Integrated analysis of RNA and DNA from the phase III trial CALGB 40601 identifies predictors of response to trastuzumab-based neoadjuvant chemotherapy in HER2-positive breast cancer

Purpose: Response to a complex trastuzumab-based regimen is affected by multiple features of the tumor and its microenvironment. Developing a predictive algorithm is key to optimizing HER2-targeting therapy. Experimental Design: We analyzed 137 pretreatment tumors with mRNA-seq and DNA exome sequencing from CALGB 40601, a neoadjuvant phase III trial of paclitaxel plus trastuzumab with or without lapatinib in stage II to III HER2-positive breast cancer. We adopted an Elastic Net regularized regression approach that controls for covarying features within high-dimensional data. First, we applied 517 known gene expression signatures to develop an Elastic Net model to predict pCR, which we validated on 143 samples from four independent trials. Next, we performed integrative analyses incorporating clinicopathologic information with somatic mutation status, DNA copy number alterations (CNA), and gene signatures. Results: The Elastic Net model using only gene signatures predicted pCR in the validation sets (AUC ¼ 0.76). Integrative analyses showed that models containing gene signatures, clinical features, and DNA information were better pCR predictors than models containing a single data type. Frequently selected variables from the multiplatform models included amplifications of chromosome 6p, TP53 mutation, HER2-enriched subtype, and immune signatures. Variables predicting resistance included Luminal/ERþ features. Conclusions: Models using RNA only, as well as integrated RNA and DNA models, can predict pCR with improved accuracy over clinical variables. Somatic DNA alterations (mutation, CNAs), tumor molecular subtype (HER2E, Luminal), and the microenvironment (immune cells) were independent predictors of response to trastuzumab and paclitaxel-based regimens. This highlights the complexity of predicting response in HER2-positive breast cancer

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Long-interval facilitation and inhibition are differentially affected by conditioning stimulus intensity over different time courses

Intracortical facilitatory and inhibitory processes in the primary motor cortex (M1) play an important role in both the preparation and execution of motor tasks. Here we aimed to (1) confirm the existence of, and further characterise, intracortical facilitation at long conditioning-test stimulus intervals at subthreshold conditioning stimulus (CS) intensities and (2) identify the threshold for long-interval intracortical inhibition (LICI) at different inter-stimulus intervals (ISIs). To examine facilitation, stimulus-response curves at ISIs of 100 and 150 ms were obtained using a range of subthreshold CS intensities. LICI stimulus-response curves were also obtained using varying CS intensities at ISIs of 100 (LICI100) and 150 ms (LICI150). Facilitation of the conditioned MEP was observed at subthreshold CS intensities at an ISI of 100 ms. LICI100 was observed at a lower CS intensity than LICI150. First, we provide evidence of a long-interval facilitation and provide some evidence consistent with a cortical origin of this facilitation. Second, the lower threshold for evoking LICI100 than LICI150 suggests an intensity-duration effect whereby a more intense CS results in longer duration LICI. Investigation of the interaction between LICI and long-interval facilitation might help to elucidate the functional importance of these processes

Cognitive abilities in preterm and term-born adolescents

Objective To investigate the influence of a range of prenatal and postnatal factors on cognitive development in preterm and term-born adolescents. Study design Woodcock-Johnson III Tests of Cognitive Abilities were used to assess general intellectual ability and 6 broad cognitive abilities in 145 young adolescents aged approximately 12.5 years and born 25-41 weeks gestational age (GA). To study potential links between neurophysiologic and cognitive outcomes, corticomotor excitability was measured using transcranial magnetic stimulation and surface electromyography. The influence of various prenatal and postnatal factors on cognitive development was investigated using relative importance regression modeling. Results Adolescents with greater GA tended to have better cognitive abilities (particularly general intellectual abil- ity, working memory, and cognitive efficiency) and higher corticomotor excitability. Corticomotor excitability ex- plained a higher proportion of the variance in cognitive outcome than GA. But the strongest predictors of cognitive outcome were combinations of prenatal and postnatal factors, particularly degree of social disadvantage at the time of birth, birthweight percentile, and height at assessment.Conclusions In otherwise neurologically healthy adolescents, GA accounts for little interindividual variability in cognitive abilities. The association between corticomotor excitability and cognitive performance suggests that reduced connectivity, potentially associated with brain microstructural abnormalities, may contribute to cognitive deficits in preterm children. It remains to be determined if the effects of low GA on cognitive outcomes attenuate over childhood in favor of a concomitant increase in the relative importance of heritability, or alternatively, if cognitive development is more heavily influenced by the quality of the postnatal environment. (J Pediatr 2014;165:170-7) .Luke A. Schneider, Nicholas R. Burns, Lynne C. Giles, Ryan D. Higgins, Theodore J. Nettelbeck, Michael C. Ridding, and Julia B. Pitche

