IPEM topical report: results of a 2022 UK survey on the use of linac manufacturer integrated quality control (MIQC).

In recent years Radiotherapy linear accelerator (linac) vendors have developed their own integrated quality control (QC) systems. Such manufacturer-integrated-quality-control (MIQC) has the potential to improve both the quality and efficiency of linac QC but is currently being developed and utilised in the absence of specific best-practice guidance. An Institute of Physics and Engineering in Medicine working party was commissioned with a view to develop guidance for the commissioning and implementation of MIQC. This study is based upon a survey of United Kingdom (UK) radiotherapy departments performed by the working party. The survey was distributed to all heads of radiotherapy physics in the UK and investigated availability and uptake, community beliefs and opinions, utilisation, user experience and associated procedures. The survey achieved a 95% response rate and demonstrated strong support (>95%) for its use and further development. MIQC systems are available in 79% of respondents' centres, and are in clinical use in 66%. The most common MIQC system was Varian MPC, in clinical use in 58% of responding centres, with CyberKnife AQA\E2E in 11%, TomoTherapy TQA in 8% and no users of Elekta Machine QA. A majority of users found their MIQC to be easy to use, reliable, and had five or more years of experience. Most users reported occasions of discrepancy in results between MIQC and conventional testing, but the majority considered this acceptable, indicating a false reporting frequency of quarterly or less. MIQC has shown value in preventative maintenance and early detection of machine deviations. There were inconsistent approaches in the utilisation and commissioning tests performed. Fewer than half of users perform QC of MIQC. 45% of responders have modified their QC processes with the introduction of MIQC, via replacement of conventional tests or reduction in their frequency. Future guidance is recommended to assist in the implementation of MIQC.

Profiling cellular and inflammatory changes in the airway wall of mild to moderate COPD.

BACKGROUND AND OBJECTIVE: The objective of this study was to enumerate total cells and the number of inflammatory cell differentials in large airways (LAs) versus small airways (SAs) of mild-moderate COPD, and against appropriate controls. METHODS: For LA, we used endobronchial biopsies and for SA resected lung tissues. Immunostaining was enumerated (cells per mm2 ) for macrophages, neutrophils, CD4 and CD8 T cells in the lamina propria (LP) up to 150 µM deep for LA and full wall thickness for SA. RESULTS: We confirmed hypocellularity in the LA and in the SA wall in smokers and COPD (P < 0.001). LA cellularity was least in current smokers with COPD (COPD-CS) (P < 0.01), while SA cellularity was similar across smoker/COPD groups. LA neutrophils were decreased in COPD-CS (P < 0.01), while SA neutrophil counts were unchanged. Compared with controls, LA macrophage numbers in COPD were significantly lower (P < 0.05), with SA macrophage numbers unchanged. A significant increase was observed in SA CD8+ cells in both normal smokers (P < 0.01) and COPD-CS (P < 0.001) but not in LA. CONCLUSION: These unique data indicate that the current model for airway wall inflammation in COPD is oversimplified, and contrast with innate inflammatory activation in the lumen, at least in mild-moderate disease. Any abnormalities in airway wall cell differentials are small, although exaggerated in percentage terms.

The main rhinovirus respiratory tract adhesion site (ICAM-1) is upregulated in smokers and patients with chronic airflow limitation (CAL).

