Copenhagen University Hospital
Recent publications
Extranodal extension (ENE) increases the risk of recurrence and death in head and neck squamous cell carcinoma (HNSCC) patients and is an indication for treatment escalation. Histopathology forms the mainstay of diagnosing ENE. There is substantial variation in the diagnosis of ENE and related terminology. Harmonising the diagnostic criteria for ENE was identified as a priority by the Head and Neck Consensus Language for Ease of Reproducibility (HN CLEAR) Steering Committee and its global stakeholders. An international working group including 16 head and neck pathologists from eight countries across five continents evaluated whole slide images of haematoxylin and eosin-stained sections depicting potential diagnostic problems through nine virtual meetings to develop consensus guidelines. ENE should be diagnosed only when viable carcinoma extends through the primary lymph node (LN) capsule and directly interacts with the extranodal host environment with or without desmoplastic stromal response. Identifying the original LN capsule and reconstruction of its contour can assist in the detection and assessment of ENE. The term matting is recommended for confluence of two or more nodes due to histologically identifiable tumour extending from one LN to another. Matting constitutes major form of ENE. On the other hand, the terms fusion/adhesion/confluence/conglomeration and other synonyms of adhesion should be limited to confluence due to fibrosis or inflammation without histologically identifiable tumour between involved lymph nodes. Tumour extension along narrow needle tracks or spillage of cyst contents following an FNA do not constitute ENE. The consensus recommendations encompassing the definition of ENE, macroscopic and histologic examination of lymph nodes (LN) and practical guidelines for handling challenging cases are provided.
Synaptic degeneration has been linked to cognitive decline. The presynaptic protein, synaptosomal‐associated protein 25 kDA (SNAP‐25), is crucial for synaptic transmission and has been suggested as a biomarker in Alzheimer's disease (AD). In the current study, we investigated the ability of SNAP‐25 to differentiate between heterogenous dementia etiologies and whether SNAP‐25 could be a staging marker in AD. SNAP‐25 in the cerebrospinal fluid (CSF) from a retrospective ( n = 187) and a prospective ( n = 134) cohort was investigated with immunoprecipitation mass spectrometry (IP‐MS) and single‐molecule array (Simoa), respectively. Both cohorts consisted of healthy controls (HC) and patients with cognitive decline of different etiologies. CSF SNAP‐25 concentration was higher in AD and non‐neurodegenerative diseases (i.e., vascular dementia) compared with controls but did not differ between AD and non‐AD neurodegenerative diseases. We found a trend toward an association between SNAP‐25 and disease burden when comparing HC, mild cognitive impairment due to AD, and AD. CSF SNAP‐25 concentrations were strongly associated with CSF phosphorylated tau (p‐tau) concentrations, thus strengthening the link between synaptic dysfunction and tau pathophysiology in AD. Our initial findings suggest that SNAP‐25 may be a potential biomarker for differentiating AD from dementia due to other etiologies. However, due to the significant association between SNAP‐25 and p‐tau proteins, the clinical utility of SNAP‐25 as a diagnostic biomarker for AD may be limited, while SNAP‐25 may be useful for monitoring disease progression or treatment response.
Background: Staphylococcus epidermidis is a ubiquitous member of the healthy skin and mucous microbiota but is also an opportunistic pathogen responsible for various infections, often treated with antibiotics like rifampicin. Resistance to rifampicin in S. epidermidis arises primarily through nonsynonymous mutations in the rpoB gene. Objectives: To investigate the prevalence of rpoB mutations and their association with phenotypic rifampicin resistance in clinical S. epidermidis isolates from Denmark, France, and Sweden. Methods: All clinical isolates (N = 942) were whole-genome sequenced to identify mutations in rpoB and subsequently linked to phenotypic rifampicin resistance based on antimicrobial susceptibility testing. Results: A total of 64 (6.8%) isolates were resistant to rifampicin. They all carried mutational changes in the rifampicin resistance-determining region (RRDR). Among 12 identified nonsynonymous mutations, 11 were exclusively observed in resistant strains, including novel mutations not previously described in S. epidermidis. Conclusions: This study highlights the diverse genetic variants of rpoB associated with rifampicin resistance in clinical S. epidermidis isolates, including novel mutations. The strong correlation between mutational changes in RRDR and phenotypic resistance reinforces the role of rpoB mutations as a primary mechanism of resistance in clinical isolates.
