Vandetanib-eluting radiopaque beads and stereotactic body radiotherapy in the treatment of liver cancers

Background: Current treatment options for unresectable hepatocellular carcinoma (HCC) and colorectal liver metastases (mCRC) include transarterial chemoembolisation (TACE) and stereotactic body radiotherapy (SBRT). The objectives of this project were: 1. To assess a novel drug-eluting bead for TACE / 2. To report on the safety and efficacy of SBRT in HCC / 3. To assess the feasibility of using radiopaque beads as fiducial markers for SBRT / Methods: In Part 1, a first-in-human trial was performed in patients with HCC and mCRC using a novel vandetanib-eluting radiopaque bead, BTG-002814. Primary trial endpoints were safety/tolerability and the concentrations of vandetanib and its major metabolite in plasma and resected tissue. Biomarker studies included blood cytokines and perfusion imaging parameters. In Part 2, the efficacy of SBRT was explored in a retrospective study of 31 patients with HCC tumours ≤5 cm and in a phase II study of 13 patients with larger tumours. In Part 3 the feasibility of using radiopaque beads as fiducial markers for SBRT was investigated. / Results: BTG-002814 was shown to have a satisfactory safety profile in 8 patients. Vandetanib was present in the plasma of all patients 12 days post-TACE, and present in resected liver tissue up to 32 days post-treatment. There were no significant changes in perfusion parameters. Blood biomarker studies showed increases in leptin, osteopontin and sTie2. SBRT offered 1-year local control rates of 94% in small HCCs and 92% in larger tumours. Radiopaque beads were visible on 4D-CT and CBCT images in all 8 cases and matching successfully performed. / Conclusions: The safety profile and pharmacokinetic characteristics for this novel technology are adequate to proceed to a Phase I/II trial. SBRT is an effective local treatment for HCC. The role of radiopaque beads as fiducial markers is feasible and warrants further exploration as a clinical trial of TACE with SBRT

Prospective observational cohort study on grading the severity of postoperative complications in global surgery research

Background The Clavien–Dindo classification is perhaps the most widely used approach for reporting postoperative complications in clinical trials. This system classifies complication severity by the treatment provided. However, it is unclear whether the Clavien–Dindo system can be used internationally in studies across differing healthcare systems in high- (HICs) and low- and middle-income countries (LMICs). Methods This was a secondary analysis of the International Surgical Outcomes Study (ISOS), a prospective observational cohort study of elective surgery in adults. Data collection occurred over a 7-day period. Severity of complications was graded using Clavien–Dindo and the simpler ISOS grading (mild, moderate or severe, based on guided investigator judgement). Severity grading was compared using the intraclass correlation coefficient (ICC). Data are presented as frequencies and ICC values (with 95 per cent c.i.). The analysis was stratified by income status of the country, comparing HICs with LMICs. Results A total of 44 814 patients were recruited from 474 hospitals in 27 countries (19 HICs and 8 LMICs). Some 7508 patients (16·8 per cent) experienced at least one postoperative complication, equivalent to 11 664 complications in total. Using the ISOS classification, 5504 of 11 664 complications (47·2 per cent) were graded as mild, 4244 (36·4 per cent) as moderate and 1916 (16·4 per cent) as severe. Using Clavien–Dindo, 6781 of 11 664 complications (58·1 per cent) were graded as I or II, 1740 (14·9 per cent) as III, 2408 (20·6 per cent) as IV and 735 (6·3 per cent) as V. Agreement between classification systems was poor overall (ICC 0·41, 95 per cent c.i. 0·20 to 0·55), and in LMICs (ICC 0·23, 0·05 to 0·38) and HICs (ICC 0·46, 0·25 to 0·59). Conclusion Caution is recommended when using a treatment approach to grade complications in global surgery studies, as this may introduce bias unintentionally

The surgical safety checklist and patient outcomes after surgery: a prospective observational cohort study, systematic review and meta-analysis

© 2017 British Journal of Anaesthesia Background: The surgical safety checklist is widely used to improve the quality of perioperative care. However, clinicians continue to debate the clinical effectiveness of this tool. Methods: Prospective analysis of data from the International Surgical Outcomes Study (ISOS), an international observational study of elective in-patient surgery, accompanied by a systematic review and meta-analysis of published literature. The exposure was surgical safety checklist use. The primary outcome was in-hospital mortality and the secondary outcome was postoperative complications. In the ISOS cohort, a multivariable multi-level generalized linear model was used to test associations. To further contextualise these findings, we included the results from the ISOS cohort in a meta-analysis. Results are reported as odds ratios (OR) with 95% confidence intervals. Results: We included 44 814 patients from 497 hospitals in 27 countries in the ISOS analysis. There were 40 245 (89.8%) patients exposed to the checklist, whilst 7508 (16.8%) sustained ≥1 postoperative complications and 207 (0.5%) died before hospital discharge. Checklist exposure was associated with reduced mortality [odds ratio (OR) 0.49 (0.32–0.77); P\u3c0.01], but no difference in complication rates [OR 1.02 (0.88–1.19); P=0.75]. In a systematic review, we screened 3732 records and identified 11 eligible studies of 453 292 patients including the ISOS cohort. Checklist exposure was associated with both reduced postoperative mortality [OR 0.75 (0.62–0.92); P\u3c0.01; I2=87%] and reduced complication rates [OR 0.73 (0.61–0.88); P\u3c0.01; I2=89%). Conclusions: Patients exposed to a surgical safety checklist experience better postoperative outcomes, but this could simply reflect wider quality of care in hospitals where checklist use is routine

Critical care admission following elective surgery was not associated with survival benefit: prospective analysis of data from 27 countries

This was an investigator initiated study funded by Nestle Health Sciences through an unrestricted research grant, and by a National Institute for Health Research (UK) Professorship held by RP. The study was sponsored by Queen Mary University of London