The role of PET/CT scanning in radiotherapy planning

The introduction of functional data into the radiotherapy treatment planning process is currently the focus of significant commercial, technical, scientific and clinical development. The potential of such data from positron emission tomography (PET) was recognized at an early stage and was integrated into the radiotherapy treatment planning process through the use of image fusion software. The combination of PET and CT in a single system (PET/CT) to form an inherently fused anatomical and functional dataset has provided an imaging modality which could be used as the prime tool in the delineation of tumour volumes and the preparation of patient treatment plans, especially when integrated with virtual simulation. PET imaging typically using F-Fluorodeoxyglucose (F-FDG) can provide data on metabolically active tumour volumes. These functional data have the potential to modify treatment volumes and to guide treatment delivery to cells with particular metabolic characteristics. This paper reviews the current status of the integration of PET and PET/CT data into the radiotherapy treatment process. Consideration is given to the requirements of PET/CT data acquisition with reference to patient positioning aids and the limitations imposed by the PET/CT system. It also reviews the approaches being taken to the definition of functional/ tumour volumes and the mechanisms available to measure and include physiological motion into the imaging process. The use of PET data must be based upon a clear understanding of the interpretation and limitations of the functional signal. Protocols for the implementation of this development remain to be defined, and outcomes data based upon clinical trials are still awaited. © 2006 The British Institute of Radiology.

Conventional 3D staging PET/CT in CT simulation for lung cancer: impact of rigid and deformable target volume alignments for radiotherapy treatment planning

Objective: Positron emission tomography (PET)/CT scans can improve target definition in radiotherapy for non-small cell lung cancer (NSCLC). As staging PET/CT scans are increasingly available, we evaluated different methods for co-registration of staging PET/CT data to radiotherapy simulation (RTP) scans.<br/><br/>Methods: 10 patients underwent staging PET/CT followed by RTP PET/CT. On both scans, gross tumour volumes (GTVs) were delineated using CT (GTVCT) and PET display settings. Four PET-based contours (manual delineation, two threshold methods and a source-to-background ratio method) were delineated. The CT component of the staging scan was co-registered using both rigid and deformable techniques to the CT component of RTP PET/CT. Subsequently rigid registration and deformation warps were used to transfer PET and CT contours from the staging scan to the RTP scan. Dice’s similarity coefficient (DSC) was used to assess the registration accuracy of staging-based GTVs following both registration methods with the GTVs delineated on the RTP PET/CT scan.<br/><br/>Results: When the GTVCT delineated on the staging scan after both rigid registration and deformation was compared with the GTVCT on the RTP scan, a significant improvement in overlap (registration) using deformation was observed (mean DSC 0.66 for rigid registration and 0.82 for deformable registration, p50.008). A similar comparison for PET contours revealed no significant improvement in overlap with the use of deformable registration.<br/><br/>Conclusions: No consistent improvements in similarity measures were observed when deformable registration was used for transferring PET-based contours from a staging PET/CT. This suggests that currently the use of rigid registration remains the most appropriate method for RTP in NSCLC.

Clinical implementation of dynamic multileaf collimation for compensated bladder treatments.

BACKGROUND AND PURPOSE: To describe the clinical implementation of dynamic multileaf collimation (DMLC). Custom compensated four-field treatments of carcinoma of the bladder have been used as a simple test site for the introduction of intensity modulated radiotherapy.MATERIALS AND METHODS: Compensating intensity modulations are calculated from computed tomography (CT) data, accounting for scattered, as well as primary radiation. Modulations are converted to multileaf collimator (MLC) leaf and jaw settings for dynamic delivery on a linear accelerator. A full dose calculation is carried out, accounting for dynamic leaf and jaw motion and transmission through these components. Before treatment, a test run of the delivery is performed and an absolute dose measurement made in a water or solid water phantom. Treatments are verified by in vivo diode measurements and real-time electronic portal imaging. RESULTS: Seven patients have been treated using DMLC. The technique improves dose homogeneity within the target volume, reducing high dose areas and compensating for loss of scatter at the beam edge. A typical total treatment time is 20 min. CONCLUSIONS: Compensated bladder treatments have proven an effective test site for DMLC in an extremely busy clinic.

The impact of virtual simulation in palliative radiotherapy for non-small-cell lung cancer.

