Predictive Value For Clinical Outcome Research Articles

Length of Stay, Hospital Costs and Mortality Associated With Comorbidity According to the Charlson Comorbidity Index in Immobile Patients After Ischemic Stroke in China: A National Study.

In this study, we examined the length of stay (LoS)-predictive comorbidities, hospital costs-predictive comorbidities, and mortality-predictive comorbidities in immobile ischemic stroke (IS) patients; second, we used the Charlson Comorbidity Index (CCI) to assess the association between comorbidity and the LoS and hospitalization costs of stroke; third, we assessed the magnitude of excess IS mortality related to comorbidities. Between November 2015 and July 2017, 5114 patients hospitalized for IS in 25 general hospitals from six provinces in eastern, western, and central China were evaluated. LoS was the period from the date of admission to the date of discharge or date of death. Costs were collected from the hospital information system (HIS) after the enrolled patients were discharged or died in hospital. The HIS belongs to the hospital's financial system, which records all the expenses of the patient during the hospital stay. Cause of death was recorded in the HIS for 90 days after admission regardless of whether death occurred before or after discharge. Using the CCI, a comorbidity index was categorized as zero, one, two, and three or more CCI diseases. A generalized linear model with a gamma distribution and a log link was used to assess the association of LoS and hospital costs with the comorbidity index. Kaplan-Meier survival curves was used to examine overall survival rates. We found that 55.2% of IS patients had a comorbidity. Prevalence of peripheral vascular disease (21.7%) and diabetes without end-organ damage (18.8%) were the major comorbidities. A high CCI=3+ score was an effective predictor of a high risk of longer LoS and death compared with a low CCI score; and CCI=2 score and CCI=3+ score were efficient predictors of a high risk of elevated hospital costs. Specifically, the most notable LoS-specific comorbidities, and cost-specific comorbidities was dementia, while the most notable mortality-specific comorbidities was moderate or severe renal disease. CCI has significant predictive value for clinical outcomes in IS. Due to population aging, the CCI should be used to identify, monitor and manage chronic comorbidities among immobile IS populations.

MiR-486-5p Serves as a Diagnostic Biomarker for Sepsis and Its Predictive Value for Clinical Outcomes.

BackgroundAs a molecular detection method, miRNA can quickly diagnose and prevent diseases, intervene in disease as early as possible, and reduce mortality. This study was to investigate the potential clinical diagnostic and predictive significance of miR-486-5p in sepsis and its correlation with inflammation and disease severity.MethodsThe serum miR-486-5p in 108 sepsis, 60 pneumonia-infected, and 101 healthy controls were detected by RT-qPCR. Spearman coefficient detects the correlation between serum miRNA and disease severity indicators (APACHE II, SOFA scores), and inflammation indicators (CRP, PCT), respectively. The diagnostic significance of miR-486-5p in sepsis was analyzed by the ROC curve. Kaplan–Meier estimator and Cox regression hazards analysis of the predictive significance of serum miR-486-5p in 28-day survival from sepsis.ResultsSerum miR-486-5p was increased in sepsis patients compared with healthy control and pneumonia-infected patients (P < 0.001). And increased serum miR-486-5p was positively associated with disease severity (SOFA score and APACHE II score) and inflammation (CRP and PCT). Serum miR-486-5p can not only identify sepsis patients from healthy controls (AUC = 0.914) but also significantly distinguish sepsis patients from pneumonia-infected patients (AUC = 0.814), showing good potential as a diagnostic biomarker for sepsis. In addition, serum miR-486-5p was an independent predictor of 28-day survival (log-rank P = 0.012), and patients with high levels of miR-486-5p had a poorer overall 28-day survival (HR = 3.057, 95% CI = 1.385–17.817, P = 0.014).ConclusionmiR-486-5p is a potential diagnostic biomarker for sepsis, and its high level is significantly correlated with the disease severity and inflammation. In addition, miR-486-5p were predictive risk factors for 28-day survival in sepsis patients.

