Morlan, Bruce W.

Background: Since QT prolongation is a risk factor for sudden death, stroke, and all-cause mortality, we developed an electronic, institution-wide QT alert system to identify patients with significant QT prolongation (i.e. QTc≥500 ms if QRS <120 ms). These patients encountered a significant increased mortality within 1 year, and nearly 40% of patients with ≥4 QTc inciting factors have died. Herein, we examined the patients with ≤1 identifiable QTc inciting factor. Methods: Between November 2010 and June 2011, 53,732 patients underwent ECG-evaluation, 1,145 QT-alerts (2.1%) were triggered, and 470 of the QT-alerted patients had ECG-isolated QT prolongation. Clinical, laboratory, and therapeutic information were collected. Excluding female gender and bradycardia, other potential QT inciting factors (drugs, electrolyte disturbances, and co-morbidities) were synthesized into a pro-QT score and patients with a score of ≤1 were compared to patients with a pro-QT score >1. Results: About one-third (N=150, 59% female) of this QT-alerted cohort had a pro-QT score of ≤1 including 42 patients with an established diagnosis of congenital long QT syndrome (LQTS). Excluding LQTS patients, the remaining 108 patients (60 female, age 59±25 years) were significantly more likely to have a QT prolonging cardiovascular co-morbidity (44%) than those with a QT-score >1 (29%; p=0.006). However, mortality was similar between those with a QT-score ≤1 (19%) and those with a QT-score >1 (27%, p=0.09). Fourteen patients (9 female; age 64±22 years; QTc 507±14 ms) had no discernible QT inciting factors (i.e. pro-QT score=0) including 6 patients with previously documented QT prolongation. Conclusions: Only a minority of patients with ECG-isolated QT-prolongation (~3%) had no discernible QT-inciting factors other than female gender in 9. Careful scrutiny of these patients with seemingly idiopathic QT prolongation may identify novel QT provoking conditions. Alternatively, considering that 14 of 53,732 patients (1 in 3888) activated the alert system without obvious QT inciting factors and that congenital LQTS has an estimated prevalence of 1 in 2000, it is possible that this universal QT alert system has caught patients with yet to be diagnosed LQTS.

Abstract Objective We aimed to develop a model for accurate prediction of general care inpatient deterioration. Materials and Methods Training and internal validation datasets were built using 2-year data from a quaternary hospital in the Midwest. Model training used gradient boosting and feature engineering (clinically relevant interactions, time-series information) to predict general care inpatient deterioration (resuscitation call, intensive care unit transfer, or rapid response team call) in 24 hours. Data from a tertiary care hospital in the Southwest were used for external validation. C-statistic, sensitivity, positive predictive value, and alert rate were calculated for different cutoffs and compared with the National Early Warning Score. Sensitivity analysis evaluated prediction of intensive care unit transfer or resuscitation call. Results Training, internal validation, and external validation datasets included 24 500, 25 784 and 53 956 hospitalizations, respectively. The Mayo Clinic Early Warning Score (MC-EWS) demonstrated excellent discrimination in both the internal and external validation datasets (C-statistic = 0.913, 0.937, respectively), and results were consistent in the sensitivity analysis (C-statistic = 0.932 in external validation). At a sensitivity of 73%, MC-EWS would generate 0.7 alerts per day per 10 patients, 45% less than the National Early Warning Score. Discussion Low alert rates are important for implementation of an alert system. Other early warning scores developed for the general care ward have achieved lower discrimination overall compared with MC-EWS, likely because MC-EWS includes both nursing assessments and extensive feature engineering. Conclusions MC-EWS achieved superior prediction of general care inpatient deterioration using sophisticated feature engineering and a machine learning approach, reducing alert rate.

