Intratumor heterogeneity may contribute to the ambiguous clinical results on PD-L1 status as a predictor for immunotherapy response in patients with HNSCC. This decreases the utility of PD-L1 expression from single tumour biopsies as a predictive biomarker. In this prospective study, intratumor heterogeneity of PD-L1 expression in HNSCC was investigated with both Tumour Proportion Score (TPS) and Combined Positive Score (CPS). Thirty-three whole surgical specimens from 28 patients with HNSCC were included. PD-L1 expression in six random core biopsies from each surgical specimen was used to assess the concordance between multiple biopsies and the negative predictive value of a single negative core biopsy. With 1% cut off, 36% of the specimens were concordant with TPS and 52% with CPS. With a 50% cut-off value the concordance was 70% with TPS and 55% with CPS. Defining a tumour as positive if just a single-one of the biopsies was positive, the negative predictive value (NPV) of a single negative core biopsy was 38.9 and 0% (1% cut off), and 79.9% and 62.8% (50% cut off) for TPS and CPS, respectively. In conclusion, PD-L1 positivity varies markedly within the tumour, both with TPS and CPS, challenging the utility of this biomarker.

BackgroundAlthough socioeconomic impact on asthma control has been investigated, little is known about its relation to specialist referral of patients with possible severe asthma, especially in a public healthcare setting. The present study aims to identify socioeconomic patterns in disease control and referral of patients with asthma in a nationwide cohort of adult patients treated with inhaled corticosteroid (ICS).MethodsAsthma patients fulfilling the following: aged 18–45 and redeeming ≥2 prescriptions of ICS during 2014–18 based on data from Danish national registers were included. Possible severe asthma was defined as GINA 2020 Step 4 (with either ≥2 courses of systemic steroids or ≥1 hospitalisation) or Step 5 treatment. Findings presented as odds ratio (OR) (95% confidence intervals).ResultsOf 60 534 patients (median age 34, 55% female), 3275 (5.7%) were deemed as having possible severe asthma, of whom 61% were managed in primary care alone.Odds of specialist management for possible severe asthma decreased with age (OR 0.66 (0.51–0.85)), 36–45 versus 18–25 years), male sex (OR 0.75 (0.64–0.87)), residence outside the Capital Region (OR 0.70 (0.59–0.82)) and with receiving unemployment or disability benefits OR 0.75 (0.59–0.95)).Having completed higher education increased odds of specialist referral (OR 1.28 (1.03–1.59)), when compared to patients with basic education.ConclusionEven in settings with nationally available free access to specialist care, the majority of patients with possible severe asthma are managed in primary care. Referral of at-risk asthma patients differs across socioeconomic parameters, calling for initiatives to identify and actively refer these patients.

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Circulating microRNAs have proven to be reliable biomarkers, due to their high stability, both in vivo in the circulation, and ex vivo during sample preparation and storage. Small nucleolar RNAs (snoRNAs) are a different type of small non-coding RNAs that can also be reliably measured in plasma, but have only been studied sporadically. In this study, we aimed to identify RNA-biomarkers that can distinguish between different exercise regimes and that entail clues about muscle repair and recovery after prolonged exhaustive endurance exercise. We compared plasma microRNA profiles between two cohorts of elite cyclists, subjected to two different types of exercise regimes, as well as a cohort of patients with peripheral artery disease (PAD) that were scheduled to undergo lower limb amputation, due to critical limb ischemia. In elite athletes, muscle tissue recovers quickly even after exhaustive exercise, whereas in PAD patients, recovery is completely impaired. Furthermore, we measured levels of a specific group of snoRNAs in the plasma of both elite cyclists and PAD patients. Using a multiplex qPCR screening, we detected a total of 179 microRNAs overall, of which, on average, 161 microRNAs were detected per sample. However, only 30 microRNAs were consistently expressed in all samples. Of these, two microRNAs, miR-29a-3p and miR193a-5p, that responded differently two different types of exercise, namely exhaustive exercise and non-exhaustive endurance exercise. Using individual rt/qPCR, we also identified a snoRNA, SNORD114.1, which was significantly upregulated in plasma in response to endurance exercise. Furthermore, two microRNAs, miR-29a-3p and miR-495-3p, were significantly differentially expressed in athletes compared to PAD patients, but only following exercise. We suggest that these two microRNAs could function as markers of impaired muscle repair and recovery. In conclusion, microRNAs miR-29a-3p and miR-193a-5p may help us distinguish between repeated exhaustive and non-exhaustive endurance exercise. MicroRNA miR-29a-3p, as well as miR-495-3p, may further mark impaired muscle recovery in patients with severe critical limb ischemia. Furthermore, we showed for the first time that a circulating snoRNA, SNORD114.1, is regulated in response to exercise and may be used as biomarker.

