Established Outcome Predictors Research Articles

Subclinical hypothyroidism predicts outcome in heart failure: insights from the T.O.S.CA. registry.

Subclinical hypothyroidism (SH), defined as increased serum thyroid-stimulating hormone (TSH) with normal free T4 (fT4) levels, is frequently observed in the general population. Prevalence ranges from 0.6% to 1.8% in the adult population, depending on age, sex, and iodine intake. Several studies reported a worse prognosis in patients with heart failure with reduced ejection fraction (HFrEF) and SH, but they considered heterogeneous populations suffering mainly from severe SH. Aim of this study was to evaluate if SH was independently associated with the occurrence of cardiovascular death considering 30months of follow-up. 277 HFrEF patients enrolled in the prospective, multicenter, observational T.O.S.CA. (Terapia Ormonale Scompenso CArdiaco) registry, were included in this analysis. Patients were divided into two groups according to the presence of SH (serum TSH levels > 4.5mIU/L with normal fT4 levels). Data regarding clinical status, echocardiography, and survival were analyzed. Twenty-three patients displayed SH (87% mild vs 13% severe), while 254 were euthyroid. No differences were found in terms of age, sex, HF etiology, and left ventricular ejection fraction. When compared with the euthyroid group, SH patients showed higher TSH levels (7.7 ± 4.1 vs 1.6 ± 0.9, p < 0.001), as expected, with comparable levels of fT4 (1.3 ± 0.3 vs 1.3 ± 0.3, p = NS). When corrected for established predictors of poor outcome in HF, the presence of SH resulted to be an independent predictor of cardiovascular mortality (HR: 2.96; 5-95% CI:1.13-7.74; p = 0.03). Since thyroid tests are widely available and inexpensive, they should be performed in HF patients to detect subclinical disorders, evaluate replacement therapy, and improve prognosis.

Operative Treatment of Tarlov Cysts - Outcomes and Predictors of Improvement after Surgery: A Series of 97 Consecutive Patients and a Systematic Review of Literature.

A register-based retrospective series and a systematic review of literature. Tarlov cysts are meningeal cysts typically found in the sacral region. They have a dualistic nature ranging from an incidental finding to a symptomatic pathology. There are no established treatment protocols and predictors of operative outcome. Therefore, we aimed to study the outcome of surgical treatment for Tarlov cysts and to characterize patient-, and treatment-related factors predicting outcomes. A systematic review of previous literature was performed and a retrospective cohort of all patients operated on for Tarlov cysts at BLINDED between 1995 and 2020 was collected. Patient records were evaluated along with radiological images. Ninety-seven consecutive patients were identified with follow-up data available for 96. Improvement of symptoms after surgery was observed in 76.0% of patients (excellent or good patient-reported outcome) and the complication rate was 17.5%. Sacral or lower back pain as a preoperative symptom was associated with improvement after surgery (P = .007), whereas previous lower back surgery was more common in patients who did not benefit from surgery (P = .034). No independent predictors of outcome were identified in a regression analysis. This is the second-largest study on the treatment of Tarlov cysts ever published. Operative treatment in a selected patient population will likely produce improvement in the symptoms when balanced with the complication rate and profile of surgery. Preoperative lower back or sacral pain is a potential indicator for improvement after surgery.

Dyssynchrony and Response to Cardiac Resynchronization Therapy in Heart Failure Patients With Unfavorable Electrical Characteristics

BackgroundAmong heart failure (HF) patients undergoing cardiac resynchronization therapy (CRT), those with unfavorable electrical characteristics (UEC) are less frequently CRT responders. ObjectivesIn this study, the authors sought to evaluate the relationship between preprocedural echocardiographic parameters of electromechanical dyssynchrony (EMD) and outcome following CRT. MethodsAmong 551 patients receiving CRT, 121 with UEC, defined as atypical left bundle branch, presence of right bundle branch block, or unspecified intraventricular conduction disturbance, were enrolled. Indices of EMD were presence of septal flash, apical rocking, septal deformation patterns, and global wasted work (GWW), determined with the use of speckle-tracking strain echocardiography. Endpoints were response to CRT, defined as a relative decrease in left ventricular end-systolic volume ≥15% at 9-month postoperative follow-up, and all-cause death or HF hospitalization during follow-up. ResultsAmong the 121 patients, 68 (56%) were CRT responders. In multivariate analysis, GWW ≥200 mm Hg% (adjusted odds ratio [aOR]: 4.17 [95% CI: 1.33-14.56]; P = 0.0182) and longitudinal strain septal contraction patterns 1 and 2 (aOR: 10.05 [95% CI: 2.82-43.97]; P < 0.001) were associated with CRT response. During a 46-month follow-up (IQR: 42-55 months), survival free from death or HF hospitalization increased with the number of positive criteria (87% for 2, 59% for 1, and 27% for 0). After adjustment for established predictors of outcome in patients receiving CRT, absence of either of the 2 criteria remained associated with a considerable increased risk of death and/or HF hospitalization (adjusted HR: 4.83 [95% CI: 1.84-12.68]; P = 0.001). ConclusionsIn patients with UEC, echocardiographic assessment of EMD may help to select patients who will derive benefit from CRT. (Echocardiography in Cardiac Resynchronization Therapy [Echo-CRT]; NCT02986633)