Abstract Within the past five years studies published from this laboratory and others have identified or confirmed CD38 as a marker for aggressive disease in B cell chronic lymphocytic leukemia (B-CLL). To learn more about the possible role of CD38 in this disease, we performed gene expression profiling (GEP; Affymetrix U133A platform) on primary leukemic B cells isolated from CD38 positive and negative patients. We and others have previously shown that the leukemic compartment within some patients consists of both CD38neg and CD38pos CLL B cells. To optimize identification of differentially expressed genes associated with CD38 expression or lack thereof, we restricted our gene profiling to patient cells that were unimodally negative for CD38 and those that expressed unimodally high levels of CD38. In both groups of patients, CD19 positive cells were purified using magnetic bead cell sorting on a Miltenyi AutoMacs prior to isolation of total RNA. To determine genes that appear to be differentially expressed in this set of experiments, we used a recently developed model-based algorithm that uses the normalized probe-level data as well as information about the underlying experimental design. Reassuringly, the gene expression profiles within the CD38pos versus the CD38neg cohort maintain congruency within each cohort when analyzing the gene expression data set as a whole, as well as within categories such as adhesion, signaling, and transcriptional molecules. Using this analytical approach, several genes emerged as interesting candidates for exploration into the nature of the CD38pos association with disease aggressiveness. Interestingly, although peripheral blood CLL B cells are overwhelmingly in the resting, G0, stage of the cell cycle, several cell cycle related genes were expressed at higher levels in CD38pos patient leukemic cells but not in CD38neg leukemic patients. Moreover, these genes encompass protein families that function at different stages throughout the cell cycle. These genes include: anaphase promoting complex subunit 5 (APC5); cell division cycle (cdc) family members; a checkpoint protein CHFR; the microtubule and actin associated protein, MACF1; the mitotic spindle checkpoint protein, MAD1L1; the DNA replication regulator, MCM7; STAG3, a meiotic regulator of chromosome segregation; and several activators of the ubiquitin pathway, including UBE2N, a known regulator of DNA repair enzymes (p-values of &lt;0.01, &lt;0.01, &lt;0.01, 0.01, 0.02, &lt;0.01, 0.01, and 0.01, respectively). We have begun to confirm these findings at the protein translation level. Through immunoblotting, preliminary data show that 3 out of 5 CD38pos and 0 out of 5 CD38neg patients’ leukemic cells express detectable levels of APC5, suggesting that CD38pos cells, or at least a subpopulation of cells, express APC5. Taken together, these gene and protein expression data suggest that at least a subpopulation of the leukemic cells from CD38pos CLL patients have more recently completed the cell cycle and maintain expression of specific cell cycle related genes. Alternatively, it is possible that this subpopulation is better prepared to re-enter the cell cycle if it encounters proliferative stimuli in other microenvironments.

5017 Background: The majority of men with prostate cancer are diagnosed with cancers with low mortality. Such men are treated with radical prostatectomy, external beam radiotherapy, or brachytherapy and followed by serum PSA evaluations. Some men with a rising PSA therapy will have local recurrence or metastasis, but many will have no other evidence of recurrent disease other than a rising PSA. The PSA doubling time has been used to determine which of these men deserve adjuvant hormonal ablation, radiation therapy, or observation. We hypothesize that additional biomarkers will predict which men with a rising PSA post-definitive therapy would benefit from additional therapy. Methods: We designed a custom array containing 526 RNA targets whose expression has been reported to be altered in association with prostate cancer progression. We included targets from Mayo Clinic prostate cancer research. Together with a second commercial array, 530 genes implicated in prostate cancer progression and 420 other cancer-related genes were evaluated. A case-control design was used to test the association of the expression results with outcome. Cases were men post-radical prostatectomy who developed systemic progression within 5 years after PSA recurrence (N=213). Controls were matched men post-radical prostatectomy with PSA recurrence but no evidence of clinical progression within 5 years (N=213). Results: Of 426 eligible patients, paraffin blocks were available on 418 (98.1%). RNA was prepared from all 418 blocks, and both arrays were both successful on 405 (96.9%) RNAs. Upon univariate analysis, 40 genes were highly significantly over- or under-expressed in the cases versus controls (1x10-22 < p < 1x10-7). Recursive partitioning (RP) selected 4 genes (TPX2, FAM13C1, TOPO2A and TSP2) that distinguished cases from controls. Random Forest analysis selected 24 genes (including 3 of the RP 4). A multivariable ROC analysis using these 24 genes generated an AUC of 0.80 (95% CI: 0.75–0.84). Conclusions: A specific gene expression pattern was significantly associated with systemic progression after PSA recurrence. The measurement of gene expression pattern may be useful for determining which men may benefit from additional therapy after PSA recurrence. No significant financial relationships to disclose.

