Breast cancer management pathways during the COVID-19 pandemic: outcomes from the UK ‘Alert Level 4’ phase of the B-MaP-C study

Abstract: Background: The B-MaP-C study aimed to determine alterations to breast cancer (BC) management during the peak transmission period of the UK COVID-19 pandemic and the potential impact of these treatment decisions. Methods: This was a national cohort study of patients with early BC undergoing multidisciplinary team (MDT)-guided treatment recommendations during the pandemic, designated ‘standard’ or ‘COVID-altered’, in the preoperative, operative and post-operative setting. Findings: Of 3776 patients (from 64 UK units) in the study, 2246 (59%) had ‘COVID-altered’ management. ‘Bridging’ endocrine therapy was used (n = 951) where theatre capacity was reduced. There was increasing access to COVID-19 low-risk theatres during the study period (59%). In line with national guidance, immediate breast reconstruction was avoided (n = 299). Where adjuvant chemotherapy was omitted (n = 81), the median benefit was only 3% (IQR 2–9%) using ‘NHS Predict’. There was the rapid adoption of new evidence-based hypofractionated radiotherapy (n = 781, from 46 units). Only 14 patients (1%) tested positive for SARS-CoV-2 during their treatment journey. Conclusions: The majority of ‘COVID-altered’ management decisions were largely in line with pre-COVID evidence-based guidelines, implying that breast cancer survival outcomes are unlikely to be negatively impacted by the pandemic. However, in this study, the potential impact of delays to BC presentation or diagnosis remains unknown

Effect of regular terbutaline and budesonide on bronchial reactivity to allergen challenge.

There is a transient rebound increase in bronchial reactivity to histamine and methacholine following regular treatment with an inhaled beta 2-agonist. We set out to determine whether the response to allergen was increased after cessation of regular inhaled terbutaline and whether concomitant inhaled budesonide modifies this response. In a double-blind, double-dummy, parallel group design we studied 41 subjects (37 evaluable) with mild asthma who were allergic to Dermatophagoides pteronyssinus, grass pollen, or cat fur. Following a 2 wk run-in period, subjects underwent a fixed three-dose allergen challenge based on their previously determined provocative concentration of allergen producing a 20% fall in FEV1 (PC20) before starting terbutaline 1,000 micrograms or placebo three times daily and budesonide 800 micrograms or placebo twice daily for a period of 2 to 4 wk (mean 18 d). The same three-dose allergen challenge was repeated 33 h after stopping treatment. During treatment evening peak flow values were highest in the terbutaline plus budesonide group. Following regular terbutaline there was no rebound increase in bronchial reactivity to allergen. Following budesonide there was a significantly smaller response to allergen and an increased FEV1 compared with the other three groups, including the budesonide plus terbutaline group. The changes in median (95% CI) allergen PC20 after budesonide, terbutaline, budesonide plus terbutaline, and placebo were 0.79 (0.3, 2.3), 0.11 (-0.4, 0.6), 0.24 (-0.4, 0.5) and -0.47 (-1.5, 0.1) doubling doses (p < 0.01). The respective changes in mean FEV1 were 0.34, -0.16, -0.01, and 0.06 L (p < 0.005). Thus bronchial reactivity to allergen was not increased after regular inhaled terbutaline.(ABSTRACT TRUNCATED AT 250 WORDS

Effect of 443c81, an inhaled mu-opioid receptor agonist in asthma.

