bluuebunny/crossref_metadata_2025_split huggingface dataset:
Re-assessment of surgical breast cancer quality indicators by the Florida Initiative for Quality Cancer Care (FIQCC) consortium.
Authors: Laronga Christine , Gray Jhanelle Elaine , Siegel Erin , Lee Ji-Hyun , Fulp William J. , Jacobsen Paul B. 
Published: February 2017

84 Background: In 2006, the FIQCC (comprised of 11 practice sites) initiated a comprehensive review of quality of care specific to breast cancer based on QOPI/NCCN/ACOS and panel consensus quality indicators. Feedback on indicator performance was provided to participating practices in 2007 to encourage quality improvement efforts. Re-assessment of adherence to the same performance indicators was conducted in 2009. Methods: Chart reviews were conducted for breast cancer patients (pts) seen by a medical oncologist at FIQCC sites in 2006(n=602) and 2009(n=636) Quality indicators included: 1) presence/completeness of pathology report; 2) documentation of surgery type; 3) documentation of sentinel lymph node biopsy (SLNB) and if SLNB positive documentation of a complete axillary node dissection; and 4) mammogram usage post surgery. Statistical comparisons of 2006 and 2009 data were performed using the Pearson chi-square exact test based on Monte Carlo estimation. Results: The median age of pts (99% female) was 60 years (range 24-94). Compared to 2006 data, improvements were made in specimen orientation (69%-2006, 78%-2009; p=0.001) and inking of margins (89%-2006, 96%-2009; p=<0.001). In clinical node negative N0 pts, SLNB was performed in 87%, up from 82%-2006 (p=0.035). Of the pts with a metastatic SLNB, 86% went on to have a complete axillary node dissection, but not statistically significant compared to 79% in 2006 (p=0.10). Compliance continues to be highly variable across practice sites with obtaining a mammogram within 14 months of surgery (79%) (p=0.002); but the range narrowed: 26%-98% (2006) and 56%-92% (2009). Significant variances also continued in 2009 across practice sites for margin orientation (p<0.001), inking of the margins (p=0.04), and performance of SLNB (p<0.001). Conclusions: The FIQCC identified quality improvement needs in multiple aspects of breast cancer care. Improvements in margin orientation/inking, use of SLNB and follow-up mammograms after definitive surgery made over the course of this initiative speak to the benefits of continual re-assessment of adherence to performance indicators to guide quality improvement.
Molecular subtyping using MammaPrint and BluePrint as an outcome predictor in U.S. breast cancer (BC) patients.
Authors: Yao Katharine , Turk Mary , Kaul Karen , Weaver JoEllen , De Snoo Femke , Stork-Sloots Lisette , Cristofanilli Massimo 
Published: February 2017

9 Background: Combined use of MammaPrint and a molecular subtyping profile (BluePrint) identifies disease subgroups with marked differences in long-term outcome and response to neo-adjuvant therapy (Glück SABCS2011). The aim of this study was to evaluate the prognostic value of Molecular Subtyping using MammaPrint and BluePrint in women with early stage BC treated at U.S. institutions following National Comprehensive Cancer Network (NCCN) standard guidelines. Methods: Frozen tumor samples from 180 BC patients (TI-III, N0-Ib) median age 57 years at diagnosis (range 28-89) were suitable for hybridization on full genome array. MammaPrint and BluePrint Molecular Subtypes were determined and survival for Luminal A (MammaPrint Low Risk), Luminal B (MammaPrint High Risk), HER2-type and Basal-type patients was assessed. Patients were treated either with breast conserving therapy or mastectomy with axillary lymph node dissection between 1992 and 2005. The median follow-up is 12.7 years. 71% was ER positive and 20% Her2 positive by IHC/FISH. 58% received adjuvant endocrine therapy (ET) (excluding 13 patients unknown treatment), 64% received adjuvant chemotherapy (CT) (excluding 12 patients unknown treatment) and 33% received both. Results: 61 (34%) Patients with MammaPrint Low Risk/Luminal-type (Luminal A) showed 5-year DFS of 97% (34% received CT and 69% ET) and 50 (28%) patients with MammaPrint High Risk/Luminal-type (Luminal B) had a 5-year DFS of 98% (60% received CT and 68% ET). Patients with BluePrint Basal-type tumors (46 (26%)) had a 5-year DFS of 80% (78% received CT); HER2-type (23 (13%)) had a 5-year DFS of 78% (87% received CT without HER2 targeted therapy). Conclusions: In this retrospective study evaluating 180 US patients with early BC treated according to standard guidelines we showed how combining BluePrint with MammaPrint can detect molecularly defined subgroups of patients who are at high risk of recurrence (HER2 and Basal-type). Furthermore, we confirmed that molecularly defined Luminal type disease is associated with excellent disease-free survival. MammaPrint and BluePrint molecular and prognostic stratification should be prospectively evaluated for therapeutic selection.
Serum proteomics and ingenuity pathway analysis (IPA)-guided discovery of response markers to androgen ablation (AA) in prostate cancer.
Authors: Kohli Manish , Oberg Ann L. , Mahoney Douglas W. , Riska Shaun M , Zhang Yuji , Zenka Roman M. , Sahasrabudhe Deepak M. , Qin Rui , Carlson Rachel , Zhang Sheng 
Published: February 2017

