SYSTEMS-2: a randomised phase II study of radiotherapy dose escalation for pain control in malignant pleural mesothelioma

SYSTEMS-2 is a randomised study of radiotherapy dose escalation for pain control in 112 patients with malignant pleural mesothelioma (MPM). Standard palliative (20Gy/5#) or dose escalated treatment (36Gy/6#) will be delivered using advanced radiotherapy techniques and pain responses will be compared at week 5. Data will guide optimal palliative radiotherapy in MPM

Pain in malignant pleural mesothelioma: a prospective characterisation study.

INTRODUCTION: Malignant pleural mesothelioma (MPM) is associated with severe pain. The underlying neurobiology of this is complex. The primary aim of this study was to characterize pain in MPM. METHODS: This study was undertaken as part of a trial examining radiotherapy for the treatment of pain in MPM (ISRCTN 10644347). Patients had MPM with associated pain for which radiotherapy was planned and a worst pain score ≥ 4/10. The following assessments were undertaken: clinical neuropathic pain assessment, Brief Pain Inventory (BPI), Leeds Assessment of Neuropathic Symptoms and Signs (LANSS), Short form of the McGill Pain Questionnaire (SF-MPQ), and Quantitative Sensory Testing (QST). The relationship of these characteristics and response to radiotherapy was assessed. Unless stated, medians and interquartile range (IQR) are used. RESULTS: Thirty-seven patients were recruited. Average pain and worst pain was 4 (4-6) and 8 (6-8), respectively. Higher average pain and higher worst pain scores were associated with higher interference scores on the BPI, P < 0.001 and P < 0.0005. Twenty patients (54%) had a clinical diagnosis of neuropathic pain, and of these, only six patients (40%) screened positively for neuropathic pain using the LANSS. Patients with a high LANSS also had higher BPI and SF-MPQs. The presence of neuropathic pain (clinically or by LANSS) did not predict response to radiotherapy, P < 0.05. The SF-MPQ scores were higher in those with abnormal cool sensation on QST (P = 0.016). CONCLUSION: Pain in mesothelioma varies among patients and may have neuropathic components. An adequate pain assessment is necessary to guide the clinician in the appropriate choice of analgesics

Randomized phase II study investigating pazopanib versus weekly paclitaxel in relapsed or progressive urothelial cancer

Purpose: Two previous single-arm trials have drawn conflicting conclusions regarding the activity of pazopanib in urothelial cancers after failure of platinum-based chemotherapy. Patients and Methods: This randomized (1:1) open-label phase II trial compared the efficacy of pazopanib 800 mg orally with paclitaxel (80 mg/m2 days 1, 8, and 15 every 28 days) in the second-line setting. The primary end point was overall survival (OS). Results: Between August 2012 and October 2014, 131 patients, out of 140 planned, were randomly assigned. The study was terminated early on the recommendation of the independent data monitoring committee because of futility. Final analysis after the preplanned number of deaths (n = 110) occurred after a median follow-up of 18 months. One hundred fifteen deaths had occurred at the final data extract presented here. Median OS was 8.0 months for paclitaxel (80% CI, 6.9 to 9.7 months) and 4.7 months for pazopanib (80% CI, 4.2 to 6.4 months). The hazard ratio (HR) adjusted for baseline stratification factors was 1.28 (80% CI, 0.99 to 1.67; one-sided P = .89). Median progression-free survival was 4.1 months for paclitaxel (80% CI, 3.0 to 5.6 months) and 3.1 months for pazopanib (80% CI, 2.7 to 4.6 months; HR, 1.09; 80% CI, 0.85 to 1.40; one-sided P = .67). Discontinuations for toxicity occurred in 7.8% and 23.1% for paclitaxel and pazopanib, respectively. Conclusion: Pazopanib did not have greater efficacy than paclitaxel in the second-line treatment of urothelial cancers. There was a trend toward superior OS for paclitaxel

