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.

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.

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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