11 Background: Currently there are no serum markers of response to AA. We performed a proteome based analysis of serum from prostate cancer patients, followed by mapping of candidate markers to networks based on known molecular interactions in Ingenuity Knowledge Base (IKB). Methods: Isobaric mass tags for relative and absolute quanititation (iTRAQ) analyzed by reverse-phase liquid chromatography coupled to tandem mass spectrometry (LC/MS/MS) was performed in serum of 3 non-localized prostate cancer cohorts. The first cohort included 15 paired untreated hormone-sensitive “pre AA” and 3-month “post AA” specimens; the second included 10 “early AA failure” (median failure time: 11 months) and the third included 10 “late AA failure” specimens (median failure time: 95 months). Differentially expressed candidate proteins were identified by comparisons of (i) paired pre/post AA proteomes and (ii) post AA proteome with the combined AA failure cohorts at a False Discovery Rate of 0.2. To facilitate biological interpretation of multiple candidates identified in the comparisons, IPA was used. Candidate markers implicated in IPA networks with statistical significance were pursued in a second, independent patient cohort for association with time to AA failure using univariate Cox regression analysis. Results: Median PSA for pre/post AA first cohort were 3.15 and 0.29 ng/ml. Median PSA for the second and third cohorts were 27.3 and 4.3 ng/ml. Between post AA and AA failure cohorts, 149 proteins were differentially expressed. Between early and late AA failure 98 proteins were differentially expressed; 47 proteins were common in both comparisons. Network enrichment analysis of the 47 proteins by IPA identified four interaction networks (p<0.01), one of which highlighted a role for 17-β-estradiol (E1). Gas chromatography used for measuring 3-month post AA initiation serum E1, estrone (E2) and testosterone levels (N=38) detected high E1, E2 levels associated with longer time to AA failure (P=0.07 for E1; P=0.08 for E2) in the independent cohort. Conclusions: A global proteomic analysis identified post AA initiation serum E1, E2 levels as potential response markers, which needs validation.
The lipid metabolome of kidney cancer.
Authors: George Saby , Choi Kyoung-Soo , Miecznikowski Jeff C. , Pili Roberto , Kazim A. Latif 
Published: February 2017

16 Background: The commonest type of kidney cancer is CCRCC. Kidney cancer is known to accumulate lipids and a detailed knowledge of the lipid species present in these tumors could lead to a better understanding of the underlying aberrant metabolic pathways and suggest possible treatment strategies. We attempt to identify the lipidomic profile of CCRCC using a liquid chromatography MS-based approach (LC-MS). Methods: We utilized 6 fresh frozen representative samples of CCRCC and matching non-tumor areas of kidney from nephrectomy samples. Lipids and other non-polar cellular constituents were extracted from both CCRCC and control tissues by methyl-t-butyl ether /methanol. LC-MS based lipid profiling was performed on a Waters Q-ToF Premier MS coupled with Ultra Performance LC. The peak detection and alignment across all chromatograms were performed using the XCMS software (v 1.14.1, Scripps Center for Metabolomics). Statistical comparisons of the intensities of aligned peaks were performed using the XCMS-built-in Welch's t-test. The XCMS data was converted to log2 ratios (normal/tumor) in order to utilize the paired aspect of this data: each patient’s disease tissue was analyzed in conjunction with corresponding normal tissue. Significance was determined by controlling the family wise error rate (FWER) at 0.05 using a Bonferroni adjustment. All computations were performed using the R statistical software and the “limma” package. Results: The outcome of XCMS was converted to a table that contains fold change, p value and mass to charge ratio (m/z) for each peak, its corresponding retention time, and the integrated peak intensities from all samples. Controlling FWER at 0.05 using a Bonferroni scheme, we found eight statistically significant lipids. Preliminary attempts to identify the analytes included use of METLIN (Scripps Center for Metabolomics) and HMDB (Human metabolome database, Genome Alberta and Genome Canada) databases. The identified metabolites included phosphatidylcholines, cholesterol esters and triglycerides, as well as other lipid species. Conclusions: The lipid metabolomic profile varied significantly between CCRCC and control. Further studies are underway to confirm the identities and significance of the lipid species in detail.
Automated large-volume extraction of circulating, cell-free DNA to improve the sensitivity of tumor biomarker detection.
Authors: Nocon Annette , Horlitz Martin , Sprenger-Haussels Markus 
Published: February 2017