Reptiles as food: Predation of Australian reptiles by introduced red foxes compounds and complements predation by cats

Context: Invasive species are a major cause of biodiversity loss across much of the world, and a key threat to Australia’s diverse reptile fauna. There has been no previous comprehensive analysis of the potential impact of the introduced European red fox, Vulpes vulpes, on Australian reptiles. Aims: We seek to provide an inventory of all Australian reptile species known to be consumed by the fox, and identify characteristics of squamate species associated with such predation. We also compare these tallies and characteristics with reptile species known to be consumed by the domestic cat, Felis catus, to examine whether predation by these two introduced species is compounded (i.e. affecting much the same set of species) or complementary (affecting different groups of species). Methods: We collated records of Australian reptiles consumed by foxes in Australia, with most records deriving from fox dietary studies (tallying >35 000 samples). We modelled presence or absence of fox predation records against a set of biological and other traits, and population trends, for squamate species. Key results: In total, 108 reptile species (~11% of Australia’s terrestrial reptile fauna) have been recorded as consumed by foxes, fewer than that reported for cats (263 species). Eighty-six species have been reported to be eaten by both predators. More Australian turtle species have been reported as consumed by foxes than by cats, including many that suffer high levels of predation on egg clutches. Twenty threatened reptile species have been reported as consumed by foxes, and 15 by cats. Squamate species consumed by foxes are more likely to be undergoing population decline than those not known to be consumed by foxes. The likelihood of predation by foxes increased with squamate species’ adult body mass, in contrast to the relationship for predation by cats, which peaked at ~217 g. Foxes, but not cats, were also less likely to consume venomous snakes. Conclusions: The two introduced, and now widespread, predators have both compounding and complementary impacts on the Australian reptile fauna. Implications: Enhanced and integrated management of the two introduced predators is likely to provide substantial conservation benefits to much of the Australian reptile fauna

Rationale and design of the British Heart Foundation (BHF) Coronary Microvascular Function and CT Coronary Angiogram (CorCTCA) study

Background: Microvascular and/or vasospastic anginas are relevant causes of ischemia with no obstructive coronary artery disease (INOCA) in patients after computed tomography coronary angiography (CTCA). Objectives: Our research has 2 objectives. The first is to undertake a diagnostic study, and the second is to undertake a nested, clinical trial of stratified medicine. Design: A prospective, multicenter, randomized, blinded, sham-controlled trial of stratified medicine (NCT03477890) will be performed. All-comers referred for clinically indicated CTCA for investigation of suspected coronary artery disease (CAD) will be screened in 3 regional centers. Following informed consent, eligible patients with angina symptoms are enrolled before CTCA and remain eligible if CTCA excludes obstructive CAD. Diagnostic study: Invasive coronary angiography involving an interventional diagnostic procedure (IDP) to assess for disease endotypes: (1) angina due to obstructive CAD (fractional flow reserve ≤0.80); (2) microvascular angina (coronary flow reserve <2.0 and/or index of microvascular resistance >25); (3) microvascular angina due to small vessel spasm (acetylcholine); (4) vasospastic angina due to epicardial coronary spasm (acetylcholine); and (5) noncoronary etiology (normal coronary function). The IDP involves direct invasive measurements using a diagnostic coronary guidewire followed by provocation testing with intracoronary acetylcholine. The primary outcome of the diagnostic study is the reclassification of the initial CTCA diagnosis based on the IDP. Stratified medicine trial: Participants are immediately randomized 1:1 in the catheter laboratory to therapy stratified by endotype (intervention group) or not (control group). The primary outcome of the trial is the mean within-subject change in Seattle Angina Questionnaire score at 6 months. Secondary outcomes include safety, feasibility, diagnostic utility (impact on diagnosis and certainty), and clinical utility (impact on treatment and investigations). Health status assessments include quality of life, illness perception, anxiety-depression score, treatment satisfaction, and physical activity. Participants who are not randomized will enter a follow-up registry. Health and economic outcomes in the longer term will be assessed using electronic patient record linkage. Value: CorCTCA will prospectively characterize the prevalence of disease endotypes in INOCA and determine the clinical value of stratified medicine in this population