There is a growing interest in developing drugs with a general geroprotective effect, aimed at slowing down aging. Several compounds have been shown to increase the lifespan and reduce the incidence of age-related diseases in model organisms. Translating these results is challenging, due to the long lifespan of humans. To address this, we propose using a battery of medical imaging protocols that allow for assessments of age-related processes known to precede disease onset. These protocols, based on magnetic resonance imaging, positron emission-, computed-, and optical coherence tomography, are already in use in drug development and are available at most modern hospitals. Here, we outline how an informed use of these techniques allows for detecting changes in the accumulation of age-related pathologies in a diverse set of physiological systems. This in vivo imaging battery enables efficient screening of candidate geroprotective compounds in early phase clinical trials, within reasonable trial durations.
Our analysis suggests that well-monitored warfarin might be equally good, or even better, for atrial fibrillation depending on the DOAC and outcome. Our analysis warrants granular investigations based on the COMBINE AF (A Collaboration between Multiple institutions to Better Investigate Non-vitamin K antagonist oral anticoagulant use in Atrial Fibrillation) data set to establish which anticoagulant to use and in which setting. New analyses should be conducted with predefined TTR thresholds and transparently reported.
Objectives To determine patient-reported symptoms and clinical factors associated with mimics and differences in health-seeking behaviour versus stroke. Design This is a post-hoc analysis of a cross-sectional survey of interviews on patient-reported factors in patients admitted with suspected stroke. Patients were categorised as genuine stroke or mimic. The surveys were conducted from February 2018 to January 2019. Setting Two non-comprehensive stroke centres in Denmark. Participants Patients≥18 years (no upper age limit) admitted with symptoms of stroke to one of the non-comprehensive stroke centres or transferred from a comprehensive- or primary stroke centre were eligible for inclusion. 592 patients were included. Outcome measures Symptoms or clinical factors associated with stroke mimics. Logistic regression analysis was performed to identify factors associated with mimics. Secondarily, the number of strokes versus mimics presenting at a healthcare facility within 3 hours contacted the emergency medical service (EMS) and arrived by ambulance. Results Of 592 suspected patients with stroke, 113 (19.1%) were mimics; most frequently peripheral vertigo (24.7%) and migraine (11.5%). Factors associated with a higher likelihood of mimics were female sex (OR 1.79, 95% CI 1.14 to 2.79), high Scandinavian Stroke Scale scores (OR 1.05, 95% CI 1.02 to 1.09, per point increase), and vertigo (OR 1.86, 95% CI 1.18 to 2.95). Factors associated with a lower likelihood of mimics were increasing age (OR 0.96, 95% CI 0.95 to 0.98 per year increase), reported limb weakness (OR 0.52, 95% CI 0.30 to 0.89) and difficulty steering (OR 0.51, 95% CI 0.28 to 0.93). There was no difference between groups in the proportion of patients for whom time from symptom onset to healthcare services contact exceeded 3 hours (52.2% vs 53.7%, p =0.78). Fewer mimics contacted the EMS first, were accepted at a primary stroke centre and arrived by ambulance (p<0.05 for all variables). Conclusion Patient-reported vertigo and migraine are common stroke mimics. Increasing age and unilateral limb symptoms increase the likelihood of a stroke. Although symptoms are similar, prehospital pathways differ between mimics and genuine patients with stroke.
Men develop larger infarct sizes than women after a myocardial infarction (MI), but the mechanism underlying this sex difference is unknown. Here, we demonstrated that blood neutrophil counts post-MI were higher in male than female mice. Castration-induced testosterone deficiency reduced blood neutrophil counts to the level in females and increased survival post-MI. These effects were mimicked by Osterix-directed ablation of the androgen receptor in bone marrow (BM). Mechanistically, androgens downregulated the leukocyte retention factor CXCL12 in BM stromal cells. Post-hoc analysis of clinical trial data showed that neutrophilia was greater in men than women after reperfusion of first-time ST-elevation MI, and tocilizumab, an interleukin-6 receptor inhibitor, reduced blood neutrophil counts and infarct size to a greater extent in men than women. Our work reveals a previously unknown mechanism connecting testosterone with neutrophilia and MI injury via BM and identifies the importance of considering sex when developing anti-inflammatory strategies to treat MI.