Abstract 13337: Left Atrial Ejection Fraction by Cardiac Magnetic Resonance Imaging as a Predictor of Adverse Outcomes in Patients With Advanced Ischemic Cardiomyopathy

Background: The prognostic significance of cardiac magnetic resonance (CMR) based left atrial ejection fraction (LAEF) is not well defined in the ischemic cardiomyopathy (ICM) cohort.We assess the additive effect of LAEF in a model to predict outcomes in patients with ICM. Methods: Patients with ICM, who underwent CMR between April 2001 and March 2019 were retrospectively included. Clinical characteristics and CMR parameters were collected and analyzed and LAEF was calculated in addition to myocardial infarct size (MIS) using late gadolinium enhancement (LGE) and CMR based mitral regurgitant fraction (MRF). The primary clinical endpoint was a composite of all-cause mortality and cardiac transplant. A multiple-variable Cox proportional hazards regression model which included established predictors of outcome was constructed, followed by the addition of LAEF. Four pre-specified interactions of LAEF with left ventricular end systolic volume index (LVESVi), MIS and mitral regurgitant fraction (MRF) were tested at a significance level of 0.05. RESULTS: LA functional data was measured in 718 patients. There were 416 deaths and/or transplants, with a median duration of follow up of 1763 days (4.8 years) The mean LA EF was 36 [2 ,74]. In univariate analysis, lower LAEF and higher LAVI were significant predictors of worse outcome, HR= 0.12, 95% CI [0.06, 0.25], p&lt;0.001; HR 1.008, (1.003-1.014) p = 0.003. After addition to the multivariable model, a normal LAEF was highly predictive of reduced risk, HR 0.24, (0.12, 0.48), p&lt;0.001. In the interaction between LAEF and MIS with MR Fraction, the highest risk was observed in patients with an LAEF &lt; 20% and an MIS of &gt; 30%, with MR Fraction of &gt;35%, HR of 3.2 (1.73-5.93), p= 0.009. The lowest risk was in patients with an LAEF of &gt;50% with an MIS of &lt;15 and MR Fraction of &lt;35%, HR 1.07 (0.81-1.42), p=0.009. Figure 1. CONCLUSION: Reduced LAEF is an important predictor of increased mortality in patients with ICM and additive to MIS and MR Fraction.

Characteristics, management, and outcomes of patients with left-sided infective endocarditis complicated by heart failure: a substudy of the ESC-EORP EURO-ENDO (European infective endocarditis) regist

Abstract Background/Introduction Congestive heart failure (CHF) is a strong prognostic factor in infective endocarditis (IE), but data are lacking regarding its current management and outcome in Europe. Purpose To evaluate the current management and survival of patients with left-sided IE complicated by CHF. Methods We used data of the ESC-EORP EURO-ENDO registry, which is a prospective multicentre observational study conducted between January 1, 2016 and March 31, 2018 in 156 centres in 40 countries. The primary endpoints were 30-day and one-year mortality. Results Among the 3116 patients enrolled in this prospective registry, 2449 (mean age: 60 years, 69% male) with left-sided (native or prosthetic) IE were included in this study. Patients with CHF (n=698, 28.5%) were older, with more comorbidity and more severe valvular damage (mitro-aortic involvement, vegetations &amp;gt;10mm and severe regurgitation/new prosthesis dehiscence) than those without CHF (all p≤0.019). Patients with CHF experienced higher 30-day and one-year mortality than those without (20.5% vs. 9.0% and 36.1% vs. 19.3%, respectively) and CHF remained strongly associated with 30-day (OR [95% CI]: 2.37 [1.73–3.24]; p&amp;lt;0.001) and one-year mortality (HR [95% CI]: 1.69 [1.40–2.05]; p&amp;lt;0.001) after adjustment for established outcome predictors, including early surgery, or after propensity matching for age, sex, and comorbidity (n=618 [88.5%] for each group, both p&amp;lt;0.001). Early surgery, performed on 49% of these patients with IE complicated by CHF, remained associated with a substantial reduction in 30-day mortality following multivariable analysis, after adjustment for age, sex, Charlson index, cerebrovascular accident, staphylococcus aureus IE, Streptococcal IE, uncontrolled infection, vegetation size &amp;gt;10mm, severe valvular regurgitation and/or new prosthetic dehiscence, perivalvular complication, and prosthetic IE (OR [95% CI]: 0.22 [0.12–0.38]; p&amp;lt;0.001) and in one-year mortality (HR [95% CI]: 0.29 [0.20–0.41]; p&amp;lt;0.001). Conclusion CHF is common in left-sided IE and is associated with older age, greater comorbidity, more advanced lesions, and markedly higher 30-day and one-year mortality. Early surgery is strongly associated with lower mortality but is performed on only approximately half of patients with CHF, mainly because of a surgical risk considered prohibitive. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Abbott Vascular Int. (2011–2014) Amgen Cardiovascular (2009–2018),

Characteristics, management, and outcomes of patients with left-sided infective endocarditis complicated by heart failure: a substudy of the ESC-EORP EURO-ENDO (European infective endocarditis) registry.