BACKGROUND: ICAM-1 is a major receptor for ~60% of human rhinoviruses, and non-typeable Haemophilus influenzae, two major pathogens in COPD. Increased cell-surface expression of ICAM-1 in response to tobacco smoke exposure has been suggested. We have investigated epithelial ICAM-1 expression in both the large and small airways, and lung parenchyma in smoking-related chronic airflow limitation (CAL) patients. METHODS: We evaluated epithelial ICAM-1 expression in resected lung tissue: 8 smokers with normal spirometry (NLFS); 29 CAL patients (10 small-airway disease; 9 COPD-smokers; 10 COPD ex-smokers); Controls (NC): 15 normal airway/lung tissues. Immunostaining with anti-ICAM-1 monoclonal antibody was quantified with computerized image analysis. The percent and type of cells expressing ICAM-1 in large and small airway epithelium and parenchyma were enumerated, plus percentage of epithelial goblet and submucosal glands positive for ICAM- 1. RESULTS: A major increase in ICAM-1 expression in epithelial cells was found in both large (p < 0.006) and small airways (p < 0.004) of CAL subjects compared to NC, with NLFS being intermediate. In the CAL group, both basal and luminal areas stained heavily for ICAM-1, so did goblet cells and sub-mucosal glands, however in either NC or NLFS subjects, only epithelial cell luminal surfaces stained. ICAM-1 expression on alveolar pneumocytes (mainly type II) was slightly increased in CAL and NLFS (p < 0.01). Pack-years of smoking correlated with ICAM-1 expression (r = 0.49; p < 0.03). CONCLUSION: Airway ICAM-1 expression is markedly upregulated in CAL group, which could be crucial in rhinoviral and NTHi infections. The parenchymal ICAM-1 is affected by smoking, with no further enhancement in CAL subjects.

A simple model for predicting the signal for a head-mounted transmission chamber system, allowing IMRT in-vivo dosimetry without pretreatment linac time.

The DAVID is a transparent, multi-wire transmission-style detector that attaches to a linear accelerator (linac) collimator for use as an in vivo detector. Currently, the normal method for using the DAVID is to measure a signal at the time of phantom-based pretreatment verification and use that signal as a baseline to compare with in vivo measurements for subsequent treatment fractions. The device has previously been shown to be both stable and accurate.(1,2) This work presents the development of a predictive algorithm for the expected signal, eradicating the need to spend time on the linac prior to treatment, and thereby making the process more efficient. The DAVID response at each wire is a consequence of both primary radiation, from the leaf pair associated with the wire, and scatter radiation as a result of radiation incident on other parts of the detector scattering in the Perspex plate. The primary radiation was shown to be linearly proportional to both leaf separation and delivered monitor units (MU). The scatter signal dropped off exponentially with regard to distance. Both of these effects were modeled; the resulting algorithm was used to predict the response from ten five-field IMRT head and neck plans. The system predicted all DAVID signals to within 5%, and was able to detect artificially generated changes in linac output. Having shown that the algorithm works, a new working paradigm is suggested, and the errors that can be detected are outlined.

Changes in airway histone deacetylase2 in smokers and COPD with inhaled corticosteroids: a randomized controlled trial.

The expression of HDAC2 is reported as reduced in chronic obstructive pulmonary disease (COPD). We assessed HDAC2 expression within the airways of smokers and subjects with COPD and effects of inhaled corticosteroids (ICS), using immuno-histology to contrast with previous molecular methodology. Endobronchial biopsies (ebb) from current smokers with COPD (COPD-CS; n = 15), ex-smokers with COPD (COPD-ES; n = 17), smokers with normal lung function (NS; n = 16) and normal controls (NC; n = 9) were immunostained for HDAC2. A double-blinded, randomized, placebo-controlled 6 months intervention study assessed effects of ICS on HDAC2 in 34 COPD subjects. There was no difference in epithelial HDAC2 staining in all groups. There was a significant reduction in total cell numbers in the lamina propria (LP) in COPD-CS and NS (p<0.05). LP cellularity correlated inversely with smoking history in COPD-CS (R = -0.8, p<0.003). HDAC2 expression increased markedly in NS (p<0.001); in contrast COPD-CS was associated with suppressed signal (p<0.03), while normal in COPD-ES. ICS did not affect HDAC2 cell staining. Our findings suggest that airway HDAC2 expression is increased in the LP by smoking itself, but is reduced in COPD. Ex-smokers have normalised HDAC2 cell expression, but ICS had no effect. The paper emphasise the pit-falls of relying on molecular data alone to define airway changes. NAME OF REGISTRY: The Australian New Zealand Clinical Trials Registry (ANZCTR). REGISTRY NUMBER: ACTRN12612001111864.

Evaluation of epithelial mesenchymal transition in patients with chronic obstructive pulmonary disease.

