Confidence Interval Of Hazard Ratio Research Articles

Subtyping of Group 3/4 medulloblastoma as a potential prognostic biomarker among patients treated with reduced dose of craniospinal irradiation: a Japanese Pediatric Molecular Neuro-Oncology Group study

BackgroundOne of the most significant challenges in patients with medulloblastoma is reducing the dose of craniospinal irradiation (CSI) to minimize neurological sequelae in survivors. Molecular characterization of patients receiving lower than standard dose of CSI therapy is important to facilitate further reduction of treatment burden.MethodsWe conducted DNA methylation analysis using an Illumina Methylation EPIC array to investigate molecular prognostic markers in 38 patients with medulloblastoma who were registered in the Japan Pediatric Molecular Neuro-Oncology Group and treated with reduced-dose CSI.ResultsAmong the patients, 23 were classified as having a standard-risk and 15 as high-risk according to the classic classification based on tumor resection rate and presence of metastasis, respectively. The median follow-up period was 71.5 months (12.0–231.0). The median CSI dose was 18 Gy (15.0–24.0) in both groups, and 5 patients in the high-risk group received a CSI dose of 18.0 Gy. Molecular subgrouping revealed that the standard-risk cohort included 5 WNT, 2 SHH, and 16 Group 3/4 cases; all 15 patients in the high-risk cohort had Group 3/4 medulloblastoma. Among the patients with Group 3/4 medulloblastoma, 9 of the 31 Group 3/4 cases were subclassified as subclass II, III, and V, which were known to an association with poor prognosis according to the novel subtyping among the subgroups. Patients with poor prognostic subtype showed worse prognosis than that of others (5-year progression survival rate 90.4% vs. 22.2%; p < 0.0001). The result was replicated in the multivariate analysis (hazard ratio12.77, 95% confidence interval for hazard ratio 2.38–99.21, p value 0.0026 for progression-free survival, hazard ratio 5.02, 95% confidence interval for hazard ratio 1.03–29.11, p value 0.044 for overall survival).ConclusionAlthough these findings require validation in a larger cohort, the present findings suggest that novel subtyping of Group 3/4 medulloblastoma may be a promising prognostic biomarker even among patients treated with lower-dose CSI than standard treatment.

Predictors of time to recovery of preterm neonates with respiratory distress syndrome admitted in University of Gondar comprehensive specialized hospital neonatal intensive care unit North West Ethiopia.

BackgroundRespiratory distress syndrome (RDS) is caused by a deficiency of a molecule called surfactant. It occurs in newborns born before 37 weeks of gestation. It is a main cause of morbidity and mortality in the early neonatal period.Therefore, this study aims to assess median time to recovery and predictors of preterm neonates with respiratory distress syndrome admitted in University of Gondar comprehensive specialized hospital Northwest Ethiopia 2020.MethodsInstitution based retrospective follow up study was conducted on 386 preterm neonates with hyaline membrane disease who were admitted in the neonatal intensive care unit from January, 2016 to December 2018. The data were entered in to EPI info version 7.0 and transferred to Stata version 14.0 for analysis. Both bi-variable and multi variable Weibull parametric model were fitted to identify predictors with 95% confidence interval of hazard ratio (HR) and p-value. P-value less than 0.05 in the multivariable model showed the presence of significant association between covariates and the dependent variable.ResultsThe overall median length of recovery were 11 day with an interquartile range of (7, 16) neonate-days. Being a product of multiple pregnancy (AHR 1.67; 95%CI (1.25, 2.23)), vaginal mode of delivery (AHR 1.6; 95%CI (1.13, 2.26)), and neonatal hypothermia at admission (AHR 1.6; 95%CI (1.13, 2.26)) were found to be significant predictors of time to recovery.ConclusionIn this study the median time to recovery of preterm neonates with respiratory distress syndrome was slower than the clinical recommendations. Receiving bag and mask ventilation and hypothermia decreased the recovery whereas, vaginal delivery gestational age at birth, being multiple pregnancy, birth weight ≥2000grams were enhance the recovery of preterm neonates with RDS.

A Comprehensive Comparison of Additional Benefit Assessment Methods Applied by Institute for Quality and Efficiency in Health Care and European Society for Medical Oncology for Time-to-Event Endpoints After Significant Phase III Trials—A Simulation Study

ObjectivesAfter a successful Marketing Authorization Application for clinical trials with time-to-event endpoints, the degree of the added benefit from new treatments remains unknown and needs to be assessed. Unfortunately, until now no clear definition for added benefit determination of a treatment exists. Nevertheless, European authorities / societies have developed 2 “additional benefit assessment” methods, which have up to now not been compared: the European Society for Medical Oncology (ESMO) developed a dual rule considering relative and absolute benefit. The German Institute for Quality and Efficiency in Health Care (IQWiG) developed a method using upper 95% hazard ratio confidence interval. MethodsWe evaluate and compare both methods in an extensive simulation study including different censoring rates, failure time distributions, and treatment effects for sample size calculation. The methods’ performance is assessed via Receiver Operating Characteristic curves, Spearman correlation, and percentage of achieved maximal scores. ResultsThe results show that IQWiG’s method has in many situations a lower maximal scoring proportion than ESMO’s rule, that is, up to 28.5% versus 94.7%. Various failure time distributions lead to strongly changed maximal scoring percentages for ESMO. High positive correlation between the methods is present for moderate treatment effects. ConclusionsIQWiG’s method is usually more conservative than ESMO’s. ESMO’s rule tends to be more susceptible for various failure time distributions. Using the lower confidence interval limit seems to be a better solution resulting in a higher true-positive rate without increasing the false-positive rate. Thus, IQWiG’s method might need to be adapted accordingly to achieve a better overall classification.