The Prognostic and Predictive Value of IKZF1 and IKZF3 Expression in T-Cells in Patients with Multiple Myeloma

PURPOSE:The report of cereblon being the target for immunomodulatory drugs, and the subsequent degradation of Ikaros (IKZF1) and Aiolos (IKZF3) was a milestone in the understanding of their mechanism of action. While recent studies have described the role of IKZF1/3 proteins in multiple myeloma (MM) cells, few have highlighted the significance of IKZF1/3 expression in T-cells.PATIENTS AND METHODS:We analysed the IKZF1/3 expression levels in T-cells from 38 healthy donors (HD), 43 patients with monoclonal gammopathy of undetermined significance (MGUS), 45 patients with asymptomatic MM stage I (MMI) and 50 symptomatic patients with MM stage III (MMIII), diagnosed using Durie-Salmon staging system, by flow cytometry to examine their prognostic and predictive value. We also combined in vivo observations with in vitro assays to determine the effect of IKZF1/3 expression on the T-cell immunophenotype and anti-tumour T-cell response in 162 MMIII patients.RESULTS:Flow cytometry analyses revealed marked differences in the frequency of T-cells expressing IKZF1/3 proteins in patients with different plasma cell diseases, patients with MMIII exhibited significantly higher IKZF3 expressing cells than HD, MGUC and MMI patients (Figure 1.A). We found that high IKZF3, but not IKZF1, expression in T-cells correlates with superior overall survival in MMIII patients treated with immunomodulatory drugs (thalidomide, lenalidomide and pomalidomide, Figure 1.B). Moreover, we show that higher IKZF3 expression in T-cells inhibits myeloma-specific T-cell response in vitro (Figure 1.C) and patients with high IKZF3 expression exhibit increased T-cell response to lenalidomide compared to patients with low IKZF3 expression (Figure 1.D). We also show that the immunophenotype of newly diagnosed MMIII patients with high IKZF3 expressing T-cells frequency shows features of immunodeficiency that are contrary to the changes induced by immunomodulatory drugs (Figure 1.E). Although we observed higher IKZF3 expression in T-cells from patients with MMIII compared to MMI, IKZF3 expression was unaffected by the tumour microenvironment.CONCLUSION:In conclusion, IKZF3 expression in T-cells is a predictive value for clinical outcome in MMIII patients treated with immunomodulatory drugs due to its profound modulation of T-cell functionality.An accompanying immunological study to registered GMMG study ID: NCT02495922:https://clinicaltrials.gov/ct2/show/NCT02495922 [Display omitted] DisclosuresAwwad:Bristol-Myers Squibb: Other: Travel, Accommodations, Expenses. Kriegsmann:BMS: Research Funding; Celgene: Research Funding. Hillengass:BMS: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; honoraria from Amgen, BMS, Celgene: Honoraria; Takeda: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Raab:Celgene: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; BMS: Consultancy, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Munder:Consultancy: Janssen-Cilag, BMS, Takeda, Amgen, Celgene.: Consultancy; Celgene: Consultancy; Amgen: Consultancy; BMS: Consultancy; Takeda: Consultancy. Weisel:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Salwender:Takeda: Honoraria; Amgen: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Honoraria and travel support: Janssen Cilag, Celgene, BMS.: Honoraria, Other: Travel support. Hänel:Novartis: Honoraria; Roche: Honoraria. Fenk:Honoraria and travel grants: Celgene, Janssen, BMS; research funding: Celgene.: Honoraria. Dürig:Lead Discovery Center: Research Funding. Goldschmidt:Chugai: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millenium: Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Morphosys: Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Hundemer:Research Support BMS, Celgene, Sanofi, Morphosys.: Research Funding.

Baseline Cerebral Ischemic Core Quantified by Different Automatic Software and Its Predictive Value for Clinical Outcome.

PurposeThis study aims to investigate the agreement of three software packages in measuring baseline ischemic core volume (ICV) and penumbra volume (PV), and determine their predictive values for unfavorable clinical outcome in patients with endovascular thrombectomy (EVT).MethodsPatients with acute ischemic stroke who underwent computed tomographic perfusion (CTP) were recruited. Baseline CTP measurements including ICV and PV were calculated by three software packages of IntelliSpace Portal (ISP), Rapid Processing of Perfusion and Diffusion (RAPID), and fast-processing of ischemic stroke (F-STROKE). All patients received EVT, and the modified Rankin scale (mRS) at 90 days after EVT was assessed to determine the clinical outcomes (favorable: mRS = 0–2; unfavorable: mRS = 3–6). The agreement of CTP measurements among three software packages was determined using intraclass correlation coefficient (ICC). The associations between CTP measurements and unfavorable clinical outcome were analyzed using logistic regression. Receiver operating characteristic curves were conducted to calculate the area under the curve (AUC) of CTP measurements in predicting unfavorable clinical outcome.ResultsOf 223 recruited patients (68.2 ± 11.3 years old; 145 males), 17.0% had unfavorable clinical outcome after EVT. Excellent agreement between F-STROKE and RAPID was found in measuring ICV (ICC 0.965; 95% CI 0.956–0.973) and PV (ICC 0.966; 95% CI 0.956–0.973). ICVs measured by three software packages were significantly associated with unfavorable clinical outcome before (odds ratios 1.012–1.018, all P < 0.01) and after (odds ratios 1.003–1.014, all P < 0.05) adjusted for confounding factors (age, gender, TOAST classification, and NIHSS on admission). In predicting unfavorable clinical outcome, ICV measured by F-STROKE showed similar performance to that measured by RAPID (AUC 0.701 vs. 0.717) but higher performance than that measured by ISP (AUC 0.629).ConclusionsThe software of F-STROKE has excellent agreement with the widely used analysis tool of RAPID in measuring ICV and PV. The ischemic core volume measured by both F-STROKE and RAPID is a stronger predictor for unfavorable clinical outcome after EVT compared to ISP.