AimsTo evaluate the current management and survival of patients with left‐sided infective endocarditis (IE) complicated by congestive heart failure (CHF) in the ESC‐EORP European Endocarditis (EURO‐ENDO) registry.Methods and resultsAmong the 3116 patients enrolled in this prospective registry, 2449 (mean age: 60 years, 69% male) with left‐sided (native or prosthetic) IE were included in this study. Patients with CHF (n = 698, 28.5%) were older, with more comorbidity and more severe valvular damage (mitro‐aortic involvement, vegetations >10 mm and severe regurgitation/new prosthesis dehiscence) than those without CHF (all p ≤ 0.019). Patients with CHF experienced higher 30‐day and 1‐year mortality than those without (20.5% vs. 9.0% and 36.1% vs. 19.3%, respectively) and CHF remained strongly associated with 30‐day (odds ratio[OR] 2.37, 95% confidence interval [CI] [1.73–3.24; p < 0.001) and 1‐year mortality (hazard ratio [HR] 1.69, 95% CI 1.39–2.05; p < 0.001) after adjustment for established outcome predictors, including early surgery, or after propensity matching for age, sex, and comorbidity (n = 618 [88.5%] for each group, both p < 0.001). Early surgery, performed on 49% of these patients with IE complicated by CHF, remained associated with a substantial reduction in 30‐day mortality following multivariable analysis, after adjustment for age, sex, Charlson comorbidity index, cerebrovascular accident, Staphylococcus aureus IE, streptococcal IE, uncontrolled infection, vegetation size >10 mm, severe valvular regurgitation and/or new prosthetic dehiscence, perivalvular complication, and prosthetic IE (OR 0.22, 95% CI 0.12–0.38; p < 0.001) and in 1‐year mortality (HR 0.29, 95% CI 0.20–0.41; p < 0.001).ConclusionCongestive heart failure is common in left‐sided IE and is associated with older age, greater comorbidity, more advanced lesions, and markedly higher 30‐day and 1‐year mortality. Early surgery is strongly associated with lower mortality but is performed on only approximately half of patients with CHF, mainly because of a surgical risk considered prohibitive.

Atrial fibrillation in severe aortic stenosis: Prognostic value and results of aortic valve replacement

ObjectivesAlthough atrial fibrillation (AF) is common, its impact on long-term mortality has not been reliably determined in patients with aortic stenosis (AS). We aimed to assess whether AF is associated with survival in patients with severe AS and to determine the impact of AF on the results of aortic valve replacement (AVR). MethodsThe study included 1838 consecutive patients with severe AS (77 ± 11 years, male 47%). Upon AS diagnosis, patients were screened for AF using a 12-lead electrocardiogram. The treatment strategy (conservative management or AVR) was selected by the heart team in accordance with current guidelines. The effect of AVR on survival was analyzed as a time-dependent covariate using the entire follow-up period. ResultsAF, diagnosed in 593 (32%) patients was associated with poor survival at 5 years (55 ± 2% vs 74 ± 1% for patients in sinus rhythm, P < .001), even after adjustment for established outcome predictors (hazard ratio [HR], 1.56; 95% confidence interval [CI], 1.33-1.84; P < .001). In patients with AF, AVR was associated with lower mortality (HR, 0.16; 95% CI, 0.12-0.22; P < .001) even in those with no or minimal symptoms (HR, 0.12; 95% CI, 0.08-0.20; P < .001). However, among patients who underwent AVR, those in AF had an excess mortality (HR, 1.59; 95% CI, 1.22-2.08; P < .001). ConclusionsIn severe AS, AF is a strong predictor of mortality even in asymptomatic or minimally symptomatic patients. After AVR, AF remains associated with poorer survival than sinus rhythm. In patients in AF, AVR is associated with lower mortality compared with conservative treatment. Further studies are needed to confirm the benefits of AVR in asymptomatic patients in AF with severe AS.

Extended Analysis of Axonal Injuries Detected Using Magnetic Resonance Imaging in Critically Ill Traumatic Brain Injury Patients.

Studies show conflicting results regarding the prognostic significance of traumatic axonal injuries (TAI) in patients with traumatic brain injury (TBI). Therefore, we documented the presence of TAI in several brain regions, using different magnetic resonance imaging (MRI) sequences, and assessed their association to patient outcomes using machine learning. Further, we created a novel MRI-based TAI grading system with the goal of improving outcome prediction in TBI. We subsequently evaluated the performance of several TAI grading systems. We used a genetic algorithm to identify TAI that distinguish favorable from unfavorable outcomes. We assessed the discriminatory performance (area under the curve [AUC]) and goodness-of-fit (Nagelkerke pseudo-R2) of the novel Stockholm MRI grading system and the TAI grading systems of Adams and associates, Firsching and coworkers. and Abu Hamdeh and colleagues, using both univariate and multi-variate logistic regression. The dichotomized Glasgow Outcome Scale was considered the primary outcome. We examined the MRI scans of 351 critically ill patients with TBI. The TAI in several brain regions, such as the midbrain tegmentum, were strongly associated with unfavorable outcomes. The Stockholm MRI grading system exhibited the highest AUC (0.72 vs. 0.68–0.69) and Nagelkerke pseudo-R2 (0.21 vs. 0.14–0.15) values of all TAI grading systems. These differences in model performance, however, were not statistically significant (DeLong test, p > 0.05). Further, all included TAI grading systems improved outcome prediction relative to established outcome predictors of TBI, such as the Glasgow Coma Scale (likelihood-ratio test, p < 0.001). Our findings suggest that the detection of TAI using MRI is a valuable addition to prognostication in TBI.