Statistical methods for relative risk estimation and applications in case-cohort study

Objective: To systematically introduce the design of case-cohort study and the statistical methods of relative risk estimation and their application in the design. Methods: First, we introduced the basic principles of case-cohort study design. Secondly, Prentice's method, Self-Prentice method and Barlow method were described in the weighted Cox proportional hazard regression models in detail, finally, the data from the Shanghai Women's Health Study were used as an example to analyze the association between obesity and liver cancer incidence in the full cohort and case-cohort sample, and the results of parameters from each method were compared. Results: Significant association was observed between obesity and risk for liver cancer incidence in women in both the full cohort and the case-cohort sample. In the Cox proportional hazard regression model, the partial regression coefficients of the full cohort and the case-cohort sample fluctuated with the adjustment of confounding factors, but the hazard ratio estimates of them were close. There was a difference in the standard error of the partial regression coefficient between the full cohort and the case-cohort sample. The standard error of the partial regression coefficient of the case-cohort sample was larger than that of the full cohort, resulting in a wider 95% confidence interval of the relative risk. In the weighted Cox proportional hazard regression model, the standard error of the partial regression coefficient of Prentice's method was closer to the parameter estimates from full cohort than Self-Prentice method and Barlow method, and the 95% confidence interval of hazard ratio was closer to that of the full cohort. Conclusions: Case-cohort design could yield parameter results closer to the full cohort by collecting and analyzing data from sub-cohort members and patients with the disease, and reduce sample size and improve research efficiency. The results suggested that Prentice's method would be preferred in case-cohort design.

The HELENA study: Hexvix\xae-TURB vs. white-light TURB followed by intravesical adjuvant chemotherapy\u2014a prospective randomized controlled open-label multicenter non-inferiority study

PurposePhotodynamic diagnosis and white-light TURB with adjuvant intravesical chemotherapy (ICT) is widely used in treatment of bladder cancer. This non-inferiority trial is designed to demonstrate non-inferiority regarding recurrence-free survival (RFS) of Hexvix® TURB followed by immediate instillation compared to white-light TURB with immediate instillation followed by maintenance ICT.MethodsBetween 07/2010 and 12/2016, 129 patients with EORTC intermediate risk non-muscle invasive bladder cancer treated with TURB were included in this multicentre phase III study. Patients were randomized and received either white-light TURB with immediate ICT followed by maintenance ICT (n = 62, 20 mg Mitomycin weekly for 6 weeks as induction phase, afterwards 20 mg/month for 6 months) or Hexvix® TURB with immediate ICT only (n = 67, 40 mg Mitomycin). Primary study endpoint was RFS after 12 months. Hexvix® TURB was counted as non-inferior to white light alone if the upper limit of the one-sided 95% confidence interval of hazard ratio was lower than 1.676. Due to the non-inferiority design, the per-protocol population was used as the primary analysis population (n = 113)ResultsMedian follow-up was 1.81 years. Hexvix® group showed more events (recurrence or death) than white-light group (19 vs. 10) resulting in a HR of 1.29 (upper limit of one-sided 95%-CI = 2.45; pnon-inferiority = 0.249). The ITT population yielded similar results (HR = 1.67); 3.18], pnon-inferiority = 0.493). There was no significant difference in overall survival between both groups (p = 0.257).ConclusionNon-inferiority of Hexvix® TURB relative to white-light TURB with maintenance Mitomycin instillation in intermediate risk urothelial carcinoma of the bladder was not proven. Hence a higher effect of maintenance ICT is to assume compared to a Hexvix®-improved TURB only, confirming its important role in patient treatment.

Double antithrombotic therapy for prevention of bleeding and ischemic events after percutaneous coronary intervention in patients with atrial fibrillation: A meta-analysis.

Background:The efficacy of double antithrombotic therapy (DAT) vs. triple antithrombotic therapy (TAT) for prevention of bleeding and ischemic events in patients with atrial fibrillation following percutaneous coronary intervention (PCI) is unclear in those subgroups defined by the 5 factors (i.e., sex, age, race, history of diabetes, and type of P2Y12 inhibitor). We aimed to assess the efficacy of DAT vs TAT in these patient subgroups.Methods:We searched PubMed and relevant websites to include related randomized controlled trials (RCTs). Two endpoints of interest were clinically significant bleeding and major adverse cardiac events (MACE). Meta-analysis was performed stratified by 5 factors of interest (i.e., sex, age, race, history of diabetes, and type of P2Y12 inhibitor) to obtain pooled hazard ratio (HR) and 95% confidence interval (CI). Meta-regression analysis was conducted to evaluate subgroup effects. We detected publication bias by Egger test and funnel plots.Results:We included 4 RCTs for meta-analysis. DAT vs TAT significantly reduced the risk of clinically significant bleeding (HR 0.56, 95% CI 0.50–0.63). This effect of DAT was observed in most subgroups of interest (HR ranged from 0.54 to 0.69), and was consistent across various subgroups defined by each of the 5 factors of interest (Psubgroup ranged from 0.290 to 0.794). DAT vs TAT led to the similar risk of MACE (HR 0.98, 95% CI 0.89–1.08). This effect of DAT was observed in all subgroups of interest (all 95% CIs of HRs were across 1.0), and was consistent across various subgroups defined by each of the 5 factors of interest (Psubgroup ranged from 0.308 to 0.828). Publication bias was found only in one subgroup.Conclusions:Compared with TAT, DAT significantly reduces the risk of clinically significant bleeding and leads to the similar risk of MACE in patients with atrial fibrillation following PCI, irrespective of sex, age, race, history of diabetes, and type of P2Y12 inhibitor used at baseline.

