality of life (QOL) from 32 to 60 ( p = 0.02). The BV was between 406 and 1783 mm ³ and did not correlate to post-operative ROM. Conclusions ACH surgery in FAI patients had no impact of ROM at 1-year follow-up. QOL improved significantly. This indicates that the positive clinical effects reported after ACH might be a result of reduced labral stress and cartilage pressure during end-range motion rather than increased ROM. Level of evidence Therapeutic prospective cohort study, level II.
Background Migraine is a common brain disorder that predominantly affects women. Migraine pain seems mediated by the activation of mechanosensitive channels in meningeal afferents. Given the role of transient receptor potential melastatin 3 (TRPM3) channels in mechanical activation, as well as hormonal regulation, these channels may play a role in the sex difference in migraine. Therefore, we investigated whether nociceptive firing induced by TRPM3 channel agonists in meningeal afferents was different between male and female mice. In addition, we assessed the relative contribution of mechanosensitive TRPM3 channels and that of mechanosensitive Piezo1 channels and transient receptor potential vanilloid 1 (TRPV1) channels to nociceptive firing relevant to migraine in both sexes. Methods Ten- to 13-week-old male and female wildtype (WT) C57BL/6 J mice were used. Nociceptive spikes were recorded directly from nerve terminals in the meninges in the hemiskull preparations. Results Selective agonists of TRPM3 channels profoundly activated peripheral trigeminal nerve fibres in mouse meninges. A sex difference was observed for nociceptive firing induced by either PregS or CIM0216, both agonists of TRPM3 channels, with the induced firing being particularly prominent for female mice. Application of Yoda1, an agonist of Piezo1 channels, or capsaicin activating TRPV1 channels, although also leading to increased nociceptive firing of meningeal fibres, did not reveal a sex difference. Cluster analyses of spike activities indicated a massive and long-lasting activation of TRPM3 channels with preferential induction of large-amplitude spikes in female mice. Additional spectral analysis revealed a dominant contribution of spiking activity in the α- and β-ranges following TRPM3 agonists in female mice. Conclusions Together, we revealed a specific mechanosensitive profile of nociceptive firing in females and suggest TRPM3 channels as a potential novel candidate for the generation of migraine pain, with particular relevance to females.
While the opportunities of ML and AI in healthcare are promising, the growth of complex data-driven prediction models requires careful quality and applicability assessment before they are applied and disseminated in daily practice. This scoping review aimed to identify actionable guidance for those closely involved in AI-based prediction model (AIPM) development, evaluation and implementation including software engineers, data scientists, and healthcare professionals and to identify potential gaps in this guidance. We performed a scoping review of the relevant literature providing guidance or quality criteria regarding the development, evaluation, and implementation of AIPMs using a comprehensive multi-stage screening strategy. PubMed, Web of Science, and the ACM Digital Library were searched, and AI experts were consulted. Topics were extracted from the identified literature and summarized across the six phases at the core of this review: (1) data preparation, (2) AIPM development, (3) AIPM validation, (4) software development, (5) AIPM impact assessment, and (6) AIPM implementation into daily healthcare practice. From 2683 unique hits, 72 relevant guidance documents were identified. Substantial guidance was found for data preparation, AIPM development and AIPM validation (phases 1–3), while later phases clearly have received less attention (software development, impact assessment and implementation) in the scientific literature. The six phases of the AIPM development, evaluation and implementation cycle provide a framework for responsible introduction of AI-based prediction models in healthcare. Additional domain and technology specific research may be necessary and more practical experience with implementing AIPMs is needed to support further guidance.
Background To assess trends in the quality of care for COVID-19 patients at the ICU over the course of time in the Netherlands. Methods Data from the National Intensive Care Evaluation (NICE)-registry of all COVID-19 patients admitted to an ICU in the Netherlands were used. Patient characteristics and indicators of quality of care during the first two upsurges (N = 4215: October 5, 2020–January 31, 2021) and the final upsurge of the second wave, called the ‘third wave’ (N = 4602: February 1, 2021–June 30, 2021) were compared with those during the first wave (N = 2733, February–May 24, 2020). Results During the second and third wave, there were less patients treated with mechanical ventilation (58.1 and 58.2%) and vasoactive drugs (48.0 and 44.7%) compared to the first wave (79.1% and 67.2%, respectively). The occupancy rates as fraction of occupancy in 2019 (1.68 and 1.55 vs. 1.83), the numbers of ICU relocations (23.8 and 27.6 vs. 32.3%) and the mean length of stay at the ICU (HRs of ICU discharge = 1.26 and 1.42) were lower during the second and third wave. No difference in adjusted hospital mortality between the second wave and the first wave was found, whereas the mortality during the third wave was considerably lower (OR = 0.80, 95% CI [0.71–0.90]). Conclusions These data show favorable shifts in the treatment of COVID-19 patients at the ICU over time. The adjusted mortality decreased in the third wave. The high ICU occupancy rate early in the pandemic does probably not explain the high mortality associated with COVID-19.