Serum neurofilament light chain levels are associated with stroke severity and functional outcome in patients undergoing endovascular therapy for large vessel occlusion

BackgroundWe aimed to analyze serum neurofilament light chain (sNfL) levels in patients undergoing endovascular therapy (EVT) for anterior circulation large vessel occlusion (acLVO). MethodsProspective study of consecutive patients with acLVO receiving EVT (12/2020–01/2021). sNfL was serially measured prior to and at 30-min, 6-h, 12-h, 24-h, 48-h and 7-days following EVT. ANOVA and Spearman correlation were run to assess sNfL levels (ie, absolute values) and ΔsNfL levels (ie, absolute values subtracted by baseline value) and their association with clinical (ie, NIHSS), imaging (ie, ASPECTS) surrogates of stroke severity as well as functional outcome (ie, mRS) at 90-days. Results175 sNfL samples were retrieved from 25 patients. While there were no differences among serial sNfL levels in the first 12-h post-EVT, a constant increase was observed afterwards (maximum day 7, median: 383 [IQR, 209–907] pg/mL, p < 0.001). ΔsNfL showed a constant increase from 30-min measurement onwards peaking after 7 days (median 363.5 [IQR, 114.3–851.1] pg/mL). sNfL levels at 7 days correlated with ASPECTS post-EVT (r = −0.59, p < 0.001), NIHSS at discharge (r = −0.50, p = 0.011) and mRS at 90-days (r = 0.45, p = 0.027). ConclusionsSerum NFL may complement established clinical and imaging predictors of treatment response and functional outcome in stroke patients undergoing EVT for acLVO.

Clinical Significance of Global Wasted Work in Patients with Heart Failure Receiving Cardiac Resynchronization Therapy

The relationship between myocardial work assessment using pressure-strain loops by echocardiography before cardiac resynchronization therapy (CRT) and response to CRT has been recently revealed. Among myocardial work parameters, the impact of left ventricular myocardial global wasted work (GWW) on response to CRT and outcome following CRT has been seldom studied. Hence, the authors evaluated the relationship between preprocedural GWW and outcome in a large prospective cohort of patients with heart failure (HF) and reduced ejection fraction receiving CRT. The study included 249 patients with HF. Myocardial work indices including GWW were calculated using speckle-tracking strain two-dimensional echocardiography using pressure-strain loops. End points of the study were (1) response to CRT, defined as left ventricular reverse remodeling and/or absence of hospitalization for HF, and (2) all-cause death during follow-up. Median follow-up duration was 48months (interquartile range, 43-54months). Median preoperative GWW was 281mm Hg% (interquartile range, 184-388mm Hg%). Preoperative GWW was associated with CRT response (area under the curve, 0.74; P<.0001), and a 200mm Hg% threshold discriminated CRT nonresponders from responders with 85% specificity and 50% sensitivity, even after adjustment for known predictors of CRT response (adjusted odds ratio, 4.03; 95% CI, 1.91-8.68; P<.001). After adjustment for established predictors of outcome in patients with HF with reduced ejection fraction receiving CRT, GWW < 200mm Hg% remained associated with a relative increased risk for all-cause death compared with GWW ≥ 200mm Hg% (adjusted hazard ratio, 2.0; 95% CI, 1.1-3.9; P=.0245). Adding GWW to a baseline model including known predictors of outcome in CRT resulted in an improvement of this model (χ2 to improve 4.85, P=.028). The relationship between GWW and CRT response and outcome was stronger in terms of size effect and statistical significance than for other myocardial work indices. Low preoperative GWW (<200mm Hg%) is associated with absence of CRT response in CRT candidates and with a relative increased risk for all-cause death. GWW appears to be a promising parameter to improve selection for CRT of patients with HF with reduced ejection fraction.

Clinical Significance of Global Wasted Work in patients receiving Cardiac Resynchronization Therapy for Heart Failure

Risk stratification remains key in the management of patients with heart failure (HF). Besides enduring standards such as left ventricular (LV) ejection fraction, the amount of LV myocardial global wasted work (GWW) might better predict outcome in HF patients who are eligible for cardiac resynchronization therapy (CRT). The aim of this study is to evaluate the relation between preoperative GWW and outcome in a large prospective cohort of patients with heart failure and reduced ejection fraction (HFrEF) receiving CRT. The study included 249 HF patients. GWW was calculated by speckle tracking strain two-dimensional echocardiography using pressure-strain loops. The primary outcome of the study was all-cause death. A combined response to CRT defined as LV reverse remodeling and/or absence of hospitalization for HF was also studied. Median follow-up was 48 months (interquartile range 43-54). Median preoperative GWW was 281 (184-388) mmHg%. Preoperative GWW correlated with mortality during follow-up (hazard ratio (HR) 1.5 (1.1-2.0) per SD decrement, P = 0.006). After adjustment on established predictors of outcome in HFrEF patients receiving CRT, patients with GWW < 200 mmHg% remained at increased risk for all-cause death compared with those with GWW ≥ 200 mmHg% (adjusted HR, 2.0; 95%CI, 1.1–3.9; P = 0.0245). GWW had significant additional prognostic value for mortality prediction over the baseline model (Chi 2 to improve 4.85, P = 0.028). Preoperative GWW < 200 mmHg% also independently predicted absence of CRT response ( Fig. 1 ). A low preoperative GWW (< 200 mmHg%) increases the risk of all-cause death by two-fold and predicts the absence of CRT response in CRT recipients.