Prognostic value of brain natriuretic peptide vs history of heart failure hospitalization in a large real-world population.

BackgroundIn heart failure (HF) patients, both natriuretic peptides (NP) and previous HF hospitalization (pHFH) have been used to predict prognosis.HypothesisIn a large real‐world population, both NP levels and pHFH have independent and interdependent predictive value for clinical outcomes of HFH and all‐cause mortality.MethodsLinked electronic health records and insurance claims data from Decision Resource Group were used to identify HF patients that had a BNP or NT‐proBNP result between January 2012 and December 2016. NT‐proBNP was converted into BNP equivalents by dividing by 4. Index event was defined as most recent NP on or after 1 January 2012. Patients with incomplete records or age < 18 years were excluded. During one‐year follow up, HFH and mortality rates stratified by index BNP levels and pHFH are reported.ResultsOf 64 355 patients (74 ± 12 years old, 49% female) with available values, median BNP was 259 [IQR 101‐642] pg/ml. The risk of both HFH and mortality was higher with increasing BNP levels. At each level of BNP, mortality was only slightly higher in patients with pHFH vs those without pHFH (RR 1.2 [95%CI 1.2,1.3], P < .001); however, at each BNP, HFH was markedly increased in patients with pHFH vs those without pHFH (RR 2.0 [95%CI 1.9,2.1], P < .001).ConclusionIn this large real‐world heart failure population, higher BNP levels were associated with increased risk for both HFH and mortality. At any given level of BNP, pHFH added greater prognostic value for prediction of future HFH than for mortality.

Progress Update and Challenges on O2max Testing and Interpretation.

The maximal oxygen uptake (O2max) is the primary determinant of endurance performance in heterogeneous populations and has predictive value for clinical outcomes and all-cause mortality. Accurate and precise measurement of O2max requires the adherence to quality control procedures, including combustion testing and the use of standardized incremental exercise protocols with a verification phase preceded by an adequate familiarization. The data averaging strategy employed to calculate the O2max from the breath-by-breath data can change the O2max value by 4–10%. The lower the number of breaths or smaller the number of seconds included in the averaging block, the higher the calculated O2max value with this effect being more prominent in untrained subjects. Smaller averaging strategies in number of breaths or seconds (less than 30 breaths or seconds) facilitate the identification of the plateau phenomenon without reducing the reliability of the measurements. When employing metabolic carts, averaging intervals including 15–20 breaths or seconds are preferable as a compromise between capturing the true O2max and identifying the plateau. In training studies, clinical interventions and meta-analysis, reporting of O2max in absolute values and inclusion of protocols and the averaging strategies arise as imperative to permit adequate comparisons. Newly developed correction equations can be used to normalize O2max to similar averaging strategies. A lack of improvement of O2max with training does not mean that the training program has elicited no adaptations, since peak cardiac output and mitochondrial oxidative capacity may be increased without changes in O2max.

Computational Prediction and Validation of Tumor-Associated Neoantigens.