Background: Bevacizumab (BEV), a monoclonal antibody against vascular endothelial growth factor-A (VEGF-A), is a standard component of medical therapy of metastatic colorectal cancer (mCRC). Activation of alternative angiogenesis pathways has been implicated in resistance to BEV. This phase II study examines the activity of combined vertical blockade of VEGF signaling with sorafenib and BEV as salvage therapy in patients with progressive disease (PD) on all standard therapy in mCRC. Methods: mCRC patients with documented PD on standard therapy, received sorafenib (200 mg orally twice daily, days 1–5 and 8–12) and BEV (5 mg/kg intravenously, day 1) every 2 weeks. Primary endpoint was 3-month progression-free survival (PFS) rate and secondary endpoints were overall survival (OS), response rate (RR), safety, and feasibility. Results: Of the 83 patients enrolled, 79 were evaluable. Of these, 42 (53%) were progression-free at 3 months. Median PFS was 3.5 months and median OS was 8.3 months. One patient had a partial response and 50 patients (63.3%) had at least one stable tumor assessment. Of 79 evaluable patients, 54 (68%) experienced grade 3/4 adverse events (AEs) at least possibly related to treatment. Most frequent grade 3/4 AEs were: fatigue (24.1%), hypertension (16.5%), elevated lipase (8.9%), hand-foot skin reaction (8.9%), diarrhea (7.6%), and proteinuria (7.6%). Reasons for treatment discontinuation were PD (72%), AEs (18%), patient refusal (8%), physician decision (1%), and death (1%). Conclusions: The combination of BEV and sorafenib as salvage therapy in heavily pretreated mCRC patients is tolerable and manageable, with evidence of promising activity. ClinicalTrials.gov identifier: NCT00826540, URL: http://clinicaltrials.gov/ct2/show/NCT00826540

BACKGROUNDThe use of rapid response systems (RRS), which were designed to bring clinicians with critical care expertise to the bedside to prevent unnecessary deaths, has increased. RRS rely on accurate detection of acute deterioration events. Early warning scores (EWS) have been used for this purpose but were developed using heterogeneous populations. Predictive performance may differ in medical vs surgical patients.OBJECTIVETo evaluate the performance of published EWS in medical vs surgical patient populations.DESIGNRetrospective cohort study.SETTINGTwo tertiary care academic medical center hospitals in the Midwest totaling more than 1500 beds.PATIENTSAll patients discharged from January to December 2011.INTERVENTIONNone.MEASUREMENTSTime‐stamped longitudinal database of patient variables and outcomes, categorized as surgical or medical. Outcomes included unscheduled transfers to the intensive care unit, activation of the RRS, and calls for cardiorespiratory resuscitation (“resuscitation call”). The EWS were calculated and updated with every new patient variable entry over time. Scores were considered accurate if they predicted an outcome in the following 24 hours.RESULTSAll EWS demonstrated higher performance within the medical population as compared to surgical: higher positive predictive value (P < .0001 for all scores) and sensitivity (P < .0001 for all scores). All EWS had positive predictive values below 25%.CONCLUSIONSThe overall poor performance of the evaluated EWS was marginally better in medical patients when compared to surgical patients.

