Selenium and Vitamin E for Prevention of Non-Muscle-Invasive Bladder Cancer Recurrence and Progression: A Randomized Clinical Trial.

Importance: Selenium and vitamin E have been identified as promising agents for the chemoprevention of recurrence and progression of non-muscle-invasive bladder cancer.

Objective: To determine whether selenium and/or vitamin E may prevent disease recurrence in patients with newly diagnosed NMIBC.

Design, Setting, And Participants: This multicenter, prospective, double-blinded, placebo-controlled, 2 × 2 factorial randomized clinical trial included patients with newly diagnosed NMIBC recruited from 10 secondary or tertiary care hospitals in the UK.

Health-related quality of life around the time of diagnosis in patients with bladder cancer.

Objectives: To quantify the health-related quality of life (HRQoL) of patients with bladder cancer around the time of diagnosis and to test the hypotheses of a two-factor model for the HRQoL questionnaire QLQ-C30.

Methods: From participants in the Bladder Cancer Prognoses Programme, a multicentre cohort study, sociodemographic data were collected using semi-structured face-to-face interviews. Answers to the QLQ-C30 were transformed into a scale from 0 to 100.

Patients choose certainty over burden in bladder cancer surveillance.

Background: Due to the high risk of recurrence of non-muscle invasive bladder cancer, all patients undergo regular cystoscopic surveillance for early detection. As cystoscopy is invasive, costly and increases the burden of the disease considerably, there is significant ongoing research and development into non-invasive urinary biomarker substitutes. This study aims to assess the level of sensitivity required before patients accept a new urinary biomarker.

Radiofrequency-induced Thermo-chemotherapy Effect Versus a Second Course of Bacillus Calmette-Guérin or Institutional Standard in Patients with Recurrence of Non-muscle-invasive Bladder Cancer Following Induction or Maintenance Bacillus Calmette-Guérin Therapy (HYMN): A Phase III, Open-label, Randomised Controlled Trial.

Background: There is no effective intravesical second-line therapy for non-muscle-invasive bladder cancer (NMIBC) when bacillus Calmette-Guérin (BCG) fails.

Objective: To compare disease-free survival time (DFS) between radiofrequency-induced thermo-chemotherapy effect (RITE) and institutional standard second-line therapy (control) in NMIBC patients with recurrence following induction/maintenance BCG.

Design, Settings, And Participants: Open-label, phase III randomised controlled trial accrued across 14 centres between May 2010 and July 2013 (HYMN [ClinicalTrials.

Dose Transition Pathways: The Missing Link Between Complex Dose-Finding Designs and Simple Decision-Making.

The ever-increasing pace of development of novel therapies mandates efficient methodologies for assessment of their tolerability and activity. Evidence increasingly support the merits of model-based dose-finding designs in identifying the recommended phase II dose compared with conventional rule-based designs such as the 3 + 3 but despite this, their use remains limited. Here, we propose a useful tool, dose transition pathways (DTP), which helps overcome several commonly faced practical and methodologic challenges in the implementation of model-based designs.

Cost-effectiveness of zoledronic acid and strontium-89 as bone protecting treatments in addition to chemotherapy in patients with metastatic castrate-refractory prostate cancer: results from the TRAPEZE trial (ISRCTN 12808747).

Objective: To evaluate the cost-effectiveness of adding zoledronic acid or strontium-89 to standard docetaxel chemotherapy for patients with castrate-refractory prostate cancer (CRPC).

Patients And Methods: Data on resource use and quality of life for 707 patients collected prospectively in the TRAPEZE 2 × 2 factorial randomised trial (ISRCTN 12808747) were used to assess the cost-effectiveness of i) zoledronic acid versus no zoledronic acid (ZA vs. no ZA), and ii) strontium-89 versus no strontium-89 (Sr89 vs.

Clinical Outcomes and Survival Following Treatment of Metastatic Castrate-Refractory Prostate Cancer With Docetaxel Alone or With Strontium-89, Zoledronic Acid, or Both: The TRAPEZE Randomized Clinical Trial.

Importance: Bony metastatic castrate-refractory prostate cancer (CRPC) has a poor prognosis and high morbidity. Zoledronic acid (ZA) is commonly combined with docetaxel in practice but lacks evidence that combining is effective, and strontium-89 (Sr89) is generally used palliatively in patients unfit for chemotherapy. Phase 2 analysis of the TRAPEZE trial confirmed combining the agents was safe and feasible, and the objectives of phase 3 include assessment of the treatments on survival.

A Practical Application of Value of Information and Prospective Payback of Research to Prioritize Evaluative Research.