Tumor progression is typically accompanied by an accumulation of driver and passenger somatic mutations. A handful of those mutations occur in protein coding genes which introduce non-synonymous polymorphisms. Certain substitutions may give rise to novel, tumor-associated antigens or neoantigens, presentable by cancer cells to the host adaptive immune system. As antigen recognition is the core of an effective immune response, the identification of patient tumor specific antigens derived from transformed cells is of importance for immunotherapeutic approaches. Recent technological advances in DNA sequencing of tumor genomes, advances in gene expression analysis, algorithm development for antigen predictions and methods for T-cell receptor (TCR) repertoire sequencing have facilitated the selection of candidate immunogenic neoantigens. In this regard, multiple research groups have reported encouraging results of neoantigen-based cancer vaccines that generate tumor antigen specific immune responses, both in mouse models and clinical trials. Additionally, both the quantity and quality of neoantigens has been shown to have predictive value for clinical outcomes in checkpoint-blockade immunotherapy in certain tumor types. Neoantigen recognition by vaccination or through adoptive T cell therapy may have unprecedented potential to advance cancer immunotherapy in combination with other approaches. In our review we discuss three parameters regarding neoantigens: computational methods for epitope prediction, experimental methods for epitope immunogenicity validation and future directions for improvement of those methods. Within each section, we will describe the advantages and limitations of existing methods as well as highlight pressing fundamental problems to be addressed.

Clinical relevance of systemic monocytic-MDSCs in patients with metastatic breast cancer

The overall aim of this prospective study was to delineate the role of monocytic myeloid-derived suppressor cells (Mo-MDSCs) in patients with metastatic breast cancer (MBC). MDSCs are a heterogeneous group of immunosuppressive cells often enriched in different malignancies which hold prognostic and predictive value for clinical outcomes. Here, we assessed the clinical significance of Mo-MDSCs in 54 patients with de novo or distant recurrent MBC. We show that high levels of Mo-MDSCs significantly correlated with de novo MBC (metastatic disease at initial diagnosis), estrogen receptor (ER) negativity, and liver- and bone metastasis. A trend towards an association between high levels of Mo-MDSCs and survival (P = 0.053) was also found in patients with distant recurrent ER-positive MBC. We therefore propose that an increased population of Mo-MDSCs may be related to the metastatic or immunoregulatory switch associated with transition to a more systemic disease. Our data imply that high levels of systemic Mo-MDSCs represent patients with more aggressive disease and worse outcome.

Tradition, not science, is the basis of animal model selection in translational and applied research_suppl1

National and international laws and regulations exist to protect animals used for scientific purposes in translational and applied research, which includes drug development. However, multiple animal models are available for each disease. We evaluated the argumentation behind the selection of a specific animal model using thematic content analysis in project applications issued in 2017-2019 in the Netherlands. In total, 125 animal models for translational and applied research from 110 project applications were assessed. Explanations to select a specific model included: the model’s availability (79%); the availability of expertise (62%); and the model showing similar disease pathology/symptoms (59%) to humans. Therefore, current selection of a specific animal model seems to be based on tradition rather than its potential predictive value for clinical outcome. The applicants’ explanations for the implementation of the 3R prin­ciples (replacement, reduction and refinement) as to the animal model were unspecific. Replacement was achieved by using data from prior in vitro studies, reduction by optimal experimental design and statistics, and refinement by reducing discomfort. Additionally, due to the stated need for a test model with high complexity (47%) and intactness (30%), the full replacement of animal models with alternative (non-live animal) approaches was thought unachievable. Without a clear, systematic and transparent justification for the selection of a specific animal model, the likelihood of poorly trans­latable research remains. It is not only up to the researcher to demonstrate this, as ethical committees and funding bodies can provide positive stimuli to drive this change.

Tradition, not science, is the basis of animal model selection in translational and applied research.

National and international laws and regulations exist to protect animals used for scientific purposes in translational and applied research, which includes drug development. However, multiple animal models are available for each disease. We evaluated the argumentation behind the selection of a specific animal model using thematic content analysis in project applications issued in 2017-2019 in the Netherlands. In total, 125 animal models for translational and applied research from 110 project applications were assessed. Explanations to select a specific model included: the model’s availability (79%); the availability of expertise (62%); and the model showing similar disease pathology/symptoms (59%) to humans. Therefore, current selection of a specific animal model seems to be based on tradition rather than its potential predictive value for clinical outcome. The applicants’ explanations for the implementation of the 3R prin­ciples (replacement, reduction and refinement) as to the animal model were unspecific. Replacement was achieved by using data from prior in vitro studies, reduction by optimal experimental design and statistics, and refinement by reducing discomfort. Additionally, due to the stated need for a test model with high complexity (47%) and intactness (30%), the full replacement of animal models with alternative (non-live animal) approaches was thought unachievable. Without a clear, systematic and transparent justification for the selection of a specific animal model, the likelihood of poorly trans­latable research remains. It is not only up to the researcher to demonstrate this, as ethical committees and funding bodies can provide positive stimuli to drive this change.

