An unusual case of oedematous prostate volumetric changes observed over the course of radiotherapy on the MR linear accelerator

IntroductionThe integration of magnetic resonance (MR) imaging into radiotherapy through new technology, including the MR -linear accelerator (MRL), has allowed further advancements into image guided radiotherapy (IGRT). Better soft tissue visualisation has led to some unusual findings.Case and outcomesA patient with T1c N0 M0 prostate adenocarcinoma received 60Gy in 20# radiotherapy on the MRL. Radiotherapy planning (RTP) scans were completed on both CT and MR (using T2 and T1 weighted three-dimensional turbo spin echo sequences, reconstructed transaxially (TRA). The MR scans revealed atypical oedema in the right peripheral zone, visualised on T2-weighted (T2w) MR Images as an accumulation of high signal intensity fluid. Daily MRL treatment includes a (T2w 3D Tra) sequence with which oedematous changes could be monitored. The images demonstrated an increase in oedematous volume over fractions 1-10 causing the prostate contour variations from the initial planning scans. Despite the prostate volume variations PTV coverage was never breached and dose constraints were always met for both PTV and surrounding organs at risk (OAR's), excluding the need for oncologist input. A single Therapeutic Radiographer (RTT) experienced in MRL delivery, contoured the prostate and oedematous volumes on the radiotherapy plan (RTP) MR and all on-treatment MR images to assess change over the radiotherapy course. The initial volumes were 53.4 cm3 and 8.3 cm3 for the prostate plus oedema and oedema alone respectively. The most significant change was seen for both the prostate and oedema on fraction nine (68.0 cm3 and 10.1 cm3, respectively). Reductions were noted after this with final (fraction 20) volumes of 55.2 cm3 and 0.58 cm3 respectively.DiscussionThe ability to visualise prostatic oedema was new to the radiotherapy treatment team due to better soft tissue visualisation than standard radiotherapy. The results from contouring the prostate and oedema volumes confirmed radiographer observations and demonstrated how oedema impacted the overall prostate volume by quantifying the oedematous variations over time. The changes in oedema volume are presumed to be in response to radiotherapy.ConclusionFurther adaptive radiotherapy work-flow developments, utilising an "Adapt to Shape" model will allow real-time re-contouring of the prostate to ensure tumour control is not compromised. Further work investigating the frequency and impact of oedemotous changes to external beam prostate patients will help to inform practice

First-in-human technique translation of oxygen-enhanced MRI to an MR Linac system in patients with head and neck cancer

BACKGROUND AND PURPOSE: Tumour hypoxia is prognostic in head and neck cancer (HNC), associated with poor loco-regional control, poor survival and treatment resistance. The advent of hybrid MRI - radiotherapy linear accelerator or 'MR Linac' systems - could permit imaging for treatment adaptation based on hypoxic status. We sought to develop oxygen-enhanced MRI (OE-MRI) in HNC and translate the technique onto an MR Linac system. MATERIALS AND METHODS: MRI sequences were developed in phantoms and 15 healthy participants. Next, 14 HNC patients (with 21 primary or local nodal tumours) were evaluated. Baseline tissue longitudinal relaxation time (T1) was measured alongside the change in 1/T1 (termed ΔR1) between air and oxygen gas breathing phases. We compared results from 1.5 T diagnostic MR and MR Linac systems. RESULTS: Baseline T1 had excellent repeatability in phantoms, healthy participants and patients on both systems. Cohort nasal concha oxygen-induced ΔR1 significantly increased (p < 0.0001) in healthy participants demonstrating OE-MRI feasibility. ΔR1 repeatability coefficients (RC) were 0.023-0.040 s-1 across both MR systems. The tumour ΔR1 RC was 0.013 s-1 and the within-subject coefficient of variation (wCV) was 25% on the diagnostic MR. Tumour ΔR1 RC was 0.020 s-1 and wCV was 33% on the MR Linac. ΔR1 magnitude and time-course trends were similar on both systems. CONCLUSION: We demonstrate first-in-human translation of volumetric, dynamic OE-MRI onto an MR Linac system, yielding repeatable hypoxia biomarkers. Data were equivalent on the diagnostic MR and MR Linac systems. OE-MRI has potential to guide future clinical trials of biology guided adaptive radiotherapy

The GuideLine Implementability Appraisal (GLIA): development of an instrument to identify obstacles to guideline implementation