Impacts of the Million Hearts® Cardiovascular Disease Risk Reduction Model on Medications, Heart Attacks and Strokes, and Medicare Spending after Two Years: A Cluster‐Randomized Trial

Research ObjectiveIn 2017, the Centers for Medicare &amp; Medicaid Services launched the Million Hearts® Cardiovascular Disease (CVD) Risk Reduction Model with the aim to reduce first‐time heart attacks and strokes among high‐risk Medicare fee‐for‐services (FFS) beneficiaries within 5 years. This large‐scale randomized trial pays providers to assess each of their Medicare patient’s risk of a heart attack or stroke and then makes additional payment if they reduce CVD risk among their high‐risk cohort. We assess whether, during its first two years, the model increased use of CVD medications, reduced incidence of heart attacks and strokes, and reduced Medicare spending.Study DesignA pragmatic, cluster‐randomized trial. CMS enrolled 516 organizations (primary and specialty practices, health centers, and hospitals) throughout the country and assigned half to the intervention group. For the 313 organizations that enrolled beneficiaries in 2017, we linked enrollment and clinical data with Medicare claims and estimated impacts as intervention‐control differences (regression adjusted) in outcomes.Population Studied300,550 Medicare FFS beneficiaries, 18% of whom were high risk (≥30% or higher risk of a heart attack or stroke in the next 10 years) and 40% were medium risk (15‐30% risk) in both groups. Intervention and control group beneficiaries were similar at enrollment in demographics, CVD risk factors, and recent utilization and spending.Principal FindingsAmong the high‐risk group, almost 40% of CVD risk at baseline was modifiable, mainly from elevated blood pressure and cholesterol. High‐risk intervention group enrollees were 4 percentage points more likely than the control group (28 vs 24%, P &lt; .001) to initiate or intensify statins or antihypertensive medications factors within 6 months of enrollment. When including the larger medium‐risk group—for whom CMS does not separately pay for CVD risk reduction—rates of initiation or intensification were 3 percentage points higher in the intervention versus control groups (23 vs 20%, P &lt; .001). Over a mean follow‐up of 17 months, the incidence of first‐time heart attack and stroke was similar in the intervention versus the control groups for the high‐risk group (90% confidence interval for hazard ratio: 0.93‐1.14) and for the medium‐ and high‐risk groups combined (90% CI: 0.93, 1.06). Medicare Part A and B spending was also similar in the intervention and control groups.ConclusionsThus far, the Million Hearts model has improved initiation and intensification of medications to treat modifiable risk factors among the high‐risk group, with positive spillover to the much larger medium‐risk group. However, the model has not reduced heart attacks and strokes or generated any savings to offset model costs.Implications for Policy or PracticeWhile CVD risk factors have declined substantially over the past 50 years, progress has slowed recently and even reversed in some groups. Value‐based purchasing efforts to date have focused on achieving control for individual CVD risk factors. This trial shows that a new “pay for prevention” approach that rewards assessing and reducing total CVD risk (combining individual risk factors into a single score readily interpretable by patients and providers) can improve use of CVD medications. More time is needed to assess whether the model will eventually reduce incidence of heart attacks and strokes.Primary Funding SourceThe study was funded by the Centers for Medicare and Medicaid Services.

AIDS-duration predictors of HIV/AIDS patients on antiretroviral therapy at Debre Berhan referral hospital, north-central Ethiopia

Background: Receiving ART treatment prolongs the life of HIV/AIDS patients by increasing substantially their CD4 count, even though the level is different from one individual patient to the other. The aim of this study was to identify the potential predictors of death of HIV-infected patients attending ART treatment. Methods: A hospital-based retrospective cohort chart review study design was conducted on 647 HIV-infected patients at a public hospital in North-Central Ethiopia from July 2012-January 2017. Kaplan-Meier plots, Log-rank and Wilcoxon tests, and Cox-proportional hazard model were employed. Data analysis was done with the help of statistical software (R version 3.2.2). 95% confidence interval for hazard ratio (HR) and p-value ≤ 0.05 was used to statistically associate with time till event occurred. Results: Among the total of 647 patients on 192(29.68%) event were occurred; while 455(70.32%) were censored. HIV-infected patients were followed for a total of 54 months, with a mean of 22.13(13.16) and a median of 21.47months. The prevalence of event was about 30 out of 100 HIV patients. According to the present study, the median CD4 count at the initial time of ART was 247 (IQR:120-375)cells/µl, whereas the median CD4 count at the time of event was 362 (IQR:225-532)cells/µl. Patients with higher baselineCD4 count,&gt;200cells/µl were 32.10% lower in risk of death than patients with lower baselineCD4 count, &lt; 200cells/µl (HR:0.679; 95%CI:0.537-0.857; p-value=0.001). Conclusions: ART treatment is effective enough in slowing down the progression of HIV-infection to AIDS and decreasing the mortality rate of patients significantly. Being Widowed/ divorced, bedridden, ambulatory began with lower baseline CD4 count and being on TDF-3TC-EFV regimen were the predictors of mortality in HIV-infected patients on ART. It is recommended that HIV patients start antiretroviral treatment early, track the progression of HIV to AIDS.

Routine coagulation tests on ICU admission are associated with mortality in sepsis: an observational study.

