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Platform trials allow the evaluation of multiple experimental treatments under a single master protocol; they are designed to allow new treatments to be seamlessly added to the trial as they become available. They provide large potential gains in efficiency through 1) comparing arms against a common[for full text, please go to the a.m. URL], 65th Annual Meeting of the German Association for Medical Informatics, Biometry and Epidemiology (GMDS), Meeting of the Central European Network (CEN: German Region, Austro-Swiss Region and Polish Region) of the International Biometric Society (IBS)

Adaptive designs (ADs) allow pre-planned changes to an ongoing trial without compromising the validity of conclusions and it is essential to distinguish pre-planned from unplanned changes that may also occur. The reporting of ADs in randomised trials is inconsistent and needs improving. Incompletely reported AD randomised trials are difficult to reproduce and are hard to interpret and synthesise. This consequently hampers their ability to inform practice as well as future research and contributes to research waste. Better transparency and adequate reporting will enable the potential benefits of ADs to be realised.\ud \ud \ud \ud This extension to the Consolidated Standards Of Reporting Trials (CONSORT) 2010 statement was developed to enhance the reporting of randomised AD clinical trials. We developed an Adaptive designs CONSORT Extension (ACE) guideline through a two-stage Delphi process with input from multidisciplinary key stakeholders in clinical trials research in the public and private sectors from 21 countries, followed by a consensus meeting. Members of the CONSORT Group were involved during the development process.\ud \ud \ud \ud The paper presents the ACE checklists for AD randomised trial reports and abstracts, as well as an explanation with examples to aid the application of the guideline. The ACE checklist comprises seven new items, nine modified items, six unchanged items for which additional explanatory text clarifies further considerations for ADs, and 20 unchanged items not requiring further explanatory text. The ACE abstract checklist has one new item, one modified item, one unchanged item with additional explanatory text for ADs, and 15 unchanged items not requiring further explanatory text\ud \ud The intention is to enhance transparency and improve reporting of AD randomised trials to improve the interpretability of their results and reproducibility of their methods, results and inference. We also hope indirectly to facilitate the much-needed knowledge transfer of innovative trial designs to maximise their potential benefits. In order to encourage its wide dissemination this article is freely accessible on the BMJ and Trials journal websites.\ud \ud “To maximise the benefit to society, you need to not just do research but do it well” Douglas G Altman

Our aim was to confirm earlier studies showing tcPO2 to be higher under clothing made with polyethylene terephalate (PET) fabric containing ceramic particles (CEL) compared to standard PET fabric. In previous studies PET garments were donned first to avoid possible persistent effects from ceramic particles. This study randomized donning sequence to avoid bias.Methods: Subjects were randomized to don either PET shirts first (PETF n=73) or CEL first (CELF n=80), switching garments after 90 minutes. Skin temperature (ST), arterial oxygen saturation (O2sat), and tcPO2 were measured every 30 minutes.Results: Baseline ST and O2 sat were nearly identical in the two groups. Baseline tcPO2 was modestly higher in the CELF group than with PETF: 66.4 ± 18.9 vs. 63.9 ± 18.8 mmHg (n.s). Independent of donning sequence, tcPO2 measurements 90 minutes after wearing CEL were 6.7% higher than after 90 minutes wearing PET (p

Potential predictive biomarkers are often measured on a continuous scale, but in practice, a threshold value to divide the patient population into biomarker ‘positive’ and ‘negative’ is desirable. Early phase clinical trials are increasingly using biomarkers for patient selection, but at this stage, it is likely that little will be known about the relationship between the biomarker and the treatment outcome. We describe a single‐arm trial design with adaptive enrichment, which can increase power to demonstrate efficacy within a patient subpopulation, the parameters of which are also estimated. Our design enables us to learn about the biomarker and optimally adjust the threshold during the study, using a combination of generalised linear modelling and Bayesian prediction. At the final analysis, a binomial exact test is carried out, allowing the hypothesis that ‘no population subset exists in which the novel treatment has a desirable response rate’ to be tested. Through extensive simulations, we are able to show increased power over fixed threshold methods in many situations without increasing the type‐I error rate. We also show that estimates of the threshold, which defines the population subset, are unbiased and often more precise than those from fixed threshold studies. We provide an example of the method applied (retrospectively) to publically available data from a study of the use of tamoxifen after mastectomy by the German Breast Study Group, where progesterone receptor is the biomarker of interest.

