AAPS Perspective on the EURL Recommendation on the use of Non-Animal-Derived Antibodies.

In May 2020, the EU Reference Laboratory for alternatives to animal testing (EURL ECVAM) published a recommendation report entitled "Recommendation on nonanimal-derived antibodies". In this report, the EURL ECVAM specifically states: "Therefore, taking into consideration the ESAC Opinion on the scientific validity of replacements for animal-derived antibodies, EURL ECVAM recommends that animals should no longer be used for the development and production of antibodies for research, regulatory, diagnostic and therapeutic applications. The provisions of Directive 2010/63/EU should be respected, and EU countries should no longer authorise the development and production of antibodies through animal immunisation, where robust, legitimate scientific justification is lacking." (1). Here, we are providing the American Association of Pharmaceutical Scientists (AAPS) opinion on the EURL ECVAM recommendation report. In brief, there has been a clear and strong progress in reduction of animal use in the drug discovery and development process, including significant reduction of animal use in production of antibody reagents. Yet, it is proposed that more data need to be generated, shared and discussed within the scientific community before a decision to implement the change to non-animal derived antibodies is made.

A systematic review of the content and delivery of education in pulmonary rehabilitation programmes.

INTRODUCTION: Pulmonary rehabilitation (PR) is a core component of Chronic Obstructive Pulmonary Disease (COPD) management with well recognized benefits. While suggestions for educational content within pulmonary rehabilitation have been detailed in clinical guidance, it is unclear what educational content is delivered as part of pulmonary rehabilitation, who delivers it, and how it is delivered. METHODS: A systematic review was conducted to identify what educational content is delivered as part of pulmonary rehabilitation, how is this delivered and who delivers it. Databases were searched from 1981 to 2017 using multiple search terms related to "pulmonary rehabilitation" and "education". RESULTS: Fourteen studies were identified. This included 6 survey studies, 5 quasi-experimental studies and 3 RCTs. Five key topics that were consistently included within PR programmes were identified as: 1) Anxiety/depression and stress management. 2) Early recognition of signs of infection. 3) Dyspnea and symptom management. 4) Nutrition. 5) Techniques using inhalers and nebulizers. Broader topics such as welfare/benefits, sexuality, and advance care directives did not frequently feature. Only four studies used tools to measure knowledge or learning pre and post rehabilitation in an attempt to evaluate the effectiveness of the education delivered as part of PR. CONCLUSIONS: The delivery of education in PR programmes is variable and does not follow suggested educational topics. Education needs to take a patient centered motivational approach to ensure effective delivery. Further research into appropriate educational outcome measures are needed, in order to evaluate the changes in behaviour associated with education.

Stomach Dose-Volume Predicts Acute Gastrointestinal Toxicity in Chemoradiotherapy for Locally Advanced Pancreatic Cancer.

AIMS: Gastrointestinal toxicity impedes dose escalation in chemoradiotherapy for hepatobiliary malignancies. Toxicity risk depends on clinical and radiotherapy metrics. We aimed to identify predictive factors using data from two prospective phase II clinical trials of locally advanced pancreatic cancer (LAPC). MATERIALS AND METHODS: Ninety-one patients with available data from the ARCII (59.4 Gy in 33 fractions with gemcitabine, cisplatin and nelfinavir, n = 23) and SCALOP (50.4 Gy in 28 fractions with capecitabine or gemcitabine, n = 74) trials were studied. The independent variables analysed comprised age, sex, performance status, baseline symptoms, tumour size, weight loss, chemotherapy regimen and dose-volume histogram of stomach and duodenum in 5 Gy bins. The outcome measures used were Common Terminology Criteria of Adverse Events (CTCAE) grade and risk of CTCAE grade ≥2 acute upper gastrointestinal toxicity (anorexia, pain, nausea and/or vomiting). The risk of CTCAE grade ≥2 events was modelled using multivariable logistic regression and prediction of severity grade using ordinal regression. RESULTS: CTCAE grade ≥2 symptoms occurred in 38 patients (42%). On univariate analysis, stomach V35-45Gy was predictive of risk (odds ratio 1.035, 95% confidence interval 1.007-1.063) and grade (1.023, 1.003-1.044) of toxicity. The area under the curve was 0.632 (0.516-0.747) with toxicity risk 33/66 (50%) above and 5/25 (20%) below the optimal discriminatory threshold (7.1 cm3). Using a threshold of 30 cm3, risk was 13/20 (65%) versus 25/71 (35%). The optimal multivariable logistic regression model incorporated patient sex, chemotherapy regimen and stomach V35-45Gy. Receiving gemcitabine rather than capecitabine (odds ratio 3.965, 95% confidence interval 1.274-12.342) and weight loss during induction chemotherapy (1.216, 1.043-1.419) were significant predictors for the SCALOP cohort, whereas age predicted toxicity risk in ARCII only (1.344, 1.015-1.780). Duodenum dose-volume did not predict toxicity risk or severity in any cohort. CONCLUSIONS: In chemoradiotherapy for LAPC the volume of stomach irradiated to a moderately high dose (35-45 Gy) predicts the incidence and severity of acute toxicity. Other predictive factors can include age, sex, recent weight loss and concomitant chemotherapy agents.