Benefit of Adjuvant Chemotherapy After Radical Cystectomy for Treatment of Urothelial Carcinoma of the Bladder in the Elderly -An International Multicenter Study.

Radical cystectomy (RC) is the standard treatment for muscle invasive bladder cancer, but approximately half of all patients will ultimately succumb to disease progression despite apparent cure with extirpative surgery. Elderly patients are at especially high risk of advanced disease and may benefit from perioperative systemic therapy. To assess the real-world benefit of adjuvant chemotherapy (AC) in patients ≥75 years old. We retrospectively reviewed patients who underwent RC for non-metastatic urothelial carcinoma of the bladder (UCB) from 12 participating international medical institutions. Kaplan-Meier survival curves and Cox regression models were used to assess the association between age groups, administration of AC and oncological outcome parameters such as recurrence-free survival (RFS), cancer-specific survival (CSS) and overall survival (OS). 4,335 patients were included in the analyses, of which 820 (18.9%) were ≥75 years old. These elderly patients had a higher rate of adverse pathologic features. In an univariable subgroup analysis in patients ≥75 years with lymph node metastasis, 5-year OS was significantly higher in patients who had received AC (41% vs. 30.9%, p = 0.02). In a multivariable Cox model that was adjusted for several established outcome predictors, there was a significant favorable association between the administration of AC in elderly patients and OS, but no RFS or CSS. In this large observational study, the administration of AC was associated with improved OS, but not RFS or CSS, in elderly patients treated with RC for UCB. This is of clinical importance, as elderly patients are more likely to have adverse pathologic features and experience worse survival outcomes. Treatment of UCB should include both a multidisciplinary approach and a geriatric evaluation to identify patients who are most likely to tolerate and benefit from AC.

Prognostic value of CT perfusion and permeability imaging in traumatic brain injury.

Currently established prognostic models in traumatic brain injury (TBI) include noncontrast computed tomography (CT) which is insensitive to early perfusion alterations associated with secondary brain injury. Perfusion CT (PCT) on the other hand offers insight into early perfusion abnormalities. We hypothesized that adding CT perfusion and permeability data to the established outcome predictors improves the performance of the prognostic model. A prospective cohort study of consecutive 50 adult patients with head injury and Glasgow Coma Scale score of 12 or less was performed at a single Level 1 Trauma Centre. Perfusion CT was added to routine control CT 12 hours to 24 hours after admission. Region of interest analysis was performed in six major vascular territories on perfusion and permeability parametric maps. Glasgow Outcome Scale (GOS) was used 6 months later to categorize patients' functional outcomes to favorable (GOS score > 3) or unfavorable (GOS score ≤ 3). We defined core prognostic model, consisting of age, motor Glasgow Coma Scale score, pupillary reactivity, and CT Rotterdam Score. Next, we added perfusion and permeability data as predictors and compared updated models to the core model using cross-validated areas under the receiver operator curves (cv-AUC). Significant advantage over core model was shown by the model, containing both mean cerebral extravascular-extracellular volume per unit of tissue volume and cerebral blood volume of the least perfused arterial territory in addition to core predictors (cv-AUC, 0.75; 95% confidence interval, 0.51-0.84 vs. 0.6; 95% confidence interval, 0.37-0.74). The development of cerebral ischemia and traumatic cerebral edema constitutes the secondary brain injury and represents the target for therapeutic interventions. Our results suggest that adding CT perfusion and permeability data to the established outcome predictors improves the performance of the prognostic model in the setting of moderate and severe TBI. Prognostic study, level III.

The impact of delirium on withdrawal of life-sustaining treatment after intracerebral hemorrhage.

To determine the impact of delirium on withdrawal of life-sustaining treatment (WLST) after intracerebral hemorrhage (ICH) in the context of established predictors of poor outcome, using data from an institutional ICH registry. We performed a single-center cohort study on consecutive patients with ICH admitted over 12 months. ICH features were prospectively adjudicated, and WLST and corresponding hospital day were recorded retrospectively. Patients were categorized using DSM-5 criteria as never delirious, ever delirious (either on admission or later during hospitalization), or persistently comatose. We determined the impact of delirium on WLST using Cox regression models adjusted for demographics and ICH predictors (including Glasgow Coma Scale score), then used logistic regression with receiver operating characteristic curve analysis to compare the accuracy of ICH score-based models with and without delirium category in predicting WLST. Of 311 patients (mean age 70.6 ± 15.6, median ICH score 1 [interquartile range 1-2]), 50% had delirium. WLST occurred in 26%, and median time to WLST was 1 day (0-6). WLST was more frequent in patients who developed delirium (adjusted hazard ratio 8.9 [95% confidence interval (CI) 2.1-37.6]), with high rates of WLST in both early (occurring ≤24 hours from admission) and later delirium groups. An ICH score-based model was strongly predictive of WLST (area under the curve [AUC] 0.902 [95% CI 0.863-0.941]), and the addition of delirium category further improved the model's accuracy (AUC 0.936 [95% CI 0.909-0.962], p = 0.004). Delirium is associated with WLST after ICH regardless of when it occurs. Further study on the impact of delirium on clinician and surrogate decision-making is warranted.