Stimulation of exposed C-fibre afferent nerve endings by inflammatory mediators may contribute to airway inflammation and bronchoconstriction in asthma through the release of neuropeptides from collateral nerve endings. The polar opioid peptide 443c81 is a mu-opioid receptor agonist which inhibits C-fibre activation and non-cholinergic neurally mediated bronchoconstriction in animal models. We have compared the effect of 443c81 (5 ml of a 4 mg/ml solution nebulized) four times daily for 7 days with placebo on asthma control in a double-blind parallel group study of 40 subjects with mild asthma. Twenty subjects (12 male, mean FEV1 83% predicted) received placebo and 20 (15 male, mean FEV1 91% predicted) 443c81 after a 1 week run-in. Efficacy was assessed by comparing changes from baseline values in FEV1, provocative dose of histamine causing a 20% fall in FEV1 (PD20), symptom scores, bronchodilator use and home peak flow readings. 443c81 had no acute effect on FEV1 and the mean changes in FEV1 after 1 week of treatment were not significantly different (placebo -0.9%; 443c81-3.8%). One hour after the first dose of 443c81 PD20 increased from a geometric mean of 0.88 to 1.48 mumol (mean change 0.76 doubling doses; 95% CI 0.23, 1.29) but this did not differ significantly from the change with placebo (mean difference between 443c81 and placebo 0.63 doubling doses; 95% CI -0.2, 1.5; P = 0.095). After 1 week's treatment, PD20 was similar to baseline values with 443c81 (0.78 mumol) and placebo (baseline 0.71, post-treatment 0.93 mumol).(ABSTRACT TRUNCATED AT 250 WORDS

Asthma control during and after cessation of regular beta 2-agonist treatment.

It has been suggested that regular treatment with high doses of beta 2-agonists might result in poorer control of asthma and increased bronchial responsiveness. We have examined change in FEV1 (delta FEV1), bronchial reactivity, peak expiratory flow (PEF), and symptoms during and after 3 wk of regular treatment with a relatively low dose of albuterol and broxaterol, a new beta 2-agonist. Eleven subjects 18 to 50 yr of age with mild asthma inhaled albuterol (200 micrograms), broxaterol (400 micrograms), or placebo three times a day for 3 wk with a 2- to 4-wk run-in/washout period between treatments. Ipratropium bromide was allowed for symptomatic relief. The PD20 (dose of histamine causing a 20% fall in FEV1) was measured before and 11, 35, and 59 h after cessation of treatment and a bronchodilator dose-response study before and 83 h after cessation of treatment. Change from baseline after albuterol and broxaterol are compared with change after placebo. Diurnal change in PEF (amplitude % mean) increased during treatment with albuterol by 6.5% (95% CI, 1.7-12.3; p < 0.02) mainly because of a fall in morning PEF. Cessation of treatment with both beta 2-agonists was associated with a fall in FEV1 and PD20 compared with placebo.(ABSTRACT TRUNCATED AT 250 WORDS

Effect of inhaled prostaglandin E2 on bronchial reactivity to sodium metabisulphite and methacholine in patients with asthma.

Inhaled frusemide protects against the bronchoconstrictor response to a wide range of stimuli that cause bronchoconstriction by indirect mechanisms. One possible explanation for this protection relates to the known ability of frusemide to enhance synthesis of prostaglandin E2 (PGE2). Studies in vitro suggest that PGE2 might protect against indirectly acting bronchoconstrictor challenges rather than those that act directly on airway smooth muscle, though little is known about the effects of PGE2 in vivo. The effect of inhaled PGE2 on the bronchoconstrictor response to inhaled sodium metabisulphite (a stimulus with an indirect action) and methacholine (which acts directly on airway smooth muscle) was studied in nine patients with asthma. Subjects were studied on four days, inhaling PGE2 (100 micrograms) or placebo in a double blind fashion followed immediately by a cumulative dose challenge with sodium metabisulphite or methacholine. The response to the constrictor stimuli was measured as the provocative dose causing a 20% fall in FEV1 (PD20). There was no significant change in FEV1 after inhaled PGE2 compared with placebo, nor any significant change in the response to methacholine; the geometric mean methacholine PD20 was 0.9 mumol after PGE2 and 0.56 mumol after placebo (mean difference 0.7 (95% confidence limits--0.1, 1.5) doubling doses). PGE2, however, protected against sodium metabisulphite, the geometric mean sodium metabisulphite PD20 being 11.8 mumol after PGE2 and 1.8 mumol after placebo (mean difference 2.5 (95% CL 1.9, 3.1) doubling doses). PGE2 conferred significantly greater protection against sodium metabisulphite than methacholine (mean difference 1.8 (95% CL 0.8, 2.8) doubling doses). This suggests that PGE2, like frusemide, has an inhibitory effect on pathways relevant to the bronchoconstriction induced by sodium metabisulphite, with little or no effect on those relevant to methacholine