Correlation of 18F-Fluorodeoxyglucose Positron Emission Tomography Parameters with Patterns of Disease Progression in Locally Advanced Pancreatic Cancer after Definitive Chemoradiotherapy.

AIMS: A proportion of patients with pancreatic cancer never develop metastatic disease. We evaluated a role for 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) in identifying a subset of patients with locally advanced pancreatic cancer (LAPC) who never develop metastatic disease and only experience local disease and may therefore benefit from local treatment intensification. MATERIAL AND METHODS: Patients with histologically confirmed LAPC entered a single-centre phase II study of definitive upfront chemoradiotherapy (CRT). All patients underwent FDG-PET/CT before and 6 weeks after CRT. Tumour volume, standardised uptake values (SUVmax, SUVpeak, SUVmean, SUVmedian) and total lesion glycolysis (TLG) were measured on each scan and the response in each parameter was evaluated. The presence or absence of metastatic disease was noted on contrast-enhanced CT carried out every 3 months for 1 year and then at clinician discretion. RESULTS: Twenty-three patients with LAPC were recruited; 17/23 completed treatment and had interpretable sequential imaging. Twenty-four per cent of patients only ever experienced local disease. Median pre-CRT FDG-PET parameters were significantly lower in patients with local disease only during follow-up compared with those who developed metastatic disease: SUVmax 3.8 versus 8.6 (P=0.006), SUVpeak 2.5 versus 7.5 (P=0.002), SUVmean 1.8 versus 3.3 (P=0.001), SUVmedian 1.7 versus 3.0 (P=0.002), TLG 26.9 versus 115.9 (P=0.006). Tumour volume, post-CRT FDG-PET values and their relative change were not statistically different between local disease and metastatic disease groups. Receiver operating characteristic curves for pre-CRT FDG-PET parameters to predict those who never develop metastatic disease all had areas under the curve (AUCs) ≥ 0.932. Pre-CRT FDG-PET SUVmax < 6.2 predicted patients with local disease only during follow-up with 100.0% sensitivity and 92.3% specificity, 80.0% positive predictive value and 100% negative predictive value. CONCLUSIONS: Our findings suggest that patients with less FDG-avid tumours are less likely to metastasise and may therefore benefit from upfront local treatment intensification.

The Use of Social Media to Combat Research-Isolation.

Research-isolation is a common problem affecting many researchers who are disconnected from their research communities. It can be caused by a number of factors, including physical isolation, unfamiliar research topics, diversity, and the nature of the supervisory relationship. All of these aspects can have an impact on both work and the mental health of researchers. Increasingly, researchers are turning to social media for support, by both looking for communities and for increasing the impact of their work. In this paper, we set out a brief introduction to a range of social media platforms used by researchers and present a discussion of the networks within those platforms aimed at reducing research-isolation. These examples highlight just a few of the number of small communities that have grown online to meet the needs of those seeking support through social media. We conclude with some recommendations for those affected by research-isolation and highlight the need for more research into the role of social media on mental health in academics.

Unwrapping 3D complex hollow organs for spatial dose surface analysis.