Background And Objectives: Efforts to ensure that funded research represents "value for money" have led to increasing calls for the use of analytic methods in research prioritization. A number of analytic approaches have been proposed to assist research funding decisions, the most prominent of which are value of information (VOI) and prospective payback of research (PPoR). Despite the increasing interest in the topic, there are insufficient VOI and PPoR applications on the same case study to contrast their methods and compare their outcomes.

Meta-analysis of randomized phase II trials to inform subsequent phase III decisions.

Background: If multiple Phase II randomized trials exist then meta-analysis is favorable to increase statistical power and summarize the existing evidence about an intervention's effect in order to help inform Phase III decisions. We consider some statistical issues for meta-analysis of Phase II trials for this purpose, as motivated by a real example involving nine Phase II trials of bolus thrombolytic therapy in acute myocardial infarction with binary outcomes.

Methods: We propose that a Bayesian random effects logistic regression model is most suitable as it models the binomial distribution of the data, helps avoid continuity corrections, accounts for between-trial heterogeneity, and incorporates parameter uncertainty when making inferences.

Smoking is associated with lower age, higher grade, higher stage, and larger size of malignant bladder tumors at diagnosis.

Smoking is a strong risk factor of bladder cancer (BC), but it is currently unclear whether smoking is also associated with severity of BC at diagnosis. We performed a large hospital-based case-comparison study, examining the relation between smoking and clinical characteristics of BC at diagnosis. A total of 1,544 cases from participating hospitals in the West Midlands were recruited between 19 December 2005 and 21 April 2011.

Sample size calculations for designing clinical proteomic profiling studies using mass spectrometry.

In cancer clinical proteomics, MALDI and SELDI profiling are used to search for biomarkers of potentially curable early-stage disease. A given number of samples must be analysed in order to detect clinically relevant differences between cancers and controls, with adequate statistical power. From clinical proteomic profiling studies, expression data for each peak (protein or peptide) from two or more clinically defined groups of subjects are typically available.

Excision repair cross-complementation group 1 (ERCC1) status and lung cancer outcomes: a meta-analysis of published studies and recommendations.

Purpose: Despite discrepant results on clinical utility, several trials are already prospectively randomizing non-small cell lung cancer (NSCLC) patients by ERCC1 status. We aimed to characterize the prognostic and predictive effect of ERCC1 by systematic review and meta-analysis.

Methods: Eligible studies assessed survival and/or chemotherapy response in NSCLC or SCLC by ERCC1 status.

Assessment of high-throughput high-resolution MALDI-TOF-MS of urinary peptides for the detection of muscle-invasive bladder cancer.

Purpose: There is a need for better biomarkers to both detect bladder cancer and distinguish muscle-invasive (stage T2+) from non-invasive (stage Ta/T1) disease. We assess whether MALDI-TOF-MS of the urine peptidome can achieve this.

Experimental Design: We analysed urine from 751 patients with bladder cancer and 127 patients without bladder cancer.

Estrogen receptor and progesterone receptor as predictive biomarkers of response to endocrine therapy: a prospectively powered pathology study in the Tamoxifen and Exemestane Adjuvant Multinational trial.

Purpose: The Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial included a prospectively planned pathology substudy testing the predictive value of progesterone receptor (PgR) expression for outcome of estrogen receptor-positive (ER-positive) early breast cancer treated with exemestane versus tamoxifen.

Patients And Methods: Pathology blocks from 4,781 TEAM patients randomly assigned to exemestane versus tamoxifen followed by exemestane for 5 years of total therapy were collected centrally, and tissue microarrays were constructed from samples from 4,598 patients. Quantitative analysis of hormone receptors (ER and PgR) was performed by using image analysis and immunohistochemistry, and the results were linked to outcome data from the main TEAM trial and analyzed relative to disease-free survival and treatment.

Warfarin thromboprophylaxis in cancer patients with central venous catheters (WARP): an open-label randomised trial.

Background: The role and dose of anticoagulants in thromboprophylaxis for patients with cancer receiving chemotherapy through central venous catheters (CVCs) is controversial. We therefore assessed whether warfarin reduces catheter-related thrombosis compared with no warfarin and whether the dose of warfarin determines the thromboprophylactic effect.

Methods: In 68 clinical centres in the UK, we randomly assigned 1590 patients aged at least 16 years with cancer who were receiving chemotherapy through CVCs to no warfarin, fixed-dose warfarin 1 mg per day, or dose-adjusted warfarin per day to maintain an international normalised ratio between 1.

Sample size determination in clinical proteomic profiling experiments using mass spectrometry for class comparison.

Mass spectrometric profiling approaches such as MALDI-TOF and SELDI-TOF are increasingly being used in disease marker discovery, particularly in the lower molecular weight proteome. However, little consideration has been given to the issue of sample size in experimental design. The aim of this study was to develop a protocol for the use of sample size calculations in proteomic profiling studies using MS.