Migraine is a common, chronic, disorder that is typically characterized by recurrent disabling attacks of headache and accompanying symptoms, including aura. The aetiology is multifactorial with rare monogenic variants. Depression, epilepsy, stroke and myocardial infarction are comorbid diseases. Spreading depolarization probably causes aura and possibly also triggers trigeminal sensory activation, the underlying mechanism for the headache. Despite earlier beliefs, vasodilation is only a secondary phenomenon and vasoconstriction is not essential for antimigraine efficacy. Management includes analgesics or NSAIDs for mild attacks, and, for moderate or severe attacks, triptans or 5HT1B/1D receptor agonists. Because of cardiovascular safety concerns, unreliable efficacy and tolerability issues, use of ergots to abort attacks has nearly vanished in most countries. CGRP receptor antagonists (gepants) and lasmiditan, a selective 5HT1F receptor agonist, have emerged as effective acute treatments. Intramuscular onabotulinumtoxinA may be helpful in chronic migraine (migraine on ≥15 days per month) and monoclonal antibodies targeting CGRP or its receptor, as well as two gepants, have proven effective and well tolerated for the preventive treatment of migraine. Several neuromodulation modalities have been approved for acute and/or preventive migraine treatment. The emergence of new treatment targets and therapies illustrates the bright future for migraine management.
We studied whether elderly women at risk for fractures receive primary care treatment to prevent fracture. We found that across Europe, women at risk are often not identified, and less than half of such women receive appropriate treatment. Finally, women diagnosed with osteoporosis are much more likely to receive treatment. Purpose: To examine the relationship between risk factors for fragility fracture (FF) and osteoporosis (OP) treatment gap in elderly women across Europe, and compare the prevalence of risk factors between countries. Methods: Demographic and clinical information was collected from women ≥ 70 years visiting primary care physicians in Belgium, France, Germany, Ireland, Poland, Slovakia, Switzerland, and the UK. Increased risk of FF was defined by the presence of 1 or more criteria (history of fracture, 10-year fracture probability, or T-score ≤ - 2.5). Results: There were 3798 women in total. Treatment gap (proportion at increased risk of FF not receiving treatment for OP) varied from 53.1 to 90.8% across countries, and the proportion of patients at increased risk of FF varied from 41.2 to 76.1%. Across countries, less than 50% of patients with increased risk of FF had a diagnosis of OP. Previous fracture was the most common risk factor, with similar prevalence across most countries; other risk factors varied widely. The treatment gap was reduced in patients with an OP diagnosis in all countries, but this reduction varied from 36.5 to 79.4%. The countries with the lowest rates of bone densitometry scans (Poland, France, and Germany; 8.3-12.3%) also had the highest treatment gap (82.2 to 90.8%). Conclusions: This study highlights differences across Europe in clinical risk factors for fracture, rates of densitometry scanning, and the rates of OP diagnosis. More emphasis is needed on risk assessment to improve the identification and treatment of elderly women at risk for fracture.
Respiratory diseases remain a significant cause of global morbidity and mortality and primary care plays a central role in their prevention, diagnosis and management. An e-Delphi process was employed to identify and prioritise the current respiratory research needs of primary care health professionals worldwide. One hundred and twelve community-based physicians, nurses and other healthcare professionals from 27 high-, middle- and low-income countries suggested 608 initial research questions, reduced after evidence review by 27 academic experts to 176 questions covering diagnosis, management, monitoring, self-management and prognosis of asthma, COPD and other respiratory conditions (including infections, lung cancer, tobacco control, sleep apnoea). Forty-nine questions reached 80% consensus for importance. Cross-cutting themes identified were: a need for more effective training of primary care clinicians; evidence and guidelines specifically relevant to primary care, adaption for local and low-resource settings; empowerment of patients to improve self-management; and the role of the multidisciplinary healthcare team.
Background The current global pandemic of Coronavirus Disease 2019 (COVID-19) has profoundly impacted medical practitioners worldwide. This survey was formed by the Radiology Section of the European Union of Medical Specialists (UEMS) to establish the use of personal protective equipment (PPE) by European radiologists committed to providing face-to-face ultrasound services after the first few months of the COVID-19 global pandemic. Results The results showed a heterogeneous picture within Europe regarding PPE used by European radiologists providing face-to-face ultrasound services. Ranging from full protection including full limb protection and double gloves to no PPE at all. In general, European radiologists were using more PPE when providing face-to-face ultrasound services in COVID-19 positive patients than in COVID-19 asymptomatic patients. In many member countries of the Radiology Section of the UEMS (19/30), there were no national guidelines with regard to the use of PPE by healthcare professionals committed to providing face-to-face ultrasound services. Conclusions Our results showed that harmonization on a European level regarding the recommended use of PPE for European radiologists providing face-to-face ultrasound services is lacking. When the position statements and best practice recommendations on standards in ultrasound are revised, we recommend adding a paragraph on PPE.