PURPOSE: Toxicity dose-response models describe the correlation between dose delivered to an organ and a given toxic endpoint. Duodenal toxicity is a dose limiting factor in the treatment of pancreatic cancer with radiation but the relationship between dose and toxicity in the duodenum is not well understood. While there have been limited studies into duodenal toxicity through investigations of the volume of the organ receiving dose over a specific threshold, both dose-volume and dose-surface histograms lack spatial information about the dose distribution, which may be important in determining normal tissue response. Due to the complex geometry of the duodenum, previous methods for unwrapping tubular organs for spatial modeling of toxicity are insufficient. A geometrically robust method for producing 2D dose surface maps (DSMs), specifically for the duodenum, has been developed and tested in order to characterize the spatial dose distribution. METHODS: The organ contour is defined using Delaunay triangulation. The user selects a start and end coordinate in the structure and a path is found by regulating both length and curvature. This path is discretized and rays are cast from each point on the plane normal to the vector between the previous and the next point on the path and the dose at the closest perimeter point recorded. These angular perimeter slices are "unwrapped" from the edge distal to the pancreas to ensure the high dose region (proximal to the tumor) falls in the centre of the dose map. Gamma analysis is used to quantify the robustness of this method and the effect of overlapping planes. RESULTS: This method was used to extract DSMs for 15 duodena, with one esophagus case to illustrate the application to simpler geometries. Visual comparison indicates that a 30 × 30 map provides sufficient resolution to view gross spatial features of interest. A lookup table is created to store the area (cm2) represented by each pixel in the DSMs in order to allow spatial descriptors in absolute size. The method described in this paper is robust, requires minimal human interaction, has been shown to be generalizable to simpler geometries, and uses readily available commercial software. The difference seen in DSMs due to overlapping planes is large and justifies the need for a solution that removes such planes. CONCLUSIONS: This is the first time 2D dose surface maps have been produced for the duodenum and provide spatial dose distribution information which can be explored to create models that may improve toxicity prediction in treatments for locally advanced pancreatic cancer.

The diagnosis of COPD in primary care; gender differences and the role of spirometry.

BACKGROUND: Females with exacerbations of Chronic Obstructive Pulmonary Disease now account for one half of all hospital admissions for that condition and rates have been increasing over the last few decades. Differences in presentations of disease between genders have been shown in several conditions and this study explores whether there are inter gender biases in probable diagnoses in those suspected to have COPD. METHODS: 445 individuals with a provisional diagnosis by their General Practitioner of "suspected COPD" or "definite COPD" were referred to a community Respiratory Assessment unit (CRAU) for tests including spirometry. Gender, demographics, respiratory symptoms and respiratory medical history were recorded. The provisional diagnoses were compared with the final diagnosis made after spirometry and respiratory specialist nurse review and the provisional diagnosis was either confirmed as correct or refuted as unlikely. RESULTS: Significantly more men (87.5%) had their diagnosis of "definite COPD" confirmed compared to 73.9% of women (p = 0.021). When the GP suggested a provisional diagnosis of "suspected COPD" (n = 265) at referral, this was confirmed in 60.9% of men and only 43.2% of women (p = 0.004). There was a different symptom pattern between genders with women being more likely to report allergies, symptoms starting earlier in life, and being less likely than men to report breathlessness as the main symptom. CONCLUSIONS: These results may suggest a difference between genders in some of the clinical features of COPD and a difference in likelihood of a GPs provisional diagnosis of COPD being correct. The study reiterates the absolute importance of spirometry in the diagnosis of COPD.

Multivariate modelling of prostate cancer combining magnetic resonance derived T2, diffusion, dynamic contrast-enhanced and spectroscopic parameters.

OBJECTIVES: The objectives are determine the optimal combination of MR parameters for discriminating tumour within the prostate using linear discriminant analysis (LDA) and to compare model accuracy with that of an experienced radiologist. METHODS: Multiparameter MRIs in 24 patients before prostatectomy were acquired. Tumour outlines from whole-mount histology, T2-defined peripheral zone (PZ), and central gland (CG) were superimposed onto slice-matched parametric maps. T2, Apparent Diffusion Coefficient, initial area under the gadolinium curve, vascular parameters (K(trans),Kep,Ve), and (choline+polyamines+creatine)/citrate were compared between tumour and non-tumour tissues. Receiver operating characteristic (ROC) curves determined sensitivity and specificity at spectroscopic voxel resolution and per lesion, and LDA determined the optimal multiparametric model for identifying tumours. Accuracy was compared with an expert observer. RESULTS: Tumours were significantly different from PZ and CG for all parameters (all p < 0.001). Area under the ROC curve for discriminating tumour from non-tumour was significantly greater (p < 0.001) for the multiparametric model than for individual parameters; at 90 % specificity, sensitivity was 41 % (MRSI voxel resolution) and 59 % per lesion. At this specificity, an expert observer achieved 28 % and 49 % sensitivity, respectively. CONCLUSION: The model was more accurate when parameters from all techniques were included and performed better than an expert observer evaluating these data. KEY POINTS: • The combined model increases diagnostic accuracy in prostate cancer compared with individual parameters • The optimal combined model includes parameters from diffusion, spectroscopy, perfusion, and anatominal MRI • The computed model improves tumour detection compared to an expert viewing parametric maps.