P1493Prognostic significance of right ventricular function during exercise in patients with non-obstructive hypertrophic cardiomyopathy

Abstract Background Hypertrophic cardiomyopathy (HCM) is a heterogeneous condition that may present crucial complication including life-threatening arrhythmia and sudden cardiac death. However, the risk stratification of HCM without left ventricular outflow tract (LVOT) obstruction had not been fully elucidated. Moreover, although recent studies have revealed the right ventricle (RV) involvement of HCM, the prognostic importance of RV function during exercise is unclear. Purpose To investigate the prognostic significance of RV function in patients with non-obstructive HCM using exercise stress echocardiography (ESE). Methods and results This study conducted on 100 HCM patients (age 62.9±13.6 years, 63% men) with preserved left ventricular ejection fraction who underwent ESE using semi-supine bicycle ergometer. Ten patients with significant LVOT obstruction (≥30mmHg) were excluded and 9 were also excluded because of the inadequate imaging quality or insufficiency of data. Among remaining 81 non-obstructive HCM patients, 9 patients suffered from HCM related cardiac events including cardiac death, unexpected hospitalization, life-threatening arrhythmias, and new-onset of syncope during the mean follow up period of 2.6±1.6 years. A multivariate Cox Hazard analysis revealed that low tricuspid annular plane systolic excursion during exercise (Ex-TAPSE, cut-off: 24mm) was an independent predictor of cardiac events. (hazard ratio: 18.66, 95% confidence interval: 3.66–338.46, P&lt;0.001) The estimated cumulative cardiac event free survival using the Kaplan-Meier method was significantly lower in patients with reduced Ex-TAPSE (&lt;24mm) than those with preserved Ex-TAPSE (Log-rank, P&lt;0.01). K-M curve according to Ex-TAPSE Conclusion Ex-TAPSE had a strong predictive value of clinical outcomes in non-obstructive HCM patients. Right ventricular function during exercise may have crucial role in the risk stratification of non-obstructive HCM.

Does selected immunological panel possess the value of predicting the prognosis of early-stage resectable non-small cell lung cancer?

The immune status in the tumor micro-environment of lung cancer is highly informative, and expression status of some biomarkers in the tumor micro-environment may have deep connected statistical characteristics which could indicate immune status and predict related clinical outcomes. In this study, a panel of 9 immune biomarkers are selected for their possible predictive value of clinical outcomes in early-stage resectable non-small cell lung cancer (NSCLC). We introduced a new way of interpreting the expression of Immunohistochemistry-based biomarkers in predicting the prognosis of patients. Immunohistochemistry were performed on surgical samples from 139 patients with NSCLC. Cox regression and subgroup analysis were conducted for the screening of biomarkers that were significant in survival and prognosis. Afterwards, Principle Component Analysis was conducted on screened biomarkers in order to extract characteristic root, which were utilized by an Artificial Neuron Network (ANN) for the prediction of clinical outcomes. Six out of 9 biomarkers were considered significant and were selected for the data analysis. The KMO-Bartlett's Sphericity test was valid (0.658>0.5, P=0.0001). The principle component regression results indicated that the survival was associated with the principle component Z4 (Y=0.316×Z4+2.298, R=0.189, P=0.026). Also, regression-free survival was associated with the principle component Z4 and Z2 (Y=0.314×Z4+0.255×Z2+2.061, R=0.249, P=0.013). Principle components ranking (PCrank) was calculated and after the determination of a cutoff of 0.2, the intergroup comparison of subgrouphigh (PCrank value above 0.2) and subgrouplow (PCrank value below 0.2) was significant in overall survival (OS) (P=0.025). A database search validated our results. Afterwards, the ANN model successfully predicted the clinical outcome, with accuracies of 94.1% and 96.2% respectively in models 1 and 2. The selected immunological panels have promising potential for predicting the prognosis of resectable NSCLC.

Alanine Aminotransferase Predicts Outcomes in Elderly Patients with Aneurysmal Subarachnoid Hemorrhage.