BACKGROUND: Clinical practice guidelines are not uniformly successful in influencing clinicians' behaviour toward best practices. Implementability refers to a set of characteristics that predict ease of (and obstacles to) guideline implementation. Our objective is to develop and validate a tool for appraisal of implementability of clinical guidelines. METHODS: Indicators of implementability were identified from the literature and used to create items and dimensions of the GuideLine Implementability Appraisal (GLIA). GLIA consists of 31 items, arranged into 10 dimensions. Questions from 9 of the 10 dimensions are applied individually to each recommendation of the guideline. Decidability and Executability are critical dimensions. Other dimensions are Global, Presentation and Formatting, Measurable Outcomes, Apparent Validity, Flexibility, Effect on Process of Care, Novelty/Innovation, and Computability. We conducted a series of validation activities, including validation of the construct of implementability, expert review of content for clarity, relevance, and comprehensiveness, and assessment of construct validity of the instrument. Finally, GLIA was applied to a draft guideline under development by national professional societies. RESULTS: Evidence of content validity and preliminary support for construct validity were obtained. The GLIA proved to be useful in identifying barriers to implementation in the draft guideline and the guideline was revised accordingly. CONCLUSION: GLIA may be useful to guideline developers who can apply the results to remedy defects in their guidelines. Likewise, guideline implementers may use GLIA to select implementable recommendations and to devise implementation strategies that address identified barriers. By aiding the design and operationalization of highly implementable guidelines, our goal is that application of GLIA may help to improve health outcomes, but further evaluation will be required to support this potential benefit

Reirradiation Options for Previously Irradiated Prostate cancer (RO-PIP): Feasibility study investigating toxicity outcomes following reirradiation with stereotactic body radiotherapy (SBRT) versus high-dose-rate brachytherapy (HDR-BT).

IntroductionRadiotherapy is the most common curative treatment for non-metastatic prostate cancer; however, up to 13% of patients will develop local recurrence within 10 years. Patients can undergo further and potentially curative treatment including salvage surgery, brachytherapy (BT), external beam radiotherapy, high-intensity focused ultrasound and cryotherapy. Systematic review shows that high-dose-rate (HDR) BT and stereotactic body radiotherapy (SBRT) have the best outcomes in terms of biochemical control and lowest side effects. The reirradiation options for previously irradiated prostate cancer (RO-PIP) trial aims to determine the feasibility of recruitment to a trial randomising patients to salvage HDR-BT or SBRT and provide prospective data on patient recorded toxicity outcomes that will inform a future phase III trial.Methods and analysisThe primary endpoint of the RO-PIP feasibility study is to evaluate the patient recruitment potential over 2 years to a trial randomising to either SBRT or HDR-BT for patients who develop local recurrence of prostate cancer following previous radiation therapy. The aim is to recruit 60 patients across 3 sites over 2 years and randomise 1:1 to SBRT or HDR-BT. Secondary objectives include recording clinician and patient-reported outcome measures to evaluate treatment-related toxicity. In addition, the study aims to identify potential imaging, genomic and proteomic biomarkers that are predictive of toxicity and outcome based on hypoxia status, a prognostic marker of prostate cancer.Ethics and disseminationThis study has been approved by the Yorkshire and The Humber-Bradford Leeds Research Ethics Committee (Reference: 21/YH/0305, IRAS: 297060, January 2022). The results will be presented in national and international conferences, published in peer-reviewed journals and will be communicated to relevant stakeholders. A plain English report will be shared with the study participants, patients' organisations and media.Trial registration numberISRCTN 12238218 (Amy Ackroyd NIHR CPMS Team)

The Roles of Standardization, Certification and Assurance Services in Global Commerce

In this article we examine the rapid emergence and expansion of standardized product and process frameworks and a private-sector compliance and enforcement infrastructure that we believe may increasingly be providing a substitute for public and legal regulatory infrastructure in global commerce. This infrastructure is provided by a proliferation of performance codes and standards, many of which define acceptable social and environmental behavior, and a rapidly-growing number of privately-trained and authorized inspectors and certifiers that we call the third-party assurance industry. We offer reasons for this development, evidence of its scope and scale, and then describe the phenomenon in more detail by examining supply chain arrangements in two industries, food products and apparel, where the use of third-party standards and assurance services has expanded especially rapidly. We conclude with a discussion of the implications for the make or buy decision at the core of the theory of the firm. We argue that as quasi-regulatory standards are developed within various industries, and as performance to these standards can be systematically evaluated using third-party inspectors and certifiers, the costs of moving production outside of vertical firm hierarchies drop. We believe this may be an important factor in accelerating the shift to outsourcing that has been observed over the last two decades