3D calculation of radiation-induced second cancer risk including dose and tissue response heterogeneities.

PURPOSE: Tools for comparing relative induced second cancer risk, to inform choice of radiotherapy treatment plan, are becoming increasingly necessary as the availability of new treatment modalities expands. Uncertainties, in both radiobiological models and model parameters, limit the confidence of such calculations. The aim of this study was to develop and demonstrate a software tool to produce a malignant induction probability (MIP) calculation which incorporates patient-specific dose and allows for the varying responses of different tissue types to radiation. METHODS: The tool has been used to calculate relative MIPs for four different treatment plans targeting a subtotally resected meningioma: 3D conformal radiotherapy (3DCFRT), volumetric modulated arc therapy (VMAT), intensity-modulated x-ray therapy (IMRT), and scanned protons. RESULTS: Two plausible MIP models, with considerably different dose-response relationships, were considered. A fractionated linear-quadratic induction and cell-kill model gave a mean relative cancer risk (normalized to 3DCFRT) of 113% for VMAT, 16% for protons, and 52% for IMRT. For a linear no-threshold model, these figures were 105%, 42%, and 78%, respectively. The relative MIP between plans was shown to be significantly more robust to radiobiological parameter uncertainties compared to absolute MIP. Both models resulted in the same ranking of modalities, in terms of MIP, for this clinical case. CONCLUSIONS: The results demonstrate that relative MIP is a useful metric with which treatment plans can be ranked, regardless of parameter- and model-based uncertainties. With further validation, this metric could be used to discriminate between plans that are equivalent with respect to other planning priorities.

Self-management support and other alternatives to reduce the burden of asthma and chronic obstructive pulmonary disease.

While pharmacotherapy is important in the management of asthma and chronic obstructive pulmonary disease, it is also important to consider additional interventions that can further reduce the burden of ill health for patients, their families and the health care system. In this review, the evidence in favour of self-management support that leads to successful self-care by the patient is reviewed, and the key components of successful strategies are outlined; areas where more research is needed are identified. In addition to self-management support, other methods of delivering care, such as telemonitoring, admission avoidance, assisted discharge schemes and use of lay educators, are reviewed.

Dosimetry of very high energy electrons (VHEE) for radiotherapy applications: using radiochromic film measurements and Monte Carlo simulations.

Very high energy electrons (VHEE) in the range from 100-250 MeV have the potential of becoming an alternative modality in radiotherapy because of their improved dosimetry properties compared with MV photons from contemporary medical linear accelerators. Due to the need for accurate dosimetry of small field size VHEE beams we have performed dose measurements using EBT2 Gafchromic® film. Calibration of the film has been carried out for beams of two different energy ranges: 20 MeV and 165 MeV from conventional radio frequency linear accelerators. In addition, EBT2 film has been used for dose measurements with 135 MeV electron beams produced by a laser-plasma wakefield accelerator. The dose response measurements and percentage depth dose profiles have been compared with calculations carried out using the general-purpose FLUKA Monte Carlo (MC) radiation transport code. The impact of induced radioactivity on film response for VHEEs has been evaluated using the MC simulations. A neutron yield of the order of 10(-5) neutrons cm(-2) per incident electron has been estimated and induced activity due to radionuclide production is found to have a negligible effect on total dose deposition and film response. Neutron and proton contribution to the equivalent doses are negligible for VHEE. The study demonstrates that EBT2 Gafchromic film is a reliable dosimeter that can be used for dosimetry of VHEE. The results indicate an energy-independent response of the dosimeter for 20 MeV and 165 MeV electron beams and has been found to be suitable for dosimetry of VHEE.

The application of functional imaging techniques to personalise chemoradiotherapy in upper gastrointestinal malignancies.