Low platelet count on admission to an intensive care unit (ICU) is associated with increased mortality and is thus included in some severity scoring systems such as the simplified acute physiologic score 3 (SAPS 3); however it is unclear whether other routine coagulation tests also predict mortality. The purpose of this retrospective single-centre study was to investigate whether activated partial thromboplastin time (APTT) or prothrombin time - international normalized ratio (PT-INR) measured on admission to the ICU in patients with severe sepsis or septic shock may be associated with mortality independent of SAPS 3 score. All patients admitted to a tertiary general ICU from 2007 to 2014 diagnosed with severe sepsis or septic shock were eligible. Results from APTT and PT-INR within 1.5h of admission as well as SAPS 3 were used as independent variables in a Cox regression. Of total 5485 ICU admissions during the study period we identified 647 unique patients with severe sepsis or septic shock. APTT and PT-INR were found to correlate significantly with mortality with a hazard ratio (HR) of 1.014 [95% confidence interval of HR (1.006-1.023)] for APTT and 1.422 (1.117-1.811) for PT-INR. HR for SAPS 3 was 1.036 (1.028-1.044). Activated partial thromboplastin time prolongation and raised PT-INR on ICU admission in patients with severe sepsis or septic shock is associated with increased mortality independent of SAPS 3 score. This indicates that APTT prolongation and PT-INR increase represents morbidity that is not accounted for in SAPS 3.

The B-Cell Receptor Signaling Inhibitor Molecules CD305 and CD307b Are Markers of Favorable Prognosis in Chronic Lymphocytic Leukemia with Both Mutated and Unmutated IGHV Gene Status

Background. The regulation of the B cell receptor (BCR)-mediated response to antigenic stimulation in chronic lymphocytic leukemia (CLL) is balanced by competing activating and inhibitory signals derived from specific co-receptors. In particular, the BCR inhibitory molecules Leukocyte associated Ig like receptor 1 (LAIR-1)/CD305 and human Fc receptor-like 2 (FCRL2)/CD307b have been independently reported as molecules associated with longer time to first treatment in CLL, although their synergic functional role and combined prognostic relevance remains to be explored. Aim. To assess the functional role and prognostic value of CD305 and CD307b as OS predictors in CLL. Methods. The study included 467 CLL cases all characterized at diagnosis for Rai stage (stages 0-I: 355 cases), CD49d expression (CD49d- CLL, <30% of positive cells by flow cytometry: 266), IGHV mutational status (mutated, M: 270), karyotype abnormalities according to the hierarchical stratification (normal/13q-/+12: 365). Median follow-up of patients was 70 months with 82 deaths. Immunophenotypic analysis was performed using a combination of anti-CD5 FITC, -CD19PE-Cy7, -CD305PerCPCy5.5, CD307bAPC mAbs. For functional assays, mouse anti-human IgM, and agonistic mouse anti-human CD305 and CD307b were used. Fab goat anti-mouse was used as cross linker. Phosphorylation state of ERK (pERK) and ATK (pATK) were evaluated by either flow cytometry or western blotting. Calcium flux was analysed by flow cytometry. Results.A significantly higher (p<0.0001) CD305 and CD307b expression in M versus UM CLL was documented, with mean % of expression of 58% vs. 33% (CD305), and 88% vs. 74% (CD307b). The best cut-off levels for OS, calculated using a ROC analysis, were 10% for CD305 and 85% for CD307b. Using these cut-offs, 331 (70.9%) and 296 (63.4%) were classified CD305+ and CD307bbright, respectively. The clinical impact of both markers as OS predictors was confirmed in both univariate (hazard ratio/confidence interval (HR/CI)= 0.39/0.25-0.60; p<0.0001 for CD305; HR/CI= 0.26/0.16-0.41; p<0.0001 for CD307b), and multivariate (HR/CI=0.41/0.26-0.63; p=0.0001 for CD305;HR/CI=0.27/0.17-0.42; p<0.0001 for CD307b) analyses. Therefore, we dichotomized CLL cases according to the expression of 2 markers (n=220) versus 0/1 markers (n=247). The prognostic impact of this combined markers expression was tested in univariate analysis (HR/CI=0.23/0.13-0.40; p<0.0001 ) and in a multivariate model including: IGHV mutational status, CD49d expression, Rai stage (stage 0-I versus stages II-IV), karyotype abnormalities (normal/del13/+12 versus del11/del17). The combined markers expression retained its prognostic impact (HR/CI=0.37/0.21-0.68; p=0.0013), along with the UM IGHV (HR/CI=2.54/1.51-4.26; p=0.0004), CD49d expression (HR/CI=1.83/1.13-2.97; p=0.015) del11/del17 (HR/CI=1.86/1.14-3.05; p=0.014). Consistently, expression of 2 markers identified subsets with longer OS in the context of both M (p=0.009) and UM CLL (p=0.004; see Figure). To functionally explain the peculiar clinical behavior of CLL expressing these molecules, we evaluated CLL cell response to BCR triggering in CD305+/CD307bbright CLL, with either a M (n=9) or a UM (n=7) IGHV gene status. A significant increase of anti-IgM response was found in 24-hour cultures compared to 2-hour cultures, irrespective of the IGHV mutational status: p-ERK, 41.2% vs 20% (p=0.006); pAKT, 18% vs 7% (p=0.037); calcium flux, mean AUC 2.0x106 vs 1.6x106 (p=0.01). This increased BCR response was paralleled by a significant down-regulation of both CD305 and CD307b after 24-hour culture compared to 2-hour culture (mean MFI 40 vs 92.5 for CD305, p=0.0009; 95.5 vs 414 for CD307b, p=0.001) with no difference between M and UM cases. We next tested the effects on BCR signaling of anti-CD305 and anti-CD307b ligation (n=4). While BCR engagement induced pERK (mean fold increase compared to the control=12), concomitant engagement of BCR and CD305 or CD307b reduced the pERK level to 68% or 40%, respectively. Moreover, simultaneous engagement of both CD305 and CD307b further inhibited pERK level to 28%. Conclusions.A CD305+/ CD307bbright phenotype predicts longer OS in CLL, in both M and UM IGHV CLL. The synergic effect of the B-cell receptor signaling inhibitors CD305 and CD307b may functionally explain this peculiar clinical behavior. [Display omitted] DisclosuresChiarenza:Gilead: Consultancy; Janssen: Consultancy; Roche: Consultancy.