Background and purpose: Radiotherapy is widely used to palliate local symptoms in non-small-cell lung cancer. Using conventional X-ray simulation, it is often difficult to accurately localize the extent of the tumour. We report a randomized, double blind trial comparing target localization with conventional and virtual simulation.Methods: Eighty-six patients underwent both conventional and virtual simulation. The conventional simulator films were compared with digitally reconstructed radiographs (DRRs) produced from the computed tomography (CT) data. The treatment fields defined by the clinicians using each modality were compared in terms of field area, position and the implications for target coverage.Results: Comparing fields defined by each study arm, there was a major mis-match in coverage between fields in 66.2% of cases, and a complete match in only 5.2% of cases. In 82.4% of cases, conventional simulator fields were larger (mean 24.5+/-5.1% (95% confidence interval)) than CT-localized fields, potentially contributing to a mean target under-coverage of 16.4+/-3.5% and normal tissue over-coverage of 25.4+/-4.2%.Conclusions: CT localization and virtual simulation allow more accurate definition of the target volume. This could enable a reduction in geographical misses, while also reducing treatment-related toxicity.

Experimental and Computational Approach Investigating Burst Fracture Augmentation Using PMMA and Calcium Phosphate Cements

The aim of the study was to use a computational and experimental approach to evaluate, compare and predict the ability of calcium phosphate (CaP) and poly (methyl methacrylate) (PMMA) augmentation cements to restore mechanical stability to traumatically fractured vertebrae, following a vertebroplasty procedure. Traumatic fractures (n = 17) were generated in a series of porcine vertebrae using a drop-weight method. The fractured vertebrae were imaged using μCT and tested under axial compression. Twelve of the fractured vertebrae were randomly selected to undergo a vertebroplasty procedure using either a PMMA (n = 6) or a CaP cement variation (n = 6). The specimens were imaged using μCT and re-tested. Finite element models of the fractured and augmented vertebrae were generated from the μCT data and used to compare the effect of fracture void fill with augmented specimen stiffness. Significant increases (p &lt;0.05) in failure load were found for both of the augmented specimen groups compared to the fractured group. The experimental and computational results indicated that neither the CaP cement nor PMMA cement could completely restore the vertebral mechanical behavior to the intact level. The effectiveness of the procedure appeared to be more influenced by the volume of fracture filled rather than by the mechanical properties of the cement itself.

The effect of treatment of cystic fibrosis pulmonary exacerbations on airways and systemic inflammation

Background: Chronic infection in cystic fibrosis (CF) and airway inflammation leads to progressive lung injury Neutrophils are considered to be responsible for the onset and promotion of the inflammatory response within the CF lung. The relationship between infection and inflammation is complex but circulating inflammatory markers may not truly reflect the local inflammatory response in the lung. The aims of this study were to investigate the change of inflammatory biomarkers and cells within sputum and blood before and after intravenous antibiotics for a pulmonary exacerbation of CF Methods: Assays included neutrophil elastase (NE) and complex, interleukin-8 (IL-8) and soluble intercellular adhesion molecule-1 (sICAM-1), fas ligand (FAS-L), and TNFr-1. Analysis of sputum cell differential and absolute cell counts and immunocytochemistry (CD11b and CD95) on sputum and isolated blood neutrophils were carried out. Results: There were no significant differences in absolute or differential sputum cell counts or sputum sol measurements following antibiotics. There was a significant increase in the percentage of blood neutrophils with minimal CD11b staining, 28 (4.1) mean percentage (SEM) versus41 (2.9) and a decrease in the percentage showing maximal staining 30 (0.5) versus 15 (2.5). There was a significant increase in the percentage of blood neutrophils without CD95 staining, 43 (5.4) mean percentage versus 52 (5.1). Conclusion: These data suggest a modifiable systemic response to IV antibiotics but a local sustained inflammatory response in the lung.

Anti-apoptotic effects of Z alpha-1 antitrypsin in human bronchial epithelial cells.

α1-antitrypsin (α1-AT) deficiency is a genetic disease which manifests as early-onset emphysema or liver disease. Although the majority of α1-AT is produced by the liver, it is also produced by bronchial epithelial cells, amongst others, in the lung. Herein, we investigate the effects of mutant Z α1-AT (ZAAT) expression on apoptosis in a human bronchial epithelial cell line (16HBE14o-) and delineate the mechanisms involved.<br/><br/>Control, M variant α1-AT (MAAT)- or ZAAT-expressing cells were assessed for apoptosis, caspase-3 activity, cell viability, phosphorylation of Bad, nuclear factor (NF)-κB activation and induced expression of a selection of pro- and anti-apoptotic genes.<br/><br/>Expression of ZAAT in 16HBE14o- cells, like MAAT, inhibited basal and agonist-induced apoptosis. ZAAT expression also inhibited caspase-3 activity by 57% compared with control cells (p = 0.05) and was a more potent inhibitor than MAAT. Whilst ZAAT had no effect on the activity of Bad, its expression activated NF-κB-dependent gene expression above control or MAAT-expressing cells. In 16HBE14o- cells but not HEK293 cells, ZAAT upregulated expression of cIAP-1, an upstream regulator of NF-κB. cIAP1 expression was increased in ZAAT versus MAAT bronchial biopsies.<br/><br/>The data suggest a novel mechanism by which ZAAT may promote human bronchial epithelial cell survival.<br/>

