Stepwise Cox Proportional Hazards Model Research Articles

Impact of concurrent medications use on outcome of pancreatic cancer: SEER Medicare analysis.

378 Background: Preclinical studies have suggested concurrent non-antineoplastic medication use may impact pancreatic cancer. We performed an analysis to examine these associations on survival in pancreatic cancer. Methods: Data from the Surveillance, Epidemiology and End Results (SEER)-Medicare with available part D data between 2006 and 2009 were analyzed. Cases with non-adenocarcinoma histology, autopsy only and death certificate only data were excluded. Drug use was defined as having two prescriptions filled within 12 months of pancreatic cancer diagnosis. The following medications were analyzed: beta-blocker, statin, insulin, metformin, thiazolidinedione, warfarin and heparin. The primary end point was overall survival. Stepwise Cox proportional hazard models were employed including each medication group as well as age, gender, stage, site, grade, diabetes, race and Charlson comorbidity score. Results: There were 13,702 cases which met inclusion criteria and had available Part D data. Median age was 76 years, There were 42.5% males, 77.1% were white and 34.0%had diabetes. Head of the pancreas tumors accounted for 49.9% cases and 49.6% had stage 4 disease and at diagnosis. The results of the stepwise Cox proportional hazard models are summarized in table 1. Beta blockers, heparin, insulin, warfarin were associated were significantly with improved survival (p<0.05). Conclusions: Concurrent medication use, particularly heparin, insulin warfarin and beta-blockers are associated with improved survival in patients with pancreatic cancer. Diabetes medications (metformin, TZD) did not have an impact in the multivariable model. Additional studies are needed to examine whether these medications may improve outcomes for patients with pancreatic cancer. [Table: see text]

Analysis of prognostic factors in patients with hepatocellular carcinoma (≤5 cm) underwent hepatectomy

To explore the clinical and pathological factors influencing the prognosis of patients with hepatocellular carcinoma (HCC)(≤5 cm) after hepatectomy. Two hundreds and nineteen cases with HCC(≤5 cm) undergoing hepatectomy in Cancer Hospital, Chinese Academy of Medical Sciences between December 2003 and July 2013 were collected. The alpha fetoprotein (AFP) level, tumor number, tumor size (diameter), liver cirrhosis, vascular invasion, capsular invasion, differentiation, surgical methods, resection margin, the way of treatments, the situation of recurrence and time to recurrence were analyzed. Log-rank test and the stepwise Cox proportional-hazards models were used to compare the prognosis, respectively. The 1-, 3-, 5- and 10- year overall survival rates were 95.9%, 85.3%, 67.8% and 53.3% respectively in all patients.Single factor analysis indicated that vascular invasion, capsular invasion, tumor size, hepatic vascular occult, liver cirrhosis, tumor differentiation, AFP, the way of treatments, the situation of recurrence and time to recurrence can affect the prognosis significantly (all P<0.05). The multifactor analysis showed that AFP, tumor differentiation, liver cirrhosis, capsular invasion, tumor size and the situation of recurrence and time to recurrence were independent prognostic factors (all P<0.05). The prognosis of patients with HCC(≤5 cm) underwent hepatectomy are affected by multi-factors, such as AFP, tumor differentiation, liver cirrhosis, capsular invasion, tumor size and the situation of recurrence and time to recurrence.

Analysis of Olig2 and YKL-40 expression: a clinicopathological/immunohistochemical study for the distinction between subventricular zone II and III glioblastomas.

Glioblastomas (GBs) are the most common and lethal primary brain tumors in the adults. Glioblastomas originates either from astrocytes that have accumulated mutations and de-differentiated or from neural stem cells within the subventricular zone (SVZ) in close contact with the vasculature. Recently, several studies have hypothesized that gliomagenesis occurs in perivascular niches with highly invasive peripheral proliferating zones. The purpose of our study was to investigate the pathological and clinical significance of Olig2 and YKL40 immunoexpression in 152 GBs in relationship to the SVZ II and III. Olig2 expressions were successfully detected in 12 (15.58%) of 77 SVZ type II GBs and 16 (21.3%) of 75 SVZ type III GBs, respectively. YKL-40 expression was observed in 45 (58.4%) of 77 SVZ type II GBs and in 17 (22.6%) of 75 SVZ type III GBs, respectively. Stepwise multivariate Cox proportional hazards models were used, and the prognostic factors to significantly impact OS were: PFS < 54 weeks (HR: 5.86; CI: 3.02-11.33; p = 0.00); radiotherapy (HR: 0.34; CI: 0.18-0.60; p = 0.00); radio- and chemotherapy (HR: 0.05; CI: 0.03-0.10; p = 0.0), and YKL-40+ GBs (HR: 1.61; CI: 1.28-2.31; p = 0.01).

Prognostic value of myocardial perfusion imaging and coronary artery calcium measurements in patients with end-stage renal disease.