Valve Selection in End-Stage Renal Disease: Should It Always Be Biological?

When valve replacement is required in patients with end-stage renal disease (ESRD), it is not clear if mechanical or bioprosthetic valve selection is better. We compared outcomes between ESRD patients who underwent either mechanical or biologic valve replacements at our institution. All patients with ESRD who underwent either mitral or aortic valve replacement from 2002 to 2014 at our institution were reviewed (n= 215; mechanical= 64, biological= 151). A Cox proportional hazards model was used to test the hypothesis that a mechanical valve was correlated with improved long-term survival. Among patients younger than 65 years (n= 123) we also compared survival with the Kaplan-Meier method. Similar unadjusted survival was found for patients who received either a bioprosthetic or mechanical valve (log-rank p= 0.55). Survival is clearly attenuated in this patient population, with only about half the patients younger than 65 years surviving beyond 2 years. In the proportional hazards model, a mechanical valve was not correlated with improved survival even when controlled for other variables, including shock, endocarditis, mitral valve replacement, and patient age (95% confidence interval for hazard ratio of mechanical valve: 0.64 to 1.62). It appears that there is minimal difference in survival after operation for ESRD patients who undergo bioprosthetic or mechanical valve replacement, even in patients younger than 65 years. The attenuated survival of the ESRD population after valve replacement makes the increased burden of anticoagulation (particularly in hemodialysis patients) unattractive. It is likely that only a small portion of ESRD patients benefit from the increased durability of a mechanical valve.

Heart rate response during 6-minute walking testing predicts outcome in operable chronic thromboembolic pulmonary hypertension.

BackgroundSix-minute walk test (6MWT) is routinely performed in chronic thromboembolic pulmonary hypertension (CTEPH) before pulmonary endarterectomy (PEA). However, the clinical relevance of heart rate response (ΔHR) and exercise-induced oxygen desaturation (EID) during 6MWT is remaining unknown.MethodsPatients undergoing PEA in our center between 03/2013-04/2014 were assessed prospectively with hemodynamic and exercise parameters prior to and 1 year post-PEA. Patients with symptomatic chronic thromboembolic disease (mean pulmonary artery pressure (mPAP) <25 mmHg) and clinical relevant obstructive pulmonary disease were excluded. The following definitions were used: ΔHR = (peak HR - resting HR), percent heart rate reserve (HRR) = (peak HR –rest HR)/(220 - age - rest HR) x 100 and EID = SpO2 ≤88 %.ResultsThirty-seven patients (of 116 patients screened) with mPAP of 43.2 ± 8.7 mmHg, pulmonary vascular resistance (PVR) of 605.5 ± 228.7 dyn*s/cm5, cardiac index (CI) of 2.4 ± 0.5 l/min/m2 and a 6MWT-distance of 404.7 ± 148.4 m and a peak VO2 of 12.3 ± 3.4 ml/min/kg prior to PEA were included. Baseline ΔHR during 6MWT was significantly associated with PVR 1 year post-PEA using linear regression analysis (r = 0.43, p = 0.01). Multivariate analysis indicated an association of HRR during 6MWT and residual PH with a hazard ratio of 1.06 (95 % Confidence interval for hazard ratio 0.99–1.14, p = 0.08). EID was observed commonly during 6MWT but no correlations to outcome parameters were found.ConclusionsThis is the first prospective study to describe an association of ΔHR during 6MWT with pulmonary hemodynamics 1 year post-PEA. Our preliminary results indicate that HRR derived from 6MWT is of clinical significance. EID was commonly observed, albeit failed as a significant prognostic factor.

CD49d Prevails over the Novel Recurrent Mutations As Independent Prognosticator of Overall Survival in Chronic Lymphocytic Leukemia