Incidence and risk factors for pulmonary exacerbation treatment failures in cystic fibrosis patients chronically infected with Pseudomonas aeruginosa

Background: Pulmonary exacerbations (PEx) are responsible for much of the morbidity and mortality associated with cystic fibrosis (CF). However, there is a paucity of data on outcomes in CF PEx and factors influencing outcomes. <br/> <br/>Methods: We reviewed all PEx in patients infected with Pseudomonas aeruginosa treated with parenteral antibiotics over 4 years at our center. Treatment failures were categorized a priori as those PEx requiring antibiotic regimen change, prolongation of therapy &gt; 20 days because of failure to respond, an early recurrent event within &lt; 45 days, or failure to recover lung function to &gt; 90% of baseline FEV1. <br/> <br/>Results: A total of 101 patients were followed for 452 PEx. Treatment failures were observed in 125 (28%) of PEx; antibiotic regimen change was observed in 27 (6%), prolongation of therapy in 29 (6%), early recurrent events in 63 (14%), and failure to recover lung function to &gt; 90% of baseline FEV1 in 66 (15%). Demographic factors associated with one or more treatment failures per year included advanced airways disease, use of enteric feeds, CF-related diabetes, and CF liver disease but did not include female sex or F508del homozygosity. Increased treatment failure risk was associated with lower admission FEV1 and increased markers of inflammation. At therapeutic completion, increased inflammatory markers correlated with treatment failure. Failure rates decreased with increasing number of active antimicrobial agents used based on in vitro susceptibility (zero, 28/65 [43%]; one, 38/140 [27%]; two, 59/245 [24%]; three, 0/2 [0%]; P = .02). <br/> <br/>Conclusions: One-fourth of PEx fail to respond adequately to initial management. Patient demographic and episode-specific clinical information can be used to identify individuals at increased risk of initial management failure. <br/> <br/>

Experiences and needs of bereaved carers during palliative and end-of-life care for people with chronic obstructive pulmonary disease

This study explored the experiences of palliative care that bereaved carers had while providing care to a dying loved one with chronic obstructive pulmonary disease (COPD). <br/><br/>Method: Semi-structured interviews were undertaken with nine carers whohad lost a loved one in the preceding 6 to 24 months.These interviews explored levels of satisfaction with disease management, symptom management, and end-of-life care. With permission, interviews were tape recorded, transcribed, and subjected to content analysis. <br/><br/>Findings: Three themes emerged from the data: the impact of the caring experience, the lack of support services, and end-of-life and bereavement support. Carers experienced carer burden, lack of access to support services, a need for palliative care, and bereavement support. <br/><br/>Conclusion: The findings provide a first insight into the experiences of carers of patients with advanced COPD. Bereaved carers of patients who had suffered advanced COPD reported that they had received inadequate support and had a range of unmet palliative care needs. Special attention should be paid to educating and supporting carers during their caring and bereavement periods to ensure that their quality of life is maintained or enhanced

Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in Acute lung injury to Reduce Pulmonary dysfunction (HARP-2) trial: study protocol for a randomized controlled trial

<p>Background: Acute lung injury (ALI) is a common devastating clinical syndrome characterized by life-threatening respiratory failure requiring mechanical ventilation and multiple organ failure. There are in vitro, animal studies and pre-clinical data suggesting that statins may be beneficial in ALI. The Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in Acute lung injury to Reduce Pulmonary dysfunction (HARP-2) trial is a multicenter, prospective, randomized, allocation concealed, double-blind, placebo-controlled clinical trial which aims to test the hypothesis that treatment with simvastatin will improve clinical outcomes in patients with ALI.</p><p>Methods/Design: Patients fulfilling the American-European Consensus Conference Definition of ALI will be randomized in a 1: 1 ratio to receive enteral simvastatin 80 mg or placebo once daily for a maximum of 28 days. Allocation to randomized groups will be stratified with respect to hospital of recruitment and vasopressor requirement. Data will be recorded by participating ICUs until hospital discharge, and surviving patients will be followed up by post at 3, 6 and 12 months post randomization. The primary outcome is number of ventilator-free days to day 28. Secondary outcomes are: change in oxygenation index and sequential organ failure assessment score up to day 28, number of non pulmonary organ failure free days to day 28, critical care unit mortality; hospital mortality; 28 day post randomization mortality and 12 month post randomization mortality; health related quality of life at discharge, 3, 6 and 12 months post randomization; length of critical care unit and hospital stay; health service use up to 12 months post-randomization; and safety. A total of 540 patients will be recruited from approximately 35 ICUs in the UK and Ireland. An economic evaluation will be conducted alongside the trial. Plasma and urine samples will be taken up to day 28 to investigate potential mechanisms by which simvastatin might act to improve clinical outcomes.</p>