Coronary artery disease (CAD) is highly prevalent in patients with end-stage renal disease (ESRD), owing to clustering of traditional and uremic-specific risk factors. However, in this population asymptomatic course of CAD is common and it has been reported that myocardial perfusion imaging (MPI) with single-photon emission tomography (SPET) has lower sensitivity. In the current study, we assessed the value of MPI gated-SPET and its combination with coronary artery calcium (CAC) score measurements in risk stratification of ESRD patients. MPI gated-SPET was performed with dual-headed SPET camera and CAC score measured by multi-detector computed tomography (MDCT) system.There were tested 77 ESRD individuals. During the follow-up study, cardiac events (CE) defined as cardiac death or nonfatal myocardial infarction (MI) or the necessity for coronary revascularization were recorded. Univariate and stepwise multivariable Cox proportional hazards-models were used to identify the predictors of CE. Eighteen CE were recorded during the follow-up. They were significantly associated with higher summed stress scores on MPI, higher percentage of ischaemic myocardium, higher occurrence of defects in multiple territories and higher CAC score (all with P<0.05). Univariate Cox proportional hazard-models showed that severe perfusion abnormalities as well as CAC score ≥1000 were significantly associated with cardiac events (P<0.0001, P=0.0056). In stepwise Cox proportional hazards-models considering age, gender, history of diabetes mellitus, post-stress left ventricular stunning, the degree of perfusion abnormality and CAC score, only severe perfusion abnormalities and CAC score ≥1000 were independent predictors of CE. There was no CE in patients with normal perfusion, normal function and zero CAC score. This study suggests that combined evaluation of MPI and CAC can predict the outcome in ESRD individuals, while severe perfusion abnormality on gated-SPET and high CAC score ≥1000 are predictors of future cardiac events.

Baseline characteristics and hospitalizations in patients with schizophrenia receiving olanzapine long-acting injection: an interim analysis from a non-interventional, prospective observational safety study.

BackgroundDepot antipsychotics are a treatment option for medication nonadherence in patients with schizophrenia. Nonadherence can lead to increased relapse and hospitalization rates. This article reports hospitalization data before and after initiation of olanzapine long-acting injection (LAI), a depot antipsychotic.MethodsData were assessed from an ongoing, multinational, prospective, observational post-authorisation safety study being conducted to evaluate post-injection delirium/sedation syndrome (PDSS), an adverse reaction that can occur following injection of olanzapine LAI. Eligible patients were aged ≥18 years, diagnosed with schizophrenia, were prescribed olanzapine LAI, and lived outside the United States. Psychiatric hospitalization and medication data were collected retrospectively for the 6-month period before study entry and prospectively throughout the study. Paired t-tests and McNemar’s tests were used to assess changes in hospitalization incidence and duration. Stepwise Cox proportional hazards models assessed factors associated with hospitalizations. Analyses were based on data from the first 3 years of the continuously enrolling study (N = 668).ResultsThe average duration of olanzapine LAI exposure for all patients was 0.768 years. Of the 529 patients who received at least 1 injection of olanzapine LAI and were not hospitalized at study entry, 8.1 % had at least 1 subsequent psychiatric hospitalization with a mean duration of 2.0 days. Of the 288 patients who had a >6-month follow-up, 8.3 % had at least 1 post-baseline psychiatric hospitalization with a mean duration of 2.3 days. The incidence of hospitalizations in the 6-month period after treatment was significantly lower than that in the 6-month period prior to treatment (8.3 vs 32.6 %, respectively; P < 0.001). Furthermore, mean hospitalization duration decreased from 11.5 days in the 6-month period before treatment to 2.3 days in the 6-month period after treatment (P < 0.001). Psychiatric hospitalization in the prior 12 months (P < 0.0001) and recreational drug use within 24 h of baseline visit (P = 0.015) were identified as potential predictors of time to first psychiatric hospitalization after beginning to take olanzapine LAI. At the time of interim analysis, 5 PDSS events had occurred, which was too few for a full analysis of those events.ConclusionsResults indicate a significant reduction in the incidence and days of hospitalization from the 6-month period before to the 6-month period after olanzapine LAI initiation, which suggests reduced relapse and hospitalization during treatment. Results should be interpreted with caution due to the observational nature of the study and use of retrospective baseline data.Electronic supplementary materialThe online version of this article (doi:10.1186/s12888-015-0669-5) contains supplementary material, which is available to authorized users.

Validation of the Combination Gleason Score as an Independent Favorable Prognostic Factor in GS 7-10 Prostate Cancer Treated With Dose-Escalated Radiation Therapy