Conduits Mediate Transport of Low-Molecular-Weight Antigen to Lymph Node Follicles

SummaryTo track drainage of lymph-borne small and large antigens (Ags) into the peripheral lymph nodes and subsequent encounter by B cells and follicular dendritic cells, we used the approach of multiphoton intravital microscopy. We find a system of conduits that extend into the follicles and mediate delivery of small antigens to cognate B cells and follicular dendritic cells. The follicular conduits provide an efficient and rapid mechanism for delivery of small antigens and chemokines such as CXCL13 to B cells that directly contact the conduits. By contrast, large antigens were bound by subcapsular sinus macrophages and subsequently transferred to follicular B cells as previously reported. In summary, the findings identify a unique pathway for the channeling of small lymph-borne antigens and chemoattractants from the subcapsular sinus directly to the B cell follicles. This pathway could be used for enhancing delivery of vaccines or small molecules for improvement of humoral immunity

A comparison of two methods for estimating 50% of the maximal motor evoked potential

OBJECTIVES: Two commonly-used methods for setting stimulus intensities in transcranial magnetic brain stimulation studies were compared to determine which best approximated a motor evoked potential (MEP) of 50% of the maximal MEP amplitude (SI50); a suprathreshold intensity relative to resting motor threshold (rMT) or adjusting the intensity to evoke an MEP amplitude of 1mV. METHODS: Corticomotor stimulus-response curves and rMT for the right first dorsal interosseous (FDI) muscle of 176 subjects (aged 10-74years) were retrospectively analysed. RESULTS: Regardless of subject age or sex, SI50 occurred at 127.5+/-11.3% rMT. Except in young children, MEPs of 1mV were significantly smaller than those evoked at SI50. CONCLUSIONS: In the inactive FDI muscle, a stimulus intensity of 127-128% rMT consistently gives the best approximation of SI50 in most subjects, except perhaps young children. SIGNIFICANCE: Setting TMS stimulus intensities relative to rMT provides a less variable inter-subject comparator, with respect to individual differences in corticomotor input-output characteristics, than adjusting the stimulator output to give an absolute MEP magnitude

PAM50 gene signatures and breast cancer prognosis with adjuvant anthracycline-and taxane-based chemotherapy: Correlative analysis of C9741 (alliance)

PAM50 intrinsic breast cancer subtypes are prognostic independent of standard clinicopathologic factors. CALGB 9741 demonstrated improved recurrence-free (RFS) and overall survival (OS) with 2-weekly dose-dense (DD) versus 3-weekly therapy. A significant interaction between intrinsic subtypes and DD-therapy benefit was hypothesized. Suitable tumor samples were available from 1,471 (73%) of 2,005 subjects. Multiplexed gene-expression profiling generated the PAM50 subtype call, proliferation score, and risk of recurrence score (ROR-PT) for the evaluable subset of 1,311 treated patients. The interaction between DD-therapy benefit and intrinsic subtype was tested in a Cox proportional hazards model using two-sided alpha = 0.05. Additional multivariable Cox models evaluated the proliferation and ROR-PT scores as continuous measures with selected clinical covariates. Improved outcomes for DD therapy in the evaluable subset mirrored results from the complete data set (RFS; hazard ratio = 1.20; 95% confidence interval = 0.99–1.44) with 12.3-year median follow-up. Intrinsic subtypes were prognostic of RFS (P<0.0001) irrespective of treatment assignment. No subtype-specific treatment effect on RFS was identified (interaction P = 0.44). Proliferation and ROR-PT scores were prognostic for RFS (both P<0.0001), but no association with treatment benefit was seen (P = 0.14 and 0.59, respectively). Results were similar for OS. The prognostic value of PAM50 intrinsic subtype was greater than estrogen receptor/HER2 immunohistochemistry classification. PAM50 gene signatures were highly prognostic but did not predict for improved outcomes with DD anthracycline-and taxane-based therapy. Clinical validation studies will assess the ability of PAM50 and other gene signatures to stratify patients and individualize treatment based on expected risks of distant recurrence