Is radiotherapy useful for treating pain in mesothelioma?:A phase II trial

IntroductionRadiotherapy is often used to treat pain in malignant pleural mesothelioma (MPM), although there is limited evidence to support this. The aim of this trial was to assess the role of radiotherapy for the treatment of pain in MPM.MethodsA multicentre, single arm phase II trial was conducted. Eligible patients fulfilled the following criteria: pathological or radiological diagnosis of MPM; pain secondary to MPM; radiotherapy indicated for pain control; and more than 18 years of age. Patients had assessments of pain and other symptoms at baseline and then received 20 Gy in five daily fractions. Key follow-up points were 5 and 12 weeks posttreatment. The primary end point measure was assessment of pain at the site of radiotherapy at 5 weeks. Secondary end points included effects on quality of life, breathlessness, fatigue, mood, toxicity, and the radiological response.ResultsForty patients were recruited from three UK oncology centers. Fourteen patients had a clinically meaningful improvement in their pain 5 weeks post radiotherapy (intention to treat), with five patients having a complete improvement. On the basis of a complete case analysis of the 30 patients assessable at week 5, 47% (confidence intervals, 28.3–65.7) of patients alive at week 5 had an improvement in their pain. There was no improvement in other key symptoms or quality of life.ConclusionsRadiotherapy for pain control in MPM is an effective treatment in a proportion of patients. Future studies examining differing radiotherapy regimens with a view to improving response rates are warranted

Counting the bodies: Estimating the numbers and spatial variation of Australian reptiles, birds and mammals killed by two invasive mesopredators

Aim Introduced predators negatively impact biodiversity globally, with insular fauna often most severely affected. Here, we assess spatial variation in the number of terrestrial vertebrates (excluding amphibians) killed by two mammalian mesopredators introduced to Australia, the red fox (Vulpes vulpes) and feral cat (Felis catus). We aim to identify prey groups that suffer especially high rates of predation, and regions where losses to foxes and/or cats are most substantial. Location Australia. Methods We draw information on the spatial variation in tallies of reptiles, birds and mammals killed by cats in Australia from published studies. We derive tallies for fox predation by (i) modelling continental-scale spatial variation in fox density, (ii) modelling spatial variation in the frequency of occurrence of prey groups in fox diet, (iii) analysing the number of prey individuals within dietary samples and (iv) discounting animals taken as carrion. We derive point estimates of the numbers of individuals killed annually by foxes and by cats and map spatial variation in these tallies. Results Foxes kill more reptiles, birds and mammals (peaking at 1071 km−2 year−1) than cats (55 km−2 year−1) across most of the unmodified temperate and forested areas of mainland Australia, reflecting the generally higher density of foxes than cats in these environments. However, across most of the continent – mainly the arid central and tropical northern regions (and on most Australian islands) – cats kill more animals than foxes. We estimate that foxes and cats together kill 697 million reptiles annually in Australia, 510 million birds and 1435 million mammals. Main conclusions This continental-scale analysis demonstrates that predation by two introduced species takes a substantial and ongoing toll on Australian reptiles, birds and mammals. Continuing population declines and potential extinctions of some of these species threatens to further compound Australia's poor contemporary conservation record

PARADIGM-2: Two parallel phase I studies of olaparib and radiotherapy or olaparib and radiotherapy plus temozolomide in patients with newly diagnosed glioblastoma, with treatment stratified by MGMT status

Glioblastoma has a dismal prognosis and molecular targeted agents have failed to improve outcomes to date. PARADIGM-2 is a phase I dose escalation study evaluating olaparib plus radiotherapy ± temozolomide in newly diagnosed glioblastoma, using MGMT methylation status to stratify patients and inform treatment schedules