Aims We have shown that 14q32 microRNAs are highly involved in vascular remodelling and cardiovascular disease. However, the 14q32 locus also encodes 41 ‘orphan’ small nucleolar RNAs (snoRNAs). We aimed to gather evidence for an independent role for 14q32 snoRNAs in human cardiovascular disease. Methods and results We performed a lookup of the 14q32 region within the dataset of a genome wide association scan in 5244 participants of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). Single nucleotide polymorphisms (SNPs) in the snoRNA-cluster were significantly associated with heart failure. These snoRNA-cluster SNPs were not linked to SNPs in the microRNA-cluster or in MEG3, indicating that snoRNAs modify the risk of cardiovascular disease independently. We looked at expression of 14q32 snoRNAs throughout the human cardio-vasculature. Expression profiles of the 14q32 snoRNAs appeared highly vessel specific. When we compared expression levels of 14q32 snoRNAs in human vena saphena magna (VSM) with those in failed VSM-coronary bypasses, we found that 14q32 snoRNAs were up-regulated. SNORD113.2, which showed a 17-fold up-regulation in failed bypasses, was also up-regulated two-fold in plasma samples drawn from patients with ST-elevation myocardial infarction directly after hospitalization compared with 30 days after start of treatment. However, fitting with the genomic associations, 14q32 snoRNA expression was highest in failing human hearts. In vitro studies show that the 14q32 snoRNAs bind predominantly to methyl-transferase Fibrillarin, indicating that they act through canonical mechanisms, but on non-canonical RNA targets. The canonical C/D-box snoRNA seed sequences were highly conserved between humans and mice. Conclusion 14q32 snoRNAs appear to play an independent role in cardiovascular pathology. 14q32 snoRNAs are specifically regulated throughout the human vasculature and their expression is up-regulated during cardiovascular disease. Our data demonstrate that snoRNAs merit increased effort and attention in future basic and clinical cardiovascular research.

Purpose: Multiparametric positron emission tomography (PET)/magnetic resonance imaging (MRI) as a one-stop shop for radiation therapy (RT) planning has great potential but is technically challenging. We studied the feasibility of performing multiparametric PET/MRI of patients with head and neck cancer (HNC) in RT treatment position. As a step toward planning RT based solely on PET/MRI, a deep learning approach was employed to generate synthetic computed tomography (sCT) from MRI. This was subsequently evaluated for dose calculation and PET attenuation correction (AC). Methods and Materials: Eleven patients, including 3 pilot patients referred for RT of HNC, underwent PET/MRI in treatment position after a routine fluorodeoxyglucose-PET/CT planning scan. The PET/MRI scan protocol included multiparametric imaging. A convolutional neural network was trained in a leave-one-out process to predict sCT from the Dixon MRI. The clinical CT-based dose plans were recalculated on sCT, and the plans were compared in terms of relative differences in mean,

IntroductionPrognostic biomarkers in asthma are needed. The biomarker soluble urokinase plasminogen activator receptor (suPAR) has been associated with asthma control and with prognosis in acutely admitted medical patients. We investigated if suPAR and blood eosinophil counts at the time of admission for asthma are associated with readmission and mortality.MethodsOur cohort comprised 1341 patients (median age 45.3, IQR 30.1–63.1) acutely admitted with a diagnosis of asthma to Hvidovre Hospital, Denmark (November 2013 to March 2017). Patients had suPAR and blood eosinophils measured at admission. Outcomes were 365-day readmission and all-cause mortality. Logistic regression analysis adjusted for age, sex, C-reactive protein, and Charlson comorbidity score was used to assess the association of the two biomarkers with readmission and all-cause mortality.ResultsCompared to event-free patients, patients who were either readmitted (n = 452, 42.3%) or died (n = 57, 5.3%) had significantly higher suPAR concentrations (p < 0.0001) and lower eosinophil counts (p = 0.0031) at admission. The highest odds of readmission or mortality were observed for patients in either the 4th suPAR quartile (p < 0.0001) or with eosinophil counts < 150 cells/μL at admission. Increasing levels of suPAR were associated with 365-day readmission (OR 1.3 [1.0–1.6]; p = 0.05) and mortality (OR 2.9 [1.7–5.1]; p = 0.0002). Eosinophil count > 300 cells/μL was significantly associated with lower odds of readmission (OR 0.64 [0.5–0.9]; p = 0.005) and lower mortality (OR 0.7 [0.6–0.9]; p = 0.0007).ConclusionsIn patients acutely admitted with asthma, elevated suPAR concentrations together with blood eosinophil count < 150 cells/μL at the time of hospital admission were associated with both 365-day all-cause readmission and mortality.