BACKGROUND: The reticular basement membrane (Rbm) in smokers and especially smokers with COPD is fragmented with "clefts" containing cells staining for the collagenase matrix-metalloproteinase-9 (MMP-9) and fibroblast protein, S100A4. These cells are also present in the basal epithelium. Such changes are likely hallmarks of epithelial mesenchymal transition (EMT). We aimed to confirm the epithelial origin of these Rbm cells, and to exclude potential confounding by infiltrating inflammatory cells. METHODS: Endobronchial biopsy sections from 17 COPD current smokers, with documented Rbm splitting and cellularity were stained for neutrophil elastase (neutrophil marker), CD68 (macrophage/mature fibroblasts), CD4+/CD8+ T lymphocytes, CD19 (B-cells), CD11c (dendritic cells/inflammatory cells), and S100 (Langerhans cells). The number of cells in the Rbm and epithelium staining for these "inflammatory" cell markers were then compared to numbers staining for S100A4, "a documented EMT epitope". Slides were double stained for S100A4 and cytokeratin(s). RESULTS: In the basal epithelium significantly more cells stained for S100A4 compared to infiltrating macrophages, fibroblasts or immune cells: median, 26 (21.3 - 37.3) versus 0 (0 - 9.6) per mm, p < 0.003. Markedly more S100A4 staining cells were also observed in the Rbm compared to infiltrating macrophages, neutrophils, fibroblasts or immune cells or any sub-type: 58 (37.3 - 92.6) versus 0 (0 - 4.8) cells/mm Rbm, p < 0.003. Cells in the basal epithelium 26 (21.3 - 37.3) per mm) and Rbm (5.9 (2.3 - 13.8) per mm) frequently double stained for both cytokeratin and S100A4. CONCLUSIONS: These data provide additional support for active EMT in COPD airways.

Reticular basement membrane fragmentation and potential epithelial mesenchymal transition is exaggerated in the airways of smokers with chronic obstructive pulmonary disease.

BACKGROUND AND OBJECTIVE: In COPD, the airways are chronically inflamed, and we have now observed fragmentation of the reticular basement membrane (Rbm). This appears to be a hallmark of the process known as epithelial mesenchymal transition (EMT), in which epithelial cells migrate through the Rbm and differentiate into fibroblasts. The aim of this study was to confirm the extent and relevance of Rbm fragmentation in smokers and patients with COPD, and to undertake a preliminary analysis of some classical markers of EMT. METHODS: Endobronchial biopsies from current smokers (CS; n = 17) and ex-smokers with COPD (ES; n = 15), smokers with normal lung function (NS; n = 16) and never-smoking control subjects (NC; n = 15) were stained for the EMT markers, S100A4, vimentin, epidermal growth factor receptor and matrix metalloproteinase-9. RESULTS: Compared with NC, there was significant Rbm fragmentation in the CS, ES and NS groups, which was positively associated with smoking history in subjects with COPD. Staining for basal epithelial S100A4, epithelial epidermal growth factor receptor and matrix metalloproteinase-9 in cells within Rbm clefts, and for S100A4 in Rbm cells, was increased in the CS, NS and ES groups compared with the NC group. There was also increased Rbm cell S100A4 staining in the CS group compared with the ES and NS groups. Basal epithelial cell staining for S100A4 was inversely correlated with airflow limitation. Double staining for both S100A4 and vimentin further strengthened the likelihood that these changes represented active EMT. CONCLUSIONS: This is the first detailed description of fragmentation and cellularity of the Rbm in smokers, which were most marked in subjects with COPD. The data are consistent with active EMT in these subjects.

Nerve growth factor promotes olfactory axonal elongation.

An explant culture system was used to test the effect of nerve growth factor (NGF) on olfactory axonal elongation. Statistical analysis showed that exogenously applied NGF (50 ng/ml) significantly enhanced olfactory neurite elongation from E14 rat olfactory epithelial explants (p = 0.025). Immunostaining showed that the neurites expressed active TrkA receptors and that S-100-positive ensheathing cells were also present. In a separate experiment, immunoassay confirmed that following a growth period of 72 h, E14 presumptive olfactory bulb expressed and secreted NGF into the culture medium. The results indicate that during ontogeny, the olfactory bulb secretes NGF which binds to olfactory axons and facilitates their elongation.