19 Background: Because of its low concentration and high degree of fragmentation, the extraction and detection of tumor-derived circulating cell-free DNA (ccfDNA) is technically challenging. An optimized ccfDNA extraction method was developed and evaluated by comparison to an existing extraction protocol running on the QIAsymphony instrument and to a manual reference. Methods: 5mlEDTA plasma from healthy donors (with IRB approval) was processed. ccfDNA was bound to magnetic particles with novel surface chemistry and recovered in 150µl. As an alternative method, the “Virus cell-free 1000 protocol” using the QIAsymphony Virus/Pathogen Midi Kit was modified for the processing of higher sample volumes. ccfDNA was extracted from 4ml plasma and eluted in 90µl. The QIAamp Circulating Nucleic Acid (CNA) Kit served as a reference. ccfDNA yield was quantified by qPCR (66bp within the 18S rDNA). To determine the DNA fragment size-dependent recovery, another qPCR assay was run, quantifying four target sequences of different lengths within the APP gene. 5ml plasma was processed and eluted in 150µl. Results: The mean ccfDNA recovery (18S 66bp target; compared to the QIAamp CNA Kit) was 87% (N=6; +/-46%) for the newly developed automated extraction chemistry and 85% (N=6; +/-8%) for the modified extraction protocol. For the APP assay, ratios between the copy numbers of different target sizes were calculated. The mean ratios were: 67/476bp = 11 (N=12; +/-6.2), 180/476bp = 8.1 (N=12; +/-3.6) and 67/180bp = 1.4 (N=12; +/-0.3). Conclusions: The automated protocol versions led to an overall similar ccfDNA recovery compared to the QIAamp CNA Kit. Using the new extraction chemistry a generally improved recovery of tumor-derived circulating DNA is possible. This improvement leads to a higher sensitivity of tumor biomarker detection, which is, besides a high specificity, very important for the use of tumor biomarkers as non-invasive tool in cancer diagnosis and prognosis. The applications presented here are for research use only. Not for use in diagnostic procedures. This work has received funding from the European Union FP7 Programme under grant agreement no. 222916, SPIDIA project ( www.spidia.eu ).
Pre- and postoperative plasma concentrations of five novel candidate biomarker proteins in patients with high- and low-grade gliomas.
Authors: Holdhoff Matthias , Yovino Susannah G. , Savage William J. , Dulloor Pratima , Grossman Stuart A. , Everett Allen 
Published: February 2017

21 Background: Current imaging techniques are unable to accurately measure tumor burden in gliomas, because they rely on blood-brain barrier (BBB) permeability that is altered following surgery, radiation, steroids, and antiangiogenic therapies. This often leads to misinterpretation of disease status and incorrect clinical decisions. The development of tumor-specific blood-based markers for gliomas is therefore critically important. This study evaluates the detectability of five novel protein biomarker candidates in the plasma of patients with gliomas: neurogranin, ICAM-5, beta-synuclein, brain-derived neurotrophic factor (BDNF), and glial fibrillary acidic protein (GFAP). These biomarker candidates were chosen because of their specificity for brain tissue. Methods: Pre- and postoperative plasma samples were obtained from patients with newly diagnosed gliomas with IRB approval. Plasma concentrations were measured in duplicates using an electrochemiluminescent immunoassay with a lower limit of quantification of >0.04ng/mL (GFAP) and >0.02 ng/mL (other markers). Results: Plasma levels were detectable for all 5 tested markers at baseline and postoperatively. Baseline levels were highly variable and postoperative GFAP levels were much higher than preoperative levels likely related to brain injury (see table). Conclusions: Five potentially useful protein markers have been identified in the plasma of patients with gliomas. Further studies are underway to assess the specificity of each marker and its ability to detect dynamic changes in tumor burden. [Table: see text]
Flow cytometric quantification of surface IGF-1R and intracellular p-AKT, p-S6, and p-ERK in Ewing sarcoma (EWS) cells.
Authors: DuBois Steven G. , Epling C. Lorrie , Tan Alice , Matthay Katherine K. , Sinclair Elizabeth 
Published: February 2017

