Feasibility of portal dosimetry for flattening filter-free radiotherapy.

The feasibility of using portal dosimetry (PD) to verify 6 MV flattening filter-free (FFF) IMRT treatments was investigated. An Elekta Synergy linear accelerator with an Agility collimator capable of delivering FFF beams and a standard iViewGT amorphous silicon (aSi) EPID panel (RID 1640 AL5P) at a fixed SSD of 160 cm were used. Dose rates for FFF beams are up to four times higher than for conventional flattened beams, meaning images taken at maximum FFF dose rate can saturate the EPID. A dose rate of 800 MU/min was found not to saturate the EPID for open fields. This dose rate was subsequently used to characterize the EPID for FFF portal dosimetry. A range of open and phantom fields were measured with both an ion chamber and the EPID, to allow comparison between the two. The measured data were then used to create a model within The Nederlands Kanker Instituut's (NKI's) portal dosimetry software. The model was verified using simple square fields with a range of field sizes and phantom thicknesses. These were compared to calculations performed with the Monaco treatment planning system (TPS) and isocentric ion chamber measurements. It was found that the results for the FFF verification were similar to those for flattened beams with testing on square fields, indicating a difference in dose between the TPS and portal dosimetry of approximately 1%. Two FFF IMRT plans (prostate and lung SABR) were delivered to a homogeneous phantom and showed an overall dose difference at isocenter of ~0.5% and good agreement between the TPS and PD dose distributions. The feasibility of using the NKI software without any modifications for high-dose-rate FFF beams and using a standard EPID detector has been investigated and some initial limitations highlighted.

Mast cells in COPD airways: relationship to bronchodilator responsiveness and angiogenesis.

We have investigated whether mast cells are associated with bronchodilator responsiveness and airway vascular changes in chronic obstructive pulmonary disease (COPD) airways. We have previously shown that the reticular basement membrane is hypervascular and the lamina propria is hypovascular in COPD. Bronchial biopsies from 32 COPD subjects, 15 smokers with normal lung function and 17 controls, were immunostained for factor VIII, mast cell tryptase and chymase antibodies. Mast cells in the airway smooth muscle, the reticular basement membrane and the underlying lamina propria were quantitated. 41% of COPD subjects had significant bronchodilator responsiveness, but this was not related to smooth muscle mast cell numbers. The reticular basement membrane had greater mast cell density in all groups compared with controls (p<0.01). In this compartment, perivascular mast cell density was related to hypervascularity. Lamina propria mast cell density was increased only in COPD (p<0.05). Perivascular mast cell density in the lamina propria was not related to its decreased vessel density. Bronchodilator responsiveness in COPD is not related to large airway smooth muscle mast cells of either type; both reticular basement membrane and lamina propria mast cells are increased in COPD patients, and perivascular mast cells may be involved in increased angiogenesis in the reticular basement membrane.

Distinctive characteristics of bronchial reticular basement membrane and vessel remodelling in chronic obstructive pulmonary disease (COPD) and in asthma: they are not the same disease.

AIMS: This study compared reticular basement membrane (Rbm) and vascular remodelling within the bronchial mucosa of subjects with chronic obstructive pulmonary disease (COPD) with those from patients with asthma, to test the 'Dutch hypothesis' of whether these are essentially the same or different pathological conditions. METHODS AND RESULTS: Bronchoscopic biopsies were stained with anti-collagen IV antibody; 18 current smoking COPD, 10 symptomatic asthmatics and 13 healthy non-smoking controls were studied. The Rbm in COPD was fragmented, non-homogeneous, variable in thickness and hypervascular, whereas in asthma the Rbm was compact and homogeneous with no evidence of increased vascularity compared to controls. Length of Rbm splitting presented as percentage of Rbm length was used to measure fragmentation; it was greater in COPD than in controls and asthmatics [median (range) 20.7% (0.4-68.5) versus 5.3% (0.0-21.7) versus 1.5% (0.0-15.1), P < 0.001]. The number of Rbm vessels/mm Rbm [median (range) 10.1 (1.6-23.0) versus 4.5 (0.0-26.4) versus 4.4 (0.4-8.1), P < 0.01] and area of Rbm vessels, µm(2) /mm Rbm [median (range) 953 (115-2456) versus 462 (0-3263) versus 426 (32-2216), P < 0.05] was also increased in COPD compared to normal subjects and asthmatics. CONCLUSIONS: The characteristics of Rbm remodelling are quite different in asthma and COPD.