Despite recent advancements, real-world use of Artificial Intelligence (AI) in radiology remains low, often due to the mismatch between AI offerings and the situated challenges faced by healthcare professionals. To bridge this gap, we conducted a field study at nine medical sites in Denmark and Kenya with two goals: (1) to understand the challenges faced by radiologists during chest X-ray practice; (2) to envision alternative AI futures that align with collaborative clinical work. This study uniquely grounds the AI design insights in the comprehensive characterisation of diagnostic work across multiple geographical and institutional contexts. Building on ideas articulated by interviewed radiologists (N=18), we conceptualised five visions that transcend the traditional notions of AI support. These visions emphasise that the clinical usefulness of AI-based systems depends on their configurability and flexibility across three dimensions: type of clinical site, expertise of medical professionals, and situational and patient contexts. Addressing these dependencies requires expanding the clinical AI design space by envisioning futures rooted in the realities of practice rather than solely following the trajectory of AI development.
Importance Cardiovascular disease is the leading cause of death in the US. However, it remains unclear how the burden of cardiovascular events in the US compares with that of other high-income countries with distinct health care systems like Denmark, both overall and by income. Objective To compare cardiovascular hospitalization rates (acute myocardial infarction [MI], heart failure [HF], ischemic stroke) and associated outcomes among adults 65 years or older, overall and by income, between the US and Denmark. Design, Setting, and Participants This population-based cross-sectional study used national data from the US and Denmark from January 1, 2021, to January 1, 2022. The study population included all Medicare beneficiaries 65 years or older in the US and all adults 65 years or older in Denmark. Main Outcomes and Measures The primary outcome was age- and sex-standardized hospitalization rates for MI, HF, and ischemic stroke, as well as 30-day all-cause mortality rates. Results The US study population included 58 614 110 adults 65 years or older (mean [SE] age, 74.6 [7.7] years; 32 179 146 female [54.9%]) of whom 1 171 058 (2.0%) were hospitalized for a cardiovascular event. The Danish study population included 1 176 542 adults 65 years or older (mean [SE] age, 75.3 [7.1] years; 634 217 female [53.9%]) of whom 16 305 (1.4%) were hospitalized with a cardiovascular event. The overall age- and sex-standardized cardiovascular hospitalization rate was significantly higher in the US compared with Denmark (risk ratio [RR], 1.50; 95% CI, 1.47-1.52), as were associated 30-day all-cause mortality rates (RR, 1.12; 95% CI, 1.06-1.17). Across conditions, the risk of hospitalization for MI (RR, 1.56; 95% CI, 1.51-1.61) and HF (RR, 2.37; 95% CI, 2.31-2.43) was significantly higher in the US compared with Denmark, whereas hospitalizations for ischemic stroke were lower (RR, 0.90; 95% CI, 0.88-0.93). Overall cardiovascular hospitalization rates in the US were more than 2-fold higher among low-income adults compared with higher-income adults (RR, 2.38; 95% CI, 2.25-2.47), whereas the magnitude of income-based disparities was smaller in Denmark (RR, 1.45; 95% CI, 1.39-1.50). Conclusions and Relevance In this international cross-sectional study, cardiovascular hospitalization rates were significantly higher in the US compared with Denmark. There were income-based differences in the burden of cardiovascular hospitalizations in both countries, although the magnitude of these disparities was much greater in the US.