With the aging of the world population, the number of elderly patients suffering from aneurysmal subarachnoid hemorrhage (aSAH) is gradually growing. We aim to investigate the potential association between plasma ALT level and clinical complications of elderly aSAH patients, and explore its predictive value for clinical outcomes of elderly aSAH patients. Between January 2013 and March 2018, 152 elderly aSAH patients were analyzed in this study. Clinical information, imaging findings and laboratory data were reviewed. According to the Glasgow Outcome Scale (GOS), clinical outcomes at 3 months were classified into favorable outcomes (GOS 4-5) and poor outcomes (GOS 1-3). Logistic regression analysis was used to assess the indicators associated with poor outcomes, and receiver curves (ROC) and corresponding area under the curve (AUC) were used to detect the accuracy of the indicator. A total of 48 (31.6 %) elderly patients with aSAH had poor outcome at 3 months. In addition to ICH, IVH, Hunt-Hess 4 or 5 Grade and Modified Fisher 3 or 4 Grade, plasma ALT level was also strongly associated with poor outcome of elderly aSAH patients. After adjusting for other covariates, plasma ALT level remained independently associated with pulmonary infection (OR 1.05; 95% CI 1.00-1.09; P = 0.018), cardiac complications (OR 1.05; 95% CI 1.01-1.08; P = 0.014) and urinary infection (OR 1.04; 95% CI 1.00-1.08; P = 0.032). Besides, plasma ALT level had a predictive ability in the occurrence of systemic complications (AUC 0.676; 95% CI: 0.586- 0.766; P<0.001) and poor outcome (AUC 0.689; 95% CI: 0.605-0.773; P<0.001) in elderly aSAH patients. Plasma ALT level of elderly patients with aSAH was significantly associated with systemic complications, and had additional clinical value in predicting outcomes. Given that plasma ALT levels on admission could help to identify high-risk elderly patients with aSAH, these findings are of clinical relevance.

OR34-4 ATF3 Is A Converging Point For AR Signaling And Fatty Acid Oxidation In Prostate Cancer

Prostate cancer (PCa) is the second most prevalent cancer and leading causes of death among men worldwide. Androgen deprivation is the first line of treatment for locally advanced and metastatic PCa. For men who develop metastatic, castration-resistant PCa (CRPC), survival is limited. Thus, there is a need to identify synergistic pathways to either prevent or re-sensitize the castration-resistant phenotype. PCa has a long natural history of development and there is a significant correlation between age, diet, metabolism and progress of PCa. We have previously reported that treating PCa cells with fatty acid oxidation inhibitors (FAOi) sensitizes them to androgen blockade. Here we set out to evaluate how the two disparate pathways: AR signaling and FAO, influence one another hoping to identify new therapeutic vulnerabilities. We used CRPC cell models (LNCaP-MDVres, and LNCaP-C42), as well as the FAOi (etomoxir and ranolazine) and the antiandrogen enzalutamide (MDV3100). Cells were treated for 48 hours, followed by gene expression, androgen signaling and growth analysis. Both FAOi strongly suppressed the androgen response hallmark (FDR q-val < 0.001) in MDVres cells, and this was associated with a significant upregulation of the ATF3 gene (etomoxir; 30-fold, p<0.001 vs vehicle; ranolazine; 2-fold, p< 0.03). Interestingly, knockdown (KD) of ATF3 with shRNAs resulted in differential responses to FAOi in these genetically-related cells. In the MDVres cells, ATF3 KD resulted in increased PSA expression with FAOi treatment (etomoxir: 2-fold, p= 0.002; ranolazine 4-fold, p< 0.001 vs. control shRNA cells). On the other hand, in the C42 cells, ATF3 KD resulted in decreased PSA expression with FAOi treatment (etomoxir: 3-fold, p< 0.001; ranolazine 1.5-fold, p< 0.004 vs. control cells). These results suggested that ATF3 is a convergent point for AR and FAO pathways that is cell-context dependent, and its expression status could be exploited to sensitize these cells to MDV3100 and/or the FAOi. Cell growth assays confirmed that MDVres cells with ATF3 KD were more sensitive to MDV3100 alone and showed a synergistic combination effect with FAOi (p< 0.01, combinatorial index (CI) = 0.6). The C42 cells with ATF3 KD were more sensitive to the FAOi alone and showed a synergistic effect with MDV3100 (p< 0.001, CI= 0.4). Examination of patient databases revealed an inverse correlation between AR and ATF3, a low expression of ATF3 in advanced cancers (primary tumors n=64, metastatic tumors n=24), and better disease-free survival in patients with high ATF3 expression (MSKCC; n=157, Log rank p= 0.01). These data support the role for FAOi to re-sensitize CRPC to endocrine therapies. In conclusion, we have identified ATF3 as a modulator of FAO and AR signaling that has predictive value for clinical outcomes using fat oxidation inhibitors in CRPC. Sources of research support: NIH, ACS-RSG

Low Blood ALT Activity and High FRAIL Questionnaire Scores Correlate with Increased Mortality and with Each Other. A Prospective Study in the Internal Medicine Department.

