Full Dose SBRT in Combination With Mediastinal Chemoradiation for Locally Advanced, Non-Small Cell Lung Cancer: A Practical Guide for Planning, Dosimetric Results From a Phase 2 Study, and a Treatment Planning Guide for the Phase 3 NRG Oncology LU-008 Trial.

PURPOSE: Stereotactic body radiation therapy (SBRT) has been used with high effectiveness in early-stage non-small cell lung cancer (NSCLC) but has not been studied extensively in locally advanced NSCLC. We conducted a phase 2 study delivering SBRT to the primary tumor followed by conventionally fractionated chemoradiation to the involved lymph nodes for patients with node-positive locally advanced NSCLC. This manuscript serves as both a guide to planning techniques used on this trial and the subsequent phase 3 study, NRG Oncology LU-008, and to report patient dosimetry and toxicity results. METHODS AND MATERIALS: We initiated a phase 2 multicenter single arm study evaluating SBRT to the primary tumor (50-54 Gy in 3-5 fractions) followed by conventionally fractionated chemoradiation to 60 Gy in 2 Gy fractions with doublet chemotherapy to the involved lymph nodes for patients with stage III or unresectable stage II NSCLC. Patients eligible for adjuvant immunotherapy received up to 12 months of durvalumab. We report a detailed guide for the entire treatment process from computed tomography simulation through treatment planning and delivery. The dosimetric outcomes from the 60 patients who completed therapy on study are reported both for target coverage and normal structure doses. We also report correlation between radiation-related toxicities and dosimetric parameters. RESULTS: Sixty patients were enrolled between 2017 and 2022. Planning techniques used were primarily volumetric modulated arc therapy for SBRT to the primary tumor and conventionally fractionated radiation to the involved nodes, with a minority of cases using dynamic conformal arc technique or static dynamic multileaf collimator intensity modulated radiation therapy. Grade 2 or higher pneumonitis was associated with lung dose V5 Gy > 70% and grade 2 or higher pulmonary toxicity was associated with lung dose V10 Gy > 50%. Only 3 patients (5%) experienced grade 3 or higher pneumonitis. Grade 2 or higher esophagitis was associated with esophageal doses, including mean dose > 20 Gy, V60 Gy > 7%, and D1cc > 55 Gy. Only 1 patient (1.7%) experienced grade 3 esophagitis. CONCLUSIONS: SBRT to the primary tumor followed by conventionally fractionated chemoradiation to the involved lymph nodes is feasible with planning techniques as described. Radiation-related toxicity on this phase 2 study was low. This manuscript serves as a guideline for the recently activated NRG Oncology LU-008 phase 3 trial evaluating this experimental regimen.

Designing a large-scale track-based monitoring program to detect changes in species distributions in arid Australia.

Monitoring trends in animal populations in arid regions is challenging due to remoteness and low population densities. However, detecting species' tracks or signs is an effective survey technique for monitoring population trends across large spatial and temporal scales. In this study, we developed a simulation framework to evaluate the performance of alternative track-based monitoring designs at detecting change in species distributions in arid Australia. We collated presence-absence records from 550 2-ha track-based plots for 11 vertebrates over 13 years and fitted ensemble species distribution models to predict occupancy in 2018. We simulated plausible changes in species' distributions over the next 15 years and, with estimates of detectability, simulated monitoring to evaluate the statistical power of three alternative monitoring scenarios: (1) where surveys were restricted to existing 2-ha plots, (2) where surveys were optimized to target all species equally, and (3) where surveys were optimized to target two species of conservation concern. Across all monitoring designs and scenarios, we found that power was higher when detecting increasing occupancy trends compared to decreasing trends owing to the relatively low levels of initial occupancy. Our results suggest that surveying 200 of the existing plots annually (with a small subset resurveyed twice within a year) will have at least an 80% chance of detecting 30% declines in occupancy for four of the five invasive species modeled and one of the six native species. This increased to 10 of the 11 species assuming larger (50%) declines. When plots were positioned to target all species equally, power improved slightly for most compared to the existing survey network. When plots were positioned to target two species of conservation concern (crest-tailed mulgara and dusky hopping mouse), power to detect 30% declines increased by 29% and 31% for these species, respectively, at the cost of reduced power for the remaining species. The effect of varying survey frequency depended on its trade-off with the number of sites sampled and requires further consideration. Nonetheless, our research suggests that track-based surveying is an effective and logistically feasible approach to monitoring broad-scale occupancy trends in desert species with both widespread and restricted distributions.

Location of out-of-hospital cardiac arrests and automated external defibrillators in relation to schools in an English ambulance service region.

