Minimal residual disease monitoring in multiple myeloma: a comparison between allelic-specific oligonucleotide real-time quantitative polymerase chain reaction and flow cytometry.

BACKGROUND AND OBJECTIVES: Minimal residual disease (MRD) studies are useful in multiple myeloma (MM). However, the definition of the best technique and clinical utility are still unresolved issues. The aim of this study was to analyze and compare the clinical utility of MRD studies in MM with two different techniques: allelic-specific oligonucleotide real-time quantitative PCR (ASO-RQ-PCR), and flow cytometry (FCM). DESIGN AND METHODS: Bone marrow samples from 32 MM patients who had achieved complete response after transplantation were evaluated by ASO-RQ-PCR, using TaqMan technology, and multiparametric FCM. RESULTS: ASO-RQ-PCR was only applicable in 75% of patients for a variety of technical reasons, while FCM was applicable in up to 90%. Therefore, simultaneous PCR/FCM analysis was possible in only 24 patients. The number of residual tumor cells identified by both techniques was very similar (mean=0.29%, range=0.001-1.61%, correlation coefficient=0.861). However, RQ-PCR was able to detect residual myelomatous cells in 17 patients while FCM only did so in 11; thus, 6 cases were FCM negative but PCR positive, all of them displaying a very low number of clonal cells (median=0.014%, range=0.001-0.11). Using an MRD threshold of 0.01% (10(-4)) two risk groups with significantly different progression-free survival could be identified by either PCR (34 vs. 15m, p=0.04) or FCM (27 vs. 10m, p=0.05). INTERPRETATION AND CONCLUSIONS: Although MRD evaluation by ASO-RQ-PCR is slightly more sensitive and specific than FCM, it is applicable in a lower proportion of MM patients and is more time-consuming, while both techniques provide similar prognostic information.

Episodic Future Thinking in 4-Year-Olds, Poster Symposium: The who, what, where and when of episodic foresight development

The ability to project oneself into the future to pre-experience an event is referred to as episodic future thinking (Atance & O’Neill, 2001). Only a relatively small number of studies have attempted to measure this ability in pre-school aged children (Atance & Meltzoff, 2005; Busby & Suddendorf, 2005ab, 2010; Russell, Alexis, & Clayton, 2010).Perhaps the most successful method is that used by Russell et al (2010). In this task, 3- to 5-year-olds played a game of blow football on one end of a table. After this children were asked to select tools that would enable them to play the same game tomorrow from the opposite, unreachable, side of the table. Results indicated that only 5-year-olds were capable of selecting the right objects for future use more often than would be expected by chance. Above-chance performance was observed in this older group even though most children failed the task because there was a low probability of selecting the correct 2 objects from a choice of 6 by chance.This study aimed to identify the age at which children begin to consistently pass this type of task. Three different tasks were designed in which children played a game on one side of a table, and then were asked to choose a tool to play a similar game on the other side of the table the next day. For example, children used a toy fishing rod to catch magnetic fish on one side of the table; playing the same game from the other side of the table required a different type of fishing rod. At test, children chose between just 2 objects: the tool they had already used, which would not work on the other side, and a different tool that they had not used before but which was suitable for the other side of the table. Experiment 1: Forty-eight 4-year-olds (M = 53.6 months, SD = 2.9) took part. These children were assigned to one of two conditions: a control condition (present-self) where the key test questions were asked in the present tense and an experimental condition (future-self) where the questions were in the future tense. Surprisingly, the results showed that both groups of 4-year-olds selected the correct tool at above chance levels (Table 1 shows the mean number of correct answers out of three). However, the children could see the apparatus when they answered the test questions and so perhaps answered them correctly without imagining the future. Experiment 2: Twenty-four 4-year-olds (M = 53.7, SD = 3.1) participated. Pre-schoolers in this study experienced one condition: future-self looking-away. In this condition children were asked to turn their backs to the games when answering the test questions, which were in the future tense. Children again performed above chance levels on all three games.Contrary to the findings of Russell et al. (2010), our results suggest that episodic future thinking skills could be present in 4-year-olds, assuming that this is what is measured by the tasks. Table 1. Mean number of correct answers across the three games in Experiments 1 and 2Experimental Conditions (N=24 in each condition)Mean CorrectStandardDeviationStatistical SignificanceExp. 1 (present-self, look) – 2 items2.750.68p < 0.001Exp. 1 (future-self, look) – 2 items 2.790.42p < 0.001Exp. 2 (future-self, away) – 2 items 2.330.64p < 0.001Exp. 3 (future-self away) – 3 items1.210.98p = 0.157