Background: Low blood ALT, Alanine aminotransferase activity and high FRAIL (Fatigue, Resistance, Ambulation, Illnesses and Loss of Weight) questionnaire scores were previously shown to be associated with frailty and increased risk of mortality. We aimed to correlate these tools with mortality and each other in patients hospitalized in an internal medicine department. Methods: This is a prospective study in a large tertiary hospital. We assessed the predictive value for clinical outcomes of both low ALT blood activity and the pre-frail and frail categories of the “FRAIL” questionnaire. Results: During a 15 months study, 179 consecutive patients were recruited, of whom 20 died. When all study participants were divided to three groups according to admission ALT levels (below 10 IU/L, 11 to 19 IU/L and above 20 IU/L) we found a statistically significant difference in the rate of mortality: 4 patients died within the group of ALT < 10 IU/L, 14 patients died in the group of 10 IU/L < ALT < 19 IU/L and in the group of patients with ALT > 20 IU/L, only 2 patients died (p = 0.042). A higher score on the FRAIL questionnaire was associated, with statistical significance, with higher risk of mortality (p = 0.029). There was a significant correlation (p = 0.038) between blood ALT activity and the pre-frailty and frailty classifications by the FRAIL Questionnaire. Conclusions: Both the FRAIL questionnaire and blood ALT activity are simple and practical tools for frailty assessment and risk stratification of patients hospitalized in the internal medicine department. Both tool’s results also correlate with each other.

The prognostic and predictive value of IKZF1 and IKZF3 expression in T-cells in patients with multiple myeloma

ABSTRACTPurpose: While recent studies described the role of IKZF1/3 proteins in multiple myeloma (MM) cells, few have highlighted the significance of IKZF1/3 expression in T-cells. In this study we examine the prognostic and predictive value of IKZF1/3 expression in T-cells in patients with MM stage III.Experimental design: We analysed the IKZF1/3 expression levels in T-cells from 45 MM stage I (MMI) and 50 newly diagnosed MM stage III (MMIII) patients, according to Durie-Salmon staging system, by flow cytometry to examine their prognostic and predictive value. We also combined in vivo observations with in vitro assays to determine the effect of IKZF1/3 expression on the T-cell immunophenotype and anti-tumour T-cell response in 162 MMIII patients.Results: We found that high IKZF3, but not IKZF1, expression in T-cells correlates with superior overall survival in MMIII patients treated with immunomodulatory drugs (thalidomide, lenalidomide and pomalidomide). Moreover, we show that higher IKZF3 expression in T-cells inhibits myeloma-specific T-cell response in vitro and that the immunophenotype of patients with high IKZF3 expression shows features that are contrary to the changes induced by immunomodulatory drugs. Although we observed higher IKZF3 expression levels in T-cells from patients with MMIII compared to MMI, IKZF3 expression was unaffected by the tumour microenvironment.Conclusion: In conclusion, IKZF3 expression in T-cells is a predictive value for clinical outcome in MMIII patients treated with immunomodulatory drugs due to its profound modulation of T-cell functionality.

Early PREdiction of Severe Sepsis (ExPRES-Sepsis) study: protocol for an observational derivation study to discover potential leucocyte cell surface biomarkers

IntroductionSepsis is an acute illness resulting from infection and the host immune response. Early identification of individuals at risk of developing life-threatening severe sepsis could enable early triage and treatment,...

Androgen receptor expression in triple negative breast cancer patients and its predictive value for clinical outcomes