Background. CD49d, the alpha-chain of the integrin heterodimer VLA-4, has been identified among the strongest predictors of overall survival (OS) in chronic lymphocytic leukemia (CLL), along with IGHV mutational status and deletion of the 17p (17p-) chromosome involving TP53 (Bulian et al, JCO, 2014). In addition to TP53, the clinical relevance of NOTCH1, SF3B1 and BIRC3 gene mutations has been recently emphasized.Aim. To test the relevance of CD49d in molecular subgroups of CLL defined by NOTCH1, SF3B1 and BIRC3 gene mutations.Methods. The study was based on a cohort of 778 unselected CLL (422 untreated and 356 treated cases) all characterized for CD49d expression (CD49dhigh, ≥30% positive cells by flow cytometry in 229 cases), IGHV mutational status (unmutated, UM, in 262 cases), karyotype abnormalities according to the hierarchical stratification (13q- in 308 cases, +12 in 103 cases, 11q- in 64 cases), tested at diagnosis, along with mutations/deletions (hereinafter, disruption) of TP53 (disrupted in 84 cases, including 58 cases with 17p-), BIRC3 (disrupted in 59 cases), and mutationsof NOTCH1 (mutated in 81 cases), SF3B1 (mutated in 54 cases)tested at diagnosis in 65% of cases, in all cases before therapy. Chromosome abnormalities by FISH were defined by using a 5% cut-off; IGHV, TP53, BIRC3, NOTCH1 and SF3B1 mutations were investigated by Sanger sequencing. Median follow-up of patients was 80 months with 173 deaths.Results. i) association with CD49d: a CD49dhigh phenotype associated with age ≥65 years (p=0.0001), Rai stage I or higher (p>0.0001), UM IGHV status (p>0.0001), absence of 13q- (p=0.0001), presence of +12 (p<0.0001), presence of NOTCH1 mutations (p<0.0001). ii) CD49d prognostic impact: in univariate analysis, the following covariates had a significant impact on OS: age ≥65 years (hazard ratio/confidence interval (HR/CI)= 3.98/2.77-5.73; p<0.0001), Rai stage I or higher (HR/CI=1.81/1.33-2.46; p=0.0002), high CD49d expression (HR/CI=2.62/1.94-3.54; p<0.0001), UM IGHV status (HR/CI=3.03/2.24-4.10; p<0.0001), presence of 13q- (HR/CI=0.52/0.37-0.71; p=0.0001), +12 (HR/CI=1.59/1.08-2.33; p=0.0183), 11q- (HR/CI=2.16/1.42-3.30; p=0.0004), NOTCH1 mutations (HR/CI=2.66/1.82-3.88; p<0.0001), SF3B1 mutations (HR/CI=1.99/1.24-3.20; p=0.0048), BIRC3 disruption (HR/CI=2.41/1.58-3.68; p<0.0001), TP53 disruption (HR/CI=3.23/2.28-4.57; p<0.0001). In a multivariate analysis model including all these variables, high CD49d expression (HR/CI=1.76/1.28-2.42; p=0.0006), UM IGHV status (HR/CI=2.21/1.58-3.09; p<0.0001), presence of 11q- (HR/CI=2.11/1.35-3.31; p=0.0011), TP53 disruption (HR/CI=2.93/2.04-4.22; p<0.0001), and NOTCH1 mutations (HR/CI=1.76/1.16-2.67; p=0.0082) emerged as independent prognosticators, along with age ≥65 years (HR/CI=3.73/2.58-5.39; p<0.0001). iii) CD49d prognostic impact using the integrated hierarchical mutational/cytogenetic model: by integrating gene mutations and cytogenetic aberrations according to Rossi et al (Blood, 2013), a multivariate analysis model was applied with the following covariates: age, CD49d, IGHV status, TP53/BIRC3 disruption, NOTCH1 mutations/SF3B1 mutations/11q-, normal karyotype/+12, 13q-. Again, CD49dhigh phenotype (HR/CI=1.88/1.38-2.54; p=0.0001), UM IGHV status (HR/CI=2.16/1.54-3.01; p<0.0001), presence of NOTCH1 mutations/SF3B1 mutations/11q- (HR/CI=1.62/1.11-2.38; p=0.0139), and of TP53/BIRC3 disruption (HR/CI=2.67/1.92-3.70; p<0.0001) retained their independent prognostic impact, along with age ≥65 years (HR/CI=3.58/2.28-5.17; p<0.0001). Notably, CD49dhigh CLL patients experienced shorter OS than the CD49dlow cases in the context of each mutational/cytogenetic group (TP53/BIRC3 disruption, p=0.0064; NOTCH1 mutations/SF3B1 mutations/11q-, p=0.05; normal karyotype/+12, p=0.0153; 13q-, p=0.0126; see Figure).Conclusion. CD49d was confirmed as independent negative OS prognosticator in CLL also when the novel recurrent alterations of NOTCH1, BIRC3, and SF3B1 genes were considered. In this setting, TP53 disruption and NOTCH1 mutations remained independent OS prognosticators, allegedly for their physiopathological roles in CLL cell immuno-chemoresistance. [Display omitted] DisclosuresGaidano:Morphosys, Roche, Novartis, GlaxoSmith Kline, Amgen, Janssen, Karyopharm: Honoraria, Other: Advisory boards; Celgene: Research Funding.

The Concomitant High Expression of the B-Cell Receptor Signaling Inhibitor Molecules CD150, CD305, and CD307b Predicts Longer Overall Survival in the Context of Low-Risk Chronic Lymphocytic Leukemia