Objective The involvement of cortical inflammation in migraine, particularly migraine with aura, has been a subject of considerable interest, but has proved challenging to demonstrate. We aimed to detect and characterize signs of cortical inflammation in adults with migraine using a novel, multimodal magnetic resonance imaging (MRI) technique. Methods We used T2 mapping to measure water content/cellularity, T1 mapping to measure tissue microstructure integrity, and apparent diffusion coefficient (ADC) mapping to measure intra‐ or extracellular edema. We compared these values between participants with migraine (with and without aura) and healthy controls using general linear models adjusted for age and sex. Result Two hundred ninety‐six adult participants with migraine and 155 age‐ and sex‐matched healthy controls provided eligible imaging data. Among the participants with migraine, 103 had migraine with aura, 180 chronic migraine, and 88 were ictal during the scan. Participants with migraine had higher quantitative T2 (qT2) in the left occipital cortex than healthy controls ( p < 0.0001). In migraine with aura, the higher qT2 was more widespread and located bilaterally in the occipital cortices, compared with controls (left, p < 0.0001; right p = 0.004). Post‐hoc analysis revealed overlapping ADC elevations in migraine with aura compared with controls ( p = 0.0069). Interpretation Quantitative MRI changes compatible with cortical inflammation were detected in participants with migraine, and appeared driven by the subgroup with aura. Higher occipital qT2 in migraine with aura might represent either extracellular edema or accumulation of inflammatory microglia or astrocytes. These results support the importance of cortical inflammation in migraine pathophysiology, particularly in migraine with aura. ANN NEUROL 2025
Aims Prompt diagnosis and intervention are crucial for first‐episode psychosis (FEP) outcomes, but predicting the response to antipsychotics remains challenging. We studied whether adding electroencephalography (EEG) characteristics improves clinical prediction models for treatment response and whether EEG‐based predictors are influenced by initial treatment. Methods We included 115 antipsychotic‐naïve patients with FEP. Positive and Negative Syndrome Scale (PANSS) and sociodemographic items were included as clinical features. Additionally, we analyzed resting‐state EEG data ( n = 45) for (relative) power, functional connectivity, and network organization. Treatment response, measured as change in PANSS positive subscale scores (∆PANSS+), was predicted using a random forest regression model. We analyzed whether the most predictive EEG characteristics were influenced after treatment. Results The clinical model explained 12% variance in symptom reduction in the training set and 32% in the validation set. Including EEG variables in the model led to a nonsignificant increase of 2% (total 34%) explained variance in symptom reduction. High hallucination symptom scores and a more hierarchical organization of alpha band networks (tree hierarchy) were associated with ∆PANSS+ reduction. The tree hierarchy in the alpha band decreased after medication. EEG source analysis revealed that this change was driven by alterations in the degree and centrality of frontal and parietal nodes in the functional brain network. Conclusions Both clinical and EEG characteristics can inform treatment response prediction in patients with FEP, but the combined model may not be beneficial over a clinical model. Nevertheless, adding a more objective marker such as EEG could be valuable in selected cases.
Background Globally, cryptococcal meningitis (CM) remains most common in human immunodeficiency virus (HIV)-infected individuals. However, Cryptococcus neoformans increasingly causes CM in patients with non-HIV immunosuppression due to glucocorticoid treatment, organ transplantation, and hematological cancer, among others. The clinical presentations of cryptococcal disease are highly host dependent, resulting in varying disease presentations in immunocompromised patients. Case Summary Here, we report a fatal case of CM in a patient previously treated with cladribine due to hairy cell leukemia. The patient had an atypical presentation, and the disease progressed slowly over a 4-year period, hampering timely diagnostics and treatment. Retrospective analyses of the cerebrospinal fluid and blood revealed that the cryptococcal antigen (CrAg) test was already positive when the patient initially presented with pleocytosis 3 years prior to the CM diagnosis. Conclusion This case adds valuable knowledge to our current understanding of CM due to the unusual time course and furthermore demonstrates important pitfalls associated with cryptococcosis in HIV-negative patients, including the atypical disease presentation and diagnostic challenges which resulted in a diagnostic delay of 3 years. Morbidity and mortality remain high, and with a growing population of non-HIV immunocompromised patients, increased awareness of CM and low threshold to screen these patients for CrAg are warranted.
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103 members
Michael E Benros
  • Department of Psychiatry
Jacob Tfelt-Hansen
  • Department of Cardiology
Claus Bøgelund Andersen
  • Department of Pathology
Mads Bak
  • Department of Clinical Genetics
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Copenhagen, Denmark