Background Oxygen therapy is a widely used intervention in acutely ill patients in the intensive care unit (ICU). It is established that not only hypoxia, but also prolonged hyperoxia is associated with poor patient-centered outcomes. Nevertheless, a fundamental knowledge gap remains regarding optimal oxygenation for critically ill patients. In this randomized clinical trial, we aim to compare ventilation that uses conservative oxygenation targets with ventilation that uses conventional oxygen targets with respect to mortality in ICU patients. Methods The “Conservat I ve versus CON ventional oxygenation targets in I ntensive C are patients” trial (ICONIC) is an investigator-initiated, international, multicenter, randomized clinical two-arm trial in ventilated adult ICU patients. The ICONIC trial will run in multiple ICUs in The Netherlands and Italy to enroll 1512 ventilated patients. ICU patients with an expected mechanical ventilation time of more than 24 h are randomized to a ventilation strategy that uses conservative (PaO 2 55–80 mmHg (7.3–10.7 kPa)) or conventional (PaO 2 110–150 mmHg (14.7–20 kPa)) oxygenation targets. The primary endpoint is 28-day mortality. Secondary endpoints are ventilator-free days at day 28, ICU mortality, in-hospital mortality, 90-day mortality, ICU- and hospital length of stay, ischemic events, quality of life, and patient opinion of research and consent in the emergency setting. Discussion The ICONIC trial is expected to provide evidence on the effects of conservative versus conventional oxygenation targets in the ICU population. This study may guide targeted oxygen therapy in the future. Trial registration Trialregister.nl NTR7376 . Registered on 20 July, 2018.
Background: Studies have suggested incremental short-term adverse events (AE) after repeated vaccination. In this report, we assessed occurrence and risk factors for short-term AEs following repeated SARS-CoV-2 vaccination in patients with various immune-mediated inflammatory diseases (IMIDs). Methods: Self-reported daily questionnaires on AEs during the first 7 days after vaccination were obtained of 2259 individuals (2081 patients and 178 controls) participating in an ongoing prospective multicenter cohort study on SARS-CoV-2 vaccination in patients with various IMIDs in the Netherlands (T2B-COVID). Relative risks were calculated for potential risk factors associated with clinically relevant AE (rAE), defined as AE lasting longer than 2 days or impacting daily life. Results: In total, 5454 vaccinations were recorded (1737 first, 1992 second and 1478 third vaccinations). Multiple sclerosis, Crohn's disease and rheumatoid arthritis were the largest disease groups. rAEs were reported by 57.3% (95% CI 54.8-59.8) of patients after the first vaccination, 61.5% (95% CI 59.2-63.7) after the second vaccination and 58% (95% CI 55.3-60.6) after the third vaccination. At day 7 after the first, second and third vaccination, respectively, 7.6% (95% CI 6.3-9.1), 7.4% (95% CI 6.2-8.7) and 6.8% (95% CI 5.4-8.3) of patients still reported AEs impacting daily life. Hospital admissions and allergic reactions were uncommon (<0.7%). Female sex (aRR 1.43, 95% CI 1.32-1.56), age below 50 (aRR 1.14, 95% CI 1.06-1.23), a preceding SARS-CoV-2 infection (aRR 1.14, 95% CI 1.01-1.29) and having an IMID (aRR 1.16, 95% CI 1.01-1.34) were associated with increased risk of rAEs following a vaccination. Compared to the second vaccination, the first vaccination was associated with a lower risk of rAEs (aRR 0.92, 95% CI 0.84-0.99) while a third vaccination was not associated with increased risk on rAEs (aRR 0.93, 95% CI 0.84-1.02). BNT162b2 vaccines were associated with lower risk on rAEs compared to CX-024414 (aRR 0.86, 95% CI 0.80-0.93). Conclusions: A third SARS-CoV-2 vaccination was not associated with increased risk of rAEs in IMID patients compared to the second vaccination. Patients with an IMID have a modestly increased risk of rAEs after vaccination when compared to controls. Most AEs are resolved within 7 days; hospital admissions and allergic reactions were uncommon. Trial registration: NL74974.018.20 , Trial ID: NL8900. Registered on 9 September 2020.
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3,392 members
PB De Witte
  • Department of Orthopedic Surgery
Pieter Kitslaar
  • Department of Radiology
Karoly Szuhai
  • Cell and Chemical Biology
Yotam Raz
  • Department of Molecular Epidemiology
Albinusdreef 2, 2333 ZA, Leiden, Netherlands