Worse Clinical Outcomes In Patients Research Articles

4089Prognostic value of cardiac metabolic activity assessed by 18F-FDG PET in patients with cardiac sarcoidosis

Abstract Background Sarcoidosis is a systemic granulomatous disease that affects multiple organs. Among these,the presenceof cardiac involvementis recognized as a determinant of worse clinical outcomes. 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) is a valuable modality for detecting active inflammatory lesions associated with cardiac sarcoidosis (CS). Generally,the maximum standardized uptake value (SUV) is suitable for evaluating disease activity in CS, but this quantitative method had limitations because it does not integrate both volume and intensity of FDG uptake simultaneously. Cardiac metabolic activity (CMA), which is quantitative measures of FDG volume-intensity, could be a diagnostic tool in the evaluation of CS. However, its prognostic implication in patients with CS is unclear. Purpose We sought to investigate whether CMA assessed by FDG-PET was associated with long-term worse clinical outcomes in patients with CS. Methods A total of 76 consecutive patients suspected CS who underwent FDG-PET between January 2010 and April 2018 in our university hospital were registered. We excluded patients whodid not meet the Japanese Ministry of Health and Welfare 2007 criteria (n=9) and those who received oral corticosteroids at the time of FDG-PET (n=5). Ultimately, 62 CS patients with definitively diagnosed were included in this study.We used a dedicated software to analyze SUV. Cardiac metabolic volume (CMV) was defined as the volume within the boundary determined by the threshold (SUV mean of blood pool × 1.5). CMA was calculated by multiplying CMV by SUV mean. The primary outcome of interest was the composite of advanced atrioventricular block, ventricular tachycardia, ventricular fibrillation, heart failure hospitalization, and all-cause death. Results During a median follow-up period of 1287 (IQR 806–1809) days after the first FDG-PET, the adverse events occurred in 12 patients (19%). Events group had significantly higher CMA compared to no events group (83 [IQR 11–330] vs. 354 [IQR 70–577]) (Figure A). Based on ROC analysis, the optimal cut-off value of CMA for the discrimination of the adverse events was 244 ml, and c-index was 0.71 (95% CI, 0.55–0.87). Patients with high CMA (≥244 ml, n=23) had lower LVEF, and higher prevalence of New York Heart Association functional class III or IV, and higher plasma BNP level compared to those with low CMA (<244 ml, n=39). Kaplan-Meier analysis revealed that composite adverse events more frequently occurred in patients with high CMA compared to those with low CMA (Figure B).Univariable Cox regression analysis showed that higher CMA was associated with increased subsequent risk of adverse events (HR 1.47, 95% CI 1.06–2.24). Conclusions Higher CMA assessed by FDG-PET was associated with worse clinical long-term outcomes in patients with CS, suggesting that measurement of the volume-intensity of abnormal FDG uptake may be useful for risk stratification in patients with CS.

P5655Efficacy of new-generation atrial antitachycardia pacing for atrial tachyarrhythmias in patients with left ventricular dysfunction

Abstract Background The progression to persistent atrial fibrillation (AF) is associated with a worse clinical outcome in patients with previous atrial tachyarrhythmias. New-generation atrial antitachycardia pacing (ATP) (Reactive ATP) reduced the progression to persistent AF in patients with pacemaker and preserved left ventricular (LV) function. However, little is known about the efficacy of Reactive ATP in patients with cardiac implantable electronic devices (CIED) and LV dysfunction. Purpose We aimed to investigate the efficacy of Reactive ATP for atrial tachyarrhythmias in patients with LV dysfunction (LV ejection fraction [LVEF] <40%). Methods This study included 423 patients with CIED and previous atrial tachyarrthythmias. Reactive ATP was programmed in 284 patients (ATP group) and 139 were implanted with a dual-chamber device without ATP function (control group). The differences in the success rate of ATP and incidence of progression to persistent AF (≥7 days) between the ATP and control groups were evaluated in 108 patients with LVEF <40% (reduced LVEF) and 315 with LVEF ≥40% (preserved LVEF). Patients with persistent AF were excluded from this study. Results During 710±337 days of follow-up period, 16 patients (15%) with reduced LVEF and 51 (16%) with preserved LVEF progressed to persistent AF (p=0.88). The mean ATP success rate was lower in patients with reduced LVEF than in those with preserved LVEF, although not statistically significant (reduced LVEF: 27.2±19.4% and preserved LVEF: 35.1±29.2%, p=0.12). The incidence of progression to persistent AF was significantly lower in the ATP group than in the control group both in patients with reduced and preserved LVEF (log-rank, reduced LVEF: p=0.0070 and preserved LVEF: p<0.0001) (Figure). Multivariate analysis showed that use of Reactive ATP and smaller left atrium were associated with lower incidences of persistent AF, while LVEF was not predictive of progression to persistent AF (Reactive ATP: hazard ratio [HR] 0.28, 95% confidence interval [CI] 0.17–0.46, p<0.0001, left atrium diameter: HR 1.03, 95% CI 1.00–1.07, p=0.030). Figure 1 Conclusions Reactive ATP was effective in preventing AF progression in patients with LV dysfunction.