AbstractWe developed and implemented a ‘CPOE-QT Alert’ system, that is, clinical decision support integrated in the computerized physician order entry system (CPOE), in 2011. The system identifies any attempts to order medications with risk of torsade de pointes (TdP) for patients with a history of significant QT prolongation (QTc ≥500 ms) and alerts the provider entering the order. We assessed its impact by comparing orders and subsequent medication administration before and after activation of the system. We found a significant decrease in the proportion of completed order per ordering attempt after system activation (94% (1293/1379) vs 77% (1888/2453), difference 16.8%; p&lt;0.001). This resulted in a 13.9% reduction in the administration of those medications to patients. A significant decrease was observed across all provider types, educational levels, and specialties. The CPOE-QT Alert system successfully reduced exposure to QT-prolonging medications in high risk patients.

Abstract Purpose: Polymorphisms in genes involved in the angiogenesis pathway have been investigated as predictive markers for efficacy and tolerability to anti-angiogenesis treatment, such as BEV. This study examines single nucleotide polymorphisms (SNPs) in VEGF, VEGFR2, and HIF-1α for their potential association with outcome and safety in metastatic colorectal cancer (mCRC) patients treated with the combined vertical blockade of VEGF signaling (i.e., sorafenib and BEV) as salvage therapy. Experimental procedures: Genomic DNA was extracted from peripheral blood for 78/79 evaluable patients in the North Central Cancer Treatment Group (NCCTG) Phase II study, N054C (Grothey, et al., ASCO 2010). TaqMan or direct sequencing was used for genotyping VEGF (rs25648, rs3025039, rs2010963, rs1005230, rs833061, rs699947, rs1570360), VEGFR2 (rs2305948, rs2219471, rs2071559, rs1870377), and HIF-1α (rs11549465, rs11549467) SNPs. Chi-square or Fisher's exact test was used to determine genotype associations with the study's primary endpoint, progression-free rate at 3 months of follow-up, as well as genotype associations with the most common grade 3+ adverse events at least possibly related (AE rels) to treatment (i.e., fatigue, hypertension, skin reaction). Results summary: The presence of a mutant T allele in the 5’ UTR of VEGF (rs25648; C534T) was associated with fewer successes in progression-free rate at 3 month follow-up (Fisher's exact test, p=0.0187). In addition, the presence of a C allele in the promoter region of VEGFR2 (rs2071559, T-604C) was associated with fewer grade 3+ hypertension AE rels (Fisher's exact test, p=0.0101). However, after correcting for multiple comparisons using the method of Benjamini & Hochberg none of the p-values were significant at a 0.05 level. At the same time, no differences were observed between the genotype subgroups and either progression-free rate at 3 months or the most common grade 3+ AE rels for the remaining SNPs that were analyzed, before or after correction. Conclusions: This study provides preliminary evidence that mCRC patients with the VEGF C534T (rs25648) variant may not benefit from combined treatment of sorafenib and BEV, whereas patients with the VEGFR2 T-604C (rs2071559) polymorphism may experience fewer grade 3+ AE rels. Further prospective validation of these SNPs and their association with this treatment combination in mCRC is warranted. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4131. doi:10.1158/1538-7445.AM2011-4131