Functional imaging gives information about physiological heterogeneity in tumours. The utility of functional imaging tests in providing predictive and prognostic information after chemoradiotherapy for both oesophageal cancer and pancreatic cancer will be reviewed. The benefit of incorporating functional imaging into radiotherapy planning is also evaluated. In cancers of the upper gastrointestinal tract, the vast majority of functional imaging studies have used (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET). Few studies in locally advanced pancreatic cancer have investigated the utility of functional imaging in risk-stratifying patients or aiding target volume definition. Certain themes from the oesophageal data emerge, including the need for a multiparametric assessment of functional images and the added value of response assessment rather than relying on single time point measures. The sensitivity and specificity of FDG-PET to predict treatment response and survival are not currently high enough to inform treatment decisions. This suggests that a multimodal, multiparametric approach may be required. FDG-PET improves target volume definition in oesophageal cancer by improving the accuracy of tumour length definition and by improving the nodal staging of patients. The ideal functional imaging test would accurately identify patients who are unlikely to achieve a pathological complete response after chemoradiotherapy and would aid the delineation of a biological target volume that could be used for treatment intensification. The current limitations of published studies prevent integrating imaging-derived parameters into decision making on an individual patient basis. These limitations should inform future trial design in oesophageal and pancreatic cancers.

Effect on therapeutic ratio of planning a boosted radiotherapy dose to the dominant intraprostatic tumour lesion within the prostate based on multifunctional MR parameters.

OBJECTIVE: To demonstrate the feasibility of an 8-Gy focal radiation boost to a dominant intraprostatic lesion (DIL), identified using multiparametric MRI (mpMRI), and to assess the potential outcome compared with a uniform 74-Gy prostate dose. METHODS: The DIL location was predicted in 23 patients using a histopathologically verified model combining diffusion-weighted imaging, dynamic contrast-enhanced imaging, T2 maps and three-dimensional MR spectroscopic imaging. The DIL defined prior to neoadjuvant hormone downregulation was firstly registered to MRI-acquired post-hormone therapy and subsequently to CT radiotherapy scans. Intensity-modulated radiotherapy (IMRT) treatment was planned for an 8-Gy focal boost with 74-Gy dose to the remaining prostate. Areas under the dose-volume histograms (DVHs) for prostate, bladder and rectum, the tumour control probability (TCP) and normal tissue complication probabilities (NTCPs) were compared with those of the uniform 74-Gy IMRT plan. RESULTS: Deliverable IMRT plans were feasible for all patients with identifiable DILs (20/23). Areas under the DVHs were increased for the prostate (75.1 ± 0.6 vs 72.7 ± 0.3 Gy; p < 0.001) and decreased for the rectum (38.2 ± 2.5 vs 43.5 ± 2.5 Gy; p < 0.001) and the bladder (29.1 ± 9.0 vs 36.9 ± 9.3 Gy; p < 0.001) for the boosted plan. The prostate TCP was increased (80.1 ± 1.3 vs 75.3 ± 0.9 Gy; p < 0.001) and rectal NTCP lowered (3.84 ± 3.65 vs 9.70 ± 5.68 Gy; p = 0.04) in the boosted plan. The bladder NTCP was negligible for both plans. CONCLUSION: Delivery of a focal boost to an mpMRI-defined DIL is feasible, and significant increases in TCP and therapeutic ratio were found. ADVANCES IN KNOWLEDGE: The delivery of a focal boost to an mpMRI-defined DIL demonstrates statistically significant increases in TCP and therapeutic ratio.

Is biochemical relapse-free survival after profoundly hypofractionated radiotherapy consistent with current radiobiological models?

AIMS: The α/ß ratio for prostate cancer is thought to be low and less than for the rectum, which is usually the dose-limiting organ. Hypofractionated radiotherapy should therefore improve the therapeutic ratio, increasing cure rates with less toxicity. A number of models for predicting biochemical relapse-free survival have been developed from large series of patients treated with conventional and moderately hypofractionated radiotherapy. The purpose of this study was to test these models when significant numbers of patients treated with profoundly hypofractionated radiotherapy were included. MATERIALS AND METHODS: A systematic review of the literature with regard to hypofractionated radiotherapy for prostate cancer was conducted, focussing on data recently presented on prostate stereotactic body radiotherapy. For the work described here, we have taken published biochemical control rates for a range of moderately and profoundly fractionated schedules and plotted these together with a range of radiobiological models, which are described. RESULTS: The data reviewed show consistency between the various radiobiological model predictions and the currently observed data. CONCLUSION: Current radiobiological models provide accurate predictions of biochemical relapse-free survival, even when profoundly hypofractionated patients are included in the analysis.