Learners' decisions for attending Pediatric Grand Rounds: a qualitative and quantitative study

BACKGROUND: Although grand rounds plays a major educational role at academic medical centers, there has been little investigation into the factors influencing the learners' decision to attend. Greater awareness of attendees' expectations may allow grand rounds planners to better accommodate the learners' perspective, potentially making continuing education activities more attractive and inviting. METHODS: We used both qualitative (part A) and quantitative (part B) techniques to investigate the motivators and barriers to grand rounds attendance. Part A investigated contextual factors influencing attendance as expressed through attendee interviews. Transcripts of the interviews were analyzed using grounded theory techniques. We created a concept map linking key factors and their relationships. In part B we quantified the motivators and barriers identified during the initial interviews through a survey of the grand rounds audience. RESULTS: Sixteen persons voluntarily took part in the qualitative study (part A) by participating in one of seven group interview sessions. Of the 14 themes that emerged from these sessions, the most frequent factors motivating attendance involved competent practice and the need to know. All sessions discussed intellectual stimulation, social interaction, time constraints and convenience, licensure, content and format, and absence of cost for attending sessions. The 59 respondents to the survey (part B) identified clinically-useful topics (85%), continuing education credit (46%), cutting-edge research (27%), networking (22%), and refreshments (8%) as motivators and non-relevant topics (44%) and too busy to attend (56%) as barriers. CONCLUSION: Greater understanding of the consumers' perspective can allow planners to tailor the style, content, and logistics to make grand rounds more attractive and inviting

In-house validation of a liquid chromatography tandem mass spectrometry method for the analysis of lipophilic marine toxins in shellfish using matrix-matched calibration

A liquid chromatography tandem mass spectrometry (LC-MS/MS) method for the quantitative analysis of lipophilic marine toxins in shellfish extracts (mussel, oyster, cockle and clam) was validated in-house using European Union (EU) Commission Decision 2002/657/EC as a guideline. The validation included the toxins okadaic acid (OA), yessotoxin (YTX), azaspiracid-1 (AZA1), pectenotoxin-2 (PTX2) and 13-desmethyl spirolide-C (SPX1). Validation was performed at 0.5, 1 and 1.5 times the current EU permitted levels, which are 160 µg kg-1 for OA, AZA1 and PTX2 and 1,000 µg kg-1 for YTX. For SPX1, 400 µg kg-1 was chosen as the target level as no legislation has been established yet for this compound. The method was validated for determination in crude methanolic shellfish extracts and for extracts purified by solid-phase extraction (SPE). Extracts were also subjected to hydrolysis conditions to determine the performance of the method for OA and dinophysistoxin esters. The toxins were quantified against a set of matrix-matched standards instead of standard solutions in methanol. To save valuable standard, methanolic extract instead of the homogenate was spiked with the toxin standard. This was justified by the fact that the extraction efficiency is high for all relevant toxins (above 90%). The method performed very well with respect to accuracy, intraday precision (repeatability), interday precision (within-laboratory reproducibility), linearity, decision limit, specificity and ruggedness. At the permitted level the accuracy ranged from 102 to 111%, the repeatability from 2.6 to 6.7% and the reproducibility from 4.7 to 14.2% in crude methanolic extracts. The crude extracts performed less satisfactorily with respect to the linearity (less than 0.990) and the change in LC-MS/MS sensitivity during the series (more than 25%). SPE purification resulted in greatly improved linearity and signal stability during the series. Recently the European Food Safety Authority (EFSA) has suggested that to not exceed the acute reference dose the levels should be below 45 µg kg-1 OA equivalents and 30 µg kg-1 AZA1 equivalents. A single-day validation was successfully conducted at these levels. If the regulatory levels are lowered towards the EFSA suggested values, the official methods prescribed in legislation (mouse and rat bioassay) will no longer be sensitive enough. The validated LC-MS/MS method presented has the potential to replace these animal tests