The combination Gleason Score (ComboGS) at time of biopsy is a recently proposed prognostic marker defined as the presence of at least 1 biopsy core of lower Gleason Score (GS) in men who have a highest GS ≥7 prostate cancer. In single-institution reports, the presence of ComboGS decreased the risk of pathologic upgrading at time of prostatectomy and decreased the risk of prostate cancer-specific mortality (PCSM) following external beam radiation therapy (EBRT); however, these findings have not been validated. Herein, we evaluated if the presence of ComboGS was prognostic for improved outcome in an independent cohort of men receiving EBRT for prostate cancer. At a single institution from 1988 to 2012, 788 consecutive men with prostate cancer received dose-escalated EBRT (minimum 75 Gy). Endpoints analyzed included PCSM, overall survival (OS), freedom from distant metastases (FFDM) and freedom from biochemical failure (FFBF, with failure defined as a rise in prostate-specific antigen [PSA] of 2 ng/mL or more above nadir). Statistical analysis was performed using Kaplan-Meier and Stepwise Cox proportional hazards models. In the 532 men with a GS of 7-10, the median follow-up was 89 (interquartile range [IQR]:57-128) months. Of these men, 259 (49%) had a ComboGS, while 272 (51%) did not. Men with ComboGS had similar age, T stage, Cancer of the Prostate Risk Assessment (CAPRA) score, and rate of androgen deprivation therapy (ADT) use (P>.05). Men with comboGS had higher baseline GS (7, 57% vs 67%; 8, 15% vs 17%; 9, 20% vs 9.5%; 10, 8% vs 7%, P=.005), and slightly lower PSA (14.2 vs 16.3, P=.02). On univariate analysis, men with ComboGS had improved 10-year FFBF (75.2% vs 54.9%, HR: 0.59, 95% CI: 0.42-0.82), FFDM (95.7% vs 84.3%, HR: 0.26, 95% CI: 0.15-0.47), PCSM (93.7% vs 88.1%, HR: 0.42, 95% CI: 0.22-0.81), and OS (82.4% vs 67.7%, HR: 0.45, 95% CI: 0.31-0.64). In men with intermediate-risk disease, the presence of comboGS decreased 10-year distant metastasis (DM) rates from 7.2% (±2.3) to 0.8% (±0.8) (HR: 0.17, 95% CI: 0.53-0.57), while in high-risk men, 10-year DM rates decreased from 21.9% (±4.1) to 9.1% (±3.5) (HR: 0.32, 95% CI: 0.17-0.63). On multivariate analysis, ComboGS was associated with decreased BF (HR: 0.59, 95% CI: 0.40-0.86, P=.007), DM (HR: 0.20, 95% CI: 0.09-0.43, P=.0001), PCSM (HR: 0.37, 95% CI: 0.16-0.85, P=.02), and OS (HR: 0.32, 95% CI: 0.20-0.52, P<.0001) after correction for age, GS, PSA, T stage, Charlson Co-Morbidity Index, percent cores positive, and ADT use. The addition of ComboGS increased the prognostic power of CAPRA score as measured by the concordance index for BF (0.709 vs 0.693), DM (0.833 vs 0.801), and PCSM (0.827 vs 0.811). ComboGS is an independent favorable prognostic factor for all clinical endpoints that is readily available but not routinely utilized. ComboGS increases the prognostic power of the CAPRA score and may identify men in whom therapy may be de-escalated

Venous Thromboembolic Complications of Lung Transplantation: A Contemporary Single-Institution Review

The incidence and consequences of deep venous thrombosis (DVT) and pulmonary embolism (PE) have not been described recently in lung transplant recipients. We sought to characterize DVT and PE in a contemporary series of lung transplant recipients and describe their association with clinical outcomes. The records of all lung transplant recipients from July 1, 2008, to June 30, 2013, were reviewed and analyzed. DVT was diagnosed by venous duplex ultrasonography. PE was diagnosed by computed tomography angiography, nuclear ventilation/perfusion scanning, or pulmonary angiography. The study comprised 117 patients who underwent 123 transplants. The median age was 63 years (range, 17 to 77 years). Forty-five patients (39%) had evidence of lower extremity DVT, 53 (45%) had no evidence of lower extremity DVT, and 19 (16%) were not tested. Fifty-three (45%) had evidence of upper extremity DVT, 30 (26%) had no evidence of upper extremity DVT, and 34 (29%) were not tested. Eighteen (15%) had evidence of PE, 82 (70%) had no evidence of PE, and 17 (15%) were not tested. A multivariable, stepwise Cox proportional hazards model revealed that the presence of lower extremity DVT (hazard ratio, 2.43; 95% confidence interval, 1.29 to 4.64), use of cardiopulmonary bypass (hazard ratio, 2.21; 95% confidence interval, 1.04 to 4.68), and unilateral lung transplantation (hazard ratio, 2.13; 95% confidence interval, 1.07 to 4.25) were associated with diminished survival. The incidence of DVT and PE in lung transplant recipients is high. Posttransplant surveillance and treatment based on findings are warranted.

High level of intercellular adhesion molecule-1 affects prognosis of patients with hepatocellular carcinoma.