Technical note: 9-month repositioning accuracy for functional response assessment in head and neck chemoradiotherapy.

The use of thermoplastic immobilisation masks in head and neck radiotherapy is now common practice. The accuracy of these systems has been widely studied, but always within the context and time frame of the radiation delivery-some 6-8 weeks. There is growing current interest in the use of functional imaging to assess the response to treatment, particularly in the head and neck. It is therefore of interest to determine the accuracy with which functional images can be registered to baseline CT over the extended periods of time used for functional response assessment: 3-6 months after radiotherapy. In this study, repeated contrast-enhanced diagnostic quality CT and mid-quality localisation CT from a positron emission tomography/CT scanner were available for five time points over a period of 9 months (before, during and up to 6 months after chemoradiotherapy) for a series of eight patients enrolled in a clinical pilot study. All images were acquired using thermoplastic immobilisation masks. The overall set-up accuracy obtained from this 9-month study of 5.5 ± 3.2 mm (1 standard deviation) and 1.9 ± 1.3° (1 standard deviation) is in agreement with published data acquired over 6-8 weeks. No statistically significant change in set-up error was seen with time. This work indicates that thermoplastic immobilisation masks can be used to accurately align multimodality functional image data for assessment of the response to treatment in head and neck patients over extended follow-up periods.

Combining advanced radiotherapy technologies to maximize safety and tumor control probability in stage III non-small cell lung cancer.

BACKGROUND: The goal of the current study was to investigate the tumor control probability (TCP) of advanced radiotherapy technologies for stage III non-small cell lung cancer (NSCLC) and to evaluate potential interplay effects between their applications. MATERIALS AND METHODS: Three-dimensional conformal radiotherapy (3D-CRT) with conventionally fractionated doses of 66 Gy served as reference for 13 patients with stage III NSCLC. Isotoxic dose escalation relative to the corresponding 3D-CRT plans was performed for three technologies and their combinations: intensity-modulated radiotherapy (IMRT), IMRT with a simultaneous integrated boost (IMRT-SIB) of 10% to the gross tumor volume (GTV), and adaptive re-planning twice during the treatment course (ART). All analyses were based on accumulated dose distributions using deformable image registration of CT images, which were acquired weekly during the treatment course. RESULTS: IMRT reduced the mean lung dose (MLD) by 5.6% ± 3.8% compared to 3D-CRT. ART resulted in lung sparing of 7.9% ± 4.8% and 9.2% ± 3.9% in 3D-CRT and IMRT planning, respectively. IMRT and ART escalated the irradiation dose by 6.6% ± 3.2% and 8.8% ± 6.3%, respectively, which was not statistically different. For the 7 patients with the largest GTVs, IMRT-SIB was superior to IMRT and ART with dose escalation of 11.9% ± 3.7%. The combination of ART, IMRT, and SIB achieved maximum dose escalation in all 13 patients by 17.1% ± 5.4% on average, which increased TCP from 19.9% ± 7.0 to 37.1% ± 10.1%. Adaptive re-planning was required to continuously conform the escalated and hypofractionated SIB doses to the shrinking tumor. CONCLUSION: Combining advanced radiotherapy technologies is considered as a safe and effective strategy to maximize local tumor control probability in stage III NSCLC.

The utility of molecular diagnostics to predict recurrence of head and neck carcinoma.

BACKGROUND: Locoregional recurrence is the major cause of treatment failure after surgery for oral squamous cell carcinoma. Molecular diagnostics have the potential to improve on clinicopathological parameters to predict this recurrence and plan adjuvant treatment. The test most frequently applied is based on detecting TP53 mutations, but alternative methodology is required for cases that harbour the wild-type gene. METHODS: One hundred and two cases with tumour-adjacent margins, considered to be clear margins by microscopy, were examined using carefully optimised molecular diagnostics based on detection of the TP53 and Ly-6D markers. The markers were also combined to provide a dual approach. RESULTS: The dual molecular diagnostic identified cases with a significant increase in the probablility of developing locoregional recurrence when tumour-adjacent positive and clear margins were compared (P=0.0001). These tests were most useful when the clearance at the resection margins was 5 mm or less. The TP53-based diagnostic was a better predictor of locoregional recurrence than established clinicopathological parameters. CONCLUSION: The optimised TP53-based diagnostic rapidly identifies an important subgroup of cases with close margins that will benefit from new treatment modalities to reduce the risk of recurrence.