23 Background: Targeting the IGF-1R pathway has shown preclinical and clinical evidence of activity in EWS. Markers predictive of response to IGF-1R inhibition are required. The aims of the current study were to quantify surface IGF-1R expression and intracellular signaling proteins by flow cytometry. Methods: Flow cytometry for CD99 and CD45 was used to detect bone marrow micrometastatic tumor cells as CD99+CD45- events in patients with localized EWS. Surface IGF-1R was quantified on tumor cells and normal marrow cells using a commercially available antibody. RD-ES EWS cells were spiked into control PBMCs and starved for 1 hour. Cells were then treated with saline control, rapamycin 10 ng/mL, ADW742 5 uM (small molecule IGF-1R inhibitor), or alpha-IR3 0.5 ug/mL (anti-IGF-1R antibody) and levels of pS6, pAKT, and pERK quantified by phospho-flow cytometry 60 minutes later. All results were expressed as the mean fluorescent intensity (MFI) of staining using arbitrary units. Results: We detected bone marrow micrometastatic tumor cells in marrow samples from 16 patients with EWS. We observed heterogeneous levels of IGF-1R tumor cell surface expression between patients (range of IGF-1R MFI = 0 – 3355). IGF-1R levels were higher in CD99+CD45- tumor cells compared to normal marrow cells (mean MFI 840 for CD99+CD45- tumor cells vs.190 for normal marrow cells; p = 0.005). In RD-ES cells spiked into PBMCs, treatment with rapamycin resulted in 1.32 fold increase in pAKT MFI compared to saline control. Treatment with ADW742 or alpha-IR3 did not impact pAKT MFI. Treatment with rapamycin resulted in a 0.52 fold decrease and a 1.20 fold increase in pS6 and pERK, respectively. Treatment with ADW742 or alpha-IR3 each resulted in similar decreases in both pS6 (0.75-0.87 fold) and pERK (0.67-0.82 fold). In PBMCs, modest changes in pS6 in rapamycin treated cells were observed, without changes in pAKT or pERK. Neither ADW742 nor alpha-IR3 modulated pS6, pAKT, or pERK signaling in PBMCs. Conclusions: Flow cytometry detects a range of surface IGF-1R expression on bone marrow micrometastatic EWS cells. Phospho-flow cytometry detects modulation of pAKT, pS6, and pERK in EWS cells treated with IGF-1R or mTOR inhibitors.
BMP9 as a potential biomarker for dalantercept efficacy against ALK1-mediated angiogensis in head and neck cancer.
Authors: Pearsall Scott , Solban Nicolas , Attie Kenneth M. , Sherman Matthew L. , Kumar Ravi 
Published: February 2017

30 Background: Activin receptor-like kinase 1 (ALK1) is a type 1 receptor in the TGF-β superfamily. The ALK1 pathway plays a role in vascular development and pathological angiogenesis. Mutations affecting this pathway result in hereditary hemorrhagic telangiectasia, a disease characterized by failed vascular development and arteriovenous malformations. Therefore, disruption of this pathway in adults may help in conditions with pathological angiogenesis. Bone morphogenetic protein 9 (BMP9) is a ligand that binds with high affinity to ALK1 and stimulates endothelial cell sprouting during vessel maturation. BMP9 is upregulated in the RIP1-Tag2 murine model of vascular invasive carcinoma; treatment with a murine version of dalantercept (RAP-041) can inhibit tumor growth. Methods: Dalantercept (ACE-041) is a soluble receptor protein comprising the extracellular domain of ALK1 linked to an IgG1 Fc region, which functions as a ligand trap to inhibit endogenous BMP9 signaling. Results: In a phase I study of dalantercept in advanced solid tumors, three patients with squamous cell carcinoma of the head and neck (SCCHN) were enrolled. One SCCHN patient received 10 cycles (30 weeks) at 0.4 mg/kg and had a partial response (32.5% decrease in target lesion size). A second SCCHN patient received 11 cycles (33 weeks) at 1.6 mg/kg and had a 28.9% decrease in lesion size. A third SCCHN patient had progressive disease after 1 cycle at 0.8 mg/kg. Dalantercept was generally well-tolerated. Common AEs included fatigue, peripheral edema, nausea, anemia, headache, anorexia, and dyspnea. Analysis of archived tumor samples from SCCHN patients demonstrated that 25% had high BMP9 expression and 44% had medium levels of expression. Conclusions: A phase II study to evaluate the efficacy, safety and pharmacodynamics (PD) of dalantercept in SCCHN is ongoing. The primary objective is ORR. Secondary objectives include PFS, OS, safety, tolerability and pharmacokinetics. Exploratory analyses in this study will examine BMP9 expression in archived and fresh tumor biopsies as well as serum levels of BMP9 and other markers; association of biomarkers with response to therapy will be examined as potential companion diagnostics.
A fully automated capillary western system for absolute quantitation of endogenous PKC proteins: An approach to correlate protein quantity with function.
Authors: Chen Jin-Qiu , Heldman Madeleine , Herrmann Michelle , Kedei Noemi , Blumberg Peter , Goldsmith Paul 
Published: February 2017