To determine the cut-off value of intercellular adhesion molecule-1 (ICAM-1) and assess the correlation of ICAM-1 with clinicopathological features and the prognosis of hepatocellular carcinoma (HCC) patients who underwent surgical resection. We prospectively collected clinicopathological data from 236 HCC patients who had undergone successful hepatectomy. Receiver operating characteristic curve analysis was performed to determine the optimal cut-off value of ICAM-1. Enzyme-linked immunosorbent assay was used to measure the concentration of ICAM-1 in 236 serum samples isolated from HCC patients and the stratified analysis was used to compare the serum level of ICAM-1 in different HCC subgroups. Immunohistochemistry was performed to test the expression level of the ICAM-1 protein in 76 cases of HCC tissues and their adjacent normal liver tissues (ANLT). The survival probability of HCC patients was estimated using Kaplan-Meier plots and differences between the groups were obtained using the log-rank test. Furthermore, independent indicators of the prognosis were acquired using a stepwise Cox proportional hazard model to analyze a series of predictors that were associated with disease-free survival (DFS) and overall survival (OS) in HCC patients. Our findings suggested that ICAM-1 promotes HCC metastasis and high serum ICAM-1 is significantly associated with alpha-fetoprotein (AFP) (P = 0.022), clinical tumor-node-metastasis stage (P < 0.001), portal vein tumor thrombus (P = 0.005), distant metastasis (P = 0.016) and recurrence (P = 0.034). We further detected the ICAM-1 protein in HCC specimens and found that 56 of 76 (73.7%) HCC tissues had ICAM-1 positive staining while only 23 of 76 (30.3%) ANLT were positively stained (P < 0.0001). Survival analysis indicated that HCC patients with increased ICAM-1 concentrations had significantly shorter DFS and OS after resection. A multivariate analysis showed that ICAM-1 > 684 ng/mL was an independent factor for DFS (HR = 1.643; 95%CI: 1.125-2.401; P = 0.010) and OS (HR = 1.692; 95%CI: 1.152-2.486; P = 0.007). ICAM-1 may be a promising serological biomarker for HCC diagnosis and an independent predictor of DFS and OS after surgical resection and may provide a useful reference for the prediction of intra- and extrahepatic metastasis.

Adherence to endovascular aortic aneurysm repair device instructions for use guidelines has no impact on outcomes

Prior reports have suggested unfavorable outcomes after endovascular aortic aneurysm repair (EVAR) performed outside of the recommended instructions for use (IFU) guidelines. We report our long-term EVAR experience in a large multicenter registry with regard to adherence to IFU guidelines. Between 2000 and 2010, 489 of 1736 patients who underwent EVAR had preoperative anatomic measurements obtained from the M2S, Inc, imaging database (West Lebanon, NH). We examined outcomes in these patients with regard to whether they had met the device-specific IFU criteria. Primary outcomes were all-cause mortality and aneurysm-related mortality. Secondary outcomes were endoleak status, adverse events, reintervention, and aneurysm sac size change. The median follow-up for the 489 patients was 3.1 years (interquartile range, 1.6-5.0 years); 58.1% (n = 284) had EVAR performed within IFU guidelines (IFU-adherent group), and 41.9% (n = 205) had EVAR performed outside of IFU guidelines (IFU-nonadherent group). Preoperative anatomic data showed that 62.4% of the IFU-nonadherent group had short neck length, 10.2% had greater angulation than recommended, 7.3% did not meet neck diameter criteria, and 20% had multiple anatomic issues. A small portion (n = 49; 10%) of the 489 patients were lost to follow-up because of leaving membership enrollment (n = 28), moving outside the region (n = 10), or discontinuing image surveillance (n = 11). There was no significant difference in any of the primary or secondary outcomes between the IFU-adherent and IFU-nonadherent groups. Aneurysm sac size change at any time point during follow-up also did not differ significantly between the two groups. A Cox proportional hazard model showed that IFU nonadherence was not predictive of all-cause mortality (hazard ratio, 1.0; P = .91). Similarly, IFU nonadherence was not identified as a risk factor for aneurysm-related mortality or adverse events in stepwise Cox proportional hazards models. In our cohort of EVAR patients with detailed preoperative anatomic information and long-term follow-up, overall mortality and aneurysm-related mortality were unaffected by IFU adherence. In addition, rates of endoleak and reintervention after initial EVAR were similar, suggesting that lack of IFU-based anatomic suitability was not a driver of outcomes.

Baseline hyponatremia does not predict two-year mortality in patients with chronic peritoneal dialysis

Purpose: Hyponatremia is a common electrolyte abnormality in a variety of medical conditions. Lower predialysis serum sodium concentration is associated with an increased risk of death in oligoanuric patients on hemodialysis. However, whether hyponatremia affects the short-term mortality in chronic peritoneal dialysis (CPD) patients remains unclear. Methods: We conducted a cross-sectional and two-year follow-up review retrospectively, and 318 patients with CPD were enrolled in a medical center. Serum sodium levels were measured at baseline and categorized as quartile of Na: quartile 1 (124–135 mEq/L), quartile 2 (136–139), quartile 3 (140–141) and quartile 4 (142–148). Mortality and cause of death were recorded for longitudinal analyses. Results: The patients with higher quartile (higher serum sodium) had a trend of lower age, peritoneal dialysis (PD) duration, co-morbidity index, D/P Cr and white blood cell counts and higher renal Kt/Vurea (Kt/V) and serum albumin level. Stepwise multiple linear regression analysis showed that serum sodium level was positively associated with albumin, residual renal Kt/V and negatively associated with age and PD duration in CPD patients. After two-year follow-up, stepwise multivariate Cox proportional hazards model demonstrated that age, co-morbidity index and serum albumin were the significant risk factors for all-cause two-year mortality, but not serum sodium levels. Conclusions: Serum sodium level in CPD patients is associated with nutritional status, residual renal function and duration of PD. However, baseline serum sodium level is not an independent predictor of two-year mortality in CPD patients.

