Citations

Single-cell diversity in the brain The cells that make up an organism may all start from one genome, but somatic mutations mean that somewhere along the line of development, an organism's individual cellular genomes diverge. McConnell et al. review the implications and causes of single-cell genomic diversity for brain function. Somatic mutations caused by mobile genetic elements or errors in DNA repair may underlie certain neuropsychiatric disorders. Science , this issue p. eaal1641

Abstract Background: DNA methylation is a promising prognostic and predictive biomarker of response to treatment in advanced breast cancer (Fackler MJ. Can Res 2014). We evaluated whether baseline and change in tissue and serum methylation would predict pathological complete response (pCR) in patients with HER2-negative early breast cancer treated with PST. Methods: TBCRC008 was a multicenter placebo-controlled trial that investigated pCR (no invasive cancer in breast/axilla) following 12 weeks of preoperative carboplatin and albumin-bound paclitaxel with or without the histone deacetylase (HDAC) inhibitor vorinostat in 62 patients with HER2-negative breast cancer. We performed an exploratory planned biomarker study correlating baseline and change (D15) in tumor tissue and serum methylation with pCR. Methylation was measured using cumulative methylation index (CMI) in quantitative multiplexed methylation-specific polymerase chain reaction (QM-MSP) assays; cMethDNA assay for serum (Fackler MJ. Can Res 2014) and QM-MSP for tissue (Fackler MJ. Can Res 2004). The analysis population included all patients with available methylation and pCR data. Association between CMI level (log transformed baseline, D15, change) and pCR was evaluated using univariate as well as multivariable logistic regression models controlling for treatment arm and estrogen receptor (ER) status. Additional subgroup analyses assessed association of CMI level with pCR stratified by ER status and treatment arms, respectively. Spearman's correlation coefficient was performed to evaluate the correlation between tissue and serum CMI. Results: pCR data were available for 61 of 62 patients. One patient with unknown response was treated as a non-responder. The pCR rate was similar in both arms (vorinostat 25.8%, placebo 29%). Both tissue and serum CMI data were available in 55 (baseline), 50 (D15) and 46 (change) patients. Elevated serum methylation based on a predefined threshold (6.9 units) was identified in 23/59 (39%) patients. In univariate analysis, one log unit increase in tissue CMI levels at D15 was associated with a 40% lower chance of obtaining a pCR (odds ratio, OR=0.60, 95% CI 0.37-0.97; p=0.037). The multivariable analysis did not show a statistically significant association of tissue or serum CMI with pCR, although a similar trend in magnitude towards association with pCR was observed for D15 and change in tumor tissue CMI (OR 0.67 and 0.57, p=0.129 and 0.147 respectively). Subgroup analyses suggested a significant association between tissue CMI levels at D15 and pCR in the group treated with vorinostat [tissue OR: 0.44 (0.20, 0.93), p=0.03; serum OR 0.37 (0.13, 1.07), p=0.07] but not in the placebo group. No significant correlation was observed between tissue and serum CMI. Conclusion: This is the first study to evaluate the predictive role of tissue and serum methylation (CMI) in patients with early breast cancer treated with PST ± an HDAC inhibitor. Methylation was detected more frequently in tissue than serum. Tissue CMI levels at D15 may predict poor response to this regimen. Further evaluation of the predictive role of methylation in early breast cancer is warranted. Citation Format: Connolly RM, Fackler MJ, Zhang Z, Zhou XC, Goetz MP, Boughey JC, Walsh B, Carpenter J, Storniolo AM, Watkins S, Barielson E, Sukumar S, Stearns V. Tumor and serum DNA methylation in women receiving preoperative chemotherapy (PST) with or without vorinostat in primary operable HER2-negative breast cancer in TBCRC008 [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-09-15.

175 Background: Inactivity is common in breast cancer survivors and has been linked to poor outcomes. Few trials have tested physical activity (PA) interventions in young women with breast cancer, who may face unique PA barriers due to demands of jobs and young families. Methods: Young and Strong was a cluster-randomized study evaluating the effect of education interventions for young breast cancer survivors.Sites were randomized 1:1 to a young women’s intervention (YWI), focused on fertility and other issues facing young women, or to a physical activity intervention (PAI). At PAI sites, providers were instructed to discuss PA with patients, and participants were given materials to encourage PA. PA was measured with the modified Godin Leisure Score Index at baseline, and 3, 6, and 12 months. Medical records were reviewed to assess provider attention to PA. Changes in weekly min of PA were compared between the PAI and YWI groups using general estimating equations to evaluate clustered binary and Gaussian data. Results: 467 patients enrolled between 7/12 -12/13 across 54 sites. Median age at dx was 40yrs (range 22-45). At baseline, participants were moderately active. PA increased in both groups over time (Table); there was no significant difference in PA between groups at any time (all p > 0.1). Provider attention to PA was documented in 74% of participants on PAI and 61% on YWI (p = 0.15), and correlated with PA at 12 months (median 100 min/wk of PA in participants with provider attention to PA vs. 60 min/wk in those without, p = 0.016). Participants who reported reading all or most the PAI materials reported higher levels of PA vs. those who read less (78% vs. 64%, p = 0.05) Conclusions: Young breast cancer survivors assigned to a PA intervention did not increase PA more than those assigned to an intervention focused on young women’s issues. However, the higher levels of PA among women who engaged with the PAI materials and those whose oncology providers addressed PA suggests the importance of enhancing patient and provider engagement with healthy lifestyle information and recommendations. Clinical trial information: NCT01647607. [Table: see text]

AbstractBackgroundGlobicatella sanguinis is an uncommon pathogen that may be misdiagnosed as viridans group streptococci. We review the literature of Globicatella and report 2 clinical cases in which catalase-negative Gram-positive cocci resembling viridans group streptococci with elevated minimum inhibitory concentrations (MICs) to ceftriaxone were inconsistently identified phenotypically, with further molecular characterization and ultimate identification of G sanguinis.MethodsTwo clinical strains (from 2 obese women; 1 with a prosthetic hip infection and the other with bacteremia) were analyzed with standard identification methods, followed by matrix-assisted laser desorption ionization time-of-flight mass spectrometry, 16S recombinant ribonucleic acid (rRNA), and sodA polymerase chain reaction (PCR). The existing medical literature on Globicatella also was reviewed.ResultsStandard phenotypic methods failed to consistently identify the isolates. 16S PCR yielded sequences that confirmed Globicatella species. sodA sequencing provided species-level identification of G sanguinis. The review of literature reveals G sanguinis as an increasingly reported cause of infections of the urine, meninges, and blood. To our knowledge, this is the first reported case of an orthopedic infection caused by Globicatella sanguinis. A review of the 37 known cases of G sanguinis infection revealed that 83% of patients are female, and 89% are at the extremes of age (<5 or >65 years).ConclusionsGlobicatella sanguinis, an uncommon pathogen with elevated minimum inhibitory concentrations to third-generation cephalosporins, is difficult to identify by phenotypic methods and typically causes infections in females at the extremes of age. It may colonize skin or mucosal surfaces. Advanced molecular techniques utilizing 16S rRNA with sodA PCR accurately identify G sanguinis.