Quality assurance of electron and photon beam energy using the BQ-CHECK phantom.

The BQ-CHECK phantom (PTW Freiburg, Germany) has been designed to be used with a 2D ion chamber array to facilitate the quality assurance (QA) of electron and photon beam qualities (BQ). The BQ-CHECK phantom has three wedges covering the diagonal axes of the beam: two opposed aluminum wedges used to measure electron energy and a single copper wedge used to measure photon energy. The purpose of this work was to assess the suitability of the BQ-CHECK phantom for use in a routine QA program. A range of percentage depth dose (PDD) curves for two photon beams and four electron beams were measured using a MP3 plotting tank (PTW Freiburg). These beams were used to irradiate a STARCHECK array (PTW Freiburg) with and without the BQ-CHECK phantom on top of the array. For photons, the ratio of the signals from two chambers underneath the copper wedge was used as an effective TPR measurement (TPR(eff)) and, for electrons, the full width at half maximum of the profile (E(FWHM)) underneath the aluminum wedges was used as an electron energy constancy measurement. PDD measurements were compared with TPR(eff) and E(FWHM) to assess the sensitivity of the BQ-CHECK phantom. The clinical tolerances of TPReff were determined for 6 MV (0.634-0.649), and 10MV (0.683-0.692). For electrons, the clinical tolerances of EFWHM were determined for 6 MeV (94.8-103.4 mm), 8 MeV (105.5-114.0 mm), 10 MeV (125.4-133.9 mm) and 12 MeV (138.8-147.3 mm).Electron and photon energy metrics are presented which demonstrate that the BQ-CHECK phantom could be used to form part of an efficient routine monthly QA program. Acceptable beam quality limits for various nominal beam energies were established and at these limits, modified profiles were acquired using the STARCHECK array. From the modified profiles, E(FWHM) and TPR(eff) were determined for the electron and photon beams, respectively. It was demonstrated that both E(FWHM) and the TPR(eff) have a linear relationship with conventional beam quality metrics.

Basement membrane and vascular remodelling in smokers and chronic obstructive pulmonary disease: a cross-sectional study.

BACKGROUND: Little is known about airway remodelling in bronchial biopsies (BB) in smokers and chronic obstructive pulmonary disease (COPD). We conducted an initial pilot study comparing BB from COPD patients with nonsmoking controls. This pilot study suggested the presence of reticular basement membrane (Rbm) fragmentation and altered vessel distribution in COPD. METHODS: To determine whether Rbm fragmentation and altered vessel distribution in BB were specific for COPD we designed a cross-sectional study and stained BB from 19 current smokers and 14 ex-smokers with mild to moderate COPD and compared these to 15 current smokers with normal lung function and 17 healthy and nonsmoking subjects. RESULTS: Thickness of the Rbm was not significantly different between groups; although in COPD this parameter was quite variable. The Rbm showed fragmentation and splitting in both current smoking groups and ex-smoker COPD compared with healthy nonsmokers (p < 0.02); smoking and COPD seemed to have additive effects. Rbm fragmentation correlated with smoking history in COPD but not with age. There were more vessels in the Rbm and fewer vessels in the lamina propria in current smokers compared to healthy nonsmokers (p < 0.05). The number of vessels staining for vascular endothelial growth factor (VEGF) in the Rbm was higher in both current smoker groups and ex-smoker COPD compared to healthy nonsmokers (p < 0.004). In current smoker COPD VEGF vessel staining correlated with FEV1% predicted (r = 0.61, p < 0.02). CONCLUSIONS: Airway remodelling in smokers and mild to moderate COPD is associated with fragmentation of the Rbm and altered distribution of vessels in the airway wall. Rbm fragmentation was also present to as great an extent in ex-smokers with COPD. These characteristics may have potential physiological consequences.

ß-catenin, Twist and Snail: Transcriptional regulation of EMT in smokers and COPD, and relation to airflow obstruction.