BACKGROUND: The detection of occult bone metastases is a key factor in determining the management of patients with renal cell carcinoma (RCC), especially when curative surgery is considered. This prospective study assessed the sensitivity of (18)F-labelled sodium fluoride in conjunction with positron emission tomography/computed tomography ((18)F-NaF PET/CT) for detecting RCC bone metastases, compared with conventional imaging by bone scintigraphy or CT. PATIENTS AND METHODS: An adaptive two-stage trial design was utilized, which was stopped after the first stage due to statistical efficacy. Ten patients with stage IV RCC and bone metastases were imaged with (18)F-NaF PET/CT and (99m)Tc-labelled methylene diphosphonate ((99m)Tc-MDP) bone scintigraphy including pelvic single photon emission computed tomography (SPECT). Images were reported independently by experienced radiologists and nuclear medicine physicians using a 5-point scoring system. RESULTS: Seventy-seven lesions were diagnosed as malignant: 100% were identified by (18)F-NaF PET/CT, 46% by CT and 29% by bone scintigraphy/SPECT. Standard-of-care imaging with CT and bone scintigraphy identified 65% of the metastases reported by (18)F-NaF PET/CT. On an individual patient basis, (18)F-NaF PET/CT detected more RCC metastases than (99m)Tc-MDP bone scintigraphy/SPECT or CT alone (P = 0.007). The metabolic volumes, mean and maximum standardized uptake values (SUV mean and SUV max) of the malignant lesions were significantly greater than those of the benign lesions (P < 0.001). CONCLUSIONS: (18)F-NaF PET/CT is significantly more sensitive at detecting RCC skeletal metastases than conventional bone scintigraphy or CT. The detection of occult bone metastases could greatly alter patient management, particularly in the context when standard-of-care imaging is negative for skeletal metastases.

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BACKGROUND: Mesothelioma is an incurable cancer originating from the mesothelial cells that line the pleural, peritoneal and pericardial cavities. These cells synthesise large quantities of surface glycoproteins, rendering them dependent upon efficient endoplasmic reticulum (ER) function. When faced with elevated levels of secretory protein load, cells are said to experience ER stress, which has been implicated in the pathogenesis of many human diseases including cancer. METHOD: We set out to measure markers of ER stress in malignant mesothelioma and to determine whether ER stress signalling correlates with clinical parameters. RESULTS: We observed that expression of the ER stress-responsive transcription factor C/EBP homologous protein (CHOP) correlated with patient survival and remained an independent prognostic variable in pairwise comparisons with all clinical variables tested. The most parsimonious multivariate model in our study comprised only performance status and CHOP staining. In contrast, expression of the ER stress-responsive phosphatase growth arrest and DNA damage 34 (GADD34) correlated with the degree of mesothelial differentiation, being lost progressively in biphasic and sarcomatoid mesotheliomas. CONCLUSION: Our findings suggest that staining for CHOP provides prognostic information that may be useful in the stratification of patients with mesothelioma. Staining for GADD34 may prove useful in classification of mesothelioma histopathology.

Significance Carbon-13 MRI was used to assess exchange of hyperpolarized 13C label between injected [1-13C]pyruvate and the endogenous tumor lactate pool in breast cancer patients. Higher levels of 13C label exchange were observed in more-aggressive tumors, including all triple-negative cancers. The 13C label exchange correlated significantly with the expression of the transmembrane transporter mediating uptake of pyruvate into tumor cells and hypoxia inducible factor 1 (HIF1α), but no significant correlation with the expression of lactate dehydrogenase, the enzyme that catalyzes the exchange. The study has shown that 13C MRI can be used for metabolic imaging of breast cancer patients in the clinic, creating possibilities for noninvasive cancer monitoring in this patient group., Our purpose is to investigate the feasibility of imaging tumor metabolism in breast cancer patients using 13C magnetic resonance spectroscopic imaging (MRSI) of hyperpolarized 13C label exchange between injected [1-13C]pyruvate and the endogenous tumor lactate pool. Treatment-naïve breast cancer patients were recruited: four triple-negative grade 3 cancers; two invasive ductal carcinomas that were estrogen and progesterone receptor-positive (ER/PR+) and HER2/neu-negative (HER2−), one grade 2 and one grade 3; and one grade 2 ER/PR+ HER2− invasive lobular carcinoma (ILC). Dynamic 13C MRSI was performed following injection of hyperpolarized [1-13C]pyruvate. Expression of lactate dehydrogenase A (LDHA), which catalyzes 13C label exchange between pyruvate and lactate, hypoxia-inducible factor-1 (HIF1α), and the monocarboxylate transporters MCT1 and MCT4 were quantified using immunohistochemistry and RNA sequencing. We have demonstrated the feasibility and safety of hyperpolarized 13C MRI in early breast cancer. Both intertumoral and intratumoral heterogeneity of the hyperpolarized pyruvate and lactate signals were observed. The lactate-to-pyruvate signal ratio (LAC/PYR) ranged from 0.021 to 0.473 across the tumor subtypes (mean ± SD: 0.145 ± 0.164), and a lactate signal was observed in all of the grade 3 tumors. The LAC/PYR was significantly correlated with tumor volume (R = 0.903, P = 0.005) and MCT 1 (R = 0.85, P = 0.032) and HIF1α expression (R = 0.83, P = 0.043). Imaging of hyperpolarized [1-13C]pyruvate metabolism in breast cancer is feasible and demonstrated significant intertumoral and intratumoral metabolic heterogeneity, where lactate labeling correlated with MCT1 expression and hypoxia.