P679Long-term cardiovascular outcomes after percutaneous coronary interventions in patients with acute coronary syndrome and cancer

Abstract Background Over time, the use of PCI increased and mortality decreased comparably in patients with ACS and cancers. Although the adverse cardiac effect of cancer has been widely reported, we know less on whether lung cancer confers worse clinical outcomes in patients with established ACS, particularly those undergoing PCI. Methods All cancer patients who were admitted in the hospital with ACS as initial diagnosis and underwent PCI from January 2006 to December 2016 were enrolled, and were divided into 2 groups according to their malignancy types: lung cancer and others. Population data was collected and clinical follow-up was performed by either telephone contact or office visit. Survival was graphically represented using Kaplan-Meier curves. Differences in survival rates were compared using the log-rank test. Analysis was performed with SPSS statistical software, version 22.0 for Windows. See Figure 1. Results 16,062 patients suffered from various cancers and 55,401 patients underwent PCI. After cross referencing the two patient lists, 337 patients were enrolled who underwent cancer prior to ACS, and 15.1% (n=51) had a medical history of lung cancer. See Figure 2 and 3. Male gender was more prevalent in the lung cancer group than other cancers group (84.3% vs 60.5%, P=0.01). There was no significant difference between lung cancer and other cancers group in the presence of traditional cardiovascular risk factors, such as hypertension, hyperlipidemia, obesity, diabetes mellitus, history of smoking, history of drinking and the family history of coronary artery disease (P>0.05 for all). Among all coronary complex lesions, calcified lesions was more prevalent in lung cancer group (21.6% vs 11.5%, P=0.04), although there was no significant difference between two groups in left main lesions, bifurcation lesions and CTO lesions (P>0.05 for all). For anticancer therapy, patients with lung cancer received more radiotherapy (29.4% vs 13.6%, P=0.01) and chemotherapy (37.3% vs 25.5%, P=0.08). Follow-up was available for 289 of the 337 patients (85.8%). See table 1. The incidence of cardiovascular death (5.9% vs 1.0%, P=0.02) was higher in the lung cancer group. As shown the Kaplan-Meier curves in Figure 1, the survival rate free from all-cause death (log rank P=0.034, Figure 4A) and cardiovascular death (log rank P=0.013, Figure 4B) was significantly lower in lung cancer group than in other cancers group during the follow-up. Figures and Table Conclusions Lung cancer has a non-negligible prevalence in patients with ACS undergoing PCI, with significantly worse long-term cardiovascular outcomes. The results of our study reinforce the importance of understanding to patients who need closer follow-up, careful evaluation, and intervention.

P795Long-term prognostic value of the combination of plasma volume status and pulmonary-systemic pressure ratio in patients admitted with acute decompensated heart failure

Abstract Background Plasma volume (PV) expansion plays an essential role in heart failure and PV status provides prognostic information in patients (pts) with acute decompensated heart failure (ADHF). On the other hand, concomitant presence of pulmonary hypertension in heart failure is associated with increased adverse events and may be related to interventricular uncoupling and impaired cardiac efficiency. It has recently been shown that an increased mean pulmonary artery pressure to mean systemic arterial pressure ratio (MPS ratio), a marker of interventricular coupling and efficiency, is associated with worse clinical outcomes in patients with advanced heart failure. However, there is no information available on the long-term prognostic value of the combination of PV status and MPS ratio in pts admitted for ADHF. Methods We studied 248 pts admitted for ADHF, who underwent right heart catheterization at the admission and were discharged with survival. PV status and MPS ratio were obtained at the admission. PV status was calculated as the following: Actual PV = (1 − hematocrit) x [a + (b x body weight)] (a=1530 in males and a=864 in females, b=41 in males and b=47.9 in females), Ideal PV = c x body weight (c=39 in males and c=40 in females), and PV status = [(actual PV − ideal PV)/ideal PV] x 100(%). The study endpoint was cardiovascular death (CVD). Results During a mean follow-up period of 5.2±4.4 yrs, 62 pts had CVD. PV status (10.0±16.2 vs 5.0±15.3%, p=0.03) and MPS ratio (0.408±0.114 vs 0.347±0.102, p=0.0001) were significantly greater in patients with than without CVD. At multivariate Cox regression analysis, PV status and MPS ratio were significantly associated with CVD, independently of prior heart failure hospitalization, eGFR, and serum sodium level and anemia. Patients with greater PV status (> median value = 4.6%) and MPS ratio (> median value = 0.346) had a significantly higher CVD risk than those with either and none of them (44% vs 22% vs 14%, p<0.0001, respectively). Conclusions The combination of PV status and MPS ratio might be useful for stratifying patients at risk for CVD in patients with ADHF.