Decitabine-Induced Early Platelet Response, a Predictor of Favorable Outcome during Hypomethylating Treatment of MDS, Is Associated with In Vivo Megakaryocytic Differentiation

Introduction Despite broad use of hypomethylating agents (HMAs) in MDS/AML treatment, the number of established outcome predictors is still very limited (Stomper and Lübbert, Sem Hematol 2019). One of them, the early, isolated and sometimes massive increase of platelets, is recurrently observed in patients with MDS treated with HMAs. It is not observed with non-HMA cytidine analogs such as low-dose cytarabine. In HMA-treated MDS patients, an early platelet increase is a predictor of overall and leukemia-free survival (van den Bosch et al., Leuk Res 2004; van der Helm et al., Br J Haematol 2011). HMAs induce cellular differentiation in vitro, by gene reactivation in the malignant cells. However, evidence for HMA-induced in vivo differentiation is still very limited. We hypothesized that the megakaryocytic cell lineage in MDS is a target for HMA-induced cellular maturation in vivo. Methods We systematically analyzed the bone marrow morphology of 34 higher-risk MDS patients (median age: 71.5 years, range 51-79) before and after 1 cycle of treatment with the HMA decitabine (DAC). All patients had been treated at a single center within 3 prospective clinical trials (Wijermans et al., Ann Hematol 2005; Lübbert et al., J Clin Oncol 2011). One treatment cycle consisted of 45 mg/m2 DAC per day (15 mg/m2 intravenously over 4 hours every 8 hours) for 3 consecutive days, repeated 6 weeks later. The early platelet response was evaluated after 1 cycle of DAC treatment. Based on the criteria of the International Working Group, an absolute increase in platelet count of 30x109/l or more compared to the pre-treatment count was defined as a platelet response. The histological analysis of the bone marrow specimens was performed by an experienced hematopathologist blinded to the treatment timepoints. Up to 200 megakaryocytes (MK) per sample were quantified at a magnification of 400 x using chloroacetate esterase staining. Results Thirteen of 34 patients (38%) showed a platelet response already after 1 cycle of DAC treatment, 21 (62%) did not. The median pre-treatment platelet count did not differ in patients with or without an early platelet response (median of 34x109/l in both groups, range 7-169 and 8-265, respectively). After 1 cycle of DAC treatment, patients with a platelet response had a median platelet count of 117x109/l (range 78-281), patients without this response had a median platelet count of 32 x109/l (range 4-155). Overall survival (OS) was measured from the time of early platelet response assessment after completion of 1 treatment cycle, i.e. after 6 weeks. The presence of a platelet response after 1 DAC cycle was associated with a longer OS compared to the absence of this early platelet response: median of 26.6 versus 14.0 months (p=0.04). Both pre- and post-treatment bone marrow biopsies of patients with an early platelet response showed higher numbers of MK, as well as significant differences in MK morphology compared to biopsies from patients without an early platelet response. Regarding MK numbers, increased MK density in specimens of patients with an early platelet response was observed both before (mean MK number per high power field 6.2 vs. 2.6, p=0.02) and after the application of DAC (mean MK number 10.4 vs. 3.1, p=0.01). Regarding MK maturation stage, more pre-treatment juvenile MK (on average 32.4% vs. 20.5% of all MK, p=0.03) and MK with typical myeloproliferative stigmata (present in 5/13 vs. 2/21 biopsies) were observed in patients with an early platelet response, compared to patients without this response. Regarding the induction of megakaryocytic maturation during this early treatment phase, more post-treatment "naked", mature MK nuclei indicative of active platelet shedding (on average 9.5% vs. 3.8% of all MK, p=0.01), were noted in patients with an early platelet response than in patients without an early platelet response. Conclusions This is, to the best of our knowledge, the first systematic hematopathological analysis of changes in quantitative and morphological MK features in bone marrow specimens of MDS patients during HMA treatment. DAC, which has in vitro differentiation-inducing effects on megakaryoblastic cells, induced maturation also of dysplastic MK in vivo in higher-risk MDS patients with an early platelet response to this HMA. The predictive value of an early platelet increase, a very easy-to-determine parameter, during this type of treatment is confirmed. Disclosures No relevant conflicts of interest to declare.