Abstract Purpose: Surrogate biomarkers are lacking for predicting or monitoring response to anti-angiogenesis therapies. We investigated whether circulating biomarkers (CBMs) of angiogenesis (i.e., bFGF, SDF-1α, HGF, sKIT, Ang-2, and PlGF) correlated with treatment efficacy in a pooled analysis of metastatic colorectal cancer (mCRC) and recurrent glioblastoma multiforme (rGBM) patients (pts) treated with bevacizumab/sorafenib (BEV/SOR). Experimental procedures: Peripheral blood samples were obtained for CBM analyses from pts enrolled in the North Central Cancer Treatment Group (NCCTG) phase II studies N054C (mCRC, n=75, Grothey, ASCO 2010) and N0776 (rGBM, n=54, Galanis, ASCO 2010). Blood collection time points were: baseline (BL), cycle 1 day 3 (C1D3), prior to treatment cycles 2, 3, 5, 7, 9, 11, 13, and after the pt went off study. Plasma CBM levels were determined by commercially-available ELISAs (R&D Systems) and performed according to manufacturer's instructions. For each CBM, a linear regression model that adjusted for study was used to evaluate the correlation with either progression-free survival (PFS) success/failure or progression within 14 days of the last blood draw for the following measures: absolute BL levels, log2 BL levels; C1D3 log2-fold change (FC) from BL, prior to cycle 2 log2-FC from BL, last draw log2-FC from BL, and last draw log2-FC from prior draw. Results summary: There appears to be no significant difference in the PFS or overall survival (OS) between the pts on these two studies; therefore, we pooled the patients from both studies for a combined analyses. We found no difference in absolute or log2 levels for any of the CBMs during the course of BEV/SOR treatment. In these pooled analyses, we found increased absolute and increased log2 BL SDF-1α levels were significantly correlated with PFS success (p=0.023 and p=0.02, respectively). After correcting for multiple comparisons (method of Benjamini & Hochberg) the p-values &lt;0.05 had a false-discovery-rate of 41.4%. None of the other CBM measures were significantly correlated with either PFS success/failure or progression within 14 days of the last blood draw (all p&gt;0.10). Conclusions: This study provides preliminary evidence that SDF-1α may be a useful CBM for determining treatment efficacy in these pts treated with BEV/SOR. Further prospective validation of SDF-1α for predicting pt progression with this treatment combination in advanced disease (e.g., mCRC and rGBM) appears warranted. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5562. doi:1538-7445.AM2012-5562

Abstract A61 Background Patients with Barrett's esophagus (BE) and dysplasia are ideal candidates for chemopreventive strategies to reduce cancer risk. Difluoromethylornithine (DMFO) is a promising chemopreventive agent that inhibits polyamine synthesis involved in the regulation of cell growth and differentiation. We conducted a pilot study to examine the effects of DFMO on esophageal histopathology, mucosal polyamine content, and gene expression. Materials and Methods Patients (n=10) with histologically confirmed BE and low grade dysplasia were enrolled in a single-arm study of DFMO (0.5 g/m2/d) given continuously for 6 months. Esophagoscopy with biopsies (4 quadrants every 1 cm) was performed at baseline, 3 and 6 months, and at 12 months (where available). Grading of dysplasia was performed by a GI pathologist blinded to clinical/biomarker data. Audiology was also performed. Mucosal polyamine content was measured by high-performance liquid chromatography, and analyzed using paired t-tests. Gene expression profiling was performed using a cDNA two-color chip, and was compared between baseline and 6 months. Expression data was normalized using the two-channel fastlo routine and differential expression was computed using a Wilcoxon signed-rank test. Results After 6 months of DFMO treatment, histopathological response data demonstrate regression of dysplasia (n= 1), stable disease (n= 8), and progression of dysplasia (n= 1). Within the stable category, 2 patients with extensive low grade dysplasia showed only focal dysplasia based upon 4 or more biopsies at 6 months. Histolopathological improvements seen at 6 months were maintained at 12 months. Overall, DFMO was well tolerated. One patient had subclinical, unilateral ototoxicity. Modulation of polyamines (spermine, spermidine, putrescine, histamine) was shown only for putrescine which decreased with treatment (6 mo., p=0.07) and showed recovery to baseline at 12 months (p= 0.01). Gene expression profiling revealed modulated genes of potential biological importance (KLF5, KAL1, RFC5, TIMM8a, TC10) and of these, Krüppel-like factor 5 (KLF5) was downregulated whereas the others were upregulated. Conclusion &gt;Further study of the chemopreventive effect of DFMO upon BE with dysplasia is suggested. DFMO treatment suppressed mucosal putrescine levels and downregulated KLF5, an important mediator of cell proliferation. Citation Information: Cancer Prev Res 2008;1(7 Suppl):A61.