Estimation of fetal and effective dose for CT examinations

Doses from CT examinations are difficult to estimate. However, they are requested more frequently due to the increase in CT examinations. In particular, fetal dose estimations are frequently required for patients who have discovered, subsequent to the examination, that they were pregnant when the examination was conducted. A computer model has been developed to facilitate such dose calculations. This model combines empirical beam data with anatomical information. The model has been verified using thermoluminescent dosemeter (TLD) readings of internal and surface dose from both phantoms and patients, including intrauterine doses for patients undergoing afterloading gynaecological intracavitary treatment. Although only limited experimental data were available, the results indicate that the model accurately predicts uterine doses within acceptable errors. This approach has been validated for fetal dose estimation. The model was also used in a comparison with the nationally available CT dose data from the National Radiological Protection Board (NRPB). The two models were found to be in agreement for fetal dose estimations.

One-Year Safety of Olodaterol Once Daily via Respimat® in Patients with GOLD 2-4 Chronic Obstructive Pulmonary Disease: Results of a Pre-Specified Pooled Analysis

<p>The novel long-acting β2-agonist olodaterol demonstrated an acceptable safety profile in short-term phase II clinical studies. This analysis of four randomized, double-blind, placebo-controlled, parallel-group, phase III studies (1222.11, NCT00782210; 1222.12, NCT00782509; 1222.13, NCT00793624; 1222.14, NCT00796653) evaluated the long-term safety of olodaterol once daily (QD) in a large cohort of patients with moderate to very severe (Global initiative for chronic Obstructive Lung Disease 2-4) chronic obstructive pulmonary disease (COPD). The studies compared olodaterol (5 or 10 μg) QD via Respimat®, formoterol 12 μg twice daily (BID) via Aerolizer® (1222.13 and 1222.14), and placebo for 48 weeks. Patients continued receiving background maintenance therapy, with ∼60% receiving concomitant cardiovascular therapy and 25% having a history of concomitant cardiac disease. Pre-specified analyses of pooled data assessed the adverse events (AEs) and serious AEs in the whole population, and in subgroups with cardiac disease, along with in-depth electrocardiogram and Holter monitoring. In total, 3104 patients were included in the safety analysis: 876 received olodaterol 5 μg, 883 received olodaterol 10 μg, 885 received placebos, and 460 received formoterol 12 μg BID. Overall incidence of on-treatment AEs (71.2%), serious AEs (16.1%), and deaths (1.7%) were balanced across treatment groups. Respiratory and cardiovascular AEs, including major adverse cardiac events, were reported at similar frequencies in placebo and active treatment groups. The safety profiles of both olodaterol 5 μg (marketed and registered dose) and 10 μg QD delivered via Respimat® are comparable to placebo and formoterol BID in this population, with no safety signals identified.</p>

Lung Clearance Index in cystic fibrosis subjects treated for Pulmonary Exacerbations

Pulmonary exacerbations are important clinical events for cystic fibrosis (CF) patients. Studies assessing the ability of the lung clearance index (LCI) to detect treatment response for pulmonary exacerbations have yielded heterogeneous results. Here, we conduct a retrospective analysis of pooled LCI data to assess treatment with intravenous antibiotics for pulmonary exacerbations and to understand factors explaining the heterogeneous response. <br/><br/>A systematic literature search was performed to identify prospective observational studies. Factors predicting the relative change in LCI and spirometry were evaluated while adjusting for within-study clustering. <br/><br/>Six previously reported studies and one unpublished study, which included 176 pulmonary exacerbations in both paediatric and adult patients, were included. Overall, LCI significantly decreased by 0.40 units (95% CI -0.60 -0.19, p=0.004) or 2.5% following treatment. The relative change in LCI was significantly correlated with the relative change in forced expiratory volume in 1 s (FEV1), but results were discordant in 42.5% of subjects (80 out of 188). Higher (worse) baseline LCI was associated with a greater improvement in LCI (slope: -0.9%, 95% CI -1.0- -0.4%). <br/><br/>LCI response to therapy for pulmonary exacerbations is heterogeneous in CF patients; the overall effect size is small and results are often discordant with FEV1.