Narrow-band imaging flexible cystoscopy in the detection of recurrent urothelial cancer of the bladder.

Objective: To investigate whether narrow-band imaging (NBI) flexible cystoscopy improves the detection rate of urothelial carcinomas (UCs) of the bladder. NBI is an optical image enhancement technology in which the narrow bandwidth of light is strongly absorbed by haemoglobin and penetrates only the surface of tissue, increasing the visibility of capillaries and other delicate tissue surface structures by enhancing contrast between the two.

Patients And Methods: Between November 2005 and May 2007 at the Queen Elizabeth Hospital, Birmingham, NBI flexible cystoscopy was performed on 29 patients with known recurrences of UC of the bladder after initial conventional white-light imaging (WLI) flexible cystoscopy with the same instrument (Olympus Lucera sequential RGB endoscopy system).

Rational selection of patients for antibacterial prophylaxis after chemotherapy.

Purpose: The SIGNIFICANT (Simple Investigation in Neutropenic Individuals of the Frequency of Infection after Chemotherapy +/- Antibiotic in a Number of Tumours) trial reported a reduction in febrile episodes (FEs) among 1,565 patients with solid cancers and lymphomas receiving cyclical, myelosuppressive chemotherapy (causing grade 4 neutropenia) in a randomized, placebo-controlled, double-blind trial of levofloxacin (P = .01). In response to concerns that increased antibacterial prescribing selects for microbial resistance, we examined our data to explore the rationale for more limited prophylaxis.

Multiple testing issues in discriminating compound-related peaks and chromatograms from high frequency noise, spikes and solvent-based noise in LC-MS data sets.

Liquid Chromatography--Mass Spectrometry (LC-MS) is a powerful method for sensitive detection and quantification of proteins and peptides in complex biological fluids like serum. LC-MS produces complex data sets, consisting of some hundreds of millions of data points per sample at a resolution of 0.1 amu in the m/z domain and 7000 data points in the time domain.

Estimating the cost-effectiveness of an intervention in a clinical trial when partial cost information is available: a Bayesian approach.

There is an increasing need to establish whether health-care interventions are cost effective as well as clinically effective. It is becoming increasingly common for cost studies to be incorporated into clinical trials, either on all patients or more usually on a subset of patients. Establishing the total cost per patient is complex, as it requires information on resource use, which may come from a variety of different sources.

Cost-effectiveness in clinical trials: using multiple imputation to deal with incomplete cost data.

Background: Cost-effectiveness has become an important outcome in many clinical trials and has resulted in the collection of resource use data and the calculation of costs for individual patients. A specific example is a Cancer Research UK phase III trial comparing chemotherapy (CT) against standard palliative care in patients with advanced non-small cell lung cancer. Resource usage from trial entry until death were collected and costs obtained on a subset of 115 trial patients.

Plasma proteome analysis reveals the geographical origin and liver tumor status of Dab (Limanda limanda) from UK marine waters.

The flatfish species dab (Limanda limanda) is the sentinel for offshore marine monitoring in the United Kingdom National Marine Monitoring Programme (NMMP). At certain sites in the North and Irish Seas, the prevalence of macroscopic liver tumors can exceed 10%. The plasma proteome of these fish potentially contains reporter proteins or "biomarkers" that may enable development of diagnostic tests for liver cancer and further our understanding of the disease.

Clinical trial design in hepatocellular carcinoma.

Researchers interested in developing treatments for hepatocellular carcinoma (HCC) face three sets of problems; one set common to all clinical trialists at the beginning of the 21st century, one set related to phase I/II studies ('early drug development') and one set related to the design of phase III (randomised, controlled trials). This review is concerned with the challenges faced in designing high quality clinical trials in patients with HCC. Specific published trials are not discussed other than by way of illustration of the problems faced.

Interleukin 6 expression by Hodgkin/Reed-Sternberg cells is associated with the presence of 'B' symptoms and failure to achieve complete remission in patients with advanced Hodgkin's disease.

Interleukin 6 (IL-6) is a potent immunomodulatory cytokine that has pathogenic and prognostic significance in a number of disorders. Previous studies in Hodgkin's disease (HD) have demonstrated the association between elevated serum levels of IL-6 and unfavourable prognosis, including advanced stage and the presence of 'B' symptoms and with reduced survival. Although IL-6 expression has been demonstrated in both the malignant Hodgkin/Reed-Sternberg (HRS) cells and in the various non-malignant cells present in HD biopsies, a relationship between expression of IL-6 by the tumour and outcome measures has not been established.