High KIF18A expression correlates with unfavorable prognosis in primary hepatocellular carcinoma.

This study aimed to investigate KIF18A expression in hepatocellular carcinoma (HCC) and to determine the possibility of KIF18A expression being a biomarker in HCC diagnosis or being an independent predictor of disease-free survival (DFS) and overall survival (OS) in HCC patients underwent surgical resection. KIF18AmRNA was detected in 216 cases of HCC tissues by quantitative real-time PCR (qRT-PCR) and in 20 cases of HCC tissues by semi-quantitative RT-PCR. KIF18A protein was determined in 32 cases of HCC tissues by immunohistochemistry (IHC). The survival probability was analyzed by Kaplan-Meier method, and survival curves between groups were obtained by using the log-rank test. Independent predictors associated with DFS were analyzed with Stepwise Cox proportional hazard models. High KIF18A mRNA level was detected in 154 out of 216 (71.3%) cases of HCC. The positive rate of KIF18A expression was significantly higher in liver cancer tissues than that in adjacent normal liver tissues (ANLT) from HCC patients [65.6% (21 of 32) vs. 25.0% (8 of 32), P=0.001]. The KIF18A expression level had positive relevance to the alpha-fetoprotein (AFP) (≥ 200 ng/ml), tumor size (≥ 5 cm), clinical tumor-node-metastasis (TNM) stage and portal vein tumor thrombus (PVTT) in HCC (all P <0.05). A survival analysis indicated that HCC patients with higher KIF18A expression had a significantly shorter DFS and OS after resection. A multivariate analysis suggested that KIF18A upregualtion was an independent factor for DFS [hazard risk (HR)=1.602; 95% confidence interval (CI), 1.029-2.579; P=0.031] and OS (HR=1.682; 95% CI, 1.089-2.600; P=0.019). KIF18A might be a biomarker for HCC diagnosis and an independent predictor of DFS and OS after surgical resection.

Subgrouping of intermediate-stage (BCLC stage B) hepatocellular carcinoma based on tumor number and size and Child–Pugh grade correlated with prognosis after transarterial chemoembolization

To find a subgroup that benefits most from transarterial chemoembolization (TACE) in terms of tumor number and size and liver profile in patients with intermediate-stage hepatocellular carcinoma (HCC). Data of 325 intermediate-stage HCC patients who received TACE as the initial treatment were gathered. Four tumor numbers (3-6 tumors) and five maximum tumor diameters (3-7 cm) as well as all of their combinations but one (3 tumors and 3 cm) and Child-Pugh grade were used as variables to ascertain prognostic factors. The respective 1-, 3-, and 5-year overall survival rates in all patients were 86.5, 47.0, and 23.7%, respectively. Tumor numbers of 4 (P = 0.00145) and 5 (P = 0.036), and tumor size of 7 cm (P = 0.015), and 12 other combinations of tumor number and size, and Child-Pugh grade (P = 0.0015) were identified as significant prognostic factors in univariate analysis, and 4 tumors of 7 cm (P = 0.0008) and Child-Pugh grade (P = 0.0036) remained significant in the stepwise Cox proportional hazard model. The overall survival was significantly better in a patient subgroup having two factors other than patient subgroups having one or no prognostic factors. A patient subgroup having two prognostic factors benefited most from TACE in intermediate-stage HCC patients.

Self-image and suicide in a Swedish national eating disorders clinical register

ObjectiveUsing a prospective design, to examine the relation between self-image (assessed using the Structural Analysis of Social Behavior) and suicide attempts/completions in women with anorexia nervosa-restricting type (ANR), anorexia nervosa-binge/purge type (ANBP), bulimia nervosa (BN), binge eating disorder (BED), and eating disorder not otherwise specified (EDNOS); and to assess whether these self-image variables add unique predictive value to suicide when considering other baseline predictors. MethodWomen (N=2269) aged 12 to 45 (M=22.1) presenting to specialist eating disorders clinics in Sweden between 2005 and 2009 were identified through the Stepwise Eating Disorders Quality Register. Data on age, body mass index, eating disorder severity (Eating Disorder Examination-Questionnaire scores), psychiatric comorbidity, global assessment of functioning, and self-image were abstracted from Stepwise and included as baseline predictors or covariates. Suicide information (prior attempt and attempt/completion after Stepwise registration) was obtained from the National Patient Register and Cause of Death Register. ResultsPrevalence of detected suicide attempts/completions over the study period was 9.2%. Negative self-image variables were associated with prior suicide attempts in ANR and EDNOS and later suicide attempts/completions in women with BN. In a stepwise Cox proportional hazards model, only low self-affirmation predicted time to suicide attempts/completions in women with BN when accounting for age and prior suicide attempt. ConclusionAssessing self-image might assist with identifying women with BN at elevated risk for suicide.