31 Background: The human prostate cell line LNCaP and the human myelocytic leukemia cell line U937 differ dramatically in their responses to the two protein kinase C (PKC) targeted ligands phorbol 12-myristate 13-acetate (PMA) and bryostatin 1 and show complex differences in the patterns of transcriptional responses that they induce. Quantitation of relative abundance of individual PKC isoforms in the two cell lines may help to link the downstream effects of the two compounds to these isoforms. Methods: Simple Western is a capillary-based automated Western system recently developed by ProteinSimple. All steps following sample preparation are fully automated in the Simple Western system, including sample loading, size-based protein separation, immunoprobing, washing, detection and data analysis. Simple Western is gel-free and blot-free, uses less amount of samples, and produces highly quantitative, reproducible information that cannot be generated using regular Western assays. Using the Simple Western system, we developed a method for absolute quantitation of endogenous proteins in cell lysates and quantified PKC isoforms in LNCaP and U937 cells. Results: PKC isoforms were measured at levels of picogram or sub-picogram per nanogram cell lysate. PKC delta was identified as the dominant PKC isoforms in both cell lines. In LNCaP cells, PKC delta expression is ~20-fold higher than PKC alpha, ~40-fold higher than PKC epsilon, and at least 20-fold higher than PKC beta. In U937 cells, PKC delta expression is similar to PKC beta, at least 200 fold higher than PKC alpha, and ~50-fold higher than PKC epsilon. Conclusions: The Simple Western system, with its high-quality data quantitation and excellent assay reproducibility, allowed us to detect both the relative abundance of the PKC isoforms and their absolute quantitation in the tested cells. It circumvents the problem that antibodies of different affinities for different proteins yield a misleading impression of relative abundance and it provides an approach to accurately correlate protein quantities with their function.
Elevated pretreatment serum activin A and progression-free and overall survival in trastuzumab-treated metastatic breast cancer.
Authors: Zubritsky Lindsey , Leitzel Kim , Ali Suhail M. , Köstler Wolfgang , Fuchs Eva-Maria , Costa Luis , Knight Robert D. , Laadem Abderrahmane , Sherman Matthew L. , Lipton Allan 
Published: February 2017

38 Background: About half of HER2-positive metastatic breast cancer patients will respond tofirst-line trastuzumab-containing therapy, but most will progress within a year. Trastuzumab resistance remains a vexing clinical problem, and better predictive and prognostic biomarkers are needed. Activin A is a TGF-B superfamily member and regulates cell proliferation, apoptosis, differentiation, and immune response. Methods: Serum activin A was measured using ELISA (R&D Systems, Minneapolis, MN) in 60 metastatic breast cancer patients before starting first-line trastuzumab-containing therapy. Progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier method and Cox modeling with both continuous and dichotomous (median) serum activin A analyses. Results: Pretreatment serum activin A levels averaged 2376 pg/ml, and had a median of 629 pg/ml and 25th and 75th quartile values of 406 and 1791 pg/ml, respectively. Patients who were hormone receptor negative had significantly higher activin A levels (median 1287 vs 450 pg/ml, p=0.002). Higher serum activin A was significant on a continuous basis for predicting reduced PFS to first-line trastuzumab-containing therapy (p<0.003), and for predicting shorter OS (p<0.0001). When analyzed using a dichotomous (median) cutpoint, the elevated serum activin A cohort had a significantly reduced PFS (HR 2.79, p <0. 002) (median 6.6 mo vs. 31.1 mo) and OS (HR 5.24, p <0.0001) (median 19.6 mo vs. median not reached). In multivariate analysis for PFS with other covariates (age, line of therapy, CA 15-3, and hormone receptor status), activin A was the only significant covariate (p=0.021). In multivariate analysis for OS, activin A (p=0.002) and CA 15-3 (p=0.03) remained significant as prognostic factors. Conclusions: Elevated pretreatment serum activin A predicts reduced PFS and overall survival in metastatic breast cancer patients treated with first-line trastuzumab-containing therapy. Activin A deserves further study as an adverse biomarker, and to select patients most likely to respond to activin A-targeted therapy.