P791Long-term prognostic value of pulmonary-systemic pressure ratio in patients admitted for acute decompensated heart failure with reduced or preserved left ventricular ejection fraction

Abstract Background Concomitant presence of pulmonary hypertension in heart failure is associated with increased adverse events and may be related to interventricular uncoupling and impaired cardiac efficiency. It has recently been shown that an increased mean pulmonary artery pressure to mean systemic arterial pressure ratio (MPS ratio), a marker of interventricular coupling and efficiency, is associated with worse clinical outcomes in patients with advanced heart failure. However, there is little information available on the long-term prognostic value of MPS ratio in patients with acute decompensated heart failure (ADHF), relating to reduced or preserved left ventricular ejection fraction (HFrEF or HFpEF). Methods and results We studied 240 patients admitted for ADHF, who underwent right heart catheterization and were discharged with survival (HFrEF (LVEF≤40%); n=110, HFpEF (LVEF>40%); n=130). MPS ratio was obtained at the admission. During a mean follow-up period of 5.2±4.4 yrs, 59 patients had cardiovascular death (CVD). In both groups with HFrEF and HFpEF, MPS ratio was significantly greater in patients with than without CVD (HFrEF; 0.453±0.101 vs 0.382±0.116, p=0.0035, HFpEF; 0.374±0.118 vs 0.323±0.083, p=0.0091). At multivariate Cox regression analysis, MPS ratio was significantly associated with CVD, independently of eGFR and serum sodium level in HFrEF and HFpEF groups. Patients with high MPS ratio (>0.386 in HFrEF and >0.415 in HFpEF determined by ROC curve analysis) had a significantly increased risk of CVD than those with low MPS ratio in both groups. Conclusions MPS ratio could provide the long-term prognostic information in patients admitted for ADHF, regardless of reduced or preserved LVEF.

1013 The Effect of Steatosis on the Clinical Course of Autoimmune Hepatitis

INTRODUCTION: Nonalcoholic Fatty Liver Disease (NAFLD) is a common liver disease in western developed countries. NAFLD is increasingly encountered alongside other chronic liver diseases, such as autoimmune hepatitis (AIH). The impact of NAFLD on the clinical course of AIH is unclear and one recent single center study suggested a worse clinical outcome for patients with AIH and concurrent steatohepatitis. We aimed to determine the frequency of steatosis and steatohepatitis in patients with AIH and the effect on treatment outcomes. METHODS: The cohort consisted of 61 AIH patients from a single, large, tertiary referral center with pre-treatment liver biopsies and available clinical data. Biliary overlap syndromes were excluded. Two liver pathologists recorded histological findings, including quantification of steatosis and steatohepatitis. One clinical reviewer recorded 96 clinical/laboratory variables. Non-parametric (Spearman rho) tests were used and correlations with P < 0.05 were deemed significant. Non parametric t-tests were used to compare various degrees of steatosis (none, mild/moderate) with clinical variables and P < 0.05 were deemed significant. RESULTS: Patients were followed for mean of 3.1 ± 3 years after diagnosis. Mean age at diagnosis was 49.9 ± 19.1 years and mean BMI at diagnosis was 28.3 ± 7. In this cohort, 31.7% of patients had steatosis on histology, and out of those 75.0% had mild and 25.0% had moderate degree of steatosis. Strikingly, there were no cases of steatohepatitis. The degree of steatosis was positively correlated with increasing age and BMI, (r = 0.44, CI 0.17-0.65, P ≤ 0.001and r = 0.49, CI 0.15-0.73, P = 0.01, respectively). However, there was no correlation between degree of steatosis and initial treatment failure, ALT at 12 months of treatment, chances of biochemical remission, development of cirrhosis, or the dose of steroid required for biochemical remission. Furthermore, there was no difference in these outcomes when those with versus without steatosis were compared. CONCLUSION: Data from this single center study suggest that AIH patients with mild and moderate steatosis have the same clinical course and response to treatment as those without steatosis.. The increasing prevalence of superimposed NAFLD in AIH warrants longitudinal observational multi-center studies focused on the frequency of steatohepatitis, and the impact of steatosis on the natural history of AIH.

1176Hepatocyte growth factor has prognostic utility in light chain and transthyretin cardiac amyloidosis

Abstract Background With the advent of multiple novel therapeutics for light chain (AL) and transthyretin (ATTR) amyloidosis, there is a critical need for validated prognostic markers in cardiac amyloidosis. A discriminatory serum biomarker may improve prognostic and staging systems in AL and ATTR cardiac amyloidosis. Purpose Our objective was to test the hypothesis that hepatocyte growth factor (HGF) is associated with clinical outcomes in patients with AL and ATTR cardiac amyloidosis. Methods 102 patients with AL or ATTR and suspected cardiac involvement were prospectively enrolled. HGF, NT-proBNP, troponin-T, and eGFR were measured upon study enrollment. Cardiac involvement was established by 1) endomyocardial biopsy, or 2) non-cardiac biopsy with concentric hypertrophy on echocardiography, low voltage or pseudo-infarction on ECG, elevated NT-proBNP or troponin-T, or characteristic delayed myocardial enhancement on cardiac MRI. Patients were followed for the occurrence of all-cause mortality, cardiac transplantation, and left-ventricular assist device implantation. Results Of the total amyloidosis cohort, 72 had cardiac involvement while 30 had non-cardiac disease. HGF, NT-proBNP, and troponin-T levels were significantly higher in patients with cardiac involvement than in patients with non-cardiac disease (p<0.05 for all comparisons). Over a median follow-up period of 1.9 years there were 20 deaths, 1 cardiac transplant, and 1 left-ventricular assist device implant, all in patients with cardiac involvement. Patient stratification by cut-off levels of NT-proBNP (332 pg/mL), troponin-T (35 ng/L), and eGFR (45 mL/min/1.73m2) used in published staging models for AL and ATTR cardiac amyloidosis showed no association between abnormal biomarker level and adverse clinical outcome (p>0.05). In contrast, stratification by HGF level of 310 pg/mL (identified by the Youden Index for cardiac involvement by AL and ATTR in our cohort) showed that elevated HGF was associated with worse clinical outcomes (p=0.0211). Furthermore, event-free survival was worse in patients with elevated HGF, with survival curves diverging soon after enrollment (p=0.0730). HGF is Prognostic in Cardiac Amyloidosis Conclusions Elevated HGF is associated with worse clinical outcomes in patients with AL and ATTR cardiac amyloidosis and has potential for clinical utility.