Clinical Relevance of Plasma Prostaglandin F2α Metabolite Concentrations in Patients with Idiopathic Pulmonary Fibrosis

BackgroundIdiopathic pulmonary fibrosis (IPF) is a devastating lung disease of unknown etiology with few current treatment options. Recently, we determined an important role of prostaglandin F2α (PGF2α) in pulmonary fibrosis by using a bleomycin-induced pulmonary fibrosis model and found an abundance of PGF2α in bronchoalveolar lavage fluid of IPF patients. We investigated the role of PGF2α in human IPF by assessing plasma concentrations of 15-keto-dihydro PGF2α, a stable metabolite of PGF2α.MethodsWe measured plasma concentrations of 15-keto-dihydro PGF2α in 91 IPF patients and compared these values with those of controls (n = 25). We further investigated the relationships of plasma 15-keto-dihydro PGF2α concentrations with disease severity and mortality.ResultsPlasma concentrations of 15-keto-dihydro PGF2α were significantly higher in IPF patients than controls (p<0.001). Plasma concentrations of this metabolite were significantly correlated with forced expiratory volume in 1 second (Rs [correlation coefficient] = −0.34, p = 0.004), forced vital capacity (Rs = −0.33, p = 0.005), diffusing capacity for carbon monoxide (Rs = −0.36, p = 0.003), the composite physiologic index (Rs = 0.40, p = 0.001), 6-minute walk distance (Rs = −0.24, p = 0.04) and end-exercise oxygen saturation (Rs = −0.25, p = 0.04) when patients with emphysema were excluded. Multivariate analysis using stepwise Cox proportional hazards model showed that a higher composite physiologic index (relative risk = 1.049, p = 0.002) and plasma 15-keto-dihydro PGF2α concentrations (relative risk = 1.005, p = 0.002) were independently associated with an increased risk of mortality.ConclusionsWe demonstrated significant associations of plasma concentrations of PGF2α metabolites with disease severity and prognosis, which support a potential pathogenic role for PGF2α in human IPF.

Impact of body surface area (BSA) on efficacy of gefitinib in patients with non-small cell lung cancer (NSCLC).

e19167 Background: Drug dosing of chemotherapeutic agents has traditionally been based on an estimated BSA to reduce the pharmacokinetic inter-patient variability. However, the approved dose of gefitinib was fixed at 250 mg/body/day. Our preliminary retrospective study showed a potential association between BSA and progression-free survival (PFS) in the gefitinib monotherapy in advanced NSCLC [ASCO 2012, #2607]. Here, we investigated the influence of BSA on efficacy of gefitinib, using data from a prospective cohort of NSCLC patients receiving gefitinib. Methods: The subjects were 154 consecutive, EGFR-tyrosine kinase inhibitor (TKI)-naïve NSCLC patients who were to receive gefitinib monotherapy between 2007 and 2012. Baseline BSA was estimated by height and weight in each patient. The association between BSA and survival time was assessed using log-rank test and stepwise multivariate Cox proportional hazard model. Results: Median BSA of the subjects was 1.42 m2 (range: 0.98-1.95). At the cutoff level in BSA of 1.50 m2, overall survival (OS) and PFS in the large BSA group were not different from those in the small BSA group in the univariate analysis, which was also shown in multivariate analysis (hazard ratio: 1.12, 95% confidence interval: 0.66-1.92 and 1.67, 0.86-3.44, respectively). Among subjects with EGFR-mutant tumors (n=125; 81%), BSA had no association with OS, but patients with larger BSA had significantly worse PFS in the multivariate analysis (1.59, 1.01-2.51). The association of BSA with PFS was highly sensitive to increase or decrease in the cutoff level of BSA: BSA ≥ 1.45 m2 vs. &lt;1.45 m2, [1.18, 0.80-1.75]; BSA ≥ 1.55 m2 vs. &lt;1.55 m2, [1.75, 1.11-2.78]; BSA ≥ 1.60 m2 vs. &lt;1.60 m2, [1.32, 0.82-2.11]. Conclusions: In this cohort, PFS was significantly associated with BSA in EGFR-mutant NSCLC when BSA level was cut off by around the median score. Our findings might suggest the need for further investigation of dose finding PK/PD study stratified by BSA level in gefitinib therapy in EGFR-mutant NSCLC.