P2774Galectin-3, GDF-15, and ST2 in noninvasive assessment of myocardial remodelling in chronic thromboembolic pulmonary hypertension

Abstract Background In chronic thromboembolic pulmonary hypertension (CTEPH), pulmonary artery obstruction leads to impaired pulmonary hemodynamics and secondary right heart failure, which is highly predictive of outcome. Thus, the extent of myocardial -especially right heart- remodelling is an indicator of disease severity. Purpose The aim of the present study was to assess growth differentiation factor-15 (GDF-15), galectin-3, and suppression of tumorigenicity 2 (ST2) as non-invasive biomarkers of myocardial remodelling in patients suffering from CTEPH. Methods We analysed the serum levels of GDF-15, galectin-3 and ST2 in a cohort of 64 CTEPH patients and in a control group of 25 patients without cardiovascular disease. The biomarker levels were further correlated with clinical, laboratory, and hemodynamic data, including 6-minute walking distance (6-MWD), N-terminal pro-brain natriuretic peptide (NT-proBNP), mean pulmonary artery pressure (meanPAP), pulmonary vascular resistance (PVR), and right atrial pressure (RAP). Results The biomarker levels in the control group were: galectin-3: 3.5 ng/l (IQR 2.7–4.0), GDF-15: 92.6 pg/ml (IQR 78.5–129.1), and ST2: 48.65 ng/l (IQR 35.5–57.0). CTEPH patients had higher levels of GDF-15 (196.7 pg/ml; IQR 128.4–302.8; p&lt;0.001) and ST2 (52.6 ng/l; IQR 44.5–71.9; p=0.05) but not galectin-3 (3.4 ng/l; IQR 2.7–4.3; p=0.84). In the CTEPH cohort, patients with a meanPAP &gt;35 mmHg (GDF-15: p=0.01; ST2: p=0.04) and patients with a PVR &gt;500 dyn sec cm–5 (GDF-15: p=0.004; ST2: p=0.002) had significantly increased biomarker levels. For the detection of a meanPAP &gt;35mmHg, ROC analysis revealed an AUC of 0.71 for GDF-15 and 0.67 for ST2. The level of GDF-15 correlated with the level of NT-proBNP (rrs=0.69; p≤0.001) and the RAP (rrs=0.54; p≤0.001) and inversely with the 6-MWD (rrs=−0.47; p≤0.001). The level of ST2 correlated with the level of NT-proBNP (rrs=0.67; p≤0.001) and the RAP (rrs=0.54; p≤0.001) and inversely with the 6-MWD (rrs=-0.31; p=0.02). Conclusion Our results demonstrate that GDF-15 and ST2, non-invasive biomarkers of myocardial remodelling, are significantly elevated in patients suffering from CTEPH. The correlation of biomarker levels with established outcome predictors suggests a use as indicators of disease severity.

Refinement of risk stratification for childhood rhabdomyosarcoma using FOXO1 fusion status in addition to established clinical outcome predictors: A report from the Children's Oncology Group.

BackgroundPrevious studies of the prognostic importance of FOXO1 fusion status in patients with rhabdomyosarcoma (RMS) have had conflicting results. We re‐examined risk stratification by adding FOXO1 status to traditional clinical prognostic factors in children with localized or metastatic RMS.MethodsData from six COG clinical trials (D9602, D9802, D9803, ARST0331, ARTS0431, ARST0531; two studies each for low‐, intermediate‐ and high‐risk patients) accruing previously untreated patients with RMS from 1997 to 2013 yielded 1727 evaluable patients. Survival tree regression for event‐free survival (EFS) was conducted to recursively select prognostic factors for branching and split. Factors included were age, FOXO1, clinical group, histology, nodal status, number of metastatic sites, primary site, sex, tumor size, and presence of metastases in bone/bone marrow, soft tissue, effusions, lung, distant lymph nodes, and other sites. Definition and outcome of the proposed risk groups were compared to existing systems and cross‐validated results.ResultsThe 5‐year EFS and overall survival (OS) for evaluable patients were 69% and 79%, respectively. Extent of disease (localized versus metastatic) was the first split (EFS 73% vs 30%; OS 84% vs. 42%). FOXO1 status (positive vs negative) was significant in the second split both for localized (EFS 52% vs 78%; OS 65% vs 88%) and metastatic disease (EFS 6% vs 46%; OS 19% vs 58%).ConclusionsAfter metastatic status, FOXO1 status is the most important prognostic factor in patients with RMS and improves risk stratification of patients with localized RMS. Our findings support incorporation of FOXO1 status in risk stratified clinical trials.

Pre-Therapeutic Total Lesion Glycolysis on [18F]FDG-PET Enables Prognostication of 2-Year Progression-Free Survival in MALT Lymphoma Patients Treated with CD20-Antibody-Based Immunotherapy

PurposeStandardized uptake values (SUV), total metabolic tumor volumes (TMTV), and total lesion glycolysis (TLG) based on positron emission tomography with 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG/positron emission tomography (PET) are established outcome predictors in FDG-avid lymphomas. We therefore investigated whether these biomarkers also have prognostic value in extranodal marginal zone B cell lymphoma of the mucosa-associated lymphoid tissue (MALT lymphoma), with a focus on patients treated with anti-CD20 antibody-based immunotherapy.ProceduresPre-therapeutic [18F]FDG/PET scans of 61 treatment-naïve MALT lymphoma patients, including 35 scheduled for anti-CD20 antibody-based immunotherapy, were included in this retrospective study. SUVmean, SUVmax, TMTV, and TLG were measured and tested for 2-year progression-free survival (PFS) prognostication, using Cox regression analyses. Receiver operating characteristic curves were used to determine optimal cutoffs for prognostic [18F]FDG/PET parameters, and Kaplan–Meier estimates with log rank tests were performed.ResultsAfter 2 years, progression had occurred in 12/61 patients (CD20-anitbody group 6/35). TLG emerged as the only significant prognostic factor for 2-year PFS in the multivariate analyses with forward selection, both in entire cohort (hazard ratio HR, 1.001; 95 % CI, 1.001–1.002; P < 0.0001) and in the CD20-antibody group (HR, 1.001; 95 % CI, 1.001–1.002; P = 0.001). However, in the entire population, where 8/26 patients with a TLG > 90 (30.8 %) vs. 4/35 patients with a TLG ≤ 90 (11.4 %) showed progression within the 2-year observation period, TLG-based separation of risk groups failed (HR, 0.35; 95 % CI, 0.10–1.15; P = 0.069); whereas in the CD20-antibody group, where 6/16 patients with a TLG > 90 (37.5 %) vs. 0/19 patients with a TLG ≤ 90 (0.0 %) showed progression, risk group separation was successful (HR, 0.010; 95 % CI, 0.0001–8.068; P = 0.003).ConclusionsTLG may improve early risk stratification of MALT lymphoma patients treated with CD20-antibody-based immunotherapy.