Objective To investigate androgen receptor(AR) expression in triple negative breast cancer(TNBC) patients and its predictive value for clinical outcomes. Methods Five hundred and sixty-eight primary breast cancer patients who received surgery treatment from January 2008 to January 2010 were included in this study.Tissue sections of surgical resection specimens were underwent estrogen receptor(ER), progesterone receptor(PR), and human epidermal growth factor receptor 2(HER2) immunohisto chemical staining, according to the judgment for triple negative breast cancer and non triple negative breast cancer.Data on age, family history, menstruation, tumor size, tumor stage, tumor grade, pathological type and lymph node metastasis were collected for analysis.Immunohistochemical analysis of AR was done in tissue sections of triple negative breast cancer patients, Kaplan-Meier method was used to compare survival between AR(+ ) and AR(-) groups, and Log-rank method was used to determine the association between AR- positive expression and 5-year overall survival as well as disease free survival. Results Among 568 breast cancer patients, 174(30.6%) TNBC patients were identified, including 84 patiens with AR(-) expression and 90 patients with AR(+ ) expression.During 5 years' follow-up, reccurrence rate was 35.7%(30/84) in AR(-) group and 20.0%(18/90) in AR(+ ) group; 5-year overall survival rate was 73.8% in AR(-) group and 81.1% in AR(+ ) group.There was no significant association between AR(+ ) expression and 5-year death or recurrence rate, while after adjusting for age, menstruation, tumor size and lymph node metastasis, AR(+ ) expression was significantly associated with decreased 5-year death and recurrence rate, adjusted hazard ratio(HR) was 0.794, 95CI(0.430-1.021) and 0.722, 95CI(0.451-0.965) respectively. Conclusion AR(-) expression is associated with increased risk of death and recurrence and is a promising predictive marker for poor clinical outcomes. Key words: Triple negative breast cancer; Androgen receptor; Estrogen receptor; Progesterone receptor; Human epidermal growth factor receptor 2; Survival rate

Smoking Status Influences Clinical Outcome in Collagenous Colitis.

The relationship between clinical and histological parameters in collagenous colitis (CC) is poorly understood. Smoking is a risk factor for CC, whereas its impact on clinical activity and outcome is not well known. In a post hoc analysis of pooled data from two randomized controlled trials we assessed the association between demographic data (gender, age, smoking habits, family history of inflammatory bowel disease), clinical variables (duration of symptoms, mean number of stools/watery stools per day, abdominal pain, clinical remission) and histological data (thickness of the collagen band, inflammation of the lamina propria, total numbers of intraepithelial lymphocytes, degeneration). Moreover, we analysed the predictive value of baseline parameters for clinical outcome in a logistic regression model. Pooled data were available from 202 patients with active CC, of whom 36% were current smokers, 29% former smokers and 35% non-smokers. Smoking status was associated with decreased ability to achieve clinical remission (current smokers vs non-smokers: odds ratio [OR] 0.31, 95% confidence interval [CI] 0.10-0.98, p = 0.045; former smokers vs non-smokers: OR 0.19, 95% CI 0.05-0.73, p = 0.016). Current smokers had an increased mean number of watery stools at baseline compared with non-smokers (p = 0.051) and increased mean number of watery stools per se was associated with decreased likelihood of obtaining clinical remission (OR 0.63, 95% CI 0.47-0.86, p = 0.003). Patient characteristics and histology at baseline had no association with clinical parameters and no predictive value for clinical outcome. Smoking worsens clinical symptoms in CC and is associated with an increased number of watery stools and decreased likelihood of achieving clinical remission. There is no significant association between histology and clinical data.

Gene Expression Signatures Predictive of Bevacizumab/Erlotinib Therapeutic Benefit in Advanced Nonsquamous Non-Small Cell Lung Cancer Patients (SAKK 19/05 trial).

We aimed to identify gene expression signatures associated with angiogenesis and hypoxia pathways with predictive value for treatment response to bevacizumab/erlotinib (BE) of nonsquamous advanced non-small cell lung cancer (NSCLC) patients. Whole-genome gene expression profiling was performed on 42 biopsy samples (from SAKK 19/05 trial) using Affymetrix exon arrays, and associations with the following endpoints: time-to-progression (TTP) under therapy, tumor-shrinkage (TS), and overall survival (OS) were investigated. Next, we performed gene set enrichment analyses using genes associated with the angiogenic process and hypoxia response to evaluate their predictive value for patients' outcome. Our analysis revealed that both the angiogenic and hypoxia response signatures were enriched within the genes predictive of BE response, TS, and OS. Higher gene expression levels (GEL) of the 10-gene angiogenesis-associated signature and lower levels of the 10-gene hypoxia response signature predicted improved TTP under BE, 7.1 months versus 2.1 months for low versus high-risk patients (P = 0.005), and median TTP 6.9 months versus 2.9 months (P = 0.016), respectively. The hypoxia response signature associated with higher TS at 12 weeks and improved OS (17.8 months vs. 9.9 months for low vs. high-risk patients, P = 0.001). We were able to identify gene expression signatures derived from the angiogenesis and hypoxia response pathways with predictive value for clinical outcome in advanced nonsquamous NSCLC patients. This could lead to the identification of clinically relevant biomarkers, which will allow for selecting the subset of patients who benefit from the treatment and predict drug response.