P5656Heart failure clinical phenotypes and outcomes in patients with atrial fibrillation: an analysis from the eurobservational research programme in atrial fibrillation long-term general registry

Abstract Introduction Heart failure (HF) is a well-known risk factor for atrial fibrillation (AF). Moreover, HF is associated with worse clinical outcomes in patients with known AF. Recently, phenotypes of HF have been redefined according to the level of ejection fraction (EF). New data are needed to understand if a differential risk for outcomes exists according to the new phenotypes' definitions. Purpose To evaluate the risk of major adverse outcomes in patients with AF and HF according to HF clinical phenotypes. Methods We performed a subgroup analysis of AF patients enrolled in the EORP-AF Long-Term General Registry with a history of HF at baseline, available EF and follow-up data. Patients were categorized as follows: i) EF<40%, i.e. HF reduced EF [HFrEF]; ii) EF 40–49%, i.e. HF mid-range EF [HFmrEF]; iii) EF ≥50%, i.e. HF preserved EF [HFpEF]. Any thromboembolic event (TE)/acute coronary syndrome (ACS)/cardiovascular (CV) death, CV death and all-cause death were recorded. Results A total of 3409 patients were included in this analysis: of these, 907 (26.6%) had HFrEF, 779 (22.9%) had HFmrEF and 1723 (50.5%) had HFpEF. An increasing proportion with CHA2DS2-VASc ≥2 was found across the three groups: 90.4% in HFrEF, 94.6% in HFmrEF and 97.3% in HFpEF (p<0.001), while lower proportions of HAS-BLED ≥3 were seen (28.0% in HFrEF, 26.3% in HFmrEF and 23.6% in HFpEF, p=0.035). At discharge patients with HFpEF were less likely treated with antiplatelet drugs (22.0%) compared to other classes and were less prescribed with vitamin K antagonists (VKA) (57.0%) and with any oral anticoagulant (OAC) (85.7%). No differences were found in terms of non-vitamin K antagonist oral anticoagulant use. At 1-year follow-up, a progressively lower rate for all study outcomes (all p<0.001), with an increasing cumulative survival, was found across the three groups, with patients with HFpEF having better survival (all p<0.0001 for Kaplan-Meier curves). After full adjustment, Cox regression analysis showed that compared to HFrEF, HFmrEF and HFpEF were associated with risk of all study outcomes (Table). Cox Regression Analysis HR (95% CI) Any TE/ACS/CV Death CV Death All-Cause Death HFmrEF 0.65 (0.49–0.86) 0.53 (0.38–0.74) 0.55 (0.41–0.74) HFpEF 0.50 (0.39–0.64) 0.42 (0.31–0.56) 0.45 (0.35–0.59) ACS = Acute Coronary Syndrome; CI = Confidence Interval; CV = Cardiovascular; EF = Ejection Fraction; HF = Heart Failure; HR = Hazard Ratio. Conclusions In this cohort of AF patients with HF, HFpEF was the most common phenotype, being associated with a profile related to an increased thromboembolic risk. Compared to HFrEF, both HFmrEF and HFpEF were associated with a lower risk of all major adverse outcomes in AF patients.

Urate-lowering therapy for heart failure

Heart failure (HF) is one of the major public health problems in developed countries. Hyperuricemia (HU) is often found in patients with chronic HF (CHF) and is a well-known independent predictor for mortality and re-hospitalization for the progression of HF. The association of HU with worse clinical outcomes in patients with CHF may be attributed to the effects of uric acid (UA) and the enzyme xanthine oxidase (XO) on the vascular endothelium, which leads to the release of inflammatory cytokines and reactive oxygen species. The presence of this mechanism leads to an interest in exploring the potential benefits of inhibiting XO in patients with HF. XO inhibitors are likely to become a new tool to improve prognosis in these patients.

Association of Weekend Admission and Clinical Outcomes in Hospitalised Adult Patients with Sepsis