Background. Risk assessment in chronic lymphocytic leukemia (CLL) is determined by the presence/absence of several negative prognostic factors, including the unmutated (UM) IGHV mutational status, TP53 deregulation by mutation and/or deletion of the 17p (17p-) chromosome, and high CD49d expression. Nevertheless, clinical heterogeneity can be observed also in the context of low-risk CLL, identified according to the absence of the aforementioned negative prognosticators. Thus, identifying novel markers that may predict an indolent clinical course in the context of low-risk CLL cases can be of key clinical relevance. The CD150/SLAMF1, CD305/LAIR1, and CD307b/FCRL2 molecules have been independently reported as molecules associated with a mutated IGHV status, and with longer time to first treatment in CLL. However, the prognostic relevance of the combined CD150/CD305/CD307b expression in predicting overall survival (OS) in the context of low-risk CLL remains to be explored.Aim. To assess the prognostic value of CD150, CD305, CD307b as OS predictors in the context of low-risk CLL, as defined according to the canonical prognostic factors.Methods. The study included 330 CLL cases all characterized for Rai stage (stages 0-I: 254 cases), CD49d expression (CD49d- CLL, <30% of positive cells by flow cytometry: 191), IGHV mutational status (mutated, M: 191), karyotype abnormalities according to the hierarchical stratification (normal/13q-/+12: 206 cases), all tested at diagnosis. Median follow-up of patients was 77 months with 67 deaths. Immunophenotypic analysis was performed in thawed samples using a combination of anti-CD5 FITC, -CD19PE-Cy7, -CD150PE, -CD305PerCPCy5.5, CD307bAPC mAbs, and DAPI to exclude dead cells. Both percent of positive cells and mean fluorescence intensity (MFI) data were recorded.Results. A significantly higher (p<0.0001) CD150, CD305 and CD307b expression in M versus UM CLL was documented, with mean % of expression/MFI of 65%/498MFI vs. 25%/160MFI (CD150), 60%/1208MFI vs. 33%/583MFI (CD305), 87%/495MFI vs. 76%/383MFI (CD307b). The best cut-off levels for OS, calculated using a ROC analysis, were: 50%/290MFI for CD150; 10%/230MFI for CD305; 80%/360MFI for CD307b. Given the overall concordance in the definition of positive cases by using MFI or % values, the latter was chosen for further analyses. Using the % cut-offs, 154 (46.7%), 234 (70.9%) and 212(64.2%) were classified positive for CD150, CD305 and CD307b respectively. The clinical impact of the three markers as OS predictors was confirmed in both univariate (hazard ratio/confidence interval (HR/CI)= 0.20/0.11-0.37; p<0.0001 for CD150; HR/CI= 0.40/0.25-0.65; p=0.0002 for CD305; HR/CI= 0.27/0.16-0.44; p<0.0001 for CD307b), and multivariate (HR/CI=0.34/0.17-0.66; p=0.0015 for CD150; HR/CI=0.47/0.29-0.76; p=0.0023 for CD305;HR/CI=0.42/0.24-0.73; p=0.0022 for CD307b) analyses. Therefore, we combined their expression in a 0 (all the three markers below the cut-off) to 3 (all the three markers above the cut-off) score, and dichotomized CLL cases according to the expression of 3/2 markers (n=205) versus 0/1 markers (n=125). The prognostic impact of this combined markers expression was tested in univariate analysis (HR/CI=0.24/0.14-0.40; p<0.0001 ) and in a multivariate model including: IGHV mutational status, CD49d expression, Rai stage (stage 0-I versus stages II-IV), karyotype abnormalities (normal/del13/+12 versus del11/del17). The combined markers expression retained its prognostic impact (HR/CI=0.47/0.26-0.87; p=0.0172), along with the UM IGHV (HR/CI=2.66/1.44-4.89; p=0.0018), CD49d+ expression (HR/CI=2.14/1.25-3.67; p=0.0058) del11/del17 (HR/CI=2.08/1.23-3.50; p=0.0063). Moreover, expression of ≥2 markers was associated with a better prognosis in the context of the M IGHV (p=0.0042), CD49d- (p=0.0002), Rai 0-I stage (p<0.0001) and normal/del13/+12 karyotype (p=0.0001) groups (see Figure).Conclusions: High expression of at least two of the CD150, CD305 and CD307b molecules predicts longer OS in CLL, also in the context of low-risk prognostic categories. A synergic effect of the CD150, CD305 and CD307b molecules, all inhibitors of the B-cell receptor signaling, may be taken into account to functionally explain this peculiar clinical behavior. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Skin Ulcers and Mortality Among Adolescents and Young Adults With Spina Bifida in South Carolina During 2000-2010.

The authors investigated 48 deaths (7% death rate) among 690 adolescents and young adults with spina bifida in South Carolina during 2000-2010. The authors used Medicaid and other administrative data and a retrospective cohort design that included people with spina bifida identified using ICD-9 codes. Cox regression models with time-dependent and time-invariant covariates, and Kaplan-Meier survival curves were constructed. The authors found that 21.4% of the study group had a skin ulcer during the study period and individuals with skin ulcers had significantly higher mortality than those without ulcers (P < .0001). People who had their first skin ulcer during adolescence had higher mortality than those who had the first skin ulcer during young adulthood (P = .0002; hazard ratio = 10.70, 95% confidence interval for hazard ratio: 3.01, 38.00) and those without skin ulcers, controlling for other covariates. This study showed that age at which individuals first had a skin ulcer was associated with mortality.

Abstract 18612: Intravenous Infusion of Ultrashort-acting Beta-blocker, Landiolol, for Prevention of Immediate Recurrence of Atrial Fibrillation after Catheter Ablation

BACKGROUND: Immediate recurrence of atrial fibrillation (AF) after catheter ablation (CA) troubles with patients. We investigated whether intraveneous infusion of landiolol, an ultrashort-acting beta-blocker, could inhibit immediate AF recurrence after CA by randomized controlled trial. METHOD: atients with drug-resistant AF treated by CA were assigned to receive either landiolol or placebo after the procedure. In the landiolol group, landiolol was infused ntraveneously at speed of 1 μg/kg/min and continued for 3 days after the CA. The primary end point was occurrence/non-occurrence of AF, defined as supra-ventricular arrhythmia more than 5 min, up to 3-day after CA. Logistic regression analysis was performed to investigate risk factor. RESULT: 31 and 24 patients were assigned to landiolol group and placebo group, respectively. There were no significant difference between both groups in systolic blood pressure (SBP) before CA, diastolic blood pressure (DBP) before CA and changes from pre-CA to post-CA of SBP and DBP. AF recurrence occurred in 5 patients (10%) in landiolol group versus 11 patients (45%) in the placebo group (P=0.016, Figure). Multivariable analysis revealed that landiolol infusion significantly reduced the risk of transient AF recurrence after procedure (Hazard ratio: 0.208, 95% confidence interval of hazard ratio: 0.048-0.897, P=0.035). CONCLUSIONS: Short-term landiolol infusion successfully decreased immediate AF recurrence after CA without changing SBP and DBP. Administration of landiolol may become a new strategy to facilitate management after CA.