Infection Risk in Kidney Transplantation From Uncontrolled Donation After Circulatory Death Donors

BackgroundUncontrolled donations after circulatory death (DCD) present 2 well-established risk factors for infection after kidney transplantation (KT): greater rates of delayed graft function (DGF) and antithymocyte globulin (ATG)-containing sequential therapies. MethodsWe performed a prospective cohort study of our 291 KT patients between November 2008 and July 2011 to compare the incidences of infection between DCD (n = 87) and donation after brain death (DBD; n = 204) recipients. Most DCD donors were uncontrolled Maastricht categories 1 or 2. Backward stepwise Cox proportional hazards models were used to assess the impact of DCD on the primary study outcome. ResultsAs compared to the DBD group, DCD recipients were younger, less likely to have undergone previous transplantations, exhibited lower dialysis vintage, and displayed a greater incidence of DGF and graft loss, but lower incidence of acute rejection episodes. There were no differences in the non-death-censored graft survival at 2 years (log-rank P = .835). The DCD group showed lower cumulative incidences of overall, bacterial, cytomegalovirus (CMV), and non-CMV viral infections (P < .05 for all). Multivariate analysis, associated DCD with a lower risk of overall infection (hazard ratio: 0.41; 95% confidence interval: 0.28–0.60; P = .012), an effect that remained when the analysis was restricted to patients receiving ATG induction therapy. Finally, there were no differences in the cumulative incidence of overall infection when DCD recipients were compared with age-matched DBD controls: 43.7% vs 47.1% respectively (P = .648). ConclusionDespite the higher rate of DGF and the use of ATG-containing sequential therapy, uncontrolled DCD policies were safe in terms of the risk of post-transplant infection.

Factors predictive of the development of Levodopa‐induced dyskinesia and wearing‐off in Parkinson's disease

The Stalevo Reduction in Dyskinesia Evaluation in Parkinson's Disease (STRIDE-PD) study compared the initiation of levodopa (l-dopa) therapy with l-dopa/carbidopa (LC) versus l-dopa/carbidopa/entacapone (LCE) in patients with Parkinson's disease. In the current study, the STRIDE-PD study population was investigated to determine the effect of l-dopa dose and other risk factors on the development of dyskinesia and wearing-off. Patients were randomized to receive LCE (n=373) or LC (n=372). Blinded assessments for dyskinesia and wearing-off were performed at 3-month intervals for the 134- to 208-week duration of the study. The patients were divided into 4 dose groups based on nominal l-dopa dose at the time of onset of dyskinesia (or at study conclusion if there was no dyskinesia): group 1, <400 mg/day (n=157); group 2, 400 mg/day (n=310); group 3, 401 to 600 mg/day (n=201); and group 4, >600 mg/day (n=77). Similar analyses were performed with respect to wearing-off and any motor complication. The times to onset and frequency of dyskinesia, wearing-off, or any motor complication were compared using the log-rank test (overall trend test) and a Cox proportional hazards model (pairwise comparisons). A stepwise Cox proportional hazards model was used to screen predictive factors in a multivariate analysis. The risk of developing dyskinesia and wearing-off increased in an l-dopa dose-dependent manner (P<0.001 for both). Analyses using l-dopa equivalent doses produced comparable results. Factors that were predictive of dyskinesia, in rank order, were: young age at onset, higher l-dopa dose, low body weight, North American geographic region, LCE treatment group, female gender, and more severe Unified Parkinson's Disease Rating Scale (UPDRS) Part II. Multivariate analyses identified similar predictors for wearing-off but included baseline UPDRS Part III and excluded weight and treatment allocation. The risk of developing dyskinesia or wearing-off was closely linked to l-dopa dose. The current results suggest that physicians should use the lowest dose of l-dopa that provides satisfactory clinical control to minimize the risk of both dyskinesia and wearing-off.

Red blood cell distribution width predicts mortality after coronary artery bypass grafting

Risk stratification in cardiac surgery is a relevant issue. Many mortality risk models are currently available [1,2], and they are used to assess riskof operativemortality, and toprovide internal and/or external benchmark comparisons. However these risk models, such as the European System for Cardiac Operative Risk Evaluation (EuroSCORE) [2], have shown several limitations, including poor performance in the elderly and overestimated mortality, especially among isolated coronary artery bypass grafting (CABG) patients. Therefore there is a need to identify new risk factors in this setting which are expected to be simple enough for clinical use, available for all patients and cost-effective. Complete blood cell count parameters, such as haemoglobin, have been shown to predict outcomes in patients with cardiovascular disease [3,4] but none of themhas been incorporated into surgical risk scores. In particular, the preoperative haemoglobin has been investigated as a risk factor of early death but discordant results were reported. Red blood cell distribution width (RDW), routinely reported in automated complete blood counts, is a numerical measure of the variability in size of circulating erythrocytes, and has been emerging as a strong predictor of adverse events for several categories of patients [5]. However, the role of RDW in predicting mortality of CABG patients has not been investigated yet. To assess predictive power of RDW on both early and late mortalities following CABG, prospectively collected data from the surgical database of two European institutions (Sapienza University of Rome, Italy and Papworth Hospital NHS, United Kingdom) have been retrospectively analysed by authors whom have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology. The primary end points of the study were early (within 30 day) death and all-cause late death after hospital discharge. All-cause death is the most robust and unbiased index because no adjudication is required, thus avoiding inaccurate or biased documentation and clinical assessments. Furthermore, to deeply investigate the relationship between RDWandmortality, cause of deaths were recorded and a sub-analysis of cardiac-related late mortality was performed (any sudden, cardiac, or unknown death was considered a cardiac-related death; stroke as well was considered as cardiac death). Participants were classified into 4 groups using the RDW quartile values. Differences in baseline clinical characteristics among groups were examined by 1-way analysis of variance for continuous variables and χ test for categorical variables. Kaplan–Meier analysis of survival was performed and estimates were compared with logrank test. Potential confounding factors were derived among variables included into EuroSCORE [1,2], on the basis of a literature review and a clinical plausibility. We used 4 stepwise logistic and Cox proportional hazards models to assess the associationsbetween thebaselineRDWquartiles and risks of early and late mortalities. Estimates were calculated as crude association between outcomes and RDW quartiles (Model 1), adjusting for demographic risk factors showing significant correlation at univariate analysis (Model 2), adding haemoglobin levels (Model 3), and adding other biochemical factors (Model 4). All statistical analyses were performed using SPSS v. 20.0 (SPSS, Chicago, IL).