Background: Sepsis is associated with detrimental clinical outcomes. It requires early diagnosis and urgent therapeutic intervention. Because staffing during after-hours is limited, we explored whether after-hour admissions are associated with worse clinical outcomes in patients with sepsis. Methods: In this cohort study, we analysed nationwide acute care admissions for a main diagnosis of sepsis in Switzerland between 2006 and 2016 using prospective administrative data. The primary outcome was in-hospital mortality using multivariate logistic regression models. Secondary outcomes were intensive care unit (ICU) admission, intubation, and 30-day readmission. Findings: We included 86`597 hospitalisations for sepsis, 60·1% admitted during routine-hours, 16·8% on weekends and 23·1% at night. Compared to routine-hour admissions, we found a higher risk for in-hospital mortality in patients admitted on weekends (20·0% vs. 19·2%, adjusted odds ratio [OR] 1·05, 95% confidence interval [95% CI] 1·01-1·10, p=0·029). Also, the risk for ICU admission (30·5% vs. 28·0%, OR 1·14, 95% CI 1·10-1·19, p<0·0001) and intubation (14·7% vs. 12·9%, OR 1·18, 95% CI 1·12-1·25 p<0·0001) was higher for weekends compared to routine-hour admissions. There were no differences in 30-day readmission rates. Night shift admission, compared to routine-hour admission, also had a higher risk for ICU admission and intubation, whereas in-hospital mortality was not increased. Interpretation: Among hospitalisations with a main diagnosis of sepsis, weekend admissions were associated with higher risk for in-hospital mortality, ICU admission, and intubation. Whether these findings can be explained by staffing-level differences needs to be addressed. Funding Statement: Swiss National Science Foundation (SNF_407440_167376) Declaration of Interests: All authors declare no competing interests. Ethics Approval Statement: Ethics Commission Northwest and Central Switzerland approved the study.

Eosinopenia as an Adverse Marker of Clinical Outcomes in Patients Presenting with Acute Myocardial Infarction

BackgroundEosinopenia is considered a surrogate of inflammation in several disease settings. Following ST-segment elevation myocardial infarction, eosinopenia is presumed to be a marker of infarct severity. We sought to study the relationship between eosinopenia and infarct severity and how this relationship determined the long-term outcomes following ST-segment elevation myocardial infarction. MethodsSix hundred and six consecutive patients undergoing primary percutaneous coronary interventions from a large volume single center were enrolled. Low eosinophil count was defined as < 40 cells/mL from samples within 2 hours after reperfusion. Primary endpoint was defined as composite of death, myocardial infarction, stroke, unplanned revascularization, and readmission for heart failure over 3.5 years’ follow-up. ResultsSixty-five percent of the patients had eosinopenia. Patients in the low eosinophil group had larger infarct size as measured by troponin value (2934 vs 1177 ng/L, P < .001) and left ventricle systolic function on echocardiography (48% vs 50%, P = 0.029). There was a weak correlation between eosinophil count and both troponin (r = -0.25, P < 0.001) and ejection fraction (r = 0.10, P = .017). The primary endpoint was higher in eosinopenic patients (28.8% vs. 20.4%; hazard ratio [HR] 1.49, 95% confidence interval [CI] 1.05 to 2.13, P = .023). A discordance between eosinopenia and severe left ventricle systolic dysfunction was observed in 55.6% of cases. Compared with normal count, eosinopenia was associated with worse clinical outcomes in patients with non-severe left ventricle dysfunction (24.1% vs 16.2%; HR 1.58, 95% CI 1.01 to 2.45, P = .044) but not in those with severe left ventricle dysfunction (42.3% vs. 38.9%; HR 1.10, 95% CI 0.59 to 2.03, P = .77) (P < .01 for interaction). ConclusionsEosinopenia is an easily determined marker that reflects worse clinical outcomes over long-term follow-up.

The mitochondrial transcription machinery genes are upregulated in acute myeloid leukemia and associated with poor clinical outcome

BackgroundAcute myeloid leukemia (AML) is characterized by rapid growth of abnormal blasts that overcrowd normal hematopoiesis. Defective mitochondrial biogenesis has been implicated in AML, which we believe is partly due to the deregulation of the mitochondrial transcription machinery (MTM) genes influencing the expression of mitochondrial genes. Here, we aim to characterize MTM gene upregulation in AML. MethodsMolecular and clinical patient data were retrieved from several public AML datasets. Kaplan-Meier survival curves were used to compare overall survival between patients, while Mann–Whitney U's non-parametric and Fisher's exact test were used for comparing continuous and categorical variables, respectively. ResultsThe MTM genes TFB1M, TFB2M, TFAM, and POLRMT were upregulated in patients with AML compared with healthy donors. Upregulation of one or more of these genes was associated with higher percentage of peripheral blood blasts (P = 0.002), normal cytogenetic status (P = 0.027) and NPM1 mutations (P = 0.009). Additionally, patients with high expression of MTM genes (Z ≥ 1) had shorter median overall survival compared with low MTM gene expression (Z < 1) (months: 11.8 vs 24.1, P = 0.027; multivariate survival analysis Cox Proportional Hazards model, HR: 1.82 (1.22–2.70); p-value: 0.003). ConclusionThe mitochondrial transcriptional machinery is upregulated and associated with worse clinical outcome in patients with AML and may present a viable therapeutic target.

The long noncoding RNA HORAS5 mediates castration-resistant prostate cancer survival by activating the androgen receptor transcriptional program.

Prostate cancer (PCa) is driven by the androgen receptor (AR)‐signaling axis. Hormonal therapy often mitigates PCa progression, but a notable number of cases progress to castration‐resistant PCa (CRPC). CRPC retains AR activity and is incurable. Long noncoding RNA (lncRNA) represent an uncharted region of the transcriptome. Several lncRNA have been recently described to mediate oncogenic functions, suggesting that these molecules can be potential therapeutic targets. Here, we identified CRPC‐associated lncRNA by analyzing patient‐derived xenografts (PDXs) and clinical data. Subsequently, we characterized one of the CRPC‐promoting lncRNA,HORAS5, in vitro and in vivo. We demonstrated that HORAS5 is a stable, cytoplasmic lncRNA that promotes CRPC proliferation and survival by maintaining AR activity under androgen‐depleted conditions. Most strikingly, knockdown of HORAS5 causes a significant reduction in the expression of AR itself and oncogenic AR targets such as KIAA0101. Elevated expression of HORAS5 is also associated with worse clinical outcomes in patients. Our results from HORAS5 inhibition in in vivo models further confirm that HORAS5 is a viable therapeutic target for CRPC. Thus, we posit that HORAS5 is a novel, targetable mediator of CRPC through its essential role in the maintenance of oncogenic AR activity. Overall, this study adds to our mechanistic understanding of how lncRNA function in cancer progression.