Comparing long-term toxicity and efficacy of combined modality treatment including extended- or involved-field radiotherapy in early-stage Hodgkin's lymphoma

To evaluate long-term toxicity and efficacy of a combined modality strategy including extended-field radiotherapy (EF-RT) or involved-field radiotherapy (IF-RT), the German Hodgkin Study Group carried out a follow-up analysis in patients with early unfavorable Hodgkin's lymphoma (HL). One thousand two hundred and four patients were randomized to four cycles of chemotherapy followed by either 30 Gy EF- or 30 Gy IF-RT (HD8 trial); 532 patients in each treatment arm were eligible. At 10 years, no arm differences were revealed with respect to freedom from treatment failure (FFTF) (79.8% versus 79.7%), progression-free survival (79.8% versus 80.0%), and overall survival (86.4% versus 87.3%). Non-inferiority of IF-RT was demonstrated for the primary end point FFTF (95% confidence interval for hazard ratio 0.72-1.25). Elderly patients had a poorer outcome when treated with EF-RT. So far, 15.0% of patients in arm A and 12.2% in arm B died, mostly due to secondary malignancies (5.3% versus 3.4%) or HL (3.2% versus 3.4%). After EF-RT, there were more secondary malignancies overall (58 versus 45), especially acute myeloid leukemias (11 versus 4). Radiotherapy intensity reduction to IF-RT does not result in poorer long-term outcome but is associated with less acute toxicity and might be associated with less secondary malignancies.

Statistical evaluation of mortality in long-term carcinogenicity bioassays using a Williams-type procedure

Several doses and a control group can be compared under order restriction using the Williams procedure for normally distributed endpoints assuming variance homogeneity. Comparison of the survival functions represents a secondary endpoint in long-term in vivo bioassays of carcinogenicity. Therefore, a Williams-type procedure for the comparison of survival functions is proposed for the assumption of the Cox proportional hazards model or the general frailty Cox model to allow a joint analysis over sex and strains. Interpretation according to both statistical significance and biological relevance is possible with simultaneous confidence intervals for hazard ratios. Related survival data can be analyzed using the R packages survival, coxme, and multcomp. Together with the R packages MCPAN and nparcomp, Dunnett- or Williams-type procedures are now available for the statistical analysis of the following endpoint types in toxicology: (i) normally distributed, (ii) non-normally distributed, (iii) score (ordered categorical) data, (iv) crude proportions, (v) survival functions, and (vi) time-to-tumor data with and without cause-of-death information.

OT2-01-02: First-Line Bevacizumab in Combination with Capecitabine or Paclitaxel for HER2−Negative Locally Recurrent or Metastatic Breast Cancer (LR/MBC): A Randomized Phase III Trial.

Abstract Background A number of phase III studies have shown significant progression-free survival (PFS) benefits with the combination of bevacizumab (Bev) and either first-line capecitabine (X) or taxane therapy in LR/MBC. The ongoing open-label, randomized, phase III CECOG-sponsored TURANDOT study (CECOG/BC.1.3.005) is investigating the efficacy and safety of first-line Bev plus paclitaxel (P) versus Bev plus X in this setting. Materials and methods: Eligible patients (pts) are aged ≥18 years with HER2−negative, chemonaïve LR/MBC, an ECOG performance status of 0–2 and a life expectancy &amp;gt;12 weeks. Prior chemotherapy and concomitant hormonal therapy for LR/MBC are not permitted, but prior (neo)adjuvant chemotherapy is allowed if completed ≥6 months before randomization or ≥12 months if taxane based. Pts are randomized to receive Bev 10mg/kg days 1, 15 plus P 90mg/m2 days 1, 8, 15, q28d (Arm A) or Bev 15mg/kg day 1 plus X 1,000mg/m2 bid days 1–14, q21d (Arm B) until disease progression, unacceptable toxicity or withdrawal of consent. The primary objective is to demonstrate non-inferiority in overall survival (OS) with Bev plus P versus Bev plus X (upper limit ≤1.33 for the two-sided confidence interval for hazard ratio [HR]). Secondary objectives are: comparison of overall response rate (RECIST criteria); PFS; time to response; duration of response; time to treatment failure; safety (CTCAE version 3); and quality of life (EORTC QLQ-30). The recruitment target is 560 pts. A sample size of 490 pts in the per-protocol population will be required to provide 80% power to reject the null hypothesis of inferiority at a one-sided significance level of 0.025, assuming a 24-month median OS with Bev plus P and an alternative hypothesis of HR=1. Data cut-off for adverse event reports was 12 Apr 2010. Interim and final efficacy analyses will be triggered after 175 and 389 events, respectively. Results: Recruitment to the study began in Sep 2008 and was completed in Aug 2010, with 561 pts randomized. Follow-up is ongoing. Conclusions: TURANDOT is the first study to examine the efficacy and safety of Bev plus P versus Bev plus X as first-line treatment for pts with LR/MBC. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT2-01-02.

A randomized phase III study of sox (S-1/oxaliplatin) versus COX (capecitabine/oxaliplatin) in patients with advanced colorectal cancer.

3524 Background: A regimen consisting of capecitabine and oxaliplatin (COX) is widely used in Korea in the first-line treatment of metastatic colorectal cancer (MCRC). S-1 may have considerable activity compared with capecitabine. Phase I and II studies showed that S-1 plus oxaliplatin (SOX) might have at least comparable activity with COX in MCRC. The aim of study was to evaluate whether SOX is noninferior to COX in terms of progression free survival (PFS) in patients previously untreated with systemic therapy for MCRC. Our hypothesis was that SOX is non-inferior to COX if the upper limit of 95% confidence interval for hazard ratio (HZ) between those two arms is below 1.4327, which comes from the non-inferiority margin of 13% in progress-free survival at 15 months. Methods: This study was a randomized, two-arm, non-inferiority, phase III comparison of SOX versus COX. Patients with MCRC were stratified according to primary site (colon vs. rectum), previous treatment (adjuvant therapy vs. none) and status ...