Intraclonal heterogeneity and distinct molecular mechanisms characterize the development of t(4;14) and t(11;14) myeloma.

We have used whole exome sequencing to compare a group of presentation t(4;14) with t(11;14) cases of myeloma to define the mutational landscape. Each case was characterized by a median of 24.5 exonic nonsynonymous single-nucleotide variations, and there was a consistently higher number of mutations in the t(4;14) group, but this number did not reach statistical significance. We show that the transition and transversion rates in the 2 subgroups are similar, suggesting that there was no specific mechanism leading to mutation differentiating the 2 groups. Only 3% of mutations were seen in both groups, and recurrently mutated genes include NRAS, KRAS, BRAF, and DIS3 as well as DNAH5, a member of the axonemal dynein family. The pattern of mutation in each group was distinct, with the t(4;14) group being characterized by deregulation of chromatin organization, actin filament, and microfilament movement. Recurrent RAS pathway mutations identified subclonal heterogeneity at a mutational level in both groups, with mutations being present as either dominant or minor subclones. The presence of subclonal diversity was confirmed at a single-cell level using other tumor-acquired mutations. These results are consistent with a distinct molecular pathogenesis underlying each subgroup and have important impacts on targeted treatment strategies. The Medical Research Council Myeloma IX trial is registered under ISRCTN68454111.

A randomized controlled trial of an early-intervention, computer-based literacy program to boost phonological skills in 4- to 6-year-old children

Background: Many school-based interventions are being delivered in the absence of evidence of effectiveness (Snowling & Hulme, 2011, Br. J. Educ. Psychol., 81, 1).Aim: This study sought to address this oversight by evaluating the effectiveness of the commonly used the Lexia Reading Core5 intervention, with 4- to 6-year-old pupils in Northern Ireland.Sample: A total of 126 primary school pupils in year 1 and year 2 were screened on the Phonological Assessment Battery 2nd Edition (PhAB-2). Children were recruited from the equivalent year groups to Reception and Year 1 in England and Wales, and Pre-kindergarten and Kindergarten in North America.
Methods: A total of 98 below-average pupils were randomized (T0) to either an 8-week block (inline image = 647.51 min, SD = 158.21) of daily access to Lexia Reading Core5 (n = 49) or a waiting-list control group (n = 49). Assessment of phonological skills was completed at post-intervention (T1) and at 2-month follow-up (T2) for the intervention group only.
Results: Analysis of covariance which controlled for baseline scores found that the Lexia Reading Core5 intervention group made significantly greater gains in blending, F(1, 95) = 6.50, p = .012, partial η2 = .064 (small effect size) and non-word reading, F(1, 95) = 7.20, p = .009, partial η2 = .070 (small effect size). Analysis of the 2-month follow-up of the intervention group found that all group treatment gains were maintained. However, improvements were not uniform among the intervention group with 35% failing to make progress despite access to support. Post-hoc analysis revealed that higher T0 phonological working memory scores predicted improvements made in phonological skills.
Conclusions: An early-intervention, computer-based literacy program can be effective in boosting the phonological skills of 4- to 6-year-olds, particularly if these literacy difficulties are not linked to phonological working memory deficits.