Abstract 167: Consistency of Blood Pressure Control Predicts Vascular Outcome after Ischemic Stroke

Background: Hypertension is the leading modifiable risk factor for stroke. Uncontrolled hypertension increases cardiovascular risk, independent of type of treatment. Analysis of blood pressure (BP) control using mean follow-up BP may not provide a complete picture of BP control during a study, because BP may be in control at one visit and out of control at the next visit or vice versa. Objective: To assess the independent association between consistency of BP control at follow-up encounters and occurrence of future vascular events among recent ischemic stroke patients. Methods: We reviewed the trial dataset of 3680 recent (&lt;120 days) ischemic stroke patients, aged ≥ 35 years, recruited from 56 centers from 1996 to 2003, and followed for 2 years. Consistency of BP control was defined as the proportion of visits in which BP was in control (&lt;140 mm Hg systolic and 90 mm Hg diastolic). Patients were grouped according to proportion of visits in which BP was in control (&lt;25%, 25-49%, 50-74% and ≥75%). The primary outcome was time to stroke, myocardial infarction (MI) or vascular death; while time to stroke alone was the secondary outcome. Stepwise Cox proportional hazard models were used to determine the relationship between BP control and primary and secondary outcomes before and after adjusting for demographic (age, sex, and race-ethnicity) and clinical variables (vascular risk factors and cardiovascular medications use). Interaction effects were assessed for age, sex, race, history of hypertension, history of diabetes, and baseline (measured after the qualifying stroke) systolic BP (SBP). Results: Among the cohort, 35%, 16%, 19%, and 30% had BP controlled &lt;25%, 25-49%, 50-74%, and ≥75% of the time. After adjustment for covariates, those who maintained their BP within the target range ≥75% of the time did not have significantly lower rates of primary or secondary outcomes compared to those with BP within target range &lt;25% of the time; however, there was an interaction with baseline SBP such that a higher proportion of visits within target BP control was significantly associated with vascular risk reduction benefit starting from a baseline SBP of 132 mm Hg. Among patients with baseline SBP in the 75 th percentile (≥ 153 mmHg), having BP controlled at least 75% of the time conferred a lower risk of stroke, MI or vascular death (HR 0.51, 95% CI 0.32-0.83, p=0.007) and stroke (HR 0.48, 95% CI 0.26-0.87, p=0.02), compared to having BP controlled &lt;25% of the time. Individuals with mean follow-up BP under control had a lower risk of stroke, MI or vascular death (HR 0.76, 95% CI 0.62-0.92, p=0.006) and stroke (HR 0.76, 95% CI 0.59-0.98, p=0.03). Conclusions: While achieving a mean follow-up BP within target range is independently associated with a reduction in stroke, MI or vascular death, consistency of BP control among those with elevated baseline SBP is independently linked to an even greater reduction in vascular events. These findings highlight the importance of ensuring BP is controlled at each post-stroke clinical encounter, particularly among those patients who have elevated baseline SBP in the post-acute period following their index stroke.

The impact of perioperative transfusion of blood products on survival after pediatric liver transplantation

Intraoperative transfusion of red blood cells (RBC) is associated with adverse outcome after LT in adult patients. This relationship in pediatric patients has not been studied in depth, and its analysis is the scope of this study. Forty-one variables associated with outcome, including blood product transfusions, were studied in a cohort of 243 pediatric patients undergoing a cadaveric LT between 2002 and 2009 at the General Hospital of Bergamo. Multivariate stepwise Cox proportional hazards models were adopted with adjustment by propensity scores to minimize factors associated with the use of blood products. Median age at transplant was 1.37 yr. In uni- and multivariate analyses, perioperative transfusion of FFP and RBC was an independent risk factor for predicting one-yr patient and graft survival. The effect on one-yr survival was dose-related with a hazard ratio of 3.15 for three or more units of RBC (p = 0.033) and 3.35 for three or more units of FFP (p = 0.021) when compared with 1 or no units transfused. The negative impact of RBC and FFP transfusion was confirmed by propensity score-adjusted analysis. These findings may have important implications for transfusion practice in the LT pediatric recipients.