PD-L1 and p16 expression in penile squamous cell carcinoma from an endemic region.

515 Background: Penile squamous cell carcinoma (PSCC) is a rare malignancy with limited treatment option in advanced stages. Brazil has one of the highest incidences of PSCC in the world, and different biology has been postulated across distinct populations. We evaluate PD-L1 and p16 expressionand its association with clinical outcomes in PSCC patients from an endemic region. Methods: Formalin-fixed paraffin-embedded (FFPE) specimens were obtained from 35 patients with PSSC. PD-L1 and p16 expression were evaluated by immunohistochemistry. PD-L1 tumor positivity (PD-L1+) was defined as ≥1% tumor cell membrane staining using ZR3 antibody. Any tumor cell membrane staining of p16 was considered positive (p16+). Baseline characteristics including tumor size, stage, grade, subtype, and survival data were collected. Comparisons between PD-L1 and/or p16 expression and clinicopathological features were evaluated using fisher exact testor wilcoxon rank sum tests. Cox model tested the association of PD-L1 and/or p16 expression and 5-year-survival. Results: Clinical features were summarized in table1 according to PD-L1 expression. PD-L1 positivity was significantly associated with larger tumor size ( p=0.027), and p16 expression, a surrogate for HPV infection ( p=0.002). There was a non-statistically significant trend to a shorter 5-year-survival for PD-L1+/p16+ vs. PD-L1-/p16- patients (30.8% vs. 60.6% HR: 2.27 95% CI - 0.61-8.42 p=0.22). Conclusions: PD-L1 expression appears to be associated with p16 expression, larger tumors, higher proliferative rate and worse clinical outcomes in patients with PSCC. provide additional rationale for PD1/PD-L1 inhibitors alone or in combination with chemotherapy foradvanced PSCC in endemic regions. Clinical features. [Table: see text]

IMPACT OF CHRONIC KIDNEY DISEASE ON CLINICAL AND HEALTH STATUS OUTCOMES AFTER CHRONIC TOTAL OCCLUSION PERCUTANEOUS CORONARY INTERVENTION

Chronic kidney disease (CKD) has been associated with lower success and worse clinical outcomes in patients undergoing percutaneous coronary intervention (PCI) for chronic total occlusions (CTO). Whether this reflects greater disease and comorbidity burden in CKD patients, or CKD itself, and the

Increased autocrine interleukin-6 production is significantly associated with worse clinical outcome in patients with chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) remains incurable with current standard therapy. We have previously reported that an increased expression of interleukin‐6 (IL‐6) receptor CD126 leads to resistance of CLL cells to chemotherapy and worse prognosis for patients with CLL. In this study, we determine whether autocrine IL‐6 production by CLL B cells is associated with poor clinical outcome and explore IL‐6‐mediated survival mechanism in primary CLL cells. Our results demonstrate that higher levels of autocrine IL‐6 are significantly associated with shorter absolute lymphocyte doubling time, patients received treatment, without complete remission, advanced Binet stages, 17p/11q deletion, and shorter time to first time treatment and progression‐free survival. IL‐6 activated both STAT3 and nuclear factor kappa B (NF‐κB) in primary CLL cells. Blocking IL‐6 receptor and JAK2 inhibited IL‐6‐mediated activation of STAT3 and NF‐κB. Our study demonstrates that an increased autocrine IL‐6 production by CLL B‐cells are associated with worse clinical outcome for patients with CLL. IL‐6 promotes CLL cell survival by activating both STAT3 and NF‐κB through diverse signaling cascades. Neutralizing IL‐6 or blocking IL‐6 receptor might contribute overcoming the resistance of CLL cells to chemotherapy. We propose that the measurement of autocrine IL‐6 could be a useful approach to predict clinical outcome.

Impact of admission liver stiffness on long-term clinical outcomes in patients with acute decompensated heart failure.

Liver stiffness (LS) has been reported to be a marker of liver congestion caused by elevated central venous pressure in heart failure (HF) patients. Recent studies demonstrated that LS could be non-invasively measured by virtual touch quantification (VTQ). However, its prognostic implication in patients with acute decompensated heart failure (ADHF) is unclear. This study sought to determine whether LS measured by VTQ could be a determinant of subsequent adverse events in ADHF patients. We prospectively recruited 70 ADHF patients who underwent LS measurement by VTQ on admission in our university hospital between June 2016 and April 2018. The primary outcome of interest was the composite of all-cause mortality and worsening HF. During a median follow-up period of 272 (interquartile range 122-578) days, there were 26 (37%) events, including 5 (7%) deaths and 21 (30%) cases of worsening HF. The c-index of LS for predicting the composite of adverse events was 0.77 (95% CI 0.66-0.88), and the optimal cut-off value of LS was 1.50m/s. Adverse events were more frequently observed in patients with high LS (≥1.50m/s) compared to those with low LS (<1.50m/s). Multivariable Cox regression analyzes revealed that higher LS was independently associated with increased subsequent risk of adverse events after adjustment for confounders. In conclusion, high admission LS was an independent determinant of worse clinical outcomes in patients with ADHF. This finding suggests that LS on admission is useful for risk stratification of patients with ADHF.