Effect of inhaled prostaglandin E2 on bronchial reactivity to sodium metabisulphite and methacholine in patients with asthma.

Inhaled frusemide protects against the bronchoconstrictor response to a wide range of stimuli that cause bronchoconstriction by indirect mechanisms. One possible explanation for this protection relates to the known ability of frusemide to enhance synthesis of prostaglandin E2 (PGE2). Studies in vitro suggest that PGE2 might protect against indirectly acting bronchoconstrictor challenges rather than those that act directly on airway smooth muscle, though little is known about the effects of PGE2 in vivo. The effect of inhaled PGE2 on the bronchoconstrictor response to inhaled sodium metabisulphite (a stimulus with an indirect action) and methacholine (which acts directly on airway smooth muscle) was studied in nine patients with asthma. Subjects were studied on four days, inhaling PGE2 (100 micrograms) or placebo in a double blind fashion followed immediately by a cumulative dose challenge with sodium metabisulphite or methacholine. The response to the constrictor stimuli was measured as the provocative dose causing a 20% fall in FEV1 (PD20). There was no significant change in FEV1 after inhaled PGE2 compared with placebo, nor any significant change in the response to methacholine; the geometric mean methacholine PD20 was 0.9 mumol after PGE2 and 0.56 mumol after placebo (mean difference 0.7 (95% confidence limits--0.1, 1.5) doubling doses). PGE2, however, protected against sodium metabisulphite, the geometric mean sodium metabisulphite PD20 being 11.8 mumol after PGE2 and 1.8 mumol after placebo (mean difference 2.5 (95% CL 1.9, 3.1) doubling doses). PGE2 conferred significantly greater protection against sodium metabisulphite than methacholine (mean difference 1.8 (95% CL 0.8, 2.8) doubling doses). This suggests that PGE2, like frusemide, has an inhibitory effect on pathways relevant to the bronchoconstriction induced by sodium metabisulphite, with little or no effect on those relevant to methacholine

Factors influencing the occurrence of airway hyperreactivity in the general population: the importance of atopy and airway calibre.

The factors that determine the occurrence of airway hyperreactivity in the general population are not clearly understood. This study was designed to assess the independent effects of age, atopy, smoking and airway calibre. In a random sample of 2,415 adults aged 18-70 yrs we measured reactivity to methacholine as the dose provoking a 20% fall (PD20) in one-second forced expiratory volume (FEV1), atopy as the mean skin wheal response to three common environmental allergens, and airway calibre as the baseline FEV1 in absolute terms, as percent predicted (FEV1 % predicted) and as percent forced vital capacity (FEV1 % FVC). Hyperreactivity, defined as a PD20 < or = 12.25 mumol, was present in 314 (13%) of the sample, and before adjustment for FEV1 was more common in females (independent odds ratio (OR) = 2.05 (95% confidence interval 1.6-2.7)), current smokers (OR = 1.89 (1.3-2.6)), atopics (OR = 1.39 (1.3-1.5) per mm skin wheal), and in older age groups (OR for age 60-70 yrs relative to 18-29 yrs = 2.70 (1.7-4.3)). However, the odds of hyperreactivity were also strongly and independently related to absolute FEV1 (OR = 0.46 (0.27-0.77) per litre), FEV1 % predicted (OR = 0.96 (0.94-0.98) per percent), and FEV1 % FVC (OR = 0.92 (0.90-0.94) per percent; combined chi-square on 3 df = 312, p << 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS