Citations

Summary: This revision to the EEG Guidelines is an update incorporating current EEG technology and practice. “Standards of practice in clinical electroencephalography” (previously Guideline 4) has been removed. It is currently undergoing revision through collaboration among multiple medical societies and will become part of “Qualifications and Responsibilities of Personnel Performing and Interpreting Clinical Neurophysiology Procedures.” The remaining guidelines are reordered and renumbered.

AbstractBackgroundGlioblastoma (GBM) exhibits profound intratumoral genetic heterogeneity. Each tumor comprises multiple genetically distinct clonal populations with different therapeutic sensitivities. This has implications for targeted therapy and genetically informed paradigms. Contrast-enhanced (CE)-MRI and conventional sampling techniques have failed to resolve this heterogeneity, particularly for nonenhancing tumor populations. This study explores the feasibility of using multiparametric MRI and texture analysis to characterize regional genetic heterogeneity throughout MRI-enhancing and nonenhancing tumor segments.MethodsWe collected multiple image-guided biopsies from primary GBM patients throughout regions of enhancement (ENH) and nonenhancing parenchyma (so called brain-around-tumor, [BAT]). For each biopsy, we analyzed DNA copy number variants for core GBM driver genes reported by The Cancer Genome Atlas. We co-registered biopsy locations with MRI and texture maps to correlate regional genetic status with spatially matched imaging measurements. We also built multivariate predictive decision-tree models for each GBM driver gene and validated accuracies using leave-one-out-cross-validation (LOOCV).ResultsWe collected 48 biopsies (13 tumors) and identified significant imaging correlations (univariate analysis) for 6 driver genes: EGFR, PDGFRA, PTEN, CDKN2A, RB1, and TP53. Predictive model accuracies (on LOOCV) varied by driver gene of interest. Highest accuracies were observed for PDGFRA (77.1%), EGFR (75%), CDKN2A (87.5%), and RB1 (87.5%), while lowest accuracy was observed in TP53 (37.5%). Models for 4 driver genes (EGFR, RB1, CDKN2A, and PTEN) showed higher accuracy in BAT samples (n = 16) compared with those from ENH segments (n = 32).ConclusionMRI and texture analysis can help characterize regional genetic heterogeneity, which offers potential diagnostic value under the paradigm of individualized oncology.

SummarySomatic mutation of the DNMT3A gene at the arginine R882 site is common in acute myeloid leukaemia (AML). The prognostic significance of DNMT3A R882 mutation clearance, using traditional diagnostic next generation sequencing (NGS) methods, during complete remission (CR) in AML patients is controversial. We examined the impact of clearing DNMT3A R882 mutations at diagnosis to the detectable threshold of ˂3% during CR on outcome in 56 adult AML patients. Mutational remission, defined as clearance of pre‐treatment DNMT3A R882 and all other AML‐associated mutations to a variant allele frequency ˂3%, occurred in 14 patients whereas persistent DNMT3A R882 mutations were observed in 42 patients. There were no significant differences in disease‐free or overall survival between patients with and without DNMT3A R882 mutation clearance. Patients with persistent DNMT3A R882 who cleared all other AML mutations and did not acquire new mutations (n = 30), trended towards longer disease‐free survival (1·6 vs. 0·6 years, P = 0·06) than patients with persistence of DNMT3A R882, in addition to other mutations or acquisition of new AML‐associated mutations, such as those in TET2, JAK2, ASXL1 and TP53 (n = 12). These data demonstrate that DNMT3A R882 mutations, as assessed by traditional NGS methods, persist in the majority of AML patients in CR.

This study describes a novel technique for the preoperative surgical planning for an osteoarticular medial femoral condyle (MFC) graft to replace the proximal pole of a scaphoid. In cases of proximal pole scaphoid nonunion or in Preiser disease, fragmentation of the articular surface can occur, leading to significant pain and disability. Osteoarticular MFC bone grafting can be used to treat these injuries by providing a vascularized osteoarticular surface. Using 3-dimensional imaging and printing we are able to precisely model the injured scaphoid, and also accurately plan the harvest of MFC osteoarticular graft. This technique allows for accurate preoperative planning of a complex 3-dimensional bone, and has improved our execution of the plan intraoperatively.

Abstract Introduction: A and T are associated with the development of cardiac dysfunction. The kinetics of cardiac biomarkers early after A or T treatment (Rx) is undefined. Methods: We studied hs-TnT (detection limit: 3 ng/ml, myocardial infarction threshold 14 ng/ml) and nt-proBNP (detection limit: 5 pg/ml) levels just prior to (baseline), and on days +1, +2, +3 and +7 during the first and second cycle in breast cancer pts treated with A (n = 11) or T (n = 11). Baseline and peak values for each cycle, baseline to baseline, peak to peak, time to peak, and baseline corrected area under the curve (AUC) were calculated. Study No. NCT01771549 Results: Group (grp) A pts were younger, 51 ± 18 years, than T grp pts, 60 ± 13 years. Three pts in A grp and 4 pts in T grp used antihypertensives. Baseline ejection fraction (EF) was 52-68% (A grp) and 56-69% (T grp). Hs-TnT was undetectable in 5/11 A grp, and 2/11 T grp pts at baseline. By cycle 2 day +1, all A pts had a detectable level of hs-TnT (p = 0.03) compared to 7/11 T pts. Median time to peak level for hs-TnT was 1.5 days for the A grp and 1.2 days for the T grp (NS). In the A grp, significant transient increase in nt-proBNP were also seen (Table). In the T grp, a significant rise in nt-proBNP was not seen in cycle 1 but was seen on cycle 2 day +1 and cycle 2 peak. AUC values were positive for hs-TnT in A pts but not in T pts, and were positive for nt-proBTNP for both A and T. Only 1 pt in A grp had symptomatic EF decline (47%) three months from start of A. None of T grp pts had EF decline. Conclusion: A, but not T was associated with increase in pre-Rx (cycle 2 only), peak, and AUC hs-TnT levels for cycles 1 and 2 with peak values occurring 1.5 days post-Rx. This study evaluating serial kinetics of cardiac biomarker in pts receiving A or T therapy, suggests that assessment of pre- and day +2 post-Rx values could be a means of quantifying cumulative myocardial injury over the chemotherapy course. *Roche Diagnostics Corp, Indianapolis, IN provided assay reagent kits. hs-TnT, ng/mlA, cycle 1A, cycle 2P-valT, cycle 1T, cycle 2P-valBaseline4.69.3<0.0027.75.0NSPeak9.6**16.1†<0.0028.06.8NSTime to peak, days1.61.5NS1.11.3NSAUC above baseline7.1±13.427±19<0.001-1.4±7.2-5±17NSnt-proBNP, pg/mlA, cycle 1A, cycle 2P-valT, cycle 1T, cycle 2P-valBaseline9490NS12480NSPeak361*359*NS209206†NSTime to peak, days1.81.9NS2.21.8NSAUC above baseline423499NS78**-32**<0.5*p<0.001,† p ≤0.01††p = 0.002NS = statistically non-significant (p>0.05)**p<0.03 Citation Format: Pooja Advani, Jonathan Hoyne, Alvaro Moreno-Aspitia, Marcia Dubin, Shelly Brock, Caroline Harlow, Tammy Wollett, Saranya Chumsri, Joseph Blackshear. A prospective pilot study of kinetics of high sensitivity troponin T (hs-TnT) and amino terminal (nt-proBNP) in breast cancer patients (pts) treated with doxorubicin (A) or trastuzumab (T). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3930.

Abstract Earlier reports indicated that the role of Nf1 tumor suppressor gene in limiting sympathoadrenal cell growth during embryologic development is independent of its ability to down-modulate RAS-MAPK signaling. This finding raised the question of whether neuroblastoma pathogenesis was also accelerated by loss of a similar non-canonical function of NF1. To elucidate how loss of the NF1 tumor suppressor gene contributes to the development of high-risk neuroblastoma, we relied on a transgenic zebrafish model that overexpresses MYCN and harbors loss-of-function nf1 mutations. We show here that loss of nf1 leads to aberrant activation of RAS signaling in MYCN-induced neuroblastoma, promoting both increased tumor cell survival and rapid tumor cell proliferation. We demonstrate further that the GTPase-activating protein (GAP) activity of the (GAP)-related domain (GRD) is sufficient to suppress accelerated initiation of neuroblastoma in nf1-deficient zebrafish, even though this transgene is unable to restrict abnormal sympathoadrenal cell growth during embryologic development. Hence NF1 exhibits different activities in vivo in the normal development and tumorigenesis of the peripheral sympathetic nervous system. Our findings establish nf1-deficient zebrafish that overexpress MYCN as an ideal animal model system for investigating new strategies to improve treatment of very high risk neuroblastomas with aberrant RAS-MAPK activation. We are currently performing high-throughput in vivo drug analysis using these zebrafish with primary tumors. Citation Format: Shuning He, Marc R. Mansour, Mark W. Zimmerman, Dong Hyuk Ki, Hillary M. Layden, Koshi Akahane, Eric D. de Groh, Antonio R. Perez-Atayde, Shizhen Zhu, Jonathan A. Epstein, A Thomas Look. Synergy between loss of NF1 and overexpression of MYCN in neuroblastoma is mediated by the GAP-related domain. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2456.

Abstract Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10−8 seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type–specific expression quantitative trait locus and enhancer–gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10−5 in the three-cancer meta-analysis. Significance: We demonstrate that combining large-scale GWA meta-analysis findings across cancer types can identify completely new risk loci common to breast, ovarian, and prostate cancers. We show that the identification of such cross-cancer risk loci has the potential to shed new light on the shared biology underlying these hormone-related cancers. Cancer Discov; 6(9); 1052–67. ©2016 AACR. This article is highlighted in the In This Issue feature, p. 932

BACKGROUNDProspective quality metrics for neck dissection have not been established for patients with head and neck squamous cell carcinoma. The purpose of this study was to investigate the association between lymph node counts from neck dissection, local‐regional recurrence, and overall survival.METHODSThe number of lymph nodes counted from neck dissection in patients treated in 2 NRG Oncology trials (Radiation Therapy Oncology Group [RTOG] 9501 and RTOG 0234) was evaluated for its prognostic impact on overall survival with a multivariate Cox model adjusted for demographic, tumor, and lymph node data and stratified by the postoperative treatment group.RESULTSFive hundred seventy‐two patients were analyzed at a median follow‐up of 8 years. Ninety‐eight percent of the patients were pathologically N+. The median numbers of lymph nodes recorded on the left and right sides were 24 and 25, respectively. The identification of fewer than 18 nodes was associated with worse overall survival in comparison with 18 or more nodes (hazard ratio [HR], 1.38; 95% confidence interval [CI], 1.09‐1.74; P = .007). The difference appeared to be driven by local‐regional failure (HR, 1.46; 95% CI, 1.02‐2.08; P = .04) but not by distant metastases (HR, 1.08; 95% CI, 0.77‐1.53; P = .65). When the analysis was limited to NRG Oncology RTOG 0234 patients, adding the p16 status to the model did not affect the HR for dissected nodes, and the effect of nodes did not differ with the p16 status.CONCLUSIONSThe removal and identification of 18 or more lymph nodes was associated with improved overall survival and lower rates of local‐regional failure, and this should be further evaluated as a measure of quality in neck dissections for mucosal squamous cell carcinoma. Cancer 2016;122:3464–71. © 2016 American Cancer Society.