Quantitative Assessment of Indoleamine 2,3-Dioxygenase (IDO) Expression at Diagnosis Predicts Clinical Outcome in Patients with Acute Myeloid Leukemia Undergoing Allogeneic Stem Cell Transplantation

IntroductionIndoleamine 2,3-dioxygenase (IDO) is an intracellular heme-containing enzyme that catalyzes the initial rate-limiting step in tryptophan degradation along the kynurenine pathway. IDO is physiologically expressed by a wide variety of human cells in response to several stimuli and it is known to have a crucial role in the induction of immune tolerance during pregnancy, infections, transplantation, autoimmunity and tumors. IDO-mediated tryptophan degradation results in inhibition of T-cell proliferation, increase of T-cell apoptosis and T-reg induction. Several studies demonstrated that IDO production can induce the increase of Regulatory T-cells (Tregs) directly through the conversion of CD25- into CD25+ T cells, even in acute myeloid leukemia (AML) patients. IDO expression can be considered a novel mechanism of leukemia escape from immune control and its inhibition may represent an antileukemia therapeutic strategy. Aim of our work is to analyze IDO mRNA expression in a cohort of AML patients and to investigate the presence of any significant correlation between IDO expression and standard prognostic factors or clinical outcome.MethodsWe analyzed a cohort of 68 adult patients aged 18 years or older, who were diagnosed with de novo or secondary AML. IDO mRNA expression was evaluated by Real-Time (RT)-PCR in blood bone marrow and peripheral blood samples at diagnosis. Patients were then retrospectively stratified according to standard risk factors at diagnosis and to IDO mRNA expression levels.ResultsMedian age of analyzed patients was 57 years (range 21-76). Fifty-nine out of 68 patients (87%) had de novo AML, whereas 9 out of 68 patients (13%) had secondary AML. A comprehensive risk assessment was available for 61 patients. Among these 61 patients who were evaluable for risk stratification, 13 patients (21%) resulted to have a favorable risk AML, 30 (49%) had an intermediate risk AML and 17 patients (30%) were stratified as high-risk AML. Sixty out of 68 patients received intensive, standard, induction chemotherapy regimens. The remaining 8 patients were not candidate to receive intensive chemotherapy mainly because of comorbidities. Twenty-three out of 68 patients (34%) were considered eligible for allogeneic stem cells transplantation (alloSCT) as consolidation therapy, after obtaining complete remission with standard chemotherapy. IDO expression in peripheral blood (PB) samples was between 0.07 and 4272.26 (median 5.60). Conversely, IDO expression in bone marrow (BM) samples was between 0.17 and 243.16 (median 1.21). Our data did not establish any significant correlation between IDO expression and leukemia risk factors at diagnosis, in particular cytogenetics, de novo or secondary AML, leukocytosis. Among the 60 patients who received induction chemotherapy, 35 achieved morphological complete remission (CR), 24 did not respond and 1 patient was not evaluable for response. Response to induction chemotherapy was not influenced by IDO mRNA expression levels. Interestingly, among patients undergoing alloSCT, high levels of IDO mRNA expression in PB samples negatively correlated with patients' overall survival. In particular, high IDO expression of more than 10 was associated with worse overall survival after alloSCT even when adjusted by patients' age and disease status at transplant (log rank P=0.02) (Fig.1). With the limitations of the low number of patients, these results from the group of transplanted patients were not likely due to differences in the incidence and severity of graft-versus-host-disease, whereas high IDO mRNA expression level was predictive of increased incidence of relapse.ConclusionsThis work suggests that IDO mRNA expression levels can be considered as predictive of AML outcome, independently from other risk factors at diagnosis. In our set, higher level of IDO mRNA expression at diagnosis was correlated with worse clinical outcome in patients undergoing alloSCT. Larger studies are warranted in order to establish the real predictive role of IDO mRNA expression in influencing AML outcome. DisclosuresCavo:Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Small-Molecule Targeting of Musashi RNA-Binding Activity in Acute Myeloid Leukemia

