Exercise-induced pulmonary haemorrhage in Thoroughbred racehorses: a longitudinal study.

BACKGROUND: Exercise-induced pulmonary haemorrhage (EIPH) is considered a progressive disease based on histopathology, but it is unknown if tracheobronchoscopic EIPH severity worsens over time. OBJECTIVES: The aim of this study was to examine tracheobronchoscopic EIPH changes over time in a population of Thoroughbred racehorses. A secondary aim was to identify factors that affect changes in tracheobronchoscopic EIPH severity between observations. STUDY DESIGN: Prospective, longitudinal, observational cross-sectional study. METHODS: Thoroughbred racehorses were examined with tracheobronchoscopy no earlier than 30 min after racing. Examinations were recorded and graded blindly by experienced veterinarians using a 0-4 scale. Horses with 2 or more observations were included in the analysis. The association between the previous and current EIPH score was investigated using a linear mixed effect model. Factors associated with transitioning from a lower to a high EIPH grade and vice versa were examined using multiple ordinal regression. A semi-parametric regression model was used to examine progression using the number of career starts as a marker for time. Models were adjusted for potential confounding variables. RESULTS: There were 2974 tracheobronchoscopic examinations performed on 747 horses. Blood was detected in over half of all examinations (55.6%). The population prevalence of EIPH increased as the number of examinations for each horse increased. The preceding EIPH score was significantly associated with the current EIPH score. Significant variables associated with moving between EIPH grades were the number of days since last racing, ambient temperature and weight carried. Tracheobronchoscopic EIPH is mildly progressive over the first thirty career starts. MAIN LIMITATIONS: Enrolment was voluntary. Horses were not followed for their entire career. CONCLUSION: Limiting the number of days in the current racing preparation and spacing races for horses with moderate to severe EIPH may be beneficial for reducing tracheobronchoscopic EIPH severity. The association between ambient temperature and EIPH warrants further investigation.

Constructing longitudinal disease progression curves using sparse, short-term individual data with an application to Alzheimer's disease.

In epidemiology, cohort studies utilised to monitor and assess disease status and progression often result in short-term and sparse follow-up data. Thus, gaining an understanding of the full-term disease pathogenesis can be difficult, requiring shorter-term data from many individuals to be collated. We investigate and evaluate methods to construct and quantify the underlying long-term longitudinal trajectories for disease markers using short-term follow-up data, specifically applied to Alzheimer's disease. We generate individuals' follow-up data to investigate approaches to this problem adopting a four-step modelling approach that (i) determines individual slopes and anchor points for their short-term trajectory, (ii) fits polynomials to these slopes and anchor points, (iii) integrates the reciprocated polynomials and (iv) inverts the resulting curve providing an estimate of the underlying longitudinal trajectory. To alleviate the potential problem of roots of polynomials falling into the region over which we integrate, we propose the use of non-negative polynomials in Step 2. We demonstrate that our approach can construct underlying sigmoidal trajectories from individuals' sparse, short-term follow-up data. Furthermore, to determine an optimal methodology, we consider variations to our modelling approach including contrasting linear mixed effects regression to linear regression in Step 1 and investigating different orders of polynomials in Step 2. Cubic order polynomials provided more accurate results, and there were negligible differences between regression methodologies. We use bootstrap confidence intervals to quantify the variability in our estimates of the underlying longitudinal trajectory and apply these methods to data from the Alzheimer's Disease Neuroimaging Initiative to demonstrate their practical use. Copyright © 2017 John Wiley & Sons, Ltd.

A phase 1b clinical trial of the CD40-activating antibody CP-870,893 in combination with cisplatin and pemetrexed in malignant pleural mesothelioma.

BACKGROUND: Data from murine models suggest that CD40 activation may synergize with cytotoxic chemotherapy. We aimed to determine the maximum tolerated dose (MTD) and toxicity profile and to explore immunological biomarkers of the CD40-activating antibody CP-870,893 with cisplatin and pemetrexed in patients with malignant pleural mesothelioma (MPM). PATIENTS AND METHODS: Eligible patients had confirmed MPM, ECOG performance status 0-1, and measurable disease. Patients received cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) on day 1 and CP-870,893 on day 8 of a 21-day cycle for maximum 6 cycles with up to 6 subsequent cycles single-agent CP-870,893. Immune cell subset changes were examined weekly by flow cytometry. RESULTS: Fifteen patients were treated at three dose levels. The MTD of CP-870,893 was 0.15 mg/kg, and was exceeded at 0.2 mg/kg with one grade 4 splenic infarction and one grade 3 confusion and hyponatraemia. Cytokine release syndrome (CRS) occurred in most patients (80%) following CP-870,893. Haematological toxicities were consistent with cisplatin and pemetrexed chemotherapy. Six partial responses (40%) and 9 stable disease (53%) as best response were observed. The median overall survival was 16.5 months; the median progression-free survival was 6.3 months. Three patients survived beyond 30 months. CD19+ B cells decreased over 6 cycles of chemoimmunotherapy (P < 0.001) with a concomitant increase in the proportion of CD27+ memory B cells (P < 0.001) and activated CD86+CD27+ memory B cells (P < 0.001), as an immunopharmacodynamic marker of CD40 activation. CONCLUSIONS: CP-870,893 with cisplatin and pemetrexed is safe and tolerable at 0.15 mg/kg, although most patients experience CRS. While objective response rates are similar to chemotherapy alone, three patients achieved long-term survival. AUSTRALIA NEW ZEALAND CLINICAL TRIALS REGISTRY NUMBER: ACTRN12609000294257.

Assessment of tumour response with (18)F-fluorodeoxyglucose positron emission tomography using three-dimensional measures compared to SUVmax--a phantom study.

SUVmax is currently the most common semi-quantitative method of response assessment on FDG PET. By defining the tumour volume of interest (VOI), a measure of total glycolytic volume (TGV) may be obtained. We aimed to comprehensively examine, in a phantom setting, the accuracy of TGV in reflecting actual lesion activity and to compare TGV with SUVmax for response assessment. The algorithms for VOI generation from which TGV was derived included fixed threshold techniques at 50% of maximum (MAX50), 70% of maximum (MAX70), an adaptive threshold of 50% of (maximum + background)/2 (BM50) and a semi-automated iterative region-growing algorithm, GRAB. Comparison with both actual lesion activity and response scenarios was performed. SUVmax correlated poorly with actual lesion activity (r = 0.651) and change in lesion activity (r = 0.605). In a response matrix scenario SUVmax performed poorly when all scenarios were considered, but performed well when only clinically likely scenarios were included. The TGV derived using MAX50 and MAX70 algorithms performed poorly in evaluation of lesion change. The TGV derived from BM50 and GRAB algorithms however performed extremely well in correlation with actual lesion activity (r = 0.993 and r = 0.982, respectively), change in lesion activity (r = 0.972 and r = 0.963, respectively) and in the response scenario matrix. TGV(GRAB) demonstrated narrow confidence bands when modelled with actual lesion activity. Measures of TGV generated by iterative algorithms such as GRAB show potential for increased sensitivity of metabolic response monitoring compared to SUVmax, which may have important implications for improved patient care.