Introduction: This study sought to identify the availability of automated external defibrillators (AEDs) in schools in the region served by West Midlands Ambulance Service University NHS Trust (WMAS), United Kingdom, and the number of out-of-hospital cardiac arrests (OHCA) that occurred at or near to schools. A secondary aim was to explore the cost effectiveness of school-based defibrillators. Methods: This observational study used data from the national registry for OHCA (University of Warwick) to identify cases occurring at or near schools between January 2014 and December 2016 in WMAS region (n = 11,399). A school survey (n = 2,453) was carried out in September 2017 to determine the presence of AEDs and their registration status with WMAS. Geographical Information System mapping software identified OHCAs occurring within a 300-metre radius of a school. An economic analysis calculated the cost effectiveness of school-based AEDs. Results: A total of 39 (0.34%) of all OHCAs occurred in schools, although 4,250 (37.3%) of OHCAs in the region were estimated to have occurred within 300 metres of a school. Of 323 school survey responses, 184 (57%) had an AED present, of which 24 (13.0%) were available 24 h/day. Economic modelling of a school-based AED programme showed additional quality-adjusted life years (QALY) of 0.26 over the lifetime of cardiac arrest survivors compared with no AED programme. The incremental cost-effectiveness ratio (ICER) was £8,916 per QALY gained. Conclusion: Cardiac arrests in schools are rare. Registering AEDs with local Emergency Medical Services and improving their accessibility within their local community would increase their utility.

Pre-hospital non-invasive ventilation for acute respiratory failure: a systematic review and cost-effectiveness evaluation.

BACKGROUND: Non-invasive ventilation (NIV), in the form of continuous positive airway pressure (CPAP) or bilevel inspiratory positive airway pressure (BiPAP), is used in hospital to treat patients with acute respiratory failure. Pre-hospital NIV may be more effective than in-hospital NIV but requires additional ambulance service resources. OBJECTIVES: We aimed to determine the clinical effectiveness and cost-effectiveness of pre-hospital NIV compared with usual care for adults presenting to the emergency services with acute respiratory failure and to identify priorities for future research. DATA SOURCES: Fourteen electronic databases and research registers (including MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE, EMBASE, and Cumulative Index to Nursing and Allied Health Literature) were searched from inception to August 2013, supplemented by hand-searching reference lists and contacting experts in the field. REVIEW METHODS: We included all randomised or quasi-randomised controlled trials of pre-hospital NIV in patients with acute respiratory failure. Methodological quality was assessed according to established criteria. An aggregate data network meta-analysis (NMA) of mortality and intubation was used to jointly estimate intervention effects relative to usual care. A NMA, using individual patient-level data (IPD) and aggregate data where IPD were not available, was carried out to assess whether or not covariates were treatment effect modifiers. A de novo economic model was developed to explore the costs and health outcomes when pre-hospital NIV (specifically CPAP provided by paramedics) and standard care (in-hospital NIV) were applied to a hypothetical cohort of patients with acute respiratory failure. RESULTS: The literature searches identified 2284 citations. Of the 10 studies that met the inclusion criteria, eight were randomised controlled trials and two were quasi-randomised trials (six CPAP; four BiPAP; sample sizes 23-207 participants). IPD were available from seven trials (650 patients). The aggregate data NMA suggested that CPAP was the most effective treatment in terms of mortality (probability = 0.989) and intubation rate (probability = 0.639), and reduced both mortality [odds ratio (OR) 0.41, 95% credible interval (CrI) 0.20 to 0.77] and intubation rate (OR 0.32, 95% CrI 0.17 to 0.62) compared with standard care. The effect of BiPAP on mortality (OR 1.94, 95% CrI 0.65 to 6.14) and intubation rate (OR 0.40, 95% CrI 0.14 to 1.16) compared with standard care was uncertain. The combined IPD and aggregate data NMA suggested that sex was a statistically significant treatment effect modifier for mortality. The economic analysis showed that pre-hospital CPAP was more effective and more expensive than standard care, with an incremental cost-effectiveness ratio of £20,514 per quality-adjusted life-year (QALY) and a 49.5% probability of being cost-effective at the £20,000-per-QALY threshold. Variation in the incidence of eligible patients had a marked impact on cost-effectiveness and the expected value of sample information for a future randomised trial. LIMITATIONS: The meta-analysis lacked power to detect potentially important differences in outcome (particularly for BiPAP), the intervention was not always compared with the best alternative care (in-hospital NIV) in the primary studies and findings may not be generalisable. CONCLUSIONS: Pre-hospital CPAP can reduce mortality and intubation rates, but cost-effectiveness is uncertain and the value of further randomised evaluation depends on the incidence of suitable patients. A feasibility study is required to determine if a large pragmatic trial of clinical effectiveness and cost-effectiveness is appropriate. STUDY REGISTRATION: The study is registered as PROSPERO CRD42012002933. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Cost-effectiveness of Out-of-Hospital Continuous Positive Airway Pressure for Acute Respiratory Failure.

