Screened selection design for randomised phase II oncology trials : an example in chronic lymphocytic leukaemia

BACKGROUND: As there are limited patients for chronic lymphocytic leukaemia trials, it is important that statistical methodologies in Phase II efficiently select regimens for subsequent evaluation in larger-scale Phase III trials. METHODS: We propose the screened selection design (SSD), which is a practical multi-stage, randomised Phase II design for two experimental arms. Activity is first evaluated by applying Simon’s two-stage design (1989) on each arm. If both are active, the play-the-winner selection strategy proposed by Simon, Wittes and Ellenberg (SWE) (1985) is applied to select the superior arm. A variant of the design, Modified SSD, also allows the arm with the higher response rates to be recommended only if its activity rate is greater by a clinically-relevant value. The operating characteristics are explored via a simulation study and compared to a Bayesian Selection approach. RESULTS: Simulations showed that with the proposed SSD, it is possible to retain the sample size as required in SWE and obtain similar probabilities of selecting the correct superior arm of at least 90%; with the additional attractive benefit of reducing the probability of selecting ineffective arms. This approach is comparable to a Bayesian Selection Strategy. The Modified SSD performs substantially better than the other designs in selecting neither arm if the underlying rates for both arms are desirable but equivalent, allowing for other factors to be considered in the decision making process. Though its probability of correctly selecting a superior arm might be reduced, it still performs reasonably well. It also reduces the probability of selecting an inferior arm. CONCLUSIONS: SSD provides an easy to implement randomised Phase II design that selects the most promising treatment that has shown sufficient evidence of activity, with available R codes to evaluate its operating characteristics

BH3 profiling and a toolkit of BH3-mimetic drugs predict anti-apoptotic dependence of cancer cells

BACKGROUND: Anti-apoptotic BCL-2 family members antagonise apoptosis by sequestering their pro-apoptotic counterparts. The balance between the different BCL-2 family members forms the basis of BH3 profiling, a peptide-based technique used to predict chemosensitivity of cancer cells. Recent identification of cell-permeable, selective inhibitors of BCL-2, BCL-X(L) and MCL-1, further facilitates the determination of the BCL-2 family dependency of cancer cells. METHODS: We use BH3 profiling in combination with cell death analyses using a chemical inhibitor toolkit to assess chemosensitivity of cancer cells. RESULTS: Both BH3 profiling and the inhibitor toolkit effectively predict chemosensitivity of cells addicted to a single anti-apoptotic protein but a combination of both techniques is more instructive when cell survival depends on more than one anti-apoptotic protein. CONCLUSIONS: The inhibitor toolkit provides a rapid, inexpensive and simple means to assess the chemosensitivity of tumour cells and in conjunction with BH3 profiling offers much potential in personalising cancer therapy

Expression of functional sphingosine-1 phosphate receptor-1 is reduced by B cell receptor signaling and increased by inhibition of PI3 kinase δ but not SYK or BTK in chronic lymphocytic leukaemia cells

BCR signaling pathway inhibitors such as ibrutinib, idelalisib, and fostamatinib (respective inhibitors of Bruton’s tyrosine kinase, PI3Kδ, and spleen tyrosine kinase) represent a significant therapeutic advance in B cell malignancies, including chronic lymphocytic leukemia (CLL). These drugs are distinctive in increasing blood lymphocytes while simultaneously shrinking enlarged lymph nodes, suggesting anatomical redistribution of CLL cells from lymph nodes into the blood. However, the mechanisms underlying this phenomenon are incompletely understood. In this study, we showed that the egress receptor, sphingosine-1-phosphate (S1P) receptor 1 (S1PR1), was expressed at low levels in normal germinal centers and CLL lymph nodes in vivo but became upregulated on normal B cells and, to a variable and lesser extent, CLL cells following in vitro incubation in S1P-free medium. Spontaneous recovery of S1PR1 expression on normal B and CLL cells was prevented by BCR cross-linking, whereas treatment of CLL cells with idelalisib increased S1PR1 expression and migration toward S1P, the greatest increase occurring in cases with unmutated IgH V region genes. Intriguingly, ibrutinib and fostamatinib had no effect on S1PR1 expression or function. Conversely, chemokine-induced migration, which requires integrin activation and is essential for the entry of lymphocytes into lymph nodes as well as their retention, was blocked by ibrutinib and fostamatinib, but not idelalisib. In summary, our results suggest that different BCR signaling inhibitors redistribute CLL cells from lymph nodes into the blood through distinct mechanisms: idelalisib actively promotes egress by upregulating S1PR1, whereas fostamatinib and ibrutinib may reduce CLL cell entry and retention by suppressing chemokine-induced integrin activation