RNA-binding proteins (RBPs) play critical roles in cell homeostasis by controlling gene expression post-transcriptionally, contributing to mRNA processing events (splicing, polyadenylation, localization, stability, export and translation). The involvement of RBPs to tumorigenesis, through genetic perturbation or epigenetic dysregulation, has been found in a variety of human cancers. The RBP MUSASHI-2 (MSI2) contributes to the pathogenesis of a spectrum of solid tumors and hematologic malignancies and predicts a worse clinical outcome in patients with myeloid and acute lymphoblastic leukemia (MDS, AML and ALL). Thus, MSI2 has been proposed as a putative biomarker for diagnosis as well as a potential therapeutic target for AML. However, there are currently no specific inhibitors for MSI.Previous work from our lab reported a Fluorescent Polarization (FP) screen with 6,208 compounds identifying small-molecules with MSI RNA-binding inhibition activity. Here, we characterize Ro 08-2750 (Ro), best FP screen hit, as a MSI RNA-competitive inhibitor. Electrophoresis Mobility Shift Assays (EMSA) demonstrated Ro inhibition of MSI2-RNA complexes formation. MicroScale Thermophoresis (MST) interaction studies showed that the compound interacts with MSI2 full-length and RNA-Recognition Motif 1 (RRM1) with μM affinity and with nearly 20-fold lower KD to an RBP control (SYNCRIP). We obtained the crystal structure of MSI2 RRM1 at 1.7Å and docking and mutagenesis validation confirmed K22, F66, F97 and R100 as crucial binding residues in the RNA-binding pocket. To further prove structure activity relationship, we used two chemical analogs: Ro-OH, an alcohol derivative of the Ro's aldehyde, showed 10-fold reduced activity and Ro-NGF, containing the Ro isoalloxazine scaffold, showed no binding or activity in vitro. Of note, in proliferation assays Ro EC50 was 2.6±0.1 μM in MLL-AF9 bone marrow cells and an average of 8.4±1.1 μM in MOLM13 and K562 human AML cells, whereas RoOH and RoNGF showed 10-fold or >50 μM EC50, respectively. Ro significantly reduced binding of MSI2 to its mRNA targets (such as cMYC, CDKN1A or SMAD3) in an RNA-IP and a direct effect in their protein translation in human leukemia cells. RNA-sequencing of 4h Ro treated MOLM13 and K562 AML cells resulted in gene expression changes that enriched for the gene expression profiling after shRNA mediated depletion of MSI2 in CML-BC and AML cell lines. Ro demonstrated a significant therapeutic index abolishing MLL-AF9+ BM colony formation at concentrations that did not affect the plating efficiency of normal Lin-Sca+cKit+ (LSK) cells. Similarly, Ro demonstrated differential sensitivity in three AML patient samples colony formation compared to normal human CD34+ cord blood cells. Finally, we sought to determine Ro in vivo activity by using an aggressive murine MLL-AF9 murine leukemia model. Acute treatment (4h and 12hr) with 13.75 mg/kg Ro in DMSO reduced c-KIT protein abundance and intracellular c-MYC. Administration of the same Ro dose every 3 days was well tolerated and showed a significant reduction in spleen weights, white blood cell counts and c-MYC levels compared to the controls. These data provide the feasibility that targeting MSI in vivo could have therapeutic efficacy in AML.This study identifies and characterizes Ro 08-2750 as a compound selectively inhibiting the oncogenic RNA-binding activity of MSI in myeloid leukemia. Ro targeting an RRM motif to block RNA activity represents a valuable proof of concept for the general inhibition of these class of RNA regulators. Overall, we provide a framework to identify and test novel RBP inhibitors thus validating this class of proteins as chemically “druggable” novel therapeutic targets in cancer. DisclosuresChodera:Schrödinger: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Peripheral blood biomarkers correlate with outcomes in advanced non-small cell lung Cancer patients treated with anti-PD-1 antibodies

BackgroundAnti-programmed cell death 1 (PD-1) antibodies have demonstrated improved overall survival (OS) and progression-free survival (PFS) in a subset of patients with metastatic or locally advanced non-small cell lung cancer (NSCLC). To date, no blood biomarkers have been identified in NSCLC to predict clinical outcomes of treatment with anti-PD-1 antibodies.Patient and methodsWe performed an analysis of retrospectively registered data of 157 patients with advanced NSCLC treated with anti-PD-1 antibodies at Mayo Clinic in Florida and Rochester. White blood cell count, absolute neutrophil count (ANC), absolute lymphocyte count (ALC), ANC to ALC (ANC: ALC) ratio, absolute eosinophil count, absolute monocyte count (AMC), platelet counts, and myeloid to lymphoid (M:L) ratio at baseline and throughout treatment were assessed. Kaplan-Meier method and Cox proportional hazards model were performed.ResultsWe treated 146 patients with nivolumab and 11 with pembrolizumab between January 1, 2015 and April 15, 2017. At median follow-up of 20 months, median OS and PFS were 6.0 and 2.6 months, respectively. Higher baseline ANC, AMC, ANC: ALC ratio and M: L ratio correlated with worse clinical outcomes in patients who underwent anti-PD-1 treatment. A baseline ANC: ALC ratio of 5.9 or higher had a significantly increased risk of death (hazard ratio [HR] =1.94; 95% confidence interval [CI], 1.24–3.03; P = 0.004) and disease progression (HR, 1.65; 95% CI, 1.17–2.34; P = 0.005) compared with patients with lower ratio. Similarly, a baseline M: L ratio of 11.3 or higher had significantly increased risk of death (HR, 2.5; 95% CI, 1.54–4.05; P < 0.001), even after a multivariate analysis (HR, 2.31; P = 0.002), compared to those with lower ratio.ConclusionsIncreased baseline ANC: ALC ratio and M: L ratio before initiation of anti-PD1 antibodies were associated with poor PFS and OS in advanced NSCLC patients. The potential predictive value of these readily available biomarkers might help with risk stratification and treatment strategies. These findings warrant further investigation in a larger, prospective study.