STUDY OBJECTIVE: We determine the cost-effectiveness of out-of-hospital continuous positive airway pressure (CPAP) compared with standard care for adults presenting to emergency medical services with acute respiratory failure. METHODS: We developed an economic model using a United Kingdom health care system perspective to compare the costs and health outcomes of out-of-hospital CPAP to standard care (inhospital noninvasive ventilation) when applied to a hypothetical cohort of patients with acute respiratory failure. The model assigned each patient a probability of intubation or death, depending on the patient's characteristics and whether he or she had out-of-hospital CPAP or standard care. The patients who survived accrued lifetime quality-adjusted life-years (QALYs) and health care costs according to their age and sex. Costs were accrued through intervention and hospital treatment costs, which depended on patient outcomes. All results were converted into US dollars, using the Organisation for Economic Co-operation and Development purchasing power parities rates. RESULTS: Out-of-hospital CPAP was more effective than standard care but was also more expensive, with an incremental cost-effectiveness ratio of £20,514 per QALY ($29,720/QALY) and a 49.5% probability of being cost-effective at the £20,000 per QALY ($29,000/QALY) threshold. The probability of out-of-hospital CPAP's being cost-effective at the £20,000 per QALY ($29,000/QALY) threshold depended on the incidence of eligible patients and varied from 35.4% when a low estimate of incidence was used to 93.8% with a high estimate. Variation in the incidence of eligible patients also had a marked influence on the expected value of sample information for a future randomized trial. CONCLUSION: The cost-effectiveness of out-of-hospital CPAP is uncertain. The incidence of patients eligible for out-of-hospital CPAP appears to be the key determinant of cost-effectiveness.

Optimization of patient radiation protection in pelvic X-ray examination in Ghana.

Pelvis X-ray examinations inevitably involve exposure of the gonads to ionizing radiation. In line with the principle of keeping doses as low as reasonably practicable (ALARP), accurate patient dose measurement is vital if we are to ascertain that these exposures are fully optimized. The study aimed to provide patient dose estimates for pelvis examination being undertaken at 10 separate hospitals in Ghana in order to provide an initial quantitative indication of each site's typically achievable radiation safety and quality standards. The method employed was adapted from established methods and peer reviewed literature, such as the International Atomic Energy Agency (IAEA) publications on optimization of the radiological protection of patients undergoing radiography, fluoroscopy, and computed tomography examinations in some countries in Africa, Asia, and Eastern Europe. Dose measurements were calculated on 323 patients (137 (42%) male, 186 (58%) female, ages, 38.56 yr ± 9.0; range 20-68). The entrance surface dose (ESD) was determined by an indirect method, using the patient's anatomical data and exposure parameters utilized for the specific examination. The Quality Assurance Dose Database software (QADDs) developed by Integrated Radiological Services Ltd. in Liverpool, UK was used to generate the ESD values. The study identified variations in the technique factors used compared with the recommendations in the European Commission (EC) quality criteria. Eighty percent of the hospitals recorded lower ESD values below IAEA recommended diagnostic reference levels (10 mGy) and 40% of the hospitals exceeded the UK national reference value (4 mGy). However, one hospital consistently recorded higher ESDs than the other hospitals. The variations in the data recorded demonstrate the importance of creating awareness by the radiographic staff on quality assurance and standardization of protocols to ensure satisfactory standards and optimized radiation dose to patients and staff.

GLI1 confers profound phenotypic changes upon LNCaP prostate cancer cells that include the acquisition of a hormone independent state.

The GLI (GLI1/GLI2) transcription factors have been implicated in the development and progression of prostate cancer although our understanding of how they actually contribute to the biology of these common tumours is limited. We observed that GLI reporter activity was higher in normal (PNT-2) and tumourigenic (DU145 and PC-3) androgen-independent cells compared to androgen-dependent LNCaP prostate cancer cells and, accordingly, GLI mRNA levels were also elevated. Ectopic expression of GLI1 or the constitutively active ΔNGLI2 mutant induced a distinct cobblestone-like morphology in LNCaP cells that, regarding the former, correlated with increased GLI2 as well as expression of the basal/stem-like markers CD44, ß1-integrin, ΔNp63 and BMI1, and decreased expression of the luminal marker AR (androgen receptor). LNCaP-GLI1 cells were viable in the presence of the AR inhibitor bicalutamide and gene expression profiling revealed that the transcriptome of LNCaP-GLI1 cells was significantly closer to DU145 and PC-3 cells than to control LNCaP-pBP (empty vector) cells, as well as identifying LCN2/NGAL as a highly induced transcript which is associated with hormone independence in breast and prostate cancer. Functionally, LNCaP-GLI1 cells displayed greater clonal growth and were more invasive than control cells but they did not form colonies in soft agar or prostaspheres in suspension suggesting that they do not possess inherent stem cell properties. Moreover, targeted suppression of GLI1 or GLI2 with siRNA did not reverse the transformed phenotype of LNCaP-GLI1 cells nor did double GLI1/GLI2 knockdowns activate AR expression in DU145 or PC-3 cells. As such, early targeting of the GLI oncoproteins may hinder progression to a hormone independent state but a more detailed understanding of the mechanisms that maintain this phenotype is required to determine if their inhibition will enhance the efficacy of anti-hormonal therapy through the induction of a luminal phenotype and increased dependency upon AR function.