Visual demand evaluation methods for in-vehicle interfaces

Advancements in computing technology have been keenly felt in the automotive industry. Novel in-car systems have the potential to substantially improve the safety, efficiency and comfort of the driving experience. However, they must be carefully designed, so their use does not dangerously distract drivers from fundamental, safety-critical driving tasks. Distraction is a well-established causal factor in road accidents. A concern is that the introduction of new in-vehicle technology may increase exposure to distraction, and lead to an increase in distraction-related accidents. The range of systems often termed In-Vehicle Information Systems (IVIS), encompassing navigation and entertainment systems, in-car email and Internet, are the focus of this thesis, since they are commonly associated with long tasks that are not considered fundamentally relevant to driving. A variety of Human-Computer Interaction (HCI) and Human Factors methods has been employed to assess the potential distraction of IVIS task engagement. These include on-road evaluations, driving simulator studies, and surrogate methods, such as peripheral detection tasks and static task time assessments. The occlusion technique is one such surrogate, where task performance is assessed under intermittent vision conditions. Participants complete a task with 1.5-second vision periods, followed by a period where their vision is occluded. In this way, the technique evaluates how visually demanding a task is, mimicking the behaviour of glancing to and from the forward road scene when driving and performing IVIS tasks. An evaluation of the technique's validity is presented. Sixteen participants performed two tasks on two systems under three conditions: static (full-vision), static (occlusion), and, whilst driving. Results confirmed other research, concluding that the technique is valid. However, the method's assessment through user-trials based on measures of human performance is problematic. Such trials require robust, reliable prototype systems, and can therefore only take place in later design stages. Consequently, the economic effectiveness of the technique is questionable. The keystroke-level model (KLM), which predicts task times for error-free performance by expert users in routine tasks, provides an alternative quantitative assessment method to user-trials. Tasks are decomposed into their most primitive actions, termed operators, which are associated with empirically assessed time values. These values are then summed to predict performance times. An evaluation of the technique in a vehicle environment is presented; twelve participants performed eleven tasks on two in-car entertainment systems, and task times were compared with KLM predictions. Results demonstrate the technique remains valid beyond its original, desktop computing based context. However, the traditional KLM predicts static task time only, and an extended procedure is required to consider occluded task performance. Two studies are presented, seeking to extend the KLM in order to model task performance under the interrupted vision conditions of occlusion trials. In the first, predictions of occlusion metrics are compared with results from the earlier occlusion assessment. In the second, twelve participants performed three tasks on two IVIS systems under occlusion conditions. Results were subsequently compared with predicted values. Both studies conclude that the extended KLM approach produces valid predictions of occlusion methods, with error rates generally within 20% of observed values, in line with expectations for KLM predictions. Subsequently, a case study is presented, to demonstrate the technique's reliability. The results of an independent occlusion study of two IVIS tasks are compared with predictions made by a HCI expert trained in the application of the extended KLM. Error rates for this study were equally low, leading to the conclusion that the extended KLM appears reliable, though further studies are required. It is concluded that the extended-KLM technique is a valid, reliable and economical method for assessing the visual demand of IVIS tasks. In contrast to many user-trial methods, the technique can be applied in early design stages. In addition, future work areas are identified, which could serve to further enhance the validity, reliability and economy of the technique. These include, automating the extended KLM procedure with a software tool, and, the development of new cognitive and physical operators, and new assumptions, specific to IVIS and/or occlusion conditions. For example, it will be useful to develop new cognitive operators that consider the time taken to visually reorient to complex displays following occluded periods

Immunohistochemical analysis indicates that the anatomical location of B-cell non-Hodgkin's lymphoma is determined by differentially expressed chemokine receptors, sphingosine-1-phosphate receptors and integrins.

BackgroundThe aim of this study was to elucidate the mechanisms responsible for the location of B-cell non-Hodgkin's lymphoma (B-NHL) at different anatomical sites. We speculated that the malignant B cells in these disorders have the potential for trafficking between blood and secondary lymphoid organs (SLO) or extranodal sites and that their preferential accumulation at different locations is governed by the expression of key molecules that regulate the trafficking of normal lymphocytes.MethodsBiopsy or blood samples from 91 cases of B-NHL affecting SLO (n = 27), ocular adnexae (n = 51) or blood (n = 13) were analysed by immunohistochemistry or flow cytometry for the expression of the following molecules: CCR7, CCL21 and αL (required for the entry of normal lymphocytes into SLO); CXCR4, CXCL12 and α4 (required for entry into extranodal sites); CXCR5, CXCL13 and S1PR2 (required for tissue retention); S1PR1 and S1PR3 (required for egress into the blood). The expression of each of these molecules was then related to anatomical location and histological subtype.ResultsThe expression of motility/adhesion molecules varied widely between individual patient samples and correlated much more strongly with anatomical location than with histological subtype. SLO lymphomas [comprising 10 follicular lymphoma (FL), 8 diffuse large B-cell lymphoma (DLBCL), 4 mantle-cell lymphoma (MCL) and 5 marginal-zone lymphoma (MZL)] were characterised by pronounced over-expression of S1PR2, suggesting that the malignant cells in these lymphomas are actively retained at the site of clonal expansion. In contrast, the malignant B cells in ocular adnexal lymphomas (10 FL, 9 DLBCL, 4 MCL and 28 MZL) expressed a profile of molecules suggesting a dynamic process of trafficking involving not only tissue retention but also egress via S1PR3 and homing back to extranodal sites via CXCR4/CXCL12 and α4. Finally, leukaemic lymphomas (6 FL, 5 MCL and 2 MZL) were characterised by aberrant expression of the egress receptor S1PR1 and low expression of molecules required for tissue entry/retention.ConclusionsIn summary, our study strongly suggests that anatomical location in B-NHL is governed by the differential expression of specific adhesion/motility molecules. This novel observation has important implications for therapeutic strategies that aim to disrupt protective micro-environmental interactions