Impact of a Posttraumatic Cerebral Infarction on the Long-Term Outcome of Patients with Moderate and Severe Traumatic Brain Injuries: The Italian Multicenter Cohort INCEPT Study

Background: Post-traumatic cerebral infarction (PTCI) is common in patients dying after a traumatic brain injury (TBI). It is unclear what the occurrence of a PTCI is, how it impacts the long-term outcome, and whether it adds incremental prognostic value to established outcome predictors. Methods: This was a prospective multicenter cohort study of moderate and severe TBI patients admitted to nine Italian intensive care units (ICUs). The primary objective was to evaluate if PTCI was an independent risk factor for the 6-month outcome assessed with the Glasgow Outcome Scale (GOS). We also assessed the PTCI occurrence and if it adds incremental value to the International Mission for Prognosis and Clinical Trial design in TBI (IMPACT) core and extended models. Findings: We enrolled 143 patients; 47 (32·9%) developed a PTCI for a total of 94. The mean (SD) onset time of a PTCI was 6·2 (11·4). In the multiple ordered logistic regression, PTCI was retained in both the core and extended IMPACT models as an independent predictor of the GOS. The predictive performances increased significantly when PTCI was added to the IMPACT core model (AUC=0·73, 95% C.I. 0·66-0·82; increased to AUC=0·79, 95% CI 0·71-0·83, p=0·0007) and extended model (AUC=0·74, 95% C.I.: 0·65-0·81 increased to AUC=0·80, 95% C.I. 0·69-0·85; p=0·00008). Patients with a PTCI showed higher ICU mortality (10 patients [21·3%] vs one patient [1·0%], p<0·0001) and 6-month mortality (13 patients [27·7%] vs seven patients [7·3%], p<0·0001); whereas, hospital mortality did not differ between the two groups. Interpretation: A PTCI is a common complication in patients suffering a moderate or severe TBI and is an independent risk factor for long-term disability. The addition of PTCI to the IMPACT core and extended predictive models significantly increased their performance in predicting the GOS. Trial Registration Number: This study was registered with ClinicalTrials.gov (number NCT02430324). Funding Statement: The present study was self-funded. The authors declare none to funding. Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: The study was conducted in accordance with the Declaration of Helsinki and was approved by the local Ethics Committees of each participating center. Patients’ informed consent was waived due to the lack of definition of a legal representative of temporarily incapacitated adult patients in the Italian legislation.11 The informed consent was obtained from the surviving patients as soon as they regained their mental competency. Family members received detailed information on the study scope and protocol. We followed the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines for reporting cohort studies.

Serum Lactic Acid Following Aneurysmal Subarachnoid Hemorrhage Is a Marker of Disease Severity but Is Not Associated With Hospital Outcomes.

Background: Following aneurysmal subarachnoid hemorrhage, peripherally-drawn lactic acid has been associated with poor outcomes; however, its clinical significance is unknown. We investigated admission factors and patient outcomes associated with serum lactic acid in this population.Methods: This was a retrospective observational study of 105 consecutive patients with serum lactate collected within 24 h of admission. Primary objectives were to determine the incidence of admission lactic acidemia, and factors positively and negatively associated with lactate levels. We also sought to determine if admission lactic acidemia was associated with patient outcomes, including vasospasm, delayed cerebral ischemia, mortality, and discharge disposition.Results: Admission serum lactic acid was elevated in 56 patients (53% of the cohort). Levels were positively associated with Hunt & Hess and modified Fisher grade, glucose, troponin I and white blood cell counts, and negatively associated with GCS and ventilator-free days. Admission lactate was not associated with the development of vasospasm or delayed cerebral ischemia. Patients with elevated lactic acid more often died during hospitalization, and less often were discharged home. After adjusting for other predictors of poor outcome, the adjusted odds of inpatient mortality (OR 0.97, 95% CI 0.79–1.20; p = 0.80) and discharge to home (OR 1.00, 95% CI 0.80–1.26; p = 0.97) was not associated with admission lactic acid.Conclusions: Early serum lactic acid elevation is common following aneurysmal subarachnoid hemorrhage and is associated with the clinical and radiographic grade of hemorrhage. Levels did not independently predict short-term outcomes when adjusted for established predictors of poor outcome. Further study is needed to determine the clinical significance of peripherally-drawn lactic acid in aneurysmal subarachnoid hemorrhage.