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Funder: Pfizer; Id: http://dx.doi.org/10.13039/100004319, OBJECTIVE: To explore translational biological and imaging biomarkers for sunitinib treatment before and after debulking nephrectomy in the NeoSun (European Union Drug Regulating Authorities Clinical Trials Database [EudraCT] number: 2005-004502-82) single-centre, single-arm, single-agent, Phase II trial. PATIENTS AND METHODS: Treatment-naïve patients with metastatic renal cell carcinoma (mRCC) received 50 mg once daily sunitinib for 12 days pre-surgically, then post-surgery on 4 week-on, 2 week-off, repeating 6-week cycles until disease progression in a single arm phase II trial. Structural and dynamic contrast-enhanced magnet resonance imaging (DCE-MRI) and research blood sampling were performed at baseline and after 12 days. Computed tomography imaging was performed at baseline and post-surgery then every two cycles. The primary endpoint was objective response rate (Response Evaluation Criteria In Solid Tumors [RECIST]) excluding the resected kidney. Secondary endpoints included changes in DCE-MRI of the tumour following pre-surgery sunitinib, overall survival (OS), progression-free survival (PFS), response duration, surgical morbidity/mortality, and toxicity. Translational and imaging endpoints were exploratory. RESULTS: A total of 14 patients received pre-surgery sunitinib, 71% (10/14) took the planned 12 doses. All underwent nephrectomy, and 13 recommenced sunitinib postoperatively. In all, 58.3% (seven of 12) of patients achieved partial or complete response (PR or CR) (95% confidence interval 27.7-84.8%). The median OS was 33.7 months and median PFS was 15.7 months. Amongst those achieving a PR or CR, the median response duration was 8.7 months. No unexpected surgical complications, sunitinib-related toxicities, or surgical delays occurred. Within the translational endpoints, pre-surgical sunitinib significantly increased necrosis, and reduced cluster of differentiation-31 (CD31), Ki67, circulating vascular endothelial growth factor-C (VEGF-C), and transfer constant (KTrans , measured using DCE-MRI; all P < 0.05). There was a trend for improved OS in patients with high baseline plasma VEGF-C expression (P = 0.02). Reduction in radiological tumour volume after pre-surgical sunitinib correlated with high percentage of solid tumour components at baseline (Spearman's coefficient ρ = 0.69, P = 0.02). Conversely, the percentage tumour volume reduction correlated with lower baseline percentage necrosis (coefficient = -0.51, P = 0.03). CONCLUSION: Neoadjuvant studies such as the NeoSun can safely and effectively explore translational biological and imaging endpoints.

Bayesian methods for group sequential clinical trials have received increasing at­tention recently. They offer an approach for dealing with many difficult problems and have some practical advantages over frequentist methods. This thesis covers Bayesian methods for group sequential clinical trials comparing two treatments using both the Bayes sequential procedure and the Bayes sequential decision pro­cedure. The main outcome measures for clinical trials are distributed as normal, binomial, and exponential and the proportional hazard model for survival time data. Under the framework of Bayes sequential procedure for group sequential clini­cal trials, the student t prior distribution for the parameter of interest is proposed as a replacement for the normal prior distribution when the sample mean is very distant from the mean of the prior distribution. The framework of Bayes sequen­tial procedure in clinical trials on normal distribution responses with variance unknown is given. Bayes sequential decision theory is applied to group sequential clinical trials. First, Bayes sequential decision procedures with piecewise continuous loss func­tions are used in clinical trials on normal distribution responses. The procedures with loss functions which consider treatment efficacy and patient horizon are then given in clinical trials on binary responses. Approximation methods of Bayes sequential decision procedures are explored in clinical trials with survival time data. Robust Bayes analysis in clinical trials is presented to address the criticism on the subjective prior distribution for parameters of interest.

OBJECTIVE: Thiopurines are widely used as maintenance therapy in inflammatory bowel disease (IBD) but the evidence base for their use is sparse and their role increasingly questioned. Using the largest series reported to date, we assessed the long-term effectiveness of thiopurines in ulcerative colitis (UC) and Crohn's disease (CD), including their impact on need for surgery. DESIGN: Outcomes were assessed in 11 928 patients (4968 UC, 6960 CD) in the UK IBD BioResource initiated on thiopurine monotherapy with the intention of maintaining medically induced remission. Effectiveness was assessed retrospectively using patient-level data and a definition that required avoidance of escalation to biological therapy or surgery while on thiopurines. Analyses included overall effectiveness, time-to-event analysis for treatment escalation and comparison of surgery rates in patients tolerant or intolerant of thiopurines. RESULTS: Using 68 132 patient-years of exposure, thiopurine monotherapy appeared effective for the duration of treatment in 2617/4968 (52.7%) patients with UC compared with 2378/6960 (34.2%) patients with CD (p

Objective: Thiopurines are widely used as maintenance therapy in inflammatory bowel disease (IBD) but the evidence base for their use is sparse and their role increasingly questioned. Using the largest series reported to date, we assessed the long-term effectiveness of thiopurines in ulcerative colitis (UC) and Crohn’s disease (CD), including their impact on need for surgery. Design: Outcomes were assessed in 11 928 patients (4968 UC, 6960 CD) in the UK IBD BioResource initiated on thiopurine monotherapy with the intention of maintaining medically induced remission. Effectiveness was assessed retrospectively using patient-level data and a definition that required avoidance of escalation to biological therapy or surgery while on thiopurines. Analyses included overall effectiveness, time-to-event analysis for treatment escalation and comparison of surgery rates in patients tolerant or intolerant of thiopurines. Results: Using 68 132 patient-years of exposure, thiopurine monotherapy appeared effective for the duration of treatment in 2617/4968 (52.7%) patients with UC compared with 2378/6960 (34.2%) patients with CD (p

OBJECTIVES: Although detection of brain metastasis can change treatment intent in non-small cell lung carcinoma (NSCLC), head imaging is not routinely performed during initial staging. In our previous study, 4.8% of patients considered for surgical treatment had asymptomatic synchronous brain metastases, encouraging us to include contrast-enhanced head CT (CE-CT) in our routine staging protocol. We present results from a large cohort of potentially resectable NSCLC patients imaged irrespective of the presence of neurological symptoms. MATERIALS AND METHODS: Patients with newly diagnosed NSCLC were identified from Royal Papworth Hospital registries. Data regarding the clinical stage (7th edition TNM), neurological symptoms and imaging findings were retrieved from clinical records. RESULTS: 1074 NSCLC patients considered potentially resectable based on the initial staging CT of the chest and abdomen (stage IA-IIIB) were included. Synchronous brain metastases were detected by CE-CT in 23 patients (2.1%); the rate of positive findings increased with stage, ranging from 0.7% (IA) to 2.6% (IIIA) (p = 0.023). The majority of metastases were asymptomatic (19 of 23, 82.6%). Asymptomatic brain lesions were smaller than symptomatic (13.3 ± 4.8 vs 24.8 ± 8.2 mm; p < 0.01); in both groups, the most frequent location was frontal lobe. CONCLUSION: Routine CE-CT detected synchronous brain metastases in approximately 2% of NSCLC patients eligible for radical surgical treatment. The majority of the metastatic lesions were asymptomatic. With the exception of stage IA in which the detection rate is very low, CE-CT could therefore be useful in routine NSCLC staging.