Caroline Kelly

Diagnostic and Prognostic Biomarkers in the Rational Assessment of Mesothelioma (DIAPHRAGM) study: protocol of a prospective, multicentre, observational study.

Introduction Malignant pleural mesothelioma (MPM) is an asbestos-related cancer, which is difficult to diagnose. Thoracoscopy is frequently required but is not widely available. An accurate, non-invasive diagnostic biomarker would allow early specialist referral, limit diagnostic delays and maximise clinical trial access. Current markers offer insufficient sensitivity and are not routinely used. The SOMAmer proteomic classifier and fibulin-3 have recently demonstrated sensitivity and specificity exceeding 90% in retrospective studies. DIAPHRAGM (Diagnostic and Prognostic Biomarkers in the Rational Assessment of Mesothelioma) is a suitably powered, multicentre, prospective observational study designed to determine whether these markers provide clinically useful diagnostic and prognostic information. Methods and analysis Serum and plasma (for SOMAscan and fibulin-3, respectively) will be collected at presentation, prior to pleural biopsy/pleurodesis, from 83 to 120 patients with MPM, at least 480 patients with non-MPM pleural disease and 109 asbestos-exposed controls. Final numbers of MPM/non-MPM cases will depend on the incidence of MPM in the study population (estimated at 13–20%). Identical sampling and storage protocols will be used in 22 recruiting centres and histological confirmation sought in all cases. Markers will be measured using the SOMAscan proteomic assay (SomaLogic) and a commercially available fibulin-3 ELISA (USCN Life Science). The SE in the estimated sensitivity and specificity will be <5% for each marker and their performance will be compared with serum mesothelin. Blood levels will be compared with paired pleural fluid levels and MPM tumour volume (using MRI) in a nested substudy. The prognostic value of each marker will be assessed and a large bioresource created. Ethics and dissemination The study has been approved by the West of Scotland Research Ethics Committee (Ref: 13/WS/0240). A Trial Management Group meets on a monthly basis. Results will be published in peer-reviewed journals, presented at international meetings and disseminated to patient groups. Trial registration number ISRCTN10079972, Pre-results.

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.

The diagnostic performance of routinely acquired and reported computed tomography imaging in patients presenting with suspected pleural malignancy

Highlights • The sensitivity of routinely performed CT for pleural malignancy was only 58%.• Nearly half of the malignant cases had a benign CT (negative predictive value 54%).• CTPA and non-specialist radiology reporting were associated with lower sensitivity.• CT specificity was 80%, and was not affected by use of CTPA or specialist reporting.• Pleural malignancy is frequently occult on routinely acquired CT imaging.

Early Contrast Enhancement: a novel Magnetic Resonance Imaging biomarker of pleural malignancy

Highlights • A novel MRI biomarker of pleural malignancy is described – Early Contrast Enhancement.• Early Contrast Enhancement is a semi-objective, perfusion-based biomarker.• Early Contrast Enhancement can be measured in patients with minimal pleural thickening.

Oral Ketamine vs Placebo in Patients With Cancer-Related Neuropathic Pain: A Randomized Clinical Trial.

This multicenter randomized clinical trial compares oral ketamine with placebo for treating neuropathic pain in patients with cancer.

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

Highlights • The manuscript details the rationale, design and protocol for PARADIGM-2.• PARADIGM-2 comprises two parallel phase I, dose escalation studies of the PARP inhibitor olaparib in combination with radiotherapy (for MGMT unmethylated patients) and radiotherapy-temozolomide (for MGMT methylated patients) in newly diagnosed glioblastoma.• This is a novel approach to phase I dose escalation trial design that maximises the potential for patients with glioblastoma to benefit from the addition of the radio- and chemosensitizing drug olaparib.

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

Highlights • A randomised phase II trial of radiotherapy dose escalation for pain control in MPM.• Comparison of 2 hypofractionated regimes (20 Gy/5# and 36 Gy/6#).• Highly conformal radiotherapy techniques used to aid safe dose escalation.• Primary outcome: pain control at week 5 at radiotherapy site.• Recruitment target: 112 patients from 10 to 15 UK centres.