Corporate Governance for Sustainability

The current model of corporate governance needs reform. There is mounting evidence that the practices of shareholder primacy drive company directors and executives to adopt the same short time horizon as financial markets. Pressure to meet the demands of the financial markets drives stock buybacks, excessive dividends and a failure to invest in productive capabilities. The result is a ‘tragedy of the horizon’, with corporations and their shareholders failing to consider environmental, social or even their own, long-term, economic sustainability. With less than a decade left to address the threat of climate change, and with consensus emerging that businesses need to be held accountable for their contribution, it is time to act and reform corporate governance in the EU. The statement puts forward specific recommendations to clarify the obligations of company boards and directors and make corporate governance practice significantly more sustainable and focused on the long term

Imaging hemi-thoracic radiation induced lung toxicity in mice

Lung cancer is the second most frequently diagnosed cancer, and the leading cause of cancer deaths in the United Kingdom. Two thirds of patients present with advanced disease, which contributes significantly to the high mortality rate associated with this disease. Radiation therapy (RT) is used frequently in the treatment of lung cancer, however the delivery of tumouricidal doses is often limited by the risk of radiation induced lung toxicity (RILT). RILT occurs in an acute phase as pneumonitis followed by a later phase of fibrosis. Because the RILT symptoms are often similar to those of pulmonary infection or disease progression, diagnosis can be difficult. Approaches to improving the outcome of RT for lung cancer include: 1. Detection of RILT at an early stage. This would allow for the timely introduction of treatment and, therefore, avoidance of severe episodes of RILT. Longitudinal imaging studies of patients undergoing lung RT, using ionizing radiation (IR) free imaging techniques, such as magnetic resonance imaging (MRI) may provide a means of early RILT detection. 2. Concurrent administration of targeted radiosensitizers. Several molecularly targeted agents have been explored in this context. For example, the PI3K inhibitors Nelfinavir, NVP-NBKM120, and NVP-BEZ235 cause radiosensitization in pre-clinical models of cancer. These agents are being introduced into clinical practise and so it is important to investigate their effect on normal lung tissues. This thesis reports the development of a high throughput, multi-modality imaging programme for the longitudinal investigation of normal tissue toxicity in a pre-clinical model. The aims of the research were: 1. To investigate novel, non-invasive imaging methods for the detection of RILT. 2. To compare the incidence and severity of RILT following radiation alone to that following radiation plus PI3K/AKT/mTOR inhibition. Eight longitudinal imaging studies were undertaken in C57BL6 and CBA mice to detect the effects of single (right) lung irradiation with or without targeted radiosensitizers. Radiation was delivered in a single fraction (14, 18 or 20 Gy) using a Gulmay cabinet irradiator, or a small animal radiation research platform (SARRP) to deliver single (20 Gy) or fractionated (3 x 15 Gy) RT under image guidance. Plethysmography, computed tomography (CT) and magnetic resonance imaging (MRI) were undertaken in representative animals from each cohort at baseline and at pre-determined time points up to 20 weeks. Histological examination of lung tissue was undertaken for correlative studies. RILT was scored using a semi-quantitative system reflecting the percentage of the lung volume that was abnormal on imaging. CT densities, MRI signal intensities, and area under the curve (AUC) or initial area under the curve (iAUC) estimations, were used for t-tests and regression analyses to determine the statistical significance of lung changes. An exploratory analysis of dynamic contrast enhanced MRI (DCE-MRI) as a tool to detect early radiation pneumonitis was undertaken using model- and non-model-based analyses. The acquisition of high quality cardiorespiratory gated spin echo (SEMS), DCE, and high resolution MR angiography (ANGIO) on 4.7 and 7 T magnets was achieved by continuous optimization of imaging parameters and gating techniques. The main findings from the work presented in this thesis were: 1. The incidence of RILT following hemi-thoracic radiation was similar whether the detection method used was MRI, CT or histological examination. 2. Severe RILT can be detected using cardiorespiratory gated DCE-MRI. Preliminary data suggest DCE-MRI may also detect mild to moderate RILT but this requires further validation. 3. The incidence and severity of RILT following RT + PI3K inhibitors was not significantly different to the incidence and severity of RILT following RT alone.</p