Preclinic telephone consultations: an observational cohort study.

Patients referred to secondary care for specialist respiratory review frequently undergo multiple hospital attendances for investigations and consultations. This study evaluated the potential of a preclinic telephone consultation and subsequent coordination of tests and face-to-face consultations to reduce hospital visits. Total hospital attendances were recorded for three cohorts (participants, non-participants and comparators) for 6 months from first specialist contact. Patients completed the medical interview satisfaction scale-21 (MISS-21). The study showed that a preclinic telephone consultation can significantly reduce hospital visits over a fixed period without reducing patient satisfaction. In total, 20.8% of the participant group had three or more hospital attendances compared with 42.9% of the non-participant group (p = 0.001) and 44.7% of the comparator group (p = 0.002). Participants had fewer follow up visits and lower rates of non-attendance/late rearrangement of appointments. This service reduces unnecessary hospital visits, seems to improve patient compliance and may save costs associated with non-attendance and follow up consultations.

Optimising stereotactic body radiotherapy for non-small cell lung cancer with volumetric intensity-modulated arc therapy--a planning study.

AIMS: The potential advantages of stereotactic body radiotherapy (SBRT) for early stage non-small cell lung cancer (NSCLC) over conventional fractionated radiotherapy include a higher biological effective dose, a reduction in accelerated repopulation, greater patient convenience and reduced demand on radiotherapy resources. Before introducing SBRT in our department, a review of planning and delivery was undertaken, starting with an assessment of optimum beam number and arrangement. MATERIALS AND METHODS: Radiotherapy planning computed tomography scans for five patients previously treated for T1 peripheral NSCLC were selected. In each the contoured tumour had planning target volume (PTV) margins of 1cm in all directions. Forward-planned three-field coplanar and non-coplanar plans and a seven-field coplanar plan were produced and optimised. In-house inverse-planning software (AutoBeam) was used to generate three-, five-, seven- and nine-field coplanar and non-coplanar plans and two volumetric intensity-modulated arc therapy (VMAT) plans. The resulting V(20), V(11), PTV(90), PTV(95) and mean lung dose were compared. RESULTS: Analysis of variance showed non-coplanar plans to have lower V(11) and higher PTV(90) and PTV(95) than coplanar plans. VMAT showed equivalent V(20) and target coverage when compared with the best non-coplanar plans, but with a faster delivery time (2min 8s versus 12min 40s). CONCLUSIONS: Inverse-planned five-field non-coplanar plans and VMAT improve target coverage while minimising the higher dose to normal lung tissue for SBRT of NSCLC compared with coplanar beam arrangements. VMAT is preferable because of significantly shorter treatment delivery times.

Barriers to the implementation of self management support in long term lung conditions.

Background Self-management improves outcomes in asthma and COPD and is strongly recommended in national and international guidelines; however implementation of the guidelines such as use of written action plans in practice is often poor. Setting A questionnaire survey was undertaken to identify the healthcare professional barriers to implementation of self-management for asthma and COPD in West London. Question Why is self-management education not being undertaken in respiratory conditions? Methods A questionnaire was designed to elicit healthcare professionals' views about barriers to implementation of self-management in asthma and COPD. Results Response rates were 33% (58/175). Results showed strong support for guideline recommendations, however implementation was patchy. Seventy six percent of respondents discussed asthma self-management with patients; however only 47.8% of patients received a written action plan. For COPD patients, 55.1% discussed self-management, with 41% receiving a written action plan. In COPD, there was greater GP involvement and less delegation of self-management. Barriers to implementation included patient factors (compliance, literacy and patient understanding), time constraints and insufficient resources. Those who believed they had witnessed improved health outcomes with self-management (53%, 31/58) were more likely to give written action plans (78%, 24/31, 'nearly always/sometimes' gave written action plans), Nearly a third of healthcare professionals reported lacking confidence in constructing written action plans (33% 19/58; GPs 43%, nurses 43%). Conclusion Despite overwhelming evidence self-management support is still not being implemented into routine clinical practice, identified barriers included time constraints, lack of training, lack of belief in patients ability to self-manage and lack of confidence completing self-management plans. Practice implications These issues need to be addressed if self-management support is to be delivered in a meaningful and effective way.