COPD is characterised by poorly reversible airflow obstruction usually due to cigarette smoking. The transcription factor clusters of ß-catenin/Snail1/Twist has been implicated in the process of epithelial mesenchymal transition (EMT), an intermediate between smoking and airway fibrosis, and indeed lung cancer. We have investigated expression of these transcription factors and their "cellular localization" in bronchoscopic airway biopsies from patients with COPD, and in smoking and non-smoking controls. An immune-histochemical study compared cellular protein expression of ß-catenin, Snail1 and Twist, in these subject groups in 3 large airways compartment: epithelium (basal region), reticular basement membrane (Rbm) and underlying lamina propria (LP). ß-catenin and Snail1 expression was generally high in all subjects throughout the airway wall with marked cytoplasmic to nuclear shift in COPD (P < 0.01). Twist expression was generalised in the epithelium in normal but become more basal and nuclear with smoking (P < 0.05). In addition, ß-catenin and Snail1 expression, and to lesser extent of Twist, was related to airflow obstruction and to expression of a canonical EMT biomarker (S100A4). The ß-catenin-Snail1-Twist transcription factor cluster is up-regulated and nuclear translocated in smokers and COPD, and their expression is closely related to both EMT activity and airway obstruction.

Vessel-associated transforming growth factor-beta1 (TGF-ß1) is increased in the bronchial reticular basement membrane in COPD and normal smokers.

BACKGROUND: Transforming growth factor-beta1 (TGF-ß1) is a multipotential cytokine with angiogenic activity. There are only limited data about its role in airway remodeling in COPD. We have previously shown that the reticular basement membrane (Rbm) is hypervascular in the airways of current smokers either with or without chronic obstructive pulmonary disease (COPD). This study evaluated TGF-ß1 immunostaining in the Rbm and its relationship to vascularity in smokers with or without COPD. METHODOLOGY/PRINCIPAL FINDINGS: Bronchial biopsies from 15 smokers with normal lung function, 19 current and 14 ex-smokers with COPD were immunostained for TGF-ß1 antibody and compared to 17 healthy controls. The percentage area of tissue and also number and area of vessels staining positively for TGF-ß1 were measured and compared between groups. Some bronchial biopsies from current smoking COPD subjects were also stained for phosphorylated (active) Smad2/3. Epithelial TGF- ß1 staining was not different between COPD current smokers and normal controls. TGF-ß1 stained vessels in the Rbm were increased in smokers with normal lung function, current smoking COPD and ex-smokers with COPD compared to controls [median (range) for number of vessels/mm Rbm 2.5 (0.0-12.7), 3.4 (0.0-8.1) and 1.0 (0.0-6.3) vs. 0.0 (0.0-7.0), p<0.05]. Percentage of vessels stained was also increased in these clinical groups. Preliminary data suggest that in current smoking COPD subjects endothelial cells and cells in the Rbm stain positively for phosphorylated Smad2/3 suggesting TGF-ß1 is functionally active in this situation. CONCLUSIONS/SIGNIFICANCE: Vessel-associated TGF-ß1 activity is increased in the bronchial Rbm in smokers and especially those with COPD.

Experimental small field 6 MV output ratio analysis for various diode detector and accelerator combinations.

BACKGROUND AND PURPOSE: The goal of this work was to measure 6MV small field, detector specific, output ratios (OR(det)) using the IBA stereotactic field diode (SFD) and the PTW T60008, T60012, T60016 and T60017 field diodes on both Varian iX and Elekta Synergy accelerators, to establish estimates for the experimental uncertainty and characterize the measurement precision under various conditions. MATERIALS AND METHODS: Data were acquired at depths of 1.5, 5.0 and 10.0 cm for square field sizes of 3.0, 1.0, 0.9, 0.8, 0.7, 0.6 and 0.5 cm. Three isocentric measurements comprised of five readings were made to calculate an experimental output ratio OR(det) with respect to a field size of 5.0 cm. The coefficient of variation (CV) was calculated to characterize the precision associated with each detector-linac combination. Another measurement set was made to investigate the influence of jaw position accuracy. RESULTS: As expected for field sizes smaller than 3.0 cm, the measured OR(det) were not consistent across all detectors. The standard percent uncertainty in measured OR(det) was found to be nearly consistent across all detector-linac combinations: less than ±0.25% for the 3.0 cm field size, increasing to approximately ±1.25% for the smallest field sizes. As the field size was reduced to 0.5 cm the CV increased to 0.10% and 0.15% on the Varian and Elekta linacs, respectively. CONCLUSION: Experimental small field OR(det) measured with the diode detectors used in this study are reproducible to within ±1.25% (standard uncertainty), with the precision of any one set of measurements can be characterized with a CV between 0.10% and 0.15%.